Wilson and Gisvold's Textbook of

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Wilson and Gisvold's Textbook of

ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY

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Edited by

John H. Block, Ph.D., R.Ph.

Professor of Mt.:dicinul Chemistry

Department of Pharmaceutical Sciences College of Phanl1acy Oregon State Uni versity Corvallis. Oregon

John M. Beale, Jr., Ph.D.

Associate Profcs!iOr of Medicinal Chenl istry al1d Director of Pham13ceul ical Sciences 51. Loui ~ College of PhamlllCY 51 Louis. Mi!osouri .

lipPINCOTT WILLIAMS & WILKINS

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TIw EIt'I't'lllh &lil;OIr "I Wilson and Glwokl's TeJrlbocJJ; of 0f"ganic and Methci nal f't1:mnoceutk1l1 Chc:m\wy is d"diewed III rhl' me",,,,.)' til /uiml' N. l)elg(ld" I1ml Clwr/u O. Wi/JOII

JainM' N. l>elgado I'JJ2 - 200 1

rofessor Jllimc N. Ddg!ldo <;er.ed lIS coeditor for the ninth 1100 tcmh cdil1on~ and was continumg In thiS rule berore his death on OclDber S. 2{X)1. Dr. Delgado Sludied with Ole Gisvold. one or the two foondin@eduOI'!lorthIS lextbooit. and he ..... as !,\edit aled 10 maintaining the .... andards or ucellence ~Ished by Gisvold and his coetlJlor Chllfl~ WitS<.N! . He IO\'ed Icaching nredicirnal chem istry 1 0 '>ludrnL~. and [his tc:<.lboo~ wa.~ a powerful aid 10 him. A gl'lKlUJle of lhe Univel1>it y or Te:<.as ;II Austi n and tire Universily of M inne~)ta. 10ime Dclgaoo ~g3n lIis leaching ~'areer /lS an assiSlant professor m the Universily of Texas Collc:ge of Ph:U1nacy in 1959. He rose lhroogh lhe ocademic r"nJ,:s 1 become prorc~sor and head of lhe Dr v i ~ion of Medlcmal 0 Chemistry and II lelllkr in relCarcir and graduate educaliOll. ~le cssenlially built both lhe gr.tdU3lc program and lhe Di\'i",on from SeTlIlch. and his publicauon o r research and ~hol:arly ..... 0I'b brought 1J,aII()I1;!.I recognition 10 the departmcnt. Although Juirnc Delgado became known for hi- reM'arch and ~holarship. hl ~ finol love and hi ~ gre~tcsi icgllCy were in tcaching and advising undcrgru(\uate and graduale SludcnlS. The Universily orTcxa, 01 Au~lin awanled him live map leaching awards. and re.::o~n i 1.ed him IWO times a.~ one of its "be.~t" profes.~. In 1991. he was .. Ittted 10 the Academy of Di stinguished TeQChers at lhe un;"cl"'lil), lind ",15 IIonotN ;as a DiSfingui<J'ied Tcaching l"rofessor. a penn:mc:nl academic titk . FOIIiIU dean James DoIUISio described Dr. Dc:lgado's leaching ~I) Ie as ~o ..... ning the classroom" because of his knwNledgc. t"OI1IlIlunlClltion ~kills. and deep ooo\iction Ihat pharmacy is a science-based pruf~ion. H i~ enthusiasm 0 and e."enlporarlCOUS use of lhe chalkboard were legendary, In OOdilion III hi ~ contributions 1 leaching allhe Unrvcl1>il)' ofTe~'Js. Dr. DcISado tru~ele(] extcnsively in Mexico and South Ameri ca to prc.'!elll IectU/"e,'lOIi pharm!II,:eulical education. Jarme Delgado's first conlributions to the T,wbook lyOrg(Uli(- "'1"/'cil1l,1 (.1/1/1 Phllmlflu/icll/ C~m. iJfry ... ere made as II chapter author in lho: ~\'enlh and ..i,hlh edilklnS. Much oflhe malerial he pf\:StnlC'd cam.. from his Iec,ure notes. Although he was proud of the.o;c OOOlribulions.... hich ....en: upandcd III the nrnl h and tenth edilions. he ooosidf:orod hiJ role as coedilor in lhe Iauer edilions one of the highlr ghls of hIS diSlinguished career. Jaime wa.~ II lrue gentlell1an 1100 a pleasure 10 ha\'e as II collaborulOl'. He will be greatly mi",-';cd by the edilon;. 3I11hor~. and prorc.~sional staff for the TI'.nbook,

Wi/bllm A. Rt'mt'f$

Charles O . WilSfio

1'11 _2002

oollea\IC and fritnd. Charles Wil~. had died '\honly aftcr Chrisnnas. He was a product of the I'ocific Northwest hal ing received all of his degrees from the Unil~ny of WashinglOO. HIS first tcaching job was 1Il the now diSl:ontinuro ph~y school at George Wa'\hingtoo Unil'ersity and then he 11101cd to tile Unlve,..;ity of Minnesota. Charles. alooS with (Miler medicinal chemistry faculty at the Unilersity of Minnesota. saw the need for tex tbooks thai prellCnted modem medicinal chemi stry. In 1949. he and Professor Ole Glsvold ediled Organic Chl'misll',), in Ph(lI'"m(IC\. "hiCh became the first edition of the Tl'XIIHKn: of M edici,wl mill PIJUrmllUfu;cill Chtm;.flry. Conli nu 109 in this tradition. Charles and Profeso.or Taito Soinc a.~!iumtd the: aulhoJship of Hogl"J InorganiC' Phl/muluu/kill Chl'mi!/,)". which included eight edition~ before its di.oominuanct:. Finally. Charles and l"rof!!S5Of Tony Jones staned the AnrtriC'Qn Drug /ooa series. Charles continued his publishing lK.1ivities after moving 10 the University of Texas llnd then assumed the position of Dean of On:lon St:IIC Uni\'~uy'5 School of l'hamUiCY. where he overSllw a major cx pansion of ils faculty and physical plant. Ahhoul!:h a medicinal chemist. Charles devoted considerable time to his chosen plwmacy profession. Siudents. and communily. ChIlf1e.~ " as an activc member of the Amelic.1ll Pharm:l\;eullcal ASSOCiation lIS well as lhc phall11:lC")l associations in exh stale ....here he liled. In addition. he was a registcrW pharmacist in eacll stale where he taugllt: Wasllington. MinllC5Ota. Te.):as. On:gon, and the Oi~trict of Columbia. Charles chllired nauonal commiuces and .seclions of !he American Pharmaceulical Association and lhe A merican Association of College5 of I"II:lrmacy. Rt'laled to these, hiS IOYllity 10 $tudcms il"lCluded organi1.ing 5tudcnl bral"lChocs o(the American j'lIannaceutical Associauon 31 Georgc Washington University. the Umvcrsity of MinllCSOlll. and the Univcn;l1y ofTuas. He "'"ali IIClilely involved in the local AmcriclU1 Red Cross blood progrum and tOOk the lead in deleloping the lIugely success(ul .student cenlcn:d blood dtiles at ~goo Stale Unh~ity . In 1960. Charles llnd his ,,"Ifc. Vaughn. helped launch the AFS (American Field Service) in Corvallis. an inlemational high-!iChooi uchangc program. lIe voluIl\cen:d for Mcal ~ on Wheels (or 0~C1" 30 yCarl aftcr his rctircrnent. We cl:" lIIn ly ml~s thiS fine gentleman and leaderof phDrmacy C"dllCatlOll and the p/larm:lcy profes5ion.

s the ,hapler,,: for the elel'ellth edition

,,'e~ being sent to the publisher. I was llO(iflC(lthat my

John II. Bkd

PREFACE

For almost six UccHdcs. Wilsoll all/I Gijl'Old's T~Albook of Organic Medicil'ml lII.d PI)(1rmOCtiuliC(Ji Chemim)' hru; been a S1and~rd in the litcnl1un:: of med icinal c/lcmistry. Generations of sl udenlS and focully have depended on this textbook 11Q\ onl)' for undergr.lduDlc courses in medicinal chemistry but also as a supplement for graduate studies. Moreover. sUldem. in other hcalt ll scicn<:cs ha~'e found certain chaplcl1l useful at one time or Mother. The current edi tors and aulhor!l worked on the eleventh edition with the objt.'Ctive of continuing the tradition of a modem textbook for ulldergrnduate students and also for graduate studentS who need a general ~view of medicinal chemistry. BecauS/:: Ihe chapters inc lude

a blertd of chemical ~nd phannacolOil ica l principles ncces,ary for understanding strucru re- activity relationships and molecular mechanisms of drug action. the book )hould be useful in supporting courses in medicinal chemistry "lid in complememing phannncology coun;es. It is our goal that the eleventh edi lion foll ow in the footsteps of the tenth edi lion 3nd rdl crt the dyn<lmic changes occurring in medici nal chemistry. Recognizing Ihatthe search for new drugs invoh'Cs both synthesis and scn:ening of large numbers of compounds. there is a new chapter on combinatoria l chemL~try thaI irn:l ude.~ a diSCUSS ion on how the proee!IS is au tomated. The power of main frnmc computing now is on the medicinal chemist's desk. A new chapter describes techniques of molecu lar modeling and computational chem istry. With a significant percentage of the gcnernl population purchasing allemalive medicines. there is II new ch3pler on herb;}l medicines that describes the ~hemical comenl of many or these products. The previous edi tion had new chapters on drug latenti ation and prodrugs. immunizing biologicals. diagnostH:: imaging agents, and biOlechnology. Expansion of chapl el"S from the tenth edition includes the antiviral chapler thai contains the neWellt drugs that have changed the way II IV is treated. Dramatic progress in the application of molecular biology 10 the prod uctioo ofpha mlilCeutical agents has produced ~uch important molecules as modifit'd hU lTUln i n.~ulin5, granu locyte colonyst imuJaling faclOl"!l. erylhropoictins. and interferons, all produel.~ of cloned and. sometimes. modified human geoes. The chapter 011 biotechnology describes these exciting <lpplications. Rcrent advances in umletSUlnding the immu ne system at the molcrulnr level have led \0 new agems that suppress or modify the immune re~"]"IOn$e. producing new treatments for autoimmune diseascs including rheumatoid urt hritis. Crohn' s disease, and multiple sclero~is. Technique.~ of genetic engineering now allow the prepamtion of pure surface antigens as vacrines while tota ll y eliminating the pathogenic organisms from which they <Ire derived. The editors ,,"C1come the new com ribmOl"!l to the elc\'emh edition: Doug Henry. Ph illi p Howen, Stephen J. Cutler. T. Kent Walsh. Philip Proteau. and Michael J. De;'nl ing. The editors extend thanks to aJl of the authors wtlo have cooper.. too in the prcpar.. tion of the curren t edition. Collective ly. the authors reprer.ent m~ny years oftcach in~ and research experience in medicinal chemistry.l1M:i r chapiers include summ aries of current research trends that lead the reader to the originnllitcTlIlllre. Docu ml':nt31ion and references continue to be an important feature of the book. We ~"'tinue 10 be imlcbtcd 10 Professors Charles O. Wi lson ~nd Ole Gisvold. the originators of the book. and editors of fi ve f..'(!i tions, Professor Roben DQerge. who joined Professors Wilson and Gisvold for the sixth ami seventh editions and single-handedly edited the eighth edi tion. and Professors Jaime Delgado and William Remers "' ho edited the nimh and tenth editions. They and the authors have contributed significantly to the education of count !es~ phannaci~t s. medicin~1 chemists, ~mI other phannaceuticnl scientj~ts. John II. Block John M. Bellle, Jr.

I"

1949

'OO
JnJ

1954 1956
1962 1%6

"h "h

Wilson and Gisvold (Orgllnic Chelllisiry i l l Pharome},) Wilson <lnd Gisvold Wi lson Wilson and Gisvold Wilson

'"
~h

6<h "h

1971 1977 1982

1991 1998

Wilson. G isvold, aoo !)Qerb'e Wil.<ion, Gisvold. ami Doerge

D and Remers """ Delgado

Delgado and Remel"S

I~h

vii

co
JOliN M. Il EAl.E, JR

PlI.O.
Professor of Medicinal CbtmiSlry and Director of Phaml3CCulical Sciences \lLowI Colk,e of J'ham,lICy St louis. Mi~souri
A~1OCia\e

ST EPU[.N J. CUTLER, l'tl.O.

Pmf~_

EUGENE I.. ISAACSON. I'H.D.

Professor Emcritu~ of MediCInal Chemistry Department of Pharmact' lIIical Sciences College of Pharmacy Idaho State Unh'ersity Pocatello. Idaho

of Medicinal Chemistry

School of PIUlITnacy
Mercer Unh'crsity Atlanta. Gcurgia

JOHN II . BLOCK, "'- ., 1.0

Professor of Medjcin~1 Chemistry
"",,,,,,'" of l'tIarmacculical

MICHAEL J. DElMUNG, R.PH ., PH.D.

Profeswr of F'Ilallnaco!OIIY alld Chair Deparlllle ni of l'tlarmaceutical SciellCCS School of Pharmacy South .... eStern Oldahoma Stale

R.PII.

'Scirnttl;

ROD NEY L. JOI'INSON, JI-I .D.

Professor of Medicmal Chermstry Department of Medicinal Chemistry Unhersity of MinncSOlU Minneapoli~. Minne'iOla

C~ge

of PharmIlcy

SI/lle Umversity Cor.allis. Ortgon

Un;\'cn;ily
WeaLhcrford. Oklahoma

J. PHI I.LIP ROWEN, PI-!.D.

Chemistry and DII eclOl, Cenler for Siomokcular Stnrru~ and Dynamics CompuLalional Chemistry Building
Pmf~ 0(

J AC K DERUITER, PH .D.
Professor o f Medicinal Chemistry Department of Pharmacal Sciences School of Pharmacy Auburn University Auburn. Alabama

DANIEt A. KOEC HE t , PH.I>.

Profl.'sSoOI" Emeritus - Pharm:Joolog y DeparUllenl of Ph:lrrnarology Medical College of Ohio Toledo. Ohio

''''''''''''of Georgia lI n"cnny

" dims.. Georgia

JA C K N. HALt, 1\1.5., R.PH . HCNP

Oinical lturer Departnlern of RadiologylNuelear Medicine College of MedICine. University of ArilOll:l Uni-'erslty of Ari1.Ona Heallh Sci~nces Center TUC'iOn. Ari l.ona

C. RA NDALL CLA RK,

PH.D.

of MediciBaI Chcmisuy

GUSTAVO R. ORTEGA, R.I)H . PH .D.

of Medici nal ChemIstry Departmem of Ph:Irrnaeeulical
Sciences School of PIlannacy Southwestern Oklahoma State Um"ersity
l>rofe~'iOI"

of l'tlarn,ac:uJ Sciences k bool of Pharmacy Aullum Un;.-cTS,ty Auburn.. Alabama

I

GEOHGE H. COCOLAS,
Prures&lr 0( McdiciMI Chemistry and
.\..wlCi.t(' Dr:an
-~y

PH.D.

DO UG LA S R. HENRY
Advisory Scielltist MDL Informano n Sy~tems. Inc . San Leandro, Californi a

Weatherford, Otlahoma

PHILIP J . PROTEA U, 1'1-1.1).

Associate Professor of Medicinal

.~""yol

Nonh Carolina at 1 Hill

i .

THOMAS J . HOLMES. ,1R .. PH.D.

Associate Professor School of Plmnnacy Campbell Unn'asily

Chemistry
CoIlI.'ge of J>ttarmacy Oregon Stale Um"crsiIY Corvalhs. Oregon

G. CUTLER,

Buies Creet, Nonh Carolina

TIM 8 . HUNTER, M.D.

Vice-chainnan and Professor Department of Radiology Uni,'crsily of Ariwn.l Tucson. Aril.ona

WILLIAM A. REMERS, I)H.O.

l>rofessor Emeritus PhannJtCOlogy and ToJdeology Universily or ArizOIla
Tucson, ArilOna

/.

If

ContribulO'S

Pmfc!uor of Medicinal Chrmistry {)cpattmcnt of l'hann<lCal Scicoce!;

THOMAS N. RILEY, I'H.D.

GARETH TI:IOMAS, I'H.I).

Associate Senior L1urer TlJc School of Pharmacy and Biomedical Scicnces UnivcrsilY of PonslTlOUlh Portsmouth. England

RonERT E. WILI..E'I"I'E ('J-J .I>.

Presldenl

School or PhalltUlt"y
Auburn Unherslly Auburn. Alabama

DIto Rcsc;u'Ch. Inc, ~n'cr. Colonido

.' ORR ..:sr T . SMITH. )' H.D.

Associale Professor {)cpattmtnt of Pharmacal Scicoce!i School of Pharmacy Auburn Univcrslty Auburn. Alabama

T . KENT WALSH, 0 .0 .
Direclor Nuclear Medicine Program Southern Ari:rona V.A. Health CIl: System Tucwn. Arizona

CONTENTS

i'rfJ1J(t

....

vii

Role of Cytochrome P-450 MOI1OOX)'gef1~ ,n

O~ Klawe 8KltfansformatlOl'l~

Contributors ......................

;x

(HA'TER

intrOOIlC'lioll . . . . . . . . . . . . . . .. ..
JoIIIl H Skrl and JoM M. Iktdr. Jr

Ovda lrJe ReactlOOS RI!ductrIe ReactJOns HydrolytIC ReactlOOS f'tlase II Of Conjugation Reactions Factors AffectIng Drug Met.lboiovn
CHAPTE R5

67 69 103 109
III

126

Prodrugs alld Dmg l..oltmliatioll

(H.lPTER

l
Propcrtie~'

Physicocilemictl/
J.,tt. H 81od.

i/l He/fllioll 10

f',,,,..,., T. Smllir " .../ C. Rmt<1dI1 Clarlc

Htstory

........

142

Biological Action .................... .

3
3 9
17 26
27

B.nic Conc~ts

""""" Drug

Prodrugs 01 fUOClIOl'lal Groups 800precursor ProdrU9S .

(hemal Deitvery Systems

'" '"
144

1S2

DlstnbullOll Aod-8.ne PropeftleS Su~ucaI Pf~1OO 01 Phafma(o!og+Cill ActlY1ty (OI'I'IboNtofial ChemIStry MoiKulaf Modehng (ComputerAIded DTug

IS'
160
160 160 160 160

CHAPTER6

Wotecl",Q!ogy alld DrIlg Discol.try

Jolm M /k,d. Jr

Seleaed Web Pages

""'"

"
..............
43

(HA,tER
D ,!uN. Hntn

COII/bill/llorilll Chemistry

IboIIt BeQan Peptldes and Ott>tf unear

StructurE'!> Drug...... MclIKuIes Supports iWId Unk.er.; SokJIIOn-Ph.Jsf Combooatooal Ch.rm~lry I'ooIIng Sl!ateglfS DttIIOrt, F'uflfocatoon nd An.lIysrs EntOdirrg CombroatonclillbrMIeS Hrgh-Throughput SCret'!'lmg {HTS) VlI'\lJaI (an S,1Ico) 5cret'!'l,ng ClWrliCal DNersrty and library DesIgn I\cfIM Card OIl Combroatooal Chemrstry: Has II
Worted ?, " ...

.. " ..
49 50

BlOte<:hflOklgy An Qvefvlew Biotechnology and Pha.rnacl!tJtocal Care lIl.er.t\l.e of BIQIe<:hnoIogy BIOteChnology and New Orug Oe<oeloplIOeill The Brote<:hnology of Re<:omb1nant ONA (rONA) Some Types of 0001119 ExprE'!>~ of CioMd ONA Mafl,ptUlIOf\ of ONA SeQuence InformallOO New BloIogKilI TargE!ts for Olll!! Developmenl
Novel Orug-SCfetf1lng StrategIeS Proces.srng of the Recombrnarll Protern PharrnaceullCS of Re<:ombroant DNA (rONA)Produced Agef1!S . OeINtofy and Pharrnacoklne(J(S of Brolechnologv

162
166

167 16.
169 170 172 173 17'

" "
53 54 55 58 60 60

Recombinant Orvg Proch.lCls The IntmieuklnS

V<1(ones PreparatlOfl

~odu<"

''''''''''

of AntibodIeS

182 183 186 187

'"

Rtsor.-te. for Combroatonal Chemistry

ConOnalooal Chemtstry Termonology .

.. Anmeme Technology Gene Therapy Afterword

CHAPTR7

GenomH:s

".
. . . . . . . -. .. . . . . . . . .

191 19' 19'

KAPTl R.

MtlObolic Changts of DrIlgs and R t latt d Orgullic Compol/llds ................. .

SIc, t "J C.rl.r Wtd Jolm If BJ"d Gfnefcll Pathways of Orug Metabolrsm '>rl~ of Drug BIOtransformatIOn

65

IlIlItll/llohiologicals
Jolm M
8<-(J~.

197
197
200 206

"

66

Jr (1'11\ of the Immune System Immunity Acqu,srIJon of Immunity

xii

COfIunl.
CHAPTER 12

CHAPTER8

A"ti.in!ectjpe Agetlts .................. 217

Jolrit M lUalt. Jr

A"ti"eoplastic Agellls
Will""" A. RtIV".

.. .............. . 390

EvaluatIOn 01 the Eff~ 01 a Sterllant Ak~ and Related Compounds Plwnols arid Their OeovatlVt'S O~ ldizlng Agents . HaiogenContam'rl9 Compounds Cat\OOl( Surlacumts

219 219

221

22'
226 228 228

m m

Mercury Compounds (Mercunals) PrewrvalM'S Anufungal Agents SynwtK Anuba<teoal Agents Anuprotozoa! Agents Anthelminw AnbSCabooos and Antlpedi(uIilr Agents AAttoocteflal Sotfonamldes Dlhydfololate ReductMe lnhlbotors Solfoot'S
CHAPTER9

""

<$\gllal Traosdoct\Cll'l Inhibitors

Immunotherapy Monoclonal Antl!)od;es R<Idiothef6JUtK Aqt>nts CytoprolKtIYIL' Agents Future Anuneopl.Jsl\C Agents Potennal FUlUle Developmerits
CHAPTER 13

Tumor Cell Proper\lt'S Alkytatmg A9l'nts AntlrTletaboi ltt'S AI111blOtlCi fIIant Products . Mlsc~laneous CO!l'Ipounc/s

230

'" ".
259 268 268 279 279

..... .....

...... ....,

"'. '" "'., ..... ....

..,..

...., .....
390

...

Agents for Oiaglfostic Imagi,tg . . . . . . . . . 454

Tim H. I/Unlrr. T. Krnt Wabh. Jark N 1/,,//

Allfimalariab
Jolrit Hillock

........................

282

SUmuiatlOO of AnlllTlalanai Research by WM Ofug Ther<lP't Cn::honiI A1k.l1olds

CHAPl ER 10

286

'" '"

Antibacterial Antibiotics
),lIln M. Btnl~. Jr.

.... ...... .....

299
299

Amm091yc0Sldes letraqdines MOIerelldes LillCOffiYClOS . . I'oiyp<p",", Uncla5.Silied AntlblOtlCi

CHAPTERtt

Hl5tonGli Sackgroorld Cu rrent Status CO\'I'lO'Iefcia1 Product\OO Spectrum of At:t\V1ty Mechanosms of Act\Cll'l Chemlcal Cl.Js5lf!(allon M\CfOblaIl\eslstcmCe fHactam An\Jboot1C5 The ~rl\on\tlS pLlctarnase Iohlbltors
C~lo5porlflS

299
300 300 300

to Ra(!ialloo . Charac:tellstlCS 01 Decay. . 8io1ogICai elfens of R;tdI<lIlOll RadlOl1vchdes and RadlOpharrnacl'lJtKaIs for Organ lmagn-.g Radoonuchde Productoon Teametlum Rad~try fluonne RadiochemIStry Galltorn Radoochermstty iodine RadIOChemIstry Indium RadIochemIStry Thalhum Rad~try xenon RadiOChemIStry. . RadIOlogKal Contrast Agents ParamagnetK Compounds Ultrasound Cootrast Agenls RadlologKal Procedures
IntJodUCIIOl1
CHAPTER 14

"56 " .

.... .... .... ....

'"~ "3
.."

"7

'"

'" '" '" '"

.so, ,.
'10
S12

'"

30. 30'

Celltral NervOlII Syslem Oepressalfts ..... 485

1:.'. " " I. 1_0<:_

'" ''''
'''' '"~
3S3

30' 302 3'"

Geoeral AnestheIlCi . AnxIoIyI\C. sed.ltrve. and HypnotIC Agents AntlpsychollG Ant\COl"MJlsant or Antll'pileptK Drugs
CHAPTER 15

..., ....
......
510

Cetltral Nervolls System Stimlllams

1:."!lrtW I. 1mtH"'1Jfl

'" 3S'
'60

Ana lept lCi ... Central Sympathomlffil'tJe Agents (F'sychomotor StimulantS) Anlodepfessants . Miscellaneous CNS-AcMg Drugs
CH AP TER 16
Melhy!~anthlnes

, '10
...

'"

AIIt;v;ral Age"ls ........ ..... ..... 367

Jolin M /knit. Jr.

Adre"ergic Age"ts ................... . 524

367 367

Clcmofl(dtlOn of VmJSeS TargelS for the Pre'/E!nuon 01 V.-al Inltiorli-Chemoprophylaxls Ow InlectlOUS Proce-ss for a Virus Nucleoside An tlrTlelabohtes Newer Agents for the Treatment 01 HIV Inlect\OO

370
375

382

Rod,.,.. L JoIuuOfI Adrefll'fgK Neurolransmll1l.'fS AdrI'!'ltfgiC: RecI'P10Ili , Drugs AIiKllng Adr'eflI'fgK Nalrotri1flSlTl!SSion SympathomtrTletK Agents . Adrenerg" Recl'Ptor AnlagonisU

'" '28
S27

'30 '39

HAPTE R 11

InhlbltlOfl 01 Hrstal'Oll'lf! Release M..sI Cell

Cholilltrgic Drugs atld Related Agellls

GtQ.v /I C""uhu tuId S""",,, J. eMllt. Cholloergoc ReaptOl'l; ChoI'l'IefgIC Neorochemlstry Choh~goc AgonlSts Choltroefgoc lIeptOf MtagonI$ts ChohnerglC Blocking Agents ParasympathetIC Po!il gangllOl"1lc Blcxkmg Agents SoL:maceous Alkaklods and AI\o1Iogut$ SynthetIC Chol~91C Blodong Agents GanglIOnIC BIocIoog Agents Neuromuswlar Bkxklng Age!1ts
CHAPTER 18

548

SliIb,l,zers

..

, , , ,

,..
55J 55J

Re<eru Arlbrns\aml!1e Devt>ll;lpITl('tlts The "DualActlng" AntihlStammes

m
m

H,stamtne HI AntagonISts

H,stam'r"Ie HrReceplOf ligands

CHA P T { R 2 2

'"
727

sn
S7J

S58

'"

Allalgesic Agel/ts . . . . . . . . . . . . . . . . . . . . . 731

Roben E. '>I"iII,," Pain .

S79
S86 S89

..

Morph,ne and Related Compound~ AntltUUlW' A9Mts Antt-mflammatory ~

CHAI'T{R23

132

'" m

'"

Diuretics ...... , ............. ... .... . 596

1)(uW1 A. KlHrlot/ ~Iomy and I'tlysIOIogy of the Nephron
IntrodllCbOIl to the DiuretICS

"m"~

S" sO<
50'
603

Steroids and Therapeutically Related Compounds ... . ..... ................ 767

!,1"IIp J. Prol~""

Sile 1 Du,lfetJCS; CarbonI( Anhydfase Iohibltors SIte ) DIuretICS Th'illIiIfo and ThlUlde-tJl:e
Otu~tlC

..
HI9h-C~ llng Of

Site 2 DIuretICS

l oop OIUltbCS

Srte <I DIUretICS; Polol15lum'5paf'119 DlUreuo MIK~~ Orurel>CS

EIl'M!f911'19 Developments In the Use of D,uretlCS to Tre<l\ HypertenSIOO and (ongestlW Heart Failure

6>. ,>6 ,>8

,>9 ,>9
622
'>8

60S

"""""
Strphor J

DIlIretlC PrepafatJOns

CHAPTER19

SterOId NomeodaturE. Stefecxhernrslty. and Nu mber'ng SterOId BIOSynthesis _ Chemical and Physocal Propertll!S of 5teroods Changes to Mod,fy Pharmacol(ll'-.etlC PropertIeS of Steroods SterOId Hormone RKeptors GnRH and GonacIotrOplllS Sex Hor/TlOfleS . Chermcal ConltaceptlYe Agents Androgens Adlenal Cortex Hom"IorIe$
CHA PTER24

767 768 770 770 770 773 775 789 797 803

CtJrdiomscular Agents
C,.,I~r

.. . . . .. . . . . . . .. .

und Gwr1l' If. C""'JU' J

ArltIanqIrIolI Agents.;md V.nodilators

AntlilrrhythllllC [)rugs Ant'hypertl'f\5lVe AgeI1ts AntJhyptrilpldemic Agents

622

""-" Thyroid Hormones

Antlth)'fOld Drugs
HA~TER

OS7
67J

'34 '41

Prostaglandil/s, Leukolriettes, alld Ollrer Eicosalloi(I!.' .... ..................... 8 r8

n...-.u J. 1/01_1. Jr
HIStory of D&OYefY ElCosarlOfd Biosynthesis Drug ActiOn Medlated by Eorosanoods COX2 .,hobotors DesIgn of Eorosanood Orugs DewlOf)rTlenl of Prostacyd,n..()e(lved Products ElCosanood RKeptors EICOSCInoods Approwed for HutI'Ioln CIIflICaI U!.e Prostaglandl~ for Oph\halmtC lise Vetellnary Uses 01 Pl"ostanoicls . EKosanotds In ClinICal Development for Human Treatment
(HA~TEA2S

SynthelJ( Hypogl)umtt Agents

668

"3

673

20

l...oea/ AI/esthetic Agellls . . . . . . . . . . . . . 676

GatrrA 1/00 HoStonc.al Oe\elopmeflt The Nef\'OUS Srstem
9'

..

. -.

t.tecNnIsm of Ac.bOO

""""'''''''''
HAPTER

factoo Infl uencmg

the

Effectl~Eness 01 the

67' 67' 68S 687

687
688

818 81B 822 822 823 823 825 827 828 828 829

~ICActI()O

lIN of Onst>1 and Our-mon of Anesthesia 5~ Pharmac.oIogIColI Ac.tlOll

StructurE Amon
21

68'

'90

Proteill$, EII1,J'mes, alld Peptide HormOl.es ........................... 830

Sir/Wit J.
C.'II~r

<JIId l/'mJa G. CUllu

830

lIistamine alld AlltihisUlmilll'c Agel/ts

l7Ir_

.......

NR,",. tutd Jr>rl:

696
'96 '"
700

INRw"~r

Protl'lll Hydro/ysates Amino Acid 5oIullOfU Pl"otems am:! Protem-like Compounds

( rv:ymes HOIII .....lES

810 831 83S

840

Htsumme ufe C.,.cIe

HtsU!l"llt\l! H, Antagonl5ts (Antlhlstam,nlC Agents)

8100d Protl'll'lS .. Impact of 81Otechnology on the Development

857

xiv

C.... r~"u

iIOd Corr.,oerootl ProduolOtl 01 PrOtl:'lns arld Pepl>des as Ph<vmac:@IJt.OI Products BlOledtnoIogy-oe..rved PharmaceutJC.JI ProducIs
(HAP TER26

(HAPIR21

858

860

Comp"tatiollal Ch emistry alld CompllterAssis ted Drug Desigll ................ . 919

J I'MI/lp HI,....." Computer GraphICS iII1d Molecular VlSU<IllliltlOtl ComputatlOllal CherTllWy CNeMew Force F~d Methods Geometry (Jpt lmlzahon ConformattOnal 5earchll'l9 MoIecu~ DynamICS SimulatlOOS Quantum Mechanics SlJucture-8.Jsed Drug DesIgn and Philnnacopilore Percepoon PredlctM! ACME

VitnmillS a.lld Rela.ted CompolIl/ds ....... 866

GM~ta''()

9"
912 923 930 933 935 939

R. 0",,(;0.

Mirhll~1

J. ()tolm/"'K. /IIId Jarmf N.

/).>/gut/o

lipid-SOluble Vitamln~ Wilter-Soluble Vitamins MIscellaneous ComIdl>I'illlOilS

(HAPTER21

86'
885
900

'"

All II/trodflctioll to the Medici" al Chem istry of Herbs .................. . 904

JaM M. RHlk. Jr.

,.,

Append'~

What ~ an Hefb? HefbaI Punty and Standard'lallOtl An Herb Is iI Drug T~of Herbs

905 905 905 906

Calclliated Log I', Log D, alld pK.

......

Illdex .............................. . 957

19

22

2'

Illtroduction
JOHN H BlOCK AND JOHN M BEALE, JR.
The di.>c.pI11le medicinal ~hcm i~lry is devoted to the dis C'O\-ef)' nI development of new ag~ms for t~at11lg diseases. MOil of thu; ac:llvily .\ uutttCU to new natural or synthcti c IlfPI'IC compounds. loorganic compounds ronl1nue to be I!IIpOIWIIm thenLp). truce: elements 10 nutritional thet-apy. IDtaciUs. and radiopharm.:ICeuticals. btu orglUlic mole

" "" m "

or

e.,.

cub "Ith Incn'asingly SpecIfIC phannaoological actiVitieS

clearly dominant. Devclopmcm of organic compounds rro'<"" ~yonU tl1KhlLonal ,yntiLetic methods. II now in clude!; I~ uc.tlOg new field of b.otechnology using tilt: ~II\ bio.:ilemistty to symhe~il.C new compounds. Tech ~ nng'"g From n:romb1l1am I}NA and sllc-diTCCIed mLllilgtllC'tis 10 fU.'iion of cell line~ have greally broadened ~ powMities for new cnUlle\ lhall~al uisease . The phar nllmt no... dispenses modified human illsulin~ Ihal provide IIIl)It ronnnient dosing schL"'ule..~. Cell'MiOlulalLng facton. tha line changed the do,ing n-gimcLlS for chemotherapy, bufJl31lll.('(l ITLOIlOClona l anlibodic~ lhal largel specific lis~ and fused rtccpton. lilat .nten:ept Immune cell -gener lied cylokines. ThKboollKlIt.'I many ospec!S of organic mC(hemai.'l: how ~ are dLlICOlcrW, how they act. alid how they developed InIOchnical agents. The POOCdS of t!'Iablish'ng a new pILatmxctIucal IS e.,\cecdillgly complex anu invoh'es lhe lalenlli (II' ptOpIc: front a v;mety of disciplil1C~ including chemistry. MiIe""'I!). moIecul:Ir biology. physiology. pharmacol "I}', p/Iarm;Ir:eutie~. and medicine, ~k"'icinal chemistry, it. dt. I~ (Oi"U.itd mainly wuh the organic, anal)licaJ. and bLo<hemK'ul IL.'pcds uf thi s process. but the ~hcmist must ~I"I prodUCIllely wnh lOOse In other dl<;(;iplines. Thus. lI1ethcillJl t'hemi~try IXCUpie.' a .~ trnl cgic po!<ition m lhe imer rllCl: of ehemi5\t)' and biology, To pro,1Ik an ullller.landing orthe princ.ple!! of medicinal chemistry. it i~ ncc=ry to consider the physicochemical I"U\lUtJ(1 used 10 de\'elop new phamlllcologleally active COIltpolilltb and lheir ""'''ehal1i~''IS of IlCtion. the drug' ~ me uboh.o;m Including possible biologIcal aclivilies of the me ubohtc'. the impo:)f1Jl'K"e of ~tereochem"try ill drug dc~ign. lOll the methods used to determ ine what "space" a drog omI~, All of the principles discussed in thi~ book nre bisaI on fundal!lc:f1l:tJ organic chemistry. physical chemis11)', and biochemiStry, The t;lriieSi drug disco,eric.~ " 'ere made by rnnaom sam pi"" ofhl&J1a" plants. Some of !his umphng, although based en anecdotal cw.lcocc, k'd to the u~e of ~uch crude plant Lhp as opium. belladonna. and t]/.'lcdrioc th:it have been IInpomnt for ttnturics, Wilh the accidental discovery of penicillin came the screenin, o r Imcroorgani~ms :md the Iqe Qumbc:r of anhbLOtic. rrom bactrrial nod fungal 'IOUI'Ces. Many of lOOse lLntibiotics provided the prototypical l/nIrflR!hat the med.cinal chemist modified 10 obtain anti
ItI't ~

b3cterial drugs with better Ihcra~utll.' pmfi~. With the changes in ftdtrallcgi~lation reducmg the efficacy requirement for "nutriccutical," tile public in.cll'asingly is using so-called nomnditional or alternative mcdiclllall thai an: sold over the counter, many out.>ide of traditional pilarlll~y disuibo.nion chanoel$. It is imponant rOl" the pharmaciSt and the public te undel1iland the rigor thai 15 mjuired for plt:M:ription-only and rnA -approved oonPfUCripuon productS to be approved rdat;\c 10 the nomrlldilionul prodUCts. II also is imponom for all pcuple in the health can: ricld alld the public 10 realize thai .... helhcr these nontraditional prodllClS are effective as clain1l:d or nOl. many of the altcm:llc medicillCS contain plwmacological1y aclin' ageRIS that eM potentiple or interfere with ph)'~ician -pre;.cribed lliempy. Hundrals of Ihousands of new organic chemicals an: prepared annually throughoullhc world, and many of them are entered inlo pharmacological scret'ns \0 delennine wbether they ha~ useful bimogicaJ ICti vLty. n"s 1)I"'es.~ of rundom screening has been considered inefficient. but it has m;ulted in the idcntincalion of new lead compounds who!ie structures have been optimiud 10 produce cllnlcalllgenlS . Sometintrs. a lead de\'elops by careful obseT\'alLon of the pharmacological behavior of an existing drug. "The discovcry thm am:ILLladine pnxt:CtS and IreatS early innuenza A came from a generol ~n fill" antiviral agents. The usc: of amamadmc in longtenn can: faciliti es showed that it aJ'iO cou ld be used to treat partillSQllian diOfders. More recently. automated high-throughpul.\Creening systcm~ utiliJ.ing cdl culture syslem~ wi!h linked enzyme asALys and receptor molecules derived from gene cloning have greatl y iLlcreased the dficicocy of random screening. It i, now practical to!iC1ttn e~ libnuies of peptide!; and nocicic acids obtained from combinatorial chemistry procedureol. Rational design. the ~lIe approach to high volu me screening. is also nourishing. Significant :.dvaoces in ",-ray crysallogrl.phy and noclear IIUIgnetic Te.'iOOlI11Ce have made it possible to obtain detailed representations of enl.YIlll:5 and o!hcr drug recepton.. Thc techniques of molecular gruphics and compullltional chemlSlry have provided nowl chemical su'uctures that llave led to new drugs with poklll medn:mal activities. Development of H IV prote~ inhib'l ors and all giotcnsin-coovening enzyme (ACE) inhibllOl"$ came from an understanding of the geomelry and chemLcal character of the I'l:spective enl,Yllle's aclive site. Even if lhe recepuJI" MtuCture is not koo.... n in detail. mILonnl approaches based on the physiClXhrmical propcnic.~ of lead compounds can provide new drugs. For example. the development of cimcli dine as an antinuclear drug involved II careful s1udy of the ch:u1ges in antagonism of Hr histaminc n:ceptOl' induced by varying the physlclll propcnics of Mrocture5 based on
I

histamine. Statistical methods Ixoscd on tIM: Com:lallOlI of physicocIM:mic~1 properties with biologicpl potency arc used to CJlpl~in and opumize biological act;\';ty. As you proceed through tnc chapters. thm" or ... hat pr0blem the medicinal chcmiq i~ trying to solve, Why ...en: CC1"tain .'II.ruClUrcS selected? What l1Iodifiealion~ were mnde to

produce more focused activny or reduce a(h~ or prodUl'e better ph~nllaceutical pmpc:nics? Was t typical molecule dhcovered rrom nlJ1dom ~,. medicinal chemist !Ia\'e a structural concept or an u~andlll8 oflhediscase process tnat mUSlIll" i ruptoo "

Physicochemical Properties in Relation to Biological Action

~H.

BLOCK

\!oJdtm drug design. romp.m:d with the pOllh-lel'J mau a change 011 (In e.flSllng
1'I"IIllwlj~t tl ffl"1<'

clas~lCal ap('Qm(N/IHld QI'

Siruct.. ", und ue "'hal JUlI'pt'IU-COIlI;n~we.ohc rnpidly as an approoch to soh.. inS a drug design probknl. '"The comblllution of increasing po","cr and decn:a1111 ro.l of dc!;ktop compuTing has had a major impact on JOlI~mll drug t1c~ign problem s. Whil e drug design incrcaslolly I' ba'lCd 011 modem computMio nal chcmical technlG~\.. II 1.1-0 U'C$ sophisticated knowlcdge of disease IIIt(l\aImms ~nd n'("Cpcor properties . A good understanding If !low the drug is tr.tnsported inlo tt..: body. di~t ributed Ihroughoutthe bod) companmcnt~.melaholicl.lly ahered by tIr Ihtr lind other organs. and Cllcn:led from ~ patlenl ~ ~u~ ~g ","ilh the struclural r;-h:lt1lCleriSlles of the 1'pI Acid- base chemistry i~ u~ to Iud In formul:allon IIILI btodlSirioolion. Structural allribulCllilnd substill,K'nl palIL'fll.'; ~~iblc for optimum pll:ulnarologic:al activity can IIIll'll be prtdictcd by statisticallechniqucs soch as n:gn:~slon ~I)"s", Compulcn/..cd conform:1tion:ll nnalysi~ pcmUls ~ medicinal chem"l to predici the drull'~ Ihn:c-dimcn~ional ~ ilia! i~ 1UII by the receptor. With the isol:uion lind W1IC!urtl determination of sp::c ific n"l:cpcors and the IIvailabilll)" ('()InpuTer $Oftwnre thai can estimatc the three-diraemionItl wpc of the rra-pcor. il is possiblc to dc.~ign moleC\j~!IuI will MIow an optimum fit to the n"<:cpwf.

17). suicide inhlbilOQ of monoomine o~idase (Ii Chaplet 14). and the aronl.:llllSC inhlbl~ 4-hydroxyandrostcncdionc: and excIDeSt:lne (se<: Chaplet 23). These pharmacological agenlS form covalent boods .... ilh 100 reccpfOr. usually an enlymc's active: silt. In Ihce cases. the cell mu" destroy the re<:eptor or cnl.yrnc, or. in the case of Lhc allylouog agents. lhe cdl woul d be n:ploccd, ideally wilh 11 normal cell. In other words, the u~ual usc of drugs in rncdicallrcal' ml.'l11 calls for the drug' s effccl lQ last for 11 finite period of lime. Then. if it is 10 be rcptal~'d. the drug will be oomilllliterM again. If the pallent does IlOI lolcnuc the drug well. It is cI'en ITI()("e Important thai the agent diS5()CialC: from !he IlX'Cptor and be e~crcled from lhe body.

DRUG DISTRIBUTION
Oral Admlnlstr.tlon
An examination of Ihe obJllwl1' course (Fig. 21) fllCCd by the drull wi tt lI;'c a beller understanding of what i invoh'ed in developing a C()IIlmcreialt y feasible product. Assullle that the drug is administem! OI"dlly. The: drug must go into solution to pa..~ through tile gastrointestinal mucosa. Even drugs administcred lIS true !lOlUlions lIlay not remain III solullon as they cnter lhe acidIC ~tOfl1aCh and then p3SS into the alkaline: intestinal tract. (This is txplailled fMIler in the dlSCUSSIOll on add- base ch(omlstry.) The ability of the drug 10 dissolve is go~cmcd by scvernl factOl"S. including ils chemical structun:. ~ariation HI panicle sill:. and panicle ~urfa.ce area. nature of the crystal form . type of lublC1 cooting. :and t)poe of tubkt matrix. By vlll"}'ing the dosage form alld physica l eharncterislics of the drug. it is possible to have a drug di s.>Olve quickly or slowly. wilh the lalter being the situatioo for many of the suo;mincd -llCtion products. An cxump le is orolly adll1inistem!5Odiuon phenytoin. wiID which variation o rboth thecrystal (onn and tablet adJuvlll1csean slgmficantly alter the bioovni labtlity oflhls drug widely used in the lreatmenl of epilepsy. Chemical modirlCauon is also used to a limited utent to fxilttntc a drull reachinll its desired urget (see Chapler .5). An eJllll11pk 15 o lsalal.inc:, llsed III lhe treatJl1('nl of ulcerative colitis. Thi ~ drug is a dirrocr of the ph:umaeologicatty acll\c mesalamine (.5all1inosalicyl ie acid). 11lc lallcr is not e!fec tive OIlllly becall'C it i~ metabolized 10 inactivc forms

or

OVERVIEW

"dnt,

a. ch(omical molecule. FollOWing introduction into tIr body, drug mu"" pass through many barriers. ~urvivc
1$

of 8tlachmc:nt and ~lorage. and a\'old signifi Ullt meubolic destrucTion before il n:achc~ the site of IlCtion. u,Q,lIy I re.::cplor on or in a cclt (Fig. 2- I). AI the Il."l"Cptor. lhe follQwmg cqui librium (Rx. 21) u~ualty holdS: iltmwle
\IIC'

DruH

Rl CCp4 or ;:: Drug-Receptor Complex "

I
Pharm:acologk Response (RJI . 2-1)

The ideal drug lIlolecule will <.how fa~orable binding ch:ar

the: m:eplor. and the c:qullibnum wit11ic to the same time . the drug Witt be expected to dl5<iOo:iMe from the Il."CCptor and reenler the systemie d~l.I1ation to be mfttoo. Major txceplioos include the alkylating 1IC'll> used III caocer chemothcrnpy (o;ee Chuptc:r 12). a few inhlbnllfS of the enzyme acetylchQlinestemse (~e Chapter
A'Im<ol ...... to n~ At

me

DRUG
i i

DRUG

DRUG---

SYSTEMIC CIRCULATION

... ' """""

_ OrugmuslpasslllrOuQhrr., ..... - . ..... Dfugador.. ,-'

I
MEtABOLITES
"'(Ioree1lyinlO~$jOC:~

Figure 2- 1 Summaoryof drug

d~bl.ltlOfl

before reaching the colon. llIe dinlc ric form passel; through a signifICant ponion of the intest; nal tract before being clea\cd by the intestinal bacteria 1 '''''0 equiva lents of 0

mesaJaminc.

""'"

"""

In conlf'llSl. these !>alnC digestive C'nzy~ can ad ...ntalle. Chlonunpheoicol is water soluble (-P mgfmL) 10 come in cootact ""ith the. taste tonllue. prodltCinll intense: bitter l:ISte,

;
be as II .wspension biller laste: rccep1 00i 00 the: tongue. Once i trolCt , the ester lmuge i~ hydrol)'7.cd by the I ases 10 l he active ant iblOCioc cblQQrnphemool common dietary fally acid palmllic acid.

~IUl

0,

,,

'tl C"OICll
""",oR
H

ill ustrated by olsala;dne. any i.:ompouBd passing lhrough the ga~lrolnle.~l inal tract will encounter a large num bel' and variel), of digeslil'e and hacltrial enzymes, wh ich, in theory. can degrade the drug molecule. In practice. a new drug cn l;l), ufldc'r in\estigalkx1 wililikd y be d~d fmm funher consideration if il canrlOt survive in the inlCSlilUl1 tract or iu oml bioavai labilu), is low. ncce!l5ilaling partmcral dosage form s only. An exceJMion would be a dru g for which there is no effective allcnw.livt or which is more effcctive Ihnn exi sting productS ~nd can be admin istered by an alter nate route , including parenlt11l1. buccal. or .ransdc:mlal.

A~

'" Ch lor .nphln lcal

Chlor ~phlnlc ol

P, lml lill

Otsalazine and ehlor.unpheniool ,I M06! prodrugs are compou nds I btu are I

-,

is tnc active drug,

to the active form. An tllolllplc of this I)'PC of

menadione. a Sl nlpk n3phthoquinone Ih:I! is convened in

the b,'tr 10 ph)l00adionc (vilBmin K:!(3),).

pilssages. 11M: laller. man)' limes. pass into the patient's circulatory ~ystcm by passi,'c d.ffusion.

Parenteral Ad ... lnlslr.ti_

Many 1imc~ there will be therapeut ic advanlllge5 10 bypas!Omg the in(\':StIRn] twrier by using pan'nl('T'31 (inp:table) d0sage fonlls. This is com ilion in patients who. becau.se of ill
ness, cannOl loJemle Of' are illCapable of accepting drugs orally. SOllie drugs are 50 rapidly and compklcl y met:lboli/.ed 10 lnacti\e products in the li,'cr (fil'5l-pass effect) IMI orallldminisU'ation is precluded. BUI thai does !lOt mcan thaI the drug administered by injection is noc confronled by 00siocks (Fig . 2- 1). Inlr:wcnoos adminisH'(Jliun places !he drug directly inlO tbe circulatory system, .... ht're it will be rapidly dIStributed throughout the body. includmg liSliIJe depotS and the liver..... here most biOIr'DnsfOlTllDlions occur (!;CC below), in lIddition 10 the receptors. Subcutaneous and intramuscu lar injtttions ~Iow distribudon of the druS btcause it mll~ diffuse from the si te of injection ioto systC'mic drculauoo. II is possible 10 mject the drug dil'C'(:tly into specifie organs Of areas 0( the body. I mra~pi nal aod intracerebral routC"5 will place the drug directly into the spinal fluid or brain, respe.;:tinly. This bypasses a specialiU'd epithelial tissue, lhe blood-brain barrieT. which protects the brain from uposure 10 a large number of mctabolltcs aod chemIcals. The blood- brain barrier is composed of me mbrnncs of tightly joined epithelial cells lining the cerebnd capi llaries. The net ~ult is that the brain is not exposed to !be same variety of oonlpoundS mat other organs 1If"C' . I real anesthetk:<; are examples of administnl1ion of a drug dil'C'(:i1y Onto the desi red nervc. A spina l block is a form of anesthesia perfOl"l11ed by injecting a local anesthetic directly into the spinal cord at I specific location to block transmission along spcriftc neurons. Most of Ihe injccti ons n patient wlll experience in II lifctime will be subcutancousor intl1llTlus.cular. These parenteral routC"5 produce a dcpol in the tissues (Fil- 2-1 ). from wlticb the drug must reach the blood 01" lymph. Once in systemic circulation, the drug will undergo the same distributi~e~ Ilonw,-,na as omlty and intrn\'enously administered agents befOft; reaching the targC't reccplOf. In general, !be samc factor.; that rontrolthe drug's passage through the gastrointestinal Illucosa will al<;() dctcnnine the rate of mo- C'rnent out of the tissue depot. 'The prudrug approach des.cribed al!l:)\'e also can be used to alter the IIOlubility charatterislics. WblCh, in turn, can increase the flexibi lity in fomlulating dosage foons. The solubility of meth)- lprednisolOlle can be altered from essentially wbter-insoluble mcthylpredniwlone acetate to ~lightly wllter-insoluble metbylprednisolone to ....<ltersoluble methylprednisolone sodium SlICCillllte. "The Wiler-soluble wdium hc:misuccin3te salt is used in or-aI. intrnenous. alld inlnunuscular dosage fonns. Metbylprednisolone itSelf is normally fuuod in !ableu. The acetate ester is found in topical ointments and sterile aqueous suspensions for intramuscular injoction. Both the sucdllllte aod acetate esten ~ hydrolyzed to the active mcthylprednisolollC: by the patient'~ own systemic hydrolytic en1.ynlCS (estcrru;cs).

WES

...

Occa<.lOIIlllly, the prodrug apProach is used to enhance !he ab5orpUon of a drug that is poorly ab&orbed from the p!Utlintestinal tnICt. EnaJapr11 is the ethyl esteT of enalaprlhc acid, an .cti\C' inhibitor of angiotcnsin-convcning entIme (ACE). The ester prodrug is mucb more readily abIOIbed orally than the phann8CQlogicalty acth'e carboxylic

...
~ ~

" '-'

En.l.prll ;

Fl C:tH5 R H

En.t.prlll!;, Ae l d :

'" m

" ., ,~

,
,

Unless the drug is intended to act locolly in the sastroinlt$Iinal tr.I!:t. it will have to pass through the sastrointestinaJ ~ barrieT illto venous circulation to reach the site of !he Itteplor The drug's route 'nvot.C'S dlsuibution or tJOrun& between the aqueous cnvironment of the gasuoimes~na1 tract. the lipid bilayer celt membrullC: of the mucosal ctlls. [M~ibly the aqueous interior of the mucosal ce ll~, the lipol bilayer ITICmbnines on the vcnovl ~ide of the ,astminIe$1JllaI tnIt"t. arid the aqueou~ environment of venous drcuIM:IIlfl. Some: \cry lipid-soluble drugs may follow the route cI dietary lipids by be!."OIuing pan of the mi.( ed micelles. I..oopotauns inlo tlte chy lomicrons in the mucor;aJ cells into 1IIt lymph ducts, M'n'ic1ng the intestines. and finally entffing 1 _ corcll13liOll via the thoracic duct. 1lx- drug's passagc through rhe mucosal cells can he passile or active. As is dlscu~~ below in th is chapler. the bjlld mernbnmc-s IIf"C' \'cry complex with a highly ordered IWtIIR. Pan of thiS membrane is Ii "C'ries of channels or hUlIIel!; that form. d isappear. and reform. TItt::re are receplon ~I 1!lO\'C oompouods into the cell by a process clliled ,}ino_ ntruis. Drugs thm resemble a nonnal metabolic precursor or illltllloediate may be actively transported into the cell by lilt WDC' iystem that \l1Ii1SportS the endogenous compound. On the other haoo. mo5t drug molccu~ are too large to ~nlCT the cell by an active lrunspon mechanism througb tile

pan'-

Protein Binding Ono:e the df\lg cnlers the 'yMemic Circulation (Fig_ 2- 11. it
can undergo sc'el1ll events. It may stay in sol ut ion. but many drugs will be bound to the serum prlllein~. usu:ll1y albumm (R~ . 22). Thus a ne .. t(jui librium mu! be comidercd. Dcpcndlllg on the cqul hbnum constant. the drug can ..- maln in syste mi c Circulation bound to albunun for a considcrnble period and 1101 be a" aill1ble to Inc si les o f biotmnsfomullloo. ,he pharmacological receplOf!!l. and t.\CI"I:llon_
Drug ... Albumin ;:: Drug-AI Wm,"
C(JllIpk~

CH,

(lh. 2-2)

Methyl9rednlsolooe; R H
Md l,1ped.-" ....... ~: R q-o)CHl llelllt\PleQliI *'Iw SodIum &!CrinaWl: R . qs()~' Na'

<"'

Another example of how prodrug design can significantly al ler biodlstribotion and biologN:al half-life is iUUSIl"'dlOO by ,wo drugs ba.'\Cd on the rellnoic aclll stnJclure used systcmically to lreat IlSOIi usis. U 1I0nmaligllam hypcrpl!lSia. Etreti rtale has I. 120-day " 'ennirtal" half-life lifter 6 months o f therlIpy. 11I oontrast. 1he octi ,..,. metabolitc. aci lretill. has I. 33IQ %-hour " termina l" h~lf- life. 8 0\h drug ~ ure potential ly teratogenic. Female patien\) of c hildbearing uge must sign statemenlll lhat they are aware o f the risl s and usually are admi nistered a prt'gn:mcy te\! before: a pn:scnplKlII i, ISSued. Acitretin. wi ,h its shoncr hal f-lifc, i~ rcconllnen4:d for a female palknl whu ....ould like to become pregnant, because it can clear her body withi n a n:a..<iOIlablc lime fr.une. When c lTccli ~c. etrrtinatc can keep a p;ltlent clear of pMIrillsis le sion~ f01" sevcrdl mOllth~. C",

ProIC'1n binding CIln ha,'c II profound clT1 on !he drug's cffl:(1i\e solubili ty, biodlS-lnbollOfl. half-lifc in the body. and inlcr.lClion wi lli OIlier drugs. A drug "illl such PQOf water o;olubili,y thatlherdpcutic COIK.'CntralJons of Ihe IInbound (oclive) drug normall) cannot be mainlallJed still can be a 'cry cffectilc ligen!. The albonun- drug t."()nlpieJr. IICt5 as a rt'SCI"voi r by providing I~rge enough concenlr:uiom of free dlllg 10 calise a pharmacological re~potlse at the f'",,:cptor. ProIein b'nding may alw hnILt:wxess tocenam body comp~rtments. The plocenlll i~ :Iblc to block passa~ o f proIelll' from nUlIemall0 fetul circulation. Th us. drugs that I10Ilnally ..... ould beC'\pectcd 1 cross the pla(."('nlal barrier and JlOS',bly 0 barm t"" fetus are n:WIllOO in the malcOill1circulallOfl. bound 1 the mother's So!rum protcins. 0 Protem binding also can prolong 'he drug's duration of IICUon. The drug - prolein complc~ IS 1 00 lilfgc to p;I!IS through tile l"I,,"al glomerul ar mcmbr:mcII. pre'entmg npid cxcret ion of the drug . Protein binding lirnil.l. thc ntl'lOllnt o f drug available for blotr:msfonnatioo (see below ~nd Chapler 4) and for ImC'r:lCt lon with ~pecirlC rttl: p1or Siles. r'Ol" CUntpic. tile lurge. pol;lr trypanoc Ide surumi II remain_ in the body
CHl 0

""-~ ""-

II
C'o/C""",,

""-

Etretinate

Esterase

H ,co

No 0

NH-C

-<:H. ,

No

I
N, ' '0,5

". I ". / /

Sur.",ln So d i um

ID !he protcm-boond fonn for a~ 100& as 3 months (tv: ~ da),~. The mamk'BaIlCC dose' for thi S drug b based on '/Icckly admlni~lratioo . AI this might seem to be an .lIantage 10 the polllcnl II can be, but il also mean! thai.

Ii",.

n:ac:1I0II$, a ~igmfi QIIlltrogdl of lime Will be requul,'d bo:fore the conct'ntralion of dnJ, fall\ below IO~ic level s. '11Ie drug- protem binding phenomenon enn lead to some
chnalLy liIgnifi~1U11 drug-urug inlCr.l(lioru resulting when OMIkus dlsplacesanolhcr from tnc binding site on albumin. A ~ number of drug~ can dl~place the anhcoogulam ...arr.,n fll)lll 1 albumln -bindi ng sit es. This increases the dfec15 ti.e roroc~nlr.!lion uf warfarin allhe receptor. leading 10 an ~ prothrombin li me (mcrca.'\td IInle (or clot fomla-

<.hook! the p;IIH:n1 have $C'rious

ad\'~

1IOII)1Iid pocenual hellKnhagc.

molecules absorbtd from the g8Slrointesiinal lmet erner!he ponal vein and are initially tmnsponed 10 Lhe li ver. A ~ignifi canl prupoI'tion of a drug will panilioo or be lransponcd into the hepatocyte, ... ~ il may be mclaboli1.ai by hep;ilic en1.ymes 10 inactive chemicals during the inlualtrip through the liver, by ... hal is known as the firsl -passeffect (Ce Chapter 4), Lidocaine is a cI:tssic example of tIM: significance of 11M: fir:sl-pass effcci. On'r 6Q'l. of Ihis local aneqhelic antillJ'rflythmic agent ;s metaboli7.cd duri ng liS inilial paqage through the liver. resulting in it being imprndi cal 10 adminiSter OI'&lIy. When used for cardiac :lrThylhml:L~, II i~ administered intravenously, This rapid nli:labolism of lidocaine is used 10 IIdvantage when "ablhllng a patient ... ith cardmc arrhythmias, Should tOO much hdocaine be OOmiRlstered InIJ'avcnously, toxic responses ...111 lend 10 d:rease becuu.'iC of rapid biOlIans formalion 10 inactive metabolite:t, An understanding of the metabolic labile site on lidocaine led 10 the developmem of lhe primary anune anaiOl:uc locamide , In COOlrol5l 10 lidocaine'5 half-life of Ics5 lh3n 2 hours. localnide's hal fli fe is approximately 15 hours, wi th 40% of the drug excreted unch3nged, 11tc dc\elopmem uf oral ly active antiarrhythmic ~nlS is discus.~ in rroore detail in Chapter

19.

,,
Cit$::d,

OH,

, "'",.,... ".
C~ H.
Lldo~.lo,

,c~ H.

OH,

In lCRC'ral. $lruo:,:turul change~ In tIM: barbilurute ~rics (see

fal'or panidoning 11110 the lipid lissuc Mores tkutasc durallOO 0{ aclion btu increase centr~J nen'ou~ SY5wm ]CNS)delftSSion, Conversely, the barbituratcs ... ith the ~'"' onset of action and IongC)! dur,lIion of aclion coma;n the mort' potur ~ide chams, Thi s laller group of barbi turate,~ both enlaS and kaves tIM! eNS more slowly than the: rroore hpopllllk: thiopental.
~..... 14) that

,,
-

<:H,

"-<r

j,

c, .

C",

<:H,

Toe,lotd,

Pt ... Metabolism
All wbslances in the: circulatOf)' 5y,I<:OI , including drugs.. InCIIIbolit(S. and nutrienl.~, ... ill pass Ihrough tbe liver, M051

A study or thoe lnetabolic rate of h drul! is required for hll new drug productS. Often it is found thai the nlClabollle:t are also Klive, Indeed, sometimes lhoe metaboli1e is the pharnlacologically active n1oolule. llle...c dru g mctuboli les can pr0vide leads for additiuna l investigations of potentially ne ... prodUCIJ. EJ:ample!l o f an inacli ~e parent drug lhat is con\'er1ed 10 IIJl acti ve metabolite include the nonsteroidal anli-

innomllIalOry agenl sulind~e being reduced 1 111<: acti ~e su i. 0 lide metabolite; the inmlUnO"uppressant Il/;uhiuprine being clell\OO to the punne: antimetabolite 6-men::aptopurine; and purine: and pyrimidine anlll1lo1;:UlboIitcs and anti~iT1li agcnlli bems cooJug:IlOO to their nucleotide fl)f11l (acyclo~ ir phosphoryluled to acycloVIr tnphosphate). Oftcn both the parent druS and il~ metabolite are acti \c. which has led to additional commercial pmduct5. lI1 ~tcHd of just one being n13rkeled. Aboul 7' to 80% of phenacetin (now wi thdruwn from the U. S. market) is convened 10 acetaminophen. In the tricyclic antkkpressanl se~ (see Olaptcr 14). imipnlmlne and amitriptyline are N-tklnethylated to desipramine and nonriptylirl(', respecti vely. All four CQlnpounds have been maneted in the United States. Dn..tg lnetabolism is discussed more fully in Chapter 4 .

Although a tlrug', mctabolism can be a SQl,m:e of fru stra tion for the nlc(hcinal chemi st. phannuci~t. anti phy~ician anti lead 10 inron\cnicoce and compliulK"e problems wilh the patiem. it is fonunate Ihm !he body ha!i the ability to metabolize fOll'ign molecul~ (xenobiotio)_ Otherwise. many oflhese ~bslallCCSroukl remam In the body for years. TIlls hm; been the complaint against nain lipophili c chemi cal pollutants. inclUding the once \ery popular insectiCide DDT. AfterClltcring the body. ~ chcmkals reside in body tissues. slo .. ly diffusin, out of the depotS and potentially harmmg the individual on a chronic basis for sc"C11l1 years. TIky can also reside in h~ues of commercial food allIrnab that haH: been slaughtered before the drug has washed out ' of !he body.

"'Ilnd.~ '

I t . c:H.,(oO)

Active

'~llId ....U

.... I...

I t CHsS

~.~
S '

"'.

S~

')
Authloprlnl I_"'.,C.ptopll,lnl

Acyclovir : R. H Acyctovlr tr lphOlphlll:

RO' O_P.O_P_OP

Phlnlcilln ' R"' OC,H s ACllam l ncphln R. OH

~

- -, .
I '
II

,0.,

\
I

-,",

CHpi:CH,H,

TIk main route of excretion of a drug and it"! metabolite! is IhroI.Igh lhe l idney. Fur some drugs. enterohepatic cireulation (Fig. 2- 1), in .. hich the drug rec:ntCfS the imestinal tracl from !he liver through the bile duct. can be an important pan oflhc agem s di~tribulion in the body and route of eKctetion . Either t/le drug or drug metabolite can reenter syste mic circulation by passing once again through lhe intestinal mllOO5a. A portion of ellheralso rna) be eJlcmed in !he feces. Nursing mothers muSi be oonccmed because drugs and their nM!taboliles can be excreted in human milk and be ingested by the: nursing infant. One should keep a sense of perspective when leammg about drug mctabolism. As explained in Chapter 4. drug metabolism can be oonccplUaliud as occumng in two stages or phases. Intermediate Il\CUlbolul'S that arc: phannacoIogieally acth'e usually are produced by phuc I rcacllons. The products from the phase I cbembuy arc ton'ened mto inactive. usually water-soluble end products by phase [[ reac tions. The lauer. oommooly ca lled ClJfljugal;on reactions. can be tllought of as synlhelic reactions that involve additi on of wHtersoluble subsl ituc:nts. In human drug metabolism, the: main conjugauoo reactions add glucuronic acid, sulfate. or glutathione:. Obvi~ly. drugs that are bound to serum protein or.show favorable panitiooing into tissue depots arc: going to be metabolized and excretC'd rl1QfC slowly for the reasons discussed above. This does not mean that drugs that remain in the body for longer periods of time can be IIdministel"l'd in lower doses Of be taken fewer tllliCS per day by the patient. Several \ariable.~ determine dosing regllnens. of which the affinity of the drull fOf the: receptor is crucial. Reeumine Reaction 2- 1 and figure 2-1 . If the equilibrium docs 001 fnvor fClfl'nation of the drug- receptor complex. higher and usually IIlOre frequent doses must be ildminisleil:d. Further. if partitioning inlo tissue stOll'S or metabolic degrad:ltioo and/or cllcretion is fa \omi. it will take _ o fthc drug and usually more frequent adminiSintotioo to maintain thcrllpeutic concentnllions at the receptor.

R.c.ptor
,CHI

,fwnllrlplyllno ; No,I"ptyllne :

R CHI It. H

1",lp,_lnl . o.llp,_lne :

I t CHI

R. H

With the possible uptioo of general anestnetks (sec ChaptCl" 14). the ...orting model for a pharmacological reo sponse consisl$ of a drug binding to a specilic receptor. Many drug receptors ate the same as those used by endoJeIlQUsly produced ligands. Cholinergic agents intcracl with

thl: same 'C~pt~ :t~ lhi: neurotr:ln~mincr acetylcholine, S)nlhcuc C(lrtlCQl;leroilh bind!O the :Ime rccCplOI1i lIS corti. '00I'I(' and h}droronio;ooe. Often. n:<:eptOl'll for the ~l11C Iipnd!lft found In a vanety of U"ue~ throuj;hou, the body. The nOIl'iI~roidal anti-inf1:umnllIOl')' agcnl~ (see Chaplcr 22)

,"hII'll the l"fOSlagJandm. fOl1l11l1g enl)'lIIc c)'cloo~)'genase. "hlth is found 1M nearly every lis~e. Thl~ clll...s of t1rug.~ has n long h~1 of ~Ide eff~(S with many patient C()mplnints. Note in Fi gure 2-1 thai. depending on which rcceplOl1i con lain bound drug. there may be desired or llmJc~ireli effects. Thl' i~ because a \ ;!ricl)' of rt'Ct'plOl"!l with ~imilnr slruclUl1Il retjuln:n1ol'ntJ. an: found in several OI'll:lIlS and tis.ues. Thus. the I1Qn$tcroidal anll-inflammatory drugs combin.e with the dall'l'd cydooxygrnase KaptOl'S al the ~ile of the inllammaIJOn and the undesired cyclOOJlygenase rttrplon in the ~iSlIUIn", ... maJ mucosa. causing ~\erc dl!iComfon and wrntIimc<; uiceruliOO. One of the ~ond generult01'1 IDlihiSlarml16. fuofenoomc. is claImed to cau'iC less sedation bccaUSt: it doc~ l10t readily penctnlte tnc blood~brain barrier. The r-~tlonale i~ that le:s;s of thi~ anllhlstD.llline is 1\ allable for the n=ptors in the CNS, \o'hich liTe responsible: for the o;cdation rebpon<e ch3f"oiCtl'rhtic of antihl$lllmincs. In contro.t, sorn.: antihistamines aTe uS/..>d for their CNS depressantllCti, ity be(:au<c a significant proportiun of the adll1ini~ ~rcd dQo;o: is cms.\ing the blood~ brnin barrier relative to blndinllt" the hiqamine H I rt.'CepiON in rhe periphery. Although it is normal to thinl of side dfccls lIS undesirn~. they ~tJl1lC!1 can Ix' lx'ne:flCial and lead to new prodIll'h ~ wcce~iful de\eloprnent of oral hypoglycrmic iIC1ll' u:.cd in the treatment of diabetes began \o'he:n it W..lS found th.lt cerulin SIIlfooamides had a hypoglycrmic effect. Nc"~flllelc,,-. real problem in drug Ihcrupy is p.lIient compll8llCe In t.1king lhe drug:lS directed. Drugs that cause seriou\ probICnl81J1d dIscomfort tend to bel a\'oided by palients.

time. lIS rat.: of melabolic degradation ~Id allow reasonable dosing schedules and. Ideally. oral admmisltlItion Many times. the drug chosen for commercial sales has been selccIed from hundreds of compounds that ha\"C been scm:ned. It usually ilIa compromise prodoctthat moet5 a medical need while dcmonSlnlling good patient accrpt:mcc.

ACID - BAse PROPERTIES

Mos.t drugs used tOOpy con bel c lassified as acids or bases. As is noted shortly. a large numbelr of drug~ can behave as either acKls or ba:ocs as lhey begin their journey inlo the paticnt in different dosage forms and end up in systemIC circulalion. A drug's acid~base Illopenics can greatly influence its blodistrihution and panllioning chlnderistics. (}\"er the years. al leaS! four nlljor definitioru; of acids and bases ha\e been de\eloped. The model commonly used in pharmacy and blOchclnlstry was developed independently by Lowry and BmnSled.ln theirikfinilion. WI acid is defined as a proton donor and a mIse is defined as a proton accrplor. NOIice th:1I for u ba'le. there;J no memilJll oflhe hydroxid(, ion.
Acld~Conj"llllte

a.._

Swum...,.
One uf the: goals is to design drug~ thm will inter;l(:t with
rteqlIoo at specific tissues. There are se.-crol ways to do thIS. includmg (aj altering thoe mulecule ... hich, in lum. can ~lwIle the biodi.lrlbulion: (b) ~arching for structures lhat \how incrtascd specificity for the: largct receptor that will produce the desired pharmacological response .. hile de~n, the affiruty for undesired reccptOl"l that produce Id-oroe responses; and (e) the still CJ:pcnmmtai approach of ..t1ll;1lIng the drug to a monoclonal anubody (see Olaptcr lilhal 0/;111 bmd to a ~pecific tissue anlieenic for lhe anti body Blodi.wibullon can b.: altered by changmg the drog's ioDIublllly. enhancing ilS ability to resi,t being mctabolil.cd (u,uUy in the liver). al tcring tile fomlulntion or physical dWlIClfriStics of the drug. Hnd eh1mging Ihe roule of !KImin ISlr.Uioo. If a drug molecule can be designed so lhat lIS bindinlto the deslr\!d receptor is enhanced r'CIati~c to lhe !lnde\.Ired rtptor and biOOistribulion remai ns favOOIbli:. smaller do;>.cI of the drug can be adminislercd. Thi~. In tum. reduces the amount of drug avai lable for blDdinlllO those receptorS ~d"e for its adverse effects. '\"bE rrlt<ilcinal chc:miSi is confronled .. ilh se ...:ral chal lea~ in ikslgrung a bio~.-ti\e mokcule. A &ood fit 1 a 0 .peelf" receptor IS dl:sirable. btH the drug would normally be uptClt(l to dissociate from lhe rec.:p!or evenlually. 1bc ~lrlC'lIY for the: reccptor would minimi:r.c ~ide .:ffects. TIle drug .... ouk! be expected todcar the body ""'ilhin a reasonable

Reprcsentalive e.lIImpks of pharmaCeutically Intporlllnt acidic drop are hsted in Table 2-1. Each add. or proton donor. Yields a cOIljuglJ/(, /xu('. TIle lallet" is thoe prodUCI after the proton IS lost from the acid. Conjugate bases rang.: from the chloridc ion (reaction a), which docs not accept a proton in aqueous modia. to ephedrine (reaction II), which is an eJ:cellem proton acceptor. NOIicc lhe di\'el'!iity in ~truclUre of thc5c proIon dononi. lbey iocilldc lhe cl\lssical hydrot'hloric acid (reaction tI). til.: \O,eakly acidic dihydrogcn phosphate anion (reaclion h), the ammonium cution as is foond in IlmmooiuIII Chloride (rellClion c), tnc carboJ:ylic acctic add (reaction d). lhe enolic form of phl.'nobarbiUlI (reaction t'). the: carbo~y1ie acid mol.:ty of indomethocin (reaction)), the imide of saccharin (reilClion g). and the proIonated amine ofcphedrine (reoctlon h). Because all are proton donors. they most bel !rCated as acids \o'hen calculaJing the pli ofasolution or percenl ioni1.a lion of lhoe drug. At the same time. as noted below, there :ur important diffcTCOCC$ in the pharmaceutical ",opc:nld of ephedrine: hydrot'hloridc (an acid salt of an aminel and those of indonlClhacin, phcoob.arbitaJ. or sacchari n.

B __ -conJugate Acid
The BfIlllsted-Lowry theory defines a oose a.~ a molecule that accepts a prOlon. The prodUCI resulting from the additioo of a proton to the base is the conjugate acid. I'harmac,:ulically imponant basell arc listed in T able 22. Again. there are a variety of SttUCtU re$. including the easily recognil.ablc base sodium hydroxide (reaction a); the basic component of an important physiological buffer. sodium monohydrog.:n phoSphate (reaclion b) .. hich is also the coojugale besc of dihydfOl!en phosphale (reaction b in Table 2-1); ammonIa (reaction C), which is also the conjugate base of lhc IItlmonium cation (reaction C in Tabloe 2-1): sodium IICCUte (reaction d), \O,hich is also the conjugate base of acetic acid (reaction d in Tablc "2- I ): the .:nolatc fonn of phenobarbital

TABLE 2- 1 Examples of Acids

Ac id
W tl)d...)(JD ... iICid HCI
_ H'
"""'....

+
..
a'~

OJ) SOeIirn cihyO'ogeri jJl"cljipllJl

~.PO.~

1-1/'0.1"

'"""'.'~'~..

(e)

Aml'IDnundoOi

M-I,O(Ml,',CI "t (0) AcetIc IK:Id

CH,COOH
(e)
~

H'

..

CH.COO

H'

()H

()H

(rcaction ,,). which is also the CQf1jugul~ base of phenobarbi181 (reaction t III Table 21): the carOO)(ylate form of indomethacin (rnction j). ,,'hieh is also .he COIlJugale base 0{ indomethacin (rextionj in Table 2- 1); the imidale form of saccharin (reaction S), which is also !he CQf1Jug:ate base of saccharin (ruction 1/ in Table 2- 1); and the amine ephedrine (reaction II). which is also the conjugate base of ephedrine hydrochloride (ren\!lioll h in T able 2-1). NotiCe thm the COlljugate: acid prodUCIli in Table 2-2 are the reactant acids in Table 2-1. Conversely_ most of the conjugate base products

in Table 2-1 an: the reactant lwes In Table 2-2. Also, noOhet lhal when:as phenobarbital. indomc:lhacin. and saccharin are unioniud In the protOl1.1t('(! form. the protonaled (1I(:1(I;c) forms of ammonia and ephcdnnc arc lOI1iud sailS (Table 2I ). The opposite is true fOl" the basic (proton ilCCCplors) forms of these drugs. The bll.~ic forms of phenobarbital. indomethacin. and saccharin ~re anions. wll<:reas ummooia and ephedrine IIlC ekctronically neutral (Table 2-2), Rcrllcmber that each of the chemical eJlllmplCll in Tables 2-1 and 2-2 can function PS either a proton donor (acid) 01" proIOli acceptor

- ----------TABLE 2- 2 bamples o f Bases

W
H,O

lat Sodun 1i'0!CICIe NtoClH INa' OH -) .. '"' '.OJ S<vUn ""''''',,0-001'" ~e ldobaao:: '000.., 1lhosPhBIe)
NI.,HPO.I:? .... HPO;' ) ..
H" H' H' -

.
..

".'.

H,PO,
NH

Icl

Ai","" 101 NH,

,d) $r)1o." "" ...

il)

CHlCOONa (CH,COO~ Na -") Phwob:totIQI oocIo."

8,.

Nil'

0
N

}--o

INa 'J"

NH

N H'

}--o

NH

No

10

~o:b,oe~_IOdo.."

l\ H,c"'"
N

0 0
(Nil ')"

H,c ..... \

c'

CH,
\

H'

H.C ......

0
N

CH.
\

""

....
"' ..

I.
"

olOa
s.cdww! .oo.um

olOa

exs~-INe.).
o'fv"'o
Ept",Q" '"

c'

0
H'

/~H ex
l\o

,CH,
HN

CH,

H'

no. "

-- .

eK

eH, H,.{.

CH ,

' ''001) 00' " . - "

'", I, play< ......... .,101 _ _ _

I~). nllJ can bN. he understood by emphasizing the COIIce~ of ("()f1Juguu: acid-conjugalc base pairing. Complicaloo

Mil lila)' S'm m fil'S{, conjugate !Icid~ and cOoJug:lle b.l)oCS 111: Il()Ihi ng more than ,be productS of an acid- base reaction. In other words. they nppear 10 the right of the reaction arro"1I. Examples from Tables 2-) and 22:are n.:wrillcn in Table 2-3 a~ complete acid base n:actiOll~. Clll'eful study of Table 2-3 \how waler fUlIClIOIlHlIl a5 II proIOIl IICttptor (base) in I\'aclion~ a, c. ~. g. i. ( und m and proton donor (base) in reactions h, d. /. h. j. I. and n. HellCC'.

wa!er is known as an l/Iul'lrfJ/eric W"'IUI'\C\'. Waler c~n be eilher a ....eal. base accepting 11 proIoo to roml the ~tJ"OOgly acidic hydrJled proton ur hydronium I(In II ,0 (rral,.1ions (I, c. r.lI, i .1:, and m), or a ....ea .. acid donalillg a proton tu form Ihe ,(rongly hasic (pllIlQn accepting) h}'droxidc anion O H (rrac(ion~ b, d, J II, j, I. and II),

AddStnnyth
While IIny ac id-baloC reaclion can be wnllcn a.~ an equi lIbrium Il'action. an Ducmpt has been made rn Table 2-3 10

TABLE 2-3 Examples of Acid - Base Reactiom (With the Exception of Hydrochloric Acid, WIHKe ConJu!]ate Base - ) Has No Basic Propertles In Water, and Sod ium Hydroxide, Which Generates Hydrox ide, the Reaction of the (1

Co"'Jugate Base In Water Is Shown for Each Acid)

+
HydiOGtllonc aod
Sndium~ (b) HzO

ConJugllte Base

"'""

H,O
+
NM:lH
H~O

_
H.o

$odomdihydfogel'l phoaphale and ~s~e

I,c)
(d)
(0)

H2PO. -(Na)~

+
+
t

t:tasa

oodam ,IIOtI(lhydoQgl'll' pho$phatu

HzO
NH. '(a-)-

HPO."(2Na *)
H.o

= =

H,O' H1PO,' -(Na')'

~

Atmloni.m cNonde &rid ~$ ~e base. \OII.'OM

(6 H10 NH J Dase. sodun eoe'a'9

AceIlC acid

ana rtl ~e

(gl CH,COOH
Chl HzO

+ +

H,o
CH.COO-(Na ' )'

iodo'iti'lhecn and iti IXrf.IOiIIC base, Indoo ...thacn 1IOdoum, &how !he ~I KId-DaM dei.stry al8OO!icacid and IOO1um acetale. respecTively

OW~ ' I"

HPO,--tN.')" Ol'n'~a .)"

NH,
OW

CHJCOO'
OW(Na'~

l'IlencIbarbIIaI and ls corotUQ<Ilo base, pte d:IaItldaI SOdIun'I

r~o
H,C
H

"

HH

>-OH

H,O

o
H

HH

>-0'

o
S8cc:hann and Ih conl\103le base. saox:harll
$IXIIum

HH

>-OH +

OW(Na*)"

(I<)

():CNH

."

(l~o

H.o

H,O

H.o'(el " )"

OW(Na ,)"

CH,

H,O

-OH

""I

H H'

/CH,
CH,

OH-

tndlCale ... llIch seqUCIICC$ ~ unidirecuonal Of' \how only a \IlW1 ~,ersal. For hydrochloric acid. tllt' conJugale basc'. , is wch II "'eak ba.o;e lhal it e.~selllially does nOl runclion ... proton llaeplor. That is why the chloride union Wa.1 nOl lndllded a.~ II base in Table 2-2. In a si milar monllCr_ ... mer is illCh weal. c(N1jugllle acid that there is I inle reverse relICtion involving Wllter donaling a protOIl to the hydroxide: anu)fI or JQd,um h)droxide_ Two logical questions to as/( al this pomt are how one predkb ill whieh direction an lIcid - b:lsc reactIOn hes and to ... 1\aI e~tcm the reacuon gCleSIO compkuon. 1lle common p/lysltal thcmlCtll nlClIsuremcm Ihat contain s this informauon ill known as the pK. The pK , i~ the ncgatile logarithm of the modified equilibrium eonst~m. K,. for an acid - base 1UC1I0II wnuen so that Waler is the base or proton tIC(:eplor. h can be dt:rived M fol lows: As.wme that a wl'ak acid, HA. reociS with water. Base + 11,0

EljuUlion 21 is ITIC.I' commonly catkd the Hendcr,on HasscllKllch I'quation and i~ the OOSI S for ~ calculullonS invoJvmg ... eak acids and bases. It is u<;c:d 10 calculale the pH of <;(Jlmions o f wcak acids. ""cak bases. and ooffen; oon si<;l ing of weal acids and theirOOlljugale bases or .... eak bases and their conjugale ac ids. Because IhI' pI(,. is a modified equlhbnum constant. il CQI'1'eCtS for lhe fact that weak acids do '1111 compktrly react IOo'lth water. A \el)' similar SC'I of equauons is obtained from the reacnon of a protOrllltcd amll1C. BH . In walrr. lltc n::xlion is

AcId

Base IlW + tl lO

= 11,0'
i~

Conj. Add

Conj. Base

(R~ .

2-4 )

TIlt eqUilibrium ConSIlInI. K....

K"" ..

Con, ConJ Acid 80,s0, H,o' + A-

defined as

(&t

2-1)

(h 2-3)

Thel'quilibrium comtant. Kj. for ReactIon 2-3 is

_ Icoo). acidJ[oonJ. buel (acid II ba!.c I

(Eq 2-1)

NOilcr that EqullllOO 2-8 IS IdenilullO Equalion 2- 1 "hen the gencrnl lconj. acidllconj. b;le] representation is used. lltcrefore. using the same simplifying as~tlmplion lhat WilIer remainS al a constan t concrntrnlloo of 55.5 M in dllule solutions, Equation 2 8 can be rewrincn as
K. _ K '" " ... . _ [Il,O'IIB) _ lronj. IICld)[conj. ba!<e ) 1811'[ [xid]

In I dilule .soIuuon of II .... rak acid. the molar conccnlnllion u.1Il CII1 be U't'aled M a constant. 55.5 M 1111) number '" based on lhe density of "aler equaling 1. 1llerdore. I L U'A'ala .... dglls 1000 g. Wilh a mokcular .... eighl of 18. lhe mobrconc:entralion of wtl!cr in I L of \\'alrr i$
Wci,hl",o I 000 I 111)0 1 - MW",o .. ' 18 1 .. ~~. ~ M

(Eq 29)

Reamongtng Equation 2-9 into loganthmic form and 5ub~titutmg the relationships e~p~<;ed in Equations 23 and 2-4 yield\ the same Hendcrson- lI ass.e lbalch equation (Eq. 2-(0).

pU - pK.+

I Icon]. base) Oil ladd]

Thus. with [Hl O] .. 55.5. Equation 21 can be \Implifoed

.1.'..,111,01 _ K.,.I~B)" IH ,O'" J[A-) (HA)

Ceq 2-(0)
Rather than trying to remember the specific form of the Hendcrson Uas.~lbalch l'qIIatJon for an HA or BH acid. n is $implrr 10 use the general form of lhe equalion (Eq. 2 II ) expre~'>Cd in both Equations 21 and 210.

_ [ronj. KidHronj. blue] [acidl

By definil ioo.

C 2-2) Eq.

pH .. pK.

+ lUll

leonl . basel (kidl

P.... .. - 1oJI K,
pll -

C 2-3) eq.
(Eq 2... )

-los [H,o ' (

The modified I'qulltbnum constant. K .. IS customarily aJII\'cned 10 pK. (the loegati"e logarithm) 10 use on the $;Ime 'nkas pH. Therefore, rewriting Equation 2-2 in logarilhmic

fom!

prodUCCli

lot K,

'"' k)I [HJO ') '"' k)I [H)O ' I

+ lotIIA- ) - log IHAI + loti IcOll) base] - loa

K. + K. +

With this "crsion of the equation, there is no need 10 remembl:'r whether the sptties in !he numctalOf/dcnominator is ionized (A /HA) or un-ionized (BlB H ~). lltc molar coocenU'alion of the proton ~ptOf is the term in the numc:r.otOf. and the n'lOlar concentration or the proton donor i5 the denominator term . What about II'rak bases such" amincs? In aqueous solu !ion~, water functions as lhe proton donor or acid (10.. 2~). producing the rumiliar hydroxide anion (oonjugale base).

(Eq.2.$)

[acidl

Rearranging Equlllion 25 gh'es

."" IIIP ') ..

CooJ. ConJ. Acid 8&w: Base B ;::: 811* + OH Originally. a modIfied equllibnum conSlant. the pK.. "lIS de:nved following the same steps that produced Equation 22. It is now morecommoll to eJ.pre.o;..~ IhI' basici ty of. chemi clil in IrmlS of lhe pK . using the relauonship in Equation 2 12.

.. - loa

- lot:

Ioc [A- [ - log [HA) (Eq. 2-6) los [cooj. basel - loa [Ieldl

Substituting Equauons 2-] and 2-4 into Equauon 2-6 prod!.ICCs

pK. + lOS

[COOJ.

lacidl

basel

(Eq. 2-1)

pK, - pK., - 14

(&to

2]2)

TABLE 2-4

Enmples of O lculal ions Requiring Ihe pK.

I 'M1II111,. rllO 01 epoedo ... 1<1 ~ ... He) (pK.96) .. 11>8 ......... IUd It pH r:n Use EfI.*oon 21'

r.pt.... Hell
The """ ItHo

1..,... 1

O~

log II - I 6 Is 0 025. " Ii 00 thai thiIfe ... 25 ~. epMKliI" lor ~ 1000 parIS ep!oedo ... HeI ... ... ... " .... !rId >010; I. pH 2 WhII . . . pH oI.boo"l ~O I 1.41< II ec:cI (pK Sj II'1d 0 011 M IOdIo..Tl I< II Ii '1 Use Eq.,Moon 211

..till..

_'''i1 ''

ao

pH ...

a+1og0"l".7

.01

3, 'M1II1 111h11 pH 01 0 , M I<.~ ec:cIl(It ."",1 lJH equI/(lO lor e*oiWong 1hII pH 01 8 lIOkIIion ~ _ H.-. Ci< BW ec:cI

11-.....

log an

WhII . . . pH 01. 0011 1.4 ............. I 1<lIu"on1 ""'1.lta _ Ih;o..gIIht II . . ~ DIll 01- I: ec:cI." PK.. SIll...." Tht pt(. "'"" ... . . . . ... .,...,., CUI"', lor 1hII I.::t IhI! ...tAOO a:aopIor ~I ...on) . . .__ n , . l(Itucn The 8QIIIIIIln lor I II 1-00 \/WI pH 01 I IOMIDnCOflllln..... ...,.. 11'1 A' 01 B t.. II pH..
pK.. + pK. + log IbIoMI 2 .. a9

$ WhII.I'II pH 0111'1 ... 1 ................. .." Tht pK" 01,. .1.1 ......... INH.) CIIIOi"I.1I3 orrd ....... pK" . . . . 10 .... I) at ............. 00 ... Itorm 10 111: M . . poDlOri i'IIO WIlli' 10 tmo H.O Sor1ClII ... " " ... at ...eIIIi: acod ~.') and ... ~I baM 01 ........ acod Ie "ill 1f"CII'I). hlollc hong . . ......, ..-eIl Noll'" moIeo CUlOlllill-.:n II noI ........ on 1NI C ...... ,OO<I

"""'I'It.e' ..

pH .. pK,., + pK", .. 7 I

Warnlnll! It i~ imp,mom to recognl:tC tlult a pK. fOf 3 ~ i~ III realily lhe pK. of thc l"OllJull~IC ""id (acid doiliJl' or protonated form. BH ' ) of lhe ba<;e. The pK. i ~ li'1L'd m lile Af'lPCodi~ lUI 9.6 fOC" ephedrine and II'l 9.3 for ammoo; ... In realilY. tlu ~ is lhe pK. of the protooated form. such lIS ephed nne h)'drochloride (reaction m on Table 23) and ammonIum chloride (~action r In Table 23). ~sprcth"dy. Thi~ IS con fUSlniltO students, phannacists. clinicians. and cJ.penenced SCICnuSiS. It IS crucial thatthc chemIstry of dle drug be under stood when interpretinll .. pK. ,l1Iue, When reading tables of pK. valuc.~. such as tOOse found in the Appendix. one mU St n:al i1e tllallhe Io qed vu luc I~ rOC" the pnoton donor form of the mOlccu lc. no maner ",hm form is ondlcml'd by lhe naille. See Table 2-4 fOf j,Cl"crul woried cnmplc.~ of how lhe pK. is used to calculate pi Is of ~()hl1ioo). reqUIred 11I1i0!0 of Icoojug:ile base III ocld]. and pereen! loo17.3tJOn D, s~i rlC pUs. JuS! how Strong <If .....cal.: ~ the aci(h \\ ho:sc re:lC1lon~ on Wlltcr are lliustnlted in Table 23? Rcmember tlt.:lt the K~~ or pK.~ are modified c:qulJibnum constant, thm Indicate the c~tcn l to which tnc acid (proton donor) reactS ",jill wmcr to forl1ll"<mjugale add and conjugatc ba'>C. The equilibriu m for a Strong K id (10\\' pK.) in waler lies 10 the nglll. favoring lhe formation of products (conjullatc acid and conJugale base). The equilibrium for ~ \\e;ok acid (high pK,.) on \\;otrr iles to the left. rncanlng tll31 the conjullate :lC"1d i~ a better proton donor than the parent ..ill is or tlt.:lt the conjull(Ue base IS a good protoo acceptor. Refer buck to 6quahon 22 and. using the K. ~w~~ on Table 2~. _ubstitUle the K. tcnl1 for each of the ocids. For hydmch loric acid. 3 K, of 1.26 X Iff' means Ihm the product of lhe molUf l'oncentnlliOIlS of the l"OllJullD IC add. ]H,O' I. and the conjugate bast'. [0 I. is huge relati Ie to the denomi nator Icrm . [.I CI1. In other 'AlIllh. lhoere ~scnli aJl y is 1\(\ unre:lC"ted HCI left on an aqueow !iOIUUOIl of hydrochlonc acid. "tthe OIller extreme i\ cphedOIle HCI \\uh II pK. of 9.6or II K~of2j I x 10- 1 Hen:. the denominator "'pn'SC'nt illg the tonccntl1lUOil of ephedrine UCI gn:atly pl'(doInlnalCJ o~er thul of the product,. which. 111 thiS c~ample. is ephcdonc (conjugate ba.....,) and 11 ,0 ' (conjugate add ). 111 other worth. lhe ptolOllalcd fonn of cphcdrirM: i, a very poor proton donor. It holds OI1tO the proton. Indeed. fn:c ephcdrirM: (1he conju gate ba.,,<, on thi < reaction) i< an c~~"<:' l lent proton lICCCp4or. A gcocr.ll rule for detcrnllnong ",helher a chemICal is strong or Vo"t'ak acid or bbc: I~

pI<"

< 2:

>lNng acid; roroJu~~ b;uc has no m''''''lnlful

'-00:

7 WhIrl. Ihit pIitQII'1t9 IDrilM '" 01 ncbl _ _ (pIC, '

....
_

~ 2''!i;

at .","eo '"

111)'85 M nihil

...

'""'*

CU'JQ31.

.51 .. 11'1

,.. ....... 110('5 in "'ak'r pK. 4- 6: ""CD~ acid: ",eul ctlnjuK3lcl bao;c: pK.II- IO: ,'cry wc~k add. ~onJU~lc bll~ ,leUtnlllt""lge. pK. ). 12: ~nuany no lICidlC I~ Ojleme In "'lIter. ~"OOJU

W'UIl,

III ,,8CC bJII.. 1d pH 80"U. Eqo...,.., 213 beca 71

an H.-. COd

,",0 """

For" po"""" Jll.I'PCIIi .cb.wo .....' II ... ,IM

IIOOfIIC

oHIO

~ as IhII 0CIr'fJ0II1II ~ II thai ragok:n 0I1hII ""os.... buIIlI!\Id

Thl dehneatlon is only appro~ll1Iale. Other propenin also bl:come important \\hen eoml.!.!nn); cauuon) In han dl on!: acld~ and bastS. l'tIcool h II pte. of 9.9. slillhtly Irn than that of ephedrine HCI. Why i, phenol cO'hidcrcd CtlfTlT ~i\'c 10 the _I;an. "'I\creas cplw.'dnoc lIe l or free CpllCdnnc i~ considered innocuou, when applied 1 tile skin~ P1ICII()i 0 h8s the abilily to panil ion IhrutJgh the norm~lIy protcct;\C lipid laye", of !he ~ lon. Because of this propc'ny. thit u trenlCly weak acid 1t.:I< carried the name carbol ic acid. Thu~

TA8l 2- 5 ReprHentative K. a nd pK. Values from tne IINrtions list" I" Table 2-3 (See the Ap~ix)

EqUllllon 2- 13 for HA acids

~rK1

Equ;lIion 2-14 for S II '

(f.q. 2- 13)

acids.
'k iO"';.lIlion ..

-5' ".ll

"''''0. r.",u..",j
hDllIIII_

Dt.,oogIn 1t0ilA

126 x 1(" e31 x '0 . 1 SOt X 1O- 1D

251 x 10-~ 316)( 10 ' 251" 10*'"
1:56 X 10- 1 316><:10-'

, ,

W.o 1M ... HO MIl)

.. " .. "
" "

'k ,ollJzft,lon ..

,oc-

(I'..q 2-14)

A plOl of pcn:cm IOmf.allOll ,"C!'SU.' p H itiuSll'1lll!S how the

, ,

tells a person lhe ac id propenics of lhe pro\tJll.3!td fonn ofllle chemical. II does 1101 repn:scm an)thing cI~ ronccming OIlier poccntial to~ic ilics.

!hi: P

~im(lly

USIng tile dtug' ~ pK.. lhe fonnulmioo orcompouooing pharn1ICis; can adjust the pH to ert.~utc nta.l"num wateT solubllily 1I0l11C form of 100 drug) 01' max imum ~olubil ity in nonpol:tr mtdi3 (lIOIlionic fonn). This i~ wllenl understanding lhe dru~ 's kid - base chemistry becornes importan;. NOIe Reaclions 2-6 11.00 2-7:
C(lIIJ COOJ
thl'/!

"" "'''

,.~

HA; _ _ I

...

H"o

Acid BaS<' BIL (10.. 2_7 ) ... 11..0 H,O' ... B,.. 01 Mid!; can be dIVided Into IWO types, Il A :tud 8H on ~ basi~ uf the looic fonn of the acid (or conjugate ba"o;e). 11.-\ acidl. go from unioni7.cd acids 10 iom;ced conjugate b:iscs (Rl . 2-6). In COlllfll.~l. 8 11 " acid.~ go from ioni 7.ed {poIar) .. ids 10 un-ioniled (nonpolar) conjugatc bases ( Rl! . l71. In SCIW!r;tI, ph.:umaceuticaJly important II A acid. 111elude Ille inorgnnic acids (e.g,. lI e l. H 2S04), enol. (c .g .. biirbnur.tte . hydnnIOlns). carbo.lyhc acids (e.g .. 10.... . m-olce uiar-"'clght or~anic acid\. Ilf)'I~lic acids. N-aryl amhrnniJic acids. sa licy lic adds), and amide<> and im ilks (c.g .. ~Ifonamides anti saccharin. re.~t ively) , The chem istry is lImplerforthe plmnnaceutically imponant lH I acids: llIcy ate all proIonatcd amines. A polyfufICtioo:d drug call ha.c 5C\mtl pK.s (e ,Il . IUOlOdcilli n). 1llc laller's ionic >.!atc IS boise<! on amo.licillin5 ion ic SWIC at physiologica l pH 7.4 (I the dl5C"Ussiu-n below on p:rcr nt ioni~l ion). pK. 3 I , ll
~

-"

..

="" =
Conj,

H,O' ... A - f _
Conj ,

( It.. . 2-6)

degree of iOlulalioo can be ~hincd signiflCamly \'vllh ~ma ll ch:lngC'l in pH. 'The CUn'e:lI for an HA acid (indonlClhacm) and BH ' (prolon:ucd ephedrine) are ~hown in Figure 2-2. First. IlOIC lhal .... hen pll '" pK the compoulld is ~ ionized (or 5O'k un -ionl/..cd). In OItK-r ...."Ords.... hen the pK. i~ l'qual 10 the pH. the ulolar conccnlr'Jlioo of the add c:qllllls ,he molar concentration of lIS C'OIIjugalc basc'. In the Ilcn<k'rson- HllSSClbalch cquuhOll. pK. '" pll .... hcn log IconJ? basel! (acid ( _ 1. An incrca!;C of I pli unit from the pK. (increase: in allalinily) cauSb 1111 HA acid (ir>domethacm) 10 bccoIne 90.9'J. ill the iomze.! cOl1jugate ba."C fonn but re.~uhs ill ~ BH ' IICld (cphcdrilM! He l) Uccn:asinS its pcn:1:nI iom/..lmon to only 9 . 1%. An i~ or 2 pH units e<iSCnually MlJfu; an HA acid 10 complete ;()f111..o.tiOrl (99%) Ilfld a BII ' aeill to the noniomc conjugate oo\e form (0.99%). Jo~tthc OflPO!oile i~ '\tl when the medium IS made: more oci<lic rclul i~e 10 Ihe drog ' ~ pK. value. Incrcasi ng the hydrogen ion COtK:el1l rmiol1 ( decrea~il1g the pH ) wil l ~hiflthe .equi librium 10 the k ft . thereby mcreasmg the COI"Ittlll r~IIOO of Ihe acid and denea~mg thc C()IlCCntmllon of (:oojugatc base. In the: case of indomethacin. a decrease of I pH unit below the pK4 will IIlcreasc lhe OOrICcntr.1Il0n of un-Iorllud (pro1(00100) in(\(lnl(lh:.dn to 9. 1'K. Similllriy. a decrease of2 pll unus resuib in only 0.99'i of the indomcthacm belllg present in the ioniT.cd conjugate base fonn . TIle opposite is secn for the Bil ' acids. 1llc pcrccnlageof cplw,:drinc p!\'Senl as the l()fIil.oo (protonated) acid IS 90.9'l at I pH unit below the pK. and" 99.()<l, 1\1 2 pl l units below the pK . The\/,' results are sUlllm:uilcti III T~ble 2-6. With thi~ Icc.lgc in mmti. return to the druwll1g of arnoxicilJin. Al phy~iologlCIiI pH. Il"Ic carboxylic acid (HA acid: PK. I 2,4) will be in the iom/oo carbolyl:ue form. lhe

"00"

, =o_cc'====.7'~='='"<',c.c . c c.o.cc.c. __ ' " .cc.c.cc.=.c_. ..

=_ .

MIG. le ! I!ln
The percent IOni7..ation of a lImg
;~

.. .. . .. . .. . "" ..
\
_

.
"

'

-_.'

calcu laled by

u~ing

figure 2- 2 Pe:enllOlllll!'d 'o'\!fWl; pH for Indomf'lhaoclfl (pK, 4.5) and ephednl"lE' (pt<., 9.6).

"

TABlE 2- 6

Percen tage Ionization Rellli"e to the pK.

Ionlutlon (%)

,.. .., " ..,

'90

90'
'00

.eo

1 0==rHP '+AHA+H
2

" ".

Figure 2- ] Pa<D9I' of HA acids through hpod

b.m~.

pnmary amine (Bil ' acid; pK ol 7.4)" III be.soc. proton:ued and 5()% In the free allline form. and the phenol (II A acid; pK.J 9.6) will be In thc unioniU'd prot~led form. A lno .. ledgc of ptlccnl lOfli~ation mal~ it easier 10 e' pl ain and pmiiC'l ",hy the w.e o f ,;ome prepanlliolls can cause problems and di'-Com fon as It result of pll e;\lremes.. Phenyl oin ( HA acid; pK. 8.3) injttuon must be ooJusted to pH 12 wllh sodium hydruJide 10 ensure complcte ionil.U1ioo aJld mlllllmil.e walcr wlubiJi t). In IhcoI'y. a pI! of 10 .3 wi lIn:suh in 99.O'J of the drug being an anionic water-soluble conj u,gale base. To 10'.\~ the concenU'lllion of phen) toin in the insoluble: acId form e\'cn further and nkllllIaln e,ccs~ alkaJinII) . the pH I~ nl1~ to 12 to oouin 99.98'1 of the drug 111 lhe ioni~ed form. E~en then. a cosohem ~y~lcm of 4(}'i; propyle:ne glyrol. 10'l clh)1 alcohol. and 5O'l water for injcclioo is uscd to cnsu ~ romplelC :;ol ulion. This highly alkali ne solution is irntau ng 10 the pallent lind generolly cannot be admini Slen:d as an admi ... ,u~ Wi th OIher i ntnl\'4~: ' IlOIIS flUids Ihul an: buffered mon: clo!>!:ly at physiological pH 7.4. Th;, dccrea.-.e in pH would n:~ult In the parent unionil.ed phmylOln pn:cipnDlmg out of solution.

AdJuSlnlCnts III pl l to maintpin watcr solubi lity can w ine unJe~ lead 10 chemical stab' hty problems.. An example is moomelhacin ( HA acid; pK. 4.:5 J..... ''''ich is unstable in alka line: med ia. Thc:n:forc. lhe pn:fcrred oral liquid ~ form i~ . W!'fX'Il!oIOO bufferro at pit 4 10:5. ikcause Ibis is near lhe drug'~ pK .. only 5(n. .... ill be In the w:uet"-solubk: fann. Tllere i~ I medical iJldkatioo n::qulnng intra\'cnous admlnlstm"on of indomethacin to premature infants. TIle intrdvcnoo~ do~age form is the lyophlhlCd (frecle-dried ) sodll,,,n ..alt. "11Ich i~ reconstiluted j u" prior 10 usc.

Drug Distribution and pK. Tlle pK. eun h:l\'c a pronouoced effoert on the phannacokinellC$ of the dru8. As di'iCus.~ abo,c. drugs an: tr.lI1~por1ed in the a.queoo~ cn";runnlCnt of the blood. 11'Io"c: drop in an IOnllcd form ... ,11 [end [odistribute throughout the body mon: ntpidly thllli will un- ionif.ed (nonpolar) moleeule). With few eJ[ccpLion~. the drug must lea~e the pol!ll" cn" ironment of tlie plnsmlL 10 reach lhe site of IlLti!)lI. In general. drugs pw.~ through the noopolnr mcmbr.uJe~ of capillary walls. cell mellibranes. and the bJood- br1lm barncr in the un-iOIll~ed (nonpohlr) form, For .IA llcid~. it the parent acid that Will read ily cross these membrunes (Fig. 2-3). n.e si tuation I~ just the OfIPOSlle for the BH acid~. Thc: un- iooued conjug:1Ie ba.<>e (free anullc) is the SpeclCS most readily cffl\~i ng tile noopolnr """mbnmes (Fig, 2-4). Ct)n~ider tile dmnging pH environ ment eJpeneoced by tl'lc drug molecule orally admin i<.tcred. The drug r.", ~ n COllIlIC' .... lhe acidic 510111ach. where the pit can runge fmlll 2 to 6 dcpcJldiOg on the> prc.stnce of food. HA acids ... i,h pK.~ of" 10 :5 wit! lend be noniOllic and be absorbed panially through the gastnc mlJC()q. (1lIc maiO n:a!OIl most acidic drup arc absorbed from lhe inleslinal tnlCl rulher th:in the stomacb i\ that the microvilli of the intesti nal muOO\ll f'TU" idc a huge surface at'l"a rcl ah \'e to that fouJld in lhe gaSiric nlUt~a of lhe '<Iomach.) In contnlSt. amincs (PK. 9 1(10) will be prolOnalcd (BII' ac ids) in the ac idic stol11 oc h

,5

TropiCllmldc i~ an antichol inergIC drug adml m~lCred a.~ eye drops for liS l1l)dnatlc respon5C during e)c ",aminalioos. Wilh a pK. of :5.2. the drug has to be buff~ near pU " to obt:lIn more than 9O'k Kmif.llhon . The: acidiC eye drops can Sli ng. Some uptOOlctri~ts and ophthalmolOllists uo;c local IIlJeMlw:ti c eye drops 10 mloimi te thoc patlent 's di .... COITlfort , TIle onl y 010111 with a rneanin[(fu! pI(" i~ the pyri. dine nilrogen, TIle allude: Ilitrugen has no acid- oo<>e properties in aqueous medi a.

'0

BH'

....
BH- + H2 0 ==r Hp + B
Figure 2-4
P~

of BH

~ids

through hpd b.Jrners

and usuall) "'III IlOl be absortlcd until reachmg the mildly .I~a lmc mtestmal tract (pli -8). Even here. only a portion of tile anunc-comai nHlIl drugs will be in .hel r nonpolar conJugate base form (Fig. 2-4). Rcnltlllber thol. the re:tCtlOns liho..... n in Agum; 2-3 and 2-4 arc cqutlibnum reactions ",ilh K. values. llIcrefon:. "hoencver the ooopolar fann of euher an IIA acid (a..~ the acid) or a B base (the conjugate base of the BH' acid) pa.'ISO the lipid b:,rrier. tIM: r.llio of conJugatc bao;e to acid (pen:l:'nt tOJIi7..3l1on) will be m:untuined. Ra<;Cd 011 EquaiiOllS 2-13 aod 2_14. ttm ratio depend!; on the pK. (I oomtam) and the pl l of the mediunl. For UlnJlpie. 0I"ICe in systemic cirrulation. the plasma pH of 7.4 will he one of the determin:tl1ts of "hetller the drug "til tend 10 rcmam In lhoe aqueous environment of tile blood or partition III."TOSS lipid IIlCmbrd'toe~ imo hepmk lissllC to be metabolilOO. into tile lldnc) for CJlcn:llon. into tissue depotS. or 10 the rccq>tor ussut'. A u<oeful cxereise IS to calculate euller the ,cun]. base VlacldJ mtiu uSi ng the Hendrn;on lla.~ ItClba1ch equal ion (Eq. 2-1 I) or percent iOllll.atioli for ephednne (pK. 9.6: Eq. 2-14) and indomethacin (p K. -1.5: Eq. 2 13) at pH 3.5 (stomach). pH 8.0 (i mcsunc ). and pli 7.-1 lrlasma) (:.cc e.\ample_ I. 6. and 1 m Ta ble 2-4). Of cour-.:c. Ote cff~'Ct of protein bind ing. diloCussed above. call greally alter any predlcllon of biodismbutioo 00scd solely on pKr

lot: 1111. ..
wilen:

o(phyt;n Cht-mICal IH<:>jlCny) ... (""

(Eq Z16)
611. .\kfi..... ~ogICalItSjkH"'" UMlally t~~ In rruUimote. ~ ali the IIIhll>llOl)' constant Ato the cffecu"t dme m SO')- of the ~ub.i""u; {ED,,, I. the 11:111:01 duM: in 50% of the .ub,.,cu (LD ... ~ or lhe rruni",um inlulHlOry ~ntr.IUon ( MIC). It "common 10 cx~ the bioIogicat ~'< as. n:c,pnX.'. IfBR or IIC " _ the R:G",ion CQefflC.em or ,lop: of" lhe "ra;ghl Imo;: c _ the i",eretpt ,eml on the ,. a.i~ I"'hen lhe phy>ical chemicml I.",oen), equals l~l To understand lhe COIlC<'pts III lhe f\e\t few pamgraph.~. it is IIec('ssary 10 know how to imcrpret defined piutnnacological concepts such a~ the ED ,,'hlch i~ rhe amount ofrlle drug nced<.'d ro obtai n the dcfill('(j ptrarrnacolo;ica.l ~. L.ct s assuntoe lhal drug A's ED ~ i\ I mmol and drug 8 's ED i, 2 mmul. Drug A is Iwice a~ potcnt a.~ drug B. In OIher word . tllC ~m;lller the ED..., (or ~ LO"", MIC. ('tc.). the f1"IOI\! potenr the s~ta~e: being tC\ted. The lo!1anrhnllc "3tue of the dcpcndem variable (ooncenIr:uion flCCC'i';'liry to obil' ''' a de:fin~-d biological response) is used to lilllo'aril.t: the datP. A\ shown belo". QSARs are IlOl always linear. Ne,errhdc'oli. u~mg logamhms I ~ all ;w;;ttplable ~ulliSlieal technique (lIlking rttiprocaJ~ obtained from u Michaeli~- Menton ~tudy produces lhe lillC:tr LillCweaverBurke: plor~ found in any biochenllSlry te~t.bool). Now. why I ~ the biological ~'poose usually Upt"fi.<.aI as II rttlprocal? Sometimes. 0Ile obtains a Maustlcally more valid relationship_MOfI.l importantly. expressing the biologi cal re.~ponse II.~ a reciprocal u~J1y produce~. po!Iiti,'(' slope (1-- ,.2-7). l.et us examine the folkwo Ing JlIIbli~hcd examplc. 1 The DR is the LD"lO (Ielhal dose In lOON of the ~ubJccrs). 'n lC IIIcchani~m of deuth " geneml tlc:pn:"ion of the CNS Table: 2-7 conlujn~ the pCrlinent data. llIc IIlOSI lethal compound In thl' a._say was chIOll~oma .tI1It:. "ith a UR (LD loo ) of only 0.00000631 mmol: and the least nc1ivc was eth:lnol. wilh a OR of 0.081096 rmnol. In OIher wonl~. it takes about 13.800 IlIne~ as man y nlillimoics of ethanol thall of chlol"promazinc: to "ill 1()()';4. of rhe teSt subj4:c1li in rhl~ panlcular assay. l.e' s plO! BR ven.u_ PC (pardI Ion coe fficie nt ). Figure 25 ~how5 the scalier and an allempl at detenlllnmg a lioeM lit for the relatioo~hip. NOIe that compounds I and II lie at Doonsidcruble: dlSl:tflC(' from the renlllining IIIIlC oompouoo\. In addition to the 13.800 times difference in activ ity. there i\ n 33.9CXl tllllCS differellCe in rhe octanoU"atcr parlulOn ooc:fficient. Also. the regression line "bose cquatioo i~ lIli. _ - 0.01100 PC ... 001 t7 (Eq 2-m is llieaning l..." statistic:lll y. The ~Iope is O. meaning thalrhe panition ooc:fficie:nt has no effect on biological activity. and yct from the plot and Table 2-7. 1\ 1\ obvious that the hlgher lhe octaooVwolcr panulon coefficient. the more toxic the ~mnpound. The lorrd .. lion coefficient (~) is 0.05. nteaning that there: is no signifICant statr-llcal relation.<hlp bc1wcen aclhllyand parlil ion coefficient. Now. Ict'~ ..ec: if the dar a ran be lincaril.ctl by usmg llle I l)gllfilh m.~ of the biological activity and panilion coefficient. NOIicc tholt as loganthmic terms. the diffen:-nce: bc1wet'n the LD loo of chlorpromanne and ethanol rs only 4. 14 Iogarithnil e units. S lItlilarly. the diffen:-ncc: betwecn ch lorprorna-

STATISTICAL PREDICTION OF PHARMACOLOGICAL ACTIVITY

u.';cd 10 e~plam and model many chemical proce~~ it has been the goal of mcdicinaJ cltrmists to quantify rhe effect of a struetur.d change on a defined pharmacological response. This would meel Ihree OOI~ in drol; design: (a) to predict biological activity In un!l$ted l"Ump()lmd~. (b) to define the ~Iructural n.-quirements rcqUIIl!d for a good fit bc"!wttn the drug molecu lc and th( ~plor. and 'e) 10 design a test set of compound s 10 mllimize the amoum of IIIfonnntion concerning qruClUral requiremem~ for aclivity from a minimum number of compound$ ~ted. This a.'pect of mediCinal chermstry is comItIOIIly refcmd to as quanutat il'e ~Imcture-acu I lIy relatlon\hIPS (QSA R) . Thr.goal_ofQSAR stlKlies "ere first propoM:d about 1865 10 1810 by emili-Brown and Fraser. "ho Jihov,ed that the padual chemica! modlfic:mon in the mokcular structure of I....,;~ of poisons produced some import:mr difference_ in th(,r K uon.1 They Jl'OI>tulatoo Ihat the phys iological acuon. ~. of ~ molecule is a funetion of II~ cbcmicaJ COnlltilulion. C This I:lII1 be expre~..cd In Equation 2-15:
(Iiq. 2m Equauon 2-15 ... ate.~ thar a defined chllnge in tbcnllcal 5WCIUre R:\ults In a prroiClable cttangc in ptry~lOlogK:al ac1IOn.11Ie problem 00111' become:<; one of numcncnll ydefinlng chem;cal struCIUn: . It ~Ii ll i~ a fCrli le area of reo;earch. What ha5 been found is rhat bIOlogical response C:ln be predicted from ph~lCai chemtCal propcrllCS \och lIS ..... par pres:!llIre. uter soIublilly. electronic par.lrllctcrs. ~tcric de....cript~. . and p;I11l11on coefficicnt~ (Eq. 2 16). To(lJ y. the pmtilion coc:fflCicnt lias become rhe si nilic nl()Sl importllm phySical thrtlllC3l m('asurement for QSAR studies. NOIe rttal Equa110112- 16 IS rhe equation for II ~tr ighr lioe ( Y _ m.T + b). ..
'/l -

JUM as nJatl"lcm:uicaJ n..)deling

i~

ftc)

All emphasw:d above. the dru, "'ill go through a series of pan'\H)IImg steps: (a) \ca,ing the aqucoos <'xtroc'el M ar nllid. (b) passing through lipid membranes. and Ie) en~rillg
other IIqllWUS environments before reaching the rttcplOr
(Fig. 2-1 J, In Ihls senK, a drug i~ undergQlng the ~1Inc: panl' I;OI1l n&phenomenon thai happens to any chell!!calill a sepa-

Hrd.opholttc

h ll

\
R
~(CH,).CH)

Po
~

CH,(ctl2).~

__

nltOl)' funnel containing w:1I('r and D nonpolar solvcm such lIS hexane. chlorofOl'TTl. or elher. The difference between tM >Cl'onuOf)' fUllIM:1 model and ... hm lIClUil U YOCCllr.J in the body iJ Ihal ,he panihoning in the fUlinei will reach an c:qui librium
at which the rule of chemkallca~ing the aqucous phase and rnlenng the organ ic phase will eq ual the rale ofthechemical moving from the organic phase 10 the aquwu.~ ph.1SC.'. This ., I'lOl the physiological SI\U:il,on. Refer 10 Figure 2-1 and noo: thaI dynamic changes an: occurring 10 !hi: d rug. such as II being metllbolilcd. bound 10 SC,'nun albtJrnm, e;J.erclcd from the body. and bound to m:cplOf'lO, The CTlY IIl:m mcnt for the drug is not Sialic. Upoo a(!numstr.lllon. lhe drug will be palhtd Ihmugh the mcmbnanc:s because of lhe high concenIflIItion of drog in the extrace1!ular flU id s relali"e 10 lhe conCCTllmlioo In the inlrocellu lar compan me nlli. In an lInem pi 10 maintain juilibrium r.uios. lhe 110w of lhe drog will be from fy~tI: l1lk circulation through the "lClnbnme~ ooto the I'fp101'l1, As the drog is mctaboli zed and c~cr~l ed fmm the body. II will be pufl~(J back across the membral\e.~. hnd the C(JOCen\rallQll of d rug at the I'eplo~ will decn:a"e. Because much of lhe lime the drug's !1lo,enw.-"t across membranes b a panitionin8 process. the paI1l1lOn coefficient has become tnc most COlJlmon phySioochcnllCliI propcny. The que'IICIIl lhal now must be asked is "'hal IImniSol;ibk: l'IOIIpOIar w ln'llI systcm best mimics the "'"aterllip,d memboOliok b.:uners found in the OOdy'! II i~ no . . . realil.cd Ihal the II-octaool/walcr sy~em i~ an e~cc lk: nt eitimatOl" of drug rmnluoning in biologICal syqcm~. Indeed . on.e could argue tIw II "'as fortuitous thall1-octanol WI" available In n:a~na ble purity for the early partition codfic icm dctcm .inati o ns. Tuappn:dute why Ihi , is so. one mU~1 undel"Stund ItlC che minl nalure of the lipi d membrane . 1lIc'IC membranes are nOi cxclu~h'c l y anhydrOll~ fany or oily structure~. As II !irst appro~imJtIOIl. they can be coo,ido:rtd bilD)"\'T!; composed of lipid, oon~l,tl ng of II polar cap and large h)'drophobic !!Iii. ~f'hol:IYl-eridcs ~ major components of lipid bilayer'S. OIhcr grOlJJ') of bifunctional bpids indude the sphingQln)ehn<o. galaclocerebroc<;ides. and ~ns. The hydrophobIc portion is composed lMgcly of ~nSl11Uralcd fally acids. nM)Stly ..... Ilh cis doublc bood~. In addition. lhere arc coo5Ilicrable amounls of cholesterol es1m. protem. and charged mllCopolys:lccllaridc~ in the lipid membra.ne~. llle final re.~ult is Ihot thc..c mem branes are bighl)' or@ oni ~ed structures composed of ~ lIanllds for Il11I1S]lOft of illlponant molcculc$ such U~ metabolites. chcmkal n:&ulal{)(s (hormoI1CS). amino acids. glucQ';C. and fauy acids H the cell and rcntova l of waste prodUCIS and bi ochemilto cally produced productS 001 of lhe ce ll. The cell ular mem~ are dynamic. with the channels formmg and disappcannl depending on the cclJ'\ :and body 's needs (Fig. 2-

ctt~

R ...

Hrdrophll lc H. . 1I

o
L.cHhln ;
C.ph."ft ;

R. OCH,CH1N(CH.1a
R. OCH2CH,~o

Figure 2-8 6enet"ill 5IfUCiure of iI bifunctIOnal phospholipod Many of the fillty clOd esters 'N11l bI!' ciS unsaluliitN

of blochenllcal e~ents withi n the cell. Somc of thtK rec<'ptOl"ll are u<;cd by "iru<;ell to gam entrJocc inlo the l'('II~ ",here lhe viru~ reproducrs. As n.e",cr instrumental lcehniqUl:l' are de,doped . and gcnetic cloning JX',,"its isolation of the genetic malcrial responsible for f0ll11lng and regulat ing the , ll"IIC lUre, on the cell surfacc. the image of a pa'lSive lipid 1lICIl1brnuc ha, di!illppcared \0 be replaced by a "ery complc~. highly orglll1i/.cd. dy nami cally funclloni ng structurc . For pU rpus.:"s of the part itioning phenomenon. picture lhe cell ular membl'llne~ a~ 1"'0 layers of lipids (Fig. 2-9). The two OOlcr laye ..... one faclOg the IIllcrior and the OIher facing lhe e~terior of lhe cell. consist of the polar ends of the blfuroctlon.al lipids. Kee p in mind that thc.sc stUfOCC!l arc upo!!td 10 an aqucous polar en ~Itoomrnt. The polar ends of the ctwgcd phosphol ipids and other bifu rocllonal lipids an: solvated by the WlIler ntoloeulclil. There are al'iO considerable amounts of charged proIein~ and RlUcopolyloOCChandc!> ~nl on the surfoce. In cootrnq . the mterior of the membrnne i~ popu b ted by t]}c hydrophobic ~ Iiphmic chains from the fally acid a
Q;h: ......

!iCnc.~

p ..rtttion Coe fflclellt

W ith this reprc:scntlllion in mind. a partial expLanution can be presentt"(! a~ to '" hy the n-octallOL/water partitioning ~y~tenl !iCtms 10 mImIC the lipid membran('/"'~ter syslcm,~ found In the OOdy. It turns OUI lnat n-octaool is not II) IlOnPllI .... as iOltially mlghl be predicted. WalC1"-saUll'llled oclanol contams 2.) M waler becau.-.e the small .....ater molecule e:hity cl usters around ocuool', hydro~y moiety. n-Oclanol saturatoo '" atcr containS Llllic of the organic phase bor;lWSC of the large hydrophobiC 8-carboo chain of OCIanol. The water in lhe n-oclaool phase a ppare ntl y a pproximates the polar prop-

.,

In addmon, the membranes on lhe ,urface of noclcalCd Cfllsha,'c >piflC antigenic marle~. majOl"hlQooompaubil.) complc.\ (MHC). by "'hkh the immun.e syste m moni lOl'l tbectllsSlalu~.11JcTcare rcccplOf)on tl"leccll surface ..... here Ilonooncs such IIIi e pincphrin.e and insu llO bind. seu ing off

.""N" ."'~ , '"

M1JCOf'OI.TS"' C......

..

DO ,Oi- / AAAAAA

\~~

Figure 2- 9 SchematIC repf\!sentiitlOll of the cell membr_

enics of the lipid bilayer. whereas the lock of ooal\Ol in the 1'.'l!Iler pha>e mimle~ the phy,iological aq\lOOU~ compart men!\. I'.lIlCh are relath'cly fre-e of nonpolar components In COIllnl,t. panltlooml! sy~tCms sucll a, hc.\OllClw;ltcr and chl()(Qfurnl/wllter contai n .';0 little water In thc: organic pha<.e thai they are poor model~ for the: lipid bila}u/l'.alu ')Slem found in lhe body. At the same time. remember lhat the nUO;lHnoVwml'r 'ystem i~ only an appfOXullation ()f the actual enviromncIU found m the IIlterfacc belween lhe cell ular mcmbr.mc:s and the c\lraccllularlinlraccllular nuid5. The bII~ic procedUI"I: for obtaining a panitioo ~"Oe rrlClI.'nl i- 10 ~hal..e a I'.eighed amount of chemica l,n a nask conlainIng 1\ measured amount of waler-saturated oclanol and OCUI noI-salUnlted I'.ater. Many lunc ... the ~\IOOUs phase 1'.111 be buffered with II. phO"-phatc buffer al pi I 7.4 1 rencci phy,io0 logical pH. Thi~ corrects for the rntio of ICOIlJug:IIC b:!.o;eV [acid ] found in "'\0. The IInlOUnl or chcmical in ooc or bl/th of lhe phases i_ dctcnnlocd by an appropfiutc lIualytical lochuique and the plll\llion coefliciem calculated from r:.l.jua l10n 2-20. lllC ooallOlIl'.-aler partillon coeflicicnl h:t~ been tlclemuncd for thooMlnds of COOlpoonds. includmg drug'. agricuhur.d chemi cal,. blOchcmical inlcmlcdllllcS aud me tllbollte~. and common chemicals. ~hny of Iheo;e delcrminatlons ha.e been nbtained in sc.eml OIlier organic <;ahent! water system~. such as e~her, chl()Tl)form. lriolelll. ~nd hoe,.11.1101:. Equ,niUfls hal'e been publ i~htxI rciating Ihe p"rtihon coefl"lci"nlS determ ined in one ".,hentlwntcr ~y~lem to lhose detcnnll'lCU in anOlher.

retent,on data dircc:tl y III the prediclion of biolog Ical response ( Eq. 222). A chemic.al"~ retenlion on a chromatographIC support 15 the result 0(. rombin~tlOrl ofilS partilioning. sierie. and eJCClronlC propcnu:s. Because Ihc."l' same pltysical ctlCnllcpl propcrtil:S are imlX>l1anl "anable, III detemumng a drug' .. biological respon.<;c'. Clcelknt correlalions have been obuuncd betwn chrom ltographlC relenllon par:unele(l; and biologICal respOI1~. WhIle Ihe modclrepresentcd by F..4jualioo 222 is useful in predicling biological 1"I:"JIOI1SC. I~ i~ IKM as definit ive., lhe IOOdI;-:ls po-esented belol'. (Eq~. 2-23 10 2-25) bccauc the precIse physical chemical prupcrties ate comb;,lCd inlO 000 chromatogmpluc: n:tenllon lenn. In (Mher 1'.'01 it I. IKM possIble ~o detentline lhe relalive Imj:01lll1CC of IIpophllicil). electronic effects, or steric influcrn:e on Ihe biological response when uSln, Equalion 222.

lor: BN

0(1", n:1~ntoon)

+ r

tEl] 2-22)

Most t'l'cenlly, Ihere has been a conccntruted cffon to calcu lme the partItion cocfficle\lt on the bal.is of the. alOmic components of the molecule. Each mom type is a.'>(JlIlCd In conlnbute 11 fhed amount to the chcnllc~1" S p;lnltlon coefficient. Because Ihis 1I.!i~umpl.ion bI'eaks- down qUIckly. SoC' eml com:clion faclors are ustd. C)"clohcxenc will !oCro'e IS an
e~alllplc.

10111' .. 6Inrbon

lor: 1'

III -

aI"ll~l 1)bon;I~

l~I"yJro~cn "too!';) double bond Cortc<;l100

.. 6(0.20) + 12(0.23) + SI"-0091 + (-OJ!!)

/, - ,I'"""''''.''~.'IL.:, fdintiocill"

(El]. 2-20)

2.%

'J"he dctemUllallOn of partlllon coerficicnlli IS ledlOU~ and IlnlC Cunsul1\lng. S{)Iue chellllcuis are tOO unst"ble .. nd eUhoer degrode during the procedure, I'.hich cun take sc"eraJ hoofS. or cal100l be. obIalned in -.ufflClI.'nt p!.ll1ly (or an lIn-Ur,ill.' dctcnninallon. ThIs has led 1 31\empiS al apPI'U~"nallng the 0 partilion coefficient. I'emllp" the nlO)1 popu lar llpproach has been high-performance liqUId chromlllGgrophy (HPLC) or tlu\I.13yer chromalogrnphy (TtC). In each case. the!iUpport phu);!.' is nonpolar, eilher by pcmlancnt bonding (usually QCladcc)"I~llane ) or a co:Iting of Ol>lnnol. mincrJJ oil~. or relmed malerials. The mobile phase uSU;ll1y contains 'lOme Walcrmi scible or ganIc sol .. ent to hold enough of the chemical wOOsc: partItion coefficicnt is Iloeing delermined in 'IOlution, SOIllC'limes lhe p;ltlll100 t"'<lefficienl i~ calculated from the relcnlion tim>! by regression ana lysi~ u'JIIg Equalion 2-21. The {lund c tenn, have the ~Ulm. uses as in Equation 2-16.

r-or purpoo;c~ of comparison. the ob!.ero'ed Ol>tauoVwatcr

p;lrtltion coeffICient (e~pn:s.so!d as a logamhm) i~ 2.86. Becaulo\: of thc com:cllOO factOl"ll. these caleulal ion~ becnme so complex Ih~t they mu\t be done by II computer prugrnm Ihal anal)!.e, the struclure and idcnlirll.'$ tho<.e <aO\CturJ.! altribut~ reqUIring cOlTeClion focIO!"'i. Con.enll.'nl ll.~ the calcu lation mClhod may be. ilS 3CCUruC) depends on lir,t detcrmming expcnmclllal partilion coemcien~ of chemicals c:xhlbitlng lCry similar Chcml\lry. T1tc .aloes for ~pccirlC atOIl1~. grou~ of alon'-' and bond cOlTCClIon factors are deri~ed rrom Ihclo-C eXllcrimcntal1), dclennirn:d partlllon coeffi cients. Tllt:re arc: 'iC"' CT'lI.I OO1mocrelal drug de,illn .-.oflwan: pac!.:ages Ihal conlai n 111{)dules that e,lIm3te a chc mi car~ partllion coeflicicnt. Some uo;c the mclIvxI de....cribe-d in the pre"iOU~ p.vagrnph. Oiht.--n uo,c quantum cbenucal paramclef'l. In all caSC)o the aillori lhm mUSI be ~31idUlcd ugam~t le\1 ",-",S dl\Cr;c chcmical MrtlClU~' I'. hose partilion cocfrlCiellls ha.&: been delcmlinl.'d by the classical sha~e fla.\k nlC'lhod There are ~ lInpler methods for eSlHl1<Ilmg lI"npllll iCily Ihat will give rl.'lW)n1lDly ~-orrect re'ult~. Tllt:o;c ure ba<;o..-d on the additive efrcci on lhe par11\1un cocll""rcient that b!ol.'('n I'.llen \o-arymg a .eril."< of ~ub<illluenl~ 00 the <;antc ll1Ok'cule. (hcr lhe year;, fairly exten" .. &: table\ ha,c I...-en de ..elopcd that COlllal n lhe contribul ion ( 1:) of u wide varitt)' of ~ubslituent.;; 10 the partlllUfl coefficient. The: method ~-an be il1u~trJl.;d chlorubenWIe. The log of? i~ 2.13 for benlene: 1U1d 2.84 foo' chlorobcn/c llc. TIlc 11" value ror the ch lori ne su lN ituent i, ~ainl.'d by ~ubtr-ICun" the Jog of I' "lIues for bt:tw:nc and chlorobt:nl&:lIC.

<1(1"1 ""CRDon) + c tbj 2-2]) This model 1Ia.~ al Icasl 11'.0 1I001111I1on,. FirM. 10 obiam va l id numcrical v3111c~ for II mid C In &jUllllon 2- 16. partilioll cocmcienL~ for a group of vcr)' closely related conlpotJlld. must be obi~jned iOlllally by lhe cia..;sical ,hake nask method. 'The retenllOO lime$ for tile same group of compoullds are Ihen ootaiocd in lhe Identical chtoll\lltogrnphic sy"cm that will bt: u<.ed for the III:W compound,. 'The .aluc~ for a and c an: obiamed u~lni EquallOll 2-21 tJ.."ng \landard linear rcgrti.~ion. Tllt: SCI.'Ond IInlllation to the chmmalo-I:J1Iphic IlIOd.-I i5 Ii!.]t chrom:ilographlC Ilppr(HmtaUOn ~ of lhe paruuon coefficiellt' u~ually only .....on: I'.hen one is delenmni ng lhe retcutlOO IInlC.~ of chemical' of Ihe ~al1lC chemica! cla.~~ and si milar substltu\lon patlent~. Becauo;e of the<.e hmllDuon ... <;ametinlC" thc medicinal ehemi~l WIll tJ..'IC. the.

10& I'

or

ror

"1m .. L OG

"n ... 2.84

1',,,,,,,,-... -

k>g

P_

2.13 - 0.71

..

While the 'll"wbsUluenllllclhod has its "mila' ions. particularly .... ht:n I~ ~ sigll1liC'.ln, resonance and inductive ~rreClS resulung from the ,HCSCnce of mulupJe subslllUcntS,

>.

it can

woO; ....ell for B scriCll of compounds that have simi 'ar

.. "

subshlulioo p:lucms.

00

ott r Plilplcochemlul P,u.meters

Then: is a senc~ of othe r cc)U~lllnlS Ih a1 mc",ure the contribu!lOll by SUbslilucnl ~ 10 the molecule' 5 tOlal physicochemical ,MQilCrtlO. 'These include Ihunmeu's I/JCOIlstan' ; Tar.. s sttne p.;If1l1Ilder. f;,: OIanon's stene parumclcr. v: Vcrloop' s muhidimensionlll stene parnmelers, L. H" 8 .: and I1lOlar n:froctj~jly. M R. The IUller has b.:come (tl;: SIX.'Qlld most Wo('ful physicochemical parnmclcr used in classiClI OSAR IIlOdcl illg. II is 11 complcJI ternl based on the molecu le', refl1lCh'-c index , molecular w("ght, and tknsil)' and elln be C'O!Isidered a mea~un! of the moll!Cule's bulk and electronic ellarnet;;r, One reason for its popularity is that it i~ ca,y to takulate from tables of atom~, u.~inl!; a mmimum of CQrTeCtion fact()l1;. Of the listed phy~,cochcmical p3r0mctcrs group, II i, IIlOSt ea~y to locate vaillC'!l for 8. r/'. /:.... and MR, A rerre ..... ntat;ve lbt can be found in Table 2-8. Table: 2-8 i ll u.~tr.ucs severnl items Ih:lt must be kept in nuDd II hen ('Ircting 5ub!.titucnls to be evaluated In terms 0( the type of fact()l1; that influclll.:e a biological rt'.'i.pOIiSC. For elt(.'tronic parameters ~uch os (/J, tm: location {)11 an ar0matic ring is importllnt bcclilise of re.IoOnUllCe versus illdue IIle effrcts. NOIice the t .... ofold differences Stt!\ bet ....een 111_ and ",_ for tbe th~ aliph;lIic subsuruents and iodo. and <;C"cralfokl difference for me[t.o~y, ammo, fluoro. and phenolic hydroxyl. Sclectwn of ~ubs[ituellts from a l"Crtain chemical dll.\.!l may IlOl n!ally test tbe influence of 3 p;trallleter {)11 biologICal ktilllY. 1lIrre IS hltk numerical difference alll{)l1g the (/J_ OT III..... val[)C$ for the four aliphatic groups or lhe four halo-

00

b-

"

i<

00

OJ

..

fi

gen s.. It IS not uncommon to iO to the lIIbles and finoJ ml sslllg paramet~r:s such lIS the ":, 'alues for :ICflyl and N-ac)1. Ne,/:'rthelelos, medicinal chemists can use infonnatlOll froln ~~ Icnsive tahl~s of plly,icochemicul parumetel'\ to lIun" imi/.r the number of snbstiluems required to find OUI if the b,ologJcal response is st' IISIIII'e to electronic. stenc. and/or partIt ioning cffOCl~.: This i~ done by selct'hng Sub~tll\JCnts In each of the nnmerica' rnnges for the dl ffcrem parnmetelS, In Table 2-8. lhere I1I1l Ihn:c rJ.ngc~ of II values (- 1.23 10 - 0.55. - 0.28 10 O.!KI. :md 0.1 1 10 1.55): three r.lllges 0( MR values (0.92 to 2.115, 5.02 to II .SS.;and 10.30 to 14.96): and 1.....0 main clu$tel"l> of (/J values . one for the altpt\3uc sur",utu elliS ami [he OIher for the halogclIS . In the ideal $ituation. ~ubstl1uem.' are selected from each of the clusters to deternllne the dependence 0( the biologIcal response: o,cr lhe llIfgeil possible "ariable ~pace. Depcndmg {)11 lhe blOlogacal n:sponses oOtaliloo from tC';[lIIg lhe n.e .... eompounds. II is po~s iblc to detcnuin.e if ltpophti icity (partilionlng) . ~teric bull (molar refracti{)l1 j. or drclron wnhdrawingldonllling properties life Important dclcnninants 0( the Iksirc:d blOlogi 1.'11' Il'Sponse .

"

QSAA Models

Cumnuy. there are thn.'C modcl~ oreqU3tloru; secn In QSAR

analysis uslllg physicochel1l1cal p:u1lnlClcr.. represenled by EqUlIUon 2-23. 224. and 225 . The..<;c Ihn!c equ ations an:: illu"lTII.I.ed III Fil\ure 2- 10. 1I'lIlg the logarithm of lhe partition coeffic ient (k" f' ) lIS the physical chemical panuncler. !-llSt. then:: is the lin.ear tnOdel (I-::q. 223). When plots of log II 8R or log DR Indicaled a nonlinear n::lahon>hip bctl'otcn biologic al Tl:'pon"c and Ihe partition coeffiC ient. a paruboltc 1"I1(I(\c1 .... as tned (Eq. 2-24). Exanllnmion of Figure 2- 10 stlOws an optimum log /' (log P.J. 1'0 here 1l1.a1imum biologi cal activity .... 11 he m :uucd bdOfl.' a decrease in IICtl Vlty is seen. One e~plana\lon for thi' phenomenon is thai hydropllilic drugs will 1~lId 10 stay in Ihe aqueous ])iut.<;c. I'o-h(.'rell.~ lipophilic chemical s will prefer the liPId bilayer. In both ca>;e5. IC>..~ drug i, being Ir.ln~ported to the receptor. n:s.ulung in II !lccrease ill the actual C()IICCnlr.lll()ll of rc:ceptor-bound

,. "
,.
""~ .,
~

fi

k oi-

TABLE 2- B Sampling of Physkochem kal Parame1e rs u-s.d in Quanti1ative S1nICture Activity Relationsh ips Inve-stJgations

~ ~

-."', -" -. -,
,._
('

SulHtm.e..t

'-007 -001 -016 037

-CH,<:H~
-CHp.CH~

.
" M

-, -0

-00<,
-~,

-ClCH~).

'W " m
~

-<>, .01<
-"cObi.
-COCH

-"", -0<

OWJ _

1 . C. Lc<>. A.. J, ~_ c ,, _ , I C.. , I ......." Mw y""-_wotry lt - . 1 _

'" I , -,'" '" -, " ,3< ~ .ro '" '38 ". ,-" , '" ". '03 ., -'55 '" -'" '" '" ". -" '" ,.. -'" "" ". '" ." '"
- 171

'00 -007 '00 ,.. '" -007

011

-067 - 0117

-031

" '00 ,.., '00 '" ,.., ... -'" , -, .. -'" '" -, . '" '" ''" 02' ... '" ". -, " , ,. -'" "..
'.
M'
-011 -0 t~ -013 -0 I~ -021

OSAR_

,ro

-12' -131

,
,

---=--.,.

.....':..::.

-061

1.00 IIBR I 12lO1t p

U . UltiIJll"' I ' I 00

-0.97

-illS

03.

\I IS

'00

_057

- 0.5\

,
... '

~.

AMI)'\o

drug. In OIher "'MIs. Ihe equilibrlUI11 ~n in RcltCtiOfi 2-1 <Jlift5 10 lhe left Then: .... 111 be 1\ group of drug~ "hose log " pI~ lhem ncar the lop of the p;arubola; their lipopt1ihc~hydropl1llic balance .... ,11 pcmllt Incm 10 penelrJIC boIh :lqueous and lipid barriers and reach the rcccplOr.
IfBlI II (los I') + r (Eq. 223) lug IIBII .. /I (101 f') . ""OS pi "+ r (Eq 2-24) 101 liaR II llog PI "\otI(jY'"+ I) -+ ( (Eq.2-m

IIIcrea;.mll bulk. 311 mea\ured by lhe decrease~ :lCtivity.

~tcrimol

parametcrs.

los

,
1011 lIED .., - 1.031011 P - 0.20(101: I')'

The mud OSAR equation in current use is the bilinear 1I1Qd1.'l (Eq. 2-25). It colbi'l~ of IWO sll1ll/;hl lines. one: asccoolng and onc Ocsccooing. 111e fJ leml ~"OIlIlCCIS the IWO li nes. There: an: ,;e\cI1I1 nl1crpR:talioru for the fJ leon. One uplanallon IS 00-' on Ille mio of !he n!.le constant for diffusion OUI of Ihe OCUonol laycr ;nlo the aqueous cnvuonmem being differcnl from the r:lIe of diffusion 001 of the aqueou~ lay~ 1010 the ocl.lnol layer. In OIller "'onls. I4-hat m;ly be ~im ulated with Ihc bil inear model ,~recognition III:u lhe nUe of dirfu~Ion frolll the ~\tnl("cllular nuids inlO the hpid bllay~dlffCT5 from lhe rule of diffusion 0111 of the lipid blla)CI' into the introccllubr environment. Anotncr interpretOlion is recognition that the kinellc, ofpal1ilioning tllrouSh the liplll bilayer differ from lhe lmclics of binding 10 lhe Itteptor. A Ihird c~planal ion lake. ;nlo :KroUnt the diffncnt volulllI."I of lhe aqucous and lipid bilayer. III lhe biological sy';(cm. Wllh this bacLlfflUndln mind. thrc:c example. of OSAR equallOIlS taken (rom the 111cdicinal chcmislry hterJturc are preselltcd. One ~ho"'s II linear relation.hip (Eq. 2-26), aniJ 1hc others show parabolic (Et!. 2-27) and bilinear (Eq. 2-28) com:lauons. A ~tudy of a group of griseoful~lIl I\I1alogues \!Krn'ed a linear relationship (Eq. 226) between the biological rcspon<;e aoo both hpoph,licity (log P) and clect/"(Ml i(' ('haracl~ (q).l 11 Willi suggeMcd lhat the antiblOllc acllVlly may depend on lhe enOlle ~~sll:m facil1l811ngihe addillO!1 of gri"L"ofulviIlIO a nucleophilic group ,ueh a~ the SH moiety in ~ fungal Clll.ynw::.

0.05

1.;.,- 0.24 11" ., + 2_29

(Eq.2-m

In adoJUlon 10 the!.c OSAR modcl~ hascd on biologICal re!jPOOse~. OSAR I) used 10 ;mal)~e plJamlaCollneuc acmIty. OtIC eJiample of thl) (Eq. 2-28) is a ,nnulmiml ofbarbillJrate ab<;orp\lon, "hich leads to lhe bilinear modeL''''

loa k"""
P - 1.2381og(,8I' "+ I) - 3. 13t CEq. 22111 diffusion I4-herc: IJ - ~ 1.271; log Po rule constant. At thi\ puiOl, It IS appropriate 10 a~L the que~lion. arc: all IIw:: de~nnination~ of partition cocfrK'i~nt5 and cmnpilalion of ph~si~al chem ical ~ u'iCful only I4-hen a slatl~ i (311)' vah" OSAR model is obtained" The ans"'er 1 a firm 5 "no." Orw: of the nlOSl useful ~pinoff~ from the field of OSAR has bren the application of C1pcrimental d!-~ign 10 the $election of new compound) to be symhcsi1..ed and k'.~ted. Lct"s assumc thai a new M:ncs o f drug molccule~ is 10 be s)n1hcsi1.ciJ bao;ed on the following ~llUClure. The goal is to tC~llhe ~ffl'(.1 oCtile 16 sub~titucnts ,n Table 2-8 at each of the Ihrec: poY;llion<. on oor ne .... <,eries. The number of ~siblc analogucs i~ equal 10 16'. or 4096. compounds. D~sunung that all thrc:c ~ilions "'ill alwa)5 be ~ubslJluted .... ilh one of lhe ~ub<.llluentS from Tablc 2-7. If h)drogcn i~ includt'd .... hen a po,,\,on i~ not sub,hlutcd, there arc 17', or 4913. dlfferem conlbmallOn'. l1Ie problem IS to "\Clcct a small number of ,ubstnuenls that rc:pn:scm lhe diffc:n:nl nlnges or clusters of value, for lipoplnhen ~. ellTumc influclK'C'. and bulk. An nnllal design SCI could include lhe mcthyl and prI)p) I from the aliphatiC cluster. fluorine and chlonnc from the halogen duster. N-acctyl and phenol fl1)l11 the '>Ubstituents bhowing hydrophilicil)", and a mnge of electronic and bull ,alues. hl("ludl ng hydrogcn. tncre .... ill he 7J , or 343, dlfferem l"OfTlbmahons_ Ob~iOll'ly, that i~ 100 many for an inilial e. alu:Jhon. In'lead. cerlaln rule<O ha,c b..'Cn tIc~iSl."d to m:Jxinn/c Ihc informmlOn obtmned from u minnnullI number of com pound~. TIlc-.c include !he follo",'in8:
I Each ..ub'>l1l1lC'1II nlll10l OIX"Ur mon: l!lan ~ .II ~lI<h Il0'lII1)II on "hich il i~ f'>IInd. 2. n.. number of li~ iIIaI each ... Moll,...,.,1 III ~ paMlelllar poslUOll IIbouIJ "" "'Ho""Wc:I~ ftlual. 3. No !.. " 'ub..U!uc:nl' -noold be f'R"'Cn! ,n I COIISUil! romb"W,OII. 4 When cl)mmnaunns or s.ub;,Ulucn~ are I .\C,,.,,,,ly. Ihc:~ ..nook! no! ,,,,cur mon: frrquc:ntJ~ lllan any other oombi"",lOfI.
M~9 1oa

t, ?

lOS BK

(O.56JIo& f' +

(~

19J<1. -

In

(i'.q_ 2-26)

A parubolk relationshIp (Eq. 2-27) "''lb reponed for I series or subslilLl ted OCCtylaled sa hcylalcs (~lIbSlllLlt cd n~pi rins) lC!.ted for anu-lI1nalllmatory 1ICllvity: A nonlinear relationship cxists bet", et:n the biologK:II response: and hpoplllltcil~, and a ~igni fican\ detnmenlal ~tCI'lC effect I~ IoCCn "'lIh ~uhsti tucnL' at po~lll()n 4. '1l1C lWO ~1I:rimol par.lIl1clen. u..ro in IhI.5 equallon were: L. defined a~ lhe length of the SUbslllU ent alon, lhe ui~ uf the bond bel",eo;:n lhoe fiN atom of lhoe ,ub,tilUcllt and the parenl lIIoleeule. and B~. defined a~ a ... idth pammeter. SIerK: cfrecl~ "cre not considered SUth~t; cally ~igm ficant at pos,lIon J" a.~ shown by lhe qerimol paramcler; for subsmucnls al posillon J not hemg pan of F.qua lion 227. The optunal 1>-111illOn coeffklelll (log Poj for the subslilUt ed Il'>pirin~ 111 this ~~<ay ....as 2.6. At tlw:: sanw:: ume:.

""*""

lull
r~

Following the5e guideh!lt:~. the initial lest "<:t can be rl:duc~d 1 24 to 26 compounds. Depending on the prechion 0 the biological 1fN~. it will be po!>sib~ 10 ~ if !he: dala ... iIl fit a QSAR model. Evcn an approximate modo:l uwally ...illindicate the types of subsl iluenL~ 10 le,t fUr1her 1ll1d wllal position. onlhe molecules 3TC ~nsi l he to SUbslituliofI and. if <;c:nsitl' e. to ... hat dc:grl:C .-ariation 11l hpop'1Ihc. eketronic. or bull character is important. JU5t 10 ensure Ihat the model il; valK!. it is a good idea to 5)'nthemJ: couple or oompourKl~ thaI the model pl'edicb ....oold be: IMCli.'c. As cac h group of new compounds I. tc~tcd. the QSAR model I~ refill<!d un1l1 the inv'$tigatol'!! Imvc a prell)' good 1<.Ie:1 .... h31 subslilUcm patterns arc imponam for tile de .. irl:\I octivity. These .. arne techniques u..c:d 10 dcltclop potent compoond~ wllh desired .:tlvny also can be used to evaluate tile inOucnce of ~ubstilU ent p;lnem~ on undesired toxic effe.:u and phannacokinetic popclllCS. In their fJIl" form, the rul~ lislc\l IIbove can be: used to Klc:ct a minimum number of compound~ for II te~t bet. u_ing ... hat are L'lOwn liS idcnlU\' mrwblu. No pllysicochemical par.lmcte~ arl: required, In It .. sill1plc~t fornI, the cquat iOf! la~es the form outJioc\l in Equation 2-29. TIIi' ~pproach ha~ becn known as II Free-Wilson IIl1alysis.7

I,. RR _ R,

or

Rl + R, + R.. + Da5e molecule - 0.729 + OS43 + 0611-1.67J + ~,14J

S.3~)

One of lhe nell<cr QSAR mci llod~ romhine~ UltiSllCal Ic..hmquc:s ""im moleculor modeling and tw bn rl:felTCd 1011., Ihree-dinwD)tonal QSAR (JD-QSAR ) bccau<;c: the 10dcpt'ndent ..arillb~. usually physicochemical par.lllll'lerI. !ale 1010 occounl spatml dlMance! among and bellOe'en pnarmacophores and their Iocalion Dt ~pccific di~lances from tile molecule. Each point h3S a location Of! x. y. and: coordinme.~, JDQSA R dcpclld~ on the mohx:ular modehng alllorithm$ and is di"Cu~scd in n"KJrl: ocl:lil in Chapter 5. Atlcmpu al includmg a variety of onentoliOlls in spacc lind a "ariely of biologil;al responsc:~ ha"e k-d 10 the use of tenus soch as !fJMNJ,mtnsIUfl(II and fi.'r.d""rnS;(JI'(li QSA.R.' IG

TopologiCAl Dl!nriptors
An altcrnate method of describmg molecular structUrl: " bn..-ro on gruph theory. in IOh~h the bond~ OOIll1CClIl1i the nlom~ i, considered It pmh tllm is 1r.l\"eNCd fmm one atom to anotber. Consi\ler Figure 21 1 conhll ning a-pheny lalani ne and It~ h)drogen-suppre~scd graph rc:prc:sc:nlalion l1le numhenng is arbitrary and not ~ on IUPAC or Chtmi(lli Abumcr! nomeoclmurl: role .., A cOlll1CCli~ ity Illblc. Table 2 10. Ii construcled. Tablr 2-10 is a t\\o-dimensional connccU\ II)' table for lhe h) \lrogensuppressed plll'nyialanine molecule. No Ihrl:Cdimensional rcpre'\entmion i~ implil-d. Funner. Ihi" I)PC of cunnectiv ity lable \\ III be thc I<.Imc for molecules with asymmetric bloms (0 versus I.) or for lho..e Ilial can e~i~t in more than one l"oofOl1natlOf1 (i.c., "chmr' \"c~us "boal " conformahon. (lllfl "ersu~ S(lurh" \e ..... u.~ lIpJrdj, Gnipll rhc:ot) is Il()Ilimlled to tile pam~ follO\ll cd by chemical bonds. In illl PUrl:st form. the alOll1S In the phc:nyl rini of phcn~lalllrline wou ld ha'c paths t"oonr:cting alom 1 With alorn.~9.10.II.and 12; al0m 8 witlllltoms 10. Il.and 12; atom 9 IOlth atoms II and 12: and alom 10 with alOI11 12. Alw. lhe gr-.ph itself mighl \II fferentialc ncilher single, dou. ble, hnd triple bort\ls nOf lhe type of alom (C. 0, and N in the

tmCi-

of 1'''

rob< li~ to

""'.

-.
bk

"'"

.~

""'" ""'" .. "'" d,.,.

49Jl.

F'~

(..o"',U'",",OI """"nbulioo,) + coolnbuhoo from ~ hue nlOkculc IEq 2-291 An eumpk I~ II "mall '<:t of phospOoru..~<OfIt:lImng acet~kholincstera!!oe Inh,bltors thaI lOere <;e lected b~ using the rulc fordcslgmngI ICSt "Ct arKl evaluated U~ flO'"ble insec_ ticides.- lllc: result is a ooll1plc~ equation Ihat pruduces II coefficient fur cuch substituent. They ure wnmmril.ed in Table 29, uammatiOfi of tlli \ lubJc .Ihow~ lhat etllyl and etho~y al Rio ethoxy arKl il>Opl'QpOxy lit RI . aM oxo al R. ha\ e minimal influence on biological ao;li\'Ity. In COIltl1lSt, ml:thyl alld I!>Opropoxy at R,; mett\()\y. propoxy. and bulO~y III R1: IlIl three mtrophcnoxy substltucnt" lit R,; and thio III ~ signifiC3l1tly Influence tile biolog~al rl:Sponsc:. lbc predicted )og IffiR fIJI' lhe: COItlpound. \\here RI .. meth)'1. Rl .. propo~)'. Rl _ 4-nitrophe noxy. olld R.. ". thio. would be calcu lmed from &iuation 2-29:

los BR

0"" ...."
~.

Jbulk lftrent

TABLE 2-9 coefficienb fOl" Subsmuenb In a set of Acetylcholinesterase InhibitOR"

It\aJ-

1I1ll1/.e

,.
R, ~ O k C,II" QCH,. OC,!! . OC,H,. OC,CI1.11 R, _ OCI!.. OC,II" OC,II ,OClC'H,.,. OC.II.

R, _ ----<ltC.H'12 It.. - O. S

NO,~~CoKo~}- Ml,~ -OI.C.H..~~

'10,)

..,. , ....
_ ...
c '

-, -,

"

0.167

om
1~&7

1:111<>\)

0 t68

t""""''P'''' ,

""
_ ... _

-, .".
\ Irt/M.I\y

"

'.
.\. N"""""""") "-N ,1r<l(>I>eno.,,;}

.
. IHoi

0...
o.~n

1 r-""1~"""'Y

"""

0.0
".,

O~!

t .67)

0.61 1

I"-'P"'f'Il') 8u",,)

0.164 0.786

_.It.~

.. """,",, l<oI ,OIU OS ...II. o''''P of kIoo:to .. _

. . ...!t_l."
I I
_~I'l

TIor_off_IO _ _ IIIII .............. _ I:

. . . . . . . . '"

II - . I ....

!r..............

Ii . . . . . . - - . . ., of ....

lO{<-<l-~-~-;-~

<~\,
12

' I

.,
0

-~ny1alaninc::

"

Figure 2- 11 Hydr09M-SUP!>lMsed (epresentatlOl'l ot phenyla/af1lrle

gr~pn.c

example). ConllCC.. ~jl)' tahles can be c:odtd

to looicatc Inc type of bond. The mosI COfTlmon application of gJ",'ph theory used by medicinal chemistI)' i~ called mo/uil" rmmlj";I),. It limItS the paths to the moICCllle'~ actuul chemical bonds. Table 211 shows severnl pos~ihle pall" for phen} lal3llll1c, includ

ing lmeal pmhs arK! clusters ('If hml'lCh, ng. Numerical values
for
l'ltCh

pmh or pmh-(;luSicr arc bl,scd

QfI

the number of

nonhydrogcn bond, to e3~h !t101ll. ~I'~ cJ(3minc oxygen 010111 1. 11lcrc: j_ only 0fIC nonhydrogcn bond. and il ~'()Iloects o:tygcn atom I 10 carbon atom 2. The formula j, the reciprocal 'lquarc: n)QI of the number of boods. For o-tygcn I. the

coonceU";I)' value i~ I. Rlr carbon}1 o~}gcn 2. ;1 is 2- ' r:!. or 0.707. Note thai there: IS 00 d,frer'l:llCe bctwccn o:tygen I and nitrogen 5. Both have ooly one nonhyd~n bond and coonccciyity "aloe of I. Similarl)', there IS no diff~nct' in \'alUC!i for a C31bon)'1 o~y~en and a Illethyiene carbon, eacll
havmg tlO.O nonh)'drogen 1Ioncb, The final connecu, II)' values for a path an' the JU'lprocal "'luaR: roots of the products of each path, fQr the s'Ond-ordcr,r,th 2C-4C-6C, tIM: m:ipl'OI:al "CJuare root (3 x J x 2) I is 4,243, The values for each path order are calcul~tcd Dnu summed_ A, nOled above, the I1lCthod Il.~ described ~ far cannot di~tinguish between alUm~ thai have the same number of nonhydrogcn bond~. A metlMXl to di,ungui~h hctcmatom. frooll cach ()(lM:r and carbon atom, t\ ba'iCd on the difference oolO.ecn the number of "alellCe dectffill\ and IXMiblc h)'drogcn atoms (whICh art supprc.~ In the: grnph), The "va-

knce" l:OOI'1CCU"U), tenn for an alcohol oxygen would be 6 ".lienee elcetroots mlllu' I h)'lIroj:cn. or S. The ""alenec" connecti",,), term for a primary IImme nitrogen would be S vaknce electrons mlllus 2 hydrogem., or 3. Tllcre are a vari ctyor additional nMXlifications rnat are dono: to runherdlffercnliatc atoms and (,\cline their envimnlll('nts Within the molecule. t-::Xcellem regression equations using topological indIces ha"c been obtailll."'<I. A problcm i ~ inlcrpreting whm tllCY nwun. I ~ it lipophilici t)'. ~Ieric hulk , or electronic temlS thaI define activity? 'The topological indices can be com:Jated with all of these commoo physicochcnll cal de..cnplor<. Another problem i, thaI it is difficult to u~ lhe c:quatioo 10 decode IO.hal molecular modirlClltion.' call be made to enhane:e act" u)' funhcr. ag;1I n bce3U~ of amhlgultlcs in physicochcnllcal intcrpn:union. Should the nlC(lic mal cocmi~t increa~ or dec~:l~ lipophilicit)' lit a panlcu lat" lOCal ion on the molecule'! Should specirlC substitucots he mcreascd Of dccn:a<;ed? On the OIocr haod. topoioglCul mdlee~ can be: vcry vl1lmlhle in cla~sificaJioo schemes that ure de~bcd be low. The)' do describe [he struclure in tenn, of nngs, brnIK:hil111. ne.tibilily , CIC.

CI_slflca.tl_ Metl.ocIs
Besides
mque~
regl'l'S..~ion afl<ll)'~i~.

[here are 0I1ler o;tJJhShCal tech-

used m dru g design. These fit under the: cla~"rlClMion of multi ... ari~le SlaliSlics and inelude discrinnnani anaJy51s,

TAB LE 2- 10 Connedi",ity T.ble for Hydrogen-Suppreued Phenyhll.nine

~

.. ...
,
N'

< -,

e,
OJ
e~

0'

...

<4

.,
X

<4

<.,

<4

< .,

C_10

C_11

C1)

, ,

::jo

, ,
X

C.

c,
0

, ,
X

,
X
X

,
X

<.,

CtO ClI C-l1

9:

X
X

,
X

TA8lE2- 11

Examples of ,aths Found in the !>hen,.!;!""ni.,. Molecule

lrd

lit Orelet" PAth 2nd Order Path

IO-X' IQ.X'-X')
1().2<:~

0.'" '.th

.th Order 'ath

I o.X"-IC.II(-1('

5th Order PlItt.

'.th-O... tu
I 0-1(' . '\O-tC

IO:!C.4C'-6('
l().:!C...c:-5~

10- X'-IC -K'. 7C.1I("

""" "". "

~-"
oI{'.~~

lO-2C.4C
2C-4C3~

,}O-X-4C-1lC

I()':K'.01(' _!l 1IoI

JO.X-4C -iJC 7(' 2C -I('-/1("-7('1IC X-IC -1'0("-7('". J 2C oIC--6C -7C-IIC'lC 4C-6(' -1C , 2(', Ie 3N..oIC-tIC. 7(' ~-IC-K'. 7(' -IX'

100lC-IO-K'7(' IX' 1('-4C-tIC .. 7(:.!I(:.ye X'.,j(' .fJC7CllC,'C

1O-:!C<.fiC. 7('.!!("

1C-4(''N-6C 1I(' .. 7(,1IC' :!C

",->c.c
!IN.4C..t.C .IC-6C_7C
tC_7C8C

2C.oIC..f(;1C
5N-'C.foC-7C

"'..-

.",

.1OX -IC.foC-7C -IX'"

4(:-fIC-7C-IIC-9C- LOC
"" -6C-7C- 12(."- "(' Ioe
~,,-I('-K'.1C-lIC.'I('

"'. ..
""y
A"~.

"'...

"C..tJ('.7C4C
oIC-K7{'-I2C
6C-1C~.\lC

-ac

l-.ri-

"" Ilfer-

'" 0" oc .OC 1I)('I1C

lie-IX'

OC_'7C_I2C 7C..80IC 7C-':!C-IlC 8C.-\lC_IOC '}C.IIJC-tIC IOC-11C-I:!C

OC 7C. llc.o~C-IOC
1.7C-\!C IIC.UX

fC-1C-IX-llC 7C-3C -9C -IfX.'

Jt:- IX'-I IC- loe:

~"-IC.6C;1CIXIIC

"",.

BC-<;ICIOC-ltC 'K"-IOCt tC,L!C

X'-SC -9C-IOC lie 1C.12(>"C -IOC-1lC fIC'JC- IOCIIC1 X"

tIC 7C-8C-'lIC-1OC1IC 6C.1(" ' XIIC tOC 7CIIC-9C toe IIC- LlC 7(". 1](" I IC'tOC-<j('J!(,""

xu
al}(! plHl~m recognition . The !.uta ~;m coo,isl o.f a mixture of ";11 i~lic,,1 aoo I1OIblat i'lical 1llCl1Iodo1oE1C't. The goa l 1.151 10111), is 10. try 10 UM:l:natn ",hal ph)'l'icochl:nncaJ p;tramclefS and ~trul:tur.a1 atlnbuU!li ~on IriOOle to a class or Iype of biological II(tl\"1l)". "I1tcn the rlIenllCJl~ an: ~Ias.~ifitd into gl'Ollplngs weh II.~ ~an:inog\'[licl
~oclpal ~omponenl analy~i~.

,""

""" I "." tr,...i-

,,~

.'" ...

.00 oc

noncan::ulogc-nlC. sWttlibmcr. 3iCu,,:l'inacu,e. and dcpres\mII..umul3ll1 . TIle tenn IIlul",'ariule i' u>ctI bec~use of the w,de "uriet)' MId number of independenl or docnpmr \'anables thai may be used. The same physicochemica l p:lramelcr'\ seen in QSAR analyses are U';.ed. bul In addluon . the software in the oomputcr progrolms hre:Ik.1 the molecn le down imo. l'lbslructu~~. Thc.sc !,tructu rul fr.\!:lIlCnUi alS() become vari ..blu. Examples of the t}picnl ~ubstrucHlres used inc lude QrblJnyl~. coones. conJu~ation. rjng~ of different silts and I)'pe'o, N-~ubsUlulion p;lncrns. and altph;ihe substitution (XU_ 'iOCh Il!l 1.3- or 1.2-disubisliluled. The end Il!>ull i~ thai for e\U a moderate-si/..!': molecu le tYPIcal of InOI>t drugs. Ihnc can be 50 10 100 \'lInablc.~. TIle lecrunquc i5 to devdop a Luge SCI of ~heflljca" well eh:nC1 emed in terms of the biological llell ... it)' that IS going 10 be' pmllCled. nils IS kllOwn as lhe lromillj/ u r. Ideally. n <JIov1d coomin hundreds. if rKlI lhou<>ands. of compounds. dl~lded Into lIC1ive and inuctive Iypi."'li. Jn realll)'. o;c:t.o; smaller tlun roo are st udied. Mrn;t of these i"v~tigations are retroq"IOOil'c 0IIelI in which the: invc~ligUior locmc ~ large dam ~ts frum severnl sourees. Thi ~ meuns that the biological ie.'ilingl ,leI)' followcd di fferent pruI<x'OI~ . Thai is "'hy clns_ )lflC'ttion techniques tend 1 u\oid u~1Il1L eom ;nuous vari 0 ables wch as ED,. LD,. and MIC. lnstelld. grbnrnry eoopointS weh as ~Iil'e or inacule. ~lIrnu lam or depressant. \111 or sour, an! used. Once the InI.lIli ng set is established. thl: multi> anale techIIII!'I 1$ carried OUL Tht: a1gQllihms are designed 1 group 0 the unckr1) ing commonalities and SC' ICCI the variables that ltal'e the g~ateM InnuellCe. on biulogical actIVit )'. The pmlicUI'e abtt;,), is then lested wi th a Ic~t SCI. of compound~ tha, lIa~e bern pol Ihrough the same biological le"ts used for lhe

jqgs.

.hy~.

;"'2

r
,

!let. For the cI~S~l ficatlon modc: l to be laM. the 1Il\'C'lIg~lor must <;cICCI ilina sel~ "'hose resull~ are nOI illlui. II vel)' 01" IQU~ lind cou ld noc be cla.'iSlfied by a ,mined medICinal ~hem l st. I'ropC':rty dol1l'. ciassificllilon rnelhods can ldenItfy \lrutturnt and ph) icochemical de~iptON lhat C3f1 be po...erful ~telOl"'" and detemnnant~ of biological a..'ti\ lIy. There are 'ielenl examples of suc.....essful appl icatIons or thiS technique II One \Iud) conSl~td of I dtver;e group of 140 tmnqulhzers and 79 !>Cdali>'es subJCCIt'd to . 1.. o-way cla\oSirlCallon slud), (trunquil i/.er; ...ersus !oCdall\ClI). Tht: ring T)'pclI mcludcd phenOlhl:lzi~s. IIlli<:Iil.,;. ben/AJduv.epllle~, b:u'bilU rn te,. dlpOcl1ylrnclhallC.~. and II "'hnely o.f heteroc),dics. Six t),-n; lie dc<:cri ptOfS were used lI1 itlall)' 10 characteril.e the mol ccu lc~. Elen'n of the~ descriptors "ere crucial 1 the cl!l.~~lficat'on, 54 had intcnncdialc U'le ~OO depended 0 OIl the cnmpn<;ition of lhe Imining 'leI. arid 4 were lillie U'le The 0\'el1llll1ln8e of prediction accuracy was 88 10 92'i:. TIle rc~uhs wuh the 54 descnpton IndICate an important IImlt,ltton .. hen latlle nu!llber> of ~lIptOfS an! u'lCd. 1lIc ITIdu~lOn or e~ctu~1OIl of de<ocnptor.;; and parunlelef'i can depend on the oompoliillOll of the tr3Jrung SCI. 1lIc tralnmg set must be re~ntatl\'e of the populalioo of chemteals thai are going to be e~aluatcd. Indeed. repeaung Ihe \tud)' on diffetent random ly ~ICCled tmining !Cts is imponl1llt. Ctas.~lfilal ion techlllqlJe'i lend lhernsel \cs to ~tudlCS hlC~ ing qu~ntit~ti~e d:rta . All inleresti ng ctassifica lion problem invol> cd 01f:I~TOI)' \IimuIDnts. III which the goa l W!lS to .o;cleet chernka l ~ Ihm hod a musk odor. A group of 300 un IQue' t'Ompoullds .... IIS se lected from ~ group of odoran ls Ih:n 111cluUc<l 60 mus~ odoranl~ plus 49 camphor. 44 noml. 32 ethereal. 41 mi nt. 51 pungent. and 23 putrid odorants. Ini tiall),.68 descnptors wete e\~!uaU'd. Depending on the approach. the number of dc'ICripiOri ..'as reduced 1 I I 10 16. 0 consl .... mg n"",lI) of bond type!!. Using ih,! small number, the 60 mu~ odor:uits could be scler..1cd from the ~m:lImnl 240 compounds, "'rlh !IJl occurocy of 95 1 97Cif. 0 1lIc U.'Ie of cla" ,focalion techniqUClli III medrcma l chern]$try has nm!IJred O\'eT )CaN of gcncrnl use. "I1tc t)pell o f descriptor. hU"e elpanded to s(XUml measurements In Ihree-

tr'\lmn~

or

lliosc u'l:d in 3D-QSAR (sec: below). Increasingly. dalabases of existing compounds are scanned (Of molecu les Ihat fIO!'scss whut llppear to be lhe desired parumclCl"S.lfthe scan i~ successfu l, compounds lnal ~ predicted 10 be lICthe provide the '\taning point for synthesiling new compounds for testing. One can see pamllels bct ....een lhe "ClItCh of chemical dataoose~ and sctttning plant. animal. and microbial sources for new compounds. Although the statistical and paHern recogniuon methodologies 1"I:I\ e been in use for a very loo g limc. lhere still n.ecds 10 be oonsidernble research into their proper usc. and further tcsting of lheir pred ictive power is needed. The goal of scanning dalabases of already_symhesiz~d oompounds 10 selt:CI compounds for phannocological e'aluatiOll willl\.'quire con <ilkrablc addlUonaJ de,dopmcnl o flhe various multi'-ar1atc lechniques.

din~l1si()n.a1 ~p;iCe ~irnilar to

COMBINATORIAL CHEMISTRY
Elegam a, II!.: s.tatiSlkaltechniques described abov~ are. the goal remains 10 synlhcsi1.(~ lurge numbers of oompounds liO promismg marketable produclS arc not mis>C<i. AI lhe same ume. tnKIilional S)othetic and biological testing an: w:ry ~y. This has led to the technique called ctmwmtlloriu/ chcmistry. The lalter uses libraries of chc-;mical I1l(llehes thai n::act wi th u parent or ba..o;e molecule in a small number of defined synthetIC steps. Return to the two cumplcs preseillcd with the discussion of the Free-Wilson armlysis above. As the number of difTerent sub~l itlJCnts is considered. lilcrally mon: thJn IO.OOOcompounds are possible. Rcmem " ber thal. lhe medicinal chemist can select subsets of subslituenls tnat vary In hpophilicity. ~tenc btllk. IIIductioo. and n:sonancc dTt:CIs and usc: the four Nles for placll1g and use of the substituen~. If this process is ",operly done. a rela1I,ely small number of C(lmpound~ will be obtained !hat show the dual imj)lll1ance of each of the physi/..-ochemical parameterll belllg evuluated al cach ~ilion on thc molecule and the effect of specilic moieties al each posilion. This rational' approach to drug tk:sign a~sulllCs that there is some urnk-rMlU1ding of the tlll1!CI receptor und that there is a lead molecule, commonly called tile prolotype molcculc. A classic eJlampie is the dih)drofolaU.: redUCl.iose inhibilor mcthotru.ate ..... hich h:u been one of the prototypes that laborutories nave u50Cd to syntbesiu and teS-! new inhibi tors. A.IOthc-;r Ullmple is ben7.odiuepine, .... hich has II delined SlI'lcture wOOsc lICtivity ,arit5 with the su bst itucnl~. What aboutlhe situation in "hich hnle is known about lhe mechanisms causing the disease p!l)CCSs1 Until recently. Ihis has been the nornul situation when searching for new molecules Wllh lhe desired phannarological rt:sponse. wilh lhe discovery of penicillin came the realization Wt microbial organisms produced --antibiotics.-- This ~tarled sctttn1IIg5 of IlIlcroblal producls, lookinS for new anubiotics. In a simi lar mIlfIlICI". thousands of syntheuc compounds and plmlt extrae", hu,e been screened for IIl11iclll"lC('1" activily. Some have ca lled this 'irrotional-- dlllg design. but it luis produced mOlOI of the dlllgs currently prescribed. This approach aiM! is ,'cry expensivc. particularly"" hen onc realizes the cost to ~y lllhesi t.e, isolate, and tCst each new compound plus lhe lime pnd expense ncces.sary to take an acthc com

pound Ihrough efficacy and ~afet y tCliling before i t ~ relca.-e 10 Ille gcocrat public is approvcd by govcrnment regulatory agencies. Combmatorial cheml,lry i~ one method of reducIng the cost of drug discovcry in which the goal is 10 lind new leads or pro4otype compounds or to 0ptimi7.e and refine the SII\lC lure-acll~lIy rd:Ulooshlps.Il.1. LIbraries of 'n::acll'C' chemIcal moicties pro~idc lhe chemlcul di'<cl"Silyorproduru that Will be sctttocd for acu~lIy. The chemislI)' is elcgant but rdatively simple. '" that the same fcw reaction~ ure reo quired to make thousands of compounds in a panlcular se ries. The reactions must be clean and reproducihle Dnd ha.c hi gh yiclds. Often. solidstnte synthetic methods are u5td III which compnunds are 'gro""n onlu polymer support Robot lCll ClUl be u'ied to reduce (unher the CO<l of ~)'mhc:!.I\. BloioglCallesung ClIJl Ills-o be autotnated in a process callrd highrhTm'ghpul $crf"f"njn~. which can tesllens 10 hundred. of st ructun:~ Ot II lime. Many limcs II IS posslblc to lale ad~anlagc of gcne cloning tcchniques. clone the tJe.o;i~ receptor. and 111C1lSUrt: the bindillg uf the newly s)nthc~w:d ~'Qmpounds 10 the cloned receptor. To maintain sonIC foo..-us 00 tll.: needed structurcs. information theory has bccn used to con.<Iruel the libranes of subslltucnts. 1llese libraries tend to maximize chemiOll di 'e ..... lty 111 lemlS of ph)'loochc:rmcllt panunc:telS. Mllfly 0( the.e hbranes an: sold commcrci:tlly hy linns spccialumg III thiS lechnique. The synthetM: methodologies con'l IN spectrum from producing thousands of retati,ely purt: c0mpounds 10 producin~ mi}lmres of compounds that an: lested 11) mixtures. Of coun.e. lIuxtUle~ can be difficult 10 chwl fy. IUld II ClU1 be difficult to detennll1C which products in the mixture art: acliv~ and ....hich arc In.lICt;ve. Eleganl methods ha.c been developed Ihal chcmicall y --Ug' cach compound With a small peptide. nucleoude. or other sma/t IIIOlecule that IS pharmacologicall)' men. When mi}ltl.ll"CS of prodllCb are obtalilcd. they are screcllCd for actJvily. Only those nullUre-. Ihat are biologically acU\e are retained. In II ~ called dccu",'O/ul;tm. lhe synthesis i. repeated in WI itcnlli.c manner. producing sm;llIer and SOIOCIlI1JeS ovcrlapping mil' tures. The scn::cning is repelUcd umil Ihe activc compound, are ident ified. E~llIn i ne Table 2-12. This simplificd outline shows how fool' .>teps will ldennfy the three active componcnt~ III a 2O-compound In'CSligauon. (Keep In mmd m. the actWlI cOOlbinlUorlal process will produce hurKl=b Ill" thou'lllnds of compounds (or testing.) M'iUII\l' tnat the project calls for 5ynlhesl7~ng 2Q c0mpounds, A 1 T. Rather than cany 0111 20 disunct synthc!ies 0 followed by 20 sepamle scn:cniRg experiments. all of .... hk-h caR take wecks. four combi natoria l syntheses arc earned out suc h thaL four mi~lUres oontaining liv~ compou nd~ each are obtuirlCd. Only the Ihn:c mix lUres thai le!it posit;'<c in tbe scn:cning as!i-lly an:: n::mirlCd. 1lic syntbesb is repeated producmg Ii'e miuures of three COIllponents each. and the tC$t ing is n::peated. 5i,; more syntheses are carried OUI UIIS lllne. producing OVC1"lappmg t ....O-COOlponent mixtures. and !he assays are rqJelUed. It is now possible to (\ctermine tliat c0mpounds 8 1. and N are IICti,e. In<tead of 20 ~ymhe'ICS and 20 1IS!i-II)'S, ooly 15 weI"C required . Further. time-tMumilll purilicatioo of each mixture ":IS not required. This procw is very sliTlilar 10 tnat carried oot by natura.l-pmduC1 chemists.1lic microbial. plam, or animal tiJ;suc is cxUXted with DVIIncty of solven"'. beginning Wl1h nonpolar hydrocarbon!;

TABLE 2- 12 Simplified Oe<onvolutlon Scheme fOf. 20-Compound Com binatorial Chemistry Sc;'et!n

Carry ou! the lynlheM producing lou. IfIIe..oompon&nt mU(lUlea.

Sg.., ~

mbdurH.

R . . . . . only

the

IIVM

miotl:Ures oonIanng iidi .. OOilipOOWiiiobi,

:::::!:~::=R epellt 1l1li iy.tlt"8sia ptOdu<::ing lhrM-eomponent mjxtUf" 1100 repeat the fCtoonlng, :::~~~:= :
Di:an:l the InacIiYll mjxturel.

,.
...........
'

Rapsll the ~ ptoO.cng ~

prodl..... and

'"~IIII

....

the IGtIIJ1Ol'>g,

,
rie ..... :lnd I~ now going to mll~ e COntact ",uh the rCl:eplor. As ilJus.tnIu:d in Reaction 21 . this is an equilibrium pnxes~. A good abJlily h) fi, rile receplOI' fayors bindmg rmd the dc:~ired pharmacological response. In COOlrusl. II poor fit fa,-ars the Tl:"eTSC reaction. With only a ~mall amount of drug bound 10 the receptor. there will be D IllUl;h smaller pharmacologICal elTecl. hJdeoed , if the amount of dOl! bound 10 the fOCCpt Ol'" b too small. there may be no discemiblc I't:'pon~. Many variablesconuibute 10 I tlros'S binding 10 the ~eptor. TIleo;e incll.lde the SI!'oc1ur:tl class, the three-dimensional .hapc of the molecule. and the Iypes of chemical bondmg irl\"oh-cd III ,he binding of the drug !O the reccplor. /l.lo~1 dru gs thOI belong [0 the SlIllIe pharmacologica l clw hal e crnain stroctuml featute5 in t"omlllOll. "The barbitumtes act on specific eNS rep!()f'\. cuusing depre~s:lIu (,(f!:Cts; hydantoins 111.1 on eNS rect'ptOC'i. prodocing an wltkon~ul sanl re.~pon~: ben;(odiu'.epi(IN t"OIIlbine with the ),-:Imlnobutyric K id (GA 8 A) reptOf'S. with re~uhing an"iolytic acthity: steroids can be divided mto such classes a, conirostero ids. IInlibolic steroids. progeSlogens. and eStrogens. each acting on specific rect'ptOf': I1OIlsteroidaJ unti-innamm~tory agents inhi bit ent.ymc:.~ i'e<luired for the prostagl:lndin ClISCade; penieillin~ and ccphalosporins inhibi t enlynx.. required to construct the b.lCterial cell watt ; lind tetrocyclillCs act ()II bacteria l ribosomc.~.

of

, of

. .. ,

'y.

o.

d.

,. '"

and ending "'ith an akohol or water. and the frnctionl arc 5I:reencd for activity. Only the activc fractions arc I'I:tained. 1lac laller lite ITIOI'e ClIfCfulty fmctionated. IIsi ng biological assays 10 follow the purificalion. In cither combinmorial synthesis or natural product isol:llion. once acti"e compounds are identified. larger-scale, mort' focused ~yntheo;es can be: done, using QSA K-dc:rived c~perilflCfltal design and/or!noIccu lar modeling (liCe below) to Yield comJlOUnd~ different from those produ.r.:ed from the eombill~toriaJ libraryof chern ical fragments. Other IIlelhod s Ihal an: used commonly in combinatorial chemistry include anachlng struclUre~ of known composi tion 10 polystyrene beads (one COf1IJlOUnd per bead) 01' ~yn lhesil.ing structutn ooto a microchip-si1.ed matrix ... hcn: II compound ' s location gives its idenllty, laner is called ,Ipalmilv DddN'$Sflbl" s)'lIIht!si$. Thi ~ topic is covered in ITIOI'e detail in Chapter J,

n.e

MOLECULAR MODELING (COMPUTERAIDED DRUG DESIGN)

The low cost of po .... erful ilesktop coolputent ghes the me~

,h '" '"

..
'" ...
~ ~.

...

\00

"" ,.. '" ,. ....

dicinal chemist the abi lity 10 "design" the molecule on tho: basi~ of an esurnntcd lit o nto a n:ccptor 00- have simi lar ~pa tial chal'lllCleristi es found in the prototypical lead compound. Of courst. thi s as~umcs thut Ihe molecular ~tT\lCl llrc of the ~ptor is known in enough detail for a reli$OR:lble csumatioo of its three_dimen~ional 'hape. When 3 good under~llInding of the gWf'llCtTY of lhe active site is koo.... n. dalab:.ses COIItamlng the thRe-dimen,iooal cOOldi nates or the chenllcals in the dmabu.'-Il can be: searched mpidly by computer progrums th:lt SoI'lect candidates liktly to lit in the act;"e Si IC. As shown below, lhere have been some dra lll3lic successcs with usc of thi s approach. but lirst one mu~ h:I"c an understanding of ligand (drug )- recc:ptor inlertlCtioos and coofOl1n~lion:tJ analysis.

Receptor
With lhe i!iOl:uion and chafllCtcrizatlon of reptOl1i tx.'<:OI11ing ~ ~'OITlmon occum:nce. it i~ hard 1 reali,.., that tho: con0 cept or IttCptOl'S began as <II postu late_ It had been rnit/..ed early thai molecu les with tenain itrueluml features would elucidale II speci rlC bioklgical response. Very slight changes in sttuClure could cau.'iC significant changes In biological lICtivity_ '!ltesc: slruclurol Variations could Incre:asc or decre3-'oe acti, ny or change an agonist Into an antagonist, This early and fundamcnluJly COllect intcrpretultOll called fOf the drug (ligand) to lit 0010 some: !iurfacc (the receptor) t~t had fuirly Strict slrucluml rcquircmenlJl for proper binding of the drug. "The inltilll receptor model V,lIll based on a "gid Iodand-key COf1Cepl. with the dnlg (key) filling inlo a rc~"Cptor (lock). II has been used to ~lplllin ... hy CCTI:un structurol

Drug-Receptor Inur.ctIons
At this potnl. let us assume lh:lt the drug has entered the sy~t~rnic circuluti()lt (Fig , 2- 1). p;iSSCd through the li pid oor-

allnbules produce a predictable phannaoolOj;ical action. Thl~ model ~ulll~ u'iCful.llllhough one must realue thaI both the Llrug :anUlhc m:eptOl' ClIn hoive comider.lble ne.\iblhty. Molccul:tr grnphi.: ... uSing program~ thai calculalC lhe prefcrred cooformalion~ of drug reccptor, ~llQw Ihal Ihe m:cptor can undergo an udjusuncilt III thrce-dnnensiooal -.tructure IOohen lhe: drug maiCSrolltact. Usin! spaceage language. the dru!! --dock.~-- with the receptor. More comple~ ra:eptOl'S now are being Iwlaled. char...:. tCri7.cd. and cloned. The fin.1 n.'(:Cplors to be i'<OiDlL-d and ch:lrnclCri/.cd \OoCI\' the reaclilc and rt'gulalory ,;Ies 00 en l)'nlC , Aooylcholme<tera.'iC. dihydrofolalc reductase. :tn. gil)\cn.~in. and III V proll:ase-(;orllcnmg enlyme are examplC\ of cnzyme~ \I hose activc sile. (Ihe rra::ptOf) hal'e bcc:n nlOdclcd, Most drug nx-cptor. probably ~ n:ceptnr.. for mlluml ligands u'iCd 10 I'I:gu lulc cc ll ul(lr b;oche!lli.~lrr and function and to eommumcate bet\l'ccn ccll~. Receptors incltodc a relatiH'I) ~mall region of II macromolc:c:uk-. \lhich may be an .solPI~blc cn>:ylne . 5trucu,.ml and functional l'Omponem of II cdl membrane. or a speCIfic Inuocellular <;ub,t:lIlCe such as a prulcin or nuclcic acid. Specific n:glon~ of tilc.>;c macromolecules arc ~ isualil.ed as bei ng orien led 111 space on a manner thai pennll~ theIr functional groups to .ntl'f'llCt \I IIh the compk-nlCnt3r) functional groups of the drul! . This inlerachoo onillate$ changes in struclure and funelion of lhe macroonolccule. willch !tad ultimately 1 the lib0 .o;ervublc biological re~pollsc. The con,epI of spalially orienlcd fUllCllooul areas fonmng II J\.~cptor leatl~ dirt.~lly 10 specific qructural requ lrenll:nl~ fl)/' fWlClional groups of a drug. \lh!Ctl mUSI complerTM'nl the reccptor. 11 now I~ possible 10 I~ale mc:mbrdllC-bound receptors, 0 alihoul1h il S1i II " dl ff!Culi 1 ciucldale the lT " ruc1Uml chern b irr. hecau<;c OIICC :;cpamled from lhe cdl me mbrJlIcs. tllC.\.C rtteptors may lo-e lheir nati\'(~' !>h:ape. ThIs is because the membr.inc: I~ reqU ired 10 hoklthe reccptor in it, correct tet hary structure. One nlClhod of l'Cl.'CptOl' isoilluon is affinity chronlalngmpby. In thIS Icchnique. a ligand. oflen an altered drug mok-c ule I.l\Own 10 coruhinc wilh the J\.~cptor, is alhlehcd 10 H ..,hromaIOj;r.lphic ( Uppon phase. A solulJon con laJllmg lhe desIred receptor i~ P;IS'iCd over Ihi~ column. l1lc: rra::ptOl' will cotnb!1I(' With lhe hgand. It is romroon 1 JKId 0 a chenncall) n::lClI'e groupll1& to lhe drug, re,ulling in lhe reccplor and drul! cO"alemly bindmg WIth each other. TIM: dnlg - rcct'plOr complex is wa,1 from Ihe oo hmul and lhen 1CtI chanlCteriud further. A more recent technique uses IttOmbi nant I)NA. l1lc: gene for the ~ptor .s Incalcd nnd cloned. II is Ir.msferred Inlo a hoclcriunl, least. or animal. whICh then produces IhI: receplOr In large enough qu~"hIU:-' 10 pemlit further ~Iudy. Someti mes il is pos~ible 10 delermine the DNA scquence of the cloned gene. My usil\! the genetic code for amino acid. the amino acid w-quenr;-e of lhe protein component of lhe rcttptor can be delmnined. and lhe receptor then modeled, producmg an eSllm3tcd thrcc-dmlCnsional ~h(lpc. 'The model for Ihe rtteptor becomes the lemplale for designi ng new lIgands. Genome mapping has greally increa.~d the infonnalion 00 reccp!Of"ii. l!aide. the human gc:1I()f1)I:. the genelic C()fIlposliion of 'iru~ hacleria. fungi. and p;arasi lcs has incll'ased lhe JIOS.,ible sit" for drug.~ 10 acl. The new field of prutoolllic.~ \tu d lc~ tl\.l, protei ns poxluced by ~ln.lCwrul genes. Tbe diSClL'i.,ion in Ihl) chaptC'T clllphasi/.L'S Ihal lhe

aoo

cdl membrune is a highly OIl;allll.cd. d)'nanuc ,Iructure thai inlCl'l'lCb wilh \n1311 mok:cuk's in ~peci fic \lay\: It~ focu~ is 00 lhe hp!d bI layer component of Ihl~ C()fIlplelii stnICIUrt'. The re!:eptl)/' components of the rTM'mbrulte\ appear 10 be main ly protein. They ~'Ooqitu lc II highl y organiad ~glon of lhe cell membr.lrte. 1lle '\.lUlle Iype of molecular specificity <;een in such prown.'> as enl.ymes and anllbodlt:'< is al..o I property of drug receptor.. The nalUre 0( the amide link in proteins provide.'> a unique opporlunity for lhe fonnalioo of mulii pk: internal hydrogen a~ \le Il 3~ internal fomla lion of hydmphobie. van tier Waals'. and lonk bonds by ~Idc chain groups. lcading 10 wch orguni/ed ~Iructures as lhe hclllli. \lhlCh conlam. about four amino oclLl residues fOl' eoch !Urn of the helu . An organized proIein Slructun: would hold the pmino acid ~.tIe chains al relau vcly filed posilions in 'l)llCe arid avpi lable for specific inleractions with a .mall molecule, Pm-ins can potentiall y IKIop! llIany dlffcrenl confonnaIIOOS in space wltl!oul ~al. lnl! their covalenl amide Im~. ages. 'They may shlfl frolll highly rolled structures w par. liall y diM)rgUntzed structures. \I'uh p.1ns of lhe molecule C.\i~li ng in "random chain" {)I' --foldt'd ~hce'" slructures. t-onllllgenl on the en,ironmen1. In lhe nl(loolayer of a cell nll:mbnrnc. lhe InlCI'l'ICIIOII of a small foreIgn molecule \l uh an organiJ.eci protem may lead to a sigmficanl ehange in the ~tructural WId physical propertieS of the IIlCrnbr",tni.'. Such change.\ cou ld \leU be lhe ini \l(lllng e~cnl\ in the tissue or organ ll'~pllIlSC 1 a drug, ,~uch a~ lOt: ion t run~locating cf0 fee .... produced by inlCr"':lion of:teetylchohneand thecholinergic receptor. 1ltc large body o r in formatIOn 00\\ al'nllable on relallOll ~hlllll between chemical Struclure and biologlClll acll\lIy ~t ronil ly ~upporlS Ihe cooccpt of fle~ible receptors. Tbe fit of drug.~ onto 01' into n\llCfOlllOll'('ules IS rarely an a1 I-Q1'none process as pic\un:d by the earlier lock-andkey concept of a m:eptOl'. Ralher. the bInding or panull msertlOll rI groups of moder-~Ie 5;7,1: 0010 or into a macromolcculil\' poot:lI appears 10 be a .:ontinuous process. ;u leaSt oler II linll ied range. as irldk~IL-d by the frequcntly \J(;Cu rring regular in CIU5C and decrease in biologIcal ac\i~ il) as one ascerKh I homologou~ ~~ 0( drugs. A range- of prodlJCti"e assocUi' ItonS b.:l\lcen drug and rtCeptOl' may be: pictured. IOohich lcad~ 1 agoni"! n:~pon)CS. such liS tllO'iC produced by cholln' 0 ergic an-d adrenergic drug~. Si mil arl), wong a.~sociation\ rtI;Iy lead 10 unprodUClilc changes in Ihe configur.llioo of the macromolecUle, leading 10 an anlllgoniSlic 01' blod,J", response. such as INI produced by antICholinergic 3pIS and HI V proIcasc inhibi lon;, Althou!!h the fuodarneollll si ructura! unil of lhe drug rcceplnr i~ generally considered 10 be protein. it may be ~upplemcnled by iI., assoeiauODS Wllh OIher 11111'-'. such as nllll:opolySlll.'('Nridr.:\ ami nuck-it

oooos.

-eids.
(and mammalJi 1M s.ellCl lll) an: "ct')' comJlIe~ \)\'. ganisn15 thoil hn\'c dr.:velOJlcd specialiled organ syMems. It i~ nOi surprhillg Ihat I'CIIlOfS un: nOi dislrlbuled e<; uall ) IhrouShou l the body, 11 now i, Il'alized Ihm. depending on lhe organ in \I hich il is IocIlH.'d. lhe sante recc:ptor class l1li) beha"e dlffen:nlly. This can he advant.:lgCQO~ by focm.i", drug therapy on a ~peciflC organ sy~tem. but il can also r::w~ Ilthcne drug Il'sponsc:s bcc:~usc the drug i~ e~eni ng 1"0 diffcrenl rc.,pon-.e~ ba'lCd on the location of lhe rectplors. An ellDmple is the ;,e lecl;lc c~trogen Icptor modulaton
lIuman~

!loon

I
flgUte 2- 12 5.elecl,ve SERMs.

'"

I~

j
Tw,"" b
o -

(SERM s). They canllOl be cL.u;;sirlCd Simply 11$ agomsts or IIltagoniSls. Rather they can be t'{)n'iidered variable agon i~b MId antagooists. Their .selecti\ ity is \ct)' COQlPIc.\ bec:lu.\ t It tkpcnd~ on rhe orgnn III ",hleh the receptor i~ lucllted. Thi\ compleA"y can be Illustroled "nh tamoAlfen 31K1 raIo\ifcne (Fig. 2- 12). Tamo~ifcn i~ used for e\trogen sen~i tile brea.~t canccr and for reducilli hone k1S~ from O'i.copo!'OIi1!'. Unfortu nateLy. prolonged treatment Hlcrease~ the l'I ,k ofendonM!trial t allcer bccau'C of . he l'C'po!I>e from the utcriDec'i(mgcn rc<:cplon. Thu s. ulmo\ifen IS an c~trogen anlngOlliS( in the llIallllwu)' gland and an pgoni\t in (I\c utcms alld bone. In contrasl . nolo, ifenc deIe'i IlOI appear to halt much I!OOlst pmpeny In thl! uterus but. lile tamollifcn. is an anlagonist in the bn:a .. t and agoni~. in the bone. There are a wide variety of pho~phodic~(c rno;e\ throughout thE body, l lleo;e el\J:) IlleS hydrolyl.t the C) die phoo;phate estm of OOcoo,inc monopho~phate (cA M P ) mid gllano<inc IIIIlIIOpba;pha(e (d3~W). Although lhe Mlb--tmt!'!; for . hi, family of cntylllCS are cA MP arnl cG MI'. (here are ditTer etICt1 in the active 5itt~. Figure 2- 13 illll~tratC'< three drug, IISed to ( n:~ 1 credilc d)~fllllttioo ('ildcnafil. tOOalafil. and l'lII'llc:nafil). Tlte<;c thl"Ct' tak e lIth'unlage of the difference, in I('(IIC Sile structurol requirement, bet"cen plK:Kphodlcster~ type S olKi the other pOo<.phOOK. terdscs. They have an .... ,!()Oant role in maintainini! a desired hf~tyle: tn:atmenl olertct ile dy~funcllon caused by a ~arict y of med ical condi111m. The drugf I.pprol-cd for thi ~ indicat ioo WCfe ,.liseovby at'cident . The goal 1'.'11$ t(l deve lop a newer trcatmelll d anima. The apptvach wn 1 dc\elop pIloO'iphodic'>4em>e 0 lIiIibitOf"S that w\JtIJd prolong the acllvi ty of cQ MP. The end ItiULI was dT\Jg~ that ,,~ IlOI efkcllle IIIh,bllOl'< of the JIIosphodicstClU"C that y,ou ld .reat nngi na. but were ('ffeetllc iWlibitOfl of lhe one found in lhe OOI'pUs calc~um. The ruodllatioo in thiS organ re,uLts In penile ereCIi Oll.

II h,ch may be calkllihe bllJl~}lIinll N'f"rl,,,,r 51'''_ 11us ,meracliull ""ould be upcctoo 10 talc place by u,ms the." same bondmg fon:es a.. are in-oll'ed "'hen simp le mok~ule~ interOCI. TIle_",. together ",ilh typlC":ll uample<,. an: col lcclal in Table 2-13. M ost drugs do IK)I po~~s." fUllCti ona l gl'Ollps of a I)pe Ihat ... oukllead 10 ready fomuwoo of ~Irong and ","SCnllan), IrTe l'cr;ib lc covalent bonds bcl ....ee n droll alKl biological rettpl<ll" In most caso, II is de<irnble to Ita\/!, liM: drug leale the receptor ",e when the CUIlCCl1lrulmn decreasc' in the c:Alr.1cd lular fluid.'!. Therefore. nM))l useful drog.'l are held

to the ,r receplo~ by 100He or ,",calcr bolld~. When relatively king-lasting or imler;ible cffccl~!lI't' de"red (c.g .. antibaclerial. :ml1C11nct"rJ. drugs dml fonn coyu le ni bond~ with the re<.:cplOl' arc effeclilc llOO useful. The olk),lanng a~nts. ~uch as ,he nnrogen mustanh u"Cd In callcer d\('!no.hefUJlY. fur.
of drogs thai OCt by fonnauon of CQ\alcm bond, (see Chajltel'" 12), Covulenl bond form:mon bcl .... etn drug and receptor is.he ba~l~ of Baker' ~ C'OIle<:pt of ocr; It'-5;It',flruINI irrt'It'rsibl.. ;nhibilwn." Con~idembl e cxper;lI"ltntal evidence on w na .ure of elllymc mhibltor; supPOl'ts ,his concept. ComJlOllnd, ,tudicd pos...e.u appmpriat .. ~tructUI"Jt fcatures for re\'cr<ible ... uoo highly <>elcctl\e a. o;oc;u.ioo wllh an en/}1l1C If. m addl 11011. the cOIl\JlUund~ carry reacti,e groups capable of forming 00\ ak-nt bon\h. the sui)<;Ir.!.lc may be IITC\crsibl y bound 10 tile drug-receptor complell by covalent bond rormation y,ith ft'3C1he groups adjacent 1o tile acu\e ~nt. The diuretIC dru g cthacrynic acId ("Cc Choplcr 18) i~ on 1I.~-lIn,utur:llcd l elOn('. thought 10 art by CO\1Iknt bond (ormation " 'l1 h sul fhydryl groups of Ion tmnsport ~y.'lems In the rcnal tubu lc~. Another c~ampl(' of 8 drug tha. co\akntly binds ' 0 the reccpto.. is selcgiltnc (loI..'e Ch .. jltcr 14). an Inhibnor of nlOlKlIIminc o~idase-B Other cxample>; of co~ ~ I('n. bond (QIlI"Iation be' .... etn dmg and bio logICal receptor , ne Include tile n:acuon of arsenicals and nk'I'Curials II. i.h r:y~el ne suHllydryl aroups. the lIlJ' latlOn of b:lcten al ceLL "all eOOSllluents b) pe ni ei l1tn. and the p/1O'iphorylat;oo of the o;ennc hydro~ll moiety at !he IICt i\(' ~i te of eholllle:>.emse hy org anic pho!;pha'e\. nosh an
e~wmplc

cro

DnIg- Rec:eptor Intera ction: Fon:es

..... Ived
A biological f"CI;po!I'iC I~ prudllCc:d by Ihe imcr-..cuon o f a tkuJ "Ith a fllllC.ion~1 or OI'J!allll.ro group of moIocule~.

CI

sufficient for a "able rombmation. COOSjlOC'nlly. drop atl Ing by \ 'inuc of tocir SIRIClural specirlC!!)' will bind 1 the 0 rfi'CplOI' sile by hydrogen bonds. ionic bollds, IOIH.llpo1e
and dipole-dipole 1I1 1Cl1llClion~. and ,an der Waal s' and 11),drophobk forces . Com ldcnng !he wide variel)' of funclionaJ groups found on a drug molecule and rttephX, !here will be h "ariel)' of secondary bomJing forces. 1 0ni7.:lI;on at physiologic:ll pH

Efh.~,ynlc

Ac i d

eli,

o-~~CHJ
S"'Qllinf

' \ .fi.....OipECH

Keep in mioo lhat i1 is ~i rablc 10 ha'l: most drug effects re'" co;iblc:. For lhi~ 10 occur. relal llely .... cak fOll-'es must be ill \'olved in the drug - rcccplOr complex yel be Strong enough 1hm (>\her bmding sites will 001 cOIllp:titi\'ely depl ete the .ile of action. Com pound ~ wil h hl!!h stfuctuml specificity lila)' orient $C," eml weakly bindillg gnltlp$ so Ihatlhe summation of their imer.ll.1ions wilh 'pcriricpJly oricmc:U comple memary groups on the receptor pru\'ide~ a l{)Ial bood strength

would nOflllully occur wilh lhe carboxyl. su lfonarnido. and alrprnn ic ammo j;TOUPS. as ""e ll as lhe qumemary ammOl1lum group al uny I'll. These !i()Urces of poIenlial ionIC hoods are frequently found in lICll ve drugs. Diffen:l1oI."eS in eleClTOnegaIInty berwce.n carbon aod OIho!r alom!l. such lIS oxygen and nnrogen.lead 10 In asymrnelric dlStributioo of eLectron s (dipoles) th;u arc also capable of fOrTInng weak bood~ .... lIh reglOrl~ of high 01' low elee.ron density. ~lICh as 1 00) or 0I1ler dipoles. CartxHl)'I. ester. amide:. ether. nitrile, and related glOOps lhat corl1a;n ~lICh dipolar furoction~ :ill: frequently found in cqu lvulel1l loca lions in muctur~lly specirlC drugs, The re lal lve impo:lI1ance of lhe hFfrogrll boml in lhe for malioll (Jf 11 drug - receptor com plex is di fficult 10 U!IO.q,'SS, M uny drugN POS~Sb groups ~uc h as cu rbonyl. hydroxyl. ammo. and imillo, wilh the structural capabilities of :!Cling us lICCC plOI'!i or donors in the formation of hydrogen bond..,
Howe.er. such groups ",< oold usu ally be !oOlvated by wmer,

t
I
00

C) ,
!..,

C) ,

Tadll.,.

Figure 2- 13 Ex.1mple!i of phospt\OdIeslf)f<He type 5 ,nhtbtt~.

TA8LE 2- U

Types o f Chemi( ,,'8cmds

Slr. ng lh (kuollmol)

i~

frequent ly found in lIIC1i .'c dru,g.<, and _ re;I>o"~bl,, ""plw",.

.."'

uon for n~ reql,l l!"CU-.cnl for many Iypes of biolog ical actIVIty may be dcr,~t'd fmm Ih" cU!1lnbmim,s of ' hi) (Tal surfllCi: 11,1 V(1n dc. Wan ls ' binding 10 u col1t~rxmdinllry nat rec~pror

Iond Typ"

Eump!e
Oi)-()-i

area.
The hl'JfOIJ/wbic bond is Ul.'OllCcfM u~ to clplll.in Illlruc the mlcl'1JClion.~ be,"'o:cn nonpolar 1\'j;IOOS of the receptor and the drug. Explanation. ~lICh II!> the "isopropyl moiety of !he droll fits 11110 a hydrophobIC ckfi 00 the .rtc}IIOI" composed Orttle hydrocarbon ~idC' chains of the amino lICid~

::0 I ,

" ,

I R-N-M-O

"
"

1._. )'C-R'
0

vall11<:, ;o;ok:IIClOC. and leucine" art' commonly used 10 (;tplain why II nonpolar ~ubSl1lucnl ~I II p.lnicular position on the ()rug Illolecule ,~ unponum for activity. Over rhe years. the cOflccpl of hydrophobic bonds Im~ dc,-doped. There has been con~idenlblc cOIltll)versy u~cr whether the bond 111.11,1ally c~i'b Thermodynamic ulJ!unloCnlS on !he gain In tn trop)' (dei:rease In ordeTUI '\UlIe) ... hen hydrophobic groups c-..,,'" a parhal collapse o f the ordeTUI ....-ater ,tnK:lUn: OIl the surf....: of the n:ceptor h:II'e been p!'IlpO'>ed to validate a hyd rophobic- bonding "lOde!. Then: an: tl'lO problcm.~ with thi~ ro~'('pt, Firl't. the term hl"droplwbic- Implies repul~ion. The ternt for Utt racllon is hydro{Jltllidll'. Secund . rind pa_ h~p~ mun: impon~l1I. there i. no truly ..... mer-frec region 1m Ihe n:ceptor. Thi, i. true even m the area. populuted by the oonpohlt ammu acid side lhaJn$. An aheroote approach is to coo'1dc:r only the C(IflCept o f tlydrophlhclty and lipopllll1clly. 1lIc ~inallng WaI<:T fIlOleculC's soI\ale polar moit'tlC<. elTecti\e/y Mtue.:'1.ing tl1c IlOnpoiar n:sld~ toW' d cacti ....

-OH'-O_

-OH-I

\!

,0,

0,,",

,
_

""",.

Sterie Features of Drugs

, I I 4""", I,"", III

""* '" Alioon. A ~, , '< T"''''", 1'1<,. v.ot.. Moo "".., .t

Regan.!I.:...." of' the ultimale IlJeCh.II1"1I1 by ... hich the drug

alldl/le receptor Interact. the urug mlhtllpproach the n:cep4Uf alld fit <"IO$I: ly tu its surface. Stene factor> LlctcnUlnro by the stcll!OChcnnsuy o f .he receptor .110.' ,urface alld lhal of the drug molo:ules an::. therefore. of pnrnary importance in dctem1illlng the n:lt ure and the e(ficieocy dthe d rug - receptor intcractlon . With the poo;slble e~cepllon of the gener l .. anc'1hetlc,. 5uch urugs must po<;-.c's II hIgh wuctuf\ll Specl ficll y 10 inl lilli e :t rC'>ponse lit a pmllcu lllr I'Cccptor. Some \ 1ructural fell lun:s comrihulc a high ,l ructural rigiLIily to the molecule. For e,;ample. arom atic n ngs an: planar, and the atOl118 anach.:d direclly to these' rings are hekl 111 the plane: of the: aromalic ring . H........'C. the quale:maJ) mtrogen and e:arbamate o~ygen a.lachcd dIrectly 11.1 the: benzene ring In the el!olillC.'loler"' .... inhlbllor ne:osugmine: IIf't' re!ilri .... ted to lhe plane Qf Ihc nng, 300 COI1se<jlM.'ntl)'. the .. patial ammgemc:nt of III le as1 thr<;e atom~ is establi~lK:d.

I'llO'OUkllhe UHIc:spondlllg groups on a biol~lcaJ receptor. 1k1~1,,-d) little IIC'1 change in free energy ,,"oukl be e~pcc:led In nchlnging ~ h)'drogc:n bond .... uh a watcr molecule for one bc:twe<'n drug ond receptur. flo"'c\ ... r. III a urug- n.'Cc:ptor combination. '>eve ..... 1 fotce:. could be involvcd , inc luding the ~)drogen bond. which woo ld rontribute 11.1 lhe stabllily of the intCl'lICtKm. Where ntllltl l)lc hyt1rogcn bond. may be fOlllled. the total cffect mlly be ~izable. ~lM.'h as lh;1I Llcmoo W1lIed by the !;\lIblhly of the prot ... in (l he" ... ond by the lUlxh1.ing innuent:c: of h)drogen boods bet .. c:c:n specific ~ p:urs m the: double helical "Iructun: of DNA. \ 'jJ/I t1~r lI'a/lls ' forces an: auraet;vc forces created Ily the pol3ri/.abllity of 1Il0lcculc\ and arc ellcned when any 1""0 uochargl'Ll aloms uppro.1I.'h cach Ql hcr very cI(.C ly. The ir IIrcngth i~ inverse ly pmponional tu Ihe !>C\'cnl h po,,"cr of thedistance:. Although inuividually \\euk. the ~ummut ion of their forres proVIde. a $lgmfic3m bolldmg factor In hlj;her.,Jccular ..elghll"Qmpound~. For example, II is not Jl'O'sible 10 di~lIJ1 /lOITIlal allane$ ""th more Ihan 80 carbon ~lontS. heeau.... the: energy of -80 "cal/mol required to sep;ullle the: mlecull'S is a pprm.,malc1y equal to the encrg) o,:qu ircd to bi'tak a c:ubon-carbon ro\ale:n1 bonLI. flat Slruo:Wr'($. suc h baromatlc nng~. pennI! do ..... npproach of Ulllrn~. W ilh VUIl tier Waals' forces of -0.5 to 1.1l " c:a llmo l for ew.:h mom. Iboot six carbons (a benlCne ri ng) would be IlCCe.,ary to ilWch lbe Sln::nglh of :a h)drogen OOtid. 1lIc urom :ltle ring

0, ,
HJC-N

~~HJ
CH J

,0--0
~,

N ,I,...I". ...
The rcla ll "e pGl>it ion, of ato"," ultached d Irectly to multIple bond~ arc aho fi~ed. For the doublc: bond. cis and mills isomers "" .. ult. Fur e,umple. uil:l h yJ\t ilbe~trol C:lIists in Iwo fi~ed stereQl<OmerIc forms: Ir(ll/3diet hyl~tllbc:strol is rstJl)-

gcrne. ",hett'as the d~ lson~r;~ only 7')(, as lelWC. In m"'$ dicthylstllbestrol. "SOtlance Int('f'aCtions and minImal ~eric mterference tcnd 10 Iiold llie two aromatic nng' and oonncctmg I:thy1c'1e cnrbot! ~tOIl1~ in the sa me plane.

,,
~

t tlnlOJ. 1~1h

r, !tult.1

,, ,, cll-Ol UntIl I " a u Itol

G~mc Iwmtrs. such as the: cis and tlie mitis i!;()f'llCl'!l. hold ~lruclUnd fcature;o; at Ihffcn:nl relative po'\irion.~ in

1llese t'!Omcri also h~ve significantly dlffcrent phys. cal and elic nllclil propenies. Therefore. their distributioo~ in the biologicnl medium arc differenl. as are their capabili tie~

~1)3CC.

for inlelXling ",iln I b,oIoglc,,1 ~poor in (I W\lctuf'~lIy speci roc manner. lbc: Unlled State~ i'toannocopeia ~og. nizcs Ih~t there are drog~ "'lin ~inyl groups ... hosc commer cial foml com ains boIh their and Z isonICIlI. Figure 2-14 provides four e~amph:s of lhese nll~lures . M~ subtl e differellCt's ubi for ~'/II1fomJ(lI;oool ;..omeN. Like geomelric Isomers. lhese exist as dlffercnl tunn~ menlS in .'pace for the ItOOIS or groups rn II single cla~~ic ~troclUrc . Rotation about bond~ al1o ... s mlcrcoo\ersion of confoml~ ti onal isonlen. Ilowevcr. an crICrsy barrier be tween ;!>OmeN is often hrgh cnough for their illdepcndelll CArSICIlCC and tl:OCl lOO. Dlfferencrs in rt::lC1i ... uy offullC\lollal groups or intel1lCtion "'rm bIologICal n:'I:eptOf"'l may be due to differences in sterM: requrn:mcnls of lhe ~rpt()f1. In certlun semirigid nnll ~ystcm,. conf{lrl1lationallo;on~rs silo .... significant diffcrcoces in biological activilics. MClhods for caku Iatin8 the.'iC cne'l'Y barriers IIfC discussed in ChapoCT 28. ~n chaln~ of (IIOnl!!. ",hrcb form an Important p:1rt of m.any drug nlolecules. are IlOl equally free 10 assumr all possiblc oonformallons; some are SlCrtelLll y preferred. En ergy barriers to frec rt)Iation of lhe cha tll~ an: present. be cause of interactions o( ItOltbont.led IItom~ . For cxample. the atoms tend 10 position them5('l\es in spacc so IMtlhey (If. tupy staggered positloos. "'tlh rtO 1 0 atom.~ d'~lly facmg .... each Oilier (eclipsed). Noobondcd imrroctlOrls III poI~.ncthy lenc chains ICnU 10 favor the must exleltded anti conforma tion~. althougn SOtllC of the partially e.>;lcndcd grmcht tonfonnalioo ~ also CJ( iSI. Intramolecular bondmg bcl ... een

Z CIomIphene

E-Clomlphene

'"

Z OOXep!n: R,' CH,C"'~It. ~ H EOoxepin: R,' It ~. CH.,cti,N(CH,1t

Z-Cefprwll:

R"H;Rt~
~.

E-CefprozH: R, CH,:
EKampiesofEandl~

Figure 2- 14

 ,,, "
~

,"
k

)'y"'~

..
,

S' "

+1\ piIow_af .....

- - ..... .
o

R . . . .R. ,),

<-

y-

11,), . ./'"

.. "
I

R)'. . . . '" . I
~ lIab11i1.~

"'), ............~

"

,..,.

J.

,tn.w;!ur. of ImidM figure 2- 15 Effe<t 01 nonc.1fOOo atom; on ..

SlIbilzeod
~ ..

moIecu~'s

rtlnhgura\lOfl

substiwcm groups ellll make what might r"'-';I appear to be an unfavomble conformation favorable. The introduction of IUOl1I~ other than carbon inlo a cham strongly mnlll"roces the conformation of the chain (Fig. 2 I j). Because of 1"CSOf1lI/ICC contributions of forms in "hieh a double bond occtJpi~ lhe l't'nlr:d bond. of ellleN ant! amides. a plnrllll' oonfigumlioo is famn:d in which minimal stene imcrferencc of bulky 511b~l i\Uc:nb occurs, Hence. an ellier may c:x ist mainly in 11M: m.ri. r:uher than the gm/Ch~. forlll. For the same reason. the amide linlnge: i ~ eMClllially planar, wilh the ITlOIt bulky substituento. OCCUP) ing the ami posillo n. Therefon::. ester and amide linl.:ages in a chain lend 10 hold bu ll )' group!' In a plane and 10 SCp3r.llC them as for as polosiblc. As compone nts of the side cham~ of drugs. (";1 c:1' and amide group<; f:" 'or full y cXlendt:d chain~ and also add polar character to thai segment of the chulU, In some: C:lSC!l. dr/NH('- IIi/ltl/r: il1ll'rtll"ljCJIu:lpPCM to innuence stlUC1ure in solution. MClhaOOnc may clhl pania.lty in a cyclIC form in soIulion becauSoe of d'polnr aurocti ..,c f~ bet ..... een lhe basic nilrogen and carbonyl groop or bcc3USoe of hydrogen bondmg between ,he hydrogen on the nitrogen and the carbonyl "~ygen (Fig. 2- 16), In eitherconformalion, methadone may rC!;emblc the confonnalion~lIy more rigid poIenl analgc.~iC5 Including morphine. meperidIne, and tllt:IT a.nalogue~ (r.ee Chaptcr 2]). and it may be Ih,~ form that lAleracts ..nth the: an.aJgesle receptor. Once-: the ,J1{erac\1OII bct"'ten the dlllg and iL' ~C'ptor begins, I flexiblc drug molecule may assume a diffc""nt confonnauon Ih.1n Ihat pred iel;:d from soIulion chemi~l ry, An imr.lnloleculor ")'Ilr(/8'''' bmlll, usually forml..-o be twten donor hydmx y and amioo group" and IlCCCptOl' oxygen and nitrogcn atoms. might be l:.Jlpc:cled 10 add Siabil ity to a panicular collfonnauon of a drug in soluhoo Ii""-c'-er. in aqueow MJ-Iulion, dooOI' and lICCep(OI' ,roops lend 10 be

11,C_....

'" 1"1"",
~

~.

\._-J~._
I I ,

<7

figlMe 2- 16 SabIIilatlOll 01 confofn\ol\JOllS by sondary bonding JOKes,

MeINdoN.HI! I 'by
"""''''''' ' bOI o<Ii 'II

-.cIonI ...... -'" by r; ' 1, In - 4

.... -

bonded to ",~.lIer. alld linle gam in froe el"lCrgy woold be achic\'cd by the formation of an intl'1llllokcular hydrogen bond, Ixu'1iculnr ly if unfllvorahlc sterk factON involving nonbondc:d mteractions we~ introdoccd in the proces.~, Therefore. Internal h)dTO(lcn bonds hI-ely play only a sec OfIdary role to stene facton in determ ining the oonform3 tionoll dIstribution of ne~ible drug mo\el.'ule"
~

l'
....H

R,

.,

,c=o

R,

Conformidlon.1 Flexibility and Multiple Modes of Action II has been proposed lhallh.c cOIl foflllalional nc~ ibilily of
most open-<:ham neurohormone~. such as acclykholil"lC. cpinep/lnno=. !\erotOOtn. histamme. lind n:llIlro physiol~ically actl"C btomolecuks, permll~ n'uhlple btologleal effects to be produced by each moJ,ulc:. b) 'lRue of their ability 10 .

internet .n a differcnt and unique conformation \\ Ilh dlffcn:m bIological reccpwrs, Thus, it h~ been ~ugge'ted thai acetylcholine may internct with the muscarinic re<.:cptor of polot ganglionIC parnsympalltctic rlCtvcS and .... ith lICet ylcholine~ Icrn~ In the fully e)Uended conformation and, in a different. mon: folded structun:. \\ Ilh the nicotinic rttc:ptOfS at gangha and at ncurolnUliCUlar JuncllonS (Fig, 2- 17). Conforma.lionaJly rigKllCCtylchohne-hke molecules h:t.e been used to ~tudy the n:-huionships bctwun thoe variou~ pos~lble oonformatlOfl!i of acctylchohne and the.r blOlog.cal effects (Fig, 2-17), (+ )-lrllll.l-2-Acctoxycydopropy l Inmcthylam muni un\ iodide. 111 which the qu:ucmpry ni trogen alOOl und acetoxyl poop<; are held apan in a confonnation upplVximuti ng that of tlte eX lclllkd cOlIformallon of acetyl "hohn.e, Willi about 5 times more 1IC1I~'e Ihan accl)lcholln.e in 115 mu~.rnnk effect on dog blood prrssure and ....a~ a5 act" I.' IIll !lCCtylcholin.e In Its Oluscannie erft 00 the glll/lta pIg ileum. n The (+ )-mm.l' isomer "1Ill h)drolY-lcd by acet ykholin.estcra~ at a r:lle equml to the r.ue of hydrolySIS of acelylcholiroe , II was Inactive 11$ I nicotinic agom~t. In contrnsI, the (_)_mm.f 1\1.lIner Imd the mixed ()-ci.l' isomers wcre, re~]lCt;'t ivc l y, 11500 alld 1110.000 as active as llCetylcholin.e in muscarinic Ic~t~ on !;uiroea pig ileuOl and wcn:'; inaclll'c as nicotinic agoll1~t ~, Similarly. the IfWl!i dlax ,aj n:-lauon5/Jlp between the quaternary nitrogen and acc:to~yl group led to maJlimaJ muscanmc response: and nul.' of hydrolySIS by true ao::cl}kholllK'Stcnse in a scrie'\ of i<;omcnc

Qua'; Ii",

H,c~....a\-CH"'*o)~ ...,c L
/\ 0

~,

..

N~.

t/",

~,

. ,,,",
~o

t/",

I ,

.",

)~,

)~,

,-,

3-T~2_elg~lin.

Figu re2 - 11 Acl'lykOOloo confoHna hoos (ontt one each of the two POSSIble rrans arid cis ~ IS represented)

ChApler 2
3-trimcthylammonium-2-aceto~ydccalins.l~ These n:..~ulb

l'Ir\"JlrocMmJ('ul l'rop/!l"rl~:r

i1l HrI",,,,,, 10 HiollJflirtJ ACI"'''

35

rould ~ in terpreted as ei ther th:u acetyk:holmc was (!Cling In a IrurlS con fomtation at the musclU'inie I'tt'eptor and 1M)! acung in I ('isoid coofonnauon al the nicot inic rect'plor or that the nicotHlic !'e.'ponse: is hIgh ly senSltl 1'1.' 10 StCl'1C CffOC1S of substi luent . bemG u'iCd to orien t the molecule. This :11" proach In st udying the cho liocrglc I'tt'eptor i~ cOI'ert'd in more: det:1I1 in Chapll'T 17.

1210 I Sli mes nK)l't' Va.WCltn.rrictor act""ty Ihan (+ Icpme phrine, Th is i~ Ihc c l 3~sical rhree-point all achrnem modeL For cpiocphrilll', Inc benzenc ring. benl)'lic h)'drox)'l, and proIOIllited 3QllllC must ha\C the slCn:'OChemistry setn wilh the (-) l)OIIler to match up "" Ih lite hydrophobic or aroQlari ~ region, anionic "i ll', and a h),drogcn-bonding ccnter OIl tho! receptor. The (+) i'iOfJler {the mirror Image, will rlOl align properly on the replor.
hlbit ~

Optkallsomerism and Blologkal Activity

hiologlCal 111.'1I"'" CS for OJ'lim/ ucfll'/Iiu lias bc:cn of panlcu l:u- impo.- IIIflcc in lhe de l'e lopulCnl of lht'(ll"ie~ 011 the natun: or \lrug-r('l:eptor int... l1ICtion., ~Io~t cOllllncrcial dru gs an: 1l'l)'lt1Il1("\ric. rt'II'aniug that they C:tllItOl be divided into ~ym metncal halles. While () and I. IJ;Omel'< hal'e the same physical pmpcnle,. a large number of drugs are dtll.<lCl'('umrrir. meaning that they hal'c t..o or more a<;ymmctric cClUers. Diastereomers ha le different ph)5ieal properties. E,II.all1pl~'S Ife lhe dillSlen:omcrlo ephedrine and pscudocphedrioc. 1be fonner ha. a mch ing point of 79" and i" <;Qluble In .. otcr. whl.'rea.. pseUcJoephetJrillc', melt ing poin t illig<', and il i. only "pmingly sol uble in w:1Ier. Keep in rmnd lhal Il'('cptors .. 11l1r lI'i)'mmetric bco:1luo;e they are mostly proIein. nICalllng t~t they ure cOllStnlClcd from L-Ult linO acids. A ligand filii ng the bypothetical .... 'Cept or . hown in Figure 2-111 will hal'l;l 10 ha~c a pt)'>llivcly charged motel) in the UPflC'r !eft corrK'I' mil a h)'tIropbobic reglOll in the upper right , Therefore, one would pn:dict rh at optical i~ner.<l will also have different biologica l propc"ie.~. Well -known cxample" of this phcnom moo include (-}-hyQ!;C)'umioc, IIhkh c~hibi lS 15 to 20 bInI'S more mydriatic 1II(1l\';ty th:in (+ )-hyoscyamlne. and (-}-q>hedrioc. which 'OOIl'S ] urnes moOn: pressor acl i ~ ity lllan (+ )-ephedrine. 5 times 11101'1:: I're..~>-OI' IICti vil)' Ih:m (+)~phedri~. and 36 li ~ more pressor octi~i!y than I-}-pseudocphe<!rinc. All of ascorbiC acid's anl iscurbutic pr~1(nie.. reside in lhe (+) isomer. A postulated fit \(I cpi rtrphrinc'$ receptor can uplain ... h)' (-)-cpincplJrine exIn

The wic.li.'''P'l'ud occum:oce of thfference~

Eph.dr In. {Eryrhro con flg ur.rlonJ

P udo.ph.dr ln .
{rllt.o conllgufil / onJ

jD
AI ......

l
Pt

S..

:_)11)1
IIC'lIYe

(-)EPIQIIPf'ole -mclIe

,~

- '"

fl9ul't 2- 18 DIagram of a hypoth!tlca1 rtPlor SIte, II'Ig distances be~ei"i functIOnal groups.

Nt)'~~~ / ,,, '"

snow.

Frequcntly, the I',eneric nart'll' Ind lCale.<; a ~pecific stcJ'C()I~TIC1', fuarnples inclu!lc ICI'ocJopa.. !Ic,ll.troomphclamlllc. deAtrunlClhorphan. levu rni.w lc. dCXlltethylphenidme, and levothyrmine. Sornet irnes the dlfTcrcna: in pharmacologlu l acti vity betwccn SlCTeOIWlllCrlo i~ draulatic, 11te dc,ll.trorolatOl')' isonICI'< in the morphine senl'.~ all: cough SUpiJl'eSsants with less ri~l of subslullCe aoo'>t:. IIhCn:3~ Ihe Icv()f("3tUl)' ;sonlCI'< (Fig. 2- 19) contain lhe anal,e~il' 1II:1,\,lIy and 5;g/ll fi Can! risk of substance aoo'IC. Whi le lite d in;:<:tlOll of <>plical l'QIanon is 0pp0s"e \0 Ihal of tile morphine senes, de~lropro pox)'phcnc contains thc :lItalge.~ic aC l'i l)" and IIIC lel'f) ; j,()li rt'II'r conta,"~ ItntilUS5ivc acti vity, ]- llure 2- 19 contain~ U:lffiples or drup ..'nil lI'iymnICtriC' I carbons. Sollie we"" ongUlall ) Ilpproved as rncc:mic miltures, and latcr a speci fic iwmer wa, markeled with cl aims or'lavin,!; fewer ad"CrMl reacljon~ In patlcnts. An uarnple of the lan!:'r is lite local ancsthelic !elobup,,'acame. IIhieh ;s lhe S isomer of bt.ip"'OCainc. Both the H and S iSOnICI'lO have good locul allC..~thcliC Ilelh ll),. bul the N i'iOll1Cr may caust dt:pro~ion of the m),ocardi um ll':ll,hllg to decll:;a.o;ed cardiac outpul. block. hypotension . bradyc;mha, and \'enlrieular arrhythm ias. In contrast, the S i'ooter soo....! ~ cardiotoxic responses bur still I',ood locol anc,thclIC acli vit) . 8ciudopram IS lhe S isomcr of the antitkpw..anl cl tDloprum. There I~ some c\idence mat the H Isomer. IIhieh COIllalns lin le or the deSlrc<I -.elect!\ I' 'il'TOIOIII n retlptuk.c mh,bllion , conlnbutl'.~ more tO lhe IIcher;e reactions Ihan doc, lhe S i<>Orner. As dramallC as the llbo\'e e1i:lffip~ of stereoo;elec1J\ lI y may be. someti rt'll's II may rlOl be COIIlt-effectl\'e 10 resoll-e the drug int o its Siereoisomers. An cxamplc i~ the caJci~m

""lUI

l ....

".It.........n

'"-j'>-'"'-<~.!.....-

~ ""'"

./'''''

R,S.V.

f.
"

""

~.

;4

I
f"lgure 2- 19 wmpit's of drug
ster~

R.S-~

EKllab " ...

channel antagonist vernpamil. '" hich iIIustratcs .... hy it is dif

ficu!!

10

cOf1oC lud..~ thaI one isomer is superior

to

tile other.

S VC'rupamil is a ITI!lI'e acli-'c phIlrmaroiogiclll stereoisomer than R-vcrnpmnil. btu the former is ITlOf'e rapidly metaboli~.ed by Inc lir;\-pass effect. (first-pISS .den to orally 1Idrnini~tcml

IlIctabolil.w as lhey pass through the liver. Sec Chapter 4 .) S- and H.warfarin are mClaboli~w by IWO different cy tochrome !'-4SO iso.tymes.
Drugs that either inhibit or induce thesc en7ymes can signi fi -

drugs IIlal OJ\:

eXl~n"i\'ely

(IUlII)' affect

warfarin'~

anlit-oogulOlion activity.

8ttau <Cl of biotrnnsrormmions after the drug is adrnini$ tCrN. I' SOfIK'hJlIC':S maL.es linle dirrc!nICC '" helher a I1IC'('mic mhaun: or DOc isomer i~ udminblerod. The popular nonSII: roidaJ anti innammalo ry drug (NSAID) ibuprofen is sold as

the .... .lC('mic mi..uun:. The S enanllomcr OOI1lains the Mil innammatory IICtivity hy illhibiting cydooxygcnase. 1b: R isomer does hue Cl!ntrally octing MnaLgcsic activity. hut it is 00I1'"CftCd to the S form in vivo (Fig. 220). Ln addition to the fact that most rtteplln arc lIllymmetrk. then: are otlter rca.'i(ln~ why 51C1\."(IISOIncrs show different biological responses. Activc mt.nspoll mechanisms involl'e Ii.~ymmetric carrkT molecule$. "hich means thaltben: ...iIl be pn:fcrentilll hinding of one 51en:oisomcr ova- od\Cl1l. When differences in phy~kal propcnies exbt, the distribution of isomcB bctwCI!n body nuids and ti s.wes where Lhe n:cqlIln an: ~ated ...111 dIffer. The cnzymes responsible for drug met.abolism an: 1i.\)mITlCtrk. which means that biological half-lives will dirfer amung pos~ible ~lcrcoiilOtners

,.u.....

erg)' diogrurn is /K.wn in Figuo: 2-21. NOlie!! Ihal somc:: of lhi: minima we rocarl )' equi~aknt, anti it IS e:!lo)' to nKl\'C frum one mmimum to ~her. From enellY di~roms. It IS difficult 10 ansv"er the qUC'S1wn. 'A-hieh of the ligantl slow or modcr.alcl)' Iowronfoollallons filS onto the rtteptor?llul ql.lCSllon can be ans ....cm! partiall), b)' a~,,"mHig thaI lo....er energy con roonllliou~ arc more high '), populaled anti lhus more likel), to intcnK.1 Wi lh lhe n.Ceptor. Ne ~ertllekss, spe' cinc inlcructions like h)'drogen bond formalion anti dipoIe - dlpoic int.:rucllOllS ean affecl thc:: cllCflY levels of diffcrcm ronronnalions. The:refOfC. the bountl oonroonalioo 0( a drug is seldom lIS 11111 cst ellCfgy coofoonallon.
Nu"'~r ur """(unn,,r<

JOO )~.-( angle ;""O:l1""nl {fA!. 2-30)

1i........ :I'..

""M

Figure 2-20 MetCiboloc "'1t'fCOfl\/el"$lOn of R- and Solbu-

of the samc moIcnt 'c. llIl' lauer rnay be a very imporlam ,mabie bau'iC till: metabolite may actually be the actl\e
lIIOIeculc.

Citlc:ulated C_fonnatlons
It MIoukl now be obviOll~ that medicinal chemists must oiltiln an aa:Uf"~te uodcr.;tandmg of lOr :.eli'e conrorm~tion of the drug molecule:. OngHl;llIy. molecular lnookb .... ere a.JlIWUI:ttd frum lil~ ronmlnll'll II "anct)' of atoms of dlfferC11l 'lIlence mK! midmion Mate,. 1"hu,. thert woold be ear00rt1 ~ultuhle for cllmon-carbon 'Ingle. double. and triple bonds: cat1xm - u~)'gen boo(]s for alcohuls or etheN un(] the c:ubon)'1 nlOlct)': earbon- nitrogen ht)ll(\s for umlne~, urn.. icks. imine<c, anti nimlCS: aOO carbon' for three-. four-. fil e . UId Ia/lCT-mcmbeT ring,\. More t"()lnplete sets include II ,,"..n. tty of hetcrool0m~ loch_hng mtt"Ogen_ ox)'gen_ and ~ulfur in \"3rioo, Olj(]ation statt'..~. lllc"l: kit~ might be 1:1.,11 31K! )liek. Slick or will' only. or spacc n il mg. The lallcr conta ined attempl~ al Kali.'i ncalty \ isuall/ing the effecl of II larger alom .such as ~ulfur rcilitilc to the "nailer oxygen. The t1imnetetll of Ihc: atom~ in the<.e ~n<. are proportional to the van tier W~ t:tdn . usually COiIe.:lcU for olMap efTCC'ls. In cootra!.!. the lI'ire models u,wll) depICt accurnle inlra:.lomic tli.\.UIOCCl. bc:tll~"i:n atoms. A 'killed chemist u,ing lhcr.e ki ts lLSuall)' can obtain a reasonably u(:.;urnte thrce-!lill"ICII,;onal rr~malil)n . Thi' is parti!;ularl)' true if il is II rnodcf"Jtcly limpk: lTJCJk:culc .... Ith con~itlcrablc rigidit),. An extreme exunplc IS a <.temi(] .... ith thc:: rt'lat;l cl)' innuihle fu.-.cd-ring \)"<.tCm. In l"OllIr:N . molcntles .... ith Cl\;tl n, {"()II~i"'mg or "'''_ tnl atom~ can a,sume man)' ~hapc,. Yd. onl)' OIl(' ~hapc or ronfonnation can be expecled \0 lit onlo the r\.'Ccplor. The t\Unlbcr of ~"{Jnrnnncrs. can be c<.lilluue(] fmm Eljulltioll 230. Cakulu\m!! lhe glQ/klllllilUmJlllJ. ttlc lo .....est encr!!)' conformanon. can be adifr.euh clHnputlll ional problem. A"unle that tbc-rc art' Ihrt'\! carbon-carbon fm:ly rot.at;&ble ~"'gJe bonds thai arerolllted in HY' ;ncremenb. EquatIOn 230sIllICS dw thete an: 46.656 different conformations. A Iypical en -

There are three eommon '1wntitllti"e ..... ay~ to obtain est,mations of prefenrd molecular shapes mjuired for a goOO fit al .he receptor. The: first. IIhith is the oIde<.t anti eon,idt'"red ttlc mosl accumte, i\ x-m)' crySlallogrnph)'. When propt'"rly dooc . .... soIu tion down to a few ang)trom IInit s con be obmincd This pemlits un IICCUf"JIC mathenmtical description of tile molecule. pt"Ovl(]lng atomic Coordlllah!.~ in threc..(]i ITlcnslOrull sp;lCe that can be dra ..... n by using a chemica' gl"Dplllc~ Jl'I"Otnun. A o;c:riouS hmillltion of thiS 'echnl'lllC." IS tnc requirtment for a ean:fulI)' gro .... n ery<'lal. Some chemi cals ..... il1 not form crystals. Ot~ form crystal s .... ith mi:l:L-d synHl\Ctne~ . Neverthde\s. with the oc\\"er com putational techni(lue~. including high-speed computers, 1:trge d~tabase.~ of x-roy ery,tallographie d;\la are now available. 'These databa-"e~ can hesearched for structures. indudmg~bstructurts, sunilar 10 tn.: molecule of in.erest. Otpcndlng on how close i~ the match. II is ~,iblc 10 obIain II prell)' good idea of the low-cncrg)' confOl"IM, jon of lhe drug molL-cule . Thi s i~ a eornlllO" procOOurt for proteins arid nucle ic ncius after obta ining the amino aci(] anti nucleotide <;cquences ..... ,~ "vet)'. Obtainmg 1ilc.'!C ~ucneC"i is no\\" hugely an aulOmmOO proc~. There also i, the debate" thaI ask!; If the eonfoon3Uon

"r-- - - - - - - - - - - - - ,

"

I' j.
~,

,
,,~--_; ~,_--_.~"'---.. , ,~"'--c.....---co.~---c.. ~
Tor.Ion
Angle

figure 2- 2. Diagram !.hawing .he t'flI.'I'gy miOOlTl<I and mlOtma M twO stJ~tltuted Qlboos connected by a Single bond are rQloJ'f'(j 360" r~lIve to I!ach other

found In the crySlal repre'iCnl5 the conformation "seen" by the receptor. Fur ngod molecules. it probably is. TIle question is ,'C'f)' diffICUlt to ans~tr for flexJble molecules. A CQlllmon tcdmiql.lt b to detcnnme lhe crystal 5truc\ure of a protC1ll accurately and then Jf)('1i. the crystal in a nonaqueous !oOIulJOII ofthcdrug. Th" allows the drug molecules lodiffuse into the lIcti\e SIte. lbc re'IUlnng crystal IS reanalyzed IIsing difftrent techniqllCli. and the bound (!QIlfonnauon of the druB can be Iktermmed rapidly ~ilhou\ r\ning Incenlue prOlein. Often. tile 'olructure of II bound druB can be determined in a day or Rause of the dra~bad.s to ....... y cryslDllography. IWO purdycomputntional methods thai require only a koowledge of lhe molecular ,tructur~ arc used . 'The two approaches are lno",n as qUllllllm. m"h("';CJ and molecular mhanks. Both are b;J'ICd on as.~umptJoos that (u) a molecule's Ihreedimcnsional gl"Ometry i~ D fUllClion or the fort'Cll acting on the mola:ulc and (I tnc...: forces can be cxpressed by II SCt of cquauon~ thaI penaln 10 all nM.lleculcs. For the tnO!il part. boUt computauonal techmques ao;sume that the molecule is in an I~ated ~y'tcm. Solvation effects fmm water, which arc common to any biolollical ~y~tcll1. tcnd to be ignored, although this i~ ch~nging with Increased compulational polioa', CalculatJQfls oow can include limitcd numbers of wmer nlOkt:ule~, where the number t1cpends on lhe amoum of Blo ilable oomputer lillle. I ntere~lingly, many crystals yo",n for x-ray analySl~ can conlP in water in the eryqa l lanice. Uigh-re<;oluuon noclear maillCllc resonance (NMR) provides another means of obtaini ng the structures of macromolulc.\ and druj.~ in 'Klilltion. l1Ic:re lite fllnda,nental dlfferellCd bell.icen the quantum and molecular IllI.'Chanic~ approaches. They ilJusulIll: the dIlemma that can confront lhe mt:dicin:al chemisl. Quamum nw..~hanics is derived from ba~ic theoretical principles PI die DIOIniC lc\cl. l1Ic: model llsclf is exact. bul the equatiolls used in the lechnique arc only approxlln:llc. l1Ic: molecular propcnu.:s are derived from the ell-ctrunic ~truclure of the molecule. TIle assumption is made Ihm the distribulion of electroru .... ,thm a molC(;lI lc can be dcscnbcd by Dlinear su m of funcllon~ thaI I'Cp'senl an alomic orbilal. ( For carbon. thl'i w<.ItJld be $. p" p,. CIC.) Quamum mechanics is eonlpulD tion imcnsi\"c, wi th the ca1culmion lime for obtaining an !lpplQxinwe )Olulion increa5i ng by approximaldy N' limes. llhere N is the number of ~lICh functions. Umillhe advcm of IIIe hIgh-speed ~upen."OInlJlers, quantum mechanics in ils 11m''' form wa~ n:Mricted to MnaJl moll-cules. In other words, il '" as not proctlcal 10 oonduct a qUllJ11Um mechanical analy si'l of a drug molecule. To ma~e thi\ techmque more pnctical. si mplifying lechl1i'lue~ havc hccn tlevclnpcd. While the com pUling lime is Ikcre ..sed. the accur.IC) of the QtJtOOl1'lC is also lessened. In geoel";ll. usc of cakulallon~ of the quantum mechanics Iype III medici"'11 cllcmi~lry IS a method Ihal is nill ..";r;,,g lq hlJfllH'IJ. It is beIng us..'d by laborulories wim access 10 IlII"gcscale comp.almg. bul there is oonsldc:rnblc dcbale _boIIl its unilly bccau<,(' >l) many sunplifymg approximations must be made for larger moJecul e~. III oontl1l.'ot. IIlCdieinal chcmisL~ are embracinll molecular nwxhamcs. Thi~ approach l~ derived from cmpirical observanon~. In contra'it to quanlUm mechanlCli. lhe equalions in molecular mcchamcs halc exact SOlll IlOllS. AI the same lime. the par:unele .... thai arc used in thl'se equations are adjusted

1 ensure that the OUICome fits eXpC':nmenlol ohscr'alions. 0 In placc orthe fundamentol clecuolllc 511"OCIUre used inqunnlum fl1ech:mic~. molecuill/' mcchanie\ u<,('. a n1()(lc1 consisting of balls (the Qtoms) cunneclcd by SpWIJ:S (the bonds). l1Ic: lOCal ene'll' of a molecule consists of lhe sum of the followin g enerGY tcrnlS:
E;,. : f'I"""hln, and OO<I'IpI'"e'~i", or IN: bond!. (.""npl E-, Ix!.!!n, iOhwl a <;enlnol MOm E,: mutuon ab<>lJ\ boIid!; E,: Ian dcr Wut, ,nlel'Xliom

"".

F..'

~1trosIod1(" lnl~'1OM

Each atom i~ defined (paranloCierir.cd) in tenns of these cnergy tCrlll . What Ihi\ mean~ i.that Ihe validi ly of molecular mechanics dcpcnlh on the accuracy of the pamInetm/,D.. tion process. H''''or1call), saturalcd h)drocarbons havc proved casy 10 par.lmeten/c, follo~ed by <;elcclllc beteroluoms such as ether oll.)'gens and ami nc.~. U nsm ur~tcd ~y~tcms. includmg arumatlciLy. cau...cd problcm) becau<;e of the delocalilanon of the eleclrons. but Ihi~ !''fllS 10 halC been -.ohcd. Charllcd atom. such a.~ IIIe curbox)'l~tc anIon and protollutcd amine CHn pro'"c 10 be a real problem. pankularl y if the charGC " delocali/ed . Ne,cnhelcs!. molecular fllCchames 15 beIng used Increasmil ly hy nltdic,nal ehcmi<;(J; 10 gain a better undcrstandmg of the preferred conrormalion of druG 11I01!!<.1lIe~ and lhe macromolecules Ihal compose a recc:p:or TI1C oompultf prognul15 are readily avaIlable and run on relanld) l~penSI\'c, but powerful. dc"llop oompute",. In summary, quanlUm UloCchanics pllcmpt~ to model the pDS'llon or dislnbullon of the clc(;lroll~ or bonds. ~ hilt' fI100 lecular mechanICS allcmpl." 10 model the ~ltJOllS of the nucleI or atom~. Qu3ntUl11 mcchanlc' calculHtloos are u""" \:olllll1only 10 g~l1crute o r ,erify moll-cul:lr mcch:lnl\'"~ p.mtm elel).. Largcr Ml"OCtures can be lotudied by use of molecul:lf n1('(."hanics. and ",uh Mmulallon lechmques such as molecular dynamic.'" the behaVIor of drug, 10 solunon or elen iu passage Ihrough hi!aycr IlloCmbnlJlC~ can be st ud.ed. 11lc only lIoay to lest lhe ,alidity of lhe OUloonlC from cilher quanlum or molccullU' mechamcs caicuiallons IS to compare the calculated SUUClUre or propcny I'> lth actual t~ perimC:nlal data. Ob\ioll~l y. crystall{lgr~phic data provide a reliable mca\ure of the !lCCul1lCy of at leasl one of lilt 1011energy conronrlC'''. Sincc thai is nOl :l.ll'>ay$ fcaSlble, OIher phy~icDI chemIcal mea.~llrc nloClib are u!iCd for Conlp3riSOO ll1c'iC iJlC ludc comparing calcu lated Iibrational cllc'll ie ... heats of formouQfI. dipole momenl~. :lIod reJaUlc confOlTllllno nal encrgie~ '" itll mea.~ured \"aluc, When ~ul!~ are in consi"ent, lhe p:lrameter I alUC\ are adju~led. Thl~ readju~l' me.nt of the paranloCtcl"!> I' analo,>golls IU tile fragment approach for C'"Jlcul~tinll oct.anol/ll-mer ranillOn coclTicicnu;. lltc 'altlCs f{ll" lhe frugmenb and the IK'compan)lI1g oonn;lion faelor; an: delermined b)' cumpnring \."alcuIH\L'Il panllion coefficicnls with a large popul~lion or c.~pcrllllcnlall)" determIned panltion l'Oemcicnl'.

Three-DlnMlnslonal Quantlt.tl"e Stnldure-Activlty Relationships

WIth molccul3l' modehng bc<.'Ofl1101 more COIllmoo. ~ QSAR parn(hgm thalirndlllonally u<oed ph)'~icoc:hc:mlcal de..c:ripwl'S on :I Iwo-dimension:tl r"olecll ic call be lKIapted to

!lute-dimensional .~pace. Essentially. the method Tajuires l/IOIIIkdgc of the thrcc-dunenSlonaJ shape or lhe 1l1Okc1Jk. 1IIIkeIJ, lC('II1lIie Il1Odelin! of Inc molecule ,~ crucial, A referI'Dte (possibly the pmtot)'pe ulQk'(:u lej Qr 5hape is SC'1ted

Iglm'il "hich all OIlier molecules are COnlpared. The original IJIeli'lod called for o\erlllpping the 1e5\ lIIolecules With the ref~nce mokc1Jle IlIlll minll\lI'(n1g the c.brr('l\'1'IC('$ in on"l'lap Then dlstalM.~ were calculated between .rlmtar)' Iocaoonson the molecule. The..'iC di.lances were used ll$ ~ariables
QSi\R regnmlOn equlllioo" While overlapping rigid ring IY.\Imu; weh ~ letr",tC)'clines. <;lcroids. and penicillins ~ rel.h,clyeasy, ilUlbk molecules elm Pffi'c challenging_ UllmlllC the following hypolhelical molecule:. Dt-pendmg DI1 the lli/ of Ihe vmOllS H groups :uld the Iype of ~Iom n:prucnled by X, a family of compounds repn:\Cnled by Ihl~ "iOkculc could h.we a nmety of coofommuons. E,en when the confoml3uons might be "novl'n wllh reasonable cerlalnly. the ref~t1I.;c poinL~ crucial for OCl int)' must be idcOlir!Cil , l~ the ovcrlap involving thc tctrnhedml carbon impur-I.VU for lIl1ivlly'l Or should the rh'e-membered nng proVI!.k !be reftrera points? And .... luch ..... y should it be roIatetl'f Assumlni; thai H~ is 1111 impol1pm pari oflhe: phamtaeophore, r.hould the fivc-mcmben:d rinS be I'OIlIled so Ih~ 1 Nh is poinlc!d down or up? The<;c 3.Il: not trillal 'lue:5tions, and ~fuI3 1)-OSAR $tOOie., hal'c dcpeoded onjust hO .... lhe Inlt<;U~ltor po'>itHlllS the molecules rdauI"c to each other. Thm: arc: severol inSlance~ III .... hich ppplln:mly I'el)' similar ~ture~ have been shown 10 bioo 10 a given receptor in dlffcl\'nI onenlacion"
1/1

ef

R,

Then: are I l'ariclY of allorithlll~ fur mtasunng the tkg.n:e at ronfonnallooal and sha~ ~Imjhlfilic" locliiding molecular >hapc: InalY'I~ (MSA). I distance geonw::try, I~ and IlMllecul:tr ~imilarity matriccs.I ~,20 ~ l any of the algorithms usc: paph theor)., ill .... hich the bonds Ihal cooncCI the atOmS of I molecule ClIlI be tho\lght of a<, JXlths bet .. cell ~peciflC potms [)II themoleculc. Molecularconnectility IS acommonly used aprlocatlOO of Iroptltheory,2. l.I 8c!.ides comparing how .... ell :1 family "f IlMllulcs overlips "'nil I .... fcn:occ molecule. then: an: ~islicaled soft\fIJI\' packages thai determine the physicochemical pardmnm IOCliUed al specific distances from tilt surface of the molecule. An rumple of Ihi~ :tpproach i ~ comparutlvc lila-lwJlJr f .... ld analysi~ (CoM FA). This tl'Chni'llle is de.<;I:ribtd III mort' detail in Chapter 3,

Dablb; Fe Searching and Mining

Ai pointed out I\oo\e, receptor. >m belllg isolalcd and cloned. TIus means that it IS po!osiblc to tktennine their ",rues 1IRl> Ma;! an: protcin" ..... hlCh means detcmuning their JIlllOO acid scqucrx:c. This can be tlone clther by dcgr.iding lbt protein or by obtaining the nucleotide <;cquelll,.'e o r the lInIC1ural gt'ne coding for the receptor and U SIIII1the triplet

genetic rode 10 detamine the ammo add scqtJC~e. The p;u1s of!he ~or \/Iat bind the tlrug (ligand)ClIn be ddermllled by si te-directcd mutagelll:si~, 'Illis alters the nuclool.l!.k !Cquence at specific poi m~ 00 [he gcne and, therefore, changes spec ific amino aeitls. Also, leep in mind that nt!ll1yenzymes becunw:: n.:ecptOffl .... hen the goal is to alter their actililY. E.tamples of lhe: lauer include occtykhohnesleT"llSe, nK)O()o lI.llline oxidase. III V protca$C.'. n:nnin, ACE. and tetrnhy(ir(). folate red ucta .... The: start ing pollli is p dataoose of ChellllClll Structures, They nlay belong to large pharmaceullcal 01" agmchemical fimls that litcroll) havc s>"nthtsi;ted the compounds m !he databa.w and ha~e lhem "silling on the shel f," Allernallvely. Ihe tlaluba.'<C.' may be COIblruCted so Ihm >cveral diffcrent chemical das~s and Sub>l.HUC.'1l1 JXluerns an: represented, (Sec dl!CUSSIOli of isostcrbm in the ne)( t st(1.ioo.) TIle first Step is to colllert the trudlhonal 01" histoocal t .... o-dnTlCnstOnal molecule. inlo three-dImensional structum;; whose inlramolecular tliSlarx:c~ an: known. Keeping in mind the prott.k'nL~ of finding the "co.. ",,," oonflll'TfUlhon fOl" nC'lblc molecule, f'!.Iso:: hit. and misses might n:o;ult from the scarch. Nc~t, the dimen~!(IIl" of the active ,ite nl\l~1 be !.ktennincd. lde:llly, the receptor has been CrySI3I1l/.Ctl, and from the coor dinille", tile intrumolecular di'larx:es bet ......:en .... hat an: 1lSsUITlCd to be ley localiOllS III\: obtaincd.lf!he recep:orcannot be cry'ilallizcd, then: an: methods rOl" csti mating the: three dllllen)ional ~hoIpc: oosed 011 ~arching cry~tul1ogrJphic data ooscs 800 matching arnino acid sequence, .of proteins .... hose: tcrti11l)' SlruCture hn.o; been delcm.incd. Fortunately. the cry~al structures .of IItcrolly tho\lsands of prutems hale been detemuncd, and their S lIlICtures havc been MOred in the Brookhn,cll PrOlein Databank. It ,. 110..... known that proteins .... ith .imilar fuoctions have similar ammo acid 5CqUCIlCCS in vwioos n:glOn~ of the pn)lein TIlese s.equcnccs tcoo to 51MI.... the ~Ille shapes III terms of u he lix. parallel and 8ntip;lmllel ~-plclltcd forms, lurns in lhe chain. etc. U\ing thi, informauon plus molecular mcchallics JXlrmTlCtc~, lhe Wpe of the protein and the dimcn~ions .of !he acti\e site can be estimated, Fil1un: 2-18 contalllS the , igmficPnt componelllS of a hypotheucal acll"C Sile. Notice that touramioo acltl residues at posilMlliS 25, 73.102, alld 147 ha"c been identified us importalll ejtl~r for binding the lig.1nd to the sile or for the reccplOr' s intnnsic aclh'ity, Keep in nllnd that Figun: 2-18 is a t.... o-dimensioo.al n:~ntatlOll of a three-dIlTlCllsional image:. ~f~. the diSUUlCC' between amino acid rc.,iduc.~ lnuSltalc into accoum the fact that each rc.'sitluc: is ahovc Of belo .... tile planes of the other thn:c residues. For an ilnlflClal ligund to "dock:' or fit into IIw:: ~i te. six t11"'lUlCC!i must be considen:d: A., LY$- G lu: 8 . Glu - Phe: C, PIle - Set; J), Ser- Lys; E, GIII- Phe: and F. Ly~ - Phe. In reality, not all SIX distaocc~ may be important. In selCC1illg potential ligunds, c.1ndidate>l might include D Pll'il ti"cly charged residue (protooated anune). aromatic ring . hydmgell bond donor or acceptor (hydroxy. phenol, amine. ni tro). and hydrogen oond acceptor 01" a negath'ely charged residue (carb())lylate) that ..... ill inter.lCt with IIw:: partate. phcn)' lalanine, <;crine. and lysine residues, respccIIIely, A lemplatc IS conStructed containing the apptoj1ri~te 1l,"1dtJC. atllw:: proper distances with OOITtCt gcomctrb. BOO the chemical dntab3~ is searched for molecules thaI fit the tempi ute. A degrec of fit or match is obtained for each' 'h it ,' , Their biological re~pon.'l:o; lin: obtained, and the model for

a.,.

the receptor is funhcr refined. New. beuer-dcfincd ligands may be synthesil.ed. In add,hoo to the In\cr.atOflllC di5tllJlCeS. the chemical databases will contain imponant physicochemical valucs ioclud.ng panition coefficients. electronic tclTTlS. molar refractivlIy. pK.s, solubihtles, and ~teric values. Arrangements of atoms may be coded by molecular conll1ivity ()( omer topological descriptON. Thc result is II "flood of data" that requires interpretation. large amoo nls of data Sloroge. and rapid means of analysis. Compounds usually muSi fit within definoo limits Ihm estirnme nbsorption. distribution, metaboli~m, and f')lcretiOll (ADM E). Chemical databasc~ can contain hundIeds of thousands of lIIolecu l.:s thai could be suitable ligands f()( a receptor. But. 00 maner OOW good lhe. fi l i~ to the reccpior, the. ca ndidate molecule is of no use iflhc: absorp1;ion is poor 01' if the drug is f')lcreted tOO slowly from the body. An lUI.Ilysis of 2.24.5 drugs has led to a 'leI of "rulcs" called the: Lipinski Rule III Fi\'e.:un A candidate molecule i~ rrlO!'e lil:cly 10 have!XJOr absorpl:ion or penneabilily if
I . The tlIQll".'uJar
W~llltH u~~~b

SOO

lbe c~kuWocl OCUUlOU"'I..:r ~illon coeffICient uCdi ~ 3. 'l'IIen: ~ mon: Ilw1 S H-bond doooD ~Alih frN:U the sum 0(

2.

N- Ilgroups 4. There an: mon= tMn 10 Hbood acccptun C\pres!lC<l as the JIIm
O- H
~nd

sites. Robotic devices an: available for this testi ng. Based on Ihc: resu lts. the search fOl' viable strucl U~ is narrowed. and new oompoundUfuyn1hl:si:t.ed. The cri~ri.a (Of acth'ity will be based on structure and physicochemical values . QSAR models can be developed 10 aid in design ing !leW active ligands. Al temali\'ely, tbe ~arch may be: vinu.;tl. Agai n Slarting with the same Iype of datnbllSC and the dimensions of the active si le. the ability of the compounds in Ihc: d:mwasc \0 fi t (II' bind is estimated. 'fhr; vin ual re(:eptOr will include both its dimensions and physicochemical charac~ristic . Keepi ng in mi nd that the receptor is a protein. there will be hydrojcn bond IICeeptOf'S and donors herine, threonine. tyrosine), JXlI'ilively and neglUively charged side c~in.s (Iysitle. histidine, glutamic lICid, lI.~paf\ ic ocid). nonpolur or hy_ drophobK: &ide chains (leucine:. isoleucine. valine:. alanine), and induced dipoles (phenylalanine. tyrosine). The type of groups Ihat will be: attr,lCted or repulsed by the type of amino acid side chain is codal into the: chemical datab.ase. The: virtual sc.cc ning will lead todevclopmcnl ofa refined model for good binding. and the ~arch is repeated. When the mode l is conside red valid. it must be tested by lICtual screening in biological test systems and by synthesizing new compounds 10 test ilS validity.
.... 1 I '"
2

0( N and 0 alOITU

TIk! r.apid evaluation of large numbers of molecules b somctimes called high/hrouglrrml sr rt:",rirrK (Fig. 2-22). The SCl'fffling can be in \ilTO. oftcn measuring how well the teSied moiC"CUl($ bmd to clOllCd ~ptOf'S or en~yme Kth'e

The term iSQs/uism has been used widely 10 describe the ~Iection of structullIl compotlent5- lhe slenc. electronic. and solubility chancte:riSlics that make them imerchangeable in drugs ofthc $arrlC pharmacoIogkal dass. The concepl

ht _ ill " fro 1'd 1 " Jif....

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~

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.;

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Figure 2- 22 HIgh-throughput

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(vul vtd and changed sign llicanl l~ In the )~;ap, 'i"'-'C il~ mlnxlul1ioll by Langmuir in 1'.1 19. Lang1UJe ~king. ~Lalion Ihal W{)Ulti t'\pbin 5illuJ ariIn pby,..:a1 JlI'I.IPC'r1i" for non ' ''MlleTic moleculc~. delilltd 1,l(I$.lt'rt$ as compounds or groups uf atoms havina the \mit numt>l:r and IlT:Ingemcnl or electrons. .hal ""on .-otkI.1nc (i.t .. II<,.h the ~rnc 1 ch.1rge as .... ell as the 00al "me numbC'r of ekclrons) would possess similar physical prolpUtie<;. Forcxample. the rllolcculc~ N! and CO boll! ~ ...:" 1. lOla! clectron~ and no charge and snow ~l1nil:lr ph)'~i~I pruf)('nle~. Rda led C.lamp!c, dc..cribed by L:Jn!!lnu ir "m CO~. N~. N, . and NCO (Table 2-1 -1 ). .... 11" UICfl:;ncd undcr.lIandmg of the SlruclUn:s of mole1.1Ik<-, ~ emph:c;is has be<:n p'aced 011 rlie number of c1cetronl ,"'ohtd. bttuu'\C \arimions in hybridllhlioo during b.'OId fOOll;llion may lead to coosidcnable diffcR:na<i in the 1II~b. lengths. and poIhnllc~ of bonds fomJed by Dlom$ II'lth lheume number ofpcri[)heml C'1~lrons. E\'en the ~n~ may \':11')' Wldely in its structural and electronic charoc1tn\llC'> ",hen il form> pan of a di fferenl funcllonal group. 11wl. nilro,~n i~ pan of II plaU:Ir slru~'lure in the nitro group bill furrtllo lbc IIfIl'" of. p)'f1Im.(!a1Siruciure m amrnortia alld

""'If...

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Grou~

of alom~ Ih~t impan ,imilar physical

or chemical

a-

molecule btxauloC uf sindlarilic, m si1.1'. dce Il'IIIIC'ptil'lly. or Slcreochemlsuy are (lOw fM:l.jllcntly n:ferrcd (() b) tile gcr.eraJ lenl! of jw.tt'rC'. The early n:cognit iOTl Ihal tornI9t and Ihioph('uc "'C'Il.' alike in many of lheir propcnlC':'i IN III !/Ie term ""K ~quilYll~"' for the 'Io)'lcne group (- -CH",CII - ) alld divalent sulfur (- S-). Thi~ conccpt b.. Ictllll ~nl of thl' sulfur YIOm in thC' phC'nothi...1fIt rin~ ,yo;tem of 1f:lI1quil lliog agen" wilh the \'i nyleoc poop !II produce the dl bcnzodlW.I'pll1C cla~" of amidc:pre' , drup 1- O1.aptcr 14). 1l1c vinylcnc group III an aro.wac: nng ')"\Icm may be I"C'placed by other alom~ i_len c \oj 1IIlrur. loch as o~yg~'n (fu ran) Of NH (pynule): ho\\cI'cr. iII_h C,"l-.K aromalic cllarncter is 'lg.nilieam ly decreased. E.umpIr<I of ifoOSlfflC pail"J Ihal poo,sess sinular Stene ~nd rl1roni(- cOlllisurat iOl1~ arc the ca rlxnylu le (COO) lind wltooanmk (SO:NR ) iOl1ll. kelOile (C- O) and sulfone 10 S~O)groups. chlori<lc(CI land tri nuoromcthyl (CF}l JIWP'>. Dllalent etner (-O-J. sul lide (- S-l. amine 1- . /l;H -). and melh~ lene (-CH2- ) grou\b. although dis-

pruptrtic'\ tu I

simi lar electrooicall). an: suffICiently alike in tneir slene muure to be fn:quenlly ullen:lI~ngeable 1 (k~igning new 0 drug>. Cornpound~ nmy be altered by I<,O/Olc,;C replllCel1lent~ of Dt()m~ or groups. (j) de,clop analogues "'nh select biological dfccts or 10 act ali antagonists 10 normal metabohtes. Each ""ries of compouoos sho\\ing a ~p.!Ci lic biological effect must be oonsldcl'C'd sepa ....llcly. for thel"C' are no ,eneral rulc<l thai I'f"C'dICl whelher biological :JC!1\'ily will be iocl"C'ased or decreased_ Some eXDmpk~ of Ih" lyJX' follow . \Vh.cn n group I~ preloCnt in a part of a molecule '" ", hlch it may be invohed in an cssentlal inlC'nlCUOfl or nuy ,"nuence lhe reacllOllS o f neighbori ng group". i!iOSlCric replace ment )o()n}Ctimes produces analogues tlwt act as antDIlOTl lsl~. ThC' 6 -Nlb and 60 H !:fOUps appear 10 play C':'isc:nual role-; III lhe h)drogen-bondlllg IIlterucllOlls of oo.'<C pair.< during nucleic aCid repl lcmion in cells. The 5ub:ilitution of the ~ig nific30l ly weaker hydroi,'<'n-bonding l.'IIStern: 5ulfh)dryl group" l"C''iUlts in a partial blockage of Ihls mtC'meuon and a decl"C'a<.c III the nue of cellu lar ')' lIIhe~is. Si mllar!y , replacement of the h}"dro.yl group of ptCTU)"lglutamic acid {folic acid) by lhe IUmllO group lead.~ to aminoptcrio, a folnte amunelubohle. Addition of Ihe melhyl group 10 the p-amlnobcn1.()11IC nitrogen pnxIuct'd mcthotrelnle. which is used ,n eaJ1CX'f dlelnothempy, (or psorUIsis. and as an immullO"uflpn:~Sllnt in rheuillatoid a l"l hriti~. A5 a bener undcTliiwndi ng of lhe natllre of the intetaCliotis bctwC'C'n drug-mctabolillng m7}tnes :md biologICal rttcp' lors Oc\elops. <.election of tSO"tenc groups w>1h particular cleclrunic. so lubility, and ' teric propcrtiClO ~Id permit the ..... Iiollal pn:par.uion of drugs th:1I act II"II.'I"C' M'lcctl\ely. AI the san..... IilT\('. ~uIL' obtained by the ~y~lematic apphcaliOll uf the pri nc iple, or i"\OSterie replacement are aidmg in lhe undc~t:mdi n!!! 0( the' nalure of lhe<.c m:eptors.

SELECTED WEB PAGES

1l1c rICk! of drug dl:sign. particl,]arly lhose a.'q)C('ts that arc romputcr imen~ile, is iocfeasmgl) heing featu red on Web p;iges. Faculty and ~lUdenl.~ nt ight lind it i n'lrueti'e 1 search 0 lhe Web al regular intC'r..-als. Man y unh'e~ty cbc'mistl) departmeou ha,'c orsanrud Web pages thai provide exccllent linkages. Li,ted be low arc a smull number of repre;;cntall\'e siles Ihat fealure: drug de"ign Itlllages. Some hal'e excellent IlI uSl ....llions. 1l1c'IC li~tings should Jl()I be coosidcl"C'd any Iype of cn~n~nt by the aUlhor. edilors, Of pubh_her. lodecd. \OmC of the'SC' ~"cs rna} diSOll'JX'ar
hlipJ/w\\ w,noh.gII'/ ISc;on:h Icnru.; QSAR; molecular roodc:hnll hnpJ/W",'''' .plwma.C1h/.tll/lfS3I"/ hup"""'''''' $Cam.:oll.oom/l, nhJ"dofau II. hi nil h(lpJ/ .... ww. i hll>-.Fn:I.dcll~ lAG E.hlml h(lpJ/Www ... .o.>t .cduIenlllnnn&khc~hnnlmonle.hlmt
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TA.8L 2- 14 Commonly Used Al icyclic Chemical

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Tm .... _

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h upJ/qq>e .<;hem.' ndiall;l.tdul hupJ{ww.... lIm:ass.edulm ,crobiulra,moI/i JIdc, 2.hlm IItlpJ/w_ .wcblno.netI

REfERENCES I. en.... s.-"1l.

1868 -1 169

2'
A . and

r.-..

Upo..u. C.... I I'IIamIIrol T... KOI. MetlooJo 4423'. 2000 23 1.ip'....... C ... . Lorrebonk>.I'~ Dumo"Y. 1I W" .... ,,_y. P J Aohr

S<JC'

2j; I~I .

26. ....""" 1 J "'m. Chem. s...:. " 1:1 5'3. 1919

')no.o.l.. R"

.&6:.J. 1OO'

2 1'-"- C.. Uo. A_ ' " I""' ......... 0 uplo;Jn", QSAR; n)'lltup/l<>boo. 1iIc<",,"u<. and SIrrK C......."h. OC. "m..... ClIomocal Soc1eIy. 199~ .1. 11"'00:11. C . and Lien. Ii. J. J MN a.. ... IH~~ ,. 19J I. .. Deanltn. I. C . and~.!i. , J Pharm . P!I.......,.,... JI.S45P. 19"N ~. K"binyi. II.; Tb< bilinear 1IIOlIo1. In K...-~ar. 101 (cd .) QS ... R in o...i,n of II ........... Molocuica. II"",.~""" J R 1'rtI<I.. I<JS.I 6 K"bon~ I. II.: J. MN. Olen' 20;"23.19117, Fm:. S.M . ond Wil-. J w . J M .... 0.. ... . 7;)\1'. I _ S WII ...... K.. Ma,.1a _ M .. ..... t.llilnl).. M no....,., of 1'_ Wi...., 'd modd ... ,n"001;''''", tho ~la.....lnp bo:1WCftl .... chenu<:d Stn><'''''' .".J ""'p. In K"" ..... M ltd.). OS ... R '" Deol", of II..... I.." MoI<cuh J It. ......... 1911-1 9 K....,..o1.i. M.O. Hone- X lkif'fi..,.... A. J . w l l .....- . N l..: J 101 ..... Oarm 45:)210. lOOl. 10 VN.u><. ..... ..... DIJbI<I. M J Mnl. CIomo , "~21.w. 2002. I I. St .......... J. II<ilua". W E.. ..... J....... P C: C_let....u-J S1" ""'" 0..",;.." .sm..,.......... IlIOIaIicaI """"IOUL Ne.- Yort:._

W."" ........

SELECTEO READING ...Ilnh.&m, D (ed ). B....""'j Mrui<i",,1 0Inn0~f)' """ !>no, 0."''')1. 6<h
td. l'ow y".t.. W,ley I",,,,,,,,,.,,.,.. :!OO}.

... Iben .... Scltcli T""lc"y, J,h ed. New Y",~. Ch"l""""" 11.11. I~. n.,"" . P M (td.): M,McI>I..- S,milanty [n [>noa Oo;;,n Nf... yon.. Chap...... " H~II . 1m n.,.,I1."" J .... lIabboon. AT . (N).1: Topol"lIocaI 11I<Ik<-...... Rclawl o...:rip"'" ,. QS"R .... QSPR . ................m. Oanloo and 8~"".

..,1ocI"'''Y"

1Iaftt""'"

r ......... R_: ~dnol-",_lnN_ W T~ """'_ R. F (N).~ ...............>IO) UInry. nil 1. New Yon.. l:bc>'....

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''''

00.... 0

~.

(ed.t. "..".... ....c

~ I)o ~.

leM. IfICI UK.

Wi le)''' Son 1919 12, 8.", ... It . """ " " ' -. s , a..m . "'1' N .., J" 23. I9%. I J Gool<>oI. I~ M .. lIomu. It W .. l).>oon. W J ., I I J 101 .....

o.cm. J7;

IlU 1994
14 8 l kn, II. It., J '"","n. Sci. 5LJ47. 1%4,

I' ChiQu. C Y.. Loo,. I P.. C."""". J G., .nd A"""""". P O. J ~"'. up Tb<. 166.2.-13. 196'J 16 Sm' _ _ E.. Nd.... . IN . o.y. I .. ..... 1.aI'idu>. J J Mod. a.. .... 9 458 . 1966. IJ Hopfi..,.,. . .... 1.. ..... II.'.... II J _ ..... Mape ....,.....: I fQm'lal '''''' "' ..............y ......i ............ "" I ou"""molarily In~.

It..bdI.C . _u.o .... ~:..pIonooJQS ... R. ..... 1 P,';1 ..... al .... ~ tMOlOb in 0.._>10) - ' II.....,. Waoht=aI"D. lX'. ....... _CIotmo cal SociC1y. 199' Ko"",li"l 8 0;- . J. ... BooJockaI ",--,;vo'Y and,~ 1InICW",. 1.0 N.., ... W T.. RoUn. R. I' (C1I>,~ ","",-hrmlW)' UInry ..... 2. New y",1 . 1!J.... In-. 1<n7. K.... I~ 8 .. ....... Hall. L H.: M....... 1ar S""',"~ o.:ocripli,,'" lhe F........"..,. p"I"lIkal S,.... N.... yon.. Anolrmic Pteu, 1999. \.ellCh ..... It.: Molocul .. MO<I<'I" I'I'ondpln ..... "'PII"""'''''''. F'<I<'A. En,. 100000 1A>n'","" 199(> Leo. ..... I~h. C.. and IIotLrnan. O. E>.rfun ... OS",R ...... 1. Itydroplloboo. EIf,c"""ic. ond St.eric" C............ w........... lX'. ............
0..",1...[ s...:1C1y. 1995. M&'IiIl, Y C. ~ ............ de!.ip. In GAl.......... G (N.~ Modic_ R....d ...,. B. /Ikw Y<:&1<. OdJ.er . 1m M"""hltf. I!. . .... Wondlerfddl. Ii. lods.). TInIIh;ft Mo:dK1ut ctonao.try 1kf1-. VOl """' .......... ,917. 01-. E. C~ and 0In1olDlJenea. R. E.o CoiI4"le' _....a dno. dooi.,.. II C""'. W,,~. M J (od.). ACSS,,.,.....,um s... ......... 112. w.......... lX'. A"",""" Chtminol SociC1y. 1919 11'4111.... K _ C ____. C. J~ M<>It<-uI .. M<ctoI/Ib """... Ootmt<try s.","",oo. C.... 1997 S,I,'""""". R. II Tb< CJori""'" CI1Crniwy <A """ OtNp and Ono, J\cb(JI,

DrIll 0Qi....... .kIi1a. C .... , ..............1 U",.,, ,,,,ty line. 2000

II Sn......... S" Ib.. hw ....... W w " II......,.. to! P_ ..... C," c. 0 M Tlwft-d"..,. ".... ,....."'" 1nOIIr1"" ""'... eli......., ""''''') - ' V""" ... poI)nydra, In K"""'" . II led.) JO.QS ... R '" Onos 0.:..",: "Il1r<Ify. MetIIOOs ..... A,opIi<"'_ \..ndeft. no..~. ESCOM.
'9 Good, A C~ I'co<ncloo. S I.. ..... Ih",*"". W 0 J Mc:d. Chcm. 36. 2929. I\I9J, 20, 1M"' . ... C" and Ih<1wII:<. W 0 [>no, Inf 1. 30;371. 19')06. 11, K..... 1 II~ and 11011 . L II MoIc<ut .. C_holly In Chemi-'lry and _ W .... rcb, New Yort:. Mldemic 1'rI: .... 1916. 22. Kin-. L II .. and 1t.1I. L.. II , M""u~ C"""""I,,i'y In S,,,,,,,,,,,,,,..;. lly ... owP'<. New y",k. II:<. Iw<h SlO>JieoI I'Iu, ( W'~l. 2.1 Ruoctw; 0: In(..".."", tbcUfn;' I........ ,..,. o..nc..".,..ion <A o..moaol SIno::1U<n. 1'01' Y<:&1<. R.... _h Suod ... I'rI:M (Wiltyl. 1983

M ..... MlgJOn. G M . ( ....). C_.pI>"''''~ S ........). I'ko.' Y<d. _ Wile)' A 1990

s.-.

. . """"""...

""

Dru,

,98().

New Y<d, A<"Id<mk 1'feJ'. 1992Topli ... I. 0 .; Qu:ultll.. l.., Structure- ... ",.. ily R.I...... ~IP> <A 1>nI,. Modie"..10Inn01-lf)' .... SC1'io:> <A M"...'lnophlo ...,. III Nf... Y..... _ Ikmlo Pm .. 1983. Y........ D.; C"""f""-"'ionoI Qa<""W)' .... Pnortocal Guolk fur """'~ .. T ...IInHj.... M~ ROIl W.. kI Pltbk" ... New Y..... W,Ie)'. I.... rxw

"'"

Combinatorial Chemistry
DOUGLAS R. HENRY
11r lenn ptrroJ'K'" shift i\ an u\crufoCd 0fI(', but in the mld198()o, II tl\lC.' paroldigrn -JurI occurred In Iltc y,a) IICY, drug~ 11ft s}",he~iled mid :<ei"l:cllcd for IICtivil y. !'rior to thell. m()l;l drug oompoonds were synthc:,iled in milligram quantil~ 10 I JNilll onc-at-a-time fashion. After . ynthesis, lhe compound ...as scnt to a blOlugt'>l. y,ho le<;ted it ID St,'eral in \1110 assa)"~ and returned the rt'Stl1t$ 10 the chemisl. Bn.-.ed l1li the assay results. lhe ('henl i,1 would apply some: MnIClUI\'-acti\tlY rdntion~hip (SAR) or u<,t chemical intuition [I) dttide ... Igt cl\;lnges to ma~c in fulure veniOlI~ of the IIIOkcuJc to impftJ\'e IICti, il) . U~lng thl' ilel1lll\"e PrusS. a chemISt wou ld be ablc 10 ,)'nthe~i/.e OIily a haooful of >lruclurn per wec~. Since Ihe yield of m.llrketabl e drug, fr"()ln rompoorKb s) mltc.'iued and tested;, OIlly Ubool I in 10,000, tIlem.ltO.5OCf:e!;S ha., been a loog aOOC\pcnM'tOOt:, la~ml! 610 12 )..ars and ~"QSting S500 to S800 million per drog. In lite mid- 1980s, thi~ approac-h to dnlg ~) nl hesi~ ch:mg~"(1 tiramalically y, itlt the inlrodu('tion of comhirl;lturia! chemi, 1t).11r drug d,sco\cry proecs.' became a hrghly {1t"'llItl oot, In y, hich hundred~ or c. en thousands o f StnICtUre,\ could br 1)lllhcsil.ed at one t;nIC. Imereslingly. biologists had for 'lOme lime been using high-throughput screening (lITS) tu paform wir in \'itro :l>say~. ronning 1l."!>IIy\ in 96y,ell mitrnIliCT platt'S and even using laboratory robotic::. for pi. perunl and anaJ)sis. 1lte bottleneck had heI.."OfllC lite "ynt!te~ of lite compounds to le,l. Chemists reahl.ed thaI symhe-.es could abo be condUCted by u,inj; n parJ Ile! npprooch. The: tmn rontbinil/(lrilll cht'mi./n y,os coined to n:fer to the paralkl,UI... wion of all po!>~lblc combinmimu of substilucnLS orrompotlCnlS in a S)nthelK: expcrimcm. Whereas !he yield from.!Ielia1synthe;is is a Si ngle compound. lhe yield from 3 combnt3torial synthesis i~ II chemica! IilJmry. Figure 3-1 Ibows 11'."0 common types of ~ltcrnical libraries-a st'orrie Wnry. based 011 Jingle pat""l'nt or IoC<lffuld "tfUCIUn: and mul tlrtr wbstiluc:ms or residue ... and a mirlU,.,.1 ibr.lry, comainlng luicly of ~lnlct un: l )"pc~. TIll.' 1 00ul number uf SlruCltJn: , in .library iseitlterthe prodUCl oflhe \"an<Itl' numbeo; of SUbsl;l1mb (for a IClICric library) or tlte 100al number of qlUl'lUI"e; ... mlXIlR. Thc: goal of oo,-"binalorial chemistry I, IU be abl .. IDb)nthesi7.t, purify. chemically anal)""(.'. and biologic:llly 1$ ~ll the stnlClUll'S in Ihe librury. using," few synthetk e~ pmmenlS as po.Slble. Thi, ehllplcrdcso.:ribcs hoy, ~"()IT1blnalo rW dlemisuy and IITS are bemg used in drug de$lgn and disMfy to find IICY, lead structure. in II shorter time.

In 1963. Merrifield '"troduced 11M: efficient s}'mi'lesis of JX"plides on 11 .<;olid su,lJlOI1 or resin (fig. 3-2).' Th, < made the r:Jpid. aUlOrnulcd syrll hc:si, of I'cl'tidc:~ Jl'O"~iblc. lind carrlol'd Merrifield a Nobel ''rile: in 1984. A ley fcatl,lre of his Ilf'PI'OOCh IS the allachmcTlI of a gro'o'mg pepl,de chain 1o an Incrt poIyIDI. bead. u.ually about I 00 ~m In diameter. ...
composed of polysl )Irene c"",~- I onked wilh uil'i nyl bcn~.('!lC . Such beads were originally dc~igncd for si7.c c~<;lusion throrn:uoglllphy . 'J'he beads can be imn1o:ri<.'d in solvents. washed. heatt'd. CIC., and .. hen the s) mhes,~ is complete:. the beads can be IiIlcml from soiutloo, :md tnc rcacuon prodUC1~ can be cleaved from the polymer. Ylclding pure products, A Ilungan:lJl chl!mi'l. Arp;K1 Furka. realilclll h31

U~,

Mcmfield" , approach could be c:<.ICndcd 1 allow 11M: ~)Ilthe 0 ". of all po!islble oornbinauon~ of a gilen!iel of amll10 acids
in u limited number of sleps. He accomplished rJus by srlil' ling and rCIIII~ ing 1'011;011' of Ihe peplide-boumJ resi n at each ~ICp in the ~ynthe~i~ (Fig. 3-3). HIS Ue~riplion of 1m- usc of combinatorial chc nllstry 10 synlhrsi/.e polypeptIdes lIP"" pe~ In the Ilungarian palenl liternlult in 1982. ApPII"~nlly. II is the first liternlurc reference to a combinmonw chcn lhlry cl<perimenl. 1 As seen in Figure 3-3. the advanlage of ,pln-and-null synIIte~i5 is IMt all 27 l ripeplick~ can be synthesized in just thret' Qepli. In~tead of 27 ~leps. The dio;ad\"l1ntoge of this approaclt is Ihal in the cnd. one oblaln ~ Ihn:e m/.rtures of bends wilh tripeptides allJIChcd. 11I1ltcr than the pure oom.. pounds thcmsehcs. If activity is detected in one of Lite mi .... lurc$. it beooInes ne~ry 10 So ~k and re~ynlhc:si/.e.)()l"nc or all of the structu~ in thai rniXlult. to sec ... hieh tripeptide i~ re\potlSiblc for the acti~ity. A~ y,e shnl! see, vanoo~ methods for /(I99/IIK pnd dt!<:o/l\vlllliog combinntoriaJ hbrnries lta\'C been devi.'oCC.l thaI rroOCt or e linu nate lhe need for resynlht!;is. The fir:sl comblllOitorial Clltrl1l5try t~perinltnts y,cre applied to lhe siudy of ..pitofH's-thc .~ho'" loeljUCrtttS of nrnioo ocids ~Isible for antibody recognition and binding 10 proteins. Early l"CSCarclrrs used !iOIid-phase resin bead~ in ,"ral~. microtlter plates. columns. and porous plastic nlCsh 'tea bags." They also used brush-like arr~ys of plastic p,ns, 8t Ihe ends of which compound~ could be synlh""ii1.ed. Other medlu lhnt have bt'cn used include paper and poIynlCr ~ItecUi alld gl;1S.S chIps-basically anything thlll can immobillt.c a MI"IICIUre for the J)\111lOSC of t."\posi ng it to reagents and soIvcnt.~ (Fig. 3-4). I'cplid..'s. of COIlrse. makt poor oro! drug molcculc\ becau<,t they hydrolYlt: in the llCidity of the stomach. A~ comblllatorial melhods were applied 10 the synthesis of drugs. a need do:\'elupcd for nIC\hods of gCfk.'raling small (mo!t('tJlar weight. <500) nonpcptille molccules as potcnlial drug leild.~, Among the fiN alternali\'CS thai wen: studied were Chiron's 'pcptoids" - rnukocu!es in ... hich the V'oIriatiOll u.."Cun in

HOW IT BEGAN: PEPTIDES AND OTHER UNEAR STRUCTURES

Combmalonal Chel11iSlT) wa, fil1il applied 10 tlte syll1hc:,is Ilf pqxides. since II convcnient method for the DUlOmmoo .)l"IIIau of tlte$e compounds wa.~ already in wide'pread

A,

H. ' -011

0-0

N
N

FI, .. H. CH3. CH2CHl, CH2CH CH2. CH2Ph

R'

>

O'v -- N
N
N

FkJull! 3- 1 GeMfK (_, and mlKtuft' (b) ~tonal tlbranes. The SIZe of the

geneoc ~bfaly IS the product 01 the vanOU5 numbers of subst'tuenlS (here. 2 )( 2 x )( 5, Of SO) The $Ill! of tlw multure library IS wmply the total nurnbef of structllfes

"' eocNH~OH
NH,
0
OCC

"
N Y - - NHOOC

Figure 3- 2 Mernfil:>ld synthe~ on a poI',mer bead SI.Ipport. The gfowong peplJde dlilln l OIl Ihed toa polymer loI!ppOr1, usually 11'1 the form 01 INII bwls. The ne)(l iIITIIIlO aCId (beanng R2) IS an<l&oed, and Its protectoog group (BOC) IS .ema'Ed WIth a<:1i:VbMe treatment. 8OC, butyloxycbonyl, DeC. d>eydohexyl-

R.

R.

N"
R. 0

_ _, _
~R~e~~.~.~.

urbod"m,de

O-M
0-8A
~,

0-""

0 "

0-'" O-ec
-CC

S91"rt" Mill

0-'"

OMe

O-Me

0=
0-""
0-8C'

0-"" 0"" 0-'" 0-"'"

0-'"

0=

0-.... 0-"'"

0=
O-ABC 0-B8C 0-CeC

0-""

O -cea OACe

0-=

0=

0 -00'
O ~,

0=

o-ecc

figure 3-3 Splth1ndmlll synthe!.ts of "'peptJdes In the f"st st~. ill tilt beads on a IJM!1l tonlOillFlf'f have a SIngle moroopepllde These afl! oIIIlI'IIXfd togetM, !hen spilt Wlto tilret' abquots and re-bealed. iutachlng it sond ptpt!de. Allet' JUSt one ITlOfI! step, ilII27 powbk- mmblnallOns wst, ~NCI among the thf~ COI'Ita,1'IefS

C Iuol"ler J Cumbj,,"'vrwl Cht-mis,I'I'

,.5

+-,--
b

...... ,,' . ........... :'. ........ ".......,".: ....... ,'. :., ' .'........ :. ....... ,
It
tt
If'

Figure ] _4 Vanous itpproaoches to ImmobiliZIng and 5eP'I1IIung ctH!lrucal compounds dUring combmd to1131 synthesrs ~ beeo'I de'<'S!d ... Tea bag synthesis b . PinS and "1oI1ypop$" Co Dots on cellulose d . Splual MlolyS 01'1 tIlocroouJ!!'

l.iOIu:ular II ('fhl. < 5)) lite anachmcnt \0 the amide nitro~ (Fig. 3-5). Allllough these Slructure~ could pulcnliully r\Jre ,ide chain functionol groups in po$ltions s imilar to diose on !he COll1!,~pon.1ing peptides. [hoe)' differ sigmficantly Illlhallney lark peptide hydrOEcn bond~ und chlrlll centeno 1'IIr) ab;o Mo\\ 'l"IOI'C rotational f1exibihty lh:ln the COI'J'e'f'OIIdin~ peptides. ~Ince the peploid amide bonds show less cklubIebond cll:l..ctcr than those in pePl i~. ~hllrrdcmon IIIJlCd ~ Slab!!,l), or pC'ptoids 10 11 numbl'r of enzymes. ~Iud.m! cll}moIrypsm. rapai n. pepsin. and carbo:o.ypepli. W:.e A.$ 7..oc l mnan 1:1Ill. dcmonslmloo in 11)9.111101 bi ologictlly achW pcploids coo ld be obtained by u~lI1g C0ll1b111;110n.aI clJemilry. l ie u..w 24 monomers to gencnlle tnpeploids. tICb 0( ",!tieh had one hydro:o.ylic. 0l"Il: aromalic. and one dI,"mC SlJe cham. Limning lhe composilion of the pcploids

in tll;s way limited the 100ni nllmber of COl1lpound~ 1 Just 0 204. Ne~erthde!>S. sevel1l.lllOIclit ligands wen: found, IIIclud ing a nOl1tJmolar a-ad renergic inhibitor (Fig. 3-63) and a si mililrly ocl;' e #-Opiale receptor ligand (Fig. 3-6b).~ BeC;lU...e of tile ca>C' of symhc:si ~, other cl~ of Imear chain

AoV____

/~JNr-..
o

I",

1
Pap..".

'"
I",

,,'"

... "'"
fogure 3-5 Compar!$OO of peptode and peplOld

:ond

Figure 3- 6 BIOlogICally iIC1Ne pe-pt~ Compound . IS an t\'adrenefglC Inh,iJ<lor. whole (ompour"\d b IS a ~-opoate fE'(eptor hgand.

" '"

NHFmoc:

.,-

....

.~,1OO 1

,.,

<0

"-

.,

""
0

,- "

<0

6
Syfllh~

"-

.,

.... -

.,
0
9 nUOlenyimetho~rbonyi.

6
a

f1gure ] - 7

of 1,4bel"llodtilzeptne5 00 a solid wpport. Fmoc,

common organ~ protect ing group

molecules haH~ been m\"eMiguied. lbe~ include oligonucle otides (DNA und RNA). oligooll.'3S. and carbohydrates.

aloohol-drlerrenl. u,erinc rclaxanl , amineoplastic. antioronvllisam. antiulcC'ralivt. analgesic. anlianhritic, :md sedath'e structures, among many ochers. For this 1'ea.'iOII, the demonstration of the solid phase ~)'mhesi5 of these structures virl\Ially opcl1('d the door 10 the usc of combin:l.Iorial chemistry in drug diSC(lvery. [n the ~ade since the fil'lil dl1lg molecules lI'ere getler

ORUGUKE MOLECULES
lbc real advance in combinatorial chemistry for drug di scov. cry pu~ Wll..~ the introduction of synthet ic methodology to yield In.oedrug hke S UUCIUIl.'S. Bunin IlIld Ellman1 in 1992 demonslrnted the synthesis of 1.4-ben1.ooia;<.epine com
pounds. using thra: compooenls; a Zaminolxnzopheoone. a protecled amifl(l add. and :an alkyl halide (Fig. J.7). AI though \toe nonnull y think of bcn;wdia;<.epinc~ as muscle 11." launts ami trnnquihzcrs. a search for drull structures con toining the bcnl.OOiulCpine sca lTo ld rl:tums anti virnl,

aled by usi ng combinatori al chemistry. solidp/la.;e s)"nthc -

Mve been discov~ for most oommon cluses of drug SlfUCture. Some examples of tncsc are sho ..... n in Figure )8. Ofne<:e;.sily. the reaction'! thMcan be perfOl'Tlled in cumbina5e5

torial chemistry are simpler lnan many reactions that _chern-

is\ L1sing standard synthetic pnxedures can ~rfonn. E,lIreniC! of lemper:uure and pressure. the use of highly cuustic reagents. illCrt ulmospiltres. and multistep reactions ZU't gen

,.,

,.,

"H"---\N ,.,JY"y'
o

0';,
"

"'.,

oo~
., N

.,

"

.,
fIgure 1- 8 &ampIes of drug-lol::e Slructurl'S thaI CMl be generltfCi by soldphils. synthfsos. (SlruclUfl'S dlilWfl from Balkenhohl, f, et al.: ComblrnllOfiai synlhesis 01small organ" moIfcu,". A.ngew. Chl'm Inl. Ed . Engl. 3S 2288 - 2337 .

~y(~o
a=(
I'll

A ,o

"'

Al -

"'

"'"

Chaplu

Co...o",<II" ,itli CMminry

47

mil)' I'~

In

c<Jmbin:llorial chemistry. Also, the relIC'

IIIc:mal i~c

Ocher clas.o;cs of IherapeulkaJly impmanl compwllds that

have been symhesized successfully by using solid -phase combinatorial chemi~lry include carbohydrates :md nalurul prodllCU,9 Polysacclwic.ies an: impCIfUnt for various tatOOhydrate - protein inlef3Ction.~. Carbohydrate: antibiotics. m eluding vancomycin and unllnoglycosides. have been the targets of CQrnbi nHlonaJ chemistry. ~~ well as complex oIigO$llCClulrides like the OI1C! s/1()wn in Figure 39.'0 /It. van

products. The yield ofreac bOltS in combinalOriaJ chemistry should be lIigh (1IO'l> or _I, but thl tan often be achieved by using :til UCCSli of It...... and thc:n ...ashing the beads anerwan:l 10 remove dle UctSi. An Important recent advlUlCe in combilllliorial rn.:m,IIry is the usc )f microwave heating in place of Sian dard heating mcthods.bIlmlhould not yield

""
b
0 0
O~

,
0

1 \ .
I
0 0O'~

"~~D , ,
o
H

",
,

1.,A "'OH
0

"

~L,

, O0 =<
o

OM

0 0

"

rlgure 3-9 Carbohydrate and Nltural product synthetIC targets . . BaI,J~lIma /XirpurfNJ lectin lIgand analogJe5. b . Vitamin OJ analogue-s c. Erythrornyon analogues. d . NlcarzlI10statlil al'l tKan<er agents. e . G.tIal'l t/'laminl! choIinII!sterase Inlub<lors.. In most cases. the mclecuies are Hsernbied by connecting \ilrge wbfriJgmenlS III a small f\\.IfI1ber 01 synthetIC steps rather than by attemptIng total syn~ F moc. 9-

.,

"

IluorenyImethoxycarbonyt. a common organoe protecting group.

ety of natural products nrc being studied. main ly in the ~a.~ of infeclious disot'a."C and cancer but ulso as scaffolds for many OIher Ihcru[)CUlic cmcgorics. Fi gu ~ 39 shows e~ am pies of nalUral products Ihal have been smdicd, including

viUllnin D anaIO!lUC$, eryulIumycin.1 il.e IInlibiotics, antican cer ncocar(llKlStalins.aod gahuuhamHle. a choli nesterase In '
hibi tor. 11

SUPPORTS AND LINKERS

Most w lid qulc combinatorial chc mi~try is condUCTed by u~ing polymer beads 10 to 150 /A1lI in dlameler. These beads

s ... elltn organic whenls. allOWi ng lhe free diffusion o f w j \ CUl and reagent into lhe inlerior of the bclld atld gf\'al ly C\pandlng lite a.allable :m:3 for the ;altachnlCnl of product. The polymer,; arc illtn. except for lhe fUllCtional g.-HUllS 1 0 ... hk h the lTlolcculcs an:: alloched. In gerle1'a1. lhe oompound~ 1 be synthcsi7.ed are IlOI attach,:d directly 1 lhe polymer 0 0 molecules. They an:: uMlaUy ~lIached usinS a " Iml.er" moiety that (IIJ mabb allJoChmcnl in II way th3\ can be ca~II y n:.er.;! without dl.'Ml"O)"ong the nlQlecule that I~ being synthesized aod fb) allow~ some room for rotaliooal freedom of the nlolecull's at1!IChed In lho.' polymer. Somelllnc~. the molL-cules attached 10 the polymer an: used directly a~ sub~lrulC.~ in in vilro a~sa)~ wilhuut removing Ihem fmm lhe

~, .

o---{

1'1"0 TFA

HM SA rwin (pep!>de pooaucu)

0-'-. H,

t'1"o TFA

f igu re 3-10 . Common hn~er tl,l!"l(toonal grwps and the reagents tha t ck!_ the product Note that dlft l'fentlmk.ers PfCI'/Ide ~tteref1t~ ,ng and sterl( freedom be!WE'er1 the product and the support HF. hydroftuooc acid; TFA. tnflooro-

acetoc acid


ChapCn" j

C"",b",,,ro-na/ C/t,,,,,,tn

49

I,

poipncr. In wch c:t...:s. If the molccule~ :are 100 lightly packed 011 lhoe pol)n1cr. the cnl.yrne nlokculc~ canlKll gain ~! 10 the: 'ub<;lr~ICS. A sinu).1/" siluallon e. Sl$ for III.OCe5S d by 'iOnIC of tile rcagcnl~ and crualy~15 used to sYl1lhe~i.re Ihe mokcules.. III gcnerd!. nbolU I mmol uf hn~cr i~ Oi!acl\cd PI'" gram uf :.olid ~upport. The types of \Olid ~upporu that IIC u..ru ioclu.Jc

described aoo'e. solulion-phao;c combi natorml chenl1s-try

often leads to a mi~ture llf products. ImagiRl' reacl1l1g 11 sel of 10 amines with 10 acid chlol"ldcs. all 111 one fla,~. and wilh the reactants and oontlitimls dwsen so lhat no rcactilln of amiRl's wilh amities llr ehloflOcs "'ith chloride, oceun-. ooly reactions between 8mlrICS and chlorides. The rc:.ult woold be a millturc of 100 am id;.$, ooe ((If each pol'..,ble oombinal1oo of amine and acid chloride. The res.ulllng mlA lure (:()\lId lhe'n be tesled (Of achlUy. under lhe a~S\lmplion lhat lhe inacuve amlUes dId ROt Interfere wIth blndmS o( acllVC mQleculcs (ROI alwly~ a valid assumpllon). If aclll'lIy is found. smaller subsets llf amllles and chl()fit\cs clin be teJIled 10 cven tually fi nd the Mruclurc(_) resl'tJ1\~ible fOf OC ' tivity . Researchcn have gone Olle "ICP funhcr by reacling multi ple kiro(b of re;i(,.1llJ1lS together 10 produce ~ne r.llhcr amar.mg mixtures. Figure 3- 11 s.how\ an example Q( a foor-componenl Ugi reaction that yields. afler appropnale fUl1her trunsfonnatioo of the intermediate product. I mUlure of carboxylic acids. estCl"S and thioest~. pyn-oles. IA-bennxha7.epine-2,S-diooes. llJId cI'cn a 11lO11OS3CCharKk. I' De1.plle the diversity of the cht:mistry. Ihc yields llfpnxiuCIS ill such lIli~lUrc-based c~pcriment~ ltre often (\wnd III t,e about9()% or beller. Although Ih,s is an exlreme e~lImple of II multl oomf1l)llenl reoclioo. it illustrate.~ lhe unlity llf 'Jlullon-pl\a.<;e chemistry for gener.lting great dll"e"'ty in chemical hbr.uies. An approach Ihal is inlcnnediate bct"een solid-pha.o;c chemiS-lry and solulionphase chcmi!itry i~ to U~ Mliuble polymers lIS a support for the product. PEG b a common vehicle in many pharmaceulical preparatioos. Depending on the degree of polymcri7.1ll illll, PEG can he liquid llf -.olid ut IUI)Ill temper.lture and show va!)" ing ckgrec~ llf solubility III aqueous lind (lfganic !IOlvcnt~ . Each molecule uf I'EG h3) lin OH group at either end: ItClC:ltz(:lt:C>-IC:lt;(:lttc> I.-t:lttc:lt:<l11 By converting one 011 group 10 II methyl clhet" (McO- PEG- OH). it is ]X)Sslble to allach a camoxylic acid funcllonahty to the fn:e Oi l and U!>C solulion-pha.c combllla lonal elK:llli~lry III s~n1hc~ile. fOf eU IllJlIe. N-aryl-\ulfllnamide structures. llti:: resu lt mg mh lure of PEG-bound w ifooamides can be separ~ted by use llf ehromatogmphy. Another type of SQlublc SlI]lp()11 i~ dcndrinlCl"lI. The~ are large. highly branched molecules wllh termirl.1l ammo groups Ihat can be used h~e the 011 groups of PEG for the allachmcnl of products. Finally cillSS o f molecules lllO\<l'n lIS nl.lOfOOs phases are II foon of " hquid Teflon." COIIsistlng mainly Q( loog chains of (-CFz-) groups atlached 10 a ~III COil alom . When thc.<;c phase~ are usctl as a SIllubJc SUppo.-l for sy nthesi~. the resulting product cu n he readily SCpafUle!l from uny organic SIllvenls and reaction by-prod uct~ by u tl"',lCtinli the reaction ml~t ure With nUl)f'OCarbon solle nls. I~ A unique appIieutioo usmg COIIlplemenlary DNA a~ a ")UPport" has !lttn reponcd by Illu...ard resc:archcn. 'f To "c nOOUntge" pairs of molecules In solulion to feact under nuld conditlOlls. they altach >hon Str~nds of oomplt'lll(':nlJry DNA Of RNA 10 lbe SlruCtures 10 "1.lp" the Structures togelher and promote reaclion. The DNA i, then rerl1QIe!l. yielding product Ihnt would nOl OIhcrwi~c be synthes.i,~'d. Using thl ~ mcillod makes it possible to pn:~ent reaclion o( cenuin P.~I~ of 51ruCiures 11.. well.

>

1'oI,'SI,-~

"",1_
1~

PuI~)'rnw: <;rOU. lon~o:d

... nh d".nyl

tabou'

CfOij;lonlln!l. 1'hc:w arc: c" ........... n:sons

II>al ,n Sile CAdu>tOII ,hrorrul"V"p/l).

T.... ur(;..:1 ~II!I. PoIy.I)"'''''' III ,,10..-11 )00lIe of the phenyl trouP!! poly~htlcroc II)L'1>I (I'EG) IIroo~ ~uoche<l in I~ (>1m. ptJ"II,OIl . The free 011 groups ur !he I'EG allow the .... achlllenl 0( l":M"ptJUlKb: 10 be ,yn'''''' il.c:(i. I'oIYK1 'llJomkl., r"ITI~. U" "super .11.IIe:' Ihc. .. reSIn, " . dl beucr ,n pullU .... ' (nl) W><l ... ntt .""')' ~QRI ... n aml<le bonIb,

ha,,,

..10..,,1), ",,,,,,,1bIc btoIoioa.l n);llenal,_ GI_ .nd ntlllk bead ... '101 a I)'JIC' of Of'IanlC rr;In but
OOiOCUmo w.nI "h(n hlgh-lcmpenorun: or h'&h-I'f"S'urc n:ac;. ti<.Jm an: ~
To ~ppoI1lhc al1l1/;hIllCill of a ,ynllll:lic larget. IhI: poly-

usu,llly nlOdificll by equippi ng II wilh II linker or Inl;l1Ol" group. Such group' muS! be ~lUble uJlder lhe feaction fUllditiolb, but they mU,1 be ~uscep'ible to a "dcavage" ~ac1ion Ihal allows rcn"lOval of the prOOuel. Some ~'ommon Imlm an: ..no"," 111 Figure 3-10. aloo& .... "h lhe reagenls thai cka\e lhe protloct from the reslll. Some <;peciah/.cd IlIIlen- have been de\elopc:d 10 nlttl panicular reOCIlOO or product conditloo~. Su-cal led tr,lCeless hnlers can be deal'cd from lhe resin .... lIh no re~ldual functionality left. Thi.~ allows tile al1achmenl of aryl and alkyl produm Ihal do 1101 have O H or NH fUrletioolility. 'l11ese linlers u~uJlly mclude II .~ily l gruup (-Si(C lh h') that is seoSIUll: 10 acods and nil be clealcd In giu: unsubslilutcd phen)\ or al~yl prodOCll>. A clas.s of hnlers Imown as "qfety-c:lI1.-h hnlers are ir.en 10 the ~)"nl~l\ conditions but h:l1"C to be ehenllcall) transformed 10 allow final llberabOIl of ~ produci from the resin. T)pically. t .... ll rcactioos are rrqUlrN III brca)" Ihe Imler (hence the name). A miller ele&3n1 iIpfJfUlICh 10 Imler chem istry is to u-<c linkel"ll that II/"e sensitive to ultrJ~iolel IUV) light. The Affynla~ group bas used the<;e in lhe 'yntmo.,is o f carbo~y he acid and caroo~ armde prodllClS. I} !--'nally. 'IOIIlC groups hale U!it'd linkers thai can onJ) be elcal'cd by enzyme:!!. I '

rIlI'f i ~

I,

SOLUTIONPHASE COMBINATORIAL CHEMISTRY

Most ordinary 8)nthclK: chemistry t:l~eJI place in !lolution. Wbm a ~actioo IIIU,I be lIl()()ificd to accommodate a solid !tIpport_ itttles tune and re-.ourl:CS III del'clop and ov"mi1.e ibeltaction coodI1lOll$. III(id. acombon:donal chcmiS-l may spmd montlls de!>lgmng 8 _ '\Ohd_pha.-.e n:0IC110n and gathering !he ~ n13tcrial~ bul then contlOCllhe enure synthesi. in. mallcr of hours or daysl MilJIY reao;:lions canll(ll e\"l:~r be ron 011 SIlhd ~uptXJm beeau,., of poor yiclds or (ailed reaclionS. For thesi: Itason~. then: has been much imerest in lIlIing solutiOII-pha~ ehemiwy for lhe rrel'llmtion llf combil\3Iorial hbr riI:s. Unhle ooe-bead onc...,ornpoond ~ynthcsis ..

Al

COOH

o
R2-NH" ... R3-{
H

Q-NC-

,,)l~Jy~D
" 0

'"

R'
N -'"
0

R'
RO

,
H

N-{

the I f'tqure to 9'V1! a reilCted

lUll" 01

3-1~~.~~~~1~~~[

,. A tomb,nalOf\i1I mO( and each can be furt~

redrawn from descriptIOn

hom Keating. T
component coodensahoo

'!OC)Idfl,de If! the

LI9' four-

POOLING STRATEGIES
Although $OIne solid-pha.o;e romblnatonal chernis.,y is ('011dUCIed by use of the ooc-bt:ad onc-compoond ~Ir,uegy. chenll<;lS hale: ooliscd numerous other approadlC~ 1 pool_ 0 ing re:ll:Ulnl~ and inlt'nned iates 10 b'erlCtlIlC h br.uics. ~ goo.l is gClM:r~Jly to :.chicII: a balallCc bel'" cell the simplicity of rlll~ing e,crything together in 000 ~tcp but then haling 10 "dccollvoluu:" the resu lt ing mix tufC :md wori;ing wi th more. bill ~rnaller, mixlUres. II has been lil crM;:d to ~lIIeonc gIl mg you :I IlIkc: and a rnagrlCt and telling you 10 go fi nd alld describe a need le in I field of hay. You can make one bIll haySlad: you know oonlain~ the nccdk. then have to deal wilhe,'cr-smaller "subhaystacLs:' or you can usc more elcH" approaches. such as d,.Kllng the rle ld ,nto regIOns. 1I~lng overlapping Il'gions. elc. The major approaches Ihal hal'C bc<'n tI.'ol'd irtCllIdc: the (0110\11"1 0&:
O_IK-ad ~mpotlnd 1011'>I 1~. WII" I" ... 'lflI~SY ope. cif.c qU'IIM"y of b"aJs IS alloo;.l~d ('" cach po6~11JIc strut,ure in the hbf-.II')' : .hose be3ds 1X>I'I ',..n ....,1)' moIule. u( Ihc hbf-~ry nlCmhcr. The beads ma), bel laUe<! In various wa)"~ (~I"" tIC" StiOfl) 10 help iden .. f)' lhe iyn. helle ~mpotlnd, The ""unlagc IIf onc-bead OIIl'..;omJll",.1d ~lralellY i~ Ihe ~Im l'licuy (If :orL:ll)'sis :mJ screenm,. The d,,",,h amalJl' i\ l~pmg .he tM...w. ",patine and ha\ In, til de;,) wllh larg~ number of ~ynthc"." ,n pano.l ld . As ad"all!> \/o'ere rTllI<lIl ,n ru/:>otie!. and IU'om;ouon. tIoc pmbIerru \/o'ere redoced, and 10(13),. probably
mo<I combinatorial e~prrimmu.

HAC + CAe. ARC + BOC + CBe. mild ACC + + COC, .... e do ."" by ~l,pp'''i 1M Ialil oc. "r poohn, mo.n ,n Figure 1.1. Nil'" .. hen we SC""'n ' he", m",uf'C$, "'C find IICHvn)' ,n 1M m,dlll" ,roup of bead5. Th~ 'ell~ u, that 8 i~ po6""'" 2 " I'CqlnrC\l rIlf'IICH,i l),. Tho final >lep I> '0 syn.he"", Aile. IIBe. und CDC, ~~p\n G "",on ",p.:or.ue.1Ond ...:rco:n (,..10,

be ..,n",l) In lhe Ih,nt """p. Sm"c II " ,n Ihc I",n! aroup. "'t In..... I C ,n posouon 3 is IIttdffi fur 11<1",,), ..... c ')'!IlhoI.., a ~lnlIlkf ltbnvy "r the .I.trucIuns. In ttvr.: crouP> AAC +

sec

10 find Aile :oJ the UCII\e .ioIl\lClun:. S"h' noc' h'~ d l!('o",ulu'iun. Thi, " ",milar 1" ilC:r~th c tX\:oo.

.oluII"" bul Us/., rcg~1 "'j) 1<>J;,e. n~I1Ic1)'. ka. e 001 a (UllCllom) ,mup. and ,f ;o<'1I\"y "a~nl .1he fu",.,oo~III""'P 11,," 'I
m,,,,,nll mll.1 be IIttdffi fur IICtOVlly _Th,,, i. ,,""lCldarl), "..,flll roO' ltuan'''DI,,c """ure_act"",)' relillon>ll.p (QSAR }iyp: .,uo.IieIo III .. hiett.....)'. a -C1UOOP is pbd .e....nl poIi. 110m. on a pbonyl rinJ. 'The t lllnc bbnlry 'S "'lftnrd mIAI"~ 10 xct .he ba,o,c,hnc lCIi, ily k.d. If aclll II) ,~dctecICd. o;cI " f .uOI,bnulc:'\ "pn:p;oraI. .. nh "ado n",,~,". one: b.nld,nl bIuc~ bubmlt'il"" uf. funcllo"",' ,roup). Subhbnonc:s tItII an: ...""n, groupo. fR)fl1 1M :"'''.. c rompuundlJl ..,II be lb. acll,e 11'" p:1CI'nt lihnwy. The "'ast ... wbhbf-olrl'-" iocnt,f), the nlO'>l ,mportant fU""KlnalllffiUl". A redUl-'W 1ibr~ry '''''''a,nml! only,""'" (unc,i,,,,,,t lI,R1uf"I i~ lhen ~pared, md the miN lICU,'c compuund" arc ido:ntirted by c"hct ,)nlhe"s Ilf' 'teno". ~ dccoo ... olulion. IIOI:'b~OIt, ddK.iun, Th'$ bcg 'n~ ""II g~""l1Ilml aIII;I """",ninillhe e"Urc hhnlry as I single ""'lUre. If act"' ,ly i, OCIt.'<:'coJ. thc bu,)d,nK bIocls arc .11\ oded 'n'" ,,,,", ~l'" 10, P. and }1. and II<lo.ln'ollal wbl,~ an: preparnl. In thel.f ""bo;ct,. the numbrr ,,( b."k1,na bklcb from .he n J""'P ill .x.:rea....:d. thc numbtr f....." lhe jJ croup" ,ncre....ed. IOnd thr numbn from ,he J' gmup i, uoch.:on~ "The l'C,ul'onl cffm 1)11 ",'1\ ")' lup. 00..-11. u",h.:on~ed) "'Ut!ob .. Im'h IrouP <:l bu,klln, bIot:l. "a, ~Ulllnbut"'J!: IIMI"lI '0 ..m"y. n.1>"P' pn>xh; pphcd "cnm"'), IU room ,n "" the &IOIl~ t:h:it...,

(u"'.""""

,,,'en

.tw,

",\\0

"""w",,,,,,,,,"

,n""'"". OIIl'bead ooc..com

pound W.oIclY,
IIn"II .i ,~ drmoo.<!I"I ...... ThIs I> the ~nolCl!J firsf dccn ..... 20 ~lIN ago whcn comt>on:r.torul chcn".uy ,,u MOIIled. Ike,"'''''''' Fi,llre J-3 aNi ''''''g''''' M~'''i '" .he botlom u( tIoc: fillure ....h three UOOI'" "r bead;. E.:h ~p I\;ls bc:ads tM.:u-

in,. vanc1y of compuunds. but . ,....... , .nonure 1)111)' "I'JII':tr'S in 0IIl' ,,( Ihe ,roups. SlippoliC the 1IC1",'C io/l'IIClure is ARC (w" prele.od hen: Ihcrc i. ""I)' "",,_in reihl)' lhe,.., proh;,bly

IIIO!It IiCtl\C.

,,',11

Orthos:orwll """ lin" The!"",, ''''''''1<'''''/ n~~ ... IICrpC'!IIbcy 1 :or.1f' unctll'l'Clalro In 'h" tylIC of pooh"S ...." d;"nbitlC Ihr

fu....-oorW JlOOpi 10 be conswkred '"1051:" of hbnoai. A, B. C, dC., ... h"b can contain m;~.u""s of ,he Wlme CORlp<!Unds. 1I000'-c~. the fu...;li(ln~l groups ~ di,tributw I""''' I..... ;on)' subsel in A and B lillan~ on ly one runc'JOIIa] &roup. For cumpk, if Wl' ho yt:. vcry lmall litnry of 5U\IClu~ -aa. abo ~nd ",,-we m" h. JI'" aa and ab inlo g""'p A. u and at inlo poup B. and lib and IIC mID poop C. If ab Ii thc aCme .. rue 11ft, IIm'tIllllJ A. B. and C would silo .... lieU"")' in A and C. buI noIll1 B. Idhnl"" thai ab (!he only suucture in con'mon) is !he 8CI,,'c 0IIl'
PositlonalKllnnl.... Th'S;$' ..... i,nlttIVC .K1't'enln, ~gy

in whoch .ull!.cl hbr.wy i, cn:aled "",II .... nlle buildin!: block Ihl 11\ one pofiili<>n and:lll buildinl bIocl l in tile OIho:r JlO$,\ion., In prInciple. by 5(:1""';1111110 fu"""iO<1a1llmup fmlll lIIe IlIOSI lid;""' subset III each pcx;,lion. ,he nlOS, ""Uve rom poo!ld o>Vllll is dIO\ro'cml. Thi' iglKll'eJ inlcllIClioos bc1""(Cn bluldw, blocks. "'h,ch {lillY comphcalc .he re..ulu..

Certain problem ~ wilh mixtures must be c()(lSIdcml" hc:n pooling. Comrie" miJ,.IUI'e) with only one or a few acti ve

can hal'e sol ubil ity prob~IIlS. e.~pecially if the OOI,ipOUOO, are poorly "Olublc . TIle illact, I'e compounds conWIICIurt:S

" '" "

tribme the 100al ionic concelllnltion bllt not to the octi vity. Someti mes. clMnpounds ,hal hllve a CtHlllllOn scaffold will hal~ many active species, arising from the scaffold Mnd not the subSlitllCnts. Thus. many poorly aclhe 5tructures may s/Iov.. addit ;I;Iy of activity, leading us to thmk. the mixture conurins 1 si ngle acti le structure (falsepositl\e rt'Sult~) . Finail). p,rllal b,ooing of inact,,'e structures Clln sometimes 1R'm tllll .clive ~tructure from showing full activity (falsetqiIIi,c ~ults) .

,0

DETEalON, PURIFICATION, AND ANALYSIS

DtIectioo. lliWym. 100 purifieaJ.ion of combinatoriallibrnries places high demands on ex isting anal ytical tochniq ues btcause (oj the quamitles to be analyl.c:cJ IIR! very small. ~mes picomolu of malerial , (hI the analysis should be noodo:Sll'Ul:tiH. to allow recovery of the ~"Qrnpou od if poss,bk, arKI Ie) the methods must be suitable for rapid .
panlkl analysis-anal ysis ,.;annOl be ,he rIltc-limiting Stcp III the procedure. No ~i ngle analyticul technique ,.;un fit all the requi ~ments, 50 usuall y some . 'hyphcn3ied" analytical ICduliques Ire used, for example:. high-performance liquid dIrorrWography wuh a ma~ spectromc:Ier detection sySiem IHPlC-M5). We describe this and other techniques in this
~~.

oJ

."

"

".

,.,
;.

".

.,.. ,. '"
0 '

..,

" A

... =

ChromatOgraphy is usually the first Slep in the analysis 0( a comb;natonal mixtu re. If we stan with solid-phase cht:m imy. we chem ically c lcavc the compounds from the suppon and filler off ,he beads. giving a solution cootai ning \Ill!' rompounds IO. C ~y nlhe..\ized. If the 5OIuliOl1 cOl113ins j ust J,lngif, compou nd. wc might use a >-peCtropholomcter. 10 measure infrared (IR ) and ultra"ioIel (UV) absorbance or n.:.esctua: directly. or cven nocif,ar magnetic rc:sonatK:t: INMR ) spWmscopy. to dete rmine the structure m the rom pound in !lOlulIOI1. If tlte sol ul ion contairl~ a mixture of compounds. one: muSi separ.l tc them before dctemllning their ~ructures. HPLC i~ a \ tandard approach. A lIalllple of ,he llIi_ture i ~ injected illto the fl ow of f,()IYClll e nteri ng p chro-lIlIIographic colum n. The componemll in the mia ture trave l dov.'n the column at different ratts. depending on their affin -

ity for lhe ~tationary pna.<ie in Itle column. and they exn or ,.1,,1/1 from the column al diffcrc:nt times. TIley are de,ected hy some optical method (U V absorption. fluorescence. reo fructh e inde~. ctc.) Iha, gil'e~ ri se to peak.$ o n a graphica l readout. Sotnelimes. the O1ltput from the column is pas..ro inlo a SpeC1rophotometcr or mass spectrometcr to generute I spectrum for cach fraaion of the output. These spectra can be interpreted 10 detcrmine the structure of lhe compound thaI caused a giYen peak.. Ii is also possible 10 use much larger cllromatographic ..:olumns and run prrpurfllil'f' HPl.C to separ.lle up to se"cra l 1lIlIIigr.lIll$ o f material for (u nlter anal ysis or biological a.~say, Chrom~lOgra phi c se~n1t ion ~ and uI18Iyse.~ can he fully autQln ated. Thus. a chemist can plllCe aI/ the reaction I'essels, micnxitcrplates. CIC. from a combina lorial eJlperimcnt i"l11 nICks and use a robotic system ,0 draw sarnpks. inject them into the HPLC. and collect the dala output into computer or dal abascs- all without fun her rnlc:nenIiOll from the chemist (CXttplto wash the dishc<;!). For Ihis reason. speed nod .0;.01 l'l.'nl handling arc special COIlC"CmS wilh COIllbinatonal experil1lents, One approach that has been adopIed 10 speed up an~lyse.~ and rcduce the M,llOlm, of solvem ,hm m ll~I be consumed is !i"pt'lT"ririml fluid dtromwograplr... (5FC). Here. the solve nt is not a comillo n organic SOIYenl ~uc h 31> acetone or ethanol . Instead. Ii is a pn:ssuri~ed gas m .e CO2 that cvaporalcs from the oulput.lealing pure corllpound behind. AnothB ad vantage SA: is ~: si nce the ..aI'em moIeculcs!ll'C small. diffusion IS rapid. and scpamlioos mke place in aboul half lhe lime o f ordinary HPLC stp;amt, ons or les,. Finall y. the amount of . 'sol"ent" that is consumed I, sig nificlln il y Io\\'er with S FC . A di Slld vuiI,age is Ihllt cen ain compounds may nOl se par~ , e us " 'e ll under SFC Q~ IInder IIl'LC' IR >-peClroscopy is o ften applied in combinmorial Cik:I1lI~ try. S,nce IR light can be reflected from materials. 01"1(' can analylC resi n beads direct ly. ",thout clellling the product.~ from them. Since the loading of product on any gil'en bead is vcry small, usually computer-enhlUlttd met~ li l e Fourier transform IR (FfIR) are needed to en hancc ~he ,ery small speclrnl signal from 01"1(' or n few beads. Inten:."'ingly. the shupe of thc beads has been found 10 affect the IR ... pectru resul's. and nallened rather Ih:tll spllC'rical beads give siroliger IR signals. ,9 NM R ~pectrosoopy gil es ITIOf'e Structural information than IR or UV ~tmseopy. but it has traditionally not been n<'arly lI$ sensilil" Compound. are c. oonnal1y c!en,'ed from solid support before: ilnJlysis by NMR . since NMR on solid resin or on resin ~oI lcn by solvcnt gives broadened peals and low resolution. A type of NMR called magic onglt Sf/ilming NMR , in wllich lhe sample is illscr1ed into the m;lgnctic field a, an nng le of abou , 55-. reduces the peak. broiidening and h1l.'l been u\eO to anal y1 swolle n polymer beads direct Iy. R~'Ccnt i mpl"OlC' -C merits and the use of nanoprobc.~ ha ve aHowed NMR anal~is o r l(X).mlo' beads beating leo;.s titan 800 polOl of compound. OtheT NMR techniques that Ita"e IJcton used 10 :malya: combinatorial mixtures include various " tlO. ~ mensionai" ' (20) NMR tec hn iques that use mulliple: magneti c fieldS. t-I PLC-NMR. capillary clectrophoresi s couplcd 10 NMR (CE-NMR ). and even NMR to detect the hinding of dru gs to receptors to identify :leli ve agen ,s. Th; ~ Inllcr k'C hnique has been tcrmed SAR ...i,1r NMR.21J Mass spectrometry (MS) is the lochniqoe Irrosl w,dely

m es

or

llsed for comblnlliorial lil:ll1lry analysis. The mea.uremenlS eun be IllUde 011 resin beads dirt'Clly.:I wide runge of <:om poull(b can be DnalF.cd. and MS analy'le~ can be highly alll<)Tn:lled. IncllMkd amon g a nLimber of MS lcchniqUd In use arc
Iomi,,,,.k,,,. A !><>lUlIOII I.'Unl4lni" , I~ rompouoili. lu IN: analYI.n1 i~ pa'M-"<l """ ~ ~1"""Il1>Il",,'er Ihruugh "" dcclrinliy c~ capiLlary. The droplc:ls 11\:01 ""~rp: frum I~ capillary bear ioIronl "k\:tric cl\:lrges !hen.....,I",,~. and Ihty hl"",lIy ",I'INlc' ;,,1<1 .mallc:r al1d ,mallcr d",plc:l~ al\lJ c,'eIlfUlilly 11110 !'"Ii:l} chulge<i ion~ Illal lI/'C \k. <\Cd by I~ '!\aM M.lri~.lIlI!Iisled '-rr dtsorplk>n/lofti1.11lloo li l1'lr>-Ol"-n;~h l (1'01/\ LI) I. TOF). Otoue a moolhful. il .imply mo:un . Ir,c, s:"lIpl" .s embcddc:d ill ~ $Ohd m.lIri~ (c . . 2.~-d.h)ilro1lbc:llI.- ~) IIIIId tbc:n rombm\bl ... ,th I I.a_. Sample mokt:ulo are , ..po.ved and ionwxl In (!Cllllc f ...,h",,, Ih~1 ali""" '" huIc: rooIc<.:IIIc: ;nnJ uI" lIN: Io3l1if'11c 10 be: lItIal)Led. The lIIIaIy~I ... dono '" 1111 1I'Ie of llme-ofn.ghl &n:Ilyl.Cf . n '" hkll iom of d,fterem IlWS Irn,d d.fferenl dl>lallC~ ;n a all1OU"l
~:lmrospnoy

o-..... J)(
o "
- N

Paptide library

"

"

'".II .ONA Iaog-P.il . . ,...

II""'.

Linker, Link&<. -

N - PIIptidllbnuy
Priffi8fONA IagPrime.

"
"

.ptromc""'"

Lonkef. -

N - 1'I&pIide library
N -~"'1ibrIry

1Ini<e<. -

,,,,,n

b " Figure ] -12 Two ways of attachIng DNA tagS 10 soLd suppor~. a . A DNA ~ IS attached WIth eath peptldl' mclwJll'~ a blfuncuonai rl"Wue b . The DNA and ptpllde grClUp!i have separale hll~efs

_.nt

QfUI'l1l'

OtMr lH&.u'lfil MS lec:hnkIUf!S. Thc", "",11ItIc: ~ondary . 100 MS (SIMS) In "'hKh lhe t;amplc: ,~ hll II) mcuJ IOfI l'liher Ih." .he electr'QII beam "self. and I'ouncr 'r J",fom' MS . A ' ."ry impol"1;a11l U'ie of MS In combin.;uorial chf:,mistry I~ ill qualil y coo.rol of ~-nn)binatOfial hbrJries. A~ much as possible. we would l i ~e 10 ha'c pure compounds gCI'\enl.cd In high yield. "'''h no ,ide: n!3CIlOOS or by-products. Wc also need to ~crif) thm c'M)' cvmpol'II.'n. IlCtually cxbl ~ In a librJry (i.c.. hat 00 react ion~ fuiled). Only r.,IS provide:) the seoslli~ity and ,nsal;lily to perform Ihis dleCI.ing "'"h both solid-phase and solution-phase libraries

ENCODING COMBINATORIAL LIBRARIES Once "'e hoi,c found a nux.ure or subl ibrJry th:tl shows blologi caloclI ... ity. how tlo wc dc. cnmne cxactl y ""R.ch \.nlc, Iun: or SlRletul'\'S an: responsible for the aclivity? We c;ao purify and IIOalylc as (\e.;cribi in the pI"C' 1OtI~ secuon. but if 00 direcl analy)i~ " available, we net..'d 10 ""{'(Ill.. or /aJi lhe suppon or lhe molecules themscl,es. using physical or molecular "ban:ode:s:' An oo\lOlb approach Ihal can be used ooly ",ilh smaJllibrnric) "10 physically label each vial of onebead one-compound l'CIoin. Thj may be practical for a fcw IeIlS of compounds. bul ",h.;al if "'c hoivc a librnry of 32.000 compounds, or e'cn 1.000.000 compournls. in a mixlul'\''!Clearly. here I~ a na.-d for a mon:automated mc'aIlS of identifyinG the Sirwtures thai are in the library. The most common approach to encoding solid-ph3.\oC. li brarie~ I~ to alillCh a chemica l .ag 10 the resin bead~ ;as the Ia!l;CI moItcUle gCI:> synthe!ii~ed. T ypically. al each step III .he reacllon. a \.IIg is al1ached .hat is unique for the gl\cn )tCp. For example. if we wc creating II tripeplide and wc I\a,c 10 possiblc anlillO acids at cach position. "'c ~ to alloch e.ther a SI ngle l;ag thm :.ay. the lripeplldc: on thl~ bead has amioo ocid Ala al pm;ilion I. Phe at j)o~i l ion 2, lind Gly III ~il1on 3:' or "'C need .0 allaoch three diff"I'\'nl lags, one for each ~,"on. Onc of the carl iCSI Iypes IIf chcmical cncoomg was the auachmenl of oIigoouc leotides (usually I>Ingle'Mrdnd DNA)

.n beads OIl .... hieh peptide) 01" pej)loids wcre being buill.11 Sioce chere lire 20 possIble amll10 accd~ and ooly foor nUcleolidc: ~. enough bases must be :!Ilached al each ammo acid a</ditiOlI SICP 10 itlentify properly the amino aei" belOl a.tached. Although three bases are used in the DNA genetic code. " ,5 cUSIomary 10 usc up 10 ~IX bases for hbrnry taggl"&For dceodmg,'he DNA lag is amphflcd by use of.he 11(11,' m"flUf' ("hl/;II ff{'(./;1)fI (PeR I he !laIllC reactoon thai ;) 1I!ied m forensIC DNA analys.s. For Ih,s I'\';a;;on, the chemical Ill! mU,1 al;.o bear PeR primer sequences. Two types of 1llIt"00rs ha,c been used IOConnccl .he DSA lag' to lhe solid suppor1 (Fig . )12). In 0IlI' typ.:. the growin~ DNA cham i~ all;Idled 10 the 0" carbon of n serine group th;a. is anchored to the soh" support by II linker molcr:uk. The gro"'"tg peptide cham is auached to the 5nine amino group. possibly Ihrough II 'pacer. In the !OCC(md Iype of lIII chor.1hc DNA chain has its own anchor to the solid "lIppon. In th is CD.'Ie. fewer DNA IW an: anachallhan the number of poIypep4lde molecules. If DNA tugs elll1OO1 be u~d, one C'Iln label beads by usiOJ: II bi nary' approach. Suppose "'e are building a triptpttdt: ",jth f our ~sible IImlOO acids al each posI tion. We can U!>t bin;ary digils 10 cn(.'Odc which amino l.cid j~ at II givcn posiUOII lIli folloWll (each bmllf)' number IS read from \be nghl) (Table 31): Thus. u .. ng 18 " iffcrcnl tll1l5 () )( 6) ....e can encode fur allY of IIlC (4' ., 64) membt,o" ufthe hbnlr) . For example. if .he producl i\ AlaGlyLy~. the Cncodilll

TABLE 3-1 Bin ary Encoding of. TrifN pt ickt. Usi ng 18 Posslbl. T.gs
AminoAdel

Position ,

I'oIitlon 2
000000

Poslt'on J
000000 010000 100000 110000

",
~

ooooro
000001 0000 '0 00001.

000' 00
1101000 001100

'"
'.p

Chapter

Comln""IQn(J/ CIw! ...mn

53

"'wid be 00 00 00 00 10 00 II 00 00, IUld J of the 18 possible lap would be alUIChcd 10 the support. alonJl: .... ith tile U1peptide. II i$ wftunOfl to usc poIyhalOiCnDled aromatic rompounIls as lags, such iI!I

higher-density ~ning platforms. The Mandan! lI)out r(W

HTS has been a 96-... cll microtilcr plate (12 X 8), Denser formaLS. up to 1.536 wells per plaIr. are 11ICre.J.~mgly being

used . This requires ad~ in liquid luandling. precision of detection. and lnborntory automation. One of the first ar:th'ities in den'loping a HTS assay is
scleclinglhe target. About 500 largetS are cum:mJy being used by dOlg companies. Of these. cell mClIlbrant! receptors. mostly O-protein-coupled recepiOfS. make up the Inrgest group (about 45'1> of the 100al). Enzymes make up the nell largcst group (28%). fol lowed by horrnoot's ( 11 'llo). unknown.~ (7%). ion channels (S~). ftl.K'lear TeCCplOA (2%). and finally DNA (2%).zs II is apcclcd lh:u the anOOllltion of the human genome ....iII add adt\iliooal UUicts. although the rote of this addition is IK)t koo"o"O, New targets must be: part of _ regulatot)' pathwa), in the: ce ll and should be: sc:nsilh'e 1 some disease: State, IK)t be: e~prc:sscd allihe time: 0 and everywhere in the cell, llIe: nc:~t concern in HTS is the: library 10 be: screened, Throughout our discuSliion, we ha,'e perhaps offered the impression thai a gh'en library for a par1iculur project was the o nly ilCl of ~'Qf1Ipounds thai ""en: ever screened for acli vil),. In facl. much !iTS invol,c:.~ screen ing compomlds that are part of Ihe corporate blorehouse of ~'Qmpounds S)llIhe si7..ed in the: past. or the)' may be: a librdry purchased from a vendor. Such libraries usuall), coosist of microtncr plates containing fmun or dried $3lllples of compound - perhaps onl)' miCl'OlllllllUi per welL The: size of such hbntnes mOl)' range from I few thousand compound> 10 rocarl)' 11 million. 111e cost of completel)' cTCemng such a library &galnst JUSt 11 single L'\Sa)' rna)' amount to o,'cr $300.()(x). so such lutgc:sclle JCfc:ens are conducted flUhn infrequentl)'. compared with routine dII)" lo-day screens, It I1as been esum atoo that one: must screen at lea't 120.()(x) 'quality" compounds (I.e .. di"erse dlllglike: structu res) to disco... er a $ingle- Iead series for a therapeuticoll), sound mrgel.:-e. As disc ussed above in the S1ion o n pooling Mralegics. one can redu~"e the SCIl.'t'ning cffon by pooling groups of structures and running asS<lys on mi~tun:s of compound:>. This also cooservd reagenlS and biological material . has smaller storage n:quireme:nlS. and requirc:s fewer jKrsonnc:J. TlIcre an. potentiol problems ",ith poolmg. A number of fact0f5limit the number of different compounds we can te..'1 in a given ""ell. including ionization. react;'ity. alld w1ubil ity. Compounds can !'!ltc-r a screening program in a nonrandom ~. such that D Gi~en assay platc may ha,'e compoullds thaI are highly similar structurdlly . This may gh'e rise 10 folse-positive hits. Falsenegative hits an. less likely to orise from pooling. Another concern is thoc usc of !'CpUc atc:s--compoulld~ from the ~ame series - in a given a~say. If only one representative of a gi\"en series is pre.<>ent. the chance of mi~ing that stries a.~ a possible lead series is greater than if multiple members 31l.' pn:stnt. Therefore. it is common 10 inc lude: st"crnl me:mbe:f1i of each senes In a given assay when pos\ible. To be: efftrthe. a gh'c-n compound muSt dJo;.sohe complete ly in the assay medium. It is common 10 add a small amount ( I'll of dimethyl su1fo~idc: (0:<.150) 10 the assay 10 assiSt solvation. 111e best concentration of compound 10 use is somewlult debatable. High concc:ntrations (10 ~\1 and abo~e) onen lead to nM.If"C false positives than !!Creening at

eaOH

x
"hen: X '(piestnls _ combination of haklgtn atorru. The balocens make the: tap show up clearly in MS analysis of the mixture. and by varying the: chain length /I. the tag can be: made flexible: eoou$h 001 to interfere: with attachme:nt of the product. Othc:rchemical tags tlw hD "e betn used inc lude: 1tOIOpic.lly labeled pepUdt$ and dyes. When it is not possible 10 Ust chemical tags. one mU5t
pIIysically labc:l the solid or liquid support ilq- lf. One: altema Ii,'e is 10 usc 1lIdiofn:queney encoding. in wh ic h tiny microchips are added to Ihe resi n o r 10 the w lulion phase. As "Mious reactions are conducted to gencrnte the products. at fath 5tep a ndiofrcquency signo l is stored in the microchip. This signal can be: recalled to ident ify tnc: sc:qucncc: of reacbOIlS that generated the product (a similar principle is u!icd "ben your dog or cat gets a small idcntincation ( 10 ) pellet Ullplanttd under the: skin of the neck), Lastt optical encoding IS ytt MOther approach. in which lhe: solid SUppOl1 oonsists orlceramicchip co"ertd with a poIypropyltne- poIyst)'rene polymer solid phase. 111e barcode: pattern ;s actually burned 11110 the ~1lImic at tach step in lhe reaction and is dccodc:d visuaJl y with use of a microscope . Finally. one can e mbed temioonductor particles inl0 the solid phase that fluoresce: III diffm-nt wavelengths. 1lIesc an. callcd "quanlllm dots" by their manufllClurer. 2J

, ,

, ,

.'

, "
,.
~

o ,.

HIGH-THROUGHPUT SCREENING (HTS)

" k
~

.,.

'.

y.

, -

Withoul the abilily 1 scltCn libraries r,apidly for activily. 0 IfIrno ",'OUJd be: 110 combinatorial chemistry. Fortuna~ly. the biologists arejuSi as adept at devdoping 1lIpid high-throughput lSSIy' as the chemistS ate at gt'nc:1lIting struct Urc:5. HTS " .. t'ltremc:ly broad topic. encompassing e:"".ymes. organdies. cells. various tissues. whole organs. and even whole li'I,mallCSting. via cassette dosing . This section briefly dist\iSIn only a part of the role o r IITS in drug discovery. with \'fIlpha~tS on a few recent devc:lopmc:ms.2-0 SIICcc:s.sful HTS programs integrate several activities. including target identification (genom ics and molecu lar biolOIY JfOUP'). reagent pn:[XI1lItion (protein upression and punflCatioo groups). compound manageme:nt (information tnIIIaJCmcnt group). assay development (biologb t and pharIIIICOIogiSl). and high-throughput libnlry KltCning (biolo-CISlS and chemists). Foi il ltdy. these activities ""ere Iulndled JePllald),. and mu ltiple IIandoffs of 5amplc:s were invol"ed. h III ba:u.. inll mOte common to inleg1llte the activities and Wre Cl.pertise. This increases efficiency of the screeni ng ptoCtsii. Another route 10 illCTtasing efficiency is D move: 1 0

11 low COOCC'nlr.uion (3 .uM). reason for Ihis may be IlQIllipedflC binding al lhe lIighcr COIlCC'-nlraliOll. JuSI as there are several ways to deleci and idemify members oI'a combinatolial hbrury. there are many " 'ays to mea sure artlritl in HTS assays. Ally sucli /llC'thod mL/Sf be occur~te. reproducible. and have a IIlgh sigllaJ-IO-noise ratio (SI N). Typical ly. the resull of HTS is a qualil,lIIve (yes/no) or Kmiquantitali'~ one {high medium low). rather than 11 precise value (e.g .. KIlO or LDlO). The methods fordeleelion in HTS faJ l into lhe categories of no"radiQlntlric alld radio
ntelriC.

n.e

Nonrudlomellic mcltllXi5 include absorbance. f1l1()ftl. cel'iCe. and luminesceoce speetrosoopy. Enl)'l\"Ie WiS1lYS are a common eJ.llmple. TIle assay is uwaUy run at or belo" the K.. value of t ~ substrlue, wllh only about 5% of lhe sub~U'3Ie consumed during the assay. arK! multiple: enzyme turnovers occur durillg the assay. Sometimes en;t)'rne reac lions are coupled. espeei~JJy if lhe IntgcI reactiOfl does IlOl produce a prodUCl lhai elln be detected directly in the assay. An ex.ample iJ carbox.ypcpoda.~, "hich iJ coupled to the reduction of NAOP to NAOPII, giving rise 10 absorbance at 340 nm. Rlldlomelnc methods ioclulk filnuon and ~mtiJl:uiOll proximity a~say (SPA). "These IISSII)'S use radioio;otopcs, KI !IIIfe Stonge and harK!1 ing an: of L'OI\Cem. In Ii Itrotion IISSIIy. a flxhoactt,'c substrole bound to. capture group is dea,'ed by il~ enl)"me. I'\!movi ng the radioactivity from the capture group. 'The mixture is mten::d Ihrough ,peeial filter paper that the captun:: group sticlLs to. bul e\< el)thmg else passes through. A sctnllllation nuid IS added, und the r;J.(hoaclility of the fi Iter is mellSured. "The Ikgl'l."C to which the radioactivity is n::tained measures the.- stn::ngth of the inhibition (Fig . 3-l3a). SPA is a newer. simpler n\{!thod (Fig. 3-13b). We ~lOrt ....' 111 the 5ame r.l(hoaCli>e subsrrote .... hich may not llIlL'C'Ssnr Ily nd. capture ,roup. 'Ille en:cyme and pou:nllal drug an:: added, enusi "8 the cleavuj!c of the ~ubqI"Jh: to MIllie degree . Now. instead of filtering. a o;pecial resin bead OOIlted wilh H

that nUQfl'")(."es in the near presence of the rlkliOOCl"'c substrale (oo:ar belllg about 20 ."m)-is added 10 the miXlure . "The lysed and unlysed substr.rte bind!; 10 the.- beads, and if the ndioocti ..e part of the sub!otnUe is stIli attaChed. the bead .....iII nUornL"e. If Il0l. tile ndtoacti>'C pans of the sUbsttUle nooting In the sol ution will be tOO far from the beads 10 cause any nuorcsccncc. The presence of f1lKlf"CSC1:fICC implies that the lesl compound inhibi ted the enl.}nlC. The ad .. nntage of SPA O\'er filtration is lhat no fillering of the solution is needed, so bcads can be: lidded din::ctly 10 the assay IlI.IXlure in "ells 01" lest tubes. Also. speciul Sl.." inlillalJon nuid i~ not needed. The bead!; for SPA call be: engineered 10 altllCh a varlety of Substr81e types. Oilter HTS a5!111y ad.-ances include lhe use of rrucmorga ni sms 5UCh as bacteria and yeast. the cloning and expression of mammalian receptors in microorganisms. probing pro. tein-protein intCfllCtions. and I'ery imponanlly, DNA and proIein armys. l1tesc arc: tOO 1II,'olled to discuss here, bul excellent reviews uist.~- ~7 "The incrtasing use of HTS to 'iCTttn for . nlOiule. absorpt ion. distribution. rr'lCtabolism. excn::tlon, and tOXICity (Am.lET) propel1lCS has been cov en::d ru; well.~'

~""illonl~compound

VIRTUAL (IN SILlCD) SCREENING

Virtual. or in silioo. ~nmg refen 10 lhe u:soe of computers 10 predict whcth~r D compound Will !;how dc:Slred properties or ocri .. ity on the basis of its two-dimensional (20) or Ihree dimensional (30) chemical ~ruclUn:: or 115 phySICOChemical propertie~. The lIIori vnt ion for USIIIII vi rtual screeninl arises from the nuod of ncw struclUreli coming from CQlIlbmalorial d'ICmISlry. the expense and time reqUired 10 run COfI\"Cntronal lITS. the ethical c()n(."crn~ about u~;ng amlllaltls~ue Instead of prediClil'e modd ~. and IlJt increasing failuJl: role for struc tul'Oi cormng out of CQmbll\3lorial progllllns. In gencnl. a vinual screening proglllm attcmpts to answer ooe or both of lhe.-.c queslions:

EnzymoI
CO- s,.bll",..,

t "'' ' '1111.(")

< <

co 5'''"11

.Ie,

SOOsIrale(')

)-- CO S'.....-,

SubIIrIIe(')

co
511...1.... ,

FilTER

EN)'IIIe

CO S'''''lfIIla,''' s..t>wale( ' )

$ N\'IIIe(')
~

t lnI'IIbIIoI

CG-sut..lla", - SubsI.. I&! ')

b Figure 3- 1) Compatlson of filtrallOll and sClntlllatlOll proXImity auays . In f,ltrallOll assay. the emyme, substrate. and mhibllor all' n'IIJIed. the un,nh,b,ted enzyme splits the radro.KlM! portIOn (. ) off the !oUhstratl'. and filtenng lhe rrulC!ule. fojlowed by measunng the radroacllv.ty of the fllle!", teHs much InhlbrllOrt has OCCUlTed b.1n SPA, the same mlXtlJre IS tr~ted with resin beads contaIning a ~ntlll3nl lhat lluoresces only In dose proJUm,ry to the radooactM! source Any ladlOaCtrlrty that won splrl off by the enzyme does not need to be ftltl'led In SPA.

now

Chllplfr J Co...bUtmorUll C~ ...ls"Y

55

I'

" d,
i~

) II til l po!II<1Jlor romlXlUnd mow

"",,",
~

~uff~iem

bmdiBI to a ~oown ADMET

\\IUI p;or1IC\Ilu oomp<)\lnd po..c\lo any ",ope,,,,"'

\I,td~Sl/Ub1e

drugs.. This led Lipinsk i to cRumcnllC _ rules for the rejeclion o f StructuI'CS. lie proposed rejecling any 5!ructuI'CS that fail two or more of !he follOWing crileria: Molecular weight ~Iloukl he < $00. Numberof hydroscn bond doocn (NH. om sItookl he fc ... o:r lhan 5. o Numher of h~ bond ottqxon (- N- . - 0 - . -5- ) shWld be rewo:r than 10 Calculated 10& P VIIIM' $hould hc 1t1" tlwl 5. Since the number 5 shows up in many of Ihc~ cnlcria. they llavc btcome known lIS lhe "rulC' of fi,C'_" ~ and si millU" rules ha.c become widely adopted by drug compa nits in their discovery progrJms. They fall under the I!eneml category of "business rulcs" -i1uidclt~ for the proper conduct of business and re.sean:h. One should be cautiOllli though and use !hem lIS guidelines and not Slnct rulcs, 10 avoid missing important drug structures lIulI happen 10 fuil the rules but still show high aClh 'ily and ~blc ADMET propcnics.)oI'The "rule of Ihe is designed 10 be H ye..<Jno filter for the rejection of str\IClIll'eS. More qlWltitati ve models des.ij!nCd 10 predict some value or le,tl of profItny haye also been de\'eloped. E.>.wnples inc lude predicting Caco-2 cell pe,,"eability (Caco-2 r;c1l.J; ~ human intestinal tpithelial lis Ihal can bt layered nnd studied III 'IIro)J' and predicling binding 10 cylochromc: P-450 (a major l i\~r
~nzyme IIlvol,ed

ve

r"

To lI\S\\ef ~ qUC'SliOIls. VIe must build computer

of

"'" <d '"

S\),

PA

of drugs WIth receptOl'S (docIHng. molecular modeling. qUllI1lum mtclllll1ics) and modds for pmIK1mlAO\lET ~Ie!i on the basi~ofchcmicaI5truc III~ IQSAR models). Like mucll of drug discovery. the vir - ' !CRt1Ilnl puxx IS a cychc one. We SIan '"'im a coll 1I0Il of <,lructun:, and run pl'Cd,chve rnl)lJl'Is on them.
Inlm1ChOO

~.del~

of the

,,"OO.hlll

of "beSt" SlruC'lUres. We then tesl ~ }UUl'U~ 1M rea! nsays or screens \0 see if the predic'IOffiC: subset

IItlm ... cre

accurate. Finally .... e iJlrolporate information

lurroed from the real llUa)'J back Into our predictive models
kllmpm'c thc:m (or future u~ .:N \.Iodel' (Qr!he ~IClion of bmdmg an~ from the rlCld g( moI~ut. modeling. TIllS mcludcs molecular mechanics Iptrdiclln& the 3D Strutl~ of molecules from the .tandpoint

.m.

Ii !hi: 1I00IIC nuclei ) and quantum nw:chllnics (predicting

!hi: ,10 AAlCture of molecules from the standPOint of !heir ekco ......l. Wt can @cocnne f:urly oceunne 3D SlnN;tures of I/;wjal~ JTlU1ecules ",nh either of these upproaclles. We all Olbo mood the mtCf'lllCllOIl of tVlO mo~ules and ,,",dice "htt/x'r they Will ~. hydrogcll Ixmdillg or electro!;lulic or j'popM.c illlcl'lll.'lion~. If wc mow !he 3D structure of a m%fIlor. "iC C1In pmliCI Vlhether a g i \t~n compound will "lil"' mco !he rrttplor v. Ilh ~ffocio:ncly tight binding 10 pre \t!IIlIOflI\OIl sub<.tnllCl> from blndmg. I.e .. an enl.)"mc inhlbl\CIt (or drug). Typically. Ihis does noc consider any cffects ,,/1fml.pOI1.. metabolism. illlCfaCtiOll v. IIh !\OI\ CIlI. ClC. Con oc<j\ll"lldy. !he cAI~ting model, for the bmding of drugs 1 0 lU'tpIotI are rat~ cruOc. Vlnh eiTOl"S of .50'1- or more. ~,cnhc~. for the PUrpo!>C of scn::enmg. thl~ I.~ ofltn aile qIWIt; II I suucwrc i~ rredlCl~d to ,how light biOOmg, il ",II Pll.lh;lbI) be ~yn!he'lf.ed and te~t~'d in a real IITS ll5Say. to OOQln t more w:curutc e,tirmne of ils :lCllyity.:IO An imcr f"oI'~ applic3t1On ofhlghthrooghpul dclCLing i$!he UnHed [lr'H;1"o Sl:t"I'!'nsu\er.'1 This I~ a PC progmm Ihal clln be oJ,..... nlolded 10 run in lhe backgrouOO lind parudp"te in ",lrid.. idt proJ1s to IoCreen large dam bases of structures aiml 'IICII tlllJttS lIS cancer nnd anlhl1lX . Or QI1 rombu"IC the predicuon of bindmglo a m:eptor flllh!hi:' iJel.lgn of moll-cules. If we stun wilh a sct of buildi ng ~~s M'III kr'lO'A n Ieplor. v.c clln align complementary buildmg bloc~~ wllh p(1C~els in the reeeptor. III confonna~ lI<~ cbat m:ulmi~e h)Jmgen bond,"g and othl'r inlerncuno ... When lhe fnlgmcnl~ arc aliglled. we can tbcn connect the fr:agnlCf1lS v. 1111 aprroprialcl y sll.ed spacer fragmcnlS to 'build" dru& molecule v. ithin lhe ~nfines of thl' receptor. Thll 3ppru.:lCh is SOrllCllmc' calkd dt' 11(11" 1 or Sln.t'IU~ ""orJ drul deSlgn_ A~ ollr mcdcls for bmdml to rcct'plOI'll 11Ilf'I'O\~. thil appro.tch I' Ix:clJ,nilig more popular.': In 1997, ~archc", 1,11 Pfiler Iool.cd :lt tbe previous 10 )~. lIorth of drug de~ISn. Including all of thelrcombin;cloruI (bemi~try effortS. \l Thcy found thai ,ioce the IntroUucuno ~ rombtrotonill chcml~lry, chemISt.' had tended 10 dc"rn I~r. more compkx. and IlIOl'e lipophilic SlruCIUres tban ID the past. Sun the )tructUn:li VlC~ IiUpposed to be ""'' &ned .. Irad )INCIUre, rJlhcr th'lll optimi~cd drug mole.1IIt<.. II 1111> bC'oonllng more difficult 10 opIimize thc.m Into

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in

n"ICllIbo1ism).~

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ial

CHEMICAL DIVERSITY AND LIBRARY DESIGN

llle universe of drug molecule-siJ.ed compound, thai could

~I

'" "- of

be ~yl1thesi~cd iscnormous. For exlunple, a polypeplilk with poMible ~1ruI: 100 fCSidues COtIId regencnlle I~ Of IUfCS. If jusl I S of tach "'en: s) nthesiud. il would be a mass comparable 10 the mass of !he knov.n universe (aboul lol'l' kg!) (}>(';lel"1iotl, J.: Uni\< crsc In the Balance. N..... Sc, ..n lisl 168:26. 20(0). Clearly. D combiMtorial chemist IlC<'ds 10 selcct clirefully the tiC:l.ffolds and buildlnll blocb that will make up lhe librJry 10 be .. ynlhc)i~ed . Sioce the 191!Os chemists hnc adopted many compulauOIlal ttchniq\ICS to aid III lhe design and foCk'Ctl on of library ~Iructures. llIesc techniques havc bC'cn borrov.ed IlIfge1y from !he fields of QSAR and molecular modellns. TIti .. foCClion !Ic~ribe~ some of the most common compulalional apprOllChc~ 10 library

lcro

dcsisn.

Typically in drug design there arc foor possible scenarios for lhe: amount of information .....1.' an: sutning v.ith J7
I. We do not know the structure 0( the Ie<:CIMOI. and we do DOl ha"f! any lnown ligandll or InhibotOR. Thl ~ '~ 'tllunly J CII>C for hlgh.1h,uul\hput III ,itro scrtt'''n 01 f!~' ~I'ng drug database, and 1obr.me:J, in the hopr 1h.I1 oomc: .. ructure m:ay "'nd 10 !he: m:eptor and ~I""\'~ at a .. anm!: pIIInl for lead lIeniopon,,,n. Oflf!n it IS $lr.Ughtrorww 10 find u l~lmg wucrUtn v. 1m m..:1'& molar poorocy. The probkm tbm btc."'OmC> one of decodln; OOv.

to modify 11M:
lies.

btruclUres 10 }itld ",OCI; th~t m"" llI)\f!t from palmi ~tandpoonilUld show .unabk bt~IOIII.'''''f

1. We do na: klIOW 11M: <In>etu,,", or the """"'plor. bill ..c do 1Ia' f! ~no'... n hgllllb or mhlbolOQ. This was 00CIl the most rommon

S'h ....hOO in o.inoll OO'IIn, 1k usu .. J lIPI,"*,h .0 scl""';n, ~truc_ 'u~v ror funher lOu"lI " '0 forod ~m.K:'ur"" ,n ~helTl,~aJ <bta_ h;ase~ .ha '" """I~,. in wuc. ure.1'o!I I""PCn'es '0 .he l'lOwn onh,bolon.. A rommon npproech 10 develop a pham,acoph~ roodel rOf lhe =q!Ior, twN 011 ",perimpo"lng I.!rUC' Urm. ... ilh bImo.'n acl""y. Th" r;an 'hen bo: uloW ai. UUJ'f'Ii q~"J In ~ chcmlCal "rue,ure dlo,>M<c '0 find ~IIUC'u~ lhal ha,c 1M """'" run<:"o.-I grou~ in lhe ~ rela .. ,'c (lOS.UOft.S. J. We do ~now ,he ... rlK:Iu .... of the IC<:"IM'" - ' ..'e b.own h,lnds <II" ,nh.b.k.n. ThIs i~ ioc.....t>ln;ly be.:onHngthe: SIlok: of aff ,"" for l 'OO\lin m.:cplon. ll'Iere lire 100 ~ no .... n '":"po. .or- hllnl'o!l (OInplnes pubhshc.-d in the 1'n:Kc.n !).:lla Bank Iha. ha,c 1l.'J,:' a't m ex",on, huonan ,lIne<a;. I'harmaccuucal com p3J'leS hn' c man y n""" enmplc . A, SOOI' II.S one dnog com p;!UY p;!lenl s B dru, ... ,III ac';~;IY for .lno...n "":"1''')1". Olhe:r comp;> n~ ore qukl ~ thi s inf"""alion If)' <k,'cl,,1' no\'d ~'I\JC"'~ ""h pakr potency . Ion&er- I~unl: lIC",,'y. fe""", M<k tff""tv, elC . Th.~ .'1 espalfy true If ,he: martel for lhe lIfelll .. a I...,., one. no.:. IC<"hn"lUU for findin, roe" drop in .h,s 'i,,,,,,,on comblllC (IJ/ pbarmaoop/looc diJ.co..ery "''"I blOwn "pnd, ,... (b) OOclonS and looiecullU" mo<khnl! of roew trueIII"'" ) SIlo: hQw ~lIthe:y fil ""o .he ~pI"'. This i. l"""n as ,1m.,,1 ,("r"~MlnJl. 100 ;, i, be.:oml"J: "~'r" impor1aOl ullthe t""e. The qu;tI"y of vIrtual ""rttlli"l1 w;ult, depends OIL the quailly of tho:: pro!~'n and drol rnoIeI;ule Ml1,IClUre~ we sun with and ,he accuI'Xy of."" ma,he:ma.kIJ funcuoos .,,", radon lhe <klltt or b,nd,n, rl'Olll,..,h ':K"IOr:!. as Slmc, dCC'fOSla.lc. hy_ droJlen bond.n.. and Iopoptuhc ,m,..,....,,,,,,, bel ... ",," dr drul Ind IIIe R!plOf 4. In the final_nano, we knov. ,hi: IWUCIU,., bIoL we 00 tIOI hne kno""n hg3fllk or mh,Ili'OI'l . Th,s is u k:s.<; h~cly ~'$(' th:ln _nario J, bul ,he dccndonl of lhe human gt:nortlC nlay ~lIange ,hal. Of the 30.000 .... noon: 1('1eI ,hal ,.,., ""' ng annota.oo fro", lhe ,enome . i' i. !:!ohm.'ed Ihat perh..,,~ IO'J nllly ha,e MKlOC rl'lev3oce 1 human d,.'l'a.'l'. Thi~ woold "'Ilfl'0 >cnL 1.000 roc ... cn1ylllC ,.rgeu fur drull """"Irocn; 10 ... or!. .. "II. RC!oC'~"'n; e~pecl 10 or more ncwlBrgClS 10 be: cloc](blcd ea.;b ~ar.!IO lb fI'O""!oCS.o he. ""'I-Ienn pr0JCCI. In many ca>C'S. the CIIL)'TI'IC or IoIrlK:Iutal prou:rn thai I 1""" encodes .... y be: d,fflCUlt 10 CfY"alille for X -Dy 1II3Iy". or 10 Sl udy .n soiuuon u",inl NMR . In ~""b~. proIe;n moIccul;or mo<klinS llUy be: u~ j"Iftd,c' ,toe SlrucllJl'e of ltoe cn',ynoc. 1\ cummooo 3j"IJ'll'UOC1I LO h()mo/llft)' nlOdt lo nl. in which ..,que"",e~ of."" ""kIlO'" n proLcon are :..~.illnal ....."Ondacy Bnd ICrtllU'y ~lructul\'S ba...."<1 OIL ' ,hoM: of ~llOWn protelllli ..i,b ,im lll! o;cqucOCCJ. IBM h... embarl cd on ~ projec. l no...n as BI~ Citne,' '0 'r)' 10 prrdle. the WUC"tU"'" and 1C<:"",or MIC!i of all ttoe prote,n pmducu of the human I"nome. 0\ .... a penod of I fe ... yell'S. U!ionll Mlp!foompu ........ Once .he elll.)'tI'IC W\lCIU_ ~ ~_n or prnIK1cd. 'onualloClftnonl Qn be: usN 10 find drull molecule! lha. m,,,,. fil ,1110 lhe m.:qoror.

hr.u'y. "'c wanl 10 1001. for ~mall cllangcli on .he b~slc StrucIun:. IU lind lhe be,! c muhmmiOlI of ,uh!"lIuems Ih~\ will
yitltllhc hight~' :ll:I;\"lIy. lhc 1i"';1 la~k i ~ 10 dclilM: lind qu:ull ify che mkul d"l'~ily. Thi s l"C(jui~~ a dclinU,oo o f chcmocal lim.iur"l, ,'rlCC t1,,"C'fSII) i~ MHmially ,he oJ"lPO" lIe of similarilY. 11lcrt' an: sevcral .... uy~ 10 quantif) .nola:ular ~jnlliarily . Two CQIl1l l101l appruachc~ in combmatorial chcmhtry llJt' (IJJ '0 define SImi lan .y U~ the cloo;cnc" uf ,!llICIum !oeach other In the space of somc phy"C<lChellucu l ur 'opoJogK."al dc.'\Cnplot<; (e.g . log P. '\Olub;li,y. or polar molec ular su rftlCe ureu) IlI1ti /b) to delin.: vhnilarily U) the nUll1bcr of simple "ru.:tur fcatures dl lhe compounds ha\e in l"\)Ilml<m (e,g . cllmonyl groups. pbcn) I tings. ".c.). Consllkr the molecule, Ln Table 3-2. ]f.he molecule, dkth)lsli lbe<;lrol. i\ uved tl~ a ~"mlariIY probe in a dalabase of drug vlruclUre!>. o;c\cral ~her structu~ ell" be fount! (sonIC of .... hich arc cSlmgclllo. but many of .... hich IIa\C other UCII\it,es). 1llc Il105t \UI"lar \,ru~IUrt'S do lIa.c es.rogcnic IICtjv!ly. anti the} hu'c \al"e~ s. milar to tho\c: of 'IOmc uf Ihe othcr dc.\ Criptors in .he Ulblc. Some dc'>CTlp'ors by Ihc", sdvc~ would be poor prediclors of molecular ~illli1arily. For c:ullnplc. one can fillt! 1I1:t1l)' \ttUCtures ""Ih ~imllar 101 P vahx" btu ..nh dlfferem srI\JClurul cbar,jC,etistics. r"Ql" this reason. there has been iOllll' COIlITO\tIliY aboul .... hal thl' "best" ' appn:o:iCh ' 0 )IRubnty and di\'crs.' y IS.'" In ,he de sign of Uplord'O!")' librdric~, lhe goal i~ 10 -.ampic I .... Ide: ~;.riely of chen"cal SU\lClures. !oO it is n:asonablc 10 usc dive"ity InclL~Urt'~ thaI f()l,;us on ~Iru"\lral d lffcrt'nces, ~uch a~ 20 nlOleclllar similarity . Wc -;elect molec ules thm arc dissimilar.o each lIIher. In ,he dc,ign of optimi/.al ion librarics. the goo l is often Iwofoltl: 10 incn:a~ potcnl.'y anti 1 0 op"mll A O~-t E.Tprop::n .C$. M inorcbangcs on the "ructUR: arc usually made at ]JIllnl, so all lhe Slructures \bow hIgh 20 ~im ilan.y 1 each other, Bu, minor changes on sub0 ... itllCnl.~ can change phy)ocochcmical propcnres antllTnhf} ,he inlctllCtion of lhe drug ... "h the reccplor. so the other dc'\C1"lptOf'i in Table )-2 an: o ftcn mon: uo;;cful m the lead OptimllD ,inn Slag<: o f a pro;"''t.1. An t~mnpk of 1\ si mpit' change Ih31 cau.'>l!S a large decrease ill binding arlin'ly il \Cell in Figu!\' )- I ~ , .... herc lhe replacenlCnI of a II atom by II. IIlC, h) I g roup reduces 3CUI-';I)' 8O-fold.19

Iuo,,,

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, hM ooe of IIIe abovc scenarios holds for u gi~en drug dl!"::Ovcry project. one common ly proceeds through a .seqUCIl\:e o f Chemica l libraries Oli d lC way 10 Icad t1i!>CQ\ery anti oprimiallion. Th i ~ process lias ~\'cru l p h:lSC5, antl . bc libraries ,1Ia1 are designed at any ghcn phase Wow varying levds o f dlVn'SlIy. size. and speciflCLty for ,he ghen rqllor. T"he 10011 of library desig n i~ '0 select a su~, of molecules from 'IOnIC largcr coll1ion soch thaI .. e are taking samples from vmow I"Cg ions of chemlcll! space. If .he li brary is :m initial or UplortJlOry lib rary ..... e .... a nt 10 sample as mUl:h c he mica l spacc as possible, !ltl .... c i\Cek structures .... il h h igh divCl'lii ly. If.11o: li hrury i, a !IIore/I1(:,ul'd library, .... e want '0 sample a smaller n:gion of c bc mica l space in W ~igh borhood of the rnos.t acti\e struc. ure d iscovered in ,he CAplorn,O!")' lillrnry . If the librllty is an opllmi~/iOll Ii_
Ass u!llin~

CH,
R R

H(67nM) Me (470 nMl

FkJure 3- 14 ( hang'ng" H .,'001 to., melhyl group his, iMge effeo on brndlllg to the 1'I-.1fTl'nobolync iIOd (GABA,J leceplor

TAIU: )-2 Simll..-ity of StructurH to Diethylstilbestrol IDES). Usinv Various DeKripton

Molecule

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Kaorwl

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decided on some mcasure(s) of di\efllity. the next step is to lICtunlly !oClcrt MruclUres from the ~I arting colle-c. tion. Typically. we sc lIX:I eitller whole compoullds fOf' HTS or reagents 10 be used in a particular synthetic Step. The seltion pruct'~5 consists of using similarity/di versity mea sures 10 pid. compounds that ;;.ample chemical space in a manner appropriate for the Iibl1lf)' belllg gcncr.ued. Thus. for an exploratory librury . .....e ..... oold pic k di\en.e structures with as muc h <;tructurnl v:mation as ~ibk. perhaps sub~I to (lme ruk:~ about slu. lipophilici ty. etc. For an optimiu lion library. we would p ick s ublitituclllS for II given scaffold thai span mlditional QSAR space ...... hich includes ste ric. electronic. and lipophilic propcnics of the substituems. The mcthods of !>Clecting structures come malilly rrom statistics Wld QSAR .-IO llley include the rollowing : RAndom M!1t1oA. tlere ....t kI the rornpllt" I""l !ilI\II;'ILJ.I"tS :lI rwodom from the .nmat rooIlccuon We .... y " bo"," the r.mdom seleclioon by filtennlthe il/'UCtura IS they an: pocled :lIId rt'~lInl unn lhat " 'c know "e do 1I0OI w.nlor lh:r.1 an: 100 s. m.l ~r 10 J1rucIU~ alrt'ady pockc:(l. Visulil ~ll",' lon. If " 'c have IiClcctw. for ex~mplc. 10 (\;:scripIUrs for ou, chemK",u 'I""'c. ;1 is difficllil 10 find di'play meth odt lIIat ctU. d.<;phy Iblll in lu gh d,"len~.ons. n.ere me p,..,jrt'. ".". medlo.b in . lal"hCS WI can mnc " WIadow" of the poinl, in h'lh-dtmemiooul sp.tt (MIl'" IWO or tIom: d,men AOII$. III .. hich poInl I standard t"H,men>tOruIl (20 ) or tIne--dtmell>->Ol1Oll (3 D) K2ltnplol: <;In bo: u!ifld 10!itt """ tho: poInls are d,S1nbulCd :lIId 10 select rornpourm A.\Undanl method for Ih" pru}ea1l"Ol i5 pnltC'll(Jl N1<npiJ<I~"1J ""'QI,-s;s (PCA). In th.s IIJ'PRl'I"h. " 'e ge""r.llc cwp'" of new Uo'iCnpI,,". the princ.pal components. Ihal AI'\' Imear comb;na. lOfI~ of the oriamal descnplon (p('. - "'.x. + "'.x, + ...) wi.h ea.;h Uo...:riplOl" (xl " 'dghu,d ( .. ) lIoOCOtllinli tu how much il romnbulelO 10 lhe: 0\"Ctal1 ~anallOll of the data. Uionin.. tr v.<: parllUon dlcm...al ipAC"C .ntO rt'liom. hkc ~ 011 I dleclcrlJoanl. " 'e can pICk molcculc5 from each IqIOll 10 bu,kI our hbr:lry. PYob;IbIy _ "'IKIQ!; ..,ill ""'e many struclure!! In them. :lIId we may J"Ck lII:'cntI from """h arc"". Some: ""ions w.1I be: cmpcy. ~ arc ICrmed IooirJ .n our collect,on. ~nd ,.e ""'Y ......,.,t 10 t.Ic.illn "ruclwn "nh propc:ny 'al...." .ha, ,,-...old help fill .hese hoi",. Cluster . " wl,.sls. Thl ~ mefhod involve, ~t'lislku l pmccdure~ Ih'" Iry 10 d.I>CO,er nalu .. &""'p'"p of compollllds ~1 on the of Sin"larily or d.stlll"ltt be' '''ecn lhem. Clu!ilCf methodt function <'Other It) parlllionini space OIl the basi~ of lhe \knslly of the ouonpounds (el .. K .mel~ ..... \ISImnl!:l or by bn!;.ma lhe compounok .n I t~hle illlICIure (hoeran:hlCal dUSIcrin,). TIle rt>Ilh 'S 10 as"ln each rornp)Ilnd 10 I,..,..,P or dustCf. Compounds ,,,th,n I du~1C1 are man: s. m.1ar or closer 10 ea.:h odIcr. on a\er:lgc. IhaI! 10 l'OII.pouno:h 'n other dusIers. ~;l<p"rln.c"'~1 drslt:n. If "'e hD.,e sellW ~ , ui>soel of struc lUre!; fro", our ( oIllion. " 'e can ILo,e any of Ml"CTlI I Slati'Iical me",urtj; 10 'I"",."fy tnt d"'e~lIy of our \.U\>ct. Further. \ht", an: S1ru'>local ..c:lechOl1 proccdtlre-s ,hal. if fol ......w. ",II m:llc "mon: h~cly lbul POllua"u,...,) IhaI. " 'c pocl......., and......., di..- JUbstt;; 1l1c<e are "",'I1U:IlI"'" proo:~teli. and lIIo:y an: "odely u!ifld ,n the design 0( npmmcnts. .lUUst...al ~r '"ey1. etC An uamp'" o f a common procedure 15 0IIt calk"d D..op",,,,01 ylrt"""" ,,h.ch ~ des.,ncd 10 pock SUbsel of p".m. that W'\' Iti " 'idd y JoCp.:u1IlCd from e;.eh ,"her as p"'~jble. G~n~t;c Yl~ lth"'s. Th.s opumllalion pruccdurt' i~ i"-'p.n:1l .... by lhe "'~y leMI.Ci aoo " alUnd !oe1e...1on ,,or!;.. To use ~ ",. ""tic alpthm. .. e "",,end that our >11.,;1;"" .s an anifK"iai . '~lIOflle." Each strucl"rt' III the ooIlccuon '5 I b:ase 01" string of bties in the ICnonM: (",>!Cad of A. T. G. Ind C. the ba>c:

Ha~ing

deSllrnlUOfI is JUst t or 0). Wc II.at1 by se'''''',nl random IInnlls of Is and Os 10 reprc-.cm .he seoomc Each slrina is mea~urctl for .Ile d"'c~;ty lhe mu~tul'\'.' In the Mnnl rcprc-.cnt. Th,s is ~alled lhe fillltu uf .... wing. Tht-n. "'c a;>ply .he Kenct lC <>per-llion<; of mUIuuon. C"roSSO'er. and rccombmauOfl. 10 aCIIrnl'e new population, of I, lnd Os. Some these ".11 b.1\"C hoShtr fltneu ,a]UC$ (mon: di, eo.ily) than otbm. Ch'n bme. t i ~e rqx::lI lhe op:~I00ns.1hc Q\'mlUIC"O,,1C ..... n lend 10 impro\'''' I0'I0'''11 III(ft tb,"CnC' rooIlcctlOllS of JiIW' lura.

or

scnn..:

M Ob! of these methods. mcluding calculating descriptor.

and mea,uring moiccuillf similority are pan of combinatorial chemiStry softwart' ~y~ tCI11 '. 1"1~ SySlemE are provided by mo lecular modd,ng and by c hemica l mformation companies MlCh as Accdry~. Oayltg hl. MOL Wld Tripoo;. They usually function in the conlext o f a c hemical structun: database . Such databasn can store 20 ~truclUres. 30 I"\"IIXk'ls. reactions. ge. nenc struc tures. buildina blocts. 1U1d all the physicochemical and Inventory dala In II ~i ngle n:poo;i tOl")'. "ornt:umcs cal led a (/II/(! IIVift/wU$t. Chel\lIcal data are indexed and accessed by strocturc or slructure 11). Bio logical datil are t)picall) indc:xed und accessed by .... say or teSI I(). For this rea~on. mOSt drug companit:S have tnditionally stored c hemical flIId biological data M'pamldy a lld u!>Cd different Sy5tems for ac cess. In the past fe w years. ,t has become: commoo to ~ton: both chemical structures and biolQl:y dau In relational datab.at:S MlCh as Orucle. This lrend toward Integruuon or the two types of data is rno(l\"U.ted in 11IfgC' pan by lhe flood of infonnation loot c ombtnulOrial chemislI)' and !ITS are generJung. M05I large phamlaCeutkal companies are ~yn thesi ~.i nll and test;'lg 1000 times as many SlruclU~S toduy as they were 15 10 20 ycurs ago. with a similar increase In lhe amoum ofinformmion that mu.t be collected. organized. Stored. and interpreled. The drug companies:ll"C taJ,;ing a cue: from large retai lefll and financial vcndofsWldadopting data 0 mining" techniques 1 se:m:h for hidden MSOCUlhons. du.. ters. IU1d predicti ve n: lalion sh.Jl!i in the mounlains of daII they are collecting in lheir datab:lses.~'

"'''Ii

bou,.,

REPORT CARD ON COMBINATORIAL CHEMISTRY: HAS IT WORKED1

A repor1 publis hed in 1998 s.ho,,ed that virtually all of the major pIwm:K:altica l fimtS had adopted combtnatorW c hemi $try to some el<lent tn their drug di~o\'ery ~~.~l The degree: of adoption r.l.Ogcd from 16 to I()()% of 1lC" drug synlhesis. wilh an ll\'erugc of 661-. Ckarly. the: pharnll' ccutkal fin\lS ha'e a big stake in combinatorial cht:mbtry. but hilS it really worked out? A, of th is writing, the: phanlll' !:Culical finns un: Mlffedng large incre~ In rescarth 1ItId de\'elopmc:nl expenses. but .... ith decline in the number c( new drugs in the pipeline. Many fim'S oo" e a large fTllCtil)!l of their blockbuster drogs (>$1 billion in sales per ye;p] goms offp.:tlcnt in the next rcwyears. Pan of the problem 1m been the puflluil of only a few. hI ghly profila ble. thel1l.~\ltJC larget~. For example . there are at least seven stali n anti cllolc~tcrol dru gs on the nlprk el: the mosl profitable one. Lipilor. cum:ntly collcct ~ aboul $7 bill io ll in salt:S ~r yeu for ils developer. Another proble m has been lhe marl.cttns of drugs lh:ll appcartd to be safe. C\'en throughout chmcal

trl.lh. but IIcre laler found 10 cause serious and even fUlal ,Ide dfu (e.g., Scldane and Bay~'Q I ). Therl: I~ link qUC5lion thai cornbi nal oriaJ chem;~l ry has btm dffCIJ' e In ~encnlling large numbers of lead ~Iruclures.

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build up .he,r in-house libnlric:s of MruclUres Illal could be "mined" for IICliI ity against newly discovered rt.~cplOO. A typical phllJ1naceuli cal finu has accc'~ to infOl'-

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can 0Ienuc:a1 Society Chemical Abstracts Service). In addi tion. large companies hale their o ....n muhimittion-rompound databases. Golebiowsld et at.~J de5cribe how Ie3d struttulCS wilh a wide I'arie'y of actiltj,y nave been obIained wnh use of combi natori al chcmi~tl")'. Some examples are ~hown in Table ]-]. demonstruting the vuriety o(s,ructurnl type~ th:lt hal'e been gencrn'~-d. An illdustl")' perspective published in 2001 reported 46 cornpOIJllds in human clinical trials 111:1 origin:wcll (rom IITS of libraries ,h31 were iden,i' fied between 1992 and 1998." What can be argued is ""hether the goal of gencruting lead structures is sufficient. in tight of Dn increasing rejection rate of candidate drogs in clinical trials. caused by side effects and OIner ADMETrelated failures. Most researchers would agree that ...e need to prallet ,he "drugabi lilY " of lead better before much testing. if any. is done. As mentioned in the ~ion on vinual5Cf'e('mng. mu.ch ....ork. is being devOled to the development of better in I'i,ro and computatiOlUlI methods for predicting ADMET propenies. Alltmatives 10 combinatorial chemiSlry are appeMing in the li,erulure. An uarn.cle is the "non-rornbinatorial" ' approach of Everett et al. ' 1lM:sc author.; argue 'hat the gool of combinatorial chemistry shoold be the quality. not the quami,y. of leads. Some trends 'hal are appearing in ,he litemture include (II} s maller libraries. a few thoos:md care fully se lected s'roctures r:u.her than 2.50.000 has,ily designed ones: (b) more allention to ADMET propenies in the early ph~ of drug discoI'"),: (e} mlniaturi7..11tioo of syntheses aud assays. using microfluidiCJ and fUlnOl/m%lO. both ror speed and 1 con5enle 0 resotJI'CCS: and (dJ an integl"lllion or genomic andcombinaIQrilll chemistry technology for beuer use human genome in(ormation in thcdcsign o(ocw drog5.06 M ost chemists agree lhat combinatori al chemistry. aflcr 20 years or evaluation. is a ~ ita l. but nOl the only. implemenl in the drog discovery toolkit that ~hoold be used . Like OIher tools, it can be applied intelligently to great benefit. or it can be misused.

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COMBINATORIAL CHEMISTRY TERMINOLOGY

1lIc rollowin& terms are some o r the most common used IR combinatorial chemiwy and HTS . Morecomplete ,Iossariei
can be round in BeckSicklingcr. A .. lU1d Weba'. P.: Combinatorial Stl1l1egies in Biology and Chemiqry. New Yorl.. John Wi ley & Sons. 2002. and in MacLean. 0 .. et al.: GIolSID)' or tenns used in combinatorial chemistry . 1. Comb, Chem. 2:562 - 578. 2000.

RESOURCES FOR COMBINATORIAL CHEMISTRY

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isoy and Dueovery. New York. Wiley_Li!s. 199ft Terrell. N.: ComtlinalOlUl chemiMry. In CompWn. R. G~ DaviH. S. G.and Evans. I. (od5.). O.dQrd Ottmisoy MlISI=. Oxfon;!, UK, 01ford Uni"n$ily Pret;1. 1998. , .... brief. highly readable InlrodllCtion)

The rollcclloo of I m0lecule'. PfOIlCt1ie<l related to abs<lrpllOO, dhtribul1on. ~ lism. ncretiun. ro~lcil~. and pIIarmaco.tmc:ticli. These fal"lOn arc bein& incre,"lni:l~ ro<I5ideretl in combifllltoriallilnry de~iln. to yield molecules that ,,011 be I1lOf1l ~uil~ble t i r.ln.al'Aptamcr: RN .... molecule that displays JPeCific bind,", 10 I ~,u,,,,,lIy. proldn. Apcamen we allen u,w tn ~. ray. In place of antibodin. 10 bind pq:Ittdc: " lands. "rra~ 5)'n thtsd: The form of parallc:l sylllhc:s" in ..'tudI . re~1on ~~I. aft: maimamod In a p;iI1r!:ul&r ~tjll ... & men!. ~ud! all end In microtl!c:\'"pI'lIC:. Such I on I ~ basis ..:: lC1lhOO JptJli4l1r aJiJrtsw#!lt I,bm".. Hlldr.bo~: .... Io"",:or ~okIlO .... hlch .... b$lIIUUltl; Ire altadlai. Common backboo :s mdude the: a ear bon bac:LborlCl of peptide! and pc:ptoids. Hf lld : .... )JPhc:rinl pmick of wlid suppGfl. Typic.lly.)l) 10 100

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the >aJucoce 011001 ...... 1<1 tDCodc \be prutncc of III .... of Iii pos,Mble . . The 'ft' of comblftallon. ,hal can be enooded IS 2". ~ Ihr. numbo:r of 1""5,1'011. in tile Sin",. ' B. .!at: A rompulIIlO.W .,..xedun: 10 allow ",lectin, chenl..:~1 IIIK,,,,a ICfOW. " '!<k I'IIlse of di~I)'_ Tl1e "",,,,1W'r$ at"f I'IiiijAAl,IIIO btlt$ on ~ b.II.i~ of ( ..",moo phyotcal ureMIl1l.::.i
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of addon" ehell'llCal or declI""'" tag 10 brad for lhe: PUrpD5CO of "n:<V<'dm, (he Iit<j .... ""'" o f ructIOn "",pi 10 "'hKh!he: bead tw been upcJerl. By JotJ. "'I the ra.ulung 111- pcm:.p. hy rrcaung DNA III "" illl polyl'l'lCfllSe ehalO n:aci IOll und analYli n, the oh,OIluc!eoli!le. the: e....,1 nature of lhe lynthetlC larget on the be;Ld c.n be dc:lerm.nrd. !!nu me ratlon : The IWOCCSI of u pl"',Ily tle5<;n blO, all of lhe spttl roe Ii!fUCI,,1CS (lui ' gc:nnic .structure Of hbr.uy 1'OCI1:U1L'. t::P; lopt: The ~I._ of I pmteon .wand ~ Ii rccognllm by an . nllbody_ ~lnjCtrprinl ' An ~lflIy of nllonlJenr (II ,. nl . ... ) IIw numtn(!lllly ~pro.cnlS I wruclu~ IS valuc.'I of ph~slCOChemocal or struel"",1 ~nptonr. Commonl). lhe nUlnbe", are bltwy (0 or I I. bul IMY """y al:;o be """nU ('" hole numben) or ..... lues. n ow ,)Iometr,.: Thnoquc: forcllal'llCknallJ ut ~"nl p;ar. !Icier; ~UCh III beach; or cc: lIs. of"'n on (he basi, of the" fllII!f... CellCC Used (0 ~p:.no(e beads thai .... ve biolotloeaJ ly !ll:11~e moIco;ules I ttached. .l...,......~ $ynlh~: An approach to ""1"uon.pM .....ynlhe"o !hal USl'll hlShly fluorin:rr"" t:001p.)IInck lIS Mtluble 5U pponS rOl' combinatonal che:ml<lf)' ~ add;""'" of "'1IIer or orpru<' !.01~en .. c.u_ I phao;c s.eparu10ll of lhe fluonnau:d klppor1 for . ubSC'ljuclli ckavlj:e of lhe ~y n(he(l~ t"'l!ft wuct .. re . ( :encrk Slruclll ~: (;cne",1 WUClur.aJ formul. o fllibnty. ron """',nl or a sro,ffold ( p:.renl "'rucw~) polus .... JulurJ { R ,nlllpl i. A ~Implc eumpk: is R,-CU,c( - O)NlIR1 Gfltcl", algorithm : M<1hod of hbory !b.", by .... IccI'IlI wbSlllllC:nl ~ for. hboary In wep>oo-ise fashoon. baocd on the filnesl' nf (he: =ulllni libr.Ll)' r..... $(>I'IC pu."..,.. (e.I . biolol;"',1 """~. ilyl, At each Slcp . lhe: wbo.lnuc:nlS an: mod.foed by UJe of the ~oc pnfICiples of m;omb,n"uon. c~er. "'UI:lIlOO. ttc. Sc Ilion of tile 'fi nest" romb,na,ion. of 5ubsllt..enH )Iclds hbm)' !hot! is locally opumal for lhe '''"' pIIl'fKR G~n nuoreaont pnMtln (G FI'): A 1"'\*''" .Klbrc:d fl'Otll )C'lly. fish (.... tlt3'J ilS o ... n nLI(RSCuIf':c . It 'Ill' be nKlllI Ii"" '" ..... nOll' poIlUOfIti 10 gc:nc:ntc moIc:cules lhal nl.lOfUCC :II d.fferenl wal-.:k:nlltK. The DNA for Ihls proteon can be onstnerl ;,"0 the: gc:nonleS of' II. 10 ,ive (10<:111 fllIOIcscenl labrt. lI iJ:h. lhroogh pu l ,u",nln~ (l ITSJ: The: po ... u. for """dly B t'>Slng tho: l<uVlly of,....pI fl'Otll """,buwonaJ 1Ibm)' u or othercoonpound w ll tion. u~U.1 l1y done by runninJ: parullel assay. in pI:rIes o f 96 or n1Otl" ... db.. A scn:en'1IJ rile of 100,000 ,,"'YI per tby il lermerl .. /,rolI/,/od,"""""",

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~y.

li ve model for SOtTte ",...,...,ny or rupon'lt. The rnotiel COI'ISIMJ of input "n0de5" (the Inpul dlt.~), a ~ of " htddrn" r>CXIes,
Ind one Of mort OUlpul nodes (the pn:dlC1ions). Each node behlva; l i~e. neuron, ,,"h. threshold value: of llIpUl bekno whICh n ...,ll not "fin:" any output. Tbe Itlltn:onncc:uoa of IIOdes allows the roet ... ortc IOwl WIth complu _ lmear reI ... tiomhips. 'J'hc, roelwoti; II lrai nW by Ilt.-i~c1y adJUSling the " .... ighl'l It lhe nodes on !he ba!>il 01 the diff~""e bet"tctt lhe: oIiuro"Cd IJld ihc pmItcted OUlput. OmbMon Il b...I")" Suat~IY for illmufyllll IClIVC' librwy_ ben by.he 'y~1enUU lc omJ li!iioo of buI lding blocks from m,~ ,ures. Clt>KI<alioo of reduced leu.'uy in ccrt:lln pool lUI' JCSU tIw the: buildtlll bIo<:t 111M ooruued In tIw pOOl

Ubrary: A C()llcct!on of SINCIUrtS, CL lhoT a t~l1otric hbrvy (based on !oOITIe scaffold plus mul tiple 1l'~1!IucJ) or. mi;(rwr~ lLbrvy (toolllll.iP, d'VC'Be IiCJ.ffolds). The nurnbn" of "flC'CifOC SUUCIU~ ,n libnry 11 c,ther tM produc1 of the numbers of rnid:un pouil:>lt '1 ta<.:h ",,"able "","ion (for. geMl"IC Ii. brary) or ';mply the ,urn of !he number of Ilrue.U (for a Il"

m,JIW'e hbrvy). U nker: A ehmlkal dIa,n Ihai ~ !he 50hd or 5Oluble: JU~ 10 !he .ynthetic targel UI ~ c:ommnl1on;al npcnme nt. The: linker to decompo$ed "hen the deS lmj compouoo is dta"ed flQlTl !he IIlIppon. U pio>ld ..,. of n.,,": A >It"l of en.ml for "..roic1i", !he 0flI1 btoav:ulabllJ.y of a c:ompou nd 011 !he t:.il 01 Jimple moltcular ", ...,...,ni~ (molecular .. eIght. < !(lO; loa p, <5: number of hydroaen-bond donors. < 5; and number of hydrogen-bond ~ep(on, < I OJ. l'y~ly.!he C11im1 ...., apphed to . btnry 10 fillft" Struclun::l from !he librvy bef<ft .ny ,ynthe5l, lakes place. Any sttuctW'e ucetdilll ' ..iO or _ \;rnma IS Il'jCCIaI. Uquld . plul!i<' chrm l$tr, : The pr!)Ct1I$ of ",m, ~ large . ~ I "ble 1ll0lecJIe II> !he lU~ fOf a eombona.onal chemi!i'ry uperi-

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OIIt>COn'poIlnd d ra ..., : "The carlini MnuelY for JOlid'p!la5e combinatonal chemi~'ry. In "hoch each Ixll.lhQ moIecuk$ of on ly. Stnalt WUCIUn: Mlld,e<! Tither than a
ml~I"'"

of $UUClutn.

Loadinl' Char:octtriRIC ",...,..., IIY of a IOlJ,d wppon lhal describes lhe amounl of . specific chemIcal IptCltlI 11\:1, can be: aunched synlMlic.lJy III a unil mlU o f ,u ppM. MappiDg: AnaJYZOn& ihc ~ of a JlfOIt'In "'Ilb n:gard to OOIR'd ",...,...,ny 10 ilknul'y lhe RSI\kIQ 1n,"OIved In ~nd'nl or acIivi. y. TypicLllly. this tn\"Ohu gelKraunl short, o~t1IIp ping se<:jllCnct:S of lhe protein. perhaps ()r1 a micfOOmy. and . ,eslIna for acIJ\;' Y Ma rk llJh Jtf"Ut'tu re: A .ypt of SUUClU" ltpoc$<:n UllIOll .n ... hlCh very Jenera! .emu;. IUd! &Ii a/kyl Of tJIcohol. can "'" LtKd 10 descnbe lhe lOubl.uIllCnl~ ,n a gcneric . "'tU rt . Uo;ed .n the W palen' IJU'nIlllrt and adapted for oombinalorill chemistry pub1!CIllo",,_ M r m btr: EuhoT (a) a pIIntCllw SUbslUlICfIl1II IIl,t n P"StllOll in I getl(r1CSInICIUR (QI R.,""'P membc:r;or Ib) an cnumt11,ed wueturt 01 g~ncrie hbrwy . .. hich COlleI'pund~ ,0 a ginn so:lec'lOII el AtbsIuucnu (a membe, of. libnry). I\1fth 'liu: "The demuy 01 " 'In:>; .n ...",....; allo, lenI1 to de.robe: lhe,,;lC of parudu. A 100- 10 :!OO-mc:sh ~lcI" ",II pass Ihrough II lOO-mcsh fillcr bul be lrapped by a 2()O. me"h filler and coos" t of partocles 75 10 1.50 I'm in d.amc.cr M icroIIrno)": Mas.l.:1 c;orl be LtKd In lhe Iamt way 1M! ~l(:lIClb an: used 10 m:lk" pnnled c,"'u ,' boards. to euhoT a1krot1 or bI""k UV hgtn from eaus llIg chemICal n: ....... i()r1' in Inlllil Ikfinro ""'.. In thOi w'y. a lillt:iry of hundmis or .1loo!4,Kl~ of compound. can be I)"nlhet.ud in a grid layout, ()\"tf. vtr)' W>3l1 area. pnbap5. frae' IOII of. ~ inch. "The n:whon, microlamly can be uJlCl6td .o~ l,ven rtetptor.lU1de~='m ng the chip under UV lighl un n:vc~l ... hit;h MfUClUn:>; ha,'c bounol .o lhe receplor. I\l l_ic!l: Compound> that 5han: lhedem'ed propenies 01 other ",oleculQ (e I .. lhe Ilffinuy for a I,,'en rt'('CpIOf) btu dQ "'" share lhe undes.rnble prupcnlu, )uch IlIo Mlso.:cplibililY 1 p'\)0 It:lISe!i. An lmporwn, clIO' ut mJl1",lto .. ptpUde mi_.a. Mim<HOJM': A compound th:tt Iml~"" III q Ulopc; Iypically. nonpeplKlc: ~nce ,hoo. can btlld to a particular IIItib!xly Mi"""opc:!o well' an ,mportant e ll$) of compounds scudocd .n ear ly combinatorial chemlslJ), upc:ri menlJ. M onomer: A member of. Kt of bu,Id,,,, block hool can Ix rcp:altdly iliCOI poc;lIed .nIfl a Iobrvy Ie .... I n"l10 aci<b .n a
ptplide library ).
N~ unll

-.

Orthogonal dt!!lgn: (aJ U.inl protect'"l grot.IfJII or Itnkers en I combirworill c~ perimcnl lhal do not inltrfc" ""h c""h Olhet chemicllly: or IbJ' pooIln, Wilt&>, In ... hich. a"'cn libnry member ~'nr in mort than one pool. ml~ed WIth othef membel1. Poob ha..... oaJy one wuetU" in C()mmtJOl. at>. Iut In !Ie'~ pool$ impliel Ihal a lIven member is Il'Spott<LbI< (or !he aru\"y. I'tp'oid: Ol',omrr of rq'ICIIin, N.$Ubi.Utuled a.lYCUICS that atIt emulate. ptpUcle, WIthout be'lII W>a'pIlbie 10 acid degnda-lion in 1M gastrotnteslinal tnocI. "h. ge d lsplYy : U'loe of baclenophaac .intst'i as vesscl$ for~. sent.", dton peptide litgmtnli of the" ~IVC surface proteI .... Hy "3f}''''11bt: ",IlL nq...no:a of !he p/1aC'lln ......Itbt_ nil m:mroet'. htnries of pep!Joo cwo be I(,,,,raled and le~ 1'loltrnl;oel't)hoR': The ense mble of .I'eric, eluooic, and hpo" Mic farton ttoOt<kd to tM\tfl: Inl('..-Tion of. drug molecule " 'nh ,,'en 'Kepl"" ~ are Il1O<l4 useful II se=htnl I thl"l'C-dllntnsoonai (30) W\lClW'e tIiotabaK' and. filtcn nl ~tnocrull'S (or \lnu:o.l l'Ilotol ith"'lll'ltl)hy: The process by geroenlelt lip.. I*'C tIw din:a "" In ccnat.n _alel. p/IotOK'OSmVC' buildmK blocks 10 d,.o;cn:tC S'1CIi on ,he ~Iia tt y Ildtlrer.sable mocroamLLys of compwn<h. " t,,: An clonpted de~~.n ,,hoch ihc 1C1511i a whd lUppOt1.

.u

lipUr

'" ,n comloinat(ll'i.ll syntho;... ,.. SlJ\IC.urt

re,,",llonO'C N): Tc.:hniqllC for amplifiealtOll

l'oIl"'~nose ~haln

of ....a.l l amou ntS of DNA. Mlnen. ",lb. fe ... nlOkcultl...:1 yoeldinl IlUffococnt nwcnal to II\iIt)7.C' ihc ~""IIC'C. Aka "Kiely used in f<ftnsic DNA .naly.i. l' voI : la) A 5Ubsel of. III ~en combina'orial . I and mi~i ... I , ~i. and I

and

mi~ ~

re:!lttl.. In Itbrary on

bead ut IOlid ,uppM cames I s.nglt

ntt .. urk : ComPUMioo.al pooccdure 1 gener-llc Bpm.hc 0

inc!il ..... l Ii

C h~p' er

J C"",b;tlllI(m'o/ Cht"ds.ry

63

number 10 the lOla) number of b\lIk1inS blocl S in the "lI<lk liblary. In ~""h pool. ~ $ubstiruent posit;"" i, held 00I\1.IlII11 by 'OCOOpOUllllj a single b\lIkhnll block "h,le the
In

equal

oJ! ~jble buildIng bloch . AClJYily in a ii'<'II pOUl implie~ lhallbe Iliven ~UbSlilue'\l allhc lIi~cn posl tion i~ esotnlial for actIvity. Prlnd pal componf nl$ .n"ly!ii~: C(lfllpUlaliOIl3J ollJ'fO"Ch \0 re duce the d,rnc:n.ionaIny (i.e . the: number of "..mable.) in " daIa analYll5, by "'t,ghling vanablesllmJf'ding \Olhdrronlri buu,,", to thr D'-crall "mallon. A pto. of pointS in the first Ii a two-dimensional (20) I I
110

<)(/I(r ~1Ii<lns ~

~. ~::::~;~::;:~':l <.\a11l points (i.e. c'Om be use.J Bmong lilt::

thaI can

10

pounds). I'roprrly spIH'f: ~lulud, .... nsional rqm~nul!lon of or! of rompounWi as points in .pace. EAch axis of the space ""IRilCn!> some de"," plor. citlw:r .... hoIe JIIOPI'My or compmfd from the t ...lH!imens,onaI (20 1or Ihree-dim"m;iooal (l O) chemical

!truclUn::. Compounds IIuII an:: ~imilar to each OIher chemluJly [in<lt. together in propomy <po>Ct. A fu~r 8lisumption ">Cd ,n librury \k-~illn i, lhal .trUCluraily similar compounds

",i!

",n >!wt !lm,lar b,oloa;..:;!) OC"',ly ,

l'roIr<:ling IIrt11lP: a..mICal group thaI ",,e.,;,bly blocks fune hooai BrouPS 011 s) nlooie brgcI, 10 p"" 'cnt lhem from cn.ertnl,nlo Wltk:med silk ~"",tio~, f or ~~""'pl~. lU' 011 group millh, ~ proIr<'led by cO'I"crting il.o an estcr, then hydrolyz,nB the ostl:r back 10 an akollol "hen l~ s)'ntlM:!;il is complelC. Itadlofrrqur nc, fM(Iding: ~ porxrs~ of embrdding into ,olid "'JII'OIl> the elec.ronic !le\'ices ,hal emil radiofrcljUerK:> \'ll'l1> upon .... mul!uioll with an eI""OI'UI~""'k '><lUIt'C. Tht .ignab can bol us.ed 10 tr..ck tIM: real:lioo hi.lory of tile ,mn beJd and lhus ,~ ma~eup of lhe compotmd,

nun",.

1Il1lChtt!,

Ratio olk pdin8: Smilei)' in which .he qUllll,i""" of .a~" on bead mfoonauon aOOu' ,he compound tdc:nmy rm~r than the IWU", of the "'~. Rtsicl..t: The portion of a chemical SlNCtun: that can be idenl, fied I. ro/mng from n partIcular huildin~ blllck. such as .he .....ilk I'C$l\Iuc in a pol)'Jleptide. In mge""",, ,11UC1Ur'<!, lhe rnMluro. an:.he liub6,it~nls lhut COffi.',pood 10 lhe Rgroups ,n lbe \IruClU"" It .... , I~u.ble poIy"w.ric """ ..,.,alto which hnke",. ~ymIM:tlc WiN,:IIId 1:IgS arc Ittoched . S.>mctime,. "'s"'~ an: simply ">Cd 10 ><'~""ngc ,ide prod\IC~ IIf a ",""lion. In chrvm:uo~",_ p/lt. t'e>ln be:Kb ~ u~d to ~pam1~ compouJllb by >lI.c Of hy the: charge on a molecule, lI"lnlbc:sis: J>reparotlon of ,ndindual "",mile", III" ~uboic" of a romblllau:",.l library. 10 follow up 00 SOnl" Pr'Ujlelly of

I""

,_.

, , ,

, , , ,

, ,

An cnzy"", th~l can R" 'crse lrdn,;cribe RNA inlC "~<VfT"Spondin~ DNA. RiboJ;jml': RNA ,"""",ule ...-ith cnlymc cHtal)'t;c activity. Itobotk i)Mtn1: An automa.ed systcm. usually conlrolkd by ~ rompuIC1, 10 IrJ~fcr materials by physical lIto,cnICnt of a dc:1 "Cf) ,Inicc or II) mo,'emenl of tIM: reaction vC!>.\oCh. RoOOCIC j)~1IU can be general pIIrpDW. and cllJXlhlc of being ~ to do a vanely IIf diff=nI I~'.S. III" may be >r~htcd. I" p;u1 of a "rn,j:r. sys1cm. \ ~r"J~ldt 1in k~r: A Ionl..:r.h:d is dca,cd by ~rfonning 'WII rtoo:1!OO! 11I>1eat1 of the c uStonla!), """. Th,s provides gn:a.er r;ontrol ""cr the timing of.he n:leas.:: of the s)nlhe.ic ta.g" Sn/fold: n.: ~ ponion of D ge"""c .ulK:tUn:. cOmmon to oil the rnetIIbm of 1M library. Note .hal in the case of I"hRrOl,cH,cOOR,. lhe >caffold COI"iS of two d;>COIlII<:"<'led ll; fra;lI1tIIh. scpar:l1Cd by .he R, su!>';.iIUl'IIt. Si'a'tngfr m in : A rc.sin inlroduo:cd mlO I combina lOll.1 eXJleri IIkM 10 rcacl ""h uTKlc:os,ruble mall:nals (,,"cess ",agcnt III" wdc: prodllC1S) and remove 1hem from the eXllen"",.I1.
1t~,1'Il>1' lnlU~r1pIMst':

St'kdh-Ity: Measure IIf a oompound' ~ tendency to bind only to cenain largeL =11101, Onlg molecules ,hould ha,'e high sc:ili\',ty lIS " 'ell ~s potency. Solid s upport : Insoluble. fUJlCtionalize<i poly"",ric nlllterial to which libr.u-y members III" reagen .... 1ILl)' be attached, oflCn via I lIn~er. allowing them to be re<ItIily Kpamted from SOlvent, UC~S' ...,agent. ~Ir;:. Typically, the :IOlid ~upport l"'clb in sol"cnt. allowin& n:act,ons '" OC.:ur In the inlcnlll" of lhe bead or other form. This greally incrcasa 11M: ava11able urfacc area for "'lIC.ion. Soluble ~"ppor1: Typically, a large molecule th"t i. 50Iubie in :lOme 5OIHn" 1lrKl. upon !he additioo of Olhtr solvenll, Kparutes into pha.'>I:s. ~ molccule can '\eI'\c as sUpPOIl fOf attaching membc;r< of a cumbinatoriallibrnry. The MI\'smage arc rnon: complete in o\"cr wlid ~uppons i, that Ioqu,d phase. Someu""" Icm\ed liquid-phase ehe:mislr)'. An example of a S<)Iuble !>IIpport i. PEG. "hkh i, -,"Iubk in pol:usol"cms bul KpilI1ne!l from organic ones. S pacer : Same: as P linker. S patially add n'!i!<llble: Ha'inl 11M: ability to kkntify p;Irt or all of the Slruetu", of a library roml"""'nt III" pool frum tis physical Iocal;on in ~ gnd I), array. S pot s)"nthesi.: Solid_phaK syoth",;s al certain pmn.s (Spotl) on u two-d;nlCn,il)nal (2D) surfllCe (e., .. a ccllu~ tuembraM). R"",emly, the: techniques of ink jet printing bave ~n applied 10 spoI symhcsis. ) ieldong ,'cry dense: amoys of oompoorKls. S ublibra ry: A ,ub<el of ~ combinatorial library in "hich. for uamplc, 1he sui)<.ilucnl a. onr position is held r;onStan. while other positions arc 'lIned. AI..o called a pool. Sullt'll'rilical nuid dm:I n,a'ognlphy (SFC): BPLC u~,ng a . 'soh-em" Sl>C:h as liquid COl under high ~,u.e. ~ 1Id11llltnge ,~ thul lhe carrier c\"aponll"'. simplifying the deteclion of .Ile ootTlpoorKls as they elute from lhe chromnlog.raphic <o1urnn. T~g: ,\ mmreac1ilc chenucal f"nellonah." 3l1acIM:d to a sohd ,uppo.)t1 lhat cam"" mfonll:.I;"" .bout 1M ",,,,,11011 ' '''lory uf the gilen ,upport aoo Ihus can ~t least p;1t\,al1y ideotif)" 1he :t1"",hed .yntlICI'" wrg~t. An C-'llmple ill Ultach,nG various DNA ba>es to 1he beatl a, each '),n1IM:tH: SICp. ~ ",sulling oiogonuclcOlide CIUI be mul1,phed b) USing PCR aoo ident,rlCd analytkall) 1'.... bag: A Iype of ",aclio" v","-",I consb.mg or a porous "",-.h bag thaI enl'il.Cs 11M: re<in but allow~ va,sage of n:agenls ~OO sul,em, _g." era! tea bag> .1Il, be imnlenOr::d in a giwll ",agem and lhe.t mampulalcd from one 1\'~g~m 10 the nc~tto g(nerd1e ~omblll;ltoria! librnriQ, Vlrlual li brar): A comblOlllonai lob",!), thlll ha. II{} p/lY1lcal U'SlCllI.-':: r.t1h~r. n ex;SI' in I Coml'lI1t.:r' Of on paper. Such bbr.. rie~ ~an be: g~""rnled aUllwnallcally aoo ~"""Ir::d "gam" ph)siocfl.omical fillers bke the "rule of rile" or be dueled IOIf) receptl)rs b)' usc of molecular mudeli"g. Vl rtu,,1 scn:r: ning: llH: \Cle<:lion of rompouoo. by C,'OIU3Iillg the" fitllC>li by u>e of L'Omputahorull mood. AIM) called '" ~",m U'.... M/"I/.

""""'Oft'!

REFERENCES
M.mr.. k/. II II Solid pha", PCPlldo: ,)"'I1o.,,,. ! The 'n,,,,,,,, of I t<lropop'iJe J. Am. Chcm. 5< .., 8~ : 2I4'J - 21~ , 1963. 2. F'IlfIa. A ComblllOlonai 20 ~_. [)no, 1A>ootwe<y Tuday H-4_ 2!ll2. J . l1uuBh,co'I. R A Gcrocnl """hod for ,he: rop,d liOIod-pha.. ,ynll,/,,,, ul tlrJ<' numba">o ,,," P<1",,,,",. 'f'tt,r"'''1 of ""ti&'THlnllbOiJ)' ,nl<1'KIoOO ., the 1<,.:1 of i!ld;I""'al lUlU"" add,. Pro<. AI:aJ . 5<:; . U. S. A ~UIJ ' ~5\15. Illn ~ S"""". II J.. K"" ... II. S.. Zud,..."...",. R N .... L l'cplood . "">du,,,," "I~"_h '" drug d.>co'rry. I'ro<:. ~"J. A.....t. Sci . U. S. A. 8'.1-9.167- 9371 . 1992. 5. Millet. S. M .1oJ .: Pn"""')"C 'Iud"", uf po-pc<de and N

,h'''''''II)''

".11.

"""-..lui"'"

wbIot"glell rl~"'" pqII<>Id <.oIiJ<>lll'Ol". Bouo::q. M.... Chmo. I... ,. ~.

2ti!\1 - 2fI6l. 19'J4

6.. 2"d..", On R. N . ..... I,..., .....,. tIl ......".,.,.,. ',,' . " r", 1 , " " .. ,. . "" G-pruocaD<OUpird oe<:qIIOA iii ........ N-(""""''''''''J,I)~ ... pepouod hbr.,.. J. Mod, a.. ... J7;2678_261, . 19'J4 " Bun.n. B A . """ 1 !1I11W1. I. A . A g...."'1 """ ."podlcol! ..... '1I00I r,w ......,btl.pIw< .yft'''''''~ "I 1.J-ho.""d,.ICpln< Ikrivativa I Am_

r""".

I ......... N _ .... ,\AIlbofJ. A hip..pord IfY' ....... 11In""", ;1\ olru, di"" ... CO)'. [)nil Tod.1y 6:
~16..2001

ChnIo . .so" 1'4 10997-10'l9I!. 1992.

M.....--.....w'''d

' '.ro>coy

<"'n"...

26. 5"."00 . II. W , /l'.h .........ghl"'. """"n'OI, <II h''''''''' ,"'Iec!ion> ..... .........ionII on file tile. """"'1C1I11lirJC!" ..... file d'.'.DI'Y , BioIc<:hooI D-"I 61 ,61 -(11. 1998. 21. V........ 0 L.. . ..... ""_wy.C P:S<nen,"''''" ........ ''oaIl, ........ 0 .. 1"",11 I...... S1. 48.I3I - lS0. 1\1911. 28 Tortlil. M I t. aINllkrnlan, J 1 1IahIhn>u... p"'.".,....... .... "'. ~ d, .... bubon. nwutboI..... -.I "~cm",,, cI "'-d '" I~ C\o'f 0,.11. 0-.. DIOI 2:0411 ..... '6, 1991. 29 Walwo. W P.. $1aIoI. M. T _ and Mu",to, M. ". Vinu.ol /lCiCU.ft,-MI ,,....,...iew. Dno, [)j,c.,,'OI)' TtJ</I~ ) ,160-178 1\I9S. 30. Sh".<I.... D Ie .. II.: ~1Id 1Ii'iOOVCf) ...... .......,.,1at tIot:k"" . CIIrt

,0l(I0'' '

"'''I"'''''''

r",,,,,..,,,,,

".
';1I - ?S. 2002

6;289- 296. 2001. prWucu.

c .....

0,..,

Opoo. Chcm. DIOI 6:4}'J-44().:!OOl_ .lI. "''I':lIW'''W.pid.Ofli..~<:lVpMn<lt1IIJa. U","'" Do,oct> """" .. >Ii. wan: ....'nload. 2002. 32. 1WIm. 1, .1.. -.I Slald. M ~ S ......1Ure-b;o>t<! 1...-.,. do,\lll" modem ... ''''''"...."h UNi....wonaI ct..",,"'1, c ..... Opon. a.. ...

_.1.

"" ,..., , cl.. v"", a..m. 62;2J70- 2J80. 1997 11 R""""", R_ .k)Maj. 0 A_ ..... "" oI<lman. Il w)lftIlICaIly Cltl~ 1.1Il.. """"" III poIymer .... JII'IIf1Cd t)"'.... , .. Dno. [)j"","flY Tod.1)
14. ~.,; ... T. A . an.I """"""'" R. W , Mo6ular ~,"COMY .'". c..... .-crlIbI< ....:ywodo ,..... UII ,if< ,I <_I _ . J AI'Il. Soc. 1 11'7B4 ~-7"'}. 1 99~, I~, II .... 1I.. .. .oJ. Li'lu ... pIwoo <I"""'''''~'''''' .y",he>i. I~'J<. NIII, A<ad. Sci U, S. A. n .1I419-64n. I~. 16.. So. . .. A .... II I'luorooo )1II/Ie>oo:: I fl"""",'.~ .. ~ f<..rirlCitll<}' i........1< Se .. """, Z7~'.

1 001." 2I3- 286.:!OOO. ) l UPOllo.ki. C, " ... 01. &ptf1ll1tnlll an.I <Um1"'~""""1 .II'P"'*< .... \II ...,,,.... ,""ubihoy on<! ".,, ' .... 'i.y it> tII""""OI)' and ...... Iop, .... >elt,n", """. Dnoa DeI,v. II... nJ-2!l. 1991, )4 Opa. T I. Vithool ......'" ,. "'-d d"...,,~ry: , ..... I""nt. Mo

dna.

o.co..

r........

"" .... ,;!1 I-62,lOO2 ()pn:1. T. I.. and (lo"rn<$.", m,",,....Ii>loc 01" .1.. <II onoI tlruJ oIIoootpooo>. 1M..... Modrl . GrapII. 11:2f>1 -214. 1 W9.,~_ . l&. 7 ...... I.. .. II "falol ..... "", " ,ce",,,, filter r"" ..,....,_. NXI 3... 4 ioohibolIm ,...I_y <II '''''....... OSAR 2 12~.llI\.
J~.

r,,...anJ

,,,&

1991 , 11 C.kIomnt. C T .. .. 1.1., Dtm."III1I""""'11f; ,~ibk ~..;u..,n. '" I .....100 ....."'_ ~" ... ONA.~ "'1I"""")'nItKI.oJ. A"I"" . Chtno, I . Ed F..,.J 4'4 '04 ..... 101. xm. ,. HUlho. 1.. -.1 11...-. 0 .' Toclonoqueo rr. ...., ... 0IId p""r~"", '" h"h!lwooJhpul <,,",""W)', CIIIT. 01'''' ' Chc,n. 11,,,,- 5;141--247. 200 I 19 VMI. B.. n K.......... I. G "'"b;",,,~,,, ~,,,",,,, ...... b)' _ " ". IR _ <II ~ !WI I ""01 onoa holld.
T~ ~2.g.al-g.a8.

"' 0."', ....._

n.l-I~

.,IIIIItoi.

11, Adan,. Ii- P.. _ It.rmI:cn>. P It II.: TIl< """tribut"", tIl ,"'.... naI c....... /III)' 10 lead " .... >1_.All""";", onaIyIoI. C\In. MftI. ~ 1:98S- 99I. 1001 )K S".lIme)'CI. D. C ... no! GmoI .......... P I) I IIccmt .... ,'c lopo .... " io """01.. dln'"'t~ ' "",,,,,,,~00BlJ <""""111~ ....1d .. m "It)'. AM. R<:p. MC'd. o..m. .).12111- 296. 1m )9 Joe_II. E. J... 01 Pi".....", 'moda;ro( l ,S-t,)quo ... .ali......... k,p .mn..,. O" IIA - I or tIuaI ' .......ionalioy J Mcd. CIoeIOl.

""'-

',bo ...,.

"*'"

""""*........

ill, ....

.",.Ie ....

42;1123 .19\l9. 010. M.mn. Ii- I .. and Cri...,llkow. II. I!.: Ik)uood ""'" oII,_y'

",II1II

cowtbOMMal , , _ r", dnI,~. I. Camb. a..... 1:12 ....1-

""1oriorI

1996

,m .

10, Shulor. S. D.....1. 0, .... ,....,,;". h"h,"flimt~ 1,,0Jlll, r", pruI<"">: S"R I')' NMII s. ....... 27~ '~3 1 -IH". 1996. ll. D, .. , . 5 .. "'" Lemrr. R. A ~ c""obi.-.ul c"'. I'otJ<. NMl ......... Sci U. S. A. 119 5~1-5)1l). 1992. !2. Nie ...... I .. II"",..... S.. and Ianda. It O . Syll1hellC nlel""'" f,It.hr impieollClO!aliun tIl " ... "oilN 1XIIIlIM.......... <,,"rni..l)'. I C"" .... Soo;, 1I~"'l l- l18n . 1993 !.l ......., .-..... Quono ........... 2002H. ~ J A.... ol . lITS ' n 1M _ m'IIaI"'''''' _ .... roI<Qf~ ..... <.,k'lY ond 11.. J. 1'I\;unu<..... Tw","'. M.. IIooI, 44;213 289.

Ii, "Ill.

' 1. ()pn: .. T. I.... aI . CIoemocal in',""'." .... m:otIaf<n .. nl in til"""" ..'" """mwn..... c""'puUlKlaai 0IId o:ombt ........al r",,",," I ~1oI. Model. CnpIo. 18;!112-~l 200D, " 2.. Mom... A. T. UpW.~ <II ...... load ""' .... /.>1_ r"" .....

oII;w'., y Dno, Oi"'' '''ay Tod.1y );!IO$~ ' O. 1998. Golebiowoki. " .. Itlopfcl>;'ij.in. S. R. lIOd Ponlod.. D 1' ; lad c._ pound, diOCO'O'eml 'rum lib8i1d. C\o'f. (lpn. CIoeno.. BIOI. 5:213--211.
,."

k<1t.""".,.

I.

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dnI,

,,!no.........
..,,'<oy.

"" ()v. ..... 1_ .. 1.1_. Ne ....

m>

2!1 On: ..... J ON, d""",..,. I hll.aoJricol 1960_1 964.2000

penpo<1"'"

In bndlmi"""w...;...._ ronl in'S dnI,..-Io U.k, "'''''h clinical trill . I)"" I);""""..., Tod.1y 6:l)(). 2001. 45. l:v"01~ J.. .. aI.; TIl< 1jlpI... ioln <II _"""""""" ct..miW)''' lead "'''''''''''Y. Dno. Do",o.",)' T"""" 6:719-715. 1001
~

Se"""", 217

........ 0 R.. "1>10.11. M.. S ~ LInd """ Dno, Oi_.... ry Today ' ; 143_ U6. :/000.

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Metabolic Changes of Drugs and Related Organic Compounds

SITPHEN 1 CUTLER AND JOHN H. BLOCK
\kuboIt'-"1 pla)'~

IIId OIho:r fOR'lgn A ~id underslandmg of <.Iru ~ metabolic p.1Ihway~ is an es'lmllal 1001 for phmmacisl~ in thocir role of sckcti l1!1 and
IIIOIIllClnng appropnatc: drug thcropy for their p:lt icnIS. M O!i!

C~Tllral role: in the c:hnunJlion of df\Jg~ C{)fI1pound~ (.ft..,Qbit/l;N) from the body.

GENERAL PATHWAYS OF DRUG METABOLISM

Drug melllbolbm reactions ha~'e been divided inlo 'wo eate pes: phase I (/uffClw(loliwlir>llJ and ph/uf' II (cunjugmiOfl) rc:acIi0llS. 1. 1 Phase I. 01' fuocuooalizahon rc:actlOns. include oxi dallve. reducl i~e. and hydrolytic bioU"lIllSformulloos (Table 4.1)! The I)U.-pose of Ihese rcaction~ IS 10 introduce a functional polar group(s) (e.g .. OH. COOH. N U ~. 511) into the xenobiotic molecule 10 produce 0 iliOn: WAter soluble COlllpoUnd. ThIs can be :.c!uC\cd by dlr.. Imr(ldUCIIOn or '<:1 the fUrlCtional group (e.g .. arommlc and ali phalic hydroxyla tion) or by modifying or .. unma.ling ul~lIng funct,onuli1<et0l\eS and okkh)'c.b to alcohols; tics (q; .. reduction ox idation of alcohols to acid!;; h)'druly~s of cs,er and 3mldes

orpnic: rompoonds entcring the body are rdali"cly liPKI IOIubk /lipopl"IIc}, To be absotbed. they mu"! U7IWT"!C the llj)oph~ein mcrnbnmes of tile lumen wall~ o f rhe g8stroi l1u:~ unallG1) tract Then. OOCI: in the bloodstream. Ihe.. mole. ~ ,,,bcan diffuSt' pas.~hc l y through other membr.lOes and be '!tnbutcd effcctl\-ely 1 rexl'l ,'arious llI'let 0Ill3ns 10 exC" 0 die .. plurmacological actions. 8ecau ~ of reabwrpl10n in tilt Tt'nal lubol~s, lipophilic compounds are rIO! e~crclcd to III)' ~lNamial e~'cm In the urine. XenobiOlics rhen 1lM.'C1 IIIrIr metaOOlic farc through ~ariou:s ellLyme syStems that dIIn!f: the pat'l'nl compound 10 render it more water soluble 1~}drophj/kJ. On Ihe melabolile i~ suffielen lly waler sol uIrk. II may be e.1.lrcted from the body. 1lle stmeme nts above ..txr. that 11 working lnowledge uf the ADME (absorplion . dI!lnbUllon. metabolism. and ('J(crt1ioo) ponclpl<!S ;s villil b UttSsrul OetellYllnolioo of drug ~g,"M!n~. Ifllpophil k drug~. or xenobiolk.". wcre 1101 melubol i1A.-d 10 poW. ~adily excretllbie water_wluble prudIlCl~. they would ImWn indefinitely in the body. eliciti ng their biologICal r~. Thu~. the fonnalK.n of water-soluble Ill('tabolitcs nol oaIy~ dru g dimi nalion. btU also 1e.ads 10 oomflOllnds ihallII1' g~nernlly pttarrn:ocologica!ly inactive nnd rela\lvely IIOI\IDlk. Consequently. drug mctabolisI11 ~lICtions ha\'e 1mdllion:ltly been n:gurded as I/c/culcilfiOfl (01' dl'lmificmlOfl) jIIJa'~ I UnfonunateJy. itl~ IOCOi ,cctlO a."SU,ne lhat drug Iilcubohsm reactions nrc alwoy~ dclOxifying. Many drugs IIf hlOlran<formw to ph:lfInacologically actl\-e met abolitc~. Tht'>C metabolite.~ may have significant activity that conln\)>ubstantially to lhe phaonarological Of toxiroiogicl1J dftlsl ascribN to the parent drug. Ottasl()ll;llly, the parent compound IS imlCuve when adnlln istcrcd and Illu<;t be melaboIicoIlly convcned 10 II bi ologically active drug {mctaboI*:~ 1 I These type~ of oompounds are referred to as proJnr~j In addition, II is Ix:coming iocrc:lI.'iingly clear that IK)I III mcI.JboiilO llI'Il oonl0xic. Indeed. many adv~ effects (~.I .. UJsue ~lmb. carcinogenicity. temlOgenicity) of lkup IU1d environnM!fllal con taminants can be attributw di lrCIIy 10 tile fomtatioo of chc:mical1y rc:acll~e melaboillcs an: highly delnmemal to tbe body." ~ TIils concept I~ ~ lIiIpOf1Un! when the pallen! hrut a disease st:ue that Inlublt) or c~ pedile~ xenobiUlic mCllioolism. Also. more and 11M: drug mclllboiilcs are being found in our sewllt,oe 5yS __ lkse rompoull(h may be 1IQf110xic to humans but .ful to othrr all1mals or tbe envirooment.

or

TA8 LE 4- 1 Gener,,' Summary of Phaie I and Phase" Met"boIic Pa thways

I'..... I .... "untdo... lb"dun K.....1kt/u

cr

O'l.ldall ...

rn<u.....

O'kI..... Q(QIdi .. <h1Jol"", 01 belll)I;". 1Il1)bC ~ - . """ ~.. '-''''""yt and 1m".... O(IdaI"", 01 "'pNII" """ 1lI000dl\: <.mo.. .......

0 ...' ..... QI; ........

""*"".

bm"""''' ...,

Oxodll_ ..

vol."" ,.bm-......._ .... --= _an, ooochoJn C.mo._"........y........ tlllophMor

')'>kIno

N.... oII:yl._. \IIIoda,..., <leamJn-. N..,,,d.. I"""""""

IS..a...t~,1II1on.

'I ",,,",x)III.... ) CIrtx>cI 'Q.1~"'" 'Y'~ ... lo-'"""'I ~)'t .. loa)

*'

C..".., -... II~, .~llmIOI

*",1fwM"",1

s....odoIio>r\. _

0.,,'-_ of ......... _
Oll..-r

aldoh) ....

m,~t,-"" I>' odoh,~

ruc:toom.

1If'd.... ln 1I....do"~ 1INIIo:!_ <>f oldrb)ola """ l~1 1I~1on rtf iii ......... ..., """'P"\t..'1:1~ IU<!>I.WlO It) d....) ... M.......... lI)oln~)'li, <>f NOn.oo omole' U)dnlllOO Q <pO'''iet and .... "" " ..,,\0:. by .",..kIt b)ru.... f
"" .. II ... C..... Mplinoo Rowtlom

_II'"

eoruu,OIOOll ",til .1011"".... IoOOd QIIIcr ..."'." I<io<h GlUI4ttuo:. Of m ,apuori<.cid <l"II"Pltm ..
IoceI)t.oon

0II0a0n. . . .-.d "'J~l_ SoH'..., cooJ"11I1o;lII

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'5

to yie ld eOO H, NH~, and O H group.: reduction of lIlO and nitro compounds to give NH2 moieties: oxidative N-, 0-, and S-dc:alkylation to give NH1, O H, and SH groups), Although p/lase [ reactions may 00f produce su fficie nt ly hydrophi lic or inactive metabolites. they gencruJ ly tend to provide a functionol group or "handle" on the moLecule that can umkrgo subsequent phase 11 reactions, 11Ie purpose of phase II reaction~ is 10 attllCh small, polar, and ionizable cndogenous compounds such as glucuronic acid, su i fale, glycine, and other amino acids to the fUllCtional . 'handles" of ph ase I metabolites or pafl:nt compounds that already h:we suitable exi5ting functional groups 10 fonn water-soluble conjusated products. Conjusated metabolites are readily excreted in the urine and arc generally dc~oid of pharmacoLogical acti~ity and toxicity in humans, o.her phase 11 pathways. such as methylation and IIC<!tylmion, terminate or anenuate biological activ ity, whereas glutathione (GS I~ ) conjugation protects tlx: body asai nst chemically reactive compounds Of metabolites. Thus. phase [ and phase 11 reactions complement one aOOfher in dctnxifying, and faci litating the elimination of, drugs and xenobiOlics. To il lustrJte, consider tOO principal plIychoacli ve constituent of marijuana . .J~- tetrahydmcannabinol (..:I9_ Tl~e , also known as ..:I' -THe, depending on the numbering system being used ). This lipoph ilic molecule (octanollwarer partition coefficient -6,0CM) ~ undergoes a[[~[ic hydroxylation to give I I_h)droxy_..:I9 - THC in humans. I " More polar than its parent compound, the I I-hydroxy metabolite is further ox idiled to the corresponding carboxylic acid derivative ..:19 _ THe- I I-ole add, which is ioni7.ed (pK. eOOH - 5) at physiological pH. Subsequent conjugation of thi s metabolite (either at the eOOH or phenol ic DB) with glucuronic acid leads to watersoluble pn:xlucts that are readily eliminated in the urinc.ll In the abo"e series of biotrnn ~format ions, the [XlfCnt J 9_ THe molecule is made: increasinsly polar, iouiwble. anti hydrophilic . 11k: auachrnent of the glucuronyl moiety (with

irs ioniz..-d carboxylate group and three polar hydroxyl groups: see struCture) to the .J9_THC metabolit es notahly favors parti tioning of the conjugated metabolites into an aqueous medium, Thi s is an impona111 point in using urinalysis to identify illegal drugs. The purpose: of this chapter is to provide the stu dent with a brood overv iew of drug metabol ism, Various pha$C [ and phase II hiotnmsfol1l1arion pathways (see Table 4-1 ) arc outlined. and represenrative drug examples for each pathway arc prescn1L-d. Drug metabolism examples in humans arc cmphasized, although di !oC ussion o f metabolism in other mammalian systems is necess;Lry, n.e central role of the cytochrome P-4SO monooxygenase: system in oxidative drug biOlransfOflTLntion i~ elaborated. OillCuss ion of OIllcr cnzyme systems involved in pIlase I and phase II reactions i.~ presc:nted in their respect;" e SlX:tions. I n addition to stcll.'OChem 1cal factors mar may affect drug metabolis m. biological foctors such as age, sex. heredity , disca>e staHl. and species variation are considered. The effects of enzyme indut1ion and inhibition on druS metabolism and a se<:tion on pha rmacologically active metabolites are included.

dro

GI dis:
~,

dro

,,' h", ""

dro

"d

Lid Mel

I""

S by I oml

,'"

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lism

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SITES OF DRUG BIOTRANSFORMATION

Although biotransfonnation reactions may ocru r in many tissues. the liver is. by far, the most imponanr organ in drug metaboli sm and detOXification of endogcnous and exoge, nous compounds. ' J Another important site, especially for orally atlmifi isrcretl drugs, is the intestinal mucosa. The lauer cont~ins the cytochrome P-450 (CYP) 3A4 iSOlynle (see discussion on cytochrome nomenclature below) and I' glyooprotein thai can capture the drug und secrete it ba<:k into the int estinal tract, In OOntl1l5t. the liver, n ,,-,ell-perfused organ, is particularly rich in almost all of the drug -metabol izing enzymes discussed in this chaptcr. Or.lll y administered

tion le\o

reI"

,=

pre<

"",

drat: inre,

~I.

AI gl!U1' IIIg< oftefi ular I

drol: "her

1
C

1H
'-

'to CH,
CooR

7
H ,C1-o,/<.l", CH,

ROL

MOl BIOl

tI' -THC-7 -<lie AeI

Of Ih chapt the IT gener xenal:

Where A H
GlcuIGnde coof.l9lLts at eiIhIIr COOH or pi"" .... OH ~OUP

lites {
RII +

= re w!'es.
basic

'I1r,

l.

,I,
M

"I

I,
jlh

.00

",.

-'Y

!hI' \lIM are absorbed into the blood,lream through the GI1I1CI must pti5 through the liver before bemg funher INributed illlo bod) compartments. Thcrdore. they are su .... ctp,bk to htp.Jhc metabolism known as thcjirsfptlSJ tffn:l hd'1)It reJChlng Ihc- systemic circulation. Depending on the Ihls met.:lboli~m can somet imes be quite significant I0Il ~>uh In decreased 01111 bioavailabilu),. For cxonlpk. in human" .\Cvenll drugs are metabolized c~tc!lsi ve l )' by lhe fiN '~I effect. " The follow ing Iis! includci some of those

TA8LE 4-2 Cytochrome P-45O Enzymes Nomendil ture

C, I' Ar'" Np""""O'pI .... UtI.... " .. bIt Nwnbor

Iku,.

1, CYI' cylochro.lle J4j() ""'-yn..,.

2. "nobot nwmbcr I"'""ty (CYr J. cyp 2, cyp ),""",)

M U.I h "" ..... IhM
~,

.10"" ldenllnol . n,l"" odd HIl UM

~,

., "'"
m

,_'"
I iOOnino:

dial';

Clpilallcn ... SuW.m,ly (CVP lA. CYP?C, CYI' lA. "" I M ..., .... , .~ _ ".... 55'!!; WtnUonol.mI .... add lotq ... _
Ind.. odu.o! ..... y_ ;g a .ub(amiIJ ICYI' IA2. C VP 2C9.CYP 2[)6, CYP 2EI. CYP 3M ...,.)

Morphine

Propo~ypheroe

4. AI"

"""*"

Nitroglycerin
Penlll7.OC11le
( ~.II ..

l'I'oprJnolol
Salicylamide

' ''''''111,. '" ...,1.0 Kid .......OWd .... ,..cud !to'Io

~.

~.

.~

;~

",.

"'. roc
",.
,~d

M, Ng

uu

p,'

"'"

~il.'

lidocai ne) arc: n::n)()\'ro so cffecl"'ely b) fW'>l'~ mct.aOOhsmlMt tnty ~ iroeffccti\e \\, hen given IAlly.1 Nitrogl)'ccnn IS administered buccally 10 bypass die li"er BecIUSC!11OSl drugs an:: adminlSlcn:d ornlly. the imeSiinc 1f'IICar!i to play an imporUlnt role ill the eIlnihcpatic metabohQlt of ICoobiotics. For c.\umple. in humans. orolly Ullminis trnll()JlfOlereooJ undergoes con,idemble su lf:"e conjugation In the intestinal wall. th Severol other drugs (c.g .. k,"I!dopg.. dtlorpromazine. and dicthylsulbeS(rol )17 arc also rqmedly mctaboli~ed in the GI trolCt . Esterascs and lipases ~Dt 10 the lAli:<;line may be partlcularly l. Impor!ant in ~111 001 h)"dmI)'sis or many e<;tcr prodrugs (see Hy cWI)tll: Rta:lions," below). BlICtenal Ilor.l present in (he .siI1It II!ld oolon apptur to play an Illlportanl role in the !l'duI:t1Oll of ltWly urorruuie azo and mtro df\lglo (e .g .. ""Ira_ wbJlno:).''' lD In(eMinal ,B-gllJCllrortidase cI1l.)mes can hylkIlIyze &Iocurooide conjugates excreted in the: Dilc. t.h..-reby 1ibc000illj the free drug or its metabolite for possiblc n::abIOlIJIIIOII (wterohepatie cio:ulatiol1 or recyding).11 AlthouSh other lisucs. such as kIdney. Iung~. adrenal Ibnd~. plllCtnta. braill, and .~ kin . have ~on1C druG ll~tnboliz lOll capabil ity. the bi()tr,msformaiions that they carry OIIt IIfttn Il!t roon: subslmtc sc: lcct i" e and more lImited 10 partie"'t~ of n::lICtion (e.g .. oxid,u ion. ,JlICuronidalion).l1 III _y i~M"""~. the filII metabolic capabllillC! of these ti<;\Wi ba'"e IlOl btcn eIpiored fully.

Sonx lkup

ROLE OF CYTOCHROME P-4S0

MONOOXYGENASES IN OXIDATIVE

810TRANSFORMATIONS
phac I n::actions thut urt: considered in Ihis .bIfI!er, o~idali\c biotransformation llruccsses are. by far. tilt !JI(JM common and important in drug metabolism . TIle It_Ill stoichiometry th3t descnbe.~ the ox id:l1ion of many ~$ (R-H) to their corre,<;ponding oxidi1.ed metabo~ (ROII ) IS given by the rollowmg cqtmtiOfl:lJ
tH t NAOI't' .. 0,

Of the:

v~rious

-+

H- -

ROil .. NAI>f"

+ liP

The w~yme sy;,.(clll$ carryll1g OtIt Ifll~ biOll1lllsformalion f t rtftned to as miruJ-!uncl;on (,.1"I(1II$ts or nwno(J)cygt'n1III'1l'.

n 111ere is a large family that Cllrry 0111 the: S.1lTle baw .lw:l1u.al n::actions. Their MIrlW:rlClalun: i~ based 011

,lIll100 acid homology and i~ summ:ui7J:d In T able 4 2. There are four components to the name. CYP refers 10 lhe cyl(). chrome syMem. This IS followed by lhe ar~bk number thai specines lhe cytochrome' fami ly (C YP I. CY I' 2. CY I' 3. elc.). Ne~t IS a callilal lener ,hat repn:sems lhe subf~mily (CYP I A. CY P Ill. CY P 2A. C YP 28 . C YI' 3A. CY I' 3U. etc.). Finally the cytOt:hrorne name ends with another nmbic number thul specifics the sp;..~inc en7yme responsible for II panicul.f reaction (CYP IA2. CY P 2C9. CY I' 2C19. CY P 3M. etc.). "1llc reaction require.~ both molecular OX)'8I'n and lhe redUCing agl'nt NADI'H (reducW form of nicotinamide adenoSIOC dinoclllide phosphale). During thi5 oxtd.all ,e j1fOCd8. one atom of molecular oxygcn (O~) is introduced inlo the subsmlle R-U to ronn R..()H and the other o.\ygen atom IS incorpor.lled Into waler. The mixed-ruoclion OXidase ~ys tcm2<o is IICtllally made lip of cvcral eomponenl~. the nlOlot important being the superfamily of cytochrome P-43-0 cn lynICS (cum.'nlly al H gcnes) (http://dmclf,(lll.Ull11.:m.cdu/ Cylochromc N 3-0.htmlj. "hich nre responsiblc for trnn~rer ring (1/1 fJ,(ystll 111"'11 10 the sub~trate R-H. Other importnm compone ms of this systcm mclude the NADPH-dependellt cytochromc P-4SO reductase and the: NADH - Im~ed cytochrome b,. The latter two components. along with the cofnetors NADPH and NAO H. supply the reducing equivalents (clectrons) ncedetI to the o\'erall metabolic OXidatIon of for eign compound ... The propoKd mechanistiC 'iChemc by which (he 9 tochmmc P-450 monooxygellase ~ystem calllyzcs ,he tl)!wersion of molecular Qxygen [0 un "IICII\'lted oxygen" spccidO is elaborated below. The e)tochrome 1'-450 enl.ymes arc: heme proteins." The heme portion is an iron-[:ootaining porphyrin called l,rlJlQporphyrin IX. lind the prOl~in portion is callcd the ill)(Ilm,,till . C)tochmmc 1'-450 is found in high coneenlrmion~ III Ihe I j~cr. the limp urga" in~olved in the rnctuboli'lll of xenobiOlics. TllC presence of this cnloymc in muny other IISsues (c.g .. lung. kidney. intcstioc:. s"in. placenta, :KIrenal cor IU) show~ Ihat these tissues Iwtve drug.oOxidlzmg capability too. The lIarne n"/(}chf()",~ P-450 is derI\'cd from tbe fae! tlwtt the reduced (F~l .) form of this cnloymc binds wilh eamoo monoIide 10 ftKRl D OOlllplel! that has a di:stlllguishlllg ~pa: lrosropic ab'oOl"Jl'ion maJ(imum:ll 450 om.211 One impon.al1l fl'amf(: of lhe heparic cytochll.l<11e P-4SO mixedfullClion oxidase system is its abili ty to melaooli/.e an almo\ot ulllimiled numberof dh'coc substr tes by I \'andy .. of oIidal;'e transformalions.:>II This \'eruli lit y is believed

be dllC to the sum!tme IlOOSpecirlCi!y of cylOehrome P450 IS well :as 10 lhe prr;encc of multIple fornl$ of the en l.ymc .1O Some of thee P-450 enzymes are selecti\ely induci10

ble by \1IfiOO) ehefl1icah (c.~ .. pheoobartiral. bem:o{alp)'Tenc. J fllCtbykholamhn:nc). I One of these inducIble forms of lhe cnzyme (qlocbrome PM8) 'l is of panicular interest and i$ dlSl,:usscd below. "The cytochrome 1'-450 mOllOOxygcnuse..~ lire 10000ted in the endoplasmic reticul um. a highly orgDni~ed and ~'OI"pl cx network of intracellular membranes that is panicularly abun dant in t,s,we, ~llCh as the liver. IJ Who!n these li.;sues are d,sro(lled by homogemzation. the endoplasmic reticulum loses ib Slructure and is cQllvened into small yesicular bodICS lno'An a5 ",;rrvwmu. Milochoodna house: many of the cytochrome ero-ymes thaI are ~sible ror the bio!;ynIheslJ of .terotdal hormones and metabolism of rUin vitllmm s. Micmsonl("S ISOlated from hepalic ussue appear to !"Cuu n all of the m..\ed-funcuon oxidase capabiliti es of inUICI hepalocyles; bl.'C3USC of this. micro~mal ~par'llliOllS (with tbe l1ec~SlIry ~'()factor-o;. e.g ., NA I)L>H. Mgl ' ) arc u.<Cd fre' quently for in vitro drug rfJCtabolism ., tudi t:S. B~'Cause of its IllembrJne bound nature. tht: cytochrome 1 50 monooxy '-4 genasc ~y~tem appc:-IU"S to be housed in a lipoidal en ~iroo lI1enl . Thi , ma y explnin. in pari . why lipophilic xenobiOficJI are generally good Mlbstrates for the monooxygenase liy5tem .... The c~t~I)tlC role that the cymct\rQm(' 1'-450 monooxygtl\IlS<' s),s tem plays In the oxidalioo of xenoblOtlCS is summanud m the cycle shown in Figure 4-1 .'5 J1 1l1C: mllill!

qcP 01 this catlllylic reaction cyc le SWt5 wi lh the blflding of the wbstrate 10 tnc oxidi7~ (Fe J ') resting st'lIe of c)"1oct\rQm(' 1'-450 to form a P-45().MlbsmllC complex. 1he neXI ~tep involves Inc lronsfer of one dec lTOn rrom NADI'II . dependenl cylochrome 1'-450 reductase to the P-450-substrole compln. Thi s ()I1e electron Ir.msfer reduces Fe" to Fe 2 I . It is this r~-duced ( 1'(,2 ') P-450-substrnte complex \hal is clipable of bindin g dioxygen (02, . The dioxygcn - P45Qsubslrale comple x that is formed then undergoe~ another OOC-elcctro41 reduction (by cytochrome 1'-450 reductaseNAD I'H and/or cytochrome b, rcduclllSC -NAD H) \0 yield whal is beliewed 10 be a peroxide dianion- P-450 (Fe" .. subslrute complex. waler (containing one of the oxygen atoms from the ongllllll d,oxygen molecu le) is r!:leased from the laller iTllemlCdiale to form an actin ued Ol ygcn- P-450subslmle complex (I'ill. 4-2). The actil':l.led o~ygen IFcO] ' I in this complex is highly eleclron dcrlCKnl and a potent oxidizing alltflt. The act;YlUed oxygen is transferred to !he subslrnte (Rln. and tbe 01idil.w Sub~lr:lte producl (ROil ) is released frool the en/yrTIC complcl to regencr'lllc the ox idiled fonn of cytochromc 1 '-450. The t ey '\Cquen,-e of ewents appears 10 center nround the altemlion of u diol ygcn- I'-450-substflllc Implex to an activated oxygen- P-4!iOsubstnlle complu. which canlhcn efft'C! tbe cri lical Ir:ln ,;fer of oxygen from 1'-450 to the subStfllle. n. )II In view or the potent oxidizing nature or the actiwated oxygen being Irnll!lferred.1 is not o;urpnsing eytoCt\rQm(' P-450 CIUI ox idiu nUIT'ICIOU!I substmlei. Tbe meehaniSiit details of oxygen lM:UwallOll and transrer in cytochrollle 1'-45O-catalyud !"ClM:IlOllS conll nue to be an .,,,e area of

Fjg~

'""" "" """

I ). H

"" ph,

p .."

~'" on Ih

'IIml

11

ely l"

quen ora I

,,""

."""
,~

"""

'ie,"ct

,~

llde c
,u~

~~.

O'YI!'
O_lc!'.ed Prod"", ROH

I' 450 (h'1! IRH I

INAOI'H) CV_ ...... , 450 Rodu<:_

o
Pr_ lId A""w.,td 0 .".,," Spec... IP (!iO IF,"11 I RH I _=-~' [P.4!iO (F.' J( ["'H I

co

I 00
0,

-"
..O~

""'omopno.t

- INAOf'H ... NAOHI

III'

Cvtod,,_ ' 450 Red_

Cytodl._ b. Red"", ...

Figur,4-1 Proposed

C<l13~ ftilC\l()Il

cycle Involving cytochrome P4SO 11'\ the O lUdatlOl1 of ~enobiotla"

'.' .
~

HI>-

'" '" <>~

HOOC

~mo

h"otOpOr!lhv,!n 110 pon .....

:ld

4-2 ~mphf~ depICtIOn of the "cped tNate<! ~-cytoc:hrome pl'i(l.\oI,ll!strm (ompiex Note thto $lmphfled lIl'OI~ por\JOn olI1d the heme (Platopor~,~ IX} portlOf1 Of cytochrome P-45() ld PfoJnrruty of the :r.ubstrate RH .de\P119 ouIabOn
figUft

... It~ " Activat.cl O'VIIII'''

--.,doW

,-

"" iO~, ~,

,,'"
H)

xi.

: Ii,,[-

","

,b-

,10<

,~

"'~

o[

.r...aab III dni! mttnboliim.).< The m.1rly type-! of o.\ idall\"e 'Q:llon earned OUI by C}lOchmmc: ,,-ISO art' c:nu mcnllro dIr 'lrClions below. Many of Ihc-c o.\l(i.1l1 \ e p;nll .... 3y~ are ~_wJ -ctM:lIl11lically III Figure 4-3 (<<I: also Table 4I, The IC'NUhlyofcylochromc 1'-450 in carrying OUI I. variCly <If IlxldoJtiOIl reactions on a f1mhnudc of ,ubo.l rmc.~ nmy l'C' ~llrioolnble 10 the mu Iliplc fl)rrn~ (If the cl1'Yrnc. Conse1f'Cl'I1).lhe studem must reali1c thaI the biulr.m~ronllmiOfl rIf, piItIIl \tnobiOfic 10 several o~ idw:d rllelabolll('~ i. carMI IlUlIIOI JU.1 by one fonn of P-4SO Ixll. rrl(lr"C likely. by ot,aJiI drffCft'n1 fonns. EAtcnshe 'iludles 1I1<lIeolc Ihal lhe 'I ..Mtln ponion~ of various cycochrome 1'-450s dIffer _one IIIIOthtr In rhc:ir ItnulI'Y SlruclUrc (ba:ausc of di fferIII ammo ~id 5eqllCl'oCe or lhe nlal.;t'1Jp of the poIypeptr.kdwn). lf. 'II......... , lkcausc lhe apoprOiem portion IS ImjUlId In .wbslrue bInding ~nd clllalylic !r.m"fer of aclh 'aleti 'l)~ thto;e ~tru':lural differcn'."r'~ may accounl for ..... me ~lr.lIC"j being prcfcrcmially or more effie,ently Qlidrll-d

by one panlCular form of c) loclirome 1'-450. Finall y. because of!he cnormous number of UOCOIlIITIOQ rc:JoClion~ thaI arc cal.!.l) led by P4.50. the reader is directed 10 ocher aruck:~

of inlere'l~l

OXIDATIVE REACTIONS

Oxidation of A,oliiatle Moieties

Ammmir h'ilro.nimimr rcJcr< 10 the mi~rd- function o~ida

ell."

lion of aronr;rlic curnpound~ (tJrt'nc.. , 10 their COfTC'Spondmg phenolic metabolues (urt'nfflsj ..u Aln\Cl<Sl all al"Olnauc hydro\}lauOll reaction" arc bc-lie\ed 10 pnx."Cr'd ,norlany through IlI1 ('po~idc: Imtnnc:drale callc:d an "~n:nc: O~Idc::' which reaming.:' rapidly IU1d 'ponlaneotl~ly 1 the arenol 0 product on mosl 1n~'~IlCl:~. T1rc Impo!1lU1tt of aI"Cnc O~ lde<I in the rorm alion ofarcllOl .. and In other metabolic ~n4lOllco-

r-

Ep(l>'<IeIi

0\ I
~/

C-C
co,

p,

-C-OH

I I

/-~-H

R-N-H - R-N

/OH

[ "'"""".""., [ [FeO]3.

/R
H

.; /

-S-CH.

","-.

--<'--R-N-CH R-R-NH+O-C [1 I "

0-<>0.

R-N-R-N-O

I
I

I
N-~o~

O=C 0 R-OH O=P M 00 '')CaIo'I 07 r'uliIIO'l-SH.-$-CH 3

S-Deal/Jtcn
arid S.(m(IMoQII

N 00000001oQll .-.d

N-Oo>de FOII.lIID.

Figure 4_3 Sdlemauc wmmary of cytochrome P-4S(katiJlyle<l orodauon rl'-o)Ctrorn (Adapted from ....11I(n. V Top Curr Chem. 83 68. 1979)

logic reactIOnS is discussed belo ...........u Our atteniioo no ..... fOl,."Uses on the aromatic hydroxylauOfl of sevcn! drugs and
XCnobIOlic~ .

7
lvae

7
"'0
Ai ... 0I0dD

7
T
OH

f~igl1 CUll1potJnd_~ comainmg aromati c IllQieli~ nrc ~usttpuble to arom:l.lic oxidation. In hu mans. amm:llk h) -

1\1""1

""'"

droxylauon is 3 major TOOtC of nlCtnbohsm for many drug.\ COfuai ning phenyl ,roups. Impol1untlhempoeul ie a~nts such II) proprunolol..... ~ phenobarbital ..... phenytoin ..... "ohc nyl bullll.OOC'.SI <l aIOl'V~tatin .$J l7&-Clhinylel;lradiol."r., and (S)( - )- warfarin .lo<> among others. undergo cXlen~ive aromat ic oxidation (Fig. 4-4 ,shQw~ Sfructure and $l Ie of hydroxyla tion). In most of the drugll ju~ mcntioned. h),droxylatlOO occurs at tile IH/rI, posilioo." Most "hc lloli e I1lctabolitc.~ formed from aromatic oxidati on undel1!o furtnc:r conl'crsion to polar and water-soluble glucuronide or su lfalc COf\Jugatcs.

.....hich ate readily ucreted in the unne. For uamplc. tilt major urinary metabolite of phen)1oin found in humans is lhe O -glueuronidc conju gale of II-hydroxyphenytoin . ~~ jO) Intcrestingly. the fJI",m-hydroxylated metabolitc of pncllyl btuv.OIle. ox)phcnooulZonc. i~ phann:JCOlogicaJly lICIi~'c and has been martetcd ilself as an anti-innammatory agent (Tan dean l. Oxal1d)." Of the 1..... 0 cllantiOlllC'ric forms of tIr oral al1licoogulant warfarin (eoumadin). only the more active S( -) ennntiomer has been shown 10 undergo ~ubS1Hnllal !II'OJI1:uic hydroxylalioo to 7-h)'dmJ.ywarfllfin in humans. ~ In COrluast. the (R)( +) cnaniiOlllC'r i~ metabolized by ],:etO reduclionlo<> (see "Stereochemical ASpeclS Qf Drug Metuooli sm," below). Orlcn. the ~bstllUl.'nts anuched 10 lhe lIfUfIUtic ring may innucnce the case of hydroxY'3tion . n As a gCllCrnl rule. mi crOSOInal aromatic hydroxylation reactions appear to pr0ceed most readily in activated (ek-ctron-rith) rings ...... helU'> deactivated aromatic rings (c .g .. tho\.c containing clcctron withdrawi"g gTOO11S e l. N' R.. eOO H. S02NUR ) life gC!lenl.lly slow ()I" resiscall1 to hydrmy lation. The ~lI l'l1tin! groups (a. -N ' H =e) prescnt in tM Intihypcncnsivcclonldine (Catapt"Cs) m~y uplain why thj~ drug undergoes linle aromatic hydroJ.ylaliOfl III hurrums.)I,.)OO 1llc ufJCosuric agent probenecid (Bt:'ncmid). ",lIh its clcctron-wi thdrJ"'ing car

b<

"

'l

'" ple-

rri l! zt'p! I,'-h

of"

in U

Prop .........

[TCI

blP~

'-"",
A10lvaSlatill

HO

rollin tcne

CH2 ....... CH 3 'CH

-,"/
S( - }-Ena-!1ocwner

.....

()

NH 2

C[

FigUfe 4-t EurnpIes of drugs and ~ that oncIt1go at"om;ItJ( hydroxylauon In humans. Arrow indICates 511e of aromatIC l1ydrolC)'lalK'ln

........

Wan...

NI'(lIleUIoI_

c. the
i~
)I)

relY and wlfamido groups. 1Ia., IlOI bttn reported to umlc:rgo

III)

ans ....

~ h)dro~y'ation.t.Il

Cllyl-

or the

(Tan-

,"'"
~ctO

9-

OH

acm ial n<. ~

coo
OH

tubo-

Arenc: mille interrnelliules are formed when a double 1:1000 in aromatIC moieties is epo~ IlIized. An:nc: OMdes are of \;g_ nilicanl to~icorogic COflccrn OOcJlUSC thcse: Inlem1l,,'dj1Ltc~ arc elcctropbilic and chemically n:act i\f~ (because of the stl1l1ned Ihree-membered epoxide ri ng). ArcllC o;t ldes are mainly de toxified by spontaneous real'r.lIIgement to an:nol\. but eOl} matic hydrntion to InIlH-dlhydrodiols ~J\d efl7ymullc conju taiion wilh GS H al~ play \'ery important roks (Fig 4-05)."' If not dfectl\'ely detoxified by the lirstlhrcc palhway~ in Figure 4-05. arcne ox ides will bind C(l\'lllcntiy lI'ith nucleophilic !!TOUPS p'CSt:m on profeins, DNA, aoo RNA. lhereby leading to '>Crious ~"('l1ular damage.'_ '" Thi ... in pan. helps nplain why benzcoe can be so tO~ IC 10 mammalian )ystcnl '.

&=y . mi proIercas
H

0'Y'Y0y"(-"0

uoo-

C~O~CI
I'oIpCl"lbOllll1lC
~ 3 7 &-T 'id .... > ... ..

ge nvali ng cloni little !lient

ea/"-

V'IH'<II:"'"

B4lI.'I'I "' ........

Hoe rvrtler 01 C/'C)If'III
iIIO I ". "I ...... ~ '" I""D 8'0IT'ai'" ''''VS V.on

OC"'''

i"

O.('.. Q ... .,.,~!e

In rompounds with twO aromatic rings. hyi.lroxyl~tioll octmprcftn:ntiaJly in the more dectron-rkh ring. For uampit. IIOnIatic hyi.lroxylatioll of diazcpam (Va[ium) occurs ~ in the more activated ring 10 yield 4'-hydroxydiatqWII.' A ~I milli/" slIuauon is Sten in the 7-hydroxy lmion d tile l/lhPSycllOlic agcnt chlorpromazine (11Kr.u.inet' and W pllruhyi.lro~ylaliOil of p-chlorobiphcnyl to p-chloro" -lI)\km)bipheo) 1. (>J

CtwlOi<lerilbly

a-

H
N

COOH

"-=(N H

Rtcenl tnvironmental pollutant .. such a_ polychlorin:ttci.l , ~a) Is (PCB~) :uK! 2.3.7 .8-leII"llCbIQl"(xlltlCnlo-p-dioxin (T OXlJ. ha.c .lIrnCtc:d conside ... "hle public ~m over Ibtif lO~kil)" aoo health hazanls. lhcsc: compoulKb appc;ar ~ be reslstmt to aromatic o.'idatioo because of the nunlCrOl.l~ riectroorrati"e chlorine: atoms in their aromatic rings. l1Ic ItICIabobc Mabtlity coupled to the lipophllicit y of these env ifllI'lIletUIll contaminants protmbly ~~x~ai ns their long peTSi,... w.:t III the bOOy once absorbc:d.

'-!(XS'f"l
I

N~a

CH 2CH aCH 1N{CH 3)2

CI

Quan titatively. the most impunant detoxilicalion reaction for arcnc ollide~ is the spoIllancous n:arraogcment to Uri le_porltling arellOl ~. Often. this n:arrungcllIent is accompanied by a lIO\cl intl1lmolecu lar hydride fdcuteride) migrat ion called the N IH sh ift . "~7 [t was named aft('1' the Natiooal [m:tilUtes of Health ( NIH) llIbor~tory in 8ethe~. Maryland. lI'hen: Ihis process was dio;coverOO. 11M: genenll feOlull'$ of the NIl I shift an: ilIustrnted with the miled-function aft)o matlC oxidmion of 4-deult'noanisole to ) i.leulcri0-4-lIyi.lroxyanisole in Figure 4-6 ..-! Aftcr il\ metabolic fommtlOn. the Hrcrle o.~ ide rillg opens in the i.lil'\:etion Ihal gcncl1lll:S the n~ n:son.:mcC-SUlbihl.Co carbocation (positive charge on C-3 carbon" resonance smbililed by the OCH J group). The f.winerionic !>pec~ (posi ti.c charge on the C -3 carbon atom and negative charge 00 tile oxygen alom ) then undel"J!Ot:s a 1.2-di:uteride 'hifl (N il I shift) 10 form the dieoonc . FinaltraosromJalIOil of the dieIIOne 10 3deu len0--4-hydro.,yani'lOle occurs .... nh lhe preferential loss of ~ "",,on because of lhe ....ealer boni.I energy of the C- II bond (compared with the C D bood). Thus. the deuterium b (('Iained in the molecuie by UndergOIll!! this intl'llmolccular NIH shi ft. The experi mc:ntal observatioo of an NI H Miifi for arom:uic hydroxylation of adrug or xcnobiOIk i~ taken as indirect ev;(ie nee for Ihe io,oll ement of lin 3l"\'IIC oxide. In addition to .he N IH shift. the zwiucrionic species may undergo direct 1 of D' to gcoer.tle: 4 hydroxyani'\()lc:. in 0l>S IIhich there is 00 rctenuon of deutcrium (Fig. 4-6).11lc ultern~t;Ve pillhway (direct loss of D ' ) may be more fa'OT'~ble than the N IH shift III some arommk ox idation re:lC1ion s. Tht:rcforc. depetJding on the sub~titl.lent group 00 the ~ne. ~1lC IUOlltatk hyi.lro~ylaliOil reaclion~ do IlOl dl ~play .ny NIH shift. T wo cxtremely imponant cllqlOatic re~ions lllso IUd III neull1ll il ing the reactivity of urclle o};id.::s. 1bc firlil of tile.'ll: involves the hydrntioo (i.e., nucleophilic allX~ of watcr on lhe epo~ ide) of arc:1lC o~ide~ 1 yid d inactive: mlll.N l ihy0 drodiol n ll.'t.abolit~ ( Fi!!. 4-05). n ils reaction is cmaly-LCd by

Reanaol()l!tT*ll

" o

J' H

OH

OH
H
R

OH

I ,

M...................... 1IICIducI
CO'JiI~

R
boo.nd T O
Of proIfti'I

M .. DNA. RNA

M
Fi9ur. 4- 5 ~ble rNdJol'l palhways tOf ar_ ~. (D<lta ... 1' from 281129, 1972, .leona, 0 Mr. and Daly, J W: Science 185573, 1974, and W (~J. Boo.ctr.atJon of Foretgn C~ New YOO, A.e.adM'u( Press,

OCH,

,, .

OCH,

OCH,

'H

._o
OCH,

D
ZwdteolOOOC

s.-

..,..-LD
OCH,
-0'

....t--D

OCH,
o

OCH,

'"

o o D

figure

~It

4-' ". GenefillftiitumofthtN"'l (stun

11'1

0-

_fOfiOIlIal cnl.yme~ called epQ.tide hydnucs. fII 111 Often. t!"'11lit hydm.e mhib,tors. such II.) cyclohucl'lC o~idc and .l-lnChloroprupl'ne2.J-o:<ide. have been used!O do:mon"~lIw: ooox,ficalton role of the:;t enzymcs. Addition of W mhlbltors IS accomp;:anied frequently by increa....:d \OX e(!he an:ne oxide being lC'..'> tOO. because fO"II:lIioo of d.h)drodiols i~ blocked. For cumpk:, the nJUtage""f} of bcn/.olalp)'n:nc-4.5-()~Ide. ns meas ured by the: : StJlmiJlu>l/lI Il"phimurium lest sy~tcm, is potemiated : tycloht~cne oxide isaddcd. lI Dihydrodiol mctabolltes bctn ICpOIlOO In the mct~boIi sm of sc\"C:rul aromatic ~dnxillbon. (e.g., naphthalene. benw{ll]pyrene, und ocher polycyclic arorHa1,C hydrocarbons), l A few drugs 1t.J-, p/IelI)toin,n phcnobarbital.7J glutethimide u ) also ..rlI dihydrodiol productS as minor 1rK'labolites ;n humans. Otb)drodioI products Wll susI.:epllble 10 conjugation wilh ic acid. as v.eU lIS cl17ym:uic dchydrogenanoo to o.mespoodms catechollllctabolite. iI) exemplified by the IIIttlbolism of phenytoin.71

.,;.:

.k?,H a e- T
3

H
!. \ jlndDopropMll

,'-

A SC(;ond cnl.)'matic rea(.,ion involvcs nudeoph illc ring openi ng of the urcne: o~ide by the sulillydryl group ~""'nt m cs" 10 yield the corresponding frruu-1.2-dihydro-lS. glul.athiooyl2hydro~y adduct. or GS H adduct (Fig. 4-5) ..... The reaction i~ catalYl.ed by varioos GS ~I S.tr:m,fcl'1lSU. 7J Becau<;c GSH is found in practically all mammalian msues, it play5 an important role in the detollificatlon not only of arcne ollidcs but also of It variety of Ot her chemically rea.:jjVt and poIcotially to~ic intcrmedlatC5. Initially. GS H addUClS formed from aTCOe ollides are modified in a series of reac tions to yitld "prcmercaplllric acid" or ,ocrcap4urie acid metabolite5.76 Since it is c las~iried a~ a phase II polthway. GS II ronjugalion is covcred m greater deta, l below. Because of their cla1rophilic and react;'c nature. arene: ollidc.~ al'iO may undergo ~pontaneous reoctions with nucleophilic functionalhics present on bioolllCTOlnoleculu ..... . J Such reaction s lead to modif"1Cd proIcin, DNA. and RNA StructufC5 and often cause dr.:amalic alterat ion) in how the~ macrUllloleculcs funclion. Mucb of the l,:ytOto~ icity and irreversible lesions C".Iused by arene O(k\es are PRSumed to re.sult from their co~alent bllld, ng 10 "lIu lar components. Sev. crnl "'CIl-CSlUbl"l!ctl cllulIlple.'i of rt' activc arene ollides that causo: serious to~icity are pre-.entoo below. Adnun''itnluon of brornobcn/cne 10 rat, cau-..:s :Ie'" C"'" livcr roocrosis.n Elllens",c III '1"0 and 111 Vllro Mud,t:5 indio cate that the liver damage resull'l from the imcf"oI<:tiOll of a I,:hemiclilly rellCtI>c metabolitc. 4-bromoben:a11e 01i/k, with h<-patocytes.'"" E~ te"si>'c covalent blndmg 10 ilcpatic tlSSUC

OH
~O>'

..,..-OI1..,a_ ......

-;~"
()ooo,

, .. ......
..

OH
H~C.

HN-VV

HN

OH
H

DAN ....
H

~ed. glIcu~)

.T "" SG

O""'N ....
CN......:o MoIM)OIoe

--

"",oQ
'
S

jHCOCH 3
OH

"".-

_ ...
DIr~z1'"

..... ci:i;'cOOH

was confimlCd by UlIC of rndiolabckd brnmobcnl'.clIC. "..., sewnl)' of nrosi~ com:lated well ", lIh lhe lLmoum of covalent bindinlltO hepati c ti s~ue . Use of dicthy l maleate or large doses of bromobenzcllC in rolts ~howcd lhallhe dcpletioo of hr'palic GS U led 10 lnocc 5C'a"C liver necrosis.

'"

'"

'"
SG

PoIycyclK: IImmanc hydrocarbons are ubiqullous en,iroomenial contllminants thai are fQl'Tlle(! fmlll aUlD emission. refuse bumHlg, ,ndusmaJ polX(Sses. cigarette ~mole. and

OIMr combustion pl'lJoCC:!;scs. Benlol a Jpyrene. a JIOIent carcinogenk agent. i~ perhaps the most exu:nsh-ely studied of lhe po lycycl ic arOlllulic hydrocarbons.'N Inspection of it~ structure revel,l s thai lItOn1alic hydro.l yln!ion of be n:m[ u lpyrenccan occur at II. numbct-ofpositions. Tllc ido!mificat ion of sc:ver~J dihydrodiol mctllbolites is viewed a~ indirect evidence for (he form:m oo pod inmh'enl('nt of :lrel1C oxides in the metabolism of benzot ajpyrenc. Although l'Crlain arenc ollide$ of beTv.oI ajpYr'I'ne (e.g .. 4.5-ollllk. 7.8-oxide. 9.10o~ide) 8pp:'3I' to d lspl .. y some mUUlgt'ni c aod tumorigenic activily. it doe.~ 1101 appcar that they represent tile: ul ti mate reacti ve spec ies responsible for ben!.o[ a[pyre ne' s carc inogenicity. In rece nt ycal'll. Cllilensi VI! s\tllli e., havc lell 10 tile: charactCriZlllion o f a .. pccific seq uencc of rtlctllbol ic ",octions (Fig. 4-7 ) IIw gcncnnc I highly reactivc i,IIcrmL'diate that CQ\'alcntly bind$to DNA. Mcmbohc activallon ofbenzo{alpyrellC to !he uillmatc c~inogenic speciC$ invol\'e~ an initial cpo.' lIdatioo ",action to form the 7,8-oxtde. \00 hlCh ;s then

CQI1vcrlcd by cpoxitk hydrn...e 10 (-).7{ H).8( H}-dihyUro~y, 7.II-d lhytlrobc nzola )pyrenc. 1IO Tlie two-SlCP enzymatic form~lion of thi s mm,,-u ihydrodiol is ~tcreospeei fic. Subsequcnt cpoxidatioo lit the 9.IO-dooble bond of the laller IIlCtlioolite gener.llcs predominam ly (+ }-7(H).8(S)-dihy lim, y-9( H).! 0( H}-ox)' -7 .8.9 .1 O-Ie truhydrobcn-,-01 trI p)'renc or (+)7.lkIioJ-9. IO-cpoxidc. II IS thi5 kcy elcctrophilic d.oI epoxidc IfIttabolite that realily reactS wl\h DN A to form m.my covalcntl y bound adduc\$.M' 1..1 Carefu l dcgntdatlon stud ies han' shown that the principal adduct in~olves DIIOCl of the C-2 amino group of droxygu1l/lOSinc al C-I O of lhe Iliol cpox idc. Clearly. t hc~ f'Cactions are responsible for gcnc(ic code al1crnlion ~ that .dlimmdy leoo to tnc m~ l ign.~nt tron.<formations. Covalent bitl(h uS ofille dioJ epoxide mo;:labolne to dcox yadenosine anti to dcoxycytidine also has been cstllblis.hcd." AOOIlle:r c~inogcn ic polycyclIC aromatic hydrocarbon, 1. 1 2-dml('th)lben~I(}-l:anthroccllC'. also forms C(lvaknt adIlucts with nucleic acids ( RNA)." The: ultimale carci~nlC rcact,Ye species apparently is lhe S.6-oxidt: that resulc ~ from epox idalion of the S.6-doubl e bond in this aromatic hyd~ carbon . Tlw: arel1C o~idt: intc rnlC(l iate binds CQyolcnlly to gu.nosinc ~iducs of RNA to yield the two adduc's.

OahlatlDn of O

.,fI".

The nk:labolic oxtdauon of olefiniC carbon-carbon doublt

bonds leads- to (he com:~pondmg cpo~tdc: (orox irant). Epox ides !lcri ye!! from olefin~ gcncrJ ll y tend to be sonlC\Ooh:ll more stable than the arc'w: o~ides fnrmed from ruutnatlC compounds. A few epox ides arc stable enough 10 be di rectly measurable in biological nuid~ (q:.. plasma. urine). Lih their arene oxide rounlc rparl s. epoxides arc $l.Isccpli blc 10 enl.}ntatlC hydrot ion by epoxidc h)'1irase: to form lffllU-Ud,hydnxJiols (also calle!! 1.2-diols or 1.2-dihJdro.ty COllI'

HO

HOA
(+ )1.8-DocI-9 TO

Figure 4- 7 Metabol!< sequel'lCf leading to the formatIOn of the ultimate cafClnogenlC specoes of benzo.. [ajpyfene (.;- 7R,85-dihydrOICY-9R, 1O-Oxy-7,8,9, 1G- tetrilhydfobel'lro!a)pyrer.e 01 ( .;-)-7,8-d1Ol-9, 10 f'pol(-

"""""' .... r

.,--'(10

Benzo(.(pyte"oI! Mdld

'"

-.

W")' it for

,".,

CH,

-dihy

~oc

CH,
1,12~'1""""""

,c diol

I fOfni

dalion luack

. , """ -,
ignant

for ge

or "'"
HO

,."

Where A_

:III

ad

OIlcn ic .s from h)d ronlly to

..,bk

PIl"ndf).W. 11'1 In addition. scvernl epo~idcs Ul~rgO GS H conjugation .... A well k1lQwn examp le of o lefinic epoxidation is the me uboIism. in hum:ms. of lhe unticoovulSllnt drug carbamuerme (Tegretol) to carbamazepine--I O.ll..cpoxKit.'" Tbe ep-Glide i~ rta'iOl1ably stable and can be measured quantil:lliveiy

in IIIe pln~lIla of l).llients meeiving the parent dru g. '!"he cpo,, ide metabolite may h~wc marked anticon vul'\UJ1l activity and. therefot'C. may contribute substantially to tile tlM:l"'~peutic feet of the p;lll'llt drug." Subscquent hydratioo of the epo~ ide produces I 0.11 odihydro~ycarb3ma7.('p;roe. an important uri nary metabolite (10 10 30%) in hunmns."

cr

. Epo".

~"" 'OINt;c hrtetly ). Like lible to

" " 10

11 " "

_1.2
~IO,I ,...,.,.dl

'~'

,,_.10,II.onya.oq.
C.~I"'epo'le

; , 10

11

"'...... .",
CI

..
CI
..",'.1: .... FI"""

$' '&wDotaI

Epoxidttllon of the olefinic IO, ll do\lbLe bond in the amipsychotic lI~nt prouipl) line (Vi"OClil)''1 and in the Il " histamine antagonist cypro/lCplooinc (Periactin)oo al'iO occu~, Frequentl y. the epol i<ks formed from the biOlrdnsformalion of all olefinic compound \U'C minor prodUC1S, beCllU.sc o f their funh.er COI1\'~",ion 1 the ~'(JITe~polldj ng 1.2-dioLs, For in0 ~tancc, d ihydroxyakofcnac is II major hum:1Il uri nllry met:lboLile of the once cli niclill y use fuL an tj .innammatory agent alclofcnac.'" The epoxide metabolite from which it is deri"ed. oo....'t"eI'. is pn"oCnI in lIunutt amountS. The presence of lhe d,hydroxy melabolite (o;eoodiol ) of 5oeCOOarbllaJ. but not tho: epo~idc product, has been reported in hUl]\.uns, ~1 I nd i~t evidence for the formation of epo~jde ~ cumes also from the i.olatiUl1 of GS I I or IIIe~apturic IIdd metabolitcs. Aflel' :tUminislralion of )1yrene to rJIii. 11010 urinary melIlboIilcs wcre idrotiflCd as the Isomeric mCf'c aplurk acid den"uu "CS rcsultillg from lIuclcophilic IIlIad. of CSII 01\ the imefll'l('di;ue e po~ide,QI In addition, styrene OXide rovalen tl y

binds 10 rut li ver microwmal J'IfOIc,n~ hnd nucleic aci ds,"" These results indICale thaI styrene o~ ,de is relm,,cLy R:octi...: loward nucleophiles (e.g .. GS H and nucleopllllk groups 011 protein and nudelc Kids), There are, appaR:ntl)', di \'I:T'>C metabollcall), gencrJled epoxides thaI displu)' ~illliJur chemical react ' ~ II )' toward nu cleo]lhil ie functinnalitics, A~'Cordingl)', the lOX icily of SOllie olefi nic COInpounds mn)' re~uh From the" lllelabolic COOI'cr sion 1 chemically reOCIII'e epmidcs,~ One example Ih.u 0 cleatl), links melabolic epo.t 'dation as II bil1lox,flCation pathwa), inl'ohe$ anatoxlII 8" 11l1s nalUt1llly 'Cum ng c~ioo genic agent conta'n~ an olefinic (C2-Cl) double bond ad",. cent 1 p cyc lic ether ox)'gl'n, 'fh.e hc p.nocareioogcnlCil), of 0 an:lloxin B, has beell clearl)' linked 10 ih 1I1ctabolic o.tidl lion 1 the COfll."spondlng 2,l-o~ide, which is extremel), reac, 0 I II e.""" 91 E!llenS1\e III v'l ro and in ~ . ~o IIlCluoolic slOOitt indu:ale thai thi s 2,l-o:u de blllds oo,'aletu ly 10 DNA, RNA. and proteins, A major DNA lKkiUCI has been ,sol;lIe(! and

""~ 1
",04_,"'"

Coo I n.wdillgto
- acdI

""'"

MCll'4lIU'1C 10d

0et_1".)

DelMllNII (mnor)

_.-

",0,CH,

-,,""iAv
~ ""CH)
OIelhytstilbt&lro1 Epoo:kIII

""

PI: " 'I - ocwaIent bit),j"lIlO

PlCI 'IS

ancUor

1'11,('1 '

aads

Chapter ", IoIrtabolir O'''''gf'J "f Ont/tJ /uW NtkurJ O?<IIIi(" C.-p.,."tds

77

dIncttrucd ~ 2.J-dihydro-l-(N"-guanyl)-]-h)'droxyana-

.. 8, .....
knt. 0' aIlIllhe cmlnogcnk estrogen ic agent diclhylstilbes()her okfini(: compounds, such as vi nyl chloride. lOll ~ti l

IIIlI mES I, IDI. '0' uodc:rgo metabolic cpoxidatlon. llte torre.,..t'n& qlOllde mClabolhe~ llIay be the n:octivc species

1'_"
All

lEi' lillie for the IXIMar loxicity seen with these comIn~nl!

group of oldin-c:ont.:linlng compounds

p-

i" "-

o-

h-

' - ' Ihe !huuction of cytochrome 1'-450. ,... ul$ ComI"k ~Ionglng 10 litIS !roop include allylisopropyloccla_,10ft. KJ'I ~Ial ..... 1119 and the volatile 311('\,l\elic tcnH n~roulll".I!O 11 IS believed lhal the olefinic moiety pr!)tOl in lbelie compounds is activ:;tu:d IIlClabolically by C)'IOChrome P-4SO 10 fonn a vcry reacTive inlermedialc Ih~1 lXIIalmrtl mnds 10 the heme portion of cylochmme p. A'll Itl , 1 The abnormal hc'.nl(' derivali \'e.~. or "grttn pig_ WIb." th.lI. ~It from Ihj~ covalent interaction ha,-c been d,Cflud as N-a1~yla,cd proIopotphyrins in .... h~h lhe ~"')i JOOictI i~ d!>rh'ed din:ctly from lhe olefin admini ~ meL \61 111:'1 . I I III Long-term administt:nion of the abo~e IItIlIOIItd Ihftt agcnts i ~ e~pectcd 10 lead to inhibition of 1\lodMivc drug melaboli~m. polenliol drug inleractions. nnd I'f"Ionred pharmacologicul effect~.

mide (On nas.el I~ oxidil.c:d eK len~i~ely to the ~ponding alcohol and carbiuylic acid. Both \I!ctabol ilCll h",,'c been isolated from human urine. II. Similarly, lhe " benl~hc" lnethyl group in the al1l i-inflarnmHtoty agcnt toirnetin (Tokelin) undergoes o~idmion to yield the dkarboxylic acid product as the major metabolite in human~. I I~- ,'''' 11M: <;elective COX -2 anti _innammatory agent celecoxib under~ benzylic oxidation at its C-5 methyl group to g" 'e hydro,ycelecoxlb a.~ a major metabolite. m Significant benlylic hydrol)laliOll OCCUr.! in the metabolism of the P.adn:ne'll~ blocker metoprolol (Lopn:ssor) to yield tr-hydrmymeluprGlot, lll. m Additional uanlples of drugs and lCnobioti cs u1ldcrgoing benl.ylic oxidation are ~ho .... n in Figure 4-8.

O.kI.tI_.1 Allylle c...Lon Atoms

Microsomal hydrolylation 01 allylic carbon atoms i~ commonlyobsCi vcd in drug metabolism. An illu'ilnui"':elliample: of a1lylic olidalion is given by the psyChoactl'~ component of marijull/Ul. J '-ICirahydrocannabinol J I-THC. This mole:cule: OOfItain, three allylic carbon centcflI (C-7. C-6, and C3). Allylic hydro~y la[;00 occurs cxten~ively at C-7 10 yield 7-hydroxy- J I-TII C a.~ (he major pl:"mn metabolite in hum:ms. ,.... II Pl1:!nlll1Coiogical studic~ show thm this 7-hydroxy melabolite is as activc as. or cvcn nM.Jfl: Ilet;1 e Illan, J '-THC per lie and may contribute signifiC3ll1ly to the o~eraJl cc:ntrJI nen.ous system (CNS) psychotomimetic effects ofthe parent compound." Il5 Il ydroxylalKm aI!iO OCCUf"'i to a minor ex tent at the allyllC C-6 posi tion to fh'e both the epimerIC 6a-- and 6.8-h)droly metabolitCll. IO, ' Metabolism does not occur at Co). prcsunmbly because of steric hindraoct'. 11M: antinrrhythmic agent quinidine is nlCtQboliled by 111_ Iylie hydro~y lation to J-hydrolliY'luinidioc. the principal plasma metabolite rQUnd in human s.llt>. m This metabolite shows signifICant antiarrhythmic act; ~ity in a",mal~ and pi>!! _ s,bly in humans. WI

n" Ih.at naylkc. LanAlud

C-Iboa Morm anachc:d 10 :aromatic rings (1r~)'I~ position)
thereby forming the torrt'Spond.. alcohol (or tarbinol) metabolite."'" I) Primary nlcohol !INboI,1t! art: ofttn o~idizcd f unher to aldehydes and tar!m)'11C acids {CH~OU - C liO - COOHJ. and secondary at.:oh)Is are con,etted 10 ketones by soluble ak-ohol and .tdm).te dehydrogenasc~. 110 A lIemati ~ely. lhe alcohol may be COI\JI'pted diKedy .... ilh glucurooie acid. I n The benlylie .-:no. atom jlics.."11t In the oral hypoglyeemit: agent lotbtJlaft IlCpIible 10 O~idatlon.

"of

..

<-

,-

A.

""

\ I

'H
Sl1'
H2.$-01I It1C1U1J' -2,.,M"ICIP!OC*'III (I:lOM)

"""""',,!

7 \'
~'TetrllhyO-~

DebflilOQ!W1

3I.!elh'UlOltI1ttv_
~te

Figure 4- a Examples of drugs and I!flObooIICS undergoing benzylic hydroll)'lauon Arrow Il"OdlCil les of hydrol()'latlOl'l

a,~
2.H)tlro-2(N'~

OCH,

l-trtdIOlJaIIaIuxi' 8,

C I

C "

".,H'.,,,.
Ha,Aov

~ --"

OH

c 011';4= '
",,"

: hoi

CF3CH~O/ ""CH 2

"""""
CH,

-AbJd Mac"'" e

~ S02NHCNHC.H
c.-,..Me<ot,6!e

H,C-o-~--f.\-CH COOH - HOOC-o-~--f.\-CH COOH I I

2 2

CHS

CHS

.~5-Merhyl3-rflflIJOfOO'lElrnyl1)yfazoi 1-yI}-t)eIlzeo--..ltooamtde

""""..,

CH,

H O
+

HQ'v"+

H ,C CH,

1
1
CH,

yH
C~H"

HCto 3

6/JH,oo.,",1' THe:

,
N

, 'V

HO-e

CH,O

OIh<:r c.\alnple.~ of allylic oxilllition include the M'OOlhe hypoolk hexobarbital (Sombulclt) and the analg~ic pcn la1.OCUlc(TaJwm). '1lIo! 3'-hydroxylmed metaboli te formed from hc.obatbital is su.sceplible to gJu<:umnidc conjugation a weI! as funhcr o;o,idalion to the )"OltO compound.*29 ,., Unolwbital i ~ a chinal barl!iturme Ocr;"'"I;ve thai c~ isl ~ in Iwo enam ,omcric fQl11ls. SlodlC!l in human s indICate thaI the pharmarol~icaJly Ie.~s ac,h 'c (R)( - ) cnamiomer is nlClaboliled more flIpidly than its (S)( + ) iSQrnCr. III Penlawcme undergoes allylic hydro,ylatioo al the IWO terminal ffil!lhyl groups of its H-bu tcny' ~ ide dlain 1 yie ld either the cu [R'" 0 mills ulcobolllll:tubviilC.'l sho ..... n in the diuffdJ ns. In hu man s. more o f the Irtl/IJ alcohol is formed,Ill, ' 1

FUr the hcpaloc:ll'C.oogcnic agent !>afrok-. aLlylic hydml' ylulion i ~ involved in II bioolctivalion pathway leading 10 the fOflllaiinn of chemically n:acti\-e mctaboliteS. I" This proce.~s i nvol vcs initial hydrox ylollOO at the C-I' carbon of sarrole. "'hkh is both al1yllC and befU.yl k. The hydroxylatcd metabolite then undcr~oc~ funhercoojugotion to fonn a wi fate ester Thi s chemically reactive ester intenncdiate Pft ~u mabl y undergocli nuc leophilic dl ~placcmcnt reoctiom with DNA or RNA in vi tro to form covale11lly bound ad ducts. '" As shown in the schocme, nucJwphihc attock by DNA. RNA. or other nuclwphilcs i~ facilitated by a good leaving group (e.g .. SOi ' ) at thoc C - l ' positWn. The leavin, group tendency of the alrohol O H group itse lf i ~ 1101 CllOI.Ig.II

(JH

'

HN

OANA I

eH,

:t.o.oI'O " '6t)otal

eH,
N
...... CH 2

...... C.,... ...... CH OH

HO
Pw" ......

r et\!
,

HO

CH, I 0

CH,

N-), N- "

t~ N
CH,

N__ '''' '7l1uon

"
0

N-x, I N

(35) NMoIhtb"a ' epMrI

!'I.e ..... "

Of 3-l'tpG'oor,'dIal8pem

...
~

,-

N-),
O, N---"'-' '.- N

.fod
~

!J.I-

., "'-

by <XI

.gh

".

10 f1lCllil;llc displ:lCl'~nl reaction s. Irnponanll'1. all 'II ic Ii)'.tot) lMloa ICIlCI1l1ly does 001 lead 1 11M: gellCTlIlion of reac0
iDlermediaces. [Ill ;mol\'ement in the biocoxificalion of oaCroIt appears 10 be an exception.
' I

n~

Hydroxylat ioo of the carbon alOm a 10 carbon),l function alilits gcnerally OCCUIll ooly to a limited ute:nt in dlllg me tabolism. An ilIustroth'c uample involves the l'Iyliroxylal.ioo of the 5Cdath'c l'Iypnotic glutctl'limide (Doridcn) to 4-l'Iydrox yglutclhimide .'I. " 1

111.1.-:e- ta.Atams a to
O.ldztlDn . t Aliphatic: .nd Aliqtc:JJc
cal L
o~idast-

(7 a1t,1s d _IDeS
SYMem plso o.'(idlle5 carbon . . . adJ;tCenlli .e.. it) to carbonyl alld imino (C - N) fuocNJalibO, An Important class o r drug.' undergoing Ihi~ type do:"dalloo is the bcnwdiazepillCs. For e"'!lmple, dinl.cpam (\'Ilium). tlunw:pam (Dalmane ). urn! nimcl1I7-cpam are OX;-

Tbr ml\edfunaion

At 2 iii.

IliItllIO their COfTeSpOIldi ng 3-hydrOJly mClabolill:.~ . I J6- ' .lII

ThtCJ carbon alorn undergoing
liydro~ylali()l1 i~
(r

to both

IIlcwn c:ubonyl and an imino fum.1ionalily .

fur d'aup.:om. !hi: hydrQ;lytalion reaction proceeds will! ~ le1eoselectivilY \0 form primarily (9O'l 3-hyftl)dlurpam (also called N- met~lox:uc:pam), with lhe 11 ~Ule ronfiguflIIion al C-l ,' Further N-demelhyl1IIOII0(!he lalltr metabolite gives ri!iC to the phannacologi. 1I1y "" 'e 3(5)( + }oxuepam.

(',~, -C5H~ ~

lH 2CH a

O'~N

HO
'-'. '"'

O,A

.. QxioatO'l

.. - t 0l0daI0'I

Alkyl or aliphatic carbon centers an: subjcct to mlxedfunction oxidation. Metabolic oJ.irnllioo at the tenninal mcll'lyl group often is referred to Il.~ W Q.rid(Jlirm. and oxidatlOll of the pcnuhinmte c1lfbon atom (i.e .. next- to-the-Iast carbon) i.~ ca lled w - J O.ridUliOfl. ' I Il l TIw: initial alcohol nJ<!tabolit.:.~ formed from tliese enzymatic wand w - I olidQl ion~ an: .>usccptible to funher ox id:alion to yield aldel'lydc. kClones. or carbolylic add!>. AllcmlItively. the alcohol metabolites may undergo glucuronide conjugation. Aliphatic w and "" - I l'Iyliroxylations oommooly lake place: in dlUg moIules with straight or branched al~yl chains. ThUs, the amitpilcptic agent vaJproic acid (1Xpa kene) undcrgoes lxMh wand w - I oxidation to the .5.h)'droxy and 4-hydroxy metabolites. n:speclively. 101. "l Further OJ.idation of the 5-l'Iydroxy metabolite yields 2-I1-propylglularic ocid . Numerous barbituruteli and oml hypoglyt-emic sulronyl un:as also havc aliphatic side chains th aI arc susceptible 10 oxidation . Note Il'Ial the scdlltive l'IypnOlic amobarb1tlll (Amyull ) undergocs extensive w - I oxidation to the com: sponding 3'-h)'droxylaled metabolite. ' 6j Other [)arbituroJcs. such as pentobarbil1lJ. 1' 5 ,." Il'I iamy lal. In and sccob;ubllal."l reportedly are mctabolil.cd by way of wand w - I oxidauon . TIw: l1-popyi side chain attactled 10 the oral hypoalyccmlC agcnt chklt'propamide (OiabillC!iC) undergoes e~lensivc 1 I hydmx),latlon 10 yie ld the KCOnd:uy alcohol2'-hydroxy. chlO<"J"lf"OP;lmide as a major urinary metabolite in humans. ' Omega and IIJ - I o~idat)on orthc isobutyl moiclY pre.~nt in the anli .inflmnmaloty agent ibuprofen (Mouln ) yields the

CH 3 CH 2 CH 2 CHCOOH
V~OIC

nC aH, I

AeocI

corm;~ jng carboxylic acid and ten iary alcohol metJIbolites. I Additional exall1p1e~ of drug~ reponed to undergo

aliphatic hydroxylation include meprobamate. no flulC1hi mide.lI. ,_I ethoo.nimidc:. I~' and phenylbut11lone. Sl 1be cyclohexyl group isoommonly found in many mec.liclIIalllient ~. and is also susceptible to nmed-function oxidation (alicycl ic hydroxylat;on).'I~ I" En7.Yfllatic IIItroduction of II hydroxyl group info :;l monosubstituted cyclohexane ring gcoerJlly (x.-cuo; al C-3 or C-4 and can lead 10 cis artd /"(111$ confonnationa l stereuisomer'S. as ~hown in the d iallr'Jmrned sc heme. An c:>.ample or thi s hydroxylution p:llh""ay is .seen in the melabol i~m of the or.tl hypoglycemic agent ace tohexam ide

(Dymclor). I n humans. the Irtllu-4~hydn)1,:ycyclohex).] product is reponedly a major mctabolne_ll~ Small alnount ~ ()( the other JlOIiSible qereoisolTM.'l"i (namel). the l"Is-4-. cil-3-. and trtm.l'-3-h)droxycyclohexyl dtri ~ati\'Cli) aho ha\e been dc:tet'tcd. AllQlllcr rel ated or.U hypoglyC\'mic Igenl. ghp!' : jdc. is oxidiJ.e(i in humans to the Imn.H- and r is-3-hydro, x)'kyclohcx)1 metabol ites in about II 6 : I 11I110_1~ Two hUfilan unnary fllClabolile.~ of phencyc lidine (I'CPt have been idi:nli fk'(l as the 4-hydroxypipcridyl artd 4-h) drox ycyclohexy l derivatives of lhe parenl compound. I " I'" Thu s. from these rcsul N. it llPJli:ars thut "'alicyclic" hyd ro~ ylati!)11 of tile ~ix-memben:d pipcridyl moiety may pamllel cI<N.'ly the hydroxyl:uiun pattern or thl: cycluhc:x) I 11lO1e1 y.

ThlIwnyIaI h

s.:0b9r!)o!oI X ... 0

CI

bJpofsn

c.r~ Aad

MetllbOli1e

OH

CHl-T-CH1~CHCOOH

~I

CH J

CH,
Te<\I3Iy AAx.1I OJI Motabolotl

.-,
C.Ha
CH~CH3

O ,""'N--", \ O
H

.. - 1

'. ,.

ElhoIuoi,odI
R

.-,

+
H

.)

,.

,)

,
H

OH

+ R
H

OH
H

1be stereochemistry of the hydroxylated eentel'll in the two

metabolites has not been dearly est3blishcd. BIOU1lnsfOlTl'l3lion of tile antihypenensive agent millOxidil (Lonltcn) yields lhe 4'hydroxypiperidyl metabolite. In the dog, Ihis product is a major urinary metaboli te (29 to 47 %). whereas in hu mans it is detected in small amounts (_ 3'1 .131. I"

R-

1 X- C I"

R- X- C -

..., 9)
I"

/ H
_ R- XH+

o
I

I c-

'MIereXANOS

Oxldntl 1...".I"lng em b.a-Mete. : . tOlil

Syste ....
Nitrogen and oxygcn fuoctionalities are comlTl()l11y found in most drugs and foreign compounds: su lfur fuoctionalities occur only occasionally. Metabolic oxidation of carbonnitrogen. cu1)on-oxygen. and carbon - sulfur systems prin ci pally invol~'es two basK: types of bicMr"dnsformalion
proces.se.~ :

Oxidative N. 0-. alld Sdcalkylulion us well as oxidative deaminatiOl1 reactions fall under this mecnanistic pathway.
2. ItY""'.ylIOOn or OIK\;oIKln 0( tho httmloMom (N. 5 only. e .,.. N hydroxylalioo. N-o~11lc formalloo. sulfo.ide. and !.IIlf""" f",
~ion~

I . l yl1ro~ylalion of the u<ll'bon alon' ~tlachcd dinxlly 10 tile 1le1C1 ....1Om (N. O. 5). n.: _llIn, ;metll ...b ..., ;1 otkn un stable and decomposes .... lIh lhe c1ea~age oflhe clrbon-httrroalOIn bond:

Several sltUCtural features frequent ly detennine which pathway will preduminate. especially in carlxm-nitrogen systems. Metabolism of some: nitrogen-comainin, com poullds is complicated by the fact Ihat carbon Of nitrogtn-

H
~~r;

Myah .\e

.'

HO

0-

secondary !'eOC1ioos \0 ram her, I1lCft: col1lplell mc:laOOl.ic products (e.g .. O~ illM:. DltnlIIe, nllrosG. imino), OIlier oxidative processes thaI do IlOl fall undc:r these tWQ basic calegorie~ are discus~ indi vWlly in the approprilllc carbon-helc:roatOm sc<:tIOfl. The: lWUboIism of carbon- nill"Qgl.'n sy~lem.~ will be discussed fIN. roljo,.~ by the nJClaOOlism of catbon-oxygen and caOOIl- Wtfur systems.
k)dro.\)IMcd productS
rrnI)' ulldergo

llive

o.Iay.

OXIDATION INVOlVING CARBON- NITROGEN SYSTEMS

MCIIboIism of nitrogen functionalititi (e.g .. amincs, am

Ides) is Inlportanl because such fUllCliOflal groups nre found

"hieh

""'"

.),.,.. bomimetic phcnylcthylamilJe!i. bcnlodiazepinc5).I~ 1bt followtng ru5CIISSIOl1 divides ni~oen-oonlaining rom.. k Into lhfte
ba~ic

In many nalurul products (e.g., morphine, COCD; ne. nicotine) 81 In numtrous importunl drugs (e.g.. phcnolhia/jnes, antiIIIUr1U11a, Incydic antidepressants, P.adn:ocri..: agents.

~-

cla.\ses:

I Abp/IaIoc (pimary. teCOOdary. and ICl1iary)!lnd alicyt'ilc (sec0IIiIIwy l/>IJ lC11iary) ! ArumIIlc: ond l1ctt"AJCychc n;lf'OI!cn compounds

=t"".

) Arnm

The SIIsctplibilily of coach class of these niTrogcon comp.lUiiIh 10 COlther a-<:arbon hydro~ylation or No()(id:aT and iOll _ mr"''OIic productS toot are fortned an: discu s!IW. The hrp.llic C'f\ly~ rr>iponsi ble for carrying oot If-Cli/"bon bydlO;o;ylJtion reactions an: ttxo cytochrortlC' P-4SO Dud-fuOC1ion oxidascos, lbc: N-hydroxylatlon or N-oxida-

lextions, however. appear to be cm alyzed nOi only by t:)locbrome 1'450 bIll also by a 5e\:ond ciD..'S of hepaTic IlmdfunctlOn o1iidase, culled I.mi"e iI.rid/IJt$ (some \lOll
IIIIIeS

caJlaJ N.uxidIlY$) .ltoO llIc:sc: enzymes are NAOI'Hdepe!w.ient fla\'OIlllludns and do 001 contain cytochrome ,4SO,I.I. ,.: They rt'quire NAOPH and molecular O1iygen
N-oxilbtlOll.

III [1fT)' OIIt

rftfi~ry Aliphatk and Alicyclic Amine$. lbc: oxida ~\"I: renlO\"al of alkyl grotlp!o' (particu larly methyl gmups)

from tertiary aliphatic and alicycl ic amincs is ca lTled OUI by IIqIatic cytochrome 1'-4SO mi1ied -fulICtion oxidase cn7ymes. 11111 reaction is common ly referred to a5 uxid(Jlj\'" N-lit(ll h/ai_.I~ Thc initial ST in voh"es (>-Carbon hydroxylation ep 1IIfm .carbinob.millCl intamaiiate ....hkh is un~able and -':iS o;p::Nllar..:ous heterolytic cleavage of the C-N '-110 11\'1.' a S'OI1dary amillCl and a carbon~ 1 moiety (alde-

hyde or l:etOllC).I'" I", In general. small all:~l groups. such as methy l, ethyl. and isopropyl, arr ren\O\'ed rapidly.'1>.l Ndc:all:ylution of the I-butyl group i~ not pos~ible by the camilIolulllinc pmhway because a-carboll hydro1iylmion callnot OfXur. The finot all:y l group flllm a tertiary aminc is removed nlOll: napidly than the second alkyl groop. In some inWlllCCs. bisdealkylnl>on of the tcrtiary aliphatic llI1lillC' to thl:: corn:spondmg primary aliphatic amine ClC'CUIS very slowly. I&.! For uample, the leni:uy amillCl imipmnine (Tofrani1) is II1OnOdcmc:lhylaTed to desmethylimipnilmillc (desipnunine).I6I>. 167 This major plasma metabolite is pharmtlCOlogically acti~e in humans and contri butes substantially to the antidepressant acti vity of thc parent drug. I... Very lillie of the bisdcmcthylaled metabolitc of imiprnmillCl Is detected. In contrast. the local anesthetic and umiarThythrnic agcntlidocaillCl is meluboIiud extensively by N-deethylationto I)o(h IllOI1OC"thylglycybylidinc and glycyl-2.6-xylidlllC' in hUlllans. 16OJ nil Numc:1llWl other tertiary aliphaT amillCl drugs an: metaboic lized principally by oxidative N-dc:all:ylation. Some of these irw;:ludc the :mtiarmythmic disopyramidc (N~).'JI, I7J thoe anlieslrogc nic atenl tamo~ifen (Nolvadu).1 ) diphenhv dmm i IIC (Be nltd ryl): 7 ' . I"c h lorprom al inc (Thornzi rIC).' 7fo. "'/7 and (+ )-a-propo1iyphcne (Oarvon).'78 When the terliary amillCl contains several different su~t i t llt:nts capable of undergoing dcalkylation. the: smaller alkyl groop is remo"ed preferentially and more rapidly. For uwnp1e, in benzpheuunillCl ( Oidrcx). the methyl is removed much ITlOOt !'lIpidly than the benzyl moiety,1 An interesting cycii7.ation reaction occurs with mctl1adonc on N-dcme1hylation , The demethylated metabolite normcth odonc undergoes spontaneoos eycJi1.lltion to fonn the en ami nc metabolite 2-c:thylidcnc- I .S-di mc T hyl-3.3-diphenylpyrrolidine (EDDP)."u Subsequent. Ndemethylation of EOOP ond isomcril.3tiOll ofthc double bond leads to 2-c:thy lS-mc:th)' I-3,J-diphcnyl- l -pyrroline (EMDP). Many times. bisdcaJky lation of I tertiary amillCl leads 10 the corn"Sponding primary aliphatic amine metabolite. which IS su!lttpcible T further ollidation, For example, the bisdes O methyl ,nctabolite of the H ,-hist..:lmlllCl antagonist brompheniramine (Dimetane) undergoes oxidativc deamination and furtherollidution to the correspond ing propionic acid metabol ite. III Olliduti ve dc:umination is discu5scd in greater detoi l when ...c uamillCl the metabolic reuetions of secondary and primary amincs. Lile their aliphatic counterpartll. ahcydic tmiary armnes are susceptible 10 o~ idali ve N-dca lkylation reactions. For C1iample, the analgesic mcperidillCl (Derncrol) is metabohud

grotJ,.r

R -N-C--

I"

R -NH +

R,
T.,."'Y Amrle

I R,

.t

"

Irnopo

ao...,.

"',.,.,,
, t

'> t

CH,

'odoc_

o.opy.al'l1ode

CI"'pto'~

( + ..... -?oopaot) ..........

(N.d""...,,)' b.. ,
inlN~1

--

principa ll y by this pathway to yield normcpcridmc: as a major pl.asma metabolite in humans. ' 1Z MOI'JIhine. N-.ethylnormorpIl ine, and (!ex\romc:lhorphan also undergo some N-dcalltyl-

ch loroc)'c1il.ine is. ir,deed. met.:lboll l.ed IQ signiflClll!l am()\lnlS of non;hJ()fQC),clill:ine. whereby the I-butyl gl'tlllf'

ation.'u
Dire<:1 N-deal kylalion of (butyl groups. lIS discu~sed above, is not possible: by the (}'-c!U'bon h)'dro~y l ution path.... ay. In viltO studies irKhcUlC:. however. thai N-,-buly lnor-

is lost' .... C.reful ~Iudies shoWN thai the /-bUlyl group d removed by inil;:'! hydroxylati'.m of onot ofThe methyl grout: of the I-butyl moiety to the carbinol or alcohol prodllCll! Further olidulioll I!enenues tile corresponding carboxylIC :tC"id that. on decarboJOylalion. foons lhe N- isopropyl deri ...

:fC,H ,
/t,~CHCH3
CHa
Nco nlllll\ikJa ..

7'H C,

2E~ 1 5-<;1rnethyl-

3.~,*" .

,Eoop)

~C,H,

A ..)-CH CHa CH, N

2

2E1I-5 rnemfl
3'~"'P'I"r~

OM"",

'-0-

- - 8f - o -0iCH1CH1NH2 -

Bra l ~ '.'"

Bd

-.el" "" MIW " e

- "'-0J.IP

~Oil~)~

popioc8Cld

Uvt. 1lIt N' ,sopropyl intermediate i ~ dc:l l~)'laled by the norII1II a-carlIon h)'dro~yta l ioo (i.e . cntbinolaolloc) JXllhway 10 Jive norchlorocyclizine and acetone. Whether this is a JCIltrJI ITlCtllod for the losS of I-bu. yl groups from arnllll's II \11 11 unclear. Indirect N-dcalkylalion of ,bIllyl groups j~ IlOl obst,....ed signi fic:mtly. The N-t-bu tyl group prc5Cnt in _y,thdre:lll'rgic anlagonis\s. such as ... mulalin" and <.albuumol. n:mains inlacl and doc.~ 001 appe ar 1 undergo any 0 1 'p'Ur1ClJl1 metabolism.''''

M 1.1dioe

Alicyclic leniary amilll,'S often gelK'r.l.'e loclam metabolites by (!"Carbon hydro~)'lalion reactions. For uample. ,he tobacco alkaloid nit-utine is hydroxylared mnia!!), III the ring carbon alUII1 tr to the nitrogen to yield II CarbUM)lamin.c inlcrrncdia le. FutthemlOre. enzymalk ox;daliolL of this cyclic carbioolamine gencr.lIcs the 1 :1C1am mcmbolilc cOl; nine. II', 1111 Form ation of loctam metaboliles also has bet':n rt'potted to occur to a minorex tenl f<.>rlhe antihistllmioe cyproheptadioe (rerioc1;n) I'" 100 unci the antiemetic diphenidoJ (Vontrol). I.' N-ox idaiion of tertiary amincs occurs ",ilh K\'mll dlllW;.191 The true extent of N-ox ide form:lIion mien is romplica!ed by the susceptibility of N-oxides to undergo in yi,'o rt'dUCllOn back 10 the parent tertiary amillC. Tetttary amlllCS such as H ,_hiSlanHI1e antagoni<;1S (e.g .. orphI'nadrinc. tnpe!enamulC). pheoothiaJiJ"ICS (e.g .. chl orproot.ll1 JIlC). tricyclic nntideprcSiantS (c., .. imipramine). ancl narcotic analgesICs (e.g .. morphine, codeine. and me peridine) reported ly foon N' oxidc prootlCls. h i SOniC iustances. NoQxidcs po~<;css pharmacologica l act jvity . I~ J A comparison of imi prn mine Nox ide Wilh imipramine illdicalcs thai the NoQx ide itself possesses antidepressant and cardiovascular actiyi ty , imilar 10 that of the parent dlllg. ,~. PH

"' 'P
i.
lob."... Io-Ef,.,tou...", ,,ne
R - Oi~

~
R - 0i 20i 3

'.-

lic

Secondary and Primary Amines. Sco::olldary anHllCS (ei ther ~t oompoullds or mctaboli lCS) are susceptible to ox id:ul"c N-dealk): lo1ion. oxidaii"e deaminattOn. 1Uld N-oxi dation n:act ion~. 1"', 101> As in Icrtiary amincs. N-dealkyJal1on of secondnry amines proceeds by the cnrbinolarni ne palh-

-0-

1 r-\ 1 CH - N N-C-CH,

C. Hs

CH,

'---l

"I

a-

CH,

f. . . ... bo ' '. . . .

aA.,.,

OH HO'',,-

I,...H
' CH
1 '

NH
HO
T..,,,..O' .

' c/

CH,

HO

1' aH aH, '

euuo ...

-N

CH,

"1 DWktlwon ofsccondary amille$ gives rise 10 the cor tnp...tJ", pnmary amine metabolite. Rlr example, the ublockers propranolol... ..., and oxprenolol ' 9' r.;4C1Sopoop~lation 10 the wrrespoodilll primary 17 flO \. N4calkylation appears to be a signifICant biotnms. IonnIoon r.:lhway for the: ~ amine drugs n1Ctham ;.wrnne w, IWand kctamine. lOO I yielding amphetamine _l'oOItnll1llne. respectively. The lUIline ll1Ct:lbolileS fonned fmm oxidative are ~osceplibJc 10 oxidll/il'~ de(lnrinll/iOtl. Thi s \lmllar to N-de.alkylation, in tlmt it imolves an oKarbon reaction to form a carbif1()o
,~

H
-c~

o
- - c-+
N
NH,

NH,

and am cannot occur. then For eumplc. dtami~.'.~. o-carbon hy" I With mcthamphcla-

:;f:'~;:::~; ,: ;,;; ~ne mclUbolite ;

,od

--

....

Some secondary alkyclit: amincs. like their teniary amine analogues, are metaboli7-Cd to their corresponding lOCI/un derivatives. For example. the allOreCtic agent phenmetrazine ( Prell)(lin) is metabolil-Cd principally to the 1actam pmdllCl 3-ox~nmctrazine .J(JJ In humans, this IlICIIIm me\lIbolile is a major urinary prodUCI. Methylphcnid.ate (Ritalin) also n'portedly yields I lactam metabolite. 6-<lxorilaiinic acid, by oxidation of 11~ hydrol p-Cd metaboli le. ri lal inic acid . In humans.:IOoI Melabolic N -oxidalion of secondary aliphatic and alicy. clic amines leads to ~yeral N-oxygernlled prodOCIS. % N' hydroxylnlion of secondary amincs generates the corresponding Nhydroxylaminc IllClabolitcs. Oflen . the5e hy . droxylamine products are susceptible to further oxidation (e ither spontaneous or enzymatic) 10 the corresponding nilrune derivotives. N-benl.ylam]lhctami ne undergnes metabolism \0 boIh the tOm'spondillg N-hydroxylamine and the nitrone mctabolitC'5.1IOS III humans. the nitrone meUlbolile or phenmctrar.ine (Prell)(lill), found ill the urine. is ~Iieved to be ro",1ed by rurther oxidation or lhe N-hydroxylamine intermediate N-hydrox)"phenrl"ltlrazine. MI ImpofWltly.

Ao1"~.'"

Kftr",."

H",-<

Ceo t>no/ai,. "'

~M"""'"

I
OH

TlwQugn

PI., .. , Nrw.a

. . . 0:1 . . . 01
"" ' " ' I' HN;-... ,....CH3
OJ

CH

C_
CH,

I"O~H
Pr<naty ........ fr'elatJoI!Io

(0l0I'"

,''4 POOP'tw(Otll)

c.tw ..... , Figure 4- 9 Metilboltsm 01 Pfopl'anoioI (0 Its aldl'hyde melAboIite by d,rf!Ct ~amtnatlon 01 the parfllt compound and by dNmlnatFOl"l ollIS pllmary atT\ine melAbolite, desI5OPI'opyI propranolol,

H,

H, H N

0)' '
Carli.. 'a1Vlll Inl9fOllodi.u.

PtI8l i 1."1ZIfIe

-,"~,~ilI~'~'~,

o-ci

COOH
H_

CDOH

_.
mU(:h less Na(l:c.idalion OCCII~ for $eC()Ol/ary amines than o:c.idalh'e ~alkyla(ion and deaminatiun ,

:()

-0-6,H-/,'-,
HN

/OH
-NH

-N

CH,

CH,

5 ! )"I"ldary .,.",
Primlll')' aliphatic a mines (whether parent drugs or mc taba

oliles) IU"C biOlrnnsformed by o:c.ilbuive (thl'Ollgh the catbioolamine palhway) Of by general. o:c.idatiye deamination amines is carried 0111 by the miXedaflinction cus$Cd above. Endosenous primary amines (e.g . doj'+1 ' oorepinephrilM:, tryptamine. and serotonin) aod :c.cll'AlitW ba$Cd on the: stl'UC'1ures of .nest endogenous ncuJ'Olnmlll: len are metabol it.ed. however. via o:c. idlltiYC deamilllbOl" a specialil.ed fam il y of e" /ymes cal led ",,,,wam/ne O~_ (MAOs),-

' C'"

..

MAO i~ a n.vin (FAD}-depcndent enzyffiC found in two Il)mt forms, MAO-A and MAO-B. and widely dis.rib-.lIn both tbe eNS and peripheral organ ~. In contrast. c,n:hrome P-4SQ uisis in II .... ide vanety of iMll.yme fonns _~III NADP-dI'pcndcnl system. Also the grealest varicty i cyp iso~ymes, al least the oot's associllioo with the meIIIdllm of xenobioli cs. are found olOStl), in the li ver and .-sI'~ mUC(l$L MAO-A and MAO-B are coded by 111'0 JtW$. bod! on !he X<hrort1()SQftlC and ha\"(~ about 70% anoacKl sequence homology. AOOIherdlffcrence between iteY P and MAO families is cellular location, CY I' en~IIJ'C round on !he endoplasmic reticu lum of the celr s 1JIIlId....~as the MAO Ctll.ymes are 00 the Ollter milO)ama! membrane. In addition 1 the ~cnobiOli cs ilIus0 .., in the reaction schemes. OIher drugs mclaboliud by fie \1100 system include phenylephrine. propranolol. limoIII and other .8-adrtncrgic Ugooi SIS and antagonists and a .-.ely of phenylclhyJamines.~ Swnunll fl.'3l1,lres. especially the a 5ub!ititucnb of the

primary amine. often detenninc whether carbon or nitrogen oxidation will occur. For example, compare ampnelaminc with its a.rt1Cthyl homologue pnenterollllC'. ln amphetamine. a-carbon hydroxylation Clln occur to form the clUbinolannne intcrrncdiatc. which is convened to the oxidatively deami . nated product phenylacetODe.61 With phentermine, (l-Carbon hydroxylation is rlOI possible and precludes oxidative deami nation for this drug. Consequently. phentcrminc would be upccled to undergo N-oxiooion I\'adily. In hurtW1$. p-hy droxylatioo and N-oxidation lin' the main palh ....llys for biotran sformation of phcmermi ne.2Ii'1 I ~d. N-hydroxyphcmcmlinc is an imponant (~%) urinary metabolite in humans.lU'1 As di~ussed below. Nhydro.l y larninc mctnbolile5 are susceplib1c to funher oxidahon to yield other N -o ~)'gcnatcd products . Xcnobiotics. s.uch as the hallucinogenic agen\.'; me5l:a li ne3JI. lIJOI and 1-(2,5-dirneloox y-4-ull'lh)'lphc:nyl}-2.amlllQpropane (DOM or "STP" ). l lo. ll\ are oxid.1tivciy denmi nalcd. Primary amine melabolites arising from N-

r"'rC~2HCH3

- V
He

/ N,

CH 2C 8H ~
NM_ IoAMIlidi\e

H'X~)
CH3
MMaboMa

.,-

70

__ .. .c.1:D'! 11'1A,.....,.. ra poniJIe. hence . dg ra _ 0" ........ (II 'MOIIIlOr'I

1'tIeoI..", ...
N~,,"/"on

IllinalJon

alion. In primary bscs disopamme. nOOlOtia (ran smil-

j
HO

nauon by

CH, CH'/CH

'c'~H2

oxi(l(jsu

P-I+,O'O")PI-

d." ...

DCH,

CH, ' CH
CH30A y
104 77
r' ",

CH 2
CHa

NH,

I '

' cH'
I
NH 2

CHa

DCH,
1-l2.~" ' illlhJIPIW i)'t)-

2..-.woopQPlWl8
~DISW"

S( -+- .... MeIrIyIo' "'" I . ...

3. __

_ _ __

dcalkylation or decarboxylation reaction s also undergo deaminmion. The namplc of the bisdcsrncthyl primary amine metabolite dcrh'cd from bromopheniramine is di!u~~d above (see !iotion on tertiary aliphatic and alicyclic amines).'' In addition. many leniary aliphatic &mines (e.g.. antihistamille!i) and 5CCOndary aliphatic amine! (e .g . propr,moIol ) ~ dcal.lr.yllued to their rorrespondi~ primary amine metabol ile~ . ... hieh are amenable 10 oxidative dcamination. (5)( + }-(J-Mclhyldopaminc ~ul!ing from decarboxylation of the ~nlihypc:nensive agent (S)( - )-a-mcthy ldopa (Aldomet) is <lemni 11~led to Ihe correspondi Ill! kctooc ,nclal>olile 3.4-dihydroxyphcnylllCCtollC. m In humans. Ihj ~ ketone is I major urinary metabolite. The: N-hydroxylalion n:action is not ~I ri cted to ...... substi tUled plimary amines wch as phemennine. Ampheuunine has been oMel'\led 10 undcrgosoux: Nhyili1)J,yhllion in viU'O 10 Nhydroxyamphelamine.!" 21. N- HydroJyampheta.rune is. however. susceptible to further conversioo 10 the imine or OJidatioo to tnc oxime inlenncdiate. NOll' thaI the o~imc inlCrmedi3lc arising from Ihi s N-o~idatiOl1 pillhway can undergu hydrolytic cleavage to yield phcnylacctooe. tnc same product obtained by the !H:3rbon hydroJylntioo (carbi

nolmninc) pathway .11). 11 Thu s. amphetamine may be con. 6 verted to phenylocctOllC through either tile ...... carbon hydrol' ylation or the N-oJidation pathway. 'The derote corottmu'l the relative importance of the two pathways is onp ml!.117-11 ~ 'The con!;ensu ~. however. is that bulh metabolic: pathways (carbon and nitrogen o,.l(\;Itioo) are probablyopa-. alive . Whether a-carbon Of nitrogen oxitbtion ~'fIMCS in the mCUlbolism of amphetamine appears !O be specieS dept:ndcnt . In primary aliphatic amilll'..~, ~uch as J'hcntennine,liIl chl~hentennioe (p-chlorphcmcnninc), 21 and am:tJl!J dine. :0 N-oxidluion appears 10 be the major biouansfortnltion pathway because a-carbon hydroJylation cannot omr In humans, chJorphenlennine i~ NhydroJylalCd extcnsivtly. About J()Ik of a dose of chlorphcfltcrrnlne is found In !be unne (48 hours) as Nhydmx ychlorphcnlurnine (free . . conjugated) and an additional 18<)' as other products ~ /'i OJl(\;ltion (pn:..~umably the nittoliO and nitro mcUlbolitcs).II. In genernl. N hydroxylamincs arc chemically unstable and susceptible to spontaneuus or en7.ylllmie oxidation to the nitroliU and nilm derivutjvc~ . Por example, lhe N-hydroIY~ amine mctabolite of phc:ntcrminc undergoes further Olida-

CH2/CH3 ()

' CH
I

( )CH1/CHa
NH

H,.o ' C;H...l... ()CH~c"""CHa '

NH2
.... 1 ophe\ao I....

NH

II

' OH

bUll to the nilro'iO and nilro prodUCIS .J0'7 The amivir.li :md ~an agent amantadine (Synunettd) i"!:poilcdly K1i'd N~~ldation to yield the COfTeSponding N.h), lkuty:and ruin:$) mcl.:lOOlilC5 in vltro ..uti

con

droll' mmg

oog~

bohc

hlalCS )CC les

",.,,-

~.= tMIIi'

""". lCCur.
of N $).l19 : and

jvely.

,,"" ,...,

AtonYfic Amines IJnd Heterocyclic Nitrogen Com pI)IJtIIb. The biotnlru.rormlilion of aromatic amines pnIld. the carbon and IlJIrogcn o~idalion reactions seen fllI" .Il1ph.me amlllCS.nI UJ For Icniary aromatic amines. ,.b ... N.N-dimcthylal1l line. oxidative Ndealkylallon as -.dl as N-o~i<k formatiOfl lake plaec.J2.' Secondary aroIIUIic InlUIC:'; nuy undergo N-dcalkyl~tion Of" N hydtOlyla lila 10 Il~ the corrcspoodlllg Nhydrmylaminc:s . Funher Oto.btlOll mthe Nhydroxylamine ~ads 10 nitrone productS. .~h In tum nJay be hydrolylC'd to primary hydroxyl _1ti. 1:I lenlat)' and secondary ;u"Om:lIl C amine$ are eIOOlIIll~red ran:l y in medicinal agents. In contru~t. primary ~ ami~ are foond in many drugs and are oftcn ..~~ from nlT.)nUltlC redUC1ioo of aromatic nitro compouods. ~ivc cleavagc of aT.O compounds. and hydro.1'1> fA aromal;';: arnides. ~,lIbllnn of primary :oromatie anHnc:s genellltcs the N h)droll}IDmine metabol ite . One such case: is aniline... hkh iiRtabolilCd 10 the ~pondin8 N.hydrollY prodUCI . W OtidallOO 0( tile hydrolylamine derivatlYc 10 the nitroso dailau~e also CIUI occur. When 0 111: considm> primary aromile ImIIlC drug~ or metabolites. N--oxldation con stItutes 1liiy . minor pathway In comparison Wilh other biOlrdnsfoc IIIlion palh ...a~~, such as NacetylatiOfl and aromalic hy ",,-)l;,tlOll. in humans. Some N--olygcrl31ed metabolites iIIIe i)r(on n:por1l-d. howevcr. For c~ample, the nnlileproiic dapwnc and its Nacetylatl-d melnbolitC' lin: mc:tabo:.II \l1I"flCalltly 10 lhelr corresponding Nbydro.ylanHIIC *"laUI e5.2z& The' N hydroxy metabolites are further l"Onju pIfd III Ilh glucuronic acid. ~lt!hemoglobmemia to~idly i ~ caused by <;e~enll aroDie anllfles. induding anil irlC und dapsone. and is a res ult the bioI;onversion of .he arumlilic amine 10 i.s Nhydro~y

"III

derivativc. ApParently, the N hydrollylarlIIne oxidi,.es tile Fe!' form of hemoclobin to ilS Fe 1 Form. This olidiud (Fe" ) Mate of hemoglobin (called nlelhem"IfIQbin or fun" hemoglobin ) eM roo 1000ger transport olygen, which leads 10 !lCrious h)\",lia or 1111('1I1Ia. a umque tl'pe of chemical Mlffocation.D Diver-;e aromatic aminc:s (especially a:r.oamino d)"t'!i) arc known to bto carcinogenic. N--01l1d.1tiOl1 plays an importllnl role in bioocti vating these: Iltl)lllatic amincs 10 potcntially reactive cleclrophilic species that covalently bind 10 cellular protein. DNA. or RNA . A wcll studied e.umple is the Cllt cinogenlc agent N.methyl-4-aminoa1.obc:llZCot.UJ.. m N--o. idallon oflhls compound leads to the c~ponding hydroll ylamine. which undergoes sulfute conjugation. Because: of the good leavinggroup ability of !he ~ulrate (SO~l- ) anion, Ihis conjugale can 1000il.t "fIO<1tal\eOllsly to fOlll1 a highly reactive , resoli:mcestllbil i1ed nitrenium spe!,:ics. Covlllenl addUCIJ bel .."ttn this species and DNA , RNA , and pmlC'ins hayc beC'n cl1llructenl.ed.l.lO lJ I The o;ulfale e~ler is believed to be the ultimate can:inogenic ~ics. Thus. the uample indicates thai ccnain aromatIC amillC'$ can be bioact.ivaied to reaclive inl ennediates by NhydroKy'ul ion and O~u'falc conJulplliOfl. Whcthc>r pnmary hydro. ylarmnc:;; can be bioac tlvaled Similarl y is ullclear. In addil1on. it is not kno ... n if Ihis bioto.iflCmion palhway ploys any SUbstlllll ial role in the toxici.y of aromatic amine drugs. Nmldallon of tile nitrogen mom s prcSCIlI III arom~tic hel C'rocyclic moieties of many drugs occurs to a minor Uknl. OcarlY. 1II humans. N--ollida.ion of.he folic acid amagonist trimc:lhoprim (Proloprim. Trimpel) has yickled approx i malely cqualllJOOUllIs of the isomeric I N--ollide and JN o~ide U minor metabolilC'S.:l 11le pyridiliyl nitrogell alom presenl in mCOlinine (the major Jllctabolite of ni cotine) undcT];~ ox idation to yield the ~ponding N--olidc me '"bol itc.m Another therupeulle agent Ilmt has bc:cn obscrved to ulldergo formation o f an N,olide metabolite is mctronida !.Ole.!.....

"'''''

ollyl

,~ida

CH CH, / y '/ CH3 C..-

...

CH, CH . . . ' / CH3 c-

~,

,<"'"

NH,

PheniIt<ITW1lI

CI .... ... . '1III~1I"Ii~.

NlIIO MNltrite

H) dracyIa 1. 18

., ~

-'

:"

"""""

tri',LJiU/ .. Inr,

1-I,0 ' o -NH

' OH
SI "I'IIldaI\I
Atomalk: Arri'III
~3i."

~(lOr"',."

..."."
NH,

NHOH

._.
AI ... II _ H

Hidoowt.&' ..

N-O

RNH-o-S02-o-NHI-RNH-o-S02-o-NHOH o.c......
N-Ao:et..... _ . 11_

r'

J:~"" "" "

2:{2 MathyI-S:""'cHIrOda2oI- 1 _~ ~hanoI

Amid flS, Amide fuoctiooalilics are susupliblc IO~ live carbon-nilroa:en bond cleavage (via a-carbon h~)I alion) and N-hydroxylalioo reacrioos, Oxidati~ dcIIt)Io ,)[ion of many N-s ubsriluled amide dru gs and l~~ has been reported, Mec han istical ly, o~ idative p,occcds via an initiall y roomed caminolamide, stable and fragmcnl$ 1 form the N-dealkylated proo:Iul1, Fer 0 example, dilI7,t'paIlI urtdasoc:s extensive N-demo:thylaboool the pluumacoIoaically ac:li,'e meuabol ile ll1,t'pam,m

desmd!i,"

Variou~

--

l.."""",

pincs (e,g., obarbiual dtalkylated, groups 1 0 some liul footureas. such as 01111 propamide,l also an: subject 10
c~te nl ,

In lhe eyelic om ides or l:.clams. hydrox ylacion of

the*"

Cavil: illy
Id:IIdi

""""

OCH,
01,0
OCH,
T "melhopr 111

CH~-): }-NH2+CH3
HzN
I N-OucIe

OCH3

dic"'lIboI, a 10 the nitrogen atom also leads to carbinolamKIn. An example of this pa ,hway is the conversion of COli . . 10 ~-hydn)};yOOlininc. lmerestingly. the laner CIIbi.alamide illlermcdilue is in tautomeric equi librium with lIE nng-<!penal metabolile :r{l-pyridyl}-)'-O.lo-N-methyl

illll)rwnideY7

Metabolism of the important cancer chemotherapeutic agent cyclophosphamide (Cytoull ) follows a hydro.lyllilion pithway similllTto thatjusl described for cyclic amidcs. This drug is a cyclic p/M)Sphornmide derivative and, for the most part, is the phosphorous counterpatt of a cyclic amitle. BeCllIJ5C cyclophosphamide itself is pharmacologically inae-

CH

CH 2 - OH

I
O.lida1m.lyleal kylbioc.ics ylalion

N-) NCe H ~

N -) N
CeHe
C.bi- ' ...d..

- ..................

, c
0

N N
H

CeHs
Or..tnea,,~11

OIazepeoYl

is un
~

lion 1 0 thy ldi

....
HN
Ite,-\AaI
fua,"-II
~

a
I

odiazc., he.l ely N \ely of chlor

m'~

O),..N""'O
..... CH 3
A,. - D, Rz. CH s R,C.H"A,- CH.CH3

SO l NHCNHCH1 CH2 CH 3

o n

aliey

r O ... pr .........

96

Wilsoo! a",/ Gu m /d ', TUI"'1l1Ic af O"""lr loIn/lr",al and P/omlO '7~lk<d C/o,.,n;,,"'

tH,
c.~

CH,
,-~

0NH 0

CH,
,.,(3-Pyridyf)~,

~--

Ilve,:3I metabolic bi<XICtivanon is required for the drug to nle(hate its antitumongcnie or eyt(J(oxic efrecK ~ key bi(J(ransfonnation paihway kadmg to the acli-e metabolite IIwoh es an initial carbon hydmx)lation reaction at C-4 to form the carbioolamide 4.hydro~ycyclophosphamide, m,~.o 4. UydroxycyelopholKphmmdc IS in equilibrium with the ring-<lJlC'no.-d dcalkylated mt'tabolite 3ldophosphamidc. Although II has polen! cytotox ic plOpcrti es, aldophosphmnide undergoe. a further elimination reaction (reverse Mic hael reaction) to gencrutc ocmldn and the phosplloramide mustard N.N-bi~2-chloro-elhyl)pOosphorodipmidie acid. The laller is the principal species responsible for eyclophospha mide's antilumorigenie prope";e~ and ehenlOlherupcutie effect. En:tymatic oxidation of 4-hydmxyeyclophosphamide and aldophosphamide leads 1 the relat;\'ely nontoxic metab0 olites 4 ketocyclophosphamldc and carbo~ycyclophospha mide, ~ively. N-hydroxylation of aromatic alludc5, v.hich 0c(:u1'lI to a nunor Ulenl. is of somc toxicological IIIIC"'-"'. sil'l(.'<' this biotransfonnalion pathv.ay may lead 10 lhe rorm:uion of chemically reactive inlcn~dlate5. Scv~1 t'Jlamples o f cytoloxicity or carcinogenicity as'WC'ialcd wilh metaboli c N-hydroxylolion of the parc:nl arom atic amitk hu ve been reported. For example, the well-known hepmocarcinogenic 2-aeelylaminoflul)I'Clle (AA F) undergoes un N-hydroxylution reaction calalyzed by cytochrome P-4SO tu ronn the CUlTeSponding N-hydrolly metabolitc (also ca lled I hydm~amic

acid) .:U1 Funher conjugation of thi s hydroXDmlc acid producc~ the COI'TeSpooding O-sulfate esler, v.hlCh ionil.es 10 gcncntte the elenrophilic nitremum species. Co\~lem bind ing or Ihili IUCtivc intermedi:lIe to DNA is Juto.,.n 10 occur and is li lely 10 be the initial e\'ent that uhim3tely lead~ to malignam tumor formation.'! Sulfatc conjugacion plays an important role in thi~ b-i04oxific3Iion J"Ithway (S " Sulfruc Conjugalion." for (!Inlier discu ...~ion). Acelulllinopll\'n i~ \I relatively safe and nontoxic atmlgesic a!;em if used at Ihcr~peulic doses. Its I~t~bol iS111 illu str~tCli the foctlhal a xeno-biotie commonly produces more than one metabolitc. lIS mctabolism also il1ustrJtcs the effect of age. since infants and young children coury oot sulfation rather lhan glucuronidation (<;ee discussion at 11M: end Oflhi5 chapler). New ph:umac-iSls rnust n:aJiu that at one lime IICCtamlide and plienllCetm VI ere IIlOfe widely used than lI(:CtllITIinopllen. c,'en though both are ronSlde~ more 10XIC beclluse lhey produce aniline derivoli\'C:'i. Besides producing lo~ic lI!1ihne and p-pnenetidin, ~ two analgesics also produce acetammophen, When large doses o f the laller drug are ingested. utensi-e li"er necrosis is produced in humans and animal s.:U I. 1"" Considerable evidence aq;ues that this hcJ"l1000xicily depends on the fonlUllion of a metabolically generated rellCtive intctrn{,dia le. l . ' Until reccmly,1.... 1A7 11M: aceepled biooctivalion palhway was believed 10 involve an mitia! N_hydruxylalion reaction to form N-hydroxyacct aminophen.:" Sponlall('QU.~ dehydr~tion of this N_hydrox

~~_N,/CHaCH2CI ~_~~~.
o
II 'CHaCHaCI
.HvO'~t-. i Ode

OH

II

,,---"""'"

Pt-osphot.lode MusIWd N.MtJ0.(2.O'lIc:lIoetI1y4}phosp\l;:Io cd F-nodic .-cd

,_" "' ;- ';",,,n,," -'

~

2 ' " E'.'

CH, .4WoFl

\ c-o I

}-,,~ \

c-o I <><,

.t ' \
CH,

000 -

c_o

J pro-

,.bind

~c_o

<><,
i'J .....

Po'.

'\c-o
<><,
I

,,"'a

~"'

- ....-

CH,

\ cI

iYS lin

ulfalc

1gesk

. tra l e~

.~

rage.

nuncr

'hop-

CLam-

mino-

""""

cuuse

toxic ,"oc. n: !n-

ho".'Imcr
(lC.

"oo

tC

VI'

an

(" , ." ,... ,,,,, .. _,010

...

....... r------,----'---r------;
-00 2

r ,ll,.~ I

dro.-

-a.
1'O!f.

- --..-.--., . III"..,., -I I
__

,~"'

"' 7,',' _VI" .....

P ...... _

/01-... ,'1'1< ... ' ......

I'

yamlde produces N.occtylimidoquinone. lhe p!'tlpCISed reac li~~ melabolit~. Uwally. the GSIl present in the liv~r cornblll~s \\;ilb this reactive metabolite to form the corresponding GSH conjugate . If GSH levels are sulTlcic:nll y depleted by large doses of acetamioophen. covalent binding of the reactive intemJediute OCCUTll wilh mocromol ecule.s presenl in the liver. lhereby leading 10 cellular necrosis. Siudies indialle, however. thaI the reactive N-acelylimidoquioonc inlermedlate i~ not fOillocd from N-hydroxyacetaminop/M:n. JA ' - JA7 lt probably wises Ibrough iOIne ot/w;'r OXidative I)(ocess. Therefon., lite mechuIliSlic fommt;on of lhe: reactive mellibolite of acetllminophen remains unclear.
OXIDATION INVOLVING CARBON-OXYGEN SYSTEMS

groups. such as indomeillacin (lndocin). ~ ,- m pnu:l)51n (Minl~).l.n. ~ and meloprolol (L.opressor).IU. I:.J have Il:ponedJy undergone significant O..delnelhylallon 10 their COITC!iponding phenolic or alcoholic metabolites. whkh an: fun/w;'r conj ugated. In many drogs lha! have scvernl nonc:qui valent melllo~y i:roups. on.c panicular metllo~ y group orten IIppcars 10 be ().demethylated .selectively or prefen:ntially. For examele. the J,4~-lrirnetllox yphenyl motcly In boIh mescaline ttl and lrimethoprimm undergoes O..demelbylalian to yield pn:dominantly the COITeSponding )-O-dC'!melh ylatcd mc:tabolitc-s. 4-0dcmclhylalion also ocrurs to a minor utenl for both drugs. "The phenolic and alcoOolic metabolites formed rrom oxidati ve ()'denlClh),lation are sus ceptible to oonjuption. panicularly glucuronid:uion.
OXIDATION INVOLVING CARBON-SULFUR SYSTEMS

Oxidlllh'e O-deal"ylalion of carboll-o~ygen systems (principally elhers) is ca!alYI'oo by microsomal mi~~d function o~ idaSl:s. l(oj Mec hanisti cally. the biotrdllsformation involves an in itial a-carbon hydroxylation to form either a hemiacetal or a hemilelal. which undergoes 5pOfItarICOUS catbon-o~y gen bond cleavage to yield the deal"ylllloo o~ygcn species (phenol or alcohol) and a carbon moiety (aldehyde or ketone). Small alkyl gTOUp" (e.g .. melhyl or ethyl) Ilunched to oxygen are ()'dealkyla!ed nlpidly. For example, morphine is the metabolic prodOCI of O-deTTICthylation of codeine.~ The antipyn:tic and analgesic activities of phenacdin (see drawing of acetaminophen melabolism) in humans appear to be. consequence orO-deethylation 10 the: active metaholite IlCetamioophe:n.:OO ~vcrol other drugs containing ether

Cnrbon - sulfur func tional groups are susceptible to meta bolic S-dealkylation. desutrurlIlion. and S-oXidat1on Il:ac lionS. The fiTS! ''''0 proce"~ in\'Ol\'e oxidatl\'e car bon - sulfur bond cleavage. S-dcalkylalion is analosous to O Pild N-dcal~ylation mechanistically (i.e.. il involves acarbon hydroxylulioo ) and hall been obseTV~od for various w lfur xenobiOlic~. Ib.'. lJ& For expmplc, 6-(meth)'llhio)purint: is demelbylated oxidatively in rots 10 6-men:aptopuriroe.~7. ~ S-demelhylation of mcthlluralU'> and S-debcozy lallon of 2-ben~ylthio-5-lrinuoromethyJbtn7.ok acid also have been reponed. In contrasl 10 O and Ndcalkylation. examples of drugs undergoing S-dealkylalion in humans lR

A-O-C1

- - A-OH +

C8ttxJnr1 Mooe!)'
i<eIont)

1_-

H
Codl 'ne

Chaptrr;l Mtrabfflic CIlt"'lJts of D",S" alUlllt/(JIW 0'11"";(: C'''''p",mdJ

:osin

99

h""
their I are
!qUI-

""OV~

__

CH,COOH CH10""", CH J

)rten ally. bo<h thy l_ "ltth-

~O

CH,O"''''

..
,~

sus-

j
V~

... .
car~

<oc-

CH,O

TflrlleIhcIp '"'

ious

....'n/y_

m~

. Iw

lion.

IimJItd ba:ausc of tile ~mall number Qf su lfur-contai ning .wcil!lls and the competing melllbolic S-oxidation pnr
mses (II diagram) . Chlllati,"C con~ersion of carbon-sulfur double bood~ S) (thiono) to the corresponding carbon - Qxygcn double IIOIId (e - O) is (";llled dtSllljlll'(Jrj()(l . A well-\:J"IO\\'n dOlg tumpJe of this metabolic process is the biotr.msform~lion aI~Ullto its con-es.ponding oxygen analogue pentobarIIiUI. , An analogous Iksulfurution reaclion also occurs _lilt tile P = S moiety present in a number of orgllr>Ophos ;.eins1icides. such as parathion. Ztll.l6J Desulfurutioo of pnduon kads to the fomwion of paraoxon. .... hich is the .:tilt rIlduboli te responsible for the anticholinesterase ae DVily of the parent drug . The mechanistic detail~ of desulfIlItion an: poorly undefluood. but it appears 10 in~olve miI)xK1ation of the S or p _ S double bond.:lI'>' Orianll!lulfur xcnobiQlics commonly undergo S-oxidation III yield sulfl)xide derivath'es. Sel'end p/lcoothia/ine denvaInU In! rIldll:rohzed by this p,uh .... ay. For exa~lc. both .wrur atums prescnl in thiorida1.ille {Me l huil)W' are susttptible 10 S-oxidatioo. Oxidation of the 2methyl thio group )ielduM acti>'e sulfo~ ide melllbolile mcsoridal'.ine. Interest iIgIy. mesoridazine is twice as polcm all 3111ipsycllotic agem .Iboondazine in humans and has beoen inlrodoced inlo clini allIfC ali Scrtnhl. ~'H

Ie ..

S-oxidalion constitutes an important path .... ay in the metabolism of the Hr hislamille amagoniSl.S ci mc lidille (T ogamc:t)- and mefiamide.2IW The COITC!iponding 5U lfoxidc deri~alives are the major humall urinary metabolites. Sulfoxide drugs and metabolites may be further o~ldized to su lfones (-SOl o). The 5Ulfoxide group J!fnent in the immUllOSur,gr::ssi~e agent oxisuran is lnetabolil.ed to a sulfone moiety. In humam. dimelhylsu lfoxide {OM SO) is found primarily in the urine as the oxidiud product dimethylsul fone. Sulfoxide metabolilC:s. such as lhose of thi0rida7ine. reportedly undergo further oxidalil)f1 to thei r sulfone -SOzderivatives.2M -

O.ld_tlGn of AlcGhei d Alde hydes

Many oxidatil'e processes (e.g.. benzylic. al1ylic. alicyclic. or ali phatic hydroxylation) gCllenlle alcohol or carbinol meUlbolites as intcrmediate products. If 001 conjugated. these alcohol products are further oxidi1.Cd to aldehydes ( if pril1lury alcohols) or to kClone., (if secoodary alcohols). Aldehyde metabolilC:S res.ululli from oxidation of primary alcohols or from oxidat; I'e dcamination of primary aliphatic omincs often undergo faci le oxidatioo to generale polar carbo~ylic acid derivatives.' 16 As I general rul e. primary alcoholiC grou~ and aldehyde funroonalities are quite vulnc:ra-

...... 'w

c-

SH

N } +HCH
N H
&(MsU ,"00)'

....

100

W.I_ urW G.woId '. Tr.(lboot (If Orra"j~ M~dk.tI(I/ ami PIrt.rmflcrN"a,/ CI.~",j$ll)

j CH 2CH 2S-CH 3
HN
C~H2CH2CH3

COOH

AovS-CH ~C.H5

SAN"O CH3 H

CX;:OSCH,R Rng SuIoMIcIe

So"'".,,,,

't,rEnda

J(.

o
CH3-S-CH3
Oii '1iI\tlyI SlAIooide

II

--0

CH,-S

0 .....

e? 3 CH

Oo''''~ Suitooe

IK 50 OJ.idalior!, Se\'erol drug u:unples in ",,-hieh primary

Otle.rO.'. 11_ Bleb._dOLIl pticn

....... 77INboIilel and aldehyde mtlabolite!i are o~idizro 50 earbI;u. ylk acid products are ci tro in StiOll5 above. Although stCOOduy alcohols are susctptible tooxidadon, Phil !UClioo is 001 often import anI because lhe reverse reacIioft. IWIloC:ly. mluction of the ketone back 10 Ihe SCOOIldary aIoobol, OC(1JTll quite rcadily. In addition, the ileCoOOary aleo-bot poop. being polar II71d funcliooali1.cd. is more likely to lit I;OI5juped than the ketone moiely,
NAO' NADH NAO NAOH

Pal' eu.,.
In addition to the many oxidative biotransfomlluions di~ cussed above. olidiuive aromalintion Of dehydrogenation nnd oxidlltive dchalogenation reICIions also occur. Meta. bolic aromal;1.IItion has bee n reportro fOf oorgC(>trel. Aromll ti1.atioo Of dehdrogenatioo of the A ring present in this steroid leads 1 the com'SPQllding pheoolie product 17ct0 ethint- l &-hOlFloestnldioi as a minor metabolite in wom en.n In mice, the terpene ring of J 'THC or J '''THC undergoes aromatization 1 gi\'c eaonabiootn6. zn 0 Many halogen<Olltaining drugs and xenobiotic!l are me tabolized by o~idal.ive dehalogenation . FQr uample. lhe volatil e anesthetic age nt halothane is mellibolized principally to trifluO!"OOCctic acid in huma\l~.z7I. Z7Y It has been postulated thai th is mctabolite arises from cytochrome P-450-mehalothane 10 form an initial carbinol diated hydro~ylation intermediate that spontaneously climinates hydrog~n br0mide (dehaloge51alion) 1 yield trifl~yl chloride. 1be 0 lauer acyl chloride is chemically reacti\"e and reacts rapidly with water 1 form trifluoroacelic ack!. Alternatively. il can 0 acylulC tissue nuclcophiles. Indeed, in vi tro studies indicate that halothllne is metaboli1.ed to a reactive intermed iate (pre. sumably trifluoroocetyl chloride). which covalently binds 1 0 liver mieroSOlFla l proteins.l .... :l 1 C hloroform also appcan 1 be mtlaboli7.cd o~idalively by a si milar dehalogenation 0 pathway to yield the chemical ly reactive species phosgene. Phosgene may be responsible (Of" the hcpalo-- and neplunt;ollcity a.~!iOCialed with ehloroform. Z12 A final uample of oxidative ddlalOilenation concerns lhe antibiotic chlommpllenieol. In vilro studies have shown that the dichlOi'03Cctumide portion of the molecule undergoes oxidative dcehlorinat ion to yield a chemically rcacli ve Ola my1 chloride intermediate that can relICt wilh water to form

AOllOH ' ' -

./

,3Itdd
~

ACHO _ '--:::".~./e::..... AC~ . vvn

bIoron"el$ion of alcohols 10 aldehydes and ketooes ft CIUI~ by .wluble alcohol dehydrogenascs j)f"e5oCnl in !he: b'1f and IXher tiSSUC$. NAD' is l'I:quired as a eoc7lltyme, "II .giI NADP ' al.w may serve as a coenzyme. The rcac IioI eataI~ by alcohol dehydrogenase is rc\"el$ibJe bul oIIat p .... d$ to the right because the aldehyllc formed is funIa 0.\idiztd to the acid. Se\'eral aldehyde dehydrogenilia. including aldehyde ox idase and xanlhillC oxidase. carry out lbe oxidation of aldehydes to their corresponding
ac.id1.1I" 111_11l

or

M etabohilll of cyc lic amines to lheir loclum metabolites ~~ob5erYw for various drugs (e.g., nicofine. phenme l tMhylphenidate). II appears tnat soluble or mi CFi iEII dehydrogenase and OJl.ulases an: involved in olidltFFII!be carbtnol poop the: intermediale carbinolamine 10. CIIbIm~1 moiety.J7I For e~ample, in the melabolism of mtdaztpam to diazepam, the intermediate eminolamine (2 b)"dlox)177t'daI.c:pam) u!ldcTgOCS Olidatioo or its 2 hydrolY IJWP tQ Harbonyl moictr. ' A mictmOfllal dchydrogenase cillin out this OJlid:uion.Z 4

ratJM'._

or

'f'"
I.ts(1azepwri

CH,

N ) N
C,Hr.

CI

N"')OH . ...... , N CI
Ca H ~

CH

N-) N
. H.

' 0

2HyO<~

"'-"

CH,

HO
11.. EtrinyI_ 18-1 lOt IlOOstraOol

CH,

CH,

H,C

CH, OH

0 CH,
l '-lHC

'"
C,HlI
",''THC

CsH"

OH H,C

0 CH,

C$H"

"""""'"

H
F C-C- Br __

I I

o
H8r

' F3C-C-a -

II

0
H,o

F,C-C-OH + HCI

"

CaoDonol
1n1o" ...... le

O-C-CI

CI - C-CI
CI

~)

/H

Il:

OH ON

-0-

CH-CH-

I NH-C-C-CI I
CI

II

II II ~ ~ -'", A-NH-C-C-CI R-NHC-C-CI

/ H

CH 2 0H

b
o
II
0

0>:Ivl 0 ..... Ide

R- NH -C-C-OH

..!::J
Coula
~

0. .......

BordoliQ ('<'r;#y?)

_connpondlng oumic acid metabolite orcan acylilt~ mi w ... t... l proIcinS.ll-I . lfO Thus. it appears that In sey~ral in ~ o~i<bIlve tkhalog~nalion can lead 10 lhe formation oClO.\ic: and ~JC"Ii"e acyl halide intcnncdialeJ.

REDUCTIVE REACTIONS
ReduclI\'e procCSSl'S play an important role ill tile: mctaboM of many compounds containing carbonyl. nitro. and Il1O VOUP!l. BlOI"tduo:.:lion of carbonyl compounds genelllte$ lIcobollknvllI'es. 11e. :I&'! ",herca~ nitro and aI.o reduclions teal !GamlllO Iknvathes.2II> The hydroxyl and ammo moi~ leta(!he mc-tabolite5 are much rt1OI"e susccpllble to COIlJuga ItOa than the (uoccJOOal groups of the parent compounds. Hence, ~i.e poct '<e<. lIS such. flldlitate drul elimina-

NADPH. ho ..... ever. the same en:r.yme system can reduce car bonyl derivah'es 10 lhelr COfT"t':Sponding akohols. '16 Few aldehydes undergo bi-orrouclion because of the rellIh'e case of o~idatioo of aldehydes to carbo~ylic ocids. One frequemly cited cnmpleof a parent aldehyde drug unde'loing e~lcnsive enl,ymatic reduclion, ho,,evcr. is the seda ti\'c-hypnouc chloral hydrate. Bioredu~1lon of this hydrat~d aldehyde yield s trichloroethHnol lIS the major nlCtaoolite in humans.lIIl1 lnlerc:.~tingly, Ihi- alcohol nlCtabolite is phamlacological1y activc . Funher glucuronidation of the alcohol leads to an inoctive conjuguted product lhat is readily CA ' cn:ted in .tIc: urine.

OH

...

ClaC-C-OH !::::::::::::i: CI,C-CH H H ,o

0
H,O
-----+

CI,C-CH 2 OH
TI"'''''': 2 101

Reducu\e pathways that are encountered less frequelllly IIntI mc-taboltsm mcludt: redoclion of N-oxides to their rontSpOfIding tertiary umi11l!S and reduction of sulfnxides 10 lollifidcs. Reductive clcD,'age of disulfide l ink~ges and reo dtIcuon of carbon-carbon double bonds also occur, bu t con\brute only minor pathways in drug mctabolislll.

"dilll of AkMhyH allMl Ketollla C L .. ,-I.

group. is cn~ frtquc/Uly in many drugs. In addition. metabolites (QIU,llJag ~etone and aldch)'dc funclionali liOl oftcn arise from olKbuve fkamilllllion of xenobiotlCl (c.g .. pmprnnoId. chkM",x:nlramine. amphetamine). Bccau-e of their ease: 01 olilbllon. Ildehydc~ are metabolilCd mainly 10 carboxylic II:KIl. QxasionaJly. aldchydes are reduced to primary alco101$. Kctones, howcvcr. are generally re~i~tllnl to oxidat ion lOCI an: reduced mainly to secondary alcohols. Alcohol mellboIul'S arising from reduction of carbonyl compounds gcne!IIly undergo funher conjugation (e.g .. glucllronidation).

1K CIIboll) l ll1OIety. p;u1;cularly the

~etooe

anyout bion:ducuon ofaldchydes and ketone~ .II6.m "They I't found In the hv~r and other lissues (e., .. kidney). As a pral c!w. these $OIuble enl,Yrroes ha"e similar physiPnies and brood wi>stTIIle specificities and ftIjIlll't NAOPH as a cof:lClor. Oxidoreductase enlymo=$lhat e.ry 0111 both oxidation and reduction reoction~ also can ~aklc:hydes and kelones.:>S1 Forexample. the imponanl Ir\er alcohol dehydrogenase is an NAD ' -dependent oxidortducWe Lh-It oxidil.eS eth:mol and other aliphatic alcohol s to Ildehydes and ketones. In the presence of NA DII or

Oinne ,rnuble enzymes. called /JI/IQ-tt'lIJ

r~duclI/j~:r.

Aldehyde mo=tabolnts resulting from oxidative deamina tion of drugs a1.o;o undergo reduction 10 a minor eA lent. For example. in humans the ,8-adrenergie blocker propranolol is -d convcrt ... 10 an imermcdiate aldehyde by N-dealky llllion and oxidative deamination. Although the aldehyde is ox idized pri mari ly 10 ItIc: corresponding carboxylic add (naphlhoxylactic ac id). a small fraction al'iQ is redoced to the alcol1ol derivative (propranolol glycol).ZI\I Two major polar urinary metabol ites of the hiSlllmine HI antagonist chlorphenlramine have been i!knurled in dogs as the alcohol and carboxylic .dd products (conju,ated) de rived. rc:.~pect l\"ely. by reduction and oxidalion of an aldehyde nlCtaboiilC. The aldehyde pret'Ill'SOl" arises from bis-N de.me~lation Dnd oxidati.e deamilllltion of eh\orphctli .... mille. Biorcduction of ktt~s often leads to the creation of an asymmetric cemcr Dnd. thereby. two possible stc:lTOisomeric alcohols.llb. 2'11 For ~xam plc. reduction of ocelophcrlOne by a solublc rJbbit kidn-ey reduclll.'ie leads to the enantiomcric alcohols (S)(-) aud (H)( + }mclhylphen~arbinol. with the (5)(-) isomer pn:dominating (J: l ralio). The preferential formatiOfl of one S1ereOlsomo=rover the other is tcrmed protl uct SIU~ose/ljl"lty ill drug mctabolism.191 Mechanistically. ketone reduclion in\'olvCl I "hydride-- transfer ftolll the redUCl:d nicot.inamide moiely of the cofactor NADPH or NADH 10 lhecarbonyl carbon atom oftbe ketoot. lt is lenc:fally agreed Ihat Ihis step protttds with considerable: SltrtO~I~("III'I),. II&' 291 Con<ooequently. it is not SUrprising 10 find many rtportS of Jcnobiollc ketones that are reduced prtftr entially 10 a predomi llilnt 5te~i<;omer. Oflen. ketone reduc tion yields alcohol IIlctllbolites thut ~ phannacologicaJ ly active. Although many kel!)11C-ronlaining drugs undergo significam reduction. only a few selected examples are pn:Sl'ntcd in detail hen:. The ~enobiotics thai are not di!>Cussed in ttlc: tex t ha"c bl'en struclUrally labulated in Figure 4-1 O. The ~eto group undergoing reduction is <le$ignated WIth an arrow. KCIOrlC$ lac~lIlg asymmetnc centers in their molecules. such as acetophenone or lhe oral hypogl)"CC'ntlC lICetohc:~ amide. us.ual1y gile nse 10 predominantly one enanllomer on reducuon. In humans. IICCtohexamide is membo!t/.cd rapidly in the !tvtr to give priocipally (S"X - )-hydroxyhcunUdc.29J. 290 This metaboli te is as active a hypoglycemic agent as li S parent compound and is eliminated through tile:

'cH~?Hl
NH,

'r

,,~~~.;7"'7;.c,

'<;

1) boI-N
2)

CI
O"' pI '", 1II

0._

CI

S(

-I , "IOJ'! "'-
Caotwd (75'11.)

R( + )-!oIeIt "" .. .".

CabO .... 125%)

"

""" 0

'. . .""'9 CH,

bdne)5. m Acelohc~amide

CH,

CIH

"

~.-

Figur.4- I O Add'loooal el\am~es of M'f1Ob<o\lCS that unde<go e)<1e!lwe ~elooe reductlOll, nol covered in tilt It'Xl. Arrow Irn:l!(illes the keto group uncler9O'"9 reductIOn

recommcrKkd in ~ .... nts \I'im 1\"1'\:11 faitull'. because of the pouible IIOCUmIIIatJon of ils act;,'c metabolite. hydroxrheumide. Wbcn chir.!llctoncs are reduced. they yield twO possible ~ or epimeric alcohols. r'Qr example. the rRI( +)tnanliomer of the 0I'lI1 anticoagulant warl'arin unck.
not

usually is

JOE' ultnSi>'e rtdUCIiOfl of liS side ch.:ain keto group to genthe (R,$)( +) alcQhol Ill! rhe major plasma mctmbolite IIunI.ms. "" ~ Small amoonlS of the (R.R)( +) diastcreomil:

... abo are fOll"ed. In contrasl, lhoe (5)( - ) enanliomer IIIkfJOd link ketone reduction and is primarily 7- hydrox yIarcd (tt.. III'OItlIIlic hydroxy lation) in humans. Reduction of the 6-lcto functiooaJity in the narcotic n.:Iltrcxonc can lead to ei ther the epimeric 60- or W:"~droxy metabolillls. depending on lhe animol !plICX1 In humans and r,lbbit;;. biOl'l:ductioo of .um:xone is highly stc.eosctCdivt and !;CllC'rates ooly

-.on'S!

6,B-naJlrexol. whereas in chickens. reduction yields only OO-naltruol. B1- - ln monkeys and guilll'3 pip. howe'er. both epimeric akohol~ are formed (predominantly 6.8-nallrexon. JOO. JOI APfXlrenlly. in llie lallcr lWO specics. reduclion of na.ilR:lonc: 10 the cpimeric: 00- and 6.8-aIc:ohols i, carried OOt by tWO distinctly different reduclaSes found in the: livc:r. m ,,,,," Reduction of olisuru.n appears nOl tobc an important pathway by which the partnt dnlg mediates its immuOOSllpprt:5sive cffects. Sludies indicate that ox isuran has lIS greatest immunosuppn:ssive effects in lho/;e ~pccies that form alcohols as their major metabolic products (c.g.. human. ra. ).J(II~JO& In species in which reduction is a minor p3th ..'aY (e.~~. ox isurun shows liul e immunosuppressive activThese findings indicate thaI lhe oxisumn alc:ooob ity. (olisuranols) are pharmac:ok)gically ac1h'e and contribute substantially to the o"cmll immunosuppressive effect of the

~ C
H 2N /

D
~

N.

Reduoed ~ More!)o of NAOPH or NADH

$( -jMelhyl

a.i(Ued~

Pher Cat..d

Uc I"" of NADf> ' or HAD'

"0

NH "C, NHS

"-0-"

C- CH a

or,

ph<

roo
pro

R.
Th<
R( ..

Iw ..'....,

R$.( + )._
Map 00asI .......

_o.sl&_,.
NH
/CH 2

1/,1/.( + ) . _

<0,

'"

-<l

"".

ami

/v-

HO
~,

......

OH

OH

parent drog. 'J'he sulfoxide group in ox isurJn is chiral. by virtue of the lone pair of elt~IIl)1U 011 su ltur. 11Ierefore. reduction of Oliisuran leads 10 ditlSlerwmenc alcohols.

Reduction of a.,B-uns.alul':ued kelOfJeS r'l:sullS in redoctiOll not only of,he ketone group but of the camon-carbon dou ble bond as l'I.ell. Steroidal drugs often fall into Ihis class. Bj. including n<nlhindrooc:. II synthetic prosestin found ID NAD many orol contraceptive drug combinations. In women, the prese major plasma and urinary mel8bolile of II()f"ethllldJ'l)ne is the redoe 3,8.5.8-Ic:tlllhydro (\eri\'ative.)OJ hie f( Ketones resulting from metabolic oxidative dtamm811011 pn:se procc.sSClIUl: also susceptible 10 reduction. For inslaoce. rab-cspoc bit liver micl'OSQlI\lIl preparations metabol ize amphetamine in 1M 1 p\M:nylacelone. which is reduced subsequentl y to l~ Va 0 lion I< 7-nill'
H
~

H,

, , ,

HO

10

... ..."".

",m.

am:

AIr,.....
OH
' .... H H

OH
' ...... H

crc"{-~) -"=~~~;;~ crC'f"CHI , ,

NHCH,
t - "E~ ....

0
1-11,o ... ,..I~
po~--

p/IerI) 12~, - In humans. a minor urinary metaboli te of (.)-<plltdrlne has been identified as the dlOI dem-~tive fOlUwd from UIO reduetion of the oxiliali"ely deam'Rllled product l -h)Uro.y- l -phenylpropan2-one .~

For some nitro XCnOOIOlM:S. bioreducuon appeaR to be

a minor metabolic pilthv;ay on ~ i vo. because

or OOinpcllnG

a,'

dl'n ,,1II1tro.nd Azo CampoulMl.

The reductlQll of aromatic nitro and v.o xcnobiotic-5 leads 10 aromatic primvy amine membolitc$.- Aromatic nitro ltl: redUl.-ed initially 1 the nitrow 300 hydrox yl0 Intenncdiatcs. IS shown in the following mctobolic

Ar-N_O _
I ,

Ar-NHOH _

Ar-NH,

,"",,,,.,.,,
Ar-NH-NH-At -

Am n:duct>on. however. is believed to proceed via I hy (NH NH) \ha1 5ubsequcntly is cleaved reduclIvely to yield the OOitesponding art)I1UItic amitre$:

oxidative and conjuG:UJ\e reactions. Under lU'Iifoc:ial anaerobic in vitro incubatton cond ll ion~. nov; e'C!". these same nItro xenobiotics an: enlymallcally reduced rapidly . Forexample. most of the uri nary membolitcs of rnetfOllid.a1.ole found in humans are either ox idation or conj ugation prodUCts. Re duced metabol ite.~ of metronidazole hove not been de tccted. l l~ When inculxtted unacrobically with guinea p'a; liver preparations. nov;ever, metroni d:uule undergoes considerable nitro reduction .J : BllCtrnnl reduCIlISC' pn"scnt in the intestine also tends to complicate In \"ivo interpR:tutioo~ of nitro reduction. For example. in ...i1S, the antlbiot,c chloramphenicol iJ not 1'1:' duted in ~i\'o by the liver but is excreted in the bIle and, subsequently. reduced by i"te~I,":lI1lora 10 form the IImlllO metabolite/: 1. 1Zl

Ar-N-N - Ar' _

ON~~CH' , I
CH. CH, Ot1
....... """"" oil

.... , . II

nilro

,
be Te!iJlOllsi. I reduclases can reduce nitro and azo compounds. jXIOt Iy or excreted mainly

muscle relaxant in humans.ln . J '

The enzymatic reduct iun of UIO compounds i~ be~1 e~em' plilied by the conversion of sulfamidochl)"soidine (Pron tosil) to the: acli'"e sulfanilamide metabolitc in the hvcr.Jll This reaction has historical signiliclloce. for il led to the disco ,'cry of w lfnmlanllde as an ant,biotic and e\cnluall)' to the development of IIUIny of the therapeutic sulfonamIde drugs. 8llCtcrilii reducUlSC!t presenl in the intestine play II significant role in reducint; 111.0 xei1Obi<Mics, p;u1icu larly those that are IIbsofbed ~y.l'J.J'4 Accordingly, the Iwo azo dyes taMrnzllle't.<' and umaranth l 2l> ho'c poor oml absorpt ion becauo,c of the m3n), polar aoo ioni zed ~u lfome neid groups pre~nt in th.e,r structures , 11>erefore, these two 8l-O compounds lire 11'IClabo1i1.cd primarily by bnctcriul re ductases present in the i nttstil"l!:. The import3nt."e of il11e~tinnl reduction is further revealed in the metabolism of suJrnsalaLine (formerly !hll icylal.~ulropyridille. Azullidille), a drug used in the trealmcnt of u!cerati\c colitis. The drug h. ab-

N-)
O,N ............. ,~N
R

H N

CIonaz8pem,

r.tr'>epem .

R _ C! R_H

O,N

o
Oa,~ct.

o CH_N_Nr-( NH

ro

'"

NH,

NH,
NH,
'2.~Tr~

N= N
Sullao 0odOCflo)'$Oidine

,-

HO

SO,- Na+

N=N

SO,- Na'

,.

-O NHS0 -Q-N=N
2

COOH

COOH
OH

-or in vivo and then aucmpting to detect the formation of the tertiary amine . Foruample, imipramine N-oxide undergoes reduction in rIIt liver preparJtiDrul.JJO Reduction of 5ulfur-containing functional grotIp$. weh IS the disulfide and sulfoxide moieties. also constitutes a minor reductive paihway. Reductive clcava~ ofthc disulfide bond in disulfinm ( Antabusc) yields N.N-diethyldithiocarbanuc acid (fm: or glucuronidaled) lIS a major metabolite in hu mans.llI . Jll Although sulfoxide fUllClionalities arc oxidizaJ mainly 10 su lfones (-S0 2"). they SOl'floetimc:s undergo reduc:. tion to sulfides. 1l1e importance of Ihis reductive pathway is SCC"n in the metabolism of the anti-inflammatory agent sulindac (Oinoril). Studies in hullWlll show thai sulioo.: undergoes reduction to an aclive sullide thai is responsible for the overall anti in flammatory effecl of the pamII dnJg. m . n . Sulindac or its sulfone: metabolite uhibiu lillie Intiinflammatory :ll;tivity. Anotnc:r example of sulfide for-

.,

HI

To

SOI'bed poorly and undergoes reducti~e cleavage of the uo linkar.; 10 yield &ulfapyridine and 5-am inosal icylic acid.J21. II The reaction occur'! primarily in the colon and is carried oot principally by intestinal bacteria. Studies in JefTI1free rats, \aeking inte5linal flOfll, ha ve demonstrated that

.. ..

'" .,;

r~

sulfasalazine is not reduced 10 lilly appreciable utenl .n~

Mhc;........ ';$ Red.,U ....

Several minor redLICti ve reacti()f\$ a1$O occur. Reduction of N~ltide5 to the Wi.espon<ting teniary amine occurs 10 some eltent. This reductive Jl'Ilhway is of interest because several leniary amines are oxidi7.ed 10 form polar and water-S(llub!.e N-o~ide metabolites. lfredllCtion of N-oxide metabolites occurs to a signifICant extent. drug elimination of the patent tertiary amine is impeded. N-OIlKk reduction ortcn is IIS5eSsed by administering the pure synthetic N-oxide in vitro

..

"" ...,

'. "" '"

<u

""

roy

Chapter 4 /oft/aboUc Chonges of Drugs '''Ill Relmeo Orgonic Compounds

f 09

F'V'" _
CH,
H

CH,

invol\"es the reduction of DMSO to dimethyl su lfi dc. In humans.. DMSO is metaboli 7.ed to a rnillOf cxten t by this pMhway. Tho: chaructcristic unpleasa nt odor of dimethy l sul fide is e,,dent 011 the breath of patients who usc this agent. J"
mattOn

~ CH,-S-

CHJ __ CH 3 SCH J

"""'" """""'
HYDROLYTIC REACTIONS

,CH,

""""" ....

,CH,

hydrolysis of cocaine to methy l ~gonine. Ilowe\er. also ocCUTli in plasma and. to a millOf C:<lent, blood ..I<U.l41 Meth ylphenidnte (Rilalin) is biotran sforrrted rapidly by lIydrolysis to yield ri talinie add as the major urinary metabolite in humans ..l42 Often. ester hydrolysis of the paten! drug Icads to phannac(llogically active me tabolites. For exa mple. hydrol ysis of diphenoxylatc in humans leads to diphc:noxylic acid (di fenoxin ), which is. apparently. 5 times more pote nt an 3JJtidiarrheal agen! than the parent ester..l4l The rapi d mctabolism of clofibrate (A tromid-S) yiclds p-chloropheooxyiso-butyric acid (CrIB) as the major plasma metabolite in lIumans.- Studies in nllS indicatc thai the free add CPIB is responsible for clofibrate's hypolipidemic effect..l4'

'''._Jsis of Estel sand Amldes

The mwbolism of ester and amide linkages in many drugs
is cm.lyzal by hydrolytic enzymes present in various ti ssues and in plasma. The Il'II:Ulboli c product.~ forrrted (carboxylic I:id!;. alcohols. phenols. and amillCS) genernlly are polar and runctionally more sU!ioCcptible to CQIljugation and excretion llwl tbc parrnt ester or amide drugs. The enzymes carrying out ester hydrolysis include cvernl nonspecific estera.o;es foulld in the lil'er, kidney. and inteStine as well as the pseudo~OOIII1CSICT1lSe:s ~m in pl a.~ma.J)6.. JJ1 Amide hydrolysis ~aI1lO be mediated by li ver mi crosomal ami dases. ester..~ and deacylases. Jl1 Hydrolysis is a major biotrnnsfonnation pathway for drugs cootaining an ester functiona lity. This is because of tile Trlative ease of hydrolyzing the ester linkage. A classie e~;unpJe of ester hydrolysis is the metaboli c conversion of iiplrin (acetylsalicylic acid) to sali cyli c acid .J }8 Of the two el!CeT lIK1ieties present in cocaine. it appears that. in general. tile IlII'lhyl group is hydro lyzed preferentially to yield benW)'ltcgoninc lIS the major human urinary mel8bolite. l l'l The

COOH II O-C-CH3

COOH OH

?i
+HO-C- CH 3

(A<:e!~saIocyk

"""'

acxI)

'f the
~

' h ti

ninor

bo,d

amic I hu lized
~lIC

Iway Igen t

s ible
~m

"""

Many paren! drugs have been chemicall y modified or derivali1.ed to generate so-called prodrugs to overcome some undesirnb le propeny (e.g .. bitter tastc. poor absorption. poor so lub ility. irritation at ~ite of injection). The rationale bt;h ind the prodrugcoTICept was to develop an agent that ,once inside the biological sy5le m, would be bimransformcd to the active parent drug. li llie presence of csterase,~ in many tiS5llC$ IlI1d plasma makes ester deri vatives logical prodrug candidates lxxause hydrolysis would cause the ester prodrug to !'even to the: parent compou nd. Accordingly. antibiOlics such as chlornmphcn iool and clindam ydn have been derivmi1.ed as their palmitate esteTli to minimize lheir bitter ta'te and to improve their p;i13tubility in pediatric liquid suspcnsjons.~ ).01 After oral administration. intestinal eS\crases

liule : for-

o -o_cH,
'c
H

~ C-OH
H
O

'c-o+
~

cH, ~;:::
'\.I

C-OCH3 H

II

OH
H

o
II

CDOH

-NH-CH

H-l-a I
HO

CH,

CooIMlo- , Inda' t*

and liposes hydrolyu the palmitate esteBlO the freeanlibiCM ics. To improve the poor oral ab6ofplion of carbl::nkillin, II lipoplulic indanyl e5teT has been formulated (Geoclllin) .:lU OllCe ontlly abwrbed. the ester i~ hydrolyzed I1Ipidly to the parent drug . A final example involves derivatization of prednisolone to its C-21 hemisuccilUllC sodium salt. This watersoluble derivative isulremcly u~rul for parenteral administmlion and il mc:l3boIited to the parenl steroid drug by

plasm. and tissue

estenl!ieS.)09

Amides an: hydrolyzed slowly in comparison to eslen. JJJ Coosequcnlly. hydrolyis of the amide bond of procainamide is relatively slow oon:i:~d wi lh hydrolysi s of the eSter linkage in procaine.no.. J Drug$ in which amide cleavage has ~n reponed 10 occur. 10 sonle utent. include hdocainc ..I.'I1 C~IIC,v indomcthacin,u l :m and pmos;n (Mini PfUS),m. Amide li !lbgd! prHCnl in barbitunlte5 (e.g .. hcJIobarbilal)m.JH as lO.'cll as in hydanloins {e.g .. S-phenrJhydanloin )J~ J" and uccinimidc.s (phcnsuJ(imide):H' ~ a", also susceptible to hydrolysis.
MI~II.n us

Hydn.,tk R cHolis

Hydrolym of n:oombinant hurtUIIl peptide drugs and hormoocs al the N- or C-I~inal amino acids by carboxy- and

- -----------, -

1Jdoc_

CH,O

-I C-O

CH3

NH,

a
>hw",""ethion

daH~

I Iiij .0"Q!tJIIaI

Pt_ _

CH,

,0
ndti

I .cll-rttv&nizal hydrolytic ~tion.~ "1 Examples of pepucks ~ proIe;n iIorrnone!I undergoing hydrolysis include h.on.m Insulin. grov.th hormone (C H), pro lactin. paral~mid "'0...1( 1I'TH1. and llna] natriuretic (OCior (AIIo'F),J

.-n.upeJlidases arid

~eases

in blood lind OIlle r ti~sues is

laching sma ll . polar. and ionb.uble endogenous moleculd, such lIS glocuronic acid, sulfate. glycine:. and glutamine. to the phase I metabolite or paR:nt ~cnobiOlic. n.e resulting conjugated prodocl5 are re latively watl.'r <;oIuble and l'I.'adil)

In ilddll10n to hydrolysis of arnidcs and eSlers. hydrolytic [auat' of QIher moiet~ occurs to I nllnor cuenl in drug
~srtt,' IIleluding the hydrolysis of phol-phatc eMer:s

diphosphate). sulronylu~as. cllfdiac ri>t'O!Iides. cubamale eslers. and organophosphate COIl1 -

Itl~ dielhyl~lIlbestrol pOIll~,I\. G I ~\lronide

alld ~u l fate conj ugates also can OIIdc'IV h)droI)'IIC clca...ge by ,8-glucuronidase and sui. 1 iW.e tnly~$. The'iC hydro lytic reactions arc discussed in .. rolJo,'inl ~ion. Finally, the hydration or h)drolyllc cItI,-agt of tpOxides and a/'e1lC oxides by cpoxide hydrase
1\ alI'I\KIcmI

a hydrolytic n:aclion.

PHASE II OR CONJUGATION REACTlONS

I'!aIc-I or rllllCtiOl1a.Ii;lltion reactioros dQ not al way~ producc lI)~i lic or ~o1ogicaJ l y iroaclive mct.abolilcs. Var_ pII.ut 11 orronJugmiou reacl10n5. hoowe~er. can convcrt b metaboIilcs 1 100I'I.' polar lind walttsoIuble producIS. 0 Iobay COIIJUBauve fnlYIJIC5 IICCOIllpl.ish Ihis objccth'c by al

C,'Keretllbll.'. In addition. lhey gcnerally 111'1.' biologically in active alld rlO41I0~ic. Other phase.' Jl l'I.'actions. 'iUCh as metb ylation and :lCCt) buon. do 1101 gl.'llCl1lJly IlICl'I.'a:sc woter solubility but mainly 'iCrve 10 lennin:l1c or attenuale phannacological acti~ily _ The roll.' 0( GSH i\ 10 combine ..... lIh chemically reacli~e compounds 10 pn:~enl dllmage to important biom.aCf'omolecules.!iUCh as DNA. RNA. and protciros. Thus. phase 11 R:aclions can be regarded a, truly detox ifying paillwoys in drog mctabollsm.... ith a few cliccp!ioos. A distinguishing fCIIlurc of most phase II reactions IS Ihat the ~'QI1juga li ng group (g ll.lCurunic acid . .\u lfaIC. n~thyl. and acctyl) i~ activated iroitial1y in lhe form ora cocnlyme bdOfe tron,fer or allachmcnl Oflhc group 10 lhe acccpling su~trule by the appropriate tr.msfcra.sc en/role. In OIlier cases. such as glycinc: and gl ulalllloo COfljugation. tile substmll.' j~ activated initmlly. Many I.'ndogenous oompounds. such lIS biliru bin. Meroid!;. ClItcchoiamincs. and histamine. aboO undergo ooujugulion reaclions and use the SIIllIe r.'fX'nl.)'lllI.'s. allhough they appcar to be mediated by I0OI'\" <;fIC('iroc U'JrosfCtllsc en zylTlCS. 1l\c phase II conjuga tive p'uhwuys dio;cus.<Oed include tbose: listed above iro Ihis chap:er. Although (Miler conjuga tj~c path .... ays e~isl (e.g .. oonjugalloo ... nh gl)cosidt:..~. phO'\

phatc. and other amino acids and conversion of cyanide 1 0 thlocyanate). they are of minor impor1lllK:e in drug metabolism and are 001 covered in this chopeer.

TABLE 4-3 T)'pe$ of Compounds. Fotmlng Oxygen. Nitrogen, Sulfur, ~nd Carbon GlucurorUdH4

Glucu,...lc Add CanJuption

Glucuronidmion is the: mosl common conjugative pathway in orug melllbolism for several reasons: (aJ a readily available supply of I>'glucuronic acid (derhed from p.gluoose), (bJ numerous functional groups lhat can oombineenzymotieally with glucuronic acid. and (c) the elucuronyl moiely (wilh its ioniud carboxylate IpK~ 3.21 and polar hydrox yl groups). which. when attached 10 xeoobiotic substrlltes. greatly increases the: ...-aler solubility 0( the conjugated product. m . ""-..1111 Formation of ,B-glucuronidc:s involves 11"0 Meps: synthesis of an activated coen/.yme. uridine-5'-diphospho-..... p. glucuronic acid (UOPGA). and subsequen t trander of the 0 glucuronyl group from UOI'GA 1 an appropIialC substrPlC . 11 7. )6Q..JI>I Tho: lrolllsfer step is cataly.tc:d by microsomal enzylfJCscallcd UDP-glucuronyllfilfUjtfllSu.Tho:y are found primarily in the liver but al"" OI.'C ur in many other lissue.~. including kidney. inleslioo. skin. lung. and brain. )6Q..JI>'Tho: sequence of events invoh'ed in ~Iucuronid:llion is summariud in Figure 4_IL II1 )M). li, Tho: synthesis of the coenzyme UDPGA uses ..... p.glucosc:- l -p/loIiphate as its initial precursor. NOie thai all glucuronide conj ugates have the fJ configu.ratioo or fJ ]inhge al C - I (hc:IlC"t. the: term ,B81IKuroni/us). In contrasl. the coenzyme UOPGA has an (Z linkage. In the enzymatic transfer step. it appur!i Wt nucleophitic displacement of the ..... linked UOI' moiely from UOPGA by the substrale RXU pooceeds with complele in vernon of configuration at C- I 10 eive the ,8-g1ucuronide. 0 Glucuronidation of one: functional group usually suffices 1 effect ucretion orthe: conjugated mcuaboli1e: diglucuronide conjugulCs do not usua lly OI.'Cur. The diversity of funClional groups undergoing glocuronidation is illUSlrnt~d in Table 4-3 alld Figure 4- 12. M~tabolic products are c l a~sified as oxygen- , nilrogen- . su lfur- . 0( carbon - glocuronide. acoordin& 10 the hcleroatom altached 10 the C-I alom of the: Slocuronyl group. Two imponant fullC1ionalilies.the hydro~y and carboxy. form O-glucuron-

111d"'111

""'not,: mIlfpIu.., .:o.I. . ....",a" II, p-hydm. )1"IIIcfo)'lOi~

Akoh<1II; Iritholomtthlnol. ctdonmp/"ImIroI . proptIIIOIol Eools: "'/ty1.Iro>:)'OOi!nwi"

fUnI_.....
"w,,, . . .

OIcf. . c: ........ 1 '1 '

111

NHydru.y .... hydrolY" ...o'c HII)'drmy.... ~ Nh,dI ... y-2-.<e1y ...... IItIf1I101."'e
c..tMIxyl C II uDdi Aryt 'ddo; """""'" 1Icid, sabcylic..;d AryLlllk,l.ndJ; """""....

r"....." ...

NItrocn (:...... , tl"

Ary ...... -.; 1.. , ..... S-,,;~ ... ,....... Alkyt, . 1" ...",,;..

AmIda, ... F....,. He s.tkJMrnidl/ll: ... tfi_ .....

TtftiOf)' omI~ c"ypmI>ep'Hli", tnpeleoMam.-

1<''''

Sutf\lr Gl..au-onIdnl
Sut",yWyI lmuPS: methlmarole. propyllhloo,",,,, dle!h)tIhM......t..mk: .cld

Cto ...... G.....

.,.

3..5-I'jTarolid,-oon.: FL 'I)l,""u' " ,. Ifi~

e "", _

E , aod

_of~ 1

., .

'

.. _.,... .. Il ~

ides. Phenolic and alcoholic hydroJ.yls are the most rom mon functional groups undergoing glucuronidation in dflII metabolism. As we have sc:c:n. phenolic alld Ilkoholic hydro~yl groups are ~sent in many parenl compounds and arise throulh ~ruious phase I metabolic pathways. Morphilll: ..k>l)6 al:c:tam ioopl1en.- and p... hydroxyphenytoin (Ihe major me ual)olile of phc:nYloin)oW . .90 arc: 8 few exampl or phenolic oompoollds that undergo considerable glocuronitbtion. Alcoholic hydroJ. yls. such .as those: prc:K1Il in trichloroethanol (major metabolite of chl0l1l1 hydrate).ZII chlonmphcnicol:!&3 and ,*opoanolol.'-' )101 are alsu com-

"..&(' .." . , . ...

......."

-> ...

Uridn&-~'~-

1>91 I e

IUOf'GI

, w.o '

........
XR
p..QlucutOllldB (JI .r.IQogB at C-,)

HO

-UDP
Figure 4- 11 Forma\lOll of UOPGA and ,8-gIucuromde (onj!.lga t~

U"dne~'~' ~ ACid (l..IOI"Go\)

("~,,C-'I

.t.c.Ioi """'''"'

T.cnIorOWl1 ....

-/<'li'j4:IUr2~

CH, CH

.,-

'CCOH

,~.

n drua

:ohohc

.,u'

a.n.o.:. toO. 1'1 _ H

S

t , ,.cIlCdR_OH

,.

' "

zn

1"""'"

hwaY5.

meny!

a few ierable

O,Ny'y,

p"'''' ale).com011",,""'"

I)

.. I' "N!'!IJe

T,.,."

".. . .'iOldI

0", .,.

Flgure4-12 StnIC1ure of compounds thaI undefqo glucufOfl,dal1Oll Arrows ,rldt<olleSitesof ,8-glucufOnlilt dttadln'l@nt.

UOPGA

R-C=C-OH

I I

R"

o
R-C-N-OH
N~ i)doOJ<)Iai''-

...

II

uron their

"

-,
I

often

matJ to!tic

monly glucull)nidaled. Less frequent is glucurooidation of other hldro)l:yl groups. such as enols..wI N-hydll)xyl-

amines.

and N.hydrolyJamides? 1 For e~amples. refer \0 the list of , lucuronide5 in Table 4-3. The carbo"y group is also subject to conjugation with glucuronic acid. For example. ary lal~lic acids, weh as the
:16

bon alom is relatively no\"(':! in drug metaboli sm. Stooies in humans ha\'e shown that conjugation 0{ phenylbutazone (Butazolidi n)JtI. Jll and iul finpyrazone (AnIUr.lne)JlJ yield the lXlI'TCSpOOding C-glucuronide metabolites:

allnb

binw to gll

anti-inflammatory agents naproltcn

and renopmfen,l 1O.J11

are

ex~1Cd

primarily as their Q-glucuronidc dcri"ali~es in

Illimans. Carboxylic add melllooliles such as those ari~ing from ch]otphc:niramine~ and propranoIoI 2lI9 (see " Red uc5alicylk: acid m . J 4) also undergo conjugation with glucuronic acid, btll conjugation with glycine appears to be: II more importllnt pathway for these compounds. Occasionally, N-glocuronides are formed with aromatic amir.es, aliphatic amitIeS. amide!. and sulfonamide!;. Repre_ scmative examples are fourKI in the list of glucuronide! in Table 4-3. Glucurooidation of aromatic and alipOalic amincs is generally a minor pa!bway in comparison with N-acety lalion or o~idali ve ptoc-sses (e.g ., o~idative deamination). Tertiary amines. such as the: antihistami nic agents cyproheptadine (~riaclint1J and lripelennamine,m. form interesling quatemary ammonium glucuronide metabolites. Because the: !bioi group (S H) does not commonly occur in ~enobil)(ics. S-glucumnidc: products have bcc:n reponed for only a few Urugl. For iru;UII1Ce. the: thiol groups pre.<iCnt in methimazole (Tapawle),m propylthiooraciI.J' .. )JJ and N.N-die!byldithiocarbllmic ocid (major reduced metabolite: of disulfiram. Antabusc)* undcrgoconjugalion with glucuronic acid. lM (ormation 0{ glucuronides auached directly 10 a car-

--"' 0
H

"""' "'If

accum

Conju wrth

tion of Aldehyde and KctollC Carbonyls: ' above) fonn 0glucuronide conju1.lItcs. Aryl acids (e.g., benzoic acid.m

ami~

glucun

C.(;11ICUIOOi<k MeuboIiIr I'htn>"Jbutuone, II. - CUZ<;HZ<;1I 2 ClIJ Sulf'"PYfUO"l', II. O llO llSC..II,

limilcc

pool"

ti~,

ro~rllt

Besides ~enobiotics. a number of endogcnoos sub>.\rate:s. IlOUIbly bilirubin)&< and sleroids.-'" an: eliminated as glucuronide: conjugates. which arc: excreted primarily in the: urine:. As the: relative moIeculaT mass ofihc:conjugale CJlceeds 300 eW'nlS 08, however. bi liary c~cretion may become an important 13. Sui route: of elimination.*' Glucurooides tnat are CJlCKICd in inaclJVI the: bile are susce pt ible to hydrolysis by ,B-gtueuronidasc cooJIIII enzymes ~nl in the intestine. lM hydrolyw:l product chemic may be reub!;()rlJed in the intestinc, thus leading 10 entero/lepalic rccycling. n ,B-Glucuronidascs are also present in many sulfa~ oCher tissues. including the liver, the endocriroc sySlcm, and lies are the reproductive organs. Although the function of these hy the anti drolytic enzymes in drug mc:tabotism is unclear. il appean that. in tentlS of hormonal alld endocriroc regulalion. ,B-gtuc ~ n.

..... """"
'

of inor Y -p/Io "",,pi

""',

"""",u

o
o
-O-S-o -

-O-S - O-P-O

II

II

""

..

"'"'

II

I OH

"".... , .-

' .... "*'I

.......

.......
<' ~

- O-S-O-P-O

~ ~

~ ~

figure 4- 13 Form.JbOn of PAPS and

fatl! COrljl,lgall!S .

1Ift""d..... may libera!( active I'lormones (e.g .. Slcl"Qidsj from dIeir m.ctiYf: glllCurooidc coojll~s.12 In lItOnale5 and children. glucuronidating processes are IIfIca aDllb-doped fully. In such subjects. drugs and endogCftI1II!i IXlIllpounds (e.g .. bilirubin) lhul are rnc\ubolil.c:d nor1IIllI} b) J!lICIIrooidalton may aocumulau: and ClIUSC serious kI\lCitY. For uampk. neonatal hyperbilirubinemia may be oIII!iI:lwbIe 10 the i _ l i tof newborns 10 conjugate bi.irubill "1111 gLPC\II'OI1ic acid. Similarly, the inability of infants 10 JIuoIronKbIe chlor.lmphenicol has been suggeslcd \0 be rnpoD'ilbic for the gra)' baby syndrome, whkh resulu from ..~ of toxic levels of the f~ antibiocic.-

Nol)~~ and tcrbtilaline (Brethine. Bricanyl)96 aJ!IQ undergo

, OTLc..j"JzUIII
CooJupuoo of xcnobiotic5 wilh sulfate occurs primarily VlIIII phmob and, QCCasionally. wilh alCQbols, aromatic ~~ anrJ Nhydrox)' rompounds.:JI9-J91 In cont~ to ,lucu""1IC acid. !he amount of available sulfate is mIner Jonutai The body usa II signirlCant portion of Inc sulfate pool 10 ~JUBale numerous CndogCIlOIlS compourxls such M "r:roid~ heparin. chondroitin. catholamines. and thynlllllC The ~lf3lc conjugation process involves activation oIll1a'p11ic sulfate to the coenzyme 3'-phosphoadcnosinerpi""'flhosulrate (PAPS). Subsequent transfer of the sulfate lft'Up from PAPS !O !he lCttp(ing substrate is catal YI.ed by ,acicld !.O!uble $Ulfocnmsferases prescnl in the livcr and IXM 1iWJC$ (~g., kk1ney, intestine).J<n 1'he scqutnce of t\et!b lII\oIvtd in sulfoconjugation is depicted in Figure 41.1 Sulf:ue oonjuglltion gcnmdly leads 10 water-soluble and 1IkI1'-e mcuboIlle$. It llJlPCarlI. howevcr. that thc O-sulfmc roIIJU-8att, 0( some N-hydro.y COfIIPOOnds give rise 10 dimtinlly rrllClive mtcrmediates that D.It to.ic. U, Pbeools compose the main group of sobsinllcs undergoin, wlf;ase oonjugauon. Thu~, drugs rontaining phenolic moiclin :an: oftcn susctplibk to sulfate formalion. For uamplc. me Mltlhypcnensh'c agent a-mcthyldopa (Aldomclj is me tIbnIilrd eltclI$iveiy 10 iill 3-0-solfate C$tcr in humans.JIIl. ... The ,8-adl"ellCrgic bronchodilator.; SIIlbuUimol (albUl-

su lfate ronjugauon ali their principal route of metabolism in humans. For many phenols, however, solfocoojug3tioo may rc~nl only a minor palh ...ay. Glucuromoolion of phenols is frequently a competing fuction and may predomin;ne as lhe ronjugalh'e routC for some phenolic drugs. In adults, the major urinary metabolite of the analgesic acetaminophen is lhe O-glucuronideconJugate. With the CQfIC()ITIitant O-solfate conjugate being fooned in small amounts ..I64 lntercstingly, infants and young children (ages J to 9 years) uhibit a differ ent urinary excretion ~uem: the 0'5ulfOlC conjugate b !he main urinary product. . -1'he explanation fOf" this 1l:\'CTSaI stems from the fact thai neonales and young children have 11 deueased gJucuronidatm& C3pKi ty because. of undeveloped glucuronyltransfclllSes or low levels of these. eru.ymcs. SulfOIe conjugation, ho ....c\..... i$ ...ell developecJ and bccomes the main route of acet:tntinop/1o:n conjugation in this pediat ric group.

o
NHCCH 3

II

?i NHCCH,
+
OCeH.Os
Q-Ghoc:o"oo"liOe

NHCCH,

o n

"".
~

~.

inc:.

,. ""

JOO

OH A(:e'.t.qJI.'

""-"

Other functionhlitics. suc h as alcohols (C.II . aliphatic C I 10 C, alcohols. diethylcne. glyool.)-.aoo and aromatic amines (e.g., anilil"lC , 2-naphthylamine.),..,I . .jOO can also form sulfate conjugates. lltese reactions, ho"'c,'er, ha\e only minor im portal"lCc in drug metabolism. The sulfale conjugation of Nhydroxylamines and N-hydroxylamides takcs place as well. occlI.\ionally. OSulfate ester oonjugates of N-hydroxy com pounds are of ronsidcruble toxicologlCllI concern becaU5C lhey can lead to reactive intenncdiales lhat are responsible

S.......",ol

\ HO
OH

NHCCH 3

fOl" cellular toxicity. The carcinogenic agent5 N-nlCthyl-4amiflCOUobenzene and 2-acelylaminonoorene are believed 10 medi:ue their toxicity through NhydroxylaliOl1l0 the COf

OCHaCH,
C).SuIIat8~.

01

NHyOI~

associated with phenlk:etin. Other pathways (e.g .. Drcne ox ides) leading to reactive dcctrophilic Intermediates ate also possible,'

responding tV-hydroxy compoumls (see earlier seclion 00 Nhydroxylation of aminet and amides). Sulfoconjugation of the N-hydroxy metabolites yields O-sulfate esters. which presumably arc the ullimlllc carcinogenic species. ~~ of sol' from the fon:going sulfate conjugates generates eketrophilic nitrenium species, which may rex'! with nucleo.. philic groups (c.& NH 2 O ' i, SH) present in proctins, DNA. and RNA 1 form covalem linkages that lead IOSlruclUrol and 0 functional al~nlion of these crucial bjomacromolccules..ooJ The consequences of this are cellular toxicit)' (tissue necrosis) or alteration of the genetic code, c:venUlally leading 10 cancet". Some evidence sUppoili ng lhe role of sulrate: conjulltion In the metabolic activation of N-hydrox)' compound!; to ~ive intennediatts oomes from the observation Illat the tkgltt orhcpatOl o~ ic ity Bnd Ilcpatocarcinogenicity of N~ hydmxy-2-acctyl -aminofluorenc depends mark~ on the level of !>UlfOlransferase actiylIy in the liYer.The discontinued analgesic pm,n1lCetin is mc:taboli7.ed to N-hydmlyphenacetin and sub!;cql.lemly conjugated with su lfm.- 1be O-sulfate conjugale of N-hydro~yphe~tin binds coYalently to microwmal proteins.- This pathway may represem one route leading to reactive intermediates that aK responsible for the hep3toto~icity and nephrotoxicity

( ...,...u WItII G~d.e, GIN'

d OU211r AMino Adds

21. .,

The amino acids glycine and ,Iutwninc are used by nlllmma lian sy5lcms to conJugaIC carboxylic adds. pamcularly ar0matic acids and arylalkyl acids .-OO'IGlycine conjugation " common to most mammals. whereas glutamine conjugation appears to beconfined mainly to humans and othc:rprimau:s. The quant;ty of amino acid conjugates fonned from lenobo CIties is minute bcclluse of the limited ayailability of amillO acids in the body and competition with glucurooidatioo (Of carbolylic acid SUbsll'ales. In contrast with glucuronic .:ill and sulfate, glycine and gluuamine are not convened to acb vated coen;(.ymes. InStead, the carboxylic acid substr.uc II activated with adenosine uiphosphate (A11') and coenz)'11E A (CoA) 10 form an acyl-CoA complex. The latta' ;nIC'1l1Uiate. in tum . lICyla.es glycine or glutamine under the influeru o f specirIC glycine or gluwninc N-acyhl1lllSferoisc enzyme!. The actiya.ion and acylalioo SICps .ake place in the IlULOchondria of liver and kidney cells. The sequence or mtIIboIk events a<sociated with glycine and glutamine conjup-

H N ...... \ , H

I C- R

COOH

I"'" of phra)"1att1lC acid is sumrnariud in Figure 4-\4. AntIIIO acid oonJUP,ICS. be:ing polar aoo water solu ble, afe n.:rtll:d mainly n:nally IIIKIlQITlCtirnes in the bile.

CSH _ Me, upturlc: Add Conj ....tes

GSH conjugation is an imponam p.1lh"';1), for detoxifying
cllemically relK'tivc eleelrophilic ~'QInpound . ~ll""2JI II is I10W genen,lIy ilCCtptcd that reactive c lec1ruphilic ~pic\

~OH

R_H SaIo:yU;c: ACId, R - OH

~ACId

manifest their toxicit), (e.g . lio;suc 1lI.'\.l\Jloi~. carcioogC'nicity. mutagenidty. ler:llogenicity) by combining covalently wilh nucleophilic gl'Ollps present in vllal tl'lluIar proIc,ns and nutIcK: acids." 019 Many serious drug toxiCi ties may be uplained also in tCTTl1.S of covalent inlenll"tion of nlClabolically

IIr.lIlda!, R _ H

''/CIal.R-OH

An:l!NIic acids and arylulkyl acids are the major sub~ undergoing glyclllc conjugation. TIle t"OOversioo of bait'*: ICid to in glydnc conjugate. hippuric ac id. is a welt~lIlIINboIic ~action in mallY mammalian 5Y5tcm5. 410 1le e~~ve mctabolJsm of salkylic acid (1S'l> of dose) 10 'olI:cJ;turit acid in humans is alKlltler iIIustrat1\'e e:urn!*''' I. IlCatboxylic acid metaboliteS resulting from oxilia~ Of b)"droI~s of many drugs are also SU'iCCpti b1c 10 gly.1IIe0000JUgllllon. For example, the H ,-hi st:lrninc antagonist boOtllr.'w:nlf1lffilllC i~ oxidi/.cU to a propio nic acid mctabolite: dill is roIljugated IIIlIh glycine in both human and dog. "I ~I IIIIWlY.l'"flllOlophcn)"lacctic ocid. derived front the me. . . .IJI 01 the anti~ychotic agent halopcndol (Huldol ). is tv.:! I!i!be glycine conjugate III the urine of rats," PIlen~lCidand isoniootinic acid. resulting from the hydro! of. n'SpI1I'dy. the lfIIicoovulsant phenacemide (PIle41 ZZiMlt"" and the antitube:n:uI05;S agent isonia:tid. ) also f t .-onJllPlN l1o;th glycine to i\QI1""Ie extent, Qlutlmlnc conjugalion occurs mainly with Ilrylacetic IOJI, iJl(:luiling endogenous phcnylaceticl~ and 3-i ndol ~la .:tiM: ICId.m A few glutamine conjugatcs of drug metaho~ line Iwn n:ported. For example. in humans. !he 3.4dlII)~)-5-mclboxyphcnyllCClie acid mc:tabolite of ~ aIiae u fgund:I'J 1 conjugate of glutaminc. 411 Diphcnylmc:"IIYUK .ad. 1 mctabohU: of Lhe aI11ihisamioc: diphenhy (Ben.dryl). is biOlransformcd funtler 10 the rotmpOnding glutaminc dcrivathc in !tie rflesus mookey.~ ' 9 klm.1 odlcr 11111/10 adds 1I./"C involved in the conj ugllt ion fI carboxylic acids.. but theM) reactions occur o nl y ()(:casionall) Iad~;u to be: highly substrate and species deptn b,"" ~ Ornithine (i n birds), aspartic add and serine nul. lIanlDc (in mouse and ham~er). taurine Hr.:CH~HzS01H) (in mammals aoo pigeoru). and hiMi. . lin Aliican bat~) are among these amino acid~.l!O

gC'rter.ued electrophi lic intermediates II- ,th cdlular nuclclr philcs.~ ~ GSH protects vital cellular conslIIuenls against chemicall y relICti VI: species by vi n ue (I f ils nucleophi lic sui fhydryl (S H) group. The SH g roop

cienl ~'Q~nds 4-15),"11 :t GSH is a tripeptide C)'-glu\mnyl<)'\Il'lnylgl)'cinc) round in ~ ti~Sue5. XcrlQl:MOlics conjugated with CSH usually

wilh <'ieclrtln-dcfi 10 fonn S,suOsliWlcd GSH addUCI.'l (Fig.

l"\!ac\S

an: IKll cxcn:ted as such. bul undergo funher biOlran~forma lion 10 giHl S-o;ubsll1Utcd N-occlylc)Mcine prodUCIll called mercapturic acids.~'" 420 .....23 1111 5 proce~~ invol\ts ('TIl';)'malic cleavage of two amino add~ (n:uroely, glutamic aocid and glycine) from lhoe initialiy fonocd GSI l ltdduct mid subsequent N-occ tylation of the n:mauling S-5ub~lituted cy,tcine residue. The fOftt1:llion ofGSH t"OfIjugates and thei r ~on "cnion 10 mercapturic a!:id dcriV3l1' cs arc outlmed in Figun:

4-15_
Conjugation of a wide spccuum of o;ub\trat~ ...ith GS H is catalyad by I family of c)\oplasmlc elUyrnes known as glutathione S_tr,msfer:tSdi. n 1lle..;e en7ymes an: fouoo in mosttissucs. paniculmy the livl:1" and kidocy . Degradation ofGS H conjugates to mercapturic lICid~ i~ camed QUt prinei pallt, by I'l:na l amI hepillic microsoma l en7ymes ( Fig. 415). Unlike other conjugali"e pha'IC 11 n:actions. GSH conjugation does IKll requin: the initial formation of an activated CQen;o:yme or substrate. 11le ;nne",nl react" lIy oflhe nucleo_ philic CS II toward !If1 electroplulic 5ubstr'Jle usually providc5 sufficient driving force. 11le ~ubslratC$ su'iCCpuble to GSH conjugat;oo are quite varied and encompass many chemically different cl3sscs of compound .. A major' prerequisi te is that the substrnte be sufficient ly cll-clfophilic. COIllpounds that I'l:acl wi th GS I~ do !IO by twO gc:nernl mechanis ms: ((I) nU(:lcOl'hilic displaceme nt at an clectron-dcncient carbon or heteroalom or' fbi nU(:ieophrlic addilion to!lf1 elcctron-dcncielll double bond. zI.....n Many ahpllatic and aryWkyl halide,; (0. 8r. I ). sulfates (050,-). Ml lfonDteS (OSOzR), "Itrates (NO l ), and organo-

"'IIE

-BtIlI(IIWIrWtIIl"W1e
l- (p-60oo nopI OlIO 1)'l).3-(2-pyrIdyl). Plopk. .: Aod

'"

CI

au
C- NHNHR

all

N
N J' 001) ... 7MNld (R -COH~J

~"'~6
N

C-OH

a II

C-NHCHaCOH

a II

!lOf.UJIlo ..

-6
N

<>.,01.... c:oo,..v..

QCH,

OH

QCH,
n.......n:w /a .e1io: o\ad
3.~.&

QCH,
C MI . . . COnp.lgIIIe ....

~"'.'"

[ldIeo~~I ... d.....,.ace11C

".,

phosphates (O-ptORh) possess eleclron-lkficienl carbon atoms Ihal react with GS Ii (by aliphlllic nucleophilic dis-

placement) to form GSH conjugate5. as shown:

TlIe carbon cemer is rendered elec1roph ilic a.~ a result of the declron-wilhdrawing group (e .g .. hal ide. sulfate. p/'Icphaie ) ,uocnw 10 il. Nucleophilic displacement orten is f. dlit'led when !he carbon atom is benzylic or all ylic or whal X is a good leaYing VOUp(c.g., haJidt, sulfate). Many industrial chemicals. wch as benzyl chloride (c.H.sCH::CI). a11)'[ chloride (Olz .. CUCHt:J). and methyl iodide, an: to be IO~ic and carcinogenic. l1lc reaclivi ly o f thee threr hali~ tOWilrd GS H conjugation in mammalian systellU i~

mo.-a

WI~"""Mduc

.-

M'd~ oIIr;Id 000"

S-So,,!jMed Cysts" "

""~~ Fi9ure 4-15 formabOfl 01 GSH COflJU9o)tes of eIecItophohc ~1C5 Of metabolites ()and their conYef-

loIOII

to mtlcapwl'ic iIClds.

)NH,

by the ftll'lmotion oflhe COITCSponding mcrcapIIIfI(: ICid derivatives.~U"l11 Orgaoophosphate inslicides. .:II II methyl ~hion. arc delo~ificd by two different GSH jIIlhway,. .) t Pathway "a" involves aliphatic nu lltq*ilic $Ubs!ilutiol! and }'kIds S-mcthylghumhiollc. Path~

way "bOO involves aromatic nucloophilic substitution and produce5 S-p-nitropbenylglutathione. Aromalk or l!eltroaromatic nucleophitic sUUsli lUl ion reactions with GS II occur only when the ring is rendered suffieiemly decuundefieiem by the presence of one or more sl1'Ol1gly clecuon-

,.....pCH 3-O I

aD-NO

$.MIiIIoI'"_"""

OCH,

It of
1 fa-

....
lIlyl
~,

"',
~us.

SG

a
2, ... DicI ...... 1Ibena'II

NO,

i,

wilhdr.!wina substlluem, (c.g .. N0 2, Cl). For e~ample. 2,4dichloronitmi:Jen"(cne is 5USCCpl ibie 10 nuc~ilic substnuliOll by GSI I. whereas ch lorobcn1.<:ne is nOi . Z 11le metabolism of the immunosuppres~he dillS IWIth ioprine (Imur~ll) 10 l -melhyl-4-ll1tro-S-{S-glut:lIhionyl)im ida1.ole and 6-men:aplopurioo is an ellllmpk of heteroaromatic nucleophilic ~ubst ltuhon involving GS H.)).... ~ InlereSlingly. 6-mcrcnpl opurine fonned in thi s reaction appears to be re~Sible for azathKlpl'lIlC'S immunosuppressivc acli"ity.'

t:s

NO,

H,6 N:C"> I.. N N H

~OOPO'"

... -

t~SG
tU8I!-''''tro-s,

NO,

{S,'''_ ....,..

I CH,

+H'N~N
&''3

I.. N N~
I .........

Arene OXIdes and aliphatic epo~ides (or ox irunes) ICPOllsem a "ery import:Ull elllSS of su/)str,ltes that are conj ugated and detoxified by GSH. n l11e three membered oxygen<.'()I1laining rillg ill thc".e ~'Ompoull!J.; is hi ghly sll1lined and. therefore. reacllve lOwlIl'd ring dcaY".tge by nucleophile!l (e.g .. GS/I. Ii:O . or nucleophilic groops prese nt on cell ular macromolecules). As discussed abo,c. arcne oxides and cpoxide5 are IIltcm lCdiary products font1l:d from cytochrome P-4SO oxidation of nromatic compounds (art'Ite,~) and olcfill.I. respccu,cly. If R:aclhc arene o~ ,des (e,g .. bcn1.o[ atpyrene4.S-oxide. 4-bromobenJ.ene oxi<ic) lind ali phatic c[!Oxides (e.g .. Slyrene oxide) al'C IlOl neutntli1.1.'d" or detoxified by glutathione SIr1\n~fera.'iC, cpoxide hydrase, or other pathWB)'li. lhey ultim.1lely co,alentl), bind locellula.. macrofuolecules and cause serious cylotoxiclt y and carcinogellicily _The isolation ofGS H or mercapluric acid IIdducts from bem.of a tp)'rene. bromobcnlene. and styrene clearly dl:monstnlles the importance of GS II in reacting wilh the reactive c[!Oxide metaboliles gcnet1lted from these compound~_ GS II conjugalioo inl'olving substilution or helCroatomS. such as oxygen. i~ seen oflen with 0IJ3nic nitrales. For example. niuuglycerill (NlIl'O!;lat) and i~de dinilr.llC (lsordil) aR: metaboliZed by I pathway involving an illitilll

GSH oonjugatiCMl Il:oclion, The GS II conjugale prodUCts. howevn-. all: not melllbolized 10 mcrcapluric acids bill in slead an: con,erted c lizymalically 10 lhe comsponding aleo. hoi deriVDli\'CS and glulathione disullidc (GSSG ).~lII 'Tho: nucleophilic addillon of GS .. 10 Ckclron-dcficlCnt carOOn-carbcm double botlds oceUI'!I mailily ill compoull(\s rBled double bonds. In most instances, 11K' wilh .....P. unsalU double bond is rendered electron deficient by rCS(lIlaocc or conjugation with I carbooyl group (kelone or aldehyde). cster. nilrile. or Oilier. Such 1l'.P.uIlSIturaled systems undergo so-called Michael addilion reactions with GS I'I to yield the c()lttspoll(\ing GS .. atJduct.otl1 .... 2t For uamplc. In rats IrId dogs. Ihe diuretic agent clhacrynic acid (Edccrin) reacts wilb GSH 10 fonn lhe corresponding GS Ii or mercapturic acid derivat i Yes.~.w NOI all ll'.P. un satur.ued compounds are conjugated with GS Ii. Mony steroidal agents with ll'$ unsllIuraled carbon),1 moieties. such as prednisone and di,iloxigeni n. IulVe evinced 00 significam conjugation with GS H. Steric factors, decrea.'ied rexl i"i ty of lhe double bond, .nd other foclOB (e.g .. suscepti bitity 10 mctabolic reduCiion of the ketone or the C-C double bond) may ltCCounl for tllest observa tion s. Occasionally, metabolic oxidlttive biOlt:lrlsfollll:lllon rell(:' tions may &enerate chc:micall)' relCuve 1l'. P. uns:ll ul1lted Jystenlll that react wilh GS H. For u ample. mctabolic oxidation of acetaminophen PR'sumably gener1l1eS the chemically reacti"e in tcnncdialC N-acetyl imidoquinone. Mi ch!lC'1 addition ofGSH 10 the imidoquinooe leads to the corrcspoodinf. mercapluric acid dcriv~ti ve in both animals and humans. " . us 2 H)droxycstrogcllS, such as 2-hydroxy17,lkstmdiol, ulldcrgo conj ugat ion wit h GS H to yield the 1"" 0 ISOmenc mercapturie acid or GS H deri~ ali ~cs. Although the exact mech.1nism IS unc lear_ il appean llull 2-hydro~yestrOt:cn Ii ox idi1.ed 10 .Il chemicall y reacti "e orthoquinone or semiquinone imermcdiale lnat reactS ",-ith GSII al cuher the electrophil ic C_I or C-4 position ..o.oo. #1 In most inSlances. GS U conjugation is rtgllfded as I de toxifyillg pathway lhat proteclS cellular macromolecules 0 such as protein and DNA DglliuS/ hamlful e leclrophiles. 1 a (cwcases. GSH conjugation has been implK:aled III causi", toxicity. Oflen. this is because the GSH conjugates ore tl'w;<m sel"cs ekclrophilic (c.i., vicinal dihaloelhanes) or gi.'c.m to mctabolie intennediates (e.g .. cysteine IIlCtabolhes of I\:i.

H-J-. ,N-OCH , 0N0

HSG
NoUogIpceifl

CH~ONO~
t~lO.
2

GS-OCH 0N0 2

H -J-.

CH 2ON0 2

CH~ONOi

, "'"

~SG

HOCH2

H -J-.ONO

0
O,N

H H
0

ON0 2

, "'" ""'.
~

, ""

GS9G

0 0
O, N
H

,
0

" , "
f,
1

IIO$OI'I)o(Ie

, ,

CH,
'CH

0 ~

CH'-C

I '

-f

E~ACId

(I'l0l1 '' JI-I"$&tUl'lItld '41....",( 2M

Ms' ,n:: o'od Derva\MI

CH,

0""-./

HO

lDIILaltSj !hal are clcctrophilic.:1A.... n 1,2-Dk:hlomcthane. h eumpit, reacts with GS H to produce S-(2-chloroeth"JIIe''''nme~ the IlUdeophilic sulfur group in this cooju. . ClIIII '*"IllJy displace the chlorine group 1 give rise 0 el.lk tluw-membered ring episulfonium iQn. Tk tu\OIImi InlCr.ICUOI1 of the episulfonium intermediate . . !be: panosillC moiC11 of DNA may contribute \0 W, . al cart;nogenk:dfectSobsCi ved for 1.2-<1ichkM"t ' -f,UHrI 'I'he metabolic convenKIn of GS H conjuJIb klI'tll.1llC cysteine meUlbolilM is responsible for the "'~1fII) associated wl\h some halogenated al kanes _ .alktnts.,1J tne ~\"1Il1OO pathway appears \0 involve ,.,wm)1 U'aIIspcplidase and cysteine conjugate ,8-lya$C.

11010 en1.)'tTI(':s lhal apparently kidney.

'~rget

the conjugates 10 the

_III

Aal!tytatioR
Acetylation ooru;li lUitli an important metabolic route for drugs conta ining primary amino groups .........l. .... l This en oompllSse.'i pri mary aromolic amine. (ArN H1) .IJlfonamides (.l jNc..U.S01NHR ). hydra1.ines ( -NHNH1), hyd~ (-CON HNH z). and primary aliphatic amines. 1'I1e amide derivatives formed from acetylation ortheseamioo functionalities are generally inactive lIod nontox.ic. Bttausc water $Olubi lilY is 001 enhanced greatly by NlICCtyJ:uion. i1 ap-

u C, .sH CH3 H

-OH

N ....... 'CHa

n C

NH

u
' CH 3

0
HNACH 3

"'" - HO

I CH
S-C'H2 'COOH

Acel8'_W_'

HO

piH
HO
HO

, , ,

O'

'"

~ ~

HO
HO HO

2 l.,dotlA'f"17jJ-eslJadioI

SeollqMoe

pears Ihallhe primary function of acelyllilioll is to lermil1:uc phll/'TTlaOOlogical oct;";l), and detoxification. A few repor1s
indiclll e. however, that acctylau:d meUlboliles may be as ac tive as (e .g., N-occtylprocainamidel ...... ... ' Of more toxic

than {e.g. N-ltCCtylisoni8l.id)....... "'1,heir corresponding parent compounds.

T1lc acetyl group used in N-acctylation of xenobiOlk'5 is

supplied by a-l yJ.coA. - Tran sfer of the acdyl group from this cofactor 10 the accepting amioo substtate is carried OUt

by soluble N-acetylll'llll$fcl'llSCS pre5Cnl in hep;ltic I"CticuloC'ndofhc,lial cells. Other c:;ttrahepatic lissU('5, such as lhe lung, splttn. psnic mucosa. red blood cells, and lymphocytes.
al5(l sho .... acctylation capability. N-Acctyhnllufcl1ISe en7y~S display broad Subslr.IIC 5pecir~i l y and catalY/.e the

atCll1olion of several drugs and lcnobiotics (Fig. 416). l. ...J Aromatic corrnds with D primary amino group. such us aniline. p-arnillObenzoic acid ..... ~'9 IHlntinosalicylic lSCid.~I' procainumide (Proncstyl), .... ...,. .......... and dIIpsooe (A" losulfon ),',30 are espttially suscepli ble 10 N-acctylalion. Arum.llk amioo metabolites rc~ulting from the reduction of aryl nitro compounds also are N-acetylated. For example. the: anticonvulsant elon:tztpam (Klonopin ) undcTJ!oes nitro reduction to its 1-amino metabolite. I'>hkh in turn is N_acetylaJed.m Another related ben:wdia:-pam analogue. niU"37.epam , follows. si milar pathway.'le 11le metabolism of a number 0{ sutronamides. such as sulfanilamide. "'" sulfamethoxazolc: (Gantunol)."'" sulfisoxazole (Oantrisi n).'1 su lfapyridine" J (major metnbolite from no reduction of 5ulf~1a7.ine. Azulfidine). and sulfumetha1.ioo .... occun main ly by ocetylation ot the N-4 posit ion. With sulfanilamioo, acetylation also takC$ pillee at the sulfamido N- I poSition}' I N-Acetyloted metabolites of sulfon-

wnides lend 10 be less water soluble than their parenl compounds and ha ve the potential of crystallizing out in renal tubules (crystalluri(I), tllcrcby ca using kidncy damage . The f rcquency of crystalluria and renal toxi city is especially high with older sulfonamide derivatives. such as sul fathia1.o1c. I. ' 20 Newer sulfOllllmides, such as su lfisoxu.ole arod su lfametho.lazole, however. arc metabolized to relath'dy water-soluble acetylaled dcri"&livcs, which are less likely 10 prttipit&1e oul. TIM: biotrdll5forrnation o{hydrazine and hydr:l1Jde deri,... th'es .1.-;0 proceeds by acet~ation. Tbe antihypenrnsi\'C h)drnlD7.ine (Apresoline)ot.SO,' and the MAO inhibitor phendzine (Nardil)""" are cwo reprcsentacive hydrazine COIllPOUntis that are metabolized by this pathway. TIle initially formed N-,,"'Clyl derivative 0{ hydrnl31.ine is unstable and C)'Ch1,t1; intr.lloolecularly co form 3- mechyl-.r-lriazolo(3.4-lI'Jphtblazine as the major isoluble hydralDJ:ine metabolite in hu mans.':\<' , ,, lbe antiluberculosis drug isonialid or isooiL"oti nic acid hydrazide (IN ti ) is metabolized extensi,<e\y to N acetyli.-;oniazid ....... "'7 lbe acetylation of 50IIlC primary aliphalic arnif16 such. histamine,n mescaJine.lIJt.lI.I\I and the bis- N--dcmc:thylltcd mclabolite of lI'( -}-mcthadol"l 'flO aim h.H been re .... ttd. In oompar1.'i01l with o.lidative deamination procr SSM, N acetylation is only a minor pathway in the mctaboh$m of this class of compounds. lbe acetylation pattern o f several drugs (e.g., isoniazid. hydrala:rioo. procainamide ) in the human populatlon displays a bimodal chnraclcr in which !he dru~ is conjuglllCd either rapidly or slow ly with acet)'I_CoA .-"lt . "I>l Thi ll pile. oomenon is termed l'UtY/lltiol1 polymorphism. Individu.ab are classi fied as huving either slow or rapid acelylator pltcno-

- -

NH,

"

NH,

"

NH,

"

1
I

NH,

"

O""~ N (CH2CH a)2

n..A--_ .... ... ;ni=_ i Iic ..... .........

so,

p.Nnn:1bIInmIc Add A .. H ' .. OM

"""'""""
NH,
Oipue

N, 2NH2-51.#.-::1 ,..,. omTh<

m']

h.gh thia-

R--{
N

",]y

~Y to

"""

ova-

.....,
ho -

: hy!nCl-

r",-

""'" ~il~

~ N-

cot;-

~h ali

.ned. ;. N-

],""
CH,Oy"

m of
dis-

3ljd.

,ruod pI><-

dual~

~"~

..

IiguN 4- 1' UampIes of )iffrem IYPfS 01 compound ,"dtIgong N-acetylabOn. At'tIWl rdica1f s.tes of N-acetyla-

OCH,
HislalOinll

MEF;n"'O(I

P ' 7 e I TItIhyt M,'''boiI' 0I3S ,65... -( -) Melh&dul

1

~)o
0 2N 1
N
R

H N N

-cd;R

,
H

~)o
N
R

NH,

Oooazcpam A _

71\ceI*,iidO IA ...........,

Nil~ , R_H

NAcelj\llted Motabglile

SUI.""th.!""'"

A.;---'>- CH i_
O

1)'peS. This variution in occtyluling ability is genetic and

i.~

caused muinly by differences in

Nocelyltr~nsfcr~.;e

aclivil y.

1lle proportion of ",pid and slow acclylat~ varies wide ly aRiong diffcrem ethnic group!!llhroughoul the world. Oddly. high prollorlioo of EsL:imos and A~illll!l are rapid acetyl.tOl'S. whereas Egyptians and some Westl'm European groups are mainly slow llCety'alor<i. 06l OIlier populations are intermediate: between these 1wo extTCmes. Becausc of rhe bi nM)dal di~lribuli on of the human population in10 mpid and slow !lCClylalors. there appears 1 be significant individual varia0 lion in lhcrupeUlic and toxicological responses to drugs displaying ac:ClyJ.uon poIymorphism........ .>J Slow acel)'l.10fS sa:m rfICIfe likdy 10 dc"<'lop adVff'S(' ll'3Clioos. whereas rapid iICC'IylalOl'S are more lilely 10 show an inadequlIte lheTapeulic ""~pono;c 10 Sland:ml drug doses. TIle antitubercul osis drug isonilllid illustrates man y of these points. 1lIc: plasma half-life of isoniazid in 11lpid acetyl:ll0f'5 ranges from 4.$ to 80 minutcs; in slow :lCetylat0f3 !he h.alf-life is about l4()to 200 minutC5 ..-JThus. for a giYen fixtd-dosing regimen. slo w acetylat0f3 lend 10 accumuhlle higher plasma concentrations of isoninid than do rapid acetylatOl'S . Higher concentr:ltiOIl ~ of isoninid may ('lIplain lhe greater thc11lpeutic response (i.e., higher r.:ure rute) anlong ~low lICClylnt~. but they probably also account for the greater incidence of adverse effects (e.g. . pcriphc11l1 neuritis and drug-induced systemic lupus erylhematOSlll 5yndl'QfllC) obser.ed among slow acctylators.~ Slow acelylaton of isoniazid app.arenlly are also more su'ICCp:ible 10 ccnain drug intcractions involvin g drug metabolism. For example, pile-

1I)'101n toxicily associHled with concomitMl use wi th ison,. zid uppcars 10 be 1II0re prevalent in slow OCClylulOrs than in rapid IICctylatOl'S.- lsonia;dd inhibitS the meiJIbolism of phl'nylOin. tiN:'reby leading to 1lll accumulation of high and todc plasma Ie\'e!s of phenytoin . I ntere.~lingly, patients .... OO ~ 11lpid acelylalon appear 10 be more likety 10 develop isoniu.id-assodated hepali. li~._"'l This liver toxici ty presumably urises from initial hydrolysis of the N-lICClylnled mcl~ bolite N-acetylisoniazid to acclylhyd11lzinc:. The lallcr IllCtabolite is further convened (by c) tochrome P-4 5Q elUyme systems) to chemically rex ti\'e acy lat;ng inlennc:diates that oovalmtly bind to hepatic tis. ~ue. causing necrosis. Pathological and biochemical stud ies in upcrimental animals appear to support thi s hy~ thesis. Thcref(lll:. mpid ocelylators run a grealer risk 0( inc urrinG liver injury by vin uc of produdng II1OIl: ace ty Ih ydl1lZi nco The 1I.rldcncy of drup wc h as hydralv.inc and pnxaina mitle to cause lupus erythematosus syndrome and 10 elicit forlNuion of antinuclear amibodic:s (ANAl) appcao relaled to acelyluor pOeOOlype. with greater prevalence in slow ACClylaIOl'S ..j6j Rapid ocetylation may pre~enl the immunological triggering of ANA formation and the III~ syndrome. Imen:!ilingly. lhe N-acelyla ttd metabolite 0( procainamide is as aclhe 1lll antiarrhythmic agent as !he par. ent drug-"'" and has a hair-life lwitt as Ion& in huffilll'li.. 11toe<oe findings indicate thlll N-acet),lproeatnamidc may lit a promising alternative 10 procainamitle as an 1llltiarrlly\hJT\IC agenl with less lupu s-i nducin g potential.

1 ,

< ,

"

"

,
is

*'

'"

'"' ,I,

I~

/ ' /"oN ,

"'vN I

-H,o

--- /'ON
,

N)-CH

N- N
3 'Ad.>" . , lriazr*!..
!H ... ]phll , " _

..........

NHNH 2

,.,:tul. _, CH CNHNH II
l

coo+<
2+

j
As EW..

NirW1On
Medialed

6 --

Cytod1o orne p ..fOO

,'.UW

u.. ""'- .-- :C~~~.~1II . Bn.:Iii "III

. methyhnlllsfl!'flISC'. and non~pocific N-methyltnlllsrerJ..<;eS and S-methyltransfcrases.j~ Olll!' of these enzymc$. COMT. should be familiar because it carries oot O -methylation of Juch important llI!'ufOlransminers as norepilll!'phrilll!' and d0pamine and thus temlinatcs thl!'ir octi vity. Besides being present in the cl!'ntr.1I and pttipheral IlI!'rvI!'S, COMT iJ distriblUoo widely in OIher mammalian ti ssues. panicullrly the livl!'r and kidney. 11J,e OIller methyhrdllsfemS('J mentiOllOO are located primarily in the liver. kidney. 01" lungs. Transferascs that specifically methylate histamiroc. seromnin. and I!'pilM.'phrine are IlOI usually invoh'ed in the melabolism of
~ cnobiOlics. -I(Wj

'"r

&'''1'1.

""

Mclh)1auon ~actions play an im ponanl role in the bios)'nb rI many endogcllOUS compounds (e.g. epinephrine -.I mdIIOnin) and in !he inacti v'lion of numerous physioq.aJly IC'!iI'Cbiogenic amines (~ .. IlOrCpinephrinc, dopa. _ , semtoIIin, and histamine), Methylation. oowt'-cr. \* '11J11e1 onJy. minor p3lhway for conjugating drogs and 1CIIObIoI1CS. Methylation ~llC'rnll y does no! lead '0 poll1T or ""~ub!c ~Ilbol jtes. CACCpl when it cltale$ II qUllter..,. JIIUIQIjum deriYlllivt. Moo methylated products uend 10 be p/IarTrIIroIosicall y ill3Clivt. althoogh there are II few

"'''''
~""'''OH 1481 R_H
No ' hiltarlilPlW" . R _ OH

nr romzyme in\'olved in mclhyl:uion rnclions is S-ad ~htthtonillC' (SAM). TIM: Ir.lIIsfer of the activated MII)'I JI'OUP from Ihis coen~yme to the acceptor Subslnlle C.!;~ '!Y;;""~by various C)'t~lasmic and micro6omal methyl. :'" (fiCA. I7)..... MClhy llrllnsr~ ofpanicu IwIll!pOlW1CC in the meloiloli sm of foreign oompounds indrIck ClkXhoI-O-flll:tby hransfel"1lSC (COMn. phenol -O-

Foreign compounds that undergo methylation include cal!!'Cools . phenol s. arnines. and N-hetcrocydic and thiol compounds. Cal!!'Choi and catecholamine_like drugs are metabolized by COMT 10 inacti vl!' monomelhylaloo catechol products. fuamples of drugs thaI undergo significant 0methy lalion by COMT in humans include the IDtih ypcnen 5i"e (SX- )'Nnethyldop:1 (Aldomet). 'lII. .01 the antipatkinsonism agent (S)(- )-dopa (1evodopa ).m isoproterenol (Isupre1)."U and dobutamine ( Dobutre~).n" The Sludent should note the marked SUUClUrai similarities bet ...een these drugs and the endogenous c8tccltolami ncs such a5 norepinephrine and dopamine. In tile fon:going four drugs. COMT selec li vely O-methyl:lles on ly the phenolic OH I I C -3. Bismethylation docs IlOI occur. Catechol metabolites ari ~ing from aromalic hydrox ylat ion of lht:nols (e .g .. 2-hydroxylation of l7tt-ethinyIe..Qradiol)l-I and from the arene oxide dihy-

AW

""

Figure 4-17 ConJ l.lgCluon of

l'~

ancl

WbsUc1tes (RXH) by methytatlOn _

t1rodiol - catcchol pathway (!\.CC st."CtiOll above OIl mridmion of Ilfllf11atk t11Qietics. e.g the cal;x:hol rnelabolitc of phenyloin)'lJ also ul'lcier1;O OmClhy l~11i oo, SubslruIC.~ unUcrgoing Q-methylation by CQMTmusl coma;n an aromulic 1.2-dihydroll.)' group (i.e .. catechol group). Resorcinol ( 1.3-dihydroxybclll.cne) or p-hydroquirlOllC (l.<kIihydroxyben~ne) derivali"~ an: not ~ubslr"lc~ fur COMT. This explain~ why l.soprtJ(creool undcTgoes cJucnshc O-mclhylatioo nJ btu (efbutahne (\\<hich containS a reson:lIIQllIM)icly) does not.J'i(I OccasIonally. phenols h..," bn repotll to uJl(krgo 0c ~th)'lauon but only 10 a minor e~lcnt.- One imernllng example in"o!:\"I',s the COO,'CfSIOO of morphine 10 ilS O-mcthylatcd deri""I;,'e. codeine, in humans. This metabolite is formed in ~ignificant amounl~ in lolcmnt SUhjeclS and may accoum for up \0 10% of tnc morphine dosc:01& AlIhough N-n1cC hylation of enoogeoous ami~ (e.g .. histumine. norepinephrine) OCC\l~ com monly . bioCrnn~fomla cion uf nitrogen-containing xenobiOtics to N-lIlethyl~tcd melaboliles occu~ co only a limited ex lenL Somc examples reponed inc lude !.he N-nx:thyl:uion of the IU1tiviral a.nd antip:arlinsoni~m Dgem IIITWlloome (Symmetre1) in dogs"'n aod the in 1';lm N-mcthywlOII of norcphedrioo in nlbbit lung PR:par:ltions.- N-meihylalion of ni~n IItoms presoenl in hctctocyehc compounds (e.g . pyridlllC dcrival;I'es) also tales..1.'1..-.:. For example. the pyridinyl nitrogens of nicoIIIlC I . 1M and nicollnlc acid'on are N-nlCthylated to yield quaternary ammonium products. Thiol-comaining drugs. soch as propylthiO\lmcil .~~ 2. 3-dimcrcapto- l -pmp.mol (Bi\L).and 6-mcrcaptopurine. ~. I. ~Il also hal'e been reponed to undergo S-mcthylation.

the inten~ity and dU nltioo of the drug action. In addition. decreased metabolic elimin:ltion lIlay lead to "-'tilmulution I)f toxic levels of the drug . Conven.cl~. UI1 i I1creaSfd rale of Indabolism decreases the imen~i l y and duration of action as well as the drug' s effICacy. Mun y factors may affect drug metabolism. and they are discussed In tile foilowlIl' ~tions. llIesc: include: agc . species and Slraln . genellc hereditary factors. scx. enzyme Induction. and enz)'me inbibuion. 12. ...l-'t!I

incl1'asc~

AI. Dlff us
Age-relalcd differences in dru..t metaboli sm are gencnlly quile apparent in the newborn. . ... [n 1I101i1 fetal and lie", born anima ls. undeveloped or deficicnt oxid:ltive and conjilgative Cn7.ymcs aredtiefly responsible (or the rc.'<l!lCed nJellbolic capabi lity secn. [n ge neru l. the ability 1 cWT)' 011 0 metabolic reactions increa~ rapidly after birth and proaches lIdult levels in about I to 2 months. I of lile influence o( age on dru g metabolism seen duration of action (sleep time) of ilexobarbllal in and adult mke.- When gil'en a dose of 10 mg/tj weighl. the newborn mouse sleeps more than 6 hours. COIIInst. !he adult mouse sleeps for fewer than S nulllllfl 'oI-hen given !he $llTlC dose. [n huma/lS. oxidative and conjugat;le (e.g .. glucurollIlia. uon) e~pabil ilies of newborns are al<;o low compared .... tho6e of adulu. For example. the oxidathe (cytochromt P. 450) metaboli5m of tolbutamide appears to be man.e.I) lowerin newborns!9<'Compared wilh the halflifeof 8)1(M\ in lIdu Jl~. the plasma hal f-life of tolbutamide in inflUlL\ II ,nore thun 40 1Ioo ~. As discussed above. in fallls I ii gate
I

FACTORS AFFECTING DRUG METABOLISM

Dnlgs and xeoobiOliC'i often are mclllbol;/.ed by scI'era! di( (el1'nl ph;tse I a.nd phase 11 pathways 10 give I number of metabolites. lbe rt'lati~'e amounl of uny panicu lar metabol ite is detennined by .he concentration aod IICIlvily of !he en zynX:(sJ respomible for the biOlransfonn:clion. lbe rate of mctabolisillof adrug is panlcularly imponam forilS pharmacologICal aclion as wdl as ilS IOllicity. For example. if the nile of metabolism of a drug is decreased. this genef"Jlly
res~iblc

OIie. resulting in theso-caJlcd gra)' IxIb~ larl~. neonal.l.l hyperbilirubinemia (or fll)ltl the inabilily o f tlCwbom babies 1 0 rubin.ltl The effect of old age on drug mc:tabollsm has not IIlI we ll Studied. There is some evidence in anima ls rIUIns thnt drug mc:1~bol ism diminishes ... ith old

,,<.

\
HOtrCH2 "....CH_L , 'C - CUUH
HO NH z 51 - )....Me\tOOP"

\
HOtrc.t!2 "....H C- COOH
HO NH2
S(-).{)optt

--/y"'-.l

OH

\
HO'y....

011. In
~".

ion or
/,."OH HO,y--"

....

affect

;>\IiInB

:lie or

: inhi-

HN

OA N...-..
~

OH'-.

HO

.Illy

;ot1Ju-

..
H

Cat ..' "" Metabc*1

metuy 00'

--

d ap~'oo

in

the

.born body tli. In

Inult$

HO

.1Ida..... lth =p. ledly

b.., N N N

"""~ n~ is
~s~

' i lu onJu-

CH,
Noc.tb ..

b..,
N

nllbiSinu:liulIS : blli-

,,'"

d hu~I

...,
. .-<12

I.. N

Much of the: evideoce. hovoever. is basal on prolonged plll5ma half-lil es of drugs that are metaboli7~ totally or ma inl y by Ilepatic m~1 enzYme! (e.,., antipyrine. phenobarbital. acetaminophen). In evaluating the: effect of age on drug n1Clllbolism, one must diffe~ntiate between lIOfTTlat" 1 of enzymat ie activity with aging and the ef0liIl fect of a di seased liver from hepatitis. ci rrhosis. etc .. plus dccrellSCd renal function. because much of the wllter-solublc conjugation prodUCtS are excreted in the liver.

Sp u:les .ltd Str.l. DIff.: .nc_

The 1TII:tIl.bolism of many drug.\ and foreign compounds is oftcn species dcpcodent. Different animal species may biotrnnsform a particular xenobiOlic by si milar Of markedly dif_ ferent metabolic pathways. Even within the same species. indi yidua] variations (strain dtfference~) m3 Yresult in signifThis icant di fferr:nccs in a speci fIC mc:tabolic pathway. is a problem when a new dl\Jg is under deyelopnlt'nt. A lleW dl\Jg application requires Ihc developer to account for the product lIS it moves from lhe site of administration to linal elimination front the body. It is difficult e nough to lind 3pa disease . It is evcn harder to plOprialc animal modcl~ find an imal models that mimic human drug mcUlbolism.

"0._

rot

Species variation has been obscr.ed in many oxidative biotransformation reactions. For uample. metabol Ism of amphetamine occurs by IWO main pathways: oxidalh'e de amination or aromali c hydro~ylalion . In the human, rabbit. and guinea pi g. o~;dative dcaminalion apPears 10 be the predom inant pathway: in the rot. aromatic hydro~ylation appeatS tn be the more important route.~~ Phenytoin is another drug that shows marked species difference.~ in metaboli sm. In lhe humnn . phenytoin undergoes aramatic o~idation to yield primarily (SX-}-p- hydroltypbenytoin: in the: dog. oxi dation occurs to give mainly (R)( + l-,"hydro~yphcn)1oin:'90 T1lc:re is II dramatic difference not only in the position (i.e .. ~IU or parol of aromatic hydro~ ylalion but also in which of the two phenyl rings (al COS of phenytOin ) undrrgoes aromatic o~idalion. Species differe!"lOeS in many conjugation reactions also hne been obscned. Oflen. these dirren:!"IOeS an: caused by lhe presence or absence of transferase enzymes involved in the conjugative process. For uample. cats lack glucuronyl tran sferase enl.ymcs pnd. therefore. tend to conjugate phenotic xenobiotic.~ by sulfation instead."91 In pigs. the situalion is reversed: pigs an: not able to conjugatc phenols with sulfate (because of lack of sulfOitansfcl1lSC enl-lnleS) but appear Ul havc good glucuronidatioo capability .oW The conjugation of

OH
HN

/ ' - - / O A N"'-O

"'"- i ""'V

$( -

)~H)d"~oon
OH

()C~?HCH3
_ _.::NH,

HO
~

NH~

,., .

Chapter" MttIJboIic Clwtgt'J of Dnl,lS muJ

H~lDrrJ

Orfl4llic ComptJIINis

129

.. ," "'2"JI. Uno,

5'11.G_Plg

....., '"' """'" .......

.H,

.H,
2'.()tH'AP
T..cI _~

.'-OH,fW>

rat and guIref. pig

7"4 Guinea Pig

.H,

,.....
~

2 ..... ,oiooopr ..'101

HN .... .... CH,

,.,,"""'" ""'" "

4O'JI. GuInN pig

.....

NAceI)14....,.1OjII16iIOI

F19ure 4- 18 Phenaropyndlne metabohlm In humans, gUinea ptgS, rats and miCe.

_~

Icids With amino adds (e.g.. gly.;:ine, glutamine) on the animal species as well as on the substflue. conjugation is a common conjugation
acid in many animall. In ~n birds I i replaced by a substnue

,,~;,;;u~ist . panicuhu'ly
~ apparently~

the amount of meUibolil.ing strains. For uampl e. in COllOiltail rabbit liver microsomes I about 10 times faster than New I I,,'er microsomcJ:~1 Intcrindividual differmetabolism in humans are COIt,ide~ be low.

itary factors ate rc.~ponsible for tile large diffefC'nces sccn in Ihe nile ofmelllbolism of these drugs. 11M: frequentl y cited example of the biotransformation of the ancitu1:ren;:uklsis agent isoniazid is discussed above under acylation. Genetic factors also appt'ar 10 influence tile role of oxidation ofdrogs like ~~Ioin . pIlenylbutal.one. dicumarol. and nortriptyline. n.e role of w:idation o f these drup; variel ....ilk- Iy amoog diffefC'nt illdivldua1s: these differences. however, do not appear to be di slributed bimodally. as in acetylation. In general. indi viduals who tend to oxidize one drug rapidly are abo litely tooxidiu OIher drugs rapidly. Numerous Iud its in twins (identical aOO (mlem al) and in fumilies indicate Ihat oxidation of these drugs is under genetic control:":)) Many P'ltients state that they do not respond to codc:ine and codeine analogues. It now is realized thaI theirCYP2D6 isozyme does not readily O-demethylate codeine 10 fann morph ine. This genetic polymorphbm is sun in about 8~ of CaU(:a5ians, 4~ of African Americans, and less than Ilk of A sians ,~ Genetic polymorphism with C YP i50lymes is well documented as evidenced by the many examples in this chapter. There is limiled evidence of polymorphism involvin g MAO-A and MAO-B. 1llc: chemical imbalances sccn with somc menIal diseases may be Ihe cause.lIlf>

c tIc: F. ,J FlS

51- Dln.... c..

The rate of nltlabolism of ~c BObi Olics also varies according 10 gender in some animal species. A marked difference is

~i"'; Ividual diffcrt:nces in tile metaboli sm of several

In humans.*l Many of these genetic or hered

obsen.-cd between female and male rats. Adult male rats mdaboli7.e 5e\'eral fon:lgn compounds at a much faster rote than female rots (c.g., Ndcmclhylm ion of aminopyrine. hex obarbillli oxidalion, glocl.lronid.:llion of o.llIlunopbenol). Apparently. thi~ .'leX difference 01'\0 (lepends on the sublitrate, be<:al.lSle some xenobiotie$ are metaboliud at !he ume m e in both female and male ral~. Di fferences in mi crosomal oxidation an: undcrthe conlrol OfSCll hormones. particularly androgens: lhe anabolic IICtion of undrogens seems 10 in crease mctabolism.-'OS Sex differences in drug meuabolism appear lO be species

dependtm . Rabbits and mkc. for uample. do not show II signifi cam $Cx difference. in drug metaboli sm. S In hu mans. ~ ha ve been a few reports of sex. differences in me tabolis m. For in>.tallCC, nicotine and aspirin seem 10 be metaboli7..ed differenlly in women and men. - ~ On the OIher hand. gender differences can become significant in tenns of drug-drug interactions baSC'd on the drug's mel.abolism. For WOfllen , the focus is on drugJl used for contrnccplion. NOll' in Table 44 that the: antibiOlie rifumpin. a CYP 3A4 inducer. can shorten the half life of on.! contruccptives.

TABLE 4-4 Clinlc.lly Signlfic.llnt Cytochrome P-450-B.sed Drug-Ontg Int.radlons

SubstnotH
Am,lnpl)h""

.....

Inhibitors
Cimcticli.. Ctpm/l(>x""",
CIar\~.oo"",.

Inckoc..-s

AgM'

SuDstn,tH

Inhlbltors

Ind~

CYP IA2

c.m.m..,.K
~loI

a.. ......

'''."

".,....-

M<-pondl""

-~

fluYoUln,,,,,

""""'.
I'I"'''''-t,d

I'h:n)_

101<1""'"
Mnl\etino

TK~ Th<q>t,~ltinc

Ib,,' .tdIIl

EryI/INm,<in l-lInvuno,..
....1 ica:1d .....

''''''rorami rot

....,.
lI,f."",on
Smllkln,
klf."",n

"'Im~

0.,.....
,.,.,...
CYP 1M Alpnd

NonrlplyllM

Sf.""'. won
c.n.'''''''p'IIt
l'hon~lOin

Propof ...fTopo>.,pi ....

"nIillridll"n~

Norfloudn

t"}oW"'''''
Cyp "2C'I
Oi"~plIm

Pb('",."n (S[.-Worfonn

"..... '"""'- .........., 0>I00 ..,z...

CinxtJd,,,..

T~'"

Trl l, . - Alf." .... '!

."".....
1..-11t1"w.
~loo.tI

-..I

" Ami<)d,p',,"

Primuolt

,~-

CVP2C19

-"". """""'"'
Am'lnpl~h,,"

,....
Atrvo, ......

~''''''tI,''' n U"I"m,,," 1 _,..wI Mclrondoil.Olc

lIil"llJlml'''"

fkI,..lr.
C&tt>;una;ocpl",

'-. """ C..... ~

..-..

t:f...tftlI

F..thooo.,,.,....
M<>daronot

o.id.oob)'NI

" >tdlnc' -" OOt

"'""....
a.hllt_ydn

eyc...... IU"""

"""'""""~

CYP 201\

ModAIiml

...........

-"".

Oill)'*'"" ......... o.>Op)'",m\tlo:

.n",,~ed ..

"""""
ttdi ..., ...
t ~ .....
,~

""~~

o...tz X ,'"
1'!otno1bttbiW ",""ylOOn
""",0.

Nr,.'rlf'I'"

Ct)"lII'QIII)'OII

Top ...."..
Am.~

"""'"""" ""'"'""'" "'jIOWIIi""

~.,,!I.

Sl. Johto', ... ,Ift

~("0.\<.".

Ctmell<i;"..

""- ...... "".,',,' ......

,,"nllllyl
' ,,",,_10

0.........,..

Q.l1ftld i"..

.....-

"'....,..
'

-"',

n............".

1I,1'abIII", 1\1(...."..

n"".tlIIit

"-K',,,,_
,

"",I

"'*-'"'"

...

Rlfr.pcnlltlt St. Jnha ~.....,

Etbi"yl~

1':lIIw>" .... dc:

l'q'l

$cnr:tll""

,
. 1 .-.1)

",Ind,,,,,,,,
'~yl

..,.....
M..;oo.'OI<
Noilitllly"

"'.""" .... roIe

'""",""" ""'..-

........ , Ind,tlllvit

Q,,,'"

N.r.dlpo.. No:.11ounn R'ION ....

.....

.. b ,,,,",<1_1... _

T Lood B_. 0 I\. _

J It. o . . l _' ''''''''''''J'''_ M'"IC

o. v _ .... W """"iIT1c, "t "',

...

:!OOl.Oo<=l Pot _ . l~(_ ,. .... ~_.... ..... lOOt. . . 1 _ 0. S 1001.);00-.1 ' ."" focto So.

~f...

H.'. D ;;_;.;,;ll;
~

ltc: :

..
h,

1&1:, .... lftduc:tJan

The
of hepatic microsom:tl entyme'>. such as !he t)'IOChrome P4SQ mill.c:d-fullCtion o~ida..<ie ~)'Slcm. can be ~aW martedly by uposure 10 dhcI'SC drugs, peQicJdes.
lJl)In;llic hydrocarbons. and cnvirorunenlal : :nou bioucl. The process by which the at'livil)' of Ihc5C drugIIItUbolw ng enq/lle1l is increased i~ termed r"~"r .. induep~)C)dic
tI;'Ii~uy

=10 II
roc

"" U "' ug's

~I

MiI.-' 1I The increased octivhy is appl!n:ntly caused by

'am-

.. incR'uW amount of newly symhe~i7.ed cn7YIlIe. Enzyme indUCtion oflell increases the rute of drug melUboIi sm and dtata.n the dur:uion of drug action. (See Table 4-4 for II bioi of chnica lly significant drug- drug intcr.>C'tions ba.~ on IlIIe Ilr\Ig inducing the metabolism or II S'OIKl drug.) 1IIdIxinS agents may increase the nue of their own 111('1lIbQtim ti " '1' 11 as those of other unrelated droiS or foreign ~ (Table 4-4).'2 Conconulam adminl)lralion of lOI<Ior more: drugs oflell may kad 10 5Clious drug imernetions INlII of enzyme induction. Rlr IOSlaQCt', II clinically
critiCal

drug Inttraction ~:curs WIth phenobMbnaJ and war-

r....!I11nducuon of microsomal cn7.ymes by phenobarbital 1Arn';l~ lhe mcillbolism of warfarin and. oon<;equcnlly. Illarbllly <kcreases lhe anlicoogulant effect. Therefore. if a patient i, re<.;eiving warfarin untk'OOijulalll thcmpy alld be1'115 I3llng phenobarbital. carefu l attcntlon IIIUS! be paid to fUdJu>t~nt of thoe warfarin dose. Dos.1ge relldJu~trnent is IIbo nttded if a p;lIienl rt'('Ci ving boIh warfann and phenob.wbtlal thtmpy suddenly Slops laking the barbilUrnlc. The .rf1.'Ctl\tfItSS of 01'":11 ronlt:lCeplive5 in ...omell on concurreal pbtnoborbital or rifampin lherapy has been auribtrted IOWen/Qoctd Il"ICtabolism of est~cos (c .... 1 7~hinyl ewUoI) cau~ by phenobarbital" and riflimpin'l .. indue~.

--

InojoU'1"$ of microsomal enlymc.~ al.'>O may cnhance the IItIabohsm of endogenous compounds. such liS ~teroidal lroo"kHld and bilirubi n. For inqance. phenobarbital clln inata<:e Ihe n~tHbolism of conisol. ICSIO"'Cronc, vitamin D. !lid bilirubin in humans. :!QI .'O'i 'The enhaIK."cd metabolism of Iltarmn OJ uldu.ced by phcnobarbit:11 and phenyloi n appeul"$ 10 be rt.SpOIlsible (Of" lhe osleomaloc ia 'iCCn in p:lIients on ~-lmn therapy willi these 1....0 IUlticOllyulsant drugs.'" IlItfcsliIlgly. phenobarbital induces glucuroo)" ltronsferase ml)!IIeS. Ihcrcby enhancing lhe ronjugatlon o r bilirubin Jlucuronic acid. Phenobarbital has been used occasionJily 10 ~~ h)"llerbilirubinemia III neon:IICS."" 1.1dd1ll0ll 10 drugs. other chemIcals. such ;l.S poI)'cyclk .-mIaI1C h)'droearbons (e.g .. benl.of u 1pyrene, 3-methylehol.mrtlll'l and enyironmental poIlutums (e.I .. pesticides, p;lIychlorillllltd hiphenyls. TeDD). may induce certain o~i "'il'e p;ithwa)'s and. thereby. a lr er drug rc~ponse.-- - . '11 Cigarr11e smoke COMmi ns minute anlll'luns of polycyclic aom,lIi(: hydrocurbons. such as henml alpyrenc. which are JIOIeIll induccrs of microsulllal cytochrome 1'-450 enl.yllleS. Tbb ,ndoction illCreasc:s lhe oxidation of IlOIlle drugs in -.im. For exampl<'. theoph ylllllC i~ nlelaboli7.cd more !IpilIy In ~m; than in noosnlOl.e .... Thi, dlffcrellCe is rd\(('Itd in lhe marked diffC'T'C'l1ee III the plasma half-life m "'''pl)lhllt between smoken(,'1 4 . 1 hour'i)and noosmoken ~r',) 7.2 hours).m 0t/JeT drugs. such as phenlloCttin. penlII0I:1111'. and propo~)"phene. also reportedly underll.o more rapoI metabolism ill smok.en than In nonsn\Ol.:ers..,r, liM Oxup:lllOnal and accidental e~posure to chlorinaloo pes-

ticides and in'IeCllcH\cs can also pimui:alc drug nlelabollsm. For instarlCle, the half-lofe m anlipyrine in worl.ers occupationally exposed to the Illsccucidcs lindane and DDT is reportedl) silnl flCllmly shaner (7.7 ''!ii. 11.7 hours) Ihan III control SUb)tCl!>.)11 A case W;!5 rt'ported in ... hlch a ... orl.er uposcd to chloriruued insecticides failed to respond (i.e., decreased unticoogu lant effect) 10 a therupcutic dose of W'drfarin. n : As di scussed ~1x)Ye, mulriple forms (i~lncS) or cytOchrome P-450have been demoostrulcti. ll . I Manychemi ca ls ~ I cctiyely induce one or IllOI"e distinct fonns of cytochrome P-4.so. \I (St:e Table 4-4.) Enl.ynte Illducuon also llIiIy affcci to~icity of some: drugs by enhnnclllg lhe metabolic fonnalion of chemically reacliye ntelabo!itcs. Partlcu larly importam is lhe Induclion of C)1ochronle P-4.so en7.yltle'S invohed 11\ lhe OAi<blion of drug~ tt) reacl;" e intermed i~tes. Fore.\ampk. the o~lIbuon or acetanllnop/l('n to 0 reiIClile inllooquinone: n1Clabolite appcan to be carried ()IJt by phenobarbnul-inducible fom\ or c)tochrome P-4SO in rots and mice, NunlelUUs Sludies in lhese lWO aniffilli s indicate that phenobarbilal pretrea1ment IllCfCases III I i,'u hepatOlox icity and cuvolent binding as well a.~ U1Crea...c.~ fOf'matioo of rcocli ve ntoelabol ite in microsomal incubation nux lures. 2~ 1_ :W'_ :W~ Indllction of cytochrome 1'-448 is of IO~ ,CO- logical COIlC~m bau"ll this panicular enzyme is inl'oIved in the nletuboli~m of polycyc lic aromatic hpiroearbons to fC~til'e and carcinogcnic Inlcrmediates. iIO. H Conseqll(nily. lhe metabolic bioocti ~~tion ofben"l.o( alpyn:ne Ill' i1~ ultimale carclOOSCllk dial epo11de intenncdiale is earned OUI by cytochrome P-44 8 ('iCe ~ion abalC on arontatte ollidiuon for the biuacli~allOll path,,-ay of benzol utpyrene to liS dlOl cpo~rdc: ).'1.1 1"hus. ,I is becomi ng increasingly appafCllt lnal enzyme InductlOfl nI:JY enhance the 1 01idty of ~ne lenoblOIic.s by incfCa.~inilthe role of format ion of fC3!..1ile metUlolites.

Enqme InhIbItion
Severnl drug.\, OIhcr xcnobiOlics including grupcfruit, alld ~~iblt ~~ler food_ can inhibil dru g I1M:labolbm (Tobie 45).Jl." With deerell!oed Illetabollsm. a drug often IIU0 muloles. karling 1 prolongoo drug action and serious ad -

."tII

TABLE 4-5 Potent!",! D~r",pefruit Interactions B",sed on Gr",pefruit Inhibition of CYP ] .....

Ii

o;'''I'''m
O.apnok

~-

1"",..><"" booo''alI.bdlly 1""'.....t ALC ,,,,,...cd Al'C. puk ..... lIOOlh pi .."", 1 _ _ Al/C

eo"""""..,.""
C)ck ..

'o"..... Iknll'mu.

AIOI'I_ ....... _,n

h","4ioCd AlJC _.aum <~.._ 1,",,","ioCd -.po_.ad ..... ma

s...--",
_ _ Ktto-...'"
0... AtC .'I~ _ _ _ _,

A "'-

.....

r.-.. II, $or," I

llI(l!.

UNiI

\er,;t: efftcts. En1-ynlC inhibition can occur by diverse: mhanism~. including substtllte competition. interference with protein 5ynthesis. inactivation 0{ drug-rnc:tabolizmg enzymes. and hepaloto~icity leading to impairment of enzynlC acIl\;ly. Some drug mtenlClioos resultint.trom enzyme inhibition ha\'e been reported in humans.' . 'I.' For uample. phc:nylbutal.onc: (l imited to VCtcrinary usc) stert:osc:ltively inhibits tile: metabolism of the n)()re poeen t (SX - ) en~ntiomer of warfarin . This inhibi tion may uplai n tile excessive hypoprochrombinc:mia (incn:ascd anticoagulant effect) ~nd many insr.ances of hemorrllaging ~ in palients on boIh wanllrin and phcnylbuta1.Onc: therapy .'" The: mClDboIism of phenytoin is inllibited by drugs such lIS e hlor:unphenirol. disulfiranl, and isonillJ id. m Imerestingly. phenytoin toxicilY as a ruuh of enzyme inllibiti on by ison ialid bl'pears 10 occur primarily in slow acet~IlItOf~.- Several drugs. such as dicumarol. cilloramphenic:ol. will phcnylbutfO.onc:,m inhibit the bioIr:msformalion ortolbutwnidt. \\<hich may lead 10 a hypoglycemic response. The gropefruit-drug inlC'raction is complcx. It may be caused by lhe bion:lvonoids or the fUnI/IOCoumarins. Grnpefru i!' s main bionavonoid. naringi n. is a wC:lk C YP inhibi tor. but the product of the intestinal nOl'll. naringenin. does in hi bit CYP JA4 . The: litM1l.IUrc: is \'ery confusing because many of the sllIdic:s WCft' done in vitro. and they cannot alwaY' be substantiated under in vivo conditions. In addtllon. OOIIlj)CJfltnts in gt'Jpefruit also at:'tiVllle P-glycoprotein ..... hich wOlild activDte tile efflux pump in the gllStric mucosa and thu~ interfere with or:al :lbsorpIion or tile eertai n drugs. The combinm ion of C YP enzyme inhibition and P-glyooprotein IICtivation un lead to inc:ooclusive resull5.'l0 The gener l .. recotllmc:ndalion .... hen a drug interactlOO is SUSpecled is that tile patielll avoid grapc'fruit and its juice.

StmlCes . tile two enantiomeno 1113Y ha\e 100ally dlfli:rent pharmllCologkul octivitic:.~. For c~mnplc:. (+ )-{fo[lTOpoxyphene (Darvon) is an aJl:llgesic . wherea.~ (- .,o-propoxyphenc (NO). "rad) is an antitussive.'~ Such diffCft'oces m activity be tween stereoisomelli should 11()1 be surprising. si ~ C1I:Ipter 2 explains that sterroc:hemical fOCIOB gencrally I!a"e:l dramatic innucllCC on how the drug moltcule intenets with the target receptors 10 elicit Its ph:lnn:lCological responsc. By the SlIme tohn, the pre ferential interoclion of one sh::reoisorncrwhh dl\Jg metabolizing en/ymes m:ly lead one to anticip;lIe differences in metabolism for the two erulntiOfllClli of a racemic mix ture. Indeed. indl\ idual enantiotl'ltl'S of rnce mic drug ofien are mctabohlCd at diffen:nt roles. For inStance. sllIdles in humans indicate tll:lt the le'lS active (+) cnantiomcr of propronolol undergoes more mpld tllCtabolism tllan the com:sponding (- ) cnantiomer.H ') Allylic hydro~y lalion or hcxob:lrbilal occurs more rnpid ly with the RH enamionlCr m humans.. JjC\ The term sllbJlrau s/t'fWlst'/:ril'ily is u.sed freqllC1ltly todenote a prdCft'1lCC for one ste~1io mer as a substrate for II rnclaboli7,ing en1.)'Ine or mc:t:lbolic
procc.~s,l\I '

f (

r.

r;

MIKeIl.n

Metaboll...n.

F~,tot U] 4
F F

Afhtdlng Drug

Individual enanl ionlCrs of a r.JCemic mixlllre also may be llIetaboli1.cd by different p:lthways. For installCe. in dog" the (+ ) enantiomer of the sedative- hypnotic ,lutethimide (Doriden ) is hydroxylated primwily a to tile carbonyl 10 yield 4-hydroxyglutelhimide. v.lltreas the (- ) enalliiomer undergoes aliph:ltic '" - I hydroxyl:llioo of ils C-2 ethyl grotlp. IOI), I~' Dramatic differences in the 1lICinbolic profile of twO enam iomers of warfarin also ha\'e been naled. In h uman~. the more :relive (5)( - ) isomer is 7-hydroxylatoo (aromatic h~droxylation). whereas lhe (R)( + llsomc:r under goes keto n:duction \0 yield pnmari ly the (R.S) v.-arfarin alcohol as the m:ljor plasma metabolite."'- 2'>1> Allhough DUmerotlS OIher examplC'i of substnne SlereQ!iC':lectivity or en:lnlioseleclivity in drug metabolism exist, the e~amples ]IIT senk"d sholli d suffice to emphasize the poinl.lIIl. H I

" "
r;

I,

OIlier fac1~ I1lso may illOucllC.'C drug mtlabolism. Diewy facl~. such 11$ the protein-to-<arbohytlrnle mtio. affect the mtUboIism of a few drup. Indolcs present in vegetables such as Brussels sprouts. cabb:lge. and cauliflower. and polyc~clic 8rotn9tic hydrocarbons present in eharco:ll-broi led bc:ef induce cn1.yrnes and slimu hlte the metabo lism of sollie drugs. Vitamins. minerals. SlDJ"\':ltion. and mal nutrition also apparently illnuc~ drug \TIClIIboli~m. Finally. physiologi cal factors. StICh as the pathological Slate of the liver (e.g .. hepatic C:I~r. cirrhosis. hepatitiS). pregnancy. hormonal disturb:inces (e .g.. thyro~ i ne. steroids). and circadi:lll mythm, may markedly affect drug metabolism.

HO

nCeH~ o N 0 H

CHlCH]

~~lhrnde

( .. I-t:n.'II .......

St.uoc:hemlCAI Aspacb of Drug M ... bol .....

Many drugs (e." . warfarin. proprnnolol. hexob~rbillli. glutethimide. cyclophosphamide. ketamillC, and ibuprofen) oftcn arc: administered as racel11 ic rniJuures in hUllIans. The two enantioolCl'S prescnt in a rncemic mixture may differ in phannocoIogkal oct;vity. Usu:llly. one en:lntiorner tends to be much more active than the otller. For tlI:lmple. the (S)( - ) en:lIltiomer of warfarin is 5 tunes M'lOI'e potent as an ond anticoagulant than the (R)( +) enantiorner. U' In sonIC in

Drug biotransformation pmcesse< often lead to the eTation of. new asymmetric: c:entCT in the metabolite (i.e .. .\kreoiSOll'ltrlc or ermntKm'ltric products). TIre PR"ferential mttabolic formation or a stereoisomeric product is called prot/uci Mercosl!/ti)ity. 2'>1 Thus. bioreduction of ketone xenobiOlies. as a gcl1t'rol rule. produces predominantly ont stereoisomeric .Icohol (<;CC "Reduction of Kelooc CarboJl. yls. " :loove).'11>.. 191 The PKferentia l formallon 0{ (S)(-~ hydro~hexamide from the hypoglycc-mic .gent ace!oheJ.. amide ':I'M and the exc lush 'e generation of 6,B-naluuol

-,~

rW~\onel'l7 lIiI (see "Reduction of Ketone ClUbon) ' for sllUC1urc) art two c.IIamplel; of liighly stcrI$Clcc-

,,~

ale biortd\lCtioo processes

b<-

humans . O\ida\l\'e biolrllllsformalioos d ispl ay product

In

~Icrcoselec

~" >m,I><

of
~

i!! fiei-

\II 1)'. 100. For example:. phcnylOin COIllains IWO phenyl rings lIS W\lCtUIt. boll! of which a priori should be susceptible III _tic hydro.. yl:uion. 111 humans. however.I,-hydro .. ),IIlIOII omu'S prrfcrcnuHy (approximately 90%) al the proIS}-phenyl ring 10 live primarily (S)(-}-S(4.hydroxypilrnyl}-S-pbenylhydanlOln. Although the other phc:n)'1 ring _ i.J:"hydrolyJated, It occurs only 10 Il minor extent lIll'll. Microwmal lIydro:c.ylation of the C-) carbon of lli31epam"oo desmethyldill7.cpam (using mouse liver pt"Cp;.. I*IOM) has betn reponed 10 proceed with rcmlltbble ~Ieroo \decu\ u)' 10 yield opIlCaJly IICtive metabolites With the 3(5)

()"'" .", R _ Oil

/'VN ~~H
('-...A_N
CeH, (lSI N.Met/O""",.". R - CHI
$1 '"

Oa"liIICIlJi(t'.

ep!fTI,

R_ H

ro-. apam. R. H

The term r"g'OltdtMifJ-l has been Introduced in drug

metabolism 10 denote the selective metabol ism of '''0 or IJIO!l: ~imi13r functional groups (e.g .. OCH,. O H, NO I ) or two or more similar atoms thaI arc positioned in differcl1l regions of a nM)lecule. For I!llarnple, of the four methollY groups present ,n papavrrine, tile 4-0<:1 1, group is rcgioselectivdy O-demethylated in severnl ~pedcs (e.g . 1111. guinea pig. rnbbit. and dog).m Trimethoprim(Trimrll, Prolopr1m) has tWO httrrocyclic spl nitrogen atoms (N and rrJ) in its structure. In dogs. it appears that Ollidation occur.; rcgioselectivcly at N) to give the cCJlTes!X"ldlna3.N-oddc.lll Nitroreduction of the 7-nitro group in 5,7-dinitroindazole to yield the 7-ulnino dcrival il'e in the mouse and rnl occurs with high rcgioselectivi ty.'"'" S"bstrnle~ umenable to O-mcthylation by COMT appc.'ur to proceed with remarkable regioselectivity, as typified by the cardiotonic agent dobutJlJllil1C (Dobutrex) .

'+ )
in-

ri~m
~l(y-

~-)
:1'W,~

ooilc

Ii

b< Qg~ oilie

1 0

-,

JiMdIllC coofiguration,I""ntC:l'Cloli ngly. these IWO ITlCtaooII'e pharmacologically act;,-c and one of lhem, oxv.epall. Il mart~ as a drug (Scru). The allylic hydroxylalion die: N-bulCn)"1 side VOUP of the analgesic pentaJ'oc;ne fTaI",n) kads 10 1.... 0 possible akohols (do' and lfllru aloobuhl_ln bum;lJl, ITII)IJse, lind monkey. pema~.ocine i~ melaoo.. Ute<! prNominamly 10 tke mills alcohol meluholitc, whereas Ibe ("II primarily tends to fonn the cis nlco/tQ1.' 2IO 1,10 TIle ~ st=<l5Clecuvity obsen'w in this biQtT'Jllsfomllltion Ioh'a ('is and IroM ge<Htll.'trH: stCTeOi~.

:thyl

Dlik I. In

Idernu-

,,'"

fllrin

r en-

p-

>i,

"

,
Watt.1'1

r:;,C, CHa Ha C,
C
I/H
CeH~

C K

, ,

SH

<,

HC,A...-

o Sle~,

=,-

:ailed

,,~

V"'-JOH

HN

,~

rl>on-

CAN'A,
H

i)(-)"",,In-xol

Rl + HH.Hy(Ir~

-~

f 34

Wi...."'" ulllj (Jil ,'Old',

T~.rl"'''1Ic

"f O,gllt/ie M~,lirilll" iIIul

/'Iu,,mt,u~rK:al

Chl'mix/n'

CH,
N/

CH 2

....... Co?' ....... CH OH H

fA

'

CHl

~
HO

HO

a a a

0 -1I)(lh)'lmion 0Ci:1I1'! ... ~dus ivcly with the phenolic hydro~)' group al C_3.~74

Ph.... uologlc.lly Active Meu.boIlte.

The traditional nOlion thai drug mctobolites are illacli ve mid insiglliflCan! in drug themp), has changed dr.lmatically in rel:"t"Ill )eaoo. Increasi nj,; cvidence indicales Ihal m:lII)' drugs nrc blOll"lln~fOOTltd to phatm:loCOlogicaJly act,,'e metaboli tes lhm COOtnbu le 10 lhe thern.pcutic 3.~ .... ell as 10.\1C effecls of lhe pa~nt compourld. MC1abolucs ~hown 10 rul\'e )ig mficam lhempeutic al:tiYII)' in humalls are li'l~d in Tanl e 4-4 .1. H'I 'The (XIrcn! drug from ""hich the metaboli te is dcrio'ed and lhe blOlr.lllsfonnll uon rrocess Involved al50 are gi~en. How SIgnificantly an actioe metaboille COOtribul~ to !he therapeullc or tO~IC effects :l.'oCribcd to the parellt drug deperld.~ 011 ils relali ..e acl;"Il)' and (IUamitali>'c unponanc.: (e.g .. piasilla oorn:cn t Illt ion). In adl.lilion. II helher the mcwbolile !lCCul1ll,,]ate\ after "'pealed adrnin ;\tralion (e.g .. desrneIhykilll1.cpam in genalnc patients) or in pat ienlS .... ilh rellal failure is dclcmllnant. From a clinical standpoinl. lII,'1ive melaboliles are e~pe dall)' important ill patients with decreased renal fUllClion . If renal C:Jlcn: tion is the major (XIl hway for climin:uion of the lICtive metllbolile. lhen lICCulllulallOli is liJ.c1y 10 occur in (XIlienb "" Ith rcnal fallure. Espccially wilh drugs soch as proc:unamidc. clofibr~te, and dJgIII)~ln. ~ution ,lIOU ld be exercio;ed in treating palienls wilh renal failure .l. 411 Many of the tQ~ir effecis St.~n for Ihe<>e drugs hn~e bt.~n anributcrJ [() hij;.h plasma Ie~els Qf their :acth'e metabolites. Por exumpie. the combinalion of severe muscle ..... CIlJ.ncss and tenderIIl'!i-'I ( m)opalh ) ) <;cen ... ilh clofibr~le In renal failure p,lIiems is belieoed to be cau~ by high levels of the IIClioe mctaoofile chlorophcnQxYI'iOb..nyric aCid.''''' ,)7 Curdiovllsculur lotidly owing 10 digitm,in and proclli llamide in Qrtephric subjccI$ iIlL~ ilc(-n aUributed 10 high pl ...~m4Ievd~ of digoxin and N:acetylprocalnamide. Tt'spcc" oc:I)'. In :well silulll ions. appropriale reduclJon III dosage and careful moniloring of plasma levels of the parenl drug and its active melabolile orten are TCC()IlllIlClldcd . The pl\.1rmacQlogi ca l act ivity of SOIlIC uIClaoolitcs has led man)' manur:acturel"'l 11.1 symhesi7.c these melabolllcs and 11.1 marl<el them:tl: separ~tc drug cnlllle~ (Table 4-6). Forexal1lpic. Q~)'phcobul:U:onc: (T;mdcaril. O~ahd) is the p -h)'droxylaled metabolite of the anli- inn:ulllTlalory agenl phenylbutazone (B ul,lIZoli din. M .olid ). nortriptyline (A~enl.yt) is lilc Nocll"IClil)"lated melabol ile of the tricyclic aoljdcpre.\~3 nt IImiInptylinc (Etavit), 0.\31.cpam (Sera~) is lhe N-del/lCthyl:llcd

...

:l -

..

CH,
DCH,

-r

N '

)-- N - NH, f
\

""" ""' anli

'm
pho

H2N
T' mel/lOJlfm

N.QOOe FormelOl

,,~

"" "'. ON. """

'00'

side

N H

"'0
~

Ih'c

"'."'o"
dc\'c

I
H0tyCH, 'CH
HO HN ....... H /CH 2

.0<
I '
C

Illmi

CH,

~ ....... H ....

ethy lSlra

.""'

inn.

'

"'~ dat1

"'" ,""

TAJlE

t....

~l'l'n.c:ologic..II)I

Active MeaboHtes In Humanl Melabollte ttydtoll'fhelUlmide

Norat)'lmethaclol NOI1riptyllM
6-MtruoP'C op!.lrtnt

............
.'oib4'I,WIII"
.....-hioprinl!

Biotransformation
Ketone reduction N-komeIhyIat1on
N ~methylatlon

Pre<ess

.lctl,."uhldol

Glutllthlon' (onjU1lation
Epoxld.ltlon

-.. ""'... ... "" ............. ..... -""""'" -........... -(Nor" hydl'lle

c.rtNo .... lt'~ine

(Irbimueplne-9,Io."po.1(Ie
TrKhloroethlnol

CNoo po Oo'I\lIrine

1-Hydforydllorpromuine ChlorQp/'lenol<)'isol>trtyl''' add

HydrD(ortl Wle
Delmeth~ldllZep;ilm

AldehycM reduction .vom.ti( lIydrollyLluon Stc<" hyOro/ySi\

KetOtIC rcdU(tlan

"lid O~lZeplm

N-Demlthylltlon and 3hyd,o>l)'1l1lon

Do9iloxin

DopNoooq'lale
~~

Dlg""ln Olpheno>l)'1lc Idd Oeslpr,m lne Phef'IObartl<uI

Alkydlc

h~rolC)'latlon

E1I., hydtolysls

o-H)'dfl*)'methylmetoprolol
Acetaminophen
OlC)'boJtazone

.,...,.Uin

I'ItdNsone "'"' ib...

().o;nldine

Predn,soIone
Pherlobarbltal
N-Acety!prOUllnllmide . ttydrolC)'propr anolo!

)H yd rOlC)'Qul nidi ...... Sulfide mellboIlle of wlind..;

Thior>dolrme

Mesorldnlne
Wlrt"'n akohok

N-Demethylilion N-Oemethytat ion IIef1zy1ic hydrl*)'l.tlon O-Deethylltlon ...... omatic h'fdroxylllion Ketone reduction HydrolC)'latlon wid ooodiotion to ketone NAcetyl.tlon Aromatk hydro>l)'1l1lon Allylic hydro..y1.1Ion Sulfoxicle reduction S-wldilIIOf"I
Ket_ recluction

IIId )h)droxylau:d mcmbolile of dia1.epum (Vulium). and -..ialtlll: (Serenli l) is the: sul foxide meboolite of the -.pI)~ilotic agent Ihioriduinc (Mtllaril ). AlIlIllnm tIt.lllR used in lreating herpes sim plex virus. 1~1I~WMer virus. and/or human cytomegalovirus must be lNoiIctivllro.,JI Thc:sc: include acyclovir, v:.locyclovir. )!CICII:lo>lr. famc:iclovir, and gllllCiclovir. which must be . ., !bltd on the pt't1tose-like side chai n to the triphos~ dniutac to Ix: cffective in inhibiting the cm;yme Dl\A poIymense. The anliviml ci dovi. is dispensed as II .K~tt and only nds to Ix: diphosphylated for ..... eI\IOII!O the: .... i\"e tripho<;phalc: metabolite. The nLICleo~ l1li1\ 1 ,* lhat an: used in treating AIDSII-I IV mUSI also IIdrrJo I SImIlar metabol ic COll'"er.;.ion to the .riphosphate IIIttMlohle J " The triphOlip/mtc deri ~lltive !ICe as II. compeeis lYt inhIbitor 0( the Cltlymc:, re\crse trunscripta.o;e . .... hich -::;::~.~ tJw, triphosphoryl:lled form of nLIClcic acilb. f.J tocl~ t.idoHidine. <lD vudi ne. l.akiulbinc:. lamitlldllll:. and didtallOSine. ()or o(!he II1OI""e recenl UM:S of drog mc:tubolism in .he *,doprtUII of I novel agenl illC lOOi'$ lhe unmple of 0IiC1 lir IICIDIlIlnKbsc inhibitor used in treating innuenu. lo-().I-{l802, !he lead drog. sho .... ed promise agai nst both Idluenf.a A and B vi ruses in vitro bul was 00\ ~ery effective _11m u~ In Ii~o. To Irnpmle the oml bioovailability. the db~1 nttr. osclwn,\........ as dc'eloped as n prodrug. AdmlnIiIIlIOII of !he II1OI""e lipophilic OSC ltami l ir allowed good pnItUlIIlOO of the: acli vc mecabol ite in various li ss lICS. cspeOil!)' III lhe Io.... cr rcspirulory lmel. The melabolism procuds III. SImple ester hydrolysis 10 yield the active rn:e c:wbctl)bo: acid.~

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1

w,ll........ R. T Deo<u_~_ _ 2ftd ..... New Y<;d.JaIIn

wiley '"

2. Dra~. 0 E. : Oln . ~11IeI I 426. 1976.1. Dnoy.r. D. It: :M:~19. 19111. 4. JoI",,". D. J.... -.I.: Bi.oIot:kaI RollCtlve 1 ~1lI''''' No .... Yori.. PIo.. m """.. 1m. , 0 ,1",. J k .. .. -.I.: ...... Rev I'IIarno8coI. 1' :17 1. 1 91~ 6 I"o<,--S D .....I Jrn. . 0 M (..... 1. MriXloI_ C__ '" ."... 111' ...... "''''''. nc . Chornocal Sor ... y. 1977. p. t '~ 1. Te-'<tL 8 .. "" J~n' .... 1'.: DnIJ M~u.b Itev. 1:}U, 1\l7~. 8 Law. L C....,...,..~ N. jt . In Wolff. M. E. (.... ~ & '1"'., M."lo;:oDal o.-.SII')'. Pan t. ~dI ..... Nt.... Y<d., WiIc}. I..........,. 1\180. p- 107 9. Gdl. E. 111' .. .. II. 1I_lk m. l'Iwmarol.ll: IH. '97}. to. WIll. M. Ii. .. II. : J Am. Clw:m. 50<. <).i;IU79. 1971II l ...,n~grI". L , Dnli Metab. 00"..,.. 1:641, (91) 12. 0...-.. D. E. . .. 01 .: In V"u.... J A. (..... ~ Cann:obIOONI A... ly ... t. ...,.....,......1 ~l'-" 111'............ DC. "'n..."" Clot..... So<ooIy. 1m, p 9) 13 Willi ...... It. T In 8rodk. 8 . II . ood Gllkuo. J k . 1M). Conc'"!... ito ll oocl"w:tnkoJ f'hartruoC""'IY . ...... 2. Iktl,n . Spnn ..... V.. lq. 1911 .

s.-. 1OW1

Dol"

"'men<...

'n

DnI,

K.."'"

p. 126.
14 ~Iand . M~ Id Md_ K.. 1..."'" ""'"'Ill. II f ,.~ alllocal ~ IIII.Ic: Pnoc.,... ~ ~ 2ftd ..... New

Von..

IS.
16. 11

tl.
19
3).

22. T....... 8 .. ................. I>no&MNI>oIi...... a

................. N<o .. Y<;d.
MOtttIIld~ ...

21. I.e,y, G ..... ;m:J C"""h ... J I" I:M.... O. J (..... ~ OI\lC\ll\)lK: Aclol, f .... Mol COnIbIIOld. New Y,.I... At-' r PtotY. 1966. p. )(11

"S. 1 . m

Morno,11on, 1971l. p- U tkn<roo" .. N. L,...,;I Mcl ...... III' . Cl . ~"'". 3:111. 191. C""II<>l I ~. M. It. .. AI.: Ik J I~ 46:0fS8. 1972. Ooboldi. ~L ~ O. Dno, ~kub. Rl:v } IU. t97~. S;M.~b."'. "'~ YllI: .....-..\;y. S II J f'baom. Sci MIS . 1975 Scl.. I..... R. k . 1'IIMmao:oI. k" U.4S1. 191) M . ..... - ' GoloJmon. P . J I'IIarnUlOOl ~:'p. """ 181

f'(,,"".

"'1'1"'''''''''.

'........ B....... mo
~19

197/1. P

C .. UIJ J...""... \.. 1'Iutmo>I. 'Tbrr 7:M. 1979 N " ' - II S A....... ~ y 8 ....1.,.. .l4 m. 19M. ll, tb),,b.O .. In H.)'*I,w. O. (cd.). o..n'" a .. . New yon.. A, c ' a .. ~. 1962. p. I !i> M.I\I"';"II. C J In LaDu. II N~ Of 01. (cds ), Fun.l ..........I. 01' "'.."1,0" .......... I>O""".lIon. blmn...,. Willoamj.t W,ll,n,. 197 1.

~. !'mo ...

IhioDe.
,~

MetaboI,,,,, and 1'"_... New Ycrt. Ita.... ..."... 1976. r

71>.

27 SMa.
2g

.-

Dru.

II.~ .....

o.r..... T, Iedt.~ C)",,'1IrunIo< P-4~""'" 'I'm.. .....

................ 1978

Bioi Chmo. 2.)')-2370. 19M 29 C.llclie. JR . AIJ'y ~ 4119. 196t>

o.-a. T,. &DJ S-~ R.. I.

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In 00mxI , I W. (td, I, tI'<>i<>socal O.tdaoon uf Nit""l"~. A~. EI_ier Nonh lIolland. I<J7K p. 383. F.omy.." A .... a l.: Am. I P"y<hiotty 1277. 1963. Throh"M. W,," ot. Mod. Pharrn.ro:oI. E>.p 15,187.1966. C"""" R...nd Ik<:l.". A. II Dni, M... b. Rev 6:" . 19n. J.,t;nwobtr. F .1.. ...1.: J. Pharm. Sci. 66: I ~711. 1977. 1Ie<:~<1l. A H.. and R""Iand. 1.4 .: J Ph.rm. I'b:orm>(Ql . 11:1095.

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' 72. 5100 ..... H~ III at. Ckm. PhInn. &.II (1"01:)'0) 211U. 1913 473 , Morpn. C. I) .. .. aI.: B"",bta J 1".8P. 191\9 474 W....... R.. """ TUlI\e. R.; inC""''''''' M. E.(..n~ cal _ BlQChtmicall'ropenoa< of DnI& SUtt.wo<a....... 1 WNIon.. ..... IX. AiiIooricM Pharmocculo<al A""""u.:,.... 1977. r lOll
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SIIme . ll . Md Abboo. S. fu.I",I"'ou.29 ItIt!. 1973. Bkid""". W F " I I I. Pharmt.coI. E>.p. Thtr 1!I0484. 196j ~. K"""";. Y.. _ Sond;". Y.: I Bioc .... m. 6' 16.1. J'I26 !.indooy. II; II .... at Bioc .... m. Ptwznoo:oJI. 24:'fiJ. I91S 4t1t!. II..,,,,,, . J . _ Orten""'.. I), M.; BioctI,m. B1OpII1" A<II 46 217.
4111. AJ ..... P W. ai, B"",Iu .... 8 """,ys. At7a I 14 M1. 1\l6(). 482. F J_ . G B I"'" ..,.,.. 26:l19li. 1967 483 Tot;o.B ..JJe...... p Dru;MctIboIi<m Cht Ii ....... BII)(:...... caL A~ Nt-<r V..... roton:d Mk... 19111.. pp 329 - 4 " 48-' Tem. II.. ............. P' DnI, ~_ !leo , 11:1. I9tL M ..... M . ... R.;dy. 0 F: PIamoanJI. llotr 42 IS. 1 9\10, <l86 M.....y. rot 0115. _ _ lIItI. 23:132. 1991. 487 W..... R. M . " aI J. A~I G. 5 (ed.) Dno; T..,,,,notn! . .... ed Sy:lntyl APiS l"rm. 1980. r 76.
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Anden.. M W (N.I: B.....i .... _ 01 F...~,i" C""'I',,,,,.il>.. Sew Y\N"l Andom .. Pro... 1985 S-k. R. C . R.. It. o..,.-oii'KlII <lI T.... ic Orup'" Cbc:mI<IIb in M.... ,,_, Ci.). CA. Cll<:m ....1 To.iroIof)- I""M~. 1995 Iknronl. O. J. B~ J W .. """ G ...... 0 0 ,...... o.-u, Met*>1..... _ l'rum Mol..,,,1t> '" M.. Londun. T.)"" & nW":;j. 19'111. 1I.""ie. B B. """Gil"" ... I Il (ech ). C""""P" ,. a..... ha' ....""'!'born: ,4 "1)' . ..... 1. &do.. Spn V' V~ ""1 Caklw<:ll. J . CooJIrIl"I"'" .. ,n ' .... ' Ift """"""'" ~, ..... DrVf M.ub ~V. 13:7'S. 1'I8L CaId"",IL t .. _ Jok",,>". W D. , ..... ): BooIuf:""'l fkw~iflc"h... 1'1 ..... Yon:. Andoml< ~. 191B C"akl-'dL J~ ..... 1'aItI_. G 0 (td< I' Foml~ C" """"", M.lliboti .... t...Id<o To}"" <II. I'ran<". IYI\.I C....orey. W A I>noJ! o.~""," .. 11. - , Neo.' yon.. ad"'" U"" '<N/)'

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Prodrugs and Drug Latentiation

fORREST T. SMITH AND C. RANDALL (LARK
ing cnlymcs. aod therefore. less Intcrpolticnt "ariability III acti valion is :;cen; since: ~uc h compounds are chemically un stablc , however, >lorage of thcsoc compounds may pro'iCntl problem. Pmdrup ellll be con,enle'ntly grouped into camer-linked prodrugs and bioprecursor prodrugs,' Carner-hnked prodrugs are <Jrugs thnt hnv;: been attached through n metaboh cally labile linkage to :l.nother molecule. the 5()-Callc:d promoiety, .... hich is not necessary for IICIh'ity but may impart some deSirable propcny 10 the drug. such as Incn:a-sc:d hptd or water Ol ubilit y or site-directed delivery. Sc"cral a(]VIIIl' tages may be gaillC(J by gellCTllting a prodrug: increased ab.;orption.Ile viation of pain at the si te of in)tion if the agcnt i~ gi,'en parenterally. eliminatioo o f an unp!easantlJlSlt associated with the drug . ~ased lo.icily, decreased IT1O;'tabolic inactivalion. loc1l:ased ci1Cmical stabi lity, an(] ~ longed or shortcned action ..... hichever is de.~ircd in a particular agem. An C(amp\c: of such a prodrug form ci chlOf1lmpheniool is provided below (Scheme ~_ I).o Admilll~tration of a drug parentcrally may cau'iC pain _ the ~ite of injection. especia ll y If Inc drug be~ins 10 preclpi' tate out of r.ol\l1ion und dama~e the ~urrounding ti s.~ue. TIlIi sl tu.uion!:an be remedied by ~puring a drug with iocrellSQl 'IOIubilily in the .adminlst~ sol"ent. Since chlor.nnphcnicol has low watersolubilllY. the succinmecster wa.~ preparN to increase the water so lubilit y of thoc agcllt Dud facilitate paren1Crul admini~Ir:lIIon. succi nate ester itself is iow li\"c as an antibacterial agent. so II must be OOI1"CT1ed 10 chloramphenicol (or this agent to be effective. Thi s ooxun in the plasma to give the acth'e drug and succin:ue. lbt: wn hydrolysis reaction can be eatalY/.cd by e'tcruo;es prc.<;cnt ID large alTl()\Jnts in the plasma. The ability to prepare Olntype prodrugs drpc:nds. of coursc:. on the ~ of eilbaa hydroxyl group or a carboxyl moiety in the drug molecule: 1l1e promo;ety shoul(J be easily aod oomplctdy removal after it has t;(:rved its function and should be 1KI1110xic. lIS il indc:c:d the cone with succinate. The: !OI:lc:ction of the: apptop,," ate promoicty depend!! on .... h.ch ptopc:nic:s are sought fa !he agcnt . Ir it is dc:sirnble to increase watcr solublhty. Ihn a promoicty ".'ontaining an ioniJ.lIble function or numcroul poIlU" functional groups is used. Ir. on the: other haod. the gOll is 10 increac lipid solubi lity or decrease: W lUct \OIubility. I nonpolar promoicty .~ appIOpiiatc. A slight variation o n the: C(Jrril'r I/III;~d prt//lTUlJ appro.ell is secn wit h mutulll/mN/rog.< in which the camer also hM acli vity. TlIc: antinroplllSlie agent c:strarnustinc. which i; u5Cd in the: treatment of prostatic cu~r. provides an e..a.npic of such an approach (Sche:me 5 2).J E.... ranlu~linc is COllIjX>S('d or a phosphorylated steroid ( 11 u-estralliol J hnked 10 I IlOI111usiard IHN(C HlC H.C1hithrough a carh:imutc: l inh~. ll1C steroid por1 ion of the molecule helps to ~'()IlCel1lrate ~

HISTORY
In 1958. AIbef1 initially coined [he Ie:rm prot/rug and used it 10 refer 10 a pharmacologically illllC'li vc compound thai is transformed by the m:unmalian sy~cm inlo an active sub51 ancc by either che mical or metabolic [llcuns. I Thi~ included both compounds thai are designed 10 undergo a 1r'msfOl'11l:l. lion 1 }ield an acth'c MIb5tancc and Iho6c lhal were discov0 emf by Sl'rc:ndip"Y 1 00 so. ~ 1\000 Si Hl3liul1~ IH"ft: dis0 lingui~hcd by I lm"pcr .... ho in 1959 imroductd the lerm drug i(llt'nlilltitm to refer 10 drugs thai ... en:: 'pccifically Oeliigned
10

n:'quino bi~1inllion. l 1besc Idea!! led 10 tnc development o f 11 number of cur

rently used drugs thai have advantages o\'cr the ir nonpmdrug COUnlCIP-1"" 1ltc: type of prodrug 10 be produccu depend~ on Inc specific IISpccl of the drug's action thai requires imprm'cmcnl and the type of fuocuonalny ThaI i~ pw;em in the actil'c drug. Grncr:llly. prodru, 3Jl1)11Che5 an: undc:rta ke" to impnl\'c patient acceptabIlity of the agent (i.e .. re(Jute pail"! a~sociate(J with 8dmini~trutiol"!). alter absorption. alter distribution. aller ulCtabolhm. or alter eli ",i natK:.o.. The chemical rullu~O(!he prudr\lgs that Uti be: pre~ i~ some_ what liml tc:d.. however. by the chenllc1l1 nal.U~ of the :letive: species. Recent ly. lhe terms hlm} dmgs and soft drrtgs were i"tToduced.' Hard drugs are compounds that all: designed to c:om.:l1n the stOlC"tul"JI characteristic~ necessary for plwmacological IICt i~ity but in a form that is 001 5u'iI:1:pti ble to metabolic Q1 cilcmicaltrllusfommuOII. In this way. the pr0duction of any toxic metabolite is avOided. alld there i~ increased efficiency of action. Sioce the drug is 001 m3oCli~atoo by nlCtaboll~m. it may be: \c:ss Il::l(illy climinlltc:d. 01\ the other hand. soft drug~ arc 3oCIi~'c compounds Ih:1I anCl"c~en ing their de,ired phurmacologiclll effect are designed to undergo metabolic inllCtivatioo to give :I. nomo~ic product. Thus soft drugs are considered to be: the opposuc of prodmgs.

n.c

BASIC CONCEPTS
A prudrug by ddiniuon is inao..Chc aod must be: convened ' into an act ivc spec ies within the biological system. 'There are a variety of mcc h:mi~ms by which Ihis con"crsion may be acoompl ishc:d. GcocraJly. the conversion to an active form is I11O>t onen carried out by mc:labolilj ng enl)"nlCS .... ithin the body. Convefliion to l1li acti ve form may be: accomplished by ehernk ~ 1 nlCans (e.g., hydrolYM' ordecarboxylatioo), allhough this is les, ~'()nllnon. ClK'mical trallsfonllutiOll does 001 drpendon the prcsenceor relatl'e alTl()\Jnts of metaboliz-

141

ON

ON

0,'
I)' In

O, N

ON.

o
NO ON.

y lin

ICnl a

",oJ
prop>-

Jhvh-

o
S<rim Su i"
111

""'"
pro"....

lipid hanII 30-

~~

~Ia

Or
Th"

".,.

'PI-

here hydroly~is oceurs 1 give the 0 PmulUrd The lIOffilustard the" OCb as an 1111.:)'131III ~I IIIIIJ (lertS a cylOlo~ic effect. The 17a-cstrudiol . . I\oIiI III IIIIliandrogenic effect 011 the prostate and, "iiI . ........, the: P'O'I'Ih of the carocer \:ells. Sioce boih IIIr Mm!Id oIIId the: muSlaru possess ..cIivit)'. estranlus.llne U Dad I_wi prodrug. NOli: that pnosp/1or')' lalioo of the MllJI(Jj I;aI\ be usailO iocrease the Waler w lublli ly.... hieh .., O'l!!\IUIlltS prodrug modifICation. 801h 1)'pt"S of esters cPoII~ and pbosphates) arc hydrolyzed by chemical or
CI1)~1C

*III I~ the

... IIJld CO:.

"""la~

nrMl.

IIme-

ital!:

ester
rll In

~u~

I. ,,\III!tiI to carril'rlinled prodrugs. biopn::cursor pro. on,. COIIIiln no promoiCIY but ruiller re ly 011 rnetaOOlbm IIiIlnlrod\1!:( the: functionality nl'Ce5-.ary to creale un aCI;"c wpa:1tS For uample, tile IlOnslcroidnl anri-innummatory ",(~SA[D) whndac IS inadi,'c lIS the sll "o~ide and must IIr ~ metabolically to the octiy.: M llndc (Scheme

S-])." Sulindac is adonini,tercd orally. abSorbed In the ~mall inlcstine. and subsequent ly reduced to lhe acuvc specie.~. AdminiW:llIon of lhe iROCli~'e form has the benefil of redueing the gastruintc)tin:lL (G L irritalJon associated ..... ith lhe ) sulfide. This c~nmple also illuSIr.lIes one of the problcnu as<;ocialed ,"'Ith this approach. namely. parttClp;ltlOO of altl'1"nate meUlbolic paths thaI m:ly maclivllle. the compound. In this case. after ubsorptiorl of 5ulill!bc. ine\'Sible rrrlabotie o~)dauon of the sulfo~ide 10 the ...... fone can I1lso occur 10 gi\'e an inactive compound. Although !On ~ frequenlly. SOIJI(' prodrup rely on chemical mechanisms for conver,;ion of the prodrug 10 11) IlI:live form . For example. hctacillin is a prodrug form of ampicillin in which the ~llIidc nilrogen and a-amioo funetiooalilics have bl.'cn allowed 10 reacl wilh ace10ne 10 give lin imidalOlidimme ring system (Scheme 5-4).9--1~ This deere3l;C5 the basicily of the o-amioo group and :du'5 pro-

1,00,oJ
r~

:u1c.

h" pri

CI~

p
0

NO

S
I)'. U

, .JL,

,,~

'"
fIII.,- r!

NN

c, ~

'0' ,

..

c,~
Ib " card

. co. .

< po.

,..

Scheme 5- 2 ActNallOO of I'StsamuShne

'44

"',/soot DntJ Gi<.'OId 's Tt.}t/)onk 0/ O'gullk Mrriici",,/ ",UJ Pharmoc~ulicul Chr",,'slry
Ad"."ed P ..:O\lg

o o
".
I

'~-

'.",,,,,, ~ .

'~-

O ~I

0 0 ".
t N.

.......
(.L " .. )

gu
(Ir.adl ..)

"" =
~lJllndiK.

S<.heme 5-3 Metabol.sm of

tonation in the small inte.~tjne!if) that the agent is ~ lipophilic. In this manner, the alKorptioo of !he drug from the small in tC!l.ine is I/lCKOsro after oml dosing. and chemical hydrolysis af.er :absorptioo regenerotell ampicilli n. In soch an approach. the lidded moidy. or promoiety, in this case a:tonc:. mils! be OOIlloxic and easily renlO"oo :after i. has performed lIS function.

c- bgxytlc Adds.nd A.nh ....

Pmdrugs of :.Igenl~ th~J contain carboxylic add or alcohol fUIICtionaliucs can often be prepared by con"cf'lion to an ester. This is the most COlllnM)n type of prodrug ~1Iu;.c: of the case with which the eMCf can be hydrolyzed to &,ve the actil'e drug. Hydrol ysis is normally accompli,lIed by C!ltel1lSe enzymes pte!ioC'nt in plasma and OIlier tiSl;ucs thai are ca~ble of hydrolyzing I wide variety of estcr Hnkaga (Scheme 5-5). O loc.luded below are I numberofthedlff('rePI J types of (';Stel'llSCS that prodrugs rnay U!ioC' :

cit pr

". -.

ho

"" "" ". -.

'" "" =
~

00

PRODRUGS OF FUNcnONAL GROUPS

As mentioned above. there are a \/lIriety of different types of prodrugs. and a comprel1cnsive di~us..~ion of each intlivKlual agent is beyond the scope of thi~ chapler. 'The major types of prudrugs (grouped according to functionul group) and blopm:wwr drugs (grouped according 10 type of mcubolic activat ion). however. lite di<il;:usscd briefly be low.

Lipase Cholesterol

.....0

Do

Acr'Y~hoI;~

Carboaypeptidase ctx.i1ne!;lerasc

." ,,,

ocl

HH . HH

'"

'" P"

HN - - --e H .

0 0

I:OO H
I

H,O

o
COO H
II t
I

I~ II... ""

5<heme 5- 4 I-tydrois of

hetacll~n

Chaptn oS I'"td"", unJ D"'~ UlI~/"'/JI"'''

145

o
Drllll-C-o - Promolety

o
OrulI - C - OH

II

II

,
o
DlUg----()

HO - Promolety

-.JL

p ro

mol.~

Dru g--O H

Ho ~promOlety

Scheme 5- 5 Actr.ratiOO of esler PlOOfligs

10" I'" of
gl~e

""""

d by

;og~

",.,

crenl

1m adJllIon 10 these a~nl~. microflor.a present within the pi prooJuce I .. ide '-andy of enl)'mes WI call h)drolyu tam. Clltmlcal hydrolysis of the 1eS ....... fuocllon may also 00X'\Ir 10 loOIl'Ie ex~nt. An addillomll foctOl' thaI has conlribIIItd 10 !he populanty 0( esters as prodrugs is !he case: wilh ",lIld, rhey can be fonned. If the drug molecule contai ns nthrr 11\ alcohol or carbo... ~hc acid functionality. an ester ~ll1Qy be ~yn lht~ittd easily. The carboxylic or alc()bI~ JTUlllOlel)' can be chose n 10 provide a wide mnge uf h!lO!*IlI~ or hydrophi lic properties \0 Ihe drug. depending OIl 1Ihi111' desired. Manipulmion of the steric and clc~11\II1ic PI\'\X'rtleS of the promoiety nllows cOlllm! of 11K role and lmI of h)lIroIyliis. This elUl be :Ill unIXlnanl conidcruliOO ,,11m die .-live drug must be n:vc3lcd III the com'Cl point II> mo'clllC'lll through the bIOlogical sy\lem. 'Wln 11 is desm:tl lo dttrease wat('T" soIubdu y. a nonpolilf IIrohoI Of carbolyhc acid is chosen as the prodrug moiety. DK,ttil lII the lIydrophil icil )' of .he compound may )'ield a ..... of ~filS. incl ..(hn~ increa!;Cd ab.iofplion, de. atastddiuo/ullon in.he aqueous enVImAlnem oflhe "lorn' ldI,and. Jongcrduralion of action. An example of inrn:ascd a.".!On by ,he addi.ion of 11 nlnpolnr cnrboxyhc add is 1" Illth dlpi,'cfrin He l (Sche lllc S6). This i~ a prod",!: fillTll of epmephrine in which lhe cD.cchl1 hydroxyl groups hlolr bttn used in ,he fOfm:uion of an c.~,er linkage with !,,,,ahl; n. I~ The agenl is used in Inc treullnen. of opeoqlt I~. The incn:nsed hpophih!,:lly rell1l;"e to cpi-

11M: agcnL, ... hen apphed . o nlOle 3iC1OSS.he fTltrnbrnne lhe eye easily !IIld 3iCh..., ... hlshoi'r IOtnlOCu l;u COI1CC'nlr~tioru;. 11)'dml),sI'" of ,he ester fUOCI ions lhen oceUN in .he romea, l"OOjunc,iu. and aqueou~ humor to generate lhe act,,'e form. eplJlcpbn~. Using p.vulic K id as the promoiety U lCll'ascs the sterie bulk around the liCi!>.\ile ester bond.... h.ch ,10"'5 the ester hydrol Y"5 rel3tl\ e to less bulky grou l)~. ye l ~1I11 allows this n:actiQn.o proceed after the drull h~ cms..cd Ihe membmne barriers of lhe eye. In addi,ion '0 Ihi ' hoi'rlClit. the catechol sy,lern i~ somcwhat su~cpt ih le 10 o~idat ion, and prOlC~ling .he catechol as the dic..~ter pre"cnl~ thi s o~idat ion and the n:~uhing drug inac,iva,ioo. DecrcasingttIC water ~Iubility or II. drug by tnc fOfmalioo of a prod"'g may ha\'e :iddiuonal be~lits beyond \imply IncreaslnS absorptlOl1 . A number of agenls have an unpleasant taste ",tlCn tI,,'m orally. This results ... hen the druG begi ns 1 djs~I"e In the mouth!llld Incn is capable or interact 0 ing ... illt [asle fC(eptOll. This can pre'iCnt ~ sIgmflCan., problem. especially," pediatric pa.ients. and ma), kad 1 0 low compliance. A prodrug wi tlt redllCC!d water .olubllllY doc:~ not diswll'e 1 an) appreciable e.\tcnt In the lIIoutb 0 and .ncrcforc. doe. not inlerac' ",ilh m~l e receptor;. This npl'rooch has hc:en u'iCd in the ~a.w of IIIC 311libaetena l chlO!" nmptlCnicll. whi,'h produces a biner [a.,te when sive n 1I.~ tbe parent drull (Sebernc S- 7). The hydrophobic ",1lmitale ester doe!; not dis..~he to poy appreciable exte nt III lhe mouth. w then: I ~ Lilli e chance ror interaction with tas.e fC(eptON. "

~phnne alll"'~

or

OH

CH.

'".
0

CH. CH, OH CH, N H.

HO

HO
F ',.111

0
epinephrine

OJ

NH .

a E>

e
CH.

OJ
a E>

'".

OlpMlrln Hel

CH'~OH CH.
xheme 5- 6 Hydrolysis of dlpM!lml HCl .

CH

OH

0"

0,"

o
CHl(C HZI,. -,ILI- '0"
P"j~dc

'" '"

ti

" "

si

Add

5theme 5- 7 Hydro!ys.s 01 chlolamphenocol pcllm'ta te .

The ester moiet), is subsequcntly hydrolp.cd in the G llme!, and [he agent is a~ as c l1lornmp~nicol .

Listed below are II number of OIher aBenl'i Ih.:at hal'C been convened into ester prodrug;; und other types of prodrugs to
ovcn:omc an unplcMill1t W it :
palm,llIIc N-Acelyl Mltfiwu'Ok
N-A.'Ct)'llul r~IOO~)'pymb/.ll'"
Ch\Qram~ruool

Ef) lhrom),!;,n e)OIobie

Oind;omye,n palmltale

Not all carboxylic t'Slc:r are ea~Hy h)'drolyzcd in vivo. Stene inhibition around the CSter in some C~5 prel" cnts the prodrug from being hydrul)'l.cd. This is 54.'t'n in the ,B-Iac talliS, In .... hich il 1$ often desirable to iocre~ tile hydl'opt... bidl)' of the agl'l1l 10 improve absorption or prevent dissolu tion in the stomach where add<alalYlcddcCQllIposiUoo 1l1lI)' occur. Simple esters of tile carbo" ylic add moiety, hoo,r,'(,VCf. are not hydrolp..ed in "i~o tQ the aclh'c carOOxylntt (Sc~ 5-8). A soIutioo loth,s problem ..... as to use the so-called double
e.~tcr

Toukandomy.-in

apprwch. in which an additional ester or carbona!!:

"-- 'E......
H

',..---,.-'_ S

I-N -YC:I
CO O R ,

C"

Eateilll

"
o

EEls E21

1-"'-0

R,

COOR ,
R J Ed. P,opyI, Butyl.
PI_l~

Stheme 5- 8 SImple estefS of P.lactams With

fts6\aI"lCl'

to enzymatIC hydrolysis

Chapttr !i Prod"'gs und 0"'1 Unr",illliOft into the R ! SUb'itlllH.'llI funhl.'r rem~'" from the hdcrocyclic nucleu,.Il. 1'1 Hydrolysis of I fu!lC1lOn IlCCIIImI ~ily. and the moiety was selected III thai dw:mic;a] h)droIysi$ of the second cster occum:d k'II". Th~\ Iii it\'n in the ~C'phalo$ponn ccfpodoxime pro1rIlI. '" hac .carbonate function wa~ used (Scheme 5_9).10 Tbe tarbonate is also susccplible to the ocnon of esterase ~,m", .., the unSL:lblc product undcrgoc~ funhcr reoc:td II IIlCotpOIakd

147

ccphalosporlll!l (cc fp<l(kuilllc proletil has bern

da.s~irtcd lIS

.m

both 3 Sot'!O)II(I- and I Ihml-gCnC'r,!.Iioo agC'm) so that these agent.'l can be admi r; L\t~ orally (see Scheme 5-10 for sev

10 I"c the IICt;\'e carboxyl3te, Thi s approach i~ fre~lItly u~ to improve absorption or prevent d;~solut;on !he ,t!llll3Cb and the SUbscqUCIll acid-catalYl.Cd dccumpucion 01 Imlnoprnicilhns and St'Cond- and third-generntion

eral uamples), To increase tile hydroptlilicily of an agem. sc\~r.al different tylltS of ester prodrugs h;tl'e been used, ioe luding succi nlltes. pltosphate~. and sulfonates . All are ioni7.ed al physIOlogical pH and , therefore, ioerease the water solubility of the agents. nmk;ng them more ~u itable for p:l/"enteral or oral administmtion when high water solubi lity i~ de~imble (Scheme 5-11).
Succinale e!>tel'$ containing an ionizable ewboxylate al"C

....OC H ~

"
,/OCH~

(1', '''''IiI)

C H, CH, 0 - t -0 ---"--O--<CH
CH~

II

F . 'PI

co,

CH, H -O--< CH,

k .... On.og

Scheme 5- 9 I-fydrolysrs rnethanlSfl\ of (efpodoxJrne p!OKetd

NH

NH

H ,

Ny

"'-/

OCONH t

o O--(:H - o-"lI_ cH
CH.
~"'H2.

NH

r--

H .

CH,
' CHI

/- N-.../

O~O -C H -O II
B"a,.' .
CH,

o
OCH,CH J

SCheme 5- 10 SOme l'Xc1mpie-s 01 double Mters of

~Iactams

o
D"'1I -O..JL C H 2-C H

o
Drug - OH

zLO- N "

HO -.JLCHz- C Hz L o -N ..

o
II

- -_.. Drug - OH

DN9 -Q-P- O N.

I OH

II

HO - P - O N

I OH

Scheme 5- 11 Surona!e and phosptlate estel1

IIId.I wbm!1pid In ~i\'O hydroly,.js of the 0::>1.('1' functlonal~~ io.ltqUlm!. 'The rapid h)'drolyM~ i~ related to the nur .. ....uJao IIIl.11.:l or the c:trbo\yl:llc on the ester hnlagc, w!tiel! Ib'I. no! ~Ulre the pa"lIclpation of cnqmc:s \Scheme 51ll. AI a rt5ull. lhc.sc agcms may be somewhat unstabl e 111 ..,jillIOn and shoulu be dbsoh'cd immedi ate ly prior to

,no-

of akoho!~ 01T\..,. another method of ill" 'IW "'ilkr solubilit y of an age,", The ~phatcs ., .ompIctdy lOIIi,.ed 3t pby~lologicaJ pH and gCl1(':r,lUy h)dn~Ft'd raPIdly in ''1'"0 by phosphmase en/.rmes. 101li/auoo or tbc phoSph~IC fUllCti on impm1s high stabilny to these .Im''ltl~er; in 'IOIutioo. and !iOluriulis for admini stration can ~ IIlYtd for long periods of Ii me wllh<M.J1 h)'dtoIy~i\ of \he'.' pl'''!'' ''' Such IIIl approach has been used 1 produce elin0 _"n~. ",tlkh produces k:l\S pain at the InJCClion ~ thMdmd.tmycm ltsc' tf(Sche mc 5- 13). Pam aCler parenttnI-.lmlOl\lr.Ition is usoci:u('(! with local irritUlioo cu used b) 1000 *l1.lC()tI~ w lubi lity or highly acidic o r ba~ic solution ~, Wllb dindimycin p/IospIlate. tile reduction in pain i~ anribt*d 10 till:' UlCTC'ascd "'lIICr so lubility of the agent.
, , 77

adm.n.<.If1IIlOII. ~e ~

tide sen 'es to increase cellul ar uptake by use of an am ino acid transporter. n.c: :m1ino acid., are then clca'cd by specirlC peptidase en'-Yme$. Amon:: rommon approach has been 10 use Mann ic h bases a.~ a prlldrug form ofthcamirICS. Mannich base~ resu lt from the reaClion of twO amitlCll with an aldehyde or keHlne . As secn wilh hctacillin (see Sc hemc 5-4). the effect of fornllng the Mann ich base is to lower the ba!.icity of the anllrIC and. thereby. Increasc lipophilicity lind absorplion . When nitroge n is prescm III an IImide hnlage. it IS!KlITICtimes del.irable 10 use the allude nitrogen a~ one o f the aminc s necessary \l) funn u Mallnich base. lltis approach was u'Cd wilh the amibiol ic tCU":lCyclitlt- the amide nitrogen wa.~ allowed to ..-elK't lI<ith fOllnaJdehyde 000 p)'rrolidine to give the Mannieh ~ mlllctrncycl ine (Scheme S- 14).21 In thi S east'. addition of the ha.'rie pyrrolidine nitrogen InlrodllCes lin addllion:d ion i/.lllJ le functionality and lllCre3SCS the waler solubil ity or the parenl drug, llIc Manni~ h ba.>e hydroIy~.cs 'Ol1lllleldy and rapidly ;n aqueous media to gi\'e the active tctrncydine.

Aao U.kagll
Aml llC!ll ha\'c oc,asionally been ;lICorpor.Iled into an azo linkage to produce a prodrug, In (act. it WIIS on 111.0 d)'t, prOIlIOloi l. thm led 10 the dlf,(:Ov,ry of the sul ronaUtide~ as the fir.;1 amib:K:terials to be u<;ed to 1reat sy .. temk Infeel;ons. 22 Although prontosil ;1Se1{ ""'liS macth'e in vitro. 11 ,,'as OCt; \t

Dm,aulllllOll ofatni~ to give umides has 001 bcc:n widely u'ltll iii I pmdrug strutegy bcc:msc or ttt.:: high chemical ..ut>illt)' of 1M amide l i n~age and Ihe lack of amidase enI)...... ~ for hydrol y~ls, 1l1crc: have been effons al UII:.. poilMj; IrtlLlII'S inlo peptide Imhges in "hieh the pcp-

o o

o
~P,udoug

Drug - o H

Sdleme 5- 12 Intramolecular deOWil9l! of surooate eslerl

CH.
H

,
H

--< ,

NH -t- H
HO H.O

HO

o
HO -

HO
SCH 1

O =~-o H

.1-

an_hid" PI~

*
~te

H1PO .

SCheme 5- 13 ClIndamyon activatlOfl by

hydrolysis

in vivo an41 was COIl>'crted by al.O reductase enZyJnes in the

gUllO sulfani lamide. the aclive species (Scheme S_ IS).

age and generulion of U llIirlOSlllicyl ie acid prior 10 ubsorplioo

prevents lht systemic absorption of tnc agenl and helps con centrate the active agcll! al the si le of action.

Allhough pronlosil is 00 looger u~ a_~ lin anli~tC'rial. this Iype of lin~age appears in sulfasala1.ine, which is used
in the treatment of ulccr.uive 00lili5. The 111.0 linkage is broI.en in Inc &UI by the action of am r..-doctases produced by microtlon.. Thi~ relc~ the ac1ivc agent. aminosalicylic acid..... hich lias an anti-inflammatory effect on lhe rolon. and sulfllPyoomc (Scheme 5-16). The advantage of this prodrug approoch is Ihal the combination of clcavageofthe u.o link-

H'
H(

QlibaRyi C.lltp "ds

A number of different funt"(ionalities have been enluated as prodrug dl:rivatives of carbonyls (e.g . akkh)dcs and l eo lones). although this approach h:H no! roond wilk clinal use. 11lese nave cenerally invol\'ed derivati ves in .... hich !he

CH.

OH

N (C H l~

OH
....0

CH., OH

,:,(CH:I~

OH

OH
0

CONH:I

OH
0

CJ
I

Sp l

hyt

H.O

CO NH - CH:I

dil.ed c
nitroge !ionali! (Sellen unne, '

exampl
Rca lThKrch

C H, 0 f'... " aldehyde

(P""ug)

HNC]
P)".......

o
o

>-S NH , o
II

11

H,N -

>-. =. -

>-S NH , -

11

'H, , Prork
r

&Matt': t " (Ac:IiYe Drug)

H,

'H,
S<heme 5- 15 Am clE!avage 01 Pfontmrl.

HO
HOOC
~.

H,

lI:ion

HO -

0"--'"

= 1'1

-<O}-'~-N H - (
o '"
:

I Am Rulurt"l

Att.'

: " . 4c AcId

o
~.S -NH -(

,'" Ile-

507

!F

htlt

lI ical

H ,N- Q

. "" '
So.MlIPrtktlnl!t
s<heme 5-16 ACIlon 01 azo reductoN' on $u lfMaI/lzlnI'

" o "

'II' b)bn.b~ed carbon) I carbon is coo\,e rted to IUl ~p) hybri:be:! C1rboo attached to t"'o h;,:teroatOllu. ~uch as oxygen.
Under h) rJmJ)'SIS cond:uonS. these fuoc:r-.1doe'l an: _ Intet! 10 the carbon)'l compounds. An twrIfIIc of Ih ~ approach is mc:then~mmc . shown belo w t 3-17).:' Methenamine I1'le1lSL'S fO l'maldehyde in the .... "llIdllil:b lIS an anubactcrral agent by reacting with
1It:~ ill' "-!Ifur.

nuckophi les pn:<oem in bacteria. The agent is admml'ter::d in enlerie-cooled eap\ule.~ to Pl'Ott it from pn:malUrc hydrol ysis in the acid io: l:'nl':rt)IIment of the stomach. After dl ~' solution of the enteric-cooted capsules in the i n:e~lIne. the agent is absorbed and mou:s mto lhe bloodstl\'atn. Clentually l:'nding up in the urine . ""hen: the acidic' p/l calaly~e.~ the chemlClll hydroly)i~ 10 give foml.aldc:h)dc. U..c of :h:s

/ '

" ~.

~. ~

FOil! IIMrhrde

5cheme 5- 17 Metheoarnrne hydfolysls

prodrog approach I'fe venll; ~hc sys~emic rdeaSe of formaldehyde and reduCd IOxici~ y. Other prodrog approaches havc involved the use of oximes, imines, and enol estell!. allhough these ~)'pes of compounds ha,c rlOI been used clinically. A number o f agents coo~ai n imille and oxime linkagt'$. such as many of the thirdgeneration ttphalO;pOrin (e ., ., cef~ui me. ee ftizoxime), but these are rlOI prodrug5.

BIOPRECURSOR PRODRUGS
As indicated above. blorridUr.;or prodrugs do IIOIl conUlin a carrier or promoie~y but rather contai n a Imem functionality that is IIlCUIbolically or chemically tr.I.nsfonned ~o the acthc drug molecule. Tl1c ty(lCli or activation often involve oxidati ~e acti~otion. reducti~e acti ~ation, phosphory l:uion. and in some cases chemic al acti~ation. Of these. oxidation is commonl), seen, since a number or emiogcnous cn/ymes can carry out these ttDMformations. Phosphorylation has been widely exploited in the de,clopment of amivinll agcnl$. and many curn:'ntly available agcntli depelld on thi S type of actiyation. 1bc abundance of oxidizing elU:)'me5 in tilt body has made this t~pe of biOllCtivatioo II populor routc. l!iOZymes of cytochrome 1'-4~ can oxidize a wide variety offunctionIllit ics. gcnerally to produce more polar compou nds Ih al can he excreted directl y or undergo phase 2 coojugation reactions and sub5equent ly undergo elim ination. This occurs in a fairly predicl:lble nUinner and. therefore. has been Sl>CCCMfully exploited in prodrug mpproaches. A good eUII1p1e of a prodrug that l1XIuires oxidathc acti . vation is the NSAID nabumctone (Rdafen) (Scheme 5. 18).:- NSAIOs produce SIOInach irriUlllon , ..hich in palicnts with preexI~ting conditioos or patien~s IIlki ng large omounl$ of NSAII)s for eX lcndc:d periods may be severe. This irritation is a~'\OCimed in pan with the presence of aJ1 acidic functionality in these agents. The carboxylic acid functionality commonly found in these agen~ s is un-ioni1ed in the highly acidic environment ofthc Slolnach. As a result. lhese lIgenlS are ITlOf"e lipophilic in nature .nd lNy pass into the cells of the psln c moc"OS:l. The int racellular pH of these cclls is ITlOf"e ~sic than thai of the stomach lumen. and the NSA ID beconM:S ioni1..cd. This resullS in backf10w of H ' from the lu men inlO these cells, with concomitant ce llular damage. This type of dllOloge could be prevented if the car-

box ylic acid function could be elirni noted from these agents; this fU llClional group is l1XIuil"('d for activity. however. Nabumctone contains no acidiC functionalil), and passe! through the stOOUICh without producing the irritation nor mally associated wilh this dass of agents. Subsequent abo sorp41on OCCUIli in the mlcstinc , and metabolism in the !iln produca the acti ve compound as shown in Scheme 5 18. This approoch, howc'cr. did rlOI completely eliminatc t~ gastric irritat ion associa led wi lh nabumctonc. 5incc il is dllC on ly in pan 10 a direct effl'Cl on Ihe stomach. Inhibilion 0( the target enl.ymc. cyclooxygenast. while having an anu inf1amm:llory e ffect. also re.~ull$ in the increased release 0( gaSlric acid ...hieh irritat~ lhe slOmach. So. while nabumtt one IndUC~ less ga..~tric imulllon than other NSA IOs. thIS unOesirablc effect was not coolplctely elimi nated by a prodrug approach. Such an dfect was also seen above WIth Lht NSA ID $O hndac (SC'e Scheme 5-1)....hoc GI irrilation "'-as reduced bul rlOI completely cillninaled. Reductive IICtiva ti on is occa~ionally seen liS a melhod of prodrug !lCtivalion but. beca use thc.re are fewer reducing enq"""'s, is generally less common than oxidative activation. One of tilt bot I..nown examples of reductive activation II fot the anuneoplast>c agent mitCNl1YCIl1 C. which i.~ used In the lrealmcnt of bladder and lung cancer (Scheme 5- I 9).;z,111 MitCNnycin C conlains a qUlllone functionali!y that under goes reductiOll to give a hydmqumor~. This II ImpCNUIIII because of lhe differen tial effect of the qu inone and h)'droquinone on the e lectron pair or Ihe nitrogen. W hereas t~ quinone has an electron-wilhdrawing effcct on this elcctfOO pair. the hydroquinone has an electron-l"l'leasing eff\. which allows these e lcctrons 10 panlcip.lle in the expubNJn of methoxide and the sutxcquenl loss of the ClUOOntalc to generate a R:acti,c species that un alkylatc DNA. Tl1c casc-Ie of e'enlS that leads to an alkylaling acllve drug specie~ is inilialed by the reduction of the qu inone funt" lionalny in mitomycin C. 11le sc: ICClivily of mi tomYCln (Of hypo~ic cells i~ minimal. however. Tl1c se lectivi ty is dclCf mined in ",In by the reduction poIcmiDI of the quinone. which can be inflUt!nccd by the !i.lIbslltuenlS auachcd to tttc ring. [n an efrOl"! to modify the reduction fIOIcntilll of mItomyc in C, various analogues ha,'e been pn'pared and te$lcd fot anlil"kOaplastic acti vity . II "'"as hoped that the redliCtJOJl potenual coold be alkrcd so that lhe analogllC5 would 0lIl1 be lICIiv-.otoo in hypoll ic conditions. such as tOOse found .. slow-growing solid tunlOl"lo Ihatllr"C poorly vasoCulariud. 1lI the...e ti~wcs with a low mygen cOllteRt it was thoughl \11M n:ducli~e nl<!tDbolism might be more prevalent th311 in nor

(PIodrug)

Stheme 5- 18 Olod.Jtr.oe KlIY.JttOn of n.abumetone

agenb:

.
pa.~ses ~~.

...
H,H

H, N OH

em ab-

IIc lJ~er e 518_

_ 0

_ 0

'F0
.ocH ,

.ate the t is due ition of tn anll easc of IOOmet:>S. th)\

.... ,
'",
0

NH

e H, OH

,.J,! H

pro.
the
00

\'l1h

r",eL. .

.u
H,N OH

thod of

:mg enivalioo. alion i~ llsed in

,
CH,/V
OH OH

-:d ,

F
-<>COHH

9)?~ l'.JJ

NH

under ",,",m hydro-

= ,""
OH

effect. pulsion ,n ale to

; aclive Ie runc'e in for 5 deter-

OH
m DluD
(pTe. $peeh:)

IlIrlQllC.

i to the .f milo-

OH

.... ,

lested ductioo Id ooly lUnd m jUd. In

thaI

S<heme 5- 19 Me<hdrnsm of actrYiltoon of mltOl1'ly(m (

~t

m nor-

IlIII b~ W the agent)' would be 5O:1cc1lvely activated alld.

~f(ft. ~1CC1i\"cly to~ic.

Althou,h mhomycill WHS the first ugent used clinically 10 be ItcO,mlW ;1$ requiring rcduct;" c activation . it is only ~Iy Ideet"e for hypoxic cells. A much mOfC selective ....... ~.amllle. is currently undergoing phase I II clini~ 1nlI5. Tirnp81Dminc is n:por1cd to be 100 to 200 lillY"S .-t IIdecll'c for hypoxic ce lls Ihan for normal cells. TIle ..<I <m of 1KIJ,.. lioon invoh~ a one--elcclron reduction . . I'J nulrt.r<l by a number enlymcs. ioclu(hng cylodlulit P45(\ and cytochrome P-450 reductase to Si,c a . . . "fIIX1CS (Scltt:me 520). This species. which IS shown ~rcmi rudie-a! . can mitllllC brl'ak) in the DNA >WIn UlIdtr hypoxic condirion~. Under aerobic cond itions, h)~ollde radical is formed. which call Initiate chaill brl'aks.

or

Phosphorylation is a common metabolic furICuon of the body, which is used to pmdllCe high-energy phosphodiester bonds ~lICh as thosc PJtScnt in ATP and GTP. The body tllen typically u.;cs these molecules 10 phosphorylnte OIher mnlec ules and. in the process of dolllg so, octiva tes these molecules. TIle type of activation achieved depends 00 the molecule phosphorylated. but in many ea.<>es, pho!;phoryla lion introduces a lea,jng group. "'hkh can be di splaced by an incomin, nucleopl1de . This is secn. for curnplc. in the synthesis of DNA and RNA , in which nucleutidcs are added 10 the J' end of D growing chain of DNA or RNA (Scheme 521). PhosphoI)lhlion IS t"Oln)nonly required for the b,oacllva tion of antiviml agent'!. These: agents an: commonly nucleosides, which must be convened to the nucleutides to h:we

I
0 0
0 ,

ce""' "
I
~

I I

-"

0 T1" p.lluml,..

'

f'\
0,'

(XN 'N I A

I C( "~..., "
,
. OH

0,

,.... NH, OH

ONA
Scheme 5- 20 ReduttIve ClCtJ'iilbOn of Inap.lZMnIn!'
eo.. ~Sb ..-.d

Brut ,

Odd iHd DNA

activity. Most oflen . :lJlli ~ir 1 ag,mls di~TUpt the synthesis or .. fUrlCiion of DNA or RNA. ",hlch is gl!rICrully accomplislled by oonversion 10 the lri phosphate. Since oo/'l11al cells are al-o invohcxl in Ihl." synlhe'i~ or DNA and RNA. ~>()mpollnds have bcl'n sought Ihal would be converted 10 Ihe \riphosphnlcs. the act;.c fonn , in greater an'KH.mI ~ in infecled cells

than In normal celLs. 'lllcrrfon:. nuckmilk$ lhll have higher

affinil)' for the viral kinase en.,.)'nlC~ than the mammalian kUlll.'iC'S art' dt'1;ir.lble and hal e grt'aler sclooh'c lo.llt-it)'. This can be seen in the prodrug idoxlIndilll'. whICh was lhe fillil agenl \0 show clinical cffectl\CIlCSS against viruSoe$ (Scheme 5_22) ..10 11Ie nucl ~ide tnlers Ill<' C('II, where i\ is phosphof)laled. In Yinllly Infected ct' lls. UlIS phos phofylalion is accomphshed preferent ially by vir.ll thymiditx: ki -

n3.'.('. because the idoxuridine is a beuer sub\;h1ltC for the viml eOlyme thao for the com:~pondlng mammalian en lyme. Therdore. the drug is llCtivatl-d to II g~3tcr e~tcntln lhe vimlly infected cells and achieves S()!lle SCle<:II\'e toxk ily. although lhis selectivity is mlher low. and lhere i~ sigmfi cam tox icity 1 IlOI'mal cells. Once the drug htls bt:~n pM&0 phoryl:ued 10 lhe trip/Kl!;phale stage. it can inll1bu DNA syntheSIS In II number of lIays. including inhibil ioo of vil'll DNA poIymera.1\C and il>C't:XpOr.ltion Into DNA. II hlch mul1J in 1IIC00lCCt base .,.unng that dis.rupl'l the ability of DNA 10 funcllo n as a templot e foc DNA and RNA syntheSIS. In addlhOil to the SC le<:li\'c toxicity menl1Oi1Cd. the prodro, approach offers the addit ional advantage of locreaSC\l crll pcnctf1ll10f1. The prodrug clln easily enter the cell via 1ICI i "~

ONA

che~

DNA

eha~

o I O-p= o

o I O- p= o
SO ....... e

l/,'0'"j

6-,
o I o - p= o

o _II II~II o-p- o - p- o - P:.....o-,

0 0 )
.1.1-

0"

DNA PuI,mer77.

6
0"
I

.1-

0"

o II II O_ p-o_p_ o

.1Schem e 5- 21 DNA S)'f1thesis

.1-

O =<
ON

N'
H

ON

o - p- o - p- o - p- o
.11

II

II

),-,

J-

J-

J-

/ 0'--1
0.

~M" 7

DNA 1'01)- " IrJtapoiah~ InIo DNA

Scheme 5-2.2 Idoxund,ne

oKIlViitlOfl

7 ,n, ma:iunisms. wllereas Inc active nuclwtide.~ !U"C p ... ID use thiS ~ and arc tOO polar to cross the .aabcone ~la pasSIVe diffusion. AROOd eumple of chemical activatiOl1 is sccn wilh the pump Inhibitors such as omcpru.ole. in this Cll~. _~Irti\'ltion is provided by the highly acidieenviron_11".-oond the pariClaJ cell of the stomach (Scheme' S-:!J, ~a11owl; protOOaIion of nitrogen OIl the bcn/.lmid -* MIl follo;ed by aluw:hmcnt of the pyridine nitrogen. ClptlllIIg tim gi\'es the ~ulfenic acid that ubsequcnll y ~b1n 9;!l1l the 105$ of ..... uter. Attachment by a ~utfhydryl

,...)11

,... ~l on the proIoo pump of the parietal

c.:t\ll)

~'C n

then

III1d ;n~ti\'DlcS this em;ymc. prevcming funher reof H' IntO the G I tract, ..... hich is lI~ful in (rca!; ng

pUK' lIIccmJon.

QlEMICAL OEUVERY SYSTEMS

11rIr "-ledge gamed from drug metabolism and prodrug bet rna)' bt usW to larget II drug 10 its site of action. _'fIiflC chemical delivery systems take advHntage of
$

higher lel'c ls of actiVit)' in a metabolIC or chemical palhway at the UlIle! s ite. A prodrug (oon of lhe aclive drug is designed to serve as a substr.uc in Ih~1 ~pc:ci fic palhway. Ihus yidding a high OOIk.'CIIII1II;On of active drug at the larget sileo Sitc-specific chemical del ivery n:quire$ that the pmdrug ",aches the targct sitc and thaI the enlymatie or chemical .... process exislS atlhe 1Mb ' s;IC fOt" oonl'ersion of the. prodrug 10 !he &ctilc drug . Many factors are I1l I'olved in lhe relative success of silcspecific drug deli\"ery. mdoomg elIten, of target organ perfUSion. rate of CO'l\"etSlOI1 0( prodrug to!\C livc drug in both latgelllIld oolllargcl SlIcs.1U1d mpuUoutpl.lI rales of prodru g and drug fmm the IlI1gct si ltS. Sitc-spedfi c chcmical del il'cry 5yMem~ represent but OIlC approach 10 the se lectivc delivery of drug molecules to their Silcofoction for illCrea.~ thcrnpeut ice ffeell\'cnes5 and lim_ ited side effeets. Other \han chemical drug delivcry. many cal"fi.er s),stems h:we been evalualed for drug delivery, In cluding proccms. poIys.acd\;!rides. hposomcs. emulsions. cellular CUm e" (erylhrocytcs and IcuLucyICS). magnetic cOlltroltargtling. and implanted mechanical IlIJn1p!l.ll As the. fate of drugs in the human body ha~ becOll.e ITl(lI"e dearly undel"\tood. re.~an: h activity to impm"\: thoc delivery o f !\C11I'C drug 1 the t:llKel sile hIlS inc reased. The basic 80.,1 0

, CH,

,.CHl

,.CHJ

,
N

<

I
5=0
H

,.

o""J:S~O

<

<

X
H,c.

0"i, S -O'
N '" NH

-.

,.

<r
X
_

, CH,

Hlc..

0~ j-O-' (i

I~

d' I
X

N'"

-.

I ~

I ~

<

(+)

e)...'") N '"
H~

r'l N S~

0 ;
H- N

I~
<
S- ATPlIse NH

SCheme 5-23 Medwmsm of actIYatlOll of proton pump 1I'Ihit:..tclfS.

of these efforu is 10 prtMcct the drug from the nonspecific biological coyifOllment and to proIe<:1 the nonspecific bioenvironment from the drog to achieve some site-specific drug cJcli very. Si te-speci fic drug delivery has been eval uated

extensively fordrugs with ~rrow lherupeulic winoows, such as many of the 81lticaoecr drugs. 1lIe s;Ie-specirIC deli,'cry or the active drug via ils prodrull COU/llerpar1 requires !hal the prodrug be readily tnLIISponed to the site of action and rapidly ~ at the site. OIl anival a1 the UU'gd si lt. the prodrug should be Sdc:cli,-cly
cofl\'erlcd to drug relaLive 10 ils rate of convft'Sion aI nonW"-

get sites. Since higb metabolic activity~" in highly perfused tissues such as liver alld kidney. delivery \0 these or gans ha II nalUnll advantage. UnfonuNltciy. prodrug

deli,'cry ofacth'c drug 10 othcr organs or tiss~ is disadvantaged fOf the same reasons. Funhermon:. it is highly desirable to have the aclive drug. once formed, migrute from the largel sile at a slow rule. On lhe basis of all these requirelllCnL~, clearly sile--specific delivery of drug 10 the target by a prodrug chemical delivery sySlem is I far more oompleJl undenaking Ihan designing a prodrog to impro\'e one I.5pect of iu overall propt'nies. Yel thm: are sc\'eraJ excellent examplel of site-specirlC chemical delivery systems in use in modem drug thcnpy. The largel sites include cancer cells. G[ tracl, kidney and urinary 1TaCI. bacterial cells. viral material. oculac tissue, and the blood- brain barrier. The prodrug methenamint. described above in this chapter (Scheme .517), can be C(lfI5i(\ered a sile-specific chemical delivery system for the urinary tl'llCt nntiseplic agent formal dehyde. J1 The low pH of the urille promotes the hydrolysis

of methenamille to formaldehyde. the active antibactenal agent. Th( mte of hydrolysis increases with increased acidity (decreased pH), and this can be promoted by administnuion of urinary pH-lowering agcnts or by diet. The pH of the plasma is buffered to abou t 7.4. and the rute of hydrolysb is low . preventing ~ystem ic toxicity from form:ddehyde. As mcmioned above. this compound is administer! in emericcIted tablets that prevent dissolution and. therefore. prem. ture hydrolysis in the highly acidic environment 0( the stomach. A number of prodrugs for cancer chemotherapy have ben designed for selecl"'e de lh 'ery of acti\-e drug to tumor tiS5Ul", based on higher le:vel~ 0( activating enzyme in the tumor cell than in normallissuc ..u Many enzymatic systems show higher activi ly in tumor cells th:an in norll1Dltissue because of the higher gro ..... th nUes associated with tumor tissue. Pcp-liduscs and proteol yti c enzymes are among those systerru showi ng higher &Clivity in and ncar tumor cells. Thus, one means of all!':l1Ipt ing to produce higher rates of drug incorporation into tumors than in surrounding normal tissue invoh'CI deriving II drug molecule with an amino acid or JlCplidc frq

~"' Capecitabine is an uample 0( Dprodrug chemical delivery

system that rc<juires a series of enzymatic Steps for conver sion 10 the active anlilUrnO!' drug specle$. '-Ouorouracil (Scheme .5.24).)) Tumors located in tissues ..... ith high le\'C1s of the required enzymes should respond best to trealment with capccilabinc. Esterase activity occurs primaril y in the liver, pllowing the inlllCt ester capecitabille to be the tlbsorbed species following oral administration. 11lc: ester hy drolysis prod uct itself shows some specific toxicily toward

><Sdllme 5- 24 MetabolIC con\'l'!f';lOll 01 capeotaobl!le

~ ,

Glnctliuue. "hiI;h prevents this molecule from ser.-ing tffecti'-e proi.Vug delivery ronn of 5-rtuorouraciL The .... 1.0 tIQY~ in\'ohcd in the formation of 5nuoroul'3 d 0IX'1If in high C()nCenlr.llions in target tisslles such as an1\, b!mI. kldney, and rolon. Thert i~ considerable cum:m interest in the general coo~oirumor.acuvaled prodrugs, and 11 number of ~' rntcsic~ .. ~btm p!(ud for drug largeling in lumor ccll.~. J.t One afdle IIIOR: iOlerwJng approaches is linking an nogcnous .....lid) emymc \0 a tUIOOf-specific antibody. SIL'ied on ~al response. !he antibody would carry the

CllZylDe to the tumor sun3tt. ""hac il would be

for prodn!glClivauon. Prodrugs acli vlUed by Ihis (nl)1IlC would be C(Jn\'cned to the act;"c species .y II tlIc rumor sileo Sinc::e the activating nogenous en-

Il'I!Ie 15Il0l oormaI.ly foond in human tissue. maxi mum accuIlly In drug targetmg should be ach ieved in Ihis antibody. .'ltd enzyme prodrug thempy. Thtlntl\'iral drugs. such as idoxuridinc (Scheme 5-221, . . . inltRstinJl eumple of site-speci rlC chemical dtli ... .,. lIl1Itsc drugs Jerve as substnlles fOf pho6phorylating ~_ round III viruses, mvJ the phosphorylated SpKlCll tit 1ttJ'T an!JI'iral agclll, 'The lC1i~'C phosphorylated speeD IIoIfW "'" aled mto viral DNA, disrupting viral replica-

.... 1M thus, producing the antiviral effccl.

' Il0l

drugs undergo phosphorylation by mammal ian cells, ilQ the

11te.~

prodrug is specific for !hose sites whc::re it J;t'J'\'es a~ a substmtc for phosphorylation enzyl1"lt.~, One of the requrrements for site-specific chemical delr" cry dro;cus.\.ed abol'e y,'as the proper inptH/ootput ratios for prodrug alld nctil'\' drug species at lhe target, The relati,'c physiCQChemical I.. """,rties of prodrug and illl phosphorylated detil'Util'e sUllgest an appropnate inputlOOtpul ratio for silc specifICity, The prodrug can readily peneU'llIC the Vlnn. and the ino.."Teao;ed poIamy of the phosphorylated derivalil'e "'O\lld se .... c \0 retam thai ac_ tive speciC$ inside lhe I'irus. The comblnlliion of incrca.o;cd polarity and vlr"l l retention of the acti I c phosphorylated ~pe_ cies likely reduces any human toxicily that mighl be associ atcd wilh thi~ active species. llte nmino acid drug .. _dopa can be considered :I. Sllespecific chemical deli,ery systcm thaI delivers the drug d0pamine to the bruin. The brain has an &Ct,,'e tmnsport s~tem that opcr,lIes to incorporate .. amino acIds inlO the tcnlnr.1 ncmlUs syslem (CNS). and ..-dopa 1$ tnlnsported 'nlo the bruin in thIS mllllncr. Once !lC1"Ol'>S the blood- bnin barrier. I.-dopa undergoes cl-..;;arbo~ylation, y, shown in Scheme 5-25. to yield the 3CIive ITIl'tabolitc. dopamine. Direct systemic administration of dop.1mine does llOI produce significam levels of the dru g in the brai n because of its high polarilY and poor membrunc pcnncability Wi well as liS facile metabolic degradatlOll by o~idative dtammatlOll. DopamllIC formed 011 the inside of the bJood-bnun boIrrier IS lrc:ld there . oowever, because of the poor mtmbnlne JlCllIlt'abitity of tnlS drug. Although some specifICity for brum !lS!iUt' is ac:triC\"cd by tillS delivery method. peripheral side effects of "-do! are the dira1 ~sult of dccarbo~yl31iOf1 10 dopamine in OIlrc:r organ syMc rns. In this case, the en1ynrc: IICth'mi ng sy~telll lnOi localiled at the target site. nlld i,-~ pn'.'iC11Ce in other IISsues lind organs leads to undesirable S1de effects. Another exam ple of the chcrmcal dchlery of a drug 10 the bruin and CNS is tirc: prodrug fonn of 2-PAM (pro-2PAM ). an important antidole for the phosphate and tarbamale acetylcholinesterase: inhibltoo; used In InscctlCIdai and ncl"\e gases. U The polar propc:nies of 2-PAM. a pe' IIl;Il'ICllI cationic spccic..~. prevern this drug frum being absorbed fol lowing ond ndlnini~' rolion and restrict toc drug from access 10 the bruin, even after IV adrnin istrdtion . Pro-2-PAM i) a dihydropyridine derivativc that undergoes metabolic and chemical oxidation to yiekllhc lIC!lH: drug 2PAM (SdICnIC 5-26). The oomonic pro-2-PAM can ea_ily cross the blood - brain barrier, and o~idatiOli to 2PAM wllhrn the bnUn c.ucnually tnrps the 3CIi>e CD.iiofllc drug specIes insIde the brain. O~ldalion of the dihydropyridine ring of pro-2 PAM occurs Ihroughoutthe mammalian s)Slcrn. notjuM in thc bruin, arid Iirc: levels of the resuhing 2- PAM are appmxi. malely the SIInrc: in peripheral tis~ue liS in the brdin. IV 00-

,.
I

"0

"0

"

5dIem. 5- 25 Decarbolfy!atlOO of L-dopa In thr,o eNS to ~ the actr.oe drug dopamll'l@

' ".
Pro-2.J>AM 2-PAM

Sdleme 5- 26 OXldaIOOf1 01 pro.2PAM

minbll"lllion of pru.-2 /, AM, oo,,"cycr. yicld~ bra in leve ls of 2 I'AM lhal af\! appro~mJalcJ) 10 limes IlIgm than I~ llChic\'ed by IV adnllni'lrJ tl O of tile pare nt drug. n 'The dchery o f drugs across the blood-brain barrier has been a Signifl\:ant 'Slille in the dc:..~ign of many thcl1lpcu!lC

Only vcry lipophilic drugs elUl cro....~ into the bl1l1 n ""Ithoul the aid Qf some acU\'c up!a~e process, ~uch a~ the (JIlt! lhal ()(X'r:Ilc..~ 1(1 i ncorpom tc tssenll al ami no acids inlO the eNS. The' fKilt oxidalio11 of the dihyd ropyridine
ring 'Y'lcm Im~ been e.llcJ\SI~cly inve~ugliled as D gClIC'ml proco.. for chemical dclh'cry of a nu mb!>r of dlllg.~ to tile .. eNS. 'The approoch Ila-~ ~n described as a chenllcaJ dclh', cry ~)"MClll. riOt j U,1 a prodrug designed 10 pcn.ctrah: the

comp(".IIId~.

blood- brnin barrier. II> Th IS process i~ a 111l111iSlqJ procedure i Ilvoh inl: dd t H~ry of the drug-dihydrop)'ndH~ derivathc 1 0 the brain via fllCile diffusiOl1 across Ihe blood- bmin hamer.
follO\\'ed by o.U(iatK)<1 to .he quntcmary pyridtne cation. wInch I' trnpped in the bruin. '!11e drug is then ~k'ased from the p)'ridine ca tiOl1 by <;CCOOd nlt'taboliclchemical evc tlt A numbcrof fUIII:t ional groups ClItl be added to the dih) d ropyridillC to faclli ' ate the deri~ali1.ll tion of various function al ;rouP>' found in eNS drugs. Since many eNS d rugs are ~n1lt1C~. amtdcs of dihydropynd ine carboxylic ilCid$ are orten prepared lUId used to deliver the drugs across the blood-bnlln barrier mlO the bruin. Addilion.:llly. these amide dcri~ aU\e~ often sc rve II) protect the ami nes from tIlcmbolie degradation bef~ they reach the target site. Primary &mines such as dop.1mine arKI oortplnephn nc arKI tIlany OIhel"li an:: readily metabolized and degraded hy ox idativc dearn ina,ion befon: reaching the eNS. The dihyd ropyrid ll1e derivat ivc of a dopamme ~'cr, shown in Schenle 5-27. has access to the

e NS via passive ~lton of the ten iary amtlle. which OIl oxidation n::stricb the ~'\.U ltitlg pyridinmm nmide to the brain . Amide h ydroly~is then dc li lers the oct;ve fonll of 1 M drug at Of near its si te of actton. The anude hydrolysib step may be slOlt,er than lhe dlhydropyridtne u.,idalton step. and thus a rescrvoir of pyri dimurn at11 ide prccuroor m,ly be ~vall able for CQI1\ersiot1 10 the IIClh 'e drug ~rcc;e.. The use of prodruj; crnl~'eptS 1 bcl.'n I'ery successful m m, the deli-'cry of !leti, e drug "flCCie' 10 the human c)e follov.lng IlX"ul applicallOO. Lipophilic eSlers of epillCphrillC. such lIB the diphaloyl e~tcr de"Cribcd above (<;ee Schcme 5-6). show better coroeal penetrauon foUO\\'i ng dtrect apphcatiOtl to Ihe eye Ihan Ihe more polar pdl\'nr dn]g epltlephrine.'" The c:;ter~ nocce.~ for lhe hydrolYSIS of the pnxlntg an:: readIly avat lable III rhe eye arKI skin . The more polar dntl ~pecies. epinephrine. is lhen IlX"alia'd ..... ithin Ihe lipophi lic ItlI'mbrane bamerli of thoc eye. arKIrhe drug n:lnalnS 31'allablr al the largel sile to produce ils unliglau~'Qma c'f~'CIs. 'T'he local applicatlOfl of the prodrul 'pecic!! to the ) 1:in or eye a llows metabolic proce:;scs 10 OCt t~ale the drug wtthoul c0ncern for competitive rellCtioru at ot her tihllCS or ~tles of lOS$. The delh'ery of drugs to the colon and 1000'er GI trat111as taken advantage of the untque. cnlymotlc processes found in colon bacteria. The glUC():Sida!;e activity of thoc'\C bacteru allows hydrolysis of glucoside dertvauI'es of drugs in thr colon and provides htr;n.:.- cOllCl:mrJtions of llClhe drug." A number of skroid drugs (Scheme 5-28) demOIlSlr.lk Increased cffectivcness in thc lo ..... cr GI trJC1 folio ..... mg admin istratioo as thet r glucoside denlauvcs. The polar glU(.'(l6id1: derivat;,cs of the sreroids arc not well abo.orbc:d Jltlo the: bloodstream from the G I tfllCt and remain Hvailablc 10 .' <rot lI$ 5ul:!l;trates for the baclertll Ihal an:: found pnmJri ly ttl iIr human colon. The prodrug approach for lhe dell,'ff)' of antlCuo(."r drup to the ~ile of action ha, been used III a numb~'r of cases 11\ an effort to incn:ase effccltl'ene~, lUId lower ,ide effect!!. Several eru.ynle systems tNt show hiSher acllllly III ani ncar the cancer cell~ have tN.,,,n eval uated for the ir abi hl~ 10 acti vate the prudrug species. In 1I10\oI case. the en/y l1lC 1ICIi1 ity ].e\el IS simply hIgher near lite fru;ter gru ..... lIlg cancerttll!!.

oeO R oeO R
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H

"-"'M
Xheme 5- 21 Othydropyndlne-based dn.'9 delr.oery system for dopamil"le

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10 T"'J', A.. and V.mona, T. Chern. !'ham. Ihll 22!4.!-1 144 1, 1974 I I. J ..., l Q. W I...",1 'A""'''' 0 . I' 1. f'lwm, Sd. bH09 76. 197.1 12. JI>l:ko. W. J.. ,..... i.. (l, p~ and !k""u'~ 0 W : dill. 1'Ii:inn. 1'1oor 14
90-'19. 1973.
1]

5-6). .. rIIr POe\oClIU of!~ eMymes tn rKlm1al liss ue ~""'rlIS the pn. "hly of rompktt Slle speci ficity for lM!it agents.
1111\ IIIYf dllCUssion of si lc~ific drug delivery ~ ...s !III 111_ Ca!oeS tile pnxIrug was in use before ils mccha .. .m(l(deh' ~ aad specificity was discovered. Thus. some ,,~wen: disrovered 1 n::present si lc-~pcdrlC drug 0 *I!,ery ... tll aflel'" 1fK') "'itn:: placed inlO therapeutic use. An t'III.IIIIOII of the prupt:nies of these agents has produced the fluntWOl\ for tile design of OIlier proJrugs wilh wgel siles <pe<:iflC tissllC$. This proce.~~ is really no different from p .... aI ~l diS(o~eJ)' process in ..... hich a unique sub...-e u obsc.... ed 10 ba,'", desirable phann3Cological effects. -' uudic$ of II> ._or.<.ties lead to the design of bcllcr drugs.

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U.S. 1979

1975 .

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dna.

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31,

Moore. H, W..... CZftI>laI.:. It Mrd. R.., Me, 1249. 1911 1 Moore. H. W : s.:......., 197~21. 1977. tye<. V. N.. On<l S,~balsl<i, W s.:1CtIo>I' 14S:.U. IQO.I II .......... W It. M"omyci~ -.I pM'""""'YC' . iii 1k! (kgu",) A~hilllnOl" ItniIMic> 1"..... V.. l . y, I...,. 1m. 1'1' n t !76 II..,..... J. M 8r J C..,...61 III. 19'jJ ltauflNOll. It E,: l'nIc. Soc-. D p, Bioi. Mcd. 1092SI . 19b1 F"""d,O R. M.... II"'. R"., 1.H, 19117, Ju""",im, L N.. On<l 51"~"jd. T It ('hem Rev 'I4.ISj.I. 1\19.1 M ,.... M ~ f'I>Ioida. U. M . Sa",. N .. d aI' I. l. C_ ... \4 121~.

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lot O""y. W It Eur J M.... CIotm. 'I6oSn. ~I " ~I". V. J J M... CIotm 23 117S. 1'180. 36. 1Wd<,., N Adv IlniC Jte.;. 11 2.15. 1%4

""

Biotechnology and Drug Discovery

JOHN M. SEALE. JR.
thmllllg about patient CaR!. Extcn".e <;cn:c:nll1g progr.ifllS once drovc d rug disco.ery on natural or synthetIc c0mpounds. Now. the recombinant DNA (rDN A}-dn"'n dru, di'iCovery proccss is begi nning 1 Ylc ld new ave nues (or tile 0 preparation of some old drugs . For example. In\ullll. ooct prepared by i'lOlatl()ll from pancreatj.c ti5SllC of boVIllC or porcine ~ies. can !lOW be prepared in:l pure fOflll idcnt.cal .... ith human insulill Likewise. hunmn gro", Ih hormone. OPCt isolated from the pituitary glund~ of the dccca<;('([. c~n no... be prepared ill lIu re form. Recombi nant ,yst~m. SUl'h 8$ these pro"ide high-yieldi ng. reproducible batches of the dnt, and un iform dosinll for paticnts.

BIOTECHNOLOGY: AN OVERVIEW
Developments in biOlechJlOlogy in recent times have Ix.-en quile dtarmltk. The yeaN betwl'('n 1m and 2001 witnes!>W

a tremendous increllllt In tnc number bIOleChnoJogy-re. lated phal'TTl3iCCUlical products in tk"elopmem. and. number
of important new drugs progressed Ihrough trials and mlO tile el lllie. A good n: neclion of the irnpilCl o r bioltchoology is Ihe GcnBank tialaba,<;c . Gcn 8 an k is an cleemmi.. n:posi[Of)' of geoe sel.jucrw.:e information. specifically the noc lootide <;equence~ of complementary DNA (eDNA ), representin the messenger RNA (m RNA). and genomic clones thaI have been isolated and sequenced by scicmi sb worldwide. l 2 The gro,,"t h of the GcnBanl. database ha.~ bo.-cn rnpld. and;1 has been incn: asing .~Ieadily since about 1992.' Figures 6- 1 and 6-2 gnlphically depict these gro ... th rules. In October 2002.1h1:: Phannaccutical Research and Manufacll.lrers As.'IOCi alion (PhRMAJ reponed th:ll 37 1 biOlcchnoklgy-derived me(hcines wen: III te~un g at various St:lges and Ilml [}Carl y 200 di ..... a."es are being targcted by research cooducted by 144 companies and the National Cancer Institute. Of t ~-all of ... hich are in hunl:!n trials or awaIt ing Food and Drug Adminislnlion (foUl\) approval-118 are new dru~s for cancer. 47 an: new drug~ for inf<'Clloos dl seaS('\. 26 are new drugs for autoimmune diseases. 22 are new d rugs for ncurological disordc:". and 21 are new drugs for human immunodeflCienty ~irus (I IIV) and acquired immunodefICiency syndrome (A IDS) and related CQnditlOl1s. I'hRMA also reported 194 roew mWlCilleS targeted for pedi aUK use.' Approved drugs derived from biotechllQlogy also trea! o r help pre vem myocardia l In far'l:ti oo. stroke. multiplc IoClerosis. leukemia. hep.lIl1is. mcummoid atlhriti ~. b!'ea.-.t cancer. d iabetes. congestive heao fatlure. lymphoma. rellal cancer. ey~tic fibrosis. and other diseases. 'The: number of approvals of biotechnology drug~ per year has Ix:ell IIIcreasing steadily. These dam are shown ill Figun: 6-3. The Ilullmn Gellome "mjeet. :tn international effort to 0btai n complete genetic maps. including nucleotide sequelK'eS. o f each of the 24 human chrolllo~ortle... has spa .... ned much new kllO'Aledgc and technology. It i, awesome to ron~idcr Ihal in the mere 30 years Slncc 1912. the sciell\.'C has reached Ihe sl:tge of auempt ing genetic c ures for Wille diseases. such as cy,tic fi brosis and i mmu llC deficiency disorUcTS .

or

LITERATURE OF BIOTECHNOLOGY
Many good litcrature wun:n on blOlechoology C)USI for Ihr phannocist and med,CInal Chellll<it. 1ltese CO'CT tOPIC'S such ~~ management Issues in biotechllology." to unpl crnentation of instruction o n biotechnology in education.I}-.u costS of biotechnology d ru gS.2.'-lOo implclnentation in a practice ~ I1ng. p~ regulatOf)' issues.~- product cvaluahon and for mu lation.~7," pallent compliance.'"-'II and fintlin, infonnal iOfl .)I-~J AdditiOflaJl y. then: are a number of gencnl te~ts. '\01 !III n:view ~l'I iclcs.M -M und a gener:ll reSUU r'l;e refer. clICe cutalogue."" Any good bi ochemi.;u), lC~lbook i.; aliiO I uo,cful resource.

BIOTECHNOLOGY AND NEW DRUG DEVELOPMENT

11lc tools of biotechnology arc also being brought 10 heM in lhe sean:h for IICW biological targi:ts for presently D\'lU 1able drug~ as well as for the dbc overy of new biological mo lecules wilh ther.lpeu' ic uliltty. Molecular clo ning of IIQvcI TCCC'pIocs can provide: lICtt'IS \0 tremendous tools for the leW llg of drug. (e., .. the adrenergic ,eplOTS). ,,-hile ci0fl1IIg of a no"el growth f:l('!or mi ght potentiall) prom a new tiM:r:lptutic agent. Biotechnology is 31'10 belllg used to screen compounds for biologicalllCtivity . By uSi ng cloned and c:.~pres>cd I:CIIC ~. ;1 is possible to gCIICT'Jte receptor pr0tei n~ to facilitate high -throughput screeni ng or d",g.~ in VItro or 111 ce ll cultun: syste ms mtller than ill anmt:ll ~ or tissues. 8 1otechnology i. being i n ~est i gate:d 111 completely lIQ,e:I approaches ,0 tbe b;ll1le agai nst hurnun diseaw. including !be use of antisense oligonudcotides and gene n:placelllcntthcrapies for tiM' tn:atmellt of diseasc~ such as cyslle ftbro5ls

BIOTECHNOLOGY AND PHARMACEUTICAL

CARE
As it affects medici ne and phannltl.;c utical C ...... biot~hnol :I ogy ha.~ forever altered the drug diSCO'o'ery ~\ and the

...

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i iii ; Iii i i

~.

u.e of monoclonal anubodies for the lreauncnl of

includ I i !bign. and pharmacogcnobioIechnology in the eMly 2hl century i5 ""one drug fits all" " parlldigm for ph;lrm~
. I

An ulldmilllndtng ofhow lhe hand ltng Ind "alltltry of btllJlharm:.cetlticah drffer< from OI~r drugs rh:11 pharmacl5U dl<pm!ot'
KM"'IodJC' 01 pIqlaI'&lioII 0I1he produd for p;llIcnl 11K. Includln, r'OIIMlIUl1OIl or CUIf1p011ndmH If mt",mI " llIienr edoclll,on un lhe divas<:. bcncfi.. of rhe pm;cri bcd boophannal"cui OCAI. ~enlial side cff1$ <It drus .nlCfaniorui 10 be a"'1In of. and d~ lI:chn"lUCli of it'l f.admmiStnluon

Pulk ,,1 cooltlieling un re,mbu""'mc,,1

melhods productS:'1

Monitormll of lhe I"lhcm f,1( compl'Jtltt

The ph.armaci\l must maintain an adequate kno\\-k:dgc of agcnts produced through lhe methods of biolechnology and

pt"""'" product

,>Iouer;

;n"ol'" an uinll

.
~

"

" I"

--------------V..r

~~~~~'~~~~R#~~~;~~~
YN'

figure 6- 3 Yearly approvals of

bIoTl'Chnology-derived
VacCInes.

drtIgs and

remain "in the loop" for new developments. Thc.language

of bioo!chnology encompasses OfllaR;c chemistry. biochem-

istry. ph)'liiology, p/larmaroIogy. medicinal chemistry. immunology, molecular biology. and microbiology. A phannaciS( has studied in all of these areas and is uniquely poised to use these skills to provide pharmacelllicaJ care with biotedmoklgical agents when needed. TIle key techniques Ihal unlocked the door 10 the biotechnology an:na arc: [hale ofrDNA. also known as g~nC:ljc I'0S;-

ouring. rONA lecliniql.le5 allow scientists to manipulate genetic programming. create ncw genomc:s. and C:XII'1ICI genetic material (genes) from one organism and losen it into ~
10

produce proIeins.

THE BIOTECHNOLOGY OF RECOMBINANT DNA (rONA)

Since its incepcion in the mid-19705. rDNA&7-74 (genetic engineering) technology lias driven much ofthe': fund:unc:nlal research and practical developmem of no,-cI drug molecules and proteins. rONA \cchology provides the ability to isolate genetic malerial from any 5OUrt:e IU10d illSC!n it ililO cells (pl:!.nt, fungal, ~1eri.I, animal) and even live animals and plants, where it is e.tpressed as pan of the recei~ins organism's genome. Before diSCUSliing lI:chniqucs of genetic engineering. B review of some of the basicll of ce llular nucleic acid and protein chemistry is relevant.'7S - n Most of the components that contribute l{) cellular IIomeostMis are proU:ill5-50 much so that I110fe !han half of the dry weight o f a ce ll is protein. HistonCll , cellular enlYmes, membrane IflInsporl systenlll, IlIld immuooglobulins an: just a few examples of The proteins that carry OUt the biological functions of a living human ee:11. Proteins an: hydmted thrcc dimen sional structute.~, but at their most basic Ie, ..!. they arecomposcd of linear scquc:ncc:s of amino acids that fold to create the spatial charocteristics of the protein. lbe!;e linear

scqucnces are called the primary SlruCI"rt of the protein. and they are encoded from DNA through RNA . The infonna sequence DNA - RNA - protein has for many tion years been coiled the biological CentI1l1 Dogma." 7&. 19lb: specirlC sequence of amillO acids is enoodtd in gene!l. GcnH are di~rete segments of linear DNA that compose the chromosomes in the nucleus of a cell. The Humun GenolllC' Projecl has re"e3led that then: aTe betwecn 30.000 and 35,000 fuoclional genes in a human. e!)Compassing abooT ),400,000.000 hase pairs (bp).10 As depicted in Figure 6-4, in the nucleu s of the cell. dOll ble-str:mded DNA unde'll0C5 a process of tl1lJlcripciOll (eatalyud by RNA polymerase) to yield <I single-stranded molecule of pre. mRNA . Eodonucleases then e~ci!le nonfunctional RNA scqu~nce~ called il1lrons from the pre. mRNA 10 yield functional mRNA.ln the cyIop1asm, mRNA comp lexc~ wilh the ribosome~. and the codons an: ~ad alld translated into proteins. The process of protein syn thesi s i. &cherichi(l CQIi bC'gins with the !lCti"ation of amino oculi as aminoacyl-llllnSfer RNA (tRNA ) deri'atin-s. All 20 of the nmino acids undCTgo this activation, an ATP-dependmt Step eatalY/.cd by aminoacyl-tRNA synthetase. Initiation illvolves the mRNA template. N-fonnylmcthionyl tRNA. ~ initiation codoo (AUG), initiation radars. and the ribosomal .~ubunils. Elongation OCCUB (using sc~et1l1 elongation ftICtors) wi th the aminoacy l-tRNAs bC'ing selected by recognt tion of their specinc eodoos and forming new peptide bondI with neighboring amino:ICid~, When biosymhesis of thesptdfie protein is fini shed, a termination codon in the mRNA is recognized. and release factors d isengage the protein from the elongation complex . Finally. the protein is folded and posllranslational jl'I"IXe.Ssing occurs.'I . n Proces.'1C5 thai might be used in thi s step include removal of initialing re$i. dues and signaling ~llCnces. proteolysis. modification of temlinal residues.1lIld attachment of phosphate, methyl. ca" boxyl. sulfate. carbohydrate . or prosthetic grollps that belp the protein IIChieve its nnal threc-<limensional shape. Spe-

now

TF1InKriptJon

DNA

.,,"""
PrO noRNA

Trlnsl.tlon

Proteins
R~Ic.tJon

Modlflc.atlon

Postlr.lnslalion.11y nWldifled proleln

~~::~:-::~~~;1~~~::i ~

occur endoplasmic reticulum or thoe Golgi

~:::~; modil'kations occur oot of the cell. is lnrlsponed I

IIJoows rONA ""ocedurcs to ....uk of. model (Of the amino

by cmelaboo

"',Ih

sequcnce the codon iiequcnce of thoc

gene into II trunsmls."ble vcctor that can be trunSl.:nbed. amplified. and prO(XIgOtoo by a nost celt' s biochemical madlinery; transferri ng it to thllt ho~t cell: and flocilitaling the lranscriptio n inl o mRN A and tr~nshuion in lO prOl ei ns. Cloned DNA can also be remO\'ed or altered hy u~mg Mn appropriate Il$triction endonuclease. Since genes CrlCOOc thoe language of proteins. in theory it is pos.~ible to erellte :l.n)' protein if one can obt:lin a copy of the ~sponding gene. rONA methods rcquire:SJ

T..:hnokJg,
in\'olyed in working with rON A gene; inscning the pltt"i<>e

An effococnl melhood for de"vl"1: and "',00"'"11 pho.I.pbodlCilCf bonds on fnl8mC"IS of DNA ( ~enr:!;) Ikrwed from lin am)" of diffcrtm WUI'CCO Suitable ~ectOl1i or ~DniCrs capable of I\'ph~a1Jnll boIb them .... 1'os.1Id tbe foreilJl DNA I;n~ed \I) them A meanS of mlrOducina the rONA ,"1 a blIctrn~l, )"ta>I. pl:mt . 0 or mammali.n 1'0'11

~-----------------------------

Prottdurt'lo f(W

IDKI sr~in. a done or ccll' thai hal. ~Imllhc ,ONA moIcc:ulc from a brJ" populauon of
<oC~n,

~"
Theil' an: 1'0"0 pnlllary methods for cloning DNA"" using
gcnomk: and cDNA,l ibr.lrics as the primary sourt'c~ of DNA fr.lgmtnl\. which. l"el>pt.'\:!ively. represem eitller the chromosomal DNA of II p.'nJcul~r organ ism or the eDNA prcparc:d from mRNA present in a given cell. l i~~ue. or organ. In the fir.;ll1Iclhod. a IIbf".!ry of DNA fr:tgments is crcall'd from a ct'1I', genome. which rc:prcscnlS all of the genes p!"C.'lCn1. The hbruy i, then ~reeoed ngainsl special DNA probe(, L)'\ing ~

ft

_Tu% ' ,
DNA Syn\t t ,

mRNA _ ,",bill

-::r

b
RNAONA Hybrid

the gtllol1nc OOI'llcnl$ 10 ,CneTatc fragments of dlffcn:nl SilC!l and composlllOllS. <;omc of which should contain the gcnclic
wquc .....~ lhal encode the pIlCific iICI;vil), that one is seckmg. creates the hbmry. WiUl I:nov.Jedgc of the proIetn sequence Ih.ll the gene spcI.:ifics. DNA plObo can be 5ynlhe \1100 Ihal should hybridiJ:c wilh conespondmg fT'llgmcnls In the hbr.tr)'. By labelmg the probes wilh nuon:sccm or r:W,OOC!lVC tags. probe molecuics thnl hybridize mid film! douhle helical I)NA can be idemi ficd and i'iOlutcd electrophorcticully. The DNA from the librury elln tllen be ampli . fied by II Icchniquc such as the polYOlcr..se chai n reaction (PCK). i no;encd inlo It \ector. and lmnsferTed into It hosl ce ll. A cOfllp;ino;on of the.'II:' mcthods IS given In Table 6-1. The '"OIId mllJor method for cloning DNA re~,,<,nts ooly gcnt'S lhat are bemg cxpressC'd'"' al a given lime and m\olve..~ first lhe i.\;Ol;uion o f the OlRNA that enoode!i the anUM acid sequence of the proIein of inlC~'it. Treating the mKNA Wl tlt the \iml entyme re,'crse transcrip(lI..<oe in the presencc of nucleosic.lc lriphosph:ues (N11'$) COU\oC:ll a sirand of DNA to be symhesi/.ed complcmentnry to the mRNA matrix. affording a RNA - DNA hybrid. The RNA strand is broL.tn down In al kaline conditions. yIelding a singletrondcd m()lecule of DNA . The DNA polymcrase reaction afford, a complcOIcmury or copy stnnid of DNA (eDNA), .. hieh on fw;ion ofa pronM.\lOf sequel"lCe can be unllChcd 10 a tl1lI1spurt \ector. Figure 6-5 depicts ~ ~aclion~ . If the ammo acid sequence. of a prolein land. hence:. IIIe codon 'iequcncc) .. ~oo""n. automated liynthe.is of DNA Ibmuglt cncnllcal oreffi'.)'m:llM: means tq>n'Sem~ a third .... a)' that gellCS can be cngiroLC,ed. Thl5 method is usefu l onl), for

I ---_",,,_ I
II .. _np
traf&rlpt

Figure 6-5 Method 101 preparaloon of eONA Irom a mRNA

dl""

Fig ure 6-( lion.

relatively sma ll proIcins . III pn 'l(: , plc. for the preparulion of a genomic library lhe cellular ongin of lhe DNA is .1Ot an issue:. whereas the cellular ongon of mRNA is ~n.ralto tIK: preparation of a eDNA hbr ry. Thcf~JOR', genomIc hbnlries .. vary from species to specie'S btu not from tissue to tl5S\It wilhin that speclC:!i. cDNA vlltlCS .. llh tissue and the deICJ optnC'nla] Slag" or cells. tlssuc!>. or species. AOOIhc:r I"'pew' tant distinclion IS tlklt the fragn"ICnt of DNA from cukaf)'OI11: chr0m0s0mc:5 will cootllin uom ( prolcin coding 'iCgrnt'nlJ] and introns (noocoding segments bct .. ccn nons). """reM in cDNA th.e ;nlrons are sphced out .

DNA ~

is relat"cI'

5' CCJOG J J' GGICC 5

Res1:rktlon Endonudeases.. 1
The restriction endonuclcase (or rcstricl ion enzymc:) is probably besl dcscnbcd as a o;('t of "m()lc:culor o;ciSSln" in tIalure. RC5triclion I'ndonuclC'aJiCS are bactcriaJ e'n:tymC$ tha. lIS the name impl ies, cica"e intemal phosphOOieSlcr bond! of a DNA moleculc . ll1C cicavage ~lIe on a segment ofOI'A lies within a specific: nllCleotode 'iCq1lC1lCC of about j;1~ to eight base pau~ . More than .50) n:strittion endonuck~'ib have becn d isco\cred. aoo thc'IC rc;lc l wnh man: than 100 d iffen:nl clcavage silCll. The chcmlC"lll ~action of the rest"" lion endoollCk:asc releases the 3' cnd of One.' base as an aJco. hoi and lhe 5' elid as a ~phale . 'The general react~ is shown in Figure 6-6. TIle n:cogniliOIl ., ites ror restriction endonuclease, !lit specific palin(/ro,nic scquctlce.~ of DNA 8J II()( more .han 8 bp long . A number ()f lhese palindro",c~ arc: lisled in Table 6-2. A palindrome is II Sl..oqucncc of lellcrs Iltal reads tM s,1 me .... ay forward and bad.""ard. for mst~: "A man.1 plan, a canal: Pananu!:' " DNA land," " Did Hannah < bee~1 Hannah did." Kc.<;tnction cndonucleases cleave DNA at palindroonc ~Ile'i 10 ylCld !oe\crol t)"pcs of cuts :

rcquira I\) DNA . Pahr lion en~JI\) cleavage group of I'n; ing in the rk 10 their use ll111ke tlleir ,

$.

When the~ DNA by lht "ector DNA cndonuclea$l ent DNA mI the firsl step
~llllndcd

D .... " ' "

TABLE 6-1 Characteriltia o f Genom ic Ve rs us eD NA lIbra ri e ,

ON

Ch. r.ct erlst le

~nomlc

eDNA

is added 10 th tates pairing , ti.'r bonds arc.

s.."""" 1>1 ......b< n\M&'rial

C

Gmomie DNA

51",..,.
.'loU
'top. -

... , ....MIII

.""~~l'~
<JI ...............

">100.000

I""".

,,.,......,

,-Cell /)f ",....

m""

TABLE 6-2

)(IIO.(XKI

AM AG l er

1'1."'...., 011 tqIIlaI~ ... ..,,,~

s..~"'lock'''''''''~

PI, """ <01 """""

,~

No
MI)bo

It"'

..,..
,~

,-

5' CCTAGG J' J' OOATCC 5'

5' CCTAG J' 3' GATCC" 5'

""'"

GATIATC MIt,,1 J.OATC

"""

f=O

f1- _0

vector and losert. A IOInl of fool' wch bonds mU~1 hc: re formed. twO on each strand althe S' and J' ~l1es, This process i~ termed liX(j/,(m. and lhe er17ynlCSthat cmal)'!.c the reaction an: named DNA 1i8(/~s. Typically. ATP or another energy liOUn:c is f'C:(jurred to dn"c the: Ilgauon Il'action. and linl.er fragments of DNA are used to facili tate coupling. Then: an: ~"em l diffcrcrl1 types of ligation reactrons Ihm an: used. depe nding OIl lhe type of reSlriction endonuclclbl.: product that was formed. The sticky-ended DNA. usmgCOIllplcmcnlary vector and ,nen end~ that c3.~i ly bbe pair 3\ the cuts. i~ probably the easiesttoacoompli~. IIlthough mcthodse\ist to ligote the blu nt -e nded ,wieties. using I)NA liga~ .

mR NA

'-,f9tre 6~

Mfdl.Jnrsm of a rl'StrI(lIOn endonl.lCiease rCiK-

.'0"an or I ;~)(
10 I~

IItt1attl'ely easy to ligale with complementary ends of other IItriA 1IIIlIcar1es. A CUt from an endonuclease like III/cHI :
t {'[lOG

r o:ocr l'

r _

5' CC GO 3

3' 00 CC 5'

more complic:lled methods to ligate into vector

lUI.,
_

D\" Pahrtdromic cleavage sitcs fO( some sc:kcled I'eIotricDOl ~_ an: given in Table: 6-2. Tloe arrow shows the ~tr The restriction endonuck:ases are a robust fNII'd ertl)'tTte5 that fonn toolOO. for investigaton; workIIImtIKf~kloflenetic engineering. About the onl y caveat to dIeu' lIS(' IS obyioo~ one: lhey must be chosen to not

tbttr CUt lJl5lde the gene of interest.

. . . LitrE -

'lar till: gene: of Illten:Sl has been e. ciscd from its nonking
1<>

.- ""

u~lca...:~

~an

lOll

re'tnl;' ak,'\-

~,

un:-

'*'

lin T.h!c

l141n II

enoomw:leasec and the 'r..'IOr [Y.';'A 11M been opened (u~ing the s:lme n:striction mrImuclc:;L<,c to break phosphod icstcr bonds). the t .... o d,rrer~ DNA IlIOlKuIcs arc brou gh t together by annealing, In W flUl ~ of !his process. heating unwinds the double ...aIcd D'l A 0( the ,'(:Ctor. The insert or passenger DNA .. .u:dIOW heated ml.tun:. and sub!lcquent cooling radi ijWI'Inl of complemcnlW)' str:mds. Then. phosphodiesIII' bond.;we regenerated. linking the IWO DNA mo lecules.

IItriA b) the

~'P'opr:iale Il.'~tnction

There an: SC:"erJ I mClho<h al'a,labk for lmroducmg DNA inlo host cells. DNA molecul es Ihat ~:111 m:ltntain IhI,:l1I<;ehe.~ by replication are called "plirons. VeclOl'll an' ~ub:.cls of rephcons. In gell('tic engn_nng.!he ,'ttlor (c-.uTler) ' ~ the nlOl'it widl'ly used mellK:od for the in<;erhon of fore'Gn. or pa~se nger, genetic material ,nto a cell. Vectors are cnct ie dements such as plasmids or vi ruse~ that can be I~galed and that hIm: becn engineered M) that they can accep! frngments o f fort'lgn DNA. IXpcnding on the ,ector. the) may hale many IXhcr femure~. includi nG nlll ltlple dOlling Mt~ (a region colllaimng multiple reslrichon en;,;yme s,te, into which an i nsen can be ill~lalied or rer"o~ctI). '>elec tron mar\(en, lind transcri p! lonal promotCf'\\. lloc: passcnl1er I)NA must integrate inlo the hosI: ceU's DNA or be ~ into the cell lIS pan of a biologically active molecu le that C;lf1 replicate indepe ndently. Irthi s res u11 is nOl achieved. the Inscne(! gc nc will root be ucccssfull y transcribed. Tloe 11I0St cOIl1m!)IlI) used biological agent for tfllllspon inll gcnes illto baclCtial and yeast ce lls is the plasnud. such liS tbe t:. (t>ii boclCnal plasmid pRR322. A plasmid is a sma ll. double-~trnndcd. closed circu lar extrachrorno~omlll DNA molecul e. nl is plasmid COIItaiM 4.361 bp and can tr.ubpon rda\lIc1y small amou nts of DNA. Plasmids OttUr in m:my "JlCCie~ ofbactena and yel\1;ls. Som.::timcs. plasmlds carry their own gene ... e.g .. ell4:. the highly tr.msmisslble G \ for allllb,OIIC ~"Iallce in some bacterial spedes. An imponUIII f... alu re of a pJa~mld is that it has an origin of replicatior1 (ori) sue that allu ...s 11 to multiply independently or a host ce l l'~ DNA. Although there can be more th:m ~ ~opy of a pl ~m,d in a ce ll . the copy number is controlled by lite plasmid it,'iC lf. Another type of cloni ng Iector is the bacteriophage ( Fi g. 6-71. BllCleriopha&c A (lambda) pos.se".c~ a genome of approximatdy 4.9 X l()'f bp and enn package large amounts of gcoetic ntaterial without affc(;ling the infecti vity of the 1)luIge. A larKe DNA library ca n be created. pal:kageU in

~;M], lhe:

1'1:

IIun. II nnah .... '1: DNA

TAIlE

.. ...

... ".0
'
,",rr

~2

P.lindromlc Cle.v.g e 511

...,,,

n l CGAA
Ha,tII

TGG t CCA
1Iht.1 OCOIC

.."

&.m Hl G! GATCC
1/"..111

Igt/ll A1GATCT

AT1CGAT

'".

G! ......nc
"potl

".,"

11..... 111
A ~AGCTT

!loIIur

GOlec
,~

.....

(ll1>ylI'llAC

111"'11 c!COG
,~,

GGTACk'

"''':AIO

COATI.co

"'"

'-,

OlT((lAC

=-

clc<;Goo

,",t GC !(jQ('C'()C

Left Arm

E. coil plasmid pBA322

361 base

pen

Figure6-7 Typesofcloi.og ve<tor~: a !N(tenophage and i plMmid

bac,eriophage .t and when lhe virus infee's. IIlsertoo ,nto bridiwion IS lhen dclecleti by screening with DNA cells. probes. In a(ldi,ion. there are special veelon; called phagemids. \'acctnia !Illd Hnovirus for cloning inlo mammahan cells. and yeaM lIfIiflCial chromosome5 (YAC~) lha. fadlilate cloning in yeasts." Diffcrences amonglhesc vee Ion concern the size of !he in.'ieft Iha, ,hey will accepl. the mc1l1ods used In the scleelion of the clones, and lhe procedure< for prupilgalion. Once .he passengcr I)NA has been creu led and!he plhsnlld ,"eelor tUI (both with the same restrn:lion enqllle)"he insc:n is ligated lO'O lhe plasmid along with II promoter (a s.hort DNA sequence Ihm enhances !he Imnscriplion of the adjacenl &<,ne). Often. a gene impaning anubllll:ic f'C$islufICC Hnled to the dcsm.'d genc is inserted as a scleelion tool. 11Ie idea behind this is Ihal if tile gene ,s inserted In lhe proper local ion. the baclerial cell "',lIgmw on a medium conta; ninll the antibiotic. BOCh.'ria tml do not conuain the resislllnCc gene and. hence. lock the required gene "'111 not grow. This makes lhe lask of $o."T'I:ening for inlegr.n;on of the desired gene eas,er, After lhe It'IOleI:ule is ligated. the VCC\(H' is finally a rONA molecu le thnt CDn be in.....:rt~-d into a ho~t cell, 11051 cells can be bactem (e.g .. . coli). eukaryotic yeast (SiH;cluJmmyCt's cu"";Sif' .. ). or mammalian cell lifles ifIClud ing ChifleSC ham~ter ovary (CHO). African green monkcy kidney (VERO). and baby hamstC'l' ~ idncy {BHK). lt i~ ea~y to grow high cOlloCe mrmions of OOc:ria and ye:lSt cells in fCrrnenlcf5 1 )'ield high proICIn concentrations. Mammalian 0 cell w lt ure systems typically give poorer proll'i n yield~. bot sometime$ this IS acceplablc. especially ~hl:n the produc:. demands ,he key posmunslauonallllOdificauons thai do not occur in bacteria. Host cells contai ning the ,eclor are grown

H b

in ~rnall scale cullUre~ and screened for Ihe <kloIn.'(l gene'" When lhe clooe providing the ~t proteIn y.ek! is located. lhe organIsm is grown under carerully controlled conditiunl and used 10 inoculate pdOl' scaIc ferrnentatiOllS, ParanIClC'll such as production medium composItion. pH. ucrati()n. ag!lJ lion. and temperature are in,'csligatN at ,hl~ !itagt 1 opu-0 mue the fermentation. 1bc hostccllsdivldc and lhe pla$rruds in lhem repliclilc. producing I he~lred "'new" proIem. ~ rerrnenualion is scakd up into tariff bIC>reac1ors for largescnle isolation of the recombinanl protein, Obviou~ly, tlx culture~ secretc lheir own natural proIems along v-ilh tbr cloned prOlein. Purification Sleps are requin.'(l heron,-, the fI'. combinaut proIeln is suitable for:sting:n a new. geneucaltJ engineered pharmaceullcal agent. Once the host cdl IUIt expressing the recombinant gcne is isolated. ;1 i~ e~nLiJI to maintam select ion pressure on ,t ~ that it docs not Spoolio ncous!y lose the plo-,mid. T ypica lly. this pressure is applied by maintaining tIM: cells on lnedium C(lrllaining an anubioto; to which they bear a resistance gerlt',

, ,

, , ,

, "
I
t;

" k

SOME TYPES OF ClONING

A listing of some lypeS of dOlling is gllen ,n Tablc 6-3.

" " ".

"

F ..nction..1 Expressloll CIoningFUflCtionol expres~i()n cloning focuses on obt;tining a ~ c iflC cDNA of Imown function, 11lere are many ,'analKMI on this approach. but Ihcy ull rely on tho: ability to scartII for and isolate cDNAs bal.ed on _ funclional actt'"1I)

..

cl

,, ~

Chilpler 6

BlOudll,ola,~

lind l>n.g Due",.......

167

TAllLE .... l

Cloning Str.tegi"
Advlntlgn

DI...:I,,;l nl;l U_ 1.J

>(

" . . mple

Pro.,..,. ,,uOOI\;M;OI1 lIIIdcrl)lnllht

JCOCIoc~I.lIik ........ ~...: ~

l(t bp. do!r","11 1 _ wnll d, ..asa 0

.... ,wI by ,""",uplc: .-...:tine ollt...

Yocld. p1IC"ti<" 'nf.......... C"I>lO.b", ," .. ""oIl_'n "....,.... ....

'111..-.
, ..... lIon

y ...... .-:toe IIIfomtlllOlO e.lCXh1!;l

!""MIn. ulk"""," _'I"", Ind

."voI ..... j'IftJICin punr.... _.

,..,....,... .........,...., ,...,.

libe"')' ....... '''". ""'1onoIIotY

Jowobw

pworo..--. CIpOCwly '''''

'1'ICe ,. , ....... ;. oat"bOIC:

"" I h illY 01 ~e liIIrard..

unrn:<lI",ud <'n;OW...-..ctoVlf)-.

.~ "'1""""'"'

VICki> ......" " InIUn'lM1OII ~rco.lh'l1 Il'uncuunally .. 1""'>I<,n; doa

to. '."I'''~ prote,n p.mrOC IIMln kit""r..,...,. ut ...1MnI JCIOeO '" rmo familia: rclauvcly ....... fll
T ., .

",,'6

,ncomplctt """ne ~-e. f'urIL1ion "'u.. boo ~poo,bIe with n,..,,,,

o.-pe...iI COlIC ...p........ . taa yitld ,... "' ...... ~ JNOS "' ........ 01
___ n '",,",ion

on ...... ""n.

d'l 7X'.,.
m . . .~

II"'zhnIa~ldoootor_oI

"""". cON"" K""",Ied,. 0I"J511 .,.......: ideIItor""'lion 01 olI I'OICnu~' .....

'lI<OIIOfIIrWcodi"''''1 ,,. , .. ,,,,...01 ~ fomobOll U)< HI'bp. t.oIIOf I""",,..e; cn>t'oI ""Ia....... to"""""

""'~
fIIzIlCJII

..... -""

be 1Ilt:z.wmi. r .g... the clc:ctrophySiologlclll nlea.wre-

~ellt .., ~aled.

. . of ioo ~Ia~ following expression of cDNAs flU!: ooC)tt:J. By iocremtn[ally 5ubdividing the c DNA~ pooh and folJov.'lng the x u vity. 11 I~ possible I/} obtain Wlg~ tDNA done that encodes the fuoctionalny. The JI!\'allIa~ of fUflCtlon~1 e.... pres.,ion cloning h thUI il dues
n:1) 011 kllOwledge of the primary amino acid o;equcnce. TIu;, IS .lIefinJlc lIIh'anlage wilen attcmpting [0 clone pro~ ofkzw abundance.
"'~

idllion, lIOCtCr.. I. aglta-

'" "P" ,,",

'due' Oulng"

rn. The

r l~

"Iy. theith t~

the

5l'-

etically til line nual

~Ha-

rPlit.-d ibiOli"

6-3.

donmg can be used 10 localize fr.zgmen[~ of DNA itl" '1lIIog gelleS pnor to isolati ng the DNA . An example II ~ Ulle of poxitiooaJ tlooing is the elooing of the gerv: ~<Ible foreyMie fibfOsi~ (Cf). By studying the jXlllems .i IMrn[1IlCC of [he di <;case ~nd [ocn comparing [hc<;e ",ith lIftl'ln cnromowmaJ marl~rs (Iinkllge analysb). il was pos1itIk...ilhout k_mg the fuoction of the gellC. to locatc the pron human c~ 1. Then. by u<ing D lc:chnKj\fe u.:..n 2S (~fQmI'$f_ ,mJA.mg. the Bctle wa.~ loclI.lil.cd to IO"A ~oce that ezw:odes II protein no .. known as the .ytlK: fibro!;l!0 tr.zn,mcmbrnne conducluJJCe regu lator ({1'TR). 1117&protcin. pn:~iotJsly unknown. WIIS $hown to !Ie okff(ti, e In CF pahent~ and coo ld :tCCOIlnt for mnny of tile , IItjl\Om.'I of the: di<;ca~. Like functional cloni ng, positioMI .hll1ng h.J., [he: IFdvan[llge [hnl specific knowledge of tile rrOlnD i, not IUjlllrW. II i~ also dinaly relevant to the ~ng of human diSC'a~. an<.! it can provide import.: ""' tzzoIogJC31 1arp!IS for drug dc"clopment and the ~_.<"I diSC':ase, Ilag)'.B.nd aonlng

ogy.. lHut'd doni,,'f. UIl:es IFdvantngc of the fact that nllClcotide o;eqUI.'IK."d COOQding imponant fuoctional donWns of proteIns tend to be eoo~n'ed dunng the pioccss of e\'oIu.100. Thu ~. nucleotide o;cqucoccs eocoding regions involved with ligand binding 01" tn;t;ymlllic activity can be used u probe~ that will hybridi:re tu complementary nucleotide SC'queoce!> Ihat mny be present <m other gc ne ~ Ih~t bind similar ligands or ha" c similar enzymatic acti,ny. This approoch can be combined witll PCR OI 9: [0 nmplify the DNA liequeoces. The II5e ofllomology-based cloning has the lIIh'antqes thai il can be IISCd to identify families of related genes, docs not rely on the puriflCatioo or functional acthity of. given prote.n. an<.! can provide OQ\'e ltargcts for drug diseo\' cry. lis u~fulncss i~off~t by thl: pos~ibililY that the isolated fragment may not eocode 11 complete or functional protein or that in ~pi[e of knowledge of the shafL-d sequcnce. [he actual fuoction of the clooe may be difficult to identify.

EXPRESSION OF CLONED DNA

Once cloncd. there are IfLIIny different possibilities for [he e~pi"e5sion and manipulalioo or DNA '\Cquences. As it concerns Ihe USl: of cloned gcoc.s in the process of dRlg disco~ery and rJcvelopment. there are many obvioos ways in \lhich lhe e.-pression of DNA seque:OCe5 can be applied. One of the lnosl obvious is in replacement of older technologies that invol \<e the puriflCalioo of protclns fill" human II5e from either animal sources or human by-products.. .weh as blood. An example or this is factor VIII. Q clotting cascade protein used for the trcamrcnl of the geoc[rcnlly linlcd bleeding dlSOl"der hemoplul13. U71lil recently. the ooly source of purified factor V III was human blood. and tf"Jgically. befon: the impact of AIDS was fully appreciatcd. stocks of faclor VIII hud becomc contaminated with IIIV-1. resu lting in lhe infection

APbef doomg stralegy involvt..\ the uo,c of previoosly ,1UZKtl !cnc:s [0 gUide idenllficatioo and cloning of evolur.'IUl!y n:laEed genes. Thi s npproach. referred to n.~ homoJ-

of a~ many ru. 75'K of the palients receh'ing Ihis prodUCt. 11M: gene encodlnl! faclor VIII has since been cloned. and rea>mbinanl fllClor VIII is now a~aJlablc as a prodLlCl puri fied fmm cuilured r.,:mllnali:U1 ~"ell~. Other recombi nant clot tI ng faclOrs. IncludlOg factors VI In nnd IX. are UJlder de~cI opnN,!nl and. tOKcthcr with recombinant faclor VIII . will eliminate the risJ.. of e~posure to hurnan pathogens. Other uample~ m" hich the e,pressioo of cloocd hu~ gene, Qff~ ahel'nall'es 10 pn'\'lously CIIistmg productS inc lude human insulin. "hich IS now a ~iable replllCement for purified bo\'inc arid porei.,e i n~uli n for the treatrncm of diabetes. arid human growt h hOlTllone. ,,"hich is used for the treatmcnt of gro" th hormone defiCiency in c hildren (dI\oarfism ). Unli"e il\5ul lO . gm" th horm(ones from other animal ~pcc~ are ineffectivc i., hum~us: thus unti I human recombin3nt gro"'lh hormone became "vailable. the o.,ly source of huntan growth hormone wlI$tOO piLuiHll')' glands of cada"el'1l. Thi. 00\ iously limited lhe ~upply of hUI1l:lJl gro",th hormone ~nd. IIle fllClor VIII. e~posed pallents 10 poIential conlilmJ' natKll1 by human ]lathogen~. Recombmant human growlh homlOllC can now be produced by expression HI bacterinl cells. TIM! ClI.pr"eSsion of c loned gene:~ can be iUlcgrated iuto rational drug design by pro~idingdctailed informatlOll about lhe SINCture aoc.l functioo 0( the Sites 0( drug act ion. With the clollIng of a l.~ne rome..' J..J1Owledge of the primary amino add sequcnce of an encoded reeeptor protein. This in forma tion can be u;.ed 10 modd its sc:rondary stNClure arid in an millal aUcmp! to delillC the pl'"otem's functional domains. such a..~ II~ ligand-binding sile. Such a model can lhen scn.e 0 as a b.1~i~ for the dco.ign of t'ltperimcnts that can be used 1 te.~tlhe model and facilibt~ further refinemc:nt. Of particular u'\C are mUlaGellC'i~ c~peril]lc nt~ th:lt use rONA te~hniques 10 change a prinmry amino acid M:(jucoce so Ihatthe ronse quence5 t'lIn be slUdied. [n OOdi lion. e};pression of I cloned UIl'get protein CIIn be.- used to gencmte samples for various biophy~ieal dC'u:rmlnatoons. such as x-my crystallography. This tl'<:hnique. ",hich can pnwidc detailed infomlation ub<)U! the three-dimensionalllloleculo r MrUClUre o f a protein. fmjucnlly requ ires large amounts of protein, which in some eases is only a~aol:lble "ilh the usc of rea>mblnant CII])feS' ~ion 'ystems. !.ikc the many strulcgies u\Cd to ~ Ione genes, lhere are m:lny 'tnneglcs for lheir e~prcssion. invo l... ing Ihe usc of eithe r bacterial or eukaryOlic cen~ aoo s.peciali/ed vCClors compatible "ith upression 111 hoIit ~11s. Slnee the!;e cells do IlOl llOI"1llaJly e~press the proIein of iuteres.t. this rnc:thod. olOllY IS often referred 10 as hnutHogOlU c).ptcllioll. II is . h" pos~ible to prep:tre cRNA from rONA. "hich can then be: u'<Cd for eilher in ... ilro expression or injcctiOIl directly Into cells. In the former silU:ltion. purified ribosomes are used in the test lube to ron,'en c RNA into proIein; for the \aller sitU:ltion. the endogenous ce llular ribowmes make lhe proIeln. A relat",el), IlCW dc"e1opmcnt for the expres~ion of cloncd genes i ~ the U'>e of allInlal ~ that have the cloned gene Mllbly inlegratc(\ into Im-ir geoome. Such trnnsgen ic an imals can poIentiaHy mIlke ...ery!Mge amountsoffC(:Olllbi nant pmtell1 .... hlCh can be ban.'esled from lhe milk. blood. and ascitt'S flUid. The choice uf D panicular cllpres~ion systcm depends onl nUlnber of faCIOOi. Prote in yield. rcquircmculs fOf biological acti ... ily. and romJXIlibility of the c~preswj protein with the:

host organism are a few. An ellample of the compatibilit} ISStiC is thai bacteria do IlOl PIOCUS proieins in c};lIdly lhe same ways as do mammlllian cells. so thai the ex~OII of human proteins in bacteria willllOl: alwaY5 yield 3n acti~ producl or any product at all. Cases like lhese may rcqUI'" expression in nuunmalian cell cultures. The choice of !III expression system also reflects the a... ai lable ~ectors and cor responding host OfPIl;sms. A basiC requul'Jne:nt for !he het erologous l'lIpression of a cloned gene: is the pre:scncc: 0( a promoter that cun funcuon III the hosl organi~m nnd I mechanism for imroducing the ~Ioncd gene into the organ iSIII. The proII1O\er is the specific site at which DNA pot)', mcnISC bind5 10 initi3te Ir.lnscriplioll and is uSU!llIy specif" fOf the host organism. As in gene cklning. the vectors _ either pl!lSlnids or viruses thai tua'e bo.-en englnc:cred to 1(:cept rONA andthm conlain promotel'1lthar direct the e~pn:s sion of the rONA. TIle techniques for iUlroducing lhe ...('(.101' ;nto!he organism "ary "idely and depend on "hether one: is interested in transient expression of the cloned gene: or ia siable expression. In the Jailer case. integrallon 11110 the ho:!I gcnome is usually required : tnmsient expression si mply"' qU ires geu in g tile vector inlo lhe host toel!.

MANIPULATION OF DNA SEQUENCE INFORMATION

Perhaps !he greate'lt im~ of rONA techoology lie'l in Ib abi lity to altu. DNA sequence: and create enhrdy new m0lecules that. if reintroduced inlO the genome. ean be inhenttll nnd propagated in perpetuity. ~ ability to alter a ON!! sequenee. literally in a test1Ube. at tile discretion of an indio ~ idual. corporation. or natioo. brings with it im portant q~ liOllS about ownership. ethics.. and social responsibility. 1nere is no question, however. Ihat poIential bene:fil5 to iIIf treatmc:nt of human disease are great. TIlere are tli~ principal reasons for using rON A tcchooi ogy to alt .. r DNA sclluences. 'The lirst is simply to clone tIw: DNA to fllCiliuue subsequent manipulation. 1ne second is to intentionally introduce: mUl!ltions so that the site.specif" cffcci on protein structu re and funelion can be studied..... The Ihird re uSOl1 i~ to add or relno"" sequences 10 obt... some desired allribute in the recombinant protein. Foruam pie. ~nt studies wi th fanor Vlli show that the proItll co,"ai n~ a small region of amll10 ocid.. that are lhe map dct .. nninant for the gene:ration o f anti-foctor VIII anuboWa in a hum~n illlmune: syste m. This auloimmune: re!>pon5t Ii the patienl inhibiL~ the DCli ... it)' of factor VIll. which i,obviously D serious lhempeutic compliC:ltion for patients ",flo life usin g foctOl'" V111 for the treauncnt of hemophilia.. B J aitering the DNA sequcnce encoding this dctennill3nt. """,. e ... cr. the ami J10 acid sequcnce: can be clklnged Ixxh to mIutt the antigenicity of the factO/' Vlli molecule und to male it transparent to any e~iMing am i- factor VII I antibodies (i.e., changing the epitope eliminates the existing antibody 1'CCOf. nition si\es). It is possible to combine c1elne:nlS of IWO protd~ one IICW recombinant protein. The resulting protein. rertmd to as a chimcric or jusioll pro/tin. 1I13Y then have some d the functional propertie5 of both of the original proteiAr.

llibilily :IIy the

protein can then b.! idenlified by immunof1uOl'eM:Cn~'i: or can be purified with anubodle\ that reoogm/.e the epitopc.

n actj~~
~r nn

~\IOn

reqllll\,

~~ur.

he helbntt of and a
Of'g31l'

NEW BIOLOGICAL TARGETS FOR DRUG DEVELOPMENT

P ',,"RCWA RICwpt B

polylfie
1If,:-

/"' = [0

exl'f"C\-

~ ~~'~"I(lI"

,.eorm

/Cr one

he ho.., jpI)' re'

Figure 6-8 Ch,menc receptors.

n... 1\ 11I~~lnllcd In Figure 6-8 for \....0 .cuplon llibeled A

.! 8. Eacll m!C:plorlla.. functional domains ,hal are rcsponIiItk for hgand bind,ng. InLegr.uiOl1 inlO lhe pl ll!lma memlnnt. aud ....1i\';uion of inlrJCeliular sig naling pathways. l "I rONA techmque one can cxch:mge these fUllCuoonl brLum tI. ~ale clli mt'ric reccpwrs IRaI. for example. con_!he h~"'ndlng domam of rettptOl" B but the translICmt>nlne 100 intrnctll~lar signaling domains of rttCplor ~ The ~1"P'ic~liOIl of ,Ile fu , ion protei n Mr.ucgy is discu~sed
fIIIllcrm ronnrctioo II 1111 the human growth

hormone reccp-

inln

tunder the ht3ding. No\'cJ DrogScl'l'ening StIlllcgies) .! .. ,tb dclllleuiJn d,fuIOX . AIIIIlher rta\Oll fir rombmmg elementS of IWO protein s rtrombillant (lfl ~cm is 1 fucilillUc its cxpn:ssion o al JlUnfl.~lion. For c~amplc. recornbinunt g lutathione S m,lrr.....e IGSf). cloned from the parn~i t ic worm Schislo J<lPfIflKwM. is ~tron~l) exptl'S5ed in E. coli and has a binJlllI \lIe fOf glutdlhtOOC. /-IC1cro1ogous sequences cncod If the funcllODal oom:llns from OIhcr prOIeins ea ll be fused. 111I1IIC'. to the ,arbo~y terminus of GST. and the resu illng fINoo rrotein I~ oAtn e~p~d 3t the S,11TIC lev,ls as GST .11 In a.idllIon. tile rewillng fusion pl'\Xem still reta in~ '" III'Illly 10 bmd glutathIOne . .... hich means that affinny o;I\I:\~y, u."ng glutathiooe that hlllo been covalently ",.. led 10 iproSe. can be used for a sin glestcp purification c(thc lu,1OIl proi(In. 11lc fUllCtional IICt; vit y of the hetcrolo""'" ~in\ th':l1 hal'\': bern fused to GST can then be SCud I:Il edIIefll'>pt of the: ('NOll protein or separately follOWing ~Imem of the fuSIOII protem wnh ~pecirlC proieues that mile. tbC' Junction between GST and the heterologous blwn. l'llnfied f\l~1OI1 protein. can alo;o be u!>Cd 10 gc nerutc .,tW~, to the heterologous domams and for other bio~uWts. SometulIcs. fusiQll prote ins are made to ... ~ Ila'OOIbllunt protein that un be {'asily identified. AI (UII!PC of tillS I!. tectmique called tpjl(J~ t(lICSi"S, in wt.ct. ,,(II~lenlcd anlibody TttOgnilion ~i tes IlIl: kIal .. nh recombinant protcins. Thc res uHing recombinant

""1Ik'

One of the QUtCOlllC$ of the progre.~s lhat has boxn made In the id(ntiflCotion and cloning of genes is that mauy proteins cncode<.l by these gellc.~ represc nt enurely new !:Irgcb for drug dcvelopmenL In some e:a.>eS. thoc genes themselves may repreSCnt the ultimate tBrget for the treatment of a <.I isease in the fonn of gene therapy. 'The clOllIng ofthecy~hc fibrosis genc IS au c~ amp le of both a ne" dru g target and a gene thaI cou l<.l potentially be used 10 tfCll! Ihe <.Iiscasc. The protci n encoOOd by lhi s gene. CFTR. is a pl\'~iou~ly ullkno", n intcgral ulCnlbnme protein that Funct ions as a channe l For chloride ions. Mutations in CFrR underllC the pathoph ),'lOiogy of cy5lic fibrosis. and In principle. replocenltnt or CQupn"'Ssion of the dcfectl\'e gene with the htatthy, nonmuta(cd gene wool<.l cure (he di ~easc. It i ~ al so possible, howe~er, th;lt by undcnotlln<.ling the structure and function of the heahhy CfTR. druGS could be designed 10 mteract ""ttI lhe mutated CfTR and impl'O"e I t ~ function. An Important outgro..... lh of the study of new drullllfgC1s is the reoognition1hat man y tra(]itiona l 1argets. such a.s en 1,Yllles and receptOfS. are eonsider.lbl y more hctcT\lgencous than pre"iousl), thought. 11lus. instead of one elll.yme or rccc:ptor. there may be ~,er.11 closely related subtyJlC" or isoform s. r:ach ",ilh the poIenlial of representing a SC'parate drug target. ThI s can be ill lbtr.1too II Ith the em;yrne cyclooxygcnase (COX), which is pI votal to the fonnatioo of ~ta glandi n~ and which is (he target of aspltin and the nonstero l' dal an1i innamm:1I01')' agent.\; (NSAIDs). Unul rccc:nt ly. COX w .... considered to he a sing1c enzyme . but phannaro. logical and gene clonIng siudicl> ha"e re' eaJcd thllt thocre IIl'C al lel~t three enZyll1C forms. named COX- I. COX-2. and COX-) . Intereslin gly. (hey arc dirFc"", ntially rcguln k>d. COX- I l~ expressed CQ" st illl\ivcly in l11any ti ssue~, "' hereas the e'pression of COX2 is indoced by innamm.-uory pro. CI':SSCS. ThUs. the dc"elopment o f COX2 ~lr:ctll'e agents can yield NSA IDs wi1h the same effK'OCY as U lst lllg (nonseleeth'e) agems but II nh fewer side CftCCb. such ll~ those on the gastric mocosa . The e lucidation of the family of adrenergic receptors is another example in IIhlCh molecular clon ing .-tU(hes ha,c revealed previously unknown heterogeneity. with the consequence of pro~ iding new target.\; for drug de\e!opmcnl. lbc adretlCrgic rccCptOfS lnedi~tc the physiological eff~'Ct~ of the catccholnm ines epinephrine and norcpinephrine. They an: abo the targets for mony <.I rugs u<;cd III the treatment of wch condltJOl\S II!I conboe~ll ve hean fai lure. asthma. hyperten sion. glallCOOla, and bemgn prostatic hypenrophy. Prior to tllc moIeeular cloni ng and puriflCauon of adrenergic receptors. the phunllarological e las~i ficat iOll of 1hi~ family of receptono con sisted o f Four subtypes: a" Ill, P" and ~. The mitial cloning oftllc a-adrcnerglC receptor III 1986 anti subsequent gene clOIl inG studies reveWcd at le .... t mne subt)'~; P,. ~ . fh a ,A. a ,R. a ll). U1A. lr]R. anti (O x- (Otapt..... 16). The evidence lhat (here arc mne ~ubt)'pes of adrenergic rccep40rs is very importam in remls of undt'notan<.ling tllC

TABLE &-4 Selected E mples of RKeptor Subtype Heteroge_ity

O'...-.n~

.........

11,.11,. ,....
0 , O. EP,.EI'"E.P, NCfVe JIOWth fIIC10f rcpIOf

Dupo....... "-'eland;n E,
k' ...... ncurou""hu..

II~ tyIOi ...

II,. 11.. 11.. 01 ..... ,.... 'II< .. tA . .. ,8_ .. ~, 0 ,.0,.,0 .. 0 ... [), EP ,. EP . liP,", EP. TrU." TrtB. Tr\C' ERR!. EIlR2 TRn.11I.11 R"Ra, KARII
0,.0,. '" (1DIIl1I""""',lf

~"-'

'-"""" Th)'l'OIil _
R.....,;.: .. ..J

E ..."'....,.-

Rc{,,,,*, 8CIod IU",*,,"

....-"-... .

L.opno.!-InJ'lIICd ...........

G,,8,,_
ltIIttIII _ ) .....

G1~,,""

...... , .. ooIlIIo" ...... u ...... - , ; CWy . . I"" , ...,.,.. . h..... I I '

1' ._....

GAll" ondIcr ben"",li","';'" ""'"I_

"1 . . . .

", ... " .. .. .... "'" CIt (Alii III

_._ ,__

""""..u I"
1 01,.

,.

=_, t

I h..... . . t ...

".)01" .... _

t ""0

om,-,",-,

phy,iology o f the adn:nergic Tt'CCplOr5 and of dc~cluping drugs tJuat can !il:lec-tively interact with the.-.e subtypes. Foc uample, In the case of the <I':!-ugonist p -umiooclonidine, an agent used to lower Intraocular pressure (lOP) in lhe ~al mcnt of glaucon.a, h may now be possible to explain $Ome oflhe drugs p/Ulrmocological ~idc effeels (e.g., bradycardia and sedahon) by in,oking interactions wi th the addilional ttractm.ergic recept.or subtypes. coruidernble inten:st is the po5$ihility thalthe~ pham.acological effects (i.e.. lowermg of lOP. bradycardia, and sedation) are each mediated by one of the th~ different <I':!-n:ceplor subtypes. If this is tlUC. it nught be possible to develop a subtype-selective a zagonist that Iowefli lOP bl.n does not cau~ br.ldycardia Of sedation. Likewi,;c , it might even be possible to take IKlvunlage of the pharmacology and develop R':-adn:nergic agents that selec-tilely 101'l"C'T hean rate or produce sedation. The di~very or subtypes of recepiOfl lind en/ylnes by moleculor cloning studies seems to be the rule rother tlian !he uccpliOll and I!J offering II plelhora of potential new drug targds (Table 6-4). To llQIe just a few: 5 dopoimine receptor sublypes have been cloocd, replacing 2 defined pharmacologically (Chapter IS): 1 seroconin receptor subtypes lil\\e been cloned. replacing 3: 4 genes encoding receptors fOl" prostaglandin E: ha'e been i~ated. including 12 additionol ahemati\'e ",RNA splice ~4nams: and 3 receptors for nene growth factor Ila\e bn cloned. replacing I .

or

NOVEL DRUG-SCREENING STRATEGIES

The combination of lhe heterologoo~ expression of cloned DNA. the molecular clOIling of new biological targels, and the ability to manipulate gene sequer~s hIlS cn:ated po .... erful new tool~ that can be applied to the proccu o f drug discovery and de,clopment.. In Its ItlQ){ strnightforv..ard application. the abilily 10 simply upress newly idcnnfted u ceplOl" protein targets offefli a novel lT1Can~ of obtaining infonn:ation Illal may be difficult, oreven impossible. to obtain

from more complex nati~e biological ~ystems. Then: 11 I rea.wn fOf" this. A newly identified prote in can be clIpre\SCd in isolation. Even for closely related ell1.yme or reccpmsubtypes, helerologous expression of the individual subt)-p: can potentially provide data thm are specific for the subtype being expn:ssc:d. whcrellS the data from nati~e biological systems will renect the summation of the individual subtyl'l'$ that may be present.. The potcntial advantage of heterologous expreSSIOn Jj illustrated in Figun: 6-9 for the interaction of a drug '111m mulliple binding si tes. In pan~1 A. ..... hi ch can represent Ik dau obtaIned from a nathe biological system. thor (\all. complex, lind lhe curve ",neclli interactions of the drug 'lila twO popuilltiol\.'i of receptors: one wilh high affinity. n:prtSC'tlting 50% of the tOOlJ reptor popu lation, and one ". low Iffinity. represenllng !he n:maining 5O'lo. The indl'-idoII contributions of these two populnlions of receptors an: IIIIiCited in p(lIIei B, .... hich coold .I!oO rtnCCl the data otx..~ if rONA. encoding the5e two rep!ors ..... ere cxpre~sed.1IIi vidually in a heterologous expression systcm. Allhougll. sorne cases the data, ftS in fNm~1 /t, can be anal)'l!ed 'lllIi success. frequently they cannot, especially if more than tWO sublypcs are present or if any one subtype makes up b than 10',l, of the totll recept.OI" populatiOll or if the afJinwes of the drug for the two receplor popu lmion s differ by Its than 10-fold. AnothC'T imponant reason for integnllmg hcterolcJeucxPfCSsion into druS-scree"in, strategies is Ihat dati CM_ ally be obtained for the hu man targct proIein ruther than_ animal ~bsti tute. This docs not mean thal organ prtpntions or anunal models will be totally repllCCd. For the 1*poses of lhe idenlifocalion oflcad compounds and the optl. llllion of selecti~ily, affi nity , etc .. howe~er, !he UOt d recombinant cxpression systems pro~idcs some obviov$ vanlages.. By combining heterologous upression with novel tional assays, it is po!I5ible to Increa.'lC both specirlC,ty" throughpl!t (tbe number of compounds th;it can be "'IIXwI

r..c.

mtil/jH bindng
,116 Interacl/on$

1
,
.bg {Drug) (M)

i.

" .

1 '

'2

10

.bg

{Drug]
(M)

eO!'NOlutI!d data from binding to multiple fec~ ~ dasSK: mass action .

have been develI glillnine nudOOliOe-binding of cA MP. or calci um. One I fuoclional a~say5 in. ONA that controllhe of genes. This approach is e~e mpJi fied by lhe

cAMP ~sc .. lernenl (CRE). This 15 , specifically defined scqueoce or DNA thaI is a bindin, site for lhe cAMP n:spoosc l'lemc:nt-bindiog (CREB) procein. In lhe un'ilimu I"ed condition. the binding of C REB 10 lhe CRE prevents the Irllflscripdon and expression of genes lhat folio .... it (Fig. 6-10). When C RED is phosphofyhued by cAMP-dcpcndeni protein kinase (PKA ). IIowever. ilS conformation changes. pt:llILining the Ir.U1scription and eJl.prt:ssioo of the downstream gene. Thus. ;ocreascs in intr1lCelluJar cAMP. such as those caused by receptors that activate adenylyl cyc lase (e.g .. ,8-adrcncrgic. vasopressin. and many others). wilt stimulate tile acti vi ty of PKA. which. in turn. resu lts in the phosphorylation o f C REB and the activation of gene tr.lIlscription. In nlllUre. there arc a limited numbcrofg~roes whose acti vity is regulated by II CRE. Biologically. howcvC!'. the expression of allnO$t any gene can be regulated In a cAMP-dc:pcndenl rashiQn if il is placed downstn:am of a e RE. usi ng rONA techniques. If the productS of the expression of the downstream gene can be easil y detected. tlley can scrve as reporters for any receptor or ellZyme that can modulate the formation of cAMP In lhecell. 'The genes ellCOdi ngchlorampIlenioo! acetyl Imnsfer'Jsc (CAT ). lud fertie. and ,8-gp]ac tOoSidasc arc three uamples Qf pcIIemial " reponer genes" whose product~ can be usily delected . Sensitive enzymatic as..<>ays ha" e been dcvel<lpCd for all of these enzymes; thus any cb:mgC5 in their transcription will be qui ckly reflected by changes In enzy me lletivi ty. By coex prcss ing the reporter gene llong with the genes encoding m:eptOt'1 and enzylTlC5 1hat modulate cA MP formation. it is f)QS~iblc 10 obtain very ~nsi t ive functiOllll] mc:asurrs of the activation of the rou.pressed enzyme Qr recep4or. Another cAu mp1c of the use of 11 reporter gene for high_ throughput drug screening i~ the rttcptor .!C.lection and amplificallon lechnology (r-SA assay . This assay takes ad vanl1lge of the fact thaI the activation of sev~ral different ctasses of lllCep4Ot'1 can cause cellu lar proliftntioo. If genes for such recCp401ll are lin~cd with 11 reporter gene. such as

CRE-l)IrodL'lg P/'OItlIn (CRES)

/
off
Repor"r~

cAMP R..poi'\H Element

on
.1.10 . ActMltIOl'l of lIar&t1ptltrrlefll (eRE)

cAMP-<ieptn-

eRe

p-galao::l()';idase. Ille ;lCti\ lIy 0( lhe n:poner ""III be illCTeased a, lhe number of ccll~ incn'af,C as II oon<;4."queoce of recepcor lelhalion. Inilially. a linU!:IIion of this assay ""as tMt it ooly worked 1I" lh 1"C(C'plOl'S lhal llOml.ally coupled!O cellular prohrerauon; by ma~lIIg II mutalion in one of lhe ~ mc~senger proIcin~ involved wilh ,he prolifer.1ti ~e respoIl<;t. howe\tT. ,I was possible 10 gel addilion::ll n:ttplOl'S to lIim ,n th,~ assay. This <oecOI1dmessenger proIe;n. 0... was cloned. and II recombinanl chinlefa was made Ihat inc luded pan of anoIhc.- ~ nlt)~nger lnown as G,. In nalive cell~. receptors lh:ltllCliv3te G IIU'C IIOIlnown for their 5limulatiun of cell prolifcrntioll. but whcn such receptors are coello pressed in the r-SAT assay willi the chimeriC' their activo i,y can be mellsured. A similill' Qr.1tcgy in\'oh'ing chimcric ptoteins has been u~ for receptOl'S ..... hose secoOO-IllC'I>.'iC'nger signaling p:nhwOy5 an: no! Clearly undtDlood. For c~ample. the develop-ll}Cnt of poIelltial ther.. pcutic agents ac,ing on the human ,rowlh hormone receptor has bn difficult because of a lad of a 1l00d signaling assay . The fUnc1iollal ;lCli vi,y of other receptors th.u arc ~truclur.. lly and fUrlCtionally relaled 10 the grollih hormone receptor can be mellSurt.'d. oollc,cr. In a cell prollfcl1lllon ~y. Doe sut'h receptor that has I:ln clonoo is the l11uri I1C nx-eptor for granulocy,e colonysti mu lating faclor (G-CSI-). By making a rtc<Hllbillllll t C'himcric receptor (onUlini ng the ligalld-bindlllg domain ofttle human .l:rowth oormune n:ceplor w,lh lhe <;ccol1d-n1C.~)engcr-coup lingdornalll of the mun:in G-CSF reccptor. il was possible 10 Sl imu JatecelluJar proIiferJlion with human growth hormone. In add il ion 10 providing a useful phammo;.'{IIO.l:icaJ <;creen for hum~n groll',h homlOflC analoguc~. the con$truClion of thi s chimeric receptor pro' ides con~idcrnble insig.lu inlo!he nlCChanism of agoni_t _induced smw,h hormone n:ccplor;IC,ivalion. The growth homlOnc- binding domain i~ c learly localized 10 tncc_lrDCcllular ammo tenninus ofllit receptor. \ .-hilc the lrallsmembrJ~ and intr.ICCllular don,ain, an: implic~,ed in lhe: signullr.1nsd uclinn process. It wa~ also determined that successfu l Sl~nal Il'lInsduChon required receptor di Il..... ri~ation hy the agonist (i.e .. simultaneous imCl'lIoCllon of IWO receptor molecules with one molecule of gmw,h hormone). On the bas,s of thi.~ mforrnation. a nltChani'IIl'based "'l'1Itegy was used for the design of poICnual antagonislS. Thu _. hu man growth hon'lOlle llDalogucs were prepM\.-d ,hm were IIlC".1pable o f producing l"C(;C'ptor dillltril.8tion and wen: found 10 be poIcn! anlagonisls.

a...

CTIltoo by lin infectoo cell line:. or in,ruduccd by an,nW serum . PuriJication of a rONA protein while maintaining Ihr fact~ that keep ;1 ;n illi oclive ,hn:c-dimcnsionul confOllllJ ,ion from this mixture may be difflCul1 because eocil step mUSI be designed 10 cnsure lhat the proIein n:mains inl&1 and phormacologically oc,ive. Assays mU SI be designed 11\31 allow the activi ty of the protein 10 be assessed 111 each puoJ'i. cation SlC-p. Consequcnlly. lhe structure and activity of thr recombinam proIein nHl ~1 be considered al all slages of puri. ficalion. and assays UIUst be tonduc'l'd to O1('1lSUre thr: amounl of puriJiI'd. inllict proIein. A gellCral scheme for purification of Q rONA prot(,n ii

as

follow~:fl

PROCESSING OF THE RECOMBINANT PROTEIN

l>ruccssing the fcmICnlalion contents to isolate a recombi nanl protcm is oflen a diffICult operntion. requiring as mueh art as sc-ierlCe. In 'he f('T1l1t'nUltlOll broth are lloolc bacterial cell s. lysed cells. cellular fragments. nuelWlides. IlOnnal bacterial protdns. ille rccombiMnl protein. and particulate medium compork'nts. If I Gl'1Im-negalive IxIctcrium such as E. culi has been used.lipopolySllCCharidt; c-ndocollins (pyroIlen~) may be present. When animal ce ll cul1ures arc used. it IS commonly IISSIJmed that virus panicles may be presem. Viru'IC:s can also he intrudoced by tilt cultun: nutrients. gen-

may be n:mo.~ by centnf1/&luon. fihBUon. ulttaliltnllioa. and tangenlial flow filltll101. ViN' partlC~ may be IIlXUvatcd by MallO, if the rONA peplillc Can ,okrale lhe procedure. COfICrnlro/i,,,, llM: ,'oIu,"" 0( lhe: nnature 1.'i reduced .... hod! HlCrca.cs the I!OIlttnlr.llion of the COOlt'nt5. (llitn. C OIICCMialion ,5 achieVllblc by the fiitl"'JllOO !>tep. t'ipttiaUy if "t".filtralion is "sed. "1ft",1 "..ri/iro/w... TIle iml,~J purir~_ of the ml:>.t""'. somc:tll1leS attOIllphMled by prl'C'pttalion of lhe proIClIII. \lsm& a ~tow. stepwise ",crease of lhe tOI1ic w'n~lh of IhI: solution (iiallmg ()III). Ammon,um sulf.te i. alyplCal_" C;lII be u~ In coklaqUfOlJ< '-OluUo..... W"" .m1Sl;ibkOlJMl' ';01"'''1' iuch Il.< tochloro:>cellc :>c,d ~nd potyclhylo:fII' II)tOI chan,c lhe dicltrK- coostl nl 01' the IOlutlon and also dr~ pra:ipit3Uon 0( prole, ..... Inlrnn~Ii"'r "..rl/iorli"". In this -"a~. the proteins 1liiy lit (l1ll1yzcd aiMIMI ",aIel 10 I'CrrIO\'C sah~ Ihal wen: u:tl in Ill! prn:ipttltllOO filep. 100 uc""'"te chroonMop:iphy II weollD .. rrIXI m some", h:1I crude oqw'aIlOII of the proIeln) based 01 lheir behavior in ~ pU or Slilt &rndicm on the: ,~,n. AnoJIhcr filep thlot may be taken is 5il.e 1!l\( lusion (J<::t filuauoo) ch~ toal1lj1hy. Gels of IIjljHOjHiJte molecular ...c-'&III cutoff, c:. yidd a SOllie ... hal lOll n:solulion !CpnIllUon of protein. of I dc-lircd molnul .......~l&hl. If. nallVe bIoclmal protein lhat ba Mn amed Ihl~ far " neMly the same moln-uJar lIelp. lhe rONA protein. no ,..",,1'11100 Wilt occur. 1'""",/ "..rifi~nI;''''. Fin.:oJ punrocllion usually ,Moh'es lhe 1I!C of hJ"'~llIion chl'QlnMlo.",'phy. typICally h.gh-perl m.loce lIqUid chron1lllop::lphy. An abu~ of o.:urrunomoI 51.lounat")' phases all()w~ varil)lU IYPCI of lIdsorpIioo chromoIDgnlphy (1IOfTlU01 and reVCBCd phase). ion uchanrc dIrI'la.lDIraphy. immuno.ffinlly chromatoaraphy. h)'dtupbo4>ot; ~1'I1Cti,," chrom~tDiI"'.phy. and -lilt excluMoo clJro. m.ltognphy_llM: protein frael"""':u-e simply collecled "'bert they dute from the Cl')Iumn .nd ...., roncmtnlil!d and for QoCtiv i,y . Sr",ili""/",, mod J.",.... /ati(lft . This Mep I:lln be lIIXOmpli;bal by uhtafiltllllion 1 n:fOO''C PYrogcns or by he""1IJ if the ~ 0 teln Qn ... ilhstand Ihli. ForrnubllOO milhl involve Itt. :t II lion inlO !>table 5OIuuons for adm,n islr:l1ion or delcrmminl Ill! opumum oonditiool for !>tab,t" y '-'hen summlti", for cllm

I'/Jrtic~/,," rt'mQI'II/. Panicul~let;

as.

Inal,.

Complicating facton mciude (a) proteins unfolding illlO an inactive conformation during po ocusing (il may 00l be possible to refold the protein correctly) and (h) proteasc:s tNt are commonly produced by bacterial. yeasl. and mammahM cells. which may partially degrade ,lit protein.

Chupll'r (; RIf)In:h""logy WN1 OrMII OI.Icu,u,.

173

ftlARMACWncs OF RECOMBINANT DNA _I-PRODUCED AGENTS

illCrbtJlb h.t>e fac1lilllled the production of "ery pure, ill)' u'o('ful proIeins, 10e physicochemical and ~11I.'tl J!IOPCnie8 of l!lese agen!' are [hose of pro..... h.:h mean.> that rhJ'mac:i~l~ must undeOitllnd the . . . ~ IMIl lilt chm1iS1ty of inS Ulbility) of proteins 10 . ., 'pll(. dio;pense. reoonslilule. and admml~tet' thcq ,.... (i:ru~. In~labllllies amollg proIci ns may be physical . ;aI. In lhe fonner case. lhe proIein might stick 10 __ \~I\ or Oocculllie. altering lhe dose lhat lhe patienl ~>t In the lalla casc. dICmICal reaction~ taking ,we 00 IhI: protrtn may alII." the type or slerco(:hcU)i\lf)' "1IIt;mu1lO lCid~. dmnge the position of diwlfide bollds, Ib.o I~PUJe ch.:IJl15 themsc:h~s, and "Iter the charge ofli1c proICm. Any oflhese can cause unfolding lion) of the proI~in and In,s of activity. rendering ., molecule usc-ic-)s as a drug. Chcmieal instability call be I dunnl the puriraclllion staid of a proIe;n .... hen D>b:ult mlctn be subp:led to acids or ba.~. bul in~lJI ) ~kI oceUI al the point of admini,tmtion when. for
Di~

'n a ~'n ,.,.,m,7.C

eoulllerpan~ .

abuut 2

to <4

t",1C!i fQSICr

chan 111<" ("'"

IH';/im/"lJI;"",

,,.,

cOllIPininll Cyl., Sa. Thr. !'he, and Ly~ uncJaxo feo:ilc p..,hn" n: uon ;n .]1I1onc: rondotions that . facilowe fonmolion 0( . . Q cut.noon. O..IlhJllntr, Oud.11OII can occur al :M IiUlfur<OnUUnlnl .m,oo ocld~ M~"I .nd CY' and al the ""'malic ~""OO lICid~ H I.!'. Trp, and Tyr. ~ rnc"on~ can oc.:ur dunng proccin prnce'isi"i ......,11 3.'1 In~, MelhM)fl'1Il' (ClI,S- R)" o"idi7AlIc '" low pit by hydro&m pnulKlr:: or rcWllular O'Ylen 1<1 yield Julfollde (RSOCH,) and a 5ulfune (R-S01..(:1I,). The !hiol &ruup of Cp (RS H) can undc'lO luccnsive olidlltioa to the rorrespondm, .... lfelllC acid (R_SOH). diwlrKlr:: (RSSR) .wlfi,,"c acKl (RSO~II ). and sulfonIC acid (RSO,II). A number of (aclon, Inc] ..... in' pi!. inOucllCC' Ihe'IC "'act,ons, 1'= - 51! groop> can be convened inl<l di,ulfide bond. (.5_ 5-) and voce ,-.,rsa. ]n the phenomenon of' disutrlde ncloanae, d,wlrKlr:: bond. btcaI.;meI ref,,"" ,n dlffermt I""'''IOM. cam'''IIlncOl '0;;1 folding of the prote,n. MaJOTchan~e.; on the Ihn:e. d,nltnsional Sl""'tU"' of lhe pept,<Jc ~'lIn ~bo1i'lh lICtivity. 0,, dIIlion of the: IU'OO\alic nnp of His. Top. and T)I TC'5,d""" i beheved to QC<:ur ... ,ancty of o",dillnl elllymc:s.

Pru!"in~

,th .

ro:;'~ ~~'" ,,~"' 1l1c pharn\;! I fl OOIICepiS of the chemical and rmulKhtyof proIcms to predici and il:mUlc potential

Ph)'slcal InstabUlt)' of prot.._ "

Chemical ah~ralion.~ are 001 the only soorceof proIein ill5ll1bill ty, A prole," is a I~rge. globular polymer that e~i,ts in sollie specific fonns of secondary. le n iaf)'. and quatemary .tru~t ure. A protein is IlOl u fi:<ed, rigid ~truo::ture. The molecule is in dynamic I1lOCion. ui1d the Sln.ICtun: sample! an 3mIy ofthrec-dintcnslonal space. Dunng this moIion. noncovalent intramolecul ar bonds can break, It'form. and break again. but th.c o,'erall \ hapoe remains ''entered around an energy minimum tnat l'eprt'SCTlts the ITlCKt m.ely (and phannacologically acu,'e) cooformer of the molecule. Any major chan~ in the cooformatioo can abolish the activity of th.c protein , Small drug molo:x:u les do not demonstrate thi s problem. A globular prole," nOfmally folds so Ihat the hyd,ophobic .ilruu~ Ire directed to the insi de and the h)'drophilic groups an: dircclcd to the ootside , Thi~ arrangement faciliuues Ih.c w3t~r solubil ity of the protcin , If the normal proIein unfolds, it can refold 10 yICId change!l In h)'drogcn bondin,. charge. 3nd hydrophobic effects. 1l1c proIein loses its globulur stroc tUlt'. and the h)'dropllobic groups cun be reposilioned \0 the outsid~, The unfolded protein can sU~lII:nt[y undergo rurther physical inlel1lC1ions. 1l1c loss of the globul:u loUUC!ure of a protein is referred to as dt!"OIurflfiQn, DenalUT\lI ion i~. by far. the most WIdely studIed aspa:1 of protein instability. In the process. the Ihree-dimensional fokling of lhe native molecule is dl.sruplcd at the tertiary ai1d. possibly. the scrontIary structure level. When I protein dennlurcs. physical .~tnoct ure rather thJn chemical composilion changes. The normally globular 'Protein unfolds. e~po!l ing hydrophobic l'(')Cidues and aboli~ing the nat",, 11medimen)1OI1a1 structure. FaclOI'S that affect the denaeUr'Jllon of proIcins are lempcralUrt. pH. ionic strenglh of the medium. inclusion of organic solUlC$ (urca. guanidine SIllts. acetamide. IUld formamille). and the presentt of 0I"g1l1ll~ soIvaltS such as alcohols or acetone. Denatunallon can be re\'ersible or uRversible. Ir the denatured proteil1 Cll11 rega, nits nmi\'e form whcn the denaturant is l'etQO"cd by dialysis. n:>ersible Uenatumtion we ll O(':ICur. Denalured proIeill5 are gencnllly insoluble in water. lack biologJCalllCti,ity. and beconlC sus-

H ...... H)<IroI)'tll. ",;Ir['OM 0( the peplide bood.~ C &II Ioal .. poI~1III:r m.n. A'pu1ate "",ldlJQ hydrol)7,1' ]00

"

_ fMWr In dilute IClds IIwl do OIher am,oo acids undc:r .... _ ."\IIId"IOO'. M. gene",] nole of I"'plI<k h)'drolysls. ,.",.I'fo 'Alp-X 01 X-A'P bonds. Thl~ PfOIlC"Y 0( Asp ~ ' } J ) " fQllullloanlytoc fU!lCloon of!he .... sp SlIX dlaln .-.,.). '""'" ""'. AJP. G]n, and Glu h}'droI)'"/-" e\Cl:fllion 4) mlly Ifll'ory occur ""~III) G]y. 5. A]1l. and I'ro, With," W!o: ,...,...np. A.n . "<1 GIn :llCC"ell-ralc h~UroIYMS fI"I()R' II _ pH hole Alp and Glu hydn)lY/-" moM ~ad, ty III high pH..... 1Ioc &!doe dIaIn <wbcnyl,rouros an: IOIB/N. /It, Gill and Asn undtrJo h)'drol~Ut ",acflon, lhat '.... mid'lt rIleor <ide cha,"~. '!loese ",ac"on~ convert neulral _ -.:id m;,dlM'1 Into charged QIlI!J, Gin is ron~e"ed to Gtoo _ MIl fQ Alp. Tho: amioo -.;Kl Iypc ,~ dU,nFd. but ... doIoa IlIlOl cka_fd. Th, s PfOCC$O I.!'. effcct"ely. pnllW}' ~ ~ ..... oon.lInd 11 may innucnce b,oloa,cal activ.~ The oleanud.woo reaction of A$l. ~,d""" is ocall"l1Ited _ .wJI Of oIl.tJ,roe I'll conditions. A r,',Ht1C.mbe,ed c,dI< -.Ie f.. mcd by ,ntr.omolc<ul. atteo:l; of !lor iWt:cp: .. 110m on tM carbooy] cartron of lhe Asn sode chlin ""'" It'ttlmlrt . Tho: cydic imide spomaneously hydrol)'Uli .., II" I "",.tlft of '"~" I_ the ~yl pC'P"11r:: and an i50
1 ,_,

,ntermrd.-

lb>;e-otal)'"/.l'd ,.,.,IIU/JolIon n:act,OIl> can o.or ,n an)' of \be ammO ac,d, e.o.e<pl gl)"i"", which ,~ ~ RaTmmllOOS yocld prolI!'m!> ... "h mi~tul'e'I of L and D ,11:001 confi,unllOIl> The n:tlC'loon <lttUr< fol kr.oina !lor _1(l0:III of the " .h).!rogcn from lhe am,oo acid II) form I,,",~, ..... >hould he ClpeocIro. the Mab,li:y of lhe carb:on...1lIIIruI. the "lie of tho: "'''''lion. Asp, which unde'llClCS ~~.KIII 'III cydoc rml(ir:: mtel III<1h:lle. racem.~ lOS __ ra..r datn (= "-",, 8~ cornpan __ other IImlOO 1IC'1\b1

'74

\\'i[..... wrd Gi, "Ad', T,..lIblJ<H; 'if O'8/lJljr MMlriMI and I'hamlllCt!:WIKU/ C~'mlJlry "

Hydrolysl5..()eamidation

0
0

...
"'0

+
0 0

NN,

NH,

0
0

""'
NH,

. .p
0

ON NN,

NH,

"'"
o
o-Amlno acid

R
o o

J)
L-Amoo acid
Carbanlon Intermediate

Planar Sp2 hybridized

If R=CHzCOOH (aspartate): self-calalysls

"' NNJi

~-R
x
./

0
~H"

,-l(
R

-w
~N '

_H'

' NH 9

~N-R

N-R N

Base-Catalyzed Il-Elimination

;,.c:""

"

,N'-.J
, /NH,

NO

H'
_N'

o
X"

)
a Carbanlon

a good leaving group

(ey.. Set, Phe, Tyr, lys)

NoH

, / NH,

(
b

Enoiale Inle" ..ediate

Flgur.6- 11 iI . Protem dec,~~ jjlJoo ructions. b . ISE~mmilllOn

10 tnly!IIatJC hydrolysi~ The lilt- wlllf:r IIJlCrface h~dI"\lflublC surface mal can fociliulle protcin rMt.fXQ likc Ihcse art commonly ef"ICounI (10:, ICe:!; and inlr.lvcnous (IV ) b:lgs. i eharacleriud by adheas the walls of the tonand drug del ivery de vices, ampuls. adhen: 10 glass, plastiC$. rubb:r. and poIYImylchlondc. This phenomclI{)I1 i5 to ~ f/,)f"(ltlmi{)". 1llc inll'rnal ~urfllCe.~ of i ntruve_ h pumps and IV dc!i\'ery bags pose particular l11ld. FIo<:culated prtMdns CiUlII04 be dosed , - . INIIIS ...hen protein moJe('ulcs. in aqueous Klr~iaJe 10 fonn dimus. Irimcf5. tetnullers. aggregalcs. Sclf-as!iOpH of.he medlum;as .....dl as !iOlvem Wt'ngth. and meleelric propen~. Mod dcnaluranls (below !he concenll'lliion that may all'O cause protem uggregaI I have a lendcncy 10 solutions. such as an ;mrnumay aggrcg31C with 'torage time Tht- j'l;(:lIce of paniculatc; ill the prepal'lltion is along with denatunllion. DecondociCd with insulin. d;\'idcd precipiulle on the wall5 of an doI.qe form container. It is bl'l,e"ed III the air-.....a tt... inter, t; procS. Tlw: concentratKHt pn=nce of adjU\"IIIIIS weh as prot_ ~ precipitation reaction of in~"n.

DelIVERY AND PHARMACOKINETICS OF BIOTECHNOLOGY PRODUCTS"

As ... ith any drug class. the medicinal chem''>! and pl"laml.lrilil muS! be conccmed w,th the absorption. distribution. melaboli~m. and excretion (A OME) par.lnW:lers of prolein

II

protein. . may

wh<, be used
is engifonn. it

d
kid

;.::~~~ (subslitutioru proIem DUly

be OOditions or

for another).

N",~.:"~'i:~M~~';~:~;::.~ ofasulfur_ groups. in_ ~

ctwn of a methionine or a cysteine. Addiusi ng a b'-letei has been produced i i 1I11.,erial rnay I of these li"lcd items l"Ontriollle biOlcchllOlogically produced protein. I 10 a human palient. the bost's im_ "Ill react to the protein juS! lIS it v.ould 1 a 0 lind llCutntlize il. This IS v.hy research has tocrea.e lOO'l human protein drugs. StICh " 'ill need to \like for long

drugs. BiOlechllololl:y-prodtoccd drugs add complexitJe, that lin: nOi encounlcred ... ith "tr~ditionu l " low-molcculur... eight drug molccule,~. ADME pal1l1ncters an: IlCt~ary 1 0 compute phurm3Col.:i~tic and plmrmacodynamic parmn_ etctS for a given prolein. A~ for uny drug. tlle..;c par~meters arc essential in cakulD ling the opIimum dose for a gi\en response. dclcmlllllng how often to admini~ler lhe drug 10 obtain IIsleady stale. hnd adJu,"ngthe dose to obtain the best possible residencc lime at the- rt("C[!Ior (phannaood)namic paramctef5). Delhery of drugs ""th the molc:cul;u- ... cighls and proper_ ties of proteins inlO lhe human body is a complu ta~J... Tlw: oral route cannot be used with a prOiein because the acld"y or the !itomoch ... iII caluly/e its hydrolys", unless lhe dru/l is enteric COOled. Pe[!l.de bonds arc ...hcmically labile. and protoolytic enzymc~ thai nA: pn:senlthl"l)tlghout til.: body ... an allack and dew!)y prou:in drug~. Il ydrolysis alld pc[!lida!oC dec;omposilion a lso occ ur during membrane 1I11115pon Ihrough the vascular .ondo!lieliulll. at the site of admini'lra_ lion. and at si tes ofrea.;:lion In the I"cr. blood. kidMys, and most tissues and nUlds of the body. II is po'~ible to CH"Cum_ VCflt these enzYme<! by <;atur.lt ing them with high conccntr,,_ lions of drug or by coodn"ni~cring pcptida....e inhibitors. O~ idath'e metabolism of arommic rings and sulfur o~ idauon ClUJ also OC("Ur. l'mIcms typically dccompo<;c into small frag ments that are re:w:hly hydrolyLCd. and the individual ammo acids are assimilated in\C) new pcptidcs. A potenllally seriou~ hindrance to a phannacoJ..inctlc profile j~ the tcndency of protcins admimstered IU drugs to bllld 10 plasma prtMein, suc h as serum albumin. If thi s happe n,. they enter a new biodistriou!ion compartment from "'hich tliey may ~Iowly e~it . Presently. the rool~ of admini,tnllion thaI are available for protein drugs :'fe largely subcul3l1CQUS and illlrumu'oCu_ lar. Much ongoing re5ean: h I~ targcted at making peptide drugs more bioavailablc. An example of this is COIlJUj;allon or interlcukin_2 ... ith polyethylene glycol (PEG). These )()o called pegylaled proteins tend 10 ha\'e a $Iov.er ehmination cle:uancc and a longer r. thall inlcr-lcuJ,;IIl-2 alolle. Another s-Irluc:gy ~.ng used i) the Installauon of a JIfOI>thetie sugar moM:ty ontO the pe[!lidi:. The wgar moiety .... ill ooJu\ tlie partition cocrncicm of the urug, probably makmg it nlOre water soluble.

RECOMBINANT DRUG PRODUCTS

Human Insulin, RKombimtn t.'IIII--II'~ Human IIlsuhn was the first pharmacologic_lIy aeti"e biol~ical mat.:rotnol cculc to be produced through genelic engillCering. "The f-UA
appro"ed the dru, m 1982 forlhe trc:umenl of type I (insulin_ dependent) diabetes (see Chapter 2.51. Tlw: illSlllin prelll is a Iwo-etmin polypeptide cOIllllllllng j I anllno lICid residues. Omin A is composet.l or 2 1 IlIllioo acids. and cham B con-

.
to .void human A:acl.on 10 the mouse

Ullns 30. 11M: hUOlan insulm molecule has three disulfide hnlages. CysA7 10 CYSB7. CysA:o 10 Cy~Bl lh and an InU'DClwn linkage. Cy~ to C)'SAII ' Insulin b ~t od by the ~ell s of the JXIncreatic islets of Langcrhans. initially a~ a single peptide chain callod proill5UIiIl. Enzymatic cleHvage of the: piOpepude releases the insulin. lI i,toncally. in<;ulm was isolated from bovine or pordne sourt'n. Usmg the:~ agenu; was no! without difficulty. BOIh porcine and bovine insulin differ In amino acid sequence. with Ala rcp1:lClI11: Thr al the C tcrmi nus of the human ch:un (8 '1l)' Bovine imul in also dIffers in sequence from hum~n inwlin. with Ala ~ubsliTUling for Thr at A, and V.l ~ub$tiluling for io;o1cucine at A IO These differences. ~ma1\ though they may seem. result in immunological reactions in some JXItJcnts. AdJu~tments to lhe formulation of bovine and porcine insulin lod to prodUCts Ihm differed in time of on~l. lime to pe;d,: reduclion in glucO'O('. and dur~lion of action. TIlt ..... pal'3meters were varied by addi tion of protamine nnd zinc ( .. hl ch yielded a paniculale Insulin with a longer duration of IICUon). and adju~lment of the pH 10 neutnllity . .. hic h stubilized the prepamlion. Insuli ns were chpf'olCIerilCd as regular (~hortduml ion Ilcli n. 4 to 12 hours), scmilente (u1lmshort dUl1lllon). lenle (inlelllictliale {I 10 3 hours \0 peak. hoo rs durJIion j). and ultratcnlC (e xtended dumllon). An a&I.\\iooa\ \onn 0\' \m.u\in ""U N{,\\ ~l'.u\r.l.1 9fOOIDliroe Ibgedom). which had an IOTcnnedime lime of onsel and ti111e 10 peak (I to 3 hours) and a long duration of ac\ion (16 to houro;.). Producing a recombinant insultn that is chemicall ), and ph),sically indistinguishDble from the human panc~ati c hormone was a major accomplishment. 11lc problem with imlTlunoreactivi ty hll.~ been elim inated. the p)'rogen r omcn! of the rONA product is nil . the insu lin is not contamillated with OIhcr peptKlcs. and the: hormone. can be bl(5),nthesi1.cd in l:trger quuntities. Human Insulin (rDN A) is avai lable as Humulino Novolin. and a number of analogues that differ in theIr phanmlcolanetic profiles. Ilumulin is produced b)' using recombinant E. t:'QIi: Novolm is p~pa~d b)' u ~ lI1g rccombinant S. t:'t'mi~l(lt yeast. 1'hcre ha\'e been modifi cations In the production procedure ~ince the initial successful bi05ynthcsis. !'rior 10 1986, Humutin was produccd by creahng two diffcrent \ectors. one for the A chain and one for the 8 chain . arid inscning them into E. coli. The A chain and the 8 chain would be secreted into the medium . and lhe two were joined dw:mically 10 fonn rONA insulin. Today. the en lll\' proinsu lin gene is used to create a mcombinanl organism. and the cooncet ing peptide in proinsuli n is c leaved by two cnl.)'mtS (an endopept idase and a carbo~)'pcptldase 8 ). yie ldIng in<;ulin (for details see Ch::g'cr 25). Insulin rONA i ~ "'lIilable in several I forms. Insu lin lispro (HumaJog ) has a man: rapId (IS 10 30 minulCS) onsct and a shoner dUl1llion (3 to 6.S hours) of :letion than regular hUl113n insulin (onset 30 to 60 rninutes, duration 6 to 10 hours). II I~ effcctlve when admimstcred IS minutes before a meal. unLike ~gular insulin. which must be injccted 30 mInutes before a meal. In lispro. the B-chain amino acids Bu Pra and B;NLys are txchanged. I n~uhn aspan (Novolog). on!.C1 IS to 30 minutes. du ration 3 to 6.S hours, with a single amino acK! subsUlution of Asp rot Pro al B:!:II. is effective whell admini ste red Sto 10 minutes before a meal. TIlt uhl1l IorIgacting agent insulin glargine has the A~p al All replaced b), GI)' and has two Arg residues 00dcd 11.1 the C

terminus of the: B chain. IllSUhn glargine. admmislered_ cUlanC()IJ&ly (SC). has a duration of IICtion of24 !O 4811oun.. 11M: alteration in basicit), of thi. agcnt causes il to precipillir ut neutl1l1 1'1-1. creaTing a depot effect. Insuli n rONA has been very successfu l. llte onl)' problem has arisen in patients .. ho have been usmg porcine ot bonD! insulin for a long !i~ . Some jlIItienb who are switched 10 rONA human insulin report difficulty in "feeli ng thelrgw. COSt level." and these patiellls require elura counseling iI the usc of the recombinant hormone .

,
i lICids and opposes the actions of insu lin. Bo~iIr: and porcine glucagons. which possess with human glucagon, ha>'e been in u~ for yearll. form has been approved by the FDA for usc in sc' 'Cre hypoglycemia and as a radiological diagnostic aid. Glucap! Iflhxes smooth muscles in the gastrointesti nal (GI) tract. decreasing GI moti lity and improving the m radiological examin:mons. In the lreaunc:nt or c,'m: glycemia in insu lindependenl diabetics. GIUC"'~ "'::":: I \M. \\vef \D C()I\'1e(\ '\'1e~1\ \D ,\\!COR. Ld\ II' vere hypoglycemia (Iowbloodsugar prolonged loss of consciousness and drug has the: benefit that there is no of bovine spongiform encephalopathy from glucagon thenpt. This condition. also known as mad co ... di5C/ISC. is causoillt a ",iou that wa.~ suspected 10 mfect animal pancreas ~

i.

'"'<'""

24

24

.-:r.....

Growth

many c luding synthesiJ

~I""
<

~lJIbo1ism . C

and;1 has been CJltremely succcssful in the s ic growlh hormone deficiency. chronic renal i Thme( 5 syndrome, faillltC to IlICIate in ",omen. Witli sylldrome. In its long history the MrmotlC' remarkabl)' successfu l and free of side effects. 11M: primary form of in the: c lrcutauon I nongl ycosyl ated protein produted in the t ' and composed of 191 amino acid residues lillted bridge'! in two peptide loops. llte .",~".""fh(; lar, with foor antipar-~J1tl !J'-hclical regions.

hGH

!O

hGH is or a 20-k Oaofmonomer. arKIS% ora ml composed about 8S% of the 22-"'1""~~:;::: 10%

fide-li nked dinw:rs, o ligomers. and OIlw:r modi"r""~.,_, From the late 19505. hG H was isolated from tra<:15 of tadavcrs. A prion ~ssocioted with the was suspcc1ed to cause Creutzrddl-laitob dJ,""" degeroerative neurological disorder. llte first use of r~'Combinant hGH in 11<~

1982~~mG:~H~~~~~: ""ere first

amino i ! seqlK'nce has . duced in rnammaliDII (mouse) cell t ultun:.

Cha ptu 6 Bi.NrcluooJov (JOO Drill f>uco-.'try

177

s.:.nautrn, the first recombin:lnl prepar.uion, imroductd

1985. rontIJlIS the natural 191 -aminQ add primary.'iCpI~1 one ~_~~~oo~ yl midlK' on the N-tenninal tnd. all cootain tbe 19 t amil1() add :Ie' wlIh tI'Ie hGH produced by the pilu;-

tissue to stimulate iodine uptll~e into the gland. organifkDlion of iodine. and secretion of thyroglobulin. T1 an<.l T. The drug is used as a tool for radioiodine imagilli! in ti)e diagDO!.i s of tbyroid caocer.
~o'd . . .

10

~
:

~~"'~'i_~;~~im~.~nSlOnal crystal structure show, with most of its nOllpolnr amino

toward the interior of the mole-

HEMATOPOIETIC GROWTH FACTORS

Amoog all Orthe: events taking place in the immune system. the bone marro .... and the blood~am. the proce$5 of hematopoiesi s is probably the mD!it complicated_ All of the cells in thl' blood an() the immune 5YStem can trace their lineage back to :I. common. parcntal he:matopoietic Stem cdl in the bone marro .... This cdl is rcfermJto 115 pluripo'~m because under the pRlpI'r stimulatioo it can differentiate illto any 0I1ler cell. The proces.sc:s of maturnlion. prolifrnu.ion. and differentiatio n an: under the strict C()I1lml of a number o f cylo~ i nes (Table 6-5) that regulate a host of cellular even IS. T...o <.Iistinct blood cclilillC3ges eltist: the lymphoid l i nea~ lhat gives rise 10 BandT Iympbocyle$. and the myeloid lineage that produces gnmulocyles (macropI:Iages. neutrophi ls. eosinophils.. basophtls. and mast cells). as well IS platelets and erythrocyles. As many lIS 20 orlhe: hemalopoiesis- aS5OCiated c)tokines have been cionc<.l :tnd e~pressed . Some of Ihe!IC are listed in Table 6-5. 11le cascade is sho ..... n in Figure 6- 12. A furtller feature orlhe pluripotent stem celilksc. "CS mc:nlion. Each slem ccli d"'ides into tWO daughtcrcd l. one an ac!i\'c hematopoietic progcni tor and one quie!iCenl , 1lIe active pn:cUT!iOT matures 10 give hemalopoietic progenilO~ and then circulating bloOO cells. The quiescent stem cells rejoin the stem ce ll pool. Hcnce. the number of parental cells is al .... .Iyslhe same. This process is ICrmcd scl/IVI~(lf.

I identical wilh IIlItunl]

";,.;l,yophi. tee Typi

:.~~,~poWdercd
i good. If Slorcd at 2 10 s<'C. rhGH 2 yean;, rilGH lIIldtrzoes rapid. predicUtble IIX'tabolism in vivo in

~'.~~nt:'~'~nd the

liver. Chcmkal1y. the metabolites are for Iny pepli(le: dcamidation of Asn and Gin of Met. Trp, His. and Tyr.

The gooadolrofollitropin :lIra

are produced in

;;;:" ~;~;~;~,jcan fUllCIion in

PRODUCTS has a molecular mass of traditional soort't for isolation I urine. which provided a prcpa1m than S% pure and WILS significamly confhc.o rect)mbinam human FSH (rhFS H) is mammalian cell line, the CHD. a and foUitropin p are the same proIein. but
Erythropoictin alfa. recombinant Epoctin Alfa. Epogcn. P.... .. il. is I glycoprotdn thai stimulates n:d blood ccll production. It is produced in
IIJ

Erythropoietin Alfa.!fI

TABLE 6-5

Cytoklnes Thllt HlI.... Been Cloned

way tbey are formulated. B04h . The ~ form is formulated with

and a lyoproteclanl) ~I\d 11le IJ fo rm COfltains 115 a $Iabilizrr and polysorbale and I dispersant. "The products Ilfe administr.ltion . 11le shelf i 2 yeUl'li when lhey are stored in ; :::::'~COIltair,c,rs al less ttmn 3O"C (nol fro1,e n) and li,ht. Human thyroid-Mimulaling alpha (TIlyrogen), is a he:tero-

Cytolll...
Ini(:r\nlk,n-l

Biologluol Function
Muhl"""", cd! foetor. c"",rol.
b...,d ..... flUllllII)'t'ioId .... m
~,

".,k"kJ.-4
lilOt, ...... t...,
~1IIi-4i
lft~kln-Il

s..1JdoQ a QOII.,.... t,o tJE

i\(U ....,.

_1I<Iflho"

II)

IIOId 7

DitJ=nI;IIIICltI otT IJ'IIIPII<.o<yu:<

C""'roI~ ilIc "''''' ot T" I N> T"2 51'""'t.,. "'" edt 1"'.......... Acto ""th n.-l ... ((...." Iil]'l!Iood bo.",h NtoIuvph,1 ~

"'"""""""Sian cdl fl<,or 150'1

c,'': ,_..,tt,hh"l f~ Oranookqoc roIooo y' sunol.oIn,

M:ootrIIf'hatIe cui<Jfoy-..,..... \lIl! nl

lbu, I is cornposW amino acids. and the IJ ;;~"~l The specirtcity of the: protein is cootrolled by
I, TSII Inod!; 10 TSllltceplOrli on nonnal thyroid or on lI'e\l-diff~ntialed canc:eroos tbyroid

;;.;,;

- 28.000 10 3O.0CJ0 Da.

...

r..,or

CoIDirofs .:to~"Y u.n.",

I1I)'do;d bi. to

SC,
IL-3 GM-CSF

IL-3

GM-CS'

Myeloid Stem

'0'0

'0'0

ColO

---"<SC~,:'~L~~~O>--.
I t
IL-3 GM-CSF SCF ... IL-3

@ .. I sc, t Il-3

IL-I, SCF

EPO

GM-CSF

!
GM-CSF
IL~

IL-7

@@@ /\ @@@
'0'0
GM-CSF GM-CSF

IL3

IL-2
IL~

1L-6

IL_7

M-eSF

IL_3

,I

G-CSF

PIo_ ..

'P' t

tiL' OCII","

Figure 6 - 12 Cyt~lnco-medaated cascade leading to diffecen\ blood cell typeS fPO. erytIvopotetln; G CSF, granulocyte coiony-stll1lulCltmg faGO!'; GM-aF. granu\ocyte-lNaophage (OIony-somuiallOg factor; IntedeuklllS. M-CSF. mauopt'lagpco!ony-stlmulattng fiICtor; Stem ceoH filCfor; 00, thrombopooetm.

/L.x.

sa,

the kidney. and II OC1ivalcs,he proliferation and differcmialion of speciall y (OI1l1mlloo erythroid progenitors in the bone flmn'OW. Epoclin alru (Epogen) is 0 16Samioo add glyC()prou:in [lull is manufllCtured in 11lamrn:alinn t'C' iJs by rONA tcchroology. The protem is he;...;I )' gi)'ro!ly laled and has a moIccullU" masll of appnuimalo.'Jy 30.400 Dol. ErythropOietin i~ rolllPQ)Cd offour IImiparnllel 0' helice', The rONA proIcin has the SlII!le amino acid sequence as n.a1l,JrJI cry lhropoicl in. Epoetin is indicated 10 treat ancn1l8 of chronic renal foilun: patients. IIII(:mia in fII.)Vudllletn:llt~'d IU Vinfa:ted pa. tienL~. and in cancer pallent' talll1g chernottw:mpy. Tllc results in the'iC ease..~ ha ve been d'-'1Inatie; mOst patients respond " 'uh a clinically ~i~nifieant increase III hematocri t.

tiOll of gramllocytes (e.~ally neutrophils) hentalOpoietie Stem cells in the bone marTOW. G-CSF is D glycoprotein prodllCed by blll$ll!I. and endothelial II . in acids. with a molecular mass of Dpproxinullely Tllc n:ati~e proIein is glycosylated. nlgra.tim selectively stimulates proliferation :uwl entiatioo of neutrophil precLirsors in the bo!IC marrt)ll leads 10 !he pllils by .j metabolic patll",ays enhancing Antibody-dc:pendent J.:ilIing. and eJlpre!>sioo of !K)mC fullClions associated nmigen s.

Filgrastim. " .. "5

Fil~m$ti m. granuloc~te colonystirn

~timuhlles

ulating factor (G-CS!'). Ncupog<'n.

the pmlifc11l-

Chapter ' /J/O,rchnoioV ,,,,d On.,

[)u~"'WY

'79

by rC~'er i~ r:llhcT high. Iwb.mloUDln ofG-CSF raluca the lime or llC'!utrophil re.:ova) lind OOrallon of fc\'cr In adults With ilCute myeloge-

.n ," IIMropcma accompanied

m ~ rel:l:'iving chlomotht:rapy ..... dh drup such as ~ doxorubicin. and etoposide. the ioci-

.... lcuLrnlia. 1k number of infections. day~ 'hat ant,biOl:"'" an: I"CqUlred. Iltld durnlion of hospillllil.ation are al so
" 1~J'lnmll~ I~ identical with GCSF in its amino lICid ""fIt'.:t, nctpllhal il coomins an N-\crminal methionine
... I, ~

.\ '."'"" - .;- >

~
~

"""'"
pi....

KIIow

we. t

0 Hot!

for expression of the vector in c . coli. TIle

ferons .

f igure 6- 13 An!Mrtll mKhtlnJSm of actJOO of the in\(!f-

;1 not gl)'COSylated. Filgra!i.im IS supplied in a 0.01 /Ii ..-IIumll.TWC buffer conlllmmg ~ 'k 'iOrbuOI and 0 .004% ~,,-.bIk SO, h ~Id be scored at 2 to 8"<: without f~7. ." t'1IJer llItse condillOOs. the shelf life is 24 monlhs. ~\nid ..tW11II ... !lrn ,tcOOSliluting: although the foaming .. ... ann the product. i, may alter the amount of drug
_
~ ~'II1Il"O

a syringe. ,,'
SargrnlllQ~lim.

,t>roami no
,800 011.

'Id di ffer-

OW.

Th,.

rculauoll

granu locyte_~ co!ony-sllmulaling factor (CM -CSf). L.cukinc. a 111)'\'1>pro!ein of 127 umiroo acid~. f.'(/Ilsi~tinl! of three ,..,1kI:ular 5UbunilS of 19.500. 16.800. IIOd 15.SO(} Da. The mJnrrnollJ) form of CM -CSF is produced by T Iymphoq'II:\. endolhclial fibrobla~lS. and moctophages. Re<.;ombi... G' I CSF. pruductd in S. rere",siut" differs from nati ve (iM-CSF only by subsmution of a Ieucme for an a-p,.11 posilion 23. Thi ~ SUbsurulI(Jn facililates expres"' III tilt tI'It' In the )'t'ast. The site of glyoosylatJon in W ltdllUbilWll molecule may possibly differ from that of W prok'ln. ~,m binds to specirlC rcceplors OIl targel ttlls _lIIlIuca proIifffiltlOO.. activation . and maturatioo . Ad.nnllJOOn to pIIlienu; causes a dose-rdatl-d increase in the pt'Ill"'v:,aI .,. hlte blood cell count. Unlike G-CSF. GM-CSF l\ I mulhlmeage hematopoietic growth factor tlwt induces ~Iy ronUl\lIl~-d progcnilOr cells to prol ifcrnte nnd differIIIlak' aIoIlg the grunulocyte and the rna<:rophage pathways. ~ ~ III ~ the function of mature grnnulocytes (lnd ....~)'It$. GM.csF incrcase.~ the chc:motac... _fwDp!. and III1l1p.UlISltic x tivnies of lranulocytes , . -)'Its. II also increases the cytoto~idty of IllOI1O'lb""';w ncopIasllC cell lines and activates polymorphokukDC)1O to inhibit the crowth of tumo r cells. 1m tS used 10 m:onSl1Iute the: myeloid ti!lSlk' ... .,toIogOIl~ !:10M m:IfTl)W transplant and fol lQ..-ing .'-' .1dImpr in acute m)'t'iosel'lO!.l5 leukemia. Tllc: preparntqllrctalG thr iocidencc of infection. decreases the num '" ,i \I;t), thai antibiotics IlI'e required. and decrcllSeS the .uJu.ll of Ilosrlul stays. S.phOsum i, wpplietl a~ II solution or powtler (for tfurlOllJ. Bo4h f()ml!; shoultl be ~tored at 2 to 8"C without Im:. 1lII- Tlw: liquid and poI\'der nnve e~pir tio n dates uf 24 .. . The ,ecollt,tutcd powder and the ;tquoous solution MId not be ..tW;~n.

SMgwl'IOstim."'

Ikcllplennin is prodUl.'Cd by II lecohlbinant strain of S. cere.{rioe cootaimng the gene for the B chain of PDGF. The proteI!! has a rnokcular mass of apprOJIltn3tcly 25 kDa and is a homodirncr composed of two idetMkal polypeptide chat05 that are hnked bydisulrtde bonds. It is. Crowth factor that actIVates cell proltferntioo. dtfferenuation. and funclion, and it is relcased from cell s involved in the healing process. Becaplcmtin is formulHtetl as a gel recommended for topi cal use in the treatment of ulcerations of the skin secondary 10 diabetes .

Interferons
The interferon~ life a family of small proteins or gJyCOj'll't}reins of moIcculllr ma.~ses ranging from 15.000 to 25.000 Da and 145 to 166 lmonoadds long. Eukaryofic cells sccn::1C interferons in response to viral infectioo. Thetr mechani sm of at'Iioo is bimodal. The immedialeeffect is the recrtutment of natural kIller (NK) cells to kill the ho>l cell harbonng the virus (Fil . 6-13). IntcTferoru then induce a state of I',ral resIstance in cells in the immediate Iieinity. preventing s~ad of the virus. AdoJitiooally. interferoos induce a CllScade of antivlrnl proteins from the target cell. <me of which is 2'.s'-oligo:tdenylalc Synthelase. This enzyme catlllyzes the conversion of ATP into 2'.5' .oligoadenylate. which activllle5 ribonuclea~ R. hydrolp.ing viral RNA . Interferons con be defined a.~ cytolal1e.~ lhat mediate antiviral. antiprohferatilc . and inmtunomudulotQry activities . Three clll..~ ses of interferon (lFN) ha\'e been chanictcrized: cr (alpha). fJ(beta). and ..,(gamma) (see Table 6-6). o- Inlerferon5 are sl)'coproteins derived from human Icukocytes. p. Interfcroos are glytOJlf<Mdns derived from fibroOlastJ and macrophages. TIley share a rccc:plor with a -interferons. }'" Interferoos are gl)coprotdns derived from human T Iympho-

-.U

an

TABLE 6--6

tnterferons Used Therapeutica lly

!nlm. ron

'e n'Ulro-

""

e cellular Ir) DuN. 1l5ing !he

SUrfllH

11

tp'II1I1",-!If Bttaplennin. ReSl'lnex Gc:1. an en poIypeptlJe that b released front cells Innt an: ...ah-fd i. !be he2ling ~. is a n:ooombinani human ,.. nled grov.1h foctOl' (r hf'DGF BB ). The " BB" """,ht\ rtw beeaplmmn is the hornodimer of the IJ chnin.

b..eo:f~ 01'"21 !NCrfm:. iIIl.llI !1iICtf...... ahl-loo Bc1a. ! I Stu !II

o..-tb

TABLE 6-7

Summary of the .... lnterl.ron5

Int. rt on A lf.-1. Int. rt.ron Atf.-1b In ..... " Int..-l on Alf.... ' Int. rt..-on Alfa_ nl "'Ifcroll :SulOIiuoo B......-..d ...,... Cood)1onuu IOnImiruu. Int.rt.ron Alfaeon ' In'""", SoIu"<)1I

T_ _

......-,$<>I'OftI

Rn(...,., " So/JIooft. "",".lor

SoIuI"", f'l"""lrr
8uff<ttd .......

SoWoam cltk>-lolr.

""1"""1<
Jnd ... oc ......
Hiif}' tdllru.l.--. ArOS ...1-.l K........ ' ....."(>I'JIa. (..,,"''"' 1o/paI"" C '>C. 1M. onr",_

""-,,~

Wdlf_
lI~ffcml

......

.....,..........
..'"

Jt.ry ,.11 JouI.cmoa. AIDS.dMod

_ _ WIId'k>'M ....m'n ..... dw-I ..., htpAI,d, B. dIroI\", htl*~,\ C
~,.

t'hron1<" """"',,,. C

~h.p:uu .. C

R I,if

,'<.

SC. J\t.I\. ,n'"""" Of

sec.-I'I

,"""""-'
iJu",""
1e&,~,>C)~

c.- 111'..1""........
f:.

,,,I,

, ""

1"1.."",,,-1

....11

IytIIpIK+I"""" 0<1110 ...

C)tc<;

nnd NK cells These: imerfen:ms :1Il.' ;tCid labi le and

used 10 be called . 'Iypc 2 i nlcrfcron .. The n.'CCplO1" for I FNY is ~m3l1er than Utat for II~-a and IFN -,B. 90 10 95 kDa ~e",u~ 95 10 110 kDa, respectively . The Ihn-e cla~'>C"s /line not homogelKlOU'. and each may conlain M!\eral diffcrcm molecular ~pecie<;. r-or eJ:llmpk. al least 18 I!cncllcally and molecularl) d'Slioct buman (\'_intcrfcron~ ball: been idenllflCd , each dini:ring Inille amlflo acid <,ub"'lluhon al po~iliOtlS 23:and 34. Interferons alfa-2a. alfa-2b. and IIlfa-2c ha"e been punfied :,ud are eilher in elinical uo;e Of" in dc,ciopmcm. A h~lIn& of comnlCrcially a\uilab1c (l"-int~nerons i, ghen in Table 6-7. A~ ~ cla:...~, Ihe imcneruns po~o;e"" SOIlIC common Mile cITKts. The: an: l1u -h~e ~ymptom~. I)('adache. fner. mu ) ell.' 1I(:hi!s. b;lCk pain. dull ... Ilau..ea and \omlung. and d,ar. rhea. Al the injcclloll site. pam. l-.icma. Ilemorrhallc. and innammation nre eonunon. DinjllC!>.~ is alw commonly fCpharmaci~t. "Ilen pn.-dlclinll drug intcrocti{)f1s " 'ith lhe Inlenerons. C) lochrome I'-4SO melabollsm should al" 'a)s be D key cOll~idcr;luon. MO!ot of tile inlerfcrons inh ibil

cells. Modulation of lhe 00--1 nnmun.e response prubabl) plays a role in Ille anUlurnor aclivlt y of inlcrferon arfa2a. The Inlerfcron is supplied a~ a soluuon or as a POlldef for ..olul1on. The !;oiution contains NaCl. The pov-def coma;", 0.9')1- NaCI. 0.17'l buman ,<nun albumin, aI!d 0.33% phenol . TIle Imerferon v.ab . if properly stored III 2 10 8"C "ilnout frecl.mg. C\ptfC In 30 moolhs. Prefillcd synn~ expire iu 24 monlhs. The solutlolls ~hou ld 1101 be sha~o:n because lilt albunlln will CaUSl.' frothing.

o.n't

"""oJ.

For tl)('

C)'loclimnM! 1'-450. causing drui;s thai arc nll.'1abolilcd by Ih, ) NIlle to reach highcr-Ihannonn:ll and. ]IO'"hl). toxi.: COllCcnlr~non) in lhe blood und li!i,"uc~.
PRODUCTS: ....INTERFERONS

Pegylated InterferonA/fa-2a. 1lI I'Cgylaled inlCrfel"Oll n"o-2a. l'eg;asy(. i( a co,alcm eonjU!31C of recombInant. lerfefOrt nlfn-2n (:'pproximOlc molecular mas..~. 20 LOa) ... d II ~lIlll ly-br.lIlched bl~-lTlOOOInethox)"polyelh)lcne JI}o:oI (PEG) chai fl (apprm.unate molecular mass. 40 kDa). "Tk PEG l1Ioiely i IUlked 81 a .ingle ~ite 10 lhe inlerferon lib nlOiety b) a stable amide bond to I)'sine Pegintttferon air. 2a has an approxlmale molccul:u- ma.....~ of 60 U)a. ~p5)1 provides sustained therJpcutic o;crum levcls for up !O a (ttl IIcck (168 lloul"ll). 11le drug i< upprQ\od for lhe tTeatl!ll:a of aduh~ wllh chronIC IlepahliS C "Ito ha~e compt1Nled Ih'cr diseao;c ami ",110 hn"e not been ptenou<ly Ireated ... ,0 'nterferon alfa. Efficacy h3$ also bec-n demonstl1lled 111", IlenlS wilb compensated c1l1t 'osi'l. Intttrferon Alfa 2b (Recombinant)Yz Intc-rfm. alra-2b. Inlron A. a Wllter-soluble protem of L6~ amino acllil ami an lIJlPI"O\jnUllt moleculur ma" of 19.200 Do. i~ fl pn:,~d from a recombmunl ,tram of 1:."". coli. I. molecule Jl'O!'!-CSSt~ an arginine at poSi tion 23 I al posilion 34. Imcncmn 3lfa.. 2b i, II broud <peclrum agenl . II b lillicalcd for hairy cdllcukemia.. condy loma acumiflma (!enlll! or \tlll""rcal ",aru). AIDS-related Ka]lO'i's ~n:oma. chroniC Ilepillil" B amI C infections. Imron A can be admini<lcl\.-d by tile SC. 1M. or IV rOUIt\. b) infu<ion or by mtrulesional rotIte\. 11le dose: IS L 10 JI million IUfday. depentiiug on Ille application. The drug. ~upplied D\ a soIulion or as a po",der for solution. and boIi forms COI1Inin albumin. gl}"clllC. and !.OdIum pha<_

Interferon Alfa2a (RecombinantJ. lZo Inlerfcron alfa b (l"t"COIllbinanl). Rl'feron A. is e ~I~ III an Ii. culi sy\tem mid purified lly u~ing hlgh-affimt) moose. monoc lonal anubody chrom:lIosr~phy. TIle protein con,i'l~ of 165 :unll"lO acid, ..... ith a molecular ma~s of appro~lmatcl) 19.000 Da. and t"Olliaut.. lysine :11 po"l(on 23 arnl hi~t,dim." at Jl'O'ilion 34. InterfMl)lI alfa-2a is u-.cd III tile trealment of hairy cell leul.emia alld A IDS -neilitetl Kaposi's 'Illf"Coma III selected palltnt;, O\er 18 )"cars of age. II j~ al'iO used 10 lneat chromc Ilepalllis C. and III patient- '" ith tbl\ disea.<;c. Interferon alfa2u can nonnalll.l.' serum abnine 3mmocrunsFcrnsc (ALn Ic~ cls. nnpro\'e li\"("r histology. and tlecrease ~irul load. n.e drug ha.~ a direcl anllprolifcrnli,e IloCU~lty against IUmor

, "
c

iliff", ibKt.. liley should IlOI be shaken. Vials of solution ..... he.t<ftd II 2 1 SoC ""thout fn:c/J ng. n.e powder 0 I III months al room icmpcnu.ul"e or 7 day~ al

and assigning the ","Sf ('om""", amino acid 10 each \'anable posilion. Additionally. four ammo acid ch:ul!CS wen: made 11.1 foclli tate ~)'nlhesls, The I)NA aJuencc: IS also COllSltUCled by c hemical synlhesls, Inlerferon al faoon-l differs from interferon alfa-n2 al 2G' 166 :uniooacids. yielding 88% homol ugy, The protc:lIl Ius a molc:l:u lar mass uf approximalely

1:1I1'>tt'M AIfI n1. 111

11I\I\IU~

InleMcron alfa-n I. Wcllfemn.

of Ihe subtype, of 1fN-a

O/II'-IIUtritrotb isolated from D human Iymph\l1li. r.d ,"tlll ,!11' . lIer i ndueUOIl with mO\l~ parninnwnw

19.400 Da.
In terferon alfuCQf1 1 is u!>ed ill lhe lrealment o f c hron ic hepali lis C viru, infeclion in palie ms 18 yca r~ of age or o lder with "Qmpcn~aled liver d isease and ",hu have unll-HCY serum :lntibodlCli or HCY RNA. 'The drug is admini stered by lhe sUbcu tallCOUs route In a dose Qf 9 ~g 3 limes PCI' week. Interferon alfocon- I is Mlpplied II.'i a sohlllon III J>ho:sphate-buffered saline, It should be scored al 2 1 8 C Without freezing. AVOId ~Iul.: l ng lhe 0 soluti on.

.""'"
" " '"
~l ~
GD.UI\.

166 amino add, wi th an 011. n.e product is a mixIftd a.:h of tbe nilE predom llluni sublypes of IFN-/l', IrInfC'!\lll ;alr.n I is indicated to 11'1:31 chronic hcpamis C ..,:,:,~ 18 ~~ of ~ or older VI ho h;a\'C 00 dCCQlI1pen.ad I""'ditt~_ n.:, c'uc! mechanism of action for inler If nl In the treatment of ih , ~ dl<;t';a<;e h.as IlOI bn

tIM t)]'!C I ISend.1i simin). Each !hI> ~I ronsisu of 165 or II'CIJrt lTII~lI!ar m:JSS of 26,(0)

n.. ~ may be 3dminiSicred SC Of

1M . with a usual

.... 01 .! ""Ihon IU 3 II Il'lC$ peT .. ec ~ . Interferon alfa-" I j~

PRODUCTS: p-1 NTERFERONS

A listing uf twO commerc iall y available IFN -fo; is gwcn III T able 6,8,

Lbl)'

.1I!d "llOIuoon cootaini ng Iromc1hamillC lmd bu ffered ITl<' .. ,II! hIlman albumin as a sl~bi li /er. HelICe. the $OllI,hJuld no! be shdken. The sol ution ~hould be )\ored al

C.. ,thout flttling, III1d ~hu\l ld be discnrUed if fJl'C7.ing

"'11JCri) Slon:d IIOlution cxpire5 in 24 months,

'""

po-

,,'

'I fer'OftAlfil'nl , ll< Interferon alfa-n3, Alrcmn N, . " lnla'fmJII C\pres.'<Cd from human Iculoc} Ie' th~1 arc . . ..woobled .... 1 a\'ian Sc-ndai virus. The Sembi ViruS 1b P' .lit\! In dlicktn eggs, 1l1e proIeln consists of at DI I~ lI1IokI:uiM !>Ubtypc:s. 'The avenlge chain Ic:ngth is 166 _, ~ and the molecular maS) r,lIlge i~ 16,000 11.1 JIll Da. Tht pol)'disperse imerfcron alfn,n] i.. ulreme ly pllftlia.'i.\I\C II 1\ prott.'ISC:d by amm l) ,.hrom alogmphy o\'cr bl.l uf 1IJIlU'ot moooclQnal anllbodn!" spec ifically mise<! b tbr proIein l'IItffrron . lfa'1l3 is i lldic~lcd fQr inlmlc~ioliRI lrealment fl rrlr;lo,1Oty or ~l!fTenl cund yluma acurnlna la Ige nltal ..sIll! p.lIifQI~ 18 )'cars of agc o r o lder, Thc.>;e wans an: aIO;l/oI.:d hUlllan papiUom:t Vi ruS (HI'Y), Inlerferon . Ll '" ~iall) usefu l III palicms "'00 haven ' l n:' .. cillO 0Ibcr modalilie~ (podophyllin resin. sUil:cry, 1lfCf)~~y ), !mMCI1)II alfa,nJ is al-o belllg IIlVCS : fot tbe trralmet11 of non- Uoojl l m's I}mphonu, : !.IqIIc\, rblno" jrw;. '<lCCi ma. and varlcclla ZOSICf. liliiii .... 0,(' III cund}Loma acuminala i< 250,000 IU/wan, ."" ",tIIl lO-g:luge IW'edIe aroulld the b;a<;c of lhe le-

'''lh

(Recomb;nant), I7S Imerferon bela - Ia (rccomblllalll ), A"ooe.t. i~ a g lyeoprotC'in wilh 166 amilKl ocid ~. II has a molc:l:ular mass o f appnl.timately 22,000 On, The ~l1e of alyCOliylauoo is at lhe a<par.tglllc n::sidue 01 POSIlIOO 80, InTerferon beta - In poo>5eSSCS. (y'teinc n:~iduc al po!>lIion 17, :1$ docs the nam-e molecule, Naturaj IFN ,,B and interferon beta- I a are glyc()<;),lalcd. '" llh each conlaininll a Sl nil ic carbohydr~lc moielY. 'The: o\"eraJl Coni' ple.t has m. proIc;n and 11'1 COIrbohydnuc b) .... eight ReCQmbin:lflt interferon beta-l a is uprt'llsed in CHO C'r:lIs con lain ing the recomblnanl gene for h uman IFN-,B a nd IS equivalent 11.1 lhe hUIlHin form ~,.relcd by libroblasl ~. Imc rferon beta-! a i~ indiculed fur the Ircalmc:nl of re lapsing fo nns Qr nlUlll Jll e liClel'O'>i~. Patients tre:lted wilh inte r_ feron beta- I a demQn\l rail: a slower progression to di~bll ilY and 11 IClI~ noticcable bn:akd(1wn of the blood- bnlin barrier

In terferon

Beta 1a

a.a

TABLE

6-8

,B-Int .rf.,on~

r " .

Ljd~
~

MlmIII a1fan3 is conlramdiealed in PCr.<OfJS scn,n,,'c

.....,)"em

In t..-f_ Bet.1. (Av_.J

CHO ceD.

Int..-f..-on1let.1b (Betn.ron)
1' ........ nr~'" col,

m \t imlllllnosiobulin G. egg prulein, und neurnyd n, ....

IDltlfmlll Ilfan3 j, su ppl ied a' a sol IIlion "',lh lhe prQIC111
sali/lC with phelKll as a preservati"e . \liQuId be stored al 2 1 sOC Wilhoul freeling, 1.1 soIUhon e.tpires al 18 mont hs, Inlerferon alfa "conSCIlSUS" inte r,

oro"

''''
C~"" r",O\lOI

Hal

Soipptlnl form

....... ,.
lUI",!.

...."'' ')6'dmill"", nu! )0114

II<
~11UIk'"

A""",

""'''pin

NIlI JI)'W>,101oCd

150 ... Of ~ mllll"" IUImL

p,y...In
N~

r.. """""""UU""

"'

Oil""nt

SIm" .. >ICf....,
Ift'ft"~b''''''

O,j.!'lo .,IhI""

.,

1~

I.
~

ok,,"" of liON-a and SC\cr.aJ The IWlge of 1ICti. ity is about lhe SlIme as lhe other ~ but ihI:' specirlC :ICIivlly I) ~rUICf,

'
I.... I

2-' e; .... _".., ....

10 ... ""'" ...... ~
hl1''''''''''''~t.

P =111>'", 1--11 C; du "'" r"",,,,,

"N..

1 ". 'y.""'" ".,,"" ",."mI IFN,. ,,~""" _'''

1f4.amiIlO.:id sequence of alfacon- I is synthelic, It

N<-.....,

tn,ll!<1_"'" ftllCWn ...

l'l; 110 """."

"'~

----

2.'iO ... cOft)" ......... ~

In,l<<'llM "I<: n:.-. &3'i; """ .... n.. J ..

as observed in gadohnium<nllanced magnetic resonance unagmg (MRI ). Although the exact mechanism of 8Cl1oo of imerferon bela-Ia in multiple sc lerosis has not ~n el ucidated. it is koo..;n that the drug elem its biological effects by binding to lipecific reccplCn 00 the $lIrfaa: of human cells. This bUl(hng initiates a cascade: of InlTaCCllular events that lead to the t~~S!ion of imtrferooinduced gene prOOUl:ts. 'These include 2' ..s'-oliB03dcnylate synthctllSC and Ih. microglobuhn. These products have been measured in the serum and In cellular fractions of blood coUected froID patienlS treated with interferoo beta-I a. The functionally specific imtrferonInduced prot eins have not been defined for multiple scle~

Adverse effects inc lude a nu like syndrome at the Mart of therapy that decreases in !;C"crity as treatment proBres....es. Interferon beta -I a is a potential abonifacient and an inhibitor of cytochrome P450. The dosage form is a powder rOf" solution lh:lt is reconstituted in sttriLe waler. ExclplCnlS art: human albumin. sodium chloride. and p/l()sphate buffer. The solution can be stored at 2 to II"C and shou ld be discarded ifit free~es. The lyoph il i1Jld powder eJlpires in 15 momhs. Afler reconstitution, the solution should be used within 6 hours. The solution should not be shalen because of the albumm content.

in coli. IFN - y is the cy tokine that is scucted by humaa Tl ymphocytcs and NK tells. It is a single-c hain glycoprotein composed of 140 amino acids. The crystal structure of the protein reveals several helical.scg~tlts arranged 10 approximate a toric hape. Interferon pmma- I b 's Indicated fOf" reducing the frequency and !ie"erity of seriOlls infections associated with chronic granulomatous disca.<;c. an inherited disorder characttri7.ed by deficient phagocyte o~idasc llCtivi ty. In this dis ease. macrophaBC51r)' to respond to invading organisllt'l but lack the !.;ey o~idath'e tll1.yl'lIC5 to di spose of them. To com" pensate, additional macrophages are recruited illto the in fected region and form a granuloma tous structure around the. $ite. I FN- ycan stimulate tbe oxidative burst in macrophages and may revtl'5t the $itualion. Interferon gamma- Ib is supplied as A solution in sterile water for inje(:tion. The sol ut ion mUSt be stored at 2 10 8"C. without frec1.ing. 'The product cannot tolerate moo: than 12 hours at room temperntulT.

phate buffer tedpowdcr c;m be frol llCIivity. It I

Oenileu/( in
diftitox . rec acts lile aT in ~ogmt~ and a highl lil l. Dcniltl n.-combinan

protem COOt
loxin fragllll ;.cquenct~ fl molccullU' n

protem as.
tor-brnding thereby chai the high-an tightly. The
cylOlo~k \ !)
lo~m

THE INTERlEUKINS
Aldtsleukm. T",:ell gro .... th factor, thy mocytestimuluting factor, Proleukin , is rccornblllant interlcukin-2 (1L-2) upresstd in an engineered strain of Ecoli conutininJ an anaJoglR of the human lL-2 gene. The recombinant product is highly purified protein of 13l amino acids with an appro~imate mo1tcular mass of 15.300 Da. Unli!.;e native IL-2. oldeslcukin is not glycosylated. has no Ntem,inal alanine. and has serine substituted for ey, II site 125. Aldesleukin uists in solution as biologically active, non-covalently bound mlcroagglTg:lle5 w ith 111 A\ernge sitt of21 1L-2 molecules. Th is contrasts with tnWi lional 50lutlllll aggregates of proteins ..... hich often fOIl" irrcvcn;ibly bow-.::l structures th:lt an: biologically inacti.,t . Aldeslcukin enhances lymphocyte mitogenesis and sUi'" latC5 long-tenn growth of human 1L-2-dependenl celllllle$. IL-2 also enlulrn.:e s the cytOlo~icity of Iymphoo:ytes. tndoc tion of NK cell and lymphocyte-activatcd killer (LA K) cell acti vity occurs. as does induction or production. In moutI: and human tumor cell lines, aldesLeukin activates cellula immunity in patients wi th profound lymphocytosis, eosll~ philia. and thrombocytopenia. Aldesleukin ulso activates the production of c)loIdnes. including tumor necrosis fact (TNf). 11-- 1. and I FN y. In vivo experiments in mouse tU/l'l(W models ba"e mown inhibnion ortu mor growth. The 1f1C!CNnism of the II1titumor effect of aldtsleukin is unkno.... n. Aldeskuk in is indicated for the treatment of rnetllSt:llIC renal cell carcinoma in adults. It is also indicated for thr treatment of met:lSlatic melanoma in adults. Rescan:Ir If under way 00 the use of a1desleukm for the treatment iii various cailCeno (including head and neck canceno), trt'atmtlll of acute myclogenous leukemia. and adjunct thenpy in tht treatment of Kaposi's SIt'COfIIa. Renal and bepaue functa is typically impaired dunnB therapy w,th aldesleukin. 51)18teraction WIth Oilier drugs Ihal undergo thminat ion by tho:st organs is possible. Aldc!;leukin is 5upplied as a po ....der fOC' w lution. Afir:r reooostilll tion, the solution should not be sbali:en. The PfCP" raliOn is solub,lu.ed with sodiu m dodecyl sulfate in I pIu-

Aldesleukin. Ut

Interferon Betil - 'b (Recombinant). 117 Interferon betl-lb. ~ron. is a protcinthat is expressed in a rccombln:ulI . coli. II is equivalent in type to the interferon that 1$ npleSSCd by human fibroblastS. Interferon beta - Ib pas$l$ses 165 amino acids and has an appro~ im3te molecular ma.~s of 18..5 kDa. The notive form has 166 amino llCids and ...~Ig.hs 23 lDa. [nterfel'Qll betll-I b contai ns a serine residue II po5lUoo 11 rather than lhe cysteine in native IFN-tJ and ~ not contain thecomplex carbohydrat~ side chains found III the naturnll11()lecu le. In addition to its anti viral lICtivity, Interferon beta-I b posYY' im munomodulati ng activity. Interferon bcts- Ib i~ administtrcd SC to decrease the frequency of clinical exacerbation in ambulatory pati~nts .... ith rt:lap>ing~renlilting multiple sclerosis (RRM S). RRMS is charnctcriud by unpredictable 3lUld s re~u1ting in neuro log ical deficit!. sepanued by variable periods of remission. Althwgh it is I'lOl possible to delineate the mechani~1It'l by .... hich Interfcl'Qll beta-lb CAem its activity in MS, it is klK)wn that the interferon binds to specific reccptOfS on cd l ~UrfIlCCli and indllCCS the expression of a number of interferon-induced gene products, such as 2'.5' -oligoade:nylate 5ynthctasc: and protein kinase. Additionally, interferon betaIb bIoI:ks the synthesis o f INF-y..... hich is belie.'ed to be In.ot-'ed in MS attacks . Interferon beUl-1 b is supphed as powder for solution with albumin and/or dextroSe as ucipient!. It should be stored II 2 to n:: Without freezing. After I"CCOmUlution the solution can be st~ ,n the refrigerator (or 3 hours. The solution should not be shaken. A major diff~rt:ncc between interferon beta- I a and betaIb ,i that beta lb causes more hemorritage and neaosis at the lIl)CCIion sne than doe5 Intcnc:ron beta-Ia. PRODUCTS; ,....INTERFERON Interleron Gammil- 1b (Recombinant}.'" Interferon pnuna-lb. Actmlmune. is a recombinant protein exprrssec!

inhibit Mahgnanlct in cutaTII.'QI 1L-2 icJ'\t denilculln d Demltull lent or ~UI nant cdl, C\ Dcn lkukil .... ater for IIlj It i~ 'u~ 210 8T ror I 10 2 houn hour'll. The d or through a

Oprelvelcin

mega. ,~ rt'CI recombmant II rtl~ion pro 10 oOtalll lhe length ulld 'ckin diffe,..; IIlg an N ' len III diffcrence: ll..- Ilisal talcs the prol megala!') ocr karyocyte IIU The prim.ary tion of Illega

II,

ustcobla~" :I

IL-Il and m fnoTlln and

thromboqtO ,ill"' after m nonmyckJld

"

0l'rc h el.m

h,~

!If"OICHI of lilt

,pro"'.

. . . tluffer. Akkslculin <hook! be stored lIS OOflr:OOstituJaI PI",.kr at ~ 10 8"C and 1Ie,-cr r~lI."n. Ra:on~lIlutcd , juls IlL' Inlfen Jnd 1h.aIlN OIICC' In 1 Ib)'$ ",thout loss of ... ' It). II npll~ ol-cr I penod of 18 rnonths.
oenl/~kfn a/hiroK {Recombinant}.'JO Denilcul.in IIIftLI"\, rt(ombinanl. Ontak. i~ an c~al1lple of II drug 1113\ 11;1\ hlel Tro"," hoo;e, O~ part OflOO molecule i ~ inlolved

he fre

d wilh :hal'llClis di~ ms but acorn the in-

Jndlhe

_d

anti hmds ;,electively with the di'iCu~1 cdl. IIId I hi;lliy IOAic 'ICCOOd part of the molecule eff.:cls a ~,II lkmkukln difiilox is a fu,ion proIein c~pn'~!Oed by a ~,lII'II>inanl \lmin of coli. II is It rDNA-derhed c)'tolOxic ((I'kUl ~~ of the ammo:.eM! SC\IlIC~ for diphlhm:l .,
UD traemmr. A and B ( M el,-Thr)J1)- th ~. follo\\ed by the """"'nct~ for 11..-2 (Al:lrThrlJ). 1lIc fusloo proIeln ha.~ a ...&c:.:uw ma.~ of 58.000 Da. We can think of thiS large ~1Ic'n" 11DOIa:u~ of diphthernt tOXin In \\hlch the rttep" 1'In.ltnl dom:IID has bem replaced by 11..-2 ....."ql,l('~. 111Mb) dl<lDlln! Ill. binding \pecilidty. Cells Ihat expm;s Iho:- hlgf!'lffilllly (a.An 11..-2 rt.'Cc plor bind the proIeln h iul) The 11..-2 OOlliponcnl IS uo;c:d liS Q director to bring the 'ltL~,,\i( ~JlC',e" in ~Ollt:ICt with tumor cclI~. The dlphlheria ~1\1n Inhibit, cell ular protein synthc, i~ 3nd the cells die. \r;al,&IWII ('tIL, in cenain leulemias nnd lymphomas. includ'" ."Ut.IJltOO, 1-11 lymphoma. upre~~ Iht hl gh_aflinity n1 n:ct,~or on t~ir cell surf~. II is lhese ce lls lhat .knikul,n d,ftitOl tillgCts. Ot-nilcul.tn dlftllox is Indicated rOl" the treatment of pe-r.;i._ .. m:urTnl\ C\ltaJII:O\I~ T -ct' li lymphoma \\hose malig_IXII\ elpres:!' the: COB componC'nt of the IL-2 re:ceptOl" . Dl'nikul'd dlftitox is supplied II~ a fl1,1.('n solution in ..... ftll" lnjtClion. II 'hould be .tured at - IO"C or eokkr. k ~ '>II~'\U:d th:u the vials be ,hnwc:d In a rdTlgCr1llOf at ~ WIf(' for Ie" than 24 !loot<; 01" at room tem~ralu re for t tn ~ hours. PrqKu-ed solulions should be used within 6 tnu, The dillS I~ adminislcrt.-d by IV infu,iotl from a bag ..., 1lu1lllgh a Iyri ns.: pump . Opfrlvtkin (Recombinant'. w . In Opre:lvd;in. Neu ". II. " Ia:olnbmant humM 1 11 that is e~pn:ssed in II ..... 11\ II,IIIl strum of . ro!i as a th,orcdo~ in andIOI" mILI 1 L"II\ prole,n. The fusion pRlIein IS clea"ed and puri r k'd iI thr "111..-11 proIein. 1lIc protem is 177 ammo acids .IrIIJIh;lllL.l h.1$ a mass of apPfO~inlately 19.000 Da. Opn:lc\.la dtffl'!"J from the naturJI I 711-ammo acid 11...1 I by lack1/1 ~1C"m1,1\;l1 proliOC' nll~ a lterullon ha.~ not resulted .1tIJI.'mIC1:\ In mo;.ai,ity e'ther In ,nro or m ~i"o. U11 ". 'hrombopoicllC growlh factor. It directly stimuloin thL: prohfcnmon of hematopoietic stern cell. U' weU as 1I'lI0I.1I)'0I:) Ie progenitor cells. This prtlCl!" induces mcgu~'''')11' I11.llur:IIU;JI1 and increa""'d pnxJllctiOl1 of platelelS. The pnm.wy henUlOpOielic octi, ity of opreh'clin is sumula11 rimtr:,U:IT)"OC) topoiesis and thromhopoie..(is. Primary ~,"'~~ IIIIl m3IUn' OMoocbM' c~pn:~s mRNA~ for boIh ~ ft'('('ptOr. IL-IIR alpha. lIeoce. boIh bone.IIId boocresoromg cells are pos)lble turgets fur 1L-

rc"'~nliion

thromboc)topema. EflicllCY h.;\l, been den)()l1Stmled m persons "hu ha"e e\pcnenccd 'it"ere thromboc)topenla (01. Io","g a pt"e\'lOU( chemotherapy cycle. Opn:h'elm cau~ many ad,'el"!il" re:llCIIClnS. Among these IU"e edema. neutropenic fe\er. headache. n:lusca and/or ,omiting. dY'PIlea. and tach) cardia. PallentS must be momlorcd clotiely. Oprcr. ekin i~ ,uppl ied 1'~ a Iyophi li/.c:d pu\\'der for reconstitution . E~eipients Include glycine hnd pho~phnlc buffer componenl'. TIle puwdc:r has a shelf life of 24 month s. It should be stotCd al 2 10 8"C. If it is frolen. thaw it before /l'CQfhtllulion. 11le TNF\ (Elancrcepl. Enbrel) lire: member> of a family of cylolines that 1U"t produced pnmarily in the innal~ Immune ~y tem by acti,ated mononuclear phagocytcs. Along wi th ILl. TNF is typICall y the first cytol.inc 10 be: prodocetl upon infection. and liS rcact;OOIi can be both positive :l.IId negali~e. On the one hand. TNF can cau~ cytOloxiCl ty and ;nnanU1l3 lion. nnd on lhe other h:md. II servcs as a ~ignallo the lIdapl i\'e irn rnuII~ rc~punse. The TNI'~ are ull endol:lenou~ pyro~cl1s. and Ihc) cnllSt chill s. fe,er. and nu-like ~ympt oms. There arc IWO fonn, ofTNF: TNF-a(coc/ic(;lIn) and TNFp (1ymphotol ;n ). 80th bind to the same rc:cc:plOr and cau~ (Imilar tffec1.~. Elalll.-rcept is a d,meric fllSlon proIe'n COIlS"Ung of the Cllr..ccllular ligand-b1llding portion of the hunlan 75-kOa (p75) TNF fe'('('ptor (TNFRJ hnled 10 the Fc portion of human 'SO/ ypc IgG " 11le Fc component of tlilnercept contains theCH: dom:un. the CIl, domain. and lhe htnge region. btu 001 the C H I dom.ain of IgG I. lbesc re:a;'on~ 11K rcspunst ble for the biological effccts o( immunoglobulins. Etancrccpt is produ(:ed In rec:umbmanl C HO cullul\'~. II OO/I""ts of II peplidc cham of 934 31111110 acids and has a nlO]e<:ulhr ma~s ofllpproximlllcly ]50 lOa . It binds ~pccilicnl l y to TNI' I,"d blocks il.~ imcr:lc tion wl,h ce ll surface TNFR ~. l!ach elancrC"Cpllnolcclile bind, 'pte,tica ll y 10 , ... 0 TNF molcclllc~ in the syno,i ul /laid of rhcumat oiJ anhritis p;ltiem,. It i~ equally cfficacKlU~ at bloc"'''g TNF-a lind TNF-P. 11le drug I~ indicated fOl" n:.'duc;ng signs ~nd s)mplonlS and IIllubtung lhe prog~\Slon of ",ructurul damage in patienls ""th rrwxlcrulely to se,trcly OCt;,'\, mcumalQid anhnti~. Etanercepl ," alo;o Indicated for reducing SIgns and symptom!> of moder:llely 10 sevell'ly octi,c polyumcular-coursc ju,enllt rheumatoid anhTl1t" in palient~ 4 years of age aoo older \\ hu h:l\t h.ad an inlKlcquDte fC<,poosc to one or mon: disease-modifYing :mlimellnlatie druj;.~ (D MARDS). Et;tltC'rcept I~ also indi cated for Il'dllcing signs and ~ymptOtns of activc nnhritis in palienl~ with p~ori~lic nnhrilis.

Tumor Necrosis FKtor (RecombinanQ.'J.J lJs

to

'''"" re.

""'''

pr, thy. 11<

f 133 15.300

am lAof

. 'Cys

""
al

active.

PIle ~"e

!eluuon

boo""
I stimui hne~,
lodu.; K) cell

cellu lar
eminoates tht

-~

factor
,,~

_ho wo.

hW,tlllic for thl: :arch i~ menl Qf

eaunenl:

iy in the
function
n.
!iO

ENZYMES
81ood-Ootting Factors
1lIc blood elollm@ ~)stem of the human body is t}ptCaJly 10 a carefltlly balanced ltotneo'>Iatie stale. If dilm3(e IX.'CIlJ"'l to a blood ve,~d w"1lll. a clot \\,11 fonn to ... al1 off the damage !>O that tIM: rrucc" of regeneration can bf:,gin. Normally Ihl s process is highly localil.cd 10 the damaged reg'on. so thai

wr
...

byn. Aft
c prepa-

(~"hrlJn L\ indicated for lhe PI"I:>('ntion of sc'ere:

.-

1upcnia. It reduces the IltCd for platclet transfu&I\rr m)do'Ml~'''e chemotherupy in patlenlS wilh ... ekIId malignancies" ho are al high risl; for severe:

the: hc:mO/llullc rc.<;pon>:e doe~ nul cauloC Ihrombi to migrate to dl~tl1lll 5l te~ or pen.I'<I looger than il i~ nceded. Lysis of blood clots occurs through lhe: oonvc:nioo o f pl:lSminoge n w plasmrn.... hich call~ fillrillOlysis. comertmg Insoluble fibrin It) soluble fibnnopcpllde~. 11M: plasminogen -plasmin con~ef";ioo IS clilal yud by sc\cral blood and tissue activa tors. 3mOflg them urokmaloC. l:allikreln. plasm inogen activators. and .rome undefined inh.bium. MO<'e specifically. Ihe conver;ion of plasminogen to pl asmin is c:llalYled by two extremely 'ipeci flC <;trine protease!>: a urokinase: pI:lSminogen actIvator (uPA) and a ti\.~ue plasminogen act ivator (tPA). Thb -=tion focuses 00 IPA. Human IPA b a serine protea'ie that is synlhcsiud in the: vacular endothelial cells. It L~ a ~i ngle c ha,n peplide oompoloCd of !J27 amino acid~ nnd h'ls a mulecu lar mass of appro:c.unulely 64.000 Du. About 7'1- of the: ma~s of the mule cule COOSi\t5 of carbohydrate. 11M: molecule conlams 35 C)'$ residuc,,- 11M:'iC an:: (ully p:tired, giving the tPA molecule 17 disulfide: bonds. 1bc:n:: arc four N-linked gl)'cos) lalloo si lc:s n::cognll.ed by OOfIl'('nsas scqUCIlC'a Asn-X-Sct-nllr al residues I 17, ,!U, 218, and 448. II is suspected lhal Thr~I bean; un O-fucOSI! residue, T here are IWO fonn~ of II'A Ih:1\ differ by the ~nce or a~nce of a c!lIbohydmie i rouP al Aspl .... T}pe I tPA is glytosylatrd at Asn1l7. A~nl"" and MI4o.I .... hlle type IItPA Iac~ \ a glYOO$yl lVOOP al A<;.n".... Alinlll i\ t)'ptcally unsubstlluted 111 both form s, Asnm con lains . high -mannosc: ohg~haride .... h.le A~n ~ub'<tilu , ent s 184 and 44H an:: complex carbohydrale SUbsllluted. During the proecss of fibrmo ly., ;, the single-chain protein is clea ved belween Arg zn and Hell .. by pl~min to yidd 2 chain IPA. T ... o-chain tPA conS ISIS of a heavy chain ( In.: A cha in. \kri,ed from lhe: N lenninu~) and II tighl chain ( 8 chain 1. hn~ed by a si nl!ic: dl"llllidc: bond bel ....een CY)l6-I and CySJ'H. 11M: A chai n beal' some unique slruct ural fealUn::~; lhe linger n::gioo (residues 6 10 36). the: gmwlh faclor region (apprm unulc residuCll 44 10 SO). and Iwo kringle domains. The<oe domains an:: disulfide-c losed loops. mo~tl y {J sheet in slructure . 'The fin~~r and kringle 2 an:: n::>.potlsib.Je for IPA bllldmg 10 fibnn and (Of the actl\"3rion of plasminogcn. lbe function of kringlc: I IS IlOl known. 11M: B Challl ~"OIllain~ lhe: '>trine: pruteuse domam Ihat CQfItains the II lsA~p-Ser unil Ihnl cleave, plasminogen.

Reteplase. Relepla!ie ( Retavase) is a Ikl~tion mu ~ variam of tPA thaI is prodoced in I'ttornbinnnl E. to/i. Thf de lelions are in domaillS re.~pon\Ible for half life. fibrin Ii firuty. and thmmbolyue poIency. It CQfISISH of the mnlle2 dom:Iin and protease dolllain of IPA but lads the l.:nngle I dom-lIln and the lrowth factor domain. It is considatd I third -generation thrombolytic agent and has a mechnnbmof a~1ion simi lar 10 thul of nltcplase. RClcpl ll.'>e al:IS dil'tttly ",. catalY-li ng the cleavage of plasminogen and i niliating Ih l'Qlllbolysis.. It halo high thrombolytic pot~ncy. A compamon at nltepla!i(' and releplase IS gin'n in T able 6-9.

is a IPA produced b) recombinant C HO ~.... II,. The molecule is a 527-amino a.ctd

glyoopl"Olci n t1cvelopcd hy inlrooocing lilt fol lowi ng modifi cations 10 the: c DN A eonSlllK.': Thrl1>l 10 Asp. ASPIIl IO GIn, boI:h w.lhin lhe kringle-l domain. and a tctraalarulll: su~i lar ion 31 I mino ocids 296 1 299 In the: protease d00 main. llx: drug is a Sterile. Iyoptuhud po ....dc:r ICCOiUmended for si ngle intmn'notIs bolas !ItIml nislralion ann ~ conSlilu rion wilh ' Ierilc water. TCrlCCtepla'iC shou ld bt administered immedl alely after n:cooMilUrion . Anlihemophi lic fKlor VIII (n::cornI!Inant ). ROCOftlbinaiC. Kogen:ttc. Blot ille. Helixale... I plasma protei n Ih~1 functions in the normal b.Jood-c1oru1ll eascade by increasing the V mo, for lhe actl, arion of dotlJI'f factor X by factor IXa In lilt presence of calcium ion!,mJ negatively ch~rged phospholipids. FaclOr VIII IS used 111 tb: In:alml'm of hcmophlha A. Hcmophilia A is a COI1gt'1IIIIl disorder characteriled by bleed;n!!:. 11M: mtroduction off~ lor VIII as I drug has Improved the qualn y of life and tb: life ClIpect.ancy of Individuals .... illl thl ' disorder. Unfor1llnately. ir has been ncccssary 10 re ly 00 an unsure SOUfa (human plasma) for rhe fill-"lor. Exposure of palien", 10 alloant igens and vi ru ses hps b..'C n a conccrn. F:lCtOf VIII dcnllll from a recombl nam SOUrtt .... ill poIcnti~lIy eliminate of these problems and proVide an c:ssc:nrially unlinllled Mpply o f the: drug. F3Clor VII1 is biosynrhesiLL'd as a ~ingle-chail1 polYPI? lide of2.332 am ino acids. The protein i~ very he~\'ily ,1)\'1). s)' lalcd. Short ly ofler biosy1llhc:sis. peptide cleav age I)CC\I\ ol"ld pl asma fal:tor VIII cil\"ulatcs a~ an SOlOa light chM associated .... irh a series of heavy chai"~ of appro~imatd? 210 kDa 111 a mellli Ion-stabih led COOlplU . FacIO!" VIII put'iCW'S 2.5 potenlial N-Itnked gl)'CQ'iy lalion suc;s and 22 c,. re~idllCS. TIll: 21().k Da ht-avy chain is further clea\ed II! protease, 10 yie ld a <;cries of proteins of molecular nllls!!XI

Tenecteplas~. 'J7

Tcnect~plu.'ie

Factor VIII.'''

"*"

Tissue Plasminogen Atrlvaror. Recombinant. 'J7 tPA (recOOlhlnnnt). alteplll.'iC (Activase). is ide ntical .... ilh endoscnous IPA. nPA lac"'_ II gly~"OSyl residue at Asnl". AI one lime. nPA was produced in I""o-chain foml in C HO I.'UIIU~. Now. large-ClIle cultures of recombInant human mc:1~nonlll ce ll.\ in fenneniCrs ~ U !I. ro produce a prodoct Sl..' th31 i~ aboul 80% \inglc-cha m nPA. Alleplll!le is used ro improve ~emricutar function follow ing an acule myocard ial ;n fa~uon. inc luding reducing the incidence of oon~~li \e heart (ailun:: and decre~mg mortality. 11M: drug is nlso used 10 lreat lI\'ute ischemic \troke aflc:r COI11PUied lomography (CT) or other diagnosti C imagi n!!: has ruled out In ttll(.T;mial heJll()fT/tllge. rt PA i~ abo used in cases ofucu le pu lmonMy Ihromboembolism and is being invesl;' galed for unstable angma pectoris. i\IIcplasc i~ ~uppl ied as po ... der for injcclioo. and In reconsUluled fonn (1IQ!l'l'l3' saline or .5% dc~lrose in .... arer) is inrended for IV infusKlI1 ooly. 'The '\Olution c:llp.re~ in 8 hoof"; at room Ic:mpenllun:: and must be: prepared jusl before: usc.

OJ"

TASlE 6--9 Comparison of the Pha~cokinetic Pa ra meters of Alle pl ase il nd Re t e p lase Pha rm.u>kinetlc
' . rll mete r

AII. pl...

t:n..ct'II<:',/,t n. I .j Vol ..... "'~C t.)

~~k .... "'. tmUl!li~1

, " -,.

" . t _plN
1\.. 16

2"""'''0

mut;lm

10

bnn al

pi'''''

protein moleculc.~ fOl'TTl a l1l<"I 100 , ... ,h~ed CQlnplcx v.ilh the light cham. ka.~'IIJIbm;inI (.:lor VIII is produced in IW{) recombinant
I~

Hn. The 9a. III 188-1::1> ..

nngle-

knni'e-

I'n\I in balch culture of Inmsfecled CHO ccll~ or in con "c,.a ClIltUR of baby h;llllSieT kKlncy (BilK) cdls. There
~ ~.I)P"
II<:

dereda

; i~rn of

of ItCOffiblll:lllt factor V Iti a\'ailable. All four

m~mg

it)' 1'>y lhnm-

a eDNA 000l51fUC! encodi ng the tfIIIn: ptpuOe Itqucncc ;nlo the CliO cell 01' BU K cell tine.
prodllCl

jJIlfJuctd by

i'\On of

!P,., 10

Ced by n<l add modili

oomaiM a Gala(I-3IGal unit. ...totbt8UKl'1U.ymedoxs not , Recombinant factor VIII .. !,,~)dl\rcr.r, containing multiple peptide homologllC:s ;11,,,,, 0lIl IIO-kDa protein and "mOIlS modifications of an iIfl' I\llIIIItly 9O-kDa subunit protC'rn. The product ronlaills .., bbJd pnldocu :mil IS free of microbes and P)'rogclls.
fktor VIII is indic~l~ for Ihe lreannenl of c.o-II hemophilia (hemophilia A) and for the prevention .4 tlUlmelll of hernort1lagic ep..o;OOes and periopenuive lIMII~nt ofpalicnl! wilh hemophi li a A. The drug i~ abo '-.1 for the In:almtnl of hemophilia A In persons "'00 po inhillttOl11IO factor VIII. Rl'roIIlbinant fIW..1or VI 11 b supplied in sterile. singledm,e 1111_ The produci is sillbiliud with hurnon albumin and lw:d. Tbr prudUCl nltlSt be stored aI 2 to S"<:. " 'Ithout 1m l1li In _ Instlloces the powder may be stored at IOOII1lt'11lperalurc for up 10 3 momh~ without loss of biologi ~ iCllllty Sh3lmg of the n:constilUlcd product should be I ..lal beciuse of the of the albumin. The drug ','. ,be admml)ten:d by inl ravenous bolu~ or drip infusion ~ boors of KCon5litution . Sur ~ amounlS of ITIOI1Se 01" hamster protein may ..,r) ,,;th It(ombinllnl factor VII I. one should he eauIIO!I\ htIt adnl1m~leringlllc drug to individu~ls with known lI'1ty 10 plasl1'l3-derived antihemophilic factor or _ill h)pe1sul.\itil-ity to biological preparations ",ith trace _ _ of mou~ or han1 ~tcr proteins.
Rn:QJTI~inanl

n.- 010 cell

"'1aII Ill\:

ac,c lIo-

I'KOffi'

Iftcr reo Id""

Dro trecogin AlfiJ.'' About 7SO.000 people arc diag nosed with sepsts In the Untted SlItC5 cach year. and of these. :tJI estimated 30% will die from it. despite treatment with inh'lIvCnOliS antibiotics and supportive care. Patients " 'ith severe sepsis often upencroce failures of various systerns in the body. illCluding lhe ci~ulalOry systcm. the ney!. and clotling. Drorm:ogin alfa (activated), rotrecogin alfa (activated) (X igris). is a recombman t form of human activated protein C. Activated protein C UCfU an antithrom bocic effect by inh ibiting factln Va and Vill a. In viltOdata ioidicate thaI acti va ted protein C hM indirect profibtillOlytic activity through Its lIbility 10 inhibit plasmillO&en activator inhibitor_l (PAl - I) IIlld to limit gel1('l'lItion 0( IIC"tt\. ted thrornbinllCtivat:.ble fibrirlOlysi~ inhibitor. Additionally, in vitro data indicate that acti vRtl'd protein C may exen an antiinnammatory cffect by mhibiting TNF production by l11OflOCytes, by blocking leukocyte adhesion to ~ lecti05, and by limiting the thrombininduced inf1ammatory responses within the microvllllCu lar epithe lium. Vials of' drotrc:cQgin alfa should he stored at 2 to Ire without fll:eling. The reconstituted IiOlu tion is stable for 14 hours at 'B"C.

"id-

Fomb,.

Antlco.gul.nt
Lepirudin, RKombinilnr. 'G I...eeches (Hirudo tMdiei (llIlis } h3\"e been used nlC(bclIlali y for centunes to treat in)u fie5 in which blood cngorges the tiNlCs. The logic behind this is SQlid: leeches produce WI agent kllOwn as hirudin that is a potent. specmc thrombin inhibitor. Leeches have been used to ptl'1'ent \hrom\:lo!lis in the mIcrovasculat ure of reattaclled digil.~. Lcpirudin (Rcnutbn) is II rDNAderivcd prolein produced in yeast . It has a moleculru- mass of approJlI matdy 7.000 Da. Lcpirudtn diffcrs from tile natural polypeptide, in that it has an Nterminal leucme instcad of i'OOleucine and is missin!! a sulfate fUlICtion at T yr<>J.

i "

lJottlng

~tmg I~ and j in the

nita!

r=c1lCt'

\n.J"",

of roc-

nronu~~<

\0 uliokn\oo
: man)'

Jd _up-

00riJ:.1g F~IX(RKombin.7mt). IH. ,.. When I per " II <kf~nlln dOlling factor IX (Christmas factor) . he~Iha B re;ull~ . lcmophil ia B affects primarily mules dlCtUllllS for.bout I S'" of al l ClI<;c$ of hemophilia. Treatunoh-a n:pbccl1Ient of fac10r IX SQ that the blood _I da!. Recombinant coagulation factor IX (IkneFill) i~ a r.~. JlIriflCd proIein produced in reoombinam CHO cells. lit< rll!lood prodlK'lS. The product is a glywptotcm of :ubr Il\a)S approxun:ttdy 55.000 Da. It CQIlsiSLS of 415 . ICtd~ In a si ngle chuin. The primary amino acid se I .e ofBcrdll isiderMlcal ..... ith the Alai'" allelic fonn of \'ed factor IX. and it has structural and fUflCtional ....."sue) SImilar to tho6c of the endogenous protein.
"'" 'Cl'ombtnant proICin is purined by chromutography. fol "'-cd by membrane filtration. S DSpol)'".M:l)'I:umde gf;1 ... titfboiUI! Jhows that the prodllCl uiS's primarily as I

other Ena,.._
Recomb/Mnt HUmiln OeolCyribonuc~ilse I (DNAse). ,..., DNAse is I humartmdonuclcase. oonnally present in sali\a, urine. p..10creatic secretions, and blood. The enzyme ca tll IY1.cs the hydrol )'~ls of utraecllular ON A into oligonucleotides. Aerosoliz.cd recombinant human DNAse (rtoDNAse). dornase alfa, Pulmozyme. has been fonnulated into an inha lation agent for the treatment of pulmonary disease in patiena with cystic nbrosis (en Among the clinical manifesUtUonS of CF are obsuuction of the airways by viscous. dehydrated mucus . Pulmonary function is diminished. and microbes can become cntr.lppcd in the ~illCid matrix. A cycle of pulmonlll)' umtlUClion and infection leads to progressive lung destruction IIlld evenlUlll deOlh before lhe age of30 for most CF p;llients. The immune system responds by sending in neulrOphils.. and lhe:sc accu mu late and evenlUally dc:'generate. releasing large amounts of DNA . TIle high levels of e~lracellular DNA relcased and the mucous glycoproteins are responsible for lhe degcneratIng lung function. The DNA-rich secretion~ also bind to aminoglycoside antibi(l(iC5typicaily used to trCaithe infec tions. In vitro studie.~ ~howcd that lhe viscosity of the secre tions could be reduced by :application of DNAse I. Before DNAse WlI.'! purifocd IIlld sequr:ncC'd from human

II,

lIIl. . .

component. CIottIll! factor lX. recombinant. is indicmd for the CQIl. II -.I ptt'o'(!I\1OII of hen ..... t llagic epIsodes in pcroons with ",,,,,Iloa B (Cbn$l ma5 ' disease). includinglhe CQIltrol ~nd prt~ of bleeding m surgical procedures. bFIl i~ wppIied 1$ I 5Icrile lyophili1.ed po ..... der. It .... be $IOR'(! .. 2 10 trC. 1be product will toleralutorage aroum tmlpcnllUre nOi above 25C for 6 monlhs. TIle drug 1tt..~ltDStab le following recon.~t itution and must be used . . . Jbool\.

"OUrces.. a pamal DNA o;equerocc from 00' me DNAse (263 amino acjd~l ",as used 10 crealC a librury 1I1al could be u.;ed 10 scl\."en a human p;:IOCTC'alic DNA hbnuy. llH~ facihtated Ihe dc~clopmcm of lhe human recombinant proIcin. The en dogenous human and recQmbinant I'fUlcin SC<!l,IeI1a'l are identkal. Recombwam human deo~yril'lonucleasc I Irhl)NA<.e) "'lIS cloned, sequenced. lind e"press.cd 10 eJC3mine Ihe potential of DNA<iC I 11.\ a drug for usc In CF. It Iw; h-n 'ihown that cleavage of high molecular-wclght DNA in to ~mallcr fngmcnls by U1:aunent ""th acrosoh/ed rhDNAse Impnwes the deW1lIlCC of l11ueu~ from lhe: lunlt~ and reduces the: ellacerbauOll--~ of ~splralory ~)'mploms requlrilli pal'Cnteral aDlibiotic,. rhDNAsc l ,s a n1Or'lQf11CrIC Ill)coproteln COfI.'I~tlng of 260 amino acids produced in C HO cell culture. The molecule possesse~ fourCys m;;duc~ and two sites that probably contain N1inkcd glyOO!>iOc~, The molccu l:lr mass of the mole cule i~ about 29 kDa. D~Ase I i~ an cnOOnucleao;c lhal clca,('1; double\lrnnded DNA (and to '>(llnC Ulcnt <ingle '\tranded DNA) Hlio 5'pho'ipl!aletcrmimued poIynuclcolidc\. Activity depcnd~ 00 the presence of calcium and mag neMum lOllS. Pulmo7.Ymc i. apllfO\'ed for u<.c in lhe tr;'UUll('nt of CF pauenlS, in COIlJuOChoo "'lIh <tandard therapK'S. to redUlt lhe frequenq of re'p!mtOf)' InfL"CtlOn~ rc'llunng p.1rcmcrnl antl biohc~ and 10 IIllpro'c pulmonal)' funehOll. The dose i, delIvered ht a Ie\<cl of 2.5 mg dai ly wilh U Ilcbuhlcr. l'ulmolYnIC is IlOl 11 replx.:nlCnt for antibiO(ic<;. brooclt(xhlnt~. and daily phy~iea! !herap)'. Type I Ga\JCher"~ dio;ea>e is a hereditary condit ion OCCUlTlIIg in aboul ! :40.000 111<11 vidunls. II I~ char actem.ed by a functional deficiency in P.glueoc~rebrosidasc C07.)'1l1C act i"ty and the resultIng kCumulatrOll of hpid glu cocerebm;;ide in ti~\IC macroJlhagcs. ",hich becomc ~n gorged and are temtoed GI/I#chu', a/Is. Gaucher'~cc lls typi ully accumulate III !he liver. <plccn. and bonc nUllTow ~nd. occa!.looally. In lung. I-idncy. and inte~tine . St:condary he matologklll sequelae: inc lude se"ere anemia and thrombocy topenla in addillon to char.IC tm~ic progl"OlShe hcpatospleIIOIJICgal). Skeletal complications are common alld arc frequem ly the most dcbihtallllg and disablin, feature of Gaucher's disca.<oc. Poss,ble sl-cletal COIllphcallOlls an: os t(."(l1'lfO'\i~, o-.teQPCnia \\ ilh <c('OIl(!al)' palhological fracture-;.. remodeling failure. '-"'teOllClel"Q!.i~. and bon<' eri,,<,s. Cere7)'rll(' (Imigluccrusc )r4-1 is a recomblllant. macroptmgewgeled vuriant of human ,8-gIUl:ocercblmidasc. purified from 010 cells. It catnly7.e~ the hydrol~i~ of!he gl)eolipid gluc(x:creorosidc to glucOl!oC and cemmidc followlllg the normal Ocgl1l!iallon path",ay for mcmhr.me hPlds, Cm.'1.)'1'I1C is ~upphed as alyophiti/.ed pnwdcr for n:eonstitutioo. The powOcr shoul " be ~rorcd at 2 10 8"C unlil used. 'The reconstituted product for IV infusion is 'tuble for 12 hou" at room rempcmture.
Cere:lY~.

g,,en here. Vaccine productioo IS D nlltullIl applicauOII of rONA tcchnology. aimed at achlcving hIghly pun: and C'lIciou~ products. Cumnll),. there are foor rONA vlI(.'Cines appml'ed for human usc. A number of othell are 111 clinica1 lrial for some rJtheT eJ(otic Ul>C.~. It \\ould appear that ~ t~'Chl1Ological lll>pmaches to I'lICC1l1e$ will bnng about somt "el)' uloCful drugs.

em

PROOUCTS
Recombivax and Engerix 8. Recombiv:tx :tnd En. gcrix8 are interchangeable for IIIlIDunll.a.Uon agall1st hc~ ti tis !l ~ i rus (l III V, seru m hcpatni s). !loth COIll;"n a 226ammo acId polypcp!Kk COOlpo<lI1g 22nm-diamcter partI. cles thaI po<'C.SS the antigenic C'piIOpe~ ofille HUV ,urfac:t coat (5) protcill. llle productS from two m3nufoctun'n an' expl'C'~~ from rccombinant S. cC'",\js;/IC'. It i~ rec0mmended that pallcul~ reccl\C 3 doses. wilh the >CI.."Ond dose I month aner thc fi1'llt pnd the third dme 6 months after tilt first. The !'OUtC' and ~ite ofinjecll"" are 1M 111 deltoid mu!oCit or. for infunts and )'oung chIldren. in the JllIcrolhlcrnlthigh The ~:w.:cinn achine 9-1 to 98'" immll~enil:ity arncq aduh~ 20 10 ]9 ycars of lISc I 1 2 month, aOcr the Ihrro 0 11osc. Adulb o>er 40 yean; of age reach 89'1 Immuroogcnic IIy. Infa.nts. yoong childn'n. and adolc!\Cems achic\'e % 10 99<t immunogenicit). The vaccine is supplied a~ a ,U\peU\lOn adsorbed to aluln. num hydroxide. The shel f hfe i~ J6 months. 1"hC' '1iL'C1l1t should be Mored III 2 10 !1C and .,hooid be discarded if fll)o J.en. FteC'zlng de<\) ~ potency. L YMErix. ,.. Lyme dl...easc i~ cao.<;C'd by the sptrochtlf &rrf'hu tmrgdmferi. The microllrganrsm is transmitted po. matily by ticks and h endc:mlC 111 hc3~lly wooded are:.s and fl)l'CSls. lllc disease produces anhritisJike 5) IIlptOIllS. A ,,!C. CUlt: :rgJlnst Lyme dr",-";ISC was (Wated by dc,elop'", liecombinant r::' e/>li that contains the gene for the OocICriJI outcr surfllCe protein. This protell1 kpA) is a ~ingle poI:.. peptide chain of 257 amillo acids with covalently bound lipid~ al the N termInus. The vaccillC is fonnulatcd ... I <.uspc:nsion wilh aluminum h)dro~idc as an IIdsorptlOll adJIlvant. In testing. ~ubjeclS tx:t",ccn 15 and 70 years Immunual WIth 3 ~s of LYMEri.l ~I 0, l. and 12 ulOnths Ucl1l(lll~traled ~ 78% decrease III lhe hl-elihood of mfcctlon. L YMEri:\ hru; a shc lflife of 24 mooths. It should be ~OrtIl at 2 10 SOC and must be dIscarded If rro7.t:n . If ~ Ihc vaccine can tolcmte 4 days !II room \el11ptllllure. ComvilX. Coowu is. coothmalioo of lIuemop/rilllJ itc j/ul'nwr type b conJugute and hep"lills 8 (m:omblll:tlltl. . WlIS n:ccntly approved by the Advi..ory Committee 00 .... l11unil.U1ion Pmcticcs (ACIP). Each O.SmL dose ~ 7.5 PI: of 1/ inj/urn~I/")'pc b poIyribosylribitoi ~ (l'R P), 125 ILg of NrilJrria mC'mngilirl;s (Mer ml'mbr. protem eomple.l (OM pc). antiS P8 of hcpatitb B surf.-:r anligen (HIxAg) 011 an alummum hydro.lKk adJUI"Mt.Tht Coml1llllee 00 Infcctiou~ DI...eao;cs. the Antencan Acadrni!' of Pcdmlrics. and lhe AdviSOl) Academy of Famll) Pb)\!' dalK reconmK'nd that all infanl5 receive !he vlICcine. 11m d()(;Cs \hould be adnllnistcrcd at age~ 2. 4. and 12 10 months. l1Ic. vaccine dlOOld not be administered to IIIrlllllr younger thall 6 wceh bcclIusc or potential SUppl'eSSIOII4

,.s

VACCINES
VaceiDC! and Immunizing biologicals arc CO\cred Lhor oughly in Chapter 7 of thI S text . SI1 no Icngthy di<;CllS~iOl1 "

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Il1Uuttr of blOlcchnology-gent1'luetl V3ol.:cillC~ are HI ""..._ (T:.bk 6-10). Some of them arc in the calegory ~ 'lbmpttll:K: ..:cines:- 1lIe<oe vacriOl'S IUl' de~igncd to Mil III etllular r'eptor<. endogenous molecules. artd ,j,() 00. I'fQiuciIll \pttirlC phann3CoIogical CffC<:N. For cumple. if I,d! I pullCUlar rect'plor ,hal bmds a ligand 10 II(lival( kedl. blndlll' IlI1 antibody !lU<N by a spccir vaccine 10 lC "1tpI1Ir ...-ill pK,'ent acti, allOO. If a lumor h.1S a n:qUII"C_ fl'll >U<.h D l"CCep'or- li g:and binding. uSing a vacdne to ...m, lIIIibody to lhe receptor or the ligand should prevent .. .,. cdluw prohfer.lI ion.
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II I hufDOllll immune response. glymphocyte..derhed tu- cdk produce antibod~ '" 1m vlITI:ations in chemlf;al . 8iok>gic1lt). these ,malions Viteod the utility of tit ....ltltd Illll1body, 'l1lc:sc unallons are caused by affini ty tile tendency for the umni ty of antibody fOf antip III llIO:Ttase with each challenge. and mutation m tile . . of IOINlic leo;:ombin;uion. These phenomell3 produce _""'~ '"Lh !hghtly different SpecirlCilies. Because the Onrl of Illll1bodyprodOCIMg ~ells PlVIde 1II0rc than ooe _'tml type of ant ibody. they are called pdyc/mwlllll/i .un. Another I)'pe of anlibody con~iS15 of highly I!omoge ~'Jqlllb&!onlI ofhybrid proteins ~ by ooe clone y pre~ B lymphocytes. These antibodics. llI(l . III( 1IInII.1Un1 'arl .... lOI1S. are highly' ' focused" 011 thei r :lnll. . ,vunt~lp.:utf dt:1~mlinants or cpitope$. and are called

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A problem with creating Mt\I" is that one can not SI IlII,ly ~pate an antibodyproducmg B lymphocyte and propagate it. Such cell.lhe only bneny In the labonlIory en,ironment. Instead. antibodyproducing ~'(' II . arc fused '" ith an i mmortaJ (tulllor) cell line to create h.lbrill(mrflS- lonll-li,ed. anti bodysecn:tlng ccll~. "!"he trick is to select the mOI1(lCtOllllI cell s thaI produce the desired antibody. The h)bridoma technique has op:'ncd the door to new therapeutic antibodies. ImaSlng agent~. rndlologic~1 diagnostic tCSl klls. targeted 111 dionl1clidc delivery lIsen ts. nnd home tc~1 li ts. In the hybridoma melhod (Fig 6-14). a ITlOOSt' or othcT small ani mal i\ 'lCnsiti~cd \uth an antlgcn. When a high eTlOOgh ti ter of antibody agmnSt the selCClcd antigen has been anairtcd. lhe animal i~ sacri ficed and ilS splcen ce ll ~ an: collected. TIre splcen cells comai n a Inrge number of B lymphocytes. and it is ~n that sOllie will be able to pr0duce ant igen,pecific anllbodle\. Bccau'C the splCCTI cells an: normal II I) nrphocyte\. they have II vcry shorl hfetmlC in ce ll cuhurcs. ll1c:rcfon:. a nrethod IIIUSt he used to cXlcnd their li retime. To producc MAb-.. B cellS:ln: fused with mll11()l'1a.l nl) cloma cells III the pre'ICncc offusogens \uch a\ poI)eth ~lene glycol. Th is procedure produces genetically hal fnomtal lind halfmyeloma cells. Sioce the myeloma cdl~ un: immortal. the longevity problem i~ sol~cd. The o;ekction f"I'OCtiS tie pend:! on t..... o different myelotn:l cdl lines: one l:acling the en~yn1C hypoxanthinesu anine phosphotibollyl tnillsferase (II GPRT), \I key enlynlC in the nllcl~otidc <"11\'oge pathwa)~, and the other l3C king the 111. gcne. a l ey gene in the pyrimi dille biosyml'octic path"'lIy8. "!"he ""Icen B ccll8 an: UGPRT ond n (-+-). whIle the myeloma C('II~ are HGPRT and 7l (-). Thi~ myeloma ~"1:11 line cannot survive III a medium conta ining aminopterin. :I lhymidylme sYIllJlCtasc inhibitor. becausc il cannot ~)'nlhesi~e pyrimidines. TIle HGPRT (-) cell li ne cannot osc the purine 5aly:age JXlth ....a)'~ IQ male nucleotide<:, fOl'Cmg " 10 U<OC thymidylalc ~ynthetllSC_ Wllh thynridy lalc syn thetllse inh ibited. the ce ll dlC,~. After fu.~ iOl1. ce ll ~ are maintained on a IIIcdium conlaini ng hypo~anthine. aminopterin.1I.IId thymid ine (HAn. Only cells thai are COl'-

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Kelly" fused bet ...ecn one spleen cd l ( HGPRT 1+]) and one myeloma cell (immona!), I.e .. a hybridoma, can ~urvh'e in HAT medium. Fused myeloma ~lIs (myeloma- myeloma) lock the: corred g... nes and canno! survive. Fused spleen ~ lIs (spleen-spleen ) canno! gro .... in culture:. Thus. only the fused hybridoma (myeloma- spleen) survives. Hy poxanthine and Ihymidine fumish precursors for the growth of "Gi'R"T (+) ce\\s. "mi~n SUWCS$C$ cells mal failed to fuse. H ybridoma~ can be isolated in a 96-... ell plate and tnEnsfen-ed inlo large.- cullure:~ for proliferation. The cul ture medium ....iII eventua lly contain a high concentralion of MAb againsl the uriginal anlig('n. This antibody can be punfied to I"Iomogeneity. Monoclonal antibodi es. being proceins. lend to be highl y immunogenic in humans. This isespcciaJly ItUe of the MAils produced in mouse cu llurt:. lI umans begin to develop anti bodies 10 mouse MAils aflcr a singk dose . This is natural. The human host is nEOUnling an antibody response 10 a foreign antigen. The hUI1\lll1 antinEOUse antibody response

figure 6-1 General nwthod:;;;;"';,;, prepafahOO of rnonocIooaI .. ~ng h)t>Ildomas and HAT medlUlll JO antibody; Ag. antigen.

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CDRJ is also referred to IlS theh)"pm-uriobk mOSt of the variability of the anlibody trated there. These must be inlaCl for specie".' ;",,; body btnding. Immune f'Csp:IIlSes agD.lllst '" dirc:clCd against not only the varigble rcgion ~. but COIIstant re:gions. HelK"e. to do~~, ,'. ';m"""",,,~, an MA b one muSt create untibodie$ that ha\c been

iJ.td .. In MAb prodlKUOII. usually lhe Vu and VI oom:llns rI a human antIbody are R'pIaccd by lhe ~lIlg reptQ frum the moose anlibody.le~\ i ng the \pecificl ly intacl. but U~lng human l'OlISt.:uU regions Ihal -.hould IlOI be Immuqrnic. Anllbodie~ like the~ arc: called rhimf'ri<-. and lhey f t k" UlllIlunogcnic and hav... :I longer h:ltf hfc in human Pltl<'nt~. Exnmplcs of chimeric MA ~ ure abcmut;lb. riluxi1IIah. infliximab. und ba"i li ximab. M~lllOds an: :I\'ai lable for the dcvelopmCIH Qf MAil<; wilh lIS 10 ICIO'l: human l'C'luenct. By u~ing tnmsgenie mice. all rllhc c:sscnlial human antibody genes can be elprt'!'SI..-d.

rivlluve i~ relellset.lloslde Iy~ of'he myeloid ttlls. The released eahcheamicin dt:nvatl\C bllxls 10 mlllor gmu\'c of DNA and cau.'lc~ double-str~nd breals and ttll dealh.

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IIrluJllmitb.so. ". Ritu.\ ima/) (RltUJlWl. Chimeric) is an \IAb directed ag;ail\Sl the: CD20 (UlIIgen e~pK.".cd on the ..n;JCC"; of normal and malignant B lymp/lOC) ltlo. The MAb
"produced In mammalian (CHO) $u'ipCn~ion culture and is H~Hllenc (murinc/hurnan) MAb of the: IgG I K type . The prulCIn I~ C'Om~ ofmurme hghl and he:l>y cha m variable f'tJ1OIl~ and human constant region~. RlluxHnab i. indicated f.... Ille lreatment of paticnL~ with relaploCd or refT".lCtory. 10"' pie or fol hcu lar. C D20( +) B cell non Hodgkin~ lymphoma. Ritu~imab binds specifically to antigen CD20 l'-tn.:In IIlymphocylt-rc:\U;cted diffcrenl;.,t;nn Dntigcn. D It)drophoblC tr.ln_rnembr'ane pruleln eJlpn."\scd on pre_ and 1lIMl/rc:8 lymp/lOC)'Ics). CI)20 is a protein of 35 10)7 kOa. -.I it lIlay 1'13)' role in B cdl !lCtil anon and regulation - ' lIIJy be calcium ion channel. lllC anllgcII is at"" u ~~ on ITJOre than 90'1; or non-lIodp.ln~ lyrnpOOma B all. but l~ not round on hem;lIopllletlC ~e1l1 cell ... pro-B aU,- IIOtTIlaI plasma eelb. or other normal US,\IK'~ . COlO re",l;lles. the early sttps in lhe: act ilation proce\~ fur ce ll~dc m.llaHOII and diffcrelltiatloo.

Ale.mu7.umab (Camp:1I h) i~ hu, .nam~ed MAb (Campath- II /J Ihl is direcled aguinst the 2 110 28-~Da cell ,urfacc I!lycoprolein CD52. CD52 I~ expre)S/:d lin the ,urfact of numlal and mallgnunt 8 U1W T Iymphocyu:s. NK cell(. monocyll:s. m;lCmph3ge~. lind lis ~uC"i of the male reproductive ~ystem. 1llc Campalh.1 11 allil' body" an IgCi, Kfoml '" nh humanized > 'arlable and C'On~tanl regIOns and CDR~ from a rat MAb. Campath-IG . A!emlUlumab " Indicated for the trc:atJll,ml of B-cell chronic Iympnoc)'uc leukemll 111 palients who ha>e been trealed ""1m al~)'I:llmg agents and "'00 hale failed on thl~ lhe:mpy. AlemlU7.unmb binds to CD52. 1lOIlinodulDtmg antigen that j~ prc:<;Cnt on the ~urfoce of esscnllllJly all II and T lymphocytes: IOO!.I monocytts. macrophages. and NK cells; and a ~UbpopulDtion of granulocylC"i. The propoo>ed ITICChanj~1Il of action ii antibody-dcpendt-nt Iy)i\ of leu kl'mic ce ll s folluwing cell ~urface binding. BaJil illlab (Silllu leci. Chimeric) is an MAb produced by 11 1Il00.<,t monoc lonal ttll line thai ha, b'n tllginccrc:d 10 produce the basilixim:lb IgG I K antIbody glycoprotcin. The prodllCl i ~ chllilenc (murincihunmn). Basiliximab is "w.lICaled for pmplI)'laxis of acute organ rrjccuon in pat,ents rc:teivlng renaltmnsplanllliion '" hen used 11.\ pan of a regimcn of immunos.uppns.Qm~ and COl1lcostcro1ds. Basilixl1l1ab i$ otliO indicated III pediatric rrnat tnlllsplJIIIII.lion. BasihJllmab specincally b,nd~ 10 tIM- IL-2 ft!ptor a chain (the CD25 anllgcn, p~n of the Ihrce-component 11.2 I'l:ccptor site). Tht:sc: sit~ at!: exprt:l;Sc:d on the Mlrf:JCC~ of oct;V:lted T I)mphocytc~ . Once bound it bloc,", the IL-2 n reccplor ""i lh e~ tremciy high arli nil Y. This .~pecific. high-arlin II)' binding 10 tL-2n compc:Iil;"ciy inhibit. IL-2-me:diated activation of ' )mph()Cylc.~. a critical e\ cnl in the cellular imrnUiIe respon~ in \lUogl'llft rrjcction.

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fusion molceule) i, an MAb derived '""" tho: CI)33 antigen. a sialic acid<lo!pc:ndcnl adhesion roto:ln c:xprcuc:d 011 the surface uf leukemia blasl~ and im ~ 1IOOt1al ttll.' of myelomonocytic origin bul IlOI on Illemalopoictic stem cdl~. CD)) bind!> sialic acid and wm 10 n:gulale ~gn:ll in8 In myeloid c..'lk The antibody .It'I:ombtnanl. humaniu:d IgG~ K. hn~ed '" Ith Ihe cylotoxic .uwoor antibIOtic ol.ogamicin (from lhe: caliche:ami<:in Iyl Mon: lhan 98.3% oflhe ammo acid, ofgemluzumab lit III human ongm. The comlam region of tile MAb COIlhuman sc:quc~. ""hile C DRs derivt frolll a nlU.antibody thaI bind$ CD)). The: anllbody I~ hnked to Nk'tl)I-r<;tli,heanlicin via I bifunctional linker. Ctlntulumab Ologamkm i, indkatcd for the trrutmc:m uf fIOOIlI: wllh CD33-positive ocute myeloid Icukclllin in ,jrst .~1II"It amoog adults 60 ycars of age or older who an: not ,~ eandidalcs for e) lotoli e: chcrnothcropy. GmlIufunl.'lb ologamicill hind~ 10 the CD3) antigen 1It,'Cld by Ilematopoietic cells. nilS Inllgen IS exprr-sed 011 6r1lllf~ leuu-mil' bl:LqS in more lhan 8O'l of JXllienlS _'tile ltI)eloid leulc:mia. CD33 IS aJ!iO expressed on d IIId leukemIC myeloid coIoo)'-forming c..'1I\. mclud lrukmic clonop:llic pm:ul'llOl$. but II is IlOI upn:sscd .. rltJnpotClII hematopoietic Slem cellsor nonhemalopoiclic II, 8111di1ll! of (he anti-CD33 antibody re~h~ 111 a lVmrlex 6It ~ mto:rnahlCd. On inlc:malil.Ollion the culichc.-umlclII dc-

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e.-

or

Molecularly. daclizunmb (7..cnapax. Chlflll'ric) is an immunoglobulin G (lgG,l MAb IIIaI binds "fIC("ificall y to tile CI subunit of lhe: tL-2 receptor (the: compleie, hlgh-affinlly activated IL-2 rc:cc:ptor consisIs of interoctmg CI. fl. and y 5ubuni(5). IL-2 n:ceptOl"'l an: e\ pressed OIl lhe ~urfacesorlloCtlValed lymphocYlts, ... hen: they mediale lymphoc) le donnl UpallSiOll and differentiation. Dadi 7.umab i~ a chunerk prutl'in (9Q<l, human and 10* n1Ou_ II!<h 11tc MAb turget" only reccntly 1ICIlvalcd T l,(.') cell~ th aI have interacT with antigen and ha~c dc~clopc:d ed from lhe:ir naIve form into their activated fonn. It i, m this ,ime Ihut the I L-2 recepton; are e~pn.'sSl.'(\. The human a(\lInO acid ..eq~IlCt'S of daclilunmb derive from conStant domainS of human IgG. and the: > -ariable domain~ are dcm'ed from the fused Eu m)elorna anhbody. 11lc murine loC'I.Iucll(eS de ri\'e from CDRs or a fTIOIJSC anti-lUa anti bod). The ind ICations for daciliumab lilt .. ophyllJll~ of acute organ rrJCCIIOfl III palienlS rc:cc:illIIg rrnaJ IT".msplall1s.l~ pall of an I mmunosuppre..~s.1nl regimen ",dudmg cyclosponne and cortlCOSleroids. n,.. mechani~m of aCliQll illlhc: same rut that of basili _unab. \

Daclilumab. U'- "'"

Muromoo<llb- CDJ. Muromonab-CDJ (m urin.:, Onhodone-OKTJ) i~ an unmodified mou se Immunoglobu Itn, an Ig{i:za. monockHUll. II binds a glyeoproll'm on the ~urfoce of mature T lymphoC)tes. " l amre T cells hal'e_ as pan of the signal tran$duction lIlochincry of the T-cell receptor oompic:Jl. I set of three glycoproldns that arc ooI lc:cth'ely called C D3. Together with the protein I.Cla. the C DJ mole. cules bcoomc pIJo'phorylaled when the T <el l receplOr is bound to a pepltde fngment and the major hislOrompatiblli ty oomplc~.1lIe pho>;phorylated CD) and ~.eta 1Il01c:cule~ trans mit infonnahon IntO the cell. ultimalely producing trnn<;enption fllCtOl"'i that enter the nuclc:u~ and direct the T-cell acti v lIy . By binding to C DJ. murornonab-CDJ prevents signal

"'_ "I

tumor ~II~ tnat o\l:rexprcs$ HER 2. T T1I$tulumab also mediates the process of antibody-mediu ted celluhu cytoto~klty (AOCC). This pmcess.leading tocell death, is preferentially exerted on HER2-ovcre~l"JItSsing eancer cells over those IhII do not m'creJlpress HE R2.
lofli~imab. ,... II.

n.c MAb mniximab{Remkatk. chi-

transdUC!ion inlO T

~IIJ.

Muromooab..('D) blocks tile: functton of T ~lIs thai arc involved in acute renal rejectiun . Heoce. it is indicuted for the: trealmenl of acute allogOift rejecllon in 1le::u1 and lil'er trdnsplam recip'ent~ m iS/ant to ~tandatd steroid the:rnpt~.

Abdxlm<llb. 1501. Abcl~mub ( ReoPm. d urncric) is IIf1 MAb engineered from the glycopn)lei n 1Ib/1II:1 J"\:ccptor o f human pI3telet~. n.c preparation is fngmented. containing only tile: Fab ponion of the antibody molocule. This MAb i~ a chimeric hurnan-!1\()Il-"<' im munog lobu lin. l1te Fub frag. ments ma)' contain IllOUse variable heavy- and lighl-chain n:g lon~ and humllf1 con~tanl heav)'- and lighH:hain regions. Abcillimab is indicated as an adjunct to percuIDrlCOUS Lnlnslu nnnal coronary angiopl3~y or atherectomy for the prel'cntion of acule cardiac i<;ehemie complications in pa. tien", al high ri ~l for abrupt closure of a treated eoron:lI)' I"tSSl'1. Abcillim:ab app<'lIt"S to decrease lhe incidence of myocardial mfarcliOn . AbciJlimah hinds to the intacl G I'lI b/GPllia receplor. ... hieh I' II member of thc intcgrin famil)' of adhesion receptor.; and the major pllllClclSPL~i fic reccptors involl I'd in ag gregation. n.c antibody prc:1'ents platelct aggn:gatioo b), pre. I'entmg the binding of fibrino,:en. the \'00 Wil lebrand faclor. and OIher adhesion molecllle~ 011 IIClivut~'(\ plate lcts. 11ac mhibu lon of blndm!; to the ~urfacc receptors may be doe to I ric hindnlrH;:C or COOfOffi13l100al effeclS prc:~ent i ng large M moleculc:s from appro;lChi ng the rcceplor.
Tr<llstuzum<llb.'H, 'u Tnl.~!Ul.u m ab (Hercepl in. human . ized) IS IIf1 MAb engllleered from the human epidermal growth factor reccptor type 2 (HER2) protein. Th is MAb is a human_murine immunoglobulin. It contai ns human StnIC\tInl OOllains (framework) and the C I) R o f a murine antibody (4Dj ) tht binds ~pccific3lly to lIER 2. IgG I " is the 1)'pe s.tnICIUn:. and the antibody i~ monoclonal. TlIe protein inhibit! the prollfeT1lllon of human tu mor cell~ th.1l o"e~ press II ER2. Tra.~tul.umab is indicated for use a.~ a ~ingle agent for the treatment of pallents ... lIh metaSlallC hn:ast cll/lCCr whose tlllll()f'<; overexpress the HER2 protem and ... 110 have IIO! ~i\ed chcOlOlhcOlPY for their mel~tatic dl~:lSoC. n.c HER2 pro!lHlIlCOgt'rte encodes a tt:lllsmemhrane reo ~plor protein of 18j lOa thut is SIlUclUTlIliy n: lmed \0 the epldermal growth fac10r R:Cepior HER2 . Ol'crellprc:ssion of this protcm is observed in 2j to 3O'i> o f primary breast cancer<. TrIlStulumnb bllld~ with high affini ty 10 the eXtr"dCC l1utar dom:un of HER2. It inhibu~ the prolifernllon of human

Ii'

meric) is produced from cel1~ thai rull'e been senSl\ i/.cd .... ith human TNF u . n.c MAb IS a chimeric human -n"IOII5e 1m. munoglobulin. The conSl.1nt regioo5 are of human pept,\k scqucoce and the I'anable regions arc mu rine. The MAb ~ of type IgG , " . Infli:\imab is indicated for the treatment of modcrotely \0 ~I'erely ilCt;"e Cmhn's disease to decrease ~igns and symptoms in paticnts who had an madequate Inj"lOllSt. to con~en tional treutmcnts. Innixilllab bind~ specifically to TNF" II neutnlius the biological acti" il)" of TNFII by bi nd ing .... ,t.IJ high affinity to 'iOIuble and l11ln~membrwle foons 01 tht TNF. Innililllall destroys TNFa-prodUc101! cells. An addl' tional mechanism b)' ... hkh inflilnnab rould ... on. is as foJ. 1011'\: b)' iohilliti ng TNFa. pat hways leadi ng lo lL- I and I .... an: inhibited. 'ThI:.;e interl ~uld ns are i nflammatory cytoki~. Inhibiting their production blocu some of llle: inflarnm:uMlll common to Crohn 's discllSl' .

MonDdonal AntibDd, Radionut;:lIde Test

KHs
Arcilumofflilb.' 1'0 Arcl tulOOfll;Ib (CEA-Scan) is a l11linne monoclona l Fab' frogment of IMMU4 . an MAb gmn-. ated in murine asc ites fluid. Botli lMM U4 and nrcitullMlllllll reacl with carci~mbr}"onie antigen (CEA). t umor-~~ ated unti ge n who~e ~x Jlfe\sion is increast'd m a ... ariel) Ii CatClnonlll$. especially those o f the G I tnICI . The prepat3l~ is a protem. murine Ig Fab fTllgment frt)lll IgG ,. forchl'1IIQ] labe ling with Tc99m. Areuumomabffc99m is for u~ ... ith standard diagl>OiOl: C"IlIU:ltioos fOl" detC:Clinl! the prc:scnoce. loclluon. and ClIN of recurrent or mcul.~tatic eolQrcctal carc inoma involving \III ]i\er. utrohepatk abdornen. lind pe lvis. with a hii>lologlCaUy con firmed diagllOSi~. IMM U-4 (and the Fob' fngn>CNS III arc itu monub) bind 10 clU"Cmoernbryoni c antigen (CEAl ... hose upression IS il"lCJ\"llSI'd m carcinoma. AreltullllllllMi T c99m i~ inject ed. hnd the rndionudlde scan i~ read 210' hours later.
Noferumom<llb Merpenr<lln. l l I Nofc tunMllllub rna penlan ( Vmuma Kit ) is the Fab fragment deril'ed front dIr munroe MAb NR LU-IO. n.c prodUC"l is a protem.lsGJ mOOOClonalthllt has been frugnlO!nll-d from NR-LU IO. NofClumomab possesses only the Fab ponion. NR LU IOaid nofctumomab am dirc:cled against a 4().lOa protem till that is expressed in a variety of cancers and some nornII tissue$. Nofetumomab i~ for tile tktectlOll and evaIIr.. in patients with smalJeelJ abdomen )

Ihnl binds tile: I liga rld . 1 l -elhox)w,,-q. lhioacetoomidopcntanoale. Ile:nce the name m~rpt'''f(lII.

ChapIn (; H'lIIulmmvB"

u'w Or,,! D...('O,'<'n

191

Salumomab pcodclidc .0.. :IN. munne) is a 10.11 for In- I II. Satumomab is pre.-0 from IlDIItltIC Illlli000y ruised 10 membnmc-c:nncho:d alr3CI of human Ina'il carcinoma hepaTic melllSlasis. It is ",*ltl, 1 ...ntibody. and 1TIOIlOC1onal.1be MAb recog!G, ~ tllllD-liSOCiattd gI),roprolt'in (TAG) 72, II mucin.like aie<;uk ';>,tth 111'IlIS~ g,rtater Ihun 100.000 Da. is Indicated lISa diagnosltc IIld in dcteo nin ing tIr (lient and Iocauon of c~lrnhepa1ic mal igl10lnt disease in . -\ "Ith ~ nOYia oo~DI mnd ovanan cancer. This . . . II u\ltll afl~ ~andml diagnostic lestS an: oolllpletoo ~ "hen adWuonal mfornlUlion is needed. The cancer mW;1 kia_I". or ~\,oosly diag110SCd by other mClhods_ Iocalil~ 10 TAG 72.lbc antibody is chl: mi aI) In(lMItd so that it links 10 r.ldioocti\c indium_I II , I' m,le<! ""th the annbody just prior 10 in,JtiOll. -,;... kcM1II1Il':!i w,U re"eal the localiution o( the s:.tul\ "hQt ipOtS." T o link the indium-III 10 lhe s:lIUproIel"- I Itnla-chdator is used. Th" is slyeyl1)I1J!.) HN.f-diethy Icnetriami ne pcnlBaceI it ac id )-Iy ~i nc hy-

IICumom.Jb

~ndelide. m

MAb den.cd from an init"d .;cnSlhl.atlon with CDZO ant,en. e~pressed on the ;;urfacc, of nonnai and malignant B cells. The anllbody IS a munne IgG, It subtype. directed against COlO antigen. It is produced in a C HO cell hne. Ibriturnomab is indkaled for uSC: tI,~ a mulhStage reguncn 10 treat palienlli with relapsed or reft1lC1ory low-grade. folhclI hIT. or tr.lnsformed 9 -t:e ll non- Hodgkin's lymphoma. including p.1licnts wit h ritu ~Jmal).refmclory fol licular non llodgkin', lymphoma . IbrilumonJ.:lb uu'tC1an bends specifically 10 C OlO anugen (human B- Iymphocylc-rcstrictoo dirrcrentiwion antigen). CD20 is expressed 00 pre- S and malure- S lymphocytes!U1d on more than ~ of S-cdl non-Hodgkin's lymphoma. When lhe CDR of Ibnlumomab liutuxall binds to the CD20 antigen. IlpopI~IS is ,nltlated. The \l ulu . n chelate binds u indium-Ill and Yllrtum-90 lighily. Beta CmlSSHII1 intJuces cellular damage by fomnng fn:e ntdicals in lhe targel cells and neighboring cell). T iutuxan is [N-[2-b;s(carbo~y melhy1)wnino]-3(p-iSQIhiocyan:uophcnyl nm>Pyl HN[Z bI s(Ctlrbo~ ymt.'thy 1Jam ino ]Z-( mt.'lh YI) et hyl lIi: Iyci 1M.',

::~~~::~::"~'~'rfor:.'~'~prcparnuon or indium I I , imciro "Kil :" the Itlldmmab pentcbtc (mu171

In-Home T_t Kits""

There are a vuriety or MAb-bar.cd in-llome tC~1 kits thal::m: dc:signed to detect pregnancy and ovulalloo. For example. a pregnancy leSI ki l targel~ lhe anligen human chononic G0nadotropin lind di'iplays a crnain ~isn if Ihe leSI i, posithe The other type of test kit pn:diCl" owlati oo by targeti ng luteinizing hormone in the unne. Just before O~lIlnlioo. lutelniJ,ing hornlODe su rges. The 1 kil is Iksigned 10 detect ;:,1 and ~ignal the time of owlalion_ Tbese te501 J.iIS, based OIl lhe complex lechniqUC$ of MAbs. a~ designed to be as ~im pie and error-free as poloslblc for pal1cnts.

~~~:~~'~i'::~~~JonaI. OOI1sisltng of the FabI I. bound 10 the

immullOJlobulin fl'llgmenl raised ofhum~n myO'<in. The drug is II procci n

l in ~cr-che lator

I penl3.1CC1ic acid for labeling with inImriromab binds to the heavy chain of human ;;;;;"' .-,;1 II I protein found in t ardiac and st elefor dclCCling the pn:sin palitnlS afta a norma l myocardiu m. inare isolated from the eAI . .

I'

GENOMICS
G""{)"JJC~l n

is a leOIl thai

lllCalt~ "'a Mudy of gene~ IIIllI

to

macromok:cuJes.

\'isuali-ze il.

........ 9;ltll pro'en prosulle canttf p:hic lymph melastasls. /'SMA has and melastauc prostale cancer les ion~. The: marker 7EII.c~.3 reacts with Inore

their funchOOS. Curremly. geno1tllcs i~ probably lhe central drivi ng force for nc'" drug disco"cry und for OO\'e! treat menlS (or disea...e. G~nc Ih.c:rup)' IS a oonccpt that is oftcn discussed . The human genome projl"Cl. "'hich was largely comp letcd in the year 2000. provided o,er 4 billion base p.111'$ of dala th31 have hccn dcPOSlled in public d:iUlOO>e<;. Scquencmg the gc:nome IIself ",-as an enormous tllSt , bul the com::lation of genomic daUl with di!>ea..'ie states, ~i te, of microbial allochmc nI. and dn'g n:cepllK _lies IS sl ill ill ils infancy. Once these problems an: M1hc:d. genonuc dllta will be used to diagnose and lreat disease ;md 10 de\dop new drugs specifICally for disease siales (and pos~,bly 'pceific for a pallerll). Siudyin!: the senelic! of biOCheUllCllI palhway~ will provide an entry into cnlymebased thcr-.!pje~. llten: ",ill undoubtedly be a ho<;t of new targets (Of drug therapy . Ikcaw;.e deciphering the mformatloo lnal the genomic sequence proVides j, a comple. undt:rtJl.k.i"l!. these benefils a~ probably going to occur yeul'$ III lhe fUlure_

Monoclonal
Ibritllmomab (Zevalin kil~ 10 Y-90 ZeYlI.lin. murine) is an

Unraveling the Genomic; Cod. to De... ,,01_ Structure-Fllnctlon R.a.tionshlps: BloInfo'lQatfc:s

Whcn consideri ng the lopie of bioinformalK:s. one must recogI\Il.e thai Ih,s is a broad lerm CO\'cring many diffcren1

pl:bnlD sulfado1ine CQ'K'Clllllltion OCCUN in 2.5 to 6 hour... and the peak plD',lna pyrlltlClhamitll: cOllCcmration occurs in 1.5 to 8 hour;. Resistance has developed. much of II involvIRS mUl<ltlOns in c lI~.r or both of the geI!CS coding fot dlhydrofolutc reductase and thymidylale synthasc. ;Jnd Progu;Jfll/ Hel. AlOvaquone and progtmnil UCI ( Fig. 9-8) ~ admlmstcred in cornb,n.atiOll (Malaronc) 111 an aloVllquoneto-proguanil HCI mlio of 2.5: I. mca~un:d in milllgnlln~ (not mil it moh:!;). l'roguani1. de~eloped in 1945. is an curly c~umple of a prodtug. It is rlletabolizcd to cydoguanil (Fig. 9-9). primarily by CYP 2C 19. The pol)"morphlc nature of Ihi, hepatiC enzyme e~plains IIohy ~~ain subpopu latiolU do not respond to proguani l: thcy ca nnot cunven proguanilto the ncti\'c cycloguanil. The ba..";s for this ronlbinatioo I( 1.....0 distinct and unre_ IlItcd mlI:anism.~ of actiOll against the pam.~ile. Alovaquooc bit >oek-cIl"c Inhibitor of the Pfnm,oJ"",,'s rnitochuooriHI eleclron transport sySlem. lind cycloguanil is a dihydrofulate reduclase inhibitor. A tovaquonc:'~ che mistry is based OIl it
AtoV;Jquo~

being a naphthoquinone Ihal ducliOll ructions as of lIS

i i

tern. It '""'''~' electron trall5pot1 chaIRs. dro, IiClecti\cly IIo'illl milochondrial electron Imnspol1. paniculart) para.~ites cy lochronoc Dcl sile. This depri\'cs the needed An> and could cau\t it to become tance to thiS drug COII"a from a mu~1 1Of\ in the e)tochrutroe . Cydogu"1II1 (progu:mi l) Interfe~ .",,' synlhesis by inhibiting dih ydrofolate reducta!lC (~

I"

-.,ok

''''yoh,.

I,

CYP2C19

0'----<

Figure 9-9 Conversoon of

2(19

Pl'oguan. ,,,""...

Chapin Ii Bimf'CIuooI~J tId D"'8 D'M:m"f"rY

liI10US

' 93

points in !he array are acquired in

II

computer for

MaI}~I1,

J ,

" ,
,

<

<

~.

As an example. """e can consKkr \"'0 cd ls: cell type] . a Irralthy edt. and cell type 2. II d,sea.<oed cc.11. Boo-. cell type$ COI'Ilim an identlcal!iel offoor gmo: A. B. C, 1100 D. mRNA II ooI:w.ed from cachcclll),pc and used toCn:Olc OtJ(X"eSCCN~ eDNA. In this ca'\C. red and green an: used. Lubeled \:Ullplc~ are mi~ed and incubated with II micl'OIlmlY thaI con tain~ the immobi li zed genes A. B. C. ~rKl D. The taggo:d moIules bind to the si tes on the lIJT!Iy corresponding to the Itk~ being expressed in each cell. A roboIic <;conrler. also I prodllC1 of silicon chip \C'ChnoloSY. extill:!! the fluorescent IlbetJ, and inlaj!e5 are ~ored in a computer. The computet" ClDtQltlpulc!he red-to-green nuoresceoa: ratio. subtract oot wtpound noise.. and ~ on. The computer crcales a table: Ilk ulICnsny of red 1 green nLIC)reSCrllCe for CI'er)' poim 0 tile maln~ . ~aps both cells t:lprns the same 11':\,,,1$ of pc A. cell I expresses ITIOI'e of gene 8 . cell 2 (the dIseased edI) cx~ more of gene: C, and neither cell expresses lICk D, Thl5 is II simplistic nplanation: experiments have 1m! (l:por1ed m which a.~ many as 3O,tXXJ spotS have been pIImI in the microarray. DNA nucroarrays CIlII detect chllIlgcs in gene upression r.ll" elprtssion panerns (e.g .. the ccll cyc le), genomic PIllS and losses (e.g., lost or broken parts of chromosomes .. cancer cells), and mutalions in DNA (single nuclCQtide: poI)IIIOfp/li5m ISNPs J). SNPs are 111.$0 of intC=S1 because tq-lNy pro~ide c lurs aboul how diffffl::nI people ~spond llin&k drug in differtnl ways.

<II

<,.

rol

'1 .... I.ics"O

~

"

'IIOI"d prot~omt! dc.scribc:s prolem e~pres.'ICd by a ge__ l'roIeomlCl is a scientific cndeavor thaI anempts to IIIdy the wm total of all of the pruteins in a cell from the po!IIl of ~lCw of their individual functions and how the interIdlon or spcdrtt: pnxdns wilh ot~r cellular componems ~ectS the function of thesc proteins. Not surpri singly. this I-e!)' complex wk. Tbere are muny mort pl"OIein5 tlmn _ .-r geneJ, and in biochemical pathways. II protein 1ft!)' ICIS by ItSelr. At prnent. we know that the cxprc:$-'iion 'll"lIIIlupIe gelll'S IS mvol\'ed for any given disease process. ~y" knowHlS the gene sequence rudy unmasks Ihc: fwIIOI'I rltbe encodc:d pnMCm or 115 relevance 10. disease. ( mly. the $Cience of proteomics is IlQI del'eloped to k pomIlII which dlUg discovery Clln be drhen by gene "!;".lnronnation. TItere have been. however. some sigIIIlcw ltChnoIogy-driI'en approaches 10 the field. Highfttll,put high-resolution muss spectroscopy allows the .... acid sequences of profein! to be detcmlincd very qoio;lJy. The ICChnique of two-dimellsional gel elfCtrOphore.. tIM lil c\\ ISC advanced the $Cicnce. of proteomics. Proteoundoubcctlly. eventually provide targets for drug and lhe detection of disease stOICS.

posilil'e ly (Ihe desired OUleomr). or IlQI at all . Consequently, drugs 1ft de~cloped for an "average" patient. TIte manufacturer relics on chnical slIIdoes to expose potenual a(h~ reactions Qod pubhshes them in Wolistkal fOl"lTlat \0 guide Ihc: physICian . Nc,cnheless......hen a physician prncribes a drug to a patient he QI" ~ h;1. 00 way of knowing the out come. Statistic., ~how clewly that a single drug docs I'lOl provide: II positive outcome in ull patients. This "Olle drug does not fit all" concept hIlS il5 basis in the gcnetics of a patient. and the science of studying tllcsc pheoomc:na i~ called ph/irmurogrlrQrnic~. A patient 's response \0 a urug. positil'e Of negative, is highly complu trait that may be influcncW by the act i~illes of many different scncs. Absorption, disl11buuon. metab0lism. and excretion, as well as the receptor-binding ~Iallon5hip, are aU under lhe control of pnMcins. lipids.:trod carbohydrates, which are in tum under the control oflhc: pauenfs genes. When Ihc: (aet thai a JlCr.iOfI'S gene.~ dhpla)' ,mall variations in their DNA baseconlenl .... as ~i7.td, genetic prediction of response to drugJI or infectious miclObc:s became pos,~iblc. PholTfmcogcnomiC5 i~ the: science. IIw. looks atlhe inherited variations in genes thai dictate drug rtsponsc and tries 10 define the waY$ in which these vllriatioos can I)l, used to predict if a patient will have II positive re.~ponse to a drug. an adv~ one, or none 3t all. Cataloging the genelic variations i~ an important phase of present re$('m:h activity . Scientists look for SNPs in a per_ !iOI\' s gene sequences. S NPs are vie ....ed as markc:rs forslight genormc Iarialion. Unfortunatc:iy, tnlditional gene sequencing i5 slow and upensive. preventing for now the general useofSNPs asdlagl\OStic tOO15. DNA microam}'ll may maloe it possible to Identify SNPs quickly in a patient's eells. SNP $Cree-ning may help to detennine a response to a dlUg before it is prescribed. Obviously. this .... ould be a tremcBdous tool for the physician .

ANTISEN SE TECHNO LO GY
During the process of transcription. double-slratlded DNA is separated into two strands by poIymc:nlscs. These strands are named the scru, (cOOins or , + I .strand) and the alllisell.lC (template or [-I strand ). "J"he antisense DNA wand serves as the lemplate for mRNA synthesis in the cell. lienee. the oodc for ribosomal protem synthesis is normally tranSmHted through the anllsense Slmnd. Sometimes. the senllie DNA .strand will oodc for a molecule of RNA . In this ease. the (l:sulting RNA molecule is called mlliscruc RNA . Anlisense RNA sequences were firM n:ported to be nBIUr-llly (lCcumlig molecules in whic h endogenous strands flllTT"ll:u oomplemcn tarily to ce llulllr mRNA . resulting in the repression of gene tApression . Hence. they rIUIy be Mtural control molecules. Rationally drsigroc.tl antisense oligonl.JCkocide: interactlOIls occur when the base pail"<; of a synthetic, specirlCally deSigned antisense molecule align precisely with a kilO of base!; in a targel mRNA molecule. Antisense oIigorllocleolides may inhibit ~ne expression transiently by maslmg the ribosome-binding site on mRNA. blocking tnlilSlation and liIus preventing protein .!iyntheSIS. or pelilianently by crosslinkage between Ihc: oligonucleotide and the mRNA. Most importantly, ribonuelease H

""=".11. ..

7 t nDZilks.az

companic:5 develop new drugs for any

,'"

,.

Wy are limited by a Iac;:k of knowledge II ~pond 1 the qent. No 0 t It predicllOIl of .... helhc:r negatively (an !ld1'Crse drug reaction).

(RNase H) (<Ill rN'Ogniu' lhe DNA - RNA duplex {antisense DNA bllldlllg 10 mRNAJ, or a RNA - RNA duple~ (anll~nsc RNA 1IllffilCling .... nh mRNA), disrupting !he ba.e pairin, inlel"JoClions and dige..~ling the RN A portion of Iii<: double helix.. Inhibwon of gene cxpressKm OCCUB because the dlgated mRNA IS no Ion~r competenl for lranslation and rc~u lt ing protein s)'nlhesi~. Anlisensc kchoology is beginning 10 be used to deleJop drugs mal might be able to control disease by blocking ttlc genet ic rode. inttnenng with damaged or malfunctioning genes. AmOflg the possible Ihel'llpcutic anti...:n'iC agents urKk'r I11Ie5tigllllon are agcnts for chromc myelogenou s leulemia. IiI V infttliOil and A IDS. tytomcgalOl'jros relinitis In A IDS p.1licms. and some: lIlflammou)I'Y dl'>C:ao;es.

AFTERWORD
C ltarly. biot~hnology has becoI'Iwe lUI inlcgr.iI part of pilar. lllaCcutical care. l>tlarm:tCisl~ need to become comfurtablt with biotechnology and II!. languOIge to delher thi ~ kind rJ care 10 lheir patient!;. 1'1tis ~haplcr has tried to preM'nt II! OH'r\I;eW Qf the major biOle..:hoologlcal arenas present i. the lear 2003. 11lc: field i~ a!hllncing rnpidly. lind elety phJn naci~1 must . ta y current with the litC'T'll1ure on biolecfo. nology.

Acknowledgments
PontOns of thiS Chapter lIlcludeli matenal from lhe kntb edit iOil chap4tr by John W. Regan. The author b grnlcflll for the U'iC of Ihis conlent.

GENE THERAPY
Gene lhempy arguably rcrwesents the ullimate application of rONA lochoolq;y to the trelll1nem of di'\C::lSC. Thc:re an: t .... Q ways 10 cnl';.ion gelle lhempy: (a) the repl:l'lTII.'nt of a lk-feclile with a normalgcne or (bj the addit ion of a gene .... hose product can help fight a dlsca>!: buch as a virdl infection or cancer. In the fOl'l'llef ca;.e. rt'placement of a dtfecthe gene. an aclual cure can be effccled instead of ju,t Ircating the symptoms. For e.\ample. on cyq;c fibrosis. 11 defective gelll' has been clearly idenlified as the cau.'>I: of the dl'ICase. It IS possible that replllCelTlCnt ofthc defc:l'tile grne .... ,m a COI'Tt'Cted one coold prodlK.-': a cure. Similar possibilit1c' e;(i'l for other inherited gencllc dIsorders such as in.ulln-dependcm dia.bc:les. gro.... m hormone defielcncy. hemophilia. IUld sickle cell ancmia. TIte ability to trnn~fer genes into other orgal1lsm~ has 0I1ler illlportalli npplic.,ions. inc lUlling lhe hcterulogoos produclion of rccombm:ml protell1s (dlscus.ed abovc) and ttlc de I-.:Iopmcm of amm.al models for !he .....udy of human disease. AIIOIIler area of exploral 'on is the introduction of rewmbinant genes as biological respon.)ol: modifieD. f()( rumple. 111 pre"enting reject ion follQlI'ing ()(Ilan II"Jn~pl alltatiQI1 . If genes encoding hoo;t maJ'Ol' histocompatibility romple.\C~ cook! be introduced Into transplanted celis. the trolJl5plal1too tb~ue nllght be n:cognizrd as "sclf." It might al'iO be possi ble to Introdoce genes for sub<;13I1'.-es such as transforming growth fOCIOf-P thai would decrea.)ol: local cellmediated im mune respon'>t!. . All opposilc SIr dlcgy ntlghL be ronsiden:!d for the lreatment Qf c.aoccr. llhereby tr~nsplumed cells ~-ould be used 10 target cancer cells. Inrn:asing loclIl cellmediated Immune reo;porucs. 1lie trun~fer of gcnes from Ol1C organbm 10 IUlOIhcr i~ termed tnulJgrmcs nd an anImal lnal has r"CCe1 \'ed such a IflInsgcne is referred to as a trtllugrnic flrtinllli. If the transgenc IS Incorpor-.otcd IntO the grrm cells (eggs and sprrm). il II ill be inhtriled and JXI~ on to socceMive gencrdt ioos. If the Imnsgcnc i~ Il14--orporated into other cells of lhe body (somatiC crlls}. It ....i ll be expressed only as long as the IlCwly ~'rcatcd Ir:Uls~nic ~-.: lI s are alive. Hence. if a tcm,inally dlff~'TCnnated. poo;utulotic cell recehcs a tfllnsgenc it will 11001 undergo furthl.'r cell diVIsion. wlK-rell~ If a trnnsgellC i~ crellted III an undllTcn"ntlated ~tem cell. the prodUCI .... ,11 continuoosly be upresse;i in new cells.

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IS9 Vrncenc,. P. N. F.nd. I Mod. 3l811,1 ~ 1M. 1998. ItrO Qb(.ho( ...... J.. .. II .' T ...... Sf!I..... ldl, 14(2)169-171,:!Oro 161. Chan, G L. C.. (i",I><I", S A. <I aI 0;1. C"'" CI,. 6&.11
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_2000

Immunobiologicals
'" BEAlE, JR.
\ystem con~titutes the body' s defclL~ against I.galIS. It pro4l~ClS the IIoo;t by identifying and dim'1lIC1IIfali/jng agents thai are recognized a.~ 1lOIl'OClr. It mlgt of iml11\lnolog>cal rc~pon!ieS affects e~nhay orgill, tIssue. and ceJl of the body. Immune 11':ino:lude. 10 pan. antibody (Ab) production , allergy. lOll, phagocyto>is. qt{)\ollici ty. tr.lllspl:101 :md rep:uoa. and lhe rnany s'gl\ll.ls Ihat regulate the:soe .' At ,130 most basic. lhe human Immune syste m ... btb'TIbN in \emu of the cell~ tllal compose 'I. E\'ery IIjIKI Ii lite iml11\lil(' syst<'m. II hether Innate and nonspenk!lldaplve ~1Id 'pec,fic. is controlled by a sct of ~pedDI1eI11' ThU$. ttm diJcussion of some o r lhe fundamenl:d~ ... bl-gins II itll the cells of the inunune sy'tcm.
lI/le

all nuclcated cells in the human body, while class 11 MHC molecule... are associated only with 8 lymphoc)'les and ITllK"ruphages. Class I M HC~ arc m~tters chat are rccognil.N by muuroll killer cells and cylotoxic T lymphocyteS. When I class I MIlC j~ coex pre~r.cd wllh ,'irnl antigens on vlrus-infccted ccll$. cytotoxic target cclls arc sig nllied . Cia,s II MIIC molecules are markel'\ indicating Ihat a coopemlive immune ~tate exist~ bc\ween Imll1unocompctcm cell . such as bc\.. een an anllgen-pre"I'nlll1& cell and a T -helpcr cell dunng the Inducllon of Ab ronmuion .

Mi le, can be found on

vinu~lIy

au.s Of THE IM MUNE SYSTEM

11_0: ~JJ_, den'-e from P/urilKJltm Slcm cells in the MI/'I'OW. lbr$e are cells tllat can d,ffcll':nuate 11110 any "'~lIl)pe. gi,en the nglltkind of .umulus (Scheme 7-

",.Iricly of rnotks of di fferentiauon beyond the qem ",."I'C ri ... 10 umqu.e cellular typc~. each with a specific . . i~ the immone ~y~tem. The fir.;t ~Iage of dilTercmia p'e!' me to t..-o Imerrnediale I)'PCS of stem cells and ~~ .Innch point. J Thc.c: cell~ arc the myeloid cells .'11\1 Ii~agt) and Lhc lymphoId cells (lymphoId hne CIII1')'log tile lincab'e funhI"T leads 10 additional brnoch., TIl: m)eloid cells diffcrentiate into erythrocytes and "":~. and Iiso l1lQIIOC)"tes and grnoulocyles. The II diffet\'ntiat~ ioto 8 cells and T cells. the cell, II the center of atlapli'-e immunity. The 5" I-Itching . . rOl' exit pathway and cell type: i, gO"emed by a .,., of rolon) -~llInu lati ng factors. stem eell factors, :md luH. These cootrol proli ferntion. diffcrcmimion. and of the ccll~.

rnicr()'j,C()f7e. o~ C"oIn obseriC dense IIlt1'llC)loplasrnic granuiel;. The granules contain inflammalory med,atOl"5 and digesti,-e en/Yme., lhat de .,troy invadi ng PJlhogens. control Ihe role and pathway of migrJtioo of ehemotactic celis. and cause dilation of Mood \'C$I'CIs at the infected , lie. 1lle increased blood flow cnsurt':!o thai an ample supply of granulOCYles and Inflammatory me diators reaches Lhc Site of in fecllon. Theil': IS a family of gr:mulocytic cells, tach member Wllh its own 'pcciali7.Cd function . Under microscopic uaminntion. SOllie grnnulocytes are seen 10 be multinuclear ;md some: monnnuclear. 1llc configuration of the nuclear f'('~ion and the sUllnmg beha~'ior provide ways of cI~ifyinl! granuioc)tcs. The group is dlSCu~!oCd bt:lo .....
II

Gr.nulotytesIf one "lews 11 granulocyle under

"/If

ubophlls 4 NtUlmphiis arc the pril'lW)' II1n:lte defense JI&iI,nsl pathogenIC bacteria. Tht:y mne up most (~to 75Sf) of the leukocyte fracllon in the blood. Microscopically. neutrophlls haH: mu It ilobl nuclei . 'Oley respond to chemical mot lilly factO!'> such as complen"ICm nlCdi;ltOfS rclca!iCd from Infected or inflamed ti~sues and nllgrate to a site of II1fcction by the proce~s of chemotaXIS. lllcJt,. they rocogma, 1Id~ to. ;md phagoc) tose in"oomll mlCHlbes.

/". ,II)

71 ..

lMotct_pwtlbllity Antlgens-Se" Mons.

immune fCl;ponscs depends on tr ...."PfUOII of "lI.:It ;5 s~lf and what is not St/f. This 101151 be clear and must be dorIC' in a "cry u)'. Th,s tn:ognition i$ achieved by the eXprc$sion II 'PXI.1hlCd <urfacc m;lIkcrli on human ~.... Ils. The major " I i man.m Involved in t h; ~ n:cognition con,i,lS of ~tm. ~ are referred 10 us the major his/i1CQnl ,~ (M ItC) or mnjor lriSll~ompa"bWfl' anti,.., Pturms u~ on the cell surfaces arc clas5 I Hunch:l~ II ~lIIC~, 80th classes II/"C highly poIymor ~ IIM!)O an: highl y specific to ellCh individual . Class I

r. rlopnent of most

Ph.gocytes
The phagocytic process is ini tiJted by contact and adhesion of an Illuding cd l wllh a phagoc:)le cell mcmbrune. Adhesion triggers a proc~~ .. hereby the phagocyllc cell enrudc~ pseudopodia tll.:ll surround tile lKIhcnng microbe:. A~ thiS procc...., progres>cs. the microbe: is IICtually SUrrouilded by the pllagQC)'te cell mcmbrone. lbcn. in\'agmallOO of !he membrane fully engu lfs the panicle. and Lhc membrane: IS rescaled. with the panICle CfIC~ inside an intr.tCC'llular VIlCuolar body ca llod a IHulgosOmt. Lysosomt'S III the cytopl a~rn th<n fusc wi tll the pha&O'>Omc: \0 form /JluJgmyso

ErythrOqttH .nd P~"'''

New St.m Celli A4ymmetric /

7' 1 1
/

"""".
My.101d Br.nch
:-G,.nulocylO

I """.h...
\IIropnl

Ptur!pot. nt "" Stem C.1Is

L,.....""kI

"-

L _"
.'.Mh
/

"?

TL~H

N.tur.1 Klier Cd

Scheme 7- 1 LIfl&lgeS of blood cell~, AJI blood cells denYe from a piur lpoleol stem cell. A vallet)' of cytok,nes direct the cells ,nto the'r specific popula\lons

S()flU's.

'The antimicrobial rompourld~ in lhe phagosome~ and

1)'!IOS()me!; kill lhe rngutred palhogen and coL)'maucally clea\'(: its ",m::nll!l into !>ITIalier pieces,

EosI_phlisS
gr.mulocY Ie!; Ihal can function II:> pha!Oless effieientl), than IICutrophiis un. They arc: pn:scnt as 2 10 4% of blood lell~ocyle~ , Their name deri yc,s from the in tense Slaining I'l:OCll00 uf lhclr Inlmcellu lar gnmult~ with the dyt eo,in, ~i nuphil gr.mulc) con tain IIlnRmmatoty med,atOrll such a~ hi,t~ lninc ~nd lcu ~OIricrleS. SO 11 makes sense that !he<;e cells ~re a~sodau:d wllh lhe ~l k:llic respon>e. Clues to the funcuon\ of OCISinophilsCQIfIC from thei r behavior in certain di!>('a;.e ~t ate'. Eos inophil counts a", clevated aoo\'c IlUflIlaI In me ussuc~ In many dlffe",nt di'leases. but they are re<:ognlled pnmarily for their d1 asn05lic role in parasllic Infections 300 1M allergies. Eosin ophil\ ha\c a unique mode of let ion that lenti- 10 their <!~. lreme imponaoct!. Un li~e IICutrophib. CQ!>l1lophils need not phagocy tose a par.tsite 10 kill It. Indeed. '>01]1(' parasiles are too largt to allow phagocytO!>ls. Eosinopllils can physically ~urroond a large paras lie. fonmng a cell ~()Ut around the invlkler. E~inophil grllnole~ rclen., e o\idal ;"... ,ub<;tances capabli: of deslroyi ng e\cn lurGt. llIu ltlcc ll ul:1f par.tsi tes. lIel1l.'e. cwn ~hcn phagoc) tO!>is fuil~. a nlCC han i'm exi'l~ to de~lroy large par... ~itcs.
Eosinopllll~ 3'" ~yte,. but much

(lgE) receptors. ComplcxC\ of antigen molecule, with receptors on lilt: CC'II wrface lead to cmss. hnk1Og of IgE aM d,stOOion of the cell mcmbronc. lbe distortion calise> Ibr ma,t -II tu <kgr.tnolate. relcbm! medialOOl of the alkllt.: reSJlUfU>". Ikcause of Il<; a.\social.ion ",ilh hYPl'r;cn~lti\il)' 1 ha~ been called "reaSin" 10 the allergy literature. 1>i<lI. 9B no..lical!),. ISE 1,,'cI5 arc clevmed in aller8)'. sy'temlC lupu.. crylhemat{)';us. and rheumaloid anhrim. Cromolyn sod,1,IIII is II drug Ihal prc~ent~ 1I1:1$t cell ""srnnlllat,on and lhIJI h l oc~ s the allergic re~ponsc . Cmmol)'n i .. u<oed In usthm.a.

I,e

Mac:ropheges and Monocytes4. s

Macroplulg.... and
~Dpable

rnonocylc~

are mononuclear cells

th~t a1:

Mast Cells aMI Basophlls

cl'lIs and ~ils al'lO rclC3l>t the lIln~mmatory 1fICd,aton; commonly associmed wllh alll'rg)'. ~lasI cc1Js an: ..sp.....,ally JH"C,...iem in the skm. lungs. and n:b31 mucosa: tllt:ir granules contam hi"lDnUAe. 8 a'iOphll,. p,cscm at ooly O .2'if> of lhe leo~ocytc frocuQl1 III the blood. alY) contain histanlillC srnnulcs. but the basophilcs foond circulating in lhe blood and 1101 isolated in conncctlve tissue. BOIh mast ~""ell~ and ba<;()phi l, ha\c hIGhani nit), Immunoglobulin E
M~

of phat:OC)"t():\o's. In addilion 10 their phasocytic apabtl ill('$. IlIt:y blOS)'mhcsiT.t and relea.>e solubl.. facb\ (complemcm. niOflOk.inc') IDat go'em the acqUired respon!>C . The halflif.. of mOllOC)tn In tilt: bltx)(htream II about 10 hours. during .. hkh lime lhe) nllgr.tle illlo tl~ and dlffcrelll iate mlO mocrophages. A macrophage i~ II In minally differentiated monocyte. MocrophagC!li PUSSl'S~ I lrue ~nah)fllical dlqrlbutioll boecausc they de\clop ill tilt: IXsues to hll'C ~pccialilcd fllnct ion~. Special rnacroplIDge<ll1t fou1ll1 111 II~'"CS sucll ns the Ii \cr. lu ng.-.. ~pIL'Cn. gastrollltcs.llnal (G I) tract. lymph nodcs. and hrai n. The>.C ~pL'\:ific I11.iICt11phages are called cilher hwioc)"les (g... neric tern)) Of b)'cu tain specialiJ-ed namcs (Kufifler ulls In liver. uIIIlIcrlm, ails in ~~ m. fll .. rolflr mocrollht"el in lung ) (Table 7 I ). Tht cnun:: macrophage I1Clwor~ is called the nlioilJl'ndulllf'~sle,.. . Other macrophalles exiSt free in the IISwcs. ",h:fto they carT)' oot more nonspecific functions. Macroph;lJa lIlO1"e slow ly II\;\n ncutrophils but M\'e a much broader 51ft. trum . It has been e'iumated that moK than 100 solubk !Do nammJlory MlbstaflCCS arc: produced by mucrophage!>. ~ SUbslalil'e!t 1ICCOIJm for mactopbagcs' proli fIC ablhlin 1Odtreel. modu illte. stimu late. and retarulhe immune I\'SpOI!;t M llcropha~ JlO!I~ss II very specmhtcd function; me,

,m_

act

TAiLE 7-1

Retk\.l loendothellal Sy,te m

as QIIIIgrn'prtSl!nling u/b (APCs) (Fig. 7- I). APCs are

responsible for the pn:processing of antigens. amplifying the

numbers of amigcnic determinam units and presencing the$e delerminam Structures \0 the progmmming cells of the imrnuoe ~ySlem. APC! internalize an organism or parI;cle and

I,.i...

Ku~<>d-I

"""
Pu ,. , . _

"Iveot. ....'oph'.TT (..... ~II') I'M......-I ...... ,upI....

digest i1 Into small fragments still recogni~ble as antigen. The fT'llgmenu are conjugated With molecules of the major
hislocomp.:uibilit), complex 2 (MH C-II ). These compk.l:es

sp...
ph'
hll

o-tn"" ~Ib
I 5,,1........11.

soa....

Mom!C"aI ... n~

are responSible for self or nooseU cell recugniuon and ascertain thaI cells being processed are 110( selr. MH Cs also direct the bioding of the antigenic determmant with immunoreac tive cells. Once the amigcn- MH C-U complex forms, it
undergoe.~ transcytosis to the macrophage's cell SUr!lICC,

.....
"'"

where 8 lymphocytes and hclper T cells recognil.e the pnti

THelpef Cell

.... 'lh 1 111' r lgE and au'Sa the c alk'1!Il" :n_u;\ it),. .

Ire. Diag-

MaeropIIa(Ie (APC)

lI1ic lupl,l_ m -.odIUm

.~

Ian'! .,'" 1 a.~lhlna.

lis 1":11111'1:

gocy uc ~a till: fnew ....

edimmu~

)d~Irt'am "
l~

;nlO IL"UI....
II Ie"
i

I poo.<,('\'

II!:C'

P in the u,

Ophagc' <Il'f

~moim c'll

~~ hY~l""

Cilk 111<1<.:[1"

:~mK"'htl'u ~7.1I. Thr ,.,j",I>c/,rJ

( e) ( e)

!oX"""""" D '\.Olub1e Into dI

re~pIMl.e

hagc5. 1lle'IC
f'i9uf,7- 1 Antigen captur .... nd presentatJOfl tell od memory B (ells

blhlie~

roe

bv a macrophage lead to clones of Ab-prodllCJrlg plasma

-< -< -< -< -< -< -< -<

)llClion ; 1M)'

gcn ' " tlK B SIIOICC' Ab and T -ttll l'tCeplor.. It IS thIS step th.:Jt ""nsfers speeirlCuy and mentO!'} mfonnallOfl from the detemunant mto the immune system through the modulation of B-cell differentintion. Under the regu latory mnuence of the helper T cell~. B cells are stimul~tcd to di(fel'emmte into pla~ma cells that produce Ab. The helper T cdls acceknlle and retard the proces~ Ib n~c~sary. ThIlS, unlike thegranulocytes, v. hich have only dtstructi, e (uocti ons, monocyu:s lind macrophage!. l'l:i\ulOlc 3nd progrnm !he imm une response.

The Lymphoid Cell Line: Band T Cells2

The lymphoid cell ime diffcrentiatcs in to two t)'l)l'5 of Iym_ phocyk'S, the Ii l)'mpl\oc) Ies and the T Iymphoc)tb. These: cells COOSUllitc only about 20 to 45/l of blood leukoc)tcs. 1lIey are ~n13.11 cells. only slightly llIrger th3J1 lin e'1thl'l'X'yte. bul B and T cdL~ can be Kkntified mICroSCopICally by large
nucleI that occupy mo6I of the: cytoplasmic 'olllme:. 1lIe nucle:i lire l:arge to contD.ln e:nough DNA 10 e:nable the: T lind B cells to biO"ynthe<i7.e massive IImuunts uf protein needed 10 cu rry out their immune fUlICtiOfls. T Iympnoc}u:s arc ifl' vol~cd in cell -mediated Immunity; B lymplnx:ytClo dlfferenlillIe into Ab-producing plasma cells. B I)'mphocytcs espress :mhbodies on their surfaces thm bind anl igen~. T Iympho") t<:.( e~pn!'s spcc:ialilcd T -cell l'tCepl~ on their surfaces that bmd major hIStocompatibility complell I (MIlC I ) and 2 (MIIC2) eomplesed with antigenic pcptode fragmem....

IMMUNITY
Immunit), m humans ean be concepluah/.ed In a number of diffcl\'lIt ways. If just the typc and speci ficit), of the immune response are considered. the ideas of "urate lind IIL'qui'o'd immunity IlI'C used. If only the component5 ttw nre involved in lile imlliune response nrc considcrt.'d. tIM! proces...:ts can be dl vldell into 11ilt/lOml and eel/ulll' ullmuflity . If the loca lion of tlte immune response i~ Con$ldered. we fin!.l that the immulll.' ~)Mem consists of $~flmJI (in the serum) immunity and mllamll (on mucosal cpi thehum surfaces) Illlmumt y.

Innate Immunity
Innate: Immunity is the most ba.\1c fonn of Immurllty and 1IlC"ludes Immune ~ySlems lhat are present III a human from birth. A clear !.l'$lIncuon must be made between mnate nnlUunity and acquired (lIdapl;"e) illlmunity, which devclops after birth. and then only after an anllgen;': challenge (Table 7 2). [nnme: immunity is the fir;! lille of defense: IIguinsl

IllvII>iOfl b) microbe~ and can be o;haractl:'ri7.cd as fllS! In rc:sporu;c. non'pecifle'. and lae\'ing in mentO!'} of the eh.!l lenge. Ae:qulred immurllty de'elops through a compkl system of n:actlOfl~ that are triggered by in,asion wllh III infectious agent . It 1 slow In response to an mfcelion. 1$ $ highly flJifir, nnd hu~ me01Of)' of prC\'ious infL"CIiom. TIle l11el11ory. or aJlantne~lIc response. b respGl15ible flY the e:~tremely mpld dcvdopmem of the immUIlC respollot with sub;.equcnl ehallenges and is a hallmllrL of acqUlrtil immunity_ 1lIere are three sepanlte eomponl:'nt~ of innate ImmU"I" that wort in COrl(!Crt to provide the ..... hoIe response. TIIttr arc phy,ical barrier;, cellular barriers. and SOluble fllClln ph)'Sleal bamers illClude the largo.t. IIK)O;t e~poo;cdorpl ofthc body (!he s\.ml. the: mucosa. and its aswciated mllCV:l The kcrulinlted layer of protelU and lipl!.l in the strlllum m J\Cum of the ,).;in protcC'Is physically IIgain~t a '1UlCI) ~ en\,lronntcmlll. biological. and chemical aSlollu1t~. 1lIe I"' tCClion affonk.'d by mue:osul surf~s. ~uch as an: found ill Ute: throot. tllOUth, rlO-c, and GI lmet. is due to a MlrfIL' epithelium. TIle ~pl1he l nml consiMs of )ing le or IIlUltlJ* layers of epnhelial ~ell~ lIo ith tight gnp junctioo\ hctlletl them. 11m t)PC of ~tructur'l: prol'ides an impermeable ph)W cal oomer to mi~rourganism~. Most of the: tUlle. epltlw:liIIII is funhe:r proI~tcd by tho: secn:lJon of mucus, ~UdI ~ plet cells III the GI mucosa. Mucu\ IS \'ISCOU) b}" oonsi~ung of gl)'oopcplide and an acidic glyooprotCin aIIfIt mucin . MUClIscan pre'ent pcnetraLionof microbial crib tlte epllhC'lium. ~ign irlCantl y <hI easing the: posslblht) of. fcetlOn by the mucosal route, Other components of the ph~ cal bam"" 111 lUnate Immunity are the tear;(oonwOII1II .. yrne). lhe uei!.lle pH of lhe: stomach. the low pH and fk.t of the: unne. pnd the c ilia 10 the lungs that cOOSlanl l) bat upward to relUo,'c in~pircd particulates and nllcrobe<; Two cOntpo!tcl1 tS of the cellu lar innate immune ~ have alreall y been discussed. granulocytes in the: blood tis~ue macroph:lges . When an i nfeclion OCCUI'll IU the: IISUI. chernocaelie: facto,", I ihcrnted at the: site migrate do",," I e. cemr,ll ion gMliem 10 tile surrounding area. These mate the: capL lIllI)' beds porous. Neu1l'optuls follow !bee. centrahon gradient lICr0s5 lhe endothel ium to the SIIC feclJon. 1lIerc arc three t)'po of chclll()\lK1Je: fac\(l\. foml)lmethu)llyl (( Met) ~pli~ rclea<;e(/ from tIw: "

n.c

'"'

""" ,

"ym,

>I,

(e) pcplide fragmenl~

prOlc:IIIS

ing hactcna.

(b/leu~otrit'flCS I

-.ecreted

b~':::~;:~:

tTani ti"l1 I na. t.

ml~'n

such 11$ C ", I engulf :Uld destroy microorganisms phagocylie ~ I " are nl'iO In"ohcd in innate immWlt. sponsc. prol'l!.ling soluble dtc11lie:al factoo; that enlwto.l

COMI

TABL 1-2 Owracteristics of Innate Versus Acquired tmmunlty

Acqul,,,, tmmunlty

t\.

rru. IIonl!

fuet()\"\;, (h) complement . an!.l (e) IIIterferoo. factor (Tuble 7-3) is WI agent that ~il 15 tile most fundamental OOcterieid31 factor IS stomach. Seerctcd by plet cdl~ in the mLlCO(i;lI lining. stomach ocid is I'C>iponsible for disp061111 of of the microbe!. that lire consumed orally. Phago; hepatocylcs produce the other bactencidal factOf';. \lo;o thcsc arc dm:e:ted toI\ard the: phagosome. v.he~ the estcd. pIlagoc)'tieally encapstllaled bacterial cell i~' "';,", The antinllcrobl~1 factors kill the 1llimoblhud 1111ClOOco. TIle!\! ~re two types of anl1mierobial factOfS. dlDIt

'AILI

'aliI III

chalmple~

' ...Slf 7-3 Bactericidal Factors

helot

nh on on. IS :l1ons. .Ie for

formation
wid noj".I,

Sit. of Action

o.)P _

I""",,,,,,,,,,,

.b;lll)dn"-o

:ponsc qmred
nunlly octOI'.
j

(-1"'*';'"

---. ,_ .
l.}'~_"'"

(",-.:draw

-~

Complement acts to kill bactenal cells Ihal are mi<;<oed by lhe neutrophil<; 1100 the mocrophages. TIlCn: orr actually 110'0 scp~r~lc Cllmple!1lcn' palhways, One. Ihe d/JlJ/m/ pm/m"l. opc:mtes In lhe adupli.e 01' w.:qu;red imnlunc:: n:sponc. The t:l3~,kal pmhway has an abwlule n:qulI'Clnent for alt Ab - unligcn comp1c~ us a ui~ger. The other. lhe aiumlllll't' /Huh Inll. reqUIfl.'~ no Ab or ultligcn to initiate :md I ~ opC'r~h\e m IIInl1le IIIl111umly. Both p.llh .. ays opc:rntc In a Ilghlly ITgu 13ted cao,ca(!c fllShi()fl The protelll~ oormally circulalt a~ 'JUlCli ~e procn/}lllCS. Whcnlhe path .. ays are acu,ated.,he pruduel of each SICP llCt"ate' lhe ~ubscqllCnl step. C
A

organ

llUCU'.

III cotety of

< pro-

und III ;urfoce ultiple :tWCCIl phY'IIM'lium

,f~

hl)Cr

called lis into f of 'nIphYJ;i '8 Iy\(}

...t

no . . .

Ily beal

~.

"'" ....
(,,)

!Spon'-l:

" ...<,ue,. n a C(lfiagenl"

.c: of in

"'~

~..,,:

! 1Il\'ad

I!:S. and plcmem ophase' IS. r.ion nunc:: re-

pn:form,:d in"lde Ihe phagocyte and '~llC Ihll' i~ induced 1Il1tspOll)( to IIlC phagoc) tic proceSlo. The Il)()<;t Illlpolta1l1 of tilt lI!Il,microb'al n-.co;h:misms is the Il!,'PlruHxy bUI'St. ",hich ~ oq&en rndical~-~upero~ilk. hydro~yl roldicals. _ hydrogcn pc:ro:udc. The: respirnlOl)' bu"'t ,s the: ()fIly ....td ItlC'Chani~ All of the active oAyge:n species !V"C iIIbIr deslrucli, c to 00I:Ier131 as \\"ell as hosl cc:11~. 50 rhey f t IlOl produced until they arc needed. Thc: dcfen~in~ :ue ~nrne- or eysle,nc::-neh bactencid,,1 pephdcs Ihal e~hibit .nln'mely broad ~IX-"<:trum of aruimicroblal ~ctivit)'. The oIdcn\ins ""II kill bllCleria {Gr~rn po:;ilive and Grum negab~~ fungr. and c"en some. iruses. The mecharllsm of OCli()fl ((!be defcn~i~ i~ IInlnown. but '<iOC"e the peplldc~ orr highly dJagtd in an opposlle IoCnsc to baclerial cell lnc::mbr.lIlc:s. cla.:lJOMahc, ""cmbrnnc-d,srup"'e interachon mIght be __ ""tel.. Q:,octen~ ........ an ab.ollll .. fa/ulrr,""nI for ,ron. aI ro rompete wi th lhe host for Ihis ciCtllCllI. lhey !o('Cfl.'te Iqh-affim,) ,idc:ropho~ ractOf1i thaI scavenge ,ron from,he 1!noI', <1(""" L..IICI"f~nil1 I.'; a ,ub<.l:In<:r pn>dtl~-ctl by lhoe lei thai b,nd~ iron iliOn: .ighlly Ihan Ihe bac.erial chdalor. jm'tnIing the m~udlng Ofl.~nisms act.,.,,~ ,0 a cnlicnl nu!nell. Lymyme is an irnponanl component of lOe amlllil' t1IlIul s)'SlCm. Th,s cnlynlC hydrolY/~ jl-4 I_,I)clhl(lic Imh.II!i In the jX'JllIdogl}can of OOI:leri;ll cell walls. LySQ--I)W IS ~nl In ahtlO$' all body nU lds. 1IlC.'ludmg lears - ' WIll. HepalOcylts produce ~n army of (ICl"~ ,,/r(l$(' pr()/~'II$ ITIbIc 7-4)lhal an: released into the ~rum dunng innamma Of rnf~ljort . 1be.;c: proteins do Itot act din:clly on bacteIII. but they augment the baclcricidal acli~ily of other anl ieolxal facton;.
ft

.j

I0-

No $tar inactive pl"oenqnte

_. I

Star actIye enzyme

THE AlTfRNATIVE PATHWAY

COMPlEME~
C._"i'~
~

~ 'h<

a sy~tent of a, least 20 sepill1Itc proIcms and that con lHluou~ly circulatc in tile hloodslrc:am.

lericidal

~ericitbl

Pemap' d In 11M: pllhc:hal of nW! C)'I~ ot MOM \If : pwilgloc lOf;Cd. robe ... lOSe: Ihal

TAllLE 1-4 Acut. Phu. Factors

Funct ion/Activity

ht lite allenlal"", (Xlth ..ay. C3 I' Ihe IItniatlltg pepllde (hg .72). In Ihe "':1\1111. C3 is sorne"hal unsrable (il is ;cnS;ljlC to protea<ocs) and spo!ltaflCOll'ly dcc(}mj)O<ot~ into II large:. lIC,j,e C3b frogmen! and a smallel'". eatalyllcall)' mac,,,'e CJa fragment CJh now I:lccomo!, bound ,0 a ~urfa!.-"C. and n has t"l) fme.. We' C3Il define I"U Iype~ of \urfoces. One. the 1lOfI.lC1,vating surface. is a surface that conlll ms ~ialic ocid Of other acidiC pol y..accharidc.~. n.e Oilier. un ac,,,aung s.urfllCe. con13I1t' nlllll: of Ihe acidic poIY'llCeh"nde< Of <lalie llcid This 'ype conrorm~ 10 II 00(:1.,,;,,1 ccil ",rf"':e. UOlkr nOfmal cir. cum<.tnncc.<. C]b will bmd 10 II IIOnacti"allllg ~urfllCe. On bindlllg. Llle CJb fl1l.~menl beconw:s ass.ocialoo .. nb foctor II. II P.g lobulin lhat as:.ociale) .. ith .n ... c hain on C~b. Sialic xIII iOCIT;iSO 11M! affinity for filClor H lOO-foid. Faclor H altcr; the \hapc: of C]b lit such II .. ay thaI ;1 becomc~ susceptible II) a1\acl.: by faclor I. a !>Cnlle ~temsc thaI c!calCli !he 0 cb:un of C]b. prodll",ng Inacti.'c iC]b. AIUlCl hy unother prOIc~sc: produce, II fmgntem dc~ignatoo CX. In Ihl~ palhway. fllCIOI' H IlCcdc!1ues Ihe dc.:uy of C]b. When fllCtor; 11 :lI1d I .. ork loget ...... r Ihey dc'lroy C]b a~ flbt II" it is produced and ,bul do"'n the pmh .. ay. If C]b hinds II) an IICliyaun~ <urfacc. lhe: abi lit y 10 bind 10 fDoCtor II i~ reduceo.l. aoo CJb blltm tt) a prott'in called f.acIOl' 8 . forming C]b8 Boullll factor 8 is clca.cd by fllCtOl' o onto a fr.l~nw:n' called 8b. The complell. C]bBb has high C]-con.erta.o;e acl,,;IY and >tlllllliules lhe palhway ft)!1/)1,'r. FIICIOI' I' (properdi n) bind, 10 tllC complu. ulcndong the half-life of C)bBbl'. Thi s frugnlCnl bind~ to lhe lerminul complemen, eomponc::n!~ (C5 10 C9). ClTllhng a mcmbrnne anack comple" and Ihll' Iy.. ing tll<" ce ll.
INTERFERONS

Cbernnca,l, _ cntwo<emmI
d """")10_

" .,J>UII ~ 1"""'" r.:ron

In/"h,,_olI prW",", Conl",1 '>f,ht ~"",pIt"'""

~~", .. k

,..".

1l100d

"""lui."""

An nnponam anli~iral ~y~tem i~ pro\lded by the onlerfcrom (Table 7-5 and Fig. 7_]). Thc Interferon<; alT pepide, that . ",lICn ~ ' nli infection OCCUI"i. earry oot Ihree dbUnc1 fune lion~. FiN. they ~nd a ~;gnal 10 n natll11l1 killer cell Ihal eM.entlully leads Co Ihe M:l f-dc<;cruction of lhe illfccccd cell. Sc<:ond. Ihcy mdt)ee an antiViral Slate III l1Cighboring cells.

----------------------------~r

e,

limiting the, iral infection. Third. lI'hen interferon I"C'Ct'pturs are bound on I urge\ ('I'll. the mdUClion of the formation of anrivirnl proteills occurs. One such protein i~ the enzyme. 2',5'- oligoadcnyhuc synthetase. This C'n~ymc cUIIlI)'7.e5 the relICtion lliul co.wens ATP into 2',S'-oligoodcnylalc. Thi s compound IICtivale1i ribonuclease R. which pos5CSses !he specIficity 10 hydrolp.e viml RNA and thus can stop propa.
galion of the .. irus
in~ide

!he ct'll.

Acquired (Adaptive) '.,.,"unity

wtKon !he host is upo5oed to art antigen or OI1anism tllat lias been COIl1acted (lrevioosly. the udal/lIIt! ;mmtUlt! r~511U11S1' cnsues. TIlC adaptive immune I'e$ponsc works tllrough the Band T lymphocyles. which possc>;s \urfuce receptors specific for each in vading organi sm. T o acOOllnt for all possible iX'""utati<ms of anligenic struclUl'e. IUlturoJ and synthetic. mal the IIo<;t mighl encounttT. the adaptive immune system uses genetic re<:ornbinaucwi of DNA and RNA splicing as I way of encoding its amibodies. Lymphocytes un recognize an estimated JOT dIfferent types of antigens through !hit genetic re<:ombination mc:chanism. far more than II person is likely 10 C:llCoonter during a lifetime. Adap'h'c immunil)' is Ab-mediatcd immunit y. based on circulalins pools ofanlibodies that react with. and inactivDte:. Ilntigens. 'These Wlh bodic:ll are found in the globuli n fmelion of lhe 'lerum. Conse:quently. IlnlibodlC's lU'e also refem:d 10 as ,,,,,,mnogfobufllu (lg). 'The adaptive Immune rc:5ponsc Iw the lHopcll), of mmID".. 'The sensitivity. 5peCificit)'. Ind memory for a par. ticular anligen Ire retained, and subsequent upos~ stimulate an enhanced rc:5ponsc. Hence. the adaptivc Immune I&sponsc differs from the innate in 1110'0 I'C.'ipecIS: SprfiCIfI and memory. 'The adaptive immune response. like the innale. can be di .. ided Inlo t~'O bruncl'les: hUIl'lOr.lJ immunity and cell-mediated immunity (CMI). Humoral immunity i5 Cll't'\llatlllg immunit), and is mediated by B lymphocy\t:S .00 diffc:ml' tiated B Iymphocytcs known as plasma eells. Cell-mediated immunilY is COIltrol lcd b) !he T Iymphocyles. 'The immune function of T l)'mphocytes cannot be: tram;fctn'd by stT\IlII alone:; the T cclls must he prescnt ..... herca.~ the immumt) of 1he humoral ~yS1em cun be isolnted from the strum and transferred. T cells arc specially tailored to deal with intn cellular infections (\uch as virus-infccted cells)... hen::u B cells KCTCle soluble antibodies Ihat can neutrnlizc JI'lthoscns before their enlry into host a:1Is. Both B and T cells posvu specifIC n:ceptors on their surfllCe$to ~ognizc unique SlImu11110f)' antigen~. wtKon B cells an: sll mul:ucd. they c:.tprm specifie mununoglobulins or surf:acc anllbodic:s tilat an: apahle of binding to the antigen. A fraclion of the B...:tll

Actlntl"'lll
~

.....

Pro'E ...

--.

~ ~

e~

___

To
,~.
,~

"'"
r~

~.

rei.

Cl<:

C3b8bP

Figure 7- 2 Controj of l~altematNe complement ~thway by actNating sorfac@s 'Nhen Ccmpffil'leill component C3b bmds to a surf", ..., there ... ~ two possible out(~ lJodeor normal condIuons, .... hen no iICtN,llong surface IS pr_1l1 (I.' 9 ' " (3b ~tonLKtl!d no., .aI ~), ~uaI additlot1 of bbld ooIaaoo H and I con ..... IS C3b In10 C3c. InactIVatIng the complel'Ml1\ pmlf1n If an <lCtJYillll'1g SUrfoKt> wrn itS iI rTlKrOOe Of ~ !ISsue IS encountered. sequential addltKKl 01 factors Band 0 OrIVl'S the alternatIve pathway to the normal properdIn (p) Intermechate, and t/1@ complement (a';(ilde ~ lIIggered The proptrdirw:onta,nmg CompooeI1 l (ObBbP) feeds back \0 the ~Innong of the pathw..y. generating more C3

....hi, of 11 Inn"

r'm

THE

Tho. II ~e I lInt'g
menl

are 7

Iyme anapt of IN classi, quenc

C7.C

IMMU
TABLE 7 _5

.........
tFN ..
1~"N1l

Interferon5 ",ociol'dng Cells

Producing MecNnlsm
IlIOtype.

MoIecvl..- Mall

R.~tor

of,,,,

AnAb pcndat Figure

T,,. I
laokllC'),n

-.ene I lnation
F,IIrut>/Io'h
T Iymphoc)'ln
Vind htf...~iM

, "

16--27 ~o.
,...~

9)..IIOU)o
91-IIO~Oo

-.olllelh hifun;-u

,,~,

lFN,\,

M'h'Fd .""",1.. "",

20-2.4 kDa

....., ..

"

"progr

l'\!Cogni Trem

of <.

"

'J ,'JIbooWlg (AI Vlrt.G-P e I Slant

'" '"

'"
m-

,,.
oc.

""""101'

"'bl,
,m
Ihi~
~

<he

+i

."
"'mo

.ize

Fig ure 7- ] The' lunct>oo of IflIMefOll. 'Nhen a VIrUS mfl'(tli a host tell, the cell eJ.PI'e<i~ mtMI'fOfl Inlerieroo iICI<IIates f1il!ural k.11er cells, Colusing k ~llng of tlw;o inlKIi!d host c!!'lls and f'I,mlf'lolllOn of the reser\'Olr 01 mfecuon, AI the same lime, Interferon IndUCes an antiVIral stale In flt'Ighbonng cells, elfeclNely breaking 1M cycle of InfOOOOf1 .

nity .nli-

.nti -

,lin5 , of

! R:-

kin-

-me"'"

populallOll doe5 not differentiate im o Ah-produclng cells bul kwm~. pool of cells Ihal reta in the immunolog ical mCllIory. Tttl's upros a specirIC anligen Il!C('plor. lhe T -cell 1l!C('Pu.timilar in SllUClUrc 10 lhe surface immurmglOOuhn ree~ 0( B cell). nils Il!C('plor is ac'I.lValed by piece of proUAd IInlillcn (~nll wilh M HC- II). ACliV1lted T cell$ ~ 'iO/uble facton such as i nterlcu~ i n~. cytol.ines. mlerII:foM. Iymphok:incs. and colony-stimulahng facl~. all of .iuch regu'ate the immune response. InletDC:lions with some of dIesc help 10 regulate the B-ce11 activity. dIrectin g the ...~ Immune response.

digc..\\s an At! jluo frugrnenlS that art' useful in understanding ils molL-cula, SlrucW~ . I'apain clips the Ab into ,10.-" fralments thaI comam the antigen-binding regioo s. lllese frag,nents h:wc been ICnned the Fab. or antigen-binding. fragment. TIle remain ing part of the Ab .f~ pap.un dlgeMion containS ''''0 pqxidc ct.wns linLed by II. dt>tJ lfide 1xInd.

c,

lting
THE CtASSlCAL CO MP LE MENT PATHWAY

=ren-

ialc:d nunc

~m

, '"" intra~l1m

unit)'

~. B

,,'M

~'ieSS

: pres~

The tlul;ical complelTlent pathway dl ffers from tile allcrna 1M p;ithway in thai it reqUires a trij;ltcr In lhe fonn of an I'ItIscn- Ab complel. Only 1'110 lJ1libodle\ can fil comple --.1gG and IgM . TIte cllISSical pathway is shown in Fi g.7-4 The >mall fragments toot;an: clc~\'ed from the procnnus 1ta.'C act;. lues such as ch<'rll()lactic )lJ mu lauon and IPrftyW,15. TIte bur o\u the naJ'llcs of some comporoents of !be pathway denotes an oct;ve complel. Note Ihol lhe dNIcaI palhway does not operale with C I to C9 in <;c'fI"ICt. Ra!iter. the sequence is CI. C4. 0. CJ_ CS. C6.

c.. C2{('G c.bC2b

.--

c,

r7>:>
/

re caB-ccll

0.01. and C9.

I"1MUNOG l OBULl N STRua URE ANO fU NCTION COO"""

\ ....."""/'.
Cheo, ....

"tbt
w.

""" '''''

All AbOI' Ig i~ composed of peptide chains ", ilh cu rbohydrllle pmLml groops. A schem:atic of the Ab ISO i~ ~ hown in !;pre 7-S. The peptide chams forl1\ the quallmlDrY ~I rucu.lre Immunoglobu lin. .... hilc the carbohydrnle moieties ICI'otll intigen-reoognition. groups and pmb;tbly as confor1IIIIOII'>IlIbilizmg units. 1be general ~tlUClure of tlte Ig looks ';';"nllt~e a Y..... nh lite antlgen-bm(itng regions :;Itlhe Wlllnltd tOO. In Ihis area arc peptKle sequences that ore "~blc" by (he immune ~ystem to allow lhe Ig II) IIlX1pue Dlarge number of anligc n~. TJt~ment .... ith either of IWO cn/ymes. papain Of pe~in.

1
J

I~

;I

b "" '_

J
palhw~

Fig ure 1- 4 ClassICal (ompllmoe-rlI

AnIigeo' B do", RegIoo.

(Fab)

Fe Regioo'

V.-IabIe R""",os

Figure 1- 5 Structure of ,mmuoogJobullll G OgGl. showong an!lgen-blnd,"'9 regoons III ttey of the rnoleculr

elemen~

Tlt'atmcnt of the same Ab with pepsin yicld~ the two Fab units JoillCd hy the disulfide bond. plus t\\oo of the diStal peptide chains. Thesc distal units havc been crystaJl il.ed ~nd. hence. are temll"d the R: fragmcnt (fOl" '"cryMallllable'"). The disulfide bond. thelt'fore, provides a demarcation between the two molecular rcgiOlls. The oomellClature of an Ab includes a hlgh-molccular-\\oeight. 01" heavy. chai n on the inside and II low-molecular-weight. 01" Ioght. chain on the OtJI.Mdc.

incorporJl.e them IntO their cytoplasm ... here the anllgens_ fragmented. The fl""JgllocnlS an: then combillCd with MHC 11. di~played on the cell membrane of the macrophage. aDd presented 10 the immunc sy5lcm. The presented anlip interact with B cells. causing differentiation to plllsma alb and Ab 5eC1\'t1on. T-helpcr celLs also interact with the 1ft"" sented antigen and arc stimulated to cause the B cells ko proliferate and mature. Plasma cells an: monoclonal (genttocally identical) lind produce monoclonal Ab. The pn:IN.

tMPOfITANT FEATURES Of ANTIBODY MOLECULAR STRUCTURE' ,

As 'lUted above. the tip end of the Fab region bind~ ant igen. Then: an: tWO of I~ regiom. <iO \\oe say that the Ab is bim/t'lII and can bind two antigen molecules . The overnll IUnino acid sequence of the Ab d,clalC:s iu. conformation. The peptIde sequcnce for mC)l;t antibodies is s imilar. excepl for the hypcrvuriable regions. The amino ac id St'qUC01(C at the end of the heavy chain (Fe) d<'temlillCS the class of the ]I! (i.e., IgG, ]gM. ctc.). All antibodies resemble each OlheT III basic ~pc, but uch has a uniquc amino acid sequence thaI. is complementary to the antigen in :1 "Iock and ~ey" intemClion (anugen- Ab specificity). Son~. such as IgM. IIfC pcntamerll of IgG (Fig.7-6). In reality, the lock-:lIld- ~ey modl."l ;~ too simpliStic. and an fit.1"lOde1 is pn'fcrt"('d.

.nducro

ANTIBODY PRODUcnON AND PROGRAMMING Of THE IMMUNE SYSTEM

'Ole m.:o.in elem!:n[ of [he programming ponion of the immune 5),,[em i~ the macrophage. A common property of mocroph;Iscs j , IllrngOC")/Os;J. [he capacity [0 engulf a particle 01" !:ell through inlagmatio!1 and scaling off of the cell membrane . The macrophagcs in\,oh'ed in [he immune response SCt in motion a unIque amplification process. so thaI I large response is obtained relative to the amount of antigen pm::e~o;ed. The mao:mphages engulf anligcnic panicles and

f ig ure 7- 6 Peotamenc structure of 'fflfflt.lIloglobuWo (lgM)

Cha pl rr 7 from Lhc: pluripolent stem cell. to the 8 and T cells. to IhI: pIlSma cells IS ~hown In Figure 7-].
ANTIBODY FOfIMATlON~

1-..nOOwIo~lruJs

205

Figure 7 1 also indicatcs thl: ocillal Ab.-produclng MCp!i. PInma cells are clones. of Ab.-producing cel!J;. ~hich l/Ilphfy the Ab rel;pon.'iC by their ~cr numl)cr,;. 1llc pla5mH cdIs can easiLy be rege!1('l'lIted if cal]ed on 10 do so by thl: -lII0I)' fuoctions. A population of plasma ce ll s is shown _the: boUom of the diagram . These un: identical and amplify l1li produce large quantitIeS of Ab. proponionally much pWer tlLan thoe amoum of amigcn thai was initially pro-

"""'.

o\NAMNESTtC RESPONSEs

kause the ptoglammed immune system has the propeny rI mtmory. wbsequenl exposures to the $.affiC antigen lire ."'~cly countered. The lICfual memory response is reIcrmI to 11., the (ltlllml!Ulic fl'Spt)tI$l'. a 'iCCondary respon'iC Ifhlgh Ab titer to II panicular antigen. nils is due 10 "memtr)' ao]]"

formanon as II result of the initial antigen St; mutu s "".~'~Ul~.~tion or immuni;(3tion). anamnestic re.~ponse is ed in Figure 7-7

n.e

.IMTlGEN - ANTIBOOY REACTlONS

,I,a Ab IJ bivalent. and lin antigcn is multivalent , so lattice

C2II occur (Fig. 78). Thecomplcx may be fibrous.

insoluble. 11Iesc chamcdictate the meDns of itS disposal. Four fundamental these proces~ : neutrahl.lltion , p!ttipua. . and baclcrio]ysi~.
teo matox like. solubJc.
01'

Rgure 1- 8 Combmlng ratIOS of At> and ant.gen BeuUSE' the At> ~ brvalent, thefe exist a 'Itt of condltoons under ....ueh OPllmal pmportoons)'!tld a stable lattICe structure, neutrall~lng the antlgeo If antlgtl1 or Ab is ,n eltCess. the !at\JCe WI~ 001
f~m

'!""" rellCllon for bacteria and for toxins (which are wull Neutralwllion is an immuoological
in the inhibi lory intemcur
causing spastIC paralySis or nuc

Once they bind the Ab. they are no longer si te structures arc covered lmd they . Examples of tOXinS are teumospas".;ltwni) and diphtheria toxin.

cid pamlysis. respecthely. When an Ab blocks the to~,"' s re<:eptOfbiJlding region. it can 00 longer bind to the neural reccpton and is n:ndered hannleSli . 11le tOlin - Ab comrie)' is soluble ~nd roqUlres rIO further proces~ing. 11le complex can then be eliminated by the kidneys. Bactma are immobi li1.ed by ncutrahllluon. When a soluble antIgen reacls With an Ab. II may fllfm an insoluble particu late precipitinI'. Such a complex canll(){ remain in the blood.Wt:am in its InSQIuble stale. TIIese 'iptcies must be removed by the spln or tbrough the reticuloendothelia] system by phagocytosis. Bactenal cells may be aggregated by binding to amitxxlics that rnas~ oeg~ti"e ionic SUrfllCC eharge~ and cross1in~ cellul.ar structures (""'ig. 78). 11le bacleria arc thu s immediately unmobili1,cd. This limits their ability to maintain lin inrC(:Iion. bul it forms a paruculalC m~tril< . This I)'pc of complex must a]~ undergo elimination through the ret iculoendothel ial system.

"

Predpitiltion.

Agglutination.

. ,I-<

8acteriolysls. BlICtl'rioly., is i~ a complement-mediated reaction. The Ia.'" live proteins in the cascade !iClfIS..'I('ntbie 10 produce. a membr.!ne attack complex that disruptS the cell membrunts or bacteria. acting like bat::itl"oICin or amphot.:ridn B. 'The II membranes l~ integrity. cell contl'nb leal.:

oot. membrnllC trunspon systems fail. and !he cell did. This type of reaction yie lds productS tll3t require no special treDtment.
ANnSODV TYPES A ND REACTIONS

Ab types and rt'at1ions lire classified on the basis of varialioos in a common section of the Fe fmgment that govem~ biolQgical activuy in I general lO'ay.
/gG.

is actually part uf the mcmbrnne rt'C'CptOf for IgA . 'The laA molecule on the mucosal s~ uf the membnllle bll'lds llNJ, gen. then birlds to the receptur. By II process uf trnnsc)'tOliII. the IgA- antigen complex is moved from !he mllC()5.ll tu tbt bloodSTream. whcrc 19O and IgM can rt'act. Because it .. distributed OIl the mOCOllll, laA has 1II11l11atomicaHy specifIC di stribution. unlike the OIher antibodtes. IgA is !he medllUW uf oral poliu vaccination (the mucosal re:u.:tion gives wly 10 syslernie prottc1ion). IgD (Fe '" 6) is present 011 the surface of II ~IIJ lind, aloog ..... ith monomeric surface 1 .. 9M tor that acti\'ates immunuglobulin produc\lun. t than 0.1 mg/mL 111 the bloodstream. and the hair-life i 3 days.
/gO.

IgO {Fc - ,., (Fig. 7-S) participates in procipitation reactions. to~in neutralizations. and complement fixation. IgO is Ihe major (10%) human 19. The Fab tip fixes antigen. and the Fc fragment can fix complemenl to yie ld 1&&lulin lion or lysis. IgO IS the only immunoglobultn that erosscs the u-.l1lsplucenlal ~rrier and the t,,:onalal Siomach. so it pro\'ides maternal protection. gG constitutes about 7S'I> of the tOtal Ab in Ihe circulution. It is pn:sent al II concenlration ofabout IS mg/mL and has a half-life of 3 lO'CCU.!he IongCSl o f IIny of the Ab types. The light ehams of IgO CIlII polistS$ either K or A variantS. These ~1ighl differences in SU\lcture all.' en lled UOf)"fJf'I. and the phenomenon is tc:rmrd isof)pk
,urillliOll. 19M.

are fourld in perwns With IS in autoimmune diseases. lhe i Ab-lI.ntigen eumplex. IS K1uaJly pan of !he mast cell. 1 Fub portion of the Ab. the IgE molecules linked. Thi s probably distortS the membrunc cells and 5timuhues them to rt'ltasc hIS\:Iminc. broochial constrict iun. itching. redness. and llrmphywlS.

;"'"m

, .A""

IgM (Fe - p) (Fig. 7-6) is present at a l"<>nCentra tion of about I.S mg/mL and has a half-life of Ie.~ than I lOel'l;.. Th is Ab participates 111 opsoni1.lltion. agghJlJn.:lIioo rcochons. nrld eompl~ nlent fixation. Opsonil.ntion. as Slated aOO\e. is I "protein COOling" or tagging of a bacterium thai renden it more ~uscepl1 ble TO phagocytosIS. A complex of !he ponion of IgM plus C3b of cumplement is that pro-tein. IgM h !he fint immunoglobulin formed during lmmu ni7.ation. but it wanes and gi "e~ way 11.1 IgG . IgM is a penIlImer. and Its agglutination potrocy i ~ about 1.000 times that uf IgO. 19M is also responsible for lhe A. B. and 0 blood groups. lhc fundamental mooumeric IgM structure is much like that of IgO. The pentamer IS held together by disulfide oonds and a )tngle J (joining) peplide. 'The: affinit), uf an IgM monomer for antigen is less than that uf IgG, 001 lhe muttimcric Mructurc raises the u"idiry of the molecule for lin antigen.

r..:

ACQUISITION OF IMMUNITY
Several types ofimmuntty must be considered wh," ,~,,., till vaccillei and other immuoobiologicals. Some are eial llnd sume are natu1'1l1. Nmura/ immuniry i~ '""",,' phagocytic \\;hite blood cells, Iysolyme in tean. and so on. A.cqulred immtlnil} IS acqUired afteT bin!:t by passage from mother 10 fetus). Thus. immunily may el1lS!>ified as

IgA . IgA (Fe - a) (Fig. 7-9) is found in exocrine gland seeretioo$ (mill. saliV1l. tears). where it protects mucous membr:tnes (e.g .. 111 the respiratory tract). It is presenl in the serum a~ a tnoootner at 11 cuncentration uf I tu 2 mglmL, OOt humans seerete about I g uf the dlmer per day in !he mucosal nuids. Secretory IgA cOll~ists of' ....u IgG-ltke unil$ linled together at the Fc regions by I peptide kno .... n as !he sretory fTllgmcnl ~nd 11 J fmgmcnt.lhc seen:tory fragment

tc'ntalt1'1ln~fcr.

;
prottlOll from malernal I Iype of ImmulUly is not I

II'Qt~raJJy ~,,.,a f't'S$I'~ /mntuIUif

Tet1IJlOrIfY 10 \he; r~.., In _ "

ItmflCiaily Uf:q..ITtd pas......

,n.Fetioo. e .... by In lII.IIo .. n or.

Ddl_Ultans of ImmunDblalogkals

Membrane TIansj:Iort
RlcapIQ'

Figure 7-9 Structure of immunoglobul in A (lgAl. the mu cOSiII Ab thilt protects the GI tr.xl.JOd the resp.1atory mucosa

Immunobiologicals include IIIltigcnk vaccines and tuxoids. Of Ab-<:ontaining as globulins and antitoxins. from human or TlIese products arc used fOf' lICU\'C or passh-e i or therapy. All of the fullo ....'ng all.' eumpiCli Iogicals:

(;hIIplfr 7 /",,,,,,,wb,,,/ogiru/s

207

anll -

'sA

ytOSIS. , 10 the ;e i l 1$

pedfic

edlator

way 10

\""-"''' It ~ oI li~e (uwal1y IIIICnu.alcd) or 'nacti .at! ."'OOOIIn'sms (C.I_. _ ICO.......,,~ or ncLetts... , Of ~ 1l>rm;K .alTllni.c~ 10 ,ndIitt ,nlmuml), and pR_ .mccttau:l dt\case or UI ~IK. Sollie ~;~ conU..n 1iP1) defilled antll!<'ni>, 1'.1. ~ poIysao;.;luori<k of H..,-.ph. ,.... UIjII<t,,~ lyP\' b Ulib)or the .unlll:c anll~n oChC'paIi[;, 8: Dlhtn MIl' IlIligem Ibal IR romplu or "lcumpkLdy .s.,fincd. ~ ,!Ied S",drlrll.. P<'rTIflSIS or fl'e Incnua!ed "ru;:e<I. Tor",d, A mOllified bactnlBI IOA In .hUI Iuos bttn made non10..: bul l'elums [he abIlity 10 sl' '''uIJIC the forn.alion of IIllli-

t,..

,-pis less
is OIlly

cen ~

I",

!!'SeMI -

r ,/ohM/in IIG/: A .!erik wlullOn coot_mini ~lIIiblldie. flQOl'llMlman blood. II ;s obtamnl by cold rth.1no')1 fBCIJl)II':1!1OII afllrF pooInf blood pI!,IMlU. ..1<I CQnI:lJIlIO 1$ 10 I S<;l proIcin. 1m Ird f<;lf ,nulImu"",ular ldm,mstr.lhOO. lO;s pnmarily InIIIIIb:I f'" ~ maintenance of Immunuy In CCTtiUn immu ~ ..... penocd and for pa!oSIVil ilnmunlQUOII .,al_ e 7, ... 1I'Id hepallh~ A IG does 001 tOlnlJT\lt 1qo;I1II;~ 8 ,irus. IIumu ilMlllootkfociency VI"" (lIlV). or OIher mfectious dis

for host

or Ig E

as we ll oOnsible 11yie lds the Ah

s to the
maSI

: cl'OS$-

'Ie

1 cause:>

lu is..

.describ-

re :mill;,wed b)'
~" i n.
(If"

btl"""",,, j"",uuw ~Iobul," /lG/VI: A product 1Im,-ed from blood plasm. fmm donor pool ~Imllar!O tile IG pool bul )It . .<d to II I~ sUIlIlbIc for lOln'cllOllS U"". lG1V does 001 trnmd Infectioo! d;src3ses. II ;~ ""manly us.ed for replace _ thmlpy in pn mary Ab delic~llCy disordcn. and fOl"!he u 7mtnl of K a"'asa~i'J d,sca.oe. ImUlune 7hromt>oc)tol... niu ... purpwa. hypogammacLobu lirw:mip In chromc lymphocyt~ Iou~.....a. ond "'-""" ~ (If HIV inf7ion , $pte tfic u......,... ~lubt<li"; Specw f" <panMlOII' oilll",...d from bI<QI plasma from donor pool~ ~It~ for high Ab "'_IpIMI ~ spec,fIC anUltn (. ,_. htpIuu. B Immune pobIillll. .-mcdI;t-lOQn Immune ,Iobulon. ~ Immune pobIillll, _"'" ' ......... IIC &'obullD. Immune ,Iobulln. l1li <)"IIW<pknlRl ,mmu"", dobubn), !.ike IG and IGIV. b prtpanIlQRS 00 not Innsmll tnf11OUi dlsrca.~. """"UII, A "",Ullon of anubodlO ('_1 .. dlph.!llcril anulOxin l1li bilo;pl,roum antolO~ I n) derived from !he ,.."m of anImals .....ww.cd ",''' SpeCifIC anlil<'M. Ant.IOlll11> I/'e ~ to ron Ie.- pMO-il'1: immunity and for tre:ll~nI .

feclan! hl.e fotmaldchyde ot pheool. TIle J>fU'."e$\ denatull.'S the proteins and carbohydrateS lh:ll are essential fot the otgam sm to h \. and Infect. host. but if lreated properly. the surface :tnhgen\ are lefl IIltaN. 1lie proce\s IIlUSI be done care fully 10 CQIItrul the un" Indmg of pnltein~ ot carbohy dr tes by denatumuOli. sHlce the prcpanluoo must be l'l'Cog " niled a.~ the original antigen. The main problems "nh lilled .,a lhoge ll "!lCCl nes un:: (a) if the v:u:dne IS not illllCu\"ated tOioll y. disease can result: (h) if the prepar.!tion is over treale,J. va~-.;:inc fail ure u~uoJly results because of demuur alion: fe) lhe product ion laboratory mu\.! grow the pathoJ!CIl in large quam ilie.~ 10 be commcrcially u>tful. puttm!! labora tory technici:ms at n~k: and (d) the pallent may upcnellC' abnonnal and h:lnnfu l ll.'''ponsts. such ill> fe. cr. oon.-ulslOns. and death. These \"X"C"lnes t)pocaJ ly arr \'iewed Wi dln) vaccines. and .;orne. hl.e the pcnu.'i..~is \liCCine. h:l~e bc:c:n associalcd " .th probkms ~rious enough 10 ..ltrJm their tcmpor.lty rem()\:!1 from the mart et.

\'XCI"'.

)inh

~y

'"

. her _II

I'liCf.llll1ivn dellOles lhe ph ysk al !Ict o f adminiSlcri ng a iIOCllIf or t01Did. Immm.i:Jlliorr i~ a more ine lu~ive lenn Jr 01 (Ii( p!"OCe)s of inducing Ill'" provjd ,n& immunity arti. lilly by lidmlnislering an immunobiulogical. Immulli-,.aIlly M actl" ot p3$Si'e.

Uve/Attenuated Pathogens. The word /II"mrmrd fur oo r purpose$ .~ill1ply nocun Iow vlrulcnce:' The true palhogen i~ a he~d phcllOlypicaUy so that it cannot ill"adc the hU lllDn ho~t ulO cunliOl gel ahead of Ihe ho~"s illll1l1111C system. 1 .(lwpathogen icity 'it,..ins such as these were ongi nally obtained by passage uf the IIIkrul:lt'~ thrvugh mallY geoer:uions of hosl anilnals. The jdc,a ...." th:lt lhe animal and the pathogen. if both "ere to su .... ive, needed to adap! 1 Iovc With cach OIher Without either panner bcmll t Illed. 0 Poliovirus IS attenualed in this f3Shion in monkey tidney lissue. In a !i"e!aucllllmed vaccine. allhgcllIcllY is sI11I ",. qu ill.'d. as i~ i llfecti~i ty (polIO vaccine )'idds all InfeclKH1), but Inc: ho!.l' 1I'lmllllC sy~tcm must be able IU sUly ahead of the mfeclloo. The I.ey problems are: fa) t/w:: 'ac~UIC c.nnOl be u'\ed if the paliclll is Immunocompronll~d, ha, rClCr or m~1 ign nney. or IS taking IInmuoosupprts>ive drugs: (b) IheM! vacci lll:S ~hou ld not be used duri ng preg.nancy: and ft"J the nucn uutcd o rganh m commonly ",'en s to the virulent ~t,..in. which wu~ the: reasoll for the foi lure of .;ome cll(ly polio vaccines. T oday. blologkal quality cootrol i~ 'cry slrlllgelll. and th.c.;c probl.ms ll:I"e been eliminaled. Live/Attenuated Relitled Strain. Il.'latcd ~t ralll is anugenlcally related so that" cnn provide Cf"OS5,mmllnily to the pathogen. r-orcumple, OO>\poJx viru~ can be u~ In place o f smallpox ' irus. The '\1r~lIlS are !Illt, gcmcally ~Imllar cnough..o thai the host's munllllC system reacts to the Il.'lalcd SlrDJn to pro,ide proIcctioo agalll,t the 00"",11 pathogen. The maill advant age is thul a true pathogen is not being u'\C:d <,() thai the chance of cuntracting the actual discao;c: i, I.ero. The proble m wi lh ~u<:h vacc l lle~ is thatthcy ca u"" an infectiOIl. Cowpo~ is ~nown 10 spn:ad to lhe ccn' ral Ilervous sys,cUI in I in 10' cu;.cs. causing a poIelltlally f:ltal form of mcningllis. Cellular Antigen from a Pathogen. The surfoc'C an!lgen (i ........ hat " recognl1..ed as f~lgn) .s h.l1"\<.Sted from the palhogell. purified. and I"CWIISmuled intn a \'3C("11IC prep'U"lllion. These allu~n can wk a number of forrru:. includi llg the cariloh}dratc c3pUle. as in N("$uritJ tMmrrR" idis: pi li . as In N. I(onorrhot-ttt!: flagella from motl Ie bacteria (Ihe basis rot all elpcrinlt!IIta.1 coolcn \"accIllC): or lbe vlI'al

.cry fmm

_w

IlriDIDgkals (Vaccl_ .nd

TwII' ,..A 1rCW' nuy be defined as a solullon or su.~nsioo of or!i,vlIltrooated ,irus. k.il led rick.ensia. ~llIed Of live! baclma. or am isell ~ dcnved from these sources. . .... .e u<.ed to CQIIfer lICti,'" un ificiall y acquired immu "IJ agaiml that org3 n i~m or I'l' IDled otgani'ms. When ad nlCrN. the vaccine n:prco;c n t~ thc initiu l CXposUTC. reo " In the acquisition of immunity. A SUbst."<jUCll t "I"~or ~halkng. (a disease) resu l! ~ in lhe anamnestic. -.y, 1t..;pot1St.

_ h
!illS. \u,:h

,_* pn:!ilIICtlOO methodsaccording 10 a lIn:atly o,'er lhe e \'lIried ..... 1IId best discussed parallcl chrooo!Ia\
lit

IIil()OS OF VACCINE PROOUcnON

II demon..
u OlZahOIi
jllUnobl~

:iliad Iqlh.lsucuion approach. . . , flMctivated) Pathogen. In thi~ melhod. the pathogen IS treated with a stronl!. denaturing disin

protem COOl. lIS in tIM: vaccine for hepatitis B. AdvamUIlc:5 oftne metkod are thatlhere 15 vinuall y no chance of dlscaS!:. contamm:uion. or revcrsioo and there ure 110 MOrage pr0blems. TIlls mclkod is curremly as close to "perfect lIPpro3oCh" as we hale. A problem is thai the Po1thogcn must be groll-n under careful conlrol or an unsure WURX" must be rel ied on. For example. helXltitis I} vaccine wl1.~ originall y prepared from the serum of a controlled populatioo of human cameN. I mallme the Impact if one of the: cameN dcl eloped another blood-borne dis.ease. Additionally. tht:-..e an: ~train specific antigens (c.g .. N. KVMrrlKJwc may requlI'e 1.500 diffen:: m pilar antigens). Acellular vuccmes may exhibit IQI\'(T antigeniClly In the "cry young and may require sevCl1llI injcction ~ for full irnmuoological competence. To be ~fc and oon ~IStCnl, the antigeniC component must be identified. GiI'c n the cornplcx nature of biological malerials. thIS IS not always easy Of" el'en possible.

tion of !he ~urface proIein. In this CIISC. E.cherirhiu roil serves as an e~ccllc m Iector. It contains a plasmid thai alii be renlO'ed. clipped open. and u~ as II cassene 1 o:art) 0 Inc virall>NA. Additionally. E. coli can be grown in t.dI to produce tilt viral !l(Jrf!tCC an tige n. To begin. lilt DNA. re.uoI'cu from the I II'US and the plasmid is ren)(}\'~ fro. the ,ector. Viral and battcml nuclcic lI(: id is tte:Uel.! "'1lha restriction elldoouc1case. ~'hich ckal'e~ tile DNA anJ plasmid at designated n:slnclion SlIes, "The DNA . d eal'ed IIlto a number of fl1lgllle llts. each of II hich I~ hg.ued inlo the . ro/i plasmid II II hga!ie enzyme. Plas~_ insened illlo E. CQIi. and the OI"!anl~nI is grown in bad fcrmentat ion. "The org:lllbm~ containing the gene fOf till vi ral !iurf~'e protein can be separated by !lCfeCnlng and PI'" flcd to ser.c as the ul1 inuuc antigen pnxlUl'eT- fl\.'C uf COllanlinaliOIl or pathogenie , 11111 particles. l1ic pure lnay then be constituted IIno a VllCcmc and used In i

,.nJ

,th

The tcchn iques of gcnellc e nglllecnng have allo ..'ed the pharruoceuucal industry to pre~ abwlutcly pure surface anligc ns while t()taJly ei1n1m:tti ng tM pathogenic organism (roIli the cqUlltioo. As shown In Fig ure 7- 10. the viru~ cootUInS surface anllgens (designaled by fillcd c;nII'J). Inside: the ~ iral capsule is II ci rcular piece of DNA contDln ing gCne! for the larious bi()logical nlOlc<:ule~ of the virus. 1lle diagl'llm shuw~. at llbou t ) oc1ock. a ~malJ piece of DNA that codes for the surface antigen . The SIrJ tcgy i. to 1.;01011' this pi ecc of DNA and Inscn it Inl0 a r.lpid ly Stu"''"g expressioo vector fOl'" produc.

Genetk.lly Engineered P.thogens. s

""'"
USE Of VACCINES IN COMBINATION: DOSING S,"

h""_

Then:: lire three basic tylJCli of "",-. cine preparalions th':11 are used cli nica ll y:
1 i~m ~e_ A i
2. A

Types of Vaccines.

"--;:~::: ::.:::.::: ;::;,:,":,;,: f'uJle~rtllu ;:,:';:~<::::::~;: 1 ,...1",'. and II

"""",..,Ie", >'Clne to ~ from IWO or more: IUaM

an or,ani,<m t/I:It C1IU5e 1M ~ d"eao;c, (q; .. polio" In ' Admln'SUlItHln o f tile muJtlpIe stnlins i~ m,ul~ for full ,.,. 1100 haU!IC the,r Inl;gen~ 1ft 001 tTQUl mmun,li"l. 'TIt. mune .y~o m mu~t mount I oq>an'" immune response IQ

Vhlt Surfaoo Protein

VlIlIIONA

3. .~" A pQJ>~"lJI~", VIICC" ", i, prcpartd from two or """'" tlla! Catl!oC d,ffen:m di ....... PoIYI'I.Jem ~1'CdOlCi ore conl-en~. rrilnUlly Ml tlt3t a eMd can 1M: , .."eft nllher than ,",veral. n.. n"ll)l"'-!t!um~ - ",belia (MMItI eu>c: is 0( tIM: poIP"IIlent I) 1'1'.
VlCCines can be admi niSlc~ cording to a variely of dosing regimens, tlcpending 011 vtICCine type and tnc purpose o f the illjcctioo:

Types of Dosing.

V"'ONA

v0
'

I A),,,gl,..Jou WJ("ciNt i. usually"",a1Ip>X ' 1~:::,:.:~::r.~,;.:::; ~!l"umcdl 'hfd"ne immunOlY." ..".,

~hOI. ~ ~lOCCi""

Paeteml PIMmkI DNA

2. In a "",llIple..Jrui"g oeglfncn. se"cnJ

"......"

R8fllr1c1lon

..
,

ReAlction EnOo"""II,.

o
Figure 1-10

// 0 L/

n
of oil

o
-:

3.

1 .he In,":o1 mult,pIe lirs! pIIl"'"t agc5. ..~ A .... 1 i. ... immunily. Also. boo!;ters ure usa! if a pallenl i,
lion schrdulc
Of

i~_

"".,..........
aurlace prole ...

pcaed 10) 1LI,'e mn up<J5ed 10), .,.~n (e., .. IeW1U<I 4 . A rood",i"iJ,urd "lUi", IS po'i~lblc only if one ;:;;;;~ ...

noc
~,

interf~
~

";th anocltc:r.

Then:

, .. 0 phpicaJ

f~

of v:occi..."

InMIt pIatmod .., E ooIi

Grow in batch aAllft

Prep.JfolltlOfl

- .. ~

. . ;

.... Iuuan or a ~u-,pcm;;on Qf the V:t(.'C.ne o n the ~uoon or in an

I!f\9lneered Ab

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,,,', ""

~tiul PrirJdples of Vaccines. As ~xJX"cted lor a li,'~ booioglCal prepamtioo. he:st dc:SU"Oy<; 11,'1' ,iml :md

.=

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\ is

atch

~n'

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_ man

k\mJ.1 ...ccmes. If !he agent IS no! J,; illed. the arlllgen nt.ly bI:: IIltemi. LII,e many biologicals. Iyoph ililctl \'lII:Cines an: _Ut 1t pllc:r rQIlsliIulion. Ice cry~tab funTled ,nsi(k !he .... j:II'IUlD structure d uring fruze-drylng ellpand dunng thlawIII JlId di'rupt lhe structure of the "lICcille. Li,'e ~lICcilli.'S an bI: inJCli~mcd by mi nute amount , of detcrgenl. Deter 1m! residue ad hering to glllSSW:lrc is COllccl1t nutd enough to Il1llS a di~tn fa.1ant It is safe to u..:c oltly plu~tic Implements Iplfied for the YllCcinc. TIle suspcllding mediulll may be 11m\c "'':ller, 'Wh ile, or more compkx 'y'lertlS containing proItIn or OIlier oonstitlH'nts den"ed fmm the mc:dium in .bod! lhe' vaccillC is produced (e.g., -"Crulll proICLOS. egg and cc:1I cullure-deril'ed anuj;Cns). Conccnlraled All 5IlspcnSJons (r-globu lins) are typical amphiphilic prolI:Ia> and aggregate OIl stor-"!.'i:. If IIlJCCled, the pantcula.es l1li) eaulIC anaphylallis . Prc.Wrl'Dli1es ma} be components '<IIOC.IlC'lO, antitoll in5. and globuli n~ . Thc.'Ie c:omp,ments an: pmtnllO IIlhlbil or prel'ent bacterial growth in I"irdl cultures It dle final produCl or 1 stabililc the alii igell~ or antibodies. 0 AIk-rSic reactions can (),;cur if the rl"Cipiclll is I>Cnsi tivc 10 <wllfthe:e additil'cs (e.g . mcrcurial compounds Ilhilner()1iI~ phcnol~. albumin. glycine. or neomycin).

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$I(I(lge and Handling of Immunoblo/ogical1. Fall..: 10 rollow the ellact rccommendauOlls ror ~Ioroge and ....ml of ImmunobioioglCais call leat! to an mlpotent ~1I01l. Dunng recorIStlluling. stonng, and handling of _aob~icals. !he most Important recollllncooalloo is 10 follow the package inS<"fl e~xtly. Va..-cillC~ should alway~ bI:: ~ at their recommended lcmpetlliure. Cenuin ' X ~ \.IICh as polio vllL-cinc . are ''nsn il'C 1 illCrea.~ tem0 pmture OIher vaccines. such as oral polio ~accine, diphthe'"' and tetDIlu5 IOllOids, and lK:cllul;lr PC rl U~'" ~!lCcine, .1111' K vaccine . intluenl~ vllCcioc. mKl Hih cOIIJugatc IK"Clrit "1I b-CV) (nmong others), arc sensi ti ve to fn.!Cljng.

2-da) IIlcuoolioo penod. Tbe disease may be de"astau",:md can lead to prteUIlK)OIII.. Without the 1:w.-ci lM.'. mtluenla I, commoo m cptdenllcs and pandemics. To clarify, lheft...) ;I GI i"fet,.1ion ,,i lh di:" Thea and I oOlillng. Influcn7.a requ"'c,, wcek.~ of incubalion. I nnucnl;l is caused by III 0 m:im genetlc Slrains coch year (A and 8 ): type A .s 1110<>1 COll1l1lO11 In humans; type B is lcSlo comnMKl. The virus mutatc, ,"cry mpldly, alld ~lICcillC~ must be tai lored ycarly. The World Health Organil.ullon (W HO) and the CCll lers for Di sca!;C Control and I'rcI'Clltion (CDC) monitor lhe migration of lhe disease: from Soolhcast A<ill. lYpe the ~tnnll~ causm!: lhe occum:rlCt'.~. pnd onkr a \I1ICcille 10 coonter lhe OI"gIUliSms nlOf<t ilkely tocnla-the Unlk'd Silltes. Innucnza A liruscsarr calegori7.rd accordmg to two cell surf!lCC protcm anllgt"n,,: hcnlaj!glullmn ( II ) alld llCuraminidase (N). F..och of these IS dJlided further inlosubtypts ( H I. 112: NI. N2).lnd"KlIQI stnuns .... lIhm a wbt)PC are named for the !ocauon, l'>OIatlOO SonjUCIll"e number. and ycar of isol3tion (c.g., Al8cijll1gf'J 90 IH IN Ill. For c:lIlinple. the: W HO-n:cOlI1lIM.'ndc:d formula for 2001 to 2002 meluded the followi ng auugcns: AlNew Caletionilll20199 nUNI ). AlMoscowllOl99 (H3N2), B/S ichuan/3791'J9. 15 J'g euch pcr 0.5 mL. A typical ~lICdne be a milllure of thrt' .. ~Irains. Slrains are wlCCICd ~lI.Ch year in lhe spring onlhe basi" of the d,'oCa..'IC trends ~I"I-cd and are n:lcll.'\ctI in too autumn. In generdJ. t~ palicnts "'00 are al high ri,J,; for complications from intltK'nza are

.... m

I'c-Noru. 6S )e..s o f . ()I" okkr IksJdc:nl< 0( nun-lnl ~ and other chronil;~ fllC,lillO tlw houo;e persotU (,If ""y .u .. 110 ehronlf; medICal oondi-

VIr.1 V_dne.u
SMAll POX VACCINE (DRYVAX)
Illcdne IS hIe 'YHXi",,, (OO""POll) ~lruS grown on lit! \l.m of a boviAl' calf. Smallpo' is D h'&hly lethal and lpnn, dio;cll!l(' thlat "'''lIS c:ommon throughout hiStory. )mIlpo' 1'1ICC11lC was used 1UlJ1IAl'ly in the Unncd Sillies '" lCIIby I~ no 1000gcr recommended. (There h.a\"e been no lplltJ calb of !illIalipox sHlec the: I 940s.) In 1982, small"" ""1'1 tltdared erndiclllcd worldllide. Wil h smallpoll. the 0( the: V1lCCIlIC outweigh t he bellcfit~: the vacdne pellenItS tile central nervol'" systcm lind pDlcllIially futnl en~ill$ OCCUN in I in 10' palicnt s. After ~xposu re to _lIpcn.lhe: ~!lCcinc can be injectcd to leSj,Cn the M:~cril y .tlbc dlo;ea.o;c.
IIfLIJ(NZA VACCINE'), 'ot. 's. ,., "
5u11po~

Adultl and children .. 110 Ita> e chrome dl~r'" o(!he pullllon;uy ()I" cmrdlOl'1l>I:ul;..- systems. 1I.:ludln,lISthma i\dulU and chlldren ... OO Ita>e ""lUIn:d medICal fol l",, -up or ho!;piluti/.auOII dunng the preccding y..at b- uo;e 0( chronic .. ll1e:moolic d,,,,,II.'<CS (including d;abe'~ melll1u~). n:nal dy . l"ulICtlOO. henlOllloblnopa.h,c>. '>r irnmulM>!Ouppn:s.'_ (lIlclud 1111 immuOOfouppn:~~ion ~uscd by nktll~al,,)11~ or IllV infection) Children and tn.... \age<! 6 momh~'o 18 y~ar')) ",110 an: m:"" Ing ion&-Ic:rm aspinn u..npy and. lhcn:f<n. ""&h' be III rid. fOl" dcl'dopinl Ite)...~ ')'1IdronE aft .... Influm:r,.l infecllOft
Women ",110 ...
IWOC)'

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pre,-

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r. Mulu-

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dunllJ .be Innum:ra ""'....... lIellhh care ~ and tho6c .n cl"'" oonlaCt ","h pcDORl> :ill hl&h n!>l.. Indudl", houw:hoId mcrnbcn Uousrhold n-.c:mbcn. (,,,,,Iudlll, cluldten) of pcnMS ,n aruuP" at !ugh "'~. Inc!ud,nll pc ......... "uh pulnlllOlU")' d,~ such as a<thma. ano.l health t= ..-""'en "'00 lIR at hlgho:r ,,~k hccau'oC of clll'C Cllnlact
It is illlpl)"sibk 10 contract IIIfluen'... from the: ~!lCeine.

A,

boht~r

n Of ~u ~ nus).
;inc ~
XI' " "

The only sid.: effI.'C:1S may be local pain lind tcndernes~ at the llljection sit.... with low-grode fever m 3 to 5'1 ofp;:ttlCnts..
Aspirin and II(!(:taminopOcn are effecli l c in COnlbilllOg tht-l;r sympl.Nns. Allergic reactions are ron: bul OIay be seen In prn.ort'S alkrglc 10 eggs. Inmlllnity 10 innuentD. l'accUlC t:t~cs 2 wks 1 devclop. Some prople fear the vaccine becllU~ 0 lIf reports o f . Stnlnge p.mIl} ~is and lack of 1Ie""C ;.ensaliOll a~SlX:iatcd wllh the 1976 sw illC' 11u V3CCIIIC. TIus ]lfQblem GUlllllm-lJarR s)'ndl'Olne. II"1IS us>oeiated only lI'itllthl~ 1976 ~acrmc and ha, JIOI hcc'n associaled wilh I'acc ines .~inee."

, "'IIKOU'
'QitN" " IM~ L,"'"

cne\PUbe m:Ltn,

""""""

...~ .-acr'Al" S I multivalenl Inoch ~Dlcd mfluenza viru s 'IInl wbunlts (splil Iaccinc). The virus 's grD'" n 00 chick MId II1iICtI"8Ied by "'llpown: 1 IIl1rJ~iolet (UV) IJgh. 0 lmnaIdehyde. The antigen typo: i, protein. The vaccinek Untied SillIes contains thimcll.:lSlll. a mercurial. as II ;teoef\"II"~. ltif/llt!JI::JJ is a respiraloty tracl mfcelion with a

POUO VACCINES"-:IO Pulio h a dangcll)llS vinal infection that affects both nluS( le nuss lind the ~rinal cord. Some children and adulls ...Iio cun lr~ct polio hccome pamlyt.ed. and some may die dUI! to =pmuory pamlysis. Polio was the ~auso: of the "inf"nti le parul)'~I~" epidemic of 1950 to 19.n ..... lIitll led to many paralyzed children and the specter of p;ltie!l t ~ spending thc:ir lives in an iron Iling. Serious ~ase~ o f polio callsc muscle pain and may make IDO\"C:menl of the legs anOlor arms difficult or impossible ~nd. ~s Mated abo'e. may make bn::uhmg difficult Milder cases last a few days and may cause fevcr. sorr throot. headache:. and nausea. Interest in polio has in creli5ed because of rCn\ kx'.iI outbreaks; large numbers of people an: unim muni7.ed. TIlere un: no drugs or special therapies to cure pol io; Itl:atment is only Mlpportil'e. Th.e s)' mp:oms of pol io m~y I"('appear 4(1 to 50 }em aner a sc>'en: infcct, on. Thi s phenomenon is known as pmtpolio muscle atrophy (PPM A). PPMA i~ oot a rein fection or reactivation of the virus but I~ prob;lbl y a fonn of rapid agi ng m polio su ..... hors. There are t ... o types of polio v1lC"Cmes. Inactivated Polio Vacci". (IPV). Thcreare severnl 5ynOII}'ms for the IPV "accine: IPV , e- IPV. e p-IPV. and the Sal ~ vaccine (l9~4 [I POL. Alcnus- Pastellr l). e- l rV is an enhanced potency poliov irus. ITIOf"e potent and immuoogenic than any of the previous IPV formulations. eI PV is ,ecommended for all four infant doses because of lhe incidence of rare CIIS('S of orul pol io vlICeine (Or V)-as...ociated paralytic POhOnl)'ditis. el r V i~ also preferred for adults for the '>ame rea!iO!l. IPV is a tri valent (,troins I. 2. 3) voecine gro...n in monkey kidney cu ltu re and subjected to elaborate preCllutiom; to en'illre inactivation (typicall y, f0ll11aldeil yde is used). llll' anllgen fonn is .... hoIe virus. 111e anugen type is protci n. The v1lC"CUlC is IllJCCted to CIlUse Induction of IICti ve systemic immllnity from p<>Iio 001 does not Stop polio cafriers. "'00 shed lhe virus from lhe om! and nasal cavitie!>.

'The WHO ha~ OOHlCalW 11"'1011 ch,ld",n e. IPV ,nsrclld II TOI'V to pre>~nt e'"IO"II'" of othclll III "int, jI\ed Ihroop, Ibo _ and mouth..:!t '" RUBElLA VACCINE}'

German measles is a diseaJ.c: that WllS OIlCC called the ':kby

measles" and was considered a nornml chi ldhood iIlne. 1 1 is a mild d i.;ca.'>C with few ~on<;eqllences. C.II.t"Crt in the IiI1l trirnc<'ter of pregnancy. In these Il1OIhefoo;. ruhella cause.. hinh defects in SO% of case.. Defects may include heart di~aloC, dcafl1oC~s. blindn~". learning disordcno. and sponlpneous abortion of the fet liS. Symplom~ of rubella are a Io.... -goo fel'cr. swol len neck gland.~. :md a 1'ItSh that laSis for about J day s. About I of evcry 1 .... omen of childbearing age to the 0 United State!; is not prOlectt'd against rubella. Also. 200 of all adulLS eseaped tlli~ normal childhood di'lCa"C or 11ft IlI.X vaccin3ted. Rubellil vaccine (Gcnn1ln measles ... ~~"Cinc. h ... ~. MerlJlu II. Merck) is 11 li,c. allenualoo rubell~ virus produced ID human diploid cell cu lture. lllc lUIligen form o f tile vllCcinr is .... hol~ virus. TIIC antillen t)pe i., protein. The vaccine ~ administered as pan of the norm1l1 itn rnllni;:.ation schedule at IS months. Side e!Tccls an: minImal. but there may bE some soreness and pain at the site of inj.--etion and SlilTntloS of the joint ~. A prob lem with the vaccine is Illal lKIminlqration of I Ih 'e virus is contraindicaled in pR'gnancy. Indic.Ill.i(lll$lJ"f Pt:rsotiS aged 12 momhllO pulxl1y ~hould Ix IInnlUnil.,W fill lIncly. Pn:"iously llrummun,zed ct"l~ or MlscqJI,bIe (Re....o"lI"n ~hould n:o:l~e the MMR VK<:,ne. The t",.I<:1II n< <me is ptc:fem:d for pcl"SOlU tikely to he: ~uSIXIII,blc: to mump and rubc:lla. Immunil.alion of suscepl.bIe I\OIlfIRlJWlI adolc COll .... WOmrn of dll tdhc:ari~g porential I! c~lkd f if preclUtlON 1\1 a"okl preGnane) are ob!.c ...ed. Almoll att dliklrm and _ adult, requ.re man: th:an _ dole of MMR VKd"". Or! lhe firs! rourmc vi~jt to the obstetrieianu!lCCOloK'"- III! immune ~tus ~hoold be eh~cd. If the ...OIIUIn IJ noI im_ mlW 18.t.1nSl ruhc:11a. lhe phy~lCian u.ould Idrmp,srcr W '31:' cine and SIn::.s .,"Otdll'i pre,nancy for J monlh!l. If ,he pallCllI ,~ . 1 ",aJy Pft'gn~nt . lhe: phYSICian ~Id IlOl oominisccr the ,-..::cine. tf uposlIlt' i.- lll.\prCtni. II\( coN blood.lbould M montlmll f W pn::sttICC of rubell3 antibodiao. o AU ~tllmmuni'4I "'omen Jhoold be vlOCCinalel.l ,mnled,~~ . fln deli>'cry of tbe baby MEASLES VACCIN E (AnE NUVAX. MERCK)} ' M easles is a "cry ~rioo~. highly eontagious disease. It causes a high re'er. rash. and a cough laSiing I to 2 .... eeu. Some pali c:nts cxperience ~x t re nle sensitivity to light. Tht rash may occur inside the eyelids. producing 11 very painful condition. In the United Stales. bet .... ecn 3.000 and 28.!XXI ca.'iC!i occur each )Cat. depending on factor.> such as ...eltbn and loc alized oulbreaks. Ou tbreuks are vcry eom mon I! neighborhoods lind schools. One of 10 ehildR.'n contractl~ measles will de\'elop an ~ar infection Of pneumonia. Measb mlly infcct the bnun (eoccphali tis) and lead to cunvu ls.ton$. hearing I~. and Illental di5.abil ity. In the United Statb-l of every SOO to 10.000 chi ldren controcting mea.~les dies

Trivalent Oral Polio Vaccine (TOPV). rol'V (Sabin Iaccine. 19(0) ,s a Ih'c altcnnated whole virus vaccine (lntigen type. proIein) eoolilining polio straios I. 2. and J. The virus culture is grown o n monkey kidney t i~sue witll lise of an elabor.lle allenllatioo proIocol. Oml adminisu1I.tioo of the "acclne yields I local G I infectIOn. and the initial Immune response is via lilA (mueosal. local to the GI tract). llIe Ig A- ant igen complex undergoes tmnSCytosi~ IICrob the mllmsaJ memoone. and sy~temie immun ity is induced as IgM and IgG form . A nlajor caution with TOPV is tllat it is a li ve val."(;inc und mu st never be injcct~'d . Ind icatioll~ an:
o Mas. >7IfXmauon eampail'lS to control OUtbn:w of pual}11C polio. o Cn"lICI;"inalW chi~n ... hoc) will tra~cI in k)~ th;In 4 ...IIC~' 10 arelIII ... ""re polio ... enderruc. o Ch,ldrm of ~nts "'00 00 not aooepI tM rn:om!llC"Oded IlIImbc:r of vattmc: injecuon!. 11lesc children may ."o",e OPV only for lhe Ihull or fourth do!io: or both. In ~uch caC$. the b:'ahll ~ pnwillo" .w-.ould .mun'Sier OPV only after IitSCIIS~ nll !he ri.\k of OPV_ IL'l.WJC,atl,d p;lnIl)tlC poIiomydlll' ... ,th paretlt~ or curellJvcrs. t- IPV it m;(Nnnoen<ied for rouune uo;e in 011 fOOf immum,jng oo..c.. in inf""lS IIJd ch,klmI.

,,'"

J .,

and death are more COIllI1l(M1 in ".0IIId .lullli tb.:m in elellX'nlllJ}' schoolc hild ren or lten~ Maos~ bas been Jinkt'dlo multiple sc leros is. In 1917. ICme epilkmlC occurrW in tnc: United Stales. and 50,000 "0\' rtpJrIw. Only 60% of tile popu laliun was Yace;
II.

.x.-m: ~Klneu

vaoxinc is romposcd or live!:luenlWW meask~ . . I) grown on chick embryo culture with an auenun

Ino:llcatiQns are

~,,1IIdU:'bOn of lIC't,ve munum.), IIj!lllnlll. mc~1n ~'"'~.

Caution. Mumps ,occine I~ supplied l'.i,11 II dilllt:nt. Use only thi~ dtluenl for reconstitution. Addition of a di luent wilh an ~nt i microbi~1 presen.'ative can fender Ihe vaccil1e inactivc. 1lIe vlICdl1e is normally administered 10 children a1 1.'1 month ) of age and again DI I I to 12 ycars. Bccau<oC' mumps vlCdne is c ultivated in cgg mcdium, can' used to be advi'\Cd m patients allergic to ellg' and egg prodocts.. Recent data show that pC'fSOfIS .... 00 are allergic to egg and egg products fail to react to the mumps vaccine.
COMBINATION PRODUCTS (POlYVAlENT VIRAL VACCI NES)

i,tllt I'rdel1l'd immuomng form for _ d1aldron and o,:my aduhi. AI_ .U chiOJllCn ~nd many !ldulls ~ui~ moll: than one M..t \LI,JR. f'rg 10 lOItiioatMJol;lllrl~l. prnons ,u'lCel'l.lblo: 10 _n y 0( the ,. .. ,..., Poiold ~Ive tM l ingle-anl'gen ,'XC'IIC OI'.he

. 1~ ...I... MMR '~I~

\Ii>II paM*> bam bd.n 1956 arc Iolel) 10 ~o:d ..-.II)' lind an: IlOl ronsldemi JU~p"ble fb . . to:n afIer 19:16 0I'th!Ke ,,110 tack ~ua!e donImcn,j 1u"o,1ud the dl'C'ase 5hou ld Ix: Va<'C,"D~.

_+

~ . . ."XCI..... ~.

Ita,"

TIlt \'ac\:I!Ie is required by l aw Qt 15 months and uguin II w 12 lta/'S of age. 'The voccine can be admini~lered

measles 10 lessen Inc: disca!ie severit)'. This

vaccIne de,'clops in 7 days, ..... hilt the the di~ is I I days. 1lIe vaocUlC In pregnancy and shou ld always peat care 10 women of childbeanng Ba:1IU'IC masll':S ' IICCU1e i.~ culti vated in egg med,um. ,,,,," IIsnl III p;lucm~ who arc: allergic to eggs 1I1K! JWOO.Iucb. For thi~ reason, II test dose rc:gime n is used. protocol is shown beluw in Table 76.

If 11"0 or more vaccines arc fn.'e uf interfefCnce with l'ach mller. !hey can be admini~tered a.~ a mixture (polyvalent) for colwcnieroce. Eurnplcs of palpalcnt vl11l1 'llCCine~ are measks-rubella ( MR). rubella-mumps (RM), lUld mea sles-mum ~- ru bena (MMR ). MMR I~ Indicated for routine imrnunll.3tlon al 15 months (110( givcn at less than I year unless Ihe chlid hIlS been e!{po$Cd or lack~ immunocompe tence). Thlt is because maternal Abis intcrfere wllh dl',dop' ment of vllCc inc immuni ly in snI:llI chi ldn: n. I f the MM R is givell lit I e.~s th llli I ycar. revaccination is needed al 1.'1 months of agl'.
CHICkENPOX VACCINE l~-n

; ;".,.,,;;,00

""""""=
~, 1l1Jlrlrup!11lk.

headacnc. and a painful ~I'.ellmi . Mumps CM be SCtiOUll I"nor to the vaccine. !he di5C:II)IC 1 ch Ild .... ilh case. The disease nUl) 0 Bet ween 4.500 and 13,000 cases in the Uni ted Stut e..\ e,cry couse innammalion of cord (meningitis); thl ~ ptf"SQns. Swelling of the Men may c~ptric:nce . which may pres a corrc$ponding infecoften sic ker than OIhc:r ~~ , ~ in childhood IllIS been i I . di:lbete.~. 1 isalivc.anenu i embryo culture wilh attenuation form is whole virus. The antigl'n type
ICh~e

Ch.denpoJ{ IS caused by varicella1.QSter \"!IUS. E~Cf)' yl'lll". about 3..'1 milllOl1 people in !he Umted Stales. ITlOIiIly chil o dren. contract chlCl.enpo~. The incidl'occ peaks bet ..... een 3 lind 9 yl'DI'S of age. Chickcnpox C1lU <;('$ a geJlCml ir.cd Tll.'ih. with 300 1 .'100 bli sterlike lesions oc~-urrinG on the sca lp. 0 fllCC. and trunk. Symptoms include loss of appeli tc. malai se. and headacI"M:. The dio;easc is usu ally benign but can lead to bacterial "Uperinftion. pneumonia. cnceph:tliu5.. and Reyc's syndrome. About 50 to 100 piC"lOUsly hea lthy ehil dren dic of tnc dIsease:. Abou12'k of all casesoccurm adull.S . who havc more scriOu~ ~ymptoms than ch,kln:n ha"l' . Vruiccll~ ,accinc (Varhax. Mcn:k) i~ deri\ed from Ii\e virus from a chi ld Wilh natuml \'ancello. The: virus has been altcnuatoo by pas.uge through II scrie,~ of guinell pig and hum~n cell cu ltu res. The final prcpardtiofl is :I lyophilized live. altenumcd virus. 1lte antigen form is II-holc virus. 1lIe antigen type is protein. "The vaccine is wc ll toleraled. II-ith pain and miTll:SS ~t the injection silc liS the on ly side effects. The '"llCCinc ha~ shown ~mendous SlICttSlI in n:ducing in fections. Illdication, are
The: 'IO.'CIIlC: Iii I'"Ommelllkd f()l" ch,ldfC'1I 12 nlOlllh.lc 10 12 ~ old .! a <Ingle dose: Adull,; ",1>0 ron: uposoJ to ~hlC ~ enp<lA .hould conllnl>Cl to """eh e vlricCU.I.."lcr immune ,Iobulln (VZIG). In eklcrly ~rson~. vlII"icell~ vactlllC: can boc:JM Immllnny to varicellaro>ter 'I!'US and ..... y pre,tnt or attcnuate herpes lOS""'" (~,ngb) IIIlXh.

m IfUflC"WOlty KqU,m1

Immumty

.,~'nSl

HEPATInS VACO NES-

-....riouJ Invcl. ,mmum1~ lOy suscepl1b1c: mdlHd . . _11lo die IoInlk:lnug.n ...,."ioe or the tn,ultnl MMR

Hepatitis i.~ a comple:< of diseases that causes fe' cr. naw;ca, abdomillal pain. jau ndlcc. liver faillln:. and tk'ath. lben: an: fi vc clinically 1Cl;0gnized lype' (A, 8 . C, O. and E) .

IhI dut.Jrrn and loOlIIe adults nd

!I1OI"e

than

()fie

00sc,

of

Hepa t itis A Vaiflf!. Hepatnis A virus (HAV; IO feetious hcpaUtl~) cauSoQ an acute d, sea.<oe wit h un abnop: onset.

212

11'11.1..", (UUJ

GiJ,"'II'~ T~xllJ.tJd

of Organic Melli~"",1 ,,,,II N""7tuJa~liclJl CIw;mislry

TABLE 1-6 Reoommended Childhood Immunization Sdledule--United States January to DtKember 2000

I d

A ..
Vaecine

,
~

,
~,

~,

... .' ...

J' b

'1 - 12

,
q

" ,o

"

Ii,

h'

om

P'

==>
_

\,,,,,,,, ... '" be Ji ... if IW'"iowIy ' ... Roo ... , ''II io . . , _ ....... _ _

~_o( ' '''

.. ,.'c ...' ..... 1"'....,,"";.._ 00.,..

00-

_<fa _

........

1qI"",""

II""" _~ _..., """'" d...,..........

00 0: ......, n. Im.!Ioo: A<I<-,. Comoniol ... ' ''''''''00'''''' 1'n<:I"'" (Aell'l ...,....- ...... R" ...Judd I".,.,.. _.""" '.o<c "' ......-.!rno (RMVT\I.I II< ooI! u.s. ~oed _ _ .....",'... "" ......... be ..... In .... ,, _ _ IM'III'R. V<>I. -<l. No, ~ J. NQ"".,., 6. 1'199) _ >I00>.0I0I10< f<H_ ..... , Md."" ...... , .. ,,"" "".""" '><C>"" Iocr- Jory 1_ ... "'" _ 1""""""" ,,<I; r... """"""1"_
"lloi. indicooc< ,"" ~ .... Ior """,.. oojrru ........ _ oll~<,"o <1111# >0<1 "-..... olli"",- I. 1'1911. Aoy _ d ... p ...... "" . - . >1000101 be (I,....... "<>oo<h-"l'_y" t,~ iw' .. """ .....,... .... Ie"""" Adotoo_ ' - - ' ...~ 10< l""""l ... , , , ' d oIori"' .... )'dO" I ' I 0ll0IlIl;' ... _ _ _ _ "'1 "" ..... """"...." ""1"""i" , .. ol"" . . -....... "'" I~ _ .....xo:i ... .oohcf ~ ",h .... ","""I.",,,",,' .............. lor dcwkd rcrommcndol ..... ' Int.......... ,. ,,",po.I,I. " ............. '1 ..... (HIIooAlJ-_''-' ........... "-101 "".,," "" lit" ..... ol .........'. 6 _ _ (lkp 11 11')' ... 2 _ Tbo _ _ _ ll<ooIo d, ,ocI ........ 1 ....... oII..r .... r"" _ . _ ...... _ ......1.11><-........... g,,4 oroontIt!.a/l<f .... r _ ........... ! -nl _ .........01_..... .... !xlarc ... 6 _ _ ,.r... " '-" '" 1l 1ll.Aa-,..I~ _"" ... ,.,. .. 101 "" ..... Hop 8 .... /U .... ...,.... .. " (ltBIG, a.h,. I: """" o l _ .......... no. _ _ .. ~ ..... I-I ........... """ "" ...w oI<rO< . . . 6.......w . l..n.n.......... '" _""" . _ 11"\. _ ... h ~ ............... Id lKC'vrli<fl B __ 11 """'"' ,.r .... h. M>l<rnAl bI<"'; "",.. Id "" .n.... ",I ...,. 00 _ ... "'" """,,', 116 .... , ....... ir .... 1l1l.o.AJ. _ i, f _ _ ~." IlHIO .. _ . ...,.....,..'00 ...... _ . I _ k) AA<hlld ......... '1 .... (tIo""'til ... II)' ..... ) ,,"""""' ... """ _ _ _ n,,"""""" 8...,. ""I'" "" I""' ...... .too.foj nI>kt ..,.... oil"" ... , _ _ , holdfro .. .., .... buoo in Of " ' ' ' ' - ' ' ' '"='"",.. '" _ 0( .... "'""'" ....... "'''~'' D .M Wenloo ;. ,,. I tal).

_1<

va<'<''"'*''

...

"""1_"" _ ...

__ ...."...... __

oh,

,_,Iotoul..

H,

J"l''''''. "'" ..

_oloonq.,_
'"

'" di,
,r

hi~

..".... , Im~

....... ,~ _ _ ""',hilJi, .... ; .. ,~"'_ ..... 1.1--11_ T_ _ t;p"' .......... Oldo.{T~) ... ...,,,~,,., . . J .... 11 1!)'eoW' If.a.U~_~_ "'" IooJ """'"t doJkheri> ..... ~. """"" ...........", """,ino 1D11'~ DfiI'. or Joplotl>eri.s _ ....... (un, S, ....... ' -.. ..".,;"" Td... " ..., 't<' I ..... 10 ".,.... on.... 1I_"w'''' JoJI_ 'YP< b (11010) _ _ . _....... I~ r... ;"f...... If 11'" """JUPIO """',,.. (I'RP-'lMP) ( _...1118 Dr C","V.. IJ.I<t<kll1o I 0<n>J .. . . 2 . ... "' ...... .......tH . 0100< ..... 6 onoooh> ;, ... '""'-.t. _ ..... ,1iakOO ",'1 10 .. I.... "" ... "" ,",_I ... o.j .. dw. """.., ""'_.. "" " .... IO .... II;!> .--:""' ~ DoM1hb com!>o_ po<io<o .t...IJ "'" 1><....., for pr'''''''Y __ , _ ; " int..., .. _2.~. 6 ,m . . . . . ..... G,od I')' "" Food ..... I>r"& ..... ~ (or ""'" "",. "To<li_ ""' .... f.... ponoI)1i< po:>iom~ . .. (V API'~ _ pol .... "", ."" .... ( IPV) _1< .. ,.,... ....... ,,,, "~ ('" """''''''' I polio ,.""". . _ ...... L"n,1Cd s...... AII<Io<,""" _01 IPV ...... : _ _ ... . " .. ,..... """"" _ 6 ood It .....,.., """ bet....... _ ..... , ,.,..,.. 00>01 poIlu. .... , _ _ (OPV) (il ....1.oIlIe 1 ...~ ... ow:ol ""*1 1..- "" 101 ...... ,"11 """,ill! ~ I) ....... ~ .... r .~ ",awruI"'1 ....... 1"""Il'" '"' 100; !) .... ___ 001 duldmo .. """;11 be In,,,l,''II;''"'' _ '0 ............ po:>lO;' _ _ '" q , I "uk ..... J) 01 _ ... ... 010 ... oewpt ,10< ,"'....... 10'_ Mol: ........ r""'" (.10,_ 01 ..."", """ <10 ..... ""<fI' .... ",," .. 'c ,"d _ ol..-"" "',....""" rnoy """'.. OPV ",,11 f", .... 11>"" ... - . . otoo.. ... _ . .... _ _ _ b..,.." """",,,, """"" """" ........ OPV .... ~ .1In ""'""""" .... oW. "" VAPP _-.do ..............,........ 000ri"II ............;"" "' .. all. IPV .<1 ..,' ' M ... fo< ....... 0( " .. ,.,.;"11 OI'v "'rpti<. io pIl)''''' ...... ~ Md .b""" """" """ ........ 1')' "'" A_ _ my 01: 1'1,",""" IP"'-"". V<>I II)<. ~ U~

"',h!y -"'. ol d,pIoe","" - ' """"" "',""" ... ""'''''"'1'<'''''''' ......,.... ( lIToi') ....... ado,""'_".-I) ..... 1~ _ . , . . , . . . _ fi _ ' " 100., ~_ on.. I""""'''''''
"".-.i...

hCI

d<_ "'" ____. . . .

'" am
W" ilia
,10
hos

"

_,..,."""""-.1 _..ui"" ("'"

oIl.""""'_

..

h",

<110_

bin i nil

Vir.

..

--

"The _ _ ...... 0( _0<1 ..., ,-...... n.otoell......... I MM~ );" ,..,., JocI .... ,... y ...... 4r<!t".,.... ""'...,. .....hrloI_ ........ ...,. okio, p od ...... _ ' "",*, llo ... ,'-<I "".. "".,,. ol tho r"" <be _ ..... _ _ . . . (If _ . . . I: _"" TlJ:oo< " ... P""1oootb ..,,'" ................ ...... ..... _ "_.,''' .... Kt DO ...... _ .... _,"'" "'~ IO. ".. Jrh ,M """;..,,- . . . . 11-12 )'nD. "V....."Io(V.) _ _ 4 1 .;." ... ...... "'" r",. _11", "'ocqtO;l>Iecloi ........ to .. _ ........... " ....... ~o(d"d I " "".. "' ...... ,"''',i.Irr) _ ....... .., "'" ...... ,.""' _ _ _ <;101>1<,."....... "C"<i ,. IJ 1"..........1d _ .. ,..., - . 11_" ...... - . _ . "'I .,. A ....... {I"" A) .. """ _ _ ~. "" ,n ..1"'" """"..t ,, _ _101"'.... _ i ,. ,,,,,,",, lrom IoaI p<JI>Io< "'alII> /0110111'11. V<>I.4t No. ... 12,0<""", I. 1m

;,.,0<,.,.,......

-,I<

_Im,.,_ ...........

sm

(-JwoIf<d,,'

-.m.,. .....

" I dc:h full

feet

Lot of tn<k --..-. ...

,,,,,,on<1OI _

fo< ..... ,r..."'" only ~ ~ ... - . . '... Dr ,..... ~ _ " " " " " I:oyOJC '" "'" U 5

r.><pon ...... o l _ .... 11 _ _

U H~

"'.

roc

ri ~ 1..

or II

denl men

.\bouI 15 to 50 tbys of IIlcubal ion art: l'e(luired befon:. lhe ih::U: ~ clinically no;:a:ablc. The primary S:ln is ~. 'The disease la..15 ~\'(' ral wce l.:s and is followcd II) romple;e reco\'ery. I lcpa\lti ~ A IS trnnsmiued ",hen the liM i~ ;aken in by mou;lI. 1lle fccalornl roulC and close ,.",,-'\. unwao.hed food. and CQIllaminaled \\'lIter QCCount for IIJIII of the routt, of transmission. The 5C~ual anaJ-ora1route .. aI'iO mu;c of SJlll:*', Children under the age. of ) fre qoemly !lavc no s),mptoms but can tronsmit the: d i-e ase to ...J" in child can: centers. An injtCt;on of hepal iti ~ Aim_ ' _ z\OOu hn 1\ OI'IC way of prc:vemll1i\ the disease but IS OIl) effcai,c for about JO da)'s_ The hrp.:it"I S A vaccine (H o' rix ) is un inllCtivated preparll ' tII)a. ;ha1 is produced by propagation of the virus in cullllred -.nan diploid ce lls and then is inacti~uled with formali n_ TIIt<lllligc:n form ,~ J)'!ied ",hole viTU5ol'!l_The antigen t)' pe is pmlriPl. The cwrse of immuni/.lltioo involves IW injtlOfls O O'ICf . .... "'OI:~ period and ~ booster 12 mon lhs after;he first IojtClion. IrKlkalioli S an:
'",,-clin, OUlSido: lhe: UnLlo.! SID~. ucqlI'o Ausu. "" Dnad&. Jap;m. N<:w 7.l1li1300. and Wei,em Europe ~ .... "b ch,,",ic I,,"t'f d,sc.. -.e ~ Imng in ~n oot,,",ak lQIIC: Pmoo; ....110 InjKI malicilions Pu... (npl,nl 'n h,aJ;--m1. .."..1,111 acto"t)' Chrld ~ .,Men cannll for child..,n Ie~ ""'" 2 y(M) of
~

",hcther a pallent is 31 hIgh risk vlICCine are tnmor.

not . Side cffecls of lho:

, _ \.::2LL it

:;

-----,....... ... . 1".....1....

'.

o.,. lopinjl coonui"" ""th f'OU< $IInl""lOn

..

Hepa t itis C Vaccine. l1cpallti, C viru, (HCV) was once ca lled hepatiti ~ non-A. non- I} but has been ret'Oj;ni/t.'<i a~ a sepant.c rnlll)'. HCV infCChOll i~ \pn:ad pomanl) by lhe parenlrr.tl route (lransfusiOlls). and un];~c IIBV. matlmlalfe.al and se.1.uul transmisslon arc Ulleommlln. Acute infection may show few .\ymptom~: fewer thull 25% lof paticlliS develop futl -blo"'n hepatitis. AdmllllSlr1llion of mtcrferon Mlpha (lFN-a) dunn!; !he tarly acute: ph:!.."" C'lUl cure nlOSl palit'llis. Unfl)l'tunmct)'. 50 10 6()q of those v.llh ~ICV Infection develop chronic ltepatili s. 1111\ i, often mamfc,ted b)' periodic incrca_ In hepali e en1)'1ne: levcl-. Cirrho'i~ de\cl'>C.. ops in 2M of chronic infeclC:CS; thi s usuall)' ret!ulre\ 15 10 20 years to develop. Pallents "'"h !lC V are at n<ok for hepa.occtlular eartioon1a. E.~lim~;es are .hat 150.000 to 170.000 new cases occur in the United State., per year. Intravenou. dl\l g u~rs. trunsfu\ion pati ent,. and health care wmcrs are al highest n\~ De\'c lopmcnl ora HCV vaccine: pro,cd diffICUlt but .... as accomplished in 1998. There: arc: 15 genOl ~pC:S. and the virus clln modulate it, IlIltigens \\ithin the h()l>l'~ body. A new appruoch usi ng genetic m:uerial from lhe "I\lSo. analogOlls lo .he appruach lo;he innuen/a ~aceine. is $ai d to be f"'OOl1~lPlg."

Side clf~ts :are mmor and usually hnll ti to SOI\'IM:SS a;

*",8j1.iott Sit e and fe' er.

Htp.ritis B Vaccine.

..-..

--I~

:=~' .......,...
1 .. _ .....

o o o "_ I . <Oft)

-_. -...
_<kl ....
"""~

poBj)'"

r<>

.-. !, ;...,:':.~~:
~

i00i._.
<II II>< __wi

: . <

:..,. .

Ikpalitis B vil\ls ( HBV ), the _ rl serom hepatitis, is a much 1JIOIt insidious. chronic ~~, trallSml1led b)' needles, 1IIU<.-o!;.:I1 contacl. blood. or s~ se.;:ualaclivil),. The highest ri.~k for ~ontructiloll of lqIIbUi R i~ tun..,ng intraH'oous drug abu~f'J. The disease "'00 10 cIrrhosi s and 1;',C1' cancer. There: an: about !lUOO nev. cases Iq)()lti ptr ycar in the Unucd States; tlf'ln(. IIJ'l, hc:colne carricr.;. one fifth dli~ from cirrtMNs. lid 1.000 die from liver calK"Cr. The hepat ili~ B vllCCine flfSl mlrodllCCd in 1981. Inll iall y. il was prepared Wi an M:uvaW vaccine: from the: plasma of c~fully <;crc:cncd . . . lugh-tl ten:arriI'rs andIor donors. In 1986. the !\'ComDNA {rONA ) vaccille (Engeri:>; B. i{ecombivu) was ..... t11 to the market. TIlt rDNA vaccine contain s onl)' lIIilunilS and may be used with hepamis B IInmllne: III in _ po!>lcltposurc: '>eIMg 1 boost the ability 0 lhe 10 TCSiSl the infection. In adults. dm:c doses should be .~'II O. I. and 6 months. In c llildo: n. the vacl.'iroe h give n MIt. I mlollth. and 9 lIIonths. AdPl1in istr~tiO<1 may be ia prtm:uure infants woosc immune systems ate no; *,<eloped. If no; immunized 8t birth. a chi ld should mu e threc: ~~ b)' J 8 monlhs. If the 100her te~t.~ po'illive kp.UJIJS B. the v1lCeine pl u.\ the imnmne globul in must IItp\\'JI at or shonl)' afler binh_The vaccine: IS 95% cffec. . is l),pic:tUy without side cffects.. A number of h,gh' . poops ha,'e been identified; heallh can: \\'mel'll . stuhul;h care \\'oO:ers, people living in high-ri sk cnvlron~.. :and dcnti~l.'i. TIlty ~hould receivc a Ihn:e-dme C Ollrse \'ICCI~. In PIlost Other C:I..'iCS. a phy sician can judge

Hepatitis E. lI epaliti. Ii. \iru.~ (lIEV) caU!its di ..... ase clrnkally ind,stmgui~blc from hepalJlI~ A. Symptoms melude malaisc. ~r1Of'I::o;ia. abdornmal pam. anhn . i,-h ~e s)' mp$Oms, and fever. DiSlingul shmg HEV fmrn II AV muS! be done gellClicall ),. The: lPlCub;tlion period is 2 10 9 wl'Ch. The d:sca..c is usuall) mild and resoh'cs In 2 \\tc:~s. "'"h no sequelae. Thc: 'aull"y rotc,~ 0. 1 10 1'1. c~cepl In pn:gnant wonM:n ",here: the ro;c SOoU'S 10 2()<I.. No OIltbrcal.:s ha"" been reponed in the Unlled Sllltes :IS of 1996, Then: is currentl), no yucci ne against IIEV.
ROTAVlRUS VACCI NE

or

There will StXIn be ~ new rut iWlru~ " UCC IPM: IlICludcd in the Recommended Childhood InllllUniuhort schedule . 111i ~ vaccine is u'led to proHde II'II$IIUnll) again,t rutaviTU~. the 111(.1 com mon ClWSC of sc'ere dran1lca in children in ,he UOlled State,. All chi ldren hJ\'c al teas. one: rotn"ru, infcellun In the firs1 5 yell ..... of life. und Ihere !1ft: about 20 deaths per ytW' in thIS coontry_ Children bel\\Un the agl$ of' and 2~ months age ha\c lhe hlghe\1 rolCS of sc'efC d'loCa-e and h.ospitahullon . The 1'Ot3\'lruS vacelne IS fin OI"J I \uccine. gi\en as II series of ;hree do'l'oC'_ It IS n:conllnendcd Ihat Inc vace ine be: adlllirll ~len:d at 2. 4. and 6 mOlllh~ o f uboe. lbi: most common ~ide dft o;cems to be: fc \er.

0'

Bacterial Vacdnes<ll'....
PERTUSSIS VACCINE

*"

I'l.'nussis. also I.:nov.n as "'hoopong cwgh. " a highly rommunl cablt inftcllOfl caused by 8oml'Il'ilu f1'l'rlU$sir. H. I"'" ,,,,"sir produ.::cs an el1lJOICJ.tln Ihal c au se~ n ~pcetru 111 of symptloms io II h<1s1. I'ertussi, occurs mainl), in chIldren. Dlld there is no dTectl\c treallne:TII once: the diseaoe bc:come:s manifest.

8Qnit'It'lIa endotOXin anacks the Inocheal mucosa and causes

extreme irritaliOll , 111c Inn amm:mlfY ~pon~$ produce lhe chanclaislic " "hooplng in~H'BlIon " associated ..... ith per. tus..,i$. l1M: s.....o llen and ImUlled liioSt.W.'S may lead to chol.i ng in chi ldren. 111c cough may lost for months and is often called Lhc "hundred-day cough." AbouI4.200 cases of per. IUssis oceur yearly in the Uniled Stales. Pertussis is most dangerous to babic~ (1cs.s thon I year old). E"en wilh the best supporti ve medical care. compliCD liom; occur. At lea.>t 5O'ii> of pertussis patients must be ~pilali7.cd. 16% get pneumonia. 2% develop convul~ions.. and I in 200 babies die~ or has lifelong comp"catt{)n~. f>C"nUJisls ' a.ccine has been hillhly l"Olltro'er.;ial in ",,"'Cnt ),eOll"S. The original ,';Jj,,,cinc con~i\tetl of killed pertussis bacil h (B. pertussis) and wa.~ ConSidered somewhal dirty." S ide effects such lIS fever and C()fIvuL~iOf1.'li .....e re common, and IK-alth au thorities In Lhc United 5t;lte5. Japan, and the United Kingdom decided Ihat the no;],; of the vaccine out weighed the ri sk of CQIltr.IClinll the di ~ase. In all thrtt of Ihe'\C countries. pertussis VOC"CUIC was removed from the routine imrnuni1.lition schedu les. AlnlQl.t immediatel y. penussis, which had been he ld in ehed, begun 10 occur in epidemics. In 1992. a new vaccine WIIS de"eloped thaI consists of baclerilll fraclions. combi ned wllh teUlnus and diphtheria t010ids. Thi s vaccine. ca lled Acell lmmuoc. Of DTaP. i~ SlIfe and highly effective and hWi bc:cn added to the routillC inullumzauOll schedule. The VacclllC is adsorbed and is used fOf routine immuniwio n ... the poIY"alent preparation dlphtheria- tctanus-penussi( (DTP) (at 2. 4. 6. and I S months and It 4 to 6 yean). Pcnussis ~lICCinaliOn is recommended for nlO!il children . There i~ abo a dlphthcria-Iet:mus-pcrtu ~sis whole-cell pertussis vllcdne (DT.... P ) 00 the martel. but il Is considered to be higher in si(k effects Ihan DTaP. Lastl y. a DTapnlib vaccine prepar.ulon IS on the mw1.;et and is recollllllCnded fOf U!oC only Ib the fourth do<oe of the series. At present . lhe only indicution is
I"dll\.""on Df actl"( ,mmumly aglin.t diphtheria and leiMU. lo~H11 anIl pcn u<s", from aile 6 "'tt~J up tD W ~~nlh blnlWy

fecI. Ih b-CV is safe and almost complete ly effecth'c and i6 a mandatory pan of the childhood immum/.lliion schcduIe. l1M: various forms of Hib-CV 00 the market are not ICier,. cally ]uivalenl. Indic1llions lire
tooll\."tion 0( anlfl(.",ally xqu,1l."d :lC1I~e ;mmunll~ ... all1lllll'. si,c dl"''''''' nU)oed by cocapsu tated llib 1/.00t ll11: immuUlt.alloo of all inf.m~ bc',inniriG Dt 2 moow ~ age, ll'C'onlillcuded in tile United Slut"" Immun".uion o r ris~ Grou~ loclud'"11 chlldn:n allcnduic tlayun: CcnlcB. pc:nons Dr low $OC'O(OOII()nIl(' IIll1t~ II1II hou~hoId ronta<'U of H,b cases

TUBERCULOSIS VACCtNE
Tuberculo!ib (T8 ) is a <;erious disease caused by M )'Cob/to num lubercul05is. l1M: organl"'" becomes CSlabll$hed in tbr lung~ and forms " 'alled-off a~ that ~Ie]d the bao:tcr. lum from the ImmullC system. 111c disease IS dlagtKKd '" a chest I.-ray. Until the 1940s, pi.'rsons With T8 .... en: to 103nalon a, special hospi tals to i'\Olale TO pallcnu. ~ ~IICC IIIC Is referred to as the baci ll us Cal mene-Gu6rin (BCO! vllCcinc and is u li \'efllllcnUDted stllli n of M)'co/NICrm. mJl';s. The antigenic form is the whole bacterium. IItId antigen type is proI ein. The vaccine is of que",ionabk efIi caey and hWi bc:c.n jooged only SO to 77% durntion of proteclion is highly que~tionable. o f TB III the United 5U1ICS is so IIJIIo' thaI the ~accllle IS indlcaled m most cases. indICations are

" ~~oo~.";~;~;=
pulmonary tuberculo>!iis

dren at iuKh risk D I""male lI.onunmdcd f Icnlly tn:ated or ,roc frectivcly tn:ated 1'c1lOO< "11\)ln: conlinuou~ly

PPO 'kl;~'~.~-:~~':':"~~::i;~,::::
I
<)

::.:';:;: =.~=,

who "",,,'c mYl"Obacteria resistant to I ",,110 cannot be K""""Cd from the: 1<11>= H e~lth can: workers In an efW lromneOi

HAfMOPHILUS INFlUENZAE TYPE 8 CONIUGATE VACCINE (Hil).(V)

H. itljlUl'tlUlI' type. B (Hlb) call5C5 the fI1(I!.t common type

tion of M l..bi'rrttlMis i.walt'l ~ K~i>llUU to (lNH) and nfamp,'" ... hen: !hen: ~ a WOO, p;M1bdtt) lrtIn>nll W;IDn of mfection. nd ... here InfectIOn COIIIn>I duift hlI,e faik\l

of bacterial meningitis ond i~ a major cause of systemic di,ea.e in children less than 6 ycaJ'i o ld. 111c chances of eontlllClinll the disease are about I in 200. Of the!ioe ContraclCe.~. 60% of all patient s dC"clop nll'ningiti~ ...... hile 40% di ~play systemic sign s, Hib i~ a tremendou s problem in daycnre centers. when: the ri sk o f contracting the di sea!ioe is 400 times greater than in the lIencr~l populution, Hlb has approxi _ mately a 10% monality mte, and one third of all survh'OI'li hD"e some son of permane nt d;"na~. such as hearin g loss. bllndl1Cs.~. Of impaired vision. Hlb can also cause a throal innammalion that results ,n fatal choking or Uf. joint. and q"m mfectlons. UlbCV is a slenk. Iyopt"h~ed capsu lar poI)~""ride from Hib 'OICCIIIC. oonjugated to vanous protein fra&menlS. The anti~cn type is polysacchande (phosphOribosyl ribitol phosphate) conjugl1ll 1 protein. The conJug:u ion produces 0 a strongC\'". longer- lasting response through the ooj uvant cf

An IIthenc cffect of the BeG VlICCine IlIClude!!. [lIN TB skin test. A red bliSler forms within 7 10 10 ulcer.lles and SC3J"li within 6 months. BeG is D h" e 0;0 it CllnllOl be Idmin i ~tcred to immuOO;\upprcssed pci bum putients. o r pregnant wumen unl ess exposed (and rhen not in the fi rst tri mester) .

;::1

CHOLERA VACCI NE
Cholera is a di~a.'\C cllUSCd by Vibrio cllO/ertli' that as &e\ere. watcry diarrhea caused by an enteTOlOl in by the Ol-serotype. of V. clw/l'rot'. The palllkmoc5 '" India. Bangladesh. Pc",. and I 'I"11C orgllllisms ne,'('1" in,"ade the emene
ate

geocs for coFonl l.lUIOfl and toxin secretion. Secretory caused by release of an emeromx ," called Cho/fro wh ich is l1Carly identical wi th f:. '"''''

Chaptn- 7 l.-.-obio/n".roiJ
IS

215

Jle.

eri-

of

binding pcptide.~ B ~nd a catalytic peptide A. B bind to ganglioside GM , on the ~urfuce of Ibr tplthch~J cells. seni ng in motion a series of eventS that ca.5C:!i dlarrtoca. The vaccine consiSl~ of whole cells of V. rltokrrl(' 01 that ha,'e been inactlvat~. Thc antigen form of W \Y1:ine I~ ... hole bacterium. and the antigen type is pro\ria WXlD and lipopolysaccharide. Indications are li>duI:tion uf achvc ,mmunity II1UonM cookTa. such iii in ",di ridualltnovtlin, to or residln, III epidemic or endemic Irras IDdi",Io.... li rrsidin, in arr..... hom: cholmo.;~ cndcmK"
MENINGOCOCCAL POLYSACCHARIDE VACCINE

~ of five The ~ptitks

llOg

....
'h<

Cle-

:te:r-

lby

~m

".,

<Xl)
Ulnr

Memngoooccal vaccine is an irlactiva.ed vaccine ~'Olllposcd ol~!ar poly'iUl:charide fmgments or NfissUIil ",ellmg;/ iJiJ. There are four polysaccharide serolype~ reprt~nted in W IY1:lne: A. C. Y. and W- 135. The Iype A poly\lll;eh.:iride toml'iH of Ii polymer of Nace tyl -O-mannosam,ne phospUle: the group C polysao:charide is nKlStly N-acct~IO-OC"e Iylno:unmunic acid. Indications are
IIldUCI.OIl of act ,ve immum!~ aga;nM sd"".ed mll;ns of N.
I/Itnilllilj,!;<

1 the
TIl<

dfi-

'oc, ;

,.,

M,hlJr)' t""ts wnng !..sic tr1ilinil\jl CoIJtae frl$hmc" and Iho!e Io"n, In dormitOfK"S Tnvclmo 'u ~ ...ilb q!KIe~ mming"d)O;,,..1 el'JeHC' tl1l nrhoid ." mSlIlUlional oonlaClS of thoAc ..... th rnen.nJ<lOOC hMl"f1OI,Uwrr~1oCd f"'BO'I' (111 V. S. fNI'~n""'i.,,) Te UOJI ccna;n memngococcal sroup C oulilreau
PNEUMOCOCCAL VACCINE

"'.-

powerful exotoxin~ are produced by CO"'"fmIC/ui,.", dip"tlttr;/Ie and Clastrit/Illm IN(mi. 1llc exolOxins are the ItlIbt serious pan of lhe d'<iea.<ie . In both of lhe abo\e disetie Stilles. survi"al does not confer ,mmunity '" s.ubsequen. infections. so lifelong 'accine boost~ ~ needed. In d,phtheria. the c~oto~in cal.l'>e-l> producuoo of a pseudomembrane on the thnmt: the membrane then adheres to the tons; I~. The ()fllani~m relea.<ie~ a polem e~oto~in that cauS/:s headache. weak~s. fe\er. and atk-n;tis. Severe diphtheria carries a 10% fatality nllC. Only a few eases per year are ICpooled on the United SIlIiCS. Temnus i ~ eaused by. skin wound with anaerobic coodi tiuns at the ...olll1d sileo A polen! uOlo~in (Ietanospasmin l is produced llmt attack~ lhe nervous systcm. The firs! ~ign of disca .... is jaw stiffness: evemunlty Iht:jaw ~s fi~etl (lockjaw). Thc disease is essenually II per;istCnltooic spasm of the ~olunuuy museles. Fatal;.y from lelanus is usually through a.'q>hy.ia. E\en .... lIh supporti\'c treaUlJC"nt. tetanu'i is abou. 30% ftllal in the Umled State.). Rec"\'ery requ,res prolong~ hospitali/.ation. There ba\'e been SO t" 90 reponed C-.lSCS per year in the United Sillies since 1975. There is no naturnl 1I1lJ1lunhy to the eXOlo~in . The genellli rule of thumb is 10 follow the childhood IIIUllUni/..:Jtion wm.-oule carefu lly and inununil.e all person~ "f questionable ImmunizatIOn staIUS. Adults mjUire a bt"lMlcr e'ery 10 )cal'll; panents ... ho cannot remember lhelr IIISI one an: due for another. CU NlCALL Y USED TOXOIDS Adsorbed Tetanus TOJCo;d. Te.anus is a di'iCase that i~ al.'lO known as lockjaw. The causative OIlanism is lhe anaerobic ~pure-fonT1lng bacleTlum CI05lrid,um t ..ta",. The organi sm on the" t" ..." id. adsorbed tetanu~ to~oid (T. adSOfbed). i. designated in.actl\ated. The ant'gen form IS "'~ oid. and the antigen .ype I~ protein. This .oxOid la,t) appr<:oxima.ely 10 years. A bolr..ter is recommended if injured or every 5 )'ears. Reaction, OIlier lh~n p.1in at Ihe si le of injection are r:IIT. Auid tetanus to"aid is recommended only for lhe: rnre .nd,vidual who is hypel"Seffiiti\'e to the aluminum adju,'am. Adsorbed Diphtheria and Tetanus TOJCo;d. This is ~colnnlCnded for ch,ldren less than 7 years old \1.00 should not get penussis vaccine (de~ignatcd OT). Ad$orbed Tetanus and Diphtheria TOJCold for Adu/u. Adsorbed ICianuS and diphlheria loxoid for adulu (desig' nated Td) IS for children older than 7 years and ror adults. It has II tov.er 1e"cl of diphthena toxoid (1 / 1~) because older chIldren are much more scnsi.ive '" " 0 ." It is u-'icd for immUOll3tion of schoolchi ldren . DTP. DTP is 0 and T 1 ... oids with 0
penl,Js.~is

ch,1

~,~.

;tioln;
lIenl~

,-"
of

""";I~

is :also Imown a~ Sl,.,pt(}("oc("/IS pnfunwtliu, diplnuxcus. The microorgani~no protects i.self from the .mme ~}~.em by producing a cap"ular polysuccharide lh~t highly amigenic. This polywceharilk is used to prep.1re dot vxcine. 1llc am igen fonn of pneumococcal vaccine is ~lar polysacch3ridc fmgments. and !he antigen type is IpJi)afXharidc mixture. 1llc antigen is 23-valent. Indica

~s

",""

-,""

-~
I~ of IIClWC ,mmumly IgaooM P""'''''1OL1'lL1':11 el,sease ..... .,.,.;1 b) ,he poep"""'lXC'al anliscn Iyp" irv;:lu<ltd in lbe: .,.,''''' (,he "!ICC;ne prolCC" alumS! pneuJ1lClC:()<Xat Pfi"Ull ..... .... poc:umococ<:al baoot=m,1l, and 0Ihe!" Pfi""IOOI."Ottal ,nr",, All aclulu .. least 6S ~ars "k!

S.!lve :cine. .ienlS. e,'en

-,
~,

All ''''''''-'n<X"OmpetL1''l IIld,~.el","I~ ... hu arr OIl Irv;:rra.Ot1'l n; Ii the cli_ bause of patJooloi;ocal cund,Uoo; o.kln:n a, k.m 2 yean ,,1<1 w.th chromc .II,..,..! 1~!IOC"Icd .~b int",ascd ri~k or pneum<XlX~al di~asc or j" comphca

='" :n!iCd
un. In oenCIi. stead.
Th<re
hell i,
10.fin. I ~-

TooldTIlIIWIs arc deiox.fied IOxiM u-oo to inniall: aclive immu.,.. H.c .. crrate an an.itoxin). 1llcy are typically produced II!' fonnaldehyde treatment of the toxin. They are ~afe and ~Iionabl y efficacious.

vaccine.

DTP Adsorbed. on' adsorbed is used for early vocei nation of infunlS in repeated dosc.~. ~tarting lit 2 to J months .

DISlASE STATES

ROMtin. Childhood Immunization Sdzedule

1'1

.1.1 III these diseases are produced not loy

Ii!'''

b3elenum but eJlOlox.n produced by Ihal OIlanism. For example.

Table 7-6 sho""s the Routine Ooildhood Immuni7.ation Schedule formulat~ by the Advisory CommIttee 00 Immu -

ni/.3uOIl I'rIo:1ICC:!o 120001, This schedule ~hould be follo>o.OO for aU chikl~n and young adullS regardless of CCi)O()Inic
circlimstllf"lttS.

It>.

aarur. w

II~ - ' Mullolly.

J I' 'AMA

UU~l-2St9. 198Q

17. COCo M\lWR 40:700-708. 709_111. IWI IS. CDC: I.........uJII_ tAr...........,., 1'01"" MmiI II. 19095

19 CDC
lll.
21

REFERENCES
...... 2002. rr 1 -81, Shtn. \\ .(j . oro.! I........ S, G' Imltll>"'*'IY f.. l'tI.orma<:y S,IId<:..... Nc".l. ~J. 11....."00<1 "".... ml<' PubIL'"",,. 2Il00. p. 2. \ Shm. 1.000i . . .. G IIJlIJIUIIOIo&Y for P!wmacy ShIIknt<. ~ .. ",k . M. 1I.....'IlOIJ " ...... """ Pobi",hcn. ::!OOO, rr Il}.ll 4 lUlL P [) . """ T...... J A.: ~ _ .....1woI_ "f ohr I.......... ')'_ 0. Pin>. J T . " aI 1 .1. 1'IIonnaa>I1"'iji)'. F'Jl/I<JrIII)'..... ... ..... ApJIruoocIL. 1nl cd Nor\oo-all. CT. AppIe'w" J 771" 1m. rr 1017 11'160 (.nd Kr~, obnnaJ
I,

22.
[) Inlmunol\lcl$. 51. Loui" MO.

0."""""''''' J

1'10,,. IIId Con'lWi

2. l
24. n .

Yo'.o . """

J Ch

lbt1........ and '... ,..,.... I.. !l1N1,,"," \\ 1""-1 Tnrt.oolo. of Mi.. 2OIlo eel I'bol.ddphoa. .... B ~ 7 h .. 1913. pp. 303-].11_ /I. I~. P s.., A-. 247 12 83. 1982 1. GIIIInt. I' 1"'..J.unrntoI.of Im ..... """"r In II"&". VI " . """ M" .... U. " I) 1<'11. ). I"""""",,,'oca\ ~I>crol:oooloc"."'" <'II 1.-I00I.111,",,,,,,011.
.... N : " ..., ....... ___ oc<. MCI

""'q ..........

"\),,,.,'IY.

,~,

8 lIu_n. I' I), S";_ Am . 2-1()82-~. 1981,

'I, llood. L ' Th. "n"'un< ')'>I.m In Alt>cm, II.. '" .1, 11.." The M,,!tw lot Il" .... y ,>/, thr Ctll New VOIl. Garl-.l. 19111. pp 'IS- lOll 10 $prill. J . Ctll 76.llS ~n. 19'J.1 11 PI<~lla. S. L, ond ...... l.n. S, A., A ....... Ito,,,,,), tJf 'XCI ..... _ , In l'II~h., SA . lind MMI ....... e. A.. Jr 'M_l V... II .... 1""ladclplola. VI II Saundtn. 19118 12. Ikrpt> ..... D, R ProIlCCl ond Pta '"I .. Small ..... In ~ y orCllo<oc<> Prooo. L'IIlJ. P I. D CI:M: M\lWR . l l - J. 1<1').1 I. COC MMW\t.u 9)7 - 901 _. 1996. ' 15 ax: MMWR .1101- 101. 1992.

26. Wlull<. C. J ""',.. , lnfcn. D... I I: ''''- 23. 1992l1. Uno. T. A. tt 01 JAMA 271 3"- .\11 . 1980. 21. HaliInL M E.: Epldcnuol loIO:II1-104.I99-l :!9 Il..ne.. S. C AM. Inoem_ Mod 10II451--l~. 1988 10. ~I". A_ ':0 ... ~ " ull "'-'lM_ n . 1m. p_lIS" 31. ~ ... I 0 St. .....1>. MO. F..... _ C"'''''"'~ _ 2002. PI' 152- 169 )2. tnno .. B L JAMA 211; IH'_ ll \01. 199-1 _ ll. It...." ... M ~l)A Eltrmi<" Bull 1Iwnl. Feb 22. lWS H)A Ittf'.... Frt>. 17. 1995,1'1'. S_6. l4 AI..,.. M , .... ol lAMA UJ 12IS_Illl. 1m 35. InLnf...", rOt" 11<1*,1;, 8 """ C. A~ L......, FoonoIaooI ,In> ,com 36. 1I.""Ul;. C "".. Ou, 11.)1<'> New.k,,,,, 1. 1>:_ 27. 1<1').1 37_ MO>l. E. e.. 0fId "II .... M I Setnln. Virol 4213_1~3. 19'H 38. H<lI.IdI:r. S. 1... onol "'onimcr. pidc:mool R.v 14.243 261.

-901. 1991 CDC: MMWR .J:J- l1. 1'l'M OX": MMWII: ~JGt-J07. 1<)Qt, CDC: .,t.\tWIt ll :t>I1- 61.5. 1'hI! CDC: M.\tWIt ;WII 1~.I991 Varin) """"'11. "IUJ 'IOXI .. live (O"""M.. t"~ I 1'."",;1>'"1 inr_ ''''"'. O....".l<Idl. o."... ny. ~krd &! C",. 1995. V........ (rn:omt,; ..... OK... vwioclta _ l '-0/X1'" ",;o<ly f.... pre",,"bone. MOl'd '" Co R'OOln~"",i Ind ~ !'> Irn: l '" Co, ()opn. I<)IN,.

M~I""'R ~I

JOHt.

'''''*

Ala.'

Th< ,

'.,.>Of",...

..

can b (in IE
~

""'p

""~ AK

"""'"

""p:f""'''''''....

,,,,.t,,,.,,,

u....'......

"'''''''J'-

....

Rappoo!I. R~ ... 01.; VK<I ... 10 1021- 1032. 1992. 40. &o,IuDOl L'" aI PtdiooInc:o 93 37....J . I'I'M
41 Fi .... p~ _ 'U.
.U, IUo:udod..

~,

,,

e. ".;

Enrlic of ami goul " activit. called time II

a few
[he

T _ _ S ...... II Soi AIL 25154--61. 1992. .u CDC. MMWR CDC SurYeoII s-.m 41:1 - 9. 1992.

""""" e.

A"'.......

1J6; I2I-lll. 1991. .

dlSCast

W'n_

Gram'l

C(l\'ereo

Sldt!Cfil

parallel

dcmOfll

clleRllC

aJlOlhe,
pa~ed

microbi
peJllcili crobial

~ Iccli ",

lxlilhe I

cmc/Jon. lich' -' til

lilic druj of 11

sen

He

"I

-= "'"
foond to

Untit 1

VA elCIllI

late. :m;p/'

dyc~. ~ucl

congencn.

... "'represcmed significant achievcments in amiinfcctive ther apy. but they also posJ;C5sed some importam limitations. Heavy metal toxicity after tn:atment with mercury. arsenic, and anlimony severely limited the usefulllCss of agent' con taining these elements.

Anti-infective Agents
JOHN M BEALE, JR.
The hiSlory of work on the pren:ntiOOl of bacterial infectioll can be lIlICed back 10 the 19t1l cemury when Jooeph LiSler (in 1867) introduced allliscptic principles for use in surgery IIId posuraurn:uic injury, J He used phenol (carbol ic ac id) a~ t .... ash for Ille hands, as a spm)' on an illCision site. and on bandagr:s applied to wounds. Lister's principles caused a .nmatic decrease in Ihe incidence of postsurgical infectioos. Around 1881 aod cominu;ng to 1900. microbiologist Paul Ehrlich. ~ disciple of Roben Koch. began work wilh a sel

II_OH

/'('0

c1l111ti!)acleriaJ dyes wKl Wlliparasitic organic :m.cnkals. His !OQl Wall 10 develop ~'OfTlpQUnds thaI retained antimicrobial activity 8t the expense of lo~icily 10 the human host; he
called the agents lhat he $Ought "magic bulle\s." AI the time thai Ehrlich beg:1O his experiments. there "'ere only ,few compounds Ihal oould be used in trcaling inftclious ikseast$. and oonc was very uscful in tile tn:atmcm of severe Grampositive :lnd Gmm-negative infections. Ehrlich dist;O\'tm! that the dyes and arsenicals ~"(lU ld stain target cells Mltclh'ldy wid that the antimicrobial propen ies of the dyes piIf3Ilded!he staining acti ~ity. This discovery was the first oooollStrati()f1 of selectj,c /Ox/city, the property of certain dlemicals to kill one type of organism while not harming IIOlber. Selcctive toxicity is the main tCllCl of modem anti mir:robial chetn()thempy. and Ehrlich's seminal discovery )XI.tIl the way for the development of the sulfonamides lind ptnKiliins and Ille elur:idalion of the mechanisms of their Irli:l:lhuoxicity. Prior to Ehrlich' S sludies. the local anlimi1JObi.tl properties of phenol and iodine wen: well known. bolt lhe OI1ly useful symmuc agents wen: the Ilerb.11 remedies aachona for malaria and ipccoc for amebic dysentery. Ehr Iio;:b's discOI'ery of compoulld 606. the effective antisyphi . IitK- drug Salvarsan.:) WIIS a b~kthrough in the treatmcnt c{utrious. previously umn:alable disease.

,.,
Arsphenamine

Salvarsan Until the 1920s. most successful anti-infcctivc agents om based 00 the group liB dement mercury and the group VA clements arsenic and antimony. Al0xyl (sodiulll arsan i. arsphenamine) was used for sleeping sicJmess.' Certain iIyes .weh as gentian violct and methylene blue. wen: also biDI.J to be somewhat effcctive, HS were 3 few chemical !l;lllt1ln'S of the quinine mok-eule. Some of these agents

JuSt prior to 19SO. great strides were made in anti i nfectile lhernpy. The sulfonnmide~ and sulfol\CS (this chapler). more effective phenolic compounds such as hexachlorophene. ~ynthetic antimntnriat compounds (Chapter 9). and a number ofantibiOlics (Chapter 10) were introduced !O !he therapeutic annamenlariulll. Anliinfeetive ~gents nmy be classified according to II I'aricty of schemes. 1lle chemical type of tile compound. the biological propeny. and the lherapeutic indication may be 0 used singly or in combination 1 describe tile agent~. In this texlbook. a combinat ion of these classifica tion schemes is used to organize the antiinfective agent-.. When several chemically divergent compounds are indicated for a specific disease or group of disease.~. the therapeutic cla..,~ification is used, and the drugs are subclas~irlCd at-coniing to chemical type. When the infonlHnion is beSt unified and pn:-sented in a chemical or biological c1lL~sification system. as for the sulfonllmides or antibacterial antibiotics. then one of these classification systems is used. This chapter addresses an extrellK'ly broad b.1se of anti infective agents. including the local compounds {alcollols. pheTlOls. oxidizing agcnts. halogen-comaining compounds. cationic surfactant~, dye,;. and mcrcurialsl. preservatives, amirungal agents. synthetic antibacterial drugs, anti tubercu lar and Dntiprow1.oal agems. and amhelmimics. Other chapters in this text are de~otcd 10 antibacterial antibiotics (Chap ter 10). antiviral agents (Chapter II). and amiBeOplaSlic antibiotics (Chapter 12). Antiinfective agems that an: used locally are called gtr micides, and within this classification there an: two primary subtypes (see Table 8-1) and a number of other definitions of s.ani li7.1llion. Antiseptics an: compounds thm kill (-(:idlll) or prevent the growth of ('Iillllic) microorganisms "hen applied 10 lil'ing tiss"e. This caveat of use on livinl! lissue points to tile propenies that the useful anti..eptic mu';[ have . 1lle ideal antiseptic must have low enoogh toxicity that it can be used directly on skin or wounds: it will exen II ropid and sustained lethal w:tiorl agninst microorgllrlisms (the

211

TABU B-1

Oetlnlt\ons "I'K\ St..Mlllr\\s for Removing Miaoorg"nisms

......,...,...

~",_o( ... .,.,...

.. h.;... t I _

rOf

Det. ......kroo

"'" p<M..- <I"",.u

...
_

,nl.,.(_ DesmIruaro .. -"AI """'"""'"' Ip Ibr ... m!MY Of ..... " 'Iy <If mic'","~"" o..rnkal Of ph)-.IcI1 trc"m<fIl IhI!. 1Iet.rru).. ..-r ..... ct.Ili'c mic,I>u ..
... IIDI ..........

rn .. OII' .... _

ReikIotr<la 0( mic_&1 '-l 1m If! 1II1I/I'...10. 1e~1 <"OII>ldered ar:cq>UrIIIe (or publo: be.ol,h ~

w"..,..

A I"""" ;............ klU or moo(We all IYJII!S'" ~ ;""Iudr", sporeo.. _ .......Iy ""10Id",, 0;"- ,ulk_ "'<'<I'IobI, k)w rmbIbi1hy oIlW"ivai A 1",0: ,hi!. kIll. """""""I..,,,, by hOt ..:aIn Of _ .. f>$..IOO'C

""'_SM,_

spectrum lTIlly be narrow or broad dependinl on IIIc I.lse). The ~gcnl should havc II \ow urface Icnsion $0 that il will spread inlo Ille wound; it sh()llid relain acth'ity in the presence of body nuids (incl uding pus). be nonirrilrlling 10 tissue .... be nonallergcnk. LtJck ~yslenm; WAleit) when applied to sl>in Of nlut'OUS nlC1nbrunes. and IK)I interfere wlIh ~a1ing. No antiscpllC a"ailable today mtets nil of these criteria. A few antibiotics. s uch lIS bllCim.ICin, polymyxin , silver su lfadi a1jnc:. and neomycin. are poorly ab'iOl'bed through the skin and mucous membranes and an: used IOpically for the treatment of local mfcctlOlls: they ha ve been found ~C'I)' effecti ve against infections such as lhese:. In gencroll. howe'cr. lhe:

lopical w;e of antibiotics has brxn restncted by concern about the devdopment of resistant microt"al stl1lilll aoo po&Siblt allergic reactions. These problem s can reduce the usefulDC$l of these antibiotic:! for nl()re serious infections. A disinf/Ilnl is an agent !hal prevcnts transmission III infection by Ihr: destruction of patOOztnic mlCtoooganismi when applied to inoninuHe obju. 'The ideal disinfect-' exerts II rupid ly letllO! netion against all potcntiall y pathogenic microorganisms and spores. has good pmclJalllll piOpcnies into organic mailer. shares compallbility ...ith 0( ganic compounds (patticularly soaps). is not Inactivaled b\' living tissue:, is nonrorrosive. and is esthetically pieasil\l (llOI1.Stllini ng and odorless). Locally acting ant iinfecth,t drugs are widely I.lscd by the lay public and are prr:scnbed by members of Ihr: medICal profession (e"cn though the d feclivCIIC'M of many of lhe agents has not bc:c:n established comp letely). The gerlllicide may be hannful in certain easrI (i.e .. it may retard heal! ng). Standardllcd methods for evalllaling and comparing the efftcaey of gcnnicide$ have oa/y rcccntly been de,eloped. Numerous classes of chemically d;"crgent compoundl possess local anti-infccti,'c properties. Some of these 11ft ootlined in Table 8-2The most important means of IJ'"C'enting transmissIOn II infeclioos agents from person to person or from regions II high microbial load, ~uc h as the mouth. nose. or gut. 10 p!)tential sit es of infection i5 ~irnply 'l"/Ishing the hllluu. In fal'\, one of the: breakthroughs in !ilIrgicaltcchniquc: 10 the 1m WIIS the findlOg thaI the: incidence. of postSUrgical infcctiol dccrell.~d drumalicaity if surgWIIIi washed their hands before operating. Rcgulw- hand washing is properly done withoot disinfection to mimmil.e drying. irritation. and senslllnuon of the ~kin. Simple soo.p and ,",'anTI water It'IIlOIf bacteria efficiemly. Skin disinfectants along With soap II1II

TABLE B-2

Common Steril"nts " net Th.ir R"nge of Un .tId.,ill GrllmvinoMs

Spot ...

... , .. ... , ,,- ... ... .. .-, .. .. .. .. '"' ... .. ,

~

positl".

n~t;".

Acld" lISt

UpophUic

H,drophllk

Funt l

.......
<,.u
N /A

Oth.,

'rlcN

A"""'.

.. ( pI{

AIdttI)do!s

{&lunora......,..
formoJdeh~dt)
'p

..
t fhiI~
~""",)

"A

,
WA

"A N'A
.. i

C!Ilorhe>. .......

H.

&I""

Ir)1!<I<:I\Jor;Lt.

<~"","" <IKl"ok

Ikuch..............

""" ,,"-Icdo ...

'" " ....

~,

..
,

(1IrP

~.

,
"A

1'tw:noI<, qual."......,.

Sororc Q.ldl.....,
~"R!II<>I.

anI'II(lII''''''

H.

...

"'A

"<-1-

~,

ible
~

usually ufil as proopernu,,: surgical M'T\Jbs and MilmlS for surgical incisions.
WIk'r Ire

, of
~

EVALUATION OF THE EFfECTIVENESS OF A

=,
or-

STERILANT
E u]uauOfl of the effect; \cncs.~ of ~nti '\Cpl ic~. di ~infcc tant s. InIIlJIhIor l>Ierilants (Table 8- J). allhough seeml ngl y ~imple

<h~

ling

'"

sing

ib<d

,"'"

c cf-

,'alu-

001,

""",

~n

of us of

opoI fact .

""'~"
~d

""""

:clion

prHlcil'ic. is an cxtremely complex lu sk. Orll: mU51 1.'011IioIer lh1: ml nn_ic resistance of the microbe. the mkrobial INd. the 'M ixture of the popu lalion of mic roorga nisms pres_the amount and nature o f organic material prescm (c.g .. blJod. fcc~ tissue). 1M CQIlCC'ntnUtOn and stabi ]u)' of the .twJflanl or SimIan!. the lime and lc mpc:nllure of ClIp<) Iht rHo and the hydnuioo and binding of the agent to ~ In ~mmary. I host of parameters must be consid(ltd (ortach Slm lanl. andCJ(perimcnUll lissays may be dim,w. SpeclrlC. saandardiud assays ofilCtlvll y are defirted for ~;h 1IloC'. Toxicity for human ~ubjccls must al ~ be cval uIIrd. The En viromnc nlal Prowcl iun Agency (EPA ) regulate>! 6sinfa:tll.nl$ and slerii1mls and lhe Food und Drug Admi nisntlOll (FDA) regula1es antise p1 ics, Therc ~rc somc problem s with improper U'iC o f the se: 'It'll). Anll<;eptics and di~infectanlS may become conlUmi~ by I't'S'Slllll1 miclOQrgan,sms (q:,. spo!'Cs). l'leudvmo.., 1It1'll,,"""sa. or Sural;a marcuUl1$ and nllly octuall y naunil Infection. Moo topieal anti..cplie~ in!crferc wi th .-IlraJing 10 some degrtt. so the), should be used ac .wJutg 10 the propI!r dirtttion) and for a limited length of

w ith;iliza

...

ALC OHOLS AND RELATED COM POU NDS

,1J.:oho1s and aldetJydes have been used as antiseptics and di sIlfrctants for man)' ycars.' Two. o.f the mo.st commonl), used IIIh~ics and disi nfectanlS are ethyl and i~propyl alcohol. The Ill1tibac1eriul poIcocics of the primary alcohols ....n'>l 1es1 cu ltures of Swplrylococ..us /IUIl'II$) incrcase iIt molecular w('ighl until the 8<arbon atom {)Ctanol is ",,"" In general. one o~ ygcn atom is capable of soIubi li1.If 5t1'et1 or eiglu carbon atoms In Wal('f. As !he primary Cb.:alll konglh increases, van der WlllIls' int('ra:tion~ iiOt p, wid the ability to. pcflC'lmte microbial I1l('mbr;mcs .-Jt*" As water solubility dccrc:ascs. lhe apparent anti miII:JI:g] potency diminishes I'ollh molecUlar weight . Branch of 1M lleohol chain dc<-rea~~ antibact erial poIcl'ICy; tf li\II der Waa ls' forcc~ brought about by bmnching ~ ftIlI pl'llClIlIte bactcrial ccllmcmbranes as effi clcnt ly, The POlI'l(IK' alcoho l ~' polclICies decrea-.e in lhe order primary >1CC'OrIdary > !I:niary. Ot-spi(e thi ~ filet, 2-prol).]rlo l (i~o I~!"'~)I alcohol) is used commercially in~lcad of lI -prop),1 7': ,bausc It is less e.l:pensi~c. lloOpIUpyl alcohol is y ~ acth'e (han cthyl alcohol against vegetati~'e _'Will l'OYo lh, but both alcohols are large ly ineffective spoies. The: acti"i!), of alcohols againsl microorga I) due to the abili!)' of alcohol, (0. denature important and carbohydrates.

characlCrislic pka~nt odor. It is flammable, miscible lIo'Uh water in all proport ionS. and sol uble in fflO5t OI'Xalllc $01vents, CommercIal ethanol coolUins -9SSf> ethallOl by \'01 ume. Thi s concenlr,lI ion fonns an a1.C01rope w,lh I'o ;Ucr th:u wSliIls al 1S.re. Alcohol has been known for centuries as a product of fcml('ntation from gr.!in and man)' OIller carboh)drates. E!h:mo l ~ Dn also be prepared s),nthetica ll y by the sulfuric add -cDlIllYlCd hydrntion of clhylelle The commcrce in. lind uo;c of. alrollol in the Unitcd StDtes is strictly cont rolled by thc Treasury Dcp;lrtmc m, y.hlch ha.~ provided lhe folloy. Ing definit ion for "alcohol": "The Icnn a/co.hol mcans tnal substance known as ethy l alcohol. hy drated oxide of elh) I. or spint of wine. from ,,'hatel'cr source or wl!:u e\'cr proces.~ produced.. havlIIg a proof of 160 or mon: and not inc ludmg the substances commonly t oown as whiskey, brandy, rum. or gin ," ~,,(lfur~d alcohol IS cthanolthat has been renderro unfit for usc In IIIto.Xicah ng be\'crngcs by tM add ition of othc:r subsianccs. Co",p/~/"')' '/f'nlllu rro o/",hv/ COl'lIalll~ added wood alcohol (methanol) and benune and I~ ul\$ullablc for either internal or extcrnal use. S~f'iall\' ilcllllIr"f'd alt;tJho/ i ~ cthanol trealed with one or more Sub~lanCe' !IO th~1 its usc may be perrnitled for a speda lb:ed purpose. Ex amples are iodin.c in alco.hol for lincture of iodine. I1IClhanol, unu OIlier substances in mouthwashes and aftt'r..lmve 101iuns. and nICthanol in akohol for preparing plant utracts. The: pn mary medi Cinal usc o.f alcohol is utcrnal, as an anliseptlc. prt-'iCn'a!i"e. mild coullicrirri!ant. or sol"em. Rubbing alcohol is u'lCd as an astring('nl, robefacicm , and mild local II.fICSlhelic, lllc anesthetic effect is due 10 the eVap0r3ti"e refrig('runt aclion of alcohol "hen appl i('d 10 tIM: skin, Ethanol ha~ c\'en been mjec!ed ncar flC'nc\ and &angha 10. allev iate pain, Ii has a low narc()lic pOIency and has been used inlemall y in diluted form a.~ II mild sedallve. a ",('ak "asodil ator. and a elll1n;nut;\e. Alcohol i~ nICluOOli7.Cd in lhe human body by a "<'ncs of ox idations:

AJoohoi Dehydrogenase

H~------.I/

o
Aldehyde

~ ~ehydrogenase

H,C~

OH

IkoItoI.

Ethanol (eth) 1 1l1roho1. wine spiri t) is a roIoticss, volatile liq uid wilh a burn ing ta~te and a

USP.

Acetaldehyde causes l1ausea. vo.mli ng. and \'aslIlaIOl')' nushllli. This fllCt has been used in 3\'crsi on thempy "'l1h the dlllg di~ul firum. "hich bloc ks alde hy(!<, dehydrogenase, allowi ng acctl1ldchydc \I) accu mulate. Al cohol is used in ttIC prllCticc of phnnn:K:)' (Of' the I)repa ra1ion of spirits. til'lCtures, and IluidcJltfllClS. S"irirs ure prtpamtions containing cthoinol as !he sole ~t ~em . 1'0 11Cn:3!; li"t;/ures Ire hydroalcohol ic mixtures. MIIIl)' nUltlc,\ UliCb contain alcohol as. C06Oh'cm , The: acttpted bactCl"lci!b.I CQIlCentTlltion 0( 1()'if, alcohol is 00Il sUppor1ed b)'. stud), !hat diseo~'~ ' hat !he kIll Tllte<l of microorganisms suspended in alcohol COIlCCIlI Tllllom be Iween 60 and 9S':It were noc slllmficanlly diffcn:nt.-COfICCnc. Imtions below 60% arc also effeC1i,- but longer contllC! times arc nccCS1l3ry , Concentralions abo~e 70% can be used

110

WiI....... UIIJ

Gin'flld '~ T~_Tl"",*.if O'7/""i~

MmiciNIl aNi

Ph"rmuc~"lIwl

Ott''''..,/,...

s.afdy for prwpcratile 'lerili/Oilioo of lhe sl in.7 Alcohols are nammnble noo n1U~t be !olored in cool. wdl-ventilall'tl are:;s.

Dehydrated Ethanol, U5P. Dehydruted elhanol. or flbsoiu/t' ~llu"'oi. contains noI1CS5 than 99'.1- ..{w of C zH,OIl . 11 is prepared commercially by a/.eotropic dishll:mort of an eth~1101 :benzetlC mixtun:'. wi th prol isions made for emdent remol'al of .. ater. Ab<;QIlitc rth~nol has ~ I'ery htgh affinit y for W1Ur'I' and mu~t be stored in ttghtly sealed WrllairorN. Thi~ fomt of eUtatK)l i~ us..'tl pnmarily :IS a chemtcal reagent or sol\'Cnt but ha.~ be<:n injected for tl1I;l local n:lief of pain m camoomas and neuralgia!o. Absolute alrohol canllOl be ingcsted bec:IlI'\C thrre is ~Iways some benl.ene rem.:unmll from the aze04rop1c di~tillation thm cantlOl be rt:I1KlIed. Isopropyl Alcohol, USP. l-.oprop~oot {2-propanol) is a colorle"S. volatile liquid with a characteristic odur and a slightly bitter tllSte. It t~ C()I'tsidr-red a suitable su/)"titute for ethanol in fllU',1 ca.~" but must not be ingested. iwpropyl ~1c000l i~ prepared coutnterci hlly by the sulfuric acid-cmaIyzed hydration o f proflyknc::

ring . Ethylenc o.tidc: is a nonsel11\'e allt.:),latmg agent aDd as such is extremely toxiC and porcnlinlly carcinogenIC . Ex posure 1 skin and mucous membranes should be avoided. 0 and mhalauon of the gl'S should be pre\tllled by LI.~ of. uppropriate respil"JtOl')' mask dunng handling IU1d !'lentil. lion procedures.

Aldehydes
Formaldehyde Solu tion, USP. Formalin IS a colorb :tqucou~ solution lhat officially contains I'lOl Ie~ than 319w/v of formaldehyde (He l lO). wilh methanol added 10 It< t:Lrd polymerization. Formalin is rniscihle with water mJ alcohol and has a ch:mlCtrri~tic pungent aruma.. FormakJe. hyde readi ly und~rgoc:s ox idation ~nd polymerization. lead ,ns to fonnie acid and paraformaldehydc. re<;pectively. 50th: preparation should be stored in tighlly closed. light-res151. corllaincl'5. Fonnalin mu,t be stored at temperat ures allow 15"C to pre"elll cloudil1C:>5. which de"dops at 10"'CI'Iempa lItures.

forms a ronlJll1t -boi ling mu:ture with water tl1;lt contains 91<:i I'IV uf 2-propanol. t'lOprOpyl alcohol IS used primanly as a di~infectam for tlte sk in and for surllic al instruments. The alcohol i$ rapidly btM-'triciolllm the coocemrnhort range of 50 10 95%. A 4O'l COI1(,.... ntr~liOl1 i~ coo sidered equal ill ll.n! iscptic efftcacy 10 a 6()';t, ~thaool in wmcr solution. A~lfVI';c iso,lropyl ulwhol. USP. is used 011 gaul.C pMs for su:rilil.alton of the skin prior 10 hypodc:mllC injection,. Isopropyl alcohol is al'<O used in phannaccutical ~ and toiletriel a.~ a soh'enl and p!'C<iCf\'al;'e .
al~ohol

HOAH

It

Formic AckI

The

The g~nnicidal action offonn:tldch)de i~ ~Iow but fut. The nlC'Chamsm of action is behe"ed to m\'ohc
(amino. hydroxyl. "00 sullltydr)'1) in protein~ and acids 10 form camlllol deri,at;'es. 'The acllon of formaldt hyde is Itot coufincd 10 mleroorgalll~ms. The COInpourd imtl1ti ng to tllucou' membranes and cau<;c, hardening d skin. Onl ingCSllon of the solution leads to 'Ie,'cre l<!Stina! dlslttss. Com:tCt dcmtatitis is common lin. and pure forllUlldehyde is 5u~pc:cted "'o~

Ethylene Oxide. Eth)'lcnc made. C l H. O . i~ a colorle~~ n:tmlTlable ga.~ thaI Jiqt.Jclie~ al 12"C. 11 has bcf:n used to steri li ze tcmperJtu~-scnsHl"e medical equIpment and cenain phanll:","eu ti eals that c:rnnOI be hem steri li zed in an aUlocla~e . Ethyleror o~ide diffu~ readi!) lhrough porou~ matc:nal~ and .cry effectively dcs.tfQys all forms of rn icTOOrganism~ at ambicm temper.llures.-

'"00

C~~H2 Ethylene O~ide

Ethyknc: oxide: forms v;ploshe mi.ttures mail' al concen trJl ions rallging flllm 3 to 804 by volume. The clplOl'ion h:uard IS eliminated ",hen lhe gas is mi.o.ed with sufficicnt concentrations of carbon dioJlide. Cumm;,If' is a commercial sterilHlH comuining 10% ethylene oxide and 9()'l. carbon dio.tlde by \'olume \hlll can be handled and released in air without dangr'l' of explosion. Slerili7.atioo is :ac<:OI1tplishcd in a se:llOO. autocla\'e-H ~e chamber or in gas-impel'll1C:tblc

...,.

The mechanism of the SenmcidaJ acuon of elhykrN: o~ilk

probably In\'ol\'l$ the nlkylaltOll offunclional grours in nu ~lek: adds and proIein by nucleophilic opening oftbe oxide

Glu fa raldehyde Disinfectant Solution, USP. aldehyde (Cidel. a 5-carboo dialdeh);,k) is used as I ~ut ion for <;ten1iution of equi pment and ;;,,"ru,~.",," cannot be autoc loved. Commen:i:tI glnulI'li ldchyde i~ . liud in alkal ine solution. The prcpar~tion IICtuall)' .w_ of two components. glutal"Jldehyde and .. htdt mixed togclhcr ilnrnediatcly before usc. tlon ooota;n. 2'k glutanlkkh)'dc buffered at pH 7.510 Slabilil.ed glutllrJldt:hyde solutions retain O~'er 8()'} original IICtivuy 30 days al\er prepa['lttr<Jn.~ stabi li/.ed alkaline 'IOluuons lose about .... '10 I1l\er 15 days. At higher pll (>3.5). I polymeri/.es. Nonbuffered !IOlutions of lICidic. possibly because of an acidic proton on the hemiacetal fornt. The acidIC solutions are stable but sporici dal lICIivity.

,,:.

..

"

"

.. "
PHENOLS AND THEIR DERIVATIVES

!)c(:ause il cun be nlCasured and tron~fem!d easily, llIC water COIllcnt, hov.~.er. precludes liS usc in fi~ed oil s or liquid pcttOl3IUm because tnc solution is ruM miscible w;lh lipophilic ointment ba.~, p-Chlorophenol. ,..ChlowpllCool is USI.'d In combmatlOil with camphor In liquid pctl'Ollltum us an c~temal 3miSCp:IC and ami -Imlant. The compound has a phenol coeffi cient o f a bout 4 .

",.

",.

"" ,'"

~.

1'nrnoI, US " , fCmains the .~Iandurd 10 which the activity of

alii ccrmicidal
<ltIII i~

p-0y

SUb!iU1OCCS IS compared. The: plwno/ clJi defined iL'i the ratio of a dIlution of a glvcn te~1
i~

ohlnfa:,:tlnllu the di[uliOfl of phenol that

I\-'qu ired to

~ill

c'
p-Chloro-m-xylenol. II-Ch loro-m-~ylc:nol (PC-MX ; Metascp) I ~. oommlliling anli~plle agenl ",ith broad-spectrum antibacterial :md a11lifungal propc n iC-'> . II I~ markel~'d in I 2'1. CQOCentration as a siulmpoo, II has al.so bet-n used IOPIcall) for the l~almem of tmea (ringworm) infections such a~ alhlele' s fOOl (linea pedis ) and jock iteh (tinea eruris I.

IIIhc same extent) a sera!" of So/nWfltl/a ,>phi under can:rorllrolk:d lime: and lcmpermurc conditions. As on C~ . _ if the dilution of a Ie!>!. disinf('CI:m1 is IO-fold grealer ~ dilotioo of phenol. the phcool cocfrt(:icnl i 10. ()!IlOOSly. the phenol coefficient of phellOl itsclf is 1.0. 11M: ~ rodflCicnt test has many drowbach. f'bcools and

.,emllClIks do not kill nlieroorg:mism\ uniformly. 5(1 l:IrW.ions in lhe phenol coefficien t will occur. MOI'I!ovcr. the A.IIOns used tOcoodUCI the leq an: diffICult 10 n:producc
na.:tly. SO high variablhty bet ... een dlrfenmt measurements laboratOries is e~pecl~-d . ~lcnl:c , tile phenol c\lCfficienl .,. lit unll!habk. ADUmber of phenols are OCIuaJly more bacteri ddul than itself. SubstilUl ion with alkyl, aryl, and halogen (es. ptuaII) In tilt pam po&ition) groups iocreases IxK:tericidal i<II'olty_ Stnll~II1 -cliaJn alkyl groups en lianet liactericidal acmort tll1m brnoched groups. Alkylatrd plx:noI$ and ~1Iln.1DOIS III'C Ies$ to. ic than the parent compounds v.llilc \ ~n, bactericidal proptnles, Phenols denMure bacterial :at low concemnllions, while lysis of bacterial cell

oocurs

al

htgher oorocentr,ltions.

" ,'"

1'llf1l01. US,.. Phenol (carbolic acid) is a coIOfIess to , . pllll, crySilliline material ..... llh a chru- terisli c "medici ... "odor" It Is "OIublc 10 the e~tem of I part 1015 parts
."tf)

JOIubie

In

lIkohol. and

~ubJc

in methanol and

Ht:.\ochlorophcnc:.2,2'-methylenebis(3,4,6-tnchlowphcnol); 2,2' -dihydrm,y-3,5.6,]' ,5', (Gamophcn, SurgJCOIl. 6 '- hexachlorodiphcnylmethanc: pHI.soHcx ) i ~ a white to light tan crystalline pov.dcr thai is insoluble in water bUI is .soluble in alcohol and most Ollie!" organic 5QI,ents. A bip/lcnol such as heuchlorophcnc: will, in gene".!. posscs,o; grealer potency than a monophenol. In addition. as expected, the: lncreasc:d deg ree of chlorination of hexachlorophene Incrcasc.~ ils anllse-ptle potency funher.

He1CiKhiorophe~,

US",

Iphen~'

salicyIJle).
OH

c'

Phenol

",'/ "-...",""""'-..,/'-""""-c, (
H H

f "" "' "". . . A""

1

HeKachlorophene

ulublts germicidal activity (l!encruJ protoplasnllC i~ CalI!>hC 10 s~ m, cxert$ local unesthclic effect$, und lit diluttd 10 avoid 1i-'lIe dc~tructlon und dcnnat ili ~. S. kI\qlIIl.I~la introduced plx:nol as a surgical antiseptic 7, and II IS still used occasio nall y as an antipron tic in f to 1.0% conccmr:l! ions), A . has been u.w to cauterize ob5olctc as un unti-loCptic :Uld

l lexochlorophcne is easI ly adso:wbcd OniO the s~m and entas the sebacrou~ glands. Because of IhIS, topical application eI icits u prolonged antiseptic eneet. e\... n in low wncen , lrations. HCAachlorupheoe IS used in concentrations of 2 to 3% in soaps, dela-genl creams, lotions, and shampoos for a variety of antiseptic U.'o('li, It is, In gellt'rul, effeclive agalltil Grnm-posih\'e ba\.1eria. but many Grnm-ncgatl\'e bactena are resistant . llIC syslemic toxicity ofhe.laChlorophc:nc in ammals afta orol and parenteral admmiS(rution had been lnown for SOOIC time. bul in the laiC I%Os and early 1970s. reports of ncun>-

toxicit) in mfants bathed ill hexachlorophene and in bum pouents deansed wnh the agenl prompled the FDA to ban its us(: in over-the-counter (OTC) anu>eptic and cosmetic prepanuions. IO HexlIChloropnene is still avai lablc by preSoCnpl ion.

Cresol. NF.
!llenc

'Crrsor' IS IICluall) a mhwre of l!tree isoOH

methylplll;'llol~:

is obtained pnmarily from clo,'c o il. It ill a pule )'ellow liquid .... lIh I 'ItOng atOnia of cloves and II pungem taste. Eugenol I~ onI) ~hghlly '\Oluble in .... ater but i~ miscible .... ilh alcohol IlnII othet" organic !I01Ienls. Eugenol possesses both local IDC>Ihetic and antio;cptic attivity and can he directly apphed a. I piece of COitOO 10 I'l'Jieve tOO4h:1chc~. Eugenol is also uSC\l in mouth .... ashes because of i.." anusepck propcny and ~ ant tast~. 1llc phcool coeffieicnt of eugenol i~ 14-",.

Eugenol, USP,

4-Allyl-2-llIclho~yphcnol

OH

I
H,

EogeooI

The nll~ t urc OCCUr! as II yello .... to bm",msh-ydlow hquid

thai has II charoctcri ~lk: OlIor of cn:Q~ote. Crc~ol i~ obIailled from cool tar or petrolnun by allaline extraction into aque0I1~ medium. lICidllicalion. and fr-.telional dlsullmion. The mixture is Dn ine\pcn~ive anliseplic and disi nfectanl . It pas~se~ a phellol cucfficiem ofZ.5. C~ IS sparingly soluble III wmer. ahboough ukohoh and OIhcr org.ln1C ~I~enl~ will soluhili/.c ii , The drn .... back to it~ U'\e as an anti septic IS its unpleasant odor. 4-Chloro-3-mclhylphenol occur! as coIorldi> cry.~IIII~, Cblorot~ i~ only <'Ii ,h lly !IOluble in watc r. Allhe low conccutrntiol1 that can be acbicved in aqueous media the compoulld Is only usefu l a.~ I prco;corv:nhe.

Resorcinol, USP. mOihydroxybc'nzelie (resorcinl, 01 l'l'SOI'Cirtol. is prepared ~ynthclically . It cry~mlllll:s lIS 'Iohllr needles or lIS an amorphous po .... der thai is ()Iublc in 'Iollllf
and alcohol , Re'\Ol"CillQl is light sellSlllvc and oxidlln Indity. so it must he "torcd in lighl. light-resistant t'Qlllaltltr<. It is milch less stable in :IOluuoo. e~lally" alkaline pH. Ikrorcino l is only a wcaX ant iseptic (phcnol coefficient OM Nevenhe L C'<s. it is used in I 103'1> soluhoos lind in ointmmli and pastes in eO!lCCn tr~tions of 10 to 20% for the trtatlMll of skill condit iol1s such as nnSworm, c:czc lna. psona'I ~,11III !il:horrhcic dcnnatil is, In addition to us ant iseptic IICIlOIL rr!IOrciool is a kf'nlloi)'lic agent. TIlls pnl(JCny nuses the unHIm corneum of lhe skill to slough, opemng lhe penelrnuon for antifungal llgcnlS,

Chlonxresol, NF.

OH

Chlorocresol

CH,

I ""'-'V''''-OH
Thymol, NF. 1~1 m-('ll!.~l is e .... tructed from oi l of T!t\'mus I'I/IX(Jns \ thyme. of lhe mint family) by partitioning llltoalkaime IIqUOOllS medium follo .....ed by acidilic:Uion. The
obmilled from the rnoIhcr hqoor arc large and colorless. with a thyme -like odor, Thymol is only slightly .olub le ill "'atcr. but it IS ulrcnJC:ly soluble III aloohol~ and OIher orgallic 'io()1\'enl~, Thymol has mild fungICidal properties and is u..ed in ;Iloohol '\O luliol\s and in du<;til1g po"'Ucrs for lhe ItealnlCllt of ti nea (nng ....orm) infc:cuons.
CH,
CI}'t.:Il~

Hexylresorcinol, USP.
resorcinol," is ..... hlte

or

I
OH

I I nolic odor. Ii to Ihe: longue it 1I0Il of numbriess. is fl'l'Cly sol uble in shghtly wluble III waler ( I cinol is an effeclive: antiseptic. posse.~sing and fungicid:d IlIopt::(I!eS. The phenol . resorcinol against S. /m'f'(Js is 98. A, I~ Iyplcal for al~)~ phcnols. hexy lresorcinol poI>.l:Csse.~ surfact.nt [)IllIIeIIB The cumpound ul.o has local ancsthetic ac:ti~ " y. Un) cinol is fonnulDted into throat . becau'l' of I' anesthetic :md anu5eplic probably of lillie value , lion in the !menge) is not umiscpl ic. and t aneSlhellC propc:ny can ark'Sthell:t"~ the porary laryngitIS.

Chllpter 8 AM;,fIj'" ,., Axmn

HO

223

1,'

HALOGEN-CONTAINING COMPOUNDS
IOOOPHORS

ld

00

"
OXIDIZING AGENTS
Ia scnenll. the ox.idil.i ng agents that are of any value as F'JlllCidal.gents depend on their abili ty to liberate oxygen .. the lis..wes.. MilIlY of these agcnlS are inorganic com-

plIIIIds. Including hydrogen peroxide, a number of metal pm.ldts. and sodium pcrborau~. All of these read in the b>IIM to gcner~'e o.\ygcn and oxygen rodicals. Other oxl~ asents..

weh as KMnO~. denature pnXeins in microor-

-~

hit:

Ulcr

cad-

<:"',

pH. ).4).

PUIIII\I through a dim:1 oxidalion reaction. Ox. id izing IFftIS ~ t'SpeciaJly effocth<e against anaerobic bacteria and CMlbe used in cleansmg OOl1laminaled wounds. 'fh.e bubble5 . . form dunn, the hbcnilloo of 01l.)'geo hoelp to dislodge .kbrui. The effectiveness of the uxidi1.ing agcms is 5OmC... hmited by the,r generally poor pcl1oC:tnlblllly InIO in-

Ele.nemul iodme (11 ) is probably the o lde';! Ilcnmcuk sull in usc today. It was listed in 1830 in USP- II a.> a tinctun and a liniment. Iodine tinclUn: (2% iodine in 50% alcohol with sodium io(bde). <;Irons iodine r.olutioo (Lugors soIu tion. 5% iodi ne in water wi lh pocassiulll iodide). and iodinc solution (2% iodine in Wlll.('r with sodium iodide) are eurn:nlly official prepardlions in lilt: US!'. The iodide ~JI is admixed to Incl'CaSC the50lubilllY of the iodloc and 10 reduce its vololility. Iod ine is one of the mosl effecti ve and useful of the gennicides. II probably acts 10 mactil'ate proteUls by iodi natioo of aromatic residues (phcnyhdanyl and tyrosy]) and oxidation (sulf1tydryl groups). MI lling with a number of noniooic and ctiiooic s.urfactants ~'an soIubiha iodlile . Complexes form thaI n.'tain the gennicidal propeT1ics of the iodine .... hile reducing ih I'oialility and n:moving Its milam propenies. 1J In some of the more lICtive. noniooic su rfoctant C()mp~.'Ies. it is c.~t imated that appro~im.atel) 8Q'I, of the dissol\led iodHlI:' r.::m~in~ available in bacteriolog ically ;sc. live form. ~ lICti\'(' col11pleAc.~. called iodOl,/ror1. arc. boch bacteriCidal and fungicidal.

lIent
~.

'""

f1ed h~ and organic m:lt\cr. Additionally. the Belion aflN: Oridl1.Cf'!i is typically trnnsiem.
Cirbamide Peroxide Top /cal Solution, U5P. Carbam ilk peroxide (Gly-Oxide) is a stable compiex of un.'a and ~en peroXIde. ]t !las the RMJlcculnr formuia HzNCON-

",d .

!\Ira-

! f 10

KtH:O:_Thecommert:iai preparntron is a 5OIulion of 12.6% abamide pc'ro~idc in anhydrous glyceri n. When mi~ed
IidI

"'Jin. hydrogen peroxide is liberated. Carbamide per~.

oucII: it used as boIh an antiseptic and disinfectant. The fitjAlition .s especi ally effecll "e on lhe trellllnent of 0011
*'mIions or in denIal The
o~ygen

bubbles chal art

iInlrd n:mo\'e debris.

Hydrous BeflZoyi f>ero)Clde, U5P, Hydrous hcll7.oyl paw.ide (OJy-S, Oxy-IO. Vanoxidc) is a white granu lar Il"'tirr, In its pure powder fonn il is cxplosi,c:. 1llc com,.....l is formulated "'Jlh 3CY.f- water to make il 511.fc:r 10

Povidone-Iodine USP. Povidoneiodine (ik.adlne, Isodine. PV P jocfinc) is a ellarge-Ir,II1~rer C()mple~ of iodIne with the llOIIionic ~urfllClant polYRIer polyvUlylpyrmhdone (P VP ). 1llc: comple x is extn:meiy .... atc:r soluble nnd releases iodioc I'ery slowly. Hence. the JlR:par:IllOO pro~idc:$ II nonto~ic. nonvolatile. and nonstaining fonn of iodine that IS noI irritating to lilt: J;l(in or to "'oond~. Approxm13ldy 10'.l of the iodine in the ool11ple~ t. biO:II allable . I'ovidoneiudine is u.sed as an aqueous solutIOn for prewrglCal dl~mfcction of the incision ~i lc:, It can also be u...ed tn trca! mf~'Ct<!d wounds and damage to the slun. and 11 IS effecli\e for local bacterial und fungul infections. A number of OIlw:r forms of P VP-iodll'le are 3nilable. includlllg aermt)I ~. foams. om' ments. surgical "rubs. anliwptic guu~c: pads. sponges . moulhwa~, and II preparauon that dl ~mfecl s whirlpool bath s and hot tubs.

- - -'",cf-- ---C"'.-1--

!xyl

ph<-

:n<.a-

"".

Povidone-Iodine

-(MIl)'

"
CHLORINE,CONTAINING COMPOU NDS

"obi
'eA)' I-

lilted I1k._
e~lI'

local
,.~

:nlrd-

ew"""ndcd lit 5 and 10'l ooncenll'3tioos. bcn~oyl pen,. *rsboth keratolytic and keratogcnic . It is used in the In:at"Ulent. knloyl pcro.ddoe indUCC!i proliferation of epiWIllI cells. lcudingto ~ Ioughml! und repai r."

local tem-

C hlori"", and chlorinen:leasing cOlnpounds have bI..'en used in the: disinfectlOO of water supphc:s for nloOR: than a century , The discovery thilt hypochl()lUU.'; acid (1 1 00) I) the lICth'c gennicidal species lhat is fanned "'ben chlonne l~ dis~h'ed m waler led 1 the developmenl und w;e oflhe first irlOll:3mC 0 hypochlonle salts such as NaOCI and Ca(OCTh. Later. organ ic N-chloro compounds were developed as diSinfectants. Thc:seoompollnds release hypochlorou, ucid IIhen di~sol~t'd in watcr. especially in the pRSCncc: of acid. Two equally plau~ible mechani~ms have been proposed for the genmcidnl action of hypochkxouslICid: the chlonnation of anude nil","

gen U loms und Ihe01. idalion of sul fhydryl group'i in proteins. Or8~mc ~"oolpOlln.dS thai form stable N-chlom dcrivuti ve$ include 3lllides. imidc~. and amidines. NChL OOlllflOuOOS oru slowly relea5e HOCI In water. n.e am.septic effcct of these agents is optunal at Irt)llnd pH 7.
HaluOM, USP. p-Dichlorosulfnrnoylbcnloic acId is while. crystalline. phoIosensi livc compound wilh a faim ch lorine odor. HululOnc is ooly sli ghtly so lubLe in water at pH 7 bul becomes very soluble in alkaline solutiOtl~. 11le sodIum sail of ~' ;u.onc is used 10 diSinfect dri nking ... ater.

1oca1i7.cd inf1i-oos (especially when reSISlant organiSlIl$ an: present). to remove necrocic h!>Sue from massi,c infeclMlM or rJd iation IloCCroois. 10 countcl1lCt odorous dlscharg~. to !lCI as an irritant. and to disinfect c)'lits and fistulas. 0\) chlorosene is m:uxcled as a powder for I\"COIlShtution into a solution. A tYPIcal application uses a 0.1 10 O.5~ COf\Ct'I1. tralioo in water. Oil ution s o f 0.1 10 0.2~ an: u.sell in urolog, and optllllaimology.

r=~ I)_~_/CI

CATIO NIC SURFACTANTS

All of !he cationic surfllClanls are quaternary IImlOOlUUID compounds (Table 8,3). As ~uc h , they are always iooi1.Cd III water ond cXhibit surface-acti ye propert iel;. The L"OmPOUI\tls. with a polar head group and nonpolar hydrocarbon d\;u, form micc:ne.~ by concentrating It the intenaccof Immjsci~ sol~enls. The surface activity of lhe~ t'()mpound~. e~emrli lied by lauryl lriethyl~mmonium su lfate. results from two structural molCties: (a) a eat ionIC head group. '" hid! 11&\ I high affi nit y for waler, lind (b) a long hydrocarbon tad. v.hich has an affi nity for lipids and nonpolar solvent>~Hs

Halazone

n \,
N,N-Dichlorodicarbonarnidine (Al,ochltln1mid) is a bogtn yellow crySUlJ1ine S()lid with a faint odor of chlorine. II is IIlOSlly Ulsoluble in .... ater and organic solven ts and is un'table 10 li ght or heal. C hl oroalooin will C.lipJode if healed above 155OC. 'The rompound IS soluble CllQUgh in W31cr lO be used In very dilute sol ution to di sin fect wourldll, II.~ ])ac king for denml Cllrie.~. and for lavage lInll irrigation. A glyceryltriacctate !iOIution is used lIS II ",.oond lln:ssmg. The IIntiscpllc aclJOO of chloroazotlon IS long lasIing becau.se of its c~tren~l)' slow reaction with water.

Chloroazodin.

CH)(CH;,)n-

I.

Q'

C2HS

H5
mi~lIe COI1Oe!IlIt-

0,

""Y " A N~
:::::::N

"

AI the right roncentrntion (the critical

o
ChlOroazodin

/ "

Oxychlorosene Sodium. O~ych lorosenc (C lorpactin) is a complex of !he SQ(Iiul1l salt of dodecylbcnzencsul fooic acid and hypochlorous acid. The complex slowly relcases hypochlol'QUs ocill in solution. O~ychloroseneoccun; as an amorphous "< hite powdcr lhat has. faint odorofchlorine. It combines the gern.icidal propertlCS of UOCI wi.h the emu ls.fying, weui ng. nnd I;cfficol) t1c actions of an aniooic detergent The agem has a maned nnd raptd -cidal action pg:u nSi mo:5t microorgamsms. including both Grnm-po<;i li,c and Grnm-ncgali,e bactcria, l1Iolds. YCllsts. viru<;c.'. and spores. O.l.ychlorosenc ;s used co treal

tion). tke molecules concentrnte Dttlle: Interface bctwttl! u .. miSCible solvents. such as water and li pid. and water-in .... or oil-in-watcr emu lsions may be formed with the ammo mum head group in the wDter layer and the nonpolar hy~ earbon chain assoc iated wi th the oil phase. The ~)"nllnl and IU1timiuobial actions of the member.. of this clau af compouoos were first reported In 1908, but it .... as the pioneering work of Gerhard Domagl; in 1935" lhatlllte. tion "~.IS directed to thei r u.sefulness as anuscplic~ dislnltc tanlS. and preserv:llhcs. The cationic surfOCtDnts ucrt a bactericidal action agaillll a broad spectrum ofGrom-positl,e and Gram-lle,atil"C t.:teria. They are also actm:~ agDin~t scveral pathogenic spme! of fungi and proi07.0II. All ~I)(m:s resist the.se agents. 'Ill! mechanism of octioo probably in\"ohes dissolution of tIIr surfllClant in co the microbial cell membrnnc. deslabJIi7""" and subsequcnt lysis. The surfacumts may alw interferc1rG enzymes associolCd with the ce ll membralle. The cD llonic surfactants pos!leS!i .severnl OIher IMope'''''' In addition to the ir broad-spectru m antimicrobial actll"'!

not'"

"~~~"'-""""~~"~"~/''-''''c~

HO/\

\/1",#

o.apltr" "",I-.'!!rrr,..., "","""

1ULE I-l Ana logues of
D i m.thy l ben~l a mmonlum

225

Chlo rid e

Head Group

C--pound

"

Iw:ethoruum ChlDflde

R=

_11Ic)' ~ highl), ","dler sol uble, stable in solution, l}QIl~taini nl!. and nOllact;,;t)' causes a kerdlQlyt;c lIC1ion and. hence. I . and other aniQn ic thrm. All of ..oap must be re frI'IIl S~1n lI\J OIlier surfllCes before Ihey are appl ied. ~!:;;::'~;:::;:~ and pus reduce the dfectlvelK'liS ~urfaclanlS are also adsorbed 011 10 rrouce or prcvem lheir action. 11Ic I surfactanL~ is 51 Qwer than that ~"'"" intended for disgloves, etc. should never be they can harbor infectious microorganisms. PJftIIi-.u and nltf'l!bacltf spp.
~Vl'11I1 dlmcullie~.

C UN lmd C. ~H " The hishcrmokt"UI:If-..~ight homQIogUCli compose: the map fl1lC'!ions. Although variations in the phy~ical lind antimicrobial propel1ies e\ist between indi vidual mcmbC'rs of the mi,\ture, they lin: of Illtle Importance III the ch/::rnistr)' Qf the Q\l'ral1 prod. UCt . Benzalkonium chlotidc: occun as D ",hile gel that is solu ble .n " liter, plcohol. and otgamc <.OIvents. Aqucou. M)IU liolls are CQIQrl ess. slighll y alkalinc. ;wd very foomy. Benull.:Olllum chloride is a detergent. an emulsifocr. and a welling agent. It i_~ used as an antiseptiC fQr sl.::in and I11I,M,:QUS nx:mbrdne5 in conccntl1llions of 1:75() to 1:20.000. For im gQ~ion. I :20.000 I() 1:40.000 concem mhons are usc.-d. For stQrage o f surgical instruments. 1;750 11.1 1:5.000 CQIICCntrd' tions are used. with 0.5~ NaNOJ uddcd as a preservau \'c.
homologues with
MethylMnzethonium Chloride, USP. Benl),ldmlClh )'112- [2-1[ 4-( 1.1.3,3-tctrametll), lbuty1)tolyl Jo~ yJc lho~)' II:lhyl1amlflooium chloride (Oiap;m:nc) is a mi~ t ure of ITlCthy l~Ied derivatives Qf rnclhylbC'nl-Cthonium chl Qride. 11 is u~d ~pecificaJl)' fot the treatment Qfdiapcrnsh In infants. caused by the yeast Cmtlbd" a'hiclllu. which produces ammo nia. 'n lC agent is also u.'iCd (IS a general 3l11iseplic, Its propenie-l ~ \',,1 ually identical 10 those ofben1.clhonium chlondc,

C. ~ lh!,

AI l )' lbenl)'ldimcthylamlllOj ~ a ""'.UUn' Qf alkylhenLyl. chlorides of the general formu la . where R rcpn:o;enl~ a mixture of ,,,,.,,,,.,,.,.,. lind uteoding tQ higher

,;7"'-,,~O~O~\;;;;/''''''''v'
",C

,;7

w ph
It

bu

dis

.\.IU

mu

OY

,;7"'/O~o~\"",
C",

Uic bi<M iofe viol

"',

Tho

dilio

C",

lena resis
1 0

,h

Gen

Ben;cethonium Chloride. USP. Bcn/_y ldilllClhyI[ 212(p-( I. J. 3.3-tctrun>eth y Ibl,ll Y )plK:noA y !ethm. y leI hY mnlOO1 I\a ium chloride (Phemero1 chloride) IS a colorles!i crystalline powder thai is soluble in Willer. ulcohol, and most organic sol~cnL~. The a(:lions ~nd USC! of Itll~ :\gelll all: SImilar 1 0 I~ orbenl.al~Of\Hnn chloride. It is used III II 1:750 ron'n tradon forslln anri<;cpsis. For the irrigation of muCQUS mem-

The eelyl derinlivc is the ~ acli~e ofa series ofa1~~~ pyridmlum OOflIPOtlilds. II i$ USC() as a general IlnIl~JlU( .
concelllr~tiOIiS

~"" viole powd

of I: 100 10 I: 1.000 roc 11II0C't ~lm. I:UX),I for minor laccralloos. and 1:2.000 1 I :10.000 for the imp 0 lion of 1I1UCOUS mCl1lbr.ll1cs. Cetylpyridinium chlondc IS allO a~ailablc ill the rOml of throat 107.C IlIle.~ and a rooutllnllt at D 1:20.000 ()ll utioo.

i ~ ~I

br.mcs, a 1::1,000 .0;011,11;011

available.

j_

u..ro. A 1:500 tioclure is alSQ

Chlorhexidine GluJnat~, USP. I.6- Di(4'-chlolUpbr: n)'ldiguanido)hcKlIl\e glocOllalc (1IIbiclclI~l i~ the Il106I If. rec, i~e of u scnc~ of :unibaclcnal blguamdes ongina/ly'" ve loped in Gr;:nl Britain. 14 "1"bo! anli microbial pn)pCn1cs of the biguanidc..~ .....en: ill.CO\cred as a l"ClIuh of earlier lestmg of lhese ~ as pas,ible antimal:mnl agt'nb (Chapter 9). Altholqtl" biguanides ~ lechnicall) not bi"'luDlemary 3mm... compounds and. therefore:. sholJld probably be cb!$rlll separute1y. they ~h3n: many phy~ical. dl.:mic-al. II/IIJ ~ c,otlill propenlCS wi,h the cationic surflOClanl5. '!"he IMp. nides an: stl"\Jllgly bask. and they CKi'l lll' dicalions at """"' logical pH. In chlorheKil1ine. ti1c posill'c t~ cotl11lc rbalanccd by gluconatc lmioos (not ~lI).l..iU:ct lionlc surfltClams. Ihoe..'\C un<.lc:rgo i n~ti val,on when .0',

""'" ,
wo~

IIlgin II is I riosw

'"""

Cetylpyridinium Chloride, U5P. I -Hcxaokcylpyridinlum chloride: is a ",hile powder Ihal is very 'I(lluolc: in water and akohol. In Ihis ~ompoul1d. the quaternary nnrog.:n alom is u member of an "rom.llte pyridine ring.

Basic
ch~

NH

NH

~I~"'"

Chapter II Anti./rl/rctive ltgenJs

227

.'1Ih anionic dC'tel1cnts and compl ex pbaIt, carbonatC'. and sil icate.

anion~ such

as phos-

Oolortoex,dine hu broad-spectrom antibactC'rial actIvity but is not active against acidfast bacteria, spores. or viroses. k 11M been used for such topical uses 15 pralpCrau,e sk.m dKInfC'Cuon. wound irrig:otion. mouthwll.~hes, and general 5mtIiution. Chlorhe"idine i~ IIQC absorbed Ihrough skin or ..:ws rncmbrallCll and doC'~ IlOC cause systemic toxicity.

o'-~il- II Y
o

DYES

OrJaniI: d)'es

were used very utensilely as anti -infecti ve IICQ15 before the discovery of the sulfonamides and the antihoIll'S. A few ealJonlC dyes still find limited use as anti IIfccIl\cs. These inc lude the triphenylmethane dyes gentian .... and basic fuchsin and the Ihiu jne dye n>ethylene bl ue. "hie dyts fonn coIorlcs 1 t'lY.Ibtue forms under alkaline condlllOllS. Cationic dyes are AClive against Gram-positi ve batmil and many fungi: Gr.mo-negative bacteria are generally ~ The difference in susccpllbility is probably relaled II !he ttllular characteristics that underlie the Gram SUoin. Gentian violcl iii variously k.nown alltUlt1C1hylp-rosanilinc chloride. cry&tal violet. IIICthyl .... IIId methylros.1niline chloride . It occurs a.~ a green ~r or green nakes with a metallic sheen. 1bc COfTIpound .!IlIDbk in water (1:35) and alcohol ( I : 10) but iMOlubie olipolar organic solvents. Gentian violet is available in ftCiJoaI suppositories for the treatment OIf ycast in fcelions. also used as a I tOl 3% solution for the: !reatment of !IIpOflI1 and yea~t infections. Gentian violet hns alsOI been - ' onIly as an anthelmintic for strongy loidi asis (thread-

crystalline powder With a mctallic appearance. 1l1e compound I~ soluble in water ami in akohol but insoluble in e!her. Basic: fuchsin is. romponC'nt of catbol- fuchsin !IOlu11011 (Castellani' s paint), which is llsed topically in lhe trealment or rungal infections. notably ri ngworm and athlele s

roo<.

Ger!tian Violet, USP.

alkyl )l ie in

: 1.000

Methyl_ 8/~, USP. Methylene blue ' 5 3.7-bb(dimethylamiOO)-p/1enuuthionium chloride (Uri sed). The COlmpound oct.... r.l as a dark grttn crystalline powder with a mcudJic appearance that i5 soluble in water (1:25) and alcohol (1:65).

ilTlgai~

11", a~h

"-.0

_ ) and OI~yuriasil.
ro r hc ost erlIy de8:osic fochsin is a mill ture ()f the: dikndes of Il)$an illne Ind p-rosan ilinc. II uists a~ a green
~ Fuchsin. USf'.

mum,",gua

...,

/ "

i'
c?

,tly"o-

" '"
ile ca

""-

I
C

c?

r ",

i'

r
c?
0

""-

""
Hel

H ,c"--"

""

, .... ""I

c?

' ""

NaOH

ml~C'J

c?

""-

Melhylene blllC has ...-eak antiseplic propenles that make: II uscful for the treatment of cystitis and urethritis. The: action of mcthylcnc blue is considen:d to be bocte:nostatic. The ~'OInpound colors the: urine and stool blue green.

MERCURY COMPOUNDS (MERCURIAlS)

Mercury and its derivatives have: bccn usc:d in med,cine for Cl.'ntlines. EI~nlCntal mercury incorponilw inlO ointment bases wa!lu<oc:d topically for Inc treatnlenl of IOI:ali:.'d infeclions and syphil is. Sc:"o:T.\l il"lOrganic ~Its of mercury. MlCh as mcrcunc chloride (HgClv and mercurous ch loride (calonltt II&1Cb) ....cn: at one: time widely u'ied as alll isep(ics. Ammoniated mercury [l/g(NI IJClI is still ol:.;:usionally used for skin inftions such as impetigo. J)looriasis. and ringWOfn1 . Mercuric oxide is 5()lnctinM!s used to trcal mn;lmma!rOO resul ting f rum infection of the eye:. Although the poIenlial inlemction of IIlC'rcuric ion wilh Ihe II~sues is gremly reduced by the low waler <;olubility of Ihe.o;e agents. lhey can be irriuning and can cause hypel1illn~i tivity readions; Ihc:n:fon:. ttlCir u<;c is not recommended. T he cornpanllively few organomercurials ~Iill in use lire employed 115 amisep(Ics.. ptesCl valile~, or diuretics. OrganOhlCilurials can be: grouped into IWO general clasiICS: (a) compoull!b .... ilh at lca.st one: carbon-mercury bond lhat does 001 ionile readily and (bl compounds wilh mercury bonded to heteroatom~ (e.g .. ollY~. nnrogen, or sulfur) that ionize partially or romp1ctcly. In addilion to its effect on ioni1.3tion. the organic moiety may incrc!tSC the hpjd solubilily of an organomercurial compound. thcn!by facilnalillg its pellCltalion inlO microorganisms and hosl ti .... ~"e~ . 'The anlibacleriul actioo of mcn:ury ~"Otnpounds is be"Clled to rc5Ult from their reaction with sulfhydryl (-SU) groups in ell7.ymcs and other proIeiM to form covalent compounds of the Iype R-S- Hg- R'. TIns acllon IS l"elcrsible by tn:almenl .... llh thiol-conlaining rompoutlds such as cystl'ine and dUIlC'rcaprol ( BA L); hcllCC'. otg;morncrcurials. reacting re'CI"'ibly. an: largely b."lClcrioslalic. The anltboctenal activlIy of orpnomercurial antiseptics is greatly reducw til Sl'fUm because of lhe presence of proteins lhat inactil'ate nltI"Cury compounds. Organomercurial amiseptics are 001 very effcclive Itgain)l $pores. The: disadl'anlages of mcrcurials for antiseptic and disi nf~'Clunt uses far outweigh any pos~ible lidl'antllges thaI they mighl have . l lence. othcr more efftivc and Ic.~s potenlially to~ic agents are prefer.tble, Nitl'Qf1"\CfWl i~ IIQllJrritating 10 mUCQU~ membrdnc~ and t~ IlOIISlalnong. TIto.'refon::, at one lime il .... ;os a H'ry popubr anllseptIC for skm and ocular infedlOns. NihOlncl-..oi has largdy been replaced b)' SllJlCnor age:nlS.

Thimeroul, USP. [(o-Carboll)pht:nyl )thlO)cthylmn eury sodium salt (Merthiolale) is a crcam-.,.'olorcd.... ater soluble powder, It is OOIl staining and nonirritating 1 li~~"", 0 Thimcro",,] is a weakly bacteriostalic antiseptic Ihal i ~ lJI" plied topicu lly ill olnllllCnlS or aqueous solution~.

s ......... Hg...............CH,

,.
PRESERVATIVES
l"rcscrvatil'Cll are added 10 lanous dosage forms !UKI COilmetic preparatH)lh to prevenl t1licrobl~1 clllltaminatioo. II p;!rcnternl lind ophthalmic preparal iolls. preservativc, In u.;cd to nminta in ~Icrility in lhe event of ~idclllal contaml nalion duri ng usc . An ideal preS<'rvlltive .... ould be effel.11'1.' at low cone:e:nlr.ltions against all JIO"~ible micn>organi'm<. be nonlOllic lind compatible wilh other coostiluent ~ of \be preparation, and be stable for the shel f life of the ptcp3r1tlOl. The: ,deal prescrvalt,'e does not I'llist. bullhere is qUilt'. bII; of I'lIperi~nce with some of them. In some cases, contbultlions of pre.....,rvative agenlS arc used to appro"Im3lc a mIl' lure of tdeal features.

p-H,droK,benk Add Derivatives

Eslen of II-hydroxyben1.oie acid (par-.tbcns) have dlstitICI anti fungal propen ies. Their to~ icily l(l lhe hUllmn hoi! i!. Iypicu ll y low bccau!I'C they undergo rapid hydrolysi s in '1\\1 1 p-hydro~)hen1.oic acid. which is quidly conjUtlllll'll and 0 e:~creteo:l. Thi s property makes Ihe parJbens uscful u r'" ser\ ativC$ for hquid dosage forms, The prcser""l'atlvc activit} gencmlly incn:asc:s 110 Ilh molecular ...cillhl. bul the lTlC1~i ester IS must I'fflilC ugainst molds ..... hereas tnc .. ....,.t ester I~ most effl'Ctive against )'C'asls. The ~ IipKl-'lOIllNr propyl esler is the prefe:rred preser.. altve for dntg til 011 (I" lipoplltli c ba ses

Ni tromersol, USP, 3-(Hydrollymereuri)-4-nitl"O-(H.:resol mllt'r ~It ( Me:tapl1cn) occurs as a yellow po.... der thai IS pructicaJly insoluble ill vr..ter and i~ $paring ly soluble in alcohol and most organic sol\ents. 'The SQdtum ~It I"obably has the "mncr salt .. structure ill .... tllch the inner.shell electrons of mercury an: occupied," The bondtng 10 IIlC'reury in Ihi ~ ~alt ~houh.l be collinear, 110 lhe ~lruclUre Iihown below I~ sonll: .... hat improbable. Nel'C'fIhelc.\~. Ihis structure i~ shown in lhe US r> and the Mud: IIII/c.r.

Mf!thylpariJben, NF. Mcthyl p-h~drollyben1~lt. IJ methylparaben. is a white cryslalline polio (\cr. II i~ 'iOIubk III ..... Jlcr nnd 3 1~'Ohol but onl)' slightly '>Oluble In Itonpoll'

tlr!aIIlC 1lO1.'enls. Methylp;lrnbcn IS used us a slIfcguaN olplII>I mold gTO'" lho

eSpially at pH > 7. Under these conditioos. chlorobutanol untkrgclC$ dllninaliOn. Solutions of pll - 5 are reasonably ~tuble al 25'C. Chlorobutanol IS slable in oil~ and organic solvents.

lIopylPlraben. NF.

r-

l'ropyl".hydro ... ybcn/.()llle . or proptlpMaben. OCCll" as a "'hite crystalline powder tlun is ~Ittly wlublc in wUleT OOt !;Oluble in mO'>t organic solvents. k" used as a preo;avativc. primarily to man! ye:ut grov.lh. I'rqI) lparnbcn sodium i, a WaICT-M)lublc o;odium sal t of the 4phcllOl ifOOp. ~ pI I of solutiuns of propylJXI ... Jbcn sodiam IS basic (pll - 10)_

Senlyl Alcohol, NF.

I3cnl)'1 ~lcOOol (phcnylcarbmol. phcn)lmelhanol ) occurs nalumlly as lhe uneSierified form in oi l of jasmine and in esters of acetic. cinnamic. and henlOic acids in Gum bcnloin, .. tor.!. ~~in. Peru balsmll. tolu ' balsam. and some volatile oi ls_ II i ~ w lubk in W'Jler and alcohol and is a cleat' liquid ... i!h an nTOIllatic odor. Scn;tyl lLlcohol is commonl y u...cd us II Pf... ~rvulhe in vial~ of injectable druGS in eonccnl ... .!tlOn~ of I to 4'l> in ....ater or saltllC solution_Rcnlyl alcohol h a<i the added ad,-unlageof huving D locnl ane~lhct ic IICtion. 11 is comnllH!ly u-cd in o Intments und I()\ion ~ as an antisepllc in the treatlllCnt of various prunllc slun oondil101ls_ l'henylethy l alcohol (2phenykthaool. oranGe oil. rose oi l. c.,H ,C II ~H :OII ) is a clear liquid Ihut is sparingly o;olub lc in water (- 2%). It occurs natur~lIy in nne oil lind pillC needle oil . It L~ usc:U pri marily in perfumery .

Phenylethy' Alcohol, USP.

n BUI)I,,..hydroxybcn/.().Jle (bulyl JIII*n) rx:cun; as a while cryMali inc JlO",der IhJI is spar. ~y oulyble in "'aler bul "ery soluble in :llooOol~ and in .,;4, or~anic SOI\'cnUi.
~rabM,

NF.

.~

Benzoic Acid, USP.

Benzoic acid and

liS tstttS

occur

mO~.

'"

"

'"

'" ...
~.

ErhyI,wraf)en, NF.
1ICf

Ethy l p -hydroll ybcn7.oate (ethylpar-

.td)lJ . ",hite crystalline powder lhat i~ ~Iightly soluble

but solubk in alcohol and 11105[ organIc solvcnt$_

naturally in gum hcnl.Oin and in Peru and tolu balSll11ls. It is found as a white crystalline sol id thai slow ly ~ubl iznc.~ at room temperature and is steam d istilla blc_" is ~Iightly solubk In w31er (0.3'l1:) 001 mon: soluble in alcohol and LI\ other polar organic so lvent . II has ~ pK. of 4 _ Benzoic acid is 2_ used elltemall y as lin antiseptic in louons, ointmen ts. and mouthwashcli. 11 IS nLOre effl-'CIhc!U u preservative 111 foods and phurrnllCCutical productS at 1 .... pH (less than lhe pK.). 0 W hen used a<i a presc:rval;\,c in emulsions. iUi effC'CtiventsS depends on both pll and diSiriootioo into the t ....o phases. II,

"" " ~"

II1d
~.

0"

o
Idlll Pr.-uwath_
1.1.1 -Trichloro-2-mclhy l-2-pro,..,a ~ \\ hill' crysta ll ine solid with a C"Jmphor-lik.e aroma. lotl'\lf"I In an anhydruu.~ form alld a bcmlhyd ...~te fonn, of which ~ublimc UI room ICmpc rn lu n: ~nd pressure. ",,,~WII)I is .oJ ig htly solubk in waler and soluble in Ii.~ and in organic 5Ol"ents. OaIorobutartoll~ used as a OOcterioslatlc agent 111 pharma ~ for injection. ophthalmic usc. and inlrana.o>al admin11 is unstable wbcn heated In aqueou~ solution,

lity

hi'

", .1<

..

O!Iorobul;Jnol,

NF.

Sod/urn Benzoate, NF.

Sod ium ben100 IC is 0 while cryMallinc MJlid Illal is soluble in water and alcohol. It is u..cd as a preservati \e in acidic l iqUid prt'p.'ltatIOllS in which hcnloic acid IS released,

Sodium Propionate, USP. SodIULn propionate OC'Curs as tmo sp;t~nl colorless crysm ls that ute IIOluble in waler alJd alcohol_ II is an effectiYe allllfungal . n l thai is used as a
preservalwe. Sodium propionate is mOoM effa.1he at low pH .

Sorbk Acid, NF. 2.4-He"adienoic acid is an effective antifungal preservative. It is sparingly soluble in water and has a pK. of 4.8. Sorbic acid is used 10 prescrve syrups. elixirs. ointments. and Il)(ioll$ con taining <:Ontpon.enlS such as sugal"i tlult ~u pport mold gro ..... th .

Potanlum Sorbate. NF. Potassi um sorOOte ours as a whi le crysUlJJine material that is soluble in wa ler and akohol. II is used in the same way lIS sorbic acid when greater water solubi lity is requ ired. PMnylmet'(urjc NitriJ te, NF. PhenyllllC':rcuric nitMe is a mixture of phenylmercuric nitrate and phenylmercuric hy_ dro;",dc. It OCCUI"!IIlS a " 'hitc <:ry5lalline mmerial that is sparingly soluble in watef' and s lightl y soluble in alCQhoI. It is used in conccrllrtlllOnS of I : 10.000 to 1:50.000 tu prtSl'rve injectable drui:s against bacterial COlllllmination. A di'ladvantage to orgllnomercurials is that their bacteriostatic efficocy is redllCed in the P'l'sence of serum.

cenlly begun to ~ive the seriOUS lInention that it desef'l'cs. This is perhaps anl'lbutnble to the relatively benign RatlU't Or the common mycoses. the nariTy or the most serious onn.. and the need for a morphological basis for diff~rential identi fication of these sU 'uclUraJJy complex fOll1l ~. Cursory examination shows that fungal infections fall intll two well-defiocd groups: the ouperfidal WId the deep-w1lled my~.11 The superficial mycoses:are by far the mostrofll. moo and are c..used forthe most pan by a relatively home? ncous II'OUP of fungi . lhe dcrmatophytes. These include yanous forms of linea. or ringwOIl1l. which are infectao. of the hair or hair folJicle~. the superfICial infCdions of thr intertriginous or nlll areas of hairl ess skin. and infect iO!\li c( the nail s. As a rule. the!oC le.,ions are mil d. superfkial. and restricted . The clIusative microbes are sj'Iialiud !.IIpn)phytCS with the unusual ability to digC51 kerutin. They hI't their ullimate rescrvoir in the $Oil. Unlike the deep-SC'1II:d myl:OlieS. howesl'r. they are frrqurnlly lransmiul'd from a. host to another (e.g" athlete's fOOl). A ~pecies of yeti!. c.. llidfl. also prodoccs a dcmlatophytelil,;e dlscase.

*'

Systemic Mycoses
The deep-seated. systtmic mytosc. have a sporadic dislflt. tion. l~ being common in bOroc p;irts of the world and .. known in other ,eographlcal IIn:aS. l1lCSe diseases ~vt I heu~roaencous etiology. DIO\C:asa caused by the liYSlCIIIIC c.. ganlsms include histopla!il1lO!ih. sporotrichosis. blaslOlll)W' sis. coccidioidomycosis. cryptococcos;s. WId ]'IOI'l'ICOt'C domycos is. The caus'lIive agems for these disca5e'i ~ inhabiting saprophy'l!.~ ..... ith the abi lity to adapl to the 11II(f' lIal environment ofllle;r host. TheO\C: organisms share ~ I mon roule nf infection. Fungal spores are inhaled inlG lung. and a mild. rold-l ike condi tion may result. 11l1s IIII!' be the only sy mptom. In the majority of cases. rnapparent. In ilSymptorrllllic disease_ diagnosrs IS often _ serendipitously. Scmlulauon... hl ch rc:nects pn:scm or,. \'ious experience with the orgllnism. mlly be dct~ It). skin teli! Of othe r immunological poncl'dure. The I~ system deals with thelle infeelinns by walling tlM.'m oIf by producing the gialll cells thm are common 11\ type IV hypersensitivities. X-ray ex amination or autopsy f~1ICId! reveals lhese lesions. As ~llIICd above. the causative CWJII' isms of the sysll'mic infecuon\ are not Iypically tllUl from one hosl to allOlhn". but infection by lhe an endemic tuea may be \'ery Cllmon. Few vclop 11110 the se,ere. deep. sPftading. and casc seen in some penons. If the infcrtion i ,i, i . i '. i severe I),.,. loms. ti~sue and orgun damagc. and. frequcnt ly. roVl.'ry from a deep-SCllted infection of thi s type is ... nied by an uncertain lIriarnl\('~lic Immune response.

0- " )-~ '0.

Ph@nylmerturjc Acetat~, NF. Acelo'yphenylmm:ury OCCUI"!I us white prisms thaI ~ soluble in alcohol but OII ly slightly IiQluble in walef'. It is used as a P'l'servlllive.

If

di_.

~~"V~'CH,
ANTIFUNGAL AGENTS

Ge.er.llntrodu:tlon to F.... I: Medic.I My:oIogl

The discovery thaI some infC(;tious diseases oould be allri bu!1'd to fungi actuall y preceded the pioneering work of Pasteur and Koch with pathogenic bactl'ria by jiC\'cral yellrs. Two mkrobiologjstS. SchOnlein and Gruby . sludied the fun gus TrichopltytQII schlN'nlt!inii in 1839. In that same yt'3/'. Langenbecl,; reported the yeast-like microorgamsm responsi ble for thru"h (Cant/it/a albicons). Gruby isolated the fungus responsible for favus on potato sliccs. rubbed il on the head of a t hi ld, and prodllCed the disease. lienee. he fulfi lll'd Koch's postulmes 40 years be fore they were formul at ed. 11 In spitc of its earlier beginnings. medicil nt~cology was quickly ovcrshadowl'd by bacteriology. and it has OIIly re -

""" II",

deC:;".'.";

Opportunistic: Fu....,lnfutlons :rI

In recem years. because of over/,C;Uous antlbiOlK:!!. the use o f Immunosuppressi"e ins, irtlldimion. and litcroi ds. a new t mycoses has become prominent. These are i nse fungal infectioos. There has been I incidence of these diO\C::iSC. t. as a rt'sult

Chapler K An,i.inft rlll,. Alltfllt disease, Of rlledical manipulation, i~ de (III.tIt o(lht llOImal defen<oes confe~ by microbial nora. 111, al10",5 organJsm~ of oormally 10'" ;rr/ltffn/ ,irultllC(, lO~tpk>illhe host Such iofecl iOlls include systemic ~andidi .... ~ilkrsis, and mucormycosis. Boclennl infections .:II. Gmn/le'g;lu.e seplicemia, l"IO!:an!iosis. and P U ll .$. _ infection. fungal infectiOns such IlS .... ith P"'''IIIQ,'IIU (onnii. and \Iral oppor1uni~t! such u ~ytomegalovil\JS ;II aliolCl such patient~. Mllhipl e infcction~ with varioos 1lliLl000&.u!isnlll are ~ommon. C. ll/biclms is a particularly .' I), opportllniSi. Thi~ yea~t is a mcm~r of the normal ...d)i.d non ofhllman hosts. especially in the vagina.. Use II ,\lIIIlYCpives often predrsposell a paticnt to infcction by (dlllliOO sp. Fungal nOl1l that inhabit lhe bowel may develop __ JIIpcrinfection with the usc of antibiOtics to 5terili7.e bo1ol:1 before wrgery. 0naJ candidiasi~ is common in ~noumhcd peN>n". in pallents on Immunosuppressive ~ and In pm.on~ with AIDS . Oppor1unisl~ can grow in al} e.'(f)' circu m., umce in which a p:1Iienl'5 immune 5Y5' ... is romprorni<ied.
r.tp)', ~nderlyin&

231

e5.

'"~ es,

nu-

.',<-"

nto

om-

oru

'h<

I'h<

b ol

.~'e

'"' ....
00<

"oJ

t'im

"" 7 II ; 'nfodlcnt5
." t

llphrtonsJD-M

B)

r. the most ~om mon types of human fungal discase are

,'"

thrdamatopbytoscs. 1'hesc IlrC superficial infections "(ee ~n3unrted epidenrri~ and "enuinr1.ed epidcnnal lip(i.e,. the hair and nail s). The scverity of an infee 00. depends largely on the location of the lesion :md the 'fe':rn of the fungu~ invol voo. Though c('nain Other fungi , ;;;Y Condidd $pp.. produce clinically smuh1/" diseases. a ; 1 homogmcou.s group of fungi. temred lhe d,.f ha .'''J. IS I'eSpoosible for tire Inajority of cases. The .rhhty of these orgllnisms to invade and PlIrdsitilc thc comiird b..sues of hair. s kin. and nail~ b closely I15sociatoo with. _rlrptndcnt upon. lheir common physiological charncler lI'ICUbolic usc. of!he highly insoluble sclcroprotcrn In The boochemical use of I.C'tlItin is nu~ and is shart'd 11'_ dermatophyte species of the family GymOQ:lscnceae. only a fcw <pecies of the family Onygenoccac. and lineae. In hum:ms. lhe Sencra Triclroph)"fOn !noIably r ,. (nalls, bean!, smooth )I.:in), T. IOflSllf'WIS (scalp, Il&lb~ T. 1'loIac(' ..m (~alp. skin nail s), T. numl('grtJ ~J (commonest causc of ad,lete's fOOl). T. I('""cosum .-:~. bea!d). and T. ....bnml (psoriasis Ir"e lesiQns of sinn. mfectloos of Mlls )l. MicrtJsporum 1M. glp. Iv:aip). M. f ..{''Um (scalp, hairless sl.:in). and M. n rnis p, !rair1fi.s sti n)!. and t..;l/dunwphyIlNl (e<:le ma) con dE mos.t cornmon dcrm3lophytes . 1'Iresr: organisms !be conditions ..oo.... n as linea (ringwonnJ. Some of alIM'IOn linea Infections are li sted below In Table S-4.

The fungus Pif)WSflor..m orbk.. llJff cau l\CS an additional type. linea \ersicolor. This organism. can~ Malasu:ill/"'f .., in older literature, causcs yellow 10 bro..... n patches or COll1lrluOIlS sealing over the tnm~ and occa~ionr, lly the Icg~. face. and The affected oreas may be idenlified by tbe inabllily to Ian Ln the sun. Regardloes!i of lhe type of funglls !haIlS CaUSLng an infec lion (Table Sj). tre:nment IS e~t remel y difficult becausc fungi. like maml1laliHns. arc eubryot..-;. Many biochemical ~ruclUres. especially the ce ll membrJncs. ure nearly idenlical,'s IltC many biochemical 'aclions. Con!ic.(jucntly. drugs that .....iII ..ill a fungu ~ will ha"e 11 to~ic effect on human cell s lit normal doses. A slighl diffef"Cl'I(."c e~i.~1S in Ihe cell mel1lbrJIlCS. Lipid bilaycn by thcnl.';ch'es arc unSiable and .....ould be unable to hold their shape and support their func lions. Sterols are embedded in the bilayer; to act as shffen;ng agents. The ).hydro)l.yl group rcpre.<iCnt~ the polar 'head group. mId the nonpoh,r sterol s ~eleton and side ~hain olign perfectly with lhe nonpolar chaLns of the bilayer. In human cells. the sterol in the membr3ne is cholesterol (Fig. SI). In fllngi , the ~terol is ergosterol ( Fig. 82). Thl~ difference amounl.~ to lire only source of sclecli~ity thm we havc In treating fungal inft.'<:lion~. New anll fungal drug development ha.s focused on this differcnce a~ II way to achie"e sclectivity. creating highly potent antltungal drug_ lha! IlrC much less toxic to the human host.

nec".

Subcut.lrneous FungallnfeclionsD'
S"bc"W",OIU m\"ffU refers 10 a group of fungal discll'lt;'l in whIch both the ) I.in and suhcuta.1COtJs tiSSllC arc in"olved but typically no dis~lI1ination 10 the i ntemal organs OCCUI'll The causali.e Ilgcnt~ are clas~ lrlCd among scvernl unrelal~ genera. They Ira.e the follQ ..... mg characteristics in common: (a} they are primarily soi l ~aprophytes of Y ery 10000 grade virulence and invaslle abililY: rind (bl in nlt)!;1 hUlllan and animal infections. Ihey gain IICCC)S as a ,sull o f a lraumll to the ti s,slK'. ~hny. if noI all. Ofganisms ha\c the potential to ~:lbl ish local infections undcrcertain CI!'l:UmstallCCS. de pending on their adaptabIlity and lhe responsc of the host. The tisslM.' reaction III most cases .arie~ wilh the aSCl11 in que-'Iion but usually ",mains a localized Ic.~ion similnr to that ehclled by II (OI\:lgn body. 1"be mIlJOr dlscase types are chromomycosis. sporotricho>iis. mycetoma. Iobom)CO!>IS. and entornophthorurnycosis. A Iype of dimorphi,m acwm p:onies infection by ngenlS of SOllle of thc.'oC groups. The organisms undergo a morphogcnt:~IS from their saproptlytic form into a tiSSllC Of parasitic ~t~'C.

Tlss.. e Reactl_s of Fungal Dis_seD

TABLE a...4 I oc:ation, of the

Common Types of Tinea (Ringworm)

''''
,-~

location

T. . c:n.n. T. . ,,..,
T"'.H""'~\

"'". .....
,.,
Sa>,

Twa "",",uln

1lle liSS llC response of the host to the infecting fungus vane.~ widely and depends Wtnewhat on lhe \,arie(y ofthc ;n.a.....e otgani~m. In dermatophyte infl"CtlOl'1 s. erythema IS generally produced and is a rc..sult of tile irri tation of the ti ssucs by the organism. Sometimes, SC"crt inflammation. (ollo,",ed by scar li ssue and ~dold formation. occur;. Thl~ results from an euggcnted Innammatory fC$ponsc and (Ill allergic rrac lion 10 the organism and ils products . With organisms thul invatlc Ir ving ti~sue. such as lho~ fC$\1omiblc fOf subcutaneous and syslemic dlscase. thcore is generally a uniform acute pyogenIC reactiOl\ that g ives way

232

Wil.WII and Gisvold's Tr:trbook ofO'sMi<'

M~didnal

muJ I'hmmucrul/ml Chrmisrry

TABLE II-S Clinical Types of Fungal Infection

' ....
CIIU<Ie<>III 'nr~

case:
lial 0
P"f'T(lJI""''''' ",bf<1'/""
TTi('~ cw"'.... "'" (..'hotel

'"

DIIUS4I Stllte

Ihro~

coag' ease
m,~

cauS(

1'1,,,,....,.,.. <If ",alp, HAI RI..ESS ,t i", 1OlI,1.

C.-.Jidotl. filM..,. IIIOCWS .... n'~

PiNnow itorru. ibl.o.:~) DtnnIlOllh)'lC$. M1m""""'.... T.vlrofthJ'W'I. Epldr""""""", C~/IdidQ alhkM> lind <dated form.
~""Stm'" ,...unmi

numt

II1II1,: iQfllOUn>e< "",.ntll!

C1w ... \li,

"l'W'''

. nd ",loled (""".

Top

AII'SCN .... boyd, Mad~".'kl m1""";. o! at. &ildiobr>l~, /oapI<M,_J<J

111""""_,,
81"l1Omyro'l"

C.... I,//W/.s Ililt<>pitJJmU c<rJ .. ~I"'_

BI.u"",,'Kf' J

"''''''''''J<J

Colic ...om, menl

i~

"""",,,,,/d,_,
i"""""

a f(

P....,,,,,,,,dloldomy<'(I$j ~ CQOadioidomyco,,, J
C,)'pIQCOC'CCI!i_

l"II'txf1('('iJlnidn blUJil"..... I'

topic: the b:
salic)' runel;

SponllrkboJ.>,\
A<pn'Jln... i~

CWr/d"..M1 CryplO<'t'l<s nr."",,,,,,'fl Sp",,,,hri.o S<NrlCLI

M\JI.'()fmycUlo<' lIi""",.,,,,,,,ls du~, i

....",,,,iI/,,,fomil""" M~r", >flI1 . Alukh'" !{III .

>Am

II}',,,,,,.... ~,
oh.l>t>iJi'

1Ii""'PI<l""" c"iu/,mur. .or

Adult, called pan Q used f scbum the $('1 calcd. fact ha Tho
fungiei lion.

HO

\ p"' ,

\ ,C",'

tage 01

\
\
H,C

", H HH

; H

C",

HO-bo

Prop/a lhal is r

'"' '" \ forms

also (u The sal

Figure 8- 1

Cholester~

embedded in

iI

liPId

b,layer

with a (

odorles

HH

Zinc Pr drous f{ but onl)

HO

/ \

\ ,c"'
,,
,"HJ

V C",
; H
H

mois\un propion.

tape.

\
j

/C

Sodium caprylic

oils. Tilt SOl uble I

H
H

.",.

Figure 8- 2

Ergester~

embedded in a liPld IJ.

III. ,1Imty of chronic di5ease oU!cornc~. Granuloma with

~lIon

and fibrocllSCOUs pulmooary granuloJrnl are poIenl1li OU''''l'DQI of infectioOn with His/oplas/tIU C apllllalWfl, Ind

Ibrombollc arterius. a thrombosis charactcriled by a purulent "",uJlti>'c necrosis and inv1l!iion of blood vessels, may be c-.;rd during tipCrgillosis and mucormycosis. 11It; large ..uubm of funglll species of mDny mOlI"'lotype$. their diselll'ttiology. and the diversity of OUICOInes make medical
~

SodiulH caprylate is used topically to treut superficial dermatomycoses caused by C. ulbielJllJ and Trichoph)'lOtt. Mi crosporum. and piJumophylOtl spp. The sodium salt can be purchased in solution. powder. and ointment forms.

a complex rleld.

Zinc Caprylate, Zinc caprylate is a fine wbite powder that is insoluble in water or alcohol . The eompound iJ used as a topical fungICide. The salt is highly unwble tomoistul'C. Undeq/en/c Acid, U5P. ](),Undeccnoic acid (Desenex. Cruu) hIlS the following molecular fannula :

Tlp lr_1 A. , ,,ts to.- De, ..

"'ph,' Is u

CoIkctJvtly. the dC'ntllItophylO!ieS are called '''n~a, 01" rins ' __ . Since the.1IC infections tend to be lopicllJ, lhcir treal _ bas been (\irectilo s.urfatt areas of the skin. The skin I I fomlldabk barrier to drug penetration. and many of the . al )gcnl s work best if an adjuvarn is added Ihll.l opens a barrier function of the skin . KerutoJylic agents such as *111c Kid or other a-hydro~)' compounds perf"0ITIl this

fu.11011 reasonably well.

FAmAGOS

AIIIIIS ILave an acidk. fany SUbsUl/ICC in and on the skin

Q/kdxmu... Sebum fUOC1ions a~ a natural antifungal agent, pM of !he innmc immune system. Fany acids have been IIStd for yean with the idea that if a substance similar to td:vm could be applied to the infected area. the effect of dE Stbum would be augmenlw and fungi oould be enldi"*II. The application of fany ocids or their .!Ol lis does in fit! hI~e an antifungal effect. albeit a feeble one. The hlgho:rmokcularweighl fally ..-ids have the advanlife of having lower ,olalility. SalIS of f.uy acids are also Wcitdal and provide nonvolatile forms for topica.l applica

~H
H

The acid is obiained from lhoc destructive distillation of castor oil. Undecylenic acid is a vi5COUS )'ellow liquid. ]t is almost completely msolubte m water but is so]uble in alcohol and nMlst organic SOlvents. Undecylenic acid is ooe of the better fatty kids for usc as I fungicide. although cure rates are low . II can be used in concentmtions up to 10% in solution s, ointments. powden. and emulsions for topical ildminisfnllion. The prepanalion should IIC\'CT be applied to mucous membtanes because it is a sevefl! irritant. Undecylenic acid ha~ been one of the agents trdditiooally used for athlete' s fOOl (Iintl> ptJiJ), Ctn flUes are low. hoWe\CT.

H H

Acid. Propionic acid is an anlifungal agent _lIl1Or1imtaung and nontoxic . A fler applkulioo , il is pres III in persp;r~tion in low l'Oncemnuioo ( - O.QI %). Sail ~~."'llh sodium, potII.~s;um, calcium, and lUIlmonium an: Il1o fungicidal. Propionic ocid is a clear, COITOSI\'e liquid _i!lJ I characteristic odor. [t is soluble in water and alcohol. TlIr wts aR: usually used because they are nonvolatik and

~k

TriitCetin. USP. Glyce!}1 triacetate (En1.xhn, Fungacetin) is a oolorless. oily lilluld with a slight odor and a biner taste. T11e oompound is soluble in water and miscible with alcohol and most organic lOt-ents.

line /I'ropian.te. Zinc propionate occurs as an anhy.... form and as a monohydrate . 11 is very soluble in wmer "only sparingly soluble in ulcohol , TIle salt is unstable to forming zinc hydroxide aod proptonic acid, Zinc pqIIOO'l3te is used as a fungicide. parucularly on adhesive

...

_e.

The: lIC' i~ity of triacetin is due to the acetic ..-id released by hydrolysis of the oompound by eSlCTll5C5 present In the skin . Acid release is a self-limning process because the esterascs are inhibitw below pi t 4, Salicylic A cid and Resorcinol. Salicylic acid is a strong aromatic acid (pK. 2.5) wuh both anti septiC and keratol)1ic ptotICI,ies. It occurs as ...-hite, needle like crySl\lls or a fluffy crystallin.c: powder. depending on how the compound was brought out of solution. Salicylic acid is only slightly IOluble in wlter but is SOluble in nM>St organic solvents. 1lIe greater acidity of salicylic acid and its lower solubil ity in water compare! with p-hydroxybenl.oic liCid an-. the conseqtl('OCe of intramolecu]ar hydrogen bonding.

""'In

Sodium Caprylate. Sodium caprylate is prepared from ap)he acid. which is a component of coconut und palm The ~t ~ipitat($ as cn:am-colored granules that an: water and sparingly soluble in alcohol. ,
... 0 '

.'

o
,:Y
~

.. .. ""

.. ""

from light bause the CQtnpound is photoseru;iun. II ~ progin i~ a,ailable as a solution and a cn:am. both in a 1'1 COIJC('ntnuion. Iialoprogm is probably 001 the first topICal agent that should be m:OlnllK'nded. While the eore rotcs fOf topical funglll infections are relatively high, they come as a hi gh price. TllC 1c,ion typically Wor5ClI!l bcfOfe it impr<l'es. Innannllution and painful Irritation an: eOI1I1I1OO .

S alicylic acid is used externall y in uin lments and solution s

for its amirlmga l and kCT1Ilolytic IlIVpCnics. By ilself. sulicylic lICid is a poor antifungal agent. m-lIydroJlyphcnol (resorcinol) p!)S...cssu al1liscplic and

kenuolytic acti vity. It

occu~

115 while. l!eedlc llke crpb.ls

and has a sl ightly sweellastc. Resorcmol is soluble in waler.

alcohols. and DrJ!anic solvents.

""

~VI'OH
Berll.oic add pos..sc:sses U]l'Pn:t:iabl e anti. fungal e ffecls, but it caJU1O{ pencWotlC 1he ouler layer of the slin in infected areas. TI!ercfon:. bcnl.Ok add when used II>! an antifungal agent must be aumj"ed with a kCT1IIOI)tk agent. Suitable mil(\um; are bclll.oic acid and saLicylic acid and bcl11.oiC acid and rt'5()I"Cinol. An old prep.1.l'lllion thaI IS 51111 In use is Whitficld '5 Qinllnenl. US P. This oinl~nI contams bcl17.oic acid. 6'W. and salicylic k id, 6%. in a petrolatum ba.sc:. TIlt cure rates from pn'panuioos m ,e lhelic arc low,
B@nzo/cAdd.
PHENOLS AND THEIR DERIVATiVeS

Clioqu /no/, USP. 5ChkJro. 7. iodo-8-qumolillOl. 5-ehloro8.hydroxy.7'IOOoquinolme. or iodochlorh)droxyqu. (Vioronn ) occu,"" as a spongy. lightsellsilive. rello"'lsit wllile powder Ihm is insoluble in wall:,.. Vioronn was 11Il tially used as a substitute for iodoform in lhe belief thai ~ released iodine in the tissues. It has been used as a powoJcr for many skin corn!itions, such as atopic dennat il is. tt:7.cma. psoriasis. and impetigo. A 3% ointment or cream h~ 11m used vagi nally II) . trealment for Trichomomu I"ugilwlis....,. inilis. TllC best use for Vioform is in the topical treltl1ltll of funllal infectIOn) such as athlete's rOOl arn! jock iu:h. It combinauon .... Ith hydrooonisooe (Vioform tiC) is W> aVllilable.

Severnl phcools and their dcrivative~ possc,s lOllieal ant ifon

81,11 propc:rties. Some of tliese, 5"'1'11 U!l hcxyln.'SQrciool s and parncllioromctuxyleool (below) have been ... .;ed for the treat ment of tinea infections. T wo pheool ic CQmpounds, cl ioqui 001 and haJoprogin. ~ still official In the US P. A third agent, ciclopirox olamine . is 001 a phenol btu ha..~ propcnies like tllosc or phenols.. All of these: agell ts IIptlCaJ" to interfere WIth cell membrane integrit y and f ... octlon in s... Sttpliblc fungi .
H

" H

Cidopirox OIClmln., USp.1S 6-Cydohcxyl. !h)!WlIOyl ...... rnethyl.2(IIl).pyridioonc: ethanolamine salt (Lorro"o' is a broad spectrum anlifungal agenl intended only for .... caluSt'. It is active Aiamsi derm:lIopnytcs as .... ell as petIt.Igenie yeast.'i (c. albic-mrs) thai :Ill: c;l.Usali\e allents for wpn. rlCial fongal infections.

H ,O

J.. lodo-2.propynyl.2.4,S.trichlorophm)l ether (Halotex) crystallizes as .... hite to pale yellow foo lib that are sparingly soluble 111 WAter and very .'IOlobl(' in ethanol. It IS lUI ethereal defhati,c of a phenol. Haloprogin is o~ as A I'it; cream for the treatment of ~upt:rfK:ialtinea infections. Formulations of haloprogin shou ld be protected

H. loprogin, USP.

Cidopirox i ~ coo)idercd all agent or ehoice tn tht lINment of eotaneous candidiasis. linea corpori s. unca ~ tinea pedis. and tinea versicolor. It is a !>eCOnd1ine lIP lhe trenlme nt or onychomycosis (.;ng.....ol"ll1 of the Loproll is rorm\lllllcd as a cream and II 1 00ion. ellCh

III 1'10 of the WlIIer-wluhle cthanolamille ~Jt_ Ciclopirox I btlJe,ed 10 act on cell membranes of wscepuble fungI at .... ronccntr.III011S 1 block the Ir.UlSpon o f ammo acids 11110 0

lie ccll~. At higher 1.:onccmtrluions.

lIIembr~1lC'

.nlegrity is

and cellular cooSiduems leal 011\.

llludeos ift Antthlngals

Flucytotlne, USP.x S-Fluorucytositle. 5-FC, 4um;noHuoro- 2( III )pyri milli none, 2- hydrox y-4 -urn i n{)- S-n uorop)nmidinc (An.:obon). 5- F1uorocyu>sine IS an UrdU )' active

.. rungal agent with a w:ry narrow ~1)C(:trum of act;v;ty. [t II illlllcaltd only for the treatment of serious systemic infcc_;~~; u~d by sU<iCepl1blc SUllins of C/IIIlUda

and C,)I'-

'I'P.

number of 1e,e1~. A main one is al the m p in I'I-hich the drug IS tntnsported 11110 the fungal cell. "The tr.tnsport 5~tem $imply becomes impermeable to jFC. TIle c}1osine dcarn,nase step is another poi nt at ... hidl ~iSlance 0CC\If$. and the UMP pyr0ph0i5phory lase reaction is a thin.! point ul which fungal ce ll s can 1:N:cOIIM.' resistant. RcgardJe.-.s of which of these mechanisms OpC:nlles. fungal n:sislallCC de vclops rapi dly and eompk tcl y I'I-hen jFC is oomini\ltrcd . After II few dosing interval s the dru g is esscntinll y uSC'le~s. One stralcgy used 10 dccrca..;;e re.~istnnce and to prolong lhe effecl of 51 i, 10 IKIminisler il wilh the polyene amibiQtic '(; amphotericin B. TIle nntibiOlM: cremes holes in the fungal cell lIl\.'1l1brane, bypassing the tl1lnspot1 step IUld IIllowIII, 5FC 10 enter. Addi tionally , loYo'er dose of 5 FC can be used. pre\enting resistance by other mechanisms for longer period.

xu~ i5h

lum

A.. tlfD"la' Alltlblg!ks::U' "

The antifungal IlI1tiblOlics make up ltn importllnl group of antirungul a.l!enl ~. All of the untibiotics are marked by the Ir complexity. There an: two da~ses: the pol yenes. wh ic h can tain II hlIge number of agents with onl y It few being use ful. and griseofulvin (anI.' mcmber of the class). of action of S- l1uorocylO!>inc t1a.~ been -::~ 10 dew] and is prescnLed ill Figure g3. n.c dru g ~ !he fungpJ cell by acth'e IIlUlSpon 00 ATPases thai II)' lr.ln'fJOf1 pynmldines. Once inSlik the cdl. 5-l1uork)1OU1lC I~ dl:aminated in 11 reaction caullp.oo by t")105ilM.' .1Ib" to yield jnuorooracil (jAJ). jAuorouracil is tit 1CI1,"e metabohte of lhe drug. 5-"'uorourucil eml.'rs inlO 11}\ of boch ribonucloolide and dcollynbonuc1eotide ~~ 1"hr; nLK)f'llli bonucleoude triphosphale5 an. incorinlO RNA. causi ng fnu lly RNA synthe~I~. This pmh (1~~ ce ll death. In the dcollynbonucleotide !ierie.~. 5 ~yuridine monophosphate (f.d UMP) blllds to S,1(l.mclli}lcllclctl1lhydrofol ic aci d. intemlpting tile one cabon pool su bstrnlc thai feeds thymi dylutc sy nthesis. ht. DNA synthesi s is blockoo. Ilni\lance 10 5 r-C is \'1.'1)' COIllIIlQll. attd il occurs ~ t a

ml-

: 111:1.

."'"
The
mecl1an i~ m

al 1\

/'" \'lIg-

h A alw

~"

POLYENE5

A numbc!r of structurally compleJI. anlifungalltnllbiOlics ha,'e been i""laled from soli bai;:tCrla of Iht.- genus Srrtpmm)"ces. The compounds an. ~lmi1ar, in thai tlley corlliun a system of conjugated double bonds In mllCTUCydil: lactone rings. They differ from the erythromycin-Iype structures (rnacrohde\: see Ch.'\plcr 10). in thai they an: largeT and conlain the conJu ga ted ~11t' ~yste Jll of double boods. Hencc. they nil! callet1 the /1OI)"t'II(' ulilibimiC"S. The c linica ll y useful polyellC's fnll into tWO groupings on tile basis of the si1.c of the macrolidtl ring. The 26- rnclllbcrcd rin g polyenes. ~uc h a! IlI1lalllycin (pima ricin). fonn one gl'Ollp .... hil e the 38membcred macrocycle~. such lIS amphotericin B and nysto!ill. fom! the other group. Al'iO common to the polycoe.~ are (u ) a stiles

OFU", -

_ .

5FUDP -

5-fUTP

SFC~

-J.+.

\
SFC. - -- "

"'U

I
5FdUMP . 5FdUOP ___ 5-FdUTP Inhibitory

CoIlfllex
dUMP

OTMP

treat-

cruri\.
n:1II\).

cnt f~'If

;mla; n-

5,lo-Melhytene-THF

7,B-DHF

136

Wil.oon aM Gm'Old'J Twbook

of O"6Mk MttlkirtllllPld PllamJUCtu,;rol

Clt<:mlmy

of hydroxyl groups 00 the acid-dcri ved portion of t/we rin~ and (b) a glycosidicaJly linked deo~yaminohe~O$C called ml'COS{lIl11nt. The: number of double boods in the macrocydk: ring dlffer1 also. Nautmyci n. lhe snuUlesl mllL'roCyck. is pcmaene: nystatin is II. hexlIC'ne: and amphoferici n B is a hep!3C:ne. The poIyenes ha,'e no lClivity agaill5t bacteria. rict eH ia. s or viruses. oot they are highly potent. !)road-spectrum antirunga l lI.h~nUl. Thocy 00 have activity a~ainSI cenam pratowa. such as Ltishmllniu ~pp. They are effective against patbogenk yeasts. molds. and derm:uophytes. Low COfKCTl' Iflllion5 of the polyenes in Vi trO will inhibit Candida spp.. Coccidioidu immiliJ. CryP'OC/ICC" J ntojomums. Hump/llJmt' r upsufalum, Bl/J.JlomyctS dtnruJlilidis. Mucor mllCtdo, ;'spt'gi/l..s jwniglJllU, CtpMloJporium spp., and FllSorium spp.

The use of the polyeoes (or the Ul'atmetlt o ( systemic infections tS limited by the toxicities of the dru gs. their low water solubilities, and their poor chemlcaJ stabilnia;. Amphotencin B. the only polyene usefu l for the treatment of serious systemic tnfectioos.. must be: solubi lized wi th a deter gent, The IXher polyeoes are irldi cat~'d only a.~ topical agents for superficial fungal in fections . The mechamsm of aC1ion of the polyenes has been studied in some detail. Because of their three-dimensional shape. a barrelhte oonpolar struclLlre capped by a polar group (the sugar). they penetrate the fungal cell membr.mc. acti ng 8!l "false membnne components." and bind close ly with cr gmterol. causing membr.11IC disruption. cessatIon of membronc enzyme actI vity. and /Q$s of cel lu larconsti tu.ents. especially potllS$iurn ions. In fact. the first observable in vi tro n:aclion upon Irl:alin a fungal cu lwre with amphofericin B i~ the loss of potassiu m ions. The drug is fungi SIalic at low roncc:nrnltions and fungicidal at hi gh CQIlCentralions. This suggests that at low concenlr.uions the polycncs birld 10 a membnlne bourld enzyme component. such 8!l an An>ase,

Amphotrridn S, U5P. 11lc isolation of IlfIlphoteridn B (Fungi;wne ) wns reponed III 1956 by Gold el al.2\I The compound WlIS purified from the ferment.,ion beer of a soil culture o f the aclinomycele S'f<'p'Otnyct!.l noooJus. which wus isolated in Venc:zuela. The fim isolale from the slreptomycete was a separnble mi~lure of two contpouoo". designated amphotericins A and B. In test cuhun: s. compound B proved to be: more active. and this is the one used clinically,JO 'The structun: and absolute ste~hemist ry ate as ~n,

Amphoteridn B IS belie.. ed 10 tntmM;1 with memtn..: sterols (ergosterol in fungi) to produce: an uggrtgate m. fonns II tr.rnsmembrune channel. intt:'mM)lecular hydrogel bonding ilUcrncfiCHls IIlllOOg hydro . y l. carbo~yl . and amillO groups stabilt/.!: the channel in its open form. destroyitog ~ympon acti vity and allowing the cytoplasmic COlltcnu 10 leak out. The e ffect is si milar witll cholesterol. Th is expl:lHtI the toxicity in human patients. As the name Imphes. ampnc.. lendn B is an IlfIlphoteric substance. with a primary anltlIO group att.ached to the myrosarninc: ring arid a carboxyl group on the mocrocycle . 'The compound forms deep )ellow tT)')' Illis that are sparingly solu ble in organic whenl$ 001 insolable til watCT. Although amphoterici n B forms salts Willi bot!I acids Itnd bases. the sallll ore only ~lighll y soluble in I01IIn (- 0.1 mg/mL) and. hence. cannot be: used systemicallr To cn:3Ie. parentaal dosage form. amphotericin B is stabtltlflll as a ooffered colloidal dispersion in mice lles wllh sodiua dcoKyeholate.lt 'The barrel-like sU\lCture of the anubiub.: (!cyelops interac:l;"e force5 with tho: ttllcellar contpoomu.. crealing a soluble disper;ion. The preparation i~ light. heM. sa lt . and detergent se llsiti ..e. Parenternl amphotcricin B is indICated for Ihe It'Catmelt of se\ere. potentially life-threatening fungal infections.. .. duding disseminated fOl'ms of coccidioidomycosis and biltoplasmosis. sporotrichosj~, North Amcncan bl ll5tom~ cryptococ(,:QSis. mucormyCOSt s. and aspergillosis. The usc: ful nc:ss of ampOOtcncin B is limited by biJIt prevalence of adverse reactions, Nearly 80% of paoem treated with amphoferici n B deyelop nephrotoxictty. Fe\'CI. headache. anore~ia. gastrointcst trtal distftSs, nl:llaiw. - ' muscle and joint pain are common. Pain at the si te ofinJlf' lion arid thrombophlebitis are freqU<!nt complications ~ intrJyenous adtrtini strntion. The drug must ne\CT be nnnistered intr.l.muscularly. Tbe hemolytic aC1;';tyof_ pOOtencin B may be a consequence of its ability to choles/eml from crythrocyte cell mc mbrane.~ . For funga l infections oflhe central nervous ~yslem {W (e.g .. cryptococcosi s). amphotericin B is mixed ""ith carbrosplnal fluid (CSl-l that i~ obul.ined from :l spinal lilp.1k solution of ampkotenci n B Is lhen n:injected throusb tap . For severe infect Ions. this procedure may need 10 It! repeated mallY limes. Ampholericln B for injection is $Upp1ied as a sterile lyost. i1il.(:d cate or powder coma ining 50 mg of anubiotll:

H,C" , ,

0
OM

" ",
HO'

""

ale Ihm

m""'~

,dn~c n

I amioo

lroy lng lenh 10

~"p1am.,

ampho-

Y wlllno ~ I grtUP
Cl')'~

rw

I insolu ~Ih both

n ... :ucr :ally. To

sodIUm

tabihlCd

nlibioll~

\hI, heat.
. 1Il-

~nl'.

11

high

pa llent~

~"""J'< """
IO

FC\'Cf.

~"",~'::'
ol _

led

....

Tho

... ..

II "'I oJ ~ium deoxycholalc 10 be disper,;ed in 10 !l1L of _ The Infusion. provilling 0.1 mg/ml~ is prepared by irItlC'rdllulIOI'I (1 :50) with S'l> dex trose for injection. NorIIII...J,~ UnllO( be used because il will break [he micelles. , . WI~nsWn should be fresh ly prepared and used within ~l 1IowI. E,-en the powder should be rdrigcr.ltcd and proID:d from light, of stcrile dosage forms'J with ampllOlericin B _/.tid ",jlh a li pid carrier have been developed with the pi 0( counlerncling the: dose-limning [oxieily of the drug .....'lnl pm:nlcnli oominislr:llion. 'The:se include arnphoImrIII B colloidal dispersioo (Ampbocil. AmpbocYlc). ::ooru,ns nearly equal p<lrts of the drug IlIld choleqero/ : in I suspen>ion of disk-li ke paniclc$: Abekcl. a I: I IllUOn of umpholcricin B v.ith I..-(t-dirnyrisloy lphos ~~kboline (7 p:uN and L-(>'+(Ii myristoyl phosphatidy l~ (3 pans) to create a suspen~ion of ri bbon-I ike Sheels; _1ipo5omaI amphotericin B (AmBi'lOlne). II small laminar ~tion consisti ng of an appro!\imately 1: 10 IliIIO 0( amphoIericin B and lipid (hydrogenated 80)' Idyl choline. cholesterol. and diSiearQ)' lphosphati~ldIoIlnc In II 10:5:4 ratio) for an aqueous suspenskll1. ~ rationale behi nd these lipid prcpanlliollS is simple: .mcln B should have II greater avidity for the lipid >dI.ckdlan for cholesterol in ce ll membrane..\. Hence. toxic " Ihould be reduced. LiPldassociated .mphotcricin B be 1,\n....11 i!lto the mlculoeudothe lilll system. concenIn the Iymphalic ussocs. spleen. liver. and lungs. IIIIM mft:Ctiou, fungi tend \0 locate. Li pase.~ elaborated by .Id~ ~ the host ~hou ld re lease the: drug from the li pid cam. making il aVailable 10 bind crgOlilerol in fU/lBal cell ":,m~ tonr:n its fungiSialic and fungicidal Kt;"ilies. I..... lISe' of each of the: approved lipid pltl'lIT"dlions 'IolIlIltduced renal tOAicily. UposomaJ amphotericin brm *I'P0.-edspecirlCally for the tre8nnenl of pulmo-II) ~Ik$s ~ause of its demonSlr:lled superiority to tr ~.Lum lIco~ychol ule -sIDhi li1.cd suspension. AIIIpIIotnK:1R B IS also used topically \0 treal cutaneous -' ..:o:ut;wws m)'COSC!i caused by C. al/m:unI. 1"'h/, .., ~ wppIJed In II ,-ariety of topical forms. including a a-. I 3'1 Jouon. ~ J% omunenl. and a 1000mglmL III The {)nil suspen~ion is imended for the: treat.oforallnd ptwyn~'f'al candidiasis. The patiem should

sw i ~h the su'pension In hl~ or her mouth and swallow II. The ,u_pc:n~jon has a v~ry bad tasle. <;0 c(IJI1 pliunce may be a problem. A ~ l llwly de\'eloping resi~tance to amphotericin

B has been described. This I~ believed to relate 10 alteration s III the fungal cell Incmbr.me.

"....,.ber

USP. Ny,taun (MycOIilat mj I ~ a polyene anu biotic thnt wps fil'lit 1",,1atl-d In 1951 from a .tmin of the lICtinomyc~te $lrl'plOml"ct'$ IIourui by Ilazen and Brown." It occur.; as a yellow to light Ian 1'O,,"'der. N),slUlin is very ~I ightly soluble In wOler ~nd sparin!!!) soluble in organic solvent!>. n.e compound b unsl:Ible to moi,Iure, heal. and lighl. n.e aglycone portIon of nystatin is called fl}SfIIlinolidl'. It con,i~ls of a J8-memhcred macrolide loctollC ring oon\ai ning single ICITlICIlC and dien\! moicti\'<> scp:lmtl-d by t\\o met hylene groups. \.I The aglynme ,11 comain _ eighl hydro~yl .-.0 groups. 0l\C C-.UOOll yl group. and tnc lactone: este:r fUOClionalily. The entire compound IS constructed by lin"ing tnc .gly cone to mycosamine. The complete stlllClUR: 0( nystalin has bc:c'n dettrmined by chemical degrndauon ond x-my crystallogrophy." Ny'lalln i. not ab..orhcd ., y,Iemically "hen admini stered by the: oral mule , It;, nearly in'lOluble under 011 condilion~. It is al'\O tOO to~ic to be admini slered pan:nle:rally. HCrlI:e, " is used only as a topical agenl. N),'Ultin i~ I valuable agcn! for the treatment of local and gastro,ntestmal monilial inf~1ions caused by C. alb/emu and otncr ClJlIlfida species. For the treatment of cUlaneous and mucocuulllcous candidiasis. il is SUp!)lied as II cream. an ointment. und a JIO"'-der. VaBjn~1 IlIb/elS tJ~ a""jJ"l>/c (Of' tbe c'Omrul of, "8i"al candidiaSIS. Oral tablets and lroche.~ arc used on tnc treatmcnt of gaSiminh:Sli nal and oral c;rndidlasis. Coollbonati ons of ny\ tall n with Ictr.ICyciine can be used 10 pre"cnt monili~1 o,er gm" th caused by the destruction of baclcnal microflora o f tiM: int(!5tine during tctmcyclinc thempy. Although nystal In is a pure COOlp<)I.IIId of ~ ll0wn ~tructure. its dt-.s:Ige i~ st ill C)(pn:s..~ In tenos of units. One milligr.lm or nystatin conl:l.i ns 1101 less than 2.000 USP UnltS_

N~t.tin,

Natamycin, USP.~ P
i~

Natamycin (plmariein; Natacyn) I polyene antibiotic obt~lned from cultures of Slrt:pwm,'-

eet ,wl/IIt'II$i$.

OH

.." , "

0'--1',

'Thot nalllmycin SlnICluIl' ConSiStS of II 26-membercd lac tOllC ring C'OIIlaining II Ictracroe ctuomoptlOft;, an (l'.,8-unsatuOiled laclone carbonyl group. th~ hydroxyl groups, II carboxyl group. Irons qXlxide. :md I glyoo<;idical1y joined m)'C()l;arnine. Uke the: Oilier polyene antibiotics, nalamycin is amp/1olt:!ric. The mechani~m action of thc: ~mancr polycncs diffen; from thai of hmpnotcricin Band n),stlltin . Tlk! 26 \ncmbered ring polycncs c~use both potas.ium ion leakage and cell lysis III the S alllC cunccntralion. whcl'\'a..~ the 38-tncmbercd-ring polycnescausc potassium leakatlc a\ low. fungistatic coocenlr.uiOl'\ll ~nd cdl lysis al hIgh. fungicidal concentrations. The smaller polycnes ~ fungistatic and fungicidal within the same concentration range. N:uamycin po5 .... <n in vitro activity against II number of yeasts and filamentous fungi. inclu(hng C(lndiiW. A.$pugilIllS. Ctplwfosporium, P,micillium. and FUS(lrillm spp. 1be dnlg IS supplied u a 5<;1, ophlhalmk suspcll..,ion inlended for the lre:umenl of fungal conjuncl i"ili . blephari lis. and
l~nlu ti ~.

OUa., ,,*.tll.all,1 AntIbiotics

Grlseofullfln, USP. Griseofulvin (Gri<.al,:lin. Gris-PEG. Grifu lvin) was fif'\t report~d in 1939 by O)l.furd ~I ill.- as an untibiotic obtained from the fungus P~nic:il/i..m grisw!.. II.. m. II was isol3led originally lIS a "curling factor" in plants. Applicalion of exll1liClS conUlining the anlibiotic 1 0 fungu.-infected I~af parts coosed the leaf 10 curl up. 'The druS has been used for many years for its anlifungal aclion in plam~ and ammals. In 1959. griseofulvin .... as inlroduced inlo human nlCdicine for the treatment of linea infectiom by lhe ~y~temic route .

der or crystalline 'IOlid thai is sparingly ~uble in watel'''' !;()Iuble in alcohol and other nonpolar !;()henl\. II is '"U) stable .... hen dry. Griseofulvin has been used for a long time forlhe sy>l<'lJII' cally dell"ere<! lreatment of refnlClory ringwonn infCCl!Ol6 ofthc body, hair. nail~, and fcci caused by species of dcmlllophytie fungi including Triclw,Jh)'uJI1. Micro$po",n~ II1II pid~rmtlphylOn . Afler syslemic absorption , griseofulvin II carried by Ihe sysle mic circul31 ion and c3pillary bed~ 10 tIw: skin. nails. and hair follicles , where il coneentrales in kenlil precursor ce lls, ",hich are gradually exfoliated and rtplll:ell by healthy lisS\IC, Griseofulvin is II fungislatic agenl. and 1\ the new. healchy tissue: dr:velops. the drug pre"enl5 mnf tion. Treatment muSI be: continued until all of the Infected tissue Iw been edoliated. because old ussuc:s will sul1 \UP' jXIIt and Iwbor fungal growth. lllerapy in ,Iowgrotollll liss\ICS, such 115 the TUlils, must be conlinued for JClmI monlhs . C()mpliance wi th lhe drug relimt'n is mand.uor). In scm"IC: case$. such as with the nail s. it is possible 10 obs.u R n.ew. healthy ti SSue: growing in 10 replace the infected lI"S11t Griswfulvin neither posysses antibaclerial aclivity Il(M" II effective againsl P," },fQJ/IQrum objc .. ltlr~, the ()I"lIlLRism 1M: causes tinea vt'rsic()lor, Few advel'l'C: effecu have been reported f()l" griseofuh'. The most common 0IJe5 !IK allergic reactions soch as .... and urticaria. gaslrointcstinal upset, headache , diulIICSS..-I insomnia. The unaI bioavaiiabililY of griseoful~ln is ~ay poP'. TILl compound is highly lipophilic with luw ...... Iet'solubillly TILl most successful YlIempcs at impro"ing absurption hana. lered on creating micmlli:te<i (uitrnlmcrosil.ai. mlCrrnim/1 griseofulvin, Reducing Inc: particle size. in theuiy . 51' II impro"" di ~soIul iOll in lhe stOllloch and absorption. Thedfi. dency of gastric absorption of griseofulvin ultramicrosllflll versus the micfOI'i1:ed form is about 1.5. Illiowing. dou, reduct ion of one third. Severnl strueturnl dcrivalivct hIli( been synlhc.~i1.ed. but they have failed 10 i mpruve absorptiot Perllllps the besl advice tllallhe phannaci~t can gh'e ~ pftII who is aboul I() u~ griseofulvin is 10 lale!he dmS '1101 fany meal. 115 .... illl salad dTcssing. Griseofulvin is a mitotic spindle poison:JiI..r,I In 111nL1 rnpidly lIlTe5I5 cell division in metaphase . It causes reversible dissolution of !he miU)lic spindle appar2!ul, ably by binding wilh the lubulin dimeT chat is rtqUutd microtubule as~mbly . 1be selecth'e toxid lY to fllllrt probably due: to lhe tissues ri ch in lish infections,

, "

""*

"

Allylamlnes aad ReI.ed CoMpounds

The allylamine ela~s
i a result of random screening compounds wilh antifungal ies in lhe !!Cries subseql.ll'nlly 10 i_ pounds "';th enhanced ~ney and polentlal IICIIftI such as tcrbinafine, I. ' Invcstig3tion of the med\antIII action of the allylamincs demonslrated that the COlI interfere wich an early step in ergosterol bio& namc:ly, the epoxidatWn of squalene calalp:w by qXlxidase, Squalene epoxidase4 l forms an epoxidE C2- C3 pusition of squalene (Fig. 8-4). Opening oftileqa

;'.;i, ;

Griseofu lvin is an example of a rolK structure in nature. a ~piro compound. The Slructure of griseofulvin ....as dC'termlnOO by Grove et a1.)90 10 be 7-chloro-2',4.6-trimeth2 OJy.6'.p.mclhylspirolbenl.ofuran-2(311)- I' 1 )cycIoheJeneJ3.4' -dione. Thecompound is a .... hile. biner, heal-sulble pow-

C haptrr 8 klti.itifffiv A"",~

239

""

9"

...
I

""

r "".....'0,

""9"

Epoxidaso

""

r ""

Squa1eoe

epo~dase

Squalene

,
n the
&II

t ini timcs Ih!:

lICCumui:uiOl1 of squaiellC .... hleh 11 membnlllc. The altylanllnd ucn

actioo agaInst delmitoph) les and other filalllen

their action against pathogenic ye!t.~ts, such largll:'ly fungistatic. Although mammalian inhibited by the: a.I1ylamincs. appear 10 be allertd . . Iwhfinc: and terbinafillC, h"c been apagt'nl5 for the ~almcnl ofTinca pediS, linea ullCa corpori~ ClIused by Tr;('hapiryll.nl rubrum . . or i:.)lidemrQ{lhyum flocar agent tolnaflate. ",hile not an and has a spectrum Hcroce,loinafUltc
~t

no!. ethanol. alld methylene chloride but i~ ooly sli ghtly liOluble in wllter. The hi ghly lipus)hilic free base is insoluble in waler. Terbinafinc: hydrochloride is a\'ailable in II 1% cream (or tupicaJ Idminislrntlon for the treatmenl of tinea pedi$. tinea corporis. and tinea crurb. Terbinafinc IS n..... e poICIll than naflifine and has also demonstrated oral oclivity aguin~1 onychumycosis (ringworm of the Ilails). II ha.~ lIot been approved In the Ulliled Slates for 01<11 administl'3llon.

. n.c alJyJamioes are weak

thai are
~ligh' ly

solub le O.l_ Naphthyl m,N-dimelhylttuoc:arballilate (linactin. Aflale. NP-l7) i, D'" hile cry.lllllllle liOlid thai is illliOluble in water. sparin!:ly o;oluble in alcohol. and soluble in most organic solvcllls. The compound. a thiocstcr of ,8-naphlhol. i~ fungicidal against dermalophyles. soch as Tridwp/lJltNI. M.rl'osporwm. and pidt,"""",yftNI spp.. thai cause superficial tinea infecliotl5. Tolnarrate is available in a conccnlmtioo of 1% in en:ams. powders. aerosols. gels. arlll solutions for thc t(Catmenl of ringwonn. jock itch. and :uhlclc', fOOl. Tolnaftalc ha.~ been shown 10 act as an inhibitor of squalene cpoltidase'" in !ill!iCCplible fungi. so it b elassirled ""ith the allylamine antim~. ToInaflllLC IS formulatL"ti into pn:pal1l1ions intended to be used wilh lIflifieial 0 finge n13ils 1 COIJllICI".K:1 Ihe iocreased chance of ringworm of lhe nail beds.

To/m,hiJle, USP.

...

~f;:~::~ of ringworm of the beard,has shown for these uses, naftifinc I ringworm

crySlalline powder lila! soluble in polar web as eillanol an4 methylene chloride. It j, sup1 conctnlfllion in II cream and in a gel for the '1In'MmrnI of nn,worm. athlete 's foot. and jock itch.

Ilk ICiIp. and linea versicolor.

(}-N(6.6-dicrystalline ma. as mellta-

Azole Antifungal Ag_ts

The 1Il01es rePf\'~nl a class of ~)'nthetic IIn,ifungal agen's that POS~I a unique mech:.llI~m ofac!ion. Wnh!hc:sc drogs. one c:m achieve ~k.'C'ility for the inrcellng fungus over the I\Q).t. Depending on the Mole drug u!iCd. one can treol inrectioo~ nmging from ~imple dcrmatoph)'lO!iCs u) life threatening. deep systemic fungal infcctioos. Research currentl} UOOrr way III the United States is amw=d at dc\cloplllg more: potent azol~ and compounds that penetrate the blood- brain barrier more effectively. 1bc first membcni of the ela~' \\cn; hI gh ly Sllb~titUlcd imidazolcs. ~Ilch as clotri mazolc and mlconamlc, Structure-activity ~ltJdie~ re vealed th:.1 the imidalo1e ring could be replllCed .... nh a bioiSOSlcric 1.2.4-ui:uole nng .... i\hool ad\ersely affecting the antifungal proptrtjc,s of thoc molecule. lienee. t.bc n~ geneTic term IJ;:p/u refers 10 this das~ of amlfungal ~gcms.
ANn FUNGAL SPECTRUM

C. ulhimn! i~ the dcvdopmt:m of mUlations in ERG II. the gene coding for C I 4-u-~'erol dcmclhylliSC. Thcc mUIJUOIII appe1lr 10 protCC1 hemc in the en/ymc poclct from blnd,"S'" u,01c but allow aoccss of lhe natural sub$tntle of the ('lUyme. lanosterol. CI"OS5-resistance b confl!rTed 10 all u.oles. IDcreascd amle eftlu~ by the ATI'-bindlng cas.<;elte (ABC I, which normally trnn~pons cho!csl~rol) and major facihllllll" .superfamily tr.msponers can add 10 flUCOfl111.o1c I'CSlS\UI(C in C. albil'all$ and C. alflbrlllrl. lncrca.sc:d production of CI4. u-stcrol dcmcthylase ooukl be anotll\!r cause of re<,15\.Vll'f

STRUCTURE-ACTIVITY RELATIONS HIPS

The basic qructural requlrcnlCnt for nICmhcrs of !he aLOIr cllISS is a "'"('akly basic im,dazole or 1.2.4-lriIl7.0Ie rilll (pK, of 6.5 to 6.8) bonded by a nitrogen - carbon linkage 10 ta.: rc.~ t of Ihe MnJcture. At lhe molecu lar levcl. the amiduz nitrogen a'OIn (N-3 in the imidazolcs. N-4 III !he triazok., IS belie~ed to bind 10 the hl!me iron of enlymc-bound CJIO' chrome P--450 to inhibit acliVlllioo of moIccul:u-o~ygtfl'" prevent o~idalion of stemltbl.subs!:mli,.'S by the en7.ymt, 1k most potent antifun gal a.to1e( . two or thJ\.'e aromatJr rings. 8t lea~t one of which i ,2,+ dichlorophcnyl.4-chlorophc n)"1. other nonpolar functional groups. Only tutkln yiekl:s effccl;"e azoic thm yjc,lds the most potent functional groupl . uch as . hal'e been 'iIIowJ '0 do the same. Sub6lilUlion at other p!ilions of !he rill yields inactil'e compounds. Pre.wmably. the large 1'IUI!plItI poruon of ,hcse molccule~ mimics the nonpolar ~, ..... p;1" of lhe substr.ue for JallO!;lerol 14tr-dc:mc,hylasc, ID sterol. in ~hnpc: and size. The oonpolar functiooality coofer1\ high ,he antifungal a7,oI~. 1be free basc.~ are i in water buI arc soluble in ffiOSI 0fJl3mc sohems.. ethanol . F10c0nazolc. which posscs..~ t ..o polar .... moieties, is !In c~ccpl ion . in tha. it is ~umdcn tly wattr ble'o be injected i ntruvenOll~ly as II solution of the fIN Clotrim<lzoJ., USP. imidazolc (Lommi n. spect"'m an tifungal drug thnl i men! of linea infections and candidiasis. in IlIcohoI and most cxg:mic sohents. It i5 . .. elk baw: can be solubIlized by dilute mlllC11ll acids.

The aloics lend to beeffCdile ag:llnsl most fungi that cau~ superfICial mfccllons of the sl,n and mllCOUS membraneS-. " ..eluding the dc: rrnatoph)'tc~ such as Tnl'hopIlJ/'''', EpidcrtnOI1hrto/l. and M kro51}(Jrum spp. and yel~'ts such as C. alhi am5. On lhe other h.lnd. they also exhi bIt tlCtivity against .. yeasts th.:ll. C" u!;l! systemic infections. includmg Cocddioidt's ,mm"'s. CryplOCQ(:cus nl.,,!ormwu. PIJfiJl'(Jidiaidl!'s bro . Jiilicnsis. Pl!'tr;l!'lIitluu" bo.\"{),i, HiIJSI()myus tl"'rmumtlis. and l/iJilOllllISm(l l'{'l'm/II"'''',
MECHANISM OF ArnON

of the aL.Olcs on fungal blOcheml~try have been ~tudied extenshcly. bm ,hcre is \ till mIlCh to be le:r.mcd." AI high in villl> cOIlCentmtions (micromolar). the alole.'l are funj:icidal : al low in vitroeoocc:rnmtion ~ (n:mOlllolar). lhey are fungistlitlC. The fungICidal effect is dearly associated .... ,th damage' to the ~'('lIlTlC'mbr.lJle ..... ith the 11)\) of ~S('nl ial cellular COOlponent~ weh as po\;tSSlum ioo.~ !U1d amino acids. 1bc f ungl~lallc effccI of thoc alo!c\ at low cOlx:cnlnl1ion has been associated wllh inhibition of membrane-bound en1),11lCS. A cytochrome P--4SO dll~s I!nzYIllC.lonosterol 14adcmcthylasc. I~ the likely target for thl! alol~ 006 P--45(} J"IOIS' ~... ..cs a heme nlOlctyas !l'lr1 of ItS slnICture (Fig. 11-5). and the basic electron pairs of the al.ole rings can OC1:Upy a bind Ing site 00 1'--450, preventing the enzyme from lurning o~cr, 1bc func, ion of lanoslerol 14tr-dc:mcthylase I~ to oxidati vely n:mo\'e II nIClh)'1 group from lanOSh:ml dunng er@oslerol bIIJo'iynthcsis, When dclTlC'Ihylatlon is mhlbited. thc 14tNtcrol accumulale<; in til\! rncmbmne. C/lusing dc~tabi l izmion. As ,his happens. rep;1ir nle'Chanbms. sudl a~ ch itin symhc~ i~. are inil i. ated to patch the damage. Thi s degrodes rncrnbrune fuoclion funher. Lanosterol 14a-dcmethylasc is also requir! for mammalian biosynthc~i s of I,"'hoIc:qerol. and the :u.olcs are ~no ... n to mhlbit dlOIesteml biosynthesis.~l In general , hIgher concentr"Jt ion~ of,he lll.Olcs are nceded to inhibi. ,he mllmmalian en/)' IlIC. Thi~ provides SCII:cti vily for antifungal ac!iun. The 1.2.4-triuolcs aPfX'ar to cause a low('r incidence of cndocrine efrcct ~ and Ilcpaloto~icily than the c~~ 109 imidazoles. possibly becausc of a lower IIffinlty for the mammalian cytochrome P-4SOenl.Yme~ i",ol~ed.-*lI Tbe pri mary mode of resislance 10 the triawl es and ifl\idawlc.~ in
The

effect~

p-

""-

I
f ,
\-

,-

I "'" 4'

h<
Squalene

".

>a'

~.

~" toc i.

EpoJCidase

~,

14
Sqw.lene EpoXlde Squalene epoXlde cyclase

fo lc pK.

t:".

..,c".

"") Ilc'

.~

0,

0<,

,...-"- A"" /-oJ

0 ._0:.::-::t.anc.leroI , ....

deLliethylase

'"

Lanosterol

'"

",/--'-./-""'-

, I ,

figur1! 1- 5 The Irlh lbltory aelton 01 azok> anulurlQ<Il agerlts on the la~terol 14'Q-del1"lethyla~ reactlOf"l

is 81'ailable as a solulion in polyethylene -100 101;011. and a cream in a eoncentnuion of ~ e allinckued f(K the lre&mlCnt of tinea pall-s. C!WII. IllICa CapIUS. lil1C.ll I'ersicolor, or cutaneou s I . A 1'1> viginal cream and tablets of 100 mg II"C Ivai lable for Yulvovagi nal candidiasi s. Ii eumnely Stable. wi th a shelf life of mon:

~~::!"".

"

"...

dOlnmal.0te i effective against a variety of well absorbed OI1I.ll y. it i I disturba/ICcs. It is al50 ellle n, Mll("e, is noI considered optimall y CIotnmuole IS noI considered suilab-le for the oi S)"Sl~ nllc Infections.
EcOOlUOk: is used

' 0

"
1% cream for the topical treatment of Joeal tinea infections and cutaneous candidiasiS,
a~ It

in wal"f and nlOSt organic SQlvenl5.

8utoconazole Nirrate, USP. 1-(4-(4-Chloropheny l)-2((2.6-<lichlomphellyl)-lhioJbUlyIJ- III-imidaloic (Femsu.l) is

an ~tremc l) brood-SPCClrunl antifungal drug that IS specifically effect ive against C. olbic(lfu. It is supphed as a vaginal cream contammg 2% of the salt. It ie Inlended for the treat men! of ~aglnal candidiasis.

used for 1Ix: Ill.'alUlCnl of vuh'0'''8I11al can(\ldHlSI). A "!Ii'IW ollllmcnl OOIl1:l1mng 6.S'1 of the f~ bafoe I ~ "Dlbble. Tillconu.olc IS more dfectile agamsi TOrN/OIlS'S g/(lbrIJIO man:: ot~ &7.olcs.

Suiconalok Nit~te, USP. 1-[ 2.4- DK;lilom-P.lJH:lilorobenzyl)tlioo Jphcnelliyl [lnuda7.o1e mononl lnuc (Exclde nn) I~ the whi te CT)'li1.:llline nilric lICid !'all (If sulcon:tI.olc. It is !>]Willgly sol uble in wa ler but o;olubie in cl hanoL The !;:lit is U'ioCd in a solut ion and II cn:am in I % concentration for the trenlmcnt n f local linea ;UfCCliol1S. ~lIch as jock ilCh. Plhlele's f(Jot. and ringll. orm .

C-J
N

,ps

""

Mkonilzole N;t~te. USP. 1 -1 2-(2.4- I:>!ch lorophenyl~ 2[2.4-dlchloroplM:-ny l IIIlI'IOOx y )clhyl I-I II-nmdmlle nlOllOnilrute (Monl!>l3t. t.h cali n) is a we3];: base '" Ilh :a pK. of 6.65 The nitric ucid '\all occu.... as while cryslals thaI an:: ~paflni~ solub lc in Wlilcr lind most organic solvents. TIle fn..oe ba.e I~ :Ivililable in an injct;l ~ble form . w lubi loud witb polyc lh y1cnc glyoo l and castor oi l. and inlcrKled fCJ: the trelltment of .'lCrious ~ySlc mic fungal i nfecl ion ~. SUCh 11\ candidiasis. coccidiOldomycnsi~. crypt<X"tlCCOSi~. pelridhJ insls. and paraootCldloidomycosis. 11 may also be used r.. the lreatment of chronic muooculancou s candidiaSIS. Although.scnous 1 01l.ic effects from the systemIC adnnnlSUlbOl o f micon.v.ole a' oomp<lrnll\'cLy rare. IhrombopbltblllL pruritus. feler. and llastrOlnteslina l Upst'l are rebtt>"ti) common.

0,< """

1#

()
N

01{/conalofe Nitr.. te, USP. (Z)-I.(2.4-d ichloropllc:nyl)-2-( I II.imidaJo.ol. I.yl)cthanone-Q.(2.4 -dK;hloh>jll'1c nyl) IIlC(hylJoxi nx: mOOOllllr.lle (O~ islal ) i~ a whi le cry~r.a lline nll ric acid ~h. II is used in cll.'am and loI ion dosage form.~ In 1'.1> C (lflC('ntnllion for the tll.'a1 mt:m of li nea pedis. linea COI'POl"Is. and linea capili~.

()
N

(cream. lotIOn. powder. and spray) for lhe treatmenf orrinfa:uon~ a,1d CUlaneous candidiasis. Vagm~1 cnams ,., s\l ppo:.iloric~ Ute alo;o avai lable for lhe trealnw:nl of 1"JgllIIII ca nd idiasis. A ~"()nce ntnllion of 2'1: of ttv.: snit is u'f.'d tn mDiI

M icooa~.olc nltrute IS wpplic:d in II \'arlC1y of dosag.::

f(QI

lopical preP.1T11 lions.

Ketoconazol., U5P. I-Acelyl-4-1 4-[12-{2.4-dichkllopile ny 1)-2( IIIjIIndazolc-l-y Imelh)'1' -1.3-d IOxolan-4-y Ilnri oxy lplw:nyl lplpC'rII7jnc (Ni/.or.ll) is P bro.1d,s(l<.Cu"IIm I I ' l.Lole anlifunsal agent Ihal i. adminIstered 01"'.111) for Ill.'alrnc:nt of sy~tcm ic fungal infectioru;. II is a weaLly. compound WI OCCUT'i as a while ctyst.:ll h ne solid that 1$ len ~Iightly soluble in W:ller. The ()flI.1 I!.oavailabl hty of LC1OCOO:lzoie deptnth 0-. acidic pll ror dl ~soluuon and absorption. Anlacids and S1Jch 3S H:-histamillc antagOl1ist~ and :mticbohnel1~ inhibil gastric secretion i nterr~ """ h II ~ 01"111 II~

*'

Tloconazole, U5P. 1-12-1(2-chl om-3' lhlcnyl)nlClooxy 12( 2.4,u ,ch loroplienyl)ethyl l- lll-imidawlc (Va&i~r.al ) is

"

f)
"

Knoconal.Ok is ex tensively metabolized 10 ina<:tive melhOO-

Iaes. and the primnr)' rotHe of e~cre' ion is

ileSllm:lled 1 be 95 10 99% bound 0
HepatOlo.~icily.
~

enlerol)(>~lic.

II

Terconazole. US". cis- I-[4.[ [2 (2.4- Dichlorophenyl)2-( 111-1. 2. 4-ui 11,,"01 -1- yllm:th y 1)- 13-d io llOI:I11-4-yl) mct hOllY I
phenyl]-4(1 methylethyl)pipemzine (Tera1.01). or tcn::ona lolc. i~ a triru-.ole derival ive Ihllt is uo;cd ellclusi"cly for the control of vulvovaginal moniliasis cau<;cd by C. fllbic/l/J.< und other C(lmlidlJ species. [t is available in cream. COIl13.in ing 0.4 and 0.8% of the frce ba.<;c intended for 7-day and Jday treatmc nt periods. n:lip<:Cti l'dy. Suppositories contain ing 80 Illg of the free oose ,In: alS(! av~ilable.

to

prolein in Ihe plasmJ.

11-

.5.
oJ

primarily of Ihe hepatocellu lar type. is the 110M !;erious adverse erfed of k.ClOCQrlaJ.l)le. K eloconazole
~

loo,," 10 inh ibit

cholesterol biosymhesis,' suggest ing

>I)'

_I:lI1OS1erol 14a-demclhylasc is illhibitell in mammal s as 'til as in fungi . Iligh doses hav e ulso bee n reponed to lower

.oc

,dr~

"

\1-

ion

1e$IOS1emne arK! conicoslerone levels. re neet;ng 111<: inhibi !ill of cytochrome P-450- rcquinng enzymes in volved in Iaml:Jn steroid hormooc hiosynlhesis.4lI Cytochrome P-450 nudaICS respomible for the nlelabolislll of variOllS df1JGs .~ also be inhibited by k... locolla zole 10 cause c nhaJICed d1'ecrs. Thus, kelocona7,ole cau)e..~ cl inically significant in~ in plMma concentrations of cyclosporil1l:. phenytoin ,
-.:Ilotrfe~3dil1l:. It muy alSQ enhance responses 10 sulfonyl1m hypoglyeemic and coumarin anr ieoagulanr drugs. Ke10c0nawle i~ a racernie COIupound. consisting of the

,I,

liS.

tV1S,4R and C'is-2R.4S isomers. An inH:Sliption of the

M~epolencies

lIl1l'
jlllC.

~1na1
m~

",d

of the four lJOS$iblc diastcreomers ofkctomn'wlt against r.ll I:Ulo~terol 1 4a-dcmctllylasc:'~ indicated ... lh: 25.4R isomer wa~ 2.5 limes more IICt ive tll:m its ~.4S ~nanliorrn:r. T he mills isomers. 2S.4S and 2R.4 R. are .:II Irss :lCtile.-<'I KtIOCOnaJ'.o1c is recommended for Ille treatmen t of tile dowlnll !ySlemic fungal i nfecliol1~ : candidiasis (inc luding n thru.Ih aod tlteehronic nHlcocutancou~ form). coccidioi 4Ir!!yroI1S. blastol1lyco~is. histoplasmosis. ehromomycosis. parxoccidioidomy<:osiN. II is also used orally to tre~t It'tft n:flllCtory cu tan>u s dcmlatophytic infections nOI re!p!Iive to topicalthl':rnpy or oral grio;eofulvin . The antifunof kclocolUllOle and Ihe polyene antibiotic ~In B are reported 10 alllagonize each mher. ~a/.oIe is also used topically in II 2% conccmntt io n trtam aod in a Miampoo for tlte m;1nagCl1lent of cu ta_nndidiasis and til1l:;1 infec tion s.

Itra conazole.

4-14-[ 4-14-112-(2.4- Dichloropheny l)-2-1 H- I.2.4-triazol - l-y lrncthy l)- I.J-diOllolan-4-yl )nICth-

U5P.

o~ytplic n y l !- I -piper.uinyllphcny l l2.4-dihydro-2( ]-n"ICth

".mons

am-

ytprupyl)3H- I. 2.4-lriul.Ol 3one (Spur.mox) is II. unique membc:rofthe azo le class that contains twO triazolc moietics in its stroclUn::. a we3kly basic 1.2.4-tri:u.ole and a nonoosic 1.2.4-lriuzo1-3-one. ltraconawle is an orally active . broad-spectrum am ifunllal agent that has become an impor1;l/\t IIlternmil'e to ketoconaznk. An acidic environnICnl is required for optimum solubi lization ~nd oral !lbsorption of itracona'l.Ole. Drugs such as H 2-histamine antagonists und antacids. whi ch reduce ~tom ach acidity. n::duce its gaSlroint ..stina] absorption . Food

I~

ncth imid.r the

ba"c
WI

' ~r:t)'

~~")" I
N==

.J

;)1\

,,"" 1'11"0.

Oru,

'"

()--{ )
H

f)

) 1.
"

I "" #

c.

greatly enhances the ab.o;orption of Itraconazole. nearly doubling its ontl bioayailability. 1llc drug is av idly bound to plaslll3 pmlCnl!i (nearly 99'10 at clinically effecth'e concentrauons) and extensively melabolil.ed in the liver. Only one of the numerous metllbolile!l. namely l-hydmxyitraron:QOle, has ~lgnifiC'ant 3.fItifungai acilyity. Virtually I1OOt' of the unchanged drug is excreted in lhe uriJIC. Thus. the dosage need not be adjusted in patientJ; wilh renal impairrnenL The tenni nal eliminadon half.life of ltrllComt"lole mnges from 24 to 40 hour!.. The primary indICations fOl" itraronv.ole are for the treatment of systemic fungal infections including blastomy,osis, hIstoplasmosis (i ndud ing patients infected with human immuoodefK: lency virus lHIVI). oonmeningeal coccidioidomycosis. par".tC(lCICidioidomyCO!iis. and sporotrichosis. It may also be effective in the lJ"Catmcnt of pergellosis. disseminated and deep organ ,andidiasis. coccidioidal meningili ~. and
CryptOOOCCOSIS.

In general, lInK:onll7,olc is more effective and beneT tolerated!han is ketOCOfUl7.o1e. Unli ke ketoconarole, it is not hC'patOlo.\k and docs not cause adrenal or Ie!lticular suppression in recommended therapeutic doses. I" Nonetheless. ill1ll:ol1a:wlec:an inhibit cylochrome P-4SQ oJli-dases involved in drug lind JlenOOiOilc metabolism and is known to inc~ase phlSIIl3 level!> of the antihislaminic drugs terfenadine and lISlemizoie.

00 hepatic melllbolism and i$ txcrcted substantially un changed in the urine. A small amount of unchanged n~ zoic (- 10'10) is txcretcd III the fcca. S ide effect!; of fl~ azole lITe largely coofincd to mlllOf gastmintc:stiR.1l symptoms. Inhibi tion of C'ytochrome P-450 oxidase! by flu COIlaloie C'an giye nse to clinically significant IIltcnctlOM inyolying increased plasma Icvels of cyclosporine. pllen) loin, and the oroll hypoglyct'.mic drugs (tolbulllmide, ghpi. ride, and glyburidc). Auoonawle does IlOl appear to InIn (ere wilh cotliCO!ileroid or andillgen biosynthc.~is in dosagc$ used to treat systemic fungal in(octions. AU~'Of1D:wle is recommended for the lreatmcnt and prophyluis of disseminaled and deep organ candidiasis. It II also used 10 conlrol cwphageal and oropharyngc:al ,andidUsis. Because of its efficient penetration into CSF. nucooa:tOlt is an agent of dV>tCe fOl"lhe treatment 0{ Cl)'ptococcal mall. gilis and for ptophyla.tb against cryplococcosis in AIDS patients. Although fillC(llUlZ.Ole is generally less eff(dj\f than either ketoronawle or ill1lCona.wle against 00Il1fltllltgeal coccidioidomyc(Kis, il is preferred therapy for coccKj. oida! mcnlllgitiJ. Auronl1,oIe lends itself to one-dose Ihmpies for vaginal condidiasis.
NEWER ANTIFUNGAL STRATEGIES

A new v.ole. vorironv.ole," is presently in cl inical \ri.Ib

Fluconazole, U5P. a-(2.4-Dlfluoropheny l)-a-( 1"-1.2. 4-tria:wI-I-ylmethyl)-1 H _I ,2,4-tn:u:oIe- I -ethanol or 2,4difluoro-a,a-bls( I HI. 2,4-trialol l -ylmethyl}bcnzyl alcohol {Diflucanj is II walet"-'\(jlublc: bis- triazole wi th broadspectrum antifungal propcnies Wt is sU IUlble for both oral and intr~yenous admin istration a.~ the free ba~ . Intt:lvenous solutions o f nucoov.ole conlain 2 mg of lhe free base in I mL of isotonic sodium chloride or 5~ deJltrose vehicle.

in the United Statcs.

(" , ,_I

OH

g<,

,
I N N~

1 '"
#-

'"

The 0l"'Il1 blOilvlulability offluconawlc:. followlIlg administration of either tablet or 01111 suspension dosage fonns. is C)l~lIenL Apparenlly. the presence 0{ tWQ weakly basic triazole rings in the molecule confer!. sufficient aqueous sol ubility to balance the lipophilicity of the 2.4-difiuorophenyl group. The 0l"'Il1 absorption of fluconazole, in contrast to !be oml abSOl'pl ion of ketoconawle or itraronazole. is 001 affected by aitention in gastroi ntestinal acidity or the presence of food. A uconawlc has a relath'ely long elimination half-lire, rangln& from 27 to J4 hours. It penetrates well in.to all body cavities, induding the CSF. Plasma protein bindmg ofnuconawlc isles!i than 10'10; the drug is efficiently removed from the blood by hemodialySIS. AucOlll7.oIe upericnces litt le or

Unlike nucona1.Ole. voricona.lOle has ":;~:~~: against a broad varielY of fungi , including port3.flt pathogens. St"eral publlcallons haye 51 the usc of voricOI1u.oIe ugainst some of the newer and fungal pathogell'l. Voriroclal.ole is more potent than 11Ii( 7.ole ~ai n~1 Asp"'SillU$ spp. and is rompamble to . zoic. another azoic lhal is in cli nical trials. in I thal are against C. a/birons. In genen.l. Candida suscepliblc to nuconll1.ole zoic. 1l!c: III vilro ICli ~ity I 111 Ii role against a variety of fungal ones. conlinue~ 10 accumu lale. oml bioavailabillty, 00\ il!i low water formulation into an Inlr.l\enous solution A scarch rOl" potential prodrug fOI1l\Ji yielded a possible candidate. SCH inaclive in vitro but is dcpltosphorylated to acti ve 4-h)droxyootynlle ester. This compound Iyzed to the pannt eompound III the -"Cf1Jrn. Po~"'''' undergOe!i e~ tensive enlctoOcJXItic recycling, and moll the dose is dinunated in the: bile and feces.

. '""

Chapltr II A"f,-j"~ril"#,

A6,"/I

245

"' N ( /
d ,

. (j
. , -

"0

#
P(l'aoonazole

"\ ~"

"~

CH,

~l

, -H O

CH,

SCH

~9834

S)lI2869 is a novel broad-spectrum oompoofld Ihal conthe ~pervll1e- phcn}l- uiazolooe side clmin common D luaconazole and posocon:lI.ole. and il di spla)'5 poIeoc)'
til

anlifllngal speclrum si milar 10 those of the laner. demonstrates bcueI' aclivi ty than iu-aconuole in models of C. olhiclUlS. C. gUlhmla. and C,ypforoc--

lW nw!ormonJ. T1Ic: or.u bioavailabi lhy (F) is 60%. afKI higher tissue-Io-serum rallo8 than lhose found for ilTaCQn;!l' lole were claimed tQ eontnbute 10 the greatcremcacy of the compound in a model of inyu.~ i ye pulmonary aspergillosis . 5)'n2869 also demonstrates considerable octivity against the common mold pathogens.

LY 303366

ECHtNOCANADINS AND PNEUMO(ANAOtNS

EchlllOCanadin~" ~nd the closely rel:ued pncumocanad lns~l

~~;::::x~
~"-,A",,

are nmurol prodlk:h ,hm were di scover.. in the 1970s. 'd 1l1e)' act as Jl(IIICUI111X'- lilivc in hi bi tors of (1 .3)-,B-d-glucan synthaseY an Clll) ,ne t"Olnplelt 1001 forms slabilizi ng glnClIn polyrnt't'S in the fung al cell wall . Three water-soluble Ikn'"au,"cs of the echlllocanadins and pn.euonocanadins an: III end-"uagc chnlC~l dc\clopmenl but 1m."C rlO4 yet been
lIIarl.e'ed. L Y 303366 is a penlylOll.ylerpheny l side elmin denyal;\'!: of echinocanooin Ii 111.11 wa.~ disco'crcd al El i Lilly. It was

, /'-\' /'~4 ""

"

'"

h:l\'e shown th~l spp. runge from 0.08 10 S. 12 ,ug/ml~ :11141 ~imil ar actiyity W8) obtained against A.J(~'gilllu ~pp. Shldie~ ~how highly poIent octi",ily of the CQnlpound in 11111111<11 mode l.. of di....scminaloo candid iasis. pulmonary a.~pe1"glllo\ls.. and esoph:Ig~al candidiasis.
AUREOBASI OI NS'Io4

hccn~ for pan:mcr.lJ use ill 2000. Studies lhe MI C~ of L Y 303366 against CIIII(Iitlu

Pradlmycin A

~~
~

Aurrobasidin A i.~ ~ ~yclk dcllSipeptidc thai i~ Ilnxluced by f.:nncmnlion in cult ures of Al.Uob<lsidium IJulfullln. Aureobasidin A act, as a tight .bi nding noncornpelill"e i nhibi'~ of lhe enzyme 111051101 phosphor) lCCnlJlllde s>mha.'iC OPC syn thase"). ... hlCh i) WI e!iscntial enlyn\<.' for fUPial sphingohpid bioo.ynlhe'is. /It unique Slructurnl feamre of the aureobasid ins is the N-lII<.'thylal\oo of four of ..even amide nul'\)<itn atoms. 1bc lad; of tau tomerism dictDted by Nmethylation may contnbute to forrlllng a ~t able wlUljon conformer that is , hnped wnl<!",hnt li l e un arrowhead. Ihe presu m(:d biolugically active confol1n~lion of Hun:obasidin-A. The pr;u.limycin~ and benanomycin~ arc nuphtMcenequ i!1OII<.'S Ihal bind ntatllHln In lhe presen~-e of ea:' 10 diSOJpt the cell me mbrane in pathogenic fungi . 80Ih dernonstr;lle good in " ilm Qnd in \ 1\'0 acuvuy agains.l Cunil.da spp. and C ....f llococcas neojofm(JIls cl inical ~Iates.

!"

""

"

""

"" -'"

"" -'"
"'0

'"'
~

............

,
o

t.-iJ-Hmp- -'L-MeVal - -L-Phe- -L-MePhe,- -L-PfO

l -HOMeVal----l-Leu- -l-MeVal - - -IL-alle

g

-.

Aureobask:lin A

Chapltr 8

'''''''",/n:rnv: AIl~"'S

24 7

AGENTS
by chemical 5ynhave u~ful antibac.,~;;,: systemic. and/or

t~aunc:nt

r'~~,::;~,;"':me chemical c1asse~ of synlhetic ::.:~: :e Ille ,ulfon3mide.~. ccnllin nitro-

~:~~~'~"':""~":,"~~;:~';':::':I~r"cions in tile following oral : . infections pl a$1TII1 or tis-

compounds (e.g. . the niuofurans and metroni: ~'" ,,;. quinolones. Some antiba<:terial agentS thai

are I:OfI"ntrated in the urine. tbty can be effective for ~radicat,"g unnary tnICt in"itmfurantoin (a nilrofuran). nalidiJl ic acid (a quinate examples of wch urinary tnICt

~~tlbactenal r ';~:;:::':;'i:w deriva a , lhe trealmenl urinary lroct infections licterocyclic groupi ngs in rhis dass include (~.g .. norfloxacin. dpronoxacin . and lot naphlhyridines (e.g .. nalidixic acid and enW clnllolir.es (e.g .. cinoucm). Up to the p:sIliCfulllC!ii of the quinolones has ~n to 1 t of urinary lmet in fections. .wry IIXt mfecuonJ. good oral abso,puon. actiVIt)' Gram-negative urinary pathogens, 1100 unnary (COntpared With plasma and are the ke)' useful proptnit'$. A,\ a WUClurt'-3Cti vi ty m"e~llgations leading
; pro",,point Ihal cenain newer I of a variety of serious infccllons. In fact. these more potent analogues lUe cl"s~ified scpar.uely (from lhe urinary "Itt1flC qenl5) as the nuoroquinolone.~. becau<;e all !If the group ha"e a 6-nuoro ~ubsti tuenl in ." p
'II studies 1uI,'c shown that the 1.4-dih),acid llX)iety is esscntlDl for system must be: annu~"~ of n;lm-

.::"~h~~:'.;'~: ':~:.;;~;,:~:~,;

1.5-

Inlroduction of substi tuenrs 01 posi t ioo II lICIivi ty. position s 5, 6. 7 (espcthe annuloled ring llIay be SUb~l ilu led with For e.o.ample, pipcOl:cinyl and 3-aminopyrrolial position 7 have been show n 10 convey mcmbcTs of the quinolone class against alom su~titut ion at position 6 is " \111m SlgmflCantly enhanced anubacterial acI \llbstuulion at the I position is esfoC:l1l1al for cyclopropyt) com-

."

mal potency. RillS condensations III !he 1.8. 5.6. 6.7. and 7.8 positioos also lead 10 acu~e compounds. The effect.ive anti b.:terial spectrum of nalidixic acid 1100 the earliest of the quinolooe (e.g .. oxolil1M; acid and cinoxacin) are IlUgely confined to Gram-negative bactena. incltJdingcommon unnary pathogcns such as &chuichia cali, Klebsiella, I1Uro#J(Jcfer, CilroOOc,u. and Proleus spp. Shigella, S6lmonella. and Pro~idel1ci(l are also susceptible. Strnins of P. lIuu8inO$II, Neisseria 80f1orrlweut. and Haemophi/u$ influr.ntAe are resistant. as are the Gmmpositive cocci and anaerobes. Ncwer members of the cLass possc!ising 6-nuoro and 7-pipcnuinyl substi lltC nlS e~hi bit an cx tcnded spectrum of activity that incl udes cffecthcncss against additional Gram-ncCllIlve P'Cthogens (c.g .. P. atrtlginosa. U. influtl1ljJr.. and N. gfHWrrhotae). Gram-poslllve cocci (c.g., S. aurtlU). _nd some streprococci. The quinoIonC$ generally exhibit poor act i~lIy against most anaerobic bacteria. including mosl Bacteroidts aoo CI05rrldium species. In many cases. bacterial strains lhat have developed resiSUIIICC 10 the antibacterial anubiotics. such as penicillinresistant gonococci. mcthici ll in-resi~tanl S. uunus. and am, noglycoside-resistant P. aertlgil10sa are susceptible 10 11K: quinolones. The bactericidal action of nal idi~ic acid aoo its congenen is known to result from 11K: in hibition of DNA synlhesis. Thi s effect is believed to be due to the inhibition of bacterial DNA gyrasc (tOflOlsomcrasc II). an enzyme responsible for introducing negative supcrcoils into circular dupla DNA."" Negative superoCllling relic,es the torsional stress of helM;al DNA. facilitates unwindmg. and. the~by_ allows tnmscnption and ~plication to occur. Although nalidi~ic acid inhibits gyrasc acti~ity. it bInds on ly to Jingle-sttaoded DNA and not to either the ell7.ymc or double-helical ON A.'" Bacterial DNA gyrasc is a tetrnmeric enzyme consisting o f two A 300 two B subunits, encoded b), the g)"rA and gyrB gCIlC$. Bacterial str.li ns res;~lunt to the quinolollCs ha ve been ident ifled . with decreased binding affinity 10 the enzyme because of amino acid substitution in eitncr A or S subunits resulting from mut3tions in citllcr gyrA" or gyr8~ genes. The highly polarquinolones are believed to enter bacterial cells through densel)' charged porin channels in the ouler bacterial MUUltiOIls lcadinllto altered porin pr0teins can lead to decreased uplake of qlImoiones and cause resistance."" A lso. there is evidence for enc:1J),-dependcnt efflux of quinoioncs by sonIC bacterial species. A quanlllati ve slnlCture -aetivilY rt'lauOIlship (QSAR) study of baturial cellular uptake of I seoo of qu inolono60 revealed an invCTllC relationship of uptale versus log P (a meaStire of lipophilicity) for Gram- ncgati~e bacteria. on the one hand. but a positive com:l alion of quinolollC uptah 10 log P in Grum-posi tive bacteria. on Ihe other. Thi s result probably reflects theob$erved differences in outer envelope SI1\lClUreS or G ram-negative and Grum-positive bacteria.61 The incidence (rt'lati vel), low. < 1%) ofCNS effects a ~so c lated with !he quinolono (e., . Imtabi lity. ttrmor. sleo::p disorders. venigo, anx icty. agitation, convulsions) has been allributed to antaconism of .,..aminobulyric add (GASA) ~ptors in lhe brain by lhe qUinoiono. Only nuoroqulll(}lont'!i having a I-pipcridmo. 3-amino-l-pyrmlidino. or similar basic moiety al the 7 posllion appear to have Ihis pmpen y.'" The low incidence ofCNS effects for most quin-

members

dass

membrane.

oI00es IS apparently due to theIr mablll ' y 't) proetr.IIC .he blood-brnm b.1mer Another propcny of.he quinolonc clas, is pholOlO~icity. e~trelllC scllsitivity to sunlight. Quinolones possessing 11 Imlogen atol1l ot .he 8 po6itioll (c.g .. lorncflo~~cill ) lutve the highest IIlCidence of ~oto~icity. while those lutving all al1lioo (c.g .. sparflo~acin) or mc1ho~y group a. cither the 5 or the 8 poIiltlon have lhe lo.... e5. incidence. 61 The nntlOOclCnal quinoloocs can be divided in.o two clas'iCS on !he ba.~is of .heir dissociauon propcnocs in phYSIOlogically relevant conditions. The fin;t dass. rtpi"eSCnted by nahdi ~ic acId. oxoli nic acid (no kmger marke.ed io the Uniled States). and cinoxadn. ~se5!ICS only the 3-cllTbox ylk aci d group us an ioni7.i1ble functional ity. The p K~ valu~s for.he 3-carboxyl gro\lp in nalidixic acid and other quinolone antibactcna l dru~ fall in the mogt of 5.610 6.4 (Table 8-6).~ 1"hese cornparuthely high pK. vnlllCll relative to .he pI<. of 4.2 for bcomic acid areallributl:d.o.he acid-weakening effect of h)dffilCn bondioIL of the 3-carboxyl group '0 the adjacent 4-carbonyl gro\lp. TIle liCCotld ClllSS of IIlllibac'cri:1I qu illoloncs cmbruce~ .he broad- sj1t'Ctrum nl.lOl"O(juiooloncs (namely. norn oxacin. cnoXlICin. cipronox:u::in. ofl olloc in. lomcfloxocin, and Sp:lrf"loXado). olt of which possess. in addiTion \I) the 3-carboxylie add group. basic piperazino funetionali.), at thc 7 position and a 6-fluoro subs.i.uent. The pK. VaJllClI for the 1l"lOr('. basic mtrogen atom or !he p~'nn group foil 10 the mllge of 8.1 109.3 (Table 8-6). At most ph)Slologically re1e\ant pll values.. signifICant dissociation of hoItl tht- 3~arbox)' hc acid and the basic 7-0-pipcnumo) groups occur;. leading '0 .igllificalll fTllCtions of zwincriunic species. As an example. ttl.: disloOCiation equilibria fOf" nornoxacin Bre ilJustrull'd in Figure g.6.1tJ. M The lendrncy for ccnain fluoroquloolonc.s (e.g . norfIo~a dn and dproflm;acin) in tligil dosc<I \0 cause crystallUria III al"-ahne urine ii. In pan. due to the prwominaoce of .he compal"'.lIIvcly less soluble z.... illerionlc form . Solubi III)' data pm;cnled for orku.acin in the 151h edition of the U"iled SWI"1 Ph(lfnl(lcQpQI'i/l dramatically iIIus.ru.e the effect of pH on water solubilit)' of compounds of the flooroquinolone cla.~s. Thus. the solubility of onoucill in wmer is 60 mgl mL III pH valucs runging from 2 10 5. falls 10 4 mglm L lit pH 7 (near Ill<! isoelcctric poi"'. pi). and ri~~ 10 303 mgt mL at pU 9.8. The exccl1en. chelating propcn lC$ of the qUlnolones pro-

, ide the basis for IOClr incompallbllily wi.h antacids. hema tinies. and n"fIoCral supplements containi ng di ~alelll or Ima len! metals. The quinolones may form 1:1. 2:1. or 3:1 chclmes wilh metal iOI1~ ~uch as ea +1. M g' 1. Zn' 1. Fe' I. Fe 'J, and Bi ' '. TIle )(Qichiornc'ry of the chc lul c rTIC\l depends 00 II. varict)' of fllClo~. such a.~ thc rclatl\'e COI"IttI!. tmllo nsof chelallne ~m (quinolonc) :md mcoal1on ~III. .he "alence (or chas-ge) on the mewl ioo. lind .he pit Sua suc h chclalCS al\" of'cll inliOluble III .....ater. corncidemal oral oomlOlstr.uion of a qUlnolone .... lIh an antacid. I hematin .... or a mineral ~upplcment can siglllficllll.l ), reduce the oral biO'IV:lI labili.)' of .1 quinolone. As an example. lhe ",soIu 1e ble 2:1 chelate forml'd hct\\ .. cipmnoucln and -en

r"..

shown ) Figure 8-7. slu m (5uch as Mg + 1in in the unnc ions Ion compamtiH'I)' Io.... cr sulublht ), cenain 10 unllC .Iur.n In plasma.

I~

or

Thc:::::;~:~~:~i~:
I

,
as n pale water and ether

po .... dcr that is

IIOluble in ml>St I

Nalidixic acid i~ useful in .he treatment of urinary infections 10 ....hieh C....101-ncg3u\'e bactcriu ~~";~ The activily against indole-positi'e Proteus . I~ ~ lany OOIe ....'OI1h)'. and nahdixic acid and IL\ congcnen; sent iOlponUOl alternatiVes for the trcatlTlCOl of unoary t infections caused by ~mll1s or lhes.e bacteria rcsi~t3/11 other agenlS. I I mctlloolilCd. and 1 i The ti parcn. I metabolite to inatll\"c glucuronide taoolilCS also OCCUrII. Nahdi~ic acid to 7 hour5. It is climlO3led. in pan. unchanged and 8(Y.I, as metabolites.

TABLE 1-6 Disso d "tiOf"l "net IJOe I. dri, COnst",nts for Antibitd. n ,,1 Q .... lnolon. $
Ou tnoton_ Nalolr ..,,1Ctd

Cinoxaein,

px,

..... .,.
.,. '" ,.. ,
."

QH"IOH(CHS

,ro

""""""'...,0 ......
~-. "".,,~ Lonott),'..';ln
1).K.I ...........

." "" H. ,."

r_ ~ ..... D

OW

,-"
~97

147

'"
7.15

no

'"
0
,~

l.Gla
8 . -. ..... ,

L. ~ ~i"'1. C.

Il'll!S. I _

-"'''-RpC. " ........ 0I:1iIt

.-

"

,J. -....

< "'"
0

p-

O ,

"

0"

o
0 ' - .......0
N

0"

"

'=_ _ H!~ ====

/"'- /''>..

N
0"

l eN,

"0"

/
HO'

Figure 8- 6 iofl,zatlon equilibria ,n the qUlnoione ,mbbaocteflal drugs.

"

" '0 I

"f'i.

I
N

P"

">..

~I-J . A 2:1

chelate of a Mg1'

I0I'l

by c!p-

" 1 ~""

It is recommended for the treatlMnt of unnary tracI inf((;tions t aused by strai ns of Gram -negative bacteria s.uscepdble to these .~ts. Early tlinic.aJ 5ludies indicate that the drug pos~esV$ pharmacokmetic )H opt:rues supenor to tho5e of either of its p~deces.soB. Thus. followi ng 01111 administlll don. htJher urinarycontenlrations of ciooxacin than of nali dixic acid or oxolinic acid are ochie,ed. Cinoucin appears to be more completel y absorbed and less protein bound than nalidulC acKl I-Ethyl-6-fluoro- l ,4-dihydr0-4-0xI)-7-( 1piper~l.in~ I)- 3-quinolinecarboxylic add (Noroxin) is a pale ye llow crystalline powder that is sparingly sol uble in water. Thi5 quinoline has broad-spectrum activity against Gramnegative and GrdITl-positive aerobic bacteria. The nuorine atom pruvides increased potency against Gram -posi ti ve organisms, ",hc,rellS the pipenl1jne moiety improves antipseudomonal activ it y. NoriloltllCin is indicated for the trea tment of urinary tr.ICI inf((;tions caused by E. coli. K. pneumonia,. EnruOOaclu dQiIC(le, Proll'us m;mbilis, indole-posid ve Prolelu spp. including P. I'ulgaris. Prol'ilfencill rel/geri, Morgonelfa """sami, P. MrugmO$O, S. auulU, and S. epidermidis, and group D ~treplOCOCci , It is gel1l.'r~l1y not eff((;tive against obligate anaerobIC bacteria. Noriloxacin in a single 800-ml!; Or.tl dose hil.~ also been approved forthe treatment of uncomplicated gonorrhea. The om l absorption of norfIoxacin 15 about 4O'lo. The drug IS Ij'll> protein bound and is metabolized in the liver. The 1"<\,,,, is 4 to 8 hours. Approximalely 30% of a dose is eliminated in the urine and
NorlfOICKin.

Enoxoctn is well absorbed following oral admlnlstrliliOli. Oral bioavailabi lity appruaches 98%. ConcentOltions of the drug in the kidneys. prostate, cen-ix, fallopian tubes. and myometrium typically exceed lhose in the: plasma. More ttt. jO'IJ of the unc hanged drug is CJl.creted in the urine. Metabolism.largely calalyt.ro by cytochrome P-4j(1 enZ~me5 in die liver, accounls for 15 1 20'l1> of the orally admini stered dolt 0 o f eno~acin. The relatively short el imination half-life of c. oxocin dictates twice-a-day dosing for the treatment of !Illnary tract infections. Some cytochrome P-450 isozymes.. such as CVP IAl are inhibm:d by enoxacin. resu lting in potentially im~ interactions with other drugs. For example. eno~ acin IIa\ been reported to decrease thoophylline clearance. causq increased plasma levels and increased toxicity. Enoue. foons insoluble chelatcs with d ivalent metal ions ~nl III ilnlllCids IIIId hemattnics. which reduce il5 oral bio.nw. ability.

,=.

USP. l -Cyclopropyl-6-fluoro-l.4-dih) dr0-4-0~1)-7 -(I-pi pcTllZi ny1)-3 -q II i no Ii necarbo xylic oc id (Cip1'0, Cipro IV) is suppl ied in both 0011 and parenteral IIw", forms . The hydrochloride r.alt is available in 2j()., 500-,-.$ 7j(). mg tablets for oml admin istrat ion. lnlra venou~ solUtiOI'll containing 200 mg and 4{)() mg IU'e provided in COfICftlID. tioos of 0.2'l1> in normal saline and 1% in 5% deJltro5e mtions.

CiprofloK~ci",

The onUabsorption of oorfIoxacin is rapid aoo n:a!lOnably efficient. Approximately .3O"lo of an oral dose i excreted in the uri ne in 24 hours, along with j to 8% consisting of les~ active metabolites. Thene is significant biliary excretion , with about ~ of the origmal drug appeanng in the feces.

1be bioa,'ailabi lit y of ciprofloxacin following oral admtDistratioo is good. with 70 to 80% of an oral dose: beiDl_ sorted. Food delays, but does nO! prevent. absorpc ion. Sit nilicam amounts (20 to 35'l1 of orully adminiSlCftOll ciprofloXicin are ~creted in the feces. in pan bec_ d bil iary excrelion. BiO!r.lnsfoml<llion 10 Jess actl~e metabolites accounts for about 15% of the adminiSletro drua. At'proximatd~ 40 to j()% of unc hanged clprofloxacin is ~I' creted in the urine fo llowi ng oml ll(iministrntion, ntis \'aI11e increases to .50 to 70'J> when the drug is injected 11llr1'f' nousty. Somewhat parn(kmcally, the elimination halfhred ci profloxad n is shorter foll owing oral adl11 ini~tration (I" ( hours) than il is followin& imra\'enous administration (I ., !O 6 hours). Ciprofl oltac-in inhibits the: P-4SO speclCS IA2.

EnoJ(Min, US". I-Ethyl -6- n uoro- l ,4-dillydr0-4-o.o-7( I-pipcr.llinyl)- I ,8"naphthyridine- J-c~rbo.ylic acid (renetre.) is. quiuolone with broad-spectrum antit>acteri.lactiv _ Ity thai is used primanly for the treallnent of urinary tnICI infections and llI.'Jl.uaHy transmi tted disea.ses. Enoltacin has been appro~ed for the treatment of uncomplicated gonococcal urethritis and has also been ~hown to be e ff~tive in chancroid cau.~ by 1I1~mt}philIH tf"crqi. A single 400mil dose: is used for these iOOIClitions. Enoxac:i n is .Iso approved for Ihe treatmcnt of acute (uncomplicmed) and chronic (complicated) urinary tl1lCt infC'C tioo$.

en

,...,

~.

"'" = ....

Tht oral dose of this quinolonc IS tYPICally 25'l> hi~r ... the parenlrntl dose for a given irwlicalion. PlObcnedd wgluflCantly ~lICC'S the renal dearnnce of cipronQucin. pn'SIIITI3bly by Inhibi ting its acu~e wbuillf secretion. CiproOo~acln IS widely distributed 10 vu'tually all pam; of the bCldy. Including the CSF. and is gClICrally C()Ilsldercd \0 pro"ide the beSt distribution of the current ly marketed ,!uino~. This propeny. together with the poh!OC)' and broad IIIllbactc:nal 5plrum of ciprofloxaci n. accoun l~ for the numerous therapeutic indica tions for the drug. Ciprol1oxacin 1110 exhibits hig.tw:r poIeoc)' agai n~1 most Grnm -negative blncri31 spedc!!. including I'. /lc rug;nI)5U, than other quino-

.....

,...,

,n"n.2.

Innt

ha' l ing lein II in

,wl-

'hy-

::ip-

Iltra-

"'" '""

"""

CipronOll;ICin is an agent of choice for Ihc lre;mncn l of bIctcnaI gastmcntains caused by Gmm-negatlve bacilli ... as cnlcropal~nic E. coli. 53lmonella (inclLKImg S. nplltt SIt"t/llI spp .. Vibrio spp.. and Mromt.mlIs hvdrol'hi.. II is widely used for the treatment of respiratory tmet 1Iftions and is panicu illfly effecli ve fOf controlling brondIIus .nd pneumonia caused by Grnmncg':llive bacteria. C i,oRoucin IS also used for combating infectioM of the sk in. idtllrnlCS. bones, andjoinlS. BoIh UllOOlliplicated and compInled urinal)' tract infections c:wo;ed by Gramnegati ve t.;t~ria cun be m~ated e rfecri~cly with ciprofloxucin. It is ptUCularly ustful for the control of chronic infec tions char1CItri1.ro by renal tissLM! invot-emcnt. The drug also has ~t applications in controlling vcnereal diseases. A roriltll3lion of ciprofloxacin with the cephalosponn IUltibi cd"triUone is recommended as the treatn"ICOi of ehoice b dlS$m1.m:ned gononi"Jea. while a singlc-dose lTtatmc:nt mciproflo)adn plus doxycyc line. a tetrdCycline antlblO(ic 10). can usually tflIdicalC gonoooc<:al urethntis. C!proIloxacin has also been used for chancroid. The drug Us bem appro"cd for postexpos.ure treatrnent of inhalullOnal

0..,...,

......

;011,1 -

InJlable forms of cipronoxacin arc: incompatlblc wi th dna solutions that aTl: al kaline because of the reduced solub&IiIy of the drug lit pH 7. Thus. intnl\'enou.~ wlution. should II)! be mixed " 'ith solu tions of ti carci lli n sodium. nlC,o;loc illin ..uOOl. Of aminophy ll ine:. CiprofloxlICin may also induce aysuJlUril under the unusual circumstance that urinary pH !lin Ibo>l: 7 (e.I . with the usc of systemic alkaliniters or habOllic anhydrnse inhibitor or throogh the action of u~asc IllUIited by certain species of Gf"JIIl-rIC'gali,'c haeilli).

also wide ly distributed inlo Il"IOSt body nuids and U\SUClI. In fact. higher C()rItenttalJOOll of oflo,acin arc: :.chlel ed in CSF than can be obiamcd ..... ith ciproflollacin. "The onU biOlVfti l abi lity of ofloxacm i ~ superi<Jr (95 to 1()()'i1,) to tNt of d proflollllCm. and metabolism is ntgllgib\e (-JOK). 1lIc amounl of an admlnl stcred dose of o noucin e~ cretcd in the urirIC' in 11 24- to 48hOi.lr period rangcs from 70 10 The~ is rdalive ly lillie bllial)' excretion 'h is qui nolonc:. Allho ugh rood can slow the or~ 1 ab.o;orption of oflO~P~'U1, blood levels foll owing oml Of" inlr~\"Cnous admini sttDtion D~ comparablc. The eluninal;on half-life of o noxacin ranges from 4 .5 to 7 hours. OfiOllac in has been approved for the tre311nent of infec lion~ of the lower rt'.'op!f"Jlory tract. inclLKImg chrol1lc bronchit is and pneumonia. cauSo..'<i by Gram-ntgatll'e bacilli. It is also used for the trealn"ICnt ofpeh it inflanmkltory dl.-.casc (PIO) and is hIghly acth'c np.11l'i1 boIh gooucocci and chla mydla. In common wnh other nuoroquinolones. onoucm is not dfCCl,,'e in the lreannent of s)philis. A smgle 400-ml oral (jose of oOO~lICin in combination with the tetracycline ant ibi04it doxycycline i~ recommended by the Centcrs for Disease Control and Prevention (CDC) for the OUlpllhcnt treatment of acute gonococcal urethritis. Ono:tacin is al"l) used for the treatment of urinary tract infection~ call<.Cd hy Gram -ncgatile bacilli and for pr()~tal.itis cau.ed by t . CQIi. Infections of the skin and soft tissues eaused by stuphylo...'oed. streptococci, 1100 GtDm neg:Ui'e bacilli may also be treated with o floxaci n. lk 'Cause oflo~acin ha~ an 1b)"lIImetriC carbon atom In li S stroelure. II is otMalllc:d and supplied commert""lally as II rncc mate. Thcf"..cc:mic mi:tlllre lias been r~s()hed. and the elWluomc:t"!I IItdcl>C'udently symtlCS.(ed and c"aluatc:d for antibacterial act;"ily .... The 3S{ -) isomer is substanlially more active (8 to 125 tnlles. depending on the baclcnal species) !han the 31(( +) i<;omer and has recently been rlwl.:ct<..'tl as levonox adn (Levllquin) for the ~mne indication ~ us lhe mec matc .

or

m.

,""-

Im in-

Sig:tered

Ot'IoXIcin, USP. 9_,"'uoro-2.J-dlhydro-J. mcthyl_1011tlt)I . t ' p'pmuin-ytt-7 -ollo-711-pyndoll.2.)-dc 1 1.4. IaIm."Jne-6..carbollylic.-id (Fiollin. Fio~in IV ) isa memo Itcroltbr qUlllolone class of anl1bactcrial drugs ",he~in the lad g po5nioos a~ joined in 1he form of 3 1,4-01Ulline till- The ring sy~tel11 is numbered beg inning with the oxamto~~,en 01 0111 Il.~ show n below.

.., of
:labo, Apis ClIvalue
lraU!-

""'I ~N

o j '"'
-::p"
N

Lomeflolfacln, U5P. I-Elllyl-6.8-d1 nuort)o L .4-dlh}dro7 _( 3-mcth y 1 1. pi P':Tlll.1 nyl)4-o xo- 3-qu inoli nccarbox y I,c . acid ( M a~aquin) i ~ a dlfluori nated quinolonc wi lli a longer eLimlllatioo half-Itfe (7 to 8 hours) Ihan other I\Icmbet"!l of .IS elns. It IS the on ly qui1lO1onc for which once-daily omL dosing suffices.. The onl b,oov3Jlability of lomcnoxaclll IS esli mated to be 951098%. Foodslows. but does not pre'cnt. liS OQI ab$orptlOn . 1l1oC' e~lmt of biotrnnsfonnatlot1 of 10meflox3ClIl IS only aboul 54. and high concenltDUOm or unchanged drug. f"dnging from 60 to 8O'i. are excreted 1Il the uritK:. The oompar.luvely long half-life of Iomc:noxacin is apparently due to its c:tcc:lIentt issue di~tribut ion ~lId renal reabwrplion 800 nOI due to plasma protein bindi ng (onl y _ L 0%) or enlcrohcpatic 1"CCyct ing (biliary excrc lio n i~ e~ti mated to be - I 0'Jt,).

l ife of (t , 4

,
()6oucm resemble:!; c lpronoxacin in II ~ anlibacteria l ",~Ind poccncy. Like ciprof1o~acm.!hi$ quinolonc is

(t.5
C YP

Lomen oxacin has been approved for two primary indications. First. it is indicated for acute bacterial exacerbations of chl"Ollic bronchiti~ caused by II. injl"tnt./U or M orw:tlla (BflJIIhmntlla) Cala"ha/is, but not if SlrrplorolU pnt,, monj,lt is the causali "e organism. Scoood. II is used for prophylU I5 of infOC1ion following tnlnSurelhraJ surgery. l.omcfloucin also finds application in the lreatment of acute cyst itis and cltronic urinary lroct infections cau~d by Grnm negative bacilli. Lol1ldlo~acin reportedly caUSC$ the highest incidence of phototollicity (phot~nsi'ivi'y) of the cum:lllly available quinolooes. Tk presence of a halogen atom (floorine. in this case) al the 8 position has been correlated wilh an increa..<;ed chance of phototoll icity in the quinoiOlle$.oo Sparnollocin. (r;i1)-.5_amino-l-cyclopmpyl 7 (3,5-di11"lethyl)Ipipera.;.o:iny1) -6 . 8-dinooro1 ,4 dihy dro-4-ollo-3-quioolincclU"bollylic acid. is a newer nuoroqui
S~rl'oxacin.

pounds-n itrofura7.one. fural.Otldone. and nitrofuranloin-have been used for the tn:amw:m of bactcrial infec tions of various kinds for nearly SO years. A fOlll"lb nitrofuran. nifunimoll. is used a.~ an antiprotozoal aserM 10 treat uypanollomiasis and lci~lTIlIlIiasi$. Aooclier Dllrohtseror:ydic of considerable IInportance is melronidat.oit. ..... hich is an nmebicide (a trichomollicide) and i~ used fill the treatment of ~ys lemic infOC1ions caused by anaerobic bacleria. This important drug is discu<;sed below in chapter. The nitrofurnns are deri\"ali,'cs of formed 011 react ion with the approptiate hydnuine or derivati\e. Antimicrobial activity is presenl only when nitro group is in lhe S position.

NO,. j( ~~,._.
o

nolone.

II

Nilroful"8RlO8 R..

..,c
OH
F

r.- NH-'......,

..,

This compound uhlbits higher poIcncy against Gram

positi ve bacteria. especially Staphylococci and W"eplOcocr:i. than the nooroquioolonc:s currently marketed. It is also more active against chlamydia and the anaerobe & Icleroidujrugilis. The acti vity of sparflOllacin again)t Gramnr:gativc bac leria is also "ery impre..,,~ive. and il compares favorably with ciproOollacin and olloucin in potency against M)"coplmnJO spp .. ugiOlfe/1o spp .. mycobiictcria, nnd Usr",io mOlfoc)"U/, genes. SparflOll3Ctn has a loog elimiBation half life of 18 hours. ..... hich pennil5 once-a-day dosing for most indica liOns. The drug is widely distribute(] into mOiSt nuids and ti <;sues. Effective concentrations of sparflollocin lin: achie~ed for the tn':atrncnl of skin and soft tissue infections, 10wt!T re:'pir:ltory infections (i nclOOing bronchitis and baclen:ll pneumonias). and pelvic inn ammatory disease caused by gononttea and chlamydia. SparflollllCin hal; .also been rccom11"lendeti for the treatment of bacterial gastroenteritis and chokeys'iti~. The oral bioovailability of sparflo~llCin is claimed 10 be good. lind su fficiem unchanged drug is ell ~ted to be effective for the trelltmenT of urinary tracl infec lions. Nearly 2O':f, of an orally administered dose is \!:len-ted as an inactive glucuronide. The incidence of pho!otollicily of sparilOllllCin is the low. est of the nuoroquinolones. because of the pl"C5CncC of the Samioo group. whieh coumel1lCts the effect of the 8 nuorosub~lituent.

The mechani~m of antimicrobial oclion has been e~tens;"dy stOOled. bul it ~ul1 is ooc stood. In addition 1 their antimicrobialactiol1s. lhe 0 ....tnS are kllO ..... n to be mulllgenic and carcinogenic ;.";,; llIin conditions. It i, thoughl that DNA damage caused 11"Ie1llbolic reaction proUUCl~ may be Involved in 1",."; Jar efft'Cts. jNiU"O-2furnldehyde ( Furar:in ) OCCIII"$ as a 1e1T1(lf1)"cllow crystalline solid sparingly soluble in water and proclically in.looIuble ganic solvents. Nitroful1I7.one i~ che mically crntely lighl sen~itive. It is used lopi cally in the lrealment of burns, ..... hen bacterial resistance " . II rna)' also be u<;ed to pn:vent b~";' i with sun . Nicrofu1"ll7.Of1oC has a broad I

Nitrofur.Jzone.

III

(If''t''',

fungi. 11 bacu:ria 'i StreJl'QCOCCus spp ..

i~

Nlbofwra... Tk first nitrohelenx:)"clic compounds 10 be introduced inlO chemotherapy ..... ere the nitrofurans. Three of these com

Hlrlerobocl~r ("frobaCI~r)

(Ierogenrs. and

b().....-ever. P. fNTUginoJlI stnlins an: resist.'U1t. NicrofttrllWflC is 1l"\aI"keted in 'iOIutions, suppositories in a usual roncentradon of 0.2%.

USP. 3-1(5-Niuufurylidc~)aminl) l-2me (Ful'OJlooe) OCCUI'$ as 11 yellow cry~tnllint'

'i1 , bmer alkrlastc. It is insoluble in waler or iUJ,JOidone Au bactericidal .emity agairu;t a rdallu-

"""O!:;';; ~pp.. nrrm/K'rIncluding S. '.n

;~

rho/tro,. is 111>0 active :ilgninsl the Gum/It' klmh/Ill. II is recommended for the 01111 .". NderiaI or proIo~oal dmrtlC':I caused by 5U~... ,~. The u~uat adult dosage is 100 mg 4 times
an ()l':lliy of

"
I'

Methc:nmnine is u.>cd intcrnally as a unnary antiseptic for lhe treatment of chronic urinary tr.IC1 Ulfcctions. 1be free': base: has pnlCtically no bacte:riostatic PO"'er. formaldehyde: rc:1ease at lhe: lower pH of the: kidne:y is required. To opInmzc: the: antibacterial effel..1, an acidifying ageRt such :as '\Odium blp/losphalc or ammonium ch loride ,cnc:ruily accornpanlb the: administrati on of methenamine. CrAIIlll Melerial stmins arc: =islanl 10 the: aclion of methc:nanunc: because they c:IaOOraIr urease, an e:nzymc thai hydroly,.c:.~ urea to fonn ammoniL The resultant hlPl unrw-y pH pre\CnLS the activollon of rnethcn~minc. rc:lMkring It lne:ffective. This problem can be overcon\tl by the coadmin istration of the urease inllibitOf' occlohydroxamic acid (Lhhotitat). Hcnmethyknc:tetra mine nUlndelate ( Mandebmine) is a .... hile crystallmc pow . der wilh a sour tll$te 000 practically no odoI-. It is very soluble in wmcr and has the advantage of providi ng its own acidity. although in its use the custom is 10 Cllrry out a pn:hnunary acidifieation of the: urine f(J( 24 to 36 hours befort Ic.Imm'.~
,~~

""'. is being used

"

Merhenaminf' Mandelate, USP.

Ilrug can mhibn nldehyde dehydrogenase .

NitrofunlHlOln. 1-{5-nitro-2-furMlICrodanlln). is

is SUItable ~;~., use. It i~ m:-

b) MIl , .... Me: dfcclS are gastrointest inal (anorexia. al.omltiog ); hoIo.1:"cr. hypcnocnsllivily reaction~ ~~. hepauu~, and hemol)!!c anemia) ha," c been obl.c:rwd. A ma.crocry~lalhne foon (MaI Improve gaslroinlCSlirlll1 to(cmnce

lIl:~unenl of urinlll')' 1r'.K.1 infcctions ~pcible ~r:lJl1S of E. roll. entcrococci. S. I l u AI.~jt/la. ETlltmcm:ler, ~nd Pr()/t'u~ spp. The

1 the

IQItffrriO! *itll oralllbsorption.

MelhenamillC hippurale ( Uiprex) is the hippuric acid salt of mc:thc:narnulC It is readJly ~ afte:r 01'111 administration :tOO ,~ ooncc:n100ted mille urinary bhlLldc:r. ",he:re II exens liS anubactenD.l activity. Its activity is increased in acid unne: .

Methenamine Hippurate, USP.

..... ltSs .. ts
The

of hcxamelhy1cne:te:ton the: liberation of i prepared by e:vapornun, aoo SlrQn& ammonia walc:r to

Uri_ry Amttl!psks
P1lin n,.d di5(;omfort fn."quCnlly ~company hactcrial IItfcc tioM of the urinary trnel. For this re;a.;;on. cenain analgc~1C agents, \uch IS the 5D.lieylateol or phc:n:u.opyridllle ..... hich COIICentr.tte in the urine because of their solubilily propcn,es. are combined with a urmary anu -mfecuvc agent. PhcnlUopyridine: hydrochloride. 2.6-di:unioo-J.{phenyluopyncJioe hydrochloride: (Pyridium). i~ a brick-red fine crystalline pow_ der. It is s lightly soIubk in D.lc:ohQl. m chloroform. Ilild 1ft

......
!me !'.1iSh as an odorless .... hile: crySTalline: pow_ I about 26O"C. 11 dissohes in water to t and libc:r.ue!l fonn:tklc:hydc ....'hen "It! minenl acids. Me:thenamine: IS a we:ak ba-;c:

Phena:lopyridine

Hydrochlorid~,

USP.

waler.

Phen:l7.opyridllle hydroch loride WI!!; formerly used I!!; a urinllt)' anliseptlC. Ahhough it is ~l\'e in vitro againSt sUlphykx:oa:i. streptococci. gonococcI. and E. coli. II has no useful anlibactenal acti"il) 1A the unne. Thus. its prncnt utility lies in ilS 1000al analgesic effect on Ihe mUCMa of the urinllt)'
~,.

Usually. phenazopyndlne is lIVen in combinauon with urinary antiseptics. For example. it is available as Am-GanIrisin, a fixeddose combination with the sulfon:unide antibacterilll sulfisouwle, and as UroblOtic. a comblllation with the antibiotic oxytetracycline alKl the sulfonamide su lfarroethi1.OIe (Chapter 10). The drug is rnpi dly excn:ted in the urillC. 10 whkh .. li,'es an ornngered color. SllIins in fabrics may be remo,cd by 500IMg in a 0.25% solution of sodium dithionite.

Antlblbercular Agents
Ever ~ince Koch identificd the tubercle hacillw,. MycQiH,c/,, ri"", lukrrulosis, there has been keen intl'fel,t in ttlc development of anmubercular drugs. Tllc. Ii .... t breaklhrough in antitubercular chcmothernpy occurred III 1938 WiTh the 0bservation that sulfan ilamide had weak bactcrio~tatic properlies. Laler. the sulfOlK' derivolive dapsone (4 .4'-diamlllodiphcnylsulfooc) was invesugated clinically. Unfonunately. this drug. which is Slill C{)I1siderc<! o ne of Ihe IIIost effective drugs for the treatment of leprosy and whkh also h.1!i useful antimalarial "'llS Con"Iderc<! too toxic because the high doages u-ro. The di'iCOvery of the antiTubercular aclivlty of the uminoglycos ide antibiotic Slrcptomycin by Wwmanet al. In 1944 ushered in the tn()(]cm eraoftuberculosis tn::atmcm . This developmcnt WllS quickly follo wed by di<;co"criCl! of the antitul:tcrcular propenies of p-aminoalicylic acid (PAS) first and then. in 1952. of iwnivid. Lale!", the uSoCfulncss of tile ~ynt he:tic drug ethambutol and, eventually. of the scmisynrhetic antibiotic rifampin was di'>CO\ered. Combinati.,.1 thffllpy. wilh the use of two or more amitubercul:u dOl,". has bn ... ell documented to reduce the emergence of ~rnllns of Mycolxl;r"num rubt'fculosi r res istant to ilKlividual agenrs and has becon~ ~Iandard mcdical pracuce. choice amltubertular combm!l.lion depends on a vanety of factOI'll. includmg the: location of the disease (pulmonary. urogeniTal. ga~troIlHc'linal. or ncurnl). the I"Csuits of w.sccplibilily k'Sts and the paucm of resistance in the local ity, the physical coodilioo alKl age of the patient. alKl the toxicities of the IlKIividual agcnt_ . For some lime. a combination of lsonilllJd 1uKi etMmbutol. with or witOOot streptomycin. was the preferred choice of tn::atment among clinician~ in thl ) country. Howe,er. the dlo;rovery the tubercu locidal pmpenies ofrifampin resulted in its replacement of the lnore to.lic a.uibiotic s.trcptomycin in nl()<;t regimen . 1lIe synthc11C drua p)"l1Illllamide. because of its SlcriHlmg ability. IS al<;o comldered a fil1ll-hne 3J:i=nt nlKl is frequently u.",d in place of C:lhamb-utOI in combination therapy. SCc: ....1d-l illC agents for tubef"l.-ulosis include: the antibiot ~ c)c1O'erinoe. kanamycin. alKl caproomyc ln alKl the 5ynthetk compound. eth ionamide and p-aminosalicytic acid (P AS). A major ad.allCe in the trealment of tuberculosis was sig naled by the introduction oflhe anllbiotic nfampin mlO therapy. Clinical Sludies indicaled Ihat when rifampi n is iocluded in the regimen, panicularly III oombination with ifoOnial.>d

propcmes.

or

n.e

or

or

alKl eThambutol (or p)"T1Il.namide:). the period reqUired flY successful therapy is shonened signi ficantly. Previous Ittat n-.eOl !iChedulc:s .... ithout rirampm required mallltenaroce ther apy for at lew 2 years. '" herea!'i tho!>e based 011 the I~ ~id-rifampin combinalion achie\ed equal or bcller resum in 6 to 9 months. Once considered 10 be on the lerg\' of woridwide CTadICItion. as D result of aggre,~ive public ~alth meas.ures IIId effect iv~ chemOt her-ipy. tuberculosis has made a oomcbacl 0( alarminl proponions in recent year'll.1>!I A combination 01 focton h15 contributed to the observed Increase 10 tubcrcuklsis cao;es. incl udinl: tile worldwide AI OS epidenuc. the general rela;wion of public health policies in many COUI1~ the incn:ased ovef"CT"()llldllll: alKl homekssnes, III map cities, alKl lhe increased emergence of multidrug-rtsistIIIC strnins of M . IIlkrcu/(JS/I. de:velopmcnt drugs useful for the treatment oflqrosy has long been hampered. in part, by the failure of die causative organism. Mycrnx.crerim,. 10 grow 10 cell cu ltul"C. Howe,er. the recent a,ailablhty of animtll mode... ~uch as the mfected mouse footpad, now pc."uts in '110 drug evaluaTions. 1llc incn:asmg enk:rgence of strains of M I"prot' rcsisUUlt to dapsone. long coosidcn:d ttlc mainSlt~ for leprosy treatment. has caused public health ofrlCials til atlvOClllc combinauon therapy . Mycobacteria Other than M. lu~rcuIQ~js and M. I,pfrlt. commonly lnown as "atypical" mycobacteria. wen: fIN established as enolOSical agents of diseases 10 the 19Atypical mycobacteria are primarily saprophYIIC speo:~ thaI are ...idely dl ~lributed in <;011 alKl water. Such ore Isms an:: not normally conSidered pan.cularl y ,indcnt Of infectious. Diseases allnbuled to atypICal mycobacterilllf o n the illco:a.<;e. ho .... evcr, in largc pan bl..cause of W Increased number; of immufI(X.olllprolllisc:d IlKIi.'iduais. the population re-.ulting from the A IDS epidem.c and W w i~])fCad use of immunosuppressive agem~ ",ith 011transplantation. n.e Il"II)<Ot common di~ase-cau.sln, spec.es an: Myc. ' .."urn (n'ium and Mycvbarlf'rium inrf/lctllu/(II'I', which hll't similllJ' geographical distribullons. IU"t: difficult to diSllllglll1ll nucrotllologically alKl dlagllO!itical1y. and an: thu~ I.'OIhIIc:red a smgle CorllplCX (MAC). mlllal disease atmbutd 10 MAC resemhles tuberculo~i~. but ~kin and illusculOlokclttal tissues may abo bocUIne jn,ol.cd . ~I(lII1i MAC and HI V mfectlOll I) dramatIC . An m"CT\\ helmtnJ seminatl'(] fonn or the dl'ICase occurs in severely immUlJ). compromised patlent ~. leadl ng 10 high morbidity IIIld iIIOnII ity. Another rclah\ely cormnon QtyplCal my~ Myc:f)/xICltrium kaMasl/ . also causes pulmonary dlS('~_ can become di sse minaled in immullOCQmpromised p;lual\. Patients mfe(:ted wi th M. kllnstlsli call usually be trtM effe(:ti ,ely with comblnallon5 o r antilubercular di\lgs. MAC' infect io ns, in contr.t.~t. are re.~is!(ult to currently a.OlJI.!Mt chemothetnpeutic Hgcnts.

n.e

or

I",m.".

n.e

n.e

Isoni azid, USP. lsonicotinic acid h}drnl.lde. iJ.oolCODnyl hydr.u.ide. or INH (N)t1nu.id) OCCUI1l as a nun)' caw less cry'-lallioc solid tllat IS .ery soluble ill waler. It I.i p" pared by n:acti ng the melhyl ester uf isonicotinic acid ... hydT3linc .

 rtmatubly effect ive agent and conllnues ollIE . drugs (along "lIh nfampin . pyrazifor t~ treatment of Illberculosis. ,uniformly effccth'c agai n~t all forms of therapy was seen as ~ing of the drug. problem Iuls been butllOl enllrely. overcome with the use of L"Ombin3to IS man ifested on the growmg not on resting forms. Its actiQn. which , I, is to cause the bacill i to lose lipi d mcdwulilJl mat has noI been fully elocidated. tlgge~s th:U the pnnci.1 isto i lhe

I~

proximately 6O'l> o f an oral dose i ~ excreted In the unne wilhin 24 hours in the form of numerous met:ibolites as .....ell as the unchanged drug. Allhough the metabolt~m of i-.onialid is ~cry complex, the principal path of inactivation JIl. volvu IlCet)laliOll of the plimary hydra711lC mtrogcn. In additlOll to lICC1ylisoniaztd. the IwmCQfin)1 hydr.l1.ones of pyruvic and &-ketoghllaric acids, t.onkounic lICid. and isonicotinuric lICi d Iulvc been isolated a.~ me t aboli te.~ in hllmans.lJ 1lte capacity 10 lnactl\ale iSQniuid by ocetyLatlOll is an inhented characteri~tie III humans. Approll imatcly Iullf of pel"'>OIIS in the population are fa~t acet ylntOl"ll (plasma hhlftife, 45 to 80 minutes). and the remainder ~low acctylllll)l"!l (plasma half-lift, 140 to 200 mmules). 2-Ethyhhioisonicotinamide (Tree ator SC) Ot'(:Ut'S as. ~11ow cryqaltinc materia! that i, sparmily soluble in ..... atn-. This nieOllnamidl-ltas ..cllk bac:1trK>sth tic activity in vilro but. becuuse o f it ~ !tpid :I(llubllity, is em~ctiye in vivo, In COfltnl~t III the isonilll.id 5C ric~. 2 .sub<ititution enhances K1ivity In the Ihioisonicotilklmidl- <;cn ...

Ethionamide, USP.

co..b);.
'~

"

::.=~:~~~:

"'C-NH

enzyme complcx is t t i of isoniuid ..... A reactivc ~pe through the act.on of tl!e.o;e enlymes on W to brlle\-at 10 :attack a !:ntleal enzyme requtred for ;IC1I] t in mycobac1cna," Resismocc to from 25 to 5OIiI> of cl ini cal i!>Q latcs is ;lS..<;QCilIlM with loss of catalase IICIIYllle!, both of which :are encoded by a Illrgct for the IICtklO of INH has as an enzyme tlult Catalyl.es the I of 2-'mns-enoylocyl carrier pro-'iIql In fatty acid elong.lllon." This e nl.ynlll: " '~, it,ltA, m M . lu~rcuIQ#s. 7~ I i t Clinical isolates milA gene. ladmg 10 at tcred prortduced affinity for the acli,'e form of INH-n:sislam StraIns also dis-

CJmla-,.e- pero~idas.:

Ethionamide is rapidly and comp lcte ly absorbed fllllowing oral administration . It i ~ widely di,uibutoo throughout lhe body and tll te~hc1y olll:taboli zed 10 predominantly inx:liYe form!! thai arc excreted In the urine. Le~s than I q, of the parent drug appears in the un ne. onSidered a secondary dru g fOl'" the trem Ethionamide is C ment of t ubercul05I~. It IS llsed In the treatment of isonlazld I"('sistantlIlhercuiosis or when the pahcnt i ~ ImoleranttO ISOniazid and ()\hcr drug~. Because of it~ low IlOlerlCY, the highCSlII)lmued dose of ethlooanude is u.sually recommended. Gastrointesunal Intolerance is the mor;t common ~idc effect associattd with its usc. Visual dl\turlxioccs and hepalotoxieity hllve also been rcpor1ed. Pyrazint:carboxamlde (PZA ) occurs as a while cryMalline powder that h ~p:tn ngl)' . I)luble " in ..... ater and slightly <;(Iluhle in pvIlI1" organIC soI\'enl5 _ lis 'iere dl'>Co\ered as a res.ult of an antiwben:ular propcn lcs " Investigalton of heterocycl ic analogue~ of nicottnic acid. with which it is iso:-;teric. l'yf"MJ nmnidc has recently bt:t:n elc l'atN to fi~-l ine status in 5hort-term tuherculOl'iis treat nlll:nt regtnlll:OS because of JI) tuben:ulocidal activity Pnd companlti ,ely low shon -tcml to~ie lty. StlleC pynu.tnanllde is nOi active against mctllbolically inactive tubercle: b'leilli, II i~ not consIdered sUi table: fOl'" Iong-tcrm therapy. POtc ntial hcp.-uoto~ici ty also ob"iatl'S Iong term use of the drug , I'yntzin amidc i ~ m:IAimally cffCCll\'e mlhe low pll enl'tronl1lCnl that c~ists in macrophagcs (monoC) tcs). Evidence ~uggCl>ts bioacti vatlOll of pyr.umamide 10 pyruiOOtc IIC1d by an amidue ~nl III mycobacteria.U

Pyrazinamide, USP.

genera lly

long-term I e ffects is . reactions are pe ripher.I1 of .

r~

and t.:paIOOlIidty.
.. lqIOIIed 10

Coadministr-~ti()ll

pre,ent the

SymptOflI.~
,ff~

of

phosphate. the antiWhercu -

~ ~

tn tQmbln.ltion with

It IS .' . . . Ilurds '" nhtn the body. I

""'~ " rapidly and idmtnlSlBllon.

'~:;otoatl fol;~ t
the CS F. Ap-

bacterial resistance to pyra:.(inpmilk: de,'clops rapidly, it should always be: used in combi nation with Olher drugs. Cros.Hl:sis.ulrlce between pynL'inamidc: and either i<oniuid or ethlOllamide is relatively rare. The mechanism of lII:'lion or pyrazinamide is not koown . Despite Ib ~tructural SJmil:mtil:$ to isonill7,id and ethionarmdc:, pyrazinamide: ap. parently does not inhibltl1lyoolic acid biosynthe_is in mycobacteria. Pyru7.inal1lide is well obMlrbed ornlly and widely distrib uted throug/>outthe body. The drug pcIW:tnlteS; inflamed me ninacs and. lherefon:. is recommended for the trcatrncnl of tubc:rculous memngius. Unchanj!;ed pyr:mnamide. thel;OlTe' sporltllllg carbollylic acid (pyruinoic acid). and the 5-hy drollY metabolite are c.lcreted III the urine . 1lIc ciinllllalion half-lifc ranges; frolll 12 to 24 Iloors ...... hl<:h allows the drug 10 be udil linistered on either once-dai ly or e"cn twice-weekly dosing Khcdules. Pyrvinlllnide and its metabolites arc re poned to intcrfere with uric acid C.lcretion. Therdon:. tnc drug ~Ld bc: used wllh grellt caulion in p;ltlt'nUl with hy peruricemla or gout. Ethambutol. (+ )-2.2' (ethyk:nedii mino) dl - Ibutanol dihydrochloride, or EMil (Myombutol), is II white crystalline po,,'lk:r freely soluble in water and ~Iighl l y soluble in alcohol.

1l~'Causc

.\-Amil\(Nllicylic ocid ( PAS) 1)('. !,!urs as a whitc 10 ye llowi~h while crystalline solid thut dart en~ on e.lpoJ!Sure 10 light or air. It is slightLy olublc In w.l1;:r bul more soluble In alcohol . Alkali nlC'lal saLLS and the nllIi!: lICid salt an: 501uble m ".-iller. but tnc salts of hydrochlorit lICld and Stl lfuric acid are noL The acid undergoes Ikcar'bcu. ylalioo .... hen heated. An aqueous solutJOll has a pH of - ll

Aminosalicylic Acid.

HO

PAS is admlnlstc:red OI1llLy in the form of the sodium !oil!. lIlIually in lablet orcap!>ule form , S)'mptoms of gastTUlnt~ nul irritation arc common wilh both lhe ocid and the iIOdlla sal t A "ariety of enlcrk.cOOled fonllS have bm used in an . 0thcI'

. . . Im an anion

Eth" mbutol, USP.

1.1 :r'S

CH2 0H H H I I I - C - N-CI.I CH - N-C -CzHs ' 2HCI

''2

CHzOH

ElIIrombulcl Oihydrochloride

Ethambutol is active only agllinst dl\'iding mycobactena. It hils no effect on encapsUlated or other nonprolifenuing fom~\. 1lIc III vitTO c:ffect may be bacteri-<M;tatic or bacteri cidal, depending on the: conditions. 11$ .\Clect;,c lo~icity towlltd mycobacteria appe;trl to be rela!ed Wtlle inhibition of the iocorpor.uion of myt-olic acids into.> the cdl walls of these organisms. Thi s curnpoond i, remarkably stcreospc:cifie. Tests hal'e shown that. although tnc tOllicities of the ,/."ro. I~\YJ. and mtSIJ isomers are about equal. their octiv,Ile~ vary consider ably , The IkXlro isomer is L6 times as lII:'l,yc: as the mts(} i'Klrncr. In addition , the length of the alkyk:ne chain, the nlll ure of the b-mnching of the alkyl substi tuenLS on the nitrogen~, and the extent of Nalkylation all ha\'e a pronounced effect on the activity. Ethambutol is rapidly absorbed after or.!1 administnl1ton, and peak ~rum !e,'c:!s occur in about 2 hours. It is I1lpidly excreted. mainly in the urine. Up to 80% is ellcreted un changed, with the balnnce being metabolized and excreted as 2,:2'-{cthylcocdiimino)dibulyric acid aud the corresponding diuklC'hyde. Ethambutol is not recommended for use alone. but in com binations wllh other anlitubc:rcular drugs In the chemotherapy of pulmonary tubc:rcu losis.

aluminum i is 1lIc oral absorption of and it is widely d i~t ributed into ti,sues, with the e~ceptiou of the III i 1c:\cI~. significantly lower. It is excreted primari ly in the unne_ both unchanged drug and metnbohtet. 11Ic N~)I tl\'e is the principal metabolite.. ..... nh siglllfK:llnl Tnc glycine oonjug~te also being fOl",ed. When ..... ith isonilll.ld (which also unt.lcrgoe~ increases the level of free isoniazid. 1lIc of PAS is about :2 Iloors. The mcch:mi~m of antibactcriltl lII:'lion to tNt of the s.ulfonamidcs. Thus. n 15 the incOlpOl"~tion of p-aminobcnzOIc acid ( PABA) dihydrofolic acid molecule catalp.ed by the drofolatc: $ynthcmSl:. Structure- activity i that the amino and carboxyl group!> must other and free: thus. c:.~ten; ond umiOO mUST hydrolysis in Vi\'O to be effecti"e, The: be onlm or IMrtlto the carbollyl Is seen in the former. For mMy yeIIf'I., PAS W35 thecbcmothel1lpy of tuberculosIs and was in combination regimens with isoniazid I-Iowc:"c:r. the introduction of the more ally better tolernte<! agents. ethambutol and relcgaTed II to altc:nullh'e drug SlD1US.
lIS

Sodium ~.~. cyla te (sodium I' AS). II ~lt. occu~ III the dihydTllIC a yellowwhite powder or crystulline solid. IT is in water in the pH range of 7.0 to 7.5. al which it stable. Aqueous solutions decompose readily and Two pH-dependcnt types of rellCtions occur: ation ( more rapId at low pH) and O:lidation

Aminosalkylate Sodium. USP.

Cha pttr II "mi'",jr<e:ln'#' ",rnu pH). Therefore. ~ l uliOlJs should be pn:paml within 24 IIcuD of ldministnll iQll.
~sh

257

L-

", ,

x-

,.

Clofazimine. Clofazimine (umprcne) IS a bJ5ic red dye tOOl ucns a slow bactericidal effect on M. It'proe. the ~utn thaI caLl~ leprosy. 1 oceLlI'li as a dart red crysud\ . . lolld thai is insoluble In .... Ul('t", I

--I

o:N~NH-o
""" I
the

~~N-CH(CH~2

The: chelllht~ of riflllllyc1ns and otheT ans.amycms has been revic ....!':d.7. All of !he nramYCl/lS (A. 13, C. D, lind III are bIOlogICally ,:1I,e. Some of the scml'ynthetlC del1\"aril"cs of rifamycin B an: the 111O,t potent ~ n()"'11 inhibilorli of I)/IIA..(!irecloo RNA pol ynlCra.~ in bacteria,7" and their acllon IS b:tclCricltbl. They have no ICtivity agairu.t !he: marnmalian elll.ymc. The mechamsm of lICUOO of rifamycliU as inhlbtton; of I'iral repl ication 1lppc'ar'S to differ from that for their b41ctericidal actIOn. The ir I'ICt effect is to inh ibit the formation of the virus panicle. :Jrpan:ntly by pn:1entmg a specific: polYJX'plidc Conl'en'0I1. 7 Rifamycins bind to the: fJ 5ubuM uf bactcn al I)NA-depentknt RNA polymcn..\a to preve.nt chain initiat ion.'" Bacterial rcslSlance to rifampm has been associu ted with mutatio ns leading to amillQ acid substiturion in the fJ subunit .7M A high Jc.,.e] of Cross-reslStarlCe bt:l"CC'n various nfatnycms has been ob'\c",ed.
Ri fampi n, USP. Ri fampin (Rifadin. Rllnaclane. Rifumpid n) IS the most acti ve agent in clinical usc for the tre3lmem of tuberculosis. A dosage of 3.\ lillie as 5 ,uglmL is effective Ilgai n\t 'ie1lSiti\e ~tlllins of M . I.rculo:ns, Rlfampln i~ also highly active. agai n ~t staph )Jococci and Nr;suritl. lIuemQpllillll. ILgimlt'I/". and CIJlumwli{1 ~pp. Gn:un negative matilli arc much les.~ S('Mitivc to nrampin. Ho ....eler. n:SlMarK."C to rifampin dc,clops rapidly in I'I106t ~ICS of bacteria. locluding lhe tubercle bacilluJ. COIlSaluc.nl ly. nfampm is used only in combination ",ith OIhcr IlI1lilul:Iercular drugs, and il i~ Ofdi11uri ly 1101 l"ttolJ1!lIended for the treatment of OIhI:!- bacterial infections when ahernalile anlibaclerial agents ~ available.

III.

"""""" of lepromlltous 1cpCIofuimi ne is used in In:allneru

..,.. IlI!;luding dapoone-resistam forms or the disease. In 10 Its ant ibacterial action. the dIU); appems 1 po5+ 0

,m

lli-

~,

~,

;00

Kh

!l.C,

ind

vo-

"

, of

anll-lnflammulO1'y and immune- modu lati ng effccts th31 ft 01' n ille in conl l'Q11ing neuritic complkalions und in SupJIItIo'Ing n-ythema nodosum ICprulum n:action~ associated _1q:romat0u5 leprosy. II is frajucmly used in combma1IOII1IIIh OIher drug5, such as dapsone or rifampin. Tl'e medani sms of antibacterial and anti-inflammatory Ir."llOO5of clofazimine are nOl known. The drug is known !O t.I., nucleic acids and conccnlr~le in reticulocndothch31 II can also acI as an electron 3CCC'ptor and may interlife " jlh clectroo Iranspor1 pi oct:Sscs, The oml absoqxion of cJof:llimine is esti mated to be ~boul ffl, II is I highl y lipid-so luble drug that i~ distributed inlo
" <SOW' and the reticu1oendothelial sySl!':m. Urinary rtOOI'I of uochang!':d drug and IfI(':tabolit~ i~ ne!!:liglblc ,
t lWfh fe after repcal!':d dcK.1ge is esti mated 10 be about ~(!.J)". Seven.: gastrointestinal intolerance to clof:lI.imine

"" AS
,~ ,

lifc

~m

,ho
hy
," '
~h

Itlatll'cly common, Ski n pigmcntation, icht hyosis and dry rasIa. and prun t u~ abo occur frequcm ly. CIofUIm.J1lC has also been used 10 treat skin lesIOns caused ~ AI ~lrtrans,

NH

hill th ..:.,., Antibiotics

.,"'iIY(It~S

'"

my
f~

"I ly

~ nfamycin~

jcin.
~,

h"

,Ok

..,
Ii

I,

'ken , Ixy1

arc p group of chemica ll y re lated antibiotk~ "'IIN by fmncntation from cullures of Sl rcpIQmICt:J .,~o. They belong to I ciasl; of anubuxict call!':d _ _ '''UIS that contain a mocrocyclic ring brid~ ~ two oonadJlICcnt positions of an IlfUInatk nucleu\, Tlr le!malW means 'handle.'lkscribing well the topogrnrlthc.suucture. The: rifamYC in.'! and many of their semideril'atIH.~ have a broad ~pectrom of antimicrobial "I), They arc nlO!ot llOIably acti~e against Grom-posltl' e 00 M. ml1rculuJis. ~Iowever. they an: also active orne Gr~m ncg~tile bacteria and lrullly vi~. RI 5mlisynlhelic <krivllive of rifam)'clll 8 . was re ti III Inlrlubcn:ular agent in the United Stlltes in 1971 . AIaId semisynthetic derivutive. ri fabutin. was approled a 1992 for lhe trearll14!11 t of Ulypica l mycobacterial infa:

..

Toxic e ffects associated wi!h rirampin are n:lati\'c.i y infreq uent. It may. however. interfere "'lIh lilcr function in \QIllC patients and ~hould n<'ither be rombll1ed "'lIh ocher poten tially hepatotoxic drugs nor uo;cd 10 patient ~ ",ith imp.llrcd hepatic functio n (e.g .. chronic ulcoholics). The incidence of hepatotoxicity wus ~ignifkanlly higher ",hen rifamplO was combin.cd with Isonlll7.id thai' ",hen either allent " 'as ~'()," blneti ", ith ethambutol. AllergIC and S('nsitmty reaCtions 10 rifamllm halC been reported. bur they are mfrequcnt and usuu ll y not ~riou~. Rifampin I~ a powerful inducer of hocp3lk c)tochmlne P-450 Ollygen:ases. It can markedly poIcn-

liale the actions or drop WI are inactinltd by these enzymes. Examples Include oral antK:oogulanlS. batbilliraies.

ben7.ooill1.epines, ()I1I1 hypoglycemic agents. phenyloin. and Rifampin i~ pJso used 1 eradicate the carrier SUl\C in 0 lISymptotnll1 ic carriers of Ndsstlria men/ng/lid/s \0 prevent
otubreau of meningili~ in high-risk art:as stich as military facilities. SerOlypi ng and sensitivity tesl~ should be perlheoph)'lIme.

HO ,,,,

/ , , ,"'0#"-

:r"-./
Rd"""",

"", ..,
r'm
t iOll!

c"" ,Sa

'"

fonncd before its use because resistance develops rapidly. However. a daily dose 600 mg of rirampin for 4 days suffICeS \0 eradicate sensi tive strains of N. men/nIl/Wis. Rifampin has also been very e(fec;tive against M. /t/IfDe in

or

!ltetl 1] by'

uperimental animals and in human!. WlK'n il is ust<! in the Itta/l11ml of leprosy. rifampin should be: combined with dapsone or iIQIT1C other leprosUltic agent to minimize: the emergence of resiSUUlI strains of M. ftpng, Other. IlOIllabcled \,l~ of rifampin include the treatment of serious infeaion! such as endocarditis and osteomyelitis cllused by methidl1in-re.~istant s. Clur~U$ or S. ~p;II,.,.".idjs. Legionnaires di!Oea!Oe when resistant to erythromycin, and prophylOlli s of H. Injlu~"w,.i rnluced meningi tis. Rifampin occurs as an orange to reddish brown crystall ine powder thlll is soluble in alcohol but on ly sparingly solublc in waler. It is un sllIble to moisture. and a dc.~iccpnl (s ilica gel) shc)uld be included with rifampin capsu le containers. 1lIe upirauon date forcapsull3 slon.od in this way is 2 years. Rifampm IS wdl absoI'bcd after oral administflllion to pro,idedfecllve blood levels for about 8 hours. Food, howe'cr, markedly redllCC$ hs ontI absorption. and " fllmpin should be adnuniSlCfelion an empty stomach. 1lIedrog is distributed in effective eoncemrations 10 all body fluids and tissUCll e:tcept the linin, despite the faet thaI it is 70 10 ~ protein bound in the plasma. 1lIe principal excrelOl"}' I"OOtC is through the bile and fecell, and high C(II)tt:ntr:uions o f rifampin and its primary metabolite. dcacetylrifompin, are found in the liver and bi liary syqc nl. Oeacctylrifampin is al so biologically ac th'e. Equally high concentrations of rifnmpin are found in the kidneys. and althou gh subsumtia l amou nts of the drug are passiyely reabsorbed in the renaltubulcs. its urinary ex cretion is Significant. Patients should be made aware that rifampi n CIIUses 3 reddish orange discoloration of the urillC. stool, ",Iiva. tear5, and skin. It can also permanc:mly discolor soft contac1 lenses. Rifampin is llso Dyailable in a parentcral dosage ronn consbung of a Iyophili~ sterile powder that, when r:oo stituted in 5% ~1tOSC or normal 5Ulinc. pfOyide5 600 mg of activc dnlg in 10 mL fOl" slow intravenous infusion. The part'nteral form may be used fOl" initial tn:atment of !Oerioos cases and for retreatmcnt of paticnts ..... ho c~ nnol take the drug by the 01111 route. Parenteral solutions of rifampin are ~t~blc for 24 hours al room temperature. Although rirampin is Mabl e in the solid state. in solution it undergoes a variety of che mical changtli whose TIltes and nature are pH and tern perature t.lcpendent."N At alkaline: pH. it oxidil.cs to a lIuioone in the presence of o~ygcn ; in acidic $Olutioo~, it hydrol)"I.C!i 10 )forrn}1 rifllnlycin SV. Slow hydrolysis of the estcr func tlons also occurs, e\en at neutral pH.

,,' ,"
cccds that of ri famycin. n ils rifamycin derivall'c is noI d fCClive, howeyer. as monotllerapy fOl" ex isting dissemu\OIIal M AC di sease. Ri fnbutin is 0 ycry lipophilic compound wi lh a high ~rr'll
ity for tissues. [tS elimination is dist ri but ion limi ted, with I half-Ii fe OYCfllg ing 45 hours (runge. 16 to 69 hours). APJlffil ,mately 50% of an orally IIdmini~lcred dose of rifabutin II absorbed. but the absolute oral bioovailability is only aboIa 20'1>. Extensi yC first pass metabolism and signifICant bllia!) excmion of the droll occur. with about 30 and 53% of tbr ontIly administcred dose exereted.largcly as meta~itcJ. 1I the feces ~ urine:, respecti vely . The 250-des'lC"I) I _ 31.hydro_y metabolitcs of rifabutin have been idcntir1Cd. The pan'nl dru, i~ 85 % hound to plasma proteins in a co. cenlr.tl.ion.independem mnnnc:r. Despile its greater poIt~ against M . lu~rculo.i;s in vitro. rifabutin is considered 10ft rio.- to rifampin for the shortterm lllerapy of tubert:ulOSll becau!Oe of its significant ly lo ..... er plasma cooccntnllions. A !though rifnbu tin is believed 10 cau~ less Jw:patOioxicit) and induction of cytochromc P-4SO enzyn>es than ri fampm. thc!Oe properlics should be home in mind wilen the dlllill used prophyloctically. Rifubuti n and its metabolitC5 Iff highly colored compounds that can discolor ~k in. un~ tear'S. feces. ctc.

I SO~

tivitT

..
C,

bjp

r~

i!e~1f

SUI

CIlIY

enlY

roc d

AI

al!air poooil

to~ic

It j, I luber
l~rgm

OfUJll
., rn

Srer;.

eH,

,
,

eH,
,

frolll ill tIKdrug.

HO ",.

H,)_~
eH, N ,......0 ",., ,c
,

OH ""

.<9

r ""
0 0

eN,

- ,p

I I
~
0

NH

eH,
-

Rlfablltin, USP. Rifabutin. the spiroi nlk1aJ.opiperidyl denvaU\'e of rifamycin 8 was apprmed in the United States for the prophyluis of dis!Oeminated MAC in AIDS iXltients on the strength of clinical uials establ ishing its effccti vellCSS. The activity ofrifabutin against MAC organis ms ~atly cx

Rilabulin

,---<0\ 0\

C jdosttiM, USP.

1)-(

+ )-4-Amino-3ir,o)(3Z(Ilidinone

an aIlllb,ouc thai has been isolated from the beer of tlln:c diffo:n::nt Stff/"OfIlYf:t'S species: S. fIlS. S. ,arrp/tt./us. and S. /fllvlldu/us. II OCCUIli Il ,10 pale yellow crystalline malcnal that is very IIOluble I-lild 11 i swble in alkaline. but un,table in acidic. solu ~, compound ~Iowly dimcrbes to 2,S bi!.(ami noxy .., .11- \6-t!ilttOPlperllZllIe in solution or standing. 1ltc IINCtllfl: of cycloserine was reported si multaneously ~ KKhI ftll,- and !'Iidy ct al." 1 be 0-( + H-allllno30 ~~ ltllQllC. II has been synlhc~il-ed by Slammer ct al. 12 .. by Smillt ct aJ.>I.l Cycloserine is stereochcmically related " _ Uowc~e.-. the l-form has sinllllll' amibiolic taC )(In)

I~

n.:

o
to exert its anlib.3cterial action 1. of cros~- l ill k ing peptide III the ccll wall~ 8-1 R:moo" ha.~ recently ,uian anlinlCl~bol ne for alanmc. ",hich acts as wb:.tr.ue for Lhc pyridoxal phosphatc-rc<]umng IImtI1r r"aIIXlIl:ISC. 1n-e\"l'f'Sible inacti\'ation of the deprheg the ccll of the t)-a lanine required t of the l-ross-Iin king peptide. C)ckll!oCnne uh ibits antibiotic act;,;,y in vitro ' . ,..Jt: ~m of both Grnm-t1Caatil'c alld Gram IlfPlUSIllS. its n:latil'cly wcak potency and frequent use to the tn:atRlcnt of luben::u losis. patlcnts II ho fait to re~pond to other \\ho are kIlown to be infected wllh

mmeted in the United StatC5) chemically and phllnll!ll.:OIogically. IS a second-line agent used in combination with OIher antilubercullll' drugs. In panlcular. " may be used III place of 5treptomyc1n ""hen either the pahC'1l1 IS scnsiU\'c to. or the stmin of M. mbtrer,l"s;s is resistant to. streptomycin. Si m ilar 10 viomycin. cuprcomyc in i~ a poIcmia lly to~ie drug . Damage to the eighth CT'llIlial nerve and renal damllge. a~ lI'ith ~Iomycin. ~ the moOre scrious toxic effect;; a.s~i1Iled with capteomycin tllempy. 1llcte arc. as yet. insuffictent c1inic.1 data for II rcliable comparison of the relalJ\'c toxic potC'lllials of capreolllycin and l'lreptolllycin . Cro"-re:s isbIX"e IlnlOllg ~trnins of tubcrclc b.3cilli is mre belween ca preomycln and stt"Cptonlycin. Four capreomycins. designated IA. 1 IlA. and 118. ha\'C 8. been isolated (rom cu ltures of S. t/lprtolus. TIle clinical agent contains prim3nly IA and lB. The close chemical relation~hip betwc<:n cllpn:omycins [A and I n ~nd viomyCin was cstablished. v and the totlll s)nthe.\is and proof of structure of the capreomycins were later accOl11piished."n.c ,truetun:s of caprcoot)cins II A and 11 8 cOmspood to those of IA and 18 but l!lI.:k the ,B-Iysy] residue. sulfatc ~It~ ~ freely wlnhle in water.

n.c

ANTIPROTOZOAl AGENTS
In !lIe United Statcs and other counlries of the tempemte l,one. pmto"1.oal discasc~ arc of minor IInpon:lllCe. whcl\'ru; OOclcnal and ~irnl dl'iClIsc\ lite widespread and are the cause of considcnble concc:m. On the OIheT hand. prot07.oa1 diSelL'\I;l$lIrc highly prevalent in tropical 1lllro Wood oountntS. ",Ilcll: they Infect both human and Wil ma] populat ions, CIIU)ing 'lIffcring. dcmh. ~nd enornlO!1~ ~l'Oll(Ullk hardsh ip. 1..-0. 10"1.001 dio;ell5CS that are found in the United State! an:: malaria. IUllCbi-asis, giardiasi~. triehomOl1.1asis. to)(opIaslllOl>is, and. a5 a dirtCt consequence or the A II)S epicJc,mic. PIII'IIlftQ+ ),slis curim; pneumonia (PCP). Although amebias i~ IS generally thou@ht of as a lmllical dise8-o;e. it actually has B world wide di~tribution . In SOllie area.~ with tempe-mte climates in which .;anitallon i~ poor. the pre\'alencc of amc:biasit has bcc:n eS.llmatallo be: as high as 2O'k of the population. 1be ellusative orgaR1~m. &1(1

";~;~: is usually admini-.terN

Ie

commonly isoru:u:id.

Capastat \ulfme. ,,:-;:~::.~i~ a Slroog.ly bask cyclic peptide i:.ollltcd ~ , i n 1960 by l iCIT e\ al.iI/> It was rck:ased lied States in 197 1 udus;"c ly L~ II tuberculOStatic C+,,"llytin, -.-, hich fl'sembles ~iomycin (no longer

C'prH7lycin Sulfate, USP.

OH

NH H N
0

HN

NHyNIof:
0

NH

NAN H
H

,JIlW/)I/ MSIa/>'lica. c:m invade the wall of che colon Of ocher partS of the body (e., .. liver. lungs. orskin). An ideal cilClI1o-

therapeuti c agem would be effective agatnst both tiM: intes tlnal and utr.untesllnal forTH!> of chc p:iIIl5lLe. Amebicides that arc effeCII \(: against both Incestlnal and UU7untesunai fornlS of tiM: diJiCIlSe are hmned 1 ~ $OmC' 0 what IOxic alkaloids emc:tme and de:hydrocmetme. the n.tro-tmldu.ole de:n vauve metromdazole. and the alllimnlarial agent chloroquine (Chapler 9). A second group of ame bicides that arc effective o nl y against inll:,;ti nml fonns of the disease includes the ftminoglycosidc untibi04ic paromomy cin, the 8-hydro~yqumolinedcrivauve iodoqulnol. the arKllic".d coo.poond carban;ooe. and diloXllnide. Otha protozoal species Chat coloni7.c the mcesltnal tract and cause emenus and diarrhea an: IJalmllidlUm coli and the flagcllalClo Giardia lumb/Ul and C""'(Hosporidium SlIP. Balanudiasis responds best 10 letracycline. Melron~oIe and IOdoquinol may also be effective. Gianliasts may be treated effectively wilh fummhdone. ITlCtl'Onldalole. Of the :ullimalarial drug qui naerino.: (Chapter 9). Cryptosporidiosis is normally sdf-timiting in inllnunocornpctenC p:uients and is not nol"mally tn:atoo , The IlifICS. can be a serious problem in AIDS patic'nts because no effecti ve therapy IS cum:mly

I'llilable.
TricoomollIasis. a \'enen:aJ disease Clu<oal by the: nagellated protOl.oon TridlOm(HIIJS I'Qgillll/U. 1$ common in the: Unlced States and throughout the world. Although il is not ~e1lCrally considered "C'rioo s. this affiictiOll can cause !oCrious physical discomfort_ Oml I1ICtronidalOlc provid1!~ cffl"Clivc tIT3tmcnt against all forms of the di"C'a~. It is also used to eradicate the orgunbrn from a.~ympiomatic male camers. PIlt'untOC}"5lis CIIntlii i ~ an opponuni~tic palhogt'n thaI may coloni/.c tiM: lungs of humans and OIher animals and. under the right condlhOnS. Clll cause pneumonia. 1l1e organIsm has 100, beert classiflCd as a proIOloon, but recent RNA Uldencc ~uggesl~ that it may be more ciO"ot ly ...:hllcd CO fungi . AI one lime. OCCUSlOnal eases of P. cllr",ii pncumoma (PCP) were ~lIo"n 10 occur in premature. undernourished infants lind in pati ent~ receivin g immunosupp:~~ant therapy. The situation ehanged with the onset of lhe A IDS epidemic. It is esumated that at Ie:l!ol 60% and fXKsibly as high as 85-:' of patients infe<:1ed ... ith HIV develop pcp during tllt-il" hfcl1nJC$. The combinallon of the anti folate trimethoprim and the sulfonamide sulfamctoo~aJ.oIe ronstilutCli the treatmenl of cooke fOf PCI'. Otlw:r effecll ve drugs include pcntamldme. tlto~llquone. and II new alll1folate. trinICtrc~3te. To..o.'i)/J/(lSffln K(>/If/j/ is IIll obligate imracellular protozoan Ihat is beSt kflOwn for cau"ng blindness in l1I.()Ilales. To~o plasmosis. the disseminated fOl'TTl of the dl"C'ar.e in IO.ohich the Iympltatic syst('m. ~keletal muscles. heart. bn"'n. eye. and placenta may be affected. has becOlTlC illC'fCasingly P'l'\alent in a.....wciation .... lth UlV mfection. A combmallon ofche ami folate pynJ11("\hamine (Ch3p1cI'9) and the sulfa drug wlfadiaZ111C OOflStllUlts the most eff",.."'I;\(' thempy for toxoplasmos is. Varioos fonns of Lrypallosomiasis. chronic Iropical dis eascs caused by p.:Itho~enic mctnbtTS oflhe family Trypanosomidac:. oct"Ur both in human5 and in livestock. The pO ncip.al dise:u;.c III human~. 5k:c:-ping sickness. can be broadly clllSliifled into t.... o mam geQgl1lphlc and ellolOGIeal &'lJUp!i: Afncan sleeping siclllCs-, cau<;Cd by Tryponowmu gum-

hi(,IIill (West African). T. rhfJi/C'Ji~"J" (Ellst African), or 1. COlllfolc".i/~: and South AITlCriclin slecpmg sickness (Chap>' disea.o;e) eaused by T. c ru::.i. Of the VDriOUS fOl'1l1s of trypanosom iusis. Chaps' disease is lhl.' most se:riOOli and gC'neralI! the Ifl()f;t resislant co chemothelllPY. LC'1$hl11llni~1$ Ii I chrome tropical dlSCase causcd by ~IlnOU' fla,gellate pi'( :wa of the: genus lJjshmania. 1l1e II1QI"e common ~iscml fOl'TTl caused by 1.. dOllO\'lIll;, called kala-lIl..ar, i) Slmi bt 10 Chagas ' disease. Although these dl<;eastS are widespn!:td ill lropicalllIeas of Africa and South and Central Americl.the) are of minor imponancc in the UnitC'd Slates. Europe. anti Asia. ChcmOlher.apy of uypallOM)mia~l~ and leIshmani asis If' mains lIOlTlC .... ilal primitive and is often less than effet:th~ In fact, it is doubtful that these' dl<.eases can be contm/1oil by che:mothe:r.lpCUlic 1TlCa.~Ures alone, wnOOut ~UCCCSSftIII control of the: tntemlCtlialC' oo"lS and ~ectOB that tnlru#lll them . ~l('avy metal compoonds, such \1.\ the aJ"$C'nicals'" antimoniDI~. are '\Oml:cimes effecci~c bUI frequently tO~~ Tllc old stllmlby SUlUmin uppeal"1j to be of sonIC val~ it long- llnd shurt-Ienn prophylu~is. The nitrofuran dC'rivault nifurtimo~ may be D major asset In the control of ~ dr>cases. but us potential to~iclty remains to be fully defeI mined.
U5P. 2-~1eLhyl-Snllroln",htolc:-l ethanol (Flagy1. Protostat. Metro IV) is the most useful 01 II group of nntiprocOl.oal nitroimidouole dC'nvati vcs thaL Nt>t been sYllthesi 7.cd in various labllnltuncs throughoul til: world. Mctronidazole was firsc nlarketed for the topical tll:'JI' ment of TriclllHlWlIll$ ,'ugm(J/is vagimlls. 11 has since bta mown to be e.ffectin, orally Ipmst both lhe lICute and C1ll'm stales ofchediscasc:. 1l1e drug also pos5CSS('s useful amebalIal actJvny and is. III facl. effCClI\e agalllSt boIh lIlteSlll1ll and hepatIC IInICbiaJ;is. 11 has alo;o been found of usc lIIl11r creaCllloClI1 of MlCh OIN-r proIo:wa1 disca5C:I as giardiasi, ani
Metronidazole,
balanl1dl asl~.

, , , ,

Mort recently. melronida~oIe Ilas been foond to po$_ efficacy again'\! obligate anaerobic bacceria. but il is incff(\" tive against facultmive anaerobes or obligate acrobo. It a paniculurly active against Gram-negnt,,'e anaerobes. SId as 80cftnmlfs and Flisr/lJocfC'nlllll spp. II is also effeai>li a.gIlJllSl Gram-poslli\'e al1iltrOblc bacilli (e.g . CloJfridiJa spp.) and coet:i (e.g .. Pt'P//JCOCCus and Ptlllidos/rtploromtJ spp.). Bause or ilS b:oclC'ricitbl action. metmnil.lll.ok_ become an important agent forthe lreacmcnt ofscrious 1111 tions (c.g .. SCplleemia. pneumoma. penlon;l1s. pelvic !nfC!; tions. abscc~sc~. ,nc.nin gitis) caused by mnacrobic battma. 1l1e C01111110n charoclenqic of IIHcroorgllnisms (b3CIenl and prOl07.()ll) sells;ti ve 10 nIClroniduole i~ that Che:y on: .. aerobic. It h:ls been speculDtl'tl thaL I reactivc intemlCdia formed in lhe microbial reduChon of the 5-nitro grwp II metronidazole oovalt:m ly bl11ds to the DNA of the microu gamsm. II1ggenng the lethal effect .... POIenllal reacti"e __

1IIld131e~

IlIClude the nitroxidc. nitJt;O. hydroxylamine, and __ The abtln)' of mctrollIdalole to act as a rlKhosensilll,Igc:I1l IS abo relau:tI !O II ~ reduction potential. I>ktronidal ol e is it pale yellow cryM:tllir.e substance that 'lpan n&ly soluble In .... ater II is stable In air but is light
ll'II\ili.c. Despite its low .... aler solubility . IllCtronidazole is ;absorbed followmg oral admlmSlJllllon. It has it large:

well known. Aqueous !IOludOfl~ of ....-id saIlS of oxioe. partw;;ularly the sulfale (Olloosol , Qumosol). In COllCemr.lllons of 1:3.000 10 1: 1.000. luive bc:cn used as topicalllfltiseptics. 11Ie <,UINituhon of an iod""IC' atom a. the 7 POSition of 8 hydro.l'.yquinohnes YIelds compounds Wllh bro.KI-specmnn amcbicidal properties.

....... volume of di~lribuliO<1 nl\d achi eve-; CffCCllllC con ;.111 ClCll!ilIOIIS In all body fluids and ti ssues . Approxim;ttdy of an oral dose is metabohl.cd 10 oJl.itii:ted or CQIljugalcd fmns. The 2-lIydrox y metabolite is acl;\'C: (>tiler metabolitcs ~ I....-t,,c. Mt1ronidazole is it .... cal: base thm posses..'lCS n pK. of2.5. Ill! it ill a(irniniSlerec:i pal"CnleraHy only as the free base
.,.. inlra~'el'lO\ls mfusion. metronidawle for in.Jlioo i.~ tllpplicd In 11010 forms : a n:adY-lo-inject 1000mL solution ....~mn' S m8 of ba.'ie pn mL: :lIId a hydroc:hlolidc ~h

OH

Iyophili/.ed powder. MI'tronida7ole . . .hloridc for injcctioo mu'\{ fil'lll he I't'COIlstiluled with .,lIer 10 yield 5 mL of a soIUIiOIl having a OOf1Cemrn.()[, 100 mglrnL and a pi'l runging from 0.5 !O 2.0. The R'I ' " SQlution mUSt then be diluted with either 100 mL 4111fl1111lahnc or 5'lo dc:~trosc and ncutrn liled wilh 5 mEq
4Vldlum bICarbonate to provide a final SQlut ion of mclroni With an approximale oonnll1luon of 5 mglmL pH 0[6to 7. Solulions of mctronidat()le hydrochlori-de _ilJbIe for intr.nellOUs adminislrnhon because: of ".'~~ ...:.dily. RecoMtiluled rnc:lromdll7;Ole hydro-'OIulion.~ are ,table for 96 hours at 3O"C, while

SIX) nlg

of

~Icrile

5.7- I>jiooo-8-quiliolmol. 5.7-<liiodo8 -hydroxyqumoline. or diiOOohydrox)qum (Yodo~in . Diodoqum. Diqulnol) IS a ycllol",.h to Ian mi crocl).l alline . lighl-senslt ive ~ubSlanee Ihal is in soluble in .... aler. It i\ reco mmended ror acute and chronic intcSlmal amebiasis bul is nOl efrective in e~lrui nteMinnl disease. B~ '(:ause a reluti vel y high incidence of topic neuropathy hWi occurrrd ... ilh its usc. 10000uinoi should not be u>Cd ruullllcly for trnlcler' s
di~a.

lodoquinol, USP.

",;:':"':;~'''::. of metronidazole: base are slable for ~. . BOIh solutions should be protecll.-d from
Furnmidc. or tulamidc , i~ the 2-furoI il II , I various 01.("1:lell'-I ty in vitro. are also :lCuve. and

Emetin. and Dehydroem. tine. 111C alkaloid_ enlCtine. and dc-hydruelnetine lire obtained by scp;arJtion from exuacls of ipecac. "They occur as le:VOf"OIaHlI"y , hghl sen''',,'c
white po .... l.krs Ihat IU'I: inwluble in water. The alkalo ids ~. readily form ..... atCT-,-olubJe sall Solution s o fthc h)druehloride salts inlendcd for inlrnlllu.",ulpr injectlOll should be adJUSted 10 pll 3.5 WId stored in lighl-roi \ Ulnl container;.

I,. I

of th-e

are more potent than polar OfICS . i ';;;;;;;;;~ -,;;;; in the treatment of a-symptomalic carhi.u"/yllro . Its tlTecthtoe~s against OCUle inlts

H1C"""-O

9"""'Y/"
N

jsa

orally only as 500-mg tablel~ and lIIay in the United States from the COC In Allanta,
E"",""

H"

,
H"

...
""

...

.....CH1

qumophcnol. or O.l'.yqulfrom \\- hich the Ilflllprotozool . The antibacterial and antl and its denvalhe~, which are be abil ity to chelate nlCtal ions. an:
O ;U IlC.

and dehydrocmc llI"Ie ex en a direct amtbl cldnl action OIl various rml11s o f E. hiJlQI) l icu. They an: protopl:llirnlC poisons that ,"h'btt proIc in s)" nthesis ,n protol.ool and mal11malian cell~ by prevcnting protein elongauon. Because th-ei r crfect in Intestinal amcbia-sis is solely s)mptomEnlClIlIC

alic IU1d lhe cure nile is only 10 1 IS.... lhey should be used 0 only III oombir\3lion wi lh other Iscnls. 'TlIe high conccmrauons of the allalonls IIChievrd in the h"cr and OIher lissues .flcr mlramUSC'lllar injcctioo provide the basis for their high cffuvene.~ against hepalic alxccsSClIlIlld other cllOtraintcstinnl forms of the disease:. Toxic cffects limit the usefulness of cmc1illC. It cau<oes a high frequency of gastroin,cstin al di'Mess (e.~peciall y nausea and diarThca). card iovll5Cu lar crfcc,s (hypotc~ion and arrhylhmias ). and ncuromu!oClll ar cffects (pain and wealnc.~s). A lower incidence of cartiiotollOiclI y has been as!>OCia'oo with lhe usc of dchydrocmetinc (Mebadm). which i~ ayailable from ,he CDC and is also amcbicidal. Emeline and dch)'dro<'meune h:wc .1'lO been uSN! 10 treal baJanlid,al dysenlery and null.' inr~lalioll~. ~uch as fa,;cioha~15 and Ilarolgorumiasis.

I I

H OH

Pen famldiMlse th/onat e. USP. 4.4' -( PcmlllllCthy lcncdio~y)dibcnl.arnidinc diiseihionille (NebuPcI1\, Pcnlanl 3(0) is u walersolublc cryslaUine salt th:lt is stable to light and air. Thc prineip.'1 usc of pemamidinc is for lhe treat mcnt of pllCurnonia caU';ed by lhe opportuni~ tic pathogenic proto1-Oan 1'. w r/IJii. a frequent secondary inYildcr asS(.ci:'led with A IDS. The drug may be administered by slow in lm\'coous i n fu~1O!1 or by deep imr.tmuscular mJCCtion for PC P. An IK'I1l'IOI form of pentamidine is used by inllalal;on for the pre\'enuon of PCP in lIigllrisl patlcnts infected witll HI V ",110 l1a,c I previous lIistory of pcp mfcction or a low penpheral CD4' Iymphocytc count. 0 0111 lilt inllalanl (aermol) and parenteral ~age forms of pentamidine I.\('llIiooalc Ilf'C sterile Iyopl'llhl'.cd po-.o.dcl'll tMI muS! be made up as steri lc aqueous solutions prior 10 usc. Sle rl le water for injection mU<1 be used to ~onslitute lhe !lC11l'I01. 10 avoid precipitulion of the pe nt:llnidinc omlt. Advc~ reaction s 10 the drug are t'1)mmon . l1lI:'oC include cough and bm"chosp:L~m (inhalation ) and hype rtcnsion and hypoglycemi~ (injection). l'cntllm,dine has been used for the prophyL axis Ill>(! tl'l:a" mc:nt of African IrypanoliOn1ia~is . It also has some value fOf treatmg \'i5oCeml leishmamasis. Pcnlamldme rapidly disappea .... from lilt plasma IIftCl" intravcnous injection and i. dislribulw 10 the tissocs. ",here il is Morcd for. long penod. Th ,~ property probably conlributes to the use fulness of the drug Il!i II prophylactic agent.
A t o",a quone, USP. 3-14-{4-Chtorophenyl)cyc lonclyl ' 2hydroxy 1,4-napht hoq uinone ( Mepron) is a highly lipophilic. wuter-insoluble ~nalogue of ubiquinone 6. an es.w n tial COl1l1l0nent of the mi lor: hondriu l c lectron tr~ nsport chain in microorga nisms. 111e structuml s im il arity belween all)\'aqllonc and ubiqui none SU!!gtSts thai the forma may oct as llIl amimctllbolitc for the laller and thereby inlerfere wuh lhe function of declroo tr.IJl~port cnlymc:!l.

r
Ato\'aquonc was ongina lly developed as an pnlimalaNI drug. but P/rnmodium f(/Icipa~m was found to dc"clop' rapid tolcrJnce 1 its action . More recently. theCffectllC_ 0 of atovllqllOnc again~1 P. CQrim; wa.~ di~\crcd. It is a tv rently recommended allemalJ~c to trimcthopnm-sulfamctbolar.oIc (T MP-SMX ) for the treatmcm and prophyl:uud pcp in patienlS in tolenllli 10 this combination. Ato",,1JOIIe was also shown to be cffecli,c in eradicati ng TO,WfIiru. gOIl(/ii in preclinical unimal studies. 11M: oral absol'ptlOll of al o~aquonc is slow and incomplrlt. in part becau<oC of the low walcr solubi lity of the drug . Aqlll" ous 5u.pens ions pro~idc significantly bener absorp1iOfl thai do lub lcts. Food. c.~pedally if it hilS a high fUI cOntent.la creaSc!s utovllquonc absorption. Significant cmerohepatk: recycling of alm 'lIqllOl1c OCCUI1i. and ,nosl (nearly 95%) 01 tilt drug is e~cretcd uoclmnged in the feces. In v;~o. atol'llqllOlr is largely confined to the plasma. .... hert: II 15 CJ.tcn~lcI) proIcin bound (>99.9'1. 'TlIe half-life of lhe drug rJIlIItI from 62 to 80 hoot'S. The primary ~ide effect is ga.~trolnltSb nal intolerance.

I ,

Eflorn ;thine, USP. OL-2'- Dlfluommcthylormlhinr... DFMO (Ornidyl). IlI1 amino add dcriyatil'c, is pn CIIlY,*, activaled inhibi ,OI' of orm thinc decarbo~yla<c, a pyrioo.lIl phosphate - dcpendcn l enzyme responsible for caln lfling til: ratc-lim itin!! ~ICp in the biosynthesis of Ihe diamine ptIlJncinc and the polyamine.. spermine and spcm lidinr. Pd). amine~ arc e~stnt ial for the n:gulatioo of DNA synt11csi, IIIJ ce ll prolifcr;lI ion III llI1imal lis.'iUcs and microorglllli sms.

,.
,
h.

'" N

'H

,.., '"
""
'"

B~

ClIIoptrr 8 A"';;"fn:ri'~ Age"'~

263

of nifunirnox. Themp), for Amencan Iry~noSOr1ll151S ",th oral belWlidazoic rcqUI/n scI'eral week!! and is frequentl), accompanied by adleN" ~rrects ~uch 15 penp/Klal neuropa thy. bone marrow di:prC'sSlon. and allergic-type reactions.

AITIC'r1ca. The ~ffecti\'~~ of benl.nld:l7.ok: is simi lar 1 lhat 0

~.". ') lI"C:d for the treatment of We,! Arrican r.lt~ness. caused by Trypmtllso/lIlt /}ruct'; XII"'"' ''~plfirnUy

'"

indiculcd for the meningococepha !If !he dlscase. EfIomilhinc is a myeJosuppn:ssh-c high incidences of IlllCmia. leukopenia, and Complete blood ~JI coonl~ mUSl be

of ornithine dttarboxylasc acrompanl~ by decarbo. ylalion and ret 1011 from the inhibitor,1IO ~lIggcq'ng enInhibitor. Only the (- ) ,.s0lO I.-omilhinc. is oclive. as the hydrochloride !>lilt. II may
[\I

~:~~;.~r therapy.

Melarsoprol.

2-p . (4.6 -Oi anll00-I - triuin- 2)' I'IIm; no)

I or orolly. Approd
excrcted in 11M! urinc. is facili laled by in-

, ,
,
,

llgmflCllnl and potentially usefu l aoti

c.-mlually led 1 disco.'cry of partK'Ular 0

"'"

~.;,~,. activity.

(Mel B. ANOball is pn:pan:d by l'C'doclion of a com:sponding pentavalent arsani13te to the trivalent ~noxide followed by ",:JC1;on of the biter ..... ith 2.J-dil1'lcrcaplu.l-prop'lrIol (Bnlish anti-Le ..... islle. BAL). It hilS become the drug of choice for the treat ment of the Imer stages of both forms of African trypanosomia.~is. Mclarwprol ha.' the advantage (If exedlent pene trntion into the CNS and, therefore. is effective against meningoencephalitic fonn, of T. !:{/mbi..nstl mid T. rbWtsinu ... Trivalent IIniCnical~ tC11d to be more toxic to the host (as we ll as the par:J$i tes) than the Com:spondil18 pentavalcm compounds. TIle: boo(ilng of arsenic .... ith sulfur atoms tends to l'C'ducc host toxicity. incn:asc chemical stabllIt)' (to o~idatioo), and improl'e di stribuuoo ofthr compound to the ar5CnoXide. Mclllt1IOfII'Ol shares the toxic properties of other arsenicals. howelcr. 'iO illl usc muS! be monitored for ~igns of ar.;.enic toxic;'), .

phenyl-4-hydm:tymc:lhyl - I.J.2-dllhia~l llle

OH

'" ,b
Sodium Stibogfuconare. Sodium al1timony gluconale (P!:ntostam) is a pc:ntu\'ulent untmlOlli31 compound intendl.-d prim.:lri l)' for the treatmc:nt of various foons ofk:ishrnatlia~iJ. It IS aVllilubk: from the COC as the dl.Slxhum salt. "hlCh I~ chemicall)' slIIblc and free ly .IOluble in water. The 10% aqueOII.!I solution uscd for ellht-r intr,lInuscu lar or intra\'enoo s injeclioo has a pH of - :U:. Li~e all 311timonial drugs. thiS drug has a low therapeutic ind!:~. and patients undcrgoil1g th<:rdpy with it shoold be rnonitort.'d curefull)' for ~igns of heavy metal poi"Oning. Other organic an1i nlOni~ 1 com pounds are u<Cd prinmrily for thc trea trncn! of schistosomiasis and other flukes.
cOONa

compounds

IS

mrunimox beT. end. the

American trypanosomiasis. In
only clinically pro"cn romt~ of the di:sea..o;e.

. .~. is Idminjsl~ omll}'_ Oral biouvuilubilil y is OOIblderuble firo;,-pass metabolism occurs. The

~:~r:'::;:':~:d';~"~ :4~;hoo;~~"~,,~The drug is poorly

.. I

vomiting. abdom~ ~.IIIOII:J.il reponed. S),mptoms of cenlml lind nermus 5~Sl~m toxicit), also fretJu~ntl)' occur

NBem),I-2nitromllduok:- I-ace.",';"

:e

;';,~:~:~; 11 is not i I inSooth

dcriVall\'C

OH

Lo'H

The umile,shmanial K tiOll or sooilun stiboglUC()nate reqUIre<; liS m1OC1ion 10 the uwalent fann. which is btlieved to inhlbll phosphofTllC1ol.:m3<;C In the parasite.

SAL may be: applied IOpleally os an ointment or injtcd intnuJ,uscu l:uiy as a S or 10% soIutiQn In pellnut oil. SUr'J min sodium is II highmolttular-weight bisun:a derivat"'e containing six summit IIlid groups as their liOdiuIII salIS. It wu de\clopc:d In Geffilllll' shoI1ly aller World War I a5 It by-product of research dfom directed to ..... ard the developmcm of potential ~nuparaSl!'" agents flUm dy~t uffs. The drug has been used for II1OIl': than hal f a cenlUf)' r.;w the treatment of carly t"as.et 0( trypanosomiasis. Not unci seve rn! decade> luter. ho ..... evcr. was surn min di-.covemllll be a Iong term prophy lactic ugent ..... hose effcctivenus after o single IntravellOllS injection is maintamc:d for up 10 J momhs. The: drug I~ "llhtly lIound 10 plasma protClns. c-. ing its excretion in the urine to be: alnKt negligible. li ,~ue penetration of the drug ~ IK)I. occur. a~nIf) because: of ItS high molecular weight an..I highly ionic chant; ter. Thus. IlJ1 injected dose: remains in the: ptuma for I \CI') long period. Newer, more cffective drugs arc now avallOOk for sllontcrm lreatment and prophyl;u:is of African ~lttPl" sicl.:nc:ss. Suramin IS also used for prophyl:uis 0{ onchoxtM asis. It is Hyai lablc from the CDC.

Suramin Sodium.

DimefUprol, USP. 2.] DIIT"lercapto-lpropanol. DAL. (If" di th,ogly<:erol is ~ fOtlI -~mclling. coIorl=> liquid. It is soIublc In wllter ( I :20) and alcohol . 11 was dc\'clopcd by the Briti'h during World War li ltS ~n anudotc for "Lewisite:' hence the nanle' Dn ush anti-Lewisitc. or HAL Dimercaprol is effective' topically and ~ystcnwically as an antldotc for poisoning caus.:d by aNnie. antmlOllY, OIe'Tt:Ury. gold. and IcOO. It can . therefore. also be used to trcat ar.I<!nic and ~nti moo) toxicity associated .... ,th o\erdosc or accidental ingestion of org3noarscnoc31s or ocganoanumOl1lal.s.

SH

'The antidotal Ilfopertics of BAL are as"lx:ilIted with the ",openy of heav) meUlI~ to react with sulfhydry l (S U) groups in protein.'> (e.g . the enqme P)'ruva\C oxidase) and in terfel\' ..... i lh thei r normal function. 1.2-Dithiol oompou llds such U SAL compete effectively with su, h proteins for thc nlCtlll b) re\'el"Slbly fomung metal ring t"ompound~ o f the: foUo .... mg type::
H

ANTHElMINTICS
Anthelmintks are drugs that hll\'c the capabi lit) of riddJIr the body o f pansltic worms or helmmths. The: prc:\"Iitm of human helminthIC III festatlO115 is widespread throughoc the globe and rcpn:s.:nts II major world heuhh problem. 1*"' ticularly in Thi rd World coontries. Helminths parasitic II humans alld other IInimals :uedcrhed from t.....o ph)Ia.~ helminthes and Ne mathelminthes. ~St odc:s (tape .. 011\11

- ', R /,,- ,

'l'bese are relat"'e!y nontoxic. metllbollcally conjugated (as ghlCuronide~), alld rapidly e:c.(.'Teu:d .

\I . o 5---0 No

"""
I

\7"
\,
No

0 ::::::::

l 0

? A

NoO-

-::P'"

No

""No'

0 - ---0'
No'

Chapl .... 11 Anli-infti .... A1.......

265

) belong to the former. and IICrnalode.~ \0 the Janer. The helminth infeson ihc: Nonh American continent I'(JI)ndwOfTllS {i.e.. hookworm. pinwOflll, and Human Ulpcworm alld nuke infcstalions arc ia the United SIIIlC\. c1a;'>CJ; of themical ~ are used 11.( amhclminllc~ phenols and dcri\"ali ...e~. plp;;:r.lline and related
rompound$ (Chaptef :::~:::;:::::~ IIIld natural products. 9). various

pi pcrazine. the two anthelmul1ics should !lOt be u<;cd togetlier. O\'er half of the 0J:l1 dose is excreted in the r~ unchanged. Adverse effet1s .~sociated with 1I~ usc: are primarily gaMroinlcstinol.

nl
.i

Y~:;~:'::';', or diethylenediacolorles.~.

volatile

IIIaI are (lttly soluble in WlIter .

was

Plpcrumc I~ ~1i11 as an anlhdnllnlic for ...... of ('UIworm , IO~-"risl ''1'!'""icli' C~. n,Jv.orm (Ascuris /"",bricoiduj infcslm ion s. ~ in I .aric\)' of saLt forms, in,;luding the citrate USP~ in syrup and tablet forms. ':::.bloxh the response of lhe n~wi ~ muscle \0 III . ~.lIS.ing. nxcid pIlmly(is In the worm. which the 1n\C'.stJnal woll and expelled In the

o
O OH

o
C;tra~,

2
N,N-Diethyl-4

USP.

ThI.Jbendazo/e. USP. 2-(4-Thul7.ol)I)benl.inudazole (Minlezol) occurs ~s a white erystallme subMuncc thul i. on ly slightly !iOIuble III w:ller bot is w lublc in stroog nuneral acids. Thiabeooa7.o1e is. basic eon!poooo .. nh a PI<.. of 4.7 that forms eomplc){e_ with melal ions. Thiubern1awle inhibits the llelrninth-spedfic cnl-yme fumlII1Ite reductase. It is not known ",hetller metal lOllS are invol"ed or If the inhlbinon of!he cnl.)' me is rclMcd to thiahendazoh:.'s anthelmintic effect. Bcnl.imida7.ole anthelmintic drugs such as thiabendal.oIe and rtlebendazole also mt'St ncmalode cell divi<lon In me taphase by interferi ng with microtubule IIsscmbly ,"~ They c~hibi t a high affinity for IU bulin , lhe pm:-ursor protem for TJlJcn)fUbulc synthesis.

citrnic or l-di cthylcarbll citrate (Heu'1I<:an) is a compound thai has sciectlve

""1>1: IplMl ascaribis. Rclath ely few adV1.'1'$e "~'.'"w,,,,o ""Ith diethylcarb.:un.17JJ1e.

Thiubendal.Ole hilS broad-spectrum IIIlthclmintic activity . It is used 10 t!'Cal entcrobiasl~. stroogyloidiam (threadwonn in fection). ascariasiS. uncinariasis (hooIo:worm infCCllon ), and trichurill!.is (\\-hipworrn in fection). It ha.~ nlso been usc:d to rehe"c symptoms IISsocialed .. ith cutaneous IlIrVa mlgl1lnS (C/'elf'ping ct\lpt>on) and the tn\'asl\'c phase: of lnchinOSI" , In addition 10 its usc in human JIlI:dicine. thiubendazole is widely used in \'eu:nnary practkc 10 control mtestinal helmtnths in livestock,

Teuahydro-I parnoatc (Anti blocking agent Ihal In susceptible hclnunths_ II IS used I II. caused by pinwonns ~nd l.tICanasi~), Becausc its action opposes that of

M*lHmd.Jzole. USP. M ('th~ 1 5 bcnloyl2 bcllltnnduolC('arbarnale (Vernl()~) i~ II broad.~pc'::l rum anthelmintic that is effl'l:tJ\'~ agam\1 a ~1Ine'ly of JlCnt;uodc: infestations, including ... hlp"ool1. pin\\-OITn. roundworm. and hookworn!, Mcbcndazole ilTC\'cJ~ibly brock_~ glucOloC uplake in suscepti ble helminths. thereby deplcung gl)'cogcn 51on.:d in

the parasile. lt apparmlly docs no! affect glucose metabolism III the hosL It also in/liDiu ~II divIsion in ncmalodcs. '1

from relell5e of I,,'c ova from worm segments danlaltd II! lhe drug.

"
/' -""'J'--'N

}-~

0\-/",

, ,

Mebcndv.ole is poorly abSOf'btd by the ond route. Adverse: reactions are UlI(ommon and usually l"OOSISI of abdommal dlscomfon. It is ler:lIogenic lD laboralory animals alld therefore. shoukl not be given during pregl1:lIlcy.
MelhyIS-{propyhhio}-2.ben1JmidaJ;okcaromn.ato! (Eskuole, URIc!) is a brood-spectrum ant2.2'Thiobi.s(4.6-dicMorophc:nol). or bI$Il, hydroxy-],5-dichlorophcnyl)~u tfjde (Lorothidol . Bithinl,l chlorinated blsphcnol. was formerly used in :;oaps and COlmelic~ fOf its antimicrobial properties but was retOOled the market for topical use beo:ause of repofts of conflICt pm. toocmlmi;is. Bi thionol has u'>C fu l :mlhclminlic (lft!pe/1it! "nd has been u<;ed as a fasciolicidC' and t3Cnincide. It i~ wlI considered the agell' of ",hoice for lhe treatmcm of infe!lltions caused by the li\C'r n ul.c Fw;rifl/u he,)o/llic/l and 1he Iq nuke "arogfHlmllu I<'t'J"nnani, Nidosamide i~ be1i~\'ed. be superiOf 10 it for thoe lreatment of Uipcwonn infl:Sl~

"

8ithiOftoi.

Alftrtdil:tok, USP.

helmmtlc thaI is not currently marketed in North America. 11 is Iwailable from the manufacturer on " compassionate
us<: b;l~is. Albendazole is wide ly used throughout the world for lhe In:allllcm of imestinal nematode infection. It is effective as u single-do>e treaunclll for a.l\Cari!l~is. New and Old WorlU hookworm infectioru. and trichuriasis. M uh iplc-dose therapy with aJbenda7.o1c C' eradicw lc pinwolTlI. thread.lI1 lO.orm. capli lanasis. clooon:hiasis.. and hydatid disease. The Cffec1I\'cncss of albendazok against \lIp!:wonns (ceslodes) is gellrnllily more Vllriablc and less imprt'Ssl~e.

rM

"

" "

"

"

p"'-"....... N

"

""

""

Albendazole occurs as a whi le erySluliine powder lhat is l' lrtua lly insoluble in wDler. llIc: orulnbsorpl ion of allx'ndarole is en!wnced by a fauy meal. '11M: drug uOOc'i~ r.lpid and utens;ye fill<l-pass ml:labolbm to the sulfo~ ;tk. which i~ the -=tlIe form in plasma. 'The elnmnation half-life oflhe Mllfoxlde ranges from 1010 I j hooK. Coo~lderable bi lilU)' ucretlon and eflteroho:'palk l'CCychnS albcndazolc su lfoxIde oa.-un.. Albcndazole is gClY:rall y well tolerated in smSIe!Joo;e thenpy for illlCMinal I'I(':lllaUldes, llIc: higb-do5c, pr0longed thenpy required for clonorchiasis or echinococcal d~<;('use Ih<-r.lpy can result in :td,'C1'SC: effect!. ~\lCh as bolY: marrow depreSSiOl1 , dc~alion of hcpmic enzylllCs. and alopecia.

or

OX.Jmniqulne, U5P. t.2.].4-Tctrahydro-2-[(iWl"""~ amino)mcthyl l-7 -nitl'Q-6quioolilM:ml:thanol (Vaoslll ~ anli'>ChistO!iQlJlal agenl thai is indicaloo for the tn:attMI~ S. nlDI/JfNl; (imesti nal '>Cblstosomiasis) infection. II sho .... n 10 mhlbu DNA. RNA. and protcm synthem schistosomes.) 'The 6hydroxyl11C1hyl group is cnhClI activity: metabolic actiVlltioo of pn:cun;or 6-nw:th) I elm liI'cs is cntlcal . 'The orol biooyai labili,y of oxarnruqulllr good: cffecthe pla~ nra Icl'ds an: achlCI'td III I 10 1.5 hoM The plasma !wlf-li fc IS I to 2.5 hours. 'The drug IS CJ(tCllSila metabolized to inacll ~e rn.::mbolitcs. of ..... hich the 1'1'1 one i~ lhe 6-carboxy deril'Dtil'e ,

has_

Niclosamlde, U5P, 5Chl oro-N(2-chloro-4 nitropl\(,n yl )2-hydroxybenr.alllidc or 2.5' -dlchloro-4' -nilf'mlllicylanilide (Ccstocidc. M unsonil. YOlllesDn) occurs as a yellowi,h .... hile . watcrinsoluble powder. II is D pOII:nl taen iacide Ihal cauloC$ rapK! disintegnltion of worm SCgJ11C':nts and the srolc~. PclY:tralion of the drug into various CI:S'OOes appears 1 be facIlitated by the dlgestiye juice~ of the 00\1. in t!wt 0 very hnle of the drug is ahsorbcd by the .... onns in l'llm, Niclos.amltk is wC'lItolenited followin, oral administration. and lillk: or no systemic obsorption of II OCCUr!, A Qllinc purge I 102 hours aflcr ingestion of lhe tocmac illc is I'CCQm mcnded 10 remoyc the damaged sook:x lUK! worm '<CgmcnlS, ThIs procedure is mandalOry in the Ire:Uml:nt of pork lapeworm infC'sla fion 10 prevcnt pos~ ible cysticen.'Q'<is resulting

'The f~ hase OCCUTll as a ycllow crystalline solid till sl ightly solublc in water bul soluble in dilute lKjutOO'i eral acids and <;(Jlubk: in mOSI organic solventS, Ie" .'11 in cupsules cOlltaining 250 mg of the drug. O~nmniqulIlI'

agcn! '! agains! In:lJ1.:MoclM; (flukes). I! has become the: a&1=nl for lilt UUIIllcnt of infections caused by ldIistoIlules). 1111: alS<.> provides effecdve I fluke). clooon:hiasis livcr fluke). opislhfluke). ~_

:?S~~:~;:';f;;"~':~~':':'i"'~'ItMfluke muscuta:'~r calcium. by i of parasile. :

0,

I
",-~;~I~i"'pm~;".~":'~"~tiO;"~':":':"'~:":! ~O% of the ~osc ~s
wille of mctuboli:es ';;"~'octurs as a .... hite crystalline solid '~bIt In IO"lllCr. It is available as 600-mg film1aNe!~. The drug is gClICTIllly well toler.lled.

I~

Ivermectin, U5P. I vem~tin (Cardomec. Eq\'alun, Ivom) is a miJlOture of 22_23-dihydro (\erivativCll 01' avermeclin s 8 , and B ' b prepamI by catalytic hydrogenation. Aver_ medinl IlTC members of a family of structurally complcliO IlI1tibiotics produced by fermentation "'itb a slIllin of Slrtpfom),cts Q'"tTm;fi/is. 111eir discovCl1' rcliuhed fll)lTl an intcnsh'e screening of cultures for anthelmintic ~gcnts from naturul sources.'" lnrmectin is acth'c in low dosage against II wide varicty of IlClJUltodCll and arthropod s that pamsilizc ani mals.'" 111e structures o f the ncrmectins ""cre established by a CQmbinalion of ~pcctroscopic\lOll and ~ - my cryslallogl'"dphic"" techniques to contain p:entacyclic 16-membertd-ring aglycones glycosidlCally linked at the 3 position to a disaccharide that oomprises two olcandrosesugar residue.~. The side chain althe 2j position of the Iglycone is sec-butyl in a\'crmecdn BI .. whereas in .,crmectin B,b. it is isopropyl. l\'ernoec1in conlains at JCIlSI 80% of 22.23-dihyd1Oncnncclin Bl a and no more than 20'1> 22,23-dihydroavmneClin 8".. Ivcmocctin ha.~ achicved widespread usc in veterinary practicc in the United Sillies and many countries throughout the world for the COI1t1Ol of endoparnsncs and cctopanasites in domestic unimals.1I5 It hIlS been found effcctivc for the trt"almcnt of onchocerciasis ("river blindness") in humans.'" an important disease caused by the roundworm 0,, coctrru ,'OII'ulus, prevalent in West IUld Ccntrnl Africa. the and Sooth and Centml America. Ivemoec1in Middle destrOY5 the microfilariac. immlllure forms of lhe m:m:llode. which create the skin and tissue nodules that are charncteri5tic of the infestation and can lcad to bli ndness. It 111'>0 inhibits the release of microfiJariae by the adult worms living in the h:08t. Studie.~ 00 the mechanism of action of i\'cmleClin Indicate that il blocks intcmc:uron- motor neuron transmis sion in nematodes by stimulating the relcase of the inhibitory nc:UrotnlnmUller GABA.'" The drug has IJcc:n It13c\e avaiJ able by the manufacturer on 11 humaniUulun basis to qualified treatment prozrnms through the World Health Organir.ation.

w t.

CH,

b '1<:o,... ",,~H y
H

CH3

CH,

H,C"

0 -.. , ....,...." " .CH,

H

ANTISCABIOUS AND ANTIPEDICULAR A GENTS

(unlLscilbiOll5 agems) ate ('(Impounds used 10 ~'()n lrol thoc mite Stlrmpl~s j fubit'i. an organism thaI thriws urMkr oomhlions of poor personal hygiene. The incide",:e of loCubies is bclie,ed to be incn"bing in lhe United States and worldwide Ind has. in fact. reached pandemic propor tion~.'09 I'l'diculicitks (.mipcdicular agenl'i) an: used to clinunate l'Icad. body, and CTllb lice. hie-a! ~ab;cide:!l and pediculicidcs must kill the aduh parosites and destroy tht'i r
Scubicitk~
egg~ .

Cro !amit Qn, USP. N-Ethyl-N-(2-me:lhylphenyl}-2butenamidt. or N-c.thyl IHTOtOOOlolu ididc (Eora~). is 11 colOI" Ic:~~. odorlcs~ oily liqUid. It is vinually insoluble in w*, but soluble: in mOSl organ ic solve:nts.

Croi3ntl100 is available: in 10% concentration III a 10lioi

Benzyl Benzoate, USP. Benzyl bcnzo.:uc is a naturally occurring ester obt"i ncd from Ptru balsam and OIher resins. h is also prepared synthetica ll y from benql alcohol and bcnl.Oyl chloride. The ester i~ a clear colorles., liquid WIth a faint aromatic odor. 11 IS insoluble in water but soluble in orGanic soh'ents. IJcnl,yl benzoate is an effecttve scabicide ... hen applied lopi~uJly . ImmediaLe relief from itching probably resul1s frotll a local anesthc:tlc effect: howe,cr. a complete cure is frc<lucmly :lChievcd wit h II sing le application of a 25% emul sion of benlyl bc:n1.Qi1tC in oleic acid, stabil il.ed with uietha noluminc . This preparation has the additional advantage of belllg esscllltally odoflcss, I1QIt5tuining. and nonirritating to the 5kin. 11 i$ applied topK:ally a.< a 100Ion O\'er the eotin" dumpened body. e~ccplthc face. Lindane, USP. Lind.lne i~ 1.2,3.4.5.6-hcxac:hlorocy,lohe~lIne, }'-benttne hexachloride. or hcnzenc hexachloride ( Kwdl. Sc:abe!le. Kwi!d:me. G \VeJ1). This halogenated hy drocarbon ts prepared by the chlorination of be nzene . A. mix _ lUre of isomers is obtained in thi s ",ocess.. ftve or which ha-e been i""lated: a. fl. y. 6. and E. The yiwrner. preSCnt to 1 to 13<:l in the mixture. i ~ responsible forthe i n~ticidal 0 Xllvity. The y isomer may be separated by a varidy of extmct;()fl ~nd chrommograplnc tt:t:hntqucs.

IU1d 11 cream intended for the topical treatment of scabia Its 1I0tipruritk effcct IS proIxIbly due to a Ioc".tl :lIlI.'Sdxno: action.
Permethrin, USP. Penncthrin is 3-(2.2-0kh~ theoyl}-2.2-dimeth) Icydopropanccnrboxy lic acid (3..po~ )'phen)'I)rnc:thyl estcr or 3-(pheno~yphen)' I)mc:'hyl (! ~ cis, Irons-3-( 2,2d ich loroethcny I) 2.2 -d iOlClhylcyc Ivpr "'. net:arbo~y l:l1e (Nix). This Jyntooic pyrethrinoid com~ is more stable: chem tc:IUy than mOSt natuml pyrtlhnns-.l i5 at !ea." as active: as ao ins.ecticide. Of the four i _ pn:sc:ot, the: I(R),mm" and 1(IlJ.cis iSQl11('I'S are I responsible: for the in>c:<:ticidal IICti vity . The product is a mnture ronsiSling of 6()'l; (RIM TlK:emic Isomers. It occurs lIS colorles..~ to pale yellow Jo. me lting crystals or as a pale yello .... liquid 3nd is insol 10 wate:r but solubk 10 most org3mc soh'eots.

Pl'm!Cthrin cxcns a lethal 3ction ag3inst hce. ticks. IlIItI. and Ilt'as. It acts 011 the lJt'n'e: cell mernbr.mes of the "". . to di srupl sodium channel oondUClllnce. h is usctl 11$1 PfIk ultcide for too trealmt:nt of l!Cad lice. of. I"" 'l()lutioo effcct~ cures in Il1QI'e The most frequent side effcct is pruritus. :about 6% o f the: patients tested.

Lindarl(l OCCUI'll as a Iight buff to t.:ln powder with a J'lCrsb lefIt musty odor. lind it is biller. It is insol uble in water but soluble in most organic wllents. It i$ stable: urMkr ocldic or nr::utral conditions but undergoes eliminmion react ions under allaJine COIlditiorl~. 11Je ~ction of !rndane IIg~irl!>t in..ecl.~ is threcfold: it is a direct contact poiJOn. it has. fumigant effect. and it aclS as a stomach POison. The effect of lindane on inSC(:tS is similar to that of DDT. Its toxic ity in hunulIlS is somewhat lower tllllll that of DDT. Becausc of rts lipid solubility pmpt:nics. howle,cr. lindane when in!!ested tends to ltCCurnulllte in the

ANTIBACTERIAL SUlFONAMIOES
1lte sulfonamide antimicrobial druGS ....ere the
ehc:mothcraJ'ICutic age:nts that cou ld be the CUn" of bacte:rial infcction~ io humans.

bOO,.

Lindane is used locally liS a Cn"am. lotion. or shampoo for the treatmem of scabies and pedlculosi).

(.'ba pt~

II A""-ill/rc,,,., ~JS

269

the dcmonStrdtion orib use-

,
G. Farbe:nindus_ a !'Cries of :17.0 I group. as

tUCCI'e on bKtcri:tl cultures. hi ~udy ProntosiJ. aod in 1933. thl! Infl'Ction~ in humans was .. he! ~atcd I IO-monlh-old i 5Cplicemia IlJId obtained a i for rnosc of thoe dJ.'>C'O ' cries relating 1 Pron0 10 Domag~. and for hiS pi~ring work in be "'II'! ~" .. ank.'(! the Nobel PriI.C in medicine in 1938. The Grstapo p'~mted him from . but after the war. he rcc:cl"ed

, :,::~,:~"~,

A IDS. 107 A primary infection lhat Is treatoo with the rombination is PCP. lltc ~ulf0lJ3mlde-lrimethopnm comhinalioo can be used for treat ment alld prophylaxi s. Addit ionally. l'Crebrul loxopla..~musis ..:an be treated In octi'e infection or ~lac"cally. Urinary truet infcction~ und bum therapy -I II round out the li,t ofthcrupeutic IIpplkutions. The sulfonamide!l are drugs of choice for a few OIher types of infections. but theirll~ i~ q ..llte limited in modem antimicrobial eh-cmothcrnpy}\)1- 1II "I'M SUlfonamides ean be grouped into three cJa.~ on the basis of their uo;c : oml absQrbuble agcnts. de~igllCd 10 give ~ystem ie di stnbution: Oflllll_absorllabl~ tl8"IU 50Ch as sulfasalazUle: and topical agents \uch 8$ sodium slI lfOC'd.:lmidc: ophlhahmc drops.

Nome_datu ... of S ... tfor..",oIdes

-,

Su/frJIlUmidt' is a llC:ner1e teml that dcJlOlcs Ihm: different

I. Antibacterials tNI ..., .. ""lf~nlllUnidn.")

UI1,IiM'JMbJm~'nI s~Ifr_ld'J

(the

HzN-S!-~r

11

II

\\

' -NH,

Y
2. Prodru" thal react III genernle ""live su lfanll.",itl.. CL~ ..... lf~_ ... tv.,~)

inxti,c II" vitro bul ~se.~~~ e~ccJlem of the drug mtracted much

...

ft

lhe rotIClOOed thm the lIl.O linkage was reductively active IIl '"tibai:t;,J. erial pnxIuct. sulfanil CC '" In 1937 wh-cn Fullcr!03 blood and urioo of
J I

,,'" study on

.
o

....

:::i~~"""'~~~IIC

Iit i and meningococcal lnfeeus]-... tcd in !he modern en! of and the OOIlttpl of the prodrug.
SIlCttSS of PronlOfiil. a host of .....-..~ synd,:slled and u:su:d. By 4.soo oompounru,1011 had been evalumed. two do7.cn havc been used in clinical 1940s. broader uperieoce wnh sulfontoxicity in some poItienl~.

3. N,WJlldw wlfonam,dcs

(o.e ..

nufemde _~)

,?0-.../(NH

O,ACH'

ICpIlICCd the latter in antimicrubial memo-

=i~~'~

indiscrimirnue use

for

infa:tions '

poItienls wi th

n.cre an: also ~hercommonly u'iCd drugs that an: wlfonamides or sulfanilamides. Among tllC.o;e an.: the oral hnlC>glyec:mie drug tolbutamide:. the diuretic furmcmidc:. and the diuretic chlorthalidollC. In phaml3Ccuticul chemi stry. p~ vuluc~ are 1101 used to compare compounds that 1111;: uwis ~. I ~ead. if a pK.. of an amine is given. " ref~ to its ~ah octing as the eooJugate acid. For example. aniline with a pK. of 4.6 Iders tu

fABLE 11-7 Ther.py With Sulfonamide Antlbact.rlals

Dlse.HllnfKtion Svlfon.mldes Commonl, Ihed

Tro.,IIICI1' ",ill pI'IIp/Iyl.o,i. <>f I'>tt..-,Jri .... rin" P ''''''''" ''''' f. rn orr ..... JI""IPI)Ia".ofa:,eboal I'iM IIIIK~ ,,( IIf''''''' he! .ft~ fiwoo tIImopy' """''''K''",," 1n:1Imt... 1!bocltrial ,nl_,
~

Tri~m."lf"".. d..........

P)'nT" ... mi ........ lfodwJ ...

Tn"'"'hopnm .... '~ Sil.u ..,lr:Pod,,,,i.... nd "",f~"HIc

C"'1.I"""'''''' IIId .. I...,.) ..."",r,."al ocular ",fn:liI>no

Cl\kImqw ......... ZIl
malanal~9)

Sod,um MllfKmtzIzoIo Combo".;o..~ WE'" quEn,OIC. odwl

Sulf".....
~

ofOroIn or A"_tfl:

r.o.:.v;.....
Sn=

1tJ1I(C"", d,_,''''
mfn:u"",

~Ien,~.r

Tn ...... hoprim<$IT'f.nlttho ...' .... Tn ..... Ioopn"' ..... f................. Sulforwno<lo:J.. (HOly 'f,.....alli> 1M: ... II\lft11'11H1t ~">'e; <IIhcnnl>e, ptn",q,ft O. amP'C,111A. !If ('<If pcnk"ltn ... "utiC paIltz'lII)
~_btltW(l

flgt

dau

su.'*"'...... al ,"f~
1'ruJIh)1v.1. ,>( ..' .. """'" m.uOl\lllOC
Od... t.c\eo ...

"'r....M_

f._

M OSI .., '"'"""'" 10 .If_ _ _

Mil'! ""' ,""",, ...1ki ... If<"''''h.~ l1!c low C(!6I of "",,\collIn IIOFd . . ~ ....... 00 .... ronm' Ie. b_!heIr ...." .... Ifoo.";, ... ..., ...1 .....d '" r,.... ~ 1

= ......

v."nal ,n,...1;"".
RnlucI ... oIl!q.o;cl fkn
Ul.;o:t .. ,." ","",Ii'

The FDA lind USN)! find

11(1 ~~loIonc~.,(

.If",."

Etr_ ...."" IlOl """,luM! ConocUi!ClilOd 'bull')' on.. Pldont!

1!.lapes """'''''''' ""tIl ""ror..mOdH
Soli<) IatoouIr&j>J11ihDt

"'"
h"

"..

und

"'"

S,de rff;I'.,( the ... If,,,,,lamiJa ""","",... mimic IIkmh'. <>*11.1

,,'"

T I'.hi

"... n:d,

h,<

II docs not refer 10

A IM'gauve charge 00 a nilroll':rI alom is Iypically 1101 smblc unless iI can be delocaHloo by resooa/ICe. This is ",hal happens .... nh ,he sulfanilamido."S. "1llerefore, !he Single pK. w.ually givcn for slIlfani lamidcs refers to the Ios.~ or lin am ide proIon (Fig. 8-8).

M.chanlsm of Action of the

s..tfGnillmkles

folinIC acid (N' form yhelr'Jh ydrofolic acid), N".Nw_ nw:thyl_ ellCtCu .. h).Jrofolic acid., Ilnd N'U_formy ltctrahydmfolic add

imermedial.es ofscvc .... J bioloynlheik pathway~ tIw tc. p!)!;C the onc-cnrbon pool 10 ani mals. bllC1erin. and plants. A key ",action involving folate coenl.ynlCli is catalyt.ed by rht enzyme ,hymidylact" ~)'nthasc. which Il1UlSfCN a meth,t group from ~.N,o.tctmhydrofolie acid to o,:o~yunoJiJJ mOllophosphale to form IkoXYlhymidinc rnollOpoosp/larc.. importlUlt JnCursor to DNA (Fig. 8-9). AlIOlhcr key ~!lCtion i~ the genenllion of formyl groupI for the biosynthesis of formylmelhionyl1RNA unilS.lhcpnmary building blocks In protein ~ynlhcs,s. The slllf~ a~ sln.zclUrul nnulogues of PA BA lhat competiti vely ,nhibll the aclion of dihydropteroate synlhase. prl',-enh ng the a6ilion of PA BA 1 pteridllle diphosphale and blocking lilt lit 0 biosynlhe~is of folale cocn7.y nll;'S. Thi~ IJCtion arrests IJi[y. rial grov.lh and cell divis.on. The cOlllpcfi,i\'e nalUK of it su lfonamidcs' action means thai the drugs do no pcrmaMII damage 1 a microorganism: hence. they Ill"C bacte~ 0 The sulfonamidcs mus, be mam'amed al minimum rif live conce ntration to urn:st the growt h of bactena Ioztr eOOllgh for !he host's immune sy~lem 10 erudicale thtm. Folate C(lCIll.ymes are biosynthcs.II.ed from dlCiary Ii* ac id in humans and mher ammals. Hocleria Ilnd prot_ must blO$ynthc!;iu them frozn PABA and ptm dinc dlphot

a~

o
R'--S-N

II

/ R.
Ceneral

II

Su/IonarricIe SII1JCtUI6

'R,
)
SutlaoHamide

Aniline

~~-NH'
g
Sullanilemido-

Sutrametha.tJne;
NI(4.6-Dlmethyt-2-pyrimldyl)sutlanilamide

r acid from Ihe growth l'ell.WIl$ for th is are poorly

is thoU baclerial cell walls

an inhI bItor of dihydrofulalc: reductase.

llIe I\lVCI"SC situation ellhh fur the aruiulalarial drug pyrimethamine. 'll TrilTll"thoprim oo.c,s /mo't ~ affinil), fUl' human (olale reducta..<;c. and this i~ !he CIlUse of some: o f the toxic cl1l$ of the drui

!Orono-cn dihydrofohc ocid (FAH l ) inlo '~ri'~ (Fig. 8-10). Anand TrimClhoprim does 001 . proIOloon' 5 folate reo hm a hIgh uffinity for bacterial folme

Sp aLbum of Action of the SulfonamidH

,"hibi! Grarn.po!>itivc and Gnno-negative hacleria. OIX"lInha. Clllam)"diu trflChotrttl/iS. and some proIo/.llL Some cmenc bacteria. slICh as E. col; and Klebl lt'l/lI. Sillmonfl/lu. Shillt'illI. and EnltmHxlclt'r spp. aro onhibited. SulfonSulronanll<k~

O-~II--q

.\

N~
HQ"'-

NH

dUUP

Other 6)!arT1)lea of folata-requlrtng ona-carbon pool reaction. :

c_ _
N'" F~FAl-\,
N'Jr-MIIIhyIeM-FN\

N'-Formyt-FAH.

"',O"i .

MeI IANA

.....,..

Fu....,.. M.. _!RNA

Ptllfldjne Diphospl!l:Ie

_Add ,

, , , , ,

"

SulIon.rnide. Sulforlu

""

~'' - <"'C) (
,

............

,-

. . ..

,
Humans

Dillydropteroic Add

Olhydrofollc AcId

...

'.

Folic Add (FA) in diet

U'IICI inJi~.

To FAH.

lire mfTl."qUCnlly used as si ngle IIgcnlS. Ooct drug., of choice for inff."Cliolls such liS PCP. IOAoplllsrnosis. nocardios is. and oIher bacterial inff,.'etions. they have been largely n:placed by the fixed drug cornbirlUliOl1 TM I' S MX and
man)' (lttK'r antimicrobials. M:my
Slnlln~

ar11lde.~

amidcs ore, hol'<c\'cr. 1I..... rul in SOli'll' urinary Ionhlatlon of S",lfonarnides

because of their high excretion fraclion throu gh too itKIn"

of oncc5usceplible

_ 'Pl-'Cic\ illCluding meningococci, ptW:URlococci, strcplOCOCl:i. .' laphylococci. IUld gooococci are now mois\aru. Sulfon-

The slllrollamille group. SO~N H2' tends \0 gain slablliI)' il 1 0'iCS a prulon. becau~ the resulting negllli'c chilI" resonance !ilabihl.rd.

II H,C-S-NHz
M

H'

273

""., ,

''t;:'"
,

,.x,' ,

, ,

'''''Add (diet); FA

~.

.~. '

"

" ""

"

.'..'.' '
o

."

""" "'"

ltlOf'l-

,
h t)' II

,
N" . FonnyI-FAH

t/FormyI-FA leucovorin) H.. (lonnie acid:

rgc

l~

Figure 8- 10 Coormued

the proIon-donating form of the funcnonal group is not charged. I/'e. can cha.rncteri1.t It :l'l an HA acid. along with carbo\) I groups. phenols. and thiols. Tbc: loss of a protoo can be IISsociatc:.:l .... ith a pK,. for aIL o f the compounds In the .serics. For cxample. the pK. of sulfisouzole (pK. 5.0) indicutl'~ that the s ulfonamide is a slightl y .....eukcr acid than acetic ac id (pK, 4.8).

SII~

TABLE 1-1 pK. Values fCH" Cli n ically Useful Sulfornomldes

Soilfonamlde
SuU d"mne i
SIIlf~ ...

... ..,
,.,

,.
u

"

H,C<~""

'0

~lf-'>a7J""

Sutn1lO.U>'Ole

,S..lr-"'>\Ql....

..

,. "

" '" m,
o

,I pi

'"

."

erysulluri.a and tIM pIC..

fko,pne the tremendous abil ity of sul fanila illide 10 l' ffcct CUrl'S of jXl thogenic bacteria. its benefits .... ere often offsct by the propen~ity of the drug 10 ca use <cvere renal damage by cryst all izi ng in the kidneys. Sulfunilumides mid their mct abol i te.~ (u\ually acclyla led at N') are e.~ cn:ted almost enlirel y m the urine. The pK. of the sulfonamido group of sulfanilamide '5 10.4. so the pU at ..... hlCh the drug is 50% 1()Il':tW is 10.4. Obviously. unless the pll is above the pK . hnle o f the walersoluble sal t i$ prcsc:nt. Because the urine IS usuaLLy about pH 6 (and potentially Iol/,er during bacteriaJ infC('tions). e~<;cntiaLl ) all of the ~ulfani 1,'lJTl,de is In the Il'laI'\'ely in.'IOlubll.'. oomonizro form in the l .dIll'Ys. Tbc: ~ulfa mlamidc coming 001 of solution in the urine and kidney~ causes crystaLL uria.
1__ pH _

The ne ..... er. SC llli~y nlhetk: sulfonamide.!! posses~ 10",erpK. values bt.'Cuu~ electron ..... ithdrawi ng. helerocyclic rinB! II! attached to N'. provid ing uddilional stllbilil y for t~ form. lIenee. the drugs donalc a proton I1"IOfe easily... lhe pIC" val ues ore Io..... c.ored. S,mpler electron withdn"1ItI groups were ulcns,lcly hwestigaled oot .... 1.'1l' found tOO tOJ.IC, poorly acu le. or both.

10'"

Met.ltbollsm. Protein Blndl.... and Dbblbutilln

Excl.'pt for the poorly absorbed sulfonamides used foruJccn. tive coli tis and reduclion of oov. el nora and the topical bm preparmions (I.'.g . mllfcnide). sulromunides and lri~ prim lend 10 be absorbed qu ickly and distributed weLL. M Mandell and Pelri LlOIed, sulfonmnidcs can be found In Iir uri ne " wilhin 30 minulcs lifter an orJl OOSl.','OI llle su lfonamides vary widely in plasma prote,n bindIJ for example. sulfiw J.aloic. 76%: sulfamethoxazole. 60t su lfamethox ypyridazine. 77%; and su lfod ivjroc. (Anand"J:! Iw published an excellent Uiblc comp.1fi. tilt: percenUige of proIein binding. lipid soIub'lity. Pltinu;-; life. and N" mCUlboiiI1.'5.) Tbc: rlltClion thaI is protcm DO is not active as an amibitcterial. but ber:lIusc the bindull rc\ersibll.'. fn!C . and thell'fOll' active. sulfonamide c,'CIJI , becooocs available. Generally, tbe more lipid soluble I fonamide is. at physiologica l pH. the I1"IOfe of it will !ifF" tein bound. Fujitll and Ham;ch' lJ have found Illat s ulf(}n:llni(le ~ ..... ilh similar pK. I/ alues. the the N' group has lhe lurgcst effect on protcin Accl!lte mctaboliles of Ih;e blc und, thell'fOf"C. )l" , themselves {..... hicb ha ve a rree 4-amino group that deem". lipid soIub,hly}. Surprismgly. the N" -acetylalw rntIlI:diIl aJthougb more Strongly protein bound. are excreted rapidl y lhan the parl.'nt C11pOUnds. Cum:nt ly. the: re lationship bet ..... een plasma proteLlt ing lind bioloJlcal haLf-hfe is unclear. Many OOlllptlllll'" tON are Involled. as reOeeted in sulfadiazine .... uh I half-life of 17 Ilours, .... hich is much ll.'ss protein bound" su lfametho:o.al.ole. wi th a scrum hair-life of 11 hours.*' Sul fonanllde~ arc eJlcll'tw primarily as mix lul"ti of ..

-.

_ ,*,,,..

.....

.. In poartr unionIled

Urlne

: 10.4 pK,.

oIimOOl .. .. 1IIgIoIy _ _ NIII ""'"

14: pH

Early approac ~ 10 adju,ting the solu biltt y of sulfanilamide III the urine ..... rn:I. Orc.o;acly ,ocrellSlnl the unne: flow. Dunnl the I.'""ty ~ars of ~lfonamide ~. patlClll' ull ng lhl: drug. .. en: Clut,"""" 10 "f<Jn'C' "0Id.." The . . WlIS Ihal ,f the IlllllXrulM fillrnllon roll<: """Id be ;ncru'lC:d, there would br IcsIo vppoo Lu nny for ~ cryM~15 10 form on .hI: ",nalll'bulco.. 2 111Cft'~"nl lhl: pll of tho: unne. The cloo<er the pH of the urine is .o 10.4 (for 5ulfam lam,de: ll"'If). thl! nlOl'C of thl: h'ghl y water .o;olublc salt form ""iII be pre,;;,nt. OrulloO<l,um bic~rOOna.e so,,,"u"," ..."'. and occasionally ~tiLl i~. given 10) rni~ u,;ne p H. The bicarlJoo:lle ,,' M !ldminiJl~ bo:fore the ,nllli l dose of ~ulfanil

ImidC' and then pnor 10 each ~"c 00sc. J. '''''pannl dm'au~es of su lflllilamidc tlw ha,"t lo... cr pIC. \"II lies, closer to doe pH of lhe urine:. Thu "J'Pr1lK"h has been uk"" ",.th ,in .... lly all ~Iforw"'des ,n (hmcal ~ ~. ba.npIcs 0/' the pK. vall11L'!!1 of some ioni,..abIe .ulfonan.1dr> an: >ho ..-n .n Table 8-11. 4 M ,~u'l di ff"",,,, ... lfonamMio 10 .,hlC'~ *' ~ [utal do!.c The loOIub,hl~ of tilt ... Ifo.wtlldes an: independent of uch Olio. and tIIo", of a nln,u", 0( '<Ilfamllmides can Slay in "' ..... wluuort al II ,"'cn pll than Crul , " nllll! Wltronamodc. Uenc.:. lrisul fapyrimid,,,,,,, US!' (Ulric Wllfa). COOLrun a m'lLu .... of ,u l(odi.~i,lC . ulr~lIICrlIIillC. and sulfamethal'IIC. Such nu. _

~,~;'~O:::;:::::,~;:;:~:::~

Chapl~r 8

""'i-I'lfurn't'losrll/.'

215

drug. N'-=elale~. and glucuronidel;, II. The N'-aceIIlIll!lueuronkles an: inllClh'c. For u3mple. SUJnSO:tIl1liiie is excreted about 8()'jb unchanged. and sulfamcthouIS UCl'I'led

20'1- unchanged. Sulfadi IlIctoolline is about

;.o;.,;,m""',

M ucrtted lIS the glucuronide. The correlaliOtl between lhC!urc :md roule of meiaboJism ha..~ 00l yet been deline. . though progress has been made by Fujita.' 11 Vrtt et 11.,'" however. ha\'e descnbcd the excretion kmcliC$ and ulucs of N :md N"-acetylwlflllllC'lhoxuole and otheT '

as it would with II singly blocled path .... uy . ~ sYTM:'llistie approach is u.ed widely in antibacterial therapy with the comhinarion of ~ulfarnethoxnole and trimcthoprim 02. ' I I. 1:)0 (Septra. 8 actn In, C(}o T omo~v.ok') and In IIntIR1alarlal thempy ... itb pyrimethamine plus a $ulfOllantide IJI' qui nine. Additional combmations wilh trimcthoprim ha~e been illycsllgaled (e .g .. with rifampin).'l!. In

To_lefty and 51. Effecb

A "ariety of SC'rioos toxiclly and hypt'BCnSlliyily probkrns hal'C brecn repuned with wlfOlllUllide and SlIlfomllllldc- lri mclhoprim combinations. Ma!ldell an\l Petri 'Ol note Ihal these problems OIXur in aboul S% of all patients. l~yperst:':lIsi tiYily reXIIOIIS inclr.1de feler. r..sh. Stevens-Johnson ~yn dronrc. skin elllpllOfIS. allergic myocarthtis. photoscnsi\l7.a \1011. and related COIIdi lions. Hematological side effect.. also SOllletllTlC$ occur. e~pecially hernolyt ic anemia in i!ldi viduals wllh a deficiency of glueose-6-phosphme deh}JllltIenDse . Other reponed hematological side effecls include Bgl'llllul(}o cytosis and aplastic anemia. CrySluliuria nmy occur. c'en with the modern ~ulfoo:Ullldc, ..... hen the patient does 001 maimain /lOfI1UI1 fluid inlake. Nause~ lind rcl:ued a:ustr(li nle~ linal Side effects !Ire O;Olnehme~ nott'd . Detailed ~ulllmancs of incldeoc'l'S of Side effccis .... IIh Inrnethopnm-sulfamcll!o.\amle ha~e been pIIbll shcd by WlJI'm'>Cl' and /)culsch ' IM and by G lttkmon <:1 al. " ..

Abou145% of trirnethoprim ond about 66'.l of sulfllJUClheyo!c arc partially plasma protein bound. Whereas about of c:\creuxl uirnelhoprim alld its ITICtabolites arc octive anr.b.:iclerials. only 20% of suifamClhou1.01e and h~ me 1I110htes are ad;"c, wi lh most o f !he IICtlvi ty cOIning from
~y

umncmbolil.ed suJfa11lclOOlHlwle. Sill metabolites of

InIDtlhoprII11 are ho ..... n.' " II is likely. thcrcf~. Ihat suJfon ..r-trirncthoprim combinations using 11 sulfon:lmidc wilh
IlIllilcr acl" 'CI urine concclltrnllOfl will be del-eloped in the IIIIUIt for urinary lract IIlf.-.:1ions. SulfamethQ.\lI7.ole and tri.'iiJjAim ha"e similar halr liyes. about 10 to 12 hours. oot .. lI:tI( li fe of the acllye fraclion of sulfumeloouwle IS Wlnn. about 9 bours.'" ( Ranges of h.alf- liles ha"e been .manzed by Gleckman et al,,116 and 0 detailed summary Ii II/Iarmacokinelicll has been made: by llansc:n . I " ) In paIntS "'lth impaired renal fuoctiOfl. <:orx:entrJtiOO!i of ~ulfa duuok and its I1lClobolites ma y greatly i~ase in 1 1M:: pialma. A fixed combination of sulfumelooxll7.oIe and tri.lIiop'im should nol be used for patiems with low creall _ ckar.loces.

Strvct.. re-Activtty Relationships

As IlOIed pbm'e ill Ih i~ chapter, ~\ernJ thou$.llnd sulfonamirks ha\e been in"estigated as antibacterials (and n\!llly as anlimaJ:uiuls). Fft)ll1thcse efforts. se\~r 1 ~lruclUrC-lICli,,'ty .. re lationship-; ha\e been pnlflO!'Cd. as 5ummaril.ed by Anund .1()l The amline (N') anllnQ group b \ 'ery important for activity buuse any modificati on of it other than to male prodlllgs resulls in n loss of actl yily. For example. all of the N'-octlylaled metabolites of sulfOllpmide arc inacthe. A "rulet)' of !ill/dies hal'C .hown Ihal the OCIl"CI form of su lfOflpmil\e is the N '- iOfli/-Cd 53 11 . Thos. although many rl'll;)(km 5ulfooamidcs arc moth more act;'!! than unsllb,tituted sulfanilamide. they arc only 2 to 6 times more actil'c if equal amounts of N'-iOOI1-Cd forms are oompan.'d. 'l J Maximal activity 'ieem~ to be exillbill:d by sulfonamidcs hctwo!l!n pK. 6.6 and 7.4. j l l . IZl> Thi s reflects. III pan. the need for ellOOgh nooiooilCd (i.e .. more lipid '\Oluble) dillS 10 be presem at physiolOSicul pH 10 be abJc 10 pass tbrollgh battenu' cell wol1 ~. In f-ujita pnd lI ~nsch III DJW relaled pK . partition coeffICients. and ~k<.1rooic (HartllltcU) parameters wi lh bulfonamide acti~ily (Table 89).

,. " >

.1:....1 _ of Miu obi.1 Reslrt'nce to S 'fann oWes

'<s1llMN above. indiscriminate use of ~ul ronuJl1id ..s has led to me erll!,'rgel1(:CI of many drug-resi~lallt stmms of bactena. 1t>r.~1K'C is most hkl'ly due to a compensatOlj' iocrease in .. bIoIynlhesis of PA 8 A b)' rt'siSiant bacleri a. 11l although odIer n\CChani~ms such as aitemliOtls in the binding stll'ngth tfSlllfonamides to the palhway enlymes. decreased pcrmc Iltility 0( lhe: cell membr'\l1(:. and acti"e efflux of fhe ~ulfon may playa role.'<U. " .. As a Illie. if a miellJbe is ~ to one sulfonamhlc:. it is ltSislam to all. Of nOle dle finding that ,ul fonulIlide resislance can be quickly nnsfCtTtd fmm a reslstallt baclerial str.lin to a pre~ iou$ly 1ICIISItJ1'C one in DOe or Iwo geoernl ioos. This rcsist:lnce propapiorI i~ most likely due to R-factor conjugation. a.~ is the (BI: for I~tracycline resistance. Srlual e~pl:malions have been reported 10 account f~ ~ri31 resistance to the dihydrofolute reciucla.'>e inhibi t~ rinatthoprim. including intrill.'lie resislal1CC. at the CIlI.YlfUllic lei'!:\. the dcll:Iopm... n! o f the abi,ity by lhe bacteria to use .. bos(s S-dco~ythymidine monophosphate (tlTM I . a!ld .factor conjugation.

.,

"

g'

~.

'" oo

If

.we

is l)'

ul

~g

or ..

uN",

~,

es.

USP. 4-A mi n(}oN-(S _lnethyll .3.4_Ihi_ adiumle-2 yl)bell1eneslil foo;mllde; N'(.5 -nrc Ih yl- I .3.4-1hiad; awI -2-) l}sul fani lam ide ; S-melh)' 1 -suIfan H:un ioo. 1.3.4-2 Ihi;ldia1.ole . Su lfamcthl1.Ole' s plasma half-life i~ 2.S hours. This coolPQl.llid is a II hllecrystalline po .... derwluble 1:2.000 in water.

Sulfilmeth;~ole.

S,UtI'll.tIc ActJvltln of Sutfonemldes 1M Fotet. Red ..ctase I..hlilitoss

If bio!i)"thcsi~ of bacterial (M" pro!:01.ool) folale cocn1ymes II bIoclcd at more than Ofle point ill 100 pathway. the n:liult "ill be a synel'istic antimicrobial e ffccl. TIllS is beneficial bn:aIst the mICrobe will IlOf dc\'C lop resistance as readily '",

um

han

the

276

WiI_ /Utd Gis,y., (d, TUlOOQ4 ojOrg""k M tdidnlJllJ",I I'/um... ,rt'uIIClJl Chem/Jlf)'

TABLE 8-9 Ch.ruterlstlu of AiKorbable Snort.nd Inte,..,.,.d i.te-Acting Sulfonamide. .a"''''pnon

...,

Sbm I" ro.n)

SIwln (9 hooDJ
t"",n"I'I<'\h:l!c
Sk~ ~I'""k

,Soolfadw.i,..
Pj'nmMl'be T"",e1i'Moprim

( I()"'111oooor< I

f 111--11 ",",,,,. Loa.!1-9d11,..)

,....

".cl. .n4--11booo1)

Sulfisoxazole Diolamine. USP_ 4 Al1IiIlG-N-(3S4me lh)' I-5-isoxa7.0Iyl)bcnlcflt:sul fooanudc compou nd wrd! 2.2'i mioobiS[Clhunol l( I : I): 2.2'-i minQd iC lhanol salt of N ' (J.4drmclhyl5isoX9:tOlyl)sulfnni lam ide. This salt is PI'" pam! by addm& enough d,~thanolamir>C to a ~ution of \IIIfisoxawle 10 bnn& lnc p~II O aboul 7_5. It is used lIS I sail to mll~e the rJru g morc soluble in,nc physiolo~ieal pH nJ.n&C: of 6.0 to 7.5 and il used in solution for ~ystc lll ic admini5ll'l lion of Inc drug by SlOw inmwenous. intramuscular. or wbculllne<lUS injec1.ion Vlhen high enough blood levels 'iiitOO1 be maintained by (lQ.1 admim~trntion alone. [I also il IUlII (or in~ti llatitm of drops or oi ntme nt in the eye for the kn1 lrealmcnt of sUscep!.ible infection~.

SuI

~ulf

H ,m

pial

In! "ocdiale

,,", CI :3 hi s

1101\

Its (
(II "'*"1

IOX~ ~ulfi

"U

r~

Sulfisoxazole. USP. 4-Amino-N-(1.4-dimclhyl-:5 -i~x awl yl )ben7~IX'SU Ifonamide ; N' -( J.4-di nlelh)' 1 isoxal.oI yl) -5sulfani lamide; 5Ml lfanaamitlo-3.4-tiimcchyhso~awJe. Sulfi'l(muole's pla~nca half-li fe is 6 houN. Thi~ t'Olnpound is a while. odorlc..~~. slighlly biner. crysl:I iJinc powder. I1 s pK. is 5.0. At pH 6 this su lfonamide has a waler solubilit), of l~ mg in 100 mL. and i!.!i 'CI)' I dcrivalhe has a solubi" cy of 110 mg in 100 mL of water.

hal

IOX ~

Sulfame thazine, USP. 4-Amino-N-(-I.6-dirrJeth)I~ pyri midi nyl)bc nlc.-nesu 1 all1 ide; /V' -( 4. 6-d Ilnclh y 1 -I')'n fon -2 midi 11)' l)su [fII. nilamide: 2-511 IfWI dnmid()4.6-d i rneih} Ip)Till,dine. Sulfamelllil/,ne's pla<;mn half-life is 7 hours. n. eompound is SlIllll llr III cncmlcal propenlcs to sul farnerv. and <;u lfadiaLUIC bUI tkles have greatcr WIlier solubi lity tIDI ei the r. Its pI(,. is 7.2. Bec au <.e it is more so luble in acid Ul1II! than su lfamer.uine is- tnc posslbililyof ~idncy damag~ free use of Inc drug ;<; decreased. llK: hum:an body appem h:mdle lhe drug unpredkl:lbly: hence . ihr're is some disf.lv to its usc in thi s country e~cepl in combinalion sul fa thmjl) (i n tri<;u lfllpyrimidines. US] anrJ in veltri nal)' rrJedkillt.

eH,
SulfiSQxazole pos..'IC~S lhe lIClion and the uses of other sulfonumides and i~ used fOf infections involving $ulfonamide-scn~itive bactcria. It is c laimed 1 be cffcclive in the 0 1n'atrl1C'nl of Grum-llC'gati~e unnary infection~_

Su/f u.ol wlfi life

Sulfisoxazole Ace tyl. USP. N-! (4-Al\litlQJlhenyl)sulfoN-(J.4-di nyl !-N-(J.4-dimclh)' I-5- i so~al.o lyl )ace1(m'iUc :
mcth)'I...s. isoxa~01)' 1)-NsulfanilylllCCtamide ;NI-acel yl-N'-(3.

4-d Imcihy 1-5- iso~:ll.ol)" l)w Ifan i Iam ide. Sui fisoxa;wlr ac~ t)' 1 Sharel Inc actions and U'ie!i of the parenl compound. ~ulfi <;()~ lIl.oIc. lllr :M:cI)'1 de ri vative is lu.<;tcleSll and . therefore. suitable (Of OI""JI adrn iniSlration. especiall)' in liquid preparul ions. llle ocdyl compound is ~plit in tnc inle.~tinlll IflICl and absorbed as sulfi soxll7.oIc:; Ihal ' So i1 is II. I"vdrug fOl" sul fisouI.ole.

SulfiJt:etamirh!. N-! (4 - Aminophen} Ihu lfonyl] It& mille; N-sutfanily1acelamidc; /V'-acel)'lsu lfan ilamllk . .w. fac:t'lamide's plasma half-life;1 7 hourlo_ This tompoulllh a "'hitc crystall inc powder, soluble in W~ler (I :62.5 It and in alcohol. It is ,"cry sol uble in hot WDler, and iii ...... soluuOll is acidic_ Ie has a pI(,. of 5.4 .

3ro

H )-LH 'N ---{

M

r"'

Sulfachloropyridazine. N -(6-ChJoro-3-pyrida.z1lYi ' su lfanilamide. Sulfachlorop)'n dazane' s plll.~nla h:alfbfe d

"""".

Chllpttor II Amiin/nm... AvnlJ

II

277

,-d!.

.... ,
p-

, "" OlnltC

- ,ul

is a v.huc . odorl~ crystalline pov.der soluble III WlItcr to the extcrn of 1:8,100 at 3TC and 1: 13.000 al 2.5"C. in hUIT\llll <;CNm \0 lhe cx tcnt of 1:620 at 3TC. and spanngly soluble in alCQhoI and acetOllC. It is readily soluble in dilute minernl 8C"Kb and bast'S. 115 pK. is 6.3.

o
US/>. 4 A In i I}()-N 2,p)'rid illy Ibe I17,CI\e N 1.2.pyridylsulfanilnllIidc. Sulfllpyridine' 5 is 9 hours. Thi ~ compound is u white. cry~ and tastcit'S$ 5Ub:!;UIIICC. II is 5mble III air . It is soluble in water :..~ooe ( I :6.5) al 2.5"C . " ~ii~.rul.acids and aqueous soill' and pobSSium hydroxide. The pIC. is 8.4. tffeet in curing pneumonia was lirst ~og. : oo...~'er. because of lIS relal,,cly high by su lfadiulioe and

,~I ra-

"

UN

N =<

NH-

---<

) -N H'

,h""kidneys. l"C!iultcd i lhe

,m'., lkcausc of ils

I

Sulfadiazine Sodium, US/>. Soluble sulfadiazlnc is an anhydrous. while. colorless. crystalline powder SQluble III waler ( I:2) and slighlly soluble in alcohol. 11$ wattr soIUIJon~ are alkaline (pH 9 to 10) and absorb carbon dioxide from the ai r. with Pf"CCipitation of su lfadial.ine. It is admimstcred as a .5% solution in Sic rile wau:r intnlvenotls ly for palicnl.~ requiring IUl immedimely high blood le' e l of the wlfOlt nmidc.

NH,
,,,,"~

was lhe fir.;! drug to hu,c lin outstanding

It
impcllls
to

U
Mixed S .. It .... c.ldes
from admin istration of sul fonhmidcs hhs been gre~t l y reduced through tnc usc of the: more solublc sulfonmnidcs. such as su lIisoJCU7.olc. Th is danger nllly he dimini<hcd still funher by admi nistering miJClures of ( ulfonamidcs. When several 5u lfonalnides are administered IOgethcr. the antibactcrial act ion of the mixture is the summalion of the acti'i ty of !he 100al su lfonamide cooccntralion pll!SC'nl. bul the solubilities are indcpendcnl of tnc prtSCfIC't of similar compoulKb. Thus. by giving. mix lure of sulfadia/jne. $ulf:uncra1.Ine. and sulfaccllllmde. the same lheraprulk lc'cl can be maintaincd with much Ics.'l danger of crystalluria, because OIlly one Ihird of the amount of anyone compotlnd is pre.<;e nl. Descripl ions of ~mc of lhe mixturt'!i u<ed follow.

~;~~~~~: h~~y, '''''y SUbSUlutcd deriva ,

US/>.

the study

llI.e danger of crystal formation in the

~ idneys

lib.",

'"
0

,p
~

NN,

\~

)\, ""
~mi'k drug cilNly rel:ucd

struclllrc and Dil timicwbial acI . alm(l!;1

. II I

Io....cr Ih~n thut of ~u lIi "'1l11.olc sulfamenuil'll:. ()( sulfa-

Trisulfapyrimidines. Onll SU$pen$ion. The oral suspension of trisulfapyrimidines c()lltnins cquul weights of sui fadia7,i nc. US P; sulfamcm7inc. US P; and sulfamcthal.ine . U5P. ei lhcr with or Wilhoul an agent to raise the pH of the unne . TrisulfapyrimidinH, Tablets. Trisulfapyrimidine lablcts contain csscnually equal quanlillC!l of sulfadi:ujne. !IlIlf. mcrazifll'. and sulf:uncthaz lfll'. SulfadoKine and Pyrimethamine. The miJClllre of su i ftJdoxine and pyrimethamine (Fwmdar) is used for lhe treal mcnl of PIMmodll.m/alc/p(Jnm' mlllaria in patients in whom

0faJ ministration. sulfunJetho\(lJ.oic i~ Il()( 1M romplckly or as ",pidly as sulfiso~al.ole. and . . ''''' IS. ooly about .5O'Jo as hIgh.

,,
2-sulfanilamiis 17 hotil"$.

SuWadlazlne SUlfamerazine

t"hloroquine resisulflt"C is suspttted. It is also used for malaria proph~ laxi s for tra\'elel1l 10 an:a~ where chloroquine f't!Si~131l1 malur;:1 is cndcmi t".

',0" 0

,,.,...-0

p' ",

0 NH, I(

SuIIadoxina

P-

HO~N~OH
Triple Sulfa. Triple ~ulra (sul fahc01.:urlldc. surf,.,;,~. midc. ulld <,ulfathial.oIe; Femguard) is uscu lIS a I.. cream In the tn:atmcnt of lIaemophlllls I"llgilllliis \agl

Topkal SulfDnamlde.
Sulface tamide Sodium, USP. N-Sulfunilylul"C1amide monosodiulIl ~a l! (Sodiu m Sulumyd) l~ obtuined as the mon_ ohydr.ue and is a white. odorlc~s. hiner. crystall ine powder Ihat;s lery soluble ( I :2.5) in water. Ikcausc tnc sodium sail IS highly soluble at lhc: phYMologicul pH of 7.4. it is espeCially suited. as a solution. for repealed topical appliculions in tnc 10C1l1 managcment of ophthalmic infection~ 5uscep(ible to sulfonamide Lht:npy.

Nonab.orbable Sulfonamide.
TO PI CAL SUlFONAMIDES FOR BURN THERAPY

Mafenlde Acetate. 4-(AminomethyJ)bcIl:t.erll'>t<Jf..... umide acdate (Sulfumylon) is a homologue of 1he sulf_ amide molecule. It is not a true sulflllli lamideI)'J!C pound. 11$ it b not mhiblted by PABA. IIll lIltibactetlJI inloll'es a mechanism that dilTcl"'l from that of true sui amidetype compounds.. This compound IS paruculart) feclll'C 38ainsl Clos,,,,Jium .....lch,i II1tOJ'lCal appl~ was used during World war II by lhe Genn;ln arm) II prophylaxis of wounds. II is 110( cfftttlvc omlty. 111Safrcntly uscd alone: or with 3ntibiQlics 111 the tn:uttnl;'OI of \100 healing. infected wounds.

o
Sulfiso1lazole Dielamine, USP. Sulfj~.\v.ole diolamIlle is dc!;cribcd with lhc: sbon- and intermcdilllc-acting sulfonhmides and al..o used m mlr.IICIlOUS and intramuscular preparations.

Some paticnts lreatcd for bums \II ith lalic qlWllltJlo this drug h.;)1C dc,'doped metabolIC acidosi ... To In
thiS adverse effect. a !i('ries of new organIC salls III ... pared.l~ 1lle acetate 111 an ointmenl ha.'IC pro"ed to Irr mosl cfficacious.

... SuHlGluiM! (SHvadenft" The silver SIll of ~u l 1Do It applied in a luter-miscible cream base has: pro,'ed
!'< 011 dft(:h't lopical antimi crobial agem. especially .I'",~ spp. Thi, IS p.1"iculurly ~ lgnificaJ1l in bccuo;e p!iCudomonads are often respotlsible I I~IIII therapy. The..alt is only !Iightly ~uble IlIld !Ill pt'1'(ll1lIe ,he C'CII wall but acts 011 tilt: cltemal cdl ft', ,SOIOJiei u.~lng r:ldiOOC1lve ~il,'er h~,'c shown cssen, .. ..t>I.wpuon ,"10 body fluids. Sulfadiuinc Ie"ds in ~ <omI!II wm about o,~ 10 2 111g/IOO mL.

IS dosely reLated 10 sc\'cr;ll al1limalari~l~ bul dlle.~ 001 have good Wltimalariul ocIl~ity by itse lf; il i~, l\uwen':r, ~ potcl1lllJ1llbm."terial , OriginaJly introducal 111 combin:uion with -.ulfa".... thoxa;r.ole, It is oow al'lillabic us a single agcnt.

~-(3.4j-trimctll(nybcn1)'llpyrinlldinc)

0 0
H3C"""-

....""'
N y NHl

U"

.=<

"'.c-~-<
M

)--'N,

",C,

.6'

"'"

.6"
HH,

reported 10 be casier to u<,(' than other , weh all preointment.

with

Approvctl by the FDA In 1980. tnn .... lhopnm as a ,inglc agt:nt i~ uo;ed only for the tre:ltn1ol'nt of uncomplicated urinary tract mfectioos . The urgumc.u for tri.nethopnm as a sin,lc agent was summarized 111 1979 by Worm.'oCT and Dcuto;ch. 1 TIley point OI.It th:Il several studies comparing mmethoprim With TM I' -SMX for lhe treu\mcnt of chronic urin:uy ITXt infection s foond no 'tnll$I1Call), relevant differellce between the two courses of !hempy. FurthemlOl'e, some p.1lients cannot wke sulfunamide products for the re~~ discus.o;cd abo"e in Ihis ehupler. The eoocem IS that when used as a single agcnt. bacteria now -.uscepciblc 10 lrimetilopnm will r~pidly de"rlop n:istance. In combirtalion .... ith a sulfon amllJe. howcver, the bactcriu will be less likrly to do so. That I~.they .. ill not ~urvh'e long cr1O\lgh 10 ca.,ity develop I'l!s istance to both drugs.

;
Sulfu.ul~J;i~

Sulfamethoxazo/e and Trimethoprim, The syncr,islic 0CI10fI of the ('( unblnation of these two drug!> is dio;cus"Cd abon in this chapter.

or
SUlFONES
1be su lfol'lts are pnmarily of intcm;t 3S ant ibacterial agents.. though !herr are SOfI'It reportS of !heir use In the tl'l!!ttnlCni of malarial and n ekens ial infection.~. They are less effective than lhe ,ulfOllamide~. PABA p.1nially antagoni/cs lhe~ liOll of man)' of the sulfol'ltS, suggt:stl ng thaI the mechanism of actiOll i~ similar IQ Ihat of the sulfonanlide.. Further, infections that ari.o;c in pallents belli!: lreated with sulfones are ~n:siqant to sulfonamIde<;. Sc"enll ,ulfoJJl:s Iwve pro,-ed useful in lhe treatment of lqlroSy, bIn among them onl)' dapSllne is clinic~Lly u>W today. It has been e!)"m~lcd thai there are about II nli!lion eases of leprosy in the wOI"ld. of whICh about 60% ~re m Asia (with 3.5 million in India alone). The first reports of dapsone: resi.<;tmlC1l pfOmplcd the use of lI1uhidrug lher:lpy with dapsooe. ofamp In, and elofallmlTle comblnlltion<; '" some gcogruphic areas. UlI The sclIKh fur anilleprotic drugs ha., been hampered by the inablilly to c uhh'ale M , I('pm" III anificial media and by the lack. of e~penmental ammal~ sU'iCcplihle 10 human leprosy , A method of isolati ng and gro .. ing M. Il'pml' in lhe: fOOlp;K1s of mice und in amllldiILO\ has been reported and has JX'rmilled a much widcrmnge ofrescareh. Sulfones ",cre

add) I~ a in aJcowDler. cther. and ben~ne.

..1
~

~~~~:brok~:"~~do~:wn In drugbody 10 m_amthrough_ , 1be the is CJlcmed il'lwmli

CoJorllllCtr1cally in !he unne. onnge-ycllow colOI' when the urinc i, Illl.:aline .iItn!he unlle is acid.
1

REDUCTASE INHIBITORS

introduced into the treatment of leprosy after it was found that !.Odium glucosulfone was effecti\'e in experimental tuberculosis in guinea pigs. The parent sulfone. dapsone: (4.4'-sulfonyklianiline). is the prototype for a variety of analogues that hal'e bce.n widely studied. Four varialions on Ihis structure ha\'e gi\'cn active compounds:
I. SU~litUlion on boIh the 4_ and "'-amino funclion~ 2. M _ IO$UluUon 011 onJ y on<' or the amino funnionli 3. Nuclear ,ubt;.liluhon on one or the ben~moid rin,s " ~""'N of one uflM pMn)'1 rinp .... ilh. helmlCychc rinl

6. 7. . 9. 10. I I. 12. Il. 14. 15.

If>.
17.

of the di subsli luIed sulfooes an: thought 10 be chieny due to the fomwion in vivo of dapsone . ~I ydmlysis of dhubstilute(i derivnrives to the parent ~Ifooe apparenlly ()(:Cu~ readily in the acid medium of the stomach bul only to a very limited ex tent followin, pareOlcral administrntion. Monosubstituled and nucleur-substiwted derivatives an: believcd to IlCt as entire molecules.
DapSOf'/f!, USP. Dapsone (4 ,4'-sulfooylbi5beIl1.ent:amine: 4,4' .sulfonyldianiline: p.p' -diaminodiphenylsulfooe: at DDS IAvlosulfonl) OCCUB 115 an odor~. wbile erystal. line powder thai is very slightly soluble in water and sparingly solubtc in alcohol. The pufC compound is light stable. bultrattS ofimpurilies. inc luding water. make it photO!lenSilive and thu, suscepcible to discoloration in light. Al lhough no chemical change is detectable follow in, discolonllion. tnc dolg should be protecled from light.

The anlibactcriol activity and Ihe

lO~icity

II. 19
10.

21

A. G.: I Am. PIwm. A..oc. 28 ;416. 1939 GiIbtn. O. L : Appl M.. lobQ. 12.:496. 196-1 t.-:h. p N . I. Am. Mtd. A..... 109-15l l. 1937. M,_. N. A .. ~ .1: Am , J Pharm. ).6,)76. I m ...~...... IJnowd SI , Food - ' Dnot ........ No.II'IItiaol llv..., ..... , ' I ' . , New",,", .. 8 ullel,n. O..,,,,,bel 191 1. V.. "oh.A_ Afdt.Du" ...... 9II: tU. I9611 Gmhon~1d, L : Milk Food Tcchnot. II,m I~S. 1:Iomo&I<. 0 .: Obch. Mnl. W""heft"' .... 61 :2$0. 19l5 Roie, F 1.... """ Swain. O. J.: ~ Soc. 442. 19:16. M .ey. A. 0 .: MiU" (;ro,a~ Choc","",,",. ~ Uti.lb wood Ud .. 1990. P. 160. c-...mt. E. R.. _ WOO<h. O. R.o I. A... f'hInn. A...... (Sn. 6i,I 42:7)6. 1953. RlPJM-. J w In "'""" . ... W. (aI.~ Tel rt.ool tJf M... otoioIoc! NIt"",phi.. W B. s.u ......... 1971. P. W . Fncdrnan. 1... "' 01.: I. In.-al. IkrmalOl . 3S:)- ' . I%(). Rippon. J W. In 8 .. ,--. W. (aI.l. TUII)(d: '" MiL.utNokitJ I'IiIt delphia. w. 8 . s.u1ldorJ. t973. ". 121 RippllOl W. In !kit"'...... W. (01.). T""boo/r; of Mia"'*""cY I'IIiIIdelphia, W. 8 . Sao>-. 1971. p. 7Jol GoIdnwl. R. C.. 1A<l !CIoc'n, L 1_: Anno . R<p. MoI. Ch:m. 29:1.\1
o..M ~,-

a"",...

22. A;'11o. L. Sd,,,(t 121;876. 19S6. 2l A;'IIo. 1...: M~ 11:]15. 1961. z.t. R,bell G., .nd l'Ipt... O~ Ot",M"VIl__ M;"'i. \hoi>ei>il}' '" PreI.>. 1970. 25. lliod1. lt "",,"ino. F.ndl. }1 1J09. 1'81. 26. I'OOIk . A.. _ s.:1IoI<r. H. : 0.:"""1<,,,,,, 21 : I n 1975. 27. llocI~stl. M.. RQM. Ii.. McCarn""",. J. .... : Mol. f'harmkoI. 521111t,

,....

M,.""

28. B.lin>ki. M GAnbokii. P.. BOllt!. P.. 1Ioroww.1. I!.: 800ph~. ..

".,

6!I:91 . 1997 29. Gold. W~ ~ . 1 ...... ioboJba A..... .: Enc)'C~Ia. t956..

JO.
~1hI..w. ,.

c-

1~5- 19$6.

New y<rt." f

-< >-+-< )-NH,

Dapwne is used in the treatment of boIh lepromatous and tuberculoid types of leprosy. Dapsone is used widely for all forms of ieP""'Y, often in combination with clofll7.imine and rifampin . Initial t!'Catment often inc ludes rifampin with dap$OM. followed by dapsone alolle. It is also used to prevem the occurrence of muJ libacillaty leprosy when given prophyloctic<llly. Dapsone is also the drug of choice for dctmatitis herpe1ifonnis and is .sometimes used with pyrimethamine for l!'Catment of malaria and wilh trimrthoprim for PCP. Serious side effects COli include hemolytic anemia. methemoglobinemia. and tOllic hepatic effects. Hemolytic effecls can be pronoul1l.;ed in patients wi th glucClSe6-pIlO!Iph:ue dehydrogenase derK'icncy. During therJpy. all patients require fl'Ctlucm blood cooms.

W. ~ aL, TctrolIcdftJn Loa. lB7}. 19'70. 31 Gnybin. J. k .: An . Inim>. Mn!. 1z.t,91t. 19116. 12. lon~",pl. R.. ~ at.: Cill. ~1IeI. 23:279. 1992. n , liven. 11. L . - ' Ikuinl. R I'n)c. P p. B..... MeoI. 76:'1J. I"t .. 34 . P.n<lty. 1t C. RI",tun. !C. 1..: J Antlbooc. 29:1005. 1'116. 1 10.1 .. .. oI~ Teliol hIM Len. l'J,2117. 1 \l1l.I. :MI. SIru~k. A p" IJocne. I. 0r00I. G . ~ at" A..ibIoL II-.. rtI.

s...-.

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1957 - 1'H~ .

37, Brit..

li~ ~ 01"

Nywr ... In FIofty.

K. (td.).

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III

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12 1
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_I C. -l.)'11<li. J L.: B,,,d..,,,,""Y j ~ 71. I9!>I l l. Bo<Idw............ 01.24 115J. 1Y75 """ Il;"en.. C. E. Ind, .... A...... .x,.

128 Shc .... d. C C : N Ena:L. 1 Mood 1O7 16400. 1982

SELECTED READING
Oloom. II R. ,~.~ T,*,"",""" . .....'.." "1"... IX ...."""" . .5.xie!y .
M~

. .. II N>!~ 23IJO I. 1Y71 S. .... l ...... iIIOot. ~5. 1m C ..... Boo.. ...... l"hannoroI. l7;!089. 19711 '/I .. 01 J ...... ctam..Sox 100:2551. 19711. ;:::;.~ K 'IMwc 218.684. 1970 . :~ .... ond PLot.<t,. E. G.: Bi{).; him BIOph)'J . ... <'II 5401'605.
~~~~I..._Cioli.

r,..

Oou.

... "'- J T"",. Med

lin.

).1 112.

IUbl.1979

(loIJ,,,,,,,,,

'. I. doe rICId <or In T..u. B I~.'. Ad.-..ce> In Dna, Rt:,;e""'h ....... 21 New yoo. A..... "'ic I~ ... 1991 Como. J. A . md D;'mu~ .. W E.: 0..1 II'*' .. ' '~"'mK ...uf.",.1 . ... """hcnpy, N ""'. J Mcd. ]JO-2113. 1994 Dnp""" .... D D~ """Kat4: I ""- J W ~ur"C)'< ... """,,Yorl. Spn.... V ..... 1987 R S.. ond H.~ .......... D. IttlH Trupool Mcd"" .... and PataI.o. u""sy New 'I'm. Appl."", &: UnF. 19119 11:>111.... II C. ond " rvv.bUu. S G a..rnoIII<-raJ>7 01 """,,"y, ..... "". R... I~ TO>.iroI. 2823 1. 19l111 , _ .;;;,. 0 . W<>1(-. J S (No. 1: Qu, _ _ A"."""' ....... A~. 2....... W''''''''II()O~ DC. Au""""'" Suctn1 for M"'AlIIooLotY 1'rnI.

qu'''''''''' .nut.ctenaL "1""1'"

Prts.. I W-i D T ~ """ Fcrnao.Jn.. P 8

110.:"'" .se-.-.:kipa

c..'"

1993

H"",,,,,,. S.. and Form;n,. A Cum:nl ..... ""'''n ... l "" ....... nl of .ubcmJlo" . OnIp4868'1.199-4

"

............ J A . "" ~ RD A ...,.......oc .,.".,... '" M....." GL Bctu><o JE. Doha R , ..... ). "" ,,""'" """ I'rIctoa: of Inr...".,.. 0... - . "CII. 1. 4t1\ .... Nc;w Vott.. a.......htnLh In"""",,. 1m K",K'f. J II ....... 0 >1. ... J II ''''''.): "'.... ,i l'" I'roIozo&. 2nd cd &In ","",. A<.Jr ...;" 1'R:u. lY'J1 Reed. 5.: A... t, ........ up<bIc CLift. I. fca 0; .. 14 m. 1992. so..p.. S. K~ '" SIk",.. S .. CurtetoI.w... d " . . .aL r: :.<~ irI",lminIh di>caw Mcd. Rn. R.. 11.581. 19111 W*,,, C. Mokaolot """' .... ,""" .... lher>pot>tit: """'_ ... , 10 Ihc "".. Imt" 1)1/ ... fne... (1)1"''''''''''''"''' Annu. Reo, "".......,.,. TOAK'f" 35:93. 1m. Vamaall<bl . 11-. Koo..u"". G S~ -.I T.lal~,I". 11 (...... ~ R...-enI ...... .....,." I...... "r"npI~ N....' Vor1..M..:e1 DdI.eo". 1992.

c.:

Antimalarials
JOHN H BLOCK

Malaria. ooe of the roos! wKkspreoo di;;eases. i~ C llU'ied by :I 1'lasIn(JI/ilim pani)ue. lis name i~ derived from lilli/I! aria (b.Jd air). and it has been cal led ague. Inlcnnineru fever. manh fever. and The ~ver.1. l The name is based OIl !he earl)' knowledge thm malaria WIIS IJ.l;SQCialcd with swamps and badly drained ~:.s. The uS(' of quinine for trealing mao laria has been lllown since lhoc 11th century. While malaria is an ancient disease. ils upsur&<, seems \0 coincide with the !\d"em of fanning aboUl 20.000 years ago. The cleanng of land provided an:as fur ponds comai ning slili waler. 111t! AIIOphf!it'l 8"mbillt' mosquito U~ !>Iii! waler thaI ) its in ponds and comaillCl'S to breed. The gathering of humans in farming cOl'llmumtie!i provided The r.ecc T 'ry corn:cnll1l1ion of people \0 form a reservOir of hosts for !he parasite and " food " for the mosquitos brttdillj in the poods,H. Proof thai the AnQPhtlrs "lO!K:IullO IS the carriei' of the causative PfOiowa was oblailiCd by Dr. Rooald Ross, who Wlb rtCognm:d In 1902 wnh the Nobel Prize in Medicine. [n 11 scenario somewhat SlnH[ar to thut In "hich delinitlve proof that yellow fever "..IS 1l1llJ5mined by the "I'd..s 111'1)1lli lI105quito v."3. required. Dr. RO!i~ strongly argued that malaria was tr:ul~mhled by an in~ ~CC\or und finally demon 'itr.tted that the par.l~i te was carried In the ~Iomath IUld sali vary gllUlds of the A'wphl'll's lIlOS<luito. The 1!lIIer di"Covcry WIU important because it helped re:<iOlI'e the dispute llbout whether malaria WIIS spread by tile bite of the IIlO!i(IultO or by drinking Will:!" comainin, mosquito eggs and Ilirva.1 Because malaria ha~ been diminau:d from North America. it only bc:conleS a potential problem "Ilen dtil,cns of this continent tl1l ~e[ IntO an area ...here malaria is endemic. Wilh internaliona[ lravel so common, Americans receive pn:scriplions lotllkean antimalarial drug prophylactically when tl1l V cling 10, and li ving in. art:n5 where malaria is endemic} Frequently. U, S. citi1.c ns returning 10 the United States from IU'eIU where malaria is endemic and citi1.ens 0( tho!ic: counlries who are coming to the United Stales have malaria aoo need antunalaria drugs. In 2002, two eases of malaria "..ere reported in Virgmill, Neilher patient had ally of the ris\': facton. inc luding imerrullionlll tra\'el, blood transfu~ion. organ lransplantation, or needle sharing, 80th li ved in the same general goographieal area. Examination of ponds in the area foond AtWphtlts mosqUit0C5 thai ini tiall y t(!Sted JlO!iitive for one of the mal~ria par.lsiles, l'lasmO/fi"", l'i"I~{ (!iCC below). The hypolhesis wllli that infected mosquitOl'S had cntcred the United Stales through Dulles Internati onal Airport or Virginia seaports, possible in cargo, Surveys of surroundi ng medical focilillc:$ showed no recent eases of lIltemational 1T8\'elcn who had maJlIIia. Followup testing of the mosqui to;:5. using mon: precise. methods, disputed the initiallindmg Ihal mo.>quiloe~ in IhI: ponds Ihal wcre te.~ted curried PIt.smQ dium spp. This linding is sull in dl~PUt('.

Malaria. "hieh infeclS :.everal hundred million Jlro1* I.'ach year. resulting 10 se,eral million deaths annually. iii comple ... disca<;e to lreal. The c3usa ti vt' agent is II groupal parllSitical protOlOO of the Plasnl(ldium gl.'llUS tra/lSIlIIlIrII by lhe female Itnaphl.'ll's mosqUitO, The impact of mal.". the human ~ies COIltinues to he deva~tuling , , 'he iml*"" dillCases ~och as !>maliI'm, plague, yellow fncr, and p*> on human hi~tory is fascinating bul. fortunately, ;1 nlOid) h.storical . 1be laller three dJse~s do reappear. but the CIII:I are isolated. Plague i~ treated effcctively ... uh anuoon and there are vaeeioes for yellow fevCT and polio, The publ ic i~ aware of oclluircd ImmunodcflCieocy s,.. drome (A IDS) bccaullC:. il is a disca .... Ihal "U1I~eI5" b! human carriers IU1d has mfccled and killed pronllncnt ~ ...110 are citi1.cns in ccOllOmieally developed countritl. Nc\" enhekss, compare the 200 1 ligure~ for AIDS lIId_ laria, After appro ... im~tely 20 yeao" 40 million pcopIt l1l'i been infccted with the human immunodi:flt;errcy ,inI (UI V). of ... hom 5 million ....ere illfCC1W and J m,llIo in 2001 , For North America, 940,000 haye])e(."OITl( Inr~ III the past 20 years. or .... hom 45.000 ....ere ,"fltd" 20.000 died in 2001 . In eomr.lst. nppro ... imately l<n of ... orkfs population has malana (300 10 500 lliese. aOOll1 I million .... ilI d,e annually: .nost md.. In OOIllraSl. there arc only about 1.500 new tases of annually in the United StDI~.s. and nearly all of ~:-::c frOlll tnl\"elers oITh'i ng from Drca ... hc:re maJano is endmii. Most prescripuoos for antrmalarial drugs an: for P'tJ of I I1I~elcrs going 10, Dnd coming from, an:as of the ,"tIIj ... here malaria is endemic, 'I1M:re are three poIential ways to conlrol malaria: tion ofthc "ector, drug therapy. and vacci nalion , Elinu.to of lhe \'ector cUlTent ly is the simplest and li\t , Drug therapy h:.~ the surne chnl1enges as t me", of antibiotICS (e.g .. resiSiaocc 10 the drug), antrmalarial drugs, .... hile effecti~e again~t certa.n ~ al<;() M\e signifICant adver;e reaction~. :md resi<tIln ~ creasing, Thus far. no \accinc has bc<:n de\eloped 1M effcet;\'e in \ iyo, The malari~ para~ite does I'lkillll_~ rnpon~. evidenced by the fllC1thal children .... ~ I!~po>ure are more likely to die than aoJulL~ .h, .~"~ o ng attacks. A T -cdl response tMt includes both CD4' CDS T cells, production of interferon ,.n ; ~ o~ide synthase induction i~ added e~idcnce ttw immune 5lstem does detect the parasite and I'I'$p"*h cordingl y, An ide al "aceinc should , 01 3 minimum. be the again51 bcMh P. Jfllciparum and P. linu. respon~ible for 90% of malaria Cllse!>, 1be ItfllJl.'hl'll.'S mMquito has adapted "cry habitats, A< JIOinted OOt abovt', II it s eggs, wall for them 10 hatch, IUld then let

m-

,\11.

182

Ooypt.,r ' Itm"'.lJu,rUd.1 organi,ms in slill waler. nt.all.lre_ becall'SC;1 IIteiy l'<illlIOI COIlIn;n p I.... "'- WOIIId feed 011 the e~s and larvae. In gencllIl. D_'!I~ IIffilllo 2 week~ to develop into mature insects. "BiI..wI) i) ~lI()lIgh lime before pKdaton; begin to popu tr 'llill "'"3I~ Clll"ltlldy. lhere Ire IWO ways 10 control the nloOS4juito ..ncr. 0nC' is to prevent conlllet between human s and the ad. IIcuuw the Anophdf's mosquilo is a nocturnal lil*r. 15 ~ IOcontrol than the "'f'<hs Ilf'S.'""'; mosquito. riIidIl.'Il dol)' feeder ~nd eanies dengue lind yellow fever. ....., ~ns 011 "Indows and using IllO'o4uito IlC1ting in ";;'~ft very effoctile. eJiIllIll.1\1OIl of the "'"Of,~/f's mosquito. usually "'1IpPbcaI1On 0( in:.ticidc and destroymg its breeding _ It !he IIIO!it effective way to eliminate (as opposed to P8r:tljmabria. AttlIlo that I!a\c been succc<;s ful at elimmat,,~1II06QU1tOeS include North America. Europe. and .To do chi<.the adult female mosquito mUSt be killed. -' tftcdinl areas (Still water) tirJined. One of lhe most ~If lII'ticides has been DDT. Dr Paul Muller re~ tbI: 1948 Nobtl Prize In Mediciroc for discovering til [)OT llll~ the malariD -(:DITYlOg Alloplll'ff'S mosqu ito. OOT i\ long l:lSdng and. unfortunately. ~umulate., in the Willie being long lasting is beneficial from Ir d",\l'lInII of lIlCISquito COI'Itrot il also means thaI these -.1Io:tdn set 1010 the food cham and can affoo both anil!ulllllll$. Indeed. use of DDT has been banned in . . CIO(liw,lCIlly de,'eloped countries. Un fortunatdy. the _ lithe ..-nOd "here malana is endemIC are ecooomi~ poor .00 ('lUtII()I (a) afforo the newer imecllC ides. 1IIidt~ ~ rtapphcd because they degrOOe; (b) fund Wld ..... tbe mfmlrllctLlR: to eliminate btftding areas; and "",Ilk rnahal facilities. SUlIT. and drugs to treal their
"~fml 00 RUCIU$OOpiC T3hdl ~iR ..01rr IS ideal

283

becalJ~ of the increas.ng problem of ""sistarot'e to comlOOIlly

._.(1''
".w

....,

C1

used antimalarials. During lhe dc:cadc: 1968 to 1978. n10fe than 250.1XX> compounds were investigated liS pan of II U. S. Army rC5t'arch prognom.'u I><'panmcnt of Defense funding of Ihi' rocarch h:tS cofllinued. In addlllOlL to human imenenIlOO. there IS evidence fo..at least fi\c mutations in the human ~pecie~ thai provide pmtectioo a&ainst malaria. The.'ie predominate in populations who historically lived II1Id continue 10 li\-e in areas endemic with malaria. The fh'e mutations are siekllng disease (formerly siekle cell anemia), gluco),C6phosphnte de hydrogenase deficiency. hemoglobin C. various thalassem IllS. and Increased produclion of nilnc o~ide (NO). SieklJOg di'\eaSoe can be ratal to h<HIlOzyg<Mes. Hetero1.ygotes usually are a~ymptommic and show II 90% dec""asc in the chance of dying from P.!lIld/Hlflllll. II l-IomozYIlOlcS wilh hemoglobin C usually are asymptomatic . 11 Erythrocyte giLlCOle-6phosphate dehydrogt'nu.se derlCiency (actually. 10 to IS'Jo of nonnal uctivity in the ~rythrucyle) can CIlUse llemolytic anemia and prehepatie jaundice when the patient takes ccr tain drugs or is exposed to sollie vinal infeclion~. Iroo.caJly. SQtn(' of the antimalarial drugs must be used with caution in pmiems with erythrucyti c gl ucQSe6phosphnte dehydrogen ase deficieocy 10 minimize the risk of hemolytic anemia. The inc~a.o;ed levels of m.idi~ed glutathione in the erythrocytes that nre deficient In this enzyme may prevent the para site from maturing in the ery throcyte . The significance or thalassemia varies with lhe type of anemia and whether the patient is homozygous or hetcro~ygOtls . The IOOSl recent of lhe mutations to be identified i~ tbe ability of ccrtain populations to iocrell5C their productIOn or NO. The si te is in the promOler ~l!iOl1 of tbe gene for nitric oxide synthIL<>e 2. ",hich generates NO front arginine . and In,ohes II mutation ch.anging II cytosine res.due to Ihymine. The result is higher circulati ng Icvel ~ of NO. It i~ not tnown how inc~ased NO provides this protection. because there appc~ 10 be no sig,nirlCant difference between blood le\e.ls of the parasi te in indh'iduals wllh the mutation and those with nomtal" NO syntha'IC. The protection may be from ~'()mpl ication~ seen With malaria that give the fticnt's immune system time to respond to the parasite. '

om
.... lIIIlmalarial drugs must be developed corutantl y. be_it proIOJ!OII delelop re5.i!tance by a vJUiet) of mech.a (w:t dl'oCU< 1OIl~ of mechanisms with the different :.~i"~ of adverse rcut1ioos. and their ocIv~ tl i i , . I Fourdiffer oI"prnlO!Ol cause malJUia. and unfonunately. no
"llft'I1X'ndou~

M.I..".
Malaria is caused by foor species of a ooe-cell protowan of lbe Pirumo{/wlil genus:

need for effective antimalarial agents.

OF ANTIMALARIAL BY WAR
Wor II ). more than 15.1XX> suband screened as possible antinJ.IIlarA~~'~t . 8riuin. II . e.~a lly

".j,,/cip<l""": This .pedes is e.1"n~led 10 Cll.IIst Ipproxi mufely J, 0( all ma.lanl. 11 c""-SC's !he mo6t ,,"Val: f<;"nO 2nd !he 11><$ okbllnating fomo of 1M d,,..ue. beau!IC pMt~nlJi feel III betvo'een acute au.d.... One I'UKlII .. hy II !ales the ""timl 110 weak i. thlll I( inrl~ up 10 6S~ or,he p.1(ient"~ ef)'lhrocyl($. p. ,i.,,-!:: Thij speci...: i~ lhe: ~ I1IOSt C:OrlIInon spift. 1IecounllO, for aboot 4()ol. of IJI IIQ/aria Cln...:. It cln ~ very clomn ...... hrcau!IC 1I.:an rrinfn:1 I,,eo- CO'Ih.. P. "."/,,ritu: While c:au~IOI only 10% of III nmhona! ca.t'S. relapses are vcry common. P. "'"(11.. , ThiillpttlC! i& !he kim ~'O/IImon.
Figure 91 outlines the stages of the p:uasile after II IS in.ited into the victim and indicol~s when: tIrog theropy might be elTedive. The mosquito stores the sporozoile fOfTl1 of the proIw.1.Wl in its $a1ivary , lands.. Upon biting the patient . the spuroroite!l are injected into the patient"s blood.

284

Wi/JII<I <JruI GIJmid's T.... /booJ,;

11/ OrJltmh.

Mrdicil1l'i /lnd PklmtHIC..wtu111 CMmiJl",

FEMAU ANOPH ELES MOSQUITO

I I
d

"
I

J,

Figure 9- 1 StagE!S of the p;Mit!ilte Ihal causes malaria aflel" In)t1On InlO Its YlCbrn Sft. dl5USSIOO ,n the> tf~t 0 IndICates SIte of anllfnalallal drug actlOll III humans
m

.,

/'

14

,b
1 dC'a1ly. thi would be a 1.'<:IOd site for InICTYenlion. befon: the pal'a-~"e can Infcct the liver or erythrocyte. In the case of drullthernpy. people Ii vi ng in arcas endemic with malaria would need 10 be taking the drug constantly. Altllough Ihis \I'ould be fe:lSlble for people lh'ing tempor.uily in the'le :1Il::a.~. it i~ 001 prnchcal for residents. It i~ true thM antimalarial drug.!! could be formulated into nnpl~med dC'pot dosage forms, but these an:: expenSIve 300 oflen requIre Inuned medICal ptl'SOrlroel to implant lhe drug . A vaccine would be nn cxcellent way \<) intercept lhe newly inJCC1ed sporozoites. This would be IIlllIlogous 10 individuals \100 h,l\e been imrn uni~ed agamst murnpiS haVing the,r immune syslem Intercept the v,rus before il enlers target cdls. Unfonun3tely. with all of the effort being expended 1 de"elop a vaccme. no vaocine effecli"e in humans hM 0 been developed. Within minUle' after being injccled inlo the palient'li blood, the spOI"Ozolles begm emering hepatocytes ..... here they become primary schi7.Dn1li and \h(on merw.Olles. At this point. there III"C no symptom ... Deptnding on the ,'It..."",{/iuIII species. the meroloites either rupture the infected hep;.to c)'le$ and enler the s)S\C'mlC cireulatlon or infcct OIher h,'er cells. The laller proct'SS is ~n with f'. \;\Y~(. P. malarilll~. and P. ol'llit'. bul not ".f<l/df1(.,,~m. and produces ~or)(]ary '>(:hizonts. This secondary infection ofthe Ii"er can be very damaglllg and is one of the sitc~ for possible drug inle,"VC'nlion. Killing the secondary schilOllls would accomplish t ...o things: proteet lhe 1I,'er fmm funherdamage and eliminalc a I"CCn'oir of schilOlllll thaI can change 10 nlerol.oil('S and enter the sy<;tcrnic circulation. As the protoloun changes from spolo, zoile to Jehiront 10 merozoite$. illi immunological cnankter chango. lktemnnauon of lhe P/asmotllum genome 11M show n thai each foml of the p;arusne proUlICes I diffeml !;CI of proteins. Allhe same ti,ne. once the merol.oiles ha\~ left the hep:lIOC)1e and an: m the ')'lilemlC circulation. tbq IIf"C susceplible 10 anock by tM p;aticnt's ,mmune ~ providl.'d it has "leamed" tl, recogni/C thC' pam,ile. Thefe. fon:. anolher si te for vaccine dc\elopment is the ITIC'r'Illl* Mage. Dependmg on the P!.umodiulII species. a melUlOilr \3(:cinc mayor may nOl provide much prolcction 10 lhe li'a. bUI it C'ould \"CdllCc wb-.cque01 ;nf<'clion of the erylhllX)'I~ lo.1ero.zoites in ,y~lemic circlllauon now infect the erythroc)"te.<;.....here the) remle for J 10 4 day~ reproductncThe reproduction ,Iage in lhe erylhrocyte can prodll\:e eiil'lel mort: meroloites or another (01111. called glllll('IIK\'I"~, 'f1n, have different immuoolopcnl ,.."'e.. from tile forms. Either way, the ncwly formcd mcmZOUel> or gaJlll'lOq tc, bu .... t OUI of thc infec:tcd crythroC)tcs.lllC new mC'fWOo ites IIIfccl additional erythrocytes and oo.uinue the cycled reproducing. bursung out of the erythroc)'les. and info:aiDJ lIlore crythll)l.:ytcs. The dcbri, from llIe (kstroycd er)tJw. c)'tes is onc of the C:.Iuses o( severe fClcr and chIlls. Abo. the patient's immunc sySlem ... ,11 respond .... lIh repealed tl' PQ!iure 10 the par:!5ite, and this wi II C(lntribute 10 lhe p.'IlirOt'\ diS(.'Omfort. There an: four possible ~ites (Fig. 9-1) for druS thel~ at this S1age of the disease:

dil d,1

d i~

tid

""

gCI

lfiu A<

pal,e,.-,

rnai

,,'"

'tgl

inl

that

I'''. .

,,'"

IOOC

M.

S'OC

wor 'Urf '>illS tnm \C,h

OC\ c I' fa

111OM

l. Kill the 'JIOfW:oit('S inJ""~ by ~ nlOS(juul) and!QI" ~,~. <pOI'OI.OI1O from enl<:rrng \he li'~. 2. Kill tho: IICIr.L(onU midi", in hep:tlocyte;, mdlQI" ~,mI .... fmm becoming meruT,Qrles. 3. Kitl tM rn..,n)lQI~ in the blood ~ndI", prev.,nt ~nr from do& opo", ,nlO CafllC'lOC)\eI..

Th

0 '

110:

can enter the "I05qUIIO and -.:I/)IWS- Some tw.VC qucd II... !he f'XWo all ItuJ """*I bo ... w malt- l"""'IOC)'"- Th'" ..'wid bkd. It..
JZ7!En:)1e5

..,noc)1C:I ~f""" lI.. y

1X'"CIoptI"'" of V8C'CI ..... thai i!lillt'li..~1C' Of block !opeclfle nlottabolle $Ie"" ;n the pMlI~'1I: .tIer ;nfccunl hu.... ns

from matLnl,

merQlOltes re.~ults in male and female Ie> AIitr toteong the mosquito. they' male. pro. , ""OIe-. In tile mosquito stomach . The Jailer reside lilt "~1I0', stomach endolhelium oocyst~. e'"Cnlually. II!)o nu,r.IIle I, 'por(l1.oites to the JTIOSIjlli 10'S !!ali ~Ilr)' gland. the C)'cle begins aguin ,,'hen the mosquito bites a So, in effoct. there are two reservoi", or "eC'Iors for 'I thr lOOIiQUito thai infects humans and humans 11lere ha\ e been sonIC &nemptJ; al II Igo!nts thai ...ould be in the blood ~ drug\ would Slop funher in the mosquito and pn:~enl the beUtg t"lIrrier,

Thr

:l1'''mKlIl of

*'"

the human gCTlome ,

.,;" lD!Ja Lbe

nne

~:~:~~~:~::~~~ P.fll/dfNJ",m . ThisAfrica I mortali ty niles In resis~

DNA SIr.md. into l'maJler ;,;,~~;,;, make it easicr to iit'qUt'1lCe lhe nucleotraSsemblc them InIO chrolnosorrlC and (bJ il and had 10 be modined.'" are at least tWO goals in decodinG the p;amsite's 10 a pro:ill thaI i~ unique 10 PIII.lmai, 5I;'lcctivel y hlXic 10 lhe procolOiln. or antimnlmiul drugS. nil hal'e goal i_~ 10 understand lead to dmg resislance, Olle: of the increase in malaria siroce tile late 199O!< resistance to chloroquille:. an anumalarial

~Ilromosomal

;;'~''l"'"~ because (uJ II was ITI(lf'e

A .. mall neid trial of irradiated P. ja/Ci,NJ",m sporowitell produced 9O'J- protection for 10 months. In additioo to the fact thai p-la'IIl(ldia gQ through antigenic dumgcs, lilt pan_ si te is very polymorphic. lllCrt" is Il"al concern lhat a vaccine thaI did nOl include a spectrum of PlflSmodwm .. arillm_~ could cause deveiopnlCnt of p"l1Isi tcs of C"en grealer virulence. Polymorphi~m in lhe human Icukocyh~ anligen (li LA) system also muy be 3n obstacle 10 producing an effecti .. e vaccine. A pocential model for Ihis problem is the obscl"\'a lion that. T cdls. ine:luding the cytotoxic T lymphocytes. in p.1licnlli with HLA -835 do not respond 10 CC'lum strllins of the parasite. II appellrS Lhat the combm:llioo or ttrtllin pr0teins produced by PI(J$nwdium Str.llnS with HLA 8 35 pre. vents a normal T-cell respon~. In othcr ... OIs. the immulIe: system of the~ patients ....iII respond to SOOIt PuuMf/d",m strains and not OIhers. lliC implicalioo i~ thaI an effecti .. e vaccine will ha~e to be "cry polyvalent. That an I.'ffCClive vlICCmc:. even one: that only re.~ponds to CC'rtuin 1'/(1.'11101/111111 strllins. has not bl.'en developed h3~ heen puuling. in thm the: human immlllle: system does adapt wuh immunoglobulin-producing B cells and T cells Ihm re.~pond 10 prucesscd antigen. The in nate: ~ide of the immune: ~YMem also responds. In OIher words. the human immune system respood~ to the variOUS forms of the PlfU"rodium parasite: jus.! as it doCli 10 other par..sitell. It has been 5Uggt'l!ted that jus.! a~ the P/asmodimn gcnus has adapted to humans, humans ha,c adapted to the par:J,sl te. lliC livc hUIllllfl mutatl()tls nlCntioocd above: are one example:. lliCrc: may bI.' 0I1ler\. Proper nutnl,on is imporl3nt in 5Urvi~in, a malaria attack. l1Ie pallCnt must r.:p1ace the destroyed I.'rythrocytcs and. di"pen(hnG on the ~peclCS of PlfU"lOdillm, hep;atocytell. Th iS requires caloric:s from a high-tjuality diet thaI pro\'idc.~ e:~~n tial nutrient) includinG amioo acid~. lipids. and lruce mmer:.lIs. TIte !>e"crilY of malaria is grealest in the: an:as (If the world with malllOUriNhmc nl. poor Slill ilutioo. Iud: of infrllstructure 10 elillllnale the: mosquito breeding an:as. and l:rd. of drugs to tfCatlhc: sid . l1Ie World Health OrganiUlion's 2002 Warfl/ IIrallh Nrpon scored counlrics on lhe ba.~i~ of their lifcstylc:!!i and ~\'ailabilily of fC~n:c:s. PlOpcr food i~ one of tho;c; rc.'IOI.IIl.-cs. ll In other ...ortis. jUM lIS the p;athology of malaria IS complelO. so is 115 control and ' rt"3tmcnt.

of malaria..
DRUG THERAPY
Anlimabriul dru l:s (see Table: 91 on pagcs 296- 297) art" good e.\ llmplcs of m\liinf~"Cli~c agents with poor se lectivc tox icity. Contm~1 them wilh the amibiOlic~ (Chaptcr 10). Tetracyclincs. c hloramphenicol. and umit1()glycoside.~ OCt again~1 OOclCnal ribo!;iJ,ne<;. but not mammalian ones. l'c'll ci1lins and eydo<porines inhibit bactcrial CC'II wall cross linling . and nlammol s ha"e cell nlCmbr.mes. not ccli wall . TIIC nuomqumolones inhlbll bacterial ,yrase. but not nwnIl1:Ilian lopoisomc:nases. The biochemistry o f P(tlsmodillm spp. i< SImi lar to Ihat of nwnmals, making it dIffICult 10 design drugs thm will not affect the patient ad.ersc:ly. In dec-d. wmc: have. "",hcations bc.oyond 11l'311ng and JXl:"cmmg malaria.

acdnes

19SOs. there has becn a trcnlCndous effort

' I' - vaccine:s. largely ba.'o(!d on ~"CII ~poromites. nlCrol.oitCli, or schili DNA ll"Chmques to dcterarid 10 di rect !lICiT ~ynthc fOl.lndatiOIl of most of these $tudiC!i. M<)I;I "lCCine ,,-or!.; ..... ith rnalariu ha.~ IX:nle~ 00 btausc" il is the prinla\)' CIIU<;C: or malaria

of research iroclude
""'_~fif ~Ie-menuo"e VX'CI"" 10 bIOI'~ cl IIII..... cI;lhed~ a. iujant of SJKln,lWlII: 10 !.lop ,"fl,on ..-.J

"g(tlIe .. ~_

,'a<"CI"'"

CINCHONA ALKALOIDS

The d nchona tree produces four alkalOoids that .....en:. I.lmil

~cently. the prototypical mOolec ules on which mOost ~nlima

Inrial drugs wen: oosed. These 1IlklllOoids (Fig . 9-2) an: the enamiOomcric pili r quinine and quinidine ~(Id thcir desmethOx)' nnalogucs. cinchonidine (fur quininc) and cinchonine (for quinidine). (Unfonunatel)'. the nomc nclatu re rOf" the two series o f alkaloids is illOOllsi!aenl. ) Their numberin" system is oowl on moone. The Mereochemistry differs at positions 8 and 9. with quinine and cinchonidine being S.R and quini dine (ci nchonine) being R.S. Uistork1ll1y . quinine was the main tn'atmen! for malaria until the ad\'enl of World War 11. \\<hen hallie in Ilteas \\<herc malaria was endemic led tOo the search for more efTecth'e agents.

Quinine ~nd Qilinidine. Quinine has been used for " fen '"," in South Amcricw since lhe J600s. The pun: alkaloids quinine iUld cinchonine were isolaled in 1820. The Slcreoi !iOmcr. quinidine. i ~ a more potent antim~larial. but il

alw is more tOllie (less selectively toxic). Quinine iJ IetlIaI for all PllUmi.ldiu", schi7.onlS (si te 2 in Fig. 9- 1) and tile garoeiocylc:!l (site 4) from P. ";'W" and P. ffI(I/ariot! but OIX for P. /IIIdl'Uru", . Today. quinine' s specllum Oof aaivily ~ COllSidereIJ 100 Ilanow for prophylactic U:IC . n:lative 10 til! synthetic agents. The rntthan ism of oction is discmloCd undcr "Chloroquine pnd Chloroqui ne Phosphate ." The mechani sm of resi sIPoce 10 quinine is poorly undt'~tood InII varie s with the susceptibility of the parasite 10 other aminoquinoline antimalarial drup. Quinine still is indictled fir malaria caused by P. /(Jldporu", resistant 10 other qaIS il'lCluding chloroquine. Many times it is ildmini!acn:d in ro.bination .... ith llyri~lhamine and wlfadoxine . OOl)":)'tIiII:. or mdloquine. depending 011 the specific form of mQ-u and geographical localiOll. Cinchonis", is a toxic syndrome: . Symptoms stan ... tinnitus, headache. nausea, and disturbed vision. If Idnu.. tnnion is not stopped. c inchonis m can proceed to invo!.!. ment orlheg3SI rointe.~linal tntC1. nervous and cartliovasaU systems. aOO the skin. Quinine allIO is indicated (or nocturnal leg cramps. t.

, ,

I , , , ,

i:

HOt"""

"v""""-N / '
Ouinine A DCIi,

I
Oulnlcine A DCIi, Clnch ...lIne R H

Fig ure 9- 2 Ctodlona alkalotds

Cinchonidine A H

ChMpier 9 ItnriMalnriaLf

287

. .""
.",

..... .,"'"

over the lack of plOper studies prov-

as with quinine, both isomers are act;\"c. and the 4-arrllrl()oquinoline I1ICC.nllC mixlUf'C\ an: used. For the 11C""CSI dru, in this series. menoquine. only tbt N,S iSOllk'T is marketed.
A significlUll difference from tnc commercial cinchona alkaloids is rcpladng the 6'-mcthol.y on quinine with 11 7<hloro substituent on three of lhe4 aminoquiooJincs. Amodiaquine is no longer usc:U in the Un ited SUIU:S.. aoo sontoquine luis fallen into disuse.

" ...

,,. ""

but its pri arrhythmias. It is I fOOd example i because it provides a speclrlnll. Qu inidine

,,~

If..
Chloroquine and Chloroquine Phosphate. ChIOfoqu inc (Aralcn II CI) can be considered the prototypical
I

~ tine.

on
III

the wne

or the anI; This group i as quinine: and has an to quin ine' 5 e9 posi tioo. Just

structure thai succeeded quinine and came into use In the mid- I940s. The phosphate $alt (ATlIlen Pho$phale) is used in or-II dosage forms (tablets). and tnc hydrochloride Mill is adminiSlcn:d part'RlcraJly. Until n'O.'Dlly. chloroquiDt ~'as

..
o

'"

""

"'" "'"
"
Melloquine

'"

Sonloquine

flgure 9- J 4A,rmnoqulOOlines.

the maIn antimalarial drug used IxMh for prop/lylalis and treatment. Notc thm the li ~t of indic:uions for many of the OIher drugs in thi~ chaplt'f includes Plwlllodium spp, re.~is tam 10 chloroquine, It l~ indicaled for P. "il'/I,(. P. mi,/tlrilll". P. omit, and su<;cepuble ~t rnins Qf 1'. /ulc'l>(m'lII. 0110ltXjui~ btloog5 10 the 4-aminoqlllnolinc senes. of .. hiI'll hu~ have been e,aluated. but only aboul duee (II' f(lUr are still in use. Even though thIS drug has been used for numy )I':II'S. illl mechanism of action i\ qill not Io.;IIO\Io'n. Its ma in ~Ile :tClion appears 10 inv ol ~1' lhe lyllOsomc of lhe parJsile-infl'cloo crylhrocyte . The fo llo .. ing action_ ha,'c bel'll suggeMed on the basis of e~perimcmal el'idenee. A very compln IllCchanism is based on fcmproloporph)'Tin IX ... hith i~ released by I'lllSmodi..",-containing er)"throcyte.~. acting as a chloltXjuine rea:ptor. n.e combill<'ltion offemprutoporphynn IX and chloroqull"le causes lySIS of the par.l~lle~ and/or the erythrocyte's mcmbrnnc . ....inally. there is evidence lhat chloroquine: may IntenCY\! ""ith 1'IIIslllotlwm'~ abIlity to digest lhe el)throcyle hemoglobm or lhe parusl te'~ nucleoprolcin synthesis. The mech:lni~m i, based on lhe drug enleringthe erythrocyle'~ lysosol11e, which hIlS an acid en~il'OnmC nl , .. here il becomes protonau:d. The protonaled (posith'ely charged) chloroqu ioe now is trapped insIde the Iy~ because the pore: mal leads out of the ly!iOSOlne abo is pasi ti~ely charged. ThIs Ie;nes chloroqu ine bound to the pattcnt's he~'obln, prelcnung the pan"'tI: from puxessing it properly.} In gcneml. chloroqUIne ~nd the Oilier 4-anlllloquinolines are lIot crfel'ti vc nguill'l e~<xrylhrocyllc parn~ites. Note Ihlll each of the IlIcchanisnt~ requires thlll the pal1lsiu: be in~idc the erythmcyte,1l1erefore. chloroquine doc~ 001 prelent rela~ of p. dlY~' or P. omle malaria. The drug al'oO is indicated for the U'l:atnw:nt of e.ttraintestin.aJ allw:biIlS1S . Effecli,'e as chloroquine has !xcn. 1\ IS poor e.tQmple of selective tolici ty, Ad'-e:rse reactlOllS i~lude retinopathy. hemolySIS in pahellIs wilh glu00se-6-poIlol'phale dehydrogen. a~ deficiency (same mutation thaI COIIfelll I'l:M"antc: agai nst malaria). muscu lar weakne~s, e~acerbati(Jn of psoriasis and porphyria. and iml)aired IiI er function. Further examples of poor sdecuvc toxiclly include off label indiealions such as rheumatoid urthri lis, ~y~lemie and discoid lupus erythematosus (p!h~Ibly as an ImmUllO!OUppressant), ~nd a "lIrtcty of dermatologICal roodl tions. If the increase m resl<;taocc: to ch loroqume continues. this "reliable" antunalanal drug may no longer he lhe mainstay of malaria trelllmenl. n.e increase in I'.jllici/Xlnlm resi~tanl to chloroquine is consiocred one of the mam reao;ons for the illC1'l:a.cs in both indocncc and deaths from malnria. Remember thai chloroqullle I\'sistance i ~ II :'Cellt phenomenon Ihal becan"le Mgnificanl III the mid- I99!k. 11M: key I'llU/IIodiwn geoe thai confe ..... resistance appea~ to be lhe p/c,., gt"Oe, ",hich codes for transporter protem. ~ Il!.w lt of the changes in the gene is lhal the pore: through .. h,clt chloltXjuine might eJlit lhe Iysosonw: no longer is po.<>iliw ly charged. allowlllg protonalOO chloroquine to e.ti t the IysoMlIl1C ,J) AI lea,t eight mutations ha,'c been id.::nlificd in the flfc,., gene:, and it i~ pastulat~'d Ihw reSi'ID IlCe IXCUIll because of an act'Umu latlon of the..e mutations. Chloroquine n:main ~ effect;"e when there are fcwer mutlltiQll~ III the pfc,., gene. Ooce the cri\;C1l\ numbef of muwlons Ot;:cuned. the para-

.. lte spreads o"cr a broad gcogrnpllleal nn:a, rendenng dtklItXjUIIIC Ine frective .H - "

or

Hydroxych/oroquine, In IIlCKt ways. hydroxyehlor oqull'le ( l'lnqutenl!) paf'JllcI~ chloroquine. SttuC'turall y, it diffeN solely in having II hydroxy moicty on one ofthc NoC'III)i gJ'OUplIo. ulo.e: chloroquine, il renw~ in the body for Ovtrl month. and piOpnylaetic: dosing is once .. eelo.;ly. n.e othef 1Il(lIcntions, both FDA approved and orf-Iabel. aIt very " .. liar. Amodiaquine. Amooiaqulllc i~ 10sted in USP25 (20021 bUI is not covered in the USP-DI for Health I'rofcsskm.l~ nor i~ it on the list of antimalanal drugs I'CCOnllnenckd b)the Cent"-rs ror Disease Control and l'revenlion. MI'Ch;iplSlically, it i~ very similar to chloroqUIne and doc:s not 1ta,"C-> advantages o\er lhe other 4-anllnoqulIloline drugs. Wia used for prophyla;cis 0( malaria, It was associated V.lth I higher Incidence of hepallll~ and agr~nuhxylosis than 'II. chl()l"'O:X{ullle. 1l1en: is evidence: Ihat the. hydl'Olluill(W (phenol) amine: ~ystem readily o~idiJes to a quinone-imIne: (FiG. 9-3). antioxid.ltivcly ulllIIor IIlCtaoolitall y, and tha product may eontribuh.' to arnooilKluine loxicity , 1lte q..... noot:. imi ne system is 51milar to lhe acetaminopllcn to~1C mtlabo"te (Chapt~ 4 and 22), Mef/oquiM Hel. The nc ..est of the 4_aminoqulllolillt\. nw:f'loquIIW: (Lariam), is marlo.eted as the N.S isomer. It to. deveklp..'iJ in the 1960s a~ part "rthe U. S. Anny'$ Waller Reed Institute for Medical Research antimalarial ~ri progrum. It differs significant ly from the other agents in 11m cht."s hy hal ing two trinuoromcthyl moieti es. at posihon~ r and R'. and no eiectronl'gative ~ub"'lIuent~ at either poIIltlDl 6' (qumine) or 7' (chloroqUIne). Mefloqulne: al() differs r... chloroqu ine and il5 analogues by beIng a schiJootieidc 1_ 2 III Fig. 9 1), acting before the pantSllean entertheCl)~ c) te. Some: evidence indicates that;1 acts by raising the pH. the paf'J$i te:'~ vc:sic~. imenenn, WIth its abihty tQ ~ heme. Menoquine-resistant $trui n< of fa!ri/Hlrom haw uppcared, Rclup!oe can occur wllh acUle P. l'il'lU thai !ta. !xcn treated with !1)cnoquinc, because the druG ~ Id elimi nate tl"le hepatic phase: of Ihi~ species... hich eM rmfI'Ctlhe livcr. Mefloqu lllc IS termogenic 111 f'JI~. miet'. and mbbil5. lln i, an FOA-requlll~d WarIllllg thaI Ihis drug can eucerblw mental dlsortiers. and it is comralndlCllted in pattents ..... acuI'e depres.~ion, a ~enl hblory of depres!iion. generaIiltIII an~ iet y dl~. psYChosIS, sc hlwplil\'nia, and other ~ l)ll)~'hi atri c disorders or a hi~tory of con\'u lsion<.

r,

8-Amlfl.qulnollnes
The othe,. major
~roup

na.s

of ant imalarial drugs ~ 011 clIlchona allaloid quinoline: moiety is the suMiitutcd .. aminoqulnolincs (Fig, 94), The fiNl'Olnpound inlm ...." on thl ~ 5c:nes "'<IS pamllqUine_ During World War II. ~ laquine. i<;OJlCntaquine. and prunaquine bec1Imc DI1libbic. Only prmt.aquine:, used during the Korean War. IS In '1111k usc tod~y. AII of the 8-nminoquinolhlCS can cause h.emol)U: anemiu in erythrocytic glucosc:6-pho'<phatc ao;e-dc lkient paticnts. A<; poonted OUt aOO'e. moo gellCtic Imil foond in popuiatiCN1S Ih'ing in art c. demle ".,1\1\ malaria, and 1\ \lfO'ides some resi\allC( 10

PenlaqUine

IlleChanism of actIOn and sp-uum of IICtlyity ~~ ."", "J>n maqume. fn, \ZlollIOnS lire 1011 in the Mruclure- IICI iyny relalion .!CTle!i. All four agents in Figure 9-4 lla ye a 6 h~e qumine. but lhe Sub~lilucnL~ 011 qu innII rather Lhan carbon-4 as found ~nts in thi~ series ha~ a " 01" bridge ~I\Ii't('fl t he two \II 1!It the UctpllOl1 pcntaquine. the OIller thret' M\C QIIC asy mmctnc carbon, While III the metabolism of t3(:h s tCreQl.;o.. .;~: oradl'co;e re.~ponsc. lhere I~ IrUle difference ~ IlClility ba:.ed un the compounds' Slcreochc l1t
(is

Although structul1IlIy relilled to the c inchona a lkaloid.~. the S-aminoquinolincs have a different mechani sm of action. PTimlKluine appe:lflI; to d i ~rupt the parn.~ites mill)Chondria. The resuh i, di sruption of ~yeml proce.~o;e~. inc luding matu ronion IntO the sub!.equent forms. An u(h anl uge is dei.troyi ng uoerylhrocylk forms before lhe parasite can infect el) thmcyll:i. the step m the mfectious process thaI males malana so debilitali ng ,

Fixed COZiLbina tioftS

Because re~htance i~ a frequt m problem III the prophy la~i~ and treatlllC'nt uf rmllari a, combi nanon therupie~ that usc two

Pnnlaquinc is the only 8-aminoquUloline u'ot for the trealment of malaria. It IS 1101 used "", Ituptcll urn of 3(:tivity is one orthe narrow turmltly u!ord anlunalarial drugs; il is mdkaltd p, O il"llf malaria (site 2 in Fig. 9. donI'. c hloroquine or a dnr i: 1 nl P. d\'a.' is u.\Cd willi pri '

~:~~,~,~p,ipro\ed I

indicm ion. omIt' and of 1'. it also

i~

1nl,"lflIto I the mosqUitO carner. 0;00 ~tudlC:~ indicate tMllhe Slereochem istry r;aJbon is 1101 illlport~nt for nn timnlarral to be lc>.S to~icily ... illl the levOl'Ol~ ISdose dependent and may nOl be thm lreal uocrythrocylic f'. 1 ;I'Il.<

Pyrimalh&mlne

...

f igure 9- 5 Sulf;tdolcHle iIr"Id pynnwlh.JmrnE'

distinctly diffell;!l1l mechanj ~nlS have been developed . One combinauon inhibits folic acid biosynthes is lind dihydrofoInle reducta'le; the OIher t'Ombill3lion iIl'IS on the par.lsi tc's mitochondria and 11$ dihydrofolate reductase.

mldlnWlDmine si milar to lrimclhopfim (S Chapler 8). "., combination is oonsidcred schiwllI icid:t1 {~i le 2 in Fig. 9-1 ~ TIle SlJl fotlul11 idc. sulfa(loxirl(', interferes wilh the parasite',

ability \0 s)'mhesizc folic acid. and the pyrimidinrol3111ine. pyrimethamine. inhibits the re<!U<.,ion of folic add to us 1(.
li,'c \clrahydrofol;uc coen~ymc form (Fig. 9-6), SutfORamides block the incorpor.uion of p-aminobenwic kid C BA ) \0 (onn dib) drop4croic acid. Note the 5ttuclum Ii PA

SulfiJdoJcine and Pyrimertklmine. The: oolllbin:nion of sulfadtuillC aOO pynmethamine (Fan\ idar) (Fig. 9-S) uses a drug from the ~ulronamidc antibacterilll VOUP and II pyri~

GUlnoline

S8'.'erallteps
Si~

of~"lflllk:fM

..., L I ,
Oihydoolulatl Redt.!d"1 (DHFRI

1...

o
, "",./,:,

,....ctI:I~.....- {

,,,)l,,,,
Figurl! 9- 6 S!I~ where wlfadoxtne afld pyometharnotle ontulltl foole metabolrsm

,,.1 ,

'---'

TeU1Ihydodulk: ACId (FAH. )

Chapler' An"m(luma/~

291

>--4'- 0

I II ,

./'0''___

ThymidyIate Synthase

5'-Monophosphale; dUMP
~"-CHrA1o

Thymidine S'-Monophosphate , TMP; dTMP

,",

'

O,llydrololata

AedlJctase

- -/

FH,. Oihydrolola\e: FH,. Tetrahydrofolale

figurl! 9-1 Thymdylilte
~I~

and tetr,lllydrofol!c acid; " ABA IS the d die folate structure. Normally. su lronam,des ~1C1:u\'e IOx iclty ~ausc humulls do nOl IIle vitamin folk acid. Never1~le". then: are fatal OCCUITCIlCeS of erythema mulli syndrome. !Oxic epidennul ro.ecrosocknm; ~yndrome!; altribulallo the sulfa1950s. mh,blls the readd \0 the 8Cl1ve ICU'lIo-

".,.

..

".

,
enough II1II dtlIydrofoiale m!OCUI5e found in mammaiJllI1. plaSmodial cells thaI folate reductase mhlbuOl'S thal $how reasonabk scl'li\c IOxlClty. intimate relationship bet ....ccn I I \, c:m mhibit both enzymes. i~ ,ooicaled for prophyl axi~ and treat~

j""

qui~llIe.

:~i::;::'.::'~;,:~r:~~~

rombtnalion is !let;'"C against allille asexual Ii:JnM. It has no activity against the sexual gaTht fi~ed combination contains 500 mc of I . A wide number in combinmion with pyri is \0 use a sulfonliinidc thaI like those of the dihydrofothi s combination. the p!'ak

c,P roguanil
FIgure 9- 8 Atovaql.lQ!1f! arid pfoguanll.

plasma sulfadoJ(lr-.e CQfI(;t:nlr.lUOO occurs m 2.5 106 hoors. and In., ptal plasma pynmelllamlllc concc:ntralioo occurs in 1.5 to 8 huur;. Re~i'lOncc lias dcveloped, much of II involv 1118 mUUluons in eilher or both of the gcnc~ codlllg for dihy. drofoolate redlK'laK and Ihymld),lale ~ynlhase.
Atovolquone olnd Proguolnll Hel. Alovaquonc and proguaml Ilel (I- g. 98) are adminiSlcred m combmalloo l (Malaroncl in an alm'lllquO!leto-progu3nil HO mhO of 2.5:1. mea.ured in m,lhgrams (nOi mlllilnok- s). Proguanil. devclop..'<1 in 1945. i~ an carly e~ alllple or a prOOru,. It is II>elaboli zed 10 cyc10guani l (Fig. 99). primarily by CVP 2C19. 'The polymorphic nature of Ih,s hepatic en1.)'n>e explains IIohy ccmlln wbpopulaliOlls do IlOIrespond 10 proguanil: they canllOl conven pmguanil to the active cyclogu anil. 'The !);&s's for thl~ comb,nlluon i, tllo O dlSlinct aod unre la.ed mechanisms of aclion agam,1 lhe palllsitc. AlOvaqUOflC is 1I -.elox:.;vc inh ibitor of the "/"""Q</i"",', mi tochondrial ckct ron tnnsport sySlcm. and cycJoguaml .s II dihydrofolate rWlK"IaSe mhibilor. Ato.-aquoncs chcnll~ry i, ba!lCd on il

being a naphlhoqumone ,hat pan,cipalcs III OX.idall00-rtdu.::.ion reoctioos as pan of i\!i qUlllone-hydroquinolll! S}l" tem. Ii is J);llIemcd afrcr coenzyme Q. found in milochOndnai elCl.1ron transport chail1$. 'The drug selectlvcly In.erftn$ ""111'1 mJlochondnal ekctmn tran\{lO'1, particularl y al tJy parmi!e', cytochrome oc, ~lIe . Thi~ dcpn.cs the ctll of needed ATP and could CIlIISC il 10 becol1\e anaerobic. Resll lance 10 Ihis drug COIllCS from a muulliOli In the pat1ISllt'J cytocltromc. Cycloguanll (proguanil ) inlerferes wilh deox ythymid)'la1t s),nthesis by inhibiting dihydrofolatc rcdu.::lu.se (S Fil:. 9~ and the pyrimcthanulIC discu...ion). Rcs.Slancc to proguaniY cycloguanll is aunbuted to ammo acid changt'5 neat" In., di~" drofolalc n.'duc"sc bmding ~. te. Its eliminat iOll halrlife 148 1072 houN) i~ much sOOrtcr than Ihal ortlle otller antilUala- jal dihydrofolate rcduda.'ie. pyrimethamir-.e (mean ehmn. !10ll hal flife of II I hours). "The combmal'oo is effe<1iw ilgainst both cl)lhrocy tic and ex.oerylhroc)!ic PhlSm~ldfl/J/l Thb drug combination i_ indicaled for malaria resislU!~ 10 chloroqu ine. halofantnnc. menoqUlnc,:md anioOdiaqulIlC I~ main slIe is the spo!"Oloi lc stage hlle I in Fig. 9-1).

101
CW2C19

0'-

Prot;p.ianl (Chloo~ Ode)

"
0

0-'

I"

,
/ '

"")~-,

;,=-

""

;,0-1
~.

1-'\_H/H H1H

I"

Taub"eric Ihifta

,- ,;'

Figure 9-9 Con'o't'fSlOll 01 proguatlll to

2C19

by CVP

fig

Chal'tt r 9 .... flli_lu, iDI.

293

I- n:-

, ... <,d'c .. .._ ..... -.

Dr

sy\,

mal
-feres

nne anti malarial dnlgs have polycyclic ring systems (Fig.

9-10) in rommon. TIle first ;s the COITIIOOII tetracycline anti-.oc, doxycycline. 1lIe stc:OfId is ooe or the ne .....er drugs .ticated for nlillaria. h.rolofantrine. The third is the: discontinwd agent uscd in the South P'~dfic. aminoocridine .

: 11 of kqs Sl te ' s
jylale

,,'"

g. 96
uamV
tlohy(e (48

nalar-

Ooqcydin.. Like the other tetfal:yclines. doxycycline .rubilllthe pathogen' s protein synthesis by reversibly inhibimg !he 30S ribosomal subunit. Bacterial nnd pla~modial ,iboIomaI subunits differ signifICantly from mnmmalian ri'Momes. and this group or anlibiolics does not bind to mam &lIiln ribo5omc:s readily and thus.'lhows good sclective toxi:~y. Allhough doxycydi ne is a good antibacterial. ils usc

for malaria is limiled 10 prophylaxill against strJ.ins of P. JalcifHlrum resistant 10 chloroquine !ll1d sulfado:tine- pyrirnelhami ne . This use noonaHy should not e:tcecd 4 months. Because lhe tetracyclines chelate calcium. they can interfere with de"elopment of the jlCitllllnent te.!th In children. 'Thc:refore. their \I..'it in childrm definitely should be shof1 lerm. Also. telmcycline photosensitivity must be kept in mind. panicu larly since areas where malaria is endemic al'iO are the areas with the greatest sunlight

Halofantrine. S\I\IC\IlrJJly. halofamrine (Halfan ) dif fen from all other antimalarial dru gll. II is II good example of drug desi;n thai incorporates blOisosteric principles. as evidenced by lhe trinuoroethyl moiety. HalofantrillC is schi"(

.ai"". .
.anI 10

mmaecl1"e

nt. It.'>

OH

"....CHZ "....CH1 CHa 'CH:a "....CH:a "....N....... "....CH, "....CH:a CM .... CH, CH,: .... CH,

a
Halorantrino

L
M,

..... ",......-

/CHa

'cH1

"....CH:a

....

j.
CH,

/CH:a cr 'CH,

",co

..-A

I
yCyp
figuf' 9- 10 Po/ycydi(: anllflWll;wial drugs.

.... CHI

"""""'" HCI

ontlcidal (Silell I and 2 in H,. 9~1) and has no cffect 011 the spon)l.()ite, gamcwcytc. Of' hep-'lK: stagCli. The parenl eompound and the N-dc!.butyl rncl:lbolilc are equally octi'-e In vitm. UaIoflllltrine' s .nedQn.snI of action again ... the parasite is not tnown. Thc':re is contradiCtory e\ idcllCe Ihm its mechanism r~nges from requiring heme to tJisrupling the lIIitochoncJria. A pronlllltnt ,,-armng cautions th:Jlltalofan tnnc can affect r\er\'e COfKlUCIIOll in c;lrtliac tissuc. Quinacrine Hel. Qumacnne is 00 Iooger available in the Uni ted States. II "'". be con ~idcrcd onc ofl he nKl'it toxic of tlw:l antimalarial drugs, even though. at one tirlll'. ;t was WIllmonly used . II actS 3t many ~ites within the cell. ,ncluding illlercalation of DNA str.lIItJs. succinic dehydroj;cna..c. mitochondrial elttlrolltransport. and dlolint:'S!erase. It may be lumorigemc and mutagenIc and has been used as II sclerosing agent. 1kc8usc it is an 1I,:ridme dye. quinacrine can cause yellow dIscoloration of tile sk.n and unne.

New AntillUllarbtl D"'9s Artemisinln. Drugs in the arlcmisinin series (Fig. 9_11) are tile newelit of the antirn;&13rial drug~ and an: suueturallr unique. compared with the cO/npoun(h m cUlTCnt use. 1b: pan::m compound. al1cmisin;n. is a llatunll product I.'Jltral:ted from the dry lea\~ o f A.n~misia allnuu h"-a:t ..... ormwoodl. llIe plant l11u~t be grown cach year from seed because matun:: planlS may lack the act;\'Cdrug. The growing condition> an: cntlCal to nU'unll7,e arlemlsimn yIeld. Thus far. the bc>t yield~ have been OOoil1<.. (mrn pl ums grow n in North Vit!'(1 nam. Chongqing n::gion in China. Ilnd Tanzania. 'I> All of the Struc1Un:.~ in Figure 9- I I are lIC1ive against tbr Pftm,rodimor gC1IC11I thot cuu<;e rni,luria. 111c kcy structun: characteristic appears to be 3 "\n OX3ne" consi'll1ng of thr enc.lopcro:udc and dollepm oxygcns. Th,s IS shown by the SOI1lCWhili si Il1pkr !>Cri es of J-aryhrioxanc.~ :It the bottom 0( Figure 911, "hieh an:: lIeU\'e agllln).! tile p;tra~ile. NOIe ilia the stereochemIstry at llO"illOll 12,~ nOl cn lleal. l1 Wlilk ~
F;9~

r
.'""
Oih)'d..,.neo Iish"

,!

' r
"
,~

"
,

........ ~ . (oiIlOkbIttl R CHl Mellood (oiI.oIub/II1 R alPl

-"-.0",. (wa* ......,

,3

....,

:<

'" I

\"'7."~

f igure 9-11 Artemis.ni1laod ..

I~

s;".p;fIed Af)fl~ R F or-C()()H

, ompouncb.

fRiOOCIHI

lhe victim's eryillrocyle, the malnria ""rnsite eoo.u ,nes the hemoglobin COIlisting 0{ fmulls (Fe~ 1) iron. coo"crhng it to toxic hemahn oontaining feme (Fe' l) iron. then rcduer:d 10 heme wilt. its ferrous iron. The heme iron rc~t~ willi the trW.\ane I11(lM:ly, n:leasinll n:acti,e oxygen and eurbon rnd ieals and tile higllly reactive Fe'v - 0 spt.~les. The laner is pQ"tulaltd 10 be lethal to the parasile..llI.)9 Wilt. the reduction of ancmisinlll to dihydru:menllsmin, no a~yrnl1letric cllfbon forms. and it b possible to form oil!IOluble and water-soluble prodrup, 8 0eh stereoisomer'S are acth'C,JUSl as wllh the sim pler aryllrwxancs, The chemistry fonning each of the ancrnisinin prodrugs n:suhs in the predominance of one isomer. The /J isomer predOminates ... hen producfllg the noropolar mcthyl and ethyl ethers, when:a~ the lr isomcr is Ihe predominant prodUCI when fl)llll;ng the ... alef-lIoQluble herni5UCCmale ester, The latter can be administered as 10-mg rectal capsules for p.1lents who cannot lAke medication ornl1y and ... hen parcmer.ll tn:a"r",'nl is flOC a~ai l IIble . Fosmldomycin (Fig. 9- 12) ns ,solaled from II SIf"f'P'QI""UJ femlCmallOll broIh in 1980. lis

' - U . foI,rndcmycln and a fosmldo!nyCln analogue.

Fosmidomycin.

OOXP $yn\hQe

'6> '

"J-OH 0 ,J-o-L"" L
l~xykhe ~

(OOXP)

_ -----.......

H,C--o~

, 1,_
I

J H,C-""

HO-~"

~CH1-o-$P-OH

II

" ...."

Figure 9- 13 No!lmt\lak!nilte

TAllE 9- ' -Co"tI,,~

... ..

D<King RaI, 11 11 for T... tmentiInCI

Ot ..... ,nd IQUons

I'rup/Iyb,,~ ond .....a ........ '" ~hJon"ll""" ... ,n.uont

l'rophyl. .ls of Millilria

EIctI lablcC <,UM ..... $00 ..... <ulflldoJ;,nc and ~~ n\l pynme,ham,.. PmpII}'I,,,... u...ln 1-2<l11~. pno< port .... antl fat ' 6 ",1..0 after Clltld,... , 'I, 10 I 'l, tabktI bavd

1'. /ak'I"'''''''

10 ....

Adwu,

""..,_ . -'" _U,

admo ... ....-..cI ~ or ... oce

1-2~onOt ..,,"

'"""d..., ro'''"'

_.
l'rophyLv. I' and ....","',.. qf P. /uk'I"''''''' ~'''''n' WI 0Iki 11'11"",,1l1l'i01 <!ru

TIO,' KlJr>r(IuJth.... '1,102 rabIm booed,. . . doari .. _

...

_ .
C

T_ _ " ... rMh.lh 2-)!abIou

1Iun ..... .....,k Adult ,abln: llO ma MO>'lIqIOOnl'

ond l DO ..... profu ..... 1
PnlJuJ,i~ tulXn 6l.~

"'I

at<>< """""" IOId

,......",

:u "'I

..

,. 14.. .. 'k"n 1-2"'Y' prior 10 *1*'''"' ond "II., ...... rat 7 cb)''lfIcr n:t\IOlI
Oi

,~betuI

.or,"

AJ./u: I

.'""

-"'II< douJy olow 1M.......

1)~IIIbIm ..

-.to

""*' ",Iy

r . - TIIl.. . . . "nlkoboo

ror ~ _ _ "'oIa)"

auld"", 1-1 pNi"''''' IINtu II

lind< Jajly ....... b.allild 0.

... dlh,
Adult>: rI ",bk1i ... dally olow for ) _>:\Ill", do)"

"""iiI<

""""'1W... .,101bI I' PIt"'1""""''''';M INMII'II I<>chklruqll,.-.I .... If_line--..,.nmnIIaniJoo

6 ... .... IIl ItJgn,; 1

Plop/,,.....;,. Oily t:o.v-III

4.....eU.,la,,,,, .. .a.
............ -....11 .... ." 1
...".,...4".......

1-2 doY' btf.... 1n...1 ..... (or

0-101 .... 2 . . P''''''Y up 10 IOO-cAloy

,....."" l00 . . ~ob'11

TtnI ...... ' of P. /ak.".,rw.

on.,! 1' " ....

1' .....

,..."" $00

J "-' II JOO mil. fC'I'I'IIIIXI

"'I CY<t)' 10 ....... ""

7 do,.. 1lIn"
Ch,/i/r,m ~*17~ nil ""oN "" """1 ... '1.... r(>I~' .. ,he ~uk .. """II<
"""""'" ~(fIJ'~ lPlII>I oil

).a.""

...,,,,
do),
t

'I ~

---"

1!-druI

M.......... uopt<:ifJ

,-

PIiu...oo.- ....<iu ,,",Iudi,,, P. /tIkiP<>-- ItId

>!X'<it~_

N"""

Not ).upirocd

1'''',",+

"of....1 IUIImb

<iC1ect1'e IOJUCHy is based on inhibiTing a biochemical palhway !lOt foond lA humans and mammaJ in gencllll-the noomcvalonmc PJlhway to (oem isoprenoids. Mammals, including human~, foem their isoprenoids solely by lhe IlICVIIIonic acid path ..... ay. Many microorganisms ha~ both pathways. Whereas the I11eVIlIQnaIe pathway starts with three molecu les of l\Cdyl -CoA fonning J -hydroxy-3-rn<:tlly lgJuwryl COCnl.}1l1C A ( HM G-CoA) followed by redllCtion 10 me\alook acid by HMG-CoA reductase (site of the 5111t;n drugs). lhe nonme\alonale palh .... ay ill carbohydrotc based (Fig. 9- 1J). Coridensauoo of pyruvate Ilfld glyceroldchydc J-phosphme by l -dcoXY-IHylulosc-5-pltosph ale (OOXP) synlhase prod~ lhe five carbon OOXI'. which undergoes I complex rrtluC1ion and l.somcriZltion to form 2C-mclhylo-er}"thrilOl-4-phosphatc, The enlyme for this reaction. [>OX!' redUC1oi504llCr:lSC. is inhibi ted by fosmidomydn. 1be basic fi\e-carbon iSQpo: oc unit. isopcmcny l dipho~phale. concludc~ the paih ..,.y. The alonls Im\e been numbcR:d 10 help follow the lsomerllalion of lhedeoxy-xylulose intermediate to form the erythritol compoond. The malarial parasite only has the nonlllCvalnnate palhway. and initial ~ tudies show tllal fosrn idornycin is re lllli\'ely 1IOIII I,Ixic ill hUlllans. 40 KcplacelllC'nt offosmldOl11ycm's N-aldeh>de with an acetate prodocesA very acthe IUItlmalariaJ agentlhat hM beendesignaled FR9(K)()98." 1 A~ thb cnapler .. cm to PfC:Io.~. fosmidomyci n and pnalogues were in phase I nn~J II lrillis.

11 HoIf-.S L S< .. ,... :!90-I~.:!OOO . 12. ~ ....... r.. ScIcooce 29.t t.19. :!(lO1 Il. lIobI. hi R. UdlI>y.lu" ..... V . Lo'""'1"". hi C....... 1 ...,.,...l6O: 1468. :!OOl. I. ENm ..... M ~ ond Pmn,,,. 1' ; Seicn<e :!9$;:!O"/. 2002. _ I!I M:olw:f.1I ... . Scoenu>I 1621. 2002. 16. PI:ooni$O. E. Se ..... m .ll. 2002.

11. ~.M F ft:d N~J)2:S8.IY8II. _ 18 Co. I' I' 0 . 1'1""", lll:101. 1988. ~ 19 Cmo.. U till Scoeoce 2010:10:16. 191!11. 10. S'"~ fl.. .. III~ lJ6 m. 19U 21. o.m.... J SC..... 247-Mll.1990. 12. V ....... J F . 01". Mom>b. f'IIh<>ll;2Jl. 1987 II Sadalr. J C ..... oL; Scicnte !oI()-.l.l6, 1988

N."""

24. Cri_ i . ..... 01 III. : Sc"'11(>:240:1}24. 1'18.

~. ~.

2ft. 21. 18. 29

.100.
.I I 32.
33. J.i
,~.

D C_ ..... Naruro HH 19" II~ ..- . L , ., I.anI 1:371. 1987 IIoff....... S t- .....: N I' ..... JMed.)U:toJI.I98&. II ....... 0 V. Mtd. 1. ....... 1+1703. 1986. I. Para,,101 T,o.IIy I:JI. 19II!I M..... 1. L.; Sc"""", 2~601. 1984 1.Qna. C.......... Hoff_. S. L: Sc.c1lC"C 297;)45. 2OOl. ..... 00d Hath Crt..,,'...... , TIw: Woold f ......... 1t<JlOfl2OO!. .. -..bIII! I POt' filo: .. bIIp:l,....,.............. ,w..hdnI. W.tluDl. O. J C~ ond Ada&u. I. S. 1 I .. .l6O:\lJ.i'.:ml. Hast.", . I M.. Bray. I' G. and Wud. S ... Se.....,., 298;74 . .!!XI! Sidhu .... II S . Vcri<l<t_PiI"l>tl!. D. ond fkloo:k. D. A.: s."..n N

MrGn:..,...

c_Oao,.

ltO.lOOl.
.J6. bttp:I....ww.darra.bo'etl&l'''''~ftln. h"n! 17 Power. G. 1I. .lcool. II B.. hrtc:r, M II ~ ..... J M .... aw:.. ~ )054, lOOl ]8 Pvoner. G. H . CIImm,",,,, J 1'1 P\o)'pradll~ .... ond 010. C J ..... Chem. Sex I 17;J&8j, IW5 :w I'oorw:f. G H_ PorL 5. D.. C "Iu. t- ...... J Am. CIw:oL S

REfEREN CES
1 Ed ....... Sc.... m 286:8. I lII - a. 10! IOJ.:.'OOZ.
2. H''''' I''*'"'. M Mon. M""ey ond M... >rio.. N... VIlfl. FOlT. SInO!i .t GO ....... 2002. 3 ~oi. f..: S<~ 29NI6 ..... 17. :!(lOl S. ..... V-",,")i. It.. C_ _ S~ ft" Sc_ 293
j

tILl!Ill. I'.I96.
40 .Iomaa. II .. Woeorw:<. J. s-krlnnd. S . 01 al. Sc:,.... ~ ~8H511. 1999 4 1 1t."'tIrft........... WioIrw:T. J....... r><lrnw:, .... C ....... 8;",q Mol CheDl. Loll . I 1:833. 2001.

r........r.
6.

7.

8 9.

U5-461.2001 lua.ouo L. ..... N.lbr<> R. Sc~ 193 ..... 2""""'-13.lQ) 1 VullltlAn. S. Ib,T)' .... E. 1 f'J'U. Ii. 1.... 11.: Sc;..",,~ 19H52-tB-1. _ ,." By...... 110' 1': SNoI<1!29S . 7-d.:.'OOZ. .........<'d<..... ltrawt I'omIw>, D J ......~. G. 1I",,1IfICU"hInl. C. ....L L.oncct; .l6O:

SELECTED READ ING

ItOll'I!.ooum. M

n.. Fe>.. Trail : In S<-an,h ol 'lIr C....., fot o\Iolara "" Vo<L.. Parrw. SU1w. a 0,",.. . 2001
0<:1OI>tr 2002. (Tlb. I.- rq>orI> IlIot ~" i.... """""... _ ....1..... ~_ '" _ ... mop two uS! .. .,..,................)

s"ic""" 298('-'91).

.... ~. ,

610. 2OO~. 10 v"" <len 1I"""'1Ir. II SilUro 27J.62/). 1978

" -.. . . ....otId Hnlh CrtanitaliOfl: The WookI Ho"1II II...,.,., 2002 , .., . -
rol' fit.. 01 h"p.J,.. ....,.wI>o. ... ""'It"~nI.

1 0

Antibacterial Antibiotics
(lHN

M. BEALE, JR
iltd 5elIn:h of the order ActiDQm)'cctalt~ led Walsman and o!i..'lociatc.~ 10 isolate ~'rt'ptomycin from S/'l'p/QmJl'(S 8 "S(UI. 1be discovcry that this amibiolic pos~d in \'ivo act ivily against MI"Cobarll'f;um /ubtrr:u/usis in addition to nu nlCrou .;;;pecies of GrJl11 -neg~'ive b.1ci!li was electrifying. [t was now evident that soil microorganisms .... ou ld provide a rich source of antibioIl C. Broad ilCrecning programs were in~ti lul~'d to find lIntibioti cs thHt might hoc effectivc in the trl:atmcnt of infections hitherto rt's istant to c.1.;sting chenlOtherapeutic agents, as ....1.'11 as to provide ... fer and more ef, fective chcmotherupy. The di scoveric) of broad-spectrum anllboctenal antibiotic$ ~uo;h aschloramphenirol and the tetracyc1illl.'s. anti fungal a!lt,biOlics .~uch as ny~tati n and grisro-ful~in (!iCC Chapter Ri, and lhe el'er-increasing number of AIlt ibiot lCS Ihat may be used to treat infectioos agents that have dc,eloped resi$lance to !>Orne of the older Wltibiotics allest to the spectacular suo;cess of thi \ approach as It has bc<-n applied in rt'~arch programs throughout the world .

IISTORICAL BACKGROUND
Sir Aklanolkr "leming' s occiderual disco\'ery of the antibac wr.I pope. ues of penicillin in 1929' is largely credited .... ith 1III,.tlmg the modem nntibiotic: era. Not until 1938. however. .tim Florey and Chain introduced penicillin into therupy, '-IJnCbCal mOOiCOlI exploitation of this irnponant disco\cry bqlll to be realized. Centuries earlicr. hU!11ans had learned 11_ crude prqllIl'3tions empirically for the topICal !real_ r!l infections, "hich we now assume to be effective hiIC of the antibiotic subslan.;:C) pieSCnL As ently as SOO !OOIC. molded curd of soybean WM o..<.ed in Chinese folk ....ne 1 treat boil~ and carbuocJcs. Moldy cheese had 0 _been uSC'd fOf centuries by Chinese and Ukrainian peas_10 but Infected .... ountls. The di5CO\'cry by PaMcur and min 1877 that anth.rax bacilli .... ere killed when grown [ll)ture in \hoe pre.~na of nain bacteria. along with ..~ ob!.nv.Jtions by OIhrr mkrobioIOl!is~. It'd VUII 1 '0 dc:fioo a"/ibiosis (Jilemliy "against life") as lhe concept of survival of the fillC$t. in ...hich ooc ~1"O)'5 !ItIOIher to presa"I'e Itself. 1be word anti ....u derived fl"l)m this mol . The use of the tenn by Ik lay public. as wl:".ll as !he medicul and sc)cntific communI.~~"; bororne so widespread Ihal it s original meaning ha~ lUoo .. l!bscured . lll942.. Wluman J pmposcd !he .... idely cited definition .. ". antibIOtic or antibiot ic substance is a s ubslancc pro~by microorganisms.. which has the capacity o f inhibi t, P"O""th alld even of de.stR.lying other microorga lAter JIfOPOSals~-o hHve sough t both to e~pand and r&d the dtfinition to include any substance produced Ib.mg organism that Is capable of inhibiting the gR.l ... th ~;.,"~II mooe or more species of micl"OOl"gnnbms in low ions.. The advances nUlde by mtdici nal chemists ..,mry I\3IWlIUy occurring unUblot1cs and 10 prepare synb .mIloglltS Iles~ilated the indusion of 5emiSY!lthctic .. ')1IlheIic deril'lllhes in lhe definition. Tllereron:, a sub_lSc~,f~ as an anuhiotic ,rthe following condition s

~ :!')S.74,

\6O"'3U. :!OO:! 2OD2.

s.:""",~

-,

l<nl-

Ied. Cb<m. 4.1

OIl. C. l. Ala

..... Chc:m.

s.",

~~ I"~. \<PI

_ 6"""'1 Mod

CURRENT STATUS
COITlnrrcial and !>CicntiflC interrs! In the antibmtic field has led to the isolatioo and ilknlificalloo of unubiot ic $ubstullCcs Ihat mlly be numbered in tnc thousands. Numerous semisynthetIC and syn1hl:tic Ikrhatil'cs rnl\"e ~n 00dcd to the total . Very few such cumpou!lds ha" e found applicatio n in gcneral medical Pfl'Ctice. ho ....ever. bccau~ in adduion 10 the ability to comOOt infectIons or neopl:lstic disease, an anllb,otlc mUSt possess other lIuributes. Firs\. il must exhibit su fficiem sclec ti l'e toxicity to be: decisively effect;"e against p:d.hogenic miclOOlXani~nls or ncopla'>1M: ti ssue. on the OIIC hand. without causi n!! significant toxic eff~l~. OP the other. Second. an antibiotic ~houJd be chemically \tabk enough to be isolated, processed, and \lured for a re.Jsonable length oftHlIC without cIclcrior:uioo of potency. The anlCPlIbility of lID lIDubiotic for oral or parenlC'fll1 admini str.llion to be corweTted into suitable d08age form~ to provide active drug in vivo IS \l1'i() important. Third. the rates of biotransformation and elimi nation of tnc antibiotiC should be ~Low enough 10 allow . COIlvenlent dosing schedu le. yel mpld and complcle enough to fociliulI: remo~a' of the drug alld ;IS melubohttJ fR.llll the body soon after adlmm'>1rallon has been di'iCOllhnued. Somt groups of amibiollc8. because of ~rta," unique proJl('rties. have bc<-n designated for spedah /.ed U\C5. such as the treat ment ofluberculosis or fungal infections. Othctsnrc: used for cancer ctlcmothempy . These anlibiotic nrc: de.o.cribed aloog with oliltr drup of the ~me tht:r.lpcutic cI,l~: antIfungal and antitubercular anubKllics nrc: discussed in Chapter 8, and antineoplastic a nlibiot ic~ are discu~sed in Chapter 12. The spect.acular success of antibiotICS in the tn:lItmerl1 of

.~

(altllou,h it mly he duplICaled or ClI M.\, br<n anlIClpaled by chemiclt !ynillesis). t. J.I)1IIMlw; proo.Iuct prod\ICed lOS a WUClun.1 analo&ue 0( I
- ' I )'

"I J"(Iduct

0( lI1rt;lboI,sm

IlIX"Umn,antibiotw;.
!iurvi~Bl

'lIIIl3l'J!1l10 the alllW1h or

j

uf one or more spe.:iu of

""... pnlsm<. . " dffdi.., In low conceflll"ll;on,.

1k IIOl~tion of the antibacterial antibiotic tyR.ICKlin from '0011 bacttrium lJacillu$ "'(I';S by Duboos sugg<'~ted the probable uislcncc of many an.ibiOl ic subslrlncc..~ in nature ad pnroidcd the impetus for tiM: sc:m:h for .hem. An organ-

human disc:ase~ has prompted the expansion of their usc into a numbel" of related fields. Ex tensive use of their antimicrobial po .....er is made in veterinary medicine. The disco"cry Ihat low leve l administration of antibiotics to meatproduc ina animals resulted in faster arowth. lower mortality. and bener quality has led 10 the use of these products IS feed supplements. Several antibiolics are used 10 control bacterial and fungal diseases of pllUlts. 11leir use in food prese...llion is being studied cardully. Indeed. such uses of antibiot ics ha\'e ne<:eSSillted careful studies of their longterm effeclS on hum.ans and their effecu on various commercial pr0cesses. For example. foods thaI contain low. leve l pmoonlS of antibiotics may be able to produce alleraic reactions in hypcJSensitive pe1"!iOll5, or the presence of antibiotics in ntilk may interfere ..... ith the lI"UIIIufacture of ch.eese. The success of an tibiotics in thernpy and related fields has m3de them one of the most imponant prodUCtS of the dl"\lg industry today. 'The quantity of antibiotics produced in the United States each year may now be measured in sen'ral millions of pounds and valued at billions of doll~rs. With research activity stimulated to find new substances to treat viral infections that now arc combated with only limited success and with the promising discovery thai some ant ibiOl ' ics are active against cancers that may be viml in origin. the future de\'elopment of more antibiOlics and the increase in the amounts produced seem to be ISWred.

during which the antibiocic is formed: (~} isolation of \hi: antibiocic from the cu lt ure medium: (d) purification: (eJ &Y sa)'$ fOf potency. Sterili ty. absence of pytogens, and ot/In' necessary data: and (/J formulation into acceptable and stabk dosage forms.

SPECTRUM OF AcnVITY
The ability of some antibiotics. ,och as chlorampheniCOl
and the tetrncydincs. to antagonize the growlh of numel'Oll\ palhogens has resulted in their designation 1$ broodS/I' Inl m antibiotics. Designations of spectrum of activity arc Ii. somewhat limited use to the physician. unless lhey arc basN on clinical effectiveness of the anubiotk against .spcclic microorganisms. Many of the broadspectrum antibiotics WI active only in relatively high concentrations against iOIIIt of the species of microorgani sms often included In lilt "spectrum:'

MECHANISMS OF ACTION
The manner in which antibiotics ae" thei r actioru aplllll 5usceptible organisms varie5. The mechanisms of action Ii. some of the more common antibiotics are summariu<l itt
Table I()' I . In many instances.. the mechanism of ICtKlll. not fu lly known; for a few (e.g .. penicillins). the site of IIC\)OI is known. but precise detai ls of the mechanism arc still ~ investigation. 1l1c biochemical processes ofmicl'IXIIltnrJa are a livcly subject for research. for an understandilll Ii. those mechanisms lhat are pe<:ulillT to the mcubolic sy~ of infectious organisms is the basis for the future de\'elopment of modo:m chcmod.crapeutic agellls. Antibiotics IlIttt

COMMERCIAL PRODUCTION
The commercial production of anti biotics fOf medicinal use
fol lows I general paJtem. differi ng in detail fo.- each antibi otic. The general scheme may be divided into six steps: (a) pn:p:mItion of a pure culture of the desired organism for use in inocuillionorthe fermentation medium: (b} fermentation.

TABLE 10-1

Mechanisms of Antibiotic: Action

Ant lblot l( Proc:ess Int"""Pted Jo"'.q'pt.dt ')'MIIe...
.. 011 MIoI.."nkinl SyolheN;t III cell ..,)t pcpI>Cb
C~!I

Site of Action

Type of Adiwitr

I C~U ...U

c_
a.ciUXIII

Ctphat"'POn""

,-

..-

8 ":l<nCidaI

Ny!',.,,"

- ,
V_o"'~

Ptlb(\it,"

Ctll ... Ucn>o>-lrfWnl

M~ptide 'r"''''''''
~k"""""" fllftCtJ<Jol M.mb<...., Ill11ruon

,,..F~at

Ba.:1C> ococbl lI_ncidal

-,..
LlIICOO1)~_

Potym}"","

Merinne -anty
1'roI~'n .~nm.,.,.
_n.~

Cblor.",phcnlcot

,. ..

,qJ~..w

"""" tft 'ymtw.oll Pro&t.n .}.""",... and

l'rnIo\ft ,yn~

fItk~IY

T~b_

ONA

"'IIIIor RNA

.......

~Y"in

ON" and mltN" 1}'1IIhet4 Cell ",",,_ mla'"

1"10.

,tJbIy

M,mon)"'" C R,L'lIIrIpI_

ON" ~)nlhc:>J.

1tIRN"'~

.."""'" ._ .... --

Back' odda[

IIA<'1c ....... MW:

tl ",'C'OI""" 1I_ ""j,ja[

II..: "" ic..c!ll

n of the fI: (t J lIS-

nd stnble

.. "'''''

phenicol

OO~~

oodspecity are of

arc: based
l

!Opecir"

biotics arc: unsl some ed in tht

-'Ith the metabolic syMems found in micruorga... and not in marnmalinn cells are the most succesdul irlfDCtl"C agenlS.. For example. antibiotics that interfere the ~ynthc:sis of bacterial cell walls have a high potential b It~tive to~icit y. Some: antibiotics sltUClunilly resemble mc:ntw metabolites of miuOOtganisms. which SIIg:-.b tN.1 competitwe antagonism may be: the mechanism II! .hich they exert their effects. Thu s. cycloserine b be~ 10 be an antilTlrtabolite for I)oalanille consti tuent of \QmaI a:!1 walls. Many antibiotics selcctlvely interfere DllCfObiaJ protein s)ntlleSis (e.g., the amiooglycosidcs. tttytlolll'S. macrolides. chloramphenicol, arxlltllCQlllyein) _.leic acid synthesis (e.g . rifampln ). Others. such PS the JUi)m}xln51Lnd the polyenc:s. arc believed to interfere with Ik.rrgntyand function of microbial u:1I membrnnes. The action of an antibiotic detemlltlC$. in general. .~lCr !he agent uens a bactcricidal or u bacteriostatic The Wstinction may be impor14llt for the treatment of bfe-thrc:atening infections. panicul:u1y if the natural ieIllr mllanisms of the host are either deficicnt or ovcrI.hd by the infection. In such Situations. a bactencidal lSob\iously indicated. Mucb won: remains to be done dlllllrta. IUld as mechanisms of oction are revealed. the dq.' 1 of improved structurnl analogues of efftctive 1t probably Will continue to Increase:.

_=

-:::0:0(

<0.

patbways. The divcrsity of anubiotie structure hilS proved to be of real clinical value. As the pathogenic cell deveLops drug rc:sisllUICC:. another antiblOuc. alUlCl.tnll another metabolic process of thc resisti ng ce ll . rcmain~ Cffl'Cthe. The deve lopment of new WKI diffen-nt antibIotics has been \ery important in providing the mean~ fortre;lIIng reslstam str3I1U of organisms Ihat previously had been susceptible 10 an older antibiotic. More: nxently. the elucidation of bIOChemical mtch.anisms of microbial rcsiSlanu: 10 antibiotics. such as the inacti vat ion of penicill ins and ccphalospori n5 by P.lacta rnaseproducing bacteria. has 'ilimulated llS:arch in the development of semisynthetic analoglK'$ that resiSl micmbtal biotransformation. The evolution of lIosot;(Jmial (hospital acquired) suains of staphylooocci reslstam 10 penicillin and of Grum-negal1ve bacilli (e.g .. P$tUtiomfHIllS and Klt'b$it'lia spp .. .Jrlreric/tio co/i. and mhcrs) often "',htant to scver-JI antibiotics has bc:comc a serioos nk.'dical problem. Nodoubl . the promiscuous and improper use of anublOl:ics has contributed to the ellK'f1lence of resistant bacterial suai ns. llle successfu l control of diseases caused by resi5tllllt strairu; of bac teria Will requIre t10I ooly tile development of new and imprmcU antibtOllC!i but also tile rational usc: of alail.ble agents.

agatnlt acti on of

IHACT AM ANTIBIOTICS
OilMI(AL CLASSIFICATION
Antibiotics thut posse~s the ,B-Iactam (a four rncrnbcred cyclic amide) ring structure an: the dominant clas~ of allenl!l culTt'mly used for the chelnothc:mpy of bacterial mfections. The fi rst antibiotic to be u,,-od in therapy. penicillin (pen icil lin G or bem~yl penicillin). and ~ close biosyntlletlC rclati\e . phenoxymcthyl penicillin (pemclllin V), remain the agents of choiu: ror the treatment of infccl1oru; caused by most spec ies of Gr-dH! posilive bacteria. The discovery of second major group of P.lactal1lalllibiotics. the CCphatOSporiM. and chenllcal tno(ilfication5 of nalurnlly occurring penicillins lind cephalosporins have provided $oCmbynthetic derivati YCS that arc: \ariou sly effCCh.e agaonst bacterial specic.~ "roo ..... n to be: rc:sl~tant to pemeillin. in p:ll1icuIM. penicillinase-pro-dueing staphylococci and Gmm-negalive bacilli. Thus. apan from a few strains that have either inherent or acqUIred re.~is tance. almrn;t all bactenlll spics are "C1I.~i tivc to one: or more of the a,atluble ,B-luctal1l antibioIlC~.

1\c ckmtSU)' of

is 50 varied tllat a chemical ",,4,:auon IS of limited v(flue. Some si nlllnrit~ s can be . . . howe.a. indicating that 50me ant ibiotics may be the "~d SImilar mech.aniStn5 in diff~nt organisms WKI "b"rucrurally imilar products may excl1lheir act;vi.ltilimilarmanner. Forexample. severnl importam ami IIlt'e tn common a macrolide structure . I.e .. a large ~~.IIJ1&. TIll' group includes erythromycin and o1cand(),ill The tctrncydinc: fllmily compri~s a group of COrll,,:::.rryc~ly n:lated dK:mically. &,el11l oompounds ~ c\w:ly related amino sugar moieties. such a.~ those IIIaI ill kanllmycins. neol1lycins, p3tOfll()The anu fungalantibiot ics nystatin (see OIaptl'r 8) are eXlllllplc:.~ of a The bacitracins. a large group ofpolyaction. The penicillins and rn i i antibiotics de-

anubiouc~

Mechanism of Action
In oddition to a brood spectrum of antibacterial acllon. t ..... o pmpenie~ conlribute to the unequaled Imporuoce of P.lactam anllb,OlICS In chemotherapy; a potent and rnpld bactcri cidal uction against bacteria in the growth ph~ and a vcry low freqlK'ocy of to~ic and other ad,c:rse reacuons in the host. The uniquely lethal antibacterial iICIiOll ofthesc: agents has been allributed to 3 M:h:cti ve inhibi tion of bacteri:1I cell wall synthesis? Spec ific... Uy. the basic I11<!ChanislII involved is inhibition of the biosynthesis of the dlpeptldoglycan that provides strength und rigidity to lhe cel l wall. Penicillins and u:phalosporins aeylate a specific baclenal ()-trnnspepudase.' lhereby rendenng II inacti.e for liS role in fonmng pepl1de cross1 ink~ of two lincar Pl'ptidogJycan strands by trunspejlli dation and loss of o-alanine. Bacteriall)oa/amnc: carboxypc:ptidaseli are al50 IIIhiblied by .8-llK.'Iam anllbiotics .

prou:!S("S of microbial pathogens are Thus. it Sttrns reasonable 10 assume ways in which they may be inhibi ted that ela.boI1lte lIIltibtotics . produce compounds that i t prou:sses. has produced many chemically different amiatliICk the same mkroorganism by different

BU'HJlng studies with tritiated ben.,yl penicilhn h.we >hown U\aI the mtehanisms of action of various ,8-lactam amiblOtlCs are much 111()I'r; wrnplu than previwsly ..~surned, Sludies in E.. coli hu\'e revealed a" mau y lIS seven dlrferent fUOC'Iional proteins, each wilh an imponant role in cell w.ll biosYnlhcsis.~ 1llcse penrc illi n-blllding prolcin~ (PBPs) have the following fU llCtional prupcn~;
P'BI'!. I. and I ~ l1l"i: ltaI1Sj~prid" ... , in vol" ed in ~plidogl/an ~ynd'lc< .. _laIcd .. nh noll donphoo Inh,bitlon ~IIJ ,n ~pherupIB<I form.. lloo nOO rapid <xII Iysr.," In ~Iuscd by atltnly<;jl\t.l~ cn1ymes lila CR:lUe nicb ,n rile noll Will for '1!achnlmr 0( ""w ~I'u"'lycan unn~ or rOO" Kpantlioo of rbuglwcr <x1I~ dunng cell div, soon 'o). P'BP 2 ,~ I lran~~ in,"OI,'nI in ~ntarnlnl 1M rod ~ha~ 0( bDr:ilh' Inhlblllon relults in <l~Kl or round r,,",,~ IIw undc1go de:llycd Iy~,s . PSP 3 i, 'Ir~~~ ~u'ml for~ptum fOONh<ln dunn, noll dl~iJIon . tl Inh,brrion ","uhs in lile f()l'm.'ron of fl lamen_ I{)ItS fQl'm:l ronurinln, rodd>apt'd PotU; 1"- can"'" ~ It ,~nor yer dear "'ho!rller Inhlblloon of PBI' J 'S [;:rhal to 1M PBI'!. 4 Ihrough 6 Ire: cubo~)'lX'plr<Wn ~Iblc f{ll" the h)druly!; .. of 1>-11~nlnc-,)-al .ninc ",rmi""l p"pudc: bond. of the cros. lrnkrn, pepltdtl!. Inhlbttion 0( liIeK "tIly~ is lipp;tl'\'ndy not lethal Lo the brr.c:'enum." even rh<lugh ( \tInge uf the: lCmllrW t>-aWr'1IC bood is n:qu.red before peptide: Croo;l hnbgc.

I pure compound and ex.hlbltcd varying ocli\ lIy among gm. pie!;. it was IlCCC!iSllr)' 10 evalLIIUe 1\ b)' 1I11croblQlogicai as!>lIy. 1lre IlIo.:cdure for .. ~y ... as dco'eloped al Ox.ron!. England.. ~nd tllC voluc became known ali the O.iford ,mil: t Oxford L1nit is defined lIS the smallest amount of penicill in that ""1M

TABLE 10-2 Structur. of Pen icillins

....L.H
Chemlu l Nam.
R Group

""==

MethICillin

2.6--Dimclbo.>.)pMn)l.

penicillin

,8-1 ""lIlm antibiotics differ in lheir affini ties for PB l's. PenICillin G billd~ ))n'fcn:ntially 1 I'B P 3...... hc:reas 0 .he fil"Sl -genrr~lion ccph'LI~in~ billd with higllcr affinity to PBI' I . Jn COI1lru.~t 10 other penicillins and to ccph:l.losporillS. whkh call bind 10 PBPs 1.2. and 3. amdioocillin binds only lu PBP 2.

The

\'ariou~

l-Emo.yII\IIfIIU,I p<rrlc.llior

~- Metb~I .).phtft,l-4-

11<lUIOIylJlcto""I..

THE PENICJlUNS
Cono_rdal Production and U.. H
Until 19-14, ,I WllS a.~sumed that the acr;\'C principle in peni cillin wo~ II. ~i ngle substlmce and lhal vori~lion in IICtivity ofdiffcn:nl prodUCI$ was due to !heamounl ofinen materials III the 5lIrnplc.~. Nnw we know thai during !he bIological elabunllion of the :u\tibiOlic. sc\'eraJ close ly related oom pound~ may be produced. These COITIpounds differ chemically in lhe acid moiety of the amide si de chain. Variolions in !hi, nlOicty prodl"-'e diffcre",,-'CS in antibiot ic effect and in ph ysicochemical properties, including ~I ability. Thu s. onc <:an speak of penICIllins as a group of compounds and idennfyeach pemcillin "pecifieally . As each or the diffcl\'nl peni_ cillins was fiN isolated. lener designations were used in the Uni.ed States: the Bnrisl! used Rom:m nUmoC:l1Ils. Q"cr 30 penicillins have been isolaled from femlClIlg.ion n"",lUres. Some of lhese occur naturally: 0Iher$ na\'c been biOliynthe. ilcd by ~llcri n8 Ille culture medium to pmvklc ~ ccnain precursors lhat m;J.y be incorporated as acyl groops. Commen.::ial producnon ofbiosynthetic penklilins today depends chreny OIl various sll1lins of Pe"icillium n%w", and P. chry$lJSmum. ln recenl years. many more penicilhns 11:1,." been j"II\'pared se misynthelically. and und oubtedly. many more will be tIdrkd to the hst in allcmpt5 10 find supenor
prodUt:.ll'o.

Cio>.."Ulto

S.""'th~l-J.41.

dobvt>l 11).4~... ro1~lpeno<'lh~

Dt<k>ut:!llin

5Melhyl~u.

c,
CI'\,.-"..
I

~ylr4-

''\Qu.",I) iponl<Oltbn

Ampic,lIin

......" .. ,"'*"f>l:~I.
"",,,,,~

luIIlJ.iciUloo ......" .......,... hydto~ ybet>" I""",dll,n HO

crclrm.

1-"..... lIOfy<loh,..yl pmlcdJin

C&rt:>oollltlib.

...c_)' t.en, ~ I
...c..m..)l-ltUortIll,
~llhn

-,-

r .....'..I'"

Becausc!he penicillin first used in chcmothel'1l.py was

not.

Chtop'rr 10 Anllbucll,nal AIlI/biUlin

TABLE 1~2--<onrinuM
JOJ

co",.ric

H.....

Cltemlul Name
.,.j. BII)I-~ 1.

It Group

,..... ,1 1...

popcnrid)brboayl.

\IaIo.~""

omillO )benoylpcnlc: illl~

a-(1 Me1/>o'" ....0Mj1-2.

.............'" My'
"""kil~n

"IIlbeaIyl

num ber I to the: nitrogen atom and numher " 10 the '-\llfur atom. Three sim plified forms of penicil hn IlOIncnclalUl\' have been adopted for gencrnl use. One uS('s ,he n::unc "pc:nam" for rhe unsub!iIllUIC~d bicyclic: s}'>lcm. incioolllg the amide,,'lIf'bonyl group ..... Ith oooofthc forego;n; numberins sy\tems as JUst descnhed. Thu~. pt!n leillin, ICII(Tldly an: designmcd acconli ng to tile Chemical AlmrunJ )y~tcl1l IL~ S-acylmnino-2.2-dimcthy lpo:nam3earbox ylic udd.. TIle second, seen m~ frequeluly in thc mcdkal tncrollure. u -,c~ the natllC " I'cnicil!anic acid" 10 de\Cribe the rinl/ ~y'h.'111 .... ilh \ubMilUcnts lhut 3' gCr>ernlly prescnt (ic .. 2.2.dimcthyl ~nd 3-carboxyl). A thi rd {onll. followed in this chapter. uses tril ial nomenclature to nartlC' the entire 6-carbon_ ) laminopL'lIIcd lanii: acid ponlon of the molecu lc jIl'niClllrn and thell di~lIngui.he~ compou,xh on the basl~ of the R group of lhe acyl portion of the molecule, Thu ... po:niclili n Gis IIllI1lN benlylpo:nicillin. penicillin V i, p/lo."ll()t)mcth ylpcnicilli n. methicill in is 2.6-dimcthoxyphen)Jpcnlcl lim. and so 00. For the """t pan. tlx- laner two ')~tem . ~I'\c "iell for nllmmg and comparing close ly similar po:n;clllin StruclUn:S. but they are 100 n:strictive to be applied to Com. pounds with unusual \lIb .... ituents ono ring- modified deriva_ tives .

SterelKhemlstry

lllllibll. In ~illu. the growth of I SUlIi" of SU!phdorot:cuJ in '4 rnl. of cullUr~ medium under specified rondiuons. Now .. pure crystalline penicillin is available. the UOl/ell Staff'S ~w (US P) defines unil a.o. the arllibiOIlC lICIivily 0I0lt 111 of US P penicillin G sodium n:fen:ncc sl!Uldani.
TlIr'll'clghl - uni, n:lationship o f lhe penicillins varies with ... flf')1 sub!.Ii1tlem and with the ~It fonned of the rite acid: I III of peniclllirl G sodium i~ equ ivalent 10 t .667 units. I \ll'penicillin G procaim: i~ equ iva len t 1 1,009 units. mid 0 1l1li of penicil lin G poca~iurn is cquivalenll o 1.530 units. The l'OI1HncrciaJ production of peuiciUi n hilS iJlCll':t.'>Cd roly ,incc ils imrodUC1ion. As production irKTea'!ed, IIrr l'05I drtl(lJled COI l espondingly. When penicillin was first bilk. 100.000 units sold fOl' $20. Currently. the same ~'P:COSI~ less IlIan I penny. F1lJ('lualions in the producrJ penicillins through the years have ~ nccted manges _lilt: m..Ule populmty of broad-spectrum ant ibiotICS and n!llM. the development of penicill in resiWUlt strains of ,om! pathogcns. lhe more t\"Ccnt introduclion of 5emisyn_ " . penICI llinS. the use of po:nidlhns in animal f~ocds and 1I1dmnary purposes. and the inc~a.<;e in marketing proo. ... In a hIghly competi tive sales area. TIbIc 10-2 ~ hoW5 the genernl st ructll~ of the penicilli ns ..s relatd the structure of thc more fUlniJiar one~ to lhei r _.!b;J;natiotls.

TItc penid ll in t1IOJeculc OOIll~ins three chirnl carbon III00llS (C -l. CoS. and C6). All natur.l.lly occulTing and microbiologically acti\'C ~)nthctic and semisynthetic penicillins hale
rhe "'me absolute configur:uion about thc>.c lht"C'(': a:nters. TItc clubon atom bcannll tlx- lICylamino group (C-6) has the .. ronfigUr.tIlOfl .... hen:as the c:.. rbon 10 ... hich the carbo~yl group is IIl1:1oChcd ha.~ the 0 confil!ur:ltion. Thus. the lIC} lamino and carbo~yl groups au frtllU to cach other .... ith the former in the a (Illd lhe lallcr In the fJ onclllahon relative to the pen:un rin!: syslem. The UlOO1S comp!)',!ng lhe: 6-am inopenicill un ic acid portIon of the SlnJCIUt'll arc denvcd biosynthcl1cally from t .... o lun itlO bcitis, I cysld ne (S_I. C . S. C-6. C-7. lind 6-mmno) and I.-valine (2,2-dimcthy1. C-2. Col. N4. and l-ciltboxyl). The absolute slc,,:uchc miqry of the penicillin' i, deslgnal..-d lS:S R:6R. as ~ho .... n belt.... .

H.

H.

CH.

,
~

Ct., ': ,, _ _

'"

1Irt lOtIIeoclalu~ of penlcillin ~ i ~ some..... hat compla and C'IImbcrsome. T ...o numhering 5ySlc:ms for the fused . be ~ychc syStem aisi. The Chi-",u:al Ab$/rpctJ illll~ lhe numbering .... IIh the sulfur atom 1100 :IS. die nng nitrogen the" poISition. Thu~. penicillins 3' . . . as 4.thla-I-;uabicyclo[ 3.2.0rheplM. occording to J)'JICm. The numbering system adopted by the US P is ~ tm'I'!C of lhe Cht'mical AbJlmcfiI prucc:dun:. assigning

,,-..( H

-,.

OJ

304
Wilson and Gisvold's Textbook of Organic Medicinal alld Pharmaceutical Chemistry

Synthesis
Examination of the structure of the penicillin molecule shows that it contains a fused ring system of unusual design, the ,B-lactam thiazolidine structure. The nature of the ,B-lactam ring delayed elucidation of the structure of penicillin, but its determination resulted from a collaborative research program involving groups in Great Britain and the United States during the years 1943 to 1945 14 Attempts to synthesize these compounds resulted, at best, in only trace amounts until Sheehan and Henery-Logan 15 adapted techniques developed in peptide synthesis to the synthesis of penicillin V. This procedure is not likely to replace the established fermentation processes because the last step in the reaction series develops only 10 to 12% penicillin. It is of advantage in research because it provides a means of obtaining many new amide chains hitherto not possible to achieve by biosynthetic procedures. Two other developments have provided additional means for making new penicillins. A group of British scientists, Batchelor et al.,16 reported the isolation of 6-aminopenicillanic acid from a culture of P. chrysogenum. This compound can be converted to penicillins by acylation of the 6-amino group. Sheehan and Ferris 17 provided another route to synthetic penicillins by converting a natural penicillin, such as penicillin G potassium, to an intermediate (Fig. 10-1), from which the acyl side chain has been cleaved and which then can be treated to f01l1l biologically active penicillins with a variety of new side chains. By these procedures, new penicillins, superior in activity and stability to those fOllllerly in wide use, were found, and no doubt others will be produced. The first commercial products of these research activities were phenoxyethylpenicillin (phenethicillin) (Fig. 10-2) and dimethox yphenylpenici IIi n (methicill in).

Chemical Degradation
The early commercial penicillin was a yellow to brown amorphous powder that was so unstable that refrigeration was required to maintain a reasonable level of activity for a short time. Improved purification procedures provided the white crystalline material in use today. Crystalline penicillin must be protected from moisture, but when kept dry, the salts will remain stable for years without refrigeration. Many penicillins have an unpleasant taste, which must be overcome in the fOllllation of pediatric dosage forms . All of the

natural penicillins are strongly dextrorotatory. The solubilit) and other physicochemical properties of the penicillins are affected by the nature of the acyl side chain and by the cations used to make salts of the acid. Most penicillins are acids with pK. values in the range of 2.5 to 3.0, but some are amphoteric. The free acids are not suitable for oral or parenteral administration. The sodium and potassium salb of most penicillins, however, are soluble in water and readily absorbed orally or parenterally. Salts of penicillins with or ganic bases, such as benzathine, procaine, and hydrabamine, have limited water solubility and are, therefore, useful as depot forms to provide effective blood levels over a 10n1 period in the treatment of chronic infections. Some of the crystalline salts of the penicillins are hygroscopic and mu~ be stored in sealed containers. The main cause of deterioration of penicillin is the reactiv ity of the strained lactam ring, particularly to hydrolysis. The course of the hydrolysis and the nature of the degradatioo products are influenced by the pH of the solution. IS. 19 Thul. the ,B-lactam carbonyl group of penicillin readily undergoes nucleophilic attack by water or (especially) hydroxide ion to form the inactive penicilloic acid, which is reasonably stable in neutral to alkaline solutions but readily undergoes decarboxylation and further hydrolytic reactions in acidic solutions. Other nucleophiles, such as hydroxylamines, aI kylamines, and alcohols, open the ,B-lactam ring to form the corresponding hydroxamic acids, amides, and esters. It has been speculated 20 that one of the causes of penicillin aller!) may be the fomlation of antigenic penicilloyl proteins iJ vivo by the reaction of nucleophilic groups (e.g., E-aminol on specific body proteins with the ,B-lactam carbonyl group. In strongly acidic solutions (pH < 3), penicillin undergoo a complex series of reactions leading to a variety of inactile degradation products (Fig. 10-3).19 The first step appeaJliO involve rearrangement to the penicillanic acid. This process is initiated by protonation of the ,B-Iactam nitrogen, followell by nucleophilic attack of the acyl oxygen atom on the ~ lactam carbonyl carbon. The subsequent opening of the ~ lactam ring destabilizes the thiazoline ring, which then aI~ suffers acid-catalyzed ring opening to fOJ III the penicillan( acid. The latter is very unstable and experiences two maj~ degradation pathways. The most easily understood path in volves hydrolysis of the oxazolone ring to form the unstab~ penamaldic acid. Because it is an enamine, penamaldic aria easily hydrolyzes to penicillamine (a major degradaiioo

c
(

n n
r

f(

IT

I-I!-I-OI+I-a-r" ......<;:(%>2
1-11

tI,
~

cc

B ar
111

th if he
R

\(f

,u ,
Figure 10-1 Conversion of natural pellic .

va

to synthetic penicillin.

tht tio

Cha pter III AIIII/1a<:urful Atlf'bwtiOt

305

,. =

P0"1-~NCHCHO ~ , I
co.C(~
~1IufyI

(C~nl-lCO,H

SH NH,HCI

-"

a..plllhl:! ..dOff aion-

o-Peonic\IIamine HCI

;~:~~:: acid. TIie scooJld palh involve~ a como( pcnicill:l.R1c acid 10 a pcndllC acid
of inllumolecu lar proces.\('s Ihal remain 10 I . Pl:nllhc acid (an uniduolinc-2dccarboxylatdl and suffer.> hyacidic fonn a liCe-

Q\idi1jng agcms also inactivate penICIllins. but n:ducing

agcnts have linle effect on them . TClllllcrulUre aff1s the nile of dclerior.ll ion: although the dry ~lIs are slablc II room
IClupcrnlure and do noc require rcfngcrll1;oo. prolOllgcd healins inacti vates the penicillinS. Acid-c:llaJy~cd degradation in the SlQlllach CQfltnbukS 'Mongly 10 !he poor oral abwrpl ion of penicillin. Thus. ef forts to obIain penicillins with imprm'ed phannacol:mcllc and microbiological propeniM h:l\'c focused on aql functionalities thaI would minimiu sc!lSitivity of the P.lactam ring 10 acid hydrolysis ... hile maimainml: ant ibacterial :teti\ ity. Substi tution of an electron -withdrawing group in the 1I' posi tion or ben/ylpcn icilhn rtt:tri.e<Jly ~nbi " 1.e~ the pcnK:il lin 10 acid-catnlyled hydrolysis, Thus. pho:no\)'nlCl.hylpenitimn, lI'- anunoben lylpclllci 11m, and lI'-hlllobenl.)'lpenici1Lm are significantly rI10K stable tllan benl.y lpcnltiltm in at!'" solutio ns, TIle i ncrea.~d ~tabilil Y impar1ed by such electronwithdr~wing group!! has been allriboted 10 dccn::ased reactivity (nudcophilitity) of the side chain :unidc carbonyl oxygen atom to ....ard panicipatioo in P.lactam nng OJl!'ning to form pcnicillenic acid. Obviously. /I'-wmnobcnl:ylpcnicillin (ampK:ll lln ) cllists as the proIOlmted form in acidic (as wcll fI.'I neutral) solutions, and the IImmOI1l\lrn group is L.fI()WII to be po .... crflilly cicctron withdro .... illl;.

l'cmcilioic

:acid!<:
I

10

i major product alkaline (as ..... en as cntydelt~led

"

", C :UUlOI be

as un inler-

IIddk cooduion.~. II Ui~IS in tquilibI, acid. ho",cvcr. and undergoes in ocid 10 form penilloic acid. The Ihml of the di.'SradalKm is pc:niciUooJdehydi.'.
decarbo~yla!lOll

of pcnaldic acid (a derivmi\'c of

solutions within a nmgc

BachriaI A_istAnc.
Sollie bacteria. in panicular lJlOSl specks of Gnam-llCpu\'C bacilli, arc natllrolly resIstant 10 the IICtion of pcnicillillS. Other normally sensiti\'c "ptX"le$ can del clop pcmclilm re_ sist:mce (ellhcr through nUlUr~1 ..... lcction of resbtmll indi ... id

Penleillenic AcId

I""
,--<0<"" 11'1".00"~''''~Clr CQH

HS+a.."
b.,

I
,,-,o'O''''''''~fH--CHO

"""
figure 10-] DegradatiOll of per!lCllhr.s.

uals Of rllrough mUUllion). 11M: beSI Ulldel"lilood and. probably, the most imponant biochemical mechanism of penicillin resislance is the b.aeterial elaborolHlfl of enzymes lhat inactivaLe penicillins. Such enl.yIDCs. which have been given the ~iflC name ~f1icilli_s. an: of lIn, gener.ll types: ,8-r3oCtamases and IICylascs. By fll1 the more important of these are the ,8-lactamases. ell1.ymes that caUllyu the hy lk"oIyUc opening of tile ,8-IKlam ring of penicillins to pr0duce inoctive penicilloic acids. Synthesis of bacterial ,8-lacWIllISe!i may be under chfOlT1oCl8OlTlaJ or plasmid R factor control and may be ei ther coostHuti~'e or inducible (sti mu he lated by lhe pre.w:nce of the substmLe), dependi ng on L bacterial species. 11M: well-known resiwtnoe among strairu; of SwpJrylOCOCCNS /lUftNS is apparently entire ly due to the prodoctioo of an inducible ,8-laculma5e. Resistance among Gram-negative bacilli, however, may result from other, poorly chamcteri1.ed "resistance facton " or constitutive,8lactamase elabor-,1tioo. ,8-Lactamases produced by Gnunnegative bacilli appear to be cytoplasmic enzymes tllat relIIain in the bactcrial cell, whereu those elaborated by S. /I~ftllS are synthe!;i~ in the celt wall lind released eXlracelIularly_ ,8-Lactamases from different bacterial species may be ClllSSified~-16 by their structure. their substntte and inhib-

species of Gram-negative bacteria. but the ir ~~"~::~ bacterial resistance Ila.~ nO! been well III' lymes find OIlle conullercial use in the preparatiorr aminopenicillanic acid (6-APA) for the synLllet ic penicillins. 6-APA is I I1""IOI'e rapidly (ell1.ymatically and penicillin.

itorspecificitics. their physical properties (pH optimum. electric point. molecu lar weight. etc.). and their immu~ cal properties. Specific lICylascs. enzymes Ihat can hydrolylt the aq_ ino side chain of penicillins. h:tve been obtained from !elm

Another;,::::,::;~

Hns. The cell envelope in mOSt Grnm-negative;!~:: more complex than in Gram-posit1\'e bactctiL ~' outer membrnne (Iinled by lipoprotein bridges 10 doglycan celt wall) not presenL in Grom-positive which Crea\es a physical twrier to t its. especially lhose Ihat arc philic molecules. however. can through pores f'" n ... d by proteins of the number or nature of porins in

the,.;.;.

ChMIJtcr 10

A""bIJr,~rilll Anr;b,OIU"~

307

Dki be an Imponunt mcclllUlism of anti biotic re.~istance. 1IIcIm.tJ ~Istancc: can n:suh from changes in the llI"finity .. P8P!. for pcnicillins.N Ahm:d PDP binding has been dtmonstl1ltcd in oon-,B- Iactamase-prodocing 5tl1lins of peni~l'itanl Nti$$criu 801.{)r~llr'l and mcthicillin-re_ S. DIII"rIl!/ (MR SA).JI Cmain strams of bacteria an:: rcsismntt o Ihe lytic proper In of penicilli~ 001 Il'm:l.n suSCC'plible to ~ir growthllibtmg effe-cts. Thus. the action of the antibiotic has been lIItl'Med from bactmcidal to bactcriOStatic. This mccha.smofresisl3nce is termed /Qlermra and 3pparently results _ impaimlautolysin !le-li"ity in the bacterium.

Extendad-Specbum Penicillins
Another highly sigmficant alliance ansing from the pn:paru tion of semisynthetic penicillins Wa5 the disco\ery that the introductIon of an Ionized or polar group into the (t posi tion of the side cltain benzyl carbon atom 0( pcnlc llhn G conftr!l &etivny against Gram-negative b."lCilli. Hence. denvali~es ",ith an ionized a-amlllO group. such Wi ampicillin and am()~icilltn. art genemlJy effcct'\'e again st such Grnrnnegative gl.'lll'ra II!l &dl~riclria. K/ebJiellu. fll~mophiIIlS, SDInu.mc/lD, Slrigella, and non- indole-producmg I'mulls. Furthell1lOfe. activity against penicillin G -sc:n~iti .. c.-. Gram PDS.ti,e specie!! is lorge ly relainc.-d . The introduction of un a-amino group in ampicillin (or amoxicilltn) crtates In addi tional chlrnl ccnter. E.ltension of the anti bactenal spcelrlnn brought aboul by the substiluent applicsonly tOthe 0 isomer. ,,hich is 2 to 8 tinJe5 more acti\e than either the I is(lmc:r or b.'nzylpcnicillin (which IlR' cquik1;'c) ag:unSi various species of the aforemenlloned gencl1l of Grarn- neg~tiye baci lli. 1"he baSIS for the e~parldc:d spectrum of nctivity aSSOCiated with the ampicillin groop is not related 10 .8-lactamasc inhi bi tion. 3S ampicillm and amoxicililn are even more labile than penicillin G to tile action of .8-lactamases daborated by boIh S. ClIlrtru and \ nrious species of Gl1Im-ncgative bacilli. including Slmins among the ampictllin-sc:nsitll'e group. Hydrophilic penicillins. such as ampicillin, pcnetrJlc Orum Ill'gative bacteria IIlOI"e readily than penici llin G. penicillin V. or II1Cthiciliin. This selccti"c pcnctr.uion i~ believed 10 lIde place through lhe porin channels of ~ celt membralll'." a- H ydro~y substitution also yklds ex pandedspectrum" penicillins with activity and sterco!IC lcctivity similill to that ofthc ampicill in group. llIe a-hydro~yberuylpcn,cll lins are. however. about 2 to .5 times Ic.~s OCllve th;ln their com-sponding a-aminobenzyl ~"OOntcrparu and, unh~e the laller. not very stable urwlcr acidic condition~. Incorporation of IUl acidic substi tuent lit the a -bcnql Catbon atOO1 of penicillin G also imparts clinical effectivcnc~s against Gram-negative bacilli and. fu~ . ex tends the spectrum of acti vity 10 include organbms resistant to ampicillin. Thus. a-carboAyl:lcnz)lpenicilhn (carbenicillin) is active again~1 ampicillin-sensi ti ve, Grum-negative species and additional Gr.lIl1-lll'gati,e bilcilh of the gcnc:n PstwkHnonll$, Kl,.h$ic.-Ifa. muOOtlctt'f. indole-producing I'rott US, SerrtJIill. and Pro\idmcill. TIle potency of carbc:mcllhn agai nst most species of penidllin G-sen.~itive, Grarn -posi. tive bacteria is several orders of m:lgnirudc: jo,.er than that of either penici ll in G or ampicillin. presumab ly because of poorer penetration of a more. hIghly lonll..cd molecule into these bacteria. (Note that a-anJinobt:nzylpcnicillins CAi$llli 1.winelions O\'er u broad pH range and. a5 wch. are considerably less polnr than cnrbc nicillin.) This increased polarity is appatt'ntJy an advantage for the pcnctl1luon of carbcnlcilli n through the ce lt envelope of Gl1Im-negati .. e bacteria vii porin channels. J' Carbenicillin is active against both ,B-loctalllllSC-producing and oon-.8-Iactar\~producing strai ns of Gramncgalivc bacteria. It is sornc ..... h:u rtsistQnt to a few of the fJlactamases prodtJI%d by Grarn-ncgatlve baclcria. especially mcml)ers of the Enterobacteriaceae family .16 Resislllnce 10 .8-lactamascs elaborated by Gnlln-ncgatll'e bactma. there-

'luidlllnpseResist.ant P ldilins
TIt ll"ailability of 6-APA 011 a comrroercial selle made pusIIhIt the synthesb of numerous scmisynthetil.: penicillins

wried

at tile ac)"1 amino side chain. Much of llie early

out done in the 1960:. wll.~ direcled toward the pn'pamtion

.drm.u,es that ~ould rc:si~t destruction by .8-lactamMeS, pitlCUlarly those produced by pcniciUin-rcsistant strains of 1."'lI$. ~hich conSllIuted a "ery s.mous health problem .Ih lime. In gcncr.ll. increasing the steric hindrance al iIIlt-nrbon of the acyl group i~ascd resista.~e to staphy'o:roocal ,B-hlCtamase, with maximal Ile$bUll"lce being lib~ "nh quaternary substitu tion .Jl More fruuful from the .-.JpoIm of antibacterial potency. however. Wa5 the obser_ that the allCyl carbon could be piUt of an aromatic .r, phtnyl or naphthyl) Of hetcl"OlllUnlatic {e.g.. 4-isoxaII s)!tem. u SUbstItUtionS at the {)"lro positions of a I rlllg (e.g .. 2.6-dimclhoxyl f meth icillin J) or the 2 pasiofl I-napht hyl systCm (c .g.. 2-cthoxyl Inafcillin]) in. _ the steric hindrancc ofthc acyl gnJIIpand confer more resistance than shown by the un.~ubstitutcd " ' Inels or those sutKu tutcd ill po$itions IIlOI"e distant Ihr a-cllfbon. Bulkier substitucms are required to con fldf((tl\'e .8-lllCtamasc: reslSIance URlOOg fi\cmcmbered IIIl1rtt'fOC)dic derhatives.'" Thu s. members of the 4-iso~ ..,1 penicillin fwnily (e.,.. oxacillin. clollocillin. and b.acil1in l require both the )-ary l bnd 5-rnethyl () mcthyl S-aryl) 5ubstitucnIS for effccn\'cllCSlIi against .8-lact8lI"lJducing S. IIUn'II$. D1Iiing the bulkiness of the acyl group i5 not without pn. howe'er. because all of the cli nically available I ~~hnasc-rtsiSlant penicillinS arc sign irlCantly less active ntller penicillin G or penici11 m V Ilainst roost oon- .8bactcr1a normally sc:nSlUve to the peni The ,B-Iactamusc:-resistunt penicilli ns tend \0 be oom "fly lipophilic moIccuks that do not pcnclrllle wcll Gram-Ill'gativc bacteria. "The isox uzoyl penicillins. parthose with an clectronegative ~\lbstituent in the 3'11 i I fI Ooxacillin), ~ the .8-lactam,

,1Kumase

lm. i:l{)o moIogilCy lamseveral ; role in ,ese enof 6~f semi-

PYlcU
~) than

ially In pen icil:tcria i~

uuns an e pepliIIIICtc lia, Ulli biothydro-

acid. Aco::onIingly, nl('thil.:i1Iin .

..

lias ele<:-

,mbrnnc terauOll
e~' also

~::::~groups (by \"CSC)fUIJICe) orrha to the carbonyl (a more labi Ie to acid-cataly~ed h)"drolysis than
G becausc of the more rapid fornmtion of the ,,', ~ derivative.

fore. may be an imponanl componem of carbenicillin's ac II' lly agamsi some ampicillinre~i>tanl organisms. ,B-l.ac1a ~ produced by Pst'wionuNlas spp .. ho-,o.ever, ~3dily hydrolyr.t cartx-n'dllin. Allhough carncnicillin IS also some.. .... hal n::smanllo slapl1ylococcal.B-laclam~. il is conskJcorably kss so Ihan methIcillin or the i '<O~a]oyl p!niclilins. wKl its inherent :mtislaphylococcal activity is less impressi ve than thai of the penici llinase-res i~tant penicillins. The peni cillinase -reslstam pcnkillins, de~pite their resiwmce to nlOSt ,B-lao;1aJnaSC\. ho-,o.ever. share the lack of activity of penicil lin G again .. Gramnegaahe bacilli. plimanly bc:cllU:le of an inability to penetrate the bacterial cdl en>'e lope. Comp.1m! with the aminoglycosille antibiotics. the p!)leney of carbcnidlli n against such Gram-negative bacilli as PSt'.uilH1l()fU'S l.('nlsi,l():fa. /'mll'u.1 Iu./garis. arKI Klebsiella pMI,mmUfIt' i~ much less impres~l\e. Large parenteral doses a~ reqUired 10 achle'"e bacteriCidal rooccnlrahons III plasma and tissues. The low 1 0xicilY of carbenicillin (arKIthe pemcil lin~ in g~ncr:d). ho .... eVl'r. usually permits (in the absence of allcrgy) the U'-C of such high doses without untoward cffecis. Fun hennore. carbenicillin lund Ulhcr penicillins) .....hen l'()fllbill<'d .... ,Ih annnoglyoosidt:$. c~ens a synergislic bactericidal action ~gamst b:lcterial species ~nsiti"e to both agents. 0xic frequent ly allo .... lng the use of a lo .....er do!;c ofthc: ITlCIK 1 aminoglYCOI>lde than is normally ~qoired for treatment of a life-thrt:Jlentng tnfl"CIiOll. lbe chclnlcal il"l(:ompallbili ty of penicillins and aminogl ycoside,~ reqoires thai the twO amibi(ltics be administered separately: OIherwi!IC, both are inoctj ,'atcd. I }engar ct al. '1 showed thai acylation of amioo groups In the aminoglYCOSlde by the ,B-Ia.ctam of .he pcnicilli n oceurs. Unlike the si t u~lioo with amptclilin. the introduction of asymmetry at Ihe a-bcnlyl carbon In carbenici ll in impans Iin Ic or no ,1~rt:<KeIlIvity of anllbaclcria l actiQlI: the irKIi , Idual cnantiomcN are nearly C\jually acli vc arKI readi ly epimerilcd to lhe r:tCemale In aque<:lll~ lIOlut ion. Because it is a derwall\"c of phcnylma.lome !lCid. corbcnicill in rt:3dlly dec:arboxylates to bcn/yipemclliin in lbe presencc of acid: therefore. il is not IIICl i ~e(as carbenicillin) orally and must be admjni~lcrcd parentcrally. E.slerification of the a-carboxyl gmull (Coi: . as the 5-indanyl e,ler) pan,ally proICCI~ the c:ompourKI frnm llCid,calalYl.ed <btructiQlI and provides an orally :lethe den,at;'c that is h)drolp.ed to carbenicil hn in the plasma. lbe phl.QrUl le,els of fre.: carbenici llin achie,'ed ..... ith oral oonunl>trllloon of such WeB. ho ..... e'er. may not 'lUfflCC for effective treatment of serious infectiOl\'i C' used .. by lIOnlC specie~ ofGromncgatlVe bacilli. such as P. aeruf(;

gn-ater potency. 111(' acylureidopcnicillin,. unlike ampki lin. are unstable: onder acidic oondiIIOflS: therefore, w,) 1ft not avai lable for or.ll II(limnistratlOfl.

Protein Blndhag
The nature of the acylamino Side chain also delermines til: ex telillO which penicillins are plasma protdn hound. Qua wive stnJCt ure-act i~ity relalionship (QSI\R) siudies ci_ birKIing of penidlhns to human 5CI1Jm lI. '9 mdicate thal~ drophobl C: groups (pos'tlve 7r t1cpcnden....eJ III the side d.. appear to be largely respon"ble for increased bmdillf" serum proteins. Penicilims with polar or iQlIl/J,.-d substll1lellb in the side chain e~ h ibit low-to- intermedIate fmellonl rJ protein birKIing. AcCOfdingly, ampicillin. anKIticillin." cydacillin experience B 10 J()IJ, protcln bindtng. aOO c.. benicillin arKI ticarcillin sho .... 45 to 55<;{ protein bt 11lose "'ith nonpolar. lipophili c: \l,JbstiulI!'nts (n.:t.fcillin" isoxu.oyl pcnlCi1lin~) ~ IIlOn than ~ pruleln bound. lk penicillins with less comllle~ acyl groups (bcn1.yl~nictll .. phCllOxymcthylpenicillin. and methicillin) fall in lhe r.t~ of 35 10 IIO'J,. PrQIein bindil\g is thought to I\'~t rkt W, ii_ availabil ity of drug~ if the fmellon hound IS \l,JfflClC:nll)' hiP thUS, the tissue distribution of the penicillins In w, hi hound group may be inferior 10 Ihal of other penocilla The si milanty of biologica l half-lives for vanous pemann. howcver. indicate.~ that plasr1lll proIehl hindlng has hl~ cifcct QlI durJtion of action. All of the commercially aVlIbbit peniCillins are secreted actively by the rcnalllCliv~ traJII!K"l syStem for anions. The revef'i.lble nalure of protem bt.oKIiIt does not con1j1Ct~ dfccti"ely ..... Ith the acu'e tubular scattion ",ocess.
Alle'1l~

to Penkllllns

noso.
A SCntl!O of n-acylureidt.>-substituled penicillins, exempl ified by llI.1ociliin. 11lt:1Jocillin. arKI piperncill in. exh ibit great('1'" !lCllv"y against cenain Gromnc:gati,e bacilli thaJt carbenici llin. Although the aeylurcidc>penicillins are aeylated derlvatl\'elj of ampicillin. the anllbactenal ~Itum of activity or the ,roup is more like thaI of carbenicillin. 1l1e acylu",idopenictl lllls 1If!.". however. ~upcrior to carbenicillin against K/t'bsit'lla spp .. I;."IIIerobaclt'r spp .. and P. tJrru.s, "OM. Thi~ enhanced activity is apparently not due to ,Blar:tam:I.'-C rt:S1st:mce. in !hat both inducible and plasmidmediated ,B- Iactama.<oes hydrolyze lhese penICIllins. More facile pen-ctralion through the cell cnl'elope of these panicolar bactcnal 'pccies is the n\O'\l li l ely e~planat ion for tile

Allergic ~actions 10 "anou~ penicillin . rJllging IM:>C\UI!' from I variety of sl;in arKI mucous membrdne rashes 10.., fe>'er and anaphyla~ls, C Ollslltote the major probkm ti-lated ",ith the usc of this class of anublOl,icl. '>I1II1:Itl:5 pbr the preYalence of hypcrsen~itivity to penic illin G throoglXW the world between I and 1(Xf of the poputallon. In the L'. State> pnd other indostriali"tcd COOlllne5. It is ~am ~ higher fisure. rankins peniCillin IIII!' Ol(ht commOll CIiI!t. druginduced allergy. The penkillin' most fn:quently" Uled in allergic reactmnS are penicillin G and amp.-iF Vinua ll y 1111 commc:reially available I il . ho-.ol"a. have bcc:n reponed to cause: such en. sens it ivity among m()),t chcmkal classes ici ll anic add derivative, has been The c hemical mechanislllS by I lions becoIne antigenic dcnee !Wggcst!i that peniclllllU or their ~arroneH1tI' odS formed in vivo (e.g .. penic,lIcnic acilb)"'1 n:act. lysine t-amino groups of protein. 10 fonn penlC;]~! ~ lei ns, which are major untigcnic: determinnnb. u , E-'! clinical observations wi th the biosynthelic pcnicllhns (j. V ilKhcatcd a higher incidence of al~ic rcactlOllS. onpurified, amorphous prcparuliOOS than with highly fted. crystalline forms. suggesting Ih3t small 3""- ' high ly antigenIC penlcilloyl proteins present In ~mple~ were a eause. l'olymeric impurilie' in

Ctuo plfr 10 been impli,ated a.s pos..~ible anug..:nic posSIble uplanation for lhe high fre~ of lllergic reoclions with Ihi~ panicul:u ~misyn die!K: penicillin. Ampicillin is known to undergo pH-depen. . poIymeri~lItion reactions (csprdlllly in OOfIC('ntratr<l IOnS) Illal IMoile nucleophilic anock of lhe mle cham II1II1'10 group of ooe molccule on the ,8-laclam curbonyl cart... 110m of a iIOIId molecule. and so on." The lIigh fre~ (J{ anligenicity shown by ampicillin polymers 10,.mer \llilh their isolmioo :md cllara.ctcriulion tn some MlpK"illin prtp;1rJlions supporUllhe theory Ihal they can conIlbuIe 10 II.IlIpidnin-induced allergy.~'

AnllbuCl~n<1I AllllmOl;r-"

309

wge

form~ have ~manl1i end a

Prod.,ts
For y~;Jrs. lhe "'O~I popular pemclllln h;ls bren penicillin G. t)l" be,l/ylpenicillin. In foct. wilh the ur:eptiun of jXlllcnlS allergic 10 tI . penicillin G remams ,heagent of choice for the treatment of 111011;: ",fr~r;:nt ""K1~ of baclmal infeclion, han :m)' OIher amibiOlic. II was fiN '"ade 3va.ilable as the wotcr-liQlublc SII lt ~ ur poI~lum. IiOdlum. and calcium. 1be,<;e salls of penicillin are 10000""tr<l by the gastric juir:e and Ill'!: 1\01 dfe<:l1\ e I' hen admllll~lrred ornlly unless anlacid~. sucll a.~ calciulil carbonalC. aluminum 11),_ drodde, and magoesium lrisillcalc. or a strollS buffer. ~uch as sodium citrale. is :Idded. Also. becau~ pemcillin is absorbed poorly from the III1e51111al IllIll. oml dose, mUSl be vrry large. aboul 5 limes the amounl nece~)IIry I'ith parenIrrnl IIdminiSlflI'>on. Only oftrr the produclion of penlcilhn had increased enough 10 makc Iow-pnccd penicillin a\ ~il oble did the oml dosaGe form~ become populur. TIle watersoluble poIassium and SO(hum salts are u>r<l ornlly ~nd p;tr_ rmernll)' to aclllc\'e high phl.~ma conccmnlllOl1. of penicillin G rnpidly. TIle more wilIer-soluble pom~slUm )'111 u~ullll)' i_ prefcrred "hen large ~ are required. SiltJ..ItiOlls in I'-lIicll h)'pcritalemia is a danger. hul'e\rr, us 10 renal failure. require use of ,he sodium sah: the potassium ~ah i, preferred for 1 "1tie",5 on sal1 -fn..e diets or WII h ct)nge)lh c hean cOIKliIlorn.

Penicillin G.

i-

y-

" 0 " of

allSsiflution
tiesignal.ioOli ha\'e been usrd 10 classify pemci1lins. M.cd 011 lheir 1iOU~. c hemiStry. phamlOCokinctic properlin. mislurM.'e 10 enzymalic sJ)C(!lrum of acti vily. and clin i~(Table 10-3). Thus. penicillins llIUy be biosynthetic. _.)'nll1etk, or fpolenhally) synthetIC; acKl-resislant or Ill; ornl1y or (only) parenternl1y :lCtive; and resistant 10 (J... 111110156 lpenicillina.se5) or not. They may have II narrow. ",.diatt. broad. or t.uroded spoctnlm of antibac1erial I."Illily and may be Intended for muhipllrpo!lC or limiled " . ,I use . lk~igllalium ofllle aclivity ~~Irum as nanuw. ""moitdi:ue. broad, or t~lroded are relah\'e and do nOl nee :-:Iy imply lhe breadth of lherapeutic applicalion. Indeed, clmlficalioo of penicillin G lIS a " narrow-speclrum" IIIIb!oIic hoII; meaning only rdall\'e 10 OIher pen icillins. Althe {J-lactama..'\Crnistant penkilllllS have II ~l\Im .tltlinly SI milar 10 Ihal of penkillin G. lhey gencrnlly are Ir)med for lhe trelltmenl of in fections caused by penicillin G-lt::mtlUll. {J-lao:tlln;l.'\C.produ.cing S. UUUIU because thl:'ir ttIn'ly qllnst JllOt;t penicillin G-senslti\e bocteria is sig Mfl(1lMly infcrior. Similarly. carbenicilli n and 1Icareillin Nlily are re<;ervr<l for the taallllcnl of infections caused aaIpICilhnresistanl, Gram-negative bacilli because they no.!vantoge (a nd h.,\e some disadvanluge!l) over ampICllllo or penicillin G in infections sensi tive 10 them.
~_

..,.,

',"

,d

g-

'*

he

I,

I~-

-f-

,I,

'.
.,
~i-

'"

<-

:=-x:
10

Pet.

WiG

~oeiltln

The: rapid clnninalion of penicillm from the bloodstream Ihrougllthe kidneys by 0C1 i\ e tubul:u ~rctlon and lhe: need
maintain an crrl:C1h'e concentrJliOlI in blood ha~e led to lhe de~elop",ent o f . 'reposilory" forms of Ihh drug. Su,pen-

"g

"

~.

'"

'"

TAIlE 10-3

Classification and ',opertl" of Add ,talbuM.

P~icil1ins

of
0.-..

hin_

:r.
;~-

,
u,

Penlcll l1 n
p;iUI~

Sourc.
I'IK111~1C

.,d

.' 1,

_')_ylpMlicilJ,n

8i<ll;)nthtuc :km"lmhtu!;

CoooI

... .,.
F.

Abso .... tlon

Plum. 'roteln
Bindi.., I"')

~ct.mu.

Goot.I (CO)

''''' .,

Aesl5tarKfl is. _I'WUIJ

PoorI20)

o...ilU_

." ""

""

Stmi.)",bl:loc
~mIIYnlht"<

SwIo'~"'hruc
~l',.btdt

.,O,a

~m;,yn(ho1,.;-

""
"h nof

'"
lin

...... ...

,I

"'I'" :ot...,Uuo

Seusynllwri<:
Stmi..m.. ...

Stmi.yn<..... oc
S<'rroi;l'nlht'o<
Stmo'}~

"'., "'"" """ "'"" ....

Good

V..-

"'-.. ....,
,~

of Act;"ity

'poan.m

e1inlal

...

' >.ai, \.10)

Go<:>d(~) Good(~)

"'" ... .,...

N-l~

1896

,'0 ,-

,,, ""
'0

'"

.'""" '''''''

. """""'"
'11m'"

Irllcmw<l,*

~MtJl""P<"'<
Mu(lI~

Lo ........ u~
l~m,1td ~ ....

Nam....

LoIIIIW u~

,-

"-

u ........ "'"

" ..,,40)
(lood(1~)

.....
"""

).2j

Nil Nil

"" "

"""

" ""
"" "

fulC'--k<J

...........,..
Lo",,!Cd 11K

\tuh,,,,",,,,",,

" '" '"

'" ...

""....,

,,,.,,,",

" h .. rded

Lom ..........

'-""'IC'II

u,..

r-,1Cd "'"
Ltmoltd u....

sions of penicillin in peanut oil or sesame oil with white bcei .... ax added .....ere lillit used 10 proJoog the dunllion of inJCded fOll1l5 of penicillin. This dl:lNge form WlIS repl:lCed by a suspension in vegetable oil. 10 ",hich alumi num IfIOr)()stearale or aluminum di~learate was adm:d. Today. mOSlreposilOf)' fonus are suspensions of high-mohx:u lar-wcighl amine ~JIS of penici llin in a simillll' base.

;,=<o i=
,

Penicillin G Proc.i"., USP.

The lirlil widely used

'> . .

amine s:th ofpcnici llin G was made With procaine. l'enicilli n G procaine (Crysticillin, Durncillin . Wycill in) can be made readily from penicillin G sodium by lreatment with procaine: hydrochloride. This 5ah is consider.tbl y 1e!ili soluble in w:ucr than the alkali mellll 5:lIL~, requinng about 250 mL to dis sot-'e 1 g. Free: penicilltn is released onl y as the compound di ssol\'cs and dbsoclales. It has IIII lIClivity of 1,009 un its! mg. A IlIl'I!e number of prcpar.Jlions for injection of penici lli n G procaine arc commercially availuble . M06I of lhe.~ arc etther su~nsions in water 1 which a su illlble dis.pctSmg 0 or suspending agent. a buffer. and I pn:sc:rvllive Iua\'e been added or suspensions in peanUI oil or se~me oil tMt ha ve bt."C:n ge lled by the addilion of 2% aluminum 1Il0nOSlearate. Some commereial products arc mi~lures of pen ic illin G PI>' tassi um or sodiulll with penicill in G procaine: the watersol uble salt providu I'IlpId de\'elopment of a high plasma C()I'tCentrntion of penicilli n. and tile insol uble ~1I prolongs the duration of effect.

-,:=x:
';,

"

o
~oicl.;n

G BIt\uIIIIne

~ r o

In 1~8. Bdll~ns ct a1..... IcpOiltd penicillin V. phenoll.yme:thylpcnicillin (Pen Vee, V-CilIiaI as a biosyntnelic product. It was not until 1953. howel'ef that ils cli nical value was rl-oogni/.ed by some EuIOJUl scicnti sts. Since lhen. it has cnjoyed wide: use because of iii resistance 10 hydroly~is by ga.<itric juice and its :ability II prOOllCC uniform concemrations in blood ( .... hen admiJIi$. lerc:d onJly). Thc free acid requires aboul 1,200 mLor ...... 10 dissoh'e 1 g, and It has an activity of 1.695 un its/mg. Fer pare nteral solutions, the potassiu m sail is usuall y used. Thi salt is very so luble in water. Solutions of it an: made fn:. lhe dry sa lt Dlthe time: of administralion. Oral dosage f~ of lhe potaSsium ~It an: also a\&lhible. pro\'idingl1lpod. rffeclh'e pl asma conccntratioo~ this p!."nicilli n. 1ltc: pheOOli. ymethylpenici llin with N.N' -bis(dchydroabiClyl~ ylene<liamine (hydrublimine. Compocillin-V) provides I very long-acting form of this compound. Its high water_ ubi lily makes it a dC':sirable con\pound for aquoous 51ISP sioos used IS liquid oral dosage forms.

Penicillin V, USP.

'" "\ ,

or

sO.

;
;

Penicillin G f'faQIne
Per*' 'n:., v . "SP "

~>
Methicillin Sodium, USP.

Pen icillin G 8~nz.thl"', USP. S ince: pcnid l1 in G benzathinc, N.N'-diben~ylethykncdiamine dipenicillin G (Bicillin. !'ermapcn). is IIIe JIll! o fa diamine:. 2 moles of penicillin
are &vlulable from c!lCh molecule. It is \'cry insoluble in water. Il'quiring about ),000 mL to dbsolve I g. Th is property ,hes tile compound great siability and prolonged duration of effect. AI the pH of ga>tric j uice it is qui te stable. and food imate doe! not inlat'ere wilh its absorpIion. It is a\ailable in tablet form and in a numbel- of parenteral pll'parntions. The !lClivity of penicillin G ben1.alhine is eq uivalent to 1.211 units/mg. Several other amines M \'e been used 10 make pen icillin salts, and rc:se~h is conti nuing on tbis SUbje<:L Other amine:s thai havc been used mclut.le 2-chIOloprocainc; L-N-lTII:thyl1.2-diphcnyl-2-hydRIlI.yethylami ne (L-ephenam ine); dibenzylamine; tripelennamine (Pyriben7.amine); ~nd N.lv'bis (dehydroobic tyl)ct hylencdiamine (hydrnbam ine).

During 1960. mcthl('illia,. dium, 2,6-dimeloolyphcnylpenicillin sodium (S1:qmllill the second penici llin produced a$ a result Of lhe rescan:h_ de ve loped synthetic analogues. was introduced for medicitll usc.

.'\, -

o
,
HI'

lieu c ill i
0

~"

./
......" '&.IXI.1un ts

o'

)=

kidn m th lite

~H'

Chapt f r 10 . A.ntlhat:fnialA.nflmork . Reacting 2,6-dimelho.tybcnJ:oyl chloride wilh 6-APA ~ 6-(2.6-dimelooxyben1.lunido)pcniciUanic acid. The mum salt iJ a "hite. crystalline solid thai is utremely tIII\IbIe in water. fonning e lear. IlCUt!""tI solutions. As with GIber penicillins, it is very sensitive to moisture. losing aboul .u- of ilS activity in 5 days at room temperature. RefrigcraIIOIIl S"C ~uce5 lhe lots in activity to about 20'1> in the _ period. Solutions prepared for ~nlel3l usc may be. kp.as lon, as 24 hours if ,drigenlled. It is extremely seMi m 10 acid (a pll of 2 causes 5O'J, 10$5 of activity in 2(1 ....... ): thllS, il CIlInoI be used orally. Methicillin sodium is panicularly resistant to inactivation ~ the pemcillmase found in SlIlphylocci and _"hal .ore rtSiswn than penicillin G to pemcillinase from Hacil.uF"fu. Methicillin and many other penicilli~_re<islam pnticil1ins induce penicillinase formalion. an observation b hili implications concerning usc of these agents in the tJeal/IleIlt of penicillin O- scnsitive infections. Oearly, the: ria pe:niciliinasc-resiSlwlI penicillin should 001 be fol lawrd by penicillin O . The ab!lcncc of the benz)'lmcthylene group of penicillin GDJ the SlerlC protection afforded b)' the 2- and 6-methox)' poIIpi mlIke this compound panicu larly resiSlnnL 10 enz)'MIC hydrolysis. M cllticillin mium hu~ I)c,en introduced for U'\C in the mlment of slllptlylococcal infections caused b)' strllins reNaIll to OIhcr penicillins. II 1$ recOllnncndcd that it nOi be lied in gener1li themp)', to avoid the possible widespread "topmenl of organisms resistant to it. The illCideTIcc of interstitial nephritis. a probable lI)'pe:r. ...uvn), ruclion, is reportedly higher with methicillin than .. ocher penicillins. Oucillin $OdiLim. (5-mcthyl~yl-4-im:uzolyl)penicillin sodiLim monohydrote (ProlIIpbIiII). is the salt of a semisynthc1ic penicillin that is iiplylUistant to inac1iv8tioo by penicillinase. Apparently. tr:wnc effects of the J-phenyl aod 5-methyl grQ\lp5 of the ltIw.oIyl rin, prevent the binding of Ihis penicillin to the ~ active site and, thereby. pnXeCI the IlICtam ring ... qr.Iation in much tnc same way as hal; I)c,en wg. - for methicillin. It is also relatively resistant to add ~ and, therefore. may be administered orally with

311

OOt is Ie5s avidly protein bound and more rapidly u crett:d. The halogenated analogues cloxacillin. dlc loxacillin. and noxacillin experience 1 5-methyl hydroxylation . l'SS The IIscor oxacillin lind ocher isoxal.oIylpenidl hns should be restricted to the treatment of infections caused by W\ph) loeocci resiSt.aIllIO penicillin O . Although their spectrum of acti"ity is similar to lnat of penicillin 0, the isoxv.oIylpeni cillins an:. in scnentl. inferior to it and the phtooxymethylpenicill ins for the treatment of infccllons caused by penicillin O-sellSit;"e bacleria. Becausc they cause allersic reactions si milar to those produced by other pen icillins. the i!iQxazolylpenicillins should be llsed with great caution in patients who are penicillin senSitive.

illin) !vcr,

"''''

)f '""

its t)' to ,inisvater

CIoxadllin Sodium, USP. The chlorine atom onho to the positioo of D ttachment of the phenyl ring to the iSQxlUoie ring enhances the activity of cloxacillin ~ium, l3-(o-chloropheny l}-5-methyl-4-iSQ.uzoIyIJpeniciliin sodium rnooohydrate (Tegopen). over thaI of oxacillin, 001 by increasing its intrinsic antibacterial activity 001 by enhancing its ()f1I1 absorption. leadi ng to higbcr plasma leve ls. In almosl all other respects. it resembles maci lhn.

. For This from

1. ef-

~"

lit of )eth-

,
.... o j; ()
Ctn, .,. I SDdium

~.

.J'O'"

,"",

0udINtl Sodium, U5P.

pi d"fect.

in so-

mi n). h llult

Dic/oxadflin Sodium. U5P. The sul>5tuulion of chlorine atoms on both carbons onho to !he position o f attachmenl or the phenyl ring to the iSQ~azoIc ring i5 ~med to enhance further the stability of the o,"acillin congener dK:loJiacillin sodium. 13-(2.6- dichlorophcn)I )-5 methyl-4iSQxuolyl]penicillin Wdium mooohydl1lle (Dynapen. Palhoci!. Veracillin) and to produce high plasmaconcenlJations of il. Its medicinal properties lind use arc similar to those of cloxacillin $Odium. Progressi"e halogen substitution. how ever. also increases !he fraction bound 10 protem in the plasma, potentially redocing the conccnll1ltion of free antibiocic in plasma and tissucs . lIS medicinal properties and usc an' the same as those of cloxacillin sodium.

icinul
Ol<Klllln Sodium

",

O).lciUin JOdiu m. which is available in capsule form. is tIDIIbIy well absorbed from the gastrointestinaltrnct. par I Iy in fast ing patients. Effective pla.~mll levels of o~a . . art obtained about I hour. 001 despile e.ttensi,e is excreted I1Ipidly through the some rim -pass metabolism I derivative. This metabo10 thai of oxacillin

Naf cillin Sodium, U5P. NDJcillin sodium. 6-(2-elhoxyI naphthyl)pcnicinin sodium (Unipen), is another scmisyn-

............ ----------------thetic pt'nicillm that rcsuhcd frol1\ the search for pelllcillinase-resiSlDm compounds. Lite nlethicilhn, nafcillin has substilucnlS III P'O"JIIonS onlw \0 the point of auachmem of the aromatic nng 10 the cnrbo~amide group of penicillin. No OoiIbt. the ethoxy group and the secood ring of the nap/lIha!ern: ,roup play stene roles In slubi1i~ing nafcillin agDJII'>1 pt'nicillina<;e Very similar structUI"C,'i ha~c hccn reponed 10 produ.."e similar Il'sulb HI some SUbsUlUlOO 2-biphcnyJp'mi1.'1 II HIS. " '

"

NaIc:II\irI SocWn

Unlike mdhicillin, narc, lh n is stable enough in add 10 remm n ~ u<;c by oral udl11; niSlmhon. When i. I~ given or.llly. liSabsorpIion is SOITlC'I\ l\aI slow and illCQlllplcle. btH sati~fllC lOry plasnlD lc,el~ mu)' be ochicvcd In ubout I hour. Relatively small amounts are ucreted through the kidneys: mosl i~ eJlcreted In the bile. Even though some cyclic reabf,otption from the gut may occur. nafcilhn g;"CR orally should be n'udminiSlcn'd e'ery;l 10 6 hours.. Thi ~ .;art 1'; reatlily SQluble in "011 and may be admini~tc:red unr.ln\UloColarly or intrJI'enl)Usly to oblnm high plasma ~OtlCC1llrullon qUICkl y for lhe lI'catment o f serious infeclions. N8f~'i l1in sodium may be used in Infections caosed wlely by pemeillm G~n::~i~hmt staphylOCOCci or .... hen stn: plococci II/"(' pn::.'iCnt ol~. Although .1 ;\ recommended that II be used c~clushc.'ly for soch ll!l>iSlam infeclioll~. nafcilli ll is al~ d fecli"eugaillS! pneumococc i and ~p A P.hemol)tic ~Ircp lococci. Becausc. like other pellicillin~. il ma y CllU r.c all ergic Side cffa:ts. II ~hoold be admini~ter.!'d with can-.

Ampicilli n IS II~ reslslaJlt to pen icillinase. and il ~ the allergic reaclions and ~hcr UIllOWard effects f()\lnd II penici!li n-S('Miti ~e patients. Because such rl:lICtiom mm. ti "ely rare. howe,'er. it may be u5Cd to treal in fections. Clll.1td by Oram-ncgative bacil li for which a brood-~ pectrum Illl\ibtottc. such as a letrlICyciine orehlorumphenicol. rna) catt'd but not preferred becauJoC of undesirable reacllOll' II lack orbactericitbl effect. Ampicillin is not sowidcly actM however, IIIIlt il should be used as a broad~pectrulll antD otic in the $lime manner as the Icuw::yclines. It is pMlicuLvl) useful for tile I~atmcm of neute urinary tract IIIfC'ClICII caused by coli Of Proltus m,robi!is and is the qnt ttl choice agaillst Hilemophillls i'if/utn;:J'I' lIIfCCliOf15. Atnpk'IIlin logclher wilh pcobc:lICCid. 10 inhibit its &cu,'c tubularu cn:t;on, has bel..'Orne a Irl:atmenl of choice for gOllolll" II recent yean:. P.Laclantase prodocing Slr~j ns of Granrnep liye bllCteriu thaI an:: higlily reslsmlll to ampicillin. ~t'olf. appear to be increasing ill the ....orki populalion. n.: d\n:l from such resistant SlmlnS is panicularly greal .... 1111 H.... fiutnZ(.lt and N. gonorrlwta,. becaU5C there are few aJIcnu. tivc Illerupics for infections cau<,ed by thcr.c llIlam.lllComplele ubwrption and CAC"relion of elTccuye concnt/t tions in the bile may contribute to the effeclivellCSfof-. c illin in the trealnlent of SlIlmonellusis and shlgelQ.i~ Ampicillin IS w:Hcr soLuble and smhle in acid. n.: pi'" ated a-amino group of ampieillin has a pK. of 7J .* and il is pro\onaied eJ(lcns;"ely in acidic media ..... hich ex

br_

Ampki/lin. US".

AmpICillin. 6-!I) ..... ammophellylllCCtamidojpenici llall ic acid. l>- ..... aminob<:lIl.y lpemcilii n (Pcnbri len. Pulycilhn. Omlllpcn. Amell!. PrillCipen ), meets anoth." goal of the research nn 5Cmisymhetie penicillins -an umi baclenal spectrum broader th:m that or pemcillin G . This prodllCt is IIoChle ugmn~t the SlI me Gram -posi ti ve orgallism~ t h~t are sw;cepllble to other pellicillillS. and il is nlen octi,'e agaiMt some Grum -ncgative bacteria 1lnd entenx:oeci tllan an:: other penicllllll~. Obviously, the ..... amino group pLays an important role in the broader ~tll'ily, bullhe mcchamsm for its lIC1ion is uni;nollln. II has b.!cn suggeSied Illat the aminu group confer.< rill :Iblilly to cross cell wall barrier.< that an:: impenetrabk 10 other pcnicillms. D-( - )-Ampici llin . prepafl:d from D-(- ). a .amlllopncnyhicetic ac id. is significantly more :M;!Jve than 1.-( + /-ampicilli ll.

ampicilli n' stabili ty 10 acid hydrolysis IUld instabl:';"~"~.:' kalioo hydrolysis. It is admi ni~lered omlly and is from the i nte~nal lraci to produce peal; plasma COII'utI. lion s in aboul 2 hours. Orul do<,e~ muSI be repcalw" evcry 6 houB because it is excreted raptdly and unc~ througll lhe kidneys. It is available as ~ " hue:, Cf)'Su!\tI!. anhydrous powder thllt is ~paringly solubk in ....lIIa ox .. lhe colorless or ~I igh.lly buff-culorcd crystallllle ~h, lhat is soIubk ill ....OIler. Either fom\ may be used adllliniMration. in c:t.p;;ules or as a sU5pcn~ion. Earlla daiII of higllCr plasma level5 for the anhydrou.~ form lhan f(lit trihydr.ue following orul admini~tration ha\'e been III,. puted.~l ... The: .... hUe. crystalline ~iul1l salt is \"C'I) in waler. and solutioM for inJCCl10ns should be lIdml~1 within I hour after being made.

..

8 acantpK"1I1111t drocJtloride (Sp'trobid) i~ tile hydr()I:hloride sail of th: cthoxycarbonylmycthyl csle:r of . It IS a ofumpicill inwith ; I Iloo. bacampicilhn is h)"droLy.r.ed plasma 10 foem ampicillin.

Bacampidllin Hydrothlori<k. US,..

"

I'"

'0#"-./

" -r-

" "

:y::
"IJ>
0

"'IV"

.,n. IISP

Orul Ubsorption of hacampicillin is n"lOR: rupid and pkte lhan thai of ampicillin and Ie.~s affected by foeti.

INb of ampicillin from oml bacampicillin exceed those oral ampicillin or ;&nlt))licilhn for lhe filS! 2.S hours bul Mufter all: the -.ame as for arnpiciltin and amo~icillin"9 j~e plasm.J b 'ds are SU5Uuned for 12 hours. allowing l'aICN-Wy dosi ng.

NrtoxkiJIjn, U5P.

Amo\lcillin. 6-lo-(-) t)-a rnino-p~,Jrolyphcn)'LaccbmldoJpenlciJlanic acid ( Amo1il . LaroPol) IIIQl ). a o;('misynlhetic penicillin introduced in 1974. .~mply the p-h)'drolly alUlLoguc of ampicil ' in. ~parcd by ""laioo of 6-APA ..-ith p-hydro1yphenylglycine.

~o

. ;=0

Carbenicillin OitodI\ll1'L, USP

"'1M 1''<1. USP

III ;!I]ulDcteriaL 'IICCtAlm is lIl'arl), idemical with Ihat of hLe ampicillin. il is reSI~t1U11 to acid. SUSCCPIi ' and ,8- laclama.'ie hydll,l L ysis. and weakly procl inical reporu indicated thaloraJly aIlmin. III possesses I I ad"nntagC':S over I gllStruintes.cin:ll absorphtPler plasma urine levels. less diarrllea. or 110 cffcxct of food on absorpIiOll .3(/ Thus. om01 iI replacw ampictllin for the treatment of "=:~~::~ and unl1ru)' trnel inrecllon~ for which oral ~ is dc~irable . Amo~ici l hn is reponedly less than In the treamlCnt of bacillary dy bcC1LUse of its greater gastrointcstinal su/!.8csIs that 01111 ab. penicillins (e.II .. am LS. at lust in their generally supt

Carbenicillin i~ nOl ~I oble in acids ornJ IS inactivated by jX'nicillinasc. 11 is a mnlonk acid dcri vall\'e and. as such. decarboxylutes readily to penicillin G. "hlch b acid I::Lbile. Solutions of the disodium sa il should be freshly prcp;.Lred but . .... hen refrigcrutct.l. may be tcpl for 2 " cd.s. It mu'il be adml nislered by injection and IS u<;ually gi\ en IIIlr.1lenOl.lsly. Carbenicillin has been effl'Ctive in tllC treatmenl of sy' temic and urinary trnd mfccllons caused by P. utf1lgimm', indo lcproducing I>roltus spp . and I'ro"ii/tnt;a \fIp .. aIL of which arc resistlll11 to ~mpicil lin. 1lIc low tolllClty of carbenicillin...... lth tllC cxcepllon of alLcrgic ilen~iti\ Ity. pennilS the U.e of large dosages in SCTioos infections. MQ:;t clinicians .jln'fer to usc a oomblll!lllon of carbenICillin arnJ gemonnclII for SCriOll<; psc:udOl1lonalnnd mixcd colifor11llllfcclions. 11le t..... o lII1tibiOlic.s arc chcmu:ally incompatible. howevcr. and should never be combined in an in1r~I'Cnou, <,(lluIIOll.

a filll' ..... hite to off .... hlte. crystalline pow. solublt in Waler. It is available in a forms. Aqueous suspensions lire st.ablc

c.rlJen icillin Indanyl5odium, U5P. Effons 10 obtDII1 orally activc forms of carben icillin kd to the el'cmual rclcase of tllC 5indanyl estcr carbcmcdl in mdanyl. 6-12pheny l 2 (Sin<lnnyl01 ycarbonyl)acctanudo Jpt:nicil b nlc add (Geoc il lin). in 1972. ApProximately 4O'k of the usua' orol doo;e of indanyl carbenicillin is ob>.ofbed. A fler nbl;orl'"on. lhe e,tcr is hydrolJ1.ed rupidly by plasma and tis,suc c~tcrases 10 YICk! carbenicillin. Thus.. although tllC highly lipoptnllc and highly protein bound e\lcr hu_, in vitro Oct" ity comp.lmble wi lli that of carhcnicillin. il5 pclivity in ~,,'o i5 due to carbenicil li n. Indanyl carbenicillin thus pro' Ldc\ an Of"~lIy acUI'C alter JUll ive for the trc~tmcm of carbcnicillinsensitive systcmic and urinary traC1 inre!.1KlnS caused b) Ps~udf1mOfUU spp .. indolcpositi\c I'roteu.f spp.. and selected ~pecie,~ of Gr,lm IIl'gative bacilli.

O;jod;um, 5terile, U5P. Carbenicillin diKLdium a<arboxybcm~)'lpeniciliin (Gropen. L penicillin released in lhe Unitcd was introduced in England and first ~l in 1967. UBLlullation OfitSS1WC. II dIffer!! from mnpicillm in having an joniz group Mlther lhan WI amino group stLbI;lituted of the benl)'1 side chain. Carbenicillin antimicrobial lICtivity. broader than llI1y penICillin. 3 propcny attributed 1 tllC unique 0 h thallhc carbo~yl group I through cell wa ll bar bacIlli. compared with 0thcT penicil

'rU:
HIt'

"

}=o o

Carbenlc:ilWn IndanyI Sodium

Cli nicnl trial s with indanyl carbenicillin revcaled a rclu lively high Frequency of gaslrointcstinal symptoms (nausea.

occasional vomiting. and diarrllca l. It seems doubtful tNn the high dose, ~quiml for the treatment of o;erious ~yMemic infections cou ld be IOlemtt'd by most patient~. Ind~nyl car ben icillin occurs as lhe ,;odium salt. an off-while. biller powder thai. is freel y w luble in water. It is Stable in acid. It should be PfQIe<:led from moisture 10 prevent hydrolysis of

effect on bl~ing lime than carbenicillin. and il is less bl.cl) to couse hypok alemia.

t'-' esler.

Piper.clflin Sodium, Sterile, USP_ Piperacillin (f\. JlIlICil) is the most gCllCl"1IlIy 1.Iscful of tile utended-spmr. acyI1.lR:IOOpcniciliins. It is more acli"e than rnnIoc!II. against susccp'ible strail15 of Gnam -negati\e aerobic bariIi

r/CiJrdllin Disodium, Sterile, USP. TicatClllin disodium. a-c:arboxy-3-thlenylpenicitlin (Ticar). is an iO\OStere of c arbenicillin in ..... hich lhe phenyl group is replllCCd by a Ihieny l group. This scmi~ynthetic pen icillin derivative . like ca rbenicillin. i~ unstable in ocid and. therefore. must be administered paremel1l.lly. It is similar to carbenicillin in amibacterial SJle<:lrulll and ptwmacotinclic propenlcs. T .....o ad\'aIluge:s for lltardllin are claimed: (aJ 51 ight ly beUer pharmacokillCtic p'openics. including higher serum lewis and I longer dur.llion of IICtion; and (bJ i!:reatCT in ,itro (JOtency against scwcraJ species of Gram-ncgDth'e bacilli. n]()Sl notably P. u.. /1j/J;'WS(I and &.cr..roi,frs/rogiUs. 1lIe~ ad\'amaGes can be cruc iul in the trealment of s<:riuu~ infections requiring hig h-dose the mpy .

such us s..,ro/ja nl(JfC~SCt:ns.

IrobfK:ltrspp .. and p_

P"()/~Us, !';n, .. ro/xJc:It:r.

.oo Q.

U~l1IgU105Q. Me~Jociliin.

howe\n.

pears 10 be more active againsl Prol"idl'nci(l SW- IIId K Im~"nllHlit,l'. Piper.JCiliin is also !lCtivt: against anae hb. bacteriu. e\peciol1y B./mgilis and S./"'CII{jS (e fltci OCOCCiI6l p.loctamaseproducing Slmins of thc.<oe organisms art. '--evcr. res istant to piperacillin. " hich is hydrolyted by ,tUS fJ-lactamase_ 'The ,8-lIIctama..<.e susceptibility of ptpmo cillin is not a~lute because fJ-lactamase-produdli. ampicillin-resistant strnil15 of N. gllllOrrhOt:llt and H f1l/t"::fl~ arc su<;ceplible to pipencillin_

s..

.".

~..!.

" "

.)* 0'
~o;JIIin

')izMitan

M ezfociflin Sodium, StMk. USP. Me1.lodllin (Metlin) is an acylureidopenicillin wilh an antiba<.1erial speClrum si milar 10 thaI of carbcnicilli nand ticarcilli n: however. there are w me m~jor di fferences. It is much more lICIive against most Klt:bsit:l{u spp .. P. /,t:/1jf/i"os(l_ anaerobic bacteria (e.g .. Slr~pIOCfJCCusf/lafiJ nnd B./rugifjJ). and H . iIljJu~fI::flt:. It is ra:ornmcnded for the trcalfnefll of scrious infections ClIused by thesc or~aniSnt!i_

Piperacil1in is destrOyed rapidly by stomach acid; fore. it is acti\e only by imnunu 'iCularor intfll'enous .... istnuion . 'The inJcctable form iJ pro"idrd as .he "bile. .".. tallillC . waler-soluble propenies are "cry ~imi1nr t( penicillins.

sodii,":'m:~':'~f :" :~ ,:~~:::::: "

{HACTAMASE INHIBITORS
'The Str-lIcgy of using a fJ- laclllmase inhibitor in com
wilh a .8-h,clanlase-scnsiti~e penicillin in the thrrapy infcctions caused by ,8- lactama.'Ie-prodocing bacterial has. unti l relatively recently. failed 10 live up to its obi .. promi <.e. Early a\lempts to obtain synergy against .lOCh In lam strains. by using combinations consisting of I mase-re$iWUlt penicillin (e.g .. mcthidllin or compclit"'e inhibitor and I ,8-lactamase-sc:nsith'e (e.g., ampicilitn or Cllfbc:nicilhn) to ).;ill .he organism... wilh luniled SUCCC!iS. Factors I ure of ~uch combinalions I the cell e iIIinase-re.~iSlnnl conce/lll"1ltions 10 prevent I

" "
o

"zI.,

ttln Soditan

Mellocillin is not genemlly effe<:t;'c against fJ-Iaclamaseproducing bactCOIl. nor I ~ it active onr.lIy. It IS available as a "hile. cryslalli nc. wOler-soluble sodium SIll! for injection. SolLltions should be prepared freshly and. if not used within 24 hours. refrigerated. Me~locil1 i n and oIher acylureidopeni~,\\\\"\\,

to'!..\\'\\'.\. ~\\~ ~ nelies. Pea).; plasma levels, half-life. and area under the lime curve increase with increased 00s3g(:. Me7.Jocillin has less
'l\"\\i\J:.

~..rot.\\\c\\\\\\ ,

Chllplu 10 A.nlibtrftrial A.lllj/MIi<"I

315

> h~ely

_((I tbe induction of ,8- lact.amascs by some penicill ina.-.e,I "N

n (Pibacilli.

p"'N m

ocillin

and Ciand K.
how(JU'

~er.ap

I3erobic

1)Ccu~).

n".

Y S.

piper.lodocing. d II in-

pmicillins. The discov~1)' of the naturall)' occurring. m~chani5m_ btIcd inhibitor clavulanic acid. which causes potent and pro-pmi'~ inactivation of ,8-llIC'Iamases (Fig. 10-4). has creatoo IISItwcd inlel"CST in ,8-lactam combination thempy. This in~ has led to the design and ~)'nthesis of additional mecha-.based P.lactamase inhibitonl. such as sulbactam alld ~. and the isolation of nalul1Ill)' OCCUlTing ,8- lac- . ~h lIS the thienamycins. which bolh inhibil ,8-lacta_ and inlertlet ..... ilh PBPs. The chemical events leadi ng to the inactivlllion of P.lacta_ by mechanism-based inhibitors al"\! very complex. In I rt"!~w of the chemiSlry of ,8-11Cla1T135e inhibition. l.,.-~ has described IWO classes of ,8-llICtanmsc inhibi lOll; claM I in hibitors lhal have I hetcroatom leavi ng group pDWon I (e.g . da,ulanic: acid and !KIlbactam) alld cltiS m 1IIIIIbitOO:lilai do no( (e.g .. the carbapenems). Un1i ~e competibl'e inhibitors. which bi nd reven;ibly 10 lhe enzyme they F"bIt. mcchanism-bia5cd inhibitors react wilh the enzyme _.-:h the same way that the SUh:stratc: does. With the ,8lK1Ima>e:s. an llCy1enzyme inlermedi:lte is formed by re(>C tatof the .8-lactam wilh an III:tive-sile serine: hydroxyl group oftbeenzyme. Ftx- norma1 substnltes. the acylenzyme inter..Ii,,~ readily undergoes hydroly~is. destroying the sub.... .00 frtting the tnzyme to allack more !KIhstl1ltt. The qltnqme mtermediate formed when a mechanism-based .11111)1" is Pllac:ktd by the enzyme is divtned by 18UIO..urn 10 a more stable imine: form th.at hydroly7.<'s tnO<\"

slowly to e\tntually free the enzyme (transient inhibition). or for a class I inhi bilor. a second group on the enzyme may he aUlICked to i noctivate it. 8 ause these inhibilors arc: also ~ubslrales for the enlyll1CS that they inactivate. they ~ somelirl1C!l referred 1 IS "suicide suh:stralcs." 0 Because lhey cause prolonged inactivolion of certain .8lac:tamases. dass I inhibitonlare paniculatly useful incombi nation with extendedspectrum. ,8-laclamase-sensilive penicillins 1 lreal infections caused by ,8- locuunase-producing 0 bacteria. Thn::e.sueh inhibitors.. cla vulanic acid. 5111bac:tam. and tv.obactam. are cumnlly marl:ttod in the Uni ted SlltCS for Ihis purpose. A class II inhibitor. Ille carbapenc m derivative imipenem. has poIcnl antib;acterialllCtivity in addition 10 ils ability 10 cause lrnnsitnl inhibition of 5(IIIle ,8-Iactamases. Ctrtain umibacterial cc:ph ulosporins wit h a leaving group at the C-) position can cause tnlnsicm inhibition of ,8-lactamases by forming stabi lized IICylell1;yme intermediates. These are di5CUssed I11()f"C fully below in Ihis chapter. 0 1l1e relat"e susceptibi lities of various ,8-lactamascs 1 inactivation by class I inhibitors appear to he related to the molecular propen ies of the en7.ymes. ~:I<.!J P.Loclama.-.es belonging to group A. a large and somcwh.al helerogenous group of serine: tnzylllCS. some wilh narrow (e.& .. penicillinasesorcc:phlliosporinases) and some wilh broad (i.e .. genena! ,B-Ioclamascs) &peeificiLies. lite generally inactivated by class I inhibi tonl. A large group of chromosomally encoded serine. P.laclamases belonging to group C with specificity for cephalosporins lite. howtvcr. resistant to inactivation by class I inhibitors. A small group of z.nl. requiring metana-

>

ad; tnc:reus admin ,'lite. cl)'s lI,:ol.inetk ;ylureido-

mbmation acmp)' for tial ~tmi n' tS 00\ iOu, weh re~I' ,8-lacu

:inin)

a~ I

penicillin

CIIt U

psoas. nle'!
10 Inc: fatl-

JlIe (II) tnc:

pc:mcil hn~

I bacilli In Ig of pcni. ~iring high

Il)'drol)'sl~.

T....1iont h. iiIlr' 'NI

Figure

10~

Mechanismbased inhlbolion of P.lactamases.

,8-11amases (group B) widl broad substl"llie ~PCClrlCit ie~-lI> are also not inacli\'llioo by dan I InhibitOl'li.

~
~x

chai

C!a>'ul:mic acid i~ Dn!llltlbiotic isolau:d from Srr''I,mm\"Cr'J dlll"uligfri.r. Structur all y. it i~ II I -()~opennm lacking lhe 6-llCylnmiliO side chllin of penicillins but posscs.~ing D 2-h ydro.l.ycthytide~ moiety al C-2. Cilindanic aci d e~hibilS >'cry weak antibacterial activity. t"OfllI);lr:lbk: willi tlutt of 6-A PA IllMl. lherdon:. is not UK.fula~ !Ill anlibiOlic. II i~. ho,,ever. P pOIenl inhibitlll" of S. (IIIft'U.r ,8- lactamase and plllSlllid-met.hall'd ,8-lanamases elabonued by Gnlm-negati>'e biocilh.

Produtb C/avu/anate Potan;um, USP.

"",
"~,

.~

, "

Fill.oo-dosc cOlllbi n:lt;ons of ampici ll in sodium aIlll ... bactam sodium. markeled under the trode name: Unas)'lIa 5teri~ powders for injection, have bet:n approved for II$t iI the Unt ted Stales. TIlC..o;e I:ombinations are recommended for the lrelilment of skin. tissue. intra-abtlornlllaJ. and I)'neel' logical infect,olu caused by P.lacl.llmase-pnxIucmg 5InIII of S. IllImlJ, . coIj, KIr'bsir'lkl spp .. P. m;rabilis. 8. fro. and i::nlt'robuc,,., and ACtnetiJbaC"ltr spp.
Tazobactam. USP. Tu.obactam is a pcnicill:lIl1( a:tI sulfone thlll IS "inlliar in struclure 1 sulbacl.am. It is._ 0 potent P.lacIHI1I~SC: IIIhibilOT lhan sul bactal1l H and No I slightly broader spe('lrurn of activity than c1avulanic has very weak ~nt ibacterial ac. i~i.y, T a7.0bactam i~ 1l':IlI.tblt: in fi~tddosc. injecl~b1c combinJtions with pi\X'l1ICl lhn.1 broa(hpcc:tru'll peni('illin consisting of an lI: I nl1 io of p!ptI. acillin sodium 10 t~.tobal.'tam sodium by wei,ht an.J .. ki.'Ied under the trude nlIHle 'losyn. lbe pharmaoo~incllO" lhe 1"0 drug~ are \'el)' Similar. BOIh halC shon half~~ (I. - I hour). a", mimmally protein bound. ClIpcncnct" ~ lillIe metaboh~m. and excreled in acth'e fom\! urioc In high conc:c:nlr.lllons.

,',,'
I1:lat in w

Th< C-2.

'"JO ;"'"

,
n
baCl(

aod..

nnd Ille potu~slum sail of elavulanic acid are available (AuXIl"ICntin) in a variety of fixoodose oral dosage forms intended for the I",annenl of Skill, re."PlllIt(ll")'. ellr. and urinary lract mfeelions caused by ,8-1actama.;e-producing bacterial ~t r.aln~. 1lle'lC" I:ombinalionS a", dfecU\'e agaill5t ,8-htclamilSt'-produci ng "'r:lIllS of S. uurl"u.r. . rtlli. K. f'm!u'lUHliul". i::11Il"robtlOler, 11. injlur'n;tlr'. Moru.rr'//ll CUf/lrrllllli.r. and II. duerr',i .. hich lilt ttSislanl to alTlOticilhn alone. The oml bioa\'llilllbility of anlO~i dllm lind pot:lSl'iu'll clavulan~le .. ~"lIIlar, Clavutanic ~id is acidst ab~ , It cannOl undergo pcnidllanic ocid formation beeause il locks an ~rnide side chain. 1'001I!.s ium d a\'ulanatc ~nd the e~lendoo-)pcctrurn penici llin 1karci Ilin havc been COlnb; nl-d in II fi.l.ed-dose . injectable form for the t'ootrol of seriOlIS i'lft'Clions I:llu..ed by,8- lactamase-producing bacterial s!r:lins. This rou lb; nation has been recommended fill" scptiCo.'mia, lo .. cr rcspirnt(ll")' trocl info:: !Ions. and unnary tract infeclion~ cau~d by ,8- lactamaseproducing Klr'bs;r'//a lipp.. E.. cmj, P. Ul'rox;nQSlI and other PSr'IIi1lJ11lOnm spp.. CitrobtlC"ll!f ~pp., C",uOOocurspp .. Su'mill nIllrcr'sC't'ns. and SlIlph"'(i'C(XXllf IIUrt'II.~. It ;tISQ is used III 00ne and joint infections eaused by lhe..;e organi~ms. 11le combmallon rolllams 3 g ofticlIfd lhn disodium and 100 mg of potas~i um cJa>'ulanalc in I ~'erile: powder fill" injection (Timenun).
Sulbactam, USP. Sul baclam is penicil1anic acid su lfonc Ill" I, I-dioxopc:nicillanic acid. This ~yrnho:lic penicillin deri> ali\(: ;s II potent inhibitor of S. UIITf:U.f ,8- lacuulI~sc as " 'ell a.~ many ,8-lactamases clabonllcd by Cr:lrn-neg~ti,e bal:iIli. SullxlClllm ha~ " 'C8 intrinsic ~ntibactcrial :IoC\l1 ity but potenuate~ the acli .."y of ampid1lin and curbc:nicillin agaillst ,8lactl1ll\aseproducing S. aurt'11f and mcmbcl"$ of the Emerobactcoxc;\C fam;ly. II Iloe-i nOI. howe>n. syroergi.te with cilhet" carbenicillin or licarcilJin against P. IluuRinosli stnlillS I'!'$ismnt 10 lhese agents. Failu", of sulb.K1l1m 10 pcnctnllc the cell cnl'c!opc is a posSible explanation fill" the lack of
S~llC rgy ,

" Cumbinmions of

amo~ ici llin

"ro!

are

.a"

.-

Fu"h

""~

teri a.

"pe

Ihien:

b "",

"~ A.

moo

instal

Approved i combination lum cndomctriti ~.

for lhe

"d,,,

IlIItibi s),ste. III its

!lvati( of lhe

~I~

by caused by
;njlu",,::pe.

drolyt

CAR BAPENEMS
Thienamycln. Thicnamycin is a novel ,8-1 ac:larn'" OIic fi"" isolHled nnd Ident ified from femlenlne;o'l of It of Struclure WId absolute spcclroscupic~JJy und by t fealu",~ of thicnamycin a", (('phalosponn~: II fU M'd lacuun and lin other respects. panu", from the elie system con"i~'s urbapcocm containin; bond between C-2 lind C-3 (i.e . il is 2-cartare-." .J1-carba\X'llCl1l. system). The double bond in lhe

ChaIMer 10 . A",ibnc,malA""InOlin
.!IUo.'1urc: creates COf1sider:lblc ring strain and increa.<;cs the lQCI;v;ty Qflhe Jl-Iactam to ring-opening reaction~.TIIe side dIaIn is unique in tWQ respects: il is a ~implc I-bydroxyctbyl VOIlP instead Qf tbe famil;lll' acy lamino side chain, and il is onmted 11.1 Inc: bicydic ring system I'lnnc:r than naving the Mal fJ oricmalion of the penicillins nnd cephalosporins. The mnaining feature is a 2-aminoethylthioo:thcr function III Ct The absolute stereochemistry of' thienamydn has been drIc""inrd tQ be 5N:6S:8S, Several additional slructllraily rtIaIcd antibi(J(ics have been isolatod from various SlrtplO~I ~pp., inc luding the four epithienamycins, which arc 1Il4l ",nc to thielUlmycin at C-5, C-6, Of C-8, and derivati\'c:s .... hieh the: 2-aminoethyllhio side chain is modified.

317

which causes il 1 have an unaca:p!lIbly short half-life in 0 vivo. Imipenem is NforminlidoylthiclUllTlycin, the most s\lCCCssful of a series of clocnll' cally stable derivati vC$ Qf Ihienamycin in which the: pnmaty amino group is convcned to a nonnuckophihc basic funetion.~ C ilastll!in is an inhibi tor of DHP-I, The C0111binalion (Prima~ in ) provides a chemically and enzymatically stable form I.If Ihic:namycin that ha~ clinically useful pharmacokinc:tic properties, TIle half-life I.If the: drug is nonetheless short (1'1 - I hour) because of renaltuhular se<:rc:tioo of imipenc:m . Imipcnem retains the: CJ(troIOIdinal)' broad-spectrum antibacterilll properties of Itlienamycin. lIS bactericidal act ... ity resul1 ~ from the inhibition of' cdl wall syntbesi! 2ssodllled lI<ith bonding to PBI':s Ib Dnd 2. Imipenem is \ 'ef)' suable to most ,8-lact.:unases, It i~ an inhibitor of ,8- laclumasc:s from ~'ertai n Gram-negatiye bacleria rc:sistam to other ,8-1acwn antibiotics, c.g... p, oUlIginosn, S. nwfCt'sct!ns, and t.nlt'mUSP.
ix/CIt"

Imlpenem-Cilartatin.

l l
a.~

oc

~~

LnS

lls,

acid more
II

a~

spp.

d. It :able m. a

\permarc, of \cl)'

lives

,,'"

ctam

.""
d~

'P"-

sun

Thienarnycin displays oull>tnnding broad-spectrum anti Drill propc:nies in vilro,M It is highly active againstl'l'105t ""obic and anaerobic Gram -posi ti ve and Gramnegative _ktia. including S. fIIm~us, p , {It!rug;oosa. and 8. frogms . fWIc"' ..... e. it is resistam 10 inactivation by lnos' ,8- laclll _ elabot'ated by Grnm-negath'e and Gram-positive bactria Ind, therefort', is effecli\'c against many sirai ns resistam IIpenicillins and cc:phalosporins.. Rc:sitancc: to IlICtamases ...... to be: a function I.If the: a - I-hydroxyc:thyl xide chain Imose !his pmpeny is lost in the ()..nor deri\'lIIi\'e and c:pi 'namycins wilh S Slcreoclll:misll)' show vmable resis-.:c 10 the: diffcrc:nt ,8-lactama5Cs. Nllll1fortunate propeny of' thicnamycin i~ ils chemical lIlIbiJily in solution, II is ITlCI' susceptible tl.l hydrolysis ~~~~.idic and alkaline !IOlu 'ion~ !han I'l'105t ,8-lactam because of the stnained nature of its fused ring .,.no oontaining an c:ndocyclic double bond. Furthermort', .11 opIimaUy slabie pH between 6 and 7, thienamydn 1IIn!DC> concerttndion..ocpendc:nt inactivation. This inac. is bc:lieved to ft'SUlt from intcrmoic:culuT ami ool ysis .. fIE ,8-laclllm by tbe: C)'Sleamine side: chain of a second 1IIkcIalf" Mother shortcomi ng is ils suSttpt ibilily to hy4ltII)tic Inactivation by reMI de:hydlOpep'ida:le-1 (DHP_I).<>l

Imipenc:m Is indicllted for the trelllmc:m of a WIde: \'ariety of bacterial in fections of the skin and tisstICS. lower respiratOl)' lraet. bones and joims. and Ileni touri nllty tract. a.s ",ell as of !lep:iccmia and endocardilis cau)Cd by ,8-1act.:unascprodocing stnains of susceptible bacteria, l1tesc: include JlCI'Obic Gnam-positive organism, such as S. aurtUJ, S. t'pidt!rmidis. cnterococci. and viridans streptococci: aerobic Grnmnegotive bacteria such as Ii. coli, Kltbs it!lla, SurQli(l, Pm,/,/,."da, Harmo/,I/Uus, Ci,ro/xJc/tr, and indole-positive Pro/t!1lS spp .. Morgont!//u morgan;;, Adnt'loboclt'r:md IinItro/xKlrr spp .. and p, arn4g;nosu and anaerobes soch as B. frugUis and Clos/ridium, Pt'jlIOCo/xuS, Prp,idostrtp'Q '<ICCIIS, eubaat',;um, and Fllsobiu:ft'rium ~pp, Some PUll ' dlllmm(/S spp, arc: n:sistanl, such as p, mf'/lophUia and P. ct'(I{ldt/, as are some meth icillin -resistant taph) lococci. Imipcnc:m i5 effective against non - ,8-laclllmase-prodocing strains Dr t~ and additional bacterial species, bul other Icss upc:lllii\'e and eqoally dfC:Clh'e antibiotics are prefcrred for tnc: treatment of infections caoSt!d by lhe,o;c organisms. The imipc:nc:m-c:ilastatin combination is mDrtetc:d as a slerile powder intended rOC' the: preparation of' soIulions fOC' intra~enous infusion , 50ch solutions arc: stable fOf 4 hours Dt 25"C and up tl.l 24 houl1l when refrigenatc:d. TIle OOnCOll1ltant

- p~

IlIbi
~

,..

" It\

,tIlnd
.f>

bm'

~"',"

,)icy'Ilble
~~

yel..:

of Iml(lCocm and an IIl11illoOglyeoside amibi oue m;ults m syllt'f"ghlie antlbaclerial activity in vho. The 1'''') t) po or anlibtotlcs are. howC:\'er, choemit".Illy incomp;lIi. ble and ,hould never be <.."()Jnbined In the same imrnvenous ooule,

adnllnl~lr'llllon

the jmparnlioo. Meropenem appcal'l to be lessepileptogcnM: titan imipenem when the two agents arc used in the treatment of bacterial meningitis.
~

c il 'um

" "

INVESTIGATIONAL CARBAPENEMS
The e~ tended ,pectrum of anli bacterinl :lClivity aS5OCi3led wnh the urbapcnc:ms logether ... jlh tnclr resistance 10 inacti VHIIOI1 b) I11O'<t .8-lactamase.~ make ttll ~ class of ,B-Iactams an aUf3Ctive larget for drug development In the design of I'IC'W carbapenen~~. S1lUt"1 ural variallons arc being investi galed with Ihe obJCCtI\e of developing analogues wi th ad \ :lIltages o,t'I' im ipcnem. I mpn)"emc:nb lhat arc particular2 dc~lrcd incl ude siabil ity 10 h) dR/lysis ('atnl)'7.OO by DHP I, ;;labill ty 10 bactcna l nlClallo-,B-Ioctamao;es ('"earlxJpellC' mases"}'I> that hydroly7e .mipenem. ac1 ivily against MRSA .JI arKI increased poteno.:y agam,t P. uenlgino.Jll. espe~u.\\,! \\l\i~I'Ot\l\~is\an1 strains. Enhal'lCed phannacoki nclle prufXT1ie ... such as ond bloo v~I I;lbl hty and a longer duration or action. ha\'e herelOfure received linle ernphhsis m ('IIrbapellCm analogue tk;,'gn . F~'rty ~truetu re- Kl i v ity sludlc.~ ~tabh shcd the ('ri tical im portance of the .11 poloition of the double bond. the 3-car oo.\yl group. and the 6-l"' hydro~)ethyJ Side cOOin ((K boIh bro.ld~peclrum Ullli h~lCt ... ri al llCri viry Hnd ,B- Iaclamase smbil. lIy In tarbiipenenll>. Modificalloos. lhercfon:. h;o,e oooccn 1r:lIed 011 \.lriall{)f1~:rr ~j tiOl1 ) I and 2 of rhe carbapenem n""lens. TIle i",llI'pOC'lIlioo of u ,B-mClhyl Group at rh~ 1 PO"1I100 e.~ the l. ..bapenem ~t:.biloty 10 hydlQly5is by renal D~JI> 1. . M Sub~lIluenl' at Ihe 2 po"itioo. however. appear to afftct pnmanly the ~IX-'Ctrum of antibacterial activity of the calbapenem hy influencing penelration iotobacteria. ~ ~llpabi1ity of carbapellClIls 10 e\ist as I;willeriunic slructures (as e~emplolied by imlpenem and biapenem). resulting from th.c >mhlocd features of ~ hasic amine function artached 10 the 2 position tmd the 3-caroo\yl group. may enablc the~ moltcules 10 enter bactena via lhe:ir charged porin channelJ.

"" ,
0

"
"
, "

"

911l1l~ "dec
Biapr-ncm is It I1Cwer scron!I'SUIC"'" earlxtpt:nem wilh ('hemkal arKI microbiological l'I opclIlC'I simillll' to those of noeropenem."7 Thus. ir has broad'sr' trum antibactt'rial activity that inc ludes most a.erobic Gr. negative arKI Grum-pos llive bacl('rin and anaerobes. Riapenem is stable to DIIPr7 arKI resistant to most p.ax. ma.o;es." II is claimed to be less sU'ICCpl:ible to metallo-, lactama..-.es thun eithe:r imipenem or mcropenem. It is .. active orally.

Th

Biilpenem.

ten ", GnU!!

'Ul.~

fever

C,

J"

~~ Ihat

"

'"
o

'"

""".
hn~.

e;lrl)

" #

Mel'Opf!Mm. Meropcnem is a '\CCondgenenmoo car bapcneltl thJI . 10 date. has undergone the 1110>t extensive ('linical evaluauon.f>6 lt has re<:errrly been apprm'ed as Mer rem for the m'allll\'nt of inftctlons caused by multlply-res.~ tant bactena and for empuical the:mpy for ,;erious infections. soch as bao:terial lllC."nmgitis. septICemia. pnc:umonia. and perilonill~. Meropcnem e~hibits greater potency agai n>! GnllnnegaU\e arKI anaerobIC bacteria than dof's imipt:nem. bot it is ~hghcly less act"e as.lIlst most Gram-po"iti\e spt: e.c-s. It j , not effl't:th'e against MRSA . Mcropcocm is not hydroty~oo by DHP-l and is resisun\ 10 moe:;l ,B-l:actamases. ioc lading a few calbap( lIcma-.es thm hydrol yl.e calbapenem. LIl;e IInipenem, meropcnem is not acti ve orally. It is pro\'ided ItS a ,rerile lyophll l/.ed PIIwwtobe made up In nonnal ~Iinoe or.5~ Oelltll)';e solorion f(K parcnteml administration . Appro~lInatdy 70 1080% or unchansed nlC."ropenem is excreted in the UrillC full owing inlraVellOlJ' or intrumu sc:ular IlidminiS(I".Ition. The: remainder is the inactivc metabolite formed by It)drolytic dea\'age of the ,B-Iactam nng. The: lower inddcRl.!e ()\' nephrotoxicity of meroperocm (eomvan:.-d ","h Imlpcnem) \\:os been cone\a\ed w\\h its. ~ater Wlb\lil'1 t.) 0In>1 and lhe: absence of the D~II' I inhibitor (,ilastatio in

CEPHAlOSPORINS

n.e cephalo!;.porins arc ,B-1Mctam antibiotICS

CtphalQspurium spp. (K prepared i or the nnlibiOl ics inlmdlK:ed since 196.5 thecic cephalosporins. I ntere.~ in CtphalO1ptm ... begllll in 194.5 with Giuseppe BrOI1.us di ~\ery tlIIt tures of C. IN"r~monl ..m inhibi ted the gt'D"th of ..... ely of Gnrm.positive arKI Gramnegativc and Ncwtoo Mo in O.\funl. having blocn the fungus in 19-'8. isolated Ilm:e i II di ......'(l\cred 10 M

Chal'lr r III AmliKJCu-rild AnlibiUficl albn N Ihal had earlier bttn lsolaled from C. wlnwJynnrmll. I: and cephalosporin C.

3 J9

'PerkW,N

lriviali;ted fOllTlS of IM)fflCnclllt-= of the type thai ha\"e bttn applied to lhe penic illins lite not con~istently upplicllblc to the naming of cephalosporins because of ~lIriallOllS ill the sub.~t ilucnt al ,he 3 pusilion. Thu~. although some cephalosporins arc named as derivau\"eS of ccphalosporan,e acids. this practice applics only to tho:: derivalives th..1t have a 3IICCtoxymethyl group.

O~:;,::~,::~:!:N~",w~asacid. The amioo 0-(4discovered 10 be bl acid

. illore IIctl vily ugail~~t Gr:unr.egative b:Ic. SoI"'QIIdlu spp.. but IesIi aclivity aga'"~t III organisms than penicillin O. It has been used in chnical trials for the lreat~nl of typhoid ncver rekasl.'d as an approved drug. . 10 dose congener of ring instead of the DespIte lhe observation S. uurrus P.lacuunase. because its antibacterial I N and other pcnicil thallhe O"lIniinoadipoyl si de chain could produce 7aminoccphalospor.mic prompled investigllt..ion.~ that of mc:dicirml value. The i I to6-APAand , pen'cilhns is Woodward Cf al .11 both cephalosporin C and the clinically useful an ell-gant S)'nthc1ic pt O(:etiure. but the oom drugs are obtaioOO from 7ACA as senti

SemJsynthetk Deriv.tlves
To date, the more uo;efu! scmi'ymhctie modifications of the basiC 7-ACA nucleus have rt'Sulted from :toCylations of the 7 -a mino ifOUl) with diffcrcllt acids Of" nuckopbilic sub~tilu tion or redlM.!lion of the acctO~) I group. Slructure-ac"~lty relation~hips (SARs) among the ccphalosporins appear to paralkllOOsc amoogthe penidllins insofar as the acyl group is concerned. The presence of an IIl1ylie accto;\yl function in the 3 position. howe\C:J". prm'itks II react"c ~ Ile at which various 7 ucyhlminoccphal~nic acid structure( can easily be varied by nucleophilic displacement reactions. ReductiOll of the 3-acrtOXYlllethylto a 3-~thyl substituent 10 pre. potrc 7-amil1Odesao:.:etylccphal~pomnic OCIU (7AIX:A) derivativC:5 can be accomplished by catalytic hydrogenation. but the proce.ss curremly used for Ihc ~"()i1lillercial synlhesis of 7-AOCA derivati\'cs invoh'es the rcalTllllgl'l11('1l1 of the corresponding penicillin su lfOlridc.l~ Perhaps the nlOSl note\Io"Ol1hy deveJopmcnt thus far ,~ the disco\'e!")' thaI 7-phcnylglycyl derivatives of 7ACA and especially 7-AOCA lite active orally. In tho:: prepotrntiOll of semisynthetic ccphalosponn~. the following improvements are sough!: (a) increased lICid sta bility. (b) improved phannacokincuc properties. particularly better oral a~ ion, (c} broadened IIm,rn lcrobial 'peclrum. /d) increa...:cd aclivity against resi~tam microorllan,sm~ (a~ a result of resistance 10 enqmatic dcstruction. impro\'ed pene. tration. increased receptor affinity. etc.). ( t'} t.le<.:rea>ed allergemci1y. and (j) Increased tolernnce ufte r JXlrellicrnl adminisIr.Ition. Structures of cephaJO/oporins cum:ntly nturiell'd ill thoc United Stales are 5hown III Table 10-4.

I nomendalUrt' of the than even that of the of II double bond '" the . I

I '

~Iightly

of

,i:';;';;;:;; AhJlfIICI.f

of lhe nature procedure n:IIIICS the saturated nni sy\lem \Ioilh the lactarn carbonyl oxygen jlCl1icilJins). According to this sysi I avallabk: cephalosporins and cepha named J-ct'l'iJt'ml (or .JJ-ccpherns) to design.:ue of the double bond. (lnlem;tingly, all known 2 lire in;;ctive. pre\umably because the P.11lCtJUn it ntttSSIlI)' ong Sll~m to react sufficiently.) The
'>Offie

chemk_' Oegrada-tlon
C ... phalosporins experience a \'ariety or hydrolytIC degrada lion rehctrons whose speci fic nmure depends 011 the intli~id.

TABLE 10-4 Structure of C.phalosporlns

ORAL CEPHALOSPOR INS

"

"
-0',
00 00

"
5

,
-s-

--CO"

- 00

s5

c,.....
Cd,...,nl

...
....
o

00

....."'"
CefU",. in-.. .. till Ccfpodoilino

...

00-

-ctfo<HClt )

"
- 00

->

-<

0-,- " HOC'

~"'"
--cH ,OCtl,

--c~CH,

<5-

t,., t,.,

0
-ctIJOClflCIM.

...m'

Cd.... mle

- 00

PARENTERAL CEPHALOSPOR INS

Generic ... .".

"

--c1t,.ocClt,

"

OIIPI" 10

Iom,bacl~riDllo"r;"""ia

321

IAlLE 10 4

Continued

0,

..+ .
O.

'.

at

(0\

CIfDI.o,,,,..

en '

- H

Me I..,

j"-NH

f-O

:X)

.\,..,
{~

J22

"',' ...... and G;"wII/'J r<:utx.r* r{ O~" ... ,\INti...."'" M/I I'h",.,,,ocrutirol Cltt-"';1Irv

TABLE 10-4 St noct ....... of

CII'pMlo5 pori ns-Cont/~

PARENTERAL CEPHAMYClNS

,L~
O

.s~

0
Ol r.., ""
~

R,

R,
0

C ........'"
Cd_

~0

--0'

ell."

Cdrncu.1OIt
NCCH,IIO\-

""'A"

>-

-t{
.~

C1-1,S~

&..
u.aI "1Ut't1l!'e (Table 10-4).7l Among 7acylaminocC'phaIospornnic xid derh'athes. the
the most rcllCl"C' SIle. In piulic di~placcmcm reactions. lhe occloAyl function of this group readily IIll1krgocs solvolysis in strongly acidic solutions 10 fom! the dc..~clykephaIOl\porin dc:rivauves. The
3-ocao~ylmeth}' 1 group I~ addnion to ils react,\,ny 10 nucleo-

latter IOCIl)l1i/,e \0 form\he desaccty lccphalosporin luclOm.~. II tlkh an: vinually inactive'. The 7 -acyl:lIl1ino !,\nJ\lp of SOll ie cephalosporins cun also be hydrolyzed under cnlymatic (lICyla~~) and. pos;sibly, nonenzymatic condnions 10 !l,ve
7-ACA (or 7-ADCAJ dcrivmi\'cs. Following hydrolysis or wI\'olysis orille ) acctoxymelhyl group, 7 ACA abo lacton11.e5 under acidic OOrKIiUOflS (Fig. IO-j ). The rcactl\C' fullCtionalily comroon to all cephalospor1M i ~ P.1at'lwn. lI ydrolysis of lhe .B-Iactam of ~C'phalol>po nns IS bc:lie\td to gi\'c inilially ceph:dosporoic acids (in "hlch the R' group is stable. e.g., R' - H or S helerocycle) or P'X>lbly anhyrlrodc:.'illCelylct:phalosporoic acids (for the 7'lICylamlllocephaJosporJnic acids). It has 001 been llOS,ible to i~nle either of these milial hydrolysis producl ~ in aque. OtIS sySlems. Apparenlly. both types of c.:phalo,pornnic ocid undergo fmgnloCntmion reactions that h3\'e 1101 ~n ch:II1~ teriud fully . Studie~ of the in vivo nloCtaboli~mlO of ornlly admlnlstcred cephalosporins, however, have dcmonSlrnted IIr) I:lCCtylgJ~cines und arylacemmidoethanols ... hich are be liC\ed co be formt'd from the corresporl(hng aryl:.:etylumi rlOOC\'laklchydcs by ml!tabolic 0~id3uon arKI reducllOn. rcqICClI\cly. The aJdeh)dcs. oodoulM. ari)C from noocnl.ymatic hydruly5i~ of~ COITeSJlOfIdlllg cephalosporoic acitb. No cvidence for lhe intnllnolC'(.."u lar opemng of lhe P.lacUlm nng by ~ 1 'lICylamioo o~ygen 10 form ouzolooes of lhe pcmcillamc acid t)PC: has been found in the ceph3losporins. At neutral 10 alkaline pH. howe\cr. ii1tr~lllOleculllf

aminolysis of tne P.llICtam ring by the a-amioo group in Ik 1ADCA derivall"es cephaloglydn. cephroldme. and cdldro~il OCCUI"$. fanning dilctopipenu.ine deri\'ati\'es?~ 1<1 Tb! fOOllation of diAlers and, pos..~ibly, polymers from 1 AOCA dcrivatives contaming an (f'-amino group in lhe acylllllUlIO side chain may also occur. cspecially in concentnucd will1;011$ and al alkaline pit values.

Oral C.phalosporins
11w: oral acti~ity conferred by the pltenylglyeyl ~ubl.lltld i~ attributed 10 incrcascd acid qability of ~ lactam I1IJ rcsul1ing from the presence of a prOIonattd amioo group 01 the 7-acy lamioo portion of the molecule. Carrier-mtdllltd tr nsr>" of these dipc:ptideli ~e. z..ilterionic ccphalolpD.. rins' is also an Impor1am fllCtor m their excellent orallll'tll' ily. The situation, then. I~ analogous to tilal of the a-am.... benzylpc:nicillins (c.g .. ampicillin), Also impomlllt for hlp lICid stability (arKI, lherefore. good 01111 activity) of Inc .... jDr losporins is the: absence of the leaving group at lhe 3 po!i;\lOl Thus, despite the pre.'iC'-nce of the phenylglyeyl side dum. il'> structure. lhe ccpha ltJSpornnie acid dcrivmi'e cepltaq. Iyein is poorly ab!>Ol'bed orally, presumably beeause or ... yolysis ofthe 3-aceto~~1 group in the low pH of the SlOI1lIII1 'TOO l'l'Sulting 3h)dro~ yl <krivutj\ e undergoes lactOllIl_ under acidic conditioos_The 3-hydroxyl dcrivalh'n and.~ pc:cia.lly. tnc LOiit!.ipondtng laclonc:s are c:onsiderabl)' k acth'e: ;n vitro than the partnt c~phalosporins. GtillU~ acyl dcri\'at;vt"S of1AOCA show ](no, er in viuo anub.aC1mI potencies than the correspoodIll1l1-ACA ana.log~ Orol acliyity can als.o be conferred in ct'nain ct'phaloJplrins by ~st~rificat ion of the 3-carixuylic acid group to f<n acidSlable, lipophilic estCr1 Ihal undergo hydrulysi~ 111 W

pllI.\.ll1!l_ C.

P.laclanla: (lrdlly acli n-fposJoxil

I-l)'drolys;s rcnul ... stcn "f parelllcr ~u b .. tJlucnt

The

C~ lcnl

c!lou!;h to s

aceto~yl ctj

h)'droIYlabl droly~is by thai i~ used

"-

The: et:phalo

In "lilt pat

324

Wilson IlItd Gi.JvoItf'. Tt.Xlboo~:

of Orllm,ir Medidlwi Im,/ "lwfJmlr"wucal

Chrm/",."

CephalO!>porins are signi lkantl) le~ NeIlS;U I ethan all butthc ,B-Iactamase-re~istant penicillins to hydroly~is by the enqmc:s frolll S. tJljrtUS and Bacillus sIIb/ilis. 1lIe "pcnicillinase" resi~Ulw:e of cephalosponns appcan to be. propeny of the blcyc lic ccpllem ring ~yMem rother than of the 8C) I group. \)csplte nalUral resistance to staphylococcal p. lacuma.se. the different ccphalosporins n~hlblt considemblc variation in rates of hydrolysis by tl1c enzyme?' ThU). of several cephalo~porin, tested in vitro. cephu lOlhi n and ccroxitin life the most resistant. and ~phalondine and ccflUo lin life the least resistant . 1llc same lleyl functionaliti~ that impan ,B-luctanlBsc resistance in the pen icitlin~ un fortunately render ~'CphalO!>pori ns vinWllly inactive against S. IIUrtUS IU1d other Gram-positive bact,",ria. ,B-Lactamases elaborated by Gramnegatl\e bacteria present an exceedi ngly complex picture. Well over 100 different enzymes from various spcci,",s ofGram-neglltive bacilli rowe been identified and charactenled,~~ differing wido:ly in s~ ificilY for vurious ,B-llICtam amibiOlics. M()<;t of these en7.ymes hydrolp,c penicillin G and ampicillin fasler than the cephalosporin~. Some IIIdut'iblc ,B-JII('tJ.lI\aSeS belon~png to group C. howncr. life "ccphalosporinascs:' .... hich hy d rolYl.e cepillliosporins n~ rnpidly. Inact ivDt ion by,B-lac tamasell is an importanl factor in detCllllining rt'siS\JlllCC to ccphalO!'iporin~ m many ~trn;ns of Gnun-negat;\'e ~iI1i , The introduct ion of polar sUb~lItuc nt ~ 111 the anllnoocyl moi,",ty of ttphalosporin~ appear. 10 "onfer siobilily 10 some: ,B-hlCtamase5.lII Thus. cdamandole and ccfOlticid. \\hl('h CQIItalll an If-hydroxyphenylacctyl (or malXloyl) group. and ceforonide. \\hicll has an Qaminophcnyl !lCCtyl group. are resistant to a few tJ-1:K1a1\laSCS. Steric factors also may be Imponant because eefoper.w::oroe, an lICylureid<xepIJa-

enz~mes.

Iosporin that COIlla,ns the same: 4-clh~ I 2.Jdioxo-l pipm linylearbonyl group prc.~nl in pi pcrncll hn, is resistant 10 many ,B-lactamase . Oddly enough. pipcr1lCiliin is hydroIy#"d by mo:st of ~ en/yme~. Two slrutu>rnl features confer broadly based resi~anctll .8- l llCtaflla.se~ among the ~phalosporins: (a) an alkoximHID function III the anll ll()llC)'1group and (hI a methoxy l ~bst ... ent 8t the 1 j)O"Joit'oo of the cephem nucleu~ h.a~lIIg a stmoclle mistry. The "tfllClun:s of sevcm l ,B-IlICHimase-n:sI>/at cephalosporins, including ccfuroximc:. cefotaximc. cefli./m ime, and certriaxonc. feawn: a methoox illlino aC)"1 group. p. L.octama<;e rcsi,tarlCe i~ cnll.mced modestly If the OXlmulO sub~tituent also features II polar fu nction. as in ccftlllidinx. \I hich has a 2mc:thylpropiomc acid i1Jb<stitucnt 011 ~ Ollmino group. Both sterk and electronic p, opctti~ of the .. koximino group may conlributc 10 the ,B-ll1Ctomase rnn tance CQII fernxl by ,hi, functionality sirlCe J)'n isomers_ more potent than (HIt. isomcrs.lII ,B-Lactamase' 1\"Sistanl 7. melhoxy lccphaiosporins. also called ceph;lmyellls barw they life dcrhcd from cephnmycin C (lin anubiotlc isolllltd from SI"Plom)'CtJ ). are represented by ce roxil;n. ccfOlNl. ccfrne1al.ole. and the 1-Q.tocephalO!iporin moxa!acta whic h IS prepared by IOtnl synthc~is. Sase- or tJ- lactamase-cautlyr.cd hydrolysis of ceflhalosp> nIlS contalning a good lening group at the 3' pos!bOII it o<x:oolpanlcd by elimi nllilon of tile leavlllg group. ~ fill)' matic process oc.'(;urs in a ~tepwise fa,hion . begin",ng "'Illi the fonrnllion of a letrahcdral Ir.lll.'lit)on S\llir. \I hieh 1JUicU;> collajlSt illlo an ac)'len~ymc: intrrrrlrtliaLr (Fig. 1().6). n. intcmtcdi llte can then either undergo hydrolysis 10 free !lit ~nl.)'Tl1e (path I) or ~uffer eli mination of the leal'in; plIIf to form re lati\'cly stable acyl en/.)me with a coojupm

T :hl\ntli" .........

-, -.

fi9uTl! 10-6 tniubnoon 0/ ~ by (ephaiospotll1$

..,.

ChMpler 10 Amlb,uia! Ami/)jOfics

325

iIIIme W\K"tUI'e (path 2). Because of the stability of the acyl

euyme inlenne< ate, palh 2 leads \0 transient inhibition of b

.enzyme. Fllrne; and Prnn'19""" have shown [hal cephalo*m arlI C('foxitin mhibit certain ,8-1actamascs by this medla- . whc;reas analogue lacking a 3' Jeallng group do not.

AntIpse..domonal CephillkKporlns
P. uuuginow. repre. . a special public health probkm ba:IIUse of !heIr ubiquity III1w: environment and their propensity \0 del clop rcsi~la/lCe IIUllliblotics. iJICluding the P.1!<Clam~ . The primary mecha IIIIM of P. laclllm resistanee apPear 10 inl'oh-c destruction 1If!he iIIlUbiotlC\ by ,8-1ac1.mases and/or IDlerference wilh

5pmc1 of PscudQmQflQS,

~ially

The MTT group has. also been implicated in the Intoler ance to ak:oholllSliOt iatC'd wi th certa in injcctllble ccphalosporins: cc fam:mdok ce(OIcllln, ccfrncHl7.ole. and ccfopt'f'J tone. Thus. di sulfiram lile n:octions. attribuled to the accumulauon of lICClIIldehydt: and resultmg from the Inhibi lion of aldehyde dchydrogenllSe-Clltalfl.cd o~ldalion of ethanol by MTT -containing cephalosporins,al mayoccurin patientS \0000 ha"e consumcd alcohol before, during. or shortly after the course of therapy .

CI.ulflcatlon
Cephalosporins are divided Into fir.o;t. $CC()fl(I'. thlrd-. and foonh genCTIuion agenlS. based roughly on lheirtime of dis cOI'cry and their antimicrobial properti es (Table 10-5). [n general. progres.~ion from first 10 fooM gcnrnllion is associaled with a broadening of the Gram' ncgati,e antibacterial spectrum. sorne reduction in acuvity against Grnm ' posilive orgunhms. and enhanced rt.~i~lance to P.loctamacS. [ndi vidual ccphalmporiM differ In lheir ph:umacokinetic properties. especially plasma protein binding and half-life. but the 5lrucIUrai bases for tllese diffcrens are not obvious.

tm prnetfluion through the cell envelopc'. Apparently, IlOl

.. .8-lactllma:;c resi~ta"l ccphaJosporins penctrule the cell a.riopc: of P. uuuginma. as ooly cdoperazone. moxaJIlC_ a:fOlaxime. ceftizoxime. cdtrillllonc, and o:eftv.idimc Mve useful anlipseudomonllJ activity. Two cephal()Sporin~. JlICtam and C('fOper.tlOnc. contain the SlIme polar runeUK'S (t.g.. carbo~y and Nacylureldo) that fllCi'itate tim into PUudOIJlOfUI$ spp. by the penicillins (see ~mcillin. licQrciliin. and piperacillin ). Unfortun~lcly. ", ~Of P. uerugillos<} l1!lliSlaO! to ce fopenawne Qnd cefo h;m~ been found in chnieal lsolat~.

Prod ..cts
Cepha/exin, USP. Cephak)(in.7a-(o-amino-a-phc'n)'l occtam ido)-3lTlCthylttphcmcarboxylic acid ( Kcne~. Kef anll). was designed purposely I i an orally acli'e. scllllsynthetlC cephalosjlOl ln. TIle oral InacUvallOl'l of ccphalosporins has been aUributcd (0 t\Oo'Q causes : instability of the P.lllCIam ring 10 acid hydl\lly~is (cephalothin und cephaloridine) and soI"olysis or microbial transformation of the JlTlCth)lace tox y Sroup (ccphalothin. cephaloglycin ). a-ammo group of cephaluin renders illlCid Mable. and redUClion of lhe 3lICetoxymclily l 10 n tnctb)'1 group circuml'ems relICtion at that site.

I'tha.se Re.ctl_s Mtd Drug Inter.ctlons

"",,?,;m,

I&t their

<

relatives thoe penicillins. the cephalosporin COInparall"cly n,"uo~ic oompourKh that. be n( their sc:lectl\e IICtions on II wall crosshnking Ili)ITICS. exhibit highly sck><:tive to~i city toward bacteria. IIIt I!IOO to the ccphalosporins reaction). 1be-e vary from , . Alleri to than wilh penic"lin~. TIM: issue the twO classes of P.loctllms is "ery complex. Incidence IS OOIlsideredto be "cry low (~irnated al Jill 7"'). The phY5ician f/ICed with the dc<: ision ()f \Oohcthcr .10110 IIdminbtcr II cephalosporin 10 II palient with a his lIIc1ud
t

cI~

n.c

lile

"" "" ..., .

" " .

Cep!:

d'

'"n

iI
an Nmethyl5thiOlel.I1IZOIe the 3 position (e .g .. edamllndole. ~'t-fOl~lan. . mo~alaclam. und cc fopenv.one) havc bren im ID a higher incidence o f hypoprothrombinemia than 'ns lacking the MTT group. This effect. \Oohich ......lCtd and can lead 10 SC:\'~n: bleeding in patients \00 ith nutritjooal SluluS. deblliuuion. !\:CeO! glIStroimestinaJ . hepatic dic3Se. or renal fail ure . is apparently due invoh'ed In vita -rontaming c~phaIO$JXIIins. vibmin K has been rcrommended for highrisl patient' i ~uch ugents. Cephaluspori ns C(In group should 001 be admini stered to pa. anll anticoagulant or heparin themp)" be ":,~,,;;,,. with ~ drugs. Ccphalcxin ox:curs as a whitc crystnll inc monohydrntc. II is freely soluble in ",ater. res istant to acid. and ubsorbed well Or.I.lly. Food docs not intmere \Ooilh Its absorption. Be cause of minimal protcin bIDding and ncarly e~clu ~ i"e renal ucn.:tion. cephalcxin is recommended plIniculorly for the lrealment of urinnry Inlet infections. It is alSQ sometimes used for upper re$piratory tract infCCli Ol'lS. lIs spectrum of octi"ity is "~ry similar 10 tllo6c of cephalothin and cephaloridine . Ccphalexi n is SQme", hat less potent than these two agents lifter parenteral administnuion and. therefore. is infe rior to them for the treatment or $CriOU5 'ystcmlC IDflions.
Cephradlne, USP. Cepllrudine (Anspor. Vclosc:l) is the only cepllalosponn dcri"DII'e 3"ailable ID both ond and parmlCrol do$age rOffl1$. lt closc:ly resembles cephalCJIID chemically (il may be regarded as a pnttially hydrogenated denvi'

TABU: 10-5

Oauifiation and Properties of Cephalospol'"ins

Clphal05porln
e."tloo~"p

Ge .....atlon

Admlnntr.tlon

Rout.

.ddRulstanf.

Pluma ","ot.ln 81ndl"9 (%1

Spactrum

1I.t.act........
Rulshnc:.

ActlvlfJ'

AntlpHucIoActivity

......
'" ... " ...
No M No

Ccplo";,... Cn.....,,,1
e~k,mln

"-<Cef."",~

,.,.
F~

"~

...
,~

FiN

""' ............ OnoL "'" ""-,

P ",...I

,,. ,No
No

'-"

,."

Cn... I",.
loo_bcf
C..r~'1
Cd.~

C..rOllICld e..r.....kIt
CCI~,lbn

c.rilO<'lM\
C<........ edil ..... l"", edpr<lo,me

""""' """"' ...., "' """"'"" """"' """"' """"'

...

"'"""'" "", "'" "", "'"-,

,,, '" ,,No

" ,..,. "'''

21~ J~

"'" .... .....

OHO

"'" .... "'" "'''''

PU"l'w.,,,,

"~

PlIo .. nihil hi: ' hi,,,,,,,01

5<)101

em"....
Cd_

e ... 'M .......

Cefto_ .....
Cd'.-...e

eetw..... _
C.flibu!tn

C",,"_
c"fpl""""

_... - _..." ""' ,"'""" _.

lli.

"""' """
N.
Th~

""' "'"
On,

. ,-"'" .
hi, ,

No
No

,..,. ., "
~

N"
No

......

\ :1-22 7g..9L

......
""'" """
Goo>

b_
E..~

'''''"' '''''' """ ''''" '''''' '"'"' '''''' """ """

" ...
No

I'uor .... . ..........

" ..... ' <I

E.1<nik<I ulended
~:"'",odo:J

,. '"
No
No No

No

,.
'"
No
NO
No

''''''' ".

I'atonllil

" ,'-'" " "" ,

ho., ,

. ,.."
"

""'" """ ""'" I'I1>II " .........

Co

boendod

1'.,,,,,,01

Th,.
ThO<

No

,-

" -" .....

Lb-I~

"""
""'" ""'" """' """ """

u_
L ",1t't'kIOO

u""odoIoJ

... ,-

,,,

E>."nJeoJ ,\ood

b.-,

tl:o: .....

No

"'"F k.odcoI ... E\I""<kd

,~.

No

,,,,No ,,.

liye of ceph~le~in) and ha~ ,'ery ~imilar anlibocLcrial lind

pharmacoknleli~ propeni~s,

Ii

Cep/lIadi'I6

acyl group i ~ lhe 1 hydmA ylphe nylgl ycyl moiety, Thi~ CIlIlIo ) pound is absorbed " 'cll afLer oml administral,on to lilt plasma Ic,ds thai reach 75 to 8I)',i. of those of Dl ... dose of its close ~t ructurdl anologLlt' I , ~ adv~magc claimed for ccfadroxil i~ ils durulion of OC1ion . ... hich permoLS proIongtd duration of a..,1ion of th i~ relml\'ety slow unnnry e~creuon of the other ccplmlosporiM. but the basis for rernams upillined complctcl y. 1lle antibaclcrial spectrum of~. and therapeutic indkullons of ccfadm~ iJ are vcry ~;mi' those of ccpho\exin and cephradine, The u -p- hydroA)'p/IrIylglycyl isomer is much n~ OCLo.'e Ihan the I. ,somer

It ()C('UI) a,~ II crystalline hydr:ale Iha! is readily soluble m waler. Cephrudinc is ~Luble to acid and absorbed a111l0.1 completely aftcr 0I'lI1 admino"lration. It is minimally protcin bound and c~CfCted almost c~cll1sil ... l) through the "idncys, It is l'L'C(}rrmlendcd for the Lre'ltmCI'lI of uocornplie:l\ ed uri nary tracL and upper respiratory tmel infectious caused by w sccpuble organisms, Ccphrodinc is ~,'~ilabk: in both oral and p~nlcral dosage fonm,

"''-<'I"''''

"",,,, '-,/ ' - -i---+""l

iiH,

J!

CefiJdroxil, US".

Cefadl'Q~i1

(DurittO is an orally

!\C-

"',.,~ "!I:$I>;"i~ 'tsc:',,,,*,,,", \\.., -~~~,'",

"rub.~,.

Cef. clor, US,.,

... "j~>I,""

Cefaclot (Ccclor) i~ an ornlly "":'

1M:.

~ ~

........

_.,rum

Ammnn market In 1979. II dlffero strucllll'B.lly from ~pha Iwn In lbatlht 3-me:th),1 group ha~ been replactd by a chlo.tom. It is synlhes:i7.td from Ihe: t-orresponding 3-mcthrllk~ilt(~eph:U1I slIlfo.,ide ester by olOlIol)'si~. follolO.l'\l b)' n:llion of the resultilli .B-"eloc:stcr.~2 "fb,;, 3nle:th)'l ;Ck~'~tpi;;'1am sulfollide ('<10''-'; ure prepared by reammgement the romsponding 6-acylanll00ptlUcilianic add !lematit Ctraclor is modrnllcly ~tablc in ocid IUld ocbie\'" oral to effcclI\'e It\d.

.... h:lt gI1!ater potency agalnt If. mj1..~n:lU' WId M. ("Ularrhalis. including .B-Iactarna...e"producmg 'Iralns. Unlike cefaclor, IO.hich Ulldcriloe~ dcgrndation In human SC'rum.lor_ IIcarbcf is rncIlIIclilly ~tDble ill plasma. It is absorbed wcll or~Il)'. Oral ubsorptlOil is delayed by food. 11lc h.:tlf-life in plasma is ahout I hour.

""

"

. I aboW j(f. of II. i I II lost in 2 houn; in serulll 1 The antibacterial " l)t.~trulll of !l(.1i1'il), is ~imilllt 17'C,, of cephalellin. but it is claimed 10 be more pocCIll WlfIC spies sensitive to boIh age 1115. CUlTl'nll)'. the t of non- lifethR:~tcnI caused b)' If. irifl,'rn~~, panicularly strums !WIt to ~mpleillin.

Cephalothin Sodium, USP, Cephalothin ~lUm ( Kemn) occu~ as a .... hlle to off-lO.hitc. CT)'lItallinc POIO..Jtr Ihal I~ pnclicall) odorless. It i~ freely ~uble in W;ltcrand insolu ble in fl"l()5t organic sohcms. Although II has been de-;cribed as a brood~pectl\lm .ntiOOcterial compound. it is not in the same class as the tetlUC)dines. [ts spectru m of ilCthity is brooder than thai of penicillin G and mote ~ lInliar to that of ampicillin. Unh~e ampicillin. cephalothin j, rc..~islunt to penici ll inuse productd h)' S. (lUrl'lI$ and pro\'ides an altema1I\'e to the usc of penicillinase-rcsiSlanl peniCillins for the lreat mem of in fections cauSC\l by soch StrdlllS.

I:~~~::~~ I!

~~~~~:';;~~,::;rommllnIlY-OCqllircd l1.-Splr-.IIOf)' and InIeI . cansed b)' ~usceplible org~nisms.

Cefprc.il (Ccf/.il) is an orall)' IIIChve cephalo<pOrln that sim illlt in structure spectrom to cefadll>xtl. Oral ab~ion " bioavailnbili t)' j, abotl' 95%) and is 1101 afby antacids or histamine -It: antagonists. Cefprol.il in \i u o octi vii)' agalllst streptococc i. Nrisse does cefadroxil. It is ~Iso nl(Jrt fir51 -gcncr.llion ctphalosponns against mem .i.,~ Enterobac:teriaceac fami ly, such as E.. rofi. Kltb .., . P. mu-a/,,/ts. IUld CllroiKKltr spp. The: plasma 1.2 to 1.4 houn; pemlll~ tlO.itc-a -day dQsing for

i~

" "
~~......

""

Ceph.tCOlhln SOdkun

Cephalothin is ~b-.orbcd poorly from the Il3.Slrointcstmal tract and must be admlnl<lertd parrlllerully for systemic in flions. It I~ rc lall\'el) nonloxic and add )t:lblc. It IS ucn:tcd rnpidly through the ~idney): ~boIlt 60% i~ lost within 6 hours of admini,trnuon. Pain at lhe Sile of inlruJllu5Cular mjcclion and thrombophlebitis following imr3\cl"IOIls injectioll have bct!n reponcd. Hyperscn.sitl\ ity rc-actions have been observed. and there is SQmt evidence of cross-sensi tivit) in (XlllcntS noted previously to 1x: penicillin "l'nsiIJ\c.

Cefazolin Sodium, Sterik, US". CeraJolin (Aneer. Kefwl) is ()11(' of \I -.erie!. of semisynthellc cc:ph:1losporin~ in .... bich the C-3 aceloxy function h~ been repl~d b)':1 thiol ..contalOing heterocycle-Iiere. 5-mcthyl-2_thio-l.3.4_ thiadia7.(Jlc . It also COIIlai n. the SOIIlCWhHI ulluwal tetr~wly lacetyl acylaling group. Ccfa/olin was released ill 1973 as a waler-soluble sodillm \alt. It is :telj\'e olily b)' JXlI'I:ntcral administl1llioll.
is the fir<! of a

,. '"

" "

m antibiotics in which the 1 atOm b)' II methylene (Cl1v group. Lornc~rbcf lO.i,h ccfaclor and h~s ~illlil!ll" phanl1aco~inctic . I . I propeni ..... 11ms. tIle: antibaclerial ~pcc rtSembles thaI of ccfador. bul il has SOlfIC-

Cef&lolin Sodium

~~''''#'''./''1~yH, o

Cda/ohn Pf'O~idcs higher <;enIm lele15. 51o""er renal e1eurance. and a longer half-life than OIher first-genemtlon c:epha}osponru.. It is .pprt)xinullely 75% pmtein bound in plasma. I higher ~alllC tll:an for most other CC'phalosponns. EIIrly in Vllro and elimcal studies suggest that cefa70hn I~ nlOl1: ar.:t,ve againsl Grum-nc:gmivc bacilli 001 less octive ~amst Grumposit;le rocci than either CC'phalOlhin or ceph.Ioridine. ()ccuneoce roles of thrombophlebttis fol lowing Imr~""'noos injection and pain at lhe si te of mtmmuscular in,lCCtion appear 1 be the lowest of the parenterJJ ccphalo0
~ponns,

Cephapirifl Sodium, Sterile, USP. Cephapirin (Cefadyl) is a semisynlheuc 7-ACA derivative released in the United States m 1974. II elasely resembles cephalothin in dtcmlcal and Jlh:,"JUICO~lIlC1k propt'nies. Uke cephalothi n. ccpllaplrin I~ unswble 111 acid and must be administered parenterally in the form of an aqueous sotutioo of lhe sodium \lilt It is modell\iely protem bound (45 10 5O<l) in plasma and cleared rapidly by the kidney. Cephapinn and cephalothin are vcry sirnilaJ" U1 DllIimicrobiaJ spectrum and potency. Cooflicting reporu concerning lhe re lall\e oceUlTeoc"e of pain al the lie of injt1Oll and thrombophlebitis aftCT II1lro\'enoos II1j1lO1l of cephap,"n and c:ephakXhln an: difficult 10 asse~ on lhe basl~ of available chmcal d.1ta.

lIenc:l1nioo c:ephalosporin~ are senslli,'c to c:efamandole. Additionall y. it is acti ve against some ampieil li n-re~isWll ~Irains of Nt'isseria and Htwnophilus spp. Although resis woce 10 ,B-lactall~ may be a faclor in determininll tk sensitivity of individual bacterial strains to CC'famandolr,. early sludy"> indicated thaI OIher factOfli. such !IS perrneabi~ lIy and intrinsic IICli ~ily. are frequently mort important. TIle L-mandeJoy l isomer is Significantly less ICII'e than !bE D isomer. Cefamandole lIafate i~ very unslable in solution and h) drolyteS rupidly 10 release cefam:mdole and formate. Then: is no loss of potency. ho....e>cr....heu ~UC:h soIuliom IIr stored for 24 hours at room lemp<'mture or up to 96 hourt when refrigerated. Air oll idation of the relea!>Cd fonn:ttc 10 cmbon diollide can cause: pressure 10 build up in the injcctial vial.

" ",-',

C.fonicid Sodium, S!erl/e, USP. Monocid is a 'aIdgeneration cephalosponn tJut is structun.]ly similar til cd. mllJldolc. ucept thai II contains a mctnanc sulfOt\i~ II:Id group atlached to the 1'1- 1 positioo of lhe tctra1.Ole I1nll. Thr antimicrobial spectrum and limited ,8-lactamase s\JIbihty fII c:efooicid are essenlially identical wilh those of cefam:utdok. Cefonkid is unique among the sccohd-gC:n&:r.llion cepw. losporins in that it hll5 an utlusually long $Crum h~lftik o f approximately 4.5 IIours. High plasma protein bindiDI coupled with slow renal lubular ~relioo are apparently It~poosible for the- loog durution of action. Despite the !up frnction of drug bound in pla Sl1Ia. eefooicid is distnbuted throughout body nuids and tissues. wi(h the e.lceptioa Ii the ccn:brospinaJ nuid. Cefooieid is supphed as a highly "''3ler-soluble dl~ salt. in the form of a sterile powder to be: reconstilWc:d fainjection. Solutioos are stable for 24 hours at 25"C and ((I 72 hours ",hen refrigeruted.

Cefamafldole Nafate, USP. Ct'famlmdole ( Mondol) nnfote is Ihe formate ester of cefamandolc. P !il'misynthetic cephalosporin that incorporalei o-mandelic acids as the lICyl portioo and thiol'"COfltaininll hetm'lCydc: (5-th io- 1.2.3.4tetnL1.oic:) in place of the IICCtOll yl fUl1C1ioo 011 the C-3 methylelle carbon 3tom. E<;[erification of the o-hydrollyl group of the o--m:mdeloyl function Ol'crcomc:s the instability of c:efamandole .n sohdstate ~e fonnsu and Pf'O>'idd sali~faclOl'}' OO!JCentrahOllS of the parent antihiotic in I1VO through .. pontancoos hydrolysi~ of the eMer at neutral to al1.aline pi!. Ccfamandole i~ lhe first second-Ilenemlioo c:ephalosponn 10 be: nutrl.eted In the United Stale).

"~

" "

""

"
Ceforanide, Sterile. USP. Cefor.mide (PrcccO proved for clinkal use in the Uni ted StDI~ in 19~_ k classified rut a secoodgeoeration cephalosporin becarv. anllmicrobiaJ p",pcllies are similar to those of c:efanu.... It e~hibi l$ eJiceHenl potency IgumSt most mcmbcts of ... EnteroOOclerill(:eae fmnily. upecially K. {Hu!umo"iM, l ("Oli. P. mirllbifis. and "'ero#xJC(trc/("JaCM. II is b$ tnan cc:famandole agamst If. inf1ut'ff~. howe>e!'. The dlll1ltioo of action of ceforan ide hC$ be:t....e n _ of c:efant:mdole and cefon icid. 11 has a serum halfljft III

II,."

The o-mandeloyl moiety of cefamandole 'PJlCaJS 10 confer

resislaoce 10 a fc: ... ,B-tactamases. SII)CC: SOllie ,B-1aC'lamaseprodll(:inll. Grnm-negauve baclena (particularly Enterobac teriaceae) thut show resistance to cefuolin and other fin;t~

"m
_n 3 hours. pcnniulIlg Iwic~-a-duy (losing for most indi o ation$. Cefordllidt is MJppl ied as the ~e"l('. cry5talhnc: diso-.n sah. Parenl('m\ solutioos are stable fOl' 4 hours at 25"C .-l for up to S days when refrigernled.

'

, , ,

< o

"

'~

<0

00

d-

,.. "

.-

of

~-

ife

"

Sodium, Sterile, US~. Cefopem7.0ne ICtfobid) t, a Ihint-gertern t;on, antip$Cudomonal cephaloIJ'lIin that resembles plpcr.ocillin chemically and nllcrobio1oPc~lIy. II is acl" '(, agamst many Si mms of P. ut'rugino$D, IIdoIc~nive Proteus ~pp .. Elllerooo'It'T spp .. an() S. murc ff(tllJ 11131 an' resistant to ccf:lJTlaodole. II is less active than ~oth," agaln~l Gram-positi\ c bacu:lia and le~s aclile em cc:famandolc against nlOSl uf the Erncrobacterill(:eac. !at pi~illin_ cdoperv.one is hydrolyud by manyoflhe
~<;eS Ih:u hydroiY/.A.' pemcillins. Unhke ptpcncilhn.

~illone

cill; (e.g .. E. coli. K./mtumoniat. PfQI'idtnda spp., S. 1f1t11"C"tsuns. IIIdolc-~;li\'e PrrH~US spp .. and 8ot"~fQkks spp.) that lin: ltSistanl 10 these ccpha losponns. II is also eff~tive against penicillin-resistllnt S. amyUlIU1d N. gl/lwrrlu~(.~. The activit), of cefoxihn and ccphamyeirlll. in geneDl. against reS.,lan, bacterial ~1r:lInS is due to their Tl'Sistanee to hydrolysis ~ ,8-lactmn3scs conferred by the 7a-metho\yl 5ubsliluenL Cefoxllln i5 a potenl compeliti\'c inhibitor of many ,8-lactalna!,es. 11 is alw II potent inducer of chromosomally mediated ,8-loclllmases. The lemptation 10 e~ploit the ,8-lactllmase-inhibiting propert~~ of cefo tio by combinlllg II "ilh ,8- laetama.~-labile ,8-laclam antibiotic~ should be lempered by lhe possibility of anlagooism. In faet. cefOllilin antagoni/.t's lhe .clioo of cefamandole again)!. E. c1OfI('fl~ and that of carbenici llin agalllst P. otruginosll." CefoKilin alone is eS\enliully inelTectj~1.' agllin~t these organism~.

"j

,7

/'" ~ ~ _s", -'"

elh

ng

P'ever, n is resi~la m 10 <;(Imc (blu nOi all) or the ,8-lacla IIaICS that hydrol YlC cephalosporin,';.

'"

gh <d of
c.tope>razone Sodium
f~ f~

The pharrllllcokinctle

propertic~ of cefoxilln reo;('mble

I"

those of ccfamandole. Because ils half-life is relali\'ely short., cefo~nin mu~ be administered 3 t1l1lC$ d:llly . Solutioos of lhe sodium ~31t intended for parentcml administnuion are slablc for 24 hours at room lemper-nun:: and I wttk if refrigerated. 7o-Mcthollyl SUbsUlUIlOO $Iabllizes. 10 50IllC extent. the ,8-lactam 10 alkaline bydrolysis. The principal role of Cefollllin in therapy seems 10 be for the treatment of cenain anaerobic and mixed IICrobic-lUl:K'rotnc infections. It is also used to treal gonorrhea C;lUse<! by ,8-loclmnase-produdng sU'3ins. 11 is cla!lSilicu as II secondgeneralion agent becau.~ of liS spectrum of .clivil) .

or"

e;o;creted primanly in the bile. Hcpallc .~unction can affect ilS clcar:mcc from the body. AltbotJgh 154 of the fn:t' anl,biOlic is reco\ered in the llrine. eoough to be effccnvt in the j by susceptible a day. I prepan:dfromtltc cryslalllnc:sosalt are stable for up 10 4 ooun at room temperature. ;";,,, they \\'illlast S daY$ wi thoutllppr~dable los~

Ccf.rv.one

l~

Cefotetafl Olsodium. CcfOfellln (CrfOllln) is Ihirdgeneration cephalosporin that is sllUCturally simIlar 10 crfoxilin. Lile ccfOx itin, cefotctan is I'CS.lstant 10 destruct ion by ,8-hlCtarnases. It is also a competiti\'e inhibitor of many ,8laclllmases and cauSe'S If1UISienl inacti\'al.lon of some of these: 1,,"~ylTlC!i. CefOfclan is reponed 10 .~yncrgizc: with ,8-lactamase 'Cnsiti\e ,8-llICtllms but, unlike ccfoxilin. does 001 appeaT 10 cause: WlllIgonbm.w

o o
C 1'<>Iet.l a.odlWII
~.

Ccfoxitin (Mefoxm) I Knu,)nthetic derivllt;\'e obtained by modification of ."~YClll C. n 7(\'-nletho.y -subst ilUted cephalO!<porin iso1IIdqlendently from various SlffplO'rll'CtS by re..~arch In Japanrl and the Uni ted S,a,ct. Although it is less

r.lcWrin Sodium, Sterile, USP.

,.f

;~'"'~ ~"~:~~':'::i;~~,,:.~;. :the Gram-positive b.1Cteri;l and' t IT'IO'it of nst EllIel'Obac,macelit. cefoKi
i stnuns of Gram-negative 00-

The antibacterial spectrum of cefotctWl closely resembles Ihal of erfoxilm. It IS, oowe,'er, genentlly more lC1i"e against

S. uunus and members of the Erueroixlcteri:lC'Cae family

sensitive 10 boIh Biems. It also exhibi ts excellent potency against H. irif/uen:lu~ and N. gmwrrhQ('IItI. inc luding ,B-lacUlmast-producing ~train~. eefOietan is slightly less active than cefoxllin against 8. frn~ilil and other anaerobc's. f"'froOOc' ItIf spp. lITe iC'nerally I'l'SIstam to cefOietan. and the drug is .... thout effect ~ainst Pseudomotlas spp. eefOietan has I rc:lath'e1y long half-life of about J.S hours. It IS admim5lcrc:d on l twice-dai ly dosIng schedule. It is excrc:ted largely unchanged in the unne. Aqueous solutiOll$ for parenteral adnnm<;tration maintain potency for 24 hours at 25"C. Rcfrigerllled SOh.ltion~ are stab le for 4 day~. Ccfotclan conl8ini the MTT group th~t lw~ beel1 a~soci all'd with hypoprothrombinemia and alcohol illiolcl1Ince. Aoother cephalo<iporin that lack~ these: propcrlies shoold be sel~led for !)iIliems al ri~k for severe bleeding or alooholi~m.

Cefuroxunc IS distribuled throughout the body. It pene. trutCS Innamed meninges in high enough coocentnuions 10 be cffcctll'e in I1lCnin~itis caused by sU'iCeptiblc organi sms. Three-limesdaily dosing i~ requ ired 10 mainluin effttu\'~ plasma le~els for most sensitive OI1anisms. such as Nf'iSM rill mtning;liII,s. SfrtjllOCOCCUS pMlHIl()(lilltl. and II. inflwtl ~. II has a plasma balfhfe of LoS hours.

CefrfH! fazo/e Sodium, USP. Cefme1a1.olc (Zefal.one) is a (!misynthetic. thmJ-gener.uiOll. JI'lrenu:r.d cephalosporin of the ccphamycin group. Like otbercephamycins. the presence or the 7lJ'-met ho~yl group cOllfc1"\ rcsblancc 10 many ,8-lllCtamasch. Ccfn~uv.ole exhibits significant ly higher p0tency against membc .... of the Enterobacteriaccae family but lower activity against HII('/rroillf's spp. than cefoxitin. It i.'l hiply acti\'f' against N. S0f10rrilt)tlat'. including ,B-11lC1Imaseprodocing ~truins. In common wllh other ccpham)eins. cefmelaiole is ineffective against indo1e-posllh"e ProII'US. nlf'robat:ltr. PrO>'idtncia, StrrolUJ. and PSf',mOOWfliU spp. Cefme\al':olc bas the ~fIT moiety a$.<;()I!iatcd .... ith in-

CefufOxime Axetil, USP. Cefuroxime axetil (Cf'flIn) IS the l-acCl)'Oxyetbyl esler of cefuroxime. During absoJp.K-.. this acid-stable. lipophilic. 0IlI1 prodrull den"ative of ttlilroxime is hydrolyzed to cefuroxime by intestinal andl(l' plasma en7ymc.~, The axetil ester pruvidl-s un oral biOllyllil ability of JS 10 SO% of cefuro~lmc. depending on condil101lS. Oral absorplion of the esleT i~ Incn:-lIed by food but decreao;cd by anlllCids and Hl'hls.tanllllC anlagOl'1.1S1S. Tht ~ effccl may be due to spontaneOUS h)drolysis of lhe CSICr III the inlCStine because of the higher pH created by thes.cdrurA.telll is used for the orailRallncnl or oon-life-tlllUltni.. in fections caused by bacteriu lhatllTe susceptible to ccfulUl' jllle. The prodrug form permits twice-a-llay dosing for such infections.

""\

l
(

cn:ase<1 bleeding in cerlain highrisk JI'ltients. It ha, D plasma half. li fe of 1.1 00u1"$.

, , " " . ,

4'

, "
Cefpodox/m. ProKetil, USP. Cefpodoxime prow ( Vantin) is the lsoprtJpylox ycarbon) lcth}1 f'ster of the dun!generotion cephalosporin Cf'fpodoxlme. This orally IICIIIe prodrug dl-ri~al1\"e IS hydrol)l.ed by CSlel1\SCS in the il'MC'SU" wall and in the plasma to provide ccfpodoxinlC. Tablets-.l a powder for Ihe prt'paratmn of an lII]ueous suspenslOO Q oral pedilltric admi nistration are available. 11tc oml biool'llil llbility of ccfpodoxi me from the pruxelll is estimaled 10 bt about SIJ'I.. Administration of the prodrug with food eIhanttS its absorptioo. The plasma halflife i) 2.2 hout\ ..... h,Ch pemlHS admll1lslrmion 011 a 1..... lcc-daily schcdult.

/"

"

Cefuroxime Sodium, USP. Ccfuroxime (Zinaccfl is the fiN of a series of a-mctho~iminoacyl-sub)tiluted ccphalosponns that consti tute nlOQ of the third-gencr.. tion a~(nts available for clinical use:. A srnallmxirnillO sub-utuent is IlSsocialed .... ith ,8-lxlan\llSe Slllbilily in these cephalosp!)rin~.71< Cefuroxime is clllSsified as a second-Ieneranon cephalosporin becaus.c ilJ Sp!.'Ctrum of amibactcriaJac\t\lly more close ly re.';Cmbles that of cefarnandolc. 11 j\. ho ..... ever. xtive against tJ-ll1Clamas.c-pmducing slrn.ins that arc rcSl'aam to cefamandole. ~uch as E. coli. K. p'ltlmlOlli{lt'. N, /((//lOfThlN'lIt. and fl. inj1l1l'lt:JJt. Oilier impoi'lal1l Gralll-ncgati,'<: pathogens. such as &rmlio. indole-posilhe !'rmtlll spp .. P. IIt1rUI;I1I0SQ. aoo 8. frogilis. are rcsislant.

.,'\
~'\~ , " "

"'\0>-Oj '

y ....

~~

'ao,

"

Cefu/O,arne SOdium

Cefpodox ime is a brood-spectrum cephalosporin ,,'ilh ~ fulllCti~lIy Qgainst a relBtl\'e!) Wide IlUIgt of Oram-poulrol and Gr,lm-negam'e bacteria. It i. also re$islant to

mIII)'

1Icwna~.

Its spectrum of IleI;y; l)' lIIcludcs SIfl'pltJroITW

SIU(JfOCOC('U$ f')'Qgt'III'S,

pMumooUJt',
1t'IIS.

Swphylococcw

UII-

H. i'lf1ut,,~. M. cO/arrha/,s, a!ld Nt"s"ri/J spp. Cef podmune IS Illso IC1I\C against members of the EmcroOOcImattac: fami ly. including E. coli. K. f.H'f'umtWliof', and P. _fllbilis. II thUI finds use In the treatment or upper and

"',~~
-

" " - ,

kJI..'l'I' fl'SpiralOry infections, such Il._ pharyngitis. broochilis.

OlIlIt media. and communily-acqui~ pneumonia. 11 is also IItful for the treaunc:nl of uncomplkllled gooorrhca.
Crfillime, USP. Cefixirnc (Supru) is the fir"l orally &cInt. third' gcnenllion cephalosporin thai i! not an ~ler pro.tu, lo be appro,cd for therapy in the Unhc-d Slale~. Oral ...,ailability is ~urpri~jngly high. ranging from 40 10 j(n, flnlnaled transport of ccfixime across intestinal brush borikr IJ1('mbrones involving the carrier system for diperkles .) nplaln ils surpri~mgly ,ood ond absol'plion.9 This K1IIII.,..as not expected because cdiJlimc lacks the ioni"f.llble "1111100 group pre:ielll in dipeptides and P.lactams p,";" i....y krtOwn to be transponed by the camer sy~tcm. I. 9 1 Ctfixinle is a brood-spectrum ccplt:llO!.porin that is resi.\.l1li UI many ,6- lac(;Ul1.:lSCS. It is particularly cffcrti"c against Com-negative bacill i, including .. coli, Kltbsidla spp., P. flfQbiiis. IIldolc pos"h'e Prot~us. Pro'id~nda. and some Gtrobucl~r ~pp. Most Pstui/omOl,uJ. Emeromll"ltr. and kftoroidtJ spp. are re..~istanl. It also has u'II:ful activit) .pnsutrcptococci, gOflococd, H. ;'Vlutn;:l1t, and M, ((Jlllr rWias. [I i~ mIlCh less acti>'c against S. Qun lU. Cefixime is .... for the treatment of a V"dlicty of respiratory tmr;:t infee10m (e.g .. ac-ute bronchhis. pharyngitis , and toruill itis) and medII. II 's also used to ~at uncomplicated un n.ary b;1 Infections and gonorrllc:a caused by P.lactamasc-prokillS bacterial Mr.Urnl.

y
~.

,
~

4'

cerO!axnr. SoOIum
11M: SJ II isomer of cefot:axtrne i5 ~ ignilieuntl y mon: actil'e
than the 111111 isomer agaInst ,8-loctamase producing bacteria . This pcMency difference is. In part. due to greatCl" rc:$iSlance oflhe ~)"II isomer to the oclion of ,8-1oclaJrulscs?1 The higher affinily of I.he sy" isornc:r for PO Ps., ho .... el'CT. may also be a facT or." CefotaXlnIC" melabolized In pan 10 the k:ss act i> desa'e celyl mtTabolile. ApproximaT 20% of the metnbolile and ely 2S r:l of Inc parcnl drug are excreted in the urine. The patt"nt druB reaches the cerebrospinal n uid In suffICient concenlration 10 be effecl ive in !he Ireatment of nWo!ningilis. Solutioo.~ of ~"C:fOOlxime sodium should be u<.ed "'''hin 24 boo",. If st<:>red. They Shoo id be refrigernled . Refrigerated soluTions maintain potency up to 10 days.. (Cdi1.Ox) is a third-geflCl'ailon cephalosporin thm .... as introduced in 19S4. This ,8- lacTalnase-resislant agent exhihil.~ excellent act i ~ it y againsl the Enterobacteriaceae, especially . roIi, K. pneumollf('t, E. c/Q(lCat. Ellltm/x,Ner lItrogelles. indoleposit ive and indole-ncgati>e Pro/t UJ spp .. and S. marcesctnJ. CeftilO~ifOC' is claimed 10 be mo re &clive than eefoxitin againSI D. /roSiUs. II is also ,'cry acti\"e aguinst Gram posili>e bacteria. its octivJly agalnS! P. fltrvSUWMI is sonIC"hal variable and lower than that of either cefOiax imt or cefOfXra,~ -

Ceftfzoxime Sodium, Sterile, USP.

Ce fti l.o~ime

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Tbt ct)I)lparllthely 1000g half-life of cefixime (I. is J

) .lIows ilto be administered on a tWlceadlIy schedn:absorption and a relatively hIgh fl'llCtlon binding (about 6S % )contnbute to the 1000g two o"IlI dosage forms: 2()()" Of 4()(). for the pn:par.uio n of an aqueous

Sodium, Sterile, USP. the fim thIrd-generation

(Cla-

wbe

I.,
It 's
IfIOI'e

;;;I;;:~

&ch'e moxalactum againM organisms. Many ,8- loctllmasc-producing straill5 are S('nsi tin: to cefoc.a.\lmt. including ~pp .. H . inj/'WIIWt, S, flUrtlU, no! all. PstudomoooJ SlnUns an: Enlei .......... d and U s/tna mQfioc"fORtllt~' are re~i5-

Ceftizoxime i ~ not melabolized in vivo. It i ~ excreTed largely unch:tJ\ged in the urine. AdeqUaT le>'cls of The drug e 1lIe ochie> 'w in the cerebro&pinal nu.d for the IreUTnWo!nl of GrJIll -llCgalive or Grdm-positi>"C: bacterial meningitis. It mUSI be iIodminiSlered on a thnce4aily dosing schedule because of it s relatively s tlorT hal f-life. Ceftizoxime 50dium is > 'ery stable In the dry state. SoIutiOO!l mainTain potmcy for up \0 24 hOllI"$ al room lempenllure and 10 days when refrigermed. Ceflriaxone (Roa:phin) if a ,8-1lll!l.ilmaSC-rc:$i51anl cephalosporin ..... ilh an t)ttrenWo!ly long serum half. Ii{. Oncedaily OOsing suffices for most indlC'lltions. Two factors contribute to the prolonged

Ceftriiuone Disod;um, Sterile, USP.

duration of :lCtlOll of ceftna:lIOne: high protein bmdlng in the pillsma and slow unnUly e)(~rerion. Ceftriaxone is eKI.::tcd in both the bile and the urine . Its urinary excretion is not afftaed by piobenc:cid. Despite lIS romparati\'dy low volume of disrrilmtion, it reach~s the cerebrospinal fluid in conCC"IItr1II.lORS that are effecti\e in n~ningltjs. Noo linelll" pharmacol;.metiC!l are obseoed.
~.

wres: (oj a 2-mcthylproptOflloouo\lnooeyl group !hat c0nfers ,8- lactama.o;e rt's islance and. possibly. 11lCrt'lISed pcrTMability through the porin channelS or the cell envelope. and (b;a pyndinium group at the )' pi)S.lioowa1 C()(Ifers l:WI~ ionic propenies 00 the molecule. Cefta7.idimc is administered parenterally 2 or 3 timn daily_ dependin!! 011 the Rlmt)' of the infectlOll. lUi serum hair-life is about l .tI hours. It has been used effta"'ely for the treatment of meningitis caused by H. irif1lum~ and N
m~njngilidis.

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CeIInuone DIE 'llun

NEWER CEPHAlOSPORIN5
CephalOliporins currently undergoing e linu::al trialS or if'eently bei ng mar~cted in the United StDtc~ fall intn tllO c ategories: (II) or.tlly lICti-'e p-lactamllSe-resistanl ccpllalo~porimi and (bJ parenteral p-lactam3SC-resiSl:ulI IUltipstw!!omonal ccphalm.porin~. TIle status of some of the'" I."OrDpounds awaits more elltensive cl inical e\alualiOl1. Nonetheless. it appears thai any a(h'allCe.\ they tepitsent ..i11 be relalh'C(y mOOcs!.

Ceftrillone CQIltains a highly acidi c ocu:rocyclic sy~tem 01\ the 3_thiOlllethyl group. Thi ~ unu~ual dioxouiazine rinll system is bel ieved It! confer lilt! unique phannocokinclic I'lOperties of th" lI,I;ent. Ceflriaxone hII~ been associated with sonographical1y detected "sludge:' or pscudohthiasis. In the gullbladderand COn1l1l00 bile duct .9J Symptoms of chole cystitis may occur in su<;ccptlble patients. especially lOOse on prolonged or high-dose ceflriaxonc: therupy. The cul pnt has been identified as the caldum cheilltc. Ccftriawne nhibils excellent broad-spectl'llm antibacterial !!Clil'i ty against both Grum -positi\'c arid Grom -negallle organi~nlS. II ;s highl y re~i5lant to most ~hromosomally and plasmid-medialed p-Iactam~ . The ~ivit y of l"C ftriUOflC againSt Enl~robt/C/~r. Cilrolx/r/cr. &rrolia. indole-positile Pro't'l/J. and PUUlJummws spp. is p;ln icu llllly impressive. It is abo efftai\'c In the lTelIuncnt of ampic illin -resistanl gonorrhea and II. lrifluen~ in fections bul geoerolly le~ ~ctive than cefotaxime lI@uinst Grom-posilive bacteria and

"I 00

Cehiburen. Ceftibuten (Cedn:) is a recent!) Introduced. chemIcally nOI'cl analogue of the oximinoctpbaIosporins in .... hich an olefinic methylene gtWf' Ie '" C II C Hz-) ..... lIh Z stcrcochemlSlI) lilts replaced the &:III ollimillQ (C. NO) j!rtHlp. This i'iOSteric replllC"t'mcnt jYld! a compourid lhat retains resistance 10 hydrolysis cllhllyucl by many p- Iactama ..... has en~ chemical Slilblllty.1IId is ornll y IICti I'e. Oral absorptioo is rapid and !}early compku. II has the higheSl om! bioolvailabil ilY of the Ihirdgctlm!iN cephalosporins.<U Ceftibutcn is excreted larscly une,,". in the uri!}e and ha.~ u half-life of about 2.5 hours. PIa>.raI protein biridingof th is ceph alospori n ;s estimmed 10 be 63'1:

8. j'"gi/is.
Soiutioos of ccftna.\ one loOdiu nl should be used wi thin 24 houl"'l. They may be ~ tored up 10 10 day~ if rcfrigeroted.

Sodium, Sterile, USP. Cefta:ddlme (",,"ta:(. T al.idime) is a .a-lactal1l~-.eresislant tltird .gcnerntlon ~... phaJospolin thai is noted for iUi wlllpscudomooal acti vity . It is IICtive against some MrJins of P. ~fJ/ginQ$a thai are re!\i~ t~11l to ccfopenl1.one and ccflrillllone. Ceftal.idinJe is ulso highly effective allainst p-Iactama~- produdng Mrai n~ of the Enterobacteriaceae family. It is generally less :teth'e than cdola~ime asalllst Grom- ~itive bacteria ~Ild 8.11t/gi/is.

Cehil~jdime

F,
Ceftibutcn pm.."I:~ses cxccJknt poIcncy agw n~t IIIlIl nlCmlle" o f the Entcrobactl::1iaceae fWlllly. II. Inj1wnr:JIL Neis~rW spp . and M. Ciltarma"s. It is not llC1i\'c Ipn S. al/r",u or P. fI~n/gi"osll and exhibits modest IIntistrqllO" ~"OCCa.I activity. Cefllbuten is recommended in the IIWIIpment of community-acquired resprr~tory 11llCI. unnary ItJI1 Rnd gYlICoolo@ical infectioos.

A. -

...

Cefp(rome.
lilClama\C rc~ista[\t

cephalosporin

i s ane~

parenknl.,

,,.
The StructUI"COfceft:lZIdllllC contain!! tWO note~'onhy featrumi Ii resislant pneumococci. and

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Chapltr 10 Allliba(1uiul A, ..,ibootles

333

1tIi. btlrOOIC',.. r. O,robuclt'f'. and SUrD/ia spp. Il\ ;:;jo,;;';~1lI11S1 P is CVIIlJXImblc wilh Ihnl of largely unchanged in the

Cefpl"",,"

Enu.'robaclerill(:t'at and P. a<'"'lIlnQ5/1, ulld (b) increased affinit)' for nllcn:rJ 1>IlPs, in particular ,he POP 23 (or PBP2') of MRSA.l ' The o/):,en'mioo Ih.:it cenain catecholsubsti tu ted cephalosporins uhlbil marked broad-spectrum arlllbacicnai act. ~i l )' led 10 the dl" c{wcry thlll ~uch l'Ompound~ and OIher ana lotlucs capable of chl: lating irt)fl CQI,Ild mimic MiUra! ~idero phom; (imn-chchll ing peplides) and thus be actiyely Imnsponed iruo bactcnal cdls yia lhe /onB-dependc:nl irt)fllf1lnspon syslem.97. 9f; Thi~ provides a nl('uns of auacking bacl~riaJ Strains thai ~i'l ccllular penetntlion of ccphalosporin~ .

./
AJlepin) ;\ a p.vcn1hm I ~ chenucall), II al<;o has :.
~i\i . )'

A calechol-conlaining cephalosporin thai ochlbils ('roellenl in .-ilm anuOOc.erial IICI1\ Ill' again'>l chnical Iso13le~ and promi'ing phammc:Qkill('tic properties is GR-69153. GR69153 i~ a pa~nlC1'll1 ,8-loctama'\C-~~i5Iam ccphakJ.sporin ... il h a broad .o;peclnlm of acti.-i ly qamSi Gmm-posllhe and Grnm-lX'galhe bacteria_

,ol '>llIphylooocci.
II is lICtil'c I .
l'W5UIl1 10 edUl7.i<hl'l"lle.

b.lClcria. in-

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~~~~.~';'~~;_~~'~"~IO'Y tr.act inftclions. stin and O).loomycliliS. and intra-abis ucn:ied 111 the urine I hours.. lll\ bound minimally 10 pla,ma
II

hn:n Ikmonsullled In the [n:auTlcm of urmal')'

.....,,'
The am ibaclerial spectrum of GR-69153 inclu~ most IIlCmber.. of IhI: Enteroba.cten~ac family. p_ II~ruglll(/xa. II. illf/llt'n::tlt'. N_ J/llllorr/i(}t'ut'. M. rlIlllrr/iu/i,. \laphy lococci. 5lrep1ococci. and It.t''''l'/(~It'r spp. II was not act;'e against enterocneei. H. fmgilix. or MRSA. The half- life of GR-69153 in human \"olunuxl"$ "'11' defl:nnaned 10 be 3.5 hour<. \ullge,ling Iha! melabolbm by cal~'(;hol-O-mclhyl trunsfef"ll.)e may not br an impoftant foctor. Tllc: rc.lall\ely loog half hfe would pC'nna! ooce-a-d:IY p.1rcnleml dosing for the: trcatmcm of many >criou~ b.'lCh:rial infC('tions. An c~perimentaJ ceph.tlosporU1lh:ll has exhiblled consldenablc promise lIgain,t MRSA in preclinical C\DJualioru is TOC-039_ TOC-039 is a parenlera1. P.lactanlllSC-~,i''':II1I . hydrl)~y_ immocephalo-porin ... ;Ih a vinylthiopyridyl side chain m Iached to fhe 3 position of fhe cephem nucleus. II is a broad speclrum alent mal e\hiblb good Beli \ "l' against nM)l;tllC'TQbic: Gmlll-posltive and GramlI<.'gati\'c bacteria. including

Cdrpime is also a fOllnh-gcllt'nuion ccphalQ-

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Cl tepitlll

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freW hne f()properties: (aJ in bacilli. lo:3dms 10 I I SlrJins of

..._.Is

I.. C.phatosportn

TOC.()39

r
streptococci, enterococci. II. irljlul'.rI~{lI'.. M . C(ltllrriwli.J. IlIld mOSI or the Enlerobacteriace ae family.'I'l A few strains of P. I"u/garis. S. mafCl'..Jt:eIl.J, IlIld Cimwoctu /reumfii are resisulIl\. and TOC039 i, inllCtive against P. uuugillQsa. Although the minimum inhibiting concentration (MIC)ofTOC"()39 agamst MRSA is slighll~ less Ih:1O tha t of vancomyclIl, it is more rapidly bactenocidal. Future clinical evaluations "'Ill detcnnine if TOC-039 has the appropriate phanl1l1Cokinet ic and antibacterial propenies in vivo to be appm~ed for the tn:atmcnt of bacterial infections in human s.
~taph~locOC<:I.

MO NOBACT AMS
The dc~'clopment of useful monobaclam anlibiotk~ began with tbe independent isolation ofsulfazecin (S Q 26,445) and other mo!lOC~clic tlactam antib iotics from saproph~tic soil bocter;a in Jupan I and the United Slates. It'l Su lfazeci n was found 10 be weak l ~ !lC11 Ie as an antibxtenal agcnt but highl ~ resiSlant 10 .8-IIlCIllI11asc~.

AZlrconam is panlcularly active against aerobic GI"3IIInegative bacilli, including /:". ( QIi, K. 1"'~IO"u"'ille. K. oxytoco. P. mirobilis, S. marcesCl'.f1S. Citrobacler spp.. and P. aerugino!lI. It is used to treat urinary and lower rcspitalOf)' tract infections, intra-abdominal infections. und gynecologi cal infections, as ""ell as septicemill.' caused by these organ. isms. Altreonam is also effective against , bul is not currently used 10 lreat, infections cauo;ed by HaelllopliiluJ. NdJ!/~rio. Sollll-llllella. indole-positive PrOle"J, and Yersinia spp. It i'i J}()t aetive against Gram-positive bacteria. anaerobic backria, Of other spec ies of PU UlIl/mmIIlJ. Urinary excn:! ;on is about 70% of the administered dolt. Some is excreled througb tbe bile. Serum half_life i. 1.7 hoors, which allows aztreonam 10 be admini stered 2 or J times dai ly, depending on the seventy of tbe infeclion. I...css than I % of an orally admini~lered dose of a.o.trconam j, absorbed. prompti ng the sugge~tion thai tbis P.lactam couJa be used 10 treat intestinal infections. Thc disodium salt of aztreonwn is very soluble in water. Solutions for parenk'f:ll admi nistration containing 2% or Ies.! are stable for 4 8 hooJ"li at room temperuture . Refrigerat~ sololions retain full potency for 1 week.

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EX lcn,ive SAR ,tudic"lUl cvc ntu ally led to the dclclopmenl uf allreonam. "'hich has useful propenics as an antibacterial agent. Early woR; c5tablisocd thallhc 3-metboxy group. "'hich "':0..> in l)an respoII, ible for .8-lactamilSC SLabi lily in the series, <.:oolnbuto;'d 10 lhe low antibacteri al potency and poor chemical siabil ity or these antibiotic s. A 4-metbyl group, however. increases slubilily to P.lactamll.<;CS and!IClivity against Gram-negative bacteria at the ~arnc time. Unfortunately, potency against Gr.tl1l -positive bacteria decreases. 4,4-Gc m-ctimelhyl subsli lution slightly dtcreascs umibactcrial potency after oml adminislralion.

Tigemonam. Tigemonam is a newer mollObactam that IOl [I is highly resislant to P.lactamases. ~ is orall y active. amibaclerial spectrum of activity resembles that of al'JrtO. nam. It is very active against tile Enterobactenaceae. including c. coli. KleiJl ie/l'I, Proleus. CilroiKlcler, Sur{ll;Il,_ EnlerQ/x;c( lef spp. It also exhibits good poleoc~ againSl H illjlf<fm:ae and N. SQ1IQrrIiO<!'''e . Tigemonam is not particIlorly aceive againSI Grllln -po~il i VI'. Of anaerobic bact~ria mI is inactive agai nst P. Il~nlginos/l.

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a
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Ad ,., "" my ,

Th.

Proch.. cts
Aztreonam Disodium. USP. Al'.treonam (A~actwn) is a monobaclarn prepared by lotal synlhe.is. II binds with high affi nity 10 PBP 3 in Gram-nel!!:llive hactcrlu only. It is inacIi ve against Gnlln-positi ve bacteria and anaerobes. P.Lactama.o;e re,istunce h like that of ceftal'.id une. which ha., the same isobutyric acid oximino.1Cyl l!!roup. AlIreonam docs not indoce chrornO'iOmally medialed P.lactamases.
0--0

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In comrnst to the poor oml bioo,'ailubility of a:i.t~ the Ol"'JI absorption of tigemonam is excellem, It l"Quld I:tcome a valunb1c agent fOf the orallreatment of urinary n.:t infections und other non~life-thrcatc ning infections camed b~ P.l actamase-producing Gram-ncglllive baeteria.

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AMINOGl YCOSIDES
"The discovery of streptomycin. (he first ami noglycoside_ biotic to be used in chl'nMltocrapy. was Ibe result ofa pl_ and del iberale searcb begun in 1939 and brought 10 fruiOGl in 19.f4 by Schall. and associMes. 104 Thi s success stirnulail

neg, ka m kaci (wil; li\"e;

gam mmr

""f,

ChapIn 10 Ant,bac,uilll NIIlbllJIlC1

WlJrkh....de searchc:5 for antiblOlics from the actillOmycctts anti. particularly. from the genus SlrtplQmyctJ. Among the lllilDy IlIIlJbK)tlcs isolated from tnat genus. se,'era] are compounds closely reloted in Structure to streptomycin. SIX of tbtm-kaJUlmycin. l'IComyein. patulllornyein. genlamicin. lObramycin. and l'ICtilmicin-cum:ntJy are marketed in lite lalled States. Amlbc lII, a sennsynlhetic den"alive of kanaIII)'t'Ln A, haS been added, and it is jXlSsibie Ihllt additional .u1lOl1)'cosidcs will be introduced tn the fUlure. AU amllloglYCOSlde anubiOlits are absorbed \el)' poorly (Ies~ than 1% under normal drcuJIlSlaoces) following oral UrurustTJlion, and some of them (kanamycin, neomYCin, nI paromomyCin) ore admlllistcred by that route for the tmtlllCnI of Il'lIStmintl!$ti nul infections. Bc:cause of their po1m! broadspectrum antimicrobial activily. they ~ also used b the' ~alllll'nt of syslemic IIlfections, T1lclr undesirable lid!: effectS, paMicularly OIOIo~icity und nephrotoxicity, have rntncted their S)'litemic use to serious infections or infe<:IioIItt ca~ by baclCnai strams resistant to other agents. Wkn administered for systemiC' infC:Clions, aminoglycoWes mu<a be gh'en ~n!emlly. usually by intmmuscular IIF'KJD. An addllJOI\III antibiOlic obtained from $trtpllmtY"' Ifl. ~ptClinomycin. is also an amillOglycoside but dIffers dlmucally and mICrobiologically from OIher members of IIIr JfOUP. II is u.)oed nclushdy for the treatment of IUlCOtnplLrlled gonorrhea.

JJ5

Grotm-

~~:

'''''' ologi-

organ TI:nlly werill. . It is bacte-

,.-.
i. 1.7
abcould
IS

2M 3

n Less

group for the chemotherupy of tubercu 10001S. bruccllosis. tulan:mia. and Y"'Slnia IIlfCl..'1ions, ParoLllOIllycin is USIW prinwIll' III the cltelllOlhcrnpy of amebic d)'scn!el)'. Under ccnalll circumstances. aminoglyCO'>idc and P.luctam anti biotics exert p synergistic ~tlon III \ 1\ 0 ~gllJn.q !iOITII: bactcnal ~trams ~hen the t~O art" administered jointly. For cumpk. carbenicilhn and gcntanllcin an: ~yllCl):l)UC hgainst semanllcin-sen.itive ~tr in) of P. aefll~"WSll and sc'erai OIher spe... cies of Gram'llC'galh'e bacilli, and penicillin G and streplomycm (01' gentnmlcin or kanamyclll) tend to be more dfc:cth'c than either agcnt alone in the treatment of cntcrococcal tndocarduis. lbe t ...... o antibIOtIC typc\ should nor be combined in lhe san'le !'Olutioo because lhey are chemically incompatible. Damap: to thea:lI ... all cau<;cd by the ,B-Iactam antibiotIC it' believed to illCTeISC pcnetr.U.ion of the ami noglycoskk Into the bacterial cell.

water, or less Jeralcd

Mecb.nlsm of ActIon
studies concerning the TI1C'Cnani ~m or IlJItlbocterialllC ' tion of the omlnogJ)'cos~ ... cre carried OUt ...uh streiXomycin. TIle specifIC actions of other amllloglyCO!>I(;ies are thought to be quaILtatively ~imilar. however. The aminogl) cosidcll oct dIrectly on the iNoclCnal nbo!.ome In mhlbit the IIllliauon of proIelll symheslS and to IIllerfere with the fidel "l' of tntnslation of !he genetic mess.agc. They bind 10 the 30S riboliomal suoomtlo form a complCJ\ that cannot imtiate plOper amino acid polymcn/..ltllon. ,m The blndllli of streptomycin and othc'r aminoglycosidc~ to ril:lowlnes alw cau'iCS misreading mut atIons oflhe genetic oodc, apparentl) n:sulting from failure of specifiC' amulooC) I RNAs to I'COOiIn,ze the proper codon, on mRNA and hence Incorporation of improper antioo acids 11110 the pepude cham. lOt. EVidence: suggests that lhe dtol(Y'\lrcptanlll'lC-containing Illlllnogl} C'oSideS differ qUluliltari\,dy from 'lI'CplOmycm in caw.lIlg ml~ readilla at lower concentrations than tOOse l'C\juitW 10 prevent initiation of protem s)nthe~I) .... hercu stn'ptOtnyc.n is equal ~ effective in inhlbllLng inlhnlion and causmg mIsread ing. lo Spectioornycin I"rt"'tms the iniliallon of proIcin syn thesis 001 apparently does not GlIISe 1II1)n:ading. All of tlte commcrdally available nminoglyroside ant1biotics arc bactericidal. exccpt spectinolllycin. The mechanism for the bactericidal action of the anllnogl)cosidcs is not known.
Mo~t

lin

that

". Th<

anreo-

u,;:ludolD. and cin_~t H. .nicu~

OI ...istry'
,I,mmoglycosldes lite so named bfxause their structures con ohmlllo sugars linked gl)'COSidicalJy. All ha"e at least CIItanuDOhcl(OSC:. and some have a pemosc: lacking an an1l1l{) poop (t.g .. streptomycin. neomycin. and paromomycin). ~ly. each o f the clinically ~ful amioogl)'COSides COWID$ a highly sui>stitliled 1.3-diumlnocycloheunt cenhi ~: in kan:Ullycin. neomycin. gent:unicin. and tobra"Jtift. It IS (\eol(ystreptam.lll'. and in streptomycin. tt is *tpIIdme. 'The aminoglycos.des are mus strongly basic llCfiOUnd$ mal exist as polyutiOlls al physiological pH. ~ lDorzalllc acid salts are vel)' soluble in Wlter. All are nlabk as sulfates. SoluliQllli of the aminoglycoside ~IIS 1ft Sllblc to outoclavlng. The high walcr solubility of the >&I)'t'Nldes no doubt conlTibulC5 to their pharmarokipor1ICS. TIley distribute well Into roost body nuids .. not into the ccntral nCrl/OIlS system. bone. or folly or live 1l$WeS. They tend to concentrate in the kKlneys are e.lcreted by glomerular filtrauon. Ammoglycoside!; _lI'P<llCntly not mctaboliled in vivo.

..,""

Mlcrobl.1 RHistanc:e 'The developlllcnt of strJIIlS of Enterob:LCterillCcae resi, tall1

to antibiotics is a well recognilC'd. \Crious n'Cdicai problem Nosocomial (hospital acqull1:d) IIlfeaions caused by these orgamSIIlS un: often resistanl to anubIOl.C' therotpy. RC'it!:lrch has estubli~hcd clearly thaI tI1ultidrull tcsistullCc alllon!! Gnun'l'ICgati,'c bacilli to a vlUlety of antiblouc\ occurs and can be tnmslIlll1cd to pre~iously nonresislunt str-UIlS of the SIIlne \jX.'Cies and. indeed. 10 diffcrcnt ~pecie.~ uf bacteria. Resistance is tl"llllSfen"Cd from one iNoclenum to IUIOIhcr by nlraChromosomal R facton (DNA) thot ~lf-l't'pllCatt and un: lrunsferrcd by conJugalion (dlfCCl conlllCl), 'The aminoglycoside anliblOlics. bc:causc of lheir potenl bactenC'idalac lion I.&DJIlst Gram' llCl!nh'e iNocllh. arc: now preferred for thc \1'Callllent of nlany serious i nfcctions cou<;td by colifonn bacteria, A pattern of bactenal reM_lance 10 each ortlte anllnoglyCOSlde anublOtiCs. ho ...e\er. has de\eloped a, lhelr

1,ICb LI,.. of Activity

A_Pip tlte amiooalycosides are clll5sified as brood-specINibiouc:.s. their greatest usefulness lies In the treat_rAritus systcmic infcclions C'a used by aerobic GramItph~ bacilli. TIle choice of allen! is generally between ,:~)tin. gentamICin. tobl"llmycin . netilmlCin, and allliI.J Aerobic Gram-n.egUIL\e and Gram_positive CQ(ci \c the e.lception of staphylococci) tcnd 10 be less sensi\bus.. lite P.lactams and other antibiotics tend 10 be la'ella! foe the treatmcm of IIIfc:ction s caused by these orAnaerobic bacteria arc invurillbly rc,\;stanl 10 the rostde5. Streptomycm is the IIlOSI dfe<:tlvc of the

t linical use tub become more I<Itk-spread. ConSt:queJ1t ly. thctt are !derial Slntm~ rtslstmli lu SlrcplolUycin. kao;lIny cin. and genulImci n. Stnlin' tlllT}' mg R factors for resi~ lallCe to these anhblotlt~ sYllt~i/.e ('n,-ymes capable of acety lal. mg. pho~phoryl~tling. or adeny lylallng Io.ey amino or hydroxyl groupsofThe ammog lyooside~ . M uch uf the l1X"enl effon in anll noglyc~lde n:sc:an:h IS directed IOward idcmifyml! oew, or modif)tng u isting. anlibiotic5 Iha! Wl' re~iSlan. 10 tntIClI VlIUOIl by b.'lCteriaJ enzymes, Re~isumcc ofi ndl vidual ami llOlycosides to 'flCcifk inactivating en7ymes can be understood. in large nlelbUIl'. by using chemica l pri nciples. Fi rst. ooe can U llIe thm if the S'U lar&el funcuonal group IS abo;em m a pOMtKm of the. ~truclUll' nonnall )' allocked by an inactivating c llq mt. the n the ant ibi otic will be res'5tant 10 the enzyme. Second. sterle facton may coMer n:sl ~mn(:e to ,111 00;;10; al rllncllonalitie~ otherwise: 5USC'Cptible '0 ell7.ymatic anack. For aamplc. conversion of It pri mary nmi no group to It secondary amine in h lbi ~ N acetylalion b) ct'f1111n arnioog l)coside acety l lr:an)fer:lCll. At lea,1 mile di ffcre nl lYpes o f anllnogl)'COSlde.inacl,vlttlllj enzymes ba"e be.!n ldemi lied and parlially charactcrized. Ii 'The \it~ of aUlII: k of thc<;e en7.y nll:5 and The biodlCm i~try of the inoctivau()(J rcaction~ is descri bed bficny. u~ing Ille kanamyc in B ,tructun:: ( ... h,Ch hold) the dubIOUS dl ~lIllCl ion of being a substrme for all of lite en/ytnc;, dcscritll.:d) for Illustrative pu~ (Fig. 10-7). AmlllOg lycosideinactj... ut iug ell"(.yme~ inCl ude {II} ami noacc\)" ltnm 'fcrnse.~ (deslgnmed AAC) . ... hll:h k"et)"late the 6'NH2 of ring t. the 3-N lt l of ri ng II. or the 2'NH 1 of fl ng I: (bJ phosphotnulsf('f'.tses (dtslgn:ued A PH ).... hich phosphorylulC the 3'-OH of ring I o r lhe 2"OH of rin~ Ill: anti noclt'01idyhr:ansfcrases (ANT).... hich adcn)"late the 2"-011 of ri ng III. the 4'-011 of n llg t. or the 4"-01 1 of ri ng Ill . 1be gemamicins and loon.,n)'d" toct a 3'hydroxyl group on ring I (see lhe secho n 00 the ,ndl"" dual productS for ~truc tUre$) and. ~'OIlscquentty. are not inactivated by tnc ph~llO Ir:an~ferase en:.t)'nlCs thai ~phorylale Ihal group ,n !he l anamycins. Gentamki n C 1 (bu l not genlamici ns C .. 0( C 1 or tobram)'con) is re~i~!ant 10 the ocetyITransferasc: that acetylate!i the 6' -amino grou p in ring I of kanamyci n B. A ll gent amicins are res'~IDnltO the nudeocidyltrans ferase enJyme that adcnylytah!S the !lonililry eq uutoriaI4"-bydroxyl group of lanamycm B because the 4" hydrox)"1 group III lhe I!'!ntamidns IS It'rl/"ry un!.! is oriente!.! ax ially. RenlOva l Offuoclional groups stlSCC'ptlble 10 allack ing an amirtOglyooside occa~OI"I ut Iy can lend 10 deri"'Rt ht.~ thaI res", Cn7.y m~lhc in:lCt l... ~ l loo and retDm acti,ity. For e:c.am ple. lhe 3'-deoxy-. 4'-deQ"y_.

and 3'.'" ..(h<k.'Oxy ~ anamycins are more "milar to lhe gaD' micms nod tobrdmycin in lhe ir p:lIlems of loctivll y ag~11t\I clinical i:solales that Tt~ist one or more of the anll noglycoside-ill:lClivat ing e n l;yme.~. The most ,ignlficalll bn:a~throogh )'CT achie,ed In mr se arch for amioog lyeoside!. re.,iSlant to bacterial enl;YITIQ ha.~ been the de"elopment ohrm kacon. the INI-(+:mu1lOa hydm~ybul yric ;o<.'id (I,.A IIB A) !.!envat i~e or kanam}ClI A. Thi s n:marlo.ab1c compound retai ns most of the Imrim..; potellCy o f l.:nnamydn A Wlfl is re;iSt anl to vi "uatly all anunog IYCOli'deinact;'llung enl)'me..~ ~ oo ... n. except tht' antIlI()o acet) hro nsfenl ..... thnl ocelylmes the 6'-amlllO group and IlK nuclool:id),l tr:m$ferase that aden)lyl ales the 4'-bydrol)1 group o f nng I. 101. 10\1 The CIlU>C of lIlnllo.lIoCi ns rt!Slsunce III en:.t)'lnatic ill:lCti vatioo is IlOl know n, but it has bn.'illf" gCSted Thai ontrotluctioo of thc L-A IIB A group lIItO hnalll) ci n A markedly dec~ase. irs affinity for the inocti~au. cnzyme.,. 1be IInpoxtance of ami ~oci n's resistance to eatt matlc inacli"alion is rc lkctl'd in lhe results of lin in "ts\lp lion on the COrllpatal" e effeah'eness of anu kacin and odta aminog lyeoside againSl clinical Isola lCS of OOcteri ll] stnIIII Io.nown to be resistant to one or IJ10re of the IInllnogl~'o:IJo side.s. 'IO In l hi~ ~ I udy. ami lo.acin was effec tive agDlnSl91t of the isolates (wi th a range o f 81 TO 1()(Kl. dt'pendiDg 01 Ihe ~pccie:.). Of the stmins suscept.ble to othe r sy~lemiclll!" useful Ilm loog tY<'"Q!ii(le., IS 'l .... cn: suscepti ble to k;mam)~ 36% to ge nlam ici n. aod 41 ~ 10 tobrnmyci n. Low-le"e l I"CSlStance associaled .... ith d i mini~hed :11111110gI Y~'mide uptake has been in certuJn SlrolJIIS of' uen' giI1lIM' io;ol31OO from nowcontlal infectioos .'" Bac19 ~uscepti bl hty to IIminog lyCOliides KqUIIt'; uptake of I~ q by an energy-dependent acthe process. II~ Uptake i~ inltian! by the binding of the cationic aminogl)"COSide 10 .. p/IO~pholipids o f the ccll mc mbmne, Electron Iran>jlOlllinked tmllSfer of the aminoglycoodc: through the ccll_ brane then oceUI");. Divalent ca lions ~ucb as Cal. and anlagoni:t.e the I mnspc:l(l of .mi llogl)Cosode.~ mlo '*'tnI cc li s by inlerferi ng wi tllt l'letr bin!.! ing to ce ll melllbra~ pbo!p/IOl ipid). The Il'SISIance of unael obic bacteria 10 t~ Ic*I action of the aminog lyCOSldcs IS apparently due to SCI1l,."e or the. ~pirntion-drh'e" actl\'e-lransport prom.! t r:ln~ I)OI"\lng lhe an tibiotICS.

OOse""'oo

M r

tht"

Structure-Activity Re lationships
Despite the coo. plexity inherent in various am,nogl)~. 5IructUTtS . ..onle conclusioru; o n S ARs in Ih is antibl(l(ic

ANT...

\
IiO

ANT2". APH2"

'"
11
NH,--AAC~

Figure 10- 7 Ir\actIValJOn of kilflMn)'Con B by I~ l.aj enzymes.

Chaptn 10 An"~I~"'" N"'bltlIO('s

331

lllve been made. Ll' StICh cOIlC!uslon~ ha"1: been fonnulaled _the bMis of comp.1n50nS of nmuraliy occurring ~minogly cwde $IfUCtIII"eS. the ll.'IIullS of selective: semisynthetic modibIoos. and the elucidation of SlIe:!> of inlll,:'lll':llloo by bac ImII enzyrtlCS. It I~ con ~enicnt 10 di!iCUs..~ sequentially .rnnoglyCQSidc SARs in IcmlS o f SllbslilUCnlS in ringl I. 11.

_m.

toward light and air. It is freely soluble in .. mer. fomllng solutions that ate slightly acidic or nearly neulral. It is vC'1)' slightly soluble m alcohol and I~ insoluble III IIlOSI ochtf organIC soIlems. Acid hydroly~is yields strep:ldll"lC: and streplOoiosamine. the compound Ihat is a combination of 1.Streptose and N-mclhy l-I.-gluCOl\amine.
~

RIIIg I is crucially Important forcharat1erislk broad-specrum IIllibactcrial actiVIty. and h , ~ the primary target for bltlrrial inlk:livaling enzymes. Amino functions 31 6' and particularly important as tanamycin B (6"3I11ioo, 2' ....oJ IS rrlOfe acth'c than kanamYCin A (6'amlllo. :Z'hy"'hid! in tum is mort: acl i'~ than l3namycin C (6'II)tkulyl, 2'-aminol. Methy lation at either the 6'-carbon or .. 6' 'fl luioo po~ition s doe~ not lower appreciably anlibaclC

tyoI - l - Htl'",OH

SIr8p!kione

r.wt .rl).

""

IIIIIICII\;t)' :md confers resistance 1 enzym~lic acetylation 0 ~tbI: 6'.nuoo group. Remo\-al of the )'-hydroxyl or the r.J\~dro~yl group or both in the I;anamycins (e,g .. 3'.4'.
n:<Iuce amibac bill poIency. TIle ge11la11licins ul~ lock o~ygen function s dlese po5itioos. as do ~iWlnkm and neti'micin. "bich 1M IIlI"t. 4'S-dooble bond. NOlle of!hese derh'ati\"C'~ is m:lIvaled by ~pholnmsfemse cn7ymes that phosphor}' ,*!be 3' -hydro~ yl group. Evitlently the J' -phosphOl")'latcd 4m1-atil'cs h.av~ v~ry low affinity for arninogly~'(>Sitle+bind + IIJ wcs In bacterial n~~. n.. modJflCalton~ of nng II (liemystrep:amine) runc IiDlaI lrouPS are posSible ... ithout appreciabl~ loss of activity IOOlIt of tile aminoglycosides. 1lic I-amino group of 1;811a ~ A ean be acyl DIed (e.l .. umi l acin). however. with ...nil)' largely retwned. Netilnllcm ( I-N-c:lhylsisomicin) rc!be antibacterial potcncy of ~iJ;Omicin and is ~istant 'Htl'ml addi t;oual bacteriainactlvating cnzyme~ . 2"- l-I y m~slwnucin is claimcd to be re:~i~HUll to b!lcterial slrnin ~ . . acknylate !be 2"- hydroJl yl group of ring Ill . whereas ~tno!liwmkin t~htb1l~ good activity llIainst bacterial JI2IIIS that elaborate 3-occtylatlng en/ymes. Rlnl III functional groups appc:ar to be somewhat less ft!oIOI'C to structural changes than those of either ring I o r l1li11 Although the 2" -deo" ygentarnlCins are slgnificlUltly actJIt than theIr 2" -h)' dro~yl countCfJXlrts. the 2" -amHlo *"1"3111'1:3 (se idomycill.) are highly acthe. The J"-ammo pwpOfgenlanlicins may be primary or secondary with high _Imal potcncy Furthermore. the 4"-hydroxyl group ..,. ~ Q.fl/ll or <,qua/oritll " 'l1h Imle change in poIeocy. Ihpite imprm'C'ments in antibacterial poIency and ~I1Qt

dideot) kanamyci n

R ()I" dibekacin ) does

StreptOmyCW\ Streptomycin actJ as a triacidic ba!ot through the effect of its tWO ~trongly baSIC guanidino Groups and the more ...eakly basic methylamino group. Aqueous soIutiorn; may be 5t()l1!(l al room tempc:rature for I ... c:e~ without any loss of potency, but they are mo.t stable if tile pll is bet"ccn 4.5 and 7.0. The solullon~ decompose if ~tcnli/..cd by heating. so stcrile solutions IU"e prepared by addmg ~tcrile disti lied Wlltet' to the sicrile po..der. TIle ellrly salts of ~trep:on\)cm conlal1lCd impurities tbal wer.: diftkult to remove and cau . a histamine-like react ion, By fOfmillg a comll'el wllh calcium chloride . II W'.l') possible 10 free the ~treplolllycin fronl the.-.e impuntlCS and to obtain a product thaI was generally wcll tolerated. The organism th;U prodw::es streptomycin. StrtplQmya$ gris<,ut. alo;o produCe5 severo l OIher autibiOlic compot.mds: hydro~yMreptOOlycil\, manni,odotreptomycin. and C)"CIoheximide (q. v.). or these: . ooly c)clonel<imidc has achieved imponancc lIS a ntedicinally useful substant"e. TIle term s/replum n:in A ha.~ been used to refer 10 "hat i( commOrtly Clllled ~trcptoolycin. and manlll'ldostrep:ornycin has been called str<'pllHfI)"(";n 8 . Hydrol<y .... ll'p:omycin dlffeOi from slrep!:omycin in haVing 11 hydro~yl g.roop in placc of one of the hydrogell !ltmnS of the su~ptose methyl group. Monmsldostrl'ptomycin hD~ a mallnose r.:~idut: allachcd in g lycosidic linkage through the h)'drol<)'1 group at C-4 of the. N-methyl . L'l lUCOS11mlne moiety . The .. orl of [)yer and col leagues ll < II to establish the ~cn:ochemieal structure of strep:omycin has been completed. and confirmed with lhe tOla] 'ynthc"s of streptomycin and dibydro~t rcptornycin by Japancse scicn. tists. CllnlCall). a probltm thaI SOInelltileS occurs .... th !he use of strep!:omycin is the early dclc!opment of re\l~tant str:llrn; of bacterlU, neccs~itllli nl! a change In lherapy . Other factors that lunll the therapc!utic use of ~treptotnycin are chronic toxiclliC">. Neurotoxic reacuons hale been ob6cned aftet'the use of streptomyc in. The!.e are char..cten/ed by \crtigo. diStumlnt"e o r equilibnum. and duninishcd auditory percept 10/1. Additionally. nephrol o~icity occurs ... ilh some frequetlCY .

.oo

"~~~;:~' occumng and semisynthetic ; b! . e ffort ~ to find agent~ with im margins of r.nfety hal-e bec-n disappointing . TIle pofor to~icily of these importam chemotherapeutic IIftIIl ronlinues to I"CStrict their usc Iw-gely to the hospital lIIuonmenl. The dlsctl\"cry of agenL~ with higher pot"ncylto~icity rdn'fIIIIms all illlpor!lInl goal of .millOgJycosidc Te'iCarch. ~ I 1I0\Io some ... hal dmed re,ie ... howe,('I". l'rice ll el~ doubt that man y signifICant tl iniclll breakthroughs umiqlycoside research would oo;:cur in the fu ture:.

,i.,

..

SlrfplomycinSl.llfate, Sterile, U5P. Streptomyci n su i ~. "'hitc. odorless powder thai is hygroscopic but smble

PUJmIS undergoing lhC'rapy Ii>.th s~plomycin should ha\'t frequent checks of renal monitoring par.unclCrs. Chronic to,lIen), rcactioru 1lI<I.)' or may not be rc'" C1'lliblc:. Minor toxic effects include rashe$. mild mal.,~. muscular pains. and drug fel'er.

As a chemotherapeutic agent. 5lreplOlnycin is active

against numerous Grnrn -ncgat il'c and Grurn-posith e baclerill. OIlC of the grea[e~t Yinuc.~ of sm:plomydn is its effecti veness against the tubercle baci1lu~. My(:uixlclerium mlHr. cu/Qsjs. By itself. the amibiolic is 1101 a cure. btu ;1 is ~ \aluable adjullCl 1 other lreaUfle nt modaJ nies for lUbcTculo0 sis. The greatest dra ... back to the usc o f strcplOmycin is the rather IlIpid development of resisulfll stnuns of microorganisms. In infectiOll51hat may be due 10 bacteria scnsili-"e 1 0 both slrcpcomycin and penicillin. the rornbined administra\Jon of lhc. ......0 antibiOtics hIlS bn -.d\'ocaled. "The possible !Ie"c!oprncm of damage 10 the (Mit I1CI'\C by the continued usc of sU"CplOmycin-conlarnlllg prepar.mons b;ts discouraged lhe use uf wch prodUCIS. There ha~ been an Increasing lendcllCy 11,1 I'eSeI"'e streptomycin productS for lhe: treatmem of tubercu losis. II remains one uf lhe agenl~ of chuice. however. (01" the lreaunent uf cenain "occupatiunal" bacterial infcctioos, M1ch as brucellosi~. tul aremia, bubonic plague, and glande~. Bause streptulllycin is nQlllbsorbed whcn given omlly or desU"O)'ed significamly in lhe gllSlrollitestirnll tract, lit one li me it was used !'littler wide ly in the treatment ur in fecuoos uf!he intestinal troct. For 5)'''Clllic action, streptomycin u~uaJly is ghen by intramuscu lar injeclloo.

Neomycin. as prodoo.-d by S. f~adia~. IS Q mixture d clO5Cly relaicO substances. Included in the "neorn)'cin complex" is nclnnroe (ongin.aJly designated _yciII A) l1li IleOmyC IIIS 8 and C . S./rad;al: also elaborates alll)(her antibo otic. fradlcm. v.hlch ha.s sume antifu ngal pnlpIo'nle$ but 110 anti bacterial activllY. This substance i~ IlOI prcent 1/1 "pure " neomycin . 1loe )trucHII"CS of neamillC and neomycin ij arK! C ate known. IIl1d the ab'>Olutc configur.ltional Mrueture~ uf 1Itamine and neumycin were reponed by !l ichens and Rine han. 119 Ncamme Irnly be oblalned by melhhnul),sis uf nco. nlyci ns and C. during v.hich the glycosidIC li nk bct .... dc:o~y)treptamJlle and D-nbose is bro1:en. l1iereron:, JlI'amme is II combinal1on uf dc:oll.)stn'ptamine and neQSan1Il1E C. hnLed ,Jycosidical1y (a) althe 4 pQSlIl00 Qf dcoxystrqlIlImine. Accordlni 11,1 Hichens and Rmehan. 1'IWfTl)"t1ll B diffeB from 1lWm)'cin C by the nature of the sugar Inxhtd tcnninally tQ t>-ribose. That sugar, call~ tU'Owmrnt 8, dUfcn from neosamine C in its stcte(lChemistry. R,nehan eI al. I~ oo\e SUla:eslcO thai In neosamillC: the configuratlOl1 ft 2,6-d iamino2.6dideoll.YLidose, in v.hich the orienl.it1Ot uf the 6-amillOmethyl group is inve ned tu mc 6- amin0-6dcoxy-ng lucosam ine in neosamioe C. In botl! inst3I1Ce~. the: gl>'c~idic l ink~ v. ere ass umed 11,1 be tl'. Hucllcnrnuch III later sUGgested. howcver. Ih:U both of the dihmmu sUI,::trs in nromycin C ha\'cthe Ilgluc~ cunfigu!'lItioo Qnd that the gl)..osidic link j . {j 111 !he one attached 10 D-nbose. The lana Siereochc:ollSlry has been confirmed by the tOlaI synthesll lll Qf ne~mycin

cn

Neomycin Sulf~re. USP. In a:;earrli for anubiotics less tQ~ic than stn'plotnycin. Waksman and Lecheulier " l i"lOUllet! neomycin (M )'cifradin, NcobIOlIC) in 11)..19 from Sin'", /QIPI)'Cu /radia~. Since then. the importaoce Qf neomycin ha~ increa5C'd slead ily. and tOlby. it is coosi dcred one Qf !he most useful amibiotics for the treatnlCnl of gastrointestinal infections. dermatolugical mrCCliQn~, arK! acute bacterial peritunitis. Also. it IS used in abduminal surgery \1,1 reduce or avoid complicaTions caused by infections from bacterial or the bowel. h has broad-spectrum acti"i ty againST a variely of organisms Dnd shows a luw illCidc:lICe of tox ic arK! hypersensitivity react iuns. It i5 absorbed very slightly from the digesti\'e ITlICt. so its ural use ordmari ly does III)( produce Iny systemic effect.. The development Qf neomycin-resi5lant stralM uf p.uhogens is rurely reponed in tho:;e organisms qainst which neomycin is effecu\e.

Paromomycin Sl,Ilf~te, U5P. 1lle isolation Qf ~ m)'cin (li Ulllalln) was reported in 1956 froon a fennt:Dlatl(ll Wlttz ~ SIrt'pltJmYCtS sp. ( PO ().t998). a Stram s'[ud 11,1 resenmk S. mnosus very closely. l1le parent organism had been Dbtllin..'ti from soil sumplcs collected in Culombia. ParomortI)' Cln, however, motl: closely resembles neumycin ItI1d stn'ptO11I)'cin ill anU biotic IICtiv ily than it dOCli uxyletrucyctlllt," un liblotic ubtained from S. rim05US.

nora

o-OIuce77~

',",

_ c .,if. . "{'\
~f.e - r~1..... ~
~

"';) t;'\ ....

NeosamiM 8 Of C

'.

Deoxystreptamine

P.fOITIOmydn', R, .H; R,.C~NH. Paromomydn II R l.cH~H.: R._H

,
_c

Neomyci n as !he 5Ulfatc sail I~ 11 ... hite 11,1 shghtly yelluw. crySlalline powder mat is \cry 'IOluble in lValer. It is hygrol:opic and photosensiu"e (but SUlbIe Q\'er B wide pH r.mge and to autoclaving). Noomycm su lfYle c<mt:lins !he equivalent of 60% uf!he free base.

--

[).RlX It

1lw: gerlCral structure of paromomycin wa~ Ha~kell et al. III as QIIC: cumpound. Subsequenlly, gruphic detennmat;oo~ ha\'e shown paromomycin tu of two fractions. paromumyci n I and palUl1lQ5I1)'CID 11. TIll absolute ronfilurullorW ~lJUCIures for lhe as shown mIlle ~I ruclUruJ formula, were suggested by Hdens and Rlneh:u1 119 and C(lDfirmed by Dcloogh ct aJ. ll m:I..'ili spectrometric studi~. 1lIe structure of p;lrool10111) IS the 5allle ItS thai ufneomycin B. e:'llceplthat parorDOIlI'" cuntains D-lltK.'OSIIminc: in~ttad uf the 6ummo-6-dcoI,+

paromom""

p.cOAnHfIe fOlloo In neomycin 8 . The ~lInc SlfUClUrall'\:laIIOIIbIup,~ found bet ... ttn paromomycin II and neomycin C.

TWcombmation of o-,lucosanulle and deoll)'~llq)Iamllle IS oiItaIned try panial hydrolysis or boIh paromomycins and is tiled ptlromanun," f4-<2-amino-2-dcoxy-a-4-glucos:yl>deol YSUl:'pI .. nuflC I. I'aronIOR1)cin has bf'Oad-$ptrum pnlibocu~ria] IICli\'ily .,;j has bten used for the trealTJlCllI of gaSII'01!llcMlllal iofee_ lI0II\ caused by SII/mo"..lIu and SlIigl'llll spp. and c:mcroplthogenlc E. coli. Currently. however, its use is re~lrkled Iqtl)' \0 the trcatroenl of inlc~linal amebiasis. l'al'Olnomy>III is soluble in water and stable 10 heal over a wide pH

....
1IIIIl("f')'

IIIwmydn Sulfate. USP. Kanan!}cm ( Kanlrn) was .g'rd In 1957 by Umcza... a and cowCll'leB,z.j; from SlnpWnam)'CtlicU$. lIS activi t), agams\ nl)cobacleria aI m.lII) intestinal bocteria. as well as II number of p;llhotIw show resistance \0 OIlier anllbi(MiclI. brought a great duI 0( 1l1CnllOO to this antibiotic. As a result. k3namydn .1Il~ed and released for medical use In a very short time .

, " " ,. ,

glucose: and kanamycin C contains 2-amino-2-deo.ly-t>-glucase (see diagram atxn-e). Kanamycin ;\ ba.~ic and forms saIlS of acids through us amino groups. IF IS ""~Ic:r -.oluble as lhe: free ba'IC. bul " is used in tbc:r.apy as the sulfm salt. .... hich is I'ery soluble. II is stable to boIh heal and c hemicals. Solutions resist both acids and alkali wl lhm lhe: pH mnge of 2.0 10 11.0. Because of possible inactivation of eithcT agent. kanamycin and peni ci ll in sailS shou ld not be combined in the same solution. l1Je use of kunomycin in the United Slates usuaJly is reStricted 10 infcctions of the: inlestinal trnct (q; .. OOc'iliury d~senu~ry) and to sy\temic Infectioos arising from Gramnegauve bacdli (e.g .. Klelwdili. Prote .. ,. EmerolxJ!'Ier. and ~rroli(l \pp.) thaI have developed resistance 10 other anllbiOfics. It hI!!> alo;o hun recommended for preopc"f'JII.e antisepsi\ ofthc bowel. 1t is absorbed poopl)' from the IlItesllnal tract: cooSCQuc:nll y. ~y\temic Infections mU!i1 be lTealed by intramucular or (for serious infections) intf'd. ellOOs inJCCllions. The<oc: in.JCIMioos are r.atncr painfu l. and the concomllant use of a local anestnctlC is indicated. 11Ic use of kanamy ci n in the trealmcm of luberculO!iis has 00l been widely advocated since 1M dl'<COI'Cry that mycobacteria tlel'cl op resi<;1Il1lCe vcry I1lpidl r,' tn fael. both clinical c.lpcricl'ICe and C.lperi lllel1l ~1 wor~ l'O ill(!icme lhut kanamycin dcvelop$ cross-resistance in the tubercle bacilli ""'ith dihydrostrcplomyei n. l'iomyclII. and other antitubc:n;:ular drugs. I..ike streptomyci n. kanamycin IIll1y cause decreased or complete loss of hearing . On deH:J.opmc:nt o f such symptoms. il$ use should be Slopped Immedi:uely. Amd.acm. I-N-amlno-a-hydroJl)ool)'rylL:mamycin A (A mllm). is I sc:misynlhc:tic aminoglycoside fil"il prepared III Japan . TIle synthesis formally m,oll'dO simple ac) latlon of the I"Jlffiino group of the deo~y5ITeplam ine ring of kanamy('m A with I -AHBA. This panicular acyl deriVD.t;'c retai ns about 5O'l of lIFe original activily of kanamycin A against sen'ilil'e blr.ai ns of Gram -1I('galhe bacilli, TIle I..-AHB A derivative is much more active than the D isomer.')Q The renlarkable fe:l1ure of amikacin is that il reo sists 31lllCk by most b,lClenD-inactl\aling enzyltll'lI IIl1d. therefore. is effectl~'e agams.t strains of bacteria thal are ~5is tant to (l(hc:r atnllloglycOIlI(les.I 'o including gelltamicin and lobrnmyt"l n. In foct. il IS ~l5I.anl to all knov. n aminoglywsidc-ina..."'tivallns en;() mes. C.lCtplthe aminotransferase lhal acc:t)'lalC:S the 6'amill(l grouplOli and me, 4' -nucleoudyllr.ansfera.~ lnat adenyJylotts the 4'-hydw.lyl group of aminogly=~.

m I, b-

III

r.;

'"
I(_m~

...... ""
0

Amibcin. US".

KM< p p 7Iine

K.7i!'lllmyQn A. A, K.3inam)'CIn B; A,

NHz. A. NH.; A. C: A, .. OH, A.

OH .. NH. NH,z

by
.~

.sisl

ichI h)'

""

Rt:!tart:h achyity lias been focused inlcnsi,ely on delerures of !be kanamycms. Chmm';lIo&ruphy the SlNCP td thai S. I..ilnulflyat;c ..s daborolcs three clo.lC'ly re;:.,;"""'. ures: lan:un)'cins A. B. and C. Commercially ; ~anamycin is all71O"il pure kanamycin A. the least of the three forms. 1lIe k.:inam)'cins difT('r on ly in the onoieties I,uchcd 10 the glycosidic o.\),g('n on lhe 4 of the cenlrnl deo~)'S1reptamHlC:. T1lC: ab-iolule conthe deo~ystrcptJlmine in kanam)'cins reported Tillioola C:I al.')6 is shown above . TIle chemical relalionamong the kanam),cins. the ~omydn~. IlrId FIle~ _YCIn) w('re rcponed hy Hichcns and RinehFFn .11 The u..amycins do not have Ihe o-ribose molecule Ihat i~ present ':_~"YCins and paronMJmycins. Pcrtlaps Fhis SlrucFurol difIS related to the lower toxici py observed with lana. The kanosamine linked glYCO'iidically 10 6 position of i is 3-nullno-J-dc:oxy-u..

, .... _ 101

or

""'"

f'_

m~.

{ein
~cin
,.~

mFg.

;.,;;;. k:7namY(:ln B rontains 2.6-diamino-2.6-dideo.\)-[)-

posnion the deo.ly!i\replamli,"~,;,;';"o lhe 4 conlalns of6-lumn0-6-deo.l)'-oA

;~'~','::oh~roc:,~~,",:ro~mYcins. The: by total

~yn-

D-glucoscs al -

...... ""
0

Pn:liminary

SIlJdu:.~

indicate thap amikacin may be: less

orO/oxic than either kanamycin or gentami cin. 111 Higher dosages of affilkacin are generulJ)' required. ho ..... ner. fOl"!he m:armcnt of I'I105t Gramnegllihe bacillary mftclioos. For thiS rnson. and to discoul"IIge the prolifenal1on of bac!.cnaJ strtlinS resistant to It. amili:acin cU""'"tly is rtcQl1\mcnded for the m:wncnl of scnoos Infeclions caused by bacterial SIr'll;ns resiSUlnltO other amilloglycO'Oidcs.

lar 111 many wuy~ to other arninocyditols such as ~trt' [J4OfTl) ' cinli. lhcy are ~umeicntly di ffen:nt Ihat their medical effh\e:nes5 i~ sigmficantly gn:ater. Gentamicm sulfate: Ii I .... hile 10 btlfr 'iUlN.aoce lhal is ..oIub1c: In waler and Insolublr in alcohol. acetone:. and bcn,-e:nc. Its ~Iut ioos an: stllble O'Cf wide pH runge and may be autoc laved. It is chcmicall) illCompatiblc with carbenicillin. WId the twO &hoold 001 be combined in the l>Ilme intrnle:rIOlIs solution. hllrodoxed in 1976. toinm) cin 5ulf3t.. (Neocin) is the lrIost lIC1i\ e of the chcmicall) n: lated anllnogl)'ell'ides called "t'hmmycins ob4:aincd fll)lll a ~ Iroin of Strl'lJWlIl.l'CU /"lll'bm'ms. Five members of !he IICbromydn COllll'lc~ ha>e been identificd chemical ly.I"

Sulfate, US,.. Gentamicin (Garumycin) was isolat .. d in 1958 and rt'por1cd in 1963 by Weinstein et a1. m to belong to ttlc ~t~ptomycil\Oid (aminocyclito1) group of :nnibiotics. It i ~ obmined cmnmercial1y from M icrOIllO nosporo p""mrt'll. U~e the OIhcr members of it~ group. it has a bro:Id spectf\Jm of III:t;"lIy agairu;t lrIany ('QfTlltloo pathogens. both Grnmpositive and Grnm.negall,e. Of par ticullll' interest is itS ~trong activity against P. IJt'ru~in()$lI and orher Gram-negative enteric b:lCilli.

Genl~midn

Tobramytin Sulf,tte, USP.

HO~!i~\'
H,C .... - .

NH~

O~\I
~

H~

C." \ . . - . o.::.fSI~
0,

_~

""'"
~

0
~.T

""

r
0

,.
T

Tobramyan

"'
~

,.

""

""

C,' R - R.- Ct! GentIII'I'IICIIl c,: R CH.. R H

Getltamicln C,.: R, - R _ H

'"

Gentamicin is effect"e: in the: tn:atment of it laric:ty of sk,n mfections for IOohich a lopical cream or Olnlment may be used. Bttau..e II offe:rs no n:al ad'"1lntage oler loplCal neomyein in the lre:urncnt of all but Jl5CudonlOnal mfections. however. it is n:cOllunendcd thai topical gentamicin he reo served for usc in such infoctions and in the t~atlllC"t of bums complicated by pscudomooemlD. An injectable 50111tion containing 4() mg of gentamicin sulfate per mtllilite:r may be: used for serious sy~lCm;e arid genltounnary ~t infections caused by Grnm.ncgatllC: bittu:ria. particularly l'$t'udommulJ. Enlt'robtlC/t'r. and SUrlJlill spp. Because of Ihede\.. loprnenl of Mr.linsoftheloC bacterial species rc~istant to pre,iously e:ffecth'e: broad-spectrum antibi()dc~. gentami em has been used for the treatment of hospitalacquired in fectlOns caused by stICh organism~. Resi~tant bacte:rial M(lllrlS that irlactivate gentlllllicin hy adenylylation and occ:tylatioo. however. appear to be emergmg with increasing frcquc:ocy. G:01amicin 5Ulfpte;s a mix tun: ofthc: salts of compounds idcn tlftc:d as gentamlClnS C,. C :. and Ca.. llIese genrmnlCIns we:re TCponed by Cooper e:t al. 11I to hal'e: the structures slKJwn in the: diagmm. The absolut e stereochemistries of the sugar CQnlJ.KlncnlS and the goomctric.~ of the glYCO<;ldic Iinkages ha,!! also been c:SIablished. ' '" Coproducc:d. but IKII a pan of the oofTuncI"Clal prodUCI. life gcntamicins A and B. 1lleir !itlUl.'ture:s .... en: n::ported by Machr and Schaffncr l " and are closely relnted 10 thosc: of the gcntamieiM C. Although gemmuicin 1lI01eculc~ arc si mi-

Facton " and 4' arc: 6".O<arbamoyl~an3mycin B MIl ~anamycin B. respccti,'c1y: faclors 5' and 6 are 6"o.e.- b:lll1oyhobrnmycin lind tooramycin; and foctol' 2 is a~ mycin. a tetrw.:yclic IlInlllogIY~'midc with an unusual tMc)\"bI: cenlrol ring structun:: . Kanamycin B lind tobrmn)cm prniIIbly do IlOI occur in fc:rmc:ntalioo broths pc:rsc bul ~ formtd by h)drolysis of the 6-0" -carbamoyl deriv-.lti les In the isoIJo. lion procedun::. The most imJ.Kln:mt propeny of tobrrunycin IS its actint) lJlPinst m<J!it stmin~ of 1'. ut'ru.~mosa. e:~ccc:dmg that ofp lamici n by 1100'0- to fourfold. Some: ge:ntllmlCmfP5I<IM stnuns or Ihis troublesome organi~m are scn<;ll;' t 10 wtnmye in, but orhers are resislant 10 both antiblOtics. I' l 0tIttt Grdm-nellat;'e: bxilli and staphylococci one generally_ scrl~ili"e to gentllmicin. Tobrnmycin 1Il0reclosc:ly ~ kanamycin B m ~truclurc: (it i ~ J' -dcoxykllnamyctn B). NChlm.cin sulfale. INoC'tII)l sisormci n (Nelromycm). is a se1l1isyn!hetic dcnlamc lit'" pared by rL'duclive e:tllyl3lioo l \ll of sisomicin. an WlIlroglycoside antibiotic obtaillCd from Micrommlrupotl in)Ylt',uis. ,v. Slructurally. ~isomicin and netilmicin ~ gentamicin Cia. II componenl of the gt':nt:unicin oompln

Netilmidn Sulf~te, USP.

~.

.d[;':
. '

HN

NH

o~\

\'

':::\"NHA o ,

5115 "I",,, R H
Nehlmbn; R CI's

my Tee

"poSt most w<uns of Enterobac1cnaccac:. P. unvgi

_. andS. DUUIU, Sl!KlITUCm and nculmicm are oomparoble ~&tntamicin in pott'llCy.'OG Nerilmicin is acth'c, hQ .... e.cr, aplR! many gentamicin-resistunt str.rins. in partIcular .-oog E. coli. E"'~rolx/Crl!f. Klcbsitdla. and Cirrobac:rcr IJIP. A few strains of gentamicin-resistant P. (l~11I8inW(l. S. ...,tJUtlJ. and indole-posilive Proteus spp. are also sensi 1M 10 nerilmicin. Vuy few gemamicinresistanl bacterial C1III'l are !lell5l1h'e 10 sisomictn, hQ ...e_er. The: potency of .:!Ilrnicin agalnSt cenain gentamicin-resiStant battC"riu is atInbIntd 10 lIS ruistance 10 IJWlCtI\'ation by bacterial enlymcs . . -.lmylylate or phClSphOrylate gentanUcin and sisomicln . El-ldtntly. tbe introduction of D 1~lhyl group in sisomicin runcdly decreases the affinity of ~se cn1ymes for the -.!ule in a manner Si milar to that obse ....ed in tile l-N-{'IIIIUICH,hydroxybutyryl amide of kanamycin A (ann kacin). \etllmkin. however. i~ inactivated by most of the OOI:lerial tlt)rDC:I!hat acelylate amirlOJl)'oosides ..... hereas amikacin II JtSI>UnI to most of lhese enzymes.. The: phannaookineuc and toxicological propc:nie~ofnetil II and gentamicin appc:ar to be similar clinically. though lIUtI.lI Mudies ha\ e indicllIcd greater nephroto~icity for gen1IDCin.

'" ublc

we r ally

're
ally

bm~

rom

~,

...

Spc:ctmomYC:1n IS a broad-spc:c:trum anllb,ouc ... ilh moderate acuvlly agamst many Grum-IJO<;IIi\'e and Gr.un-nc:gali\-e bacteria. 11 differs fll)lll streptom)cin and the ~rept.llmine containing arnlnoglycosides in chcnucal and anllbacterial propenies. Like streptomycin, spc:cllllOmycin mterfen-s wllh the binding of IRNA 10 the ribosomes and Ihus With tile initiation of protem synthe.,,~. Unhke ~tn-ptomycin or the strcptamine-con!ammg anliblOlICS. ho ...ever. It doe!! not cause mlsreadmg of tnc mc:Mc:nger, Spc:ctlnom)cin exertS a baru-riQ5talIC action and is inferior 10 (l(hcr aminoglyooside~ for n10SI 5)'Src:mIC Infections. Cum:ntly. it IS recommended as an aJlerTlllllve \0 penicillin G s:a11S for the trc:atml'nl of IIncomplicated gonorrhea. A cure rate of n~ than 9()<l, has been obse ..... c(l in clinical ~lUd ies for this Indication. Many phySicians prefer 10 use a tctrncyc hne or erythromYCin for prevention or lrealment of suspected gonOlTht:a 111 penicill in!lens;ti ..c pallCntS because. unlike the'IC agents, spec1inomyein i~ lneffecu ..e against syphlhs. Funhcrmore. it IS considc:nr.bly more: c:xpensi\c than Crythrom)CIII and mosf of!hc:
tel1'aC)'C'h~.

TETRACYCLINES
SiJDmlcin Sulfate, US,.. Although il has been appro~'ed .. buman use in the United Siaies. sisomicin has not been meled In this country. lIS antibacterial potency and effecetIe!I, against aminogl)'C()!;ide-inacti..aling c:m:ymcs re~"'tbose of genwnicin. SisomJCm also exhlbtlS phannaIIetics and pharmacological ptopenic:s similar to lhose rI Jt:IIblllicin.

Chemistry
Among the ll'lOSt IlIIportant broadspectrum antibtotiC'$ ~ membef"i of the tctI'3C)cline f:UTUly. Nine sucb COIIIpou nds-rc:tracyc line. rolltetrltCyc11 ne, ox )1euocyc1 i1Ie:. chlortetracychne, demeclocyclinc:, meelocychne:. methac:ycl ine. doxycycline. and minocychne-ha\e been introdl.lttd into mcdicaluliC. Se~erul others posse ..; antibiotiC' acl i~ity . 1be tctl"oICyc line~ are ob1ained by fenncntlitlOn procedure.~ from Slrl'pwm)'u$ spp. or by chemical trJJ1sfoflll3tion) of tbe natum! prudtJCl~. Their chcmicJI idcnlitico; ha\e been cstabl ished by degradauon studie, IIntl coofirmed by the ~yn lhe.sis of three: nxmbers of the: oxy tetracycline:. I~' '''' tHlemctbyl-6-deoxyterr.ICychne. I~ and anb) dl ""hlortetracycline. .... In their (0) fOlTi'l~. importam nxmbers or the: ' group are dcrivllllvCS of an OC1ahydr\)!\.;l.phthacenc. a hytlrocarbon syStem Ihm comprises fool' annulated six-membered rings. 111e group nnme is derived from this tetracyclic 'y5' tern. The amibiotic ~pectru and chemic al properties or these compounds are very simil ar btn not KlcntiC'al. The siereocn.:mi s\ty of ~ tetrltCycllllC'l i~ \ ery complex_ Carbon IItOlll~ 4. -la, 5. 5a. 6. and 12. art' potentially chi",!. depeudmg on subsmution. Oxytetracycline and dox }C)'chne. each willi a 5o-bydroxyl substituent. ha\'C six asynunc:1ric cemef1l: tbe othcl"l. lacking chnallty at C-5. ha\e only fi.e. Dclernllnalion of lhe complete. aMolutc Mereochcmistty of the IClI'lIC)clincs WII' a difficult problem Detatled x-ray dlfrr:ll'linn llIIalysis'~7 1"'1 CSlabll ~hed the ~t crooc:hc ll1ical formula bOO .... n in Tuble 1()'6 us the oncntah()llS found in lhe mllUI'II] and 'lenllsymhetic terracycline'. Theoc Sludie~ alO\() confinnc:d that conjugated sy"'clIIs niSI in the btructUJ'C from ColO Ihroullh C-12 and from C-I through C-) and tnat the fonnula ICp.,('lentS only one: of 'ie'end canonical forms elist ing in llio<;e portions of the: molecule:,

,,~

~,~

'cli<:

""~

mal

"'"~

.oh,-

....

vit) gl'n-

;tam

""',
b le, The -nocyditol IlIItibiOl:ic spectinomycin hydrochloride IT_in). isolated from SrrtprQmyus $plIIbilis lind ooce .ailed lCIil'lOSptocin . ...as f,1'S! described b) Lewis and Clapp '" lis SU\Jcture and absolute stereochemistry h:l\'e Ilea confirmed by x-ray el)'~I1OVo1phy.'l It accUn! as the tile, c!)~tamne dih)'d:lochloride pentahydr.llc.... hlch is in the dry form and .ery soluble in .... ater. Solutions lpeCtinomycin, a hemiacerll1. slowly hydroly-t.c on standand shoo ld be prepared r re,o;hly and used within 24 hours. ~"adnurnstercd by deep intrJlIluscular inj~tioo .

......

grour-

n.e

Sptinomycin Hydrochloride. Sterile. US,..

hyJ-

""'~
,,~

,,""

~m

".

""

Structure of Tetracyclines
The u:trncyclillC$ an: amphoteric compounds. forming sal ....
.... ith either lII.'i(1.< or bao;es. In lICutr.u i'OlUlions. these bUb-

pK&J. ..... ere oppos,te those of I..ttson et aL ''''' Th,s bna a.-.signmenl has been wbslanUlIted by Rigler et al I~:

"
Tfl....,,..,h ...
~y.b ...

ell,

"

C>
H

0..,...._)'<10 ... 1>emr.I)d;...

M.'hac)d,,~

Clh 01,

"" "

"

.
" "
H

The appnmmate pI(" \ alu.es for each of these gfllllp5 ill

the six

letOM.')'f ll ll(' '>lI11li

in comnlOO use are <.ho\I.n

(T.bIt

10-1). TIle values an: ta~en from Ste~ns et al ..''' 8e1ItI and GOYlln,") and Bamnger e\ a\.' Thc pK. uf tilt 1

OM

0"

C>

[>O.),,)chnc

M"".,)<"....

N(C'H,l,

" "

eH ,

"

" "
The

"" '" .

""
OH

0"

"

~lalll.'eS e.'(lst nlaHlly ..... 1;wmeriOllS.

acid -.:I lh, ... hich

dimcthylam ono group of mll"locyC\inc (not h)ted) ,'I ~.O. All imcreMmg PfI1"PCrty of lhe tctrul:yC\inc. is the,r IIbIlIQ 1 urxlcrgo epnnent;lIIOll 3\ C-4 in solu tions of 'OIcrl1'ltlhalr 0 pH range. TIlesc isomers are called f"pllt'lmrw:/mts. Undc:! addic t"Ondil ion~. an equilibrium is eS lublisll(. d in abooll day :md cuu )i\ts of approximmdy equal amou nt s of lilt I"t> menl oThe partial .\lruCIU n:.~ below indicate lhe two forms d the epimeric p.ur. The 4-c:pitetr~yc1 incs lta vc been 10;01_ alld ctmmctenzed. They exhibit much less lleti vi ly 11L.1n .. . ' Ilalural " Isomers. thus acoou min8 for the dc\.Tt'aloCd 111mJlCutic value of IIged ~u tions .

an' fQrmed lhrough prolOnal.Jon o f .be rnol group on C-2. t~ i... as Cl')'Matliroe ~'()II1potJtwls Ihat an' 'ery soluble m WaleI'. l1lcsc 3mpholerk annbiOiks ",II cryslallllC~ 0111 of aqueous so]ution!i of their SOltiS. howevc:r. unJes~ ~tahih l.cd by ~n uten of ac id. The: hydrochloride \:lIb n~ u~ ml)SI COIll-

monl y for oral adminiSl mtioo and usunily arc cnc:lp!oulatl-d bccauo;e the)' ;,re biner. Wmcr-soluble ~l1s may be IlbiailM!d al so from bases. 'lieh as sodium or potas~iu m hydroxides.
bullhcy an: IIQI Mah le in
!klh~ aquoou~ .'.olulion ~.

Waler in soluble

an: funned wilh di,-ulem aJ>lI pol yv aJcm 11W:'als. The unuMlal ~lruclul1ll groupings in lhe tctrncyclillCS pro011' three ocldn), COIl'>lants in aqueou~ 'IOlutions of the add ~ II" (Table 10-7). The paniculill' funcuOflnl l! l"OUp< responsibk for each of the themlOd) IIIl1nic pK. ,'alut, \Io ere determilled by Leeson et alYo as sho\lon in the dlllgmm belo\lo. The'C ~pmgli had been identified pre .. iou~ly by Slephens el al. I' a.~ the sIte;; for prot0nauOtl, bul their earher assignmem). \Ioh ich produced Ihc: ..alues re~pomi bk for PI<..: and

..
Strong acids ulld Strong base$ att:lt'~ tctr~)'Ch ncs \1011111 h)'dru_yl group on C-6. cau)ing a 10<;5 In lICtil'it) thl( zI modirItlItion of lilt' C n ng. Strong ac:id~ prodl)t"C dcll)"drII through a reaction in"oh'ing the 6-h)"droxyl group and ~a-b)dmgcn . Tl~ double bond thu~ formed bel""n PI'I tiolls ~a ~nd 6 InduceS D shift in the POSJllon of tilt do. . bond hct\lo'ccn C-IllI lind C-12 to a positioll hct"'eenCII and C I la. formin g lhe: more cncrgelic~lIy favored~,.,.. "ysteon of the Ilaphlha!enc group found In the inoctil'c anbj. drolelmCyc1ineN. Bu-.cs promole a react ion bct"' ccn Ille 6hydroxyl gn)llp and the kL!IOlIC group at the II posltiol. causin g the bood bet\lo'ccn tllC II a\ld lID Ul0m~ tO Clelle. form ing lhe laclone ri ng found ,n lhe ;Ilacti"e i$Ol.(trlICythllt TIlc'iC 1\\ 0 \lllfa\"()l'Ub!c reacuons ~Iimulated research Ihat ILII to the dtlelopmcm of the lnon' stable and longer...... CQmpounds 6-dcoxytc:1l11C)"clinc:. ITIClhac)chnc. do'Y<1 cline. and IIImoc)cli ne. Stable cbelate romple.\ e!I are fonncd by Ihc: tclfllC)dllD with many mctal ~ includJOg calci um. magneMum. and_ Such chelalell arc usually vt'l')' insoluble 1Il1ll'".i1er. IIIXOIIIU for the impall\.'d ubsorplion of nJO!>I (if nOl all)tetrlllC, dl.,

TABLE 10-7 pka Valu~5lof Hydrochlorides) in Aqueous SOlution at 25 C

pK.,

T"""'J<h.. C1I\oo.." ... ycl_

~iIJQ,li ...

.0

).3

O')_yfb..

7J 7J
U

o"'l"'ld,,...
Mu"X) d'....

P'. " " " U "

U

pO<

'" 'J
9 ..1

"

"

"

Chapter 10 ItnriiIMrma/ Allribimia

343

.Ihc p'cscocc of mill.; cakium-, magneslum-, and alu milIIIlI.(omainlllll anhlcids~ and iron salt~, Solubl e alkahnI7)!rs, .... 115 .sodIUm bocarborulle, al'<) decrease the gaslroinlcslilllli:MtpIion orthe ICIr.lC)'cli~~, ,,~ DeprotOllaliQn of ICWt)"I:llMli 10 more ionic ~peciC$ and IIIe ob!.crvw IIlslabilily .lIo!>se prodUCl5 IIlll.lkahnc solulil)lls may acooum for Ihis IDIwl'l'atlOfi. l1Ie affinlly of Ie"lncydi~ for caklum callSClli *-em 10 be iocorpor:llw mlO IlCwly formIng bones and leelli .. lClrlICyclinc-calcium Ol1hophosphale complexes. Dc[)OSIb oIlhese antibioti.cs in leeth cau<;e a yeIlOl" discoloration . . dartens (a phoIochemocalll'action) O\cr lIme. Tetrocy~ 31l' dislribUlw lOW the nulk of lacmlin!! nMltl!cl""\' and .~I cross the placemal barrier inlO the felus. "The possible efJu of these agents on the bones and lteth of the ehJld WAlId be coo~KIered before the,r use dunng pn-gIlancy or doiklr"fn unoer 8 year!; of age.

..m..hm of Anion _!lid Resln...tote

The )lrong binding ,ropcnies of the IClrucycllllcs wilh IIIclal
ca"scd Alben I to suggcsi ,hal their antibacteriQI prop. tlIin may be due 10 an ability 10 TerllO\e essenllal metal IIIIi as chelalcd compounds. Elu.cidmion of (icllli is of lhe ..:hanism of IiCtlOn of the letmcyclioe~, '" howevcr. has *lined more clearly lhe specIfic roles of mDillC!iium Ions in . .caJar ~scs affected by the<ie anlibiOlics in bacleria. Teuacyclines IIrc specific inhibi,QI"'i of !melerial protcin synIksil. They bind 10 lilt 30S ribosomal subunit and, thereby, ;;;;",he bindmg of aminoac)"ltRNA to the mRNA - ribo_ romplex. Both the binding of mninooc)"l tRNA and 1M bonding of tetracychnes at the ribo<oom:1l binding ~ite lIIfIlIl: nlOl8llOlum ioo~. I,. T elrncyclillC's also bind 10 mamribosomes bu, with Io....er amnill~. and they appartaII~ do not achic,c sumeicnt iutr.lcellular COllccnlrutions .. iIlleriere .... nh pI"OO!'" synlnesls. The select;,c toxicity of

the tetracyclines towan! batten!! depends blrOllgly on the M:lf-dc~troctive cupacity of bactc nal cclb 10 ooncetItl1lt~ these IIIcl1ls in II!c cel l. T etracyclines emer bacterial cells b) ' ....0 processes: passive dIffusion and acll''!: tnmsport. The acti\t uptake of telraC")'chnes by b;K1cnal ctll~ is an tnergydepe.rKltm process Ihal ~uires adenosine triphosphute (ATP) and JIUIgnesmm 1005. 'I\l Three biochemicall) d,Sllnct mechanisms of I"CSISiOlJl(.'C to tctmcyclillC's ha~e ~n dC'o;cribed ill bacteria:'''' (0) cffiux mtdintoo by tr'lIl~mcmbrnne-sp;mning. ucti~e-trJnsport prottins tnal reduces the intrw.."el1ullll" tetrat)dine coocentration: (b) ribosomal proccctJon. in which Ille OOclenaJ prOIein symhcsls apparatus is f\:oJered re,i slam to lhe action of lelmcyclines by an inducible cytopla<;mlC procc,": and Ie} ell"l,ym.:llie olidalion. Effiux nJedul1w by plasnud or ehmmosomal proIein detcrminant ~ rn-A, -E, -G, -K and -L and ribosomal proccction llietliatro by the chromosomal proIe-;n UetcmlinanlS It l-M. ..0. and -5 are the flI()l;t frequclll ly cflOOUntered and most clinically sigmficant resIstance mechani~m~ for IClrncyclint~.

-u.

Sp Icb .. .,. of Adiwlty

M\c tl!c ~st sptttnlll1 of acti~ il y of any kno .... n antibacterial agcnts. 1llcy are actnc agaInst I wide rnnse of Gram-po!;lIj\t and Grum-nc:gauve baclcria. spi rochclcs. mycoplasma. rickclisiat!. and chlumydi:oe. 'Tht>ir poi~nl ial indications are, therefore . !Il,unerous. 1llcir bacleriOSlatlC action. JKno,e'er, IS a disad\llIJIage in lilt treatment of life-threatening infection" such as scptic(nlla. endocarditis, and rnenillgi,k lhe amiooi:lycosides and/or cephal()/<,jlOrins usually an:: pfdcrttd forGram-ncgat i\e ~nd the pcnicll10m for Gram-posit!>t Infections. Ikcausc of incomplete: ab~orptjon and their effectivcness ': lgO I1l)1 the natural b'lClcrial floru of Ihe intestin.c, lell1M:yclines may induce superin-

Thor:

IClracyclillC~

_WI

HO

/~

, ,

'"

,
,

, ,

,.

'"

'of

I
'of
ttoleiracychne

5,8-A.I'.l1y<1rotetr acydl ne

ftenons caused by tnc pathogenic ytast Candida olbicwrs. Resistance to tttrllC)'clmcs among boIh Grnm.positi~e and Gram-Iltgati~e bacteria is relathely comlllon. SUpc'rinfeclions caused by resistant S. (""t'u.. and P. (It'l'Ugillo.ra ha~e resulted from lhe use of these agcm~ over time. l'aremer.tI tetracychnes nlll) cause severe liver damage. especially .... hen gi~en ;n ucessi\e dosage to prt'gnan! .... omen or to patients .... ith Im~ired renal func1;on.

Structure-Actlvitr RelAtIonships
The IlIrge amount of resc:arch carried ootto prepure SCn\lsynthct;c modifications of Ihe letnlCyclim:.s and to obtain indio vidual oompounds by 100ai synthesis revealed several intere<;ting SAR~. Revie .... s are available that di!iCUSS SA Rs among lhe telracyclin.cs in delllii. Ibl~Lfll their molecular and clinicllll)TOllCTties..l'" and their synthesi5 and chemical pr0perties.lo.!. 16) I&.'_ 1<11\ Only a brief review of the !>alient SInK:ture-acti\'ity features is presented here. All dl.'rwati\cs 1.'<)11taining fe"~ than four nngs an: inactive or nearly inocti\e. The simplest tetracycline derivati~e thaI Tl:talDS lhe characteristic broadspectrum octivity associaled .... ith this antibiOIic cllISS i( 6-dcmcthyl6-d<.'Oxytctmcycline. Muny of the precise stfUCUlrDl fealures present III Ihl s molecule must re main unmodified fordcrhath'es to retain activity. The integrity of substit1lC'nts at c-arbon atoms I. 2. 3. 4. 10. 1 I, II a. and 12. representing the hydrophilic' 'foOlLtncm and ellStem" fllCtS of the molecule. cannot be \'iolata! dnstically without delcterious effects on lhe antimicrobial ptoptnoes of the resuiling derivatl\cs. A-ring subslitucnts can be modified only ~hghtly .... "hoot dmmatic loss ofantlbactenal potcncy. The enoli ud tricllrbonylmcthane ~ystem at C I to C-) must be in(llCt for good lII:tivily. Replocemem of the amide D C-2 with OIher funcI tions (c.g . aldehyde or nitrile) redUCt!. or abolhhes activity. Monoalkyilltion of the amide nitrogen reduces actIvity pr0portionately to the size of the alkyl group. Aminoalkylation of lhe amide nitrogen. accomplished by the Mannlch reaction, yields dctivatl \'e.~ that arc sU~lIlmally more .... ater ISOIuble than the parent lelro.cycline and ~ hydrolyted to it in vivo (e.g .. rolitetr..cyctine). The dimcthylamino I:roop at Ihc 4 position mU'it h~ve the a orienlat ion: 4-c!pi lctracyclines are very much Ie.~s active than the natuml isomers. Removal o f the -kJimethy lounillO groop reduces acti vity e\'en funher. Acti,; ty is largely retained in the primary and N-rl1tthyl secondary amines but rapidly diminishes in tnc higher LlIkylamines. A df-AlB-nng fusion wiUt a ,8-hydro~yl group at C12a is IIWDft"ntly abo ~sscntial . Esters of the C12a hydroxyl groop are inactive, .... ith the exception of the formyl ester. .... hich relldily hydrtJlyl.C~ in aqueous solutions. Alkylation at C-Iln also leads to inoctiv!: rompou nd., . dcmonstrnl1ng the importance of an ellOlil.llble ,B-ditctonc: fuoclionaii ty at C_ I I and C12. The importll/lCt of the slutpe of !he ttlracyclic ring system is illustrated further by S1Jbstantial loss in antibaclcrilll potency resulting from eplrl1tril.ation at C 5a. DchydrogenatMJn to form I double bond btl,,ten C-Sa and Colla markedly deereases act;';ty. iIli does aromatization of ring C to form anhydl"Qletr&Cyclines. In contl":lst, substilucn ts at positions 5. Sa, 6, 1. 8, and 9. represcming the largely hydrophobic '"nonhem and western" facc~ of lhe molecule, can be modified with varyi ng degrees of sue~, rcsu hing in retention and. iIOmetime,~.

Impro\'emcnt of antibiOlic acu~ Ity. A Shydroxyl group. a III O~)tetnlCyclllle and do~ycychoc, may influellCt' p/1annacokinetic propc:nics but does not change antimtcrobialllCliy ity. Sa-Epitctrncyclincs (prepared by tOlal ~ynthesis), although highly aclive in vitro, are unfonunDlo!ly much IeII. imprtS~Lve in vi \'0. Acidstable 6-deo~ytetracyclilltS and 6demeth)-I-6-dcoxytelracydines ha\"C1 been used to pttjlilt I variely of IIlOIlI>- and disubstilUted dcrivad\"t!S by eltfo. ""lie subsmulion reocl;QIU at C-1 and C9 o f the 0 nll& I 1llt ITIOit useful rewhs have been achie\~ with the 1lIII0duction of substitucnts at C 7. Oddl). strongly electro'H,'" drawIng groups (e.g .. ehlCH'O lonclrncychne! and nllro) Mld ~trongly electron-donating j;fOlIps (t.g .. dimethylum.oo [nnocyclinel) enhance activity. This unu\ uaJ eircu m~taOl;t 1\ reflected 111 QSAR studies of 7- atld 9-substilUted tetnc)' c1incs.l~ I~l "hieh indicated a SQuared (parubolic) depndenccon u. Hammet'\ elcctronic substi l1lC'nt oonstanL and. vitro inhibllion ofan coli stram. The effect of introducllc substltucnlS at C-S has rIOt been Mudicd brcau;;c this poatlIOI canllOl be ~ubMilU(ed directly by elasslC eicctroplll lic_ matic substitution reacliClrul; thus. g-subslituted dt:l1\atI\eI are available only through tOlal sY IllhC'sis. l611 The most fruitful site for semisynthetic modificatlOll Ii the ICtnICyclioc5 has been the 6 position. Neither the: 6amethyl nor the 6,8-h)drox>1 groop i, e\sentiaJ for antilJic.. rial activ;ty. In fact.. dOl yeycl ine and mdhacycline are IJ'(ft acti\'e in vitro tban the ir p.m'nl oXYletrac)"cline agatnSl_ bacterial strains. "The conversion of oxytetracycline 10 001' cyeline. wbich can be accomplbhtd by reduction of mo:tt:. cycline. '69 IlI\CS a 1:1 nlUltllre of doxycyciinc and eptdol1' cyelinc: ("b ieh has a P.oncmed methyl group): if the: C1l1 a-fluoru dcrivathe of nltt hllC~ 1 1I1t LS uscd. the ,B-mrth)1 cpimcr i~ formed exclusively. I 6-Epido~ycyclinc is mud! less acti\c than doxycydinc. 6 j)erlltthyl-6---dcoxylClIX) cline:. synthesized rommcrcially by cltalylic h)drogenol). of the 1-chloro and 6-hydro~)'1 groups of 1-chloro-6-dt '0 yl letracyclinc, obtai~ by feflllCntation of a mutant MIWI of SIrt'plom),CCS aUrtto/a",fIS, 111 I~ slightly more potc!II tbII tctracycllne. Man: succe'iSful from a clinical SIlI",1pM. however. is 6..(iclnclh)I-6-(\cmy-1-dimcthylamillOlelr.llo:l cline (minocycline)1l":l bcc9Use of hs activity against tttnq cline-resistant bacterial qntins. 6-1)co~ytetrocyclincs alilO po!lses, important chemicalllld pharmacolOnetk advantages over their 6-oxy counteTplf1l. Unlike the lauer. they are iocapabJe or forming anhydt,*ur eyc hnes under acidic coodllloru because they can/lCll! ddtt dnue al C-Sa and C-6. 1llty an: IlISQ more stllblc in . . bccau.-e they do not readily undergo ,8-kelOJle clea\"3ge, .... 10"'ed by llICtonizatioo. 10 form iSOletTllC)'cl inc:s. Al il lacts a 6-hydroxyl group. nltthacyclinc shares the in~ ity of the 6-ox Y letracyclinc5 in stTOflgly occtic condl tion:d sllffers prototropic rearrnngement 10 the anhydroteltllC)clik in acid but is stllble to P.kelone eJe~vage followed by IanoIi~allon to the iSQIeuacyeline in base. Reduction of the .. hydroxyl groop also drDlTI:Ulcally changes the soIlIIlIij ptoptrlu:s of tetracyclines. This effect is reflected In si cantly higher Oll/water partition oorfficienlS of the ~ tetracyclines than of the tetracyclines (Table I()..S)"l The greater lipid iIOlubility of the 6-dcoxy com~nds" important phan1l300kincllc consc:queocts. LI>1. '" 1kM, doxycycline and rninocyclinc: nre a~bed more COI\II*td! follo .... ing oml administnttion. exhibit higher rr.octlM!"
r

Chap(~r

HI AnlllNlC'lrntli Anllbim,a

345

TABLE 10-8

PharmlKoklnetic Proptlrties of Tetracyclines

',C

, , -.

"- N

......... CH.

"
OH
Subotll-.b

I
" II
0
OH

'"

""

1 'y N', , (
0 0
1101...... of
_1vh1)
1~1iU6
,~~

II

,,...P'

"

"

,--

, I ....~

-,,

"

,. ,. ,. .... 5 .' "' , " ..... "... , '" '" " 0 , , , '" ,. " " ." boo" ...... , '" " ",,01.10 " " " () .\........... r"""
, ......yd...
~

..

'... ~w.,
,~
,~,

~,

~,

00
~,

-I

~,

Il<00>0. J R ..., ~ Iond. S, Adv ""'" , ' 01. ClIo ..... ",1 6 1. '\ _ _ ..... QoIu.... J 1...-.1 K- . ~ a.; I ___ s.: ~lII l lo1. 1W>9

,., --" -- -.. "',., "" . "", " " ... "" > "" ..." ,. " . '" " . " "" n" ,. " . " '" "
!\ht, b.d Or ..I,
h",,_
b~

O ItVlb :11or>

~-

,-,

e m""""'"

'.7) "" I
~

...

n~

~"

'" I(l~

~n
~

_n
~"

'!-'101

IM ~

1.10

II

,s-,~

1 ~71 ,

, , , ,

,
,

plow protem bmdmg. and II:wc higher ,'oIUme5 of di stribuIIlII and 10\\"('1" renal dC31110CC r'J I l'~ than lhe COITC~pondin!; "" ytttrao:yc liM's. Pobr subsll lucnts (i.e .. h)drox)'1 gll)(lil"i) 31 C -5 and C-6 <Xt~a>c lipid versus .....ater solubility of the tctTllCycline!i. Tbt 6 positiOn is. hmIe,cr. cOllsiderably lOOn: sensit!>c titan LIIr ~ po>lti on to thi s effecl. Thus. dox)t)'cline (6-dcQ"y-S.}1Ctrxycilllcj ha~ a much higher partition coeffidenl than tetrat"ydine or oxytell1lC)"clinc. Nonpolar SUbsliluems with posith'e IF \'alue\: see Chapter 2). for example. 1-4i1neth)l;unino. 7--chloro. and 6-melhyl. ha\e tbe OPPOSIIC dfca. Accordingl). the part ilion oocfficienl of chlor1ctTllCy. . is ~ubstllllli3i1y ,reater than Ihal of letrncyclmc and ply creal.:r than that of dcmecloc)ellne. IntcR$tingly . .mocycline (S-demclhyl6deox y-7-dimelhylmninOtell1lCya. ) has tbe highc:sl parmion cocfrlCicnl of tbe commonly

1 _

renal clearllllCC and longer dUTllli{)ru; of action of doxycycline lind minocycli ne compared ..... Jlh Il105e of the OtiK'r ICtracyclines. especially letl'1lC)"chroc and oxytctnlCytJine. MlllOCy cline al'<O expericnces slC;nlficum Ndcalkylauon tatalY7.ed by ty)ChroIne P-450 oxygenascs m the Ii-c.-..... hlCh ronuibutes to its comparath'ely low renal clearance. Although .11 ICtracycline, ure d islributed widely into lisstIC5, the more polDr ones rowc larger volumes of dis\t1bution th:lIllhe non polar compounds. The mol"C lipldwluble Ictrm:yclines. howe,er. di~mbutc bell~r 10 poorly vascularized tisstIC. It is al50 claimed mal the dmnbulion of doxycycline aoo mioocydUle mto bone i~ less than that of other tell1lCycline~.1 1'

P.oducts
Tetracycline, USP. ChemICal studiC$ on chklnetracyealcd that OOI1trolled catalytic h)'drogeooJysi~ liC'leccline I"C,lively rcmovt'd Ihe 1-chloro atom and so produ~cd IClr.ICYcline (Achromycin. Cyclopar.....u1mycin, Tctracyn)_ Thll proces.~ ..... as patented by COIlO"er I7{o in 1955. u.ter. tctnlCydine was obIained rrom fermentations of SI"pllHIl)"c~S SJl'P bul lhe conuncrdal supply stili chlcny dcpt'oos on hydrogenolYbis 0{ ~h lonclra<:ytline.
,~

, ,

water-soluble COllI oxytclrllC)'clinc can be IIllributcd to In i their oompamtivc difficuhy in IIr k! membrancs. lhe tetracyclines JH1l'bat rI1Ctal ions in the gut acid--catalYlcd de'lrtlclioo in the stomach. With bdillf)' excretion of I 10 cause a higher incidence from rc~i~lanl microbial ~l l1Iln~ 111e rTlOI'e ,~,'. howe\er. are extretcd In higher ronccn In urine (e .g .. 60% for ICtnlCycline and 70% 1IrOJ:)IWllC)"Clinc) than the more lipid-soluble romroonds !q.. 3)% for doxycycline and only 11% for minocycline). fanl passi\'e renal tubular rcabso,puon coupled with '-fI1Ictlon~ of protein blndmg 00I11 nbute.~ to the lower
ItlOR\

..-' H

"""/""

346

WtLwo, 0IId Gi.nvliJ , /'f.nmd "f Org<ll,jr Mfdlmrr,/ u",II'rn''''wj('~uliCil/ Chemisl,)'

TetnICyclin.e is 4-dimcthylamino-l.4.4a.5.5a.6.11.12aocIlIhydro-3.6.IO.12.12apentllh}droxy-6-nw:thyl - I.1 l -<1ioxo2naphthaccn.ecarOOumide. It is a bright yeliow. cry~llI1tin.e sail that is stobIe In air but dar\.;cn~ on exposure to ~trl)flg sunl ight. Tctr:lCyclin.e is stahle in add o;olutions with II pH abo\e 2. It is some",hal IIlI.Ire ~Ulb1e in alhhn.e solutions Ihan chlonetnICyclln.e. but hke t ~ of the other tctrolCYcI,nc:5. such solutions mpidly lose potcncy. On.e grJITl of the base ~UIIl'~ 2..500 mL of wa.ter rmd 50 rnl of alcohol 10 dl~solvc it. The lIydrochlorick salt i~ used nlOS{ commonly in medici ne. though the fret: ba'>C I ~ ~hM)rbc:d from the ga~ ImInle:>linal tract about e.:jlllll1y wcll . One gr;un of the hydrochloridr: salt dis.'iolv~ in about 10 ml of water and In 100 OIL of alcohol. Tetracycline Iua.~ bcl'OlllC tile mO~l popular IImibiotw: of its group. largely because its pla.o;m.a concentration appearll 10 be higher and ~ enduring than that of eithoer oxytetracycline or chlonclrat:)clrnc. Also. It i~ found in higher ooocenlr'llU(ln In the spinal fluid than the other tlO.O ronlpound'. A nu mber of combinatiom of letl1lCyl'l ine wilh agel\t~ Ihat increase the rate and the height of plasma concentrntions arc on !he market. One soch adjuvant is magnesium chloride he. hydrnte (PD nmydn) . AIM). an insoluble tetracycline u poIlooIphate complex (Tetrel) is made by mixing II solution of telrncychn.e. u~ually as the hydrochJoridr: . ... im a solution of sodiu m nw:taphosphate. TItel'e all: D variel y of claim~ concerning the efficiICY of t~ adjuvanL~. TIle nK.'Clwni~m 5 of their acIioos arc not clear. but repot1edly tn. In t ~ agents enhan plasma cuncentruuons over those obtained when tctracyclin.e h~droch loride alone is admini$tered or-~l1y. Remmel'$ el al.I . 1.0 Il:poned OIl the effccts that ~Iected aluminum-talcium gIUCQllat..-, ~'Omple"ed IO.Ilh SOffit' I('trueyclIIlCli ha"e on plasma conccntruliOlls when admini,tcn:d (lOIJly. intr'llmuscularly. or intrllvCOOU5ly. Such complues en hanced plasma levels in dogs IO.hen mjected but not when liven orolly. 11w:y also observed enhanced pills ma levels in cxperimenml animals when complexes of tetracyclines lO.< ith aluminum metaphO$phate. aluminum p~rophosphme. Of alu minum--caJcium phosphioicodiJactates wcre administcred otally. As noted abo,'e. the lCtl'XyclillCli can fonn smble cheltlle complexes With metal ions s.uch ascaklum and mag nesium. which relard abr;orpt ion from the ga5lroimesli nal Ir'IICt. Tltc: comple.ll ty of the sySierns io,'oI\OO has not pc:rnlilled uneqUIvocal suMtamiauon of the idr:a tlwt these IKljuvanls l'OmJlCle with the tetrucyclines for ~ub5tllllCC5 in the alimentary tracl that lO.ould othc:rwise be: free to complex with these anubioue~ and !hereby Il:tard thctr absorplion . Certainly, there is no evidence thn t the metul ions per se act &5 buffen. an idea alluded 10 sometimes in the literature. TCU'llCyclin.e hydrochloridr: is also availnble in ointments for topical and ophthalmIC administration. A topical solu tion IS used for the management of acne vulgaris. Kolitetmcycline. N-(pyrrolidlnomethyl)lcllllCyclllle (Syntetri n) was introduced fOl" use by intr,lmuscular Of intr~ "enous ioje<'t ion. Thi~ derivative i~ made by coodcnsm& tctlllCyclln.e IO.lIh pyrrolidln.e and formaldehyde in the presence of It nbulyl alrollol. II is "cry $Oluble in water ( I & dissolvcs in ~bout I ntl) and provides a means of injecting the IIntibiotic in a !iI'IUlll m lume of

solution. [t has been rccummended for CiISCS IO.hen the 0t1I dosage fOl"m~ are nOt ~uitable. but it is nil longcr "",r.lel~ used.

o
ChlonctrltJ' clin.e (Aureolllydn hydrochloridr:) was isolated by DvJ gar ll l In 1948 from S. l"'nofD<'i~l1S. Thl~ compound .... hdt wa~ produced In an ex tensive search for IIoeW antlblotics. ....... the 1i ....1 of the group of highly succes)ful letr"oICyc1ine\. I! soon became estabhshed as a villuable I1I1tibiotic with lJIwd. spectrum llCIivi l ie.~.

'1

Chlorte tracycline Hydrochloride, U5P.

ChIoil8llacpJio" HydIO../t.... o6t

It i) used in nledic ine chiefly liS the lICk! suIt of the C'OftIo pound IO.hose ~ySlemalic chemical dc-s igna.tion IS 7<hkJrv. 4- {dimethylamino}- I.J.4 a.~.~a.6. l l. 1 211_ octah}dro-J.6.lo. 12.12apc:nuUt}droxy-6Ulclhyl- I.1 l-<1iox0-2- lUlpht~ carboxamidr:. TIw: h) drochloride suit is a cf)'stalhl1(' 1IO'/t.i5 wilh a bright )eJlow color. IO.hteh ~ugge.'ted II) brand IL&IIIt. Aureomycin. It is stable in air bUI slightly phot~n'Jlj\l and $hould he protected from light. It i~ otIorle and IHtk'! One gram of the hydrochloride lklIt will dissohe i n " 7~ nt l of wlllcr. producing a pi-I of about 3. [t i, only )"~ soluble in alcohol and pr.tctically lniO[uble in other ~ solvents. Ornl and parenterul form s of ch ionctr.teychlll: arc III longer used because of the poor b,oovailDbi lit y alid infmcr p/l:lmlacoli:llICtlC ptOpenies of 1Iw: drull. It is sli ll n!albIN in oilltlllcnt form) for topical lind ophthalmic usc:.

RolitetritCfdine, U5P.

Oxytetracycline Hy drochloride, USP. Early in 1 9~ Finlll)' et al. Ie reported the isolation of OX) lelnICydine (11' mm)'cm) from S. rimusus. This compound ...,...as soon xx. lied liS Hchemica l 31l1110guc of ch lortetracycl ine Ihat sItooo\'IJ similar Hntibiotic pmpeniefo. The structUIl: of oxyletl'aC)< WIIS elucidated by Hochstein et 11.1 .. I' ,) and thiS lO.'or[( pro",,~ the ba~i~ fOf thc confimla1ion of the structure of lhe: othtf tetr.te)chnes.

I I. 12a-octahydro-3. 6. 10. 12. 1 2a-pemahydro~ y I. I l-dio\ o2-naphlhaccneearboxamide. Thill>. It differs from cliionetnlcychne on ly ;olhe Qbsence of the nleth)"1 group on C-6.

...
(hytelracydlne Hydroe/'lloride

o o
,r
HA....NH.cH,

" .
"-

, "
~

"-

O.. )\CIllICycii ne hydrochloride IS II IXlIc yellow. bluer.

rompound. The amphoteric ba.c , ~ool)' sli,hlly soluble in waleI' and ~ hghll y soluble in alcohol. It is odortc.~~
IIId stable in all' but dar~ en~ un exposure to ~I rong sunlight . ~ hydrochloride '>l'I 1I is:l. stabk: yellow powder lhal is !nore bIntr than 1M r~ b:be. h is much more soluble in ,,",uer.

~ltioe

Dtw14doc,dina Hydroctoloride

II

dissol~Hlg

in 2 mL. and

n~

soluble

In

alcohol than

_ free buse. Boll! compouoo$ are inacli ,ph.'d rapidl y by albli hydru~idcs lind by lICid M:lJ mioos below pH 2. 8 01h ~ of oxylclfllCy, line are absorbed rnpidly and equally d from the d'gestl\c 1tOCt. 'iO the ()I1ly real oo\'anuge the ~ base offen over lhe hydrochlomk <;;III lS Ih:al it is le\~ hmr. Oxy tclr.ocyclinc hydrochloride is also used for pan:lIItr.II oomini~lr:llion ( inlr~ vc nou~J y und intr.ullus-;:ularly).

ItIPthacy(/ine Hydrochloride, USP. The sy nthesis o f Mhxydu"IC. 6-dro.\y-6-dcrnclhyl-6-mcth) Icne-5-0 \ )'10:1' lX)'C1inc h?,drochloridc ( Rllooo rnyci n). repo rt ed by Black t!Od ~ Ill. '" in 1961. WM ocoompU ..hetJ by choemical modi lilcaion of O~YI;:I rac)cJine. II bas an anlibionc 'peclrum like ilia! of lhe OIher leu'OC) cli nes but g[l;'alt'T' poIcncy: about 600 III( of mctlJaeycl lne is equ iva1cnl illIg of let l'llC) ctme. h~ ~Iar value lie~ in it~ longer .\.Crum holf life: 00sc_ (I f ' lXI ml produce conu nuous se rum anllbacto:riol OCl,V;ty for 11 boor-;. lis loxic mani fe"lation) and oonlJ'aiooicatlorni are tllibr to lhose of the: OIher tetr.iCyclines. The rrealer stabihl y of nlCthacydioc, boih m v,vo and In ram. n:~uhs from mooific311011 ill C-6. Removal of the 61I)~\)\y r roup mar\.cdly ill\.'tt;!,.<oC~ the stabil,ty of ring C 10 aci(b IU1d ba.'oC~, pre 'emi n!: the form:uion of iSOlClrocy' d.<. by ba>eJ;. Anhyd rotelrucyd ines still can form. how-

Dcllleelocyelinc I~ a ye llow, cryMallill<' po ...dcr Ihat is odorle'" and biuer It i~ spari ngly !IOluble In water. A 1'1 !IOlulion ha..~;'1 pH or about 4.8. It h:l'i an antib,ouc spectrum like Ihal of other tctl'llC)cline\. but il is \Jighlly more ocli,e Ihan lhe othe rs again" IIlOSI of the IIllcroo'llani,ms for whIch lhey are 11,,00. Th; ~. together wllh ;ts ~Io"" er rdte of eI iminalion through lhe "Idncy~, malcs dcnlCCloc)t"line 15 effeethe IL'l the other teu<ll:)cll~. 111 aboul three-fiftm of the dose. Lile the other letnlC)'clincs. il nmy cause Infrequenl photos<:n~H" "y rcal:liOfl~ that pmtlilce erythema "lier e \pct'>u[l;' In ~unlight. IJcmedocycline may proJllce lh" reaction !IOnle" nat moOrt': f[l;'quent ly than the OIher tetracycl ines. llle incidcl1(."(l of diSC()lordtion and monhng of liM: tc:eth In )oulhs from dcllleclocyclinc "ppear> 10 be us low as th at from other lelmcyc lines .
Medocyclin~ Sulfoulicyfat~, USP. MeeJocycl;nc .7c hloro-6-<lcox)' -6- de II It: Ih yl-6- II ~th )'lcne- !I-o~ ytetl1lC yc I f nc sillfO'oaJicy lul c (M ~'Clan). i_~ a ,<nll~ynlhct ic deriv ative pre-

pared from o\)lclrok'yclill<',I"" Al lhough medocyelinc ha~ been uSoeti In Europe for mallY yeaf'j;, II became h ailable on ly rclad\cI)' ,,---ccntly ,n tlK- Uniled Statt'S f~ II ~lngle ther.apeuue IIUIl C:oIlon. ttie treat me nt of acne. It i.. a"QoIable as the sulfosulicy late sail in 11 1% cream .

II> a ye llow dark .~~~;~d~<:':"~'~"~'Y~'~'~dJ;~'~f~~'~ri::I.::tti()n under ~trongl y10acidic

1

i~ slightly 'iOIuble in water wI,e!lL~ . II ~bould Ix stoced in

,-",\\

',,", I

A'

lighl-n:sismnl 00fI13ine .... in

pi,
H

a cool
-

~ oiI--.. . . Mi
~
H

.'"'. a

pl a~-e.

Mccloc)chne sulfQ):lh;:),lale t~ II bright) ellow. cryslaillne powder lhm is slight ly ~I uble In ... Iilcr alld Inwl ublc in OfgQII1c !IOlvc nts. It is li gh t '-Cnsi li \l~ noo ~OOuld be qon.'d 11\ li ghtrc,i~tunt containers. DoxycycliM, USP. A more recent addillon to 11K- leU'll cyclt ne gfOtJp of illIllblOlICS a'ailllhle for anubaclcrial IIK-rapy i~ "'o~)'cyclinc , ",6-dco~y !I,oK)tctnloCydille (Vibrllmyein). first rep0rH.'d by Stephens et al.'"' 'II 19!18. It ,,"liS obtained fir'>! in _mall yield, by Q chemICal tnln~formallon of oxytetrocycline. btU it i~ now prOlluced by calalyue hydrogenation of nlCthacyci iile or by r~'duction of " bcn/)'JtncrcupIan deri':I.I1\ c of nlel hacyd ioc with Raney Il ickel. T11c latter

et ' l. it is

~:::~:;~::~.:l "asiniw!aS. lmrl'(Jflld",u. loo III 1957 by fl . ~tm of

7-chloro"Hdi mel hy l amino)I.4.~a.5 .5a.6.

Dcmc:c loc)cline.7-chloro-6-de-

piClCC!>! rroduce~ a nearly pure form of lhe 6a-melh)'1 ep;-

mer. The 6a-melh) I ep;mer IS more: lhan 31Hnes as active as lIS ,tkpnuer. 16\1 Apparently. !he difference in ooentalion of lhe methyl groups. IIIhich ~hghlly affeels !he shapes of lhe: molecules. causes a substanlial differeoce in biological effCCl. Also. absence of the 6-hydm~)'l group produces I compound IMI Is vcry siable in acids and bases and that has a long biological half-life. In addi tion. it i~ absorbed very well front the ga~trointestinal tl3Ct. thus aliowi ng a smalier dose to be administered. High tis~ue levels lire obtained with it. and unlike Other tetr.lCyciine~. doxycycline apparently docSllQIllt'Cumu late in patienlS wi th impaired renal function. Therefore. it is preferred for urcmlC paLientS with infCClions outside the unnary tmet. lIS low rernll de1U'Jnce lIIay limit ilS effecli~'eness. lIo"'e'1:r. In urinary II':lC1 infections.

,
;

"""""M
Perhups the n'lO'tt outslBnding property of minocychnl' is its activity toward Grnm-po::l&itive bacteria. especially ~. loc;Qcci and Slrcplococci. ln foct. miroocydine has bccndf Ih'e against Slaphyloooc:eal s.tnull5 that are resistant 10 metbteillin anti all other letrncycliroes. including do~)'Cyclille.I" Although it is doubtful that minocyciine ""iII replace bIcIcn"idal ~nts for lhe treatmen1 of hfe-thrratening staph)>> coccal infections. it may become a useful alternati\'c for die trealmc:m of less sc:rious ti~-ue infections. Mmocyehne It. been n:conllllcndcd for the trealment of chronic bronchtld an!.l other upper respiratory tnII:t infections. Despite Its rda tively low renal clearonce, partially rompenSilled for by hip serum an!.ltiss ue Icvel~. it has be.!n recommended for !be !rculment of urinary tract infectious. It has been effCClII'C ill the cra<iicUlion of N, mtnillgitidis in asympion1ll1ie c:urim.

l ,
(

~ l
t

Dol{)'cyeli.... a hydrochloride Doxycycline is avai lablc as a hydrllle salt soh'aled as tile herructhanotate henllhydrnte. and a monohydratc. Tbe hydrate fann is sparingly soluble in wain- and is used In a capsule; !he monohydrate is wllter insoluble and is u)C(i for aqueou~ suspensions. IIIhich are sUible for up to 2 ....l<li IlllIen kept in a 0001 place. Mi nocycJine Hydrochloride, USP. Minocycl ine. 7-dimc:th y lalll i l'IO-6-de mc:1h y1-6-droxytetrnc)' cline ( M inoci n. V.:ctrin). the mO~1 potent lelr:tcycline cumnt ly used in tllernpy. is obtlLined by reductive lnethylution of 7-nitro6-demcthyl.6-dco'ytctmcycl illll. m It wa.~ releasc:!.l for u<;c in the Untied SUlleN III 1971. Because minocyclinc. like do~ycy cline. locks the 6-hy!.lroxyl group. it is stablc in adds and doe~ 1101 dehydrutc or reammge to anhydro or loctooe forms. Mlnocychr1oC i~ ....dl absorbed Of"Jlly to gwe hIgh plasma and US!oUC Ic,ds. It has a ,'ery loog serum luM-life. resulting from slow unnary ex~oo and moderate protcin binding. 1)o~)'()'cIUlc lind miroocyclillll. aloog with o~)tel rncyelinc, ~howthe least in ,'ltmca1cium binding oftheclinicaJly available 1ctrllCydlllC!l. The impro\'cd dls1ribut ion pooptrtif'l' or the 6-doo~ytct rucyclines ha"e ~n allribu1ed to greater lipid solubility.

!oil".

NEWER TETRACYCllNES
The relTlllfkably brood 'iptClrunl of antimicrobtal actilLt) G !he tetl1lCYciulC.S not ... ithSlandmll. the widesprcild emagm:t of bacl('rial genes and pLasmids cncOOing tetl1lC)'Chne~, UUlCC has increasingly imposed limit;atioos on the clllueal applications of this antibiotic class in recent years. I.. n;.. situatioo has prompte!.l 1'l:SCan:hc:rs al Lcdcrle LaIxnIOl'lel to rcinvc\tigate SA Rs of tetl1lCyclines substitu1ed in the: IrOmatic (0 ) ring in an cffOflto discover analogues that miI!II be effe<:tive against resistant strni lls. As a result of t~ effort.~. the glycy1cyclincs. a clrw of 9-d imethylglycy~ mi no--( 0 MG) s ubst it ute!.lte trae ycli rw:'Sexempl ifled by DMGminocycline (D MG M INO) and OM G-6-nlCthyl -6-deo~)'It tracyciinc (DMG-DMOOT) ..... ere disco'ered.'" If' 111e glycylcyclines rcUlin the broad spectrum of KU\lI) and potency exhibited by the original tetracycli1JC:j, tetracycline-sensuhe microbial strains and are highly Itti.t against bacterial strallliJ that cxhibll tctrBC)'Clinc ~~i)l'"' mc:diated by ernUl. or ribosomal protection delemllnanb. r ongoing chnical evaluations of tnc: glycylcycline<i CSlablilll rovorable tOlLicologleal and phannacokirw:'tic profilct foI lhe~compoullds, a new ell1.'\5 of "sccond-gencrJtion"1rtncyclincs coul!.l he IhullChtd.

,.
m

~ 'I ~

",

'" '"

~ '" " '"

oc

x. N(CHoI.
... H

i-(~)o"iI"""" (OMG-MIHO) i-(DI".~'N'ltyI .. ,i"o) e "",e~,)'Ie j 1)1f\i'l I ..",cII<w (DMG-DMOOl)

Chapltr III AntibftrilJl AllfibWlks

349

MACROllDES
An.Jng the man)" antibiOl:ics isolated from the 8C\inomycctCll II die group of chemically related compounds called the macrolidt~. In 1950. pKrom)"cin. the fi~ of mis group 10 be IIkntificd H a macrolide. compound. was fi~ reponed. In 1%2, crythrom)'dn and carbom~cin were reponed a.~ new antibiotics, and the~ .... ere followed in subsequent years by other mocrolides. Currently. more than 40 such eompournls ft kllQWn. Ilnd new oncs are likely to appear in the fu\tlre . Of all of these, only two, eryttlromyein and olcandomycin. ba,'c been available consislently for medical use in lhe UnIted Sillies. In recent ycars. intcrest h35 shifted away from _I macmti(\es isolated from soil 'IIlmplc5 (e.g .. spi. 1IIII)"("in. jo5amycin, alld rosamicin), all of .... hich mus far .,c pro"ed 1 be clinically inferior 10 cl) thromycin and 0 tnnisyntlrtic dr-rivaUve$ of crythromycin (c.g., cJarithro~ci" and IIZlmromycin). which Jul\"e superior pharmacokiIttIC P'OflCrtieS due 10 their cnhanced acid siabilily and improvtd di,tribulion P'OPUtiCS.

Mech.nl....s of ActIon and Resisblnc:e

Some !ktwls of the mcchaniun of antibacterial acuoo of crythromycin are known. It binds sclcctl\ely to I specifIC site 011 the 50S ribosomal subunillo prevent the translocation step of bacterial proICIn syntbcsis. 191 II does not billd to mammalian rib050mc_~. Broad[y based. oonspecific resistancc to the antibactcria l ac1ion of erythromycin among many spccic.~ of Gram-ncgati,'c bacilli appears to be largc[y related 10 the inability of the antibiotic to penetratc the ce ll walls of these organism~. ''') I n fOCI. lhe se nSltivi1ies o f membenoflhe Enterobactcriaceae family are pH dependent. with MI Cs ~a~ing a.~ a fUIICtlorl of irlC1l:asi ng pit Furthermore. protoplasts from Gram-ncgali,'c bacilli ..... hich lack cell Wills. are sensiti\c 10 ery1hromycin. A highly 5p('ClfM: resislllDCe mechanism to the macrolide antibiotics occurs in crythromycin-R'5istanl s\rJins of S. aurcus. ' '''' I~ Such strains produce III cnlymc that mt:lhylaies a specifM: adenine residue at !he ery1hromycin-binding sile of the bacterial 50S ribosomal subunit. lbe methylated ribosomal RNA I"l:mains active in protcin synlhesl s but 110 looger binds crythrom)cm. Bacterial resistancc to the linoomycins apparently abo IX curs by this mechan ism .

.y.

IS

r~

.. ,

,mi-

teri-

",,-, ""

,10-

h,lls

-elahigh

,,,,

Ie m

c.uniltry 1k macrolide

icl'!i.

Iy of

.~

e5IS-

nical

!Th'S

D"U~\

p'ighl i"'~ c)" laMGlyleHI)"

=-

""'.

/"',.

;ai~st

have three common chemical ~tristics; (a) a large laclooc rinll (which prompu:d the _lIMerofidc). (b) Il kctone group.llnd (c) I glycosidically bUd amino sugar. Usually. the ta.:lone ring h:u [2, 14, or 16l11OmS in it. and it is oflen unsawrotcd, wim an olefinic poap ronjugaled WIth !he kClooc function . [The polycpc " .. yelic lactoncs. 5uch as nIllomyt:m alld amphOl:ericin I;~ amamyt:ins. such as rifampin; and the polypeptide .......! generally are not included among the macrolide .utJioIics.) TIley may M,C. in addit ion 10 the amino lUgar, 11XIItn.1 sugar that is linked glycosidicllly 10 the lactone NIl (Ite "'Erylhrom)cin.' below). B('Clusc of the di methyltmUIO sroup on the sugar moiety. the macrolides are ba.'iCS tIta fonn salts wi1h p K. values betwcen 6.0 and 9.0. This brure ha~ becn used 10 make clinically useful .!-:l11S. The 1m bases are only slighlly soluble in water but di s!iOll'c in 1OIIItII'1\a1 poilU" organi c so[vcnts. They arc stablc in aqueous IIIkAions I I or be low room tempcrDlure bul are inaclivated ~1I:id5. bases. and heaL lbe chemistry of macrolide antibilias been the subject or se..-eral review5.'9O, 191

antibiQ(ic..~

Spub"m of Activity
The spectrum of anlibactcrial activity of the more potent
macrolides. Aleh as erylhromycin. ~mblcs that of penicillin. "They are frequently activc against bacterial Slr,.ins that are resistlllll 10 !he penlciJli ...... lbe mxrohda arc rcncr.lJly cffectivc against most specie!> of Grampositive bacteria, both cocci and baciJli. and eKhibi l useful cffcct;"eoess against Gram-IICIl"ive COCCi. especiall y NeU:Jcriu spp. Many of !he macrolidc.s arc liso eff('Ctivc agaJnsl TrtpotlcllllJ pal/idum. In COOtTaliltO penicillin. macrohdei arc IIJ() effe<:live againSl MycoplaJlfIil. Chlamydia, Campylobacrcr, and ugiQllclla sJIP. Their acti..-ily against most species of Gramnegative bacilli Is generally low and orten unpredictable. 1hough some strain s of II. i'lf/uellwe and IJruulla spp. are sensitive.

ProdMCb Erythromycin, USP. Early in 1952. McGu ire ct al .'!111 I"l:poncti the i~lItioo of erythromycin (E-Mycin. Erythroi;Ln.

*'

Its. If

lbh~h

r",
.~.

tetra-

...,CHo

I
11,C' "

_.-"'0
-..0

~.

,
0

"\ ,

..

'"
' ' ' 00

0'"",/

'

0_

Pb"ltydll

350

W,1.Jorr lJIW Gm'Q/d', TUlbooi. "IOrJ/.(IIu" Mroir",,,1 and I'lwmwlN'l<lica/ Chcmw,.,.

free bao;e ha a pK.. of 8,8, Suturated Ilqucous loOlUlions (/e. ve lop an alkuline pH in lhe: range of 8.0 to 10.5. It i,tl' tremely unsUlbIe at a pH of 4 or below. TIle optimum pH for stability of crythromycln is at Of near ncotrolity , Erythromycin lila), be u'<I:d a~ the free base in I>tllI do:!.ace forms and for topical administration.. T o O\'m:olne its bit/(( ne,s anti im:gular oral absorption (re~ulting frum aciJ o.kstruction and adsorption ontll food ), \arious entcf'ic-CCIIled and delayedrelease dose form! of erythromyCin b;tse /g\f been dcvelopcd. 1'he..e forms havt' heen fully !>UceC'Ssful .. oVCl'I:oming the bitlcrnc~~ bul hllve solved onl), margJlIiln} problems of or-~I a~ion , El')thromycin ha.o. been ch".. cally modified ... ith I"nmarily t.. o olfferent gools in mllllt la) \0 increa.'I(l either iL~ water or lipid \l)lubili,y for pan-nteral dongc fonns and (b) to iocreao;e liS tll.'id stability (lid ~sibly its lipid solubility) for Impro\cd oral absorp;l\& Modified deri~ativcs of the antibiotic lire of t ... o types:..-id sailS of the dimethylanllOO ,roup of the desos.aminc: moict~ (e.g .. the glllCohc:pton:tte. the loctobionatc. and the: ste;wa. lind cslers of I he 2'-hydro,,),1 t;/OIJp of the deso~anll nc (c, ... the cthylblJcclnate and the propionate, available Wi the lauryl sulfate .salt and Io.""wn as the c;,tol atc ). llw:: ~I earule sal t lind the cthylsuccinme and proptOllllt estel'll an: used in or,ll dose forms intended 10 nnprOie II> sorption of the antibiotic. The Mearate relca.'\CS cf) tlttotn)Ql ba..e ill the: '"te~tinallmct, which i~ lhen absorbed. Tht nh}~ succ ln~te and toc estolulC are absorbed largely irtlaa and III' hydrol)'1:ed partially by plasma and tiS<;U(' e~terases 10 1I\of free crythromycin, llw:: que.~tlon of bloo I ailabllllY of the: .. tibiot ic from It, 'ariou~ oral dosage and cocmical forms hzt caused con,idc:rabic concC:1II and dbpute Oler the IW' I decades.200 - 11 h genc:rall y belie\'ed that the 2' -cSlCf\ pet :;e have liule or "" Inl ri n.ic antibacteria l llCtivit }~ and. therefore. must be h)drolyzed to the p;"Ireni antiblOUc III Although the clhylsuccillate I~ hydrolp.L-d more cfflCaIIJ: than the: estolalc in ~ho and, in fllCt, pro~idc.' higher icl'dl of erythromycin fol lo"'lng IntramulOCu lar adnllmsu'atMlll,_ equal d05C of !he atolate ghCli higher IcvelS of tht flft antibiotic following oral udl1li m ~tr:ltion.2Il1.~ Supcri()roni absorption oi the cstolate is atlribuled to both i1!i greala' ItII stabllllY al1d higher mtnnsic absorpuon than the eth}1soco IUIte. Also. or- I absorption of the e~tolatc. unl ilo.e thai of"" .. the stearate and the cthylsuccillllte, is not a.ff1ro h). fool or OUld ,oIume con!Cnt of the gut. Superior bloo\ailabi of aclive antibiotic from 0/111 udminl'tmuon of the estoIat o'<er !he ethybuccinatc. st':;lrate. Of C:f) thromyr.-in base_ not ntees,~ly be: assumed, howc>cr, because the cstolW, 1Il0le eJ.tcn 'i~cly protcin bound thnn crythromycin it~lf MellSured fr.tCtions of plasma protc:in binding forl'l')~ c;n2'propionate and ef)thromycin base range fTOOl O,~" 0,98 for the fomler and from 0,73 to 0.90 fOl' the 101C1C1. indicanng a much higher levd of free erythromycin p\a.'ima. Bioavailablhty studlCJ; eompanng eqUi\'a\ttlt of thc t:'nteric-eootcd ha5C, tile Sicamlc ~~I1. toc t:'th)lsuconail' ester. and the 1!.~1I)1~le I!.~tcr in hunmn "oluntCt:'l'SllI1. showed dt'llyed but shgbtly higber bloon,ilablht) for free base than fOf the stearJtc, clhyl~ucclna'e, or est<>blt One study , oompanng lhe: clinical cffcctl\croe~ offttllll mended dosc~ of the ~lCaratc:. C'\!olatt'. cthyISUCCi~. free base: in the trealment of ",spir-J tory tfOCt In~ fa.iltd 10 tlcmol1!itnuc substanlial differences among thtm. Two other clinical st udies. rompanng the: effeet.i\'CIICSI

lIotycln) from Sfrt'llfom,I\'f!J u)'fhmelu, 11 !ICh ie~ed rnpid eOirly IICcq>lOInce as a ..... eLl-tolerated anti biotic of value for the t~amM:nt of a ~lU'lCIy oioppcr respmuory!lnd soft-tissue II\fecllon ~ caused by Grnm -pos im'e bactl:Tia, It is ul'iO cffe<:ti\'e IIgallllit many \'cncrcal oiseases, illcluding gotlOI'I'f1oca anti ~n>hili~, anti prondes a tI.<;c:ful altcmmhe fOf the: treatment of mally Infecllons In palientS allcr&ic to penicillins, More recently, erythromycin "'2c~ shown to be cffecti~e therapy for Eaton agent 1 >lM:omollJlt (My"o,I/(U1fI(l fH'CU"WtlUltJ, \'enereal diseases caused by chlnmydia. bacterial enteritis cOlused by Carrrp)loba"fer }tJlmi, and Lcgionnain:.~' disease.

",Ot,

( '--"'''', "" 0--( ~ &i. ""

".

~.

'"

TIle commen:iltl product is erythromYCin A. ,,'hich differ;

froln ils blOliymhctic precursor. crythromycin B. in ha~ i ng a hydro~yl group at the 12 po:;ition of the agl)'c~. 'The chemical st l'\lCto~of erythromycin A was repOl1ed by Wi ley et 1I1.11 in 1957:tnd it~ ~tcn:ochemi~lry by Ceimer llll in 19M. An eiegam ~ynthesb of cf)'thronolidoi: A, the ~glyoooe present m I:f}thromycin A, was described by Corey and associules.I'H The amino sugar IIUached through a glycosidic link to C5 is dcsosamiroe, OI structure found in a numbcT of other macrolide antibiOl 'C~. The teniilJ)' amlllc of dcsosnmi /Ie (3,4. 6-trideoJOy-3-dimcthylanlino-o-.I)"lo-ocJOO'Oe) ~'onfcl"$ a ha.ic characttr to t'rythronl)'Cin and pro~idcs the Itlt'ans by \\hich ocid salls may be prcp:m..>d. llIC OIher carbollyor-Jte ~t ructure Imked :IS a gly~idc to C3 ib called d"d;"o~ (2.3.6- trideoJO)-3-mcthoxy-3-C-ll1tthyl-l-nbo-hc~ose) anti IS unique: 10 the t'rythrumycm molecule . As is common wilh OIhe:r macrolide arllibiotic~. compound~ closely related to erythromycin ha\e been obtained from eulture filtrntc, of S. tr}"fhf<lclu. T\\o 511Ch analogue:s have been found , Crylhrol11ycins H and C. Erythromycin B dlfTm; from cf)thromycin A only at C-12, al which a hydrogen has replaced the: h)"oro~)'1 group. llIC B analogue: IS more acid btable bot has o nly llbool ~ of the IlCti~ily of el')'lhromycm. TIle C analogue: dlrfm; from crythromycin by the: replxeme11l of !he nlCtoox)"1 group on the cladinose /I/olety with a hydrogen mom. It appears to be as IICti~e DS I:f}throm}'cm but is pre.<oent in \<t'ry ~malllln1OUnlS in fcrmen. !DIIOn IiquOf'i. Erythromycin i~ a ~ery biller. wllite or ycllow-white, cry~ talhne powdt'r. It is soluble in alcohol and in the othc:r CO/Tlmoo organIC sol\cnt~ but o nly slightly soluble in water. lllc

"'II.

111*

dle de,clopment of atherosclcrosis lind is known to occur in

Severe hyperlipidemia may lead to life-Ihremcning macks of ocute pancreatitis. II also seems Ihm Soevere hyper~pidemia cnusts xanthoma . Considering !.he effeclS of insu~n on lipid metabolism, as summarized above. one can rarionali7.e th~t in type II diabetes, in which the patient may lIttuaJly have an absolute e~cess of insulin, in spite of the ~,ide~ of glucose tolerance tCSts. the effcct of the e~CC'S51"e insu lin on lipogenesis in lhe Ii "er llIay suffice to increase ilK Ie,-ds of circulating triglyccrides and VLDL, In type I diabeles. with a deficiency of insulin. lhe c irculating Icvd rn lipid~ may rise because too much precursor is available. fIlth fatly acids and cnrbohydnues going to the livcr, The: relalionship \)ct,,'een the carbohydrate metabolic rnanifc5lations of diabetes and the devciopment of microand macrovascu lllf diseases /las been studied cluensivcly. se.. l>l lt is becoming increasinglyclcllf thm hyperglycemia plays I major role in the developmem of vascular complica tioflS Ii dJntes. including i11lcrcapi lIary glOJncrulosclerosis. prelIl3Jure atheroscleros is, relillOp.1lhy with its specific micll)lIJIeury~ms and retinitis prolifenms. leg ulcel'!!. and limh ganFtrlC', Fi~t , hyperglycemia caust~ an increase in the act ivity a( lysine hydroxylase and golactosyl trunsferasc. t""O importan! tnzynH's involved in glyroprotein syn lhesis. Increased !Iytop~ein syn thesi~ in the collagen of kidney oosement o:moome may lead to the developmem of diabetic glomcruklsclerosis. Second. increased upmke of gl ucose by non-insu.lin-sensitivc tissues (c.g .. nerve Schwann cc lls and ocular \ellS cells) OCCUr5 during hyperglycem ia. Intracellular gl uCI'lIt is conve ned enzymatically first to sorbitol and then to fruct~. ll1e bui ldup of the.'iC sugar.; inside Ihc cells intIl:llSeS lhe o:.mOlic pres~ure in ocular lens cells arid Schwann cells. r~ulting in increased walcr uptake and impamng cell functions. Some forms of diabetic Cal:lraC\s and diJbetic neuropathy are be lieved to be caused by this pathlI'l1y. Third, Ilyperglyccmia may precipilllle IlOI1cnzym"tic
diabelc.~,

glyrosy illtion of a variety of protein~ in lhe body. including hemoglobin. serum albumin. lipoprotcin. fibrilHlgen, and basement membrane proIein , Gl ycosylalion i~ believed to alter the tertiary structures of proteins and possibly their rule of metabolism. The rate of glycosylation is a function of plasma glucose eoncen\mtion und lhe duration of hyperglycemia. Needless to say. lhi~ mechani~l1ll1light pl ay an important role in both macro- and microvascular lesion . Finally. hyperglycemia increases the rute of aggregation and agglutinizution of circulating plalelets, Platelets play un imponam role in promoting atherogenesis. The increase in the rate of platelet aggregation and ag glutin i:rution leads to the development of mi CTQCmboli, which can cause tran sient cerebral ischemic allacks, strokes. and heart attacks.." Concepls of the therapeutics of diabetes mellitus havc been reviewed by Maurer.60 Thi s review cmphas.i7.es that insulin therupy docs rIOI always prevent ~rious complic ations. Even diabetic patient~ con~idcred under insulin Iherapeutic control experience wide fluctuations in blood glu~'OSC concenlration, arid i\ is hypothesil.ed Ihat these fluctuations eventually cause the seri ous complications of diabetes (e.g .. kidney damage. retina l degenerntion, premature atherosclcrosis. cataraclS. neurological dysfunction. and a predisposi tion to gangrene),

Insulin Prepararions, The various commercially avail_ able insulin preparations are listed in nhle 25-7, Amorphous insulin w...~ lhoe fi~t fonn made available forciinical U.' C, Further purification afforded crystalline insulin, which is now commonly called' 'I't'gular insulin." htsulin injection. Usp, is made from line insulin crystllis. For some time:, regular insulin so lutions have been prepared al II pH of 2.8 10 3.5; if the pll were increased above tile acidic rangc. panicles would be fomlcd, More highly purified insulin , bowc\'er. can be maintained in solution over a widc:r pH rnnge. even whcn unbuffered. Nelllral insu Ii n solutions have

TABLE 25-7

Insulin Preparations
"'rtide Sizc

(~m)

Action

Composition

..
B --J.3 7.2- 7.3 72-1.3

Duultion (hours)

....,,1 mJ'<",ion,' USP ,.

Prompt ,,,,,,ha lill<:

..,luI

""PO .."""," VSP

~;nc

JO-4Q 17!J'!,) 2

",,!",nwm.'VSP f......xd ,,,,.lin"In< .......... ""'.. US!' Globin i_lin 1DJr<'ti<>n" US!'

.""" ,.....

-1'<>""00:1;".

....., ""'""

+ ZnCI, 1",.lin + ZnCI, + burt..

h""ba

S-,

1..... lin

+ LnCI,

1" buff..

" ,

Insul'"

+ Zr.C1, + bulflo'

12_1,S
~4--).8

2>1 -36
1~18

<I"

Intenned, ...
Loos,.,ung

Glooln' ' ZnCI, .. ,"""I'n

I'rol;omlno (.ill<: i_lln ~'USP

1'\vWn,"'" + ....ulla + ZQ
Pror"",,""'7.nCt, in.",hn
~fi"

1_1_7,4
1,1_7,4

I._ln'uh.
"

Imermeti,"e

''''
t8-24

""",,"<lon,' VSP

'Oar .. oI_c ....

'OIobIo (.\1>-',0 ".tlOO USP ""'" 01 i........ oJ ",,,.1 fn>m
11,0-1--' ".t100 USf' ...... ofiooutin, _ .. ' , " (O.l-O.6 ..,.100 USP ..... , of,_I .. ~
. , . I' ' "

.....

"'""'-

_blood.
mal .... _

"'" """'" '" ,he

off"" be ....... 10 the 1<fI\I'

00<"""""...... __

15% of tnc 14-hydroxy metabolite IS e.lcn1ed in the urine. Biliary e~cretiOfl of clarithromycin is much 10weT than mat of erythromycin. Clarithromycin is widely distributed inlO thoe tissues. which retain much higher coucentrat ions than the plasma. Protein-binding fmetions in the plasma rangc from 65 to 70'1>. The plasma half-life of clarithromycin i~ 4.3 hours. Some of the microtllological p OpCltito!i of clarithromycin also apptal' to be superior to those of erythromycin. II CAhibiu greater p"eney againSi M. f1I1~unwniat. u8iQnt/la spp., ChilUnydia pntumomat, H. uiflutn::tlt. and M. Calar rlwli.r than does erythromycin. C1arithromycin also has ac livily D.gainstunusual pathogen~ sU(:h as 8orr~lia burgdorf tri (the cause of Lyme disease) and the Mycl)bac/trilm, 01';1'111 (X)mplu (MAC). C1arithromycin is significantly more lICIi\'e than erythromycin HgainSi group A slTCplooocci. S. pntumoni~. and the viridans group of streplCK:ooxi in vivo because of Its supcnor or.lI bioavailabllity. Clarithromycin is. ho"ever. more expensive than eT}"lhrom)cin. which must be " 'eighcd against its potentially greater effectiveness. Adverse reactions 10 darithromycin are rare. The mosl common complainlS rel:lIe 10 gastroi ntestinal symptoms. bUl these seldom require discontinuance of thclllpy. Clarilhromycin . like erylhromycin. inhibiU cytochrome P-450 oxi dascs and, thUS. can potentiate the act ions of drugs metabolized by these enzYme!li. Clarithrorn)'cin occurs as a .. hlle cryMalline solid mat is practically insoluble In .... aler. sparingly soluble in alcohol. and freely soluble in acet~. It i~ provided as 250- and 5(X).. mg oral tablets and as granules for lhe preparnuon of aqurous oral suspens ions conlaining 25 or 50 mglmL. M,ithromycin (1.ithromax) is a semis)"nlheuc denll<lth'c of erythromycin. prepareO by Beck man reanangcmcnt of the cOl,cspondlni 6-ox ime. folJoy,'ed by N-mclhylatioo and reductioo of the resulting ring-ex . ponded IlloCtam. 11 i~ a proIOlypc of a serie~ of nitrogen-oontaininl, 15membc:red ring macrolidc.s kno .... n asawlidu.m Removal of the 9- kelo group coupled wilh incorporution of a weakly basic tertiary amine nitrogen fUrK:tion into the macrolide ring incrcase~ the slObil ily of azilhromycin to acid..;:atalyzed dcgradatiOll . TIIese changes also iocrease the lipid soIlibility of the molecule. thereby confemnf IInique pharmacokinetic and microbiolQgical poopmiesJ'

before or 2 hours after I meal . by as mU(:h lIS 5O'il. are charncteri7.ed by from into t tissues followed by a slow Tissue plasma concenlllllions, I a highly variable and prolonged elimination half. I&,::,; to 5 days. lbe fraction of IW thromycin bound .... protCms is only about 50% and does not influence on its dlstnbution. Evidence indicales mycin is \qely exacted in the feces

~" P'~""~!"'!" "'~.m ooxurs. the urine.

r

" ,inhibit significant ly

potential drug

P-450 enzymes to

IloCtive lj!aiMI Gram-positive I . relatives. octivity of azithromyci n api nst H. inj/Ilen::m'. rhlliis. and . coupled with life sc hedule for

tal and other sellually tr.Insmmed mfecuoru

"""

myd;a trachoma/if. N. gOftorr/wtot. and Urtap/OJIrI(J IIrealyficllm suggestS mal apy wilh il for uncomphcated urethritis or have advanlOges over use of OIilcr antibiotics.

Olrithromydn. Azlthromycln USP.

lipid-soluble

'. "

.. ",CH,

The urnl bioavailability of azi,hromyci n is good. nearly 40%, provided the antibiotic i5 administered al least I hoiir

-"

Dl,IH","h)'CIn

Cbaptu to

A,"ti"'lC~rnH

A,,,,,bioticr

JSJ

OraUy IWJmini~lcrt'u uinlhrolll)cin is llb\o(lrbcu rnpiuly inll)

largely from Ihe small imeslinc. Sponlaneous . . . .:) 51~ to CI') IhromycyclalllHM: Ol'CU'" III the plasma. 01'...1 aiLlbtlny i, csumalcd 1 be about IW. bUi food doclI 0 ah.orplion of the prodrug. 1lr]o.. pllll'lllil le,ds and IlU'ge volunle of u,I;lnbut ion bchcvci.l 10 r<"ul! frum its rnpli.l wd l-perfused lI~sues. ~uch :1.' lung part'nmLlCOS3. 0:1.<;;11 rnllC(ltS;l. :and pt'O'>talk lI S. OOfJCemratCli 10 human ncutrophils. 111c is ~tim;ncd to be 30 to 44 hour... M~ activ ... !1lCtabolite (62 to 81 % in roonnul excreted in the feces. la!l;ely ,iu the bile. -'Ill orol or p;1n:nlcral adm,"I~lrnllon. Urinary .....;at'C()\lnt5 for less !han 3'1 . The tncide<lce aoo :len'rily of g3slroirllc)(lnallldn'~ cf1.'i~laled """h dirithtomyci n at... simllur to those sa!n or:al tt') thrum)'cin, Pn:linlltiliry stui.liCli i ndleme Ihal i.l iC,__,ycin un(] crythromycyclamitle do TK)! interacl ~igni Iiwith q -tochromc P-450 O!lyg~'tla~s. Thus. the 1i~cli rnterftn:nct in the o){ilbti, ... lTlC1aboli'm of drugs I.'i phen)'toi n, theophylhne:. and cydOl'ponne by the-.c be lt~~ with dinlhromycin Ihan with erylhru "rt'COtnnM:ndci.l M an allemaule to erylhof bacterial inf\'lL"lion, of the upper t.ruclS, such as pharyngItis. tonsillili s. pneumonia. :Inl.l for bacterial mfcaions of Dnd ~ ~kin, TIle ol1C(:.daily dosing !>ChcJi h ad\'nnt ag~'OUs in terms of beuer pa. Ie" place In therolPY rt'malnS 10 be fully
pIa.~nla.

Ihc oleandohdc. The tn;ICctyl (!ern;!tI"': fClhllh the in ,;vo anuba<'tenal lti,:tivity of the P.ll\'rll anublOlic bul POSse!o"'~ ~uperiO( pham\;lC"~;nc:tlC I'fOPl'AJes, II is hydro!) zed m 11\0 \I} olc'lIldom)cin. Trolcandom)cin :achle\'e~ morc rnptd and hlghcr pla~mll concenlr.lltorlS followmg 01111 IIdminis.tr.tltOll Ihan oleandomycin phoo;phatc. and il lIa~ lhe addItional lId vnn l3,\;e of belllil pmcticully taSteless. Ttolemlllomydn occurs as a \\ hile, crystalline ",ltd thlll. " nearly Insoluble In \\aler, It tS re lali ,'cly t;tahlc m the 'oOIid \late but underg~ chemical dcgr.KI~uon In cuher !lqUl.'OU_ lICidic or allaltnc conditions. 8ecau~ Ihe anuba<'tcnal 'pi.'\!troll! of ;\Cit vily of olc~ndo l1lycin is eon~Kkrt.'d inferIor In thai of el)thromyeln. lhe pharmacollllCuc~ of trolcandolnyclJl have !lOt been stu..hcd utcnsilely, 0nI1 absorptlOO IS apparently good. andoocaable blood le"els or oleandomycin per.;ist up 10 12 hours after a 500-rng do!.c of trolcandumyein. Approl lrnate1y 20') I ~ ft.'CovcrL>d in the urirn:, witb most CllCrcIL't' in Ille fcce~, pri marily as u rc,ull of biliary e\crelion. 1bcrc is some ~pigll.~ !ric dislrc~ follo", ing ordllldmm'SIr.lIlOO. \\ ith an incidence ~imilar to lhal caused by ef)'thromYCln , Trolc-oIndomycm I' tbe most potenl mhibllor of cytochrome 1 '-450 cnJ)'1nCll of lhe contrllcrl:iully a vail~ble nHlctolil.lc~. 11 flta)' potenllutc the hep,lIic IOxiclty of cend,n anlt -innamnlalory Slcroid~ ~n(] Ol"dl colllr eplllc drug~ as \\dl as tbe lO\ ic effca, of the.... ophy lline. carbatn:ucpine. aOOuiazolaJ1\. Sc\ eml allergic rt'actions. Irw:ludmg cbQlestalic hepatll", julie al'\() been reo I'O"cl.l \\ith the u;;c of lrolc~ndomycin. App' UI'cd mt:dical indicauon- for lrule:mdomycin arc cu rrently limi tc(l 10 the lrealment of upper f('~P""3lory infectious caused by \l.ICh organisms as S . IIW}f/t'IIl'$ and S. {HIl'UllIO<tlltt , It rna)' be con,tdcred an allemalll'c to orol forms of cf) throtIl)'CIn, [I is gl'81lablc In cap"ule~ and as a ~u~pension ,

ib triocet)'1 dcriv Iriacety!o1candomycm (TAO), rea~ ~n I to erythl'Olll)cin for limucl.l , oral dosage form. Olcandoan(] a~ialC!l, ! t1 1lle !o'-ruclur,: pro]lO!.cd b)' Hoch~tein Ct al.. >IX and m t elucil.lmcd by Celtner,! 1 The 9 structure consists of IWO sugol" and a 14ring designated an nle(lllflofidc . Orte of tnc 1'K'.'iCm In erythTOlll)'cin: the other sugan; arc IHlked gl)'cosidil-.. lly to lhe POSItionS. respectively . of oleanoolide ,

Ole~rl(lomycin. ~s

lINCOMYClNS
lllC l incom} cm~ art' sulfur-comainlng antIbIOtics isolau:d from Sfrt'IIWIIJ'CI'S lincQ/I1(,"l;$. Lincolnycin i~ tile must ac live ~nd medically useful of tile compotJnl.l' nblaitlCd frum fenncnlalion, Extemi\c cffons to nM.k lify the lincom)'dn SIJ'UI.'urt' to 11lI['II'O,e its antIbacterial an(] pharmacological propeni~ f1!,ultcd m the prcparutioo of the 7-cbI0f1l-7deeny derivuli\c elin(]atn)'cin Of lhe two ani ibiOlin, clinda mycin appear.; 10 have tile gn:;:Ilcr antibaclerial f/Olcrw:y aoo beth:r ph;trln:K:o~ i ne:tic provcrties. L",coll1ycin~ re;;cmblc macrolidc~ In antiba<'terial ~ p'trum and bIOChemical mcch:\Disms of x tion , 111cy 11ft primari ly acti\c IIgain" Gmm flO"""C Ixk.,eria.. panicular!) the cocci. but art' alw cffeclt,c against rKHl-spore-fonmng anac:robic OOcIl:nll, actioomy celc~. nl),etlpla,nm, anl.lMltnc species of lI/(w",,,lium, Uncomycin bin(]s Itl lhe 50S nbo-.omal ,ubunil hI inhibit protein ~yntbo;;i~ , It, action may be bacteriO!ilaltC or bacteriCidal depeoomg on a variety of fao:.:tor<. inchtdlllg the conccntralion of the nntibiotic. A pattern of bacterial n:,i,lartee ~nd cross-R',i'larw:e 10 lincom)'cl n~ simi lar 10 lhal om.cr"ed witb the rnocrolidcs has been cm.:rging, I~

...,DI,

H ,/ .c-.......

01,

""

0-.,

Products

~::,::-:;:,;'~':m::,~"""~ ains Ihree h)dro!lyl groups lhal are

I II

one in each of the sugar; an(] one HI

Lmcornycin h)drochloride (l.u'Ic(lCin). ",hich diffcl'li chemically from "Iher

Lincomydn Hydrochloride. USp,

major antIbiotic classes. was isolated by Mason ct al.= Its chemIstry "'liS tk.~Ix'(l by Hoeksema and cowortrr<o.lll who IISsigncd thc SIIUClUre. later confimled by Siomp and MocKc1l3l'.Ul given in tnc diagmm below. Total syntheses mlnc antibIOtIC wcre aceorllplish.ed independently in 1970 in England and the Umted States.ll-', n" 'The structure COtl !ain~ a basic function. the pyrrolidUle nitrogen . by which waICr' 50luble salts WLlh an apparent pK. of 7.6 may be formed. When subjccled to hydra'-1I1olysis. \incom)cin is clea\'ed at ilS amllk bond into IraruL-4-II-propylhygric acid (the pyrrolidillC moiety) lIl1(/ I1lcth)'1 a -thiolincQSam ide (the sugar moiety). Lil'lComr.ci n.reJatoo antibiotics h.ave been reponed by A'1oudelism to be prod\lCCd by S. /UIf:ol"C".fU. 'The<;c antiblOucs differ In structure at one or more of thrtC po~itions of tile lincomycin structure: (a} the N-mcthyl of Ihc: hygric acid moiety is substituted by a hydrogen: (b} the ,,-propyl group of !he hygnc acid moicty i~ 'itlbstituted by an cthyl group: and (e ) the thiomcthyl C1her of the a-thiolin cosannde moicty is sub~ti l\ltcu by a thioc:thyl ether.

Isc\"cn greater in ~"o. lmprmed Ib&oifllOl and higher tissue le"els o f chndamycin Ind it.-. greater ptIf' !ration into bactcrin ha~e been attributed to a higher part11Q ooeffrcicntthan that of lincomycin. StruCtural modiflNlH. at C-7 (e.g.. 7(S}-chl0r0 and 7{R}-OCH l ) and 0{ the C-I alkyl groups of the hygric acid moletym appear to miMu II(:ti vity of congeners more through an effeo:t on lhe paltI.... coc:fficient of the molecule than through I ~e~ifi: binding role. Clw1ges in tnc <}'thoolincosamide por1lOll" tnc molecule !;Cern to decrease activity marll:edl~. 00.'=1 as eVlden(cd by the marginal octivity of 2deoxylinrom)rlI. its anomer. and 2_0_me:thyl hnoomycin.117 u" EltttpciOlbIit thi s an. fally acid lIl1(/ phosph:lle csters of the 2hytkm groupof lincomycin and clindamyci n. which are h)dmlymI rapidly in vivo to tile p.1rc:nt ~ntihiotic5,

o''Crhnoom~cin

CH,CH,CH, ~ N2 "
_

0 ~11 I ,. C-HN-C-H.

ttO-b-o,

~.

' ""sa<,

used fIJI' the ltI:atrl1ocnt of infections caused by Gr.unpo~ith'c organi'ms. notably staphylococci. P.hemoly tic streptooocci, and PIlCUI11OCOCci. It is ab..orbcd moderalC:ly well ornlly and ulstributed widely in the tissllCS. Effecuvc COflCcntl'lltions are ochle"ed m bone for the treatment of \laphylOCOl:cal o)tcomyelitis bUI not in the cerebrospinal flUid for the: treatment of ITICni ngitis. AI one time. lincomycin 10.'1.$ coru;;idcm:l II nomo.\ic compound. with. low incidence of allergy (l1I'>h) and occ.slonal gastrointestinal romplaints (nauo;e8. ~ol11it ing. and diarrhea) as the only U(h'ersc cffecl~. Recem repons of scvere diarrhea and the developmcl11 of psel>domembt'anou!; colitis tn patients treated "'Ith lincomy~ ,n (or dilkiamycin). !K)we\cr. have necessitated reappnllsal of the rule of these lIntibioric$ in thempy. In any c~'cnt. elin dam)'cin is suvc:rior to lincomycin for the treatment of 1I10St mfections for which these WlLibiotics lU'C indicated. Uncomycin h)'drochloride occurs II.~ the mooohyt.lr.rte. II ",hite. (rystallinc w lid that is stable in the dry ~tate. It i~ readily 'iOluble in waler and alcohol. and its aqueous solu tions lI/'e sUlble a1 room temperature. It is degraded 51 ly 0"' in acid solution, but is absofbcd well from the gastrointesti nal tmet . Lincomycin diffu~s well into peri toneal Dlld pleural flu,ds and into bone. It is c~erctcd in the urine and the bi ..... It is a\ ailablc m eapsule form for or.rl adntinistm1ion and in ampules and vials for parenteral administr.ttion. Liocomyell1

I~

ClinchmycJnHydrochlorkM. USP. In 1961. Magerlein llIi ~ al. reported tllat replaccnl('nt of the 7{Hrhydru~y group of hncomyclll by chlorioe w ith in"ersioo of con ligurntion re~ul1eu in II compound with enhaoccd amibactcrial activity in "lIru. Clinical experience ""ith this semisynthetic de';,a liH:, cliOOam'{cin, 7(S}-chJoro.7--dcoxylinoomycin (Cleot-.,,), tt\t~ '" \1:'f\\'I. " - ~~\~ ~ \\'0. ~\'i

forms and as the 2-phosph.ate e.-,ter in <iOlutiOll.S":,;~::~~ cular or intnwcllOlls injection. All forms are d
~ \\\ ~'l\\(.'!\\

Clindamycin i~ reoommendcd for tl1l' ItCatll1('llt of ... \'anety of upper respiratory. ski n. and ti~,uc infem. cau'iCd by su<;ccptible bacteria. Its act;,;ty agallls.t :.Irq cocci. ~laphy lococci. and pneumococci is indi~tabI) , ~nd it i~ one: o f the most potent "gems Mvllilable agalll51 non -spore-forming anaerobic bacteria. ~he &.,,;,~ in particular. An increasing number of report mycm-associatcd gastroimestinal toxicity. \\ hlCh rang< scventy from diarrhea to an occasionally Sl.'rious mcmbl1ll1OUs coli tis. have:. however. causcd some expens \0 call for 11 n:apprais:tl of tile in therapy. Clllldamycin- {or may be ]XInicularly dangerous in or tiCIllS IlI1d has caused dcath~ in suc h whICh j, usually revel"\.ible ",hen the now believed ,; ''?~" (n,m ~ "'0 resist:lnt stmin of the anaerobic illleS\lnal bactcnum IridiulIJ tl!ffieUt.ll'l The intestinal lining is damaged ~~ glycoprotein endotoxin relea>cd by lySis 0{ this The glycopeptide lInllbiotic V3J1t;'Otn)'e;n ha.~ btcn ti.'e in the trtatment of elindanlycin-induccd brullouS colitis and in the control duceU bacterial I in ; be rese .... ed lulitb and in penieillinallergic pallen!> for scven: outside !he central system. not be used to treat rutor)' 1l'lII:t i caused by bacteria sensllne 10 !NIfcr antibiotics or in prophylaxis. i I Clindamycin is absorbed rapidly from uact. e\'en in the pre,sence of food. It IS avai lable IS crystalline. watcr-soluble hydrochloride h)'dr.t1C: und the 2-palmittue ester hydrochloride salts in

.,,.,

W \\\ \'rIe ~

~.

ChM pt"'T to ,4n"boctnial Ant.biotlCs

CJindamycin P"lmltiUe Hydrochloride. USP. ClirKIalI)'tIft palmitate hydrochklride (Clrocin PedUltric) is the: h)'6tdIIonde sail of the palmitic acid esrer of cloom)'cin. l1le ~ bond ;$ to 100 2-hydroJO)'l group of the linoosamirle lUIar. The ester serve.~ as a la~tele!is prodrua form of the llllibioll(, which hydrolp.e5 to clindamydn in the plasma. IE ~l form confcn watel' solubility to the ester, whIch ;5

lSS

1I'lillbk: as granules for reconsllt ulion inlo an om] solution

.,

b" pediatric use. Although absorplion of the palmilale

j~

r.

'0

,I

OJ

\P'e!" than thai of the free base. there is hllie di fference in .: '~'~biolnjlabili ly ofthc IWO preparations. Reconsti tuted .... ... of the palmitate hydrochloride are stable for 2 weeks lit room lemper.nure . Such solutions ~hould not be rdngcr.ued because thickening occurs lhal makes the prcpaIIic:D difficult to pour.

ci n and vancomycin interfere with bacterial cell wall syntlle: sis and are effect]I'c only agwnst Gram-poslul'C bacteria. Neither antibiotic apparently can penelTlltc tile: outtr enl'elope of Gramncgali.-e bacteri a. Both the gramicidins and tile: polymyxins interfere with ce ll mcmbrdne function s in bacteria. HOII't:I'er. the gramicidins an: effect1l'c priman ly against Gram-positivc bacteria. whi le !he polymy.ins are effect;'c only against Gram-negati,'c spcciti. GramlCldins are neutral compounds that an: Inrgdy incapable ofpenetnn ing the outer cnlelope ofGramnegatil'e bactenn., Polymy. ins are highly basIC conlpoullds that pcnctl1lle tlK: outer membrane of GTlIm -negalJl'e bacteria through ponn channel s to act on tile: inner cdl membranc ,1 l'he much thicker cell wall of Gram-positive bacteria apparently bars penetration by the polymyxins.

Cfnd.mycln Phosphate. USP.

Ciiooalllycin phos.

I*- (Ococin Phosphme) is the 2-phosphau: cster of clindaqm. 1I e~ists as \I zwinerionic structure thai j~ very soluble .I'*f [t is inkoded for parenter.oJ (in lTlwenoos or intl'll~~Iar) admimsU'1ltion for the treaunem of !ierious infec and lnS~ wlK:n oral admin istration is not feasible. Sohmonl of tlindamycin phosphate are 5mble at room te mpmIIIR: for 16 days alld for up 10 32 days when refrigemtcd.

POLYPEPTIDES
the ITlOIit powerful bactencidal antibiotics are those till pn'f::'" a poIypepude: structure. Many of them have : ':soIlited. but unfonuna tely. their clinical use has been by !heir undesirable side: reactions. pan icu larly renal _Another linlltation is the lac k of system ic aclil'ity ; , , _ peptide. following oral administmtion. A chief of the mcdicmally important members of this class The antitubercular antibiotics capreoChapter 8) alld 11K: lntilUmor anti and bleomyci n are peptide:! isolated The glycopcplide: anli biotic I'ancobecome the most important member of is isoLlued from a close ly n:lated actinomycete.

tnc:

most are gramicidins): (c} I

I'

animals: IIJId (d) many of such as heterocycles. antibiotics may be neutral depending on the numor guankl.ioo groups in their it was assumed that neutml compounds. . i . posscsllCd cyd opeptide struCIUn:s. lI'en: de:termined to be linear. and Willi shooA'n to be due 10 a of of !he terminal amino

of""
1

Vancomycin Hydrochloride, U5P. The isolallon of 11K: glycopeptide antibiotic \' lIncOlllycln ( Vancocm. Vancolcd) from Slrl'plom),ct! oril'ntO/i3 (n:named Am,'colmoPJiJ ori I'n/o/iJj was descnbed in 1956 by McCormick et al .m The "'1lani ~m originaUy .. as obtained from cultures of an Indonesian soi l sample alld subsequently has been obuuncd from Illdian soil. Vancomycin was in trodu ced in 195811.~ an antibi otic acllve against Gram-posilllc cOI."Ci. panicularly streptococci. staphylococci. and pneumococci. 11 i1 not at'lll'e against Gramnegbliloc bacteria. wilb the cxception of Nl'ilJl'rio spp. Vancomyci n is recommended for U'\C: lI'hen infec tions fai l to respond to tn:atme m with the more common antibiotics or whl'n the in fection is known to be caused by a n:.~j5Iant organism. II is paniculnrly effecth'c for the treat menl of endocarditis ca used by Gram-pGSlII \e bacteria. VallComycin hydrochloridc is a fn:c-nowinll. tlln to brown powder that is relalively siable in tlK: dry \ tale. It ;$ very soluble in water and insoluble in organic !;01Ie nIS. n.c salt isquile 5table in acidIC solutions. The fltt base IS an amphoteric sublitance. whose mucture IID.~ determined by a combi nation of chemical degnillati on and nuclear magnetic res0nance (N MR ) studies alld x-ray crystallographiC analySiS of a dose anaIogue.!.!J S light sten:ochemlcal and conformational n:vision5 10 the origi nally proposed structun: were made Illtcr.!.!< m Vancomycin is a glycopeptide contai ning lWO glycosidiclilly linked sugar:\. glllCOiSC and ~ ancosaminc. and a complex cyclic peptide aglycon containing aromatic m i dues linked together in a unique resorcinol ether sy~. Vancomyci n inh ibits ccll wall synthes.is by pt"el'ennng 11K: synthesis of cell wall mucopeptlde polymcr. It does -1'0 by bind i nK with the o-o.Ill11ine-o--alnni llC terminus of the uridine diphosphate-N-acttylmuramyl pepcides required ror mucopeptide polymcril.aUon.~JI> Details of the binding ..'en: eluci dated by the elegant NMR Sludics of Willillltl!lOll ct al.m TIle action of ~ancomycin leads to lysis of the bacte rial cell. The antibiotic docs not uhibit crossresistance to .B-Ioctilms. bacitraein. or cycloserine. rrom whIch il differs in medunism. Resistance to Vancotn)'C1O among Grumposilile cocci is rare. Hi gh-le~eI resistance in clinical isolates of enterococci has been reponed. however. This resistance is in resJIOO!ie to the inducible production of a pmtein. encoded by vatlCOm)'cin A. that IS an altered hgase enlymc thai cauS" the iocOlpOlation of a t>-alllnlneo--loclll1e dePSIPCptide in stead of the usuaI1l-3Ianine-D-alanlllC dipeptide in the peptidoglycan terminu s.UII The resu lt ing peptidoglycan can seUI undergo cross-li nking but no longer binds vancomycin.

"'0 ""

0
0

MO,,,

"

"'" )
I
~

I
0

"

'" '"
,

'"
"
",NIl, .

""

""

'"

'"

'" -'"
on a oncea-da), dos.ing t.ehc:dulc. Orally adnllnl",em! IncopJani n is not abwrbcd ~ignincanll y alld is n:t:Ol'Cred4(l" unchanged in lhe (<<Cli , Teicoplanlll exhlbns e~ce l lenl antibacterial art!11) against Gram -ptKlU\c organi5ms. including staphyi<lctn.. streplocooc i. entcrococci. CII)SIridium and Co" ..f'lJ(Ktrn. _pp .. Pror,iOflimlcuriulIIl/(,)/U. and L mw"JCyI~MI_ h not acti ve agaln't GrJm-ncgau''eorgarusms. il1dudin ",~,'~. $rria and !II)'coboct~n"m spp. T eicoptanin imp;;ail"i ~ cell wall s),nthc) i .. by complex ing with the temucuJ ~ nine-D-aIDnmC dlpc:p4ide of the: peplidoglyC<ln, thus pm ing cros.~hn king i n II 11101lllCr entirely analogou_ to the of v:lllComycili. In general. Icicophmill appcurs 10 be Ie.... toxi..: lh:tn laIP myci n. Unli ke lallcomyc in . it docs not cau"C hi,mnmlrtl: lease following II1lr~I'eI10U~ infusion. Tciooplanin a~ also has Ie,s potential for causing nephroto~icity thun IIID rn)'cm.
Bacitracin, USP. 11Ic. organi sm from \IohlCh Jotmw:.l1 at:' produced bacitrolCin in 19-45 i. a strain 01 &in sub/ills. The organism had brcn isolated from dcbndsl .. suc: from acompound fracture In 7-)ear-old M1UpIt1T~ hcoce the name "bacl tr:tCin ," BlICitracin Ii 001\ from tilt hctlCl1lfomllS group (H. subIJ/is}. Uke t)1'OOtrl:l !he firsl u.sc: ful antibiotic obIaincd from bacterial cultw bacitracin is II complc~ mixture of polypept ide!.. So fir. f leaSI 10 pol),peptides h~\'c been isolated by coum~ distribution techniqUC<\: A. A I. B. C. D. E. Fl. Fl. Flo. G. The: conunereial product koown as bacitl'1lCln IS. ml .... of priocipa.lIy A..... Ith )mallcr amounu of B. D. E.1IId F llte official US!' product IS a \Iohite 10 pale buff",.. thai is odorIe\s or nearly so. In the dry SUIte. bar."t,~ stable, but II rapldl)' dcteriorale) in 3Qucous .wi..... room ..empel'lllun:. Because il II liliiii It storai in I1ghl cont:lll1CN.. stabi lity o f aqueous solutions IS pJl and tempefillun: . S hghtly acidic or roeutl1ll

Vancomycin hydrochloride h alwny~ adm inblercd inll'll\en()\l~iy (ne"er imlllnluscuiarly), either by ~Iow injtiOfl or by l'()nllnuOilS infu510n. for the lre.llme m of syslemic infcctiom. In V,OfHerm therapy. the to~ic ~Ide reactions an: uwally ~ht:ht. but cOfltinued U.'ie may lead to Imp:ufl'd :mdi tory acuity. renal d:unage. phleblus. and roshcs, Because il is not absort>t:d or signlfi('lllllly degl'3dcd In !he gaslrointestinal truel. \aOCOlTl)CIn may N administered orally for the In:alment of 5taphylococcal enterocolitIS alld for pseudomcmbraIlOOS colitis llW)Cialcd IHlh C\indam)cl1\ therapy. Soo-.e.COflversiOfltO aglucovancomycin likely {)Ccu"" III the low pH of lhe MOl1lao:h. The 1 3uer retain~ about thl'l.'C-foun hs of the octil'lly of l'ullCOl11ydn.
Te/Cop/im/n. Teicoplanin (Telcholn)'cin A J Targocid) is a mlllUre of five closely related glycopcp4ide antibiotics pruduted by the actmomycete ACfill()P/IU1~S f~icllO"IW:t'li cus.1-., 1.011 The leicoplan in factors differ only In the acyl group m the IIOI'1hcmmost of 1\100 glOCOf,llnuJIeS glycmidically hnlcd to lhe cyclIC pcpIidc aglycone. AlIO(hcr sugar. Il-manrtOllC is common to all of the: tClcopi3nlns. The Slructu ~ of the: telooplanm factors ",ere determined independently by a combination of chcmkal dcgradationl-O I and SptI'O'oCOPIC.u l .tl methods In three differem groups in
t~.

,..(1.'"

The: tcicorl 3nin complex IS ~i milllr 10 v311comycin stmc lurolly 3n.d microbiologically bUI has umque physical propcrtie..~ lhal conlri bute some potentially usefu l D(h am:lgcs.J.U While retaining excclk:nt watl!r solubllily. tcicoplanin hru; Significantly greater li pid solubili ty thall vancQmyci li . Thus. teiwplan m is di'itribulcd rnpldly Into IlSSUl!S and pc:nctnuCIi ph.allocytc.~ ""ell. 11Ic. CQfI1plcx has D long elimination halflife. nnglng from 40 10 70 hou~ rt'SUltlng from a combin:lnoo of $low USliUC release: lind a high fmellOn of proIein binding in lhe plasma (approxmkltely tJ(')%). Unhlc vancom)cln . tClCOplanln i~ not imlallng 10 tissue" and may be adnnmsterro by mtDmuscul1lf Of m,rn,'eoou~ inJCC, ion. Be caust' of ils IoIlg half-life. Idcoplamn may be ad nll nistered

C ....,Mn 10 AIlIlOO' ,..,"'/ Anllbi<1lln

351

"

..

","

o' 0
0

110"

'" -<'

0
I

'" -<'
,r

'"
,r

--<0 0'1
~

\'IH

"~

-<'
HO,,_ ,

_. ,........OH
",

,
-CH 2CH,CH~CH(CH,)Pi1 .cH ,(CH,>'CH(CIiJ, -CH ,(CH,),CH~ -CH ,(CHJ,CH(CH,)CH1CH, -C H ,(CH1>,CH(CI\1>

a temperature of 0
Ii
I

10

I .

mtlals preci pitate InacUVation. OTA also inacth'Dles boci lI'3Cm, 10 the disro\cry that a divalent ioo (i.e .. Zn l' ) for activity. In addition \0 being WDleT soluble. I soluble in low-molecular-weight alcohols but ot')!ank: $Dlvents. II-.eluding ocetOflC,

a i i .I addition of ac id. The salts from willi ion. wlIh

dfecl through mhibltion of nlUC'QPCP"dc ~"CII wall 'ymhc~i). lIS OCllon IS enhanced by ,.iIlC. A lllJough bocl1l'1K:lIl has found its widcst use in topical pparJtions for local infect ions. it is quite effective in a number of systemic II.Ild local infecuons I'.,lv:n admim~ered parenterJJ1y. Ii '" flO( ab..orocd from the gastrointcsllnal tract: occordin@ly. oral adlmnistr..atlOO i~ without effecl. c~cept for lhe IreaUlli'tlI of an~bic infecuons within the alimentary e Unll1.
PolymYlfln 8 Sulfate, USP. Polymyxin (Ael'Ol>porm ) wasdJCQVered In 1947 alnloO'l simuhaOC'OUsly in tlu scpa rate lnbornlorics in the United SIale!> and Great Brn ain.1olII lJQ /I.., often h~flPCn~ when simIlar dtscoveric, ore m ade In .... idely sepamtctllaborntorics. dIfferences in nQI1~I1' clalure. rdcrring to both the antibiotleproduci ng orglll1l~nt and the antibiotic itself. apptall!d In referrnces to the pol). myxins. Slott lhe org:utl~ms first tksignalt'd as B<...iIIfI.J prJ' /ymp:a Ilnd H. aUOS/N,1'JU Grttr I'.CIl: found 10 be Klcnucal spco;:ies, the name H. /H)(IIIJ.I'.m is u-.c(] to refer 10 all of tlu: strains !hut produce the closely rclalc(] polypeptides lulled pofymy.uns. Other organ isms (e.g .. sec CoIistin" below) also produce poI)'myxins. ldentifitd \00 fM an: polymyxins A. B,. 8 1. C, 0 " 0 ,. M, oollSlIn /I. (polymYXin E I ).coh~un B (polymYXin E:z). circuhn~ A and 8 . and poIYpC'pI'l1. 1lIe

IdlVl1y of bacilroclll is measured 111 IInn~ per mill! potency per milligr.lm IS IlOI les~ than 40 US !>

exC<'pI for malerial prepared for pall!nlcrat USC'. D potency of IlOI ~s than 50 unilVmg. II is amiblOlK: 111<11 i~ ocli,-c against a wide vaJH:ly
I

It

few Gr.un-negativc organII) exerl il~ boctericid:11

"

known structUre!! of Ih,s group and their IlfOIXn,C$ hne been

"!he sulfate usuaLly is u5ed in medicine bceaU5C. when used systemically, it cau!'('s less kidney damage than the 61MI'$.

reviewed by Vogler and Sluder.m Of these, polynl)',Iljn B

oit acid (isopdargofllc acid). a fallY acid ,soIaled fn:JIII

of the other polymyxins. The 8 1 component Conlll,". isooclanoic acid. C 1H 160 1. of undetermined ;::~~= SlrucruraJ formula for polymYilin B has been synthesis by Vogler CI al. ll ! Pol)'m)'xin B ~1I1rale is IUCful against man)' Gramp tive orli:ani~m.s, Its mam use in medicine has been in Iopal applications for local infeclioos In wounds and buml. fir ~uch IUC. II freqLlCnll)' is combined with bacitrat'ln. ..W is crr~th'c against Gram-posith'c orgamsms. Po/)m,...1 sulfate is absorbed poorl)' from !he gllStll)inresllllll ua:t therefore. oral administnuioo is of value OIll)' in the tn::l menr o r intestinal infections such as pscudomon.al CillU.

Polymyxin B sulfate is a nearly odorle.~s, while to buff powder. It is freely soluble in WlIlI:r and slJ&iuly solubJc in alcohol. lis aqueous wlutions are slightly acidic or nearly nc:utral (p H 5 10 7.S) and. when refriger.llw.. stable for at least 6 months. Alkaline solutions ate unstable . PoIymyllin B was shown 10 be a mixture by Hausmann and Crnig.:!.Sl who used countercurrent distribution techniques 10 obtain two fl'llCtions Ihal differ in SITUClure only by one fauy acid oompcmcnL Polymyxin 8 , ('omams (+)-6-mcthyloctan j

, , C1HJCH,-CH , ,
NIH I (H,C),CIiCH,- CH I

Nit CO
CH -C~H,

CO '"

cb I
I

CH-NHC"O~C-NH-CO-CH- NH--co-cH-NH -CO-(CHJ.-CHCH,CH,

CH"CH,NH, I

CH,CH,NH, I

~
I

~Hl~-CH

cp Nr ,

I H

I CHOIiCH,

~
NH , CH- CHOHCH,

CO CO
NH HaNCHpt,z-CH

, ,
,
,

Co'

NH

ChIllI,.,r HI Am,bacltrial "'nliblOlks

359

iIf1lOlU due 10 Shigt'lfa spp. It may be g" en parenterally

, mtmnuscular or Inlrathc:cal injc:ctioo for system ic infeeThe dosage of polymYlI.:in ~ measurrd in USP units. milligram contAIN not Ins than 6.000 USP units. Some altuooal confusion on nomen.ciluure for Ihls antibi04ie ~lI Wallie Koywna et al..!)oI originally named lhe product )'(in, and that namr i5 used still. Pank\llarly. il has the basllo for '1Irianl5 used as brand names. such as ( d)Myein, Colomycin, Colimycinc, and Colimieina.

anesultolUlIe (ColyM yein M), the mcthanesulfonate radical is the anached alkyl group. and a sodium ,alt may be made through each sulfonate. This pro"idesa highly water-soluble compound that is "cry suitable tur injection , In the cnjec!able form. it is gh'cn inlramuscularly Dnd is surprisi ngly free from \Ollie rellCtions compared with polymy .. in B. Colistimetnate sodium does not readily Induce the (\e"clopment ofn-sistanl strai ns of microorganisms, and there is no eviden.ce of crossresistunec with the common broad-spectrum antibiotics. h is used fur the same conditions mcnlioned for colisti n.
Gramicidin. USP. Gramicidin is obtained from t)1'Olhri cin. a mixture ofpolypcpudes usually obtained by utl1lCtion of cultures of fJllcif/UJ brel'is. Tyrothricin was isoluted in 1939 by Dubos n7 in a planned search to find an organiwc growlDlI in soil th.;!.t wou ld have antibiotic activity against human pathogens. With only limited use in therupy now. it is of historical inlCl"C!it as the first in the series of II"lOlkm antibiotics. Tyrothricin is a white to slightly gray or brown white powder, with lillie or no odor or taste. It is practically insoluble in water and is soluble in alcohol and in dilute acids. Suspensioos fordmical Ule CDn be prepared by adding an alcoholic solution to c~lcu luted amounts of disti lied water or isotonic saline solutions. Tyrothricin is a mixture of two groups of antibiotic compounds. ,he gramicidi ns and the tyrocidincs. Gramicidin! are the more active compon<'nts of tyrothricin, und this fT1llC1ion, ....hieh is 10 to 20% of the mixture. may be scparaltd and used in topical pn:parutions for the antibiotic cffect. Fj"e gramic.idins. A2 A). BI B~. and C. ha,'c been ident irled. Their StructURS ha~e been proposed and confinned through lyntheslS by Sarges and Witkop.ZJO The grnmieidins A differ from the gl1llllkidms 8 by hl"ing a trypophan moiety subWtute(! by an l.-phc!ny lalanine moiety. In gramicidin C tyrosine moiety substitutes for a tryptophan moiety . In both of the grnmieidin A and B pairs. the only diffCl'Cnec i the amino acid Iot'ated al the end of the cham. which has the OCII lral formyl group 011 it. If tlult am ino acid is v.tine. the compound is cither valine gramicidin A or valine-gramicidin B. If lhat amino acid is isoleucine. the compound is isoleudne-gnutllcidin. either A or B.

CoIinio Sulfate, USP. In 1950. Koyama nnd eowork~ !mlated an antibiotic from Al'roOOcifl"$ colistinus (8 . ~lII)';W ~ar. coIisllows) lhat was gh'Cn the name colistin (d)'Mycm S). h ..... as used in Japan and in some European years before it wos made a~ai lable fo.in the United St311:S. It is recommended espeof refraclOf)' urinary unct infections ~ by Grnm-IICiath'C organisrru such as Al'roOOcrl'r. 110. f.schuichia. K/I'bsielfa. PSl'udomorias. Sa/mOo and Shigl'lIu 5PP. (bernie-atly. colisti n is a polypeptide. reportl'll by Suwlci '" ",hose component IS colistin A. 111ey probelow for colistin A, which differs the substitution of D- Ieucine for the amioo acid fmgments in the structure. Wilkin ~n and Lo ...eUo> ha~e the Structure and have sho ..... n ma l colistin A is poIymyllin EI . T'IrO forms of colistin ha,oe been made. lhe sulfate and forms are available for use in the is used to make an oral pcdilllric .,;;~,, ; is u5('d 10 make an intra state. the salls are stable. and I stable at OCid pH from solutions are 6. Abo\'e pH 6. solutioos the sailS are muctl less

ho;;

....

armno

USP. In colistin. lh-e the ct-aminobutyric II Ii ' sodillm

NH- CO I I (H,C)zCHCH,-CH CH- CH,CHaNH, I I CO NH I I M-i CO C~HIIH: ~ CH, I I I I I (H,C),cHCH.-CH CH -NHCO-CH- NH-CO--CH-NH-Co-CH- NH-CO-(C~.-CHCH,cH. I , , 00 CH. CHClHCH,

, , , ,
CO

NH I HzNCH,cH.-CH

CH. , NH

H,NCH.CH,-CH

NH I

CO CO I I

, ,NH

CH-CHOHCH. I

COIielin A (Polymyxin E,)

l-Val-Gly-

.-Ale o-l......-AlII- &-.........-val &-Vai- c-Trpo Ktu- .-T,p- !>-leu- .-ll'p- o-leu- .-TrpoNH
vaIne . IIf8ITOcIdin
A

'""'"
I
(CHm

?"

",,_0

?"
I

I ,-"'leu-Gty",,_ 0

,-AlII- D-Le\I...,AIf,

.,.v.t IN'' o-Val- c' Trp- !>-leu- l-Trp- o-Leu. c- Trp-

0-""'" I..Trp-NH
CO< I

I l-Val-Gly-

......... o-Leu- l -A!a

I)-VallV.~

'''\'* o-va/- l-Trp- C)-Leu- .-Phe- D-L..... . Trp c-leu- l-T.p-NH

e
(CH,),

Vah -1I'1mk:idin

?"
I

........ !;>-l""- l -A/a D-Vlll-l-VaJ- D-V8I- LTrp- o-l _ .-Phe- p. ....... L-Trp- o-Lau- .-Trp-NH

II mixture of lyrocid1l-.es A. 8 , C. and D. ,,~ struclu~ hau: been dclcnnirtCd by Craig and l'O",ori;ns.:~ m n.e 5), nlhe,;J of tyrocidme A WIIS reported by OIino el :II. lI'IO Tyrocidiroc:
j.

~llcntlon but do IlOl fall

11110 any of the pre\'loIHly con~::".~~laI;

L-Val

,.".

I-

L'Om -

.-Leu _

,Z

...Pro

groups. Some of these ha\"C. quitc specific acll\ itie$ ."'i a narrow spectrum of microorganism~. Some na\'c f_1 usefol place m therapy II> substitutes for OIhcr InlibiOlict.1f which n:sislaoce has dc\cloped .
Chloramphenicol, USP. The liN of the widely \lilt brood-spectrum antibiotics, chloramphenICol (CbICit:llJlf cetin. Amphicol) W.lS l.IoOlated by Ehrlich ct aJ .ZfI.: In 19-1Thcyoblailll:d it from SIrt'IHIJmYUJ l~nrJlda .., .. found in a sample of wil collected in Vcnclltela. chlofDmphenicol hn.~ been iwhlled IU a prodUCI of orgoni,ms found in soil 'i;lmples from widely :;epaiM places. More impomm ly. its chemical ~truclOre was. lished quickly. and in 1949. Comroulis ct al.tco. rcporled sy nlhi:sis. This opC'ncU the Vt"3)' fOl" the COIllntercial,.... tion of chlor.arnphenicol by. totally synthetic mult. h the lir.;t and MI ll is the only therapeutically imporlant ;;... otic 10 be so prodoccd in oornpctilion with miC1"Obl1JloP:tl procc.~!oCs. Diverse sy nthelic proccdure.~ have been WI!oped fur chloramphenicol. 'n.c: commercial process po pJly u.<.ed Slans .... ith 1,_rntrOOcetophc:nonc .:IM
~

- ,."" - "'" I I

...,

I ,
Z

lIfiUiJdi ..... ,..

l\ioodllio'lfl B
T)'I'OCIIine C;

_0

... . ... . ..... . ... .

L-Ty.

NO<,

....

.".
o-Ty.

,.".
LTY"

o-i'l.

. ".

Gramicidin acts a5 an ionophore in bacll;'rial cell membr.me.~ to cau-.e the loss of poIDssium iOfl from the cel l.161 Ie IS baclcricidal. Tyrothricin and gramiddlll are C'ffectil'e primarily against Gram-posit" ,c organisms. 'The,r uo;e i~ rc:stOCIW \0 local appi icalion ~. Tyrolliricin can cuuo;c IY'is or erythrocytcs. which makes 11 un_unable for the tremlllcnt of systemic i nfel,!lions. lis applieation~ should avoid uil"l:Ct contact with the blood~I"\'alll thn. Ul,;h open woonds 01" abrasions. It is ortlinarily l safc 10 lise tyrothricin in lroche~ fOl" throoit Infections. as it i~ IlOl absotlxd from the gaslmnlestin.:11 tract. Grumicidin is a\"3ilable In a \ariety of topical preparutioos COIltaining other anllrnotlC!'i. ~uch as bacitracin and ncom)cm.

CI ...... 11jIo'oenicoI

UNCLASSIFIED ANTIBIOTICS
Among che many hundred..~ of antIbiotICS lhat h:&\ e been evalualed for acll~ity . SC\'erdJ ha ve gailled ,ignificllnt clinical

ChJOfDntphenicol lS a ..... hile. crystallme compound tba very stable. It is very sol uble in alcohol and othl:r pdf orgllnic !>Olvents but only slightly soluble in water. It bai. odor but h.as II very biller castc. Chloramphenicol JlOl'sesse5 1,"'0 chind carbon acOlWl che tIC) lamidoprop."lIlC<hol chain. BiologICal act h1ty~_ all110St exc1usi\'ely in che rHhrw isomer. the L-IIt'"' the I" ond 1..40")lltro Isomer.; are vinually lIIaclhe.

Chloramphenicol is very stable in the bulk s[:uc and in <did do6age forms. In solution. ho..... e'~r_ it 5lowly under. tm V1fioos hydrolytic and Iight'Induced ~aclions.w 1lIc IW2I of these n:acliOll~ depend on pll. n.:0I1. and light. ~I y.

SlI/mOtltllfll)'phi. S. ,mtumOl1iat. B.JfIIgilis, and N "ltn/II-

i)tic Il'actioru; inc lude gencral ocid- base-calaly.red hy~)'si~

of the Ilmide to II' Ie 1-(p-nitrophenyl)-2-ami nopropil-IJ-diol and dichlorooccllc acid WId ulkal inc hydrolysi~ IIbooc pH 7) Orthe a-chloro groups to form .hcCOi,espond III o:r.o-dlhydroxy deri\:ui\'(~,

Themc:tabolism of chloramphenicol ha~ been in~CSligated tnoo&h1y. - lhe m~in path in"ohc:..~ formation of the 3O-,Iocuronide. Minor reacliol1~ include reduction of the /1IiInI group to the aromatic uminc. hydrolysis of the amide. a;I b,"drolysis of the a<hIOl"~mmido group. fol lo .. cd by tdKtion to give the com:~pondmg a-hydn:nyaccl)1 deri~a of ccllain bacterial spc:<:ics are re~i~hml to chlorI!IIpbcmcoi by "inlle of the obi lily 10 produce chl orampheniODIlCdyhl1lnsfmasc_ an enqrne thaI acely lalCS lhe hydroxy III the I and J positions. Both the 3-~eI0;ly and the ~Ioxy ~Iabohte!. I~k antiOOclerialllCtivily. ~'umm;JUs ~truclural analogues of chloramphenicol ha~e Rea 5)nl he)i~ed 1 provide a b;L for corre lotion of struc 0 Sis . . l\) antiblOlic action. It appean;. tllat the p-nitrophc:nyl may be ~ploced by other al)'l ~,ructUn:'li ...iU'OO' ap...;;...; \o<is in X li\ity. Sub\tllutioo on the phenyl ring ~I-eral diffeTent types of groops for the nitro groop, a II!)' unu~ual ~tl\lCture In biological products, does nO! ptatly detre:l'iC acliv ity. AI! ~uch compounds yet tested are K'\i1"C' than chlor,unphenieol. As p;trt of a QSA R study. t'I al.!!>? reported that the 2-N t-ICOCF) derivative 1.1 blllCS ruI ~I he .<. ch lor.tmphcrncol agailllll Ii:. coli. lIOOlflCalion of the side chai n sho"'$ Ihat it POS~selI high ...,fll:lly in 'ilructure for antibiotic act io n. Con~ersiOl1 of fir Ikohol gTOUp on C - I of the ~ide chain to D keto group appnriahle loss in xth- ity. The relationship of the of chloramphenicol to its antibiotic activity will bt IetIl clearll..untllthe mode of action of Ilti'> compound lIo-<t.D, Bruck rcpons on the Imlle arnount of research bzi ~n dc\'Oted IU tltis probkm. Ch lomrnphenicol u lb ilxleriO'>latic atlion by 0 strong inhibition of proIein ~. The details of ~uch IIlhibitioo are m. yet undeterand lhe precise point of at'tion i) L1nknown. 1)lng bct ... een the attachmcnt of amino lK'ids to and the final fOTlnation of protein appean;. to he in-

Stnlin~

gil/dis, 8ecause of il~ penetration mto the ~nttal nervoo", sy!ilem, chlOl1llllphcnicoi is a paniC\ll:uly unporlam alternative therapy fa.- mcnmglti '>. It is not recommended for the treat ment of unnal)' tracl mfections because:i to I{)'l- of till' unoonjugmed fonn is e~creted in the urine. Ch loramphel\ k:ol is also used for the \featmcnt of ri cketts ial infechoos, "ucll ruI Rocky Mountain spOiled fevCt'. IkaiLiSC it i~ bitter, Ihts antibiotic is oommi5tered orally either in capsules or as the palmitate c.~ler. Chlorampncnlcol pallllltate i, in~luble In "'ater and may be suspended in aqueous I'ChICIeS for Itlju ld dosage fonm. 11Ic e,ler forms by reaclion "'ith the bydrox) I ~roop on C-J. In the alunentaT)' lr"oICt, 1\ is h)'uroIYl.ed slo ... ly 10 the atlile antlhlotlC. Chloramphenicol is oonunisterro parenterally as an IIqUCOllS suspcn'<lOn of I el)' fine ~tllis or ruI a !>Olution of the !>odiuln salt of Ihe succi nate ~'Ier of ~hlornmphcnicol . Sterile ch loramphenicol sodiLim '>uccinate has been uiOCd 10 prepan: aqueOIlS 'iDlution- for 1I1U'1llel1OUS in)CCtiott.
Ch/oriJmpMnicol PiJlmitiJte, USP. Chloramphenicol palmi tale is the pal mil ic ocid ester of ch lOl11mphcnk:ol. 11 is a ta~lele.~s prodrug of chlommphrnicQllntended for pediatric Lise. 'l'be ester mu"" h)'droly-le in ~ i \o follo"" ing oral absorption \() pmVllk- the actlle foon. Emitle <>erum Ie"els "'~~ assoctated with early f()f1llulat;ons of the palmnate, but the manufaclurc:r claims that the bio~natlubihly of the current preparalion is comparuble to Ihal of chloramphenicol It<;elf. ChlOI'iImphfi'nicoi Sodium SuccimJte, USP. ChIorJm phenirol sodium succinate is the waler--.oIuble ~"um salt of the hemi~ucdnate e~ter of ,hlornmphcnicol. ikcuuse of the low solubil ity of ch lorumphenicol. Ihe sodium ~uccinate is pn:fcm:d for intTllvcl10US administrallon . 'The al'ai1 ablhty of chlommpbeniool frot1llhc eMer followmg inll3'enou~ administration i~ c:stimated to be 70 10 7~": the reJn;llndcr is c~c~h:d unchanged. - 17D Poor 3\'ai lab1llly of the active form from the eSier following intl3l1lw.cu lar injectlOO pre_ cludes auaining effective plasma Jevel~ of the antlbiOlic by this I'OOte. Or.tlly admllli~tcn:d chlorJmphcnicol or it.~ p;tlmitate cster actually gll'cs higher plasma Inels of the acti'e antibiotic than does intl3,eroou.~~ adnllnISl~n:d chloramphenicol sodium SLlCCmatePO, 1 I Nooelheles~, effective cOflCcntmlioos are achieved by ~I t her rullte, Novobiocin Sodium, USP. In the .\Carch fornc:w antibiotics, three different re-carch groop" Indep<'ndent ly iwlatcd oo\'OblQCtn, ~Ill.'plooivicin (A looln)Cln) from St",pwmyus spp. (t was rc:poned first m 19:i:i as a product of S. f"ht'rQ;{/es and S. ";''eus. CUrTcml y. it i~ produccd from cullLlrc.~ of both species. Unti l tht: common identity of lhe prodUCl' obtllll1<'d by the dim'rent research groops Wrul ascerTained, the nammg of thiS compound was confused. Ill> chemical idl:nmy "''3$ eslabli shed as 7-[4-(CarballM)lo~ y)tctmh)'dl'Q-3-h)droxy:i
mclho~y 6,6- dimethylpyrnn2)' lo~yl-4hydroxy-J- 1 4-hy

1"'.

1")

(' ro1

~~~
~,",

b-

ld II ~ IdueW U\

Itibl1~ ;a1

e~'cI

s.:"ne

coner-

"".

:
....

~~:~~~,~,~::~,~"'~""~;:dru8" madeof serious blood Ii I . instances it an extremely

In\IlII>

Tlr broadspectrum acll\ity of chloramphenicol and it." effectj,ene"s in lhe lreatment of !lOme in(ecuons not

und other to~ic lIu~-c re~u llcd from the .oo.oos and w idc~prcad usc of chluntmphenleol in the kausc: of theiOC reactions, it i, recom~ndc:d thaI it in the tn'atOlen\ of inrOClion~ for which other ruI effccl;'e and IL!SS hazardous. When propCW1: ful ob<el"\'ation for unloward reactions, prov ide, !iOllll' of the very heM !heropy for 1 of serious infecl ions.is recommen&ed spirteally for lhe iOCrlOOS infecllon) caused by stl11ins of GrdmGram-negatl\ e bacteria that hll"e developed re o 10 penledlin G and :tIllpicillin. ,u{;h as I/. inj1ut!II;:JIt!,

droxy - J (3 methyl -2- bu lenyl ) benluillioo 1- 8- nlClhylcoumarin by ShLink eI Ill .TI~ and Hocl.cma et a1. 17 ' and confirmed by Spencer t'I al.1U n~ Chemically, oovobiocln has a ullIque -llrocturc: among anlibiOlics. though, like SCI eral others. it JlO"iOCSSC~ a glycosidic sugar l1Ioiety. 1lIc ~uKar in no\'oblo(: in, devoid of ils curoa-

mate ester, has been named fli1"iou and is an 1I1~ with the configumlion of L- ly~O"e . 1lJe aglycon moiety hps been I~rmed nO'Vlbio.;ic llcid. No\obiocin is It pale ye llow. somewhat phoIoscnsiti"e compound that crystalli~('S in tv.oehemically identical forms with dIfferent melling points (polymorphs). II is soluble in ~hanol. ethanol. and acetOllC but is quite i n~ublc in less polar 'iOlvents. Its solubili ty in witter is affected by pH. It is readi ly soluble in basic solutions . in which it dcteriomtes, and is precipilau:d from acidic solu tions. It behaves M a diacid, forming two serk-;; of sall$. The en-ohc hydroxyl group on the coumarin moiety behaves as a nnher stroog acid (pK,. 4 .3) and is the group by v.hieh the commercially available sodium and calcium salts art formed. 1lle phen-olic -OH group on the bcnumido moiety also behaves as In acid but is weaker than the former, with a pK, of 9.1. Di~hum S3lts of novobiocin have been prepared. The sodium salt i~ ~tablc in dry air but loses activity in the pn"SC1"ICe ot IIK)lsture. TIle calcium salt is quite Waler insoluble and is used to make aqueotlli 0011 suspensions. Because of il.'i ncidic ch:anlcteristics. OO\Iobiocin combines to form .!-alt complexes wiLh ba)ie anti biotic$. Some of these v.l1s h~ve bo!cn investigated for their oombincd anti _ biotic effect. but none hu been placed on the market, as they offer n-o advllOtage. "The action of novobiOCin is largely bacteriostatic. Its mode ofacllon is IlOl known with cenailUy,!hough it does inhibi t bacterial protein and nucleic acid synthesis. Studies indicate that novobiocin and related coumarin-containing anti biotics bind !O the subunit of DNA gyrase lind psibly interfere wilh DNA supercoili nal7flllnd energy trJnsduction in bacteria.1n The effecti~eness of n-o,'obiocin is confined largely 10 Gr.'Im-positi"e b;Actelia and a few str.'li ns of P. .... /garis. Its low activity against Gram-negati\'e hatteril is apparently due to poor cellulllF penetnl1ion. Although crosS-resiSlWlCe to OIher antibiotics b ~poned IlOl to develop with novobiocin, ~sistant S. ao,,",WS strains are known. Consequently. the medical use of novobiocin is n::;en'ed for the trelltment of staphylococcal infections resiSlDnt to other ~ntibiotics and ~ulfas and for patients aller-

gil' 1 these drugs. Another shortcoming that limits the ~ 0 fulness of novohiocin is the relatively high frequellC")' ri adverse reactions, such as urti caria. allergic raslw:s. hc-patGtoxicity. and blood dyscrasias.

Mvpirodn. USP. Mupll"Oein (p!oeUdomonie acldA,b: troban) is the major component of a family o f SU'lK'IIIrIII! re lated IIntibiOlics, pseLKIomonic acids A to D. produced ~ thoe submerged ferme ntation of PuudomllllflS fluQnKtIJ. Although the antimicrobial properties of P. flIlOrt'SMlSWm recorded M early as 1887. it wa.-; not until 1971 that F,,1Ic! et :.I.n, identified the metabolites responsible for Ihi, Itti. lty. The structure of the major and most pG(ent meuIJoIit pseudomonic acid A (which represents 90 to 95% rJ active fraction from P. fluoresce/IS). was later confirmed IIf chemical sy nthesis1N l0 be the 9-hydrox)"oonaooic acid~ of monic acid. The use of mupirocin is confined to ex ternal applations. ZIG Systemic admini.stration of the antibiotic: mpid hydrolysis by eSlerases to monic acid, v.hieh is i _ in vivo because of 115 inability to penetrate bactcria. Muprodn has been u.sed for the topical treatment ot impeti", eC7.ema. and folliculiti s secondarily in fectcd by SUsceptl bacteri a. cspecially staphylococci and ,B-hcmolytic strtpoloocei. The spectrum of antibacterial activity of mupil1Xill. confined to Gram -posi the and Gmm-nea3th'e cucci. incW ing ~taphylococd, streplococci. f'ltisstrio spp., and M. rt8r/!{j/is. llIc: activity of the antibiotic against most Gram!Itt ative and Gram positive bacilli is genel"lllly poor. wIth. exceplion of H. irlfl"~,,:{Jt!. 11 is not effective again.t entailoocei or anaerobic bacteria. Mupirocin interferes with RNA :6mhesis and proIcln~ thesis in suSCC"ptibk hactrna.:nl. It specifICally 1Dd", \ersibly binds with bacterial isoletIC)'1 transfer-RNA J}. thase to pre"em the ilKOI potalion of isolctlCinc into b;oclmil proteins. m High-kvel, plllSmid-n1C(hated .. talloCC in S. Uur~u.f has bc<-n attributed to tile II modified isoleucyltRNA that docs not bind Inhoerenl resistance in bacilli is likely due to penetnllion of !he anribiolic. -

resuru.

, , '"

o.ypl" r 10 Am,hue/rOOI,o,mib.orlc,

363

,
o

"/',,,/
o

Mupuocin is supphed In a w3Ier-ml'iCibic ointment cong 2% of the anubiOlic in polyeth)' lene glycols 400 and

""

OIIitwpristinIDalfopristin. Quinupristinldalfopnstin ~)lIn'rid ) is a oombinm ion of the strcplogramin B quinu-

n..ith the strc plogrnmin A d:llfopri stin in a 30:70 tal lo. , ,od i 13 Jla. respecti'ely. and therefon: are suiu -

?i~~~~"'~~~;''f'~"~";~'i~'f:" ~;n'~'~"~'i:;,~a 0' ~

. in fennen-

11IlrI'"roouS admmi stmlion only.

of lIC1hity of quinupri slinldJlfoprisli n is _ .,again1 Gnlm-positi"e bacteria. The combination is Gram-positive cocci. . S.

tk

~m

"'"

cidaI against strrp'ococci and I1la11)' slaphylococci. bul bacteriostatic against . lardl/Ill. Quinuprhtin and dalfoprislin are prolcill ~ynlhesis lnhibi10I'!i thlll bll1d to the 50S ribosomal subunn.. Quinupnsun. a type B slteplogr;tnun. binds at the same SIU: a.~ lhc mllCrolides and has a si milar effect , resulting in inhibitiQn of pol}peplitle e longation and early temtination of protein syntk~i s, Oalfopristin binds to I site roear that of quinupristin. The binding of dalfopriSlin ~ulls In a conformational change in the 50S ribosomal subunit, synergisti cally cnhandng lhe bmding of quinuprhtin at its targel site, In most baeteri~1 species. lhe coopcnlli \'c and synergistic binding of these t ... o compounds to the ribosome is bactericidal. Syncrcid should be: re~r.'ed for the u~mrnent of M'rious infeetions ca used by mullidrugresistant G..~m-po<;ithe organisms soch as ~aneomyein-ltSi,tanl Jaf'dum. Lmcw lid (Zyvo~) is an osa:.olidin~'<Iiooe type antibacterial agenl lh.:tl inhibits bacterial protein synthesis. It acts in tile urly translation stage. preventing the formation of a functional initiation c()llIple~, Lincwlid bInds 1 0

lInezolid.

The combination is mostly i

again~1

;;;~;;;

orglUlisms. although M. I;(l/orriwlis and spp. are s uscepuble. The combination is baeteri-

P rilllrIamydn IIA

the ,lOS and 70s ribosomal 5u bunit$ and ~"enl~ initi ation complexes in ,'01~Inll the~ subunits, Coltectile data ~u~e~1 that the oXlIlohdlooionc' fJ:Inition their riboWmal mlerae tiQn bel""C<'n the two subumK Formation or the early tRNAfMoo mRNA -7OS or 30S i5 ~nntcd. Lincwlid i~ a newcr \}nrhetic Pl!cnl. and hence. ero:.s-rcsiS!WlCe between the anlibacterial ugent and OIh... r inhibi tOl'"l; of bacteri~1 pr0tem ~ynthesi~ hlb nOl Ix'cn loCCn. , 0

REFERENCES
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Line7AlIid is a bocterilKtllti ... agent al!ain';! nlO!\l suscepublc organisms bul d isplays baclericidal octhity against soll1e Slrains of pneumococci. IJ. jroStlis. WKI Clostridium INrjnnlltns. TIle iooicatlOM for lrllCl.olrd lilt: fOl' complicated ;Ind un complicated skin and soft-tissue infections. community and hosptl:ll -acqUlrW rnc:umoma. and drug-rew;ulI1t Gr.ufl-posi Ihc mftiQltli. Fo.'pholllyCUl tromcllm mille (MonuroI) b a phosphonic acid epo~idc lIeril'alive tmu ",,-as initially i~l:ned from fenncnl:uions of SIn-IJ/(m'""("rs spp. The SltUClurr o rlbe drug is shown below. Maling tnc tmmctkaminc sah greally c~ panded lht therapeulic ulility of this antibacterial bccau'iC water <;()l ubihlY increa.'iCd enough to allo"" 0I'll1 adminl'>lralion.

pos~ses

13 Su,"~t. 11 ., ,, l'roc '1011 Acad, S<i. lJ S A 1561>4. 1911 14 Ct.w, II T. eI .1. The ChcmI'*'Y oI .~ .... t1 ... I'nIlCCU. 'II. 1'1'111<""" U"'l!NIy~.. I~. P 454 I ~ S~1wl. J C .. 0IIId Ilcntt)-l.opro. K II. J, Am. o..m Sec II 10119. 1 ~9 It> D...:hclor. f , II ." oJ_: Ill .. "", tU;H 7. t'oW n I C. - ' Frni.. J P J A.... Chcm. Soc 81 29t1. I'" 18. J P. .... I'uoIe. 1 W : J PILarm. Sc>. t(l;5OJ. 197t 19. HIoIIo. J 1>1 J Pbatm 'ici, /)5;IIM.1976. 20 S<h .....'''_ M ' J l'!wm. S<i, !I~.Ml. 196'J 21 Scto......n,-M A....... IIucI;" .. In. F It J 1'hann. Sc> ~1:lllt.l~ 22. hlOholl. P . J ..,..... ft . G. 1Iid 1(n...."",. It ; J PIoarm S<i.loIlf'

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13. s.:..,lman. A D.. IIid F.............. N R. J f'haIm. s..~ ~: 715. If' 24 S)W.. II. II . ..... Mon"," .... M J. A.!lrnierub. ('bco""",," lotll

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H. Du .... IC. JI<'lI>y. G_ It.. ud \ .......... A It. ...... imimlb,.". CIIocmoIher 39"1211. tm. 26 A,nbIci. II p. I'M T... I. II Soc, 1.urMl. 1 289-_nl. 19111'-.. 01
27, l.m~ W .. and 1I""""Ict. A An!lln;""ftIb. A,.nIJ ('!w -

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Fosfomycin is a Drood-'IJCCtrum. bactericidal antibactcrial tIw InhIbits tbe growth of .. co/i. S. nun-lIS. and Mrmllu. Klt'bm-liit. CitmOoclu. Entu/ICOCCUY, and l:."fllrro/xJc'tr spp. at a COllCClltr.lIion k:~~ th:!n 64 mgIL. Currenlly f(.fum)'!.'in is n:commcodcd tIS ~ tnilit-dol.c ther~py for ulK:Qmpli catcd unnary tnct mfcctions. It possesses in \ itro efficacy stnuJar 10 thai of nori1o~lICm and trimcthopnm.sulramc!hcn . 31.01c. "oo;fomycin covale ntly inOClivatcs Ihe ti~1 ClIl.)rnc in the bacteriall'e11 ""all b.os)nthesis pathway. UDP-N-acctylgluco..:unme enolpyrul'}l Ir~nsfcra.~ (MurAl by ull}I:111on of the cysleine -! Ij re~;due. The inactivation ll'3Cuon ac ... u.... through llueloophillC opening of Inc !.'po~idc ring . Rc~islallcc 10 fO!'fomycin can occur IhfOllgh ... hrumo~omal mutations thaI ll'~u1t in rcdllC\"d u))tale or reduced MurA affinll y for tnc inhibitor. Plasnlidrnediatcd resistance nlCChamsms in"olve conjugative bioinoctil'alion of tnc antibiotic ",ith ghnm hi01"1('. 1be freqlJ('OCY of rcsi~tant nllJlDntS in in vilro Sludie' hal; been low, and there arP'"ao; to be linle CrosS-I"CSlstance bet\\"('('n r~fomydn and other IlJUlh"lCtcriaJ~.

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1971,

.uo

2-12 IIun!. A II.. ~ 01. I Am. Chem s.oe 106.4891. 19lIooI, 2-13 8a/ll&. I C I .. .. al ,I Am. Chem. Sue. 106. 891, 1\1801 W 8 .......... R. N~ andl'l:lm.. 0 H. ON, un. 1'l'U 2.3 1010-. 8 A~" aI. Sc u I02.J76, 19-1' N6. SIoIfel. W ~ ond C.... L C' I Am Cheal, Sue, 1],145. l\IIb) 247 R....... C.,owIKa>lclibr.O.V, I Am.Cbeoro,So<.8!I.:!Oll.1'* 24K. 8c0l0di<'t. R. G.. owl L...nJlI)U.. A I'. J 1I><terio1 S<I.24. 1947 249 S\DIooly. P L .. 01" Rull . .IohoI> " '-"""111 !tOOl'- 11,.1, 1 7, .... A .... """"'. G C, .. al. ~ 111(1;261. 19-17 lSI, VO&In". K" owl Suodooo. R. 0: ,""po. ' lia ll:.J..IS. 191'i6
I~ VO&I, K~

!!It

m,

A.. a-.. Sue 76..,.,2. I"'! .. al, F~ ,." 2O:lt>.S. IW>I

w...... Co:ua, L C

2S<I, K<I) ....... y .. ..... J A""boo!. IA I J4H. 111.50. S."uki, T. ... II .. J Il1000hom. ~.41. 1963. 1X> wil.......,.". S~ _ I ......... L A., I Clem. Sue, 4107.1964

u"

1\15. 1.<O<fq.

R~

-=I C___ ,. P: Allllmicnlb A,eool>

a..01I0Ihn J5

1:!fo7. 1991, 1'lIfo ""~. J .l.L., 01 A .... - . . a..m.""", 2:81 1. 1951. 197 .... ,Ioy. P F .. J Am C"",,, k 'N606l. 1957 198 C.ln......... D.. J Am Oocm. Sue. 87 11101. 11165 19'1 C"",y. J . ot.1. J Am Chern. Soc 101:71]1. 1979. 100 SIopllcn .. C. V~ eo" 1 Ant ........ (1""'1"1 22:551. 1!loW 20 1 lIhIuI. L 0 .. ot aI. Cwr ncr. I(a; 20610. 1976 202 "'tll",- P G. ... aI J PMnn $0:. 68:lso. 1\17'9. lIll. Yol." O. J . ot II J a'D. Plw"'E .~ , 10625. 1980. Xi' T~ .. T. 8 .. ., 0" ~ 2\1.103. 19801 lOS, CfIM. u. 0_ Ik.~ . M 0 .. """ 1.clIo1. M Anllmicnlb. A,..nos C1cmolm J2;561. 198'J 206 T"""" ... PL ., '" AI'JII .).I"""""'" !8U9. 196\1 207 Janoct~ II S_ ot III. Cha. 1'ftIialf. (Plulo.) 14 1093. 1975

U7, Oooboo. R.I 1 br Med..70:I.I311 m. PIIMIini. A.. and C..... L C: 1 Am, Cloonu. 50:.><, 76111ll1. 19301 lj9 "' ..... T P~ .... Cral,. L C.: J AnI. Clem. Soc, n 627. I"" 2110 ClImI>. 101 ....... SIOU. Soc, Chem. Jpu. 19 17.\8. 19M
261.

262,
M}
~

2M,

S,"""''''. O. -'

266.
267 2b1!

:!M
211

lOI N","""'" P.

Z09 Dnnol. W

210. CI"""",. 21 I, 11(1/0. 7 . ., aI.: Am. 1 I'll)""" 110310. 1'.1115 ~ 111. S'W'I'II .).I C.. ond IlJoW. II P.' Ann. 1'IIamI>rudIn. 261 OW. 1m. 211 IIn.IM.O .l.L .,.1 1 Antlbo<ot.(ToL)oI4 11 (l29.19IIiI 114 hIcn. I) II.. Frwdcl " A.and M.. T." .... O ""'" 4( 7~ 1\1\11. 11', Court<r. F T, eo 01 AnI'n .......... 3'1 116. 1'191. 116. Rmplrn. R N. -=I PCIm. [) ". Dnrp 4lI;5iJ1\l. 1\1\14 217. Suboll. 8 A ~ aI An.ibKohcJ An.....al 1\ISol-1955, N.... Yorl. MC\ti ...1 &Ioycloptdol. I'm. p. 827, 111. lloo: ...... lm. F. A., ., aI.: 1. Am. Oem. Sue, U U27. 1960. 119. CtI ....... W O. JAm. Cho:m. So< 1111797. 196"i llU 101-. 0 J~ .. at AnI ........... AIfiII> Chc-",," $#. 1\l6l. 221 Ikd ....... II- .. oJ. I ....... Che .... So;- 116.4ID. IW>I 121. Skimp. 0 .. """ "'... I(~lbw. F A. I ....... o...n. Soc 89;2~~. 1967 2!.l 1I~ .. ,,"h. G 8." II J Chern. Sue C 12111. 1\170 ;!!.I MOfftIoIIl. 8 . I . Tt!nlIcdron I"",. W. 1<nO W ""","""II" A O~ .. at. I Am. Clem. Soc 116:.50u. 191).1 nt. M 4,,10101. B. J.. .. aI J MI'd. CIocm. 10-.113. 1%7, 217. IhFFI'l . 8~ J 0.... Soc', ~. T_. I 1!>Th. 11173. 128. 8_,-.1... 8, J ChcIOI Soc ........ ,ft T.-. LlO"..5. 1971, 129. 8..,~ . I O. fU,y I"rca. Ots. 1370. 1\179 2..10 SIII'J<"'. It.. """ \\Ill."". 8 JAm. Clocm Soc' lito 11161. IW>-! 231 SkOm. D II .II.....,.~ ... I, K. S~ and S ..... n... "'. P Ii, An"u, lie" Ilia-

~ Y SUoIc J MN.. n .lOIS. 1917 C~ -.I 001 ..... H C AnI, I 1>0" 0I01d, III 1146. C, M~ " 01 ~."", lnreel. 1>0. 1".)84.1981

no.

1\l7\l

271. 213
27. 275. 276 278 IN
2~

...,......Oonnoolber

m.

A ...... AIMlmoft. 0 S I Meml>r 11001 $\lU1, 1"1 8o,hch. I .... al' Scio;ncc 106:417. 1'141. CootroUli .. I. ot aI, : I, Am. Clc .... So.;, 7 1:2J6.3. 1114<j Loooc.LM . andTMlImaOI,II I) I A.... C!cm. Soc 1I:1<171.I~ Eooa. Anal I'roti.... en., s.o... ,. GIal...... A~ AN'~ ..,,>b. ....."" Che ..... 655. 191\6 11"""""- C. ot ai, J M<d a..... 11>;911.1973. 8nd. T. D, Cbloraonphenocolln $o:1w1l,Cf. R. J .. and Ib ... ...,.F (<<10.). fupm"leII,"1 Chemoo"""'f')'... ~, 1. Ne .. y....t. A<ad<loio: I'm IW>I. p. 119 SbaI, L and Marl .. 'I. I. 211;111. 19$4 KauIT...... R. E. ., aI. I. ~_ 99%3. 1981 K W 0 ... aI. J, CWo, PbaomIocoJI. 24 .1 81. 1\1801 Shoml. C, 11. ., aI. J Am. Ckm. So.: 78: 1170. 111:16 Ikcbrlna. 11.. .,.1, J Am. Chern. Sox, 782019. 19.1oto S,.,,,,e . C II .... al I Am . Chom Suc. 78265'. 19$6.. $p:..:n. C .. .. 01. I Am. Soc, 8&. 140. IIISS. Gellon.. 104 .... al ",""", Naol Sci II. S. A. 13 441. I"" SU,I ..... A~ .. 01 .. I'rt>.. Nail ,,<ad. Sc . II S It... 7~ 4141. 1m fIol .... A. T ~ ~ aI NOhrI: IJ.I 411\. 11171 C1>&ln. E. B. and Md"-. O~ J Cbem. Soc'. Pnl T..... , I ~

~in~.btdn.

1m

Dru"

,C].

o...ro.

"'*"

1977,
l'appa. K. A, J Aon. Acad. 1km..!oI. 281 lillllhfi. J ,ond ,

lan.

19\10
I~n

282 IIu""". J _
214
C~

2i3. Golt.t. J . I'cny. II10tbef )7,)2. 19\13.

1 0 .. C. C. and A,.nb C!cmoom )),156. 19!19,

o.nn.

00Id0nan. R. C. ' .....,..,.

SELECTED READING

aI AnI:i~ An","", I'1SS_IIlSto. New yurt... M.... Ea:y<h., I,' 11lSto. I'- 606 1J3 Shcldl'l<k. O. \l~ .. III. N......, n o 2J}. 1971. :tlI ...... 11 ........... M p . lno! .... ' " _ I), 11 J Am. Clem. Soc', 103. 65110. 19111 ill Ibm .. C, M C1 01 : JAIn Clem . .so. I ~6915. I'llil 2J6 Petl.,,,, H. R ~ Nieto. M Ann N Y AcwI. Sci. llLlU. 11174 l.I7 \\,.0 ... -.101 P~ "III TotnloNronlelt. 40-~.I\l84 D8 110 ........ C. T SC ....... 21>1)011. I'l'IJ 2J9 Pomon. F .. ., 01 .' 1 A ... boot:. (foLyol 3 1.27/i. 1978.
II .~

""'m 01(0:723.M1m !.l2. McC.noucl.

240. 1I.voI....., M II .. I'II~. M .. and C _ l1i. C .; I, Anflbiul. (I'''k)'\l) JU71l. 1918. l~ I Co.unclli. C .. ., II .. J An~bklI. (Tot~,,) 3762 I. In-t

1 1

. ...
ee.

Antiviral Agents
KltIN M BEAlE, JR.
\1!U1It!i

an: unique

organi~ms.

Th<:y are the

~nmllcsl

of all

,
,

elf-replicating orgllnlsms. able [0 pass lhroogh fillers thaI tetailI the .I.maJtc)! bacteria,' The simplest viruses conlJUn a : amount of DNA or RNA '>Unuunded by an uncompli proIem COOl. Some of the mooR: complu viruses hu,c : 1 Vi IIIpd blllycr mcmbr.me sUll'OUooing the nucleic acid. mu>1 replicate In Ii, Ing cells. whICh has Led many to II\.lI \ iru'iCS an:' IlOI c,'cn th'ing organisms but thai , MJIllL'how ui" III tht interface of Lhc IiYlng and the Hng.' n.e rfIO!,[ !sic requirement is for the virus 1 0 clll\tr prufoolld or subtle changes In the host cell 50 liral geJ1('~ are replicated and viral proicins ure ex ...~ _Thi, will rt'_~ull in the formation of new yiru.'ieS. Iy mall)' more than the number Ihu\ Infected tile cdl Ily_ Viru"-!" cond uct no metabolic Pfocc~scs on their : me)' depend mIldly on a host cell, which they invudc piI"lSlllI.e to subvcn subcell ular machinery. They use l1li of the cdl'J cqulpmcm for . i of viral nuc leic IIId (',pression of , irul cel l' s protcin all cell's eneraY Store! that . llle VIruS tums I cell 10 ilJi Oll<n purposes. wbvcnmg I cell. An mfcctlon thaI production of more: viruses than initialed the: I~ called apnxll<eli..,! infn:liQn. The: actual number . , i ruse.~ produced in an in fe.:ted cell is tenned l 'his can rungc from 10 to more than of ,'ell infected, the nature of )i form of life. I A typical will cnler lhe nuclcu.~ of the hQj;1 II . where tran~bed illlo IIIcssenger RNA (mRNA) by cdl RNA poIylllCTllsc. mRNA is lhen tr.Inslaled inlO thai fac:ilit.atc ~mbly. matunuion. virus into surroundi", tlSSUC:5. "",. their replication 10 S) nthesil.c mRNA. one type of nucleie acid Thi s featu re differentiau:!!

Nucleic Kid COOlent (DNA or II./'OA) Viral morph.JIIllY (Ilc:lk:ai. icus.1ho:drul) Silt of rqIIicallon in ~11 (cytopl~sm or n...,kllS)
Coating (w"c)opN or nonrnvdopcd)

Serologicaltypin, (anll",ooc .ign:uu~) Cdl t)~ ",r~trd (8 l)mphoo;ylC"S. T Iyrnphoc)le..

cyt~)

mt!fIO-

The Baltimore: OasslrlCatlon Schc:me4 (Table I I-I) gi,'cs an alternate Illean.~ of relating the different virus types. The following hsts some virus t)PCS togcther with d,, eases that they ClIU'IC:
RNA
.i",~: I'icum.\"iru~ ..

(poloo. ho:paliUj A. mU' o\lru,):

tfl&",'iru~ (rubella. equine c:occphalit,,): n3,' i,;JU~ (yell" .. (ev~r.lknglJC' (ever, St 1..tlUts tl1<."qlIIQhl;~): buoyaviru<o (en

DNA \"IfU~; ho:rpr$\lru.~ (he~ mid !oClfn); pIIpO'.'iruso:s Ipolyoma. ..-an.): ..."'" .fmeS (~r.ltOl)' <:Oml'laonlli); pro.' ifU~ (wnallpo~); 1""""0\ ,,'u, Ic~'1t( dIstemper )

rhlbdo"iruso ("C<lcul", JI'" tnelIsks); TCO'Iru...,; Of Ma,'IN5o:i /diantlca): fikl"IJU) (a...ta. Matbu'l); ~na"ifU>n (Iymphoo;y\oc dl()nomc~n.n"l.Js): ~"ruses (hul1"Wl Immu nodclkt(ncy ~yndronlt) (HIV )

~phahl". hemorrhagIC (~'~r): ltlllIitj, ); m)':o.(),iJU~ (mumps.

II has b\.-cn ~linw.tcd that ~ ,ruS('~ cau~!l"OOt"e than ~ uf the infectious disca.'\CS thM occur in the dc"eloping counn;c.. ' Bacteria l infe<:tion, 1tC~"O\lnt for only lSii-. Tablc 11 -2 pmvidcs a synop.,i~ of viru~ types with their possible therapeutic modalities.

"

TARGETS FOR THE PREVENTION OF VIRAL IN FECTIONS- CHEMOPROPHYLAXIS

Imlfttlnlz;;rtien
Prt!''t'ru'Qn of 'iral inrcctiOf\~ by confcmn, artificial/I' QC". quired QCIWt immmmy ..'uh vacc:incs is the main approoch

..

i dispersed

,
,

the: In the cytoplasm.

ho~1 ~"t:II:

iII't

classIfied on the basis of number of fea-

for prevcnting most virul d,seaSC5. Safc and highl)" dfc~ ti\ e vaccines lIrC available for the pre,enlton of polio. rubella. meas les. tllUlOP'\. innocnl.:t. )"cllow fc'c r. cnccphaliu,. rabies. smallpo:o. (now ~'()n.'idt:red 10 be e radiClIt~d lI<orldll<idc. but still of intcre~1 from a biological warfare ~1Undpoi nt) . iU1d hepatilis B. VlICdllC' dcvcklJlC(l to pre"cnt infccllon with herpc:svino$. EiJ'tcin-Hurr I inos. cytomcgalovirus (CMY). respiratory ,)ncytill! "irus (RSY). and human im munodcliderocy viru, (II1V) ha,e so far proved IIIcffe<:tJve or unreliable. The de,elopmcnt of a IlCW \'lICCine lhat is effecti,'c againsl a chronic di~ase-("au~ing \"Irus such IIS IlI V (acquired inullunodcficicncy 5)"ndrumc [AIDS!) can be a daunting ta.~l. lllc primary principleS of ,accine de\C1opment apply: llle ~accinc muS-! be ~urrlCien tl) IIl1llgcnic to

367

.................-------------------------------368

w,t.u", (JM O/$.'Olu', TUIbtxM: of Orga",'.. Mdle",,,/ aM Ph(""ttIUC~..ljCtJl eM,";'I,.,.

TABLE 11- 1 ealtirTlOnl ClassifiUltion Sdle me for Viruses

II SiVOlr.orl!kd RNA \'ItII>eS Al Poo.oIl""_ I' ..... R:';Ab~c~Iu ...... .,A) It ~n .... lopd
('J~

< I ""......~ (polIO, '

(tI)

(AI..,,,-,,,,"

he,-."

A. """"'...... )

LUI) PI.....""'" r~"".'" Ilf' I'korna>'l"l' h y ) MSl *""~ 2) ",.. dopcAI (a) Ie'lllh..... ..

IO TOC~ ...' ..~. (rub<II .. ""ul"",,,,,,,,,pbahlol. SmdIbI.) J Ltll ~lnWIJVSa {)~l_ <Joncuo! f......-} (10) Ikloaol
ii)

r._.

eoro....m..
but ~~ RNA 10 ... COO'''I1.CU 10 Of<IA .\ 'Irion-."""laItd "",,~mc ( .......... ""......,pWC)

8) .,.,..u",. _

I) ElMIo!Xd Lll Rcuo>"IfVWS (0) Or.;:omr.,ro;e,I

(01)
Larti.I~

NcpI, ........ '" RNA IO!'I'<"'''' "","",y lO<:dklllr.,\I(l'llA. .... I ) Ew<ck>p:d

(I) Ikll.:.l

'tl

a .........>Ociab:d "",,-lObq,n I,," ~ t)"1t)

(II M.... ltll~ i ...... .......,..J.. _ .... vlRlt. I""'lII'Iy""" ' ''', fikn iNtI h,) St"Ok ''"lip: EOe (CNtMmp_ ...... I~n...au.. _y ....... ..,........... ) II) 000I!Ie.1Ir'MId!:d RNA .. no.cs
Al
N~ k>pcd

I) 1e""Iotdta!
(I)

Rc<Mnl<

fb,
III )

Roll""'.
'...nI

s...p-.omn.Jtd DNA .iN...e.

A)

/'o!onm"',,..d
lJ
L.

(I) ....... ""1<\151:0 (,IN "" <Ii","""", adt .....

_'.II ",,,,,)

IV)

(bI ll ~'~,*,XI14 1)o.~lr .... JedDNA'_

"'l f'Juclt_ '"rhc3tl<,'Ol

n N<looen",,1ope<J
t.l kos' ....1

m SIlIAII(II.:\I.... DN....'H

(...,..".,..... SVotO. poI, ..DI.......,.. popil~)

l"') MII~m- .. >r<l.aIrI'I'ki~. hrarONA (aIIeio';NI) 21 Eiwelop:od-"",Ie_ 1)1",.1.,

fa} k~ Adi"

(,) 1kipe>,,"'...... (b_ON... )

(Ii I H"pAdno",... IviriOli t1iC..".idaiu RN ... lhII is _

.,.,1 '0 DNA by ""'COC '''''''''"~)

BJ Cycopt.mktq>lIC.....

I) k~1 'oed".1 (.) Indo;ro, .... 2) COItIIIIc>;$)'1tItdotU)' la) Poo>'lNS

c>_~

I) ~w"lIuoll

la' T ,Jotritl, ~.
I'b) 8 1C1COOp'1 .I.

Cha pl er II ,",'lIil'H"'/ Ag~nlI

369

TABlE 11- 2
fMnilJ' A!il ent
I N ,~

Class ificatio n of Viru ses Ca using Disease in Humans Vaccine ChemothNapy

\i...Polio; thrt:<' IoCn)lHlt< '" ... ,.. m<nill(1l," ponoiil Variety or ~,mptOfOll
CQO\n1O.lI1

"""""', 'N<

~""'"
r.u ...l .. vl ... :oeo

U ... IflIl ~,11ed """"'.... /.ery

.ffocuI~1 N~

1111180\',....

.QId.

pnruDI(lItO&

(01'''' 100

N_

.... rDllypt<1

""-

tkpolid. (.......lIy mild on<! ""ely

",,",,)

Ul>.,."",
~.I~

l'iN'

N_
"I1CfI\I&ICd '' .... licncrol1y

N_

'''~

~1!oU',nwo (M""'!'''

orboY'N>C$1 bbi""",
, lin",,,

err...",,,,)

",_
N_ N_
N_
N_ N_

Rlm1llJ"" IJI'OIIl' 1:1

""~)

I\qIlhDI C viN)
("""""

..

"'lCIl........ ".....
Yel"""
..... ph:ihlu. b<:llI<lr'rlIq;k fe""",

f." .... donp,

A~n..-l'!N.~ly
.rr"'1;v~)

"". ...... "...,

\...,uIar <t(lfJWU" "N'
'>!noq ,,""

llep:,"ns lIespillllory ittr"",itoto

"In""t"aItd \IN, (crr"",,,.)

N_

,N_
RI"',ir'in

a.. .w.
hal''''''''''' hnat/hItn,. 'N>

"~ N_
lIo.piritory Ipf<Cllon 1I pmllory inf.... -tion

N_ N_

N_
An. "IN virus (d(""" """,
~IIJ

"",,">My. )'!lCJ1ioI .-iN!

1Iorhlli-.r\l!( IIoapI ,in><
~""iN<
~"'\,

"n.""",1 An.""",..:1 I'm"

.'1_

(\j()'jI. .,(foc,h... )

"N_
AmaI!H...

..,.-

....
!'e-t... ,. ",oW flllu ..
""",,phalolJ<. htlilUl'l'hagic f.".,

A" ......I "N' (1(lW, .tftct,,,c)

~-~

--

N_ N_

N_

"N_
lIibo"","

!..._qtic cho.k"..rn,n,ni.

Me",,,,,to.
1I~"'(<wCf

'-M""b"""
t-"""

",\1><$

UclnlJtl'ila,;'" (ew:<
G3s1mn"cn,,, ,II Inf.m~

Colorado ."'. r.....

""~ ld'/lCr

...

"""1n.:,;1td .iN' (.(1"",1., .......

unkn(l\'t'n)

,...

...
N_
AZT. dd!. ddC. lt~"ud"..

AIOS ond AJDS",I ..I wmpk.<

(ARC)
T ..,.11 I(u\;~mii. J~lhp/lorrul.

...... ,II1V-l, II1V-2)

..... \It11.V-I,

_TIII}'~
H11.V -~)

TABLE 1 1-2
Family Agent
1)1'1' \ , 1..-

Classifia t ion of Vlrus.s

ca~ ing

DIMa M In Human s--ConriflONi

Olseas.

11u ........... ftorpe< \.Ompl<_ 1

...... ' ' 'Tot>. wn ....1"-"""" Cho.l< .,." (doiklml)............ ,"'1"1

~

,0-.:"'........

lnl",hun, 'ft

",..

,mnlll ...... """""",.. >I.

.nf<co ....... """""""1et!IoI>. HurLn . lymplofwna

luro ... h!d v...... I~m.:a.y

U"'-'ftWB'

,,1',,,,,,

(_101

1'Ip>oo.. , ,n!.<

"opo II"",~' """

1'uI~"m."'"",

l'tdJ!IbyU..

IK ,i",,)

"'"""~

11 ....... -.....'....

II_pod .., or,!> 11qIMi",B',n..

t_",lIO(d ",bum, htty

cll'u,t)

v..,..,..... ("",po. lt"orr

...."',;,t)

"tn,,, """
II~ ...."'''''' HI9

Et)lhenoa. ""'->1)1'"

,.

induce an effeah'e amibody re.~poo>e. elen in very yoong pa. tic-nb: the nlCcill(" must 1101 cause the dl5Ca<;C Ihall! is de~lgned 10 pn:~em OI'cau>e some O(hc!r toxic m::mifeqalion a" tlleearly killed vaccines did: and iOcally. lhe vaccine: shou ld produce a la~l ing form o rimmuniLy . wilh a minimum rcquircmenl for ~1C'r OOscs. lbese requl!'ClIlC"n .... are difficull enough 10 Il1CCI for ,iruSC', lhal cau>e acUle' infections. 1be chronic casc~ are mtlCh more compllCmcd. It i~ difficult 10 ole!'l.'Of11C Ihe lendency of 'OIlIC viru<;c,~ 10 undergo rupid mUlalion. leading to multiplC' anligcnic cpitopes: thi~ make~ developnlC"nl of a bm:KII) effccti, e voce,ne: much more difficul t.

Bloc;hemkal Targets for Antlvlra' TlMrapy

Wllh lhe dil.colery of anhb,utlcs and anll-ulfeclile agents. the sci.:ncc of tn:aung bacterial inFectlOl1~ 1I101ed For.o1lrd al u rup!d rutC'. The dcl'clopillCnI of u-.c rul antivir.ll agcnts (ani ibiOlk~ ami ul1!i. im l age illS). in con!m~!. has historicall y laggcd beh,nd. There are a numherof !'Ca~on~ forthi ~. Unlike bacteria. ,iru'loe'i ",ill 001 grow in simple synthetic culture media. They must mf~t human 01' untlllal cell, 10 propagale.' For c.'(nll1ple. the I1lO'! oommonly uo;cd cell cu llu re~ in "i",logy derive from pri mmc~ (inc luding hUlllan~ and monley~). rodcnl~ (includll1g hamsters and micel. and buds (especially chlClcn~). 1be'IC cullure method> are ,cry reliablc& and are in w,d\:."pread u-.c for the propagation of virus panicle,. bU I they an: ilion: dlf1iCUIt 1 pcrform than lheir 0 bacterial counlcrparts. HeIICC. drug-..c!'Cening tcehniqllC ""nh VIfUSC'\ ha"e Inen longer to ~.:uch up with t~ In

b;loCteria. Another po~sib1e reason for the Jag in ami l i,w de, elopnlC"l1t lie' in lhe comp3rutive "'ochemlCal ~.1llJlh;:t of \ mIstS I';s-!.-I' is bacteria and their U.)C of the biodltw processe~ of a 00<;1 ce ll. 11IC:re are fewer ~pccia lll.td ..... for poollemial allack by chemolher.lpeulic ugenls. The npt ~pcctllCul3l' SIJIXeSSO of Immunization procedures klr pn=,ention of certain I'irul di>eases may ha'e contnbWd. a relali,e lock ufint..:"rest in ant!I irul chenlOtherapy. A'* feRlllre of mild I' irul inFl'Cllons. such a~ is thai clinical syrnpiulitS do 001 appear n ,\ .. ell eslabh,hcd and the immune processes of the ha' c begun !o moum a succes,ful challenge:_ Thu.\. fOf common I'irdl infections. dlCIIIOtherul'Y is Simply Il0l proprla!c choi~'t of trcatnICI1I. Chcmotherupcuti~ 3gt'nlS" nc:edcd. ho" e,er. 10 comlmt I'irosc.' Iha! cau!iC ~I~" chronIC infecllons. stICh a .. cncephaliti<'. A IDS_ and panicularly in patients with COl1lpromi~ Immune!<)

TH E INfECTIOU S PROCESS FO R A VIRUS

l)c'p,tc the ir ~ ' lOplic;ty ~Iath'e 10 bacteria. viroSC!> ~II p sc<,s ~ l'~rie1Y of bi ochemk:l l lurgets fur polcntial alla;l.. chcmothenspeullC agents. An app"'priale ehemlal pound may intclTUpi each ofthcsc_ Hence. a thorough ~Ianding of the ~pccirlC bu.w.:hcmical e, enl~ th:it ()CC'UI' .... ~irdl inFection of lhe hos1 cell silould jluidc lhe di"CUI~ sile-<'pccific Ilnlivirul agents. The proce,~ of \' ira l can be loequell1."Cd III SC'len ~bg~:

In'

Chllpter 11 ANmrai All'rnl~

371

"

1. .-\drcI'1'I''''', anach~~ 1 of tile ~,rus '" ~rt<'ifk ~~OI'I O<I lhe !IIIrf..: of the hosl ~Ib. spt"C,f", ="I"'U"" JIIOC'~. ~ iN", penelrouon' of ,he "I\l~ mlU (he tdl. ~ (;'...-"' Id,~l of "11lI1 ""","'ic .nd from the prole'" COlli . l TlOIIKnpI_, prod1>ctlOfl of m:al mRNA from the ,',ra1 JI'C'
I TI'/IlU/,l/w,t, .ynlile."" of \lroil pmlcins (Ct,O/II proIdn~ .,Id en_ ~'me, for n:r ricationj .nd vir~J nllCltic ockl ( i.e,. the ~n l M I tt"""ll1e or complinenl"')' ,o ;tnndl. This pructU U~ the IIo>t
(d\~

-'

IOUpre:"l1 .-...1 Ib<Ilun"n. few or many >nI r-uo:.n. ,n,'oh'cd ,n the n:phcailOn IM ..... esa. Tbe "raJ pro!nil\. modify the: hoM l-cll ,uxhUow the \1m gn>ome 10 rq.liclOl,

,noes.

with II cy tokioo co receplor. 1- 16 SubSla ntial evide.ICC indi' cates thllt viru~~ enter eells by t!"tl,K',ws.... a proces.~ that involves fu sion of the v,ml envelope: .... ith the C\' II membnanc:. intemlll'mg of componenl~. and dis!oOlution of the membOUles o f V iN~ IU1d ce ll. Various reccpton and corttepiOfS faciliMc this reacTion .n 19 Bcfore a vi ru s clln begin a repli callon cycle ... ilh in a host cell . it5 OUler cmc lope and capsid mu st be rem()ved to release iu nucleic acid genome. For complex DNA nruSC'S such as vaccinia (i ts bUldmg receptor I ' the c:pidcnnal gro .... th factOf" receptor). the uncaating process occur; UI , .... 0

"" "",n~ bo),t and \lral C"qllJel;, l1Ic mcch,m<m. by ",hoch . , occur< an: oomplu. Th" u; ofl, .. (he "age al which the ctll 1'1 irT1',~,bly mod,foN IIIKl ".".. lUaU)' ~ 111ed. Aur.bI. of the virar pamd,_ Ne ... "n'al ( 001 prutem. as.cmble _ aIpSId. (tbe proctm en,.". thai WI'TWnd\: nockic kid . . -"" ..cd moln:u\eJ In Ihc:~).nd VIral ~1IQffiC,.'

stagcs '1 ;
I. lW6i ttll pIU1ially del!ra.ie lhe en'~iopt' and rnp<od to ~ve.al a pomon of lhe "nd DNA. ",Iu~h ~~ as a It:n'pla\c for mRNA 5ynlhe$;'t.
~tI)'.ymc:s

1 RNa., of ,he IMluR' ',ru, from 1he cell by budding from 11M: I;dl ",cmbnone "I" I\Ip1UR' of the e<:11 and ""r,-al of the pro,,,,.,,
",,1110 cell or indo. ,dual 10 Individual fuwclopN, ,ru.es !)-pally USC' bulk"", on tM pi....".... tnen~. ~ndopI",.rniI;
~hrm. '" Galp
~

2. m~NA' code

for,he S) mheio. of ....111 clllYmcs. ",h",h complc1~ ,he deSradalioo ()f lhe proIein ~OOI. ~lIo",j"8 the diU' 10 full~ emCr tIM: host.

The proteins of the viral en,elope: and capsule an: the

prinm)' targets for anllbtxhes symhesized In response: 101mmun ll.lltion TL'Chniquc~. Protein synthe,, ~ inh ibilOf' ~uch as cyciollCxim ide and pu,,"nycin inhihit ttlc utlCo;.ling process. but they ~ nlM 5Clective enough to be u.>cful as ant l" irJI agent.'> . In the crinea] founh lind fifth <l:Ige\ of infe-ctiOlt. the virus usul'p) the elM'rgy-producing IU1d <ynlhetic functions of In... host cdllo replicate ilJl own genome and 1 synthcsitc ,jrJI 0 enl.)"me~ and ~truclural protcins.~ Simple RNA viru Q,'~ con dltCt both replication and protein ~ynttlcsjs in the tyloplasm of the ho/;t cdl. llICSC rontain speci nc RNA poIymcrascs (RNA rcphcascsl rcspo!ISlble for replication of the gel1()l1lC . Some single-slnlodt:d ~N A , il'\lsc\. such as polio, il'\ls. ha'e a (+ )- RNA genOlllC Ihat se ....cs the dual fUtlClion of n\(,~loCn gcr for pr()lein sYnthc.sl~ and tempilite for the ~ynt hc~is of a complcnlC ntlll')' strand of (-}- RNA . from ",hich the (+)RNA is repl icated. In poli()~irus (a picornavirus). the nICSsage is Ir.mslated as I Si ngle large open reading frallM' '" hose product IS clea'oo enzymat icall y into specific viral enl,ymes and StruclUT"JI protcms.I~. 11 Other ~NA viruse.~. ~ltC h liS influenzu vi ruses. ~"()I1tai n (- }-RNA. which se ....cs as the templatc for the syn thesis of a oon'plcmenuuy str~nd of f +)RNA. 1bc (+ }-RNA strand directs "r,ll protem 5ynthc:sis and provides the tenlplate for lhe replicattOlt of the (- }-RNA ge nome. Cenllin antlblolles. such as the nfamycins. Inhibit viml ~ NA polymcmo;cs in vitro. bUI oont: has yCI proved cl inically u~ fu l. Biooctivated fomlt of the nuclCOliide analogue rib:lviri n varioosly inhibit ri bonuc leolldc s)"nthesis. RNA symhesls. or RNA cappmg in RNA VII'UliCS. RilY" irin has been appro,ed for aerosol u"t'atment of se'ere ll)wer respiratory infeclil)tlS caused by rcsp.mtory syncyt ial ~ irus (RSV). ~etro" iru:leS constilule a special daS/> of RN A ~ iruscs that ~ a RNA-(\cpcntknt DNA polymerase ("'.t'~t' m",xrip,uH) required for \lrul rcphcallOll . In these: \ IruSCS. a singlc Slrond of complc:mentary DNA (c DNA) i~ ._ynilleSil-td o n the RNA genome ( f e'''''fst 'fllll..-aipliUl!/. duplica ted, lind circulariJ.ed to ~ doublc-stmnded proviral DNA. The proviral DNA is then integrated inlo the hosl cell chromo!iOmal DN A 10 form the templalc (llpo ..inu Of" ..,rogent') required for the synthesis of m ~ NA~ a!1d replication of the viml RNA gel'lOm1! . During the proce!lS of cDNA bi Ollyn-

nrmtnnrs. Nonm,eioped 'lfUSoeS t)'lJM:ally

eDJIC by Nplurc of the l'IIxt ttll.

Tht Inhial auachmem of viru l panicles to cells probahly .'oh'e! multi phasic intC'TIIClions betwecn .. imJ attachment ..... 1) and host cell surfllt:c receptors. For instance. In .~ of the alphahcrpes';ruscs. inlernali /;ation imol\"C~s IQIQ!k of c'ems that In,olve differc m glyroprotei ns and
Hmot cell surface molecules al differcm Stagcs. Different a<1 wrfxc proteins may be u~ f()f the inilia! attach mc nl aI muy into 11I1gct cells and for ecll-Io-cell spn:ad across IIJIPOSCtl populalion~ ofcells.Thc pattern of ~ystcmic .... produced during IU1 acUIC 'irul Infeclion in 11I1gc pan tpmd, 00 tl'lc ~peci1ic Ofgans infecled and in many ca...:'~ tht capacilY of tht: viN'lt:S 10 infl!(:l di<;crete populations ~ crUs "'lthin these OIl1ans. This propeny is called lisJ" t' .,, Thc tissue tropism of a , il'\ls i~ inf1ltCnced by Ir ''''iCtion bet"'ccn a vanelY of hosl and v;ml raclOl"l. ,iJIbough lhe specific vlml anachmc nt proteins and spem:t'ptOl'S 011 target ce ll s ~ importunt. a varicty of viru~-host inter.J(.1iollS can play an imponant role in .rtmIIIn,"s the tropism of a viru~. Increasing aUcnno n is r()(;'U,;cd on cUrn:<'ptors in mediating viral binding. entry of HIV. I into largC1 ce ll s rcqu ill'$ the of bUlh C D4 ' and a SI!'eOIld COIlXeptor protein '"" ,,., G-pmtein- L"OU pled 5Cven- lmnsnlCmbmne inclOOing the chemok ine receptor protci ns Cel ls Ilmt e:tl)o ds CI).l but not the an: reslSlanl lO H IV infection. 111)<;1cell ular reccp(III be- '""grins. hcpanlns. sial iC acids. gang lio< idcs. _~". phospholipids. and Inajor hi , tocumpatibilit y anti _ (to name a few). There is suhslalltial e~ i(knce lhat lhe fOf" inllucn7A1 "iruo;es IS !he peptidoglycan acid. ",hleh binds a protcin frolll the ,iral surl"oct'. 'l and hemalUl lulinm . the vi ral enveOIher.and the C\'ll. i, I in fecliOll tnler.k1IOf1 of s.poci fic glycoprotem molecules I Wt 51 00 !he ,,ml C\' II surl"ace ... ith an IIIltigcnic ttttplor molecule 011 helper T lymphocytes along

r.1MWItt.

371

Wit...... an.! GuwiJ '~

Trt'fN>o,i: .>jOrga"ir Medwl",,' curd I'hi,>7rI(U't~'k,,1 C","",;S'I'I'

thesi s.. RNase degrades tile RNA strand. lea\ ing only DNA. Onrogem(" (clIl'ICer-cau~ing) \ .ru~. 5uch as tbe human T -cdllculem ia Hruses (HTL V) and tile related HIV. are n:troVlIll~. ReU'Q\'lrnl n:\'cn;e tnmloCriplltse is a good target for d~moclleropy. belli' inhibited by the tripho'\phala of cn1ain dIOeoxynucICQ<;idc.,. ~uch as 2'.3'-dcoxy-3'andoihymidine (AZT. '(iOO\'lldine). 2'.3'-didooxycyndine (dOC'yd. ukit .. bine ). :md 2'.3'-didoo~ y-2'.3'-diddiydro lhymidin.c (04T. stavud,ne ). nil of ",h,eh h:. ve been appro\'ed for tile lrealn~nt of A IDS. The nornenclamn: of these agenu; i~ straightforward. A 2' J'-dldeoxynuclcmtde is referred to as ddX . ",hi le the uns.1Iur~ted 2'.3'-dldcoxy2'.3' dlrkhydronllCloosides are nwned d4X . 1lle didooxynucloo~ide tnphosphalC:s ~ incorporated into VII'llI DNA in place of the corresponding 2'-dc<)xynllClco~idc (i.e .. 2'-deoxythymidine. 2' -deoxycytldlne. 0( 2' ' Oeoxyadf'nosine) uiphosphate. Zl. 1J Thts reactIon temttnatcs the \'iml DNA chain. since the i,l\.-orporn,ed dideoxynuclcOliide loch the 3'- hydroxyl group reqUIred to form a J',5'phosphodie!iler bond "'ith the ne~t 2' -deoxynuclCOIIUc tri~phate 11,1 be incorpornted. The DNA villlSCs con stitute n lletcrogeneoo s group ",11O"C IIcnomc i~ composed Qf DNA. They replicate mthe nllCicus of a host ce ll . SQme Qf the DNA vinl sc.~ are SImple 5!IUClun:S. c()n~i~t ing of a single DNA ~tmnd and a few enlynlC.~ surrounded by a capsu le (1:.1; .. p.:1I"\O\ irus) or a lipoprolein en\clope (e.g .. hoepami, B villl~). Other.>. ~uch Q.~ lhe hcrpe$vi IllSCS and poxvlllleS. nrc: large. complex StJ\lcturt' wi lh double-~tmnded DNA geoome~ and several en'(ymes ('nca.'ICd m II cap,u le and surrounded by nn en\'elope consisting of several n~mbranelt DNA villlses contain DNA-dependent RNA poIymel':lSfK (Im~'iI"asr:s), DNA poIymellL<;I:s. and \3T1QU~ OIhcr cn/ Y les (depend ing on the rornp1c~ny of ll the virusllhat may provide t~Ct5 for antiviral drugs. 1bc most ~l.ICcnsful chcmocl~mpcullC agent ~ disoo\en:d Ihus far nrc direch:d ag1\inst replkution ofhcrpe.wlruses. The nocleo~ide analogtJoe$ idolmridillC. lrifluridinc. and "idar b,ne .. block replicallon ttl herpcwilll~ by three general mechanisms: Firsl. as tlte tnooophosphaics. lhey interfere wilh the biosynthesis of precursor nudcoltdcs reqUired for DNA ~yn ' lhesis ; second . DS lriphosphates. lhey competiti"ely Inhibit DNA polymerase: and third . the triphosphales are incorpo raled mto the grow ing DNA itsclf. resulting in DNA thlll is brill Ie and does not fUflCllon normally. AC}clonocleol'ides (e.g .. acycloguDoosine) an: biOOdhated sequeOli ~ll y by viral and host cell kinascs to the acyclooucirot,de ItlOIlOpho:I:phale nnd the :tCydomocloosloo tnphosphate. n:specli\e ly. 1ltc Im tel' inhibits virJI DNA poI ynw::rase and terminates the "irdJ DNA strand. since 00 )'hydro~yl group i~ a\'ailable for the subsequent Forrnat ion of a 3',S'-phosphodieSlcr bond with lhe nelH nucle<xidc triphosphate. "The 5!ructure of acyclovir "'lIh the lCyclosugar ch:un ro!ated into a pmlOC confi,luraIIQn (below) sho"' ~ elemly Ihe absence of thc J'-hydro~yl group.

'" I)
HO~ '

Ule stages in \l lml replicillion require IInponant 'IruJ. Spt'('irIe procC'Ssing Qf caum virol proIein) by viral or ~Uu lar proteases. RetroviruSd. such as IIIV express IIut:e gene! as pn.'CUI"SOl' polyproleins. Two of these gcne products. ~ IgnatN the pS5g:.g and pl6O&agpoI proteins for tlteir Joa. lion on the lIenome. undergo cleaval!e at se~el'lll Slies b) I virolly encoded protease to form ~trucl urul (viral COlli) pr0tei ns (p 17. p24. pS. and P7) and enlYInc:s reqUIred For tq!hcalion (reven;e tTUn).(;ripta"c. tmegrnse. nod protease). 1h dcmonSotrolion lhat HIV protease. II memlx'r Qf the asp.:ut}1 proIea!iC flUluly of enzymes. 15 essential for the matur1lo, and mFectiv ity of HI V partlclesl-< has ~linlOla!ed map Itsearch effon., tQ de\elop effccth'e inhibitor,; of thil step. 1lle-.e efforts ha\'e led to -.e~erul C llndu;\;ttcs. ,\()II"IC' 11lX. on the marlo:et and many that nrc: in cli nical trial ~. To complete the replicalion cycle. tlte componclll arc 1\ssembled illlQ the IIlatll: \'i ml particle. or ,iri"". sim ple. rKlIM.'nvelopeti villlses (e.g .. the picol1l3vi ru ~ polioll rus). the genome and only a few enlymes an: encastd It) cap~.d protei n ~ to cnmplete the virion. Other. tl'IOI"C WII"*,, \'iruses arc en'eloped by one or more membntnes ooruatnq carbohydrale and lipoprotein cQmponenls deri\'cd from ho~l ~'C II membrane. Once the mature virion has been assembled. It is ~.ad,\ for release fll)m the ce ll. The: release of cenam villl,ajt.J.. poliovirus) i~ rlCCofUpan ied by I ysi~ of Ihc host cell meIlIbrane and cdl death. Son~ Qf the en\'eloped villl SC'>. bow ever, ~ released by b"ddmg or I'.{/)('.\ IOsi~. a proce~ ,","Oh. mg rU~ton betwcen the virnl envelQpe and thecel1 membrall: This pr1Xes.~ is nearly II reversal of the en try ~ tb! ho~t cell mcmbrane remai ns intacl under these condit_ and tnc: ce ll may ~u""ive. Chemoprophylaxis is an allem3t1\'e tQ acti'e ImlJlllW. lion fQr the p:vcnlion of vil'lll infection . With Clle lllllJHoPtJ lu is. one use~ a c henncal agt'nt Ihal interfere<; ",ith I *F in early viml ioreel."ty. 'The immune system is not d~ stimul ated by the drug oot is required 10 Il!5pond CD ~ acli>e infc:aion.1t ""ould ~m lhallhe TOOSI ~ulo;a. moprophylactic agenls ....oold be ti1o<oe that prevent pc:.kk lion of the virus into the hoSI cell. [n pri llCiple. thl' t'IIt achieved by blocking any 0( three ~teps pnor to the lUI'! the rcphc3lion cycle: (a) anachmcru Qr the vi rion to thtlnt cell via ilS receptor complex. (b ) ih entry illlQ the ~U et1docylosis. 0( (c) release of the vlrol nucleic acid fnprotdn coot. At present. only a si ngle class of age nls alfe<'ll Ihc$c early stages of replicatlon., j 16 "The adamanta~ (amamadine and nttl~nuldine) ha"e been appru\'cd (Of c.U'Qlling influcn:t..a type A infection. These dlllll' aprn. interfere wilh 11\11,1 Stages of infll,K'n/.a type A viral "PD tion; preventing the carly Mage Qf vlraJ uncootllli and turbing tlte laiC stage of 'iral assembly. C lillical stl.ld~ shown that amantadine..oo nmantadlfiC all' e(fti"eif,1d pf()phyl a~ i~ and tre~lment of acth'e .nflllCllI..a type tion.

,,raJ

n.

A'"

Aman tadin@, USP, and RimantadiM. Amanl<IIiuE. atiamantanamlne hydrochloride (SymmetreIJ. and on mel hyl derivative rinulllIadine. a-mcthyl-I ad.:tmantut. thylamine h)drochloridl' (Aumadinc). are unusual._ cyclic llIlline~ wilJl tile followlOg ,tJ\lctun:s:

,,

h-

""

;)1

00

!p.

.~

'h<

AlILlIlladine haJ, been u-.ed for )cat"; as u'C'alltl!'nl for hrL:m~" s dl.sea...;e. BOIh of lhe<.e agents '" III .. pttilically d!Jbtt replication of the inn uenla type A \UlJo,c, al 1o,,"' ~nlnl iom.. Runam:lIlllle I~ generally 4 10 10 lime., more alive Ihan amanladm~_ 'n'l: adamantananllllC' hal'\: two lII:clI:tnilms in C(IUHlKHl (f' ) they inhibit 1111 carly <,Iep in ,lr.Il replicauon. most likely "lmJ ulK:oollng, " and rb) in ... ~ns they aff('C1 a later Mep thaI prub:lbly invohe-. ,01 :mI'mbiy. po;.~lbly by inlerfenng with hemai!glllunin p!O:e'\lng The m:un biochemical locU5 of a..mn i~ the InIIomu I}PC A 'HlI~ M2 proIem.... bieb j, an inll:grnl memIn_ proIcin thaI fUllClion~ a. an ion channel The ,".12 chanIII is proIon t r.m~p()n ~)"lcrn. B) imcrfermg ",jlh the WtIOll of the M2 protein. the ooamimlunmllillc, mlubn lCIdmediared di_'soci!!1 lOll of rile ribormcleQf'roIdn complex m1y in rt'phcallon. They abo IIllerren- It, IIh Ir~lhnlCrnbr ne ... prI1t>II pumping, mainlliining a high imrncel1u lar proton conI:CIII1UOII rt:lali, e 10 the extr..cellu lar eooccmr.mon aoo enLIIl .-idic pll-ioouced l'OOronrumonal ~hange~ In the glutin;n dtmng jh IIllr.lCellular Ir~ll\po!1 al a later ,"Thceonformauonal change~ In hemaggluullIn pre'em "fn of the na'oCent viru_ panicles to the cell mcmbnmc:
... tI()Cytosi.~.

---

70 to <)()<k prutI:Cm'el 7 agamst tnnw:nLa type A. "The drugs h:.\e no effC(:t on InfllW;'lIla t)"p.! 8 "The primary side effeets art: rdlled to the central Ilen'Olh ~)""Iem alld are dopami nergic_ TIl" " not surprhi ng, <ince :ml;lrllalhllC IS used In the treatment of I'Urkl n'On' $ di'-Ca'<C. Rmtant.tdirle has ~ign;f icantly fel',cr ~idc efl"ccb . probably becau.>C of its e~teIlSI \'e biotransformalion. I.e" 1han 5O'l of It dose of rimantlld lllC I.~ e\ereted unch.lngcd. and more than 2O'k appears in lhe unne lIS melabol ites.:!lI Am:mladme "excreted largel) unchanged m the unlit.'.
INTERFERON AlFA (l NTRON A. ROFERON A) AND INTERFERON BETA (BETASERO N)
INTERFERONS ~

Inl erferon~ (lI'Ns, are cX lremcly p()telll ey toline~ thai po~. \C~~ anliviml, irnm"oomodIlJllhn~. and amiproliferau .. c: ac-

,
M)

,h<-

varinnl.' of inn Hen/a Iype A ha'~ been n..'Cowred frot!t IIII:lnt;idine - and I1m:uuadine-trealed p:llicnh. 1(C,,~ltith inhibnory cunccntrdtlOflS locrea.-.cd more than 1\folJ ha,'\, been a.....:w:illled .... ith Illngle lIocleolide ~:::~th31 lead 1 ammo xld wbstllunon~ in lhe Imll~ 0 ~ dumaln of M2 . Amantoome and nmantooillt.' tTO:>.!o-su,;cepllbihty alld rt:;;I.)CiOCe.!' 21> "-!tadine and riinantadillt.' are appru"ed In ,he UlIlted forpre"elllion and treatmenl of innuenl~ltype A \ IruS ,Senonal prophyluis .... Itlt ellher dmg i~ about

R~\i~lunl

tioos, N IFNs are )lIthe<il.cd by jnf~'Ctcd cells in respon~ to ~anoo~ loollceN (Fig. II - I) and. III tum. el idt either IU1 arlm' iral "ale III lIt.'illhbonng cel!~ or 3 natural killer eel! respono;c: that dc<>tro)S the: initially IIIreeted eel! (Fig. 11 2). 1llcre are thltt da~scs of human lI'N< th~1 possess signifiemil allll\'lrdl activi ty_ 1lJCse an: IFN -a (1t"IOIl! than 20 .ubtypes,_ I"N -P (2 subtypcs). and IFN - y. IFN-a i\ uS(."(\ elllllcall) in a r"CI,:omhinum funn (~:I ne:<! IlIIerfelOll Ili/u). IION-P (Betasemn) i. a recombinant foml lnarl.:Cle:<! fur the tn:a, ment of multiple <den:>!ils. IFN - and IFN-P are prodtJC('d by almost all cells III rt'. spono;c: to "Iml challenge_ Inlerferon production is not limite:<! to \'iral >tlmuli. hm...\\'r. A '"lIIlc:ty of otllcr triggas. including C) tulanes ~lII.h II!> intcrlcullll-i. intcrletJ llll-2. and tumor IICCflI'oi\ factor...... ill elicit tile product ion of IFNs. Both IFN a and IFN-P an: elici ted hy C~[lUSun: of 3 ~cfl to double ,tmulled .. iml RNA. IFN -a i. produce:<! by lymphocytes and macrophage,. "11111' I FN- P i, bio'~nthe'i/ed in Iibrohlll5t~ and epithelial cdls.IFN-yprodUCIlOII is /l,')tlicte:<! to T 1 )"1lI' phoc)"IC' and natural l lllcr ecLl~ re'pondll1g to anllgcllle stimuli. mltogcn.,. and ~peclrlC c) l~i lll'!<. IFN'a and IFNP bmd to the: same rccc:plor. and the gc~ fO\'" boIh an: eill-oded on ('hNfllOWfUC 9_ n:ceptor for INF- y is ul1l'lue. and onl), 0I1e \1Ih1)'pe h:l$ been ident ified. The genes for Ihis molecule art: ellcoded on chmulO\OIne 12. INF-y ha.~ It'<s :mllvillli IICli\;ty Ihan IFN fI' and IFN p bUI mo~ potent

n.c

'"

lyPe 1 Inleneron.
tFN-u IFN/3

Type2 InIef1elnI;
IFNl'

,-"
Irrdlqd~

M,!ogen-I~.....rated T

M,tugeo. or lMclll.
Indtqd by 0..011 SlIarded Viral RNA, R I :~!IOt. ideo lIICaI

""""""'" ,

80th ....... "Wdon

'''' ,
Figure 11_ 1 Typo:>s of ,nll'rleron

fIecepIor I.)nIq

Ei"ICOCIIId on
C~1QfIlOtOIT1e

t2

""'"

o
Il'lIected Cell

FN

FlgunI! 11- 2 IntMI'fOll mechanlSlTtli.

eff((:t$. INF-y i, especially effective in activating macrophages, stimulating ull membrane expression of class II major histocompatibi lity compieltCS (MHCII ). and medlaling the local inflammatOry re!ip0n5C5. Most animal viruses a.-e sensitive to the antiviral actions of 1f<"'Ns. The instanccs in which a virus is insensiti~ to IFN typically involve DNA viru5CS. ll On binding to the appropriate u llu lar receptor, the IFNs induce the synthe.\is of a cascade of antiviral protei ns that

irnrnu~gulatory

contribute to viral resistallCe. The: antiviral cffe\."\' 0( thr IFN$ an: mediated through inhibition of.lll V,nl pencuation Of" unooalnl Synlha.is of mRNA 11w:: "",1_,1on of ,i ..1 pnlI~In$ Vin' u",mbly and n:leue

With most viruses. the IFN ~ pn:dominamly mhiblt 1"1_ synthesis. This tliKes place through the imcm!edillCY of It"'V

"" /):1.;': :-- IFN AI)8jlIOI"

Induction 01 antIVIral
protein It"~11I1e

2"S..t')I,goMen,tMol aynIhe\aN

AT9 _2'S'~--' ""~T... ".".'."

Hydrolj .... VI,.I ANA

Figure 11 - 3

IFN~

pri!domin.lnlly Inhlbtt protem synthesis

Chapter II AIlI,../mi A~IIIJ

3 75

HI<,

()H

()H

()H

HQ -

P- O -P- O-

P- O-,
0

111111

/'

s of the

'Z.!!i'~"

O- H

f igure 11- 4 StfUClurt of 2'.5' -oIogoodenyIate

,I

protem

yof lFN.

iIduccd proteins such as 2' S -oIigoadc:n)'la\c (2'.s'-OA) syn~ (fig_ 11-3) und D proIein kinase. either of ..... hich ~ inhIbit viral protein ~ynlhc~is in the pl'l:M"J>CC of double!I-.:Ial RNA. 2'.s'-OA !ICI;vlIlCS a cellu lar endoribo~ (RNase) (Fig. 11-4) that c~aves both ~lluJar and IT.II R.~A. The protein kinase sclc'CIi\cly phosphoI'ytates -' inactIVities I'ukaryotic initiation fllClor 2 (e l F2). prevent_ .. Iflillalion of the mRNA - ribo!>OflIc complc~ . IFN Illso 1Ikt. I ~ific phosplxxllcslCr:lSC thai cleaves a ponion .\RNA molecule~ and. thereby, interfcltS wilh peplide -bj:1\ion,JO The inreclion sequence for 11 given viru~ may 'or IIIhIllIIcd at one or severnl Steps. The principlll i nhibilory d'ffmamong ,-irvs families. Cenain ".ruscs can block
Ik prodkM:1 or !ll.!tivil), of selected I FNiooocible proteins 1QIl

C. chrome hepatitis B. KaJl'O'i's san:oma in HIV-infcc:tcd pmien.s. other malignancies. and multiple .clerosis.

NUCLEOSIDE ANTI METABOLITES

InhlbltaiS of DNA Pol' ..... ras.
/doxurldine, US,.. Idoxuridine.5-iodo-2'-deoxyuridioc (Stoxil. Ilcrplcx ). was introduced in 1963 for the treatment of herpes si mplex lcnlluis. '1 The drug ,~ an iodl/llued analogue of thymidine th:u inhibil~ replication of a number of DNA viru<.e!! in vitro. TIle sU.'oCcptible VH\ISCS include the hC'rpcll'iru,;es and ponirusef (VlIIXinia).

I.

"lhus roumer the lFN effect. IRIs canlK)l. be ub<;()fbed orally: to be used wl1Ipeutkally It) IIIUSI be given lntr.lll1uscularly or $ubcutanWUsly. The: okIJicaI cITc<;ts are quite long, 50 ph;Imt;K;okinctic parllm~ d,fficult 10 Octermil1oC, 1lIe I1Ilti~iT'J1 Mate in pcriphblood lOOIlOIluciclll" cell s typically peaks 24 hours after oIlFN-o: and IFN -P. then decreases to ~hnc in 6 .,"1." Both recombi nant and natun!.l INF-u and INF-fJ are qrO'iN for usc in the Uni ted States for the treatment or lorna acummatum (vencoreaJ ....1If1S), chronic hC'patitis

'", I

H Ac

NH

.'
HO"

376

Wi/. '" IWI GinVJNJ'~ T<'.llbtd ufOftO'lk Ml'IIM.... / and P""mw>C<'Mtiml "

eN","''''

The nJeChonism of action ofidoxuridine has IlOl bec-n completel)' defined. but sc\'ernl steps ate in"olved .n the activotionofthedlUg . ldoxuridlne~nt~n the ccll and is pho:;phorylaloo al 05 by a viral Ihymidylme kinase: 10 yield a mooop/losphale. ",hich IIlKkrgoe.~ funhcr biolr.msfonnation 10 I triphosphate. 'The: lriphosphate is bc:11c\'ed 10 be both I substrate alld an inhibJtorofviral DNA polymerase:. causi ng inhibition of v,ral DNA synthesis and faei litaling lhe S)'nlhe~is of DNA Ihut contnin~ the iodinated pyrimidine. lbc: al terN DN A is more susceptible 10 slnmd breakage and leads 10 faully tr-oInscnptKJn. When the iodinated DNA i~ Iran'>C1ibcd. the results arc m,scooinll errors in RNA lind faulty pmtdn s)'nlhcsis. lbc: ubilily of ido~undylic add 10 substilute for dooxylhymidylic acid in lhe symhC5i ~ of DNA may be due to the similar van der Waals r-oldii of iodine (2. 15"\) and the thymidine methylgmllp (2.00"\). In the Umlcd Siaies. idoxuridine,~ approved only for lhe lopical IIl'Jtmenl o f herpes simplex ~ i l1J~ (HSV) );ernli lis. although oolside the Uniled St31es u solul ion of idoxuridi 1M: In dimethyl sulfoxide i~ an.ilable: for the lreatment of herpeli labta.lis. genilalis. and 7.oslCT. Tl1c uSC: of idmurid,ne is limited ~U'ie lhe dl1Jg lac~~ se lectivily; low. subtherapeutk concclllroti ons inhibit lhe growlh of uninfecled hosl cell~. The: effc:clhe COO(%Iltralion of idoxuridine: is al lea.~t 10 tima gn"ater than that of acycloVir. ldoxutidlllC occun lIS a pale: yellow. cryslalline solid lhal i~ soluble in Wllter and alcohol bul poorl)' o;olublc in most organic o;ol vent~. The compound is 11 weal: acid. with a pK. of 8.25. AqUC:OUJ s.oIulion~ arc: slight ly acidic. yieldi ng a pll or aboul 6.0 . ldoxutidJlle is light and heat <;ens";'e . It i~ <;upplied 3~ a O. I'W ophtha lmic solulion and a 0.5% ophthalmic oinll1'lCI1I.
USP. Trifluridinc. 5-trinLl()fl)ff)Clhyl-1'dcoxyuridine (V iroptic ). i~ a noonnalcd p)'rimidinc nucleoside Ihul dcmonslfllics In vi1l\) inhibitory aclivity Dgainsl HSV I and 2. C MV. \':tCCinia. and some adc:novirusc:s. JJ Trinuridlne po!>'iCSSc:S a trinuommc:lh) I group in5lead of 3n lodillC alom al lhe 5 po!>itioo of the pyrimidine ring. The von uer Waals r.tdiu~ of the trinuofQmcthyl group is 2.44,.\. somewhal larger Ihan thlll of Ille iodine 1110m. Like idoxllndine. the antiviral mechanism or lrinuridinc innllvc:s inhibition of ~,raI DNA synthesis. Trinutidinc 1II0llOplw:lSphate is an imwcTlIible Inhibilor of thymidylalc synthetasc.llnd the biologically gcncflltcd triphosphate COlli petitively inhibits Ihymidine: tri~phate incorpornlioo illlo DNA by DNA polpncra'ie. [n addition. trifluridinc in its triphosphale fonn is incorporuted inlO viral alld ~lJ ular DNA. creating f!"llgile. poorly fuoeMn;ng DNA.
Trif/uridi~,

Trifluriuine is lIPP((Wed in the Uni ted Stata for the ~:JI. nICnt of prima/)' le!"llloconjUllClivitis alld !'('Cumnl epithdial ~ernliusduc 1 HSV Iypes I and 2. TOpical tnnundlllCw.o.. 0 sonIC emcocy in patienls .... ilh acyclovil- re~i~llInt HSV ClMIM:OUS infeclions. Tri nu ridine solution, are he3t sen,illve ml require Il'rriger-.ltion.
Vidarabl ne, USP. Chemicall y. vidarnbillC (Vira-A).II 9-p-o-arabiooful"IlIlO!iyladcninc:. The drug is the 2' cpime! of natural adenosillC_ Introduced in 1960 as a candidat~ awcaOCtt agent. vidaroblllC was found 1 have broad-Sptcb 0 activity against DNA vil1Jst$ ..l< The dl1Jg is acu ve 3J!:illll!l hcrpesvirusc . pox \ iru!ic:~. rhabdovil1J-.es. h('JXldn~virus. atXl some: RNA tumor viruSCli. Vidar-Jbinc was man.ctc:d in dr United StliteS til 19n lIS an ahemauve 10 idoxwidme hi' lhe trealment of HSV lerohli~ and II SV eoccphahlls. AIthouglllhc agent was i nit.all y preJXlIl'd chemically. Iii. r.JII obtained by fCrl\1C nlat ioll wilh ~troi lls of St'<'P/(JlIII"CtJ anti
bioric,,~.

",C>.
I

of vid arabinc i, complctcly 10 DNA ,iruscs. Vidarobine inhibits vir-oil DNA )yntltell! En7ylllC!i wilhin the cd l phospho!') laiC vidaDbine: 10 tbt IIphosphale. ""hlch competes willi dc:o~}'adc:OOSIlle: IrlJiDpilate for virul DNA polymerase. Vkl~ntbine In~ also i/lCorporutCd into ce llu lar and ~ir-JI DNA. where ild as a chain tl'mlinator. The triphosphate form of ~id:lnltit! also inllibits II 'iel of en7ymc:s lhat aTe: inH)h ed 11\ mt:tItj.a. lion of undine 10 IlIym.dine: ribonl.lCko'"de redl.lCt~se. R.'i.~ polyadcnyl asc. and S-lII.lelKlSylhornocySI~ine hydrolase. Alone: tinIC in the United Statcs. introvellOUli \'id:ora/iI! .... as appnwed for usc: against HSV c:ncc:phall\l i. ~:: herpes. and herpes or varicella ~o:ste:r in immUlWX\lihj'" mised patienlS. Acyclovir has supplanled \'idarublnc dl1Jg of choi ce: in lhese ca>cs. In the Ircmment of \'Iral en<:cphalliis. \idar.tblnc ~lf be adminiqered by COOSt3nt 00",' intm"enous IIIflllOI cause: of its poor ""IllCT solubil ity and !"lipId 1\1C13bohc coal,," ~iun 10 II hypoumhine denv31ive in vivo. The...e coupled wi th Il'lc availabi litYo f les$ IO~ ie and more: c:f~ IIgenL\. ha ve cau'iCd intntVeOOU5 vtdarnblllC 10 be .. tI from the U_ S. ITIlIrl.ct. V;darabine occurs as a while. c/)'Slaltinc monoItydr.tl~ IItI is soluble in water 10 lhe e~lenl ur0.45 mglm L al 25~C.11tt drug is sti ll avail able in the United Slates a~ a ] 'J. for the treatment of II SV keratitIS.

1be antivirul

~ction

Ill"

Ol".

CIuIptfr I I

A~I,...rulA!fmU

377

Acyclovir, US,.. Acyclovir. 9-[2-( hydrox}C:lho~y)rnclh ,11-9H-guanUlc (7..(wir.u). is the n\()'>l effe<:tive of a !il;!ries of
qdic nllCleo,tde.~ that posses~ Pllllvlr~1 uclivily. [n t'(}n1 rast "lib InIC nuckosides thai hn'l" II noo-e 01' a deo~yriboq !1Ipr all;M.'1ird to 11 purine or II pyrimidine base. the group ... htd [0 the base in ~yclO\';r is similar to an open chain .p. alben lading In b)droxyl Sroups. 111c climcaUy uscfI' anli~lml ~pcc'rum of lICychJ\'ir IS limited 10 herpesviru.o;es, II is IIl()SI octile (in vitro) pgllinSi HSV l)'pe 1. abiM

., ... ,...,
."
1';' om
!!lSi
f~

! limes less

again~1 ~ISV

type 2. aoo 10 limes

Ie~s

polen!

IIi;unSi "lIricclla-'lOSICr virus. An advantage is thlll IInin -

fIrd human l'eJls are unaffected by the drug.

lerie propenics IpK. YDluc'i 0( 2.27 and 9.2.5). solublll1)' is i ocrca...ed by both sltOtlg IIClds and b.a:leS. T he injccmble form i~ the sod ium sa lt , whieh I~ supplied ll'i a IYOImi lut-d powder . equhalcnllO.50 mglmL of aclivc acydo\'irdlssolved in stCTill' watcr r ... injC(1ion. ~DUse the solution i~ qrongly alkahne (pH - I I), it mUS! be admtnl'\lered b)' dow. constant imrn'cnous infusion 10 a'OId imlalioo and Ihrombophlebitis at the in)CCIion site. Ad\eriC reacti<)lu are few. Some patienls t~pencrlCe occas ional gastrointesl inal IIp''l:t. dininess. headache. lelhargy. andJOim pain. An ointment composed of.5% lIC)'clo~ir in a polyethylene glyeol b;I<;e IS Il"ailllble for tIM: treatmtm of initial , mild episodes of herpes gcnllahs. The ointment is not an dTecli"e pre,'enler of recum:nt epl~ .

A'
~w

nli-

The olhl1mu.' effect of acyclo\;r i ~ the inhibition of \ il"dl ""'syntJysi~. Trull por1 imo the cell and mooophosphoryIIIion arc accomplished by a Ih)'midine kinase thai is enmdedb)' the ,iru.~ ,I);elf. The affimt)' of ac)'clOVlr for lhe .i1Ilh),nudirtl' ~lna);e is aboul 200 tllnc:~ Ihal of the com: !plOdlng nuunmahan enzyme. Hencc. ~me );eleclivlI), is milled. 1~/_)'nlC~ in the infectt-d ,ell catal)'7.1: the convero(thc n\OflOphosphalc to acyclo~ir trip/losphate, which IJn!ItIll In 40 10 100 times greater ~ntratiOlt~ in 11SVaacd than unmfected cells. Ac),clo, ir triphosph.ne competi b rnOOgCI1Ol1li deo~)'gua~me tnphosphate (dGTP): latt, ac)'clo~ ir triphosphate cornpctitin:ly inhibits viral ot.A poI)'meruscs. The tnphol;phorylated drug is also IncO!"~ inlO villi] DNA. wlM:re it acts as a chain tenninnlOT. ......... It Ius no 3'- hydroxyl group. no 3'.5'-ph&..phodie~ !If bond can form . This meehani,m is cssemially a SUicide *bIoon because: lhe lamirnlled DNA template comaminll .,."',r:J$ a ligand binds 10. and trre'erslbly inaclivw.cs. D'\A polymerase:. Re~i~tarlCC' 10 acyclovir can occur. nlQ<it otIm by dc:fklenl th),midirw: kinase activity in HSV isolatcs. I.r)-rkwir resi~laoce ill vesicular stomatitis vi IUS (VSV) isolilts i. nuS('(! by mulations in VSV lhymidine kin::J..-.e Uf. IN oftta. by mu~tion~ in ,iral DNA poi)'meta.<;e . ToroOOsage forms ofocyclo,'ir are available for systemIc .eom and parcntcr.ll. Or.al ac) .. Io,ir is used in lhe imtial 1al/n('t11 of genital herpes and to cootrol mild recurrent IIl'IOib. II has been approved for ~hon-Ienn l ~amlClH of IIiDgIes and ,hic~cnpox cau~ h)' varicclla-losler v iru ~ IntrJ'Cnous administrulion i~ illdicated for initial ~ ItI:1.lm'11t infcctioos in immunocompromised patiems "Ior!he pre'enllOll wid treatment of sc:'.en: episode<;, The .... abJOrbed slowly and incompk!tdy from the gaS/mllltract, and its 0I'1l1 bioavailabllity is OII ly 1.5 to 30%. rt'udo:k:~s. acyclovir i~ dislribul~d to vi nually all body iUi(litUio:nl s. Les~ than 30% i~ bound 10 protei n. Most of kcWg i~ e1CIl'led unchanged in the urine. about 10% ex~'lllthJlh.: o(:iUbo~y metabolite . .t,qdoo.'lr occun as a chemkall), scabk...hite. crystalline II1II il ~lightly M)iublc in water. Because of its ampho--

Valif(;ycIOllir Hydrochlorick. Valacyclo, Ir(Vahrcx) is the hydrochloride saIl of tIM: t,-va l)'l C5ttr of ac~clo~ir. The compound i, a water-solublc crystalline solid. and it is a prudrug intended to increa'iC the biooVHilabllilY of acyclo,ir by increasing lipophihcny. Valac)'clovir IS hydrolyzed rnpidly and almost completely 10 acyclovir following oral administrallon. Enz)'matlC hydrolpis of the prodrug is belie"cd 10 occur during cntcro/tcpatic cycling. The om] hioavullabllity of vatrlCycluvir i, 3 to S times that of acyclovir. or about .5()'l..'" ValllCyciovir has been appro\ed for the trcatHlent of lle'llCS l.Ot.ter (shingles) III inlmun()Ct)nlproml~ patients. The side effect profile obsen'ed wiUt \'lIlacyclom is comparnble in blOequivalem doses of lII.'yclovir. I..e55 than I'J: or an administered dose of valllCyclo~ ir i~ I'\"covered in the urine. Most of lhe dose is eli minated !IS acyclovir.

fincr.!
In-

'IC~I',

""".

'"
o

ale"
OCI~

'"

abinc

jhyln

RNA <. j8bmc

003131

rpmas tnc

Gancic/ov/r. Gancklo\"lr. 91( 1.3-dih),dro,y2-IHopoxy)lIlCIh),11guanine) or DHPG (Cyt()\cnc). is an analogue of lICyciovir. with an OOdition.al b)droxymethyl I rouP 01\ the acyclic Side chai n.

mn

~::::

~rn"" "

~'"

Iltlh;ll

C. Tho mmenl

"
GncU .w

Th," 'itrucllll'llJ .nodific;auon. ",h.le mai malnUlg thl: :act.vi.y against HSV and VSV posse<;~d by acyclovi r. grem ly enhaJl(U the act.vi ty ag~iru.t CMV infection. Aner oommtSU'IIItKln. like acyclmir. gllnc,cI()Vlr IS phosphoI)lated in.~ide the cell by a ",mlly eocodcd proldn kinll$e 10 IhI: nKH!Opho!;phate . n Ilost l-ell cn7yllle'i cat alyze the for InaLion of the tnphospo:lle .... hich rellChes nlOll: than Io.fold higher ooncentrallons In mfectc'd cells than III unlllfccted cells. This selectiv,ty is due to the entry and monophosphoryl3tioo SlCp. Funher phosphorylatIOn with ce ll ular CIl/}'n~ occur.. and the lriphosphate that is formed selecu"cly inhlb.t,<; viral DNA pol}mcrnse. Ganciclovir triphosphate i, al'i() incurpornted into vind DNA cau~inl <;tlllJld breakage and cessation of clon,alloo 'The clinical usefulncss of Ilanc,clo'.r is lun.ted by the toxicity of the dru g. Ganciclovi r causes mycillsuppI'CS'iion. producmg neulropenia, Ihrombocytopcnill, /lnd ancmia TIx-se eITect!l lire probably associmed ... ith inh.blUOIl of host ce ll DNA polymerase:" Potential ce ntrnl ner.oos "Y'itcm side effect, inc lude headaches. bchav iornl chllJ1ges. and COII,ulslOns. Ganciclo"i r i, mutagcnic. carciroogcnic. and terntogenic m animals. Toxicity li mit,<; its thcmpeuric u-efulncss 10 the treatment and 'iuppteSSioo of sightthreatening C MV retinitis in immu nocompromised pallents and to the: pre"cfllion of lifcthreat ening C MV infections in at-risk Imnsplant p;llicnb.1 ' Onol and pan-nteral dosage forms of ganciclovir an: available. but oral blOOvailability is poor. Only S to IO'J, of an oral dose is absorbed. Inlrn'cnous admim~tmtion is prcfemblc_ Mon: than 'X)'h of rhe unchanged dru g is excreted in rhe uriII('. Ganciclo\ ir for injection is available WI a Iyophilil.ed $Odium 511lt fOl' Ittonstimt ion in Ilormal saline. S'* (kxtrost: in water. or 1ll!.'1moo Rmger' s solullon. TI!csc solutioos are strongly altal ine (pH - II) and mu ~t be administered by slow. toruitant. intm\'C'l\OUs infusion to avoid thrombophlebitis.

VSV-infcctoo cells. penciclo'tr is first phosphorylated b) viral thymidine kinasc'" and thoen funher elaborated to the triphosphate by host cell kin!ISCS. Pcnciclovir triphosplwr IS D compet itive mh.bitor of virnl DNA poIymC'~. Thr pharm3CQl, ineuc p;lmmcu:rs of pc:oc lclo"i r IITC quite difTeJ ent from those of acyclovi r. Although pencic lo~ir tripllo<.phate i~ about 10000foid less poIcnt in inhibiting viral DNA polymerase than llCyclo~ ir tnphosph:otc. it is present in thr tissues for 100lger periods and III much higher t"OllCenlrR'N1115 than acrclo,ir. Bccou"C it is possi ble to rotatc the side cha of pc:ociclovir into I pseudo-pc:ntost. the triphosplloc)lIttd mctabolnc possesses a 3'-h)droxyl group. nus relatiooshrp is shown below wit h guanosine. Pendclo"ir is not an obbgate cham tcrmm~lor. ' but it does compc:tith'ely inhibit DNA elongation. l'enciclQvlr .s excreted II"IOI't ly uncNn!td in the urnIC.

Gual108lne
Pencidovi r (Oemir) has been approved for the topd treatment of Itturrent hc.orpl'lliabial is (cold ~\) in add\. It i effective agai ll ~t HSV I and HSV 2.! II is nvai lalMe. cream containing 10% pc:oclclovir.

Famcidovir and Pertdclo vir. Famciclo\ ir is a dillCetyl prodru,l of penciclo"ir:'" As II prodrug. " lacks anti ~'r:ll (!C. tivity. Penciclovir. 9-!4-hydroxy-3-hydroxymethylbut -l-yl! guanine. is IIJ1 lICyclic guanine nucleoside analogue. 11te structure is similar to that of acyclo\ir. e~cepl in penciclo\-ir a side chain oxygen has been repillCed by a clllbon atom and an extra hydrox ymcthy l group i~ preent. Inhibitory concentrntions fOl' HSV and VSV 1UC typically ... hhi n twice that of ac:yclo,ir. Peociclo'i r also inhibits thl: growth of hepatitis B virus_ Peociclo,-ir inhibits vi rlll DNA synthesis. In HSV- or

Cidofovlr. Cioofovir. (S)-3-hydro~y2-p/IoIIphonomtG OXYJlffiP) I cytosine ( HPM PC. Vistilic). is an acyd onudco. tide analogue !hal pos...-sSd broodspectrum aeth'ity "lETI I>Cveral DNA \'iroses. Unlike OIher nuclc:otidc: analugueJrW are acti vated 10 nuc lcoide phosphates, C idofovlr IS a p/Qphonic acid dcrhau"e. 'The phosphom c acid is not h)'1hIp:ed by phosphatases in ~ i \'o but is phosphorylated by editlar kinascs 10 yield II diphosphate . Thc diphosph:ttc lICIt. IIl1 antimetabolite lodeoxycytosinc triphosphatt (dCTI'J.Q. dofO" ir diphosphate is a compc:'1i ti,e inh,bll(X' of ,d DNA J polymemsc and can be incorporated into thegro.-., viml DNA strand. causing DNA ch3in Icnn inhtioo.

Chapter I I Anll! .rot Ag'~11

3 79

Iby

"'" "'" Th< ffu-

lNA " he lions :hain laled

~hip

--

high IhI'rapeUl1C ,ndcl ~am).\ CMV and has been a.ppr<ncd for treatllli CMV reunltis In AIDS piIIienb. CidofO\lr is adminlSlrn:d by ~Iow. OOf)5lanl LOII'lII clOllS ,"fliSlon In a do5c of S mgll.l O\('r I Iboor pcnod
!IIl't

CMlo(O\lrposseSSC'~a

obli.hlbil Inged

wet'k for 2 \\oeeks. Thi~ Irt'atmcnl is followed by a ID;iJQlelWlllCC dasc CH:ry 2 .....ech. About ~ of a dose of eidofallr is ucrcled unchanged in I~ urine. 1'. 1 1h. I'd.,. nl2 to 3 bouf'(. Tllc: dlpOO:.pliale anli metabolite, in conlr..SI. lIB an e~u~mcJ)' long half-life (17 10 30 OOuN). The main dose-limiting lo~ ici ly of eidofolir In\'ol~e, raW impmnnenl. Renal function I11U<\ be monitored closely. i'lttn:alnll'lll with probenecid and ptt'hydrutloo wilh mtrowC'. . normal saline can be used 10 reduce the ntphroloxicil) drug. PlIl.JcnlS must be advised Ihm C.dofOl ,r IS not a (1ft for CMV mmiti~. lhc dlsca>.e rna) progress during or

"die

iDIoIIin! lR'aUnent.

'"
~~

II ,
OH

"I

"- .,',o...............P"'OH
OH

bulle IIbnOllllllllt1(', 1m:1 tH,\lIlg IncR'asc!; or decreases III blood Ca" leI cis. Nephroto~ ici ty i~ common, and thIS ~ide erfed pm:ludcs the U\C of Foscamct 111 other 1IIrcctlon~ cauJiCd by Ilerpe)liru~ or a., ~ingle-a@tnl thcr.!.py for Hl V mfectlon. FOWarnc1 is an C'.\cel1CI1I hiland for ffiC'laJ ion bll14,lIng. ~ hlCh undoubiedly conlrlbutc>' 10 the electrolyte imbalat'lCCl. 0bserved \\ollh the use of the d rug .... H ~pocakemia. hypnnlJgneSl.'lnilI. hYllol.aIClll ia. and hypophosph.alcln;a and hyper phosphaiemul hre observed 111 paucnlS I~aled \\ollh foscamcl. Sidc effect., .~llCh a~ p~ n:"l hcsia~. tctani. wil.llf('s. and cardiac lIrrhylhmia~ mny rcsult . Since fo"C:tmet is nephroto~ie. It rna) augment lhe toxie effects of Ofher ncphrototk drugs. 5uch lIS ampOolericin B and pcnlarm(iine. ~hieh an: fre' quently u'icd to control opponuni"'i~ IIIfrcllon~ III patlems with AIDS. Fo:camct !iOdtum allablc as a stcrile soluuoo IIIteodcd for slow IIItr.llefl(JU~ infusion. The solutIOn is eompallblc wnh normal <>aline .1Id 5'if de ,!rOSe in ~ Iltcr bul ,s Incompat Ible wuh cakrum-cootammg buffer.; 5uch lIS lactated Rin, cr'~ 0;0IUIIOII and 100ai parentCl'lI1 nutrition (T PN) prcparJ' lions. F~!lrnet R'octs chemicall y With ad(i ~It~ soch ltIi mid;voJam. vaocoln)clII . lind pentamidinc. (her I!(y.i, of an injected c:M.e of (O'>Camel b excreted um: hunged 1 the 11 urinc .... T he 1 0llg dimi nahon halfli Fe of fosca rnct is thoughl to re~uh from il~ rcvc~ib1c )oI;:(juestrdlion imo bOlle.""

I,.,

RevelS. Trilnscriptue Inhibitors

early elenl In the replication of HI V- 1 IS reu~~ IBn' 5Clipl.lOn.... hereby genomic RNA from the \' irus iSroRl"erted mto a eDNA RNA complet. then mlo doublestranded DNA ready fOf intcgrJlron illlo lhe nosl chrolllO:Wlne. The enlynl!: thai C3tOllpcs this ~t of rt'actions IS trml' u .'npUl.II', ReI e~ trun~"T1pla>e actuall y opC'l'lIll'.~ twice pnor to Ihe IntegrJllon stql. Its fi~t fUIII:l ioll I" the en:atlonof the cDNA RNA complc\; n:\c/'SC tr.mscriptas.e 1ICt.~ alOrJe In thi_ ~ICp. In the ')Ccon(i "cp. Ihe RNA chain IS dlge~lc(i away by RNII.'\C 1 while n:1'CThC tmnscri ptase cre~ t l!S the ooll ble1 SlrJl1dc(i un,mcgrJtc(i DNA. All of the clas~ieal antirctrol"iral agcnt~ arc 2'.3' -dideoll)" nllC'leOliide anyIOl!ue,. These compounds share a ~'()nunon mccham~11I of aclion in IIIhiblti ng the rt"CrM: tnln<;CnptllSC of Ul Y. Ikcau.~ l'C>cr.c IratlSCri(ll1lSC acts early in the 'Iml infection sequence. inhIbitors or the t'tlZyme block II('UIC m fcctlOll or 01'11\ but are only .... eally actil(' in chronICally Inf~'Cled UIICjI. (lien lhough the rt'>eN tntno;cr; plUC Inhlbi tor> -.hare eomnlOn mechanism of action. their phamliICQlogical und lu,ieo/ogical prolilcs differ (irnnUl!lcally.
An

tOPiCal
aduh ~_ ~

lable

fo$Qmet Sodium.

)OnlClh

",ud eoagai nst

;ue~ thai

. pho>-

I h) drol' cellu: acts u., ITP). O-

of ,-,ra1 ,ro..... ing

Trisoti1um pho\phoooformmc I' an Jlyrophosphate analot;.uc llul inlllblt' ",p1i~at iOIl .bld liCSliruse.~ (C M Y. HSY. and YSY)allll rctroviruses I ~IV),"" FOloCamet ( FOSC!lvir) is talen lip slowly by thc ~cl" aldoes IlOl. undcrgo 'ignifi~lIni lIunlCcllular rnct3boli'm. :lI'TIe1 i~ Q l'C'\cl"ibJc. OO!lC<.>I1IJ"IClllilc i nhibit(lr al Ihc P)~tebindlng .itc of 11M: I'iml DNA pol >l1lCra~ and "lfI"oC' lranscri(llll.~. "The ulll m.1te cll"i:~t I' inhibllion of t~ 'lit or pyrophosphate from deoll}I1OClcotide 101'110'>IIId a cessation of the IIICOI'1'O"IIIOIi of lIueleo,;i(\e ... f'I\.o.le<; inlO DNA {wilh the COIlCo.mlam n:lea-e of "fIh:IteJ.~ Since the inhibition i. f1()III;ompetill\c ~I to nucleoside Inpnosph:uc bllxlin,. fO'iCOll'llCt ..., 1)l'lnli,tlcally \\o 'ih nocleo<;ide triphoo.ph:lte antin~' . (e.! .. IJ(1Q,udine and dltial'l!))lne triph<l!iphme') in illl'lIbcuOll of v1l1d DNA synlhes ls. Fo>camci doe. IlQ( . . . ~11\'lIli(ln by virJI Ufce1iu laren/ynle1 and. helll't'. M dfli"e lIgIIlllst resistml! V iral 'tr.lIl1~ thm are defi :mt in ,illlll) cm:odcd nuclt~i(ie ~ma'-Cs. "

""'I'S'

Zidovudine, US" . Zi(iovudi rJe.

3'-vjdn-3'dco~ylhymi

I' a <.ec'I)Il(ilme drug for tile In'all1lol'lIl (If n:1I"" C MY In A IDS p.ment!>. The drug eou~ mCIlI-

dme or AZT. i~ ~n onilloglic of lhymi(iinc th:11 plllise~~S :mll,iral !!Ctillly ogain)t Ill V I. H IV~2. HTLVI. und a number of other 1'C'1I11\'iru~~. This noclcoside \las )ynthcsil.cd III 1978 by Lin and 1 'ru1oOtT" .as an IIltemlcdiate ill the prcparulioo of IImioo acid analogues of thymidine. A scrccmng ~1'lI11I dlrocted IO ....ard the Ident, flCation of agenlS potentially cffcctll'e for the trt'almcnl or A IDS paticnh led to the dl<;OOICI) of its unique anti,'lral prop:"nlCS 7 yellC5 later"" '1lIe: nc~t year. the cllmcal cffCC11>el'lCSll of AZT III pallent.~ "'"h AIDS and A IDS-related complex (ARC) \\011.'1 denlOn\lllllcd."" AZT i.s IiC1I1C against rt'Iro~i-

ruses. a group of RNA vi ruses responsiblc for A IDS and somc kinds ofleukcmil. Rcuoviruse!l possess I revcrse ITalISCri plllse or a RN Ad irected DNA polymerase thai directs the synthesis o f a DNA copy (provinll DNA ) of the vinal RNA genome that is duplicaled , cin::u larUcd. and incvtporat~'d into the DNA of an infco:ted ce ll . The drug cntenl tile host cells bydiffusioo and i~ phosphorylaled by cellular thy ntidinc kinase. Thymidylatc ki nase then convcns the monophosphate in to diphosphatC5 and triphosphotcs. Thc rate-tJe.. termi ning step is COOVn"S1on to the diphosphate. 50 high leve ls of monophosphorylaled AZf accumulate in the ttll. Low levcl~ of d iphosphatc and triphosphate are present. l j. ik'udine triphosphate competitivcly inhibi15 rcvene (Tan. scriplase wi th respect to thymidine triphosphatc . 'The 3'. azido JIOUP prevCntS formation of a 5'.3'. phosphodiester bond. 50 An causes DNA chain tcnnination. yiclding an incomple te proviral DNA .-'Il Zidovudine moroophosphate also CQITlpeti tively inhibits cellular thymidylQte kinase. thus decreasing mtracellulu le ve ls of lhymKline triphosphate. The: ant ivi ral selectivi ty of AZf is due to its greatef" (lOOX),1 affi nity for HIV revene transcriptase than for human D NA ~ymerases. The human y-DNA polymerase: of mitochondria is more sensitive to zidovudine; th is may oontributc to the toxici ty as ....da ted with the: drug', use. Re. sisllll1(:e is conullOfl and is due to point mUllitioos at mu ltiple $ites in reverse transcri ptase, leading 10 a lower affi nity for the drug .'-l Zidovudine is recomme nded for the management of adu lt paticnl.'l with symlXomatic HI V infection (A IDS or ARC ) who havc a histOf)' of confirmed PlIewmocysfis carill ii pncumOfl ia or an absolut e C D4 (1'4 or T H cell ) lym phocyte C()tIJlt Ixlow 2001mml before thentpy. Thc hematological lolticity of the drug ~I udes il.'l use in asymptomatic pa. tients. Anemia and granulocytopenia are the most common toltic effectS associated with AZT. For oral administrat ion. AZT is supplied as I()().mg capsules and as a syrup oontai ning JO mg AZf per mL. The Injectable form of AZf contail15 10 m"mL IIIKi is injected Intnl vcnously. AZf is IIb50rbcd rapidly from the gastrointestinaltract and distributes well into body compartme nts. in cluding the cm:brospinal fluid (CSF). It is metabol ized rapid ly to an inllCtivc gluc uron ide in the liver. Only about l.'illt is excreted uochangrd. 8ecJiuse An is an aliphatic azide , it is heat and light sensiti ve. It should be procectcd from light and Sl~ III 15 to 25'"(;.

larl y, whe re it inhibits reverse trallscri IX~ and is joc~ rated into viral DNA to cause chain tcmu nalion m HI\ infected ce lls. The potcocy of di danosme is IO-to l00-fold less than that of AZf with respect to an(i\"iml lI(.'\ivity and cytOiolCidty. but \be drug causes less m}elosupPrc.'ilIioo tImt AZT cau ses.'"' Didaoosine is recommended rOl" the trealment of palicllb with advanced HIV Infecllon .... ho ha\'c recef\'ed proIontcd treatment with AZT bill have bcC()rne intoleram to, OI"apmenced immu nosu~sion from. tlv:: drug. AZT and dJlltI synersisticany to inhibit HI V replicatIon ill VilfO. nod ddl ll cffecti \Ie agai nst some AZTresist:lnt SI nti ns of H I V ."~ Painful peripheral neuropathy (tinglina. nUnlbne~!>., and piln. the hands and fed) and paocreatins (nausea. abdonu nal pllil. clcvated amylase ) are the major ~li lTli ting 10lCici\1('S of didanosine. Did:mosine is ghen or~JI} in the fann 0( buff ered chew~ble tablel.'l or as II solution prepared from tht powder. 80th oral do>.age form_ are buffered to prelell acKl icdccom~uion of dd l to h)'poltanthinc: in tlv:: stl.WlUdt. Despite the buffering of tlv:: dosotge fom' ~. oral bio(l\':lIbb!~ ity is quile low and highly I'llliable. Le~s than 20% ofa ~ is excreted in the urine:. which suggc.sts elC tensl\'c mrtD lis m..56 Food interferes with ab.o;orption. so the oral drug mw be given at least I hour before or 2 hours after meals. II.p. dose therapy can cause hypcruncemia In some plltimtli brcause of the iocn::ascd pu rine Io.m.

o
DidaI1JJI 'Ie

Zakitabine. USP. ZalCltabll1t". 2'.3'-dKko~ycytidtDt. ddCyd. is an anal0l:uc of cytosine thai demonStruu:s :leU'" against HI V- I and H IV 2. inc ludmg stnlins resistant to AIr Tbe potency (in JlC'ri ~ral blood monon\lClcilfcclls)is ~ lar to that of AZf, bUI the drug is mo re aell vc in populD!I* of monocy tC!l and macrophagcs as .....ell liS in m./;ng (dh. Zak itabi ne cntcrs human cells by eatrier facl htW:d di sion and undergoes initial phosphory lalioo by doo~yC)tidllc kinase. Tbe monophosphor)' lated compound IS funhcr tabolizal 10 the activc ntclaboille. dideOlt)'C)1idlll('S'* phosphate (ddCTP). by cellular kinases.11 ddCTP itlbiilo reverse tnlnseri plase by oompetilll e inhibition "Ith den' Mosl likel y. ddCTP causes termi nation of the vintl DNA chain.
Zalcitabine inhibi ts ~t ~i ~~."'~~~.~~'N~~ "~~~~1 low concentrations. Th is cffect mal contnbu le 10 it tOlt ici ty.5t The 01"111 bioouil ability ZlIldlablnc: adul l5 and I e.rrco:t is thesias. Iowa do

.~.' III - . ./
Didanoslne. Didanosinc: (Videll, ddl) is 2' .3' -dideoxyinosine (ddl). a synthetic puri ne nucleoside analogue that is bioactivuted to 2'.3'-d ideolCy ATP (ddATP) by host cellu lar cnzymes. 'J The rnctabol i ~. ddATP. accumulalCS inltacetiu

,~,;.,;, .'" ~

entl months o f therapy ., . A potcntlally pancreatit is is an{)l hcr tOXic effect of treatment .... ilb tU:. Tbe drug has betn approved for the treatment of III V

lIdu lLS wIth IIdvanccd disease \O.ho an: irnokrnnt to AIr or ",110 have dlst'alIe progression .... hilt' rea-ivin8 AZT. d.iC is combulCd .... uh AZT for the tre:llment of advan,,_ed lilV infeclion. tioQ
In

5gvudiM, SlanM/irIC, 2'3'-di<kh)'dro-2'deo~ythymi dine (I>JT. Zeri l). is an unsaluraled pyrimidillC nucleoside \hit h rdaled to thymidine. 1lw drug inhibits thoe replication of HIV by nlnanism similar to that of ilS close ~"OI1ger1('r. W '" SLavudillC is bi03C1iv:tte:d by c-c:lIular c:nzylIlCS 10 a
The triphosphate oompcmh'dy inhibits the in wj.b'atlOll of thymidine triphosphate (lTP) into retml'iral !)SA by reve:rse Irunscriptllst'.61 SlIIvudine al.'lO causes lermi "M of viral DNA elongation through ils illOOipoialion
~.

DNA,

II is interesting thai the untlalurnl stereoisomer (- }-{.\j. ddC exhibi lS grealer !lIl1i"lrW 3C1i\lly against IlIV than the natural enantiOl"ller( + KS}-ddC.~ Both tnanllOlI~ are bi oactivoted by cell ul!lf kinascs 10 the c('lfTc:spolld ntg lriphu!. ph3tcs.'" II00h SddCTf' 'sonler.. inhibit HIV n:verse tnrn ~pca.se and are incurportUoo into vlrW DNA to caU$e cham te""ination. (+ ).S-ddCTP inhibIts cellular DNA polylfl('r ases mIlCh nMlre strongly than (- }-SddCTP, upl:lIning lhoe greater lox icity aSSOCioted with (+ )(S)ddC. Initial meta bolic comparison of SddCTP isomers has failed 10 explain the ~Ier poIency of the (-).bomer against HIV. There fore, although the ;ntracellullll' >iCX\llllulatiQll o r (- )-S-d<.K:Jl> .... as twice that of (+ )-S-ddCTl'. the lauer .... as I ~ time~ more potem as an inhibitor of H1V reverse tl'lln scri ptasc. and the t .... o isomers were incorporated into vil'lll DNA !II ooll1parnble rotes. 1lle puUIc: .... lIS soh'cd wilh the disro,'c:ry of a celluhlt 3'S-eXQIloclc:ase. ""hlch was found to deave lenninal (+ )S-ddCMP incorporated into virJI DNA 6timcs faster than (- )S-dllCMP fll)ll1lhe viral DNA terminus. ResislllllCe to lami\'tldme de,'clops ropldly as a result of a mutation in oodon 184 of the gene thai encodes HIV RT ",'hen the drug is used as monothcrap), for HIV infection ,'" When combined with AZT. hu.... e"er, lan\ivudine cau'\ed s.ubstanliaJ increases in C()4 ' cOlints, elevated COlintS wet"c: sustained over the course of thenpy.1>7 1lle codon mutation Ihat causes I"C$lstlllK'C 10 lannnldine suppresses AZT resislIllICe.&7 thus increasing the suscepcibility of the virus to the drug combination ,

n.e

"",

~yO

""
Suvudtne is available 11$ capsulCf for ocaI adminislIlUion.
acid stable and .... ell absorbed (aboot 90%) fol has a short hlllflife e~cn:ted largely ulIChanged As .... ith ddC. the primary dosepc:npheral neuropathy. At the reoom ":;:;~~~II; 151020% orpatie:nls ape)C I neuropathy. St3vudinc is m::)I' treaunent of adults with advlllICed HIV
OH Lamtwdine

,m,:';

_rule

~r n:ec:i~ing

,~~':~~,~:1.~~~:, appro~ed

IIkKIeosId. Anti.".'eboltt.. Ri bavi rin, USP. Ribavirin is 1. ,8-t>-ribofurlU"lOSyl.l.2.4MIK.I~n II. thiu.ole-J..camo~amide ,

thernpics or I or mlllllll)ological deterioralhoese tlK.-rapie.\, .3' -dideo~y3' -thia I 3TC. or

side arutlOlue ",llh I moiety. The struclure of ribavirin

The: compound is a purine nucleomodirled base and I o-nbosc 5uglll'"

i~ ~hown

below,

activltv again.~1 ~tudied,t>J 601 Pn:limi. siudies indicated Ihnt il exhibited good - - 80';1:) and a plasma halflife: of

",, /",-(,0

r
Ribavinn mhibits the replicaTion of I very wKie Varlety of RNA and DNA viruses." includmg orth(lmYllO\';ruSCS. paramyxuviruses. arenaviNSC:S, bunyaviru~s.. herpes... ifUSCS. adc:novlruscs, po~virus. vaccinia. innuenza \';NS, parainnucfl7J1 vil\ls. and rtlinovirus. In spi lt of the brood sptCtrum of IICIIY;ly o(riblwirin. 1 drug has been appro\'ed 1M: for only one lhenlptutic indiclllOll-lhc In:atment of seven: lower ~plrnlory mfeclions caused by RSV in carefully selected ho~pilaJi~ed infnnllo lind young chi ltlren. The mechanism of acllon of ribavirin i~ 001 known. The broad anTiviral spectrum of ribavirin. however, suggests multiple modes of ac1Wn."" The nuclco!litle is bioanh'ated by viral and hoIil cellular ~ina.'ieS 10 give the monophosphalC: (RMP) and Ihe triphosphaTe (RTI'). RMI' inhibiTS inosi ne rnonopho.\phatc (IMP) dehydrogenase. Thereby pre\'cnting 0 the OOIWen:iOll of IMP 1 xanthine mooophosph:ue (XMP). XMP is required for llullllOSine lriphosphale (GTP) syntllesis. RTP inhibi T viral RNA polymerase. It nlso pn:: ~ents S the end capping of ~iral mRNA by inhibi ti ng guanyl-N'methyltransfenlSC. Emergence of~iraJ resiStance to riba~irin has not been documented. Riba~irin IX!CU Il:l$I. white. crystallillC. polymorphic solid that is soluble in wmer and che mi cally stublc. 11 i~ supplied as Y powder to be recoostltutec.l in an IIqIlCOOS a/:":rosol CO[\taining 20 mglmL of stenle water. The lI(' osoj is administered with I. smull-panicle aerosol generator(SPAG). Dct.eriOf""Jtion in respirJtOf)' function. bacterial pneumonia. pncumotho"'J~, and apnCH hu~e been reponed in severe ly ill infnms and children with RSV in fection. 1"1le rule of rilxtvirin in these e,ems has not ~n determined. Anemia. headache. abdominal pain. and lethllf1!Y ha,'e been i\'ported in patients ~eivin g or,L1 rilxlvirin. Un labeled uses of ribavirin inelude 3c:rosol treatment of innucnu typeJ A and B lnd 0flI1 treatmetlt ofhcpatitis. genita! be'jKs-' and I asS/! fe'er. Ribaviri n docs not proteCt cells ngnlnst tIM- cytoto~ ic effeas of the AIDS virus.
been complicated by tnc fact trun the vattine apparently ClII modu late its antigenic structures In lIS chronic inf1iOltl $Iate.7tI

NEWER AGENTS FOR THE TREATMENT OF HIV INFECTION

When HIV-I was chamctctilCd and Identified as the cnuSlltive agent of A [DS in 1983.1'CI. 11 scicnti~u from all ower the world joined in the search for a prevention or cure for the disease. Mapping tnc HIV- I genome and eluci dating the replication cycle of tnc virus hll\'e supplied key informauon,n Biocncnllcal targets. many o f ... hich arc protelllS invol,'cd in the replication cycle of the ~ il\ls. ha"e been clooed and sequenced. These have been used to devclop mpid. nlCChanism-bWiCd a.o;says for the virus to complement tissue cu Iture 5Cn"CnS for whole ~irus. St"eral of tnc biocncmic.al sleps thaI ha~'e been chnmctcrized have served 11$ targets for clinical candidates as well as for succcMfu lly hcensed drugs.7J. l' Despite the many ad~ances in tnc lutdc:rstanding of Inc HIV ~irus and ils tf"C8tmetlt. IhcTc is rKlI yet a cure for the Infection. Emergent resislIlnce1' 1 clinically pro,'c n drugs 0 such a.~ tnc rc~crsc t.-.mscriptase inhibitors and the protease inhibitors hu complicated the picture of good thcmpcutic targets. Thot idea of us.ing I vattine as a tncrapeutlc tool has

Thot chronology of \'lICcine de\"dopment mj uo;e in the 20th century is nothing shon of. medial mli"ll(it. DIseases 5IJCh 11$ smal lpox and polio . ... hlCh once: tIIVlIgaI large populations. hal'c become distant memories. 1bc ted!niq ue of sensiti]ing a human immullC \ystem by e~posurt to an antigen so that an anaml1($tic response is gei"oClM on subsequent Clpoliurt seems quite sinlple on the surfatt Hence. it is natural that a ~~"Cinc approach to prnrotul! AIDS be tried. The SUCl-C:SSC~ IIChic~ed so far have invohtd liveJl1l1cnUlllcd or killed .. hole-l-c:1I vlICClncs and. in _ recenttimcs. lUombinant coat protems. Succes.~ with vaccines of the li,c/allcnualCd (10 ... 1,.. lenee). killed ",hole I'irus or the recombmant coat prI)\nIl types havc primarily involved acute vlml disea.<;c:s in "'hid! a nllturui infection and reco"cry lead to Iong-tcrm immurnty. This type of Immunity is of lhe humoral. or anlibOO) mediated. tyjK, and it is the basis for succesSl"S in ImmUIIL/' ing the human population. Causatile organisms of rnnlill( il1fcctionsUo o(M respond to vlI(:cincs. The AIDS \ irusca~ a chronic dio;ease in ...hich infection jKrsj5l~ despltC. suo.c antibody ~ 1 the virus (at le35t mitially. H[V eM 0 em:umvcnt the humOl1l1 response 10 infection by QttxkiJc and killing CD4' T cells). These T cells. also kno .... n lilT helpcrcells, upn::gulatc the immune re~ponse. By endicatirtl the CD4 ' cells. the HI V V '!\IS ctTect i"ely destroyli the illmunc system. Cell-mcdllllcd immullC responses are mba! to ,he prevenllon and treatmcnt of H[V infection. To bt effective. a va~'(:ine agai nst IIiV mu,1 elicit an apJli'll!'ll'llR cellular immune response in addition to a humoral I't"SJIIlIIIf In other .....ords. the \"acdnc must hn\e the potenhal \0 ICI on both branches of tnc ImmullC sy~ttm. The initial 10'00; on ~acChlC de,"elopment focused 00 '-"> typic ~aria",s ortk IU V en~cJopc glycopmu:in @pl20~ tained by recombinant DNA tcchniqUt.'i . This t:ugct ...1Ilo~ <;t>n because of coocems .bout the ~fet)' of li'c/lltmuan ~acci l1($. The gpl20 glycoprotein i~ coat protein. -'" grem ~are is take n. a ~irus free vaccine is obminablc..\Imover. glycoprotein gp 120 i~ tilt primary target for III"\ItraIii. ing antibodies associated with tnc liN (anachmel'll)SlqI. HIV infeaion.n Early \"acciilC!l were SO incff1i~e!hl!. NaTional InSli lutc of Health USjKnded plans for masw , cl inicaltrilll~ in high-ri~k individuals.? Thcre are I numht of fCUOOS why the vaccine failcd.'19 There arc multiplf" types of the \liru~ throughout tIM- ...orld; the virus can by means of both cell- free and cell-associated ft:lflm; virus has demonstrated it~ own immunosupprt5SIIC. , _ nopathological. and infcction-enhancing pmjKnics of ~ of the envelope gl)'copt'Qle;n; and vacciocs rn.~c IIOIIICaI able to stimulate and maintam high enough !e'"els of Unity to be cffectlve. T he failure of the first generation of AIDS vxcinn III to I rce~amin~tion of the .. hole A IDS \accinecfTort." As guide for resc~h efforts. I. number of cntem for IlII . . . A IDS vaccine ha'"e been de,clopcd. 1"1le "idcaJ" AIDS III: ci!1C shou ld (II) be safe. (b} dicit a protective imm"'lfsponse in a hi gh ph.It)()j'\ion of vaccimucd indiwidulh, stimulale both cellular and humoral branches of the ",.;.

V.cdnes.

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aged tet:h-

; roted rfoee. !nting

~"~

'ohw

. _V IIU_ XUlelll which unity.

lbod~

'Iunll.;hll.Hlic causes strong IV c:m tacking nIlS T licaung tbe im cnlical

1)>I(m, (d} protect compol1~nlS against all major HIV subI)'JIU. (~I ,nduce long-lasung proIcctioo, (/) ,nduce local immumty in bom genital and rectal mucosa. and (gl be prnctical t world .... ide deli\cry and administrJtion . It is ooc yet Ulm\n how well the second-gencrauon AIDS voccillC'!i "'ill ,,"sfy the oOO\e crileria or .... hen one might l"CC('l\e appro..al fof widespread use In human s . A new era in the treatment of AIDS wid A RC was ushered at "llh the :uhent of some eli nically ue:ful, poIellt inhibitors of HIV . For the first time in the hblOry of A IDS the death rIIC re~cr.;ed ibcJf. Then: an: sen!ml different classes of 1kIt1!~ that Cllll be used tQ treat HI V mfeetion. These arc !be QUCIcosIl:le re,erse \r,mSl.:riptase inhibitors (NRTIs). the 1OIUIUC!eQ"lIk n:'-':rse tronscript:lloC Inhibiun (NN RTI~). _IlIV prote~ inhibitor.; (Pis), the HIV enU)' inhibitor.;. -'the IIiV integrose inJ"buOI1i ( IN). fu;;ently, at least 14 *tR'!rO\lr.1 a~,'ents belOl1gmg 10 three distinct classes '''Rlls. NNRTIs, Pis) ha,-.: been licensed for use in palicms the UlI1Icd StatC!i. All of these agenlS an: limited by rolpid *,,'rlopmC'nt of resistance und cross~isul/"lce, so com.only t~ drug$ are used 3t the SlIme: time:. each IlCling 31 IdrlTerc:nt point in HIV replication . Tht$e drugs cnn effect hmatlC rc:doctions in .. iml load. but evcntually. as resis~ dtsc:lop~, the vi rus n:as."'!"~ itself.

coding forlhe enlyme. Cross-~lStancc bet ... c:cn structurully different NNRTls is rfIOI\" oommon than bc:t",ecn NNRTls and NRTls. In the future. clinical use of the NNRTIs is ellpcctalto u<;c oombm<luons wi th Ihc: noclrosldc:s to ~ tOllicity to 1he latter, 10 take ad .. antage of addilive Of" syner gistic effecUi. ul1(1 to reduce the emergence of .. irul re~i~ tance.'s, til TIle tricyclic compound ncvirupine (Virnmunc ),.: the bi.'>(hel~roacYI)Eiperatine (BHAP) deri .. a1ive deluYi radine (Rescriptor). J nnd efa,irenl:1U h~~c been approval for use in com binotion with NRT ls such U5 AZf for tho! treatment of III V infection. Numerous others, including the quinmaline demative GW-420861X.1I< the lett:lhJdroimi dazobcn1<xhazplllOne (TIBO) analogue R-82913. and calanolideA" are in clinical trials.

...nudeoslde Re.erse Tr.nKriptaH

~bttors

(NNRT1$)

NeviriJplne. Ne~implllt(Vir.lmune)ll is rfIOI\" than 9O'J, absorbed by the orol mule and is ..itk:ly dlStnbutal throu&JIout the body. II diSlributes well into bn'ast milt and crussc:s the plaet:nta. Tl1UlsplOlCCntal eoneentrJtions arc: aOOtH 5O'l> those: ofscrum. The drug is e~tel1sivcly tnltlsformcd by cytOchrome 1'-450 to inllCti\"e h)'dro~y latal metaOOlltc:.~: il mny undcrgo clllcrohcp;,tic recycling. The half-life dccll':ase~ fll)rn 45 to 23 hoon; o,er a 2- to 4-",eek period bctause of autoillduc.ion. Elimination occurs through the tldney . w,th less than 3% ofthc parentl"Ompound CJlcreu.'d in the urine .r.l [}osage forms arc supplied as a 50 mg/5 mL oral suspension anti II. 200-mg tabiet.

.-optiate $pone:. 1I to (l<;t

T. '"

n.d HIV- I re~erse trullscrip use fltCilit3lC5 the ",tidy of dTec1s of a 1lO\cl compourKi on the '.anctics of the ~n ~ ftaodom screening of ehemical In'emories by the
irKiusU)' !las led to the di.scovC'ry of !>evcnl '"\Rlls of the enzymc. These Inhibitors represcnt seve:ral ftllnUy distinct clusscs. The NN RTh ~hnre 0 Ilumber of ~biochcmica.1 and phannOCtllogk:nl prope:nie~. u . ".11 tlllkc the nuc:Jcoside antimcmOOIiI~s. the NN RTls do nOl ~.rt blOOClivation by ~inusc, to yield ph&.;phMe estcrs. "!'ley I\"e 1101 Incorporated into thc gro .... ing DNA cha in. In~y bind to an allosleric site lhat i~ distinct from the (nuclOOloide triphosphate}- bindlllg site of reverse pease. The inhibitor ean oombillt with eitho!r free: MhIu1ICboulld enzyme. int~rfenng With the ac1ion of Suell blndlllg diSlom the enl.)" nlC .Ml Ihal II cannul die c:nzyme - Illbstr-'le eomplell yt liS normal ralc. ... o.ct formed he complo doI':s nul decompose a. the !lie 10 )ie:kI products. Increasing the substrate .:mtM.J0II does not re'crse these effects. Hence. \'iRTI~ nh.bit 1\ c lassical \1IJrl(."Qmpcti'i ..e ;nhibilfon pat_Ill! the cn'yn\C. Ibt NNRTls arc c)ltrenlCly poIcnt in in vitro lOCI! cu lture Mi)' and Inhibit HrV~ , at nanornolur l"lll'CCl1lrutions. ..... RTlt mhibit re,'crse Irolnkripta~ ~Iec:ti Ycly: lhey do not ... tbt transcriptases of other re,ro\lruSC$. inHIV 2 and simian immunodefieiency virus (S IV). 1'."XRTIs hI,e high therapeUIIC indiccs (In COIlumt to III-.D:oodc:s) and do not inhibIt mammali:m DNA poly. The NRTI s aOO NNRTIs are e~pccted to e)lhlbil a effect on Ht V. SInce they inlCTaCt with diff~ll':n' on the eru:ynlC. The chief problem wnh the iI. the rapid emergence of resIStance amoog HI V ....: ... Resislance is due to poinl mutations in the gene
~ullcal

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OeliJlfiniine. Dclavl rdlllt (RcIICrip!or)ll must be used with :II least t .... o IIddmonal antill'tro,iral ag~nUi to tl1':31 IIIV I infectioos. The oral absQrption of tk:la~irdillt is rapid, and pea~ plasma conantrouons develop ID I hour. Elltensi\e metabolism OCCutt III lhe li\"~r by eytochrome P-450 (CYP) isozynlC 3A (CYP JA)orpossiblyCYP 21>6. Blo&vailabl iny is 85"'-. Unlile nevirolpme... hich is 48% protem bOtllld, delavirdinc is more than 98'}, protein bourld. The half-life is 2111 II hours. alld elimination is 44<;11 in fece~. 51 % in urine. and less than 5% unchanged in urine. Dda.. inJine indue its own nlCtaboli~ll1 .lJ Oral dosage forllls all': supplied 115. 200-mg cup'u le and a 1000rng tablct Efaviren:t. Efaviren1. (SustiYllf' is also marKiatc:d for usc: with at least ''''0 other :mtill'troviral agent~. 11lc com pound is more: lhan 99<J, proIe:in bound. and CSF CQnCCntrotionl nec:cd the free fraction in the serum. Metabolism occurs in the h,er. The half-life of a single dose 0( cfllvirc:ru: is 52 10 761lours. pnd 40 to 55 after multiple do!;c:s (the dlUg illduceJi it); o .... n metabolism). Peak (:()Il(X'"ntratiun is aclUc\al

in 3 to 8 hours . Elin)inal;on

I~

14 l'l34% in urine (as fJ\Claoo.

lite ) and 16 to 41 % in feces (pri marily as efa"irenl.)." The 0nI1 dosage form IS .upphed as a capsule.

I ",A",

"IV Prot_as. I ..hlblbas

A unique: biochemkaltargel in the HI V- l rephcation cycle was reveakd when HIV proIcase was cloned lind ex presscd ..... 1"1 in &chuichil/ co/i. IIIV protease i~ an enzyme that c!ea\"cs gag-pro propcptides 10 yield active enzymes Ihal fUrtCiiOO In the mawr-Ilion and propagation of new virus. The clltalytically ocIIVe protease is a symmctnc d' mer of two idtntical 99 amino add subunits. each contri lltui ng 11M: triad Asp-Thr-GI)' to the act;"c sile ..... S1 The homodimer is unli~e monomeric aspartyl proteascs (renin. pepsin. cathepsin 0). III hkh also ha\~ diffrrem sub:'iU'~le specificities. The de.~ign, of -orne Inhlbitors""- ... for H1 V- 1 proICa'iC c:~ploil Ihe C: , ymmctry of the en/yme. HI V- I prott'ase has active SHe specificity for the trilld T)'T-P!le Pro in the unit Ser(fhrJ-Xaa-Xaa-Tyr-Phc-Pro. where Xaa is an arbitl1ll)' amino acid. HIV ~ca~ inhibit~ are dcs.gnetl to mimic the tronsi tion stalC of hydrolysis at the active sile: these: compounds lI/'e ClIIIed IINlloglN' mhibllon. Hydrolysis or a r!"idc: bond proceeds through a tronsitiOl1 state Ihal is !/P" hyhridi7.ed and i1eocc. tetrahedral. The analogue inhibitors pos....ess a preexi sting "fI' hybndi7.cd IXntcr that will be drown into the lK.'1 ;\'e site (one hope. with high affinity) but will I1QI be cleavable by the enl,yme. This pnociple has Mn used to prepare hundred;; of potentially useful trnnsi ti on state inhibitors."" 111 Unfortunately. \'el'}' few of thc.~ are hkely to be cl inically successful candidates fOl' the trcatment of HIV in fection . Since HIV protease: inhibitors are 3imed at a!Testing replication of the ~irus at the matunuioo SlCp to prevenl the

spread of IXlluhu' mfecttoo. they should Jl'O$SCSs good ontI bioovailability and a relat;\'cly long duration of a;:tiOil. "long half-life is al"" de:sm.ble bo\:lIU<e of the Loown dc:,~ 111('111 of resistance by lilV under sc:1C:Cli'e amivl1'ltl ['1ft$" sore.''" Resistance dc"elopli by point mutations. Most of the early proteasc: inhibitors are higb-n~ weigh!. dipeplide_ 01' tript!ptitlc:.-likc structures. gcneral~ w;lh low water solubility. n.e bioavailability of thc:sc: aapouuds is low. Dnd the half-life of elinllnation is vcry"", because of hydrolysis 01' hepatl(' metabolism.1III Str.alepe. aimed al increasmg water solubdity and metabolic subi~ have led to the devel<lpmcn\ of severdl highly promlSI., clinical candtdate~. Saquina\';r ( In vin5e )." indinalir lCrwvan).11'1 ritooavir (Norvi r).<>O nelrlll3vir (Virocept).9 . alld_ pren~v;r{Agerl('~t! halc been appro"cd fOl',he lIl.'atna: of m V infected patients. A number of othe .... are in clutd trials. There i5 an important caution for the usc of prote.a.'iC ..... i.OOI. As a class. they cause: dyslip,demia. .. hlch ioclur.b devated cholesterol and triglyceridcs and a n:disuibutioa!i cause the " protease paunch." b\JffJII body ral IXntrally hUIllP. facial atrophy. and brelt" cnhU'!;cmcnl. 11Jcse ~ also cause: hyperglyccmia.

'0

Saquinavir. Saquina"ir (ln virasc)" is well tokl I foll"wing 0011 IldrniniS'Mioo, A~lon or '\aqUlTl~''''.
poor but is increased with a fally nl('ol. Thc drug doa III distribute inlo the CSF. and il i~ approximaldy 98lA- to.! 1 plasma proreins. S:Kjuinavir is extensively meubolUd 0 by the l'irst-pas.~ effect. Bioavatlability i~ 4% from I . . caJKulc and 12 to 15% from a soft capsule. SaqUIII3W Iotttn p24 anligen level$ in H IV -in fecll'd patients. e!elales CJ)I' COllnl~. and exerts a syncrgisliC lmlivnal e(fcc .... hrn c.blned with reverse tran scriptase ;nhibl1~ ~lICh as AZT ddC.'J-fl Although Hl V-1 resistance IOsaquIll3~iraod. HI V protease inhibitor.; occurs in vivo. i. is bclit:~ ID less stringent and less frequent than resistance to the ft\'eII/ transcripl4SC inhlbitoB. WI Ncvcnhelcss. CroS$-I"CSISla!Xr ~ tween different HI V protcase inhibi.unI appclll'5 to be ca moll and addit;'e.~1 suggesting that combilllltK* inhibitOOl from this cla.o;s wou ld IlQI i scribing. The drug should be used in combination I least two other anllretro"iral drugs to minimi/.e ! Dos!lge fomls an:. I nvin,se (hard cUp5ule) and Fono.iISC I cap!iule).

o..ptu II A",i>-iroJ AltfllJ

385

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higb fnction ofhcpat1c melabolbm. Subsequcnt synl~is of oonsx;mmetric derivatives OMP-8SO 'o' (bclow) and OM.> 8.51 1 I yielded in vitro antiviral po;:ency comparable wilh thai of lhe already-approvcd Pis. 111esc were sclcclw 11$ clinical candidalC5 on the basb of lheir favorable plwmarokinelics in dogs. In a second approach. random screening of chemical inventories yielded ,he 5.6-dclJydropyrnn-2-or.cbased inhibitor lOl PD-178]9() (below ). This compound. III addi tion 1 having good potency against HI V protCa5C aud 0 good anli-HIV activily in cell culture. cxhibits high bioavallability in experimental animals.. PO-I 78]90 appears oot to sI'Ian! !he resistance profile or the other Pis. and no ~ irus resist.nt 10 the compound emerged, evcn during the prolongcd in vitro selectiO<1.

...m.vir.

"If

:cularnerally ecom-

phon

:alc,ies lability nisi ng (Cn:';!IfId :un eanncnl clin Ical

When OOUlInlStl:rN with . high fat did. indi(Cn~ h'an)\IO achlC'es II maJIimum setum cooccnlnllion n'f of the oonlllllStcral dos&:. 111&: drug is ~ bound the plMJl1a.. It I) u tcll5h ely melabolil.ed by CVP 3A4, IIId iIC\"('n !1Ielabohtc\ ha ve been identified. Oml bioovaillllillly is good. wilh a I" .., of 0.8 :!: 0.] hour. The half-life or tlimmation i~ L8 hour. and tile elimination producl~ are ~ in f~'i:es IU1d urine. lndinavir alsocau5es dyslipide... Tht lIvailablc ~ge fOl11ls Dre capsules of 200. ]]], _.mmg.

,e inhlbof
~,

include,

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bulfalo :r agcnt~

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r
fj

tolcrui(_~

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linavif I~ doc\ nOI

:tabohred ~ h.ml ' "If 10WI:"

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!lI&:n com , AZT and and othcr ( ,'cd UJ II&: .. ihe re\'I:N istan&:e II&:-be COfTl iRalion' "I !tlonal ~. Ion \\-lIh at
re.~isll\ocC

to

lova~ (!,uO

Ii\orwvir, Ampre~vir, and Nelfinavir. Ritonavir ...... ).... :lm~na ... r (AgellCl1l5e),<W and nclfinavir (Virafll' (liCe SlruclUI1!5 00 page ]86) have similar properties -.lcaIlion:uy ~1Ji' emenls. All cause dys lipidemla. and they -"':1 !oil of drug inlcrncuons. mainly because they inhibit riP ~A" 'fhc...: IIgellls mu~t always be used wilh at least . r antirelrt)\ lru l agcnts. Used propcrl y. IIIe: protease ' IOn lilt' au iUlpotIanl part of H1V lherapy . ~ ,..mber of nonpeptidc inhibitors of UlV proIeasc have ImIl1e\-clopcd U ~ a rcsu h of two very different approaches. \'UII11*. tix' Cl ~y!l\ll)l;'lry of lhe acti\'e si te of the en.'U uplouw In the sirucru~-based design of the symt)l:lic ult'a deti~auve O M 1'-]23. 101 TIlls inhibitor ex potrnt actl ~lIy ugalll~1 the proIease III vilro. excellent . .KrV actllily 111ccll culture. and promisi ng bioavailabi l.upemflI.'1l1al :ulUual s. In phase r clinical lrials. how~n the bioo,'aHnIJHuy of OMP-]2] was poor and highly . po6sibly hccause of it~ low wlllcr solubility IU1d a

- '"

,
NO
OH

.", ,

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Oipcpride Pis conlaining 2-hydroxy-]-amin0-4-arylburanoic acid in their scaffold showed promisi ng preclinica l resuill. JE-2 141 1OJ (below), conlainin g the aJlophenylllOfSlat in

,r
0

O~NH

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I
0

,r

NH,

N.. . . . :::::::0

~""C",
Arr""."avir

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N-!-~J lS 'xCH,

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387

r:notny. exhibited potenl in yi tto ~nn III V acu I' ll)". JE2 147 apptan 10 fully retain i1$ susccpublilly apmst II variety of H WWRS n:Sblant 10 multiple apprO\'ed Pb and uhlbus IV rood onl btoal'31b.bi lily and II good phannacolo;melie prome III 1 11,0 animal species. AI<;G. emergence of resiStlince was ron,ldtrnbly dela)'ed v.ith JE-2 147.

'~I.A'"
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HIV Ellb, InhlbttOf'S

R-

Enuy of li lV into a ce ll is a com plex PfUCe~s Ihat inyohes 1I:"er.tl spec ifIC membfane protein inlerac,ions. Ini,iall y.
\'Int glycoprotein gp l 20 mctJiu'e.~ lhe vi rus allaclllue:m via IIJ bmtlmg al least ,wo host me mbrane: recc:plors. C D-l

"_NH~NH
"'-40-3100

BI the: che:mo/.mc CQI1.'<'<'ptor. Th is biyalem Intcraction in dttcn conformauonal change in the: ",ra1 fusion proIe:i n

'0

IP" I, ProIel n gp4 1 ~IS as !he anchor for III' 120 In the: "irus.

Seye:ral pos:ill\ely charged 9 to 14-met" pcpudes have b..-en descn bed a~ capable of bloc!..,ng ,he CXCR4 coroccplOf. A smaJl molecule. TA K_779. 0!I c~hibi ts highaffinity binding ' to the CCR5 ~Of. specifically blocking R5 isolates.

Ililth the eonformlluooal change:. the: \iir~1 em'e:1ope fu'iCS _Ith the: host edl mem~. In OOditlOn to gp I20-chi'moltae IKt'pror imcr ..nioo. ,hi' fU~ lon lICtiY ll y of gp41 is Cllntntly bemg explored as a oo~cl target for antiretr\)\'iral thtnpy. Al le:a~1 one: agent fmm e:ach class is in cl in ical \t;lmg.

~o

0t , .tald_ Aec:.pto .. Binders

Mot! IlI Y1 i!;(llme:s rely on the CCR.'i con:ccptOl' for emf)' Ilj !oIr.iln'j. In later stages of the d i~a<;('. oolO.e\cr. more ,-orcnlC $Clc:clion varianlS of the vi ru~ e:merge: in about .(flo 0( IIIdi\ iduals. v.'hich usc the CXCR4 coreceplor m 10 CC R5 ( R5X4 slr.lins) or the CXC R4 receptor _f1X4 waIllS). Bieyclam compound A MD) IOOIOl' was .., fn( Impound ioc"'mified as a CXCR4-~ific mhlbuor "Intc:fferes v.ith the replication of X4 but not R5 ",rusc.... Thtrompound is cum:ntly in phase 11 cli nical e\aluations. ~"used a~ an injectable agent ro:lIUSC of Its limited bit)-llililabi hty .

."'I0Il

TAK7n

Inhibitors of gp41 FlIISlon Ad:Ivity

The: fu'lon of,he HIY- I \lrnl cn\elope lO.uh oo...t pI:lsma

membralle ,~ l11edl~led by gp4 l. a transmcmbnll1c ..uoonn of ,he li IV.] glyl-0pr04ein subun it complex. Pcntufuside'llf'I (T20 j is a 36mcr peptide that is derived from the C-tenni

Tetrazole

md rc~al of gp4l . PenUlfusKle IlJlPCIIllIO .ohibn lhe f()llTlalion orlbe fusion-compelcnl confoonalion of gp41 by inler-

ils C- and N-temlinal rc~al. l'cntafuside is a potent inhibitor of HI V-l c li nical lsololes, and it is currenlly m pha.'iC II clinical Inab. feong .... llh the in leroctlOl1
~I ... ecn

21 1Ir....... Eo .:, _ 11.....1<11. '" I I..... ): 8:ulc V,"""sy M...... lolA. IJlaook..dl Sc ...a, 1m. p Z$7 22. M'I>OIya. IL.ondlttlldn.SPrt.oc. N.., Acad ScI USA UI91L 23 Z-4 n, 26.

Integr._ (IN) Inhibitors

T .... o closely rt'lau!t1 t)'pe5 of small mokcul('s that bloc l Slrand Il'l1ns f('r cal.:alyzed by ret'()mbinanl inlcgm.e M~C been id.!nufied. Both I)pes s how In vilro anllvmtl acli vity. 1lIe dileto acKb '01 (alx)\"e) inhlon S1tl1nd tr.tnsfer catDJy~cd by recombinam Inlegruse with an IC,!(! ic.o;s Ihan O. J ""M . M Ull!lio ns that CQIlfenro rc.siSlance to the d,l.:eto add~ mapped lICar conM:rved resldtteS in the IN enzyme. This findmg demonSlrntc.~ tMlllIe compounds have a highly specifIC ITleCMrazole lOli denvali\'(' (.:aoo\(') re\('.:aJcd Ihat lhe inhibi tor w ..~ cenlered ililhe aclive ~itc of IN rICa!' acidic calnlYlic residues.

JoIuKoo. M A.. '" al.e J 8u Chom l(iJ;1534. lYU. .. ""~ N E.. to 01 I'm< Nad. And. xi. U. S. A. U.4b116. I_ Hoy. A. J.: s..",;n. Vlro!. l.ll. 1992. It a)dcn. F' G. n.,_, R. II .~. II I). '" 01. N Entl, J Mot
.'21111%, t'189

''''.

n
28.

:!9

.10.
31

nism of action. X-ray

cry~tallography

()f the bound tet _

)2,

1) 14.

Acknowledgment
PorIiOll5 of this ICXI "ere laken fro m Dr. Arnold Marti n'$ chapter in lhe lemh ed n ;oo of thi~ book.

lS.

J6.

17
l8.
)9.

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s.:.....

*'

'*"

1:5 """"' 0 .. II< 01 .. I.aoaIlJlI:l..o. 19'91 I&.. 'l.bLo ..tI. It., and F.ricUool. I. W: AnflU. Rev. H.o.;hrm , b2;~l. 19' 11 CIoow, Y K .. aI. N....... )6LMO. 1'193.
'It

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9J. R.:",h. 5. II .. .. ai, I'roc , Noll. And. Sa.. U. S. A 9U2911. 1m .100 'W o V A . ~kmll. I) p" Chooo. T.c.. and It"", M. 5 J Inll. 00 . lM,IEU 19'n ~. Crus. J C . .. oL A......... Chtm. 0..,,00<1 ... , ~; I/II . 1991. 96. ~ Ie ... "L "IIbY'roi Chern o.. .. ood .. , 4;115. 1993. 91. c...n.. J It . CI aI.: NO!..., 3 74~. 19'r.I

11. ...1. I Am. o..m. Soc. 117:118L. 1m ~ 1.qII. I) J ....I.: Proc N.. , Aad Sci U. S. A '2;13'. 1m tI '-<11"''''If. St l,w, .. rom and COl' , 5 '>(IOIS, 1000. p. I tl """) ...... S, .. aI "",,,,,,,,,,,*, AJeIII$ Cheu.oI.", lUIO, 199)
It..,~ :

~ ~. N A .. ...'

s."""" U8;lSlI,

IIIW.

98. woi.X" .... N..... )7J :117. 1m 99 Ito. I) 0 .. .. al '1M"'" In. ZJ. 1m )00. Kqeyama. S.... ol A"( .. nim.... "",lib a..mucllef. ]1=110. I !IIIl . 101 Ool.J.l<u. 0 .. .... - l"-rn. """""h""* 11:257. 1'.1%. 102. Pno wI. J .... aI. l.lioo.q Mod Chom. l :21H. 1999 IOJ. YOO""", ... K.. .. aI.' I'ru.:. N.d Aoad Sc,. U. SA .. %Jltm. 1999 I (loI U<ndr;'.. c.. '" "' ;blh Coo(c", ... c on Rcuo';m>e> M<l Oppon ... ,,,,.
In(..,';".. .... A""', (110. 1999

,.0)

lOS. R*. M.. .. II ""'" NOIjI AcIod . 5<;, U. S A. %S69&. 1m 106. Wild. c~ ..... Proo Nod. Aad. Set. U. S. A 91:9170. 19901 101. u.. D . .. II. ScIe1lCC 181:M6.:!I'Dl. lOll c. .,.... Y .. II rr.x Nod Acw1 ScI U. S A. \I6 . L~ 1999

,!

1 2

Antineoplastic Agents
WILLIAM A. REMERS
The chcmOlhcrapy of neoplastic disease has become increas I;tative. Another differc:nce is Illal imnlune mechanisms IIIIl other hosI defenses am very Importanl in killing ~ma'" otltcr foreign ct'!ls. w~as they playa lesser role in kiU'" cancer cells. Nevertheless. cancer cells o\'emxpress cenail ant igens. afMi aru ibodie.'l produced by recombinant DNA IeChnology exen a sclccti"e cytotoxic effecl 00 them. titative differc:nce~ in proteins found in signaling palhllllll that control cell prolifcmtiOll. differc:ntiation. and the lrod~ tiOll of progr~m1lled cell death (apopl~i9 al..;o pro~ide IJ(. gCl!l for aoticaocer drugs.1 Because cancer cells hal'e 0I'tt. come the body's surveillance sy~lem. chemotherapeutic agents must kill every c1onogenic nUlrrgnant cell. bccaIIiC even Ollt! can reestablish the IUlllor. Th is kind of kill is n 1mlllCly difficult to effcct because wuillCOplllStic ab'Cl\l til cells by fim-ordcr kinetics. That is. they kill a constant m.:. lion of cells. Suppose Ihat a patient had a trillron leuktmll cells. Thi~ amoum would cauSl' 8 s.eriutJ5 debilitation. A p0tent anticancer dl\lg might rc:dllCC' this population 10.001fold. in "'hich ca.<;c the symptoms "ould be alleViated aDII the patient would be in a ~tate of remission. After ccssano. of thempy. toowever. tile remainin g hundred million laM mia cells could madily increllse (() the original number. Fur thennore. a higher proporuoo of ra;;Sllllll ctlJs ... ould lot pre!ll:nt. whIch would mean mat retrtatmcnl ..... lIh the sanz agent would achieve a l(:Sser n:SPOIISC than before. Fe.- IIIrI re~. lIIultipiedrug regimens are used to reduce ~ !he number of neoplastic t'ClIs. TypK'al prolooois fe.- JeuU. mia contain four diffemnt anticancer drugs. usually ",ith dIf. fercnt modes of act ion.

ingly iOlportanl in n:CCllI years. An ioolClllion of lhl. importance is the establishment of 1\ medical specially in oncology. in which tOO phy~ician pr.IClicc;o; various protocols of adjuvant therapy. Most cancer patients 11011' receive some fonn of cl1cnlOlhmtpy. c\'cn lbough it is merely palliall\c in mall)' cases. Thc ""Ialivcly high to~icil)' of most anlicnn<:cr drugs

ou--

has fO'o lcred the development of ~upplclllenlary <.Jrugs Ihal may alleviate Ihe!.C lo~ic cfftcts Of ~limu latc the regmwlh of depicted normal cell~. The terms Nma, aoo nnlflla.nic discl/se actually encom pass morn thall 100 different tumors. each wilh ils own
unique charoclcrblics.. Drug.'! IIClh'c agains.t a cancer of one tissue onen are ini.'ffeclh"c against calKers of ocher lissucs. E\'cn cancers of the same IIpparent type respond widely 10
:I

IrJl1icular Ihcrnpeutic prococol. Consequently. il has

~n

difficult 10 ntnkc progress 011 a broad fronl of neoplaslic

di~scs.

Cancer chemolllel1lPY has rccehed no spectacular ~ak Ihrollgh of the ll11d thai tl!.: discovery of penicilllll provided for IInlibacterial chelllOll!.:npy. There has been subslantial ~ in many 8!ipCCIS of caocer research. ho....e'er. In panicutlll". an ;lICTeascd ufKlc.on!;artding of tumor biology has Jed to elucidal ioll of the mechanisms or act ion for antineoplastic agents. It also ha~ provided a basis for the mom 111 lionaJ designofnew agents. R~nt 8(]\' !IOCC!l in cli nical tcchniques. mcluding large cooperative Studies. are allowing morc mpid and reliablc evaluation of new drugs. The rombi nation of thc$e advantages with improved preliminary screening system is enhancing the emergeoce of IlCwer and IIl()I'e potent compounds. AI present. m Icast I Odifferent neoplasms can be "cured" by che nlOlhemp), in mOSI pIllienl~. Crlrt' is defirled hen: II.~ an I:Xpcctalioo of oonnal 100gevilY. 'These neoplasms an: acule leukemIa in childrcn. Hurlr;iu5lynlphoma. choriocarcinoma in "otllen. Ewillg's sarcoma. Hodgkin'~ discao;e. Iymphosarconla. mycosis fungoides. rhllbdOl1lyosarooma. rdinoblastonla in chi ldren. afMi tel>licularcaICinoma. ' Unfortunatciy. only tllese ,dati"ely rare IICOplasms are madily cumbie. Con~ideroble progress is being made in the trtatIllent O(!:on'asl cancer by combination drug thempy. For CW'cinoula of the pancreas. colon. liver. or lung (ellictpl sl11IIlI ct'li carciooma). ho....evt'r. !he outloot is bleak. Short-term rerni~sions are the best that call be t'llipected for mOSI patit'ms .... ith these diseases. l11cre an: ~nl reasons .... hy cancer is more diffICUlt 10 cum than bacterial infecuons. One is that them an: qualitath'e differences belwc:cn human and b:.ctcnar ttlls. For exampk. baclerial cells hll\'e distinctive cell wal b. DOO their ribosomes differ from too-.e of lIuman ttlls. In contlasi . the differences belwttll normal afMi neoplaslic human cells are rnost lyquao

TUMOR (Ell PROPERTIES

'The basic differences bet .... ccn cancc:rttlls afMi ncornW are unoollIroUed ct'!r prolrfcrnUOII. decreased cellular diffCfentiution. ability to ;nnKie surrounding tISsue. and ablhe),.
cstablish IIoCW growth at ectopic sitc.~ (metasta~b). COI'l!IW) to popular bt'lier, 1'\01 all tumor cells proliferate r~ridly. Prolireration rates vary widt'ly wilh ttoe cell type. Thus.. I).. phornas and normal intestinal mucosa both pmliferaIC filiia' thllll solid turn'mI. Acuu:: leukemia cells IICtu:tlly prohfrramore lilowly !toan the corresponding precUr'1Wll'S In ~. bone marrow. Dc:lclopmcnl and are cornrolh:d by afMi death. I tillted cells ii~. ,..,.:,~~" .~i' I death. Cell

390

by !!evere crllular inJury. "tlich is chanK:terlzed by s ..-clling

_ly~is.

100 50

The procc of Ilpoplosis is a oompleJI: but carefully orch$ratrd sequence of evaus. ScicntisUl dt~agrcc on the re l.UIC ImportlU1Ce of factors such as mitochondrial damage.

ahhOllgll many Ihlnl.: thai .... hen stress racton reach a critical
k,tl. the mnochondnal mcmbr.i[)C. potent ial changes, and the mitochondria leak OT rupture. rc.~ul!inll in their o .... n deItrUClIOn. This cauSt's the release of factors Ihm trigger prolfOi)tic cn/.y mc~ called ca~pases. Otht:r investigators Ihink dill the prirnury apoptOlic signals activllte cllSpase$ d irectly a tllen ca~paSC':S allack mitochondria along wilh Oilier eelIIbr OI"lIanciles. Cancer can be considered a fail ure of cells 10 un(\e tgo ~IS. In IK)I1Ilal cells, >oeIlSOl$IO cell aboonnalities lead 10 .tthdra.... al of $urvivaJ signals. resu lung In cdl death. In roIlr.ISI. cancer cell- circumvent the need fOf 511",i"11 sigub II) Increasing thei r abundance of anu -.poptOlic proteins. ''lII0I18 theoe anli -,popf()(ic prou:ins. memben of the 8c1 -2 fwlly, mcluding SAX and BA K. ha\'C been identi fied wilh tie InlliRtiOIl or progn.'~s ion of a variety of tumors. 11Iey 1IIo;~ the release of cylOchrome C lIJld 8[lOp1osiN Ictivati ng Iktor from mitochondria. Ccll~ ~Iso have 1\ voriety of w ntor Sl,lppre,~sor protei ns that ~ tQ DNA d~nUlge by shuu ing down cell d ivision or b)r mducmg apoptO!i is. One imensively studied protein i$ p.SJ. IIohteh blllds to the n:gulatory sequence of genes and 'I'>I t~ their tl'llnSC1'ipi iOll . Many mutaliOllS produce p53 in 11D1~oIded form. resulting in a oonform:llion unsu ilable for 1"1 10 rt'lulatOl") sequences. The development of half aU CIIlCCf'<; i~ tnought to result from mlsfoldi ng of p53 . .... n:sc:an:h has produced compounds that restore p53 .. iU arth~ conform:uiOll. Thecoocept of a cell C)cle is based on e~pcrimenl s usi ng 'Hlth}mldiJle radiography and flQW eytometry. These exptrlmen1S ~howed dlat DNA synttw:si~, !l~ mc!l~ured b~ inIXIIpOI1Ition of I ' H lt liymidine. takes place at a specific pe:lOd. known a~ the S phase. in the li fe c~cle of a divi d ing ttB.Pcnods between tilt:: S plia.'iC and cell division (mitQsis .w plttu<l /lire tcmJed G I and G~. A circu Ill!' pictorial model tf'l 12-11was deri\'ed for the clockwise pRI&I'tSsion of the ttl] t)dc. TlIe duraliOll of each ph:l.<.e in the C('II <:ycle varies ,.....In:abIy wllh the cell Iypc and wi lhin single tumor. T~ dumuons arc as fQllows: S. 10 tQ 20 hours. G:, 2 10 IIoon, and M. 0.5 to I hour. G , i5 highl~ variable IS rouJt of IlOOIher phas.=. Go. in \\<hich die cell is not active cdI dn ISK)fI . Most anllcancer drugs block the biosynthesis

"' ~
#

" ,. ,
.~

cell cycle , - specific

5
cell cycle ,..-- nonspecific

1 ' -_ _ _ _ _ __

Drug Concentration
F!9ut. 12- 2 Ceil cycle speofloty

or tmnscri ption of nudeic acids or preve nt <:ell division by

interfering with rn itOik spind les. Cells in tke DNA synthcsi\ or mitosis pllllSes are highl y $usccptible tQ these agenlS. In CO!ltrast. cells in the ruting Slate are resistant tQ man~ agents. Slow-grow ing tumors clwactcri$ticaJly have many cells in the resting Slate. J Antitumor .genu are d.ssi fJed OIl the basis ofthcirdfectl on cell survival as a fuoction of dose . For many drugs. In<:I uding alkylating qe nts. cell survival is exponentially relaled to dose, and I plot of log cell survival agoinst drug concentration (Fi g. 12-2) gha. straight line. These drugs uel1 their cytoto~ khy rcgan1Ies.~ of the cell cyde phase and arc \crmcd non -cell cycle phase specific. Otht:rdruG s. including .ntimet.bolites and mitOik inhibitors. which act at one phase of the cell <:yc le (ce ll cycle phase spt.'Cific). show a plateau after an initial low-dose u poI1cnlial region. The proponiO!l of la beled cclls in tissue after a specified interval (usu. ll y I hour) fo llQwing injection of [JII )t hyrni_ d ine or 5 -bromodeoxyuridine is known as the labtli"l1 ;nda (U). CompariJOO of the LI with the proportion of prohfcnll ing <:ells in DNA synlhesiJ provide:!; die growth fraction. Doubling ti me5 for tumor growdl arc ('lI1 (';UJ.ated from the growth fra:tion and cell cycle times. Rarely are they as r.lpld as predicted becau$e of tumor <:ell loss Ihroogh lJeCf"OSis. metastASis. and d ifferentiatiO!l . The cell-kill hypothesis sta tes that the e!Tects of antitumor drugs o n tumor cell populations follow fir.;t-order kinetiCli. Thi s means that the number of cell s kill ed is propoftlonul to the dose . Th us. c bcmottw:mpy foll o ws an exponential or log-kill model in whic h a co nstant proponion. not a con,tan! number. of callcer cells are killed.' Theoretically. the frn<:tional ll:ducli0n5 possible with cancer chemotherapy can never Il:dutt tumor popu latioru \0 7.cro. Complete eradication requires II10Ihcr effecl. such as the immune response. A modified form of the fil'Sl..f;)l"der log-kill hypothesis holds that tumor repessions produced by <:hcroothcrapy are described by die relative growdl frICtion prc5CIIt In the tumot at die time of tll'almCnt.. This idea is consi5tent wilh the finding that very small and very large lumorsare less responj sive than tumon of intermed iate size.

,
M Mitosis

G:z Resting
G. Resting
SDNA Replication

Figure 12- 1 The cell life cycle

Stem cells are the cells of origin (If a l't:lI Ime, ,,'hich m:untain lhe potential to reSCroer.lIc the cell popul:mon and from" hleh the dlffercntnllcd cells are derived, The:y ~ itnport:mt in the chemotherJpy of human tunlON bcl':mse they must be eradicated completdy to effect a cure. Trcal1Ilt'lIb Lllat afford substllnual reductlOOll In tumor burdens can produce reml~sions, bul the tumor may recur if $OfTlC of the stem cells remain. 'IlM:lr er.idic:uil)f\ i~ dl fficul1 bccau..e nlUny are in the pha.'iC of lhe cell qdc." Drug =i~tWlCe 10 Chemothempy u>ually in"olvb Ihc sclcc1ion of cenam cell populalloos. Populations of druJ;-I"I!"'" tunt cells can be produced by dooal e.'olutioo Of" mutallon. Drug -rcs is'um cells In Il S~ 1.IC cullure arc gcnernted (It ~ frequency oonsi~lenl with ),;nown r;ues uf gcnetic mUlul inn Mutagenic agents mCRiISC lhe freq~ocy of gener.lIioo of drugre~i"tnnt cells. This effecl may hal"C dmical ,mportJnce!:lt ca use: many an,itulllOf" agent$ are mutagenic. 11Ur.K:.. lIular effects ,hm C:IUse drug fI!'>ISl~ltce may be ~condary hI cellular adaptation or altered ellTynlC lelcl~ 01' propcnic~, For uample. rt:!iISlance to mcthotre_~ate iIl' Olib iocrell.~ Ie.'ch of the target t:ntynlC, dlh)drofol3te reducta.'Ie. 1 Other modc~ of resiSlllm:c 10 anlm\l:'aboliles mc lude rcduct:d drug Imnspon into ccll$. n:duted affinity of Ihe moleculur t:lrget. Mimulation ofr.&ltemate bi~ynlhetic p:llh"a).... and impaired actllatloo or increased mc:t .. boIism of the drul A Il\;IJOr faClor in Il':sistaoce to all.,)'latlllg ag.:nt~ j, the ability of tumOl' cdls to rcl)3ir DNA le~ion~, ,uch :1$ c!'()i>.~1 inks and brcnkage of DNA strands caused by all<ylation Cd l ~ ~1<!Ctcd for re~ifotlUlCC 10 one drug IIlaY ,how Cl'O'\.\-re,,~umce to other dru,~, even if their chemical stroctun.-~ all': qUill' different; rllOSt of lhese drugs art: dcri~ed from natuml pm..locc-, howeler. One type of mollXular explnnalion ror Ihl' fonn Qf multiple drug n:si,t:tncc I' overexp!'CSl;ion of nlCmbr~nc gly_ CO])I'OIt'IIlS lermed Pgfl"C"Oprol~i/lS, .... hich function as drug emu~ pumps. Thb ol'ere~pre~.\tQll j, a~~iated " 'Ith gene amplification, I M.,.,I amiIlCOpJa.>lic druJl~ :Ire highl), lO~ic to the patien! and must be Iidnllni5lercd .... lth e~treltle caution. Some of them rcquill': a cl mical ~tung "here ~upponl1e care i~ a, ailable. The: tOlliCiI) usually uw ohes r.lpldl)' rroli(~r"JIll1g M~ue.~. ~uch as bonc m~rrow and lhi: 1l11e,lmal epithelium, Individual drogs produce distincth'e IO~ic effech on the hem. lungs.. kid,IC)'!i. and other OIlan~. ho",.ler, ChcmoItlCmpy is seldom the 1II111al treatment u'iCd aaln ... cancer. Ir the. cancer i, well defi~d and aece~~lble, "Irlery i, prcfem:d. Skin cancer; und cenain localil.cd tuillon; are trealed by rlKIlothempy. GcrICr~l1y. chemotherupy i~ ImporInnl ... hen the tumor is 1I1OfX'r.lble Of" has mela.\l .. \lled. ChcnJothcr.lpy i~ findlllll ,ncreasing uSt" a, an "adJu'~Jm " after ~urgery to en~ure thut re" eel" n.-main 10 I"Cl:lencnlle lhe pan:m tumor. 1llC er'll of chemolhcr'llpy of mahgnant dlscase ,,~ born III 194 I , '" hen lIuggllls dcnlOOstnued Utatthe lldnumstnlllon orestrogen~ produced regreuioJls ofrnetastalic pnJ!ilateeaneer.' In the follOWing year, Gilman and Otl\l:fs began clnn eal studies on the nllrogen mustards:uid dlscovcred that mcchlort:thammc ""as effecul'e ag;lIIm HoogLm's dl-.t'a~ and Iymphosarrotrul..~ 'J'be$e same two disca.-.es werc ~atcd with cOr1isone acetate III 1949. and dr~malle,lll1hough temporary. remissions resulted.'o The IlelIt decade ",as marKed b) the desill and dlscolery of anlnl'lClabohte.\; nlCtOOtreute III

au

!'N\). 6-nlCrtaptopunrIC III 1952. and s- nuorouracil in 1957, Additional aIL)I.ttmg agenb ~ueh as I1lClphalan .nd qdo pho<;phamlde "'~rt: dcleloped during thti pcnod. and the: acU\ tty of natural prodUCh ~ueh as actinomycin. milOlltynA C, and the \ mea all.,uloid, was discmcf\:d. During the 19605. prlJires, cOIlhntoed in all of Ihese areas with the di!oOO\"tI'l' of cytosine arabinoside, blcom)clll, do,orublCin. and C/If. mu~tine. No. cl StmCfUn:.~ 'lich as procnrball rIC. dacarbattnt:. and cis-platinum cumplelle\ were found to be highly actl''t. In 1965, Kennedy repol'led thaI rt:mls.,iom occumd in;l(l'l of postmenopaU<o:l1 "'omen'" IIh meta.~t"IIC breast tanctT 01\ Ifl!atnlCm with high (!oo.too; of e\t~'Cn. " Much of the leadershi p ~nd financial 'upport for the (bel OPlllcnt of ontlncopla.~lic drug~ dcfi\c~ from tllC !'latiuM Cancer lnsmute (NCI), In 1955. Ihi~ OI'ganll.ation CSlahli'hd the Cancer Cht:rnother.Ipy National Sc"",ce Ccmer (_dIE DI' ",ioo uf Cancer Treatnw:n,) to cQonltnmc a natlonal.nIuntary cOllpcmtl~e cancer clicmOlhcrup)' de~dopnlent pr0gram. By 19S8. Ihl'> effon had c,olveU into a mrgclcd thr delc-Iopll\ent program. A massl.e SoCTttnmg sy~tcm 111.11 t\' tabli!ihed to dlsco'er new Itad comJlOllnd). and I~ ur ..:unple~ huve been 'UbnI1I1L-d to il. The: current hlgbly autQmaleU NCltumor ccll cullurt loCl"Celll ng s~slc'n oclllC''nl oper.ttlUnal qalus m 1990. It cmphasi/.c~ rigorousc-nd p!lID6 .. uch lIS roel cc-Il I.,illing and tumor rtll~sion. r.ttht'r \hII earher gm"th-inhIDl\ory end point>. alliin u>o a wide I1n cty of ~pce t fic Iype~ of C,UlCer, Including many solid tunu model~. III the i nllial stage of ~n.-cnmg. Ne,,' drull Candldael ITe being screened al a rate of about 20.000 per )ear._lIIt input dividal aboul ct]u~lIy bet .. een pure compound!." c~mlC"" or frolCliOOS frurn Ilatuml products. The proent it ~I'm o;crccning panel contain, 60 human tumor cell lirlr\. arr~nged in 5t:len subparoeb that rerre .... nt dil'en.c hisloiorie\: leu~cmia. melanoma. lung. colon, I<id~) , 01'1\1)','" hmln. For routlrll: e. aluallon. each samplc j, tested ula ~~ C()llIlIl\.K)U5 dnl); CJljlOSure protocol u"ng li~e 10g,,)"~JlICtd euncc-ntrntIOl\' Manlllg at 10 .... M fOf" pure OODlPOOnU\ ~ 100 I-'linll. fur e\tmcts. Antuumor octilll,es arc ~ at three- dlffcn:nt lelel~ or n:spon~, Gl w i~ ttv;- q oonccntmliOll that pruduce~ 5<Y.f mhlbilion in cell proltfer III ion rela,ile tQ the tol1 tful . TGI Itumor growth IIlhlblliotl i, the drug con.:entrntoon r.&t ",h,eh there is no ne, proIifmtioo. and I.C.... is the lethal COIICCnlnll1on of dfU! tbtt produces a 50'4- redue\iQll in lhe numbtr of tumor ctI; rclm ll'c 10 the conlJ(ll. 12 'The primary NCI scn:cmng dam are n.-poned In I mt. . ,mph formatlFig, 11-)) 111 "'hich lenlcal n.-fc~ '-obtalllcd by 411 er'll);lIlg the negatil e log, ~ GI .... valua for. uf the cell 1i11C~ tcsll-d. i_ ploll~-d along the drug concentf1lllOll n~ j ~ acid th~n h()rizomal ban. are plOlled for the indi\iduii negalll'e log ,n GI..,s of ellCh hne "ith n:spect 10 the len n:fen.-nce oor This grorilleal reprc!>Cnt31i0ll pro~itJcoi I dw iIClcnlolic fing.:rprint fOf" a gln'n ctHnpound. di~pla~lI\g dtt indiVidual ccll lines Ih~( un: mon: '>c 1I ~ 1("'e than OICra, (ban. 10 the right of lhe reference) or lc.~s. sen~i1il'C lliII aler'llgc- (00 ..... to lhe lefl of the reference). Thll!>. Pigllll' 11, ) ~hov.~ thall'o!on cancer cell lines art: mon: senSItII'f" a't:rJ.gc to s-nuoroufllCll (SFU). "hereM cent",1 fIt~. ~ystem (CNS) canctr ce lillne~ arc mort re~iqant than J\U' age to il. 12

~ ,..... '" ,.,.,,. ....

SR wru NOlI s.,n Cd! ' - C......
A~9

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RPt.I14216

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010110114 OMS171

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4.91 4.91

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Fig ure 12-3 NallOl"lalll"lSll tules of Health teslll"lg result profI le fOf 5 fluOfouraol

A seoondary ~tage of prel iminary scrun;ng on selected compoonds IS perfOlTl1C'd In \'i,'O in xeooa;l'llft models b), using a ~ulY;ct of ceJllines found co be active in the primary In vitro scrun. Two xenogr.lft models in CUrrent use arc the se"ere CQIllbllloo immuooder..:ieocy (SC ID) mouse and the alh)'mic node I1lO1.lSC. 8 0th of chese mouse uJOdeI~ have defi cient Immune responses tMt pemlit tr.&llSplalltacionofhuman cumor cells \\ ithouC rejection. Consequencly. po(ernial ant itunlOrdrugs rna)' be \I'sted againM hu man IUmors in un in vivo model. llIese models pudlCt human cli nical tumor responses bener than the older allograft modcl~ that \\ere based on trdnsplaming mouse cunlO/"i such :tS 1'388 leukemia imo che same strain of mouse (s)'ngenelC tumon). TIle importam anhlUmor drug pachtuel was discovered b)' using a ",enogrnft model. An in ~ill'O s),stem lhat is II good pudictor of human clinical octivicy i~ che hu man-lUmor-colony-forming assay ( HTCFA). Thi~ system uses fresh human tuulOr tissue: from individual pallents. n It is valuable In selecung chcmothcnpeut ie agel1\~ for individual tumor types and o,,:ca~iOllall y ~ific patients. but II~ USC' in largescale primary sc-rc:ening has IKlI been feasible. Compoolids with ~ignificanl amilumor IICdvity urc sub jted 10 preclinical pharrnacology :tnd tO~Jcology evaluation in mice and dogs. Clinlc~1 trill l~ ma), be underwrinen b), the NCI. They involve thrcc discn:te phasc:s. Phao;e I is the clinical pharmacology stage. 'f'be ~ge iiChedu le is developed, and lo\i cit), paramcters an: e~labh~hc:d in it. Phase II invoh'cs the tktemlination of activit), against a "signal" tumor panel, wltich include:!. both solid and hematological type . A broadbased mu Iliccmer study IS usullll)' undCrlnken in pha...e III. It features fllnOOmil.:ltion schemes designed to S13uSlically ~Dhdatc: tnc cfficacy of the new drug in CQIllparison to ullcrna lh'c modal ities of themp),. As might be antici pated, the design of chnical trials for antil\CQPlastic agents is very CQIllpllCatOO, especially in the mailer of controls. Ethical con~idc:rations do nOl pemliL patient~ to be left untreated if an)' ll'a5OII:I;ble thenpy is possible. A number ofpharmaceuticaJ industry laboratories and foreign IIls11tutions hal'e made significW1t contributions to the del'dopmt'nt of anticancer drugs. OrganizutiOflll 5UCh as the: Uniled Kingdom's Cancer Rc.warch Campaign. the Eu~ pc:an OrganilJ1tion for Research on lhe Trc:ahfICm ofCan<:er. and the Ja~ Foundation for Cancer Research ha\'C' broadened intemation:1 coopt'ration in anticancer drug reo 1 search.

mechlorcthanline) ,howed wlt-eti'e toxicity. c'pL'Ci~lI)' to lymphoid u ~suc:. This ob:,enalion 1 10 the crucial suuc:s00 tion thm mtrogen mustards be L<"SIOO again~ltumors of the: lymphoid systc m in animal s. Stu.'<:e8S in thi ~ area ...... as fal Io\\ed by cllutious hunl:ln trials thal showed medx:hkft. Ihllllline 10 be us.c:ful agam,t Uodgkin'S disease and l'tnIJO l),mpholli;lS. This work "as cla~~ifioo during World War U but was finally publi<;hed III :1. c1l1S1iteal paper b)' Gilm. and Phillips in 1946. 9 TIllS paper described the Chetllical trunsformuion of nitrogen and sulfur musur<ls to c)'dic "onium" emioos and e~lIIbltshed the: nucleus as the IQc., of their inlcraction with cancer cells. The now familiar J1Ilt tern of 10~ic'l)' 10 raptdl)' proIirer.umll cells in bone: marroor. and the ga~troinlcst lnal !rolet was est abli~hed. AIk)/tlIion is defined as the: replacement of hydrogcn 01 an atom by an alkyl group. 'Tho! alkylatIon of nuckic ac4 Of [lrolcin~ involves a 5ubslilUllon relll.1ion in which a nu cleophilic alom (nu) or Inc biopolymer di~pJoc~ a Ic:II'1III group from the alk)'lating agcnt, nu U

IIlkyl- V __ all),lnu

+ 11'- +

Y-

ALKYLATING AGENTS
Toxic elTecl.'l of sulfur mu\tan! and c:lbyleneimine on ani mals were described in the 19th century. I. ~ powerful I'esicam OCllOll of sulfur mustard led to i l ~ use in World War I, and medical uaminauon of the victims rel'caJed thal tissuc. wen.' damaged III siles distant from the ~a of con tact.' I Such lIyslemic effects included leukopenia. bone nwrow aplasia. I)'mphotd tissue suppression. and ulcerution of the gastroinlll.,tinal tract. Sul fur mustard was sho ...... n 10 be acti"e against animal tumors, but il w!l.~ tOO nonspecific for climcalll5C'. A varicty of nitrogen mustards \\'cre ~ymhcsil.c:d belween the twO ",orld wars. Some of lhesccompoonds (e.g ..

The relICtion rdtc depends on the nuclc:ophilicny of the alom (S. N. D). "hich i~ greatl)' enhancoo if the nuckqJ/tik i< ionized. H ~pothelicall)'. the order of reactivity III ph)'SIJ)logical pl l is ioni/.l:d thio!. llI11ine. ioni/.cd phosphatt. mJ ionil.c:d carboxylic acid.'I> Rate dilTerene<"S among l-artOUl arnines would depend on the degree: to '" hich they are proIOIatoo and their conjugation ...... Ith OIlI(,r groups. The: N-7 po6lc lion of guanine in DNA (Scll(,mc 12'. below) is ~~ nuc1o..'Ophil ic. Reaction orders depcnd on the stnK1urc of lhe olk)l.JIllitl agent. MethaJ1C sui ronates, cpoxides, :tnd v.iridines ,i.e 1' and-order reaclions lilal depend on OOfICemral iOlls of the: 11lylating agent and nuc1oop1lile. The snu.uion is moo: C(Do plu with .8-hal(JalkyJamirlc:~ (nltrogcn musllll'ds) and J haloalky lsulfides (.<ulfur mu"uu-ds). because the.<>e ~ undergo neighbOring-group reactions in ",hich the IIItroF1 or sulfur 8tOm dl<places the halide to give stnllncd. tJvtt. lnembcn:d "ooi um " imcmlediates. Ttw::sc "onium" react with nuc1c:ophilc:s in second-ordcr [lIlXcsses. o\'craJl Il'oclion kinctics depend on Ihc relali~c I':Ilt1 the: 1\\0 ~Ieps, Ito\\e,cr. In the case of mechloret~ the Ilziridinium ion Forms rapidl), in wuter. but re<lCtJul with biological nuclc:ophiles i~ slower. Thus, lhe ~inttJg arc s.c:cond order.IJ In comrJ,t. sui Fur mu~t ard forms thc Ie" Slable episuU..ium ion more slo ...... ly than this ion Tt'1I('1.'l ""ilb . nucleophlles. Thus. the neighbonnggroup Te;actlOll ;,; limiting. Dnd the ~irv.:lic~ are firsl order. II Aryl -sub\.t;tu,ed nitrogen mw;,at'ds such as ctt are relatively ,table 10 aziridinlum ion formahon bt\ ItO the aromat ic ring decrease~ the nucleophllicit)' of tlx IIliJI gen atOm. 1llc:sc: muslllrd~ reattllCCordmg to fiN-tkrb neties. l The: ~tabilit y or chlorambucil allows it to be lWI orally, "'hereas mechlon:lhamine is gh'cn by inua '';'; admini~trallon or freshl), prepared soluuons. TIx: C " mem for frC!ihl), prepared ,;olurions is based 011 the graI.t dccompo.;uion or the 1IZiridinium ion by inlCfllCliOll , wmer.

-Eth)lcnc: inuDCS and epo:"dcs arc Slrluned nng sy<;lenlS, l1li they do noc react a.~ readily as aziridlnium or cplsulfoo.aIMS " 'I th nudeophile~, Their reactions are second ordc:r Dl an: cnhanced by the presencc of acid,16 l3"amples of IIlllumor agents comaining cl hylcncim illC groups arc !rieth ykIIt-llItlaminc: and thi()lrpa.

CH, B<
HO-tH

I HO-CH I H-C-OH I H-C-OH I

CH2Br
M~obrOfMoI

01
HO-C-H H-C -OH

be

A iIOIllewhat different type of alkylalinll &lcnt is tnc N-

, , , ,
.
r

is an in~'CSlillatiooal bcnroquinonc subsmutrd , . dhylrflC';m;nc: grouf!S and t arbamatc groups, IxMh of OII'K:CroISlatic, 9 Aftcr acl;valioo by reduction of quinone ring to l hydroquioollC, the ethylcncimillC JIlUPS alkylale DNA to produce cl""()l;s-Jinks. Some ~A -protein cffi!,s1ink~ also are fonncd,

~iquone

!,,'m

alkylN-nilrosourea. Compounds of this class are unstablt: in aquWUJ solution under phySiological conditions. Tlw:'y produce caroolllum ions (aJ'iO called C:ll~"illm ;OIIS) thm can alkylutc and i!iOCyanat cs thm can carbamoylutc. For c,, ample, IlIclhylnilrosourea ik-COlllPOSCS inilially to form isoc yan ic acid and IT1Clhyldialohydro.idc. 111e latter ~pedes decomposes funher to mcthyldial.Onium ion and final Z to methyl carbonium ion, the ullllnalC alkylaung $peciC$. Z

~ -+ H 0 - CH"N=NOH + O-C-NH CH3N-CNH1

c,H,OC~

,.

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<I
o

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DIazohydrO><ide

lsoc,_x ACId

I
CH l ' -+N 2 -CH1N=N + OH
on the nitrogen alom~ of the nitlUSO\lrea influence 1he nlr'Chanism of dccOlnposilion in water, which detcnl1 inc~ the species genel"~led and controJ ~ the biological effecls. Carmustine (BCNU) undergoes an abnormal basecatalyt ed deconipOSition in .... hlCh the urea O~Yllen displace; chloride to gl, e I cyclic lIltcnnediale (Scheme 12- 1). This imemllxhutc decom~ to 'my1 d iazo hydnmde , Inc ~ cursor to \inyl carbonium ion, Dnd 2-chloroelhyl i~yanatc. 1llc laner SpeclCli gives 2-chl~th yJamill!', un additional alkylating agent, n Some cl inically important alkylali ng agents arc not acli\'c unlil they ha\'C tN..... n tl"dnsfonncd by metabolic proccsses. 1lIc Icadmg uample of this group is cyc'opho6~ idc.
Sub~\1lUcnlS

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. as cross-link in gcallerr in te"tile agents lhatlncy be lried in

c~mOlhocr

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.,

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:wch as 1,2:3,4-dirpo"yootallC 1II,:til ity against Hodgkin 's disease. M OOt compoulld'! became an r'Slablished drug. Oi il (milobrooilol) givc~ the corresponding dicpIi till'lltion al pH 8. This dicpo"idc ( 1,2: I pOlent r.lkylaring lICti"i ry thus <'ugge5ling that dibroI t such (1$ dibrollIodulcitol

-w

H2C=CHN = NOH + O=CNCH 2CH 2CI

Scheme 12- 1 Decompo5ltJOO 01 carmostme (BCNU)

H2C-CW+ N2 + ow

cO 2 + H2 NCH 2 CH zCI

1",0

+0

O-N
lCH 2CH 2Cl

... hich I ~ oolwer1ed by hep.uic cytochrome P450 into the C()I'Tesponding 4.hydrox y derivative by Why of the 4-hydroperox.y intermedmle (Scheme 12-2). The " -hydroxy (kriva ti\'e is caroinolaminc in equilibrium wilh the open,<hain amino aldehyde form. Nonenzymatic de<:omposition of the laller form generates phosphoramide mustard and acrolein. Studies based 01\ I Ip nuclear magnetic resonance (NMR) have sho .... n th aI ,he conjuga'c base of phosphoramide mustani cycJizes to an l17.iridinium ion,:IJ which is the principal cl'I)S5-linti ng alk:ylatCM" formed from cyclophosphamide. The maxim.a! "'~le of cycli1.lltion ocCurs at pH 7.4. It was suggested that selecti\'e toxicily lowani certD.in I1CQJllastic cell5 might be based on their abnoomllity low pH. This .... ould afford slower (CM"mation of at.iridinium ions ..... hich would persiS! longer because of decreased inactivation by hydro. ide ions.z2 Cyclophospllh mide has been resolyed, and ,he enamiomers ha\'e been tested against IUU"IOI"S. The levorotatory form has twice the therapeutic index Or the dextrorotatory form. ~ Ifosfamide. an iwmer of cyc lophosphamide in .... hich oue of the 2-chloroethyl subSlitucnts is on the ring nitrogen. also has potent aMilllmor activity. It ~uircs activallon by hepati c enzymes, bul ils metaboli.~m is slo .... er Ihau that of cyclophosphamide u and invo lves substan tially more dedoloroethybtion, yielding a chl()fl);j(etalt metabolitt.

~~-NHCH2CH2CI

..

,.,.."

Othereluunplcs of a.]tylating species are affOfded byar binolamine~ as found in maytansine and vinylogouscartJino. lamines as found in c", rtain pyrrol i1.inc diesu: I'lI.2<i

OOy
04N,
1...-',-0

5<hame 12- 2
AI:tN~tlOll

of

-w

H1

fH ~CH2a

HO- P- N

H o

CH 2 CH1 0

cydophospt1~mlde

cxam~lI:. tiM: sc"luitcl'pene helenalin has bulll of the<;e sys

terns.

H,

CI
CH,
IlI)leO":r ,

o
Alkylation can also OCX"ur by free radical reactions. The nltthylllydr.lI.incs are a chemical class prone 10 decomposi tion in this manner. These compound s " 'Cre IC~lcd a~ untieu [nor agenb in 1963. and OI1C of them. procarb.v:inc, was found 10 lIa~c a pronoonctd, btll r:lthcr specific, errcct on Hodgkin's dl.'lCasc.JO ProcarbalillC is relall\cly stable lit pH 7, but air o~idation to aloprocarb;y.inc occurs readily In the presence of rnClalloprotcins. IMlrnerization of tlli s al.O compound 10 the concsponding hydr.l7oll(', followed by lIy drolysi ~. ghes mcUtylh}drdl:loe and p-forrnyl-N isopropyl ben7..amide. The fonnalion of mclhylhydrnzinc from procamazinc ha~ b..'Cn delllOlIstmted in living organisms." Mcthyillydrlllinc is known 10 be o~idi7..cd to looh)"1 divine, wllich l'an dooomposc tOnlll"08cn. methyl radical, and Ilydmgen mdic-al.u The methyl group of ~arbv:inc is iOCOiPOrated imact Into e)"loplllsmic RNA. It has I'KM been estaDli ~hed conclusively, Ilowc\"cr. tllat the meth yl radical is the methylating species,

When milOnl) cin C is redllCcd en7yrnatically to II, !>CmiQIlUlO!II' radical. dLs.propOr1l011 and <ponlanl"OUS elimination til meth;mo/ affO! [hi: vin) logoos carbl lJOlanunc ~ystem. ~ ~ the carbamoylo\y group from thIs system gllCS a ~llled carbomum ion thai can alkylale DNA (Scheme
l1le liThI alkyla1ion ~Iep fC~U1tS from opo:ning of [he ilIfl<Jine ring . and togcther .... nh the \ lIlYlogoo~ carbinolamI~ J).

car-

. 11 al1o"'~ mllom)'cin C 10 cros)-hnk double- helical llI'<iI..17 Molecules like mllOrn) em C are said to act by 'biokductl'c aJkylallOn.':!II AoodleT t)PC of aikylarillg 'pt'(,-ics QCCUN in a.,8- uIISII lu IWd arbon)'1 compounds. 11lesc rompound<! can allylate kophiles by conjugate: ooi1l1l00. Ahhough !hc-re all:' no N.1bi1>hed cliuicaJ agenlS of this type, many nalUm] prodICb actll'!: agDi"-~t c~pcrimcnlul IUI1lOfS contain a-nICthylcnc

b,~

Ia.lOIIt' or a,P.unSOllurmoo leH)Ue flJOChonalities. For

0
/

CH~OCONH2 ~OCH3

<,C

-
-

H, N H,C

CH 2 OCQNH 2

....... OCH3

NH

NH

I---~ -CH)OH
w
CH 2OcONH:

OH

CH 2 OCONH 2

H, N H,C
OH

ONA
OH

N NH,

NH,

I..
<~

CH,

\ DNA
NH,
Sdll!me 12- 3 M.tomyon C IKIIVill10fl and ONA <1Iky\atlOfl

CH3NHNHCH 2-o-CONHCH(CH))2

---

0,

j j 0, -CHaN-NH- CH3NHNH 2 + OCH

--

Dacarbazinc wa.~ origi nally coosidcred an anlmlClabolile because of ils clOIie 1"e..<;Clllblance 10 5-aminoimidawle-4-carboxamidc. an intermediate in purine biosynthesis. It now appears. OOWe\'er, to be an alkylating ageDI.)-I The iwlalion of an N-dcmcth)1 metabolite suggested that there might be a 5Cq\J(ncc in which Ihi. DlClabolnc was ~drolyzed 10 mcthyldiJl7ohydroxide. a pn:<:ursor to methy1carboni um ion, l.'I but it was found that !hi nctabo l;lC was les.s acd\'e than sLan; ng material agaJnst the L..c .... is lung tumor. An alternative mode of acuon WILS proposed in .... hich dacarbazinc undergoes lICid-c:ualy~cd hydrolysis to a di:lI.ooium ion ..... hich can r'l::lCt III this fonn or decompose to tile C()['Je~ing carboni um iOIl (Sclle nlC 12-4). Support fur the laller mechanism Wh~ alTunIed by a rom:lation bctwCi:lllhe hydrolysis rates of phenyl-substmlled dimethyltriuines and their antitumor

.ruvitics. J(> TIle interactIOn of alkylating agents with macromolecules

such a.~ DNA and RNA has been ,tudied extensive ly. No mode or :lCtion for the let hality 10 cunt'er cells has been e~tabl i~hcd cooclusively. however. A good working model WILS dc\eloped for the alkylation of bacteria and viru<;es. bol there arc uPttna,ntics in ClI tr.lpolat, ng il to mammalian cell$. The present worlmg hypothcsi~ i~ that most alk>lating agentS produce cytOtox ic. mutagen ic. :md can:mollcnic erfects by rt:v:ting wit h cellular DNA. They al\O rtact with RNA and proIci ns. bot these effects are thooght to be less .Jigmficant.JJ The most IICIhe cllmcal alkylatlllil agc:ms an: bifunctional compounds cap.1ble of cross-linking DNA. Agents such us mcthylnitrosoure(lthat give simple alk.y lation lite highly mutagenic !'Clati ~e to Ihelr cytetex icity. The crossImking process can be either inlerSU'lllld or Imrnslrand. Intcrstnmd linl s can be I'erirled by a lest based on the thermal denaturation and renaluralion of DNA. When double-helical DNA is Ileated in water. it unwinds and lhe MrandS liCpar1lte. RcnalUr~t ion, in .... hleh the strands recombine III the doub le

is slow and difficult, In Conlr1lSt. Ir the 1....0 5U'llnds ~ cross- linked. thc:y canlJOl sepamlc. Hence. they rcnmllflllt !Upidly on cooli ng. Imer..trand cross-linking occurs "tlli mechlorethamine and other " two-almed" mUSlards. but 111:. cording 10 Ihis test. busulfan appears to give in~ hnks.J3 In DNA, the 7 position (mlregcn) of guanme b especially suscc pl ible to al k.ylation by mech lorethumi ,1C und OIller 111trogen mustatds (Scheme 12-5).'" Thc alk.ylftted Strucr.t hils a pa;.; ti\'e charge in its Imidazole nnll ..... hl!.-tt ,tioo, Lhc guanine- ribose linhge susceptible 10 cleav3gC. n.. cleavage results in the dclehOl1 of guanine, and the rtsul\llll apurinic acid" ribosc- ph<.Isphme Imk is rtadily hydrolYI abk'. A lkylallon of the imid:u.ole ring also activate!> 11111 cleavage of the 8.9 bonei,'~ Other COf\sequcnces of the positi\'ely charged pwIlIt 51ructure are facile exchanae of the 8-h)d~n . .... hKh QI be ulied as a probe ror 7-alk.y lation:"" and a shift to the allliled pyri midine ring as the prcfclTI.'d tautomer. 1k Ima effect has been cited as a po"Slble basis ror abnormal ba pairing in DNA rtplication. bol thI S has 1101 been sumt- ated . One example in .... hieh alkylallon of gualllne does lad 10 abl"lOOTlal base pairing is the O-WthylatiOl1 productd ~ ethy l mcthanesulfonale. Thi, eth)1 deri vmive pairs With Ihymine, whereas guanine rl\)flllally pairs wuh cylosinc,"

hc:l i ~.

-- -

CONHCH(CH 31 2

!yO
.,..... NVN,

CH,

8 ..

H N I ' N .......... N
H

""H

> N
Ny~

< N
I
Scheme 12-4 "'wauoo of d;Karl)azllw,

NXCONH2

N'

'

- (N ', J
H

, ,
+

a
J~

a
I

a
I
Scheme 12-5 Alky\lluon of guan..", In DNA

CIlbtr bal.e ~ilions of DNA auac~cd by allr:ylating agem, N2 and N) of guanine; N). N J. and N-' of adenine; (M of Ihyminc; and N) of t)' losinc. The IIltpOl'1lUlCe 0(
t i mlllor allr:ylulioo reactiollli is difficult 10 ussess. The pbphalC o~yscn~ of DNA are aJkyl':l.led to un appreciable IUMII. but !he signirlCance of this feature is unknown ..u Guanine 1$ al~ ImplICated "'the Cl"OU-link'ng of doubleWlnl DNA. Dj(guumn-1-yl) derivatives have ~n idellti
r.d.noog the products Ofn:aclion Wilh ma:1l1on:lhami~.J fan alkylation has given 1'.04' -di(guanin -7-y l)-bulanc. dtI5 prodUCI is considered to han: rt:5uhed from inhIIIlnd hn~inll .\I Enlynlllik hydrolysis of DNA cru~s

If cells can repair tblllag&: 10 the'r DNA btrorc: lhe I'IC'xt cell di\lsion. the etTecl'l of al")latiOO will not be lethal. Cell~
ha\e <kveloped I complex rnechalll~rn 10 1ICC00nph)h Thr~ repar r. rnit rally. II l\.'COgnh iOll cntyme di;covcl'li lin abnonnal rei\lOn m lhe DNA. This n..'COgnllion bnngs aboutlhe operation of an endonuclease. '" hieh male~ a si nglc:-,tl"doo bn:al. in lhe DNA. An eAonuc1casc lhen rcrno,es II small '\CgmcTll of DNA cOIIIUlning lhe damagetl b.a~~ . Finally. the [)NA " reslored 10 its original SlNCIUI'C by replllClIlJ! The bilses antl TeJOlIllng the ~trund.'" Thus. lumor cells ""ilh efficient rrpillf fO('('h;IIli srns be rela\ll'el), resistant to IIlkylallllg agents . Tumor cdb outSl<k Ihe cell cycle. in the restinll p/1a.~ (Go). will have a rulher long time I() rep"ir lheir DNA Thu~. slowgTQII III!! tumors ~hould not rt:'>pond '" cillO alk)laung agents. and thIS IS obser.. ed chmca lly.

"",11

W:td by milomycin C lias gi\(:n fragments in .... hich the ; : i l covalcnlly bound 10 lhe 2-amino groups of 11'.'0 nc: reSIdues. pmlumably from oppI)Sl le SIr.mds orille : hdix ..oo

":"-,Thus.
-=.'as

AlI;yLaling agents also inu:rnct "' llh C'lIynlCS and OIhct the repair ell/.ylllC' DNA nuckolidyltrdnsfer fi Lil lO leul.C'rnia ct'lls is inhibited strongl) by BCNU. ~~ne (CCNU). and 2-<,hloroethy l isocyanmC'. Becau~ 1./2dIJofOethyl)-I-nilwsourea was a poor inhibitor of lhls ;ft. n was coocluded Ihallhe marn intC'r.lCtiOQ WIth the cartx.moylauOrl by the all.yl isocyanmes generin tbe fkcontposiTioll of BCNU arMt CCNU .... Aliylaling agent5 can damage li~~uc:~ WIth low mnoue ~i 001 they are lllOS1 c)'toroxic \0 I'lIpidly proltfCI'lIIlIlt: ~ thai have large: pi "'I10rtlOOS of cells in cycle. Nocleic In: especially $u'ct'plible to alkylalion when lheir ~~ an: changed or unpain!d in the process of replica Thus. agents are 1TK)!;1 crfecti'e rn the laIC

Proch.cts
Mechlorelh _ amir'll: h)'tlrochlori<k. Mu>targen. mlmgcn 11Iu'tmxl. HN: . NSC-762. 2.2-dichloro-N-methyltllethylmnine hydrochloride . IS jJl\'pared hy lreallng 2.2'.( n'OCth)'limloo)diethanoi 41 II lth Ih'OII)'1chloride. It occur.; as h)llroo.copOC leaflels lhal arc very soluble in 113ler. nIl' dry l'ry~t ol, ore ~t able at temperatures up 10 4O"c. 11I<'y are \cry Imlaling 10 mucou~ membrallel; and namlfulto e) c,, The ro.npountl i ~upphed m rubbcr-~Iopp:n:d "iOlls l'olllammg a IlIlAlun: of 10 mg of mechiorethalll>ne hytlrochlunde and 90 mg or MJdlum chlori<k. It h, tli lulcd wuh 10 !IlL of sterI le water imn'ICdiatel)' before IIIJCClion 11110 8 nlpldly flowmg mlrnvmou~ infu~iOll . InlrdCl l',Iy injecllorls are llIOIllt:linlC.'> givcn to control malignam effusions. The n iridiniullI ioo formctl from mechlorethamine UI body Iluids iJ; hIghly react,,e. It act) on \<lnOUS cellular cOllljJllOC'nlS w,thin lIIinUI~ of otlmimSll'Dt'on. I...esli [han

MedtlOl'f'thamine Hydnxhlorick, U5P.

~t~~= Some all.ylation may occur al any sage in

I llhe resulting lO~icity is usually e"prc~~d II enter the S p/1ase (Fig. 12- 1). Progres~ion [Ilroo~h ~Ie IS blocked al G :. the ~milotic phase:. and l'e!1

fllils.4S

rtro"etro Ilnchang~'(l in the unnt'. bul n~ than SlfoI IS excreted in urine as m~ctlvc mewbolil<!!. In the firsl 24 houD_ M 1:Chlon:th~mllle is cffl:"Cti\e m lI odi:km ' ~ dlsca.'o('. Cllrrem practit'C i~ to give It in combination with OIller agents. The combmallon with UIlCTlSlInc (Ooco,in). rrocamazlnt'. and predl1l'>01IC, kllOwn liS the MOP!' regimen. w~ considered lhe m:atfl"l('nt of chuice_ Other I}mphonla~ and lUycosl~ fungoldcs can be: treated with nlCChlon:lhamme. lbe most serious H1Xic reaclion is bone lUarnl\" dc:prcsslOfl. which results in leukupema and Ihromboc)topt'nill. EI1~i, is pn: __ lel1\ and la~ls ahout 8 hoors. Nau<;C11 and anorexia per..ist longer. These glislrointe\linal erfeelS may be pre>tllled by the antiell1Cue compound onlianSCtrOll. In:;L(hcnenl t.~Ir1"':l ) iltu)n prodU<.:cs i l1tc~ local reaction) at thc _ilc of inJl.'CliOfl. If il occurs. lhe immediate applkillion of sodium thlol;ulfate solution can proll:"Ct the II~S\IC~ bccllu<;t th iosulfate 11)11 reacl ~ \"ery r.apidly .... ilh the llI_ lIidiulUIllIOIl fomloCd from nlCChlortlhammc .

0_01q,

I~

or undc-r refrigcrntiol1 for proIongt'd Innes. AI l~mpI.'fMum abtl\C 35"C. ,I hqulfies and tk.'Composltlon is n"lOl"C rapid. Ifosfamide u ~ua lly i~ adn1ini~ttred in a sOOrt infusion. S"'dc:~tro:;eor normal sahne. Usc within 8 hoursofrec ..... tul.on " rt:Cotmnclldcd. Phanna(:uI"netic stud ies indicar Ihat II is handled ill the SIIII1C ... ay :l..~ e xecpt thul fl"l('tabohsm IS 1c..... e~ tens,,t. half-l1fe of 7 hours and a Tho ,~"" d,cal!oll for i IS in eombmalion ~ffti\e DglIJnst I, sarc-ont:l. einvma.~, and I cu ~emia. Its linll tillg lo~icity i~ in the unl\ai1 tract. e-;pecially hemorrhagic C)'~liti~. ",hich results from dJt e~crctiOIl of alkylatin g metabolites III the unnary bladdtt_ Vigorou~ h}'dr Jtl<JIl and/or admini~trJtion of meSlUl R nttded 10 prelem bladder tbmagt . t'i ~ nausea and \"omiting. ulopecm. and eNS effects.

r...,.,

,oc'"

Cydophlllphamide. USP. C)clophosphamKlc. e}loxan. NSC 2621I. N,N-bi~(2-ch lomcthyl)letr.m}dro-21 '1.3.2-oXIll.apho.<.phoril1C 2amn.:-2~ ide. i~ prcpaR-d by treating blo;<2<hluroethyl)pho'iphol"dmide dichloride With propanolamille:'" The monoh}'drute i~ a lowmc:liing solid el) soluble m Wltc!". It I~ supplied as 25- and 50thaI IS ," mg ",hlte tablets. as 5O-nll!, ullil do\C C:lrtOIl~. and a~ a powderl 100. 200. or 500 mg) m ~terile vUll~ Rlr reconstitution. S mtl100 rng of SIt'rile Water for InJCCllon. USP. is added. n.: 00Il do....., of C)clopho~ph~midc i, ~ blOMailablc. wnh an 8'" first p;m loss. It must be metaboli>!ed by liler microMlmcs 10 become aclilt. Amonllthe mct"bolite~. phos phorumide mUSlam has antitumor actil il). and acrokm is tOXIC 10 lhe unnary bbddcf. Tbe ocroleill toxicity ClIn be decreased by intral enous or I)ml ad,nill1,tratlt1 of the ~o dlUm :l3.lt of 2-mercaptocthane ~ulronlC acid (n.:sna) .... tto<.t su lnlydryl gllJtl p 1:' ICS ct.llljugate oolilll()ll 10 100 double bon..! of acrolein ..... In the plasma, n)C)il1I fortH) a dl~ulfidc, .... hich is coolened sclecll"cly 10 lhe act,,'t suli11Y..!1) I ill ~lIal tu buies. e)clophosphllmlde ~ :t(hanlagt'JI 01("1 other I1U:}laling 3gCI1I~ in thm il l.~ llClI'C orally un..! parenternliy and t""JIl bc gi-'en in fl1lCt;ol1.lil.-d do!.c~ over prolonged period,. It is 1lC' Me agamst multiple mydt.llnll. chroniC lymphocytIC leu~e min (elL). and acute Icukemia (If children. In combination "'ith other chemothernpeUllC Iq:Cnt~. It ha~ gi-'en complete rt':1ll'SSiOflS and clen cures in Bur~ctt", lymphoma and acute lymphoblu,lic leukemia (ALL) 111 chik!rell ..... The 1110) 1 fn: quently eocountertd to~ic tff~'Cts are alopecia. nuu!<a.. and vomiting. Leukopenia occurs. but thrombocytopcnm j, Ie~~ rrequt'nt than .... lth 0lht:T alkylalillE lIlIcms. Stcrilc hemor rhagic cY'l1ti~ may "ult and cven bc falal. Gonadal \upprt"'sion has hccn reponed ill a number or patiell!), Ifosfamide. IfusfamiOc. IFEX. ~I olo~an . NSC.I09724. 3-(2-chlorocthyl)- 2/<2 <hloroethy l)amHlol-telrahydm-2H -1. 3,2-oxa7.aphosphorillC2-o~idc. i'lUpllosph:tmldc:. is prepared from 3-J(2-chloroclhyl)amiooJpropannl by trealment with phai;phorw o.o;ychloodc: follo..... ed by 2<hloroeth}lamlllC." It is ~uppljed in I and 3-g vials as an off ... hilc Iyopluli/.cd po .....der. 1lte mtact \"13l~ may be ston:d at room ttmpcruturc

,
aliiI\('. i, prejXIrcd by nylahull llC ethyl eSlcr i phorus o,ychlorllk:. and a.dd.~ Scored 2'1118 mblc ..... are !lOll Oral ahsoqllion IS t'rJ"Jlic and incomplel~. "'Ith bloovallablli,y mnging from 2S 10 89%. A pn:parnhOll provided for parcnter~1 fomlulotion. It contuins 100 I melphalan. which is dissolved in I lioll. and then com billed with final I1Ig of d.potaSSium phctsphale. to and Stenlc Water for InJI!Cllon. t;OI1. Thj~ pn:parulion ~houid be u...::d promptly. 'There is 110 signirlCant fiN-pass effect with inacllvated b',,:,;~:~:~ but the drug i~ drolysi_ I r I illatiOil IS i i ' 6 10 8 mlllUtn 40 to 60 millute5 . Most of the drull is cleared by ~~ mechamsm ... Melphalan 1\ acti.-e against multiple myelom~~'~,::~ ~ octile against breast. te\ticu ilir. and ovarian 1lte dilllC'Jl to~lcuy is mainly hematological. . thai the blood conn t must be: followt'd carefully. \"omitll1g !Ire infrequent. bul alopecia OCCU~.

Chlorambucil, USP. il aminophcnc. NSC3088. Ih ylbutyn<:: acid. i~ ~ lICill wnh cthylenc oxiOc. Chlora,nbucil is soluble in "b.-.orptlon is errlCient pnd rehable . lets are supplit'd. ehlor:llnbut:11 IK1S masl siov. Iy and is the ~l1y nitrogen mustnrd tlcrivaulc '" U!>C:. cially in lreatment of ell and primary

Chapter I! A.nlitt<Opk/slic ,,&'n"

"IU~

40 1

apirl. 0011 in :005Ii 1IIicalC: amide. 'P'lrenl

_.w

lUId HOtigtin's di Many p;ttienl~ dc,clop progrcsshc. but re,crstble. l)'mphopcnia during trc:lItmcnl. Most p3lients also develop 100000rc:lated and raptdly rc:~er,;;ble neutropenia. For these rulOl\.~. weetl y blood coonts arc: mllde to dctemlille the: tollll wldilTerc:mial lcutocYle levels. 11IC he moglobin levels are dsu dcterTmned for monnorins both toxici ty (low ootmts) wi nflClICY in Cl.l. (raised ewnl~).
lusuffan. USP. 8usulfan. Mylerun. NSC750. 1.4-di. hlll'tl\:lnc<u lfonyloxy)bulane. is syn l he~i7-Cd by treating 1,4 IlilUnedIOI wi th mc:thonesulfooy l chloride In the jX"C-.l\ence of I')ndlnc. w It IS obtaincd as crystal. that lire SOluble m ace me JOO alcohol. Although practica lly insoluble in water. il dioolves slowly on hydrolys Is. II i$. ho",c,er. sUtblc in dry bill. It is supplied 11$ scored 2mgtablets. 8usulfan is ....clL absorbed or.tlly and metabolized r.. pid ly. IoIIICh of the drug undergoes a pr"(I(:elill lnol',n a~ "sulfur OUIj1ping in which inter,lCtiOl1 wilh thiol compounds such &lut31hiooc or cysteine: resu tlS in toss of two !!qUI valcl11s of tnethantsulfonic acid IIlKI formatioo of 1\ cyclIC sulfonium ittItnnediatc invo lving the sulfur mom of the thioL'" Such II!fOOIUnl II1tennediatcs lire stable in vitro. but in vivo. tbey .: reidl ly OOIllcn.ed II1tO the nlCtabollle l hydrox ythl0lane U-dioxM.le.f>l Thai tIM: sulfur atom of this Ihiolanc does not _ from a ol(:thallCSulfonyl group was ~hown by the -'y quantitatl\c i<OlallOrt of lablded mclhallCSu lfooic acid ill !be urine wll(:[1 busulfan ~'S is oomi nistcrc:d to IIni lI1al5.<oI Onl doses of busu lfan arc gencraUy w(':11 tolemtl'd. The Ih.<:tfpJOIl has ttrTH>l"dc:r kinctJc.~. "'It h a nlean log lime o f J6minuICS and a 200ur dur.tlion to the end of nb5Ol"ption .... \'1Iacs for nl(:an pla!il11a OOIlCCtltr.ltion X tinl(: an: ~ de jn.Ient. with peat levels of 24 10 130 nglmL for 2 to 6actkKes. The halflife is 2.1 to 2.6 hours. 1'De mall1thempc:utic uSC of busulfan is 111 chronic gnlnu b:)11C leu kemia. Renllss ions arc observed in 115 to 90% of ]IIIiI:tu Il\er the first course of therJpy: it is IlOl cumti,'e. noc'fa It IS u~ in prqxtmhl'e R:glmc:n~ (bone 111:1m1'" *I4II\c) for booe marrow tmnsplantmion in palicnt~ with _ leulemias. Toxic effects an: mos,tly limited to my ek:iupprcssion In which the depletioo of thMllOOcyte5 may k::Id w hemorrhage. Blood countS should be done 01 least 1UtI). llJc: rapid dc\tfUCUOl1 of gr.muloc)tes can cause ~oce",ia. which might result in hlncy damage . This amplication is preVented by usi ng allopu rino l. a xlI!lthioe .... ~ tnhibllor.1I6

omer u1llielltions

are

Iym~om~

Ctrmus t;ne. Carmuslinc. B,C N U. BCN U. NSC 409962. 1.1bis(2-chloroc:thyl}-lnilro$OUrca. is synlhcsi7.td

by Ireating 1.3 bis(2 ~hloroct hyl)urea wllh SOthum nimle and ronnie add.t>6 It is lo ...melting \Oohne powder that changes to an Oily hquKl at 2rc. This change is considered a sign of decomposition. and Mlo;:h !i.:lmples should be db carded. Cannu5t ilIC is most stable in petroleum ethcrorwater at pH 4. It is tWminlsteR:d intra,enou5Iy because nl(:tabohsm i,~ ,ery rapid. Sonle of the dcgmdation prodlK."ts. however. ha,c prolonged halfli'e<; in plasma. Carntustill(' is supplied a.~ lOO--rng quantities of lyophilized powder. Whc:n it I ~ di luk.<d with 3 tnl. of the: supplied sterile: diluent. ethanol. and funher diluted .... ith 27 mL of Slenle: water. a 10'1- ethanolic solution cotllaming 3.3 mglm l. i ~ obIained. l)iotnmsformlUioo of c:trrnustioe is rapid and c~ten 'ive. .... ith mosl of II dose rc:cOI'eT"c:d in urine as melabolitcs. The: ha lf life hIlS an a-phase hulf li fe or 6.1 minut~ s pnd a fJ. pha...e half lifc of 21.5 mi nUI~'$."'7 8 ecause of its ability to cross the blood-bralll barner. carmustine i~ used again~t brain tumors and other tumon (e.g .. leulemias) that ]g,e nM:Ul:Stui7.oo to the brain .... It also i~ used as secondary thc:mpy III combination With other agents for Il odgtin' 5 disc:a.<;e and other lymphomas. Multiple myeloma respond, to a conlbinaltoo of carmustine and pred nlsotlC . Delayed rnydosuppresslOll is the most f:qUl'nt and serious tOXicity. This condition usua lly develops 4 to 6 wtc'ks al\er treatmcnl Thrombocytopenia i5 the most pr0.nounced effect. followed by leukopenia. Nausea and vomit ing frequently ocwr about 2 hours aner treatment. Carmustine IS given as a smgle do:se by Inlm'cnous inJeCtion at 100 to 200 mglm l . A repeat course IS not gh'en unlll thc: blood elements return to normal levels. which l"C\"juire$ about 6 ...eeks.

,ed in If' geon I;'M are Ibt car unrmry rom lhe: lddcr_'" sna an: tocludc

)sme. L'

<hcnylulninorIM: b) phos. roch loric "lIublruabsolu te .ion kit i~ JO ms of thol solumng log 'Ie gl)col. \,. of solu

It:lphalan. matic hy ~:1fI Eli",nutcs and I nonrenul

It also I~ tc;nom a." ich mc:lIn\ <lausca and

Lomusrint!. Lomustine. CecNU. CCNU. NSC79037. I H2-chlorcthyl) ]3-cyclohex yl. l.ni trosourea. is synthesil.td by treating ethyl j(2-chlorocthyl}-3nitrosohydamoatc: with cyclol"tc.lylamine . follow. ed by rc:nitros.atioo of the rc:sulung intermed iate. (1-{2-chloroethyIH3-cydohexylurca.09 It is 5IIfficit'tltly ~table to metnbolism to be administered ornlly. "The high lipid solubility nf lomusltnc alloW'! it to cross thc: blood -bmtll barrier rapidly. Levels in the CSF arc: SOCJ higher than those in pl35ma. Lomustinc is ,upplied in dose p;tCb th3t t.'Of1tain t... o each of coIor-codc:d 100-.40-. and IO-nlg c1lpSulcs. The: total dose prescri bed i~ obtained by appropriate combination of these capsules.

Ob

1In. chlur &nunophen Cnylbulyric chloride.'" Ilh. Its onl d 2mg tab--

ast to~ic of clltcd espe

oi>uline.mia.

dise:lS(". For th is condition. it is used

Oml absorplion of IomuS)inc IS nearly complctc .... ithin 30 minutes. II is OOIl\"(~ned rup;dly into cis- and Irans-4-0 11 metabolites by liver microsomcs. The hal f life of the ]XIrent drug is 1.310 2.9 hours. and the peak concenTrotion Ormetabolites IS reached 2 to 4 hours after dosing . Lomustine is used against botb primary and IllCtaMalic bruin tulflOfS alld as sccoodary therapy in relap~d Hodgldn' 5 disease. The lnorit common ""verse reactions are nau5ea ~nd vomiting . Ihromboc)1openia. and leukopenia. As in the case of carmustine. the myeIQSu~~sion caused by lomU5tine i5 delayed,1\"I Thc reeommended dosage of lomustine is I JO mgfm l or aJly e very 6 ...... eeks. A reduced dose is given 10 patienTs with compromised bone marrow f unctioll.

agenls such 115 mechlorethamine, (MOM> program). To~ic effects, II bocytopenia. nausea. and vomiting. occur in most pafltllUNellfOlogical and dermatological effects also QCcur. ConcwI'Cnt intake of alcohol, certain amine drugs, and lIIining high tyramine le,"Cls is contraindicated. The monoamine o~ida5e-inhit:Hling propenics of may potentiate catcchol amirocs 10 produce hypcncmJDll

ri~:i~~;~~f.~::

Oa carbazine. NSC-45388. catboXllmide, .. pared from

Dacarb.uine. DTIC Dome, Ole ,

"

colored solid thaI is "cry sen sitive to light . It docs bill deeomposes e~plosively ... hen heated abo ...~ Water solubility is good. but !lQlutions muS! be rrom light. Dacarbaziroc is supplied in vials I 100 or 200 m&- When reconstituted .... ith 9.9 and I respectively. of steri le ....ater. these 5al1lples g~':'i:::': containing 10 mJl'mL at pH 3.0 to 4.0. StICh 5 be stored at 4"<: for 72 hourll. Irijccted dacorbal.ine disappears rapidly from caU5e of hepalic mellibolism. The half life i~ about utes. Excretion i5 by the Il'IlIIl tubules. and in the excretion fraction. 50% of the drug is intact and N-demcthylated metabohle.u D:III;atba;tine is indicated for the trcatll1t"nt of malignantlllt.lalloma.7(r. 11 plastic drugs is superior to its use nausea. and "ontitinll arc the most frequent Leukopenia and thrombocytopenia. however. an:: SC'riOU$ effects.7lI Blood counts ~hOtJld be done. :m;J Dacarbarinc is also kin' s disease. The recommended daily dosage IS 2 to days. with repetition at 4 ....cek intervals. the drug during injcction may resuh in severe palO

Th iotepa. USP. ThiOlepa. TSPA, NSC-6396. N,N'.N". triethylerocthiophosphoounide, tri~ I-uiridinyl)phosphine sullide , is pre~ by treating lrichlorophosphine sulfide with aziridine I and is obtained as a ... hite powder that is water solUble. II is supplied in vials OOIltaining 15 mg of thiotepa. 80 mg of sodium chloride, and SO mg of sodium bicatbon~te . Sterile water is ""Jed to make an isotonic solu tion . Both the vials and solutions must be stored at 2 to So These solulions may be stored 5 days without loss of c. potency. Thiotepa blood leyel s tlecline in a rapid biphasic manncc. It IS eon\enC'd into TEPA by o~idat;'e desulfuril.lltion, and TEPA le~ls exceed tOOse of thiOtepa 2 hours after adminis trnlion . Aziridirlt rnctabolism abo QCcurs. with libenltioo of elhanolamine. ThiOiep3 has been tried against a wide variety of IUnlOfli and has ,iven palliation in many types. although .... ith \'111) . ing frequencies. 1lIe most coosi~lent results have been Dbmined in breast. o,arian, and bronchogenic carcinomas alld malignant Iymphom:ls. It i ~ a mainstay of high-dosc regi mens in treating wlid tumors when followed byautolopls bone marrow transplantation . It also is used to OOIltrol intra cavity effu~ions resulting from l"ICoplasms. Thiotcpa is highly toxic: 10 bone marrow, and blood t'OOnts an: neccs..Iary ' during therapy. Procarbazine Hydrochloride, USP. Procarbazine by drochloride, MUltilane, M ill. NSC77213 . N isopropylO'. (2 rncthylhydra;r.ine)p-toluamide, is prepared from N isopmpylp-toluamide in a process inVOlving coodens.atioo with dicthyl v.odicarboxylaie. nlethration with nlCthyl iodide and hase. and acid hydrolysis? Althougb soluble in watn, it IS unstable in wlution. Capsules coruaining the equh'alelll of 50 mg of procarb3zinc 1$ its hydroch loride are supplied. Procarbazine is rapidly and completely absorbed following oml administration. 11 readily decompo!ieS by chemica! and metabolic mutes. wilh a halflire of 7 to 10 minutes, to produce highly react;'c species including mt:thy l diazonium ioo, methy l radicals, hydrogen pero,tide. fomt.llldehyde, and
hydro~yl rndical ~.J)

ANTIMETABO LITES

t arc enzyme i with the active si te as ifthcy .... ere the Alteowh'e!y, they may bind to lin especially when they resemble lhelic pathway under feedback

Iized) into the active inhibitor. For e~all\plc. rine is convcrted into the COlltSponeJIIlg

i , StCP in the de novo 5ynthesi~ of

--------------------------------------.... ,
l

g1r;:in'~

with nisorlC' ohrom

HO

0'V NH,
OH

4tient~.

oncllr-

ds con-

weal baJ.ine

SIOO .

DTIC. 1:010:-4all. prt'limelh

lVory-

51l1-Wlr_ifI

I"f~'

NH' NH

01.

melt

25O"C. -otcclcd
IIIIIOn_

g ei ther ) .7 mL.
liS mlly

HO

OH

HO

OH

.rna be.w min

to i\ the

.......,

.......
'"'W. WO"

!tllstllllC

II1hnco-

~)(Ia.

1ICtlOn'.

WO"!(

'"

~-, d If the p:-rn.Ied.

-00,

11008-

,for

10

\ uon of

HO

OH

HO

OH

HO

OH

HO

OH

Sdleme 12- 6 De f1(M) synthesrs of punne nllcleotides (Slmphl-.rdj.

~,

HO,CCt-lO<,CO,H

HO OH

....... HO

OH

-"'"

HO

OH

HO

OH

Goar;,IIc ACId (GMP) Scheme 12- 6 Con rmued

Scheme 12-(6). An anlllTIClabolilC and U ~ IMlMfotm:lhon prod lIClS may inhiblill numberof different cn/)'mcs. Thus. 6-lTIC'r. clptopunnc and its ~nnbollle:'i intcl1lCt \\ Ilh moOre than 20 cnzymcs. This llluluplie.'Yof effecls males IId,fficull todecKk
which ono!$ an: cruc ial Il) m., anUlumor lleu yil),. The 3nabol ile.~ of purine and pyrimidine antagonists may be irlCQrpof'dled i 1110 nuc leic ac ids. In Ihi s I:\'cn l, plil1 of their antitumor effect might resul1 from rnalfurlClioo of further macromolecular ~y mht'si ~ because of the abnOfTllaJ nucleic
;!CiQ~.k1

Arter the f()l"muiallon of the anl1mclniJolilc theory by Woods and Fikks in 19-IO,I.l.Il> amimctabolues based on a VanCI) ofkoo ... n nutricnlli were prepared. The fil"lil purine lIllaloguc 10 show anl mmlOl' activi:.>; in Illice. 8-naguaninc. was synt hes ized by Roblin ," 1945. 1 Thb compound was imro-

,N
0

H,C- N

NOz

NA-N
I

I..) -N>
H

ductd inlO clmical Inals btll "as abandoned In oeWa' IUld ~ df('Cti\'C' ~enb. such as 6-~ and 6-lhiogU3n11lC. de"eloped by H,l(:hmf: and Eho.... ' Mercaptopurine was synlhe~ l/td in 1952 and ..'a'l to be active againsl human leukcrma In lhe To be active againSi be convcned imo it ~ 11 enzyme hypoxalllhine-guanille NeoplllSm' thal Jaclthi s enl.yme are 6-Thioinosinale is II potent ,nhibllor o f the phoriphonbosylpyrophosphale mlO mentioned abo'e . It also sinic acid 10 adt'nyl~ ~id al IWO Slages: (/I) lhe inosinic acid wilh aspan me 10 gi '<! adenylosuccm,~ (h) the II>S.~ of . . lICid from give ad.:nylic I I o r ioosinic acid '1l1e mode 6-mercaptopurine i~ l"OlnpliclllW by lhe ribo<;e diphosphate and lriphospbale anaboli,a.: live em:yme inhibitors. and thI: tnphosphale can ruled InfO DNA and RNA In mh"lIt further dwo tiOl1 .17 Still rt1Of'e cOlllpln ,~ the abll ll Y o r 6-lhlOi In 3C1 as. substrale (or. methyllrnnsferase lila! adc:nosylmelhioninc. ",hich COII'ern. il imo nosinale . TIle IUlIe r l'ompound is rc~ponsible metabolite activities o r 6- mel\:aPlOPUrinc.~

rl\"

as

,m""',,,,,;"

6n_ "

"IiIre(R _H/ 6 ~lelll"""c"lilre (R .. CH ,I

o
O-p-O

b
HO
~ktabohc

OH

HO
R .. R,_ H

v.aa....

dcgrnd:llion (calaboh<;rn) of 6-mercaptopurlr1<' '" ",an~ ilives 6tllio)(amhi~. whIch is ox id i/cd by )(anillrneoAidasc 1 yie ld 6lllIourio.: acid."" Aliopuril1()l. nn in0 ltibrlil' of ~lIl11hrnc oxidase. increases both the polcncy and wlOliclly of6-mcrcaproptlnnc. Its main ImportarlCe. ho ..... croft". lias an adju\'anl 10 chemothcrnp)' becau..e II ~'CIII~ WIt Kid I.:idncy lO.\iclly cau'iCd by lhc release of punncs dewro}ed C:lJlC('r crib. Ik lcrocyclic dcnv~lI~c\ of 6;;;,popurine. such as al.arhioprme (Imuran) ......rn: dc10 prott<.'l il from carabolrc reactions. Although :lIa' iIIropnne Iw alllilu!1lor UCli~ity. il i. not ,ignificDnlly bencr 6-mcfCPpropurinc. II ha s on irnporlaru rok howc.'cr. .... immullosupprrssi ~c agent in organ Ir Jlhplanl,.""

R .. F. 1'1 , .. HOPO, FU:llwabr.e

In comruSI /{) tire su'>Ccptihlhly of UOcIWllollle amblllo,idc 10 atknOl'lIIc dcal1\1na~. its 2l1uoro tkn- all'C. fludardbirn:. is slabk: to Ihl' enzyme. FI"darablne i, prepared as the 5'rnonopho\phare. Fludarolbine Ira .. gOOl.l :11." ~I' ) agamsi eLL. 11 b cOlnCl1l-d 11110 Ille ~"()IU"spondlllg I nl'no~phalc.9I! whIch inhJbll~ ribonuclrollOc ltdu<:1a~.w 2-ChIoro-2' -dro... yaden1Ilk~l nc dcamina...e. osine (cladnbmel al...o " I"CSISlam It is ptIosphor)lulcd in cdl~ 10 the Inpho-,phatc by C) lidme klllasc. and lire 'nphuo.phale IIIhlbm Cn/)l1lCS rcqulo:d fur DNA n:palr.""' Cladnbrnc is highly cffl'ClI\e ag~in~1 h'lI/)' cell Icukcl1lill.

.U

r 01

ID~

r"

~.,

~ear.

Thioguanine is COIl'tned mto iI' ribonuclrotide by thc ;;;o~tlll.)"mc: Ihal act~ on 6-nlCrcapr~rillC. It i~ cOllVcned 11110 the di and tnpho>.ph3I c,.9. 111c~ "PCCK':S inhibIt Ihc' same enzymes tllal un: mhibilcd by 6-nlCrcapto,. 'Iluoguaninc is abo incorponatcd illlo RNA. und Its my mc:ubolite is incorporuted into I)NA. The sigmfi o(~ "frnudulenl-- nucleic acids in IClhaillY 10 nco-

--

N H

:;;;01'

must

,,,.,
1V

;;;~ is ulll"nain.~j

!r.l-<.C.

lUg.

of 5

~of

",line. illl,"

id ami

.ire, s
nnll-

H"U'C

IJnunc arabinoside (V ida."db,nc) wa.~ fi~1 pn:p':II'w by synlllCsi~'IoI and laler isolaled from cullurc~ uf tpIOII!)"C<"s uII,ibimicrn.yo, It ha.~ a sugar. I:r-ur~blllo)". i'rpllnc:ric .... i.h o-riboM: atlhe 2' posilion. TIns Sltue m.rge makes II I compcllllVe inhibi lor of DNA poly "In addition 10 ItS an"ncopl:Llolk IICIl\lty. adenll1C bas poIcnl amh-irJI action . Ademne: arnbH~ide of its den~DII"CS IU"C ltm ltcd III .heir antitumor
II

~ hhl~'"

~n

';~;:~~~~,::~:.~::'~;' Thl~

ambiJlOOidr dcr1\"l1li\c~. enl.) me wilh locir Ic,'ct-

111c in'ellllon of 5 fllJOfOUrocil U\ an amimctabolue of ur.IC11 by Ilcidclbergcr in 1957 pn:l\"ldrd __ of our fon:lIlO!>I uamples of mllonal drug design_'OI Slarting with the obscr"allIIn ,hat III cenalrt tumors urolCll wa, used more ,hart orotic acid. lire maJor p~ursor for nllClelC acid pyrimidine bio-;ynIhcsi< in normal ris.,uc. he <kt'ided hI "yrttlle,i!.c an ami metabol ilc of uroci I Wllh only one: rnOOllicullon In lire struclure. The 5 pI~llIon Wlls chosen for a 'UhslllUC:nI 10 block [hoe con\C~10n of untlylare 10 thymld) lale (!>c:helne 12-7). Ihu ~ diminishmg DNA biOS) mhoe~is. Fluorine ehostn ~ lhe substltuenl hccau-.e the increased octdny caused by ,''' IndUC' li,c cffect ... a~ e~pcclcd to eau-.e 11M: rnolc1:ulc 10 bInd ~trongly 10 ell /) lnc~. Thc. .e ehoiee, ... tll' ... 'ell founded. a\ j.lluorouro\CiI soon bccanlC one: or .he nlOSl ... id.:ly u..ed anlincopla~tie I's.:nl~. II i, a main,'a) III Ihc IhcrJpy ade_ lIocarCllloma of Ihe eul"n lind ~tllm, Side effcc.~ are both dose and ...:hcdule dcpcrwlcm . 'They IIw:11.Idt: ut}'elosuppre .... ~ion on boIu, ad"nnisU"allon and mucO!oni~ on prolonged infusions. Chhc:r\\.I'oC. the drug;~ "'ClilOlcr-.aled. 5-Fluorour-.lC11 I~ OCt"31W by lInaboli\1I1 10 5-1100n:r-2 de'Olyurid)"he acid. Th,s COf1\eTSJOf, may pnxttd by 1...0 roulcs, In one: roule. 5-l1uorouro\Crln:acl' .... ,'11 nboA<: I pIK. phme 10 ~i"e II, nbo<;i<k. \lh ,eh is ptKKphorylutcd by uridine l.:inasc.1O The n:SUltl ng cnrnp!.)lllld, 5-n uorouri dyhc acid. is

"'a.,

or

SH

T
HO
R

HO

R-

~ CNHCH (CH~)lCO}H

&',H

Scheme 12- 7 11"110 IhymKfylate

Con~

of

urlltyl~le

HO

_.

2'-dco.\y den":tI,\"C by ribOflucleOlidc reduC:la)('. 5-Fluurour.ICil al\.O may be u".In~fonned din."cdy 11110 S n l)(lll)Uridylic acid by a phO!>phoribos)'lIr.lIIs fer:be. which
Ib

comened into

of It CystCHlC residuc: in the cnl)'mc adds !O of the nuorouracl l 't"he s ~i l ion Ihrn
melhylcnc group J -n I ' by the I nun ly. Ih" Mcp .... ould be h)l.Irog<:'n of uracil 1 the methylene group. rt~uhJn, 0 fOnl):J.lion of lh) mld),blO! and dlh )drofolalc; hm" C\tr. nuormc i~ slhble 10 tran~f('r. and 11 terminal product

i, pre..;,cnt in cenain 1\J(1'IOfS.1lt1 An alLenuuivc pharmaceutlc:1 1 based on S-nuONllrncil j, Ib 2-dro:<yribosidc (nOlluri dinc) ,'111 Thi5 compound j, phospOOr)lulcd by 2'-dcoll)'Uridine
~ ma.'I(: .

po .....crful ~'OInpclili,'c inhibitor of Ihymidylule ,ynll\clll.'IC, tile ell/ylnc lhul cGOveru 2' -deo.\)'uridyhc ocld 10 Ihynlid) lie add. Th'5 bloclage Is prob;ibly the main lelhal effect of 5-f1uorour.1Cil ami il~ nIC w.OOlites. 1OO [n the inhibiting reaction. LIM' sulfhydryl group
h
It

SAuoro-2tko~),urid}li c:loCid

,ifoed as a K.:.. i TlK: rmc-di:lermininll cnqll1e in , ,n"~.,~,' 0 "

is dlh),drop)'nmidinc dehydrogenase

""I~F _

O""'N)
HO

o
OH

o
HO
!>-FluDt"' ..... )U'<oc Aad

HO ,.O HO
5fil.orcuaol

HO

20e00<,., .......

The IC1fl1hydrofuranyl dcrival l\c of !i-fluorouracil. ICgafur IAcnfur), \lias prepared in R us.~ill. 100 11 i~ active: in cli nical (attand less myelosuppte>;. ;ve than S- n uorourncll. II has
p.trOlnlestinal and eNS toxici ty. however. T egarur is a..ly metabol ilcd 1 5fluorouracil : Ihu. II ma y be consill 0

!!lid I prodl\lg.l<T1

,H
+ SH

(Ftora'~)

'......

6 POSlUOll "lids 10 the )\3It. Ortb-

'er of the S tiling In IhI:

Ic\er. the~'

c.-cllabinc: WItS designed mlionally as DlunKW_~ l l'Clivc -'tumor_activated prudJ\Jg of SfluorQllr.JCil, which would 'Ie ~\S likely 10 produce ,'iCvcrc d iannea. It is 11 carbamDte tm'al,ve of S'_(\oo.ly_S_fluO(oqtidine . On oral admin iSlraM conwned into 5'..(\eQJIOy.S.fluomcytidill<'- by c)'n1$ ikaminase. wh iCh is in higher concentration in n~ny in mosI normalliSliUCli, wilh the notable uceprJ. hn~r ACli>':lIiOll 10 C)'IOIO.lM: specks by Ihymidinc:

.,.1bJn

>duct re\ulL~ II e<roalenl l) auk! be cIOl-~'

=~~Iast OCCUrli prc:fm:nlially al tumor sl1e~.IOII Delhil romplu 1IC1i>'atiOl1 pmce\oli, capecnabule still extome of the sign ifICant to~ ,citiel' of ,nuorouf31:il.

In genll"it~bme. nuonne aloms replace tbe by"'ro~r;1 group and tbe hyo.lros<:n 1I10m III the 2' JKl'lUon of C)tidll1e. 00 After n~ anabolism to d,phosphate and triphOsph:uc nlelabolnes. gemcitub,ne IOll1bns ribonuclroude I\"dLIClasc &lid compele~ "ith 2' -dro~ycy"dme tnphosphale fOf" allOO ,1110 DNA. These efTcc,-~ produce a:11<ycle-spec;ific CyIOloUClIY Gcmcllabme has become a fiN-line lrealmcm for l(lCally advanced and mc:ta~1I11k adenocan:,ooma or the pa~as. Trin UOrolhymid ine (Trifluridioe) wa~ designed by IIcidc:lberger a~ ~n anlimcwbolite of thymine.")' llle ribo)ide i, ~~l1tial becau<.l! l1lamll1~lian cells are unahle to con\'~ n Ihymi nc and cen ai n analogues 1010 th)'midine and ils Bnalogues. Thymidine lma!.e ron\cn s trinuorol.hymid ine InlO lrifluoroIhymldy lic acid. "hleh is a potent inhibllOf" of thymldylnlc s)nthcta<;e.101 In rontra\t to the ~tablhty of most tnnuoromethyl g rouJl'>. Ihat of tnnuoroth)'mldylic acid is eJl traordin:uil~ labile. Ii react ~ .... ,Ih glycine to gil e an anlide: UI neulrnl pi I . I 0 Kinc:t1C ~tudie' hal e sllo.... n lhat thl~ reaction 1Il\"oh'cs initial nucleophilIc all!lCk al position 6. followed by los~ of !IF 10 I!ilc the highly reactile din uororrlelh) Icoc group. III Glycirle then IIdds to this group and hydrolysi~ oftbe remnlning IV.O n oonroc atoms follo\lt~ (SchenlC 12-8). The in leBCtion of lri nUOl"l)jh~tnidylic acid wilh thynl1d~la l e s~mhclase apparenlly fo llows II si mil ar course. Th us. nfler prcinculxtlio n. it bccollle~ IlTCvcrsibly bound 1 ItIC Cn/~Il\e. aod the 0 IOI kinet ics are noncompetitl,e. Cylosllle nroDlIloside was s) mhcsiled III 1959! I: alld 1~ler found lIS II fermc:nlalion prod\iCt. III Its ' truc .... re is notcwor thy in thai the' IlrabHlo~ 1ll00c:ty is epimeric Illlhe 2' posillOO \It It II ribose. This mod,flClitlon. after :mabolism to the: tnphosphatC, ('lI.use~ II 10 inhibll the ron,'U<;;1OO of cylidyllC acid 1 2' -droxyC)tld) lic acid. '" For a oumber of )"ea~, this 0 inhlbmofL V.II~ bclie\ed to be the main mode of acllon of cytosllle III'lIblO(l'iide mpnosphatc: howeler. 1\ Willi ~hown reccntly lhal lanOilS dI:o~yribonuclCO"ide~ v.cre JUS! as ef fectlve as C~ 'O!iIlIC IIrnbil\O~ide in rc:duclllg cellular level~ of 2' -dco,~cylidy l k add. I " o\hcr modc~ of IIClion lIIc1ude the inh.ibilion of DN A-depernlcn l DNA polymel1lSll' 1& and ml~ coding foliowloS Inc:orporation into DNA and RN A. III CyIOSllle arabinOide is readi I) transpor1ed into cells alld phoIi. phorylated by deoJlycy tldioc kmilSe. It ;tel'> predomHllUllly in lhe S pha.o;eorlhe CC'11 cycle. Tumorcc:1I resistance is ba.~ 011 low lel'cl, of dc:o~)c)'tidine kina!lC and the elabor,I\iOll of deaminases that COIl"cn cytosirll' arablllO~lde mlO uridlne LUlIbHlosKX. m Panially purified Cytidine deanimase is 111hlbl ted by letrahydrourid,rll'. 119

'llroI'J""

i l ca.labuli,," n of Ihi" en

OMCOC,H"

"

....
O~N
" r

NH,

J)
HO,_,
HO
(Oftcn ... .....

'"

O...J

"

""

-....... o;;

HO

Z 1 ...

1"-"""' ,

......

O,rd"'-

A rocw analogue of C) tosine arnbmosKie is cyclOCYlld,ne (ancilablllC). This al\3loguc: a pparenlly IS a prodrug thai is ~lowly convcncd mto cytosine W1lbinos,de:. It IS reported 10

HO
HO

HO HO

,...-.
(T ,o/Iwo OCIIJ1T.::Io.)

HO HO
ScMInf: 12- 8 Reilcnon of Influofolhymodme w.rh gl')'Clne

be resistant 10 dcaminalion and to hal'l: n bener tlltrnpeutic i~ lhan the parent compound.I::O A number of pyrimldme nuc l~1Ik IIlJ.JI()l!;uc:s hale: one

for compounds that might inhibit the"!: dcaminasn. In"

ory. 0 pot ent dc~mina.\C inh ibito r would produce a synapIICdfea on the antitumor neti v; ty of the IIlllmtl.!lbolltt.. though it might rIOI. be !OCti le itself. Two I)'pes of tit;';;'. inhibilOB have emergoo l'CCell1Jy. Ooc type is Ihr a naloglll: in ",hieh the pyrimidine ring has been to a se,en. membered ring. The fi r.;t exllmple of t W~ 2'-droxyooform}ein (pen IOSl.llli n). Iln '~~;::;:~ side produced in the ~me c ullutn lIS lhe myein.ll~ It ilrongly Sync:rgi7~ lite action of form)Qi against organisms thlll pnxiuce dcami nases In triul s II sho,," ed a sy nergi stic effect on the IlC"IlIltoef adenine II1I.binosidc and c)losine IIl1Ibinoside. A ~. type of adenosine dc~minllst inhibitor has the ponion tlochanged oot is modifi ed in lhe . Such modlrtCDIIOIIS hal e been ~.gncd 10 Sile of the cn1yme and toke odvamoge 1 adjacent lipophil ic: regions. t27 EHNA 0 an D r.llional1y ~igntd . nhibnor.

more or one less nitrogen in lhe heterocyclic ring. 1lley IIrt known as lI7.l1P)'nmid inc ordeuzapynmldinc nucleosKics. 5AZ8Cycidlllc wa~ syl1lhc~ l.ted in 196J by S6rm In C~ec;ho:slo
\'alda III and late!' ""1lS ,sola((~d as an tIlUibiu(ic by Ibllka. III The IlJ('Xk of ileUM of Ihl s compound IS co mpk.1. . ml'oh lna

n,"

anabolism 1 pho~ph lllC: derhall\'e~ and dcaminallon to 50 v.lIundme In eertllin tumor s)'Mcms. it is 1~lcd into nucleic acids, ",hich may resuh in misreading,'-) ()n.co of ils main dftclS is the inhibilion of Of'OIi d},lalc decarboxyhl<;C (Scheme 12-9), ... h)t'h pre,'rnts lilt new ~yn lhesis o f pyrimidme nucleolidc~. Il~ TUl1lor resi ~larKe is based on decreased phoI;phor} lmioo of the nucleoside. decreased iocorporalio n
into nuddc acids. and increa>cd RNA and DNA polymernse nel i~hy.ll.! Other pyrimid ine nucleoside alllagOll ist ~ that !\al'e ~ciled clinical study include dihyd ro-ja;.:neytidme and Jdeal.auridine .....

ci""

HN

N~N

l..N
HO
........,

l..NJ-)

t ~.....".,_)

HO
OH HO OH
3-OelllllUlo Ie

.,...,.

Resistance to purine ~lId pyri midine am imeUlbohlc~. ~uch Ib adel105loc arubmos ide and cytosine arabinosilk. by ne0plasti C cells l h~1 produce dc~llI,"ase~ has slI nltl lmed a seatdl

Arte r the dj~"el)' o f folic acid. a numbe"";';~: ::::: ba.'ied 011 its structure ,,"ere synlhc:si~ed and Ie

'-

HO

o
........

HO

',.--taiL,'E EE

o
NAO~.
~CIOI'71 1

',H

o
HO OH
0".."", _

-H

'

!In the5)'nergiov

:5.

HO OH
Scheme 12- 9 De novo

Ot..oo,io ..

>lile. c,-cn

kamil\ll.'ie he purine

expanded [his type II Iluclco~iotic forformycin n clinical ti'llies of

"-SYfl t~s

of PYrlmKline nud,otides

(~ mphfled)

A """"" : adenine

c moiety the ocliH , bllldlll,

. The N,n,methyl derivative of folic acid was fouod It_antagonist. bul n had ItO antitumor acthity. AmilDE
dIlly finally was found for 1he 4-am lllo-4-dcoxy de\"to Inllnoplcn n. and its N 10-methyl homologue. Rletho,,*{amemopu:rinj. 1;tII

umple 01

IfIJ......N:rCH2NH-o-CONHCH(CH~11C02H II.J..)"N

?Oz'"'

,
analogUCI
..... 'I0I)l .....

as anliTre-

R_ H ~1.UiCCI l .1, R - CH.

Methotrexate .nd related CQlTlpoul'lds inhibit the enzyme dihydrofolate reductase. 111e) buid so lightly 10 II ,hal their inhibition has been Icrnw:d p~udoir,"~rsiblc. TIle bruil\ of this binding strength is In the d;arni rK1pyrimidioo ring. \\ hlCh is proIooaled at physiological pH. AI pH 6. meloouculC binds sioichionl('trically with di hydrofolate reductase ( K 1 10 10M). but al lIigher pH the binding is weaker and CQmpetitive with the ~ubsmlle.'1'1 Folate acid antagQni~ts kill ce ll s by inhibiting DNA ~yn thesis in the S phase: Qf the cell cycle. Thu ~. they an: most effective in the logan thmk growth phase.')Ij Thoc'ir effect on DNA synthesis resull~ panially from the inh,bition of dihydrofol:ue ru1UCt3SC ..... hich depletes the pool of tetrohy drofolie acid. Folic K id is reduced stepv.'ise to d,hydrofolk .acid and telruhydrofohc acid. with dihydrofohc reductase thought to catal)'/"'" both stcps.')1 As shown III Scheme 12 10. tell1lhydrofohc Kid IICCqJt5 the fJcarbon atom of ~rine. in a reaction requ,rin g pyrido~al phosphate. to I ,ve ~ ,}/' o methylene tetmhydrorolic acid_ The last compound transfers

-s,."" '
I

~i
N H

DR

10-FOIll1)'I1etTehyd'0I0k k.od

S.Forrrr,elrah)'drololC AcId

Scheme 12- 10 InterCOl'lYl!'lSlOOS of folK acid denval....es

a merhyl gruup to 2'-dcox)'uridyJate to gh'e thymidy laLe in

therapy" with methotreAall:. 11

metllOlrc~ate

pre\"~ms

the lethal dfecIJ

a tt'at1ion ,aUlI~ by lhymidylalC symhewc. Dihydrofolic acid I ~ gCtICralOO in this reaclion. arK! it muSi be reduced bock to lelrnhydrofolic lICitl before another molecule of Lhymidylmc can be syn thesized. It i~ partly by their efT~ in limiting Ihyrnidylme symhc.osis thai folic lICit! nnniogues prevent DNA symhesi~ and kill ('('lis. This effect has been
renned Ihymillf'lus dl'lIIh. m TIle inhibition of dihydrofol ale reductase
producc~

on nonnal ""U. by O\'crooming the bk>;;

of tctrah)drofolic acid prodUCtion. In addition. itlllhzbu'l aclive tran~porI of mcthotre~lIte inlo t-e lls and st;mul1lel

emo.t . I .'" RCI.-cntl y. it .... as shown that givin, thymi dine ","h~'
In:xatc 10 l1Ii"" bearing Ll210 leu~emia inc~ased thciI \ i ~aJ time . TIlls findmg oonlradict~ the tde;t that , dcfidency is the most lethal effect of mcthotrexate 01 mors. It suggests that the blockade of purine bioi; might ha~c greater effCCls on tumor t-elh than on : : cen~." Cons<.-qocntly. the admini,tration of th) might proIl.'d the nonnal e(' lIs ft'lulIlc 1 t~ tumor 0 Unfonunalcly. the U\C of such thymidine ft''lCue I Inals .... as disappointing. N\lmerou.~ l.'Ompoun(h elo..cI) relllled 10 ~""w. h:ave be<-n prepared und t~~tcd agai n", 11OOp13-'1D5. structural variations. ~och as al~)' lalion of the amlllo panial reduction. and remo, ~1 or rciocatlon of he";"" nilrogcns, lead to decreased acli~it y. Pirilft')li m and

oilier

linllialiooli 011 nucleic acid biosynthes , Thus. N' .N,o meth ylene le lrnhydrofolic acid is oxidit.ed \0 the COI'l'eloponding
methMyl dI;orivan,c. whICh gives N'. formyllelrahydrofolic acid on h~drolysi$ (Scheme 12- 10). The laller compound i. a formyl donor \0 .5aminoimilivole-4-carboxurnidc ribonuclcotlde In the biosyn thesis of punroell.')) N-Formyltell'llhydrofollc lICid. al<;o known as leucovorin and citrovorum factor, is inlcmmv~nibl~ with the N IO. formyl analogu~ by way of W1 isom~rase-catalyt.ed reaction. It carries the forminuno group for the biosynthesis of fonnimiooglycinc, a prec ursor of purines (Scheme 12-6). Lcuconll'ln is used in "ItSCOC

I'"

kUk..-e analOlluCli of metOOcrexate in "hich one or t.... o 4411S tn the pyridine ring are replaced by carbons. and
6r~nzoyl

ghmmllc acid chain is replaced by a n~ JipoJ*jllt ,roup.Uke metOOcre~ale, both compounds inhibit di iIydrofolale reductase; ho.... ever. they do 1101 interact .... ith 6r rtduttd folate transport system used by methotrexate. ntly, they are lICti~e in vitro against some forms of ~ute resi$tal1Ce. Their i!"!Creased l~hiljcity ullo .... s . . tnlnsport by simple difru$iOll. I)1 I

CH,Q

--

nutrient for normal ce lls. many tumors dtpend OIl exoaenous 5OO1U$ of it. This provides a ralionale for the selective action of agents that interfere with the uptake. biOliynthcsis, or func tions of glutamine. In 1954. naS('rine was isolated from II Slr~plomyas speciCS.'l It WIIS found to antagonize many of the nJe1abo1ic plOu:sseS involving glulamine. with the most important effect being Ihe collvcrsion of formyl glycine ribonuclCOlidc into formyglycinamidine ribonuclcide (Scheme: 12-6). I"J A related compound. 6-diazo-5-o~o-t.-norIeucinc (OON). was isolated in 1956 and found to produce similar antagonism. l.... A study involving iucub:nion with ['C]lIl11scrinc follo"ed by digestion with proteolytic enzymes and acid hydrol ysis ~ S-II"'C)carboxymcthy!eysteine. "hieh showed lhat l17.&5Crine had reacted covalently with a sul fhydryl group of cystei ne on the enzyme.'' OON is a rllOn! potent inhibitOl"" than DU\Serinc of thi s cozyme and of 1M enzyme !.hat COfIvcru uridine nl.ldeosidcs into cytidine nucleosidcs.'-ttl Although both compound~ ~how good antitu mor uctivi ty in animal models. tlley have been generJlly disuppointing in clinical trials.

P ....ucts
Merc.ptoptJrine. USP. Mercaptopurine. Purincthol. 6mercaptopurint. 6MP. I...t"ukerin. Men:akukin. NSC-755.6purinethiol, is prepared b1. ~ting hypoxanthine with phos-phorus pentasu lfide l"', I... and i~ obtained as yellow crystals of the monohydrate . Solubility in water is poor. It dissolves in dilute alkali but undergs slow decomposition. Scored .5()..mg Illblets are supplied. The injectable formulation is in "ials containing 500 109 oflne sodium S:\Jt \lf6-mercaptopurine. which ;s recollSiitUled with 49.8 mL of Steri le W:ue-r for Injt<:tiOll, USP. Mercaptopurine is 1101 acti\'e until it is anaboli:ted to !he phosphOrylmed nucleotide. In this form. i1 competes with endogcllOlls ribonudeOlidcs for enzymes tllat OOfwen inosinic acid into adenine- and x~nthinc-bascd ribonucleotidcs. Furthermore.. it is lIIcorporated into RNA. "here it inhibits funher RNA synthesis. One of its main metabolites is 6Incthylmercaptopurine ribonucleotide. which also is a potent inhibitor of the ronversioo of inosinic acid into puriflCll. I" Despite poor absorption. low bioavailahility. and Iir"Slpass metabolism by the li ver. mercaptopurine has oral octivity. Peak pla,,",a levels of about 70 ngfntL are reached I to

sites of dihydrofolic reductases from ce lls are identical. Baker proposed 10 the active silCS of these enzymes i inhibitors to lake advlll1tage of Ihu~ affording species ~pccirl("i ty. One of lIS " Baker' 5 antifol. ., shows activity tull10fll that arc resistant to methoglutamate are the donors of the three- and and the t....o-amino groups the three-nitrogen atom {Schemes 12-6 and 12at five different sites of nucleic Although glutamine is nOl an es.o;ential

2 hou", after ingestion of a 15 mg/ml oral dose. After a bolus m}l'Clioo. plasma levels of 5.000 nglmL un: reached within minutcs. Renal e~cre\ion is mpid. Men;:a~OJ)\lr,",c i~ metabolitcd by S-mc:thyllltion follO"o\'ed by II-hydroxy lation. It also IS oxidi zed to 6 ' ltllounc acId. Merca~opunne is \l.'\Cd primarily for treating acule leuke mia. Children respond ben.:r than adults. I..., "The chIef toxic effect is leukopenia. Thrombocytopenia and bleeding occur with high doses. 8cc~use lhe leukopenia is delayed. one mllJit discootinu.e the drug tcmpornrily at the !irst sign of lin abnormally large drop In the ",hne ce ll coum. "The tolerJted dose \~Jries with the indivIdual patient. A 110purinol poIemial~ the tffcct of tl"ll!fuptopurine by inhibiti", illl metaboli sm. It al.;o increases ils toxicity, howe~cr, If allo. JMlrinol is g,,en for poIentialion or rtductioo of hyperuri cemi a resultin g from lhe kill ing of leul;emia cells. Ihe doses of meTClIptopurine must be decrea1.ed. I ~ Thioguanine.l1I1oguanineTabIOlc. 6 thioguan ilW: . Te. NSC752, 2-amilM)purine-6-thiol, is prepared by treali ng guani~ with pOosphoros pentasutfide m p)ridinc. '" Scored 4{)..mg tahlets arc supplied. Om! thloguanllle iJ poorly absorbed , An mjectable fonn is supplied in 15-mg ~ials. 11 is l"l.'Con~titutOO by ,Klding 5 mi. of Sodium Chloride fOl" Injtclioo. USP. TInogunnine is convened by hypoxanthine-guanine phosphoribosyl tTllllsftrJSe into a nucleotide fOl"In thaI inhibits. number of reactions in RNA and DNA synthe;;i ~, ine ltH.ling the acti vily of pOosphoribosyl pyrophosphate amidolrnnsferlI)o('. the initlDl en7)me in,olled in purine biosynlhcsIJ. 'Jl The 2' -deoxyri1Jos.e triphosphate ItIllIbolile of thioguanine is exlensively iriCOiI)()lau~d illto DNA in place of the natural summlte. Thioguanine is melaboli/.ed 10 mClhyllhioguonine , Ihiouric add, melh)"lthiox:anthine . nd thionnthine. Thi ogu:mine is u'led in trenting :acute leukemia, especially in combination ... itll cytarabinc. 1'-3 Crossre.~istance exi st~ between thiogunnine and men:nptopurine. The chief toxic dfect is delayed bone marrow de".-ession. resulling in ieul;oJ)l!nia aud eventually thrombocytopenia and bleeding. The usunl initinl do<;e is 2 mgi\1! daily by the oral route. If there is no clmical improvement or leukopenia after 4 ...eek' tht- dosage is increased to 3 Ing/kg daily . In CQf1trast to nlCI'I:aptopurinc , thioguanine may be C(N1tinued in the u ~ual dose when allopurinol is used to inhibit uri c add for. nmtion.

The cum:nt FDA approval

kemiu. in ..... hich it tl<hibits pLetc responses. e'en i in a variety of OIher toddty in mos t p.llient~ i a lemponry dccrell.-'Ie in IInlbOphi ls. which commonly lead s 10 infectio ns, TIw:re i~ allOl prolonged suppression of helper Iymphoeylcs.

Ffudarabine Phosptktte. , FLAM!'.

Thioguanine, USP.

cont::uning 50 mg of nudarablllc mannitol . and <;Odium hydroxide ttl The IIHact \ ID Is sh-ould be Sl~ at 2 to S"C. rcconstitu led with 2 mL of steri le water: Ihis solutioo II " bte for 8 hours at 2~"C, It should be d,scurded aflcrtmJ bccau"t the ,ial contains 00 nmibac terial . tion is by ~hon intmvenous infu<ioo or a continU()IJs in fusion , Afttr infu <ion. nudarnbinc: phosphate is phory lated by serum pho'<phamses and comcnOO i ()fl)3(kl1QSine ar.lbiooside (2- FLAA). declinc bicxpoBemially, with half- "~es 2I-l..AA emet' cells by a carrier-mediated proem und.:rgocs intr.lCellular phoSphorylauon by demyC) lina!>C to the acti,c form, 2-F-ara-ATP..... Aooarubirtc: phosphate has good aclivity in G.L I ' ing clinIcal trials, it al"l) sho .... s activity lymphomas alld mycosi~ effect is myelosuppress ion. \I 'I ily also occur.

~ 11Lls

Ffuorouradf, USP.
I-luoroplex, Efudex. 5-I-V. , I inedionc. 2,4-dioxo-5--nuoropynmidllle, i. d.:nsing S-cthyli<othiollronium bromide

""'
aoo

Cladribf(lf!. Cladribine, ~ustDlin , 2CdA, NSC I050 14-F. 2-chlorodeoxyadcoosinc. 2-chloro-2' -dco~y-p.[) aderoosille, is prepared by a muillstep procedure from 2.8dichlOl"Olldcnine and [)oxylose.':\oO and is ~upp!ied a.~ . I mgt
mL sierile soLullon III 0.9% Sodium Chloride for Injection. USP. "The de.~irtd dose is Tl:nMl,ed from lhe vial aoo diluted with roorm:al 5alinc (01" Infusion over 24 hours. These 'IOlulions are stable for 12 hours, Infusion i~ conti nued for ~ to 1 days. Halr. !i,e,s of 35 millutllll (a) and 6.7 hour< (/I) were found (01" cl.adribine , III 1\ is completely cleared from pLasma in I to 3 duys after lhe infu.~;on i~ Slopped. Cladriblrle is ~. phorylall:d in cells to the acthe triphosphate by deoxycyli dine kinase , It acts by inh ibilillg SCVtrJ! enzymes rrquirtd for DNA repair. and it is resistant to adcnosille dcaminao;e .

from lighl . Topical fonnulations Efudex Solution, which COIItains 2 compounded with propylene ~Iycol. t mnillOnlethane. hydroxyprupyl ce llulose. paroixns, disodium edeUltt and EfuOO L 'OIlIain s 5% nllorourncil in a vani <hing creJm ing or ... hite petroIalum. steary l akohol, pulysorbate 60. and mcthyl and """,~ I-luorourncil is unaboli1..ed to phosphate, a potent inhibitor also is con~ened inlo nuorouridille incorporuted into RNA DNA , pIwe-'ipecilicity fOl" the S phase. Pla.~ma levels of nuorourncil an: erratic arta 11igb plasma levels llre obtained after parenternl lIon, but the pllDrmacok.illdic characteriStICS lin' I-luorou racil is Ii . i the hHr.

"

aoo

istcrcd doo;c IS excreted in urine.

Illi

,-

,
-

Auoroumcll IS clfccti'll III the palliative managcment of arrilloma of the bn:a~l . colon, pancreas. roctum, and SlOma:b In pallenI!' who rannot be ('!Ired by surgery or other Tlle laplCal formulations an: used with favornblc _It> for the lreallnml of premalignant l erulosell of the;

_?'-".:

and superfICial bas.al cell carc inomas,'''' Parenteral ad

S lrolllon a/1lW)Sl mv-"nubly prodoces toxic effccts. Leu b:JpmLa usually follo...-s c"cry COUN of [hemp),. with the
Iof,'CSI "hlle blood cell countS occurring belwcell d:l)'s 9

sion of acute gmnu loc)"tlC ku"em ia of aduhs, It al-;o i. used for ulher acule ]eul erllllls of IKMh and ,.hi Idren, IMl Remis~iol\s have been brief unless follo ...ed by mamu:nance tiM:'rapy or JI\cn 111 comblllauon \\'ilh OIher anlll1eopla,tic agenl . 1 Side effect.. Includc severe leul.opt'nill. Ihrombocytopenia. and ;mc,mlD.. Gaslrull1lCSlinal disturbance'l abo an: relalnely frequent Cnpcciiablllc. Xcloda. N"-pcnl) lo~ycar bonylS -dco:o.y-5-fluorocyudlnc. IS prrpared from S'-dcoX)Sfl uOl'OCylidinc and ,t-pe nl ykhloroformale. 171 and sUPJllied as ISO- and 5O().mg lableiS. Amotptloo in lhe p,u'Olme'ti 11:11 lract is raPId. .... ith lIIuimum blood Ie,'cis obtained in approxunnlci), 1.5 hours. Thi~ compound is a prodrug of 5' dco.\)'-S-flU()l'()tlridillC'. 10 which It ,s ron\ ened by meillholK' oxidat ioo. Further mct:lboli.m produces 5-nuoro-2-dcox),uridinc 1Il00oph.",phatc (F-dUMP) and 5-nuorourocillripho.Cilpirilbi"..
phllle,

l1li

<od I,

or

1.

,,-

mo

"

alkr !he fiN coun.e. Gutmmte:stmal hc.II""hagc -rOCCUf aod may c,'en be fatal. Sc om:l1ins. esophagopha'.";;"ii~ dl~rrhca. !musca. and vomiting arc '<Cell commonly: ~ 'alUld dmnahlis also occur. 1"hcmpy must be d,!oCOfl ' -.llfleulopt'nlll or gaSlmllll('slmal to~icily becooln 100 It\'~ Topical adml nislrnlion is conlrnind iculcd in p;llIcnls . . de,'clop h)'persc:n~i n' il)'. Prolooged CAporiliTC 10 ultra]J

. . . i1dialion may incrta.,< the intensity of topicallnll;un .

~ n:acl;on~.

'"

F!owridi,.., USP.

Ao.\uridinc. RJOR. fl uorodL'Ox) uri . NSC -27640, 2'-d.,'<.n y.,5nuorouridinc. 1-(2dco~y-[} lII':IIlOloyl)-5-nuorourociJ. This compouoo I~ prt"p:lred by ~nl monorncrcuri -.5-noorourncil with 3.5-<11-0-//' , ) !2.dcolyrioo~yl- l ~hloridc fo llowed by alkuliroc hy_
1Ii).>is.1~ It is Jupplied in 5- mL \,jal~ COOUiin lllg 500 m);

l1lc: eUlTI'ntly appro\ cd indicallOn for c;tpeCllilbme i, mel~~1Hlie brellst cancer rt',.;o;tanl to p.'lCliluci and unthrucyclincs. SignifK'anl 10~K'1t1CJ; include bone m.lrmw dl'prt'S.ioo. dianbca. mutagenesi '" mice. re\er>ible fC11l hl Y impai nncnt. lcr~tOllcnicily. hypocrbiltmblncnll;l. nnd hlll1dmouth syndrome. DruJ; imcr'.lCtiolls occur \\lIh anlacid, and
lc:uO)HlIin.17~

line

....

fIo,umllllC as s1C:rilc po ... der. RClCon~lilutlOn i~ by the IIbtion of .5 ml of ~Icri lc water. 'The re,u lung solutions IeIIlC' \lore<! untkr refrigenl.lion for 11()( mon: than 2 flcuundlllc
j,

u"Cd for palliutioo of gD~troinll:.sllnaIIlOc

regional inmt-arteriul infu,ion. When

><:~.'I:I melalolal;c to the lh'cr in paticniS \It no lire cooIOCUrabk by surgery (Kocher mellI1~. 1M It i~ admlllj~

b rontjmlO\l ~

in this manner. i, h3.< ~ilm jficom advanl~gcs o~er 0110: 1 Iloxuridine i. calaboh/.ed r".Ipldly 100oom: ,I li"eli tile ~ame lo~iC" reactions a~ fluoruun: il.

CJ!nbi1lf'.
h 1\
Ir,

Cylarabirlt'. C) losar-U. aJ'lI-C. cyton/), llIhidc. NSC638 78. 1 -IN).nrabi nofu ran\1'; y Ie yll)USP.
~~"lhesi1.Cd

from uraci l llr.lbiooslde

In

a mute

In-

~.-; ~ltuttd .... ilh 5 mL of slaile WlIterconlluninll

':~),':~::;~:; lrealment .... ith phospOOru) pclllltSulfKk. it ammonia. Ifill 11 j. supplied lIS the frtt/.e. vials conlainlng 100 01' 500 mg. l1lc: 1000mil
bailyl alcohol

GenlCitabmc. Gem7.ar. 2'-droxy-2.2' i~ prepared from 2-droxy2.2-difluoro-Dri bose nnd c)lnsine. 'w II 1\ supplied:.." II lyophil il.cd poIItlcr cootainilll: mannitol In 10- and 5O-mL ~i:lls. Recom;liluuon pro~idl's wlullon. conlammg 20 mgtm L or gemcilabmc:. 111ey ~re infused intnl\'cnou~l)' !II II d l"IC of 1.000 mglmz o\'er 30 nllnu1e.~. once \\cckly. for up to 7 wed..... Clc:at'IlIlCe half-li~c:s r-~ngc: from 32 to 91 minute.; for a JO-mmulc infu sion, or 2.JS 10 638 rmnUICS for long<'r Infusiolls. GcmcitablllC is 3 fiN-line trealment for locally 3(hatlCed or IllC'la<;Ialie :.dcnoean:lI)oma of the pancreas. 11 IS also used in combinal1 Q11 .... ilh ci.;pl lllin for filSl-hne lrea llncnt of inopernble locally advanced or mclll<;13,ic 1IOO-<;mlIli cdl lung cancer. 'n.c lunlllng lO.\l(:ily ,<; m)elosul'p..t'~ion. 11m 10licily requiTl'~ a complcte blood counl before each dose: . Other
G@mciro7lbin*!. di noorocytldme.
Ild,'crsc effeo:ls mclude fc,ct'. nl!m. lel'lltogc:nicily. and mild

renal to)(iclly.17' Penmstalin. 2' -dcoX)'Coform)CHl. dCF. NSC21832 1. (H.., 3-(2-deo~ y-.tNH"l)tllropctllofumnosyl}3.6.7.8-Ielr.lh)'droimidll/o14.5d 11 1.3 }dIUl.cpin8-o1. Tlti. compound is obtained fr'(lm extraciS of SIUplfH1ll,{,t'S UllI/bi Q{icltil7~ :lnd formuloll:d 10 100mg vials a~ a lyopliili1.ed po.... dcr. Mllunno.] (50 mg) and sodiu m hydroxide (10 adju~1 pH) are incllldc:d. 1\ is admlm~lcred IIItmH:nou<;ly. u~ually as ~hort ,nfUSHlIlS in IJ,()looic ,;olulions. I'emoslalln c:o.hlblls first onier. l\\o-l"(lmp.1nmcnl c)(crelion bch avior. m PCniOSlalm Isan imwcrsiblc mllibnoroflhe cnl)"1TIC adenosine deamina..;e . 11Ie re.w lu ng IICcumul:tllOil of droxyMkn()';Ine nnd It~ phusphOl') IUled oongencN inhi bit_ DNA .yn t hesi~. It is ITlOIIt effeclilC: against Iculemi!l!i and I) mphontas. especially h:ury cell leukemia dose- lim i\lng effects include renal dy5functIOn. neurological tox ICit y. and tel'Cr.Ible granulocylOpcnia.
Pentosrilrin.

:~~

10 mL of sterile ....a ter .~ I\'e 50 mglmL of eytarn solution s may he stored III roomtclIlpt'rature for
of "inns<: anabohze .... y. nucleolide. ",hich :!CIS II~

;'~~~;~~~~'~ with

20 mglmL of cylnrabine:

lh~

polYlllerase after incorporaII is ~ifl(: for the 5 ph;Ise of the is rlO4 orally nCli,'e becauloe of Uleninaclive uracil arnbioo,idc catalYled by
forcyla-

by lhe usc
or sequenlial bolus of 100 10 200

mw

'''''1be

l ....~ is indica led primaril y for irldocing the remlS-

4'4

",IJOfI lInd Gu.md'.. TrMboo of Orlf'''' .... MWK"tnal mId P/o(I.-.cn/Iit-al Cltrmwn' sodium q1r i~ available tn 2O-mL Vials cOOlllmtng 100 ~ of al.athioPfinc. A7..athioprine t~ well absorbed when laleo OflIlly_ It converted ell ten~i vc ly 10 6-mcn:aptOflllrine. TIle marn rndr calion fOf" 1U.: lIhiopnne .s as un :Kljullt't 10 prevent Ibe ~ja:. lion of renal heterotransplants. It is contraind icated in ~ tlents ... ho show hypeNel\Sitjl'uy 10 .t. 'The chie(to~ iccff~ are hel11atoll)jl;~al, expressed us leukopellla. anem.a. . . Ihrombocytopenia. ConlpictC blood coonlS shook! be per. fOf"med at least woekly. and tile drug slloo ld be disrontllud if lhere is u rapid fall or pen;i~lerl\ dect'l:asc in leuloc)1tl. Put1ems wilh imp:!ired ~nal funcuon nught ehmllwc dtr dotg lOOn:: slowly. which n:quite..~ uppropriate reductlOlld the dose. A1.athioprine should not be lalen with .llopuriD. wllich blocl5 'IS I1ICllIbohsm by ~untlline ollidase.

Methotrexllte, USP. MClhQl~nle. mnClhopIenn. ,Q methyl aminopterin, NSC.740.4amino-N ' nlelhyl.plcroylgluumllc acid. Lo( + J-N [p [[(2.4-dmmmo-6-plcridmyl)melh)' Ilmcthyl3millolbrnl0).] Iglullllnic ocid. i~ prepared by combmlng 2A.5.6lelr:r.hydropynmld,I'le, 2,Jd.bromopropi onaklchydo:. disod.um l/-(nIClhyhmnno )/)eJlwylglutammc. IodIne. and poIlIsMum tOOlde. rol\()v,ed by healmg ... ith lime ... atcr, IU It is Isolated lIS the nlOnohydratc. a ye llow solid. Recent \Iodic, i.",hcal<.' that Lilt ~'OIl1men:ial prt'paratiool'Oll' lOin~ u number of illlcuritics. includmg 4-amino-N'II-methylpl.cTUlc ocid and N -melh)lfolic ocid.17l Melhotrexate i~ ' soluble in ulluline .o;.()lulions bul dec"mpows in them. II i~ supplied as 25mg Inblel~ and in I'iuls OOIlI:uning either 5 or 50 m8 of mcthom:~a1c sodium III 2 mL of solution. The 5mg 'iaIllple contam~ 0.9O'l- ben!.)' l alrohol as prescnati"e. 0,63% sodiulll ch loride. and '\Odium hydroxide to gm:: pI! 11.5. The 5O-mg \ample OOIlmin~ O.~ bcrllyl alcohol. 0.26% 'iOdium ch loride. and Mldium h)dru:o.ide to g.le pI! 8.5. A pre~..."alhe-frec Iyoplu lil.ed preparalion i< rucOIllmenOcd rOf" intr~lhecal admini~trntion 10 prelent Of" II'!','I( tumor ccU~ in lhe CNS, Arter or..l admmiSIr.Uton. mcthotl'!'XDte i~ rapidly bul tnrompletdy abolofbed. Approxinllltc ly 50 to of the al). 'iOI'bed dot, is bound 10 pla~ma protems. C)tOlo~ic lel'el" are found UI ccrebroo;plnal nu .d "'hen high dosc~ of mcthotl'!'xate :tl'!' g,,en. M()!I;t of the drug I' ClI.lTeted in lhe urine unchanged. Blthough :>omc 7 - h)droxymclhotre~ate is f"und folio ... rng hiXhdo!oC tlltrapy. I>las.ma leI el decay r~ brpha,ic or tJOl'sibly triphaSic. MtlhotreAaIC binds tightly 10 dihydrofolate I'!'ductase. blocling the reduetion of dih)'drufolale to tClmh)drufolate. lhe ach'" form of the ooenzyn1<l:. ITO II i~ ~peeific for the S e phase of the cell cycle. /-.'I clhotre~ale undc:rgoc~ polyglutamation inlrucc:lIularly. fonning a pool of compound. thaI is retained fOf I1l()11tll~ . Resistarwe 10 melhotrexale del'Cl~ by an increase in dihydrofolute redUCta'<C. "hich result . from gene IIIllphrlCallon. Of" by defectl'e tr.m~pon into tumor celb.~ Metltotrcxale "'as tilt' liN drug 10 prndUCl' sub~lantral (al. though temporary) n.:missiOl1s in 1cu~cmnl., \I(Ilt i . Shll used fOf" thi. purpose :tgaUJ..'I1 acute lymphocylic leulemra and ALL Becau-c >1 ha. MIme ability \I) eUier the eNS. it is used in the In:am1<l:nl and prophyluls ornlCningcalleukemia. The dl'>Co\cry Ihat mcthotrc~ate affolc:d a hrgh percentage of apparently pc:mlal1<l:nt remi~~ron~ in choliocureinoma in "'Olllen jU';;ufied usc of the lenn /rift in cartCC'r chcm"t~ apy.'HI Melhotrexate is used in combination cllcmOlhernpy for p.l1hotilc management of bl'!'aSi cancer. epidermoid canCCf'S of the head and IlC(:l. and IImg ranccr. 11 IS also u;.ed against ~Ien:. dIsabling psonasis. 'The most COlllrl1Qll tOXrc reactiolls are ulccr.lIil'C Mmnalltis.lculopcnia. and abdomi nal distl'!'ss.. A hrgh ~ of IlICthotrenle combined ",ilh 'I leucovorin "rescue" produce.. o;.()rrle respon).t"s 111 osteogenrc SIlrcoma. bul .1 can cause renal failul'!' rn some patienls. Thi~ condrtlon i~ thought to re.~ul l from crysmltrlatlOn of lhe drug Of" ru metabolilcs 11\ acidic urine. and it rs countered by hy dration 3nd all.alinilatron. I II

ANTIBIOTICS
Nine drfferent antibiotics or their semisynthetIC :uuk.lpt:l al'!' cslllbli.JJed clinical IInticlln~:er ligen",. und other :mtibta ic~ arc undergo;n!! clmical dc,elopmcnt . Some 0( the!< llj!enb ha"e been IIppTOved reccntly: howel'er. othn1 11M been kno",n for a long time . FOf" example. docti~ (actinomycin 0) "'11..~ firsl i!i()laled in 1940 by Wllk .nutt '" Woodruff.'''' ahltough ils octi~it)' agamsi ';;"II.';'",'~.~ dc-.cribcd until 1958. plicomydn. on.:;"~""". dl'iCO"Cred as aurcolic acid had to be redi,.
e~tabhsMJ

m-

thi~

"

d lcnlOtherupy of cancer. h much simpler loday, screen extr.!Cts of micmorgani\m cultures ''''i,y in cell cultul'C5. The production or antrlumor agcnts from mrcrobt.ll mental ions has.'iOnlC ~pecial advantages and over chemica l synlhom. So~ bI()!I;ynlhesc:s can be lrolled 1 affom nol'el 0 This ha.\ been uctinomyein\ r... and mentation condil ions can
; III.

trasl to species thaI fonn cOl1\ple~ r I mycins. The fcmICntatron in Slrepl{)myct!t been developed similarly to prod"'-'e almost C. In l>Omc cases, \uch as w.lh do~onrbicrn. anubiOlic Yield has been diffICUlt. ThiS results )II'C product and intcllsl\'C ~arch i The actinomycins OOIllpnse II largc number l~ted structures. All oflhem conlain lhe samc

USP. A'f.ath,Qpnnc. Imumn. 6-1i1 nlt'lhyl-4-nitroimidazole-5-yl)thio)purine. r~ prepared rTUln 6-men:aptopurinc and 5-chJoro.I-~lh)14_nitrotmlda wk. r., It is ,uppJied a.~ .5O-mg scored laoll.'l..\. The Injecmhlc

A~iJfhloprine,

OCliooctn. peptide lIII.101lC unit of I hi~ I nioe fonus pan the laclone 310ng the firth .mroo ac.d from the c~. alloi-oleucine is the ~1I1d :IIlli11O ac1d. and t oc1d u~ually is sarcosine, The thin! amino acid.~ able. consisting of I..-prol ine. I..-hydro~yprolinc.

;"h

Chaptu 12 .4,,"'.I'fJphmir "~1S

41 S

. or OIhcn produced by controlled biosynthesis. AClino1I)'Clns thai ha\'e two Identical penmpeplide 1ac\0I'IeS are o;I\ltd 'SOQ(."'rrlQmI'CIIIS: tOOse: wi lh different pc!nlOpc!p4ide are called tlruJoo(tinolnw:ins, The indi~ Idual pcntaptJll<Je 1000tOlJl!S are IksignalCd Q and p. depending Ofltheir lllldunenl to the 9- or l-corbo~ylic acid~, respectively. Oac-.m)'Cln (ac lillOOlycm D. actillOOlycin C t ) is an isoacunolII\'t'm .... Ith an amitlO ac id ><'(juence of l..-lhreonll1e. D-valine, L.,.oImc. \aI'roSinc. and l..N- nlcthylvaltne, Actinomycin C). b i, used in CiC'rmany. differs from actinomycin D by lD-alIo! SOleOCHlC unillOslcad of Irvaline in both lhe Q and 'dwns.11III

"/, "v.""
CH 3 CH 3
1'111: mode of aclion of ICt ioomycIMs iI/lIJ 1\ now i I

0
Figure 12- DactH'Iomyon ,ntefcalatong DNA

bas been studied cxintcn:a,r i pmcc~s. unllUlds poutill/Jy 10 po:mutlhc nal pheno.ltl7.OIlC': fil be1wecn suc<:essive b.a..e pairs (Fig, 12G-C pair.; are especially '\lIitable because lhe JIUUPS of the guaninc:s can hydrogen bond with I of IhrwnillCli in lite IlCtinol1lycin. This lhe u-bonding between lhe horlcmcyclic II I ~tabi L ily i~ conferred by the inlCT!he f'l'nlllpt'piirk l/lCfi1ll(! dl.lIns ,lfId DNA. lit in the mmo.. groo\'C' of the double hell.l. oppo;site dil'C'Ctions 10 C'x h OIller, and tlK'y male 1'iII def Wll,1t5 ifl/er.lClions wilh the DNA. ,.. I propCfUCS in lIIelting I CIIIcocfficicru dethe actioomycin s 10 DNA. u'I.I:llIy by making it Less II I ring or changing lhe stereoI acid abo1i5hes aclivilY. and replaceand 6-melhyl groups by other sU!JstilUentS of the 2 ' 11111'110 group also ~uces
and certain other i
,

""'""""'"

aboul whK:h the: windi ng or unwmdlng can 11'1,,, pJ3(.'C,'Y! lu contr~~t, 100000i~rase II CIC3I'j"S both ~tr~nds. allOWing t'OfTlplcte rowt io" or. ii_ ha.s Mn ~ull1!cSlcd . p;l'sa~'i: of pan of the inlllCt double 5tr.md through the g;lp. Drugs !h~1 inhibit topoiS()mcrascs bind 10 lind Imp the ('O"alelll conlplc:~ formed bclWCC'1I phosphate groups on tIM: DNA and tYffl!i;nc residues on the: Cflzyn'll', prelcnting SlI~uc:m 1losure of the brokell )trund or SlrundS. TIll! CXlcnl of drug- Iopolsomeruse- DNA complclt:5 (onmlfJofl rJotos J10t l1t'(~'-:JriIJ cont'Ime wilh C)tOlo~ieil y.'YJ

I I lhe:

are thought!O crlllI . and thcly act by

one or strands of the phosTopoi'iOmerasc I culi one of ,;;;;; lhe OIher 10 act as II swivel

Anthrncyclincs are another large lind l.'Omplc.l family of antibiQfJC$. Many rTII:mben of til is family wtre /nveslig'uoo before a useful antilUmcN' al"lII. daunorubicln. wa~ isoJ;ltC'd from S'f ..pmm)'C ..s (,Ol'nll..onlbidIlJ rind S, IH'UC f'tir.s. Th1$ sign irN:1lI\1 dlsco,'c?, was made: I/JdeperK.lcntJy in Frull'-'C;lnd II,dy in 1963. r\W. ~ DaUilOnJbicin p!'O\td to be IICIt,e against acule leukemias. and il become an establhhed clini cal age nt_ It II'aS pushed InlO lhe b:tc1o;ground. however. by the di S(:ovcl)' of do... orubicin (Adtiarn)cin) in S. fH'lKYtills var. CMJ 'UJ in 1969. I'llii DoJiorublcin IS acdve ugai n,1a broud $pectrum o(rumors. including both s.olid and hormalologlcal Iypes. II became one of 1m: I1lOS1 widely used antineoplastic llgcnts. l97 A th.N \Il11hrncyehnc, ",hlCh was 1('ntly approved for dinlcal usc ,n the United States. is idarubicin. This compound is 11M: 4-dcme!tIQ.ly :.l1alogU<! of daUIIOru hiein. It ha.'i C'nhanccd antiUlinor poIcncy. and it appears 10 be less cardiOlo:o:ic than daunorubicin lind doaorubicin. Epi rublcin. tnc 4'-hydru:o:y cpin'll'r of dO.lorubi ctn. i, ;tvatlllbic in Europe. II also is considered less to~ic Ihan doaorubicin. with equal Of g rea tcr IIIIt;IIIIIIO" acti vi ly, The 4-hydroJiy analogue or daunorubicin. cllnnioomyc,n. '~aled from Art;",, fll(J(fllfTl cunninllfa. ha5 been e~DIU:lttd in Russia.''''''

I
R,

'.,

" " I
HO

"
OH

CH~

HO

A,.OCH,.~. H

DaUJ100lUbic.n and dollorubicm exhIbit bIOlogll.-a1 effm~imi lar 10 lhose of actinomycin. alld lhey are lhoughl 10 il\lef calale inlo double hellcal DNA and mhlbll topoi.sot.ktasr n.lll: Reduct ion of ooxorubICin followed by inlcrtabtiol causes DNA strltlld sciSSIOn. 11us '\C' SSIU!l IS thoughl to~ from the Iliac" 0{ hydru_yl radical s gCller-lled from I'tdnI cycle~ involving doxorubicln;IOJI In contr.lM 10 daul'lClCUblcil. acloclllotn)cin and relaU!<i rornpoond.\ do IlOl IM"eI' lpogcnic phage in OOclcna. They are bclie~'ed to mtcrfc~_ with RNA ~yntht5es than wi lh DNA ~) nthesis. AdOlClflOo myclIl lad ~ tile card,OIo.tl ci l) ,tlov. n b) daunorubtcln-' c\o:<orubicin.lO ' In C()mr:'~1 10 the actinomycins. anllll-dC) cllnes are IIICWtoll7kd in the Ii \CI". Daunorubicin i~ readily OOI1\Crted . . liS I)-hydroxy unalogue. daullorublciool. ""hich is further ck:au:d to lhe aglycone.zoo The: l4-h)droAyl group ofOOll)rubicin mukes ille." ~u<;cepl iblc 10 n:ducllon mlhe Il-\:Ir bonyl group. The: l3hydro~ydcrivall\'t'. adriamyci nol.l\o. ever. is foulld among the mcmbohlc, along Vlllh lilt j..
dellll!thyl-4- ~lfoIC. 11oI1i d~ullOlnyci\'IQ1 and adri:lll1)<.lnrl arc active against neopb~lic cdl,. bill lhelr ratcs of . .
lite

A, " OCHJ,. 1'1 2 " OH

R, . H, Ra_OH
R, . OH,R 2 "H

low.:!OiI

Many nll1hracyclinc.~. including 011 of those with ~nli'u mor activity. occur as glyt'OSides of the anlhracydillOnl:S. Tile glycosidic linkagt: u~uu!ly involve.~ the 7-hydroxyl group of the anlhr.ICyclinooe Illld the ,B.aoorner of a sup with L. configur:tlioJl, Amhmc.w:lmont' refers to an aglyoonc contaming !he: anlhnlquillOrlC chrOfliopliore within a linear hydroc:u1>oo ~kelel011 related 10 that of the Icuw:ycl ll1es. '''' Tile amhrncyctiAl)l1oeS differ from each other in the number and location of phel101ic hydmllylllTOuplO. the degree of Oil;' dation of the ,...-o-carbon side chain aI posilioo 9. and the

H,C
HO

pre.ellCe uf II. !;arbollylic aci(] ester al po:;ition 10. Thus. daunorublClI1 is a glycoside formed between dauoomycinone
und t-dauoosllmine. and dUllOl1,l\)icin IS its ]4-hydro~y :lJUI' logue.200 In (1)IllnlSt. aclacioomycin A has akla~ioonc In

~ NH,
.. H

~R

A(lnsmyanot

R .. 011

l"Ombinutioll wilh a tmaccharidc chain.:!(I,

,
tctruhydropyranyl widely used in Europe. and il i cline in '\al~: howc'er. II is IlOl appro\cd Slau:~ at lhi ~ tune. l'il1lf\lbki n accumulalc~ IfIIIR: than ooxoruhicill In lumor ccU~ and ,ht)w~ in animal nMXlc:I~.7Of> Valrubicin, II I " in v.hteh the amioo group has a and the 14-hydroxyl group is conlcned to a has been npprol'cd n.-cently for intnllcsicular urin~ blllddcr in patienl~ wilh carcioo1lla BeG. In sy.ICnllC" C"ut"1.tI:ation the \akr.1I1! Iyztd , but Ihe trinllOlUaC'Ct)1 group is t I: hollel..... melnooli)1I1 occur.< in IhI.' l -hour penod bladder. Al"IOIner anlhracydllll! '~::,~;";:::";,:;;;;::~,:~ is ~am)cin. II hich is u
lUlU.

H ,C

o
H ,C

OH

It diffel"'i from Olner 3mbl1lCyC"lJnes

",d
It<;('lf

,
7
i~ not

II.n

,
antineoplastic drug, I

o
.y

1
I
HO

'"

CH"

"'"
OH

/ N

CH, HO CH, CH, OH

"""

'w o

I
o

, ,

H,C. -r- _0_ " '~/ "N"

" ,
Ej:orubicIn: R I
..

011, .. ~ .. R3 '"

R. '" H
z

/'-PnnAIIcIn; R, .. H '" A" .. R. " H. R .. o -~

YIoInbdn: . .. H,

A,," OH, R," coc.Ht.

R. " COCf"~

1IWog1II:. mcnogwi l. has 11:CC1\'W phase II clinical and is under considcralion for approval. Menogaril IbI: lIOjlalO6\e moiety replaced by D ITIClhmy group IlrId ~hiral it)' at the 7 position. [Iltlso differs from n~a. n by the ilbllCnce of [he l()..(:arboJllelho~y group. 10
wuctura! changes result in a change in (he mode of from inlcrcalmion inlO DNA , lIS found for ooglllaocher Silt' and type of cy iolOxic process. localizes in [he cytoplasm. ruther than the very Ii 011 DNA and RNA synMenogaril is not more effeclive 1u1lKn. 001 its much lower cardior.alacliyi.y mighl offer clinical ad -

"

~ro-

", 'm "' " d,,, '"

d,
,~

o
HO

DOCH, /">ov""'-,cCH, OH
HO

"" ",
,lo<

OH

CH,

The Dureolic add group of antitumor amibiOlics incl udes aurwlic acid (phcamycin. mithramycin). the olhomycins. the chromomycins, v!ltiamycin, and relalcd compounds. Plicamydn is thI: only membC':r approved for clinical use in !he United SUltCS. It is resllicted to testicular carcinoma and hyperralct"mia that is resistant to other drugs. Chromomycin Aj is used in Japan. and olivomycin A is used in Russia.l ~l Aureolic acid group compounds have complcJl; structures consisti ng of an aglycone and two carbohydl'llle chains. The aglycones Drc: tCll'llhydroamhrncenc derivativcs with phcno li e hydroll yl groups at positiOfls 6, 8, and 9 and a pentnnyl side chain that is highl y Ollygcna ted. The carbohydrnlc c hains ~vntain either two or three 2.6-dideollY sugars of novd Structures.l ll Pli camycin and rdated compounds are weakly acidic owing 10 the: phenolic groups (pK. _ 5). They readi ly form sodium s:aJts that show brillillAt yellow flLJoOl'eSCence.l1l TIle ehromophore is responsible for complell fonnatiOfl .... ilh di valent me:tals such as magnesium and calciu m. Such com plu fonnatiOll is required before aureolic acids can bllld with DNA.114 The nature of th is DNA binding is uncertain at thoe present time:. Intercalat ion has bttn suggested. bUI the nidence for this (lfUCCSS is in.complcle .11 ) Whatever the C)lac1 n.~tun: of the binding, pl icamycin and other uureoli e ocids inhibit DNA-dcpendenl RNA polymerase. and Ihis ef fcct lends to ~'ell death .116 11M: discovc!), of bleomycin in 1966 resultcd from a progrJm cstllbl ished by H. Umc7.awa to li/:recn microbial culture filtrales against cllperime:nml 1Uman.. 217 Bleomycin is a mill tute of closely related COIllpoundS that is panly reso!\'cd before formulation for dinical USC.}I' Thc prncntly u<;cd commcn:ial product. Bkno)(ane. comains bleomycins Al and B2. A varicty of other Ilntibiolics have Slrvctul'Cli similar to those of the bleomycin!. TItey inc lll(k the pltleomycins (which differ from blrornycins in having one thi:uoJc ring partly reduced), 7.orbamycin and the :r.orbonamyeins. antibi otic YA 56. vic'ornyein. the lally '>Ornycins. and the pl~. tomycins. 191 New bleomycin an~Jogues also h3\'C been pre pared from bl eomycini e acid by controlled bio~ynthc.sis . Blcomyc ins and their ~n3logues occur naturally as bluc copper chcl atcs. Removal of thl' copper by chemical reduction or cO~luinll agents affords the antibiotics as while solids. IJ9 2 Coppcrfn.-e bleomycin is !he JICIi\'e species for chemotherdpy, and it has lower toxicity. Bleomycin com plexcs readily with metal ions. which is a key rae'or III Its mode of actiOfl. Inside the cell, bleomycin forms chela'e witb Fe(ll ) thaI has square pyramidal gCOITICuy.2l1 Nitrogen atoms from blC(Hllycin occupy (h'e of the positions in this structure. 1be ~ixth position mlly be occupied by the carbollyl group of lite cllm3mate function. but thi~ grou p is

o
HO

OIivose

, ....
o

~CHl ~\/ ";o

~\~f~iI
o
H~

/1. ' 1
~ Myearose

HO

HO

o
o
HO

OH

OANH1
~Aad

A_OI1

I!IIIom\'CIn A. BIeomyeI'I B,.

R - NH(Cl-i,bS(CH.h
A. NH(CH,l.NfiCNfi .

i\..

HO

o
HO

o
OH

~~OH

0yO
NH,

A, Felli) Chelate

1Udi1) d,spl.oced by 1ll0kculJr oxygen. TI,e resulting compnmay IlI"C rise 10 hydro~yl radicals and superoddc r.ldi.. TIw:se highly reac!l\'c radicals lin: genCf1l1ed dose 10 the obi:IIt helix_ allll they CIIU!IC clclI~agc of the phosphodie5ler ke.h, Th" dcg!lidlltioll of DNA strands is though t to be lhe ~. . ". ..... (I"eN 10 ceIIs.B!rom)"!;'in is 1Ila.;:thal1:d by au IIltnICCllullir cnlyme bitom}'Cill hydro/asi', lin aminopeptidase that h~dro11m Ihe carboxamidc Sroup of the ,8-;' lllinool:tnine elirOollo_ Jnldue to the oomespondins earboxylate. This StlllCa cbangc increases the pK. of the (Ntnllno group from -J109.4, "h,eh results in poorer bindJl1gl() DN A.:UO OlclaFelli) sull occurs. bu. the. production of hydroxyl ~ h dra:;flca.lly n:doccd. U2 Bleomycin hydrolase: Ie\'.. 1IUOOr ttlli help to determine their mistance to bleo!'" Thus, oquallloos cell carcinoma is characten/.cd by ul) uptab of bkom ycin and 10..... Ie...el~ or the hydrolase , he,,i.IIly Sfilliithe 10 bleomyein.ll.1 8Ieom)'t'lRS ull(k'1o ..... 0 different inactivating reactJOOs ... mlklly 31~aline condi tions. One IS llHgr.lIion of the group to an adjacent hydroxyl group of.he 1113nmUle: The resulu,,& product is called an istlblco .~~ Coppcl-chelalcd bleomycins do not und!:rgo this votI011. They are. ho ..... ever. slo ..... ly trun~formcd into cpi ~"tfIS.. " .. hieh IlrC r.lCCmi~.td alille caibon alOIll ~ubsli .,.nll: 2 position of the pyrimkline ril1l.:US Eplbleomycltbullboui 25'1 of the antitumor acti~ity of the parent

....'.'tII

such ILS PEP-bleomycin (peplom)"cin), .... hich posse.~ses less pollTl()ll:lf)' IOllidt)' .:l. The mllom)cin~ wen: d,..cu\crro in Jap;m in Inc late 195Qs.. and one: of them. milOlll)'i:in C. W3..~ rnpidly de_eloped lI~ an ~nlicaoccr (1"'11 ,11" Unfortunately. the initial clinical Uper1cnce with Ihis compound in tnc United SImes wa~ disappOInting. It ... as noI appro_cd until 1974. follo ...ml! <:1\cnsive sllldie~ and the e~lJlbhshmenl "f S:IlISfOClory dosage ~hldu1c~. Portiromydn. the N-rnclhyl homologue of mitl)mycin C, was disoo\cltd :u the Upjolm COlllp;lny.U1 It has receh'oo clinic-dl sludy. but it iJ noI )C\ an appro,'ed agem. SlnJCtUn:S of the mllom)cins were elucid.1loo at Lc1Ierlc
l..ahorUlorie.~ .

These compound_

h~ve

an

unu~ual

combina-

tioo of Ihltt differc:nl carciooslmic functions: quinorlC. car-

bamate. and aziridilX',:ua l1Icy:'lre ammsed In such II way lhm the moIulc is n:1~lIvely unn:aclive III its nalural slate.
Chemical or CI\zymatk reduction to the ,orrespollllilig hydroqui~ is. however. followed by the kl!iIl of methanol (wuter from mitomycin 8 ). and the ~sullins mdolohydroquinone beconll.'S II bifuoctiooal allyl~tlng agent cllp;lb~ of crms-linkilll! tloubie-hdiclil DNA (Scheme 3)" ~Z'I Mitomycins boood to DNA may undergo SOCCI!SSIVC redo~ cycle(, exh of .... hleh results III the gcncrutioo of h~drogen peroXide. 11l1s potent oxidizing agent cun CIIU!IC s lngle-~trand cleaVOlge of the DNA.l.lO Mitontycilis are unstable III both acids lind basel. Mild acid hydrolysis ~lts III opellln, of the lI/Jndinc nlli and IQ!lIi of nlC'tllanol or ..... mer to g'le mitoscllC::ll such all 2.7dilimino-l - hydro~Y111itosene. lJI Clltolytic hydl'Oilenolion follo .....ed by n:o~idation gi I es l7.indioomitoscllC::ll.....'hich retain significant IU1lOIlnt of autitutnOr lrIiv,ty III anim:Us. l l l

_.1

o.
Bicom)!;mic llcid is oowincd by chemical degJ1ldation of ~,.,.,. A or Cflzymalic degrndalion of blcomyem B~ . It .:II be InIlsformed ~adily ,rno semisynthefic bicolllYcins

x
H,C
e, )(. CH,O ~~ornycon 0, )( . H,N
~Itornycon

H,C
Mltornycon A., )( _ CH.O, Y. H M;tornycon C, )( _ H, N. y. H PorIirornycon, )( H, N. Y CH. BMY-25067, )(. O,NC.H.SS(Cti 2JI'/H

Many mitomycin analogues ha,'c been ~parcd by panial synthesis, and two of them h:we receIVed clinical trials.ml).b Unexpe<:1ed tox ici lY has led 10 their withdrawal . howcver. The present clinical candid;ucs. BMY2.S067 and KT 6149. oonlllin disulfide substitlK'nts on the 7amino group. Control of the quinone rrouction poI~ntial is ~specially strt$.~ in analogue Sludies. because rrouction is the key step in bioactivation of these moleculcs. lJ }

o
H,C
N

yR,
R,
R' , R' .......... /'~

was i$Olated from S,rtplQrn,.c~.< uchromoR~n~$ in 1960.:Jf> It is the nitrosomethylurta derivative of 2.dco.ygl\IC~.lJ7 Thc simplicity of its structure and the CO$t of ~paring it by fermemation have led to the developmem of practica l syntheses from 2- am ino-2-d1.."()~yglu rose. m StreptOo1.QCin is an altylati ng agent si mi lar in reactiv ity 10 other nitrosomethylurea"~. e~cept Ihm its glucose

St~p!07.\lCin

HO -CH2

HO HO

o
OH

R . Cti, ChIaro2D4ooo, R . CH,Oi,Cl

S/feplo.:crl,

moiety causes it to be especially luken up in the pancreas. This effC(:t is detrimental in that il producel! diabetes. but it makes lhe molteule especially effective against malignant

lRsulioolllas.U9 It is an approved clinical agent for thi~ IF" cifk use . Thc ehloroethyl analogue or SlR:pt01.otOCUI, TOlOlocin. sho....s 11000d anUtumor :ICIivity in anllllal\ MIl 001 diabetogenIC. Acivkin is another antibiotic thaI h:lS received ell" study. It i~ obtamed from SIf'f!pWm\T~S :O'icrlls. and n flMt lions a.~ an inh.bilOf of the amidolrnnsfCl1lSC$ ,"~oIva1. purine and pyrimidine biosynthesis. ZoII The W\lctu~ ofo VK:ill shoo....) a chlorine atOf1l thai can be replaced ~:ldtly litcau~ il is localed Oon an imine group . A cy$tc IIlC n:<oldur. the active site of on amidotnmsferase replllCeli this chl~ affording alkylation and irreversible inhibition of t~ CII:.eyme. l'ha~ I clinicul studies rel'ealed CNS to~iclly fOf ..... vkin . Conversion ofthc allubiotlC to .botenlc acid, a boot CNS toxin found in mushrooms.. by excltan~ of the for I hydroxyl group. might be responsible for 11m 10.1. In 1978. scientIsts lit the Upjohn COOlp.1ny IqlOMi isolation of CCI06S from S'1?plfJml"CU ::.r/~nsis.;0.1 n. oompound IS composed of th~ pynuIo(l.2e1indoltnc joined by amide bonds. Two of these subumlS:are ~ln identical, bulthe Ihlld has acyclopropanc ring . The~ iscur.ed and twisted in ~ och a mannerthm it makes . pm1I\ fit in the minor groove of doublehelical DNA.:'" It p!tb DNA SC(luences rich in adenine and thymine . where t~ C'1'" clo,r.ropanc ring can alkylate N(3) of an adenine (I~I' 12 5).-.... CC- I065 ha s remarimble antitumor potency. but oko layed Ih'CI" toxidty in mice prevented its clini cal de-ldo:tmen!. NulT1('f'Qlls analogu.es of CC-I065 were 5yrtlhc:;uzt and one or them. adol.ek~in. has been intrOduced IIlIOe!_ cal uiab. 24 ' TIus analogue retain.~ intact the 5ubullll Oon the cyclopropane nng, but the other t,,"oStJbunits lin: SI lied. It mains sigmfielllt anll1umor activity w,thout witlayed toxicity. Compounds In the enediyne class of anUblot lCl;~_ lumor pot!'OCie1i in the microgf'llm per kilogram ~I" mice. and they have a remarkable mode of DNA. til'll Although the glms structures of these compound. dtrrct w;(\(:ly, they have the common lemUTC of a mediumWIII ring (9 or 10 carbon s) containing one olefinic bond aOO ~ acetylenk bo!1ds .l-<II On activation, Ihls system ,.,.; ~."M I

CI

OCHC0
H NH

2'

+ Enzyrne-SH ---

;- .

N
H

N H

="
o

Spe' in. chlod~ and ;s

Ihi~

J I:h(lll:lIl d II runc-

/ohed in

rc uf llei!lKhly be

at chlOnne . .r the enty for oci

~s.due

p ~nown

: chlorine ; loxiclty, )()f1ed lhe

f,J41 Thi~

.line unilS : \.rtuall)

MrlIClure a prec i<;e

! i

Figure 12- 5 . ((1065 bmdll'IQ DNA

II rrc:fl"f' :n: the cy(Fig, 12 y. bul deI de\eloprHhe~It.ed.

__ btt\,..c:oc: dU'lldical. which can

inlo dintIII hc:arin~ l/'C ~.mph

)III

lhe de -

showanll' , ntllgc III ch:al"llc Ind~ dIffer

Ilum-~w:d

1d and I"n
,"'On \'t:nni

ckal'e itr.Inds of douhlehclical DNA. This process is iUusfor the calicheanncin cllromophort' in Figure 12-6, U\lbOII begIns with lhe loss ofCH,5S and Micllxl addiof thlolalt 10 the 1.2-double hood. The resulting loss ibn in the: IO-mcmbo.'red ring containing lhe enediyne 1Ilow~ Ber,mancycli/.alion loa bicyclic s)'lIlcm conI benzene: diradical. Th;, dll"..uical c-an remo\'c hy radicals from lhe j'_mclhylenc carbon or 2'.tJeoxyrim'u ..., In DNA. which leads 10 cleavagc of thf:, OI.lIIble-strand SCIssion oct'U~ at ,itC'S such as mAGGA. "here geometl)' is flWornbk: OIlw:rwi.-.e. only iIIllIIIl is cleaved. ~~:~m is obtained cu ltUfeli of Mic",moI!lItWporo ssp. Calieh<'ullsis.- It occurs as 1I1t of seven related oompoOC:lIll. of which c~tichenm i ~'.tbelll()Slabundam compo...ent. has been inl'cshgnred C.~\'dy. lkspite the rcman.abk: potency of ealicheamiII ~Atttmc todci ty ha~ prevented its use. To overcome Itm!tllion. conjugales II-ith IllOOIx:kma l ~nlibodies have dt>dopeu. The: OOIlJugate wnh a humant:l:ed mono:IlII1body "nown lIS gcmtul.unmb has been approved Cll'l:Ct thcmottler py. [I is dc:..""ribc:d under monoclonal .. Otht:r Ml'diyne~ of interest as potential antitumor .-ll11k dynemyem. esperamidns. and neoearcmo-

~imu lt aroeously

.":)<1

from

,.

Dactlnomycln, USP. Cosnl('gen. actinomycin D. IICti nOIO}ein C ,. actinomycin IV. NSC-30j3. is obtamed from the fem lCntation of sek":led ~ruin$ of Slrrplonl)'Crs 1"$. It l~ Mllublc in alcohols and alcohol-water rni~lUn:s: however. these: 'iOlutions ~ vel)' sensitil'e to light. Vials oonlaimnt: O.j mg of Iyopllllil..c:d powder of the drug and 20 mg of mann ito l are s-upplied. For m:on~itution, 1. 1 mL. of Sterilc Waler for Injection. USP is added to lhe vial. The It~ulting solution is Mable for 2 10 j momhs at room tempel1lture. Only min imal metabolism of ductinornyci n oceuNi. Its pmlonged llalf-life Inay be explained by signifICant retcntion in lymphocytes and granulocytes. Daclinomyeln intemrllllCS l between tlte base pairs of DNA and .nhibit5 topoi.'iOmcrasc II. It select ivcly inhibits the synthesis of t)NA dc:po:ndcnl ribosomal RNA and messenger RNA.l-fII Dactinomycin is u'iCd ~amsl m abdomyO!'lll"COfTlI and Wilms' lumor in children,! It can be lifeSllling for women wilh ctlnriocarcinoma rcsistalll 10 methotrexate. In combination with Vlncri~UOC and cyeklp/losph;lInide. it has received 'iO'OC use III solid tullton in children. Tode reactions include anorc~ia. nallSc:a. and vomiting. BOlle marrow t1cpn:Mion. resu lting HI pancytopenia. may occur within a ...eel. afler thf:,rapy. Alopecia. erythema. and tiswe injury may oct'Ur at 100 injection sile.

(HI"'''-

HO

_#

" O /l', 0 0
OH

CH, L,-- CH,

5'" ,,0

acH,
I

H, C

o
OH

HO

NHCOCH,

HO
H
OR

-A--- H
OR

Figure 12- 6 ActIV<llIon of c;thchei'lml(lrI

Daunorubicin Hydrrxhloride. l);uJl'IOf1jbicin h)drochloride. Ccrubidinc. dmmomycin. rubidomycin. NSC 82 15 1. IS obtailled from the fCntH'nlal,on of Slr~PlQmJr~J 1N~/iu). I~ The hydroc hloride sail is a red cry~lallinccom pound tllal is ,sQlublc in \\lIter and alcohols. I):luoorub,c'n hydroctiloridc is avai lable as Iyophili/cd powder in 2(}.mg ~iaI5. In Ih,s forni, II IS stable 31 room tcmpcraHlrt. but after n:constiuuioll wi th S 10 10 mL of \ I('rilc Willer ;1 ~hould be used """hm 6 houlS. A IM:" IiposomaJ formu lation of daullOI'Ubicin koown as Daun"XOIlII: I~ 111 pila'>C II clinical l rial~. Sigmficamly ~lICed loxicity. including cardiOloxkny. ha~ been chumc:d r~ il. "The long Icrnunal plasma half-lift or daunorulurin lnu1t~ front ext('n~i ... e tissue bifl(ling. II I ~ I\'~dlly mcmboli llod 1 0 d:lI,lnorubicinol by reduct ion of liS \3-k:ctO group. Th,s metabolite i, one-tenth as activc a~ dauoon,b.e.n. The drug and sts l1)CtaboliCI.' are elim;u;ued by hcpatootl nuy e.\creuoo. A number of ecllul~r Icsilll1.' may cont r.bute 1 the: a.uilU0 mol" cffC(1~ of daunoruhle. n. It m'c:n:alates into DNA and inhibits the lignloll alt;v;ty of l0p0iwrncmsc II. rcSlllling .n tlocreascd ~ylllhc,i .. of boIh DNA and RNA. Redox ,ycling of 1M quiOOl1e (unct.orm lil)' gencmte.' hydroxyl ami ~uperox tdc: r,odicah, IIhreh pc:roxtdiu liprds and dama@e cellu lar ml.'mbr.me,. This effect may produce c<I"ltolOxicit) because: hean cc:tl~ an: relaU\'ely ~Ii,icnl m amiolidant dcfcll'iCli.m

Daunorubldll is u>cd in the treatment of cytlc lind grunulocylk leu~cmi:l~.!\! TOlie bone mafro" dcpres'JOIl. '-tomalU ts. alopecia. artd Ic~l inal d"IUm;ttu."e s. Al htght'r dose~. eardiac ck\l.'lop. Sen'f"(' and progrcs~"e: ~-oogest "e may full,," imlial tachycardia a.nd anflythm.as. The usual dose of d.:lUnorublC in is 30 10 45 for 3 d3)'" II i, udmmi~lcrcd inlr~,cllou,t)'. ta~.nl jl'f"e,ent I.'Xtr~\a'l;ltiOIi. Doxorubicin Hydrochloride_ USP. drochloridc. Adrium)ci n.,N"IS;"C,~',, ~23127. ' rnycm. is uOIamed from ..' I llJ Vat. filI'JUU. The orange-red 1I~"dles 1IIId ulcohols. l)olorubieln hydrochlondc is free/.c-dried 1JO",dc:r in IWO dilTerenl ~i7.cS: 10 rng of Lactose:. U5 P. and 50 250 USP. The'\C'
I

bod;;u;ssucs. ,.. lI h about

le lllS. II is u len~i\"ely rneuboli/cd ;ltId as gtucllT'(lmdc conJ"g"'e~ or the parenl hydroxyl redu"ion prodUCI.

ilibe 7-deQl y:q;J)'COIIt' aJ.o i~ formed. Dispo!IlIioo ;md eh",-

--.n C3I1 be

C'\plairw=d by

a two-compaf1ntc'lIt or II Ihll'C-

model. I1PQSOmt-cncapsu];!'lcd do:o.orubicm

formuhUlOOS forchnicll.l trials.

The model! of OOl(orubicin al\' sum lar 10 those hnbcd for daurl<Jl\lbicln.
Dluorubicin is one of the IflO!>f effecti '-c IIlltltUmor agent~. kbI5 been usro succe\sfulJy !O produce "'gfl'ssiom in acute letl;tmms, Il odgkin's di<;eusc and OIller Iymphornfl~. Wi lms'

UOIl pcnod in the unn~ry bladdcr is no;,ghgiblc. Sy"k nlJoc toxicity is geno;,rally low "'hen the drug is in.~l illed into the bladder_ Nel'Crtheless. some pallents an: sensitIve to amhncycJillCll 01" CrenlOphor EL Imtable bladder s)'mptoms an:
COIIIll'lOfl .1:I1

~,

", 50

:ctO'iC.

, mL

=1, /K' I J.

rro-

lied 10

""~.

Bleomycin Sulfate, Sterile. USP. Bleomycin sulfa te, Bleno.\anc. NSC-12j066, i. n mixture of cytotoxic glycopeptides isolatcd from a Mr:lin of Slreplom)'Ct'J ,wl;dlfuJ.11M 1UmOr. llI:(Lroblll.~tom~. soft-tissue lind OO!IC SIII'I."Omas. breast 1bc main compotlCnt is bleomycin A;: (-M%). and bleomy. ~iooma. ovarian carcinom a. Irtlr!sitiooull"C1l bladder cafcin B! ( - 20 tu]{)'l.) lilso is pre.'\Cnt. Bleomycin i. a ..... bitish 1WmI. rhyl'Uld carcinoma. lind slIIull.cC'1I brollC~cnk carpo",'de:r that i ~ readily soluble in ",'ater. It occurs natur:llly CIIOml.:~ Combmation cl!emolher py with II ,'ariel)' of .. as a blue copper complex. Out the copper is remmed from odI!t agent, JJ being developed for $pecirw: tumors. The the pharmaceutICal form. It i. supplied in ampuls COIlulIning _hmlung lo\icilK:s are myc:low~sioo and cllnilOiollIS units of , terik bleomycin ~ul fa(C_ The blconlycm untl 15 n~ ~ i~ II high incidence of bone marrow dcJlll:!isioo. ba.o;cd on inhibuOf}' octll'ity against MycobtlCl~rium SlIWtrJ'IIIIIII'ily of leulocytc~. ",hicl! usually reaches us nadir III nul/lS in culture: 0.1 mg orblcomycin equal. I unn . Bleomy_ III \II 14 days. Red blood cells :md platelets also may be cin sulfate is reconr;t ltUtOO by di.\SOlution m I to j mL of ~!IftI. Thu~. caIl'fu] blood coum, are essentIal. Acute Slerile "'ater. DjW. or Norrn:Il Saline for Injection . Id'I \eIltnr:\llar faitu~ has occu~. particu larly in p.lli el1lS Blcomydn undcrgoe~ rapid mllial distributio n wuh a halfIKnl Ing J 100ai tkl5e exceeding 11M: cum:mly recommended life of 10 10 20 minull::S. '" hieh is followed by an elimination jj(l mgfm~. Card iomyopathy and t'OOge~li\'e heart failure half- life of2 to 3 hours . It is inaetivated readi ly in 1he liver lIlY be tll(OUnlered sc\'eral weeh li fter d i'CO/1tinu ing osc and ~jdney and cxcfeiL'(] in the urine. Ii Adnal1lydn. Toxicity is augmemcd by irn~lired liver llIc mode ofbleom)'cin action inl'oil'c, binding 1 DNA 0 hlllC1ioo. because this is the $ite of mcmbo li5111. Thu ~. cva lufollOwed by ,ingle- or double-,\1rand cle~vage. Tr:ln.ref IIlOn 0( liver fUllCtion by eonvenlional labornlory tests is RNA abo rnlly be clea I ed_ Thb cleavage is caused by IICt,,'e IIIIOII1mendcd be fore individu al do~ing. 0.\ ygen spt-cie~ that arc gencrJled in II step", ise p!'IlCCS.' from The ~lTl('nd~'d introl'enou~ dosage schroule is 60 to l blcomycin-Jron -o~ygen eomplexes. The j)I'OCC5S is cell ij ..gm II 2 1-day intentals. This do<;c is tlecreased if I"CT cycle specific. "'ith the m'lln efftel in the G: and M phases. iIIII.1ion or bone marrow ~'e~ are ma(\cquale. Care mu51 Resistance 10 b~nycll1 is afforded by the cYlosolic cnM"'-m 10 al'oid utr.Wlb.aliOll. 7y~ bleomycin hydrola.v. ",hieh remol'es WI amide group from the molecule. ThI s i~ c.~pcci ally problc:mllllC "'ith sarIilMubicin Hydrochloride. ldarublcm hydrochlonde:. comas. ",hich ha\c hi gh lelds of the hydroillSC. IrMII)cin. IDA . 4-0MR. 4DDM. NSC-256439. <kIc~th IJ I('(Jmycin i. used for the palllatll'c rrcauncm of squa_j1bwlOrubicm. has been prepared by a number of synm T1lc hytlrochloridc salt i~ fommlnll:d in sinmous ee ll ean:inomas of the tlCad and ncck. esophag us. slin . Mt,. routa. and llenitourinury In"'t. including peni s. eer\li~. and ~ li315 comaining j Of" 10 mil o f ontngc I)'ophilized ,<ull'a!'~ II al-o is u""d :.gain~t tcsticu lar cnn:inorlla. espe. "",der ~nd IS n..-constitut~'(] with j or 10 mi. of Sodium cially in cornbillmion wilh ci~pllltin aod I mbla,ti ne:1OO The 0I0nde for Injectio n. The.o;e solut iolls an: stahle at least 7 um refriger.lIion. Admini<1ratWn is intral'enou~. with pri ncipal toxicll ie~ of bleomycin are in ~ki n and lungs. OItlCr lissues contai n an aminopeptidast thaI ntpidly in3CIivales it. eft mell to avoid e.\tr.:wasation because of the poIen t I'esiaction. Bleomycin has \ery little bone manuw lo.\ iclly: thus. u nllly be used in combinalion "'ilh myc1owppressi\e agents. PulJdaoubtcm dlffen from d:lunorubidn by the lack of a memonary toxieity;s IIIdUCt'd m about 10'.t0 of treated patients. y PUUP '" the ... position. Like d:lunorubtcm. it imercawith pulmonary fibro!;is and death occurring in about I'l-. DNA and mhibits topoisomcras.e II. Imr.llenou~ ldarn_ Thus_ cumulatllc dosc..~ of more than 400 uni lS are no1 IttIf approled for thcr:.py of ocute nonlymphocytlc om~ndc:d. Skill or mucoo~ membrane: toxicity OI.-CU" III la In combination wilh cytambinc. II also is adlle C!''' the blast phase o f chrome m)'elogenolls leukemia. about half of patIents. Anaphylacloid react;OIlS II1'C possible in lymphoma patien!." 1k N!" dose-limi!mg toxicity i~ mycJosuppmision. e~pe The fCConmlCndcd dooage i~ O.2j to O_j() unitoJkg (1010 'ltI!kope nia. It appears to be le\, cardiO(o~ ic than doxo,.,., nand daunorubicin.l3<> 20 unit.oJm~) gll'cn imntl'cnously. in tramuscu1:trly. ur sulx:utmlcou~ ly once or twice v.-cek ly. For maintenance of lIodgkin's d isease patienlS in remission. a do"" of I unil daily or ~bidn. Val",bie;n. V;.lstltr. nlCdna. N-trin uoro5 units wt'Ck ly is gil'en. Blcoounc is stable for 24 hou ~ at UI)~~orubidn. is prep-Jred by acylation of N-trin uororoom k'lllpcr-dture in sodium chloride: 01" y~, dcurose sol ulda.orublcm_:07 It is suppl ied a~ a 40 109/mI. solution tiuns for injection. Crnnopbor EL in 5- mL sinilie-use lials. It ~bould be 2 to 8"(;. The mual do)e is 800 nlg admmistered Neally ~ a .....eek for 6 "'eels. Valrubicm i~ indiM i tomycin. USP. MIlOInyei n, MutamycIII. mllonlycm [or 8CG.refroclory carc;noma of the urinary bladder C. NSC-26980. I~ obUllncd from culture~ of Slr~plom)Wl pb:"nts ",110 .annor ha\"<, ey5ltetQlny. co~SpllOSItl as bluc_vwk:'t t'T)'<;.(ak 1lO1 It is SOl uble in wllter S)'lItnlte mebbolism gh'es N-lrin uoroocetyldoxorubicin; and poiII/" org:IAIC soIH-ms. Vials conuai nmg either 5 m, of t>er. the ex tent of ~tnbol ism during the 2-hour reten mitomycin and 10 mg of m3JInitol or 2Q rTql of milOmycm

and 40 mg of rtUIl1nilOl are supplied, The unrocoo~litutc:d prodllCl is suable at room tempcnl1ure for al least 2 years. The drug I ~ rocoo~litul<!d by adlltng 10 mL of Slmle Water for lnjL'Ction. USP. AdrmnbtmliOfl i~ intru\'enous or introve~ieal , 11 is I'llpidly cleared from lhe v3scular eomp:lnmcnt. and liver mc:tabohsm is the primlll)' mcans of climination. Although II IS a relati\'dy stablc compound. mitomycin C iJ ac:th al<!d by reduction 11.1 a bifuncllOfl:lI alkylatlll8 agent Ihul crosslinls complementary DNA strJnds, r~sulting in inhibition orDNA synthesi $. The 2-amin.o groups of guanine re~iducs are alkylated. and the pR'ferrcd DNA sequence is Cp(;. lllere IS no cell c)'de speciliei ty,:..l Mitomyc in i~ useful in treaung di ~~nllnated breast, gastric. pancreatic. 01" colorcctul OOcnocarcin.omus in combination ..... ith 11uorourudl und Adriamycin (FAM progmm), It is u<ied in combinat iOfl ..... ith eyclopho6pham ide and Adriamyein for tun, canc.!r. Complete remis~iOfls of supcrf'ocial Ir.U1sitiOflal cdl carcinorna_~ of the bladder havc Ix",n obwined in 60% of patil'nts gIven intrJ\'esicul mitomycin C instmaUon.~.2flJ The doselimning to_ielty i~ myelosuppressiOfl. cl'laruclemed by delayed. cumulativc pancy\OJ)/:'nia. Fever. anoruia. nausea. and vomiting also occur. Mitomycin ut 10 to 20 mglm~ i~ given as a Ningle dose by intrll\'cJ'lOtlS ca lheter. Nu repeat dose sllould be given unultn.: Ic:ulocylC. and platelet counts ha\e ft'W\cred (-S .....ccks).
Plicamycin, USP. Phcamycin, Milhl'lll'in, aurcolk acid, nmhromyein. NSC-2-iss9. is obtailll-d from SIrt'f'Wm\'Ct's pllca/ur lJ or S. urgjffuct'us a,< a )ellow sohd. II IS soluble: in polar organic <;OI,'ems and aqUeoU-.'l alk.ali: OOv,C\eT. it is ~usceptible 10 air o~idauon In alkali. Mllhrnmycin readily form~ comple~CII ..... ith magncsium and other divalenl "lelal ions, and these conlplClU:.~ ha~e drolSlicully altered optical rotIItiOfls. Vinl~ containing 2.5 mg of mithnlmycin as a frtCl.t-dried powder. together with 100 mg of mannitol and sufficient disodium phosphate to gi\'e pH 7 \\.-hen diluled \\.-lIh watcr D~ su pplied. The drug is recoflSl iwtcd by IIIjccling 4.9 mLofStmle Walerfor InjccliOfl, US P. Shon imr.l.\'enou. infusion~ lire used chnically. Plicwnycin IS used in the t~atmcm of advanctd embryonal tumon. of the testeS,l)') It hns been largely ~upcrscded. howc\er. by newer agents. such w; bleomycin and cisplalin. fusently. the main use of mithrnlll)cin is in Pagcl's di~ase, III \\.-hich It reduces alkulinc phosPO:IIasCacli yity and relie\'C'S bone pai n, - I! alw is useful in treating [llilients wilh o;cven: hypercalcemia or hypercalciuria re<ult ing from advanced metastatic eancCT involving bones. Plicamycin may produce 5e\'cre helTlOn'hagmt- 800c marrow. livt!. and kidney lo~icily also occur. The lower 100ul dose u~d for hypercnlcemia rcsull~ in less tu~icity.

bolus, MCUlboii lcs demonSirotc triphasic 111_ clearnnce with II sOOn inmal phase. Strepto~ocin ~ 5pOO13ncous dcoompo!>illon to fornl Incthylcarbonium ... which alk ylmte DNA and inhibi! new DNA symhcsls. Streptolocin is indicated only for me!astatic islet cell \Y. cinoma of the pancreas.lIb7 Therapy is lim ited to I*ICIII "'ith symptomalic or proarcs..i\'c di'il.'asc:, because of enl renal to~kity of the drug. Up to two-thirds of pM.... treated with it e~pericnce renal \O~icity. Adequnte h~ i$ recommc:ndcd to reduce th i~ to~ici!y. Nausea and "omitIIf: OCCUT in more than 9()<1, of paticntJi. whkh occasIOlllU} Ifquires diSCQrllinuatiOfl of drug !htrapy. Li>'er d)'srulltta also OC'CUI'll, Stn:ptozoc:in is mutagenic. carcinogenIC, -' teratugenic in animals. Carcinogene.~is following topical a posure is a possible hu;uU. After ropid injection. linch*, ' drug is rapidly clcamI from lhe plasma. The half-lilt it ~ minu!cs,
intravellOU~

1_

PLANT PRODUaS
The: use of hi gher plums in treuting IlCOplastic di!a!r datcs to antiqui ty. DiO!OCOl'ide!l described the u.~ of roIdicine for this purpose in the first century. In more reo:cn! yen seicnlisl5 have HllC.mptcd to select and liCrtCn systeJIIII...., plants reputed 1 ha\'C antitunW)l' aclivily. If activit)' is ~ 0 lished for one member of II plnnt family. OIher mt'ItIbm" this fami ly are sclccl<!d and tt!Sled. A major impetus research was gi,'cn by HlU'!wcll at the: Nel. ..... ho "';..;. . an extensivc system of plant collection, .scn:cnin" and __ tiOfl .~ More than 100.000 plants ha\'e been SCTee~' thi s program. Resin of the Illay apple. Podopliyllum /W1mfwnl, Iw", been used as a remedy for wlU1S. One: of itJi COftS\Itur:I& ~II01oxin. has anunc:oplastic actIvi ty. but it IS hi to~ic. This lignin inhibits mitosis by de!lt~ing lilt II1II:turol organi ~..IItion of the mitotic appamlUs. Z Early drm. ti~ of podophyllotOlin sho\\.-'ed poor clinical K tml)'. III newer ana!oguCli. such as lhe cpipodophy lloto,\in den>1\roCl etoposide and tcniposidt:, are much better. 80th of dietr analogues differ from podophyliolOlin in inhibiunll . . isomerase II nl1her than microtubulc assembly.:rti

111_

R\::O/"

o
HO

HO

Sr,."tozodn. S\n'pto~.ocin. ZlInosar. NSC-8S99S. 2(). methyl 3n itrosoureido} 2 -dwJt y-I)-II ucopyrnnose, is 0btained from cultures of SfnptQmyct's (Jclirof7wgt'm's <ubsp. J'frt!I"utJJ/fcur'" ur syn\he~il.ed from u-glucosamine. lM It is readily soluble In ..... ater or saline. Vials containing 1.0 g of l)'Qphili:ted powder are .wpplioo. They sllouJd be refrigff' atl-d ut 35 to 46"F and prolcctcd fmm light. llle drug is n:coru;tituted by adding 9,5 mL of eilher normal saline or Sterile WalCf for InjecliOfl. USP. Unchanged drug is rupidly cleared from plasma pfter an

E\CV'I<Itt

R. CH~

T ............ A.Q s

------------------------------------------------.
TAILE 12- 1

Vinao Alhloid s

~ nd

Their Analogu es

'M~
.enl~

.her-

""" iting
Ilion
~~

,","

,od
,I exogcd is 35
AO

.,'"
)lehl

~~

,--... v"., . .,.

0

'''.co CH,ro
tCH,),I'CH,cQ H CH.co CH.co

'. " coo

H
('Il , C IIJ

ou
H

" OU

.
OCU)

, ,

OH

I._

CH . CH.

CII,

H H

"'~OU
0"

OCH, OCH, OCH , OCII,

~It,

lcally
The: \'inca an.:alojd~ an: a fam ily of important nnlllumor from plants. 1l1cse compounds were isolated from the pm.. mklc Cm/lnrnmhus rosro :tllhe Eli Lilty COlllpany,m 1ky MI"e oomplex Siructu rt"'i composed of an Indolc-conmoiety, calhar1lnthiOC'. and an indollllC'-conllllning ~. ~indoliOC' (Table 12 1).lH Four clOM:ly rel atcd ~'()m pJIIlIb luI e antitumor acti ~ny: vincrislillC. \'inbla~li lie. YinfIlUtlllll'. and vinleurosinc. Among I h.j ~ group, vjncrj~ljnc

"",b-

:rs of
isolaunder

o Ihls

""'"

: lon&

uenlS.

ligh l)'

inblalitioe are prow:d clinical agents. These two 1'0111~mds arr used aguinst different I)'pes of tumor.; , de.~plle
trwnilarity of their .Lructurrs.. A number of sc misymhclic .,,nd!. have btcn pn:pared. Among them. \iOOR'lbinc In.\e in advanced lung cancer:tOO was fClC'('ntly appnwed dIr FDA. Vingl)cmale:tOO 6.7dlhylironllblastme show T..:anl antitumor activ ily.17~ Vindesine is coosidcred to Ie ~incris.tlne pharmacologically but 10 be Ics~ ncuan..:. IH \'UlCli alka loids cause mitotic arreSI by prum()!i ng Ihe dis

-~ erivlIy. but ati\'cs

,-

solunon of miclUlubulcs in cells. Microtubule crySUlI cooullmnl! tnc 1I1loioids arc: formed m the C) lopIa5m.~76 Vin bla>une I~ the IllO't at:UI'C compound, ... hcreil!i \ Incn sline is the only compound to cause im:I'crslblc inhibition of IIU1osis. In Cells call rc\>llllle mitosl$ follOWing boef exposure 10 other Vitll;3 alla loid~ IIfler the,e cornpoullds are wilh df"Jwn.l71 A plant prodoct of hi~h current inlel"Cl't in cancer chcJ1"lOtherapy is p;lClitaxel (Taxol). Thl~ compound was isolated from the bar .. of tnc PacifIC )CW IItt Ttulu brt'l'iji>lio by Wam CI al. III 1971.179 At that lime. II .... as found to h.a\C antitumor achvlly : ho"""elU. thc're W-JS hllle cnthusiasm for its funner (lcwlOplllent until ~l1lly . ... hen Its potential for human clinical actll;!y wa.~ suggested by screening against human lun~ in immunodeficient miee. II is now lhe world' ~ Ica.:hng unl incopla.~ue ugen t in Icrn.s of bales. Pacli laxel is active again~1 refractory ovariun cuncer. metastatic 1M\:as.t CllllCCf. mctastatic melanoma . nnd non -smallcciliung cancer. Pacliuuel mh.biL~ mitOSIS by ocllng lIS II. spmdle polson : however. ic acts by a unique mechant sm In prumofing tnc assembly ofnllcrotubules and Slabilll.lng chem &gam!;! <kpolymc:rilalion. ZIlO This mcchalll~m IS in COOtrllSC to tnat of compounds h~c the vinca al kalOids . ... hlch prevent the assembly of microlUbulc~ . [llilially. pacliuaxc:1 was OOtaillCJ oll ly from the !>ark of Ta.l"us br~,ijo/;a. II. slow -gro ... ing u"!:e conlailling only a ~mall amounl of the drug. 11m procc~~ IS expcnsi\'c aud a threac to f()fl.$1 ('COlo&) . Con~ucntly. the manufacturer. BriSIOI Mycl1i Squibb. tJo:o\cloped a tOOtc based on partial synthesis from 100dcacciylbaccl4tin III .... hich is obtailled from lhe needles of TU.lUS mlccll/a. a Europellll ye .... tree . Becau>c needles are ropidly regcnerated. Ihis I' a les~ desCf\lt:ti\ c !m-Ihod for obtaimng pachtQxel. Furthennore. 10deacctylhaccatin 1 1I!~:111 important intcnncdi~te for chc s) nthesis of analoglM:$. One such lIIlalogue. docclaxel (TBXotere). has been pR'pared aI RhOne-Poule!1I; Rorer. It I~ more '" ater soluble Ihllll paditaxel and reponed to be fIl()f"I: potent agairu;t solid tumon. bill it is n:llII.i\"ety more toxic lhan pach Ul.\d.Zl I DocelaXeI is approved for nICI.IISlallC breast cancer and for 1IOn-5mall II lung c~ after patie nts havc failed prior cncmodH:rnpy.

,r

"-

, ,
H,OO

- ." ~
HO

"

"

<J
H

(0

0y
0

y'
0

H,OOC;;""",-OH

H~

"

,
H

"

C, "
OH

Vlnorelbili'

~:R.

7
N"
0

potsomer.I$C I. Cytotollicity i~ caused by douhlc-~tJ'1llld O~A damage . which occurs during DN A sy nthesh when repliQ. tion en~ymes Internet with The ternary complcll formed flOlll DNA. topoisonll':l1I,<;t I. and the dnlg.ru Many other pl3nt ronsulllen t~ ~how slgnifiClllU. anlltualOr acti vity in lIrlimal s and hD"e becn given clinical ev,llI3tlOl. Somr or the more Important compound;; arc: hornoharnIlc toninc. anguidinc. and mayt3I1SirM.' .lJI6

X "0
As llOIed abo~c, colchicine, obtained from the crocu s Colchicllm alltlU1ltl(llt, h3lI long bcen I.:nown for Its antitumor activity . It is curre ntly not u>Cd clinically for this pull'O'\C. howevt'l". lts main use is in terminating IIC\Ite Illtacu of gOUI. Among colchicine derivuti\'es, demecolcine (Colccmid) is aclive against myelocytic lcukrmill. but only lit ncar-toxic Ooscs. Colchicincs have WI unusual tri cyel ic structure con taining a trop:Ilone ring. Tllc:y inhibit mitosis It mrtllphne by diliOrieming the organi/.lltion of the spi odIe and listen.m

Products
Etoposide. EtOJ)Q"ide, Vc:I'csld. VP-16.2 Il NSC 141 S4(), is a SC'nlisynthetic delivati ~e of podoph)I101olill. k is ~upplied in j-mL 3ntpuls oontaln ing 20 mgfml 0( W drug plus 30 mil of benT.yl ak-Ohol . I!O ntl; of polysort. SO. 650 mg of polyethylcne glycol 300. and absolute~~ This mi~turc: is diluted with either j% \k:c.1fOl,e or o !It ~a ljllC to give a final concenll:atiof1 of 0.2 or 0.4 m&fml. Etoposide also is ~u pp!ied as S(J.. rng capsu les "hich contain SOI'bitol. 1bey mu~t be stored at 36 to 46"1', Tllc: pharrnaco](ineticsof etopo5i\k fit D two-compannn. model. A lemli nal half-life of 1 hours is iodcpelldcnt!l* dose and method of Ildmini strJ\ion. Aboul 43% of a~ . recovered in the urirM.', of ... hich 66'i1- is ullchangtd 1hI. The primary nlCtabol itcs fouOO in plll.~ma are picro h)drou adds aOO picro lactone: the m~JOT uri nary ntCtabohlt" (. dclTll':l.hylepipodophyl1ic :w:id. Oral bioa\'ailability i\ IboI
Etopos ldc has marked schedule: dependerM.'c. with C}" to~ic effeets in the O 2 pim.'I('. II causcs protein-hnled O'l~ strand brea](s by inhibiting topoi'lOnlCl1Ise IL Althou~ 5) poside dots 1101 bind directly to the DNA. il ~:tbililCS covalent 1II1cnnc:diate form or the I)NA-topoi~ a OOntp1ell. Etoposide in oombillatlon wit h other ehemothc:rapetitK agents is the first choice trcamlCnt for small cel1lun!~~~ It also is effc:elh'e in cornbinution wi th CHller Dj;l'nb lor refractory testicular lUn1Ql'S. and II has been uo;cd or in oombination against acute oon l)lnphocytie "'. mi as. Hodgk ln's dl'l('3SC. oon - liodgki n '~ lymphoma$. Kaposi' 5 l(JIfComa. It is ~'OIltraiOOica ted ill paliellts \\00 Ikvc:lop hypc:rscn ~i ti ~it y. Dose-I inmillg bone marrow suPJIll' sioo is the most siglli flClllll lO~ici ty. and reversible a~."'m occurs frequelltly. Nau~D and vomi ting are uwally trolled with SUII1dard tht:mpy . On intr.l\'enou~:",~~~:; tion. the di spos.tion of etoposide is blp/laJ.le .. ~ 'I IKin half-life o r about I .j hours and an clill1in;ation IWf-a or 4 to I I hours. Teiliposide. Vumon .

CH,O...,..,,- /--..,
)- NHR

QCH,
CoieI'oo .. R .. ccx::H 3 Ct*:etTild. R. CH 3

'''''.

lrinoteean 1I11..~ been approved recently for fifliHine ther apy, in combination with S-FU and leucovorin. for patients wnll metastatic colon or rectal carcioomas. It i~ a semisynThetic analogue of Clmptothecan.l l l Camptothecin was isolated from CamJllOlhtca Qcuminll/(I. WI ornamrntal tree found in China.u.o It is very insoluble in water. but its sodium !IlIlt. prl'pared by alkaline hydrolysis of the laclOOl: ring. ~'ed promising lIIltitumor activity. Cli nical tria ls ,,"'ere evenTually dlsconllnued because or unpredictable tOllic effeelS. lrinotCC luis a basic tcniary amine group. which cUn lin be prolOllated to solubil i1.e the drug. Tllc: lactone rinll nemain.~ inlaC1 and in.crea.<;ts aclivity above that of the: ringopened sodium salt. Camptothtcin and irillOlecan inhibit to-

R,

R,

m ,
CamptOChecan: R,. ~
.

o
OCN

hincte:.n: R I. ~R2.

II

EI.. maleic acid to adJu t the pH oo",?," ~ adju ~t the total volume to 1 mL T'iI prepar.lIioo is Slable for 4 years al room tcmpcn1Ul\' diluled with allellSt fi ve equivalents o f !lOCIlum chloridt liOll before intl1lvell()Ul; illfusiOIl. Tenipo:.ide is highly protein bound to 3100111111 play~ biupOIIelll1al decay. MO!.It o f the unnary ~,,,,,' as ntCtabol itcs.

<A

..u. smgle agcm.

~na.

\ClllflOS.de is act"" agoln<;\ KapcKi"b

uom

".-

"'"

00

lymJlhomas. multiple mydonm. cervical Clillcer, lid Sl11lII1 cell Iling cancer.:<I(J It j , octi \1: in 1:(Imbilllllion Wilh ClW1lblflC' agamst refractory acute lymphoqtk leuktmia, q.rn ISthe only imhcauoo appro,-ed by the FDA. Thc:doso:inIllng 1011cily is Ieulopenia. ThrombOC)lopcnin i~ also mltr,ed. CllcmicaJ phlebitiS allhc injection sile;<; common. .~! I'Ilih clOposide. prolonged tre:.nncn! wilh lcnridc may QII!e secondary acule myc~cllOUs Icukcnlla. I

." ,'" ...

,'"
~,

/c-

Vinblastinoe sulfalc. Vclban. \ID('lJleualblastilK'. VLB. NSC-49842. is an antitumor ullabd Isolated from VilltYi
1'{JJt'(I

'flflblutiM Sulfate. USP.

L.. the pcrillinklc phUlI ,21l

hoi

"

k II soluble in water and akohol. Vials containi ng 10 mg rI ,tnblaslmc sulfale as II Iyophilil.ed plul !In: !iUpphed. II llmlllSlJlUled by the additIon of sodium chloride $(IlutlOR

r.'nl~

lonn,ection preserved \\ nh phenol or benzy l alrollol. In\la\'enou~ vinblasline I~ I1lpidly cleared from pl asma and
rlimm:Jtro in ~ triphasic pauem. The: app<lll:m volume of

Vmcm;.lIne i~ effcclI\e ag~inSI acutc leukcmia. In com bination with predni..one il pn)dUl.:e~ complete "'mission 111 ~ of cbi ldren willi ALL. I.... II is used in tlte MOPP JlIUl!l1Im of comblll.;lIIon chemolherapy for Hodgkin's disease.:<IoO Other lulT"lOf'S llim respond 10 "incnSline in combinallon witb Other alluneoplashC agents include lymph os,lrCOllla. rctieululIl cell sarwma. rliah<.kJmyosan;oma. neu roblasloma. and Wilms' tumor. Allhouglltltc tumor ~pc:ctl1l of vinblastine and ~ illCri5line are ~im ilar, there is a lock of cros5re~isumce between the. 1""0. Because villCri~tinc: is less mytIosUpprC'SSl\e lhan ,inblaSline, It IS plderred m combi nalion wilb myclOlO~ic agents. The nlO>t !'Criou s cliniclll to~kily of ,-incriSI inc is neurological. wilh pareMhcsla~, loss of dc<:p tcndo<! rcnucs, pain. and muscle weakness. Tltcsc symptoms can usually be revC'f'SCd by lowering the dose or '\Uspcndmg thentpy . The rapid aclion of ~inrnS!lnc In destroYing cancc:r cells may result in lIyperoricemia. AdministratK>n of aUopuriool can pI'C\'cm IlIi ~ cOl11plication. Vinon:lbine IIlf1l11te. Navclbint:. i5 a new semisynthetic ~ inca alkal01d dcri\'cd from .inblas line by loss of one: carboo from nng C' and de:bydnilion in ring D'. botll in tile catharanthinc moiety . It is limned 3'.4'didehydr0.4' -dL"O~y.C' norvincalcukublaSline. Na\'c:lbine is supplied in ~ ials containmg 10 mg/m\. of solution In 11 \'01 ume of I mL ofWaler for Injl:cl1Ofl or 10 mg/mLof solulion in a mlunlC of 5 mL or Watcr for InJCCuon. Unopened viail; are stable at room lempcrowre forup lu 72 hours. It is diluted 10 a C()ncentra tion of 0 ..5 to 2 mg/mL witb 0.9% Sodium Chloride Injection or SOl Dextros.c Injeclion for imrnvcnoos infu~lon or slow imnl\cllOU pusll adnuruSU'llllon. lbe pnmary mecbamsm of actlOO of "inorelbine is bindms 10 lubulin. wblCh Inhibits microtubule a~sembl y. It may be more specific than OIltcr ,'i nca alkaloids for mitOllc mi cT't)+ lubulc.~. Vinorelbine ha~ been approved by lhe FDA fOf'trcalment of unl"C5lable ad,.:mced non -~ mall cell lung cancer. The most Important ~tde crfeel is gnlnulocytopc:ma. Paclitaxfli. I'aclitaxel, Taxol. is u diterpelle obtained from tltc needles and bark of the "CSICro yew. Tluu.f bred /IJliu. 21'9 or by partIal ~yntJ\e"is from closely relalcd com pounds obtained from ~Imilar species. It is formulated as a cl)OCcO\nled sterile wlUlion contammg 30 mg of pachluel in a .5mL ampul comaini ng u mlXlure of 50% polyoxylmcd ca~tor oil. Cremopbor EL. and .5!n- dchydnltcd alcohol. US I'. II is usually rccon~tilUtcd in 50 1111. of D5W. Solutions sboo1d be u.'iCd within 24 boorsofrecQl1S1Jtuuon. 1t is admin istered by imm\ellOUS mfusioo only. Dis~ilion of paclilDXc:I from pla.~ma follows a biphasic eliminaiioo pallem. Approx imately 97.5'll of it i~ bound to plasma proteiJls. Ck:;Ir.Jnce is lriph~k :md results mllinly from hepillic extraction and biliary excretion. Ek ven nlClalJ... oIl1CS ba"e been delecled in plamla. bul IlOI idcntificd. M Paclltul'1 is a mnOlic ~ndJe poi!Ol1that XIS by l unique proce~s. II promotes a~sc:mbly of mlcl"Olubules and slIIbili7.es thcm against dcpo~ncril.ation. Thi s process blocks cycle I'aclnuc:l is IIlgbl )' acli ve qoi nS! reo travcrse in mitosis. fractory ovarian callttf and effective against melllStat1c brt'a.<;t cancer. mclllSlatlC melanoma. and non-small ccil iung canceT. II is used in combinations containing ooKorublCin.
Vi~/biM

~"'

"

boo,

4'

I 1(....

!)NA

''''

"

ellli" I1<:cr.

"

I~

Om.

". n""

""0011011 IS 310 4 time~ the blood volume. A large portion '7]'t) tS n:tamed in the body. bill l'oOOle is ucreled mlOCI .,,11( and bile.,,n TIlere i~ some mewbolism 10 deacclyl OIIbIastlnt:. wilich is IIlOIl: active than lhe parem compound. The mode of nelioll is lubulin binding. which inhibit_ mi crotUbule IIs-.embly and microtllbule spindle (ormalloo. nti s III C,IU"CS accumulalioo of cells in metaphase. Vlllbla.stme has been used for lhe pallialion o f a Hlncty ~astic dise;lsel!. II is one of the nlO)( effec:ti"C ~msle IlfIlb against Hodgkin's di'\Ca<;c, and il may be used in IlXIIbilllllion che molheropy for palienl~ who ha\'e relapses . , trralmt'nl by the MOP!' progrnm. A.dvanced testkulnr IIlII ~Jllumon respond to vi nbl a"IHIC alone or in rom . Beneficial effects an: also obtall'led agaill~1 ,qmcyllc lymphoma. histiocytic lymphoma. mycosi~ .des. Kaposi' s sarcoma. LeuererSi ....e disease. re\is .dIonocardooma. and c:m:irlOm:I of the bre:J.lot. The Ii mil' -rlOllCily is leukopenia. .. bich reacbe~ ils nadir.5 to 10

Tartnff!.

after lhe lasl 00<1::. GaSlroinleSlinal and ,~~;~~~:::'

<k-

F' pe.;,lI
C~IfI

",.

ibu

If-life

"C

: glu-

Il>io'lpul' Om,

><XI

1.

ThO'
II I"

wlu-

sunt: VCR. LCR. NSC67574. I ~ lsolmcd from \"11<"1/ _ 1..111 The <U.lflile is II cryslalline ~hd thaI is ilIluble II is supplied in ,'Ials eOlitUIOlllg eilher I IIlg of ~u lfate and 10 mg of Iuctuse, or 5 mg of villerisof . Eacb sile III1ll an ocoompanymS t' !oOdium chloride solution con 90 mg of sodium cbloride: and 0 .9% benzyl alcobo1. ht~ituted phannaceutical may be scored 1'1 days In utfngcrmor . After administr1ll ion. vineristille is rupidly di slribut~'d to ~Q and bound 10 formed blood elc:11lcms. El imin~tl()f1 is 'we ..... Ith more than llalf of the: drug cleared witbln 20 ;;'.'~" The primary modi' of eli mination is hepalic e~trac . . 'I1"I11I5ll:uon intu bile. Vincristine binds revel'llibly 10 lubulin. stopping 1111erotu __ l.ISembly. whkb arre:.IS cell division in metaphasc.21 lempornty a~ causcs a cdl cycle block called sWfh ~~iJ. Resistance. to vmrnstine resull5 from i~ased le\'els of Pglycoproteln.

.:.~;~>tiM Sulfate, USP.

Vineri~tillC "ulfal(', Ooro\in.

428

It",,,,, "n,1 GISI'OIII's Tt;tl/H,,/k of Or/l!lnlr .IIdi""""

",,,II'harntl.,u llliml eM"'''''''

CIspiaton. and rilgrastirn (a human gnmulocyle colony,slIml>' bung factor producc:d by recombinant DNA technology). Hypcr.c:nsithny (J(:curs in -oIllC patients within 10 minute$. St:utm8 an infusion. II has been suggesletlthatthe allergen .s lhe Cremophor El dilucnl.- RC"m!iblc pcriphcnllllCUropalhy is common WIth pffllonged infusions. Bradycardia. gastrointestinal disturbances. nuli~e ,ymptoms. bud tOlbl body alopecia aJ..., occur.

or

bgands ...... :mil ormaplalin. a 1'1. ( IV ) complex WllO'ie!oJl ligandli include four chloriOcs and I.Z-diaminocydoheunr Ommplatin must be reduced 10 thchloro-J.2-di amlllOCydo heone PI (II) for acthation. 10"1

[)ocetaxel. TWlOlere. RP_56967 . NSC628503. i~ prepared from II. precursor obcairICd ffflm lleedles of the }ew plant.m It is supplied !IS a 2O-mg sample In 0.5 ml of poIY'>OfOOtC 80 or a) an 8O-mg su.lnple in 2 ml of polysorbate 80, both In single-dose vial~ with diluclIl ~uita ble for mjection. Samples ~hould be kcpt al 2 t(J SoC and be proICCled from light R('C(lmmcnded dos are 60 to 100 m,) m~ IV O"cr I hour every 3 weeks for breast C:lJlCCl'" or 75 mglm] for non - small cell IUllg callCCf Docclallei is indicated for breast cancer after failure of prior chemochenlpy and for non- '\I11lI1i IUllg carcinoma after failure of platinum-based therapy. To~ic tffecL~ include neu tropeni:l. nuid retcn tion . mutagenesis. rash. and rlCuffllogical symploms,.m Pcripheral blood ooums ~hou ld be performed because of myelowppres~ion. Ph:umacokinetics indicatc a thRe_comp:lnmem model ""'Ih halfliH'! of 4 and 36 minules alld 11.1 houl'll. n.c drug i~ 1)4% protein hound.

Docetaxel.

C"pblin

MISCELLANEOUS COMPOUNDS
In 196. . Rosenberg Invcsligatcd lhe effects of electrical 5 r.elds on OOctenll lind found tmu Escll,.nchia coli fom"ICd long liIaments Lllslead of d ividi ng. - ~le ,ubsequently d;~ coverro ,hal this effecl wa~ cnused not by the electrical cur",nl. 001 by a compla. [PI (CI).(Nlhhf fomle(l from the plat,nUIlI eleclfude in the presence of ammollium lind chloride IonS.)!IO This d,i,Covery wa$ followed by !eSTlllg I variely of pl atinum neulml comp le~c.~ against 1Uml'rs. with lhe reslill that ciHlichiorod lammincplatillum II (dspbtin) c\entually became el tablishcti as a dil1lclIl agent,.IOl Thi~ platinum L"{}Illplex i, II potcnt inhibitor of DNA poly mcmse . li S aC"tivity and tOllid ,y rese mblc those of the al kylatinll agellis. Con~idcrablc evidence has been obtained fOf" DNA DII,,/jng by !he plalinuHl I;"QrrIple,O . 111 "hich lhe 1"0 chloride.-. Wl.' dj~plrxcd by lllirogen or 01ygcn IIlom. of purioos. "ln~ evidence inc illdc:.~ focilitutL'tl renatLLr.ltion. increa.'\I'd sedil1lC':ntation coeffiCient. hyperchmmidty of the DNA lI1tr~ ... iolet spectrum. and seic<:tl"C rextion oflherom. plex With guanine o,er other baM:s,JQl Man y other plminum complexes have been found Ilctive 3lla;n I lurnocs. Ck-ncl1llly. they fall into lhe cl assirK:at ion of cis isoll"lCTli in .... hoch one p;l.Ir of ligands !lI'e monodenlate anions of imermc:diatc leaving abi lit y (ql.. chloride) or bIdemate anioos (e.g .. ma/onale). and the Olhcr pair 1lJ"C 1110110or billcntate amines."lJ Arnoo~ the nlOTe ~ignificullt ana logues IS carboplatln. lhe currentlcadet" In ~ MlOng plalinum compkxes ..... hlCh rs approved by lhe "'1)A for treatmcnt of ovur;UIl cancer and wh ich al-"O is used ;mai nstlung. gcnitourinary. and head and ned. cancer.:IiJoI Other platinum cornplc.tCS current IIIteresl are ou\i~llt\. wnlch has o1!.a!atc: and 1.2-diarnirooc~"CIohcune a.\

Arsenic trio\idc ha~ been u'ICd In a "'arlcl}, of IhcraptW: roJe.. Including I"'f1Ntic infcetion\. rhcumaus.m. and a\oIIa. R~cnll y it ",as found act,,c agamst protn>cloC)he IcvI.emia. which is chafllClcri7-cd by trans location of PMURAR If gene c~prcs,iOlL The act;'c ~~ics i~ dimclhy~ acid ..... h,ch is formed from ar<'Cnoc uio~idc by Il\eT ndl)~ .rn.nsf~'I'lI~ Cl1.(Ylnc5. This species producc, DNA fraamcataIion chHrJctcri sti c of apopto~I~. H)Wuxyun:a has been koo .... n for IIM)R: .han 1 yean. 00 001 it. anlHuntor activity .... a~ nOl di<;co,crro unlll 1963 ~ is IlCtl\C against rJpldly proliferating cells in the S)ntbN pha$C, during which II pre vent \ Ihe fomlahon of dI..'O\)nro. IIUCIc<>tJdc) frotn ribonuclcoudes. It, mode or actIOn i~" bitiOlL of ribonuclCQUdc dipho:spnatc reductase. an rnry. L"OnSI Stlng of I.... 0 protein ~uOOmts ...IOI It doC"'! this by InIC!fa.. IIlg with lhe iron < onillininil ponlon of one of the.o,('''
unil~.~

o
HQNHCNH 2

II

or

Another \"Cry old <.:tln lpound recent ly found active ..... IUlTIClI'\ is guanuoJe. 110 Th,~ diamiJ>OlnalOlc rcsemblc!llttdrux)"urea III il~ hbllrty 10 Jllml DNA S)mhf.;b by 1II1n.... the Rdooion of nbonucicotl{]e). It is clrnically lICtJ'f IIlducing ",misslOIlS of ocutc adult Icu~ ... mih." I In 195.t Kidd fOU11(\ Ihat inje.::tions uf guinea p i , _ caused re/!;TeSSion) of certalll tnm'PI.. mtd lunlOl) In na::c :mil mts. I I. Subsequent III. e~tillat.on re' caled thallllot. mors rcqul1ed l -Il.'p:lragine as a nUlrient, but the r"estdC( of the C01.ymc l-a.sl"'rngillasc: In the gllillCa pig serum I:r9IIII! I deficicncy in this Dn1loo acid. JI' 11M: praclical pit ....... of l.-asp;;omgmase for clinical trials folloWJ Ihc disr:o .. cry" 1:. coli prnduce!i u form of it lhm h3.~ uotlllcopluSllC actJf ity.J,. Thus. mass cultures IU"C hllrvc~led and treaJcd ammnlLlum !;Ulfatc to rupture the cells. and the libcr.llcdellI.yme is l'\OIated by \OI"em C.ll lrocUon and chromat

Pwotatr... d 11~ ' ISla' 010.

hry pun: material is obcuined by gcl fihrmion or affinily drOI11:nogruptl)', followed by crystatl i/atioo. The E. eQ/; enll- has molecular mass of 120.000 1 141.000 dal1ons.. 0 .ilOeloctric point of 4.9105.2. and a Km of 1.2 X 10 ',II} Eaiter prepar:ul()n~ of 1.n.~paragina.'iC contained cndolo~ from E. coli. btu these are absclll in lhe PIl",r new prcpaI3IlOOJ, Clear-a,1Ce of the ell/YIlle from plasma is due 10 lUI

iamunok'iJcaJ n:ac1ion In which II combint's wilh proIein. Tlti ruction may lead 10 ~nsiliulion tn some p~lI~nlS.

eUlic hma.

:uke-

'lAR-

..cole

Ihylcnlfl<~,

jJ. II

hc~i'

rilx>-

inhi nrne

:.fer-

"

hliml!. 1'000 canllOl lo\crole t.-asparaglnase from 1::. roll lllif:ht be tn::lled by the preparation from I-: nl'inia mrfll/>roro. l16 Tumor resi~l uocC i. basal on the development (If ISpInlglllc ,ynthctase hy the tumor ce ll s.'17 Pcsasp.ugali<' is II modified veNion of Ibparagina..e in II'IIcIlthe C1I7yrne is CI)YUlenll) conjugated Vo'ilh .. rands of fCII)"mmc n)Ol"lOf1)etilolypropy1cIV,' glycol (PEG). which rooIecular wcights of about 5.000. It i~ u~d in combi won c~ltlOlheTIlpy of patient. with ALL v. 00 are scllsitive II .~tural 1 .-lISparaginase. AlIRwlune (he:.\amclhylmelamine) i~ approved by the: RIA for u~as a single .@eOlforl"C!l;sllmtOvariancancer. ll ~ iI rapIdly IlV,'labolil.cd to penlamcth~lmelamillC. letra.m)lrnelamine. and sevcn OIheT comfl'Ollnds. Pc:mUIIlClh,I8:'bminc abo has alll ilu!nor octi vily. A sugge5lcd mode of ~ for . Ii(('taminc is hydroxylat ion of one of Ihc: methyl poIpS to g,\'e the corre ponding hydrox)'lTIt:lhyl COnl,...., ,,, Thi$ COltlpound IS a carbmolanunc thaI can 100iC ~tde I(lIl 10 form an immoniuni ion capablc o f either 1II.)l.uioon of a mocromokculc or hydmlysis 10 pentmnclh ,knfbminc. This process could be (('peated in converting paumeth)"lmelaminc to an alkylaung agent or to teU'luncth-

Among the nc .... cr Wlllncopla~lic drugs. 4-[(9-ucridinyl)ammolmethanesulfon-m-anisididc: (m-AMSA) sho\Oo'ed II .... Ide spectrum of 3Cti ~ity in l'arly climcal trials. II afforded '>01TIt: remisslons in refl1lClory casc..~ breast cancer. maltgnam melanoma. and OCUle myelocyuc lcukcmHI. Leukopenia is the limiting toxicily .m m-AMSA (aJl)~ril1C) is an acridine rn,ri~atlve that is thought to bind to DNA through intercalation. It does not affect DNA synthesis. howe,cr.1) TImi compound was rationally desIgned as one member of a groupofacridmyluminomethane.~ulfonam ides.J2 Pn.::viOt"ly. a number of other acridirIC derivativcs hll/J shown anliwmor activity.

or

NHS02CH a

m.t

DCH,

The clinical importance of :1IIthnIC)'cJines SlImulated the

screening of IlJIthraquinones wnh panlal anIhracyclme siructures. One of the be~t of these anulogucs i~ mitountrone ..... hich tms two hydro,;yl and 1\000 2-[ (2hydrollyethylamillO)eth)" lIamino wtKIi tucnts on the anthrnqui fIOI1C nuck'us. 2!l ule ooxOIUbocon, mito'(llntlUOC" Interca' lates onto DNA and ,nhibits DNA tOJ'lOlsomcrnsc [I '~: bowevcr. it i, not a sub~1r.l!e for reductases and does IlOt form o)(ygcn-free mdkal) in a redm cycli ng procc.~,. Consequclltl y. il is less cardiolOxic th.an do\orubicin. M itoxantrooe is apptmed forinducmg remissions in acute nonlymphocytic leukelma. usually in combi nation \Ooilh cytarabine. HO 0 NHCH,CH, NHCH ,CH ,OH
synlhe.~is lind

~~lgJ)'(ual bis(guonylhydrnI'.OIlC ) (nllloguazone) has .lIlIIDOI' !lCli vny in hurn:lns. It interferes with polyamine

-.~

,)1'IIItii~ to block nuc leQr Imd mitochondrial melabol islll. \;!O

am~l

h,
"hflll
,'C III

erum
ml~c

....} of liS octions arc relaled to the fUIK1ions of spermidi nc. ~Iidt IllCSemblcs in structure . Thus. n competes .... il h sper~.fOf the: Inmspon carner and inlr.lCeliular binding site. llko IMinns spenmdme biosynlhesis. lIS amiprolifernth e 5 on ccll~ can be jlfI:vellled by udrnini~lering spenni. . III M:my other bi,(guanylhydntJ.oncs) have Ix~n pre"ml. but nonc: has proved s uperior 10 the melhylglyo)(aJ
tnl'JtJll'.

ID IU-

\coce
,."
Ihal
11..1.,\

NH

CH3

NH

&\lon

H~NCNHN-C-CH=NNHCNH2
M,lQgl"rone
(~ 8Is(~IIlO"oII )J

II

II

NHCH,CH,NHCH ,CH,OH

"'lIh
d~-

H,NCH2CH~CH2NHCH2CH2CH2CH2NH,
Spe!rrodI oe

h,

PUl)Xalllrone IS :111 anthrdpyr.uole Structur:al1y relall~d 10 milountrone in h:l\'mg two phenolIC hydrox)' ls and ;;ide cha ins ~'OOtaining I1l11ino g roups: Ilowevcr. its qu inone ring

is modified to form part of a pyrazole ring with a nitrogen atom on the next ring. J : 1 'The mode of action of piro~antrooe is intcrcalation lind interfercnc.: wi th DNA synthcs i~ by lem plate inhibition. Cardiotoxicity is low ~ause il doe'i IIOt urKlc:rgo redox cycling, '11 Piru_anttU/lC' is pre..;ently in clini cal lrials.

hne been de\'e loped in an cffon to limit side effts. o.e of these se lecti\'e agenl~. beluU'otene, has bttn lIIlf"O."ai lor usc in patients with eut41lCOUs T-ce ll ~mphoma that If Il' fractO!')' in previous syMe rnic thcnapy . }II It is adtninbtl'fftl ornlly in gelatin capsu les,

o
OH
CH,

HICH,I,NH,

TretirlOln

The 3ntipant~itic !.lrug suramin sodi um (Chaptcr 8) has long been used to treat trypanosomalllll!.l filari al infeetioos. II also inhibits re,'ersc tru"~ripWsc in RNA tumor vil\l5t's. Antitumor activi ty was demonstnued m hormornIlly refrnc ti l'e prostate cllrlCt'r'lI> and a!.ll'anced 0\ IInan cnremoma. Sur amin acts by a variety of biological rncc hun isrns. ind uding mhlhiuon of hyaluron idase. urease. hcxokinase. RNA polymena'ie. DNA topo1wmel'llSC II. and ly'iO!iOlTl:ll enlymcs. no II affects ATP ~ynthesis and degradation and inhibitS mitochond rial en/ynll'S, Signal transduction in cells is inhibited by SUnimin bin!.ling to tumor growth facton; and protein k,nases.)JI Summin may al'ioO mhihit anglDgCnesls and induce normal ce llulltt differentiation by increasing tissue glyeO'laminoglyeans. 1U Although :mlitumor acuvlty was found for ga ll iu m nit mle in phase II clinical trial s. m its approved use is for the treatn"K:nt ofcanccrrelale<l hypC':rcakC'mia.. 114 It has pnl\'ed superior to calcitonin and etidronate in thiS uSC'. TIle clin icallTUlteri al is the oonahydl1lte of Ga(NOJh. RC'li noids regu lme ecllulllr growth and induce di fferentiation in a ..-ide variety of pJ'Cn.coplaslic and nooplaslic Ct'-II types. and they induce apopto!i15 in certain cells. TIle actioos of ~it:unin A metabolites and of synthetic n:ti l101ds on reti noid receplOl'll regu lates the ellpres~ loo of speci fic genes. which control many importan t ccll ullll' proteins th:l\ have It pivotal role in Ct'-lis. Funlic:lIl101e. l'eunoids inhibit expres sion of ornithine decarbcnylaSC' and tissue transglutaminase. enzymes highly c~pn."Ssed.n eerui n tl.ll~. Retinoid receptOl'!i are c1as~ ifil'd inlO tWI) subfami!ies: the rctinoic aci d receptors and the retinoid X n:ccptOl1l. which function as ligand-dependent fact~ for gene traPscript>on .'" Each subfamily contalOs Illm: distinct i.'IOfonns. TretillOin (tron,rretinoic acid) is a normal nlC[;,holite of re tinol (vi tllmin A). II cun Induce normal differentiation in a \'ariety of malignant ec lls. especillily acute promyelocytic leukemia cells, and its differentiating effects aJ'e augmcnted by. variety of other agents. Including eytOlO~ic drugs. eytokines, and polar sol\ent ~.J.16 Topical tretinoin producr:s regression of baQlI cell cllrci noma in 1011 palicnts nnd redUC'CS the silJ:of cutaneous leJ;ioos in A IDS-related Kaposi 's

Bexafotene

p--

Sllrgnarnostim (GMCSF. Leuk ine) i ~ a natural hun. prote in produced by reconlbinanl DNA techniques "idt ycllSl or bactenD as the ~ organism. This partially Jlp ~ylated protein coolllins 120 to 127 amino ac ids and !We internal di sulfide bridges. The yeast-dcri\'ed product IS" proved by the FDA to promotc bone marrow recovery II patienls with leukemias or Iymphomas ... ho aJ'e UOOtIl' l( PtJIologous bone m:urow transplantlltion."" Filgmstim al!iO promotes the production ofneutrophil\* cu~ in the bone murrow. This granulocyte coIonyS!n. Ipting factor (G-CSF) is a 175amino acid protein manurl(' tured by rewlnbinalll DNA technology. It is idtntQl. sequence .... ith the natuml protein except for an N'len IllCthionin:e necessary for expression III . roiL It III! glycosylation because of its production in E. C()1i. Photodynamic thcrnpy i~ a t .... o-stnge PI occss in \Illicb.. p;atient is injected willl a poowscnsiuzing agent lind ... after this agcnt has diffused throughout the body. Wcrqi is applicd to the tumors. TIle one D.I1ti ncoplllSlic ~ ti ler IIppmved thus fa.r i~ porfiOlCr sodium (PhUlQfrin 11\.. is a poIyporpltyrin oligomer linked through etha" and t!If bonds. and it forms al!gn-gatcs with I combined nt(414 mass of about 10,000 daltons, When subjected to lastl' it gives !til orunge-red nuorc.':Ccl>\.'e and oxygen to form spccic.~ thul allack DNA cleavage. This ~ is used for palliPlion completely obstruCted esophageal non -smllll cell lung cancer.JoOIl
!

sarcoma,"}
Widespn:oo use of tret inoin and related nalUmJly occur ring n:tinoids is limited by undesiruble si de effects, whi ch probably arise from their activati on of multiple receptors. Recent ly. compounds SC'lective for the retinoid X receplOl'S

Cisplatin. Cisplat in. Platioot NSC- II9875. COOP,;,;', prepared by treati ng potas.~il.lm ehloropl:llinite With. nia ..Kii It is u watersoluble while solid su pplied in ~ials coolllining 10 mg of eisplatin as a lyophil ized ....... ' . For reco(ltitution. 10 ml of sterile .... aleT is added ... . resulti ng solution is diluted in 2 l of 5'k delltro!ie ia 0.33 N saline contllinins 37.5 g of m~nnitol .j4l Cisplaun ha~ a triphasic disappcaruoce cur. e I ith ... ... lives of 20 minutes. 4810 70 minutes. and 24 hours. <"*-

OJ,.

Cha pt~r

12 Alllltlf'('pum..- Aynl.l"

431

""" " r~

s reered

. . filttation and tubular secretion in .he I.:idncy remol-cs of the Ibc. Interaction wilh DNA is the primary mode of c1spl:uin ar;\!llty. Intraslrnoo crt'JlSS-.linu ate produced and caU.'iC dwlgcs in DNA conform:llio" that "ffecl n:jllication:J.u

Cl>pIalin is used in oombination with bleomycin IUld vin\lb$tine for metastatic It!.\licular tulllOf1l. 111;, oombinaliOl1
rq:.rcsents a significant imPfol-cmem o~cr previous treat_ )OJ As a single 19m1 or in rombilW.Jon with oollorubioa.cisplalin is used (or I~ remission of metastatic ovarian , 'U. Other lun10Q thai ha,'c shown scnsi liv;t)' IOcisplatin .c!udc penile cancer. bladder CII/ICCT. cervical cancer. head -'lIfCk cancer. and small cel l canccroflhe lung. 1be major __ limiting tOllClIy is cumulative ",nal insurliciency as,so. o;IIICd with renal lUbular damage. Hydmtin!; paTients with iln.noou$ fluid!, before and during cisplatin tRauncnT re6I:eIi thI:' incidence of renal To.\ici ty significanTly."" MydoliIjlpI"tSSion. nausea and vomi T ing. and otolO.\icity also occur
~Iy.

and it produces peak serum lcnls of 0.3 10 2.0 111M .bout I to 2 hours laler. Approximately 5Q'l, of a dose: i~ degtud.:d tn tho: li>'cr 3nd exCreted as urea and CO:' Acctohydroxalnlc acid iJ; major nw:tabohte in human~. Hydroxyurea is lIC1ive agaInst melanoma. chronk myeJocylk leukemia. and n-.etaslaue oV"Jn:t.n cartcU1OlTla. II is used in combination with tudiOlhempy fur hcad and III.'CI.: cancer. The main toxic ity is booc marrow depressioo ClI~sscd as leulopenia. anemia. and. occaSionally, thrombocytopenia, GaSiroirueSTinal toxicity and dermatological reacllOl1.S al..o
~,

umall with

(jays. once e\'ery 3 weeks tine oourses. MCUlStatic ovarian tunlOI"S lite treated with 50 mslm! illll1lvenously once every 3 weeks . Pretreatment ~ion is recQITllnended for both rt'gimeM. WI

-alm l inTrJ\'('llOIJ sly daily for 5

The usual dosage for metastaTic TesTicular tunKlOi is 20

lyco-

I \WO

CbopJatJ",

11')' in

"i>

lO'"
Ip~

IImuufac-

;al in ni nal
000

-h tile Iht:n light

;enSl-

Carboplalin. I'lmIplatin. CBOCA. JM8 . S5C-24 1240. ci.l"-diommine{ 1.I-eyciobuT anedicarlxixala IlIlp1atinum ( II). is prepared by T reatment of cisPI (NH,hh ... S11>"CI" sulfate fol lo ..-cd by the barium sail of I. I-eydohunedicarbo.\ylic ocid,lo It is aboul 10 tinw:s as soluble ~aIef'" dsplatin, and iTS rate of hydrolysis is much ~Iowt'l" . . tbat of dsploti n. Hydrolysis of the cnrOOuJato bonds )ltlds tnlOsient aquated intermediates that bind tu DNA. c.t.opbun IS supplied in ~ials containing 50. 150. and 450 .. of sterile lyO!)hili7.ed powder plus an equivalent amount ._nitol. TOe vials have a shelf life of3 years. Fur ro:con. .... !hI: drug Typically is diluted with 500 mL of Sodium I.\Ionde for Infusion or D5W, and it is administered by

......

II). It este r
~ IM

light.
wnh .chial

=""

cu lar

Plasma clearance of curbopllttin is bi phasic. wil h up to tYl- ucreted in Tbe urine. There is lillie bound to plasma ~ and no true metabolism, Cartlopial in is approved by the FDA for trt'alment uf all-.:tel (wanan cancer. It is cross resistant .. ith cispl:ll in in rumor. Activity also has been reponed in non -Mllall cell . . c~er. head and IlC(;I.: cancer. and tClltlC"lllar cancer. 1lIr llIUaI dose- liml1i ng toxicity is booc marrow supprese.speci3l1y thrombol.:ytopenia Ncpllmloxk-ity is much I;OIIlrtlOO than with cis.plalin."'" Hydroxyurea. Hydrea. hydroxy prepared from hydroxylamiBC cyanide . Jot ? It is a crystalline . Cap.;u les cootaining 500
~IlS.

l..-AsparJglttaSe HC 3.5.1.1. colaspaso:. L-a~!X(mginasc: umidohydrolasc. NSC109229 { culi). ',..;111/1 asparaginase: (NSC-I06997). (S an cnl.yme isolated commc:n:ially frum . ooli and E. CIIml/J \"Ora. [t has four subunil.S. each with a mulccular "'~ht of 32.000 to 34.000 and one OCh~e ~itc per subunrt. '11le i ~olnle i~ I1QI pure. and the polency varic with The batch. Consequcmly. balch pou:ocies are IlIted in tCllllS of tho: international a~p:tr.lgtOase unil (I U). wInch is the enzyme ac:ti~iTy thBI releases I I.unol of mnmonia from LasparJginc in I nllnu~ unc.k."f" lho: ~t cond'l100~. Lyophilized asparnginasc is provided to 10.<XXlIU viol, also OOIllaining 80 mg of manniTol 1 c(J/i}or 20 mg of de~1TO'iC and 0.6mg of ~ium chloride ( . ram/UIOO,"). It should be: $Ioretl under refrigera tion. Re<:QnstilUtion is with 2 to .5 mL of normal saline: or sterile water. The 1l.'CI)II5IilUll'tJ drug is gi\'en by infu,l1m or by Illlramus cular injection. Allergic reactions can ocrur In up 10 2.5'1> of p<lucms. They ",elude: life-Ihreaten"'g anaphyla(:11C shock, The manufacturer recommends skin tCSling befOl\' adminiStration. Patient s allergIC 10 lhe E. coli preparation may he swllChed to tho: F.,....i"i(J prepar.... llUlI: howc~cr. lhe crossover .... naph)IOCIOld rate IS about 25'1> In chIldren. 1.Asparaginase cooJugated WIth polycthylene glycol (PEGAsparaginase) cxhibits minimal immunogcnicity. although gastrointestinal toxicily may he greatu. AsparJgtnase has very poor extruvII...cu lar tissue pencttution "00 is slowly and unpredictably eleamJ from plasma. Elimina\lon is biphasic, WIth a.n initial half-life of 4109 hours and a Icmlinal halflife of 1.4 to 1.11 day~ .J-'<l ASpMlIgine is required for !hi: biosynthesis of proteins. Although nonnal cel1~ can symhe~lu aspumgine. tumors 5UCh as ALL laclthis ability lind depend 01\ l.'..Iogenouscom pound. Admimstmtion of aspatugin:N~ reduces !hi: concenImtion of aspar~gine in pll1.~tna. lnu.ting it unavailable to tho: leul.:emia cells."1 Ao;paraginasc: (s used In combinallon chemutherapy to indUl"( remiuioos in ALL. lind PEGI1.~par aginc has s/Mw.n act;"lty in I1On-li odgkin's lymphoma. In addItion to hyperstnsHl vlly. Silk dfecu include gaslroill\l.'III;nal damage. hepatic toxicity. and pancreatitis. Pe-gaspargase, I'egasp<lrgase. l'EG-L-lISpar.l8inase. ila modified verMOO of lit cnzyme L-asp<lmginaSl.'. It is a 00\111Icnl conjugate with units of monumethoxyprupylene glycol (PEG) with molecular mas.~ o f lppro.\irnalt'ly 5.000 001. tOIlS. Pcga~p<lrgase is supplied Will phosphate-buffered sa li ne SOlUTion conT .... ining 7.50 lUfmL The usua l dosage is 2.500 IUfm~, prefel1lbly by 1M injealOll. Generally. it IS used in

Asparagi nase. I. ASP. 1.ll!;nusc:.

' I'. is
n~

mbo'
... dcr.

d ,'" I.S or
half
Ilnct
Kl~lyurea

hydro.\yurea inhibi ts rt'!iults in decreased levels

is well absorbed afler or.u adminisUlltion.

combination With ()tht,r clicmotherapeutic agents in ALL pa. tlents who are hypcrseosithe 10 t asparJgina..e . TOllic ef fectS include allergic IUCllon~ such as bronchospasm and IUlaphyl:uis. Dcple!ion of serum proIeins and antlOO:tgulanlli also occurs. Altretamine. Ahmami lM!. HClIaJen. ho:urnethylme la mine. NSC- 13875. N.1'1.1'1',N'.1'1".1'1" -hellan-.eth)'I -I.J.5-ui :tZlllc-2.4.6-triamine. is preparOO from dimcthylaminc and cyanuric chloridc7t> and formulated as 5O-mg hard gelati n capsules that ulso cl)nt ain laclClSC and ca lcium Mearale. l1tey shoo ld be , tOf'e(I ut room lemperature in II lightly sea led holtle contlllll lllg a desiccant. Administl1ltlOO is ooally. and lhere u ron.ldernble vanalIOn in the bi03v:ulabi lity and phannacokinctlc,. It i~ rapidly metabolized hy N-dcmcthylallon through hepatic microsomes. The main metabolite, ioclutk pelllmnethy lrnclaminc and tetrumC1hylmcl:unine. A po!>.~ible mode of /lCtion involvc:s hydro~ )'1;11100 of a melh)'1 group to the l'Qfrespondi ng hydro~ymeth}1 denVllti,c. a carblllolaminc that can lose hyd",~idc ioo to form an imlTloniulll ion capable: o f cittK-r a1k)'Iation or hydro lysis to the n1()llol11<.:thY]lImillC.n TIlC FDA hilS uppnm:d altn::tnmine as II si ngle: agen l for treatmem of n:.~IMant ovarian callCe:r.71 It abo is IIct;"e in combination rellln-.ens agalll~t Ihis tumor, Ga.,lroinleslinal to~iclty. manl felited as :mon:'"ia. nausea. and ' omlhng. is dose lim iting. Neunxo"icity necuT'<. but it i~ u~ually rever..ible.

[lression. which usua lly ;nvol~e., leukopenia. Other to~ic d fects include nausea and vomi li ng. Cardiac 10xicu) c.occur ... ith loog-term adm[lUMralion of high dotIc:s of I1lItoI.. an tronc.

Gallium Nitrale. Gallium nitmte. Gan;te. NSC]S200. is prepared by the reaction of gallium metal wilh nitne Kid. The clinical material is suppl ied as .500 m8 of the ~ dral~ Ga(NO ,h9 H:P in a 2O-m L singJc:-dQo;c: nip-top ,111. Alw I"escnt is 28.75 mg of sodium citr.ttc dlh ydr.u~.-J sodi um hydrox ide for pi' ndju~lInent to 6.0 to 7.0. The d.ui, dose is diluted in ].000 tILL of 0.9% Sodium C hloride InJtC. tlon. USP. or j% Ix_mosc Injection. US I'. for intrn,CIft\ infusion. Ga lli um IlItr,UC is 3ppnYoet\ for trealmg cllJloCef-relaled It1' pcn:a]cemia. \J.I It sho ........ d IIntl lu mor activity for paue,,", ",ilh lymphoma in [lhn..e II trial~. 'U Galli um nitrate prob:tbI} ",orks in hyperealcemia by inhibiting calcium resorptP from booc. although the pn:cl>e rnecil:an NI1 is unk_. Major side effects include hypocalcemia and ncphrotol~ On continuous II1fusioo. the drug uhiblls tHphasic cli_ tion with an (l" half-life: of 8.3 to 26 minutes and a fJhiJlife of 6.3 1 96 hours. I)ct ....c:cn 69 and 91 % of the !be 0 was rc.'Co .. ~red in the urillC."'" Aflenic Trioxide. ANCnic lrioxido!. Tnseno".~_ acid anhydritk. As 1 0 J i5 supplied in solutions cont:unllll' mgfmL for injl,."Clion. It is ~'orcd at 2.5"C and reconslltll!d hy dilution with 100 to 250 mL of S% [lemosc ror InJCCID ot 0.9% S<xhum Chloride: for Injection. Administrat._ by intr.tvcnous mjection o,er 2 hours. The: u5ual dose isOlj mgfkg perday until bone marmw remi5sioo occurs. \tiltH. tOl a] number of tklSe.~ limited to 60. Arsenic trioxide: is indicated for patients with acute JIV" mydocytic leukem ia challlCteriud by tflln~locatioo of PJIlj RAR-OI gellC expression ... ho ha,1' relapsed a(tcrretillOHl DllIhraC}ch nc therapy. Ad,'crsc reactioos inc lude leukOC)1l SIS. nausea and vomiting. fatigue. edema. hypogl)~' dy~pnca. CQIlgh. ra~hes, headaches. and di a.ines.~. They", all y do not pre"ent conti nuation of thera[lY .
Bexarolene. The retinoid class drug bclll{{l!e~. T. gre tin gel. LOG 10069. 4-fl -(5.6.7.8-tetrallyd~3~~ll penl:1II1ethyl-2_napluhenyl)prupy llbcn7.oic acid. is in 7S-mg sofl gelatin capsule'. It is slorL'd ill 2 to u~1I1 dose: i~ 30 mglm 1 peT day as 3 ~,"gle ora] ~ with a lnC'aJ. Be'(aroIinc i~ indicated for cutaneous T-cell Iyrnphc& in patient~ refraclOl')' to prior systemic thcr.tpy. After adrninistrmion. it is absorbed wi th 3 T mo, of 2 houn.. ~ 99% bound to pla~ma proteins. ~rid the tem\i rmlllaJf.jif~ appro"imalely 7 OOuffl. 1bc metabolites ,"\"ol~e: at JXbitlons 6 and 7. Ad,'CfliC reactions ineludc ell:,"3lm lesterol and tn.@ l y~rides, headaches. nausta. rosh. and. kopenia.J'l

Mitoxantrone Hydrochloride. Milo~antronc hydrochlonde. Novantrone. D HA D. NSC-30I7J9.1-4-dih)dro"y5.8-bisI12 -1(2 -hydrox yC1hy I).lm ino ~thy Ilammo 1-9.lI)..ant hra cc!1l:dione dihydroch loride. I) HAQ (free b:ISC), is prepared from 2.J..dihydroxyquiMl.arinc by treatment with 2-(2ammo-ethyl-amino)cthanol followed by chlOOl/liJ o~ida hon .\1~ It is supplied in vialsCOIllaining 10. J2.j, ot Ij m L of II 2 mgfmL stenle solution that is smblc fot }cars III roOI11 lempcr.tlure. Sodium chloride. MXIium acetO le:. 311d acetic llcid are present a.~ inactive ingredients. TIlCse prepamtion~ aredilulcd with at least 50 ml. of Sodium Chloride for Injec11011 or 5'1> (k"tfOSC fot Injuon and adnllnistered :is an infu<;K)n. Mitoxantrone i~ bound up tl) 78% to plasma protei ns. lbe .o;enmt COllCentrallon-lilnC' [lrolile Is lit hy II three-comp.1n ment modcllhm has an o-pltase hal f-life 0( 2.4 to 15 minules. ~ing 10 distribution into formed blood elernenlS; II ,tJ.phasc ha lf llfe of 17 minuteli to J hours. com:sponding to rahstribullOO mto blood and vanous \Issues: and II ,...phasc half-life of 2.9 10 hours. I'"' Hi llhest COII(."cn lrJtions of the drug arc found in the li ver. pancreas. thyroid. S[l lccn. hem1. and boflC marrow. Large: amounts of drug may be retained in lhese organs for prolongcd pcnods. The mode of III;"l1on of mllm.antrone ;n\"OI,es mtercalal>on lind Inh ibilinn of topoisomerase II . ')0 In conttmllO doxorubicm. it does not undo!rgo redox cycling to foml oxygen free rndicals. bceau..e i l~ redox potentia] is out~ide the rOOU/.1;'e capability of n1llll1lnalian rcdul1ascs. Mito\llJltrone is appro'cd fOf remission-induction therapy in acutc nonlympllocytk Icukcmlli. whct-c II Iypll."ally is used ... ilh c)UU1tbinc. '" II alw is active against other kukemia.~. breast cancer. and ovnriun cancer. The dose-Jimi ting toxic effect is myelosu[l-

Sa'9"'fflOstim. Sargr,IIIlO!otim. Leu]","!: (yeast.dm Immunex ). Prolanc ( lIocchst-RooSliCI), Leuconw ( tI derhed. Scheri n.@). gmnulocytl'--llIDCrophage colon) Iming factor (GM-CSF). " produced by !11<.:thods using as host organisms StICchar l)ml'cts Ctf(\1

,-.

d Y

" -

, ,

,-

1-

[-

<

f:" t'fIli. It conl:uns 120 CO 127 amino acids, and '-: Intlaf}' l>IruclUrc i\ mamtained by two di,utftdc: bndge.., ho lII'gimne sItes Ute >;Iriabty Ill}cosyhltcd in the y~~st. oierww prqmrouon. L.cukinc dlffen frum native 5l1rgrurnos.by rubstnuuon oflcuc1nealpo"lIIon 23 and byadlfferent ..tIoIl) .Inlle maleup II h.as a 'pecilic OCUII;I)' of about 5 lOT Vlmi of protein. l..cukine is available commercially al}ophllized povo'der in 25(). and SIX)."'I!: amoum~. It is ICroII>IltUIW luth 1.0 mL of SIt'flle Wale!" for In,e:lIon. lSP, to yield II clear i~olOnic Mllullon m pH 7.4. Funhcr ~ions In Q,en- ~hul11 chlondc should mcludc O.I'if: \ I ofll\unan serum albumin to reduce :ldsorption to thl:: wrf;JCc. Vials should be di~arded wuhin (I hOUN of rrron.tilulion because there is "0 Ptllib;ictcria1 prc~""':lIhe. !1Ie also i~ $upplicd HI 250- :lIId 300-,ui l;al5 and is _"!luted lilt Leukmc. l.cuoom:u. is aVHllable for m\c~' -..iooal use fmm the Schering CorpomliOl1, M OSt ~~ of ",:"",;m are adnunblen:d by in fusion. although n IS ..1I.e by lhe subcut:meoo rouiC Sargllln)().lIm IS u~'d Iu prorl1()le bone m~rrow !"COO"!!!), .prMI("l'> urKkrguing aUlOlogou~ bone marrow lransplanla"' II aJso redUttS lhe J;e1'Cnly and dural.1OI1 of neutrofollo",lnll ~ulld:1fl1 chemolherapy "Ith mydol<uppresIII: lIl!ems. Ille mode of action of sarglllmoslim I~ an -.:rK1i0ll WIth high_affinity ~Il reccptOQl on neutrophiL... tr;m<;ducllon may 1lI'ohe oouplinlllO a G pmleln.'l8 ~IInenl with ~urgronIOSl im . trn,re i~ a bipha~ic inin circulallng leukocytes. includilljl all inl1ial iocrcru.c 4105 and a <;C("()nd Increase olcr the 1 toxicities are pencarditis. ,enou< thrombol.es. Othcr side clfcets a nu-IIke syndrome and bone pain. The laller is IIWI.... th IlOII5teroidal anti-innammatory agenb.
Filgr:lllllrn. Neupogen. lIrunu locyte-CSF TIus oornpouoo IS manufactured by ra:ombilUlnt u~llIg E. LVIii a.< the hO\1 organiMn. It l'()main~ ident ical with tilllM! on the nalurol proIcin for an N-temlinaJ rnc:thiOl1lne f1CC('.)5.I!)' for ujlf"Csfa coli. is <upplicd ill single-use ~i:ll~. elKh 1. ._ of Iilgrustim al a <pc:clfic activily of It IS formulaled in 10 mM sodium 50 111& (If manmtol. . m!.. Water for InjcrtiOl1. Thi. lnonth, at Jli lo 46F. The recom5 Ilslkg PCI' day. OOllllm<lered subcut:mci< IIIdicaled to dl"Cre:<.'Ie the incidence of in fcr oonm)dOld m:thgll:lflCie< receiving my~ticanccr drugs associated with a sigmficam seven: ncutropenia wi th fe' cr. A complete roUIil and platelet COUnt should be o/:l(airw..'d poor to aOld twice'" ('('t ly dllnng theru py ..... ith fitgrasob!;erv\.'d atJvcn;e reactioo to fit -

~"-\l) Of

Porlimer Sodium. I'orfill"loef O(hum. Photofnn 11. " a hght'lenslti.,.e poIyporphynn oIipmlCr linked by ether and ester groups. II is I purified product from hematoporphyrin deriYlllhcs. and it exi<;tS as IIggreg3tc~ WI th combined 1Tl\":Ike. ular mas;;es of appro~Imatcl)' 10.000.\.00 The drullls supplied as 75 mg of a freeze-dried cn"e or powlkr for mja1ion in vials. ElIch vial is recOll~tilUted wtth 3 1.8 m!.. of either 5'Ndexlrose or 0.9'J. Sodium Chloride for Injrctlon . The usual dose is 2 mslkg by slow injCCIlOllo'cr3 to 5 minutcs. Illumi nation by laser light i< provided 40 to 50 hour,; laler. Photodynamic thcr JPy u~ing porfimer sodium is mdicated ror palhlltioo of s)"mptOlll.~ m palLcnUl with compLetely or jllInially obstructing ~hagcal can~'Cr or microinvu., i\e small cell lung CIIIlCC'r. Ad~cl"l><' reaction~ illCludc ocular sensitivily. ehe~t jllIin. and I\'~pir:uory dl.'il.ress.

HORMONES
Steroid horrnolle~. including cstrogellS. androgens. proges tillS. and gIUl.'OCQI1icoid~. act onlhe appropruue targetllSMICS al lhe Je\ cI of tronscriptioo . Gcnernlly. the effect ;!i dcrepre.'l~ion uf genetic tcmplme 0pl:rnllol1. which stimulmllS the ce llular pnlCC'SS. Glucoc()l"1iCQid~. lIo",e,",r. act on lymphatic ti)slIes to il1ljlllir glucose uptale and prote,n ~)'nthc~". Tar~ get cells contain in their CYloplasm 'pec ific protein rccc:pt~ with ~el') high offinities for the hormones. Binding of the hormonr 10 the ~ptor trnnsfonns the receptor stnlClure. folJov.ed hy migrot ion of lhe resullmg oompleK IIItO the: nucleus. [n the nuc1e".~. the comp1e~ "IIer-JCts with un IICccptor sitc to IIInueoce unnSCription.Nom\31 and ", ... Il--differenualcd ncoplaSh C target ~lIs hhc ~ number of hormone rece~~. and they depend OIl the hormones for slImulatioo. 1<>1L.ess differenuated neoplastic ~Jls beCQII~ independent of hormonal CQIItrol and lose their <jlC("iflC receptors. Thus. some rrooplasms are hor1110llC dependent nnd rc~ponSl\e to honnonebased thempy. "hercas otheT!; are Independcl1t and unresponsivc. Assays of the number of hormone receptors pr!:loC"nt In the neoplastic cells ~hou ld be wluable in predicting the probabillly of a f~vomble respon<;e. HOIlIl()Ila! effects III bRa.,t CatlCft" are oompkx and not complete ly understood. 11lt honnonc deperKkncy of breast canccr h;t, been lnown si nce 1889.""'" ~lId removal of the o,'arie~ of prenICIl0p3usa[ wOllM.'n. "hich decn:3loCS estrogen kl .... s.s an e..<lablished treatment . Some patients ",110 do not respond to thi~ procedure do respont.lto odrenalcclomy. whiCh ~uggestS that the h(lm1l)llC dependence is not simply rel:l1ed to estrogen~.- Remission after at.I.rcnalectomy IIC' curs more often 111 pallcms wllh estrogen receptors than III tOOse lacking receptOr'S. Admi nistrution of C!otroge ns to po-;.tmenopausal women with nlClUSlul;C breast CIUlL'CT resulted in objech\C remis~IOIls in about)O'i; of cases .....1 This response appears purat.lo~lClLl. but the: estrogen levels resulting from drug treaU1ICnI are much grealer thall phY5ioiogicai lev~ls. It has been suggested that hIgh cstrogen levcls interfCtt '" IIh lhe: penphcrn[ 3I:lIon or prolactin. II pituitary hormone thnt ~lso Mim u[atcs Im!lIst t i'~ue :16I Eth inyl ~trut.liol is given orally in 1he treatment of breast C:UV:(T in posllTll'lIOplIusul "'omen. and estTlltlloi d;p)pI()lI;llC or benlOOte is used parenlcrolly. Tamo~lfen IS an anueslrogen that has been used ~\IC-

c1ca1"1lll of

follow first-onlcr

the .... rom concenlnltion and 1In.'~ under cur.,.cs. The c:iimlnation half-hfc is

m the treauncnl of I'O"tlllenopau~1 ..... omen. It has very low tox ici ty.WI TorelllifclIC. 1 ana logue of tumoxi fcn m differing only in the prescoce of a chlorllle substituent on the ethyl croup. h:L~ been tntroduced =ntly. It is similar to IanlOxtfm III plmrmacologtcal properties.
A

tt.~sfu ll y

OPO,)',
H,C

/~.--\ H ..
H

Androgens arc acthe aganm metastatic breast callCCT In about of postmenopausal \Ooomen. Their mode of acuoo is not compktely understood. Inh.bltion of the ",lea. of ..... pitu nlll")' JOItadotrophill~ h.1S been SUggCSled. bullhe situation must be Illore eomphc3led than this becau.'\C cen ai n androgcn~ are active in hypophyscctomi1-Cd p;.IticnlS/ltl Other u.;c ful effeclS of undrot:ens in advuncctJ breast caocer arc stimulation of the hematopoietic Sy'itCTn anti 1"C,cN.:lI of bone demmeralizatioll. Testosterone propionate IS the androgen most fret.jllCntly u.~ as:dnst breast eaJ"lC('r. Other compou ntls an: 2a-methylteslC}';tcronc. f1uoxyme~lcrune. and 19nor_17o- methyltcMoslt!rone. Tcstolactone is pre fem:d in some eases because il has no androgenic side effcct).

m-

Three anude dcmat"cs of trinuoromcthylaniltM hilt been approved for lISC in combination ther~py of ~ caocer. ll"tey are nutmnide. ni lulU lllide. and bicalutamtdr A ll of them h3'e 1111 elcctroo-..... ithdrowing group wch. nitro or cyano at the 4 po!'lIion. Sub:!;lIluents on the ani_ nItrogen "ary from llo<.Ibutyl in nutamide. to dimeth)lh'" toin III nilutamidc. to a comple. functionality COlII'I I nuorophen} lsulfonyl III bicalutamide . The.'iC compwtD bind to cytosolic lIndrogen rcceptOl"ll and block the dT<CI of teMO'olcronc und other androgc ns. n Their good uoraI. sorptlOO' makes Ihcm dcslfllblc lheropelltie agents.. II ..... tamide is claimed to be selective for penphcral wop rettptors. u,
A

CH,

~O

H,C H

H
e ....

"'"
Taat:I,,,,. be used 10 induce n:missions of di,semi. nated prostatic caocer. It is IKlI t-cnain whether their effect is due lodl~ interference with periphcnal androgens. inhibit ion of Plluilary JOIllIdoIropItin . or both.m l>idhylst ilbt.s\lu l lS Ihccompountl InOSt .... idcly used foratlVllnced prmtatlC cancer. and II bendi ts more th:m 60'1> of p;ltiems. Chlorotri3 nisene alo;o is used. EstrJt1lUstlllC pho~phate ..... IL.~ designed 10 carry the Ililrog.:n nluslard grou p select,,ely into cells wi th CSlrogL'fI receptors; howe"er. it dClCll not aJ kylme thcm.Jn It appears 10 act as an ant iandrogen. and it promot:es mlCflllubulc disassembly . l1le main theropellhC use IS In prostate carcinoma.)l)
E..~troGen~ e~n

,_R _ HC

I
OH

ProgCSlcro1lC and it~ lInalogues :Ire octhe against ttflll neoplasms lhl11 are stimu lated by estrogens. They e~t!r1 antiestrogenic effects of Unccrtlun mcch:lniSIQ. neoplasms treated by rrogesti n~ an: nlCllStatlC ~""_ carcinoma and alll-allCed n:nal cell earcinoma..l1C> one su)petlsions in oil. nICgestrol acetate. anti pt"olle~lerone ;}ecWte un: used against endomet rial l 1tcy provide regressions of sc.,eml lIIomhs to 3 )'eII\:;,~ about JO% of "'0I1ICn.17<l McdroA)prugesterone eauses regression of renal cell c:trCinolllll In less thatt I of men and wornen.

G1ococortlcoids caU!iC pronounced lleute challio in

Lymphocytes in the Ihynlu' and lymph are db.oh-ed. and lymphopenia ocrlllS in pcTiphcral Wood. Jn In l)mphocylK: tissues. ,lucocOl1iooids promoIl: iplpII)'Il, by. I'C(cplor-rnedialed IICti\c process thai. induces
CIIdonucltolyllc cleavage of DNA. This propel1y is used 10 lih'Jlltasc In the U'I::llmem of leukemill and Hodgkin's di.\eM, In

~~d II~.

"hleh profound icmpornry I"CIlrt:SSIOIiS are observed

fIlIlowlO~

the admini~lrnliQn of corti!lOllc derivatives or o\CTH.1 i'redni solle is the corticoid u.u;llI), cltoscn for Ihis ~. IIlld it is all1lOSl always used III combirnll ion with

bi:'r

agents. such lIS ~hlorelhamiroe. ,-.:nSlUlC, and prucarba7;ne. Such oombinluions are c(feeLDmamlaming lhc
remission~

chcmother~peutic

in ITIlInycascs. Glucooorti-

, &

,...
"

line b, ling

""*

ttc-

alu-

...

prOOuction of androgens.. l79 i"rronisonc and cortisone lin' u~ in t/lt treatment of melaSUllic breast cancer. 'lklf .'~Iue In thi~ condition deri~es nOl from an IIntineoplasIE effect but In al1e~ lating specific com pIk at ions. such as ~pcrcalct!lIlia nnd ane111ia. MllOlanc i) unique ~mong antitumo r agcllts in ils highly wltl"e effect on one gland. the adrenal t"OfIe~. II has a cyloto~ic :lCtion 011 adrenal conical cells. in whkh it ~ the mitOt"hondria extensi\el y. loSl This l'rrect Il'ads ."tll death and IItrop/1y of the gland. Mltotane is used ~rK'lllly agalllst adrenocortical camnom&..MI!

abo are useful in !reaung metaStatic prostall: cancer "~nl~ "'00 ha\c relapsed after castr.uion. The ratIOnale du, usc i~ Ihal they inhibit rt lca!iC of ACTlI from the: fIIIIWY. v.hich lead!.loadrelllll auophy and decreased :Jd~-

An imc:rc:!iTinl new approach to treating hormone-dcpendent bfusl cancer is to selecth'ely decrease the biosynthesis of estrogens. This effect is produced by inhibiting the en zyme aromat8SC: ..... hich col'llrols the con~ersion of IeSIIlISTerone: and androstenedione: into estradiol (see Chapter 23). A ~ariety of chemical Slructul't:S inhibit this en7.yme. The ui117.ole deri~a\i~e anaslrowle was the fil"$\ arumatase: inhibitor rclea>cd in the United States. 3M More recently, the 6-methylene deri~ati~e of androstenedionc:. ('Xcmestane. has been approved . Exelllestane is an irre",cl"$ible inhibitor of 3l'01natuse. It acts as a falloC substrate and is processed as un intermediate thal bioos 10 the active site of this elUyme ..MII> Both 1lllM11'lIzole and exemC.lihlll<! life used in patients in WhollltanlOxlfen is no longer effective, Very recently. the uiazole Ietr01J')1e "''lIS claimed to be the fil"Sl and only aromatasc: inhibitor to show superionly o,'er lllmOltifen in clinical uials..lf1

e N ;~
NO

eN

0rH-Q-CI
CHCI2
M,IOI_

C1

AoothC'f way In Ii lIlit the prolifer.ltion of OOrrlM.m e-depcniI!IIl~moo IS to inhibit the release of gonadotropins from 6r lIIII:1ior pituitary gland. This relell<;C i~ controlkd by .aOOtrop1n-releasing hormone (UI-IUI). a nonapeptide. . , f can be blocked errecti\"C'ly by continuous adminiSlI'lltlcmain IInlllogues of thl~ hormone. Lll RH has tile ~~ Kid ~UC:llCe 5-oxol'ro-HI'"Trp-Ser-Tyr-Lys-Lcul'fo.GluNH1. SYllthetic anaJog~ ..... ith a ()-amlllO lKid IplIdIOII6 uhibit reduttd degrad.auon lind locre:lSC'd dul'llThey produce a transient surge In LH and follicle-stlmhormone (I-"SH). follov.ed by II sustained ~asc, results In marl.edly reduttd te!.toMerone alld es.lrogen

-....

tna in

-ar 10

11< letrial

bl~

ItJl)'

.'"

Irll;cr,

:et..k' 10'>

LtuproIlde is a nonapc:ptide thaT is identical in SlruclU~ _lib LH-R l I. ex~'Cpt that ()-Ieucine rcphl....es the natur~1 gly.Ihe SiX!!1 amino acid. and the termil1llJ glyci[}C rc~idue a!tJUccd by an ethyl substitucn1. It is used for palliation iJlllilUtic cancer. Triptorulen diffel"$ from LlI -RH in that 6r ,-,IYClne ruldue is replaced by l>-uyptophan ..MIl It is :";';';clas t/lt parnoate salt, ... hich pro ... ide) a depot form ...-ut duration ... ben gJ"C'n OI'1IlIy. Go<;crclin aceT ate ,11-'it01"IC' re,iduc: sub';ti tuted with. l-but)'1 group replactile ..&Iycine I"CSldue, and a sc-mocarba"f.lde group instead "r.""t.~ II 15 IISCd for pallialion of prostatic clII'I:inoma, Iorfflbnetriosis. adl':lllCed breast cancer. and endome-

A thoo'ouJ:h diSCUSSIon of !he struclUres. nomenc lature. propcnies. and dose fOfm~ of the steroid homlOnes is pre<enied in Chapter. 23. Only the products nOl incl uded in delllli In that ch:lplt:T are desc.,bed below.

Products
M ltotane, USP.

MIIOIane, Ly\Odml. o.p'- DDD. C8 -

313. 1.I-dichloro-2-(o-c hlorophenyl}-2-(I'-chloroplw:nyl) ethane. is obluined a' a conSIIIUCnl of commercia l ODD, "hlCh I~ prepared from 2.2-dichloro-l-{o-chlorophenyl) ethanol. chlorobenzel\ol", and sulfurIC ocod. 1II 15013110n from commerciul DOD gives milOtalle crystah Ihu t are wlubl e in alcohol and other organic o;oI\'ents. - Scored 500-rng tablets

by a l11ulustep s}ntlw:SIS from 17a-hydro\y prr~ lone. 1'01 II IS ~uppl ied a~ light blue \COred lab leiS contlJll1III 20 or 40 mg of megeslroJ acelutc. Megesuol acetale is IOOiculed for the pallial1"e tn'atmal of IIh:anced mast or endornetJ1aJ am::illOOlOI ",11m method~ of lrea lmenl are In npproprmte. No scriou~ sided fccls or at!"er;e reactions ha"e beell reported. There is., hott.tver, an IIlcn:a>Cd risk of bini! defccts in children ..... mother.; take lhe: drug during the fir.;t 4 momh~ ofpreglWlC) In high doses. 11 can cnuSt: weight gain without illdlll:", fluid accumulalion. 11w: u~ual doses are 160 mglday In fOIl" equal doses for br\'asl cancer and 40 1 320 mglday In 60 I"ided doses (Of endometrial cancer.

are supplied.
Ahoul 40% of a ~ingle 0I"ll1 dose of mitotane is abwrbed . Only 10 1 25% IS excrtu:d in urine as an unidenlifioo nlClab0 olile. and 6O'J. L\ excrel~-d uochanged in MOSl of the remainder i~ 51 00:-d III fally t is.~u.."S of the body. Mi lOiane i~ indicated 1IIIIy for treating mopc:l1Iblc adrenal conical carcHloma. Frcqucmly llCCurrinjl sideeffccts include gllSlrnmteslinal dl5lurbances. CNS depres~lon. and sltn to~ idly. The usual regimen is g to 10 g dai ly. divided inlo three Of four doses.

reus.

Oromostanolone Propiona t., USP. The senlls)'nthetic androgen drorilOSlanolooc proplOnale. Dmlban. 17~ hydro~ y -20 - me: IhY-5a-aOOrO)tlil1- 3-one l>rupionate, 2a1
propiullatc. i.~ prepared from dih}'drolC5IOS1Crone ill D route inlul ~ing condcnSlluon .... ith ethyl forro.ale fol1o"'cd by hydro~nal ioo to gil'e the 2amethyl deri"3I1ve uOO then reacl ion with propionic ullhydridc:J'} ThecompoUiod is supp lied in rubber-stoppered vials l'OOlainmg SOO mg dromoslanolone propionate In 10 mL of sesame oil. wilh O.5<;i, phenol as a pn:senative. l)romost:molorn: propionate is used in Ihe pallimi"e treatmenl of mt'taSlalic brea.\t carciTllJlTla In posullenopausal womCII . II I, contrainthcated In prelTlCT1Op3usal womell and in carcinoma of the Illale brc:a~l. The nlOl>l conlmon side cffea is 'irilism. although this is less inlense lhan Ihal affordl:d by lestostcmne propio nale_ Edema occurs llCC:t:Slon ally.
nw:thyldih~drowilosteror""

or

Tam(lxifell C itratc, Noh'lldtl.Ill2-[4 -( 1. 2 -di phcn)' 1- 1_btl Ie n y I)pilellox YJ- N,N-dunelh), lett. amine cilrate. is pn:p;ln:d by treating 2-eth)'ldcox}ta. 1.(1.n wnh 4_[(2-N,N-dimelhylam iroo)ethoXYlphen~1mapr si um bromide.19) followed by dehydration aOO scparauoalll the E. and Z isomel'$.JII-O The cit nue salt of the Z i!OOOltl B sol uble in walCf. Tablcls conl.aining 15_2 mg of tamouu. cilmtc, ... hich 1< cquivalcnl to 10 mg of tanM).'(Ifen. an: ~ plk d. They shou ld be prtllCCled from hea t and light. M O)t of a d<be of uullOxlfen is excreted III bile a:s COllI'" gales of meUlbohtes. N-Dcmethyltamoxifcn I~ the rn~ metabolite. and ilj long-tenn levels c~cccd lOOsc ofwno .... fen. It is t~~IIO account for a large ponlOII of lhe iIIIII!Imor actIVity. Tamoxifen is a IlOIlSleroidal agent that has ~1JO.,.n poiI:I antiestrogenic propenie< in animals. In the 1111 mcxkl. rt .. pe1ll"i to exen its antit umor effects by bi nding 10 estrop reccpton;. JWI 11l1s blOOing cause, D conformaliom! o:t,.. Ihal decrease., DNA tnm!oCription. II is cell cycle 'JICCIfl for the mid-G 1 phase. Tamo~ifen i~ u.;cful in the palh;Wlt lreatment oo\aoced hn:asl cancer in posl~ ",omen. There are no knowII cootrnindical ioni. n.: frequent side cffC(!ts are hOI nashes. nausea. aOO l'omJtq They are rarely loCI'ere ellOUgh to require du.;c redllC1ion. Tbr usual dose is one or IWO IO-mg l.ablets twie\' daily.

Tamo~ife(l

Citra te.

or

Tonmlfene Citr.tte.

T on:rnifene ci\J1lte. F'~".

Test o/adone, USP. Te<ito l3Clonc-. Tesl3C. I)-homo17 o'ou -androslaI.4-dlcn-3.l7-dI0flC. l-dehydrolc\toloclone. is prepared by microbial tmnsfon1l31ion of p..oge~ ter_ OI'IC.J'J' 11 is soluble in akohol and 51ighlly <;ulublc m .... alet. The compouOO IS supplied as a \tcrile aqueous suspension provi ding 100 mglm L of tes!olOCIOne in rnuiliple-dose vials

of 5 rnl~ T.mleIS l'Of1111ining 50 mg or 250 mg of tc\tol:W:lont:

al..o are supPlied. Te.~loI3Ctone is u>Cd in the palliative lI'Calment of ad yanced or d isscminuted breast canc:er in poslmenop;iuSilI ,,omen. It is COIIU"auodicated 111 breast eancer in men . T CStoIlICIont: is devoid of androgenic act;I-;ty m the commonly used do<cs .

( F;)-1.2-di pheny l- I - 14-( 2-dlmelhylam i noetho~y )p/ICI)f' 4-ch lorobulene. is (IT't'pared by fnlCtional crysta lhUUOl the hydrochloritle .\.lI lts of the mix tu re of gc:omelricJl mel'S. Ii i~ supplied as 6O-mg (ablets IlIso conl:1inlllg ~ The' usual dose IS 60 mg once cbi ly ul1ti l d ise.uc piopca renews. 11w: drog is we ll absorbed O11l 11 y and 99J'It 10 serum proIelns. Pla.\m:l concen\J1ltions peak "'11biit hours and lhen folleN' lInear pharm:ICokinr:tlcs. wilh I cIatance nne of 5 Uhour. The volu me o f di~tri bulion IS 311lL The drug is exlensi"e ly metaboii7.ed by N-delnelh) Ialim T on:mlfene c llnne is IndlCaled for metaslalic brust".:~ in posmw:nopau~l women with estrogen-receptor 10' or e~trogen-rcceptor- unknown tumors. Complelt bko. COUllts. calcium level~. and liver function lem should It doric !:lefOR: ih admin istr.l.lJon. Side crfts mdude h)~. cemia. hOI flashe~. s .... eating. nausea. aOO ~agln31 di

Megestrol Ace tate.

M e~~trol acetate. M egace.

l7i1'-

Flu/amide.

1-1ulaltllOc:. Sch-\J52 1. Dro&eml.

acelo~y-6-rnel hyl-pre8na-4.6-dien_ 3.20-dione.

is prep;.Tl!d

Eunex. H udn011l. Flugen:1. Seb.1tro l. 2- nW:lhy l"",[ ;,;.;

('lllm('nt :n OIher SIde ('fho .... inaitCy. ndueing I In four Iy m di-

..Ic~.

i,.

(Z).

".

"Icthal!Olybc n lmllgnc romon of ,ofne:r I~ motife: n are sup-

}.itnn_methyl)phenyl lpropanamioo. is prepared from ).tnfluoromethyl-4-niT roon il inc aoo isobul)'l')1 chlorido!' ..I'JI! k is supplied ps 125-mg cap:iu les that are stable for 5 ye:ars .lIr:a StOred at or below 3O"C, Admi nistrolion i~ mi . Fluwmde is CJuensively and rapidly me:tabolil.cd. One: . . aflc:r dosin,. only 2.5% of the tIrog in plasma i5 undllng-c-d. The: major mc:tabolite: In plasma is a-hydroxynut-i<Ic; ho .... c.'e:r. the major me:taholite found in urine: is 2.noo-Snitr0-4-(ui nuoromcthyl)phc:nol. which re.~ul ts (rom dea"age: of the side chain. FI\ltamide !lets as an androge: n receptor an tagonist. InhibitIII the upta~e: and binding of testosterone and dihyd roI!!IIOStc:ronc: lW It is approved for treaunc:nt of oovaocffi ,ostatc C1IllCcr .... hen combined wllh an inhibitor of sonadoI!I!M-Jelc:asinS hormooc:, such as leuprolide. l'he 1110SI com..., side cff(Xts are gynecomast ia aoo nipple: pain.

uSlIlg pho!.phoru~ o~ychlonde fo1to .... ed by sodium hydro.ide. II is a"ailable: cOinmen: lul1y in 14().mi caPMI les tha. are : orJl1y active. One til 10 cap:iulc.~ are u)Cd dally. and they may be loken with "loCals 10 lessen gastrointestinal Upsel. About 75% of the orol dose is absorbc:d:"ll l'he biological half. life is long. and the drug undergoes de~bt ion 10 e:5tntmuSline follO\\ed by ghw:uronlde conjugation and chminallon m bilc and urine:. l'here also i5 some: lTICl:tbohsm of the alkylating functionalllY , E-.t",l11u~tinc was designc:d to have: an c~trogcnic mol(Xulc carry the alkylating nitrogcn mustard fUllCtionality sekcIl\'dy IIlto cells wit h estradiol honnone rcCqMors: howe:ver. itll1;ly not act l> an 31~ylatmg agent.J72 II " acthc 111 prostate: cancer bo:cause of its e:>tml!enic (antiandrogenic) effects. An other JlO'~,blc: mode of oct,on IS bind,ng to microtubuleas)OCialcd protcins to promote microtubule disassembly .H) T he dose limiting toxicity i ~ gastroime:'linal upset. Gynecomastia al~ occurs.

.10 I:OOJ U-

pnnmry
,amo~.

c am nu -

n putCllt d. n "p('"ragen I e:hange: speciH..:

IIiIut.Jf7lide. Ni lutamide. Ni landron. 55-di lllCthyl3-14Il10-3-( hi n IIOI'Officth yl)phen YI] . 2. 4-, mida.:ohdinc:diooc:. is !IppIN:d I.'i 5O-mg Ulblc:ts that also contain lactose: . The u.sual a/y dose is JOO mg for 30 {bys. followed by I'so mg daily. AhsorptIOl1 is rapid and complete following 0r.I1dosage:. and Ibere is modemte binding to plusllla pro.ei ns. Metabo lic o~i IiIooo of one of tIM: methyl groufK produce!> 0 aoo t. iWlIK'n; .tIidI ate ClqUlllly potenl. "ilwamide i~ used in combination wi th SU'lical castration '" metaSlatlC ~Ulte cancrr. It blocks tc:st0SICT0fIC at androp RC'I:ptors. U Gastroi nteSllnal and e:ndocrine side c:ff(X\S (I(QII". and there arc: low im:;dcm:l'S of interstit ial pncumoni and hepatitis. CIM:SI x-roys should be pe rfonned before 8enpy b; ini tiated. Inhibition of liver cytochrome 1'-450 -)'l1lC!l may reduce the: mc:1abolism of other drugs.
Bical UUlmidc-. Casodcx. N-/4-<:yano-3IrinllOrolllCth yl) phcll yl)-3-[ (4-n 1I0rophe:nyl) su I(onyl ] 2hy ~y-2-llIethyl propionami dc. i~ prepared by Hcy lUlillg 3~hinoorometh yl anil i ne with the appropriate: acid !iIIwidc:.- It ;5 formulate:d in 5O-mg tablets Wt also contain 111:.... The: usual dose is ooc: SO-mg tablet once {blly. l'he dI\If is wc ll absorbed orally. and the oral clc:ar:trICe is 0.32 1AIIIIIr. The peak conccntrotion is 0.77 pglmL, aoothe halflift i~ 5,8 days. 8iealu tumidc: i~ formulated as a racematc. The inact ive !,\')auntiomcr Is metaboli~ed by glucuronidatioo; the Kth'c ," (IWltiomcr is oxidized to an inactivc mc:tubolltc. fol"-d by gJucuronidation. 8aJutrumde is approved for combination therapy with .UIRH analogue for trc:atmcnt of advaocffi prosUlte: canm [IS response is measured by decreased prosta1e-specific atiltn levels. Adverse Jeactions inc lude gyncromu~tia. . . pain. and inhibit ion of 'pemlacogenesis. "IlK're is an _"ICtion ",ilh coumadin.;j01

Acetate. Lc:uprolide acetate:. Lupron. is a synthetw: nonapepllde analogue of naturally occurring gonadotropin reka..ing hortnone (LH-R H). It 's supplied In 2.8-Ill L multiplc dose 'lUis containing 5 Ing/m!. of the drug and hcll!.)'1 alcohol n..:..e vials ~hould be rcfrigc:rntcd unlil dispellSed, Lc:uprollde is u.'oed for palliative treatment of advllllCed prosUlUC callCt:r. There are no .. no .... n contraindications. S)'l11ptOIllS IlIaY worsen dunn, the fir5t few wc:c~s of tJUt nloCnt. with increased boflc: pain l.'i the usual mamfeslation. HOt n "~hcs and irritati(1fl 31 thc injection ~i1e also occur.
leuprofi~

Jalhau~e:

'1Op3u .. al
orni t i n ~.

lOh!titmlde.

'he n'KMol

!ion. Tht

::areston. pheny l )!al1on of ;e:31 .<.0~ lactO!oc:.

Triptoraien Pamoate. TriptOl1llcn pamoalC. Tn:15tM depoe, ,s a synthellc nonapeptide analogue of LH RH.)IIJ It is supplied as microgranules (or injection. lyophilized and comblllcd with mannllol in singlc:-dosc vial . The umount is equivulcnllo 3.75 mg of triploralcn free base. RcconsllluuOI1 i~ by inj.:ction of 2 ml. of Slerile Water for Injection into the v,al. Triptora.len panlOOtc 's '''co by mmtmuscular injection once monthly. It is indICated for palliallon of advwx:c:d prostatc cancer III paticnts for .... hom estrogen and on-hiectomy are not indicaled.- The moun 1Khc:ro;e effttt is hot nashes. Hypersensitivity und unaphylactic reaction. ha\'c been 0bserved. Gosenlin Acetitte. The ~ynthetic IIOOJpeptlde goscn:lin acetate. Zolnx. i~ all analogue of LU -RH. It is supplied in pre loodc:d syrinllescontammg 3.6 mgofagellt (or monthly 1M oomi niS1nttion or 10.8 IIlg of allent for 3moothly administntl;on. 11lc lIlain indication is palliallon of adv~ncetI prostate ClII'Cinoma. and other usc..~ include advanced breast can ceraoo endometriosis , AdvcNC reactions include hot nashes aoo If'Jglllal bleeding. although the drull IS SCncrally .... ell tole:rntcd ...., PhammcolulCtln arc: determined by n:1c:aC.' from the depot site. l'he "olume of d,stnbullon is 44. 1 L m men lind 20.3 L in ..... omcn.
Anastrozole. "IlK' aromatasc inhibitor anastrol.olc:. Ari midex. 2.2'-[ 5-( 11I- 1.2.4trial.oI- I-ylmeth)"I)-I.J-phc:n)"I -

)j;re.~~ion

.. boo""
580 L

.... ,Ihm _1 1 a cleor

i~

alio n , "'1 1St clllloCer -POMt.H !e blood hoo ld be

~yperca l

io;charge:. Eu lcl m . /4-nllro-

fstTlmusrlne Phosphate. Estnullustine phosphate:. UIrIxytc:. Erneyt. NSC-89199. cstr.l- I .3.5(IO}-trie:nc-3,17 $dioI-3-[ bi s(2-chloroc lhyl)carbamatc [ 17-d isodium phosJIll*. is prepared by treaTing c.'itrOOiol with sodium ~drox it IOIIowcd by niuugcn mUStard chloroformate. ~ Tbe ....-$OIubie disodium phosphat e dcri \'ali\'c is made by

438

Wi/.wn IUU/ G;.IW/J', Tr,i,i><HHI of O'll,mic Mrd,,'11W1 wul/'h/,mUlC,m;co/ '

CIt,IIUJJt)

Anuslromle ill iOOltllled for fi rsl1 inc treatment of locally adV1lJ1(:ed or metasl.;ltic breast carcinoma in postmenopausal ...omen Willi estrogen-positive or unkno.... nreceptor types.- Side effects illCludo:. va.~lIntallon. gU$troi I1le~tinal disturb;IIl(."cs, and hot n:I~Ilcs. The atOllmtasc inhibitor letrowle, Femur.!, 4_1 n( 4 ,crJnophcnyl) I .( 1.2.4 trhuolyl) methyl Jbcnzoni trile. is prcpan-.d by treatmg 4-1I-<1.2.4-triuol)"l)mcthylJbenl.om trik .... nh KOI- Bu and 4-noonlbcnl.Onltrilc.- It is supplied in 2.5-rng tahlclS Ihat also contai n lac1O>e. 11le l15ual dose is 2.5 IlIg onco:. daily. OrJI alKorption is !",Jpid aoo completc. and stead)-state phl... ma concemr.mons arc achieved in 2 to 6 ""locks. I'hammeokinctics nrc non linear. and the RICan terminal elimination half-life i. upproxnnate.ly 2 days. Melabolism produces an macti\'e compouoo in ...hlch the triuolyl IlTOIJP is replaced by hy droxyl . l...etro;.!oIe is indicalw for locally ad~3nccd or nlCI3S1atic breaSt earcinOll13 10 women wilh poo;iti\"e 01" unkno ..... n t.'otrogen 'eplon;. 1.7 Ad"erst: real1iol1~ illC lut/e nausea lind muscle pain.

"""

o:.nc J<h(2-methylpropiomtnle). is prepotred by treating tho:. appropriate 5-bnJmo compound wilh sodium uial.Ole.- II is suppllai as Img lablel~ lhal al.-o C(MJtain IlICt(}S('. The uMial dose i I twICe dally. eOlltinUl:d until lumor JlI'OttI"I!ssiOll is app.lrenL Thi ~ compouoo i~ well ah.orbal orol1y and dim. ilUlled aner hepatie metabolism. "'hkll inactivates u. The mean terminal ehmination half-life is upPrO~imately 50

SIGNAL TRANSDUCTION INHIBITORS

Ill,

Cell cyek' progre~sion can be I' ;e .....ed a.~ a sequence ofe'at) regulated by a cascade of proto:in kinascs. llICSI' kllwa
arc t'Onlrolled by four kllO""n ,nechamsms: prOicin-prolni inter.ICliOll!l (cychn..ocptndcnl l.in3Sl'S ). pho<;phQryIM'ion.. tracellulM sequcstrnlioo. and ptUteQIyllc tlegrlldauO!! IlIIJ. nasc.~ or their regulatory componcnts. 1l1C protem tyfOl.l/lr I.inases phospho!}'I:!te specific lymooinc residuc) of a l'arieI) of funcuon~1 proteins. lbcy provide a coollnon mtt~ (or transmining mitogeme Signals and regulaung nUlTOe ..a cell ular prQCe~), The role of pnMcin tyro~ine 1.1!kI.;c,; in tumorigcnesi5" c"idocnt ,"Ihelr ability to tnmsform norn131 ("CII~ II1to _, I tic phenotypes ""~n e~pn:).o;ed in mutated. Ilnn:&ulalll forms or when produced in abnormally high le'el~. Half ci the known protooncogcnes encode for protcins ""ith prOlai tyrosine kinase activity.~IO For eumplc. a hybrid p fonned from lhe lllil protOtHtcogene from chromosome 9 .... ith the ber gcne 00 ehronloOl>Olnc 22 I'ncodc!IlI fusiOQ pr0tein .... ith tyrosine ~ inast IICtivlly. Thi~ protl'm maintllll't Ibr leukemic phenotype in human chronic myeloge_, ItuL:mia.~' I In another CllllffiplC. the t'rb--2 protOOl1COJ1e!le 50 cOOts a I 85-kDa protein thai;, \cry ~Imilar 10 lheepldma growth factor receptor (EGFR) 0100 has an e~tnw:tlluLf. tntJ\snlemhronc. lind cytophl.~mic domall1. A single point_ tation in thI S gene cau\'"; O\trt~PfC:S..~ion of the Iss.UlIr protein .... hich becomes a factor m a vanety of solid.

Letrozole.

mors:"
1)e\'elopnICnt of nontoxic inhlbiton; of protem t)'JIlIIiJt klnascs 111 tumor Cf:'11~ is a problem because thIS type !If en,ynle b prcscnl in normal cells. There al'O ure ~nc J'It'O' lein kin:t.Scs and other nuclootidc-dcpelldcnt Clll)'mt\. Ne,-enhr:less. a nalurnlly uccumn, IsofialOOC. gene-. inhiblb the protem tyros.ne kll1asc: of EGFR ",ithout ~~ icantly affecting !.CrillC alld threonine kina..el!. A s) nlhrtK compound of the tyrphostin clas) .nhlbk. the I:.GFR insulin receptor I) rosine kinase. Sewnd-gcncmllOll t),p. \tins thai lack hydro~yl groups are mClabolrClllly. and IICtl\'e against human tunllJ('\ in immuoodeflClCll
mice.~11

Exemestane.

E~elnestane. Arorn~in.

h lIn irrevet'!;ible

aromatasc inhibitor relatw structurally to aooM[cnedi. ooe.- lt is ~upplied in 25-mg tablets thaI aL.;o COtllam mannitol. methylparuben, \lnd polyvinyl ~Icohol. TIle u~ulli dOloe: is 25 mil once daily after a meal. The dl"\lg is rnpidly ab5OI1xd. bouoo 9(Xl-to pl~ma ptUtcin.~. aoo lIS blood Ic:vcls dec line exponentially "'Ilh a me;1O temunal hal f-life of about 2-l hout'!;. Elttcn~lve metabolism induOcS o.1.idation~ uf the 6-mclhylcne group and reduction of the 17-keto group. Eltemestane IS effecti\'e and SC' lect;\'e for trealing .'lOme poslmenopaus.ul women .... ith hormone..dc:pcndent breast call1.'('r. ",ho<;e di<;ease has progrcs.<;I.-d (ollowinillallloxifen treallllCflt.- Adler.;.c TCOk1ions ,nclude a low incidence of nall:SC~ und faligllC.

11IC microbial product Mlturosporinc is a nonsclect;,el" ICIIl tyro,illC It.:illlt'IC inhibilOr or EG FR kinase. A sunpilr dlanilmophthalimitlc. analogue I. i ~ a poIenl and st~ II1hibuor of EGFR klna.'\C.~1J

C.....,ter 11
aromatIC hclelUCycie group

Anlmrop/w/u' A~r"/J

439

:7

occup~

the acknll1c pod:el of

'O

the ATP-bmdmg 'lie.

CH,

" In-

r 10-

,,~

;ety

Il~m

""

"""
i~ i~

H"~" OH

~ N

1 I "" u N

plaslated .If of OH

;Mew

.,~

,~

'Fo
N
H

pro~

FlavopirlOoI

the !lIle-

en-

,nunl lular.

N
H

HO ~

"",,~,o

11111,1-

d tu-

.''''
Staurosporine Analogue

"-

~,~

'"pro0'
igllif-

I
N

\
N

"IlIC~. i$lC1l1.

progn:5J; in obcammg selecuvlty in ~eplor inhibilOf" ha" been madc Il:ccmly :It No-11111), Compounds in their sencs o f 2+ ]lhel1)'hlminopyrimidw> Ihow remarkable selc.::livily (I,OOO-fold) againsl plme-

Con~lIkrable ~1'O'llIC kinase

A /O ,
CH,

, -

thctic over

Mabie

leI-dI'rm:d groWlh factor (POO P) IYmiine kina..:, ,ornpan::() tllh the EG FR s and other procell! kll1a~5.~14 T heir newly IWJ'OI cd anlilUIll(M" agcm imatinib (GIcCI'CC) iuhibi lS POOF ~Dl' ~Ina~. and 1\ is al!>O Il1ght)' potent ugainsl all] I dar It
prod~

NHCH 3

'i cicnl

this effect by billding in liM: pocket of the

Hydroxystaurospemune (UCN-ol)

.pmmpter
ecl1\'C:

e.l)lIIC IIIaI oor1ll:l.IIy hoId~ the adcOOSll1e lripho~phatl! used ~ lalinn. Gkenc abo poIcnl ialt~ Inc, ~tJ\ ity of ~ ~ III. The combined c:(fcets m:al..t: It ~ u!idul agent
'" IreItment of chronic mycluc) tic kuLcmi . T.-o . mall mhlbitors of C)"chndcpcndcnt linases. flan)~ and UCN.o I (hydroxyst3um'lponne). an:. lit c li nical fIIk. FI.zIIopctidol is a oompctitilc inhtbitor uf AT!'. Its

RIlS protcm is central among the many Ol"ICQgene- or pmlooncogc:nc-c:ncodcd prottlllS that sen..1! as Slgnallr.lIlsducclS on !he. pathway from the OUter membr.lJlc to !he. nucleus of cells. II :.cts a~ a oommon n: lay point for signal, from various

n
N

CH,

H~' N l

p
N

~N

N H

AI
N/ " 'N

N "-"

""
lmablib

gl'O'lo'th fllCl0f3, Single-b;u.e mutatIOnS In the gene eno..'Oding the: 21-kf)a ras proICm an: found m lu nlOn, especially colon and pancn'allc carcillOflUS. 41) Ras proItm is localiud at the Inner ~urfacc of !be: plasma It strongly binds guamne nuclcotidC$ and hydro10 GOP, The proct'~s of cyc ling betwet:n the atGTPbound foon and the mactl\'e GOpbound form o;crvc~ II.~ a switch for normal cellular growth and differentialion , Oncogenic I'lIS proteins do not hydrol)'!.!.' GTP and are, therefOf'e, jll.'mlallently in the ItCtive sMe, lb l'roI ei n tyrosine kinascs at lhe EGFR initiale a sequence of events that promote: GOP rele;ue from illS, allowing it to bind ATP and assume an active conformalion, POMtran slationalmodifiealions of ras. especially !he addil)(N1 of a fames)'1 ,ubSluuc:nt, provide the lipophilicity requirtd (or ils memllr.an.: binding. Famesylauon of ras is a tomplell ~ 1II\'oIving initial rellClI(HJ belwem fames} l pyrophosphate and a cy<;tcillc ~i due ofrllli to form a thiotther linkage, Thecysleine j, located th~ residues from the end of tOe coon terminal residue. 'These Ihlff ~rruoo acid residues are cleaved from ras. and the resulting tcnninal carboxylIC acid grou~ on tOe cysteinc is methylated to the ~'OITCsponding o.tcr. 41 Cum:m research is focused on inhibiting fDll\C5yl tllln.ferase. Cen ain tetTllpcptides. such liS CV FMNI I" show poIcn! inhibit ion of this em~yme. Further modification of the letl'llpeplide Slructure into a benl.Odiazcploc derivative restored II nonnal gTO'ft,th pattern in IlIs-lran,formed ~lls,411 Another research objecli\e is inhlbllion of I1lC':thyhransfCl1l!ieS mat t lltalylC the esterifICation of cY'ilelOC residues on famesy lated ras. 1be most potent inhlbllor at thi~ li me is a famesylthlosa1icydic acK! daivative.41 ..

(J-pyridylj2-pynnlldine-amine. is pn.'p;tr('d by multlWIJI $ynthesi ~.4" It is $upphoo as the f~ base in UX)ml at sules. Samples ~hould be <.tored at 25"C. 1lIe usual dtMqn are 400 mc/day for patients to !he ChronIC phase of lhe .... e:L'ie and 600 mglday for patients e~pcnt:ocing D blast criWL Dosage should be adJtI$lOO if Soe'ere hcpatOloxicity. flwd retenllon. neutropema. or thrombocytopenlh occur. lmatim!) i, indicmed for chronic myclocylic Icu~c",11. t acts by inh ibillnllthe lyrmine kinase BRCABL. thu5 pit' veming it from arresling apoptosis. Thi S agent is ....-elllbsorbed orally. ond the rnullimurn conccn'llltion in blood r. achieved within 2 to " hours. It IS 95% bound 10 _ proIci n,~ , llle maJOr IllCtabolite results from N-delTlClhyl, allon. Ehnllnallon h3Jf-lltneS are 18 hours for Ilnallnlb'40 hours forthe Ndc:methyl metabolite. E1cretion IS matnI,in feed. Ad\ erse relk."tioos Inelude: gasU'Ointestinal irTitatlOll. ftIIIIII retemlOn. neutropenia. thrombocytopenia. musculoskldtl pain. headache, and tCTlltogenitity and fenillty 1n1pillnneJl ill mit\',

IMMUNOTHERAPY
Cells of ncopla~tic potential are tOflt mllally prodoced 111 tItr human body, and our mlmlillC suro'eillance system dnuO)' them. n.e devclopmenl of IUmors implies Il\;\t thll iris not fUl'IClioolng properly. E\idence for this fllCtor In (311)0 nogel'lCSl~ 11'1C11I<Ies fuJ a high r:lle of cancer In OIll;tn~ planl pallents whose immune syqems are su~" dOlgS ~uch as alathloptine and (b) a high ~orrelation bc1 .. ea calKer and immunoddici<'ocy diseases. such M bacterial. viral infcclioos,l0 Stimulation of the body', inunUMI~~ should pro~ide a val uable melhod of calKer trc3Ullert, i)r. cause it ca n cra<hcate the neop13stic cells cornpletd). ~ stan:h in thi~ area is e~pandjng rapidly, aoJd some pmllHloIlt leads are etllCrging, The firsl attempt 31 imrnliOOlherapy was made in tile I by Cote)'. II ho tt1ject~'d bacterial tox in~ 1Oto cancer ~ His result! wen: generally unacec:pted because of rathcrn trnagant claims, Ilis techniques ha"e been fCvi,ed in ~ yea ...., Mml oncolOJiru now use a Ih'e-bactcna lubue +vaccine. b;acillus CalmctteGuWn (BeG).:1 This ~ i~ gi\'en to certai n pallCntS ",110 ~ D fullCtiOlll1ll 1 syslem as detennincd by sensit;v'IY to dinitroch 7.cOC,4ll Renl1~sions have bcc:n obtained in malignant nollla. bn:a~1 t aocer. and leukemia, Unfonun.atdy, tauses a number of undeslrablc e/Tccl.'l. 1I1CIuding re,(.f, perscn ~ nivlly, and Ih'cr disorder; , Other inulIlItIOiSlimu currently under in\CSligalion as anlicancer agents 1ft mClhanol c ~lrnctcd residue (MER) of BCG, COn"It'AIc1 rilllll (N,nl<llIm, H(}rdr/f'/Iu penuSlis vattlnc. and S)lIlIItI pol) nuclCO\ldes.~J The acti\ityorthese bacterial ~ thought 10 be nl('(loated by 3 protein known as tumor~", (aclor (TNf). TNF prodoces hemorrbagit necrosll 01 ti'e tfllllSf,lanled IUnlOl' t\'ll~, and it is s)'nerpSlie "nh ferom,: Unfurtunately. TNF does not show IICIJ~tty primary tumor; .... hen usM alooc. Clininl tnaJ~ ba!aI expecled synergIsm wllh interfcrons are in progrns. " IlallOn of TNF by agents soch as mitomycin C and ,.

CH,

H
N...yCO ~C H ,

, , ,

...............SCH,

O,H

Farnlql1:lw-lIl ,rdc: Acid

Pf'och"b Im.tinib. Imatinib. Gleevec. STI571. N-[3-[4-(4methyl-pi pemzi nomethyl}-be1V,Q)'lamido I2' Inethy Iphen) 11.4_

Istep :.age\ : dl n~IS.

"P-

....,

suggest lhat II r!Ugh! han' :I role ill

t-otnbln~lIon

chcmo-

Qhe..pproach to 0 \ efCOfTlrllg the dl fficullll.'\ of RCG ther_

fluid

ci ll. 11

I ab00 is

<""-

,rum

:thyl"",, am ly

wnh immuOO5Lml propn1 K!!!. One such COInpound.le\anusoie. an anlllelnunuc agenl found lO be an immullOSIunulant by Rcrl()U.)O; .1912. 110 pn'sentl y under ciinicllilmestigm ioo lIS II poten llIIIlcancer drug_It appear; Iu be mo'l effective in patients ..MIl small lumor burdens. and it ac t~ by stimulating the ~" \'rtl('$S o f Iymplloc:yte.~ 10 tunlQr ontigens. Advall' UJl'S of levami50lc ioclude oral DCt ivity nnd few adverse: ft'IIOnS. Lcvamisole may nledinte the potenl iation of in trkuktn2- induced T lymphocyte prolifemtion.U. It is wd In combmation wilh 5-FU in treating t'Olon caocer.

,, '~IO dt:\elop sl mplcrchemi c~1 <;IruclU~

effecb of dlp/ttheria IOllin to cerUlio leukemias and Iym. phomas th;1I e~pre>S the CD25 component of the 11..-2 I'l:(e~ tor. It is IndlCaled ror treating cutaneous T-cell Iympllorna 10 p.llients \I' hose malignant cells expreu this rttCIXor.

p,.och.cts
Interferon A/fa2a. Imcrfemn alfa2a. Roferon i\ . rl FN, IFLrA. is a highly purified protein containing 165 amioo acids. It is manufuctured from a simin of E. roli bearing 8 genetically engineered plasmid t'Ontai ning an interferon alfa-2a gene rrom human leukocytes. n Vials contain_ ing 3 million IU with 5 rng of human serum aloomin and 3 mg of phenol are supplied. A preparalion of III millIOn IU also is available. 'Ibe.se preparations should be ~I()red 01 36 to 43"F. Imerferon alfr,l-h is used in patients 18 years old Of' older fOf' treatn'lrnt or hairy cell leukemia and ciu'onic myeloge nous Icukemia. It is conlmindicated in pcroons who develop hypersensitivity. Most patienlS de\'elop flu li~e syndromes consisling of rever, fatigue:. myalgias. headache. and chills. Ga.~roinlestinal and CNS symptoms also occur. Caution must be used in administering this drug to patients wi th renal or hepatic disease , seizure disorders. or cardiac disease. Mctabolism occurs by IlIpid proteolytic degradation during reo absorption in the lidney. UIC elimination hal f-life is 3.7 10 8.5 hoor.l . Interferon Alfa2b. Interferon alra-2b. Interon, IFN alfa 2. rlFN-/l2, a-2inlerferon. is I highly purified protein produced by . coli containing a plasmid with an alfa-2b gene. This plasmid is obtained by Ic:<ombinant DNA tech nology using human IcukocYICS.oU7 1l1e drug is $Uppl1ed in vials COIltaining J . 5. 10. or 2S IU . Sterile: water diluent also is supplied. RllCOn stitutl wlutions are stlIble for I month at 36 to 4~F. Hairy ccilleukemia is the present indicalion for interferon alfa-2b.1t is also useful in treming malignanl rnelanomo and renal cell carcinoma . Hypcl1iCnsilivity to th is protein has not been oo'>Cf>'ed. PotienlS develop a nu-like syndrolllr, eNS effects . and canJiovlISCu lar effectS. including hypotension. anhythmia, or tachycardia . In terferonAlfa -n3. Interferon II.lfa-n] is. glycoprotem produced from cultures of human Iwcocytes lreated with Sendat \irus. It IS purified initially by chrommosroplly usm, a mouse monoclonal antibody that binds 10 multiple species of human inlerfcron. Sub5c:qUCJ1l purifICation involves incuhation at 40C and pH 2 to kill viruses and gel riltrution chromnt~rap/ty. It then has D specirIC aclivity of about 2 X 108 4 IU. ! The drug is supplied in l -mL vials containing I rnL of phosphate buffered saline sol ution, phenol as a preserva tive, and I mg of humbn serum albumin liS a stabilizer. This solution shou ld be krpt at 2 10 !!"C. l1!cropeutic indications and side rffects or interferon alfa-nJ are similar 10 those Uescribed for interferons alra 2a and alfa-2b.

nui" : Jellli

~"
The mductlon phase of the inllTlutle
re~pon~ of both B

.n lhe .troys <'S tem

nn.-

:d by

1.1 and

-=

(=m I, be 1 Re. lI,mg

189(),. itent~.

~ c~

r.;=;:il~

F~

""".

~,~

mela-

BCG

r. hy~Ianls . .h< 'c'c'c' ,helle

K:L\ J\

::ro<;i~

....,-

oen,i lIlterpin I ",00

\bla<;-

., T Iymphocyles is regulatoo by intcrnctu)f1$ between . IOphOlie~ and subpopululions of T lymphocytes known ~ litlptr T ulls. This intcr.lCtion induces the production of <>Iublc ,I), coproleins. Iyrnph~ines , whi ch i oclude interfcr Interkukms. and B-ll gmwth and differentiation fael)'mpholiroes in nanomolar 10 picomolar COIK"ClIlmtlaUSC profound mhancmg or $Uppn-SSllTg effectS on .......... ~ cell s of the irnmune ~ySlcm. 4U Ong iMnfm)llS are secreted by cells in response 10 viml infecOf other chemical or biologICal Inducers. Three: map . .~ of mterfmJn~-alfa, beta. and &amnia- have been ...rlCCl. They bind 10 s pecific high.affinlty ret:c:piOl'!l on surf'1ICeS. which ind\lCe!i a !ieQueocc: of mll1lCcIJu lar tleM!.. IIlduding the induction of e nqnJeS. Thi s process ~ weh tffccis as rc:lease of other cylokines such as .meu~1n -2 and TNF, cnhancc:rnenl or nlltumJ killer cell .:u\n~. Inhibition of certain oncogenes. and irl!;rca~ed ~pc_ oifll.' q tOlo~ic ocri>'ity of Iymphocyte~ for lurget cells.'l! illlrft'fOOS al fa-h. alf3 2b. and alfa. n] promote the inun u I response to neoplastic cells. which results in sig. .... C) lotOllic lty in some: mstaoc($. ~ are lhe drugs IIfdloice for treaung hair) cell leukemia.4 l1ley also an: IIIj ~ agamst renal cell cancer. multiple my "~mclanoma. and KlIposi ' s s.:m:ollla in clinical lrials. AaJdoc:r impor1am Iympholme is inlerieukin-2 (I1..-2). )).s !1)'CoptOlein inlemcts wlih specirlC receptor.;; 011 T -ercells 10 acti vate t))eif c)'toto~iclly. Ie Dlso stimulatcs WII;'bV1 UlOO and proIifemt ion of antigen nonspecific natu.UIIIer cells. \I hlch are invol ved in immune funttionsassoiItd I'lih tumor ~urveil1ance . Thc.~ effects are thooghl II toe: medialed llirough the induction of intcrferon gamma. !IlaI1 IJ....2 is now produced by recombil1am gene tcchnol'1)', , .. Jueh has pclluined ellICnsi\'e clinical trials against a 1Wt). of tumors. In some of these trials. U.-2 is gh'en in ~1Of1 \\'Itll Iymphokine-activated ki lkr cells. Deni dlftuIox IS a cytotoxic fusion protem composed of 6r IrlllDO K id Iil'qlll'T'lCe> for dll)/Ilhena toxm flllgmtnlS A B foilOlll'Cd by the seque:occs for 11..-2. It i5 produced in t. ro/i ell~Slon system based 01\ reo:ombinant DNA . Demlcukin is designrd to locah/e the e)'lotollic

Aldesleukin. 11..-2. aldesieukin, ProJeutin, Trcclcukin. interJeutin_2, 11..-2, T-cell growth faclor, in the human form is produced in mature T lymphocytes. Cleavage of the 21}amino acid signal sequence then results in an active protein

containing 133 anuno acids. It I~ glycosylmed and has 001: disulfide bond. .... hich is e$.~ntjal for acthlty. Rooombinlim IL-2 i~ produced by . that carri~ Insrrted. modified human IL-2 gcnes. Teceleukin I~ oonglycosylared but con fonns to natural IL-2 in amino acid sequence. e~cept for an addiuonal N-terminal methLOnilM: . Proku!.:111 i$ not gl)'OO5"ylated ond differs fmm the nnlural protein In lacking the tenni. nal alanll'lc and having $Crine rather thaI! ey,tei ne for residue 12.5. 1L-2 acth'u) is SUllldutblCd 10 IU m an a.~y based 0 11 stimulat ion of T -cell growth in \itro. ProIeu!.:m IS Iwall abk ill glaM vials COI1tain ing 1.2 mg of Iyophil;;':ed powder (22 million IU) plus o;()(hum decyl ~ulfate It is reconstituled with 1.2 mLo f wluuon supplied to gi~c 18 11lIl1lon IUlm L. Tl~leu!.:i ll i~ )upplied in vials containing 100 II1g of IL-2. 25 mg of human albumin. and.5 IlIII of mannitol per million IU. It I< reoon SUluted ..... Ilh Sodium Chlondc for Injection. US P All formu lations of [L-2 require 5tornge at 4 to 11"<: and protection from light . IL2 usually is adminlQC1"'d intnweJ1oously. although lhe 'ubcutalN.'QUs and imrnmuscular roules are used. The infu sion can produce !;.nere hypotension and life-threatening cardiovascular to(1cIlY llihen gl\'CII at the rl1:l.t unal1y toler alc:d dose. Patic: ms l'I:Ceiving such D do$e IIlUSt be monitored closely. and facilities must be available to trcm thl'm for hYjXltcnsion. tachy~an"a. pulmonal') ederl1:l. and (OI.~asiorl ally) deli rium . TIle drug Is rapid ly ciCllrcd from the bloodS1ream foilowlOg pan:lIletal adminiSlr3lion. The climi nation is blphasic for.n intfll\ellOll5 bolus injeCtion. The primary roule of cli min~t lol\ is renal. With cal~boll s m oc~urri ng III lhe relllli tubules. 1L-2 mter.tClS With specific receptors on IIICtl"all'li T Iylllphocylh. TIle l"e.wlti ng eomp tell is internalized. and signal tnm.<;ducUOll . pOloiib ly iO\'olv,ng cyrosine l.. ioa.'IC ac"vily. oc curs.~!11 Effects of I L-2 IIIclude Slimul:llion of T cell "rolli,th and Il'gulation, prolifefllilon JUKl nnmu oogloouhn pnxluccion m B lymphocytes. macrophage activity cnhllrlcemCllt. and especially genenltlon of Iympho!.me-adivaled ~lller ( LA K) cells. LA K cell. gelM:nlted iii ithilltUIl100. known as /u,nQfilljillfm;IIg i.l"m(Hl<.IC)"It'l (Tlu). an: thought to be the ulumnte mc:diatOfS of lL-2 toxiCity. Thc..'l"3py With IL-2 involl' in vilrQ genenltlon of largc IjU<lllllcics of LA K ce lls. which lire ,hen infuSl.,d with IL-2 to mediatc 101IlOr cell Iysis.~:t This procedure IS !.:nown I\,<; lUlo,lIi1't' inu""IJOllu-f' I'I'Y. Antitumor activity has been !ibsenI'd in metaslal ic renal cell cam:er. chronic I) rnphocytic leukemia. mal ignanl IIlelanoma. lIIaligl\;u1\ lymphoma. and colon cuncer. All patients receivlOg IL2 ellperieoce a nu-lI!.:e S)ndromc:. 1llC major dose-limiting side effect is pulmonary edema rewlung from locreMc:d ~api llary penntabil icy. OIhcr side effects include <;cvere hypoten sion. llihlCh can be fatlii. sinus IlIIChycattlili. Illental stllte cha.llges. prurilUS. nausea Dnd ~omiting. and Il'nal tox;city.~)O

cmi

The usual dose i~ 9 or 18 ma!l.:.g (ll.'1' day by IV injecllOll fOIl five consecutive days every 21 days. OcnilCU!.:JI\ dif'itox is IndICated for cutaneous T -celli)... phoma 11\ palienL~ whose malignanc cells express lL-2 '=!'" Ion; .~J I After administnltion. it exhibits tWl)-Companmtrl heha\'U With a dlSiributlOll half-lifc of 2 10 .5 nUnute5" a lerminal_phase half-life of' 70 to 80 m;nuICS. It is metaI!oli7.cd by proleolytie dcgrudacion . Toxic m:mifesl~I IOI\). elude h)'ll'rn'Cnsilimy rcactlOllS in 69% of p<lUc:oIS. ..W result ill hy[)Ol:ension. bac~ pain. d y5poca. rash, che-$! pia and tachycardia. Patients al<;o nperi~nce vascular icak Ii)1Idrome. G I toxicity. and infections.

Bacillus Ca/metteGuerin (BCG). Tw o nCG PftP'D' tions an: appro"ed for intruvesical Creatmc:nt of cartl_ ill situ of the unnary bIOOder.~n Conn:JUght BCG(I'henC)'I is a freeze-dried su ~pensioll of an allenu ated strain of M_ 1H1C'~"um 00";$ cnat has been grollin on potato- and Ill'" crill-based medium. II cOlllai ns 27 109 ( - 3.4 X lo'C'C:Iby formi ng unus ICFUslJ and S% monosodium glulamalt per \Ial. The TICe BCG (NSC- 116341) is suppl ic:d In po.. scaled ampul s chal contain 8 x 1 CFU.equivalcnt 10 0" 50 mg O( Ihe drull . The vial ~ Should be stored at 2 to S"C. protected from light. Pcl"!lOll.~ handling BCG prqwa!H'P shou ld be protec,ed by masks and gl0'01's. Aflcr atlnuMtlltion, all equiplT1Cnt and mhlcrial should be ~onsideltd ha1.ards. Inll1l\~ical BeG pt ....llQ1CS all inflamnutory re.lll.'tioI th~ urinary bladder C hat is associatc:d wilh redllctioo in c.anom3 in ~itu lesions. The mech3ni~m of JlClion is not lOO9:l in detail . bul l \'ariety ofproct's~th;1I ... imulate ~ io _ re.~pon<.e have been ~.... nsldered . T ox ic effects of BC<i. elude hemaluria, dysuria, and bacterial urinllfy tl1lft luro lionS.

n.e

MONOCLONAL ANTIBODIES
The conccp! of u~;ng !U\ubolhes for the selecllve of CIll1CCf cells IIi'lIS proposed fi/"li' by evcr. it cou ld not be reali1.ed until KObl er and I onstrlucd the practical production of monoclonal ;ll'il; from hybndoma cc:1I hnes in 197.5.)1 Silll:'e then.;;;;';;;; diagncr.;tic and thernpelllic monoclonals ha\'e been although C-'\.Iablish.ng them as clinical agents has be(1l cult. 'The Ii ...., monoclorull ami bociles 10 human CII'K'CI' were dc\'cloped in mice. They lire elUY to usc in humans resul ts in an inlmune
human 'm'~~ ~~ .'m' rnolloclonals. Human monoclonals arc difficult and an: not internal i/.cd inlO lUmor cells. Tho:lem has been partly wl-'ed by the dc\'dopnICI\I or alllibodie~ that conta," the variab le region of ITlOU5C.' antJbN. ics (which binds wi lh antigens) and ,he oomtant Il'JIOI tluman anlibodies (the effttlOf part 0( lhe moIecu~). ~ more recem de\elopmcm IS the humamzed antibody. iii hich only the colllpicmentarity-detennining n:giOllJ of .. \1Ifi able domains are ret.:lJned from tbe 11lI)USt; clonllls. ~ 11Icsc anhbodies . only of mouse residue.~ and are relICtion. The fi/"lil humani7.cd

Denl/eukin Dlftitolf. The ~) IOIOxic protein dcnjlcu~ in diftilOx . On,ak. is cornpo5ocd of the :Ollino acid sequences for diphtheria toxm fmgmcms A and B fol1011i'ed by lhe 'Iequencc" for IL-2. It IS prcp.1n.:d hy recombinant J)NA lech noIogy . aOO eJlp!l.'J;sed in an E. coli symm. The do!iage fonn comain~ 1.50 flg/mL of drog plus EDTA, ~upplicd as , frmcn so lution for injection in single usc vials. It is S10red fI"07n. For rewn stilUtion. il i$ brougtlt 10 room Icmperulure and diluced to 1.5 mL w ith stcnle salJne in >Of1 plasllc IV bags.

Iynt-

,,"" IUbol~

""'o\enl
mmouu ....iwod in chomar oc. humin de"".d
in
hum~led

~hich

pam_
~y n -

lmouse only)
>p;ImmouN

o.r,li1td on mouu

noma tCys)
<11'("(1-

ant, body. Dlherw _:'H=--_ __ humin derived -

,la!>.,"" J ,boo,
:: und nSlra-

gl)clony-

1lI011\

J b,u-

Figure 12-1 Mooodon.ll antIbody

on in

care,-

oow,
mnm: G m-

infec-

.lCIion ho .... de m )Od ie\

~~,

""",.

d im r ce ll s I lhelr nl: 10 lie lhe n:p:lre

Nl CA~IPATH - IH . mduced rcnlissKJn m lWO non- Hodg\II's lynlphoma patienlS and ~ho"ed no delectable llAMA."" Ai shown in Figure 12-7, ant ibodies CO[l.SiSI of IWO Idl:miQI bg:hl chams and 1""0 ,dcnllcal he ..-y chams.. ",hich form I Y~. Anl ;g.. n bindi ng occurs lit lhe ends of the anrn; Dl'the Y. aoo each arm is :tn IImige'l-biOOi ng fr~gn\en t (F.. b). !'IlIa eac:h antibody molecu le can bind t...o u n tige n~, llle ~ ollhe anns vlll}' cuenshely m sequence and pro~ide W btIKlinl specifici lY for the anllgen, Each I'unable domam I'OInIM thn:e comp lemcmarily-delen nnllng reg ions l('!)Rsj to gh'e a 1 00lii Or six for bind illg each amige n mOle. . (Fig. 12, 7),~'3 Tlu IIlOIIOClonal anlibodleS hal'e been appnwed for CIUl=-dlemotherdPY. They arc humanIzed moood onal a.lIiboda in .... hich only the oomp\cmen larnydclennini nll Fab rc~ an: of fnou.'>e origm. T rasllUumab (hen:eptin j i~ IWO,-ai for breasl canc.:r, II III;:Ia"ulely binds .... ith high Jr'lIIly ro tOO e~ lr.ICe li u l ar domain of human cpidenna! "",,'!h factor receptor 2 protein (Her 2). Th i~ binding inhib prohfmtion of cells thai o\'ef'expn"ss Her and mcl.liales

wmty-dept:ndtnt
Ril1m m~b

cylOt:oxici ty.~'"

prot>-

meric I1bodion of .4~\ A dy. m O{ l he mo no-

,0

AMA i nic al

(Ri lux an) i~ directed ~galllsi the C 0 20 untlgen . . is found on Ihe \ Il rfoce of 8 l y mphoc) le~. Th is antigen '-'~ on more lhan 9()<;f. 0( B-cell nOll- HodgL. ins I)~ bIlt not 011 nonnal cell,. It rcgu latcs early ~teps tilt ilch l'ahon prut't'S5 f,", cc ll -<yc le inl riar ion and ce ll aRrn:nriatlOl1. Admini'rr~r ion of rituximab results in mpid apktion of circulau ng and tissue-bound B cc ll ~. IItcatsc' lllOIlo.;:lonaJ anlibodie~ by thcmsehes may not be lO\ic enough to kill cancer cells. cXlcns ive effon ~ have kat I!IIde to conjugat e lhem wi lh highl y IOxic subslances 11$ radionudidej. lo\ ins.. and IlIIticam.'t'r drugs.. The 13bIclidc COOJ ugales also prol ide diagnostic agents for tu-

rllors. Siructures 0( rhe conjugates I),pically consisr of rhe monodon."IJ ;u\ubody jomed 10 a ImL.er molecule ..... h,ch IS in lu rn joined to rhe cylotoxlC agenr. -1-0(1 LUlL.en an: auachcd to Ihe t"'amillO grou ps of Iy,ioo rc~;ducs of rhe monoc lo nnl or 10 aJdch)de gl'Ollj)S fornled by pcriodarc oli(!arion of carboh)'dl1llC re!.ldllC!. on lite ron;.tam region~ of the !l"IOIlOdonal:"" For r.l(honud l dc~. the OIocr coo of the 1",L.er has a c hc l~l ing group. suc h a~ elhyle nwiaminelclrnacetic :ld d (EDTA) ...... hich c~n bi nd rndiOOCh \e metah stich as -rc, III In. and O\Iy.-I-O(I IrIHnunOlo~ins such ~5 ricin. abnn. aOO dlphlheri a ro,\," nre so pOl cl1llhat 000 Illolccule cun ki ll a ce ll.. R,ci n cOlls i ~ ..... of 1""0 whuni ls. the en/),l1lC'-lIClj, .. A chain nnd lhe targeting B chaill. which are jollied b) a disulfide bond.. 1'hrnlpc:uuc agenl~ are des l g~d 10 rowe the B chain repllK.~ by a monoclonal antIbody large ted lO tumor ee l b. laking ud ~anl age of the labi lity of rile disulfide bond ..... l For :I.IllICancer drug~. lhe W'ategy i~ to join the drug 1 the hnke.. molecu le through 0 a funcuonal group Ihat cun be h) droly l.ed. II IS ~xpcc1ed that rhe conjugate" ill be imcrnalit.cd m Ihe: callCcrce ll and rhen IIle drug ",ill be: rc!e3'>C'd. Gemr u/ulnab ologamicill (Mylo1lU'g) is II chemotherapeutIC lIgent composed o f II recomblnam humamud IgG. K amibody conJugaled ""Ih lhe anl .lIlmol' an tibluric ealic heamic lll (.;ce Fig. 12-6), The antibody 0 portion bi nds 1 the CD33 I1Illlgell. ", hich i~ expressed 011 11M: surface of leu kemic bl~ in ,nore than IIO'>l- of pauefll~ ... 110 hale acule mye logenous leu~enlla. The resulting rom, ple~ is intem aliLCd, and the cD lichclIllIicin <krhati l'c i_ released inside 1)'!>OSffl1lI"i of the leukemi a ce lls ",hC:TC: il birod$ ....'Im DNA and produces doublc-"Inmd brcaL.~. An ahem 3U\'e str.uegy for chemothernpy IS the use 0( monoclonal U libodie) as carriers for enzymes to tu mor cdl li surfaces. 'The cn/)'lll(') conl'ert rdatlve ly IIOIli0lic drug preI.'U~ (prodrugs) imo Ie,, \e anucllflCC[' dru~:'"

Limitations encountered in cancer chemotherapy with monoclonal &nubodies and thc:ir conjugates il1Cludc lact of !;Clectivity for tumor ttl Is, hetcrogeneily of tumor tttl anti gens. insufficient drug density to kill IUmor tt tl s. 10$5 of immunogenicity because drug conjugates bloct recognition sites. the HAMA effeo:;t. and lact of internalil.ation into tumor cell$. Intc:rnalillilion is essential with toxins. but less important with radioouclides .-

Riluximab. Riluxan . i a genc:tically cngi nc:cred chimc:ric monoclonal antibody directed 1 the CDW 0 untigen on mulignanl B lymplwx:Ylcs.'" Ii is supplied IlS solu lions containing 10 mg/mL in 10- and SO mL ,ials. 1bcsc soIutiOOJ should be itOKd al 2 10 s<'C and protecled from sunlighl. PriQr to administration lhey are dlluled to fin~1 coocc:ntnltioos of I 104 mg/mL in infusion bags con laining 5% dc~ t rosc: or 0.9% NaCI . The n::l:ommended dose: is 375 mg/m2 infused 111 a f'Jle of 5{) mglhour. Rituximab is used against malignant B Iymphoc}tes tltat 1:.ll]lRSS the CDZO antigen.lbe. mean serum half life is 59.8 hours. with variabi lity possibly n::nc:cting the tumo r burden. Advel'l'C reoctions include hypersensitivity Of una phylllCtic reactions. cardiac M'hYlhrnias, nausea. falig ue. and urticaria. Fc:,'Cr and chills may occur during infusion. Gcrn lul.umab Ol.ogami cin. MylOlarg. CMA..(j76. consists of the antitulnor lIIllibiOlic calicheamicin conjugated with II n::oombinanl humanized IgG4 K monoc lonal a/1libodt thai largetS the CD33 receptor in myeloid leukemia cedIs. 1 It is $upplied as 5 mg of a lyoph ili1:ed powder for injection. which is oombirn:d with NaCI and 50ttium phosphale: in 20-mL vial s. It is reconslitu ted with 5 mLofStc:rile Watc:r for Injection. Before infusion. the dn-ired volume: is injected into 100 mL of O.9'k wHne. During these procedures it must be: protected front ~u nlighl and direct nuon::scent light. The infusion period is 2 hours. and !be LlSual 9 mg/m l. Gcmtll:w mab orogamkin is indicated ill patients "'00 arc: 60 years of or older. have CD33-positive ocute myeloid leuk~mia. and arc: nOl candidates for OIher chcmothc:ropy n::gimc:ns." 1 Binding of lhe antibody with COB llntigen forms a complex that is intemal ized in [he tumor cell. 'The: calicheamicin derivative is then n::leased inside the leuke mia ce ll . where it binds 10 DNA. Arter infusion of a 9 mg/m 2 dose. the: half li yes of tOllil and Ilnconjugalc:<1 calicl1camkin are 45 and 100 hours.. respectively. Adverse: n::!lCliQll s in clude se,'t're myelosuppression and mUCCY.>Ultis.
G~tuzutmlb

Rllux/mab.

Ozogamicln.

dose"

Radiolhc:fupeu tk agents arc cho<.e n for theIr abililY to c. centrale in 'lpeCific l i'-StJc.~. weh as hone lind thyrotd. as.'d] all tllc:ir energ) and Ihc:lr rudiol<lglcal and biologICal IIIIf. lives. Un fonunOlely. lheir cytOl olidty I~ usually !lOIliffilltll to Inc largeted Iurn.or. arid they gcocrnlly produce lhe sy"," toms of radiauOll ~id nc~s including nau'l:ll, 'onulIlII,..r diarmc:a. Somcl1rncs lhe to,. IC effects CJl leoo 1 hair Iob..r 0 bone: marrow damagt'. Chromic pll()<;~hale P 32:trld socl11.1111 r,hosphute P 32 ~ Illin the i<;()lope: 1p. "hlch dc:cay~ to'S by ,Behmll\lllOl. wllh mean ]JiII1iclc: energ} of 695 l eV. 'The: for il",1 to reduce: perrtonc:at Of" plural cffusion~ caused by n.... zw... disca5C. "herea~ the latter 1~ u'\Cd agaln,t hcmatolOllIca1 aacer~ such /is polYl:Ylhcmin ,c:ra. chronic m)'e loC) tk JwU. mia. and CLL It s selecti,i ty is based on the: c:0I1CtIllnIi0I of phosphorus III rapidly proliferallllg nc:opIaSik cell .. 'The: 1.11 1 In ~Ium Iodide I 131 deca) s with a halfliit iii 8 dnys eoemil both ,Bund ),md iut ion 11!C fJpartid es ..." for apprtJ~imatcly 90'.10 of local irr:ldrat lon effects. 11u\ IfdiophilJlllllCCtJlical is u-cd fOf" boIh diagnosiS and Ihm,t because 11 ooncentrDtc:J III the thyrotd gland and Ill\-e. IWO t)pes of radiation. Ih therapeutic usc is for paJI\Q)I In scllXt CII.W~ of Ihyrtlid catc lnOt1la . Strontium is a member of the alkaline canh mtta1~ ml then:fore:. SlIlullU" to calcium in the nlleal propeAI('S rnch'mg accumulation III hone. "1lIc flI(hon lJC lidc: ~r. <.upplitil liS \trontiunl-89 chloride. is a pun:: ,B-emmcr \\-rlh a Nlf1tkof 5{).5 da}s. It i~ indicated for n:lief of OOIlC Jlolin In p.:tlItIIl with skdetal mc:ta'!a;:e<;. Samarium belonf.~ 10 the l:ermm group of lant ~~ The: radlonuchdc: I~ Sm is fonnu!:ued as a chelate ""Ith~ enediamine-tct rnmcth}lcllCp/lo"pllonic oci<l (EDT1-1PI ill. productlriown as samllriuln SM 15 ~ le~idronam. Thlsc:WlaiC ooncc:ntratc:J in an::/iS of booc: turnover in assoc wnh hydrolyap.atue. wllc:n:: II emits fJ panlclt'$ of .... ';. , .... and 810 t eV. It is used III patients .... 110 ha,'e ost .. mClU~tPtic bone: lesi(lIls.

II""

aac:

o-p

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,

1/r--- II -O P
I

Cfm~o
, I

0/11

o" p )\-i~o
0

RADIOTHERAPEUTIC AGENTS
lbe. jJiopcrties of radiation and the uSC: of mdionuchdes
and radiopharmat:euticals for organ imaging are di5Cussc:d in ClIaptc:r 13. Only the radiophannllCcliticals used as ami neoplastic agent s are described in this chaptcr. Rad iophar macc:uticals used as diagl10Sfic agents arc: generally c hosen for their abilily to produce: ,..rays. which can pt'nc:ltI1Ie tis rues for n'llIdvely long di slII/1Cc:s to reach scimillation cam eras. In contrDSt. radiotherapeutic agents prodUl:~ ,B particles (elecu-ons), which trnyel only short distances (about 3 mm, depending on their energies) to initiate cytOlo~icity.

Samanum SM 153 L81Odronam

P .... ucts
C hromiC pMs~e P Phosphocol P32, crl!ro~. i ~ <,uppl~d as ~ SU5pCll'OOl'l. 11 mL vial~ cont aining NoCI and NaOA c in water ",lib. bentyl alcohol. "The radioact ivity is 15 mG. with COIlCUIIt tion up t05 mCilmL lbe. u~ual dose IS IO toZOmCi ltmp1

Chromic Phosphate P 31.

.wally. 6 to 12 mCi intrapleurall ),. and 0.1 \0

O.~

mCi

~dl

__ ilially.
(bromic ~phDle I! used for introcavilllty instillation to

air-

lied

nip-

'00 '00

!ed\llCc: effusions caused by melMlatic disea-.e. II decays by ~mission. with a half-life of 14.3 days. Adverse R'llCtions !Elude Il'1IIIsitory r.idialion ~ickncss. bone mllrrow dcpresIlia!. pleuritis, per;lonitis, nau sea, and abdominlll crumping.
Sodium phosphate P 32, soSodium PhospMte P 12. dIIm radkophosphalc. is supplied II!l an aqueous sohll ioo of 11III1lUR: of NaHlnPO~ and Na~H12po. with a pH range 015.0106.0. II cO'lIa;n! 5 mCih'ial (0.67 mCl/mL) of radio..,;bvil),. expressed as a pure tJ-cmincr with D half-life of 14J dn)'~. Sodium phO!iphatc P 32 is indiculed for In:allncm 01 polycythemia vcr chronic myelocytic leukemia, Dnd ... QL Ikpression of leukocylcs and platelets rcquiltS mooi~ of blood and bone marmw at regular intel"'lals. SodIum iodide I 131, 1O(:lIum ra~ dIoIodlde {Ill I ). lodQIope. Theriodidc. is supplied in cap.Jes focOflll use, or in aqueous solution for orol or parentel1l1 lit. Iodolope capsulcs cootairl I to 50 mCl, llfId lodQIope oral 'IOlutions concain 7.0S IIlCilmL. Sodium iodide I 131 .les contain 0.7 10 100 mCi, and oodiulll iodide 01111 ooIl11iom, 3.5 to 150 mCiNial. Stock solutions are ~~d "If dilution with Purified Water containing O.2,*, sodium ..... Ifate as a reducing agent. 1l!e dose iJ individualized elCh palient. SodIum iodide I 131 is used (0( palliation in selected cases clhymid can:iooma. 'The uSlIallollie effecl is radiation sick

lant

....
~

lion

with EDTMP.~}O This radioph:umacc:utic-.I1 is sopplicd m 2 or 3 mL of fro~en solulion conlained in lOmL vials. 'The radioactivity at calibration is 50 mCilmL. Prior to admims tration or the drug. 500 mL ornuid is admini~lercd 10 pl'Olect the bluddcr. 'Then the drug is administered by IV inject ion over I minute. rollowed by sarine. II i.~ ucreted in urine as the: intacl COOlplex to the: extelll of 34.5% in tile first hour. The Iotal ucretion depends on the tumor burden Samarium SM I ~3 leJtidronam is Ind icllted for relicf of pain III patients ",ilh Q!;teobl:lSIIC metaStatIC bone: lesions." It is also used in anl.::ylosing spondyhtls, Paget'S disease. and sc:,'ere rheumatoid :utiJritis. l'hc malll side effcci is radiallon sic kness.

. ,,,,,,
'00.

fo .r 00"'

CYTOPROTECTIVE AGENTS
Highly c) IOIoxic anllncoplastic agents ~ a vanely of se:riOtt!! side effects in patients. This problem has slImulated the: search for compounds thai protect palients from cenain specific toxicities and thus ~mll t lhe IIntmeoplasliC agents to be given in large r doses. Th.e following Ih,,:e widely diffen:nt cytoprotectl ve agents hal'e been approved for clinical use in the United States. Mesrta is the sodium salt of nlCrca(1totthane~ulfonic acit!. Although il is oxidized to IIle corrtspoodmg disulfide III blood, it is reduced back to the: free thiOI in lhe: kidney . There it reacu wilh ul'Oloxic ifosfamide met:Ibolites includmg 4_ hydroxyifosramide and acrolein. This propeny led to ils use in preventing he:morrhagic cyslitis in palienlS n:cc:iving irosfumide. The organic thiophosphnte nrnifo:.tinc is used to detoxify IIle n:acti ve mc:tabol ites of cispllltin. especially in lhe: I.::idncy. 11 is dephosphorylaled by alkalHic pho!;ph;ttase to me active free Ihiol. This transformation OCCU/'$ seleclhel y in roonnal tiSSIlCS because: they hal'C: higher .Iuline phosphalase activo ity. higher pH. and better vascularilY. Dcxnl1.oxane i$ the S( + )isomer of r:l.l.oxane. II is a polent inltaCl::Uulat chc:laling agent that is u~ for canlroprotcetion in patients receiving doxorubicin.,n Dcllr1l.l.OllllllC hIlS two imide gll)tlps thai o~n intrncellularly to fonn a compound rel aled 10 EDTA . Thiscompound complexes with iron and interferes wilh free radical gencrntion associated with doxorubicin - iron complues.

Sodium iodide 113'.

npy

lUOO

:Iutl i'lied f-life icnl\

.de".

"',., ,""allon
710.

th)'I-

lastiC

lll'Olltium 89 Chloride. Stronlium 89 ch lori de , MellIS' I!II. "SrCh- is supplied 115 a solution in Watcr for Injection alfllaining 4 mCi of radioactivity (1O.9 10 22.6 mglmL) in II).ml VialS. The usual dose: is 4 mC; by slow IV inr::tion. . . cIo6e may be re~aled afler lit leasl 90 days. After 1IfI(tIOI1, me drug is seleclh'ely locali1.ed in bone mineral. ~. a pure JH:miner With a half. life o ( 50.5 days. Sttontium 89 chloride is used for relief of bone pain for J*lelll! with skeletlll metllstascs. Because il is toxic to 1lOI'. .. bone. tile benefits and ri~l.::s of ilS use mu~t be assessed .

5M '53 LeJf;dron,m. Samarium S M 153 1rutroIIam. Quadramc:t, is formed by COOlple\ing 1 "501

~um

P 12.
miDih 2'l1
tRlm-

rape.

P ..... Mesnct, Mc.~ lIa. M e~nc x . sodium lIIercaploclhallCsul fonPII:. is ~pared from sodi\lIn bmloclhallC~ulfonale hiourc:a. and ammonia,'" It j. supplied in 2-m L glllpul ~ c()fllaininc tOO mglmL of the drug ptu~ 0.25 mglmL of EDT.... , and in IQ-L rnuhidol.e vi al s conl;lin ing 10.4 mg of he'll ),! alcohol ali pre'>CrvHli\ c. Prior 10 intrnvcllOU s admini$lr.ll ion ill \ diluK-d "nh >arious nll.\!urn of dellI/Use and NaC!. or .... Ilh lactated Rmger's !;Oiulion 11,1 gi,'c a final OO/)C('ntrallOO or 20 mglmL. The dilu ted MlIUlion> Uf\! Slable for 2-1 00u1'5 at 2SC, bul lhey shoul d be rrfri gerJled and u'lCd within 6 '-tl'll of recon\lJlulion. Mc.na is O~ Idi~ed 11,1 the COf'T'CSpondm g di<ulfidl: on ClIpo!>Urc: 11,1 DX)'gcn . 1lw: LlSUal dosage is 240 mgllll l , gllen :11 Ihe s;lIne ' line ~~ the fiN jfosfamide

injccl iOll. Me\l\a

j.

indicated for ifo..famidc-induced hemorrhagic

agem. is ~rI by In:atmg l1IacellC lelraJlIllidc "ilh .sodium as 2.50 lug of Iyophililcd powder in "~~ gether wilh 2S mL of sodium lacl.llle [)I" IlIg lyophilized "",,'der wilh 50 '" " , For reconl:J1UIlOn, il is diluted to trose or 0,9% NaCl. lemper:lture. The dose as a 10: 1 111110 doxlnlbicin. The uSllai dose is SOO mg/m2 of dcx;;';';' Il!Id SO mglm l of doxorubtCIn. AdnlllllSlmlion IS by IV push or rapid IV drip J(} mIilUle.~ before oou:I"UbN:., l administered. The mean plasma COllccntmtion IS JJ.5 IIIL afler a 1~ . nllnUlc infuS lon .~'l DeXrll7.01l1l!le is iodic~ll'\J for reducm,G the cumulauIl: a.diOlo~icily of OOXOrubICI11. It may odd 10 the myclWJ 51011 cauSl'd by Ihi s chemOlherJpculic agenl.

C),sti lk A1I('1' inlra\'enou~ admin j<h'lIlioo. it j, ropidly I)X;' dilcd 10 the di.ulfide. Once In.he kidney, il IS reduced 10 lhe free IhlOl, "hich react"~ wllh urotoxic ifosfam ide nll'laboll1cs mcludmg acroicin Il!Id 4-hydrox) Ifosfamide. .. l11c hal fIi,,, ofmcsna :md Il\ disulfide in blood are 0,36 and 1,11 lIours. !"e.'peeti, ely. and lhe ki nellC~ are dose dependenl. Side effa:u include diarrhea. limb pain. headache, nausea aud faliguc.1l!Id bad laste in lhe ItlOUth. Some paliell~ life hyper_
seilS ""'c"

FUTURE ANTINEOPLASTIC AGENTS

M()St of the earlier ~an:h in anlineopla.,tic dJug d"~. '

was relnted 10 inh ibi ting the ~) mhesi~ and fuoction of OS\.. Today. 3 variety of OIher targct ~ are under ime n~h'c lft\e1I gation . and they shou ld rro~idc oncologists "ith ~Ipllfi new approache~ to lheropy. Although thiS f\'S('artflllb )'et pruduccd an npp!"O\ cd agent. in c linical lria l ~. l he fo llowi n~ IlCW I chcmOlhcnlpyan: of spt.'Cial i nten:~I : in involved in nlCtasta.iiO, angJOgenes.is inhibllOl'5, techoology. and tclomer.lSl' inhibitQN.

Amifo'linc. Elh ~ lol. s.t2-(3-amiooprop)lamHlo)c:lh)'11 dlh)drogen thlophosphalc. is JlIl!PiIlCd by treahng 3-abronMXthylammo)pmpylam ine w.th sexllum tI\iophll'phate," 1 i~ ~upplied as ~OO mg of lyophili lCd PO'" der in I0-I1lL ~,"gJe-USl' viak Reconsti tu tion is by addi lion of9.1 111L ofO.9'it NaCl fO!' HlJcction. The usual stan'"g d~ I) 9 10 mglmz gll"en once dad)':I.S a l~-lIIinUIC infusion ~Iartmg J(} minuh.'s before ctlemolhcrapy. Amifoslinc i, indicatcd fOt reducing the cu mulative toxi cily a\)()Ciatcd Wllh repealed do!;es of cisplatin. It al"" reduces the incidC'nce of xero:.lomUt in pahellls undergomg postoper alive rndialiol1 Ircat mcl1l ~ 111 whi .... h lbe parolld glands are c~poSl:d. Toxic ctTccb of amifo~tinc illCludc hypol:enioo. "",cre nauSl'.a..1l!Id "OIl1IlIng. Antlcmetic medicines includ inl! Oc.\amethasooc Il!Id a ""rotonin S- HT j arllagoniSl are uSlmll> adnulli,tcft:d. Tmn~lcm hypoccnsion may requi re interruption of Iher:lpy. o.xrazoKan., l):U,U.O \aJM:, {.n-l.2bi(3,S-dimopipCIWIIl )'ljprop:l1le or Zinccard. n poIent irllr:ICeliulur chel ali ng

Amifosti~.

Protases and Metastasis

The abllily of cel l, from primary tlll1loo; to ary sites (nW:ll15tasis) is the major C~Il ~
Metastasis involves tumor cells entering and I cliialion and Invadln adjllCC1lllissue II of the ClItraccllular rnalrill by t;;8<;('<, Thi ~ process occur<; ;;,';;'~ , lhe elaboration of protense inhibitors. The proIeasc:s and inhibi tor.; Ippcar:<i 10 be: in malignanl cellS,~'l M llln~ proIein i of rneln lloproteinhS4!~. inc ludin g coliagen3SC'. Slrol1lc:lysill'i. and ll1atrily~U1s. TIle5C n be acth'ated by II ea.'iCade Induced protea.<oes. cystelOe P'~'O/"'C'"~;;",, Among the syntlll'ti c ~.

CH,
CHC,H,

NH
C- NH1C~1.NHCNH2

II

II

....

Nalamostat

Chapt rr 12 Am",rop/<ulk" Ag....u

447

l
)

.., ate E64, an mhibitor of ~ C)'lolcine protcllla)C cathcp.. B.~" and nafa.ll1osw. a serine proI:ease inhibitor. Suromin

IiIoclli melanoma and mammary tumor in\,;tsi>'cllC:S$, possiill)' by "uubitmg hep"rina~. cathepsin 0 sel.Telion. and uri..,. plas.nllflO8C'" activDto!'"
KCl!ptOf. .u....::t

TNF-n is a po ...ctful Qil1lulanT loans,oscnesis. 1llesecreI;{)II of this r.-tor by m:w:rophagC$ in pl"Ol\ulic c:i1lCC1"$ IS decreased ~i,"ificantly by IlIIol1lide. a'luIJ>Olmt-J-catboxa mide deriv:uilc .....

~kll.nesl.

Inhibitors

Antl_n_ Technology
n"H!.... ~ngcr RNA (mRNA) can urnlcrgo lICquence-"pecific, high-affmity binding 10 II COl1lplcl1lCnl,Iry oligonuc1CQ1idc sctjuence by Wat.. on-Crid: hydrogen bond ing. Such a complel1lemary agcnt i~ called an rlllri5f'IIJf' oligQfMr. By binding ... ith mRNA. the anliSotn.'>C oligomer can imerfcrt: ",ith ilS lranslatioo inTO protein by ribosomal bloc!.:ade. Complexes bct ... ccn mRNA and DNA-hLt anll.'>ClI;;C oIigOlludeolilks also can ICtlvatc RNase H. an eru:ytn(' tbat specirl('ally Ck:3\es the RNA ~tnmd of a RNAIDNA du plex.i..Jmluuions oolhe U.'>C of unu<;cnsc oIigomers include poor uptal.:e into cells and instability to degradalion by nuclca.~s. Cellular uptake has been incn:a5.ed by microinje<;:lIoo and by the addition of llpofe<;:lin. a cationic lipid thai ;ocn:a....) cell pemlCabilily:lII Stability 10 mu:leases is unproved by repltl('cmcnt nf nile Ilhosph:llc o~ygcn wilh .ulfur Il) gi~e phosplKlrothioate nligonuclL"'Otides. The phosphOTl)lhioale group is ch irdl, bUI rucematC1l an: I!crlCrully u<.ed. m 0I1ler modifications 10 the ollgOl1l1Cleotide baI.kbone include Il.'plac1llg tho: phosphate .. nh varioos affiltk:s and acc:\als. and by usmg 2-f1UQfl)-2-tIeo~)'suga ......n l'eptlde nucleic ocid~ 111 ... hd. the sugar- ~phalC backbone is rrplaccd by N-(2-anunoeIhyl) Il lycillC unlls ha,c shown SUlbllity in ,ilm to delflldalion by nl,lClea.'>CS ..... 7 No\e1 antisense oligomcrs ha'e aoo been pl"l:pan:d "'lIh modified pyrimidmes. such as ~-(pro pyn-l -yl)uI"'.IC.1 lind 6-a/..lllh)mldme .~7J :md modificd po_
Singlc-~trantkd

,
h

Ji

,.

,.

,. "

li-

~.

r.; .,,
)

10"

".

I,.

An&l"llcnesis IS tile formation of new blood \'I:~sels. 11 is a IIttS>JIry bul care fully regukltcd COtnllOnem of normal polll!h arid \\OUllU healing. Uncontrolled IlngiogenC!iis i~ a dnolng factOf in wlid tumor gro.... th. TIle proc('~s of angio~I' I~ CQ11lplCl 311d requires the coordinated inlC1'lK:lion tllalhiplc cdl t)1lCS. Multiple sites for dNa Intervention ole (\pettea .... ' Endogenous angiogelM!!iis mhibltors .... ere In umx:~ weh as carti lage ... hkh lack blood \'CS5Cls. ~an:h afforded a proIein named c:anilagt'-Ouil't'J /II, ."'l Lanllnm i~ a mapoolllponcm ofoo'iCmcnt memhit. f'epti(k."li balCd on il~ struc1ure, ~l.lCh ;.., CDP(;Y XlSRNH:. mhlbn angIogenesis and ..ollt! I\JrnOf growlh.<6J I'IiIcIet foclOl" 4. 11 heparin-binding poIypcptide. inhibil.~ ..WI col()ll ,an,er cdh in micc. Heparin pn:parnlions line promOlc angiogenesis, but they strongly promolc the llllian,iogenic acTivity of small molecu les. Synthelic hell;l"'w~titule.~. including sulfatcd cyclodc~lrins- and sura~ inhibit angiogcnesis. and they are promoted by an"WK"cortiCOMCroids. These conu:ostl't"Olds an: Important ..... butlheir l!lucooonicoid and m;neralocOl1iOOld propClIUse 'iCOOUs side cffects. Related <tclUub that lack ~~';odc cffe<;:ls ,"elude II a-h}droron:isone , tetr~hydro .~ . and mcdrollyprogCStC1"O!le KetlUC ....... Tllc: amibi;."fumagillin Inhibits angiogcnesis In tUIllOf'O. and a nlOK ; III"I:IIOIIIIC. AGM -1470. rcdllCCS tho: gro... th nile of lImg ca"tf and melanoma in mi-.... 7

~ OH

~,

/" _,,----01-4
H

o
OCH,

'" 'oc

f'

".

.~

Tetrahydrocortisone

Fumag~hn

OH

o II

CH
N

C-

I '

l'

"

Unomide

448

Wi/IOOI and GiJ>ooId'~ TUlbooir

"f Organk

MaJi,..,w/ and P/wrmau ulical CIr~mlllry

rine,. such us 3-( I f/imid:u.ol yl)prOI)y l guanine. 4U Thc.<oe oIigol1lefS also have en h:lIlCw slability to Iluc lea.~,.~l'

HO

..

G
6 - :- 6

11 /

6 - :- 6

~t-1l

rty
FIgure 12- 8 Sd""'~ structure formed repeal sequence occu~ In

lA--G
3'

"

H2N ~

saM

quinone also show inhibi tion

4-C, o

~\

er
Telosrase Inl.. bitlls.

C '

~--<

Base

Telomeres are llucleoplOtl'in structUIn loc~ted at the ends of eocatyOlic- chromosomes. They proICCl chromosome ends from fusion and dcgntdation and en sure complete replication of chromosomal DNA. In human 50malic cell s. telomcrtS Ita"e 1.000 to 3.CXXJ repeat5. They gradually short.!n with e,'ery Cl!lI division. This shoncning i, thought to limit their prolifmuivc capacity. Canccrcclls. in contr.lSt. can mainlllin their telomere length and thus become immortali ~w. They do this by reactivating tclomerasc , a specific reverse: tnm scripl:asc .... ith an endogenous RNA templDte .41~ Selective inhibition of telomera.'iCi /los been recogni7.cd as a potentially important new method of cancerchemotlll::rapy becausc cllIlottr cells have relatively high concentrntions of teIOhk!tase. and it appe:m to be essential to their wnoival. whereas this enzyme is undetectable in normal somatic cells. One approach 10 lelomerasc inhibition is to usc antiscnsc DNA to target the Idomcrnsc RNA componc:nl. 4n Another appronch takes ad vuntage o f the remarkable pmpcny or 11'1 omeres (and ceruin ot.hef guunine-rich molecules) 10 form Gquadriple~es (Fig. 128). These structures arr associated ..... ith tlte telomcT'J.'iC reaction cycle. Hurley '5 group recently disco,ered toot cationic porphyrins, such as letramethyl(N. lllCthyl-4-pyridyl)pot .,nine (TMPyP. ). can intercalate tlte G -

TMPyP4

POTENTIAL FUTURE DEVELOPMENTS

Recent sequence determinations of the human .. , I!a" e opened the way to important new diagnosis and treatment of caflCClll. They ble to distingui~h genetic differences belween t and normal cells and to locate differences withtn with the DNA

cancers. In some cases, il whieh canccN are likely to respond t pies. nnd which tUmorl\ will not respond, palient with a resistant tumor ncedle.~s drugs ..tt1 Changes observed in

......, of drug~ can also be u-.c:d La predict thei r toxic cffc:ctS.

P\:!tu.~

the nlO! Importan t future use of DN A mlcr(XJ.rrJ),

tdmology will be 10 iderll;fy no:w targe ts for dm!; Iherupy. for example. elc' !lIed producl ion o f II s pecific protein may
II: ,ndkaled. and
arn agom~

may be oovc1otll:d 10 in h ibit

A Il('fllat i~c l y.

IIflltSSion of the gene that codes for ;!.

the

p:tteln lTI<ly be d irectly IImagoflll.ed. AI tile: pre.~n l tunc a ...M of manufacturer:s lin: producing DNA chl ~ for clin e rtSe3fCh. Many mdUSln:l1 and ocademic laboralOrk'l> are tbem in dru g discovery res.::ut:h. ProIeom lCS ;~ II comp iernc nlary technique to genomic. It IIK1Il \'cry ACYl'. but l Dborutori e~ nrc beginni ng 10 UcI~ nllirle

-s

D: enure spectrum of humun proteins. Thi s n.'<ocarch is imparw1t bccau$C the number o f different rn RN As produt"\!d

28. I.ia.A..... al C~CIoomoIbcT II"" ~l', 'Y7~ ~ ...... h~ G. - ' IlmetllhalD. I Am 00enI. Sox 7U860. 1%6. JO &lIa.$, W. C_no~. Rep lli. 19bJ. ,II. CI1.hner. U A. 01 lI. Pruc:. Sue .,.p U"" 1311169. 1969 31. T ,uj" T. """ K''''''' .... t:. M J "m C,,",m. li<,., U 1992. 197 L 3J. K,ollo. W . and y"". w. I"rcno:nn. 21:2114. IWd .\01 I"" .......... n. 11. _ Von 1k.Jtnbe.-" A 0 .... """,. I'twmawI 19, 1~. 191'0 j~ S._ I l ... aI . Cu.cerRt:l..lO;I ~ '.I97f) )6. Sa .... CO ... al. Coa<n T..,.. Rep 1>\ '11. 1"19 37. l.I0<II ...... 0 8 .. "'......... booi<'I) <II .lkylllO<Jn. An "'......... I. .Sanon:lk. A. C_ Md JoI!m. D J l<d.l IboMIbool uf EJ.p:nu>mul ~. ,,,Ul.pan L "" ... , ...... SI"'''Ino.Vnol ... 1975. p 7, 38 K",,". K W, .rt lI .. J \101,11001, 1922>. 19M .w 11..... It, C J 8~ AI~)I."n. AfCM' 1..ondun. H"'...... ooIIl.

cell! (e.g . as detc:nni ned by DNA microaml Yh:chnoIOj!y)

"",.
1M

.~

shows no com'l:lIion with Inc " um ber o f differenl propn:xIuccd in the 'ioamc ccl1~. Furthermot'e, ~rtcr their ~s. protci ns undergo ,nan) small chemic.. 1 ehange
TllChnlq~

_an pmfound ly affect their octh ily.

,.,~

for pre-

arrays of thousands of pruteins on a sma ll gla.ss slide' 11M: been de,i-.ed. TlK:~ lIrrny~ ~huw promi~ ii, Ikviee~ IIIcmble quick screeninj; of pote ntial drugs 3gainq prote in 1qe\1, as we ll as i !knli fyi n ~ pole ntially to ~ ic inl cn!(;tions "IIIIIl protein" nOi invol v~'d in the d isease process:""

IUUENCES
bI:Imd. C CO: A,.-. 01 mo.,." in -.pi"'''' <io>tav th s-nU,.
A.C .. 0IId JoIlth.. D. I (..... ,. IlmMIboot .... &prn"dL:lI~. fIf. 0111 . .\8. I. rw-w Yor\. S!"'''FVorla&- '974. r , t "$ood. R. r- . Ctll~lw of ",,",1IIOIlIcftpy In 1Jorr. liT . _ Von Hdf. D DIM.) C....,.,.,.CIIonxllhrnpy II:u1d1ooo1i ~r.lcd. N"",... I~. CT. AppI<\<>rI II unac. 1994. lIP 3_1 4 , \.Iac ..11op. W I . Of ,I, I r- ~ I C . ....-n ln>l. 7();'1. 1981 , SduftI. F M.. I, C....,.,.,. 33' 13. t9n ! \onIIo. L..oo S,mon. II . CIIItft Tn:aI lIep M lJ07. 1m, So__ ... II. T C~. II"" .u17'~. 19M 1 ,,4 " G.. .. al' I:h om, ... R"""" . AcU ~U7. IY8Il c '.... ;..C. _IIodp.C v C..ar!l.o.I::!93. 19-11 Ct A__ ""'11,1"-- F S .sclCllCC 103 40\1, 19-11> ,, __ . O. H C--.." 1:9-13. 1949 11' t. B I C~ 18 1551. 19M a.,.d. M II... Tho ru. ..... I ...,dop,,""'" . In ~oede!Mobn. I f..lf'd.), Cu""", Th<t-....,. In o..n.k.y. ~.w Y",~ . M.,.,.llloJ,.lno. 1 1'1'. 11-22. 99). I. s.t_. S, Il.," .1. C.""", Ch<~hc. 6: 10J. 1981 j ~ho'. ... F /<d.J: TN t<:>IlccIcd J>IIIffl' "r POIJI Ebrl"'h. v<>I I I f ' . Pup''''' """'" 1~. lIP ~II. !l~V_ .. al.J ~ F..>.p "'" 11:2M, 1911 IS 1, I A~ .. II DrIop for """"' ...... .the .. In 8"'F'". .... ,od.t McdocuolI Chtrnootr)" I'" ftI.~ .... YIrl. It, ,1<}.1_~e.

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38'1.

NewVcrl.A<.' , _~ 1960, PI' . 427~} . OociuI"""y. T P. """ Wh,1e. A : A.... . . A.... 7181. 196.5 Ho .. """",. I' R...... Ken4d1. to. C: Eo.dtitll"'''''rr ].I 4 11\. 1'IoU Don. T L. ThiN p..aI'ooaI C.,..,.,. eM""''''' 1'I",..<bnp. 1'11,1...... pi"... I II I.iPl"II<OO. 11)57. PI' 2'12-296. lion. M tot ..... Slmw. J A. SI ........ 17"'9. 1971 . ........ 0l0I. 0 M~ " aI: AM. I........ ~Icd. 53'1>71. 19IJO eo,..D IL" aI. I. MNI. Chnn. I~ U). 1976. Dlilta. AS . .. 01.; J . Med. 00tuI. 21 lOlL 1978. PIuonlt. P V ... "L II",... CMCei Reo. T..,..lO:IOl, 19').(

431 uti M,I..."._ e N..u .. 2Sti;W ..... 7). 434 I. Irnmu..... 14 7.2429. IWI 43$. 1.o8ulllo. A. F.. .. II Pro< 1'1..1. And. &1. U. S. A. 8Uno. 4.l6. T..... fIC". P. R.... aI UH>I/uooklar I) 2M. 1<J091 43'. It .... G .. or.1. ' - - 2; 1394. Iqsg, 4.11 ~ 1_: A....... Mop M.... Chtm.. 29:117.1 9').1 419 C.,.,.. P.... II.: 8 ..... 0. . II 10J.2000. _ 440. 11"""-.:11. 1 D ..... \!..!(c.... T 1 8.0.."''' +'1)' l:U9.I~ 441 Chua. MM. ... aI 0"",1Um. U.......,.... A<~ lII29l.1iJ1' 44 ~ Pa.IMt. L"'" Fi.II"""" I) : 5<.., ... B-I117.l . 1991. 44) Smon. PO' F"SI;B I 4188. 1990.444 C...... n. 1_... 01.: CIu"'IC.... JlI9~~;~ I . 19119 014', Colunobal. " .... aI.; II...,.. 97 101.1001446. f_.J M ~ .. III Clln CInc<tl IR:117.1OOO 4-47 . K....."IOIWI. 1001 .. .. aI U,S 1'_ ~.7 1 4.w. 1'dt l. 19'1t 4-1 Mododo. J -.I Siot,'o:B, F..: 000<""'C " 123.1000

432

R. A.. .. II JO ...

OnooI.' .... I,I98'7.

.ug SyN. I 8 ."" ' ....,... F. To"""". APJII. "--'>l. 2l:1"

Cha pl ~r 12 "",mfflPIaJltcA,gml<

453

,
s:

P.d.. O 1I ~-.lII""'.1> O. Palrnt.l.lJO.lll . ~~I Good .......... " NlM:I. MN. 8io1 13 ~N. 1986. ~\: huIIe. D, ... at- o...h. Mod . .... "" ..... .ctIt 1011 11\10, 1'f18 151 5<t.-........ c. H. I Am. 0..", s.." 77-1>2.11. I95S. I~ liNd.. " .... .01 ' I'or J C_ (.lin. 0IIr0I. IS, I In. I'llil. III I'ipa. J A . " I I / l>II ClIo;m. 12.236. 1969
W D,; U.S. P_n, ~.1601.6 14. Au . .... 16. 19&11 III M"...ui, P.. and IhA. .... 0 8 l'lly""', I!c~ 73: I 1991
'~M,I ... .

480. In!'

....... lIu .... Guool",

s.q...n.,,. Ct)IIt<JItIIm'I. " - "<)9

860.2001 . 48 1. V.... la. J C.. .. II. S<1<1I<t 2'lLl104, 2001 4112. M..... I St~ ~ I 670. 2000 483 MocK.. th. G.1UId Schrt,b<:.-. S. lkitnce Z~Y 1700.:1000.

SELECTED READING
Dun. R. T. - ' Von 110. 0 O. CIII<'CI'~ 11_......... 1'0....-1111. CT. ... ppIeIon oJ: t...n&e. 1m Fo)e. W 0 IN.)' C-. ~'" A ...... DC . Ad",'". Cl cal Society. 1m H"~ T C I....., l'ftdII:liOiI <J( It.......- '" C _ ClIor'_':opy 1'ic'"

..
~

l1'li

....
4l 1 ..
~

H ~ ... J :"""". It .... Med.. Choo:Jn.ltI 1'1. lW} ... It<dwood, S. \'- .. II C _ b'),llll. 1992. . . - . - l>I~ ... aI. J Bd CtImo. l66( 15) 9661 . 19'11 ~ 11_ ~ Tht1 .to) I. 1991........ M. A~ .. a1' Sex"", 20lil: 10. 1990. snI_ N., " oJ: C~ _. 3Ic903. 1991 \Wont. T. F~. " III.: Sc .."", Un1, 19I1O.

10.&"""""".

yon. AIoi! II . U ... 1988 Il,dman. J ..... """ Tnl""'. T it.: C....-rr Chtnouth<np)' Od..-.L Blad
",,,II s<knOLr", PIl~I~. 19\1). K"ppl..-. II K (~.), /0-1"",1 Compl.... In Cln",..- CI\t,noMli<ntpy. N.... YOil. W.lnI><'tn. IW]

Fulkman. J., .. 01.: Sd""", loU 1490. 1989 1M. ",nih. J W ... ~1.: , .... ",. A,,. A._ C.,."."n II .., .I I.W. 19'.10. 1 M!ldleU, M. A. and W,I~ J. W . "nnu. 11"1' M... . CIIn1, 21139,

1lIboJ. D.. .. -.I.; N...... :WS:55S. 1990.

, _ _ b... M .... "I... A." .......

,m

O'dwn. It il led): !'nne,pI<> olC""".. Booohct"P)', Ncv. Yort. lh''CIl

~cl.

A_. R.... Mm. 00< ... 29.291. 19').1 1.to""""',. 7~J 8 ""'l CIIo<m 21:127.1993 fi ~.... It. S., Uu. 1993 f>21. 1911}. m hllmler. B C .. eo 01. T~ I.dt, 34:1001. 1993 m "b'my. IC S.. .. 01 T.. ~ I~' J~.2IS. IWo! n wJC.al.. M II: I'.."e, NaI' Sci . u, S ....
S~

U:I,.J

It~

0.>

1993

PInod<o."

rrr....

19117
M .. ..,

(J(C_

~.

a-...-. G, (~I: Drut 1t.....>WKe '" the T..,......'"

Umoed Kmp.om.Catnbn.dfc U.. ,=-C) I"r<n.

S,,,.

..

''''. m
,

z.. ..

"'cad.

~! IS!:l.

"","" .. G . _ IlxUr. M 1M.): 1lk: TO.lI:ny 0( "'.."'..... Orur s"" yon. 1'nJ."""'."...... IWI Sclotloty. It. L M,1iInn, G. "' .. and 1Utao.. M I ,000000).I'n ... ,pko< of ",,,,, . nc<>pI..c1l: Oruz 0. . ...".,.". """ ~oiotY. 1'... yon. \bn;..1
OcU .... I9')6, T.. i<..... II '" (N.): Can<tr Cht"""""r...,c~"<> N J .. Ilutl""'" 1997 WnIlM. Q. 1... Jr M,,,,,,,,1Mat A""bo<.Ilf,o _ C _. 14"", yon.. M....-I

""

"" Lit!p:r. J.... 01. S<I"""" 276;561. l'in.

'M.

."..11.....

I\oIII!IIuIl. S. E. ... II. l:I""'htm".ry 16;1IS73. 1m It. T . .. 01 JAm. (.1M:m. Soc 120,'\611. IWI! I'm) . P L .. .01 . J :'11. C100mt 41 Un. 19911

rre....

T ...... ,.,

noU ... 1984

""

):m.

, '"

...

1:!'f1 .

Kl .

.em

1 3

Agents for Diagnostic Imaging

TIM B HUNTER. T. KENT WAlSH, AND JACK N. HAlL

Diagooslic imaging CIlCOllIpasses II group of tecllniques used in .he diagoosis and l~all'lM.'m of disease. 11le.q: teChniqllC.'S
often use chemical ~gl:nl$ 10 impro"c lhe inform.llion pr0vided in the imaging. This chapter is II discus,ion of the pODmlilCol"i!Y. chcmisuy. and physics of tho!;.e agents used in rMdicaJ imaging. Medical imagmg lechniqu.e$ often p!l'senl 1e:<I.., risk 10 pa. tients Ilian dire(:1 s urgical visualil"uion. Also. lhe)' often pr0vide information or treatment methods that are simply 001 available by any other means. What these techmques h~l\'e in common is thai lhe infonn:lIion i5 oftcn (btu T10l al ....ays)

displayed as an image for intcrprelalion by a physician tnlined 10 evaluate the meaning of the image in the C(lntClll
of pathophysiology. Also. all oflhe techniques use physical

energy needed to tlCCelc11Ite an electron across a pokDllll diffCTCIlCt of I YOIL TIIC second type of ionil.ing radi... is called dlrtlnIaKllt'lic rodiafiOll. EleclrOnulgndlC __ tion is lUI electric nnd magnetic disturbance tlult tS prqIIgated through space at the speed of light. This t)'pe ofndiJ. tion has no mas..~ and is unaffected by either an ckctntllol magnetic f.c:1d because: it hIlS no ch:u-ge. TIIC.se 1""",.110 arc shred br radio waves ( 10 10 to 10-4 cV). micll,l\l"J\'eI (lO-ti to 10- eV). infrared (IO ~ to 1 cV ). visible lighlll to 2 eVl. ultnlviolct (2 to 100 cV ). or It-rays and gamma ('/! 111)'5 ( 100 to 10+ 1 cV).1lIe Yariousfonnsofe~ radiation differ in thc:ir frequenc)' and, therefore, thdr 5erg)'. Th.c energy of electromagnetic radiation can be aJtt. late(! in elccuon vol ts from the following C\juation:

phenomena (electromagnetic radialion, ultrasonic

waye.~)

that con pass through tissue to COflvt:)' the internal infonnation rteeeSsaty to create 1111 image. From that point, the techniques of medial imaging dherge in their physiul means. methods. and the information IDat they C1lll provide. Medical imaging began with Roc:mgcn's discovery of x11IYs in 1895. and it has been the domain of diagnostic radiol ogy since !hen. In its earliest day~. lhespecialty of radiology used x-rays to produce im~ of the c hclit and d,cleton. At the ptl!.'lCnt time. dIagnostic radiology uses ioni:.dng radi:uion (x-rays). magnetic re50nance imaging (MR I) techniques, 111ilionLlt"lides (nLlt"lear medicine). and hig/l-fmjucocy sound waves (ultrasound) to prodt"" diagl105tic images of tile e body. Today. r-Jdiologists and other physici1llls also usc diag/lOSt ic imaging techniques 10 guide themselves in imervenlionru procedures. such as organ biopsy or abscess drainage.

"" --:.
"here II is Planck's constant (4.13 X 10-" eV-II). I t the fmjucrocy (hertz), c is tile speed of lIg/lt (cmlsec)." A is the wavelength (em). TIIC difTerellCt betwccn x-ray... Y-l1Iy s is based on where the)' originutc: x-11IYs oomt' Frtootside the nuclcus ...... hile y-ntys origirllde in the "::::, an atom. X-f"il)'s and y-ra)'s can exhibit some PI properties, so they arc sometimes called phOf/HU. Applying a very high voltagc (2Q.OOO to 150.00) \ to a glas5 vacuum tube Ih:1I contains "'''~~;~;'~~ anode produces Hay' used III diagnostic ~ I). TIIC cathode is a filament tlult is heated 10 I temperature. which prov ides a !':Qpious ""~~~ TIIC electrons are accelerated toward the anode (tungsten). When tile ICccleraled anode (called the IIIr81'1), X-I".I)'S are producro. lion of X-I",l)'~ is a continuoos spectrum, and the It-rays, which will IlOl travel Ihrough the body film. arc absorbed by a filta- (aluminum). An modifICation of the X-11I), ~yslcm is nuoroscop)'.ll"".... it)' allows one to visuali~.e organs in motion. posillOl patient for spot film exposures. in..ti1l meW hollow eayities. and, most importantly, arteries. Figure 13-2 shows a schematic of a system, With COI1"emional 1II0gnlph)' (Cf) (sometimes I ph)' teATt) scanning, organs are uccording to how welllhey UllcnU91C x-rays. of xra),s by ti ssues is H romplex process that many racton, includmg the energy o f the JI -n.y the density of the tissue. Bone has an average about 1.16 gfcm J which !lC<:OUnlS for its ability most of the radiDtion it encounters. cr S(:anning 3)uscsordinary

lNTRODUCTION TO RADIATION
Radiallon is the prupagalion of energ)' through space or malteT. In chl-mical reactions. 0111)' tile yalcroce electrons of an atom are affected, and the nuc leus remains urochangtd. Nuclear reactions rna)' result from bombardment of a stable nucleus with high...,tlC.gy parlicles or decomposition of an unstable nucleus . TIIC nuc lei ofatom s are of two kinds: stable and radiooctiye . Radioactiyc nuclei have more imcrnal en ergy than nuclei with a SUlble ammgcmcnt of protons and neutrons. 1bcy obtain stabllu), by emitting energy in the fotm of paniculme and electromagnetic radiation . loni-dng radiution is radiation tlult when interacting with matter can causc changes in the lIIomic or noclear structure of matter. llle first type of ionilting radiation is particulllle. which includes alpha (al. beta (/1). positron (P ' J. proton (1'1). nnd rocutron (n) panicle.li. Radiation is cnerg), in the form oflineticencrg)' and on the lIlomic scale is usuall), measured in electron volts (cV). By definition. an 1'1lrotI 1'("1 is the

454

"". . 'lI

ommendatioo of the Interrullional Union of Pure and Applied Oacmistry. lhe following notation should be: used ror t~ idenlificalion of a nuclide:
~X\.i
p

.5

Example: 'lll~

""11 (1

llilll lion .dill-

dill-

"~ rties
,,~

letie en.lleu-

.("
tu ....
!clli.

where X is the symbol ortheehcmical elenlCnt to whIch the nucl ide belongs. A n:prescntll the atomic ma.r;,s (numbl'r of neutron s plus lhe number of prolOns). and Z representS lhe atomic number (numbtr of protons). Tht right side of t~ elcment is n:scrved for the oxidation Siale. and N represcUlS the number of IIC'UII'OnS. For most medical applications, il SUffiCd to indicale lhe e:le:pr:renl chemical symbol and the mass number (i.e .. Il Pl, I_I J I, or iodine-I J I). '!'he rndionuclide lit the: beginning of the decay sequence is referred 10 as the ptJunl, and the radionuclidc produced by lhe decay is n:fern-d to as the daugh/rr. " 'hlch may be suble or rad~ive. llIc:re are five Iypa of radioactive: decay, distinguished lICCOf'ding to the !\alllre of the: primary rndialion e'ent. A ,..Id~he: nucleus ma.y decay by nne than ooc: method. The dominam method at any givcn ume depends on such faelors as the: size of the: nucleus and the balance: of proton~ and ntuU'Ons. The types of decay described below are in order of how comlTlOnl y they arc: used in currenl di :lgPllY.>tic nuclc;;r medici ne prnclice:
I . I_ r i c I ...nsllloo (IT j.iiOr\'le;ic PBII'Iition is. deca~~, invoh pna ndther the cm5~101'1 nor the capture of p;u1M:lt 'The nuc"'Ut Jimply ~hanlt'lo rrum h5gber 10 I lower enclJ)' ",,,,,I by cmin;n, )"na)". Tho:Kr~. both IIWIi number and .tomic

"" ,,""
.~
from
ating high

ne

lIscf ulate

rohs)

J. I J-

""" 13- 1 SchemMIC dl<lgril/T1 of an Hii)' lube producJOg '"'I'I1iv1 poilU through ttw pa\>enl MId e.pose the pholo,.;~ i.m The photographIC ' 11m WI. oot stop the ",rilyS. III pt,sIlC $CrHf\ (l)iIled WIth fluorescent particles thilt are ItII lied by the ~-fil)'S ernolS hght to e~pose the lilm Within a If(-ughl hIm cassette ki HiI)'S piln thrOl.l9h the body. some an scattered. so a ITIOYlng gnd dew:e compos~d 01 !ll:l!nitJllQ strIPS 01 lead and plastIC deaNses the sca ttered~ ~ that degrade the Image

"them

...'" ,,'"
..y
"'-I'lIY uable

''''''-

lribu-

,'"

_ I-

I mto s inlO loopic

!d 11>-

""00 u"'"

wgl'llrisi ble ...alion

.ilY 0(

,""""

g. I J.-

..I"twatieal reconmoctions to produce images of the body the Ulal and other planes. In the process. il can incn:ase II! IiWility of small differences in the radiographic densibetween tissues 10 a far grcmer ute", than ordinary ...... ~ .... lC film can. bdionllClidcs undo'rgoing transform:llion p.ooc:sses. ":~;~::Ikr:tQ'. in mos\ ca<ie5 invoh'c Irnnsmutaone I inlo another. A nucltu~ may undergo RImI decay~ before n:aching a sUlble: configurnliOl1. A nudarpanicle:. citner a proton or a ncutl'OO. i~ called a nucif!lJfI. A1f'tC1e' of alOm with a specified numher of ne:utrons and IftIOIIS in ilS nucleus is called a nuclidf!. Nucl illeli with Ihe _ numlx-r of proIons and a different number of ntulrons R ~kd iSOl(//~I. NIIClidcs wi lh SlIme momic mass are *d iJOhars. Nuclides with the same numbtr of protons "lIOInic mass but at two energy leyels are called iSQ~rs. The nl.lClcU5 has energy levels analogous to lhe orbital "~"i shells bul at a higher energy. The Io"'er energy lc,'eI c6d the grooruJ (8) :stal~. and the highest energy 1e,'eI CllIed lhe ~Ias/abt~ (m) S/QI~. Nuclides are all species stable nuclides.

II

Fluor II - _ Sc 111

mple'"

more than 2.500

In lICCOf'dance wi th a Itt-

Figure 13- 2 SchemaIK dirlgIam 01 ~ tluorOSCClp+C \.IIlpt WIth the x-ray lUbe localeO beOInd the pallent and a lluoresctnt scrl'm-IrTYqI! Irlteruaher system pos.>tJOned on the opposite SIde. ~lColbon of faint fIoorl'SCJOg imagt' by the PrTYqI! mte-m.tfier Increases bnt;JhUleSS IeIIE'l and contrast The reft-llme fluoroscopic Images un be shown on a teleYlsion tamera for COI'l'II!ntent vaewmg dunng the tlWllll"liltlOn and stored on Videotape, Yldeo dISk. or computl!!' lor !atl!!' VItWPIllJ WIthout distortlOP"lOl destructIOn of lhe Images

~-

Orlglnallmage
Reconstruction

in lhe CaM: of an eleclron. " rer- e..ents clIIL'fJ!y cqu..... 10 ""'" (III - 9.109 x 10" kll al ~. and <" " IN: >peal Ii hllhl (3 x 10" mI...,). By USlnglhe P",,"" unu'! 11 can he ~ lhallhe mu'~ of nn ellroo is equ lvalenilO O~ll MeV,"fM.
c.lln! _,h,/mWn _/ialif,... 11 ilo u.cd 'n a 1'ptC'~hud '""""" technique <"I11n! "",il"'" rmml<Hl l<1IW>/t:rupIo. WEn
....... mplc:

whe~

':F-':O +

}'"n}

p' + (' / - X-ray TUbe

2 ")'-flI)~ (0.:'\ 11 MeV )

4. ikl" pIIortkJ<o ~."I!osion (Jr). ~ nude~> t'mlli' neplJ'"''

Iron ,,hen. noculron chanl1C!> 'o. pruIOII. A l'""'Y .....) .. ~

"'" Xl:OInpany lhe cmis.ion of ~ IJ pa1lidc

~ampk": '~ \I
I'!

'UXt'

+ I> +

")'-rny
o",,:~

S. Alpha-partkJ<o mllssloll 1ft). Tho: nucleu. millS an

"h'e h C"<.>II.iSlS of . helium noc!.:us w,11>o\11 lhe ckx~roM.lt .. em,sslOll orlbe .. panicle ",.. efi the: n""Ieu, on an u dted Male, the: t'''~ t'r>CflIy I~ hberated on the fonn of. ,..~
Eumple: '~Ra-'~R n

~lIc

l'"r'lIy

CHARACTERISTICS OF DECAY
II is ImpossibJc to pmiicl "hen an ",dl,idu3! atom oil rudionudidc will dL'C H In qU<lnlilalivc y. lransformalion occurs I I I rule tru.t i'i specific rndionuclnk and l~ expressed as ils life. This i~ lhe lime Iii of aloms decay. The IICU~ lIy of radionuc1idc~ pre. ~scd in Ihree WUys: (II! in i or nllcrocuncs (,uCi):(bj in . i and (e) in bccqucrels (Bq: I Bq .. A quamil)' of uny radionuclidc thai 10'0 dps. Thi s ntlmber was cl10scn a son- lhi ~ !~ the number of di ~i nlegrulion g of radium. TIll: inlem all()l1a1 ~y'ltm

Radiation DetaclOo"S

Figure 1 ] - ] Sc:hematic dlilgram of a Compult'llle\f .utailomography (An system thaI producP5 thin cross-sec1.lOOaI,mages of the body. An _-faY lubf rotales around the pattent, and 1M Iransmllle<! . -ra)'!j an! detKled by a CIrcle of mOVIng radoabon detectors The absofptlOl'lS of x-riyS by trssues of dif ferl'fll densnll"S .tie MSiyiOl!d nUlTl@ftUI v"lues (CT num~)_

The computer uses comple)( algOrithms \0 recorrslfUct an anatomICal cros.s-sectlOllill ,mage on a leieYMln mOlll1or

curie: is sli II widely used, und we 10 the official unil. A rele'anl is the following:
I mllhcune (mCi) ., 31

lhe becquC'1\'1 as lhe offiei31~"~";":0:';~~:~::::

~um:ls

number remam undlangc:d The IiNllhlCT nuclcm i~ the: !.arne chemical r lelr.cn! u the origmal nllCku~. 'The onginal "ue leuo bl:fcn thr transitl(lQ "wd 10 be .n a rneIaStDbIc: (m) ~c_
~amJ'lc:

(MSqI

7,Tc-:;Tc + ,. ... ~)
&/001 (mainly !he Ie
~tM:II).

l1Ic bil.sic cquallon for radiolll:li ,c decay follows in lenllS of 1II01l\\:

N," No , -AI

is "I~'"

2.

~:lIron n plu~deooy l .;C1. The nocktJ~eapllln')"c~11't)fI

from ,he: ele.:lron

I proIOO

ctwJ of the ~ a M Ull"!!,

E.umplc:
1~

and

Ii :" H _ '~1Tt'+4' pm;

,.... y

N, (number of at oms al lime I) and No (number '" ,. . al lime 0 ) can be I't'pl3Ced. ho\\e,~. with &CU,llIes:

J . l'ot;lttuf1 r mis.ion (13 +).

nucleus cmll~' poIoil,ve dlron

the /lClivi ly at lillie I. A i~ where Ao original the physical halflife): and
A ~ of

"hen _ protool (h~np 1 a nn11ron. A l"ray ~)' or ~y IlOl 0 k<:utnpany lhc: cnmo ion of the polS moo. A posinon (parhdc of

8nllm:lllCf) cmulC!d from lhc: nuckus ~ ilS klrocuc energy. how,,'..... by ,mcnctlng VI uh wrmundinl alOm'i. II fi.wly <;Om. bille, .... ith rree el<.'ctron from one of the sum)llndmg alom'! III .. inleracti<Jn in ,, '"ch lhe Inl ma ..., of both pmuclQ ...., ,I,en up al 2 l'"rlIys of 0.:'\1 1 MeV emllla! II 180" 1 earn 0 other Em sle", 'i lhoory of ~hO\',",ly ' lalCl Ihal IlI:W and ene'lY an: I!tjuwaknl and '" ~~nlCd by the followin, ~IIOII:

i~ lhe

ac;~~,;:;,~,,~,,~,"~c~"~Jm~c;~.,~;:~~~
iC\M1y

pic of a r',t(,hOOClivc decay cakulalion 01 May t 4 ~1 12 /lOOn C.S.T Whill IS the ,'::M.", oM., . .... ES.T 1 (Nole (alcul.JlJOnS 01 ~ ~ Il'!-sodll.m tCXIode had an

rout~ ~arlabOrlS

In tIme ZOfIES-eI3psaJ tIme In Ihl'l caSl!

(I." (~,2~)

!S

~- ,

A _ (200

~;) (, I 16)

(200 ~i) (0.2.$5)

A - S IO~;

BIOLOGICAL EFFEGS OF RADIATION

fitJho;orp!.OIl of 1000iling r.ldlalloo by living cells al"3Y' ,,;.;;.~ effects poIcntially Mrmfulto Ihc Irrudmted OI"gana An uOOc;;irJble aspect to the medical use of\he..e types _1"*11;1/100 IS lhal a small number of the IItOffiS in the body ~~"ill ha, e electton~ rem(wtd as a resull of the eocrgics ~ phOton>. Radiallon th~1 does this is often called Jll:Jn6 mdiutlml and l~ damuging to body tl\~ues. There_ ,in usin!! lonil;ing I"".Idi3l ion, as in usini: other pharrna';~agents. thc: risks must be oolancal wllh lhe medical Ib pr<)\"Ided for thc: pallent. The IImOtmt of r.tdiatioo enefJy absorbed by tisWt i~ radiumm uh:wrlNd dou and is specified in r.w.s or tails. A dose of I rad IIllplies 100 crgs of energy abpt'f gfllm of any ti~~ue. The unit of exposure for xam y f1KilatKIII jn air, the roentgen, is u~ 10 specify le,ds III the en~lronment. (One roentgen is lhe of f"8(b~lIon th~t proJuces I clcctro<OlllIlC unil of of either sign per O.(Xll293 g of IIlr aI STP.) The uooal ~ystCn1 of units (SI) has adopted the gray (Gy ) - 100 rads). but again we will use i . In the Cli5e of x-rays or yradilltion the roentgen and r..d tum 001 to be 11M: major differrncc heh...n ciccI 1 (X-I1IY$ or ")'-rJy~) and paniculmc type apanldes) lie.~ in the ability of eiecU"Omag TiI)'S \0 pcnctr.ue mallcr. Whereas fJ panicles lra,cl .". rev. milhmclcn btfort e\pendmg all theIr encrg). :t}'"f.IIys di~tnbute lheir cnergy more diffusely lind tra\'cl ,,;,~"~ of lissU('. Therefore, panicles rndintoon dO'<Cs. wocrea> x_ lind ")'more unifonn doses m a less oonccmratcd way the Irradiated ,ohmle of tis~e. The rndiation IS mort' ulICful (or a thcr.tpeUIIC ~ of a but oot: for a i ' dose. When cells are is primarily by ionil.lllion and produce dlll1Ulge by ioniJ.lltion. prodoce damagc by free rndieals. :u-e atoms or 11)0lecule~ wi th an unp;ured eleelk cffecb of large doses of mIIialion were deri~cd from I ~t odies ofthc ~to,"ic bomb 'Urvi~Ofll al Hi .. Radiobiological dl1ll1~ge from large can be caused by two different ;m.~ the: dirul ~ffecl of radiation, absorpt ion of r1Khlllion cnergy I biologienl ~ ue or target. The other, called

the indirect <'jJec/. involl'e~ aqueous flcc radicals lIS inlenncdiaries in thc transfer of rudi~I'on energy to the blOtoglCnJ molecules, All bIOlogical iySlcmS COIluun waler as the most ahonda.lll molecule (70 to 9O'l. and radi()lysis of "ater i~ the I11OS\ lil<ely c,ent In lhe lI1iliation of luologlca] dama~ . The absofplion of cnergy by It water molecule: result~ in Ihe ejection of an eleclron with the fonnallon uf a free rJtiieal ion (H 20 .. ). The free mIIlcal ion dl~iate5 10 yield a hy_ drogen ion (H ' ) and a hydro.,),1 fo.."C r1Khea] (H().). The hydroxyl free rut.llcals combine to fonn h)drogcn peroxide (H:Pz). "hich is an o)'id i/mg agent . In addI tion. hydrogen free radi~al~ (II ) can form, IIhich .nn cllmbine with oxygen (Ou and form a hydroperox y-free radical (/lO:). 11M:sc: 1"'0 reactloo intermedIates are "ery reacthe chcnncall) and can anack and alter chemical bonds. The only ~igniflCllnl 'llIr_ get.' molecu le for bioioglCnl dam:l);e is DNA. Types of DNA damage include single- and double-challl breakage. and intemlolecular or inlmmoleculnr cross- linking in the doublestr:lllded DNA 1I100ule. With the direct effeo::t of r.tdi~tlon . the ~e makes cell replication Imp05..~lble, and t'ClI death OCCOIlJ. In the mdirea e(fOCl of radIatIOn. If the damage IS oot: lethal but changes the gellClic sequence or ~tructure. mutations ~ur thai l11;1y ICJd 10 cp ncer or birth (If genellcally tlamaged off,pring , Some effects of radiation may develop Wi th in a few hOllrs ; OIhcrs may t~I<c year1 to become apparent. Consequently. the effects of ioniling rlkiialiOli Oil human being.s ma) be classifitd a) S{)nlatic (affOCllng the lrrnd,attd person) or genetic (nffecting progeny), Radiation dose. call only be eSl immed and ils 'measurenltnt" is called wdia/i(NI dmimeln'. In tile case of ~ -flIy e~posure, moSI rndiauon 'doscs m the InerutuIC are de scribed as the entrance e~posure (in roentgens per mmute) 1 the paticnt. In dlagnosllC nuclear medlcllIC procedurc\. 0 p3lienl~ are ll"Tlldimcd by mdluphnrmact:ullcah locali1.ed III o;'Crtain organs or distributed throughout their bodiC'$. Since the r.tdioouclides are taken Inlernally. there lit\: many ' anabies. and the nKliation ab>orbed do<e (r.a.d. or rad) to Indtvidual paltents cannot he ,nellSurcd bul only estimated by ealcu latioo. 1lle methods of caieulallng Ihe ab..orbed tIo!.e 10 paticnls from rndiophanna.cutical, were chunged in 1964 lind then n.:vlscd by the Med ico l [mernal Radiation Dose ( MIRD) ComnliuC"C under the uu,pkes uf the Society of Noclcar Medicine in [991. Although thc: effects of radiation are not \(lIally under~tood, the benefils llSso.;,:.ted with low dilSt!"> o( radiatlnn almost always outweigh :Iny poIcHiial ris~s to individual [>il tienlS. A IMgt number of sciemlfic and ad~iO\Of)' groups ha,'c published nd; estimates fm ioolZlnl! radlaliOfl. but the nMN w.dely qooted is rc[lOr1 numbtr 5 of the Nahonal Academy of Scicnces Commince on the llioioglCal I:.ffccts of lonlling Radiation (BEIR- V).I Under normal cireum~\.alIC('~. 110 radiatinn worker or palient undcrgoinj diagl"lO\lIc In,'csligation by radlophllrlT\;lo;'Cutkal or r.tdtOgrnPhic pmcedures .hould e~er suffcr from any actItc or Iong-tenn inJUry. T)pocal rndlatton doses to paticHis from l1IdiophanlHtCeuticals are SImilar 10, or les~ Ihan. those from rJdiogml'tnc proc'Cdures . 1lle fir.>tllItificial rlKliolluclide (phos.phmm-JO) "as produced by the French rndlOChellllSIs Frederic JoIsct and [rene Cuoc. Noclear medicIne became a spCC"lIlty in 1946 "hen radionoclidcs became a,ai lable from cydotroos and nuclear rcactOfll. [n many medical centers. nuclear medicule i, cnn -

sidered pan of diagflO$tic radiology, although in some bcales it may be a freestaooing discipline or reside. in ~ pathol ogy or illlemaJ medicine depannx:nl.

TV"""'"

RAOIONUCLIOES AND RAOIOPHARMACEUTICAlS FOR ORGAN IMAGING

MedICal science provides a framewor1o: or paradigm in which I() undc~tand disea<;e and to maintain lx:ul1h. Nuclear nx:dicine is the broneh of medical science thai ~'OI1lributes 10 medkine by tlx: use o f the radiottlK:er method for diagnosis and use of in vivo unsealed rndioacth'ity for therapy. Nuck'ar medicine in"olvo:s tlx: admiDistrotiOf\ of radioac tively labeled COIl\POILndS W Iffla a biological ptOcc:ss. This process may be mechanical <l:aSlric emplyill8, blood flow. cardiac wall motion) or a variety of OIher physiological funetion,. Within tlx: COf"Ipt of a "r,l(!iot/'llCff" is the implication Ihlll the agenladministered "'ill not dist urb the fuoction ing oftbc process you "'ish to examine. In nuclear medicine. this concept is used to trace phys iological processc..~ in vivo and then compare them to ~nown normal images or levels. These an: tlx:n evaluated ",ilh a knowledge of pathophysiol ogy to allow diagnosis of dlSC&se. The data can also be u!icd to follow the palient for improvement after I~atmcnt. In clinical practice, nucicar medicine also makes use of in vitro diagnoslic method s (radiOimmunoassay ) and in vi,'o radiophannaceUlieallheropy. These lUSItwo are not further ad dressed in Ihis chapler, and there is minimal discusslQn of invcstigatlQnal diagnostic radiOlraccn.. The. specially of nuclear medicine did not become avail able to the privale hosPItal until tile 1%Os. after tile inlroductlQn of tlx: molybdcnum99ltechnctium99m gene rotor Dnd tile gamma (scintlll:llion) camera developed by Hal Anger (Fig. 1)4). The. lno>.! common use of nuclear medidllC is to image the distribulion of rndiopharm:.ceulicals in specific ti ssues or organ sySleflls with a scintillation (Anger) calT1Cl1l fOl" diagnostic purpoSC$. Fundamcnwlly. thcl!c instruments oreamerns allow in ~i,o detC(1.ion andlocali7At>oo of radiotrnCers. The. pUl"p05C of tile gamma camera is to record the location and Intcnsity of the radiatlQn ",jibin the imaging field. Rudiation in the form of gamma photons (occasionally,,;rays) imti:llly enters tlx: camera through IIx: collimator, which usually is a sheet onead with multiple sma ll . precisely made holes. II CO\'ers the detector crystal. 11x: purpose of the COllin13lor is to decR:ao;.e scanered rodiation and increase 11x: o\'crnl1 rcsolullon of the 5)'~em. Photons lhat are not blocLed by the col limator then entcr a large Mldiulil iodide (with a small amotlnt of thallium) crystal that absorbs .,.. l1Iys. The absorbed cuellO' III the cry~tal is emilled as a nash of light (called a scintillllliQII), which is proportional to the energy of the .,..ray. Coupled 10 the bad: of tile Na l('ll) cry~l an: photomultiplier ( PM) lUbes 111.11 CCNlVert the light nashcs to electrical pulses IHOj)()f"\lQnal to tile amount of light To 1000Jliu tlx: original source of the photon (and create an image). a computer assigns )l- Y spatial coordinates to the vanouJ .,..rays coming from the p.1tient and stores this information in a matri~. After collection. the digital image is COlwerted into an analogue \'ideo signal for display on a

,_ ' . A

. '"

PMT.....

Figur' 13-4 Schematic: diagram of sontl llatlQn UIfIlI1 (Angef) system WIth a mu/tlt1Ole lead colhmate. alla:htd eliminate ~allered ")"fays), wn.ch IS used 10 VisualIZe I!S$i.It!I an<! organs after a dia9noslK dose of a r~!U adminIStered

video moni tor. The images obtained with the iClnull_ comer.! an: called scintigrtJrru, Klrltignlphs. or JroIU clear medicine imaging studies invol Ye the images that represcntthe functional in the body. Especially when inlerfllCed dYllllmie tent." information etcn 5tlCh as

""

'"1 is a schematic of a ''''' I )6

system. 'The S I>ECf systems usc one to thn:c scintillation tOB that rotllle about the ti SPEer is wilen i sioDal . organ~. 131 llcpicts a perfusion .san

"'~.
A

~w,,_H' ~~m;".

uses

Figure 13- 5 DynamIC study of the Irvef ,md blll<1Jry S')"IIffl1 With a gamma cameril Thts is a normal study aftet' H'liKtIOl"l of Te99m mebroferun. With each linage a 3-ffllf\ute time exposure The $ludy W<15 done on
a pallenl WIth SlISpKted acute CholKystltlS (il blockage of the duct to the ~Ibladdtfl If the palltnl had acule d'>c1~cystJl!S, thl!-radlOtlacer would not hallt' eotefed the gallbladder. Tl'1e.mow in frame 16 shows the

normal locatlOO of IN! gallbladdef

,,- TV_
Computer

,""

Figure 13- 6 Schematicdlagramof oil rotating tuple-detector sclntdl.:lbon CMOefa system for Single photon erT\ISSIOO computed IOmogIclPhy (SPECl) demomtratlng" "cold" spot IeSltIO If'I the bro1ll'l on me sagittal VIfW (opM MI'OW)

Figure 13- 7 SPECT rTl)'OC<Ydloll perl\Mlf\ study tmng thalllum20t itS the radlOtrolCef SPECT images afe Ihftoe..d,rnens.ooa[ and are oftl'n .".eMeI In tomogr.phlC slICes. The long ",rows II"idlCate the iIboormally c:\Imlrushed myocardial perf\Mlf\ In the antl'nOf wall 01 the left vtntnde dunng Stress (exerose or phaliTliKG1og1Q1), compared WIth thai of the same p<ltJl'nt dunr>g resl The stress and fest Images are ITIiI td1ed In spattallocat'on for e.JISIl'f companson The r./ng/e shorr ilrTOW indicates an add'tlOflal iIbnormal afea In the II'Ifeoor poruon of the left ventnde The abnorrTlo1l,tll'S IndICate that the patoe'1t has a h..gh 11Ir.e/,1lood of !.I9ruflCaf1t coronary artffy narrOWIng, wtuch C<Vl be confllmed by cOfOflafY .ngoography

TABLE 13-1

PfT R.diotrillun

~ '" 7 ., 7" '" C El7 'J

I' 18-lIaIuj><fodol

'" Isn-s..ru.,II.....,..,(RlG
HI n...-lopa
F I8 nututth)hpoP<n* ~ 18 n\llJtOlltl<,1
/10 .",..." (f'l-I ~I
~II

1'1.1 .............
CIl~

C I I (orf_1 CII ft>nJ!Ie

Clt Figure 13- 8 SChemat'c diagram of iI PH lmag'ng ~ystem WIth multiple sootlllalJOf1 detectors tha t localize the posrtron decay iliong a hl"lf' By U$lng muillple posr\JOflsensotNe detectors around the patll'l"lt, the af1l"11hdatJOf1 pholOll~ are iKqUored alol"lg fTIiIl"Iy parallel "fIl'S aocl fTIiIIly angles IoImultaoeous.ly WIth four fll"lgs of detectOfs(OI1ly one flng mov.-n). After u~ of reconslructJOf1 aigoflthms, the loternat diStubuhOfl of the radlOiK1Mly <.10 be delerml'll'(\ ilnd d~ on a cathode f~ tube

~)I

CI I Inoo. .... CI I 1I'IOthooD,...

C 11 .... lhyl>PI""n)IOO

C_I L roo.klpride

O-u .. __

OH"",....
()'I~

<Wboln d;". 1<l<

Rubidi ...... 82

- -------Figure 11- 9 PT whoIe-body ,mages perfOffned to <!elK! metastases after I",echon of 4 mCi (148 MBq) 0'1 flUOOOf l'ar.-1-2-flvofo-2~u case (f-18 FOG) A . Normal whoIe-body PET.mage (coronal VIeW) obtained ()fl oil palJeol wittllymphoma after trUtmf1 ,1 WIth chemolherc1py and fadiotherapy. 1M patll'lll fasted for 12 hours 10' ma,n\.am the blood glucose level bel\~eei180 and 140 1Tl9'100 mL If the blood gluCQ5C! INeIIS not '" th.lt lange, F-18 FOCi uptake IS decreased In the h.i1TlOl'5 becaw the iTM'ChilMm of uptake IS iIf1 incleased late of glycolysIS (Note oncreased blain and cardiac: uptake becaw of high glycolybc rates II') mese organs) B. PET whoIe-body Image obta,,'\l!d With the _ ted1nlque on a patlEflt With panCleatIC UfOl'lOffiil. Abnormal IoItes of F-18 FDG uptake are seeo In the upper aboofilen. postenor medlCIStmum. and left Iowet' neck (,;Jrrows) ~steflt With neoplastIC In

Q.el'ilet1t. (Note lflUeased brain. but not cardlilC. uptake of f-t8 fOG in thts patlEr'll who had a desirable blood gluCOSE INeI for tumor imaging.)

, . . . ~:~~:~:~;;.', (fill - 20 rninUIe!i), oxygen -15 (f In 01 . nitrogen- I] (" ll - 10 minutes). and fluorinellill - 11 0 rnimllcs). Table 13- 1 shows examples of positron nIlIiotl'lllX'l'li thaI have: been inve.~ligated in

tr.: nnlifl(: lher.uure.

. . ;.,~ managcmcm modality.
~ 139 shows I'ET whole-body in~gelI from patienL~

PRODUCTION

":':;;!.:; '~:~;~::'dicine are artificially a

i~

is

neutrons. pro4oo!l..

on atomic nuclei and

artifICial production T"C<juires pn:p:u1IliOl1 of II target systcm.

target. and chemical sc:parotion of the radio{rom the target material. 1be radiochcmi-

..

final product I productiQn of a nuclear reactor. cyciolton. Of radioi_

where Cd-1 12 is the stable target material. I protOfi (p) is the bombarding paf1ieie. two neutrons (2n ) are emitted from the nucleus. and In- Ill is the: radionuchdc produced. The introduction of radionuclide gellerutOfS into nuclear medicine arose from the need to iKlmini ster large doses of ~ short half life radionuclide to obtain belter ~tatist ics in illiaging. In considcmtion of radioac1i'e (parem and daughter) paiD. we can distinguish lWO general cases. depending on which of two radionuclidcs !las the: lon ger h~lr l;fe. I r the parent has a longer hllif-li fe than the <bughler. a state o f 50called mdiooctj "e equilibrium is reached. That i.s. after I cenain lime:. the 1'1110 of lhe di sinl egrntio n I1It~ o f part'nl and daughter become constant. In the secood case. if the parent half-life i ~ shortcr tllan lhal of the daupller. no equilibrium is reached al any lime:. TheldOl't'. the gCllenl principle of the radionuclidc gctlC'mtor is that the longerli " ed parem is bound to some: adsorbent m~terial In ~ chromatogntphic ion exchlUlge column and the dJugtllcr is eluted from tn.: oolLimn with somc soh/ent or gas. There are more than 100 pos.~ible genemtor systems for clin ical usc, but there is only one in rout ine use in nuclear medicine (the mol ybdenLlm-991techllClium-99m $ystem). All orthe mol) bdcnuf\l-99 lIt!he pre.'>C.nt time i~ obIaincd as a fission prodLlC'l 0( unaniurn-2JS in a nuclellT rt'actor.
1~;U (n. rlUlon) _~to

noIalion ofacyclouun pro'lied (p.2n)'U In

OIher nodlOliochda:

By use of cleglUlt inorganic 1"'.I(liochemislry, the loolylxlc nLlm -99 i~ separated from the other radionuclides. Molylxle-

... Figure 13- 10 (r(l';~ sectIOn of a radioouehOe gener.ltor for the productoOO 01 tedme1!1,lm-99m (T(99ml by sterile 09% sodium chloode elutIOn 01 a stenle alulT\lna (AI,O,) co!\.111111 lhal has ~um-99 {Mo-99) ~ SOf1:JI!d on It. (Counl'S)' of Duponl-Ph.lfma,

SI, ... --t

1WIrnca, MA.)

l1u",-99 (f,n .. 66 hours) decays by ,B-paniclc emission \0 p cchoctium-99m (lin " 6 hours). ... kich decays by isomeric
( IT) 10 lechoePium99 by cnliss ioo of a )'-rny ( 140 ~ eV).11lc :miooic molybdmc ("I9Mo04 2) I ~ then loaded on a colu m?1 of alumina (Fig_ 13- 10). The molybdate ;0I1S adsorb firm ly to the alum ina, and the gcner~' Of culurnn is autoclaled to slcril i7.e the SYSle nl, 11w:n ,he rest of the gCllCr<l\Of
I I"~nsi l iun

is assembled under aseplic oolKlilions inlO ils final form in a lead-s/1lddod COIll 3iner. Eoch gencrdPor is eluted wi th steri le I'IOtIl\;lI sal iJW:' (O.on. sodium chloride). l1le column is :1i\
morganic ion cxch.an~c column. 300 the el u3te: coolains 50dUlln pcnechnctapc, so the chkKidc IonS (el ) are uehllngLOg for the pcnechllCI~Ie ions ("'LL I cO, - ) b\l11lQI motybd:ne IOns (MoO, -J). ]be I11CIhod for caleut:ni ng how much daughter is presem on lhe column at any l!i,en lime is more oomplex. because il must eorus ider Ille decay ral t'S of the parent and daughter (Fig. IJ I I), The simplified equation f(~ any ea..e in "'h ieh hOlh the p:trcm and the daughter an: rudioacli,'e and in equilibrium is liS follows:
A., ... IA~)A"I(~ "" - r -~~ -

"
0 .'

02
1.\ Elution _
2nd Elution

A pll

" here A,. is the activity (mei) or the pall'nt . A" is the aclivi ly

or the daughter, A,. and A.., an: their ~pect,,'e decay coo SHUns, IUld I is lhe IIIllC Since the 1ll.~1 elul ion o r the generator. In the case of Mo-99 (till .. 66 boors). only 87.2% or the atoms decay 10 Tc99m (t,n - 6 boon). and 12.8'k or the atoms decay din:etl) to Tc-99. 11Ie gent'rulor system can be eluted sc\'eral linxs pt'I' day 1 obtam more activilY (mCi) 0 per day ~Ju<e the locrease: In Tc-99m IS a logarithmIC fu/lCtlOll.

" -. " "

,

""

TECHNETIUM RADIOCHEMISTRY
I:kment 43 in the periodic table. technetium. is a nnnsition JI;oU:DletaJ and is the onl)' "ani fidar ' clement Wilh a lower ItOnIic number than uranium. All 22 known iSOlopcs oftcchltIium an: rudiooctive. andlhere lUll eighl nuclear isomers. Because no ",-able iSOlope~ of ~ec hnelium exis~. ~t.c chemistry ., been poorl)' ctcvelopctJ; however. milligram qll3l1tilies rJTc-99 (a weak ,B-particle emitter: 'In - 2.1 X I~ )'ears) ~ now available for dctennination of the struelUres of Ihe tdulclium complexes. and more than 150 struclUres have bttn chamcu:rized. The chemistry of technetiulII is similar klth3t of rhenium and is dominated b)' formi ng compounds bj' bonding betWeen the clectron-deficient metal and electroqllJve groups. which are capable of donaLing el"'Clron p!ifS. Some examples of these electronegative groups are lIl/hydryl. earbox)'lic acid. amine. phosphat!'. oxime. h)'drolyL p/Io)phine. and isonitri le. Basicall)'. lill technetium rudioptmrmaceutieals ate .w-~Iectron donor complexes. Compounds thaI comain "'0 or more ekoctron donor groups and bind 10 a metal are called ehellJ/illg ligen's. Ttochnctium as :I lran~irion sta te cleMI:!I1 can have ox idari on Sl:lles from I 10 + 7. As a pcnech~c (TcO. -) ion. technetium will not form man)' compl exes. allhough it can be reduttd to spclieslhat will complex wilh a varicl), of monodcmate. bidcn IW. (II' pal),dcntate ligands, The oxidation Slate of techncIIIIn In variou s oomplexe!i and the oclUal StruclUre art' fur several of the compounds. Deutsc h et pI,: c laim tbe oxidation ~tmes tll3t are most common in the chcmisi are + I. + 3. nnd + 5. Techne tium (TcO. ) be reduced b)' n stannous Sllh. ascorbic acid. sodium nnd electrolysis. The most common reducing . ion bec"use of Wnter solubilit),. ~tabi l toxicit),. and effectiveness at room tcmpcmture. l . of the chemistry of technetium are presented b), :md Schwochau.' but the stercQChcm b try of thc romplcxe~ is nOt shown. An excelb)' luris.~n ct al,h covers all coordina tion eoOl u.<cd in nudear mcdiciOi'. with a special emphasis T,99m complexes. radiopharmaceuticals are b)' far the 0I0~1 com used radiOlrncers in da),-to-da), diagnostic nuclear prnctice. In fact. most cameras are tI\:to ....urt mOSI ' thidncss and the I Tc99m radioarc prepared III the hospital or local nuclcllr combi ning '>9", I cO 2 nOllr.illiooctive comporeaction vial. The primary chemical ~ in the vial are the oomple ~ing agent (lig:md) and Nlcing agent. us.uaJJ~ some smnllOll.S saIl (Slannous chioU-, >tannous n uoride. or s!OnllOUS tartnlte). A ftcr prcparnof1hc radiOl'hammeeutical. wsts for radiochcmical pu. ;a, !Muld be eamed out to ensure thm the radiotmeer is in nght tllemical form. The anal),tical I\1Ct!lodS used i~lude ~antllhin_layer chromatography. column chrornatograI t e)l traction. Likel)' radiochemical impuritjes sodium pertechnetate (N a'>9", I cO.), some insoluble (i.e .. reduced hydrol)'1.ed technetium tTC021 or f colloid). and a complex different fmm lhe (i.e .. 'l'im-fc-monodcntme rJthcr than ~'c-

bidentatc ligand). 11Ie ~tcrile serum vial~ comaini ng the StWlnous sal t anti the ligand are I)'oph ilized under a sterile incn gas atmosphere (i.e . ni1rogen or argon). The ligand in the l"Caclion vial dctennincs the final chemical Structure of the \l9n'Tc-comple~ and the hiol ogical fate after illlrnvenous in jection of the radiophammceutical.

Tec;hnetium Radiopharmaceutlcals Technetium (l"" Tc) Albumin Injection. ~~"'Tc albu I

min for injection is a sierile. colorless 10 p.11e )'cllow solut ion containing human albumin (MW -60.000) rudiolabeled with Tc-99m JlCneehne1ale. 11M: reducing agent is ,tanl1OUS mnrnlc. which reduce) tile '>9n' l C04 - to an unknown oxid~ lion state and is " 'eatl)' chelated b)' the tarlrnte and posslbl), fomlS a CQmplex wilh su lfh)'dryl groups on the albumin b)' ligand exchange. The precise slructure of the stanoow. technelium - albumin complcx is currentl ), unknown . TIle p.1tient n:ceivc.~ an intravenous injecti on of 25 mCi (925 MBq ) of Tc-99m albumi n, Mulli ple images of the blood in the hean are tate" b)' electrocardiogram gating ( RR interval). The rising portion of tile R wave "."oincidcs with end-diastole. These i mages are stored in u com pUler to reconstruct a 1II0Vle of lhe bealing hean. This procedu re i~ somelimes called II m"I';g/l/cd uc1I,,;siriulI ( MUGA) or a ratli''''''c/ide \clllriculogm/ll. InformatiOlI obtui ned b)' this tec hnique irn;ludcs cardiac chamber wall III00ion and calcu lation of ejection fraction. Indications for ~he procedure inelude evaluation of e!TeetS of coronary ancr)' disease. foll owup of coronary anery b)'pliss Ilm! pa tients. heart failure. Ilean lransplant evalumion (preoper.uive and postoperalive). eardiom)'opat hie~. and dl'ccts of eardi OIoxic drug, (i .e .. doxorubidn).

.w-donor

.aoov.ll *'

Technetium (""' Tc) Albumin Aggregated.

""tII I c-al-

,all
,~

,ra',~
~

'h'

bumin aggregated is II steri le whilc su>pcnsion of human albumin aggregates formed b)' denaturing human albumin b)' healing at SO"C at pH 4.8 (isoclectric paim of albumin). The precise struclure of the stannous technetium-albumin ag.gregaled cOlllplex i. nntno,,",n at this time. 11M: particle sir-e nnd number can be e~timated with a hemoc)'tomeler grid. The panicle ~iJ.c of the suspension should be between 10 and 100 J.UTl. with no panicles greatcr than 150 foIm. This agem is used clinicall), to image the pulmonary microcircu lation for pulmonary embolus and 10 assess I"Cgional pulmonary func tion for surgery (i.e .. hmg trnnsplant~ or resection). The paucm receives an intravenous injection of 2 to 4 mCi (74 10 148 1\1Bq) of lhe Tc-99m- albumin aggregate,>. which lodge in '>Ome of the ,m"l1 pulmonary nnerio1e~ Hnd capillarics. and the distribution can be imased.11M: numbcrufaggregates recommended for good image qualit)' alld o;.afe~)' is 100.000 10 500.000 p.:1I1 icle~: thu~. onl), a small frJction of lhe 280 billion capillaries ~rc occluded. Multiple ima ges of Ihe lung are obtained 10 ass.ess lung perfusion. 'lbe distribulion of the p.'nic1e~ in the lung is a function of regional blood now: consequentl)'. in the nOfmnl lung. the panicles are di~!ribated umforml), througooullhe IUllg. When blood flow is occludL-d because of emboli. multiple <;cgn~nlHI "oold " (dccre!lSl:d mdiooct,vit),J deFects art. <Cen. nlis procedure i, almost ulw~)'s combined with D ~enol1133 gas lung "eIHila~ion SCJn (shoul d be nonna! in pulmonary enloo Jism) and !;lIme-da), ches t mdiogrnph x-ra)' (shou ld be nomlal).

Albumin Colloid Injection. W<l>'fc_alburmn col loid injeclion is a sierile. opak",enl. col orll'.'IS dispC'rslon of col loidal human albumin labeled wi th T c99m penechrICla te afler il is reduced with a swrlllOllS sn ll. lbe precise structure of lhe siannous rcchnclium- aLbumin colLOId comple~ 1$ unknown al this time. 11Ie particle sbe m~y be e~ununcd with II hemocytometer grid. TIM:: panicle 05.0 .urn. After.he patient size nngc of the colloid is 0.1 1 receives an intr.llenous injection of 5 mCi ( 185 MBq) of Tc-99m - albumin coll oi d. the agem is cleared from the blood by the reticuloendothelial (RE) cell s. These RE cells arc located principally in the li"n (85%) and splcen ( I ~). and the rcmailllk-r lIre in the bone marrow. kidney. and lung. An initial dynamic now study may be obtained to determine liver and splcen perfusion in cases o f abdominal trnuma. Liver lind spLeen imaging is u<;cfuL to detennine organ si7.e. the pr~nce of ~pati c metasU\S(:s. and the degree of hepa t()cdl ular dysfullClion in diffuse liver disease (i.e" cirrhosis).

Tedlnerlum

f"'" TcJ

peptide: wi th hi gh-a ffinity blndin, to somatostatin ~pttn (su blypel> 2.3. and 5) present in many types of cancer. iteluding lung cancer. It i~ approved for use in patientS "III are kJl()wn to ha.-e, or an: highty suspect for. maligll3l1C) and uhibit puLmonary le~ions 00 cr and/or chesl H I) Cher 170.000 new ca.scs of lung cancer arc diagnosed cadi )elU' in the United Stales alone. and the alternati ve II1nhc:G for detcnnining malignancy arc needle biopsy. which h,~. estimated 15% complication rarl!. and surgery. The precise Slructun: is cyclo-(I.-homoc:ystci nyl -N-mrm.
yl -L-phenylalany l -L-tyrosyl -o- tr~ptophyl -L L ysy L_L_Ial)LL

Technetium /'""'TcJ Apciride.

Th is new rndiollacer is

a synthetic peptIde that binds to the GPIlb/llla adhesionmolecule receptOB found on activated plalc1els. This allows the dct~'Clion of acute venous thrombosis and is f-ood and Onlg Administr.lIion (FOA)-approved for detection of acute lo ..... er e~trcmity deep ,'el1OU5 thromb05i~. A Lyophili1.ed p"'por~tion of 100 I-'g of bibapcilidc in the presence of heal will splil and then romple.ll to 20 mCi T c99m penechnctate. Images of~a of concern are acquired at 10 and 60 minules.

( I. I ')-su lr ode with )-[(mercaptoacctyl)am;IIO]-LallII)H.. .-Iysinamide. A technetiu m Tc99m a.Iysyl-I.-cysrei nyl-L pL ex of dcpreotide: is formed when sterile, IIOnpyrogenk!Oc dium penechnetaL Tc-99 m (I 5 t020mCi) injection, Ino. sodium chloride i~ added \0 a nonpyrogcnic Iyophiliud 1111' lUre of 50 /-Ig of depreotide. sodium g lucolieplonale di!rJ<!mte. stannous chloride dlhydrale. 100 1-'8 of edetate dilodium dihy<!mte. and enough sodium hydronle II' hydrochloric add 10 adjuSL the pH 10 7.4 prior to lyoplnllQtion.

Technetium /'""' Tr:}Bkisa te Injection.

A ~teri leoolor

less liOlution of bici.s.nte is complexed with Tc-99m penech oc:tate after redllCtion wi th a stannous -.alt. The precise structure of the technetium complu is jN.N'-ethyleoc:-di -Lcyslcirwo(3-)oxo 1 9''''', C[techOC:llum(V) diemy l estCf. This rad iophllTln :K:eu ti cal i~ a neutral and Iipophilic complex thot Cf'()Ut5 the blood-br~jn ballier and i! sc: lecti\'dy retained in th-e brain. Thercfore. this rndlOU1lCer is used as a brainperfusion imaging ag~ m . After intravenous injection of 20 me i (740 MBq lofTc-99m bicisare. about 5%ofthc injecu:d dose is Iocahed within the brain cells 5 minuh!S after injection and deillons tmtc~ r.. pid renal e xcret ion (74% in 24 hours). Thi s rudiOU1lCCr is used cLinically to evaluate dementia. stroM:. lllCk bmin perfusion (. 'brain death "). ecrebral vascular reserve. or risk of stroke (ilCtlu.olamide challenge study) and to locali/e a seizun: focus for surgical n:mov.1.

Technetium f""' TcJ Disofenin Inject/on.

ur

Technetium (Tc- 99mJ Depreotide Injection. T echne tium de prco1i lle injection is a new rndiolabded syrl1hctic

colorless solut ion of di sorenin is compl elLed penechoctate after reduclion with a stannous salt. ~ cise structure of the tec hnetium complu is time. Costello et 01.1 specify. however. mat this Tc99m~ lidofcnin a smgk' tium (J1l) distorted I with nlllion number of 6. A newer Ii 99m rncbrofenin, which is rl"IOI'e bromIne on the benu1lC: ring. In the pn:scnce oflugh bilirubin levels. there is less renaL e~cret ion because higher lipid solubil ity. In addition. lhe .... hich makes it phannllCy. The patient reech'cs an in travenous injection ( 185 MBq) of T c-99m disofeni n. which is taken hepatocytcs in the liver by lICti ~e anionic the radiopharmaceutical is elLcreted in bile. i canalicul us. into the bile Qucts. With ~"'m gall bl adder nn<! finall y elLcretion via the common into the ~mall bowel. 'The I 'b~": : mulation 'l bladder nnd small bowel CiLn be visuaLil.ed hours after injection. An uample IS secn in The primary cli nical indication for th,S"" acute cholecystitis. In acute cholecysti tis. lhere . ~ of the cystic duct L eading to Lbc gallbladder. The is not visuali~ed becall.'IC the ndiotracer cannot Some other clinkal conditioos that ""

wii" T ;;;;

0:::

i~

"~

all.' common bile duci obstruchon, btliary leak Wlllel)'. bllillry 1Ilrnia. and l choledochal 1:)"1.

'Y
,h

y.

" *' '"

).

h-

L-

> ,. ,,.
~

"-

TtchMtium ("""Tc) f1fi)meta~jme Injection. A SICf ietlllorieq liOIUlion or examc:lI17ime is complcArd .... ,th ToIItneciltlClate after reductoon .... jill u SlnnnOO5 ...all. The lKtisc MntCtUrc of the l~hf1oClium oomplC'.JI. ;\ unkllOwn al lime. Juriswn ct al.' 'peelf),. ho",e~er. tllal analogues " t/liJ CQlI\ple.~ 1'c-99111 pmpylene amine O~ lme provide II tli1nellUm (V) square pyromidal complex with u cOOfdi nnnumbn" of S. This rndiopharmactuucal i. lipid-solu ble _Ib=fort', croo;~ the blood- bruin barneT and h trapped .lItuJIlhe bnun. The possible mtChani\ms proposed (Of 10OOUIIOl1 include: binding 10 gI Ulnth.onc. change In IOnic and dlemlcal degradation. The pallenl rtcci,"eS an in -

OH

>

,-

s m~lIOn of 20 mC; (740 MBq ) orTc-99m U:UJlC'IIn a romrolled cnvironmenllll SlatC. Thc ~'icm is ,I'ollh l'O\~ eyes (20 mmutes). In a qUlcl room and indJrecllighung priorlO injeclion. The nKIioptuulnocCU i~ irre\cNibly bound to tlie br:!.IlIlIflcr 10 minUles. Some IIldiC~hons for Ihi~ sludy are locali1~t ion of M'ilure .eyal\llUon of dernentia. identir.<:allon of dnlg abuse-in' ' (OJ broin defecb (i.e.. cocaine). and evalua lion of Stro~c . 1'IIe!lOl'lMi ,lUdy i~ n:prc<.entoo by II h()mogerleuu~ 311d ~ym ~~ dl>lnbul1un of rad ioactivi ty throughout tile bnlln. Ccr*lbr lCuvity i\ u ~ually gre'3ter than !icllyity in the re~1 of blain. Thi~ is the IIGent of cboicc IOdttcnll ine brain death lpatoenlS on life !ruppon 5y,tenlS. The nlajor usc of this "";";"Uli'31 lit Ihi~ time i~ for lhe radlOlabeling of kulO<')lcs as an :Jdjunct 111 the locall/.lltlQll of lnal infa:tion and innammatory bo .... d disca<.e.

"die

,.
;,

I, m

,-

,r

Ii-

,-

" ,. "

"

A stcri k. '~~~'iOlution ~'QI1I~ining 50dium rm.'drollatc (melhylene ~ nme) and II ~tanJlOOS salt is complc~c:d ..... ilh Tep:n~hnclatc. A structure prop!KCd by l-ibson ct al. v lite lhllCtiulU medronu te complex is ~ho .... n below. l)e Lip) c1 al.l(I specify. ho .... ,cver, thai Tc -99m bone imagi llg IUl.' mi"lura of many l"Ompooenls (polymc1'" and ) thall'an be 'it'pat'IItOO by hl gh-perfomtance anion chromalography. Thtdtnlcal use ohh" 1I~1ll is for in\'cstig;uion of ~kclelal ,,"= "IICh as mc:la'iflllie d ise;l.sc 10 the bones, OSICQInyePqtf5 di<o('asc. fr-$tures. primary bone tu nlOf'\. a\':I~' IICClOSIS. membolK: bone dio;ease. and IolN: or Infected p!O'othe.~. SIJ'CSI; fr.IiCtufC~ can be dl:lj;noscd by bone ........ hen lI-ru)5 Iln' completely normal. Bone: radiol(r.lplly i~ ooc of the most commonly performcd nuclcar '"Incdl:lgrrnllc procl-dures because lhe " holc-body surallowl evalUlllion of lhe emire skc lcHm. which cannot dorIC 11., cO-;I-effcctively by :my othl.'r irnllgllll: modality . TIlt patu,'nl receivcs an int ....lvenou ~ injection of 1.5 1020 11~55 to 74{) MBq ) of Tc99m IIIctlron;ue . ..... hlch loclIlIII bone 1II.'CQI\Ilng to the degree of IIlCUlboli c acti vity, -99m nlCdrooate is:lbsofbc:d onlO hydrollYII]XItth! cl)'\lal' Ii 111.'.... bone formauon .... ith about.so 10 6O'l of the: do!ie diStributed throughoul lhe slelell)n ..... ithlll J . the rat i~ tlI'R'tc:d by the lidney~, boneunagmg allcnl. Tc-99n. o~ldrooate (a h) tbe carbon of nk.-drooate) h~. highcl" hlnd .,

Thnelium /""'TcJ Medronat e Injection.

The th nctium mert,atidc oomple~ is a stcrile. colorless solution of mcr1i:llide complexed ..... ilh Tc-99m perteChllClIIte aner n:duction wilh a stannous sail. The precise structUJ'C is5hovo'n below. This radiopharmaceutical is !he agCOl of choice 10 provide information about n:lative function of the: kidneys and urine oulflow because il tw a higber ClItl"ilClion efficiency than Tc99m pr'ntetate. [Ildi cations include n:nal anery stl.'oosis in nonperfused kidneys, R'1I31 trunsplam as.sessmenl. and oulnowob>UlIclion. lltc patient receh'es a bolos intraVCJlOO5 injection of JO mCI (370 MBq) of T c-99m mertilltide. aud dynamic images arl! obtained every 3 to 5 seconds to study blood flow to lhe kidneys. Sju.cnlial slatic images arc then oblained for 20 10 30 minUles 10 evallJ.llle renal cortical upIJllc, ClIcrt'tioo. and tubu lar clearance. Delayed images may be required to e\'alullIe ]XItiems with obstruCtion or renal failure. Normally. IhcTe IS prompt sylT1l1'lWic bilateral perfusion. good con i,al accumulalion bilalerally with visual iution or the collecling systems by 3 to 5 minulCS poslinjecllOll, and rnpiducrellon imollle bladder. with oodelaylo iodielle partial or compkle OOsIru<:liQII . An older renal imagins agenl. Tc-99m glllC('ptnte (a Tc 9'Jm hydro~y acid complu: sec below for the ligand), is now used as a II1lII$CbelDtion agent for rndiolabeling monoclonal anlibodies.

Technetium /""'TcJ Mertiatide Injection.

-,

-,
o

.~~,;;:~,~"h;Ydro.,yapalite ery,lal s in bone: however .

Indicate no :Jd'':Irltage to use of this agent

466

Wil.wn <1",1 GiJw>l"', Tt.,'lbooIc /./ Org"'lil" ", ... /iel",,1 (m<l "/Ulrm",tUlic<11 ChemUln

A steri le. t"Olorle~s or ~ Iight ly yellow sohlliO<l of sod ium pentela le or cakium Iris()(lIum pemctate is oomplexed .... ith Tc-99m perlecillll;tate aner I\.-dUCl1on with 11 stannou~ sail. The p!'eCI.)oe ~lructure ofTc99m pentct:lle i~ unknown : ho",cvcr, Juri sson eI al.6 ~~Ied the possIble ~t ructUR' below. The pnmary di nical use Ofl hls agcm is for R'nal ~lud ll:S and glomeru lar filtrJlion rale (G FR ). bul il is (J(:casionally used for brain death and Min WI110r locali/AUon. The palienl ft'cei\'C's UII imnn'enous illJl'CliOll of J 10 20 mCi ( I I I 1 0740 MSq ). and the \;idneys are imaged for 20 to 30 minulc~. TOO GFR i~ cakulaled by 11 quantillll h'e method uS;IIg 11 combillat;OfI of Imaging and t'OUnting lhe radlOOCtivlly in ~rum and unrlC sampll!.~. Noonul e ~troct ion efficiency i, 2~ (SO 10 140 mUmin ),

Techne tium ~Tc) Pentetate Injection.

succcs.,ful su~,cal splenic aged RBC .

lransplam ~

by using lIeat-lYat-

A ~It. colorless solulion of 'OeSllllnibi i, $y nttw:si/ed by rcao:.1101 \I'l1h Tc-99m pencchneulle afll."f" reduction with a UIIntIOIII

Thn(ltillm ("'" Tc) Seslamibi Injection.

+
COOH

o,,--II/N "
N

.)

/l

><XX ~
~tenle

TlIChnellUm (V) P....el8t.

Technerium ("'" Tc) Red Blood Cells (Aurologous).

n:action \ial containi ng ~tunnous cilmte (Ult rlllug RBC ~il) is u.)C(i 10 l'lllholabel U pal;ent' red blood cells ( RB C~) ",ilh Tc-99m pertechnelUle. Bnefly. the paticnt's blood ( I to 3 mL) is dm",n wi th add citrale de mo"", (A C D) or hepaon ( 100 units) used .as an antK,."Qagulant, 11'1' blood is labeled .... ilh the patient's n~mc and Iwspilal number and added 10 the ~I eri le n::Ktion l'i:11. After mi~ing and incubation for.5 mmute'S. sodium hypochlorilc (6 mill i~ added 10 the \ial to o~ idi /.e excess ~tannou.~ iOfls (Sn"~1 to stannic iOlls (Sn '.). A c lt mle buffer is added 10 adjust the pll to about 7.4. Then. 30 mCi {I. IIO M8q)ofTc-99m penechllC1ate is added to the blood in the vial and mi,'lll'd and IncUbated for 20 minute\. Without further prcparut;oo, the pmicn t reo cei,'c'i ~n int r~'cnou~ injc:ct ioo of 25 mCi (925 MBq ) of hi s or her o ..... n rad iolabclcd red blood cells. Three different ~tud ie~ c:tn he perfornl\.-d after Injection of the Tc- RBC. Fi~ . the mdioouclidc ,entriculogmm siudy for evalualion of card iac function can be done: a", ",ilh Te;99m albumin (discussed above). U!iCofTc RBC~ i~eons;d, ~ the superior technique because tile Tc-99m red bloud ce lls ft'nlain In the circulali ng blood ,olumc. wheR'as the 1"c-99m albumIn leah Into lhe extracellu lar spac~. Thi< leakage iocrea!oC'S the background radioar:livity uroolld the 0degrnd::1Il0fl orlile blood pool image. heart and contnbules 1 Second. the Tc-RBC., arc used for IlOIlm l'asive localizlltlon of the preoperative sile of acth'c ga)lrui nleMil1ll1 (GI) bleeding. P'JtienlS >Ue in';""'C1cd "" th their O\\'n Tc, RBC\' \lhidt remain "'Ilhm the cln:ulating blood loo g cnough to c."mvasate and accumulate wit hin the bowel lume n III lhe sill' of blding. llle lillal use ofTc-ROO; is to c,'a luate the splcen after ""duma or to confirnt an occe",.oty ~plcen or 10 sludy

place tluillous ( lO1 11) ehloode fOl' m)'ocardiaJ perfU~IOII" uging. The shorter half-life of Tc-99m (6 hours) than urn. 201 (73 hours) IIJlow~ adminiSlmtion of a larger dose. ",lid pm,lde_ bener image quahly. Another majOf dirr~ ...... from 11-201 is that Tc.99m scst:lIl1ibi e ~hibits l iul~ .. rt\Ii ... lributi!)n:' 01' fflO"emenl out o f the myocardium back I. lhe bloodstn:am. Th is c)'t(J';01 binding of sesuunibi ..""', more flexi bi lily in the ;muging time. al lhough It also lales SC'paMe se~tall1ibi injeclions al streSS and at rtlti", v.hich increases the eltpen.'IC of Ihls method. The !)Iher rndiotrJcers cum:n tl ), used to e\ alualc m)(IQ' dial perfusion include 11-20 I and Tc99m tetrofosmin. My"" cardial perfusion studies usually "~R'SS" or;~.; ('reased blood flow imagc, ",;Ih n:\ling images. The can be brought about by phy~ical lneans (treadmill. bic~1 or by phamlarolog1cal ~asodtlahon (wllh dipyridan'lC. udct\OSillC. Of dobummil1<!). Myocmuium with si.llmf"ad! mlrrowL-d anerial 'lJpply may appclII" 10 have 00I'TIIll1 flow 111 re\l but. du nng incR'ased hlood flo\l during~ denlOnSlr:.te abnorma l blood flow rda" "e to areas wllh lit mal arteries. Theft' are a \'ari cI)' of proIocols for lhe WN re~ imagmg session . even Orlc tluLl combmes TI20lltCIII Ilnd Te;-99m-<C~t am ,b , (~trc~s). AddiliOflal IndicatioM ' the use of the Tc-99m-~tamibi comple~ now inclwJc dti: ptroperali,e locaJi,.aliOfl of parnthyroid adenoma lNIiII early d iagnosis of brcaSf cancer,

The prec;isc structure of the lechnetium romp-In Ii Te 99m ( MIB I ~ ~. where MIB I i~ 2-melholtyi-ooutyl isonitrilt. This was the fiN Tc-99m - labeled agent Inlroduced 10 re~II .

nccm

compare

j,qCHJlPCH;,

HP:>(H~C)pC~,
N .

C C I/ ,
C .N

Pi,C{CH,lPCH,

HJCO(H.CJ.CCHi

,N

/ cI ~c
I
N

To

CHA~

CHrC\CH.).OCHJ

Ted1neIIurn SeslamibI
Technetium ("'"Td Sodium Perrechneta!e.

~':~.:
and charge similar (I ). is conr:cntr:ued '" the Ihyroid. ~Jh'lII)' 'IOm."lCh. gnd choroid plexus 111 lhe brain. din.'CIly from the Mo-99ffe-99m gene t1llor 10 Ihyroid. Meeker ~ di"ertlCulum (stomach tissue in line). and .wi,lII)' glllnd~ for tUrt1()l"; and to

--

I' ,-

"

<-

,h

0-

fill disrup! the blood- bruin b.mier (i.e ., tumors. abscesses. 'III"ll~). Unlike the iodide ion. the penechnetnte ion iJ not COIIverted to thyroid hormone but ooly trapped. Thyroid nodcan Ippear nonfuoctiooal, wi th liule or no radiOlrattf pucnt. These nonfunclional notlu lCl ba.e aboul a 2O'J. iI*b.hty of being cancell)US and generJlly require biopsy. 1): patient receives an intra.c l"IOIls inject ion of 5 to 10 mC. 1113 10 370 MBq) of Tt-99m ptnc:chnetatc. and images are aIumed of lhe thyroid 0 to 20 minutts . rler injection. The I11III dose: ror the other imaging procedure~ is the same for Mtdel" s d,veni<:ulum and salivary Elands. and 20 mCi (740 MSq) is used for brain tumor imaging.

*'

,. ,.,

,-

"-'.

,,-

'" ~)

'0-

... '"

A S!cri~. coln:u solution 0( 5uccimer (2.)-dimercapiosuccinic ~KI) is umpIued v.ilh Tc-99m pencchnctatc aner reduction \11th IIUIII1(lUS ~Il at acid pH . The precise ,trocH ofTc9Y.n aR: 1m) iiIIttil1\cr is unkllOwn: however. Morenl CI aI.' I wglIfIIal the possible slnIClUre below. Tc-99rn O;UCCl1llCr i~ "cry C"""..;.,'~ror dcnlOllslnlIing the- functioning renal parench)'nla. ':' about 4O'i: of lhe dose ill boulld 1 the renal.:OI1c\ 0 I lour after injection. The patien! i ~ injected I'o'ilh S mCi ISS MBq) of Tc-99rn succirner. amI lIluhiple image~ nrc am. 21Q 41111tU'l! laler. nils study rnn be useful for c~nlu~l II! Imlllr.luma, rel'l:lJ ma.~s (e.g . IUITlOI"I, cysts), and renal annl- Tc-99m SUCClmct" IS the diag_lIe agent of choice ldiildrt'n who ha,'c chronic urill3f)' tract infections causi ng ..camllg. If the pI! is IKIjuMed !O 8.0 10 8.5, 11 technetium (\'HUoCci mer cumple~ is formed. which is useful for imag_ III IUIIl(:01 2 Blower 1:1 al,l1 ha~e polJ)O"oCd the following ft"I1Ife for Tc-\I9m (V) succimcr.

rhnerium t""'Tc) Su:im.rlnjection.

des . The panicle: size of the: colloid is 0.1 10 3 ~m. Arler intruvellOU~ injection of 5 10 10 mCi ( 185 to 310 MBq) or Tc-99m sulfur colloid. the radiopharmaceutical is rapidly cleared from the blood by the RE cells or the: li.a. spleen. and bone marrow. Uptake of lhe Tc-99m-~ulfur colloid depends on the relative blood perfusion rate and the functional capacity orRE cells. In lhe normal p;ltlent, 85% oflhe: rndiocolloid is phagocytized by Kupffe:r cells m the liver. 1.5% by the spleen. and the trmaJnder by the bone marrow, lung!. iUId kidneys. 800c marrow imaging $lUdie.i Ille pc:rfonned I hour afta injtttion of 10 mCi (370 MIlq) ofTc-99m - sul fur colloid. Nonnal bone mHITQW will U1kc up the mdiocolloid. hut diseased bone marrow appears as --cold" defect.~ in patients with tumor deposits in the marrow. Tc-991n- sulfur collOId is used as a CC(Indary agent 10 Jivaand spleen imagillg if Tc99m - atbumin collOId is not avaIl able. It IS used as lhe primary agem. ho:lwe,er. forGt studies such a.~ gastroe.s.ophagcal reflux (GER) and ga.~tric emptying of solid food. Gastroesophageal refl ux imaging i ~ pcrfooned after ha'lIll! the pallem swallow acld,rlC:d or.mgc JUICe mixed Wllh Tc99m- wlfur colloid. Normal patknL~ tuo"e no GElt Thl ~ Sludy reponedly has 9<0 sensi li ~ity in detecting GER. Gastric empt ying imagilill i~ pcrfOfl1"led aftcr the patient ",.. allows SQhd food (i.e .. ~rambled eggs or pancakes) rndiolabeled with Tc-99m sulfur l"Q]loid. In tleneral. the normal gastne: ernp!yilltl half-lHoe IS lcss Ib.an 90 n!lnutts for loOhd

food .
Technetium (""'Tc) Tetrofosmin Injection. A sleri le. ~'()lu<less solution of tctrofosmin is comptexcd v. jth Tc99m penechnetale afrer reduction with II ~tllnllOO , salt. The pre. cise 51ructurc of the lechlloCuum complex i5 sho.... n below.' ~ The formulation contallls gluconale 10 rorm a weak lechnetium ( V) chelu te to kecp the technelium in the (V) o~idation state for tran'IChdation to form the techlloCtium (V)-te lrofos min COf11IIIcX. Technetium (V)-letrofosn1m IS another cationiC T C-99I11 complex IhM tb.allous (lOi n ) chloride ,,"umu Illle~ in .table myocardIUm. Myocardial uptllkeo(thi ~ agent in hurmll1~ is aboul 1.2'k 5 minu tes afler ;ntrd"cnouS mjcclion and decreases 10 1.0% al 2 hours. Thi~ agent was less specific for detecting isc hemia (66*k.) than n-WI chlonde (77'10) in I small 51udy (252 parients). It appears. hov.uer. \0 ha.e fltpid clearnnce through nonlarget organs (h"cr) and thus fe ....cr hl gh-backgll)Und imaging problems.

r--- O

)--S,
S --------OH

ITe
o

-0

I'-- S --I
o
SH

T\!dInetJ ........ (Ill) So' U"'"

HOOC

II

CooH

\-- S7\....S.) S~ OOH

HOOe

Technetun

(VI"_ .,"".
Tedmcfrom poly_ with Tcin dilute: hydrochloric iii with gelatin A colloidal pani -

ions

I -

f"""'"

FLUORINE RADIOCHEMISTRY
TllC useful rndioisotopeoffluorioe for organ imaging is fluorine-18. !-luonne-IS is producc\l in a cyclotron by the '''O(p.n)' 'p nuclear react ion. Fluorine-IS (I,f.! _ 109 min utes) decays by electron captu~ and ~itron ~mission to oxygcn-18 wIth y-ray cmissions of 51 1 keY ( 1 94~). Fluorine-IS can be allac:hcd to a number of physiolO:ilically acth'e moIecu~ and, with the great ~rength of the C - F bond. appears 10 be a very useful label for radiopharmaceuticals." RadiOlraccr production involves ~Iatively compl icated syn thetic pathways. nowe\'er, and the prepar:llion of high-specHic-activity compounds presents many problems. "The shoo half-life of fluorine-IS maJ.:e.~ it nece~sary to complete the synthetic and punflCation procedu~ within) hours. Consequently, a separate chemistry system (black box type) is needed for each compound. The chemistry of fluorine is complicated. bul some compound~ can be fluorin.:lted by 18p- exchllnge reactions:and direct fluorinallon wilh clemen1:11 fluorine ( 'IPl ): also. compounds with an aromatic ring may be fluorinated by <;e ...~ra l synthetic reactions. For example. panially fluorilmlc:d heteroaromatic.~ are readily 0btained by the conversion of an amino group on the aromatic ring 10 fluoride, with u<;e of the Ball$chienllnan and several related ~:IC'Iioo.~.

capfu"" to stable 7.illC-67 with poncipal y-roly emlS~IOIIS rI 9) keY (3S'l- ), 185 keY (24'). :and 300 keY (l6'i4>J. TIt radiOlr:ICCr is iwlate\l by dissolution of !he tatget In h)drochloric acid followed by iwpropyl ether extr.JCtioo of thr gallium67 from tile 1.iuc and other impurities. The gKlliul!\o 67 i~ bad:-c:xtr.ICted from the isopropyl elher inlO 0.2 M hydrochloric acid. evaporated to dryness. and \limh-ed II stcrile, pyrO:ilen-free 0 .05 M hydrochloric acid. Oaillum il an amphoteric element that acts a5 a metal at low rH bill forms 'MOluble bydro~ide:s "hen the pH is l1lioed abo\( 2.0 in the absence of chclahng agents.. At high pH. rllm. hydroxide acts as a nonmetal and dissohes in amrl"lOlllJ" foml gallalcs. Gallium forms compounds of o~idnt ion SWtI + 1. + 2. lind +): however. ol1ly the Ga >l stale " SI.1blr in aqueous solutioM.

Gallium f1Ga) Citra Ie.

TIle gaillum (III)-c llmc c:a.-

Fluorine

r ' F)1. F/uoro2-0e0xy.o-G/ucose.

The

only F-IS radiopharmaceutical pn:!iCntly available i~ fluorine( IF}-2- fluoro-2-deo~y-D-gluc()';C (F. 18 !-lXi). The pre. dse structu~ of F- IS FOG is ~hown below. It is the on ly PET agent approved by the FDA. Ibmacher el al. lo intro\luced the curre llt method of synthesis of P-IS FOG by nucleophilic fluorinatioo, UliC of Ihi~ ru\liotracer for diaguootic imaging in oncology hao; increased dramatically in thc last se,'cral years. It i~ used also as a myocardial viabi lily agen. and in e'aluation 0( seizure diSOl"ders. 11 The high gl)'coI)"lk .-ateo( many neop1a.smscomp;l~ wiln that 0( lhoe surround ing tissues f:ICi lllatCS tumor imaging .... ith this glucose analogue. Because of the wldesprt'ad anatomical distribution of metaStases. a woole body imaging technique u~ing 3 Ill morsped fic I1ldiopharmaceulical is very useful for tumor dctec tiOll and mapping t(1 evaluate the extent and relotive metD bolic activi ty of the disease.

plex is formed by IId.:.hng the requi~ amount of~" citratc (0. 15 M ) to gallium ( Ill) chloride and adJustl1ll pil io 4.5 to S.O wllh 50(lIum hydroxide. The ptoposc.l ~ IU~ of gallium ('7Ga) citr.lte i. shown below. The patd rCCC"ivcs ~n imravenous injection of 5 to 10 mCi ( 185 11).1 MlJq) of gallium (b1Ga J citnne.llnd wholt-body ima,cslft Ihen obtained 24, 48.lIl1d 72 hOllrs after injection. Galli_ loca]i:f.es at sites of in fl ammat ion Qf inf~tion Ill> wcll varicty o{tumors. It is used in clinIcal prnttice in the and evaluation of rtturrcncc of lymphomas. Gallium il.t!l normally in thI: Ii\'er and spleen, bone. n~ lacnmaJ glands. and bn-ast tis.~uc.'. There is alw some ~ lion in lhe bowcl; conscqucmly. the patient may trquIItl luative wullor eoemas to e\'IICUJte this radioacti~ily pm 10 the 4S-hour inUlge, A~ more specific radiOlfll(."I'~ bee" t.lcveloped. Inc nouspeci fic I1OI1nallocali/.llllon 1ium radioactivity luis limne\l ils clmical use.

.1

of,.

HO
HO

Ho l.~-N,
18 F \

IODINE RADIOCHEMISTRY

OH
The useful radioisotopes of iodine iodine I)I:and iodine-l23 because i i cal characteristics. lodll'lt- I) I is obtained rrom production 0{ tellurium- I) 1. tion m U(n.fiuion)nlTe or lurium- 131 (I'I"! - 25 minutes) sian to iodine- I) I. Iodine- I) I (1 ,12 by {j decay to stable xCllolI- I)I . wilh fi\'c ell1i~siou~ or 80 to 723 keV. The major (82%) provides good tis)ue pc:oetration .;..,~

GAlUUM RADIOCHEMISTRY
The only rndioi'iOlope of gallium thaI is presently used is
ga11i um67. wh Ich i~ produced in a cyc lotron by r,roton bombardment of Uline lI1el3ltarge\ by H "'Zn(p.2n) 'Oa nuclear reaction . Oalliu\l167 (I, f.! - 78.2 hours) decays by electron

Chapt .... U Qr iodlne-131 are the high rudi:mon long half-lire. and the poor )"111)'~. lodmc- 123 {I~ Caplure to teUunum-123. cmt~ion of IS9 leV (83%). ",hich of iodine for organ tmaging reduced radia i is in 11 cyclotron ..... antimony meTal target with 0 partielc~ IICa.n l~iSh (o:r.2n)IH reaction or an iodine target protons by lhe IW(p.5n)IH nuclear rea<:123 decays b)' electron capture to iodlllC. relatl" cly expensive to produce and curl availabil ity for rudiobbellng compounds.
III

A~IIlJ

for DilJlIlO5lIC lmallng

469

':'~"""~:~P and :astatine). In aqUCOU\ SOIUIIOn. com VIIH \Oo'uh the h:tlogens (nuorinc:.
are \.;TK)..... n with JU least fi~ different o.\ida1We!:

OIher

the regional lymph nodes. bone. bone lT1lI/TOw. and 50ft tissues. After an initilll report by Kimmig ct al .20 of 111 1_ MIBG uptakc in neuroblastoma. successful useor this tracer was described by others. TIle increased uplakeof lj' I-MIHG is 50 tissue spe-.:iflC lhat it can Clilllblish the diagnosis of lICuroblastoma in a child with. tumor of unknown origin. 111e palienl is trealed with LUlorS solution (up to 40 mg/ day) 24 hours before and 4 10 7 days after administl1ltion of the radiophaml~ceutical. to bl()(;k thyroid uptake of free "' 1-. The Ij' I MlBG is administered by slow intravenous injection 0.3 to O.S mCi ( I ! 10 III.S MBq). and patients are imaged 24. 48. and 72 boul'$later. Occasionally. the patient ~i\'rs:l renal imasing agent for bener local illuion of the adrenal tumor.

CH1-NH - C - NH
NH, . ~.~

howe"er, In nuclcar medicine. the - I and + I \late<i are the: mosc siglllficlim. The - I o~ idau,," II) sodium iodide (Nal ) is unportllllt for wilen II redoctant-fn:e !iOluI \ tarting l'OOlpound for md iophu rmuceu ticals. 1,'QIllffi(1Il method~ t ' rudioiodille into orrompou nd , lire iSOlopc' uchanse rt'octions. electro~b<;titution of hydroSen in :IC1i.atoo aromat ic sy\I ~ubSlHution. and addition to double replOCj;'ment of aromatic hydrogen in activllted syj,fcm~ i~ uSC'd for protein labe li ng. and clccU'O.) can be generated by D "ariety of oxidl/ins fa} ehloramine-T (N-chloro-p-tolocnc \ulsodium. (bI en7.ynJoe oxidauon of I (loctopcroxi ar.l /t'J iOOosen 1.3.4.6-tetrochlora-3a-6a-diphenylThe actual IOdinating molecule de:pends on the agent bul i, probably HOI or H:OI ' .

Sodium lod;ne (' 131 OJpsu/es. ) The major indications for thyroid imaging with sodiuln iodide (12.l1) are for evaluation of thyroid morphology, for ectopic thyroid tissue (e.g .. lingual or mc<IiastiMI). and for subtilemal thyroid lissuc. When thyroid nodu les are bernS e"alunted for po!isible thyroid cancer. 12.l1 basan IIdvanlageO\erTe-99m pertechnetate scans. although 1-123 Is more expensive. This is because Ihyroid cancer celli somet imes relain the: ability to I1'lIp. but I\O'l funher pIOCUS. 'OOJIIC to thyroid hoill~. Unlike)odine. Tc-99m pertechnetate is only I1'lIpped by the thyroid and in a nodule may give the false impression that a nodule i~ not cancerou s. The patient fa~ts befon: m:civing the or.al dose of 0.4 mei I IS MIlq) of !\Odium ;odillC Ill}I). Imagcs ore obtained of the thyroid and surroundi ng a~a <I to 61'lours 3fter ingestion. Sodium Iodine (W I) Or~/ (So /ution or C~p!u/e). The Ihyroid callCt'r patient recel\'es an orol dose of S to 10 mei (18S to 370 MIlq) of <;Odium Iodide: (13'1). which localizC!! in residual thyroid tisslIC aftcr " tOlal" thyroidectomy and function;ns thyroid mewllI.~is ffOOl thyroid carcinoma. images of the .... holt body lire obtained 48 to hours IlIler. 1llCSC metastlltic rudioiodidc survtYJ are used 10 detect ~ sional or diSlant mctastll!jC\ for largt~ 150 mC; (S.55O MHq) inpatient ther-.apy for thyroid cllfCirooma. Any thyroid bormont medication should be discontinued for2 weekslTJ ) or <I ween (T4). In addilion . the patitnt should have blood drown for 3 thyroid-stimulating hormone (TSH) test to ensure thai TS~I is elevated bcfo~ adminislration of the therapy dose. to permit lIla~imum sti mulation of thyroid tiSMIC. Thc patient should fast befUf'C receiving lhe oral dose of mdiOiracer,

Inj ection (I- U I - Me ta lodolobensuanc su lfll1c Is 111 1

i shown I is this trolCff and may ha\'C more fasoraIUmors of the adrcnlll meand IUIIlOl'S of neuroendocrine on 1-131 mtl<l_iodQ.

,
t

,;
that tlJoe I I neurons and ehromaffin cells by on active . inlO oorencrIS I mahgnam tumor or the (ympathcuc ",hleh OCCUIli most often in ehildn:n. 11lc I crest ongin and consistS of cell~!hat form sySiem. ('ai led X)mpmhc~iu. tbat adrenal medulla and many other pans of the Mcta'llaSd m:ly be found in the Iher (Wlge IV) and

1-

INDI UM RADIOCHEMISTRY
Thc most ustful l1Idioisotope of indium is indium-III. .. hich is prodoced in a eyclotron by proton bombardment of a cadmium melDltarget by a II :Cd(p.2n)'" nocltllf reaction.

g-

IndIum-III (l,n - 67.4 hours) <kcays by elffitOIl capture to stablc.cadmlu m-I l l with principal )'n1y cmissioos of 172 keY (91%) and 247 keY (94%). The r:adiotnlCeT is isolated b)' dissolution in h)drochloric add 10 form IIt ln-chloride and ~panlled from cadmium and OIhcr impurities by ~\'eral dissolution and ClltlllCtion steps. The lail e:uJat"tion is done with iwpropyl ether, el' aporut ing 10 dryne.~s. and di ssolving III Sterile. pyroSen-frceO.05 M h)drochloric acid. In aqUCO\lS !iQlution, 1 0Yoer valence SU of ind ium have been described , lIes OOtthey are unstable and are rapidly ox}di:t.cd to the tri"mnt stlllC. In acid SOlulioo, Indium salts are stable at low pH oot are hydrolyzed (above pll 3.5) to form a precipiUlIC of indium h)'drox ide or trioxide. Ind,um ""ill remain in solution abol'c pH 3,5, oowel'er. if it is comple){ed with D weak chelallng agent such as Mldium citnnc and stronger chela!ing agenL\ ~uch as g. hydrox y quinoline (oxine) 01" diethylenelriaminepemaxetic acid ( DTPA). Monoclonal antibodies or peptide~ are radioJabeled by indium by U Sinl compounds called bifwK'/iunal chela/ing (j8~l1/s. llifullClionlll chelating agcnts an: mole<:ules that can both bind ITlC'IIiI ions and be aUachl'(j 10 Ulher molecules: ont example is the cycli C anhydride of DTPA

'ndiMm Radloph., 'UM:evtkaIs

Indium r" lnJ Chloride Inj ection. IndIUm (1 11 ) chlotide I~ ~Ienle, colooess solution that is radiolabeled with indium - Ill in a hydrochloric acid solution (0.05 M) and has II pH of 1.5. II is primarily u'iCd 10 nKlio label other l"Om pound~ fOf U1>C m ci,cemogr,lph) :md whitc blood ce ll labelmg .>tudic~ and is paniculurly recommended (or radiolubelmg monoclOlJ:'lI wlIIbodic\ for mc:taslaliC cancer inJ:'lgmg. If thi.\ age nt i~ injt.'Ctcd immlc llOU , ly for clinic31 use. the pnIl cnt"~ 1l100d ntust be draYon into the S)'rin8c C()t1tllinin8 the rlKlloph nmlaecu lica l 10 buffer lhe ngenC10 a higher pH to eliminate the burmng 'lCnSlltioll on injection. Wilen lhe acidic compound is mi~cd With blood, lhe indium- I l l chloride binds Ijuickly 10 lransfemn, lhe iron-hhlding protein in Ille plu!>ma. The localwlllon of .he Ilxilum (Ill) chloride In bone nllllTOW i~ prob,lbly expl~ incd hy its nb lli1y to bchnvc.lnt:13bolically lil e 1I'0Il and yel not be incorporated inlO hemoglobm in the RBC~ In lhe hone marrow. "The localil(alion o( the radiolt'llecr in IUllX)f'S lind lIb$ccsses is probably due to increased blood now and capi llary pellllability in the area of1issuc: damage. Tmn"(cmn rece ptor; h.:tI'C been iiuggestcd a~ II mcan. of loc~li]..at ion but not pro~'ed al thi . lime:. Indium r "l n) Capro~ b PendetHk. Indium capromub pcndClidc IS a new IlIdiotracer for $tagi ng paticnts with ne ... ly d iag~ proslalc cnncer and for those with sus pected reQCCurrcnce btu a negalive loculizalion w;lh II stan d~rd clal uation. Indium ( Hll n) Oncosclnt CRIOV (Sarumomabpendetide). 1l'l' ~lInpl lrted structure of indium (1II In) satumo.. mllbpcndctide is shown be low. Antibotlics are ~ hcterogc nc OO~ group o f proIcill5 i!iOlmted from human and ani mal serum and are called immIlRus/o/",/hu, They are di vided into ciu.SC:II on lhe IxIsi~ of diffcrclX."<S in struclure and biological propenl~ and are Iluigned to major claso;es C1'I lIed IgG /8O'l-).lgM (lcn).lIlId IgA. lgD. lgE/< IO%). All al1libodle$ howe a gCilCl'lll \Iructure consisting of two heavy chains

(MW -55.000) and two light chains ( MW -20,000) of Ily coprotcins, held 1 0000elhcr by di~ulrKlc bonds. Many tumm express antigenic markel'li on thei r ~urfllCes lhllt pennI! d!:ttc lion with radiolabeled Wltibod)es. Antibodies are prodllct!! by B Iymphocytcs and pla~m D cells sensitiud to an anugtll Hybridoma technology pennits the manu fllClure of brp' quantities of antibody directed against specific antlgem. DIagnoslic antibodies are o f cwo IYpes: pol~clOlUlJ and If(JIII)clonal. Each chain ha~ a variablc region for antigenic bindiq and I C()t1stllnl region for COITlpltmcnt fiution. PoIytlonal antibodies inc lude nume:rou~ antibody species ofvat)<jnr'" finity fOf lhe antigenhindi ng su rfllCe~. Monoc lunall1nlJbodies are 8eACmted from a done or a \ingle Wlllbody-produriJII cell and ha ve uniform affinity for their pntigenic dcttrwnant.: 1 Monoc lonallintibodlCS are produced by immunmlll a mouse with purified mnlCrinl from the surface o(thr~ lumor ce ll. (See Chapter 7 for additional inforrnauon.) Tbt antigen used in OncOCint CRJOV is a tumor-a5Y'CIilft(\p. coprocein-72 (TAG .. 72), a highmolecul nr-weiglll glyoop!Otcm expressed by colorcctal and m'orian can:il1O!!W..!l Tht mdiolabeling of Oncoscint CRiOV !1lOllOC'lonal Dnti~ was del'eloped by Rodwell!.! as D site-specific me:thod IIW'If a bifunctionlll chelatc. Briefly. carbohydl1l te nlOlClid 011 lilt moooclooa l antibody /Fcoo'Uanc region) are o~idill:d lIrii pcrio<ime. and the aloJch)Jc groups on the IIntibody an: If..eted with (>-al1lioo groups of 81ycyltyrosyl-ly\lI\e-N-d$ylene Iriami nepcnta:ICClic xid. The Schifrs bw: ~ (i mine) is stllbllizcd by reduclion Yo ith .'IOd ium cyallOboroojdridc . In- I II i ~ chelmed to I DTPA-cllfboh)dr.l\t attached IIl lhe COOSlanl region ()f lhe monoclonal antlbol) The specirlCity of mdiolabeled anllbody imaging for ,"'; Cll~-ecdS Ih"l of gal hum (6~Ga) citrate ~ udie~ Sitd of .. specific upude hal'e been reponed, howcver . uch IS rtteI surgICal wounds. an inflamed coloo. bone ff'JCI~.1IIlCl mal eolo~lollly ,tOllla. A ncw method of labeling \11th TI 99m has n:cently been ~ppro,ed by the 1-1)A

mob"

:ly-

Indium ('''In) Ox/ne (8-Hydroxyquino/lne). The inIII... U J1 )-oxi~ complu can be fomlfil b)' liddi ng t ~ re....red amoum ofS-hydroxyqu inolme sulf:llc to indium (111) ddondc and adJusung the pH to 6..5 10 7.5 "..ith HEPES burrer.The Jl<'C'C ir.t StructUre! of indium ( Ill ) oxine as deter.ned b)' Grccn;>.l i~ _hown belo ....,. The p;ll1ent hllll -1 5 to 90 .... of blood dr.! .... n fOJ' a 1..5- to 2-ltour in Vitro process of ~tlMll and labeling cellu lar clements ~""h a, lcul oc)tes 01' plat(']eb. hllug~ are acq uired 2 to 48 hoof)' Mlcr reinjectIOn of the labeled cells. In the ease of ind ium-I l l leuko\)~. the procedure is performed 10 confinn the presence II' _nee of lI'I fL"Ction. This technique hlIs rep1l1C't.'d gallium !"'Ga) dtrote im.ll:!!ng for lICute in fection bccau<;c of greater ~1r.Clly and bencr imageqU:l.ht),. Some chronic Infect ions 'ICb .Il~ I)!;ltoIll)'clitis may be il11:lgcd bellcr with gallium 'Gal c"rote after 11 nZtc.phO!iphatc bone >ean. Al'IOd'ier IIrtbod of radiolabeli ng Icukoc)tc' that ha.\ become: popular Il'ott Tc-99m- HMP AO (he.'llamcthylpropylcnciln'llDC o.l in'le) . Fmally. IndH.m ("l ln HabcJed platelets are u!oed to detecl *umboc;cs. mcasure platelet li fc span. and monilOr the soc~ of lidllCy transplanl'.

~-

"" :en.

Another Indication for Ihb lechniql.lt' i~ cVllluallOO for a CS F leak after surgery Of trauma. 0rlC' variation of c"aluatm& for a leal is to put cotton plcdgets in the: nostril~ for 24 hours and eheek for llboonnal rudioactJ\'it) on the pledgets.

'g'

2-

Di-

.~

ling

"" I

; a f-

cing

""'-

=.T ho glyTho

zing

.,...

bod,

Jsing n the with

~ ~

.Ileth-

fann rohy-

,ecuie

bod,.

'"~ f 000-

=nord "'

th Tc-

,Indium ('''In) Pentetate (''' In-DrPA). T he IIldiurn WI-pcnlctatc complex is fo nned by ILdd mg the required _u of calc.um or sodium pcntelUlc (I)TPA) 10 the in(III) chlonde and adjus1 inj; lhe pll 10 7.0 10 8.0 wilh "::: h~Urox ide and/or hydrochloric acid. A ~d EJI It of indium (Ill ) pentc!atc is \hown below. "flxo paundergoes a lumhar punctLire under "mle coodl tions .-I ftCC'i\'cs an mtr:lthecal injCCtion of 0.5 10 1.0 mC I ( 18.5 J1.0 MRq) o( indium (II 'In) penlet:l.ll.'..... hlCh dl~trlbul'-'" Ihc cerehmsp'lIal fluid (CS I'). 1ml.al itnaJ:es an: ob_ " 10 en'>IJI'I: a good intr:llheeal IDJCCIlon lmage\ of the , ana] and CSF spaces of the bn!.!n IlI'C acquired at 0 71 boors 10 IISSC'S CSF flow or leak ugc from the nom la! {~'PJCe. TIle normal CS F flow p;!ncm ,ho""~ Ihu1 the ipllamlllCCu tical asce nds to the bu,i lar ciste rn ' in 2 10 4 flQw~ over the cercbru l ron\'exilic~ in 24 hOlIr;. 10 72 hour;. there sltould be II i:f'.ldual c leaf'JI\(.'C Ihc CSI' ~ ia lhe choroid pICJlu'. CiSlemogrophy I' helpIII tlot!u;Umg (or ~'Ommunleatlllg h ydl'QCC'phaJ II~ becauliC IS lIboormal CS F no .... InlO the laterul "enuielc:s o ( Inm 10 thl~ d isease. Then:: iJ 31-0 an MR1 method for ng thIS type of hydrocephalus. 1111 ~ dl<;Casc 111:1)' be wrg,ICall)' by shunti ng CS F 1 other area. of the body. 0 I'>lhe pmlOneal space. and thIS radlou'III.'Cfcun be used ~.1hc po"i'lbility of II blockage of ~""h ~ ~hunl.
1

Indium ('''In) Pentreoride Injection. A pL"QpO!iC'd stnICture of Ind1Um ( ''' In) pemre04ide IS ~ho"'n below.l.I PentreOl ide has a bifu nclional chelati ng agcnt. DTI'A. h n ~ cd 10 octJL'()lidc ..... lIlch is a 1 000g-acling ana loguc of the hlUMan hormone SOtllIllO,t .. tin. St>lnalos1wi n i~ a pepudc hormone oon~i,t ing of 14 mnino acid . It is [JI'CSCnl in the G I 1ract. pancreas. cerebra l conn. bnll nstcm. and hypothal:unus. Somatosta1in rcet'ptOl'S h!1,'C been found 00 many ce lls of neuroendcJcri ne origi n. Neuroendocrine tunlOl'l\ arc smllll and slow growing . whIch ma~cs them hard to detect b)' cr or MRI . SornalO'italJD rect:ptonl are e~pres~ tn IIC:Il'ly all tumors of ncuroendocnne origm and can be imaged "'I th the: DTPA-octrcot ldc I lllIlogue . ..... hich chelalcs Indium ( Ill) chlonde.

NH
DPhe

CysPho

, , D-Trp

Thr(oI)

S-S -Cys

, nu , Lys

t!'l(lium PenI,lIQIde

Indi um (II ' in) pcn lreOlid~ binds 10 <iOn1aloMal in rcccpt oo o n man)' cdl surfoccs throughout the bod)'. The paticnt ret.... ivcs un II'I tf'J\COOUS injC~'lijM1 of 5 mCi ( 185 M Bq) of III In pent rcotidc:. and .... ilhi n an hour. the radiopharmaceuticlil diffuses mto the extrucclJullir nu.d "p;iCC and eonccntrotes 10 IUm0r5 CQDt:llnmg II large number of somatOQatm rccepton. Who .... -body imal!e~ arT oo.:ui>Cd 4 1048 houn aftcr In)CChoo 1 locaJiLC the pril11:ll)' tumor and sucs 0( metll"laSl:<'. Nor0 mall). lhe pHU lIlII)' gland. th)'TOId gland. !i,'C'!'. <.plcen. hiIlC)'S. IlrilW) bludder. and . in fTI()l;t palients. the oowel are visualized on 1he Image.

THALUUM RADIOCHEMISTRY
TIll' only uo;tful rudK)l)Olopc of Ihallium is tooJhum-201. .... hich i~ produttd in n cyclotron by proton bombardment of a thal hmll metDllIIl1Ct by a .!DJT1 (p.)n )lOl Pb nuclear ~ae lioll. The lead-20 1 (/112 - 9.4 houl");) I~ allowed to decay hy electron caplure to 11-201. Thall ium-201 (r,n - 73_0 hO\l~) decay~ by elcclron capl\l~ to stable mcreury-201. v.ith princip:1l )'"ray emIssions of 135 l eV (2'l) and 1671.eV (8%). and mcrcury-201 daughter x-rays of 68 to 80 ke V (94.5,}), all of which cao be used fill' org.l0 Imnging. The thallium target I~ dissoh'ed In hydmchlonc acid. ~nd the Pb-WI i~ isolated from the thallium-203 by ion ctch:mgll column chromalography. TIll' lead-2Q1 (lOIPb) i~ allo\Oocd 10 decay on the columo to thallium-WI. TIll' thallIUm-WI (lOIn) i5 renlO\'ed from the rolumn by iOll e:tch:mge. and the chloride 'ilI11 is formed by udding hydrochloric acid and e\uporollng 10 drylleS!l. Theo the p~1 i~ adjusted 104.5 to 7.0 with Mldium hydroxide and lhe .'>:III j~ ~I erilll..ed. The solulion i~ made isoton ic \Oollh sodlum chlondc ("OIllaining henTyl alcohol as a prrscrvamc.

injeclL-..l with 1.0 mei ()7 M Bq) of '11-201 chloride to pr0vide informll1 ion under normal cond l' ion ~. An clDl1lplc ilo shown In Figure 1)-7.

XENON RADIOCHEMISTRY
Thc uo;tful rudioisotope of ~enon for DrgWl imagmg ineno.I)). Xenon-I)) I, produced in a n\IC lear rcllClor as a titproduct of uranlUl1l fission by the oocirar reaction ~"l:In. fi~~ion)'))Xe. Xenon I)) (t,n - 5.) d;oys) decay~ by ~ particle emi,sioo to cesiu mI)3. \Oo ilh ,...ray cmission> uf 81 keV (36%). Gasc~ u'>Cd in lung "cnlilalion stUdies mu>! lit chemically inert and. al lhe conccmrntlon~ used, be ph))io. lo~icDlIy irocrt. Xcnon-I)) i~ chemICally LIlcrt IIJ1d LIlsolubk in waler. v.hich make, II msoluble In body nuids. Unfo''OItIlle phy,icnl char!ICicriSlicsof xcnon- I)) includc poor i~ quali ly becnuo,c uf thl: low tissue pcnc:trntion of the 10.energy )'"ray. increased patienl do<;c dllC to .8-partlClc mil'" 5ion . and the low ,...ray emission (36 )'"rolysilOO diMnirp tion~), An alternatIve \Ooou ld be xenon-127 ..... hich i, able and not cost-effecti,e.

,
j

, ,

Ulla''''

Thallium Aadiopha,.. aceutlc:als

Thallium fO' TI) Chloride. ThalhuJlI chlonde I) the only rudooph.arrn:ao.:eulical of thalhum-20 1 eUITe"lly IJl use. ll!e rrlO"l common clinICal USoC'i of Ih,s I"'.tdiotmcer ~ for the e\'uluation of m},ocardlal perfu'iion Dnd myocardIal via bility. In rl'Ccnl yean. thullium-201 has nbo Jx.-cn u~ to e'-alume a vanety of typc~ of cancer as \Oo'c l1 as hypcrparalhyroidi'iln. Rescan:h using rudiolabc:1ed mlCfO\pl1eres wllh human voluntecrs dcmon\trated that the myocardial distnbulion of Ihal101J~ (l) chloride correlotes with regiooul blood pcrfu~lon. Thal lium (lllI TI J ch loride accuntu lation in myocyte~ requires an intact ..ooium-polassium pomp mechanism within the cd l mc:mmllC'. Accumulation in the ntyocardial USloUC therefOftl refka" "iable ti~~uc as well as blood now to the m)1>cardial t,,~ue. Con'CT'Io!ly. in clil1ical imaging s1Utli&:.~. the an:a~ of ntyocardial infarction (not vlllhle '\Car) are ~i~un t il.ed as nonpcrfused C'rotd ") ureas. Although the Tc-99" t-oosed myocardial pcrfu~ion r.tdlotmc-c~ (seslumibi and tctrofo<Omin) are n1()'illy bound m the heart cell. 11-201 is corllinual1y_ p;!ss"'ely moving back out of the cell\. Th,s phrnonll'llOI1 i~ ca lled tilallium rrfimri/JI,/um. Currenlly. the nm<;\ rommoniy performed test in all of nUoC\ear medicine is the e\ aluation for siJ!nificant narro\Oo ing of lhe coronary artener.. To do Ihl s.. the patient submIts to either physiological' '",f'US" (lI'CaduIIII I:.lc-rcisc) or pnamlacological "st~~" \Oollh an 1OIra"ellOU~ infu~ion of a ~asodi lator (dipyrid;omo le or adenosine). dcperwlmg on pIIy~ica l condition. AI ma~101Um strt:~s. the: patient is injected wilh 2.0 to 4.0 mCi (74 to 148 MBq) of thallous (I) chloride. ...hlcll locali/.C'S in the hem mU!iCJe (myocardium) 10 proporlion to rrglOl1al blood flow and cell \'iobility. The "Mres5 tes'" acccntuates the: myocardml p!..>rfU)lon abnormality beC8U'\C areas of significant arterial narrow inK cannot !'e.'pood to the increased blood now demands of the 'ltn:."!l as well as the normal aneries can. Imagt':'i o f the hean arc: obIruned iml11C1.lIate1y after Stress. and the damagetl myocardium shows less 11-201 chlonde uplake than surrounding normal heart mU!'elc, Four hours aftcr S1Jl!.\S. the feS.ting pmicnl i~

Xenon Radlapharmac:eutlcals
XlMon rJJXe' Gas. Radioactive xcnon g:L\ I~ 'iIIppIla:I at ~tandard pressure and room lempcrnturt' In ~!lIII o;ealcd glass vial (2 mL) in ~,of 101020 mG (371h~ 740 MBq). The g lll.'~ \'ial can conl"in atmOlOpheric ainu mixlllre of 5% ~cnon and 95% c~rboo dioxide and I~ sulubk for Inhalation by the p.:&tient for dlDgl1OtK: e"alu3nOll of p!IIimonary function and ilT\:tging. The general ~ure. volves mixing the ~cl1On-IJJ gas In airoro~y~n in ac~ circUIt ~pirometcr ~~~Icm thai del;'c,-.; the rodiooct;lC PI and KbK~ l hing t])e go_ tl1ixtu~. The inhalation Slully OODsi'l ~ of equilibrium and W:L,houl pha.o;es. v.ith the paid Sluing or supme . In the .... ashoul Mudy. the pahent elhlJfl, the \cnon-IJJ ga.~ inlO an actIvated charcoal ltap 10 poeOd e~JIO!'ure of Ille lechnologist. Im;lg" are obtained COIlt ... ou<;ly for approxim:llcly I 0 lIlinUIC.~ with the gmnma (rrt} cumcr,!. In the normal equilibrium ~udy. theK is l1li illiU homogrnrous d"uibution of the r:sdioactive ga~ throu~ the lung$. In lhe washout pha.o;t. lhe xenoo-13) p" tb KOOlly from lhe lunp. In lhe abnormal study. tht . now into the lungs of ~enon-13) ga~ is dclaycd.1TId die ol,u n ow i~ also tlcloyed. The'\C Bbnonn~l lun!: 'cnulan findings add significam in formlltion In lhe c\'aiualion 0( pimonal}' embol ism (blood clOlS in lhe luogs) \Oo'Jlrn COonI:ttnrII v.nh lhe ~hs or a lung blood perfu.1on Mud) ... nll T. 99m aggregated ulbumin.

p b

RADIOLOGICAL CONTRAST AGENTS

A photographic film containing 8 radiographIC properly called 1I m(/iollmplJ. although il i. 0:0Inn1Ol'l1) If' ferred to as an XfIIl or a film. llIe K lati\'e differenct III\OoCCII the light and dar1t; aKas on a radiogrdp/lic 1~1r' flcclJi whal is called rodiQgmphic rontnul T I1KhogrupillC Imnge~ or the bod). such as ~l.eletaJ. nal. arwl ,1Ies1 ~ruys. ha~c fi~e r.adlOgl1lphlC den~lllt\;

'matr.

CblI"tcr 1J A,.rnl&jiH IJia,. .....rk l""'I'''g

!pI tknsny. (31 densu)'. fluid (~ft lis-we) density. bone

473

leak;um) denslly. and metallic density.

, "-

i~

". P. '" ,"

Y-

81

When:as lmdilional ntdiological "film" studies lIal'c betn used since J 895 nod continue 10 be Ii lOainllay of ..iagI3!ijIC medical imaging_ they have their li mitations. Man y oq:an, and tissues of the body do 1101 ~how up well 0f1 Imdi IIOIIlI r..diographic imagc~. FQr example. tlte livcr. spleen. bdneys. int~lillCs, bladder. and abdonunal mU.'lCu l:llull: all lillIe \'ery sim ilar rudiognaphic densities and are dlrrlCUh. if 101 l~iblC'. 10 dislinguish from tach 0I1ler. From the earliest days of radiology, mLICh effort ha$ been '"'OCt<! 10 developing compounds Ihm if swallowed or In-

,oed would i~asc the radiographic contrast between vaT' 1M tissues ond organs. Injection of air or ulhe r gases inlo
I Gl lubt in lhe esophllgu~. stonmch. or duodenum or into I m:1&I lube in the colon providc$ incn:ased radiogruphk IllIIlInt for cvaJuliting the gUI: ho\\.cvcr, the infonnati on tlUined by this technique is li mittd, aoo mort: opaquc ~ub"'l'S lI:wc been de.'cloptd. AllY 1gent or compouoo Idmmi5tcred to a patienl to im. '""~ 1M ,bllali1.ation of lUI orJ!an or tissue is called a ((}fl. IIIUI agtnl. Contmst agenl s can be cb ssilkd as neS:ui .. e or p;lS!Ii\c. Air and other gases an: negativc contrast agents lKau~ they rendl' r a structure. such os the gut, more trun si ll' (CIIl. An agent that increases the radiographic opacity of an 0!pIl Of" tissue is a positi"e contrast agcnt . The majority efCOllIl1lSl IIgcnl5 llsed In diagnostic ntdiology an: po$lIhe CIIIIrlSI agentS. All Ideal COllU'llSt agent should hl"e the follo .... ing proper . (a) ready Ivai lability and low COSl; (bJ eJ,cdlent J,II)' ~iOll characteristics lit the x-ray energies used in IIfcnoI;tic radiology: (c) minimal tOKiclty and ready patient IXtplllf\Ce; (d) chemical st llbility: Ie} high wMer solubility .TIII kJw viscosity Dnd no significant osmot ic effect.'; and !he ability to be admini ste red for selective tissue uplake t.u:retion. /'iocompouoo has all of thesc characteristics. Barium slIlIIId a \'aricty of iodine compounds. howe,'er, produce ;'~nt ~ical ~"OI1trast with low palient tOXklty and .'~ly low cost, The useofbarium and iod ine compounds lindlo!oaical cont mS! agem~ is based on their ntdiographic ~1Il!J'ICe and their distribut ion and elimi nation from the Io;ty. COfIInlS[ media an: u~d in very large quanti ties and ftlll-Uilly administcred O\CT a soon time:. !Inurn sulfa[e is a nearly ideal conU'llSt agent for 01111 wid m;W 5lUdies of the G l tfllCl. It produces a metal like densi ty I1diologicaJ studies. is ruddy available at low coo. and. used pmpcrly. has minimal pancnt morbidily and morMany water-~uble barium compounds are quite btu bariu m su lfate is an inliOluble \\,ollite power tllal is _ llled in Wa[CT lIS a colloidal suspension. The majority of commst agen ts used [0 opacify blood vcsand i~ase COIltrol5t in so lid organs _~ucll as the liver ..: "'lter-lOIuble organic iodides. Iodine absorbs JI-rny~ efIyat many cnergy levels and produces a type of "cal Of" "'bone"' density OIl radiographic studies. Its den. torncwhlu less than tha[ 0{ barium qJ lfate. is quite bk. llllillhc 1980s. most watCT-SOluble contrast agcnts conof triiodinattd bC"fl1.(Joc (ltid s.ahs. In solution, they iuoclate into tWO particles, u t ri iodin~ted anion and II C~ t whIch consists of either a sodium or mclhylglu!:omine

m-

. "

w_

,d

,. ,,'" ," ,m
~

n-

(mcglunune) ion "fhcsto; compounds (Tallie 132). known as high-t/Slnolur ((HllruS/ media (lIOCM ). ha, c In effect three iodiroc atOfTlS for el ery two ions In solutIOn. a 3: 2 ru[io. llley an: often calltd imrie nllia 1.5 C()II/rf1S/ I1l1rlll$ or ,riiadmmrd m{"'lJmus.~ They arc mainly representtd by dimri/,OlIte arw.l iOlhll om~te compounds and firw.l frequcn[ use in urography and cooU'llSt-cnhanctd CT ~tud ics. One muSt admin iS!er the 1 3tero;olublc iodln.1ttd organic " compouoo~ m fairly high conccnlmlioos to IIChicvc sati5fllC' tory radiological COOtnlSl. It is not unusua.l to administer 100 ml or more of a 6O'\f- sollllion of one of these compounds intravenously for urogrophy. A typical conccntTlltion llsed for intravascular ~tudics has an osmolality 5 to 7 times greater thatl that of nonnal plasma. lllercfore, administrat ion of these age nts can be associated wi th OSnlotoxic effL"Cts. such as local pain, nushing, nausea. and vomiting. The com mon triiodm3ttd contnlst agcnts lisltd in Tab le 13-2 repre ilCnt what are comnlOnly t ailed i",,;cor highas",oIarllgcnl5. TIley an' relath'ely inexpensive and ha.'c been m use since the 19605. Much /"eSCan:h has gone inlO developing watersoIllble compounds with a highcT mtioofiodine to osmotic particles. The first com mcn:ially available nonionit tontnlst agcn[ was metrizamidc. which dissolvcs in woter in It norw.lissodnted ronn. giving three iodine atoms for every molecu le in solu tion and i$ ~felTCd to lIS a rQlio-J r:omraJI a8~m. Melrizamide was mainly used for myelogrnphic studies of the spinal canal and !\as been largely replaced by ne....er agcnl5. This has ltd to the de\'clopme:nt of ionic IleX:UOO[lUIttd dimers. such as ioxaglale (Hexabrix). and nonJOl1Ie watCT-wlublc contraS! agcms (Tablc 132).

d-

""

O=C-NH

"' "y)
~

" "'

,I
~

'" ,,-

,'"

A/'
Iouglate

I. 'D<X'I-YH'><O>"

,,0 ',cxo'[JI~'"

"
i-

i,

lopa midol. iohcxol, and ioversol nre newer' Iowos[[}olbr. nonionic" conlrast agents (Tablc 13-2) Dnd are heavily used around the .... orld for many types of ntdiological studies. These type., of agents, known as /0'" osmolar CtHuras, media (lOCM). produce far fC ...CT osmotoJ,ic cffects. such as local arm pain. nll\hing . and nal1SCaand \omltmg. TIlry an: gene.- ally considered '\.lIfer tban the commoo io",c lriiodina[td contraS! ogcnts and. in many locales. have replattd them in daily pr:tCtict'. 1lley ate vcry expens[vc. howcvcr. compared w ith [he ionic age nts. In the United States. they mal. cost up 10 10 to 20 ti mes as much as [he ionic agcnts. :? ~

TABLE 13- 2 Diagnosti[ Imaging Agents and Pro[edufes

[0" ... 001 c-r.. t 'D ' ''b
21 .".
",~",oOII102.9

"" "X~~
CONH_CH_CH,OH

c-,-i!Il: _ _ ,

..o...,\,)f'"_HI_ ,.... I " I

C""",, 000 (2::6."""'- "":''-1<)

")_$11(-"""- __1I H" ,,,60(60!! , ",' ,,, ,

~

b
HO - a.. - CH-a.. - N-c:ocH,

" "' ''" 1~ I'IM! oodi<.mo d~"-I

M ",o/Io~11:z. ...., ...

HJ' I ~ 9,I(0!0'II""' _ _ "'~':':'::':'::':::d' '"+ ,.., ... I_? I

-)
OH

/1: ......... 16 (Wl . .p. .. ,.. _'''_, 1&1 toOl"." ~I _'oI.teI_ =11 _I

HOCH'r" - CHJ1NOC
, IoheIUll

...... _

' Iii] r-_-, ...... t~.,IIto!A:ao\11

Ht.-.,....po.,_ ... _
lor,mIo 0."._101/_

"""_1 ....",."..1

.... 1 , 1 _Ko..."" . 5.,o"

I; ' ..

'0;...... '- 'I,.

IIrI<'<tIl'

p."'"
J

O""""IM...... I-C...,., '-'"'

l'bo""litIpr< I'I - '-'~ v~'_ibll_l- '11' cd

""""'">I. (d""""",
In geneml. high or moderute osmolality und high ""~OSIIJ lITe the hallmarkli of all iodinated COOll'llSt media. BcauIt of this. eonsiderublt' ~mQdynamk and Jubjecti'e rif1l are cuul'ed by administrotion of Ihc<;(' agenlS, I mtially. "'__ sh,Os ropidly from the interstitial and cellular spw:es the pllllima after :nJeCtion oran iodinated contrust 3ECi1l, n.. b typically ac:comp;lnicd by vasodilatation. l..x:aI pain'WIUllIIII. a metallic t;lSle in the mouth, and fiushmg.l-. there is an osmOlle d,uresl~ as these agents arc: cu:mtd lit lhe kidncy~, 1\11 of the ...:u.ersoIubie iodinated COOIn5? mt'd,a are cb' colodc.\s liqu ids wilh 00 visible precipitales. lllcy art "" coos and. w~n spi lled. produce a some... hal slicky Even though lhey arc: ckar liquids. lhey ~ often ... , 'dyes" when their adminblmtion is being expla,L1t'd III ~ lienls. The sodium "lIhs arc shdltly 1c~5 "isrous tlwI nJeglumine salts. ContrllSt media. iscoslly can also br Itduced by heating the m to body lemperature prior luadmull Il1l1ioo. The .... alcrsolublc iodinated conimsi med,a ha'e tive ly ~mall molccularsiJcs and low e~mical re~uvL1y body fluids and tinul'!i, I\genls of this clllSS include wate meglumine, dialriwale sodIUm, iocet;un,c acid. pamide mcglum ine. iopll.ooic lICid, iopronk acid. ~ mate sodium. ipodate sodium. and Iyropanoaie _;Their pharmaceutical ehlll1lCleristies are similar 10 of utracellular tracers. They lIa.'e low li pid d,stnootc throughoul the t'xtraccllular 5pacc. I penelmle sign ilicunlly ;nlo Ihe intracellular ~pace, ...:tlersoluble iodinated COIllnSt agenls arc: ekand t~ body by glomerular fillralion. 1lley are nellbn' sorbcd nor secreted by Ihe renal tubules. When fullCl;on is compromised. l!lese contrast agents~" nMed in patI or 1001I.lly IhfOllgh the Im:r and (II. vicarioos eIIcn:tioo occurs al II. ntUrCh slo\\'er 00

CI"-i".~"

o.-ii

1"''*-sJoa-1 e..m.t....... _ ...!1

(,1o'''I,!, ') M.." "" ,." 'M _ct:_id ,."'" ,101 . . ' ....... 1 ......... p' ... .,) ~I""" 'I

'*"

......1-.'...-1 Opcr..-,.....,. ... _'''I

".r... '

; "_ R_ _ "

+,

','GlI.>:;....

'ii;;':-;';;

l_
CT ' 'I

'..

,__

MRI"....
~ .. r-'oI., ,DQ .. MKl_.... l'boI 'I" , 'O/BS ' ", , - . h '- , ~_ A "Jr ,,,,,,0 . . . _ _ .. ,~5J _ _ I(JCIIOn I-.!\:loy ,t-:u, '991 _ , b!ioI_Ul. 1'1091, K..n...., /I: '01 llNt>0)lII)-

""" ...

,.:, ...

) No . . . . . . . _

......

_...,1" ......

9ru1l3Uon b) normal glomcruhlT fillr.UlOII III II heal!hy p ...... The half-time for the renal clearance portion of ... ~r-soluble cootrast agent is I to 2 hours III II pallent WJIb IJ()I1n3I renal function. The ....'lIter-'iOIuble organIc io!ides are the IMgest group of radiological COf1lr~st ~nt5. -' the ImponlUlCe of their clinical uSt' is only llpopro;1Ched lJy blrium sulfate.

NIt CO

1'1 - '''''''' 6 011 HO-6-1'1 1'1 -t(-0I1

"-~-,,"
I

Ctl,

Dlatnzoat8 MegIunwle

""'"

,
On the ocher hand , there is II hetC'l"OgerlOUS gTOOp ofwllterinsoluble compoooo.~ of iodine that only rarely find U$e as radiological contrast agellt s. These compounds consist of estcr derivatives of iodinated vegClllble (poppy-seed) oils and iodinated pyridoneli such lIS propytiodonc (Table 13-2). In the ca~ of iodllCd oils. unsalurnted vegetable fnuy acid moieties are iodlll~tcd by addition across double bonds and are then cooI'encd IIItO l'ariOOS esters. Some water-insoluble aromatic iodides hal'e also been used occasionally IS radiological conuast agents. These substances are more resistant to breakdown from exposure 1 light and air. but like the 0 iodi:t.ed oi ls. they canOOl be usa! illU'l1v3Sl:ularly.

CH'-~-N-CH,-bl'1-COOH

""

sny

-"" ,
,

"'" = liter

A/'

o
Iodlpam;ae Megk.Irnkle

into

!'his "d

ncr,

Ib,
ear,
V;!I---

CH~-CH-COOti

'i'"

'""
PARAMAGNETIC COMPOUNDS
MRI is a unique method of medical imaging (Fi,. 13- 12). When a palient is placed in a large. strong, uniform magnetic 0 field. one can use <>maIler. .... ell-dJreclt'd gradIen t field~ 1 selectively excite hydrogen nuclei (protons) in a selected small vol ume of the patient"s body. 1llc exci tat ion is done by use of radiofrequcllC'y fields. and once the exCitation fields are removed. the excited protons lose the energy they ga ined . 'fhey emit a weak. but detectable. rollJio wave. whose ~m!llgth and manner of decay CIUI be used 10 gcnemte diagnostic medical images. The tesla (T) has been adopted lIS the official ullit of magnetic field strength for the intematiorwl system of units . The conventional unit. the gauss (Gl. i\ 10.000 urnes smaller. MRI is normally performed at 0.5 to

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1be images produced by MRI are $uperficially similar 1 0 the cross-sectiooaJ images of the body produced by CT. MR I. however. has the "'kkd advantage of not uSlllg IOIIt1:lII& radiation. such lIS ~ - rays or ,.rays. and easi ly prodUj ex quisite soft tissue images of the body in any desj red plane (coronal. axial. sagi nal . oblique. etc.). With MRI. image 00II -

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.tlecmr imaglflg of various Of];an~ ~nd II~Sun. such as lhe ;"e!". the RE ')~tem. the Iymphatir system, and the blood pool For e~3mpk-. gadobcrnate din ..... glumllle ( MuIIlH3~) al pdoxetK' acid (Eovist) accumulate in the inlerSlltial ~ lind the urine:. 11ley are eliminated by both ,he renal alilepmoblhary route.~. and then:fon:. they can be used as <o:lti,c hepatocyte and bi liary excretion comrll..~t agents. Manga~ ( Mn l ' ) i~ mongly panmmgnc:lk. but it is lO\ic if used a~ 3 free ion. To makr it i\.Ilfe for U~ in humans. ,.;oo~ mangane~ eomplucs havc been developed ns MR I C'IlIImSt ~genls, At this time. the only pan:nteral mangl"..... se C\WIpallnd used in humans i~ mang3fodipir trisodium. This COIIIpound t~ delivered to U5sues ..... ith acu\,e metabolism. ..ml!the pancreas. nmal COI'1e\. G lt r:tCI. hean. and *.!renal

images and a hIgh ~Ignal lnten~"y on T2 images, Tap watCl" ;s inc~pens;'e. n:adil) ....allable. and n:adily accepted by pallc:ntS. Unfonunately. liS abIlity to image bowel contents and to con\fa~ttIM: bo ... eI ",th surrounding organ. and II-lIh pathological proce~<;e!I i~ not alwa)'$ good.

ULTRASOUND CONTRAST AGENTS

Diagnostic uhl1lsound Illiaging usc. high-frn:tucllcy sound wa ... es from I to 12 MH 7 to produce cross-sectional Images o f the body. A 5111all handheld transducer connected to a largc:r electronic box is used to scan the body pan of Intc:n:S! (e.g .. the aIxkNJ ..... n). and the n:~ultanl image. are di'!'iayed on a computer scra:n. 11tcy may be later pnnted on film or ~torcd digitally. Vanous body tissuc::s ref1('(1 the IIOUnd "an's in charactcristic fashion. and dillgllOStic ultt3SOUnd IS Simi lar to tIM: sonar imagmg used b) aquatic mammals and submar ine:s. Diffc:ringti~S I)e5 (e.g .. tIM: Ih'e!" and tIM: right kidney) ha"e dirfen:nt acouslic properties. At tIM: intmace between tissuc::s with diffe:n:nt acoustic properties. the soooo wa\cs un: n:f1ccted bock to the tmnsducer and are displ:lycd on the screen. ~howing lhe interfuce and the tissl.ICS Qt the interface. Unfortunately, ga.~contailllng ~truClUI1'S (lungs, bowel) and bone~ c it~r abll(lrb or SCOller I1IOSt of the <.OUnd WB\"es and art' not usu:llly imaged satisfactori ly by ultrasound. SQlid organs (Ii\"er, spleen. kidne)'s), organ5 containing nuid (heart, gallbladder. urinary bladder). blood \"osels. fally lis. SlIe. and muscles. howc\cr. are usuall) amenable to diagnm tic SOIlOgl1lphic inlllgUl,. UItra(lUnd finds "idespread application in diagnmtir radiology. obstetrics, gynecology. and cardiology because it produces di:lgnO'\tic results comparable or elen lOpenor III some cases to OlIM:r imag ing techmques tnat require tIM: u~ of ioni1';ng rad iatIon. Ultrasound mao::hifICs are olic:n ponable IIIId may be tnken 10 the patient's bedside. Moreo\CT. diag_ nostic uhl'llsound ha, no known harmful effects. Contrast agem~ an: not used for most diagnostic ultrasound examinatlOlls. Much research is being conducted. bo"'c:\"er. to devclop safe. ine~pens.ive ultrasound conlrast agents that may be inge~ted orally or injected intra\'cllOUsly . Ultrasound n:hes on tIM: detection or 3COU~tic cnergy (MlUnd wa,COi) rt'n('(1ed at ti.~ Interfaces "ithin the bOOy. Gases create: pronunenl 3COUMIC interfaces with body tissue~ and can be: adapted as conlrasl agents. Microbubble.~ rontalllll1g air orOlher gases intnxluced into the bloodstl'C'aJll may act as a cont rast agent by increasing the ultl1lSOUnd signal renCl:ted from lhe >csscl contents or from the 5tnx:tuTO fed by tIM: ve.~ls. Agc:nts n:lyinll on microbubbles may be class ified as (a) SlIIbi lized or encapsulated microbubblc:s. (bl polymer microb:llloons wid gaseou~ liposomes. or (e) colloidal suspensions lInd emu l ~iOlls. These agcnts allow visual i~atiOll of small l"tssc:ls. idcnt ificp t ion of tumor vascularity. improl'ed contrast \'isual i~ution of solid org:IDs. and Improved vi_uali7_ alion of the heart ch3mbe1'5 and \'lIscular grufts and condUItS and are generally >"cry -.afc:. ~y are deslg.ned i>O 1M) large bubbles form In the body. and they ha"e relau\"ely oJt.on lifc spans and IIM:n breuk do" n and di ssipate. 11tc problems gellC'l'lIlIy eocoontCt"Cd .... ith ti"M.'m arc thcn "'Slablilty during pass3lle through the IM:an and lunp and theIr limited time of action . Research into uttr.lSOUnd contrast agems IS In us infllllCY and \\ ill 1M) doubt produce useful productS in Ihe near futun:.

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Specially designed parenlcrul paniculUle agents can be ..cd 10 e~anline ti"M.' RE 5ystem. One WlIIy to do thi~ is to _palate a par~lnagnetie material into 3 hollow Slt'\JCture tOIIIpOSed of surrounding lipid layers. The 5il.e of these lipid ~XC5 (liposomc~) is then manipulated ~ Ihat they will ~ sdecti\'ely filtered by the RE ~)stcm. producing MR I (On!nl\t enhtmecment of the liver. spleen. and lymph nodes, trptndinll on the Iiposome si7.e and other ehamc tenstics. PuI)'SXchari!lc-coaled su~rparamagnetic iron oxide pantm (SPIO) can be specifically designed" ith u~ful proper Itt. lMserorltain a cryqallinc COf"C composed of iron oxide lUlllf)icxes "lth ferrous (Fe H ) and femc (F)) ions. 1lIe tat is cooted with !lc~tran 0( anotM:r latJe polysaccharide. !heir ~llC is bct"een I and 10 #f1\. and theIr biologieal dw.IclCTlSIICS can be manipu lated by chang Ing theI r poIy_ ..... l... ,de coaling. Large panicles accumulate tn the l i~er lid 'Illec:n. "hile smaller panicles rematn in tIM: circulation Ilnd tcOO to IIggregale in lymph node.-i. Ferumo. des d Fmdcx 01" AMI-2j). fcmxal1 ( Re~\ iq ). lind ferumo~tran ICllrIlblClcx or A[l. I I 227) are three ellantple~ or ,uch agenlli. "'~USC maIn MRI effect of Ihe iron oxide particles i~ on n irna~e~. they darken the tissue in "hich they aecumulate. enl MRI COOtmst agents ~ being de,'eloped for imlJI..td 'isuah~atiun of the G I tract. One mcthod of illlprov.. bo\\eJ ',~iblli t ) is 10 dis!'i!lCC 11M: bo"el cootents with ... ._ ~hqutds. AIr IS 001 widely used. becOluse it reqUIres 1011 of the ~lon\aCh ortIM: rectum, and it ha.~ unpleasant eet~. Perfluorocarbon compounds h:we tIM: same "CO".-IIC suscepllbility as water and will dis.place bowel con fot Intproled imaging. 1lIey an', fMw,e\er. txpensi"e "idcly used. CJi,)~. ,uch as tIM: formulation used in Kaopectalc . upcrl*amallnelle Iron oxide panicles (SI'ICX), son ..... naturoll (lrnulritional supplemen ts. al.o m~y be used us gastro~lnal [l. IRI COntrolS t agents because o f their di~tinct c fIecb ()Ol tM: T, or Tl n:laxation limes of bowel contents. IIIIww. and bluebemes. forcxample. conmin high ~moulilS rlllllllganesc. A Ithough all of these agenl' arc poIentiulJy I'tlol. they are generally rc:ser.ed for 5pedal imagmg situ3. Then: an: no generally accepicd MRI contrast agents for Imaging tIM: bo"el COntenlS. All of them ha, e SOItlC ~ of dl~lant:r.ge that limns their u~. such as terrible II. e~cc~~ile C05t. unpleasant aftcrerrCC1~. or the prodoc0( ucc,s"e lln:lging artifacts on some mJ.agmg 5C' ...""- 1bc most uni"elSally ac~'Cpled bowel contrast agent illap ..~ter. It giles the bowel a low ~ign:ll intensi ty on T I

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RADIOLOGICAL PROCEDURES
Modern radiology h~s many unaging procedures thai u~ contl1lst agems (Table 13-2). Some of the "tore common procedures are di.;cu)~d below Illld iIIu~trntcd with uampk~ to ~how the uJ;C'fullX'~ of contra~1 'gents. Although it is IradJl iooal to thin~ of radiologicnl Mudies a~ u~ing film. c~ccpt in the case of or MRI. one ,hould n::aliJ.e that the digital telolu,ioll Il:ls COIilC IU diaJ;llOS4ic imagillg. Many traditional nldiogl1lphic studies. ~uch as Che$1 r.l(hologY. 00 longcr U'le traditional radiogrnphic film. Instcad. ~-roys arc ucd to "uposc" an Imaging plate inSlead of a piece of film Thi~ imaginE plalC can create a digital signal if properly prococd. The clCCtrollic ~ignals from digital imagmg plme<; are then used 10 cremc radiological Imagc~ thaI arc read from computcr monitor.; instead of film view boxcs. Thus. imaglllg stud I':''' Clln be ston:d. mllOipulated. and transported "-Ofldwidc dIgitally OH:r local area oct"orkJ, or ovcr wide arca networks. Diagnosuc radiologists. ho,,-c,cr. perform the same type of stud.es and use the same contrJSl agentl. v.. hether the ~lIldies are film based or computer based.

and oomlal body II.\SUCS. II also fn.'quenlly sM' blood les..els to beller adl"llntagc.

absct'i.!;e~)

ArtHlography and Venography

Angiognw"-v refcrs to the rudiogl1lphic \"i~uDIiJatlOll" blood lessels by co.lIraq injcction directly into an arlIT)' (lineriogruphy) (Fig. 0 16) or u ~ei n (Ieoogmphy). ThtR are many types of lU1eriogr.lm~. mduding tho:o.e from embra! al1giography (vi,ualil.lliion of head and neck 1~'l..~M

cr

' .."'avenc,," Pyelography, Intravenc" .. Urography, ExeretOf")' Urography, and Camp... - Fd TOlhograph,
"The mtl1lvenous pyclOj!ram ( IVP)
one of the oldest and most fundamental diagnostic radiulogical ~tudi cs u~ing COl1tru St material. It i\ II mailKtay of genitourinary (GU) radio! OIlY and delineatC!o the kidneys and the urinary tr.IC1 (renal caliCes. pelVIS. aoo ureters) lIS lIIcll as the bladder (Fig. 1313). A more modem nallle' and one that bt'llcr describes the relevum physiology in\olled III the study is t!.Xcrno,)' IIft/grallh,.. NC"enheleo;~ the Ic:rm /VP has been in common usc fOf" so lollg thai ;t still i~ the name used rnoo;r frequently. Excretory urogrnphy i~ based on the rapid renal clearance o f lII"3ter-~lublc iodinated benzoic add compounds (whether they an: low-osmolar or hil!h-osmolW'" agems) after they III"(' injected mtTll\"enously. In oorl1llll individual~. the iOllie and non ionic water''iOluble iodinated contrast agem\ lITe all ncn:ted by glomerular filtrvuon. M:my body and head CT studies (Figs. 13-14 and 13-15) u.'ie intravenous ~"Qlltrast rnlllerial 10 improve the quality of the study. "The type of contrast material and Iheir dose, are similar to t.hmc In ncn:tory urogruphy except that higher volumes of contrast and a ~ rapid injection system lI oftell u~d. "The eontra~t materia! increases the I\:la1l \'e eontmst between spacc-occupymlt le~ions (tumors. cys.ts. and
i~

figure 13-14 CT sun of the upper oJbdomen 10 a IllIddIeqd adult. The IfT\iIge Ii an .wal VIeW 01 the patll'nt's upper tbdul1ll'll ~ as jf 1001009 up from tht> pauent's feet Thr III\Ir!lB nght side Ii on tht> Irft !oIdr of thr Image The Irver (IJ. ~ (I(J, and spk!en (5) arl! paltl~11y vtSUallled TheIl! IS a
~ ~t

(0 10 the ~ple-en, With a caklflt'd rim

Figur. 13- 16 Same pauent as 5hown In Ngurl' 1315 A Cl'l"t>btal arteflog'iIITI was perlormed 10 delineate tht> vascular analomy of the patll'rlt'!. AVM 101M (aW', a dJ91lill !.Ublfacuon thooque was used m whICh dtg,t.)1 ,mages obtained pnoI to InjI/'CtiOn of thr contrast agent were wbtractt'd from the conl1asl agent Images by computer

ungiogf""Jphy (~ isualilation of the ~'Of0l\a1)' l1I'1er11'1), aonogrnphy (\ lsualiatioo of the nbdOOlin:l.l Of tllor:l.cic ION). and pcriphcrnl ancnogmp/l) ("i~mlll.mloo of the DIIp anerics of lhe upper and 10l'o"er extrcmi lic<). Ar\mography is wide ly pr-.k:tk~d fOf diagnosing VCMCI

!l<lmJwiJlg or blodagc, aneurysm fonrullioo . and ~111!.\ of bleeding. The type of COll1ms t used dcpeJld~ on the Ics.o;el beiJlg injected and the pn:fc~w::e-. of !he phy~ician performing the study. Veoogf""Jp/l). the ~'()Iltrast opacificaliOl1 of venous structures. is performed Ie,s cummonly than ancnograph y. The omin mdication for ~cnogf""Jlmy is to dla.gnose ~p \'eoous thrombosis In the lower t.J.trerniue~. based on chanses in ultrasound by a nlO\'lng rentclOf" (blued). Il igh-quai n y modem diagno.,t ic uhrJ.SOflogruphy coupled with Doppler imaging technique~ has largt'ly replocetl lenogrnphy in the .....oriwp of suspected deep l'eoouS thromboses. Sonogf""Jph) is ellSy to pcrfoml. is much safer tban lel-.ogr~phy. and causes much le~\ palknt disc-omfor1. VenogrJph) i~ still u..oo In scltclcd cases. pamcularly "hen sonography is equh'ocal o r !hen: i. a pa~t hi~tory o f documented ICnouS thrombosis that requ,res deulled elaluation of the I'enous IlfUltolllY.

Ch.letystograph,. and ChoI.ngiograph,.

Choll'cl'$IOS'W,hy rcfen. to l"(Nltrast "lsuahwtlOl1 of the gull blllddi:r. Modem gallbl adder v i~u~[i~utIOl1 and diagnoo; js rely mainl) on abdominal ul~l1Iphy Of" nuclear medICine and rarely u)t traditional .....d iological techniqUClo. Ond ctJOlety~togrophic agc!l1s con,!,t or Dlml~ue~ of 2.4.6-triiodmau:d :l.ILylht:nloiC aci ds. They hale lariOU$ subs!.ituents in the I and 3 pOS"II.1f1~ and are absorbed orally. follo..... ed by hepatic excrelion. Oml cholC\:y\togI"'Jphk agenl~ include iopanoic acid. locelllmic acid. sodium tyropot003tC. and sodi um lpodatc.ln general. the..c :lgenL~are bound 10 scrum albumin and conened by the li ver illlO waler sol uble glu(.-urunide coojugates. Thc!IC conjugates are excreted In lhc bile and Mored in the gallbladder. thu5 facllnating g~lIbl:tddcr visualization.

Rgwt 11- 15 AxIal CT scan 01 the braon of a pattent WIth

itliCdtl"lOUS

mallonnatlOll (AVM). afU!r 1fl)tlOO of an In-

IOdinated contrast agE!nt (arrow)

lodipami(\(' rneglumme (Cholografin) i~ rhe main a~m u ....'d for illt ntVerlOO~ cholunj;iography, Under idea! circ um~runce.~, iodlpamidc meglumine produce~ e~('C llenl vi~uali/' ullon ofrhe mtr.l/leparic and urr.1hepatic bile duelS as .. dillS rhe Gallbladder. Or 1 eholc:cystogrnphy generally produce) .. better ~ isuahlutlOlI of the pllbladder ilSoelfoot pooIl'r \isual ilauOll of the bile duc15 Ihan i ntraverlOO~ chol~III!:IOGr.lphy,

oon,i,ts of a watcrsoluble gel lhal is a 2: I mmurt (,f d ialri'1031c nr.cglulllinc and iodip.1mkk: tn<.'gIUIllIIII:. II). he~ol and other Iow'm-molar agents arc also usrd for h)\tef osalpmgogrJphy. and they may produce ~lillhlJy lower lilCI(k1ll;'C of abdUf11illal pain and dl'\C'Olllfon afler 1hc pn:rcedun

(Sa lpi~)

C;",sbointestl_' Studies
Trnditlooal GJ Imct studies hu\'e used various pn:parJIIOIlI of b.1rium su lfate to op:rcify the hypopharynx ~nd esop/l:tj;U> (banUIll swaJ lowj: the lower e;ophagus. ~Iomach. and doodcnu m (urpcr g"-~trol mCS1Hlal trKI; UGlj; the ~1II31l OOvttt (~mall bo .. cl follow-through; S8I'T); and lhe colon (ban. crrc:ma; BE ) (Fi,. 13-111). In the liE. the lxmum is Itdmlm ICrcd per rectUIll as an enema. u;;ually "'''h the IlI1cntlOll al visua li 7illg lhe cmlfCly of the colon and Ihe fcnn ina]1lIO\1 pon ion of the iieum . Gll>lrojlltc~1 illallnlCI studie, arc utllO d iagllose pept ic acid di<;c:",w- (ulcers). benign and mabplll tumors. and such condil ions all GER and infiarrulYl101) bowel cond ll ion~. If there is a possibility of a G I troct perfonl1ion., III1itf .'\Oluble agen t i~ used in placcofa banurn ~u l rale ~par.rtila If there j, le akage of oomra~1 from Ihr: G I trnct ill\o Ik peritoneum. retruperitoneum. or medin't inul'll. waler-!oOIubk agt'nts an: ~'CneraJJy r~pidl) absorbed by these tissun .. idt nount",,',am patlC'nl effecl~, Bmium pn:par.ltlOll~ Il'C ~ late and "'Ill not be easll) cleared from these spacc"l. U__ mlJtro with feces may produce 'iC\cn.: pentoniti~ and be: IrrrIhre:ueninll 01".11 conlru~t m:llcri31 is oftclI u'\Cd as P.1M of an abdom,iIM

Myelography
M ydosraphy in\ohl!lo in)'uon of COI1tlllSt material into the mbal'lllChnoid spacr, usually in the lower lumbar o.:g;oo. for \ isuDJozaJlI)n of the ""'11:11 cord. J>el'\ e fOUI..~. :mil subar.ichnOld space. It hall been JOnlCv.hat supe~ b) It10dem MRI and irnalling of the spinal canal. und It can be perfOlmed by itself or in coruunction "j th 0 subsalucm CT ~! udy of the spinol callai. Umilthe advent of the low-osmolur controlS! agents. iophend), late ( Pal11opaquej WIIS the standard agen! u'ied for myelography. II was first n.:placed by mem7..;amide. which has I!QW been largely wpplamctl by lollexol :rnd ~u1ll1ar agem~. whICh G"e improved image detai l and have lowcr toxicity. Greal cun: Inust he t"len who!n perfonlJlng contrast inJeclion IntO lhe suoof'lChnoid space. Impropu techniquc could . lead 10 a dcvlI!>tallng illfeclion or spillallllJury. and the uS<' of the .... rung contrast 1gent can also h;1\'c de\'nstating result~ ~h a~ cOlwulsiuns and su~uent. 5e\'crc arochnoid 111nammmion.

cr

ttystero_lplngography
Hysft'mlfll,""gogrrwhy refer; to \'isualrlaliOfi of lhe utcnnc C:I\ ny :md fallopian lUbc<i ( Fig. 13-11). Contr.lSt IT1lIleriaJ is
inJCC1cd IIItO lhe uteru~ through the ~' ieaJ carul to ~ Ulennc analo my and lhe patency urtbe fallopian lUbes . Most prncll1lO1l<!rs u<;c: sonl<! type of watersoluhle contl1l.St material for hy~lerosaJpingography. Ihough ill ihe past tile U!iC uf o ily ugents ~uch a~ EthioOol was popular. One popu lar agent

FigureH- l1 Normal hysterosalprngogr<lm performed In <l yoong wom.JIl <IS p.Jrt of ,)1\ InferWrty wor~up The cootroHt materl<ll outlines the u,~ (U) and hilS ~ tlvougtl p.Jtet'll fallopl<ln lUbes to spon Into hef pentoneum (""ows,)

Figu re H - 18 Results of a ballum enema perlormed on elderly man BMlum iIbsorbs Hays very well <lnd h.Js ~ appeal<l1lCe tNt ~ the lectum and!ol9ffiC*l portIOnSal colon. In the l;tum. ill.lfge IUITIOf (<lI fw~eoordes tilt iIf'Od narrows the banum roIurm

Cluopt... lJ rr stud) to opacify the oowd A relulivcly di lu te barium MlIi"'" nll.\lure or J d,lule <;()lutJ()<\ of ionk COnlrnq malerial .In! ,",uh a na~'oring agent an: commonly used.

At:~msfor O/0t:'.fm.r InofJ~Jt!~

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Arthrograph,.
A.rthrogrophy " radIOgraphic ~ i5Ull h~allon of the intenl;i1 \II\II.'turc of a Joint. The shoulder, hip. ~'le<' , and wrist arc 1'11\1) coounonly I'suuhl.ed by ul'lhrogruphy, al1hough the
prtudun: may be: applied to OIher jo ints. ~uch 11$ the elbow Of alllle. Some form~ of al1hrugruphy, l'S[)CCiully knee I1hrogrnphy. have been completely n::placed by MR I studr t An Dl'lhrognllll i~ obtained by injectmg a .mali amount

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1110 10 mL) of wau:r-sohlblc. usually low-osrllolar, COI1Ir.lSt .mal into the joirn '>pact'. The ronlraM agent may be .~td .. uh a local anesthetIC 10 reduce pallen! dl'SCornfon. IIIIl air or carbon dioxide may abo be injl.'Ctcd 10 produce ,dooble<OOtrut effe<1. In the laller case:, the ... altt-l.Olublc romtaSt n>alenaJ outh JleS tho: ,urfllCC of the JOlllt. ulClLidmg fit ,"nI c8JI"ulo: and cW'liloge surfaces. '" berea, the gas pro~a

nepbrinc may be adnIlOlstcn.'(]. and atmpIJr.e ..' used If there is a vaso\agal reaction wilh hyputem.ICIn and broldyCardl1l Severe rc..-tiOll" IITC those that are life threatening. Tlrey Include sudden cardlOvll.'iCular collapse and death. Q" \lell II!i !jCvcre hypotension: st\ere shortnc:s.~ of breath ..... hc.:/mg . or laryngoetk:ma: I~s of C'OIISCIOUS./W:SS; massI' e hll e' and angioncurollc tdema: ventricular cardiac arrh)thmia,: un gina: and myocDn.lial infarction. 'fbeir treatment depend, ott the patient 's signs I..,d ~ymploms :Ind include, IIllm' cnou~ fl uids. oxygen, variO\J~ drugs (including e pine phriuc, di . pltcnhydrnmine, und atropine). ~nd possihle card iopullllontlf)' resu>eitalion (C PR). incidence of adverse reactions to r.ldlophannaceull CoIls is cstimated to be less than 0.006'.1 . Mou relll;'uon~ are alkTgic and occur .... llhm minutes arr ... r mtt;I\'cnou_ m,teCllOIl In the case of radiolabekd murillC IInlibod lc>.. an onmph) loc lic rellC1ion may occur. although serious reaction~ (If lhi~ type have not been reported.

nr.e

ncgDUle-oontrast effcct as it di~tends the joint sp:lCe.

SlI!l.chd Prod.cb
Barium Sulfate.
The many l"OnHlrereial prepaflltiOIiS of
bariu rn su lfate differ in thei r density and Iheir llbllit) to COOl tire bowel .... ~II. The>e char.K:teri~lIc~ are UctcrtulJted by the panicle ~izc: of lire barium su'p!'llsiolJ. ib ~ isco,ily, and it~ pH. which in tum are dctermiJred by the addition of'm:11I amounts of flol'oring agents. suspending a~em'. and so funh. lbese additi,'es are lhe proprietar) secret of tIM: manufactun:r and do impn:!'c tiM: diagnoslic pmpcni!'s oflhe barium colloidal ~uspcn slOll for GI r.tdiolOjliCIII StudlCS. Barium sulfate prcpMalioru. are u5C'd to study tiM: ewpIta. gus., stomach. and duodenum as pan of l1li ..SOf>IIagr:lm or UG I serie!! and are gl"en OI"'Jlly. M ost pilhent., find thoc laSte of these dense mi.\Hlres acc.:plable (Ihey arc: u,uidly li'en II stra .... berry or lemon na\or). but they d"lr~e tIM: hea\y texture or the barIUm. Barium sulfat!' ~u~pensions are alo;o gi\'en OflIlly to ~Iudy tire enlin: ,mall bol'>cJ (S8FT) or t'\.'\.'lall y to examine Ihe colon (IlE) ( !-ig. 13- I 8). Typical b.,rium ~uspensions range from 30 to more thun 120% weight/volume ( .... Iv). and bet'ause they are collOidal suspensions. they I;'IInJlOl be gi'en imrJI'Ilsculatly: ti>c l"OlloidaI panktes would produce fatal pulmonary !'mbolrsllI 'The barium suspell$iom uo;ed forUG I or BE studies an: too dense 10 be used fOf gut op;lCificahOll dunng cr Mudle, of tiM: abdorn!'n, because they ~ unacccplllbic roldlOlr:ap/lie amf!lC1s. Instead. conmw.'reial barium prcP.lr:ltIOllS an: dl ' luted to I to 4'1> \l1v. DiDlril.oate is classified as an Ionic tltonnmene contrnSI agent arid is a~ailable in the rncglulllure, oWdium. or eombinUIIOI] of mcgluminc ~nd sodium '1I1h of lhe fully sub~titulcd triiodubcnl.oic acid. II ha. a l1loli.'\.'ulor wcight of 614. and the organicully boutld iodine I;'ontenl is 62%. It s IilIlts ore used mainly for angiogrophy Dnd excretory urography, 'The diutriwatc. mcglununc (66~) and d latril.(JDlC sodium (10'1 combintlllOlI may be used orally or reaally to delineate the GL tracl . Thl' p"'jXlmtlOll I~ loolCaled \I hen !he use ofl)anum sulfate iSpo(enual1y wngeruu' (i.e .. .... hene\'er a suspecled perfomllon of tiM: Gltract exists). becau\e watc-r-50lu blc contras.t agents are Ijuid:ly absorbed throoj;h the peritoneal surfllCC . TIl.: high oo>moiaiity pre,ents "'Dtet absorption lind kllCls to r:lpid IrallSil Ihrough the G1 tllM."l..

.1,

I"

Adverse Reactions
~lCal c..,.ur...~t agcms CUl' be tlt~t'n orolly 111 large
1I!lCU~IS. and liQffiC of li>cm are inJccH:d imrnvascu larly III vamamount~ .... uh 00 ill effects. Ne\'ertheIeM. any rndiolog Qicontrasl matcnal nm~prodoce an untowllfd pallent rcac-

11,1-

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r,

.m

",

hIll'

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:um

""

. . C'en MIdden death . . ) j Unlowan.l pillICnl c\ent, occur dim cootrnu matenal IS aspmned or ",hen It Ical;s from ~ GI tflll:t H)'Irrtomc ionic .... atc-r",)iublc conl~ ag<'nts lit JIIlIC'nually dangerous if a~pll":llcd inlo lhe lracheobhHloigJ lltt. 1llcy !lrC vcry imtauna and reponedly ha"e .MCd pulmooary cdt:ma. Any conUUSt nt<Jlerial that leab \lito/tIM: bo ..... eI into the abdomen, pelVIS, or ehc~t is polt'ntl.dly Ijuile dnn~croos. especial ly barium su If:lle. 8 ariull1 suirw II Inso luble. and its particulate nature mean< n i~ poorly (ieaml from the mediastinum. peritoneum. and retropcrilO IIItm. Watt'f solubte agents. on the otller h:",d. are rnpidly tMol"bcd from the mcdia,linum , peruolleum, and rctropcri.-um. almost as quickly a~ iflhey had bn IIIJI!Ctlod intraonou!Jy. In gelw.'l":Il ..... atersohlble agents thalku from the (II uact ClIU'C no \igniiic.ml problems beyond a II'Dn<tent .dllnmallon. 'tbr; 11IIflI\eIM)lh or intra-arterial injllX'llOll of Iodinated ~ malerial for pyelography. COIItmM~nhanced cr ~ and anglOj;.r.IphlC studlc>. opens the doorto a d iverse mtnt of cunlra)t reactions. most of \lh,ch are l1Iinor at ~a"ly lrealffl. III IIl<)I" reactions lIw.'lude arm pilin, a fedIII of gC1IC.'1":I1 boo.Iy w:lrmth and di<oCOInfun. nHld nau'<Ca at ,omiltng. a \Irong metallic m~tc in rite mouth. and mild IIbCIirlOi (hiw;:), M illO/" rcaclion~ di" ip;lte in u few minllt~\ 11th patient rea.'suranee and ob..ervatlon. Irnernw:thate or moderate n:act ion.~ an: lhose that requ ire \o)IIIe form of therapy but are nOllife threal ening. Depending tlw:COOlrasl aboent u'\Cd ~nd on h.ow ~"OftIra."1 reacllOH" IITC tfintd In a ,i\en IRunution. modemte reactioru; occur in 11matcly l 't of con~ mjectlons. T1tcy Include- diffi alit) breathIng. !<eH''!'e hiH!s. severe nallSC.a and \0I111l1Og, ... h}potcn~iOH. wheeling. and other '"mlar n:aclions. TII'.,ncm I1Ingcs from adnlllll~ll":Iuon of Intra\'ellOUS fluidli III tile u...e of intr~lellOU~ diphcnh}dllllllure for hIles. Epl-

Diatriroate.

, "

"

" C

Figure 11- 19 lymphanglOgrarn of a I'\CJ(malleg after EthlOdoI iIdm!nlSlfatlOO.

The r""glumine saIL dilute solution (1 8% w/v) is u'\ed for cystography after >l.cnie eathctcritation of the bladder.

, orl ph)
lodjpamide Meg/umine. ludip:nnidc meglunllJle is. i-onic d imeric contra~t agent lind i~ giH'n a~ the me~_ ~l t . .... hich is highly w.ucr <iOlubk . It has a moltt1.lbr.-apl of 1.530 and an organicall y bound iodine content n(-'9" lodipamide meglumine is v~ry Sll'OI1gly bound to 'iC'rum ....

'"
/o

;j 1

()~t

'"

lop

COlt

Ethlodol, Ethiodol is a sterile preparation containing ethyl eSlefl; o f the iodina ted fally Ildd~ of poppy-seed oil and it is used for lymphangiography, It cont ains 35 10 39% of Ofganicall y bound iodine that has been added to the double bonds of the fatty acids. Because Ethiodol is an oi ly substance and IlOl miscible with plasma. it can not be adminrs.tert<! intravascularly. For lymphangiography, it i~ Injected imo tiny lymphatic s of the web space of the h:ntd or rOOl. The Iyntphat~ cany tiny globtr lC!l or Ethiodol to regi onal lymph nodes. ... here they are partially fillcred by the nodes and localized in them. The iodine In !he: Ethiodol m:U;cs the r.ode~ sufficiently t'lIdropaquc to be \';sualized on plain film radiotraphs. A \ymp\lan\l,logram typically is Ul'oCd \0 evaluate lymph nodes in tl\c groin, pelvis, alld abdomen in p:rti cnts " 00&\;.\11" ~i!\Case and _timer> q.Mt m;r.\i&nal'oCW;. A typtcal norrn.al\ymphangiogrum of the lower leg is illustrated in Figure 13- 19.

I<:al

,ho of,

h,

di<;(l

"'"

""'im

lobitridol, lobitridol is a low-osmolar non ionic mooomeric COIltmsl agent. II is similar 10 the other age ms in its c lass and fioos usc in ncretory urography. angiography. and

CT.
locelamic acid i~ II highosmollll" i\)!lie monomeric contrast agent and i~ IIllCd us an oral chokcystographic .g~nt for the radiographic visu oliZlltion of the biliary tnlCt and gallbladder. It has a moItcUlar ..... eight of6 14 and an organically bound 10(iLne content of about 62'1. A dose of 3.010 4.5 g is given orally 10to 15 hoors befOl"e radiographic c~ Dm i nation. and uoou t 60% of Ih is dose is exc~tcd in the
focetamlc Acid. urine within 48 hours. A typico l mdiogmph of a gall bladder is illustrated in "' gut!: 13-20 . i

Iotte..ol. lohc~olls I low-osmolar noniooic monomeric con rraslll8Cnt. II finds widespread usc in excretory urography. cr. myelography. and ll11giogmp/lic pnx:~'(lure$.

Figure 13- 20 R.JdH;Jgraph of mrnlStriltiorl of IOP<1f101C acid

a"""""

Clulpl t r IJ A.g<-IIIJ for Diugllmlic: lmalm,

and I~ ucreted by the li\'C'r mto!he biliary syslC:m unDldifiw. UnfonunalC'ly, iodipamidc meglumme produces II li&/lloodence of adve~ p.1liem relll:UOI'IJ, such as urticaria IIId h) poIcnSl(ln, and intra\"C'nous cholangiography has genemly been dlscoruinue<l. Modem uilrafast helical (spiral) -'Canner:.. ho",e\er. can produce exquisitC' high'lXlfltrast lWd~s of the H"C'r and biliory syslem. 000 lhese sophistiClICd cr lOCunni ng IC:chniques huve renewed interest in the 1$ of intl1lvenous cool angiography.
l1li

48J

Iopromifh:. lopromide i~ 11 Iow--osmolar nOllJonic mono omeric contrast agent. It has a molecular wcigbl or791 and lII1 organically bound iodine a)n1ent of 48. 12'1:. It ISdesIgned f(W" inlravascular injcaion.

cr

lotrol. lotrol is a 10'" -osmolar nooiooic dimenc conlra.~1 agenl. It has a llIolecular weight of 1.626 and COOllllUS SIlL: iodine atollls per particle in solution. [t is de;1iigned for i111111va!;Cular injection.
IOllenol. loversol is a low-osmolar nonionic m0nomeric conUllS! "cnl II has a molecu lar weigbt of 807 and an iodmc contenl of 47.2%. Its m.ain uses are in angiography and ucretory umgruplly.

lodixanol is IIlow-mUl(llar nonionic dimeric OOIIUaSt ogent. It is designed for mtTllVllSCUlnr inje.:lion and "used for ucretOl"y urogruphy. angiography, und cr.
Iodilllnoi.

IofMmldoi. lopam idol is a Iow-osmolnrnonionic monoIIIIIfIt" OOIlLl"llS! agent. II has a moia:ular ""cight of 717 und OIlan~ally bound iodine cootent of 49%. Allhough the >iIIlOIallty is much iowC'r than thaI of the ionic contrast ....... lhe viscosity is "cry similar. II is used for a variety Ihllgiographic procedures. elL:cretory urogrophy, Ilrthrograjiry. and Ql'"JI und rectal v;slJ.Jlizatioli of the GI tmel. It is j\lllablt In solutions rontaining 30.6 IU 75.5% iOp.1midol.
fopjnolc Acid. lopaooi c lICk! is WI ionic monomeric CIlIUmt agcllt. It has a molet:ular weight of 571 1100 an organnlly bound iodine conlcnt of 66.7'1>. It i~ u-.ed a.~ an 01"31 dtokqstographic agent for tIM: rndiogruphic visu:llilllion IfdIC bthary tract und gallbladder. A ~ of 3 g is g"'en ItJ mouth .... ith ample WIIter about 10 to 14 hours before ~ic C'lamlnation. It frequeruly produces mild GI
IIICOIUrott.

Ioxagl.'e. I01agll11e 15 a I_.... /llmo//t/ iomc dmrerk cootrast agent that is fomlu laloo as a com.bined solution of its meglumine und sod ium salts. II has a rnolecuhu "'dghl of 1.269 and an orgoll ically bound iodine rumenl of 60'*>. IOlaglale is used in angiography. atlbrogrllpby. urography. vcnogrJphy, and hy~terosa.lpingography. This agen l is not suita hle for llIyeiography.
1 lan i, a 1 0lL:i 0w-osmolar nonlOnic nloOltol1leric Ioxi/an. contrast agenl. Like other agents in its class. II IS mainly used by intrJ.vlI.o;("ular injCl.'lion in excretory urogruplly. llIlgi ogmphy. and CT.
Melrizamlfh:. Metn/.amilk IS II low-osmolar IlOrllOlUC n)()fl()frl('ric lXlfltrol.,1 agent It has a molecular ",'eight of 789

lin U/Iline !.-eight 19.9'*n albu-

_ j,

figure 13- 21 MRlof lhIl bra," of 36-year-old p.1b1!nl With Single ~ of Mute WNkness A. Tl-'M'Ighled a!!lill1ITIol9C Without contrast agent I<Jken 3 days ~tl'f B. T, wetgllltd 1rn.Jg(' after IntJoM'OOIIS IIIjKt10n of gaOOpentetate dlmeglumlne. wInch ha\ cOflCl'f1tJated mthe !elt frootallobe (arrow} The p.il lieIll was diagnosed as hil'o'lng a cffebfovasrul.r accident. (Courtesy of 8er1ex tClbofoillones. Inc.)

an orgaillcally bound iodine content of 48.2%. I! i~ used mainly In the r.xliocrnphic examination of the ~plnal cord and ccntr.allll'rvous system (i.e .. myelography, cistcmograph)'. and \entriculography). The nlO6t frequent lol(herse effects arc: headache. nausc:a. and vomiting_ Metnzamlde ....as the first commereially available nonionic COIlll1lSt agent. OnSite 1""00001IIU1ion of the Iyophlhled pov.der i~ necCS)03ry because of the instability of nlCtri7.anlide in ""Iuti!)n. It ba~ Ihrgel y been reploced in daily prllCticc by lhe newer 1 .... 0 O$molar conlrD.St agcnt~.
M RI AgentJ_ Thoere an: many ty])CS of MRI COOtr:l.'i( agcnlS. Atll1c pn::scm time. only lhe cx trllCcllular gadoli nium chclmes hJ\e found .... idespread use. These agents. in general. are highly soluble in wat~r and can be adrllln istcred by imruveoous injection. They W'C classiftcd as ionic or nonionIC. and they an: cither Ii ncar or macrocyclic chclull!S_ Gadolinlum-ba"ed cootr:u.t agentS are administered in a typical dose of 0.1 mmoUlg. v.hich c;an be increased to a total dose of 0.3 mmollkg forlhenomonic agent gadoccndol in ""tiems v.ho ha\'c poorly enhancing tumors or equivocal scans. Figun: 132 1 illustrates un MRI Mudy of a boIi" before and af1er mjeclion of gadopentelUu:, dimcghuninc .

~nd

11 IIkw1c<. P J.. Sonp. I _ C1:u~. S . J N""L Mcd .1201'''5. !9'/t 14 F""'ltt. A. M.. CI at.: J r-:Il<l . Mcd. Jl:~. 1992. Ij P-.hnt... A J. CIarl, J C~ and OOUkh ..... II WI"'. J A["fII IUdoa
1~2S:51. 1m 16. 1..........._ K . Comm.. II It. and SaodJon. (J. J Slid. Mcd.!Jm

17. }b,,\,n... R A. and UOh.C K.: N..d . \kd lloot21:739.19'N t8 B.""" .11. R. N h" I AWl. Ibd~ li<lIopto 37811. 1986 I ~ Si,...,... J. C .. 01. N ~ J. Mtd. mu. 1981. 20. K,mm'l. B.... '" . J r-:""l. Mod l':t"IJ. IIJ8.f 21. Kohlc.-. G. P. and MIIll(in. C.: NO"If" nt..49'. 1'17' U Cok ...... D. CI. ,I . !'roc. N.. t A<:"Od. $d. U. S A 78;3199. I.t 2.3. Kod,,<lL I D ....1. """'. N.rtd. Acod. Sci U. S 1\ U!631, I . 24 Gftca.M.A~-.J IMf-,J CI .... ""t Mnl.2'NI7.1911 25 a.H, .... IN II. .. at I..r. 51;. 4~U'3. I!I9L !6 ,,",>IIor. H. IN ~ 1S9"36 I. 191621 Wolf. G L Ihol"*'&) l.w,j~7. 1986 18. Wb,,,,. II. 1.. w Itokltn. IN J Rad"""lY 1~':I9. 1986 19 l'Wft<lk. M. P.. ...1. It"... R..hol. :1(1,)72. 1995 .10. b .. ) ....... H ... 01.: li.od,()Iocy I7H11. 19'iO. )1. Wold. G. L . " al In,'" Rodool. 16..o.t. 1991 12. ~ W II.. M,C\o.ro' . 8 L. and S.......... 0 P . ~ Ro6Il

"..

13:137.1993
l.I 1'1

I. F.. C.. 'lid Beny. C In'C>!. """"". ltI..I02_ 1991

SELECTED READING
81l<ohbo<l. I T .. Sc.b<n. J A. t...:HJI>oIdi. I' M. ond 1""""'_ J \t TIl Eo. 'Miall'lly"=Cll '" MedM;alI .... 'n . Sol" .... ",,_W,lliorm. '1,,&. .
.. f __ ........." ... Col..,. u1l1wloolorJ.. M""IIaI .. k>Jo ....... C _ - . R,,-. VA. A""""",, Colq. '" Radillll:'l)". 1991 Comm~1to< ... tho: RII.>koc><aI Errtdlo of !on", .. Ibdaoto<oII (BUI h Health Eff""b of I'..<poo."'" .a Lo\fr t..:,.h uI """"..... R.. """" No 1""",1 R"",,,,,,b Coo"",1 V.""""8"'" DC, r-: ..""",I A..""""',-.

Propyliodone. Diooosii. ~ commercial prq!iU1Ition of propyhodonc. a pyndooe eQer. was oroce popullll" for usc: in bTOl"lChogI-~pby. [I consists of a v.hite pov.der suspended in an oi ly medium Dnd was used for bTOl"lChogrnphy and laryngography (exmninatioo of the larynx). Olller melhods of illlaging. ,och a,< cr, u hruSQnogr~phy. and MR I. as ....e ll as modern fiber optic broocbo<cO]ly ha\c largely replaced blo.lChosr~phy _ Tyropanoa te Sodium. T yrupanootc !!OdIum is a highosl\M)lar IUI\IC monomenc eontrd.~t agcnt Ihat is g;~en by moulh for the mdiographic Vi~uli l ilalion of lite bihary tracl and gallbladder. It has a mo lecular " 'eighl of 633 and an organically bound iodillC C(KIICnl or 51.4<),. A dose of 3.0 g i ~ &i\C'n "' lib w:Ut'f 10 to 12 hours before radiogr pbic .. 5 c:xaminauon_ This agem 1 not recommended for c hlldl'\!n under 12 yC'aJ'$ of age.

C""""""", ... ONp --.J C _ M""'-.

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,

1 ",nbcrJ. R. L lI od......,.. An IJI..-cd 1I,,,,If)'. Sr. Lou, .. Mo.b)~Y.. .. IIooL 19':12. A. Tho Pothoph,...."...,,, Ib>u a( " ' ' ' ' ' " Medo<.nc. N.- ,"'Spn..,..._V~. 2001 II. W ltd.. ThoC.... _ Mcdill M.....w lIallI"""" . ........ 1

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d"" l'raI:I=. Nl,,.ul\. c t'. Al'I'lelon & l"""'lIo. 1987. Kun'l<k. S.. Abe. It ~ .. 01. Al:cI ..... modc
~tl~918.

.......

1991

REFERENCES
SII....w Retan:b c......"t \U 5 >Coonnlln ... Mlhe 8101oC1ClII ar"", '" 1 ,*"", lIad_ Ikahti Effb '" F.\p;oo.un: iii 1 -' t...n.:t. a( . ........., IIwli.......' flEllIV .... _"'_. D.C., S........d ......"'y 2. lahcll.!!.. c<" TIwIt",n" c~,..,,>Iry "'" IKiw:r,um radiopharnll' c.... ocat . In L..f!lWU S I. (N. > ,n l....-pnic Chcm,W")'. New Vorl. I""" Wok) /It. Som. 1983. 3. i'I""'''~n,k. 0 J> F'h)>ICI...,henliaot "'"""'P'< ,a lhe I""'P"rllk" of 1Cclo "," urn ,odi<>phannKru"cah. In SMipOO C 8 ted 1. TC.lbooO, or T1iNf)o """ I'no;IICC_ 2nd cd. No... y",1... Gordoii A ll roach. 1990l " U)Cbluen..O K ......... )'loII20:R6~. 1995 j. Scti .. oc"",,. K , A".., ... C'tIem 1111 F.d. E:nJl lJ:2""'..38. 199-1 6. lun""",- S.. CI .... CheRI. IUv 93 I t17, 1993. 7. CO>Iollo_C. fl. ...... I. N""I Metl. 24.\53. L9IIJ 8. Ju,hWII. S .. CI al .. 1""'1 0.."" 2!I.341. llIIl6. 9 L.."'-<on. K .. c<.1 J Am O>tm Sr>c. 102:2476. 1980 10 de L..ln~. C. l., C< -'.. N..,t. Med.. ""~. 17 161. 1990 II. t.koRni.. J L. C< 01. I.... J 1'1..,1 toted B..... I Ltlll. t980l 12. 0hQ. It _C< 0I~ CI,n. Nucl. Med. 10".j(Ml t""'

\.(of;"'"a<t. 11.. JI.uW..,.... T

1'1........11. M. _

IWI. ~ ................,..,.

P., --.J W....,.., I!. I \1111.0 Ph ....... It ........, tlooic C......!...... boIm. VA . Sio:ItI)" or
M >ltt. U. 1..a...1: T-..u...IIh<ot _ _ 0tM. ,n Cbrnmuy ~ "'''''" ~I<d"" ... PI b, SQ6JoIOfl;lob. 19\111.
~

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1'.1....... E.. Stu . J. _SOIlU .... H. W .; Pt-....1\ca1 ",,,,,10,,, ~

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. "=-Il'" I'...
r '.

IlI'T"d,,:"ulOlIlb . 1992.

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1 4

Central Nervous System Depressants

EUGENE 1 ISAACSON

The common (icnonllll:1iOf of 11M: drug das.'>C"'i considered in

mil mapler of ncunlfla] lICtivity in thoi: cenlr~J ~oos ~~~Icm (eNS), Ihall~. Inc br.lln and spinal coni. In IIIOSI ca5/.'l the bruin is the inLt'ndcd larget. In a kw cases. "in \kclctal mu<oele rela~ilI1l~.lhe cord;, a[", targeted. ThI: drug classes:IR: lhe Ilnxiol}tiC'o. SI:d:llile-hYPllOIics, rmeru1 ane\(hi:lics. anTiconvul'am_~. ami amipsychotlcs. The
rnmarr tlinical md'calion for an.liot) lic droll' i~ in liM: treat 1111:111 oftllc anxiety di'\Ordcr;, which are condmons char:ICImud by cxce.\si,'c or Inappropriate :Ir!XIet)'. Example!. of IIIno: di!oOl'den ~ posIlr.lUm:lIic 51ress disonkr. gcncruli ,.cd .. ,Jet)' di~rdcr. panic aU:lCls. social phobi a. and obI,cssi vel~i'c dio;order. Thc mlljor chnical illd kalion for the Wativc-hypllQcic drugs i~ in the treatment of .;orne of lhe WtnOlas. v.hich are failures 1 gel adc:qullIe ~Iccp. 0 Ge,.HI ~ncslhclIC agcnls are used 10 pmdltCe UllCOnf:IOOSI\eSS and loss of perceplion 10 painful wrgical ptOCl". Anlicon\"u l~"1In' dru~s lite used to pr"Clcm Of lc~scn k suddo:'n excessill" electrical activity in br.J,in IlCUIl)Ill; thul III chal1ll"lcri~'ic of lhe epi Icpsies. Anlipsycoocics ~re used ~ tllooght disortk"rs (psyeh0'ie5), most l1OI:ably the sehlqlhn'nias. "Tbr fir;1 foor ela.,ses of drug~ oftcn hale a number of Wudural feawl'el> in OOnllTlQn and like .... i<;e oftcn ~hart.' 111 kill one mode of action. po!illi\"c lnodulation of the action 4)'";munobul}ric acid (GADA) m GADA" receptor.;. Addl .....1). many a.nticonvulsa.nts Illso ha>"c an o_cmll boulertpper sh~pt Ihat has been D~~I)("iated with neuronal 1'01t. tal MJdlUm channel block. leading to decreased neuII:IIlI elc1tution. Channel blocl of other inorganic cations. IIOUIbly Ca:' . may conlribule ,ignificantly to Ol"ernll Ktioo in sortie insIlIllCt!$. AnlipsycOOClcs lite crouped InIO ...~ and Dtyplcal categorie,. BOlh cUlegorics \hare a ~'om fe.lllure . dopamine-lile structure. often h)drophoIy ~u~tituted, This fc;)ture can be relaled to the most Iy {'lied llClion of lhe se ageflls. COrtlPOClIIll"C umage>of dop.:unine ( DA):1I D1 and DJ recepton in the: limbIC .;..~. In recombinant D: re<:eptoT cuhure.~, antipsychotic ba"c bten obsc.-.'ed to act u.~ ,"I'cr;c agonlSIs. For :;;;;; agonism 10 be a ,ignificam mode of actioo. there be proof thaI lhere i~ a baseline !e"el of doplllilinerglc in the lImbic system. Pn:liminaty indicators sugth.tt baseline 3I:11>"ation will be found; 110. inyclK agoc"meal posslbihly, I The stI\l{'lUre.\ of pre5('nl-day . nOI illC(JnsiSlCnt with in,'cr.;c antagonism a mode of am iJ!"ycllot ic action . A defect,"e galillg in the processing of IncomlrtS cnlironmclllal I by the limbic ~ySICID appears 1 chal"llClCrin: IIChi7.o0 Tbe resuiling inability 1 dlsllngulsh relevant from 0 I I c>"okes the posilh'e symptoms (c.g .. iUogidisordered thought. delusions, and hallucinations),
I~ dcpres.~ion

The defec1ilc mcc han"lII appean. HI re,ult from e~ce.'\iI'c limbic D! and DJ ~l\ation. The fun.dartJcnlal diffcrellce~ bet ....een typical and mypical DIlIipsYCOOCIC5 reportedly are thai the atypical agcnt~ are (Il) le~s PTI)IWl 10 produce CXlrdP)r.llIlidal symptoms (EI'S). because: they are less able 10 hloc~ \triulu D1 I"!,)O;cptors vb.-ayis hmbic D: and D , rtCeptOK and (b! nlOre actl\e agalllsI negatil'c symptoms (social witiKIrdwal. apathy. anhedonia). These diffc-renccs Ilf"e uamined in a gn;!~ter detail under Ihc headi"g. Antip.yellotics. TIle foregoing IIltrodll<.1ory conden~alion may be u!oeful in orgJllil.lIIg and clarifying major S1ructurul and biological acliyity relationships throughout thi~ chllpter More details ahoul. and -.omc UceptlOll~ to. these gcnern illation<; are pre..cntcd under the di'\Cu~siOll hatling~ that follow .

GENERAL ANESTHETICS
'The classl1.:al inhalilion ~Ihoetics. the general aDClothelic alcottols. Ihc anesthetic phenol Oip." an. the b.:imitumte.. lhe nelilUStcrolds, and the ben/odlll7.epine.~ I1J"e posit lye modulmO!" of thc aclion of GAB A on GAHA,\ rtC{'pton by binding to 1I1l0.leric binding sites (different ~I t~ exi~t for each drug group listed).l. J A umfyin!: theory of 31lt..'Stlle.ia po..es that gcneral 1lIk'~the:lic\ act by facilillllioo of GAHA,\ receptors tl) promote chlonde ion ~."onductlLIlt..-C.1 and al Iln~ thelic concc:ntr~tion~ . .III least ~ of the agcnts (ethanol . phenobarbital) depress lhe function of ionotropic glulllmatc I"a.-cptors (ucilalory). which m~y oonlribut~ to the o\CI1II1 1UIC~lhClic effl:<'t in those cases. 4 LIpid and protein t"omponclll5 of neuronal cel! mcmbrnncs hne long bten illlpliclI.ted 115 the: snc(~) of :tcIion in the Yl1riOO' theories of how the siructurally din'rse chl:'tnieal agcnt~ produce gcnerdl ane~lhe<;ia. Itnp lit"ullng allostcric binding Sites 011 GA nA " n:ct:ptOfll as imponant tn ancsthc!;ia does not mean thai other proposed ~ite. of octioo ~hould be ignored. By their nature. many of lhc ~imple anesthetic agcnl~ could affcct a broad I1UIgc of neuronal component!>. AISQ, none of lhe e"i"mll lhooncs of IUlCsthl..');ia i~ ~futl'd. Inhibition of lIOdiutn ioo channels by s.tTUt"lurally dl~ptl\'c hydrophobic binding to channel protein i~ con~idcred likely by many 1II\c.~tiptors. Silii. it i\ inlngulIIg thai the apolar Sil t'S of action implied by the Meyer-O>"~rtoo relatioosh,p,'1 thcoril.ed as long aso a~ Johnson and EYflng 6 to be ~i tcs of a bioao:tl\'c protein. might sigmrlCantly be ~IIO$tcric modula101')' ~;ICS of the protein of GABA,\ TCt"eptors, Chmcally. Ilcncnl ancsthc!;.n for SUTllC'1') uses mull'ple drug TCsilllen. Somc drugs rnay be used to augment the gcneral anesthc:tic ugcnt (c.S., neurol~ptic~ and oploid analgesicj), Other drugs /I1lly add an actiOfl (q; .. the: s~elctal

rm-

,,,,ion

48S

mllscle relualUS). Also. drogs such as anticholiocrgics mlIy be used to decre:a.'IC: adverse crfect~. Conslilt a cllrnnt rlledical le~tbook for the ways in ... hith these agent~ are IIscd together. Our ptJtpOSe is to COIlsider OIlly the: lCocral anothetlC agent. General anesthetic agents can be bro.'ldly clltegorized as tho&!: useful by the: lfIhalation route and those u''i<'fLIl by the intra,'enous (IV) I1J\lte. These are dictated by the phYSIcal Slate of the agents.

ions. The nuoride ion e~peciall) and oulate W't responsible for the renal dan~e lhe agent produces ... hen used to pro. duce deep anesthesia over prolonged periods. Because 01 the poIential for renal damage. il has re,tticlcd appliclnootl an anc<;thetic. 9 1115 ,;aid 10 be ~fe .... Ilen llsed by intCTT!UttaI inhalation I'-~ nn analge~ic dllring labor.

Inh.latlon AlM$thetlcs
The mhal .. lioo ~Ihetics in use ure halothane, enfiul1lnr:. i!;Onurane. methoxynurane. sevoflul1lnc, de:lnunrne. and nitrou ~ o~ide. Older "ems ~uch as ethylene: and cydoproparw: an: obsQiete beeau!ie of a fundamental d)(.'mlcal prop1'1ly-they are explosive und flammable wht!n mi~ed wi th o.t)'gen. 11us :>dd~ an unacceptable le,eI of danger to the: production of aneslmia.

USP. Ualothane, 2-bromo-2.(:hloro- l.l.Itrinu()fQCthane (FiUOlhane). C H(CI)CF), a volatile liquid halogenated hydrocarbon (bp. 5O"C). was introduced in 1956 and gairtCd rapid acceptance, largel) because of il5 nonflam mabilily. Alkiltionally. tile drug has high potency and a rt'1~th'ely low blood/gas partition COC'fficient. Acrordingly, indLICuon of and n:co,-ery from anesthesia an: relat;"ely 11Ipld. In actual pr.w:ticc. lll\rJVenOUS SOl.lIurn thiopental b usually lise<! to induee ane~lhesiu. Most of haloth:mc is elimmated Intact In the expired aIr. 111crc is sufficient rClIClIvlty to oxidall'c pruccsse., howe_er. to allow up to 2O'l of the adnU11I)lered ~"Ompound to undergo Ir)(.'labolism. The lrifluuron)(.'thy l group IS qUill'.' Slable: tile C - H bood. however, i~ de~t~bl lized and i~ lhe probable \lIe of n)(.'labohc entl)'. Metabolites are chloride lind bromide ion~ and trifluoroacellUe. Additionally, I05S of HF yields the olefin I, l-difll.lOro-2.(:hloro.. 2 .. brooroclhylene. whK:h reactS " 'ith lhe Sit group of glutalhione. A low locllknce or hep;uk necll)Sis is afoSOCil1ted wilh halothane. This hall great ly redUCC<J it.~ use. It j, ~UgJ;I'~led that the olefin mIght lead to mc:tabolilCli that prodLlCC.' an imm unoreactive re,ponse ?' ~ Halot hane has a narru ... margin of safety. Respif'JtOl) dep'ssioo h notable. and mcchanical "enillation and incn:ased oxygen concenulltion~ an: often n:<luired. Opioids or nitroLlS oxidl: are oftcn needed co oblain adequate 5urgical analgesia. (herJII. nalotnane IS IlOl nlueh used today. Methoxyflufilne, USP. Mctho~ynurnoc. 2,2-dkhloro1,1-dlnuorot:!hyl methyl elher. OICl1Cr l-OCH, (Penthrnnel. is a volatile liquid (bp. IOS"C). The agenl does not hll\"e a high wpor p~surc at room tempernlUfl:. so contentnuions in lhe inspired atr arc 10..... ThiS, togclher "'i th a large bloodlp panltion coefficient, produces a slow induction of ane~tlH!sia, featuring an e~cit;;lIory pll:!."C. Acrordingly. induction may be maOc wi th i ntrnvenou~ sodium thiopental 'TllI' compound is \el)' soluble III lipids: consequently. reeo"ery is slow. The agent producesucdlent rural ge)!11 and good mu,de reluat ion. Methoxyflurnne IS 3S much as 1~ mctaboltl.ed. Apparently. all labile Slles are allacked. Metabolites include diehloroac:c:tale. diOuOlUmetho~yacelate, oulull!. ami nuoride

H~lothane.

USP. Ennur.me. 2-ch loro-l. I.2-tn nlK)l'l)t Ihyl diOuoromc:thyl ether. HF1COCF:CHFCI (Elhraocl.lu \olatile liquid .... ,th a \~por pn:"~ure at room tempelllOUt: aboul threcfounhs that or halotharw: and a bloodlga~ partition coefflC~nt also aboul threc- rounh~ tllat of ha\oth3nt. Consequently. mduction is relatnel)' c~y. although an IIln. ~hon-lIC!i ng bitrbiturul c i~ gcncrdl1y u'lCd ror this ptJ~, Ennurnnc is ~id to be re latil'ely easy 10 work ... ith andlD have II relathely lov. frequency of oo\"erse caroio'lo;(IIla effects. Respiration i deplt'.~sed, so 1I\.:cehanicul ,entilalKll and o.tygen suppkmematioo are used. At high ~ IR I ~mall percenrngc of (XIuems. tonic-clonic COIl' ulsive !II.'1J,. ily is !<ICCn. Accordingly, ennUf'Jne ~hould not be u.'.Cd ia pal}ent~ ""ilh epikptk foci. As much a~ 5<N of adnllm~tered drug IS rnr:tabl!ll~td. Oinoorornetho'ydifluoroaceulCe and fluoride ioo Ila\'e beta reponed a$ metaoolil(':S. The nuoride conctntl1ltion. hoot e\er. i~ generally thooght 10 lie within safe limllli.'Q USP. 1,0fluflUlC. l-<:hloro-.2,2.2-trifl_ Ihyl dinuoromethyl clncr. F1CC(H)C:lOCF1 (Fornne!. ~, close !it11lC1ural rc latil e of enflurone lUId share, many Pllflti ties with it. although cOOngCll m the: decll'Ql.'ncephatop. (EEG) ami tonic ....donic oclhlty are not reported. It \lot> differ considerably in utent of ffiCtabolism: only about O.!'I I' metabolil.ed. 11 Metabolite, are nuoride ion and mflllOllceUlIC. Nei tncr kidney nor lher damage ha~ been n:pn:.j for the drug.
Desflurooc (Suprane ), FC(U!)-O-C(Hf. C( H)Fl. has an otl'g(\., partition coefficient IIbout onefi and a blood/gas partition coerticient one-third Illat ofiwn. ~ne. Its phy)ical propenies confer ptmll1'\a('~metic POj.Iti lies clamlCd to be 1;upenor to tl\oo\c: of lsonurune. Del.fl ami isoflurane are metabolized 10 about the l>IImc euent
Df!sflur~ne.

E"flur~"e,

Isoflur~"e,

Sevoflurane. Se'o numr~. FC(llh-OCIt(CF1n. an oillgas partition coeOicienl about one_half that of i~ line, and the blood/gas panilioo codficienl is aboul one.... thai or i~flurune. PhamracokinClkally. it reponedly~. ad\'anta~ orrapid uptakcrurd rapid elimi nation It 1<; metatoliJ.Cd to about the: same extCTlt as enflurane. Nitrous Oxide. USP.
2

~E'~:~~~:,~~,= i 'ic. but such high cooccmrntions are In I

Ide, N 0. is a gas at room liquldundcr~urti"
nll~lure ~uired

Nilrous o.tide, nitrogen

1Il0II0II.

(u p 10 80%) to achieve anc:sihc:5ia thai alit. dangers of h)po.till uiM. AC(.'ord ingly, it i~ TltItI)' u'ofda the sole anest.he:tic agent. It is uften used In combmaUOI'I 04 her agents, pcnniu ing their usc 31 lower conccntr.llrom k has analgesic effecls that ha,'e been reported to ~t f D general d..'Pf'\"'ilion t effect on ~ynap!lc tmnsnussion 0( . . 1IICsS:tGes. 11 It i~ a posl ti"e mOOula\{)( of GAllA on GABA,

ChaplU 14
ItUplOO. which woo ld constitute a basi~ for its general

C~lIlrol

Ntn'Old S)Jltm iJtprtJJllIIIJ

487

anes

..::uon. '
u ltnl ~OOrt-IC!ing

anr.veaolllS Anesthetic.
ooroitunltc:S may lItwnllni>ttrN imra\enously in aqueous solutions 1 induce 0 .sthc:sil. lllcttaOer, the m.umainin!! 'olali le anesthelic lilborwlllloul nurous O:c.ide is used. Respiratory depression iI ~ .... iib the barbiturates 31 aocslhelic doses; consc:qoemly, IlIese atenls are IlOl used 1 malDlain wrgical ancs0 ibEsu.. Uncoo5(MJusness 15 produced withlD seconds of intra-:ous injcclioo. and the dUnilion of actioo is about 30 ""es.1hc rupid onsct o f action is allribuled 10 nlpid pani DOnIni from the blood. across the blood- brain barrier. inlo .. siteS of aclion in the brain. Thiobarbi lliratCli (thiamylal. diope:nLaI) hale an eJ\ceplionally hi gh lipidlwaler panitioo crc:fficienl. which is ron~idcred 10 be lhe basis of Ihis rapid ~lUoninl!. The ,cry shon dunn ion of action is nltribuled Klll'p4rIlIioolng from the br.un Into peripherol liss ues-i nitIlIly 10 ... ell-perfused ti ssue.~ and 5ubsequently to body fat. Mrtbohuilal is not a thl000rbilurnte. but ilS structure confers )'(\l!X'lties thut produce an ultra-.han act ion (see the discuslim undl'r the headin g. Mcthohuilal Sodium). The struc11m of the compounds arc gi"e n in Table 14-1 . Irlt thohexlra l Sodium. Melhohexi lal . <;(Khum( :!;)- IMhyl-!'i-llllyl -5-( l methyl2 penl) IIY]) baroiturote (Brevi III Sodium). i~ an N me th) I barbitur.ttc ""lIh 0 pK. of 8.4. 1:cJSIK ;oOOui 7.6 for the non- N-mclhylmcd ~'01I1pounds. This pK, _hange increo.o,cs the concenlrolion of the lipid-soluble Iiet:ocod form a1 ph}siological hydrogen Ion concemratioos. TIle compound a l ~ has uten,i.'\, hydrophobic character ,wi I . the lipidl I high. Fi lias an ac<:e~\lhlc 'lie of metabolic maclll'3tion. the . If 10 lhe 1riple bond (heroll. the compound has the "0"1",,,,: to I:l]'idly penetrate the CNS after inl ra\enoo~ ",1:\ ,.coon and lhen redlSlnbutc rapidly 10 other body siles l1li11 un.Jc:rj;o r'Jrld metaoolic in.acl ll3I1on. :10

The sodium $lilts of the

Thiamylal Sodium. ThiamyhlJ. sodium !'ially I !'i-(lITltlhylbulyl)-2-thiobarbiIUr8te (Sunta] Sodium). ;s a highly hydrophobic thiobarbi lur8te that has SINCfunal features closely rdated to !bose of thiopental. II has bioiOlical propen ies ~imilar to !bose oflhiopental. intTa\'enous IdrrunisU1l00n indoces uncon~SI"Il'Ss ...mllin seconds. and ronsciooSl"leSS is regained wi thin 30 minutes . Sodium, USP. Thiopental sodIUm. mlum 5-ethyl!'i-{ l -methylbulyl}-2-lhrobarbilurate (Pentothal $0dium), is the mt)S( w)dcly used ul lra-sho!1...ing aneSlhetic oorbilunlle. Addilionally. the compound is the prototype for tile ulm-short-...ing OOroitUfllt~. Mosl diSCUSSIOns of hcnr. SlruC!ure influences durnllOn ofacuon In thiS group of agents "'late specificaUy to iL The compound's onset of ... ioo is about equal to the time ~uired for it 10 Ir'JI'd 10 the brain from the site of adminisltlllion . ConsciousllC!s< is regained within 30 minutes.
Benzodiazep/n e s. Benloo llue pincs alone ca nnOi pr0duce surgical ancstht'sia. Some oflhe mOl'C CNS-deprenanl ben7.ooia1.epines (e .g .. dia7.epuln and ImdUlolam), howelcr. are used intfllvenously 10 hldut-e anc~the\ia. [)i uupam has a "ery high lipidlwater parti tion cocffk,e l1l and. conse quently. is highly depoii~ed and "cry 1 0l1g IICting. So. it is usually nOi chosen for indUCtion for ~horttenn aJ1slhenc procedures. Midalolam has a lower lipid/water panitioo ooefflCi~nt. ",hich i rllpru~ cs p/lllmlatokinelJc properties. It has a marked amnesiac effect tha1 is valued rn this use. Its physical and biologicalj"openlc' ma~ e it a ffl.-quellt choice for induelion anesthesIa. 1be scd:in"e e(fecl of these compound!l can be re\erscd by nunw:cnll. fromida te . Etomidate (A nlidalC) rontaln. II 4-carbo:c.ylic acid ester-sub:ihlUlcd ullldill.oIe mOlCly. "hlCh IS aJ!iO presenl in a number of oompound~ thai are \tructural \"IlIialioos of the triazolo and ImodaJ:olo benzodiuepine~. It is II positive aJlosu:nc modulalor o f GADA.. receptors. S, nce 11 is a hydrophobic:ally 5ub\Uhtled imidazole. I Side cffcci of
Th/o~n tal

.1.2tnntlOf'Ol: IIEIhrane). i~

bough an ullra I this purpose. jrl""th IIl1d !Q card,Qvascul.. kal \cnli l3tion nil do;es in I n\lII~lvc actil" IIIlI be used in

mewboliz\.'\!, ion hal'e tll:en ntrlllion. how

,mlls. 'o

.2.2trinuoroe (Foraoe), IS a
~manyproper

,up.'Ialogrnm lOI1ffi. II doe11) about 0 .2'1 and trinuoroabC'cn reported

H:}-O-C( HJF !bout QI)Cfiflb

dUll of isonuI~ic proper. nc, Desnul1tIlI." .anr exlen!.

H~CFJb

TAILE 1...1 uttr. stMM1:Acting

h;b

B.lrbitur~

lIMd to PR+do.lCe C l ner.tll Anast! r ria

Ihal of i'lOnur boolOOl:-third )IIed]y has !he: h is mel libGen..-it Hlme 1'rop,!etl 'Y HI,.,.
'''IWICI,,~aj

Substlt uenu

-ogcn

mono~

supplied us I I good anu lgein lhc: in~pirc<l 1Iw. anendant rarely used :I.' lbinauon W ith ttntnllion s. II 10 Iffillt from lissinn of pain

"

",
CI-t~CI-l2CH2CH-

"
o
s

tJrwMi SOCk..,

.oo-.rn

\"'

CH~CH2C1-1iH-

CH,

AIlIIGA BA~

the drug that can hal'C serious clinical consequences is depusioo of steroiOOgl'nesis. The oompound is a base. and wall'r-soluble salIS can be made for intravenous administration .

ILI~ called diswdOli... an ..SII, ..sia.! The prevalence of hall.

c!nations and ucitcmenl i~ higher In adults than in chtklml. The drog may be used us thl.' wle ugent (mllin ly for muD surllical procedurcs in childre n) . or it clLn be used 10 induce anesthesia that i~ then nl(umained by OIW: ofthc potent inltao 18\1011 agents. or it and nitrous oxide may be u<;cd togctha for general oncstlw.-osill.
NHCH 3 HCI

ElQmo(!ate
Propofol. Simple p/1cl1Ols arc rorely seen among uS('ful eNS depres~ts. possibly because of tissue destruction and gcncral toxicity latJI;cly due to the phenolic hydroxy group. It is likely that the 2.6-isopropyl grou~ ofpropofol (Oiprivan) favorably innuence the biological properties of the hydrol yl group. Plopofol is usefu l for inductlOll and maimenance of anesthesia. It is 001 water soluble. so an emulsion i~ gLlen intralenOllsly. PcllCtrotKKl into tl\.t brain is rupld. as is redistribution to mhl'r tis~ucs. chllf1lCteristics of compounds with II high lipid/watCf part ition coefficient. The drug binds ulloSlericaJly to GADA" reptOrS at a ~i le diffell'nl from the benl.odiuepinc SLle. 2

",0

ANXIOl YTIC. SEDATIVE, AND HYPNOTIC AGENTS

1lIc: It~t of un~ 100yliC. sec.bliu:. and hypnotic drugs is <./1M one- ben/.odiIl7.c:pincs. bIlrbi tur:Ilc.~. and a nlLscellallClXll group. In additio<l to the short Ibt of agents reviewed. I number of drugs belongLng loother pharmacological cln!a rnay pos~ one or more of the an)(lOI)uc. ~u~e . .:I hypnotic properties. The'\C dassel> include li .-anuhl>LI mines. antiadreneTgics. anllp!lychotic,. nnd anlicOllyul;aMI IlS prominem e~all1ples. Additionally. other atcas art bti!ll nplored for sleep-promoung agents. Adenosine-2A rttep. tor (Au) agOIllSb and melatOrt1l1-2 rccl'ptor (MT2) IoImI!II lire under tudy.'J Both udcnosinc and nw:IUlonin an: Ihoop to be inl-ot-cd in n:uuml llIcdLntion of sleep. Ade.1QI;.J)C iI cOrt~iden:d a pol>~Lble endogenous sleep-producins qatL Melalonin affects Clrcadipn m)'thms lind rna) be a ...euri
IIli~e.- hypnot ic .

OH

o
Alphaulone. 5a-~gnune-3a-ol.I I .20dione. is 1on8- discontinued anesthetk. but it may be instructi'e. It WIlS introdoced into the clinic as II conseqt.K:oce of Il'scurch begun after recognition of the anesthetic propcrlie.~ of cholestcrol and then a number of 3-hydmxy stl'roidaJ metabolites. Aner!he: dLSC1lnILnualion of alphMalone usc. it was found thai a number of such compounds. some erKlogcnously produced. are positive allosteric modululors at GADA" receptors. Negative allosteric modulating sieroids a also known. and some stcroids are posilivc or negative modulalors. depcnding OIllhc:ir cono:enlnttiOn. It is beliel'cd Ihat modulation of GA B A ... functiOrt nmy be a normul physiological role of such steroids. Collcctively. they are cnlled neumsleroids. Research in the area continuo.

AlphaxakNte.

KC'lamine, (~)-2-(0chlorophcnyl)2-methylumirlocycloh~~WlOIW: hydrochloride ( Ketalar). has a different mode of IICtion from the other anesthetic qenl$ in this rcy)ew. Ketamine WIlS designed us a stlllClunll relative of the medically di!lOOnt!nutd agent phencyclidine (PCP) (iICC Olapter 15). with which it shares a number of biological properties. Blockagc of glutamic ocid N-methyl-o-asparuue (NMDA) recc-pton uplaiM many of the LlCltonS of the 1....0 oorupounds. 1'be inddcllCc of hallucinations is mUoCh lower wilh kctamine than with phencyclidine. KI'lIUI.ine produces a senS(' of dissocialion from el'cnts beinS eApcrieoced. followed by ancsthe.~ia. lIIIalgesia. and sometimes amnesia. The anesthetic Slate produced by kelllmine has lliso been described as cataleptic aneslhesia. II is

Ketam i(H! Hydrochloride. USP.

Unoleamidt: lind 9.IO-octadeccooanmlc haye. al>o ~ implicated recently a.. possible emlogc:nous slttp-produciIIJ agents, llley are positive n1Odulal0l"S of GABA" rcceptOl'\." Anandamide (and OIher endogenous cannabLnoids) pIl'SIe ubly do not bmd to GABA ... receplori. Some of lheir rob in the CNS fun~1ion nre di'\Cussed in Chapter 15. Futthcr .... ork shou ld clari fy tile exact role and importaocc ilL.lktp of Itnolcamidc: and 9.IO-octadeccnoamtdc. As well" agents clasSC'J as anxiol)IIcs. 5(:datin:s, and hypnotics._ Illat these groups of CNS depressants have an es~taIy c lose: relationship with ntlticonvl1lsa01~. Strong e~idcl1<:c-, dicates that in many cases lhe neuronal effect~ .... ith an)(iol)tic. o;cdatilc. and hypnotiC effceu. npmdy positive modulalion of GADA ... recc-ptOOl. also Il'lale 10_ convul~lInt effects. In addition. Other mechanisms of actd. soch as sodium chlll .,..,.1 blockade and calcium T clwwd blockade. may predominate among anticon,'ulsanb; JO. ~. IIPI'Ioptiale to discllSS them o;cparatc ly.

1<:"'*

assoo"

.enaodl.a.plnes and Related CompoullHls

8cnzodiazcpines and benzodiuepine-Itke drugs bind II' ben:todiuepinc reo:ognillon SlIe. one of sel'cnJ :lI1osIm sill'S thm moduli11e lhe effcci of GABA binding 1 GABA. 0 receptors.:!' The GABA" receptor is a Iigand-S3tedd ride ion channel. It is a protl'in anchon:d in the Cf:1I . . .

J."

111-

" =

""

"'-

pcntomerie. as arc OIher liga!ld -gat~-d iOIl chann The fi\c polypeptide subunits Ihallogethi:'r mw.e up II SUUClun: come from !he ~ublll\i t families <>. /3. 6. tI. 1T. ,. arw;I fl. 1'bcre Il/l'! six i~ fOfTll$ of lhe tl' polypeptide (<>, 10 ~). four of lhe fJ ..... Ih tWO ~plice vanants. and three of liE ., Mth rwo variants. l're5em ly. one form of each of the IIthrrs.~ lnown. Each subu nit has an utr.K:ellular Ntenni _ l1li domaon. Itv:'n three nl('lllbr.mespan ning domain~, an invxdlular loop. a fOl/r1h membrnnc-5J"'nning domain. and uU'aCdlular C tennlnu~ . Atlcast 16 different GA 8A A rtteplOrs IIllve so far bee n ldenrified in rodem brain . The subunit eomposition of rhe ~ors ha~ great bearing on the response to bcru:odi:u.epines and Olher ligands. MO!it recept()l') C(ln~iSl of a. p. and roombllwions, Of these, a" /h., and ~ arc most comn'lOO. Oher highly upre$sed comblllation. are a], /h., ~ and a~,

lnno: ~n(/

i~

lxnr.odial.epines. Negative modululOl'S dimini sh lhe posilive effect of GABA on chloride n ux. In whole animals, they appt'ar 10 increase anxiely, produce panIC attacks. and Im_ pro\'e memory . ~Carbolincs .... ere once wspected of bemg the endogenous modulators oflxn1.ooiazcpllM: bindmg sites, Now, th is is not considered li kely, Ma ny ex perts in the field now think Ihat there is 00 endogenous ligand forthe: ben1.odi aapine l'eCognition site (alktsteric modulatory ~ ite), There are also compounds thai can occupy bentodIV.epine modulll1ory JIleS. have 00 efreet on chloride nux themselves, lInd block posit ive and negative nlOdu latoo, They have been ca lled variously (1III11glm ;J/$. ~/lro ",odl/lt"lIrs. and fI/lll/roli:i,'g al/osi/lrie moa"IUlQr,f. One such compound, nu~ mv.ell il, is used cl illically 10 counteract t'-' sedatt\e effect of beru:odiv.epinc:s.

" r

"

I.

1-

The bcnl.OdilU.cpi nc recogn ition sire is in the extmcellul ar ~ tClnllnU5 of the a" It"l.. It"J, and <>5 subun its. GA8A A fCCepIllS ,",Ith 14 or ..... subunits do IlOI. respond to benz(xh ... ep.es.!4 alld ..... wbunits ho!\'e an arginine midue replacing liIIidUle at posilion 101 of lhe ucr-..cellu lar N-lenninal do1I'I;I1n; "I subunits arc fC(lu ired for sedalive amI hypnotIC dfects. and to a Jc,~r cxtent. IlI1tkon vulsan r cffects of lxnl:IIdi.a:ttpinrs; II:! subunits are required for the IlI1xiol)'tic d Ims of ben1-Odillltpines; and aJ and (\oj suoonilS may be ...'\lIved In other action~ of benwdiazcpincs. Ir an argilline replaces hIstidine in an Il'2 ~ubtlnit of the GABA receptor, k receptor is re~islnm to the sed:lti ve effects of benzodiQze pines and zolpidem. If argimllC replaces hi~tidinc in an It"J 1lIbuo1l, the anA iolytic effect of ben1-OdilUl.'plllC$ is ktsl." Although lhe binding domain of the ben~odiazepi nes is (CII$I(Je~ 10 be In !he N terminal domain of the a umt, lhe btnr.odlal_ cpllles al,l.() fC<!uire a ~ subunit for most positive aIlo!.teric df~"CIs, Amino add res iduc.~ in the tr, subuni t that bI-ebecn idenlified as ley binding si tes within the ben1odiIIl'pInt bindlllg site are T)'r 161, Thr 162. Gly 200, Sc:r 2().$, 1br206,:and Val 2 11 , In the YMloon u, PIle n has been iden!irlCd .l. _21 A number of com pounds lillU huve struc1UtUl chaf'dC teris"" broadly re lated to the ben1odiucpinc.', incl uding I1CUroKIIOC flavanoids, imidawp)'ridines, and p)'rolZoiopyrimidiIu. can act as posit i\'e modulators at lhe bell7.ooiazepine lIlogllllIOll sne on one or more of the GAB AA receptor _)PCS, Compounds may produce a ll the chal'1lCtcri5lic IICiI:ns of ben7-Odi1l7.cpi ncs ()I' be selecti ve. as 1U't', for example, wlOl}uc navanoids or the sedative- hypnotics wl pidem .-I zakphon. \I~ cJas~ical ben7.odia7.cpincs arc positwe modulalors, ... y probably oonsc:lectively for all the rtCeptOl" subl.ype,~ thit rcopond to benzodiazcpincs, SOllie have been claimed llbe relatively S<' I~ti ve as amiconvulsams. Such drugs, ..... ith rely pan of the spectrum of all possible ben/.otii:uepine ac. .~ba\'e been called fHlf1i(lf (lgOflisFJ. This term can mislad. ~nce m this use, it appllcs 10 drugs that do not I!a\'c II the possibl e Qualillllivc octions, ... ther than being al ~ pant on a si ng le IICtivit y scule between an agon;" and lin
qoni~t.

"".

,):]
o

,
CH,
Ftumazeni l

,0 C- O-CoHo

As noted ufllle r t'-' headmg of generul :mesttk'tic~ there arc OIher alJo.reric sites tilal ra:ogn' 1.e respecti\"dy. oeurosteroids. barbilunlteS, Inhalation IIIlCSrhet ie8, alcohols and the phenol Diprivan (scpa ... tc si res), The convulsanl~ picrotox in and pellty~ [\I,'tetr,t:lA) le have definite binding siteiO on GABA receptors. The field of benzoola1p!nes '" as opened \O.ith the synthesis of chl ordlu.epoxidc: by Stembac.'h and the: diSCQvery of its unique pharmacological pmpertie~ by Rand:lll .n Ch IOllh aJcpodde (see lhe discussion of imilv idual compou ndJI) is II 2-amino bt:n~-Odi:ucpinc. and other amino compounds ha\ e bt:e:n synthesiLtd, When it was WSCO\c ..... that chlordia7.I.'~ --d po~ide is r-~pidly mctabollud toa sc:nes of acthe benzodiazpin -2-onc:s (sec: ltv:' &cnerul scheme of mc(abolic rel auonships ), ho\O. cvcr, elllphru;is shifted tu the ~yn rhcsis and testing of the latter glOUP, Empirical Structure - activity relationships (SA Rs) for antiallll.iety activi ty have been labulau:d for this group {analogous .statcmcnlS apply for !he older 2umioo group) .ll, 2.1 The fol lo .... mg genero l structure he lps to \'isualire them .

0
X'

\1~
N.

0 , 7

Some ,8-carbolincs are negative nMJdulators at ben/OOiIIq)Int

modulatory sittS, Additionally, there are GA BAA IttqlIOI' subtypes that recogni/.e benwdio1.epines but not ~ ~Iines and subtypes that reoognit.e /:karbolines but not

An clectronegative sui,)"limem at posi tion 7 is .....-quired for acti vity. and the I\'1OI'e electronegati ve it is, the higher the activity. PO!iitions 6, 8. and 9 should 1101 be substttuted, A phenyl at position 5 I"OI II01CS acu\'ity. If thi~ phenyl group is onho (2') or diorl/w (2'.6') Substituted with electron at tractin g s ubstiluents. acti vity is increased. On the other hand.

pam substitution decreases activity sreatly. SatUl1luon of the 4.5 double bond or I 5hifl of it to the 3.4 position decreases activity. AI!;)'1 substhutioo III the 3 position decrease5 activity: substitution ",jlh a hydroxy does nol. The presence or absence oflhc 3-hydroxyl is imponant phanllocokinctically. COIT1pounds "'ithout lhoe hydroxyl are nonpolar. have long halflives. and undergo hepatic oxidatioo. COIT1pounds with the hydroxyl arc much more: polar and are readily COIWet100 to the uctetOO glucul"Omde (see the o.erall melllbolic relatiooship scheme). The 2-<arbonyl function is optimal for acl;'ity. as is the nllJ"OBCn atom It posit ion I. The N-substiluent should be small. Additional research yie lded compounds with a fused lriawlo ring. reprc'ot'nted by lriuzolam und alprtlloliull. Mid1l7.olam. with a fused imid1l1.010 ring. also followed. These compounds are melllbol Lted mainly by hydrolylation of the methyl substituent on the triuolo or imKlalolo ring. 'The KSUhing hydrox y compound is acti.e bul is quickly conjugated. The oompound~ are also metaboilled by 3-hydroxylation of the benlodiu.epme ring. Interestingly. an elec:tronaltractinS group at position 7 is not required for activity in ti"lese compounds. The mctllboli5111 of benl.odillZCpine~ has received much ~tudy.l'. ~ SOll\e of the lI\ajor metabolic rel ation,hips are shown in the scheme below. The benzodiazepllle!i gellerally are " 'ell absoriJed from the gastrointestinal C I) tract. although lhe !TlOie polar comG pounds (e.g .. those .... Ith a hydrox yl at the 3 positioll ) (elld to be absortJcd more ,Io-. Iy than the more nonpolar compounds. The drug ~ [elld to be highly bound to plasma proteins: in general. the more nOllpolur the drug. the gfeUler lhe binding. They are al<>o vel)' effectively distnbuted 10 lhe bmin. Generally. the more nonpolar Ihoe compound. the grealel'" the distribution to the brain. at least initially. W~n diuepam is used as an al\el;thctic. il millally dis.uibutcs \0 the bnlin and then mtiSlribute$ to SIIe$ ()Ubide the brain.

Compounds without the: 3-h)druxyl group ll!iuaUy hal"! Ion!! half-li ves and undcrso convenion to the 3h}tIrm, compoundJ by hepatic O.tidallOO. Compounds with the ~ hydroxylgl"Ollp ha\'C short half-lives because of f"dpid COltfll" galion \0 the 3-glllCuronitlc. '" hi eh undergoes urinary umtion. In addition \0 lower abu'ie potcntial. and a mllCh &J"CaIa" margm of safety than [he barbiturates. the drugs ha"e ftl>tr dNa interaCtions. Espenally noteworthy IS thaI !hey do .. promote the lIlI:t.abolism of otheT drugs.

Chlordiazepoxide Hydrochloride, USP. Chloolwtpodde hydrochloride. 7-< hloro--2(mc thylamino)-S--phtn)J 3 11- 1,4- bcnzodia~cpinc 4-oxidc mooohydrochioride (Librium). is nbsorbed well from the Gltl1lCt. Peak plasma Ie-.ri! are reached in 2 10 4 houl11-. N-demcthylatioo and hydrol)'SII of .he condensed amidlllO group are rapid and c~tensi.t. producmg demoxepam as D maJOf melllbolile. Demol~ in tum. is coo"ened principally to nordll7.epan1. Norttlepam. III tum . is COIWcned princIpally to oxcp;am. .. bdt uBdeI"J!<>eS conjugation to the C.\ell'led glucurooKle. CldICf roules of metabolism can occur. for e.tam pk, O(lCning o(tbt sevenmembered ring by hydrolysis of the IlIClam ifUUP.

I N_C , .,
' ... !

H........ .....-CH3 N HCl

,CH 2 C-N
\

Diazepam, USP.

7-chloro- l ,J-dlhydro-~ meth)I-5-~n)'I-2H- I.4-ben7.odH17p,"-2-ooe (Vlliuml "

Di:u.epam.

HeI'ropem _

CI

0 0

Cb-'IlJltl ---

"o::::V~ - ".A::~I~~OH N o
J

o
o

"

IN

0
OH

Chwpl cr 14 C..mrol N~,,'O,,~ SYJlrm 1R",...",,,u

491

ve

"J-

=.

JU-

..,

Icr

IIIr filS! member of lhe benwduvpin200e group to be '1IIromd_ 11 is vcry noopolar and is rapidly absorbed. Diazepam ~ melllboillcd by N-demcthylaliOll 10 nordal,cpam. which DIhc:n metabolized att:ordins 10 lhe: general !oClicro.e. II is 'luly used for !iC\cral anxiety S\atc~ aoo lias an addilion~ 1 "ide mngc of IlfoC5 (e.g .. as an anlioonvlllSU/lI. a premedicaIIOIIm ollC!lsll\.esioiogy. and in various spastic disordel'5) .

allon occurs 1 yield nord:t7.c:pam. 3-HydroxylalMII1 o(both 0 pnvcpam and nordncpam occun..

CH<

/CH 2

CH
CH 2

CH J ("(

~-C'

~.

1yl

CIA..,...J-..C=N'

'cH 2

J):

CH, C~N

N-C,

ib-

Ids

.~I~

he.

om.

"".
ich

"," ,.",'

Oxaupam, 7-chloro-l,J-dihydro-) ~'Ikuxy-5-phenyl-2H- I .4-bcn1.()dia1.pin-2-onc: (Seru). can kronsidcred a proIocype for lhe Jhydrox y oomJlOlloos. For !be ~ereochemistry of th is and ocher 3hydroJlY compounds, Ilr tile chapter dc31ing ",ilh metabolism. It is mIlCh more poI2r than dia;.:epam. for example. Metabolism is relathd) ....,Ijl..Cated. and lhe duml1011 of action is short.

OXillelHm, USP.

Loralepam, USP. I...onuepam. 7-chloro-5-<2-chl0r0phenyl)- 3-dihydro-3 -hydroxy- 21f- 1.4-bcn7.odia/.pin-2-one (AliI'Dn). can be recogni1.ed as the 2' -chiaro substituted analogue of Olt:l1.epam. In keeping v.ith olcraJl SARs. lhe 2' chloro $ubstilucnl mc reases acuvity. M ~tabolism is relalively rapid and uncomplicaled becau'\t: of lhe 3-hydroxyl group in the compound.

~-C'?

(yN-C'cHOH

CI~C-N"

("(

'cHOH

CI~C=N

."
(b-uepa te Dipotassium. CIorv.c:patc dlpol::l'isiullI. l-d\1oro2.Jdih) dro-2(-,,05~ny l ll1- 1 .4-bcn1.OOial.e ,.3-carboxyl ie acid dipolus~iu m sail mo nohydrate (Trun Ide). c~n be considered a prodrug. Inactive itself. il underraptd loss of water alld then d<'curOOx yialioo 10 nonJa1q"UII. v. hieh has a long h:llf-life and undergQeS t>cp:uic "\II'mion 10 oxu1.cpam. Despi tc the: polar eharolCtet" of the *'Illo IIllrmniSiered. !xocauloe it is qutekly cOlivened in Ihe G1nct 1 a noopolaroompound. il has lII1 oleru" long half0

> 1

Halazepam, USP. Hblvcp;am.7-chloro- l .3-dihydro-5pheny l- I (2.2.2- ltifiuoroelhy l)-2H IA ben1.00ia;.:pin2-()1lC!I (PlUapam). IS well absorbed. It IS :lCt1\'e and present In plasma. 001 much of il~ activity 1~ due 10 lhe major melabolitl:ll n.orda/.epam :Ind oxazepam. The drug is lnll1keled as an anxiolylic.

"'
CI

H 0 I go N-C
PH-COO-K+ C==N

CI

IN
0

KOH

fitufpMn, USP.

~epam. 7-chl0r0-I-(cyclopropylyl}-l,J d i h ydro-~ p hen yl211-1.4-bcn1.00IDZpin-2-oIlC

lmuan).1Ias a Ioog ol'erall h:ll f-hfe. ElIenSIIC N-dealkyl

Temazepam. Tema7.epa11l. 7-chl0r0-l.J..dihydro-3-hy droxy-l-mclhyl-5-phenyl -2111.4-benl,oolupm2one (Resiori I). also occurs u a mmor oncuiliolilc of diu1.c:pam. It can be vi~uaIi~ed as ,v-methyl onl.c:pam. A small amounl of Ntk-methy lalion occurs. Metabolism proceeds mainly Ihrough coojugalion of the 3-hydroxyl group. ho"cler. The dunllion of acllon is shon . II is markeled a..'l a hypnotie ;.aid 10 have little or no rl'Sidual cffect.

CH,

N~OH 0
IN

N /O~}
N
CI N

!f.N

0
F/urazepam Hydrochloride, USP. FlurMcpam hydrochloride, 7 <h lom-J-j2-(diclhylamioo)elhyl]-5-( 2-0uufI)phc-nyl}- I. 3-dihydro-21f-1. 4-bcnzodiazpin-2-<.JIlc dihydrochloride (Dalmane). IS IIOOlble all a bell1.odi:u.cpine marketed allOO<!it uclusi\dy for usc in Insomnia. Mc:taboli~m Qf the dial"),1 aminoolLyl side chain is exu:mi~~. A major mClaboInc: ill N I-dcalkyl Ouruepam, .... hich has I "cry long haIr lIFe aod per;ists for ~~c:rul day~ after adrninistr.ll ion.
CH~-CH2- N (C2H ~ ) 2

o
Tre .......

CI

Midazolam. Thi s drug is used imrnvcllOUsly as a sedati vc _ hypnotic und as an induction (mc~thctic , Funher mfO! malion ClIO be foond in the SC(:tion on anc,thetics.

o Jt a o
Alpruolam, USP.

I ,0 N-C
C-N F

p H2 ' 2HCl

F.... ~ Hydf<;x:hloooe

Quazepctm. Qua7.epam ( Donal) and liS lIl"\ivc IIlI:UbDhtes Icponcdly are relatively e lective for the bcnrodiutpine modulatory SIICOO ( .... I) t)'PC I GA8A ... rettplon llr rtCCplON .... jth an 0 1 subumt) 3nd are hypnotic agent>. 07.cpam i~ nlCtaboli!cd by oxidation 10 the 2-oxo romJXll*l and then N-dcalkylation , BOlh I1lClnboltte~ an- active. firM reponed ly is the m~ poIenl and selectivc. The~OJfttl, 3bydl'Qxylptioll and glucurooidalion OC'CUT.

Aiprol.olum. 8-cbloro-l -mcthyl-6phmyl-4H'NriazoIo/4'),/1l 1.4)benzodial.cpine (Xana;o; ), is

jP,

rapidly absorbed from the GI trJiCl. ProIcin binding i~ lower (- 70%) than Wilh InOSI Ixnl.odiazepi nn. 01idali \ e metabolism of the mc:thyl group 1 the methyl akohol follo\Oooo by 0 tunjuSJltion is rapid : ~'()(1o;cquemly. the durnllOn of action is short. The drug is a Ilighly polent aoxiol)'tic on a milligrnm basis ,

N' )
IN
0

CI

Zolpidem. 7.olpidcm (Ambicn)ha~ auracll:d a!l~. a n::lau"cly sclecth'c positll e modulator al the: .... 1 bcnrodiazc:pinc bindmg site. As such. It i$ a hypnotic. It is SlId 10k ~Iativcly rllSt in action and to prodU'-"e no ;I('1i,c lTICUbole Mctaboli sm of lhe aryl methyl Groups wO\I ld be uprol'li howcvcr. the ",suIting compounds would rlOI be longhled

o
Triuolam, 8 < hJoru-6-(tH:hlorophenyl}- l methyl-4If-J-triaroIol4,J-alll.4 ) beru.odia7.tpine (HaldOll). has all ortlv; characteristic benzodia7.tpine pharmacological actions , It is marko:tcd as a scdativc - hYPncMje drug ~jd to impair linle. if nny. daytime function, It i~ mpidly metaboliled to the I-methy l alcohol. which ;$ then conjuG.lled and excreted.
T,I~zo'~m.

0/<><'
' - C -N

USP,

"'0

/ '"
' CH,

Zaleplon. ZalepJ ( Sonata) i~ anotht-r ..... 1 5Cd&>f on hypnotic wi th overall biologica l propertics resembling tM!I of 1.olpidem. II may ha ve 11 more rnpid onset and lenni.... of action Ihan l,olpidc:m,

Metabolism involves the aldehyde <k:hydrogcllulie and the

QlOChrome

system.

hrbiturate5
appear 10 exen J11()61 of their characteri stic CSS effects by binding [0 an allosteric ~ogni tion site on GABA ... n:<:eplllrli thaI positively modulmes the effect of the GABA,,-GABA combination. In addn iun. by anachi ng 10 Ik barbilumle modulatory ~ itc . barbitumtes can increase .lIoride ion nux without GABA auaching 10 its receplor site _GABA... _Th l5 has betn lennet.I II GAiM ,mmmc ~f!rc', II Ilboughllo be rc lmed 10 lhe profound e NS deprc~~ion Ihul IIri:lttUIlIte$ can produce. The first hisloncal SCt1a1l\C- hy pOOIlC barbitumt e. 5,5-<1i M)lbnrbi1l.lric acid. was Illtroduced in 1903. With lillie. _y mcn\l)c,rs were added. and lhe barbl1ur.lIes dominatt-d ill: !ab1tvc--hypn04ic field un,,1 the ad vent of the bcnl.OdiIItpines. The bcn/.odi:m~pines hte much safer to Ilo;e and Ute rc:placed the barbiturates as the most broadly use ful !pl. in sedalive- hypnolK- applications. The barbiturat es lIIl: !i.!i-disubstituted barbituric a'ids. following scheme shows how the 55-diall.yl com ~ an: synthe'ill.ed. SUm.tiWllon of th ioorea for urt:1t in fnC:tion prodlK:e~ the 2-thiobarbitunllcs. ustfu l as indue(lit twbll\lr~tes

Considc-nuion or the structure of 5,5disubstituted barttitu. ric aci ds rcveals their acidic character. 'tbo!.e withoot methyl wbslJII,ltnlli Of\ the nitrogen have pK~~ of about 7.6: those with II ItlCth}1 substituenl ha\ e pK. s ur about 8.4. The free acids have poor water solubility and 800d li pid 50Iubilily (the lauer largel y II function or the two hydroclltbon MlbslilUents on the 5 position. although in the 2thiobarbitulllles the sulfur atom increases lipid solubility). Sodium salts of the barbiturutCli ~ readil y prepared and are water soluhle. 11leir lKjuwus solul ion$ 8e""""e Dn "I!:aline pt!. A ChLlsic incompatibil ity is the addition of an agent ..... i'h an acidic pH in wlution ...... hich results in fonnalion und prtCipitauun of lhe free willer insoluble disub.~lilUtec/ barbituric add. Sodium salIS ofb;ubiturate! in aqueou~ solu tion dompose lit \'arying rutes by base..catalyt.ai hydroly ~ i s. ge neralinll ring-upened ~lls of carbo:o;ylic acids. 11le names of many barbiturules end in 0/ (e.g .. phcl'lOOOr bita l), uppearing to dellOle an allkhydic compound. because chlorJI hydmtc was widely reoogni1.ed as a sedlllive - hypnotic asent when the first batbiturates \\"ere introduced. l ienee:. the suffix WIIS an effort to illdicate a therapeutic, r>OI n chemi ca l. class.

Stntlcture-Actlvlty RelMlon.hlps
Ex.tl'lt$l \e syn thesis alld testing of the barbiturales O\'er a lOll S lillie span have produ\:ed well-defined SA Rs. which ha ve been $Ummari 7.ed. l6 Both hydrogen atoms at the 5 position of harbituric acid nlust be replaced. This may be because if 0IlC hydrogen is available at position S, tautomcrization 10 a highly acidic uihydro~ypyrimidinc: (pK. - 4) can occur. Consequently. Ihe compound i~ largely in the anionic form at physio logical p H ~. with lillie nonionic lipid-$Olubk compound available: 10 CfUM the blood- brain barrier. Beginning wi th lower alkyls, there is an i~rease in onset and a decrea<>e in duration of action with increasing hydrocarbon content up to about seven to ninc: lotal carbon atums ~ubstiluttd on the 5 position . Upophil ic ity and an ability to penetrate the brain in the fim case and an ability 10 penetrate liver microsoflll's in the second mlly be involvec/. Also. for mon: hydrophobic compounds, partitioning OUI of lhe brain to other SJ les C be involved in the second instance. lbtre lln is an inverse correlation betweell the 100al number o r carbon atoms substituteo on the S position and the duration of action. .... hich is even bc:ller when the characierofthocsc: substituc:nl5 is takcn i ntu IICCOUIit. for example. the relalively polar character of II phenyl substituent (approximates a three- to fourcarbon aliphati c chain ). br-mchins of all;yls. presence of an isolated double or triple bond. and so on. Additionally . these group!! can infl uence the ease of oxidall'e metabolism by effects on bond strengths as \I'ell llli by influencing parti tioning. Metabolism of the barbiturates iJ di~ssed in Chapltr 4 . Suffice it to SJly thaI increasing the lipid/water panition coefficient generally increases the rate o r metabolism. uc:rpt for compounds with lin utn:mely hiSI! lipilUwattr J*1ition coefficient (1'.1 .. th iopental ). which 'end to depotize alld arc thus relatively unavai lable for melllbulism. Metabolism general ly follows an ultimate ( ...) Of penultimate (,...1 ) oxidation paltern . Ringopening reactions :u-e usually minot". N-methylolion dcc~ases duration of ..:tkKI. in large pan. pobdbly.

,ho-

1 =

(i.e .

'20,.

.. ~I

, ,i>< ,fier.

n.:

""""""'A,

~la\

H..... 'CCXX:: 2Ha

...... ccxx::2HS

"-.

/::",;;
hlC\,

More t '')I

"ed.

~Ied:

n -"""'oat~

Ilive

....,

I lion

by illCl'C'asina the CQI"ICC'ntnuioo of the lipid-soluble free barbllUric acid. 2ThlobarbilUrate have a \'cry short dUnitlOn of action because the lipid/wll ter p:1r1ilion coefficient is extremely high, promQtlng depotil3.ti()ll, Barbiturate'! find uoe IS &oedIInves.. IS hypn<MICS, for nlduction of anellthesll, and as anticonvuisanlS. Absorption from the: GI U1\C1. is llood. Binding to blood proteins is SubsUlllIial. Compounds with low lipid/II'liter pattitiOll coefficicnts may be cJ(crcted intact In the urine. lllosc 1\<I1b higher ll pid/..... atC'r partitlOll coeffi cients are ucreted after metabolism 10 polar mdaboli tes, Some of the more frequently used barbiturates lire described bric:ny in the following Stions. For the SlfUCturcs, the usual dosages required to produce sedatIOn and h)'lIOOsis. the times of onset, and the durntion of acnon, see T able 14-

USP, Phenobarbital. 5-elhyl-5-phn!)'~ bafbituric acid (Luminal). is a long-acting IiC'dath'C' and /I)l" notie, [t is also a valuable anticonvulsam. especiall y in gener, alized tonic-cIOllic and partial seizures (~ !he discuSiIOI OIl anticonvulsanlS). Metabolism to the p-hydmxy COllIpound followed by glucuronidation accountS for about 90t of II dose, Mephobarbital. USP, Mephobarbital. JmethylJ. ethyl-S-phenylbarbituric acid ( Meiharbilal), is rTJeUibolan, N-dealkylated to phenObarbital. which many tonsider to a;:. toIl nt for almost pJl of the activity, lIS priOCiPid use it IS anticonvulsant.
BARBI TURATES WI TH AN INTERMEDIATE DURATION Of ACTION (3 TO 6 HOURS)

PMno~rblral.

2.
BARBITURATES WITH A LONG DURATION OF ACTION (OVER 6 HOU RS)

BiJrbitiJl. BWllal, S.5-dielhylbaTbituric acid, although ducontinued as I sMall\'c-hypnotic, is imerc$ting becau>oe ort he biologkal consequence of its low lipid/water partition coc:fficiem. It i~ slow ly eli mina tcd, n~tly intact, by the kidney,

Barbilunlte$ with an intermediate duraliOll of action ~--' principall y lIS sedati ve-hypllOlicM. They include Amobll"" tal, USP. 5-ethyl5-illOpCnlylbarbi turic acid (Amy tal)... ilS "'llIer-!iOIuble sodium salt. A mobarbila l Sodiunl, usp, .5-allyl-S-isopropylbarbituric acId (aprobarttllal. AI..-, HUlabarbilll1 Sodium, US P, the water-sol uble !oOdium!od: of S-Kr-bUlyl-S-el hylbarbituric ocld (Butlsol Sodium),

TA8LE 14-1 8arbttura t e$ U$ed a$ Sedative5 and Hypnotics

: ...J-,N-R,
.J;.~~ o I 0

"
<>-n.tk Him.
~1.ryN.. ~

SubSlllu ... ts

Sedatlv.

A. lonll Du,MIoo,oI AcUon(_

"

,',
~

6 houR)

"
CH,

.... .... ,." ,."

H'"
'00

Hypnolk

............
0 1 Ao;tion

(min)

....... _ ..... ,....,

AlfiObalbOl. LISP
~~ ..

MepOObaIbtal, LISP

c.... c...,

00(CH,)rCHCH~CHf-

30-100"

" "
-

.15-30

30-"'

....'"
>0-30 >0-30

B. ~, .. "oedIMli Duo.'1 "'1 01 ActIon () to 6 houri)

-USP

CH]C ..... $l:xMom,

BwsdSOOtm

CH)CH,-

CH:t<=H:P"I-

1"'

"'-'"

'00 '00

C. Shott 0ur.1Ion oIlIoclion <'"- ttt.. 3 hoon)

~SOdIom.

USP N/ItTbJIM $ndoom

$eoobarbUlUsP
Seowal

CH,a-t,-

CH,CH,cH

,t'
CH,

~-

...

CH.-CH<>I...,~

CH~CH,CHiH-

" "

"
''-30

'00

H'"

"'-30

IlARBITURATES WITH A SHORT OURAnON OF ACTION (UNDER 3 HOURS)

Rarlmurotcslhat ha\'1: Subslilucnt~ In the" position promoIII, more rnpid melaboti~m (e.g .. by illCfCas.mg the lipid! 1-aItf pam!!on cocflkient) than the miennedilllc group in-

.1Idc PentobarbitalSodlum. USP. sodium "-ethyl-5-( Inylbtu),1 )barbi lur:uc (Nembutal): SKut'llrbit.a1. USP, 111)'.,-( l-melhylbuly1)barbnuric lICid (Seconal): and the so-

s-

ohm salt sodium secobarbital. B..rbiturllt<!S .-..ilh an ultra-short dUralion of lICtioo 1111' dis_ Msed under ar\e.'olhetic agents.

Mbcellaneou. Sedative -Hypnotics

"_Ide ronge or chemical structUIl'S (e.g .. intidc~. amideli. *':!bois) can produce sedation and hypnosis resemhling tIosc produced by the barbituratcs. Despite this apparent JlruC\urul diversity. lhe compound.. have gerK'rally similar lnII.1um charnclcnSlicf and chemical properties: a hydro~ portion and a ~mipoJar portion thai can participate li lt bonding. In some cases. modes of action arc undeler. d M a worl;ing hypothe..~is. moSt of the ~gcnl~ can be m-.I:Jooed to act by mcchanism~ ~lmilDr to those proposed for b:utiturutel. and alcohols.

this may be because tcniary and secondary akohoh are not mculboliJ.ed by OXidation to the corre.sponding clltboll)lic acids. Replact'mem of II hydrogen arom en the alt}1 group by a halogen increases the al~yl poruon and. aocordlngly. for lhe 10wcr-nKllecuhlr-w~ lghl compound~. Increases poIcncy. CatbamylauOll of alcohols generally IIICIl."MCS depressant potency. Carbamale groups llIl." gcllt'rnlly much more resiStant \0 IIIt'IaOOlic inactivation than hydmll}I functions. Most of tile alcohoh and cwOO!1IUles havc been super.oedW as sedati,e- h)pooucS. A number of dlfuOClional compounds (c.g. diol clI!bamates) ha\c dcprc.~santlC'liOl1 OIl the cord In adJllioo 10 the bruin lind are relained principally for their M.eletal musclc Il'luam propenlcs.

Ethch/orvynol, USP. Ethchkmynol. l-chlom-3-cthyI l-pemen-4-yn3-oJ (Plucidyl). is a .scdathe- hypnotic Vonh a rapid onsct and ~h-oft duration of action. ~ Ictaboli sm. pr0bably in\ohin8 lhe hydrux) I groop. accoun,s for aboot 9O<J ora dose. Acutc o\erdosc share\ sc.cral feature.\ Vonh barbltUrale o\"crdose.

CH3 - CH ~\!OH
CI

:;'Cc= CH

I \

CsCH

.wIDES AND IMIDES

Glutethimide, USP.

Glutethimide. 2-clhyl-2-phen)lMf'probam,He, USP. Meprobamalc. 2-mclhyl-2-propylmOlCtb)lcne d.eai"bamllte. 2-mcth} I-2-propyl-l.J-propanediol dlc3fbanl:uc (F..quarlil. Miltov.nl. is ofrlCially indi cated as an anunnAlety acnt. II I~ nlso ~ scdathe- hypnollc pgcnt. 1\ has III number or overall phannacologlcal pmpenic~ resembling too.e of bcnr..o(lLaapines and barbiturates. "ThI: mechanism of :lCuun underlYlOg anAiol}tk dfo;:1S is unI.noVon but rnay 10\"01\"1' effo;:t~ 011 conducu\ny m specific brain UIl."as.l7 II d<x's not ap]X':tr to act through eff~"$ on GABAcr!:l!." 'y~tcrns. n.e drug is effecl;\c against ab .... no.--e sel;tUres and rna) ",orscn gcnerulll.ed Ionic - clonic ;,eilurc~. ~lepmb;l.nUlc is alS() a ("("ntrall) II("lIng ~kclclal mu<;clc relaunt. The agents in this group lind use m a Dumber of CQDdlllons. such UJo Slr.lln, and 5pr.un..~ ,h:d nuy produce acutc mu.)C1c spasm. They have Inlemcurooal blocking propcnic~ at 11K' Ic,d of the spinal cord. Vohich are /i:lJd 10 be partly rcspon., iblc for slclctal muscle rcJa.,,"ion .~7 Also, the gelK'r.t1 CNS dc:,)re~~mll propenl!') they possc~ may COI1tnbule 10. 01' be mainl} n:~ponslblc for. the ~I.cletal muscle rela~ ant activilY. Dillydric 1:00npo"nd,.nd tlll'Ir cari);trnale (urethane) dcrivulI\"es. II, described abovc In the discussion of meprobamate. are pmml1lcm members of th.:: group.

pmnnllde (Doridcn). hIlS m(my slrtlCmrol relaliollships m Iht: IwbilLlrlllCS and I'e$Cmbk.~ them in nlany 1TSpc<:IS IIoIogJcaJly. It is an e ffCCli\"C~ scW!th-e- hypnexic. It i, 'cry ~c. and absorption from the GJ tract is <;OUlc:whal erntic. ~Ictabohsm is l'xlen~i\'c:. and the dlllg;s an en/yme Glucrr. In the theTllpeutic lIosagc runge:. :Khersc effects lend II be Infreque nt. TQ.'(ic effects in Q\'erdQsc lITe lIS !Ie\ere as, ad ~Ibl)' ~ Iroublc\OfflC Ihan , Iho'\C of the' barbilu-

Ak,lIoi. and TlMlr Ciu"bamate llrivatives simple alcohol ethanol has a long history of use
and hypnotic. I~ lnodes or ""1100 were deunder the all('!i;thetic heading and nre SIIid 10 apply .... alcohols. It is .... Idel) used in selr-medication os a ;; ; ve-hypoo4lc. Because this use has w many halards.

o
II
~

CH ,- CH ~-CH 3

"""'" .

H N-C-O-CH -C-CH -

I
I

;.

O-

C-NHR

II

CH,
Meyer I chain M opcObii'I >ale CausOP"odoI
R .. H

R .. -CH(CH,I,

. ""

Chlorphenesin Carbamate. Chlorphellcloin carbilmate . 3.(p<hlorophcno~y)-1 ,2propanediol l-clllbarn:uc (Mao-

late). i~ tile p-chloro substituted and ' -carbamate Oe"" 1'1;\1' of the: lead compound in the dc"clopmcnl of this group of agents. mephenesin.

Mephenesm is weall) acti~e and shortb,'ed becau'\e of facile metabolism of tho! pri mary hydro~)'1 GTOUp. earNm),lalion of this group increases III::lh;ty. p-Chlorinat ion in~aso:s the lipid/water panition c~rrK'knl and scal~ off the pam posi tion from lIydro~ylalion . Metabolism. still fai rly rupid. in"olves glucuronidation of the IICCORdary hydro~y l group. l'l1e bloiogicaJ half-life 111 hU lTI3ns is 3.~ hours.

Cr~O-CH 2 -CH -CH -O-~-NH ~ ~ I'

OH
O ....prw!1
,~

and formate iOll. In hydroalcohohc solutions. it rom" ~ hcUl lu(c tul wi th eth,mol. Whether or not Ihi. compound iJ the ba.~IS for the IlOloriOUll and potentially lethal eff1 01 the combmat ion or Clh:moI and chl()f"JI hydrate (the .. MII."U} Finn") is comro\cl'lilal. Synergl'rn bet"ttn IWO d.ffemtt CNS depressants also could bt: in~ol\ed. Additionill). ethanol. by increasing the conccnlnltlOn of NAD H. e~ the rcductioo or chlorotl to the- rt'IOI\' acti "e nlClabolitc tll\:hbTOet haool. :md chloral c an in hibit the melUbohsm or nlcohd bocauo;e it inhlbH.s aJ.;:oOoI dehydrogenase . Allhough IIi. ~ullgt'!oted thaI chlor:11 h)drnte per o;e may 111:1 ~ a hyptlOllC; Chl oral hydr~ te " ,cry qu od,ly con, ened 10 Im;hlonxtharr.i which is g.:ncrJ ll y assumroto account for alnlOSl aU oftK hyp'lOlic effect. It appears IQ h:t~'e potent barbirur.lle-l!1r hind ,"& to GAllA ... f\'~'CptOfS.
Trido f os Sodium. Tric1ofos 'lOdium. 2.2.2.uichlorotlhanol d'hyd rogen phosphale ltlOIIQ!iOdium salt (TncQ~ Iirri tating 10 the G I mucosa. Ib active melllboh te.tnehlorotthanol, also has unpleaSlim G I erfeclS when ghen 0I'lII1y Triclofl)'l is In.: nonirritallng sodium 'kilt of the pho:!.pha e.~ter of tnch lorocthaool amd is readily com'cned 10 lf1dtIg. TOelhaool. Al"Coniing ly. Iridofos sodium produces eM d. feelS si milar to those o f oral chlQnlI hydlOltc.

MethOCilrbamol, USP. M c\hQcarbaJilol . )-(o- meIhoxypheooxy)-I.2propanediol i-carh:Jnmlc ( Rob3xin). is ~Id to be more su stalllcd In effect than mephenesin. Li Lely silc~ for metabolic HIUtd indu(\(' the !oCIndary hydroxy l : group aoo the 'wo ri ng posi tions opposite Inc ether funclion~. The dthydric pw-enl rornpoond. guaifcne~ln. b u~ as an expc<:tonlJlI .

~ a , C-CH' I o-p-o
OH
f ridolOll $Mom

Na'

c ., ,

'oH

R __ ~_NH~

Carisoprodol, USP. Carisoprodol. N i)OJH0l'yl2 mc thyl2propyl. I.) prol'~n .. dio\ dkarbam~te. 2'I11Clhy l-2propy l 1.3JII"OI!'lMdioi COlI"bamate isopropylCarOOmalc (Soma). is the rnooo-N-i ~y l -substiluled n::lali\e of mcprolxl.mate. The $truCtl.l n:: is given in lhe di o;cu)sion of meprobamale. It is indicated m acute ., ~ eletormlscu\ar colldi lions charoc:teri1.c:d by pai n. ~lIffncs). and spasm. As can be expected. a major s ide erre" of tn.: drug is drow",incs.~.

Paraldehyde, USP. Pllr.tldch)dc. 2.4.6trirooh)I,.... OXalIC: paraceto ldehydc. i, rccoglli/llble a_ the c}'die of acctaldchyde. It h a lIQuid with II S\(Ol11 chanoctetiaL odor dcteclabk III !he: c:\PIn::d air and an unplc~ These propenie.. hmil it~ use almost exclu~i\'cl y to Itn ill$UllO tional .-cui ng (e.g .. in the trealment of dcti riuln trelllC'm~ II. the past. ",ho.:n cont;l.\/lC1'\ "ere opened and lOr :tdmltlCd then recloscd amd allo,",ed to stand. falahtlOC ottumd. cau)e of oxidmion of parnldchyde 10 111acial acetic add.

CH,

AlDEHYDES AND TH EIR DERIVATIVES

For c tle mical reasons that an:: easily I1ltiooali l.ed. few aide hydes are val uable hypnot ic druSN. T he aldehyde in u'C. chloral (as the hydl"llte). is thought to act principally Ihmttgh a metabolite, tricblorocthaool. Ar:elaldehyde is used liS the cyd ic trimer deri vali \'e. patllldcbyde. whic h cou ld al.w be grouped as an ether.

)H 0 ..............CH tH CH
3

....... CH,

'--

.......

ANTIPSVCHOTICS
Chloral Hydra le, USP. C hlorul hydrnte.trichloroacetaldehyde lTlOIlOb)'drate, CCI)CH(OHh (Nooec). IS an aide hyde hyd ratc stable enough to be isolated. TlIl' n::lall\'Cstabil ily of th is gem-diol is largely due to un unfu\oruble d ipol e- d ipole n:pu l~ion between Ihe uichloromethy l carbon and the carbony l carbon prest'nt in the pan::nt carbon)'1 com
Anllpsydlotics are drugs Ihat ameliorate mental abo~~ that arc characteristic of !he: ps)'chosci.1ne psyc~ from tbe milder behaVioral dis.onkt1i, such :IS thl' III diwrders, in thnt thinki ng tends 1 be: illogical, bll.am. 0 loosely orglllli/.c:d. lmponantly. palicnlS ha\'C dlffM.'lll1) ~anding n::ahty and tbei r 0"111 cooditioos. Tbcl"t 81\' hull ucinations (usually auditory) 3nd rJel U SlOns. In the sc hi lophrcnia~. in add ition 10 these s}m

pound.-::e
ChIQnlI hydrnle is unstable in alkaline solu lions. undergoing the !lit step o f the haloform n::action 10 yie ld chloroform

"
~

,(

"' Y
N

'Y

.,
.-

"I

01. M ike

~.

-, ,\

ulltd fK'S.I' ... r"''''''''''I$, thell' are ncglll;\" ~>mpcoms repc mente<! by apill"Y. <;OCtal withdl'aWliI. and :mbedoTll3. Cog8Ulle dcficlls nuy also be ~cd. p.,)choosc'~ can be organic and related \0 a spe.."iflC IO~'C mtmlCat ic_g., dc:linum produced by central anuchohncrglc ~nlS). an NMDA ;lIllagon;~t le.g .. phl:llcyclidinc), II dcfiIIOIe di~ase ~~ ('.g .. denlt'lllia) or lhey can be idiop.!Ilh.c. Idiol)'11l'lic ps}cho'\C$ may be acute or chronic. l<.Ii orwh1c acute psychOiIC reactions have been fCP'Jned to rollow nrremcly severe ~hon-Icml Mrc\s. Schilophrcllia is a group 0( ~hfOl1ic idlop:llhk psychotic di,onlcrs ..... ;'h the ovemll 'lmplomolOjlY dco;cribcd alMm:. The IeI'm mlliIIS)'COO/ic was ~Iow in gaming ~pUlllCC. ..... n ;5 widely aclmov.ledged that anllpsychotics actually IIimIm<Jllhe underl);ng thought dl'>Ordcr that IS the chtcf dlnctm$tlC of the SoChizophn:nia.~ The lIgenb often havc I tlIming cffect in agitated psychotic: patients: hence, they ~ ba\'e been referttd to as IIIlljor ml/rqulli~n, Finally.

was c.~abhshed, Dunng the same lime. arnphctallllnC-11)doced psychos-Is was Uelemlined fo bc: cau<iCd by Q\'c rach \'a lion of mesolirnbic DJ rcct:pton and judged to be the c\osesf of the varioui chemically IIIduccd model p"ydlosc$ 10 the
schiwphrema~.

~.

JI)'_

u"

muse they lc'iSC:n reacuvity to emollonal stimuli ..... lIh lillic cffM on coo'ICiou~llCSS . they an: referred to ali IItumltl,/icI. ThI: mo~t freqlk'nt uS("!; of the.\C agents are in tHanic disor~
lien
~nd the ""hi/llp/lrenil\S. In the manic disorders. the

,,~

, cf-

'r.m-

"imer

r1MIC

taSIe.
$).

MII\J

In :I and d b<. id.

ralion~

iditTer
Inx ICI)

,lty 11./1;e oflen

~.

'""

ap:nl> lIIay block DA at limbic O 2 anti OJ receptors. reduc ~eup/K>rlll. dclusionnlthi nking. arid hypcructi~ity . In the dIIook Idiopathic psyc~ (!>Chil.op/lrenius). both con\en(tyr,ca l) and newer (mosf are atyp.cal) anlipsyc OOtic IftICV 10 IICI 10 benefil po!>iti\c ~ymptolliS by blod.ing [)A ~ :md DJ Inobtc I1'n'ptOf'. I The b.l.<;('s of the atypical tJIIIP'\ lICIi,'uy again" ncgat;"c symptoms may be <;(,roIO..2~ m:rpIor (5- IIT:A) block. blocl ~t receptors yet to be .... mulled. and possibly decn-ased S-Inalal [)2 bl()C~ .I, JO A "-Ol1lpcloli\ e antagomsm 11:0. been ticmOmtruled :tJ O~ ., D. rttepUIl'S . Alo;o, in m:ombinantly upres!led rcccp"'- tn"~ agoni~m has bc:cn dcmCNhtr.ued. For this to ~!II vivo. a ground state of dop;mllll('rglc aclhily must \!eIM""n, Some preliminary signs indlcale this is likely.' In tt..: ~hl ~.Ol'hrenias. which ha" e an cxtremely tomplex J&I multiflll:tored etiology.J I, .'Z the fundamental Icsion np-!ICIl' 10 be a dcfeel in lhe bruin' ~ infumlalionalgal ing !1leChII ~hihl llbnormality in the 'tarlh: re,pon!>C' may be N III infanc)l. but the di"Ca!iC does Il()I enlC'Tgc until III !he sond decade Of in lhe th ird decade of life. BasiQIy lbephn, sy>lc m has dilTlClIlty discnnllnating between .xl im:Ie\'81l1 stimuh . i'ert:t'pt'on IS illogical. Profll)lll this, thought and :IC1ion~ bc:coIne illogical. AI_ thIl' actual slllICtural ()( nrnllomical k~lons (all: not .... the basic defect appears to In"oll'e OVCrnctJ\lI)1 of IopBlnrrgic IICUrollS in the mcsolimblC J)I<;tem . Some in-.ptoo IoUggC'!\t Ihal thi~ is the causc of mOIlI. if /101 all. I !be C\)lIImon symplOllls of Ihc iJiseasc. Negative symple.I_. !oCeial .... ithiJru."'al) may be tOl"idcred ....'toniJary 1I(MOOlli, Ollie" argue thut all or P."., of lhe foregoing i~ ~\ely n.'ductiooiSf. and tllat Olher Icsion~ cau'\C some: III of the symptoms. A. mJOf rt'ason for the recent imert'sl in the negathc of 5Chil~nia hoi. born the Imroduclion of M It ~ to typical. antlpsycOOt.n. T ypical anli, began w.th the scrrtMilpllOUS dHiCQ\ery of the dIQIlC actIVIty of chlorprom:l7jne. Many cuIOpounds ')1Ilhc~".cd. u~'Uall) .... ilh dllorpruma;o:ine as the model. tilt antlPSYCOOtIC poIcntialas.'iC'SSed A clear association the abilily to block DA al mesohmbic OJ reccplors

"*'anI

l1Ie cun"cntionallypicnl amips),cholic, are chllr3Cten l.cd by the prodUC11Q1l of EI''S, roughly approximating the ~)'mp toms of I'orkln'iOll' s dl.seasc:. These are re\'cl'loible on !liseonti nuing or (lccrell,ing lilc (lose of the dNg an(l are ussoc;ule(l wilh bloc~adc or DA al Dl striatal recepton;. Afler ~lhtained high-dosc thcTUpy .... ith antipsychollcs. a lale-appearing EPS . tardhe dyslillCsia, may occur. Thr o"cra ll symplOlmllology re.'\enlblcs !he symptoms o f Iluntllll1too ' ~ chorea. The con(li lion is thought 10 ari'iC from biological tOlnpen)allon (Increased O2 aell \lIy) for the striatal D2 block of unllpsycholic drop. AtypICal anllp"ycOOt.tS dale from the discoH'T}' of Clol.11pine. its anufl'iyeiKNlC ~nies and its mIlCh lowcr produclion ofEPS. Some in' C~I igIl\OfS expm;s concc:m lhattypical antip"yebotics, cspecially by producing EPS . inlroduce drog-induccd effect, that are hard 10 distinguish from ncgath'e symptom s. Thi s leads to Ihe vicw Ihal dimlni'hing EPS can accounl fOf pen:ci\'l'd decreased II('g~ti\'c ~ymptom~. It is, however. rCporll'dly a l..o more active again~t negalive symptoms of schi7.0p/ln:nia. ;oo.:pcndc:nt of redut! EPS, and has n umqlK: . notnbly c~pandcd. receptor blocktn, pr0fi le. Compounds are now under ,ymhesis and beinl tcstt-d atlhe ~ariou5CNS m:ept0fS3I .... hlchd01.11l'lIle ICIS lo detc:rmine lhe rule of these recc-ptor.;; III 'iChif.ophn:ml. Also conlriOOllOllo lbe devclopmcnl of IyplCal anllp5),COOtiC'S was the IIllrodlidion of rispcridonc. II has reduced EPS. has locreasc(l activity againSl ne3lm: symptom~. and. in lKkl llioo to liS OA blocling ubility. i~ a 5- HTlA anlagoni ~I One view of the drug is that it combines ~INClUl'lllly the features of an anlldcpre.... ..alll and an amip"ychollc. and so the ' .... 0 (lNg effl'tt~ are 3l1wned. Related 10 lI11s i, lhe \;1:'" thot 3 1 ita.,t some ncguti"e symptoms (e.g .. (lcpression. with (ll'llwul) are 'it..... on(lury 10 the pClI!itive sy mptoms. 111e \icw hru; nlso been Dlhulltcd. however. that 5- HTu rel:cptors are in~ol,cd in pan (the negati,'c symptoms) Of '" IM>Ily in seblt.ophtcnin. So far. the evldencc appears to be that 5-HT 111 blocking &genls do 001 relten posit;"c effects ofsch.zophre_ nia:lO The view that S-HTu o\'er;1iCti~lty IS the '-OUI'I.'C of negat"e <;ymptom~ (.,.." of the ba.~is ps),chom) is not d.sprovcd at preSCnt. though somc"..y it has born wca"ened.1(l One result of the de"clopment of alypical anhpsycOOtIoCS ha.~ bct-n a renewcd inlcm.l in models of psychos-is Olher Ihan the amphclamlllc model . In hne with pos~lble dual III \,oh'ement of 5-HT ~ntI OA. the lysergic aci(l ditlhylnmide model has bee" ciU:d a.~ beller filling ~h i1.ophrenill~ thun lhe ~lnjlhetall1ine n'KXlcl. But, Ihi s has been disptned. JIlten:S! in scrOlonincrgic involvement i~ still high and i"\'olves cltlCi daling the rolcs of 5- HTft alltl 5- HT1 receptors. Imerest remain~ in undc"taTiding tbe psychosi~ prodllCC'd by sc:vernl ccntl'lll anltchooltne'ilcs. MuscanlllC (M I aud M.l agonl~IS appear to offer lhe best approat;'h al thIS time . 1 1lIe rolc 01 the M, replor a..';tll'l synlhesls or M)-specirloC drugs .... f'hencycltd",c-",duced fl'iyeho:siS has ~n proposed as a superior motlcl for schl~"Phrema because u p1eiC:niJ both posilhe and negalivc ~ynlptorns. JO It sugge~tS th:it dcfieilli in glut3mincrgle fUllClton occur in !o('hil.op/lren.a, Rc~ulls of

r
agonl5l5 of NMDA receplOfli O"cl1Il1 rowe: IlOl been produclive: because of!he ucitJllOf)' and neun)loxic effect!! of the agent) teSted. IdcnuflCal;on of susceplible IlnplOf sub(ypes
:IS

largd$, II);"g glycine modulation or group I[ I!lelabocrupic

agonisI5 10 modulate NMDA recc:pton. h.a.~ been prOJlO!iCd 10 circum"cnl the problem~ a~!IOCiHled with the
rttCplOf

NMDA agQlli~'s. The ionotropic glutamic acid fl-Hmino-l-hydroxy-Smelhyl-4-isoxQ7.ole propionic lICill (A MPA) receptOrs are activated by bnin-penetr.uing ampak;nc~. There IU'C suggcS"'lions llull 'he.~ agents exen some amipsycholic actions by increasing glulaminergic octiviLy. 111c irl<hvidual amipsychocic compounds are !lOW consid rred. 1lIc ~ubsl iluted dop;Imine mOllf is useful as an organi1.111;01101.1 dev~ . Atypical antipsycholics are mdicau:d .... hen they occur. Future gro ..... h in this area ~Id be iQlcl\$ting.

M3ny potentially useful phenothiazine do:riv:lllvCS ha\'c been

phannacolOilically. Consequcnll y, the large body of information pcmlits accumle Slatements about the structuml fealUre~ awcinll'U wi lh activ ity. Many of the features were summnri~..ed and Intcrpn:ted by Gordon et al. " l11e bc:sl position for SUbsli tUlion is the 2 position. Activity increases (with wme excepl)on~) as declron-wlthdmwmg :wility of lhe substituent lncreasa;. An(llher possibly imponant struCturnl fealun: in the nlOR: potent compounds is the ~ of an unshared electron pair on an IllOn1 or liomS of thor 2 substituent. Substitulioo at thor 3 pl)SlIlOO ean improve actJvi ly over nonsubstnuled compounds bul IlOI as significanl1y as wbsllIulion al thor 2 posi 1100. SU~ll l ution nt posi lion I has a delelcrious dfcci on unups)'chotic octivi ly. as does ( 10 a lesser extent) subslitution utthe " posnion. synthesized and
c:valu~'ed

position S IS in II posillon :analogou~ 10 lhe l1-h)dnuyt d dopamine. and II WlI~ also assigned a ~ceplor-blndmg function by Gordon el al .~ A sublititoenl at posilioo 4 nup interfere WIlt! rttCplOI' btndm8 by the sulfur alom. The Ihree-alom ehai n between position 10 and the armno nitrogen i~ rnjuired. Shortening or l~ngtMn i ng lhe ehain_ Ihi, position dmsw.:ull y dc:<.:1\:asc:s acti~ ily . The thrte atOlll ehai n length may be necessury 10 bring lhe protonated amino nitrogen into proximity wilh the 2-substilUenl. As CXpl.'Cled, bmnchi ng with large groops (e.g .. ~n)n decreases octivi ty. as does. branching wilh polar group! Methyl brunching on lhe IJ posilion has a ,ariable effe<:! 011 acti~ ily. Mor-e important ly . the :llltipsyeholic potent')' of /(111 (the more octi\'e) and dalro isomenl differs ~atly. r. has looibecn I.en 10 wggCSllhat II pttti~ fil (i.e .. recct*JI sileoc:cupancyl is In\olvcd in the actionofthcseeompoundl. Decreases in sile from a dimcthylamino group{e.I..... 10 a monorrtelhylnm ino) gKatly decrease aehvlly, as dod' fecth'e ~i1.c increases. such as lhe 000 thm OCCUN "'1m NJidielt!ylomino. Once the fundamentalrnjuirement ofllli'f[ n'I'/' si 1 of alxlot that equivalent 10 a dimcthylamino i~ IIIlIIItairw:d. as in fu ~i ng N.N-d iethyl substi t u~nts to gcnerate I pyrrolidino group. activity ca n be enhnnced wi lh inc~as!III ch ain length. as in N rsub~tilUted pipcrilino COlnpooO<J.. l11e eritic:nl si1.e or groups on lhe amino alom SO~ the import:Jnce of lhe amino group (here protonatM ) U rttCplor attachment. l11e effcrt of the added ehain \cQP. ()I'I the eritleal sile requm:mcnt is md. could be Incrused affini l)'. II a~ to ha"e been I\:asonably pro>cd lhal tbr proIonated 5peci~ of the phl-nothiazines ean bmd 10 D~
rec:('pIOI'S.ll

1l"Y~Y"'l1

~10~ R, N
R

I , ' /. cA 2 -CH-CH2 - N\ : : I

R ~~

Ro-

Metnbohqn of the ~hlazil1("!; is complex in dtUIl bul simple o\emll. A major roule i~ hydro~ y1:mon of* tricyelie systcm. The u~ual pattern. for "'hich there an: p ehemical reasons. is hydroxylation pc,ru to the IO-nitrop illom of Ihe rintl OIlier than the ring bearing tile ciertrolilumcti ng SUbSI illlen! al Ihe 2 posi tion. Thus. IIIe major inltlll rnetabol ite is frequenlly the 7-hydrox y tompound. Thisl;(& pound i! funher mc:tabol ilcd by conjugation wllh gl\lClln.! ac id. and lhe conjugale is ucreted. Detailed re~ie"''' 0( metHboI itcs of phl-llOIhlumes (as well as SA Rs and pnar.. cokinc:tic: faclOl'!') are available.)I

PROOUCTS

The $ignirlClllICe of these substiluem effectS could be Ihal

the hydrogen atom of the protonatcd ammo groop oflhe Side cham II bonds with nn electron pair of an ntom of the 2 ~U~ljUlcnt to develop a DA-likt 1Itr.lngcmcm. ~Iom end Snyder. from X-I'll)' cryS tullogmphy. prop<bed thut the ehl ori ne'~lI""ti!Uled ring of chlorprorno:dne b.:Ise oould be ~lIpcr imJl'OSed on Ihe aromatic ring of dopmnine b.1SC with the sulfur O lom aligned with the p-hydroxy l of dopamir1cl and the ol iphatlC amino groops of the. IWO compounds also aligned.J6 l11e model used here is based on the ime~lation oflhe SAR~ b) Gordon el al." and on the. Hom and Snyder 1'f'OPO'S31 bul in"oIves the protonaled speclCS r.:llher lhan ,l1l lhe free base. l11e effect of lhe subsulucnl al the I position might be 10 interfere wilt! lhe side ehain's abili ly to bring lhe proton;aled amino group inlo proximity with the 2 subsli tuern. In the Hom and Snyder 5Cheme..16 the su lfur otom ot

11Ie strutturcs of the phc:nothia:dne below lIIl:l gi\en in Tnbie 143.

derivali '~

dtsaIbeI

Promazine. I'roma.dnc, I 0-[ 3(dimethylammo) prIJII)L (phenothi :lI.Irle monohydrochloridt (S~lrine ), WIIS IrIJIIdueed into amipsychotic therapy after its 2-chloro-\Ub!.ttIUled relmive. 11lc 211 sublilimc nt I'iS-{J-l'iJ the Kl substituent gives a milligram potency decre35C as an 8011fi't dIot ic, a.~ encompassed in Gordon's rule. Tendcney to EPS is also lessened .... hieh may be signifiC'oInt. especially 11'. decreased less than antipsycholie potency. Chlorpromazine Hydrochloride, USP. ChIoL ",_ 'dnc hydmdlloride. 2-chloro-l 0-[3-{dimclh) I:LrlLlJII) pyllphellOlhi:wnc monoltydroc:hloride (Thor:uinc).... .Ii .. first phl-nothluine compound inlroduc:cd into thcf1p)". h

~l\oIIrlt

N.m.

I'rop r~ t.ry

N __

".

Poop,",

DI.lky~mlno

"
a

Side Chain

f'roo'naMII hyd..",,01 bodo USP

5p8me -(CH.hNlCH.). HCI Clbpo,,"OOODl8 hydItxJbod&USP ~ -(CH.I,N(CH.l. HCI

"

''lr:h'

Thordanne hyctodWloode. LISP Mil lit M

, ,. d ,

M10" ...... '" $' ,,'6

! .:

1'"* LISP

"'".
PltxJbperazre m ' t'e.USP

,. " "I ,.
0<
~

1.

"""-

C'.
-(CH.),-N

LJ

"

N-CH.-CH,-OH

-(CH,',-N

" LJ

N-CH.-CH 2 -OH' 2I-ICI

_I
~

.ti-

tierul as an anli~ycholic, Other UlotS ure in nau..ca .. 11)111.11'"g and hiccoogh, It is the reference compound in ,,"IIY compari<;()OlS, thm is. the compound to which 01 hel'll .rompMed, The tlrug has signilicanl setlalile and h~po
If propcnie~. possibly reneeting cemrdl and peripheral ..:ndrcl1~rgic bJOI:king octil'ity. respectil'ely, Effects of ",,""'I anlkholi II('rgic acti vity are eomlllOfl, As wnh the pbenoth'aJ.mes, the effects of other CNS.-dcpressant .... weh as sedatha anti anesthclicll, can be potentiated,

and a greater o mlligf1llTl pocency lIS an antipsyehol ic, EPS are higher, The 2.cF, I'e~us the 2-CI is associated wi:h these changa, Ovcl'lll1 . the drug ha., uses analogoos to II\ol;e of ehknprumal.ine, Th iori d:l1,ine hy drochloride. 10-[2-( l-mcthyl-2-piperidyl)cthyl l-2-(methy lthio)phenothiaJ,;ne rnooohydrochloride (Mellari l). is II member of the piperidine subgroup of the phenolhiv.ines, The drug ha~ a relnllvely low tendency 1 produce EPS , The 0 drug has high anlicholrneTgic activity. anti this actil'ily ill the Slrialum, coonlerbollanci ng a w1all1l DA block. may be responsible for the low EPS, II also has been suggested Ihlll lhere may be illCreaseti DA 1tttpt:0I' selectivity.... hieh may

CI

."

:yPS

Thior;da:zllle Hydrochloride, USPs

be responsIble, The drug h:as sedal1ve and hypotens.ive aa ivity in C011111\(jll w Ith ch lmpr0111~1I.Ine lind le.s IInticl1'oClic IICt"ny. AI high~, pigmentary retinopalhy has been ab~l"led, A metabolltc of tile drug is me'lon d:lZI nc: (d ISCussed
nc:~ I ).

logica l I"openaes to the COfTtSpondlng phcnothlll1j~, Thus. thlOlhixcne (Z-N-d l lll('lh)'I-9-13-(4- mcth)'I - I -",~ nyl)propyl idene l1h io~an thene-'2-sulfonamidc ( Navane). di~ plays propcn.t'!l simIlar to tho!;e o r the ptpenlljnc Mlbp ... of lhe phenOlhiui nes.

M esoridazine Bpsy/a tp, USP. MesoridallllC be.~ylllte. I0-[ '2- (methyl -'2- PI pendy1kthy 11-'2 -( mClhy lMl11i n)' I) phel'lDtkiazine n\(jnoben~~nc:sll i fonatc ($cremilj. skares mallY PfflPtnlcs wltk lkiorid:l~inc:. No PIgmentary retinopatky kas been reponed. oo\\,eler.
Proch/orp praz /np Ma/pare, USP. Procklorpernzinc: mllk'ate. 2-ekloro- I0-1J-(4-metkyl-I-Plpcrui nyl)propyl lphenotkittlinc: nllllenlc (Comp"llne). is m tile piperazine ~ubgroup of tbe pOetM>lkiu/jnes. ckarncleri,.eU by high m illignlm unll!)lo)chotic potcocy. II hIgh prcl'alencc of EPS. and low sedalive and autonomic effects. l'rochlorpenui ne is 111<n poIent on II nlll hgram ba; ,~ lhan II~ 1I1J.:)'lamino coonlc'llan. chlo'llrO[llal.l llt. Btcau~ of tile hI gh ['Irel'ak'oce of EI'S . oo.... e'~. II IS u'\Cd rnamly for its unlicrnenc effcct. nOi for Its all tl ps)ChoilC effcci.

A dibel17.01V.ePlnc deri valil... in usc is 1o":"pll)t.Mll'dmIt e, 2-ehloro-l l -( 4-mc:lhy l- l -plpcrn7.lnyl)dibenz!II. JJ[I. 410~azcpillC ~uccinatt (Daxolin). The 5tructural relatlOMllp to the phenOlhia7j ne an"p~)'chotl(:s is apjXlrent. It " an effs: .he anti p"ychotk aMI ha~ side cff....:ts <,imiJar to thost 1\:' poncd for the phe11O't h,vll'IeS.

""-pM naz;ne, USP.

Perphemv.i ne.4-13-(2-ehlorophcnothia;eine- I O-yl )propyl [pipenv-ineelhanol: 2< hloro- l 0- ( 3[4-(2h)dro~yethyl Jpipmlll n~lJpropyl(pheoothla7jnc (TrilarOll). b an effectivc ullllp~yChotlC :lIld anTicmctic.

F/uphpnaz;ne Hydrochloride, USP. lbc member o f tbe pipera/jn(' ~ubgroup .... ,th II mnuoromcthyl group 3. lbe 2-posi llon of the pllenothla7.lI1c ~yMc:m und the: most potcm antipsychotic phenothlDline on a 11l1ll igl1lm b.a~is i~ tl uphena1.inc h)'dnxhlorick. 4-ll-12-ftrinuoromethyl)phernm n- 10)'11propyl l-I-plpcnllioo.: lh;lnol dihyd.rochloriuc. 10(3-14-(2hydrox yethy I)pa petnl ny Ill" up)' 11-2 -Iri n uoromcth)'1phenoth ill7.ill<' dih)'drochloridc (Pe rmit i I. Prohxl n). II is also avai l_ :.ble lIS ''"'0 lipId-wi uble t,ttl'!. rOl' dcpOllntramu<.eular injection . he: en~mhme (hepalt11OlC acid eslcr) aMI the decnl1OO lC: e)oter. These long-acting prepal1l1iol1s ha\'c u.e in treating ps)"choik p~uenlS who do not tale their mhutioo or are subject to f"'<luent rel:lp.e.

The dlben1.OcJillzepme deri V3tll'C: i5 cl<llll phlf (Clooft. II is not a potent anti~ychotic on II milligrJ111 ba,i. (I0Il the onentatlOn of the N-meth)'1 pipenlljno group 1"('11ll~. lhe chlori ne IllOm). It is e(fccl i~e ugai n\! both pos,ln-f.wl neg;!!j\... s}'mPlom~ of ~h l7.ophrenia und ha~ a low ICndtIt) to pmd ucc EPS. Then: an: lega l I't'!luiction~ on Ib IH( ~ cause or II relatively high fn'qucocy or agranuhJC)'tOlii~ AI a rule. two 0I1ler anhps),chotics arc tried be fore I'tCOIInlI therapy wi th c1ozapine.

Ring Analogu_ of Phenothia_lnes: '1doxa U.enes. Dlbenzo __ eplnes. and Dlb enaodlaaeplnes
The nng 1lIl3Jogues of phcnOlhivnlC\ arc: 51Il1CtUr.a1 re llilil't,s of lhe phc OOlh i~line nnllpsychoues. Mo,t , hare mnny cli nical paopcmes .... lIh the p/!cnothiuines. T he . hbenzod iazc:pill<' clO/~1 I)111C has some importun. dlffcrences. howcver. n()tably low produ ..tion of EPS and redllCtion of I1Cg ati\c ~ymptl}m~. II IS an Import:mt atypacal afltlPSYchotic.

JXN-,O
CI N---

N)
CH,

'--N\
Fluorobutyrophenones

Thlo thlJlene, USP. The: thim,anthene ~)'~tem d ifferll frolll the phenOlhilL'lIlC sy~tell1 by repla''C lllCn' of the N- I~ moiety .... uh a CMOOn mom -'oubly bonded to tbe prop) lKiene sldc chai n. Wllh the sub.-tltucm m the 2 po'iltlon. Z lmd E ISOIncrs are produced. 111 1ICCOIda_ .... lI h the COIICCpt that the pre!oCn tly useful Dnt lpsychoiic~ can be: 5upcri mjlOO\C:d on DA. the L ISOI11oCrs lire the: more oc.ile ani ipsychotic homers. The: compouMl~ of tile gruup ure \try ~lI1l1lar 111 pharmllCO-

The nuorobUlyrophc:nones belong '0 II "~" ~""'"", of COntpoonds. mUllY of which poo>se:.s high U;~~ activi ty. Only a fcw of these are used In the I whi ch Clln be misleading ubou t the importance of !he and its e\'ol\'ed relat jlCS. Thc 5t ~lUr.J "'<Iu~I ellW:1Ib ill

Optimal actlyity is

~n

~p-n\lOl'O ~ub<;l1lucnl IIIIlICuvuy i~ ,;cell. ullhough

who:n AR, i, an arumal,c system. aids activity. When X - C - O. opti-

OIher groups, C{ II}OI I and

C! II JaryI, alw give good activity, Whcn n - 3, lIClivn)' ft opt!!Il:,I: longer or moner chaills decrease aclivity. The

ibphatlC anlllMJ numgen is requin.-d. and highe ' aclivity is

lmI ... hen

>

n I) IIlcQrponned intO a cyclic form . ARl is an ~Ilf: nng and is nec<kd. It shout,J be allachcd d'I'CClly ~Ibe " position or (occnsionaJly) separated from it by onc -..cflIng DtORl. The Y group can vary and a$.\I~ act ivity. ."" UlIlIlple is lhe h)'droxyl group of h:llopemlol. The cmponc:d SARs could be COllqrued 10 suggest lhat ~ 4-11r) I plperidmo molC1y is .upmmpmable on the 2-

/Rl<perda.l) has the ~troctural features of a h)brld molecule bct.. een a but yrophc:nonc anllpsychollC and a tTVodonc-IiLc antidepre$~nt. It bcnefiled refractory psychoti c p.ll1em, .... Ith parkinc;onism control led at one-temh the dose of llnllparkmsoman drogs u-ro wl lh haloperidoL.oo COC:\I~ung an"'!:Iy and dept\'ssi,'e ~y rldromes ..en: a]so le\.c ncd. II is reported to dec~ilM: the l1<:gahl l' (l'.g .. wichdruwol . apathy) as " cll a~ the: positIve (c.g .. delu sions. hallucinatIOlI\) ~ymptol1l. of ..chi/ophrcnia. TIu s i~ rcponedly II con'>l.'ljuctw:~ of the I,:mnpound's oombin.ltion S-HTr D2 receptor antngonislic propcmes.. (}.cr.aJl the ' ","SOilS for the da:re:ts...d 1:.1'5 and dTa:ti ~ c:no:,s OguUl~t negative symp'olll an: Sl lll under in'c\tig:lIion. It i~ an imponant alyplC~1 antipsyc hotIC .

Risperidone.

R.spcrid~

. -0

IiX:n)lcthylllmmo llIoiely of dopamine: and. lIC('orthngly. wu!d promote IImnil)' for D: and Dl rcceptOl'l>. lbc long
\'-IIL~1 ulY.ilimcm could help prorlIOIc m.:c:ptor lIf1ini!), and produce receplor amagt)l1i~1l1 activity andlor in~c:rsc ago,>Ill"

,
The diphenylbutylpipcriuinc cla.~s can be conSIdered a modification of tIM: fll.lOrobutyl't1phe:nooe class RC.'<.'au\C.' of their high h)drophobll' dmr.acler. the compounds arc mherl'ntly long acting. l'enfluriOOI hns undergone clinical IriDI~ in the United State\. all(! ptnloOl.idc has been appro,ed for antipsychotic U!oC'. Olentll. ~Idc effa:ts for the two comJ'O'lnds re!oC'mble thoM.' produced by the fluorobutyrophe_
"~.

Some membc..... of thc: d:l.Sli nrc extrt:rne ly poIent antipsy dIou<: agems and O 2 and D. receptor nntagolllMs. EPS are ~Iy marLed In some nlem~N of thiS class ..... hlch

..y. In

to a poIem I)A block In the \trimum aI aJnlOl't 00 oompenc;;II01'y striatal anucoolme-rgie blIX'L. \be of the compounds do no! hne the ~tructur,,1 fe-atum; NO:lOIIed .... lIh efftive anlicholil1O:!rglC ach\ Ity

pol". be dtIC

,
y

'.

/IMop!rldol, USP. Haloperidol. 414-(p<hlorop/lt'nyl }4.II)droxyplperidone 1-4'-II-floorobul yrophcoone (Il aldol). potent anupsyclllxk usc:fulm schiwphn:ma and in psy. dioO\e' ~~.ocIJted .... ith hnlin damage. II is frequently chosen tllI: agenl to lerminale mania and often ust'd in therapy IIlrGille, de la Tnuretre's syndrome.

a.

a a
F F

v-

, ,

OH

CI
Oloperidol. l - jl - 13-(p-Ollorobcn. ].6-t!:lrah yd m-4-py ri d yl-:2 -benzi nl ioJv.ol i,";""",. may be us..,d al"nc as It preanesthetic neuroas hll !lntiemetic , Its mo,t frequenl use is in i (lnnmar) ",ith the narclllk agenl fenlanyl ISabhnta~e) prt'anc.\thelleaJly.

a a
F

~:-yCF,

./'OH

CI

p <

/J-Aml_ketones
ha\e been cl.amincd a.~ anll])\), cholies. They e\'olled OOt of m;c'arch 00 the 31~ alO1d lobeline, TIle o,'emll ~t ructu nd fc:tlun:s associated .. tlh acll~tly can be ~n in the structure of nloOlindone . ]n additIon 10 the
Se,eral ~lIII1inoket\JrlC:\

'.

"

P.amiooketone group. there most be an al)I group positioned as In molindone. It might be conjectured that the pr0ton on the proton~tcd amino group in these compounds Hbonds lI<ith the electrons of lhe carbony l ox)gen atom. Thi~ would produce. C' tiook center .....'o-atom disUlOCC. and an .. aryl group th.at could be 50perimposed on lhe analogous fealUres of protonated dop;Imine.

Olanzapine and Quet;aplne. OhllWlPInc: (ZYJRlI and qlM.'tiapinc (Seroquel) possess lri cyc lic sy~Iems greater c1c:<:tron dcn~ity than chlorprom:uille. They Ihlll J'l'. '>Cmble ek)l..apinc:. The drugs nrc al)pieal anllp .. ychol~

M olilKione Hydrochloride. Molllldonc h}drochloride. 3-(' th Y1-6. 7-<Ii hyll ro- 2_meth Y1-S- morpholl oometh y I ntJol e4(SHronc monohyllrochl oridc (Moban). i~ about a.~ potent an antipsychotic as trinuopc ....JJ.ine. O\cmll. ~i(\c effects resemble those of the: pheoothiannc:s.

'I

-s,~

'1 ~N-CHI

o
Ben._I....
1be bennmides evoln'd from obse ...... aIlOlis that lhe g:l>troprok inc:tic and anliemetic agent IllCloclOf'l""dmtdc: has anllps}chollc :lCtivily related 10 D~ receptor block. II was hoped that the group might yield compounds lI<u h dmllni~hed EPS liab.lity. This expcctaliOO appcaN 10 ha\c been met. A II bond bet ..... eell the amido H and the IUI,han:(] ell:ctron_ of the metoo.1.Y gnup to gcncrute a pseudo ring is eonsillcrell important foram ipsycholk activi ty in these: compounds. Presumubly ..... hen the protortalcd allllne is superimposed (Ill Wt of prolooaled dopamine. thi~ p!oC\Ido nng ..... ould superimpose on dopaml!1e's aromatic nng. l 11lesc features un be S<'('n in sulpinck and IC/IlOliprick.
O'emll. lhese two eornpounlls ,hott ld bind Ic~ "'. to D: r'CplOfS and pcm ll t mOIl.' rcc.:plor scl1"'ily n:ceptor subl)"JlC5than typical anli~ycholiCl. nll~ could count for decreased striatal D1 -blocking oclh.ly . .... ould prolIuce les.~ d,sron,rUf\ ill patients. It .... auld br . e~tlng to !itt testing resuttJ or lhe'\e drug,' actl' liteS 1M! brood rdnge of receptOfll. as lire pRSC.'ntly helng II('CII for c10lapHlC. Wilh respt.'C1 to the ulypicol antiJlSychOl ie~. I lon g Ulllle past may , hl.'<l .;ome li ght on the I I The fiel d of reliplake-inlllbning antidepressan ts aro5I.' o nl y II ,'cry small ~tructur:d ch:mgc was made In an.u chotic drug. and the 111.' ....' 11(11\"11> noted. (The 1IIl1l1'S) acti'II) remained.) So. mall changes ill Mructurc: ell ducc amlJlSycl1olic<llhat nrc IKII\I.' agamst dcpR:~"'\e . toms. Lilcwi ~. ~mall changes In structure could prO! .decllvity among D~ Il.'CCplON. Almo,I 40 year. ugo. il was notcll thaI I less unplea .. ant for patients Ihan ib ~ystem is far morc Iludoophil ie t hun I . t The I.'mphasi~ at the: 111111:. grum potency tric}clic electron ckn~lIy . ncll.'ao.at electron Iknsity of the thl!> Iowcr affinity. appeal'> 10 \ ;"Idate the: Ihlorul.uIIlC ~nd apJICu ..... to alluw n~ !iC11ivlI)' I)~ Il.'I.'eptors. Lc~S(:ning blocks on. for elllmpk. l\.'Ccptor,. and possibly mcsoconical D: rec.:ptro eoo ld prolluee drug, Ihat ure much Ie' .. unplcawlI (lalienl. Addiliolloliy. a less Jntcnsc: D1 block ~0II1d the effc:c,-~ of other blocls to male up IOOR.' of the lota l OClion (e.g . S HT trul"JIUf\cr block). Sc-o"ffl!l;';

RetnOx/pride (Roxiamj. Rcm(lXI prnM: " a D~ receptor blocker.40 It is said 10 be as dfective as haloperidol with fe ..... er EI'S. Negolive symploms of schi/ophl\'nb nrc duninished. 1be drug is e lasS/..'<l as an atypical lIntiJll'ycholic. The substitlM.'nts on the aliphatic am illO nitroiCn and lhe: ~ubo;ti tu enlS 00 the llIl)ITUIue ring are i nl~tlng.

prt!(ul ,,"Ith u~ re-

ic~.

have nngs with ellh~lIced nuclcopllility. Of ."(1IIfSe. otll<'r ~tructuflll fC:llure5 could be innuencing I"l..-:ep.. !If\e('tiVlty. fot example. illC"Tl:asins stene hmdr:mee 10 IMJlIOI" binding by lhe- protofUued amino j;rotiP Of 10 the IIIlJ binding.

.b~ycholics

AIIti",_k. Ageiits
LITHIUM SALTS

fie: lithium '\OIlts u:;ro m lhe UnilOO Stliles are the carbonate
klrlltytlnlle) and the c itr:ue. Lithium chlonde I ~ IlOl used t.:.:~~ of its hygroscupic nature and because it i~ more IIlWlIlg th:m the earbonme or citl'lltc to the GI tract . Tht IIth.e ~pecies in these salUi is the lithium iOll. The ...: e~f'lanallon for its IlIltimanlC IIC1I.ily is that II I"e'Cm Wa the sodlUl1I ion (as ....'ell as paln'isium. magnesium. and ~um ions) and can occupy the ~ium pump. Un like the mm ion. it canllOl mainlain membrane poIe-nlims. Ac'llllmgly. it might pre"em uccssi,e rclea.<oe of neurotrJns_ 1m (e.g. dopamine) that charncterile the IIIHnic stale . "-y of the: octions of lithium ion ha\e been revie .... ed .... lildlCl:1l1on5 for lithium salts are acute mani:l (oflen II ilh jlOIml DCuroleptic agcm for immcdlllle control. ~ince lithi\ ~Iow 10 t:l);e effcct) and ~ a prophylllCtic to prevent IroUTC"IICc: uf the n13nb of bipolar mal1lc~dcpres..o;hc il hie'" ~m sailS are also used in se,'CR: reeunalt unipolar ;ion.. One CffOC1 of thoc druB that nughl be pertinent 1rw;n,;t1oC' in the synthesis of pn:~ynaptic '\Crotoni n. Some all' <.peculated thai simply c\"emll!; oot tran~mi~lon. pre:. - . dm\'nllard mood ~wing. for CJlample. coold be a for antidepressant lICtion. 1kGu!IC of liS watcr :.olubility. the lithium 1011 is C.lllen \t~ distributed in body II'Pter. II tends to become in~ohed fie DWIy j'/I)'siological procc~ inlol, Ing sodium. pocalcium. and magnesium ions. hence. many ~Ide .1It~ aild potential drug int('mctiOlI ~ ('.Ills!. The margi n of ,trny is low: therefore lilhium ~hould be u..oo only when d.ltlelSCan be monnlli routinely. In lhe desired do>c _ effCCls can be lldequalcly controlled. use of lhe- 1 iCily of IilhllJllt. Ihere i~ ~ub~tamia l 11\. m. ...;IDde<;ign of ~fer C<JlnpoundJ. As more is learned aboul ; '$speciflC 1IC"l~ the li kelihood of slICccssful dc!.lgn a:mpounds designed to oct 011 ) pecifie t;lrgcts i~ in _~. Actually, carbamazcpine and "alprOiC acid ...... hich SlXhum eMnnel,. arc proving to be effecti vc.~ The.'IC drup are dio;cus.oo in the anlieonvul~nl sectiOli.

ron,l)

among uld a..:

,,"hi..:h ! intero\er a 1Ulnted e,'enh

toOO).

"h<:n
~tif")

Khoo;lI:i..:
In

pm

"1\

<.ym[)Ide

iMwm Carbonate, USP, and lirhlum Citrate.

Lith .:.bonate (bk:d ith. Lithanc) and lnhium c lll'llte (elbal51 lie the qllS comll1C"rcially ouilable in lhe Unned

OR ANTI EPILEPTIC
untiCQIII'ulSilllr and unllcpilc(mC" 111 this discussion. Stnelly ~pt"Ilk IUl anticonvulsant i~ an agent thm blocks e~ produced se izures in laboratory animals. anti
tcmt!l

an untiepileplic drug is II. drug used mediclI.lly 10 control the epilepsies. not all of IIhieh an: OOI1vubile. In humans. A classificatlOll of the lyJlb of epilepsy has been widely ~eptoo because its accuracy facllllllh:S diagno:sis. dru1. 50lection. and precise di<oCu~~ion of seizure di.wnlc[")."""" TlIe m:l.jor cbssiflCalion Iypes are (a ) genef'Jli7.ed seizure5. whkh ('SSCnt,a1Jy In"oh c the entire brain and do IlOl ha,'c an app;irem l()Cal onset; (bJ uml utend seiwrcs. which involve one en lire ~ide of the body; (cJ partial (or focal) 'lCi7.urcs that h~\"e a focus (i.e . begin locally); (d) CTTJtic seizures of lhe nc .... born: and (1'/ unclassified selZUI'CS (se"ere seil.ures associated with high IllOftalilY such Ihat tilll(' docs not pemlil a precise eluegonlalion). Two major type~ of genera lized seimres arc the gcnenll. i,..cd tonlc-clonic seilUte (grand 1TI31) and The ooooon\"ulsile SCIl ures 01" a~nce (pclit mal) seizures. The 1)'pl cII1 general ited 10nic~cJonie seizure i. often prcded by a series of bi lateral muscular jer\:s: followoo by loss of consciousness. IIhlCh in tum is foliOlled by a series of tonic and then clonic SPD-' IIlS. The typical absence seizure (classic petit mal) conSi'ilS of II sutlOCn brief l!h~ of cons.;iousncss. soolC"linll!!i ..... ilh no 1llOC0I" ocli"'lIy. although oflen \OIllC minor clonk motor acti"ty cxist ~. MajM I ype~ of focal (partial ) epilepsy Ute si mple foca l und c01l1ple~ foc:!l sci/urtl!l. A prolOlypic simple partial seizure is jacksonian motor t'piiepsy in .... hieh the jaclsonian march m:l.y be Stro. As the abnonnal di'il:lwrge pi"lXeeds o"er the conical sile inl'olved. lhe visihle seizure pn:!gresses over lhe are:. of The body controlled by the OOI'tical si te. TlIe complex partial sellUfe' is represellted by the psychomotoror temporal lobe: seizure. There is an aura. IlI<'n a ~"Onfused or bizarre but seemingly pulpO'\Cful behavior lasti ng 2 10 3 minule~. often wilh 110 memory of the c~ent. TlIe seizure may be mi<4iasno:.ed 115 a psychotk episode. This 1$ an 6trcmcly difficult epile~) 10 trcat. MIlCh effon has be<-n made m recent )e:l.1'I to develop drugs tl) conlrol It. For broaJ con,itieration of how SlrllCtUre: relate~ to IlIlticpi Icptic IClivity. lhe clas~Ificatlon of lhe c:pi l('ps~ is tradition ally further condensed (gencrali/..cd tonie-clonic seilures. . imple partial seizures. ~"Oll1plc!( panial seizures. 311d ub sell\:e seizurc:s ). The broad gencnll pallern of ~tructura] featurcs lISSOCiatoo with antigellCl31izcd tonk~donic seil.un: act ility is di~mible for barimurates. hydamOHls. oxazoli dlncdloncs. and wccinim ides. Thi~ SAR also applies to sim pic parlialloCi7.ures. It applies wilh less certainty to eontplex partial <.eizUR:li. .... hich are relati\"Cly resistlUlt to trc::ltmcnl. Wilh fcwer effecti, e drug entities. o\'eraU S1rl1CIWlII conelusion~ are more tenuous. The othe:r gencl'IIl sci1.ure type fot IIhlch a broad SAR p:llIem among the: Cited compounds CIUl be 'iCCn is the absenee scilure. These feawR:S arc citoo under the heoolllg. SARli Among Amioonvulo;.ants. Lile ..... ise. llIli1l1al modc l~ charncteristically dis('"em three tylX'S of acli vity: oclivily againSl electrically induced con ~"Uisions correlales with actil'i'y againsl generaJi1.cd tonlC -clonic and partial seilures. and acti vily against pentyienetctf'.I7.ole (PTZ)induced sei7.urcs OOf1't"I~tes ..... ilh antiabsence ktivily. Of lalt!. a fourth modc:l. activity against pi locarpine and kaln ic acid '\CilUres. is slild to prcdkl proteCtion agall1~1 temporal lobe epilepsy (a complex partl31 seizure). Each of the epalepsy types is characterized by a typical abnomlal pattern in the EEG. The EEG indicates sudden . exCClls.i\e eleetrical oclivity in the bnun. Antiepileptk drugs

IICI to pn:~cnt. Slop. or Ie.~sen th ... OCt" Ity. The precIse causes of the wddo.-n. e.\cesshe electrical dis.:hargc~ rna) be: many. (Iud noc all are unc.lc~ood. A worL:ing hypoche. ... is thaliherc i.~ a ~lle orfocu~ of d:i.malloo or abnormal and. con~l.ICn lly , hyperexcitable IICUrons in the brain. The~ can rlre ClC<'S' .. i\"ely and somelimes rocrull adpccnt neuron~ that in lum Induce other neurons 10 lire. TIle location and the extent of Ihe abilomlal firing delemlinc the epilePl'Y. An addition to Ihi~ theory i ~ based on the kindl illg model .... Experi mentally. a brier and _ery localiled electri cal )timulus i~ applied 10 a site III the broin, with loog imer\"al~ betwccn applications. As the prote!>S i~ repealed. neuronal aftcrdio;charges grow both looger and more inlense at lhe original site and al new <.tICS f:IT from the OIillinal site. It ... thought thai clwlges occur m neurons III the dio;charge "lie. and lhe'le neurons in !Urn ind~ manges in neuron) far rrom the sileo Progressi,d y more .se,.~ ~ilures can be indoced, and these can arise from secondary foci tlial ha,e been kindloo far from the ... ilC of stimulation. A major mtxleof ocuon of nntioon\"ul"llnISCan be positive allo ... teric modulation. of GAllA ... receptors. Thi s is prob;lbly lhe mode of oction of beluodinl.cpincs and a major nlOlk of lK.1ioo of barbi!Urates. On Ihe basis of lhe ~lruClurc of batbiturate. somc inorganic cation blocking lICtion would be cxpected as wcU-,oltagcgaled sodium clwlncl for phenobartlllal and cakium T dwtncl block for S,S-dialkyl mem ben;. OXlWlhdine-2.4-<ii0fK'5 (only tnmethadlone: remains) and succimmide$ appear to let _ia caklum Ttype channel bloc~. Some sodium channel block could be e~pected nmong phenylsubslIluled sur:cmimldes. "The majOr mode of action for phc'nytoin (and probably I1lOOOpllen) l substllutoo hyd:mtOln_). carbnnta7~pine. oxcarba.,.epint:. va lproic add. felbamate, topirJmate. lanlOlnglne and lOllisamide is reponed to be voltagegatcd sodium channel block and is In accord with IheirMruCtUres. Thi~docs not exclude OIher e~pected actions in some of the example.~. Direct block of ionOlrop.c glUtpm~lc receptors has so far not )iclded clinically useful drugs. Some ,olluge-gated s0dium Channel drug!' are reponed to be anhg lutamate as well by blocking glulanl;lte Il'leasc. Side effect~ of duttl ioootropIC glutamic acid receptor blockIng has been a ~ous problem. Ilecause of this. presem IIpproac~ arc to U'iC!he modulatory route. That IS. lessen ionOlropic glutam~te activIty b) (0) usmg drug_ that act at the glycine modulatory site 01\ NMDA and (b)devdopmg anlngonists of member; group II and group III metabotropic receplon nnd agonisisof meta botropic group I glutamic acid I\.'l:cplors. 1'hcse drugs ....ould lo ..... er ionOiropic glularninergic IlClivily. Adcnrn;ine. which mny be an endogenous anli~on\'ulsanl . oontinues to sef\e a~ a modcl hut. for reasons ~uch as poor brnin distribution and an lIITlIy of cardiovascu lar effects of agooists. h~s not yet yldded useful drugs. Elaborahon of roles of receptor subtypc~ may gi,c leads for drug de<;ign.

StrllClUl8

connlClfllO

antlXllW\.llsanl drugs

-NH

I
0 Qyp.nlo.1oe1r '\

An o'emll p.:iuem in the foregoing is that R and both be hydrotarboo radicals. If both R and R' an: alkyls. the lendency is 10 be 1ICl.i"e against absC'rn (pelil mal) and not oclhe against gener.!.I17.ed tOOIC (grand mal) or par1ial 'iCllUres. If one: of the h) subs4:itucms is an aryl group. IICIh'ity tends to be toward genernli7.ed tonic-clonic and panial i\eilUftS IOI! anuabscnce 3Clivity.... A cooform:uional analysis of the aryl-col1laining erotizcd tonic-clonic agenlS indicate~ that the COIIrOl'Jlo tional urTImgelTlcnl ofthc hydrophobic groups i~ imponat'l

B.rblturates
Although sedati\c-hypnotic batbiturates conlinonIY~~ lnticolwulsant ])f"OpCr1iClo. only phenobarbital and ~ barbItal display enough antioonlulsant select"'lt) antlCpllepUc.. For the wuctures of these agent . Table 142. and rord.scusslOll of chemICal jHOpulIt$$K* section on barbiturateS under sedatil'e-hypnouc-aru agems. "The metabolism ofphcoobarbital imohcs p-II) ylation. follo ....cd by conjugation. Mephobarbital is utens;'ely N-demcthylatcd in \)" is thought 10 owe nKl'\l of ils activity to the mctabohlC' pia barbitnl. In keeping with their structures, both agenb cffective against generali7.ed Ionic-clonic and pIUIi.II
1UI"I.'S.

ror ...

Hydntolns
1be hydantoin s are close stl"llClllral relat"es 0( the
rates. differing in lacking the 6-o~0 group. 11Jey rnonoac)'lureas rathcT th;m cyclic dioc)lureas. A~ qucnce of losing I carbonyl group. tbey an: "''' acids than the batbilunues (e.g .. phenytoin pK. aqueous \OIutions of sodium saJl5. such as of dium, generate strongly alblline. solutions.

SARs Among Antkonvul_nts

Se'cml major groups of shown below.
dru~

h;t_e the CQI)lIllOll suucture

pO.,......

ChlIptrr 14 C"lIml
hydro~ ) l

"""'<H<' 5," /"'" /:Np,.. ..IJII/S

SCS

group. 11le drug ha\ II spectrum of oct" " y ~m1l1Dr to Ih;u o f phCn) IOlll. II RI<ly wOI'S('n IIbsence loeilure.~.
A '~N_H

R~..,kA~

.
~=:::. ."--. 0...., 0-

"
,',
i; ;
i,

Ethotoirt. Ethotom, 3-cthyl-5-rhcn)'lh)'damoin (Peg<lROne). i. N-tkall.)lau:d lind p-hydmx) laled; the Ndc~lJ.y l mcwbolitc. prt' ..... ']\ably lhe IICli"e compound, is hJ.e .... isc ~tPboliled by phydrol()I~ tlon , The hydroxyl ~roup i~ lhen
cunJug~led.

_ ...
"
Z'.
=

0CH,-CH.en""

",
<><,-

The compound i used again~1 gCncT1l1i 1.ed <;eilures. bUI usua lly on an adjutlCtive bas,~. owing to its low potency.
In ,eneral. agcnts Ihm are no! completely bmrlCllc-d on Ihe appropri~te carbon have lower po!:ency IMn Ihc,r mo.-ecom pletely brunched COIlnlerpans.

Oxazolldlnedlones
Replacement of!he: N- U grou p al position I of the hydantOin sy~lem with an oxygen atom yiclds tile oXlQOlidine2,4dione system. The o U lohdinedione s)'~tem IS sometimes equated with aUlillbscnce octivi ty, bul Ihi trophism probably is more d ,ctated by .he faet that the re<j'Ulslle brunched alom of lhese oompound~ is su bstituted with IQwer altyls. Arylsubsututed 0~ a;tol idi ne-2.4-d,ooes MIC showl! actIvi ty aSllinst gencruJi7.ed Ionic -c lonic '\Ci LU~. The oxazohdinedione group of antiCOfl\'ul sants used clinically has shrunl. to one c l inicall y useful member, Toxicitil':'l assoc iated with !he: group may be: the problem.

0-

n",

"

"

Tbr:: compouoos hal'e I trophism toward antigeOl'raliad UIIC-clooic rather than antiabsence activi ty. This is not an
~hou ld
se;lUn:~

R'

ve lower

c-clonic lrot'arbon d,rected ~ and no!

...,..C,

actI\lty o f the hydantoin ring 5y!i-lcm, All of the cUicaily useful autigeneralized tonic-clon ic compounds !Table I ~) pos~ lin aryl substituent 011 the 5 position, ~lIlgl0 the br.anched lllont of the general phannaH)-dantoins ,.lIh lower alkyl subsmuents repon 01)' hase antiabsc llCe activity,

: anUi en onfonna portan!.'"

y display
I ~. 'or II!>C Ill!
. (;()Il\ult

~ ="" n~ iolyli<'
.. hydro~vivo and Ie phc:no~ent ~ ~

l'IIMyroin and Phenyt oin Sodium, USP. Phenytoin, lJ.dipben)lhydantoin (Ollautin). is the first anticOlll'ulspnt hlch it WILS c learl y demOllstra ted that anticonvulsant llCcould definitely be scparmed from sedallve- h)'pnOl ic m 'lly. It is often cited as !he: prime example of an anticon_ .cIin,IS I sodium chaul\Cl blocker, Il, " One cffccl i'.euronaI sodium channel block is to decrease presyna,t-ic acid release. gi vin, anticonvul sant IICtivity, " I\aoIbtr ,onscqucncr is 10 reduee Illutllll1lltc-illdoced is"'~ damage 10 neurons," '2 Tlle drug i~ useful agai nsl IIsrirun: t)'pes except absence. It is sometimes noted that fill !h, 1$ inoomplelely or errntically absorbed from ~i tes i'UniniSlllltion, This is due to its very low water solubility. IIellbob5111 proce-eds by stereospecific p-hydrollylution of . .un.tic ring. rollowed by conjugation.

""ric

Trime thadione, USP. T rimethadione, 3,5,5trunelhyl 2,4-oxMolidiOf'diunc:. 3.5.5-trimethadione (fridKmc:). was lhe first dru g mtroduttd specifically for tlt:ati ng 3bsence seil.ute.'i. It i~ import~m a.~ a proIOl)pe 'ltntcture for am.iabsencc: oompound~. DcmulloiogICal31ld hemalOlogiclllloxicities limit its cl inica l usc. The drug i~ metabolired by N-deITleth}I;'lion to the putati ve aclive metabolite dimelhadione ,~l Dimethadione i~ a calcium T mannel blocl,;er, Di IllI':lhadiolll': is a wOler.~luble and lowly lipophil H: compoulld and thllil i~ ClICrc-led as such without further mctaboll ~m,

A '~,0 A'
CH,

5 'l,A. a N a
I

SMc:dnlmldes
In view of the actil'ity of antiepileptic agent' such as the oxalOhdine-2,4d lOflCS, subSUMed succ mimides (CH~ rephacei 0 ) " 'en: a logical ehoice for synthesis alld eulualion. Three are now in clinical use,

p1ial <;e,.

;
!

baro,IU'

Ie

c) clic
COll-c

r orgao u; 3). Thu,.

) 1O!n ",.

therupy. It was, as and anticonvuls:tnt under the na~ NirvanDI . becauseof tox,dty, Presumably, mepha prodrug tnat arneliOl'lltes some 51.in and blood di~rs-of the inocth'a tion of mcphcnytoin and itJ; dernethyl by p-hydroxylation and then conjugation o f the

PhenslJxlmlde, USP. Sollll': trophj~m toward antiabscncc: acth'ity is altributed to the succi mm idc: system, 11le - Cl I 1- could be vie"ed ~ an a -al tyl brunch condensed into the nng. Phc:nsullim ldc:. N-mcth)'1-2-phenyl~uccinimidc: (Milontin). is ul.Cd primaril) lliain ~t obsence sei7.urts. but it has \ow p!l(etlC}' alld i\ relegated to secondary SUIIOS, The

phtnyl substituent CQfIfers 5(lnlC activity against genc:ralized IOnic-clonic and parlinl seiwres. N-demethyl:uion occurs [0 yield [he putative active metabolite. Both pi'lensul[imlde and the N-demethyl metabolite are inactivated by p-hydro}lyI3lion and ronju!ation.

III the (Z,icis-sulbcnc double bond. In human s. the cpo~Kk repol1edly is con~encd largcl y to the IOS. I IStrtulS-diol" The epoxide IS a suspect In the idIosyncratic reactions cam. nlazepine may produce (e.g .. aplastic anc:mia). With this .. mind. compounds de.~igncd to lI,oid the epo~tde sud!. oxcarbalpinc (T rilepta1) were dc,cloped.

""f!tnsuxfmidf!. N-demelhyl~t ion and p-hydro~ylation of p;l(C/lt and meuboIite occur. Methsullimide. N.2-d1methyl-2phenyl~UC'Cini m ide (Celontin). hIlS some use against abseoce and comp lcJl partial seizures.. Ethosuximldf!. USP. EthosUlimide. 2~h) I 2methyl5uccmi mide (Zaron.in), conforms very ....ell '0 the genend slI\Jl,:1ul'lll panem for antiabsence activi ty. TIle dru, i~ more ac::li.'c and less tOJlic than tri methadione. It is a c~Jcium T channel - blocking drug, Toxici ty pri m:mly involves the skin and blood. Some ofthl: drug is excreted intact. The major metabolite is produced by olid3tion of the ethyl group,

IS reduced 10 the monoh)droxycomp!lOlt undoubledly stereospecifically. The monohydro~y ~ pound is considered the mujor acti,c rt'lttabohte. TIlt ihc IS used against p.1rtial seIZUres. The major mech:tnlSll d action is ,.ooiul/1 channel block.

O~carbaJ.epinc:

Miscell... e.us Agents

I'rim idonc, 5-cthyldlhydro-5-phl'n}I-4j. ( I H ,511}- pyrimldincdiOfl(' (MysoliM'j. is !oOIlletimes ok~bed as II 2-dco~)'oorbi turmc. It appe ars 10 at1 ~,. through convel'$ion to ~oobarbital and to phal)kth~" lonyldiam,dc ( PEMA), ' 1be cfficat') i~ agamst all t)"Jlf$1I sciJ.urClj u~'ept ubsclJCc. TIle agcntlms g<ood o,t'r.IlI ~ but ~ 'iCnous toxic cffcct~ do occur.
f'rimfdon~,

U -.

-r.

M ..... rylu ...:r '

The two chemical classes. urcas and morooacy lureas. ha"e D long hiMory of producing compounds wi th anticon"u lsanl activity. 'The numerical yield of clinically useful compounds has not bttn great, OOWC''CT. Most of the simplcroompound~ have J(>OO by the way. For convcnience: o f youpin,. carb:!maztpillC and oxcarba7.r'pine can be considered N,N-diacyl ureas.

/H ,N , "'CH
N' H

'

Carbamanpinf!, USP. Carbamazcpine. 5I1-i1 ibenzlb.fl la1.cpinc:.5-carboxami(\e (Tegretol), for SAR discussion pu rposes. can be viewed ei ther as an cthylcneblidged I, I diphtnylurea or :an amioo.substituted tricyclic sy!ilcm. TIle two phenyl.~ substituled on the urea nitrogen fi t the pattern of anligencralil.ed tonic activity, The o,'crall shape of the molecule suggests lhe mode of OCt ion. sodium clmn nd block. Carbal11a1.cpiM' is useful in geM'raIi7b:i tonic- clonic and pan ial !iCilUreS,

"""""'"
Valproic Acid. Many carboxylic acids ha,"e ant"". sant activity. although often of low potclJCy. possibl) .. pi beclIur.e exlensi.c dissociation at physlolQgJCal pH~';' poor p.1nitioning across the blood -brai n harncr. VIIpIr ao:.:id. 2propytpentanoM: acil.l (Dt-palrncl, hn ~ and i~ used against SC:'er..1 SC'I.U!'C types, They mclOOe~" cal and alypical absence: SCI/ures and absence sei~ general ized tonie -clonic sei/.ure. Mechanistically, tht is a sodium cnanll('l blocker. This is in ~ structural fcature~. It i~ also reponed "'"'~"~, ' cis. again in conformity ,"'ilh Its Struclure. McuboIMt. conjugation of the carbo~ylie acid group lind oxidaUaI one of the hydrocarbon chaios. Many of tnc SIde eh:a
mikl. A rare. but poIentially fatal, fulmmllIe ~~~=' caused concern, however. One tends 10 look. to Mom (l to the carboJlyl acid as belDg lahile and g u toxiphon: .

The drug has the poIcntilll for serious hernalOlogicul loxicity. and il is used with caution, Mc1abolism I!locecds largely through lhe epoxi de fonnc<l

Chapter 14 Ctnlrol NUWJU1 S),Jlr", Drpfl'U4mu

507

--

I. lde

CH 3CH 2 CH 2 CH 3CH 2 CH,

VtJ/IptOt: Acid

io......

his in ch as

"cH-COOH

foct thllt llalXlpentin (Neuwilh incrcliSCd hydrophobic dliiiac tcr. its mech:mism of octKm does nOi appear to involve illlmlClion wi th GASA A I'ttC'ptOl'S. A binding ~i te on aIc1um clmnoels has bei:n identified. but !he mode ofaclion ri the drug is considered unclear. TIle druj: is said [0 have 'BOOO p/larmarol;inelK: profile and 10 elll6S the blood - brain Rna "'"ell. II was inlroduced for adjuncth'c lherapy of remory partial seilures and. set:ondaril y. gcncr.. li/.cd WIDic-clonic SCilUrelI. It Wall liIudied lIS a single drug lherapy for \'afiOUS o;e i2Un:S.-'"

~pentln. De<pile the ImtIn) i~ a relative of GADA

lafflOtrigine, Lamot.rigine (Lamktal) has been foond cffceth'e against rcfmclOry partial seiwres. It is said to act by blocking sodium channels and preventing glutamate release.~! II is a memm of a gfOl.lp of drugs 1 reduce gtula1m. male release and thus reduce neuronal celt death in ischemia. One trial .... ith lamotngine did 00\ detect stowing of the pr0gression of 1I111)'Qtrophic lateral sdl'rusis (AU). Anothrr member of Ihe gfOl.lp (sodi um channrl blockers .... ith amiglut:lIl1ale effccl). riluJ.olc (Riluld) (2-amino-6-(trifuroetnoxYr bcnzothiuole) is uJed to slow proglnsion . 1k bottle-stopper shape or both drugs is readil) :IJ'IPlIrent .
p

a "I

6 ~J , "'-1
H,N ' "'~ ""

....""e

COnl-

OH

drug ism of

lyl-4.6e~ de,h) lma ype' of ..afcty.

(Gabitrll), A glance lit til'llabille's ~tru C1\lrc "W'SIS an uptake inhi bilor, Reportedly. it blocb GA ll A r Telle:lS a major mode of ib anticoo>'ulsant octi> ity, Its .: '" againsl partial sci1.Ure.~.
_COOH

r~.b1ne

Zonlsamide (Zo~ran) and Toplramate (TopiJ~l(). Zonisamlde and Toplrumale ha l'e, respech l'l'ly. the: su lfonal11ide and sulfate antido as the small diameter end poilU' groupand an ntensh'e hydrophobic groupas the l3fge diam elCT end of the boule stopper. Both :are sodium channe l blockers. Zonisamide also blocks c.akiom_T channels and Topamu increases the dfect of GA BA and antagoni zes glu tamate Iminic acidfAM PA rtteptor.;. Each of the: drugs is emplo)'l'd adjuocu,dy agatn t parti:1I sco.urn.

o~

xh"""

~N

icon .. uly In pan mxIucC\ IIBlpro..: pOlelll:) IdclYpi un: .... ,m the drug \\oith il~ , SA Ie>' ~m i, b) .laUOIl of
'fech~

Fdbamate (FcJbatol ) has bttn used sucIlIIfuUy In refr..ctOl}' palients wi th genentliud tooic-c lonic and romplu panial seizures, The mechanisl11 of may in,... I"e lUI intrnlCtion wilh the stryehninei n-cnr ICplOI' on the NMDA roccplor,'" .. is al<o a sodium I blocker, T he drug is associated .... ith a serious risk 11.1$11(: anrmia. II is used .... ith eJ.tn:mccaUlion after other l'Ulsant hal'C been tried and a care fu l nsklo-bcnefil ~Wtnt ha~ been made.
p

Benzodlazeplnes
For details of lhe chemiSlry and SA lts of the benwdiue ptllC\. see the discussion of IInll.iol~IIC-scdalil'e- hypnolic dT'Ug~ Among lhc present dinically useful drugs, the SIruc IUm! features associated with antiCOnvUISlUlI activity are idcmical wilh those aSSoOCialed wilh aru.iolylic- sedaIII'e- hypnOlic octivily,ll Animal models predict that benl.oed di11lepines are mode~tly cffeclil'e against iencrlllil_ ton ic-clonic and partial SC'llUrell and I'ery hiih1y &elll'e

lilt;' ha.~
l)'d~

:nerulinl

IIgainS! absence sciJ!ul\'S. Th.~ difference in seizure control tIt)J,.~m diffen markedl) from th3t of the barbiturutes. h) dantOiIlS. and fTl()l;t other chemical CQmpounds ""hen they are lII)'l or diarylsubstituted. [)csp.\e the hilh effecti,'encss of benlodiazepines as D group In al1lmal moods. only a few ben~OOiazcpine!l have achieved e~!ablishcd po'iitions in anti convulsant therapy. Beo.-ause sclech\e untiCQnvulsanlS should be 111I3inable among agcnt~ acting at GADA A DcnlCldialcpillt allosleric modulatory ~i tcs. Ihe number may increa.'II;l in the future. A problem wilh the bcnloo.lh17-cpines ha~ been decreased cffectheocs..~ O\er tirnt. When physiological adaptlltlOn of this type occurs. il usually happens with seliath'c agents. If sedation wcre divorced from anlk:onvulsant action. possibly the laller mighl be sustained.
Clonarepctm. USP.

,
6.
7

..
Q.

C.....,,"'.

10. 1I 12.

plOd _ ......nd U'" ' c ~ t. .. ~ at olcobool Md _: :1 ... MY SIOClIrno. ""~. 4 n35. 1119] ~1Jt .... I( "" 0 :01 ...... t.eua. In Wolff. M 0 1.... , a.,:r Mtdoc:IW Oiaa,wy.,.., ilL ..... <d.:s.... Yori.. JtM lli llc) 1981. P. I>2lI ..... rrl......n IbrmLl). .............. f II . Ey""l. II~ -.I M J The 1(..... '" a..11 M......u 800kJsy ~"..' Y<d. John w,ley a Som. 19$-1 .. Cohtft. L" St J A""""II. 1'173. SIo<~. 1. O. 1_. ..... Slnmin. L : """~ 6l; H4. IYM. M. J .. ..... M;>:".,. It L.: M~'" 2251611. 197] Ihl!. H A. J l'lwmlOCOl Elp. Thet 2OJ:191. 1977, lk>lIld1y. J) It . " II.: Anr>~ 4ym. 19" '01','....J C .. H.,*,,,!. S_ 1. II . ond l)olllhiet'. C .. A, .. ' 4

"s-.

I'ob_. jO;66,.

,, "I..

OS)' 63~7. t 98j,

0.""".

13. TIUL,. K S.

WId~.

I. Il.; Aadu. lIop Mod 0.... JUI

C"Iotw:epam H2-chlorophenyl}-3-

dihydro-1-nitro-21f-IA-bcnzcxhupin-2-one

(Klooopin ).

partially select;I'e at benzodiazepine allostme binding siles on GABA... recept~. ill useful in alnence foC'ilUreS and in m)'oclooic seil:ures. Tolerancc to the anticollVulr.ant effect oftcn devclops. a common problem with the benzodiazepines. Metabolism involl'Cs hydfOll:ylll1ion of the 3 position. followed by glucuronidation and nitro group rcductioo. followed by acetylation.

I (""""'yN-C

14 1I...... J K_ _ J.... C.It.: Lif.S<' 68 ,6II . :!OOO L5. Wei. . . . .. D R.' N En,I. I Mod.).44 1241. 2001 16. x . II .. .. al. J Mod. 0.:.... "", 18Il.I. 2001 17. X lt. . .. aI. I \lot B,,,1. 29(7)9. MOO II. Itt1Wd.S . ftaL I BIOI. 0.:.... 2741331'0. 1m. 19 lluhr. It .. It 01.; M.... P1>onRocoI. 49 101iL0. 1991'>. 20. lluhr. It .. .. 01.: Mol. ~. '2'672. 1997 21. Buhr. It .. .. 01. J Nturochtm. 141310.. 2000. 22. S!<mb.ocb.l. II In GInn," . S.. Mu .. ini . 1!.. 1tIII l1onda1L. L 0 The Ikfowdillpt ...... New Y.n:. Ro.,'"" Pm>. 1972. p. L 2J. CIIik\tuo. S J. An~..,.iely IFill. In Wolff. M F (.... ), IbrJr _ Modicillll Cbcmi,uy. pouI lJI. 4111 I. N... Yor\. Wi~ -.I ~ 1981. p. 981 24 ~bL"" D. I . Ilt>d Shookr. It. I.; Btn'.oduou1"""' In au"". " I""" Nt... "'<d. Itll'"" I're!.o. 1974. p. 11 (Mel "$ II 25, Oou JJ ", J) J. SIYder. R.I_ and Itb."klb)'. 0 11. " e,.t J MIl ~34'. "10, 1983

""

J'*'"

",f.",

ON~C-N ,

CHz

_ In T c .. ..... Joo .." 21> DIIolw:Io. Doa ... R.I', (td.)..

",('el

Mtdic",,", WId ~ .... ppoll<:Ol1. 1982. p . 33~. 27 Bt, F M ~ and <lIber E.. _ I'cAIC>!. I. S (...... ), ~)... hoIl.. ' ..

;.:~'_~"':":"~~~~.:::~._~~~~~. ....
<d.

28.

c...... 0 I. arid twnrno..I.O. S.' yon.. McGro .. . IIoLJ. 1964. po m.

1962

yon.. MorNl DoUet-. 1977. P. 1089

o:u"" 0...,.. ....

29 MxtiY. F. J and Cooptt. J It .: J. 1'hatIIIIroI. Elp. TM 1Jt11l

Diazltpam. For details on dial.cpmn (Valium) sec its di <;cus~ion under anxiol)'lics and sedativc- hypnotic agents. The drug is mainly useful in treating generalized tonic- donic status c:pilepticus. whIch is an ongoing and potc:ntiall), fatal gentTalil.cd tonic: -donie scil.ure. Chlorazepate. See the detailed diseussioo of c:hlorazc:pate rrran.\cne) in the <;ed:uII'c:-h)'pflotic:-anxiolytic oCClion. lIS principal anticonvu lsant use i, adjunclivel), in c:omplex partial seil.ure5.

30. l1(>'oOky. M. ll riw.... L. L and I\UI>OO. P \I J ML, " ". .,e,

)t

12. 3}, 34 13

:!OIII. Kort-. It .. .. 01 . I'Wc NOlL Acid. Sc>. lJ S. A 9U6~, Lc-.. ,.. D. A Pro<:. Nld Acid. Sci. U S It. 98;4!<)1.:n:n F.Idtr. C. C ; Lif. Sco . 68:~. 2001 ............. J .. .. 01. U(.. Sci. 68 :2.1.49. MOl. GonIon. M . Cool: 1 T~ D H. - ' Tt<ItW, It. L _ _

"""""'. Lllii. t9b.l l6. Iklno. It. S. WId Snydn'. S H. Pro<: ..... h.t 5<'> U. S 2.\25. 1971 31. Miller. D. D, .. 01 J. ;\1tll a.m.. JO: 11U. 1911
38. 1(. . . . C_

-c:"';:;,"'!!:"';,._:';;;",,:~hobc4110 ed. No..Wolff.... ........]a ~' pouI ltI.

COftdllslon
Olemll. there has been progress in rel.!c:nt ),c:un; in the int~ doction of antisc:il UIl! dru gs. M O~1 of Ihe progress has in~ol~ed voltage-ga led sodium c:hanllC l blocking drugs.:M> Good reviews an: availabtc:.J1. J.I

"

REFERENCES
t SoI- .. PO .: _ . It.,.-. 5]:119.1001 1. 1.tIr\jpw. B_ -.I ~ It. III' . Suod..,. ... "", .....,...,.... !If 1IIIIn<I_ at oct IOU ..... OABA .. ,_...... Ad .... BlO<hetn. P.)d.,I....... cd 47;J6!I. 1991. 3 Cbrbrb. \.I ....... .kiIIMoofr.. 0 It It. J Mod. Chem. 43 1427.:!OOO , ""~."..." F.. A.uayu. L 0 .. ""11, ... 0 .. .. aL OABA- """ JII>-

.ut_
.,
I~I

110 ..... I. '" t ..n S,""""'UIJI'

I IMemIlI<lILII F.n<).koptdo. '" 1'1",,,,,0<01,,1') - ' ~ r-c .. '1'00.. Perz''''''''' 1971, r. ,I C"""",.,,,,,, ,,., 0...'(....1I0Il on.d T"'''''no!ofr ,." lilt I..........".;d 1 'Fl. Apo ... .. Iop<o) ""'''"''''" lH8'9. 1981

o.u,....."

H.
~M.

1>1....,.. I)

J "'",u.lI.p Mod. a...m U:R IWI An,..-. T .. MOOg< . IJ J . ~h,n . M .. on.d Iti&bl!. 0,: J Me<!. Chern .
.l.j11~.!OO1

",oJ"n. l.

N~,. Vorl..

Ih.,,"

f're""

SELECTED READING
Ooo:bob, M., ...., ",.",..",... 0 A II (jA 8A" " , _ I"...,. pled MlII elu ....!,........"'i ..1 d><"'"i!) and bI'*'I!y J Mcd. Cht:m.
nl~27.

Clow .... J .... SpKI-. \1 It ,,, ........ IN II (nil M..Jj""""

Omo\lr). mI ~. " ..... John W,k) It. s... .. 1%1. P I. I "''''''' .\t. G. I)dina. J It.. IIIIl ...........,,',. P II J />11 a..", N' '4l. 1\1116.. ...,..C. F.""" 11m... P A.' "' ....... II.,. Mod. Cbem N.ll. 199-4 1 KoGrfel.T Kuhn..R . _AJlIl ...... JLJ Mod,Clot", JlI-1 4 1J.I~ m:l Il H~ -.I Om.... """", II M._ "' ....... _ ~ . "",.. '" UIII. 19'11 II<II"".~. G .. \leni. G. 011"1'1'<. C.. .. aJ J Mod. Chrm J0768. 19111 5pool.... A......a W. .",. W S. In EIl~ G P ...... .... <1oI. 0 B. lod,)..

,on..

:!OOO

"",""'"L:w

Coofoni "I. D P. "'"'1)0 .hl I A_ """ Scban..-. E. I. ROftIII~. in """"poltpu< ..... 1l w.earrlI. Annu. Rep MN. Chc:m Ubi. 19911. R",,~Ity. M ~ lin"""". L I~ H~. P II. CUf'ft'lll ... _eI . . I"'*hn 1<1 III<- . , . 1 ..,.._'" <tl .................... J Mod Chcm .u

..w

.n,lOOl.
33 11 9.1001 W.. r>bt<J<1". D R " .,;.or II tile
1 Med. 3-U 12-17. 2001.

1'" ,.." .. ''''''''',~Chrm,'''Y, ,,"..1 "' "'tllftltun. OC. flun ..... ..,.",.

Sinn.... P G. : A""p')"hoIiI: ""'.... ,~ o/ll<If*none .. r", .....,,-,,,,,,, 0/ tIIct...,...><" .," 0111 and ~ off""lJ. 1'IIamIxoI. R.....

C<....,.

(96). p 261 CoJml. /10 0 P. '" 01 AanII. ittI' Me'!. Cbnn. l}:t.l. IWI!

"'' 'l>rr '" rnoIoocul.. modki.... N &osl

<

1 5

Central Nervous System Stimulants

EUGENE' ISAACSON
Thi s c:haptcr di~u''''5 a bmaIJ range of a.!'enl ~ that stimu late the c.:nlnll IIeI"\ oos ~ystcm (eNS). TIM: Qnaltplit:$ (" la~~icaJly are a group of lIi;cnls .. ilh a homed range of list: because or the general natu re of the-iT effects. 1lIc "~lhyLumlhinn have polen! 5t imu l ~tOl)' proper1ICS, malOly cortical at low doses but wilh morc ge neral cffcct~ as lite dose i~ incn'ased. The umml ~\"",pulhfHmml'lk ugt'nlS amphcwmine and close rclali\'~ hll' c a1ening and Ilmidcpn:slI.anl II"'PUlie'! but medically an: used nlOl"t: oftcn as 1I1101'\:.l;antli. The
""/Ji/CpTt'$$<JrIf dm~s

are used most rrequentl y In dcpn:~ sil'c disorden. arid ca n be broadl}' g rouped into the mollOamine oxidase: mllibitor<i ( M AOr~). the monoam ine rcupIIiLe mhibitors. :lIld agents acu ng on lIUlorc:plOI'IO It. ~ mall group of miscellaneously acting drug ... which loclude<l a number of IllIlh.lCioogen), cocalllC. and cannabiooids.

Penry/enetetrazo/e. Pent ),Ienc:tetl'llloie. 6.1.8.9'1('\110 h)'dro-51f-lelrvolo/ J.S-a / a/.cpinc:. 1.5-pc:nlamcib) lene\tl ru/olc (M euwoI). has been used in o;onjullClion .... lm .. ekeuoenccphnlognlph 10 help locate e pilepiic foci. It is M a.~ a labOl'lllory 1001 in delt'm Ulling poecncu:s of ~1lIlII nnticoovulj;(ln l drugs in cJlpcrllllent~ 1 anima ls. lbe drug i1CU as a c()fl\"ul~nl by interfering with chlonde eondUC'laln.: It blllds 10 an allostaic sue on IhcGA BA A ~orand .... ~ a negaU\'c modu lator. (hcrdll. 11 apfICaN to 5h~ Slmfllr c ffts o n ch loride cooductance .... ith sc,'eral ocher CI)II\~ slvc drugs. U1el udi ng piemto xinm.

cool'lude!l the chaplC:r.

ANAlEPTICS
The ImdniCHlal analepl iCll an: n I!roup of poeent and rel~ll\'cly IlOnsel~li ~e e NS ~ limuI 8n lS. Tllc con,'ul" ve dose lies ncar lhe, r IUIlIleplic dO'oC. "They can be illU~l rated hy picrQIoxinin and JX'nl),ieneICII'll/.oic. Boih are oboIole!e a.~ drugs bul remaUl V' iLlabiC l'CSt'arch lools in Iktcmumng how drul!~ acl. d Nc ... cr agenb. nMXbfinil and do)(Dprtlm. an: moo: <;eke",'c und ha'c LI..e in n:.l\:o lepsy and as respiratory stimu lunlJ;.

Modafinil.

Modafim l ( I-'ro~ igil) has o"erull ...~ De)$- promollng propcnies similar 1 !hose of ccnual ' ) - ' 0 lhomi mClklo . II is considered an atypi cal (t.-norepiIlCJ~'. (NE) receptor ~t imu l :II"1 and is used to treat daytime ~ ness in narcolepsy palicnh. Ad"e~ reacllCHI~ al thet'ajnli. doses are reponedly IlOI .severe and may IIldude om~ ness. aMiety. and IIlwmn ia.

Pi<rotol(in.

l'io.:I"OIO'(lI1i n. the lICti>'c ingredient of pkroIOMn. has lhe: follOWing structure:

"'6
H /

',0

,
"

' , '', ,:,"c=o

"

--'

'

"'0

....,..

According to Jarboe et al .. 1 the cncircled h)dro:c.)'lactOl1)'1 moiet y i~ mandalory for \lC!I\il y ..... lIh the: en.circ lcd 2-p!opcnyl grou p a_sIStl ng. l'icrotoxinin e ~ens it, e lT~ts by interfering .... ,ith lhe IIlhibitof)' effecl' of }'-3l11inobutyrie acid (GA BA)al lhe: Ic>cl of the:GABA ... ='Cplor'~ chloride channel. The drug is obw1cIC medICally. Phannacol~kally. II 1Ia., been u.<.eful in detcnnimng mecltani,ms ofactiOl1 or <.edali vc-hypnotic~ und antioonvulo;ants. 8 utyn:llaclooc~ b.nd 10 the picrQIo:c.inin . (le.

Ool(apram Hydroch/O,itk. USP. Doxapnlm. -2 4 -( 2 -nlCH'pholl OOCtlt y 1)-3. J-di pile n y 1 -pyrn lid i I1OI'Ie .,.. .:hloridc hydru lc (I)opmll1). ha s an ob~ u rc nlOiu l;u lIn lsm of 111:11011. O verall . 1 stllnulates 011 pcriphC'r~1 elU"lllid ehel1lOl'eCCplOfS. It h:ls u...e tory stimulant postancSthetlcally. ovcrUosc. In chronic obstrueti~c Ihe IIpnca'.

51.

Ch.p!~r

15 Ctmrol ft/,n'QUJ SYSltm SnmulilnlS

5' 1

.etfa

,,'" ....
~.

*l:tet-

MTHYLXANTHINES

mlial

;act\
IlICl~

TIc ~urally OC'CUrring

melhybanthi~ a~ caffeine. tnc:-

"yllm.... and thc:OOrominc:. Sc:c: Table 15 1 for lheir stOIC' and OCCUITI,'IlCc: and TabLe: 152 for their rciaul e poten. Clffell1e IS a widely used CNS stimu lant. 11leophylllnc: IOnlI: medical use: as a CNS stirnullllli. bUI its CNS. amulal1l propcrtic:li are ellCoun!ercd more often as some"'" 5tIWe, and pote ntia!! y lifethreateni nl:. side effect$ of ~ in bronchial asthma therapy. lboobrumine hus very :.ale eNS acti vily (probably because of poor physilchcmi. p'optllies for distribution to the CNS). Caffeine il often used as il occurs in brewed coffee. Irn'l'd 1<'11.. and cola beH'ragcs. In most lubjts. dosage lIS 10 250 mg of caffeine acts as II l:()I'1ieal stImu lant and 1ac~lUIL'Scle3r thinking and wakefulness. prunlOlel an abil10 oonccntr"te on the task !II lund. and les.ens fahguc:. '" lilt m IS incn:;l5c:d, side effcct.~ ondlcaung e.. ~esslve _~hOO (e.l .. rcstIeSSIlCSS. 3lll1iely. ner\,(>II~ne~s. and _Iousness) become more marked. (They may be p~sent YII)'lng del:l'reS at lower dose lelel~.) With further in~ in do!;age. convuls ioos can OC(:u r. A rcview of the ICIiOrr.. of ..:uffeine in the brain with ~pcd a l re fen:nce to it:wlr) thai contribute 10 liS widespn:ad use ul'I)eaJ'll to be
IItf.rt.~e.-\

mllar mul

keful-

fmpa

)brine: Ilc:epi pculi..:

".Oth

J'hr CNS cffecl~ of theophylline ut low dose levels ha"e

tIIU 15-1

X"nthine Alhloids

been lin]e studied. At high 00scs. Ihe uondcncy to produce convulSIOns IS greater for theophylline than for caffeine. In addition 10 being COI'tic,,] slimulanlS.. thropnylltne and r.r.ffeine are medullat)' shmu lants. and both are used as such. Caffeine may be used In trealing poisomng from CNS-dc.-press&nl dOlg though il is !lOt prefer=! drug. The impo!1anl use of theophylline and its pre]XIrlluon~ in hronehiol aS1hma i~ discussed cI~whc:re. Caffeine "Iso is reported 10 have valuable bronchodiJacing properties in asthma. Finally, bct:uusc: of central ~asoconSlriC1ive effects. caffeine flUS value in lreating nugraine and tcnsion headaches and may ha\'C actual .nwgesic properties in the lallet use . The CNS"limul.uing effects oflhe melhylxanthll1CS were 0IlCC attributed to their phoo;phocbcstC1'llSe-inhiDiu"& ability. This IOCtion I~ probubly im'le\'3Ol at theropruuc doses. E"iIkIlCt" indicates tRat lhe ol'crall CNS-stimulant IOCtion IS relaled more to the ablilly of these: compounds to IlIIlagoniLC adenosIne lit AI and A, ,, receptOB,'-' I> All of the mIc:li of these recqMors are sull un<kr sWdy. 1be adcOOSUlC I'ttt'ptor subtypes and lheir rharrnacology ha\'C been reviewed.' 7_ ' Problems "",th .he pre~m COl11pound.~. such as caffcme and theophylline. arc lack of I1,.'\,!tptor selecti vi ly and the Ub,qUItous nature of the varioll' reccptor sublypc.!'. C affeine :Ind theophylline Ra,'e pharmaceutically unpor tam chenucal propertIes. BOIh are well); BrtlnSlcd bllSC$. The reported pK. vul uts are 0,8 and 0.6 for caffeIne and 0 .7 f theophylhne. These \a!uc.~ represent lhe bllslcuy of the imino mtmgc:n 11 position 9. As ilelds, cafftine ha~ a pK., abol'e 14. IIlId throph)'lhne, a pK., of 8.8, In thcophylhne. a prtI(OII can be donated frum po:;itlOfl 7 (i.e .. it elln act lU a Broostcd acid). Caffeine cannot tion.'lte a pnXOI\ from po<;" lion 7 and doe, IlO'l act a.~ a Blllft'iled acid at pll I'alues under 14. CaffcillC dot'~ ha.e deciroplllhc ~ite, at pDSLlioll" I. 3, and 7. ln addit.ul1to Ll~ 8mn~led acid sile at 7. throphylltne has electroplliltc Slles al I and 3. In condenscd teml. hoth eompournh arc electron-p;tir (\oIlOn', but only theophyllme is 11 proton dQrnw in n""'t ph~rmaceuticlil ~ystelll~. AlthouJ,:h hoth compounds are qude soluble ill hot water (e.g .. caffclllC: 1;6 at W"C). neither i~ very '01 uble. in waler at room IcmpcrulUrc (caff.. ulC: about I :40. thcophyll me ubout I : 120). Consequently. a lanct)' of mill tures COonpk:lIC) designed to lnerease \OIUblhty are 3,a.ilable (e.g .. Citlllted caffeine. caJTe.ne and sod ium benzoote. and \heoph)llillC ethylenediamine compound [aminoph)JliI1C)). Caffeine In blood .s not hIghly proiem bound: Ihco!*'yl. hne i) about SQ<l. bound. Diffcrences in the sun.,utucnt at the 7 posnion may be lU'oiled. Additionally, e:lffeme ,s

A'N 6
I; J
~th) l

~o ,. . r
N

g7

O#<:.N

h}'d,,'"

II1CX h

(R. R'&R .. H)

""".....
,.
C><,

TABLE 15-2

Rel"tlve Ph" rmacoiogical Pot~nelel

of th~ X"nthin

-c:sp.ra nl dOlg and on

"""'"

,
CH,

'"

cam..-. Sourc_
T.
CcIIM.t..
C"CQI

Ca'I : . .

tH, "", c". "

TIOC4A .....
ll'eubiW'LII"
' I . ""'"'

.' ,
2

-,. ...'" . ,- ,
Stl..-

c........

01....

ShC.t.Iol .-y C d lac MUKt DII. Stlm .... 5tl_

NIh U1ion tatloo\

,
2

, , , , ,
2 2

""Ion

,
2

"""*_

more hpophil ic than theophylli ne and reputed ly achic\'e~ higher bmin oonce ntrutiOlls. The hal f-l ife of caffeine is 5 to 8 hours, nnd thai of theophylli nc, ubout 3.5 hours. Aboul I" of each compound is excreled uochanged. The oompounds ~ rnetabolj~ed in the li\fi. TlIe major metabolite of caffdne: is I-methyluric acid. and thai of theophylline. I.l-dullethyluric aeid. lo Ndthet- oompound IS mctaboli1:ed to uric acid. and they !Ire 001 eontnlindicated in goot.

CENTRAL SYMPATHOMIMETIC AGENTS (PSYCHOMOTOR SnMUI.ANTS)

Sympathomimetic age illS. whose effects ate manif~tcd mainly ill the peri phery. are di scusscd in Chuptcr 16. A few simple ~tructuml changes in these peripherdl u~cnts produce compounds that !Ire more resistant to metabolism. more nonpolar. and better able tocross the blood-bruin namer. 1'he!.e effeeu increase 1M ratio orcentral to peripheml IICti ~ ity. and the l/lcnlS lin: designated. somewhat arbitrari ly. as ci'I1tml sympathomimetic ugel1u. In OOd il ion to CNS-stimulating effects, manifested:L~ e~_ cital ion and increa.o;ed wakeful ness. mM y ecntml sympalhumimetic! aen an anon:~iant effect. Centrol sympathomimetic (nondreoergic) action is often the basis rOf' these effects. Other central effects. notably dop:unine~ic IIlJd serotoninc:rgic cffecl~. can be opcrati~e, howe~er. I In some agents, the 111110 of eAcitation and increa!ied wakefulness to all()ll:xiont effects is decreao;ed. and the agenl~ are market<.-d as anoru ianls, Representali~e structures of th is group of oompounds are gi~en in Table IS-3. The structures of lhe anorexianlS phendimetnlljne and sibutnmine and the alening lIgents methylphenidate and pemoIinc:. \I!lC':fu l in allention-dc:fieient disorders. an: given in the text. Struclllral features fOl' mlny of !he age nts can be ,'isualit-ed easily by considerin/l tMt withi n their structure they

contain a ,8-phenethylamll1.e I1\OIl'ty, and this grOUpi ng CiIII gi~e some se lecti vity for presynaptic 01' postsynaptie nmdrcnc:rgic SYSh!IIlS. ,8-Phenelhylil1l1illC!, given peripheral'). loch ce nU'al llCth'ity, Facile llJ('tabolic inacti ~lIIion hy mmoaminc: o~ idases (MAOs) is held re.~pomlble. Braochlll'''. lower alkyl Croups on the carbon atom adjacent (/I) 1 dir 0 IIllI1IlO nitrogen increa$eS CNS rdther than peripheral Klml)' (e.g .. amphetamlllC! , pre~lImably by n:tarding mctaboliS/llI The /I brooching gencrotes a ch iru l center. The dutnl/SI j~mcr of .tmpheta mine is up to 10 tink'S as pottnt as the 1t!,'Q(Hi isomer for ale"ing acth'ity lind lI00ut twice ali ICtlW as 11 psychotomink'tic agent. H ydro~ylation of the nlll or hydm~y l:llion on the fJ carbon (to the nitrogen) dtclCL !. lIC1iviJy, lallle1y by decre:L~ing the ability to CI'OM die blood- brain barrier. For example, phcnylpropanolillllUlt. CTOSI die with a ,8-011. ha~ aoom IIl000h the abi lity hlood- bmin b.1frier of ilJl tlcoxy congener.

T....LE 15-3
Slgnlfi~nt

Sympathomi",.tics With

Centr.1 Stimilant Activity

ily (and' a neurotOXin, destm}ing sellllOninc:rgi-c in ex periment:'! anlmals).'l, 1.1 Mcti>oxyJ or mct hylencdioxy ~1I~t i tution on the rq lend s to produce psychotomimetic agcllls, sUggestiRllnIpiStil for dop.ulllnergic (0 2 ) receptors, N-methylation Increa,<;eS OCIi~lty (e.g .. com~ 01Idh.. phetaminc wilh dexlIOOmphetallune), OI-N-meth}1at1Ol crea.<;eS activi ty. Mono-N substit~nts larger th:m meth)i*, crease txcitatory propco1ies. but many cornpounth ~: anon::o;iant propenies. Consequently, some of these., an: uO\Cd as 3110rt:o;iallls. reporlcdly wi th Il:$s abuse pot!'lUli than amphetamine. 1llere can be some dcpanurc from the basic fj.'~::::= 1Ill1lnt SUlJCtun: "'hen rompoonds act by mdirm n lie mechanisms. A ,8-phenc:thylaminc lilC' suuct=. eVfi. can be ~huahJ.ed ID such com]'lOll nds, The abuse potc,uiul of the mon: euphorianl and 511_ tory of the amphclamincs 3nd amphetamine-like well doculllented. They produce an exceedingly dlsu\d addiction, A~ntly, both a euphoric "high" (possibl); luted to errect~ on hedonistic ~ reccpt0r3) and a """ plnic depression (especially among amillC!-dcpletilll contribute to comptllsi\'e ILO\C of these agenls, AbuSf of drug~ (especiall y meth~mphetnn1inc) in reached di 'i.:l~trou5 propottions. Recognized n!edic:1I.I indicat ions fOf' ":;:;;:;~ and some \'ery clo!;.e congenen loclude n

::~~~:~(F;'~' :C~I.;,;B':")~Of the aromalic lIy. Other oclh' i t i~

t J

*'

dnor

MlI\'s

disease. auention-dc:ficicnt no4 the preferred a/lentS rOf'

,.

d.~_~~."~.~i~~;: ;

MIll!\aol(1i11t., , ....

P!lentOOTnlJlll
Ben2phetanw>e

cr

" C", " " " CH, " "

CH,

50mC condllioll~. slICh lIS

milin use is 10 decrease

CH~C.H.

"

C,H, C,H,

disorders of the unipolar type. mine has long been superseded by other MAOls and the mOfioaminc: reuptale
~i ll1t S.

~i\c

FooIUa ' .oe

The compounds and thdr

met:lbol ile~

elln ha,c

= "" "

for action is qUlle Simple. 1lle compounds hIes resemble NE and can

mulTiple actions, In a fundamental

M'nse.~",~~~:;:

Ch.llpt~r

15 Cnrtrol Nr,..'<HlS Sptrm

SJ"~uIQlltJ

S13

.-.
11!; can
~!I)".
~

II!; ""ith

ICt i" ity olism).

,. "'"
as the:

Xlro(S)

IIld post~)"napue prllCt"S5eS involving NE. ~uch as syntheliis. mease. reuptal.c. and prc~)"naptic and pos4~ynaplic receptor f:tI''atl(lft. Al.'iO. becau..c: dopamine (OA) and. to a lesser "lmt. serotonm (5-hydroxytryptamlne 15-HTI) bear a 51IUCani resemblance to NE. proccsSot"S in OA and 5-HT-acti.I!rd s)'j;ll'n,,~ can be affected. To Illustrate the potemial romplct;ty. the n:a:ptor acti\'atiCllls that eun be associated lu~t one paIlulleter. reduction in food int(lle. reponedly ft 1t, P,. rho. ~ HT ' R. SHTu . :'i HTlC. I) .. and Oz.

been reponed to be the major actin: metllboiice in"oI,ed m NE and OA release."

.,/h

J acuve ring OT crease\

laminc. "' "" oss the mme.

l'Roovers
AmpMtamine Sulfate, USP. Amphctlllnine. C::!:)-lJM!)1.2.amiooprnp:lnC ( Benudrine). a lhe rolCl'mic mixlilt has a higher proportioo of c:mliova.'>Cular effects than .....lIro isomer. For most medkal uses. the dextrorotatory IIOIlltr is preferred. OUrroamphetamine Sulfate, USP, and o.KtroamphetIIIIiM Phosphate. Dex troomp/letamine. (+}-(S)W) IpIle11Cthylamine. fonns ~11tS with sulfuric acid (Dexe.me) and with phosphoric acids. The p/lo)pllate i~ the more Qersoluble Sill! and is prefcrred if parentcral admi nistra_ tal i~ ~uired. The dc~trorotatory io;omer lIa~ the (S) con ip"atiO<l wid fewercardiova~ulilf effects thun lhe levorota II!)' iN) l'<!mer. Additionally. il may be up 10 [0 times as poItnI b lhe (H) isomer as an akl1 ing agent and Dboottwice poIeIII a p"ycho!OIIlimetic ageo!. Although 11 IS a more jIlteIII pi)ChOlOmimetic agent than the (R) i.'iOfT"lC1". it has a katr!aliO of aiening 10 p"')"cholomimnlc effect$. The major mode of actiOll of de,ll troamphet;lmine is re1M 0( NE from the mobile pool of the nef\e taminal. I'IIItr mn:hanisms. ~och as inhibition of upt(lke. may nwe a .1 COIll1ibl/tiooto the overnll eff~ts. The aJeni ng actions _toi~ased NE avai lable to intcracl wi lh postsynaptic !!tq"lon (Il,), Central ,B-receptor IlCt j ~al ion has classically m ron~idcred the basis for most of the ~norc:xi:mt effC(Ct. Thr pocychotominlClic effcx:ts are Ii nked to release of OA ..,,,"111100 of postsynaptic recept~ . Ol and rnesolimbic f\ !UtiliOf'< would be involved. Eff(!l;!ts on j-IIT systems bI,'e been linked to some bchavlO!"lll effecl$ of dextrO..p.eumillt. Effects via j-HT receptor-. would mclude HTJ~ nnptors aIld. theoretically. allllddi liooal recqlIOI"S

Methamphetamine Hydrochloride. Methampheta. mille. (+ )-1-pheny l-2- melhylaminopropane hydrochloride: desoxyephednne hydrochloride (Desoxyn). is the N' lTlelhyl analogue 0( de:~troampOctamine. It has more marked central and less periphera l action Ihnn lk-xtroarnphetamine. h ha.~ a vel)' high abuse potential. and by the intl1l~tnoo~ rOUle. ils S(llts (Ire known 11.' speed. "The ovcnall abuse problem pre. ..en ted by lhedOlg is a national disaster. Medicinally acccfHable uses of methamphetamine are analogous 10 those of
de~ l roamphet(lmine.

:crease' ease. p.

,. oct i ~ neuron'

;he ri ng jing tm-

retluUll ' .,on de-

ethyl de Is retam e age nt' potential

Phenrennine Ion Exchange Resin and Phentermine Hydrochlori~. USP. The fm:: base is a.a-dimethylphenethyilimine. 1. p/lenyl -2-methylaminopropane. In the mill preparJI;OO (lonamm). the base is bound with an ioo-('.\_ change re.~1Il to y~1d a s low-~Iea5C product; the hydrochloride (Wilpowr) i~ 0 wDter-sol uble sal t. !>hentemline h;I5 a qUllt('rnary carbon atom wi th une methyl oriented Iike lhe methyl of (S}-amphet:nnine and 0111' ,nethy l oriemed like lhe methyl of (H)-amphetaminc. and it ~poncdly has ph~nnacological propcnks of both lhe ( N) and (S) isomers of amphetamine. "The compound is used as an appetile ~uppre,sanl and is a Schedu le IV agent. indicating less abttse potential than deXtroamp/lctamine . BenzpMtamine Hydrochlori~. 8en/p/letanllne hydrochlonde. C+ )- N. benzyl-N.a-dimethylphenethylamine hydrochloride. ( + )-l.phcn)1-2-{N-methy l-N-bew.yllmine)propane hydrochloride (Didrex). is N-beru:ylwbsU1utOO mc:lhamp/let(lmine. The lar1!\' (benzyl) N-substiluenl decrea\0e5 eJlcitulory properties. in keeping IOoilh lhe gC/l('T'JI structure - activity relationship (SAR) for the group. Anore;o;iam propenie~ are retained. C laSSically. amphctamine-like drugs ... hh I(lrger thun N-mclhyl substi\Uenls ure ciled as W"IOf"l:xian t lhrough cemral p agonism . No claims f("K ~c1cc tivity anMlng ,B-receplor 'ubtypes ha"e been made in such citallons. The compound sha~s mechanism-ofaction characteristiC$ with nlethylphenioote. Overall. it is said 10 reduce appetite wilh fewer eNS excitalory effeclS than de.\lllXImphetamine.
D~rhylproplon Hydrochloride, USP. Becausc it has two l:l1ge (~Iath'e to II or methyl ) Naltyl WbsIl\I.l('OIS. di -

r:l1Cthyl'

iuJrenc:r~. 00100 '

stimu la dru g., " trueth e ~ibl )' reo posteu gdrug ', eoflhe-.e ear" !lOI~
tam"~

51IT1
Dextroamphetamine isa strongly ba ~1C amine. wllh values 9.71 to 9.94 ~ported. AbsoI"ptlClll from the gastroin~ IJlCI occurs as the lipid-'IOlubie umme. The: drug i~ I\UI ,tly protein bound. Varying amounts of the drug are IntaCt under ordinary condition~. The amount is IflCallt under condi tions of allmli ne urine. Under conpmducing systemic acidosi.~. 60 to 70% of the drug 011 be t\creted unchangt,(]. Thi~ fact cun be uwd to OOvon IItJeatmg drug overdose. Thr a-methyl group retard~. but doe!; rIOI tenninatc. me ~"'by MAO. Under nK)l;t oondltlOOS. the bu lk of a dose 'htroamphewnine is mctabol i~ed by N-dcalkylation to "I)"'-toneand ammooia. Phcny1acetOfie is de:graded furto l:au:oic acid. lIoprl1f11ental animal ... about S'il: of a dose accumulates especially the ce~bl1ll eone'(. the thalamus. and '1lI"JiUS callosum. It is fil1>t p-h)'dro~yIDtcd Dnd then ~ )btcd to produce p-hydro~yoorephedri JlC. ""hich !lOIs

Parlin I although ~~ion In r: hidl II. ~t effe.;h re por1edl) :~. In al

oarnphe'la IOIlIbly the inl iderrn-

lor derre"

ethylpropion hydrochloride. l-phenyl-2-diethylnmmClprOpa n- I-f.II1C hydrochloride (Ttnuate. T epanill. has fewer sym. patlMlnti nlCtic. cardiovascular. and eNS-stimulatory effects than antp/letUl11 ioc. It is reponedly an aoorexiunl agent that can be uSC'd for lhe treat ment of obesity in patients with hypenen~ioo and eardiovascu lar disease. According 10 the generali1.llliOl1 loog used for this group of drugs. inc~asing N-al kyl ~il.e reduces centrul a, effects and increa.-;es {J efree\). e\en though lhe effects are ht~ly medialed principally by indirect NE release.

rompk ...

hunal t.w. ir rneubo1.\ neuronal

.'nln.

FenfluramlM Hydrochloride. Fennunulllne hydrochloride. ( ::!: )N-eth)I-a-lTICthyl-m-{trinuoromethyl)phene_ thy lamine hydrochloride (Pondimin). is unique in thi5 group or drugs. in that it lends to produce sedatiOl1 rather than

UCIUltion. Effects are pit! to be mediated principally by ccnt!'lll serotooinergJc, !'lither thlUl centrol nuradrenergic. mechanislTI5.. In large. doselI In expenmemaJ animals. the drug IS a serolonin neurotoxin.l~ It was Wlthdra""TI from human use anCT reportS of heart valle damage and pulmonary hypc.nen~Ion. From its SItuC1ure. more upolur or hydroIlilobi echarnc:terthan amphetamine. tropism for serotonincr gic neurons wou ld be expected. U lewise. the structure ~ugge~ts an illdirect mechan ism. If un Indirect mechanism were opc."l1Itile. tnen all postsynuptic 5-HT receptors could be activated. Evidence frotn :.el'erul studies indicatcs thai the 5lrr l and tne 5HT1(: receptors an:: most I"eSIXHLsible for the !l3licly effcct~ orS UT. S1fT may llsoinnuellCC the type of food selected (e.g . Jov,'er faller food intake).' I 1lIe (+) isomer. dexfennummine ( Redux). has. greateT tropt$m for 51fT sy ... ems than the r..... "Clmc l1uxture. II. too. was " ithdr~wn because of toxici ty_

PMndimetraziM Tartrate. USP. The opticall y pun:: compound phcndimctnll'.ioo tannllC. (2S.3S}-3.4-dimethyl2-phenylmorpholinc .. ( + Hllnrutc (l' lcgine). is ~"()f1sidcred an effective aoon:x iam thai j, Ics~ ~bu'iC pronc Ih~nllmphct amine. TIle stcreochemistry of ( +)phendimetrazillC is as shown. 110
H

HaC - N

H,C

keted compound and " about 400 limes 8.' potent t i tht: 1l f!r)"thro ncemate_ 1lIc absolute configul1ltion of earn ci the Ihftl.J<lUCth)lphenidate isomers has been determuw'l Considering thaI the structure is fai rly complex (rclalll"C 10 amph!:lamme). il i~ likely !hat one of t/le two componnb orthe IhftQ racemate contains most of the lICtivity. Evi(lM:r indicates that the (+) -(2R.2'R)thrto i<,Orner is inl'oh't'Id pnnciRally in the behavioral and pressor effects of the fXt. mate. v As is lilely with many centrol p!iycliomOlor su_ lanls, there UI\: multiple modes of aclion, Methylphenidate:. probably largely via liS p-hydroxy . . tubolilc. blocb NE reuptake. acts as a postsynaptic 1&0lIl'" depletes the Sllnle NE pools as reserpillC'.1IJld has effe('b. dopaminergie s)'stcm~ ~ucb as blocking DA rcuptue, Meth) Iphcmdatc is an ester drug ""lIh inl~tinll ptww. cm:inetic propcnks ari~ng from it~ SltuC1ure. 1lIe pI(" II> ues are 8.5 and 8.8. 111e protOIIaled form 111 the 510t11d reportedly re!lISts eSiCT hydrol)sis. Ab~pllon of the Intal drug is very good. Aftt:'T absorption from lhe gastrOlDt~ InlCt. however. 80 10 904 of the drug is hydrol)'7.cd r.IJPII! 10 inocti ~e ri1ll1 inic add.:ll) (The e~lcnt of hydrol ysi, may Itt about 5 linleS that for ( + ) versu, ( _ ).1 1)Anothc:r 2 to 5.. 01 Ihc racel1l1lte is o~idilCd by liver microsomes to the inactJtC cyehc amide, About 4% o f a dose of the rJoCc nllllc reponed) rrache:s IIIe brain In cxperimental anlJ1\al~ nnd there II po hydro~ylaled to yil.'kl the putlltile oct;'e metabolite. Methylphenidate is a poIent CNS stimulllllt. lnd"... ",dude n.m:oIepsy and llnention-dcficit di<;(lfijer. Tht:.\III( lurr of the (2H.2'R) isomer of the Ilrrffl ~IIIIC mutlR shown.

1'hendImeI.tu:..... "TaItrll1e

SlbutriJmine. Sibutfllmioo (Mcridiu) is !o3.id 10 be an uptule mhibitor of NE and 5111'. These mechani sms fit its struclllre, It is reported ly an amide:pres,am and an anore~i am druB. Th is me:ch:lfli~m implic.~ that IICtivatiOIi of all prc.~y lIaptic and pos!synapl ic l"1:ptors in NE and 5_ HT systems IS pos.~iblc:. The data are not completely clear. bul studies 10 date: indicale tlut liN' receplors principally in"oh'ed arc ai, PI. and 511Tx l '

M.II

.,IpI ... okWIOI Hyt!.w ...... idot

'illc compou nd I~ described u, havins an o~.'rn the CNS likc tha i of IIlcthylpllcnidmc_ Pemolrne to " wcch or admin istration. however. to tal~ panial cxplanation for 111C delayed effect may be thai of the acIJOIl' of the agent. as obo;c"'ed in flIIS. is .,~. the r.ue of s)'nthesis of OA.

ANTIDEPRESSANTS
MethylphenidiJte Hydrochloride, USP. 8 ecau'ie methylphenidate ( Rilalin) hal! 1.... 0 asy mmetric centeT1i_ there are four possible borneOl. The I/tuQ I1iCCmate is the mar-

Mono? ..1_ Oxidas e Inhibitors (MAOb)

Anude]nS5llIll thempy usually nnplie~ ~; again~t major depressive disorders of the: III

iJ ~nlered around Ehret groups of chemical agents: the \IAOls. lhe IllOIIOamllloC reuptake inhibllOfS. and aUlon:ccpkIr t\('\C'tlS'UJ.('1'lI and anUigonists. Elecu"Oshocl therapy is _her option. The highe:>l cure or rcm,S!ii1Ol1 rJle is

JChoewed wIth electroshock thernpy. In some patients.. espctilIl)' those .... ho are suicidal. lhi~ may be the p!'eferred ther-

,~

,-

II!')'.

MAOls and monoamine reupilIke inhibi tors ha-c about

... \.:une respoo",= mle (-60 \07(). In the United Slaies. !he laner group i~ u,uall y chosen over ,." AOls for unrideprc.
IiIlI

inhibition was alnlOlit always regarded as im'versible . From the be,inmn,. how'c ver, it was known that it "'lIS pcKst ble to hale agents that act uclusivcly by oompetiti~ en;r;yll1C' inhiblllon. For uan1plc. II has long been known thaI the harmala aU.. alOlds harmillC and harmaline act as CNS sumulantJ; by compe""'c lIlh,blllon of M AO. Reversible (COIII petiti"e) lIlhlbllor~ ,;elective for eac h of the two major M AO sub types (A lind B) are reportedly fonhcoming .

thempy .
MAO I ~

..00

A IICV('1l'. problem associ a1(l<j wil h lhoe

Ihal

ha~

1001

"".

,aloch

idly

,b<

of

:11\,1:

"

iI,

'omIa major factor in rdcllalinll them \0 $Ccond-lilY drug IIIN~ ;5 thaI the original compounds Inhibit Il\'er MAOs 11~.-tfSlbly III add ition to broil" MAOs. thereby allow ing ritwy pres.sor amilleS Ilml notmlllJy .. oold be mocliv31 ed "nen wir df'U systemically. A numbC'r of ""Crt: hyper _ I'e ~POOO\l:S. !iOmC fatal. hal" folJ()\IIw inge\fion of c foods high in pn:ssor amines_ It W3S hoped that the de,'clop_ of agentJ; 'itlCh :as sckgilioo that prewm:tbly ~re 1I ,'cr M miglll sohe this problem. TIle upprooch ofusm g MAO AO .n:a"'lly did so lve the hypertensivc problcm, but the eom !JlIIfId was IlCH an antidepressant (it i~ useful in Parkinson' s li!ca.<.e). AUOIhcr appro~ch using a revc~ible MAO I h~~ ,ltlded antideprc....'IalHs that lacked the hype rte nsive "(Itto;e effect. AllCHher pmmll'lent side cftect of M AO I ~ lortho<>Iatic hypolension. said to ari...e from a block o f NE tdtalCd in the penphery. Actually. 0IlC MAO!. pal"g}" linc. _l\ atd clinically for itJ; hypotenshc action. Finally. some rI. the fi~ compounds prodlK'L'd senou~ hepatOlol ,eity. 1'),!IIds available today reponedly are safcr In Ihls repol but ~ffcr the stign'a of as..;ociation with the older l"OIn-

o/"\-c~~-~-o-'CI ~ Moclobcn ude has reech'ed consldcruble anelllion abroad . A revero;;,ble mh.bnor of MAO-A, II .s considcml an effec tivc IIIIIJdcpn'ssant and permits metabolism of dietary tYnlmillC. O!A Metabolitc~ of the drug are implicated in lhe acti~lty. RC'"en;ible IIIhibuOlli of MAO-A (RIMAs) rt'portedly are antidcprcssalll "ithoul prod\ICing hypcnensile crises. Re versible inh ibltoo; o f MAO S have a lso been Slutb ed. Presently. se lective MAO B in h ibition ha.~ failed 10 OOITI.: lmc posi tively wi lh a nt idep reso;u.nl activi ty: sclegi linc, however. has value 111 lre:.lin.: l'ark inSQn'~ disease . TIle clinically usefu l M AOI antidepressantS an: nOl1sc lccti, ~ !)c.Wceli inhibiti ng melabolism ofNE IU1d 5- HT . Agents selecth'e for a M AO thaI degr.Kle:s 5- HT hnc been under study for 'iOtne tnne. The structuresofpheneiline and tnmylcypromine are gi'-en III Tablc 15-t

"0

.......

!fecI 1011

~u .re ..

.\

[[1:(:1. A
QIlC

thm

merea...:

lsI
d ll'ected

typc and

the role of amJll'"). IJlOIlia7jd is an effecli ,c 1IlltilUbcn:ular !!.gent but I I ~cry polar compoond. T o guin bettc r penctr.llion into the: 1I!robut:'trHlItI /Iil~rculos;s orga nism. II mort hydrop OObic ~nd. i';o n ial(id s ubsl illlled wit h an hopropy l group on lit ~ic mt rogen (iproniazid). W' ~S desill' \cd (tnd synthcIt wa~ inlroduced into cl in kal pt"IIClicc as an efTect i\'e __.ut<'~I\ ulu 31lcnL eNS stimulalJoo W'"" llCHed. howc'n-. : .:I the drug was withdrnw" . Later. il was dctenmned in apmmtnlDllUlimals and in vilro experimcots with a puri MAO lht MAO inhibi tion. R:l>ultin, In h igheT $ynaptic of NE and 5-HT. could account for lhe eNS cffccts. oompound was then reinlrodoccd inlo Ihn"npy as an .....~o;ant agent. It stimulattd WI intcnse mtere!.t In hyIlllIDeS and h)dr "'l.ide~ :IS antidetlrt'SS3IlIS and i Mugurdt~d .I'kru\~ drug tnatment of depressio n.12 It contillued to be "'" in themp)' for sevcrd l yea'" bllt e,ent ll~lIy W3S wllhht,ft becuuse o f hcpatOloxici ty. The prtSCnl clinica ll y usefu l irrevenoibit inaclivllloni can .~rt'd nl ha"i~ntb;a>l..'d inh ihitors of MAO.v T hey .o."OII,cncd by MAO to agcnls thaI inh Ibit the cll7yme. CMl form reaclants lhat bond co"alently with the en or tbcofXlor. A lXlflSCQUCI1Ce ofim:verstble inactiva !hit the action o f lhe agents may continue for up to ...n\ dler admm islnllion i~ dio;conlmucd. Comcquem ly. *up IkgBded by M AO or drugs that ele\ale !e,'cls \tAO subslrulCS canIKM be adminiSiL-rcd dunng that timc. for ~ long till1C'. bca\use the agents thnt opened the field .. ta OOnunated il were im:versiblc ,nact.v~tor. MAO

The b,51ory o f MAOI devclopm.ent

dlustrnte~

PhefJelzirH! SUlfafft, USp, PheIlCI1., ne $11lf1l1e. 2..(phe nylelhyl)hydnu.lne $ulf:ase (Nardil). IS an effecti\'e antide pressant agent. A nNXhDl1ism-ba.~ itlaClivator, it .rre,'tnibly inactivates the e n:rylnc or its cofactor. presumably after oxid.lllon to the dialinc. wh ich ClII1 then break up inlO nLOlccu lar nitrogen, a hydrogen alom, and Q pbcncthyl free mdicaJ. TIle latter would be the octile species in irreversiblc in hibition. l.~

1(.

Tranylcyp romlrH! Sulfa fft, USP. Tranylcypromine ~ul fate, ( )-mms.2'phcnylcyclopropylamine s ulfate (I>-ol/"' nate). WIIS syntt.e.il.ed 10 be an amphetamine IUUllogue (v\SU . alil.e the a-nlCth).t of amp/lctaminc coodcn.scd 0010 the ~ c:ubon atorn).:" It docs ha"c -.orne ampllC'tanunc-hte ",opcrties, which may be why II has more immediate eNS Slimu lant effects than agcnb that al1 by MAO inhiblt.on alone. For MAO ,nhibition . there may be two components 10 the

TABLE 15-4
GeM.k Name

Monoamine Oxidase Inhibitors

f'r"tJpMtMY N. TM

A. t , ...",

.-

Structu..

""", ,

ICtlon of this agen!. One is thouj!ht to Dri~ bccau'\C mmyky~ rromme hIlS strucwral fealUrc5 (the basic nitrogen and the qua~l-lI' ch.arxter of the 0- and .8-cyclopropilne carbon 1II0ms) that approximatc the tr.lnsitlOl'l stIIte in a rotlle of nle1l1bohsm of ,8-ary lllmlJ'It).J1- 21 As a- and ,8-hydrogen atom5 are temo\ed from the normal wb>.tI'lll.c of the enzyme. the quasi 1Tcharaclcr dcveloplo o\'er the a ..8-carboo syMem. Duplication of the transition ~3te pennlts c\tremely Strong. but rc,cntble. attachment tl) tIM: enzyme. Addittonally. tran ylcypromine h I mcc hant'mbased inactlvRtor. 11 i~ metaooti/.cd by MAO. with one ciL"Ctrun or tile nitrogen pai r lost to Onvin. This. in tum. produ\:cs homo lytic Ihsion of a cnrbOIl - carbon bond of cyclopropane. with (lI\e etl"t,"Iron from the fission pairin~ with the remain ing lonc nitrog.:n electron to gcnerntc an imine (protonated ) and with the other residing 00 I methylene carbon. Thus. a free radical is ronncd thai re3iC:tS to form I covalent bond wtth the en/yntc 01" with redllCed nav;n to tnactivale the enlyme.;I'J

Monon .. Ine Reuptnke Inhibitors

Origt!lnlly. the lllOll()/Imine reuptake inhibi tors" ere a group of clo:;dy related agents. the tricyclic antidepressants. but now they are quite dh'ct"'>C chemically. Almos t all of the agems block neurona l reuptake o f NE or 5 HT or both (i.c .. lire selccti""). Rcupta ke inhibition by thC"<e agent s i~ at tIM: levcl of the rc<.pcelhc morooanllne trnnsporter viII compettll 'c inhibition of binding of the ITtOIM)(Imine to the \ubstl'll.tcbi nding com~Irtment. Probabl y the same Stle on the protem h mvohed for inhtbnor lind rIlt)Il()iIlntttc. but thts has not yCI been pro'cd. The mechanism 0{ rellplakc by monoamine transportCfS has bern 1e,ic"ed. lIO The net cffect of the drug i~ to HlCn::a~ the levcl of the moooom.ne in the synapk. SllsllIltIed high syltllptic IC"el s of 5 UT. NE. or both appear to be. the basis for the antide pn::s..~nt effect of these agents. There is a time lag or 2 or more weeks befOl\" antidepressant :letion devclops. It is considered that (in thc case of 5 IIT) 51IT lA receptor'l and (in the lasc o f NE ) <>:! reccptors urlllcrgo desensitil.u tion and tmnsmiller n:lease is mainlalllCd. Of course :leti v3tion of po<;t ~y naptic m:.:eptors and sust:Uned tl'll.ll .. mi ~Slon is tIM: ulti mmc result of sustllu1ed ~ynaptJc Ic~els of neurotnms tlutter. It

the ..ub>.tr.ltCbtndlllg CQtnP'U1ment of the tl'll.n~pofter The OIcl'll.l1 eo~pt or a ,8-arylaminehkc s)\tem wtth IIIkIrd struclUl'llI bul ... usually an aryl group. appean \Q be appIic. able w many newer con1pOUnds-Klecti\'c SCI'OIonln rcuptake inhibllors (SSR ls). seleclt' c norepinephrine l"Cupul;c inhlhiwrs (SNERI ~)-I hat do not ha, e a triqdlC grouptn, 111e TCAs are wuct.uru.Jly related.o each other ~nd. ~ sequently. POSIoCSS related biological pro1X't1ic, that CUI br sut1unariJed IL~ charnctcristic of 1he group. lltc dirllC1h)" mioo r otnpou nds lend to be .scdatm-. when:as the t"l1OlI'> !1lclh yl ll' lati\'e~ tend T be: ~t imulatory. TIIC dimcthyl romO pounds lend towuru hi ~ her S liT to NE reupttdc block IlIt~ in the: HlOoonlCthyl compound$. the proportion of NE upgt.r block tcnd~ to be higher lind in some ca><,' b ~"QIbidmd sclCC1t\e NE Il'IlpW:C. The compounds ha\'e antlCholinerp: propc:nlc~ t.tw.ally ht gher in the dimethylttillJoo eomptJllld. \Vhen treatment is begt.tn with a dimelhyl compound. a mlicant accumulatIOn o f the: monomcth)"t compound de\dop1I as N-dcn~hylallon ["II oceeds. The TCAs arc extremely lipophtl ic and. accordingly. '-cJ) highly tis~uc bound oot~idc the eNS. Since: they ha,e lit!chol inergi c and norudrencrgic effCC1.~. both cent ral and periplt<!rttl .. ide effects an: otien IInple~~a nt and SOInt:ttr!\l'j_ gcrou~. In ove rdose. tit<! combinati on of effects. lIS wdl .. a quinidine ltke cnrdiac depn:s.~nt cffect. can be lethal 01 erdosc is compli cated becaus.c the agcnts are so htghly p!!>tein bourn! that dial y\i' i~ in.cffCC1i\'e.

PRODUCTS

Trtcydk Antidepressants
The SARs for the TeAs are compiled tn detail m the eighth
edit Ion of this text.Jl The intcrested l"C;ldcr is referred to thi s compilmion. In \u mmary. there is 11 large, bulky group e tlcompa.-.s ing two :uum:uic rIng", prefcl'lI.bly he ld in a skewed atrJngcmcnt by a third !:cntml ring. alld a threc- or. somctimes, two-atom l"Iiuin 10 an uHphmk amino group that t ~ mo nomcthyl or dimcthyl ,sllb!;titUled. The features can be visualil_cd by consulling the Struelllrc~ of imipraminc and dc~ipmmine as exampl es. The O\Cl'll.lI amtnge01Cm has fea tures thai !1ppf"OXJrnaIC n fully e~tended Irons confonnalion or the ,B-arylamines. To n:latc these feature~ to the mccha msm of ICtion. rcuptake bloc ... ~ iSuahle thaI the basic ar rangement is the same as that found in lhe ,8-arylammcs. plus an ~trn aryl bu lk) group that enhances II.ffinit)' for

ImtprarnJIlC' h chloride . 5IJ.(dtmeth~lamit1())ptopyll 1 0.1 l -di h) dm-\II dibe:nllbJlazepine mooohydrochioridc (Tofl'll.nil) . ~ tbt bf cornpourn! of the TeA s, It is also a dose. relati\ e elf. antt~yrhol1<:: pIM:nothia7.ines (repl:tee lhe 10- 11 bridf ".. sul fur. utid the eompound is the anti~ychotic agent IMolnal ine). It ha ~ weak~r D~ post~ynaptic blocking aclt Vtly till. pronwlUle" nd mainly affects amincs (5 HT . NE. and D~I via the tmMpot1e ..... As tS Typical of dimethylamino poutld~. anticholinergic and scd~T;'C (centr~1 l it block l ll f~t~ tcnd to be marked. '11le compound per ~ ha... a tmtklq tOW"Jrd a hi gh 5-tiTto-NE upta"e block rutio and can be called a <;crotontn It:l.nsport mhibi tor {S ERTI 1_ toW bohc inxt i,allon proceeds mainly by oxidatilc h)dro.J. lion to the 2 pCl)uiOll. followed by conjugat ion ""h runic ac id or the conjugate. Urinary excretiOll ~ (about 75%), but SOtltc bIliary e~cretioo lUp 102S'l1 occur. probahly becausc of the large nonpolar grouptn,. 0.dat;" e hydroxylation is not as I'lI.pid or complete as chII tile nloOll: nucleophilic riog phcnothialtOe nn lt P~yc." ronscquent ly. apprecinhle NtkrnethylHtiol1 OCCUr'I. \\l1li buildllp or nOtinupl'll.m in.e (or desi miprJtmnc). '11le demcthylated metHboIitc j~ Ie .. s ant icho1trlCTJtC, 'OCdati\e. and t1"IOI"e ,timulatOl)' and i~ a SNER l 't C quently . a patient tll'ated wi tb imipramIne ha.~ 1\\11 pounds that contribute to acth 11) . 0.. crull . the: effetl ~ <;clecti ' e 51 rr 'CtSU$ NE rt:1lptakc. 'The: ilCltVll} 01 cb norimiprumine IS tennmaled b) 2h)droxyIMion . by conjllgalton and e\cn.'1Ion. A second N-dctntth)

Im;prami~

Hydrochloride, USP.

"'...

Tho

on occur. II<llich in tum is followed by 2- hydroxy lmioll. aJIIJugalion. and excR:lion.

~"IO

he-

UPak~

11/",

lul('. Nortri ptyli ne is a SNE RI )I: the composi te action of drug and melllboltte is nonselective.

ng.

,'" ylu-

>00-

~n

Imopr_.,..
OF EV...-.e

R .. Oil
R .. H

,m:

Nortriptyline Hydrochloride. US,.. Perttnem biologi c~ 1 nnd chemica l properties for IlOI1ripcyline. 3(l0.11-d[ hydro-5 H -diben1.O[a.tI]cyc lohcptcn -5-y lidt::nc:)N mcth)' 1 -1propananlillC hydrochloride. 5-(3-methyl-aminopropyli dene)-IO.I I hydro-5H-dl benlo[a,d)c:y,lohc:plcne hydrochl oride (A.'ernyl. Pamcl or). are given obo"e in tile disclls~ion of anutriptylinc:. Metabolic inactivation and elt mi mllion an: li l e tho<.c of amitriptyline. Nortllpt~ line is selccti l'e NE Ir.msponcr (NET) IIlhibitor.JI
The structure and

wke

<red

OtJ/prilmIM Hydrochloride, U5P.

<rglc

"", sig-

IIiImI ptopenles of de.<;lpnuninc hydrochlondc. 10, 11 -<ll hydR>N-lIIl'thy i5H-di!)enzl bJ1azepl ne-S-propanamine monoII)droc hloridc:. 5-(3-mct hy l ~ n1i JlOprop)'I) 1 0, I l-dihytJrolH-diben:t[bJluepine hydrochloride (NOijHllmin. PenofrMel, are UI'lCUSsro uJW.ler the heading. Im'prullullC. aOO\'l:. ,...g Inc-yehcs. des ipram in.e woold be considered .... he n '"' anticholinergic e ffccl.~ Of a low level of ~Uli Of1 nrc 1!IpOfWIt. II is a SNERI."
Clomip ramine Hydrochloride. Oomipramine (A naml) is up 1 50 li nlc~ !IS polen. as imipmmillC in some 0

10

11

,"-___ "'I'" ''''

!~d-

. .,
~lIpt)'lne

,
3

HC-CH -CH -N
R _ CH,
R_ H

,
/

CH3 . Hel
R

very anll' I P';I ~

NortrlPlYlintt

,II

"""
Ovpro-

This does IlOl imply clinical supcnonly. bul i1 . . Ill' in ronnati\'c aoom tricyclic and. pos~ibly. OIher l!IIpW.e inhibuors. The chloro replacing the H substi H l('nt
"~ys.

.d~

..51/.

:lead

< "'" w" l1

!)mil -

"!be

InCTUse: potcncy by incltllsing distribution 10 the: llOS.OOI it is Ilnli l dy thai this I'oould glle the potency lllpillide Sttn. 11 might be ronjectllrt'd that a H bond be IOft'II the proIOIlated amino group (as in vivo) and the uniWtd electrons of the chloro substituent might stab;l iJe ~ hylamineJjke shape and gh'c more effICient C'OITI)X'titioo tnlllSpOl1cr. The drug i~ an IInm:k~nL II is Ilsed .oh<es~IIe-(:ompuI5ive disorder. an ~nxiety diMlrdcr thJ I .y hal'C an CIClllC ilt of dcpres~;oll.
kI

Protriptyline Hydrochloride. USP. Protn ptyli ne hy droc h lori de. N nl('thy I 5H -d iben7o( a. til eyc Iohepcenc 5 propy lamine hydrochloride. 5-(J'lnCth) laminopropy l}-5H -dI ' bc:nlo(a.d!cyc!oheptenc: hydrochlondt:: (Vi"letill, li ke the' OI hercom pou nds undef oon~ldcrat ion. is an cffcclI"c arlllde pn:uan l. The basis for ilS chemk ul naming can be .;een by ronsu ltrng the naming and the' strtlCtUlt of imipramine. Protnpty line is. Slruttul1ll isomet' of nonn ptyhne. lnactivallon can be expected to in,'o/l'e lht' reJ:l! ll'ely loca h7.ed double bond. Because: It is a rnononl('thyl compourn!. it ~ $Cdatil'e potcnt lal IS low.

,I\;ul
D AI

k) d ~IlCY

CO Ill-

o
Allitriptylfne Hydrochloride. USP. Amnn pl ylinc. 3JO.ll-dihydro-5 fI-d iben wi a. d)e yel ohc: ptcn-5 y 1 idenc) N. .! dillltth) I' ] ' propJnam lllC hydrochloride. 5.(3-dimethylyIJdc lie }-1O.1 l-dih )'dro- 51f-dibenl.o( tl.dlcyclo/lepb)iWchloride (Elavil ). i~ one of the most I1nliehoilllel'" ,r. 1Iid sWativc of the TeAs. Becau~e it lacks the ring elcr ~nriching nitrogen atom of im i pr~milll'. nl('tnbolic in ~~ mai nly procccd:s IIOl at lhe analogous 2 position :;.,'~"". bc:n1.}lic ] 0 positiOll (i.e .. toluc:nc:1ike met abolism ~ nates). l)ecallSC' of the 5-exocyctic double born!. 1;' isomerli an: by oxidatioo metaboexcreuble melllbulilC'S. As I~ compounds. Nmeth)'lntion !)IXUI'S. is produced. which has a le~s 11ll1icholincr arn! more sti mul:ml action than omitri pl y

b aMy

\ k lil'

Trim ip ramlne M aleate. For de1H lis of ' hcrnical nomencla1un:. consult the description of imipranllne. ReplllCc, mcm of hydrogen with an a-methy l ~ubstitucnt produce, a diml carbon. and trim ipr.unine (Sulluontil ) is used as 1he racemic mi~1ure. Biological propen ies repon ed ly rescmble lbose of Imipramine .

I -C-CH- N /CH I CH
'I '

'........,.
CH,

-.... CHl

Doxep ln Hydrochloride. US,.. Do ~cpin. 3-d ibc:nl[b.t' Joxepin- I I (611)ylidine N.N-di meth yl lpropananllnc:

hydrochlonde, N.N-dimethyl)( diben1.[ b... lu:c.epm1 I(6H ) yhdt:ne}propylami IIC (SillC'Quan. Adapin) .s un o:c.a congener of arnitriptylule'. a.s can be $('Cn from il"l structure. 'The o.tYl!en .5 1Oll"re5tingly plaC'C'd and shook! innllenee Olidalhe nle'woohsm as ....ell as postsynaptic and ptn;ynaptic bInding affinuieJi. The (2) iWlller is the nlOl'e IK:tive. al though the drug is marke.ed us .he mixture of isonle'rll. The drug ovel1l11 is I NE and 5 II T rcuplake blocker with signilielm anlichoilllcllic and Cdau. e propen'eJi. It can be antici pated that the IMlf- 01" dc~- n1cwbolue .... 11 contribute to lhe ovel1lll act,vity pallem.

./'9

,
2

CH '011, /3 HC -CH -CH - N . HC I

the center ri ng. and one ri ng is moved ~ lighll) forward from the tricyclic' aJl-in-arol'''' aJTllJ1gt'menl.) Tht net effec1 IS thm the ,B-arylamilll:-lile group.ng is ,...3C011. as in the tricychcs.. and the compounds can compctr '" the substratebinding si le of the ~rotOflin trunsponer p ... (SERTj. As in the tricyclics. the extra aryl group can NJ eXt", affinity and gh<e fnvornble competition with the 5Ubstrate. St'rotonin. Many of the dillll.'th) lamino tricyc1ic~ art'. III fact. SSRh. Sma: they are eX leosilcly N-dcmethylaloo In "h'o w ... COfllpounds ..... hich are usuall y SNE RI~. howe,er.the<mI eff~'C1 is not IOClecl;\,e. Breaking up the .ricyclic s~ breaks up an anticholinerg ic pharmaoophoric group IIIrI ihcs conlpoundS with duninished anucholinerglC cffca. OItt::IlI. this \limlnisht's unpleasant eNS effects aod cn:a5C'S cardio.ru.cu lar safety. Instead. side effects relaln!. serotonin pn.'dominate . In nuoxetine (Prozacl. prOlonated in IIIG the protoo;lloo amino group can U -bond 10 the etherru.) clectron5, .... hlCh can gcner:tte the ,B-arylammo-liJ,;e gMIp. .... ith the 01 her aryl serving IlS the char.acteri~uc "Cltra" .,t The S isomcr i, much more <;ell'Cthc for SERT tlwt 1<1' NET . The: map metabolite IS the N-dcmethyl COI4C I whICh i ~ I S polent as the parent and more seiec1il'" (Sm versus NET). Therapy fOl" 2 or TtKIre wt'eh is required for the antidqtm Wit effcel. Somutodcndritic SIiTII\ autOTeceptor de:",,:: 1.lllioll with chronic el<J)OSun: 10 hi gh le~el ~ (If 5-HT ~ .. all<:epted el<plDmmon for the delayed effect for th.s m:I serotonin reuptale IIIhibitors. To illustrate P difference be.ween selectIvity r(lf I SOO and a NET. if.he /K,m !;Ubstilucnt is mo~ed to the: posilion (and is le~s hydrophobic. I),piclllly). a NET tained. Thi s nnd other SERT~ have anxlOlytic JIC1i"ity ~ of .;clernl po!'Sible nle'dlanisms ... ouJd be .gon i~ d 31fT n;:ceptors. dimilllshing synaptIC 5- IIT. Prc..umably.~) Ie.'el s of 5 II T Illight be hIgh in an anX IOUS SLate.
Fluoxetl~.

abolishe~

CH,
Maprotiline Hydrochloride, USP. Maproti hne hydrochlondt:. N-mc:. hyl-9.1 O-ethanulmthrncelll:9( IOH)prop:!namilll: hydrochlorid( (Ludiomil). is somctimes described a~ a .ctrocycl.c mther .han a tricycl ic antitkpre~<.IInt The descriplion i ~ chenllcally IICCUr~te. but the compound. 11oI,H1ethelCM. conforms to the o.emll TCA phannxophon-. It is a dibenlObicydooctadiene and can be vie ....ed:iS a TeA with an cthylellC-bridged centrn l ring. The compound is not Mron gly anticholillCrgic and has ~tunulant properties. It can lIa'e effects on the cl1JllioV' lscular system. [t i~ a SNER I. II .

is_

H N-CH,
Ma~1\8

HydfOdlionda

Amoxaplne. Consideration oflhe structure of alllOupilll:. 2-chloro-.l 1-( l ' pJpt'T'UIRyljdibem:- lbJ1 11 .41oll3zepine (A.;cndin). reIRf~ the fact tnat many antidepressants an: very c looely related to amipsychoucs. Indeed. some. Inchld ing 31 1lOxapine. ho,'e significant effects at DJ rttepl O1'S. The Nmelhyl -~ubsti tlllt-d relative of umoxapine i, the antipsychotic Ioupine (I.mitalll:). The 8-hydroxy metabolite of IIlllOxapine is reponoo ly acti\'e as an antidepressant and as a I) l receptor blodoer.

@:O
N

CI

In the StruclUl'e of paro~ellne (Pa~~1 ami no group, protonatcd in 1'1\'0 could II -bond .. itll - C l lr O - unshan:d electron . A with an e:ttm aryl group re,ult). highly selectile SERT. A~ e~pectcd. II i~ an effecuI't_ pressanl and anxiol)1.K-.

Paroxeti~.

S.Iective serotonin Reupbke Inhibitors

Struct urally, the SS Rls differ from .he trieyclics . n thm the .ricyclic syste m hn~ Ix.-cn taken apm1 in the cemer. (This
PlfO>letl1\8

Chaptn I! Cr",,,,/ Nrnv>IU Snlrm S"'''''/<UlIJ

519

lhtly ,Tho

Sl'nl.

for

SMn/ine. Inspection of ~rtrahne (7..o1ofl) ( IS.4$) red. the ~ for SERT inh lbillon. The CI sub IUlIImIS aloo ptt"dicl 1tOp1Sl1l for a S HT system. "The dr pidtd ~lcrtOCheml ~tl)' is importanl for oclivuy.
11 NHCH3

Mein

,wb00"

"'"

;N. ls.

,cr.lll 'stcm
lMwr~min..

"

, ><C,

ReboJletine. Mosl of lhe acti. ily of rd!o,\eu nc n:side~ in the' S.S isomer (T1le marLrted com po!.md ,s NN and SS.) Ii is t l3imoo 10 be: ~uperior 10 nuoxeline in se'e~drpn:~sion. It is marl eloo in Europe. AI least three uicydic compounds. desipr~ mlnc. nor1riply hnc . and lhe technicall y telracychc maprouh')e an:: SNERl s. They. of cou~. ha.e typic~ 1 charac teristic TCA side effCC::l ~ but IO" 'er ~ntichollllc!l;ic and I I, aJllih i"aJ nlll ic (*<Ialivl: ) effects than dill)elh yl compoun~h. SNERh ure clinicu ll y effecl,,'!: amidepress;IIHs.

, and

"'
F

....
0

I ", H
,

Teets.

din

ltd 10

The t: iSOlnef Qr nuvlIllImine (I...u\ox) "~'111 can fold after protonalion IU the ,B-al)'lamme.hl e P'PIII&. Uere the "urrn'" hydrophobIC group " aliphatic.

\ ivo. xygen

O ..~ ,

....o'cH,

0
II wou lt! be e:>'I"-"<:loo Ihal III Ihe ea.<;c of SNER I ~. (t. p~'y . lIaplic rc....eplOl' would be dc-.ellsiti/.~'I.!. afler" hieh ,ustUI 1100 NE 1....ml>'mis~IOn would be \ la o ne or III01'e poslloynaptic re t-eptors: P" and fJ! receptors are pos.sibi!i lie~

~roop.

aryl. ~ fM

XlI.uki.

..........
'~ '>c

'0

'-./"--.'"'

SERT

Itpw.-

.cnsili is lhe

j " ",.,

CitJIopriJm. Citulopr.lnl (Cele~ll) Is U I'lIcemk mi'\lI.l~ -.l1~ "cry SERT !>elect; vc. TIle N n\Qllod.:"mclhyluled com .00 i~ ~hght!y less potenl bul is as selecIllC. TI)e 111) 1 IIIICIIIS arc imponanl for act;vity. The ether function i~ ...,anl and probably interacts With Itle pmtonaled ammo w I,\e a ~ullable <Jtape for SERT bulli ing.
"

tt,.

Newer (Nontricycllc) Nonselective 5 -HT iIInd NE R."pUke Inhibitors

~nlly.

one such compound is d inic:llly used In the

SERT
or1ho

UnitOO Stales.

. is ob-

y. One

SHT 'A ymlptic

0
0

Ven /a faJlin(>. T he ~I ru ctun:: and ocl ivily of \"enlafaxinc (EffexOf ) ~re 1IIlK."<:ord with the gener~ 1 SARs fur the group. As expected. it j, ~n effL'CI;" e ~midcprcssanl.
CH.

0 ,
"

,1I.ctl_ Norepinephrine R_pbke .... Wtu.

Tlitdl.Ctl)" 'Qlt of n uo ,~ine opened lhe sub)ttt of SN ERl s. Ibi il. mO\ emc:nl of II para SUbslilUCnl of n U OXtUIlC (and >ell 10 an ortlw po:.ilion produce~ I SNE RI.
CH,

.:" 0

\,

OH

.,\il). ~n \'ilh I~ .truc ture

i :1 VCI)' ! antidr

-Selective Serotonlnergle Re"ptillk. Inhibitors and SHY:IIl Antagonists

0 / 0

/ CH,

" "

\0
\'-oActinc l ~ /I SNER I and is lin an lldepreS!>ant. Mlbl "'., rc~ides in the P iSOnlc r.

a
The ~t ruclure, of lhese IWO compound, denve from I~ of lhe nuorobulyruphelWlt1e ~1I" ps)thohCS. They h~\ c fJ-al)'lami/lCh~c stNCturc( thaI pcmlil bind mg 10 the S ERT

~\

C)-~o
c,
MIsc:elhlln_us Antidepe en.na
Buprop ;on.
"The mechan ism of actinn of bul"OjO(l (Wetlbutrin) i5 con~idered compln and reponedly in,lIIoa a block ofOA reuptake \ia the dopamine Irunsponer(DAn but the oH'ralJ antidepn:ssant action is i1OI1Idrenc:rgic. A !Drtabolite thaI contributes 10 the O\'e",1J acuon and ,IS f _ tion can be e3.'o1 ly r.ation.alizcd.

and inhibit 5-liT rcuptll~c . In tllC$C compounds. tile addi tional hydrophobic su&,UlUcnl can be vielO.'c:d as being a1 lached 10 the oilrug;:n of the P.arylamine-like group. Additionally. they are 5 HTv. anlagom~15. ThaI a ma!;!olll sm may

or may not afford antipsychotIC

e{fecllvenes.~

is dISCussed

under anlipsychotiC5. Sl lTlA antagoni_ appcarlo ha"cami '1S depressant and anliol}lic IICti\;lia, TIley may act. a1 least In pal1. by enhancing SlIT ,,, :iCt1\ltle$. 'I Also. some of the effls m.J.)' be mediated through SHT~ agonism (perhaps

gtoernlly!oO for S-IIT-actlng :mlidtpressams.) Some of the ~idc effects of SSR I ~ an: con,Klered 10 be mediall!d throo~h SHT lA rcceptoxs. so II SilTVI binder would reduce them. J 1lw.: tWllcompounds yield the !I:Imccompound on N-dealkyl mion. It i~ a scrotonin rcupl~kc inhibi tor.

,.) 0)---'
o

SHT... Ag_ists and Partial Agonlsts

BUJpirone. "The initial compound In thi s -.eries. buspirone (8uSpar). ha~ arUa OI)lic and anmlcpressanl octivilie~ and is a panial SIIT t " agof1l~t. It) 8nxiolytic acth'ity is re

O r

ponedly due 10 I\S :tbility to dlmllli~h 5 HT Il'lease (vi. 5HT I... Igonism). High shortteon syn:r.ptic IevC'ls of 5 HT an: dl:1r..cterislic of an:uely. A Iso. SInce 1\ I~ a pamal agonIst. II can ~umulate po!>lSynaptlC Il'cc:ptOl'l ... hen 5-HT le,els Ire low in the synlp!.<.'. a.~ i~ the case in dtpre;~i()ll. A number other ~pirooes ate in dcveluplncnt IU anlliolytics and anti
depn:s~1nl> ..w

'

.'"

1MIa><11I

MISCELLANEOUS eNSACTING DRUGS

<;('Chun dea l~ , ea.,;ly undcrOlher t
Thl~

Anblgonists

t('fon CNS and coo ld be

M i rtilZiJpine. Minl7.apine (Remerun) .... a~ recently Ill troduced for clinical use in the Untied States; il s parent mi an'll'nn (pyri d}1 N replaced with C II ) wa.~ long lnoy,n to be an an tideptns;lnl. II ,s reponoo 10 be fasler acting IIDd

Th<

'" and in hne

lar

dntll~ al .::

more poIent than eenain SSRJ~. The mode of action giVe!> increased NE r..-tea.'Ie via (f2 NE receptor IInl agoo ism and lIl(."!'Cased 5- HT rclca.-;e via antulloni~m of NE a;, helerore. ccptlll"!i located on senlmnincrllic neurons;'J. '"

ohcicntific inl~n:st ~,;: ca l psychosi$. Phencycli dine couse it gives in formation aboul asp;t.natC glutamic:: acid receplor. and It ~

dentally diSCO\'cred

as a model for schizophrenia.

CoclUne as a CNS stimula nt i Research on why it 15 so meaSUfe\ that mighl millgate the: past tWO dccl1dc:s.

J 1.Tetr.ahydrocannabinoi and ,ts ~)~ ".~ for many 1 determine the SARli. 0 sti mulus the:
receptOl"!i . I

ull!ler

inve~tigat ion.

1P-ArJI_ lno H.II..dnog_

A I~op<:ny of the l,B-arylamioo hallucinogens IS altenllion cili'le pclttplioo of st!lnu lL Real ity is di<;torted. and the user
BIlly untkrgo depersonalilat ion. Lilcm ll y. the effcct s are Iha.e of a p~ycho~i~. AdditiOllally. the dnlg.~ ~ an produce .met)'. fear. paille. fnmk halluc inatiOfls. and addi tional 'lmploms thai rna)' Ix: found in a psychosi., Accordingly_ !hey arc classed as hallucn-.ogens :md PSycOOWrl1 l1netics. lbi) group can be wbgmupcd into those thaI posscs:s an

"1"00 'olves OAT ).

A~

fanna-

wloIethylamine moiet y. lOOse Ihal posse~ a phen)'lclhylam l1101ety. and lhoo;e Wllh botb. In the first b'TOllP. thc:re is I Slructul1Il resemhl nr>et to the cenll'll! llCurolnmsmiuer 5HT. antl in the second. there is a SlmCIUl'II1 l"e.'iem bl nnC1: 10 NE aod DA. This It.'iernblance is sugge~tive. and tllere may be some selecti"it)' of effect ~ 00 tile w;pe(:li\'e trnn ~m i1ter l}\ttms. With structures of the comple"it)' (oolld in m;my rI tbese agents. howc\'CI'. a si"en structure may possibly IiTfd flO( JUS! the close~t structurally related ncurotron~mit In'systems but other syS{cms as wetl. Thu~. ~ phcneth) lam lit l)'stem COIl L aff~t not ooly NE and DA 5yMcrrn; but d ako 3HT ~)'slen"" and an indokthylamine sy!otem could IfJCC'lOOI (01)' 5IIT but also NE :md DA sy~(ellls.
-.oot.ETHYLAMINES

OC',
t-l2,5O'melho>:y... methyp/IenyI)2~
100M. STP)

3.'Meth)'ll:>ed!oo,.,,,,.1MW>I

'"""
~'.(l sy)

Dimelhyltl')'pt.. mi~. Di~thyltryptammc IS 11 .cry _ hallucinogen. ICti\'c only by inhalal..oo or mJCCl.ion . 1Ib I RIon duration of action. It possesses pronounced sym ,.oomlmeuc (NEJ SIde effects.
~Iocybin

Psilocyb in is too pho.pllork .."<I ester of p.ilocin aoo appears to be con"erled to psi locin lilt ICti,'c speclC:S in "i\'o. II occu .... in a mush1'Q()m, PSi/I" nltt -ukulIi' . IJ.o4h drogs are acti"e orally. with I short tImbon of ac:tion. S)lIlhetk ftmeth)lsubstitu led re lau,,'s ha,'c a mucb .,duration of action and enhanced or 1 potency.'I Thi s .. IIUCSIs !hat p'llocin I~ metaboti7.oo by MA~ .

and Psilocin.

The presence of mcthox yl or dio.\ymc lhylene (methylenedioxy) sub!.tiwcms on II 2-phcnethy l:unine syst~rn is II cbaracteristic of mall}' p"'ycholomimct ic compounds and wongly suggests DA involvement.
AGENT POSSESSING BOTH AN INOOLETHYLAM INE AND A PHENYLETHYLAMINE M OIETY

10 nut \it the chltpof abll<.C

A,

r in(e re,'
rfi,e<;O;I,I~

lid

popu:ta;1-

",a~

Qids. Ii I' forclirll' :;sung bemeLhyl()o

eelS !Oervc

-H
P....... ,
I~ENYLETHYLAMtNES

R,_R ._ H R, _ 0f'010H)7, R~ .. H R,_OH,R._H

(+ )-Lyserpk Add Oiclhylamide. Boch an indoLethylamine group and II phenyk:thylarnine group can be secn in the structure of too extraonl illllrily potent hallucinogen 1)'sergic uci d diethy lamide (LSD). 111e stcroochem i, try Is l'lIcttdmlll)' import!!nt . Chir.dlly. as sho .... n. must be mai ntained or IICthit)' is 10"1: li "~wbe. the Iocalioo of the: doub le bond. as sho",'1I. is rrqmred. 11 Experimentally. LSD bas mnr~cd effects on serotonllW:T gJC and dopamincrgic neuron.~. The ba.<iCS for all of liS COf\lpLe~ eNS k UOIIS an: not completel), unOen;lood. bow-ever. Recenll)'. its actIOIIS havc been suggested as being n.ore typical of '>Chi1.op1\renic VS),CholIC reactions than the model based 011 umphetamine. For n.ore on th i~. see the discllssion of ut}'pi cal unlipsycbotics (Chapler 14 ).

; of abu<.,e
j OIl dru~

inlcnc,c In

re ~Iudil"" W:L\ gi\en lnrmbinoioJ I ,ySlcm i.

lIlIa/inc. Mescal il'le. 3,4.5_trinlCtho.'()phocnetbylarn _ . II I moch-suldicd hallucinogen with many complex efa 011 the eNS. It occurs in the: peyote cactus. The oml rtqIIlOTd for lt~ h:llh.lCloogenk effects is "ery bigh. lIS I!o SOC) mg of the sul fate salt. The 10.... oml potenc)' ;;';.yresult5 from faciJemet:lboli ~m by MAO . a-M ~lhyllDcrl'ases eNS [lCti\'itl' Synthetic a-methy l-substituted rdIIIJl'tS arc more poten!. ' . ltI The lIrug~ OOM. M DA. a nd !)I,lDA (ecstasy) arc ex tremely potent. oongerous drugs of

...

Dissociative Age .. ts
Phencyclidine. Phcncychdll1e (I'CP) .... as introduced lL~ I dl~'OClatl\'e anesthetIC for anlmal~. lIs close slruCturnl n:1~ ti\c lctamlnc is Mill so used and lI13y be used in hUnlan\ IChapler 14). In hUll\an~. PCI' prodU(."C's a sense of intu~ica lion , hallucinogcnlc c~pt'nclICe~ nOi unlik e those produced by the anticholinergic hallucinogens. and often amnesia. The drug affects many (yslen". including those of N .. ::' OA, and 5-HT. II has bi..'en pl"llfllN.'d Ihat pcp (and cenain OIher psyehOiomimcuc~) produccs a unique p:!ucrn of acli I'allon of \entr:lliegumcntul prea dopammergic neuruns. '~ II blol:h glotamilM'rgie Nmethyl l)-aspanate n:ceptors." This Xllon is lhe b~si~ for many of its CNS effect,. pC!' n-.elf appear; to be the octl\e llo'Cm. The ps)'chouc sWle produced by thi S drug is al~ cited as ~ bencr model th3n amphct~milJC P' .(.~" for lhe Pl'ychotic Siale of schll.ophrenia.40

Del euent_lntoxiunt
.J'-Te trifhydrocannifb inol o r .Jt'TH .:C.'~:;:~f:~;~: con'cnllOlls fornumbenng THC: that ehenll~lry rruducn .JI-TUC. and lhat on lopyran ."y,u:m rc,uits in 11 .J"-TUC de~ig.n~tion . nOid i.XlII\enlioo b used hen:.

CH,

CH'tO CH,
(_).:,1."..". Tet,ahycIr~

"

o
Euphoriant-Stimulant

/ H
CI

TIIC IS a dcpn:MIlnt ","h appOlrenl SIII1101l1ll1 ~,~... arhmg from deprc"ion of higher cenle .... M an~ eITect.. 1)\lled1y ,"bjccti'd) eonsuued as p1ea.'>lIIII. an: cvideftl low oo.;;:s. TIlc in1crc~led reader may COINlit u ""'~:
I)gy I C~ I for a dCI~liled acCOUnt , AI hlghcr doscs. p5)'cl nll.'lic aclion~. incl uding dy~phoria. hallucinlltions. and l)\lia, can be: lI1ar\(ed. Structural fealurc~ assocwN :lClI l'lty among cannabis-dcri,ed oo",pound~ ha,'c bent vic ... cd. l N()(ably. lhe phenolic O H i~ reqUired for Certain SA lh (especially <.C"par.1110f1 of poteocy ant/OflleT\) for callnabiooids 5Ugge~lrd aClion al 1''''0 receptors fur THC ha"c been dlsco"cred. 'The receptor for CNS actions" CH,," C Bl occurs in I li ",'iIe"'. 11lc fiN natur"lligand found fOf Ulllldc (\eri\"atl\'c of 3f",ochidolllc acid. naluml cwmabinoid, are ardChldonle ocld all(! 2-Ilr,ochidon) I ether.... Ilinoul ~ystem Dppcar~ 10 fUlICtion II.~' ., ,y'lclll al bulh slilllublOry .ynllp...e, . apo.e ... nlC ~~nhptlc ,ran~mlner ellu..e~ flU"',,)naptlt '>c:~ of cndocmmabinoids thai Ilf(: lhell I I rcrepH:.r; located pre~ynaptically ... hen: till:) e,eltalory and inhi bitory ncurons.~l 11 11)111 appear all br.un an:a!i and
t t
I

~H)Ood"''''

Cocifine. Cocaine as a eophonunl-\limulant. psychol()nll melle. and drug of abuse rould IL~ ""ell be dl<;("\l.scd wilh amphL'tamine and melhamphclamme. ""llh "' hlCh il ~han:s many biological properties. AI low dows. 11 produce.~ feci ings of ... ellbeing. dccrc:l~ed fatigue. Dnd Il1<'reawti alen ness. Cocaine tends 10 produce ool11pulsh'e drug-~d:ing behavior. :lIId D ful1-blo .... n 1<,1~ic p'ycllo~i , may cmerge. Many of thelit: effecl~ appear tu be related 10 the effects of inefCased
..." ...,\.",";"\,\) .,.; '\::l"" ~"" ''''~..''''\'''''' ... ,,\, ~"'1",...?--\.<;. ,~~

~hct'rol

?~~~@~~~

(0 1 and D, receptors:lf(: pcrtlncll1). Cocaine is 11 potenl DA reUplllke blocl er. OCh01l by l."OInpelllll'e inhihi tion of Ihe OAT. A ptw:TM:lhylanlillC molCly ... lIh added ~t cric bulk may suffice for thi, a!:lIon. An IIlICl'al.:llon bi:t .... et:n a h~drogcn
alom 0II11le n"tug(n of Ille prtXonaled fonn of cocal1lC and an oxn:cn of lhe ben/oyl C_Ier group, or :llIernali\"ely. :In UlltnCtion bet",ecfi the on)haroo ckclron pair of tbe free base ",Irugen and lhe c:I.fbon~1 of the bcn/.o~1 ~cr group. could upprolumutc tillS IllOIcty.

sckctl\'c cDnnablllOid
not

good. Designing drugs

cn:d the most

research

o OC~ ~I c 0 .:::,/":::;/

,n lIIalll18111111g
RE FERENCES
I J.. t>"". c. It. !'on.... L A.. ,.".j Bud~ . liT . J Mtd. " ' . 7:!9. 19611 ! I... ll ........ T C. ond 1'.,1..... W 10 S"":nc,, 197''112. 1'977 , FmlhoIm. 1I 11 .0101" I'twm:oroI Ik. , $1 U 19\1\1 " tnly. J W J Mod. CbrIILlll'l7. 1l1li2 ~ ...,11_. \t .. and Ihttr. J II A_. II.., Mod C"tw.. "''' . () s..~ ..... S II . 01 01 Pro< Ac.d Sa II ~ 10, 7LIlIIiO. 7. Tlo.::ler. A. L. - ' ~ J . c.-w... .... lie> net.:. 1") 8 1 :'-' M D A ....... II.., M.... C10cm 28 m. 1991

"'.1

"""~
Considerable n:sc:arch o n drugs affecting lhe OAT h:L, been publi~IM..'() in recent YC;IN. A review of pharmaoolher.lpe011C agents for c(!Calile Ilbu'oC j <. 3l'uilahk .41

'l \).,.., ...... ~:c':: 10 AINO>d.M \1 1'. A""" Rtf' M.... Chern lH "~~'... J. P.u,lu<.1"',(IIItUIhol,""ol'cafr.....
('II"" .....

p.,-,,;p...:u ..,.

h um RnII 11.......... ,

"'en."

19114. p. 1.

C hllplrr IS ern/ral N~nmn S~~'~m SlOl"~I,,,m

11 ... 1><1011. I, E. : ...... i>nll1Ier.. ~ 2!1. 2000. fII'lOI II 100' , A""- N V ""ad, Sci. ~:1 ~7. 1m , I..... y. I, A: A... S Y Acal Sci 1OS21J9. 1m I~ (,"'W.III. "- __ eo... E. lore Sol. 1635. 1Q169 II. V .... IL lulL 'I Y ""od Sci ~:2n. 1917. IlaU<ltd, I. C G . _

523

)9 Fo.Ia. A C .-..I Ft>u- Q. E- N ....... 3~,m. 1917 40. 1I""..,.. 1-I . 8n_.L. I...... ..... - , P H 1 MI C!Itm ..... ' n,

care 1.... 0 tapC'noid .he dillen The letpC'

, C'Ioorto...,,"

' I C..-.oLl. r I.lklMiI.LL._n:.... M 1 I ' ...... Cloom.'2!721.

,."

[), ...... D ..... Scholl;",. G 1 Mod Chern, 46b, L9bS l.....t """"". A """,*;h Chern 9111-'0. 19M $100I'I", ..... A. IIId I1l1t. G.: 1 Mod. Chern. 12::!66. 1969. .. I'otnc~. t:. S.. ., II. 1 ~. P p n..r. NLl52. 1l1li7. .... 1'm:1,1 M . and \A}'t"... I' Q: M<1n)lphm'lIMr. In l);.Ji P _ 1'oITnt.1. S. (ods.). "")'<""'""",,,",,'1(" '''''''' pan 11 Nc ... Yorl:. M..".l IltU..... I977. p 1287 ll, Stu! ...... Nil . <1 &I.: J 1'harn\IoroI up. Thcr 141;)(10. 19'1I7. , 1I'' ''lrl"d. 0 V \ .... 1: Ann. N V ""ad s.;,.!\O IJOO..OOO. 19S'l D hllM-lh. I. E.. 0JId BUI)eI". A.: Prna ..,.". II", JO;2C. 1986. N. 5tnIp<u"Ui. I. D.. Elhs.. D. B...... Allen. R C, An ... lI.ep Mrd. n..... 26'.N? 1991 ~ Co-. A. L Ihochrta.1'tIarmoo:d 11:249. 111M . e .,. A I. Mod. Pborra. CIlr-.4.Jll. 1961. Be..., e..... M- . 1 F J Am Chrm. Soc IBU2, 19M. II. ...... B.. and Mo'... 1 F 1 Mal. PIIarm. Chrm. 5,215. I~

"ow,

...

Edny, II ... 01 .. AlIa N. Y Aad. SO. 191.0. 191 1

1I

' .J HolI, ...... I~ E..O'I~.

'J2:~.

K.._S.ebhit.M

J')~,~

1987 ..... M......... L. A.... II. N.. u~ 346:561.1\1\10. 4$. D.o"OM<. W. A .,,"1.: Science 2SS:1946. 1m 46. Mhoolom. 11..... 01' I..", N",I /\cad Sci, U. S A 9ILl602.200! .,. e,..-r\WI. M ... II. I'roc. 11.. Soc, I..ondoo B 2M'2O!I. 199!l .... 1'0',1000.11 I and Ni<:tJIl, II, A, N.{"~ 'lO;S88. XIOI 4\1 0NI.s-t.u. T .. M..jq,1III, T ond t:onu. ~ .. Nt"''''' 29:729. 2001 Ktr,!lo!f. A. C _ II ........ 1'0' Q. NaIt\lOI29717. 2001. S1 CIIri ..1e, M I.. _ VIOl"",. C W . N.ru~ 4 tlH27. 1001 51. O.\! ..-,.I>, V . <I".; Nau- 4IO;Sn. :!OOI. n M"""I-m. II. and I'me. E. N......, 410:16J. XIOI

so

It

$.hOi'

II. B. I BIOI.

-.en<.atlon, erfecls. reo

C\idelU 11\

...... \0. 0.. __ CIorl.. 1 8_1", 8 . 1......... II4-U49. 199)

a..m

2!18 14766, I\IIIJ

SELECTED READING
C...,t. P L I_II. f I . ..... K....... M I . ~,." ifni . . - 0( ron ..... """"" Pr.-clwcal ""flIt<'\'. 1 . ..... Chem 41272L
t'1nIhoIm. B B, Bolli, t: . Hoi ........ L <I 01.; Ac1ioM 0( raff....... Ibr In,n ... "h Iop1Ii .. r.... nce 10 r _ !hal conIn .... ~ In ~ , "'Ideopr.t " ... I'honnaooI II .... SI:IIJ. 1'199 H.lfonl. J C. G . lind 81_11. J. E., 1,,,,,",acoIoay of 1I'\"rII,c "'f'l'fWl<ln, I....,. o.u, R... SoIll. ZOOO. 0,", K'f. B . SwdIJn. W .. lind ' .... W'Jnponjr-n. I : SrtuIon,n, dop.vn,nr and ...,...,;,o:p'-;nr I.......,.,,,,, in !he ""1111 "",,,.,,1< 1)"Itm ,11(/ !he..illhibo-. Prot! !)no, Rfi. SoI.l'J. 2000 X""'a.1 -N. and ...... 1. C.: PhaaQ.....yol~...,..,..,. ........ ...t""'"""""" A... Rep. Mod. a..... SoIIW. 2000

01" .... 8 I"r<la. DNa Reo. S09. 2000

'l 1lIairb. T. C" and J<qrnICn. E. Co. C.... r:ot ......"''' ')'>ICm ..

phnml:K:ol. s)'choiomi s. and pam ciall~d wil h "c been reo forOClivilY
recepton;

II iI II
11

xtlOieen cn-

II Dvnt<. II. P ..... ), 100',1000 and Gi..okt, T... bool of OI-pni< /oIoIku,,", ond I'harlnl<ctlti<lol Chemi."y. IIlI! ..I. 1"',~lpho .. I, B Lipplnrot~ 1982.~. 183. f.md. D. A. ..,d H.m""", II . L~' """,, liep. MnI , Chern. 34:!. 1<)"19 ()(" .... 8. . <101 ., """. Onol lies. 52;10). 1m. 11 8 " .. 01.; 0111. 1'11<1 2:nl. 1%1. s-.rn. A. T: ,......... 201 120. 196-1 SIoIlA~lNI llof........ A.: lirl~ A,,'" AttII3B ~21.1955 Booo .... M 8. 8 - . M. L and l!off- . " I . I. "'),<hopNnna-...,.,. 9HlJ. 1'187.

,,,,,,\ani.

...

""pI....

""_oct>!

ibe

IdC,'lllll

In immullC'

l)tptor i~ lhe'

ide.' Other
me~'\CnJo!cr

eqcr 1JOIl~ cannJ-

~'(Trol

=<;am ,,),n-

iplic sy nthc .ned to CBI nelu[)e both : CB 1 recep-I affect boIh considered
tel' 1~ con.~id

Idc\eloprn,

\l<ol_Chom II

1917,

__ II, I. 19lI1 ,.,J2tIO. 19111 l2.1'J91

[In,,!' B IN

yen. Spn"F'"

1 6

Adrenergic Agents
ROONEY l JOHNSON
Adrl:IlC~jc

drug( are !:hcrnical agents that e:c.erl their princi -

pal phamlxologica' and thaapeulic ('ffeels by cilher enhancing or reducing the activity o f the various componcn l ~ of the sympathetic div ision of the autonomic nrrvoos sy~ tern . In gencrnl, 8ubslnnce~ lhat produce effects ~hnilar 10 Slimul:uioo of sympalhe1ic ner'OUI ocl] vi!), are known as symp(lIllOlII;melit's or ,ulr.."ug;c $Iilllilltmu. Those thaI decrease sympathelic acthi ty are referred 10 as synl(Nllholylics. fmlimlrtntf(ficil, or (Jdrr'1ltrgic-b/(}(iing ugt'nls. Because of the important role lhuillic s) mpalhetic nervous sy~lcm plays in tOe normal functi()l1lng o f the body_ad""".." ilie droll) find wide use in !he lreUlmem of a [lu mber of disellSCS. In addition 10 their effects on sympathetic nrn'c acti vi ty. a number of

grou ps si tuated (mhQ 10 each other. the ~ of hydroxyl groups M found in catechol. Ii ..... pounds thaI comnm such an arrnngemcnt ofhydrolt),1 uc:nts are highly su~ptible 10 oxidation. ClIlecholantilltl. such as epinephnne and NE, undergo o.\idatlOn in the pretence of oxygen (ai r) or other 0~ ldi7.in8 agents to proa..:t orrhoquinone-ItLe compounds ..... hich undergo furthcrtn: tiolls 10 gi "(' mix lUres of colored products. H~oce. wlulH:8 of ClIlcchoiamine drugs oft('n III\" 51abllil.ed by the IdoH. of an antioxidant (reduci ng ligent) such a~ ascorbiC acid Of lIOdium bi~u lfit.e

O~

adrenrrgic agt:nts produce importan t effects on the ccnlrJI nc:n'OUS system (eNS). In this chapter. those agents lh.al
adrenergic neurotr.m~m ission und lOOse th ot OCI directly 00 the \'BnOUS I)'pes of adrenergIC receptOI'$ are discussed.
affC\:1

O~
Offl'lc>Oulnone Epinephrine and NE each pos!iC$S It thuS. each can exist as an enantiomeric e nanl iomcr ..... ilh lhe (H) configuratIOn I~ lhe body and posw:s.<;es the biological i Catecholamincs are polar SUb'ltllllCeS that contatn acidic (the arunlmk hydroxy l ~) and basic limine ) fUrlC1iooal groups. For eumple. lhe lhe epineph rine cation III\" 8.7 and 9.9 and III\" lhe p/lt'nolic hydro.\yl group and the group, respecti ~e l y. Gunc llt n I I" I lions of the \'anous iOO17.e<i and epinephrine al pll 7.4 3nd (Fig. J6-IA) is prest'nt toanc~ tcnt Ii for both cUlccholumincs. TIM: l.willenonic in ... hlCh !he 3liphatic wnine phcoolic hydroxyl grou~ is Thus. al ph)' siological pH .Ics.~ than or NE exists in the nonioniled form. for lhe high ..... oler solubi lity other catechol am Illes, such !IS

ADRENERGIC NEUROTRANSMITTERS
StnKblN and Physlc;oc;h.... laaI
PrGfIl!rtMS
(NE) I~ the ncurotrllnSmiller of !he: poslganglionic sympalhelic neurons. A~ a re~uh o r sympaihetic neo'e Slimu13t ion, il b released from s)'mpalhetk nco'e ('nding s inlo the ~ynaplie clef!, where il inter-lets wilh specific presynaptic and posl ~ynaptlC adrenergic receptOr.!. Another endogenous aUren('rgic receplor ugoni"t i5 epmephrinc. This compound is not rcleao;ed from perip/lt'raJ sy mpathetic 1lC0''' endmgs. II~ i~ NE. Rat tler, it IS syml\es iled :md stored in lhe adrerul medulla. from .... hieh il i~ relea..oo inlo the circulation. Thu~, epinephrine is often rer('rTCd to as a neurohor1TlCIOr, Epincphrin.e i~ also biOloynlhesi7.ed in Cellai n neurons o r thc e NS. where both 11 and NE sen'e as ncurotrnnsmiuers.
N~pinephrinc

H,., OH HOY '<>",.., " " NHA

B'")'IIII: I!sls
TIle biosynlhc~is of the eplllephrine lIl~olva a illustrated in Figure 16-2. ;, place III adll'ncrgie and in ~Ylllpathct i ~ neun)f1 S and in the adreo.allTledu lla. as the precursor for the cmecholamines. It I lIcti~ely into the uoplllSm . .. here" is lCC1ed on )-nlOnoo.\ygenase (IY!"Q<;inc hydro.\ylase) 10 form droxyphenylalalllllC: (l -dopa). Tyrosine hydro\)"lut_ Fe l ' -contamint! Cn1.)'nIC that reqUIre'> I

HO

NorepinepIlrlne: R .. H Epinephrine: A .. CH,

Epincphnnc and NE bdonl!: l() lhe chemical cfass o f wbSlana'S known a~ the c/lll'rilOllIIlIIl1l'l. Thi S name WIlS gh'en to these compounds bccall'le they ronta in an ami no group allached to an aromatic ring thlll contains IWO hydroxyl

A
HO

I
HO

'"

NH,R

B
H" '0

OH

NH2R

flgu,. 16- 1 (allOt'll( IA) Cine! l'oVlltlOnlC (. ) loom of norepcl'l@phnne(R .. H) itIld I'J)OnephnN! (R ..
(HI)

1gemcnt
COI1l-

subsli!am U1c.~.

he

rre~-

I
HO

"
A
T)'I"OIine

NH, Co.H

U SC!! lctl'llh)droblopicn n as II oofaclOf. The ell/yllle plays a l ey role in rhe Il.'gulatioo of calocholamine bi()1<,)l11hesi~. as it is the r:ne-Ilm itinll \ICp. For example. adrellCrgic !lCn'c st imulauon leads 10 OCI; \tallOO of II protem ~ "llIse thaI phos_

prod '~

w:rrcacoIution\ add ition : acid or

TyroSM Hydro.:y\aIe

phoryLales tyrosmc hydmx ylaS<'. thereby incll.':lsln, Il~ lII.1l~ ' lIy,' In addItion. through cnd-product mhlbmon. NE markedly reduc:cs I)"rosine hydroxylase XU"Uy. 1'lle bas" of Ihls feedback InhiblUOfl i~ ~Iie"ed 10 be a rompt'llIwn betwn the catedlOlanlille product and the pten" oofllClor. l11e '<C0Ild enJ)'malK: step in catecholamine b~)'nlhesis is the dccarbo,\yJ:uion of L-dopa to give dopamine . Tllc enzy me Ihm Cll.rriC\ oullhis tmnsfonruuion is laromauc 3mioo
acid decarbox), lase (dopa dccart)(uylase). It i~ a c)"loplasmic enzyme thaI uS(', pyndoxal phosphat\! as n cofactor. In udd ilion \1,1 bemg found in c~lecl\Qlamloergic neurons. 1.-llI'OInalic amUIQ ndd decarbox), lase i~ found in hIgh concemr.l1ion~ in mall)' CHher lissuc~, IndOOm,!! Inc 1i,C1' and "idne)'s. II cx hi bilS broad )ub'lrnte specificity. in thaI 31l)1nalic animo aci ds. M1Ch as L-I),lU!iine, Lrhenylalanmc. Lhi.udult'. and L-tryptophan. III audl"on 10 L-dopa and L.5-hydro~)'trypl() phan, sen.e 85 subslr.nc).. dop:!mllJe formed III tnc cyloplasnl of tnc neuron is ocli,-ely Irnnsponl'd inlO 51or:age 'esides ..... ~ il i\ h) ..troxylated ~e~peclfieally by lhe Cu~ -romainmgcnlymedopmnine .8-ml)noo~)gena'IC (dopamIne .8-hydrox~lase) to givc Nt::. Dopamine ,8-hydrox) Ia.<e: l"CI.lui1l!..~ molecular ox y_ gen and uses llscorblc acid :I) II cofacllX". [ I clhibils rJlhcr wide . u b~trute 'pocificily. T he NE fomlCd i~ slored in Inc vCl;icle~ umil depol arization of the lIeUllln init iates lhe pmcess of 'csicle fu~ion "ilh Inc plasma mcmbrnnc:: und Cx l1\lsion of Nt:: imo lhe ')napti~ deA. AdeoosHlc In~phnle (AW l lUId the proIein chromogr.min A are rdc~d along wilh Nt::. In lhe adrenal medulla. Nt:: is corl\"ened to epmephnne. Thi~ reaction. "'hkh m,ol\1:\ the uan~fer of a nlClh)"I,roup from Sadenosyl nlClhionmc 10 NE. is C3l3.lyd by pIlen) 1_ clhaoolamine-N'lTIClhyhl'1lllSfel'1l5e (PNMT). [I OC\.'U1"!i in the ~) topla."n, and the epml'phrine formed " u"lIn~ed uno lhe ~I011lgc grnnule~ of lhe chronmrfin eell~. Al though PNMT is highl y Iocali/.cd in lhe adrenal medulla. II is also presem in small llmOllnt ~ in hean and brain li\sucs.

HO HO

'" A

NH,
C0 2H

HO

on alo m ;

"lCrs. 111e

:sileti b)"

j""". ",.,....
HO

LAtomatJc Amino ACId

n.c:

lain both

ali phali~ 'aluc~ for

i bUled to !d ami no < popula es of NE tion fonn

!han95~

'" '"
Dopamine

NH,

1 Oopamne jH-4ydroxy\a$8
OH
HO

,.16- 18).
o f Inc

ofIC

IDouI J'l

,inephri~

IICCOU nb

I
HO

a.~

we ll a"kJpam i ne .

'"
A

NH,

NorepMphrir.e

!.

NE, lind
1

1
HO HO
A

Phenyteth8l'KlLamlne . N-methyttr_tera58

ctiOlh .

a\

lc.i~ wke~

Uptake .nd Metaboll5m

11M: e NS.
~)'qe m.

OH
NHCH3

JS

.Ine scn.c,
I yros l~

nmsponed
L-dih) and

"TIl

Iase i, an

E pinoIpI'~

...

~lI.}gcn

r;.r. 16- 2

Boosyn1hesis of lhe Galechol.Jmlnes dopamme,

Y>fIlItIeI)tlflne,

"ntI

~11"ll'

11le acllOn of Nt:: al adrenergic receptors i, It'mlln:ued by II l"Ombinal ion of pro<..~ses. including uptate mlo tIM: neuron and inlo e~ lr~l\CuronD ll i~. diffusion a .... ay from lhe 'ynapse. and ITICluboh sm. Usuall y. Inc primary ma:hamWl fIX" lennin~lIon of II"1C achOfl of Nt:: is rcupta!.c of Inc calccholamme 11110 tl"1C ner.c Icnninal. This ~) is lem1c.d Ilflwu- I and in> ot. es 0 No ICI -dependent tran~mbrane U"ansponer thaI ha.. a high affini t)' for NE.:' llu.. uptake ~ys tern also Intnsports certain llmHlCS Oilier Ihan NE imo tl"1C

J'lCl'\'e Icmunal, Imd il Cll n be IJlockcd by ~uch drugs liS cocainc and some Qf lhe lricyclic antidcpn's.-'<afl\.S. Some of the NE thaI rttllters lhe s)mpalhetic neuron is trun poned IntQ ~tOl'llge gr~nulcs ..... hcre il is held in II \Iable eO/lIple" wilh AT" and protein urllli ~ympalhetic ncr.. e ;l('tivily or sonle other Mllnulu' cauc~ IltQ be rdeased Into the ~ynap;c cleli. The Imnspo1'1 of NE from the eytnplu <;m into lhe SIOI"dge gnnu1c~ is carried OUl by an H -dependent IrJn~mcmbr.me vesicu lar IrJnsponcr.' In additiol1to the ncuroualuptake of NE di'ICUssC'd abo\'e. there exlSIS lilt utraneuronal uplake process. uplllke-2. Thi~ upake procc~~ I, pre\Cm In a \\oide \,ariety of cel1$. including glial. hepatic. and myocurdml cclk It has reluu\'cly low affinl.y for Ne. Allllough 11<; physinlogical ~jgnificancc is unknown. II may play II role in lhe dispolihlOll of circulating ClllhoIamll1e~. since calecholumlllCs Ihal ure lal-en up inlo CJ(tl1lllCuronal lissllC\ are metabolized I1Ipidly. The IWQ prmcipal enLylllM in\oI,cd In calCChol;un inc melabollsm arc monoaminc oxil.b-"" (MAO) and c:uecholO ffiCthyhnnsfcI'USC (COMT) ..... 1 Both of these cnlyme, ure distributed Ihroughout the body ..... nh high COOCCTltl1lllOflS found in the II,Cf and I-Jdney~. MAO I~ associaled primarily

wilh lhe ootC'T' membrane nfthc milochondna ..... M e COMT ;~ found prirruuily in thecylnplasm . The Wide tj s~lIC disuib. UOIl of M AO and CO MT lIx1icates that both act 011 caJechrJb. mmes lhat cnler the circu lation and lhe e"'lmncuronalli\~ liner being relcll.wd (rom nerves or lhe adrenal gland or all!' being admini~tell:d e~ogcnously. In addlliOll, the r.... 1bII COto.IT i, IlOI pre!;Cnt in sympathetic neurons ... hcrc~ IlIt RCuronal mitochondria docnmain MAO indica tes th:it MAO also has u role In the ffiCt1IboIism of in~uronal c~ mines. Neither COMT nor MAO ex hibils high substrute specific ,Iy. MAO nxidal1\cly (ieaminalC5 a Yllriely of COll!poo" that eontam un aminQ group aUlICllcd tu a terminal 1bcrc are twn types of MAOs, and the.<;c ~hiblt diffcml ~Ilbstrate ~leclJvily.1 Forexamplc:. MAOA ~hoW$Mlbsnr preference fOf NE and SCrolOllin ..... hile MAQ.-B shao, Sll1lte selcclivity for p-phcnylcthylamine and ben/~I:un'1II: Similarly. COMT catalYI.C5 tile mcthylation of I "aricty c atcchol-conlaining molecules. The lack of Slibstr:lIe ~ ticity of COMT and MAO is rnU!1lfe\led ,n the mel;llxi,; dispositiOll of NE IlIxI epinephnnc. '\.hoy.'n in Figure t6-1 NO!: only do both MAO and COMT u<;c NE and

ept""....

OH HO'Y"'''~'CHO _:::""::0,-

OH
/,-~NHR

HO

OH HO'y",,, HO OH HO
b

I",
HO

CH,OH
HO

~H

NHR

G,.,.

3.4Dlhyd,oxyphenylelhy1eoe N(lI'ITI8tan8phrlne: A H
~1.1II>ej:t'.me:

A. CH~

COMT

'J MAO 'J~

OH
CH~H

HO,A",

Co,H

HO

figure 16-] Metaboll5l1l of noreproephnoe Ind ep.nephnne by MAO itOd COMT.

Ch~pt .. r 16
II subslnaes.

Iul"".",,, <\1It"'J

527

:Ol\.1T suibu:cOOlali.\Suc<i )r after 1 Ihal :ru. lhe IMAO !Chola pound~

bul each also acts on lhe metabohlc5 protIuced

)Cellic-

""""'.

Iff~n: nt

Jbslro.te W5 ~ub lamine:_ llielY of e speere:labolic IT 16-3_ x:phnne

by the OIhc:r. 'Jbco results of exlensi "e research on calecholamlne meub1lI1"" lII(hCalc thai m lhoe adrenergic neuron) of human brain al pcriphcro.l IISSues. NE i~ dearnmatcd o~idati'cly by ~I"O to gIve 3,4--dihydro~yphcnylglycoluldehyde, .... hICh dlen I~ reduced by u~hydc reductase 10 3,4-dihydro~ yphcnylc!hylcne ,Iyrol. II is prirnaril y thi~ glycol metabolite that ill'l"le$-d il110 the circulatiun, whcre it undcrgnes !TlCthylaUOI1 by tile COMT that it encounters in nonneuronalliS\oIJes. The product uf mcthylHtioo. 3- rnethoxy-4-hydro~yphenyl edt~kne glycol. is oxidized by alcohol dehydrogermsc and "'kh}de dehydrogenase 11,1 ghe 3-methoxy-4-hydrox) mandd!r Kid. This rnelllbolitc commonly 15 rt"fem:d to lI. ,'anil~lmandehc acid (VMA). and althou gh It can be the end ~\K'I of tn'ra1 pathways of NE metabohsm. 3-nx:thoxy4-IIydroxyphenylethyiene glycol is it5 prill('l~1 precursor, .. ~ o~idauve deamlllauon of NE and cplnep/tnne at extl"1lII:IIRl!IlI.I SItes such ali the liver. the aldehyde thai IS formed lI.()lw.lll.ed usually b)' uldehyde dehydrogen:e to gi'e 3.4diIt)dro~ymalldc1ic ocid. Mcth ylat ion oy CO~-rr Ul."Cu,," alnlQl;t e~clusively on thoe .rah)droxyl group uf tIM: catechol. regardlc\s of whether k catechol i\ NE, epinephril1l.". or one uf the rnctuboli(' ,.,:.dUCK 1'01' example. the aclion of CO MT on NE und cpiKplvtnc gh'es normc:tanephrine and me:mncp/tnnc:. respec'MIy. /It rot,..erging pallem uf NE metaboli,nt of NE and ipit .. phnllC in ....,hkh 3-mc:tooxy-4-hydro~ym.:l1Idclk acid aI 3rncthoxy-4-hydro~yphcnylelh}lene glycol an: rom. . end products thus OCCUIll. rc:ganlles.s of whether the 6nI mdabolk step is oxidation by MAO or methylation by roMT Under normal clrcum~lmCCS. 3-mc:tho"y-4-h)dro~ymaJ1oklIr; acid is the principal urinary metabolite uf NE. though ~nll.:tla1lloonts of 3'l11Cthuxy-4-hydrox yphcnylethylenc ~)rol are excreled along .... ith vurying quantilie~ of other ....bohtc . both in thc free fonn find a$ sulfate or glucuronIrolt:COIljugatcs, Endogenous ~ pinephrine i~ e:xereted primarj) a mct.mephrine and 3-l1 lCtho"y-4-hydro~ymand~ l ic ul

ADRENERGIC RECEPTORS
""~I

rglc: Rec:.pto ....

(ad1'l!~pton)

UkJwst' "',as the fim tu propose tnc eXl.~te:1'ICC of IWO gend t)lItS uf adrc:nergk n.x:eptOl'!l
in mamtAhM tIssueS, He designated these: adn:nergic rtCCptOl1i 0 III /J. lib hypothesi, was b.a~ on the differing relalive ~lk'tII;il:!i of a series of adrenergic reccptor ugonislS 011 var... $IllOO.IIh musclc preparations, In the curly 197()", the 'ery that cer1ain adrenergic agoolsL' and ant~gonisL~ nlubru:d 'lI1ious degrees of selectivity for presynaptic and )naplic f>'adrc:oergic rc:cept0f'li led to the proposal that , )01911e a n:cepton be design.;ltoo al and that pn:syn.;lP!II;. rtftJl&Or5 be rc:fem:d tu a~ tr::. HI Later. a functional of the: a n:ceplors .... as proposed .... lII:rc:in a l iUpklh were: dtsigrmted as those t~t weI\" excitalOl)'. 11') It'Ceptors purportedly mediated mhtonory 1'1.'~1I Funlx:r developmcnts rc:,e:dcd. howen:r, thai . . . el, and (I) recqlIOIlI ~'OOld be cither pn:synaptic or po>t _

synaptIC aoo either exdtatOl)' or I1IhlO1lory 111 theIr respo:lIlSCS. Tho!O, It betame cle:ar that I1Cllho.'1" an anatonuul not a functional clasSlfie:atlon sYSie m .... a~ a.~ generally useful ,n ela.....~ifylng ad~ncrgic receptor.; as a p/tll1ltlacologil.,d classifical10n ba~ on the: rc:l:othe poIellCy uf a Sl:nc~ of reteplOl'" aaoni~1S and antagonists. 11 Pharmacological and molecular blOlugical melhods ha"e sho ..... n that 1\ IS ~~Ible: 10 \oIJbdi~idc the a l and ll':: receptors into additional ~ubtype:s. Although lhe subtyping of oorencrl1ic n:ceplO/'lj continue:s to c:\o]vc, at pre..ent, tile al and 0:> l"Cl:e:ptOflo each have been divided into at least thrc:e subtypes, " hlch have been designated 01 ... 0"111' oil) and ou,. a !ll' ux-, re.<'pecli,cly.H I' The: mukocular ba...b by .... hith IlCtl\ation of 'Ntd~nerl1ic n:cept~ protIuces lhe appropnate IISSUC It\poon~ hll~ been Iotudied ex te:nsh'ely. Both rt'Ccptor foUblypeo; belong to. ~u pctfaITIIly of n~mbr-JIIt' n:ceptOl"ll "ho!.c gencral \tnJCtun: CQIlS\SIS of sc:\en tro.nslnc:mbntne a-hehcal '<C:gment~ and .... hose signal-truno,ducl ion mechallisnI in'ol,c coupling 10 guanine nuclc:otide-regulatOl)' protein) (G protern\ ). The:y differ from cach other. however. in the ~ond-mc:sscngc:r system that is uffected. l ... 17lllc a,-adrenergic ll,.'Ceptor is couplcd 1 the e:nz}nle phospholipase C .ta a G protem. G~. 0 When ;;timulutcd by IICtivatiOll of the lI. -adrellCrgic receptor. phuspholip:l!ooC C hydrolyll:s Imosphmid}linmitol-4,.5 -bisphosphate to give the '><:cond nx:\'>CngcN iflO!,ltol -1.4.5- tri phosphatc I l n~I.4.5)P ,1 and 1.2-rliacylglyccrol (nAG). Ins( 1.4.5)PJ Mrmulatcs the relell."C of CII!' from the sarc0plasmic reticulum , .... hile: DAG 1lC1;",:IIe:S protein ~ina.<;c C, all enz)'lDc: thai pho!;phoor} lates protcrns. Q:r-Rocc:plor acU\ ation also can incrc:ao;c the innux uf e.>: trace"u'ar Cal- via ,00tage-depe:ndcnl a.~ ..... ell as nort-"oItagc-depc:ndcnt Cal' channe ls. Actr,.. tioo of a r adrc:nc:rgic receptor; lea(:!. 10 a reduction In Itt.: calalytlc octi \ ity of aden)') I cycla.c. which in tum re<;ulu. in a lo .... cring of int11lcdlular le\d\ of C)clic3.5-adenosine monoplKr..ph.lte (cAMP), lllc Ul-adrenergoc receptor- mediated inhibit ion of adenylyl cycla.-e is regu, luted by the G prOlein 0 1 a--Adrcncrgic reccptors uf the CNS and in pe:npheml t,ssues Ilffll(:lll numlx'r of irnponal1l phy.,iological fUl1Cl iuns.l~ In particullll". a n:.:eptor.. are tn\'ol~cd in control of the Cardlova.o;cular system, For cxample. constriction of 'a<oCUlar smooth lIIu.',de 1\ medi:ued by both pusljunctional and a !ldn:netgic repOl'S. though the predomHl:l1lt n:ceplor medlllllng th,s effed is O"r.ll in the heart, actnal,on of (I I receptors l"c:Sults in a -e lective inotroptc response: wllh lillie or 00 ch:U1t;e HI heart rute. 19 Th,s is in contrast to the fJI receptor. "hl<;h is the pl\"dominnnt poslJullC\lonal ll,.'Cc:ptOl' III the heart, mediating both inotropic and chrooouuptc cffls, In the omin. lICtivallon ur po5tju nct.ooal O"'J replors Il':duccs ~ympathcl ic outflow from too CNS. "hieh in tum causc~ a lowerin" of blood prc:ssurc. Xl 1be prototypical a 1 I\.'~e:ptor i, the pn:~ynaP1 ie lr l'l.-'CcptOl' found on t~ terminus of the sympathetic ~uron. 10. 11.:1 Intcl1lCtion of thb rc:ccptor with Ilg00I~\S such as NE and epinephnne resulu. 111 Inhlbt11011 of NE I\"lu!oC from the neul"OO , The: Q1 n:ceptors not ooly play. role in till: regulation of NE I\"lease: b,,1\ also rc:&ulm the rc:Ie-.Ise: of Other neurotro.n~nIlUCfS. such as acet}lchohnc 1100 trotomn. Both (11- and (I:-adrt"rtergJC retl.'ptOl'5 also play aJllmportant role III the rcgulallOJl uf I number of metaboliC proteS!0C5. ~uch as in,ullll 'IOCrc:tlOO and glycogenol}sis ,u

fr,_

P.AdIIl"llrgic Receptors
In 1967. almost 20 year; after Ahlquls"s landmar\: paper profIOl'mg lhe exi~tcJ1olX> of a- and P.ool'roergic recepoo.. Lands el al.u !>lI~eSled lhal fJm:cpun. al'iQcoukl be subdl ~ Idtd into P, and p~ Iypc:~. ScH'nt/-:en )can. bt er. A~h C l IlI.N identified a third subt)pe of preceptor in brown adipose tis,ue. They im tiall y rdem:d to thi~ a~ an atypical receptor. bul it lat er became dc,ign.lted thoc fJ , ~ubt )'pe.' ThC'iC fJadrcocrgic recCptl)f ~ubtypc, di ffer in t Cl1n~ of the rank. order of poIclicy of the adrenergic receptor agoni~t~ ~E, cpmcp.h . rin..'. and isoproterenol. The fl, receptors ex hibit the agom$t potcncy order i'lOprOtereool > epi nephrine - NE. ",h ile Ih. reccplors uhibit the aguni" potency onkr i~erenol > epInephri ne NE. For thoc fJIrcccplor. ltleagoni~t pOleney (Ikr I~ i'iOpf'Qlcrenol - NE > qllllCphn nc. The fJ rece ptor-. are located mainl y in the hean ... here the) mediate the JIOI'itiH: inotropic and chronotropic effects of the catecholarn incs. They are also foond on lheJu .. tag1oo1erul aH-ells ofThe kidncy. ",here they an: invol ~ed in incre~ ing renl11 'iCcretion. The Ih. rcceptor~ are located on . mooth mu o;c lc throughout the body. "'herc they are in volved in reluxation of the . moot h 11I11.~ l e. producing such eff~-ets as bronchodilation and ~ a ..o,hlatinll. They are ab o found in lhe li\cr. where they pronlOlC glycogeooly) is. Thc fJl nx:cptor i~ locmed OIl brown adipose ti""uc and i) ;1I\olved in the SlJ mulalion of lipol ys;) . Like the a l.adrenergic !'eCq)IOI". tile P.adn:nc:rgic receplors belong to the wpcrfnmily of nlCmbr.anc: receptors ",11O'>e gcrl('r:l.1 structure ,:onS;!>IS of !>e\cn tr:l.n~mtmbrane a-hehcal J;egmcllls and '" ho<.c signal -trdnlloduclion mechamsnls In 0 \'ol\c coupling 1 G prclns. AlIthrce ,B-rccCplOfS are coopled to adeny lyl C) d nsc ..... hll:h catnlyles lhe COIl,er<ion. of ATP to cA MP. Thi~ coopling " ~ lP the guanine nuckollde procein G,.!S !O> In ,he absence of agoni ~t, guanosine dlpho<- ph at e (GOP) is bound Te\'l'noibly 1(1 the G , ~("ein. hnc,:*-,,ioll of the ngoniS! .... tth the receptor IS beli eved 10 bnn g llboul u cunfomlallonol chllllge in the protein rtteptor. whkh CIIU!oC~ II reduclion in the affinll y of the G, protcin for GOP and a concomitallt incren>c III affinity for guallo~ine tri~ phalC (GTP). 1lIe a, SUbtlillt of the G, protein. with GTP bound to 11. di~socialc~ from the reccptor- G proIcin tcrnary compk \. binds 10 adenyl)1 c)da'iC, and acll "ales the C'IIl_ yme. 11It: bound GTP then unde'l;OC$ h)drolysis to GOP. and tile ~eplor-G, protein oornplu returns to the basal "lIlle. The int rncellu lar funelion oflhe ~mc~scnger cA MP appears 1 be acli \'31ion of pJ1MCIll II nase~ ..... hich phospho0 ryl at e ~pedfie protcin~. lhereby altcnng their fun.ction. T hus. the ~phoryb !t'<lprotciIl5 medilltc lhe ;\C,io n, o r cAM I'. whic h functions as Ihe meo..lintor of Iho: ocllon of thc dru,!; or neurotransmittcr Ihal origi nall y IIItWlCtCo..l with lhe p-n.'CCptOl'.:1 1OO action of cAMI' I, tenmnnled by a cia"", of en l)'1 1lC'Ii koown as phospohOOic~te11lSCS, II hich calalY1~ the hydrolysis of cAMP 10 AMP. C loning oflhegcnc and comple me ntary DNA (cDNA ) for the manunalnUl p-adrenergK: reI,:eptor h;l.s made it poMible 10 el plore through single point nllll ntl()l1Ji and tile construction of chimcrIC repl0f'i the Structure- runelion relnllonships of the rcceplor.211 Through ,lIch sludic':s. )\ ha. beell ~ lhal the adrenergic agonl"t. bindlllg ~l l e i~ wllhm the transmembrane.spanning regloll ~. ",hile the cytoplasmic regions

or lhe receptor IIlteract wilh the G. protem. Spec;r~. asp;:u1ic aclt! reSIdue 113 in lnUIsmembranc n"glon IJI &'IS . the oountcrion to the cationic am;oo group of the adrtnesp; agorust. II hIlt tl'o'O .serine residues. lit pos;tlOll5 204 and 111 III lrlUlSnlCmbrune region V. form h) dl'Oilffi bond. I'o'lIh eatcchol hydrox yl~ of the adrenergic agolllsls. The' ~ dl'l.)xy l group of ad~oergic agonlSls is thoughl to form I hydrogell bond with the side cham of ltsp"ntgllle 293 tranSlllCl1l\)rnn-c region VI. whIle Ihe phenylalanine at ~it il\n 2\10 ill the same IJ"JnsmembN>nc rtgion; I to interact wilh the cmechol ring. Infonnution IiUCh .... ill 00 doubt aId in the fmuTe de~ign and ~yn the";i ofi::~: and Improved adrenergic rtteptor agonlS{S alit! anIJIg Mole\: ulur biologicullcchniqUC!i h;wc !oho.... n the ui of adrenergic ~cptor polylTlOl'ph ; ~m for both the ~ . . ,. adrenergic receptors. II is postulated that such pol phl~In.' may be an important factor Ix'hlnd Ind"id\!al difllr en.;e~ III ~"fIOO!oC'> 10 dru~ actillg at thC'.sc rccc:pt<n. there may be an association bet"' t'C1I the pol~II1OfphISl\l!o adrenergic receptO\' genes and di sea.-.t: stmes. ThIs .1\11"-

as "

t81111y be an DCtile al\'a of l\''\Carc h ill rt~ults could ha\'e n greal impact 011 the tllerupcut ic use of not only the current adrcnergic 81so tht),C thm are yet to be dcveloped.

the~~r~"i'"::"p;';~:~:: ...

DRUGS AfFECTING ADRENERGIC NEUROTRANSMISSION

Drugs AH.ctlng Cat nhola 111_

Biosynthesis

Metyrosine.

thai affcci cat a fcw an: u...ed allt

u .

i , differs .t ruclUrnl1 y from tyrosilll' , the prc.;cnce of an ((-methyl group. It is a compellti.'c .... _ tor of Iyro-;inc h)o..Iroxyl aso:. the first lind nltc-1ilmllng in calccholarnine bios)nl~is. As meh. nM:tyrusllle much more dfect;\c inhibitor of eplnephnnc and NE duction thall aGents that inhibit nny of tI'M: hrr lIl \'oln'd in cau:cool:uninc bI05yntho:!.l<. Although ~lIIC IS used as It rna-mic mixlUre. it is the I - l possc~.oi lhe IIlhlbllory aI,."Iillly. MetY I.)!;I1M: I' orally ill dosages r:l.lIging from I to 4 gfda). I~ 1I!itd pall y for tile preol"(!lnthe management of tOlna. Th" coodi tion in\'ol ,es chromuffin produce 13rgc lIffiOUllIS of NE and ep,nephnlM:. I the.-.e tunlon. ""hich occur mthe adn:nal medulb. IItl: oclli gn. pat icnt .. frequently suffer h)'pcncn'l\~ Mctyl'll'oitle reduces lhc frequcncy und !;evcril y of t sode.~ by sigllificaotl y IOll ering catttho13minc (3.5 to 80%). urine. Ikcau 'iC of its . I i~ a potenllnl serious .ide effect. mon ~Ide cffect of metyroslnc .

~::'

.I

HO

Chal>!~r

Hi . ..ltir~"~rll""

"~r"iJ

52Y -- - .-

.... A.I.ns.
RHerpine.

D. ugs AffecUng c.atec:hoblmlne Stor.ge

Rc~rp!llc

'" ,.,

ti.

C<

". "
~.

of

II><

"'.

in<!

is the proIOI),piclIl drug affcctlng Ibc 'nICk 510r3gc of NE in 5)'mpatlw:lk IlCl,lrorul and ncu~ ..... of !he eNS and of cplllephnne in the ooil'n.aL medulla. ~("hOm, lite I10t I. mited .0 NE and cJllIlcphnnc. 00'" ever. II al'OO affed.' the slor.age of <,eroloniJl and dopanlille in dIe'r I'f\pectll'e neurons In ltJe bruin. Reserpine is an 'OOole ,/taloid obIain;.'d from the I'QOt of NIIII'm/ji11 "uTli'm/nl'. a thmllmg _I!rub foum] in Illdia. Other alkulOld cons.ilucrns , oIlllls pl.lnl lh~t pos5C~s phnnnacologicaLacli vily 'iml lnr to dial of rc~rpinc arc d~rpidint' und rcsdnnlunlne. Reser!'I.e bUld~ extremely tightly with the ATP-dri~cn monoIIIIIIlC trunsponcr tM. Irnnspor1S NE and other biogenic IDIIIlL$ fl'l)lllliM: cytoplasm !II'O the slOI"Jge 'c~iclcsY Thi s \uid'ng leads 10. blocbde of the Inlnsponer. Thu~ in symJIIIheuc neurons. NE. ..... hich normally is transported into the 1IOr.Igt nslCkli. i5 IlIStead IItctabohud by n\ltocbondri:tl MAO in the o:) toplasm. In addition. there is a gradual loss fI leslCle--.ored NF. as il is llsed lip by release resulting fmm ~ympalhetic lltI'\'e acti vity . It is lhoughl Ihal the ~Iorage lNi<:l!$ e'emllally become dysfUnctHlItal. The end result i$ ,\ltpktIOO of NE In lhe sympmhelic nc:UI'OI1 . Analogous rlJCdI art' ~n In lhe adrcn31lltcdulla wllh epirtcphrine and ltJ'()!()!ICrgic neurons.

whole root of R. \('T{H'IIWI(' are tL'Cd III the Ircatll'ltlll of hypcnell\ion. l'repar.moll~ In ""hlch reserpme i~ combmed with a diurellc also are alallable. as diuretics IOCrtaSe the efrlCacy of rcserplne. GU<Jnefhidine lind GUilniJd~. Ncuronal blocking as"nll; are drugs thaI produce thC'ir pharmacological effC'Cls primarily by prcvennng the r\.'lease of NE from sympathetIC net"\'e lemllltal,. I)N8~ of thl~ type enrer lhe adrenergic neuron by way of the uplakc-I process aoo accumulate within the neul'Qllal ~tOf'Jge "e,icl~, Then:. the)' stabilil~ the neuronal sroruge vesicle mcmbralles, ma~ing thenl les~ rc~pon sive II) ncn'~ irnpul)C5. The ability of the vc:,iclt~ to fuse with rhe neul'OllDI membrune is dimini 'hed. resulting in Inhi bitWn of NE rekase into the ~ynaptic cleft. Some of UI<"it agents on long-ternl admlnlstmlion also can produce. depiction of NE SI()1"C5 In ~ympathct ie neuron ... S lructur:dly. the neurvo:al blocling drugs Iypically pol>'i('~ a guamdino molel), ICNHC( - NH)NH!I ... hich i~ attached 10 either an alicyclie or an aromalic hpophillC group. llltSe structural featum an: seen in gU:lJlCthidine (lsmelin) and gu:madrel (Hylofd), which ure uscO dmically in the treatment ofhypcrtension.llIt pn:SCIlU" of the vel)' ba~ic gUlll1idino group (p K. > 12) in the'>C dlllg< mean, Ihm III phySIological pH they IIrt es~ntt:llly tomplete ly pmton nletl. Thus thes.c: agents do nUl gCI into the e NS .

NH

II

N ............... NHCNH:!

..
/'~

111

e ,m

OC- ~

II

~
GuanettDle

on< lieaL

OCH, "

libl-

$ICP

I, a

'111 po14I:

R'

OCH", ~.

0111 ;6'" . R' H. ~. - . j"-OCH,

"""

'oi-'ben n::serpirw: IS gil'l.':l1 orally. it ma~inlUm effcct is secn ... I couple of weeks. A sustuincd efft up 10 ~vtral '". I~ sec:n after the last dose has been 81'en. Reserpine ~"."". I'dy mtlabolil..ed through hydrolysis of the tStCf 111 ~IIIOIt 18. This yields nlClh)J rescrpale and "-..\.tnntethoxybc:n1.Oic acid. As is tYPICal of many Indole ~.;... I't'>trpine i~ ~usceplible 10 tlc:cumPOSIUOII by hsht .. ~.bllon . 80th lhe pure alkalOId and the po..-dI=d

Although gUDnelhidllle and guanadrel have vlnu.lI), the !i1IJl1C mechanism of action on sympmhC'lic neuron~. thC'y differ in lhC'ir phannaookinetic plOpet1ie~. For example, "'hile guanethidIne 1\ aMorbtd incomplelel y afler oral admini-.rolion (3 to ,SOIl.1'luanadn:1 is well aMorbC'd. with a bioavailablhly of 8SIJ. J These IWO agents also differ in terms of half-life: Guancthldint: has a half-life of aMt S day5 .... hert'a) gu:madrel has a halfllfe of 12 houl1!. Both agenls are partially nlCtaboli 7.ed (-~) hy the lhcr. and both arc ust'd to treat modcrote,to-scvcre hyperte nSIon, ei lher alone or in combumllon wilh another am ihypcnr.nsl~e agent.
Bretylium Tosy/afe. Ar'IOther AeuNnal hlocking ab~m is the aromallc quatern:l.l)' arnnlOlliurn compound bn:iyhum losy late (Brelylol ). Thl\ ~ent is used as an antiafThythmlC drug. [t$ antiarrit)thrllic IICliOlts are not belie~ed 10 be dl.le to its neurOf\llI blocllllS effect~, oo..'C'"er. This agenl is diScussed 11\ more detail in ChaplCl' 19.

CH,

B,
Bretyli..rnTosy\a1e

SYMPATHOMIMETIC AGENTS
SymplIlOOmmlotik agcnts pnxtuce effec1s re.o;embling lOOse produced by slimulatioo of Ilk: symp:uhctic nervou s system ,
They may be classified as agents thai pm duce effects by
:I

direct, indirect, Of milled llJo1Xhanism of action. Direct-acting

agents elicit a symPllIhomirlJelic ~sponsc by interacting direttly with adrenergic rc:ccplOn. Indirec1-lcllns agents produo:c effeels prinwily by causing the Il'Ju. ;e of NE from < adJt:nergic nerve 1efI11inals: the NE lhat is re leased by the ,oorrcct...,ung agent activates the rcceptOfli to produce the response. Compounds with D mixed mc:chanlsm of action interact directly wilh oorencrgic reccplON And cause the release of NE. A~ described below, the t1Icchuni~m by which an agent prodllCe!l il~ sympathomimetic effect i~ related intimaId)' tu its chem ical structure.

IIffinity for the rect'ptOf than the DIller form has . ThIs lih for both fI" lind ,tJ.rcccplOf agoni'ils. For eplocphnne. NE. and reilled compounds. the nlOU poIent enllmiofller (N) eonfigurntion. Th is enantiOlllcr i_~ typically selernllQ). fold more poIent than the en:ml;omcr wilh Ihe (Sjconlirmlion. It IIppeal'S that for all direct-acting. ,tJ.p/Im)~ ethylll.mJne-dcrived agoni Sls that an: struclur.lIly $lllUbr NE. tile n~ poIent ~n:lJ1tiomer i~ cllpable 0( IISWrnilll conformatioJllhat results tn the atr.lngemem tn ~ 01 C3lKhol group. the amino group. lind the ,tJ.hydrolYI':::: in I f~hlon ~mbling that of {-HR)-NE. This e~pI:Il ur stcreosciect il'ily is b:tscd on the presumed IntCT1lCtlOll II IheSC Ihrce cri,ical phannacuphonc groups with Ihm ~ plemcntary bi nding arcus OIl the rl."Ceplor and is kl1OllQ. the Easson-S tedman h~poIhoc!;is.17 .lfI Thi s three-potnt Inti action is supported by recent slIe-dIl'l:Cled flIulagcncs~_ ies~ on the IIdrenergic rcccptor and is Illustrated in Fir-

has.

16-4
of the amino group m phcnylcthy~mllk'S. Important for dIrect agonISt &Clivity. ll1c amlnogroup~: be separJIc:d from the lII'QmallC ring by two carbon I for OI)lUnal octi vity. Both primary lind secoodary amine'! \It found anIon: the poIent d lrccHlcli ng agunislS, 001 ;;~ or quaternary amincs (ClUJ 10 be poor direct IIgonist\.. nature of !he amino subsmuent dnun.:JtieaiJy affcclll tb: ~ c~ptor lIClecth';ly of the compoooo. In general. as ti1c IJJl 01 the ni1rog~n substituent increases. a-receptor agoo;~ Ktl dccrea'lCli and ,tJ.rect'ptor activity i~ases. Thus NE. .. ;5 an effect;l( PI~n:c~ptOf IgOllisl. is liso a potent (f ... htle ~plnephrine is a potent agon Ist al 01. PI . and PI m:crtors. lsoprOlercooi. oolO.e\er. is a potem Pl - and PI-lt(t\*' Dgoni\l bUI tms liuie amnily for 4' receptors. The n.:lllwtol ,he subSlitut:nt can also affect PI- and .B.z-rcceptor selecti\1t) In ~\'erJl instances. it h3S been )oown that an N-rtn-~
preS<'11CC'

TIle

Direct-Acting Symp Uaoonlinetics

7

STRUCTURE- ACTIVITY RELATIONSHIPS

Structure- lCI;v;,)' rdnllOllships fOf a- and ,B-lIdrel>C'rgic TCceptor 3gonl\tS hOl'e been reviewed,u15 The paJ'l:nl SU\IClUre

for many of the ~y mpmhomimetic dnlg~ is ,tJ.phenylethylamine. The manner in which ,tJ.phcnylethylll.mine is substi tuted 011 the ,"t'll and para positioo s of the aromatic nng and on the anuno. 4'. and 13 posItions of the ethylamioc side ehain innuences 001 only the mechanism of sympathomimetic action bot al<;l) the receptor 'lClcctivl ty of the drug. for the di~ -acung sympalhonllmttic llmlllCS, maximal &Ctivity is 5eeIl in ,tJ.phenyielhytarml'lC derivatives COIllllining hydroxyl groups in the mtlll and pam positions of the aromalic ring (a CIII~h.oI) and II. ,tJ.hydroxyl group of tile correct stereochemical cOll li gur.tlion on Ille elhy lamine pottion of Ille molecule. Such struclurul features are secn in the protOtypical direcHlCling eompounds NE. epinephrine. and isoproterenol.

HO

s.""
Se,2G7
,,,

OH ""

\-Phe'"
H, -..,?

"." '-... .A>",,-,,"-/ NH,

~Phonylethy\amine

"--

co;
Asp1l3

A critical factor III the intel1lC\Klrt of adrenergIc agonisllI

with their recepton IS ~te~lcctivity. Direct -llCting sympathomimetic<; thaI exhibit chirality by vinue of tile pre.~na: of II ,tJ.hyd roxyl group (phe nylethanolami!le.\) invariably exhibit high stcreoselectivity in produci ng Iheir Ilgonistic cffCCl~: Ihat is. oroe enallliomeric fonn of Ille dt\lg has grealcr

f~presentJn9 theIflustrallOtl of Figure 16-4 mleractlOO of

groups of noreplnephnf\(' WIth Ihe areas on the adrl!flef9" receptor mlltaogeneSlS studIeS.

lhe~~~~~~~~~i three

JlUUP enhancc~ fJ1. select!' II)'. For uarnple, N-/tort-ootylnor tOInc(lhnnoe iCollerol) 15 9 10 10 lime:!; as plMent an agonISE
111 lnC~al fJ: receplOI"I than al cardiac PI rcttpl~. Large IIbIuwencson the ammo group also protec1li1e amHlo group underJOln, o"OOh\'C dearninatiorl by MAO.
OH

!.ekeliv;ly 10 the fJ: receptor As in 1.hc ea....: of the resorciool rllodific:mon, Ih, ,, Iype of SUbslllUl10fI 1;" C~ Igcm~ IIlat flO( metabolized by co~rr and Ihus show Irnpro\'cd or.!l bloo\ailabillly.
~how

arc

OH HO

He He

, '" '" Isoprotereoo

NHCH(CHlit

, '"
h

HO'y-">",/",,, NHCH(CH al2

OH
Resorcinal

OH
Metaproterenot

He
N-/6f1-Butylnorepineptvlne (Colterol)

HO
Albuterol

Mrthyl or e1hy l substitu tion on the If-Carboll of the elllchain reduces d irect n..-ccplor
agoni~1

acliyn),
/'t'nl~yl

Imperium!),. i

howc~cr.

an

of action ofthc Ilhenylcthylam -

Mtxlifical10n of the catl'Chol ring Clill also bring aboul selectivity al a reccpto" as il appeao> that the calechol
moiely i~ more imporlam fOf agonist IOCli vilY at a~ fC(;eptors Ihan al , receptors. I'ot e~amplc. removal of the: II-hydroxyl gI"QUp from epinephrine givl!,~ phenylephrine:. "hid. in 1.'0/1trasl to ep;ncphrill<'. is sel'U\'c fot" the radrellCrgic fl'. ccptor.

. I by IIIU\;lIlg tile conlpoun(l re.~iSlam 10 metabolic Ii by MAO. Such rompoulld~ often exhibIt en0IlI1 cffecu \cne;s arid greater eNS VII)' than their ~s that do 001 contain an a-alk)' l llrotJP' a-Subsualso i affects ~cplOr ~lecli v lI)'. In the

a..,.

a-mcthyl or ethyl wb<.tillllil compounds t sclectllil)' LO\\.urd ,he fJ: , .. h,k In the case of 0 rt'C\'plon. Il-mcthyl ~ubstilu EJ'o compounds .... ith selmivi.), IO...-~rd the tl:Ill!pAlIQ(ber effect of tNubslilUlion is .he inmxlucllOO of a
~",cr ..... Ilkh

OH

has pronounced effects on the stereoPhenytepnnne In addi! ion 10 the ,B-phcnylclhyl:unine class of adrenergic receptor agonisls. ,here " n second chemical class of COntpounds. the irniu~lt)hlles. th~1 give rise 10 n-odrenergoc receptor agoniSis. These illud,:uohncs can be: roon-.elcctivc. or they can be sclecthe for cither the "'1 - or ol-oorell<'raic receptors. StruclUrully. unidaJ.ohnc:$ for lhe most pan lt3.'c the heterocyclic ImidaJ.ol ine nucleus linked 10 a substilUlcd aromalic moiety \fa r.oIC: I)'pc of bridging unit (Fig. 165).1-1 A1thouSh modlrIC311011 of the IrllKia7.o1rnc nng generally l"C5ults in compounds" IIh sigmrocanlly reduced ag<mOSl xliv ily. theft' arc C.lample, 01 so-called open-ring Imldouotino Ihal1lTe highly !tC1 1~C. The optimum bridging Unil (X) is usually a 5ing le amino or methylcne group. The: nature of the aromatic moiety. 0, \\cllllS 110" it is ~ub~tiluted . i, quit~

I ' for octivity. For e.lumple. \\< .Ih n. it j, Ihe 1!1)'lhro (IR.2S) l'iOIIlCr Ih:.1 I m netiv ily al receptors.

HO'''','''''''./."t ~, NH2 h CH 3 'H

H", OH

Although 1.hc catechol moiety I. an Lrllponanl '-lructurnl In Imns of )ielding oompouoos wi lh mumJaI agoal 'rcct:ptors, il can be fl'placN wilh 1 moieties to provide selectl' c adrenbeen uSI:d In seICCli,'C: .8l-rcceplor Ugoni'I" For c~!Unplt:, of the cilu:chol function of i,oprolerenol "ilh gl ves the urug IlIcluprotcrenoJ. "tllch .8:reccptor a~on iSl Ful1hcmlO/"C, ~incc the nng is not It wb!.trnte (Of COMT, fJ IIg0 n;'b thaI th.s ring Siructufl' lend to ha,'C bellcr absorption
~ .~ ." tllan their C;l.Ie-

In

I'

thi~

approach

hu~

="1''-'-91
~'" ,,"

lmidazoline

''''

In anoIher IIppruach. n:place 1IK11.hydroxyl of the catechol structure "'"h II agents. such u alOOlero!. "hlCh

F"l9ure 16 - 5 General struCturo1l1uturt'S of the II'nIdazolIl"'le ....adreot'fgoc I~tor ~1StS

f1c:lIblc. However. agonist activIty IS enhanced .... hen the aromatic rin, is substituted with Il:ologen ~ubsliulcnl!i ittI' or small altyl groups like mcthyl. p;u1,euhuly when lhey arc placed in lhe twoortho positions. SUlCI' t/le StructUIl:-3Cti vl\y n"lationships or the imidllWhl1C..~ an: qUill' different from Iho5e of the ,8-phcnylc:thylamincs. II ha.~ been postulated thRI the Imida7.olincs intt:11lCt wilh ..... OOrenel'goc (t'(~p tOO' differently from ,he way the ,8-phcnylcthylamines do. paniculurly with regard to ,he aromlllic moicty.)7
ENDOGENOUS (ATECHOLAM'NES

"!"he tilrec naturally occuningcatccholamlne~dopanllne. NE. Bnd epineph rine are used as therapeutIC .gem~.
Dopamine. Dopamine i, used lIIthe treamlCllI ofshoct. II i~ ineffecti>'c ol1l1ly. in IMge pan because II 15 a substrate for both MAO and COMT. Thus- II is used IIItra>cllOOsly. In contrast with ,Ilt: calccholanlll1C..\ NE ami epinephrine. dopamine IIlC'Je:tSCS blood flo .... to the kidney III dose.\ that have no chronot:ropic cffect on the heart or that cause no iocJeuc in blood preSSIl n". The inc~ascd blood no .... to the tid ney~ enhanccs Il l0mcmlllT filtrn'ion r'dtC. Na ' eKcretion. and . in IUm. urinary output. T he di lHtioll of~nlll blood ve.~ scls produeW by dopamine is the resu lt of its agonist action on ,he I),-dopilmine fl.'CCplOf.

ox idizing agents. and oxy!cn o f the air. It is IlOl cffll'1 by the oral MIle because of poor absorption and rapid ~ oJism by MAO and COMT. Although IllIruvellOlls infusion of epinephnne Iw ponounced eff~ts 00 the ClinhOVllliCu lar system. Ib use ill treatment of hean block or cin:u13tOf)' collapse is InMN becau$C of Ib ,cndency to indlll,."c cardiac arrhythmw ~ mcrca:sc~ ~y~tol ie pre5.\UIl: hy increasing cardiac OUtput. -' it L owers d ill~'olic pressure by causing an O\'eraU lireN in pcriphcml rc~istance: the nct result is lin lc change In mUll blood pn!5~ure. Epinephronc is of I'lIllIe as a conStrictor III hclllorThagt" nasal congcstion. AI'iO. it is used to I'nhance the 1Icti1ll\ o f locaL allCSlhcllcs. L U.)e in the$e two SiluatmllS Ilk> IS advantage of the drug 's potent ~t imu latOf)' cffects 011 Q If ceptors. The ability of epinephrillC' to stilllu l:otc Ih. ~r has led to II~ usc: by injecllon and by inhaLatIOn 10 bronchial ~lTlooth lllu~;cIc in a.~thm:t and III anaph) 11Cl1C~' tions. Sel-cr'dl oVCr-the-counter prcpanltlOllS (e.g .. fill. lIIatcne. Bron~ aid) used for treating broilChiaJ ~hll\a II'( epl nephnne. Epinephrine is uo,ed in the tll:al ment of open-angle Jl coma. whe~ it app;.rcll,ly rl-uucC$ intraocu lpr Itrel\Sllrf '" incrca~illS 'hc nne of ou,l1o .... of aqueous humO!' from Ihr anterior chambcrof ,he c)'e. 1bc ini'ation often cxpc~ on in~tillation of epinephrine imo the eye has led 10 III! dc ,-eloprne m of OIher prcparutions of lhe drug llut pokao hally are not: as 'mlllllng. One such uample is d'l'I,cll1l

" "

ti-

" " 11

'0

" " '"

a

mn

HO

In doses slightly higher than th()';C reqUired 10 increase renal blood no ..... dopamine stimulates lhe P, I'CCl'ptOl'll of the heart to increase eard iac output. Some of 'he effects of dopamine un ,he heart are al..o due 10 NE relcasc. Infu~ioll at a MI'C sn:a1er than 10 #slkg per minute rc..u lts in Mimula tion of '"'I I'CCcpl Of'l. lcading tu vasoconstriction und an in crease in ancrial blood pressure.

Dipilfefrin. I)'p...cfnn (d,pi\'alyl cpinephnn~. ~ i~ a prodrug of epi nephrinc Uw is formed by the C)(mfg. tion of the ca/echol hydroxyl groups of epinep/lnne plvalie acid. Di pi,errin i~ much IfIO(e lipophilIC than. nephrinc. 3nd it a.chle>-~5 much bener pcnelr." ion ofthe~ when admi ni~tered topically !I$ 3n aqueous WlUliOll (Of trca ' me n! o r pnm:ory open.ang le glHIIComa, It IS con,-encd. epinephrinc by e~ter'.I~~ in the l'Ornca ami ~nLerior ch.lJrillJ Di phefrin offers the alIvamuge of being Ic~s irriWliJll_ the ~yc than epinephrine. IlIkI because of ilS more tfflCa trol'hpon into the e)'l'. Jl can be used on lower concerH .. _
than ~pml'phrille.

PI.,

Nort!pinephrine (NE). NE (Levophcd) i~ u~ to ll1ainuun blood ~re III acute h)"potcnsh'e states fCSuil ,ng from $IIrgical or IlOIlSlIrgical trauma, central \'asomoIor depression. ~nd hcmorrlulge. Like theOlhercndogcnou~ catecholamines. it is a suhmatc for IxMh MAO and COMT and thus is not: cffective by the oml routc of admini\trnllon. It is gh en by intral'ellOOs injection. Epinephrine. Epinephrine (AdrenoHn) filld\ usc in 3 number situatiuns because of its pOIent illlulUlOf}' efrects on both (f- Hnd ,8- adrenergic l\.""cplo""'. Litc the other ca tc cholam il1C.~. epinephrine is ligh t sensiti\c ami ea~ily ox idllcd on c~posure to airbccause of tile catechol nn!; sy\'cm. The development of a pink to brown color indicatc<i oxida 1;"1' bn'aldo"'n, T o mlnimiu o]l;idauOll. solutions of the drul1U"C Slab,h7.ro by tilt: addi tion of reducing o.gcnts such IS sod,um blSolllfite. As the free amillC'. illS used in aql.lCOUS solution for inhaJahon. Litc other aminc.~. It form~ salts wuh acids: for enmpk:. those now uscO inc lude the hydrQo::hlonde and the bllaMrate. Epinephnne is destro)'cU Jeooily in alkaline 5OI uti()r1~ and by metals (e.g .. Cu. Fe. 7..n) .....eak

o
II
(CH3l:sC-C-O"","",,,,
A

or

s'

, 'CH,),CCO,><

a-ADR ENERGIC RECEPTOR AGONrrn

Phenylephrine. Phenylephrine (Nco-Syr..: .... ~troct ure \hown abo>e under "Structure- Activity Rc ships") IS the prototypical 5('lcct;\"e di rectacting Q'I'~"'; agonhl. It is II potent V ;lloOConstrictOl' but is 1l!SS potent

"II\'C

ntclllb-

: in the linutl'{\ mas. It ;JUt. and

~ "'~

iccl't'll-'iC in mean
ilal!:C

or

!>Cu\"lty 1S taJ,.e~ 00 arc eccptOl"l to reho:

:tIC rc",,'

eptq1hrinc and norcplllCphrinc (NE). It I' IICU\ C100 tlcn g,,'<'n 1JI'aI1). and ilS dur~"on of actIon IS about tlOo le<' Ihat of Cpl' Kp/Innc. II l5 mclaboli/.e(/ by MAO. but ~lIIee II ia;;!.s the gl1ioI moM!ty. it I~ not I11Claboli7.cd by COMT. II is relaoYely oontol1c wnd produces linle CNS stimulation. When ifPIled 10 mucous mentbranes. it reduces eonge'<lIon and ,....llIng by CO.bUlCIlIIg tnc blood H,s~ ls of the rnembr'.uM!S. lbu one of its m.:un U'iCS i~ in the relief of naS31 eongcstioo. III !be e)'c. II IS used 10 dilale the pupil and to treat openangle paucOllQ. It al50 i~ med In spilU.l anestheSIa. 10 prolong the ~ia and to pK\Cnt a drop in blood pJl:ssure during fit p'oc:edure. Another usc is in the tl't':llment of ~\crc hy p.:mI~ion resul ting from el lher shod: or drug admimstr.llion.
Mf!fhoxamlnc. Aoother M'leetive dire<.1pcting ai-receptor agonist used Ihcmpcut ically i~ IllCtho~llllline (Va >(\,)1). Thi~ drug is P \'3.SO(."QIlSlnCtor that has 00 stimulant a1JOn on tile hean. In fllC1_ it tends to slow Ihe I'entrieular .: becaLI$C of IICl i~IItIon of the cnrolid ,mus rdlc:x. It is

Naphazoline. Tctrahydrozo/ine. XylometazoJine. and OlC)'rrNiI'tazoline. The 2-an11J,.)llInKbzolme~ lU.phal.o11111: (Pnvlne). lelrohydro1.oltnc (Tylinc. visinc). xylomctamillie IOtrivin). and oxymchv.ohne (A frin ) are 3Il001~1S at both al ' and a r adrencrgie reccpt~. llM:<;c agenl~ are u!><'d for their va<;()(;oIl,[rielivc effech ~s na., ..1 and ophth~lm1c

deconb'i:Slunts. They have hnuled acreS!> 10 the CNS. ~Incc lhey essentially exist In an lonl7.ed fonll 31 physiological pit because oflhe I'el') basic nalure of tile Imidazohnc nnl (p K. 91010).

R -n
N N H

_g.. Pn
hma usc

gle glau
:ssurc by

mpotrnt!han phenylephrine as a vaSOCOlls.trietOf. Metnex .uJIt IS used primarily dunng surgeI)' 10 maintain adequate n:ml blood pre:.sure. (':Specially in conJunclion 100 Ilh spinal I!leSlltila. It docs not slimu latc the CNS.

from the ;.cnclloCl.-d :d to the ;11 poten pi\efnn,

Proplflt:)

OH
'yNH,

CH,

!;Slenr..;amne "It II tllan CPl' of the eye on for the ",,'ened to rch3mbcr lfitall nll ttl t cffieK'nl

Midodrlnc. Midodrinc (proAmaCinc) ~prescnts anotber example or a dimetho~y-P.phcnyklhylaminc derivachat i~ used IIle\"Jpcutically for its "asQOOIIstriclor propcna.Spccifieally. II I~ used in chetreatmem of~)'mptomatic ~i(- hypOll.'n~ion. Midodrilll: is the N-lllycyl prodrug If tile toeJccm'<' al-rtteptor agooiq dcsglYlllldodnnc. Re-

H,C
Xylometazoline: A -CHz

::cnII1lIlOll'

N-glycyl m()lety from midodrinc OCCUT$ readily die: li'cr IS well :co thTl)llghoul the body. prf:sumably by
... lIo{l~
,..h~s.

OH
" " NHCOCHzNH2

H,C
Clonidine. Clollldmc (Calapre') I~ an eumple of a (phc' nylimino)imidawlidme dcri\ahle lhal POSSCSloe.' >clec Ilvity for I~ aradrencrgle rttcplOf, n.e 0'1:t,2 "'"0 1\ 3(X):I . Under certain condition", weh as inlravcnous infu5ioo. clonldinc c~n brieny e~hibit ,.socQ'hcrieti,c ao:.1t\ity as II R'W II of stlmulatioo 0( penphcml n-a.Jrencrglc rcccp-

I
OH

!Syneplmne. ity Rc lallnn I 0' I-receptor potent titan

--

10I'"'l. Ho ..... ever. this hypenen ~ive effecl. if it (I(.'Curs. is fol lowed by a IIIuch.longer lasting hypotensi"e effcci lls a result of the ubiTi ly of clnnidin.e 10 Cl1ler il1to che CNS and ~'imu IlIcc ~ fCC\:plor.. 1 0c;,IOO in regions of the bram. ~uch as tile nudeu\ traclUS 'KlIilarius. Stimulation of these (II reccptOl' bring.~ aboot a decrease in ~ympatlletlC outflow from the: CNS. "'hich in tum leads 10 decrca'ICs in peripheral .-ascular resistance and blood presStlre..Il~ .. Bf1ldyeanlia i~ al'>O rroduccd by cionJdme as II J"C)IJ lt of a r:entr:lll) ind~cd facilita_ tion of tile vagus llCn'e and Slilnulatioo of cardiac prf:Junc liOlUlI a :-oorenergic I\:CCplOfS. W TllCse phannocolOj;IClII ilCtion' have made domdmc qUlle u'ICful in the trealment or
h.ypcnen~ion,

CI

N=< J
N H

H N

half-life o f clooid inc r~n!;cs frt>m 20 to 25 hour) ... hile tItI; for guanfocinc i~ about 17 houl"!l. Guan abcnl has the 5hontII durntion of action of!hese t~e agerns. wi th a tulfJifr Ii about 6 hours. Clon odine .nd guanfacine :m: cxcn:tcd_ changed in the urine to the extent of 60 and 5()'i,. ~. t,,ely. Very lillie of guall:lbenJ; I~ Cllcreted unch:lllgtd_. unne.

CloI'Ikine: R H .-Hydroxyclorlicline: A . OH ApfacIonIdine: R . NH2

CI

NH
CH=NNHCNH2

II

" "'

."''"

"

"

1'he:ibl\\\y of claa.ru.ne ud ,'" an:t.1~ 10 u.m an 1U\l1hypcnensl\'l: effect depend~ on the ability of I ~ cornpounds 001 only 10 Internet .... nh rIM: III n.-ccpcor bUIIII'>O \0
gai n enlry jmo riM: eNS. I'or example. in the ca;;e or donidine. the b:L~iciIY of the guanidine group (Iypicall y pK. I3,6) is decll!',,-~d 1 8.0(rhc pK. ofclonidmeJ bccau'ie ofitsdll1,X1 0 allachme'1I10 the dlchlorophcn) I ring. ThU$, at ph)'\lologicaJ pH. dOI'll(ilne .... 11 exi'-lIO a 51gmlicanr Ulcnl In the nomooil.cd form requlI'ed for ~I!e Into the eNS. Surn.lilUI;OI1S 00 the aromal ic ring also affe(!\ Ihe ublli,y of cloni dlllc and ils analogue, 1 !luin cntry into Ihe eNS 10 0 produce un IUIti hypertensive ceTl'Ct. Altlloogh various halogl'lI and allyl '\lIbqi lulioos cun be placed al the two orll",

C\
Gullrtabenz

CI

o
II

NH

C H~NHCNH2

II

CI
GU8I1Iacioe

positions of the (phi:nylimioojumd37.()lidine nuclel,l\ \\<uOooI afreell ng the amnily of the den-alIve!! to ..... ard tr:! rettplor<. such sllb!;mulion~ ha\'c a m"tltd eff~t on tlli: lipopllllicuy
of the compouoo. Halogen sub\titucnlS such us chlonne oo o;e,.' l11 W pfm Ide the optirnJI chamctcristi cs in thi~ ..... gard . This distribUl j~e l)/lcnomcoon j, S<!Cn ",jlh O!le of the metab oIiles of domdme. 4-hydrox)c lonidine. Th i~ COnlpound has good affinity for (12 ~plors. oot ~I oce il is tOO polar 10 gel into ttw;, CNS, It I~ 001 an effect,,'e anl1hypenen.~i \e ageol. 0 In addlUon to bmding 1 the O:l Dd ..... netgic receptor. clonidine. IIlo ",ell as some other inlidal.olmes. sho",s high affini;(; for ",hal has been ICTml-d lhe "i nlidalOlinc" ..... ecptor. ! Some Mud ie, ha,c implic~ l cd a ro le for the imidamline rctept'""" In lhe Muhypenensh'c ~ffects of donodillC. 1 .... HO\loc\"Cr. other ~udies ,"'ohing boIh site-duttted rnUlIIgent'Sis of the ct2A-ad~ncrgic receptor subt)pe and !!cnetic-ally engineered ~llOCkoul mIce deficient in either tile a z..or av.-adrclll;'rgic reccptor subtypes provide endcnce thaI the hypolensile n:.sponloC <If Ihe ,.z-reeeplor ngon;,ls liI.e elonidioe primarily i n "o l ~~~ Ihe a .u.-oon.'llcrgie rtCeptor ,ub!ypc.' ....

Aprac/onldine ~nd Brlmonidine. thcr~pcut.c use lIS an ullllhypcncnsi\"e agen,,:.-;';';;";:i. bn found 10 pro~i.:k benerlCial effects on lnumbc:rof s.lual ioo~.1 Thest: illl: lude migraine prophylu is. ~,,,,_ opiate wi thdra"'" syndrome. and anc'Ihes.ia. Tlu; JI prompted lhe developmen t of analogUCll of clonldlnt fill ~ cific u:.c in !>Ollie of tlte aoove urcas. T .. o ~uch ~"1 / arc aprnclonidine (lopitline) and bl"imonidone (AI Both are sl'ieCli H' UJ receptor UJ;OlUSlS" IIh al:a2,.. 30: I and 1.000:1. respcclI'cly. 1lLey boIh lower i'~~ prt''I...\ure by decreasing lIlIut:Qtlll humor pflxJu.."oon IIIIh creasmg aqurous humorootflow. AprnclollIdinc b IISCd ci ficull)' to cOllIrol cle"lItK:mS in inlrJocul pr j'l"e!>w.n' tbltea (...-cur during laser surgcry on the eye. Brimonidine u<.ed III such a manner; in lLdditioo. il is approved forIN' U"l."atlng glaucoma. AIlQther example i, liLllnidinr naf1ex). "hlCh finds usc III lrca!ing spastici!) a.'OOf'*<i 111UI\IPIc !\Clcrusis 01'" spllllli cord injury. 8 y slI mubua( adrenergic rtC~ptor.;. 1I is bellcved to ~asc lhe of excimlory amino lICid ncul\llmnsmi ucl"!> fronl .pula! (I in tcmcuron s.oU.

~ _N

Guam,lHi>nz and Guar,fadM. Two analogues of cloni dine. guanabenz (Wytcnsin) mod !!uanfaclne (Tenc:x). are also used ns anlihypenen"ivc dru!;s. Their mcchanbm o f action i'i lhe "lllllC as thaI of CIOllidillc. Slructurally. Ihese two compounds can be con,idcred "opell-ri ng imidamlidines:' In Ihc.'iC: compounds. the 2.6-dichlorophe nyl moiety found in clonidine is COIIl"Il-cttd to a guanidmo group by ~ l",o-alOIll bnd!;C. In the ca~ o f 1!U;U);)~nL thl~ bOd!;e i~ a - CH - N- group .... hile for guanfac1l\C' .I.s ~ - C U:COmoiety. For both compound.~. conj ugation of lhe guanidino mo iely wilh Ihe bridging muiet)' help' 10 decn,:u!oC Ihe p K. of this nornl~llIy 'cry b;1~ic group !IO that al phy~lological p/I a sign ificant iXl"ioo of each dill!! cxists in it- nooionll.cti form. o.ffcrencn bet ... cen clonidlne and ilS two analogues are ~n in thelT elimination half-life "alurs and on lheir rnctaooh sm and unnary clcrctiOI1 patterns. Tlle cl lln malJon

Br

iI

N =<J
N H

H N

Brlmonldine

CI

N =<J
N H

H N

ChajHtr

I.. . Adr~r~" A~"'IJ

535

Mtthyidopa. A phen)lrlhylanulle dc:rhall\-e chal IiIows seleclility toward the 0': receptor is u-mClhylnorepi
(Fig. 16-6). As discussed aoo..'c under "StfUC' Ift-A"",I), Rela\looship!i,'" the pn:sence of an ,,-methyl ,oup ,n the COIRCt configl,lL'lluon on the phcn)klhytanllllC _leus )lcI.Js compounds with illCreased palcoc)' at Il:z re
.jiw,,~

!11M and dcc:rem;ed pOIC:rtey al

fli

n:ccplOl">. Alltlough a-

w)llIortpmcpilnroe is I1QI g il't'Il as a drog. 11 IS ,he metaic product of the: drug nlcthy\dopll (I.a-methyl-J.4-dihyRl)pbcn),lalallIllC. AldofIlCt). SII..:e lne1hyldop;o ;s a close

l1l\I(:111"11 analogue of l-dopa. II is treated as an niccmal!: "~1C b) the tl1l.)'Iroe laromauc alllmo add decarbo:\yllit The product of this initial cDqrrnl1ic rellCtioo is a-ID\:lh. lidoplm.roe. This inltnnedialt. in tum. is actal on by dop;t_ P.hydro~ylafoe 10 give Ihe dillslcrec>iSOlllcr of amhylnoRpmcptmnc. IOhich po6SeSSC's!he (RJ configuraIII lhc cW'boo wnh the P.hydroxyl group and the (S) ~'Igunuion aL the c:1lrbon WIth the a-mcthyl ~lIbslilUcnl fil. 16..(j). 11 IS postuhued that o--mt'thylnorcpirn:phnne acts OJ m:cplOf1 in the CNS in the <;alUe lnanner asdonidllX'.

to decrease: s) n'p~theuc ou1ftow and IO\\-'er blood pressure.l& Since methyldopa serves as an altcmatl' substr.ttc to L-:aromatlC ammo acid decllfboxylose. It ultimately decreoses the coucenlr~tion of OOpallline. NE. cpinc'p/lrine. and $-Crotonin in the CNS and pc:nphl'ry. Methyldopa is usc.-d o nly by 01111 administr.uion sin it~ l.-'Iueriooic cha1"llCICr limIts its M)lubility. Absorption can range from 8 to 62% and appears to ;rwolve an um;no acid transponer. Absorption is affected by food. and !\bout 4()<l, of tluit absorbed is convened 10 methyldupa-O-sulfate by the mucu;.al intestinal ~Il~. Enlry into the CNS also appear.; to invoh'c an lICU\c tr.mspon process. Tbc c~ter hydrochloride foalt of methyldopa. methyldopal r (AIdortX'I ester). IUS developed lIS I highly watersoluble derivuli\'c th:u coold be used to ma~e parenlel"lll pn:pnr.ttions. Methyldopatc is cOI1\'ened to mc:thyldopa III the body through the aclion of estcrases (Fig. 16-6).
DUAL .... AND .B-ADRENERGIC RECEPTOR AGONtSTS

HO

t
HO,V'"'''> HO '/'''''&

EII8faS81

X
"

NH,

CH3 C0 2H

11\Cre lire synthttic direct-octing sympathomllUClics ... hose 'ht-rnpc:utic use: rclic! on their abilit) to !let :It both .... and .B-ndrencrgic reccptors. One c.\lImplc is dobulamine (Dobutru). Structunlly. dobutamine can be vie ....ed as an analoguc of dopal11l1lC ill which:l. 1-( meth),I)3-(4-h)'dro~yphcn)'l)propyl ~ubslt tucnt has been placed on the amino group. Thi s substitution g"'e~ a compound Ihat po:;scsst'S an asymmetric carbon atom ThUs. dobutamrne UISIS liS a pair of enantiorner.;. wilh cach enamiom('r posses~ing a d;<;tincl pharmacolog)' ..w llJe (+) enanhomcr Il a potent full agOfli~1 al both PI and Ih. n-cr-pt0r5. In oonlr.tSI. too (-I ~Mntiomcr i~ .'lOme 10 tunes less polem at 13, and Ih. receptors. llJe (- ) ~nanUOll1C'r is. however. a potcnt agon;sl m al rcc('ptOl"S. l>obumminc docs r"IOI act as an agoni5t at tile tloparmnergtc: re<:cp:ors that mediate Il:nal vasodilanOfl.

Dobutamine.

I
HO

L-Nomatlc AmIno Acid Oecalbol!)'lase

'"
A

'7

OH

T CH,

'"

NH,

"""~""
In \"i\o. I"Ilc:\'l11k dobutamine incrca.o;es the lnotropk acu "it)' of the hean to a Illuch gcmer c~t('m Ihan ;1 incrcll.ws chronotrupi!' activity. This pharmacological profile has led to it\ Ul>C in lreallng congeslive lii:nn fnilurc. Since PI reccp1011 are in\'ohed ]lO'>lli\'cly in both motroptc and chronotropic effecls of the hean. the sdecti\"(' Illotropic effcci ,,-'('n with dobutamine ClitulOt simply be due to liS actlvlly at Pt recep:ors. Rather. thi~ effect is Ihe rc<;ull of a oombinniioo of the inotropic effect of {+ }-dobutamlne on PI rcccp:ocs and th~1 of {_ }-dobutaminc: mediated through a l reccptOO'.'" Thu, this is ~ c:ose when: a r.ICCmic: m;~ture provides II rI"KJI""I' de~irablc p/larmarological and llii:llIpeUlic effect than would either enamiomer alone . Dobutamioe IS given by introvenous mfuSIOfi. since 1\ i, not effecli vc orally. Solutions of Ihe drug can exhibIt a slight pink color lIS I result of oxidation of the catechol function. It has II plnsma half-life of about 2 minUICS. It is rne\.llbo1i~ed by COMT and oonJugalion but not by MAO.

Dopamine II-Hydroxylase

(I R,25)-o.Methylnorapinephrina

...;,;.
'"

MetabolIC CClnVl'f1.lOl1 of melhyldopat!' artd 10 o--fTlI'lhyjoofl'pmeponfle

536

~ iu- mid Gi.rmld.r To'/butlk ",0'1""'" MrJiciNl/ <HIll Plonmwuuurl</ C/o,mUlry

,B-ADRENERGIC RECEPTOR AGONlm

IsoproIet'enol (I ~uprel , WUClure shown aoo..'e unJc:r . 'SlruclufC- Aetivlly Relationships") is the prolotypical ,8-adrenergic re,,;-plor agonist. Because of lUI isopropyl subslJlution on the nitrogen alom. il has "'lnua1ly 110 effect on " n:ccptors, Ho .....ever, II does OCt on both fil aoo IJJ. rcccplOf". It thus ean produce an ilX'rease in canhoc output by st imul:uing cardiac fJl receplOf" and can bring about brollchodllmion through sti mulmlon of fJI receptors m tile rcsPIl'Jlory lrael. It also pmdUCCli Ihe metabolic cffects expeeled of a polent fJ 3g01H~ . lsoprotcrenol i~ availablc for use by inhalation and injection. liS principal clinical usc is for lhe relief or bronchospasms usociated "' ith bronchial asthma. In fact. il is one of the most poil'nt bronchodilators available. Cardiac stimulation is an occasionally dangerous ad\l'f'SC effect in ils usc. This effecl of i5Opll)lerenoi 00 the heOUl IS sotnl!tlllles made: usc: of In lhe ire3tmenl of hean block. After orJ.1 administratIon. the ab!.orptlOll of isoproterenol i~ ruther emllic and undependable. The droll has a dumtion ofuclion of I to 3 hours after inhalalion. The principal reason for itS poor absorption cilar.ICtcriSlic$ and relmively short duration of aclion is its facile metabolic tral1~fonnation by ~ulfllle and glucuronide conjugation of the ring hydroxyls and methylation by COMT. Unlikc epinephrine and NE. isoproterenol does rIO! appear 10 undergooxldal i~e deamination by MAO. Sma: il i5 D calccool. it b sc:n5iti"'e 10 light and air. Aqueous solutions become pink on ,umdmg.. The problems of lack of ,8-reccplOf selech vity and rapid metabolic Inacli ... ation associaled WIth isoproicrenol ha~e been o,'eruolllC al kaSi panially by the design and de'elopIncnt ora numberof seleclive fJradrencrgic n:ccplOfagonisls. 'J'hcse agents II:lax slTIOOIb musclc of the broochi. !,Ilerus. and skelc tal mu.-.cle ,'ascul;\( supply. They find their pomary use liS broI\chodil;\lors in the treatment of acute and chronic brollchial asthma and other obSlruCli ...e Iluhnonary diseases.

Ifoprore~nol.

A/buterol, Pirbuterol, and Salnwterol. Alt.'! ..tI ( Pro"en"l, VenlOhn, ~tructure shoo ..... n above ulldtr "S.M' ture-Acuvily Relalionships' ). PlrbulCroI ( MaxalrJ. and MImelcrol (Screvent) are uamples of sela:th'c JJrreccptOr .. onlSlli ",hose stlttli ... ily results from replacemenl 0( thr m"'lD-hydroxyl group of the ca/.ecboi .,ng ..... ilh I hydro.t.) methyl moiely. Pirbuterol is closely reluted SlruclurallylO albuterol: the only difference bel .....c:cn the t ..... o is thal prn. erol contain~ u pyridine ring instead of a ben7.tne nn,. AI in the case of mclaprQIerenol Md terbulaline. these dnap are rIO! metabolitt(! by ei lher COMT Of MAO. InSlead.1b:) are conj ugated wilh su lfate. They dllls are active orally._ they exhibit a longer dur.1uon of ao:.1ion than iSOf~(Autat The duration of acUon of ICrbtualine. albuterol. and put. erol is In tht: rJ.nge of 3 10 6 hours.

CHzOH
Pittouterot

OH HO

and Terbutallne. A.~ pointed OUI in the discussion of structure- activit y rclaliOllships, modifiea lioll of the catechol portion of R fJ agonist has resulted In the tJe"clopnwml of selective 1JJ.-n.'CeplOl' agoniSis. FQr example. rnelaprOlerenol (A lupent. structure ~hown abo"e under "Structure- Activ1ty Relalionships") and tl'routaline (Brican) I. Brethll1(') are resorcirt()1 den. atl\'cs thal. are IJJ. ~1e<1ive. Mctaproterenol is less /h. selcclI'e than eithcr terbutaline or albuterul . Al lhough these agents have ~ lower amni ly for IJJ. rc(ejKor.! than isoproterenol, they an: much more efreclive ",hen gi'en orally, and lhey have a longer durJ.tion of lICIion. Thi s is because they are not metabolized by either CO MT or MAO . Instead. their metaboli ~m primarily invol, cs 81ucuronide conjugation. Although bulh lnelaprotere1101 and lemutaline exhibit sigrtinclllu .8:-re~'Cptor sek'Clivity. lhe common cardiovascular effects lI.~socialcd wilh other rtclrenergic agenLS ean also be seen with these drugs when high doses an: used.

Meraprote~f1ol

Salrllelerol is I panial lIgonist at /h. recepiOl'\ and hII potency ~lInilnr 10 that of isoproterenol. It I~ very Ion.... ( 12 hours), an effcci Rllributed to the lipophilic pben)lalj substitucnt on the nitrogen atom. which is b.:lieved to IDl/I act ..... ilh 3 site outside but udjacem to lhe acti~e !il( agent a'>5OCiate.\ wilh the /h. n:ccplor slowl1 and dJ~ from the n:ccpior al an e'en slower rate. '

n.

Formoterol .nd L~valbuterol. ArIO!her...., /h.-leceplOf agonJSI is FormolCroi (Forudil). lbi lon& of :!Cllon ...... hich IS conlparabk: 10 that of sahnclaol. been ,uggeSioo 10 re5lJlt from its as.sociation " 'ith br:lIle hpid bllayer.'l Foonoterol has a much flster~" action than docs salmclerol. BOIh of these Iong,ocllnl are used by inhalauon and are rttonlmcnded for ~. nallCe trcallncnl of u~thll1lt. usually in conjullCuon With. inhaled L'Of1ieostcroid.

!lite ;.;

H N
(R.S)

" , NHC(CHsh

HO

NHCHO

'"

CH,

'"
'"
OCH,

OH

All of lhe aboH~ /h.-rttep!Of Dgonists possc:ss allmI ehiral center and arc u!'cd as racemic mlxlures. ~a'''1

,--

-------------- ....
Ihe I'1lCclllic mi ~ lUleof lhc /11.11) arid (S.S/eMntionw:rs. As menuooed abo'e. n I~ tM (1I/I"OOw:r orlhe phenylelhanolamil)CS thal Jl'OS.-'ieSSCS the: pharm:aook)gkal aC'IJ\ ll y. Corlttms ha,C' been l"al..ro aboullhe u.... of ~l.K:h r.occmic mi"lun: ~ uoder the belief thaI the lnacti\e (S) isomer rna} be !"e'IiJXln~i ble for somc of lhe ad,,~NC cffecls seen wi lh lhese ageliLS. Levalbulcrol (XI ptnI'll. the (II) lsorner of mcClilIC alhureruL, ",present~ lhe line auempt 10 aJdn:ss Ihis i.SUI:. 1\1 0 chintl
~SI'~ ~nlef1i

)utcrol

alid i-, used

a~

SIro.:-

nd .<>atlor agof the

dro .. y-

oilly 10

plrbutng_ A~ drogs d.lhey Uy.a nd

rClal dislres.~ cuused by I:.\cesSI~t uterine act" til'. lis Ulenne inhIbitory ciTecls are mon: sustained than liS dft~ on the cartliO\lISCu Lar \)'5tem. \lhich an: mlnlm:ll oomp.:u-c:d .... lIh those c:m.-..:d by nonsclecll ve II !!gonists. The canliovascular cfrecLS usually asSOCialed W ith 11$ oomlnl'ilrahon are mild toch)'card ia arid sl ight dia. tolic pn:ssun: decrease. Usually. , It i\ adnllAlSlcred HllmtUy by mltll,eoous Infusion 10 ~Iop premalure labor. Subsequently. II rna) be ghen OI"dlly.

OH

Metc:!lOI,

plroUI-

Another sy mpalhonllJllelic drug Ihal fiod ~ 1M lIS a broncho(liImor is lhe tl"-elhyl calecholamine. isoc:lha~ Thi ~ agent is weaker Ihan io;oprolcrenol al ~l il1lu lati llg PI. ret:qlIon. In addition. ItS /h. ~ Iecli ~ it)' IS not as !real Il.~ 1M liCen Wllh drug~ weh I\S lerbulal inc o r alhulcroL. Bl'CUU\C ultbc ~nce of the a-c:th),1 group. iSOC:lharioc is not mebboh lcd by MAO. Because' il ooil lain~ the eatechol ring ~loItm. hollc,er. II is llloClaboh,,ed 4uitc effectively by COMT. It alw is O-~ulfaled 4u;te effecmt'ly. l.'>QC'tharinc bI. dUl'1Ilion of lICtion slIl"I:" 10 that uf l~uprOlen:lMll .

~tha,irle.

H
N

'"
HO

CH,
Allodrone

'"
A

OH

OH
HO ",A", /-V NHCH (CH~a HO

pJ oAdrenergic Receptor Agonists. Sc:lcclhc dlrectacting IIgonl'l\ for the ,B,-adrenergic n:ccptOf have been de"c:I~. btll they Ioa,e not been approved for thcl'1lpt:utic U~. ) Becau.'oe Slimululion of [he fh l'e<..'Cplor promotes lipolysis. these agents may h3'C poIenllal as am iobesny drugs aod us drugs for the tn:atmenl of oon - insulin-dcpcndenl dia-

I""
lsoetharine

betes.

Indlrect-Adlng Sympathomlmetlcs
IrKIJrc:ct_octing 5ymp3lhonmneti c\ act by n: le:'~Hlg cndogeoous NF.. llley enler lhe nervc eoding by way of the ;}(:'\l\e upl:l~e proces~ and d"placc NE from ils ~Ior.lge granu~ Cenain qruelUrnl d ,aructenSlics Itod 1 IllIpan IIKh ~ sym0 pathom imetic 1Illivlty 1 phcnyleth), lami roes. As wuh lhe d,0 fl'(1-ocung agents. thc J)''<II\.'C of the calechol h)'dro~yl s enhmK:CS lhe poIenc)' of iod ,rectoctmg phenyk:lhylammes. Ho we,'cr. lhe indlll'Cl-aclmg drugs Ihal are used thernpcu.i cally al\' not catCf:ool dcri vlIl"tS aod, in mo!iit cases. do IlOl c\e n comain a hydrox yl UlOid), . In comrJSI wllh the direclaclinjil agcnl~. lhe presence of a ,B-hydm.. yl groupdc:creases. and an (Hllethyl group incrca..'iC~. the effec.i,CIIe$S of loditttl .lICtlng agent~. TIle J>U''iC1II.''C' of Mmgen ~ub!.titucnts deerea'iCS lodill'Cl OC"1t ~i l y. wilh substituenlS largtr than methyl rendc:Tinll !he C()tnpoond ~lM ua ll y infICmc. Ph<:n),ltlhylaminc! th.::tt contain a lertiary ammo group are also mdfecli' e a~ NE-n:leasing agents. Given the fOl\'guing StrucHlre- act; v;ty comidc:nllion,. 1\ i~ ea,y 10 uodcNOnd II>h) ampnclllnnnc
and ,Hyraminc: are orten cited as proIOI:ypicaJ indirecl-llCung

fitolterol. Ollolle",1 (Tom~latc) i, lL prodrug of .he P l1of1ecl"c adreocrgic agonis.! coltcrol. the N /crl buty l anakIpIc: of NE. The presence of the 1\1 0 ,,toluie aci d eSters
btrolkml makes II coo) itkrJbly I"IlOI'e lipophilic than 001 tmlI. Ono!terol IS odmini<;lc rcd by in halalloll for bronchial IIlhma and re\C'l'jlh\c bronchospasm. It I ' hydrol Yled by t'oIrraSl.-<; in the lung and other t ;s~ues to produce the act he .... cobernl. 81101lerol has a longer durauon of lleUon iban isoproterenol (5 10 8 hours) WId is tneUlbol i/.eti. after ~droI)s;~ of the esters, by COMT and conJLlgauoLi.

J lias a ; K tmg
ytal~yl

) intcr-

e. Thi'
ocime\

actmg
mlUtln )I. 1Ia.~

H,C

<_>

C -O'-V"''''
I
A

Y"

NHC(CH,h

H,C~C-O

nw: m lsc:I Of

""=TO

droll'
, ainIC-

'ilh an
OH

I
HO'- V",,,,/,,,-,,NHC(CH,h HO
A

Since ampbct3111lnc -typc drugs e ... ert lheir primary crrct"1S 00 thc CNS. lhe)' are di.cu.sscd III n~ detml in Chapter 15. This chapter discusses those agcnts that exert the" effccts primaril y o n the pC'riphery.

~ytnpatllomimclics.

CO,"

Nt<,
HO
Ampt1etamine

p-Tyramine

~odrlne.

;)\1:1'01

.. aaoni~

Rilodrinc: ( Yutopar) is a sdec the /h.-rcccpused to control premature labor and 1 T"e'CI'llC 0

Although p-Iyrlmnw: is not a clltncally w.eful agent. its a-mclhylatl'IJ Ocri vame. Il}drox yamphetamine ( ParNnnc). I ~ an effecuve. lodirecl-lICll ng $y mpathomimctic drug. Ilydrn... yomphetaminc has litt lc or

HydroKyampMtamine.

no ephcdnne-like , CNS-sumulal1nl actKm. II is used II:) dilale lhe pupil for diagnostIC eye exanunallons and fOl"" surgical '" ocedures on the eye. It IS used sornetlnlC:!l "'Ilb cholinerIIC bkx:Lmg drugs like au"Opme 10 produce a mydriatic effect, "hlCh is more pronoulK."Cd Ihan lhat produced by either drug alone.

TA BLE 1~' Rel. t lve PTe$sot" Activity o f the I ~ of Ephe d rine

1 _ . Retative Actiylty
IH-I-~

01...( , H'phe<It"..
1...( ~

I-phnirlfl(

l.(" )-1'~OOotphtJl1I"

" " , "

HO
HydroxyamphetamlM

UI.'( !

).I':>eudo<Jlho'dI!'"

"'-

l-( + '_PseudoephedriM. 1.-( + }-J>..eudoephedrine (Sudufed. Mrino1. Drillonl) is tile IS.S} diastereoisomer of ephedrine. 11 is a nalurally occurring alkalOId fll)fTl the i!pMdro s.pecies. Whereas ephednne h.:ts a milled mechanism of action . pseudoephednne :letS pnnclpaJly by an indirect nw::chamsm. The structurnl basis for II1IS diffell'llCe in rnechani~m is the stereochemistry of the curban alom posses,~ing the P.hydroxyl group. In pseuoo.:phedrinc. Ihi~ carlxm alOm possesses tile (S) confi gurnlion. which is lhe wrong Slereochemistry atlhis cenler for u direct acling effC(!1 al oorenergic receptors. This agcnl i~ fOll!ld in many Olcr_the-coumer nasal decongestant and l'QId mcdicauO!\..(. Although il is less prone to irocrease blood pressure th.:tn cphedrine. it should be used wilh caut ion in hypencnsi~c ioo" iduals. and it shou ld 001 be used 111 combinauon "',lh MAO inhibilOl'S.

~tcm) of ~arious 'Pl--cies of EpMdm. Mahuang. thl: pIIII COfltllmmg ephedrine. was Lnown LO the QmlCSe in 2.00' IIC. buLthe acti,c pnnciplc, ephednne. was nOI iWlaLed 1885. Ephl.odnne has 1"'0 asymmctrlc carbon atoms: thus. 11m' are four opttcally ::eti,e forms. The t"y,},rQ racemate" called "cpht..>drine," and the rhrfo mccmalc i~ ~t'IO\\.. ~. "P'Cudocphednnc" (\fI-ephedritlt). Nhlur~l ephcdnnc i$l~ 0(_) i'\elmer. and it is the mosLlICti\"c oflhe roor 1'iCHllC". II pre.\o,()f"umine (Table 16-1 ). Thi~ is largely duc LO the III:! LII.:1I Lhls ,~om~r has lhe correcl (N) cOl1figuratlon at the 1;11' boll atom bearing the hydroxyl group pnd the OOtrtd iSi configuration al the carbon bearing the lI\ethyl group b optm,al direcl action al adrenergic receptors.

OH

CH,

OH
NHCH3 NHCH 3

CH,
o-{-)-Ephedrin41

L-(+rPHuclo&phedrVle

Propylhpxedrine. I'ropylhcxcdrine (Benzcdrex) is lin analogue of ampi1ecam ine in ... hich the 1lf00natic ring ha~ been replaced wilh ~ cydobcllane ring . Thi~ drug produces yasoronSirictioound 11 decongestunt effecl on tile nasal membr:Ines. but il has only about one_half the pressor effect of ampnelDmine and produces de<:idedly fC""cr cffects on the CNS. lIS major use is for a local YllSOConSiriclI~e effect on nasal mucosa in the symptomatic Il'hcf of nasal congC:Sllon caused by the common cokl. allergiC rhtnt\ls. or si nusili$.

Bphedrillc dccomposes gradually and d1irkcn.( lI'hen aposed to light. The frcc IIl kal oid is a stronll base, aIId. aqu.cous JiOIUlion of tile free alkaloid has a pH aboIr I The ~It fonn has 11 pK. of 9.6. The pltannocological activ ily of cpi1ednne Il'SCmbk:s_ ,of eplf"lcphnnc. The drug acts on both a- and P.ad Il'CCptOf'. Although it is I than I also causes IlIOre: pronounced I eptnephrine. and il is cffecl;"C ... lIen given <nil). drui i~ 001 metabolized by cUher MAO 01"" co~rr R it is p-hydroxylatoo and N-demcthylatod by cylOChronK" 450 mixedfunclion ()xidases. Ephedrine and ils salts are llst-d omlly. imnll,cl1Oll\ly. lrul1ll1sculmly. alld topically for a ~ancly eotldnioni. as allcrgic disor<iet". colds. hypotcn~iye conditions. arod colcpsy. 11,~ IIsed locall)to conStrict tile 11:10;.:11 I calise deconge.~tion and to dilate Lhe pupi l or tilt Sy'lenllcully. il t~ effect;"e for ~h ma. hay feler . caria.
t

Pfopylhexedrine

or

SYllipaU ollllw.etics WIth Mixed Merhanlsen of AcUon

'Those pnenylethylamint:S conStdered 10 halC a mixed mechanism of action usually ha~e no h)droxyls on lhe aromatic ring bul do ha~"C a P.hydrox~1 group. D_ (_)-Ept!ed,ine. o-(-}-Ephcdnne is the c las..~ic uatnpie of a sympalhoomimct1c with. mued mcchanism of action. This drug is an alk.aklld Ihal can be obtained from the

dnne) i~ ~tmi lar In su uctUIl' 10 exccpt N primary instcad of a secondary anllne. This gives an agenl Ihat has slightly higher and lower centrol stimulator)' act1Ol1thall

~nylpfQpanolilmiM.

------------------...
bOo 11.5 a nasal decongc>;tant IS iliOn: prolonged than that of

ephedrine. It IS effective when give n orally. l'henylproplln(}1Ieu,... ..... as acoouTlOll .-tive COIllpoocnl in over-thc-coonler apptute 5uppus.anls and cough and (.-oId medical ions until 2001. .... hr:n the Food and Drug Administration (fDA) recomrncfll.ll,d Its removal fro,u slich lIIedicU1ions bc,ausc slud a sho.....ed an illCl"eascd rist.: of hclTlOl"Ttlagic stroloe in yOllng 'lll:lmCn ",110 look the drug.

ably. the antagonistic oclions of these ugcnts III presymlptic a:z receptors contributc to their 'lIl"diac sumulant effectll by cnhanclng the release ofNE. 80th agents hal'C a dirrct vawdilulory lK1ion 011 vascular smooth muso:.: lc tnal may be ~ promlncnl than lhelr a-reccptor arn~gOllISlic cffeelS.

~ o- CH,-fJ
HN

OH

CH,
yb
_
Met"raminol. MClarnmil101 (Anunine) is slructur~lly _br 1 phenylephrine C)(a:pt Ihal il is II primary inslcad 0 Ii I ~ondury amine_ It POS"CSSl'S a m;}lcd mech:mism of Etion. 1II';1h ils dirccl-acling cffects malll ly on u-adrencrgic r=p\0fS. It is USC'd p:m:nlcru lly as 11 "usopressor in the lreat _and prevention Oflheaculc hypotens;"c "lUll.' occuning ~llh &pinal ulK'!;thesia. II also has been u'iCd 10 lreal sewcre ~"JIOlC'nslon broughl on by other Iflmmas Ihal IndU~"C shock. unnl

plant

2.000

N HN -CH,-fJ

,"'~ ate i~ .'n a~

is the

eN il,\ t fact .' car

The amagonist" action nf lol:l1.o)inc is relal;vcly wcal::.

but its hisuminc-lile and 3oC('Iylcholincli),;c agoni'>lic ac nons probably 'OIlIribule 10 'I~ va'iQtliiatory acti vity . Its hiS, tamine-It t.:e effects inc lude stimulation of 8a.~1n<: lCid ;;eel etion. rendering it Inappropriatc for adm inislTlltion 10 patients .... ho ha,c gastric or pepnc u~,.,. Ii has ba:n uscd 10 treal Raynaud's syndrome and other oonditiOllS involving periphclOll vasospasm. T olazollllc is available in an inJCClllble form und is indicaled for U)C in persislenl pulmonary hypen cnsion of lhe ne",bom .... hen su pponi~e nll'lISures are not SUCtt:SSful. PllCntolam lne is used 10 prevcul or control hypencnsivc cpisodc5 thaI occur in patients "'Ith p/Il'ochronwxyloniJ. II can be used as an aid in Ihed,agr"llXis of pheochromocytoma. but measurement of ,alc,holantinc Ie\cls is a safCl"aJid n100fe rel iable method of diagnosis. II also has been used ,n oon\bi nat ion .... ilh papavcrine 10 tn:al impotencc.
IRR EVERSIBLE .... RECEPTOR BLOCKERS

d IS!

.p for

OH

OH
Metaraminol

ADRENERGIC RECEPTOR ANTAGONISTS

s that
1I!~it.;

""'n.rglc Rec:.ptor Antagonists lllliLe the p-adrenergic- receptor antagonisls, ",hlch bear
dear wuclunll simi luritj~ to the adrenergic agon i% NE. T 'pM.nc.and isoprolen>nol. the a-adn:nergic receptor an E

e. it'
dul'll-

IICOOISti coosist of a number of 'OIlipoundS of d iverse chern01 SUVCiure lnal he'll" hnle obl"ious rcsc:mhlanee 10 the adtllCrglC receptor agonists.~
IICmSELECTIVE .....RECE PTOR .6.NTAGONISTS

eNS
Tho Jther.
Ill.'

Agcnts in this class ..... hen gi~cn in ndcquUle doses, prodlKC a 510wly dc\"elopin8. prolonged adrenergic blockade that is not o'cn."OmC by cpincphn ne . In CSSCIICC. thcy are ;fTCv!':.,.i. ble blo<:kcrs of the a-adrenerg;' reccpWf. Chemically. they are p-haloalkylamlues. A lthough dlhenamine i~ the protoIypical ajCnl in Ihis das.~, it IS pheno)(ybcnl.ll1tline that is used Ihcrnpeulically looay.

1'.

Ph,

'I,msuch I nar-

,,"" nchi.

_.

um-

I S II

JhOfl :uon

oc

ToIawJineand Phentolamine. 1bc: agents in Ihis cll\."5 lit struclunllly sinlilar 1 the imidazol ine a-lIl!oniSIS. such 0 ~mphazolme. Ictrohydrol.Oli ne. and ~ylQrnelazoline. 1bc: ~JII' of group auaclll'd \0 the Imida7.oline ring dictates llbethc:r an imidMoline is an agonise or an antagonist. TIle fWl)lt .. cscnlathes of the imid:u.ohne if aniagoniSlS thai an: .std Ihcmpeulical ly are IOlal.Olinc (Pri~oline) and phcrnol trIIiIx (Rcglli ne). Both are oompelilivc (re"crsiblc) blocl ing 'FfIl'. Phcmolamiuc is the rn~ effe.,:live if antagonist. bul IIIIher drug is useful in treali ng cssential hypencnsion. Ibtofctieally. lhe va~odil:uory effects of all ..... ~rnagon ist bId be beneficial in IhI: management of hypenensioo. T oIu.ohne and phen tolAmine, however. have bot h ifl - and frIIUagOIllShC aclivily and produce tachycardia. ~l'lIm-

Ph J

N-CH2CH 2CI

11

A"N~
R/ V

CI

j
No

-<-ReooptOr Comple~

block ing 1ICI':1)lchohne. h;~tamine. and ~onl n tuqICOIl. liS pnlTllU)' phannaoological t'ffeels. ('Specially I as<K1I1_ . rnay be aUnbuu:d 10 II ~ a-OOrelll'f'gic blockmg capabIlity. II.; would be UpeclOO of II drug !hal produces such profound It blockade.lIdnu"'''rutiO/\ is frequenlly as~ Iatcd Willi rdk\ Inchycanlla. il1Cf"t'til':d cardiac OUlpul. and po!ilur.ll llypolta~ion . l'here IS 111.;0 el Idcnce Indicating Ih:lL bloc~ade u( 1ft\)'naplic O'! m:eplOB oolllribulCS 10 lhe IllCrea>cd Ilean.,.. produced by p/1cnoxybcnlarninc. The onset of action of pllcno~ ybc lll~1rnl ne '-~ Sloll. bill the effecl~ of a \ingle dose: of drug may lasl 3 to 4 da)'~. ~nct essenti ally new ~ceptON need 10 be made 1 I\'plllCt' 1m..: 0 thaI hal'e been mhibited iTTl':versibly. The princ ipal eff~ following ils adlllinistr~tiO/\ are an illCl\'~ in pt'riphmit blood n()ll'. an incll'ase III d.:m Icmper-lIUI\'. and a of blood prt:..qure. II has 00 effect on the paTllS)1IIJ*ht' ~yslem and little effecl on the gaslromlesl1l1i1l tracl.. 1"he ... common ~idc effCCI ~ are miosis. tachycard13. naq] ncss, and po!illlrJl h)pott'nsion. all of whICh an: I\'Wod ~ lhe prOOUClion or adnmcrgic bloc ~ade. Orol phcnll~ybcnzami nc is used for lhe preoj)Cr:lhlt __ age nl('nl of patients with pheochromoc)IO/\liI ancJ 1ft" chronic nll1.lUlgt'n"ll:nt of palients whose IUm0r5 are IlOl a.nable 1 su rgery, Oll ly about 20 1 30% of an or.ll dolt" 0 0 absorbed.

Jov,"*'

Reversible Drug

SELEalVE tI,- RE CEPTOR ANTAGONISTS

One group ofluPJ:. sd eclhe Ol"I-m:c-ptor an1agoo ists are the qUIlla1.ol!_ EIamples illCludc pra7~1II (Mi nipll'S.). ter:L7.osin (Hytnal..t do~lI7.osm (Cardura). SlnICllIraJl). 1he.'iC': mitt agem:i of llutt components: the quinazoline rin~. lhe- popero.a ring, and lheocyl mOiety. llIc: 4-ammo group on the line nng is \'rry importanl fVl" (II -receptor amnlly. AI pr-.tJ.()f(in. Lrr.I.I.osin. and doxaLosin po!iloCSS a PI moiety attached 10 the '1ullluotinc ring. this group Clllilf ~placed wllh other heterocyclic moiettes (e.g .. piprob moiely) withoUI loss of affin ity. The nnlUR: of the lie) I ~ hns a significant effect 011 tht' phannacok inclic l" OjO:r11t'

PriJzosin, Te razosln, 0 0. iJZ05;n,

AIkylaled ReceptOl

Figure 16- 7 MechaIlISl11 of ,nlKtlvallOn of ,..adret1(1f9K receptOfl by P.haloalkylamlnes.

Oulnazohne ring
~,~'-,

The nlCChanl~m \\.-hereby ,B-haloaJkylnrmllCs produce II. long-lasting. U TC',crsibk' a-adrenerglc rtteptor blockade i~ depicted ,n Figure 16-7. 1l1e muial Mep in"ol~es the forma_

non of an Inlemx:diatc az.ridlnlum ion (elhykoc immium ion). "" hich tllen fOl1llli an initial re\cnoihle cumplex .... itll the rt'I..'C'plor, 1lle posl1ively charged llllndullum IOn clcclrophilc: lhen reacts ",ull a nucleophilic group on Ihe m:cptor. re..w h~ m!; in the fonnmioo of a cu\' ak nl bot1<.l bcl"ccn the drug lind the receptor. Ahhough the UJ.iridiniuIII iOl1l11lenned ial e
ha~ loog been bclic:,ed to be lhe active: re(:cJl1ori.'~ )' l ating ~peclC'. il was nOI uillil 1976 lhm il was demonstrated unequ l\ ocully Ihat the w.iridioiullI ion~ dcrhed from dllx:nam-

~r /~azlnemg

N~/

1A rN

NH,

PrlZos~:

A ..

-0 o

inc and phcno~ybcnJmille are capable of &-recC'ptor al1:)" 1alion.~

Terazos~ :

A.

The *'11011 of phcno~ybcnza mi l'lC (Dlbcnl:yline) has been dcscllbcd a~ repm;enllng a

Phenoxybenzamine.

"chemlCa] s)'mpatheclom y" beeause of ils !>C lecl;\!': blockade of the excilalory responses of smOOlh muscle and of the hear! muscle. Allhough p/leno(ybcn/.allllnt: is c:1JXIble of

Chwpltr 16

"'Jrt~~r,II' "'l:r~IS

541

>1'.

These drug, are used in the lrealmenl of

hy pene~ion .

"". "". ,""

~

on. A'

Ocx

en

nile

They di late boIh anerioles and ,ei ns. AgenL~ in th is cla....~ offer dl)!.11lI,'I advantllge'l over tnc Olhcr a-blod.5 because tlity produce periphernl vasodilation ""itholll an il"lCRase m bean nile or card iac output . Thi s advunlltge.:II least in IXIrt, 15 attributed to !he fael thaI pI"1U_osin bkx:ks poslJuneuonal <II rrccpcors sclCClinoly ""ithout bloclmg prel>ynaptic lI'] recqxOOl. Theo;e agents al so lind use in lhe treatmenl ofbcnign prosIalic hyperplasIa. when: they he lp impro\'c urine now

thIne h It ~Jccth'e antagonist of the " I ra:cptor. Thl' onl y difference bet .... een these two compounds is lhe relatj\'e ~te /roChenustry of the carbon containing the camoo1CIOOX) substituent. In yohimbine. this group lies in the plmlC of the alkaloid ring syslem, wh ile in corynanthillC . It lies in an tuial position and Ihu~ IS OOt of the plane of the rings.)6
~

m.:e

-.

Kt\ tCrnl ring

1<<<

~,

um

~UJ

,,'"
-tt-

llan-

~~.

!'e I"

Allhough the a(hcrse cffects of theo;e drugs an: usuall y IIIIlIlrnaJ, the most fn:qoc m one. known as theftrsl '/Ios~ phe _ . is sometimes severe. This is a dose-dcpendc:nt dft.I:I ewracICm.cd by marked e,tceS5i ve 1)01;IUrJI hypotens ion hi 'yncopr. This phcnomcoon can be minimiUd by giving .Iruual low dose at bedume. Tllc main difference between pr3Z05m. ler.!7.Ql)in. and do,t awIOln lies in lheir p/tarma(:oIdneti c properties. A.~ rncn WWtl abo> e. these dlffrn:nccs :u-c d,cUlted by the rnuure of iIIe :11')1 moiet y anached 10 lhe piperazine ring. A oompari!OIl of these three agents wilh respect 10 !heir QrJI bioavai lItImty. halrhfe. and duration of actIon IS sho"'n in Table 1~1. Thesc drug~ are me mboll l.ed e.tlen~i\cly, With the nleubolllCS e,tcrctcd in tile bile.

"- I

N H'.' H

"

H
~

H ..' 3COZC

..'

bH

Yohimbine

"- I

N H'" H
H'" H3C0 2C

"

Ighl)

rMlSulos;n. The aryl sulfonamide tanlsulosin (1- 0' _1 represents the first in the class of subtype sclcctivc (f, KtpIOI' antagonists. It IS scleclive for the II IA-adrel1eflic m.'qlIOr. which s.:cms to predomin~te in lhe prostate. II is

.,..,.,..

...

OH "

). aoo

)11M'"

lfIIICU,ttl for treating benign proMalic hyperplasia. for which

(il..:Imiml'lefed o..II:e dai ly. Onhostalic hypol:ension may IIQI be as gll:at ""ith this agent a~ with lhe oonsc lccli,'c quinaooj,ne!..

-al ine nanJlOugh

Yohimbine inerca.<;es hell" Me and blt)()(l pn.:ssure as a resu ll of Its blockade of (i'J receptOl'S 'n!he eNS, It ha~ been used e.tpenmcntuUy 10 tn:at malt: erectile Impotcn,.-c.

w,~

'""" ridlllC
~r\lu.r.

lie... -

0 K/l"* '" H,CO

h

"

CH,
Tlmtulolln

~~O

M irfazapine. The tetracyelic mllCU..aplIle (Remcronl is another example of an a-antagQIlI~1 that shows select ivity fOf" tr~ n:l'CptOTli ver<U.~ trl rcceptors. n lJl udadc of ccntral ir: rel'C'ptOl'S n:..~ullS in an incn:a.'iCd n::1ca.>;c of norc-plnephrine and serotoni n. Thl~ ha.~ prontpted Il ~ use as \IIlllnhdepressant. This agent ~I ~o has uct i" it y ut oonadrenergic rcceptOl'll, It i~ a potent blocker of 5- HT1 and 5- IfT) serotoni n rcccptON un<! al histamine H I receptors.

SlUCT1Vf .., RECEPTOR ANTAGONISTS

YoIJimbine and Corynanthine. IloQlnerie indol e alka OO""n as tnc yohi m~ ex hibit d,fferent degree..~ o f
deo:u\lty towlU"d the "1- and ~-adn: llCrgi c receptors. de[Dliog on the ir sten:ochcmislry. For eJ(ample. yohimbl11l' .. \elective antagonlM of the ~ J1.'C('pt:or. .... hile eorynan Mlrtazaplne

IMlE 16-2 Pha rmacoki ne t ic Properties of I'rl105in, Tl!razosi n, a nd Do.azosl n

IJ.Adre"I!,.k.1 wpto, Antagenls ts

STRUCTVRE - AOIVrrv RELATIONSHIPS

- "" . ,- " '-

.loe.... Ilabllity
-;Q

Half-IIf.

lho..... )

Our.lIon of Action Ihounl

,-'
'-U

...
,. "

'The firS! fj blocker was not reported until 19511. when Po ...c ll and Slater' dcscribc-d the activi ty of dichloroisoprotcrenol
(DC I). The stroclure 0( OC I is like tnat of isoproten::nol. C.\ccpl that the catechol hydro~yl groups ha.e been replaced by two chloro groups. This simple structural modification. in"olving the replacement of the aromatic h)'dro,tyl groups,

"

/wls provided the basis for ncarly all of the approaches used in subc,que!\l effort!; to design :lIld ~ynthesl/.e thernptullcaJly u'iCful ,B.rtteplor antagonists,!) Unfortunately, DCI is not a pure IInlagonist but II partial IIgonist. The summn1ia! dirttt sympathomimetic action 0( DCI precludtd ;15 de"elopment as a chnically usdul drug,

t)'pt. Although II "'"35 001 released for tJ..'C In tnt Unn(ll SWts. II WI) lhe first canlioselecthe P I IIntagonlSl to tit used Cl\ltn.~i\cly in hutn:lJU;. Because il produced ~,'UIl IOlI lC cffects. ho-..-"t\"tr, 1\ IS no longer m gcneral U~ in 1lIOII countrlcs,

Ih
ProrIethalol ....as the IlC'lIt important fJ antagonist to De delle, ibed, Although 11 had much less intrinsic \)'mp,athomimellC acliyi ly lhan DCI, ,I ..... as ..... lIhdra ..... n from chnicall~t Ing becau~ of IgIOItS thaI it caused IhymlC tumen in mict', Within 2 )'~ of thiS 1'q)OI1, !lOwe\'cr, Black and SlcphenSOIlSI' dt'scribed the ,8-blocking lIC'tions of propnil'lOlol. II clO&e \Iructurnl relative of pronethalol. I'ropranolol has become onc of the most Ih-orough l)' siudied lind widely U 'iCd dru gs in lhe therapeut ic anll~rncnturium, II b Ihe Standard lIgainsl which all other fJ wlIagooisls are cornp:tretl.

OH
",NHCH(C H~2

As m lhe s)'mpathomimetJ~. as the Itrr-bulyl and ' I the arnmo functioo I ll!lbgQniSIS. II must be a livil)'. The ,8-bloc~ ing agems exhlbil high slereosckctl\'lIY production of their ,8-block in g cfrech , A~ ... ilh Ihe S)'. t!lOmimctlc ugents, lhe configur.tli()jl of lhe h)'dro~yl.baf. ing carbon of Ihc arytoxypropanolamine qdc cham pI~)' I cril ical role In lhe interncllon of ,8-alllagoni'il dIU,> "I\II~ receptof5. This carbon mUSI pos.ses<; the (SI config for optimal amnily 10 lhe fJ receptor. The: enantlOflll:f the (RJ configurntion is typicall), 100 IUlIes Ie,s potnII ~ available dala mdlCale thaI the phannacoI;;;~~"",~"~ll)' IIlIft t",<: enanhOl1ll:"r IIltl'f"aCl5 .... ilh lhe III a nt.:lnn.er art.:llogou~ to thai of tilt features of lhe aromatic por\lon of the anlagufU~. ho.,,,t'o_ appear to pcnurb the receptor or 10 I ner Ihat inhibh~ ocli\"arioo. In ~r"e flil" tlwt all of lhe /J-anmgonl Mic activil), reSltle~ III 1 proprunolol and most other fJ blodCI"l> lIre as raccmic milltures. The onl)' eJiception" an: I lill1olol. and penbulolo!. wilh which the I

ID.

an

u.-.ed.
Propranolol
1'l"INanoloi bekmgs 10 the group of ,8-blocking agents known as UfY/oXJProptlllln(lmlnl's. This leoo rellc-c1s the fact that an - OCI-I r group has bec-:n incorporated inlo lhe molecule bcIween the arommic ring and the cthylamino side cham. Because this structur.d fUlure is frequentl ), found in fJ anlagooists. lhe assumption i, made Ihm the -OClir group b responsible for lhe amagonistic propenics of lilt moleculcs. However, this IS t1()\ true; in fact. Ihe -OCHzgroup i~ presenl in se~eral compound~ Ihat are potent fJ ago-niSl~.O(I This taller foct ~gain leads to the corlCiusion that it i~ the nMurt 01 the aromatic nflg aM tl.i s\lmtituenl.i tna\ 'ts the primary determinant of ,B.an\1lgollistic actiyity. 'The aryl group also affects lhe absorpciOll. e,cretion , and metaboli!>ITI of the fJ blocUI1I.&1 The: nature of the aromallC nng IS also a dettnninanl in the {j, sekcti"i ty of the IIfllagOlllsts. One common SlI'OClural feature of many caniioselecm'e amagonlsts is lhe presence of a pore substiuoent of 'lUfrlCicAi ~Iu 00 the aromatic nng along with the absence of mtw subst ilucnt.~. Practolol is lhe protOl)'pieal ellllmple of II fJl antagomst 0( Ihis struclul1ll
NONSELECTIVE

fJ BLOCKERS
I"rupr:molol (lnderal) I~ the It IS nonseleclllc I .... ell

.""'"
In addition, i Illcm 0( :r. ~ari('ly of other sthil.Ophrema. alcohol ... i

ant:r.gol1l~I S

1!1

cOl1d'llotl~.

bella\ ior. lhe nlOSt Some of the cllfdiovascu lar s)S1cm. B)' blot"iall; I the hean. propranolol slo ...s the hean. oonlrOCtloo. and redllCCS CanllOC OUlput. s)' nl p;ithellc acti.-!!)' and blockade of "asculilf

,ro.i,~""",<",,,r ...~..""

"

"

IKIm,mstr.mon may result In IIlcrcascd pc:ripher~1 res istance. The anuhypetW"nsh'c action. al least In pan. mlly be allribIIkd 1 us ability to reduce cardillC output. as well ~s 10 ils 0 iUflIRSSion o f n::nin release: from the kidney. Because it
c~hiblts 00 Sl'IeChl U)'

uch

00 lor

K-

pa

M-

1"-

,'"

,~

Mill
",-

Th<
,ilO:

ural

I\Cr.

ran.

art) IJICf. plol.

;all)

for P, reccpto~. il is conll1lindicllcd ilIc pn:,.encc of condition soch., asthllUl and brunchlli!. A facet of the pharmacological fICtion of pfOpranolollhul '- ~l\'ed good deal of anc:mion is lIS so-called mem branc-slab,li1.ing IlCtivily. This j~ II nonspecific effect (i.e . a mediated by a specirIC KplOI"). which is also refclttd 10 lIS II 10m/ anC5IhClic effect Of II qllinidinl'/ili(' tlltel. Bolli manlKlItln') IlOllleS5 memmne-starn!;1in& &cuvil),. SUICe tbe(OOCCnltllliOllS rtquired to produce Ihis effect faT exceed IIIo:Ic obtamoo .... ilh normallncrnpeutjc doses of propranolol and rd:ucd ,B.bloc king drugS, i, is nKlSl unJi~ely trun the omsprrirlC membnHle -stabililing activi ty plays any role in die: dinicaJ c: frltacy of ,8-blockmg agents. The metabolism ofproprallOlol ha~ recei ved intense stooy. Propranolol is ..... ell absorbed afler oml adminisuauoo. but ~ndc:rgoes e~tensive first-pass metabolism before it 1UCht!! the systemic: cireulation. Lower 006es are e~ll"lICted ~ ~nklently than higher dosc~. indicati ng that the l'Xlrac IIOIIj.OCt:M may become saturated at highc:r~ . In addl11m, the active cnantiome r is cleared mon: slowly man the enantiomer.~ Numerous metaboliles of propranolol have been identikd. bul the "lap metabolite til people. after a single ordl be. is naplllooxyLactic acid.. which is formed by:a ~s of Rtabolic n:artlonS involVing N-(iealkylmion. deanllnmio n. aod midallon of the resultant aldehyde. One metabolile 0( ..,lCIllar Intem;t is 4-hydrollyprupranolo l. This compound plUnt P anlagonist Ihal has liQIlIC intrinsic: ~)'mpathorm .rill; activity. It is not known what contribution, if any. 4lI)Q"oxypruprnllOloi makes 10 the pharmacological effecl'! 'IIlftcr admilll~lrJtion of propmnolol. The half-Ii fe of pro,..to! after a si ngle oroll ~ is J 10 4 hoUl~, which mC1tRlIO" to 6 hour<; afler long-teon therapy.

_'' "1:

:r "

)ical

101 (Canro!. Ocupress). limolol (Blocadren . TlluOptic:). ic:H)o bunokM ( Bctagan). sotllolol (8etapacc:) and ",,'Iipnlllolol (Opti Pmnolol ). Siluelurc:s of these compounds an: silo".." In Figul"C 16-8. TIle first fi~e of IheloC agcot s are u!>Cd to tl\'at 000g-tenA managehypertcnsion. Nadoolol i~ al~ used III lhe 1 menl of angina pectoris. \\ hlle tll1)olol nods U'>e in the pmphyiluas of migraine headaches and in the theropy follo".. inS myoearlilal infarctlOfl. Sotalo1 is used us an anuarrhythrnic in tn:aling ventricu lar arrtoythm iall and alnalfibnllallOfl be CIlU'>e in additIon 10 its P.adrenerglC bloddng aCllv lly, this agent bloeh lhe in",'aru K eum:ntlhal dela)~cardlac n:polam.:auon. Caneolo!. llmolol.lc:>obunolol. and IlICtIPflUlOIoi are used topi cally to treat open-angle glauL"Onul . TItese agents lower intraocular pl"CSSure ... ith vll1uaJly 110 cffect on pupil 'IJ.e or 31,.'cornmodation. 11Ky Ihus o ffer WI 3I(hanlllge over many of lhe OIher drug~ u.'<ed in the treatm('nt IIf glulIComa. Although lhe pn:ei"ll mechanism \\'hereby P blocl('1"!i lo\\ er inlraoeu 'lir pres~ure i~ n01 1:1IO... n \\ llh ('enain ly. 11 is belie~'oo that they may rc:d~ lhe produehon of :tqI.ll"OOS hurnor. "\'en though the'\c: I14:cms are adnlllllstcred into lhe eye. systemic ab<.oor"pion can occur, ~Ing soch ad\.-n.c: effects as brad Yl:anl ia and acul e hron(;hospasm III palients ",;th bronchospasliC d l>Ca.~. I>mdolol pOS.'iC'St'S modest rnembr:lIle-,whili /jn!; acU\ it y and signifK.'""oInl inmnsic ,8-agoni\llc acti vity . Prnblltolol and 0 ca n c:olol al~ ha,'c panlal agon;,tic tlCt ivily but not 1 the: degree lhal pindoiol doe$. The P antagotll'ts .... nh partlnl 3gonistk activity cause ies> ~Io'" ing of thc fUIiOI hean nile than do agen ts wlthoul this capabi lity. 110e panial agOllistlc activit y may be beneficial in patIents ,,100 an: IIlel) 10 e;o; hlbit severe: bradycardia or ,,110 have lillie canlillC 1\'''-' ...... 1.' . Timolol. pllloolal. PI." nbuloloi. and I.'OInooloi ha'e h;olf-life vatuCll In the Sll lIIe mnge as proprouolol. 11Ic Iuolf-hfc of nadolol. howe \cr. IS about 20 houl"$. mali:mg " one of the longesHK.'Iing {J bloekel"l>. Timolol undcrgoe~ fil"lot-pass metabolism but not to the ~me c~ lent that propranolul does. Tirnolol and penbutolol are metaboli1ed Cl<te n~hdy. "ilh li ule or no unch;onged drug e~creted m lhe unne:. Pmdok,l is mctaboli,cd by lhe li ~er 10 thc ('. cnt of 6O"l>. "ilh the: u remaining 4O'J, being e.\cn:1oo in the unne unchanged. In oontrast. 11000101 undergoes ~ery linle hepatic nlol.'taboil srn. Most of this drug is e~creted unchanged in the urine.

\lit II hlol.
;, Q

/:I,-SElECTIVE BLOCKERS

can
~ur

1bc dio;covery that,8-bloeli:lllg

latc'

O~NHCH(CH,)2

"".-

,-

OH

Otfwr Nonselective P Blockers. Several other nonselCC!J\t {J blockef5 are used cl inieally . These include nadolol (~). plndolol (Visken). pc:nhulolol ( Le~'alol ). cal1eo-

m the: treatmenl of canllOYoisculardl~lIse, sueh ~ h}perten ~ion . SlInllllau:d a .;careh fO( cardi(}!;Cleetive Pbtockcl"l>. Canliosekct l\'c P anlagonists are df\lIlS Ihal ha~'e a greatCl" affinny for the P, receptors of the hcarllhan for p: receptOf' In other ,,~ues Such eardioselc:etl\'c IlgCnt~ should provide t .... o ImpoMUm therapeutic :ld valll.:lges. The fir\! :M.h:uullJC ~hould be the lack of all antagonlSllc effe:!.' on the p: rc:ceplOf<i in the bron chi . TItcore!ic:ally, Ihis ... ould make P, bkx:lcrs ~fc for use in paticnls .... ho hllve bronchitis or bronchlul lI.t hnta. TIte oC(.'ottd IdV1lnlage should be the abscnec: of bloct..adc: of the vascular p: re,ejl4oo ..... llI ch met/iate ,asodilation. This ..... ou ld be Cl<pc:ctoo to reduce: or dunlllatc the u"lC:n:ase III peripheral resistance thaI wmetinlClo occurs afler the administration of nonselective PanlagOIllSts. Unfonunalci} . ,;mh an:

agcnL~

u~ful

o
O--y-- NHCH(CH~2
H, C
OH

Metipranolol

P9llbutolol

OH

..,,,,.
Fig ure 16- 8
Nonse~,ve

P bkxk~.

osdecrivil), is usu~ II X q!lserved with P, an1agon isl~ at on ly relatively low doses. AI norma l therapeutic doses, much of the se lectivity is lost. AI present the following .B,-selective agents arc used therhpelHically: IIccbulolol (SCCiIllI). a l(,l1 olol (Tcnormin). betaxolol (Kerion\'. Belop1ic). bisop rnlol (Zebcla). csnw lol (Brcvi bl oc). and mctopro lol (Lopressor). SUU.:lUrcs of thesc agents aredepicled in Figure 16-9. All oflhesc agents e~cepl esmolol arc indicated for the treatmen t of hyper1cn~ion. Alcnolol and Illeloprolol arc also appro ved for use in treating angi na pectoris lmd in therapy following myocardi al iofarclion. Belaxolol is lite only p,-selective blocker indicated for the trc31I1l(,111 of Glaucoma. A~cbu!OloJ and csmolal arc indicated for treating ceMai n cardiac arrhythmias. Esmolol was dc::signed speci fically to pos5CS.~ a vel)' shon duration of action: it h.as W1 elimination half-life of 9 minotes. Th is ngent is admi nistered by oonti noOIlS imra venous infosion for control of ventricol ar rJte in

patients with atrial floller, ~ tria l fibrillution. or ~inos tad!!cardia. I l~ rJpid onset aJld shon duration of action reodcrl u.seful during sorgery. after an operation. or donns tim gency si lOation, for shon -tenn control of hean f"JIes.ludfCl:ts disappear within 20 to 30 minutes after the infi". is discontinued. EsmoJol IllUSt be diluted with an In~ so lmion be fon: administration: it is ilX.'(lmpatible \101m*, diulIl bicarbonate. Th' . lit I i . (Fig. 16-10). The i, I antagonist thai docs nOi edlibit I ";~~ effect\. The acid ~",; an el imination of 3 to 4 hours :md is e~e""ltd IImarily by the k.idneys. tn the class of p,-se lective block.ers. only accbutolol pa sesse~ imri nsic sympathomi me tic activity. This "I'U\ vel)' weak. however. Acebutolol and beluxolo!

Chapt~r

16

ltuI'nN''''1c "A't'no

54S

H,cc
1

II

O " " ' fNHCH(CH3h:

O" " ' fNHCH(CH3h:

OH

1
NHCOCH 2C H2CH 3
Aoobutolol

""
4-

OH

C H~ON~

Atenolol

0 " " ' fNHCH(CH3)2

0 " " ' f NHCH(CH,)2

I "" 4-

OH
4-

OH

6H2OCH2C~OCH(CH312

O " " ' f NHCH{CH3h

OH

Figure
bk"'~

16- 9

I'Jl-~

,;,

.."IM JIIC-Slabi li,o:ing activity. bUI the activny is much ritr than rh31 'iCCn .... ith propr.rnolol. The half-life values of acc'oololol and n"ICwprolol arc comI*JbIe to Ihal secn Wilh propnmoloJ. and IhoJc of alcnolol IllbOOpm1ol ~ about III'ice thai of propranolol. ~:3.)Iolol.

,fE........

~ ~ ~

'"' "
,d

,.
4-

"' ,-

CH 2CH 2C0 2H figure 16- 10 Metabohsm of esmoIoI.

Wilh II half-life r~ngini: between 14 and 22 hours. has [he IlXlgest dur.llion of acl;,," of the ,B,-'>elecli-'t blodCB. LIke propranolol. mc'lopfolol has low bioo vai labllity because of significant first-pass metabolism. Although !he bioavaHabil. it)' o f bcla~oIoi is \'cry hIgh. It is metaboh;ted t'~ I(,llShc l)' by lhe Ii~cr. wilh very liule uochanged drug c~crclcd in [hoe UrillC. Atcoolol. li~c lladoloi. Ilas low lipid solubi lity and does not readily cross the blood- braul bamn-. h IS absorbed incomplete ly from the gastrOlnlCSllrlal UlI.::t , the ()fII] bioavailability being appro:tim31c1y~, Link of the absori:led po",oo o f the dose IS melllbohzcd; IT10iSI o f it IS r:tcreted UJlCh~lniled in the urine . In the cw;e of bisoprolol. about 50% of II dose undergoes I\c:patic metabolism, I' bile the remai ning 5O'if. is e:tcrc:ted in the unne unchanged, Ace butolol i_ one of the very few /J blockers .... hose me , tabolite pLays II sigl1irlCant rok in its ph;!rrl\aCoIOJ;ICI] actions. This drug is IIbsorbc:d well fmm the gaslmlmestlnal tnoet. bUI il undergOl'Sexleusil'e firsl -p:lS5 metnbolic con"ersion todi3C't1oloi . Diac:erolol i~ formed by hydrolyllC convn-sioo of the amide group 10 the ami llC . followed by lICelylatioo of lhe IImirIC (Fig. 16- 11 ). After oral admim Stnllioo. plasma k,-cls of diacc:tolol are higher than tho!;(- of IICC'btJtolol. Dill' celolol i~ also II selective /JI-receptor pntagooist Wi lh partial

NH,

Labe!alol. Labctalol (Nonnodync) is ~ phcnykthalJol. anllroc derivan.e that i~ ~ compcti ti"e inhibitor It bolh fJr IUld ,8:-adrenergic receptors IUld al lhe ai -adrenergic 1<9' 101". It is p more poIcnl fJ antag<lflisl Ihan a amagoniS!. Sun II has 1""0 asYlllll10clnc carbon atOIllS (I and I'). II C:U!b _ a nll~ture of four Isomers. It is Ihis IIlIxtUrc that is 1M clinically in lrealilig hypcnension. The diffcrem ISOIlIa'\ however, 1'O'SC5S dirferent (l'- and P.amagonislic IlClililid. The P.hlock ing act ivity resid.:s ~Id)' in 1m: ( I R.I 'R) L'>!)I!ItI, " 'hilt Ihe 1.I -antogOl1i'lic aclivity is Sl'CIl in Ihc (] S, I'RJiNI ( 1S. 1'5) iWlneN. with the (15. 1' R) isollIcr pos.;c'sm; Illgreater IloClivity.6' Labc:talol is a cli nically uscful aIlhhyprrIcn~i.'e agenl. The rntionale for ils usc in the managemetllol hypem:nsion is lhat illl a-ll'Ceptor-blod,mg effeCls ptodtn .asOOilulion and ilJ, p.1l'(."('ptor -blocking effccls prt.nu rel1cx lochycan. a u~ally associaled ""lIh .a.o;odilauQCI. Alh lhough labctalol ls very well absortrd. II undergou elkiSI\'C rin.I-pas..~ nw.:labohsrn.

NHCOCH,
Dh 'et.olol

Figure 16- 11 MeldboilSn'lof ilCebutolol.

CaT\'cdiloi (Coreg). like lubt:lulol. i~.' blocker Ihat pOS\oI:S'lCS a i-adrenergic reccplor-blocktn~': tivity . Only Irn: (S) cn;tnlioJllcr possc~sc.~ lhe P.blocklill II: livilY, while both enamiolllers are al1lagonl,l, of the /11* rcncrgic n."Ccplor .... This drug is al..o IIllique in llial f pos~s)oC.'~ anlio,li(\anl octi"lly and all anliprult fcrau\'C dfca OIl vlI..'.cular smooth muscle cells. II Ihus has II. ncu~ lI'e effect and the ability 10 pro~ide major clU'diO\~ orsan protcction.'" It i) u'lCd in tll'aliliS hypcncnsion" COflgclili\e hcan fll.llull'.

Cilrvedi/ol.

REfERENCES
allOlll<hC XIII Ily: .1 has lillie !nembrunc-slabi lil.l ng ~'i\'ily. It has a longer half-lifc (8 10 12 hool'5) Ihanlhc p;lrem drug and i) e~erelcd by lhe J.idncy~.

fJ BLOCKERS WITH tt"RECE PTOR ANTAGONIST

ACTIVITY

Sc"ernl drugs h~"e hl!en ct.:,elopc:t.llh~1 ~s both p. and a-receptor- bloc"ing ocl i.ilic.~ Wilhlll 1he: :;ame molecuk. Tl'.o c,'(ampJr:~ or such rnoleculcs art' 11I.\)('lalol (Nofmooyne) and c~'cdllol (Coreg).

~. ;:'~i:",/"".' til 1)9 . I J """""-" Rev

17:333.:~

L lIcnodeIu. M. S" OM! Ti~ K. F

A_-aPI ,f".0.. A,l> ~ ..U1J. 9. Ah1qw ... R. P Am J "'Y>-KIllj).5S6., 19-18 10. 1 ...,... S Z. 8_hem 1'Iurnut:oI. 2317':11. t,'N II 1krIIIe1_ S".oo ....lInF. W A: LIre ScI 21 m. 1m.

OH

1
HO

"
A

H N

,.
CH,

\. A

CONH:
latletalol

12. M~h.l c. 81O<hem. ~ . .11:0167, 1981. I). l1) lwoJ. I) 8., .. 01 . f'Iwmot:oI R.~ .\6;121. I~ 14. II ""'"" I 1' ... 01 ~m""'" Ite~. "7:2/)1, I ~ I' lIitNe. I I'" ..... lIuff....'. R II.. Jr.; "".... Orol ll....7.31. I"'" 16. lIuffoio. 11 11.. 1<. """ ll ieb"" J P Ph:Im>aool Thor 61:1, If'! 17. ILlr.S\iIoltI.J.M.,ond ll...t>l<.J P Mod. Me"'"

OCH,

O~N~O

"
" '"
21.

Ir .

N.",,",,'" A J.. aoo;l II,.,.,... J I'

I

I\o..ruc..

In Llmbonl l_ E.I .... ~ TIlt

'" "-

OH N H

"
A

198!I.p.1

I" A
Co_

, ,

22 ~.~~"",' R_ Ir . NodIoI .. A. J.. one! lIidolr. 1 1' . W.

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"""
Illd

s ~

21 1 ," A. 101 _ .. 111-' 1'1...... 21091. 1%1 . U AfclI. J RM N.. ~.109 Ill). 1984 ~. G" ....... A. 0 .: A~nu. R.~ 8;""1><,,, $661~. 1~7. ~ ldk".,,1l. ilL .. III : T~ ~ Sco. 7:.-44. 19M ::1. S~. I' " Walooat. S' !Mond~. P $r.....:e21!11l!i7. 1'Moi ~ J~ .. aI.: ......... , Rov Phomu.roI. Tu. kol 32J67. 1\192. 11 U...hor. It- II........ V . ond lnod. P A.. T ..... ,...,....,.,. So,

rI"

O.U....'*',.
~.

H W<b<r. A. E.: ........ Ikp. Mcd. C/Io1n. H-19J. 1998. $4 H..... el. I G, one! ~ I' S.: 1 Mod. (.'Ioo:m 111:6. 1911>. '3 I ~. E. ... aI. I "'..... Cllrm. M:14JJ. l<J08l S6. l'en). N ... aI. 0. I. Pbao.-.-oI. ".1".;1, l\IIIl 51. 1I00m. K I . -.I M>rtham, A .. Dno.. .s1 /007. 1999 $~ "-II. C. t:.. ..... S ....... I 11_ 1 .............. E>p. Thtt. 121480.

,,..

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".;I 81Id., 1 W MClS"J.ICft..... 1 S: I_BII.I961.

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the

perntof ucI:
the

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!le'

10 !luJII' 11.. N.. ...... Drvp 11;81 . 1'./lI1 II Rlldnd. O.... :al 8lod1om,,,ry :!9t.ru, 1\190. 11. ... -. J D. -..I Nuv-. C. It._""-mI;.\IlI",rap)' ); 220. 1'183. JJ T....... D. J. Ad,,, ... p..- CMI'C~ - ' ",1MCd ' la. \" ""0111", M . E. (~.J, 8""","" Mo.l,dnal 0..:""",),. 4lh 0.1 . p;on III 10( .. YOI'\; , ""'" "'-dry ol Sono.. 1981 ~ '1'"lIol>. A. S and Ruffolo, R. It. Jr Su"", .... ''''''''It ", ... """",;", .... "" 5.......... por .....,.... and ~,"' .. In Ruffolo. II It . led). "'Ailn:noo<'plon MoIoail .. 8 """cY. 8 iocho"",ary. and =p +.'0' T'Top'e.. in 8a"" CI,"",al I'IIormarok'l)'. V(~ ~ 1I.>cI, Kqrt. 1991. P 75 J! HodII<. I P Su,,,,'Oun:. ",,,,,;ly n:bloon.I,,1"" lor ",,,,.eM,,, """'1 .... 01 II-odn:no<cpon. In Ruffolo. II. 11. .. I. led.). /l-Adre"""rllw" Molulu I!i ...... y. 1:1"",,,,,",,,,1)'. _ 1'NnnI<o.""&Y """"'", in ....., a.1D>f;SI ~ . ,01, 7, R~",I. "",,..... 19'11. P 105 '" wOOd. L. H.. """ StnIman. "- 8iochem J 17,lll1. 193.1 J1' RntI'oIo. R. 11., Ir . - ' W_1. I. It. J. 1'IIooI,,~ I:.o.p. Thor 214

60. Ka'ICf. C . Cl al~ J Melli. a.., .... :!O:6R7. 11117 U RMldtII,J 0 .. II ........ D W G.. ..... SIuW. . R. (l a." PhIImIllVL,,,.. 12:105.1987 62. \lo'al~. T .. .. 01 .: 8iO<hrm. 1'IIarmaroI 37: 115. 19IIlI 6J Gold. E. II .. .. 1I. I M.d. Clttm. ~ 1.I6l. 1'l'8264 Sio/loU, A. J. Cl . 1' Cbirali'y I 26!l. 1989 M L~ P G~ ~, ... 0 z. . .nd Ruffolo. I< R.. Jr l'b.vm. No,..

1 "'-

2:12.1995 .

*'"

SELECTED READING
Coopa. J 11. .. Bklono. I' K , "'" ROI". R H TIw: BIO<"'n,,,,~1 II .... 0( N<:u~, 7th td. New von.. o.J<oN U~"m.oI)' ""'"00l0I_ D.

''''

s.. F""", ""... 0

,*", I>IcContoy. It tt<h. ): C....,hl>I.n" .....

I;

WI,1 1Il)

g !!CT,-adhal it effect ro<tt.tuillr

In,<I. S Z . C"on). L. IIIkI Ma.... n~ R Hy" .... ., _ 2:}n.

,..,

",rnJ

J! ...... ,.,e. A.. Timn ............ P. II M W. M ~ .......... Z .. ..-. P A ~ ... Sohm""'b;:rp Am.. I"""""""" J 11 8. 1981 lie..... W T . - ' ...., .... W. I...: AMih)\IOfICt'>I lce"h . I. \\'ullf. ~I It lttl.). Du,,,,,', MNo.< ...:J a..m;"I)'. JlIo ..L I"'" III No .. V<wt. ..... '" olty & S<-. 1981. P. 2M II Bri<u. 0 . t1 oL l2ur I 1'Iwmac0l, 2to11:ll. 191M ~ Fnwh. N ~ Thor. bIlI7~. 199~
11 1Ioo"f"<L I'~ t111 A... N Y AQoI, Sc>. uun, 19'J'} ~ Ibd. G A : Ann N Y Soi 1l812N. 1m II 1dac1ol.1.... L II~ t1 aI . Sc:ieooot 273;110 1. 1996, lInl R E... aI.: ScICli 213!103. 1996. '" blJoIu. 11. R., I. ,t1 01 . Ann . 11."" ~ T"",," }3;24J. 1\193 , 1>;'" J., - ' QoI'nlln. J F-: ~ IMm. 19lLS II bffi>Io. II. 11. .. Ir ....1 . J .\p. Thtr. 219,447. 19111 'I] N'I ..... T L t1 aL; 1'IIarmaoto""ij'l) t:24'. 1'1119 rutt. 11., 8 ., t1 al.\"" Pb4tfnI<uI. 49: 182. 1'1% , ~ G. P.. l.. ow.I<ro, A.. ...., RaIor. K " 1<",,,. . J 7:,SW.

""ad.

<,

D..... inl 8 .."" Sc:>ell ... ,,11 Clon"'.1 Mod"" .... "'" 41. In Adnn.: .. .. ~ S- 0..,." Acadt""" Prnao. 19'18. ltimk. 1 P.. 1klnIlint1l. 1110' e. _ Ruffulo. R. 11. .. lr ... _ ,8-"'*",""'p. \(00'0: From "'" Gmo: "" the Cl",,,,. I l>IoII!o. ........ 8>Q/<1u """ ~ fi'J*li' SuNIa.sinca.-. 1 I>Ird a-.. '8:3-1 I', 1m. 1I0I1n1:.1. D 8 , CAah<Ibnll ... " . )'m"",1ICtIc dnIp. - ' un _ ' ........ In III1R1onan. I G.. ..oo U"""nl. I.. I:. (rd,~ The 1'h;om,...~...,.;,:.1 /lw, p(n... ~ .. UI;e" 10th ..... New yon. ..\I<fu,. H.II. 2001. p, 215, LcfU>w;tt. R. k IklIf....... 1:1 1I .nd Ta) .... 1'. : - . . . . -..... Thr: """""'"'"' and _ ' " motor ......"". 'Y""""" In lIanImM. J O. umlHnl, L I:.. '""" I. The PIwmIc"""""a1 o-.O(1'he"'l'""!IC>. 10th .... , New Yorl. ~kGr-.. ,..Jhll. 2001 . p. 115 ~bln. II 0, ' ,8-Admt<rPc .... pi""', In II=--:h. C .. Siorun<> . .. G . and T.)..,.. J II. , ........ Ck "') . ..... J.

odI;,_... ...".

""'*

P"""".rol.

T,m ................ P IJ M . W M . (.11 .... A. T. _

M emb...... and R-..<n. Od\l<tl hrpmCNI ~. 19IIl'I. P 181 , ItulfQlo. R R.. k . 8.-.." ... II. "" , -.lIl_,! P: ... _,lJ-Adrc~ Fto)O" !he Gene It, the CI.nlc. 2. StnlL1""'Ac1;, "Y R.~"" ...., Ttorr.....i< AppJoQlJI>M. 1. "'I Cbcm 3BJ.6II I. 1995.

e..."".... I'" ,._....

'TbooI.ol. M 1 M C ....

.... 1..,.., N
~"

""hol.-

""

E.,.

AdfmerJIo "'"""""', In

Illllllo<h. C .. S......-.a. P 0 .. and T.y .... J

M""h.k~

II . (011<.). Con ............ ,'. M. h-;.,w CIIC ..... ) 01, 3.

and 1<"",,1""" OdOfd. PnJl'lfTlf.'f'

1 m"

III'IIl. I'- 1.Il.

I. 1~.

,~.

1 7

Cholinergic Drugs and Related Agents

GEORGE H. COCOlAS AND STEPHEN J CunER
Few ~yslems. if any. h.we been studied a!> cl1 cru;;n'cly 3'1 tllose innervilled by neurons 1hal rclea.<;e acetylcholine (AOI) 31 their en(hngs. Sioce the classic similes of Dale.' who describe!.l the lICIJOfIS of the estc,,; and ether<; of choline on isolated organs and their relationship 10 muscarine. pharnlllCOiogIS\S. phy~iologius. chcmi~ls. and bIochernlUS h:!.\"c: applied Illcir lnowlt.'dgc to undefl;tand Ihe uction~ of the cholinergIC ncr'l: and ils ncurouansmiucr. Advances In the applicatiOlI$ of biOlethnology and ehl'mblry have develop! p!"Obt~ thai have uncovered the complc\;ty of the action of ACh 00 coohnergic ncumnS and I'ttCptlll'1i. unkno ..... n "'hen ACh "IllS first dcnlOrlslr.lled in the frog Iw:an in 1921 by Locwi lIS the ~llbslancc J"('lcascd by vagus nene stimulali.on,l dillIes uan\mission of impul.1C5 from lhe nKllor rtent' 10 sUIetal muscle (i,e.. lICurOll1u;,cular jlllll.1ion), The Qlltwwmic ,,~n'OllJ S'mrm i ~ composed of 111'0 dill StOtIS: l)'mpwMricandPllf'(m'mPl"M/fC. ACh stf','O 1\1_ rotrdnsmiller at both sympathocll~ pnd par.t>ynlpalhctlC PIt" gan;itonic 1Ien't' ending~, postgan~hl)llic nen'e fibers inlk paru~ympatllt:lic dIvision, and Willi: postllangJiooll' fUn (e,g .. salivlU)' and ,~eat gland~l in the ~yll1pathctic !Ii.'.... of lhe aUIOllOlmc nen'OII~ .},Icm, The aUIonom M.' 10'\. system regulates the acth' ltit'~ of ~mooIh mU>cle and gLtJD. lar secrellons, 'Illest. a~ a rule. runclil)ll below tbe Icl~" consciou~nc$s (e,g .. re~plrution, circulation, dll1estlOll. bot!:t temperuturc, 111C1;,ooli,m), 111-1: t ..... o dIvision_ hal'e COfltml ing effects 011 the Internal enviroolTlC'nt of lbe body. Tht ~~ patheTic divi<;ion fn:quem ly d lscharge~ as a un'l, e.piII: during condltiol1 ~ of ruge or frighT. ailll t"pend~ elK''lY Tk p.mu;ymp.-uhclie d,vlMon I~ organized for di'<CT'ete Ind kJaI. ;~cd discharge and ~turc~ and COIl.ervcS energy, Drugs and chemica ls thaI cauS(: the par:asym~tll.' sion 10 reKt an: ternM!d pilffU."InIHllhoml",ellc, v.ttmII tilOfoe bloc!.ing lhe lICtion~ are ca lk"d l"mlJ''InP<'lhdTw Agenl~ that minllc the ~) mp,'uhctlc division arc J\'nI'",!~ mnie. and those that bloc!.: the IICtil)O. are I)'mpal AlIOIher elassiliclttiOtl used to de\Cribc drugs IIIld ~belllio.:alt octing on lhe rtenous ~y'lcm or lhe ~lllICmres that the innervale is ba...:lI on Ihe ncul'OtranSl11l11cr rdca.<.ed _ ncf\'e endmg. Drug~ octing on the aUlOllOrnic ne"w'~) arc d,vided into lut,muXIc. for tOOse postganglionIC ' ) . lhetic libetli thaI release norepincphrirw: and epincphnnt, dwlmt'rgi., fur the remaminillibe,-.; In the:wtonOmtt: ... ,'ous system and the mOlor fiber- of the \ollIattc MI'\\'\ relelbC ACh ,

11l1s chapter iocludes lhe drull~ and

chc mical~

dial atl on

chol inergic nerves or tnc lir.sue~ they innervate !O either mimIC or bloc!. the aclion of ACh. Drugs tl131 mim ,c the W,.1iO\l of ACh do !oO eitllcr by aCllng direct ly on the cholineI" I!ic ra:cplOOl 10 the h~e or by inhibi tinl! acetylcholinesterase (AChE). the tnlyme Iha! Inacfivaldl ACh at thc nave lemlina1. Chemicals thai bind orcolllpt:te with ACh for bindIng to the rN'eptor mal' bloc!.: chobnergic llCurotr.msmissiOrl.
CM,

H,c-N'-CH2-CH2-0-C-C~

I II I Acetylcholine CH,

CholinergIC rw:n'cs :tIl: found In thc penphcrnl llCn'OUS system and ccnlrul ncrvous sy~tem (eNS) o f humans, Its presence in the eNS iscum:ntl y receiving the nlO~t aUentiOfl. as re<;earchel"!l are beginning 10 unloc!. ,he mystenc.~ surrounding cognitive irnpainncnt and, mo'l par1icularly. AI7.henneT's d,SCase', SynaptIC lemllnalJ 111 the cc:bral C()I1e.'(, corpu s striatum, hIppocampus. nnd sc\'cnd OIhocr reg ions in the CNS are rich in ACh and in the en/ynleS Ihal synthesi1.c and hydrolYI.l' Iht~ neorotrnn~mmer. Many expenlllC"nlll show Ihal agonisl~ mlll anlagonists of choli nergic receptors can modify the oulpul of roeurouansrnlllCfS. including ACh, frol1l bruin preparJtlon. , Although the functIon of ACh In the brum and brainSlcm j~ IlOl clear. it hIlS OOcn implicated in mcmory and behavioral acliYity m hUllUlns. J 'IlIe ~ri"hrrol "eO'rmJ s)'l'lem con,j~l~ of those IlCr\'e, uulside the cerebrospInal uis and includes lhe somatic nco'cs and the autoIlOIlllC m:rvous syqc m, 1llc wmlllic nt'n'(!$ are made up of a stn!;Ol'}' (a ffen:nt ) nerve ~nd a nlOlor (efferent) 1\Cf\'e , The "",/Or ~o'r,r arise from the spinal cord nnd project urt inttrtupli:d throushout Ihe body to all .kdetal mu sc le, ACh me-

CHOLI NERGIC RECEPTORS

There are IWO di~Iinct rect:p1or type_ for ACh thII dtIIt! in compositiun. locanon. and phannarologieal fulll.'lnl have spedfi ~ agol\i~1lo and anlag\)l1i~IS. Cholinerg1c It'.:",. ha\e !lottn Ciuuucler11ed a.~ nkolimc W\ll musca'ln" !;II basi8 of their abillly 1 be bound b) the n3turully 0 alkaloids nicotine and l1Iu~urine, respccUlely, R subtypes that differ in location and ~pccirK'ity to and antagon;sN hale been idcnllr'l'd for boih t~ nto: and muscari nic rcceptOlli.

Nlc:otlnk Receptors
Nicol1nie recrptors are coupled dIrectly to ion clw\l~h when octll aled by Ach. mediale I'CI)' rap,d respoIl'O

548

TABLE 17-1

RadII of Alluoll ilInd Alk.li Urth

kink ".dius
EH..,;t I.... Hydr.teel
lliOdius

c.tlo",
,~

" , " c.

N.

o.el-

i .... -

". ,,"
_T,..Io.U J

C."

M,"

". '" ''''' ,...

I.H

C A}

.,
, ".. , .,
.1.9

(AI

'"'

", ,...
U~

1.13

" n
....,... ........._ s-u..p. k- 5
,

~,

pre-

bers
figure 17- 1 H)'dr<lled callOl1 showing' highly structured IheI of wate!" around the catlOl1 (AJ, a less SlrUdured Ia)'t'f UfIlU"Ong the If"IOeI' wate!" shell (S). and watt'!" In a "normal" I!o!~/O (With perml~Wrt from the autl'\of and the Royal Socr
01 C~lStry)

,""

I'n-oo..

'91,.

~_

\ 1on

'OU~

nduelof
~,

ra"'i;ll1)" Th<

Ill'

ocald. vi

dunndj

,/wi,

="

~omj

.1}"Ii<. niea"

"_

!II Inc:

p lcm /mpa' e. and I: ner:s lh;n

respoo.ible ror lhe eleclrkaf excitability o f Imt and l1Iuscle cells and (01" the sensiuvity 0( :.ensory cdI$. The cllanrte lS an: pores that open or elose in an allar.-othlng fashion on IInle !lC.Bld ranging from 0.1 to 10 .UistCOOds to provide aqllOO\lS pathways through the P'" 01 membr.me that ions can tran wer<.e. Facton affecting ftcti"ity of ion pores include both the charge and si/.!: of IIr IOn. lOll S In aqtteQU\ !iOlution ~ h)"druted. The waler 1IIlUnd the ion is chnrocteri/.ed hy the presence of t .....o di .... . . "oakr struclUres: a tighlly bound. highly ordered laycr i;ltely surrounding the ion and a second. less ~true -.! b)"e(' (Fig. 17- 1). Io n transport through a channel re,m some denuding 0( lhe surrounding water ~hc ll . The ~ or organi7.anon of the walcr structure dclermifll!s lhe ~ I"tt.juircd to relllO\e the hydnuion shell and i~ a factOl"

in the scketivity of thaI ion chnnoel.' Table \7-1 li slS the effect"'e rOO .. of al~al; and alLaltne eanh cations. 1lIe nkOlinic ACh recel"or was,he fil'il !leul"\Xrunsminer isolated and punfied in an oct,,~ fUfro. It is a glycoproteIn embedded into the poly,ymtplic mc,nbr.l,Je ,hal can be obUlined from the electnc organ~ of the manoe ra)" TO'1M"dll CII/ljt)mill and the cittlric eel f.."11rf'l'lwrnJ e/ec/ricltl. TIle n:ceptor j , piClured lIS a cylllldncal protCIn of about 2.sQ.OOO Dol lind ~onsi51S of five-Mloomt polypeptide ch:llns. of \0 hieh IWO appear 1 be idenlicuJ.1.' The ~obun" ~OlChiometry of 0 ,he jlQtYIX'P,idc unIts from lhe "/"or/1t(/o rect'ptor is a::../J. y.A 11Ic: ptptlde cha iOll of the receptor ~ IIrran~ed to form an opening In the cenler, "'hlch is tho: ion channel. Each trcham conlaill.~ II fIl'gati,-dy charged blndmg sitl' for the quaternary ammonium group uf Aeh The receplor 1I[lpl':l1'i to Clast u, a drmer 0( ,he two fi "e-subunit po/ypt:pllde chuln tOO[l()fflC1'i linked through:l disulfide bond bel ...een Hchaups. A Structural protein of molecular WClght 4l.(X)O bmd.~ the: nicotiniC recclKor to the mcmbrane (Fig. 17-2). Wi,h so many ,'anable, in .he 5uoolll .... many combmallons of mcotinic ,ubtype receptoN ure available. When the n('UrQlranSfluner ACh bllld~ to the nicotmic receptor. 11 cau~ a clwnjlC in Ihe pcnneabllity of the nll'U1bronc: to allow pa~!>l1ge 0( small CallOl"lS Ca: ' N~' . and

dirfer )(I :ul<l

epWI'
on the
umn~

...... ... --

ceptur i,(.
; 011111<:

I~ and. ~. Ion

Figure 17-2 Model 01 the nl(O[111I( rl'<eptor COtnolSII!"ig of flVf! pmtl'm suburlll5 embedded In a ~I membrane. bitsed on electron rmcroscopy and neutron SCillleflng datil.lMJ9f!d lioos repreohgosxdlande chillOS on the uppft p;lrt of the receptor . A 431< protem IS bound 10 the reptor 011 the cytosol" !oIdeof theceUmembriine . The A(hb<ndII"Ig SItes ilfl' shown on tht two-subunl' protems (Repnnted ~lh pem'"IISSIOO hom lindstrom, J M . et ill . (old Spring Hilf!lor Symp Quilnl BIOI 4893, 1983 )

sen,

K .... The ph)6iologkal effect is 10 lemporarily depolarize lhe end plate. nils depol:ni1.Dlion resullS in muscular conIl1ICUOIl 111 a neuromuscular Junclion or. as occun. in aulQnomic !anglia. I;Ofltmualion of !he n.coc impul!oe. Neuromuscular nicotinIC ACh ~plOI"ll are or inle~ as wget.S for aUlOlmmune antibodies In mya..lllc:ma gravis and for muscle relaJIam~ u'<Cd during lhe ~oursc of surgicul procedull'S. Nicotinic rccepiOCli in aulOIlOIll1C ganglia. when blocled by drug\. can play p role in the control of hypenension.

ink rcceplor type could noI mediate the actions of AQ. Research on cholinergic fCC\'plOI"S lias increas.ed SInce ~ 1980s. as thc.sc I"\!ccplOl"S reprcsent poienuaJ largetS for U9rful drugs for di!oCa!oC statCS that are boming more prt,a\nII bccau~ of our increasing population of aged person ... 1k outcome of these stOO les has been the dis:.-Cf)' of SC'o'm j . muscarinic rcccplor subtypc~.

H,C-j -(CH,I.-r-CH ,
NICOTIN IC RECEPTOR SUBTYPES
Niooumc rcccplOl"ll locau:d In lhe neuromuscular junctIon differ from Ihose Oil n.cumns. such lIS lhose in lhe eNS and aulOOOffiIC ganglia. in that they Ilal'e different ligand spedficiucs. NlCOIinic fCCeplOl"S 31 the neuromuscuhu' JUl!C1lon (N I) arc blocled by succinylchol in.c . d-Iubo!:urnrine. and dec31neihoniul11 and Mil11ululcd by phcnyhrimethylallllllonium. N! IlIcotlnlC reccplOl"S are found in aUlooomic gungJia. They are bloded by hexamclhomum and uimethaplmn but Slimulaic(] by tetrllmethylamnM)lliulll and dlluelhyl-4-plw:nylpiperazinium (DM I'P). Nicotinic fCCepior subtypes have als.) been idenlirled in many regions of tnc CNS; ho .... ever. !heir phannaoologicaJ function i$ noI yet fully ulKkmood 10 Even so, greal ancmpls are being ml1de to understand Inc role of SO many receplor subtypes. particularly thol;c found in lhc CNS.II. Il

I"
CH,

CH,

r r' "c--r'-'CHJ,o-i'-CH,
CH, CH,
Muscannic rcceplors mediate their cffCCb by ac:\i. guanosine triphosph~te (GTP)blnding pnJ(clns (G ~ The.;e n:ct:plors havc .st,cn protcin hcli~es th~1 tl1lll.~

1'" -N'-CH,
"-'II;
Muscarinic Receptors
Muscannlc receptOl"S play an essential role in regu lahng the function.~ of organ! inllCTVlled by Inc autonomIC neo'ous sy~lCm 10 maintaill IloIl1C01<tasi~ of the organism. 11Ie actinn of ACh nn muscari nk reccplors can rcsuh in ~timu latj.on or inhibition of tnc organ system affected. ACh stimulates secretions from sahvary and S" 'cat glands, secretions and contraction of thoe gUl. and constriction of the airways of lhe re_pmnory tr.tCt. It inhibIts oolliractioo of the hean and rclaxe~ smooth muscle of blood vell..'lclJ. As early as 19110. it became apparent tllat a si ngle muscar

L,

the plasma membrane. cn:ating four C)(trac"'~I:I'"";':M:'::;:; I and four imraccllul:ar domams (Fig. 17-3). 1 domain of the fC(:~plor contains the binding ~i te for AQ. 1bc imrnccllular domai n cou ple.~ wilh G pnxeln~ to in... biochemica l changcs that result in ptuumacolot;icJ.I .,. from rcccplOl" activatIon.

MUSCARINIC RECEPTOR SUBTYPES

Evidcn(."C from both pharmacologkal and biochcmICI/ ies shows lhat subtypes of muscannic ft.'CCplors m in the CNS and periphentl nen'OUS system. I '. 14 donin, studies hoIve reYe;)1ro the CJllSU:ncc of fi" e . molC\:Ular mammali311 mlb(annlC rcccplOf prokJm. clOflCd re<:eplOl"S ha"e been identified as m , lO m~. II..... method of idemificauon. muscarinic rcecptor 'ubc)"~ been defined on the basis of their affinilY for ~~?"! nms and anlagorllS-iS and the phannacoioglCaJ dfca.\ ca usc. TIles.e receptors are dcsi gn~ted .. ilh 't t ~ubscripl numlK-rs a$ M l to M,. The I tion adopted for~ rcccpIors is matthc defined ~ubtypes M " M!. and M ) l-orrespood to tilt

Jf ACh,

Ilee lhe for u.\COf"e\ alent f1~. The: sever... l

Figure 11- ] HypothetICal model of II mus.tarll'llC receptor showing the Ioc.atlQl'1 of ~ uansmemtxane hell(IIl pl'01en doma'l15 arod the ~~tracelllllar al'ld mtracellular dom.lil15 conne<:\lng the seven .... helocal pl'otems In the rnemblane (ReprInted from Goyal, R K. , N Eng! J Med. ]211024. t989, WIth peUI& SI()J1 Irom tM author and the M~ts MedICal Soot>ty, )

aoItydefined <;tJblypes m,. m1. and til). The m. gcoct\erived p!UCIn "referred 10 as lhe M. subl)'pe and has many pharIIIIl:Ological propcnic' simi lar to those of the Ml subtype . TlIe m, re,,:cplor geoc pmdllCt doc.., IlOl hale an equivalent phwrnxvlogical profilc_
Evcn Ihough molecules do not hale CAml'e ~lecllvlty on mus.:arinic receptor subtypes, 111 I !'CC!pIn hne been defined as I~ wilh high affinny for piiNZtpinc: and low ~ffimty for compounds such as AFDX 116. 'Illey hale been termed 'It' llml bc:\:llUse of theIr Ilwibution within pal1lcu lar hruin \ 1I11ctUn:S. In adJilion 10 wCNS. M I rel.:cpLON un: located in c.t ocrine glorlds and .'Kllmt pngha In hurnans. these l\.'Ccptors Sttlll to affecl IJOtiII ancntion. r.apld c)e movemcm ( REM ) ,leep, elllOIIINI responses. affective di"Jflkl'$ IllCluding dcpression. a,l modulation of SIJtS~. They arc belicved to panicipate 'higher bnlln fUllClion~. ~ueh as memory and learning. All.II:LWi,t; dIsease n:liCarch has implicated cholinergIC neu I\IIlI and ~plon;. but e~idence does not SOOI'.' conclusi,cly these are Ihe pri mary cau-es ortlle di-easc . M, I'('ccpton; IIn't been iden ti fied in ~ubrrlucO!'ial gland' and sonIC sn100l h ,'_They ~ locmcd in parictal cell~ In the gaslrointesti.IGIl traCt and in penpherul aulonomic gangha. soch a.~ wlOIruI1urul gangha of Inc srom!lCh wall . When Sil lIluJ:ued. II, rtCcplOI'S cause gastric .secrction,U Although McN-A).IllS 15e~th e agonist. pircn7.cpi roc HCI acts a~ an antag()-

rust and has bl'cn used OIIlside tnc Unlled States for the tn:amlCnt of pcplit ulcer di'easc.
Ml RfK~rors. M 1 ~plors are ldenufied by their high affinit), (or n-.ethoctr.llnme , a poIyanune. and by thl:o:ir low affinity for pll'('nupmc. Mz receptors ure also called rordiar nlUscUlinic receptors becuuse thcy an: located in lhe: mria nnd conductmg tissue: of the: hc:an. Their ~timulallon CllU!iC5 a decrcm;e in the stnngth and rale of cardiac mu!>cle tonlr.te I,on. 11t.cse effocbl may be produced by affecting imracellular K ' and Ca: ' levcl~ m Ilean li~sue. MI receplors actiVDIC K ' chanllcl~ 10 cause hyperpolari1.mioll of canliac cells. re~ulling in brudycanlia. Thesc ret.'t'plors may also act throogh an inhibitory G proceln (G,) 10 reduce aOcn)'late cycl~ x livity and IoI'.cI cychc )'S-adenosine rnonophosphatc (cA MP) le~el~ in cardiac cells. LowcrcAMP Icvels decrease the IlJI\OUnt of fn:e Cal ' in ~lIrdiac ~'CJls and slow down the hcan rate. I.. M~ receptors can also sel'\C as autortceptors on presynaptIC terminals of postganghonlc cholillClltlC I1CI'\CS to inhibit ACh releasc. The balance oflhe effects of nlultiple mu.\Curinic n:ceptor SUbtypes dctemlincs the Silt of the 1111'wuy of Inc smooth mu\Cle In lhe: bronchioles. Conlraclion 1 pnmarily tnc result of lhe IK'I;on of ACh on M) l'I:C('ptors $ (~below) following stimulatloo of the vagus. At the SOImc linlC. ACh ",ullula":s inhihnor Ml aUlon:ceptors located on nerve cnJing' to limit release of ACh_ In asthmatics. rw:uronal M ! ~ptor:; in the lungs do not fuoction normally. "

AI, Receptors_

actlv\lllng protelllS ). trai\<.ecod r donmin, trncellular ! for ACh to initiate leal octioo

fIlI~al ~tud 111'1: loclued

Molecuhl1 Ie different
*1Il~. The

In another
)\)'pe\ ha\C

e.:tivc a1l(}o :ffect ~ they Ikttc ..... and Jre con\'cn1C0iogically the gCJlCII-

H~-!'-CHl-C==C-CH2-0-~-~-'"'
I
McN--A+3043

CH1

M:J RfKf!pton.

M, recrptor.. refcm;:(! to as glandular

PI_G'

glands and smooIh mu!OClc. Their effcct on tOC<IC organ \),stellls is ITIO!itl y ~,imulatory. Glandular "ecretlOll~ fmlll lacrimal. 5a1i\ary. broI\ch,a1. pancrelltic. and mucosal cells in ttJc, G I tl1lC'l an: ch.'rao:tcri~tic of M \ I'I:CCplOl' acll ~ation. COlllntCtion of ~ is ccrJI \Inooth muo;clc is also a re~uh of MJ reeeptor stimulation. The.;e sltmulam effcc" are ,nedimcd thfQ\lgh G pr()(ein I>Clivalion of pho;,plM)lipa~ C (['I.e) 10 fOOll Ihe secolld mes.srngcrs mosilol Irlpllosph:.te alld diacylglyccrol mAG). Oi'ICo'crit!'! in the p.,~t Ikcade ha'e revea led Ihal lhe endothelium can cootrol the lone of valiCular smooth muscle by the synthesis of a poIenl reh.... ant. endotheliumclcrl'ed rela..'(ing faC'lOl' (EORF). IlOW Iclcnufied as nitric ofl.iik (NO). and a nsooonstriCior whstlmcr. rndothelium dem t'd t'OIlltOCting fartO!' (EOCF). The s} mllesis and releasr of tl'lcK suhstallCC\ cootnbute to the tone of the \"ascular ep!thehum. M J recrptOB. ~hcn activated in endotheli al celLs. e-.au.sr the release of ED RF and oontnbulc to ,tL . M)(iilalion. ,.

I11USC:ll1nJC receptor.;.

are located m

I'S,

I h

c:~ocnne

or))

"'"'

-_CO'.--

". I

_._

1\1 4 R'ecptors. li ke M l rcceplolli. U(;t throuSh G, PfOl.ei n 10 inhibn ndcnylatc cyc1I1..<iC. also function by 3 direct n'tlulmory action o n K ' and C3 .. ion channcls. M . rcc:eptors in trw.:heal smooth mu-.c le. when slunulatl'd. inhibit the releru;e of ACh'" In 1tJc, same manner tnat MJ rc:lCplors 00.

M. Receptors.

T1t.e1

_..
A single drog- recepu.... oomplex (;an aclivalc Ilevtn1G prolein molecule and each in lum can rema in aUQI: wilh Ilarget mole<:uk'. c.g .. 3n en~ylllc. and cause' ibr"" dUCIion of mllny lIJolcculcs. amplifying the result oflht tlal drog-rcc:eptor rombinatioon. M . M j and M ~ ICti v8te PLC. nusing the release of IP, and OAG. "bdl tum rdease mtrncc llu l:u CI 2 - and aC'li\"3Ie proIC'tn w~ l'CSpel::thely. Ml and M4 receptors produce inhibitlOl1of nylate cyd:asc:. The plKx;:phoi lIOIiitol,) req uires the brcakdo,,"n of membrallC-bound ~~',' inosi lQl 4.5-diphQ"phHle (PIPl ) by PLC to II', and which 'iCrve as <;Ceond I1ICsscngers in Ihe ce lI. IP) Cal. from inlrncc:lIular ~I~ in the er\dQplllSn llC IQ elevalc cylOllOli(; free Cal' . The Cal. . depenclcnl kinases (e.i. troponin C in mU'iCIe) bind~ to the Cal < -bInding protein (;~modllhn. '"lIIC'S calmodultn-dcp'nclcnt Ullll'lCs. ~ l.naSC'S phorylate cdlspeciflC tn:tymes to nusc muclc coal DAG i~ liptd-h l e and acb. in the plant: of the ihmugh IICu"a tion of proIein kina.<IC C to cause phorylallon of cellu lar rr'cins. also leadini to ~" Il1JCtioo {Fig. 17-,,).U.

M s RfKf!pton. A greal deal of I'ClIeanh rema.ns to he p'rformt'd on the M, SlJocla.o;;s of receptors. Si~ the M, recrptor messcnger RNA {mRNA ) is foolld in the ~ubst:lntia mgra. il has heo!n \uggC'~ted tnat I\h recrplors may regulate dopallllllC release at lemlinals "'Ilhin the ~triatum.

BIOCHEMICAL EfFECTS OF MUSCARINI C RECEPTOR STIMULATI ON

the ~}oap<;e 1II"ol\'ioll !It'Cond messengers is much _lower. aboul 100 nu lh'<Cl:Olids. compared wilh the few milli'iCConds al syn alN'S ~hcre ion enanoels are acti Hlled din:ctly. dela}'ed rextiOfl 10 receptOl' stim ulation i~ due to (;ascadc of biocllC'mical e.-ellb lnat mUSI OC(;IIr to caul,(' lhe pb:tnll3Cological resporl>e (fig. 11-4). The.srqucl'lCC of c'ents in 1he.<IC sccond-mes..<lCngcf \y5temS begins cs ,,"tlh acti\'alion of the rrceplOB by an ason;S! and in\'ol," the aC'l .\,aIIOO of G protrins thaI are boulld to a portion of the mtrncc:l1ul ar domain of the muo;carinic ra:c:ptor.::<I G proIcms are JO ca lled brcause of their inlerol(;lion ","h the g uanino: nuclCQIidcs GTP and guunosi1lC diphosphate (GOP). nlcy trnns late drog-t"e(;cptor interactions m the surface of the cell 10 oomponcnts in~idc the c.::lllo creutc the biological respon'iC. G protcin, con"i ~1 of thn:e ~ubu nit~. cr. {J.. and ,.. When the rcc:eptor is occupied. the ... ,u!).mi t. ~hieh has en7ymallc acti "ity. cata lY/.tS the con,crsion of GTP 10 GOP. Thc it subunit bound ~ tlh GTP IS lhe: II(;lh'e form of the: G protein thaI (;an associale with 'llrioos ell/.ymes {i.e . PLC and aden}13te cyclase):md ioo cnanno:ls ( K and Ca"). G prote lllS ;m and the 0 ~ubullit may cause acli\"3tioo (G.) or In.act i~3Uoo (G,l of the en/ymes or (;hannc:ls. Roccnt SIIM,lIes '<I.Igges.ltnal fJ and Ysubuntls also cootnbulC to pharo macolOl!iC'..a1 effccts.!'
Trnn sm i !l~ioo 31

n.e

Phosphoirtositol System.

,moo.

C""plcr 17 CItol'''''J" DrullJ Md Nt~d Asn"r

553

AdMy/<Jtf! Cyclase.

Adcnylatc cyda.'\oe, a n~mbrJne

E)me, is ~ larget of muscnrinic ~('ptor actIvation. 'hie IotCOOd me.....wnger cAMP is ~)'mhe.~I/~ with,n the cell IdrnosIllC tnphosphatc (ATP) b) the ..11011 of aden)', t")dlL\(', The regulatory corrects of ('A MP are many, as it
(III

the G proIein in heart tissue octS directly to opt'n ~ K ' chaf1nel. producing hyptrpolaril.:uion of the membrane and slowing the heart rdle.

1CI1\'ilte a variety of proIeln ~inasc:s. ProIem killllse!l aW~u the phrn;phor) lotion of enl.yrne~ and ioo channels, IIImng the amount of calcium entering Ihe ce ll and thus IIft!!ng muscle tonlmction . M uscari nie receptor activAtion ~, Io""er levels of cA MP. reducing cAMP proldn-deJC!lknt kinase acth-ity. and a I1'laution of nll,lscle ('onlme P. SOllie M\C suggested that II GTP,"lhibiIOl)' protell' (G,) * t s the activity of adenylalc cyclase. causing MnOOth

CHOLINERGIC NEUROCHEMISTRY
Cholinerg ie lIeuron~ ~ymhesile. store. and re lease ACh (Fig. 17-5). Thc neurons also form choline ocetytlr.lIlsfcrase (ChAT) lind AChE. Tllesc enl:ymcs are synwsilcd ;n the WIlla of the neuron and d i"'ributcd throughout the neuron by axoplasmk flow. AChE i\ also located oulSldc lhe neuron and is associatetl with the neuroglial cdls in the synaptic cltfl. ACb is prepared in the nenc endmg by the tr.msfcr of an :liCe1)'1 group from lICet)' I-cocnzyme A (CoA) 10 choline. The reac:lion is catalY/.cd by ChAT. Ccll fractionation Sludics show that much of the ACh is conlllined III synaptk \'es.icles in ~ nervc cnding but that some is also free in lhe cytosol. Choline i~ the limiting sUbstratc for the symtie(i\

-k rcluation (Fi,. 17-4).~ N

bl ClNnnf!!ls. In addition to ~ action of proIein ki,:"'WI pho!;p/lof)'late kln eh:alUlCls lind mothr)' ion coo~. G proI!'1I1S are coupled d'lttll )' to ion channels 10 rplale thei r Kuon.:A The Ca l < channel on the cell mem_is 8C\l\3ted by G proleins .... Ilhootthe need of II second .-s.\C1Iger to allow Ca-' to en ter the cell. The a subun it of

t,+m ""...

lwolMl

"""".

e
"'"
,

s.......

"""

rc

eral G

c.o'

r:~: trich
~ na~.

iah:d lie pm-

"'"

(/)~
Pyrvvale

"" ,

"cwTIe!"

11\

./

of adr

'"''
CHOUNEAGIC NERVE TERMJI'W..

, "",[
Cho/iM41

OA

""" """"" .,. ..

fIIj.:\,"n.

r""'~ e phtK~lc
1;011-

Flgu ... 17- 5 Hypolhl'llCai modi!! of synt~. storagC>. oJOd reINse of ACh . (I) ACh IS rele?" d f,om stOr<1gl' granules under thl' ,nllUI'fICe oilhi' nerve iIC\IOO potentlitl and ca2' 0) ACh iIds on PQStsynaptJe cholrnefgIC. IKI'plor... (3) Hydrolysis of ACh by AChE OCUJI"l m the SynilPtJe deft. (4) A high-affInity uptakl' system returm chot,ne to tne cytosol. (5) ChAT syn~~ ACh 11"1 the cytosol. and the ACh IS stored m granules (6) Glucose IS cOlwelled to pyruv~te. whtc:h IS converted to ac:I'tyt.(oA 11"1 the mrtochondria. AcetytCGA IS released from tM mltochondr .. by an ilCetyt c.arnef (7) Chotlfllt 1S.1so ta~ert up mlO the neuroo by , Iow-aff,n'ty uptake system and converted partly to phosphoryIc:hot,nl'

HO-CH2-CH2-!'-CH~HS
CH,tHJ

CH~HJ

2-Hyd 'OXOI hyl Irielhytarrw Iionium

of ACh. Mosl choline for ACto sy mhesi ~ comes from the hydrolysi~ of ACto in the sy napse. Choline i~ recaplurro by lhe presynap:ic lenninal as pan o f a hrth-Ilffinity up:ake sy!iU'm under lhe innUt'nce of ~ium ions to synthes i7.e ACto . Severnl quaternary ammonium bases act 01.> OOmpetilive inhibitors of choline upral e. tkmkholinmm (IIC-), a bisqu~temary cyclic hemiacetal. and the triethyl analogue of eholine, 2hydmx yet hyllriethylammonium, acl m the presyIlIIpric membrnne to inhibit tbe high-affinity up:ale of choIme inlO the neuron. 1lIe.'iC rompounds cause a dela)'ed paralysis at repeti ti vely Geti voted cholinergic synapso; and ca n produce respiratory paralysis in teSt animal s, The delayed block is due 10 the depletion of stored AOI_ which may be re,crsed by choline , The acetyl group used for the s)'nthesIS of ACh is obtained by conve",ion of glucose 1 pyruvate in 0 tnc cylO!iOI of the neuron .and evemu ol fonnatiOil of acety lCoA, Because o f the Impermeability of the mitochondrial membrnne to lK\:lyl -CoA, thi.~ substrme is brooghl into the cyt~ by the oid of an acetyl "camer." The synthesis of ACh front c holine and 1lCe1)I-CoA IS caUll p.ed by ChAT. Transfer of the acctylKrouP from acetylCoA to choline may be by 3 rdndom or an ordc:n:d reactioo of lhe Thcorell-Chance type, In the onlcred sequence. acet )'1CoA fiN binds 1 the truyme, form ing a complex ( EA ) that 0 0 then binds 1 choline. The octtyl group is transfcrred. and the ACh formed dissociates from the enz)'nlt ocli"e sile. The eoA i( Ihcn It'ltasc:d from the enZ)"Ine conlplex. EO,

to regcneruU: the r~ enzyme. The !;Cheillt i~ dl ugno.mmrd in Figure 11-6. C M T is inhibi ted on vitro by "/IruNIDCIb)~ 4-( I-naphthy l ~ inyl)pyndinium iodlde:6; howe,er. its li1futot. tory activity in whole animals i~ unreliablt .u

Irans-N-Mothv!. ( I 'OIIjlthylvinyl IPvrldlnl urn iod Ide

E
EA

EO

Figu re 17- 6 Ordered 5)T"itheSl5 of oKetyknohne (ACh) by dlCMone oKetyl1ransferase (ChAn

Newly formed ACh is re leased from the preliynapuc_ brune wlltn a ocn'e oction potential invades 0 prcsyrgpil; rltne temlillllJ. 21 11M: release of Acto re.~ults from drpol!zalion of tilt nerve ttrTl1inal by the action poIenhal, .1Ii:;i allen; membrane pemlCabililY to Ca~ -. Calcium clltm nerve ternlinul and causes rclea;.e of the contents of se,'!niI sy nap:ie 'e.~icles coolai ninl! AOI onto the 5ynaplic cleft, nio bu rst. or qunntal n: lease, of Acto cau~ depolari(atio;oo rI the postsy naptic nlClI\branc . The number (If quanla of AG rele:Jsed may be a~ high as severol hundred al a neUronlliJallar Junction . ,"'lIh each Quantum COIIlamlllg between " and 60.000 molecules. ACto is l. rele:r..~ spontarc&5~ in small aml.IUnr.s from Illtmbr.utOi. This wniiiI afTlOUnt t t i on the c holiocrgic recep:ors on tilt postsynaplic nlem After ACII has been released into the sy naptic clell. ill COIlCt'ntrat ion declt'ase5 rapidly, It is genel1llly ICCcptedlloool thelt' IS enough AOIE al nen"l.' endrngJ 10 hydmlyLC choline and ocetll!e any Acto th ot ha.~ be.!n liberated. fU' example . there is sufficient AC hE in the nerve juncllOll' nit rntercostal muscle to hydrotyu about 2.7 x 10' AO molecules in I millisecond; this fnr e.ceeds the ) X I molecules released by one: nerve impul'it. N

TABLE 17-2

Confonnational Properti es of Some

Cholinergic AgenU
Compound

""') kMllnc ....""Ide AC'CI)ldlOllllC <h1o.1O\lo

fIIeoMnIn

."
+K~

plOIDClIOft

"

f ~ ~2S.3I1.'\,j: M"",an ... J.xlodo

M<1II,If"",.. thi<l< klJldo

fitu",17 - 1 SpatJiII onentallOfl of 01 -CS- C4- N atoms In

""
OfOUNERGJC AGONISTS
a.n_rglc StereDC..l:emlstry
1lIItc Icchn lques h:we been used 10 ~tudy too coofomt:uional prq.. nlCli of ACh and OIm,r cholincrgic cl'.cnllcals: x-ray CI),'>tallogrJphy. nucie3r m311IlCIiC re"Onaoce (NMR). und -*cular modeling by cmnputation. Each of Ihese rne\h~ 1II:Iy repon the ~p~lial di,tnhwion of moms in a -*cule in lenm. of t~ion angles. A torsi!>" lingle is ttilltd as thoe WIgle formed hcl"ccn 1"'0 plane~. for examIt. b)' tile OI - C5- C4- N atom~ in ACh. The angle be~cm the o xygen and nitrogen atom~ i. hcSI depICted by _ of Newman projections (Fig. 17-7) , A torsion angle l1li a llO"iti,," sign "hoen the bond of too fronl atom is to too nghl to ecl iP"C lhoe bond of lhe rear atom. 1'if <p3UaI oncntation of ACh is de'iCTibed by foor lorsion (Fig. 17-8). Theoonfonn.ation of tile choli ne mOlely of ACh has drawn tr~ 3ltcnt ion in sllld ic~ rd uli ng MrucHlre 31m phamtoco~I activity. Tile ton;ion 3ngle (1: ) dClel\llinc..~ too ~p"J tial ~a!ion of the cationic head of ACh 10 Ille c~ter group. lay d,lfrnclion studies h3ve ,hown Ih31 the lOI"iion ~ ng1c ,1";1 on ACh ha, a value of + 71". Many ~ompoulKh thm .lIUsoui nic receptor agoni'ls containinll a ~holine com ....-e.g.. O-C-C-N - (CHJh-hll'c a preferred s)"ocl i(poche) COOform.1ti on. wi lh 1) value<> rJng ing from 68 89" rTlible 17-2). Intemtolccular pad,ing f~s in the '!I')'lIlI as \1'1'11 as dectrostatlC InIC11lClIIJO.~ bet....ecn the .p:tI and the I'd)!"'!" ollygcn of 100 CSlet" ~ tWO dominant f:octors that Ic:ad to a , Ii CQnfonnalion In looCT)su1 state. _ cltohnc esters display 3n anllperi planar f fmlu) l"Onfor .,.. between too onium and e~ler gll)\lps. For tx:unp1c. ~) I ~holine chloride (I). + 178) i, ,Inbililed in thh ...., conformal ion by sevcml hyd rogel! bo!1d~. Acctyhhio~lntlOdidc (T2. + 17 1) i~ in I hi~ cnnfnrmmioo hc:causc .ik prrsence of the bull..ier and Ies..~ electronegntive su lfur

( .. )oAC'CIyH~1lIl1lcth)"''''~11lC ioJido: ( - )-AIlCt)I\II)-a,II<Ih) 10:Il0)l,.......1.1..

Cl)'ouI f"",,'"

."
~g .1

+71

C I)'>IaI ""'" 8
( t )<UI'2S).Meth)I-l.utHflI"e.h)t., ............. I.l............. ""1Ide

-+ (J8

( + )-IrDIU(IS. l.l..)-Aa:to.rc.... Iupo.,.,'llnmcth)!

- . o I 1 ........ Ii<..

4 1.11
~

CartMIrn<'''''''~I''' bromidr

11
t 7fi

AC'CI)lIl1ilo;:hohne """".... A<"",)I .(II". SlIr<Iomcth)lo:hoI.ine iodklc (ery1h"'1

.,.".. 511<1.... 11
""_ _
~ "OCI """

~ 111

grarrllnoo

...._methyl _ Its inhlbi -

, .... _

",~ .... j ~ ,orod ..... - ' . I ' ... ~nIo..l ~'" I ....... 1 _ " '... "'" y",
t ~7I.

'3 ,hot,,,,,,,,"

"'''-' I.

h ,p"'. I)

I'll ., til

Iptic menl-.resynupti..: n dcpolari tiaL wh ich , enters the: l of 5C~'eroil : cleft_Thi~ 1n1.ation of nlll of ACh

!Ul'QIllU..cU'cen 12.000
]ntlineou~Iy

3tOm. and ( + 1 mllls-( IS,2S}-acelollyqcloprup)hnmcthyl amnMllnum iodide ( T):. + 137") is fi~ed '" thIS ~onformallon by the rigidity of the cydoprop}'1 ring . NMR ~peclfO<;COpy of cbolinergic ntolecu lc._ '" -olullon i~ nlOre li rllllcd Ihan CT) st3l1ography in delineatiollhe confOl1l13\1on of C Ol1lpound, and i~ ~Iri cled to dctemmllng too ~on;ion angle OI - CS - C4- N. Most Nf-,'IR data art in agreement willi the rewh~ of ll-rd) diffrnclion $tudlCll. NMR .~ t ud ies indicale Ih.1t ACh and "'!'thocholine 3pp.m: ml), are tIOI in their 1II0St slable trllIlS confonnnlion bUI elli~t in one of two gau~he confornlen 11) (Fig. 17-9). This may rc~uh fnlm Slrong intramolecular interactions 1h.1t siabililt lhe conformation of lhe:se mokcuks in solution." Molecu l:.r orbital c3lcul3tions ba'icd on the pnnciples of quantum rneo.::han ics may be u~ 10 dc:terrmne cncrxY min ima ofrullltmg bood~ and 10 predict p""r~....ro ronforl1lOltlOO$ for too moleculc . 8y mcan..~ of molecu lar mechanic ... theoretical cooformatlOn31 analySIS ha!. found thai ACh halo WI coergy min,,"um for the I) torsion angle at about 84- and mat 100 prcfcm:d conformatiOll of ACh ~"Off\'f;poIld~ cloo>ely in aqueou~ solullon to thm found in lhe cry\lal Mate . The Mlody of intcnlCti()t1~ betwccn bnnoleculc, and ' m~1I

smull le by actina

Thi ~

membrane.
lie cic fl. lIS C'CCptoo lhal JmI)'1.e mlo

xrnled. For

10' ACb he 3 )( I(t

:x

jul1C1loo of

CS-Ct-N-Cl ' J OI-C5-Ct - N , CIj-OI -C5-Ct

,
C
,. a

,
C I
C-O - C-C -N- C

C1 - C6 - 0t - ~

cf ,

! . ,
Figure 17- 9

Figure 17-8 ACh tOfSIOIl a~~,

556

1407'- aNI Ginuu's TarJ:,ov,t o{Orr-K' Mnlic'bta/ wtd Pita,,, w"tK'tll C/"",utn'

He
H

CH,
H

CH,

HC

H'"

CH,

HC H

CH1N (CH,)~

( + }-m.llls-{ L S.2S}-acetoxycyclopop)ltJI. 1.3-dloxolane. IIlCthylammonium, and naturally occuni ng (+ )-(2S.3R.SS\mUSI;arine are more potent than their enamionler1 and Iuw very high ratios of activity bet"'~ n the (S) and (R)l5omm (Table 17-3). A similarobo;c:rvat ion may be made of ( + :lCety1-(S}-,8-melh y1choline. (+ )-C'is-(2S}-methy1-(4RHtimethylammonium- I.)-dioxolane. and (+ rlrllllf-{ISlS). aoctoxyeydopropyltrilllethyLamrnonium. all of .... hid! an (S) configuration at lite eatbon atOlTl thaI 10 the eatbon of ACh. Each of Ihese acll ve mu ner as aoo 17-3) show the receptor in gU illC3 cllrbon adjacenl esler ~IlIOI'5 are I'lOl COI'Isldered muc;curinic coumerpatl ...

Fig ure 17- 10 Geometric ISOmeIl of

,mU'iGlnne -

,""j"

molecules is of great in terest :too mlportancc toward tile undenlanding of drug action. These studies are challenging btc'ause of the large size of at least one molecule. For thoe fitSt time, thoe conformatioo of a neurotmnsmitter has heo:n determined for a molccule in lhe bound Slale. ACh is tronsformed from the gauche conformation in the free 5181e to a nearl y frlms conformalion when bound to the nicot inic receptor. n The: a.:th-e conformat ion of muscllrinic agonists 00 their ~ptor has a dihedral angle of Tl betwccn L 10 and 11 7".ll The par.lSymp;'lIhomimctic effOCls of muscarine ...ere first reported in 1869.1-< but its struc1ure WaJl no! c:lucidatOO until 1957." MUSC1lrine has fOll1 geometric isomef'S: muscarine, eplmuscarine. allomuscarine. and epiallomuscarine (Fig. L 7. 10). None: has mcemc ror plane ofsymme:try . Each geometric isomer can e:>.i~t as an cnamiomeric pair. The acthity of muscarine, II. oonsc L ective muscarini c m.:CJllor agonist. resides primarily in the naturally oceu";ng (+ rmuscarine en antiOlllcr. It is C$.'\Cntiall y free of nicOI:inic IIcuvity and apparemil' has the optimal steroochernisl1)' to act on the muscari nIC n:ttlllor sublypes. Syn!hctic molecules wilh a sub!i.tuucnt on the carbon atom thaI oorrc:sponds \0 the fJ carbon of ACh also 5how great differences tn muscarinic activity betwe<:n their isoml'l'. Mety1-( + }-(S}-tJ-melhyL choline:. (+ t-cit-(2S)' nI<!thyl-(4RHrimel hyJammonium-

"

CH1 -N- -CH,

f"'
I

CH,

TABU 17- ) Equipote nt Mol.r R. tios of Isomers on Gu ine . Pig Il e um: R. tios Re l",tJv. to Ace tylcholiM
Com!! ound
(+ )- A.,...y 1-{Sl-1I....1ll ~Ic

hoi,,,,, d, Iorillo

ohloriJr ( . H15.JR.'-S~M...-.rinc 1O'Ii.k ( 1--(111 ..1.$311)-"'_... iodiJe I + ki.oIl$)-MtdI)10{-ur.~) .... ' W llOOW_t..J.<b<<"- IOIIi<Ie {- . kU('2I'~ Mm.yI-(U).m_,"" _ _ I~ iodOk
(+)-1"""': IS.lfl-.A.rft.)'Oy<kIp......, trn.ttloy\Wunorl, ......... k

( ~ IAIlI)I-(R\.p....u.~lchol"...

1~.0'

(S }/(It) Ita1Io

",,.

o,n"
'00
0.01>'

6."
00....
.",

I . )-I"""lt R,2R)."""""-,-,,,yclop"'l) ttnmothy _ oodWo

'"

W 'I .... P. ..11<. I" -II>.\.llIIIt. ..... 1 _......,.,.. J II<t ..... 11_ 0..
j _

1I1;cot." H ... 01 1'1..., I !9'&7t. 11101

" " , , - p D~C_l.a.oo<I

c..,... J r ..... 2lO,~ 1961

l.l~n

. 1\163_

pyllri -

R.55)have Xne"

(+). H)-Iri 5.25)-

C .-! N '0 \

p ,/\

0,

c ...

/ CH,
0"

h have

"....,
figure 11_ 11
tflllOf '
~ POlhetlCal

arinlc e num(Table carinie at the cotimc IS theIr

slIucturt! of tllf muscanmc rr-

Sttucbi __ Actlvlty Relationships

Mthoogh muscarinic reccptOl"!i Mle ~n cloned and the . .no acid sequences are known . thei r three-dimensional ~1Ures rerunin unresolved. Thu s, il i ~ JlOI pos.~ible to usc: _ Informlltion alone to dc.~ign 'lpeCific drug molecules. Snmt IS!S sun usc: pharmacological and bioc~mical t ests 10 tkk,lUmc opIimDI ~tl'\Jcturul requiremen ts for octivity , ACh il l R'lath-ely ~implc molecule , The chemistry Dod case of te\IIng for ACh bIOlogical :lCllvity h:J,e allowed nUlllCrotJs dlrmkal dCnV3!"'eli to be made and ~lUdicd. A herJlion~ on ":~_~ ule ma)' bcdllided into Ihree categories: the ooiunl .. the ester function, aod the choline: moIe!y. The ooium group is c....~ntIDI for Intrin sIC act;vuy and conuibules 10 the affini ty of tlte molecule for tile receptors. ,.uaJly through the: bindmg cllCTJ.Y and parllally because ri '" IletlOO a~ a dcu:cting lind direcllnll group. Molecular _ ling dalll ~how the bindi ng ~ite to be a ne:g3livdy dllipod tip:u1ie acid rt'Siduc: tn the Ihlrd of lite .'le,entrun.~-

mcmbrnne heh~ es of the mu scarinic receptor ..lfI Hydropoo.bie pockets are located in helice\ 4 . 5, 6. and 1 ufthe: muscatinic rettptOf (Ft,. 11_ 11 ).17 The trimclh}'lammofllum group is the optimal functional moiety for activ ity. though wme ~Ignificant cltccptions are kno ..... n (e.g . piiocarpmc, arecQline. nirotine, and oxotremorine), J'hospholllum, 5ulfomum , ar;('t1OI1lUm l'IOStercs. or substiult:1Jls largcr than methyl o n the nitrogen incn:ase the Sil.c of the onium moiety. produce diffusion of tile posilil e cha.rge. and intcrfcrc stencally lO.uh proper dI\Ig- n:c eptOl" I nlcrnctjon, n:sullmg in d.:c n:asetl aclivily (T able 11-4). The ester group in ACh contributes to the bindmg of the compound 10 the muscarinic receptor because of hydrogen bond fonllalioo with Ihreonine :md asparagine residues at the recq:>lor SIIe:. A compari!iOfl of the cholinergiC octivuy of 3 ~ries of alJ.:yhriUlCth),lammoni um compounds IRN (CI'h). R - CI -C~ I show. n-amyltrintelhy lammon_ iu m.JI which may be considcrcd to hal'e It si l.l' and ma ~, Similar to lholoe of ACh and to be one magnitude lO.cakcr a~ II mu scarin ic agonist. Thc presencc of the acetyl group in ACh is not as critical as the si/..t: of the rnolc:culc. StudYing a sencs of n-alkyllrilTlClhylammooium J.llits re\"calcd1'l thaI fOl" maltimal muscarinic (ll:tivity. the quatcrnary ammonium group ~ Id be follo ..cd by a chain of fhe atoms: this has been rcfcnal to as the[il't'-<Jlom ru/I'. ShQnening or le ngtheni ng lhe cham atoms that st:Jl'Irotes the ester ,roup from the OIllum lIM)1cty reUUl:CS milScannie aCIi~ity, An (J' ~ubstitution on the: choltne motety decrenses boIh nicotinic und lIlu scari nic acti vi ly, but muscarinic acu~ ily is dccrelllied to ~ grealer c~tent. Nicotimc acti~ Ily is decTeased to ~ gn:ater degree by substnllIJon on lhe p carbon. Then:fore. acctyl a -nlCthylC'holinc, nhhou!! h lcs.~ potent th.1n ACh. has more nkOlinic than muscarinic aaivIty, II<hile acdyl' P.mcth)'lcholinc (mcth3cholinc:) elthibits

or

TA8LE 17.... Activity of Ace toxyethyl Onium Salu: Equipote nt Molar Rat ios Relative to Acetylcholine
CH, COOCH, CH.
N.M(,

c.t Blood PRuu..

tntert lne
I ( tt.I>I>tt)

Ff'09 Hu rt

>

r.;.

"' ~.H

N'Mdt, ~. H, N' M.,LI N Melil, WIZt, N "Mh It.<

.II",

S 1M.

... """ .
"

,., '" , ..,

2.!1 (Gu' .... 1"11

.,.. . ..
,

.,"" ,
,,.,
10.003"

, ,., '"

IZ (11."".0
J01Gu..... "'a) 2,~ ,\

"" '''''
'"

d - L47),

0.. _ _ e I,... II II I ' I _ .. Clot I ;;. I I ... """ . .... <:... I"'" ........ II. 0 _ .... """pl< . N H J """ .... E." no.. j j t II. 1 9)~. SitIoIt, It t . Not" IIo. K.. 1_ -.I 0"' ~ 1(. /. _ . ~ E>p. no.. 56 41.1, t'.l6.; lloIIo.' .. ..-dI..., 11 II 8r I _ . ~ 190. llW/ . In. 11. 11 t.:onIi ... r , ondT,..,.,. ..... I!iorm.1) P II B. I 1_ 7, 10..' .
I

.,

"

" '" ,n '" 01 """'

"

" "

'" n,

o/Icd olOCO'f)Io; I:I'

""1"1.\'
figur. 17- 12 Companson of the geometries of o~otrerl1()o nne and r'IlIJSUnne

M I and M2 rettptOri oot :uso has good select;.',ty fOf N. muscarinic n:ceptOl1l. M2 n:c~0I1I bind to AF-OX 116 . . gallamine, a neuromuscular blocking agrnt. M, I'tOejlUl\ high affinity for 4-diphenylaceIOly-N-rnelh}lptpendine: (4- DAMP) arid hcxahydl"Q)Liadifenidol (HHS,D) also rJl hlblt affinity for M , and M2 rc:cCptOl'J ,2 1 T~~ has been n:ported to be a ptJtati vt M. rect'ptor anlasolll!1l Figure 17- 13 includes Struclures of M)rne n:ccptor ~btl'P" onmgoni,ts.

'*

more muscariJlic than Jli!:OI in ic activ,ty. Hydrol ysis by AChE I~ more nffecled by ~ubsl11uttQf1i (HI lhe {j than the <r carbon. hydrol)~j~ mle of racemic IlCelyl P.melhylace Iylcho"ne is about 50% of thai of AC1I: racemic acetyl a "01 's hydroly.Cd aboul 9()<J, liS fa ....

P .... ucts
Chloride. ACh r hloride exrns .C"'~-~ ful SUlllulant r ffecl on the pants)'mp;ithelic nervou, OJ Allempts ha,'c been made 10 t1)C il as a chohnel!K" but il dur,ltion of action is 100 short for sustsUled dre.:.. baust of mpid hydrolysis by estcrnscs and lack Qf <PC~'' .. ily when admilllstcrW for systemic eff~s. II is " depre.\SIInt and DIl elTective vasodilalor, SIII"u11I110I1 01'. vai\ us and the pilrJsympathttic ne ...... ous system ~::::: tonic action on smooth musclr and mduces a now !lalivary nnd lacrimal g lands. lis c:,n1iac-dc:pre~~anl n:su hs from (IIJ a negative c hronotropi c decrease in hcan rale and (b) a negative inotropIC on heun muscle Ihal produces 11 dec:Teast in the f(Jl(! myocardial contractions. The vasodi latory action of Ani pri matily OIl the IUImes :and the an('flol~. with di~"t.1 do fect on the peripheral vascular system , BronchUlI m_ lion" a characlcnShc side dft .. ben the drug ,~, sySlemicall y.
A c.etylcholi~

n.c

Oxotremorine. o.'OIrc:mormc I H pyrrolidonoj-4pyr. rolidmo-2-butyne l has been n:ntded as :I CNS muscarinic \ ti rnu 1~!n1. I l~ action on tbe brain produce.~ tremOl1l in r~ peri menial anim~lls. 11 incrc:ases Aeh broin le~'c l ~ in r;J.t~ up 10 40% and ha.~ been , Iudied as a tlrug in the treatment of A I/.hd mer" \ dbcase. Although eMlier Mudic~ ~u gge..~ted th:lt th,~ appr""",h uf eleyat lllg Ie"el~ of ACh to treat AI (.heimer' 5 disea'oC i~ useful. th ,~ brll t'f was h'ghly dispu,ed by many n:sean:hcn. Ne\mhcles..~. oxotremonne. as I cholinergic agoni'l. facilitate>- memory stomgr.oo llIese findings ha ve ~'ed as ,mponantirads III lhede,elopniem oflgenls useful III tn:all ng AllhemJers dlsra.~. Although il pos.sessc:s groups that do not occur m othrr highly aclh'e muscariJlic agenb. OXOIn:monne'. Imn.f CQIlform:ttion shows thaI distances btt"'ec'n JlOS.-,iblr :!C11,'e crnters contSpund with {+ r musc:atine( Fig.17- 12).' Arecoline. Are~"Oline is on alkuloid obtuined fmm thr <;ceds of lhe belel nul (An-I'a /"IUrcllll), I~or muny years. nplivc\ of the Ea~t I ndir~ ha ve con~un ..:d the betel nUl as II s.ource of II cuphoria-cn:all ng suD<tancc.

H3C- N '-CH2-CH2-0-C-C~

<>
TI

I '"'

(HOUNERGIC RECEPTOR ANTAGON ISTS

CharolClrrilallon of mU!ICallme n:cCptON can now be extcntli:d be)'on<! the phamlxological obw ..... aliOllli on organ s)'stcm~ (e.g .. smooth muscle, h<!on) to dctennine SInK:tun: - acli ~ity nd:uiol15hl ps. DI ~MlCilillon constants of antagoni~t~ from radiolig:md -bino(l ing experimcnts 011 the various 1ll11.;cari!)k l\."Ceptors h!!"c played a major role in idcmifyi ng tllco;c reccplor~ and the selectivity of amagon i~IS to the fi. c mu-';corinic receptor ~ubtypcs. Antogoni,l< wllh high affinity for unc rec:rptor and a low affinll y for the 04her four receptor type' are \'ety few. ho",'r\er.lIoo Illany anUlj;oni ru bind 10 se"erJI 'ubtypc'\ .... 'm c'lual affi nlly . M I receptors h:a1'C been kkntlfied a.~ lhost wilh high affinity for ptren1.t'pine lind low affinilY for. w mpound such as AFDX 116. 1 >jn:n7.epine: can dl<oli nguish bct""ttn M , and M 1. M . or M} btn has ~igniftcal1t affini ty for M. receplOI1I. Unnbadne: can distin guish bctwC<'n M I and M. n:ceptOl'J _Mcthoctr.lmillol'. a poIymrlhyienetelrnmine. not only discrim inates belwccn

I is atropine, a noosc:lccth'e muscarinic :lIllllgonlit. block ~ the depressant e ffeet of ACh on eanhac musck its prodUCtion of pcnploual yasodilalion (~::;;:"::;,: feets) 001 does not affect the d.:rletaJ mU5C\e (i.r., nICotinic effeet) produced ACh chloride is a hygroscopic powder lhal an admixture with rnannilOlto be dissolved In for injection ~hortl y before use. II j_ a ~ hon-acll nl when in lroduced illlo the anterior chamber of lhe especia lly useful after calaract surgery du ring I of sutures. When applied topically to the rye. II therapeuuc yalue because of poor corneal penctra\lOl rnpid hydrol ysh by AC hE. Methacholine Chloride, USP. acet} I-P.melhykhohnc: chloride or ( 2- h)dro~ypn.!p) rnelhylummonium chlonde acelllle, is the acetyl ~

One ofthc most elTeeth'r alllagonisls to the

rnethylchoh nc:. Unlike ACh. methacholine, ~:~~~!'::: hi hl y in the body IU giyC sustaiJled

p';;;' "

for 1101 , 116:md

cptors

ylPlpcri1D) bul tCamide :J.go nisl . subtype

AF-OX 11$

I lit , obacIt ..

a flOwers ~y~len1_ ic agenl.

effecl ~,

. ~prcific. a cardi:1C

on of the

'-~ ~~.NH-(~-NH _(CH," _ NH~CHoJ._NH ~~_./

mdllCCS

a
~t"IOdI.I."

"".0 -

from Ihe

anl dfcci
t cause, a

Pic 1lC1l0Il e f()l\':e of of ACh IS dlstlllCl d II OOfIstricIg i~ given

"
Thi~

Figure 17-13 ChemKal strualllf!!i of partIally se\e("tM! m\tSC(lflfll( antagonISts.

Iottof ACh I . Atropll..:' mU)oCJc ond scarin lc rf contnlCtion

~"allable In

.1;011 i) accornpamoo by hllie (I/I<XXI thai or K'b) or no nicollnic eff~l.

H C-N'-CH -CH-O-C-C" ,
~ ! ~

!"'

1"'

..,.

C",
Methecholino Chkll'kie

lerlle water Ilng nllOUC : eye and 1\ ! place menl II has hllte ,tratiOO lI1lI.I

lC

ch londe. ypcop} l)tri' ester of p. lrftcienl ~I:J.

:tic sl1l11ula

\Ietlachollne can eMSt lIS IS) und (N) enarniomei'l. AIthe chemical IS used as lhe raccnnc mixture. liS mus00tt1C xmlly resides pnndpally in lhe (.',) lSOlner. The II ralio of nluscannle: potency for the\oe cnanllOnlcrs is '.to: I (+"Ace(~I-(SJ-,8-",clhylc:holi IIC i, hydmly led by AChE. the (R)( _) iwmer i~ I)(JI (-~AcetyHN ~P.lncth}'l !Wine IS ......eak compehlivc mhibilOl" (K,. 4 X IU -~ M) ~.~obIntl1ed rrom the eicclriC()fgDn or thc eel (E/term ,/tncUJ). 1lle hydrolysi, rate: of the- IS)( + ) is()<ller llibout 504'1 Ihllt ACh. This rate probubly compcns:lle5 b.,. decreased a ~soclauon (affinity) o ..... ing to the: ,8-

IIlCthyl group .... ith the: Uluscaril11c n.'l:eptor ~;tl;! and may account for the: f;act thaI AOI and (+ )-acetyl-P.mcthylchollne hnve: equilllolnr muscarinic potencies in vj.o. (-~ACC\yl (N~P.mcthylchohne ..... eakly inhlblls AChE nnd Slightly rcinfl)l"Ccs Ille Ulu)oCanuic oct;.ity of the (S)( +) isomer in IhI; r.K'C[11ic ml;\[urc :tCctyl-,8-methykholillC. In tn.:- hydrolY1ii~ of the acetyl II- and ,8-nlClh}lchollne.~ Ihc grcuu:st \Icroocllemical inhibllOl)' efflX"ls occur .... hen lhe choline: IS Mlb<.lIIulI:d in the {J position . Th,s aho DpPl'an; to be (rue of orgll1>Ophosphorous IIIll1bllOf"S. The IR)( - ) and (S)( + ) isol11er. of llCe!}, I a-rncthylcholine: an: h)'drolr~ed at 78 and 97'" of the rnte or ACh. re.spt:Cli>d),. Methacholine clllOl'1de :CUN a~ colorl ess or "'hilc crys lals or as a .... 1I,le crystalline j'IO ..... der. II I~ odorless or ha, a dighl odor and is \'ery deliquescent. It is rreely solubk in ..... ater. akohol, (M' chlorofOl'111. und liS aql1COU~ solution is nc:ullllilo lilmo ~ and billCt'. It IS hydrotyad rapidly in nlkaline: !IOlulloos. Solulions Ill\' I\'lali\'dy ":lbk to heal :lnd ..... ill keep ror al least 2 or J .....eels .... hcn rcfllgerm~'<I 10 delay gro .... th of molds.

or

or

O".bachol.

Choline chloride (,""",lItwnate I ~ nonspecIfic in liS 1K.1ion on mu\('m-imc .... 'CCplOl' subtypes. The pharmoco-

560

Wil...,., and Gi:rmld'J TurbotJt 11{0."",... Mwicmal and I'Mnrtllff""OlI ClwmiJfry

CH, CH,

logIcal ar..'tivity of earbachol is ~imilar 10 thai of ACh. It is an ~cr of choline aOO thus posscs...s boIh muscarinic aOO mC(l(rmc piOpCHoe!i by cholmergoc receptor 5l1 mulallon . It {'lin also act indirectly by promoting release of ACh and by its ""caI: anticOOline~terase octi~ity . Carbachol fonm: 11 carbamy l ester III the !aCllve SHe of AChE. which is hydroIyu d more: slow ly than an Deetyl estl!r. This slower hydrolysi~ rotc reduces the amount of free enzyme 000 prolongs the dur.llion of ACh in the synup .... Carbachol also stirnulale~ lhe: aUlonomic ganglia and CHUSC'S eontnoclion of skc:1eml mu.~le hut differs from a true: mU SI;arink agent in that il OOcli not Mve cardiovascular acti~ity despite the fxt that il sccm~ to affcct M: rttl'p4otS. 1 Carbkhol is D miotic and has bc:c:n used 10 reduce: lhe Inlr.Jocu'3I" tl'nsion of glaucoma .... hc:n a rrsponse cannot be: obtarned wilh pilocarpiOl' or neoshgmine . Pc:nctnltioo of the romea is poor bul can be I'nhanced by the use of a wetting agcm in the Oplllh:oJm,c solution. In addiuon 10 its topical use for I lauooma. ClIrbachol is used during ocuillf surgery . when. more prolonged miosIS is requ,red than ('an be: 00. l~inc:d wilh ACh chloride:.

H"t-N"-CH, -CH-O-C-NH,

I I CH,

BetMne.::hoI Chloride

Pilocarpine Hydrochloride, USP. Pil ocarp ine nlCWlhydrochloride is lhe: hydrochloride of an alkaloid from the dncd leanl'l~ of Pi/oca'P'u Jl.bimmtli or P ".;c-/lJo phylluJ. in which it occurs to the c~ tent of ahool OJ'), ,, gether ..... ,th other alkaloids,

obI_

Piloca'pino Hydrochtorlde

Carbachol Chloride

Carbachol differs clienllc-dUy from ACh in iu Slability to h)'drolysls. The carbamyl group of carbachol dcc~ llie c:la:trophilitity oh he: carbonyl and. thus. can form resonance: SIIllCUlt\'S more ea)iJy Ihan ACh can. The re,;uh is that carbachol is less suscep4ible 10 hydrolysis and. lherefore. more stable ;n aqueOU5 solutions.

Bethanechol Chloride, USP.

BClhllnc:chol. ,8-melhyl

choline chloride carbamate . {2-hydm~ypropy l)trimethylam monium chloride: carb~mate. carbamylmc:th)1cholinc: chloride: (Urn:ho1i..e), is nonspecific in its !ICIiOll on muscarinic rttl'p4or sulMypc::<o but appcars w be more dfeclh e at eJiciung ph:lrmaoological:lt'lton of M, rttl'p401'5'" It has phann:&OOlogical ",~-x"ics si milar 10 lhose of methacholine. Both 11K I'Slers of P.mcthylcholine and have feeble nicotinIC :It'Ii v;ty. Bethanc:chol is inactivated moOre 5lowly by AChE in v" ,o than is methacholine. It i~ a carbamyll'ster and is expected 10 ha' C siability in aqucou~ solut ion~ si nHlar 10 that of camachol. The co.,in use of betlwl\Cchol chloride i ~ in lhe relief of urinary retcntion and abdominal distention aftcr surgery. The drug i~ used ordUy lInd hy su1x:uta!leOlls injection_ It must 1lC' er be IKImi nistered by intrJmnscular or intlll"enous injeclion because of the danger from cholinergic overst imulalion and loss of seleclive action. !'roper adminislr.llion of the drug is associated with low to.lk,ty IUld no serious side: cffccts, Iktl'lanc:chol chloride should bt used with clIution in asthmatic p:w:knts: .... he:n used for glaucoma, il produces frontal headaches from the: constriction of the: sphiocter muscle in the eye and from ci liary mU!II;\e spasm,. [1$ duration of action is I hour.

11 O(."c urs !I.~ culorless, lran sl ucenl , odorle.~s. faintly crystals that arc soluble in water (I :0,3). alcol1ol (I :J~' ;; ; chloroform (I :360). (In Ihis chaptcr. a solubill1 y Cll"' a) 1:360 ;lKllcales lhal I g is solublc in 360 mL of lhe' ~ at lSOC. SoIubllltres at othe:r tc:mpc:ratUItS arc: so I . Itl ~ hygrOKOplC and light; its 10 htmus and ponify lhe lactone group to give tive hydro"y acid (pi locarpic acid). lahon al lhe: ethyl group position occurs t C\lent Dnd IS another major piJlhway routes rt'so ll in loss or pharmacological ]'ilocarpine ;~ a nono;clective agoni st on lhe re<:ep4l)f"S. Despile this. it rt'portedly acts on M J nlOOlh nmo;cle to cause eontracl ions in the gUI. I'ye .u ... I n the: eyc. it prodllCCS puPIllary oomlrictlOfll
sis) aOO a spasm of accommoliatron. 1llc:sc: e:'~~:"~';'::~1 ble in the trealment o f glauooma. The pupil ~pasnl of the: ci liaI)' muscle redo inll'llOCular ItMP establishing bener drainage of ocuillf nUld of Schlemm. located near the comer of the iris Pilocarprne is used as a 0.5 10 0.6'l. so[ul ion u lu) in treating IlatIComa. SySll'mic e((ls i sweatrng. ,'IlIlrvation. and !aslrie secrelion.

Pilocarpine Nitrat e, US/>. ]'iJocarp;ne '~;:;:: curs u_~ shining white erysti11 ~ 11131 arc not h) are ligtll !.Cnsilive. It is soluble in water {I : (I :75) but insoluble in chloroform and I'lher. lions lite slightly acid 10 litmu s and may be the autocla'e. The allaloid is incompatible: ....rlh iodide.~. si I"ef nitr~lc. and rc::tgenls Ihal

in lhe:

ond lhe:ir iUbs!nllC

,AILE 17- 5 Hydrolysis of Various 5ubsb'ates by AChE and BuChE

.""
&1I1'IM

substr.t.

Sou.,.
lIu .... til """Inc ItRC

1I. ",tl...

llat.

\.:rI)khol.". \.:rI\ k"""''''~lnc

~

~) 1~"1<1h)khQl"...

So""" Ittl(,: I!.o""" It IlC

IIlImlIn ROC
Ii"""," MRC 800-,... MIK" 80>,.. MRC

""""'"~ J."'~h...
"yr)kllC>bl'lt Iortr)'lWochn)il'lt

,~

.....,1dooI, ..
~~ItoIIt)II<CI_

f-,I-"

....,.1 .... " " IJIOOI ..... . ''''''yrlIer

'.(\1<000)0111)1 "'....,

Hu .... RBC" III111W1IU1C 1I_ 1t1lC

II_ IUK ' h,,,,,,,, IUK

'" , .," , , ,
'" " "
'"

".

.. ......
""'
lIu_ til
"' .....

1I.I. t; _

pIIo._

,.,

".t.

H, ..... pblJ...
lioN plll>ml<
lI~pI .. m:.

,10>0"" pi......
'~pI"'''1

"'""" ,, Hwnanpboo_
I..."" pa.mo

........

ml

""0 "" "" ",

l!l11
II

H",,_ pbI.ma

tc

,.."..,"'......
'I0000 pi ......

'" ,

Human IUK"

.I4opooI ill,. ''''''' ' ) " Ool~ "'~ onoIIloIM<dC_ _ . ~ ........ _ . "I'I""u"""'Iy""';..... _ ... ~ ............. """)IcII<~' .. ~ IW.

1'0." - ........ .......,....

Y orI.......-... ,_

l<;lbl .

" "

....

"'"

!lIE IS associalcd wilh the oublde surface of gl il.1 cells In

to)n;q1SC ~nd catal) lCS lhe hydroly~ls of ACh II) cooliOle'

lenl

00.)

!lCid

~n

:able

'~h

"nic Tli in

. mio-

'""

alua-

=anal
~,.

,"'" " b,

.r "" piou~

-.I 1CtI~ lei .... inhibition of AChE prolongs !he: durutlon I.nc:urotr:msmmer in thi: jul1C1ioo and ptOOlICc:.~ pluuma . .~II cffect5 ~Im.lar 10 tlIOliC obSCf\-ed .. hen ACh i\ ad !kI'ed. 'rb:!>C onhibl1OfS an: indirecHICtmg cholirlCf'gic p""- AChE inh IbItors h.:a\"c been used on the treatment 11II)'llMhcnia grn"is. atooy in t""" G lt ract. and glaucoma. 'Iky Ioal'f also hoen 1.1-00 as ugncuhurnl mscclicidc.~ and JC!\'f gases. More recently. tkey ha ve received allentioo as ftI!'Iom!tUC drug treatmc nts in ~It iertt~ ~lI fferi ng from A 1 1,t-unc:r's di'iCusc,' 7 BuChE (pscudocholirtCStcl'llSl:) i, located in hum an r Although its biological func tion i, not clear. " ha.. aul)1~ propert ies similar to those uf AChE. The 5ubstrate 'Ftfo.:ny is broader (Table: 17-51, and it muy hydrol)'lc estcrs and drug moIC'Cules in the blood_ l1Irtt dlffcrent chentlCllll,'1'OUplngs. atttyi. C' rbaIllYl. and .. po yl. may I"QCI .... ith the cstcratlc site or AChE. AI the chemical reactions lIl"C simil llT. the lH'IC'~ p.1ramfo.-cach type of wbstrnte d iffer and l"Cliult in di fferences lietl.mo !O~lcity and usefulness .

the hydrolysis of ACh by AChE IS rel'crsiblc cnJyme-'ubstl"llte complex formation. The association rotc (t ~,) and d, \sociatloo rotc (1 ,j are I1:lalilely large. lllc en7yme-'ubst ..... te eonlplcx. E... - AOI. may abo form an acel )'I~I.)'n'IC in termediate at a role (t1lthat is slo.... er than c lI l'ICr the a.''''OClaIiOO or d i~sociation rates. Cboline is rele:a.'iCd from thl~ oomplc:~ .. nh ,....., formation of lhe acctyl-enl)'mc IIncnned,ate. EA. ThJ~ Intermedmte " 1hen hydrolyf.ctI 10 TCllcncmtc the free C"")'f1'IC and IICctic acid. 1lte acetylali on rotc. /c~. is the slo .. est ~tep in thi ' i>Ctjucncc and is rotc- limiting (see disc ussion be low). Kinet ic ,tudic~ with d,(fcrelll ~ulKtnllcs and inh,hitoJ') sUj!gest that lhe: acti vc ccme r of AChE con ~i~t, of 'iC\"cr'l.1 major domain s: an artionoc sill.'. 10 which lhe trimcth) lamnMlllillm group binds: an e~lerntic Sile. which cause, hydnHYsis of the e~ter porIlOrI of ACh: and hydrophobic s ile' . .. hich bind ary l substrole~. OIl'1Cr unch.:arged ligands, and the ~ll)"1 porIton of the acyl mOIl:ly of ACh. ThC're is also a pcnphc"'dJ aniooic ... te_ rell1O\ed by .tlea~t 20 A from thi5 actileccn1er. ..hich allostcrlcally regulates aclt""y at the o:sterat,c ~,tc." Tl1e anionic snc ... as belle'cd 10 have been formed by the ')'<arbu~ylate group of 11 glutamiC ocid residue ..... but mon.:
!ill.'p 111

The inll131

te ocIC but

cohol
sol u:ed in (alic". Ilolds.

H~-r-C H1-C H1-O-C- CH3

1"'
CH,

ij

H~

lEand
,ffe r In ific.ty,

H~-N-CHJ-C HJ-O- H

1"'
CH,

o
+ H-O-C-CH:s

II

Figu~

17-14 Moch.m1Sm of hydrolysis of

ACh by AChE. A. ACh- AChE reversible com plex Ao>tyIatJOn of estet'ilUC sne Co Gf'neral baSlKatll1yzed hydfolym of acetyillted en zyme. D. free enzyme

rettm Sludie!l 5Ugj,-est thai lhe aromalic moielie:s of Irypl()ph~m IUld phenylalllllinc residucs bind the qU(ltemary Ilmmo-nhlln group ()f ACh in Ihe aniooic 5ite through calioo- 'II" inIC1'lloClioo~.)O 100 locati()11 and sl)alial o rganization in the estenui.: lOne by serine. histidine. and glulamic acid resklues constitute lhe e!lltrdlic site. 'The triad of these amino add residues contributl!..~ 10 the high catalytic efflC1cncy ()f AChE (Fig. 17. 14).~ 1 AOIE altacu the ester sub5mlle through a serine hydro. .tyl. f()lll\ing. co-.'alent acyl - eillyllle complex. 100 serine i~ al.1ivated as II nucleophi lc by the glutamIC acid and hiStidine 0 miidues that .'iC:f\e as the proIoo sink 1 i1ltack Ihe carbonyl carbon of ACh. Cholinc is relcased. Icaving the acetylated serine residue on lhe Cffi'.)"Inc. 'The acctyl-cnzymc inlcmlCdi

ale is ckaved by II gtocl1ll ":'~ ~:::: generate the f~ cn/.ymc. h is indicated by kj .

Carbam:ucs Sitch as cru1xlc1lo1 SUbstnlCS f()l" I

mcdi ate (E ). the nllc of acC'tylation. of the carbamyl -cn~yme

a~

also able

i is than th.:lt of ils acetyl countcrpart. 'The !'iue limits the o pli llUll runelionn! capadty IIlg carbamate subslralcs to be senllre,cr..iblC'

AChE. In the mechani sm aOO," c. depends not only on the

k) b

, . '"

>.,
EACh

>,

>,

'\

'- A

>,
(

" ,0

CX

., ,
,

,.",

" \

'-c - " _

,.

_ _ ex c..twllylill>ng .....~

blu ul<;() 011 the type of carbam),1 ltamic acid

c.~tcr. I~ ters

of car-

111.1-327

R-O-C-J\\toI:

II

TABtE 17-6 Inhibition Constants for Antic:holi,..stet'as. Potency of Ac:etylcholi,..,t. ra.. Inhibiton
R."..-sibl. -..d tnhlbltors
A_II'.."""
SemIN"ersl~

1f,IM )

abeltrrcarbamylaling agenls 0( AChE than the mt'thylcar

...,1

II R-O-C -Nt-tCH,
al din .... lItykarb... nyl
allalogucs. H

O"'".....i~m
I'.Jrup/I<lIIIUln
~,.,.,;""

o
R-O-C-N(CH,),

Ph)_'lI"'lne

II

Pyrido><I"""",
t ....".nlble Inhibitors

401C10' 101C10' 101C10" 30'11l' IO-11l 10 IC 10' ~O )( 10

If, (moUnIlnJ

Orpnopho!<phalc e;;1~r.i of selected ~"OInllOllnds can also ~ry the .w:rine residue in the oc,ive sile of AChE. The ~).i~ rote (.I;~) of the phosphorylaled serine IS eJ.1n:mc:ly p. and hydrolysIs to the f~ enzyme and phosphoric add ,Im'lIIlnl i~ SO limned that the InhibillOO is considered lototnIbie. These org:mophosphorous compounds an: used in k \n'at/I1I:TIl o f glaucoma. as a.griculturlll Inscclicide~. and. _times...~ nero'e gases in warfare IIIId blOlem.lfi..m. Fi nally. II'mI: lIa.e either been or are currently being evaluuled for 0IC13lnst AI~lM:i mcr') disease. Table 17-6 shows tIM: n:laIJ\r poIellClCS of several AChE inhibitl)fS.

19 I( 10' 12 1C[0' IIICIO" 6)ICIO' 2.1 )( Ill"

', "lbI.lnhlbltors
1'IIys00figmlne, USP. Physostigmine i. an alhloid ob-.d (TOtn the dried ripe seed of I'h)"sos/lgma 'f'/U'llosunr. l~ as a whitc, odorless, microcry~tamne powder that \/iihtly soluble in water and fr ly lIOluble in alcohol, db";onn. and tIM: fixed oils. The alkaloid, as Inc fltt oo.<;e.
s1pICICnsithe 10 heal. light. moi~ture. and~. undergoI( r.Iptd decomposiliQn. In solutioo it is hydrul Yled to .ch)1 cartwnic acid and eserulint', neitncr of which inhibits IDlE. E.~ro1ine is oxidi~ to a red compound. rubrcscr_," IIJ'Id then funlM:r Oc~"()JTlposed to c.<;eri ne blue and c.o;er !lroY,D. Addit ion of sulfite 01' ascor bic acid "",~cnl~ o~i ,w1OO of the ph~1I01. escrolinc. \0 n!br"l:.~rine . I l ydroly~is tit! take pl ~. oowever. 3nd the phySO<;ligmi nc i. inact;llICIl Soluti ons are nM)S1 Slah le al pH 6 and Should nt:vcr 'Ie umhlro by ncal.

m 10 re-

lan stcp

;eNc ..,

ne inter

:..,er rh:r.n tylmiool ~ slo ... er

!droly~i~

alltl"'

bI t""' of

e nne ! l
Iy of the

Phy sostigmine b a n:1:llively poor carbamylatinll agent of AChE and is often con)id.cred a reversible inhibitor of the cMymc. Its cholinC'leru)o(: inhi biting properties vary w,lh the pll of the medium (Fig. 17-15). TIM: OOlljugale add of physostigmine has :I pK , of :lOOut 8. and as the pH of ,be SOlution is to"'cred. IIMIn: is prescnt in 11M: proI0I1:Iled fonn. Inhibilion of cholinestCfllsc i~ greater in 3Cid medIa. !iU"e~l ing th:i, tnc proronated fonn makes II rontrioolloo to tnc inhibilOf)' OCIII'lIy .... ell as its carbamylatioo of ,he enzyme. Plty_ligm ine ...lIlI used lirst as a lupical application in the In:allnt'nl of glaucoma. lIS lipid solubi lil)' PfQPCI1ies peil1ll\ adequalc absorptIon rrom oi ntment bases. It ii u.o;ed sY-Mcrm cally as lin antidote for atropint: poisoning and OIber ant icholinergic drugs by illCreasi ng the duration 0( llelion of ACt 11.1 chol int:rgic si tcs through inhibition of AChE. l>tlys(>slIg mine. nlool; with Olhcr cholinomimetic dru gs acting In the CNS, has been ~llIdl~'d ror use In lhe In::umenlof Althei m s di~lISC.loO Cholinomimctics Ihal are CU lTcnll y us..>d or e' which have been reccntly evalualed in the treatment of Alz heimer"' dlscllSC include donepelil. galantaminc. rnctriro-

, "

.,

E~'

" ,-. " , \

lOt PX phcosp\'"t<IfyI SIbIIra.

564

~d_

"'''/ G ....',>lds TrAibook "I O'1l0l1u: M('didl1lJ/ "tid Pltarmoctwtu;al ChrmiJiry

HsCHN-C-O

""
" I' , C

0' -

" I
,

c',

1
C",
(/111 bkIa

Esorollne

(0)

I
" I
Ruble_nne

./
'-...

!
eS8nne bfown

naIl'. nvastigmuv:.. and tacrine . ? It is anticipated that this lisl .... ,11 ront inoc: 10 grow as the etiology of this disease beconW!!l bener understood,

Physostigmine Salicylate. USP.

1lle salicylute or phy-

sostillmine (eserine salicylale) may be pn:parcd by l"Il'utraliling an ethcreal sol ution or the alkaloid with ~n cthereal wl ll\10n or salicylic acid. Excfi!i salicylic acid is removed rrom the pm:ipit:lted prodUCI by .....shing il with ether. 1besalicylatc i$ less dcliquc'iC1:nt th an the 'itilrutc. l'hysosligmine ),.D licy late oceurs as a white. shini ng. odorless t'1)~tal 01' while powder that is sol uble in water ( I :75). alcohol ( I : 1 01' chlorofoon ( I :6) but much le5.~ soluble in 6). etiler (1 :250). On prolonged ex.posure to air and li ght, the

tum ltd, 1lle red nlay be relllO\'ed by lIa5hln&1k crystals with alcohol. although this cauSol.'S loss of the mf. pound 115 well , Aqueous oolut ioos arc neutral or ~IiPll! acidic and Lake on II red roloratioo after II period. Thecoli:t atioo ~y be la~ en as an indc:" of the 105.~ of actn, !) phywstigmine soIullons.
cryslal~

~HN-C-O

IT

'"

PI " I - t.gmonB Salicylate

Solutions of physostigmine sali cylute arc i with the usual reagents that precipit:ltc and with iron salts. lncompaubllily also oocurs kooiuot chloritlc: and related welling agents llCelu.S!" sa licy late ion.

20

, , , ,
pH

"

occurs as a while, Physostigmine deliqUCSI:l'nt in moist air. It i (1 :0 .4). and ether (1 :1200). It has the sal icylate salt 0( bemg compalible in oolulloo nium chloride and related compounds.

S~~";'~";":U~S::P -::::.i:~~~;~~;~j~ ~

figure 11- 15 Effect of pH on inhlbtt!Ol1 01 choiInfstl'f.JSe

by physosll9l1llilf
a~d

neostigmine

droxypllcnyl)tnmcthylanlOlOlllum bromide (

NIstigmine Bromide.

~:::::~i::~

------------------...
NIt Of

the: dimtthylcurb.'lmic tiler of 3hydro~yp/l('nyhri mcthylammoniurn bromide (Prostigmin bromide). is used L~ anI"""" !O nondcpolnri1jng neuromuscular blocking lkup and in the IrearnlCnI of myastheni3 grayis. II OCCUI'$

groV1S, D condi tion c(lused by an auwinlmuoe mechanism thai reqUIres an Increase in ACh concentl3tion in the ncuromuscular junclIOII 10 susuun normal muscular IICt i~it)' .

mya~thcniD

bmer. odorless. while:. crystalline powder. 11 is soluble ill .'JICT IIIld alcohol. The cryqals are much less hygroscopIC llYn those of oeo!iligmine rnelhylsulfmc lind thus may be lIItd in tablets. Solutions Ire st:Ible and may be sterili.,.ed

"" boiling. Aqueous solutions are OCUli':!! to litmus.

eH,
H:,C-W-CH,

O-C-N

Neostigmine Methylsulfare. NrostigmJoe nlCth) Isu l fate, (nt -hydro. yphc ny I)trill)(' th Yhunmon iu m lI)('lh ylsu Irate. dimeth>karbamall: or tliC dimcthy1carlmmlc estCr of 3-hydroxyphenylLrinlt.thylammonium methyl5llifate (Prostigmin meth> lsulfate). is a bitter, odorless, "'hlh:. crystalline PO" dcr_ It is very soluble in watcr and soluble in alcohol. 5011.1tion~ arc stable and can be: sterih~ed by boil"'g . The com pound is too hygroscopic for use in I .solid form and thus is alway5 used ns an injection . Aqueous <;()lutlOlis are neutral to litmus.

"

/H' "-eH,
OC -N

NOOSIIgmino Bromide

'h< om-

htly

Ilor-

,of

list ofphySOSllgminc. a~ a proIOIype of an indirect-ucting pmsym~imetk drug. facilitated the: dcyeJopment of lli&mill(', in which a trimethylamine gl"Q\lp was pluced pori' In dimethykarbamatc group in benlcnc. Beuer inhibition -t cholinestC11lsc was observed when these groups ...ere pIIIzd _ta 10 each OIher n in neosngnlll1e. a n~ active .r ~ful agent. Altllough phYSOI01illminc contains a mtth ~malc funcuonal gTOllp. greater chemical stability tolTd hydrolysis WIIS obIained with the dmlClhykarbamyl pi.lIIp In neostigmine." Neo5Iigmine has a half-life of about 50 minut~ after oral .lI'I!nvenous adminIStration. About 80% of ~ single I1l1rnalCUlar ~ is ClI.crcled in the urine within 24 houR; ap'Mllnately 40% is e.creted unchangcd. and the remaindcr uxCltkd l1li metabolites. 0( the IlCOStigllline thaI reache.\ fir bvcr. 98% is mctabolized in 10 minulcs 10 3-hydro.y,tIa)luiTTOelhyl ammonium. ",hlCh has acti"ity si milar 1 0. t. WfRer than. n.eostigm ine. [t5 transfer from plasma 10 r.e.noJls and then to bile is probably panive. Because cellu Itr membranes pcmlil the passage of plllSma proIeins ~ymhe ud In Ihe liver into the bloods~am thll)llgh capillary walls .I)mphatic vessels. lhey may IlOI presem a barrier to lhe ~. of quaternary amll1es such as neostigmine . TI1C !Ipid hepatic metabolis m of ncostigmillC may pro~idc a *'"'1111111 gadlent for the CQIltinual diffusion of this oom~.,. A certain amoum i ~ hydro/yled ~Iowly by plasma

"

/ H ' "-eH,

NeosIlgmtne MctITylaul!ale

The rnethylsulfate sail is used po:o.topcronH']y as a unnary stimulant and in the diagnosiS and Ircannenl of mYll5thenia grol;s.

PyridOSI;gmlne Bromide, USP. I')'~igmine br0mide:. 3-hydroxy-l-mclhylpyridinlum bromide dimcthykarbWllatc or pynooSligmioe bromide (Mestinon). (lI:CIlr;; as I wllite. hygrosropic. cry~lall i tle powder with an ag/l"Cable, characteristic odof. II is flttl, IIOlubie to "'liter. alcohol. and cliJoroforTII.

o
O-C-N

II

T
CH,

I
Br.

/H' "-eH,

dtohne>Iense_
Neosugmine has a mechanism of action quitc similar to .. ol physostigmine. It effectively inhibit.'i <:holinestcrase I about IO~ M CO!IC\'ntration . Its activity does not vary wIIh pll. and at all ranges it uhihits Similar c(ltionic propertil IIiS. 17-15). Skcletal mu~1e is also st,mulllled by nco.,rae. ft property lhm physo\ligmine does not ha'c. IIfCI; of IIWStigmillC arc Si milar 10 those of phy sostig. . bul differ in ex hibiting greateT' miotic OCIivity. fe"'er .. Eu unpiaSatit local and syucnuc manifeSiatlon s. and pier chtmical stnbility. The mosl frequent application of Rllcminc: is to pR:vcnt awny of lhe i nteSlinal. skelctal. and 1iIddt. mUlCUlaHlre. An important use is in the treaUllCnt of l>yridostigmioe bromide: is about onefifth a~ toxic as ncoStigmltle. It appe3R to function to a maimer sinu lar 10 thai of neostigmioe and is the nlO6t widely used anlicholineslerolSl: agent for treati ng myu~thenia gra\ i~. The li"er enzymc:~ and pla.Ql\3 cholillCSterase nlClabolizc the drug. 1lIc pnnclpal metabolite is 3- hydroxy-N-metllylpyridini um. Orally administered pyritlootigmioe has a half.Me of 90 minutes and a dunltion of action or between 3 and 6 hour;;.

n.r

"bo-

Ambenon /um Chloride. Ambenonium chlondc:. IonIyl bis ( i m inoo:th yleoe ) I bis [ ( ,,-ell lorohen-,y I )d Iet hylaml1K\11 -

NllbeilOll'um ChloflOO

;'1111] dichloride (MytclllSC chloride). is a " hnc. odorlcs.s po,,der. soluble in water and alCQhoI. slightly soluble on chlorofurm. and prucuc all y insoluble in etller and atct~. AI1Ibc'.oonium chloride b used for the trelltmem of myas then la gr:a\is 111 patients ,,00 do not !"e'\flOOd SIItisfllCtorily 10 1M.'OStlgmllle or pyrido>.t igmin.c. This drug acts by ~u pprcs5ing the act ivily of ACI!E. It pclSsc"S5('lI a relalL"ely prolon~cd durdtion of oction and causes fe wer side C ffl~ts in the GI tnll;t than the other anli cholilM!$u:rnsc agents. The dosage requirements ~ary con~id erdbly. and the dosage must be ind" idual i1.ed according to the re.~pon~ and to!cronce of the lXuicm. Because of its qUhtcm ary am l1H)flium 51ru<:WIl' . umbcnonium chloride i, aiN!rbcd poorly from the Gl tract. III modemlc doses, thl: drug dot-s not cross the blood- br,lIn barner. Ambeoonlum cl!loride is not l!ydrolYI.ed by chollllc~tcrn<e$.

carnetl!) kn.(' bi~( n.... lhylcwbanlic acid) and thus is c(ll'IJWI' ble 1 a bi ~pro:.tignllnc molecule. 0 It occur; 11.' a ~loghtly hYIln:KCopic po"der IIw is loOluble in water Of ak'{)j\t}1. Optllh:ltmlC 'IO hninn) of tJ-c

ha,e a I' ll of 5 to 7.5. Aqueou) .soluUoo~ arc stDblcand be Slcntll.ed by heat. It s effie;acy and 10\lelly an: 10 tkQo.e of othe r polen! :mt icholine~tcrase inhibitor o.inofl II is It longactong miotic used to treat ,,'ideangle g"'';' and xcommodatwe ('~ropia. M :o.~jll\aJ effect OCCUr!;
after !idmlnbtrutioll. and the efrcct may persist fordoyt

Demecarium Bromide, US!'.

Oemecamlm bronllde. ( m h ydro~ yphcny l )trime th yl ~ l1llnollilln l broillide. deca mclhyleneb!~lmclhylcarb:lmalel (lI ul1lO1'S01). b the d i('<;\cr or (ml!ydm~yphc nyl )trimclhylammollIum bromode " It I! de

. cornlllol1ly I inhibitor lhe trealJl1Cl11 of S) mptOfllS of mi Id-to-modcrale di);ea)C. Doncpezil IS approximatel) 96'1 protei n~. wilh an climmation hulf]ife 70 hoIll'li. tabolilcd pOl'It"lpally by thl:' 206 and 3A4 iSOl)'lnn

"r

P....50 ~)stcm.

II I I II --'O-C-N-(CHll,o-N-c-e.-~.

CH,

CHl

"--1
B.

j
/ Hl

I -CH,

CH,

CH,

I
o

 freely hcdrug nd may pamble drujl:'_

Edrophonium I:hlotide. cthyl(m-hydro~yphenyl)dimethylammonium chloride (Ten"Ion), is a n:'-eNible anlicholinesternse aaenL. h is biller and 'Cfy iOIubk in waler and alcohol. Edrophonium chloride lII,tedion has a pi" of j.2toj.j. On pan:nteral administration. cdrophonium has a more rJpid onset aOO shortcr dunuion uf IL"tion than neostigmine. pyridosligmine. or ambtnonium, 11 K. 5pCIC'IfIC amicurare Dgl:nl and :.eLS within I minute to allel'iale overdose of dtul)ocurarine:, dimethyl d.tubocura. n~, or g:lllamine trieth.iod ide . 1'he drug is also used to tcn nilIMe the ac:tioo of :my one of these drugs when the physician 1IO desi~ It is of no "aloe, howc,ct', in teoni nati"" tIM: ktIOII of lhe depolarilina (i,e., noncompetitive) blocking IFIll!. such as dccamelhonium and S\JC('i nylcholine. ln addi tion to inhibiting AChE, cdrophonium chl oridc has a direct lioIiDOmimel;c effect on skele131 muscle, which is gn:ater tIIan that of mosl other anticholillC5lense drugs. CH,CH,
H,<:-N'-CH3

drophonium Chloride. USP.

Metrifonate. Metrifonalc is an orl\anophosphnte Ih.1l was originally devtlupcd lO lreat schlSlosumiasis under the lnKle name Sllarcil. It is an irreversible cholillC$'UJ..'\C inhibitor wilh some selectivity for DuChEo"l:r AChE. It achicl'cs SU~lained cho liJII:stera.o;c inh ibition by its no-ru:nl,)'mmic memoolite dichlOfVQS (DDVP). a long-acting QI'g:lnopl1OlophatC. Its use in mild to-moderate Ab.heimer's disease wa.~ ~os pended n:ccm ly because of ilther.;e effecls experienced by sel'eral palie111S during lhe clinical evaluation of Ihls product. To~icity :lt the neuromuscular junction i~ probably unribulable 10 the inhibitiun by the drug of llCuroco., ic esterase, I cummon fealun: of organophosphates, Ri llastigmine. lI. ivIISti&nllne (E~elon. EA 713) is a pseudoirrevcOlble noncompetitive cnrMmale inhibitoc of AChE. Ahhou&h lhe half life is approlimntely 2 hOIlI'!', the inhibitory pioperties of th. ~ agent lal.l for 10 houl'\ because of the s low dlssocialion of the drug from the el:l;Y"le. 'The FDA approl'ed it'! use in mild-tO-l11odcrule A ....heilller~ disease in April 2000.

.~~

shoun.

Ja)'1>.

I
EdrophOr>lum Chloride
Rivasllgmioo

hmcthIndcnlIure n~ lied fur !inlCr', plll.sm:l

I~

nll,'-

; 01 lIu.'

EIkuphonlum chloride IS sLructurall y related to DOOStigIIiDe methylsutfate aOO ha'i been used as. potential dio.gnoslie l&CDt for myaslhenia gral is. This is lhe only do.:gcnerative JIe\IIOOluscu lar disease thut can be temporarily improved by *UniSll'lltion o f an antieholincslcr.lSe agenl. Edrophonium cltbide bnngs about a rapid increase in muscle stn:ngth " ' l signiflC:lnl side effect.s.

..,....6-01

(NUntam;ne. Ga lul1lurn ;nc. 4a.j.9,IO.II. 12-hexuhy~3 methox y- ll -meth yl-611-benT.ofu ro-I )0.,) ,2 .ef) 12111:1;(Ni"al; n. Remmyl), is an alkaloid extracted from _ ous plant uucojrtm nt'SI;,"''" (L) belonging 10 the Amr)'HidacC'ae famil y and from the bulbs of the daffodil. 'I<II'('IJU$ I'S~JUI(mard$j'us. It is a reversible cho linestcrnsc .tibIt(ll' that appears to have no effect on blllyry1choline.~ler. tit. In addihoo, II act.S at allosieric nicotinic .si t($, funber arNtIcing ltS cholinergic activity. Galuntamine undergoes ..".. and minor biUlfllnsfommtion wi lh :lppro~imulely j to Ir\ tmdrrgoi ng demethylulion. It is primarily e~cn:ted in the

Tacrlne Hydrochloride, TocriJII: hydrochloride, I ,2,),4-tetrnhydro-9-aminoocridi JII: h~drochluride (THA. COl\ne~), is u n:ven.iblc cholineslcl'lI'-C inhibitoc lhat has been used in the treatmenl of AILheimer'sd iseoa.'oC for ..:veral years. 1be drug ha.~ been used to increa.'>e the levels of ACh m 1hese patients on tlte basis of obs.ervDIIOO~ from aulopsj,e( that concenlrution ~ of ChAT nnd AChE arc rnar~edly redllCed in lhe brnin. while Ihe number of muscarinic n:ccpL:0I'll is :lllfIOISt normal. TIle use uf the drug j , not withoul cuntro-"eDY, as coonlctmg results on efficucy hal'e been n:poned. n 'The drug hBS been used In mild-lo- n1OderJle AI~.heinlCr's dCJ1lcnti:l.
NH,

-.

Hel

OH
T llcrrl10 Hydroohlorido

1 _ ...lbl. Inhlblton .....

BOIh AChE and BuChE are mhlbi1cd irrelcn;ibly by a group of phosphate e,(crs Ihat an: highly lO~ic (LD", for humans is 0.1 to 0.00 1 IIIg11tg). These' chcnllcal s un: ncne poio;oru; :100 ha'e been used in warfare. in bootcrruri.sm. and as agricultural insecllc,des. TIley pemlit ACh (0 occomullile al nerve endings and exacerbm e ACh-like lIClions. 11te COI1lpounds belong to :I cla<.S of org:lnophosphorous e:.ters. A general formu l:l for such col1lpooOOs follows:

I
Gaiantamioo

...mere R, alko~y Rl "k~ , alkyl, CIt tertiaf)' a""'" X a good !N.,;nll group
(e II , F, CN . lhiomalm, p.nItrophenyt)

II is usunlly o~yg... n or sulfur but may al<;() he se leni um , When II " other than oxygen. biological IICti~;'I!ion is required before the e<H'npound becOllles cffecm'c us an inhibi. tor of cholinc~ter:ases, Phosphoroth,on3l1'l> rN jill /'( 5)X] hnc much poorer dectrophihc chaillCtcr than their oxygen anaIoguc.~ and lITe much IIcaker hydroge:n bond- forming moleeu Ics bcc~LUse of the sulfur ~tolll ,"" 111(';1' antkholillCqcf'~se

IICti vity , ~ 10' -fold IIcaker tllan their oxygen analogues. X i~

the leaving group lI'hen the molecule: reacts with the e:n1.ymc. Typical kn;nl1 groupo; include nuolide, ni trile. alld pnitroplw:no~y , 'The R gl'Q\lp:'l may be alkyl. alkoxy. Ar)'1.lIl)loxy, or arrllllO, The R moiety ,m patts lipophi lic,ty to the mole cule: and contributes to H~ absorption throu8h the skin.

Inhibition of AChE by orgnnopho~pllorous COinpound. ta"e~ place in two , teps, !Il;sociation of enlyrne and inhibitor and the phosphorylation Slep. completely :mal"lOla 10 acylation by the sub<;tr:ate: ( Fig. 17- 16). Ste:n:mpttif~ is maudy due 10 Internet,ons of en,ynle and inhibilOr. the C:Sleralic site. The seri ne n:~idoe at the ester.nic ~itc forms a stable pto. phoryl ester witll the OI'gnnophosphorou~ mhibitor<>. Thil $bbilily pennits labe ling studiC)c.... to be carried out on !hil_ other cnlymt'S (e.g., tryJ)"in, chymotrypsin) that 11a1"t tbe serine hydroxy l a~ part of their IICti vc: ~ itc:. Although insecticIdes and !lCn'C: ga'd lITe irrcl eniblt .. h.bnQn of choh/1C.~!C:r.lse~ by forming 3 pho-.phor}lattd 'Itf.

8
"'7.,.., .... p'
~ "n

~,cf r
_0
5e<- 200

/'.
N NH

~
A

..........

81
0-....

I
8
9 0-<_'
figure 11- 16 Pho\phofyIat.on and fea(t,voJ' bOn of d~'rll'Stl'fasl'. A. Phosphorylation of senne by ISOftuorph<Jte B, Phol;phoryta!ed ';f!f~ at tht f1.teratic $lIe C. Nudeoph~1C oJtOO on phosphor)1ated resodue by 2PAM D. Free
_
5-200

OH

."......'
N NI-l

""'""

'"'

t lit 440

o
Enz-P-CHa

CH,
H, O

II

tH CH( ...... CH,

Figure 17- 11 Aglllg of phosphorylated en1:YfTll'
_ at the e~teratic Jill' of the enl.yrne. it is possible to n:activa the enzyme if aclion IS Inken ~ after e.c.posure to 1bt$t poiwn~. Several compounds CIIIl provide II nuc1co-

I -O HC-C
' H

0
/

H
H, CC-

,, /
F

I
IWnuorprnlle must be handled v.jth exl!en"IC caution. Contact '" ith eyes. nose. mouth. and e,'cn Sl-ill ~tlould be avoided because il Cllf1 be absorbed readily through Imact epldemus and more so through mucous tissues. Since jsofluorphate irrcven;ibly61 inhibi ts (holine.slcrasc. its activit), lasts for lby5 or cvcn weekS. During this period. JM:W cholinesterdSC may be synthesi7.ed in plasma. el)"throC)tcs. and other ce lls. A. cotnbi nation of D troplTll! sulfate and magnesium sulfatc protectS rabbits .gai nst the toxic cffects of isofluOl"phate. A.tropille sulfate eoumcrocts the muscarinic effect. and matncsium sulfme coun tcrocls the nicotinic effect of the dn..g. 1 l'iOfl uorphme hali been used in the.- treatment of glaucoma. f cholhlophate Iodide. USP. Echothlophate iodide. (2n"ICre.ptocth)" l)trin"ICth)" lammonjulli iodide. S~ster ,,jth O.Odiethyl phosphorothioate (Phospholme Iodide). occun; as II .... hit e. crysm1!inc. hygroscopic solid thu t ha.~ a sli ght merellj)lan-h ke oOOr. It i~ soluble in waler (I : I) and dehy droted alcohol (I :25): aqueous solutions have a pH of about 4 and ure stable at room tcmpenllure for about I month.

."

" ,. ici ly

mds hibi

."",. stu, and : the

C 1Il-

I scr-

jilihc anack on the phosphorylated en~yme and cause n:genIt ion of the free enzy me. Su bstances suc h us choline . h ~ mu.)la.mine. and hydroumic ac itl have led to tile Ikvdoprnent of loore efftivc cholinesterasc n:activaton. _h u nicot inIC hydroxamic acid lind pyridine-2 -aldoxime Rlluodide (2-PAM ). A proposed mode of action for the 19!1J,-ation of chol inesterase that has been inactivated by M/luropllate by 2-PAM is show n in Figure 17-16. a.olincstcrn.C.~ thm ha\"C been c~posed to pllosphorylat DIg 38cnl1i (c.g .. sari n) become ref fllCtory to reactivntion by dIoiinestcrn.o;e rellClivators. TlIe process is cal led "R"'R and octun. both in vivo and in vitro with AChE and BuChE. AJiDg occurs by JXlnjal hydrol~lJS of the phosphorylated .airty th.u I) attached to the \trine residue at the estCTatic lilt of the cnl.)'rne (Fig. [1.) 7). Phosphatc este rs usctl as insect icidal agents ure toxic and IIIU5t be hantlled with extrelne caution. Symptoms uf toxicity ~ !l;lWC'a. vomitin g. excessivc sweating. sali vation. nliosis. lndycardia. low blood pressure. and respirntot}' d ifficult y. "IIbich Ili the u>ual cause of death. The organophosphatc in\CCtiddes of low toddty. such as III3laIhioo. gcroerdll y cause poiwmng only by inge!.tion of rtlati~cl y large doses. Pllrtlth ion or rTll!thylpar.lIhiun. howne\". COIU5C poi$Ol1ing by inh~lation or dermal abSOfption. '-\lse these compounds are so long aclin g. cumu l:r.tile and tmOI.IS lo. e manifestation s may result after sc'erdl small d
-~.

CH,

H,C- N'-CH,-CH, -S-P-OCH,CH,

I I CH,

OCH, CH,

o
H,C" H,C/

II

CH- O - P - F

CH,

Echothiophate iodide I~ a long lasting cholinestcrase in hibil<1f of the irreversible t)'pe. as is isoflllOl"phme. Unlike d"IC l ~lter. however. it i~ It quaternary !ill)!. and when applied locally. it s distribution III ti ssues is limited. ",hich can be "cry desirable. It is used as a long-acting lnticholinestefllSC agent III the treaunent of glaucoma. Hexa elhylletraphospha le (HETP' and Te troJe thylpyrophosphate (TfPP,. HETr and 'fEPI' 1U"e compounds that also show anllcholinesterasc: activity. HEfI' WI\S de.eloped by the Gcrm:ans dunng World War II and is used as an insecticide agalllSl. aphids. When u<;cd as insecticides. these compounds ha"c the ad"antage o f bemg hydrolyzed rapidly to the n: latl\el)' nont ox ic. water-solub le compounds phosplloric acid and elhyl alcohol. Fn.. it trees or "cgetabics sprJycd "'n h this type of compound n:tain roo hannful n:sidue after a period or D few days or weeks. depending on the ""cather conditions. Wor\ers spra~ing '" ith these agents should use extreme caution so that the Vlpors are ooc

'1 4 ducts
IJofluorphoJte. USP. lsontlOl"phate. diisopropylphQ<;pII:IoI1uorid:lIe (Floropiyl). is a colorless liquid soluble in fo1ICf 1 lhe tx lenl o f 1.5-1'>\ at !SoC. ",hicb decomposes to 0 P't: I pH of 2.5. II is soluble in alcohol and to M)tl"IC e.u~nI peanUI oi l. II is stable in peanut oil for a period of I year .. dtromposes in water in 3 fllw days. SolUlions in peanul <iI can be sterili1.ed by aulO(;laving. The eompound should lit 5lOml In hard glass contairll!N. Continued contacl with lit ~ is said to hasten deconlposil ion. as evidenced by lkoIomion.

,,"""

breathed and OOTlC of rhe with the eyes or skin.

Y~por

or liquId comes in contact

U U H .CH,c-O-j-O-j-O-CH,cH.
H,cH,c-O O-CH,cH.

lyme, yielding m:llathion acid. a slt ll poort'r mhibitor (# AChE. Phosphmases H carbo)(yest er~scs funner ~ nd ill' malathion acid to dUTlClhylphosphothi08te. The rncubolic reactions an: ShOWll in Figure 17- 18.

T01 rBothylpyropllosphllto

M ala thion. Ma lathion. 2- )(dimc:tho~ypllosph i nOlhioyl)thio )bul311CdiQIC acid dleth)"1ester. is a ,,uter-Inwluble.- phosphod ithioatl! e.~ter tha i ha.~ ~n lilted us un agricu ltural in.sccricide. Malmhion i\ II poor inhibitor of choiincstel"llSeS. lIS errc:cuvellCs.~ us a safe in'iCCt icidc is due to the dIfferent rntC";'l at whkh humans and insects melabolil.oC the chemical. M icl"USQlTlul o .... i<!:uion. whIch causes de~ul fur:u>on, OCCUfl'l ~Iowly 10 form the phosphOl hioa te (111<ll no.\oo), which is 10.000 l ime~ more acti ve than lhe phosphodithioate (malathio n) as a ,"hol inest~rase inhibitor. Insects detox ify the plIOspholhlOilte by a phosphatase. forming dimelhyl pho6phoroIhlO<lle, which is inacr i~'e as an inhibilOr. Humans. howe'er. can rnpidly hyd rolyze malathion by a carbo~ye$ter.ISC 1:11

PiJrathion, Parathion. O.Odielhyl Op-nitropbc.,1 phosphorothio:u e (Thiophos), i, a yellow liqoid that is fm'1!" 'IOluble in aromatic hydrocarbons. ethel'. letOllC"l. estm. and alcohol~ but pr:telica ll y insolUble in wuter, petroklllll ether, kerosene, and the usual ods. It IS dtcooll~ PI a pit above 7.5. Parathion is It cide. It i, a relati"ely weak ever. enl.ylllC:'i present in II ver mtcroSOlllCS and i coo,'en par~thion (p/5(l < 4) 1 0 hibitor of chol ine~lernse (p/5(l metaboli7.ed by liver mierosomes diethylphosphate; the 1:llIer is inact;"e as ;Ullltt~ersible linestefllsc in hibitor ....

""''!!.':

Schradan. Schr.Kian, oclllmcthyl p)rophosphorarmdt. O M PA. hisl bisdirncth)lamillOphosphonOllli I (Pe51 III ), is a viscoos liquid thaI i~ miscible ';;.',';;; 0lC and soluble in most organic sohems. It is not by all:ahCi or water but i~ hydrolyLed by acids. used as a $ystemie insecticide for plants. being

CHJO

"p' CHaO " S-CH-COOC H,

/

2 (10.000 \I:'OOS mDrll.:tOJl! tI$ a Ct1e irnhiIOI)

MI'S-.Q,

6H -COOC H s
2

"' ....... 77. (rU S''I.l

CH30~p~S
CHaO
~tt..In

S-CH-COOC 2 Hs CH 2 -COO
k:id (pooo- ChE nhb.OI)

O,rnelt Phosphale
( __ toe)

:::>~:

_ ....
I

",,-",-

CHaO,p'''S CHaO/ 'OH

0 ,0-00 II64IWIiJiIllOlUCliOllle

Fig ure 17- 18 Comparison 01 metabolism of maliJlhlOtl by mammaJs and Inst'CtS.

..

",e,

CH,- O j -O -

II

)---00,

0,
CH,-CH,

P...1hion
(low anti-AChE aetMtyJ

Paraoxon (high anti-AChE actMty)

,
ttplams wirl\ool appreciable injury. I"SlXts feeding OIl the /IbtII are incapacitated.
II,Cal; inhibil~ of cholillCSlCI1\SeS in ~itro. mOo it is metabolized 10 ,~ very strong inhibitor h ~ toJ.Yml"lhyl OMPA. H )dto~)'melhyl OMrA i~ not stable

ride. or 2'pyridine aldoltime Ill('lhyl chloride (ProIop;1m

Scbr..dan is

.\I

ch lorille). i~ a while. rllmhygros~:opic. cry,w.lhne pCJIHli:r tilal i~ ~lIble in water. I g in less lhan 1 mL
chloride is used 115 an antidote for poisoning by parathion and Il;'lalOO re-~' icide.~. II rna)' be "ffeel;ve
I'ral ido~irne

ailS metabolized funhocr 10 the:

Nrnclho~idc.

which

i~

against

SOI1lC

phosphates thaI

Jua~e

a quaternary nnrogen. It

wnt Inhibitor of cholillCSterase,M

Pralidoxune chloride. 2IrIlidoJ/itne Chloride, USP. bmyl-l -mtthylp)ridiniurn chloride ox ime. 2-PAM ehlD-

is nlso on effective antagonist for some carbamate!!. such IU JlCQS1illmine I1lClh) Isul fate and p)'ri~ligmine bronm;k:. "The

mode of IICtion of prnlidoJtirm: chloride is described in Figure 17- 16.

li~or

microsomal

(0,

O",A
('A uk choIir EE111f898 inhlbilOf)

HydIecymeth)'lOMPA (SHong e/loliOO8lerll98lnhlbllOf)

QMPA-N-methoxlde (&trong ehoUneslllfllS8 inhiMOfj

Ne'enhelcs. SlruclurJ! pcrmuta"on~ hit, e rr~ulu:d in anpounds Ih~t do nO' hn"(, Db,iOlls re l;lIIooshlps to the ~ molecule . 11x: follol'omg dasslncallOfi delinealcs the INJIIr chemica! t ~ pc, cllC1)U lIlcred:

01-

Prelldoxlme

C~1or1do

'The biologIcal half hfeofpnl.!idoxime chlon(k in human~ is about 2 hours. anc.l il~ effecth'e~ss is a funcrioo of lis conccnlrnlion In plas ma. "hich reaches ~ ma~,"u'm 2 1 03 hours after ()111] administration. l>rnlido~ime chloride, a quaternary ammonIUm com poI.IIld. i~ IOOliI cffecth'c by inlnUllU'iCuJar. suoculancou<;, or inrra\"clJOl.ls admmislmlion. Treanncnt of pOIson ing by an antkhoh tle5ICru.se will be most effect;.,!: If gl"cn within :I few hours. lillie \\'il1 be accomplished if lhoc drug is used " lOre than 36 00un; after parathion poisoniog /u.s occurred.

P""", ~r:ta0U'-

Sotall~~ :1I ~aloid> ~W ~)nthclH;

unatogu"'>

S)"mhc:uc amlrKllllooholl'lle",

Amlllooknhot tl~n; Aminoaleohols Ammoom'Je. ~ hstfll:ule...

,,<

CHOUNERGIC BLOCKING AGENTS

A wide ...ariely of tissuc<; respond to ACh relc;j,~ by the neuron ~ eJ!ogelJOl.lsl)' administered cheRne a1 , 10 mmllc Ih, s nru1\Jlramminer' s IICtion. Pcriphtllll cholillC'rgic re.:;Cpl()l'\ are loculed 31 para~)'mpal heli c postganglionic ne"" e cnthnp In s mooth mUliCle. _ymp:uhelic 1100 parotsy rnpathclic gangli~. and IIC'uromuscular Junct ions in sl.elcml muscle.'. Allhough
ACh activates these reccptors. there arc antagonists that ure sclecti\'c for eac h. Atropine j, nn effectivc blocking agent at p;lnlSymp;nhetic postganglionic lennjnal~. Li~e most cia....,ie bLocking agcnts. II OCI on all muscari nic receptor subtype\:. dTuOOcurnriroe blocks the cffC(:t of ACh on sl elclill musc le. wh ich i, activmed by NI nicOli nic ITptor:>. IIc.~amc'thQ. nium block.'! traru;ilioo al N! nieotinic receplors located in aUlonomic gangli a. Anticholinergic action by drugs and chernica l ~ apparent ly depends on their ability 10 ~uce the number of free receptON that can interact wilh ACh. The tht:orlcs ofSlcphen 50n"" and Ariens~7 h3 \'e Upl3111cd the relatlonshtp between drog- reccptor inter".lCIioo~ and thl: OOScn"C:d biol()gical reo spon~ (see Chapter 2). llttsc lheoric.~ indicate that lhe amount of drug - rl!(:cptor complex formed ot a givcn time depends on the affinity o f the drug for the receptor and that a drug Ihal OCIS as an agonist must al'\O fIOl>scss anOlhcr prupcn y. called ..ffictKJ or in/muir acli'II.,. AOOI.hcT e ~pla nallon of drug - n:cC'ptor irncl1lCtions. the PalOn rJtc theory."" defines a biological stimu lus as proporllonal tu liM: r"Jle of dNa- receptor internctioo~ \&1:(: C haptcr 2). 8 0th of Ihe"C theories are CQITIp.1llble with the coocept thai a blocl.tng a~nt tnat has high uffinity for the receptor llIa y tk. en:alot the number of av:oi lnble free receptors nnd the efficicncy o f the endo&enous llCurolrllnsmillcr.

The chemICal clnsMncalion o f anlicholincl'l1 'C5 actlllJ 01 parasympathetic pmtganglionie nerve ellding~ is compIl' cated somewhat because \QITlC agents. especially the quaII:I' nary ammonium deri~athes. act 00 the ga.ngha that ha.l." I mu~arin ic component 1 !heir ~timulaliOll pallcm anl_ 0 hi gh dosc~. at the ncurolllu"...ular JUIICt ion ill skc lClallllUSCI!. There ore c\'eral way~ in ",hich !he ~lruc\tJre-lCtiI~ relationship cOli ld be COO~ldered. but m thl' d l ~SSIOll_1 follow. m aener"JI. the oomideralions of Long I.'t al .... . . ba<.ed lhelr ]lO\tulatiollS 00 the I. hyoscyamioc ,,~ being one of the mo!i'I ac11,'e anllchohncrglcs and. t~ havi ng an optimal ammgclllcnt of groufK. Amicholi ncraic l'ompounds may be OOftsodC'red tluU have some si milllri ty 10 Aeh but cootain addition:l1. SllIucnts Ihat enhance lhelr bmdmg 10 the chohnat" ~

ct",,'"

ttpOoc_

I - - r,IC~Hi>JN ,-c ~I--N I L.::.

C

A, a .. bulllygroupf, 8.g,eych!'f aromatk:

C .. H. OO

earboxamicle
A~ dcpl cted aOO'e. nn IIIltichulincrgic agen t ma}~"

a quaternary ammonIum fUIJCl ioo or I teniary :uninr tha pmlOnmoo in thc biophasc: to form II callooic Spcc1e\. 1k n'''ugcn i5 separoted from a piHlIal earbon atoln thai may indude all C~lcr. ether, sub<;tlluc:nl groups A and 8 comam al least one moicty cupable of van tier Waal ,' im cracllons !Otlle ~urf"ce and one eydoaliphutic or other h)drocartx:.!';. (Ot hydrophobic bmldll1g II1tCract loo ~. C may be: II) or carboJ:II.JI1itle to undergo hydrogen bondi ng wllh tbr ~

ccplOr.
THE CATIONIC HEAD

gcnc rully considered thai the amicholtQC1"gK." h.a,'1.' a primary ]lOlnt o f attachuW;'nt 10 choli ntrJic through tnc ml;rmjc Item/ (i.e . the posni\ely cMr]cd Ilen). For qualcmary ammonium l"Olnpounds. thm: 4uc~tlon of ", hat is Impllcd. but fOt I

It

i~

Sbvcblre-Acth,tty Relationships
A wide variety of compound.~ poeS~ anticholinergic a<:111 ilY . The de"eiopmem of ~uch compounds nas been largely empiric and based principally 00 atropine as the prOlotypc.

subsUlucnb on

a parasy mpu\hormmcti c

lhat cause: d,iTu'ion or the ooium cnarge or produa: 1 Ihun -opt nnal dru g- receptor intcractlon resuh in

I"".

n com parenl

rJ pa1lSympathom imetic propen ics and allo .... the drug to a:t as an an tagonist because of ot her bondi ng inlernctions.
Al'tens M hll.~ sho wn that carboc holi nes (e.g .. bcnl.ily lcarbodtoIinej engage in a Iypical competi ti ve action wi th ACh. Ibou!b they are leM effective than the COITeSpOIIding comjlWids possessing a ClItionic head. suggest ing that hytiro. pIdnc bonding may play an important role in these .ng- receptor intcrnctiOO5.

e~cdlcn l affinity late i~ consistent

major

but without intrinsic !ICIivity. This postu with mO~1 ant i mu'\('~rinic drug\. ""hether they possess an c'''cr group or nOi.

PARAS YM PATHETIC POSTGANGLIONIC BLOCKING AGENTS

J>arnsympathe:tic postg~nglionic blockinl! agents an: also known as ant imuscarinic. anlicho!illn'gic. par1lliympatholytic. or chol inol)IIc drugs. A ntim~arimc drugs act by conlpctit i,'c anUlgoni~nl of ACh binding to mUloCarin;c reo ceptors. Endogenou~ ncurotra.nsmitte ..., II'Ic!udi ng ACh. are relalivdy s mall mo 'ecu 'C!i. Ari ens67 noted that compc:lill\'e reversible anlllgonists gellemll y an: largcr molfi'ules capable of add iti onul bi nd inll to the rc:ceptor ~urface. The roost poIe nt antichol incrgic drugs an: derived from muscarinIC agomsts Ihat contain one or ~tilTle'!i 1""0 large or bulky groups. Aricns67 SU ggcJited that molecules thai act as compc:tllJ\e re lersible antagom~t ~ gencrally are ClIpable of binding to the activc site of the n:ccpt or but have an addillona! bi nd ing inter,ICtiOl1 tha t i ncrease:~ receptor affinity bu t does not contribule to the int ri nsic activity (emcacy) of the drug . Several three-d imensional models of Gprotdn-coupled l'ttejXOI'S. including the mll5CllfllliC reccplor, ha\~ been reponed. Dc SPIte kno .... ledge of wir amino acid sequcnces.. II is not yet JXlSsible to pro"ide: an Il nambigUOUll dcscnplion of the (lQck inl of molecules to these l'tteptOrS, Thcconceptsof Arien~&7 and others. howevcr. nppcar consistcll t wi th thc binding si te modcl~ proposed. 8 ebbi ngtOll ami 8 ri m blecombe~1 pr0posed in . 965 that Ihcre is a relativcly large 1ln'!.1 lyi ng out side: the agonist- reptor binding sile .... hen: van der WlUIls' interactions can llike place between the agOllI'" and the receptor area. This. too. is IlOI illC'OllSisten, with contemporary theories on cholint:rgIC receptor Interaction ... ith small mole cu les.

tunl! o n comph quater ~ hOH' a and . III mu.,.;1e -octi \ It~ j.!.ion ....1'
TH(

IR "" 11<1 llOle(;ulc refore.

HYDROXYL GROUP

hcml(; al\ ~31 , ub-~rp(; rc

AIiIII)ugh IK){ requisi tc for activi ty. u sui b bly placed alooIdle hydro~yl group enhances antim uscari nic lletivi ty over

_el, IO'IUoa

similllt compound without the hydroxyl group. 'The 0( tile hydroxyl group relath'e to tile nitrogen DpjIeJn IO!)C'; fair'y critical. .... ith the diameter of the reccplive .u estimaled to be about 2 10 3 A. II is assumed thai the: k}'dmxy l group contri butcs 10 Ihe Mrcng th of bind ing. proba bI) by hydrogen bonding to on electron-ric h ponion of the !KtpIOI'surface.
tIlf ESTEAATIC GROUP

....)' of the highly potent antimuscari nic

!Mill eSler grouping.

compound~

pus-

, (;Onlllin t!wt i~
\C~,

rc

1be

. a (; h<lin
jet)' 1be aromallC muicly h) dn1\)1 IIh the ~

lmd this may be a cont ribut i ng feature Inffectivc bi nd ing. Th is is n:asonablc because: the agonist J.e, AOI) possesses II simi lar fu nction for binding to lhe .... lIlI::. An esteratic fUllC1ion is not necessary for activity. sctr&l types of compounds do not JXlSsc.'>S such a JOIP Ie., .. etms. lIffiinoalcoholi).

Th., pawtk Action.

Organs controlled by the aut onomic nervous system U $u:tlJy arc IIlnen'atoo by both the sympathetIC and the p..tr;tsympa thetic systems. There is . continua. state of d)'n~mic bahmce betwcc:n the tWO sysIC llIs. ll\COfl',icall y. one shou ld achie\e the $ume end resu lt by cither sti mulation of one of the \y\. tcms or blockade of tile other. Unfortunatciy. then: IS usualJy a hmitation to this t)PC of gCllffilli;wtlOn. 'There arc. ho ..... e'cr. three: predictable and c linically useful !\'SullS from blocking the muscannic effCCUi of ACh .
I Mwlrialic "0'': dilution of,he pupi l oftl1l: eye: and rycl"I"'S"', U p;!IOly.i, of the clt iary "ruclun: of lhe ey~. resUhUlg in a parnlyws of oco;ommouauOII for ncar VI."on 2. "'""spI1smQdk ~tN. kr.o.-emllOM.Ad mot;IH~ oltbc GIInK1 .00 the genHounnary traCI 3. "'",iJ"wrr rjfKr_ mluced all~:Uion '"f1fIJiolalOlld'}. ~ ~ ~"llIon raMidrolk}. and mJuad aclli .00 P'l''' -~~

e ~eT'h1f

CYClJC SU BSTITUTION
U.lfMIIOq

.....

of the active compounds d iscu\sed III the fol....... 1tCl1OIl~ reveals that at least 0I1C cyc lic ~lIbstitUC':nt 'fblo1. thletlyl. or otha) is a commoo feature in almost ......ilohnergic molecules. Arom atic 5ub:sl:itution is often ..til oonncctiOf] .... ith the acidic moiety of the C!itcr fu ne__ Vmually all acids used. however, are of the hryJ substiIIr4lcet,k aci d Varlely. U!iC of aromatic ac ids leads to 10 .... d lllYof these compounds IlS anticho' inergics blll potential as local :lnC!;thellCS. 1I ..... lfCtion ..... ith the IpparelM need for a cychc ,roup. 1 POliti (lU t that the "mimetic" nlQIa:ules. rich'y ""th poilU' groups. undou bled ly require a comple-.y polar n:ceptor area for cffect ive bi nd ing. Ag a conr. II is implied that a re 'at ivcly nonpo lJU' area sur~h sites, Th Us. iocreasing the binding of the In thu peripheral area by introducing nat. roonpol JU' It.l-. aromatic rings) should achicve compounds .... ith

These three getlem l effects of p:srasy",p.atllo lytics can be expected in some: degJtt from any of the: lnown drugs. though occasionally one muSt adminiSter ratller heroic doses 10 demonstrate the effect. 'The mydriatic and cycloplegic

effeets ...... hen produced by topical appilclltion. are not subject to IIny greatly undesirable ~ide effecti because of limited sy\lemic ab~orp"on. 11us I~ no! true for the \ySlemlC antispasmodic effect~ oI:Maincd by 01'111 or parememl adminl~tra tion . Drugs with effeetil'e blocking acllon on the GI troct :m: "eldom free of adveN: effects on the ocher organ~ . The same: IS probably true of drup used for their amisccrej(lry e:ffects_ Pc:maps the most common side e:ffects expc:rieneed from the: oral uo;e of these dru gs. under ordi nary conditions. arc: dryness of the: nlOUth . mydri:lsi~. and urinary retention. M)driatK: and cycloplegic drugs IIl'C ge:neml ly prescribed ur used in the: office: by ophthalmoiogiSts_ Their pnncipal use ,~ for refr:ochon studie!l In the pnxc:.'ili of IitlJng len<;c:s. Thi~ pemlil~ tIM: physician to e~amine the eye retina for pos.\ible abnomt:llitic:s lind diseases and provides controlled condltion.~ fur the proper lining of gla.'~!lc:\. Ikc:ause of the: Inability of the Ins to contract under Ihe innuc:nce of Ihc:sc: drugs. then: is a definite danger to the paljenl's eycs during the: period of drug flCtivity unless they 3rc pl\cctcd from Mroog light by lhe use of dar!. glasses_These: drugs Illso an: used 10 treat inn:lmmation of the cornea (keratitis). innllmmillion of the ins Dod theclhary orgllns (Irith :md iridocycl i li~). and innanlillation of the choroid (choroiditis). A durkcolored iri s :lpptllfS 10 hc: more difficult to dilate than a lightcolored one and m3y requIre more oonccntr.:ued solutions. Caution ID the use ofm)driutics is adviable becausc:ofthe:ir dtrllOll~tnued effcct in raisinj the Intl'1lOCllltll" prc:5Sure. l"upil dilntion tends to eau'>e tIM: iris to re~Irict dminllgc of nuid through the: clIlIal of SchlemM1 by crowding tn.: anguillf space. thereby leading to incn'ased intraocular prc:5Iiure_This I~ particularly true for paherllll with glaucOlI\&tou'i conditions. Atropine IS used widely a~ un antispMmooic bccau"C of its m:II'icd depressant effect on par.iSympathetically innervated smooth muscle. It lIPPC:ars to bloclllll muscarinic ~eptor subtypes. Atropmt is. howe:~~r. l he: Slandanl by which other ~imil~r drug, an: mea5urro. AliiO. atropine has a blocking acllon on the tmllsmission of the I10Crve impolse. ruther thall a depressant effcct direc1ly on the mu...:ulature. This 1II.1ion i~ tcnnc:d MUrolrop'C'. In contrast wllh lhe action of an antisp:bmodic iWCh II!i papliICrinc:. which appc:a~ to act by depr-ession of the lIlu'\Cle ceJl~ and is termed ",rm:" lorro/,Ic. Papavcrine . ~ the standard for comparison of musculo-tropic anus~modics and. although 001 strictly a p:wsympathol)tic. i~ treated together with il\ ~ynthc:tic analogues below in Ihls chapter. The ~} nrhetic untl~pasm()dic, llpt)ClIf to combine neurot ropic and 11lu'\CuJOIropic effccts in greuter or lesser l1lc:il!>ure. toge:theT wilh a certain IlRlOUnt of ganghoo-bloc!..ng IICIhity for the quatcmary dcrivati. c:s. Anticholinc:r&1C drugs ha.e II mmor role III the management of peptic ulcer dio;e:lSC.1'I1 For tile present. the most rational thmIpy in~ol,ing anticholinergic drugs seems to be a combination of a nonirritatin& diet to rrouce acid sretion. antacid Ihc:r.:ipy. and rrouc"on 01' emotional StfCSS_ Most of the anticholinergiC drugs arc offered ellhCl" as the chc:mical nlooe. or in cOll1hill~tion with a eNS depressant !oUch a~ phenobarbital. or with a neuroleptic drug to reduce the: eNS contribuUon to parasympathetic hY(ICTaC'li vlly. In addition 10 the anti<;eeretory effccUi of aIltichohnerglC1C on hydrochlonc IICld Mod gastric acid secretion. there have becn !;(JOlt e:ffort~ to usc. them as anli~ia lagoGue.~ :llId anhidrOl ies. Paml ysis agllaM 01" parkinsonism (I'arkinwn's disease).

lirst described by the: English phy~ician James Park in!iOll ~ 1817. is another condi tion that IS often treated with antlC/ll). llnergic drugs. It IS characleri:r..oo by tremor. " pill rolltn,," cog.. hec:J rigidit y. fcstinating gait. sia lormc:a.and masl-like facies. Fundamentally. it repre<;ents a nmlfullCtion of the ex trap)'ramid:lI syMem. I".uidnson ism is chaTaC'leri:r.ed by p-I)gressl"e and selective degenenuion of dnpammergk Inrons. .... hich ongmate: in the: 5ubslamia ni gra of the mldbnwt and terminate in tile ba.~1 ganglia (i.e .. caudme nllCleu~. PIIIUl1Icn. and pallidum). Skeletal musc le movement is co. trol led to a great degn:c by patte:rns of elicitation and mllibttion resulting from the feedback of inform au on to the: C(WtO and mediated through the p)'T3midal Ilrid e~trap)'Tllmtdal pathways. The b.1sal gangl ia structure,. ~uc h as tile pallidum. corpu~ striatum. und sub..t:lmi:l nigra. "Cl'\'e lIS data ~ ~ for the: p)r.lIllidal pathways and the structures througlt .. hlth the utrJpyr.llllidal path"~Jys pu.... on their ....... y ~ tile spinal cord 10 tile oortcx. Lc: ~ions of the pyrumidal pathway~ lead to u persistent increllSC in mu<;c le lone. resultlill in an ucc:ss or spontaneous mvoluntary mo\emcnts. aioII With ehangts in the refle~es. Thus the basal ganglia art r.... trona] in maintainmg !lOnnal motor conlrol. In par\;inSCJnllm. there is degeneration of the substanti a nigra Dlid eorpus,o;WtUIil. which are in\'ol ~ed with controlled integration of_ cle mo~emcm. The neurons in the substantia nigra and bNI gangJj~ use the neurotrnnsmillc:r dopamine aod intcrxt shol'1 cholinergic intcmc:urons. When dopamine 1lCU1'OII1 liegenerate. the balance between them is ahcred. The inhlbil(:r} in nueoce. of dopamine i~ rcducc:d. arid the oclivity of cboIt.Cf'JIic neuron.~ is iocreased_The priocipal goal of anuchc& crgic drugs in the treatment of patLin50llism is to clnt. . the IICt j~ity of cholinergic neurons in the basal gaogli,. T he usefulness of !.he belladonna group of al kaIOld,'~ the treatment of parkin5ODislO was an empiric di~CI} Since then. chemists ha\'e: prepared many synlhe\Jf _ IogllCS of ~troplne in an cffort to retain the u'iCful anllutIU and umirigidi ty effccts of lhe belladonna ulkaloid II bile Ito docing the lid I'er:;c: effccUi. In this proc:CloS. it was cJ.i.srol-eral that antihisl:lInine drugs (e.g .. diphc:nhydrJmi~) /t'IItIcd tremor and rigidity. 11lc: antipartinsomanhl.e ktl\-IIY of. tihmaminc~ has bc:c:n attnbuted to lhcir anllciKllillCflK' P'tt ertie~. The octivi1Y of the~ drugs is Cllnfined to those l1li can pass through the blood-brain banier.

rro..

SOLANACEOUS ALKALOIDS AND ANALOGUES

The solanaceous alk:lloids. represemed hy ( - )-hy~ atropine I( - }-hyoscyaminel . lind scopolumine (b)<*.'~l are the forcrunnel'$ of dll: class of amimlJ.'iCarinic ihtThc:sc: alltaloids are found principally in henbane mus r1ig~r}. deadly nl ghlshade (Atropa IH!lIiU1a1rM).Ind,.. son weed (Darurtl .1Irt1nlfHllumJ. There are othc:T all I that are mernbe~ of the solallllceous group (e.g .. IIJlI.*IIt inc . noralropi ne. belladonllinc. tigloid ine. olC:tcioidUlt!. lac~ o;.ufficiem therapeuuc value: to be con.~ideml III tlibkl Crude. drugs containing the:.;e alkalOIds hale bmI ... since: early times for their murked medicinal Plvpt,'\It\ which depend largely on inhibition of tOe pal1l5)'mpatbc!l' nervous system and stimulation of the higher IIm'(JI!I ta

IH'_'

rlaruon III II anllCho-

1m.

I rolhng:' mast-like of the tJ[~ by proergic IlCU:midbrnin ideus. pu n! is con Uld inhibithe: corte,," .pyramidal -paIhdum.
through

Belladol1na, probably as 0 ronsequencc of the ww knl Jllt"Sthcnc .:Ii,-i l ), of afl'OplllC. has been u~ lopicully

!lOti.

u proccsway from

!S

'Udal path:. rtSulli nl! !1IIS. along 1111: fuJ\C-

(insoni~m .

)f]lll~ ~I ria

;!II

of mUl>-

Hnd ha!>lll
wilh

and various itching dcmlalmes. Application of sum t'IC!II aniOUnlS of belladonna or its alkaloids results In mydri~ tnlt-mally. the drug causes diminution or secretions. U'l(Tta.<.t'.~ the heart ralc (by c.lepn:~~ion of the vagus !lCI"\'c). .xpre.~se( lhe motil it)' of the G I Ir.ll.1. aOO act.~ as an Ilmi~pas mo(ile on various smooth muscle~ ( ureter. bladder. llIKl bi lircy truet). [n addition. it directly Qimulnte.~ tile rcspil'lltory CC'l\lC:r. The multiplicity of a<.liOl1~ uened by the drug is lrolcdon with some disfa,'~, bccall-o;e the physician seeling _ type of reqxlllSe unavoidably also obIains the other"'. The lIt'uon of o;copolamine-contaimng drugs dIffers from ~ COIll.aining hyoscyanullI: and aU'ollllll: In having no DIS 5l1mulauon: rather. a namJlic or -.edathc errecl preIbnln.:ltl!S. T1le use of thi s group of drugs I~ accompanied by. faIrly high incidence of reilCtioM because of indh'itlual 1IIioI.)llCl1Isics: death from ou:nJosage u,ually rewlts from rnpiratOl')' failure. A compiete treatment of lhe pharmacollilY and uses of lhese drugs is 001 ""ithin the 1iC0pe of this 11'.11. The introductOl')' pages of this chapter brie n y review QlIe of the more pertinenl points in conroection with the alp octivitks of these dru g typc...

I" analgesIC effect on helllOtThoids. cenain slin infec-

1ef3O:!

F.on~

de-

SthKtwrai Considerations
All of the !101.m:teeOlls alkaloids are Ners of lhe bu:ydic MUllOaIcohol 3_hytlrox) tropane orof rehlled anunoalcohols. f'bI: structural formulas that follow show the piperidine ring ')~m In the comnlOllly accqlIed m:ur confonnalion beCIII'jt thl~ form has the lowest energy requlremem . 11t.c aher_ lilt OOQt form can e~i5t under CC'rtain condition>. however. becau.c the el"ll;''1!y b:tnie!' h 001 greal. In spection of the 3k,drolytrupane formula abo indicates that el'en lhoogh ibCft i~ no opti cal activi ty because of the plane of ~ymll1etry. tlIro \lC:reoisomerie fOfm~ (tropine Dnd ploCudotropinc) can mil hccaul\e or lhe rigidi ty imp;u1ed to the molecule through tIrt ethylene chain acl'QS..~ the 1.5 position~. l~ uupilll:. the uiaHy onentC'd hydro~yl group. /TfJn$ 10 tile nitrogen brodge. is de~ignated If. IIIld the al ternate cis ; ... Mal ly oricnted hydroxyl group IS desl&rulled p. The ~ derived from scopolannne. tIll/lIely ~opine. the a~ial ori~ntation of the 3-hytlroxyl group but. in IikIIlIOn. ~ ,B-oncnted cpo~y group bridged ilCrosS the 6,7 ptlWoons. as shown. Of the sc\'el'1ll different solanaceous IIUlottb \:nown. il has been indicated Ihat (- I-hyoscyamine. 1IropI1It. and scopolamine are lhe r1lO!.t important. Their lInIctures an: \ho .... n. bul unlll11uscarinic activity is a~soci IIld whh all of the solanaceous alkaloids Ihat possess the 1'I!pirte:hlc IUtal orien tation of the esteri fk-d hydro~yl poop. Studyi ng the formulas re\'cals that in each case tropic Kid i~ the uterifying acid. Tropic lIC id contains IU1 easily rlCtl!llled asymmetric carbon alom. tile moicty aI.~nting lot OI'Iocal aclivity in these oompotrnlh in the absence of IImnuation. 11t.c proper clllmtiomorph is necessary for high _Iv:arinic aclhity. as illlI-~ tnlled by the pocenl t - )-hyo~1It Inoompmson with the wca\:ly acti\'ct + )-h)oscy__ The nK:c:mate. atropine. has imcmlCdlate acti vity. Tltt mart.ed dirrcrence in anlimuscarinic potency o f the opiCII mtlntiolllOl'phoi apparently docs 001 U lcnd to the tM:Iion

liJI!Ilhllory of coolinInllcholi n-

~~:,a~
IC

Coids for ~~\ery.

ana-

APlilrcmor iI ",lIi te re ~sco"cn:d

I\'il)' Ofall-

el reduced
qic prop. !bose thaI

OK),omi llC. KbYoscine).

laic

d rug~.

~-'<0plandjimalkalQiu.

H)'O~C)'(l'

OI1 lhe eNS. masmuch as boih seem to hoI,c the ~me degree. of actiVlty?1 The solan:tC('('IU\ oll:lloids ha,e been mothftcd by prt'paring othcT estCf'l; of 3-lf-tropanol or mal;tng a quaternary of the: IlItrogen m lropanol or scopine with D methyl halide. These compounds n:present some of the imtial allempt~ 10 scparntc the \ nned actions o f IlIropinc and KOpOlanlllll:. Few :tminoaleohols ha ve been found that imJXln the SlIme degree. of neurolropic IlCtivity as Ihlll cxhibited by the e'ter for11led by combinlllion of tropine with tropic acid. Similarly. the tropic add ponion is highl y specific f~ the antIcholinergic action. IU10d su"'tllutlon by other acids decrea-,.c~ neurotropic potency. though lhe nlu!\CulotroplC lICtlon I113Y iocrea.'oC. The earliCSI attempts to mOllify the atropilll: molecule retau>Cd the troPIne ponlon :lnd substitutcti \'arlouS acid\ for tropIC acid. Be~idcs chant:m, the acid residuc:. othcT changes hoI,'e been directed lOIll'art! the quatemizallon orthe nitrogen. EJI IU1Iples of this type of compound an: methscopohunine bromide. homatropine nl('\hylbromide. and an isropllle l11otthylbmn udc. Quatemll.:lt ion of the leniary anlllll: produees variable effect... III lerm~ of increasing potcncy. l)ecre:t<CS in acti ~ity IlI'C apparent in compari ng atropine with mClhylatropinc (no lonicr ul.td) aOO o;copol:,minc with mcthscopolamine. Ariens CI a1. 7l ascnbed decreased lICl1vUy. especially lllhen the group, al1achcd to mtrogen are larscr than methyl. to ['IO"slble dtcrea.-.e '" .mlllty for the anIOnic )ite on the chohncrgic rettptor. lllc:y anributed this dccre;tScd :lmnity to I ~'OItIbinauOlI of greatcr eleclron repulsion by ~uch goup<; and greate!' stenc IIIterfeTeoce 10 the approach of the catl(NllC head 10 the anionIC sile. In general. qualemll.llhon reduce5 panuymp.uhominlCllc OCllon much fJlOI"I' than parasympatholytic 0CI1On. Thi~ may he partially duc: tn the add,tional blocl lng at tile para)),mpalitctic gungliooloouccd by quatet'nil.atlOn. ""hlch could offloCt the decreased affinit y at the postganglionic ~l1e. Howevcr. quatemi/..ation Increa.\C\ lhe curnrifon n activity of Ihcse alkaloids and aminoester~, a usual COltscqUCIICe uf qU3iemi/ ing al l aloid). Another d isadvantage in conl ertinl! an allaloidal base 10 tile qUDtemary form is thaI the qumemil.ed base is alY;orbcd nloOl'C poorly through the III1CSIll13J wDII. )0 that the octi vlty becomes crr.tIlC aOO. III <iOIllC IIIst:mce~. unprediclable. Ba.c, (wch as alkaloidsl:are abwrbed through tile lipoIdal gut "".11 only III the dis~iatcd form . ""h,ch can be upected to UISI for a tertiary ba>.e. in the !>mall intestine. Quatern3l) nLlTOgen baSCIi canOOl rel'en lO:ln und,ssociaJOO form. e,'en in ~IC l1lL'dia and. presumably. may have difficulty passini .hroogh the gut wall. Since quaternary compounds can be absorbed. OIller le~s cffieiclll mechani~ms for absorplion probably prevai I. Qtmternaty ammonium compound, combinc rovcn;ib ly with endogcnOl.l~ ~ubManccs in the gut. s1lch as I1lUCIl1. to fonn neutral iOIlpair ~om[llexes. These ~'OfTlplc,es penctntte the lipid mcmbr.me by pa,-,si\'e diffusion.

p_u<ts
Atropme I~ the tropme ester of racemic tropic acid and i~ optIcally Inactive. It possibly occurs naturoily in "moos So!;m3CCx, thoogb . IIle: claJm. ""tlh JustifiW cation. that lllhate"er IW'OpIIll: is isol3ttti from natural sources resulu; from mcemi/.3tion of (-}-hyoscyamlne during lhe 1,soI"tion proce..\s. COfllcnllonaJ methods of al~a1old
Atropin~.

ine) but

In this lel(l bn u.'iCd

piOpcn i~.
,mpathcli~

USP.

'oos cell-

or

.1>-- '

'"',
(w.!)

hoi

, - ."
(chair) TROPINE
(3co-~dro.:yttopl1M Of

",.
(boa!)

A"

pOI
(chllr)

by

3ft..T~noIl

PSEUOOTAOPINE (3p-Hydro~ .. 01'

3p..Tn;I~nol)

dm
fil m

"'"

.... ""

of'

"

mal

1 m\">

,,~

a rn! clcs

corn

cone mil.
SCOPI NE
(e 711..(poq~OlI)'IropelM

Ihe t:

~'" AIm
'Ion

or II

7Il-Epo.y~~nol

Ihc~1

admi
and

A,

n<;c~

tncu! thoui
lions IIItda

IllClJ(

pre.1)
lI<ln~

"
o-e-

,,,

calla!
I" an (gripi

dwna.

M
ATROPINE (or hyo.cyllm..... j

Au
It IIlCI

SCOPOlAMINE
(orh~.)

the

~.

(arcti( """"lll~ Da
li nd

IsoI:niOll are u'iCd 10 ublain a crude mixture of atropine

Ill'al~nl I"uh culd dilute proctSS nmk .... ulropine. an

h)'Q5()'amine from the plant nllltcrial. This crude mixture is raccmiud 10 au'Opme by rel1uxlI\g In chloroform Of by

alkali . lkcau!IC the flICCmmmon

officialliml l b set on the hyoscy -

umillC conlcnt by reS\rk1i ng atmplllC \0 11 maltimul1l I(voro-

in chlorofOl'm ( I : I ). and in ethel' ( I :25). SaIUI1l1C'd ~ solutions are allaline in reaction (pH - 9.5). The fIN ' is u~ful when nonaqueous solutlOtls au to "'" madt. iG as in oily vehlcles:and ointment bases. Atropine Iw IP'ha lf-life of about 2 to 3 hours. It IS metabolit.ed in lilt hI'll to several product~. including tropi!.' acid and tropint'.

,hlon!
A

i oouct

lIc\C'ld
hi ll II~ m mg, at( chocul

Inlion under specified

~"Ofldilion~.

Atropine occuo; in the (OfIU of opI ically iMCIi>'C. while. odoricsI; crystals pos.'lcssing a bitter taste. II ;s IlOI \'ery !lQlubIc in 'uter (1:460. 1:90 at 8O"C) bill is more 1lOIubie in alcohol ( I :2. I : 1.2 lit 6(fC). It IS soluble 11\ glyemn (I :27).

Atropine Su/f. t e, US" . Atropine sulfate (AtlOplsOla prepared by netltralizi ng atropine in acetone or ether JOIIfII;II wilh an alcoholi!.' solution of sli tfurK- acid. With taft II1II to prevent hydrol~is. The salt occurs as colorksl ..,.1'

lhe nlll

or as 11

",hll~.

cryslalllllc powder. II IS cmorc-cem In dry air

and ,hould be protected from light to prC\'cnl dC('Qmposilion.

-"

Atropine: sulfitIc is f!'ttly ~Iuble in \\"3Ier (I :0.5). Hlak!). Ilol (I ~.5. 1:2 ..5 at boiling poi nt ). and 111 gly~'Cnn (1:2.5). AqucowI soluhons al\' 1101 \'ery '(:I.blt, thoogh o;oIUlions may be 51mli/cd al 12O"C (15 Ib prn..~ure) 111 an wUlocla\,,, jf me

pH is kept below 6. SIc:n h 'lIuon probably I ~ best effected by the: U~ of 3S1:ptic techniques and a biK1~nulogical filter. II has been suggested Ihlll Ik! n~ than a Jo.duy ~uppJy or all aqueous solmion ~hould be made anll Ihal for ~mall
<panhlie<; the best p1'IX\'dlllll IS 10 use hypodermIC tablets

nl steri le dl,tliled owl1ter.1l KondritJ...... and Z\ irbhsH howe llUdied the k i ncllc~ of alLaJlIlC' and procOlH111a1YJ.ed h} *oIy~ of atropine in aqLM:OUS solution. The region orma~i
lies between I)H ) lind appro,l(imult~ly 5. They !\a1'C alo;o proposed on Cllnall01l 1 pr'l:lIicl Ihc halflife of 0 atropine untkrgomg hyJroly~js m conStant pH and tcmpc:rn
~151abih l y

"" The

xl aqllCOU~ C fm: base

acllon of alropux or 11\ ~lt\ is the SII'IlI: It produce:. I m) dnllllC effecl by p;ll'lIlyllng tht- iris und the ci liary mu), de. sod. for tilis reas.on. j. u..ed by the ocuh~t In iritis 1100 romea! innummmions and lc~ ions. lts usc i .. r"Jllooal in the'!: OOIlditions i1<.'Cauo;e one of the first rule. In the treatment of IlIlbmnmuon is rc:$t. "h kh. of course. is lIct"Ompli .1lclI by .. pand)'\IS of muscular motion . Its u<;c III the C) c (0.5 to 1% iIOIlItions or gelatin di \k.~) for finml!: gl~ is ""deprcad. "tropIAC i~ administcred in Mnall ~ before general anc~ .,ia to ie!;sen oral and aIr pasl4ge <.CCn::t ion~ and. ",hen .. ministered wnh mOf"phin.c. to 1c:s>t:n the re'p'nltOl)' dcpre..\ I/Ot1 1l11luccll by morphllle. Atropinc CllU rcSllc~,nc..~~. prolongeJ pupi ll ary .:lIlatlon, SCS aj loss of I'isual :JomntOdauOI1 and, funhermon:. &iles I'$' 10 arrh)"thnllti such a.~ atnOl emmular dl'~'OIlOI1. 'cn lnCIIl:u" ultaloyslol~. and elen ventricular fibnllatloo. En'o !bough etht-r has been grOOually replaced by other al1CS Ihrt,,). thereby eliminaung prub1c:ms" nh re'p'r"Jtory Sl'e. IiOOI cau:.cd lIy ethe r and dl'" rL'(lulring atropinc. surgeons ani a!lCSthesiOllogh ts tooay cooti nue 10 u-.e il as an atle~thetic J1tlt1l.'dtcam 10 t\:ducc uce.... ~I\C s.al ilary 1100 :1I rv.ay secrcIicJM and 10 prevcnt ,'agal rene~es. lilt .blltly 10 dl) 'iC(.fC'ti()l1s has also bttn u..ro 111 the soa11td "unu,. tablcts for ~ymptOtnalic rehef in collis. Inca t!wtic preparations. atrop me Of" belllldonllll has lJt.-en u<.ed II an uOli~PiJ$modic to IC'>e n thc $nlOO1h t1lU~1c ~pasm Iptpll1g) onen a.\,....xi~ted ", llh cnlharsi~ . AlroplllC may be used to lreal SOIOC I)"pcs of an1t)thmias. .1l'ICl'ea5CS the he:ut rate by bloc ling the cffecb of AU 00 W''lIgus. In thi~ rotltc~ l , il i~ u)Cd to In'at effIam relet"S,blc: tnd)an'lt)'lhm las that may ICcompan) acute m)ocardml in fll'C'liQn It is also used O~ an adJUIICt to H'ICSthe"iJ 10 protecl t,!~l n ~1 brndycardia. hypotcn~lon. and e~cn caNilic arn:.o.l iducal hy the ~~elelal 111U..;o:1e rdaxanl sucdn)" kholine

Iryoscyanllnc "a Ic,orotatory 01 laloill obtaitM:d from V-Jriou~ oolarlllCcous species. One: of the contlOCrcial IiO\Irce.~ I ~ Egyptian henlxme ( H )"OJc)"/lmIIJ IIIIIli("us). in .... h,ch It oceUI'li to the utcnt of about 0.5'1. Usually. it is pn:JIIIIl!d from the crude dru g In manner SII1I1I:arIO IMl used roratrupin.e and I~ punrl('d H the oxalm. The fret' base: IS obtained ea..,ly from thl$ ult. It O!:curs as "hne needles that are spanngly solubl e 111 waler ( 1:281). more '>(lluble in ether (I :69) or be:n7.cne (I: I ~), ICry soluble m ch lorofonn (1:1), and fret'l y svluble In alcohol. It i" used u~ the sulfatc aoo hydrobromide. The pnncipalll'asott for the popularity of the hyllrobronude has been ih noodeltquesnt nature. llIC salts h3\~ the ad~an, lage Olvcr lhe: fn:e ba;.c m bemg quite WIIter solublc. Hyo..cyamine i, the 1f'10 foml of the: rncemic mixture k!!o",n:ls atropine. '11101: 1/1.!):1ft! ronn does tM)I exisl naturJlly but has been syntht::sl~.ed. Cushny'~ compared the: act;' illes of (-..-hyoscyamine:. (+ ..-hyoscyamlAC. aoo the racemate (atropIne) in 1'XW and found gn:alcr lltripht:rJl potency fOf" the 1_ ) isomcr and twice lhe poIcllCY o f the racematc. All lalet" , Iudies hnc e~sclll iall y confi nned Ihal the ( + ) il\Oll1ol:r i~ only wcakly IlClil'e and thaI the: (-) isomer is. in effect. the DCli ~c ponion of D lroPll1C. InS[lI.-.::tioo of lhe relative doses of atropine su lfmc lind h)O!OCyaminc sulfate ill uslmtes the 1I1ffcrence~ ICry nIcely. The princIpal critici~m o Ucll'd agum>l the usc of hyoscyamine su lfa!c e~clos;'ely I) lhat u 1~00~ to racem i/.e 10 atropine su lfatc r.uher eMily lD soIuuoo, 50 Ihal atropIne \l,l1falc 1)),,011 botl1CS the Iltore ~Iable of lhe two. All of the i'lOntcrs beha"c vcry much lhe same:. in the

Hyoscyamine, USP.

eNS.
Il yoscyam inc is u.sed 10 treal disorders of tho: urinary trao:.:l more i\O Iha!! any other anli"fl(lSmOO",:. though there is 110 e~ldcnce lhat it has ally adl anlages 01 er tile other be:lJadonn:. pn:parJttons aoo the S)"nthc:tlC lIn1lCliohncr"cs. It IS used 10 11l'3l 'pasms of the bladder and. In Iht) manncr. serves as a urmary ~l imul:ll1\ . It is u,.cd together ",Ih a narcoti c 10 countcract thc )p3"11 pmlloceJ b)' tIle narcot ic wilen lhe lu1tcr i.. used to relieve the pain or urelhrul ~olic. I~ yoscya mine pn:parJtion~ arc 1,11 used a\ anu'p3$modics In lhe: .-.0 ther...py of peptic ulccl'li.

Hyoscyamine Sulfa te, USP. H)oscyamine: sulfatc ( 1..c"~1Il sulfate) i ~ :, " hill', odorless, crys tal line compounll
of a dcltque'iCcm nature thm al..o i~ affec ted by lighl. II ,s <;olubk: in" Ulcr ( I :0.') and alcohol (1:5) bul alm05t iM()l ublc in cther. Solulion, of hYOSC,.-JIIlIl1c:. 'ilJ lfat~ lIR' lelthc to lllntos. This drug is usc.-d as an IInllcholtnc:rg'c In IIIe SlIme manner and for lhe <;;allle 1l1{hcations as alroplllC aoo byoscyamine. but 1I pus.sc:ssc~ Ihc dl~!ldvallt age of bei!!!: dellquesccnt .

.,ark ~uch plasm.

n the 1i~cr

""""'.
Ill,.

Scopolamine.

"'~.
.tropisol) h II"solulion I care: 11.<;1,'" crystals

AIIoIher usc: for alruplne .ulfalc cmergeJ folllll< mil- the ...."Clof'mc:m o f the orgaoophosp/latt'S ..... hieh an: potcnt mIIbIIIIf'> of AUE. AtrOpiAC j~ a _pecirlC antldole to pre_enl W mU!II;aril1l c effect . of AOt accUl1m13l1011. ~uch a..~ 1011111, abdolnilml crumps. Ilinrrhca. 'oIIlh'III;OI1. ~wcfllin!:. bronmxoostriction. and exce~~h'e broolehial <e(rclions. It is _ IIltrJI'c nously but does rIOt prolecl agamst res.pimtory llillln' caused by de~~IOO of the respir.uory ttnlet" and lilt musck~ of rcspirauOtl.

SI.:QJlO lamine (hyO'iCine) is fouoo in Vat 'OU~ mc:mbe" of the Solanaceae Icg .. II. lIig~'" 1)"htJIsia m\"/J/IfJrtlld~s. Scopolia ~pp .. and /)mllrrl m"'~/). Scopola mine usually i~ isoluled from the mother hquor remaming frotl1 the bolati'lll Olf hyO!oC)~mill('. 11)113(";'11' is lhe older !!ame for Ih i~ nlkalo ill . Imlgh Jroll/}llI",ln~ IS the acccpted name in lhe Unitcll Statcs. Scopolamine IS lhe: 1~1'tI component of the nlCt'mic mi.llUre Ilmt is ~nown as tIImSCIllf'. llIC al~aloid I) r.w:emi'.ed readily In tit.: pre.;cnce of dtluic allali .

The ailalOld occurs in tnc form o f II levorotatory, ~ iliCOUs hquld that "onl)' slightl), soluble in w:ll~r but very soluble In akOOol. c hloroform, or ether. It forms crylita1line salls wilh IllOSl acids. with the h),drobromide bei ng the mo~t ~ta ble and thc nM,l'\l popu larly IICCtploo_ An aqueous solution of the h}'drobromide comaming 10'lI; m:rnnitol is said to be ICS!i prone to dccomJlOSIUOO than unprotectcd solutions. 'The commcrcially available ul1nsdcrmal s)'Mcm of scopolamine comprises an outer I:I.)'I'T of po l)'mer film IIIId II drog reservoir con ta,n ing scopolamine, poIyisobut)'lenc. and mineral oi l. IOhic h is int('rf~ v.ith D micropofOUs mcmbtanc tocomrol dlffuslOI1 of the drog, In th l) dosagc form, scopolamine IS effective ill prc~enting ",ion sidncss. Thc action is belie.oo to be 00 the conu or lhe \'esubular appan1tus. Whereas aU'Oplllc stimulatC5 the CNS. caU5mg reMiesMICSS and talkatl\cllC)$. 1IC0polamlnt: usuall)' atUi as a CNS depresSIInt.

H&

O-C-CH'-

II o

Scopolam ine Hydrobromick. USP. Scopol am ille h),drobromitle (hyosc inc h)'drobromidt) occun as IOhitc or colorlc~ s cry~tali. or Illl a whi te. grnnu lar powder. It is odorless and tends to effion:scc in dry air. It is freel), solublc in water ( 1:1..5). soluble In alcohol (1 :20). 001)' slight l)' sol uble in chloroform. alld Insoluble in ether. Scopo lamine I ~ a competitive blocking IIgent of the parJ.sy mpathetic nervous ~ )'~ t~m as is atropine. but it differs markedl)' from atropine in lUi DCtioon 00 the higher nc ....e centC!'. 80111 drugs readll)' crm.s the blood- brnm barrier and. e,'en in therapeutic doses, cause coofusion. )XI",cu larly in the c!tlerly. A sufficiemly large dose of scopolamine will cause an indl\ idual to sin ~ into a restful. dreamless sleep for about 8 houn.. fol lo",ed by a period of approximatel), the same Icngth in which the patieR! i, in a semiconscious ~tate. Dur ing this time. the patienl does not remember events that ta ke place. When SI:()polamin.e IS oomillistered wi th motphin.e. this temporary amnes ia is termed n',i/iglll slup.

Homa tropine Methyibromlde. USP. HOOlauUjOW( melhylbro!1l1de . la-hydroll y.8- me thyl- 1ull.Slflltropamwa bnNllide mandelate (Novatropine. Mcsopin ). occurs as a Ill trr. white. odorless polOdcr and is affected by h&Jn. 1lrt CQIllpound IS readil)' soluble in water and akohol but lJldg.. blc in ether. The pH of a I % solution is S.9 and thilt Ii I IW wlulion is 4.S. Although a solu tion of the eomJlOUld )'ie ld! a precip,1.lI.1.C: with alkaloidal reagcnts. such as *1. curie p0(assium iodide test solutioo. addition of alb1l b!. dro""dcs or carbonat~s does not cause the prec,pitate'" OCCUN wi lli n<.Htq~aternary nitrogen sui ts (e.g .. al/qlllle. homatropine).

O-C-CH'-

I"

Homa tropinf! Hydrobromidf!. USP. Homatropille h)'drobmmide. I nll.5n1I-tropan -J lf-01 mamklal.e (ester) hy. drobromide (Uomatroccl ). IXCUI'li as v.h,te crystals Of as a while. crystalluw: polO'Ocr that is affected b)' ligllt. It i5 solu ble in water ( I :6) alld alcohol ( I :-W). less soluble in ch loroform ( 1:420). and insoluble in ether. Solutions ate ",compatible with alkalmc subsumccs. IOhich precipitate the free bilse. and IOlth the common~ agent s thnt preeipllatc alka loids. As with atropine. so lutions al'l: steril ized Ix:.~t by nitration Ihrough a bacteriological filter. Homatmrinc h)drobrollilde IS used topteall)' 10 paral)'u the ci liill)' ~1rUCtUI'l: of the e)'e (cyclop legia) alld to effect mydriasi~. It behuvC5 \'ery much like alropine bIO I Is we aker and less tOllie. In the e}e. it actS more rapidl)' but less pt.I'SISlent ly !han atropine. Dil:a.tion of the pupil takes platc in about IS to 20 mmutes. and the IICtioo subsiOcs in about 24 hours. By using II miotic. suc ll ll.~ ph)'SOIitigminc, 1\ i~ possible to restOl'e the pupil to nonnaJit)' in II few
hoo~.

II o

Homatropine mcthylbmmide is transported poorly ~ the blood - brain barrier because of its qualernary _ ilium group and. therefore. has far rewl'T stimulant po..... tics than olropine. It docs lIo\'c all the c hlU'OCtenstic: ~ ernl p~J'1I~ympathetic depressant properties of MtNpIJ: and is used to rcduce o\'enlCCrCtion and to Il'lk.'c

_m<
Ipralropium Bromide. Ipr;u ropi um bromide, l~~ dro '" y -I-oll0-2 -phenyl prt>p(I)( y}- 8 rnethy I 8-( I melh) ~ 8-azollinblCydo[J.2.lloctane bromide (AlroVent). is . . . tcrnary ammomulll dcri'lIlive of atropine. It is fll'ely in water and ethanol hut insoluble in ~lI loroform and eIbet l1le salt is stublc in neutral and acidi c SO lutions bul ~ hydrolyzed III alkaJine soIUlions.

quaternary ammonium denv:ui>es:lS coolraSlcd wllh the IeT-

liar)' amine- type ester<>

some effe<:llVc appear 10 be counteTpartS.
~hghlly

synl~iud originally. Ahhough 1I:~niary almne estC~ II/'e in uSC': roday. the

quuternaries. as a group. represenl lhe more popular type and

more poIenl thnn their tertiary amioo

The accompanying fannul. shows the ponion ofthc:llropille molecule (enclosed In the CU(\ed donal IlIle) belic~ed 10 be responsible for irs m~jor activity. This j, SQIllt:lirnes called the: ljltlSmfJl'lWr;' group and cOtnparcs with rile Imulilt'siopilork group obtained by simllat disSCC1ion of the

CQCalflc molecule. 'The validu), of Ibis C()fIClusiOfl hlIs been

ampl y borne OUI by the many active curnpounds ha. rn g only

I' ~impJe dielhylamioocthyl residue replacing Iii<: lropine portion.

Ipnillopium Bromloe lpntropium bromide i~ u~ in inhul:llion Ihcrnpy to produl:e dilation of bronchial smooth muscle for acute a~thmallc IIl.II:U. The drul1 produceS bronchodilation by compelil i"e Mlbllion of cholinergic ~cept~ bound to smooth musc~ oflbc bronchiole~. lpnnropium may also OCI 00 the surface of Ol!l$t cclls to Inhibit ACh-c:nhanccd release of chemical iIItIlmtDn. 1l1;,: drug has a $low onsct of action. ",ithin S to IS minutcs after being administered by inhnlutioo. and IlIoukl not be used alone for acute aSlhrrullic allocl s. The prak therapeutic effcct from one dose is OOscrved between I and 2 OOurll. The effects of the drug last for about 6 hours . It Ms a half life of 3.5 hQUn.

."'''''~ panlum

"'insoluI. The I

as II blt-

"' : "r==;'t ......'! ", :" '..

..
'"
'.

."

HO..........

. ...

nat of It mpound as mer-

" ~"

........

"

-,,:

- ...2
'.

....

(bh h),-

'... ...... ','," .......... ......

,

/ .:

\. c:-o

.., ..

Ulle 111:11

lIropine.

S YNTHETIC CHOLIN ERGIC BLOCKING

AGENTS
g l_kohol Ester'S
The wlanul:eous alk.aloids are gcnerull y agreed to be potent
JiWlS)mpalholytic<;. bUI they ha,'c the undesirable properly of producina a wide runse of effects through lheir nonspe afic blockade of autonomic functlon~. Efforu to U'iC the lIIispasmodlc cfft'Ct of the alkaloid.~ IllOSt often re.~ult in Ilk effects such as dryllCSS of the mouth and fluctuations pul~ rute. Therefore. ~ynlhcsi~ of compound5 pos.'iCssing IjItIClfoc: chol inol )tic actions has been a very de.siruble field tf \IUd) . Few JlfOIOIypical drugs were u 3vidly dl ~sected mtile mind~ of researchers as :uropille in utlemplllto modify [I ~l ure to separate thoc numerous useful activities (i.e .. ...spasmodic, antl<;ccrelory, mydriatic, and cycloplegic). IbI carly l'C-'iCarch was camed out III the prc- and po5I - World War II era before muscannic repllll' subtypes 11m known . E.fforts ~t ~)'mhesis star1ed with ruthl'r minor deviallons Do !be atropine molc:cule. bUI 11 I'C-vie ..... .of the cOOln'lOllly MIldlllgllloday indicatcs a marted departure from the rigid III'JIWlI: amin.oalc.ohols and tropic acid re.~idlJ('S. Examinmion rI~ SlrucHll'I:S of antisp~smodics sho",~ thatth!: acid por. .. lias Iw:n de~igned to provide a la'l!e hydrophobic - ' y r.. ther than the Slereo.specific reqUll'C-mcni .of (S)rape acid In (-HI)'oscyaminc that was once considered iIpon.anl. One of the lJI~jor developments in lhe field .of .mtinoaIroho1 esters was the sua:essful introduction of the

1)'
II
I(:

across

yammo-

properpenphatropine

:lieve GI

TIle Ilffill1Ollleohol portion of CueDttoplnc may be considered a simplification or tile atropillC lJIolecule. [n eucatropine. tho! bicyelic tropine has hecn replaced by II roonoeyclic amill()a\cohol and mandelic acid n:place~ ltopic acid (sec under "Products"). Although simplificllion of lhe 11I1\lnoalcohol portion .of the atropine prolotype h ilS been II guiding principle in must research. many .of the ami<::holincrgics now used !>Iill include I cyelic Ilffillloaleohol moicty. The IminoalcohQl cstcr anli chol inergics are used primanly as antispasmodics or mydri alics. lind cholinolytic compounds ela~scd as aminoaloohol 01" aminoaicohol cther an,t!o\:ucs .of atropine are. wilh few eJ:cc ptions. used as anti parkinsonian drugs . Aoothcr Important feature In many or the symhl't ic anti cholincrgics used u antispasmodiC"! is that they colllom a qUlltcmury ni lrogen. prc~ulllubly to enhance activily . The initial syn thet ic quaternary t'Ompound m<'thalltheline bromide has served as II forerunner for many CMilen. Thesec.om pounds combine ant1chollncrgie IK:tlvlly of the anllmuClU'inic lype with SOfIIC gang lionic block;Klc to rl'mforec the p.~rusympathetic blockade. FornlatiOll of a quaternary am monium moiety. b.owevcr. imroduce.~ lhe pos~ibililY of blockade o f volunl:U')' synajl">eS (curunfonn acu~ ll yl; this can become (:~idcnt wilh sufficiently high doses.

3-{3-hyhylethyl}i5 It quaI)' soluble .00 tlher.

Produds
The antimu5C;u1nic compounds now in usc are dcscnbcd in the follo",ing monographs. C lidiniunt bromide. J hy droJ: y .\. mcth ylqu inuc Ildi ni uIn bromide benzilate (Quar

411 rupidly

Clidinium Bromide, USP.

~..un). i~ a wllite or ncarly whi te. alm051 odorless. cryst oll ine

powder lhat i~ OpIieally inacll\e. II is soluble in ""otcr and alcohol bul OIlly "try sliglltly 'iOlublt in ether lU1d benl.erIC.

lIIodic acti vi ly of atropi!IC and i~ nonirrilal ing when inSlil1ed rcpeatedly into the eye. If not neutTllli,.cd after the refl"lK1ll s.tudics. itS efft:Ct dissipates "" Ihin 24 hours. Neutra!or .,. wllh a few drops of pi1ot:arplne nltmte ~ullon. I 10 2'toften resultS in complete rcco\'ery in 6 hours. lt is supptic.:l !U II rc~dy-rnade ophlha] nllc <;Glulion In conecntrJ.tiorts Ii ei ther 0.5 or 2'J>.

I
Clidinium BromiOO

OicycJominft Hydrochlorltift, USP. Dieyclomnle II) drochloride. 2-(dielhyl:unino)tthyl bicyclOOc\yl-I-carbul ylate hydrochloride ( Benty1), has somc mu\Curinic m:tpla' subtype select"ily. It bi nd~ more finnly to M I and M J WI to M ~ and M. rccep1ors.1~

This anticholinc rgic agent i~ rnurl clcd alonc lind in combi. IllItion witll the mioor tr:ltl\jOillltf c hl()rdiaztpo~ide (Lib-num) in a prodUCt known a~ Librax. 111e rationale o f lhe combimuioon for the 1re3UlIcm of 0 1 eomplamlS IS tbe usc of an anxiety-reduc in g agentlogether with an anticholinergic agent, based 011 the rerognil.oo eontnbu tion of Il1lxicty to the development of 11M: diseased L-ooditioo . It is \uggestoo for peptic ulcer. h)'pt'f"Clllomydria. ulceruth'e or SpastK Lvlon, an~iel y s.tat('lo wltll 0 1manifeslll1ions, nervous stomach. irrilable: or Spa"K rolon, and OInc",. ClidinlUm bromide is COIlt"!lndlCated In glaucoma and OIIM.r condition~ that lIlay be aggrn"HtL-rl by lhe p:tta~yrnpalholytic action, such as prostatic hypertrophy in elderly men. wh ich cou ld lead to urinary racntion.

He,

CycJopento/atft Hydrochlorldf!, USP, Cyclopcntolate hydrocllioride. 2-di rnethylHminocthyl l -hydroxY(Jphenyl cyc lopcnUmcacctale hydrochlorillc (Cydog)' I). is a crystalline. '" hile. odorklls wlid Ihat i~ "cry soluble in water. easil y soluble in alcQhol. and on l)' slightly soluble in ttIM-r. A ]% solution has II. pH of 5.0 to 5.4.
OH

Dlcyclomine hydrochloride has one e ighth of lhe _ rotropic activi t), of atropill<! and approx imately IWI~ tbr musculotropic IICli"ity of papaverine. Thi ~ prcp;lTlIhOll, fl'\l inlroduced in 1950, has rninirni~.ed the adveI'SC effects~. clated with the atropine-type compounds. It is used for a spasmoIYlle effect 011 "anQUS smooth muscle spasms. ~ ulafly those .~soc ialcd with lhe GI tract. It is also u~fuI. dysme norrhea . pylorospa~m, and bili ary dysfunction,

HC'

Eucatropine Hydrochloride, USP. Eucatropine chloride, euphthalmine hyclrochlOflde or 1.2.2.k1 rdmethyl-4-plpcridyl mandelate hydrochlOl"Kk. powsICI lhe IIminoalcohol moiety eh:lTaCleristic of one of the ~ local ane!)lhclics (e.g .. ,8-euca ine) bul differll in the ponion oflhe ester by being a mandelate instead of~ .... ~te. TIM: salt I~ an odorieu ..... hlle. granu]ur po.....ctt-r, ptI'o. ing solullons that are neutral to lilmus, It is very soluble. wal~, fn.. ely soluble in alcohol nnd chloroform. but ~)moc " insoluble in elher.

h.
31'.

II is used only for itS effllCt~ on lhe eye, where it act ~ as II. pam.~ympatholytic, When placed in the eye. it quicll)' produces cycloplegia and mydriasis. lis pnmary field of uscfu lness IS in n:fr.IClion stud ies. Cyclopcntolare hydrochloride can be used , however, as a mydrialic in the mall~gemem of iri lis. iridocycli tis, k<,raliti ~. and choroiditis. Although it dOC$ not seem 10 affect Intraocular tension 5ign ificllnlly. it is best to be \"eT)' cautiOUS wi lh palients with high intraocular pres. sure and ",ilh elderly palienlli wllh possible unrccogni1.Cd glaucomatou~ changes. Cyc lopcn tolare hydrochloride has one half of 1I1C IIntispas-

""" I .-7

"e" ...--""
0

HC'

coo,

II

c-o

Euceuopone Hyd,ochlolide

"'"

"The acuon of eucatrop lllc hydrochloride clo<ely pmIIeI that of atropine. though .. IS much less potent than the It is used topICally in a 0.] mL dose at ill mydriatit I solut ion Of" in the fonn of \ m:llllablets.. U'iC of concentI3I from 5 to 10% is. however. nOi uncommon . Dilation.

stllled racllun uUllon to 2'1>.

bllie HnpaHlTlrol of accommod:l1ion. takes place III aboul 30 mlnules, and lhe eye relurn~ 10 norm al in 2 10 3 hours. Gl ycopyrrolull'. 3hydro~y- I .I dimrth}tpyrroJidin ium bromide tf-CyelopcntylmalKklate IRobmul). OCCUr'S as a ... hl le. "'ryWlllme JlO" del' 111:11 iJ SQlubIc In ... ater or alcohol but pracl i",ally insoluble in ",h\on).. form or ether.

Methantheline Bromide, U5P. MClhamh.clme bronude:. d icth), I( 2-h ~dro~ ~et h)' I)mc:th ~ Inmmoniu m brolll ilk
xunthclloC-9-carboxyl:Lle (8anlhillC Bromide ). i~ a .... hlll'. ~ lightl ~ hygrtl!!O!:opic. crystalline: salt that is ..alu blc: In ...lIter to producc: solulion.~ .... "h a pU of about 5. Aqueous solullOll:! 1m: not qabJe :md hydrolya in a fe ... days. 1bc: broInlde fonn is pn:femblc: to the "cry h}groscopic chloride:.

G/ycopyrro/ate, U5P.

ons of

W hed

nc hy
arooll'

~qMo r

" , lhan

"
I
Glyl::q:lYl'fotal8

he neu

,kettle

on. firsl ;IS asS()-

j for its

.. panoc.seful on

fl.

c h)'droOS!oC:S.\CS

~.2,6- tO:I

he early toe acld.c a bcn/J> pro~id :olubk Ifl tI ahuo"l

GlycopYfTOlate is a typicu l antic holi nergic and poso;es,."<cs, alldcquale do~ge 1e\"C1~. the atropille- lil~ effet:h ch llmcl.:'rISUC of Ihis class of drugs. It has p spasmolytic effcci on the .u5CIIlature of the GI traCt a~ ... ell as lhe genilOurinary tr.>Ct. kdimlnlShes gastric alld parK.Tealic secretions and the quan\II)' 0{ pcr;pinuion and salivu. Its ~ide effects are typieall~ rImpInc-li ke also (i.e . dryness (IF the mouth . uri nary relen181. blurred vi,ion. constipation). GI~copyrTOlute i ~ u more p!lknt antagoni~t on M I thon on M~ and M J receptors. 1lM: to.- am nity of f\h ra:eplOfll may. in part. e~phlln the low ~ of IllChycaniia dunnlUSl' of thi~ dru g as an anti 'iJlloIII01.hc.7<> Because of its quaternary ammOnium e harac11:1. cJ)'oopyrrolale rarely t UU'd CNS di~t urbaOCC'\. though II Klmelently high dosage i l ~an bring about gllnghonic and lI)'oocunll junction block. The t.ll\Ig is used as an adjullCI in the manugcn1<!nl of pcplic tbr and other GI ai1l111;'nt~ 1I)'IOCiated I' 1110 hypcmcid ity. ItjpmnollhlY, alld spasm. In OOI\lIl1On ...i th other anueholin~ liS use does not preclude dietary restrictions or use aftll!D('id~ alld sedatilCs if the)!: arc iodie-aled . Mepenzolatc bromidc. 3-h)' iWxy-I. I-dimcthylpipendini ul11'Pmmide bcn7,ilme (Cantil). . . III IO:tivity about one-half Ihal of atropine in I\.-dud ng O-Induced spasm) of the gu.nea pig ilC'Um. 1bc: seJective a;tion on COloniC hypemlOt.hty is said 1 rellCle pain. 0 and bloaung and 10 he lp cu rb dian'hca.
~nlolate

Thi s drog. introduced in 1950. is a potent antldlOhncrgle agent und actS It! the nkolin;c cholincrgie n.'cepl OfS of tltt y mpalhctie and p'lrols}mpmhetie sy'tems. '" ..... ell IIll at the m)'OIleuru.1 j uoction of the jlOI>Iganglionic chol iocrgic fibcl'). Like other quulerrnory ammonium drugs. methantheline bronllde ii absorbed ioom.pletely fmn the GI 1r.>C1. Among the condllioo~ for .... hich nloCth~lIIhehne bromide i~ inuicalll(i are ga~trilis. intestina l hypcrmoulity. bladder irrt ((.b tlily. cholirloCrgic ~p:!Ml1 . pancrcatili~. hypert>idm.i ~. and peptic ulcer. all of .... hich are man;fe~I Q1J1)II.~ of par:t.l>~m pathotonia . Side rcactioos arc alropme-li le (mydrlas.s. cydoplella.. dryness of mouth). The drug is controlindlcaled in glaUCQOl&. T01,IC doo;es may brmg aboul a curare-tile actioo. a not 100 surpri~ing facl .... hen " is ConSidered that ACh is the mediat ing fnelOr for neurJI trlm~miS.'>ion at the somatic myooeural junctio n. This side effe" ",an be countcrocteu .... lIh neosllllmine mcthyl~ulfale . Ox}phent:ycli mine hyurochlondc. 1.4.5.6-tetl1lh}t.lro-l -methyl-2-pyrimid III yl )nlCth y1 u pheny Icyc IoM ~ aI\CgJ ~~Olate monoh yurochloride: (Dancon. V i~trnx). was introduced in 1958 and promoted as a pcnphaul anticholinergic- ant isccTl:lory agent ..... ith hnle or 11() eUI1lll:-ltke acI"lI~ and lillie or no ganglionic blocking tICI ivily. Tbese ICt;' it>es are probabl ~ ablic:nl bccau!oC: of the teniary chanlCter of the molecule . This III:ti~ily is in COntrast .... Ith that of compounds that couple anlilnuscarinic (l(;IIOn wilh gangliOIllC blocking action . '1lI.! tel'1 i;lry ~hnrnctcr of the nitrogcn pronlO(es intestinal absorpuon of the molecule. Pemaps the lnoe;t signiflCanlllC' tll'ity of this COOlpound is its marl;ed ab>1il~ 10 reduce both the vol ume and lhe acid conlent ofthc ga\lric juic'es. a ~r able action in \ iew of the more recent hyJlOlhc"<ot's pcl'1aining 1 pcplic uker Ihcrap~ . Another impor1l1nL feature of thiS 0 compound is its low IO'(icit)' in eOlllpari-.on with many of the other available nntichol inergics. Oxyphencyc lim ine: hydrochlonde is hydroly~ed in till' presence of ut'eSSive moisture and heal. It is absorbed from the GI tract and has a dur.lllon of aclion 0{ up 1 12 /louf"'. 0

OKyphencyclimiM

Hydrodtlori~.

Bromide.

II..

,p

c(
pal1>Lkl ~

OH

Sr -

HsC,-

......... CH)

C - O -~

,he laller. lie III 2'l !ntl1>tlolI' !ion_ '" nh

II

\; \

,.

the two-clll'bon chain illlerprosthetic distance than is apparen t al firsl gl ance. This. combined with the Ocxibi lily of the alicyclic chain. would help to mini mize lhe distance diSCTt'pDOC), .

I
Oxyphc:ncychmine hydrochloride is suggesled for use in peptic ulcer. p)'IOf"Ol>pasm. nnd functional bowel syndrome. II is t'Ol1truindicated. as nre OIher nn ticholinergics. in pnlients with proslntic hypertrophy and ,Jllucoma.

I
Mesylafe, USP. Bcnzlropine rnesylak, 3""(di~n)'lmethoxy)-1 aU .Sall-tropane methanesulfon.1le (Cogenti n). has 8ll1icholinergic. antihi~aminic, and local ... esthetIC proptnies. Its IIIlticholinergic efft makes il appltcable as an antipatk insonian agent. It is about as potent_ anticholinergic as atropine and 5han:S 51:lIlIe of the sidt dfect' of this drug. such I1S mydriasis and dryness of mouth. JmponaotJy, however. it does not produce centllli stimulation but instead uerts lhe chaTllCleriSlic sedlIt i\e effect of the antihistamines.
Benztropi~

Bromide, US,.. PmpanwJine bromide. 2-hydroxy-ethyl)di i5OpfOpylmcthylammonium bromide ,anthene9-cnrbo~)lhte (Pro-Banthinc). is prepared in a manner exactly analogous 10 Ihal used for met hamhocline bromide. It is 11 while. waler-soluble. crystalline substance. lIo-ith proptrtics quite similar 10 lOOse of methanlheline bromide. lis chicf difference. from melhanthelinc bromide is in lIS poIenty. ,,'hlCh has been esumaled variously 10 be 2 to , limes as gn:at.

Propanfh~ine

o-c",

, ,

, , , , ,

".

I
BonZlroplll$
Mos~te

The tremor and rigidity charnctensllc of partin:sonJYll m

Ami .... lc.hol Ed:.. , s

The nmi noalcohol elhers thus far introduced have be~n used Ill- antiparki nsoni:m drugs ralher Ihan as CQnVentiOllal an ticholincrgies (i .e .. as ~pasmolytics or mydrialics). In IcneruJ. they may be considered closely relaled 10 the antihistaminics and. indeed. dQ ~SCS$ substlllltiallllltihist:uninic properties. In tum, the antihistamu-.es possess anltcholinergic activity and have been u.'ICd as ~miparkinsonian agents. Comparison of chlorp!lenoxaminc and OI'phenoorine willi lhe antihistn_ rninic di~nhydrJmine iI1uslrute.~ the el= similarity of SltuCture. The use of diphcnhydromine in parkinsonism has been Cited abo'e. Iknztroplne may aJ.50 be oonddcred structur.al relalh~ of diphenhydramine. though the .minoal coho! portion b tropine and.llierdore. ~ dislamly related than chlorphenoxamine and orphcnadrinc. In lhe slructure of bem.tropine, u thn:e-carbon chai n in ter.'cncs betwee n the niltOgen and o~)'gen functions, wherca.~ the others e\lnce a IWO-Carbon chain. However. the rigid ring slructure possibly oneo,," the nltrogcn and Ol!ygen functions inlo ~ nearl)'

n:lie\ ed by benzlropine mesylate. and it is panicu l:u1y ,-mt ble for those patienlJ; who Catino( tolerute central ucilaUol (e.g .. aged patienlS). It may also have a useful effect in IIlIIim izing drooling. sialorrhea. ma.~ k -l ik e facie.,. oculogytK" crises. and muscular clllmps. The usual caution exercised wi th any anticholiqic_ glllllOO'lla and prostatic hype"rophy is ~rvcd ..... ith dis drug .

,.
~
~

" "

J" g'

Orphenadrine Citrate. Orphenadrine citrute. N.N4met hy 1 II-me th y I- a-phen)' IbenI.y lox y jet hY II mine citrw -2-( I ( I : I) (Norflex). introduced in 19S7. is cJoscI)' n:lated 10 "phenhydramine wucturo lly but has much Io..... er taminic activit), and much higher anticholinergic XIQ. Li kewise. it laclr:.'l the 5Cdat"e effcclJ; characteristic u "" ~nhydraminc. Pharmacological tcsting indiclIlCS IIw it. not pri mari ly a peri pherully acting antichol inergic bti il has only w~ak effects on smooth muscle. on the c}'e." 00 secretory glands. It does reduce voluntlU')' muscle spi1& however. by a central inhibitory actioo on cerebral _ areas. a centrol effect simi lar to thaI of atropine.

'. ,.
'". D
q"
ho

,.

'" "-

an_

'"'

'"

""

""

appar-

of IhI" screp--

1959. has a rdati"ely w..ak vi<'C1'lI1 antichohnerglC. but a ~tll)ng nlCOl ,ool}IIC. acuon In lernlS of liS abili lY to block niCOlinc-lIlduced con,'ulsions. 1lIererorc. its neurotropic IIClion i, TUllier low 001 InleqjnaJ musculalure and blood VC!l~,s_ It ha.~ a relati,'cly sirong mu<;culOlropie lICllon, ",hidl is aboul equal 1 lhal of papaH!rinc. in C()mpal'bOl1 ",jlh 0 IllO!>I symhclic anticholinergic drug~. hs !\Cuon on the c~e. a1lhough mydriatIC. is much Io... er than thai of atropmc . lllc.>e weal: anticholinergic efrecLS add 10 il5 uscfulness in Par~lnson 's ~} ndrome by nllmmi1.lIlg Side effech.

Orphenadrlne Cltralo

sy lme . lfooalc )Cal ant apphDlcm an Side c fmoulh. 1Ilmulaffect of

Thi s drug b u'il.-d for the symP1olll~ tl e 1rt':nmelll of Parkin 100" disea.'oC. II reltc,e~ rigidll) bencr Ihan II docs 10: 11101', and in ccn ai n cuses, II may OCL'CI1IU;,le the laller. TIle lIrug wmb31s Incntal slu", ~hnes). Ilkinesi;,. ad)IIUl1l1a. and lad: ri mobility, but this effect seems 10 lIlIlIini,h rulher r~pidly "1m prolonged use. It is best U>cd a~ an IIJU 11<:1 10 Ihe other t&t1\1S. >loch a.... bcn/.ir0JlIIIC. pnlC)ehdlnc, crcrimlllc. and lrihu >phcmd yl. in Ille trca l melll uf l'<ll1l lysis agmms. Orplietllidnlll" cilrale i~ allo() used as an adjunct to ~)t, ph) \ iotherapy, and other 11IC'l.'iUreS 10 rdic\c p>lin of local muso:le tpI>m (c .. nocturnal leg c rumps ). The drug has a low incidencc of lile u~ual ~Idc effecls .. ml~ group. n:Ullel ). dr)"ne.~.. of mouth. nau~a, ;,nd mild
UClIJIJOfI

B'POI'Id(tn The drug i~ uscd in alilypes ofParkinsoo's di<;c:ue(poeol encephalilic. IdiopathIC. aneriosclerolic) and helps to eli ml nale akines.ia. rigid ity, and tren1()l". II is also used in drugindud eX lrapyramidal disorders 10 ehmi nate symptoms and pc'nnil ronu nucd uSC of lr:mqu i1i~rs. Blperiden is . 1 50 of valuc In ~paSt;C diwrdcrs nOl relmed 10 par~insonism. stICh as mul"plc sclerosis. ~pmal cord '"Jury. and ~bral pal\ y. It i, cUIltrluOOiCalcd in all fomls of epilepsy. Blperiden hydmchloride. a-5-oorborncn-2-ylo-phcnyl- I-p!reridincpropanol hydrochloride (Akineton hydrochlondc), is a wtl' le. o pt; ,--ally inxtivc, cry1>tallme. odorless po ... der thai is hghtly soluble in Wilier, ether, 31~ohol , alld chlofOfOlTII and spar ingly <;Qiublc in methanol. Bipcridcn tlydrochloridc has all of the actions described for biperidcn , TIle hydrochloride i$ u<;cd for tllblet ~ because it is bctler ,,,ited to thi .. dosage form than is the laclllic ~It. As .... ilh the free bllse und the laclate ~a lt. Acrmlomia (dry ness o f lhe mouth) and blurred \'ision may occur.

Antoi_kohols TIE dc\'Clopmcnt of

tism arc , 'lI.lulI cnalion n mimilogyric

~,N-di

cilmlc :110 dl '

jnhhi~

actiOl1, : o f di IlIt it I( JeCausc ye. and spasm.

lOOk pia<:<' in Ihc Ib thrse Dnti~p>lsnlOdics wcre equally efficacious in partl 11 'I'IIIism. ~'mlI of the d rugs In Ihi' e lass of alllil11uscarmic agems bulky group<; in tbe \leimty orh>drol)1 and cyc lic ImlllO funcllon~1 group<;. TIlesc eompnunds a~ simI lar 10 litE c~ aminot:'iter umichohncrgic compounds dcrh'OO !rum atropine . l1w: pre-.encc of the al~"Oho1 group scem to wb!.tnutc adeq1latc ly as a prll"lhell C group for Ihe carbo~) I fuactton in creating an effeclivc parusympathc:llc block ing ~t. '!'he arnll1QC!;ler grou p. per \C, , \ nOI a neces..~ary ad JIIICI 10 cholt nol)tk atm"y. pnl\'idetl lhat OIher polDr goopms', such a.~ the h)'dro~yl , can ~ub~litutc ItS a prll"6ruc group fOf the eurbox) I function . AI1OIhc:r struclUl1ll ftM-ure common to all aminooleohol al1licholincrgics is tile J'fJIIll'IOf'I"OIXInol arrallgcnlCnl, ... nh three carbon s ;nlen.-el1.. bet""ccn lhe hydl'O~)' 1 and al111110 fUllCtioo~. All of the .lIOIIcohols u5Cd for par~ l ysis agll an~ are Icniary alTlinc~. 1Ieau'iC' lbe c\c)lred locu~ of action is ~'t"nlr:ll. forrnalJon of a qrAlWiary ammonium moiely destroys the Ullliparl;in >on;an ""1"'Hle:!.. These aminoalcoho!- halc been quatCmlloo, ~\li~Ver, 1 en hancc lhe anticholinergic lIel1 ..;ty 10 produce: 0 IItspa.~modic and anl ;<ecn:IOf) compound . ~uch a.~ lridl Ilutillyl chloriOi: .
~n,

wnll1oalcohol~ a. par.l'>ymp.1lholyt;cs 1940s. Ie ",as \OOfl cstablishl"d, ho ....e'cr.

8iperiden Hydrochloride, U5P.

Procyclidinl! Hydrochloride, USP,

"""~

Biperiden. a--5-OOI'bomen2y l-(tphm) I- I-pipcridincpropanol (Akinelon), mtroduced In

U5P.

Procyclidine hy drochloride, a-cycloOcxyl.o-phcnyl. l-pym>l ldinepropaool hydrochloride ( Kenmdrin ), Wlb inlroduced in 1956. AI though It is lUI effecl1vc pcnphcral anticholioergic and, Indeed. has been u5Cd for peripber.ll effects sundar!O liS melh ochlOl'1dc (i,e.. Iricyd ;u1}o l chloride). ilS cli nical woefulness lieS In ilS abilily 10 rdle\c \'oIumary muJ'C1c spast icity by Il~ celllraJ action. 1lJerefore. it has been used with SlK.'tt!;/i in lhe treatment of P.~rkln!>Qfl 5 syndrome. It is s:lId to be as effcctivc as uihc~yphcnidyl and is used 10 rNuec mu<;clc rigldlly In posteroeephalitic. ancriosclcrolJc. and idiopathic types of the diseas.e. liS effect on tremor is nO\. predictuble lind probably should be supplcnlCntoo by combination ... ilh ocher sinlll3r drup.

SynapIlC cleft

Transmonlng

.~on. ~IiI'Igl(' ~
Syoapdc',IIk:lu

" I ,-_ __ '/

~.

No _

R~

Transmitting tuon. w ..ductlng

No'

o
o

eo"

NeurotnlnltlVllers tMnd 10 Itc~ kMung the pOeb)'flllC:ltlc ahe and causlog the veceMng f'I8'UI'Of1 10 trafl$lTlile -.gnal

-,a a-

fig ure 20-1 1 Rl'pI'eser1UIlIOI1 of the actIOn of a rlNrotransmltteo-

lie llI:uron may rcsu It in eilhcr ~csklc formal ion or thc nCllrotranS/lllucr IItlllg tr..nsponed 10. and metabolized m.1he mi lochQlldria of lhe cell. Many drugs act by imerfaing wi lh either Ihc symhesi s and/or actlOll and/or metabolism of the nc:Urulllln.nllm:r. For example. the enkephalim arc be lieved to acl as elldogcIIQll~ painkillers by inhIbiting , ubslnoce P. B ncul'QlrallSlllluer that tran~'nils pain signal~ across lhe synaptic cleO. II i~ Ihou!;hl Ihal the acUVaiion or B JllIIIl-Ir.msminmg neuron callSC:S both the pre~ynaplie and po~l5yllapcic ncuron~ to rclcasc enkeph;tlilb. The enkephaliros produt"Cd al the J'lfI:S),napljc ~i'e mh ibl1 lhe release of Subst31lCe 1'. " hlle Ihose produced nl lhe posIsynaptic sile hypopolari/.l: lhe poiilsynaptic rn~rnbr.U1e. which makes It more diffiell1c 10 generate !he ~ynaptic action potential in Ihe rccc il ing neuron . Olh.cr dru!;s act by replacing the nc:UI'QlI1U1'lIllllcr.

SOllie !lellrotnlllsrniucl'll. sU("h as gl)cinc: and }"amilKlbf. tanoic a.:id (GABAI. act as Inhibitors by openi ng ioI channels and alloWing ions to now into !he IICUTOIIca. ing hypapolaril.lliion . This llIakes the internal flla Q(. membrane n:lali \ ely IIIOI'e el~runcgal i\'e, aoo so I h r _ requires more inlc n'iC dcpol~ri7.ation if il is to lransm,ll ~ignal. Elhanol i~ belie."Cd 10 lei by indueins GABA rctqItors 10 open lheir CI - ehal1nc:l~ in the brain. This IOhiblls tilt neitabi lily oflhe affccU'd neurons and so reduces Illl'ir.wil), 10 IrJJlsmi l nen'e "npolses. HOll e.ct, the ability 011 neurotrJn sminer to ei lhc-r excite or inhibil a IlCIITI)I1 appea1 10 depend Oil the rulillre of its I'CCC'pfOf rathc-r than tlS_
lUre.

Transmillct-gllled ("hannels arc iOll sclc<:IiI e. and thcir If> ceptor sile~ are highly sclCClive for a pan icular ~ miuct.' The I1I'llI 10 be eharacleri1.cd was the IIttlylcbolil!

TABLE 20-1
Am Ino Ackts

E.a mple, of Neurotransmitters

Small Pe9tlcles
II.Try-{".l)-Gt) PbtMtI\OIlJ M1-CnI:t.....lln

H,NcH:zCH~HzCOO~
'tAlnonotlulanoor;: acid fGASA)

II

Try .OI)-Gt~_1'IIc

t.<'ll(OIl I

..... ~'n

",NC" 'cH:iCOOH
Gl.ltamIc: acid

. ;:00-

ThIs drug. mtroduced In 1957. is II potent anticholinergic, prodllCing atropinelike effects peripherally. E~ cn wilh its quau:mary nature. ,I docs no! cause' s)'lnpalhelK' blocl.ade at [he gonglionic level except m high tio5.1ges. 118 p'.tloClpa l lliSl:mgu,!ihmg feature is ils long dUTatioo o f action. A single cb\e can provide anllspasrnodk and anll!iT'l:IOI'y effectS for long as 12 hours. It is used as adjunctive thc:rupy In the treatment of peptic ulcer ~nd Ulher cOlldil lOIlS of the GI II'1II,:t asSOCiated with h)'JICrnlOtilily and hypcroci<hlY. II h.as the u!>U3.1 side effecl~ of anucholrncrgics (dryneMI of mouth. mydriasis. diffic.:uil urination) Ilnd is cOlllraindicaled 111 g loucoma. prostatic h)"

000. by a phenothiazine (e.g .. ethopropazine): and by " Ihioxan lhene structure (e.g .. mcthix~ne) .

third.

penrop/ly.

CIC.

, ,

" ,.

,f

,r

,.

Troplumidf!. USP. Tropicamide. N-ethyl2-pIK' nyl-N[4.pyridyl melhyl)hydrac ry lamide ( Mytlnacyl), IS an cffee b'"e antichol inergic for ophthalmic U!iC when mydriasis is produced by re laxation of the sphincter muscle of the iri~. allOWing adrenergic irmervllhon of tile radial muscle to dilatc !he pupi1. Its ma... imu m effcct is achicved in about 20 10 25 minutes alld la$l5 for about 20 minutes. wnh complete ltCO.ery in about 6 houts. lis action is mon: l".Ipid in on!)Ct and wears off II10fC l".Ipidly than that of most other mydri:un. Tu achlcve mydnasi~. either O.j or 1.0% coocentratiOl1 m:&y be used. though cycloplegia is achieved OIlly with the I!n1I'lger solution. I ~ u,';('s are much the same ;l'l those: deImbed boove ror mydriah~ in general. but opinions dIffer OIIl1bethcr1hedruC is 3$cffecu ,'c as homauupmc. (Ofuurnpie. tn achieV in g cyc loplegia.. For mydrlutlc uo,c. howc,'cr . nammation of the fundus and treatment of acute iriti~. ndoc:ydili ~ . and ~crnUIIS. il IS qUilt adequate: and because of it, shorter durat ion of aclion. It is k~s prollC to in il iale a II!oC in inlroocuJar rressure than the more potem. 1000gc:r\bung drugs. As wnh other mydrialics. however. pupil dilaIl'Il can lead to i~ased intrnOCular pt'USure. In eomtllon _ilb OIhcr m)'driauo.. 1\ is COf1tlUltIdicated in paticnUl wnh Ibl>Coma,eith~ r known or~uspectc<.l. and should 110t be used the I~eso:ncc of a shallow anlerior chumber. Thus far. 110 allerJ;it n:actions or ocular damage ha.~ bc:c'n observed wilh *rIsdrug. 'The ability to clone the variOU) muscarinic rcccp1;11 wbt}pc$ has allo ...ed the ob...crvatiOQ that lropicamide ball modest selectivity for the M. rccCplOf.TI

Oiphemanif M ethy/luffate, USP. Diphc:manil methylsulfotc. 4-(diphenylmetl1ylene}-1.I-dilllcthyl pi peridi niulll methylsulfate (Pr.mtal). or diphemaml methylsu lfate IS a rotent choli nergic block in.!! agent. In the usual dosage TlIllgt il acts as :lI1 effecti ve parasympatholytic by blocking nerve impulses at the parasympathetic ganglia. but il does 001 m \'oke a sympathetic gangliOl1 ic blockade. It IS c laimed 10 be highly specific in IlS actiOfl on those innervations that acti vale gaslriC sccrctioo and GI l1lO(ility. Although tl\is drug can produce atropinclil<c side effects.. they rarely occur at recommended doses. 1lte highly spccir n3tun: o f liS acllon lC un g~~tric fUtlClions makes the drug useful in tlte tn:atmcnt of peptic ulcu. and its lack of atropine like effects makes ils use much less di strc!i.SlOg than other antispasmodIC drugs. In additiOl1 to its act ion in decreasing gastric hypennoti lity. diphc:maml melhylsulfate is nluablc in h)'perhidrosi~ In low doses (j() mg tw ice daily) or lopically. 1ltc drug is not well absorllcd from the GI IntCt. pan icularly in lhe prt.\Cr1CC of food . and should be administered bctwn lneals. 1l1c melh ylsulfalc salt was cnosen as the best bc<:ause the chloride IS hygroscopiC and the bronmk and iodide iOlls ha.c u hlbited tm ic manlfestalions in clinical usc: .

CH"so..

,.

w.

Ethopropazine Hydrrxhloride, USP. Ethopropa.dne hydrochloride. 10-12-{dicthylaminu)propyllphenolhiazine monohydrochlonde (P'Jl1>idoi ). IDtrodllCed to thenpy in 19j4. has antim uscarinic activily and IS especially useful in the symptomatic tn:atment of parlinsoni~m. In this capacity. it has value ID controll ing ngidily. and 1\ also has a fa",,,able effect on tremor, sialorrhea. and oculogyric cri'\eS. 11 is used o ften in conjunction wilh other :mu parlJ nSOf\ian droSS (Of complementary IICIlVily.

T.~

lIKellAftll!DUS
IiIthcf stnIClUral modificat ion of c la.\sic umimuscarinic aplS can be found in lhe drugs described be1ow. Each of mem h.:t~ the typical bulty group characterislic o f the usual .mcboIincr,ic molecule. One modificalion is rcpre...crlloo ., the diphen)'lmethyl~ne moi~ty (e ..!!., diphc:rnani l); I sec-

586

Wi/.wn ,,,,,I Gin'Old', Tv.11>oo

of Organi<' M~dicultll and

PloamlOCflljlcai Chr..w"'l

Side effects are common \I Ilh Ihis drug bul are usually 001 ~\'cre, Drowsines~ :md diulIlCSS AI'C tM most common Side effects at Ofdinary ~ le\els. and as the dose in tTeII~. xerostomia. mydriasis, and otheo; become evident. It is COIltl1lindicaled in COIldillon~ such as gluocoma becausc of lIS mydriatIC effect.
Pilpa~rlne Hy drochloride, USP, Papal'erine hydrochlonde, 6, 7-dirnctho~ y-l-verutryli\Otjuinol ine hydrochlo-

are located near the ot"gIIIlthey inncrvatc and ha\ c preg~II'

onic fibers that st~m from the Ct'rviC'a1 and thomcic reglOld of the Splltal cord. S\"l''f1(Jlh~ric gallha conSiSt of 22 pa!IJ that lie on either side: of the vct1cbral column to form IaItral ch:lI ns. These ganglia are COIlnccted both to e;loCh OIhef b) ncn'c t!\lnks and to tM IUllloor or sacr.ll regIOns of the !iplfIIII cord.

ride. was isol:ttl'd by Merck in 1!!48 from opium. in which it occuo; to tIM! extent of about I", Al though its natural origin is closely related to morphine , Ihc pharmacological actioM of p;tp.lverine hydruchlonde are unhi.:e those of morphiM, Its main df1 is as a o;pasmoly uc on snlOCM h muscle. acunl as a dll'CCl, I1OI15pccific reluant on Iascular. cardiac, and other :.mooth muscle. BC('ause of its broad antispasmodic actioo on ACh muscannlC I'ttC'ptOMl, it is often called a IIOOSpttlrlC :lnmgoniSl. Papalc:rlne hydrochloride has been used in the tre:l1ment of ptripltcl'lll vascular dlSQkrs. but liS use is limited by lack of poI~ncy. f'apalerinc hydrochloride interferes .... ith the mechanism of muscle coot11lCtion by inhib iting lhe cyclic nuc leotidc pllol;phodiesterascs in smooth mUloCle cc ll ~ re~ponsiblc for conl'ct1i ng cAM P and cyclic gunllOSine mOllOphosphate (cO MP) to5'AM P and 5'GM P. respn.1h'cly. The increased levcls of cAM P and cGMP aro associated wuh musclc relaxation through lheir phosphor)' latioo of myosin lighl-Chain kinase.

He'

GANGLIONIC BLOCKING AGENTS Autonomic ganglia hove been thc ~ubject of interest for many yCliTS in the study of interactiUlls between drugs and I1CnOllS tis.~ucs. 1lle fil'S! imponam account' "'lIS given by Langley and described the sli mulming and blod:mg actions of mCOIine on sy mpathetic g:tnglia. II wa~ round that small amounts 01 niCOline stimulated ganglia and litcn produced II blocbde of ganghol1lc transmission because of ptTSislent depohuization. From these e~pennlCms. Langlcy was able to outline the generil pattern of innervation of organs by the autoroomlC nervous systcm.lumn't/lIKlI"~rk ganglia usually

Usmg the syrnp'::Uhetic Ct'rvical gangllOll lIS a model It\'caled tltat transmission in tM autonomIc ganglloo ii moo: complex Ihan formerly be lieved. Traditionally. !>Iimuilliol of autonomic ganglia by ACh was considered 10 be tilt nICOtinic action (If the neurotransmitter. It is n(lW undm.lood Ihal stimulation by ACh produces a lriphasic re.~poose ill sympathellc ganglia. Impul5C transmission through lhe glion occurs .... hen ACh is relea.~ from pregonglionic!ibm and acti yatcs the N: nicotinic fttCptors of the lICurotl31_ bronc. This lriaers an increase in sodium and poI:ISoSilD conductanceS of a subsynaptic lTIC'o,brane, resulting ill. imtial excitatory postSynaptic potential ( EPSP) \11th. IItencyof I milli.~. followed by an inhibitory pos15).,. tic poIcminl (fPSP) wllh a l:tlCncy of 35 mlliisecolW.b. III!. finally. a slo",ly gcnerating EPSP ",ilh a lalency ofiltlm! hundred milli5CCOllds. 'The ACb released by PfCgalIglK* fibers al~ ac1ivatt\ MI mllSCllrinic reccplOOl oftheganJlm and probably of the smallintensity nuoresce.,. (SIF) cd This re<;ults in th(l apptatarlC(l of ~ slow 11'51' and alluw i! PSP in thc neurons of the ganglion. XI The inillal EI'SP. blocked by conyentional compctitil'c nondcpolaril.in, pili ionIC blocking agenlS. such as hexamethonium, ~nd is COl' sitJc.ored tM primary pathway for ganglionic trallIM.lOlThe slo\lly generaling or laIC EPSP i~ blocked by ...,. but not by the u'adnlonal ganglionic blocking 19cnb. 1'IiI receptor has mUIiC.nnic propertics bccau~ ~ C3usesge~l'lItion ofthc I:uc EPSP without cauSIn, the~. "Pike ChamctertstlC of ACh. Atropinc abio blOl'b ~ EPSP produced by methacholine. There may be mort tbt one type of muscari nic receptor in sympathetic ganglia. AIropine block5 both high-affinity {M ,j and low-affi mly 1M muscarinic receptors in lhe ganglion. MI In additiCll1Q tir cholinergic p.:nhways. the ctrvical sympathetic ganglKIII a neuron that contains Q catccOOlaminc.~2 These IICUlUNi cells. identifitd initially by nu orescence hlstochemicallllJd. ies and \ OO"'n to be smaller lhan the postganglionIC IIC1WtW. arc now referred to as SIF Ct'lls. Oop:imine has been rted as the nuorc.~em catC('hoiarrunc in tM SIF an. IIl'C common to Dlany other $)'mpatlx:tic ganglia. Dop!G II apparently mediates an increase in cAMP. \lhlCh CII\IIeI lippcrpolarization or postganglionic neurons (Fig. 1719). nr IPSP phase of the transmissioo or sympatitctic pngh' lowing ACh adminlStJ;ition can be blocked by both . . . . and a-adre~gic blocking agcnts.l"1

,III'

'qangli~,1OOli

Musalmc CIdii ..gIc

22 pall-';' III lateral other by he splnul

PRE GANGLIONIC CHOliNERGIC FIBERS

-+
I"" , ,

""-blocked -t
~
,
bIod<ed

" N,cotlnie ChO\\ne,Qi POSTG.\NGUONIC NEURON

by he>comeltlOniom

IEPSP .EPSP
.IPSP
POSTGANGlIONIC SYNAPTIC

by

COPalll/n
-

.\lupi...

f-bloo'l"" by """"""'viC ..........

IIt'IIegOnIIIS
~,

'~Ic

DOA\MINE

nodc:l reJ is niOl'e

...
IIlropone

eomrrw.s

lIIlulation

Lhe lli~'Q ,",,,,,ood ;ponse In J IIle gan-

""

-1-blocked by

f igure 17- 19 Neufotransmosslon at the sympathetIC ctrl'ical ganghon .

fibers amem)l.)USSium lIII: In an "'1m a \0~~n:lp

~IC

)IIds_ and. 0( se\'eml

;anglionic : pnglioo SIF) cell. ad a slow

i~

UEPSP

wilE gantnd is con1II'j,Sjon.1IO ,. atropine ~. nils doKholine :lheinltiul u the late IIIOfe than IIIgha. AtIinity ( M 1 ) ion 10 the !Dghon has ~ llCuronu l lllcal studic neurons. <'Cft idenu : cells tMI

If. similar nomrncinional type of gungltomc Ir.!nsmission IIC'tIn III the parasympathetic ganglia. it has tJ()( yet become rnde!lt. With the anatomical and ph~toIogicaJ differences bd,,'a:n sympathetic and para~ympat hellc pnglta. II shou ld lot no 5I.Irpi<;c thai ganglionK agems may show ~ sc leeu'ity bet"'ttn the two types of J:ungha. Although we do noI ,- drug classifications such as "p:1IUSympa.thetic ganglie lillie bloc~ers" and "sympathetic ganglion,c blockers:' we 010 fil'Kl that cenllin gangl ia have a predominant effect over mum org ans and tissues and that a nondi scnminant block.:Ie of ~u l onOlll ic gangl ia results in II ehun~e in tl>c effect ((the autonomic I"lo:r.'ous system 011 th~1 orglln (Table 11-1). Sane of lhe commonly known gauglionic blockers has yet

been Identified as a 'iCleclh'e blocke-r of parasympalhctic ganglil!. Van Ro<Osum u ,,, has ~~ie .. ed the mechalll~n~ of ganghonic synllptic trurlsmission. the mode of IlCllOn of gunglionic ~lImulwll$. and the nlOdc of lICIioo of g~lionic bloclmg agents. They ha\"(~ been classified as blocking agents in the folloVr lllg manlier .

Depol.rtalng C...gllo .. lc Blocking Agents

Depolnrilill g blocking agents are actually gangliOllic slimu lant~. Thus. for nicOline. smail doses give an IIClioo bimilar to Ihrn of tl>c naluruJ ncuroc:ffeclor ACh. an octioo known as

TABU 17- 1

Resultll of Ganglionic Blockers on Organs

R..... lts of Ganglionic Iloc:kade

C~ul .... ~ .... m H.~n

hr,o'ympMlleck

Tl<hycanJo.

Anorit>ln

v.,,,,,

Syn"""''''
Sy~
r-y~oe

Vuodit.uon

o.lol'''''

,~

au.es hy -

""""", oc

G'_ I;ri....,.
Jril

Cit""l' lI1ItI('it blgler

''''

''''''''''' r_}'1IIPIIlbotoe
hl",,~
hl*'J.~

119). The :angJi:l fol1111 atropillt

SoI"..,-(I"
s_&'-dl

._ ..", .n .

'-""'"
AOo.
""of;) ....... ooL so, ' - c. v

."'- .......
Urinary .elc

c"""'..

M)'Jn.. ;~

0.,""

l_u.o..A.: MIo<oI,.,.

1otooI. 1m

!he "nlOOl:i nic effect of ACh." Larger amounts of nicOline. ho ....-e\I:r, bring about. ganglionic blod: char.!Cteri7.~ iniuilly by depolariz.luion. follo ....ed by typical CDmpcliti"e Intal!ooism. T o ronduct nerve impul5Cll. !he cell must be able to elIIT)' out a polariution and depoluri7..ation proces$. and If the depolaril~ COI1dition i$ maintained witOOuI repol&ri7.11lion. obviously rIO eonductioo oceurs. ACh itself. in high conce ntration. will bring about un autoinhibilion. Chemicals thai cause Ihi s type of ganglionic bl ock. are IlVt of therapeutic si&nificance. The classes of ganglionic blocking agents that are described are therapeutically IISI:ful.

' N -(CH,),

I T(,)fI
. N -(elol",

n 5 (I( 6. actrve" gar.gliot1ic bIodI.lItt (feeble eurariloml ..dirt,') 2&n 9 to 12, weak ganglionte bIod..
(strong curariform acttVlty)

As sllo.... n. thei r findings indicate that there is a cntg disTancc of about fi ve tt) si ~ carbon atoms bet ..... een the IIIIlum centers for good gU Ilglionic blocking IlCtion. Intcrc~t,"gl). the pemulllcthyk:ne and hexamcthylcne ConlPOUndS arc d fcctive antidote.' again,t the curare effCl,:t of the (Iec'llllclil) lene oornpound. He~wnelhomum bromide und he:xamdhonium chloride emerged from this rescan:h as cllIIically 1Iid11
product~.

No .. d.palarizl. . Cass p.tltI_ C- ..gllonlc alockl... A.lluts

Compounds in !he class 0( oondepolarwng rompelitl"e gan. gllonic blocking agents possess the neccss.:uy affinily 10 Ill tach 10 the nicot.inic receptor sitcs thai are specific for ACh. bill they lack the intrinsic actlvily necessary for impulsc trnnsminion (i.e .. !hey cannot effect dcpolaril.alion of the ce ll ). Under uperimental oonditions, in the prescnce of a fi~ed concentration of blocking agent of this t)PC. a large e nough concentration of ACh can off/oClthe blocking octiun by competing successfully for the: ~pecifi c recepton. When such a ooncc:ntnllioo of ADl is administered to a ganglion preparation. it appears Ibal. !hi: intrin sic activit y of !he ACh IS as gn:aI as it was when no anlllgoniSl was present. the only difference being in the 'at&er concentration of ACh required. It is evident. !hen. that such blockmg agents are "compehth'e" with ACh for the specific recepton in\'oI"ed and that either !he agoniSi or lhe ant.:lgooiSl, if present in suffIC1cntconccnlrnUon. can displatt the Other. Drugs falling IIIto thi5 class an: tctnlCthylamrnonium salts. hc~ametho nium, and trimcthaphan. l\1 ecam}lamine posse.'I.'iCS a cornpeti livc comporlent in ils action hut i~ also IIOrlCOmpetilive. a so-called dual antagonist.

lIIo..depolarlzl... Noncolllp.tltlve

CanglJo.k alocklng A ....ts

Nondc:poIari1.ing TlOfIOOI1lpetitivc ganglionic blod,ing agents produce !heir effeetnot I t the specifIC ACh leeeptor sitc but 111 somc point farther along !he chain of e~nts that is 1ICCaSIll}' for Il"IIlSm;ion of the nl''''IC impul sc. Whc-n the block has been Imposed. in.creasing the coocenttation of ACh has no effect; thus. apparently. ACh doe~ not act cornpelltivcly ..... lth the blocking agcnt at the same rcccpton. Theoretical ly. a pure noocOfllpetitive blocker should ha\'c a high specific 3ffinity for the IIOrlCOmpelitivc rccepton in the ganglia and a very low affinity for other cholinergic synn pses, together with no intrinsic activity. MecmnylUluinc , Q mentioned S above, has a ooncompetitivc component but is also a compet itive blocking agent. The first ganglionic blocking agents used in therapy ..... ere tetraethylammonium chloride and bromide. Although one might assume thai curariform activily would be a delerrent to their use, the curariform activity of !he tctraethyl compouod is less than I ... of that of lhe COltc."pooding tet~th ylammonium compound. A few years .fter thiC introduction of !he tetraethylammonium compouods. Paton and Zaimisu inycsdgaJ.ed the uscfulness of the bis-trimethylammonium polynlCthylc:nc: salts:

Tnmcthaphan camphorsulfonate. a mo no!;ulfonlum ~ pound. bean; KNlIC similarity to the quaternary WIIIt1OtII. types because It. too. i~ a completely ionic compound. Although it prod~ a prompt gangJion-blocl.:mg actlOll III parenteral 1II,tlJon. ,ts action i.s short. and 11 is usa! ~ for controlled hypotension during surgery. Aln~t "molIMCOUsly wllh the imroduction of chtonWOOanllllc (_ long removed from the market). announccment ..... as m:tdr ri the powerful ganglionic block ing action of mecamylanl1ne.1 secondary amille ...ill1m" qUluemnry anllllonlUm ctunM:1tI. As e~pected. the 1~I1Cf compound showed unifonn and J1If"' dictable absorption frum the G I tract as ....1,'11 as I kqa durntion of action. Its action was s imilar to that of i1exllflldll. onIum. DnIg5 of thi S class hl,'e limited usefulness as diagncMK and ther.lpeutic agents in the management 0( pcnp,'-oc,aI . . cu lar disca.<;CS (e.g .. thromboangiitis obhter.IIIS. Ra)'llM'I dlseMC. diabeuc gangrene). pnncipal ,l"It:l1Ipeutic Ir.:'calion ha! becn in the IreaUnent of hypenen~ioo LIm"tIP block.ade of the sympathetic pathway . UnfortuM!Cty, III! action is nonspecific. and the parasympathetIC gangha. ... voidably. are blocked simultaneously to a greater Of ItWI extelll. causing visual disturbances. dryness of the ITIOlIG. impoten.ce. urinury retcntion, and constipation. Con~tipal,ca in panicu lar. probabl y caused by unabsorbed droll in ttr inlestine (poor absorption), has been a drDwbacl bt(4( the condilioo can proceed to a par.llytic ileus If CAtm-nUM is not exercised. For this re:l.SOll. cathart lC'i or a ~). . thomimctic (c.g., pilocarpine nurate) is frequently tned simult.:lneously. AllOIiler l!d\'CTSC effect iI' the prodIo: ,ion of ortOOslllllC (~'UTllI) hypotension (i.e., dim.! when the patient ._Iands up III an creel ~itioo). I~ admini'lrallOll of the ganglionic blocking agents !'\'Wls di minishe:d effCl,:tivenc....~ because of a buildup of 10''''''' though s.ome an: more prone to thi s tllan others. Bcc1u.ttl the many :;crio us slOe dfects. more effeeli"e hyp<lltllCf agents have reploced thi s group of drugs. In addilioo to these ad"crse cffects. there arc ~vml bIi t.:ltions to the usc of these drugs. For instance, theyan' tmndicated III disonkrs charocterized by severem... of blood flow to a vital organ (e.g .. sc\cre coronary . ciency. recent myocardtal infarction. n:llnal and thrombosis) as .....ellis sltuatiOIiS in v.hich there lind... large reductlOllS III blood ,olumc. In the taller. the dication exist~ because the drugs block 11M: normal. strictor compensatory mechanisms ncccssary for hOIl- sis. A potentially serious complication. cspecillly III male patients with prostatic hypertrophy, i~ unnary

n.c

Chaplu 17 CItol,n,'7lic O"'IIJ uml R,/u/(d Agr",.

S89

....
:nue;!) olllum lingly.
&It

1IOn.111ese drop shoukl be used with care or IlOl 11.1 all in \he presence of renal insufficiency_ glaucoma. uremia. and OI'ganic pyloric 5tenosi~.
T rimerhaphan Camsylate, USP. Trimcthaph:m camIylatt, ( + }-1.3-diben1.)' ldecllhydro2-u~oi m ida1.or 4.5()lhieno( l ,2 - II'Hhiolium 2'oxo- l O-bomlmesulfonate (1 :1) (Monad). consi5lS of ",hilC crystals or II. cryMallinc po ....der "ith II biller Ut5le and II slight odor. II i~ soluble in wllter IIId alcohol bUI ooly sli ght ly soluble in acetone and ether. The pH of II 1'1> aqueous solutioo is 5.0 10 6.0. This ganglionic blocki ng agel\! is sIlOI'IlICllng and is used fOl' certain neurosurgical procedures in .... hrch excessh'e bleedi ng obscures the operative field. Certain craniotomies lit included among these OP(:I ations. l1le action of the drug di~ vasodi lation. and becau)oC of its transient actlOll. it II Wlbjectto minute_by_minute control. This neeting action. booA--C:"er, makes it use less for hyperte nsi ve cuntro1. 11lc drug it iodfective when givCfJ orally. The usual route of admmisntion is IntnvellOUs. T rimcthaphan camsylate is indicated ., me treatment of hypertcnsive ernergencics to reduce blood pressure rapidly. These emergencies may include pulmonary ~)'Ireru:ll!iion associated wilh syStemic hypcrtension and IaIIC di$SOCling aneurysm.

NEUROMUSCULAR BLOCKING A GENTS

of ACh al the moIor end plale a.e called "ruromuscu/lJr blocking lJgrnlS. 'The therapeutk use of these compounds is pnmarily a~ adju"anlS in surgical anc.~thesia 10 obtai n rclUht ion of ske letal mu!iCle. They also Dre used in various orthopedic procedures. such as alignment of fractures and com:ction or diskx:anons. 'The therupeutically useful compounds in thrs group !iOme ti mes are referred 10 as possessing ('urarifQrm or cururimi Iffnic acthity in referetICe 10 the original rcprc.sC'ntoti\'e~ of the class. v.hich v.~ obtained from curare. SInce !hen. synthetic compounds have been prepared with Simi lar activity. Allhoogh all of the cumpounds falling into this category. nalunJ.I and synthetic alike. bring about su~tanlialty the same end resul t (i.e .. volunuuy-musclc relaAation). there ar~ some significant diffe('('1lCe$ in mechalmms. The poU;ble e~istcnce of a junction between muscle and nerve was Sollgge51cd as early as 1856. when Claudl: lkmard observed that the si te of action of curare .... as neither the nerve rKIf the muscle . Since that lime. it has been agrttd lhat ACh mediates transm ission at the ncuromuscular jul1Ctioo by D ~l,K.'nce of events descnbcd above in this chapter. 1lIc: neuromuscular junction consists of the &.lon Imprn.@inlontO a ~pialil.ed area of the muscle kno .... n as the muscle end plale. The uon IS covcred with a m)elin sheath, cOHUlin;ng the I1OlIe.'l of Ranvier. bUI is bare at the ending. The nerve terminal is separated from the end plale by a gap of 200 A . The su~ynaptic membrane of the end plate ConUli05 the cholincrgic receptor. the ion-conducting chnnneis (which an: opened under the innllCnce of ACh). and AChE. One of the anatomIcal diffCT'tnces between the neurolllUicular junction.nd od1cr ACh-responsi>'e sitd is the absence in lhe ronner of a membrane barrier or sheath that en~elopcs the ganglia or constitules the blood - brain barrier. This is import.ant in the accessibility of the si~ of action to drugs. particularly Quaternory ammonium compounds. because they pass through living membranes w'th considerably greatcr difficulty and selectivity th:m do compounds tluit can niSI: in a nonioni~ species. The es.stntially bare nature (i.e .. lack of lipophilic barriers) of the myoneural junction "ennilS ready IICCCSS by qUDternary ammonium COmpotlnds. In addition. cumpounds with considr:rable moleculardimen sions are accessible to the IceeplOl'S in the myoneul1l1 jutIC lion. As a ('('suI! of this property. vlltlations In the chr:mical ~truc\\Jre of qU3tcmariC$ hal'e linle innucnce on the potential ability of the molecule to reach the cholincrgic receptor in the neuromucu11I/' jUllCllon. Thus. the following types of neuromuscular junction blockeT$ have been noted.

A~nlS thaI block the transmissioo

cf-

11C'lhy~'ho

useful
n comlomum 00. AI,lOll 1m ~ only

5;lIIul-

"'""'.,
t

(nov.

mille,

II.

"'"

anclcr.

"..l()f1a;cr

<aJllelht.gnOStlC

:rnl

"II~

ynamrs

Ie aPI'IiIhrough ltly_ lhe: Iia, ulla;)I" b!>C"r

f " -

-'CH,-N

N-CH, _

: IUOIllh.
In

.1Ip;l1l0n.

the

becllU!o('

Tflmelllaphan Camsylate

enlC~Me

-asympaprodUc"

admin i ~

lil1inc"$ rohmgt-d esuhll 11\

oleranet'. cellUse of

polcn~i\e

Itfeumylamlne Hydrochloride. The secondary amine 1ICQrll)' lami ne II ydroch loride, N, 2.3 .3-tct ra mcth y 1 -oorb-2 IIAWrIIIlI! hydnx:llioride (In,~ine). has I powerful ganpiorIic blocking effect that is ahnOi!Ot identical to thaI of he_a.tbooium. It has an advantllge over most orthe ganglionic bIodrng agenlS in being absofbed readily and smooth ly from 6! GI trlIt'I. It is nrcly used. hov,ever. the treatment of jiJdtutt-to-severe hypenension because severe OfI~tat ic Ifpw'nsion OCCUR when the drug bloc~~ 5ympalhetic gan-

rot

eral linuCUll'

"'CH.

Nondepol.rtzlng Blockl... Ag."ts

Tr.tdi tionally. nondepoluri:ing blocking agrlllS is a term applied to calegorize dnolll that compete with ACh for the recognition site on the niCOl' nic ra:eplor by pre"cnling depolarization of the end plate by the neurottansmiller. ThUs, by decr'r;lIliing the effective ACh- receptoroombirumons. the end plate potenlial becomes too small to initiate the propaioted aetion poIent'a!. T his rc.~u lts in paralysi s of neuromu~ eu ill/' tl1Ul:Smi.'lSion. 'The action of thc:sc drugs is quite analogous 1 that of atropine 81 the muscarinic reccplOl' sittS of 0 ACh. M:m)' experiments suggest that the agonist (ACh) and

,a~

reduction )' msuffiCf'rcbrnl

3\1:

He'

bc'en
CH.

contraln~a~on

1QIllCOSlaIn

older lry n:lcn

the :mtagonist compete on a Of\C-to-one basl~ for the end plate receptOl'll. OnJgs in this class are tubocurarine. dimethyltubocumri n.e . pallCuronium. ~nd gallami ne.

yellowish white to gra)'I'h .... hllc. odorless. der that is ~oluble In WalCT'. AqUC-QUS !iOIUIIOn~ or"~,, It) heat sieri li lmion. The structural formula ~.OC~(.:;:':.~:::;~' thought to be Ih.at of la ('ICe 51 I ....Ofl,: or Evcretl el al"t7 the SI1lICIUrt' i now that of lb. The monoqu lltemary nUlure of Ih thus has caused $Orne reaso;cssment of i 'i thcorctkal basis for the bloclm,l action. previously L~~umed a diqu31emary structure theless. thi, does nOl negate the earlier diquatemary nature of the molecule pro' i IICtion than does II monoqUlllemary nature imatdy fourfold tess pOIent than dimethyl dick). Further. (+ "ifoOtuhocurarine chloride (1c) h;to. the activity of Ib in lite particular te~t used.

D.po........,.., Blocking Agents

l)'Illgs in Ihe category of dcpolari/ing blocking agent s dcpolari7.e the membrnnc of the mU5Cle end plate This ckpolarilat;on I~ qUite similar to Ihat produ<.-ed by ACh ;tself al langtia and neurumu'\Cular Junctions (i.e .. ils !I()-(;alled nlcO'lmK: cffo!C\). ",ith tlte result Ihm the drug. if in sufficient ooocen tr.l.liOl1. evt:ntually .... ill prodlK'e a block. Ei ther smooth or mluntary muscle ..... hen challenged n:-pealcdly with a ckpolari!ing ugent. eventually becomes insc:n~illve. Thi s phenomenon i~ known as 1II(hYlm)'lI~ris. or dt's.mx;/;tp/;/)II. und is dcnlOfl.'itratcd convmcingly unokr suitable experimental conditions wilh rcpelued applications of ACh Itself. the resulls indicating that wnhin a few rmnutCS the end plate be t"Orncs lI\SCnsitive 10 ACh. The statements above m:.y imply that a blockmg aclJon of this type is clear-(;ut. but under experimental eondltiOll$. il is not qUite so unambiguous. because a block that begins with depolarization may rt'gain the polarized State even before the block. Furthcmlorc. ckpolaril.llhOn ind~ by ill(T('a.\ing the potassium ion conccntnlllon ~ 001 PfC,ent lmpu lsc Inm ~mlssion. Fo.-Ihc$c and Olher reasons. il i~ probably besl to consider lhe blocking action a dc:scn,itll,alion unt il a clearer picture eillerge.\. Drug~ failing in thi s clllSS are dl:camethonwm and succinylcholi ne:.

,,'0
7

' ,p

0
10'

"'" "

,
/"

" 2\ 1

a,

'"' 9
10

11
0

eM ... re and eM ...... Alkaloids

Onginally c..rou W1lll 11 term used to de!.cribe oolkcuvely tbe \'cry poIcn! arrow poiSOllS used sioce early lilllCll by the South American Indi ans. The arrow poi'i()lJs were prepared from IIUlllol:rQUS botanic J;OUn;e~ and often wcre mi.t!UR:$ of R\erJ) different plalll ell!tlICts. Some wcre poisonous by \'Irlue of a oonvulsalll lICIion and others by 11 paralyunt action. On ly the laller type is of value in ther~peutics nnd is ~poken o f ordinarily DS curare. Chemical investigQtit)ns of the CUI'lU'e!i .... ere 00( especially successful because of dlfrICUhics in obtaining authentic \OImplc.~ with definite botanic origin. Not until 1935 .... as n pUrt' crystalline ulkllloid. (/tubocurur;ne chloride, possessi ng in i:fCal measull: the parnlyll ng action of the original cur.are. isolaled from a planl. WinICTStC"if\Cr and Dutcher.... ill 1~3. i$Olaled the 'lDlT1e alka loid. TIley showed. ho""e'er. that the botanic source was Cht.mdool'flilrUiIIOJllnJ/omm (Menispermaceae) and. thus. prOlided I known source of the drug. Follo",;n! the de~'elopment o f qU3!lIitalhc bioassay nlelhods for dctenllilling the (JOIel'lC y of curare UtlOCIS. a purified and Slandardi7.cd curare wll.~ dc"eloped und marke ted under the lrude name: IntOC()<;lrin (purified C. 10tIII'1II0Sltm e~ t racO. the solid J;OIltent of ..... hich ('OIIsiSled of al~t one-halr( +}IUbocurarioe solids. FollowinG Ihcsc essentmlly pioneering dc\,clopmcntJ.. { + ,-tubocurarine ehloride und dimethyltubocurarine: iodide appeared on the tn:t.r~et as pure: entities.

" "-.,./ # "", " "

'"

"'"

"

0'

embarrnssmcnl cau!iCd by o'ert.los:lge. somewhat higher ooncentrJtiom. tl-tubocur.lnne the open ion ehannel lind add a ChoIineslerase I '~ Ily or fully. Often. I until the mJu.i mal curare oclion live orally membranes III the G I tract. and ;1 usually IS Injecled IIllm'eROllsly. d-Tubocunuine binds for o nly I mill isecond 10 "'~ lor. yet its pharmacological elTe.:t of mu-cle

' ' '::0;.:

Tubocurarine Chloride, USP. Tubocur.lrinc: ch loride. (+ )-tubocurarine chloride hydrochloride pentahydrate. is pn:P'I~ from crude eurare by a process of purification and erySlalliz3tKHt. Tubocumrioe chlonde occur! as a while or

duced by admmiSll'IItion 0( the "~,;~::r~:'::= wr~. IDSIS for up 10 2 hou~. ~ I the phannacokinetics of the droll. f/Tubocumrllk' intnl\enously. andIS dislributed proteins. lhe drug panmenrs. IIlcluding

al'~"""2!'~h:~~30~O~~77~]":~;~':~~~ '
I

ns long
TOI.I~h
",n

the

to be 1!'t\'ealed ;nun!: the It all had I). Neverr.ns that a rblocl..ing

I\approxmile

;0-

has Iwice

()( d tuOOcurarinc: is eliminated unchanged by the kidne:)'ll. Its half-life is 89 minutes. Tubocurarine:. in lhe fonn of a punned eXlr.tcr. was used fi~ In 1943 as a muscle r"daxanl in shoel.. thernpy fOl" mental dtW)n\tors. Its use marl<t'dly redu(:ed lhe incidence of booe and spine frnclu~ and dislocallon~ frum ~o'l\"ul slon s due lO~hock . Following Ihis. il wll.~ u'ied a) an adjUllC1 in gellC11I1 anesthesia to oblain complete mU'il:k rehtxation. II usc Ihat persists 10 Ihis day. Before il' use began. slIIisfoc lory musc le rela~alion in varioos surgical proccdur~s (e.g . alxk>mi nal opmnions) was obilltnable only wl lh "de~p" aneMhe!;ia "'Ith the: oruinary general an('sthelicw. Tubocul"1lline pt'nnitJi I liper plane of anesthesia, .... ilh no 5:OCnfice in thc: musck relal.lt.on so important 10 lhe: surgC(ln . A redOCM dost o f tubocurarine is admini~ered ",ilh eth('r btcausc elher ;lse lf l1li curve-like action.
IffefOCurine Iodide, USP. Metocun ne iodide. (+} Q.O'dmM."thylchondmcurnn ne duodlde (Metubll!e iodidl'). iipn:pared from natural crudecurttR: by extlllCling In.;, ~u~ "Ith methanolic potaSsium hydroxide . When lhe: ('."(trnct i. trela/cd with an ellces~ of methyl iodide. Ihe (+ HubocuraIIIlC I~ convened 10 the diljua lemm)' di Illelhyl ether and cl)'slalll1.es out as the iodide (S<ee " Tubocurari ne Chloride: ....-e). Dlher ethers bc.~ides lhe dimet hyl ether have been ggde and !('MM. For example. the: dibcn:tyl ether was oneIIurd as acil le as tubocurarine chloride , and tbe diisopropyl IlOIl1pOUnd had only olle-half!he OCtJI lIy. For comparison. *'t dUTlethyl ethc:r has approlllm3tely " time;!! lhe ao:.1ivily of ubocurarinc chloride. ~ phannacolo~ical aclion of th is ~ompou nd is lhe: 5IImc !hat of lubocul1lrine chloride. namel). a nondcpolariring tallf)"titi\'(' blocking effttt on lhe: ,noIor ('00 plate of skeletal wtcles. It is considerably more potelllihan d-Iubocurarine. illY/lever. lind has the added advPllIagc of excning moch k1s effeet on respiration. The effecl on respiratio n is not a ~IJlIIiCan l factor in ther.tpculic do\es. At'Cidentul ovC rtlOli ICC IS counteracted best by fOI"l.'ed re<,piralion.

Sr.,Ii . tIc: CoaapoMnds With eM, I.o.", Acth,lty

Curat"t. unul relalhely I"tCCnllimcs. remall10ed lbe only ~. ful cUl1ln lmg agent: and it. too. ~uffercd from a lad of SUt.ndardi/.lltion. 1lle original pronour".'cmcnt in 19)5 of the structure of (+ I-tubocurarine chloride. unchullenged for )5 years. led Olher workers to hope for octi> lIy III ~yntheti~ suhstanec.~ of le~s eompl('1\ily. TIn: (jllatemul)' Iltllftlonium chal1lCtcr of lhe curare alkaloids coupled Wi th the known activity of the I'llfious si mple onium cOlnpOIJlld~ h.ardly scemed 1 be coincidental. and il was naillral for rc<ocatCh 0 10 follow along II~ lllles. Ont' of !he synlhel.c cOlllpounds disco,'crcd WIl! markeled III 1951 as A au-dll (gallamme triethiodide). A vlriely ofOlhcrneuromuscular bloclmg agents ha>'(' fol lo .. ed.
A trlJcurium Sesy/a te. Alrncurium bcs)'late. 2-(2-carbox y~lhyl }-l ,2.3.4-lctrahydro-6. 7-diflletho~y-2.mcthyl-l ve IllII)' Jisoq u inolm iu m beou.enesu If onatc pc ntamclhy letIC ~ (Tracrium). is II nOlldcpolari:ting neuromu'\(.'ulor block ing agcnt Ihat is approximately 2.5 li mes more potent than rfhlbocumrine. Its duml io n of oclion (h~ l f- l ife. 0.33 hours) is much shoner Ihun thaI of d-Iubocuranne. 1"hc druG is 1111:laboi ized IlIpidl y and noncn1.ymatical ly 1 yie ld laudallO!iltIC 0 and a ~ majler ljua\(131)' rompou nd (Fig. 17-20). which do not have neuromuscular blocking x,ivily. [n "11m e~peri mcms show thaI alfilCunum bcsy[ale breaks down al p1/7.4 and 37"C by. Hoffman elimination ~ac1iOll." Atrncunum bes)I~le undergoes cn1.)'nl.lllic decomPOSlllon of lIS ester funcuon 1 yie ld an tnac1 ivc qualemary alcohol and Ijuater0 nal)' acid. AChE inhibilOl"5 such as IlCOIiligminc. edrophonium. and pyridostlgmltIC anlagonize par:o.JYMS by atmcurium besylale.

Ool(l)cu rium Chloride. 11M: mo lecul ar ~Iructure of 0011 IICUriUrtl chl oride. 1 .2.3.4-tell1lhydro-2.(3-hydro~yprupyl }6.7 .8. lrimethoxy2-lIIethyl.1 {J.4.5-lrimclhoxybenl.yl) isoIjuinoliniu m chl oride succinal e (Nuromax). Ilrov idc., the

agent u~ the: SlIe of ,ion;5 mh tbE mhtbilol""lo.

e(Ten~tIOll).

1 respmllOl)"

tllonally. In II: may enter ,e hlochde, !Tac1ion e;\~ 10\1 i. needed drug i. m1lc ()Ugh lipOIdal !I"lIpeU \lc1l1l)'

o
-0-5=0

II

to the: recepQl1II)sis. proIOUsly dUring tins :lCUOIl \\ ,nnc is IlI"en tnd to plasma r.l1 body com . About 45<J.

2
AlIllCtJI'ium Besylale

HOUMIVI fLl MINAflON

ESTEll "'YDIIDL Y$I$

N ......

'i:H J CH"CO

OtC",,,,.Ot<

LNO'I

'If.

... .... N

CH,_CIt.CO.Otc "'z",.o.CO.CHJ'CH('"

o
rlgure 11- 20 Hoffmcm eiomln(ltlOfl and hydrolysis reactlOflS of attacunum possibility for to stereotSOl"llen: 4 d ,1 pail'l' and tWQ meSD fomJs . Of tile 10 stcreoisomcl'l'. 3 a~ aJl -lrims configur.nion. and these are the only active oncs.1I\I DoxlI(:urium chloride is 11 longoctin g I"IOIldcpolari li ng blocking ugenl. The drug difrcl'l' from drugs such as gullium and Jmocuronium in that it has 00 vagolytic activity. It i~ used 11$ D skeletal muscle relllllant in surgical procedure$ expected to Ia.<;.t longer than 90 minutes. Gal10mme triet hiodide, II'-phenen yl-tris( ox ycthy lent) ltrisltl"iethy lam moni II mI tri iodltie (F1:u.c:dIl). i, n , ~dctal muscle n:laxant that ,,"ulsbr bIOl. ~ illg lI('urumuscular tr.msmissi()f1 in a manner ~IIILt 10 Ihal of d -tubocurarinc (i.e .. II oondcpolaril.ing bloc .... ~gent). It doc s have some diffe rence\. however. II Iulol strong \'lLgolylic effel:1 and II Pl'r~iSlenl dccrea.'\C in IIi:I.<fI)muscular fuoclion aflcr 'ucces,ile doloCs Ihal Cllllnot be (I"olf CQme by chohncsler.tr.e Illhibitors. Gallamine mctluodidr al'\O has mU'iCurin ic alllagoo islic prope-nles and billlh .... grt'ater affinilY to the M~ rt'CCptors lhan to the MI n:d:\*i Thi ~ latl!:'r char.-cten~hc may cause ils stro<tll".I,oJ)"UCx lion ..... 'JIO

G.II.mine Triethiodide, USP.

co .

co

Ooucurlum Chloride

O-CH, - CH,-N-ICH,cH,).

,. ,.

_ _ ,e-CH,-CH,-N'-ICH,cH"'"

,.
Gallamine Triethiodide

TlIe drug is cOIIU"aindiC'dted in IX'Iicnts wilh I11Yhthcnia

p:nis. and one ~Id remember that its act ion is cumulllbl't. ...... ith CUI"llIl!. Tlle antidote for gallamine triethiodide nemugnunc:.

l'UIN ... ""

~,.

MivM:urlum Chloride. M,val'urIUIll chlondc: . 1.2.3AttrWIydro-2-(3-hydrox ) prupyl)-6. 7-dinlCt ho~y-2-mcth} l 1 ~),U-trirllCtho~) benzyljisoquinolinimn chloride. (E)4Oo.'t\Ild'OOlc ( MiviICl'OIIj. is a ll1i~ture of three sle reoiSOlIlCI1I. K InmSlrtllU'. cis-trims. :md rois-cis dicstel'1l. each of which \u I\l'urom uscu lar bl ocking propert ies. 11JC ciscis isomer is !boot Of\C-tenth IlS pot"nt as the other isonlCl1I. Mivacurium dIlonJe is a shon-acti ng nondcpolanJing drug used as an IIIJLIIICl to anc:sthcsia to relax sle1ctal muscle, The drug is ~dmlp.cd by plasma cSlcrases. and " i~ li ~c1y that amiclloRsItra.-.c ag,,1llS uy,ed as antulot"s could prolong rother than /rIa sc the efreels of the drug .

anhcholinesterases,ll!ld potassium ion compenti,ely amago-run: it, when:a~ liS ac1lon IS mcn:a~ by mhalallon anesthctic$ ~uch as Cther. halOl~, cnnUr:lI'I(',:md methol>nU1'1IJIC. Tlle laner enhancement in acti" il ) I~ espttially imponalll to the lIIlCSlhctist because the dNg is frequcm ly admHlbtcred Ib an adjunct 10 the al1('~thc. ic procedUIl! to the skektal musc le. Perhaps the most frequent all,'eN relK:tion to this agcnt is occasional prolongDtion orlhe IlCUromuscular block beyond the usual tilllc course. a ,iWDti(N1 that can usual ly be eontroll .. ..... ith ncosligmim:or by nlllnual 'd or mcchamcal vem ilatioll. since re~pirdtory dimculty is a promincnt manife<;tation of the prolonged blocking 1IoC1t0ll. As indicated. the principal use of pancuromum brormde is a.~ an adjunct to an.esthcsia. 10 Induce rclUJIalloo of ~~ek'tal muscle. but 1\ IS also used to flloCililate lhe management of palients undergoing mechanical ,enulation. Only C\peri cneed clinicians eqUipped with facilitIeS for applYing aruficial respiration ~Id administer it. and the dosage Mlou ld be adjusted and conlrolled care fully.

n::w

Pipecurium Bromide. Pipccurium brotllidc. 4,4'-( 3(1, 17 ,8-dihydro~ y -j (,..androstan2.8. 1 6P.ylcne)bi~ 1.1- d imcth ylplpcnlliniulll )d lbromi lk diatt1atc (Arduanj. b a IlOfldepolanJ';fllI muscle n: lallant s nnilar. both dlClIllClLll y and cl inically. to pancuron iurn bromide. It is a long-lIoCting drug indicated II..~ no !ldjullC! to alll'~thcsia and in patientS undergoing meehamcal ventilatIOn. Ve<:ulOllium Bromide. Vecurontum bromide. H3tt. 17(J-dl hydrox y -2p.pi pcridino--j 0-allClrosl PIl -16ft-y I I-rnethyipiperidlllluin brom ide d,a.cc:tate ( Non:uron). L~ the If'IOn()quaternary llllalogue of P.1l1Curonium bromide. It belongs to the clas.~ of nondcpoluriling nc:uromuscular blocking agen ts and produces eff('Cl.~ simi lar to lhose of dru gs in thIS clas~. It is ull',wble in the pre~ncc of acid" and undcrgoc~ gt'llJuDI hydrolysis of it~ ('Mcr functions in aqueous solution. Aque01.1' 'iCllution s huvc a pH of aboul 4.0. Th is drull is used mllinl y to produce skeletal muscle reluation dunng ~urgery and to assist in Ct)ftlrolled respiration :lfter gcncr.LI anelOthc~ia has been induced.

.....orh by tel" ,.imilar ; blocki ng.

. I t h a~ a

in Ileu m01 be mer;lethiodi<lc bulds wllh I receplor. goI)'uc LtC-

hncuronium Bromide. Although pancuroniul\l broale. 2,8.16(J-dipiperidino--50-wldrostalll'-J(t. 17,B-dlOl dla.:ztJI/;' dtnlClhobromide ( Pa \ulon ). is a synlhetic product. il ~ on the naturall y occuning al l alo1d malouctine. buill III arm'" poisons used by pri nu tilc Africans, PrlllcuroItIIIIl bromide acts on Ihe nicotin ic rccepiOf and in (he ion dianne!. inhibiting normal ion nU~l!S. ThIS bloding agent is solublc in water and i, marketed .ooncentrut ions of I or 2 mg/mL for int ravenous adminis. 1'bIII. It is a typical IlQIltkpolari7ing bloder. with a poLtIr:)' appro~im:Llcly j times that of (+ )-tubocurarine chlo,. and a duration of action appro~imately equal to the Itaer. Studies Indicate that it has Imk or no histanlllll'-releasIII potl'I'IIiai or ganglion-bloclinll acti " ily and thaI ;1 has IIIIe rifrct on the circulatory 'ystem. e~cept ror causing .1II"'t rise in the pulse rale. As one might e~pect . AOI.

Succinylcholine Chloride, USP. Su~.c in)lcholtl1(' chloride:. choline chloride succinate (2: I) (Aneetlnc. SucO!otnn). i~ Dwhite odorlc5s CJ),,'II1I1inc: substance that IS freel y 'iOlubk In water to g"c soIuli()fl.' with a pH of about 4 . It i\ ~table

CH,

H,

I
OCH,

t.4lvaeurium Chloride

o
CH,

O-C-CH.

II

,.....CH,

CH,

"-

H,C

II . H,c-C-O

'

./

2 B,

H,c
CH,

CH,

/
o
H,c-C-O....

II

"

Pipeculllm Bromide

CH,

O-C-CH,

Ii

,
H.C-C-O

CH,

./

H,C

. I
B,
drug, ~

Ii

./
Ve<;oronoum Bromide

in acidic solution s bul unstable in alkali . Aql.lCOU~ solunon, ~hOll'd be refrigerated 10 e!\Sure stability. Suceinykholine chloride is ch:iracteri/..ed by ~ "cry ShM dunmOR of action and D quid. reeo,cry because of II ~ ",pld hydrolysis afte!" injection. I! brillgs about the lypic3J muscLllar pamlysis calise(! by blocking nervous IrarumiSSKln al the myoneural j Unc1ion. Large doses may cause temporary respi f'lIlOI)' depresSKln, as with similar agcms. Its action. in tontrast with that of (+ )-lUbocumrinc, i~ nOl anlagonu.ed by rlroSlllmioe. ph),wstigmine, Of tdrophonium ch loride,

These amichulinc'ICrol.'iC
probably 1l}'droIYI.cd by

oclunlly prolong lilt

of 5OCCinylcholinc chloride.... hICh SUlllOitS

cho llllC~lcruses . of.Cllonorlhls cu~-Ji~e ~gcnt

is..aid,

urmeccSS3ry If The proper supponlVc mcilSul'C!. :arc

.,'11

Succinykholine chloride tuas I diS<lod\'amagc:, that the u~ual antidotes eaunol tennmate I t~ ti It is used as a muscle reluant for the slime i other curare IIgents. It may ~"", periods of relaxation. depending on

Chapter 17 ChoIi"'rwk o.vlfS aM RrlolM A.Jm1l

Injtclions are givel1. In additioo. il is ~uitable for COIllinuOlls LIIIr.I\(D0U5 drip adminisU1l1ion. Succinylcholine chloride sOOu ld oot be used with thiopcnw sodium because of the high alkalinity of the luuer. If IIW'd together. they should be adminiSfeft'd immediately after IlLiAlIlg; hov.en'f. scpamte Injection i~ ~feT1lble.

595

'" WIlliam<. P. O . eI .J.; I'harmoocIIoaY 2J In. 1992. 46. Gllbtl B T .. Md Lt.od'-. P. L.: J """' . . ..... E>p. 1lorr 26) IIJ J.

.7 ,

M.II.n..~.
IW . ~

4l\.. Ikn

,,,. ,,,.

a., C!Ioii....tera'" llIhil);l(ln In AI,.""i....,.' Ob..llot_ A..:k

Inllm'-_.I 1999 A.. II . V,_;ab, k . I" and To) Ioo-. P 8""",,,""'Y l'J;Uu..

R EFERENCES
I !We. 1111 , I. 1'I'Iarm;IoroI. E>p The.- 6; 147. 191 ~ . 1 1.",;. 0 A!'tb. Oa.amtt. (Pfl""F"1 1'9:lJ9. 1921 . ). ZoIIMorJ.... S_ ..as.,.lrt . I..IL"'-_ ~. Pk=_, . 16:5"1. 19')4 ~ Frw*. H. S _ ..... We-. w y : 0. ................y Soc. 204' 13). 19!1. S. lIilk. B ' AIIII~. Ite. PIIy'i<>!. )11, 1)9. 1976. .. \tIrbn. A In C......... C. U . Puou. 0 . and N~. 0 I.. I...... '. ~ Fu.ct-. A... dim. EI"..., ... Bu ..... 1. Cdl 19!IO. p. 191. 1. Cbani<'"" J. P.. O'~IIIt ...ThIo..-y. A_ >Old CIImnooII,. p , ScICtlC<! .

"")'WI.

s.t_"""

WU3S.I9&6.
.. Js'$ R_ ...L 1."' "",...1. A . N.(....). The Eat) .... ofBIQIocIcal

.. S.IUII. r B , ~ 164/l]. 1!iJ9.l II DI=i. J. A Bi<>!. Pl1""'-'149:1116.. lOG! 11 lbrIny. M. Dd. Pll"'iu""Y 49: 1U. 2001. IJ. Ouyal. II.. K. PI. EnJI. J. Mod 32 1:1022. 1~89 1-1 B_L N 1. M .. .. II ~ 17\SUfIIII.t12. 1 9SIl ~ tot.t>dII ... P CI 01. Prot- "".",..01 , Olft. ~. 7: 13. 1919. _. 1 Doods. II N. e\ .1,. ,..,.. l'IIonr'IIOOI . Oln , 1'IunNroI, 7:47. 19119. 6 11 Sames.. r J : LIfe Sn. 52:52 1. I'J
11
~

Mcllllnlleo. vol 3, New York. PktIum I"feoI" 19U . Rlflety. M A.. e\ al . Scie1ICC 208: 1445. 1\180.

49. &I, ldw<l, 1'1.. Prebal K.. and N.nn. M. Aft", ... CIorm. I"'. &I. 6: 61'. 1'l67 . :10 Ollkl,'bn', A . .:< 01. I 8iu1 Chnoo. 268:11083. 1991 5 1 Sloa{fe\'iJWl. A.. e\ Ill: J BIOI . o..m , 261116-40. 1m. jl. W,l ...... I. D. 11"""""" M A.. aDd C;; .. sbco-.. S 1 8101. Oorm. 2.10 149II. 1'l61 31. Ell,.. S.. Knyn. 0 .. and~. F L : J ~ >p. 1lorr 79' .lO9. I~l. 5". Eft' . A .. CI Ill. ,..,.. Blain II ... 98.431. 1'3 " Oan. . R. [). Mol ~ 1961 56. Cah-ey. H. T 8 .. 1 I.. I'hamIaI:d 16:1919. 1967. '7. Sumlllml. W K.. .. aI; N En.1 J Mod. 31,,1241. 19M. 58. Mollo)'. O. W .. e\.1.: c.... Med. A....,.,. J l.u 29. 1991 . 39. Hco.Ih. 0 P ~ Poioom. Od....l. ~"""'" I"ro.. 1961 60. ~. It A.. and Cl)h::u. J A. 11lr .." ........ uI eo;lI'n>e'. In Clon<tooo .... T w.. llarnl. 1 J.. 8IId 1\anJey. II $ 110. 1. $............,_ A.cI;'-\.y of ""'y"",,- Ne", Yod..t,cs1 """ I'ful. 10)6.1 61 . LM. J. T _lh. 11:. C , Alii. 1. OphIhalmoJ J~ 016. 19S1 62. Comroo. J. H.. . t aI.: I 1'IIAnnao:oI. F-<p. Thct 81281 . 1~6. 63. J C, Boochem. J 34 '26. 1m

1'Iw,,_.

m.

a.. ""

a..

M N.I ...,,_-.. T~ T"' ....... N M_ ..... DaIun. P A.. B....Jkl ... "'.. " ....

>I. 17: 1511. 1961.

~.

11 c.rorld. !04 p~ ~ . n.... ,&J 19. I99J !1. Ik" I; . M I.. and Ifvlne. R. p,; Nil ..... JI1:Jlj. 1'184 :1 Ik-rri<Iae. M I.: Ann" Rey tl iocbtm. 5<), 159. 19ti1 :.c. Oopwn. [) E.: A""u. Re>' Neurooci. \1 - 1. 19'M :1 Hap. T~ Md N.ta, H~ Biociu.. 800ph,... ACII :!'JI ;~. 1971 :I. C...I1..... C. I, e\ Ill .: J MI, CIorm. 12,1l4. 1969 l'I Aquil,,"\lul. S. 1>1.. e\.J.; MIll 1'batmKoI. Todeol )0:129. 1979 II ; ............ V p~ Tmoob 1"IIr"r' <>l Sci. 1.312. 1986. :9 N 'e. T .. 8IId Grob, D~ J Ncwo<Ior:m, 15 14U. 19611, III ""nlll"",,. Po, Ftmooy. J. and RIllF"'. A $ V~ 101'" 1'barmoroI. 8; 269. 11172, lI.t&Ky.A" F'n'I ....... o.nn.IU.I915 It Ik~", It. W.. e\ II 1'Itoc:. 1'1...1. Aad. Sn. USA. 11:612 I. 1981. ).1 t;.Jodnll. 0 . and lIac~",I1 . U.: J, Med. o..m. 3M161. I99J }I Sd"" ..Jtbc.... 0 .. &lid II .: 0.. Muoari .... Ill. a.lltlC Aln .. """ fiori, I'~ lo!oplJ V"",I. 1869 Ii Hncgct-. f!.. _ 11 tw:. P.: Iltl> a",,", Am ..:i:2J1lJ. 19j1. lfL T",mpp-Kalh",,~"'. S.... II.: J Med. Oorm. J5:J44l\. 1'H2. 17 T""k. D. J.. .. II~ J Mcd. Chern. -".ll6:1. 1'1 11 ....-. E. J.. ..! S"......; A.. M 1ft ~ H. 11.). QIwIU\al"~ " " _ 1ft 1'IIIrmIooIoo. A.......-dIm. 1,1"' ..... 1969

lD. .......... M. Ii. - ' Od ....... A E.; &I. A... 27~. 1'2.

_)'I. O. M~ J Cdl BIOI. -'6:" . 1'191. \{ill 11.. DoeIri<-IIl.c. ond "'" LJ.nkkbta. R. 5 11m. 1'.193.

66.

61.
J . I'II~. 1'ati1

.....
6'),

70.

71. 72.

101"""""". I.. A. and 0......... R. M" En.ymo!o& .. 25 21). l%.l SItp/orii\tOJII R. P 8, J !'MIU,,",O!. C\rtoIDItIft 11 179. 19j6. AI-. E. J ' Ad\'. II .... 3:23S. 1966. P - . W. 0 M' 1'Itoc:. 11.. Soc. Lon<! B 134;11. 1961. ........ J P.. eI Ill .. J. 1'IlarmKuI. >p. nor.- 111 29. I~jb AMA 0.., E~ AMIMII l!iJ9.l OIIcI," Ail ....' ... Malonl Af..ociaIiaol. 19')4. P. JI9.t 0)",,,1.1... &lid Nodor. K.: J. PIwm. I'!I.vmllC<ll, 9,209. 19!7, A"""" E. J.. Simonu, A M_ ..... V'" R_ .... I. M 10 Anent. E. J. Itd.~ MoIm.'-~. Now vorL ~ Prno. 1 9601.

DIu.

, . lOS. n , K<IIl<In ...... A A.. and Z .. "t>h.. P. I. Am. PIwm , ANIC. Sci Ed. 46.
531. I~"

""PI"'.

,.. CUny. A. 11..; J ~ )(1:176. 190-1 7j . Doo<Io. H. N.. eI II.: "'" J ",,",",-,oI. l5O:ll.l . 1993 16, Fudcr. M ....... M<:"IC~. 101 . N3un)n .Scturut..l<bl/rp ""'~ . PIurmak",. )47;591. I') n. l.aumoo. S .. """ B""""I. N J 81 J I'IIanNooI 109 1110. I') n . Itano~. A. a . (td.): I~ ~IoptILI rl l'turmacok!rJI and ~14. 51. 12. 011111 ...... II k1Ckln "" 51;II1II1."", AJCftIJ. ...... 1 B..h.. SpntI.... V...... 1910. ~ _ 79. Skol. v . L 1ft K..te,or'" D. A (....). Pt"'iIIU .....,. of Goa,I....,
T"",..".I>ooII. Berlin. Sp"'j<r' V....... 19110. p. 1, (Ill Gm:ftpd. P.. and Kebobo .... J W. ' Fed. F'ru<: 11 11l!!9. 1914 iI. Hamnoro-. It.. 8IId Ci.;1ortu. A.; ute SO. ) 1;229 1. 1911. Volk. 11.. L.. &lid ","""",I.. J C I'cd. Pro.:. ~ 1 91J. 1910. U . v'" It-..m. J M.; lilt. J. N~. 1,91. 1962.

1'1 InJ. II II Sden", 1(:26-4. 1'1019 1Q. I~~ 1>1 .. .. II 80- J. I'IIaImacoI 110: 14 13. 1991. II tr 1m A.. ood 8m'" ...1Iot. R. W" ...... Drul R.. 2.141.

114.

as.

v..,

II .......... J M_: In!, J

~.

1 -103. 1961.

! acllOI1 drug i~

Il Ita!. L. N.. Nobnc. T .. . "" Chlbo. S , J C.llhov. "" . PIurmofLOl, 22: ~1 . 1991 Il.w.:n-. K. L..! V~ . P M. 8, J 1'twmaroI, 106~n. 1992. " . ....... M A .. and II""""","",,H _ . E. I.: J. I'\wm, Sci. 6.)716. , 19'1

"M.

Br. 1 ...........". .)81 . 1'1019 If>. O~ ..a~. J 0 .. $l:ionIol91;467. 19043, n . E,t'rtII. A. J.. ~. L. A., &lid Wil~lnson. S Chem. COlt""""' 1(110.

hI<JL W 0 M .. and

Wi"'"""' . . .

z., ...... E. J

Ill. SlmiaU. J II . e\ aI. II , J , h. .'.., SS:J5. 1913. 19. US"'" andlhe USPOOCtOClNl}'ofDno;N ....... R",h"k. MD. Un.Led Smco ""'"'-....,.;.t C.JII'~nl""" 1994. p , 2) I 90. 811/b. It. E.: M"'. Phoat" .~ . 1986

''''.

-".

lurntiOl1 iUludole
' !Illable.

nero

III

omptly. tions n.~

or 10111' sc\crnl

1 8

..

Diuretics
DANIEL A. KOECHEl
A diuft'lic i~ defined as 0 chemica l thaI lllCl'l:ascs the mtc of urine formatiQII. The prinlllr\' /Inion of most di Un:'IM:S is the dirttl inhibillO<\ of Na' tr:mspon III one or moo: of the four 11la,lOl' anatomical si tes along the nephron IO-hcre Na + reabsorption ud~ place. Because the Nil' 1r.lIlspon systems al tach o f ther.e Iocalion~ an: unique. ~ is a different <;e( of relah" c ly rigid ~1J"ctuml fcalum! thalli diuretic rnuSi pos~s., to inhtb!! Na' rl!llbsorption m each si le. Of addinonal irnportlloce an: the 5000111'\' (or inairt'clj el'('/JIS thaI are triggered as II n'Sull of the diu retic's primary action. 1lIt: nature and magnitude of many of the observed secondary efflli depend 011 the locus of action of the diuretic and the ~ponsc of nephron ~itCf, "downstream" to lin mh:meed deh>cry of nUld, N:l'. or ocher ~Iutes. The ~
IIrc quite chllrnctcri ~tic for eac h class of diurer;c~ and are often highly predictable if the re3dcr has an urxkn;ulIldc\"cm~

cells. distal convoluted tu bule (al'>O refem:d 10 as the rum di!ilOltubulr). comW!Cling moole (also re ferred 10 as the Imt fli!iIOIII'huI~). and lhe cofh eal and medullary coilectillJ tubules. Each of these nephron 'iegmenlS COlL~ists ofuliTtilNCtumlly and fUlIClionally u.uquc cell types. 1l1e ph~ioln&K"1J role of lhe glomerulus and each nephron sc:gnw:nt i, di .. cussed below Il.~ n rd:ncs 10 tnc handlingof lIuponmusoltnn lind waler in nonnlllly hydr~tetl (nornlO,olem,e) and !Ic~). dr-ned (hypovolemic) persons and in pallenl~ ut"flicled w,th various edematous disorders (e.g .. rongesti>e hean fll1urt.. C1lmosis of the Iher "" th ascite~. and the I\t'phmtic 1)11dromel.

fUNCTION
F.nctlon of the Nephron When the ph'S. Voillme Is NOill al (Nal iIIovoiemla or Euvolemla'
As blood is deli'erect 10 each glouw:",lu.~. many (bul 001.01 of its componen ts are filtered into 80", man ... ~p;Ke tMIuP the "pores" In lhe glome rular Capillary Ioopl.. !;c"enl cochemk1l1 properties of each blood L"OlLlponen\ dictale tlIr extent to ",hio::h it IS renlO"c:d from the blood b) glolllcnU filtrnuon. These mc1ude the ooruponenl's rel.nile n,..,k....br ma" (M,). o"el'1l l1 charge (applie~ primarily 10 large mokeu1es). and degree and nalure of bindmg to pla~ma pi . .1Ii. For example. plasma proIelllll ,,"h an M, in e\~of~fYJl D~ and red blood Ct'1I ~ are 1101 read,ly filtered .... heITOIS "",. M .. IIOII - prolein.bound cmnponents (e.~ . Na', Ie, 0. IlCO.) -, ,10c0se. and ami no acids) an: readily IiItelTd.' 111e mit' of filtrauon of pl ..... ma componenlS that ~ un M, of less thun 50.000 l)a alld arc 1101 bound 10 pb!./III

ing of oormal renal ph~lQIogical pnxesloCS. Collectively. the pnnl.lry and secondary effects Indul...,d oy a diuretic detemline its dectrolyte excretion JI'I"em. A diuretic usually posscs<;t'S sollie combination of rIlJlriurt'lic. rh/oI'"Uft'lic. sal
urrlir:, ko/iurrflr, bir:urbomuurrrir, or c/J!riurtlic proptrlitJ. depending on whether it enll.loc..,., the renal excretion

of Na' . CI . Nu K ' . HCO I 01" Cal . respectively. [n this ctlapler, the nOl"llIul function of the nephron i~ presenll:d, mdudlng the four major reabsorplive ~i tes rOl" Na'" and OIher importam solu tes and the renal physiological e,ents that occur ",hen ND and water reabsorption are altered by the pall(m's ~t Dte of h)dration. dl.scase. or mtale of d,ureti cs. Thi~ i~ follo ..... ed by a disc u~.~jon of eac h class of diuretlc~ m current U'ie. A koo"lcdge of tnc important stlUClUral features and the sitch) of ."lion of each class of diuretics ~hoo l() give the readeT a bellC\" urideo;l:lnding o f lhe factors th:u dictate Ihe nalu re and magn ilude of the anticipated diure$is and the L<soeiatc:d secondary effects.

'CI-.

""'\I-

protein~

ANATOMY AND PHYSIOLOGY OF THE NEPHRON

1lIe fUllCliolllll Ullil of the lidlley is the IlCphn:m with its acromJl'lllyil\8 gkJmerolu~ ( Fig. 18-1). There at"(' approximately a millIOn nephrons HI tach kidney. 1l1e blood (or. 1lI0re appropriatcly. the plasma). frum ... hieh all urine: is formed, is broughl 10 e;loCh Ilt'phron within the glornerular alpillary IIttworl (Fig. 182,. Many plasma componentS an: filtered into Bowm~n's ~'e. Dming the p'ru.:css of urine formutiOll. the re~ult ing glonw:rul!lJ" filtr.l1 e flow$lhrouj;h lhe coo'oluted and str.ighl ponions of the pro.\ lm:d lubule. descending li mb of Ilenle s loop. thin and thick ponion~ of lhe a .....-e ndillg Ii II1b of n enle' s \Qop. area or the macula den0;3

IXpends d,ltt1!y 011 Uw: h)drauhc (II)Uro:iratic l pit \"11' the ren!! ,a.culalUn: (Crealed b) rhe pumpon, htanl." 1cnth 10 drive "".'er and o.oIUI~ ()U' of tile glomeoular ~ IeII into 8000.man, split .. Keillri m"c~ly 10 the pb._1na .... "IlI..: ~... re ( the~" ""'''lure crealed by the pla,nu proI~,n ...... h," tho , .... lure) ...... hieh tends I<) holJ or "","etll the li1!noioOil or ... and j;()jUlt:S am .... the ,Ium..oubr capillal"ln ,mo Booo
Fo!!ows the '~lr..",na! "'''''!> Ih3lalktw (II"h ntpl".... '"

-'
(i.e~

the littration ml.. throogh .1' u'" n ~Iollicrular ClIfl,II;uy_ oj

tubuloslomcno!ar fecdbacl t

Clear!y. the CaNlOI!l..'iCU!ar and ",nal fUlIClloo.ol OUt.. an illdi"i()ual will ul<>o affect tlie mte of filtrnllOll of pI_ componentS through the glonw:ruh. l n addilioo.1'leOOaItIo the elderly usually ha"e a redl.lCt'd glOllll'l\l lar IiItratim .. (GFR ), tlioogh for difrerent reason., .'

59'

Cluiptr r III Oi.. ~rirJ

597

CQ!!TEX
~(ld\'

!he: rrn:d plilS.mll now i~ diKelcd inlO the pcT"itubular caf'lllarics (Fig. 18-1). Each minute only I mL of urine is formed from the 125 mL of glomcnLlIIf fiJtr~te .s Thus, appro~i malely 99% of the glomerular filtrate is nonnally reabsartxd. The IWSflJWr qUl/ntiry of each filtrable pla,ma componenl that rraches Bo,"'man'\ "{I3CC-lhe jillt'rrlllO/ul of a substance- depends directly on the GFR 3nd the concentr,ll.ron in plasma of lhe porIion of lhe filtrable substance thaI is not bound to plll!ilTla proIems. ThoIt is. the filtered load of. SU~lance equals the GFR (in millilucl'1I per minute)lil11('li the ooncentllltion of unbound, filtrable sub'\lIJJ<.."<, in plasma (In amoun t per milliliter). ' l1Ie glomeru lar filtrate that houO\Cs the filten:d load of a given solule is rcfem:d to below as the ilmr;,wl fluid. sil"lCe it cnlC,., the lumen of cach nephron immediately upon kavmg 80... man~ sp.'ICl'. In the follo,",ing discu..sion. attention focll.'iC~ 00 the perc.:nt:lge ofihe filll'red load of Na ' and other l ey !!(Ilule) Ihat is rcabsort:led (i.e., tran<porIi from the luminal nUld mto n:nal lubulc cells, wrth ~ubsequent passage intu the inten.lilium and ultrmately into !he: n:nal vasculature) DI various ne phron siles. There are four map anatomica l .ire" along the nephron Ihat are respon<ib1c for the bulk of N~ i reabsorption~ (Fig. 18- 1); 5i/r I, the convoluted and .traight portlOf\S of the proximnltubulc; Jilr 2, the thick :t.>Cending limb of Htnle'$ loop: silr J. the distill COI1voluli lubule; IIJld sir" 4. lhe coonecung tubule and tbe 00I't1'Cll1 colllXling tubule. The actual transport processes in,'oI,'cd m Na' n:absatpuon at each of tllcsr Sites arc: highlighted In Figures 18-3 through 18-6 and are discu~ in ordcf",

he /111<' ing Ill -

COO'llcal CoI.C llng Tubule

asuuclogICal
is ti",
Hype<olmoial

:solulC~

I dchy

Inl .... llt .....

:d wnh railure,

!!ED!J!.LA

Ie 'yn-

ligure 18-1 Anatomy of the nephron, IndICating the four 'IIip' Sites 01 sodium reab5orptlOll (f-4).

not ull)
hrou~h

ThefnK'liIH/ of lhe 100UI reoal plasma flow Ihm

i~

filtered

1 phyM' tlile the

;nero1"r lko:;ular ! mole totem.,

roIkctilcly by the glomeruli per unil lim.. (i.e .. tlie fihmtion lrIcIioo) is about orlC Iiflh .2 Thi. means Ihm only one fifth lei' m.) of the plasma 1 )I\!M'nICd to [hoe ~ klneys in a glv~n pmod undergoes "''''al ion al the glomeruh (i.e" abolll 650 III. of plasma flow through the kidneys each minute. appro:.._I), 125 mUm mule of whICh is fihcred through the gil)ICNIar capi Uaria.). The remaining four fifths ( 0.0 80%) of

SITE 1
The convoluted and straighl pot1ioos Orthe pro\imaltubulc an: rt'~pon5ible fOf" the re:l.b>.orptioo of Abolil Mit at"'" filtered kIds of N. , a . e.l.1IId
8U 10 9()ojI. of tile filtered IoaKh at HCOJ
.....

. 50.000
Glomerular

.... '

....

. ' 10,,"-

phus.p/>;tlc,l and

. CI cd I

PO>O-":'"

Capiltery Loops

Etterent Anarlola

l:$$Cnt rall~ 100'l0 of the fi Irered load. of glue"""" .",rno xid~. and Iow_M, pr'OIel", IO

UI"I''''

phlsma

luminal
Fluid Thus, under nonnal elrcumSlIlI"lCClI, the pro:llImaJ tubule has a tremendous reabsOf"pthe ClIpacity. 1bcre are prill1:1.flly IWO driving forces fOf" this high reabsorf.c"e :I\1i.. ity, RM, becauq: lhe pla~nla in the pc:ntubulru- cllplJlaries (J:ig. 18-1) has .Iowet hydraulic pres.~ure and a hlghet onootic pn:\sure than the lumi nal nuid Of" lhe plllSrnu dcl i\l'rcd 10 the glomeru lus (because of Ihe remQyal of ... mer bul nOi protein from plll<mll during .Illomerular fi Ilrut;on ), .here i_ a nel InO\" Clllcnt of the lummal nu id contents in II rcahsorpt;"e dira1ion,I Sccund, the Na '/K _ATPase, 5trlltcgic.dly located on lhe antiluminal Il-.embrolle (somellmes refe=<! 10 115 the bt,5OIw..rul, puimbulll,. Of" contralumi",,' ml'mh'a/~' of the pIU.\i mallubuie cells. caUllys the rountellr.utspot"t of in~lJu lar Na' Into lhe interstihunt .nd e~lrucclJulllr K ' IntO lhe pro~.mal lubule eells 10 (Fig. 18-3). The stOleh,umetry fOf" thts eounlcnran~port is 3 NIl ':2 K ' . This activity e~atcS a defici1 ofintl1lCc llulat Nu ' ,a surfeit or i11lr.ICellul~r K . "nd a yuha,e oricm.. ncgaliH:ly i n~idc proximal IlIbule celis. U) 'd In re.<;pOI1$C to the 1K.1ion of the Na ' /K. -ATJ>ase. Na

_ _ Oensa ~ Cells
tlM'''''I<.:

M8cllla

,'a",ulaof ... al~'

0""'"

Plodmal Convolu ted Tubule

Granular Cells Bowman" Space

Renal

Allerenl Arter iole

Sympathetic
;taW_ til

pl;L,ma

and lion r.IIC

1(:\

Nerves Fipt '8-2 Ju.lagIoolel ular app.lraM (KiA)_ Uflne IS .;". from the 1,ltratlOfl 01 pla'llTla through the glomerular r.lIUy loop!!. Into Bowman's space_ llM> JGA IS of paramount """"'~;;,;';:f()f the operatoon 01 the tubuloglomerul~r feedbiIC~ ,wtll(h al~ a nephron to regul.:u/! the glornl!ruiclr .oon rail' of lIS own gIonlelulus.

''''"

IDI,,"W!!!
IN.'I 20_

IIt'J _ '.0 .....

c[
Figure '8 - ] SIte I: The N.J' Irall5pOl\ systems 'esp:lO'lSIbie for the reabsorpllOn 01 Na ' and associated solutes m the prO~i ~ tubule A. Transcellular reab5orplJOn of Na' /HCO l - , whodl is controlled by carbonIC anhydr.ne (CA). Ac:ewolamlde and other CA, ,ntl,botors block Nil ' reabsorpt,on by thIS route 8 . TransceHular reabsorp\JO('l 01 Na' coupled to glucose, am,no .tOds. and phosphate C. PariKeilular tr~ of Nil '1(1 - ~ convneroally ava~ <tgenU Irlhibn Na' reabsorpllon by routes B or C. Na '/K' -A,TP~ is indicated by filled orr:les on tile anli luminal membrane.

in tile luminal fluid moves down tile cOllcenlnltion grndienl mto proximal tubule: cells by. combination of 31 least three distinct processes (labeledA. 8, and Cin Fig. 18-3 ). The first 111f..'(:hanism of N~ ' reabsorption al site: I irlvol ve~ carbonic anhydrase (CAl. .... hich is located in the cyltJPlasm and on liM: bru~ border of proximal tubu le cell' (Fig , 18-3A), H . lIe~flIted liS liM: resuh of the lICtion of intrncell ulat CA. IS CJl.changed (i.e., coumertransponed) for the: fihercd Na ' in tile IUffiU\:l1 fluid. 11Ie Na' thaI mtel"5 proxin\:ll tubule cdls duri ng the exchange for H ' i. then pumped into the interslltium by thoe N u ~ fK " -ATPase in the: an ti lu minal me mbrnfle. The H ' secreled (i.e" tf3JU;poned uphill or against its II~ dlent) into the luminal fluid relICts there wilh the mtered HCO l - to gencmte carbonic lICid. The carbonic lICid decomposes. bot h spont uf1C()Usly and with the aid of the brush border-bound CA, to carbon dioxide and water. The carbon dIoxide diffuses into !he proximal tubule cells and is COIl\'erted back ;nlO HCOl - , which subsequently p:lsses from the proxilllllltubule cell!!" RCI"OSIi!he anLiluminal mcmbr.lIle,

and mto Ille mtershtlUn) by llilly of an Na ~ fHCO ,- $Y. poner in the ll.miluminalmcmbrune. CA IS very pleRuM ~ the CQlwoluted portioll of liM: human proximallubule tu. noncxistem in the sJrolight ponl(lfl, Thll~, the ~jn descnbed occur prlm"rily In lhe convoluted pomOrl oftbc proximal tubule and IICcount for the rcab"<ll"plion of IIW 20 to 25 .... of the fillercd load of Na' (or aboul one tIDnI of lhe filtcre.'d Iood of Na ' that i~ reabwrbtd at ~' le 1) _ about SO to 90% of the filtered load of IICO l .f.!l ll1e seeond mcchalIIsm by llihieh Na ' nKl''l.'$ ow or tilt luminal flU Id al sile I in"oh'es tb eOlransport mto prof. tubule cells along with glucose, amino lICids, or phosp/ult (RS. 18-38 ). The lutter three i.OlUleS cRIer proximallubt* cells against their concenlnluon grudicnlll. The rc;a~ of the Na that enters proximal tubular cells by these I"' ce~o;es is completcd iii hen it is subsequently pumped into tbi: Inlerstitium by the Wlti luminal membr.rne - bound Na ' fK ATPase and then pa.,,-'iCS into the adjacelU prolubular ap!lories. TIle an1Ol.lnt of Na ~ reabsorbed by this typt 0(('1)tr' n~pon varies and depc:nd~ on lhe fi Itcret.l loads of the tIwer J soIUles. Such CQlranspon. howe"cr, I liM: mechanism which I ()()% of thoe filtered lood~ of glllCQ'le and a/T1l1IO JCdr. and SO 10 90% of lhe filtered load of pho~phale arc ~ rcmm'ed from the luminal flUid and subsequently IS !i<lfbcd, Th ird. Na ' i~ renm.orbed at si te ] along with CI' (Fie. ] 8-3C). 10 As thc reabsorplion of Na ' OI."Curs in tile ""'" proximal conmtuted tubule accompamed by ~ glOCOSo!, ammo ar:id~, and phosphate, the concentnll\lll" CI within lhe luminal Ouid lends to rise. As a InUIt._ COIICeRll1lllon ofCI in the mId 10 llIte proximal tubuk"'" nal fluid c-,-ettlh tilal in the Intersuuum. and a fNlfllall"/(lr/y (i.e., hetwc<:n Ihe proximal tubu]1II" cells) , lhe interstitium: Na ' follows, Additional Na ~ /Cl i~ tab!iQfbed frtlnJul/U/llrfV (i.e . Ihrough cells) in lhe proA tubule by tnc COlnbination of a Na' fH ' !Illliponer II1II or more Cl fanion nntipone,.,; (not ~hown),IO CoIlccti,cty. lhese si te I Na ' -U1Ul.~ponmg ~ ~ mo"e 65',1, of the filtered load of Na ' from the I~ fluid, and they do so ;$/J$lTlIIllcally (i.e .. thoe OIimolahty I the luminal fluid entering the dc.l.cending limb of H~. loop is sim ilar 10 thaI of the Inlual glomerular fihralt~ As the IUlnlnal fluid mInes through the descendln, of Hcnl,,'1i loop, the higtl (Hllif}/(.fil,. (i.e.. eoOC('ntrJtic~r -.olulcs) in lhe surroundmg medullary intcf"titium prox in\:llcly ]5% of the filtered load of wate!" out

'*

<h':

luminal fluid by :'. from lhe imerstillUll1 to be added to the: Il OIher words, the luminal fluid b eonccmr.ued as II through the lIesc"nding limb of Ilen]e'sloop.u

~'"''''''

i~.:~;~~

SIT"
Whcll the luminal flUid entelli the thick ;L'lCendmg Henle's loop. it CQnICS into cont llC1 with tubule celli arc impc:nneablc: 10trnnsport ~y'lem for ITIC'mbr.lI1c- boultd watCT 3.td possc;.s Hen:, as at site I, the mujor driviug force of Na ' is the creauoo of un mtrucellulat by the anlilunllnaJ membrane- bound Na ' fK elcetrollCutml . i . . Icm located on lhe luminnl IncmbrJ~ thie"

~rE:~:~~~';~

"',m,

C","plu 18 Di~"II('1

599

n-

"

counlertrnnspon system on the anliluminal membrane and tI'Ie INa '11K C()lr.In'pon system on !he luminal

no

~,

.'. ...
ion
~

"" i'" "d ,,.

w,

"

membrane of the thick ~nding limb cells normally at:count for the .nbsorplion of up w 30% of the filtered load
dNa' .'" !lIthe reabsorptionofup 1020 lo3O'l>O(the fillered load of Cal ' ,'0 the rnairlCcnancc of the high osmolality o f the medullary imCf'Slilium (which is absolutely critical for the norm~1 (un.ctioning of the human roephmn).' l and the ability of lhi ( nephron SCgl1leOl [0 reabsorb more Na' ~nd Qlher solu les than usu31 when proximallUbu le Na ' transpon has been inhibited.&. " Th is latter CQIllpC'IISD10l')' phenomenoOn ClI.pluins .... hy diuretic, that IICt primarily al s ue 1 are 001 particularly efficacious. The descending limb of Henle's loop is responsible for the conccntf1!ltion of lu minal fluid (i.e .. Il!mova] of .. ater and addition o f Na'), whi le the thick ascendmg hmb is Il!sponslble for the di lution of lUminal fluid (i.e .. rt'moval 0( solute from the luminal fluid without eoncomitant removal o(wDter). lie~. colleclivl'ly, thrse two nephron segments produce a mas~ive o\'craU reduction of luminal fluid \'olunIC and solute contcnt. Inten:stingl y. IhI' osmolal ity of the lun.i nal fl uid in tile tenninal portion of tile thk k ascending limb of l-knle'~ loop i~ tlOI much different from that of the fluid that I'mI'" the dc)oCending portion of the loop (though drastic changcs take place in between). As the luminal fluid leaves the thick asceo(lI na 11mb of Henle's loop, it come~ into contact ..-ith the m(lcu/(I dt'IIS// ttl/s, II speciahled group of tubu le cells that communicate wllh the gnlnulor cell~ of the affertnl arteriole be10nlling to the same nephron" (fiB. 18-2). The macula densa cells are like the thick ascendmg hmb cells. in that they house b<Mh the antilumin:d membrane-bound Na + IK + -ATPase lind the lumi~1 membrane-bou nd INa + 11K .12Cl- cotransport system. 1bcir uniqll('nes~ lies in thei r ability to detca changes in either the rate of lumina! fluid flow Ot the solute ~'()mposit ion of the lum inal fluid. which in part dictatei Itow much solute they remove from Ihe luminal fluid. Signals:are then transmitted by way of the grnnu lar ce lls to the affell!nl arteriole !l$sociated wit h thut nephron? When fluidlsolute delivery pa.~t the macula dcnsa ce lls iocrt'a5I's, a macuJa densa-derh'ed sub6la~ mediates constriction of the afferent arteriole wpplying tnat particular nephron and a reduction in GFR ensues. Thi5 is commonly n:fenm to lIS rub./IQglo/ttdbof-k.. On the other hand .....hen nuidiliOlutll delivery past the mxula densa cellsdecrtases. a signal is transmined from these cells 10 the gtallullll" cells SUlTUUndin~ the afferent arteriole, whICh rt'!ioUJI5 in the n:lease of rt'nin .

nol

, -

,,'"

~~,

.pll-

-..

, by

,=

,~

cids Inlly cabSitt 2 The Nil ' tr~ l"I~ !iYSlems r~ble b the reabsoipllon 01 Na' ~nd associated ~ull!"S In the W(1U!f..... n'll!a~ coruc~1 ;tnd ~ullary portlOflS of the thld< ,as. ng bmbof HenIe'sloop ThecollectM! ;t(ooosof the antiluIIINl membrane- Ixlond N~' "'. -ATPase and the IUffilf'lil] iltlltuoe-bound lNit'/1K'I2C!- (OlloWlSpOrt !iYStem iI(. CDurll for uISCf!IIuIaI ~uon of Na' /Ct, 11"1 aNa' /Cl000 01 ] 6, and the gffiefauon of a lumen-posltlve potenual hi drNeS the leabsofptlOfl of Na + and other Uhons VIiI the /lMilCrIJ/ar pathway (dashed line) D,uletlC ilgents thaI block III rtabsorptK>rl In the thICk ascending 11mb by InhtbrtlOn of Nlumrnal rnembfane-bound tNa' 11 K' 12(1 cotran~sys. '1m ItlClude fur05emldt!, bumet~nlde. tooemlde. elhacrynlC Id. ~ a number 01 mIscellaneous .Jgel"lts Cited 11"1 Figure 1a-

,Fig.

fi9ure 18-1

""y

nale,

0' "'"
0",

Ulnt-

;o~ e~

! imo

=h-

l inlUl

reffill\al

ily of
IImh
ap-

"

,.lc~

1iI~

0'

.id. In
(Iow~

'N.

uf

I~

1mb of I< thai ununal 18-.4).

::.rptioro If t-;a' K. Th<

~)~

1'1

:crtdinp-

Cl:lls then t rnn~poru Na ' . along with K and CI . from Ik Jr.nunal flUId into the cells of the thld, a.tlceoding limb ratioofl Na -: I K ":2CI .,o Rca~ion oftheNu . . tIIltf1lthick a+ocending limb celh by t hl ~ ITlhani~m i$ ...... 1I;'d \0 hen it is pumped acti\'cly into lhe Intclltil ium antJluminal membrane- bound Na '/K '-ATPase and IItm p;iS'ie'I into the 5ulTUUIKling vuscul3ture . CI \:nt~ the +Wr)titiulll through CI channel ~ in the ~ntilurninal mem. . and by Cotrnn5port wllh K . The luminal K 4 Ihat a'Companies Na" 3nd CI imo the thick ascendin g limb ttU, m:yclcs pa.~he!y downhill bacl imo the lumin:,l nuid. fir K' thut enters the thick ascendmg limb ecll~ by wily .dtcamiluminal membrnne- bouod Nu '/K '-AT!'uloC recy. !b hick Into the inte!"$ulium via cotrnnspon Wllh a . , the nef result is lhe lran~pon 3 Na and 6 0 tile lummal flUid into the Inten;lIuum. ThI s results in _ It'iClalion o f a lumco-posith'e trnnscpuhe lial \ollag\:. p!lI>IU\'C luminal e'l'"ironn)('nl dmes I"l1Oft' callom ,K' , Cll~' , Mr ' ) from the lumen Into the mlen;tiperlICClIularly (i.e .. between the thick asceodrng limb dtl.1O, II The combined activities o fthi' No . IK '-ATPasc-

_na(lr

"the

SITE]

or

Following ilS !ioJoum past the macu la !knSl! cell~. the luminal fluid CQfTIeS into contact wilh the thi rd major si te rOt the reabsorption of Na' , the relati\'ely short, water impermeable. distal convoluted tubule (Fig. 18-5). Again. the maJOf driving force fOf Na' reabsorption from the luminal fluid at site 3 invol\'es the derlCit of intracellular No' produttd by the ocuon orthe anu! ummal rroembrane-bou nd N.-/K'ATPase. In this inSlance, the luminal membrane- bound Na /CI cotransport system mo~"I'S luminal flUid Na' downhill and luminal fluid C I uphi ll into distal convoluted lubule cells. The reabsorptioo of Na ' IS compleled .... hen the :mtiluminlll membrnne- bound Na ' I K ' -ATPa.'Ie lIe-

 a(11<)1

I!IO>'CS

pmal1ulllly from the lumen Inllllhe

,1lICrSI_

~hown)

I, Ie'" ,!y!sI

K ' in Ihc princ'pal C1:1I~ mo,'et """nhill into the lum,. fluid through K' elwlnel~ in the lumma\ membrane H ' jt'ner:olW HI tho: 'nlCn.'alalW II. I!IO>'CJ "",0 tht-I~ flu,d by ....ay of ltv H' _ATf>ae 'o the: laller two processes predominate, OIIC' ~ "iew the: acli."jue~ at site 4 as an c~chang<' of luminal nw. Na' for principa l cell K ' and intercalated cell H", exchange of luminal flu id Na + for intl'll"ular H " normIIJly is associated ","h the: ~absorption of only 2 10 of the: filtered load of Na ' .~ III'1d the distal location of c;'llchangc system dictate~ the fi nal ocidi ty and K" ~ of the urine, 1lIc: amount of Na' ~a~ at !lIe 4 and. thertfOll' the amounl of II ' and K ' prescm in the final urine 1ft modulated by
J>I~..,. .1Id "'n~l 1c:vc:1~ of 1TU/ICF1Ilororuro.d. lite ...~ ronc:- lhe hillhrr the t c~el. or eirc:ulalinx alOOslC1t111C, fir gn.lC'f the N.' ",absorpIlot1 and K ' and II ' acrt!lCll Lununal flwd laic and ofNa'
"0<

.,>(! K ' '" ,.

Bc:c~USoC

No'

,
Figur. '1- 5 Site 3. The Na' lrill5pOlt systems responSible for the reabsorption of Na ' and CI - In the water-lmpermeabkdistal con~uted tubule Ir'lhlbltors of the luminal membraoe-bool'ld ~ '!CI' cotransport system IflClude the thlallde ilfld thwIde-bh dlurt,mcs tl\'ely pumps it into !he intel'1Otitium .... ilh subsequenl passage into lhe ~urrounding vasco l:llure: IfItr.occ:llulpr C I- enters the intcf1illtium through channels in the antiluminal membrane, Appro~ i m.atcly ,5 to 8% of thc filtered load of Na ' is reab~ at si te: 3,.. tl

-I

of Na' .nd II ' , .. he,ea.~ .lkalos.. faHIO"lI

udlanrt

'ri!t! fUc!

SITE 4
The connecting tubule: (i,e,. laie: distAl tubule) and the: conical rollc:ctmg tubule: house the foonh and final major si te: for the reabsorption of Na t from !he luminal flui(!l' (Fig, 186), 11us portion of the: nephron is composed of twO distinct ~'(:II type$: the principal ulls and the inlumlllft'd ulls, The: priocipal ",lis nrc: important for Nu - reabsorption and K ~ !;CCretion, whereas the imercalate:d cdls (subtype A) are im portant for the: generation and ccretion of H ~ , The intercalated cells possc:.~s only small quantities of the: Na '/K ~ ATPuo;c on their ami luminal membrnne:s. bUlthey conlain abundant qllllnii ties of imraccllular CA, which C:IIal1'/,l:5 the formation of carbon ic IICld from COl and .... ater, Thc: carbOlllc acid ioni1.c:S, yielding H ~ lind HCO)-, The H ' is thc:n pumped IlCth'ely imo the luminal fluid by the luntinal membrunc: - boond H ~ -A TP:isc:, The driving fon:c: for the: reabsorption of Na in the principal ee:lls is once: again the: deficil ofimral,'el!ular Na ' crea ted by the Nil '/K" , AT~o;c on the lllltiluminal mcmbranc:, ",hlCh coumc:nr.mspotls 3 Na ' uphill from the principal cells mlO the IIItCflilitium and 2 K " uphill from the interstitium into the principal cells, In =ponsc to the deficit of Na ' in the principal ccIL~, the Na" in the luminal nU ld mo\'e$ downhill inlo the principal cc:.Jls through Nu ' channels in the lum(nal mcmbr~nc: and i~ subC(jucn tly pumped Bai"cly into the i olersti ti urn by the unl iluminal nll:mbranc:- bound Na '/K " , ATPa.<;c:, These e~cnts crt'ale lomen'nc:gath'e tr.msepnhelial voltage, In response 10 Ihis voltage di fference. ~me combination of the fol lowi og three processc:s occurs:

'8-'

Chaptu 18

DtUl'<'IIl'S

60J

..,
., ,'" ,.
"d
h;~

of diuretics that inhibit the reabsorption of lU $ile~ t. 2. (lI' 3 ( i.r . Slles prm IITIllI to s ue 4 ) uJllm3ldy .:rea.<;('. to ~ar)'ing degree<. the lurnin~J nuid now role ~"d 6t pucc:ntagc of the filtered load of Na' deh"cmi 10 Slle ~ Thus. many djumlc~ acutely enh :mcc the urinary loss of K' and rna) be as~i:lled ...ith the induction of hypokJl Itmla (i.e.. nbnorrnally low leve ls of K ' in I""" clI'I:ul:'l;n&

The

cJasse ~

...,.

Ftlnction of the Nephron During Reduced Plasma Vohune IH)'povoleflda)

'Ihrn a paucnl'5 pl:L~ma \'Olume decn':ases below norma] ~'po~Qlem jal b<'cau<;c of ~uch events lIS he.llorrh:lge, diar-

'"'

IIa. Hlmn ins.

o:xce.~~i'c

s"'cming. or

over,.calou~

usc of

-,,'"

_lic~. a casc allc o f imrarenal and ex trarenal signals that ~lS('S urine anti t'lectrol )'lc 00lPUI occurs in an Dnc:nlpl

101\'.<;lore Ihe p lusma \'oIu111c and mean anerial pressure,l. The many signals .null in
\)c!maK\l 1l'na1 blood flo ... ani! GFR l~ pn'l"m:lt tubllk ~ab!.orpI:lon of MltUIQ IIIId " 1I-

Itr" "

t~ ~nin ~~II()Q from ~ ~I

granuLar ~II ... .. hoch

ItIds 10 iocn:a'IW ~,rcu l~lI nllc.'~I, of anGlOlen~in II (I ~~ nt .~rklor) and ~ I """,asa,h,,,uoo ohnudmn:toc hQnnone {AOII )... h ICh .,1lI

.. the rollcclln, wbliia to

i",,~a.e

...u:r ",absorptioo

Wllrn hypo,o1cmia is the resuh of overlealou$ usc of ~"K:S. lite tompcn!l3tory RdoctKlflJi In urinary wattr and cIertroIytc OUtput thaI occur are common ly re felTl;!d to as "di",..ric brakm8 phenome"on. The compensalOry cas~ of event~ IncntiollCd above has basica lly put on tlte ..;.~ 10 cominucti diuretic-Induced increllSC:\l in water and

,"",,:~~;> te l'Xcre lion. TIcu . the efficacy of tlte diuretic IS ~ig"i ficantl) . No diurelic inducc~ the loss of urine tlte \a me composition as eXlrnCCliular flu id; tltere.000'U/.caklw. u<;e of these agenls re\u lCli in hypovolemic pIttOt, "Ito are frequentl y Icfl wilh clcclmlyle and/or .... -base derangements.

'2 diu of the Nephron During D15eiI_ lUtes Associated With Retention of

IIitr Flukls (Edematous States)

.: "",.

.""
by

r..Dlly. the kidne YM of indi viduals wnh congc:sllle heart ,cirrhosis 0( the: liver wi lh :asc,tcs. ()( tlte ncphrolic !'Ifdrome reed"e ~ignuls thai are intcrpn:ted 10 ntcan Ihat Ire being h) poperfuscd. Thi~ may occur " heUM:r or not an oclual pla~ma volume reduction. The kidneys 10 ll1ain body fluids and 50Iutts by a combination . . . prottMCs dlscu.~scd In the pre" ious paragraph. Ulti~~ . edema ensue~.

;;;,';S

1-

""

IffROOUOION TO THE DIURETI CS

CTtIbarting on a discu ~slon of the vari ous clas~s of one: must undersland the differeoce belween the PO'~IK'l' and effic/le}' h~ they ~Ime 10 d,uO::llcs. the dnmrunanlS of dlurelic efficacy. and the shoncom

logs 1)( many of the previou~ ~t ruclure-acl1vlly ~1:Ulonshlp (SAR) siudies Wt Ita 'e in\'oh'ed dlurel ies. A clear d isti nctlOll musl be made bclween the u<;c of the lerrru. poleltc'Y and rfficun. I 'The po/rllcy of a diureti c is related 10 the a~ule lmount o( drug (e.g .. ml lh,rams 01' milligrams per .. ilogram) requit\.>d 10 produce an cffeci. The ""lIriH~ porency i~ con"eneent means of comparing 1"0 diu ..... tics and i~ CJlpre.~ as D milO of equ lcffccli"e dlKc\ The potmcy of a diureuc is influenced b) il\ ab\C)rpItOfl. distrlbulion. biOlrnnsfonnalioo. c~cret iot1 . and tn hen:nt Dbi lilY 10 combine ... "h ,,~ n:cepior (i.e .. ils Intnm;.ic aCI1 ~ jty). The potency of ~ diun:tic is important for e;.tabhsh, ng ,ts dosage bul is othcrwise a n: lati\'c ly unimportant charnclCns tie.1ifficucy n:lates to lhe malt,mll.l diurellc Cffl"C1 anamable (usually measured in lerms of urine .'olumc: per unil o f time or urinary loss of Na ' or NaCl per umt of li ll ie). NUmerotJl factors contributc to the effic;lCy of a dlun:lic. First. lhe anatonucal ~ ne of action and lite capacity of the Na reabsorbing ~i lcs do"'n>ln::ant play major roles 1M delerminin g the o"crall eflicacy. ThaI i~. a dlurelic '~ efficllCY i~ detennincd in part by ... Itether il acts at site I. 2. 3. or 4 . Diurelics Wt inhibit lhe I1!OI.b<iorpt ion of No' al lhe SlIntc anatomical site arc u~ u a ll y ellu icmcaciou~ (I,e .. e\okc: 5mll1:11' m;t.~imal responSClo) but rna) "at) in pilIcncy (i.e .. the amount of <il urelic ncce'Siry to produce ~imilar effb). 01 urel ics thaI act at 5ite: I by mhibltmg CA ma) inhibit lhe reahsorption of 20 10 25% of the filtcred luad o f Na ' bul are no! as efficacious as 0Ilc: might l hin~ . because the three nt~jor ~ ites of Na ' reab~rpllon downstream (silt:'!; 2. 3. and 4 ) compensate by reab-orbing most of the ex tra Nu ' prescnll'(lto lhem. 0 , urettcs that tnhib n the n:aMot'ptIOrt of Na al ~i le 2 are the most efficacious becau<;c sill' 2 is normally ro;ponsible for the reabsorpuOlt of up 1 3O'l> of !he rilierrd 0 load of Nil. ' . and the IWO Na' rea~i\'C' ~i le~downmeant (si lts 3 and 4) are relalt\'cly low capaci ty SItes. DturellCli thai act at site: 2 freque ntl y are n::fem:d 10 as Itighuiling or loop dlurelics. DiureuC!!I thaI act at ~itc:s J or 4 an: lcss efficacious because these tw(> si te~ an:: resptlllsible fOl' IIIe reabsorption of only 5 1 81jf. and 2 1 J% of the rillered 0 0 load of Na ' re ~pect ivt l y . Second. tlte e m cllC> o f a diuretic tkpelKls on its conccll' lralion al lhe sile where it mh ibits Na tra nsport. In all but a few cases, diun:lics interfere wilh lhe pmccsscs re"pol1sible for lhe reabsorpllon of Nil. ' Ihat are located on the lo minal membrane. and hence. their intraluminal l'QftCtn lt'llJion is of cri lical importance. llle concentratIOn o f a dlureltc agent !hat ultimluc:ly is presented to a lumi nal ~ite is dclmn iood hy how we ll it is rillered al lhe glomerulus. "hcther it undergoes IICI; V tubul~r secret ion In pm.\ ima l tubu les. hnd ... hetller e it undergoes nomonic hac .. diffUSion 10 lhe diStal nephron segments. All diuret ic~ enter luttlUlal flUid by tlte process of glomerular filirJlion bullO vary ing degrtCs. 'The amount WI enlers the lum inal nuid by lite rillration p!'OUSs depends on lhe GFR. the plasma concentration oftlte diuretic agenl. and the eXlent 10 ",hleh lhe diuretic i ~ bound 101he predommam unfiltrable plasma proIei n. albumm. In liddinoo. all bul a few or lhe diurellcs anam relati>c:ly hl,h conccntraltollS 111 tlte lumUlal fluid of the prm imaltubule by a two-Sl~ procc:ss commonly re ferred 1 as (Jcri\'e mlwlllr su,..r;II" (Fig. 0 18-7). The unliluminal memhranc of tlte proximal lubule houses a SCI 0( bidirectional liCIlI e transport SySlctn" Ihat particip:tlc in !he firsl Mep of acli ve tubu l:ll' secret ion of a

MOil dU"ics pUS from lhe

~IJCulaIlK'

Into the Int .... llllum with .,lativ, . . . .

ArSOof'H2 RCOOH

===
, ""

,
H'

tl

ArsH

RN..,

Int ... stltlum

ArSOzNH 2 --~

H '--" R

RCOOH

Figu re 18- 7 Actr.-e tubular secretlOrl of a drug IS a IWOS~ proc~ that IS Iocabndonly 11'1 tilt' prounaI tubu'e "'ell of the nephron The first step I~ the <KtM! lfllflS9Ol1 of a drvg tholt can eJ(Jst is an organ" anlOrl or an organiC (atlOO from lhe Intfflllllum InlO prOlllmal tubule cells by way of the or!Janic anlOl'1 trarrsport system (OATS) or tile organ" cation transport system (OCTS), respect~ T~ ~tems are located on the ant,lumlOal membrane of proximal tubule cells The second step ,nvollleS some combmatlOfl of pa~ve dlffuSlOO of the uncharged drug specIeS or 1IC\IYe transport of the charged drug species from the proJ(Jmal tubule cells Into the lumInal fluid ActIYl' tubul seaetlOrl contflbutes In a majOr way to the twgh luminal flulCllNI!ls of most (IIurew.

diuretic. The organic ;anion tr.lIlspon system (OATS) trans portS endogenoo~ and CAOgenous organic anions: the org::mic catioo tmnspon system (OCTS) handlcs endogenous and ClIO ogenous organic emions. ik<:ause most diuretics are weak organic ac ids (e.g.. carboxyl ic acids or sulfonamides) or weak organie bases (e.g . IImines). they uistllS organic an ions and calions. respccti'"cly. and are lilery to be handled by the OATS or the OCTS. Although the OATS and OCTS ate bidirectional. they transport diuretics prill1llfily in I sule tory directIOn (i.e . from the interstitium into prollOimlltubu le cells). E'"Cn diurctics that an: ClIOtensively bound to plasma proIein! may be secrcted avidly. Imponantly. neither the OATS nor the OCTS possesses rigid ~tructural rcq uircmcnts for the respective organic anion or cation being trunsported. The SCCQfId Step of acthc tubular sccn:tion of D diurctic in\"ol,cs its passage from prollOimal tubule cells into the luminal fluid, probably by a combination of passh'e diffusion and 1IC'U,c tnnspOrI. In addition to the filtration and IiCCTCtion processes. the concen tration 0{ a diuretic in the luminal fluid of the more diSlal .segments of the tubule is determined by the agent"1 lipid/wuleT JXU1ition coeffident and pK Ill! ..... ell as the pH of the distal IUlninal fluid. Thc.<.e factors nlOdulate the con centration of diurdic at sileS J and 4. Weally addic di. urcties ..... hose undiS50Ciated fonns possess I favorable bal ance: of lipid and .... ater solubility. may undergo pH dependent diffusion (refuled to as _;0'11(: Md dijfusiorr) from the distal tubular luminal fluid Nclr.: into the blood stream. This frequently dcc,eases the luminal fl uid concen tration and the rcnal ucretion rate of the uiurctic but proIoogs its plasm.1 half life. Diuretics thut are weak bases

follow a si milar course if the urioaf}' pH is 011 the alUIit side. ",hieh favors the presence of the uncharged drullP cies. Weak organic acids or base5. wOOsc uncharged fer. posse.\$ on unfavorable lipid/water panition coeffiCletlt.1I1I n.ot unde'110 nonionk bacl diffusion. 1llcse diuretics will. retained within the luminal nuid and. ultimately. \\10 It ucmed. Thus. diuretic agems may rcach high ..... , tions in luminal nuid following glomeru lar m\f1ltioll. tubul1l( .secretion.. and lillie or 00 subsequem noruonir diffuswn. Diurctics thai IICt at siles 2 and J as ",ell as that IICt at sile 4 inhibit Na' tBllspon processes on !be nal membrane and must anain rclatively high lurrunal concc:ntrutiOtls. In contrast. the CAinhibiting diul'tlic:.11111 act at si te I must anain adequnte concentrations wlthin_ nal fluid as well as intracell ularly. and the aldosttlOtIC onist spironolllC1one must auain adequate imracelluJar centrations at sile 4. Finally. the efficacy of a dJurctic is also dctnml!led., the patient's plasma volume and rcnll fuDt"tion s&anII, cumntly administered drugs that reduce: the GFR. and cum:ntly administered drugs that bind compefith"ely ICI* OATS or OCTS and reduce the active tubular ~cletioll. l u m in~J fl uid coocentration of the diuretic. Mnny of the past SA R studies involving diuretics conducted in whole animals. and the results maybe mi preted unless caution is uerdsed. Generally. compc I varied chemical strueture are administered to lJIimalt.IIM nnked lICCOrding to their abllily to produce changes volume ur Na output oven ~ribcd period. COlIC. are then drawn about which functional groups arc !be imponant for optimal diuretic activity. l"tIe noyice mrII ..

ill;;;;

.mber time tile resu lts from ~uch studies ClIn lIOIllCttssaril y !ot Inltiptcted III a ranking of the Hllnn~ic al:U\'ily of the a,mL\ under ~Iudy. DIUretic SA R sUld ies C()flduc1ed In .iIOIe llJ1 l1nals Yield results that ~rc p composite of differ ~ In the ~jon. plasma protein bllllhng. dl ~l ribuuon.

bIotr3nsformaliOll. excretion. IICU Ie IUbular !i'TelIOll. intn n-

aoo o;ecoodary cffecb (e.g.. chaugcs in the GFR) IIlIi11: \ moos agcn~ Unfortunatel y. most. If not all. of these
\JNbIe~ art' IlCglected dunng muw.l dim-elic SCrI:Cm ng proo:rdUIl'~: therefort'o it ma y be Il!>sumcd clTOI'\COOsly that dif-

lit kllVtty.

kiuj(o in di nn'uc acllI'lly are doe to d iffcrcOttS III IAltillSic

&:!lIlly. If OIIC IS ImcK-~lcd 111 the mlI1nSlC aclL Vl1y o f the

..,nl)('rs of a group of diu rclic~, a closer appro t imatiOIl can be .chie.,w by Cltaminulg the agents OIl isolated nephron

qmems on .... hlCh re lated prototypic diuretics are koown

tllII.1. Scn:ral such studies line bc!cn cOnducted.l l JJ It tlwld IlOl be !I MJrpOo;e when Il'sLllrs from in vivo and in
lInl SAR ~ul(hcs differ. Thi~

occur. bec1lu.o;c, of the Interplay ilchl-et:1I numerous p.l mmclers in lhe In ""0 stud ic~ (i.e .. bioipl.iQn.. distribulion. and slI(: h) thai can be eliminated in IpO(>elly tksigncd in v;tro study. A lmo<;t all structun:- IIIC' ''It)' dalJ cited in the upcoming por1ion of thi s ehllpler came tum .. lIole ammlll and human 11I,csllgano ns.

thllt retains CA-inhibitory activity. The mOIety to .. hich the sulf:l.IlMryl group is attached must possess aromatic character, In addition. within a gi~en seri cs of heterocyclic sulfon anudes. tiM: derivall ves with the highest lipid/wat"r partition coeffICients and the lowC!it pK. values ha,c the greal est CA inh ibitory and diuretic activities . The SAR studies I n voJ~ing the ",ml-diJulfllmo)"lbrfl~rfll!S revealed that the pltrent 1.3-di sulfllIlMlylbenl.ene lacked di uretic acti vity. but key substiwl ions (summariud in Fig. 18-8) led 10 CQmpounds with d iuretic aclivity.ll The fint rommcrclally avai lable analogue. dlC"hlorphenamidl: (Fig. 18-8). is ~IIni lar to acetazolomide i n it~ CA- inhibitof}' acdvit y. but it is also 0 chlorumic agent. SUbsequently. chloraminophc: namidc (Fi,. 18-8) ... hen liven by the intl1lvenoos route was shown to pos~~ less CAinhibitory actIVity bul more ehlOntretic actll'ity. lloor diufclic acti ~ ily follo", inl! the oral IIdnunistrdllon of chlornminophc:UIlIllHJe precluded Its nllln. eting,

PHARMACOKINT1CS

1be clinicuHy available CA inhibitors are absorbed well from !he ga.~t rointt"-"tinaltract . arc dlslributw 10 the sites of
major importance for CA mhibition. undergo little. if any blotl"dnsfornllltion. and are e~creted primarily by the kidneys. ALl CA mhibitors allain relam'cly high ooocentrutions in renal lum inal fluid (by a combination of glomerular fi liration and lIC ti,'c tubular o;ecretion) and in proximal tubule ce ll s.

SITE 1 DIURETICS: CARBONIC ANHYDRASE INHIBITORS

the available CA inhibitors are used infrequent ly dwretics. they not only played nn impor1ant role in the *,tlopmcllt of other maJorcla.\.'iC~ of diuretics IMt are eur!1liiy in ..... idl:spread use bot al<;o aided In our uodentandlng IImll: rcnnl phy ~ iology. ShOr1 ly after i l ~ introduction for ~.1Imcnt of bacterial illfections. sulfamhunitk (Fi g. 18 observed to produce a mild diuresis charocteri.7..ed by ill: prtl\o:OCC of urinllry Na ' and a subsw nt ial amount of !("(), n II was subsequently ~hown that il Indll(:ed thi ~ through inhibition of renal CA.~ ~ Ho we-cr. il Wa5 IINuvely "eal;: Inhibitor o f !"eIMI C A. and the dose ,!Ceded tIeR ;wJequate di ure~ls was as...ociatcd wi th seven: ad 1ft)( crrtcts. T o Im pro"c on the CA-mhibl tory propcny of ..,l;unldc. many ~ ulfailloy l-contai r" ng com pound, I.SO;NII!l " 'cre symhesized and !iCm!ncd for lhe ir diuret ic Utnly ,n "im and their ability to inh ibit CA III vitro. Two of CA inhibitor.. emerged: simple heterocyclic sulloJe~ and m/.'"l<l-disulfanMI)' Ibc:nJ1IoI;l dt-rivati\"(~s (Fig.
""~gh

SITE AND MECHANISM OF ACTION

CA is located both mtrucellu larly (Iype II CAl and in the lum in al brush border mernbl"JllC (type IV CA l of proximal COI1,oluted tubuk: cells ( Fig. 18-1A). Both of these silc I localions an: major targets oflhe CA inhibitors.' Thi s group of diu~t ic~ also inhibilS intracellular CA in the intercalated cells of lhe connecting and conical collecting tubult"S (i.(" . site 4 ; Fig. 18-6). During the first " 10 7 d3y5 of colllinuou~ lhempy wilh a CA inhibitor. se,'eml note .... orthy events occur that lead to an IIlCrease ill Na ' and HCOJ - ucretion : (<II inhibl1lon of the intracellular CA in proximal tubule ce lls decreases the available H ' normally e~cn:.nged for lumlllaJ flUid Na' . tbus decn:asmg pro~imDI tubule reabsorpllon of Na' (Fig. 18-1): and (b) inhibit ion orCA on the luminal brush bonier mcmilr.me of prmilllaJ tubule cells cau ses a decrease in the production of carbon dio~ide within Inc: lumrnal flUid aIMi a di..-crea.'\c in the proxim al lubu le uptake of carbon dio~ide. The nel resul t is a decrease in the reabsorption of lICD] . Orlol' nlig ht assume' that a massive diuresis would follow inhibition of the punio" of proximal lubule Na ' reabsorption under the conlrOi of CA (i.e .. one third of the 65% of the filtered load of Na normally reabsorbt"d from the proximal luminal fluid. or about 22% of the fil tered lo."Kl of No '). HO"t",'er. Na ' reabsorption ~i tt"S downstream (especially site 2) C()OIpellSllIt" for such an action by reabsorbing much of the addilional Na ' presented 10 them.6.. II. 13 Some of the lu mina l fluid II CO} is ~absorbed downstream by a non-CA-medialcd systcm.ll Thus. the actions of the CA inhibitors ultima lely ~sult In lite urinary loss of only 2 to

'I".

... .

fIIucrvRE - ACTtVITY RELAT IONSHIPS

~riR.'.tl(hes in vo lvi ng the sImple h"f"rocY"/lC suIfQllor",(J.,.~

the. proiOi ypic CA inhibitor. 3C1:tal.Olamide llt -J(I (Fig. The S41lfamoyl group is essentllli for in Vit ro CA-

: : ;\ :~~:;~ aoo for diuresi~ prodUCtion in vivo. The n atom mu.,t remain ulisubSli tuted to rewhl : and I ~I tro DCU' '"CS. 11us feature uplaills I 'itJrfonolllides exccpI ~ulfaJ1ilamidc an: CA or I:~crting diuresis, In contrast, of a I group on onc of X"CI.:U;OlanUde's yields Incthal.oIamidc (Fig. 18-8), a product

t-yK),S

'J

H
N - C -C~

"
I

Melh.az~ III'I'Ikie

(tleplu_)

I
I1ETERQCYClIC rULFONAMIOES

. '. " . ' . . NH>','. . .. ... ..'. . . 0 .'. .... . .... .. . . , . ,.' ' .' : . .. . HoNOoS '.. ' "..... ... .' ... . " . . .' . ' . SuIIaniiamide
"

" 'jQt '"

.'

'' 'of " '

,I'

meta-01SULFAMOYlBE NZENES

MIuiI'NoI au.tIc: ..tioity Ie OIJ ..... .cI when IhII PCW!tbl II ...... titulad with:

01-,8<-, CF,-. or NO,-.

S'oi)tlilutjon ....111 an.moo (- NHu group ~ eetillily. bull duo,ulI UibOlllc anhyCfase .... oibob f adMIy

Iocr,,,"

-An ..... obI ......

H,NO,S

IUIIMICJ1I rrOetv II 01

""""'

The .... moyt n":"51y can "- . . P'Food WO\h. Ilion, Iy I" " 'CIJlhiIiC group

(e.g., e.bolyl.~) !hIIr ..... y ro I I dIureIic 1)(;1' I(:y whiIo:J <kIerNSlng I;artlonIc aoh)'draH InhIDiIOfy 1ICtMIy.

~
Figure 18 - 8
~I

s.ulf,mi\clml(ie

of two das.ses of C<lIbonIc anhydritSl! MlbllOfS based on the ICtlOl'lS 0/

5% of ,lie Ii l1 cred load of N~ ntH! lip to ~ of the filtered lo.-wl of IICO l . SecoOOarily. the CA inhibitors enllallCc the uri nary e.~cre lion of a substam ial amount of K " ,'I . .u l1ie urinal)' loss of

bccau.;e the prDA imal tubu le actions of CA mhlbnoo. pre.st'nl a grealtt pen.:entage of the filtered load of Na " 1 sile 4. increase the now nile of lu mi nal nu id 0 through the dIStal CO!l~oluted tubule and collecting tubule. and decrease lhe avai lability of iruraedlular H at site 4. All three ehanges fa\OI' ~hatk.--ed uehange of lumll....1 nuid Na' for mtrnccllular K at site 4. The Urin.lry concclilTalWn of CI IICtually decrease, after the admi nb U ion of CA in ".at

K'

Inc~

hibi torll.' l lienee. CA inhi bitors are primarily natn~ bicarbonut ure tic. aoo kaliuretic agents. T oward the e oo of the fi r.;1 weel: of continuous . . . with II CA inhihilor. resi~tallCe develops 10 its dium.:e. feet." This i~ primarily due to two facton. Flr:sl. _ , marked reduction in lhe filtered load of HCO l bix ... CA ilihibi tlJl') produce both 2Q'I, reduclion III tht (]I \"ia the Ulbuloglomerular fttdlMck mechanism. and I lion ililhe pl3Sma conccntl1lt ion of HCOj Whm;';'~ leu IICOJ - ~nt in the luminal nuid. lhere is 1m wa:a reabsorption 10 inhibit. Second. the metabolic 1CIdoN\ :lied by these dlUn:IIC~ pro,ides II sufficient ~ ~

o..pla' III

l)',,",ies

60S

... -CA-generated IIllrucellular II . 10 e tehan !,,<, for the luiiIlIIl fluid Na' , The Na ' reab~)rplio" al "Ie I progres>ely R:IUms 10 It I\CDr-normaJ role, and diuresi~ wal\C'.

ADVeRSE EFFEm

Nur high ly predl club le alh'cr<e

W CA inhlbitOl"1i:

errccI' are as"-lCiRied ..-uh

, Oc:'dopiIKm of met:lboh" ",,;00.;, duf KI tIw: ""q,I km of

uro,

fI) polakmJI due W llIe n:na1 Iosi of K J ~pIU' m mluc:uon 1M lheG nt ..... lIkhijrJKlIn KIlle nlCt.h~Ied nl 1110 j u, I~g Inm"", IJlJ" appara IU~ IttluSC of ~i!l1C r lhe.' ,ncrcaJed II+.>w /'lie or lumlllal nuid p.uI lhe 1NC\l1~ dcnsa (e ll ~ or the 10;"..,..-..1 ,..,absorptlOn of the ..Jdouonal w;>iulc ~Ied II> lhe IlKUII "II~ (i.e . lubull>lllomcrulat fdback)' . 1j
~
j T~1"C

u vely restricted use tod~y because of its limited efficacy and ,he rcfr.ICloriness tllat develops to its diuretic acllon within lhe fi rst week of continuous tlM:nipy . However, i, remains the nlO!it impor1llllt CA inhibi lor IIvailable and scn 'es as the prototypic agent In i15 class. Acetazolamide IS absorbed cx II'I:l1Idy ",ell from tIM: gaSlroin tCSllnal tract. is bound exten sively to pl asma proteins, and is not biouansformed. Peak pl asma le ve ls are auainc:d ,,ithin 2 104 hours, Its onsct of IIC'tion 1 ~ abou1 I hour. and its du t'3lion of oction rangcs from 610 12 houn;. Acctamlamide is removed lOOIlIy from the plasma by the kidne)'~ within 24 hours. 'l1le renal handling of acela701amide iny()\ves its fihnu ion at tlte glomeruli. lICIivc tubu lM secretion e ~clusively in the proximal lubu le.s, and a vary ing dcgl1)t' of pH-depcll(knl nonionic back diffusion in lite dista.l segments of tlte nephron. Although In vitro ~Iudles ha~e 5how n N -[ 5-( a m inosu If on yl ). 3- meih y 1 1,3.4-II!illdiuol -2(3 ~. }-y l idcne 11lI.!t'1\1I11ide (NepW.ane I (Fig. 188), 1 be D more poten! CA inh ibitor lhan tIM: prototypic 0 acetDl.olamide, it is scldom used as a diumic (for 11M: AfIlC reasons sialed for acetazolamidel. Methazolamide displays Improved JlC."ne1llliion IIIto ,he eye,z' a propeny that conlributes to its usefu lness in the lreatmenl of glaucoma.
M~thazolamich!:.

.. ..... rfOlWTli<kI."'IOtiattd h)"ptfXn~,,,v"y """"lIOn', such Uf\I("U13. dlUS fe.cr, blood dyo<Cl'IlSia" and intc.~tI,,~r ...... phIIl"

USP, nlC."ihl17.o IIiIl1 i d".

(A mhrbilorl may al"" be as..~ialed ..-nh the production ~he!;1a!i (Iingling in the cAtre nllue~l. drowStnc--.s. faIpt, anorex ia, g:L~tminlestinal dl~\I.ntmnccs. and urinary ~It The: lancroccur becau'le ofa reduclioo in tile urinary ruK1KItl rotc of Ci trllle, a nor111al unnary compol\Cnt Ihat : . in mamtaining urinary Cal' sall s in a IIOlubi li7..cd : (A ,nh ib,ton can exaceroln c the symptoms as.o;ociated .... cll"\'hoo;is uf Ihe h'"r.)'1. ,." Cono;cqucntl y. tlM:lr use hId be avoided in p<ltil:n ts will! Ihis disorder. CA tnh ibi rll...,JI(Ioced al l..alini7;J tioo of the urine decreases the lIonnal IInlnaJ nuid tropping of nmmorlla (NII,I ill lhe form of . .:anum lon~ (N It,. I. This leads 10 II subsequent rWucDlI1lhe un narye~cR:tion of ammomum 1011.... Under these IIt\ItII'it1lllCCS tIM: hi gh ly diffusible ammon ia i~ dll'ened from 11K luminal n uid inlO the ~yM .. mic cin:ul~l jon , wh .. re i l1li)' conlribule 1 the de~elO(lnlCnt of hepatic encephalop0

."

..,

Dkhlorphenamlde. U5P. LIke tIM: othcrCA inhlbtlOB. dichlOlplM:namlde. 4 .5-dichloro- l .3-benzenedi slilfonam~ (Daronide) (Fig. 18-81, is se ldom used as 11 diuretic. link is known about its phatlnacokinetics. Like aliter CA inhibi'O!"lI, it rWuccs intraocular pressure and may be use ful in tIM: tre~ lmcm of glaucoma. 'l1le imponaoce of dichlorphcnam~ and " hloraminoplM:namide is lhat they ultimately sen'ed as ~tepplng stones away from the "pun::" CA-Inhlblllng diuret ic~ and towanlthe dcvelopmcm of tlte tll ial ide and Ihia 7.ide-li kc diureti cs, which are effective natnurclic and chloruretie 3gent~ witl! minimal CA .i nhibitory acli vity ,D. .lO

QlJjor u<;(l of the CA inllibilors i~ in the treutmcnl o f ..._~)6 CA b a functionally Imponant enqme in tIM: t)(. .. htn:' II plays I l ey role in lhe formation of aqueous InhibillOl1 of thi~ ocular cnJ:ymc rWuccs the rate II fomution of the lIllucOOS humor, thcrcby reducing the ~ulnr pres~lIre as~i~ t~'(l willi glaucO/n il. Inlere,tingly, IlfIllIction in the inlrnocular pressure usually peN,IS 31 a _ .. tw:n rc:sislancc has del-"Ioped to the remll effects of wCA Inhibitors." CA inhibitors \wi le been used pruphyiI<1Ol1y to coumc:taC1 acute mouni:lln sickness. .... 1 tlCt as 0 'miS for the treatment of epdepsy. and to creat" an .ibl11K uril\C in an nlltmpl to hn <;ten the renal excrelion of "". oox;QUs weal.. add, or 1 mainl{lill tIM: urinary solubi 10 ri cerulln poorly waler sol uble. er\doi!c:nous weak acids IIJ1C acid) .....

"'" r.

SITE 3 DIURETICS: THIAZIDE AND THIAZIOELIKE DIURETICS

Chloram inophc:namide became a logical key inlermediate in lite de l-e1optnenl of diuretics tllat lacktd the uodesil'1lble propcn,es o f tlte CA inhibitors. When chlor.lmlnophcnamide was IreatOO with ocy lali ng reagents , cyclillilion resulted in lhe format ion of 1 .2.4-bcn.J.othiadiuinc:-I. I -dio~idcsl' (Fi g. 18-9). 'l1le u~ of aldchydts or I..clOI"ICJ in place of the acylating reagents yielded the corresponding dihydm deri,ati,-es. "The: productS of Ihcsc: reactions became: known as thiazides and hydrolhinides. respectively. Hereafter. they are refcnW to collectively liS the IIIi1lz,de dllt~I;CS, 11Ie IIIia7idcs were the first orally effect i~e salurelic agenls whose diuretic activ_ It)' .... :L~ not innucnced by the patient 's acid -base: St3IUs..

STRUCTUR E- ACTMTY RELATIONSHIPS

U5P. Accta7.0lanmJe. N-J S-{amilM"l!iul IHJ.4-thiadilUoI -2-y l[accwmde (Diamox ) (Fig. 18, was Introduced III 1953 as tlte Ii'" Oflllly effective, non ..... w diuretic avatlable 10 the ph)"~K:ian. It has a relakttuol.mld~,

SA N. studies have been conducted witl! the thia7idc diureliesU,.lO (!iCe Fig. 18-9 for the numbering of the thilUide ring posi tions) , Brien y. the 2 position can tolerale the pn::scoce of relali,'c:ly small alkyl goups, such as C H)-. 11Ie 3 position is all extremely IInportani site or molecular

E~hullstive

CI'*;o .. I . ouptoer... I ooe

_Ia \
ICeIoo I sl

f igure 18- 9 Development of ttll(l~de ilnd tlydrothFaZIde dlurella from d'llorilmlf'\OPherlilmlde

nlO!lificalion. Substituent, In the 3 positK)l1 playa dotr role In detemlining the poIency and duration of.roo. tI the thiazide diuretics. In additiOn, certain substiluclib 1 m" 3 position r.a,'e yicl!k.--d compounds that arc relatJ\"ely liltcific inhibitors of Ihe diuretiC IIClIOn of tIM: \hill/.ides. If .. Los!i of the clUbon-carbon double bond between the 3 Md 4 posillons of the benI.OIhiadia/inc I . I-dio~ ide nocitu.. crease1 !he po(cllCy of thi~ cl~~s of diuretics appro~lInMd) 3- 10 IOfold. Direct subsututK)l1 of !he 4 . S. or 8 . .~ an alk)1 group usually diminishes diuretic aetJllty. S. 6111UII0li at the 6 position wnh an 'ac'li'aling' groupl'CIo !lCIIlaI fIT diuretic lK1J\1Iy. The be-.! ~ incbk 0-. 8r , CF,-. pnd NOl"grou~ . The ~IManlO)1 group In t!w:' po--itioll is a prerequhite for diuretic activity. Tablt II-I Ocpicts thi.: co mmerdaJly a~ailablc diuretics deri,ed (101 the man y alterat ions p!:rfomlCd on the bcnwthiadla1.111t-U dlo~lde nucleus. When I, was dio;;ro'ercd th~t the su lfamo) I group fJ(I'II' the acu vullng Puup In the n"'UI-t!lsulfamo),lbcnzcno be replaced by several OIm clecu-onegali,e groups .,.o~

. . ,m

Thiil:tlde Diurelks

'XX"..
PO

I ., , ,C-R ,

1I1NOIS

0' ' 0
Generic N. ....

S'" NU

-H
Hydrolhi.nide Oiuretics
H

'.
-CH, -S-CIlI - D

'nr;,e ". . I
7 i

11

II.NQ.S

- -

" "S0 ' o

' I I N-f(.

H}druDl URtL. EoOJo-.. , Or\'tic

IIl~" ...... h'1II1,,",

'.
- H
-H
-CH,- D

0,

,
" ,

USI'

S-oIUNn. o;"" ...... i~

N,.. .......M

lIondrullu ...... hu.lkIt. US!'

-C'. -Co,

"

Tndok.".,IIF,........ USP
Mnh) <bhwoJc-. USP

-Ote!,

"""'M ......
Crd".h,uidt. USP
Anh~ ..l'"''

-c",o
o
- CII,-'i-C1I,- C,,,

-([)

" '" ,

Chapler 18 O''''r fiN

607

SUBSTITUTED
metaDlSULFAMOYl.BENZEN

CH,
and
In

t<'ly Ilion

Sob-

~ e~

0-.
181

"""

from . 1.1 ra to
~. Do,_ode~'"

~ld

o
eo. r'!h,\

th

o
Ood

none !Hygr~M. lhaIolOne)

Fig ure 18- 10 Repn-'seotawes from SIll classes of thoazode-~ke druretlC>. These dlurellCS WI!/I! dtrn:1oped as an outgrowth of the thiaZIde resNfrn that 'ol'Oived moIeculal modIfic.atJon of arom;lhC solfafTlOl'll-<OOtalrllng com-

""""

0( dillft"tk :tCtil it y

that 1

(Fig. J g8). a ~( of dnm:tic~ become known as IMautlrUk,. tl;Ufflics. 10 Fi gure '8 10 re~nt (he most 8(:.

I"""

~~:",~ ')::O:f;~~achbut theirClearly. lhese diuretics ate "':"~ , '. 5eri~,. sitd of action. cffi caci e.<.
UCf"Cuon patterns. and ad\"rrsc dfcrl5 re'll."mble of the thia/ideo;. For throe rrasoos. the IhiU7.idc and diu~ic~ :m: difoCus~ as a gro.,p.
ACOlClNETta
) t~

undergo hule. if IIny. biotrun,ronn alion (e' cePC mc frm.ltle ~nd mclola7..one~2 ). and an: e.-ccretc:d prunarily by the 1.1 d flCys.'z. 01.~' Relmi"e1y high lumina l nuid concentr:lIions of these. dlureliCl are anaincd. u,ually by a C Ombln allOO of glomerular lihr:llion and ocU" e tubular .secretion by the: OATS in lhe proxllnal wbule (Fig. 18 7). The luminal nUld cooa:ntrution of these diuretics i~ cril ical for elicitalion of
diurc~ i s.'"

of the thl~lIdc and thlazlde like dlUrelies are absortx:d after oral adllllniSll1ltioo. except chlomthial'J tle (only 1 of which is ub->ot-bcd ).'1 "Their onset of action 0'\ Within I 1 2 houN.. and their peak diuretic 0 IOnhm 3 1 6 hou,.;.41 MI,' " diuretics in 0 bound exten.s; \ ely to p{uma protems (or tu CA for chtunhJlidone and mctolal'.onc: '1. ~2).

The diuretics m thi~ class differ pnmanly In potency and duration of ac, ion. 'z. O . , .... The differcllCe~ in potency J (\\.-hich an: refkcted in lheir dosages) are dctenlUm:d mamly by lhe chcmi C IUIll,lre of the moiety all:tChc:d 1 lhe: 3 pt:K-i. 1l1 0 (ion of the bC':nlOlhiadip:ci ne oucleu~. lOhich modulal es the overall lipophilidly of lhe diuI"Ctic.a 1O "J1w:, diffcrel'lCCS In durat ion of acuon are dictaled pnmarily by the dcgn. e of plasma protein bindinJ!. (or n:d blood cell bmdmg) lind their llpid/wate!" panitioll coefficiertl'j.' Of 111(: latter values along with the:. pI<. of the drug and the pH of the luminal nuid

TABLE 18-2 Important PharmiKOlogtul P.r.mtlten of the Thiazide DluretlC$

U..... Deily Adult On.1
,hi..]. or Hydo olhiadcle
(Trade N _)
~.USP

Partition CnH k l ...t

(E~""',O)'''

Plasm. Prote in
"nd~
, ~)

Delli, .

Ita~ ling)

( 1)1...1)

BmlIhi.t!..... USP

".
0.37
I
~)

DI.....st...

Optl.....

Itypertenslon'"' (hoIorst"'

.....
, , , ,
,., , ,.,

DI ..... tlc EffKt

~ .-

TA

(houn}41

-,

Duntlon
('-'

... ..........
)

" ",
'"

DO

"-"

""'-"""
-lOO
2~IOO

'-lOO

'-"
12-111

(ihno.. Hy""''''
I i ydrooll\onKll.iu..Jc:.

OSP (HydroOIURIl..
&'MlnA. Orru<J

.
"

,'-'-'"
Ll.j-1t'
1U-X1

X'I

'-"
,'-~

H)'drofIu" .. d "w... USPID ...1"...

-lOO
I~

"'-I
Tnc:No", .. rt "MI.. USP(M...... ydrift.
,~

.,... .
"-0

."

n,

'"
n,

",,11>2-1

N.,..I
8tndro/lUmWI,UJdo

USP IN ..","",)
Mdi)do.hou ..... USP
(A qa

"
I"

U .. I~
2.3--10

,,.,
'-'-,
I~

,
,
7_11

'-"
>~

rr iitIeli. ......1
I~

1'o;II)1Iu:uide. USP
( RmeK)

,
,~

,....
18--14

C),<loIhioll<le. USP ("nh)'drnnl

I'

I'

...
.00-',

OoIo _ _ ~J." """ """", .. 1<1 J ""'iII) ..... u~ ... . . , . . _ ....... d....1'J of~)"', .. ~ .... I. _ , C lI-.ofTloa ... ... 10lI0 001. Ne.' voot... ~ II", :1001., 11"/\

J G ..... ' In t ' "\, L. R.1'""P...... L.oM

determine lhe ClIent 1 which each member of the class 0 undcrg~s l'I'absorpcion in the distal convoluted lubulc by nonionic back diffusion. Man y of the diuretics in this class have long half- livcs. in pan because they undergo significant nonionic back diffusion. I'cninent phannacQlogical mila on the th iazide and thialoide-hke diuretia are presented in T abks 18-2 and 18-3. ~pectivcLy.
SITE AND MECHANISM Of AcnON

The site of action of the thiazKle and thiazide-like diuTl'tics

dlffcrs slightly fm m one species to allOlher. In llumans.lIow. ever. it appears SlIfe to cOllC lude that all of these diuretics block lhe reab'lOl'ption of Na ' (and. thereby. the reabsorption of C I ) in the distal convoluted tubules by inhibiting the luminal membrane- bound Na' ICI OOIransport system...........09 (Fil. 18-5). Thus. all diuretid in this class are ~ponsible for the urinary loss of about 5 to 8% of the IiltCt"ed load of Na . Although they diffcr in their potencies ( i.c . lhe aJ\lOUnt of dNg oeeded to prodoce a li~cn diuretic response). they arc equally efficlICious (i.e.. they can all e~e" a sim ilar muimal diuretic Tl'Sponse).l" JO. '" As a result of their IICtion at site 3. the thiazide and thia :rJde-like diuTl'tics secondarily alIef' the renal excretion nne of important ions (lIl!erlhan Na' and Cl . Inhibition ur Na"

and C I reabsorption al site 3 uilimately results in the ddrIcry of more of the filtered load of N. + to site 4. ASI ma there is enhanced e~chan8e of luminal fluid Na' for pnlll> pal ce ll K ' which results in an increase in the urinary c.taf. tion of K . Most of the thiu7J de and th ia1.ide-like dill1'COO possess residual CA;nhibi tory activity Ihal can be um ated with I slight increase in the renal ClIcretion !'lit tI HCOj Unlike the "pure" CA mhibit Of"S. the thiando:., thiazidc-Itl:e diuretics usually do no! evot.e devek:lplklltl I'e.\istancc: due to dNg-induced derangements in acid __ balance . lienee. diuretics in this c1as.'l may be refermllu rullriurnic. Ch/Onlfl!fic. sil/Ilfl!/ic, kf/liurttic. and ~U'ta'l) weak bicaroon<lfllftH;C IlgenrJ, Importantly . Short-t~1lll tbcr apy with II thiazide or Ihiuide like diurelic results in IiIIIt: or no c hange in Ca H ClIcrelion: howuer. long-tam ~ with lhese agents may lead to reduced Ca H excmion.
ADVERSE EFFECTS
Foor of the adv~r'$C effects lIS50Ciated with the Ihinde" thia7Jde-like diuretics are hi ghly predictable becau~oftla chemiclL makcup or their 8ite of action along the nejboa

ChHpltr 18

DiUrt!fic~

609

I Pa ra m e t e rs of the Thiazide-Like Diuretics

.."'" ....
"
S (IV ,

Pa rtitio n
C...tficient
(Gc:t ",noll

etedln
M~

H, O PO. 8uff )"

PI ",sm '" PToteln 8inding

0 -1 Da lly Adult Or",1 Dou ge R",,,,e ("'9)

Diuretic effed
.",..,

t%)'"

Optim ",' Diu.nls"

Hypertens ion'"

(hoIJrs)U

th.Qurs''

....
,

% P",.. nt
Oru, h.uet" In
Uri ......

Ou.at ion
(hours) .... ' ..."'"

,_.
'1*.......)

0,]-11

,.
31.1

"
71-1'.1

,.,.,
~200

I~S-j

S (otall is 11\')

""
00-'"
(ROC)
~,O

lS-""
I,!S-~'

,
,-,

~""':16

" ,..,
''>-OJ

1&--24 12*24

B--20

Ol-ro

, ""-,
~IIJMOO.

(ROC)

"..,

lS-lOO

12.S-50

"-n

44 (<nI) 6S (IV)

IS (Otall
83 t lV)

_',n.. _

deliv-

resll lt. prind-

e:o;crelIrelics asSOC Irote of .d c and nenl of d-base

~d 10

as

:n:me ly m therIn linle therapy ion:l6

ncpllriti PeflK)ns . .., "'" hy~nS1I1"c t<.> I)rlC <.>f the Bt:"nlS ,n Ihis cI~s~ ""ill JItIblbly be hypc~nSllive 1<.> all <.>flhem , C","_hypcrSt,,,,lIvrty ...... may occur betwttn the ,hi3zidc and th,vide.hkc d'Urt!IICS, CA inhillilors. nnd ,he sulfamoyl.~ollla'ni"g loop dlllrt!lIc, ,uch "f...,..,mide aOO bu ....,tanide, , IIYl'oLalcmin il m product of the diurel,cinducro ,ocrease ill !hi: lena) C;(~fl:lioo <.>f K ' , Inmllly, thc:sr diufl:llcs pn.xlucc. slight trduction in the cardiac 1NI'puI. Slight trductl<.>flS in plasll\3 volulTlC' and blood prr:'lm", omu WIth COntinued II~, These I~ttc. chan~d an: frcquc:ntly ....ae,ated with incfl:a~ in (he pro.. imal tubule fl:absorption of "~Io:r and soluleS, renin "'Ie....,. IlOgiotensin II formation. al .klo$terunc: secretion, The ,'ombinal,oo {If the events i~ freOfK"t1y fl:ferrro to II> tile d,uf'mc I>ro);'-"9 ph~"(Imf''''''', ~ dwlGes usWllly help mitigate the diu""lIc dfn:l. bu' the blood jWI'S<Ilfl: trducllon pets,,"," On'asiona]ly. a patient may cxperieocc h)'percalccmia (If hnlCr .ic~mia an .... long-term use of a thiazide (If thi~jde-like di . llftlie, This resul~ from !tiufl:,icindU<:ffi Il:dvction of the pa. _ ' $ pl3S11\3 volume .nd a concomilant contpenl>lltOr')' iocn:UfoC .. tile prm.,maltubule reabsorpl,oo of luminal nuid and wiule!!, lII>11t:n I s;llIllllon. ~ Ca" and uric "",id tJurn u~ual w,lI be: ~ p"",imally," The seriousness <.>f tl!esc two ad"cn;( cffe,;:t;depends in p;t" 00 the dura"",,! and eu~nl of the plasma ,1lIumc rcductioo ,

.wi fe"cr. blood dyscrasiao, aOO inten;titial

cide a nd oflheir lephron .

The prL-cisc: mechanisms behind some o( Ihe ad"er.;e efhb of the thi azide and thiazide-like diuretics are nOi well lIIIIr:rstood, Thc.'\e include an aCUle reduclion in Ihc GFR llIF,ully ofter intI';! ,'enoos adm iniSlralion )2) Hnd hypergly:raiL It is unm.:cly thai lhe reduced GFR is rela ted 10 the l' fcedhack mechanism, beeau'\<! the m~jor I of is distal I<.> the macula densa suggesled that the thiazide ' act direclly on the renal vaseula-

lure 10 dcpress lhe GFR .3l,) Nonetheless. the acute reduction in the G FR involves all diurelics in this class, with the possible e~cepl i<.>n~ of mctolawne and indapamidc, ' 2 This is p.1nicularly importantt!) indivi duals with pree~ iSli ng impairc:d renal funclion woo rc:quire diuretic Iher~py. Thiazide ~nd thiozide-like drugs are frequenlly ineffecti ve in indi vidu3 1 ~ \\i00 have a GFR below 15 to 25 mUminute, Mctola7.one l , ." 016, 53.'" urn! indapamide'2 may be useful in such cireumstances, c:d ThillZide and thiazide-li ke diuretics can be invoh< in sc\'cral poten tially serious drug interactions. The first of these may occur if unadjusted doses of U '" are admini~len:d to individuals oolong-Icnn thiazide or thiazide-like diuretic thempy. 1lJC proximal lObule handles U + and NIl+ similarly, During 100tg-ternl th iazide treatment. the rc:sulting reduction in plasma volume triggers a compe nsatory increase in the pro~imal tubule reabsofp1 ion of Ouid and solutes, T hus, more Li ' is reabsorbed than would be in nornlOVI)!emil.' individuals, l1le resu lting elevaled plasma level s of Li ~ may provoke serious Li loxicity,~' Scoond. ~"(lncum'nt admi nistration of II thiazide or thia7.ide-like diurelic wilh large doses ofea 2 -containin substaoces may ~uh in hypercalcemia because of the ea + -retaining propen y of Ihese diuretics. Third. concurrenl use <.> f thiazides and thiazidelike diufl:tics and nonstcroidal ami-inOanuIIBIOf)' drugs (NSA IOs). which inhibit pl'()!;taglandin synthesis. can ~uh in the NSA IIfi antagonizing the induced diuresis. In addi t ion, NSA I Os can increase lhe ris k of renal failure in patients whose margina l rena1 function is being maintained by the in tmrenal fl:lease of proslaglandins. Founh. when thiaride and Ihiuzide]i ke d iuretics:ln: used along with cardiac glycosides (e.g . digoxin or digilo~jn) in lhe treatment of c<.>ngeslive hean failure, !rCnoos lo~icily can result if hypokalemia occurs (see discussion below).

USES

llmu;1\le and thi :l7jdc-h ke dlurehc5 IlR: I'-\Iremdy useful in the': lreaunt'nl of edema :associalc<i .... ilh mild-10+modmtte conb'eSu,'c hean failure. cllThosl~ of the h,'cr. or lhe ncphmlic ~yndrome. 1kc3use ctkilla is a symplom of:lll underl)'ln8 disease and nOl a diSl!'asc i!.'\tlf. lhe underlYlllg disease shoul d be lrealed fi n,1 if possibk. If treaUl>cnl of lhe underl ying disease does nOI remove the edema fluid, then diuretic lhempy may be indicated. C:ml ion is a lwlIY~ necess:uy when Ihia1.ide or thillZide-li ke diuret ics are l'ood lllini~tcred wilh can.lix Illycosidoi for the treaune nt of edema :associaled with eongc~ti\'c heart failure. 'The5C diureti cs IMII to pronlOlc hypolalemia. a oon.dition Ihal enilancc, the gcnernl toxici ty of the': cardiac glycO!.ides. If>.~' COI1lbi natioo diuretic lher.lpy (i.c.. a thiazide or thl37 ldc-h l e diuretic plus II K +~p;lnng dmretic) may p!'CVCnt K ' loss under tl'w=se drt:um<;taI'lI.U. If combination diuretIC thcrllpy is mstitutoo, the reCipient shoul d be. ;td"iscd not to lal e K ' supple ments. to a\'oid 5Crioo.S hypcrlaLcllllii. 'l Thi:ll.lde and Ihia1.ide-hl.c dIUretIC'S are also useful in the tfl'atme nt of tertai n non<:demlltuus disorders. Thc. C incl ude " hypc rtensi ool. diabetes insipidus (en ll('r the n.::phrogenic or the neurohypophyseal fonn). type It rellill tubular acidosis. and hypefClI.kiuria. The'OC diun:tics are primary agents in the treatment of hypertension-ei ther alone or in combination with OIher drugs. deptndmg on the !;evcrity ofthc cOlldit ion. Thhv ides generally lo ....cr blood llT'CSSure 10 to IS mm Hg W.thllllllc fiT$! 3 to 4 day~ of COI1tinuous tfl'atmcnI." After apfll'Oll im::.tety a "CC~ of conunuous treatment (about when there is a concomi tanl reducliOO in pl;lSrna volume). the kidney' readjuSl to the ,nllml effCClll of the diuretic, and the dlurellc cffect want'S while lhe': blood ~s\ITC reduction is mai ntained." Th i. readjustment OCt:ut'S provided Na ' intake is not increased. Some individuals with hypcreald uria (an elevuled urinary concentration of ca lcium) are prone to the fomlation of Cal' -containing storlCli within the urinlll)' trllCl. Becuu.'\C long-ten n use of thi al ide and thia/ide- li~e diurelic' decreases lhe urinary excretion rdlC of Ca~' , they may help pre,'ent Ca~ + -contaming .lOne fonllation."" 5CI

though these propcrtie!o are true atlrii>u1C:S for ~ny elm diuretic.;" the organolllert:urials ha"c II number or Imlltallons. Fir-ot. when gi,en orally they ea.nrlOl be: on to c liell diUre5i~ because: of pOllr and eml1lC absorptioL Second, afler parentc:ral adminiSlnltion there is I 1- IO!' hour Illi !II the onset of diurtsi~.fIQ Third, lhe,r IIbthc) lOgger I diuretIC response depends on lhe IIdd- ~ oflhe indi vidual (i.e" they are incffecth'e when the Wlllr alkalinc) .bI. ~ Fotltth. they are ca rd ioto~ k lind ncphrolu).ic' 11tc orgi!llocllercurials became obsolele with the introo.luct;... of the thlazides and Ihiuidc-like di urellcs. funwcmitk. lit IIletanide. and elhacrynic xid. All of the laller agem lit or lIy effecti ve. equall y effec!i\'C' !II both acidotIC and .. lotie condlllOlls. cllp;lbl.e of inducing relah \ely I1lpid d;';;; .... hen gi\'en partntcralty. and relat"'~ ly nontOXIC

5.S .. tt.moyl.2 . mllllabelllaoic Add ..... 50 S .. tt.moyl.3 .mlnabenaolc Add Derivatives

Bumetanidft, USP. 'The struct ure of hu nielallldc. ~t. t) hUT1ino)4-piM:no~ y_ S_~ulfamoy lbenzoic acid ( "alDCl~ shown in Figure 18- 11. Furosemide, USP. The structure of furos.emllk . c hloro- N _ u rfury I-5-sui f amoylan Ih mn Ihe acid (laSIi ~ f sIlo .... n in Figure 18-11.
STRUCTURE - ACTtVITY RELAn ONSHtps
.j.

SITE 2 DIURETICS: HIGH-CEIUNG OR lOOP DI URETICS

The dlul"I:tics in th l~ clas.~ ha,'e e\tn:nlCly d,,'ersc chemical
struCtures. 57 Although bricf nlCnlion i. mOOc of the organoIIICrt:urial diuretic~. primary allcntion is focused on !he: agents wi th cl in ical ulility: for example. furosemide (a S~ulfamoyl-2-ami nobcn.,.oic weid or anlhrunilic acid dcrivative), humctanidc (a S_~u lrallloyl_3_a lllinobcn.,.oi c acid or ")Ctalli lie ocid dcrivati vel, lor;c:mide (a 4_amino_3_pyridi ncw lronylurea), and cthocrynic al:id (a phc nO\Y3Ceti c add de rivAII\C).

'The dc"~I()pment o f the': loop diuret ics is IIll outgroy; th d rescan:h in\ oI"!II1!: the thiuidc and th t3.l.idc-hle dtllftttO, 1'hcre lire Important qructund TCqUirements that are 10 the 5_sulfamoyl_2_amioobcn7.ok acid deriuu ,cs 5_su lfamoyl_J_lImi nobc:nzok ocid deri ,'uthcs (Fig_ fiN, the subst itue nl at the I position must be acitl~. carbo~yl grou p pllwides optimal diuretic IICti vlly. ,,, ,. . gllmps. su(: h II, a telnl7.ole. lIlay impi,n respectable IIClivi ty. Second. a su lfamoyl group in Ihe S p!'Crequisne for OpIimal high-ce il ing diuretic ' lhe " ocliv~"l1g" group (-X ) in the" Jl"'iition . C F , . as was the case with lhe thi:wde5 and diuretlC.~. or beller yct, a phcnoX). al~o~y. I or henlOyl group. I nI~~tingly, subslllution of one IIlIIer fiH': fuochonal groups for the a or eF, thla/.ldes or thllujde-li~e diuretics dt('l"I:iISI!li ";,;
JIC \I ~l t y.

o.-ganamez curlals
1bc oq!allOlllercurials ",'Cre the mainstay of diuretic thcrap) from 1920 to the early 19SOs.~ Theyelicn diul'I:$is by inhibiting Na - reabsorption at ~lIe 2," and they bluntll'w= subscqllCnt e~cluonge o f Na ' for K - at Sli e 4." Thus. lhey an: nalriuretic and chlororetic and minilnall y I.aliuretic. AI-

T hese t ..... o Sl'rics of 5-5u lflUl1Oylben7.o11: greall y in lhe nature of lhe funcllonal ~ubMitu tcd inlo lhe 2 and 3 positions I Imll diUreTic octivity (Fi g. 18- 1 I). The he toleroted on lhe 2-alll ioo group of the mninobcnl.Oic acid~ are extrel1lCly limited, and dcviation~ are allowed 011 the few lnoieticJ. only the furfuryl . hen.,.y!. :and thieny lmc\hyl (In order) nlOieties yiel d dcrivat;"e!j "ith maxill'l:ll livlty. The ~u bstjtllCms allowable on the )..amioo tl'w= 5_sul famo)' I_~iooben7J)ic oclds ';-.111 vat)' ho",c'~r. wilhout jeopardizing opcimal diuretlt' . .~ Hl gh-cei h ng d lufI'tics acid SCrK:!l famoyl-2-8minobenZoicthai ila ,'C 3.l.oscmitk:. those I I ~ries include and piretanKic. OIIly

~~~f~M~~""~~~ "

Cha pi n 18

f),,,",,O

611

- .
'"

nIU'
' I~

M'

-min

b,
~

Il a-

I
H,

I
.... (CH ,)~-CH~

-o~
H, NO, S
tl-.)

&.0, _ _
(~ I

COClH

Fi9<- 18- "

Ri!SUIts from StnKtut'e-iKfMty If!i4oons1ttp m.dIi!s dade fed to

die deYeIopment of (Uf~

rrwde and

bume\all~

."

bullltl:utide arc commercially available in the United

,rlne

Ic~. ~,

fIroscmidc alld bumcillnidc dltTer pharmacologically pri. lUll)' in their poIcndcs and bioovailaDilities. Bumetanit!e
IBn

'"~ d 'h< ~ I 1J.

".,
Irt'\!(

poItnt than furosemide; it ~uces an cquicfreclive s m abol.lI 1/4OIh the dose.~ .. The bioovailabilily of

"'''',
1urd.
"
~

... hen ooministcffil oralty i~ ab(MJ 1 6O!O 69% in KIIIl&I subjects but only 43 to 46% in mdividuals with end. . ~nal di~aSC' .' The bioavailabllity of bumetllnide In

~mHk

IOfIII.1.I individuals

IS

80 \0 9O'J>.f

.' l

Aller paren teral admmislr.Ulon. both furosemide and bu.unide lIa\'c an curemely rapid onset of action (3 to 5

luminal fluid concentratloos of the loop diuretics. 11le endogenous wcak organic acids compete wi th the weakly acid ic diuretics fOl" active tubular Sc:CTl:tion into proximal tubule luminal fluid. Often. the effects of the endogenous weak acids can be overridden by IIlCn::asing the dose of these di uretics, Caut ion mList be exereised. however. becuuse an increa..<;cd incidence of adverse effects is likely to accompany higher doses. A small percentage of furosemide is conven ed to the corresporiding glucuron ide. arid 88'l> of the administcn::d drug is excreted by the kidneys, BumcUlnide ulldergocs n10fe extenSI\'e biOl1llnsfonnation in the human. and 81 % of it is excreted in the urine (4j'l. as unc hanged drug)." StT[ A NO M ECHAN ISM Of ArnON The cve nUi \hul contribute to the tremendous efficacy of furoscmide and oomclamde un: multifacc\ed. First, these di. un::tics IIIhibit the INa' fI K ' flCl COIfIInspol1 sy~tem SoClUed on the luminal membrane of cells of tile thick ascending limb of Hcnlc's 1~ 1,'1 {Fig, 18-4). Importantly. !he carbo:Kylate moieties of fUl'Of;f:mide and bumcUlllide an:: thought to compete wlih CI- for the a --binding Slie 00 the INa 0/1 K' flCI- COlmn~port system, Because sile 2 is such a high-capacity site for Na" ll"absoqKion, up to 30'1> of the filtered load of Na 0 that is normally reabsorbed III this nephron scgmen t may be excreted in lhe urine, In addition. n::absorptioo ofthis3O% of the filleted loOOofNa 0 (and Cl ) is required to mainlalll the hypertonicity of the medullary inlentitium,l l Tbe hypertooic lIIeduliary intersti tium allows us 10 produce concentrated urine by drawing water out of the dc""l'nding 11mb of HenJes loop by osmosis and 0111 of the col lecting duct by osmosis ... hen ADU l~ present. Thus. ....hen ,~ dl ull"tics inhibit the rcabsorpllon of up 10 30% or Ihe filtered load of Na' at sile 2 ..... ithin minUIC5 lhey a1sodcstmy the h)'pertonidty of the DYdullary interstitium. 11le net resu lt is !hal ..... hen Na 0 and CI - are not reabsorbed 31 site 2. water is no longer removed by oslnosis from the

:.11\.;( tnl)' l.

,r the

in the

ureli"
diffCT llil bot
ma.\III ClIIl

;,y1-2pinole
Ifllplc. !llSing
~p of

' iddy.
\1\11)'_

5-\ulJcund Jc acid .crni<k

__ Dullilion of X"tion follo ....;ng parenteral themp)' is Mrs,). 21n1rs for furosem ide and 3.j 1 hours for bumemnide. 04 IIoIh diun::lics have an onset of action of appro:K imately 30 6Ominut~ afterornJ therapy. but furosemide Ilasllilightly durauon of acuon than bumctanide (6 to 8hoors ver .,.4 tQ6 OOurs).~1 Once ~ agents rcuch the bloodstream. fttyareutenstvely bound to plasma proteins {93 to9j'l.).1>J degree of plll5ma protein binding 'ielen::ly limlt$ the .wnt of each dl\lg that can be removed from the plasma ~ ~rular filtnl.tion, but it does not prevent either drug .. \almng high n::nal luminal Ouid conc:ent~ns by IUve tubular secretlO<1. 80th diuretic, are ... eak or!;anic kids and an: sa:n:tcd aVidlt,inlO tIM: IUllllnal fluid of tIM: -.w.unaitubule (Fig. 18 7), ~ This is Important for twO ;;;;;;;, First, it is responsible for the relatm::ly rapid n:onal M'l'tJon (henee. the shot1 durntion of action) of both di ftIICS: and second. It provides for the delivery of 5Ubstlllltial -.ws of each diuretic to their lununal ~ite of llClion. The factors discussed above tllnt detennine the luminal actlllratioo of diurctics are critical when the.se agents an:: .nt In indl ~iduals with un::mia. Uremic individuals freh.we a low GFR and high circulating lel'els of weak organic acids, bot h of which lower the

6 71

IVi!wn

/If..1 OicJl'Q/d'~

Trrllxx1l. 110rganu' Mnlirin<l/ <lnli f'hamllll''',fic,,/ Ch~miJf"'"

Illminal fluid ,n the descending limb of Henl e's loop or from the lvlil'cting wooil' . L.argc amounts of water. Na ' and CI l i t excreted. SonJ. high conccmnlllon.~ of furoscrmde alld bumr:tonide ~ attained in pro~lmal luminal fluid by way of the OATS alld delivered to the INa '/1 K' nCI- ceMrJnspol1 lySlem It site 2. Third. although these diuretICS increase the flow rIlte of luminal fluid past the macula Iknu cells. the eJlpectcd redl,lCtion in GFR (w hich normally would milJgate the dluresi~)does oot orxur. This is b1Iuse tile.o;e efficacious dIuretics inhibit the I No' II K nCI cO{r.msport system in the luminal membrane of !he macula densa celb and so decruse !he uptake of tile.o;e solutes. which in turn inh,h,ts the tuool~lomerular feedback mhani~m from decrea.~ing the GFR. Founh. these diuretICS also tnIllslCntly incn:ao;e teMal renal blood now by enhancing the int~nal rdc:l!>e of va sodilator)' prost;lglandins. Fift", they induce a redistriootion of intrarenal blood flow that i~ tbought to par1lcipille In a positi"c way towan! the magnitude of the dlure$is,n All diuretics that act at sitc 2 are equally cfflcacious alld faT Il'M)I'e cfficacious than diuretics that act II sites I, J, or 4, As mentioned abovc, becau'\C of thcir sitc of action alld dru;lI(:y. these agclll~ IU'C clHnmonly refcrred to as 111011 and h.[(hteiling diuretics." Iligh-cc iling diuretics secondarily cnhancc the urinary loss of K ~ and U ~. Fil'lit. by inhibillng the INa " I K 'naCl'lWUlsport ~'QIllpl('.'( at site 2. they preven t the gencrution of a lumenpositive lrun;.epithclial voltagc and. tilerc:fore. the panrccllular reabsorption of K' and other callons. Second. inhibition of Na' reabsol'ption at sitt 2 ultimately (\elivcl"!i n~ of the filtcred load of No ' . al a faster ratc. to liite 4. Th IS leads to an cnhanced CAch:mge of the Nu' in the lumi nal fluid for !he K" in thc principal cdls and the H ' in the inteocalutcd ~Ils (Fig. 186). When the loop diuretkll are used in "slIbmuimal" doses for the treatmenl of hypcTlen~ion , lhcy nre uHcndcd 10 create a diUI'l'Sis similar in InagnitOOc 10 that produced by the Ihiatide alld thilll.idc-li kc diuretics, Undcf' these ci~umstances, loop diu~lics usunlly !If\! associate" with a lower frt:queocy of hypokokmia than the lhilll.idc and thiazide likc dmretics becaus.c their dUlll.tion of action is sllOncr, and the kidneys havc more limc to n::adjus!. 'IU. ~1 When the loop diuretic~ IU'C lIsed to treat acUtC edema. howe,'cr. higher dosages lITe freqUC'ntly used. and !he Na" and K " 106$C~ exceed tho!;e accompanying thia/Jdc therapy,JIC When the loop dIuretICS inhIbit the I Na '/I K" ncl- cotransport system ill the luminal me:mbrnneofthlck ascending limb cells. they in turn decrease the IUlnenposill'e trun>epl' thelial voltage that promoIeS the p.-traCC'l1ular mo,'cme:nt of luminal fluid cation s such as Ca:' inlO the interstitium (Fig, 18-4), Hence. loop diuretics may illducc the renal CAcretion of up to 20 to JO% of the filtcred load of Cal ... provided the pla~m~ \olumc is OOt allOwed to decrease.'o I( plasma volume: decreases 115 I result of the dmresis. there iJ an ac companying compensatory Incre351: in !he prm.imal tubulc reabsorption of fluid and solutes. About 60% of the filtered load of Ca" IS reabsorbed in the proximal lUbuk during normovolcmia. and the percentngc ofpro~imaUy reabsortled Ca z , wiH increase in n statc of pla.~m3 volunle reduction. n.crefore. during diureticinduced hyp:wolcrnia. less Ca" is dellvcred \0 the thIck ascending limb for the loop diuretics to inhibi t. which will blunt the loop diurctic '5 calciureuc effect.

AOVERSE EFFECTS
Four highly predictablc advcrse effects are a5!iOCi2led. fUTUsemilk lind oometanide:
I. lIypoblnnic albkwil; ~IIS from ~ cnhancro c~~ lamlnal flu'" N.' for ,ntracellular K' or II ' lOllS" SlIt' CaUl"", IJoould be ucrci.ed when ronc"mlll Ihrnrpy .,111 drun:IJCS IIId CardlX gI~ " InstJlulCd ~ ~.";
2,

k ll'" inlcn~l rlQ the lOX ICIlY of lhe cardiac ,Iy~rcb.' IlIlhe ~ ICI1!I. and Cleclrutylc tOllSoCll may DOl be ~ panied by chanJU in the GFR beausc of ~ nfCCl!:l'" IIcnts Oft the tubuloglornenll.. rdboct 1'1111:1111'<11, lerm u'"' of Ihc!.c: diurelic~. Ioo_,cr. may reduct: pl~'" Ill1M'. If th,~ CoOO.tlOO is ,nOVo'ed 10 pers'S!. ~ alxI1IC' IUC: 0;';"; changes ,,"c piX!:, OIl<' of "'hith i~. 1M'

"",d

Thr....ii ,

J.

&cau!;e diureticinduced ~ma voIUIIM' reductIO"

, ..asul fUbAAprron of PUIN AOI'TNlty tr.ndlcd by ~ piIIII mal tubule (e,lI .. "ne acid), .\oOfTIC bonlcrlllle hyporurra.mic iIIII ~idr.W$ OI..y devclop 'ympoms uf gout on Ionc-imll d,,,retlC lhenpy, For ilrrular ~ COfIC1III1:nIlldrruoi,...~ of loop diureuc~ and "o;odJu;led doMos of U' may klld tOXltl! U' IOxicily.' 4. furosemIde and ilul'1lC:lamue are .. m,lar \0 lhe CA III 'J I, thuu:ide>, ;urd thia7.~Ir~e d,uret,c, ill ~Stnll' ",lf~1 l!IOM:Iy, (ulI<lionat ,roup h:lo bera :l$loOCi:Iicd wllb Ir)pt !iCnslll~lty rNCbOIlS IiUCh at; "rt,,;:ool. drul fc>'e<. blood oty<m. ~ Ia .. Inll inl~I')t11i~1 II<phriu~,

1c:Ids.,.

Th,.

Sc,'eral unforeseen adv"SC cffC("\s arc lISSQCiated .idt tr: Ioopdiuretics, For cxample. they arc unIque amongdiumLl in producing ototo~iclly. Usually. hearing loss is tempmt) but II may be pemulICnt, Ot()(o~icity may be .. rectly with rising prasm~ ('Uncentrllt ions of tile loop diumir;~ Accordi ngly. illdividuals with IllIpaired renal functo .. pear to be at incn:ascd ri~k because: they ha,'c a ,....t,..... ability to cxcreTe these efficacious diuretics," Allhough fit milligram dose of bumetanide is 1(4Oth thai of furo&analt these agcnts appear to be Ijuitc $irnllnr in their OIOioll; Pl' tcntiat C~ution i~ nceded if loop diuretic~ arc adlllini~ to potK-nls who are recti"lIIg any of the available aml~ "oside al\tibiotjc~, TIre OI()(oxicity of thesc twO clas~ tl drug~ may be IIdditive.~' Otho.'r ad~trsc: eff1l> of ful'06nllll and bumetani(\e incllKk h)perglycemia. nausea. \~ and my:1lgIQ. NSAIDs. which IIlhibit prostaglandin synthesis. may the natriuresis produced by loop diumic:s. In pilt~nlS. prec~isting impaired renal function ",110 are 0/1 dtUn::tic dtf apy , NSA IOs may incn::lSC the risk of renal failure by bbJ. ing the intrarcmd synthcsi~ of \'asodilator)' proslagl the 0IlC thing that may be suStarning renal blood 11O'J .. these pmients. '

v.oc"""

uses
High-cciling diuretics ~ cffective for the IJ'UII!d edema that may accompany congCSlivc hean failuft', om.:.. sis of the Ih'CI'. alld the nephrotic syndrome. A 1IlOSI . . . tant use of furosemide or bumetamde is III the tre.1lmr.! pulmonary edema assoc Iated with ,ongestivc he:u1 No group of diuretics is more effectivc than the k:qr' u.rctlC1i ill this sitUllllon, but they must be u'\Cd " 'lIh C.llrml caution, O~crl.ealous use may redllCC plasma volume)O.verely thatlhc resulting tlccre<lSed \'ellOl.lS retum 1lIlIl~" output eJlacerbitlc lhe hean failure .....

rar.

ChaplU 18

f)"Urfk~

613

~ ~lle

",
4.

lith loop

~pK'bOr(~ ~ma

,acc:om..",.

'he lonl-

Loop dJLIIl:tics may be used for the m::aunCnl of cenain II:IIItdemalow di~. Symplomauc h)'~rcakemia may IE treated WIth a loop diureuc. provided 00 reduction in ~ Yolume oocurs aod Inc nuid used for replacement of Ik IInnary losses IS calc ium free .'" In addition. fumsemode "lIren u!iCd for the tn:annent of hYpc'ncnsion. Some (IIVCS~ believe. however, Ihu\ becUUM" of ils rela\l\dy ~hon "1':11100 of action. il may be less dTecuve than the Ihia;cide II thiazide-I ike diuretics. It ha~ been ~uggeM~'(/ lmlt {urose-.Ie be l'e.o;erved for hypenen\ive p:l1 icms with nuid reu:n\I0Il refrac10ry to thiazides or plttiems with impaired renal
r.act10li ....

Appn:u.nn;atclY 20% of lhe do<;c is elcreted unchanged the unnc..11. 1)

SITE AND MECHANISM OF ACTION

.....UonN educnon
In-

lib 10

In ienual. fu~mjdc or bumet:lludc: I ~ preferred o"er ~nic acid (another site 2 diuretic) becau'\C they ha,'c I broider dosc:-~pon<;c curvc. less OIotoJl.lCily. and less pllromte!;linaIIOJl.ici IY.u
4-AmI"o-J-~rkll"esulfo"~ure.s

Llkc ruro~midi: and bumctanide.tOlliemidc iro(h",:es diuresis by inhlblt.on of the INa ' I I K nci coU': msport syslcm on lhe luminal mcmbr.IIlC of thick ascending limb cell~ (Fig. 111-4). Thus, tor..crnide must reach udetjuatc Icvel~ in the luminal nuid . I ligller do<;cs. which have been stooied in isolaled nephron segments. also inhibit the ernuJl. of CI from the thick ascending limb ccll~ by ti>c CI channel~ on the basoI .. leral membrane." Whether thl~ lICCOnd MIC of aclion is clinically relcvam remams to be dc:temuned.
ADVERSE EFFECTS

i'Ie

pro~'.

moe indi,iSlranQn

=1"",

fOfSMlide.

The $lruclUrc: of tON:midc.-. I-isopropyl-J(De-

"'c"cre
,h,bnon.. ulfatnoyl

[14-i3-methyl phcnylamino)pyridinc l-3-~u lronyll urea

IlldeJl.). is shown below.

Tor.;emlde may produce fatigue. diaHlcs~. muscle c:nmps. nau!IC1I. ami onhoslluic hYPOh:nsion. At thl~ carly date. no evidencc of OIotoxieuy has appeared In humans. but studies in cats have sho..... n torscm iOc 10 be similllJ" to fUl'QM'.midc in I)tO(l)JI.[.;; polt'mi:II. 7~
USES

lit h)'l"'" d dy<;qa

with the diurctlc\

",-0 ,roc
D

CH,

/CH, SO:!-NH-C-NH-C - H

."....,.

I o
Top Flillie

'-""
CI',

ji:ued di

llurelics.

Tor!ICmidc i, useful in the trcatmem of mJld -t()-modemle hypc:ncn~ion in dose;. of 2.5 to 5 mg gi"clI oocc daily . These doses lowe blood pressure as effectively IS 25 mg ofliydrochlorothill7Jdc but witl'lou t producing dlu~i5. Ilighcr doses of ton;cmidc ( 10 to 20 mg) an: "SS(riated ..... ith signifICant diu~is and arr effecti,'e in treating cdtma IS*)CIMCd with congest;'e hean failure and cirrilosi~ of the II"er.11, n

:tion apough the

OS<: III

""""" i!.k:.

Phe_qac:etk Adds
COOO

mxie po-

lini,lered

The phcnoxylW..'Ct ic lICid group of high-ccilmg dlurel1Cs Wll~ developed liM introduced inlO clinica! usc: ~bout tnc \ame timc as furosemide .

TliI1odoi

lI'IiooS I)'"
SfII1JCTURE-ACTIVITY RELATIONSHIPS
~ ~ittaing of many 4-amino-3-pyridmej;ulfony lurcas ~:,,;~;kd;; that maximum diurt:tic acl.vny was auained with

'lasSoe\ of rosemidc

~omnIn8.
~ilh

Ethacrynlr: Acid, U5P. The structure of tlhacry'lIC acid. 12 .3d ie h Ioro4. (2 -met hy Icoo- l-ox obu ty I)phe no xy Iacel " acid (Edecli n). is 5hown in Figure 18-12.
STRlJ{TURE - ACTlVITY RELATIONSHIPS

my blunt

enl

relic !herby block"land illS. !I flow In

de.:JO Torscmidc i~ e~ly related structurally to I'itIoxIn. a loop diuretic that was 51!ldlcd e~lells"'ely m the lit 196(l" and carly J970s but abandoned because II prooioIIctd 1ransitional cell carcinoma in the unnary bladders or -"'Cf ~ of the ruts that had recei\"~d hIgh <kKcs u"cr an "
II- 10 22-month period. nlARMACOKINETICS

nmenl of

'1'wmide is approximately 80'1- blOllvaitable

aft~r

uraJ ad-

re. cirrho)St unpor-

~mc:m of 11'1 (ailult.'.

loop di

h e:\U\'mc .me so~ nd cardiac

.-rMr.U1OO. It.'! extensive plasnla proI~In binding (98 to , is Similar 10 that of other loop diuretic . ~ak serum '_""~'\laIions a", generally alUlined wllhm I hour. and the .ti-hrc Ili 3 to 4 hours. somewhat longcrtlwlthat of(U!1l5C' (2 houn.) and bunlClamdc (I to l .5l'1ours). T()f"';Cmidc I metaboIil.ft1 b) the bepatic c)tochrome P450 systcm. Ale prtnW)' products result from the oXldalton of the: _lie methyl group 10 hydroxy and c:ubo~yl dcrivali,-es _ptlfIJ hydro~ylmjon of the n"ICthylphen}lamino moiety.

mentioned abo\"c. cerulli organomcrrunlt~ can elicit a diurct>c rrspon~. but bcc-.IUSC o r Ibm heavy metal OOlUent, they arc: too toxic forwidesprcad use. Consequently. a search was undenlllt:'n for ~ non- mercury<Of1tnlmng oompound thm like the organomercurial5 " ou ld reoct with sulfhydryl containing f't.'Ceptors in renal tis5IJe but be Ocvoid of ht:Jlvy mewl -type lOX icily. Because une of [nc commcrcialJy a"BIIable ocganomereuriah (nlCl'SlIlyJ. Salyrgnn) posse.'\SCd 8 pllClloxyllCc:tic acid moiety, the phcnoxyacelic acids W!rvcd a.~ the ehcmicalroot for Oc\"clopmcnt of new non - mercury containing diuretics. Hundreds of phcnolyacaie acld~ were
CJ.amined.~

A~

Within the phcnox yxeue acidscrics (Fig. [812). opImlal dlurt:llc XIJ\ny 15 achlCVcd when (a) an oxyacetlC K id mOlely IS plscc:d In the I position on tnc belllene nng. (h) a ~ulfhydryl reactlve acryloyl motety 1 located ptJr(l 10 the 5 oxyacetic acid group. (e) activating groups (i.e .. CI or 01 ,-) occupy either the ] j)OOtion or the 2 and 3 posnioos,

CI

CH,

'\ o

CI

o
Figure 18- 12 Ethaaynoc aCId IS a htgh-cetbng diuretIC thaI re.1di1y rNOS with many sutfhydryl-<on~lnIl19 ~;Ies (top) Indacnnone. a structurally rel.at@d lugtH:et~ng diuretIC. ~b $Ulfhydryt fHCtMty (botrom)
(d} alkyl su\)sliluerlls of two 10 foor carbon atom5 in length

d uratIOn of action are 3 10~ minutes and 2 10 3 houn.. rnp. li vel)', EthacrYllic acid is IIlghly bound to plasma p . . . (>954). Ethacrymc :IIC"J is handkd and C.tC:lcd prcdt nluely by the lldoc)~. Very hllie of the dlllg iJ 1'C11IO\'td r_ the plasma by glomerul ar filtrolilon becauo;e of it~ ex binding 10 unfiltrnblc plasma pro(eln~ such a, albumin !WI. ever. Ihc drug I~ iiCCl Clcd avidly IIlIO lumi nal flUI.I prOllimal lubule wllh lhe as,istanC<! of the OATS 1f1, Ig.1).bS, ~I. n High IUllllnnl fluid concenlrJlIon~ of abIcryni c acid are es...ential fur its diuretic QCt ion . ,Id ultl~. C.tcrclion. Ethaeryn ic acid is biOlransfomJCd by a palh .... ) a. pletel)' differenl from lhal of furosemide or bumct.amde, Em. III:rynlc acid alkylales the thiol group of glUIDthtone II' (Fig. 18,12: KS H - gluuuhiooe), and lhe ~ultutg~ pte subsequentl) IS OOII\cncd 10 lhe cd~rynlC It cine and Clhaerynic acid-N'lICCtyk)"'lclne (the acid) cOliJugales. Ethacl)noc acid--cySICII'" IS quole in vivo and in vllm; it readily relea.r,e;e cysteine aIId crynk acid. Elhacrynic acid, elhacrynic acid-glulJtIuoII. and clhacrYllic ac id-9slcine Dre tquicffic:lCIO\I\ dl mo ~au~ of the aforementioned Intcrcon"cl1;lon~,~ App1lIl malely two third~ of the cthocl)'lIic acid appean In the in the vQrious forms cited: the remaining onc third i~ f..in the bil e.

tnc

ora

SITE AND M ECHANISM OF ACTION

Likc fUfOSC'm ide and bumcWlide. cehacr),",c aCId

Rloc~~ ~;obo.orpI"'" of up to ~ of !hi: fihfted loiii pi III il~ 2 by Inhlbnlnl!hl: INa - 11k ' I2Cl COIIaInfX"I 'I IocIIICd on !hi: IUlTUnat "",mbranc of cell_ In ilIt Ihd ~,. inl lo mb of Ilcnk::" loop and In !hi: """u~ Ikn..a...:1h 18-41 Ruche!; h" h Ie"els In luminal flUId brnu.., of 11>.,;\1'1 I"" OATS In Itubul;,,,-elb III 1M

occupy the: position a 10 the carbonyl on the acryloy l ll1(liety. alld (t} hydrOllcn atoms occup)' the lenn;na1 POSilioll of the carbon -clU'bon double bond of the acryloyl moiety. These structural features seemed 10 maxim ize both the diuretic !\CUVII)' and the in " jIll) r.lIe of relICtion with various $ulfhydryl containing nucleophiles. TIle com:lation between diuretic actiVi t)' and chemical Il'aclil'ily within Ihis series of diuretics was strengthened by the finding lhal reduction IW epoxidalion of the carbon-catbon double bond in the acryloyl moi<'ty yielded C()mpound~ with lillie or no diuretic activi ty

orchcmical rUC1;1 11),.71. 7'1 The design and synthesis of cthacry",c acid appe:II1.:d \0 be the ultimate in terms of .. the rational Dpprooch 10 drug de~lgn. The need for designing a
diuretic with hi gh sulfhydryl reacti vity was foiled. however. .... hen indllCnroone was found 10 be a lIighl y efficacious di . ufCtic. incapable of reacting wit h sulfh),dryl-cootaining nu clooph\le~ (Fig. 1812).fIO Indacrinone was withdrawn from clin i cal trial ~ because some individual~ deve loped abnonnal liver function tCSt rcsull~.
PHARMACOklNfnCS

Because clh:ICrYI1IC acid Indtll.:es a ~'Itnn "~m.' Inc rcnal ClIcreuon 11I1~ of Na' C I , K' , and e.:' natriuretIC. chlQrurctic. saluretic. laliurctlc. " . agem .

ADVERSE EFFECTS
Ethacrynk add may produce all "f'h<""~1 with furosemide and bumclanidc uccpt lho<.c pm;ente of a ~ulfamoy l group. Usc of w:Ulcd ~ausc 11 is ~ OIotolk lhan fUl'O'O('ml(\e lIICWIide IUId u produces man: fCCb (I.e .. gaslfl)mteMmal contammg loop diurc\lCs. In , as ::~ and bumctanode. serious drug IAter.Ktlon\ .I cthacrymc lIC id is used concurrently wuh Li. sides. aminogl~"OSide anubiOlin. or !IISAIDs I~'

In spite of ethacrynic :!oCld'J unique cbemical $UUCture and nod reacuvit)' toward various nucleophiles. il has man)' phantl3CQlogical fcacuI'CS In common witll tbe 5ulfumoyl conblmng loop diure1 lc5. ACieronl .wniniSl1Illion. onset of III:UOIl is about 30 minules. and duralioon of llClion is 6 10 8 bours. Aflef parentcl1Il adminisll1Ition. onset of aclion and

""th,

~,.'" of advcrse e:Ffc:cu of furosemide arid bunw:la-

phcnyl)elhanc (eRE 1(904) "'; 2-(aminome,nyl)-4-( 1 1dimclhylethyl}4-iodopheool (MK-4-I7) 17; and 6-ch1~

~:'JiCld has the indications cited for furosemide and ~ Ho'...e:\'er, .... hen "hIgh-ceiling diuretic is indio ID lnc U'r~url('ll' of 1m individual who has II ~llOwn
111 I 10 ,~ulfamo)'J-conlainll1l! drugs. t lhacrynic br all appropriMc ~ubsli[ure.

2.3-dinydro-l-( 1"(nOtJrop) IH{II~uiool inone 4-oK.1IlC ( M I2285)." In each Ctie the sulfated IIlClabohlc: undergoes actl\'C: U1buill/" $(c,ellOO by the OATS in pl'(mrnaJ IUbular ce ll$ and.
hence, Buains high le\'e:I~ ;n lumina] flUId. Th.e nega,i\'ely charged su lfale: nMlicly prolmbly binds to the a --bind ing s ile on the lum inal mcmbr:mc _ boolld INa '/I K 'l2el coImnspon sysll'm or Ihick lIsnding Iirnb and "':ocol~ den""

DI.retks
biocrnnsformed 10 high-cdhng of their ~O H moieties (Rg. ThI: met3bolitc:s e~el1 I diure.~is by Inbibi oIl11e IN.IIK'ncl cotnnspon syStem on the !lI('mbrane of thick Jimb cells (Fig. 18
I (o-hydro~y

cclls. In addl lioo. clOlOline (ooly .fI~r being hydrolYl.ro m V ivO 1 ozoli~, a carboxylic ac id) und muzolimine JI!lIIJoeS$ 0 diun:lic oclivily by \"Inuc or lheir :lelions on !he IraIlSpon proct"5SeS in ,nc. cells or ,he thid :l'iCcnding limb or Uenlc$ loop. O"l.oIil1OllC IS Sttn:lcd oct.,c ly inlo proximal lubule luminal fluid bylhe OATS. Thoc high c()f"lttmrtuions oromlirlOOC delhcn:d 1 the Ih ld.: a'iCtnding limb cells or Hcnlc s 0

. rCH ,-CH,-O-@-,
0-80, Actr.. MI'''tJoIItto

~va

" A N - O - 50s

o
,

a
7

Figure 18- 13. Vanous seer!1lng/y unrelated iIgeOts Ihat block Na ' reabsorptIOn in the thICk <tSCend'ng hmb of Henle's loop The p-rec:I'K' mec::hilrll';m of actIOn of muzollm,ne IS unknown AU of the other agents are lnacuve as such and must be b+OtranslCll"l"l"led to acllY! metilbolltes before their OllJrebC. actMty
can be v.pres~ In each~, like 11.1r05el'l1lde, bumetarllde, lors.ernteW. and c\hrynw;:: ~. the ac:tM!: me\aboIllcs

Mve an anIOO'IIC I1"IOIety that may pt'f1Tll1 bonding 10 lhe (1- -binding SIte on the INa ' /1KnO- OOtrilOSpCM"t ~lem In
IhlCk ascending limb cf!ll!i

loop mhtb,t .he lununallTlt!mbmne-bound I Na '/ 1K ~ nCI CUlrllnsporl systcm" 90 (Fig. 18-4). llIe pn:<:tSC medla. nism(s) by ",'hich mUl.Olimme e.lertli n diuresis remains to be detl'mlined. 9 ' II has been ~uggested. ho"'e,er. that muzol

CHzOH

HOO=CH

0
H

tmllle inh tbtts.he K fCl- COlran.'IpOI1 system on thl' bawlateml mcmbmnc of the Ihick ascending hmb cclk .... hich m tum inhibits the INa' / lK 'nci cOlnmspon system.~: Nonecfthese miscellaneous SlIe 2 agents has been marketed m the UntIed State~.

o"'-./-../
(.t.Ideh,ou Forml
AidosIflfQPe
(~r.I

FDm'J

SITE 4 DIURET1CS: POTASSIUM-SPARING DIURETICS

A flegattve fea,un' of all of the above-dl-">Cussed classes (If dillretic~ in current uo;e i> Ih~ttllcy increa.'ie tile renal excre.ion rate of K ' and thus can tnduce hypokalemia. OVCl'" the yean.. thl' c~mically distinct diurellC) ha~'e emerged thm IPc~a~ Na and CI excretion without a cQl1COmiU1fl1 inl'rea-c in the un nary c>;crelion r.ue of K ~, 1bes.e agcnL~ are Imown as poIlll~';um"'IHmng diurt'lics or tJllI,koUurelic ilgents. Although lhe K ' -sparillg dturetil."s are derived from completely different chemicul root~. they act aI si te 4 (though not all by the same mc:chani'IIlJ. ha"e ~i milar efficacies and electrolyte eJtcmion pallcmS. and shan: cmain ad"erse e ffects. The K ' -"Pa nn g diurelic~ indude spironolactone (a spirolaclone). rianllcrenc: (a 2.4.7 -tri:lPlHl(r 6-arylpteridine), and am.loIidc (a pyrvinoylguamdine). A m:ent ly appro,'ed 'pirolaclone. eplerel1Olle. i, diSCU Ssed latcr in thi ~ chapler. H

PlOges!ezOflll

~o~
~

H,

0
Sprtn:llec!Cne

Spiroi<Kton_, Ald_tec one AIc' g'CHIlsts Spironolactone, USP. The struc'u ~ of sptmnolac,OIlC.
7 0'-(acclyhhio}- 17P.h)dro~y-J,o.lop~gn-4~nc-21- carboxylic acid .,..lactonc: (Aldactonc). is shown in Figu~ 18-14.
STRUCTURE- ACTIVITY RELATIONSHIPS

(.AIrIac!Qne)

Coe<IOI .. !amatO''''''''''",] !.-. actrve akJoI;t_

In the mtd -195O<. II W:L~ obscr.'ed that progesterone inhibtted lhe ::mllnatnuretic and kaliuretic crrech of aldosterone::. the primary mincruloc()rticoid in hu rnan s.~)'" An illlcnsive cffon ..... as launched 10 de_clop ... erotdal dcrivau"es that po$~c.~ only the anti mlnemloconiooid atli, i,y 0( progestcr0IlC.9:!- .... Spiroooillctone W:L~ se lccted from u host of dcrivall\e~ for rurther exannnalion.Y7
PHARMACOKINETICS

Figure 18- 14 Aldoslt'fOPe enhances the pasugt of No' 110m the lummal tluzd 11110 ,ubul.Jr cells and the !Uk Ii. tntracenular K ' tnto,he lummai fluid .11 Slle 4 f'ro9tilP!Jt ,nh,boIS Ihese actoons of aidostt'font! oo t has undeszlabl! monal ~ effe(1'I Splronolaclone and (anrenone also tlve/y m,bol lhe actzoos of aid05lt'fOPe at ~Ie 4 .md azt .lIed WIth a lower freQUl'f1CY of ........ ll "","lal sode effects

SpironolactOlle is ub.'\Orbcd .... ell after orod adnlln.Slr.iIlOn (bioav:ai labilu). > 9CY.l). btOlran~for",cd rapidly and extcnsively by the h,cr ( - IIO'if,) to c:," ~nonc. an ~cl i\'c mel~bo hte (Fig. 111_ 14). bound e~ len~i _'e1y 1 plasma protcins (fTl()I;l 0 IIkeIY:L canrenone). and excreted prlmanly:l" mcwbolites ~ In the unll('. Some biliary e~~relion 0( lne,a!)ol iles ~I '\() ocCUrN. It. un'iet of IlCtion i~ ~Iow (12 to 72 hour<),w nnd its duration uf action i, qui.e long (2 1 J days):'1 0

sITe AN D MECHANISM OF ACT10N

Spironolactone intublls the ~absorp"on of 2 tQ J'l. of the filtered load 0( Na ' al ~,'e" by compc,.uvt'ly inhl blling the aclion, of aldosterone".l!> (h g. 18-6). Under rtOft.lIIl circ um-

stances. aldosterone entel""i the principal cells of ~~. . ing lUbuk (i.~ .. the I:tl~ di~t~llUbule) and the cortical roI\ca. ing tubule. where il combines ..... tth a cytowlic n~ccptor.1k complcJt nlOV"Cl> into tnc nucicus ..... here i urns synlhesis of additional quan!Htt'"$ of the Na'/I ATra,""". tOO_lOt and IUlllinal llIelllbmnc ~h~nnels II\;u 11ft it,oIved in the cJtchallge cf Na ' for K ' ImcrclL.tal III II ' -ATPase that acll\cly pump' H ' mto,he luminal at ,i,e .; is also affec,ed. Thus, pa~,age of lum, n:11 natp 1\1 inlO, and K ' and II ' OIl' of. ,he connecling tubuk ccJ1,. the cortical collecting tubule cells is enhanced. I'".:: mtrac.:ellular levels of Na' ehcitc:d by the ection~ o~ 016 I rone stimu l:ttc the bas()latcml mcmbrdne-bound N./I' ATrasc. ll Because .;pirooolactOllC oompcti,hdy I . the5e actioo~ of aldostcrone::. lOt II rnhaJK.'CS ..... a'rr. N~' . C] c~erclion . 1berc:fore, spironolactone .s a natn-. chl()t'\lrelic, saluretic, and untikahuretic agent. U,,/iQ" (JIM, K ' -i'fH1ri"K diu,t'fic-s. J(Jlronol.jC'/HIt' rrqul," III

0."

'

prt1tnct IJ/l'lrdogelllJUI IIfdO$ltr(jllt ro I'Urf liS d,urtrf(", liQII. Bccau.'tC it inhibit, thc reahsorption of ollly 2 toJ. II

Chllptrr 18

D"trtHir~

617

IiheJtd w.d of Na' . ;1 (and the .ne 4 K ' -spann, di "'0) tIti n-Iall\-el) low efficacy.
IoIWEftSE EFFECTS

proximal lubule. 8ecause it IS a weak IWgllnic; base. il iJ IISSUmed to be handled by the proximal tubule 'l (R,. 18-7), Its onset of lelion followins a Stogie onal dose i~ 2 104 houl"'i. and il~ duratlOO of action is 7 1 9 hours."' 0

ocrs

ODe mill" anllCipate !hat inhlbilJoOl1 of lhe eJ(change of lumiwould lead 10 IlItntlOn of Ihc laller 11'110 ion.~ in certl1i n indiv iduals. hnporIIIX 1(/1 crse crTecl~ of spirooolaciorle include hyperkalemia aI mild melabolic ocido<;is. ~pcciall)' in individuals with ~ n:nal funclion .... .16 Th.:n-forc. p;1tients lakinK ~pirono ""lOne mou ld be wamcd IKIItO take K ' supplel1lt:nts. Caumu~l llso he cxerciSt'd ,,-hen administerin, ~plronoloc. ... nh other drugs. such as anG>Otcn~ln-co""ening (ACE) Inhibitors. II1GlOIen)in II recePlor antagoand .8-adn-rtCTgic blockers. Ih:1I may alw ev(j,e inIn IK -' pi =. In additioo. ~pironolllCtonc may proJYnecomastia in men and breast lendemes.~ and -.ntll dlSturbarlCd in women bccauseofilS residual hor.:mI activity. It Gynecomaslia occurs in apPrO~Hlullcly 6 I~ of males given 50 mg/day orles, and in up to 52% tIo6e5 above 150 mg/day. Ocher advo!rse cffecl ~ include IIIIIOf laslroime~rinal symptoms and r~she.~,)l, ~,

-' fiutd Na t rur intmccllulat K ' and I"

SITE AND MECHANISM OF ACTION

Triamtcrene "plulI~" the Na channels in the lumina! nk!ntbranc of the principal ce lls al site 4 and therehy inhlbllS the elcctrogenic emry of 2 to 3% of the filtered load of Na' inl0 these cdI5"-" (Fig, 18-6). As triamten:nc's attion decreases tlk! principal ce ll concentration of Na ' . lhe amiluminal membrane _bound Na/K' -ATPase lICtivity abo deCfUJ<es . This I~ 10 decreases 10 the cellular extrusion of Na ' and the cellular Uptake of K . Bause the $eCn-tion of K ' and H t at sile 4 i$ linked to Na ' reabsorphon. a eoncomltanl reduction III the ell:mion rate of K ' and H ' OCCUI1i. U"/ikt' !",rotWlil('lOtlt'. trillmtt'fC'nt' '! diurelir arriQtl d~! nOl depC'nd 011 Ihl' prl'Sl'nct' of afdos/uonC'. Trianuer. Clio!, like the IXhcr K 'sl);!ring diun-lics. tl:Is a low efficacy and IS a mild n:J.triuretic. chloruretM:. saluretic. and anttkali . umic ago!nt.

ADVERSE EFFECTS
Like the other K ' .sp:tring diuretk~ whose primlll)' ac,ions are elicited at Slle 4. triamtcrcne's major ad .. cr.;e effect is lII Then-fore. palients llI1:ing triamlcrcnc hyperkDleml . should be warned oot 10 take K Wpplemenls. Caotloo IS also neWed ..... hen adnllniSiering UiamlCTt'rIC along "'lth Dlhcr drug.~. such u ACE mh,buOQ. angiOlensin II rc<:eplOl'MtagOIIi5ls. and .8-adn:neJ1!ic blockers. that may al'lO Sh-c ri~ to itlCll':a..-.es in I K+Iv .. _, In addition. it ;!ppCar:s to he unique among the K spanns dllln-lics m being lISSOCialed with lhe formation of renal Stonc:~. ApPrOximately I of 1.500 Indlvid. uals laking a triamlen:ne-containing diurelic e~penences ncphmlilhillSis.,1)4 I~ The 510nes conS;SI of triumterene (with 01' without it~ metabolite) 01' lri:trnterenc along with calcium o~alale or uric acid. II also Illay produ~-c nausell. vomiting. leg clUmps. and dizl.incss. ll
USES

may he used alone as an e.>:1n-mely mild di10 n-mol'e edema fluid in Individuals ..... lth CQrlgestive (allun-. cirrhosis of the liver with a.scnes. or lhe nc;.;;~ t')'ndrome or In an amihypenens"'e agent . lIS pri_ 1151:. however. has bn in CQIllbinalion wnh diutttlc$ :C' - II si~ 2 or 3 in an iIllempi to reduce the urinary K ' ~Ialed ..... Ith the!ie latter group" of diuretics.
~ '

T'&.ml_-6-arylpterldlnes

Slructure of lriunllerene. 2.4 :::::~';;'~~~;d;Th<:;:(Dyrenium). i$ sho\\.-n below,.7-

o
H,N

NH,

""
!TlIOCTURE- AcnVITY RELAnONSHIPS

Triamtcrene may be used alone in the lrCatment of mild lema associaled ..... Ith eongesllve hean failure 01' CirrhosIS of the li\'er With 1lSCnes. bul il should 001 be given to patients "'itll impaired renal funclion.lo. It is 00110 he used .lone in the tn:atmenl of hypenenslon ...... 1 Its primary use is in 0. eombmalion wltll hydrochlorOlhi:u.ide (01' other diun-lies that act at si te 2 01' 3) 10 prevent the hypokalemia associated with the laner diuretics.

OO:~h:~: ";;.;f;ro;~ lastruc" ahosl '~It ~

,od
1 ;-

Py lno,-Iguanldlnes
Amilor;de Hydrochloride, USP. The struClure of amilootle hydrochloride . 3.S-dia mino-N-(aminoi mi nomclhyl)_ 6-.:h 10rop)'llll.i nccarbo~anl ide monoh ydroch Ioride d Ih),dr.lle (Midamot). IS shown helow.

"'" r.
"' ,.f

lind cenain dihydrofolule reinhibitors. it has liule. if any. of their JlCtivi) ies.'2

l" ....
." ...

.~.

i$ abl.orbed rapidly but inoompJetely (30 10 i I tratl.41 bound to plasma pro.160%. blOlraosformcd e.ltensi\-cly exen-Ied primarily by the biliary route and via the renal roule as unchanJC(l druS (2()<,e) and (8O'l-). It enters the lununal fluid of the nephrons fihr~lion and lItlive IUhular :'ieCn:llon in the

CJl~j('C-NH-C-NH2
H2N N NH2
H,>dIWbide

NH2

a-

Amic)r0(le

STRUCTURE - ACTIVITY RELATIONSHIPS

....

An utensil'c screeni ng procedure that C'XlI.mi ned O\'er 25.000 agents was undertaken in an attempt to disco\'ct an anlikaliuretlC agcnt that did AClt !la\'C o\crlapping hormonal activity likc that of sPlroooJac1Olle. 101 Promi sing OCtlvlty '" as OOItd with appropriately subsututed pyraziooylguanidmes. Optimal diuretic llCtivity in this series is ob<.cr...ed wl'lcn the 6 position is ~ub:ltitUied with chlori nc. the lImino groups in the 3 and 5 positions are unsubstitutcd. and the guanidino nitrogen. are 001 multiply substituted with olkyl groups. Amiloride cmerged as the IT'I05t acti\'c CQI11pound in the se

ofhypencnsion. hs mOSt common use i~ in combination ... ,. diuretiC); thlll act lit sites 2 or 3, to circumvent the rnnalloll of K ' commonly aswciatcd with the lallcr lIgents.

MISCELLANEOUS DIURETICS
Mannitol. USP, The prototypic osmotic diuretic l).fIIU. nilol is I water-sol uble, lipid-insol uble , heillihydroilyalcQ. hoi, Because of its lacl of lipid solubility. manmtol (loin;" diffuse across the gastrointestinal epithelium and _Itt given by the intnavcnous route to obIam syStcmic dfuu. Once it enter,;; the bloodstream, hull.'. if any, is bound III plasma albumin: it~ di stribution Ii confined to elUxclluir nuids, and it is nOi biOlrJnsfomJed, It enlCr,;; renal IUJIIlIIIII nuid only by glomcrullLT filtrntion; it is neither secn:tN reabsOl'bcd, 11Ic: net I'CS4llt of its renal lutndhng is t,,'OklId, fiN. il is cxm'ted pnmarily by the l.dnc:ys; up 10 8O'i II a 1000g mlBvcnous dose appa1S to the urine ",itltlll I). hour period,~' Second, high luminal nUld conccnlJaOOlll rI OIlinnilol creatc an osmotic effect, and a great deal of. wllter in the luminal nuid is retained within the lulTltnlrl the nephrons. This osmotic effect preventS the re~ of up to 2S% of the filtered load of walel"."'" Mannitol therefore, may be: used prop/IylOClicaJly on a hospital keep the nephrons open (i.c.. pre ... cnt them from coIl"';~ in an allempt to a\'oid acutc renal failure in ~nain eiltWstmlCcs. It has also been useful ror the i't'duction of cc"br.. spinal n uid volume and prt!Swre. Becansc intta'CIIOIIuo. lions of mannitol may Cilpand the ciltrllCdlular nuid \-oo.mr. they should not be used in patients with sevCfC rcnaI dWEll or cllfdiac decompensation who may not be able 10 w:m: the additional fluid load and may subsequcntly dc\'cklpput. rnonary edema, Aqueous solutions are nwlable In of cOr\Ccmrotions for intrJ\'enous usc, 'The adult ronge for the induction of diuresis is from 50 10 200 t/!4

PH ARMACOKI NETICS

Amtloridc contains the stroogly basic guanidine moiety and possesses I pK. of 8.7. Thus. it C'XISlS predominantly as the charged guanidinium ion in the p H range of most body tis SIlCS and flUids. It is IlOl surpri~ng that amiloride is absorbed incompletely and ermticlll1y ( 15 1 20%) from the gastroin 0 testi nal tract. an c ... ent that occurs by passi\c diffusion of the unch~rged form of m~1 drugs. Amiloride I~ bound 10 plasma proIcins 10 a modcrotc tlcgret' , is AClt biotransf(llllled, and is ellm'ted in the urine (20 10 50%) and in lhe feces (4QIl,). 11Ic: fecal content may represent unabsofbcd drug. Amiloride reaches the luminal fluid by glomerular filtr.ltion and ac1ivc tubular secretion. 11Ic: proilimal tubulc (Fig. IS 7) is in ... ol ,'ed in the laller proccss. Jl Onset of oction occurs within 2 hours after ()f"JI administrotion, and duration of action may utcnd 10 24 houn!1

'*

sern..

ocrs

SITE AND MECHANISM OF ACTION

U t c trillmterene, amiloride inhibits the electrogenic cntry of 2 to 3% of the fil tered load of Na ' into the principal cells of the connecting tubule ond conical coll~t ing tubulc (i.c.. Slle 4) by "pl ugging" the .;odium channels in the luminal membronc (Fig. 18-6). In tum. the driving force for K ~ secretion is reduced or dimirlllted.6. II. JII ute fnomlercrtC, nmiloridc does nor rcquirf tht prtSC1!CC of (lldQSlefflRt to product! diurtsij. It induces the urinary loss of Na +. C I , and wat~r and. tl'lcrefore, is u natriuretic. chlorurctic. sal. uretic. Bnd antikaliuretic agcnt, though with low efficacy.
ADVERSE EFFECTS

J".

hoon.
'TMophylliM .

The prolot:ypic ilanthlne. ttoooph)I~Dt.

known to promote a "'eak diuK'Sis by sti mulation of function and by u direct octioo 00 the nephron. AlllntPl b infrequcntly used a_~ :I diuretic. diuresi~ may be lilt ob. -;crvcd side cffect whcll it is used as a brond.odilutor.

11Ic: mUJor adverse effect of amiloride is hyperkalemia,

which also may be obi;erved with the Other K ' sparing ditlft'tics that act at sile 4. There fore, patienlJi takin!: mniloride shou ld be "amcd 001 to take K ~uppletnents . Caution is also needed "hen administcring antiloridc along with other drugs. such as ACE inhibi ton. astgKlicn si n II receptor ant3g onistS. and ,B-adrencrilc blockers. that may also gh'e rise to increases in 1K -0- Iplb ...' Nausea. \'omiting, diarrhea. and headache lIlay also accomp,lDY the use of nmiloride.'~
0

EMERGING DEVELOPMENTS IN THE USE Of DIURETICS TO TREAT HYPERTENSION AND CONGESTIVE HEART FAILURE
Allhough the precise mcchanism(~) by which the tbiIzQ thia7.idelitc. and loop diuretics lo",er blood ~ in.,. pcrtCllsive patients is not known , 1\ is thought to lII\ slight reductions in plasma \'olume and cardiac ",.. put. well as direcl reluation of the Va'iCulatun: . (h'Cr the)Ul' the adverse cffects llSsoci bted with these drugs "'CfI:. ~~ cred relati ve ly mild. Recenl ly, however, !OCvernl of the ... tf.known adverse effects of these drugs havc attrJCIcd aner. because they appear to be more troubling than pn'1 thought, First. diurellco l/lduced increased K ' ~;;; leads 001 only to varying degrees of h)poIrr;alcmia. blot to decreased cardiac and sl clctal mlL~1c: 1K + I. Such

USES

Amiloridc may be used alone in the treatment of mild edema I15sociated with congcsti ... c hean failure. cirrhosis of the liver with 3~ites, or the nephrotIC ~)'ndrome or in the treatment

Cha pter 18 II I>... ,mcs

619

_IK - l.mp'llrcardillC pafommnce anddarnage hcan. brain. lid bdlll:y '~lS. 'OI Second. dIU~Iic."-Ir>duccd reductions plasma volume lIlilllcr increased Yl1lpalhchC 10Ile ~nd iI:rtascd renal ttrcUon of renin and. ulurrwcly. incn:ased plasma levels of angiotensin II. In addition 10 bemg a poeent 'l\OConstnCIOI". angiotensin II slimulatcs al~lC:ronc. secrclion. Allhough the mechanism of aldos,crone'~ octions at

o
/

"'-

IIIC 4 in lhe nephron have been ~llOwn for " 1008 !illM:. its lIb'ilrenalllCtioos have largely been ignored. Recently. ;1 has
m obsc:ro'ed thnt diuretic-induced incn:ascd aldosterone b'tls oot only "ause changes in electrolyte: Ir:lnspon :II sile ~ "llh ultimate damaging hypolaiemih but also produce cr at t'trafCnal aJdo>terooe ~plo~ in the \3<;euialUrc. II Ie<ld 10 v..scular damage. and in the hc:u1. "h,eh lead unllx fibrosis,lO!l 11Iesc OOSti VlllionS help to uplam Q) diuretic induced redUCItonS in blood prc~wre 00 001 IICCnanly protect some hype"cnsi\'e ulllividuais from other Q'diov;&ular problems, !.Magh and Scaley lOll, 11 (1 ha~e anus'\Cd clinical cvldence

CH,

"" '" I <.

, ,
H

,,~

inal

pld_ .1 J01

""

<'"r .
'00

.~-

:tng)

'"

E.
0124

'"''' po l".' ,go

."

the thiulidi:s in treating hypenension without imlncing h)'l)Okalcmia or in ati!N secretion of aldosterone, Funhc:mlOrt:, when spirois used in combination with B thiatide. thia.o:ide i , 'I martedly blunts !he retial and e~trure .:lions of the ('levllIed levds of aldosterone brought ..,. by Ihese lau('r diurelics, III the ~st . spironolactone bas not ('njoyed wldc..~pread for se.'ernl wdl-documemoo reasons, lOll, 110 First, its IWIIIlII cffecti.'(,nes5 is usually not observed for ] 10 5 Second. its residual hormonal Silk effects hal'e prounacceptable rates of gynecomastia in males and men ilTfgularilies in f('males. e,~pedlilly when doses e~ =<ltd SO to 100 mg/day , 1lIcse hormonal ~ide effects can II largely lI~oidcd by giving ~pironolactone in doses of 12.5 .2Smg/day. EplcreOOIlC. a Spl'Cifir: afdosurtHu! allWl(onill recemly ap 'ed by the Food and Drug Administralion. appe:ar> to c. much lower affinily for androgen and progesterone : " " !han spIronolactone and reduced incidence of dl>tUfbmces. ifill If this finding is confillTlCd in addi: chrueal studies. epltrenone or an<Mher d"'1 II-ith the ,.rnf'lCity of eplerenone llUly ('merle as I very usefu l and improve the trelltment of hypcrlension (and ,,'e hean f:lilure ) when used alone or m combmauon ocbcr diuretic~ or ACE inhibitoo.

_ben used :llone is

"oflu/~cr;I'f' !IS effect i~e as

o/doStrrrHlI' IInlll8oo;sl,

SUMMARY
TIle major tinving Force For the reabsorptIon of Na ' at all Four Na' re;!.i>sorptlO<\ SItes i~ the deficit of imrncellular Na '

created by the activity of the basoIaternl membtane - bound N:l /K ' ATPa.~ _ Itl response. the luminal nuid Na ' mo\'es 11110 the Na ' -deficient cells by a luminal membrane- bound Na ' tmnspor1 ~ystem tb.1t15 unique 10 each of !he fOlll' s liC$, Most diuretics mU SI aU;!.'n sufficient concentration in lununal nuid 10 inhibil a luminal membrane- bound Na tr.msport system: this iJ usually accomplished by a combinatIon of glome",'ar fi hmuon and actJve tubular secretion, The: chemical stM.lClure of II diuI'Ctic dict:ltes which of the four N:l tr:lI1sporting siles II-ill be InhIbited, The site th~t I~ inhIbited is one of lhe major delcrminant~ of the efficacy of the d, uretic. The historical development of many diuretics has in, vol~ed molttular modification of tbe chemical ~11'U('ture of su lfarnoyl-cootaining compounds, This has yielded CA in hibitors, II-hich inhibit the reabsorption of Na '/HCO ) at si le I: the thiadde and th,nide]jl1e diuretks. "hlCh inhlbll the rtabsorpuon of Na ICI- at SIte ]: and the hlgh<C'lIini diurelics. " ,hid! bloc" Na '/CI IK - /Ca h n.1g1' reilDsorption !It site 2. Diuretic effieacy has increased with the~ sponding changes il} tnc SlIe of action of each of lhe three classes of dJUrelics. Predicbble secondary effects that de pend on a diurellc ' ~ sile of action ha\'e aJso \ urfaced.

!8- l ide .

DIURETIC PREPARATIONS 4 1
~lhluIde (Eit~, HydreJCJ Or~l, 5()..mg tlblets

,n hr-

,..01\ ...

,PUt a,

-OIl'

,"". .d",... 11
Diu. etics

Jt.IlI,(XI

CIofmide CAquu,
N OI ~vlit..bIe

ChIotofhlul+, USI' (0hIrl1. GMItricJ 0.11: 150-. 5O().mg Ulblitu. 5O-mglml 01'11 ~ PI.ltflleo-al, 5O().mg INs. for 'nlea"'" 0>I0nhMid0t>It. US#' (HyplvIOll, ~ Generld Or~l 2h 50-, l 00.mg I~blltts
am..1diJC)

tiow.l)
lo.mg tlblf1l

In the United SUItes SUlles

"'''00 \I' a1..o

, us,. (N~_ln)

~xoI.",. (NefroYn) Not ~v~;t..bIe In the United

hungc,

Cydolhinidfl (AnhydrDllJ Oroll: 2mg ta blet. HydrodIIoroIh/nj~. USP (E.idrl". HydroD!URIt., Or.-ric,

Or,,'; 20-. 40-. 8O-mg tablets: 8, 10 mglmL oral solution P a renl ~ral : ' 0 mgfmL lor IV or 1M use
Torsemi~ (Derna~")

Or,," 25-. 50-. l00-rng tablets; 12.5-rng capsules (MiCfoz lde): 10-. lOO-mglrnl or,,1 sol"'-ions HydroflumethluKh. USI' (Oiucllrdin. SIIlurDlI. Ge<>ericJ Or" I: SO-mg t " blet'i Indilpamide (lozo/, Generic) Or,, 1: 1.25-_ 2.5mg tablets Mefrvside (4ayc"ron) Not available in the United States MelhydolhlilZ~, USI' (Aqu"tensllon, EnOllron, Generld Oral: 2.5, 5.mg table ts

"'"""

Orll; 5, 10'. 20-, , (1O. mg I"blen Parente,al: ' 0 mglmL lor IV use

Meroluone Or,,1: 2.5-. 5-. 10-mg e. tended tablets (Oillio. Zaro_oIyn); 0.5mg prompt tablets (MykrolC) PoIyfll/uide, USP (Rene.eJ Oral: 1-. 2, 4mg tablets Quinelhuone. USP (Hydromox) Orlli' 5O-mg tablet'i
USP (Me' ahydrin, Naqua, GMefic) Ora!: 2., 4.mg ta ble ts Xifmide (Aquaphor, Dluff!"anJ Not available in the United States
Trid>/o~rhlnide,

It - S~ ri ng Oiu retiC'l Amiloride Hydrochloride. USI' (Mldamot', Generic) 0.-11 : Smg tablets EpIe~ (Insp'a) Ora l: 25. 50-. loomg tablets Spirono/;K'one, USP (AidmOlle, Generi(J Or~ l; 25, 50-, l00-mg tablets Trillrnfel'el>e (Oyrenium) 0,,1; SO " loomg t~blets; SO'. l00-mg Cilp\ules
Diuretic Combination. Atnlloridfo/Hydrochlorot hlulde, USP (Modure ric:. Generic) Orlll: 5 mg amllorlde hydroch loride/50 mg hydrochlorothiazide Spirono"'ctonelHydroch/orathin~, USI' (AldM'azHh) Oral: 25 mg splronolactonel25 mg h yd. ochlorothiazlde 50 mg spi.onolKtonelSO mg hyd.o<hlorothi"z,d. TriarntennelHydrochiorothiuide, USI' (Dy uKh. M""lI<*) O.al - cap'ules: 37.S mg tfiamtetenel25 mg hyd,ochlorothi az~ (Dy.uidfl SO mg tfOamterenel25 mg hydrochlorot h,azlde (~ 75 mg tri., mte,ene/'SO mg hydrochlorot h,.zide (G...-.. id O.,' - tablets: 37. 5 mg t,i.,mtetenel25 mg hydrochlorothiazide (Mauodll 75 mg trl~ mter~nelSO mg h ydrochlorot hluide (Muzi/ltl Osmotic OluretiC'l M annltoJ (Osmi t ral, G~erlc) Pa,enterlll: 5, 10, 15. 20, 25% 10. IV

, , ,

Loop or HighCeil ing DiuretiC'l

BllmeUln/de, USP (Bume", Generic)

Ora l; 0, 5, 1_, 2rng tab let'i Parente rlll: 0.25 mglrnl for IV or 1M use EthiIoynlc Add. USP (EdecrlnJ Or" l: 25-. 5O-mg tablet. Pa re n te ral, SO-mg (billie) for IV use furosemide, USP (U s/", GMefic)

" "
M

U5Il'

REFEREN CES
In ... """,. 8. M. and 8 <,< .. ,,1:0::<. It . II I 1t"'P. Prat . U :3~. 1978. 2. Van<!<. , A J.: IImal I>k><!d!low and ,~I ... flt""'i"". In V.nder. A. J. (.,d.). R..... , l'hyliok>Jy. ~ M. N.... Yorl;. McOnwll i1l. I WS. pp. 24-50, 3. Ca{nlny. Il. J.' Am, J. Mcd. 61:4110. 1917. 4. floIliIlay. M, A. II"'P "'-'. J):101. 1978. S. Valun. It. Sod,um and WI!" !raIl'l""l. Sodium Nj....,... In Valun. It (ed.). Rrnal Fu,.,,,,,,,. Mh.n 's .... rn...n-i", A u,d and Sol ... BaI~ in Hool.h. """""" Lin". B"""" "- Co.. 1983. PII, 119- 159. .,t..u. J, 8.: Am. J C;tnliol. S7:6A. 1986. 1. SuU .."". L P .. IOOId o..ontho,n. J I. ( b.)' 1'IIyslolocY of It.. Kldn<y. 2nd ed. 1'II,'-I<lpllia. Lu" I'dtt.... 1982.pp. 213-21.'. 8, Dul:\oo.<. T 0 .. Jr.' Ann. N 1' , Acad, 5<;, 429:528. t9S4, II StIli" on. L. p" and er...,\h.:om. J J. (N',): 1'IIy.iok>Jy of til< Kid .... y. Znd td. Pb,laklphia, Lea I< F<.biee<. 1982. 1'1'. 114- 115. 10. ~. O. W.. 8",,),. C. A. and Ike" ... F. C. lr.: ~ ... I IrWUpOO of rl""",,". 1m"'" xIII!.. oodium. chloride. and wilier. In Brenner. 8 . M. (ed. ). U... nner '" RIOI"', TI\c: K,d... y. Yol. I. 6th ed. l'hib<k lplli .. W. 8. Soundr ... 2(100. PI' 375-4 15, II . SlOi.......v_ P. II .. rod Koeppen. 1.1 . M. : IIOS!'. I'noct. 19:125. 11184. 12. Sull,,~. L P....... GranOWn. J ), (<<1<.): 1'IIY"'*'lY or tho Kiolney, 2nd <d. Pbilaoklph,a, l.dl '" FdliF. 19112. 1'1'. IlS-137 13. Koeppen, H M. and St;Won. B, A.. 1Icr>&! tr.w.pt>n mcclwti...... NaCl and ..;o1cr ... aI:..... l~ion olon, ,t.. nep/lroft, In Itooppen. 8 , M.. .00 S!..,\"". B. A. (edit.) R.nol l'h)"iQIor;y. 2nd rd, S,. Lou, .. Mooby 1'197.1'1'. 'J-76. I ~ R"daJ. .... V. M .. Jr .. et aI.: J. Ciln. In " .... 49:1336. 1970. IS . Vand<r, A L K .w f"nction>. anatomy. and ~. In V......... A. J (~d,). lte ....1 I'hylliol<)ay. 511t ... , New York. MoOr,w 11011. 199~, p. 14 16, Etoo)-'.... G, o.u,1'1I<, ( ft"'!'.) 6:87.1981 17 V.....". A. J.' Cootool of "" ,lium and ....!.. excretiool: 1I.,~I.tion of pl~""" volum<:and "",ool";ly. In V......... A. I. (N.). R..w I'hyslot_ "1)'. Sth <d. N... y", ... MoCnt... _HiIL 1m. PII. 116-144. 18. ...evy. M ; " ""p. Prx-t. lJ;9!I. 1978. 19. Ros.<. "- M. and Gil""",. A, G , l'Iwma:t>dyllami<;a: M harusm. of """ ""lion ond!t.. ... Iali"",' np 1>01,,'= drua cooa:ntratiOll ..... d r..,.. In Oiln .... A. G ....1 1.... ,1. "Tho l'h;umK'.'1ont ... 7!1t ... '!~ ... Yorl. M>cm,llan. J9l! ~. PI' JS~ 20. Mol ..... J. V.. <IIId She, ~ h. M I. l'lWmorot. R., ;).103 1$. IWI 21 Sehl.. ,." I!.. 0 ...,... R_ ~ W';dti.Jo, C.: PIIu,.... AmI JOJII: 1983. 22. Wiu,..... M_ .. al f11uget'> ..... h, 4O!i:34. 1981. 2J 51 ..",.. M R_ and ScuU",,,,.. h. II Bull. Juhno Hopltm....,. 41 . 1938, 24 . M..,n. T.,:utd Koihn. It., N~tu ... 14(,'1(,.1. 1!I--l(l. l!I. Ilocl."",n. W W.. ...1., I. Ch" In't>-i. 1~:63'. I~ 26. Mil.... W . ... 1k>........ M. lnd Rublin. R.O 1 .....,0- . 72:4893. 1950 17 ROO"n. It. O. and Clapp. J W J Am Cbc:m. Soc, lH8"ll 28. S ......,.... J \! In Gould. R F (.,,1.1, M,,,,",,ul. Design. Adv~ 'nChomi 'lJ) ~ ~5, Wa""",a DC.n Chemic. 1 Soci"y. t\l64, PII. 87 WI, 29 M... n. Til' I'hy,,<>I. Rev, H3~S, 1967. 30 Allon. It C,' In C.-.go< . ~ I . t.,d,), DtuJetk,_ChomtWy, ~~; '-'BY and MI"',.... New York. J...... W,ley" Son .. lila.!. PI' 31. Be),<" K 11. rId II .... J E.: ",arm...,." Re, 1.1;'17,1*1 32. W.; ...... I. M. 000 Moo~~, G, ft .: Oiu.t!l~s ..... oIh..- .... """ , , ,n tho mobili,,,,,,", of oUo1T11 n .. ,~ . In G" ....... A. G_ ... I "Tho ''har''"''~ II .... oJ "Thoro.pou"".. 7111 L Mo. nrLl6omill.n. 1983.1'1'. 887 -\1(11, JJ. tzaf, A" and Cou-..,. II . S Dt,,,,,u,, . In Id , A. _ ('mal (ab.l. Ronol P.'bop/!),,,OO>ilY. 2nd 0<1 .'1.,... Yorl. Odonl L 1'=>. 1980.pp. 145 -161. 34, Wt..IIOn. "- : Arn. J. Cltdiol. S7:2A. 198(>. 3' &ik. A "='on. G. and WnrhL F S.: AcI:l1'll) ....... x-II 1982. , Wiko C. S.,o.U"'hC'. fn 1.1"""...... 1.1 .\f (... ,'.II......... "' ..." The KIdn<). <al 2. blll .... 1",llIdc:lp/"" "' B S .."""" !219_1n2. 37. II ......... C. R.. and CafNn)'. I:.. J J. PI\arm>roI. up Tlo!t IoU 1963. 38. Ye"')'. R A.. Bnthn, . C, A.. and M, lk" 0 L, T<).UL'aI. ~. 1:m. 1%5.

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191 - 796. 1266- I Z'JII), ~2 I..,.. R. M. J.. ...:I s~ ''', I. II ..... . "'" />kt;ob, B 7. 198). 43 Am. '- H""". Ph:arm. lH73. Ion"

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L 11,..

.u Shim,,"_ T.. ... oJ .. J Clift. In'",. , 82;721. 19!18

~, AloiA Drul E.'alualiono Ann Ol ' 1'1')5 Cbi<.,.~ A......., .. M t"d"," l

. . Mod. 1.ftI. ] N5. 1995 _ 41 21, 19\19 II Bryrr. K. H .. Jr,. _ _. J I'.. Mod n ... MItTJI"'III "7.13. lin , .. K... R. T.. Wd ..... D. It.. I and ..... <fI/I. H. L. J C.... /,,,--. 56;
"
1~1Jf'Ol. M., " aI.; KidIq" ' ... 18;4n. I'IB!I IQ fwdM, M, ~. J II.. -.I ~d_~ It I!..:
a~,

"J .1m. "". 101-106 __

"n

",II :::;;;: G.: f'roo''1IM1ti.,. I , m . 1974 ., 8 ........ A 0.., 0101. C'rn: Res.24869. 1!i'61 86 a..-.~. R. P .. .. 01 J 1'Ir>rn-IxuI. ,p Tbo-r l!IH15. 1\1\10 81 Goniy. It P . Nal';ortI. and Cnngoc. E. J . Jr. Ellr I. I'IIIrm1lI 200: 1 ~1 . 1991 !!II. Sh'n~a,.. . T .. .. Ill. Euo- J f'lnatrn.rul. 23K:3 17. 199.) !19. Ore",., J. KI<III. It .nd U.idenft1<h. O' N.... yn 5.;hn,,lct..,

c..

90 1k1Wll><. I. It. r-"',.<ha.-rm. I .. and Man, ...., M.1dooradP, M J 1I.prn<'t> . "'.7tll . JWj.
1'1
~ ~. I'II. /J~R.._Gtrp. 1t

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JO-l.ZB9. 1911f.

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-101.

b74. 1987 .

Pr""" . .

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(Dyaz,de)

" .... N 'i A<->d.. S<~ 1960 I, r...... L Annu. II ... . f'IIamuoro/ 1:,)99. 19t17 11. A~ ........ I'ano. JJ :lOO. 19116. o II< a III , M , ,,,",,I'\Jo..,,, 0 . " J C1on . l'IwmICI~ U ;JS7.197J. ~ c.....u. P W. CI" NqWon 12:1>..1, 191J.

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9Z. ""',...... J and J""""-. It IL " - R... ",,,d . ' I 2M. 19\10 9) Landoto . It L. 01 III J Oi. I' Mom"'" 13 1194. 19'j5 'H. ao..." ....... F _ Eqd. J r, . ho ' ioooklcr~~96.IW.1 _ 9'j Cdla. J A ~ _ K....'" c. ,\I. J ~. a.... 794801. 19'j7. !II> Cdr.. J A . II"", ... "- ...... .... II,., i . It It J 0.. 0.... N 74 .1.

""",K) (M;au,dt') .... ide)

Generi(j

" I'II .... F'. G. M.e Ural O lft. Nonh Am 1 ~,325. 1~7. j"1 ImM. J L. S<hrrud,. M.. _ G~ . Cf{)Il"" . 1:.. I'b:artnaroIosY 01 ""'" d,urclico: SI*Ie of the .". In 0 .... 111.1<1, J _ ., I I. (edo.). "oJI' . _ , . Nophrolocy. Yol. 16. ChK"..... Y... IIoot MWkol, 1987. If. 1)7_ 138
. . . . . M.. and Greon. N K...... y Int. ~.lA3. 19H lit ~~. Ii. J~ ern-.. '2107. 1967 ~. C I .. Cbo. K C _ and 0...., .. II AM N '(

" "'"" i.rIt. 16:6.). 191~

<no Cd'" 1. A.. an..r T~,~ R. C. J Or.- 0.-,... 14 1 109. '~9 98. II,."... It A .. Muit. R. D .. MIl Cella, 1 A .. I 0.1. Oneow. l!I-96.

''''

w
100.
101

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A .. and CoIN",. J. W.: j),Urclin In Ik' .... I A .. lind I. II (.....J. B""fIl,aJ . of Ph>nnact1l<'IY Jrd N . "",I_I.

102.
~.

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I)9,.l6l. 19t16.
III Ejo .. C D. M)'Ort, 0 W . ......... hoG. M . N e An:h. In"'"'- Mtd.

'" R".... 1983. PJI. 41 0----'22. '. CI al J 11101. Chern. 151,10338. 19112. II J Cdl. Riot 104lnl. 1'W7 /-A'k ",. . lib o/T"' .... ~klIIC')' (WK"lIo>II ",..,. IIIC ...... Jl. 1. 1. IN ) McdK"" . New Y.n. JoIInr

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1936, , _. I. M. I.<-wy. R. / . - ' M...... . G il l Pharmo>L E>.p. n.. 01196. 1962. " .... A.. ... Heel. R. c.: 1Jn>J. 21U!6. IIIII-l
Can/iul RI~A. 1986.

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C.... . l'IIy"oI I'IIarma;:()I tU '~1 2. I~ F 11. F A.. k . .. oJ AnrloloaY 1lI.125. Illn . " 1ttt1lOd. It . .. ..... S~'n. J It. MK h""'$mII 01.." ... Ind elln"",1 _ oIlIi"rclK"'. In B""' ...... II. M.. nd Rtcwr. 1'. C .. k (edo.). Tho K><I .. y. I . 2nd ell. l'II,bololpM". W /I S ... ndon. 1981. PI'

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J Mod. 2113 S36. 1970. 11 o.Iqo. I Art.n<im~l<lf,""",h"". Ja loW, 1\/83. I-W. Lm . .I613. 199-1 'll ~;wu. oL 0 ... F'IIarmard 1'hn ,..90. 1\193 ., Otqcr. R ........""ndf"""""'" 18 131 . 19M. 'lI I I ,I' IL. - ' ~ ... "' ..... M.e A"";""7l<ifo",d.",,, 31,131. 1981. ., ~C.I . f"_A _ _ Brop.oo.K. N Dru&<49121. lm. loodrrI. D A : A....... Rev P!wmoroI. To.o. ....... 2 UM. 198' 0..-. f.. I r The (oryku.y)ocel>< ..-.I ' ..... Iy 01 d,,".,d. .. Orp. E. ._ I. Icd.). Oll.Ift",,_ O.m.huy. ~ and Modo.:-r. NA" Y...... """" \\',1<, &: SonJ. 1983. PJI. 201 - 166. loodnrl. 0 A.. (;io.-alcl. 0 .. lind Clfnury. Ii. J . J Mod. o..m. I ~' &lI. 1971 ., loodrol.D A.. Smilh. SA.,..-.l c.r"",y, E. I.. I 1'harrnacuI. up. Ik! 2OJ:17~. 19n. III iIeSoIm.S.J_ ......:J Mod. Oo:," 21: nl.1971. , 1I<y<r. K. H.. t<.L I I'han-n:nroI bop TIler. 147;1. 11ItJ-I. Ila......R 1.. Mdc..r.... ny. I~ J I ~ . F p. ",.. IH : I48. ..

'l_., II.' N "-"II

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2001

2001

371 p11<1 2)JlOb. 2001

SELECTED READING

Go'''''''''.''

fI

, Sdormro.ana. I

...

Inn"""", nI dll.mtc. l1li m. lulruloJlom<nlt. fd

II-n:ft ...... R M_ .... Beeu"' ....... R. Ill. """, Pn<t. L1 3S-4&., 1978 a.-.,..... .. MIl ..:.~_ HR. A_ It.... M'd. 41 :26$. 1990. Am. F... ~ ... 3.1:200 - 21~. 1916. '''''''' . ,...... J. L-. s.:tr-lr. M Md G.u....c........ . ................. 01 loop dorimocs: S...... 0111>0: WI .w.- Nep/IroI. 16137 I SI. 1917 K"'l'I"'a. 8. M~ - ' S t - . B A .: R...... .......,..,... ........ """" NaCI -.I -... ",ob><a , __ ...... lint ,.. pl..... In K... 1t . 8 M . " S, '''''- B A. I..... r. It..... ~.......,.. 20d cd. St. L.<:rut... ~ 1997. PJI ' 3 76. P.llclncU.1. R Am 1 Cardool 37:M - IM. r986 . SIc-inrnCII_ Pit .. """ Kucp".". B M. 11""". I'racI 19:12$-1 3-1. 19114 We ....... I. M , ..... Mud,.,. G. II . [);urnitl..-.l "'.......... r. <"'f'k'l,n the nI(l/)oll .aU<)f1 u( odmrIl1uid In Gilman. A. G. I .I (cdI..~ 11no 1'IIArmaI:uIi'licll Rar.i, oHTh...,p",-,U<s. l ib N . Ne", ... ~..t. M""' ... I.... 19113. pp &87_901 W,Ico . C . S.: Di .... ',.". In Rrmnor. B M. IN .). B..,..".,..t R......" . 11no K>dnt~. YoI. 2.. 4\dr cd. PIb ...... 1pInia. Yo' R Sr,"kn..:!OOO. ~ 2219- 1l!ll.

I 'kond 114'

1 9

Cardiovascular Agents
STE~EN

J. CUnER AND GEORGE K. (OCOLAS

reduce peripheral va .... ular i'esistull(:e. ,asodilator.;. indudils orgaJ}Qflitratcs. :lllgiOlCll!lin-converting cn:.tYIlIC (ACEl IIIIlibitors. and angiOTensin receptor-blocking agents. an: ~ to impro\'c cardiac output in w ille patients with Conge;lllf heart failure (CHF). TIle coronary circulation supplies blood tu the myOWlill ti ssues 10 maintain cartliac function. It can react to thc~ inS demands of tile heart by dilating ils bloOO Iesstb_ provide sufficien l oxygen and other nutrients anll to \"e!OOl( mctabolites. Myocartlial metabolism is almost exd~s;,dy aerobic. which makes blood flow crit ical to the support tI metabolic processes of the heart. This demand is IIII:t clf.. lively by thc nomml hean because it extracts II Il'latildy large pmportion of the uxygen delivered to it by the tOIOIII,) circulat ion. The coronary IlloOO flow Ilepends strongly" myocardial melnboliSIlI. whic h in tum is affectetl by.J, done by tbe hean and the cfficiency of the heart. The (U\)nary sYStem normally has a reserve capacity that alW.s ~ 1 resJXlnd by vasod ilation to satisfy tbe needs of the Ia! 0 Iluring 51rl.'nuous activity by the body. Coronary :uherosclerosis, one of lhe more pi"l:,ulenltW ovltliCu lar lli'ICases, develop<; with increasing age and ..~ lead 10 a reduction of the reserve capacity of the con'IUj system. It mOST ofTen resu lts in multiple stenosis and IIIab:i it difficult for the coron;l()' system to meet adr<[WlteJ)'!Iie oxygen needs of Tbe heart that occur during phr.;ical emcilr or emoti onal durc.ss. Insufficient romnary blood nl)lI ("'Ill cardial ischemia) in Ille face of iBCI'Cased oxygen den. produces angina pectoris. The principal gool in the prevcntion and reliefofupa is TO limit the oxygcn requirement of lhe heart SIJ WI alllQUnt of blood suppli ed by the stenOSCll arteriCli ;1 II!! qume. Nitrate esters. such :lS nitroglycerin. lown- tWIll. blood pressure and, in tum. reduce the wort. of the left II' cle. This action is procluced by the powerful ''lI!ootlL", cffect of the niTmTCS on Ihe anerial ~ystem and. II) 411 roll grea ter extent. 00 the \'cnous syste m . llic result is ~ cartliac filling pressure and "entricular ize. TIlls redttaI tile work required of thc ~cntricle ~nll Ilccreases the (U}vs requirements. allowing Ille coronary system 10 !>au,f)' oxygcn demands of myocartlial tissue and relieve pam.

llle treatment and ll)cr~py of cardio ~ascular dio;e;l.~ have urnicrgooc dr-mml;c changes silll."C the 195()s. Data show Ihm si nce 1968 and corllinui ng through the 1990s. there 1'13$ been a 1l00iceabie decline in mOl1ality from cardiovasculnr disca.<;e. The ba~s for ad\'anc(!S in the control of hean di~a'iC have been (a) a better undcrs'~nding of the disease Slate. (b) the developmellt of eff~live therupeutic llgcrns. and Ie) innovative medica! imervention techniques \0 treat problems of the cardiovascular system. The drugs discussed in this ct13plCr are used for their aclion on the Ilenn or mher parts of the vasculor sy~ rem. !O modify the 10l.al ou tput of the hean or [he disllibulion of blood \0 the circulotory system. These drugs are used in the tre:umen\ of angina, cardiac arrflyrhmias. hypertension. hypcrlipidcmias. and disordt!r.; of blood coogulotion. This chapter also iocludes a discussion of hyJXlglyeemie agents, thyroid hormones, and antithyroid drugs.

ANTIANGINAL AGENTS AND VASODILATORS

Most coronary artery disease conditions are Ilue to deposits of atheromas in the intima of large anll nu.. '<iium-si1.ed ancries serving the heart. llic process is chal1leterized by an in sid ious ooset of episodes of cardiac Iliscomfort causcll by ischemia from inadequate blood supp ly to the tisues. Angina pectoris (ungina). the principal ~ymptom of ischemic heart lliseaM', is charlll:t~ri7.cd by a severe constricting puin in the chest. ofTcn rndiating from the precordium TO the left shooJIler and down the linn. llic sy ndrome has been Ilescribcd ~i oce 1772 but nOl until 1867 was amyl nitrite introduced for the symptomuTic relief of angiha pecToriS. I h was believed at thaI time that unginal )):lin was precipitated by an increa.'IC in blood pressure an<! that tile use of amy l nitrite reduced both blood pressure and. conromitamly. tile work requirell of the heart . Laler. il was gener~l1y accepted that niTrites relieved angina pectoris by dilating the coronary arteries and Illat changes in the work of the heM were of only s.econdary importance. We now know thlltthecoronary blood vessels in the alherosclerotic heart already are di lated and that ordinary doses of dilator Ilrugs 110 not significantly increase blood supply to the lleart; in,tead. angilml pain is reHel'ell by a reduction of cartliac COI15umption of oxygcn.1 AlthQugh vasodHaton; are usell in the tre~tment of angina. a more wphisticmed unllerstanding of the hemodynamic response to the'IC ugents Ila.\ broadenell lheir cli ni cal usefulness to otller cardio\'!lSCu lar condi tions. Because of their ability to

Intermediary Myocardial MetaboUs.

Energy metaboli sm by lleart I ply of high-energy phosphate I adcnIKine Triphosphate (ATP) thai SUllied in contn>ction. ion exchange ilCrosS and other energy-dcmanlling processes. Because

622

--~--------------------------

......

G'~""_

..

'<=<

GllJQDOI.

~<--

''''
HOP
AlP .. 2 NADH
PyfU'lltUe(2)

_... -
"H,o ""
MiIochondIioo NAO-+ 2 FAD 6 NADH 2 F"DHa

4 AlP .. 2 NAOH

PynMIe (2)

..,..

Ace-CoA (2)

,,;..
cyde

NOfUML GlUCOSE METAeOliSM

ISCHEMIC GlUCOSE META80llSM

Figure 19- 1 Normal and 'ChemIC myocardial metabohsm of glucose A total productlO!1 of 36 r'I'IOI4!s of AlP l'('SlJits from tne aerobtc catabohsm of 1 mole of glucose and lISe of NAOH <Jnd fAOH2 In the OXIdaI';oe phosphorytalJQn pr~~ In mllochondna. ~ O)()'9l!1lIS not available. NADH and FADH,Ie".eI~ fM and shu! off the tncarboxylic aod (TeA) cycle. Pyruvate is converted to lacta!e Dr'lty 2 moles of AlP are formed from anaerobic: (atabohsm of 1 mole of glucose (Adapted from GII,II"'rH, E R, el aI CilldtOk:x}y ful'\d.lrn@ntalsand f'l'actKe, 2nd ed By Pl'fflmSlOfl mille Mayo FoundabOO. RllCIw!.t, MN.)

_=mll: of AT!' in hean muscle. a cOI'!'espondingly (;lie of ATP production in the mUochondria is re-

SMOOTH MUSCLE RElAXATION

oni','m,"'"" m', is ~robic. and

h'

the amount of ATP

the

fuel r~myo . I . and glucose

and Wll'cr. A l:uge \'Olum.: of the cell consists of mitochondria In which '''''o<arfll&mem~ from FI'A breakdown are metnbolil.cd the Krrbs cycle. n.c m:luced nnvin and niooundinudcoII\k.lo fOl'l11ed by this metabolism are ~'\i by the elect ro.Hrun.~pon chain beC:lu.'>C of the presen Wo)P (Fil. 191). In the hypo'l.ic or i!iChemic heM{. the Ol)"gen inhibits the e!a:ttonmmspon cham fuoclioo un llCCumulati on of reduced flavin and nicolln A\ l m;uh. fany acids are oon~er1cd to tllan bein; 0'\K1i7.cd. To compensatc for thi~. U>c and I . increa.~. but the rC"~ultino instead. II is eoo\encd to lac Io!o. of efficlcocy occur.;; as a result of the change melabolism (rom aerobic 1 anaerobic path 0 ATI' are (o"nttl from the o,\i but oo ly 2 moles are formed I 1000S high--(,lIergy ~tore~ the fuoctional capacity of the ro'''''' ' ' and is reflected by the pro-

,..,..

...

ur

The cootrnctile aclh ity of aJitypes of muscle: (~mooth. ~lele lal) is regulaled pnmarily by the: re\c:tSlble phos~... ,. lation of myosin . Myosin of smooth muscle l"OOSI~t ' of twO hea~y chains (MW 200.000 each) Ihat an.' coiled to prodlM:e a fila InenlOU$ lall. Each heavy cham is :lS$OCiatcd Vwllh two pairs of light chams (MW 20.000 and 16.000) that !ien.e a.~ subSltDte:s for calcium- and calmoduHn-dc:pc:ndc:nt protein ki nases III the conlnlClion process. Together With actin (MW 43.000) they panicip':llc In II cascade: of biochemical cvcnts that are pan of the processc.~ of muscle coo tTllC."t1OO and R!louallon (Fig. 19-2). Cyclic nucICOli\k~. cyclic lKlcn()!;inc lnonophosphatc (cAMP). and. especially. cyclic guaoosine monophosphJtc (cGMP) plJY importam roles in the regul:lUoo of smooth mU"l'1e tcnsion. cAMP i~ the mediator aSSOCiated wnh the smoot h muscle rda.un! properties of dl'\lg~ slM:h as ,B-adrenCfgcc agom~s. It 3CllYacn; lhe ~c ln kinascs thai phosphoryl:uc nlyoMn light-clmin kinase (MLC K). Pho~photylation of M LCK inacti vatcs this ~in:l.St and pre"cnts its actlOO with Ca:' and ClIlmodultn 1 phosphorylPIC myosin. "hlch mter0 actS with 1I(.1;n 10 cause contraction of ~mOOlh mU"l'lc (Fig.
192).

The <lll:1]\lty of cGMP in \mooih muscle reluauOfI is ar (<<led by uogenou~ and endogenous agents. It i ~ sU llgeMed' that ni\rova>odilutors ulldergo metabolic tr~llSformation in

---------::::::; 9--------Ca'do.m eNoMtI c;a2.

eo"

, ......'

~ ~------AIC8\l1Of

Flgur.

19- 2 . RegUlatlOl1

smooth muscle ContriICtIOII (CJIIl1acltOn IS trtggered

eM
Wi i """'"

Ca 1 . The lflCrease ofiree Cr'

Ca10 -CM complex btnds to h hl -tNln kIflaSt' (Ml O O and g

by an

II'I~

af

bindll'l9 10 CdImoduhn (e M)
Its actrva\JOO (Ml(K') MtCK'IiO-

pI1or',{ates
. MLCK- iPO.h
Myoain-lC

m~n.

wturo COITGI

MlCK' .,-'--

- - MlCI( - - M)'08irH.C-PO.

_,

- -+.

w.t/l lI(t1n to produc:e conlf(l(lIOn af smooth muscle Myosln IS dtph , phoryl<l ted ,1'1 the pre-..eI1C! 01

"'"
Yascu l ~r

j
Re"utlDn

phospha\ilse to uuse muscle lion. The p agonrsts iKtNalt~~ cyd.He (AC) to raISe levels 01
whtch In 11..1'1 actJvates IrJniWI,
~\e MlC K. ONCtroibrlgllg prewnt m~ ( OfItroKtJOn

smooth mU<;ele cells to fonn nitric o~ide (NO). NO

mediates smouth muscle n:laxation by :lCtivaling guanylate cyclase \0 incnollse imroccl lu lar cOOCC'nlr.uions of cG MP. cG MP kti~\c.\ proIC"in ki nases that c;m n:gUIDtc fl'C\' Cah le'" cls in the muscle cell ~nd cause: rl'laxalion or SmooIh musck by phQspIlorylllting MLC K. A shoft li,e(! free radkal gas. NO is widely distributed in the body md plays all imponam role by its effect through cGMP on the snlQOlh muscle vasculature. It 1$ s ymhesil.od in too vasc ular endodlClial cell from the: scmiessenti;ll amioo add I.- argi nine by NO symllase. After production illihe cell, it diffuses to the: smooth muscle cell, w~ il ac:li ~ales the enzyme guanylate c )-c lase, which leads to an increase in cG MP and th!:n n1UliCIe n::laxation (Fi,. 19-3). EndoI;heliumderi"ed !Cluing factor ( EDRF), relea..w from lhe endothe lial edl 10 mediate liS smooIh mu.sclc- rela.\ing propenies lhroogh cG MP, is idemical wilh NO, InhibilOl'lI of phos.phOdiestcrasc~ of cAMP and cG M P also cause smooth musc le rcluation. 'The!.e inh ibitors incn::ase ccllular Ie,'cls of cA MP and cG MI' by preventing their hy

drolysis 10 A MI' and GM I', respectively. Drugs such 1\ pi paverinc (~Chaptcr 17) and thcQphylline (sccChapttr 1 which n::lax smooth musc le, do:.o in pan by inhibltlnl phOdieSlera<oc!i.

METABOLIS M OF NITROVASODILATORS
After ()f'Ill administnlliOll. organic nitrates arc "'...... rapidly by !he liver. ~ idney. lungs. intestinal mooxa. -.asc\llar tissue. B uccal absorption rWIICCS the im ~~ __ hepatic de~lfllct ion of lite organic nilrates because of tile cllrdiac OUlput is delivered 10 the li,e('. 111lll!lienl bul errective circulating level of tile IntlCl nitrate before it is inacti vated.' Organic nitratcs. nitritcs, nltroso oompoonds. and. ely of other niuogen<onlalntng substances. such as nitropnlliSidc. for the Itl(KI pan cause their ~~",,""" effects by generaling or releasing NO in si lu. ln some these drugs arc "ic ....ed as " ft:placelllcm a~nts" fo.-thee. dogellOl.lS NO genera ted by the: NO synlhase I arginine. The mechanism s by .... hid lease NO have become beller 1 shows Inc oxidation that an: common in ture of these

,b".""

EiIdoIhaHzl Cell

of NO aoo + 3 (as woold occur In all1nlOllla.

00'

.,-,f,--_
"'M' I

Guanylllta e-,.:iaM (Ge)

j
MLCk' .,- - "'-CO< -

biological nitrogen compounds). The i o~id~ t iOll Slale of +2. Compoorlds such as nitrusoamines. and ni lruthiols wi lh ox icllllioo I NO n . ll

-'-- .. MLCI(-PO.

Figure 19- 3 MedlitnlVn of nlu oYasodilatOfS NIIJII: 0J0.Jde (NO) fOI'lMd In smooth musdt from rIItroYo!SOdl latOfS or from endothelial cells (EORF) act .... ates guanylate cycla$ol> (GC 0) G( 0

activates cGMP-dependent proleln k,nases that phosphory1ate myosin hght-<ha,n kinase (MLOq, causmg Its Inactivation and sobseqlll'fll ~Ie rela.lliluon (see also Fig. 19-2)

NO by homolytic ~moolh musc le. I

phnOM

Illlhiollc as the most aburldant Ih iol

ChapIn I' CanlItJ''QJClI/tt' At""rs

625

Nitrosyl Vasodllatory Subst..ncel and Their Oxidation Stata

of
NitrOHyl , I+ .....nd Structur' Nitrog . ... O.ldUlon SUIte

f .... LE ,9-,

On

n Con' UlUse5

Influx of

M), The

'- ",,"" "..,,"

'i.,_
TI -

to~n

'.0 -""0 -0'<0

R..()..N.Q

.J

:- phos-

d causes

.I

combine; act\OO 0 1

~ "''''It , .... ~hM~

., " .,
., ., .,
C.'lri .. S7,I.,:.t'l'l'. .....
i~

p....

n''''''~

M--S-N-O , <>-NO,
.... :<1(),.
[(C"h,I'o-.~.o"

.J

of rnyoslf'l de relaXa*"ylale of cAMP.

)OIr.....,.,do

' _ f......... O{;, ..... ~')1 _ ...... _ .... f""'" " ...........

~tMI

atJng II 10

paUpter 18). ing pilus

Ch

a.~

:taboli/ed :0SlI. and

nmc:d l ....e
allO\\o~

JOlly IS<J.

it organIC

1d a vatl ' sod ium oolO&lcal

-ne way~.
Jf

predC'd II)- metabohc c h~ngc, 11101 follow a variety of path!;. aionad'onnallun of nnrogl) ccnn to lhe dmnrutcs and the m'~2!.C! of int rJoCcliutar cCMP prect'dc vDscu lar rellUDlion. SalIlI).JI)'I-commrllnl: oompound.~. suc h as cysteine. react dtnnicotlly ",ilh organi<: Illlrl,tes to form morganic nitme II.Ift. Tbc release of NO from an orgamc nllmle. StIch a.~ IIII'OgI~mn. appear; to occur in a ste pwl)I: fashion involvIII noncn/y".al1e Dlld cn'Ymane SlCps. Because nllroglycena reqUII'C) a thrce-clectron reducllon to n:1c15C NO. thlol s .,. \:It IrI\'ulvcd in the procc:~s. Nitroglycerin may decompo!C IIOIIaIl),mallcaJ1y by mter.tetlun WIth a vpriety of thiols. ... II:'l CYSlc:inc or Nacetylcy'leine. whIch nllly be prtSelll .H~. 10 fonl] a nHlUloOIhlO1 illtem~dlate hefon: IInrlc'lo., C'IILym:l\lc tnmsformation 10 release NO. Nltroglycenn Iho readily n:le:tSC) NO by acllng on an I'n1.yme ~yMem 1b:hed to the ce ll ular surface n~mbnmeof ~mooth musc le. TIc poccss ma) inc lude glulalhlotlC-S-l ransferasc:.~. which roller! nllroglyecn ll to a \asoiroxllve nllril e. which thell M)' rc:lea.o;e NO 11OllI'nlymalieally.' BURS Of NITROUS AND NITRIC ACIDS
~ic acith. ""c organic acids. "III form eSlers ~ . l'hannaceut~ally. the important ones arc:

The phannacoo)'r1amIC ao:tion of r1itroglycerin

NitTOUl add (HN 0 2) Wt'f'S may Ix fom~ readil) from an alcohol and nitrous acid. 1lle usual pnxedurC: is ") mu sodiu m mtrile. 5u lfunc add. and lhe alcohol. Ort!onic mtntes ~ generally very YQluile hquids thaI are on ly slightly r.()lu+ ble in water but soluble in alcohol. Prepar llons contaimng .. water an: very ullstablc: becau'iC of hydrolysK The organ Ic mtr.ltcs and mtnlCS and lhe inorganic mln la have their primary uti lily in the proph)' laxis and Irt'~tmc:nt of IlIIgi na pectoris. They have a more linuted :tpplication ;n IteIIlillg asthma.. gaslroinlesllnal spasm. and cenam case:;; of migraine headache. Their application may be: regartlc:d as C1Iusaltherapy. since they 0<.1 by sUbstitutinl! an I'ndogl'nous faclor. the production or relea.o;e of NO. ",hich may be 1111paired under pathophy!iological cilUlmstanca associolC'd with dysfunction of the endntbel ial tis..,ue. Nit~IYCl'rin (glYCl'ryl trinitrate) was nne of the fi~ members of this group 10 be: introduced into n~idnc and remams an ImporIanl 1I1I'mbe:r of the group. Varying the chemical Slructun: of the organic ni\Tates yil'k1s diffl'rences III speed of OtL'iCl. rluratioo of action. and potcncy (T abk 192). Althwgh the numbc:T of nitrate C1> ter groups may vary from 1"'0 to si~ or more. depending 011 the compou nd . there is no dlla:I relutionship between the nurnbet' of nilratl' groups and the k:~el of acti vity. It appears thatlhc: highcrthe olllwau:r pantllon coefficie nt o( the drug. the grealer lhe potency. The ooenlatlon of the groups within the molecule .Iso may affect potency. Llpophilicily of the nitrogen omlc-commmng OOntpound pr0duces a much longer response of vasodll alory acllon. The lIighl y lipophil ic estcr nitroglycerin pcnncates the ce ll n'lt'm\mine. all owing conllnual fonnalion of NO within the l..:lI. The same erred appears to OCC\Ir (or sodium nItroprusside. nitroso compou nds. and Other organi<: nitrate and nitrile 0tl'rs.
ANTlANGINAL ACTION OF NITR OVASODILATORS

the en-

~ay from
~rug" ~.

fable 19 :npound" fca lhe form ?,<,:r lhart Uld n'lOSt ha.' an

ron
P

",ilh an $ul fa1e, 1IIIntt. and mlmtc. Sulruric acid fonns organic sul futes. of ...h mcth)1 sulfate and ethyl ~ulfatc: are e~Qmples.

The action of' !ihon-acling sublingual nitl1lles III ti1c rei ief of angi ll' pectoris is COIllple ~. Although the subhngual nill"~Ies relax vuc ular smooth mu scle' Hnd dilule Ihccoronary ancrics o f normal human s. there is 1;1111' Improvemenl of coronary blood flow when these: chemIcals arc: admimstered 10 IIIdi viduals with coronary artery discas.c:. Nitrogl ycenn IS an ef fective anti anginal agenl becau'iC: 11 causes redislribution o( coronary blood now to the ischemIC ~gions of the hean and reduces myocardial ()~yge n demand. This laller efft

JrU~Mdc.

of ... 1
~-,

Relationsh ip Betw"n Spud a nd Duration of Action of Sodium Nitrit e a nd certa in IrlOrganle Este"
CompcMl ... d

TABLE '9-2

In\'ollC'\ \xPO~UI\" b 111 Ihl' If.! nII grouT"

Adlon Begins Iml ...... t )

M._IImum l Effed: Iml"""_)

"'m)IIILI"'"
/Io.,..,.t~~

OJ,

. , _ do",1r.\I<

, ,

rpm.eto
malian IIh ,11,1-

""..... "''''It fl)' lhmyl U!1nIn.1"lr

Ib ")1IIntol "tnlHIr.II<:

" " "

" " "

.,

Duration of Action Im ;nut... )

., " .,
,OJ

'"

'"

IS poduced by a i'edUClion or vcnous 101M.' mulling rrom the nunlle vasodllaung cffect aod a pool ing or blood in lhe pen l)licral VCIn~. which n:sul,s in a redl.lCli()1I in \'c nuicu lar \'oIumc. suokc ~oIumc. aod cardiac ootpul II also cau~ reductIOn of pcriphcl'1li resiswx.'C during myocardial c0ntractions. 'The COITIbincd va.'IOdi lutory cffects cause a de crca:;c in cardiac work and n:duee o.'(yge n delll~od. PRODUCTS Amyl IHtrile. isopcmyl Rllnte I<CIl,)~IIClIzCUt>NOI. is a mixture of isomeric amy l ni trites but is principally isoamyl n'tnte. [I may be prepared from amyl alcohol and nill'Q\JS acid by sevcl';Il procecJures. U~un lly. amyl nilrite i ~ dispensed in ampul form aod used by inhalalioll or orJJly in alcohol o;olulioo. Currenlly. il is reI,.'QfIlmcnded for treatmg cyanide poison;n,: although not lhe best 3n1id(MC. il docs not require IIIlrOl\C IIOUS mjeclions. Amyl nll rile IS a yellowi,h lillUid ",ilh an elhereal odor and a pungcnt laSl.C. It is vollllile and inflammable al moon lelnpcl';llul'r. Amyl mlnte yupor form~ an uploshc mixture in air or 0'\ ygcn. I nhaialioll of the vapor may invol\c definlle exploslOil tmurds if a source of igllltion is jlfe.'oCnt. lIS bUlh I'I)()IIl and body tcmpemlures an: wilhin Ihe flammabili ty runge of amyl nitrile nllxlures Wllh either air or oxygell. It IS nearly in'lOluble 111 WlIter but IS nllsciblc With organic solvcnts. Thc nitrite also will decompose into valcric acid and nitric acid.

Amyl Nitrite. U5P.

.lI!oOdilating IICt ion and. because it is absorbed tllrough tht skill . is prone to Io'8 U!o/: headaches llmong ... orl.cl'S i.SSCXWN With II ~ manufuclurc. Thi~ trans.dcmulI pcnctrJliOiI is IIIIIy mtroslyecrin IS uscful in a pa,~h formula'ion. In medltine. II has the: action t)"pi~al o f nitrite~. but liS action denlopl more ~lo""ty and is of lon];CT dUl1luOli. Of all the ~I coronary vlI,,OOillllory df\Jg~. nilrogly~erin is the onlyonr capable of SI inllliating the production Qf l'Of'OlUlry collatml circu lation and lhe only one ablc 11,1 pre'cm C"pcriilkh~ myocanlial infarction by coronary occlusion. Previoosly. Ilk- nitrates were thought tQ be hydrolrlC'd IIId reduced in the body to nitrite~ .... hich then lo ...cred Lhc bIool pressure. This i~ not lrue:. ho ... cvcr The mechanism di 11111011 of nitroglyccrlll through ils formation of NO IS described al)()\c. Nitroglycerin tablet illSiabi lity WII$ reponed in moIdod sublingual tablets.' The tablcts. although uniform ... Il!'o _ ufllCtured. lost pou~l\Cy boIh because of ,ulaliliwtIOll ci II1roSI)ccrin into the ~umJolII\ding nmlcrials in lhe con..unaand inteTUblet migrallQn of the octile ingredie nt. Niuql)" enn may be htab,lu:cd \1\ molded tablcts by lI\1;orpcniIIIIl "fi~lIIg agcnl ~uch as pol)'cthylcnc glycol 400 or poI}'" ylcllC glycol4000.~ Ln additIOn 10 sublingual tablets. the: thr has becn rormuLated intu an equally efTccli\'c hngual ~. .' for patlcnts woo h:ne problems ",ilh dissolution of gual preparJtions becau~ ofdry mucoos IIlf'mOOIlCS. T dermal nitroglycerin preparalions appe ar to be less clfmtll Ihall other longlleling nilr~'e.~. :t5 absorp:ion from the: i "Ilritible.

of,_

Nitroglycerin. Gl y~cryl trinllrute is lhe trinitratc cslcr of gly~en)l and i.~ li~led liS availnhlc in lablet form in lhe U,,;ftd Sf(lft'S l'/wmll'f:o(J(>4'ia. II is prepared by ~an:rlll1y addmg glyccnn to a mixture of nitric and fuming su lfuric acids. This rcllCtion is Cllothennic. alld lhe re:.c1ion mi~lurc mU'it be cook'il tQ bct we~n 10 and 2ifC. 1'he: eSl.cr is II ooIorlcss oi l. with a sweet. burning laste. It is only slightly solublc In "'akr. but It is soluble III orgllflic solvents.
",,-ONO,

Diluted Erythr;tyl Tetranltrate, USP. Erythntol_ nitrate. 1.2.3.4-butallClCtroi. tCll1lnllratc (N- ~HCanii i~ the tetraniln:tlc cslcr of crythritol and nitric acid, II II,.,. pan.'il III a manner analogous 10 that used for nilroal) The result is a solid. crysrallil'll: matcrial. This .:>ter II Ycry uplos"c and is diluted with lactose or inen dllUC1lts to P<'mm $;Ifc handling: it is slightly 5 in waler and 50Iubic III OI'J!l1mc solYcnts.

other-::

N_ ,- -' Troll""" tgual

I I H,c-ONO,
>-OHO,

"'"'

Ni~obId

Nibt>g..,n

Nibt4fTi Nilrob1d IV

Erythrltyl Telfanillate (Gardi"te)

N"N"i!f01l
n

n ...

lAlulbllll

_,
.
in

requires slightly its ~ fTect . which is of I

I. "'"

Toanade ....NilfO
Nitroglyctrin is used c~lenshcly as an cliplosi.c in dyna mile . A solution of the cster. if spilled or allo ... ed 10 cvaporatc. will leavc a residue of nitroslyccrin . To prevCll1 an explosion of the residue. Ihc ester mUSI be ~omposed by IIle additloo of all.ali. E"en so. the material dispensed i~ so d,tulc that the fis k of UplOSlonS does not cllis!. It has II sirong

~ncril1~':::~;i~~"~,OO'

load as a /"Cliuh of
circulatory ~ystem vllSOdill1l1ng ~~~'~iOO~,;:~:; results in a reduction Qf blood pressure dunng \tressful situations and is an 1l11portl1n1t vcnting the ~lpitallon of anginal auack

Diuled PenlHl}'thritol Tetnnflrate. USP. Penmuythritol ttlr.\Jutrnll'. 2.2-tHs (hytlro.1ymcthyl)-I.J-prop'::lIIe rl't!'3l1itrarl' (Pl'rirnlll', l'en/ritol). is a ..... hile, ''1}'SmUine .,,1lh a ITlClnng of 14O"C. It is msoluble ,n .....:1 il soluble in acei IClrahydric alcohol and is It powerful uplosi\(', Acooo dingly, it '1 lactose. mannl1ol. ~ other suimble IIIcn dlto p<'mli t safe handling.

'm" ...,

....

...

TIME (ma:)

I C>,NOt-l,c -C-CHPIQ, I H,C-ooo,

PentaerytMtQl T eI,anltrata
(Perilrate) (l>allll!ol)

"'" -

000,

,., , '"
,

\. "'" , ""

.,
'"
I ~ide

"

dumtion of !\Ction. d,ni (lsordil. Sorbi crystalline pov.der. Its watl'r wlu-

figure '9- 4 Dlol9ramma!JC rept"~tatlO!'l of thE> mtmbrane act.on potent.al. as recorded from a PUrklnje fiber. and iWl electrogram recotded from an isolated ventrICUlar f,ber The nlel'nbrane resttng po\@flttalis90mVrelalM'totheextenofof the fibef. At the potnt of depolaflZatlOl'l. there lSa rap!(! change (phase 0) to a more POSIU~ va lue. 0-4 Indicate the phases of dt>polalllatlOll and repoiaruallOfl Notf that p/'Ia5ti 0 alld ] of !hi! membr.me acbOn potential correspond III lime to the ,nscnptton of the QRS and T waves. respectIVely. of the local electrogram.
hean is mcdimed by two inwardly du"t'C:ted iomc c um:nts. Wilen the cordioc cell poIentiaJ rcacllCll its threshold , ion channels in the ITlCmbrane art. opened, 000 No' enten the cell lhrough ion channels. lbese channel s give nse to the fast sodium current that is responsib le for the rapidly rising pha.o;e, pha.<;c 0, of the vc ntncular action potcntial (Fig. II).. 4). ll1c sc:ooold CUffCnt is cauo;cd by lhe slow ItCllVallon of an Ltype Cal. ion channel lhm allows the move:ment of Cal' into the cell. Th i$ "slo w c hannel" contributes to the maintenance of the plateau phase (pha.<>e 2) of the can:tiac action potentiaL We now undcmand that the Cal' that enIe:rs with the action poIentiol initiate.~ a second and larger re lease of Ca l + from the sarcoplaSl1l1C reticulum in the cell. This sc:cundary release of Cal is surftc icnt to initiate: the contmctile procc$s of cardiac muscle:. Contraction of cUrdiac aoo OIlier muscle occurs from a "'action between actm and myosi n. In contrast to smooIh "a,'\C\Ilar mUscle. the: collirncl ile proce.u in canhac lIlu'ide: involvCll a e:omplex of proteins (troponin s I. C. lind T lind tropomyOl;ln) attached to my06l11. which modulates the inter action bctwC('n actin aod myosin. Frtt Ca lo IOIU bmd to troponin C. uncovering bioding sites on the actin molecule: and allowing interaction ..... ith myosi n. causing contr.w:tion of the muscle. lllc schematic diagram in Fig ure 195 show~ the sequcnce of e:vcnlS. tO Contraction of vascular smooth mu scle:. like: Ihm of cardiac muscle. is regulated by the coocentr.aion of cytoplasmic Cal ' ions. TllC mech~nism by ..... hich the ~"Ol1tl'"3Ction is elTa.1ed, ho ... e\cr, includes a cal clUm- ~nd calmodulindependent kinase 1\$ opposed to n Cnl' -scnsiti vc troponin- tropomyosin complex ( Fig. 192). TllC ICtivDting effect depends on a different typcofrcaction. lllcclcvated free: eytosolic Ca lo in vascu lar smooth muscle ce:lls binds to 3 hi gh-affinity bind ing prolein, ca lmodulin.
0

;;'i;" Ii ,;'"''''

it

1Ibot~

I mg/mL

""'"

n. mo:tl-'. llladdng on& of tt>& nitro substoMIona

I~

'SMO"'"

IIoIorbIde Monooitrate

dimtrate, as a subl in gulII or chewable tablet. is in the treatment or prophyhu.is of ocute anginuJ When It i~ gi,"Cfl SIlbling~lIy. the effet'! begim In . .... ,th a o;OOncrdurutlOn of acliOf1lhan .... hen orally. Oml tablets are not effe<:live in acute angi the ons..'1 0( action ntngell from 15 to JO min of metabolism involves denitnmon to . This metaboli te ha.~ a much longcr parent isosorbide dinitrate. As such. this metabolite is llWi.:eted in a tablet form that has btoo'lIllabtlity .... ilh much Ie,s fim-pass mc tllbo!han isosorbide dinitrure.

COUPLING MUSCLE
has been tdated 10 ion nuxes through the cell l).:polari1.3tioo of the lis.\lIC in the atria of thc

ION CHANNELS AND CALCtUM

Calcium ion~ play 1 important role: in the regulation of m Ullin)' cellu lar processes. such ali synap'ic trunsmiss ion and

STIMULUS - - - . ,

ea2 ----1 I--ceII membrane

Tr()pOl"",nn, ...

~ cah CornpIe~ .. rnI I Interaction Act'" ... Myosin I Muscle CootractlOl'l

Ca'

Figu... 19- 5 Sequeoce of events Ihowtng exeltatlOl'l-conUiJ,lIon coupling In cardiac: muscle

muscle contnlction. The role of calcium in tlM!se tellular functions is as I !;eCOnd mcsstnger. for cxample. TC,ulating enzymes and ion channels.. The entry of eXtrlllCel1ul1lT C. l ' into the cytosol of myocardial cell~ and the n:Jease of C.2 ~ from Intracell ular Storage sites is important for iniTioli n conll1ICtions ohhe m)ocardium. Noonally. tile concentration of C.1 in the cxtrlllCelluhlf nuid is in the millimolar ronge. v.hereas the intnlCCllulnr concentrution of free C. l is 1CS5 than 10 ' M. even though the total cellular concc:ntnuion may be 10 J M or higher. Most of the Cal. is stum! within intra\:e ll ular orglllJClles Of tightly bound 10 intrnceJlular proteins. llle free C,l' n....d ..... to satisfy the requirements of I contnlCtion ~wlting from I stimulus m.y result from acti,'alloon of calcium channels on the cell membrnne and/or the rclcase of taJcium from bound internal stores. Each of these methods of im:rcasing free cytosol ie Cal' involves channels that are se lecl i~e for the calcium ion. Calcium channe l block ers ~uec or prevenl the iocrease of free cytosolic calcium ions by inte-rfcting .... ilh the transport of calci um ions through thev poi($. c.k:lum is 0flC of the most common clements on earth. Most calcium involved in biological ~ystems OCCUr!! lIS hydnlllyapatite.a suttle, stabilizing ~truL1urc like that found in bone. The: rcmaimng ealcium is ionIC (Ca 2 '). Ionic calcium functions IS a blOChemkal rcgulator. more often Within the cell. The Importance of calcium ions to physioiOSkal fuoclions was rcaliad nrst by Ringer. who observed in 1883 the Cal + in cardioc contrACtility. role The IOnic composi tion of !he cytosol in exdlllble cells. including cardiac and smooth muscle cells. is controlled to a large elltefll by the plasma membr-~ne. which prevents the free mo~ement o f ioos acl'OSl; this barrier. Present in the membranes are ion.carrying channcl~ thut open In rl:SlX>n.St" to either a ch."lngc in membrJne potential or binding of a ligand. Caldum-sc.-nsluve channels include (aj N~ ' to Ca1+ exeluln~. " 'hich transpons Ihree Na' ions in n:tum for 2 one Ca- +; (bj a voh~ge-dependent channel. .. hich provides the route for entry of Cal' for c~ci tation and oontrllCtioo in cardiac and smooth muscle cells and is the focus of the channelblocking agents used In medicine: and (e} recepror-opc:raled Cal' channe15 mediated by lipnd bind ing 10 membrane ~p1ors as If! the action of epInephrine on the o -adrcnergic ~ptor. The membrnnc oftne SlIrroJc:mma within the cell also has lon-collduct ing channels thaI focili-

tate movement of Cal' i(.MIS from MOI1Ige loci in the wroplasmic reticulum. Four types of calcium channel,., dIffering in 1000000n II1II funcr.ion. have been identined; (u} L type. located in skdrul. caniioc , and smooch musc les. cau~ing contl1lCllOO 0( mulde cells: (b) T type. found in pacemaker ~-e1l5. causing eal' entry. inactivated at more neoti~e potenrials und n~ rapidly lhan the L type: (e) N type . found in neurons and JCtJIII in tr.lllsmllter rcJc:ase; and (dj P Iype, located If! PurtJ!Ije cel15 but whose fuoctJOn is un\.oov.-n ,n th,S lime. Clilcium antag<>mSlS act ooly Oil the L-type channel to produce their phamulCologicul cff~ts. The L channels II'! so called because once the membrane has been dc:poIanud. their lllClion is long laSling. Once the n"ll'mbmne has toea depolftm.cO. L t hanncls must be ptoosphol)latcd to opaL Although there are similanties between L-type c.k-ium channcls that Clli~t in cardiac and SmOOlh muscle:. then: 1'1' di~lincl differcllL-es between too two. Cartliut L ch:uwl) arc activated through ,8-adrencrgk sti mulat ion \"1" cAMP dc'pendent phosphorylation pruce$S.11 .. hile L cMnnels ia smooth muscle may be regulated by the iOO$lwl ~ system linlie<! to G proteio--coupled. ~ptor lln\.ed phoI.pholipase C nctivntion . 11
CALCtUM CHANNEL BLOCKERS

or

The L-Iypc calc Ium channel. acted 00 by calcium clwlad blockers. consisls of five different subuniUi. dcsignakd III lI':!. p, y, and 6. The 01 subunit provides the ce ntral port" 01 the channel (Fig. 19-6). C.lcium channel blockers ~ br divided oonveniendy IfIIO the three different chanor:a clas...'1e5 of !he proIQ(ype drugs that ha"e been used: phar)-bi\.yllimincs (\erupamil ). 1.4-dlhydrop)ridLncS ( nifedipinr~ und benlOlhilll.cplne~ (diltia/.c m). These proIOIypc aapounds sometimes are tcnned the nr.;t generation" oleacium channel bloc\.ers because two of the groups of at.! claw=<; ha'e been e.lpanded by the introduction a "K(. and" gener.!.lIoo of 100ft poIent analog\lC!i (Table 193). The spccine Cal' channel antagonisUi ver~pamll. nlf~ pine, and dil1iU/.cm interact m spccinc silt.$ on the calc .... channel protein. The~ blockers do 001 occlude the c~ physically bul bind 10 ~ites in the channel. 11$ they can p-omote both channel activation and anlai:onism. Affinl~ b binding sites on the channel .-and. depending on the ~ of the channel. The channel can Uist in either an 0fK1\ jO. re~ting (R). or inKli "oled (1) state. and the equlltbn~rn hr tween them is dclcnnined by st imulus frequc:nc:y and ....

or

ea

a,

Figure 19- 6 Sch(omaTIC leptesef1!i1tron of an L-typf C; ch'lnnel.

Chllpler 19 ClmIiQ .....r w/"' Ag"III.'

m~ t hnuc,

629

TABLE

1 ~)

First- a nd Second-G.,... r" t IOfl C.ld um

01'1'1 ,...1 Blockers

"""''''''

R",
Ge.,....U_
V......... ,I
Slrod,!",,"

Classffic.tlon
.....,1aI~)~

Generlltion

$I""'"

U DIh)l!ro9)'rid"'"

......'

.....!*"il

"'mlOOipollC 1'<1ool,..-

..... "

,-

""'

....

l.,.a'ptllt Nl<'V<liponc

NionWlf'I"O

Irane potemiul (Fig. 19-7). VcrnJ'llmil mid dllti~7.cm do 1'1 01 -.:J 10 a channel in the resting .';IDtC. onl y afler the channe l ~n opened. TIley are ionized. wDIn"-solubic C. z+_
mil)' bl(k: ~ c"" thai reach their bUlIl;ng si tes by the hydro-

philic pathway when the channel is o pen. Vernp.:unit uoo diluv.tm arc usc dependent (i.e" their Ca z , -blod-ing acti v-

If is I funcllOO or lhe frequency of contractions), An inC'\Iuses a rcduclio n. rather

anliunginaJ. and antihypertensl,t acth lly. 1lIc:) lkprcs~ tile cardi ac neurul 1lC1\\-ort, and so ~ Iow \inus node aU10maticity, prolong atrioventrieular (A V) ood.:iJ cond uctance. and dcpR:ss myocardial oontr.lC1i1ity. as \\cll as reduct' peripheral VlIscular resI.mntc to PfC"ent a roronary vuscu lar spasm. Nifedipine and OIher 1.4-dihydrop),ndlllC'l are more cffecti vc at causing ,asodllation than affecllng ~mal.et" and tension ["C!;po!Iscs III the hean. This is opeciall y trllportanl hccause ..clcclivity occurs a~ 11 conscq\ll,'ncc of di sc asc Sli'Iles. Uypencnsm:: 'mlOIlth muscle is more sensl tllc to Cal ' channel blockcrs than IS llOI'Tl1OIen'ille tiss ue . to This makcs vernpami l and dillilll.C:m more u~eful in l'iChemic conditions. as they havc a more profound effcct Oft CardlOC muscle calcium channels.l~ The inhibition of Ca l Influx 11110 Cardia!. lIS~ue by Cu~' alllugonbt> is also the basis fOf" the usc of these drugs as arttiarm}thmic age-nts" The Ca~' channr l blocL~ dampen Cal . -dependent automaticity in the regu lar pao:cmake-r ce lls in the sinootrial (SA) node und depress the origination of tttoplC roci. Culcium unl.llgonists can block reentry p.:Ith ways in myocardial ti,~ uc. an intcgrnl component or arrhythmias. Nume rous side efrcct ~ III llie hcan. sl.K:h as bradycardia. dt:creased cardiac l.'Ontruculi ty. and reduced AV conductancc. an: tr.ICW to Cal ' channel - blockmg activity.

Nifctlipinc is a llCulrnl i . I pH aod can c~use interference In the open or clo'lCd stale. In the timed Siale, cun lruvcl'oe the phospholipid bilayer [0 reach its illKbn& site bause of its lipid solubi lity.
CAROIQVASCULAR EFfECTS OF CALCIUM ION

PRODurn

Ve-rapamJl, 5-1 J.4-d imetlx)1 ),phC"llCth )'1)I1l('tnylumilM) 1 3.4-dirnetoox yphen yl}-2- i~yl vlllcro -2-( nitrile (Cli lan , lo;opcin), was introduced 111 1962 as It
Ver;,,,.. mil.
l."OfUI1ary vasodilutor and is the proIOf)pe of the Cal. antagoni'll! usn! in cardiovascular discases. [t is used in the- t11'31me m of angi na pectoriS. arrhythmias from ;<>el"lc mie myocardial ~yndrorllC$. and "'p.....e-mricular :uril) thmia.~. Vt'I1l.pamirs major effecl is on the slow Cal. channel. The n:.o,ult is a slowing of AV conduction and the si nu ~ ..~te. Thi ~ inhi bition of the action potential inhibi1s one limb of the reentry circuit belie,'w to undc:l'"lic most paroxysmal supr.Iventricular tachycardias that u<;c the A V node as a rcC'nlry point. It is catcgori7.cd II~ It cla.... IV pntiarrhythmic drug (~ ~ "Classes of Anllatr1iythmlc Drugs' below), Hcmodynami clilly. Icrnp:mul cau~ a Charob'C' in the pre load. aftctload. conlr.lClili ty, hcan rate. and coronlll')' bl ood flow. lbe drug reduce~ ~)'stcmic vascular resistance and mean blood pres~un:. with minor effects on cardillC outpul. Vcrapamil IS II synthetic c01llpound posi'>C\sing slighl ~truc lU rnl similarity to papalcrill<:. II tUIi be ..... paroted 11110 its opticlilly acthe isomers. of \\-hlch the le\"OIl)Ialory enantiorner IS the rllOSt potent. It is ~b'iOl'lx:d rapidly afler ()I"'JI administration. The drug i\ me taboli7.cd qu ldly and , ~~ 3 result. has 10,,' bioovailabllity. 1lIc: livet" i~ the mam ,ile of first-pa.\s 1JICtabollsm, fonnmg scI'cOlI products. The PfCfcrentinl I1tet:tbolic \tcp invo lves Ndeal kylali on. followed by O-dernethylation, and subsequent conjugation of the product be:fon: el im ination. 1l1e n"lttllboilte!! ha,c no signifICant biological activity. Ver~pamll ha~ an elimination half-life of npproximntely 5 hours.

r\II

e.!' antagonists yel developed are vasodi1:uQf1l. Vaso-

IIbuon is due to the uncoupling of the ~'OI1tracti1e llIechaof '"..<;oCular smooth muscle. "hich I\.'<juires Cal. , COf;;. artery muscle tone is reduced in healthy hu man~ but ft I""'t"IIlarly pron(MlJ)CW in a condition of coronary SpaSIll. Pmpber.ll arteriole resistance is reduced more than "ellOOs The vasodilatory effecl of these drup i~ !he ba.~is fOf ront rol of angina and hypertension . I) vel'llpamil , nifedipine, and dihillZCm CUll cause , they an: not equally e ffecth'e at blocking the clwmch found 111 various tissues, 11Ic: phenylal)~". 'er~pamiJ and tile bcnmthia7.epinc dilli a7,cm ha,'c cw iac and vascular adioos, 11les.c drugs ha ve Ilrn;ar-

.@

19- 1 5chI.>matIC repr~t.lbOll of ao IOfl chanoel an equilibnum 01 rt'StlO9 (II'), operi (0), ilnd 1n1l-

'CD /

ex
-

S
N

ex

S OH

CH 2 CH 2 N(CH 3 )2

Figure 19-8 BlOtraralormallOOS of diltlazem

The route traveled by II Cal + .. vernpamil. to il~ receptor sile parollcJs thaI obser.ed with many local aoe~lhetic-lil.e antiarrhythmic IlgCnls. II is be lieved lhal ,-crnpamil. lil.e most orllle Cal . channel blockers, crm!ieS the l"C1i membmne in an uocharged (OrullO gain access [0 its si le of action on the intracelluhlr side of the membrane. Data show a greal!'1" affinity of \'C'r.lpamil and other Cal + ch:mnd blockc'" 10 the inactivated Slale of the cOOllncl. 16

"""~lIch a5 lIannel blocker.

artery spasm and reduces myocardial o,(y~n dellWlll b) decreasing heart rate and reducing ovo!rload. Dilllazem 11]0. drochloride is used in patients with variant angina. The .... ha.-. electrophysiological propenies sinlllar to those of II'fto pamil and is used in clinically similar tl"l'atmem alI'Idlt ... as an antiarrhythmic agent. hut it is less polen!. TIle drug is absorbed rapidly and alnlOSl completer) mthe digestive tl1ll:"l. It I"l'ache<; peal.: pla.~tnII lelels 111. 1 hour after administrutioo in gelatin e~psules. Oral fOfTllllJ. tion~ 00 the marlet are susulino::d-I"l'lcase prepar:llioos pIIviding peal; plll')nlll levels 3 to 4 houl"ll afler admil1l>lflliol. Dilti:u.em hydrochloride IS melaoolwed eltens,,cly. oral dQsing. by fil"lll -pIlSS IllCtaoolism . A.' a result. tnc bio:Iavail ability is aboul 4O'l> of the adminiStered dose. Thelhf undcrgOl!!! !>Cveral blOtransformations. including lleU!)1Ilion. oxid~live O and NOcmethylatioos. and conJu~_ of the phenolic metabolites. Of !he: various metabolites 1!119-8 ). on ly lhe primary metabolite. deac"elykhltWfa.. phamlllCOlogica lly actile. Deacetyldi Ih.uem Iw aboul-lll. 50% of the poIency of the parent oompou lld.

Nifediplne.

Nifedipinc. 1.4--dihydro--2. 6-dimetll)l....

", H 0

O-C-C>1o

Diltiazem Hydrochloride. Dilli:lI.em bydrochloride. (+kis3(accMyr5-12(dimethylllmioo)el byll-2.3-di hydro2-( 4nlClho~yphenyl) 1.5-bcnwthio/.epin-4(51 /)(lnc hydrochloridc (Cardi~cm). WU) dc\eloped and introduced in Japan a.~ II cardiovao;cuillf agenl \0 treat angina ptoris. It was oMel'\ro lodiratc peripllcrnl ancries and ancrioles. The dru g incrc:w;es myocardial oxygen supply by relieving coronary

(2nitrophenyl )--3..5-pyridinechcarboxylate dllllclh}1 d1cf (Adahll. l"rocanJia ). is a dihydropyndine dcrhlllive" berus no ~truetul1ll resemblance to the OIl1eTcakiulII nists. It IS 001 a nilrate. but its nitro group i~ ~ .. iI., antiang;nal effect. 11 As a class. the dihydropyridinct pc-. sess a 1%1IIr:t.i pyridine ring that is partially salUfJlI:d. To ... positions 2 and 6 an: substiltlted with an alkyl group !Nt . . playa role in the agcm 's durntion of 1IC1I1,lI\. Also. fOlta) and 4 are carboxylic groups that must be protc:cted "lIII .. ester functional goup. Ikpending on the type 01 nter ut these ~ite$. the agent Clln be di stributed to I'anous or the body. Fi nall y, position 4 requires an arontalic II ....... lion pOl.'.cssing an electron-withdraw; ng groop (~e.. a N02) in the Qrfho and/or mt'ta posihoo. lbc pfQHype of this clpss, nifoolpinc. has potent ~ eral vasodilator)' propcnies.. II inhibilS the \"Olllq,.e.<~,' ale. calcium channel," the vascular smoOIh muscle but hal: or 110 direct depreSqnt effect 00 the SA or AV node!.. thoug.h it inhibi lS calcium current in normal and .'".

NO,

NO,

NO,

fXXJC
CH,

H,COOC

COOH

CH,

CH,

H,cooc
CH,

COOH

CH,oH

H,cooI:

~O

CH,

cr.;,

f igure 19- 9 N,fedipll'\e metabolism

anli3c tissues. N.fedipmc i) more effCl:I11'C In

.-fw><.c, anginal cpisodc~ UI't due

IlIbed in .he .reannent of "a_ past;,. angl n:. a~ ... ell as k: IIIIgm:. pectoris. Because of ils strong va.wdilatory ",.,...nlt"', 11 is uS! in sell."Cled p:ll.cnb IU treat hypcnensiOtl.

'0 coronary vnsuspasm arid

pal~nts

, ...--'
1I,oo-C

I I
"
,p

3,jpyridinedicarboxyhc add. 4_( 2.3-dich Ioruphcny I) I.4-d Ihydro- 2.6-<li n~thy I. el hy I melhyl ester (Plcnllll ). is a 5ond-!~roerallon dihydropyri dine channel b\ockerof the niredipine Iype. It IS IllOI'e selec live for vlSClIlar smooth muscle llian for myocanllal IISSl1e and serves as an dfecuve ,lbOdilaJor. llle drug is used In the l!eatmenl of angl~ and mild tu-rnodcrale e\scnllal hy peo ension, Fclodlpinc. lil.e n'lOSl of !he dihydropyodmes. e",hi bilS a high degree of protein binding and has a Ilalflife ranging from 1010 18 hours.

~odipine.

Felod i pu~ ,

"

Nilerllr-o 011
~

""

\,f!!tl'PHIe i~ absorbed efrICiently on 01111 or buccal IKImm. A ~ub-.tanlial amou nt (9O'k) is proccm bound. Sy5.,..ilablhty ofanoral ~ of the drug 11llI)' be appro.\if 65'l- Two mOCl l\'C mcl3bol tle~ are the mlljor of nifedip"''' metabolism and are found In equil ibother (Fi g. 19-9), Only D II".II,:C of unchanged *'JJflIllC I ~ fllUI1I.lul the unoc.1 !
'/I ilh e~:h

is a $pro<~

Ilradipine. Isrildipine. 4-{ 4-benwfurol1a7yl) 1,4(lIhy dro-2.6-dimethyl3S pyridineeatboKylic acid methyl I melhy lelhyl esteT (DynaCircl. is another ~ndgcncr.lll()n dihydropyri dine type channel bl ocker, This drug. like the other sccond-gtrICratiOfl ana loguc is mort: seJecth'c fOf'vascular smooth musclc than for myocardialtis~ue. It io, effec tive in tbe treatment of stable IIl1gina. reducing the rrequellcy of anginal au.ocu and Ille need 1 usc nitroglyccon. 0

most o( the <;ccondsencra1.,.,.lJr ~mooth mu<;cle than myoclll\lialllSsue. 11 longer .ult Il-' 00u1'!o ), and less negali> e inotropy than the pro1 mfhpmc. Amlodipme is used In the u~:mllcnl of ~IJblc 311gma and in lhe manage ment of mild-Io.. .okr:IIe tsloCnllal h)JlC'rtension. II is martelcd a~ the benwlfonic acid sal t (besy lau~).

Nicardipine Hydrochloride. Nicardipine hydTO!:hloride. I ,4-dihydro-2.fHl imc th yl-4-{ 3- nl1roplle nyl r 3.j .py ri dinedicarboxylic acid n~lhyI2- lmclhy l(phenylmcthyl);lmi no)elhyl ester hydrochlonde (Cardenel. is a It'I(lrt: potent vasodilator Q( the systemic. coronar) . cerebral. and renal vasculature and Iw been used in the tmt1mem of mild. mod eratc. and evere hypertc:nslOIl. llle drug I~ also used 10 the management of stable angina.

"~,

CSlcr (lJaypn:ss). IS a 'CCOIId-geocr lion dlh)'drop)ndiIr .. channel blockcr of the nifedipme type . 11 is more selerthc (Of" \'lIli(:ular smooth muscle: Ihan fOf" myocardial tis.we aad 1'oCrves a~ an effc~cli~e ~1IS1xblolOr. The drug is used 1.l1li ttcatment of mild-to-moderate c5semilll hypertension.

I I
H,CO-c/
0

i-O-CH,CH,-H-a-t,

'i'"

(Co,dooo)

Nicaoidipi".

"'-

'" r

."

"'-

'"

I
H.co-C

o
Nimodiplne. ()-lIIlrophenyl)N"lXxhpi~. 1.4-o(iih~dro-2.6-dnne~hy l-4J,5 -pyridiJkdic:ubo~yh(" :lCid 2-nlClho;o;y-

ctllyl I-mclhylelhyl ester (Nimolop). is another dlhydropyri-

"'-,/
Nitlend.... (91, .. ' I~

dme calcium channel blocker btu differs in thai it dilates the ceTebral blood vcs..'lels mon;:o effecil"el), than do lilt 04hcr
dih)'dropyridirle den"Qli,c~. Thi ~ drug is indicall.'<l for lremmem of subarachooid hcIlMlfThaJ,'C-associuled lII:urologkal

BftPridii Hydrochloride.

!lepndil hydrochloride. ~

dcficlI\.

[ (2.mcthylpropo~y)melhyll-N- phcnyl- N-(phcnylmt'thyl~ 1 pyrrohdint.'Clhylumine hydrochloride (Vll.'.Cor). is a ~

generullon altyl .. minc-IYpe channel blocl.er. ~truclUrally relmed 10 the dihydropyridllles, Its aclions lire k" ..... than those of lhc three proIotypical channel blocul'S, ~n'I' pamil. dillia7:em. and nifedipll1e. In addl1lon 1 being. C,' 0 channe l blocler. II inhiblt~ s()(hum flow into the heart "'" and Ic:ngthcllS card iac repolan/~lion. causinll bnd~ Caution should be used if il is lIi\en 10 II palient .... ith h)JI(U lemia. !lcpridil hydrochloride is used for sUlble DoglI\a. l'Iw:
dlllg has a half-life o f)3 hours aoo is highly bound 10'","0
(99%).

Nilo/dip/ne. In vilro ~Iudic~ ,how lhal lhe effccts of nisoldipine. 1.4-dihydro-l. (}.(Iimethyl4(2-nilrophenyl)lI(."id methyl 2-me.h} Ipmpyl C5ler (Sular). on ("ommeli]e processes arc .<;elcclive. wilh grc:llcr potrncy 011 vascular smooth muscle than on cardiac muscle. NisoldipUlC is highly I1lClaboliled. with five major mclabolites identified. A~ with nMJst of lhe d ihydropyridines. too cytochrome P-4SO (CY P) 3A4 i~~lroe;5 mainly responsible for lhe ITlClabol i~R1 of ni\Oldipine. The map biotransformation palhway appears to in\'ol~e the hydroxylation of the isobutyl ester side: chain. This particular metaboille has approlimalely 10% of the activity of the parent compound.
J,5. pyridirk.'e'.Irbo~ylic

AftUtill. DlhbotlC Agents

"",,-0

C-O-CHo-CH

/'''
\
'"

Platelet II(ti\'atiOIi and pIDte1eta~regatlon play an Importa role ill lhe palhogcnesl~ of lhromiY>se". Thc!;c. in l11l1I. an imponum rn1e III uo.\Ioble: anllm3. myocardi:il inf";~ Slrnk~. and peripherJI \'asculllf tllrornbo~. Since man)' Col d'OI'DSCUilu di<;cases an: associaled .... 1111 pialeln IC1J lIIany agenls pos.'l.:SS'lig unllploldct or antithrombotx have been in\e.... lig3tOO, Thb ha!i l'C\'OlutiOlliled c;udi(J, .... lar mediol:inc. 111 ..... hich vascular Stenllng or anpJpIlSty be used ..... UhOul mmpromisi nll Ilormal hc:nlOl,tasisor hc:l.ling. Ahhough most of lhese allents acl by nM:Chanlsms. many of.he newer allents arc'~~~:i;:~'''. 10 rultail,onilt: the GrU b/lib receptors or p I 1
Aspirin. IICetylsalicylic lIC id. rnu an I effect 00 platelet aggregation IIQ\ only bccau.e of ib 10 IIlhlbil CydOOllYg<'fIa.e oot Qlso because: of Its aIIdIty IICclylalc tile enzyrne . Aspirin IrTC\'m;lbly inhlbltHY'

Aspirin.

Ni rrMdipine. Nitrell(lIpine. 1.4-dihyd:ro-2.6-dimcl h~l4-(3-nilrophenyl}).j-pyridIlKCal'bolylic acid methyl C(hyl

!lcnaS(: (COX) (prostuglruldi n H ~ynthasc). zyme invol\'ed in COIIle",ng arach,donate

".,'.k.'.".......

Gl and ulummely Ihrornboxanr 2. an inducer of platelet ago !rtgalion. A~plnn's mechanism of action includes nOl only me mhibition 11\ the blosymhesi~ of IhromboltallC 2. bUI ulso Is ibilit), to acetylate the smne residllC (529) in the poJype'PbCIe chain 0( platelet prostaglandin U synthetase I. This upWDS ...lty OIher oonsterotdal anti -i nfiammalOl')' agenu that 1ft; capable of inhibiting tht: COX enzyme do IK)t act 11$ IDllthrombot'cS- they aren't capallic of acelylating tllis enI)'me, Since pl otelets CllnOOl synthcsil-1.' new enzymes. aspi nn's ability 10 acelylate COX IIL~ts for the life of the platelet to 10 days) and is. thus, irreversible,

possessing this system ha\e been eVDluated as poIcnual anti thrombotic agents. These agents have 3 unique IIII:ehanism. in that they inhibit the purincrgic receptor localed on platelets. Normal ly, noclcotides act ll-~ agonisES on these receptors. which Include lhe PlY Iype' , T ....o PlY n:cc:ptor subtypes ( PlY I and P2Y2) found on platelets. v.hen stimulated by ADP. cause platelet aggregahon. Clopidrogel acts as lin an tagonist \0 the PlY2 rettplor. It is probably a prodrug that requires nlCtubolic activation, since m ~itro siudies do nOl interfere with platelet aggregation , Although platelet aggregation is nO! normally secn m lhe first 8 to I I days after oonlinislrdtion \0 a patient. the effeCI lasts for se\'em days after thl: drug therapy is discontinued. Unlile OIher thieoopyridll'lCS currently used , elopldrogel does 001 senously reduce the number of ... hlte ct:1!~ in the blood. and therefore:. toullne monitoring of the wllite blood cell coun l is 110 1 necessary during treaunenl.

Dipyridamole, 2.2'.2",2"'-[ (4.S-di- l I"peridiny lp yr imidoI5.4-dlpyrimidine2.6-d iyl)di ni lriloJtelW:iSl'thanol Wcrwntine). may be used for coronary . . myoeanhal Insufficiency. Its biggest usc today, howt\"U. is ali an anmhrombotic in pallems with pnlIithetic hean .1II.-a, It is. biller. yellow. crystalline po...-der. soluble in oIiIu~ acids. methanol , or chloroform. A formulalion coowning dipyridamole: and a<;.pirin (Aggrenolt) i~ curre ntl y being lII11rletoo as all antithromubOlic, DipyridanMlle Is a long-acti ng ~asodilalor. Its ~llSOdilatlng kIIOn is ~Iect"e for lhe corooary system: it is indicated Iong-Ierm therapy of chronic angma pectoris, The drug ~ mhibns adc:nosille dealill tIaSC III erythrocytes and mterkrts VI Ith the uptake of the \'asodllalOf adenosine by erythro(}1eS. l1ie'iC actiom poiemime the effrtt of prostaeyclin t!'GIll. which actS IL~ all illhibitor to platelet aggregation,

DipyridiJ~.

TicJopldlne. Ticlopidine. 5-[(2-chl oruphe nyl)methyl J4,5,6.7-tetmhydrothieno 1),2-elpyridllle hydrochloride: (Ticlid), i~ useful in redocma cardiac eve nts in palients wnh un~:tble angina and cen:brov.s.cular evenlli m ICCOIldary pn:\'cotion of stroll:. It tx-Iongs to the thienopyndlllC class and facil itated the de~eJopmc:nt of c1opidrogel. One of the drnwbacks to this agcnl is its side effcct profile. which indud.cs neutropenia. ~nd patiems n:cciving this alllitllrombotic should have their blood levels monitored , Jl~ nlhlll1ism of OChon is similar 10 Ihat of clopidroge1. in that il mhibits the punllCfJlic rcu:ptOB on platelets.

GPIiBliIiA RECEPTORS
(Pr'nt".. wiIh ASA Aggfeoolc) Clopidrogel, nlClh)'1 ( +)-( S) u-(Z<hloqtc:1I)' I)-6. 7-d Ih ydrot hie 0013.2 < I pyridi nc-5(411 )-ace lilt e IUlfIlC (Plavix). i ~ u<;cf ul for the pnevent alive management of IIIt!IIII.bry iSl:hemic events. inc luding myocardial infarction. ,and ~ascular deaths. It may Ix classirlCd as II thieoobecause of its heterocyelic 5ystem. Several I.gents

""""'"""

CkJpidrogel.

"ridine

Located on platelets is a si te that s,en'"s 10 rerogniu und bind fibrillOi.~n. This site is a dimenc glyeoprotem that allo ....s fibcinog.-n 10 bind. leading to the final step of plalelet aggre gation. T1le n:cc:ptor must be actlV.ted before II ....ilI alisocia.e ...-ith fibrinogen, and thiS may be accomplished by thrombin. coll ngell. or thromooxane Al' Onu: the reu:pt or i$ aclivated. fibri llogen most likely binds 10 the platelet through the arginine-glycineaspartic add (RGD) sequellCCS at residues 9596-97 and 572-573-574 of the If chain of fibnnogen. This particular fealure: has been IISed in !he design of IlOIIpeptide

antagonists lhal mimic the RGI) srS/em in which a distance of 15 to 17A (16 10 18 aloms) separules the amllle gmup of

arginine aMittle carbonyl oxygen of aspartk add. Eptifibalide. Epufibaudc (Inlegrilin) is a synthetic cycl ic heptapeplldc thai acts as a GPIl bilIla ~eptOl' antagonisI. thu s callS; ng inhibirjoo of platelet aggrea:alioll. h~ Slructure is based on the natural product barbourin. a peptide Isolated from the venom of a pygmy Tllulcsnale (Sis/nmu milarud barbourij. As pan of !he SlruCtun:, there IS a sequence arg,"ulC-glyeine-aspamc acid (RGD) thai can bind \0 the RGO receptor found on pI:lle1e1S and block ilS abi lit)' 10 bind wilh librmollcn. TIus agent is used in the IreU!mem of

Abch.nnab ( Reol'm) is a chmJeric Fa fngmcnt monoc1ornal anlilxidy Ihllt can bIRd to !he GPlIt' IJ Ib I"C("cplOl" of platclcls and block the ability of fillrirqat to associate wilh the platelcl. This results in less pi Itt aggregation. Abciximab is useful in treatmg unstable IItpl and as an adjullCt to pen:utullCOUS coronary intrnentIDI (PCI). 1lle hul f1 ire of ubciximab is nbout 30 minuta. "ttbIk its effects wben bound 10 too GPlJaIl lJb may 1a5lllpwll hours. A signifICant dnll'.bHCk to using abcixinab Iics OOSI. v.hich is approximately $ 1.500 for I si ngle dose.

Abcix/mab.

unstable angi na and for angioplaSlic coronary intcrvcmiollS.

Tirofiban. Tirofiban is a IlQnpeptide Ihal Dppean unrelated chemically to eplilibalJde. bul actually has many ~mi larilies. The chemical archi lture incorpouuC$ a sysu~m!hal.
is minucitanll the argminc-glycinc-aspanic ac id (RGD) moiety thai is present in cplilibat ide. This can be ~n in the distllnce between the nitrogcn of the piperidine ring, which mimic$ the basic nitrogen of argi nine in tile RGD sequence. IUId the carbo~ylk add, which mimics the add of aspartate in the RGD \Cqucn . The basic nitmgen IUId the carboxylic acid of ull)fiban are separnted by approximately I S to 17A (1610 18 atoms). This is the optimum distance _n in the' RGD sequence of the pl atelet n:<;:cplOl". Tirofiban is usefu l in treating non - Q wave n1yocurthal infarction and unstable ungma.

ANTIARRHYTHMIC DRUGS
Cardiac arrhythmias are caused by II dl\lui"b3n In tm~ dUChon of the Impulse through the myucardW ~." d,soruer.i of impulse formation. 01" by II rombmDtlOll III factOCll. The anTiarrhythmic agents usc:d JOO8t commoa/ya. fect impu lse eonducllon by altering conduction vdooty. the durotion of tbe rdmctory period of hcal1 muscle till& TIley also depress spontal"loCOUS diastolic dc:poIarilita. eDu~ing I reduction of automatidty by ectopic foci. Many phannacologieallgen\.'i an: a~allable Ify_ ment of cardix: arrhythmia,. Agents suc h as oxygen. pOCII sium. and !KXlium hicarbol\ate relieve lhe underlytol of some arrfIythm;a~. OIber agents. such lIS diS1Uli$.. '"" prlloolol, phenyleph rine. cdrophonium, and ncostlgrruroe.1Il

ror

-""""'"

 the

syStem by affe<;;tmg hean muscle or _the IUIOfM)lIllC nerves 10 !he hea n. !'inally. there an: drugs Ib:.t alter the cle<;;trophyslological nw:chlln isms causing arrbythmlas. The lauer group of drugs i~ discu~ In thl~

canho~ascu lar

....

\hthm the past Ihe ~ades. research on normal ctudiac iI'I>Ue!l and. III !he chnical setlJng. on parients with dlstur1iIncc~ of rhyt hm and conductioo has broughl lo light ,ofor-.lion (III the gene~is of cardiac arrh)thmias and !he modc III' ICIIOII of antHirrhythmk agents. 10 addi t,oll, luborutory k$IS havc be:cn dc,eloped \0 mea,ure blood Ic\cls ofaoharm,thmil: drugs wch ~ phenytoin. dlsopyramide. lidocaine. J'IOClIioamidc-. llnd qu inhltne. to help evaluate the phannaco~ of these agents. A.~ a resu ll . it i~ po$Slbk' to maintain -'yM3te pllISllUI le\el\ of lhese dlllgs. "llIch allow~ the dtokian to use!hese and other agent' more dfc:ct.i\"cly and .1lb grtaler safety. No ocher climcaJ inteoention Iub been IIOrt effectl vc 31 reducing monul il y nnd morbidil y in corowy ellTC UlUts.

0 .2

0.'

0.6

.K
Figure 19- 10 Norm.JI electrOCd'ogram. (from GallOf'l9. W F R _ of MedICoill PhysIology, 9th !!d. San franosco, Lange MedICal f'ubhCiltlOr1~. 1985.)

c.dlac Elecboplttyslology
Ibr Ik-an depcnd~ on the synchronous inlcgr.uion of deem;:aJ Impulse tran~ml ...~ioo and myocardialti~1lC response to .~. out liS (uncHon as a pump. When the impu lse is refrom tile SA oodc. e~ciUllioll of the hean tissuc takes in an orderly manner by I spread of the IInpul-.e the speciuh1.cd automalic fiberli in the atria. the and the Purl.injc fiber net"ork in the wntric1es, sprt'adtng of impulse, produce~ :l ch:ml<:tenst ic electro!:anhogl'llphic pall em thaI ~an be equated 10 pn:d ictable myoi:IIdiaI c.:1/ I1lCmbr~nc potcnt;:lls IIJld Na - and K ~ fluxes MIll oot of tile cell. A .\inglc fiber in lhe lentriclc of lli\ mUlCt heart during lk~oIlc phase (~ phase 4. h g. 19-4) has a memlmuw: ""tial (resting potentinl) of 90 mY. This potential i~ creby differenual concentr.uioo~ of K ' nnd Na ' in the lIular and utr,J('ClIular fluid. An actl 'e tr.mspon syson the nICmbrane is responsible for conccntratI is (lI,uloCd by I decreased K ioniC cum:nt Into the lIub.r ti o;suc lind a ~low inward leakage of Na' until ill lhreshold potential (60 to 55 mY) is rc:achl.-d. At Ihi" inward ~ium cum:nt ~l""kn ly incn:a.'ib. Ind a II lhe membrane dethis property. I II I rate of dc:poIari (MRD) is phase 0 or the spi kc action (Ft&. The form. dur:tllon. re\lI ng potenti al lel'el. nnd amplitude iflt action pocential are characteristic for dlfrcn:nt types ~ocardi.:ll ccl1~. 'f'he rate of nse of the response (phase. 11 Ttlaled to the level (If the Illc mbralle potential al the ahtimulallOll and has been termed mt'mbmnc rcspon::",'JI, lC'."~ I"ICg:lh\C po:llcnlia ls produce smaller slopes of oand an: charocteri/.ed by slower condl.lCtioo lilll(':');. SA node t:OITe."ponds to the iru.cripwave on the electrocard iogram (Fig. 19 10). is dhided Into three phases. The greatest '. '" represented by phase 3. in which of K ' ioo." OUt of the cell. PI\ase I
repohuizauon IS c~uloCd by an Innux of CI IonS. Dunn, phase 2. :l ,mall in",ard IIIO\Cll1enl of Call ions QCeul"'i through a slow channel mochanism thai is believed to be impol"tant In the procClo" of couplt Itg c.\citatioo wilh contraclion . The procc.~~ of rcpolnril:ltion dctermirICS the dur~lIoo of the action potenual and is represented b) !he QT ,nteo-al. The actiOIl potcnua l durullOll is directly rel~tcd to the rerrac_ tory period of cardiac muscle.

MM:hanlsms of Arrhythmias
'f'he cum:nt ulldl:r>tandmg of the eltxtrophY'lologlcal mech anhms re~ponsi bk' for !he origin and perpetuation of cardiac arrhylhmias is thatlhe}' arc: due to altered impu lse fOOltalioo (i.e .. change in aUlomaticity). allered cood uetion. or both. acting simuh:meoosl) from different 10000allOO\ of !he heart 1lIc b'CncrotiOIl of c~rdi11C impulses in tIK- normal hean is u<;ually l'Of\fined to "llI:daliled tissues that SpOIltal"lCously depolari/.l! and Inlliatc the action potential. These cells an: locmed in lllC righl al riu lil and ~re referred to!l.~ the SA. /lfNit' or tllC fXlCt'"tW;cr ulls. Although !he ~pon tancous declrical depolllnlatlon of lhe SA pacemaker ccll~ i~ Indc:pcndc:nt of the nervous system.!he!>e cell~ are innervated by both <;)mpathetic :mtI pal"oISympathetic fibers. "hich m.:Iy C'.ouse lin increase or decrease of the heart r~tc, respecli vely . Other spccl~1 cells in the normal hcan that possess the propc:ny of automatic,ty In:l)' ,nnUC-1ICe card iac rh)thm when lhe nonnal pacemaker is ~uppfessed or wilen pathological ~hange, occur In the myocardium 10 nude lhese CC1l5 the donllnant SOIm:e of cuniillC rhythm (i.e . e<;;topie pacemakers). AU lomalldty of sub~l(/iary pacem~ers rna)' develop .... Iten myocarthaJ cell damage OCCUrIi because of infarction or from digilali s to.\;city. Clces.<;ivc vagal tone:. cxccs.\ive cate<;;holamine relea..~ fn)m sympathomimetic nenc fibcl"'i 10 the Ilean, or e~en hIgh cmochol amme levcl.~ 10 plasma. 1"llc de "eloprnent of automaticity in specialized cell ,. "lICh ...<; that found ill special atna! cells. cenam AV node cells. bundle of li i~. and Purl mje fibers. may lead til cardillC arrh) thmia<;. Because prodl.lCtlon of e<;;topic Impulses IS often due 10

f igure 19- 11 Reentry mecl'lal'llSl'T1 of PUrKln)e fibers. a. Notmal cooducllon of Impul~ through tnangular f(lngemenl 01 CalliK libel's. b. Umdlre<:tlOl'lal bIoc:k on left arm 01 triangular

category are placed lhere: because: chnical 3CtKJni. 'That patients do IlOl th iS da."S. howe.er. should 001 OUt 11 m the SlIme CIIl5S. I agents. IllO!it drugs have I gnvate: the rhylhmia ",,,,~ ectopIC be"L~ a dysfunction in the left or ~u~Iuined IlIChycardia. C lass I antiarrhythmic ugelll~ (see below) especiul1y proorrhyth mic in myocardial infarctioo p;ltteM

secuon allows ,mpuM to reenter the reglOl'lal

tem and fecyO!

Condl,lCllng ~ys

CLASS .. MEMBRANE-DEPRESSANT ORUGS

Class I amiarrhythmic agmts llredrup that ha>e mL'n stablli1.ing properties (i.e., they shift memoonn negatl'e potential ~). Drugs 10 th l~ class act f~ channel~ and interfere with the ,;:.;.;:,; , i/.lOg charge i~ transferred ocross the mcmbrane. II ~ul11cd that these drugs bind 10 the Na' channel ~t~ function. preventing Na ' conductance as 1000g as 1~ bound. The protOlypiclIl drugs in thi~ class are nnd procllil1Dmide. During the 19705. '\Cveral drug\ stUtliL-d for their antiarrhythmic effects. Most local ane5thet ic~ Ihat affected NlI' membrane channtll. they wcre grouped in a single cia.o;,<; (dass I). antiarrhythmic propenies of lhese chelmcab IuIC that lhere an: sufficient diff~lIC\'.~ to place them intO rale subgroups.ll CllI~s I antiarrhythmic drugs can be subtll~1<kd bao;.is of the relatl\e ease wnh whieh they lhe Na' ion channel. Drug~ in clan IC, ~och l.\ Iorcamide and moriciline. are I nel - block ing ugentJ; of the class I They slowly dis.o:;ociate fron1 the Na' channel. slowing of the conduction time of the impulse 1 hear" Cl ass IB drugs, .... hich indude lidOC3l1lt. I and D1c~ilelinc. di~soeiate rupidly from thl: Na' antlthus have lhe lo .... est potenc)' all sod.um ers. They produce hule. if any. change m action durution. Qumidine, procain:ulllde. antl drop lhat ha>e an intermediate rale Na channl'li. nllc agents. and they tiswe to cause L'eSS3UOn Studies have shown that Na ' I of Purl.inje fiber cells normally uist in at least tlute' It rc)I00. closed near the resting potential but able opened by stimulmion and dcpolarbalion: A. lowing Na ' ion~ 10 pass selectil'ely the

defed in the spooUlllOOWl phase 4 diastolic depolarizatKln r oT wDve"). drup thai can suppt"e'is Ihl~ portion of the cardiac stimulation cycle are dfedh'c agents fOf these tyJlC!i of armYlhmia. An1lythmias are also C/lUSOO by di~ in the conductIOn of impu lse5 and changc~ in the refrolCl<>ry period of lhe myocardial tissue. Phann;M.;ologicai intervention is based on Ihc"C 1"'0 properties. The Purkinje fibers branch into a network of inh,'rlacing fibers. panicularly at thcif most distant positions. This creates sevcraJ p.1Ihway~ in whkh a unidirec l10nal block in a localized all'a may establish circular (circus) microcellular or macroc:cllular impulse mO,"cmenlS thai reenter the myocan1ialli~rs and .;Teate an lIfI'hylhmia (Fig. 19-11). Unidu'eClional block resulls from localized m)'(lClltdial disease (illfarc,,} or fro", a change in depcTldeocc of the tissue 10 Na ntu:es thai c;l.uses I loogeT condUC1ion time and alloW:!! the lis.~ue to repolarize to p-opagate: the retrograde impulse.

Classes of Antl.rrflythmlc Drugs

Amiarrhytilmic drugs CUll be plllC(d inlO four scpar"J!e c lasses. based on their mechanism of IlCilon or pallcm of declrophysiological cffects produced on hean lissue. Table I~ summarizes the four-pan classification of antiarrhythmic drugs as first proposed by Vaughan Williams in 1970 1~ and expanded in 1984.:10 Note thai drugs wilhin the <;ame

TA8LE 19-4

ClasH. of Antiarrhythm ic Drugs

IA
III

OUlnidl ....

~n.m>de.

di,;opyramitle I ..!or...... pb'nytQOn. 100000n>de..... ~IIcu ... Erainide..l\tcarn..k. poplf<-

SIu1< ... d~noIi""..r .........

..M.... ,~
SIoJ,o,~

,...,.,nidt. murie"J....
jl-Ad u .. ""'lim 1~I, ,,op"" 1

"

,,1t

'" "'"""

A - . brrI~I.1Ma.

C'*iIn LI Id bIotl<n le..f.. """"""",,I. "'~"""n' I

Olocb ...... , , "'..-.dCa,

....

tmd affini ty o f the Thc: I. t the ion channel the membrone potential. Because: of this. R. A. channels can have different kinetics an1I)lhnuc drugs. A re~ie .... of the I'eC('nt Ih:u the antiarrhythnuc drugs ha.e A nels but relatively high affinity for both. Regardless of which ehannel Slate: I I antiantl)thmlc drugs. the unblock'"g rate mines the amounl of dep'I~...ion presenl al normal

inllCtivatL-d~~"~"~:,':M~:b;;I'~i~l~,~~ d

ClASS II. .8-AORENERGIC IIlOCJ(ING AGENTS

fAdrrncrgic block-ms drull cause membr.me-smbili/ing or ~~nt Crr1~ on m)ocardial tis~ue. 1beu antiarrflythIIIic properties. 110.. C\ cr, are considCtl:d 10 be pnncipaU)' the ~It ofinhlblllon of IIdrenc:rgie ~lImu l ution to the heart. TIle I'fil!l;ipal clectroph)'siologkal property of thc$e ,8-blocking .,nts IS ~lIClIon of the pha\oC: 4 slope of potential sinu s .CClOpIC p;act:maLcr cells such thallhe heart nllC dccrea'iCS aJ ectopic toch),cardias arc either \ Iowl-d or CUIl"eried to IlllUS rtt)'lhm.

Cl.&.SS III. REPOLARIZATION PROlONGATORS

Dlup in thIS class (e.g . aml00aronc. bretylium. SOUllol. 1001ftk. dofCtillde) CllU!>C .\oCveml dl ffcrent electrophysio logical dtlngn on myocardial tissue oot share one common effect, prolongUlg the action potent ial. which increa.0;e5 the effective .f,XlOiy period of !he mcmbr.lIIe .::tion poIcntial without lllaing the phase of depolari1.a1ion or the: re;;(ing membrane poIntlJal. Drugs In thiS clMS produce their effects by more one mcchanism. Setalol is a K ~ chanocl blocker and blocking propenie1>. 2. Amiodarone that abo proIOIlg !he action poI<'1ltial that are unclear. alo;o h"ve Na channel - blocking

partitIOn 111 the membrane as readll)'. on_et of ~ drugs' s action wouk! be dela)cd . Furthcrmort', l-onccntration of Ibcsc drugs in lhe membrane would be ~uced. Therefore. drup lhalllCl on !he channel only in the lnactivllkd (closed) state wouk! have a reduced effect in ocidotlc condItions. ACidosis ma)' also proIon, the effect of these drugs. Euemal llCidosis fltCihtale1> protonatiOIl of receptor-bound drugs. Because only neutral drugs can dissocia.e from clo6cd channd~. recovery IS prolonged by llCido&i$. AlkalOSis tends to hypcIpOlllril-C: !he cell mc:mbnllle and. thereby , reduces the effect of anl;arrh~thmic drugs. Bause ofthis..alLalosis I"OllKltCS the formation of more ofthc freeb.1se antiarrhythmic agcnl. illCrcasing the rate of recovery from the block. AlkalOSIs-inducing salts such as >Odium lactute have been osed to coonleract toxicity caosed b)' the antlarrfl)'thnuc quimdine.

CLASS I ANTIARRHYTHMICS
Quinidine Sulfare, USP. Qulnldinc: MJlfute is lhe sulfate of an alkaloi d obtained from various species of CincilONJ and their hybrids. II is II dcXlt'OrUtalOry dia;.tcrt'Olsomer of quinine. The suit crystalhl.es from Wilier as the dihydrate. in the form of tinc:. needle-like. while crystals. Qtllmdll1e $u l. fale cont;l;ns 0 hydroxymcthyl group thai saves lIS II link bc:1 .....ttn 11. qUlllOlinc ring and a qoinuclidlllc molc.y. TIle structure! contains two basic nitro&cns.. of which the: qUIAuchdine llI\rogen is the stronger base (p K. 10). Quinidine sulfulc is bittcr and light sensilhe. Aqueous solulions an: nearly l1Cutral or shghtly alkaline. It i~ soluble to the e~tclll of 1'1> in water and more highl ), soluble in .lcohol orchloror~.

. ." "'-'Al'OUM CHANNEL BLOCII:ERS

not: all C. 2 channel blockCf\ ~s IlI1l1arTb)th -

,
ions dunn!! 1ft cardiac cells. . ~eropamil.

of Ihis d35S of antiarrhythmic blocL the slow inward current

,!,'. ~:,,'''b~'. actiondru g m poIenprototypical

blod.s entry of Cal ~ into the slo,,-re<;ponse tiber- foond node wid the AV oodc. slow ing conducllon vel)' and 'I1Crea.~lI1g refraclOrinc;.\ 111 the AV node.

r-'"

ICllon of elas) I local i, pH dcpc:lKic:nt and may

mic drug~ are wcak bases.

from 7.5 to 9.5. At
I I I 11
I

base lind the cationic form. loni/.able drugs. s.uch

~

P,:;,:;!:~,::;:: ;~~::!;'~m)'ocardial cells. clectrophys iologicul

nll ~

", , ,

"""""" (0000ra1

(Ca~

has been attributed in pan to the increase in COIlCtiltruliOll wi .hm the iJ.Chellllc areas of !he heart. ion ehmtnc:ls ocellof the anllarrhythmic ~genl. the effcct of pIlon the antiarrhythmic acti~it)' the free base 1I!1d c~ lionic acti,e form ofsomc drugs. form of the Na' channcl blocler call pene1 the: lipid phase of the sutn')l.l,1IlI1I\~ cell bloc~ the ch:II",d. SmU chanSCS 111 pU can alter thoc drugs eff11\ellCS8 the charged tO-lIl1chargedlllok'Cuhu ratio in Ihe cells. AcidcKis exlernal to .he myocard,al cell cationic foml . Bccllu>c this specie~ docs nut II

Quinidine sulfate IS the prototype of antHuTfl)1hmic drug~ and a clll.~s IA untiarrhythmic agent acconling to lhe Vaughan Wilhams claMlticallOll. It rcduce.~ No' cum:n1 b)' hindlOg the open ion channels (i.e .. State A). The decreased No ~ cotry into !he myocardial cell depresses pIuIsc 4 diu.~to1ic depolari1.a1ion and shifts the intl1lCellular threstlold po;>tenllal toward l.Cro. Tbcsc combll1ed actIOnS dimll1isb the spontaneous frcquel1C)' of pacemaker ti!+.Sueli. deprt:.'IS the aulomanot)' of ectopic foci. and, to a Icsser e~tCllt, rc'ducc impulse formation in the SA node. This last action result~ in bnJdyeardia. Dunng the: splkc action poIenllal. quillldinc su lfate dccrcasc~ tl'lllSlIIcmbr1lroe permeabilit)' to pass"e innux ofNu' thus slowlOg the process of phase 0 depolurization . ..... hieh decreases conduct,on ,doci t),. This is ~wn."

....

a prolongation of tlte Q RS comple,; of ela:trocardiogrnms. Quinidine sulfate also prolongs aClion potential dUTlItion. which results in a proponionme iocrcase in tnc QT interval. [t is u.'\Cd to !rCat supTlIventricular and vemricular ectopic arrhythmius, such as atrial and ventricu lar premature beats. atrial and Icntricular tachycardia. atnal OUllcr. and atrial fibrillation. Quinidine sulfate is used m~t frequently as an oml preparatinn and i~ occasionally gilcn intramuscubrly. Quinidine ~ulfale thm has been :tbsorbcd from too gastrointl'Sl inul tnlCt or from the ~ite of intrnmuscular injection is bound SO% 10 serum nlll\lmin.'1 1lte drug is taken up quickly from Ihe bloo..lslream by body tissucs; consequently, a substantial colICCntrntion gradient is established within a few minutes. Onset of action begin s within 30 minutes. with tlte peak effeel al1~ined in I to 3 hours. QlJlnidine is n~taboli7.ed primarily in tnc liver by ~drmy lation. and a .mall amount is e,;creted by tlte liver. Because of St'rioll~ ~ide effect~ Dnd the advent of moTl' effttlivc oml antiarrhythmic agents. quinidine i~ now used less. excepl in selccted p:uient~ for long-term 01111 antiarrhythmic thcmpy.

more stuble in waler than is PTocainc. Aqueous solutlOIlI' procainumide hydrochloride have a pH of about 5.5, A ti netic study of cl1l: acid-catalp.cd hydrolysis of procalnamd hydrochloride sholO.ed ;lto be unu sually slable 10 h)droI)'_ on the pH range 2 10 7. even at elevated tempcraturtS. lt

C-~-CHo -CHo~N,

II

".C!1P'o

-,

Pro<;aII\IImio:!e
(P~l

(p.ocan SRI

Quinidine Giuconate, U5P. Quinidinium gluconmc (Durnquin. Qu inag[ute) occurs as an odorles$. very biller. ",hite powder. In conlrast with the ,ulfatc sail. il is freely iOOluble in waler. This is impornml becau"e tll.!re are cmergencies when the condi tion of lhe pallen! and the need for a rapid re~ponse make the Ofa.l roote o f adminiqr,uion imlp propriate. TIle high watcr !;Illubility of lite gluconale salt I' long with a low irritant poIcntiul makes if valuable when an injectable form is needed in these emergencies. Quinidine gluconate fom1s a Slable Ilqueous wlution. When used for injection. il usually contai.ls 80 mglrnL. equivalenl 10 SO 111g of 'lu inidine or 60 mg of quinidine sulfmc. Quinidine Polyga lacturonate. Quinidinc pol ~galae luronule (Cardioquin) is formed by reaellng quinidine and polygalocluronie acid in a hydroa1coholic medium. It contain) Ihe equivalent of appmximately 60% quinidine. This salt is only slightly ioni7.cd lind slightly <;oluble in water. but siudies ha\e shown Ihal although equivalent doses of quinidine sulfate give higher peak hhxid levels earlier. a more uni form 1100 suslaincd hlood level i~ achie\ed with the polygahu:turonate \"It. In many patients. lhe local irritant aclion of quinidine sulfate in tlte gllStrointe~tinal tr.ICt c~use' pam. nau,;;:a. vomiling. and espo.-cially diarrll.!a. often precluding oral use in ndequ~te dose.,. Studies with til.! polygalacluronate sail yielded 00 evidcnt'C of ga~!roi ntestinal dislI"tss. II is aVIllIable as 275-l11g tablets. Each lablel is the equiva lent of 200 .ng of qui nidine sulfate or 166 mg of free alkaloid. Procainamide Hydrochloride, U5P. l'roI:ainamidc hydroch Ioride. II-ami nOoN-[2-( d ieth y lam i no Joclh y IIbe n7.arn ide monoltydrochloride. procainarnidiurn chloride (Prooeslyl. Procun S R). has emerged as II mlljor ant iarrhythmic drug. It was developed in Ill.! course of research for compounds slrlIClurully similar 10 procaine. which hud limited effect as IIlI antiarrhythmic agent because of its e<:ntml oervous sys tcm (CNS) side effects and shon-lived action due to rnpid hydrolys is of its e~ter linkage by plasma eSlera!ol.'S. Because of its amide structure. pmcainarnide hydrochloride is also

Procainarnidc hydrochloode is nlClabolized throo,b .. action of Nacctyltransferuse. The prodllCt of enqmalic labolism of proeainamide hydrochloride is N-accl)I'';;'; namide (NA PA). ",hich P.'s!;CsSt's only 25% of the IC!i of the parent compound:" A study of the di~position 01 cainamide hydrochloride showed Ihat 50% of ti1c drug e,;ercted unch;onged in the urine. wilh 7 to 24% fC(.'OveRd. NA p A .27.~1 Unlike quinidine. procainanllde hydrochloode bound only minimally 10 plasma pfO!cins. Bcl\O,ctn 7~ 95% of lhe drug is absorbed from the gaslroimt'l;tiiW Pla~ma levcl s appear 20 to J{) minutes after adminiSi and peak in about I hour.N Procainamidc hydrochloride I ,i1 III

i. ii the mide hydrochloride for \elllricu[ar t3ChYC3";"',";i;a;,:, ",~;~ dine for atrial arrhythmias. even thou~h II effective in dtller t)IX: of diwrtlcr.
Disopyramide pitate. cetamide

clllSS and)o i in its Ihat decreascs phase i conduction ~cJocily. and hlL~ trieular tachyarrhythrnias . Oml i t produces peal.: plasmu levels within 2 hours. bound nppro~imately 50% 10 plasma protein and 1if~ of 6.7 hours in humans. More than 50% i unchanged in lite: urine. ThcrefOlll. ' !

'A~:~'~;:;~ ',',mi, li

"

feelS of dry rn . urinary . of ils cholinergic block ing larily to anticholinergic drugs.
o~

'I

,....--N!io
I ,-

;!

...... =.., ""

AI

ChHpltr 111 CaniiovtJJClI/ar "lft~U

63 9

Udoc.. ine Hydrochloride, USP. Lidocaine hydrochloride. 2-( dleth) 1l/llu1()}- 2' ,6'-acetOl ylidide monohydroch lor Ide (XyJocainc). was cooce;vw as a derivative of gramine (3-dlmethylamlOomcthylmdole) and introduced as a local IlleSlhetic. It is now ~ing used inlra"cll(lUsly lIS. 61andard
"'tlll~J agent for suppression of arrhythmias aSS/X'laled lrth IlCUIC myocardial infarction and cardiac surgery. 11 is

at drug of chotce for tM parentcl1Il treatment of ~malun:

OfIItncular conU'aCl.ons.

o
~-C-CH.-N

II

/""""

'-""",

lidocaine

~-

'"

jections. Udocwne h)'dl'Ql:hloride is noI bound 10 any elten( 10 plasma proteIns and is f,:ollCcntmtcd in the tissues. II is meiabolized rapidly by lhe Ih'e!' (Fig. 19- 12). The first Step is tkclhylOlion with the formallon of lIlOIIOI:\hylglyclneJlylidide. follo'4'ed by h)'droI)'~is of lhe wmde.Jl Mel aboll~m IS rnpid . lhe half-life of a single injeclion ranging from l~ 10 JO minutes. Lidoclilne hydrochlonde IS a popular drug becau,o;e of ils rapid IIClion and ilS rdati\'e freedut1l fronl lodc effec1~ on the hean, especially in lhe absence of hepatic disease . Moooethylglycinexyliditk. the inillal met.:lbolite of Itdocallle, IS an effec1lve antillrrfl)'thmlc ngent : its T'IIpid hydrolysis by microsomal amidases. oo. . . e.'er. pre"enl~ lIS use in humans. Pm:aulion~ mUSI be taken so thatltdocaine hydl'Ql:h londe solutions con.aming epil1f,:phrine salt~ are not u'\Cd as cardiac depressan". Such 5OIutions arc intended only for kx:al alleSthe.~in nnd nre rKlI used imr.lvenou.sly. The aqueous solutions .... ,thou. epinephrine may be autoc:la\'ed ,o;e\eralti~. if nee
C~<3ry .

class IB :mtiarrhythm.c agent ;." ~" -,,"'- ckclrophysiological propcnies If lIIyOC2l'llial cells (rom that of procainamide and quinidine. kblnds wllh equal affinity 10 the active (A) and inactive (I) ion channell. II depres.... diastolic dcpolari1..'llion and __ Ilkit)' in the I'urkirlje fiber network and increa.<ie$ the fu;b(JU.Il rt'fractOf)' period Il'lalh'c 10 action poIcnllal dura_ as do procainamidc and quinidine. I. d,ffeB from the two drugs.. hQWt'"a". in lhal ;\ does IlOI decrease, and -reven enhance. conduction velocily and i~rea'\e$ I1l('mtr.e responsh'eness 10 stimulation. llIert a.re fewer dal~ lI1Ii1bIe on !he subcellular mechanisms l6pOOSible for the ...mythmk: IIClions of lidocaine than on the mon: estabdrull quinidine. II has been ~ tnat lidocaine llule e(ftcl on JIlCmbmne cution e~chanb'e of the atria. ion entrance imo .entricular ttlls dunn!! excitation mnl,lf'nced by lidocuine becau,o;e il does not alter conin \his ..n:a. Lidocaine hydrochloride doe:'i Na ' i during diastole. as ()o all other antiru'drug'!. to dlmimsh automaticity in myocardial tis 11 also allers membmne responsi\'eness in Purtinje fi a1~in& incn:a.~ conductktn velocit~ a.1ld ample ~;.",;. potemial at the lime of excitation. I 1.JcIoQ.mc hydrochloride admimstmuon IS limited to the ~l route und is usually gin'n intravenously. though .... plasma Ie"ds are IIChieved afler inlmmuscular in-

'*'

Phenytoin Sodium, USP. f'hcon).oin sodium. ~.5-dI pile ny 1 2.4- i nuda:rol id i Il<,.'(] ione . ~.~ -d I phcn)' I hyd:m I01 n. di_ phenyl-hydantoin sodium (Dilumin). has hccn used for decl!dc:s in lhe control of grand mallypo!s of epileptic !>evure. It is Struclurally analogous 10 the bartlltUrak'S but doe$ noI poIlse~s Iheir eXlcnsi\'e S(.,(]ntive propcr1ics. The oompound is available as the sodium salt. Solullons for parelllcr:d adminislmuon coma in 4{)% propylene 111)'001 and 10% alooOol to dissohe tlx- sodium salt. Phen),loin o;odium'~ caRhovaM:ular effects .. ere UIlOOVered during observatIOn of toxic mamfestallons of the drug in p.atienl~ being treated for sei7,ure diloOl'ders. Pbcnytoin $0dium was found 10 cm,l>ie br.KfycanJia. prolong the I'R inter. val, and prodUCt T- wa"e IIb!'lOl'm;ttilic:S on eleclrocardiogl1l m~. 11 is a clas~ 1B antmrrflythmlc agent. Today. phenyloin sodium's grea.est clinical u,o;e :u ~n antiarrh) thmlc drug is in lhe 'reiltmcnt of dlgJlllli s'mduced ~ITh} Ihmins." liS oction is similar 10 lnal of lidocalllc, It depresses \'cmncular auton,all cily produced by digl1uhs. wilhout adveI"SC in'r:!.vcntricular conduction. Because 1\ also re\'c~ the proIon gation of AV conduction by digilalis. phcn)'oin sodium I' u!OC:ful IJ\ sUpr:.1\tnlricuI3l' tilCh)'cartlla~ caused by dlgilal" IIl1oxicmion. Phenytoin <.OdIUm i~ located in high amO''"t, in the body li<sues. espeCIally f~t 000 li\'cr. leadmg to large: j:'radicnls

-\CH a /

NH-C-CH - N\

I C2 H~
C2 HS

CH,

"""'"

.''*''''"''

Arr-ta ..

"-12 t-Mtabohsm of lido-

CH,

between the drug in tissues and the pl asma cOIICcnu"Jtions. It is mctabol iud in !he li ver.

Mexijetinf! Hydrochloride. Mcxilcunc hydrochlondc. JnlCthyl-2( 2.6-~ ylylo~y)cthyJamillC hydrochloride (Mcxi til ) (pK. 8.4). is 11 class [8 antiurrhythmlC !tgCnt that is cffec uve .... hen givcn either intl1lvenously or ornlly. It resembles hdocainc in possessing I xylyl moiety but otherwise is diffcr cnt chemically. Mcx ilctLl1e hydrochloride i5 an cther and i5 not subject to the hydrolysiscornmoo to !heamides lidocamc and toeainide. Its nlCan half-lifc on oral administnl.tion is uppro~imaldy 10 houlli.

T ocai nide hydrochloride i~ classed ~s II IfI antiarrh)thnuc: agent and u'<ed ontll y to prevent or treat ventricular ~ ond tochycardia. The Ur"u, is ,h'en in 400- to 6OCI-mg doIa e~'ery 8 houl""l.

Flecainlde Acetate. Fl ecainide acelate. N-(2-J'lLpendr nylmethyl)-2.5-bi s (2.2.2-tnfluoroc:thox ylbcn7.amide 1MnoaccluLe (Tombocor). is a class IC alllianf1)thmicdruJ ..1III local ane.~thetic activity: It is a che mical deri vative ofM zamldc. The drug UndergOCll biOlrnn~(orm3hon. formillli mcta-Odcalky lmed C()mpott lld. who$e antiarrhythmic P"'P" ertie~ arc hnlf as poIent as th\1liC of the parent drug, ard I mcta..().dcalkylatoo loctam of nCCllimde with lillIe p/IanIIacological lClivity:)o I-lecamidc: acetate i~ givcn orally 1O.IIIppress chronic \'cntricullll" cctopy and vcntricul;u- taclr'';;~ II has o;onlC limltal.,ons because o f eNS side effects.

.....

MnxPaIJl'Ol

Although not subject to hydro lysis. mexiletirle hydrochl ()ride is nw:tabohud by oXldah~'e and reductive proccs.~s in the livcr. Its mctabolitCS-.p-hydroxymcxllctinc and hydrox y mcthylmcx rlcunc. arc 001 pharmacologically ICti vc lIS antiarrh ythmic agenlS ..... M e~ile tirle hydrochloride, like class I anliunhythmic agents. bloch !he fast Na' channel in cllrdillC l"C lis. II j. csp iall y cffcctj\'e on the Purtmje fihers In the hean_ The drug incruSts the rhreshold of excit.abihty of myoeanhal cells by n:ducing the rotc of rise alld amplitude of the octlon potcnti~1 and dccrcusc:s automalLcily. McxHetine hydrochloride is used for long-term oml prophylaxis of ventriculattaChycllrdiu. The drug is gh'en in 20().. to 400-mg do5es c~'cry 8 hours.

OCHP.

Mor/ciz/tle. Morici zine. ethyl 10-(3-morphol lllop" " nyl)plw:nothi(ll.inc-2-cLlJ't;imalc (Ethl1lo~.ine). is a p/l('m azine dcri~'at ive used for the treatment of malignant ~'rnIf1I lar anhythmiu. It is catcgorized as a class IC antiarm agent. bloc"ing the Na ' channel with I : I .stoclliomruy. lk drug has hight'f affinity for the inactl\';ltcd state m. III acti vllled or f1:Sting SLmcs. It appears to billd 10 II SIlt' 011 111 external side of the Na I ehollnel mc:mbranc.J7 Jt Ius bell used to supp"'ss life-threatening ventricuillf arrh)'tltJru4

Toeaitllde Hydrochloride. Toeai nide hydrochloride . 2 amioo-2',6' -proPlonoxyxylidlde hydrochloride (Tonocard ) (pK. 7.7), is an analogue oflidocoinc. II is ornll y acti ve and Iw clcctrophysiological propert'es like those of lidocaLIIC." Total body elcarance of tocaintdc: hydrochloride i~ only 166 mUmin. suggesti ng that hePlltie clearance IS nOl largc. Jkcause of low hepatic c learancc. thoe Iw:pat ic cxtraction mtio must be sma ll: therdorc , rocain ide hydrochloride is unlikely 10 be su bject 1 a subStanti al first-pass effect. l11C drug dif 0 ft'l"S from hdocatnc. in that 1\ lacks two ethyl groups. which provides locamldc hydrochloride rome protection from fifl'it. puss ht:pallC elim inalion aftt'f oral ingcstion. Tocainide hydroch loride is hydrolyzed in a mnmler ~i mi1ar to thm of lidocaine, NOlle of ilS metabolites is octive.
~.

~-C:-LIP1o

II

~-C-CH-I%

'"
Tocalllicle

JToroocerdl

enamiomer al<;o produces a ~ult . the (S) enantiomc:r i than the ( N ) enantionw:r as pn clWltiomers also display terislK:<!. The (N ) cnant iorncr patle metabolism i$ polylllorpllic

-, "".

ally. Ten jlC1ttl1t of CnllCa.,ians have a rWllCeU capacity to It)dru~ylate the drug to form 5-hydru~ypropafcrlOrtoe. Thi~ iIOI)morphil: mctaboh~m OCOOlIms for the imenool\ldual 11II:!blhty III the re lalionshiplo bctl'ocen dos.e will COlll;cntro100, thll.'>, 'ariabilny on the ph:umacotl)namlc crrect~ .em.: drug. The 5h)tIro~y metnbohtCli of both enanUOOlCB ft 1I.]l'Otelli u the po1rem compound III blod.il1g No ' chan.m. Propafe~ also del'fl$.'>C1i lhe: sklw inl'oard current of 1 lOllS. This drug has been uloCd (or acote lenllination .IonSterm SUppre!iSIOI1 of ventrICUlar lIIThylhmlas. It I~ kwvJ 111 e~c('...... of 95'k to ai-acid gJycOl'rotcl11 in the: ...~ It IS abt.<M"bed effectively. bot bo'lII\ailabollly IS est" to be ICli~ than 2(Y.t bttall5e of frN1J".IS metabohsm. I '} is el iml nmed as 1I1lChailsed d rug. llw:mp)' wilh may prodllCc effeclS thai can be anribulffi to (R) cnallliomer<:. nlU s. the effl'(;IS m:ly be mod of an enantiomer-enami{)l11CT inle11K:tion -'til pallent) are treatcd witll the racemate. \Q

c.

uro

O-CH,-CH-Clti/MIc:"H,

p."zOllooe

"'"

""

"'m it

II aIluarrhythnucs are d,scu,S<!(j under the heading.

Syr-tcm Jl1hibilors.

MI AHTIARRH'fTHMICS

:':.:~'nlruduced as class :

AmKJtlaronc. 2l'lut) IJbenwfuran)I-4. 1ihtth}lilmino)ethQ~y IJ.5..tJiioJopllCnyl lelOne (Corda

Bretyhum to!>yl(lle. (Qbromobcn 1)'llethyl dimcthylammonium p-tolucneStJlfonate (Bretylol ). is an ntn:mcly biller. white. ery~ta lli nc powder. The ~I"lemi cal i~ freely o;oillhle ,n w:ller and alcohol. Brctyhum tOS~ lute is an Iltircnerglc neuronul blocllng agent thai al:cumlilalC!; selecti,c1y In the neurons and displaces norcpincphnne. Becall."': of this prop:ny. brctyhum Wid used imtially. un(k,r the lrudc name of l)areOlhm. a~ an anllh)'penell.~i~e agent. II e~used postur,d decrease in antnal p!'e."Surc.' This U<;C was discOlltinlied becanse of the rJpiu devdopnW:nl of toler ance. emltie oro! IIbsorption of 1M qU:llernary IlI11l1101llum compourKi . and peNislem pain in the parolid glllrtd on pr0.longed themp), . Currently. bretyhum '" re...:nffi for use til vemricular lIIThythrnias toot are resiSlIlRt to OIhe:r therapy. Hret )'lium dot-s not suppress phase 4 UepolliriLal ion. II eOIl1nM.ln action 0{ OIhocr 311liarrit)lhmlC ~gen\S. II proIOIlgli the effcrhve rcfru...-lOry pcnotl relallve to the oction potential duratlOl1 but tIocs not affect eontIuetlon lime anti is eatc},'OriLed a.~ a cla.'s 111 antian"ll)lhmk agent . Ik<:ause brct)"hliin does n.ot ha\e propenie~ .. inlilar to those o(the OIhcr ~ntinr rhythmic ullenl.~. il has been ,uggeqn! that I~ actiOll is due to iL~ adrenergic neuronal blocking pmpenies: the antilU"rhythmic propcnies of the orug, lIo.... e\n-, are IlOI affected by administration of reM:'l'inc. Brel yl iu(1J is also a local anes thetic. but 11 has n.ot been posSible to o.:mollstnlle soch an effeci on utria of e~peril1lentnlanirnal~. CJt~'C'pt al "cry bigh t:OfJCCnlrnlioos .... 1lIerefon:, lhe: prttlo,c rneclmlllsnt of the lmuarrhythmie lICtiOll of hn:tylium remains to ~ ~,ed .

Bretylium Tosylale.

III acuort and is especially effO;:li"e in

an anuanll'nal agem. [t has \'ery

SlIlll, mythm III pallent) whQ have ba:n ueated JI/tCI current shock for atrilll fibrillauon:'o Like class lengthens the effel:tive action poIenlill dur.tllOll IS Ii

tl"le drug has a brood

~pectrum

, ~-i-o-~ ,
l)ofeli lide. NI,H)IIH4-mclhal1e~ulfOIl)'I ami nophen y l)et hy II,net hyl:1I111 00 Ipropo~ y;rhen yIlme thane~u lfonal1l1lle (TikO\>yn). act) by bl ocking the cardiac iort channel carrymg the rapid component of the delayed n:~"\lrocr pOIassium eumllls (Ib) and is uo;ed to leTlI1in:de suproven trieulnr lIITh)"t hlllia.~. Pfe\'cnt the n:cum:nce of ntrial frbnllattoo. and tn'at hfe-threatt",ing ,'('ntricular lIIThythmias. Unlike SOI alol and ibulilide, .... hieh arc aho melhancsul(OI" ami ides. il hall no effect on adrenergIC n:ccptOf'l or sodium channels. respo.>etivd y. !>oreti tide has high specifICity for the tklu) .. rcctiflCr poIass.um c"rrents.~\ -d

main Illnil~lion I" a slow onset may not be imtiatoo for ~"er.l1 days. may nOl be obtuined for several weeu. lICher;e effects involVing many different l)'SIcms. lt also inlubll5 metabolism of drugs cleared ouIIb\"C mlCl'OSQlnal cn7yltll'!i. It contains iodine In iL~ ;mtI, a~ a resU lt , has an effect on thyroid til ul' to II % of pallenls principal effect I~ tIM:: inhibillOO '1 orT.lo T J .Scrumn:verseT J (rT3) of the ~ as .... ell ~ the lenglh As a result. rT , levels ha'!! been adequocy of amiooaronc therapy

Doferilide.

o
"-S-O!,

" II II o

lbutmde. IOOtilide. N 14 1 4..(elllylheplyhunioor I-hy droll.ybutyllphenyllmethanesulfonanudc (Conm). a class III amiwm)thmic belonging 10 the. rncth:meliulfOllanilidc class of agents. is indkated for rapid eorm:'rsion of auial fibnllauon or alnal nunc,'r 10 nonnal smus rfl),thm. Unlike tIofetilidC'. il is IK)( highly specific for the dchl)ed n:clirlCT potauiulI! rorrenlS (luI and <Ioe$ hnc 501111: affinity for sod,um channels.

myocurdial ti ~sue . II i5 distinguished frolll the other claM 10 drugs (amiodarone and brelylium) because of it~ P.adrtrltf iic receptor- blocking action.

11oC- 8-~

II II o

CBe'''p''''') ""'""
(Cona l)

Azimilirh. Allml hdc. E- J-1I15-(4-chlorophcnyl~2fw any IInlCth y 1cAC' lanli IIO}-3-[4-{4-ntelh y 1-1-plpcr.u.1 n~ Ilbut)J 2.4 l1nid.aioltdlllCdione. is a class III agcnl Iha1 slglllf~
blotl.s lhe delayed n:difier pooiSslum current . II.s. lJlCiuWf the Ilr component. Its abdily 10 blotk muhlchanncls lII\ be due to u lack of the mcthanr sulfonamide: gIl)\\P" . ~'OI11!lIon to other class III agents, I'.hich sleclil'cl) ... lhe Ikr potass Ium current. It is bcliclI:d that blocking Ikr and Iks potasiulIl currenl~ yiclds con sblem cb!..1D antiarrhylhrnic effects at any hean rate .4ft

So ralol. SotaloL 4'II hydroxy2.(isopropyl:unilM)tlh ), llmclhylwlfonani lidc (BelllJXlCC). is a rclathcly new aral iarmylhmil; drug. chan!cterilCd ITlO:SI often lIS a class III agenl. and although il has effects lhal are related 10 the class II agents. il is 110( therapeutically comidered n class II antiarrhythm ic. It con tains II chmll center and is marketed as the racemic mix ture. Because of its enumioll1("l'5. its mechan ism of action ~pans two of Inc am iarrhYlh rnic d rug c l a.~ses. 'The 1(-) c:namiomer has boIh ,8-blocking (class II) and potlIS.~ium channel - blocking (class III ) activity . The d( + ) enamiomer has clllSS III propenics simi llll' to those of the ( -) isomer. but its affinity foclhe P.adrerocrgic receptOr is 30 to 60 limes 10II0"er. The <;OIaloi cnamiomer; produce: diffcn:nt effects on the heart. C lass III aclion of J sotalol In the s inus node is associated with s lowing of sill us ilcart rotc. ""hcn:as p.~n erglC blockade OOI\tributes 10 the decrease in /t.cart rote 01>served wi th I or d.IM)laloi . Sotalol is 001 metabolized. nOf is It bound sign if ICllIIlly to proteins. El imination (lCCurs by renal ucteuon. with roore titan 8O'l- of the drug eliminated unch:mged. SOIalol is eharnctcristic of class III antiarmythmic d rugs, in tlult it prolongs Ihe dUr/mon of the action potl'ntiul :md. thus. increases the cffeeti\'e n:fractory period of

CLASS IV ANTIARRHYTHMICS
7.em block the slow inward Ca z " currents (\"ollaj, e-~ ' cltanncl ) in cardiac fibcr<i . This slows down AV conOuo.1i IIllCllhe sinus rule . 1ltese drugs lire used in controlhnl.' and paro~ysmaJ tachycardias and arc calegori7.td Ii I V antiarrltythmic agents according 10 lhe Vauglwl \\ II . classifieation.20 ( A IIIOfll detailed dc:scnplion of channel blocl.ers is ghen abo\e .)

Verapamil and Diltiazem.

Both \l'flIpamil and dib...

ANTIHYPERTENSIVE AGENTS
HypenclIsioll is a conscqUClII._'e of many dhease~. llc~ nmnically. blood pressure is a function of lhe amouot

a----, , -

- ......

blood pumped by the heart and tnc e~ ","h .... hich the blood fIov,~ through the periphcroJ vlISCu l:llun: (i.c. n:$lstance 1 0 blood flow by peri phcrnl blood ve.~St:I~). Di)rCasc~ of (01111'10'
Dents of ~ l'Cnlrol and periphcl'lll nervous sy\lcm~. which qul.le blood pres.;ure and abroOililaJities of the hormonal ,)\lffll. and dbc:a.<;e~ of the kidney and periphcrol \'a.<;eulll1'

"

11:1""00, .... llIcll Pffecl blood volume. call Cl'\:alc II hypenenwl e Male in humans. Il ypcnension i~ generoll y defined as .Id "hen the diasto lic pre~ure is between 90 and I().l nun HJ.. nlO(\eralc: v.!w:'n 1 is 105 to 114 mm li g. and seven: 1 "ben II 1$ above 115 nun IIg. 11 is estimmed lhb! about Wt of the adult population in the United Stale,ol (about 40 IliOion) are hyp...'1tens;.-e.
P"'ftory (esSt'mwl) h Wen~'w(}ll
IS

the moOst romrn<,m

iorm of hypcncnsion. Ahhough ad vance, have been made IlIc: Idcnliri!;alioo and cOl11rol of prim:ll)' hypcn<,nslOl1. k tliology of this form of hypertcn~ion has no! yel been M"cd. Renal h\~nt'''5I(m can be ere.ned by c"penmen1111)' causing renal anery \ tenosi s in animals. Renal artery 1Im06is abo may occur 111 patholOGical conditions of the lIIne-y. such as ncphnM. renal artery thrombosis. renal atlei)' infal't"lIoos. or OIher oondillon~ that restrict blood flow IIIouth the renal aMery. Hypcn.:nSlon illso may originate lrom p.iltholO1! k al stales In the CNS. \uch as mlllignaocies. t....:ws in the adrenal medulla That cause: release of large _ t 5 of catccholanllnes create a hypenensh e condition lIo"<In all f,heoc/rrmrK!'r.Y/lJma. Excenive secrctiOfl of alde)*,one by ehe oorcnal conex. often beCIlU'IC of adenoma.... prodllCeS hypcncflSl,e: dlsorUcB.. Anmal blood pressure is regulated by 5C'ellll physiologl~.!;",~oo;~.~.uch ItS hean r~I':. strok.: ~olul1"le. periphernl vas , resistance. blood ,essel elllSticity. blood vo l, and visrosny of blood. Endoseoous c hemicals also 1/1 Import~nt pan In the reguilluon of anerial blood frrnUre. The periphcnll vaSCular ~yslc m is innuenced ,~y by the: ~ympa1he:tic-parnsympathetic ool31lCC of the

autonomic ne .....ous system. the control of ",hlCh originatcs in the CNS. Enhanced adrcfll.'rgic activity is a pnnclpal rontributor to primary (essent ial) hypcn cnsion. 11lcrupy usi ng antihypcnenshe: ~gems evoI~td rapidly bc-twc-cn 19~ anJ 1960. Dunng that timt. a number of drug~ for the tltaUnen! and oomrol of hypcnensive d,sease were discovered. De spi lc the many years nf experience, trealmem remams emp,ric blxllUse c/1.c etiology of the: principal form ofh),penension, pnmary hypcnensi-on.ls unknown . The first drugs used 10 produce symptomatic relief of hypertenSion were tr-adrenergic block ing agenT S. TIlesc drugs h:1d limitation~ because their duration of action ,,as fill" tOO short lind side effectS precluded 1000g-tenn thc-rapy. Contemporory theropy of primary hypen cnsioo use.~ one of several drug classes lIS the fiN 00lIf"SC. These drugs may be diuretics to reduce: blood volume. inhibitors of the renin-angiOlens,n system (ACE IIIhibitors). and agents tnat reduce peripheral vascullll" resistance (e.g.. eaki um channel blockers. vasodlla tors. and .~ymlxll lletic ncrvO\l ~ system dcprcs$anL~). The antihypertensive: drug el85se!l discussed in thi s section melude ACE mhibieors. sympathlCtic IIl'fVOUS ~ystem derressants, and VlISOdi lmors IICting on smooth muscle . CalcIum chanocl blockers and other vasodilu lors are included in preVIOUS d, s_ cuss iOl1s in this chapter. D,uretics ate dISCUssed in Chapter 18.

The Ael"n- Angiotensin Syst.... and Hype; hnsion

The renin-angiotensin \yslem is a honnonal system lhal
plays a celllrni role in the eontrol "r wdium excretiOl1 arid body fluid volume. It interacts elOM'ly with the sympathetic nervous s)stem and aldosteln...e secretion in the regulatJoo of blood pressu re . Figure 19-13 shows the relaltonslu p of the cOlllpoocnt parts of the renin_ a/lgiOlensi n sy.tem aJld thl'lr main physiological effects.

Re, P ;llIs.

,/

of

Sodt.., IKld FIuod

Retention

~"pneraJ

""'H"" An"utnoo

19-13 ~n-anglOteos," system ad presufe (ootrol

, ..,
f'Ion(I

...

p, ; \e"re

ASP-ARG-VAl.-TYA-tLE-HIS

r RQ..PHE-HIS-LEI)-VAl-lLE-H15-fI (AngooI_oooenl

(COOHend)

ASP-ARG-VAl-

j '"' TYR-llE-HIS-PfIO-PH~I5-lEU
~1.n'k1 I)

~'dM.

ASP-ARG-VAl-TYR-ILE-HIS-PAO-f'HE-HIS-LEU

j
(AngooIentIn Uj

."..,J...j
ARG-VAl-TYR-lLE-HIS-PAO PIlE (AngooI-.n III)

j
INACTIVE PRODUCTS

"""""

Figure 19_ 14 BlOChen'llSUy of the renm- iWlI}IOtenstn system. formallOfl

.

of lglOlenSInS from IgIOlen-

The rdanonship btllOtel'l the renm-angiotensln sysk'm and blood pre(SUft' in humans h:u been koown ~mcc before the beginning orlhe 20!h century. Ti gcl'Moot and Bergman? dl:mon~lflIlt-d in 1898 thai when Injected in a host. kidfloC), C~U'lK1 pnxJlIttd 11 potent vasopressor res~. The substance Wa.'l named n/ll/l. Many years laler. Ihls wbsmnce
wu.~ ~hown 10

require

cofactor

10 produ~

.'asoconSiric-

lion," Eventually. in 1939. this lIypcncnsh'c ~ub~luoce was isolated. idcmified a5 ~ dccapepidc. :md lalcr called M/I;(}+ lens;n. This ooraclorCJi.l~led as IIf1 macth" precur\Or. angloc Icn.~inogcn. Luter studlCS revealed thaI angIOtensin t:lll~c:d in two form~, the biologic;llIy inacti \'C detapeptide IlngiOlcn~in I and the activc octupeptide nngiOlcnsin 1I.' 9 lbt: precUI'OI' of IIllgiOlensin. angiOlcnsioogen. i$ a glyeGprotein of molecul;lf lO.eighl ( MW ) 58.000 to 61.000. synthesized prilTlllrily in the li~er and brought 1Ol() the cIKu latory system . Rcnm . an nspanyl protcn'>e (MW 35.000 t040,000). whose pomary soorcc i~ the kid"ey. cleal'es 100 Leu-Val bond from the asp;tnie acid end of the tlllgiotensioogen poly. peptide molecule 10 release: the tkcapepudc IIllglOlensi n I (Fig. 19 14). The biochemical conl ...",ion continuc, with too clea\'agc of a dipept ide ( 1 I i~-LeuJ fromlhe carbox yltcmli nal orDngiOlen~in 1 by ACE 10 fonn the octapeptide DngiOlen,~in 11. a potent vasooonsuictor. AngiOlensIll 111 I ' formed by Kmoval of the N-tcrrmnal a'i{Xlltate re.~Idue of angiOlcnsin 11. a reaclllHl catal yletl by glulamyl aminopcplida~. In con trast to angiOlcnsin 1I. angiOlcnsin III lIa. a Ic,~ potcnt bUI ~ignificllllt regulatory effet.'ton sodium ucn:tion by the renal tubules. "The regu lalNy octiOl! of lhe rcnHl- lIllgiotcn~1O sYMcm in controlhng sodium and pO\assiu m ba lance and :ln~ria l blood . pressure i~ modified by v-.sodilaton. called J.ilrilu. Proieolytie enzyme, thai circulate in lhe pla~ma fonn kinltlS, Kalli_ trein is acti"aled in plasma by OO~lutIJI mnucnces 10 act on

a tinin. cailld in. IO.hich is COIII'erled to brad)kimn by enl ymes. Br.>dytinln enhances release of the pt\)\\.ag PGE1 llnd l>(jl ~ within ccnain lI'sues 10 produce a ";ooch-.. lory effecl (Fig. 19-15). BradyklOin i~ conl'ened 10 li'I3ctJIt prodUCl!i by ACE and other earbo~ypcptjdalb. A ACE causes acti vatlOO of aJ1giotcns.in and lnactllatP III brndykinln. actions tMt appellr to be oppo!ille. lhe ba' I of lhe ~y~tcll1 seems to ravor vu:;ocollstriction. ACE is a mcmbmncboulld enzyme anchored "a .... mcmbrnnc through a ~ll1gle Iransmc:mlJomc, donwn '" IIC;If the carboxy-temuna l cXlrenllly. The enzyme IS. contulntllg glycoprotcm with II MW aboul 130.000.lt is nonspecific peptidyldlpeptide hydrolase. widely diwituel In mammalian tio;sI/CS, tMI Clclll" dlpeptides from IIIeCl' CS boxy terminUS or I number or endogcnotls pepudeJ. Til minimum S\ruclur::ll requIrement for binding and MI. of a sub\trllle by ACE i~ thai it be a tripeptide ... ,tIl I carboxylute group. A gel1Cl1Il ('J(ception is lhat lhl~ docs not clca,-e peptl<b with a penultiOl3te proIyl This accOUntS for the blOloglCtll stabil ity or unglOleru.1 The IInponant binding points at the active SlIe or Dcalionic ~ite to Utll1lCt u c:uboxylm e ion and can poIariu Dcarbonyl group of an llJllide il more susceptible to hydrolY~l~. In the a nucleophilIC allack of theamidecllfbonyl by the

to""

.......,
Cds :lin

1fIac~ ..

.- -.--! I""
Pn>duet, Vuoc"H

Figur. 19- 15 B ,adyk.mn formatlOfl iIIld t1CJI

Chaptn III Curow''UJr ,,/m' "'~"fj

645

I I I I I I I 1""(... I
I

'---------,-,----------' ------' ~

I
NH

"" (~ ,
"()H

~
~.

1-\
NV

Zn-

\
~

,C=o
NH ,

'.

JYU"-Suc gll1ndllls 1a.<.O!h la m:oo:;:tw(' \Ithoogh fiLion of ~ balll1lCe

-"
figu ... " - '6 Model ~ng d l'oJv9 of the histidine-phenylalanine res!u of angIOtensin I by ACE to form tne ll\apt'Il1Jde Mtj()lemin 11 and thfo dipeptde I!5Idut of tu5ttdine Clod leucine

/~
H. H.

C",

C~

I
/ CH ,

Ii

HzN

/ N't,.

,6..
CH ,

PH , ' CH
~

:> the ('ell

I I I I I I I

0:. , .

C=O

N~

I '

'C'

", NHt

n locoted IS a '-Hlei~tributed

)),lt i~a

n the car.ide~, 11lc: ! de:lI\age: ~Ith II free IS e:n/YITIC '1 re\iduc, e:n~Hl II ,"" fACE ll", IIC lOll th~t l1l to male: IC , there IS ')'<arbonyl

poop of a gl utamic aeld residue to ellu.;c hydrolysis of the pcpido:, Figure 19- 16 SOOW5 a hypothetical model of the l1)QroIysis of angjOlt'tlstn I by the acth-e: site of ACE. ACE oiiu In more: lhan one form. Sont:ilic ACE Ihat regulau~s NoW prc~wre. fQUnd in nlOl>t tiSSIIC.$. dl rrrn; from the isoc: n1)1111.' ACE found in 100 tl!.~l is, Somalic ACE. in rontrasl to IellinlIar ACE,coolains , ..... 0 binding domains, The principal w''C SIIe: for hydrolysis IS the: domain located in the: Cl!mIilllli half of somalic ACE. 'I
UNIN- ANGIOTE'NSIN SYSTM INHIBITORS

bindi ng poinlS III the IICti ve site of ACE are thoo ghllo be an arginillC n:siduc, which providc:s II cat iooie site thai allrnclS a carboxy lale 1()11, and 11 I.lnc ion. which can poIaril.t a c;wbooyl gJOllpofan amide fUl1CtlOl'lto make: 11 more su~plible 1 hydrolysllI, Ilydrophobic pockets he bc:11I'c:c:n 1hc.'IC group!> 0 in the active ~i'e. a.~ does a fUllClionol group thai ronns a hydrogen bood with an ~nllde carfJonyl. Figure 19- 17 ~how' the: hypothe:tlcal binding of capmplil In the OCII"e: SlIe of ACE.

CIptopri/.

Captopnl, 1-1(2S}-J-mc:rcaplo-2-mc:thyl- l owpropionyllproline (Ca poten ), blods the conY .. ~ion of qiocen~in I 10 angiOlen,in 11 by inhibit ing the con verting aIZ)'IIlr, The: ratlooal dc:.'c:lopmc:nl of captopri l as an inhibi .0( ACE was based 00 the hypodlCsls thai ACE and earuypqM~ A functioned by similar mc:chanisnls, II .... ..s IOltd !ha! d-2 -ben:tyl~llCdnic acid~ 11'11" a potenl inhi bitor rI carbo;o;ypeplidase A but not ACE. By usc. of Ihis <.mall .......I!e as I prototype, captopri l WIS designed wilh I earlilnyl group on I proline and a miol ;roup was mlrodocc:d IDcwh.1ncc tile binding 10 lhe llOC ion of ACE. TIle important

CapIopI I
(Capo!en)

UJlnopri/, LISinopnl, J.I ~ -rS- I-carbollOy3-phcnylpropyl l-L-lysyll-L-proIillC dlhydrale: ( Pnnt VII. ZotriIJ, i~ a Iy-

",-

-.

CH,

/ CH:i

CH " /N

f"" 0_
I
Figure 111-17 Acc.omrnod.Jtoonof U!l' toprll to t ~ (lClNe Sile of ACe.

Nfi,

I I I I I I

+/, NH2 -

sine derivahvc: of enalapril al. the active n!Claboli!c of tnalapnl. Like all ACE inhibitors. il is IU1 active site-directed inhibitor of the en1.ylllC, ",itll the lillC ton used in an cffecuve binding inlerao:lion III a ~oiclliomc:lnc r.uio of I: I. 'The pharmacological effects of hsinopnl an: Mnlilar 10 those of cllj)lO<prj l and ella/april.
H.
C - .OC~.'"

los, of la,le secn wilh Cllplopn l. 11Icse sid!: effect!. similar 10 those of the IlICrt"apltXOOtaining drug pt'IlicilJa. mille . 11Ie absence of the Ihlol group In enaillpril maJea

~m1

"""

mil)' free it from l/lese side effc.;:\s. The half-life (\ 11

I hkqlfil (pr . M)

"
BeniJzeprii Hydrochloride. Bcnucpril h)'drochlrodt. (JS}- 3-11( 1S}- I...camelhcny).. phenylprop}lJaminol .. 2.1tllctruhydm.. 2.()xo-l j(.. I bcnl3zepinc .. l .. acctlc acid estcr h)dtucbloritk' (Lolensin) .. is metabolized rapidl) 10 active dlacid benuaprilat. As with the ACE prodrup. mut,lgenicity has been found, even though tbese dnlJI the placc!lla .

(I.stlll) ACE INHIBITOR PRODRUGS

Many new ACE Inhibitors became IIvaitabk for the !feal men! of hnlCncnsion followi ng the clinical effectiveness of
enaJapril. Erual:lpril is a non -Ihiol <oluainin~ ACE inhibitor dc\oid of the side effects of I'IIlih and Io<;s of lhe: sense of llISIe characteristic of the th iol "wllIaining compound captopri l. With the: ClI ception of lhe phosphoolll-coniaining fmi .. nopril . thcse antihypenensive agenls have a 2(S) .. amilK)phenylbutync acid eth~ 1 e.ster moiety differing OIlly in the ~ubsti1uems on the amino IIfOUP. They have the common piOpet1y of actingllS prodrugs .. being con,en ed 10 the active en ~.yme inhibitor following obsorprion ond mclaholism by liver and imestinal enzymes. 'These drugs (Fig .. 19 .. 18). li ke lhe protOlypical drug eaptopril. are used in the treatment of mild "lo-moderale hypenension. eitllcr alone or in conjurw: .. IJon .... ith dlumics or calcium ch.anncl blod.crs. Table 19.. 5 compares some o f illClr propenies.

,.-<
oOO""M

QulniJprll Hydrochloride. EniJ/iJprll Maleate..

Enalapril maLeatc .. I-I N[ (S}-I -carbox}. ) . phenylpropylJ-L-alan}II-I.-prolinc . ' -ethyl ester maleate (VasOIee) .. is D long-xling ACE inhibitor. It requi res ac:l1 vDlion by hydrolysis of its ethyl e!iter to form lhe diadd enalaprilot .. Enolapril is dcvoid of the side cffeels of rush

Quinapril (S) .. r( S ) .. N .. [(S)21 ...carboxyJ -phcnylpropyll tetrahydro-J-iMlquinolmecarbox}lic acid I drochloridc (Acurclic ). foom the t body .. It is tnOnl potent than ocli,c form of cnalapril..

Ct\apt .. r 19 Cardk/'"(JJ('!tla. At""11

647

o
up-

He>

" 0
t
~

C<X>C,H,
C~CI'<lCH

0
I CH,

I NH-CH- C- N

COOH

HC-COOH I
HC-COOH

o
I
I I

I(;H,I<-P- CH.-C-N

0 Q0 H0 I
,
H

o o
Foeir1opril Sodium

coo.

lCilla

"=

(CHmCH-CHOf~

I deale: is 11

Ioridl.:. 3.0~.

..('Ihyl 1 the 0
110
~ Ci'O!o'

figure 19- 18 ACE Inhibitor prodrugs

f
.Ioridt.

TAelf 19-5 ACE lnhibltor Prodrulis

,.
.2.3.4leI

.....,.,
f . . . .d

"lei',.

Me1l1bollt.

Metabolite Protein Iinclint (%1

Metabolit. Plasma
tll> (~1

Mode of bo.tlon

hr-

mlhe 1 10 the

...""

Fe "'Pol

Q 5 priI

QouMp'lI.

"',.,""".
F .&iopilal
IlMnlpnt.,

,..., " '" '" "

10-11

", " 1:1-17

11.0

...., ,-

'''''''''''' ,........
RmW'I..,. 1

pyrrohdlllt: of coaJapnJ hall ~n replaced ..... uh an oclllr! dromoole systcm. Much likc cnalaprilate. IJ'lIndobpril_ be hydroly/.cd 10 tninOlaprilate . .... hich IS the blO:lai.'e 'lit"

ties.

Ram/prj/. Ramipril. (lS. 3&S. 6aS}- 1-(fSj-N' I{S}-I-cMboxy - 3 -phcnylpropyl] alanyl] octahydrocydopenlll ] b 1 pyrroIe-2~;uOO~ylie acKl l-ethyl cster (Allin). is hydrolyt.cd to rlmupnlal. its acti ve diacid form. foster u..an enalapri l is hydrol)'1.cd 10 ilS acl ..c diacid fonn. J>l:aL ~l\Jrn concc:ntTlltlOlt~ from a singlc oml d<J5c, are achicved bel ..... ecn 1.5 anti 3.0 ~ltJf'l!. The romiprilate forrnc:d completely suppre~~ ACE oclivllY for up to 12 hours ...... ith 8O'l: ,nhibi lion of the enzyme ~1I11 ooo,ervcd nrler 24 hours,

"
_ c_ T..,,,,,: t-:14

" ,>

".'1iI<,)
ANGIOTENSIN ANTAGONlm

"

" g. ,

tt

" /,"'/"'~'/'"

o c-..... .. ~.

"

..... "X'~'
.

'=0 I
"

"'~.'C.)

FoJlflop,iI Sodium. Fosinopril .;OOulin. (4S)-4-cytlohexyl -I-I]] (RS}-I-hydrQxy-2-mcthylpropoxy )(4-phcnyl-bu tyl)phosphinyl)acelyl)-t-proJinc sodiuJIl salt (Monopril ). is a ph()s phol\J,'~'QOlnining ACE inhi bitor. It " irntCli ..e bl" SCf'\'es a~ II prodrug. being completely hydrolyzed by intcsIInal and It'-cr en1.ymes to !he aclivc diacid fo<;inoprilat.

Administration of D competili,'c antagonist can Inhibit . . . tensin lIto producc a vasodilutory cffect. SIIICC the s.ubldt for this receptor is an octapeptide. much of the carlier wert was performed by using various peptide systems. One MI.-Ii agent. ~ralasin. is an oclupcptlde that differs from ang"*'r sin by t .....oamino lICids. This agent's use ..... os limited be it had some partial agonislie propertics. Ncvenhekw., ~ scrved as a lead in the dc,-clopmcm of other agents m._ uscful in al1lagoni~illg the DIlgiOlCnsin II receptor, n., significaIlllead in the development of this class came a series of Imidazolc-S-acetic acid dcrivali~es thai ,,'~: Pf"CliSOI" I"Cliporl5e to angIOtensin II in tCSt animals. M..... lr modeling re\'ealed thatlhc imidll7.oIe-S-accuc actd roIIW uploited to morc tlosely mimic the ph:umacop/loR 01. giOl:CTlsin II . The first suctcssful agent 10 be de through thi~ method is losartan. Latcr. fourothcr lIitPb_ inlrodlK~d inlo the U. S. markct. These tend 10 be biplnyf methyl dcrivath'cs thai possess certain acidk IIIOietK. which can intel1lCt with various positions on the 1(F'CI much like the .~ubstl1ltc. angiotensin II. Since the lat~ I thi s particular class Iua5 reccived a greal deal of .;.,. . In the carly 19905. the receptor for angiotensin II .. -r. ~ 1 uist as four iiQ1.ylllCS. AT , . AT~. AT,. and AT.. 0 AT I heing responslblc for smooth muselc ront~ pathcuc pressor mcchamsms. and aldosterone ~Ie&r
ANGIOTENSIN II BLOCKERS

"

.b

LOJartafl. Losartllll. 2-butyl-4-chloro-l-(p-Co-IH-e1111.01-S-YI-phcn yl)bc n1.y II i mida7.olc -5- melhanol 111(-,.. tassium salt (CozarT). was the first nonpcptldc imiibmlrl

.'"
Tnndolaprll. Tnmdolapl'il, 1-12-1l -ethoxycartJonyl-3phtn)' lpropyJ:umno)jN opionyl]octnh)'drolndole-2~arbo~)'lic acid (Ma .. ik). is an indolc-contaimn, ACE inhibi lor ttlal is Struclllnll1y relaled to mOSt of the agents discussed alxl\"c. Ennlnpnl is vcry similar III tntndolapril . ..... ilh lhe primary dlffereroce QlXurring in thc heterocytllt syste111~. The

be introduced a~ an ()I"~ lly activc angiotcn'in II DO "'Ilh high spccificily for AT, . Wllt:n administemltoJlllUrl' it undergoes ulcnsive firsl -pass met3bol ism. \11th . . ~ methanol being oxidil.cd 10 a carboxylic add. Tht5 lism is me<hUled by CY P 2(:9 and 3M i>Olymes. 1k \ methanol metabolite is apPl'O~imalely IS limes _ .... than !he parent hydroJlyl compound. Sincc lhe ~ . ~yl compound has affinity for !he AT, naptor. \II: speaking. II is not a prodrug.

Candesartan. Cnndcsarlan. (+ )-1-1IlcyclOOel) carbon)'I)oxy Itthyl 2- cthoxy- I-I 12'-{ I H_tetrwll_S.)l I ' - biphenyl 1- 4 - yll mClhy l l-1 H-benlimidalOlc-7c

* (Alacaoo). like Josanan. possesS('<; the acid,c tctnl7.ole

')>ltm. ... hich mOSI lilely plays II
1IIII0000n.~m

TelmiS<lrtim_ Tclmisar1:an. 1.4' -d IlTll:th) 12' pJO1'1)'112.6' bi- llf-bc nJlmldalOl J- J -y l)melh)' I]-[ I , I' -biphen) IJ

"'-Ie

role in bmdmg

10

the

lhe acidte pun~,n II. AllIO. lhe: Imid:uole 5y)I('1I1 has tlllI I bC'nllmldazok possessing an eIkr nlUSl be hydrolyud 10 lhe: free (l)lwer;ion wl..C'S
1 0

11 rttc:p:or similarly

-2-c;arbo.ylic acid I"hcmhs). does !lOt appar 1 ~ar any 0 blrul:lura] relationship 1 this class. but there is actually a 0 greal deal of 01 crlap 111 the chemical architecture '*llh OIller agt'nts. The first, and 1110<01 ~ignilkant. difference j, the replacement of The acidic IclrJlole ~yslcm with a ~implc CIII'bo"ylic acid. Th t~ acid. like the lelnlZole. plays a role 111 receptor binding. The second d ifference is the lack of a carboxylic ocid near lhe 1IlII<I:1l.ole nitrogen rh31 al..o COOl ribules to receptor bll1thng. A~ with Irbcsan an. howel'cr. there IS 1101 a need for this group 10 be acidic bul, !"lliller. 1 be 0IlC 0 lhal partici pm~ In reccplor bindmg. The: second II1l1d~()Ie ring . much like II purine base m DNA. c~n hydrog('n bood ...ilh the' angi(M('n) m II rttc:plOr.

Ih,)

~h

",
m'

i~ ltl!

, I

til much

~'Qt\\'ersion to the free

Ibsorptlon from the

gaslrointcstin~1

,,",' plur:e during tl1lC1.

-,

!II-

,~

,"
,oj

",. , E
oc.

'''' ...
~

"~
.

.......
Vabartan.

TeIo,tl ....

anco~ \

"re ly l_

100.

r ym.

u od lh

Ie \0
s-

)nist

Irbe.;anan. 2OOtyl. )-[) 2'-< lI/-teIl1lZ01-51hll .l hlphcnyl]-4-yl] mcthyl ]I.)-dial.aspimI4.4] Il0l1- 1,,~ooc (A\'apro). li ke losanan. POSSCS!iCll the acitl,c leIIIXIlt system. whtCh mo:5l likely pl:l.y~ a role. \imi lM to lhe "*lfOUl* of ilIlg.KltCnsm II. in bIndi ng to the.' anglOtenSm U~pt(W". In addit ion. the biphenyl system lhat sel"\'~ to otpnte lhe tetnl70le from the al,phattC nit rogen b 5,,11 pres A nlaJOf tli ffert:nce in this agent h that ,t d()('\ 001 P:)$.'.'~SS fr ICldic side chain. E>en.'iO. i~!>lInan Ila.~ good affinity die angiotcnsin II receplOr becau)oe of hydrogcn bonding ...1Il the carbonyl moiety of the amide' sys tem . AI!IO. this pIOk."'I.Ilar agent does not requirt: metabolic IICti "ation as can wran does.

~rt,jln.

Val"<aJtan. N( I-(J~opentyl t-N[ [2'( 11Ilel r'J7.015-yl)[ 1. 1' biphcnyIHyl )mclhyl ltAaline (Dio\'lIn). like losanJn. POSM'~sc.~ the lICitlic letramle .'y,tell1. which most likely plnys II role. ~i milar 10 th~ t uf the acitlie ~roups of WlgJ()I('n'in Il . in bil)lj lng 10 the angiOl('n~in II reccpl Ol'. In addition. lhe biphl'nyl ~y~tem Ihal senes to !iCpantk: the k:11"3101c from the aliph:llic niuugen i~ ~Ii ll prescnl. In addition. [here is a carbo~yhc ocitl ,ide' chain in the , .. hne moiely that also '<Cn'eS to bmd to the anglOlensin II rettplor.

".

.bo-

.I.

:MCIlI

"ICIly

ADRE NERGIC SYSTEM INH tBITORS

;,)(yl-

. 'Ill

)")'

"'......
~t

III 1M

Drugs thai reduce blood ~urt: by dt:pfl:'''Srng the ach~lIy of the sympathel1c neI"Voos system ha.-c' btcn used in effective agentS in the lrelltlllent of hypertension. This Clln be accomplished ,n ~verdl w3yS: (a) depleting the stores of nl'UrOllllnS mll1er. rb) reducing the number of imptJlscs tmv-

elmg m sympathetic nc:ryes. (e} :mta&on iling the: actions of the: nc:urottansnuuer on the e ffc:ctor cells. and (dJ Inhibiting llI:urotnmsmuter release:,
AGENTS DEPlEn NG NEUROTRANSM ITIER STORES

FQll remc:tiles ~ from spccie~ of R"u...oljio. a pllUU genu s belongmg 10 tile Apocyn:M.-eae farmly. were reponed lIS early as 1563. The fOOl of the ~pecies R. .1i!"'~fII;"1lI has bc:cn used for cent uri e~ as an anlidote to stings and bi tes of in~. to reduce. fever. as a :>Iimulant to uterine contractions. for insomn ia. and panicularly for tile In';atment of in~a n ity. Jill uSC' in hy~nension was rc:corded in the Indian literllture in 19] II. but not unti I 1949 did hypolensive properties of Rarl'K'oIjio spp. appear in the Wesle rn l i terlilUre.~l Rllu"'oIji(J preparations were introdueed in psychiatry for the tremmc:rll of schiJ.ophrenia in the early 1950s. following confirntllli on of the folk remedy repons on their use in mc:n tally tkranged palients. By the end of the 1%Os. however. the drug had bc:cn replaced by more: efficacious neurouupic agents. Reserpu\e and its preparations remain useful in the control of mild essential hypertcn5ion. The effects of reserpine do not corre late well with tissue levels of lhe dr\lg. The pharmacological effects of re.o;erpinc ....-ere still rnsc:m in anilNIs .... hen il could 00 longu be detc:cted in the bnr.in. jJ Resc rpioc: depletl:$ catc:cholaminc:s and scroto,."n from ce ntral and periphend neurons by interferi ng "'ith the uplake of these amilleS from the cytosol into the vesicles and grunules."'" As a consequence. norepi nephrine cannot be stored intr.mc:uronall y in adrenc:rgic neurons. and much orthe I1OI"Cpmcphrinc in the cytosol IS metabolized by mOllomninc ollidase (Fig. 19- 19). Thc bindin g of reserpine to the stOl1lgc vesic lc membrane is finn. ~nd as a !tSUJI. the storage grallUIf: is destroyed. reducing the ability of the net\e 10 COOCt'ntnlte and store norepinephnne. Since reserpine: actS on both centrul and peripher:al OOrencrgic neu roll~. its antihype rteru;i\'c effC:Cls ma y result rrom l\Curotransmitter depltlion from both of thelic ~itcs. QM:mlCal m" csligalions of the acth'c components of R. se/'ptnlm(J roots ha" e yielded sever-.Il allaloids (e.i.. ajmahne. ajmalicinc. ajmal ininc. serpentinc. and scrpentininc).

Rcse rpme. wh Ich is the map act,ve constituent of RlllfIH)/' jill.)$ was Isolated in 1952 and 's II much .... ea1.cr base dial the alkaloids JUSI mcnliOllCd. ReserpH~)ld allaloids an )"0himbinc- Iikc bases that havc an addItional funo:.:tional J!Rlllp on C-IS. Only three nat urall y occurring alkaloids poosa< reserplne-h l c acti,;ty stll)l1g enough for use in trealln! hy pertension reserpine:. de<;c:rpidinc:. and rescinna,mne. ReserpIne: is ab'iorl>c:d rapidly after oral 00111111,51_ Fat lissuc accumulates reserpine slow ly. ",itll a muimal Ie,'d reached between 4 and 6 hours. Afler 24 hours. WlUII amount~ of reserpine are found in the h"cr and rat. hut no:. i~ round In the brain or OIocr lio;sues. Rcsc:rpillC i~ fTII'1IiIo. hied by the livcr and IIIlesl i~ to methyl re.'>I'rp:tte and 3.4j trimethoxyben1.Oic acid.
Powdered Rauwolfia Serpentina, USP. Rau ....olfia (Rsudillin. Rauscrpal . Rau llu!) i~ the powdered .... hole rool of R. UrJ~11I;"" (Bemh). It is a light tan 10 light browJ po .....der. ~pan ngly soluble on aloohol and onl} slightly . . ble in water. It conlDIOS lhe: 100ai alkaloids, of ",lIich mao pine accountS for about ~ of the total octi"ty. Onrlly. 1 dosage of 200 to JOO rll g is roughly equiva lcn l to ~ 14 of reserpinc. II is u>Cd m the treatment of mIld or modo hypenension or in combrnm ion with OIher hypolmsM agents in '\even: hypertc nslon.

Reserpine, USP. Reserpine (Serpasi!' Rcscrpoid. fYI. Sal. Santiril) is a while 1 light yellow, crystalline ..ti Mid 0
practically ",soluble in water. obtamcd frum "arious \pm!!> of Raulwljill. In eornrllQn with otlier eompounds "' Ith. indole nucleus. il is suscl.'JItiblc 1 dccompositioo by tip 0 and oxidation. especially ....Ilen in solution. In the dry discolonll ion occurs rapid ly when rc.'II:rpinc is u~. li ght. bul Ihc loss in jXltcncy is usually ~malJ. In sohrOOl reserpine: may break down with 110 apprc:ciablc colordlqt" ....hen Cllposcd to li ght. e~pecially in clear glass COIII'fI'",," thus. color change cannot be used ali an rndell of lhe of lkcomposit1on. Reserpine ISeffecti vc omlly and pan:nteMlll y for the uumenl or hy])Crtension. After a smslc intra\"C.fIOU5 iJoo,oe. lIr onsct of antlhypertensi\'c action u'iUally begins In ~ hour. After InlTllmu!ICular injcctlon. the: lTWimum effMDI: curs within approx imately 4 hours and last.-. about 10 Whcn it i~ gillcn or.illy. tile mu imulII effect occur, ... about 2 .... ec:b and may persiSI up to 4 wecks ~fter tIx 00sc. When used in conjunction "rlh other hy.,wdrugs in the treatmc:nt of sevcre hypertension. the \bil) varies from 100 to 250 ~g .

S<nM" M_

.,..

"

....

Guanethidine and Related Compounds.

dine has bc:cn classified traditionally lIS an ~nergio; IDi ing agenl bccuu"l: it con prevent thc release of 1l(Ht""'~ rine fTUfll postganglionic IlCUronS In response: 10 stimulation. GuanethIdIne and OIller compound!; di in thi5!1CC1ion ha\e OIher actions on eatccholammc Ii~m arid can couse significant depIction of these antiDCl I IIdn'nergic rlCurons. llIey do nOl illlenCre with rele. " epinephrine from the adrenal medulla.

fIgure 19- 19 ActIOfl of reserpH"le al ildrenef9IC nerve

ending

.,
!J
~
Pe..rpina
Sf .....

ul.. ,'than

~ yu
i h),-

'~P

'\,

,
/

;)!,<,CS~

olti()ll. uilllai
\1"1111

""'-,
o

II

,,(labo~-~-CI1.-H-C=~

1,4.5

, I

...

(Isma'io)

....-....
Monosulfilt., US/>,

"' ,
Rall-

Guanethidine monolIIIfille. [2-(hexah)'rlro-l (211}- utocinyl)el llyl Jguanidine suI. '- Jbmell n su lfi1l.e ). is II .... hilt. crystalline material that is 0:1) soluble In Wiltct'. JI .... as one of II senes of guanidine IqIOUnds prepared in Inc scarc h for polen! Ilmilrypanow"J'tw:,m is an absence of eNS effects. such a.~ tp-es~ion. becllU'ie tnc drug i~ highly polar and does 1101 SIytI'CISS the blood- brain barrie!". Guanclhidine nlOllOSul-

~thidine

.,.b..

sulfnle i~ ta~en up by Ihe amine pump located 011 the neuronal membrane and retained in the neroc. displacing norepinephrine (rom its StOl1lge SIles in the: neuronal granule. Tl1c. displaced norepinephrine. is mctubolized 10 homovllIlillic acid by milochondrial monoa/mnc. oxidase, depleting Iht' neT\'e ending of the: neurotfUnsmiucr. The use(ul ness of IIUllnethidJne monosulfale also resides in the fllCl that once II is laken up by lhe neroe, it produces II sympathetic bloc~ade by inhibiting relensc. of nonc.pincphrine tlult would occur on neuronal membrane re"JlOllSC to Slimulalionl i by the l\Cro'e actioll ptl(enlial. Guanethidille monosulrme slored in the grunules is released by the Ilero'e action ptl(enlial but has ,ery low imnnsic actl\i ly for the adrelK!rgic /'eCeplOl"S on lhe posljunctional mcmbrune. Moder-ue doses for h prolonged period or large doses may produce u~,rnble side effects by cau'lng neuromuscular blockade alld adrenergic nerve conduction blockade. Guanadrel Sulfate. Guanadrel sulfucl'. (I,4-dioxaspir014.51dec-2-ylmelhyl)guanadlllC ~ulrale ( Hylore!). is Si milar 10 gunnc lhidine monosulfmc in the manner in which h reducl's eleVIIled blood pressurt. II acts as a postganghonic !Jdrenergic blockinll agcm by displacing norepinephrine in adrenergic Ileumn SlOI1lge granule.!;. Iht'reby pre,cnting release of tilt endogenous llI:urotr.msmiul'r 00 nero'e stimula lion. Guanadrel sulfate hns a much shortcr half-life (10 hours) than guanethidine: monosulfale. whose half-hfe i$ nteasured in days. In the stcpped-(:are approach to hyper1cn~ion . guanadrcl ~ulf:l!e is usually a step 2 agent.

hght

'"
'0

produces a gradual. prolonged fall in blood pres~um. IlIIIly.2 10 7 days of .hemp)' are required before the peal: I~ reached , and us.u:tlly, this peat effect is maimained .. 3 or" day~. Then. if the drug is di<;conlinlled. the blood
1ift!UR n:tums to pretrealrnenl lelels over II period of I 10

,,.
I

Because of Ihl s slow onset and proIooged duration ilCllOl1. only II sing le daily dru;e i_~ nccdL-d. c..ucthJlline ITIO!IO'Wlfale IS melabolizc:d by micrt)$QIllal ".~'~.,,5 to 2-(6-carboxyhexylamioo)elhylgu:anidinc and inc N-oxide (Fig. 19-20). Boch melabolile ha, c. 'CI)' ..tal. antihypencnsl\'e pt opcni0e5. Gu:allCthidinc. rTlOO()~

",.01",. I

G.......
(HyIorel)

SElECTIVE ... ADRENERGIC ANTAGONISTS

The principal clinical use of u-adrenc:rgic antagonists is in lhl' treaJmcnl of eatechoJDmine-dcpendcnt hypenl'nsion. C llISSic drugs such as phenlolamilK! and phenoxybell1.llmine an: nOI1\po:cilie blocking ugellls of both "I and It2 receptor; on the presynaptic membrane: of the: lidrenc:rgic nc:uron. Speciftc anlagonist~ of at rOCt:plOI"S arc effecllve a11lihyper1cnsivl' agl'nts by bloc~ing the vasoconlricling effect 011 smooch muscle and noI interfering wllh the oclivatlon of fI'l receplOl"S

651

Wil_ UI"/ Gisl'I>ld'. , ,.ltbo<Ji vf GrllUl,ic MrtlirinallltU/ PIIIl""" cl""ttrnl C/ormlJlI"V

on the adrenergk neuron. which wtw:n octo vutc{] inhibit further relea'iC I1Ofepincptuinc.

or

Pr.lzosin Hydrochloride.

The annhypertensi\e t'ffect., ur pnll.o~in hydmd luntie. 1-(4-a nuno-6.1-do11Clhoxy-2ql,ll!lV.oll n)' 1...... -( 2 f1,11"0} I)pl pcrazine luo,Klh) (]roch loride ( Minipress). nre due to pcriphcrnl vasodilatIon as a n:.~uh of lIS blockade of Q-I -adrencrgic ra:cptors. In ligand-binding Mudlell, pm1.0!;!n h)drochlomlt has .5.000-fold greater affinl II) for n I re<:eptOl"S than for some n r oorelM:rgi c n:ccplUr.I.

OollazOf;n , 1 )o1l3/.QSm. 1( 4-atnioo-6.1-dnnetllO.\y! quinawlinyl).4-( 1 .4-~nlOdio~an- 2-ykarOunyl )piperaL.iBe (Cardurn). IS a quma~oh ne compound that sc:lectl"e!y In/IiI. lIS the 11"1 subtype uf II"-adrenergic rect'pton. This .111 ~ very usefu l In lhe managemenl of hypcncnsion ~ ",ith phrochromocyiomp.

CE NTRAl lY ACTING ADRENE RGIC DRUGS

o
~

"""-.. ",-",,"'1/\ /' "--I

,
~

II
o

1ltc u\(: of agents that directly affcct lhe periphcr:tJ "" nenl of the sympathl'\K: IM.'....'OU~ sy~tCtn reprcscnl5l111 i .
A ~ appro;ach 10 mClIilfying ~ympalhf'lic in Oul'nce on the cWi> vlt.'\Cu lnr sy~lem i~ Ihrough InhibilKm or redUCtion ofC'lS control of blood pres.>ure. Sc"entl wide ly uS! ~""'HW ItCI by stimu lmmg 2 m:cptors. ", Inch III the C/l:S mb;eI ~ympathetk oulflow 10 the clltd io\:tl;CuLar 'yStcm and Pf'l" ducc~ u hypotcn~i'e effect.

wm npproach to the lre:llllll'nt of hypertcnslon .

"""
(MO~

'"

-","

nj

Methyldopate Hydrochloride, USP.

Mnh)'1oJt I t

i'rv.osin h)drochlontk is readi ly abwrtlcd. and plasma concenttullon~ reoch a peal.: nhout J hours aller OOnliniSltUtion. Plasma halfMe i~ bet .....een 2 and 3 hours. PI"lIl.()'i;in hy dmchlonde i~ highl ) bou!ld to phlm:1 proIei!!: II does nut cause react ions. ho .....e'cr..... ith drugs thai mighl be d,sp!;,ctd frum ttw:,r proIl'in-btoolng sile;;; (e.g .. card IIII' glyooside.'s). It may cau!IC \C"1'1l! oI1hoslallc hypcrtcn,ion because of it ~ lI'-lIdn:rocrgic blocking action. "'hlCh pn:-,enb IhI' renex \'1'11O\l~ constriction that i, ach valed "'hcn nn indi vidual \i t~ up fmlll a prone pos'l ion ,

ad,'"""

hydrochloride. L3-(3.4-d ihydrollyphenyl)-2-mcth)l~ ethyl e,~lcr hydroch londc (Aldomet eSler hydroi:hklridf~ .. mcth) ldopa. k)",cr.l blood pn!\surc by inhibiting the OUIfltrI; uf sympathetIc VllsoronstrictOl'" unpulses from tbr "'Early sHxliC!>' had suggesl ed Ihal the hyputell'ilH :JCtKIII rI n meth) kIopa was due 10 the pcnphernl propct1lC'S Ii fir tllUg as a decarboxylase inhibitOl'" or a fnlse ttUnSm ll~,
~

Tl'r.v.osin hydrochlurlde.'. 1(4-al11 i 00-6.7 -d Iinc t00" y. 2-q I,Il1lal.Ol III y I)-4-( tI'l mhydro-2- f uruyl)plpcrawlC mooohydrochlorio.: ( Hytrin). I ~ a ,Irutluml congener of pr.t/.osl n hydrochloride. It po:so;cssc~ ~iml lar ~Icct he propcnicl> of ~pccifically inhibi1ing O'I -atlrencrgic n:(Cl'tOl"S. 11K' dlUg is ~" ghtly k:s.~ potent Ihan prn71,,[n hydrochloride. T er.l7.0,in hydrochlondc ha~ a h~lflifc of approximately 12 hoof". "'hkh is nluch longer than that of l)f1IZ()S.in. Thi~ Icl\d~ itself 10 a ullcc..Jai ly dose 10 ~'Qntml hypertension in many paticnts.

Terazosin Hydrochloride.

Meth) kt 'P"

{NI;toh'-l l llC current hypulht:.,j, cl)llCem ing Ille h)JlIMcnsl'c altO Ily or nlelh)oIdopa invohes the eNS :1$ the site of aruea Melhyldopa. on conversion tu lI'-nlCt hyll1Ofepincphnnr. on ir)-adrenet);ic rcct"ptQrS to IIlhibil the n:lcnse of ncphrinc. resulting In (,k :crea.cd s)'mpalllelic outl"lovo the eNS and ItCti~ation of parasympathetic 001110 .... Methyldopa is used a.~ p Mep 2 agent and i~ "'~~u for patient ~ with high blood preSSUfC ",1100 an: not mspcw. 10 diuretic thempy alOlll'. Mcthyldopa. 5uiUlb1e ror onI is a ''''' "tenon and is 001 "UIublc enough for pa~nlrnI. The problem "~.IS sohI'd by maling the ester. lea'iat amine free to funn the walCf-soluble hy{]nx-hloride ~I IS supplied as a ~Iallle. buffeml <;ululion. prtMectro "lib oxidllnls WId chc!nling agenls.

m-

...

00'''1

a"

Iny-2-

V.U1C' inhlbgtne IS ociaeed

Clonidine Hydrochloride. OOllidioe hydrochlontle, 2I12,6-d Ich Iorophe ny I)i mino lim idaml idi lie l11onoh ydruc h loride (C.. ap~), WIIS the first antih)'penensive kno .... n to act !be CNS, II ....-as synthesiud in 1962 as l deri"ltive of tJIc, kno .... n o-sympathomimeti c drugs napha/.oline and lOla

norepinephrine from the neuron when sllmulat~-d . The cffect of the drug resu lt.<; in decrca.'\C:d sympathetic tone in the helln. lidneys. aoo ~nphc:ral blood \tssels, 'The: drug does 1lOI produce: orthostatic hypotcn.<,oo.
~

....

roIlI1C'. poIential nasal va.socQllStrklOfS. oot instead it proved .. ~ cffrcthC' in the trcatrncnt of mildlO-seven:: hypen!'n-

~,,,..

=,d

impol'-

carilioof CNS kaeioo' educes

""pro-

llIupalC lalall10c itle), o ol.unow ! br.un, Cllon of of the incr.

'Ie

1I(>f1

ocli~ q
ad~

inc,

,.
tlllcnded

fptll1~;\C 01".1 u~,

leml u..c:,
I ing lhe v
~

Clomdinc hydrochloride oct.<; by both ptriphcrnl nnd cennI meclwlisl1ls in the body to affect blood prn;sure, [15IimIIblC'!. tilt periP.'K1 aJ o-adrenc:rgic rec:c:pcocs to produce VISOtunSlOction, resulting in a brief period of hypentn~ion. CIonidillC' hydrochloride acts e<:ntr.dly to inhibit the 5ympa!betic tone and cause hypolcnsioo that is of much Iongcr ..-.cion than the ini tial hypc:nen,(jve effect, Admll1istl'lll ion ol t/omdine hydrochloride thu~ produces u bipho$ie change ill bJQod pressIlfC', beginning ..... ith a brief h)'l)('ntllS;vt effect - ' folJov.'ed by a hypolcnshc effect that pc:rsi'ils for about 4 1Iwrs, TIlIl; blphasic response is altcred by dose only: Larger ibIes prodllCC a greater hypenensivc effect and dl.'luy the _ of the hyptXensi-'C' propc:nic' of the drug. ClOIIidioc: ~dlochloridc: aclSon O~ adfC'noreccpcocs located in the hindlnan to producc il~ hypotensivc action. Clonidine h)'dro-~ also acts cC'ntrlllly to cause bradycardia and to reU:t plasma levels of renin. Scnsiti:cation of barorc:ccplor 1'Ih"'1y~ In lhe CNS appears 10 he responsible fO( lhe brady..wll transm iued by way of the \':tgus flCnoC. The ccntr:J.1 .mwusm that results In dc:crc:ased plasnu renin i~ 1lOI ....11. l!o'Ac,a. The: hypotensivc propcnies of clonldine ""mals can be bloctcd by applying a-adrenc:rgic blocking IJftIb directly to the brain,'" Cionidinc: hydl'lXhlonde has ad~antagn over antihYP'C'rtI!oIl'e drugs suc h as guanclhidi ne l11()I"IOSulfllte lind prnlosin iyOrochloride. in that it seldom produces onhostatic hypotIIIIve ~dc: effC'Cllli, II does, l'Kn>cva. 1I1IIC' some sc:dati\C' ~ that afC' undc:sll'llble; it al\O may cause conSl1paiIII1l~d drync:ss uf the l1Iouth, Oonidme hydrochloride is distribu ted throughout the kd)o. ""ith the highest concentnllions found in the organs .dimmatlon: kidney, gUl, and li\'er. Bram t'Ol1Cl:nll'lllion< low but higher than plnsmll c(llll:cntl'lltions. 100 high IIIILtliUlllK)II in the gut is due: to an c:ntcrohc:palic ('y(' Jc in .... donidinc: hydrochlonde is secreted into the bilC' in . . . hIgh concentrati ons, The halfllfe in humans is aboul II hours. Clonidll1C' hydrochloride: is metabolized by the Iiod) 10 fann two major metabohtes. p-h)'drox)cJon,dinc: alll$ glucuronide:. p H ydro~yclonidine doe1I not cms.~ the Iiood -brai n barricr and h.as no hypotensivc cffect in hu0

~-C-~-N=Ct1~

II

Guanfacine Hydrochloride. Guanf;)Clne hydrochloride, N (mni noi mi nomet hy 1)2 ,6-<1 ich lorobi.' nl.e neacet II m ide:
(Tenc:x). I~ Mructurnlly related to cJonidine hydrochlondc and guanahenz DCelnle and r-hal'e$ many or the,r pharm:Icological propc:n ics, 11Ic drug ha.~ a 100lger dUl'lltioo of aclion than either clooidine hydrochloride: or gunnahenl acctate, It 1a.s\S up to 24 houlS. It also requires mIlCh longa (8 to 12 hours) for a peak cffect to occur aftcr the drug is admln,sIcred.

II II HoH-C-~-C-~-~~
~

o
VASODILATOI\Y DRUGS ACTING ON SMOOTH MUSCLE

.....11. II

kit hllnll'

"..,.

C>=: " " .. """"'"

"

~
0

II

Redueuon of ancnal smooIh muscle tone may occur by l1Ial1y mechan Isms. suc h as reduction in sympa thetic tOllf.'. Mlmulation of ,B-adrenaglC re(epc~ or el'cn direct action on the v~lalun: without Interfcrence from the llUlonomic inn.crvlltion , DruIlS llCling on the ancriolar ~n1OO4h mu.;cle also increase sympathetic ren('.l activIty. cauSinll an increase in hean rote and canhac outPUI and sumulaung renin release. .... hich increases sodium retenlJOO and pJ:tsma volume. As a result. ;1 is tOlUmOll to (oOOl1Ii nister 'laJurctics and ,B-adrcnergic blocking drugs with these ~eIIIS, Anlihypenensil'C' agents lhat prod.X'e l'asodilatWII of snlOOth nlu~cle can be: div ided into two categorics: direct lIe!ing and indirect-acting vasodilatOl'l, Indirect-acting V!lSOdllolocs may be: distingUIshed from direct-actI ng vasodlla101'.1. in that they produce: the,r cffecl by illlerfenng with the: vasoconstri ctor slimuli and Iheir primary Mtc of action is IlOl ",-,ssarily the vascular smooth muscJc: itxlf. Indirect-actIng ,'asodiloIOB inclutle ~ympatholytic drugs. snch u reserpine; a-OOrel1('rgic antagonisls, such as pl'll7.osin hydrochloride: ACE inhiblton;and angkltcnsin II receptor antagonists. such as sar.dy~i n. Direclacting va.~ilatON IIIclude: hydralazine hydJ"Ul.'hloride. o;OOlum nitroprusside. poca'lSlum chann.el openers. and calcium chanllcl-blocking agelll<. W Hydrallll.ine hydrochloride, l - hydrn~inophthal31in.e mooohydrochloride (Aprc:soline hydrochloride). onginaled from the wor~ of I 1'0 . C KlIlIS!0 aucmptml to prod ucc: some: unusual chemIcal

Hydr..liJzine Hydrochloride. U5P.

Guanabenl acetlltc. [(2,6-dichloro.yllllene)aminolguanidinc monoacelalc (Wytcnsin ). is ayadt'tnergic qonist thaI red~ the release of

NH
N 0
NHNHC-CHa

II

G!., '" ,...",

NHNH

y-O
CH,
Figure 19-2 1 Metaboll9Tl of hyd,alazIIIII! h)'drodllonde

compounds !UId from the obscTvalion~1 that Ihls compound

had amihypencl\SI\c proper1irs. II OCCUB as yellow crystals

and ;~ soluble In water to the ellent of about 3%. A 2'1> aqueous solul;oo has a pl'l o f 3.5 10 4.5. lIydrulU7ine liydroch loridc is u~ful in lhe treatment of

,oodcrnIC-!n-!Oe\crt: hypertension. II j,often used in l"OOjuOC '

lioo with le'rS polen! lntihyJl("f1ensivc agclIls because side effects occur f!'l:qucntly .. hen it is used ~Iooc in adequ;lIe dc:Jsa. In oombnlalions. ;1 can be u.sed In lower and sara dose<.. lIS action appears 10 be ~-enlered on the smooth mllscle of the vascullll" ....'alls. wilh a ~;l~ penpheral ~islancc

HydralmAC' hydrochlondc i~ more effectin: dlnal!' when roadministered wilh drug5 thai anlagoni;a IIdriUkip lrunsmission (e.g., ,B-adn:ncrgie antagonists. ~rpllll', ... t"lClhldlJ\e rTIOIlOSulfatc . mClhyldosra. and clooidlne h)QI' chloride). When given wi th diurel ic~, it is u.'Iot fu I in till' trdI ,nenl of CHF. SodIum mtroplLl sodium ntlroferricyanide, disodium ptnlacyanorullO$)1Ia ratc(2j Na:IFe(CN),NO) (/'lIpide. /'Iuropress), 's ontoi' mosl potent blood prcs5ure- lo .... ering drugs. It$ u;oe II Ii 10 hypcntnsive emergtnd",~ becau~ of its shon ""';;; of IIClion. The effa:ti\"cncss of sodium nitropruSSIde "'. anlillypencnsive has ~n known since 1928. blllllOl 1955 was its tflicllCY as a drug Clitablished...., The 1Irut. fcrs from OIher vasodilalon;, in that vasodila11on Ql'N\ both \'enous and llJ1erial vascularbcds. Sodium mt is a redd,sh-brown water-5Qluble '7,~;,:~::' by hgbl when in solution. 11Ie I lhe heading. 'i cG MP. Sodium i i tit yielding thiocyanate. kidneys, patico;nls wilh impaired rennl function may I hlOCy~nalC IQlI.icity.

Sodium Nitroprusside. VSP.

10 blood now. TIlls ~ llS in increased blood now through lhe peripheral blood \e~sels. Jt also has the uni'lue pm!,!,"),
of iocTCasi ng rellD I blood flow. all important cousidi:rulion in p;uicnl~ wilh I"Cllal insumcieocy. Hydralaline hydrochkHide acts Oil vlIscular smooth mus cle 10 cause relualion. lIS mechanism of melion is unclear. II interferes .... lIh Cal. emty aoo Ca~' releast: from in~l loIar ~tores and rcponedly causes !ICIivahOO of guan)-Iate cyclase, !'elIulling in incn:ased levels of cGMf>. All of I~ bIOChemic:!.! events can cause vasodi lalioo. Ab'\Ol"fHion of hydrnlllZinc hydrochlondc Inkcn urnlly b rnpid Md ncurly complete. 1llc maximal hypotensive effeel is dcmon~trnble within I hour. The drug is cxcrcled rupidly by lhe I.idncys. and wi lhin 24 hours. 15% oflhe loud amount adminiSicred appcal1i in lhe unne as metabolites or un ehMged drog. lIydrnlazinc hydrochloodc undergoes benlylie oxidation. glucuronide fOf'Tl1.:luOIl. lmd /'Iacetylation b} the microsomal enzymes III lhe lissPe5 (Fig. 1921). Acet_ ylation appc:1l1i 10 be a major dctermmant of the ....lIe of hepalie remol'1ll of the drug from the blood ~od, lherefore. of systemic availabllity .1Jl Rapid llCelyllllioo results in a highly hep;ltic ex traction ratio from blood lind gremer (ir.;I-paSS elimination. lUI.,

II'

Snell"" Nj~ .......'LC.

PI...... )
POTASSIUM CHANNEL AGONtSTS
agents that CUll be' classified in thIS dlll7-Dxide and minoll.id,1. 'These drllgs are al~ Jiu", dUJIlfld OfMrlur. TIlCSe agenls !ICIivalt potaSSium ChallOtls, ..... hlCh leads 10 a decrease lar Cal' and reduces the tlI.CIUlb,lity of slOOOlh pnmDl")' IICtion o f lhest. drul!lllS 1 in the plpsma memtrrune of I emux of potassium from the cell I polari7.1l1ion of the memtrrune. which produces

(~.,

"The:

IWO

H~do

....,.

(....

- ..I

"~.on

membrane exCitation and wbsjuc:nt 'as(xhla-

..

the so(hu m salt 7~1()fQ-3-mc!h) 1-2H- I .2.4-ben.t()(h;:xli:17jnc 1.1-dlOlIilelilY)ll'l"t;1( IV ). DUl7.oxide lowers peripheral vascular reIk't. increascs cantioc output, and docs /lOt compromir.e .II1II blood now. 1'IIi\ is D des-su Ifamo)1 analogue of Ille benmt hial.ine di .niN and h.1S Dclose structural ~ i milar;!), to chlomlhiuide . hZ\' dc,eloped rntcntionally !O incn:asc the anll hyptncnI1f action of the thill7.i(\CS and to mmimil.e the diure:tic cf~ is u~ by intrll'cnous injection as a rapidly octing anti-

IlMloxm, USP.

Diazollide is used

a~

o N.1~NH
I

'

o
MroxdI s.Mille

o
Mf"IO>J(III

Figure 19- 22 Actl'latJOn of mlooxid,1 is u>ed for severe hypencnsion tllllt is d,fficult to cOlltrOl ... ,,11 other anllhypencn'''e agents.. 'The drug ~s 'iOniC of lhe CharllClcriSlic side cffecUi of dirc:ct \ a.~ilalor) drugs. It cau ...... ~ium and ..aler rc:tenlion and may reqUIre: coadmlnislratlon of a dlurt'uc. Mlno~id,1 also cau't'S ~nc~ tDChyurdia. "'h,,,,h can be controlled by usc of. P.1KIrencrgic blocking agent. MillOxidil topica l )(llution is used 10 treat alopecia n,idrogenilica (male pUllcrn bal dncs'). Allhough tbe mcchani~m is nOl clearl y undcriwod. lopieal miooxidll i~ believed I() ;nC1\'a~ CUl af)('Q(lS blood now. v.-hicb may ~tilllu1ale hair growth. The '" 1II0I:llioo of hair growth IS allnbuled 10 VD-'iUdilation in the ~ idnity or applicallon of lhe drug . re:~u hinll in beller nouri~hmcnl of the lornl hair follide\.
Mino~ldjl

nical ly mergk: c. gua. hydroc treat

rc:ductlOl1 of blood presacn'lcrJted or maJignDl1t to serum protem, and cau~ iIr nccdcd .. hen it is used in l-onjUncUon with other :"'.'''''' drugs that may be displocc:d by dl3.1.ollide. U1jtchon is given rapidly by the tntra,cnoos roule to .;.~ maximal effect. 'The Inirinl dose i ~ u~unlly I mgllg body weight. " 'ilh a second dose gi vcn if the fi 1St injection not lower blood pressure s.:.li~r:N,:t{)[ily within 30 minFur1hc:r dosc~ may be given at 4. to 24-hour inlelVal s Imkd. Orol anllhypenensi, e therapy is begun as <;()OO as
ptnensi'- agcnt c In hosl"taliled
.~

ssiJc.

) Ifer _ of the imlted jill'lltiOll

~~

Thr InJtion has a pH of nboot 11 .5. '" hicll is necessary ttII,m the: drug 10 its soluble Mldium "lilt. 'Thc~ is 110
fQ/lt dl('mical decQmposilJon aflcr MOr.I.ge al room ure for 2 y..ars. \Vll('n the: solution is C.\posed 10 II darl.cn.~ .

..

01 urml

fU"

rag di l rn

"',""'," "' r
of the j"el\
Ii ~er.

j'"i'\'Jc

or

......
'I0Il

MII'lO.k;h1

(Lorlnni

~t)< ...- )

POSITIVE INOTROPIC AGENTS

b, "'"
~u[fC1

Minoxidil. 2.4-dlamlno.. 6-pipendlllOI[)('oJ-OXide (Loniten). wa.~ de\c lopcd a.~ a rt'sult of ~Iaccmcnt of a uiamlnOlri:wne mo,ely by triamiTImldlne. The triaminotnuine< were inillally observed Ie polen! \liSOdiiators in eat~ and dog,~ following their of N"oxlI.lc~ in lhe:se animals. The tnu,nes ......... :tMin humans because ofthc:ir inability to foon N-oxide ll:llllnllte~: this led to the di<;C(lvery of mirooxidi I. M inoxidil *: only direct acti ng va,.ooillitor Ihat I\.'iluirc~ Inctabo li", C!J\;d1OO to produce its ant ihypenen~iYc effect (Fig. 19It II cOlwened to minoxidil s!.Matc in the liver by a
",,"fe!"ll.~ Cnl.ynlC ....

1""' =

it porcu

Thr anuhY)ll'nensi,'c propenies of mi!lOlIld;1 are si milJ./"

~ru,i u~e lracc llu. cle. 'The

!b:mntl~

;;;;~of h)dr.llazlne hydrochlondc . mthal mlnoxidll ean .

a1ItnO!ar V3..'iCular I"rl\ISlmlCC. Mlnoll.idll C.\C~ il~

An II hy per lhi tO!")

Fie.

lC1ioo by a du'ttt cffcct on anenolar sm.ooth 10 hoIvc no cffcct on the CNS or on the lIC'Oous system In animals.'" The serum balf-1Ifc and the antihypeneUS1\e effect nlll)' laSl up 10

=.

Agen ts lhar succes..~fully increase the: fon:c of OOlltractlOlI of the hcan may be pan,cularly useful in the treatment ofCII F. In CHF. the hcan cannot maintain suffICient blood flow to various orgarn: to pro\.k\e oxygenrich blood Agcnts that increase: the: force of contlOClion allow gre:DlCI'" amounl5 of blood 10 be distributed throoghoul the bod) and. In tum . reduce the sy ntptolll.'l usweiak'd wi th C H F. Most of the posi. live inouopic al!ent ~ c..\hibll their effects on the foro:: of c{)IlImction by modifying the coupling ul('(:h3nisrn Involved in the mYllcurdi:11 cornr:tClile pmccss. Digitali~ gl)'CO!.idc~, a mixtu~ of prodocts io;olined from fo~glo\"c. Dillllll/I.! spp._ ..ere: tim used as II hcan medlCallOll as early as ISOO If{" \\hen in the E~r$ Pupy ....$ the ancienl Egypttans rt'porIcd their ~UCttSS in usi ng these products. Throughout hl'>lory tllese pl3nt cxtracts ha'e also been used as arrow poi'lOlls. cnlCtM:5 . and dillne\)e,. 1lw: dlChotlllTly of lhe po'SOnouS e ffcc\) and lhe beneficial hean propenieJ i~ slI ll evident tooay. Cardnoc glycosides are Silll used today in the tre:attnl:nt ofC II!'" and atnal fibrillDl'on . ... ,Ib care: ful allentlon p;lid to mOllllonng the to~jeily ~ agents po!>--

carl.lenol idcs arid Inc bufadil'nolidcs. These differ In tIM: substitutions at the C- 17 posi tion. where tile cDn.lcr>Olides pot;sess WI unsutur.lled butyrulllCtolll: ring. ..... hile the buflld ienolidcs ha,'e an n-pyrooc ring. Phamlocologirnlly. boIh have ~imilar proprn ies and are found In many oflhe ume natuml SOtm:cs. Including pllUlt and lOad species. By far. the mOSI Imponam source.~ include 1 >i,illJlis purpuuu arid D. hilUm In 1785. William Withering published . An Account of 11M: Fo~glo"e and ItS Moolcal USC's: With Prnctical Rl'mar\~ on Dropsy and Other Disea5e!i.' in which he describes the bencficial use of fO~lllove in dropsy (edI!'ma). which oOcn clIists in C HF. Even with n:cem advances in synthetic orgnme chcmimy coupled with the usc of rombinntorial chemistry. no new therapeutics have di~pl!K:ed the cardiac glycoside's. Funhcr1TIOfe, the perennial U~ of these agents o"er mlUlY centuries is c,'en more remarluablt' " 'hen one WIIsiders the useful life of a ""block buster"" drug In tOOaY's markctplllCl'. This remarkable fact I~ ba.o;cd. qui te simply. on the unique: ability of nature to produce elltraortli narily b,oactive substances. which chatllCteristically possess boIh a lipophi lic ponion;n too steroidal ring nnd a hydrophilic moiety in the glycO$idic ri ngs. Thc thempeutic u~ of these agents depends largely on a balance between the different solubility chanlCtcristicl. o f !he ~teroid AfUClure. and the type and number of sugar unilSattached to II. Although the fundamental pharmacological proflt'noe$ reside with the Ac:roidai nucle.a. the sugars play 11 crillcal role In !he bioloeical dfe<,:ts elicited. since they iocrea.~ the ...... Ier solubility of thl' liPId 5y~tcm. making them mon: o"nilablc for tmnslocation in WI aqueous en\"ironment and. lit Ihe &IInle time. all owing tr.lnsportat ion across fauy sues, These propen ics unique ly ba lbnce each OIher and al low successful trunslocation 10 the recept i\"c sites in .he body. UhimDIc:ly. the lipophi lic Slc:roid al ~ plays a specific role in the ligen'" onSCt and duration of lICtion. As !he sieroi. daI rings are modirled with polar groups (e.g .. hyw"OlIyls). the onsc:t IOCrcasc..~ aOO the duration ofllCtion decreases The Mlgat residucs are ~ul:ritituted on C-3 of the steroid and genemily are digitoxose. glucose. rhamnose. or cymarose. The cardioc glycoside,~ elici t lheir cffl.'Cls through inhibi tion of the Nu '/K 'A TPase pu mp. Inhibit ion of Ihi~ pump increases the inlfUCellu lar Na + ooncentratioo. which nffects No '/Ca!' ClIChangC. This iocrea.~s intracellular concentn tions of Cal- . ..... hich is available to acth'D1C the contractile: proteins actin and myosin. thereby enhancing !he force of rontraction. A lso.;t is suggested lhatlhese ageniS ha,'c other compcn!illtOl')' mechanisms includllti baroreceptor sensitivity. which TCSult III impro,'ed conditions for patienls suffering from C H F.
rompourld~-t he

The Cardl X glyco;;ides ioclude two dlstioct classes of

the chief acli\"c glycoside In digltali ~ Leaf. ""lIh I ml dip to~in equulto I g of digitalis leaf therapy. In paucnn wfIo m's~ dosc~. digitali ~ i~ \ery u",ful for nmirnenarn:c thtllllJ") bec:tu ~ of the: longer half-li fe It pro,' ides. The looger dtil"llion and increased half-life ore dl.le to the lack of the Cll hydrullY that is present III digo~ i n . In digo,in. thi ~ h}drol} plays t.. o roIe!i: (u} ii <;e,....~ as a ~ite for metabolism. '111lod1 reducc:s the compoooo's half-li fe: and (b) it gi'c.~ II"ICn 11). drophihc charnclCr. .. hoch resull~ III greater water 5OIubW!) and ease III renal elimlllauoo .

OIgRa11a
(CryslOdiglo oj

O;go)lin. Digollin (Lano~in) is II purified digita lis preparation from DigiwliJ lanaul and re~nlS the most widely u.o;i'd digitalis glycoside. This "'dde use is primarily due to its fast onset and :;bon half-lifc. PosItion 3 of the Aeroid is lubsllluted wi lh three digito~osc: residues tM . ..... hen remmed. provide a genin or aglycone steroid that is still capablt' of receptor binding but ..... ilh altered ImllTmllCOkiIII:tics. Digitalis. Digitillis (Crystodigin) is isoluted from 0./11mIll/ and /J. pu~lUua, among Oilier DilliwliJ spp .. and is

m:~~. ... : ~~".", ;""~;ri~":~.;"~ormal hean I I ..

function,

1I"'';''k~i.

<'''haptff I' Cmiim'fU<1Uar "'~NJ dl!Udl. Thm i,. ccnllin calcium channels und slorage Silc~ fOf" rncium must be: activmed by eA MP-dc:p;:ndant protein ki~. SUK'e cAMP plays an indim:1 role in the contractility JII""'S!>. ascnts tMlmhibu Il5l1egroidation will proVide more alcium for clll'diac contraction. One: phosphodiesterase e nl)1lIC tllat is invol"ed in the hydrolysis of lI1yocarolum tAMP IS F-III. Amrinonc . .'i-amino {3.4'-dipyridin}-6 J(H}l1li: (InocOf"). posses.~ po!oiti\'e isocropic effects as a mull If it, abilil) to inhlbitthl~ ~phodl~lcrose. In 1999. the t: S. Phnrm3OOpOCil (USP) Nomen(lOltull'; Committee and ~ United SUIII$ Adopted Names (USAN) Council lipp!QI'cd chunging the nonproprietary nHllle and the CUlTt'nt offICial l1"101'1ograph litie of amrinonc 10 inamrinonc . This dtlnSC in nomencJalUll'; was a mull of amrinone be:ing coolisa! lI>'jth IImiod3l'OllC because of the slmi lanl y of the l1li1($. This was IqiOl,ed 10 cause C()I1fusion between the ~I~ thai led 10 medication error;. some of II>hieh reo IUliaI in serious injury or dealh.
1111

657

"lin

II:mp~

durolC-12

dro~y

""hl(.;h

'1:

11),-

Jbility

underlying disease involving the li ~er. kidney. jXlllCll';:I.S. or IhYll)id. or il may IlOI be anributllble to any recosmzable dio;easc:. In recent year.!. lipids ha,e been imphcatlln the de\'eloprnen\ of atherosclerosil 111 hullUlRS. At~fOI(;lt'tmis may be defined as degcllCra\ ....e change. in lhe II1tima of uM:dlum and large pneries. This degeneration Inelulle, the accumulation of lipids. complu carbohydrates. blond. and blood prodllCts and is accompanied by lhe formation of fibrous tissue and calc ium deposItion on lhe inl1m11 of the blood vessels. 11!ese deposits Of"/lllIqUt'S db; I ease the lumen of the artery. reduce its elasticity. lind may I:ll';ale foci for Ih romb; and subsequent occlusion of the blood vessel.

Lip'pr"Oteln Clasns
LiP('f'rrlftiru ate mllCll)molecule~ consisting of IiII'd subst3m:es (I:holcstcrol. lriglyceridc~) IIOncovalcntly bound " 'jlh protein IIIld carbohydrate. These combinations solubi h/.t the lipids and prevent lhem from forming insoluble aggreglltes in the plasma. They h:lve II, 'pherical ~pe and con~I,~1 of a 00111'01 .... core sUll'UUndcd by a monolayer of phosphohpids whose polar groups IU'e oriented toward the lipid phase of Ihe plu'ma. Included in the phospholipid rl1OllOlayer lire a small number of ch.ole.~terol molecules and proteins tenned "(1QllpoprOl",i1lS. The apolipoproceinsappear to be: IIble 10 solubilize lipid~ for InIn'\pOf1 111 an aqueous ~ulTOllnding such as plumll (Fig . 19-23). The VllriOUS hpoprotei ns foond in plasma can be: separated by ultracemrifugal tethllique~ inlo chy lonlicrons. vcry-lowlIen);ly lipoprotein (V LOL). intcrmcdiate-dcnsity lipoprolein (IOL). Iowden.~ity lipoprotell1 (LOL). and hlgh-dc:nsity lipoprotein (HOL). The.se correlale with the clcclrophomic seplll"diions of the lipoproteins as follows: ehylonllcrons. Pll';,8-lip0pr04c in (V1.DL). broad ,8-lIpuprotein (l OL). ,8-lipoprotein (LOL). and a-lipoprotcin ( IlJ)L). Chylomicrons contain 9()% triglyccrides hy lI>el&ht and on,inate from u:ogel1Ol.ls fat from lIIe diet. They are the least dense of tile lipoprotems and mlgr.uc!he lea.\! underlhe

Ammon.
(11lOOOI')

Milrinonc. 1.6-dlhydn>-2-metllyl6-0"ol.HlIpyridine-5..:arbonilnle (Pnmaoor). I~ :tnoIher dipyri6ne f'hmphodieslerase F-lII inhibitor Ihm possessc~ phar..cologiclIl prope"ie~ similar 10 Ihll'\t: of amrinone. The IlbiblllO!'l of the dcgrudation of eA M I' resu lts in un iocll';ase !lie cardiac muscle' s ()(Ce of conlraction.

MiWnone.

"'ilmona
(Primecorl

AHTIHYPERLIPIDEMIC AGENTS
CIIUSC of death in the Western workl loday is dlsc:llle. of which the most pn:\1Iknl form is mhen>...ID"_oo.hean disc:llle. Although many clIuS3th'e fllClOl"5 of . diltase 11ft: rerognl led (e.g . smoking. s\rcss. diet). alhdiscllsc CUll be treliled through medicalion or

..
\IJ> (X'f' iunl lc~-

hean diSC"''''; il is a tC!l1ll used to ::~:',~IcVlled plasma le\'el$ of lipIds Ihat all'; usually in lipoproteins. l-typerl ipidcmill may be Cllused by

H~~~,~:~~:,~,~":,,;most jl(e\'aknt lndicalor for 5U~ep

Figure 19- 23 HypothetICal mode-I col lipoprotein partICle.

Innuence of IIJ1 eleclric currem, Ch), lo,nicron) ~re normally abolenl in pla..~'TUI ancr 12 10 24 hour<; of (as""g. '!11c VLDL II composed of abool 6(n, tnglycmdcs. 12% chokslerol. and lSr,t phospllolrpid~, II OI'Iginates III !he Ihcr from FFAs. Ahhough VU)L can be isolated from plasma. It is cataoo. "I.ed rapidly into IOL which i~ degraded funher 11110 LOL, Normally. 101. also is eatabi)lil.ed rapidly to U )L but il I( usually not lsolalCd from plann. The LOL conSiSI~ of 5O'lt cholesterol and I~ triglycendl.'s. This is the majOr e~ teroI-cafT)'ing protern. In normal persons. lhl$ hpoprotein accounts for about 6S% of IIIe plasma chole.'lerol and is of mlljor conccrn in hyperlipidcnuc disease Slll,e$. The I.I)L is formed frolll lhe inlrnascular caloboli~m of VLOL. The II OL IS cOl11jl1Md of 25~ chole~lcroI and SO'iI- protein and IICCOUnlS for about 17'10 of the ,otaL chole~lerol In plasma

o FIN)' F8\

+\oIe$I"," + ....o .. -".'~,-"'~":"'- ""'~I. Olo,loo,

ExoiI'_ P.thwIW

....... -VlOl..

~ ni'-LD.~-"
................

Co.:..J

.,............

[0

,~,

Upoproteln Metabolism The nne at .... hlCh cholestcrol and

uiglyccridc~ cnler lhe cir-

f igure 19-24 E~~ and endogenous pathway! d pClpfOle.n metabolrsm_

"--- ...

culation from lhe Ih'cr and small mtestlllC depends on the supply of the lipid and protcin~ ocssary 1 form lhe lrpo0 protein complexes. Ahhough thc protein component mUSI be synthe~iled. the lipids clln be oblai rl(:d ei,hcr from de 00"0 biosymhcsi, in 100 ti <.~ucs or from 11k: diel. RcductlOl1 ofplasma lipids by dici can delay Ihedc:~lopment of at hero$Clcro.!is. Funhcrmon:.lhe u);(' of drul!S t~1 dccrt'a!oC assimi_ lation of lipids imo the body plus dlct deo:R.-aSCS monalilY from cantiovus.cular di);('lIse .... Lipid u;m,[lOI1 mochuni,ms eXI,! th:u , hull Ie chole!ilerol and lrigl yccridcs IUOOnglhe lher. mlestillC, and OIlier tissue,. Normally, pl~~ma lipid~, including lipoprolein CholCSlCrol, ate cycled into) and OUI of pla,rna Ind do no! cau..c cXlen~i~ llCCumulalion of deposits in the wal1~ of nt1ene~. Genelit f;ICI{)nI; and chonge~ in hormone levels :lffecl lipid lrons[lOl1 by altering t'ni)'nlt ooncentnllion and apoprotein oonlem, as ....ell as lhe number and oc!i~ily of lipopro!ctn reccplon, ThIs eomplcx relalionshlp nla1:~ the: lrellment of all hyperli . poproIdllCllll3S by a singular approach diffICUlt, if II()I 'm_ proctical. Lipids an: Ir.msportcd by both t.~<Jgen()l1$1Ulll t'ltl/ollenouJ p<lthway~, In the c~ogenous p<llb"'ay, dietary fat (Iriglycer' ~ and chole5tcroL) is illCOl'JlOl1ltcd into large lipoprotelll \Xlrtlcl~ (ch} lonut'TOlls). which cnler the lymphatIC system and arc then p;&\sed into the pI!l.~ma, TIle chylomicrons are IICled on by lipoprotein lipa.1'!: in tile adipoo;e ti\suc capillarics, forming trigly~'t'ridc:!. and nlOnoglyccride~, The FFAs cross lhe cndothelial membrnnc of the (':lI)llIary and an:' 111.. oorporulcd Imo InSlyccndes '" the IlSSUC fOf" stor gc as f:Ll Of are u.~ for Cllerg) by oxid311\'e nlC1abolls m. TIle chylomICron n:'f""3JlI rn the cap\llul) n:achc.s the liver and is cleared frolll the cil'l:ululion by bi ndinll to:l I'CCcplor thm recognizes the apoprolcin E lind 8-48 protein comrollenlS of lhe chylomicron remnant . In the cndogellO\lS palh ....ay of Lipid Iron pon, lipids arc sc(;R.-led from the: Ii,'cr, llle;;.c ~ uiglyccride~ and chole~, terol combined .... IIh apopTOlein B-100 and apoprolein E hi form VLDL. The VLDL i~ acto:<! OIl by lipoprotein lip<l;;.c in the cupIllme, of adipose lissue 10 gcnerote FFAs and Dn JDL. Some 101. b",d .. to LDI. receplOr'S in the It,'er and is clc:1l'ed from plasma by endocytosis, ApproXlllliltcly ~Jf of the cIR.-ul:uinll 101. is convencd to COL in the plasma by addi tion;,l loss of triglyccrides. Thi s LI)L has II half life in

plusrna of nbout l oS day~ und repR.-scnh 60 10 7~ dmr cholestcrol in pla'rrlOI. The'\(' LDL. pankles bind to ux. reccplOf'$ in c.\lrahep<lt ic li~sues and 1111: remo>cd frortt plasma, I.e> els of LDL reccplOl'S > 'ary dependmg on thr of c~tr.thepa'ic ti,sl.K':S to b,nd LDL to II~ ~'holeslerol, nr extrahepatic lI~ue sutr...'<jucntly n:lcasc~ tlDL. eholeqcrol loan be adsorbed onto HOL IIml the c C1>tcrs formcd b) the en/,),OIe lecithin-cholcsterol fcra;;.c (LCAT), llIesc C'.teN l\R: lJ"~nsfcrred from HIl. VLOL or LOL m plasma 10 completc the c}ck. lbr: .... ays for plasma lipoprolctn OICiabohsm by Ihc.~"'~ and endogenou .. Iutcs are Sho .... n in Figure 19-24

fltt:;:

tfypet'llpoprotelnl:::oI_

are,::;:~:~j~:!;~~;~ hypcrlipoprotciocmias ha\c been I'

0li~mb7 thm CR.-ale Lipid d,SOf'dcN

"::::
(~

ellCh of .... hich i~ trealc:d differently (fable 19-6), The abnormal lipoprotern "",Item characteristic is call5Cd decrea~ in the acu~ilY of I in the pla,ma . Bccause the Iriglyceridcs found

conlt pr1n1.ui ly from c\ogenous 'iOU"~~~~~.:~:i poprott'inemia may be tn'aled by , dlctary fal . There are 110 drugs al pn'~n' 10 counteract type I hyperlipidcnua Type II hypt'rlipoprotcincmia has IJe(:n lIa and JI b, T ype Ila i~ chal'aCterilcd by dC"IIIa! LOL (P.lipoprotcrll$) and normal lC\cls of This subtype dIsorder is ,'ery common and hy disturbed catabolism of LOL. Type I lI a. in thai this hyperl ipiOcmlu has elevated additioo to LDL le .. el ~. Type II II oftcn clearly familial and frequcnl1y nul domilWlt IIbnornulity '" IIh complete upres.\ ion in IOfancy , PallCnts h,c been dictary I'CStriCllonS on cholc\terol and o;:J!urola! type of hypcrl ipopmccinernin re.\ponds 1 SOllIe 0

....

...,

TABLE 19-6

Characterization of Hyperl ipoprotel nemia Types

Abnr.o .... ,ity

ItJp.rllpoprot.I ...... I.

EllKboph_I,
M..... -e fb~I""""""",,mla

Uttr_t.lfuge
Clear. ' ....111) I., ... of

Appea'''nc.
of

P'"sm.-

foUIi
TtI"lyatldel Chol..terol

M"''''d) elc'1I1Ni

Sbrllll), W rno.lrfakl}

.''""
" ,

~upopnllo<IIII.~ Pn:-~ 1 ,,,,,,., I: 1111 eie>'1ItId

<hy ............... "" lOp LOt. .....".cd U)l." VU>l. """a,d VIJ)UU)l. "" ."'M>nI"Iai
VLOI. inrft'......t

DnlIId 1\-11,......"'..;n """"

..... -r.h,.'.(1jeln' ek> ~

'\II"""" 1110",

""' ,..., ,...,

~1o~1uI) . -

.......
~I'"

.It,*,,<!

SI,pl, d",..nI

Hero. Ilr don_ ltel. ,,)' e"""",,

~J ...1<>d

Sl.,rotly lurbld I<.l

o.:."Ni

1'fe.1I-l'P"I."'" dc, Md. my k 01"'''''. """',

\lUlL, ... , , .J. <~,~ """""m ...

...

Torbod.. 011 ~ rh,lton\;""",, ""p,1o

".".<it dc,..-<I

",,'" .....,,', "'""" ~-

SiI~c"".d

. ......

:;If 10-

MtpI6l from '" C I....". Mm. Ow:m, I I: 199. 197$. ''''''''-110.'1''1 bcon ""'" OIUoJ'''I 01 ~ C r", 2j _

""'.I!..

r ,""

LDL

"""

,,""

11>< ),ma le wl

run~

'L 10 path

-,

dlC'll1OIncrupy. The ~"OI1lbincd therapy may bnng LDL le,el. bao:k 10 normal. Type III is a rMC di'lOl\ler charocll"filed by 3 brood baml rI. P.hpoprotein. Li"e type II. it is al 'l(l familial. Pallents ~ falombly to diet alld drug tncrJpy. In type IV hypcrhpoproteillCmia. Ie,el~ of VLDL au ele",ltd. Because this type orl ipoprotcln IS rich In triglycerides. pI~m~ triglyceride level s!1fe eleva lOO. ' 1111' I11ct;,bolic defect Ib:it cau~s type IV is ~ti II unl.oown: Ihi~ form of hypcrlipld rmia. howe~~. ~~ to die! and drug therapy. Tn~ V byperiipopmteirocmia has bigh levels or chy lomien;Jft$ and VLDL. m;ull,ng In high leve!\ of plasma trig]ycerih. The biochemical defect oftypc V hypcrlipoprolcincmi~ 11Il0l undcn;lood. ClcarnlK.~ of dietary r~1 i~ impain:<I. :md of dietary fat i ~ indicatedlliong ".ilh drug therapy .

"'100

ype I
"",.

""'"' 'Olein
<~,

perh ke of

"~~
t)'pe~

el' {If
ride~,

.u....'1l
'type
:el\
013

Clofibrate. ethyl 2-(p-cbllll"Opht-n(Dy )-2 nltthy lpropionate (Alromid S). i~ II stable. colorless III pale yellow liq uid wil h II fainl odor alld II characteristic INt. It I~ soluble inorganic sollents but in'<llublc in ".Mer CIol'ibrJte is prepared by II Williamson ~ynt htsi ~. ronbing p-chloropheool ".itb ethyl o-bromoisolx"yrute. or " !hi: interaction of II mmure of IICClOroc. pchlorophc:ool. -' chloroform in 100 pn:>;cllCe of eJ(ce,~ poIus~lum hydrox de. The acid obtained by cilher of thc.'>C methods is e'teri fled II &i"c clofibrate. Both acid ami ester au ItCtilc: the laller. kIIocver ... prefem:tl for medicinal uo;e . Clofibr.lle IS h) <lroIptd rapidly 10 2p-chlaropheoo~y-2 1I11.'IhylproptOllle IICid by ~cruses in vivo 300. bound to '<'rum al bum in. clfI::utme.~ 11 blood. The acid ha. been in'elitigaled a, a hypoh pidemic ~ . II i, absorbed more slowl y and 10 a smaller extent ... I~ the eMer. The alluninum sail of lite acid gi\e.~ e\en ~ blood le'e ls lI\;tn p-chloropheno~} 2 mc:th) IproplOllic

CJofibralf!. USP.

Ie\el, by en~ncillg n:rlloval of triglycende<; from thl: ei reuIm,on arid c~usc~ n..ducti,)n ofVLDL by st imulati ng lipopnr Icin lipa.-.e to illCrea!oC lhe calabo/i'lIl of this lipoprotein to LDL.<W Ck.ltibr.lte Io\\'cn; trigl yceride Ie,'d s 111 the o;erum mucb IltOre than cholesterol le,'e1 ~ and decreasc<o Ic~'d . of I:FA~ and phospholipids. The 1000'('nng of cho~terolle\els may re~uh from mo re thun one tllechJni ~m. ClofibnHe in hil>its the incorp.,rulloo or llCetate imo the sy nlhesi< of cholesterol. bt:lwa!n the acc t~le and me\ ~loll3te step. by inhibiting sn-glyccryl-3pItophale acyl tnm1feroL'>C . Oofibrute also regu lates cholc,terui ~ynlhesis '11 tit.t li lcr by Inhlb,tlng microsomal n:tlUClion of 3-hydroxy3 metbylgIUlaryl-CoA (II MG CoAl. cutalyzl"il by HMG-CoA n:tlUCt~. C lofibrulc may lower plasma lipids by n1l.'ans otttCr than impainnl'n1 of choleSlcmI bIosynthesis. \ uch as iocreaslng uCre1iOll through the !>tliary tract. Clofibrute i.\ tOler-lied \\'ell by most pallents: the ntoSl COU1tll0n ) idc effects ore nau-.ea und. to a smaller extent. other gaSlrorntl'stillal dbu"C)s. The UQ ....se of ant icoagu lant. if usctl in conjulICt iOfl \\ollh this drug. shou ld be reducctl by one: th,rd 10 ottc half. depending 00 the iodi\iduIII responsoe. 50 lhal the prothrombIn ti lllC may be "cpt willlin the desired I1nllts.
CH~

Clofibrate (Atromid)

-r-0-C-C-O-~

OH,

!tid."
CIolibl1lle is lhe drug of choice III the treatment of type In hypcrhpoproteinemi as lind may also be use ful , to a Ie,s.:r rumt. In types lib and IV hypcrlipoprotelllcmias. The drug I DOl dfec11l"e In Iypes I ~OO 113. Ool'ibrate can 10". er pllI.)lna COIlCClltratH)nS of botb lritJycendes ami cholesterol. bul;1 has a more consistent e1ini CII effect on trig lyceride ... ]t al'l(l affl:C1s lipoprotein I'la .. n 13

In
I~

~Io<.o

co anti lise of

Th i.

ml of

Gemfibrw:il. 5-(2.5-d imeth)lpheooxy)2.2-dintcth) lpentanOlc acid (Lopid ). ;! a congener of e1ofibr~tc lhat wa.. nsed fiN In the tremment of hypcrhpoprotciocmia in Ibc mid -1970s. Its mechanism ofacuon DOO use an: siulIlnr to those of dofibrale. Gcmfibro1il reduces plll~ma le" d s of VLDL In glycerides and \lImulales clearance of VLDL from pla~l1la. 1ltc drug has lillie effe\., 00 cholesterol pla.ma ieI'd. but docoi cuuse un incn:ase of II DL Gcmfibro/.il i\ uosorhed quidly fmm lhe gilt alld excfI';led

Gemfibrozil.

ullChanged in the urine. The drug hag plasma lull( life of 1.5 hoor'S. btH reductioo of plasma VLDL conccntmtioo takeli between 2 and S days 10 become evident. TIle peak effect of ilS hypolipidemic OClion may lake up to" weeks to beconle manifeM.

"'-

J----O'-

}--,CH,-Cl-l-CXXlM

U!ie of thyroxillC in the treatment of

not ..."hout ~d\'el'l>e eff~l~.

hyperlipi{\('mi~ ~

FenofibriJttll. FenofibrJte.2-[4-{4-chI0l00c:nzoyl)phenoxy!-2-mcth)lpropanoic acid 1'I1lC'\hyleth)1 ester (Tricor), has structural featurn Itpi'"Cs.ented In cloIibfate. The primary difference Involves the second aromaue ring. This imparts a greater lipophilic charncter lhan exiSts In clofibrate. resulting in a much 1lI0re potent hypocholtsterulcmic und triglyc eride-Iowering ugent . Also. this structurnl modification resullS in D lower dose requirement than with clofibrute or geml1brolil.
"" 0 I I / '"' O- C -C-o-CH

The drug increao;es lbe frequency and St,'enty of IlIIg .. tal auxu and may cause can1Jx arrily\hmi:l$. D-Thyroxine poIenliale5 the ocliOfl of anlicoagulanu SId as warfarin or dicumarol : thus. the dosage of the arllicolc. lants used concum:ntly should be reduced by one: thllll_ thoen, If ~. fu"her modified to mailltaill 1M JIIO' thrombin lime wilhin the desired limits. Also. it limy if.,.,. . the dosage requiremellts for in\ulin or oral hypogl)'ttII\lo; ~gcnts if used concum:nt ly with them.

Feno/ibratl
(TrIcor)

""

""

Dtilxtrothyro)(irHt Sodium, USP. DextfOlhyrol ine sadium. 0.( 4-hydroxy-3.5-di iodophcnyl}3.S-dii!JOO.[)-Iy~ sine mooosodium sail hydl1lle. <;Odium ,,.3,3'.5S-telraiodothyronine (Cholox in). occurs lIS 110 hght ycllow to buff powder. It is stable In dry air but discolor!! 00 uposure to light; hence. it <;hoold be stored in lightresistant cootainc:lll. It is very slightly soluble in watcr. slightly soluble in alcohol. and insoluble in acetone, chloroform. ami elher. The hormones IICCreted by the thyroid gland have mllrked hypocholesterolemic IICtivity aloog with their other wellmo"..n actions. The finding that not all active thyroid principles possessed the same degree of physiological action~ led to a sean:h fIT congeners that woold caLl5t a dttlClISe ill Strum cholesterolle,els without other dfeels such lIS angillll pectoris. p.:alpilDlion, tmd congestive failure. D-Thyroxine resulted from this 5t3rch. AI the dosnge re,!uired. howevcr. Lthyroxine cOfllamination must be minimal: otherw ise. it will exert its chnrncteristic actions. One route to optically pure (alleast 99% pure) D-lhyr1Jxine is the use of an L-am ino add oxidase from Jnnke venom. which acts ooly 00 the L isomer and makes separation possible. The mech::r.nism of action of D-thyl'Oxine appears to be stimulation of o,idati,c catabolism of choIC$terol in the liver through 5tirmdalion of7-a-cholesterol hydroxyla.<;e. the ralelimiting el\l.ymc: in the ~'Of1Ver'S1OIl of ciMJIC$tcrol 10 bile acids. The bile acids are conjugated wilh glycine or \.:Iurinc: Dnd c~CTeted by the biliary ruute into the feces. Although thyroxine docs not inhibi t chole~terol biosynthesis. it increases the number of LDL rcctplOl'S. cnhancing removal of WL from plasma.

ChoiestyriJmioe Resin, USP. Cholestyrumine (Cot.I. Qucslnln) is the chklride form of a Strongly basir ..... cxehange resill. It i 110 styrene ropoIyrner ""th di.,.,. ben/.ene wilh quaternary ammonium functional """" After om! ingestion. cholestyTllm,ne resin remains in trointe.~tinal trolCl. where It readily exchangcs chloride iDII for bile acids in the small iml!.(tine, 1o be e~ereted a~ bile QJtr, in the feces. OIole;,tyr~mine rc~in i~ also u'iCful in 10'/1' plllSma lipids. The reduclioo in the amountS of rca bile acid~ l'CSults in increased catabolism of choleMmll. bile kids in the Itva, The decreased eOflCcntrallOil 0( acids relummg to the Ihcr lowe!"i 1M feedbad. im by bile acid of7 (Ih)drolyl~. the rate-ltm1tl1'l& In the cooversion of cholesterolw bile acids. ifICfC~1lJ tit breakdown of hepatic chole~lcroi . Although biosynt/leslll chole~tcrol is increased. h appears that the mte of CilIa is I:rcatcr. resulting in a net decrease in plasma chok.lltlfl levels by affecting LDL e leamnce. The increa~ 0( Ul. receptors in the liva that occur'S ...ocn ils rontmt 0( terol i\ lowered augmcnlS this biochcmiall e,en!. CholestyramillC resi n does not bind with drugs tlYt neutrJI or with amine salIS: acidic drug (in the amoo could be bound. howeva. For example. in animal ~ sorptiOIl of aspirin given cOI1Cum:ntly with the ttSlD dcp~sed only modcTlltcl y during the first 30 minut~

the,..

Choieslyrarrine Rosin
(Cho/ybII.j
(Questranj

"

CboleSlyramine resin is the drug of choice for typc lI a ~pcrl ipoprotelnemia. When u~ in conjunction with acon trolled diet. it ~dllCes ,8- l i poprou~ins. The druB is an insolublepolymcr and. thus. probablyoot ofthesufest beclllSl';1 is 101 absorbed from the ga'>UUinle$un:l1 U'lICIIQ cause syslemlc !Olic effccts. Col.-stipoi (Coiestid) is II lqhmoIccular ....cighl. Insoluble. g.ranularcopolymer oftentIhylencpcntamineand epichlorohydrin. 11 funcl ion.~ liS an lI\IOO~xchlingc. ~sin-scquestering agenl in a mann.er simi brto!hal of eholestyr.&mine !'eliin. Cole'ilipol hydrochloride m.luces choleslrrol k,rls wilhoul aff('('ling triglycerldes and ~ms 10 be rspedally cffccli ve In the tn::llmcnt of type 11 b~ptrlipopro!ei IlC mias.
~tipol

HydfCKhloride.

I~

r~

diac

synthesis and, sobsrqucntly. il s pla~ma products. lDL and LDL. Plasma triglyceride le,cls an: reduc~-d because of the decn:ascd VLDL production. Cholcsterol levdsan: lowered. 10 111m. becau<;e ofthc 1kc."a.'iCd,..ac ofLDL formation from VLDL Allhoogh niacin is lhe drug of choke for type II hypcrlipoproteinemills. ils use is li miled because of the vasodilating side effects. Flushing OCCUI"I in pr.K"lically all paticnts but grfl('r.!.Ily subsides when lhe doIg i~ discontinued. The hypolipidc:mic rffeclll of niacin may be due 10 liS ability to inhibillipolysi~ (i.e., prevent the relea>e of FFAs and glycerol from fany tissues). A~ a consequcnce. then: is II reduced rescne of FFA in the h~er and diminution or hpopnwcin bios)nthe..J~. which reducn the product;oo of VLDL. The decn:ascd fonnution of lipopnlleins le.1ds to a pool of onused cholcsterol normally incorporoted in VlOL. This excess chokSlerol i~ then ellcn:ted through the bi liary
~, .

~h

agu

.". pro-

"'-~

'+-''''-./i .'-C t

~m lc

rl'Ol

mid, liooinyl

(Cclllllld)

'_seve/am. Co1esevelam {We khol, is one of the ..n recent additions to the class of bile acid.sequesterlng
acmt.~. Its structu~ is r1lIlter no'cl. and II first glll/lCC, i! ~lII'li 10 look like the previous examplllS of cholest)rJmille !lid coIe!itipol. [t doe!I I1(M posse,~ the chloride ion~, 110.. Mr. and. stnctly speaking, i5 I1(M an anion~lchange resin.

~"

I g:l~. ;01'1'0

all' mnJ in bile

Niacin (nicotinic acid) may be administered:ls alum inum niCOlinalt (Nicalell). This is a complell of aluminum hydro.y nicotinate and niacin. The aluminum salt i$ hydrolyzed to aluminum hydroxide and niacin in the stomach. The aluminum salt IiCCms to ha~e no advlIlI\agc o~er the free IlCld. Hepatic reaction appears more prevalent than with niacin. Nicotinic acid has been esterified to prolon, JIll hypolipidemic effect. PrnlaCi)1hntoi tctranicotinatc. has been IJlOr'e effective ellpcrimental1y than niacin in ",dllCing cholesterol Icvcl~ in rabbits. SorbilOl and m)"Qinositol hellanicotinate polyestcrs hale been used in the tn:atment or patknl$ with atherosclerosis oblitcr.llu . The usual maintenance dose of niocin is J to 6 gfday given in three dividcd dosc.,. The drug is usually given at rne3J times to I'l'dute the gastric irri tation thai often iICCOIIJpanics large dosr.~.

""" bl
~Ion
li~m

This COOlpoond has good

Mel dlhydroxy bi Ie
acid~.

se lecll ~ity fOf boIh tile trihydro~y

'I :S
tel'l,JI
ok~,~

1bc selcctivity for thcse hydrox y_ IIIal deri\olives lends wmc insight inlO the reduced side d'l'fCIlI coIesc\e!am posses.<oes, contp;m:d with cholestyl'll_ and colCStipol. Unli\:e the older agents. coie5C\rlam does not have a hi gh incidencc or causing consti pation. This
from the compoond's ability to "pic\: up' water beeIUSC' of its affinity for hydrollyl systenl (i.e .. hydroaen knllng WIth eltherlhe bile acid or wUler). [n tum. this yklds IOfter. gel-li ke materials that are e:lsier to c~crct e.
lI:III\ts
~SJt05terol . i ~ identical ...ith

r'ootIr>k: Aci<I
(N"OIIIC""

LOL

onn)

..,
.1>Co'l

Sitosterol is a planl sterol , .. hose SlNCtul'l' thai of chole$terol. elct'p! for the substituted erhyl group on C-24 of its sidc chain. Although the metlla ni~m or it~ hypolipidemic effect i~ not clearly understood. it is suspected Ihat the drug inhibits the absorption of dietary cholesterol from the gastrointcstLl\:l1 troct. Sitosterols are absorbed poorly from the mucosal lining and appear to compete Wi th cho lcstcrol for absorption siles in the ime.~tine.
.....O\o~

,..:,

a.l"",

/,,-

""

...

I' //;1>1,('"'
""

(WBlchol)

Iiicotink Add. Ni4::otink acid. JpyridinccartlOx} lic qI (Niacio), is effecthc in the trl!31menl or all types of ~perlipoproteinemia except type I. HI dOSC!l abiwc those pwn all a vi tamin su pplement. TIM: drug reduces VLDL

Probucol, USP. Probucol. 4,4'l( I-nlCthyle th)'lidcne}ml -S81 bis(thloHbisI2.6-his( I. I-dimethylcthyl)phcnoll . (Lorelcol_ i~ a chemical agem th:lt was devdopcd for the pia.<;tics:and rubber IndUStry in the I%Os. 'llK' probucoI molecu le ha~ two tcn iary butylpltcnol groups Imked hy n dirhiopropylitkne hnd~. giving;t a high lipophilic eharneter wilh slronS antioxidanllllOJXlties. In human,. It causes reduction of both Ih'cr nnd serum cholesterol le\'el" but it does IlOl nller plasma triglycerides . It redtK-a LDL and (to p Ie.,scr extent) HDL 1c"eI~ by a umquc: mec h:lnism that is Mill not "'early \kli....,,,lw . The reduction of 1101. may be: due to the ablht y of probocollo lnltlbll IIiC ~ynlhe_" s Of IlpuprOleu. A I. a major protein component of IIDL."" It i5 effect;'c at redllCing le"eI~ of WL and is used in hyperhpop OIeinc:mias charncu:ril.cd by elevated LDL levds.

the surface of cell mcmhr.tnes . After bonding und ellllocyto~i~ of the rcceptOl' and LDt. Iy..osonUlI degr~dation of 11m. oomple)\ m the 'U maJ.Cli cholesterol ~"Iilable fOf uot" 'lIullll' membrane synthi:si '. 1\ i\ senc:raJly K'ptai "lotal pl:lsrnu cholesterol is IO""ered nlOSt effecti\'cly hy ~ ducing LDL Ie,d s. Therefon:. the population of LDL ~ t<n is an important component of cleanng the pl~ Ii cholesterol. HMO CoA redUCUiS(' inhibitOR conlribw this by dlI'Cclly bl o..::king the !l\.1ivc ,lte of thc en7yme. 'ThII :M;tioo has twofold cffect on eholCliterol Ic,'t'b;. causes a tkcrcasc: in de no,'o choie<;ttroi and ;'><';"";"loC' ;n N:p;t.\,.: ductasc inhibit Ol'5~" patien.." "'lIh fami lial

.,,-<

r ;)1-'-1-"--<~
Y-' '"'

;)1-

the 5ubsume. HMC-CoA. d enr-ynle I reductase_ and an: lactoocs and prodrugs. hydrol)'~is i li"er to lhelr rcspc:cll\'e ,8-hydroxy ac ius. "";". . trnst. is administcn:d as the 'iOdwm salt :M;id. t

:t.~~ ~,~:~:~~~

,,

Probucot (Lorefcol

HMC-CoA Redudll_ '"hlblton

DI'\lgs tn this class of hypolipidcmic agenls inhibit lhe en7.yme IIMG-CoA reductase. m.ponslble for the eoo,asion ofIIMG -CoA to mevalonate in the sy nthetic pathway for the 5yn the.~isof chole!;tcrol (Fig. 19-25). HMO -CoA redUCtase is the ..... Iclimlting catalyst for the ilTt" 'ersible con\'C:rsion of HMG-CoA to mcvalonic acid in the s}' mhi:si , orcholcslerol. lllC :M;1;vity uf HM O-CoA reducln)oC i~ al<;() under feedback regulation. When cholt'Sterol is available in sufrlCient amounlS for body needs., the e n:.eymc act l ~lty of UMG-CoA reductase IS suppresscd. Elev~ted pla, m~ cholesterol leve ls have been cOlT(' lated with an iocreasc in c3l'diovlISCu l~r di;;ea>e . Of the plasma lipoproceins. lhe U)L fmetion contwns the most cholesterol . The source of chole5h:rol in human s is dthc r the diet or de 1'10\'0 syn thesis with the reduction of HMC -CoA by IIMOCoA reductase ru. the rale llmiltng ~Iep. Inge~ted cholesterol a.~ the free alcohol or ester is talen up after intt'StinaJ absorptffin and tran sported tu tile liver und other body orgnns through the c~ogCIlOll.~ pathway ( Fig. 19-25). The WL dehvelll cholesterol to pc:ripherul cells. 11115 process occurs oftel' billding of LDL to ~pc:ci li c LDL recCptOOl located on

a potent mhibltor of
origina lly from the fermcllmliOll ':;i~; i~;';;';~~ /til/us Il'rrl'lH and MooasCiLt " t",~originaJ HMO CoA reductase inhibitors. me\,aslutin (forme rl y called cu lturc.~ of Pl',,;cillium cil/Illm I dra .... n from clinica l trials bc:(-auJ;e i ullered phology ;n dogs. Thi s erfcct ....as rIOt ooscr"ed stalin . I~or inhibitory efTects Oft HMC-CoA reducmc:. IlIClOflC rmg muM be: hydrolYled 10 the open-ri n! ,;,. :M;iu.

H,C,"VV
loYa5Iallll
j l.4evaeor)

.
I.4evtolonale

HGG CoA

f igure 19-25 HMG-(oA ~ I'NCtlOrt .

Chwl" t r 19 . c,ml;,mrJCII/itrAgrnlS

663

:)'tothl

'" 'M'
~.

Simvut.Jtin. Sim\"l.I'\.Iatin. 2.2-di/l1Clhyl butanoic add, IlJ, 7.8.Sa- he: l ah )'dro-3.7-<Ii me t hy 1 [2-( tctrahydr0-4-hy8 oxy6-oxo-2pymn2yl)cth),1 [ I naphthalenyl ester (Zo(111'1. is :m analogue of iovastat in. 1"hese two drug~ have _) slmii:lt propcT1ies. Both drugs. in the: prodrug form, Inch the: 1I,"ct uochanged after oml admml~lrnIlOI!. ""here iIIty undt:r~o e\tensivc melnboli'l11 10 a number or open hydroxy acids. includi ng Ihe aclive ,B-h)'drox)' 1I('id,. The)- ~aiso highly bound 10 pla>ma protCIII~. 1"hese ac\KIf1~ raLe the bioavailabihty of sim'a.~t3tin rather poor but hener !Un that of 1 0vlhluli n. which has bL'('n estimated 10 be 54.

lo ... er than tOOse of the agenlS that part of their architccturul Ik~ign .
H"c-CQi.
H

a lactone ring as

-"'V"

rut,

CH; CH-C CH, - CH CH,COOH H.

OH

OH

. . -

,
Fluva,,,,Un

~O lll

"' f(..-

H"cl',,"" , , , -

(Le.cot)

Oro" r ,'"
~.

,,'"

tUUI!

~'Y

Sfmvaslatln
(Zoeor)

1.3,7.
i\

(I~)'-

1CV I

II,

"",. ""'or " "",.

"~.
lnOi(;

r~

"Ith

ova ,<h<

1'rn'ilstil t ln . Prdva.~tatin. sodIUm 1.2.6.7.8.8ahcxahy Im-fJ. t5.6-tri It)drox y. 2 melh yl-8( 2 mctlty I_J-Ox oIwlo.t y)1lIajlhth:tlerlell.:ptallOOte (i'rdl'achol), is the most rapid-octIIC of tllc thltt IIM G-CoA reductase inhibitor drugs. reach1111 ptA t'QIlCClllration in about I hoor. The wdiurl1 salt oltlte P.hydmxy ad d i~ more hydrophilic than the loctorle bms of the lither tWQ agents. which lIIay u pl ain this prop1ft) In addition. the open form of the Jac\OIlC ring oontribIIt$ to a more hydrophilic agent. ""htch. in tum. results III bs eNS ptnctf"dtiOI1. TIliq e xplaills, ill part . wlty prava~wtill fe ...er eNS side effects than the mon: lipophilic lactone ella' 0( tlu~ class of :l.ientJ.. AbsoI"pfion or P.,I\lIStalin foJ r.,.,,'lDS 0l"Il1 admtniMmtiOIl can be Inhibited hy resiM sUI:h .dlOle~tYf"~llI inc because of the p~~nce of the carboxy lic OJ function on the dnr l:. llle 1 !!Clone fOlTlls o f 1 0va5tllt;n . hlm,aStalin tm: Jess uffcctcd by eholcst),ramioc.

Atorvastatin. Ator,a.(tati n.] R-{R .R")]2-(4-nuorophcn)'I)-b.ddihydroxyS-( l mcth)'lelhyl)-3pllCnyl-4 I{phcnylanlinoj(;arhonyl ] IIJ-pyrrolc~ I heptanoic acid (Lipitor). also poIJ&SCSsc.~ the beplanoic acid s ide chuin. "h.eIl 15 enllal for inhibition of HM G-CoA red~1asc. Although the side ChlLi n is less lipophilic lh311thc lactOllC furm. the high amoUl1t of hpophiLie ~ubstitution causes Ihis ugenl to ha~e a slightly higher ie"c] of eNS penetration titan pr.lI"a5t3hn, resulhnl in a ) Jight iocrcase ill eNS s.1k effects. E,'cn so. its CNS profile is much IO"'er Ihan that of lova5t3t lll. 1 CH h OH 0

"""""",,,.
(LipltOf)

HOCOO
=

CerivlIStali n (8a)'eol) is one of the IlCwer agents in this ela.~ o f cholcstC!mJ.Joweri ng llgenl~. It cllfTi,es, ho ....elcr. I higher locide~ of malxlomyoJY~ls and. IS a rc~uh, was ~0lunt3rily withdrawn fmlll the nmn;el by its manufocturcr in 2001.

C~,(vilstiltin.

CH

nw,sta tin. FlUl'aStalin, JR- .s-(l:. ]( j: r 7 ]3-(4-n u 1 IIOpbenyl)- I -C 1 - methyJclhyl)- I I/ - indol - 2-yIJ-3.5- dlhyhly-6-heptenoie acid monosodium .\.all (Le'iCol). is ~cry oIIDillll' to pral'!l.Statin. 11 possesses a hcptulloic :todd ~idc cillo tltal is suptrimposable o.er the lactollC ring found in "'bl3tm and ~11Jl\'aSialln . It is thi S side chai n that is recog....J HMG-CoA n:dllCllse. A lw. mL>Ch like pravaSl:uin. ,ide effC'("ts of this lipid-L oweri ng ~gern arc much

ANTICOAGULANTS
A theory of blood c lOi ting illlroduC\:d ill 1905 wItS based on the exi<tellCC! of foor factors: thrombopl:t$un (thrombo~ i nase). prothrombm. libnnogen, ~nd iOlli7.cd alcium. llle clotting "-'{jUCOC"C p!'OIlOSC!d was thm ""hen tissue damage occurred. thromboplast in entered the blood rrum the platelets

664

Wi!wn mid GinO/d's Tr.TlbfNJ4

r>f O,.,(lJlir Mniir""'/ and Phurmacrwlk"J eltr",;J'".

TA8L ' ~7

Roma n Nume ric.1 Nome nct.ture of 8100d-Clotting Fntors ilnd Some Common

-t .... ,

Synonyms

. -- ....
ICI

" '"
y

....!. ilia' 1)(' J...1J(a'

II' IW'

,y
y,

Caldum
I'roocoolCfin. ~~ p.!MJhll.1abi1e r.,,,w C'TlIn MOfIber .. ...,. ""'" \IIoCd) Pmo.'OII'''''"- ~ r...............odb ... ,du I. SK:A "'nu I"'n~",h' I... fa.: ......... " '->phil", ,k",",iln. pillclCf (1)/_ I. aN,hattopholic fattot A ~ (1'fCl. CIoro_ lCfw'ac"". II .................1>0" II .

,-~;;;;_"...:~=cr:"' _. " I Ex\I.-.c ",., ,y _ :'::::=,......

VI ' Thao,'C( I 1"1

__I
_

'Vl1l "
x

Iv Co"" ~
" ........,....,. -

.,...,.. ......."1.,,,,'11_ ' ' lOr......

,.

ilwon<IrI'

.."hem.,p"l", r...;, .. D S,...n!'tn.n r.......... S...... f..,.... . ~..," ttl

I'Ibnt.t d"<lOoobo""''''~ ......:ale.. I PTA).
..,Iooonuploil", ra:100'c

'''ibr~''lDOI'_'

I-~
(. . !)oJ

"
'"
XIII

11"80""'" [,,;00'
nbrin ...... hri ... r....". fibnR4i<'.l.alJI.cJr_ (""'00'

(qcIoCIW

...
I

Fq.,

'1111 , r .... ".

and rt"aclOO with prothrombin in lhe: presence of culcium to form thrombin . Thll)Ollbin then rt"actoo wllh IibriJlOl!en 1 0 form in-.oluble fibrin ...... hich enrnesllL'd red blood cells 1 0 create a dot. ~ concept ,emaincd unchullc/lged for almost 50 ytaf'S. bul ;t ha~ now been modified to acconunodllte the disco~ery of numellJU5 additional faelon that enter inlO the clotti ng mechanism (Table 19_7).

Figure 19- 26 S<heme of blood coogulatoon and fibrlOlOtJIII ' . a votam,n K- dependent factor, '. mhlbnoon by ~ n antithrombin (II.

Medn-Ism of Blud Co_glliatlon

~

nu,d nuture o f blood can be attributed 1 the nat cells 0 (cndolllctiol) thai ll\~iOl1ai na ,\(}nlhrombogenic en~ iron oneOl1 in the blood ,essel~. This is Q re~ult of allca~t four phenomena: (o/ the maintcnance: 0( a t/llllsmurni ncgaJ i'e electric chargc thai pre~cnlS lIdhe<;ion between platelets: (b) the rt". Ica.e of n pln~maloj;cn actiwlor. which acti~atcs thc fibrinolytic pathway; (e) the release of thrombomodulin. M~'Uractor that act;~atC$ protein C. a ooagulatiOIO faclor inhibitor. and (dJ the rell:asc of PC I:. a potent inhibitor of plalelet asgregalion. The proce..-.s of blood coagulation (Fig. 1926) i n ~()h'es II series 0( sleps that occur in a cascade and ttTTJUn:lle 101 lhe formation of a fibrin clot. 8100d coagulalion occurs by acti~ation ofcithcT an IOllli nsic palhway. a relath'ely slow process of clot formatoon. 01" an extrinsic palhway, .... hich ha.~ a much faSler rate of fibrin fonnulion. BoIh pathw.y~ merge imo a common pathway for the: oon~crsion of prothrombin to thrombin and sub~qllCm tnlnSfomlalion of fibrinogen 10 the insoluble strands of fibrin. Lysis of imnwascular clot.'! OOCUflli through a plasminogen - plasmin sy$lcm. "'hkh con5isIS of plasminogen. plasmin, urokina.'iC'. kaJlikn:101. pl asminogcn IlCti~alOl'i. und some undefined inhibitors. The: imri1lS;e pathway refen 10 !he syslcm for coagulillion that occurs fll)Oll !he interaction of factors circulating in the blood. It IS activated when blood comes into COlltllCt wi lh I

damaged Iessel wall or a foreign subslQoce. Each of dr plasm.:l. coagu lation factors (Table 19-7). with the eUCfII.G of fllClor III (tis.sue IhmmbophlSlIOl), circulates as an inactrw proenzyme. EJlccpt for fibrinogen, "hieh fl'"('("ipiUOltJ. 5bri n. the..o;e facton are usuDlly uctivaled by eI'07ynt.llh; Jtmowl of smal l peptide in the cascade: of reaction> dW make up the clotling ~l>tl'lCe (Fig. 19-26). 11Ie l.Ir..cloning system refers to the mechanism by which ibMI" is generJted in plasma nftcr the addit ion of ti~1.IC e~lfJ."j). Whoen vanws tissucs. ~UC'h as brain or lung (COIOWJIII( Ihromboplastin). an: atIded to blood. a compleJI bi:btU thromboplastin and factor VII in lhe preo;cnce Qf ~ ions activlltes factor X. bypassing the time-consumlill iItjII of the intrinsic pathway that form factOl" X. 11Ie inlrinsK: and edrinsic pathways inlcract I. "'" Small amounts of thrombin fonned early after SM1\lbbol of the Clltrinsic pathway acce1o:rale doning by Iht inlnMir palhway by activating faelor V III . Thrombin also spmII, the ckMting nile by xli-'lIing factor V. Iocalcd in W c. mon pathway. ThromblOl then OOI1\'ens the soluble fibrinogen into a soluble fibrin lIel by octing 00 Gly-Aq bonds 10 remo~e small fibrioopcptides from !he N t~ enablin,lhe: n:maining fibrioogen molecule 10 pol)';';; II also acti~lIIes factor XIII. which SIllbilo,es the fin pi in the presence of calcium by cross-linking bcll>mI" chains o f the: fibrin nlOOOf1lCr through intcmlOltcular"';'tam)'I- lysine bridges to form an insoluble ma~

Antkoagillilint M.chi!lnlsms
In !he milieu of biocnc:micals bein, formed 10 facili,.* doning of blood. tnc: coagulation cascade in vivo II

...,
",

,..",

''''''''''

I ...

ond

ccplion

0"" '
fi
that

nac,,~e

. he reprintic 'rombm
/l II'PCIS.

'"' 1&

IfIS

I'lll'ling

>e,,,,een
:ulcium
.&
~[epi'

n vivo.

lu\allon
J1lnn~ I C

up Ie romprotein
~,,'d~

1y - Arj!
IlIIHlUS.
~nu:.

;win gel

:.en

the

,..glu-

IIlte
1~

the

con-

by :I. balaocll of inlnbilll'fS 111 the plasma 10 pre'em alJullbt blood in the bOOy from soIid,fYlng. Thrombin plaY$ a p!\"I1I1i1 role III blood 00II,u1al;00. 11 clC3U:S fibrlllogen. I rtachOll thaI imlimc'I formalJon of the libnn gd. II<h,cll ronShlUU$ the frnmc\OooO: of lhe blood dot. IU ,nenhoned .oo.~. il acti":l.les the cofoclOl'! foctOl' V aAd fadO!" VIII [0 -=tderalc the cooguimion process. ImillC' cndOlhclial cells t\press receptor. throlnbomodulin , for Iinomb;n. When """"bin I~ bound IOlhmmbonlOduhn. II doc, 001 ha\'c coo!!uWll lICtilily. which thus proven ls elm formation beyond ilarn:Igtd areas and 1)1110 inlact endot he lium. In this bound iQlt. ho.c\'cr. thrombi n does acli,-alc proIe.n C, II hieh [nen NCti\'illes two cofocl0r5 arid impedes blood dOUHlIl. Thrumbin al'o() IICl i v ~les fllClur X III. lellding to cRJ!;)-hnking Ii the fibnn gel. TIle actj\ ilY of thrombi n j, Il'gu laled by Ii> IrlllCu\Dtion by pla,ma protein inhibi tors: (II-proteinase illtibltor. <l';!-macroglobu lin. amithrombin (antithrombin III). and hep.'lrin cofactor II. These belong to a family of proteins ca lled U rpiflf. an acronym fur urin~ pm/ellSf intlbllOrJ. AOlHhrombin Ill. an Orglobin. nc:ulIlIhLes tlirotnbm and the <mnc protease' in the coagulation ca<cade-Xa. IX a. oX .... and Xlla. Al1hough antilhrombin III is a slowacting lIiIIbuOl'. it becomes a rapid-liefing mh lbuor of thrombm in ~ presence of hcpan n. II cJl'Ifln " a nalUmlly occurri ng Jl'ltiroagulunt that l\'quire~ Illuithromb in III (M.'(' abo~e) for btoIogical propeny of pre'cnUll, blood clot formahon. blllds at the Iy~me site of the anuthrombm III molecUle. caIlsi ng a change in the cOllfn/mation of antithrombin III aI i~as.mg i t ~ anticoagulant propefl ies. Ilcpann can then IilloQCiate from alllllhrombm III to bmd 10 anotocr ant ib nbi" 11 1 molecule. An additional sy~tel1l . which controls Il'II'3Illed coagulatiOl1, invohes prulein C. a 'Itamin K-depctIdc:l\l 'ly~en In the pllIMna. Protem C I~ CQIlvened to 11eri~ protea'>C ",hen thrombin and factor Xa. forlll~"<I in lilt blood in the coogulanOll CllSCaOc. Internet with thrombo.oduhn. The nowact"atcd protem C mh lblt- factOfS V and V and. in w doing. bloc h furthcr production of throlnbi ll. III /'nlIcin C al'iO cnh.,nces fibnnoly~l. by causing Il'lease of lilt tissue pla.<iI11ll'1Oen acti\lIlor. The bIOS}nliw:sis of prolh rombin (faciO! II) depends on tdequJte supply of vitllInin K. A dc:flC iellCY of ,il!tmin t: I'tSUhs In the foonalioo of. def('Cti\f;~ prothrombin moleMe. The defCC11>e prothrombin IS IlrlligenicaUy ~i nll lar 10 IDrnl3I prothro",bi n but ha~ reduced calcium-blOO mg ubilt ty -.Jill) btoIogJul aclJ\lty. In !hi: pnsencc: of calc iu m iOlls. fIOI1lIaI prothrombin adherc~ 10 lhe . urface of pho~pholipid ItIic:ks ~lId great ly incll':ISe> lhe a.:ljvity of tbe clOltl n~ ..:lwti'lil. The de fcct in the abnormal proIhromblil i~ in lilt NHr terrlllllal poniol1. nl which lhe ~ond e!trbo;)~ yl rc~i ,. has IlOl been added 10 lhe }'-Carbon ~tom of >OIlIC glu ..oc Kid Il'"'<~ OIllhe prothromblll molecule 10 form 1"" Cll\tQ1)gJulamic acid .11 Admllll struliOll of '1Illm ln K untag"">I~ decrca~s syn thesis of a biologica ll y 1JI,.1i Ie prothro", '- molecule and incrc:ac~ the clolllng IIIf1C of blood III ......n ViUlmlll K i, cri tica l to the formalion of cloning fllctt'm \'11. IX. and X. These fac101'll lin' i; lyooproteins thai hal'e r(dol)glulamic acid residues 3t the N- Ie:rmi nal end of the JqXU.Ie chain. The cnzyme involved in fonning an llCth'c Iftthrotnbin is a vitamin K-dependcnl C::lrboly lase located .tk microsomal fr.JCIIOIl of I"er cell . It ha~ been su~I/tliled

ge.,ted thut vitllm in K drilc., the carbo!l.yla.se rt'actlon by ab'ilntcung a pmton (rom lhe l'CIah lely unreacll I"C melhyknc: carbon (If the Illu lamyl residue. fOffili ng :1 2.3-cpo1 ide. Oral anllcoagulants intcrfcre with thc: }'-C;lIbo~ ylation of g lu lamk acid 1"\'._ldllC'\ by pll',c:nhng the Il'ducnOil of Illamin K to liS h)<lroqull"lOne foml (Fig. 19-21). Ilc11lophiJia A. a blood disease crumlCtcriled by a deficiency n( roagu lalloo factor V III. i~ the nlOSt romrtlO<l mherned blood l'(l;!gulaliOll dlWlder. Treatmem of Ihl ~ disca.'ie O\'cr lhe paSI 2_~ }C:ll'< ha~ dcpended on the ooncelllmtion of the anuhemophihc factor [factor VII I) by C'T)'oprecipibuon alld Immunooffimty chroll1:lIogmphy separation tcchnology. The: impact Oflh l~ thcrJpy ha' been dnnini~hed by lbe 110:\eroce: of 'Iruse.' that cau<;c the ac'luired II11111unodeficielllO:y )yndrorne (A IDS ) and 0I1ler k-.s tragic l iml dl~asc:s in hurnan~. Rccombmunt amihcmoplulic factor prcparutions have: bc:cn produced Sll~ 19S9 "'lih U'ioC of manllllalilin edl~ geIlI'1iCIIII)' altcred to secrete human faclor VIII. Kngelklle and Heh."lulC: arc recombWlult prcpar..tion~. obta ined from gerli!t ically altering baby h;un"er ~Idne) ceJl( thai contmn hiSh cuncenlrluions of fllClor VIII. RooomblllaN (actor Vil a. an a.:ti\c factor in the e!l.tril1~ic JXlth'" ay. 110W in phu~ II I chnlcol trial, (NOlO So!,cn). has bc:cn used to treat JXllIcntS \I'uh hernoplliha A factor VII deficiency. Hcmophilla B. anothe:r genetic blood dlsordcr. II hich COIhUlute, about 20':f> of he mophilia cases. b cau!>ed by a deficiency of fao:tOl' IX and ha.._ been \n:aled from C'T)opteclpllatcd fraction. obiamN from pla)ma. Monocl0ll31 antibody technology has produced Ull c,~ntiall y PUll'. cllJTic:r-frec I'f\"p:Ir'Jtion of nati lC: factor IX (MOI1OIIlIre). Recombmant technology h:b 'i01~ed lhe: problem of linllll:d supply ulld ~lml COl1lummalion of the;;e criti." al bl ood fllCtors.

Platelet Aggregation and Inhibitors

8100d pl;III~ICb playa pllOlai role III hemoslasis and thrombus fonnation. Actually. they hal'C: two roles in the cessation of bkeding: a hc:",O~1nl IC function. In \lhich pl ate lcts. through theil m.lS_. cnu!tc: ph) ~Iel l OCclUSion or openings III blood \"esst:ls. and :I thromboplaslic funcuon. III ",hich the: chcn ll clIJ c()l1~lit ucnts of the pl:IIC1clS IUlc part in the blood coag ulation mt:chani$m. The circulatory system I' ~lf-sc:al ing because of the clOItmg propcn IC( of blood. The: pathologIcal fOlTl1at loll of clot_ wilhin the c irculalory sy<.tem, how elCI. creatcs a potenually ~riOllS cl illical ~itu.atioo lhal must be: dealt \I'lIh Ihrough the use of anllcwgulanlS. Pl ateiclS do not adhere to in tact endothelial I:clls. The)' dd become affi.( ed to sube:ndQtlrehal tissol", which ha,c been c:xposed by inJUry. 10 cause henlOSt a.~ls. l'Iate:lels bind to collagen in lhc ve_sel wall and trigger OIlier platelcts 10 Iidhen: to tllen\. This oohe~lvcne.ss i_ accompanied by a change in ~hape of the platelets and may be cau~ by IOObi lil..:1UOII of calcIUm bourld 10 thc platclcl mcrnbrJnc:. The growlh of the platclet mass drpcrlds on the adenosine diphn$phate (A DP) re lca~ by the fiN fe:w IIIJhering cells and enhances the agllll'g31ion proce",'. A .secondary pha'ic: (ph:!"!: II) im medialely fol l ow~. with additiOl1al plaldet aggrc:gauOI'I. In 1111, 'ieC(nJary ph:!.e. lhe platelets undergo a sc:c:rc:lory piocecss during ",hich cn;ynloC\ wch a~ cathc~in and acid hy drolll'ICs. alonS lIith fi brinogen. an: n:lca~ from tt gnanulc~ in the pl:llclcb and ADP. An >, serotonin. and calcium arc relea .;cd from (knsc bodie's in the pl at elets. TIle den'ic: bodlCS

. . . . ,. . . c,
~,~

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ro.

1: 1""

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0,

o
"vv~"

Figure 19- 27 MNhafirsm 01 olCtlOl1 of V1tamon K and $lIes of ilctN)n of wilrlar,n

are likened to the SlOI1Igc grunulcs II.~SOCialed wllh adJ\"llcr!!ic !leurons. IncJ\"ascd levels of cAMP inhibit platelet aggregation. cAM P acth-all:s ~pecific dl:'pendenl kiRII.'ieS. which form proIem- pnosph:uc oompleJIcs thai che la.e C1llcium ions. The rWUCIle\'el~ of calcium inhibit aggregation (Fig. 19-28), lnhibitOl'!; of platelet aggregation can increll5C cAM P levels by I.'lIher 51imuhuing adenyl;uc cyclase or inhi biti ng phosphodicSIt'rase.n SubSlllnCC:ll such as glocagoo. adenosine, and isoproterenol increa!ie cAMP level s and inhibit platelet ~gregalion . Drugs such as IheophyiliBe. aminophylline. dip)'ramidole. papa\" crine, and adeOO5HlC inhibit ~ies lerose aoo aggregation of plalcicls. Epinephri!le. collagen. and serolonin inhibillldenyiale cyc lase and ~,i mulme platelet aggregalion.n The role of plmelel5 in arterial thrombosis is

ATP

5' AMP

"-'

3',5' Cyclic AMP

ProIeon ... F"hospt\ate _

0.&.101' 01 Cs'cun Fftle C*ium ( C a " ) - 8culd Cab"rn neaH"')' lor 1ibQ iiiOItll!iJM"'ll ~ 1iGO'''Y-or;

.......
j

Figure 19- 28 Role of adenosme 3'.s'-cy<IIC monophosp/'I.Jte (cAMP) In Inhibition of platelet aggregatIOn.

si milar to lhat in hemolilasis. 1llc: facton COIIlribu\Jllf venous Ihrombosi s arc circulatory ~tasis. CXCeliS;\'c JCIII'II" tion of thrombin fomUitiOll of fi brin, and. to I Jco,o;er melll than in the artery. platelel aggregation. Aspinn. sul fl npyr:t7.QOC. and indomethacin hal'c an IIIfIIbi. lory c ffC(:t on platelct Dgl!rellmion. They inhibit cycloo:l! gcn~. lhe cnzyme 1M controls the formation of pmslJJIItdin cndoj:W::lO~ idcs !IDd incn:'aSt'$ the Icndrncy for 10 aggrcgn le ?~ A ~pirin also Inhibits the plmelcl-reJcoa~ Ita' lion. Dipyridamole inhibits :tdenosinedcaminase .nd..tc.sine uplake by platelets. A ~ a resUlt. lhe i l'lCre~ conccntrmions of mlcoosine mhibit ADP-induo:cd vrP tion of plalelet5. Among lhe nlany phannaoologicbl actions of pro!UIbId ins is the ability of some to sumulatc or inhibit the lioll of platelets and aller the clolling time of blood. 1'toIbglandins are synthesized from 2O-cnrbon pol}u!\WunIII fany acids containing from three to fl,'c double bond>. fatty acids arc prescm in the phospholipids of ~l! . . bninc:~ofDJI mammalian ti~s.ucs. Th.e main ~ursorull"' taglandms is ar..chidonic add. AllIChidonic Kid IS Idr from membrane phospllOliptds by the clU,yn:w:: pho! A~. Once re leased , arachidonic acid is mcwboil1.ai ~ cydooxy&cnase ~yntheta.'iC to room .ms tablecydic oxides, PGG1 and I'C HI' which subsequently art funned into PG ll and Ihrumboxane A l (TXA 1). The~. 5ion to TXA! is aided by the enzyme: thrombou synthel.l5e. 1llc: formation of PCI! can oc:cur _~ cally. Blood pluteleTS cOllven arachidonic :reid 10 ~ whereas PG ll is formed mainl y by the vascular emlodldltoll

Cluaptt r 19 C..niim'tIJC..lar At.rmJ

667

Ik.tI PGII and TXA: are unsmblc :\I physiologk-oll pH and IClfljJti ..IUI'. Their half-lin'S aK 2 10 3 minutes. PGll inhibiu; platelc:l agglt'gatioo by stimul:uing adenylMe cyc-Iasc to inm'ase cAMP Ic,-cls in the platelets. PGll is also VIIs(xlilalor and, as II Te$ult. ~~ pote:n! hypolensivc fIfOPCrtles when given intr.l\"er'lOll~ly or by intni-ancriDJ lid IlimSlMltion. TXA 1 induces platelet asgregmion . Togclhcr with PG I:. TXA1 plays II role in lhe muintcnnncc of vuscular IIomeo!!lasi~. In uddil ion 10 being a platelet agg.rcgator,

alkalies. The effectS after adminiscr:uion noquire 12 to 72 hours to de.clop and persist for 24 10 96 hours after d,scontinuaroce.

~
0
....~

TXAl is II polen! vasoconstriCtor. Retllroalion of clolling is impor1llnl in blood tranSfusions. III ."oid thrombosis after surgery or from ocher causes. 1 0 pm'cn' rtttJlll'nllhrombosis in phlebili~ and pulmonary em IioIlsm. hnd 10 lessen the propagation of clocs in thecoronary tItme$. nus relarti:llion may be acoompli..ncd by .gents Nt mac1iv,le thrombin (heparin) or 5ub:i;Ulnces thaI pre~1 fir formation of proIhrombin in the li,'cr (the coumarin deIJ\loU,'e! and .he phen)'lindanedionc dem'ati\'cs).
Although heparin ,s a u~ful lllllicoogulanl. 11 h:ls limited applications. MlUly of the anticoagulllllts in us.e today were 1It"eloped followin, the discovery or dicumurol. an antico"ulan! present in spoiled sweet clover, The<;e compounds a\\ orally effective. but there is a lag period of 18 to 36 loon before tooy increa~ lhe clotti ng time significantly, Heparin, in COll1rust, produces an imm'.'<Iiute anticoogulant dfKt ~ftcr intruverIQII injection. A major dlsOOvlllltage of IiItparln i. Ihat the only err1i\'e thenopcutk route is paren

mi.
Dic:umarol and rel:lted compounds an: 001 "hamin K lUI 1ICOOJ5l!i in the classic sen~, They a.ppcar to III:t by interfer III "uh the fUllCtion of vitamin K in the li"er cc.11s, which f t the S,les of .liynthesis of lhe clolling factors. Inc loomg jIIllhrombin. This lengtoons 100 clolling time by decre:llling die amount of biologically lICth'e prothrombin in the blood. ThediS(:overy that dicumaml and related compounds were jIOO:nt reversihle competitors of vi tamin K cooguhliUpro IIQIing properlies (allhough al high levels dicumaml is not fe"o'mCd by vi tDmin K) led to the development of anti - vituIll" K compound such as phenindiolle. which wItS designed _pullCCOI'ding to metabolite-antimetabolite conceptS, 11le ttU~ compounds of !he phenylindunedionc Ierit'S an:: char kltnll by a phenyl. a substituted phenyl. or adiphcnylace 1)1 poop in lhe 2 position. Another requirel1lCnt for acti.'ity I I keto group in lhe I and 3 positiom, one of which may kIrm the enol taUlornet. A second subslllucnl. other lhan ~do",en .1 the 2 posilion prevents this keto- enol tauto-1EI1'im. and lhe resulling compounds are ineffective 115 anu n:.gulanlS.

Dicumarol is used alone or 11$ an adjunct 10 heparin in !he prophyluis and treatment oI"imr.,,ascularclotting. It is used in poslOperat;"e thrombophlebitis. pullTlOO3ry embolus. acute emOOlic and thrombotic occlusion of periplK.al arter ies. and ~um'nt idiopath,c thrombophlebi tis. II has no ef fect on an already-formed embol us but may pre"ent funlKr intravascular clotting. Because the outcome of acute coronary throl1lbosi~ deprnds Iprge ly on eXlension of the clot and formation of muml Ihrombi in 111e !lean chambers . wilh subsequent emboli/.llti()n, dicum3ml has been used in Ihi s c()nditioo . It has alo;o been adrninistl."red 10 W'feSt impending gangrenc aftt:!" frostbite. The dose. after (\ctermination of the prothrombin clottin g time. ,s 25 to 200 mg. dcprndlllg on the size and !he condition of the patient. The drug is gi.-en orally in the fonn of clIpsules or mbletS. On the seoood day and thereafter. it may be g,,"en in amounlSsurrlClcnt to main tain !he prothrombin clotllnllimc at about 30 leco..ds. If hemorrhages should occur. a dosage of 50 to 100 mg of menadione $Odium bosulfite is injected. supplemented by blood transfusion .

Warfarin Sodium, USP. Warfarin sodium. J.(a-acetonylbcm:yl)-4-hydroxycoumarin sodium salt (Coumadin, P:mwarfin ). is a white. odorless, crystalline powder. with a slightly bitler tD~I e; it 15 slighllY !iOlublc in chlorofonn and soluble in alcohol or water. A 1'1> SOlution has a pH of 7.2 to 8.5. By vinue of its great poIerocy, warfarin sodium al first WlI5 considered unsafe for use in human5 and .... as used "cry effectively as a rodcrllicide. especially agaill5l rats. AI the pooper dosage level. ho .... ever, it can be u~ in humans, especially by the intn~'enous route,

,"""ucrs
I'Ioflmine Sulfate, USP. Prutamine sulf:uc luis an untiCOIgulant effect. but if used in the proper umount. it coun lerm the actIOn of heparin and is used as PO untidote for the *111 cMCS of o.,cnIosal.oe. It is administered lntrJyenous ly . , dose that depends on the circumsulIlccs. Dicurnarul. 3.3'-fIlCIhylenc:bisI4hy _)'COIImannl. is a whiteor creamy white cl)staliine pow a .,m a fainl. pleasant odor and a slightly biller tasle. II prICIic:ally insoluble in water or alcohol, ~lighl ly !iOluble ctoloroform. and dissolved readily by IIOlutioos of filled

e ,
1-

DicullVro/, USP.

(e-

' .)

Warfarin Potilssium, USP. Warfarin poIassium. 3-( aacc\on y Ibe n7. ~ [)-4-h ydrox ycou man n poIassiu m salt (Athrombin K), i~ readily absorbed aflerOr.lI admi mstration,

and 11 Ihcrupculic hypopruthrombinemlOl i~ produo::ed within 12 10 24 hours al1er oominiSIr'Jlion of 40 to 60 rna. n ils sal! IS lherupeutically int<!rch:mgeablc wilh wlirfann Mldium.

H,t<-C-N-lCH.h.-N-C-'*lz

II

II

"

"

Anisindione. us,.. Anisindio~. 2-(f/"lllethoAyphenyl}I.J indandlOfIC. 2-(p-.m~yl)-I.3.indandione (M ,radoo). is 11 p-mc:lhoxy coogenerof phrnmdionc. 1I is a ...'hIlC. crySIlIIline: powder. slighlly iiOluble In water, tl\Slcle<iS. and a~ well after onll admini"lrolion.

In 1?42. p -aminoben/.cllC'5ulfooamidoisoprop) )rI"adg. l.oIe (an anllbaclerial sulfoo;umdc) was found to ....... hypoglycemia. lbese rc:wllli slimulaled rc:-<.earch for~" velopmcnl of synthetic hypoglYl'tmic ilgt"'nlS. se"en! 01 "lIicll arc: in usc today, Sulfooylure3s became "idely avniloble in 19~5 rot trcullllcnt of nOTl - ketQSi~-I)1"041C nulll diabetcs and:llt iIiII IIIe drugs of COOICt"'. A second class of compound . lho!biplnidc!l, in the form of a single drug. phenfonnin. 11:11 befI used r.inee 19~7 . Phenformin wa~ .... ithdmwn from the U $ m:arlet . hov.e\er. because it cause., IlIClic acidosis. f.... ",hich fatalilles ha\C' been rc:poncd.

In insl"l\cc~ .. hen Ihe lIfmC may be alkaline:. an omnge color may be del~led. Thi~ is due 10 metabolic products of W1isiooiOl1e and is not heltlllluria.

a1o-CI1,-~-C-~-C-N1o

II

II

5.llfon,t"rea c
The sulfooylurc:a.~ may be reprc:)Cntcd b)
the foIlO'llo" I",,.

SYNTHETIC HYPOGl YCEMI( AGENTS

The disco,'cry that cenain organic com pounds will lower
lhe blood sugar lelltl i~ nO! recent In 19 18. guunidine WIIS ~hown 10 lol'.cr ,he 1lI00d ~ugar level. Tho: discovery that cena;n Irypaoosome~ need much glu.cose aoc.l will die in its ab<.coce was followed by the disco"cry lhal galcgine lo ....-em! ,he blood sugar Ie\el and ..... as .....{':lIdy trypanoddal. This led 10 lhe de"dopmem of ~vernl \ery !K.1;\e trypanocidal agenlS. such as the bi!l:lmidines. ditSOlhiourc:as. bisguanidilteS. and others. Syntllal in (trypanocidal I1t 1:250 million) and pent:unidinc are outstandi ng ellarnples of very active tryp;anocidnl agents. S),mhalin lo,,"'el" the blood ~ugltT level in normal. depancrealized. and completel), allollllnized animah. This may be due 1 ~uced oxidalh'e aclh 'ity of mito0 chondria. rc:suhing from mhibi tion of the "lol'dI:uli ~ms that $imuhaneously promote phosphoryl:IIIOT1 of AOP and stimu1:lIe o:tidatioo by mcotinanllde adenine dinucleotide (NAD) in the citric acid cycle. Hydrollysti lbamidmC' lsetllionalr:. USP. is u'iC'd as an amiprotozoon agent.

eraJ

~truclUre :

"-{

__ ' _H_C_H_"
o

" , " ," II" ,

~-,: -

Ii

(1"""->,

}---o -p<",-o,~

lbese ~ ure:l deri\'auvcs WIth lin arylsulfon}1 gotI!I the I positioo and an aliphallC ,roup al lhe 3 postllllll.. nr aliphatic group, R', confcOilipopl1llic propenies 10 ~ culc. Ma~inlal activity results .... hen R' consists oft/no! sill ClIrbon atom.~. :IS in chlorpropnnllde. tolbulamldt," lICetohellmnidc. Aryl groups al R' geocrnlly ghe IO~" ro. pounds . T he R KffiIIP on the uromatic rinK primml) IIIIIt eoces the duration of octioo of the oompound. Tolll\llalDilr disappean quite rupidJy from lhe bloOOSiream Iry bel", .. taboh1.ed 10 IIIe inacti\'c COUbollY compound. "hidt iii Q creloo ruptdly, CIiJorpmparnidc:, tW:IWC\'{'T, is ~.... more slowly and persi~s in the blood much lonlt!' The mech.anism of acllon of the sulfooylureas IS IO. ~~ lale tnc. ~lcasc uf insulin from the runctioning {In'ill It imacl pancreas. [n the ab'\CrK:c of the pancreas. the) ..... no ~ignificanl effecl 011 blood glllco'iC. T he sulfony llml may lIave Ollie!" actiOIlS, ~UI;h as inhibition of 5iX1W<gll.>C"J.gon and acliOli at po1<\tll!(:CptOf mtr.lC("lIular si~ W) crease in~uhn activity, For a time, tolbutamide. ch lorpropamitk. and amide wt"'re the only 01"111 hypogJycemic agenu. quem ly. a second gcnemllOli of these drugs becat'nr IIIIable . Although they did not presenl a new mechod "'wcring blood glucose le\e!,. they were more potatt" the ~xi,t ing drugs. Glipi7.ldc and glyburide are lIIe_oI generation om! hypoglyccmic agents. Whether the)' are lirst - or scc()lId-gcllerJtion Df1II hy"";'

Cl'mlc drogs. this (;fQtlP or agcnls n:mains a valuable adjuncl 10 thempy in adulto()flset diabclCli pacients. Accordingly, Ihe Wlf(NlyJUrt'as are noc indicated in jU\cnole-ooset diabetcs.

hour. ll1c main route of breakdown is 10 butylamine and sodium p .IOIUCIlC su lfonamide. Ollorpropamide. l -!fllchlorophcnyl}-~ulrOflyl J- J..propylurea (Oiabincq:). IS a while. crystalline powder. prncllcally insoluble in waler. 'iOluble in alcohol. and ~nngly soluble in chloroform . [I will form waterSOluble suits in b:lsk soIUlions. Thi ~ drug IS more: resistant to coo~ersion 10 inactive metabolitcs tlwt is tolbutanude and. as a rc:Suh. h3~ a much Ionget' d UfUtion of action. One <;tudy sho"'ed Ihat about half of tllC dl\Jg is excreted as n"lt'tnbolrtcs. with the principal one bcinf hydroKy laled in !he 2 posilion of the propy l Side chain.' After C()Iltml of the blood sugar level. the maimenance dose is usually on a oncea-day schedule.

Chlorpropamide, USP.

rolbutamide, USP.

Tolbul(lm lde, l -butylJ -{I' tolyl-

pyllhmdl:\ ' o produce for the desevernl of

suJrOIlyllun:a (Orinasc). OCCUI"5 as a .. l1l1e. crys.udhnc pow der lhal IS insoluble in waler and soluble in ak:Qhol Of aque ous alkali . II is stable in air.

--I-N-C-N-O'

55 for the nd an: still . the blgua. has been 1 the U. S.

from

" "
II"

, , 'c"n'nlo

~is.

Tolbutamide is al:lsorbed rapidly in responsive diubclk p3lK'm~. TIle blood sugar Ic\el reaches a nllmrnum aflcr 5 10 8 hours. II is oxidized rupidly in vivo to I-butyl-J-(p carboxypb:nyl~ulrol1ylun:a . which is inacti ve. IllCluoo.. ~Ie is frt'C'ly soluble al urinary pI! : if the unne is strongly IICldilied. ho",ever. a~ in the UJe or SUlfosalicylic acid as a proIelll precipitam. I white precipitate o f the free acid may be formed.

n.c

Jov, iriS gen-

-.
}I

USP. T o la:amidc, l -{l""II'.\ahydro-lllaf-cprn-l yl)-J-{Ptolyl,ulfooyl)urea (Tolinase). is an analogue of tolbutamide and is reponed to be efreetile. in general . undeT the !>Dill(' c1o:umsumces m .... hkh tolbutamide is u!>Crul . T o lalamidc. howel'er, appears to be: more potent than tolbutamide and IS nearly equal in po!Cl1CY to chlOfJl1"OP'
Tolazamlde, amide. In studies with rndioocti,'e tolll7.amidc. in\'e-sllg3Iors round Ihm 85'k of an orol dose appt:~d in Ihe unllC' as I11ctabolrtcs thai were more wl llble than tola/..lmide itself.

grou p m
TIle

o
~-o-

lII/ilIlOll.

o lhe moleof three 10 IIImde. and

lO~ic

II

II II '11"
o

--S-N-C-N-Cl+CI1CHoCI1:.
H-"

COni-

anly mOuoIbulllmide ' bcms me h lch i~ ex

Tolbulwnide ~Id be used on ly .. hen the diabetIC pa!!mIlS an adull or ~how~ lIdul!o()fIsct diabetes. and lhe p;lllent mookilldhen: to diclll!)' res lriclU.>nS . To lbul:lmidc sodIum, 1 M)I-J.(p- Io!y l ,ulfonyl)ure~ monosodium suit (Ori nase OilrlROSHc). is whne. crySla lline powder. freely M)lublc in .1Ler. 'iOlubie in alcohol and chloroform, and very slightly

."-

"lttaboh7.cd
t o ~Iimu :dls of lhe lhey have
fonylun:a~

rolbutamide Sodium. USP.

toIubic 111 elher.

Acetohexamide. I-!CplICdyl. phenyr}!;\J l fonY'I-JC)clollC~)"lurea (l)yrne.lor), is rdated chemically and pharmacologically 1 tolbutamide and chlor0 propamide. Li~e UlIl other wlfooytun:as. acetoheXIlfflHk ]o\\'ers lhe blood sugar re~et. pnntarily by Mimurating the release o f endogenous insu lm .

AcetoMxamide, USP.

!adion
~ite~

of to in-

,,}--S 1111 -..--C-N-Cl+C*+C'+CH, , ---

" ...."
o

o
00,0-0-

II

ICetohe \ lS. Sub<;c1Ul1e avnilJlCthod of ()lent than

1C

(0yme\001

.._--A~'C. oIlexamlde

\CCond-

I hypogly-

1"ltll "'Oller-soluble !;all of Iolbutmmde is used in lI'"J~e_ IOOsly for Ihe dlagllosi~ of mild d,pbetes n"lt'llttus and of r.tllOnmg p.1ocreatic 1~let cell adenomas. TIte sterile dry potrder is diSSOh'ed III sterile waler fOl" mjcction to make a dar soIulion. which then should be admini,tered wllh;n 1

,. mctaboli1.ed in the liver 10 a reduced for111. Ihe a- hydrux)ethyl dcri~at ive . This mctabolrte. thoc: main one in humans. po5S"SS('l; h)'pogJycemic ocllvity. Acel(loC:X:UllIde IS illlennedihlc betwcen tolbulamide and chlor-

O~',,-

FI

r<,

""
II II h}-'II-:-'-:~ 1/
0
0 0

GUpizide (GIUCOIrol)

~-""-""~' \\

o=c

"HN-Clit-CH,

G""""", (OIaBela. Mlc. onase, Glyrwse)

propamide in potency and dumion of effect on blood sugar Ic\'cls. SlruClUrul1y. glipil.idc. l -cyciohexyl -3- lIpGlipizlde. r 2 - (mclhylpyflQilM.'Cllrboxamido) ethyl] phmyl J sulfonyl ]

-U-~- c -='o

" "

urea (G lt>OOU'OI). is a cyclohe.(ylsulfQllylurea !lJ1alogue simi

Ill!' 10 acdohuamide :md glyburide. The drug is absorbed roptdty on onl adminis!r:ttion. Its serum half li fe is 2 10 4 houn, 1100 it has 11 hypoglycemIC cffecl lhat r1Illges from 12 to 24 hours.

to 4 houlll, whIle the hypoglycemIC effects range fmn 11 to 24 hours. MClnoolism of glipizidc is generall) . .~ ox idation of the cyclohe,ul'le rinll to the p-hydm.y ud hydroxy nletaOOHIC5. A minor mC:l aoolitc Ihat occon: volves the N-acelyl dc:n vative, which moults from the ICCIy 1~lion of Ihc primary amine following hydrolysis of amide sySiem by amidase mzymes. Gllmepirirn, Glimepiride, 1-[ t;,.[ 2-(3-ethyl-4-mecb)~ 2-0.\0-3 pyrroli ne- l-J;arOOxam ido )elh yllpIlen) 1\sulfOll) 1 ~ 3-{trans-4-methylcyclohcxyl)urea (Amaryl), is .'ery fUIIIla' to gli pizide wi th the exception of their heterocydic nI\F 1 00;teoo of the pYTaJ.ine ring found in glipizide, glimrpulllr contains. pyrrolidine system. It i5 metaboliRd primrir through oxid:mOl1 of the alkyl side cham of the PYrroll~ wilh D mioor metabolic route involving acet) lallOl'l 01
amllle ,

Glylwrlde. Simihu' 10 glipizidc. g{yburide. J-IIP-12-{5chloroo-anisamido}ethyll-phcnyl]sulfonyIJ- 3-cycl~x )'1urea (OIQ Bela. Micron:t'ie. Glynase). is a sa;oodgenenuion oral hypogl)ccmic /lien!. 1lie drug has a half-life: elimination of 10 hours. but its hypoglycemic effect remains for

up 10 24 hoours.
GlipizlM. Ghpiljdc. l -cydohell:y l3-ll p-(2-(5-methylpyrwne<:ariJoxamido)ethyI1phenyIJ5I.IIfonyl)urea (G llICo1roI), IS an offwllile, odorless powder witll a pK. of 5.9 , 11 is in<;()luble in water and alcohols. bul wluble in 0.1 N NaQ H, E\'c n thQugh on a we.ight b;bis il is approximately 100 Ii illeS more potent than IOlbulllmide. the max imal hYt" glycemic effccts of the.~ two agent., are simllQr. It is rJpidly absorbed on orol admini'lration, wi th I serum half- life of 2

Glic/azide. Chem ically, glichujde, 1-(3-a/,ubic [3. 3.0 !oct-3-yl)- 3-p-tol Ylsul phonyl urea (OJ amicron I. v"y simi lar to tolbutamide. with the exception of !he cyclic heterocyclic ring found in gJiclazide. The pyrroI increases its lipophilicity o"a that of tolbutamide. ... increases its half-life, EH'n SQ, the p-methyl i~ susap: 10 the some o~id"live metaboli c rnlc p ~ obsen.ed f(l" butamidc, Ilnnlcly, il will be m....1IOOli,.oo to a clUi:wllyk acid.

II o
Gt,pui(IB
(GIUCOIId)

II II S-H-C-tl-{
H H

GIimej;w ide

I" o

s-H-C-"'I-<

"

''''''''''
I S-N-C-H-N I" " o
o
mia. ~uhini In shakiness. headache. cold ~"'eats. anxidy. and changes in lnc:nll.1 Siale.

"""(0larni<>0i1)

""
o

Ionsulf_,.lureas_Mebgllnld_
Th: I1'lC:lDglinide..~ are non~ulfon)'lun::a oral hypoglycemic .1115 used in the management oflypc: 2 diabell~s (noo-insuiii dependent diabc:lcs mellitu s.. NIDDM). 1'he1>C agenl~ lend III ha\'t I rapid 0!lSC1 and a !ilion dUI1IIiOll 0( action, Muctl lkI: the MJlronylun::~. these indl.JCC insulin release: from lill('honlng p:lI1crc:Ilic p cells. 1bc: mechanism of action for

I
(PrandirI)

,12 'gh
~y~

o rn~ m-

""

hylU~ Ii lar

""Inly
~-

ng~.

II ATP-dt:pendc:nl K ~ channels. l1Ie K ' channel blockade: oiepoIari~u the ,8-cc1l mcmbrnne, which in 10m I~ads to (a!' innu~. im:rcasc:d inltll~"i:llllJDr Cal ~. and Stimulation rI Hlsuli n secretion. OceauS!: of this different mechanism of I:\JOIl from the ~ulfol1yJun::lI~. there an: two major differ.
between these seemingly similar clas>Cs of agents. The liM i~ thai the metaglinilk~ cause much faslcr insulin ,.xJuc1ion than the wlfonylureas. A~ a I\'..,uh.the metaglin_ lib lobould be taken during meals. lIS the p;mcn'as .. ill prokt lD54Jhn In I much shonerperiod. The.'iOnd dlffereoce IIIIlthe effecl'l of the mct;tglinid6 do IlOl las! as long as Ibt: effects 0( the sul fonylureas. The effe-cl~ of Ihis class IppCIC 10 laSlIess Ihan I hour . ... hile sulfonylurcas continue IhllnlUlate insulin production for seveml hours. One itdvan... of a short dUmlion of actiort i~ thai thel't! is less risk of
~lyccmJa.

lilt metag.inides. however. differs from lIulI o(the sulfonyl_ llle mochanism of action is through bmdmg 10 spc_ aIk tcx:cplors in the p..ccll n~mbr.lI1e.Ie:lding to the closure

Although natcglinide. N-(4-ililOprOpyl_ cyclohexanecarbonyl}-I).phenylilianine (S tanix ). belongs to the mctaillinides. il is a phen),lalanine den"al;ve and reP'll!itnts a oo"cl drug in the management of type 2 diabetes.

Nateglinirk.

"'"
lo

T1IbtzoUndlones
The thiu.oIindiones n'prt'lICnl a 00\,,1 nonsulfon),lurea c lass o(hypoglycemic agcnts for the treatment of NIDDM. MIlCh like the sulfonylun'as, the use of these agents requirtll a functioning pantn'as that can successfull y .'leCn'lc inWlin from P cells. Although in~ulin may be relea.~ in normal levels from lhe: cells. pt'ripheraJ sen.,ilivity to thili hormone may be r(.'duced ()( IlICking. The thiamJ idillC'd lollC.'Ii are highly selecti ve agOlli sls fOl' lhe pero~isome prolifcrntor-J1!.1h'stcd l'C(.'I,'ptor-l'(PPAR which is responsible fOl' impm~ing gly_ cemic control. primanly through the implt)\'cmc:nt orinsulin sensiti \'ily 111 muscles and adiJXllit tissue. In addillon. they inhibit hepatic gluconeogenesis. These agents nomuJlI.e ,IuCOSt metabohsm and reduce the amount of insul;n nc:cdcd 10 achievc gly~'CmlC cOlltrol. 1bey are only eff~he 111 the pn:seoce of II1suhn .

bi~~
101-

"

~~~

ylic
~lInide. Repaglinidc. (+ }-2-Cltlo~y-4-IN_[ 3_ .tllyl1 (SH 2( I- piperidinyl ) phenyl [butyl Ic~rbamoyl W)llben1oic acid (Prandin). n'prtSCnts II new cJllSS of _ Ifonylurea or.JJ IInXlglycemic agents. Witll. fast onset . . . iJIon dunnion of action. thc medication AAotilu be .... lth meals. II ;soxidized byCYP )A4. and thecarbox!Itt It1d may be COIljugaled 10 inxllve ConlpoundS. Less . . 0.2'1: is excreted unchanged by the ~Iuncy. which may Ire an acJl'lIntage (Of ekkrly patients "'00 ~ renally imjIIIn'd. The mOSI common side cff",'Ct involves hypoglyce-

n.

Rosightazone. (:t: )-5-[ [4-[2-(melhyl-2_ pyridinylamino)etho~y Iphenyllrnethyl}-2,4-thiazolidinedione

Rosiglita.zone.

(Avuoolu). i~ a .... hitc 10 offwhi le solid "'ilh pK.. values of 6,S and 6. 1. Ros:igllla7.o!1C is readily ",Iuble In ethanol and buffeml aqlleOU~ 'iOIution wilh pH of 2. 3; 'iOIublhty decreases "'llh increasing pH in the phy~iological rungc . The molel:ulc h.as a ~ingle chinll center and IS pre..~nt ~ a r.JCemIItl'. E,'cn !iO. tile l'nanliomcl1> are funo:.11Qnaily indistin-

a-Clucosld ... Inhibitors

The enzyme &-glocosidase is pre,',ent in the brush bc:lrder or the smal l mteslil'\e and IS responsible for c leaving dlCUry C arboh)'draICS und foclljlatinll their absorpckln intOo the boily. Inhibilion of th,S cnlyme allOows ICSI; dietary carbohytlrllt tOo be: avaI lable f(W" al!!iorp4 ion arid" in lum. less 8Y3ilabk ill the blood follOowlng a meal. The inhibitory )JIop<:illCS or these agen's arc: grea test for glycoamylasC", foIlOo ....c:tJ by lollcrose, maltase. Ilnd dexlrJnase, respecti"ely" Since thc$e do not enhaoce insulin secrelion when used a.~ nJOnothcrup). hypoglyccmig is acncrolly not a COoneem when using tw agents.

gUishable because o r rapid ;nlcrcOll\CI'lOIOfI.

TH
.mll

"" cies
do"

o
",

...-\I"' -

PiogJilazone. I'ioglnazonc. ( :!: )-~_ 1I4_[ 2-(5.ethy l-2pyndmyl)c'lho.\'J [phenylimethyIJ-2.4-lhlllOOhdlllc<honeIAe101;), is an odorless. ",hi tl'. crystalline 1'O""\kr Ihm mu~1 be
cOfI\cned 10 sail such as its hydrochloride before il .... III howe IUIY wuter solubil ity. Although the molecule contains

one chiml ~'enrcr. tile compound is used II.~ the rucernic mixlUre. Thi~ is primnril y due to the in v;vo inlc:rcOllVcr"ion of the twu enanli orl1cr:s. Thus. there arc no differences in the pharmaoologicaJ activity of tile 1110'0 c:nailliollle~.

AcarOOsc. 0-4,,6-did"'( lxy-H[( IS.4R.SS.6S} 4.5,,6.trih)droxy -3-( hydrOoxy meth yl)-2-cyciohexen-l-yll ami no ]n-ll-glucopyronosyl.( 1.4 )..o-O'-D- glucopYI1l~11- (1,4 )-D-glllOOSt (Precose ). i~ a nalllrally occumnll oIi~ chatide" ",h,ch i~ obtained from lhe micloorganism /k"",. Oil/lilies uwherls,s. It is a ""hi'e tOo Ooff-.... hne pov.der tNt is soluble in '" ater and ha ~ a pK. of 5. 1. As one: might expect. its affinilY for a-Illucosid:ue is based on it being I poI)~. charid<: that the m/ynw;: IIl1empis 100 hydrolyle. ThIS allotol HCarbosc: to acl as a compeliti ve inhibitor. ",hich in Iu'Il reduces lhe inte~tinal absorptioo Oof starc h"dextrin. and diloOol' c harides.
Acarbase.

'"S

PO"

.h~

Sian

B"l ro"

po

,~

'niOo \lley

"'" I ente

..,

""""
""
0 0

Lev.

0 ,,('

Bhgnklln_
Metformfn. Mctformin. N.N_ t,limeth)' lumdodlcartJoni _ nudic d,amidc hydrochloride (Ghx:ophage ). is a b,sguanidme. nus class Oof agents is capable Oof reducing ~ullar ab-sorphOon from lhe lIaSlroinu:s ti nal ITaCI. Al'iO, they can decrea....e glucooeogeoesis .... hile increa)U\g g lucose Uplake by mu"C~ and fat cell s. 1lle;;e effects. In !Un!. lead 100 IOoWI!( hlood glucose levels. Unlike 1he ~u Ifl)llylureas. IlIese are 001 hypoglyce mi c agcnl~ but roIlier c~ n IlCt as amihyperglycemles. 111;<; difference in nOorncnclmun: is due 100 the inabi lity of dK"~ agents to stimulale the release Oof In sulin from the pancreas" Often, mctformin is l.'QOOministeretl w;lh the non iMJlfooylureu tOo improve the efficacy Oo f t~ agcnts.

~" U::,.,

""~

..,

--

..,

""""
0 0

yell( ble i hydr pH (

m,"

whi( thy"

(PIlICe If)

'".

..,-

Migfltol. Mi ghtol. 1 _(2 hydroxyelhyl )-2.(h)drol~ methylH 2H-(2O'.3,B.4aj ,BJl-plperidioe (Gly!>CI). I Ibn) IJOjirim)'cin derivali>c" is chemically kno ... n as 3.4jprpmdinctriol. II is a while '00 p:.le yellow po ....dc:r thatllo in water" ..... "h a pK. of 5.9. In chemical strUCIUR:" th, J " is >cry similar 10 a sugar. wi,h lhoe hetc:roc)'chc ntlr'llp serving as an i50Sleric I'qllacClTII'nt Oof the sugar O~ ~gc:n. n. feature allows re<;ognition by the &-g lllCO$id:lsc: ., . . .

Ii. "

lInIIe. This resul ts in lumpcll t i~e inhibit ion of lhe enzyme IIIId delays comple:>. carbohydrme absorption from lhe gaslI\)InleslinaJ trxl.
OH

dos:lge of 100 .ul!; of le"othyro~i ne \Odium i ~ c linically equiva1cnt 10 30 10 60 mg of Thyroid US I' .

Liothyronine Sodium, USP. UOI hyrouine ~()dium. 0 (4_hydrox y -3-iodophen) 1)-3.5 -d i itJdo. L-th) rox IDC IT"IOfl()SO. dlum salt (C~ tomd ). I'lhesodium "<lIt ofL-3.3'.5-tmodothyrollInc. It OCCUIli lIS a light-Ian. odorless. cry<;lul li nc ]'10\\ !ler. whic h is slightly solub le in waler or alcohol and h:l.~ a speedie I'OIlltioo of + 18 10 22" m a miJlture of diluu:d 110 and alcohol.

sh border "mil d ietary 110 the body. arbohydr.uc

or

OH

a"~i lable 111

I!llpI!rheS of owed by su -

THYROID HORMONES
Iksiccated. dcfulCoo thyroid substance has heell us;."<l for !!WIy years as replace mcntthel"Jpy in th)'roid g lund dcflciellOt<. The efficacy of the "'hole gland is oow koown to depmd on liS thyroglobuli n cOOlcnl. 111;$ is an iodlllC-tontaillin. globu lin . Thyroxille was obtained as II cryslall ill<' dtn"luve by Kend.,n7l> of the Mayo C linic 111 1915. It v.o.-ed much the salll!' action lIS the whole Ihyroid sub1WICt. Wner. thyrox iroe was sy nt hes ilcd by Huri nglon nnd Ibrger in England .17 Later ~tudies show~'d Iha l an c I'en more poIrnl ,odinc-contaming hormone e:>.i'led. whICh i~ oow lrIDIr.n:as triiodolhyrun;ne. F.;vidcn now mdi cates thal lhy l'O.Iioe lIloy be Ihe stul'llgc form of IIIe ho nllt)IIC. whereas tnlOOothyrunine i~ the cin:uluti ng for11l. Another potnt of llew i, that in the blood. Ihyroxine is bound I1lOIl: fi rmly to the globtJli n fr:v."tion (han is lri iodot hyronint'. which can then min" lhe lI.sue ee l),. U Olhyrooi ne sodium oceul"li in vi""J together with levuIhyroxioc sodium; II has lhe "<Ime quall tall"c XIIVIlICS Ili thyroxine but IS more acti"e . It is absorbed readily from the gaqroi ntcsl!ll ul trxt. is clearctl mpid ly from the blood ~t ream . and is bound nlOll' 1~ly to plasma proteins tl\:ln is Ihyro~illC. probably becau"C of the 1c~s acidIC pheoollc hydroxyl group. lis use, an: the s.ame as Ihose of levOlhyrox me Mldhlln. includmg lrCallocm of~lIc Insurticlcncy. rmle ,nferu lny. and cenain gynecologIcal dl.'iOrdcrs .

occ thc:se do

oOIlothl'm py. IlSlng Ihc-c

S".4R.5S.6S}

lw,o(cn- I -y IJ 3ptra nosy l . ng ()lig~ .n1)Hl A./;II.... der that 1\ ught cx pect , Sa ]'IOlySlIC '
1l., ~

3110.... ,

1ich In turn n. and di ...";I-

ANTITHYROID DRUGS
U lpt'rrhyroidi5m (excessi"e productioo of Ihyl'Old hormones) usuully requires surgcl)'. but before surgei)' tile pa lient mUSI be pre pared by pre lirn inory abolilion of thc hyper_ thyroidism through the use of antilhyroid drugs. ThIourea and re lated compound. show :an amith),rotd activi ty. but they are too lox ic for c1 mlcal use. The Il"IOI"C useful drug~ are 2thiouruci l derivaliH'S and a closely re lated 2-thioirnidalolc dc rhmil"e. All of these appear to ha'-e a similar ma:harusm of actioo (i.e .. pre"cnllon of !he iodmallon 0( the prt'CUN'lI'S of Ihyroxine und ui iodothyron;IlC). The mai n diffcrence in the l-ompound~ lies in the ir relah ve lox iClties.

tNothyroltlne Sodium. US,. L..evOlhyroxlllC sodium. Q.(4-hydro.ty-3.5-di iodop hC' nyl)-3. 5-di iodo-2- tyrosinc molO6Odlum sal t. hydrale (!iynthroid . L..euer. L..e'oxinc. Ltvoid). I' the sodium s.alt of the /C'WI i'lOHlCr of Ihyro~lnc. _lIkh i ~ an active phy~iol ogic al principle obtamcd fron. the Ihyroid gland of domcst icated ani muls used for food by hu __ It I~ al<;o prepared 5}'mhetically. The "lll! i~ a light )"CI"""". t ILSICICIi~. odorless ]'IO",dcr. It i~ hygroscopic but ~ta bIe in dry lIif al room Icmpel1lture. [I is "UIu ol c in alkali ~"dro~idc ... 1:275 in alcohol. and 1:500 in waler. to give a pH of aboul 8.9 .

s= c
Z..( hydrox)'I. a desoxy-

/"'

.."

1,4 .5-PlllCri U is )oOluble

!.

"""'""
~S<rium It" . I. ~. IA\ ~ ' ...... ...,

Ihis agent lie nitrogen xygcn. Thi ~

U:I01hyro~i ne deM~

a,<;

a s.ub-

sodi um is uSt."<l in reph,,:c lllcnl Iherapy of thyroid fUl"ICtioll (hypotll}'roidlsm). In general. a

T hese compounds arc absorbed wc ll ancraml adm'niSUlItion and excreted In the: urine. The 2-thiouracils. 4-keco-2-th,opyri midillCs. are undoubtedly tautomeric l"Ofl'pounds and can be represented as fol lows:

Some 300 rclll'cd Sl ruclUrcS have been evalu31ed for antithyroid acti\;ly. bul of Ihe~. OI1 ly the 6-all.:yl-2-thiQuracils and closely relaled structures possess useful clinical acti vity. The 1nw;1 !ierious adverse effect of lhiour3Cil themp), is

REFERENCES
P . Ad . DnlI- R.n. 10:93, t 97j 2. A _. W SA... Kan I 84lll. 1972. ) , ~i<t.1!... 1_ I r.. ..... 8nom~..1d. F Am. I. CanJid II _, 1 1I.0b0-.

11......

I1gr:mu100;,: ylos is.

Propylthlouritcl" USP. I'lOpyhhiouncil. 6-propyl-2thiouracil ( Propacil). is a 511lble, while, o;ry.stal line powder wilh a bitter Illste. It is slightly soluble in water bulreadily soluble in a'kalille sol utioo s (sal! fonnalion).

32K. 1%8. 4 lparro. L 1. 00al.: I. I'twmaroI up. ",.. 1 1 ~7)9. 1981. 5 f ... li:!Cb. M. Ear UUII I I;I;S""",. I),12:I. IW3 ~ "". II a .... p . Annoo. Rev - - . . - . T.... oed , Itdl . 1976 1, S. I .. ..... r....&. II. L , I Ph:onnocol Itop. n.."., ll3 1t14. 19Wi 8. ""-i. S. A J I'IIwm. Sci. 62 123. 1913.

a..ma.

(P' ......,

16 s-,p._. M C_ "'" K... R S C;n.. 11. Ili>oenlIn;bi:Il. R OIIL N...).s.:~At<1I. """"-"l lit III. 1Y79. 18. TriuJt. D. I.. Calcium ......""1.... I", Ant"""''>: '''. P N. (.... ), C. . . ....,..1.. I~. lid N. Ne,.. Yort. 11..,,,,, l'reo . 19\10. 19 ......pon ..... ,11,l1li1. F M.. I" ~ E.. ~1r.....o-I"""" E . ., ~ ()II,. , K. H. ( N).). S) ......... _ (III Can;!...., Anto}"1hu " Sc I. l

9 I'u"';. S. A.. I I'llarm 50" 61:2012. 1913. 10. McClOll. D. 01 II C...... I'robl . CIIIlioI. 10; I. 1915. I I 11eJch1ef. J.. 01 II Eur I a...m.m 1105:261. 1981 12. 8md.... M. I ,.......~ . bt, .. 56:1j9. 1981. 13. ' ... Z_ ..... P A . ond .... Mod. J C~ f'mI. 1'IwmaooI. 51, J9Il 14 AI~'n-. J.. 01 .1 , N..nt" S<luneII.I!ofp Arcll. PIwmacd.. lJ7 .pI 1988 I ~ SIMb. H. 1_ ..... 8n"""". M 0 J Mol. C~II 11109. I"

a....

C 19801 ""'''''. Rel.. UlJ6.

This drug is usefu l in the u\:alment of hyperthyroidism. lbere is a delay in appeal'1lllCe of ils effects because propyllhioonldl docs nOi interfere wilh lhe activity orthyroid hormones aln:ady fOllllCd and stored in the thyroid gland. This tag period may vary from severnl days 10 ... eck~. depending 00 the condition of the pollicnt. The need for litrecl equally spaced doses during II. N-hour period is often Mre~d, bUI

S.. - . a A....... 11J70. PI' "'1J..... 72. 20. ........... W,I ........ Eo M J Oin. ~. 2-'129. 1911.1
1 1. CAPS
1"" ~\llp.. ",,:

Am, I Canlt<>I. 6 1;~ I . 1988.

evidence now indicates that 11 si ngle daily dO!.C is as crfective as ~lUlu~c daily doses in the tn:aunml or most hypenhyroid
p:ltJenl5.
USP. Methirnuzole. I-mcthy limidal.ol e2lhiol (Tapa7.ole). occurs as a while 10 orrwhile. cryslal1i!le powder with a ch:InICtcriSlic odor :mil i~ f~ly solublc In WIlIer. A 2% IIqIlCQllS solullon has a pH of 6.7 10 6.9. 11 should be packaged in wcll-closc:d.1ighH~si'lanl containers,
Methlmazo~,

21. W..... l<y. II 1_: AMII. Rev, PIo..-nlIOtIJI To.lOIroI 1 1:427. 1991 2J Campbell. T J CanJ;"'-.o R.. 11:>U. 1983 U Yaol. A . J . Mol. I'IoannamI. ~-<nO. 199-1 23, I~ L. M .. ...J ICJoltuna. 8 0. ; A ...... Rn """"-d T_ 001. 2-';387. 19801 26. Nle .. AS .. IIIIl S"""I. [) 0. Clin PIo.armacoI . hp. The;- IHll.
1'113 J . AnD. N. Y Ac8oI. Sa. 119:310. 1911 21 O..,s,n ... E. V . 01 II.. O la. 1"hIrmIcoI. T1ter l'UJ9. 197629 J.. .. aI . 0 .... PbarmKoI . ",.. 11 1).1. 1m. 21
lI:ochW~.

30 Belf.
31

f.I_.

a.. 01 01..

Am. I. ConIioI. 35212.1975

.w

Ii,....... T J., and larr~. C. Am, J ConIt<>I 21 ,U. 1971 11011......... (l. Ano ~ TOAoed. 11.1Sft, 1960. )3 II.U.... R HMClII ~ AnI . ....... I nJ 13. 1969 Ik<:ket,. A. II . InJ C'ItioMD".... E. C~ """&nd. Mod. I. J~

n.
J~.

c..

I );((). 1917.

AIIIk'nM. I L . Ma>.on. J W . 1IIIl II""". MD. 0""'1 ..... s1fln

~) ,
I

)6.

31 lB. lIJ
oI().

I'I1B. o-tolef. L 01 IL A..... ' C...:buI ~5:S01. 1981. SatU. T _ .. aI~ &or I 1'IwmaooI. lItl ,'49. 19901 ~. 11: .. .. III. a. I ~, 102:669. 1'191 Ihl. I. T . Dtoff. II J ...:I f... D. Cba. ~ 21

...........""
rr_....)
Methimazole is indicated in lhe treallllenl of hypenhyroidism. 11 .5 more poIenlthan propyltltiotlnldl. The side effects are similar 10 those: of propylthiouracil. A~ ""im ocher antithyroid drugs. patients using this drug should be under medical supervision. Also. like the other antilhyroid drugs. methinUl7-01e is mosl effective ;r Ihe 100nl daily dose is subdivided and gl"cn at 8-hour intcrvals.

I\!!I I.

1Iuf_.

.u I'Irf>. I 0 . Md V...,.... W,III2hIII. E. M

4~

01 ."... S. 8 . L . _ V....... _ . f...: 8. IkAn I. )JIZ!i 191] 41 11:_. R.. .. aI O' ... l'Ioarm .... 11:"J8. 1981 4 2. Wllt. D. M .. Elb.....nIo.A J ~ IIIIl,-,=, ........ 1 II A ..... PIw 111<161. 1993. .oj. N><l.o.........,. K~ .. al .' Cimlll""" 66:202. 1982.
t

!In._.

Borer. E. W_ SIOIt.C.. ........... II

..

8. J I'IIMma<d \1

Y IIIl.J M..t.T",oatIn

4 . 16. 46. Sal.",.! I.nd 11"'01;0. R. II . Canlool. DwiRe. 15 131-1"- )til ';1. Tilfl"lCdt. II .. IIIIl EJ.erpooan.I' 0 .. s.:and Arch. I'hy>iul 8:ll.! I'" 48. r . . f _ ....a 11.1...... 0 A J up Mod 11 :19. 1<)4()

(;k aplu III

C"rriIUI"tlJnl/'" A,gmts

675

.I'J

L. a;o/ J &p. Med. W:!H. 19SoI 50 SIIopro, It. and Roonl.In. J 1'.: KtIIcm,w)' lB225. 1984

S~~

01

QIannoI;: S"""Un!'. o.o. ..r",........ Fun."\JOII -.I Tho..".111": Putt ..... . I'no' y",i,. JohII Wilty .. .son.. 19'10.10,

coot.,
lSI

N S,.

I"""'~m

"

! I I:hIon. MR. -.I RIIII'IIaa. J f . 8""'..........,. ]0;71 18. 19'J1 !2 1IM.,l II: Ilr J r I ~50. 1""9. 11 Ik S M _Shon. P A.. and 8n>dir. P I' B. J PIwoaOOC\Jl . fJ.P. Thtr 118 IW. 19St1 }I. ItiMner.N J 8001 Cbent.2372111. 1961. \l .... f.a .... U S .. -.I LiihaJl.O. I' .. I... , J N",,~. 2;127. 19bJ J6. MuI"'" J M. Sch~n"'. Eo. Ind 8nn. II J . fu. ... 19S1. fl. U'Pnctwd. D.. fI oJ . f...... J ~. ~87. 1978. ! 5''''. 5 z.. orr.! c. ..erv, I. Hy~ D11. 1980. " sun.., K~ 8IId MOIMCI. II; l'1ou""","",\3c\lkIo' 12:1013, I~7.l. 10. .~. K I) Dora-lKl,.. VWI<\J....,.., In B. J , .. 01. 1M ,). ~. Ne .. Yort, ~h l ll U ........ _. 1994. P 171. tl. Clnm. fl .. Or\ooy. J. -.I MCtrf. R. "--,,,,,,,,,n,l. 6 19. 19~1 ~ z.. ' R ~ Kl>ChW~. I (.1i., _ 1).""20. 1972

,"'on

6' ~. 0 W. " oJ ~ bp ,.".. 1II-I'I\6? (97) 66. lrty. R. t., .. 01,: Cln;uLMK... 6O:12l. 19Il0l. 67 I..e>y, R. r " ........ Ilc'. _ T~ . 7 499, 1977

'w_ ,;}.

68. N _JolO. P T ... "L A... ~. T<W<QI. J6:J,). 11m. b9 K.~ Y A."'" GtuoIcI)o. S. M .. JAMA :U1,WI, 19IU 10 A,nIdI, M- F.. .. 01 . 1. I~pod 11. ... :M--SIIII. 191U. 71 s"",no. 1, .. "" """". Nal. And. Sa.. U S. A. 711730. 191~

12.
14

J...,ua-. eM."'" s""... 1 w ....... Itcnwol. 10133.

c.ro-"""",..

So"""

1) T~ I) A. (td..):,... ...

PuoImooo. 0..:, ... 10._,,,,.. $0<"1) of

1~78

" 76
77,
18

'1 ,... 1 H ... 01- C.m&bt ..... 111811, 193$ ,

CltruCaI P.d,o"',IY. (97$. H'''''''"'I. M~ .. "I.; Proo. N>t~ And.. Sc, U. S. A. 7 1;300. 191. "llioon>s. It C ...... Ituby. M- W.: I. MM. CIoc"" 13:%1. 1<n2. KmdaIL E. C. JA~lA 64 20-12. 191' Ibmn,-. C. 11. ond 8 ....... C, : Ih"" ........ 1 21:169.1927, c;r...,. M A. and ~",Ioo. W C. N Enll J Mcd. 212:8811. 1\165,

m.

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47 L.

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~ ,.

20

Local Anesthetic Agents

GARETH THOMAS
Local llllCSthetics are blocking drugs Ihal, "hen administered locally III the COI'TeCI cooccntr.mon. "block" the IICOCS Ihm carry Ilcr.... c 1Inpul"<:ii In local areas of the body. 1lIcy do 001 block ooarsc touch or movemcm. and the action is 1"C\"c:l'!iiblc. lbclr method of adlllll11SlrdUOO is go\emed by 'lOCh properli~ as iOllie;l),. ~Iabtl ll)'. dUrJllon of lICtlQlI. waler solubili ty. membrane pcnne:lbilily, and point of application. "hile Ihdr nlOdcs of IICUOO (II un<kr hcadmg. Mechanism of A~lion) depend on thei r lipid solubility. pK \a!o(xhl:mon. and proachieved eventually by his protege Richardson ..... 110 ~ phaced lhe cologne In the tllCn rece ntl y jnlrodu~'ed F...au-Cologne spray .... lIh dher. This achieved lempclDlu/'l'5 ...... allo"ed nuno.- surg<'Ty 10 be carried out. Richanhoo _ 0Ihct "'oBert impro,ed the effICiency of lhe .... ......wu~ b)using a pelroleum dlstilLale. then elhyl brolliide. PI! malely l'fh)J ehlonde. Tbe SIICCXSS of lhe Rieharilion $fO\ In"pln..'!! Koller to search for a local ane,'II.hellC thai rould ~ sufely apphed 10 lhe eye. Koller quahfil'!! in medicine in 1882 and went on 10 !pC' ciuliu In ophthalmology in Vienna. Hi, c~pencnce M. eye surgeon made him increasingly aware of the nd fot I h...:al uoc~thctic thai could be used in thccye. ln 11IS4, "'~ he WII~ collabornti ng wilh Freud to ~Iudy the cffccl lllcocaine on faliguc. a colleague n:markl'(\ tllar the dillS numbed his tOilguc . Koller arKI Gaertner in\l~;,.tJgated Ihls clllm-.l found !hal a di lute aqueoo~ 'iOl ution of cocallle hydrochloride caused local anesthesia of the cornea. SreUlilIC'r ""51' 11" KolJe-r's resulls on his behalf al an ophillairnology in Ile itklberg 10 Seplember 1884. ~ince Koller rouJd II(I! afford lhe Lruin fnrc from Vienna 10 Heide lberg. KoIle"-l paper resu lled In lhe imlllediale .... itksprrad UloC of c... : in Europe IU1d lhe United Stutes.. Koller aho ~ the use of cocaine lIS a local anesthetic In ear. 1II.lSt. -.I Ihnxil opcrullon~. At lhe time. ho ..... cvcr. lillie Wll~ Jmoq !lOOUI i l~ addictive propenies. In 1885. degmdallon siudies by Camels and ~~In ~ ge_led Ihal then: wen: SOU SlrUclul1Il sirniJarilles bcI"'tn le cocaill<! and allOfJi1ll:. Thi.~ led FiJehnc at tile UDlv~rsll) at Bre$lau (I"IO~' Wrodaw) on Poland LodetCflmne "helhenlrOo pl1ll: had any local anesliM!lic IICli vity in the C)t . A~ had been 1)o(IiatOO from the fOOCS of belladonna In lUI Ii! Mem. II Gcmt.an apoIhccary. Filellne round that atropne liulc local anesthetIC atlivity and was 10lllC. causllII ~ im lallon althe do<.cs required ror any ath vity. Earlier. La! sen 500.....cd Ihutlllropine could br spill inlo lTOpIC acid" II nitrogenous ba.'iC called 'ropl~. Uoler. in 1880. ~ S)'nthe~ il.cd a >cries of phy~iologically acli\'c compo: I, which he: culled tr<!fNlIII!s. hy eSlerifying tropine ",Ih I 11ft ely of aromal1C adds. Fil ~hne in~cstigDled IlM'se M'rrtI.,.. thelic unaloguc.~ of atropine for loclil !lnc,.hclic acti~.t} foulld thm honmlropinc ( Fig. 2O-1a) was less uTilDlillf,1P

tCUJ-birKIUlg chamctenstics.
Although gh 'en 1 00001l y. the dn'g mu)' c~cn a ~)'slcmic effect bccau.;e of tr.lnspon in tht: blood !rom the site of adminblrnllon to OIller areas. such us the tl('an and cenlru.1 nervou~ system (eNS). Thc>,e sy~lcl n ic dfeclS, wllkh depcrld on the conccnlr.uion of, he local anc.~lhcl'C ,n the blood. Wl: u'Ually SC'dalion and hgluhcadedlk''<S. but r\'~lle~~ness. nausea. and all1.lC1y may :llso OC'Cur. Ill gh ph~~rll<I COOCl'ntm hon~ can resu ll In COfIvul<'lon,. clliropldy, and coma wi lli 1"C.Sp111l1 0l'}' and cardiac depn:....~lOn. Local ane~thl'lics an: used 10 ~ne'late lhe p31n caused by ~ Wide \'W1ely of siluallons. They ~re used In denllstry. in optullaJrnolOl!Y. in minor ).llrglCal opc:ratlOl1~ inc luding en<IoKopy. and in rehe~lng pall1 111 Inlr:lO.111ble medical contiiuon~. 'lUch liS tulllOl' growing In the SJlllle. Local al"lC!)liM!tics are also used lopically for Ihe Icmpor:try n:lief of P'lin from in<;eet bitc~. bum~, and 04iM!r type, of ~urfllCC "uund~. n.cy lire paniculariy effective "hcn they lire u~d o n mucous membranes. such as tiM! mouth. \agina. or reClum

HISTORICAL DEVelOPMENT
The Mar1 of lhe Sl'arch for .... ay~ 1 relie\'c pam is losl in 0 the pa5I . l'toplc h.1\c used religiOUS c. .orc ism. hypnotism. u acupunclure. hypodlermia. nc .... c compre!i.~iOfl. aod drugs. Each of lhesc rtlClhods h:L<. had lIS ~nod~ of popu larity. and 1"00"1 an: slil! used in one form or MOIhi:r. The modem development of the uo;c of drugs to mducc locill aneslhcl;ia probably ~taned in lhe mid- 19th cemury. 11M: earl ieq reoonk.'!! UloC of hypothcn nia a, a local DlIe,thelic. howcvcr. is believed to be by UolTl'y. Napoleon's chicfwmy surgeon during the relreal from Moscow. Il l' recortlcd Ihat ul11putal ion.~ wcre carried 001 in 'lUbl.ero lernpcrnlUre~ had a higher patient survival r~le than those carried 001 In wanner condi liOilS. Late!" m lhe CC'ntury. ToolllP"OO reporled Illal Cther acted a~ II rdnger.mt .... hen poured 111110 the ~lon. These Db~I'VllIlOilS lay dormant until 1848 .... hen Arnon I'CporIed that he had used a pig' ~ bl:oddcr fil l... wl lh 4'1\1Shed ICe 10 alle"i:l.le '!! lhe pain eau.sed by inciskllh made in the <'lm. This was followed by 51"1O.... s unsucccs:.ful auempiS 10 find II \iable way of using refrigeration as a local anc.~lhetlC. Succ-ess W;IlI

,0"
OH

676

(') Figure 20- 1 a. Homatrop,ne. b. lIenzoo!troprnr

"""""0 (.)

o=t
~
CO<,
(b)

CH, I CO<, N
CH,
ON

.. ho re-

EIIo-deres that OI1 and dure by nd ulli~prny

CO<, CH,

CO<, CO<,
(d)

oco-('
OOCO<,

I CO<,
H CH, H (.)

CO<,

oco-(

Figure 20-2 The Incorrect structUies proposed for cOC3Ine (.) aod t,opor.l' (b) by Albef1 {,"horn and Georg Mertln9 Structures of methytlfloKelOlll' alkamine (el . illpI!a-Eocillfle (d). and bef<J-Euc<JlfIe (_I

11

cou ld be
~pe

. to

cc as all ecd for II 14. whIle

:t of conumbed aun lmd chlotide nsemed

1l~lIl1g

ould no! Koller" s COC.U IW' IIllcoocd \ knov, n

III
~ug

0 . ....

betv,ecn m;il yof her I1ITO\Iropllle 1831 by "JlChad ,lIlg eye er, 1..0:;lCid and tlelloorj', pounds, , a vbri:ml~l n

theeyes and a beller local ~"hetie than atropine, ....,licrcll..'l brnloyltropint: (Fig, 2()' I b) WIIS a strong local anesthe lic but nused tOO much irritation 10 be of any clinical u"!:. T he ldmurlCallon ora benzoyl groop in the SllU(:fUres of the most lCh~e atropine analogues and a lso in cocaine. howc\'er.1ed filelme to teSt the acu\'i ty of lhe ben/.oyl derivatives of qui 1II1Ir. cinchoninc, hylinK:owninc. and morphine. His resuili. .tllt'll ....'ere pu blished in 1887. showed th:u these ben1,()me ~ acted as local IllM:sthctics. but many had unwanted iICIe effects. 8y lliKS the to~ic and addictive crfecl ~ of cocaine ....ere tqmnmg to e()nCI'm the medical world, and many workers _ seeki ng II safe s.uhstitule, In 1892, Einhorn , t prores.<;Or olchemlsiry at tne Uni\crs l' y of Monich. suggested tl struelWt for cocaine (Fig. 20-211) based on the: Sln>l:lureof tropinc ..",-sed in 18g3 by Merhngl at the University of Berlin IFiI. 2()'2b). Merling decided. on the basis of these illCOl"T'C>Cl AnlClUrt~. to synthesize II benzoyl analogoe com ai ning on ly I p!jICridine ring. He produced a compound who!lc: suucture '"IIi ~m"ar to tnat of the: .... eak ly lICtil"e mcthyltriacetOllC lIbm ine llnalor,ue of atropine' (Fig. 2()..2c), It WItS marteted lhe name alpha-Eucaine (Fig. 2().2d) but ......dS not pop-D . lI.'I il caused a burning sensation ..... hen applied 10 the t)"t>.11 was rapidly rcploced by bela Eucaine ( Fig, 2().2e). 1M th,S ~lso caused eye irri tation. Einhorn, on reali!ing Merl ing's ~s ..... i'h lhe benl.Oale

..xr

dcriV"Jlh'e$ of plpc:ridllK'. auempled to ~)'IltheSt.re actl I'e benzoate COllll)OUnds ba.-.:d OrIlhe simpler hexane ri ng. HiJ syn theses. v,hich wen: based on the redUCtion of aromatic ben zoate esters. failed . so he decIded to 1I:l\'e a number of unll'lated aromatic bell7.oate esteo; It'lited for local anesthetIC activity. Some were found to be act!Ve. bul more illlpOt tantly. seleral of the phenols formed by the hydroly~ls of the: (:l)ICrs ....'en: also found 10 be active. and III 11196. Einhorn intrud~ Orthoform (orthoc,I1ne') inlO clinical use . Prob le llls wilh its pruc.luction and its ~ide c(rts led him 10 introduce Onhoform New III 11197. Einhorn 's ....ork v, as Im ponant in that il gave the 1I00t indication that a be'UOilte esler was not e$S('ntial for local anestheSIa. Althoug.h. lhe: OfthofOllllS were rt:lathcly sue:ssful as lopical ancsthellcs. their poor waler solubllily made lhem unsuitable for OIhcr mali einal US<:Ii. Corusequently. Einhorn allempted to im prol'e till"" water solubihty by Introducing ami ne-containing Idiph:uic side chai ns. He rt:asoocd 1t\;U the formation of their amine hydrochlondes would Impro\'e water solubilily witl\out llIaking the preparation too acidic. One of Einhorn ' compounds, NirYdmn, was introduced in 1898. Its IIctivhy was low. and it had to be o~ in high dose.~. v,hich caused to~ic effects. Itt 1898, Willstaller dctenni nocd the correct MIU(:IUTeli of both :uropine and cocaIne. HI' followetl t hl ~ by s)nthe.~umg cocaine in 1901.

~ ily

lind . Iing 10

N co,O<,

0<,

o=\oooD
H

O'(H~

" {d

Einhorn's clinical ~W:~"eSs wnh tile poorly water soluble Onhofonns re-.uhed In the introduction ofelhy l 4-aminobcnloote mto dimcal usc in 1902 under the n3me Aneslhesinc. II ..... as later giwn the al'prm'cd name of bcn;tocailll'. Rilscn had noticed in 1890 thllt this water_i nsoluble compound had numbed his longue and so 10 Impro~e IL~ water wlubi lity, it had been rormu lated as the hydrochlonde. As aromatic amines are weak ba'\e.~. ho ..... ever. tile re~1I1ll ng solution had proved too acIdic, and he had di1>Coonted il5 cl inical use. In 1902. Foomeau In Prunee designed .drug whose Sln.oc lure iocorporuled fuocllolUIl I!rotip5 !;]mi1ar 10 tho!ic found in the ~trucll.lrc of the cocaine molL--cule, He did not include the piperidine ring. ho.....ev("r ..... hkh he COO5idered to be responsible for the toxicity of cocaint. Hi, compound, which he mnrketcd under lhe nmne Stovaine. was tbe first Ilonim tanl local anesthetic lhal cook! be gi~cn by injol..1ion and used as I safe substitute forcocainc. S to,'alne was 1 :lIcr g;"("Il too uppro~ed name of wllyloc:linc.

the 3CClanilide :lrmloguCli he had synthe$IlL-d :'IS poIcntli antipyretic agenL~ also c)lhibiled IOCIII W"IC~thetic aclil il). l~ 1931. his synthetic ",-00. lcd to lhe produclion of cloclKntnr (Nupercaine:). a Iong-ocllng local anesthetic th:lt ..... as ~ larly useful in spi nal anesthesia.

Earliu won. in 1885 by Coming in the United S laleS- had shown that the anesthctic effect of cocaine coold be cnh:lnccd by the use of tourniqlll":ts tv keep the drug from being camed away from lhe sile of application. Thi s increased the cffectl~clll'S$ of lhe drug and allo ....ed lo .... u ,"-s to be used. A pplic:ltion~ of the tourniquet techniq ue II ere limi ted, however. In 1900, the public:ltion of lhe obscnation thaI adrenal UtrllClS caused blood vessels 10 oontr.lCt resulted in Bmun dernonslml mg Ih31 mixtures of cocaine and adrenal extrnclS were nlOl"e c(feclive than cocaine alone. TIle iSOlation of adrenaline:. the acti\-'(': component of adrenal Ulract~ and ils subsequent ~lruclUre delermmalion led Bmun in 190-110 design II dru g based on the structure of both adrcn:ll me and Einhorn's loc:l1 anesthetics. It was marl eted il$ No\ocaine and was Inler II\'en lhe approved nllllle of procaine. Procaine dominaled lhe local allCSlhetic m:m.el for haifa century and is still in u'>C today . In the ne:XI 30 or so lCafS :lftcr the synthesis of proc<tine, large numbeT"$ of compound!; .....ere lested for local anc:.~lhetic activity. but none of import:lllce cnlerged. Mie..'oCher. work ing for Ciba in Swilzerland. found. howe"er. thaI some of

At aoo..n the 1W1T\C tinle that ~'iocllllCainc was develop!. an invcslig.ation of the chemic:ll siruciure of the at~.10.:1 gramme al Siockholm Unh'ersily resulted in ErdIITWl ~ thesi:dng its i<;Olll('r. isoglluninc. As luck would lIa\"e iI, Enl man tasted isogr,lIIt inc lind found Ih:lt his tonj;UC went nWllb ReaLi7Jng its potential. he lested ils open-chain precursu.d found thaI it ul"l uhiblled local anesthetic activily, For tk next 7 yeat'\. Erdtman and his student I..()frcgcn synthc1;/.t(! and te~ted compound!; wnh sim, lar S{ructuml cnar.lCten5t1O. Their search was rewanled " compound~ later. by the ... C()~cl")' of ligroocuinc (Lidocai ne, Xylocaine). Thi~ drulll1l rnaO:Cled m 1948 by Astra in Sweden, and becatJ.<oe of ~ rnpiduy of aclion. oonimlanl and reLatilely safe n311m. h:ls become lhe Icading local anesthetic. In 1957. scientists m A B Bofol"$ n:placed the acyclic !fl. liary amino side chain of lignocaine: with . cyclic ttni~ amine fOl" no reason Ofher than il produced rICI\'el COffipi'lThis irrational Bppro:lCh led to IWO useful lucal ancstbcnn. mcpi~acaine (Carbocaine) ~r>d bupillacainc ( Marcain). BuFiIIIICaine was long lIl.1inl, producing nel'\'C blocks for up. g houn;.

&.pro

. . . .

A large nUlIlber or acti vc compounds halle now bectl,-)". thesll.ed. but Jigroocoinc. procaine. and many of the: Jft--19l" compounds are Sti ll in current use. In 1974. Il ughes (wi I ; and, in 1975.' dclcn nincd the slroctures of the natlll'lll JU"

G.-,
(dIme/tlyl6ir.lOrToefI>J-I}kIdol9

romrol 19t11lS. methiOl1illC..('l1l.:tphahl1 (mcHl1l.:cpha.lil1) and Iwcme-enl.:ephalin (leu-cnkephuliu). 1be hol:uioll of thocM: IfId other pcptidai ..... nh sImilar aclivlly opened up a possIble new struclurdl roote to llie synthocsis of loca l anesthetic lients that has )'ct 10 be (ull), cxplOlted.
H.T'YGIy.QIy~Met(OH)

,.)
Figure 20-4 Representations of myelm.ilted (a) aTld unmyI!!ll'\iIted (b ) axons
(UtHl ..... hlch

Met-eokephalin

THE NERVOUS SYSTEM

The ner.oos \),stcm con~i ...s of SCI10;0ry and moIor compoIII'nt$. The scnWl)' l"Omponcm n:'ponds to ~arious external
saimulaOOns..... hi(h 1\ tr.ubmllS in tlie form of a nene impulse 10 the eNS for imCi"Jl'Il'1UIion. The 1t1Ol1)f (omponent lithe nenoo' system cames a signal from lh: eNS to the WOpt1Dte pan of the bod)' to clicu the n:sponse !O the !olimulatiOl1.0nc of tl!e,se 1l'''f'OII.<;eS is the senS:lImn "nown IS pain. Nene impulses arc now "nown to take lhe form of M electri cal impu l<oe. Expcrimemal e~idcnce suggests thaI bOOt ~umulullon and the transmi,sion of a ocrvc illlptJ l.;e may be blnc"cd by thoc action of local aJle,thelk agents" CooseqUt'ml),. understandmg thiS achOO Kquirtli a "'nowlalrc of the Mructurc und action of the nervous system. The basic building bloch of the IICn"llUS s)stem an: the II/'''''C crUs or /1(: ,, 1"1111$. A"5OCiated wlllltl!e ncurons are the ,Iial C"~lIs. In human ... lhe complele sySlcm comams o'er 10 btlhOl1 neurons and abolJ t 1 to 15 lime ~ that number of 0 ,Jial (eUs. Extending frum the brain. the Cfllnnl(md u"'r~ 0( the nt....ous systc m. i~ the cluste r o r neuron ~ alld glial ttn~ that formlhe pinal coni. The brnin logelncr wi tllthe 1flln.11 cord forms thoc eNS. b~tendtng outward from the eNS i tile peripherul ncrvous system ( PHS). The motor and ImKIf)' C'Ompool'll1) of tile PNS lire subdil.. idcd in tI) somatic !WId ,cgctalive syslems. SOinatic ~)')tCnlS control conscioos Nnction~. such as phYliical lllO,emcntS. Yo hilc the ,cgetattvc ,)'SlCIHS control uncOllscious functiOllS. T1le motor v<'gcUl1IVC system i. referred 10 lIS the autonomIC" or ;",YJ/ultl"r), ",nous system! and cOl1lrol~ body functions such liS brcuthIII- digeslmn. and ncan beat. Neurons receivc. cl)nduct. aud tr.m~mit clcctrn:al ~ ignals tile form of ioole cum:n~. A typIcal ncuron usually a"IIlSiSlS of a central cell bod)' from Yo hich radiate OUt a HumIter 0( tht n. braoch-lil.:t: protuberances (Fig. 20-3). These \niches atC' of tWO tYf!C'. a single b....llIc h known as the

acts liS a conductor of sign ol~ frolll the eell body. and a numbc1" of OIncr !lepar~te branches I.:nown as tile dCltdnlcs ....-1I1(h IICI as antennae. rectI viliS signals from the a.lOO of other neuron~. Bolli the axons and deodn les of ncuron .. can c,\hibit an a.~toni sh lng variety of branch ing. but axon br,lIlChing is usually ,implcr. Thc ICTlnin:d br.lrlchc.~ of the axon end III S)'tII'IHk blObs. .... hlch are also 1.:00..... 11 as t~nn;n/iIIJUlIlHIS or axon It'ivndri". The aAOIl anses from a thicl<,ned area of the edl body called tile U."UlI Ilil/ud. Its mcrnbr.lr)e is utainly COOlpolo('d . of hpids and prot:eins arM! i~ !.:no.....n as lhe (Uoif'mma. Many of the axons of the eNS lind PNS a~ p:trtly coIered from near the axon hillock 10 tnc ~yJlllptic "nob by a sheath of m)"I'U" (llI}elinated uons). but some axOIlS do not ha,c this type of covcnng (unmyel inated axonsj. The m)'chn shc:llth of PNS myelinated axons loS not continuous blll is broken at about l -mm intcrvals to cxpcXC tnc a~ol~lmna to lhe utracellu lar fluid. These exposed alcas ...... lIich alt abolJt I ~m long. a/"C kno ..... n as the nINIt'S vI &,miu. The d"tance bet .... ~n lhe I"IOdes is oflen referred to as the ;"'~m(}{/al db/(1lI1:# :.

A segment

of the PNS mychn sheath COrt."SIS of a Single

glial cell kno ..... 11 as a Scll"a"'l erll. tii:htly ""-r~ppt:d around the 8.\011 50 as to form lieverul lightly bound laycrs of the same cell (Fig. 20..'b ). In unlllyeli nl/ted Ulll)ns. thc S!:h ..... ann cells si mpl y surround lh: axon and art: 001 tii;htly ..... rapped around;t (Fig. 20-4h). The eNS myclinuted sheath is a much morc compl icated stRICture. In all P)C5. howc'cr. the lIIain fUl1C\ion of nlycllO is to act u.~ an insulming nmtcnal. electncally insulating tne uon from Inc ~lr.tCCliular nuid. A nerve COn)ISlS of myeh nau:d or unmyelillllll:d ncrvc fibers (Fig. 20-5a). These llenc fibers consist of chains" of neurons. Thc junction bet ..... ecn adjacent neurons III lhe chain con~iqs of the sy naptic knob of the Ir.mSlflllling neuron scparntcd by a gap of about )() to 50 nm from either the (\cndrite. a~on hill ock. or ce ll body of the OIncr neuron. This

....... I~

I
....7 ,.
f..

)sr.ath

f knob Synaptic
ttl

FigUfe 20- 3 SchematIC eNgram 01. neuron. RepresenLlllOfl of the v.nery of branching found dntes.

cIe<1-

680

Wi/JOn and GuroM's T....'hoo.t

tif Organic M~dlcilt(Jl aM I'ltormacrwrk/Ji CMmiJlf)"

,
~

""""" ...

0",..1;111*

01 F\ar?,1It

S)'NIPIie dell (_-cell boOy")

_ ...
11'16..0 _

...

"'"
'..... ' 11

'*'

"~

EndoneUrium IlUl'roundIihII
ihlllIIIUIOI"I

'""

(.)
Figure 20-5 Rep!"e!oeOUitlOM of iI secuon of "'~

(')
Irom Thomas. G .
MedIci~'

Cherl'ustry. An Introduc\JOn ChlChesler, U 11; ,. John Sons, l id I and a cr0!5S sectlOll of a neIVe Ib )

perIIIlSSIOfl of John Wiley &

gap is known as the s)'lJ/lprk c/('fi. undlhe whole area where lransmis.~ion and reception of the irnpul<;e from ont' neuron 10 the other (l(:cur is koown as a $)'nopSf!. Tlle nerve fibers are enclosed in different layl.'rI of proIectivc tissues ( Fig. 20-Sb). For example. in II spinal nerve the individual nerve fibers .... hether myelinated or unmyrlinDtcd. are wrupped in a layer of pI'OU:(1ive OOfIflCCIiv(' tissue knov.n as the mdonewrium. ~ endoneurium-cooted fibcts are grouped in bun dles known as [usdcles. Each (a.'lCiclc i~ COIled wilh a Layer of connccth'e tissue: called the ~rln('urium . Tlle complete neT\'C consislS of a number of fascicles embedded in tissue through which nm vwious blood vessels, the whole structure bei ng covered by a layer of connective tissue known 1\$ the
rpineurilu/I.

Neurons are e:tci tl."ll by electrical. chemical. and mechani ca l Slimuli. They oonvey the information provided by this stimulation in the foon of electrical signals. 1bc precise natureofthe infoonalion carrieddcpcndlion the type of neuron. ho~e\"CT. For e:tample. a m()IQr neurotl will conyey electrical signals that cause a panicu lar muscle to contract. In all cao;es. the signals take the form of changes in the electrical poIential across the neuronal membranes. In myelinated neurons. a change in lhe membrane: potential in one node of Ranvier will stimulate further changcs in an adjacent node and 50 on: that is, II change in electrical potential Ht A sti mulates a change in elcctrical potential al B. which in lum initiates B change ;n the elcclrical potential at C and so on (Fig. 206). Thc process whereby the change in potential j umps from one node to another is known as SIi/laWf)' cOIlduCllon . II resulU in the movClllelll of an electricul impulse that is refem:d to as either the lU'1"l"t' ;mllil/st or lief;"" polential along

the IUOIl. In unmyelinaled ncrvcs. the change in poknLillaf one sect ion of the membrane sti mulates a change in of an i mmediale l ~ adjacent section of the mt:mbrnne. l1n ncr'ie impulse~ are U":lIlsmiued or conduc!cd alonllD sheathed wllh myelin at speeds up to 120 nV5CC Of';~ but ooly up to 10 mlsec in unmyelinated 1lIi0lU. I~ Deurons, the 5tn::ngth o f the nerve impulse is mamllmd an aotom3l1C amplification system. but many rom ha~e roo 5uch systems. If the center 0( an axon I will be transmilled ill both directions 20-7). 1l1e ~ynapse allows. howe\"! r. only of the impulse from tlle uon 10 lhe next neuron. i. one di~etion . Consequently. an impulse will ooly one direction along a nerve fiber. most ce lls, the electrical potential dirr.""~,,,,~. the inDer and ouler surfaces of the cell membrane ;! dut the movement of ions across that mcmtN-.me.' lhe imerior face of the membrane is potential diffaence, such as chloride ions.. in the mlerior of thr For a cell aI rest (i.e., a cell that IS IlOl s.ubjcc1 stimulation ), thi s electrical poIentialls ~nown " pOlt'"tia/ and can vary from - 20 to - 200 mV, .... 1Im COlwentioo the exu<K:ellular side of the membf'anc III to be 0 vollS. 1l1e resting poIential of neuron~ i5 aboll mV , The actio" poI/mila/ of the axon i changes that occurs when the axon is stimolated. trode!; implanted in the axon (intfflCe/lu/ar that stimulation causes an initi al depoiari l..ation !nne by abou t 20 mY . Thi s is fol lowed by the rapid the membrane' s potential to a nlIlllimum yalue of about mV. The is then 5.'Iid to be depoloriud.

III

) C

) C

) C

Figure Z()-6 RepfesenUI1IOO of the lrat\5fl'\lSSlOl" of a ne!\Ie impulse along a neuron !lbtI" by saltatory Coodl.lCllOO

rest ing potemial I overshoots the r slowly recoyenng 10 resting potential (Fig. rapid rio;c and rail of lhe potential is t

- -----------Stimulation
( o.'1IC1lon 01 mo . lmenI 01 nerve ImpulH
(

")

1) (

""
duKtIOllS

.. Dio'ectlori 01 mo.lmenl oI_ImpuIH

flgUnli 20-7 SbmuialIOfI at the Cl"flttl' of an o1l101'llesults IfI a nerve

IITI~ ~ng

Ilansmtted

In

both

Il/IJ. and the point at .... hich II Sl:tr1S. theJiring I~\~I or Ihruh lIldof the axon. No IClkin potential is produced if the sti mu Ius is below the Ihreshold potential . Once the thrcsJlOld level is reached. howevcr. the actwn potcntial ",III occur regard ~ of the strength o f tlte Stimulus. FunitemlOf"C. 11M: amp'" bide of Ih i~ IlCtion poIcntial is independent of the intensity of Lhc Slimulant. The action polcnnal is said to obey the
"IIII-or'rlolltmg " 10 .....

The pcripherul nco'e;s of mammals cOllsist of bundles of

held together in a fibrous cn\clope called the ~pi. IItIInuIII. The change in potential for the<;e syMcllls i~ the RIm of the action potentials of all the lI.1.OI1S in the system tfem~llular recording b al1enlpted. Each non m the sy .. lrm hu a dIfferent lhre~hold potcntial. and so the number I1l00S firi ng will initi;dly inrn:ase wi th increased intensity of the: "imulus. Evenlually. all the axoos In the t1Crve ..... ill f~. Illd at this point. funhcr increases in the intensity of die ~timulus will cause nu funher ;nc~ase in the si7-c o f the 110I0Il potenllal. In bundles of ml~ed t1Coes. there will be muluplc pellks in tile action potential profile. however. bccaw.e thr differing types of ncoe fi~r Wi ll h:lIe difft'f\'ot ronduclion speeds. The elcctricul potential across Ihe lipid rneOlbrJt1C of an non is mainly due to the tr.msport of small inorganic ion~. w.a::h \Ill Cal . Nu , K . and C I-. across the membrane by actil'e 1.11" passive transport, Active transport usually inl'oIvcs fir IDltn'enlion of a ClIlTicr protein that physically carnes till: I0Il to the otheT side of IhI: membrone. It can occur against thr electrochemical and wncenlr.uion gTlKlienl~ ac~ the IIMObrane (uphil/J. Passi,'c transport 0f.'CU0i by tite diffusion til the ions through water-fi lled ch!mnels (ion channe ls) btDed by the intclral protcms of the ntcmbr.ine. The ions ..:J\'C from lugh concentf'Jlion to low CQIICCntmhon (dOlin Mil II rnle~ on the onIcr of 10" or more ions per second. .-!Jich is 100 times faSler than !he acti ve tT1lllsport of ions. I'Nive transport of the ions is usually in the oppositc dirlUI \0 octi"e tr:mspor!, For c~amplc. Na + ions are Imn sponed Into an axon by passi-'e lransport but out of an lUIon byIlClII'C lrun~pon . Similarl y. K ' lOllS may he trnnsportL"Il
IIMOIlS

OIentialof 1 potential t11e. 1l1e.<;e I an axon Of' more. . In large lIamed by aller neu

or

e impul'IC .,:on ( Fil, nsmiS$ion e .. in only I tra.'el in : bet ... een i~ due to u11 axon~. Ide of the :If union . e neuron. Iy OUtside
'Ie r~$linN

by : IS taJ.:en bout -70 ' potential l lcroelecflgJ show the memo 'Id rise of
lOUt

whe~

out of an bon by pa5\j'e Il'11nsport but mto an bon by lII:uve tl'1lll'iport. A small nlO,'cment of ion$ acl'Q<S a mcmbrancnn L ead to the generJtiOIl of electric ficlds tMI !If(: t'fIOI'IllOUS by macro5OOplc stnndard~. For example. the transfer of one ion paIr peT millIOn. lhe cation leavi ng and the anion cnlering the neuron acros.~ a membrnne. ~sults in an electrical poIen1J.ai of about 1.50.0CI0 V cm ' I , l1le hi ghclit densi ty of Na ' Ion channc:l~ occurs at the nodes ofRlIIlVicr.o l1le myelinau:d internodal sections oh he neuron contain fur fe .....er NI channels. In addnion. these Internodal regions an.: e lectricall y in~uhlled and so do IlO'l contribute 10 the lICIioo poIenlial. COOstqucnlly. the potential produced at lhe nodes of Ranvler muSt be strong enough \0 pnxluL'e un efft'Ct up to I nun away. Ion channe ls are formed by group<; of inlegral protClns thai run from one side of the membrane to the other. 11K: channels I1/"C sc lecti~e. allowing the passage of cenain ions but preventing lhe pass.a.ge of ather,;. Thl~ suggests that par!S or the channel must oct as I selective filter. Funhermore. IlOme of the channels are IlOl permanently open: changes in the conformalion of the pmtems that form the channel cffeclivelyopen and close the channelllS though it contained a gale. T hese }111ft's usually opell brieny ill response to \IIIr. iou s membl'1lne changes, ~lICh a~ I change in voltage acmss the membrane (\"()llIIg~'}I(/(l'd chmulf!lr ) or the bilKling of a ligand to a receptor (lig(j/uJg(l/~ chamvls,. Ovl!!" 50 types of gated channe l hl"e bttn di'\CO'eretI .1 The a~olerml1l1 is more pcmlCablc to K ions Ihan to Na ' ions. These: iom dlffu~ out of lhe neuron through the 51). called plJllIssium I~(J/( clwr",~IJ, whebe opening does 1IOI1Ppear to Il"quire a spttific mcntbrnne change. The moventoent of K lOllS i! ooncc:nt rallon dri"en: K ' ions !Tl(n'e from inside the neuron ..... here the concentration is high. to the utracellular fluid. where the coocentralion is lo ..... er (Fi g. 20-9a). Thi s tendency of K IOnS 10 leak OUt of the neuron (dri\'~n by Ihl! C lHlUIIJrtllion grlllli!!!I/) is ballln~'Cd to Willi! c~tent by a lilltited nlO\cmcnt of K ' ions bacl 11110 IhI: neuron. both by diffusion through K ' channels and by active lrunspon mcchJllisms such as lhe sodium pump. These

+3'

1. Th is IS :k toward lanul ion '1J before ),8). The It' pol~fI'

MilliYo/ls{m~ ~~.;;;,;;;~,;;:=f 1:::~A~.""';;;~lanz;';;'~IU;';'

Resting potenlllll

FIgure 20-8 Changes rn ~ potential 0/). WI'Ied dUfing a nerve mpui5e

Ex_IIvLer nuld High .ooJum Ion c::onow"-'ion Low pot " .Ium Ion .......... ,U.1on

btrKeltular n uld

:-

'ilr grrtlli1t COI'IIIolrllion

SOcIium Ion

SodiI 1m Ion
allAC'ed by the

SodiI." Ion

Intracellullr lIuld Low lOdium Ion COI..,.,1Irllion

.. - .... "~OOMin

;rr~",-

reme,ad /rom !he

HIgh potasaklm Ion cone.~t""1ion

(.)

tntrllClllullr lIuld

(b)

Figure 20-9 Movement of Na' and K' lOrn iKfOS\d membrane becauw of differences In concentratIOn b . AttractlOl'1 of poSIlIYt IOnS InIO a cell by electrostatIC dltrdCtlOl1 and their removal by actJve traMpOft
rtlO'o'cmenb ur K ' I\'suh in a poIe",ia] diffcrencc across the mcmbrane. ",tuch ,s a major coouibulor to the equilibrium polrmial lhat CXlsts bel",n lhe opposilC fOCt'! of a biologi cal membrane in , f}()I'IT\ol CC'II 31 I\',t wuh a swi 'ehed-on .wdium pump. Its \';due (or a particular ion when 11\(0 sysaem i~ in C(lu ilibrium and The ccll is 31 resl moly be cakulaled by u~inil.he Nern,! equation : RT Cu (F.q. 20-l) V~ - - F I,-C . ,

where V is the DQuil ibriulll poIcnl.al. V, is Ihc Imcm~1 poIennal. Vo is !he cAtcmal potential, C, is the mternal conceOlra11011 of lhe ioo ( nM)1 dm- I ), .s the u lcrnJ.1 ("(lIlCcnltation of the ion (mol dm J). R i~ lhe tdealga~ cOIl~tam. and T is lhe Icmper.l1ure (~K), F is Farold"y', coostanl (96.487 COlIlombs). and I. is .he charge on lhe .on. The :uolemma of a oeuron 31 ~I With a ~witchetl-on KKliom pump docs not allow thc frtt ntO\'CnloCnt of Na ' lOllS. even though il conmin) ~'hannels Ihm al\' specific for lhem If lhe ~iu m pump i, w, tlched off. howe vcr. the eonccnarulioo of Na slarts 10 blllhJ up in the cell, as lhe memDrdnC i~ rlO4 complctc ly imperllICullle 10 Nu ', The Nu ' ions pass illlo the cell down lhe l-oncClllrnlion grJdiclil utfOllgh lhe StH:p[Jcd sOI/iuII! iOtI dUll/IUds, al(led by un aHraction for the anions to the cel l, This m",1lI'd 1Ii(J\'emcnl of Na' ncolmli,.e~ lhe IICgalive charges of loOflle of lhe-e anions and ~ /'CdlICe'! (tkp..lan~"'J lhe membmnc pocenuaJ. ",hid! allows a grealer COtlCCntr3lion of K ion, 10 Ica\c lhe cell

c..

Cal. iorl$ will also ,",o,c Imo a CC'II. altruclal by lhe aniOf\S po,'rm:lllently presenl .ru;.de and", III al50 leal. oot of
ce ll s vaa coleumr ehllllllris. Similarly, o!lder the appropnale

n'8. 20-%).

eoodilioos. CI iorl$ mo\c in and 0111 of cells. lAc mo\'ellltll ofooch orthesr IOOS also con.rib\lICS 10 the n'lC'mbl"3lle pok. lial of the cell, ",hich (or a edl lit resl can \'at)' frum -20 10 - 200 mV, 1bc more pelltll'ablc a mcmbrnnc i 10 II parbI:' ular ion, lhe '1'IOf'e closely The membrune potential Ip: proaches the eqUll ibriom poIent;al for Ihm ion, The inilial dcpolurilalion of the neuron (Fig, 20-8) \\'1\ shown by 1 ,lodilldn and H u~ley in 195310 bedoc 10 illCrtl,~ movcmelll of Na' in.o thc neuron, ",hlCh is followed almost immedi:tlcly by illCR:a.;cd nM)\'Clncnl of K' ion~ OUI oflllr neuron, Cons.equcnlly. the galcd ion clmnncls ofneurooslIf tx-Ioe\cd 10 hc I\'sponsiblc for the ttansmiltance oflilcacID poIen"a" .hal carry mronnalion 10 and from the body o(tbr ner.e cell, II is lhoughllha. ltIe action poIemial iJ lril~ by a Sliniulatioo Ihal causes ntOlI'IC'n'llI)' !JIifi o( tile _ brone potellual of a small \Cdion of (I'lc OJCmbnlnc: 10. kill negaU\e ~aluc: (dt'poIun;Juion of ,hr mrmbnl11t'j, n.. causes lhe gated Na ~ channels in Ihis seclion of the _ bmoe 10 open, "hich allows Na ~ to cmer lhe II Thn proce," depolaril,es lhe nICmbr.ut.e still further, unlll tile 1(, .ion poI"ntial rc:rche~ a critical ~alue (lhefir"'rg lirrrJlriilll. "hen il lriggCI'l' Ihe opcnmg of large numbers of adjactnl Na c hannd~ I,() that Na ' ioo s nood imo lhe auOll. 'ThLI procCM, cuminuc, UIIIII Inc ,oembr~ potent.al of Ihi~ tee, lion of nlCOlbmnc reaches aboul +60 mV, ",hi.eh IS tile., libriom polcnli:.1 (V .. J for Na' iOlls "hen .1Ie cell .1. resl (ealcul:llctl o.,ng Eq. 20-1). AI uns poin . all ilJC rq' channelsofihc lIIembr.mc should be: pennancntl) opctJ, n. .l tll:<IIOli is !lOt reached. ho"e\cr, bccau'>e each ch~nnd 'an aOloma.ic clO!om, mechanism !hal oprl1llcl> c,'en Ibou&It lhe cdl IIICOlbrdllC is suI! depolarized (Fig, 20-10) ClII't

(=l

cklud

""""" ~~-,
Neu ....... resI. awaiting

JQ

.........

Figure 20- 10 Cycle of (OOfClm'l(lIlOrldl chilOgeS tIldl occur In

--

Na' lOt-. !low In and an 8dioo. pot.. ~ ..... generated .. the

.....

Mll1"bflne Ibmulatad .no: lhe wodjo", channel

S<ri.m channel

Ae:,*riUltJon OOIT'Illate
SodIum channel (k 18d,

IUIOm811ca1y ck I "
and repoIa;izaloon 01

!he "*"01)0 ..... occ:urw

Neuron II resI awa.lIng Ihe next iJllnUilto:>g ~I

..... ,Ibi_s

ol

sodium channel

....
AlI~' .

I ,.

p'_1I'orr.lu!tI1IW

_.... -

'=~" . If."bfat. . . t ~'~.~.:"':.:_=="=:.:"=...__ ._........!he

Conj~t.

COnjI.IgIIteldd binds to

NH(R1

ieceptot and **'d<.s IIMI Open Na' chaMeI

add bindlllo
Inr..-Uular nuld

'IICe,l401 and tkrl<sthe dCIi ~ Na' chal"lllll

RN{R'h" H" ~ ANH(R'1z Hydrophlllo; pIIthw'Y

1 """""

figure 20- 12

R~eseru"tIOIl

01 the mechanosm of acloon ollot.Jl aneslheuo

In

blodung do:;cd and

open sodium channm.

This is a glycoprotein thai consists of five integral proIt,ns. lllffl: are about 20.000 pcr mm J of these Il':Ccptors
reo:;~pcor.

ill me synapse siles of muscle cells. When tWO flCelylcholine IIIOIec:u les bind to the receptor. they cause a change in cooformation of the proteins thai opens the channe l. The channel lin a cluster of negatively charged amino acid residues al its rnll1.lICe. which is thought 10 prevent the passageofnegativc ionJ.. lts diameter is about 0.65 om. $0 it will allow the pasYFofposiliyc ions slXh lIS Na' . K ", and Cal . In muscle cdls, Na" ions are the main coolributors to the change in ikl.bane potential (- 30,000 ions per channel pcr millisc0*). C. ~ ions m.a/i;:e a .small conuibution becau!;C their oll'lttllular concentrnlion is much lowcr th.an that 0( N. + lOti. while for K ' ions. the leakqc OUt almost balaoce:s the 'lIUge gradient-driven inward movement

.. b; .""
,bil

""".
;00 aus-

~ ,

~~

of,

MECHANISM OF ACTION
Elperin'oCntal work h3li sllown that the main s ite of local ftSIhetic action is on the cell mcmbr:me:. Local anesthetic'S do II(lI appear to havc any appreciable effect 00 the: intracel . . fluid (axoplasm). Various thcoric.'i have been put for.1fd to clplain the: mechanism 0( the: action. IO Man y of 6ac postulate prevcntion of conduction and formation of Elion pucential by either fully or panially blocking the: Na' I0Il channels. Blocking iJ believed 10 be achieved either .,. the drug molecnle causing a physical block in (he channel. ike I con: in a 00UJe. or by the: dNa molecule distOl1ing _ channel. If ellOllgh sodium channels arc blocked. there '&'Wid be: rIO significant changeli in membrane potcntial, the flJl~g poIentill.l would rKlI be reached, and conduction of action potemial along the: neUfon would be prevented. Blacking of conduction would automatically prevent the reletic of neurotransmiller 111 the presynaptic site . Increasing Ik Ca' ion concelllr,!lion of tilt u trace llular fluid may othrr enhance or reduce the activity of. local anesthetic by lffIina the: opening of sodium ch.annels. Shanc$" suggested in 1958 that local ~theticJ acta!

P''' i'ruc-

by incrcasill& the surface pn:ssure of the cell membrane. which \I'ould result in the closure of ion c hannel s. In 1968, Mctcalfe and Burgen'l l)loposed that the nerve impulse wa.~ blocked by the drug increasing disorder of the mc:mbr.mc. which caused diStonioll ofthc ioo channels. However. bDSO"I on thc work or i\evcrul research groups ( Rilchic'o in 1915. Hillc: ' ill 1980. Strichart1." in 1980. and Slrkhart1. anti Ritchic ll in 1985). it is lI(IW believed thaI the main mechani sm of local a~thetic action is associated with the blockillg of sodium chanrocls (Fig. 2(). 12). StrichartzU also showed, In 1991.that the rttcptOJ" for the blocking action appe:aro; to be about halfway dmo,'n the sodium channel. Work by Schneider and Dubois' in 1986 illtlicated that belUocaine blocks two diffcrc:nttypcsof sodiUm chanrtcJ. 1be:irwork suggested that these: chanrtcls havc different affinities for the: drug and so differillg nllCS of inactivaion. Other investigations in 1986 by Moczydlowski et al .' of the blocks impoilCd by local anesthetic agenlS illtlicatcd that there are at lell~t two ~itcs of IICtion of local anesthetic agellls alltl nOl oroc in the imcrior cntmnce of the chonnel. as pn:viously proposed by Hille. 1lM::ir work also ,upponed the idea of II wide intcnlal I:ntryway into the chanrtc l but a OOfIstricted cxtenlal cntry. This internal entry was large enough 10 allow the: passage of Ofganic molecules. but the C:lI.tcmal cntry was small enough 1 0 pn:"cntthe: ingress of organic molecules with a single methyl group. II ..... as. howevCl". I~e eOOllgh to pctmitthe cntry of divalcnt cations such as C... and col' . 1be: obsC'rnlions made by Mocz)"dlowski CI al . .... ere: supported by the " 'ork of Mach'cr and Roth!" ( 1987) on a singlc isolated neuron (CI1Iyfish stn:lch TCCC:ptor). which also suggested the uistenet of ~ptor sites that can discriminalC between the structu rc$ of different nlH!sthe:tics. l1tcse deduclion~ wcre supported by those: of ElliOl et al.' 7 in 1987. wllo concluded from Their in~estigation of the illhibilion of sod ium curre rI! in giant squid lIJ(on by benzocaine that there were at lellSt two sites (or the action of the drug. It is an important featurcofthe: local anesthetics in clinical use thaI their structures include: tertiary amine groups thai coexist ill c<Juilibrium with the coojugate acid at physiological pH:

RN(R'), U:oc.I .. . " " &I_III< ' IC"",,)

Experimental studies carried out by Naralmshi and Fra'tier' If in 1971 and Stricharo: and Ritchie 1J in 1985 indkmed Lhal tile Silt of IICtioo of local ane~lhclk5 is only accessible from the interior of the neuron. CooscquemJy, iii neutral rnok:cu~ CTOSS membnlnes more ~ily than charged molecules. the dnJg must cross the llIC!mbr.tllt in ils urw.:harxed form bcfOfC it can enter and bklCl.: tnc ion channel. Once inside the neuron. experimenlal eYldence ~uggCSIS ll'\at tile action of the drug is main ly due 10 i t~ chargLoU fonllllntl (hm Its binding to the rtccplor is vollage dependent'" , ~ An.alysis of the ",ort of Suiciulnz, 'ii I1c. nnd Ritchie ha~ shQy,'n that the block caused by many local anesthetIC agents depends ()f1 the number of channels open: the gn:acer the number open, tnc gn::uer the block. This s.ugge,;ts thai the oct].'ity of the locul anesthetic agent depends 00 it enlering the chn nlltl from inside tile neuron ("the hydrophilk: pathway")_ However, blod:s can at'Ise cvcn if the channel is 001 open, Thi5 is cxplaioc:d by the local alM:..~thetic agent entering !he channel directly from the mc:mbr.me ("the hydrophobIC pathway"). 1be rclath'e effects of these ' ...0 pathway1 appear to depend on the lipid solubility of the: drug. but both appear to cont ribule 10 the blocking effect. Local ane<;thelic agents are removed fmm the site of app li cation by the blood fIow;llg through tile tissUC!I Hnd mem -

brones in the area of applicatlon_Metabolism occu~ through a varicty of routes in both the plasma and the It~cr. E!;ttr-typc agents ~uch as procaine an: either eliminated by hydruly~is ill the plasma. catalyud by plasma e.~lcraSl'~, or III the hIe!", cat:dYled b), specirlC hl'er c.tenses. Tlw:: 4-aminobenzoic acid (PABA ) produced III thIS Ii) drol)'sis mhlb;ts the acuon of sulfonamide., Il o"'eltT, 1br; PABA i~ e~creted in tlte urine, ]Xlnl)' III Ihe form ofcooJIIgales. The dicth),lamiooclhhllol is also e~eretL-d 111 the unnl: b\l1 aboul 70% is metaboli/f.'d by the liver, Arlllde-based local anesthetics ma)' also he h),dmly,.ed by plasma e>ItJ. ases. but the rate of h)'drolysi\ is usuall), ~Io ... er IIwl tlw fc.' the cOIlt:sponding estCl" agems, Conscqucmly. amllk kJC1I anesthetIC agents ~ moOre h~cly to be h)drolyud III Ibr; Ih'e!'. Amide local anc~thelle agents an: also metabolized by oxidation un.d N-all::)'IHtion in the liver, For example lignocaine is metabolil.ed by both hydrolysi s an.d N-dcalkyl:ttiDrl (Fig, 20- 13). 1be imporulnce or lile Iher in the Rletaboli!illl of amidc-~ local ancslhetK"S means [lult use of tbc:se agents til patic:IIIS .... ith se~en: Ii>'cr damage \hould II: avoided. as any tOXic effec,~ of the local anesthcllC agm ",ill be incn::ascd because: of a reduced rule of mctaboli sm. The deliver)' o f local anC~thcl;C agent"> to the lil'cr for metabolism appears to be relaled to tllcir dcgree of bindin~ to

" "

" " "

d o

r,

, " ,

"

,
[

, ,

, " ,
d

" b

1
CH,

2, 6Oin\ethyblnlltne

I
COOH

"

HO '/ _ '\

UGNOCAINE

IO.Id.UOn
F>"
HO

J
HC

Q3-H)do ....

NHCOC~, C,",

NH,

NH,

.~do ...t-2.6

CH "'" .-HydI'Ol()"2.&-~yIidine doo,oe~,,...!......

Fu.....
~!ed

F....... ~ ~

00fTIII0UrIdII

Figure 20- 13

~bobsm

of lignocaIne.

Chaptff l(l i..a/ /l.II<'Slhrlir /l.g<"nu

687

~.h

type
.i~

in I'cr.

; hy lhe )nJ u,
"n~

~"" !Slcrm for

rob,

n .h<

,,.,,'

plasma proteins. fuperimemaJ work by Tucker 1,'1 aI. (1970) sbo~td that amidebased local anesthetic agents bind ITIOfe l'I'adi ly to pl asma and tiss ue procei ns than do esler-based "enls. The binding of amide-based agents often Invoh"es !he anrsdV:-lie binding 10 ltt-acid glycoproH:in. This binding II usually stgnlfteanl, rangmg from " 10 9S'k of the drug. Howe'"a, many facton mnucoce the con<:cntrauon of plasma protei ns; for e~ample. cancer. smoking and tmuma ~;;c the concen tration of plasma proceins. ",hile ond fl)nl11lCept"-CS 1I'lCn:3S11: their coocentrallon. Plasma protein (OtICentnllion m:!Iy aJ'iO be altered in many diseases. Qb. ~lOUsly thcse changes wi ll innuel1ol.'C the quantity Dnd rale of od,,'cry of Inc local an.estllctic 10 the li ver, W subsequent ilh chanb>e'l in the systemic lo~kily of the drug . The elimination o f local anesthetics and !heir metabolites from the !i,'cr depends on hepatic blood now. If Ihis n()\ll' is n:duced. it can resu lt in an increao;e in conccnll1llion of agcnl'i and their mctoboHICS in the body when large doses f t -'ministered o\<er long periods. This buildup may ~u h uun increase in the syste mic toxici ty orthe local anesthetic

Wt It blocks the nefY!: trllnsmis.sioru. to lhat region. Field block anestheSIa is brought aboul by me same drugs used for mfiltr.l1Ion artcsthesia. II0wc1."ef. the technique produces a larger region of aneMhe~ib with a lowel dose of the local anesthetic than is required by !he infihrolion tcclmlque.

Regional Nerve Block Anesthe.la

Regional nerve block ancsthesia is usually brought about by eUhocr injection of the UllCsthelle in a SllllDble sol\"cnlliY5tcm Into the nerve or infihllluon of the :tneSthctic illto the tissue SUfTOundi ng n nerve or pl c~us suppl)lng the n:gion to be IInesthctiu.'d. For ('ltample. ~pinalllllC~thc5ia I11l1y be broughl about by injcction into the t'erebrosprl\.;&l fluid in tile sub arachnoid space. Denial anestheslli IS broughot about by nooding the area around the nerve by irye<:lIng the: anesthetic i1110 the adj llCclit tissuc. 11le local Dne~lhetie agent used for II nel"'lc block depends on Which nervI.' i~ to be bl",,ked. !hoe length of timc the ancSlhoc~Ia is reqUIred. and the medical eondil ion and physique or ttic' palienl. Dunuioo of :teuon IS 50C usually prolonged by the U or vasoconstrictors !lither than by increasing Ihe dose. Th is approach reduces the chan~'es of the drug spreading 10 rellions tho,t do not require allC!;thesia.

Ignu-Iplion oli'ln
Idh<

.nt.<

.""~

ADMINISTRATION

agem .Iism.
)f

Intravencun Regional Anes:tltubl

regional an~thesia is used to llnt'lithetil.CII large region. such D.'i a 11mb. TIle anesthoctic IS injected into a suitable ' cin in a limb lhat t1aJ had it) blood flow IUlrieted by II tourniquet. Thor cfficiel"ol:y and safrty of the technique de pends on prevcnling artcn~1 now ror the dU r"Jtion of lhe anesthesia. Lignocaine is fn:qucnlly u!icd to produce intra,e nous regional anesthesia. bul bupi....cainc is not approvtd for this purpose because of its long dUr".lIion of acuon.
Intrn1."ellOl.l~

Topkal or Surfac:e An_tltesla-.o 21

DII!.'Ct application of a local ane<ahctic agent to the ~k ln 01" mllCOlls mcmllrane bloc~s the sensory nerve endings. "1l"Ie local lUlCslhctlC may be applied in Ihc form of a liquid. spnlY. ("Ium. Oin lll ltni. (If gel. II appeal"l!i thaI the foml used is oflrn !iClectoo subjcc1i\cly. For e~amp le. ill the use of local JDtSthetic agcnl!; lIS pn:mcdicauOI1 in I!llStrointt:loli naJ elldos ropy. !he p;lIients pn:fel"Ted spr.ays. c'"Cn Ihough the ckgrtt of lIlCSlhe~ia was the SlUm: for spnlys and gargles. Anesthesia of lhe mucou~ mcnlbr"~nes of the ear. 1lQl.C. aJld ftoaI is usually brought about by use of aqueous sol utions of !be wts of tetracaine. lignocaine. or cocaine. TIle ,asodilalor dTcct of r;QCaine reduees bleeding in surgical procedures. \klwever. all local ar>estlletics are rapidly absorbed thl"QUgh IIlIJCOUS rncmbr.1l1cs. and SO their use may be llCcompull ioo It) IWl I~ased risk Of tOlic ~ystemic reactions. As a result. ~ must be carefu lly corllrolloo.

lIIe-

ing to

Spinal Anesthesia
Spinal aocsthe(ia i~ camed OUt by rnjccting the anesthetic Dh'Cnt ;1'110 the !\Ubarx:hnoid space III the "Pillal cord. The !1l1C$II"IeI;C IICIS mainly on lhe ~rvc fibers and bloch lhe pain reg ions or lhe body SI::(,cd by the sections o r the ~pinal cord affected.

Epidural An tlt la

"let duse of the local anesthetic in a suitablc solvenl syStem

IlIflltratl_ Anesthesia

D lP}ttted directly inlo the area of the body that is to be lne:<.lhcti~ed. 11w:se arcas range from the skin 10 deeper lis lIltS. The moSI frequen tly u.'il.:d local anesthelies rot infiltra lion art' lignocair>e. bupivllClline. and I'rQeainc. The tedlmque produce~ a good degree of anC'Slhesia in a m.llzed urea withoul di$rupting generuJ bodily fUllClions. Howc'l:f. the use of th i. technique may require large ooncen nions or ane~thctie to bri ng about the desired degree of IKSIhcsia. Wllh an allelidam increase in lhe risk of loxic ')~mic n:xuons.
~Id

The dru g is injected into (lie cpiiJuml space between the ,cncbroc and spina l cord. This nu mbs lhoc 11CIWS leading to the utl'fUS and the pelvic area and leads to pam relief durin!

labor. Epidural

anest~;u

may somelimes Catl$e headaches.

fACTORS INfLUENCING THE EffECTIVENESS Of THE ANESTHETIC ACTION

Slisceptlbliity of ,he N.uron to AnIUtl......

j>ain inromlauon is carried by !he largely unm) dinatod C fibers. while .!-harp pain is Irnnsmlued by mythnatcd A6 riber.;. The scnsltivi\ y of 111.'1'11.' fibcr$ tn local OlicSthclie ap pears to ' aty lICCOI"tIing to the Sil.C'. anatomital type. and ckgrec of conductance o r the MOl.' fibcr-. In gcnernl. lhe

Block Anes:thula

A.IOiUlion of the local allCMhoctic is injected SUbcU lD/lroUsly II. point adJlICmt to lhe m:a Ih;u is to be uncslhctil.ed. so

order of onSCt of local anesthesia with increa.\ing conc.:entration of agent IS often small nonmyelin;tltd fibers > small mydinaltd fibeN > large fibers. However. this order is not stnetly followtd III practice. Some mydinaltd librrs are blocktd wilh lower concentrations of local anesthetics than some nonmyelinaltd fibers .... hile Inrge fibers are often blocked before smaller fibers. FunhemlOl"C. in experimenlal work, the outer libe rs in llle nerve are affecltd lirsl. regard less of their nature. fupcrimcntal won: by "runt. and Pc~ In 1974 suppontd by the work of Chill and Ritchiel.l in 19&4 suggem INII the diffcre:ntial blocking of roc,",'C fibers depends on the lengtb of non Ihat has 10 be e~poscd 10 lhe local anesthetic 10 bring about ane..~tlM:sia. Shotter nerve fibers have ~hotter internodal dislances and in the early stages of llIlt~thesia are fully e~posc:d 10 thl: local 3ncSlhetic. with the i'tSultthat they are moce readily blocktd than longer fibers. In mosl patients. the iCnsaaion of pain is the first 10 be lost. followtd by tern perature and touch. pH of tIM btracell.1ar and Intr llular

carries it a.....ay . Vasoconstrictors such as adrenaline also reduce lhe rate of absorphon of a drug by nllo .... ing the mtIIbalk nile of the local allC5thc:lIc to keep pace with the nile I! ""hich it is absorbed inlO the blood\tn:a.m. This also reduce syste mic to~iclly. Hu.....ever, prolongtd use ofa va.soconstJic. lor on major ancric: ~ may cause irreversible tissue damage and can lead to gangrene. The main Y~5()COII~trictors ill current use With local Itatbeties are adrernaline (epinephrine). noradrenaline (1ltIftPi nephnne). and fclyprasin. Solutions of local ancstheun often contain either adrcnali ne or a sy nthetiC analogue such as phenylephrine. The effect of v~nstric:t()rs dcprndsOi the local ane.~thelic agent used; for c~ample, adrenaIlIl( Sit" nificantly prolongs lhe action of lignocaine bill has Ic:s.~ effl with prilocaine. The concentrations of "asooonstrictlXS an: kept as low as possible 10 reduce the risk of unwanted!oldc effects. such M cheSt pains. palpitatiom. and incn:1ISCd hcatt rate. I A)Cal allC.'ithetlC prcparntions eontaiOlng vasocOllstlic tors sho!.lld ne,er be used on digits. since they have no altD native blood supply. Consequenlly, l\'.'llrictiOfi of blood supply can eaUI\e nccnxi~. a form of cnfOl'CCd cell IbIh. Additiormll y. preparations containing adrenaline: !ihould nee rIOfmally be used on patiellL~ with db-eases including poc.:rIy eonu'OIlcd diabetes.. eardiova.<lCUlar disease. and lhyroto:o;.w;o. sis. Cocaine is a va.'IOCon5lrictor ~nd ."D probably 0... somr of its effOCliYeness to this propcny.

Flu....
L...ocal 3llCSll'Ietics are normally weal bases (pK. - 8.5). which are only sligh!!y soluble in waler. Consequ.::ntly, they are usually marketed as aqucou~ soIution$ o f their more "DIu ble salts. TIlese solutions are often quite acidic. which makes them less prooe to bacterial and fungal CO<ltaminUlioo. 1 lowev~. an aqueous sol ution of the salt of a local aneslhetic will oormally contain betwccn 2 and 15~ of the free ba5c in equilibrium with the salt. Although the drug is lTI.1inly transferred through tnc cell mc:mbnme in its free basc form, adminislr.uion of the drug in alkaline solut ion doe5 not enhance its activity. Thi~ is bttall!\C the structure of the drug is eOlltrolltd by the pH of the e~tracellular nuid and IlO4 the pH of tbe dosage form. Ooce inside the neuron. equilibrium is rcestablbhcd. 80th the free base aocJ its protOllaltd form are kno ...... n to be ac:tiYe. but it is IlO4 known whether they bind to tile snme receptor site. Ho .... e\er. it doe5 apPear lhal the oroton:ah:d base ploys the major part in anesthetic :lCtiYlly.111-O. ~

Neuron StiMUlation

'The effectiveness of thl: bloclmg action of a ghcn CI,IOCmlIlI

tion of a local aneMnet ic agent dept'll<ls on the freqU('ncy II1II extent to which a nellron ha.~ been x:ently stimllialed. Thr greater the frequency of thi S stimulatKm, the moce elTttlt the local anesthetic agent is in blocking a responsc. I.. 16

RATE OF ONSET AND DURATION OF ANESTHESIA

The IInle for the onSCt of action appears 10 be related toft
type of lissue bcing allcsthctiud. the lllethod of ildminlsu. tion., and the pC:lcentaltC of the loc-al anesthetic agCOIIli iii unprotonated form al physiological pl'!. Since the dc:grte rJ protonation is indicated by the pK. value of the dru,. knI anesthetic agents with a low pK. "olue and high lipid 9.lIIIIIity usually have a more rapid onset of a<.1ion than those." highcr pK. values and 10\ll"~ lipid solubility. For uampk. lignocaine, ..... hich i, about J5<:t Ill1protonatcd:l.l pH 7.4. us. ally hns a more rapid onset of llCiion Ihnn bllpivlICair.r, ,,'Id is about 8% unprotoolned atlhls 1'1-1. The tinle w.cn for*

is proponional to the lime that Inc agent is in eontac1 with nerve tJs,;;ue. As carty as 1903. Braun di~overed Ihat the addition of adrena Jill<: to solutions of local anesthetics increased and prolollbocd their action. It is now :MXepttd thal the addition of "a'iOCQfI' Stric:tOfS weh as adrenaline to loo.:al anesthetic solutioos prokings and intensilics their action. The agent i, confinl'd to its 5ile of action by reducing the rate at which the blood

The anesthetic 1K.1ion of loo.:al

une.~thetics

bo remeUirolle al mluc:es oslric-

-g<

I unc.~ norepi

~hel1CS

such nds on nc: 51g seffeel

IC

or;

are

cd side

~hcan

mstnc o IIller Jd supde.th. uld nOi

poo<l,

toxico:!i sornc

drug II'> diffuse: from iI.~ ~ilc of applicmionto ils sil.: of aclion "II! nlMl affecl lhe rate: of on5l:t of anestnesia. lo Repor1cdly. n. :'I the ume taken fot the: onsel of ane.<;Ihe5ia can be reduced by the use of the hydrogen carbonate: form of the: drug. 11m duo I'lOl increase the to~icity o f the local arsthc:ue agent. but il Iw bel;:n t"epotled to reduce the pam associated 1I'lth injection and Improve the effectiveness of the block in MJ1oe eusc'. The durauon of acuon apptllfS to be related to the lipid IOlubihty of ll..e local WK'5theue agent and ils ability to bind 10 protein. A~ a gcncr'JI rule. tnc llIore lipid soluble the drug. the longer lhe dumtioo of its action. It is diffleult. to classify local anesthetIC"; m terms of the duration ofalll'sthesia. ho\\ . (I-cr, because although thl: period of action depends on the: (\OSC. lhe relation~hip bet wccn d~ ami domtion of allCsthc:sU. II II()( clear. In nlOS! cases. increasing the dose increases lilt duration of thl: anesthesia. but the: relalionship i ~ 1101 lillear. For eUl1lple. doubling a dose does II()( neccssarily double the linle of action. The dose: used cli nicall y is usually delermined b)' factors SllCh ..~ ~~Iemic !Oxicity. poIerICy, and the time for which !Itt. D!lt:sthe~iu is requ ired. When long periods of anesthesia IR lajuiml. iI is bener 10 repeat upplic:uiorn; rathcT than IIt large doI;e~. This kcqlS dose lelels 10 a minimum, ""hieh Ttducc:s the le\"'" of any possible: systemic toxicity.

Centr.1 Nervou. S)'Stem

All anlldc-~ local anc:slhctlClll clln stimulate the CNS. cami ng symptOlllS r:mging from resllcssnc.'\!l 1 donic con 0 valsiolls. Slimalmion may be followed by depression 'If !he eNS and death. usually from respiratory fatlu~. 1l1Csc: un w.lnted 'Ide effects appear to be related to the. poIeney of lhe one'i1helic. It is therefore pos.,ible to predict Ihe..<;e 'iide cffccts from a knowledge of the. drug and its ooocemrotlOll ill thor bloodslream. Unfonunalely. ooovuislOlls nn occur with lillie Of' no wMl'IIng bllt can be prc\"enled or ~topped by the use of scdath" ~uch as diazepam or barb,turales. cs, although near-anesthetic ,Joy:. of the laller are reQUlml_ OIller Iypes of local a/lI:l:ilhetic call stimulate lhe CNS sys tern but often lead to drow,jllC~s. IOOI\idual c"rnpound~ lIIuy caase other unwanted side effects. hol\.ever. Fore:tample, at blood concentrations of S .... g cm'. ltgooClnne may produce: muscle twitching. dysphoria, and euphoria. Both lignocame and procaine can produce symploms of sedmloo, followed by unoonscioosrlCS5. Cocaine:. in rommon I\.lth some 0Ihc-r local aneslhelic agems. has. an effecl on mood and bell;Wior.

BI_dJO - P
Amethoc.ine (telme.inc), ben1.QCame. hgnocame. and poloen ine h:lve been reported to induce metncmoglobinemia. This is 3 condition in .... hleh thcle"eI ofmclhemoglobm in erythrocyles etceed.s the nonnal I to 2'if-. Mcthemoglobin is hemoglobin Ihnt contam~ in}n III in~tea(l of iron 11 ami so cannot transpon oxygen. Conc.:ntratiOlls of abool IS'" resu lt III the appcaronce of cyal\(l!!;l~ III whIch the lips take on a purple-blue colof"dtion. II igh concentrallons are rare but are associated with a hi gh mortalit y nile. It has been wg gested tMt methcmogloblnemia ma), be due to either the presence of an aromatic amine in the 1ocot1 aoesthc!ic or the metab()li ~m of the local :lI1e~l hc:tic to an aromatic amine .

SECONDARY PHARMACOLOGICAL ACTION

l..oI;;tl anesthetics do IlO( rely on blood circUlation 1 reach 0 !heIr ~i le of action. 11$ !hey are usually administered :11, or dose 10. their site of llClion. SySl.cmic side effects arise beausc the loculallC:Sthctic agent is carried 1I.... lIy in lhe blood briorc 1\ can be fully metabolized . Con~lICntly. the chemi n l and phaonil\:ological properties of local anesthetics arc vi maJOr" imponance in determining not only the cffecthe am of the dNII: bu. also ilS $ySlcmic $ide e ffects. local anesthetic agents can affect the fUllCtioo of any or pns in which c!ecuical impu lO\C: tr.tnsmission occurs. The _ and the eX lem of these unwanted side efft'ClS depend OQ IIIe drug used. the concenttation of the drug in circulation. die site of application. and the tec hnilluc used. lltc S<.'Cond.:u"), dfcclS of local anesthetic ag<-nts in these .s.ilualion~ are disMStd in Ihls section.

II;Ientta"ICy and
~.
.~

'111e

'fective

W_,", H llng
Local anesthetICS may interfere with wound healing. Thi s IS panicuhuly impor1ant in surgery carried out on the: hands and feel.

10 the InisttaII In us

Hyp.o . .nsltlwlty
Hypersensitivity 10 local anesthetic-. IIppeal"li:o be related to both chemical StNClure and the mcthQd of Il(lmini'Mlllioll. Allergic reactions occur most frequently wllh esterbased local anesthetic agents (ben:roic acid deri\"aU\es). Advene effects include allcrgic dennaliti~. aSlhmatlc allnd , Of'. in e~trcme cases. death due 10 anaphylactic shock. Individuals sulTering a hypeNnsiti\e reaction rmm one: local antslhetle agen: are oftcn senslli"e 10 compounds wilh si milar Siructure. For example. pati ents sensitive to procaine are often also sensitive to amethocainc Amidebased local anesthelic agents do not usually pr0duce hypcrst'nslIl\ity rellClions. although lhey may be respou~ible fot other unwa,lled effects and ha~e been imph c:ued in m:llignan: hyperp)re,ia. FamIlies "",th a history of this di<;easc should only be trealw wllh cstcrbased local
ane~thclics.

" " of g. local IOlubil6e With :lImple. .4. usu, which

tI:dlov 'Y'- S)'St_

LcnI anesthetic .!!efllS usually affl'Cllhe cardio ....scu lllf sys!till by dccrca~ing

f~ "'"

the force of conlraction, ell'Ctricalexcilll bdlty, and cooduclion of the myocardium. A high systcmic WiltCnlfluon of locul anesthetic is usually necessary. howt\.~. before any of these effecls are observed. Occasionally. low coocentr.ttions adminislercd by infil lr'Jtion cause cardioQlCUI..,. collapse and death. The rellSQll for cardio\ascular ooIbpIc: is II()( 1.nown.2\O il appcal1i, howe\"er, lhal local anes ktll: Dgcn\ll rnlly act as antiarrllYlhmic agenls by bl ocking fit Na' . K . and Cal. channels responsible for thenclta\lOa of helIJ1 muscle. r-or C.\ample. man)' workn'J believe 1lu! hgoocainc: may mluce the possibility of Na ' channe ls optning during depolarizalion. Recovery from this type of Nod, hol.,e\er. i~ usually rapid.

I'atch teSting frequenlly pro\"kIc:s adequate I\. arning of h)'perscnsitl\'ily. When Ruzlckaet al. (1987)cooducled al1erg)

0l,0i,0l,0l,1-t<I
Pi'<P ' ....

Ii)_ ,I ' X"H,Ol,N( C,Ho l,

"""""'"'"
throat. CocaIne IS of oo,,-~il.lcr.tble illlerest, Ilowe\er, ~ or lhe llt'live agenls thm were developed from its 51~ Tctrodotmin and saxitoxi n an: nalUrally occumng knI ane.~lhoctic ag<'nls but are too to~ic to be of clinical use, TeIfO. dolOXIII is found III lhe lissue and OI'gllllf of fish ofthc onla Tt'fmaJon'ifo~J. and !\aX1I0... 1II is isolall-d from 50IIlt 1111rine dinonllgc llmes. These compOlllxh, which are high!) lodc to hU lIlans, are struc1lJruily differem but IIppear 1 NIt 0 lhe me mechamsm of adion. lbc:y an: lhoughl 10 bIod the cox ternal opening of the Na channel. Interest in !bat compounds centers on the fact that they could lead 10 Ib: dc~doplnent of new local ancl;thctic agenls and their Uklf lool ~ in llCurochemical research work and in in,'CsogllllII the molecular nature of adion poIcnliais and sodium dIa4

tesb on 104 patients who ... ere ~ no .... n 10 1\3"c had an allergiC reaction to ben/,OCIIHlc and procaine, howcver, lhe re~ults ~howed that prid teSting didn...!. indicatc an allergic reaction and inlracutancous testing f":lI"ely gave a hYpeT'lCnsitjvc reaclion. They ooacludc:d that COfIt;IC1 aller,ic p.uicnts could be inJC"Cted .... ith local ancsthetlC ag;!nts ... ilOOut a ~Igni ficant risl. of a reaction, tl YpoieMiOl'l caused by loca l allC~thCfie agents is ofte n unrelated 10 the: lype of dru, used and can be: pR-venlcd by premedication ... Ith a soilable 'itdati\e. JJ

STRUCTUR E ACTION
A large number of COlllpoundS ....iII producc a conduction blocl., Mosl of the locllI ill1C~thelie :lI:CII\5 in gCllCral Ul>l.', ho ....cler. rna)' ron,'eniently be classified inlo four basic t)PC:S. namely. lhose Ihm ad by hypolhernlia. alkalOids. derivalives of bcn7.olC :leid and ani line:. and miseell:mrous compounds, The benl.oie acid lind anilil\c group J:onl ains 1110,1 of lhe local aneSlllcnc agents cum:nt Iy in ciiniclil usc, It is not po"sible 10 relale the chemical SlructUre$ of local MCSlheucs 1 lheir activily bcc~use liule i~ l.:!lO"'on about the 0 structures of the: n:t'Cptors, It is posSIble, howc,'cr, to picl. ou t ~irni lar struJ:lUral fcmures bet .... een !>Orne of Ihe :ll:li\'1' comJlOUlllb in common usc.

tlt'IS.1O

Ben.ok Add and Aniline Derivatives WIth 1oc_1 Anesthetic Activity

Most o f lhe local lIneSIllclic :I.!:cnb In CUrTc:nI medical lilt arc of lhese Iypes (T ables 20-2 IltId 20-3). 1lIc benzOIC Ini derivall\'e!I am (,Siers tllOl .... ere developed from rocaine. .... hilc the ani line derivatin'S are amide.!; de,eloped from 1\0: grammc. Both types of dcri~'ali.c ha ve che:mical 5INCIIMd lhal normally hal'c the gellcoral formal:

Agents WIth Hypotltelhlle Action

L.ocal anesthelic~ thalocl by reducing lhe lemperallirc of lhe :m-a being aroeSihetiJ.oo are largely of historical interest. Most of lhe chcnllcal agen\5 used, 1Io....('vc(. produce mtense cold through rapid CV".tpOl'lUlQn and, hence, lin anestllctlC 3C. tion. One of the nlO'\l errecll~C "lIS eth yl chloride, whieh is sl ill in U.'oe loday a~ a lopical local atll!Stllclic. This agent should not be: uliCd on ml.lCOU~ membranes Of broken skin, ho..... c\er. and prolonged use may elluo;.: chcmical froslbile.

BOlli lhe: CSlcr and N-subsmuled amide fUnc1ionall'ilUf'

are bioiso:.lere.~ (Fig, 20 14), which u plains the ~UtTetlCl! of lhese groups in si milar ~itiOl1s in the ~truclurtS or1lx:al anesthc:tics. The lipoplll llC caller i~ usually enhe:r a eartoc)dic /I" a hctcrocyclic ring s)'Slcm, whi le thc hydrophilic CCOl(!" b nonn;l IlY;l secondary 01' a tCr1 iary amine thai mighl orml&!l not be cyclic. TCr1iary aminc:s are more useful. sintt tbrJ Ilt'e less irritating tO lissuc, 'flxo hydrophilic cenler may lie anachcd to lhe: eslcr or amide by eilber a ~hort hydfoc.tlol ch ain or o~)'gcn , nilrog~n, or su lfur atoms. Most ofille Ion( ilJlCSlhclic agent., in common. howcvcr. u-.e a shon hytiocarbon chain , 1lle lipophi lic ~nl..,r is belic\ed 10 be: large!) responsible for !he lipid solubi lil) or the: local anesttri; agenl and its ability 10 pas~ through lhe nonPQlar Ilean d

Alk.loIdsM
Alkaloids an: OOtamed from plants and lIttS , The 001)' one in gcneml cli ni,a] use is (X)I;'llInt. " hkh becllu!;C of its addIClI~e profII:r1i1's is largely restricted 10 usc with tllC ear, nose. and

'"00,,,, 0=\=0
N
H
COP , .

"'""'"

H , .. ~".""":;-* "'C>< HH
H

TABLE

2~2

Eumple, of the Ester-Based Lour Al\esthetlc Ag.nts

Upophtlk Gnlup--&t"r eo Idalng Goo 'p Hydrophilk Group (If An),)

"." ure.

""', ma

"'.,

"''''' " .,,., """

Ia,-e

<u

"'0""
lluyloane bydfOl:hlurkio

Iins

acid
,~

.~.

ure~ Mepry~

hy4nxhlondo

3
:oce
o..)~"" hy,s",,:hiond<

'"'" "'.,
"" !r
(~

CH"c~H~HP=-O-COOCHaCHzNlCaHalI. Hel

H,..

I'lprIucaIK h)'llrtthl"..de

~_,>-COOCHrCHaC~-b .Hel
HI'I -o-COOCHaCHi'I(~. Hel

CH,

",,' ,b< """

c.-:al

jigln

~. hydrwlllorilk

d~

aely

lelic

,.,...

rh)~

, .r

TABLE 20-3 Eurnpl., of Amld ..a.s.ct

L~I

A,"sttMtic Agents

EIIJo;a,,,,,

" ,

b b

"

;,

,t

p p o

,
;,

t,

h , " ,
p

- c

, ,'.

II

o
- H

-c

II

o
Figure 20- 14 Ester and amide f\JI1OItIIII grouP'l Me bioIsosteres (. e, wucture IN:' NYe s.m,iar SIZes, sha~, and e~orlIC i!i'l.C' lures)

,,

'I>

Chapter

l(l

UKulll ....

J''''"'',. "gnus
~

693

U -

'\

l~

C-O-CH~2 NH
G>

.- /
~tic

CHzC~

roN .. poiafIzatlon FlO"" 'P \ ~ -0

of CII rborl)'I group

EIec1ron CIOnO<$

- I' "1

'c~
Eleclron ..... "'IlIOf1 decrMH poIanutitwl of C!utlOi'1l group

van : : ~.....

van :: WaaII' fIr.HMn..... 11 "lie

..:IQoIe allnocloon

Figure

the btndlng 01 an ester-type local oJr"It'SthetlC otge'I1l to a

receptor Slte

die ~1'11 membrane, Lipid solubilit y plays an important pan 'litho! action of local ancsthttic,.\. since: ,he,. action depends Illlllleir ability to penetrate: the cell membrane of the lUOO. The hydroplllilc center provides the local 3nesllieuc agent "lib some of ils ..... ater solubility. This iJ an rsscmial factor
Ulll1lnsponing the drug \0 the membrane a!ld. once in~ide !he cell. 10 the recc:plOr. 1be hydrophili c center also allows !he drug to pcnclr'.lle 11M: pol~r OUler face of the cell membnI.IIe, cnabl ing the drug 10 n:ach the lipid hean of the mem!nne. II also allows !he drug to pa.'iS through the inroer polar flee of the mcmMnc IntO the cdl. The hydrophilic eemer iJ also believed \0 be jnval-'ed in the binding of the: drug 10

lilt ttCepior. The beSllocal ane<;lnetlc action is obIairted when ttle lipo-pluhc and hydroplllhc nten are in balance. If !he hydroplulif center is the dominant structure. !he anesthetic lICIion of the drug is weal:. ~ince its membrane penelr\uion is poor. Slnli larly. if the lipophilic cemct is Ihe dominant blructure. knl anesthetic action is again poor. In this case:, !Ile agent an pt'llICtrate the lipid rncmbnllle of tIx: llXon, but rt~ soIubilII)' in hoIh extracdluLar and intracellular nuids is poor. The pK. "a lues of I local anesthetic agents ha"e been used lSI mrasure of its ionization and. hence. of the lipophilic-toIr)doophilic ral;o. At physiological pH. tIx: mtio of ioni7.cd 10 un;on;1.OO moIe<:ulcs in solution rnay be calculated by timg the appropriate form of tile Hcndcrson-Hassclbalch I'ljIIJlron. which Slates for weak monobasic acids
pK. _
p

,, +

Joa:I~ioniud (onn] 110flIud fOffll]

(Eq. 2G-l)

IIId for ....eak monoac;IdlC bases , /ionlled foonl ~ pli + "";non-ion,ud fOl'tll]

CEq. 20-3)

~,

~-

"""

\Iost clinically useful local aneslhetics are ....e~k bases dut ha,'e pK. vo lucs in lhe mnge of7.5 10 9.5. ThiS implies !hal compounds with pK. volucs below 7.S aTe not suffieiently ionized 3t physiological pH to be effeetive in bri nging .trout anesthesia. even though tlx:y C;uJ ]lCllClratc ttle uon. IarooinlSl. drugs .... ith pK. "alues abo,'c 9.S an: allllO't full y l13i.ud ~t phy5iol~kal pll. Conseque nlly. these drogs arc 1m dTecti\e becau.;e they have diffICulty pcnctmling the

ttll membrane. The panitioo ooefficu:ntJr of Slructurally simrl ar local an.tic~ have been u-.cd as p measure or lheir relative acti vo II) In vivo nperimenls ha~c shown that .... ilh a ~critS of

reached. After !his point is reached. the IICIrvity decreasc). even though the partition coefficient irocre;l!;CS. Unfortunately. the ir>en:ase in acu"i ty IS often accoolpanit:d by an increase rn toXICity. A Sludy '} oflhe homolog()U$~ formed by .w~itUling ttle aryl ring of local anesthetics by alkyl. alkyloxy, and ~lkylantHlo groups showed Ihm tile panitioo coefficient~ of the memben. of II series increase.J wilh an illCrease in the number of !llCthylenc groups in the ,ub~lrtuent of the series. In 8'-'JlCrul. the muimum acllvny in a IoCne~ was achie,ed for the to ~ homologuc~. 511111111rly, subsmulion of !he: h)droptulie center showed that the panJliOll coeffICient 1Ilcreased With the nurnheT of earbon atoms. which was also accompanied by an inc~ase in kt i ~ity. The use ofpiperidmo and pyrrohdino groups as h)'drophrhc group" gave prodoclll with a degree of activity lile th:!t obcained with a diethylamino group. 11lc:: rnorphnl ino group. howeve r. ga,'c prod UCl~ with lower activiIY.Jt. Local ane.~thctic$ Ill\:: beheved to bind to pla~ma and t i~SiJC proteins by van der Waals' force,. dlpole-.Jlpole attructroo s. and electrostatic forces {Fig. 2O-lS). I-'X'1I1 anesthetic actiV' ily or benwic acid-ba5cd drugs mtpro"e~ if the aryl hpo-ptnlic center has electron-donor Jubstrlucnu but dc::crellscs with electron-acccptor .wbslituents. Therefore. it is hlo.ely that el~tron donor substituelll~ Increase the binding of the local anesthetic agent to the n:ceplOf, hul eketron-acceptor substitucnLS reduce this brnding. Buchi and Pcr1ia~ ~ug gested that this latter was a consequence of electron acceptors withd ... .Iwing elC'CtTOf\S from the carbonyl group. ",hlCh dec::rcase~ ilS polarization. Thr~ rWoceJ the strength of the carbonyl group's dipole and. conseqlltntly..... eakens its dr])Ok- dipole allraclion with the recep(()r. Compounds whose SUUC'lUte\l Contllln amrde fUllCllonal groups tcnd to bind more strongly to n:cep4or srtes. For uample. Tocker and co ....orl;ers (1970) reported rhal 95% of bupivacainc bound 10 pl asma and tis.~ue proteins, cOlllpared with 55% for pri locaine. Tocl;cr alMl MUlher'l (1975) also showed thai the more potcnt and longer-acting agents are more uten~hely bound to plasma proIcms. This is 001 the only fllC'lOf affecting potenCy. oo...c''Cf. For c1iampk. amide 1:M;)f1ch are more resistant 10 hydrolysrs. '" hich will also effect the duralioo of aclion,

c..

Mlscellan. a?Sc Agents

$everJ I different classes of compounds. other thun Ihose discusse.J in the preceding se.,:tions. exhibn sonIC local anes thetic activity (Table 20-4 ). The~ compounds an: usually

rrlattd Siructures. on in.crtast in IICtivi ty cQm:spond~ 10 an ~a.~ in panition coefJidcnt until maximum activity is

TABLE 20-4

Misc:eUaneoul Compounck With local Annthoetk Act ivity

CH""""""",
PhNHCOO

~H---CH,-N

0
_Hel

"""HCOOC><,

C~CH~zO-oCOCHaCHI-{~)

<~Y'N

--

{ '>-

OCH1-{

'>-

CHpt,CH J

Co
He!

CH~Il-oN~~N-o-OCH;C~-

Wtalr; bastS willi d is lincl hydrophilic and lipophi lIC rtgioos.

In addition. a wide variety of corn pounds. i'lCluding ben/yl aIcQhol. phenol. and some amihistamines. also show some loclli anesthetic activity.

1_ 5 . ond GIll...... A. nlH 0........... _ G.tman, n""'b,, .I "'.. 8"". 01 7111 .... Nno V<WL M.. .... 19&1." -..I
302- 321

Tho",,,,,,,.....

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1. 2. l. 4

7. WIII_. S.1Id G,nl~. D. (rd>.): Ref"" ... lI<ocqMor - ' I"" C!oaMd Noone""!.! ..... Stopple"",, . Trelldt PIwmaool. Sci 1'4 . Mocl)'lllooo'.... E.. Ur" .. AM Guo. x~ and ""_1 J ........ 1'1 Y. Ar .... Sci . '"19;269_292. lorn. 9. Set 7 "I... M. P. and 1Nboi.. I. M. 1:1.",. J 5O-.!I23 - ~JO. 1\186. In R""hIe. I 101_. and Gremz:. N M.. l.ocaI w, A .. ,., In 00007" =

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J._

II . ~ A. M . ~ !ley 10-'9-273. 19~8 11. M=alf~. 1. C.. an.! 8""JC11. A. S. V. N.."", 2'!o"~-S8A. I_ ll, SlndIatu. G II . and """hie. I. M.' Actio<! .... ml aneothoua . . . d .,b of....,ibbIo: I i - . 111 SIn<"twu. Go R. (.... ~ t.oo.t " dcIic" H~ .... E>.ptnmental 1'Ioarm>>I<>IY Ikfj, SpnoftI'
V~I9tU

" 'lk. 8 ..".,.,..,..<JItnnI ........ c", .. ...".."....,. ."""' ..... rcccpl<n. In fink. II R. .....,. M"" ...... """ of AneWclOl, .... ~ Pn.>pno .. A~ Nn. Y<WL Ita..,,, I'Iuo. 1980. JIll. 11 13 S'richant. G . R~ J o.nt. R... 6O"1oWlO-l;I61. 1911 16. Mxh "el". M. 8 .. ..... lIoIh. S H lIr. J .""'"'."",.. 1J9:-IJ-SI.

I~

17. 1)"01. JR ..

~1987

""

"')'don. I) A. 1Id Hendr)'. 8

M~

Pfl .....,... Ald..,.

.. IIr J IuIe><Il. 47;21J. 197', 21 N.... M / ; M~J I'h.vtna<:olo&y at. Gl""", OAfon!. Rbrlod SricnM>r", 1'l0iii.:.0_. 1987. pp. 16-17,

, .... O T ...... M...... L roo T""k

18. 1'1......... T~ """ I'IV.ICI". D T. Neurooci Res. . 1>5_99. 1911 19 It 'l<hoc. J M ...... I:lr<el\lant. P.: A..... ". 1Ie.- ~ 6AOS-4l1.

...

.l6. alOC/Ii. J....... "',lia. X DesiJII .... 1o<aI &neW.tucL 'n AlIt .... E. J (1OiJ.). Pru.s De>ip. vol. Ill. Nt... Von. "'ad III"' - . 1912. P.

UJ

SelECTED READING
Nul. M J MedICal I'll""""""",, Cw.:.. . .mI ed. OL.;l ",ell S<:",nlOr", Pubh.:aI""'. 1997.

I''''MO. L. lout woo. 5 .Go. . . . . . O.. -ao."",... J. S A....m...t. <JIos,y 69.614-6U, 19lII.. JI ""*'-. S. T~ IbJClolcld.. J aod 8.n. .... S I. ' "..wh. ......... 67
JQ.

11l'J'II_ 110I.19I!II )l. Hall. A. It" Kulil- K W . and Ru"'""l. 8 11. , Mod

To~lroI , I (~):

lll-ltIO.l986.
I) Monindalr. W (<dol M;\I1i~ "Tho liura ................... lOd> .... I. ' ~ ... PIWi i ' " ...1CaI1"rru. 1993. PI' 9'H- 10'1.
)I

Mu/Iudi. P. J...... AI8odr. A. "

AlII! """...

Doua

SIIboI. 15:

m-lli. ]986. 1S lIac!oi, J....... I'trha. X SllU<tu",.oct.-"y .. lah"." .... phy.""lw::nli. <101 JIf1J!'Cf1;'" ofl"',:a.I ......"h<1ic.. In '.-cll:lo. P. (.... 1. l<><al A_',"",(oo,IlIqcl<)prdia 01 ~ ..... n." .. >nolklo. J"t. <11 I. New YIII\. I~ 1911." 19

ReynoIdl. J E. f'_ and PI I, A . II (M): Tho)'k!rd Ir,du. Ihb I, Rahway. NJ. Men:l A Co.. 1\196 S....&r. W.: DNI Di....,''''Y' .he E,oIu,ioo of Modem M<tlic ...,.. 0I1C1>~>Ier. U, K.. l ohn Wiley ok Son., t9U s,..i,hI, T M _ .... liolfool. P (<<b.); "''''Y'' Dnlc Truunt .... py,IKlplco IInIJ ",...i: ~ CI on! ~ IInIJ ThtnpnIti<:t. ...... <'Ii. A..;u..,t ADIS !"moo. 1997 T ........ c:;. J . "",_",., N P. """ MM>eh. Ii N PrilKlpln ~ ....... ..... y ODd Phy......,,". S:an Fnnc......, Canfield PreM. XIOO. ~ (; ; MO'd;.:' .... Cbcm,>Iry. An Inl .. >d ..... i<J<l OoichC>lcr. U. K. JoIwo
W;~y .. s.- 2000 V"rt. O . Von. J 0_ lI>J ........ L 1'Iond.vnento1. Yort.. ..... w,...,. '" So-. 1'l'l9 ~

kMc- H p~ Oak. M. M. MMl Riner. J. M burJb. OIuIdtoJI ..."'..,........ 19'19

~. oklI ....

EoIi ...

lIihemo""Y New

... ......
~n

""'ll< 01. 2:

,. ,

-4.10.

"

2 1

.
as the mOllocationic conJugale.species (aN Hj + ) &I ph) logical pll (1.4). l1le MIlio o f the concentrations of the t_ mel'S N'H/N"-II has been calcul ated 1 lie: " .2, ind~ 0 that in aql.lCQlJS solulion. 8O'k or the hisumille 1TI()f.... _ exiSis as N'-H aoo 20% uislS as N "- H. Suuctum-activity reilltionship studies suggest thai die .. NH) ' ntlmocation is imponam ror agonisl activity llliIIlmine receptors aoo tlult transient existence of the more lip> philic uncharged hiSiamllle species nJ.:lY contribute to u. localioo of cd l membranes_ Other 51 udi es suppon lilt proposal that the N '-H llIutOOlCT of the hl~amine rtlOIIOi:IlIIIl is the phannacophorie spccic~ at the H , receptor. IIlilu I,J tautomeric $yst!':m i, important for sek-ctive Hr l"t(epki agooism_

Histamine and Antihistaminic Agents

THOMAS N RILEY AND JACK DERUITER

Histamine is a P.nnidal.o/ylclhyll1J1l1l1e dm~~li\'c thaI is presenl in essentiall y aU .1\:ll1l111UI;:lII liss ue.~. TIle major
phy\iologicat actions of hlSlamine are cenlefW on the can:li ovascular ~Y~lem, nonvll:.cular snMXJIh mu.'>Cle. I:.\ocrine glands. and the IlIrenal medulla.' In a general sense:. hi sUi-

mine plays an important role as a ",hemlCal

TtlC'SSeng<'f""

component of a vuricl), of pathways ,hJI have evolved on multicellular orgam~ms. allov.i ng them 10 communicat e effi ciently and clTccll\'ely. 11le mvo lvcrTlt'm of hislumine ,n lIN:: mediation of allergic and hypersensit ivi ty relICt ions and the regulation of gastric acid secreliOll has led 10 the de\'clopmenl of importam drug classes use ful in the treanncnt of symplOms lWJOCialcti wllh allergic and gastric hyprrsecrel' ory disonlc:ro.

St.,eDCheml.tr,.
HISTAMINE
NDCill!ndature

Histamine. lnown lri viall y us 4(~. )(2-ami noelllyl)i midawle, 5tnJelul1llly i ~ composed of an imidazole. heterocycle and etllyluminc side ellaln . The metllylene groups of the amj~ ethyl side cllain are designated ll' and /3. The side clillin is attached. via the P.CH l group. to Inc4 position of an imidn ole ring. The imidll7.olc N at position J is dcsigntued the pros (71') N. II here ... the N al position I is termed the rele (1) N. TIle Side cham N is distin guished as N".

HiSlamine is an achiml molecule; hiSlamine ltteplOO."" e,'cr. are known 1 exe.., high 51 0 ereosclccti vity Iowai'd ligands.~ Mole<:u lar modeling and sl~ric -activity rc lationsltp st ud ies of the influence of conformatiooaJ i~merism 01 aclivity of hislIlll1inc sugscst the i mjX)flancc of IruNrotameric structures (AS . 21 2) in the ,e(!,:ptor KIll I~ III Ihis substance. S tudies wilh COfIform~lionaJly ~1iI lamine analogues sUlliC-';;1 that IIhile the lriJIIS rot_fI1 hiStamine pmsesses affi nity for both H I and Hl h n:ceptor'S, lhe IJlluche conformer dot's no. OCI at HI SIIr$.

'"

HISTAMINE LIFE CYCLE

Knowledge o f lhe: blodispos,hOO of hiw1Il1I11C IS I to under:>landing the: involvcme nl of thi s Mlbsturl\."e i pathophysiologie!l as well as the at'tions of . thai e.ither enhance or bloc k its :letions. the Iife cycle" of histamine pharmacological inler. enlioo.

BI05J"UII:si. and Distribution

1_I_lIen ;and Ta",tcmlrlsnt

Hi slmn;ne I~ a ba!,IC orgonic compound (N O', PK.l - 5.SO: N~, pK.J - 9 .40: W . pI(., - 14.0 ) capable. o f existing as a mixture of different iOlllc and uncharged tautomeric ~es {Fig. 21 - 1). u H i~lami ne u;st~ almost cAc lu ~ivc l y (96.6%)

...

ci pa.1 storni,'C cells. mast formed from the natunilly via the t I i of ei ther the dl'nt enZ~ l1Ie Ii aromatic amino acid speci ficit y is higher for HOC.

OiMllltr 2 1

HiJ"'mln~

and Anllhislomitlir Ag~nl.f

697

hysiotautoeatmg :at,on

""~ h,Sla'
hpo-

.....

N",

tr:in~

n oh< o:auoo hIll' a :ep.or

V 'H
N

chiru l

""

..

r
-

"'~ll1r

N""

N""

/" oh<

,"'M

ies of d hI" ICr of

~,~

te~.

""'

Figu re 21 - 1 HIStamIne tau tOlT1el"S am:! cat ,OOS

...

;.rt:ant
1Ii(JU~

Jand~
;p~m

fI '"
/-

Ie for

"
r nn
~" dine.

elude anuoromethyl histidine ( FMH) anti c('nain navoIJOIds. although no HOCIs Ral'e prolet! useful clinically. HiSlannl1C is found in almo:st all mammahan tissues In ooncentrations runging frolll I to more than 100 lJ.g/g. Thi s substance is in p;tnicularly high concentration in skin. bron chial mUC()S/l. and intC5unal muoos:a. It is round in higher conct'ntrations in mammalian cerebrospinal nuid than in plasma and other body nuid~.

St., ag. e nd Release

"

'1"".
:2) or
~rate

J) In

Figure 21-2

..HIStamine rot.JrMf1,

Most histalnine is synlllcsiud and SIC<! in mast cells and ba.-.ophi lic gnmulOC)'lts.o l'rotem -comp!exet! hiStamine i~ then ,tored in sccmory gnrnules and released by e~ocyt05is in response to a wide variety of Immune (ami&en and anti body) and JMHlim01UIlC (bactcri nl products. l<enobiotic.~. phy~ical effects. and cholinerg ic effects) StimUli. The rclea.'iC of hi stamine 11$ one of the mediators of hypersensi tivity reat 11005 is initiated by the interaction of an antigen - lgE com

plu with the mCll1brnnc: of a histamioe stomge cell. This mteract ion triggers activaTion of intracellular pItosphol:.inasc C (PKC). leading to accumulation of inositol phosphatcs. diacylglycerols. and Ca:! . E.r.ocytOlic release of histamine (0Im'5 the drgnutulation of histamine .'!lomge cells. lI istamine is released from mast cell s in the gastric ml"""" by gastrin and acetylcholine:. Neurochem ical studies also suggcst that hi.,tamine is stored in sclected ne:uronal tracts in the central nervous system (CNS ).

Once released. the physiological cffect.S of histamine are mediated by specific ct'll-surfllCc receptors.7 E.r.tensivc pharrn:lCOlogical analysis suggcsts the cxi stcncc of at least three diffcrent hiSlilminc reccptor subtypes. H lo H2 and H J Histami ne H I receptors havc been detected in a widt' variety 0( tissues including mammalian bnain; smooth muscle from airways. 13SlrointestinaJ (GI ) tr.ICt. Icnitourinary s)'lItern. and the cardiovascular ~ystem ; adrenal medulla ; and crldothe lial cells and lympl1ocylcs. TIlt' stnlClUre of the H , rttcptor has been dctcmlincd and shown to possess .'oCvcrul important fcalures tMt distinguish it from the H. receptor.T1w:: H I-reccptor protcin has a molecular mass of S6 I:.Da. The deduced l:qucncc: of the bovine H ,-receptor protein ICplc:sents 491 amino acid residuu StnlClundly. this reccptOl" contains seven hydrophobic tr.ll1Smcmbnmc domains ( fMs) charnclcristic of most G-protein recepton. The: third intmct'llular loop of the receptor is "cry large (212 am ino acids). and the intracell ular C -tcnninal toil is relativcly shon (17 amino acids). Site-directed mutagcnesis studics havc provided cvidence for \ht' binding domains of H , agon ists and anl.llgonistS. 1be third (TMJ) and firth (TM5) transmembrane domains of the receptor protein are respoosible for binding hisl.llmine. Aspaftllte ( I01)ofthe human H I rttcptor is esscnTial for (he bindi ng hi stomine and H I antagOfl ists to the rect'ptor. pcm aps by being involved ill an AspCOO- H) N - R il1teractiol1. ASparDgine (207) of the. TM 5 domail1 is l:nown to intt'rael with the N'-nitrogcnofthe imidazole ring 0( histamine. while lysine (200) has been shown to interact ..... ith the nucleophilic N"'- ni trogcn of the M!Ufllt ligand. Signal transduction of the H I l"C'."Cptor involves the

or

lICtivOlion of phospholipase C (!'LC). resul1ing ill illOSiloi phosphulc accumulation and calcium mobili1.ation in moll tissues. Hz repton ha\'c been detected in a \O,oidc variety of tilsues ( ~notably for thcrapc:uticconsiderauon. myocardial ce ll s and cell mc:mbnane:s of acid-secreting cells lpnnetlll oflhe gastric mucosa) and mediatc the gastric acid sat"'..,. ocTiolls of histamine. lbc: H I reccptor has lhe gc:nc:nd dWI("' tCriSticl of a G -protein - coupled receptor. with a moIccIIl.IlWl.'iI o f 59 Id)a and nonessent ial N-glycosylation silCll ;. the N-lCmlinal rc:gion." 11le most notablcdiffercnce bc:tll-UII struetUre5 of cloned H , and HI rc:ccptors is the much 5/II;ftI" third intraccllular loop and longt'r C-tt'rminaJ loop of tIE H2-receptorprotein. A TM J aSpar1lIlcalong with an npata and thrc:ooine residue in TMS is appare ntl y responsible fabindil1g histallline. 1be physiological and pharmaoologicll effects or Hz-receptor ligands are mediated by a Sfimullla) G ,-protdn-ooupled n=u:jltor..... hich in turn Ktivltes tJy __ ny latc cyclast'lcyclic adellOS"inc: monophosphutc (cAMP) .. tnlCCllular liCCOOd-mcssenger syslcm. Thc: cloning of ,he humnn hi stllmine HJ receptor in 1999 evokcd considernblc renc:wed interest in the field billao Thc: ti l rc:ecptor is propoSt'd to fu~ mine reptOl"li.' t i a neur.tl autorc:p1or (presynaptic) serving to IIlOdoItIa hiSfamine synthc:o;is and releasc: in the eNS. Subf,cq. -s studies have also located UJ sitcs in peripherultisSIK. lidding the gllStric mucosa where this receptor may ~pll'l"1} control g~t ric acid secretion Dnd on the canlioc sympadri: termil1als ill the myocardium . Although signnlTntnsdllCliol nlt'Chanisms of the H, receptor have not been fully dutidated. iOCTCasing evidence suggt'S1S that. thi s .tttptlll" belongs to the superfamily or G-pmtdn- coupled rccqtton.. A new hislilmine receptor. the H4 5ubtypc:. was fIlS! Ito ported in 2000 and chamcteri7.ed L~ a J9()..pmino acid. 0,. coupled protei n wi th 40% identity to the H) rcceptOl".I(In. new receptor exhibi ts a vcry restricted locaJil.alion; e~1ftJ" sion is primarily found in il1les,illlll tissuc . spl:n. lllylllRl. and immune IICtivc cells. such as T :lIio nc:ulrophils." gcits an important role ror Ito reapeosinophils. which sU ton in the regulation of immune: function.

or

N"
o

T.

P,lldutat f>tu;p!lIl1e

figure 2 1- 3 e HIStamine bIosyn thesrs

.H,

usSAA4 H/ N '-..;:/ N

io l

all

",.

""

lar in

HMT

ner

''"
.H,

""

IIte
r~

o
OH

".1

"" "".
in-

999 PRT

$to'

,ion

iale

..ent

Iud

~e ly

o
OH

"'k lIon
ON y~ ... N

oci bo
1 /
~.

1'1_ 10

"-?

G,'
(h"
",.

nUl.

"'" " ..

ImkIIm>Ie Acetic Add Riboside

figure 21-4 Metabohsm ollllslilmlnf ALD-DH, alclehyde dehydrogenase, PRT I~""

~bosy1trans

T_inatl_ of His" hlne Action

1m principal ways cxiS! 10 t('nnillOle the physiological
dferu ()( hisllImUIt):
Cd/III", 1Ip'"tr ArumaJ studies 1\.1.c dox\IlUI'/l1al the uplal.c <J h.~tammc by many cells.. In JW1.cular. uplaLc i. I t~mpel1l ' tun: and. panially. Na' -dcp:ndcnt JlI"OCOS in rabbil gasw a:\anIk. and the ruswr"OC ;1 mruboli~ed once in the cell ()r>Jt~J;'i:PI;"" of alII. Some II, ~-co... ~ininli !lSSIlC' uhibll ~ hon"-'lcnro\I.' Ion of sen"II.,ty 10 (he actions of Ioo>wmoc. pc:rI\ap!< as I mull <)f IO;Cplor modJroQl1on. /IIt/llho/,.,,,, (1-Ig. 21 .4). " llIe most common pa(hw~y for ler m,nMi", lu~lan"U~ action invol.,.. cnqmat;" ,nxt"lIIJOO.

('llI al y:r.cs the tmnsfer of a mcthyl group from Sadenosylt. methionine (SAt- I) to the ring l!"Ir-lIllrogcn of hlqamJIlC'. produclllg N'nw:lh~lhisumHlc alld SOOenosylLhorn!xy, (cine. lli s!anunc is also ~uhjccl to oxidmlw dcaminali()f1 hy diamiJle OXidase (DAO; EC 1.4.3.6). yielding lI11ida/oie ocetic acid. a phy~iologicolly inoct;\c prodtlCl excreted In the urine. Similarly. N'-melhylhi~Ulminc is eoon.~ned hy both DAO and mOrlOOml1lC' ox idase (MAO) toN-nlClhyl im

idawlc IICCI!e acid.

Func:Uons of Emiotienous Histaml_ as Related to Phil'hI.,ohtgK..lln'trventl_

Hi5tarninc C. hiblls a wide varicty of both phy., iological and palholosical fullCtKm~ in different tissuts alld cells. The actions of hislanlille that are or mteres! from both a phar-

The cnlynlC:

hi~tumine NmClhyitrunsfcl1lsc (HMT ;

Ire

11.1.8) i, widely distributed II1110ng m:ll11mahlln tiswcs and

I1l:11,.'Qlogical and thetupeut ic point of view mcludc (a) its important but limned roJc lIS a chemical OIediator of hyper'iensim'i!y reactions. (b) a major role in the l'egu latiort of gastric ocid .'lCCreuon. and re) an emerging role as a neurotmn~rniuer III the eNS.

HISTAMINE HI ANTAGONISTS (ANTIHISTAMINIC AGENTS)

The t~ arlllhiswmint' historically has referred to drugs that antagoni7.e the octiO!J~ of h"tamlne al H I retcptors rather than Hl receptors. The development of anlihlqumine drug~ began mon: th an five decades ago with the disl,;ovcry thD! pip:rox:m could IlfOIl!Ct animal s from ttt." bronchial spasm induced by histamine. I;! This finding was followed by the 'ynthei~ of a number of N.phcnykthykncdiamines wi th antihistamimc ocli"ilics superior to tho>oc of p1pt"roxan. 11 "unber traditional structure- activity ,tudie~ In this sern:s. based largely ()f1 the princi p!cb of isosterism und functional group modification. led to the Introduction in the 1940s to 1970s of I vanety of H I amagoni$ts containing the diarylallylamillC Framework. I~ Thc<;e H I antagomsl$. referred 10 now U5 the fir{/s(:'ntruuQI' or clll$simi antihistamillCs. an: reluted structu rully and include a number of aminoalkyl ethers. elhylenedi!lll1ine.\. pipcr37ines. propylamincs. p/>cooIhillO'jne!l. and I,llbenl.QC)dohepte/lCl;. In addiuoo to II ,-rettplor antagonism. these compounds display an amy of OIher pharmacological activi ties that contribute t"lOIan! dle!"apcutic appliut ions and udn'n,e reactions. More recently. a number of ~eOlw.l-geooration or " non:sc:drlting" ant ihi~ta mines have /)e,en de,'elopcd and introduced.'" The secondgenenllion agenlll bear some structural n:sembl!llK% to the first-generation agenlS but ha"e bcc:n modified 10 be more iq)CCific in action and limited in their di~tribution profiles.

pig ileu'll.'~ By conlr.l.SI. the pA1 value in guinca pig atnl (l Iz recep1or) I~ 5.3. Thus. one may cooclude that pyrilalll!Jt is a weak, noncompctilh'c mhlbltor of h1stamlne at tht atnaI reU:ptOl"" ww.I a compcm ive mhibilor 31 I-I t recepwn.1be structural featul"Cli required for effecti,'C internction ""Ib these l\'Ceptor~ an: d iscu~sed below. Snme II I antagoni>b also block histamillC relea'iC. 1bc COllCentrations requlIN. howe'cr. are coosidernbly higher than tnose required tOj duce sign lflCllnt hist.:llnmc receptor blockade. The H,IIIIU!t onists do 1101 block antibody production or an tigen-antlbodj interactions. 1M

Structu... -Actlvfty Aebltion5hlps

'Jb.: H1 antagooists are now conunon ly subdivided mto 111"0 broad groups-tile first. gener~tion. or , Iassical. anlihlSlmines and the second-gcllCrntioo. or . non~'11 ing. antihhtlmines-ba.wd prim:uily on their general phannaoolop;!ll profilc.;.'<>' 19 The differences betwccn lhe~ t... o series 1ft discussed in more detail III the scction$ that follow. lltr most dclllilcd publ ibhcd SA lt analyws for H, antagoailb. OOwever. focus on the Siructural requin:nlCm~ for the lint gCIICr:ltion agents. I. I~ From these studies. the basic 5tIW. tural requ irell1cnl~ for H ,-rect'plor antagonism ha,'e 11M identified as thme shown III Figure 215. In this SIfU(1tue.N is aryl (incillding phenyl. SIIbstilllltd phenyl. and hetno.)l groups such liS 2-pyridyl): AI is a second aryl or aryl~ group; X is a I:onnecting :110111 of O. C. or N: (CH1i, rtj1t5Cnts a carbon chain. usuall)' dhyl: ww.I NHR' rc:ptUCIll'iI basic. tCTTl1inal amillC function. The nature mtlle ~ atom. as well as the diaryl substitution pattern and _ moiety. has been u<ocd to subclassify the first-gencrulion_ hisUtmine~ as Ind i,uted in the .'lCCtion.~ below. Thi s diaryl substitution pattern is present in both thl: filiiwxI sccond-generation anlihistwnines and is cssenuaI Itt 5ignif ICant 1~ I-receptor affinity. FunhemlOf"C. !iC"na! 51udies sUDesl Ihal the tWO aryl moietiu nlUS! ~ 1IbIr. adopt a noncoplanar wnfom1ation relauve to coch othtrfll opIi mal interaction with tile II , reccptor.lO 11le 11010 aromabC systems may be linked. as in tilt tricyclic antihi5tanu1lfl (phr:l1OIhiv.mcs. dibeDJ.QCydoheptanes.. and heptencs. ek bul again lhey must be ooncoplanar for effccth'e interactioo . Most H I antagonists contain ~ubstltlltnts ID .of the ary l rings (usually benzene). and the'iC influcJ1Ct" histamine potency lIS well as biodispos ition. a.~ discu~ indi\'idual c lasses of compounds in the "e(."Iions belo'" In m:lny of the fi...-t -gellCr.Ulon. or clasSICal. 1IIIiIa~ mines. lhe leoninal nitrogen 310m is a sin\plc dimeth) moiety. 1l1e amine may also be pan or a heterocycllc!ltli: ture. howe,cr. as illustnucd by the pipe rJlillC~. somt IfO pylaminc.~ (pyrrolidines and piperidjllC~). some phc:"..t lines. the dibenzocyelohcplenes. 3nd the second-

,< .

s.u

Mechanism of ActI_
H, aD1agon l~ts may be defillCd as drugs that compc'li ti vciy inhibit the IlClion "fhistamine on tiu IM."S containing H , re" ceptors. Tmditionully. H , nntagon ists ha\"e Ilcen evaluated in vitro in I1mllS of their ability 10 inhi bit hi~lamillC-induetd spasms in an isolated strip of guinea piS ileum. Antihistamines may be cvaluated in VIV() in tcnns of theIr abili ty to prot~1 animal~ against the letllal effects of hi'ltamillC admini,to.' ..... d intfUvcnously or by at:nlSOl. To distingui_h compclith'c antailoni~m of histaminc from OIller nlOdes of aclion. the !Ilde~ pA i. applitd to in vi tro usay~. The index pA: is defined as the in\'Crse of tht" Jogan thm of the molar oooccmrntlon of tilt antagonist thal reduce. the response of a double dose of the agonist to th~1t of a si ngle onc_ 1lIe more potent II , antagonl sl$ exhibit a pAl \'alue significantly highe r than 6. Although there are many pitfallS"tO be a-oided in the imerpretation or~t ruc Illre_3I,."1..ivity relationship (SAR) siudies using pA1 value...... the following cxample illustr.lles disti nguishing competitive Hmagon;\I\l. pA l va lues for Ilyrilamine (llIcpyrumillC) amagooi,m rJngo.' from 9.1 to 9.4 wi th human bronchi and gu incH

",
"
/

,
X-(~ -

Figure 21 - 5 General al"lbhrstamlne structure

Chaptfr 21 lIuIWtI;n.- WId A,.,;~jsl<llltUlic AgrM/J .uihistamJllcli. In all cascs.. the amino moicty is baliic. with pK.J rongmg from 8.5 to 10. and thus 1$ prc!Iumed to be JIOOln3ted when bound on the m:cptor. 11Ic moiety is also DI,otam In the do:vclopmcnt of stable. 'IOlid dosagc forms throIIgh sail formauon . "The carbon cham of Iypical H, antagoniSis consiSl.~ of IWO II" three atoms. As a reJ;ult. the distancc between the cen tral pomt of the dUlI'yl ring ~ystcm and the temlinal nitrogen 110m in tile extendL'(! l"Qllfonnmion of thc.<;c l"OlllpoundS Q/1ges from 5 106 angstroms (A). A simi I", distance between rhrse key moieties is observed for lhose antihistamines with as conform.ational freedom. In some serie.~. bronching of tIrt carbon chain reliuhs in rc:duced antihistamimc activity. Thtre are ex~plions. howcvcr. as cvido:n"d by promcthaalit. ",hich has p:au:r ac1ivity than hs nonbnmched counII:fpIIfl. When the carbon adjacent to the temtinal nitrogen am 1$ branched. the possibility of asymmeuy CXISIS. Sle_11I1'C UI -m:cplor antagonism is typicnUr not oblCI'I'td. howe'er, '" hen c hirali ty exists al this site." AI;;o. in compounds wllh an asymmetrically substituted unsaturated ... boo, chain (pyrrobutamine and triprolidinc). one geornetric isomer typically di splays higher receptOf affirtity than the X connecti ng moielY of typical ii i antagonists rllay S:lluratl'(! cnrlxln - oxygen moic ty or simply a carbon MrogC'n \It om. This group. along with the carbon chain. 1Iftp:M"J 10 serve primarily as a spacer group for the lcy jiUmacophoric moicties. Man y antihista/lllnes containing lenonalOm in the COIlnectingmoiety aRchnl anduhibit kcth'e n:ct'ptor binding. For example. in the pIlenir~C!i and earbinoumine. this atom is chirol. and in analyses Indicare that enantiQmCr5 With the S configura .;;. ;;; higher HI -receptor affinity .U .; Q-roemny. the first- and secondgcfICration antihi stamillC5 ~bslantially more lipophilic thal\the enUogcnous ago_ histamine (or the Ih antagonists).lJ This Jipuphilicity rcsulL~ primarily from the presence o f the two rings ~nd the substituted amino nlOiclie~ Ilud thu.~ may _ .., ~flect the diffcrent stn.telural requi~nlenlS foramag1l:I'j;US agonist action al H I receptors. 1\t II3IU~ of this conneaing moiety and the: stn.teturDl of the aryl moieties ha,e been uo;ed to classify the u indlC31ed in the sertiOll$ below. FunherX connecting moicliCli. i the alkyl ~tdo: chain Of tcnni . the various drugs account fordiffen:oces III antagonist potency a.~ ""ell a.~ phannllCOlogical. ..." . and adverse reaction profilCli. 1bc ability of to display an array o f phannarologicalllCtivitics . they contain the Ilasic phannacoplmre re i to muscarinic as wcll as adrcnergic Dnd reccptors_ The relDtionsh,ps of arllihistamine these Q\'erlapping ilClions (II, antagonist. anti and local anesthellC) havc been analy/.cd.

70 '

.._.1

Ph Ii

tologleal CDllskler_tlDRS

I antihistamines havc been used c~tcnSlvcly for I (sneezing. minonflca. and itching \10K. and throat) of allergic rhinitis (Ita) fever. polli -

nosis). chronic idiop;lIhic urticaria. and a number of ot/w:I'" histamine-re lated di ..... SMI. 'These uses IU"C clearly attributable to their antagontsm of the 1\ol.1ion of hi5WTline at penphcral H I m:cptOl'S. "The drogs best relie"e tlx: 5)"mptoms of allcrgic diSCllscs at the beginning of the season when pollen counts are low. Although tlx: symptoms of the commoo cold might be modified by untihi~t:tmines. these agenlS do not pre"cnt or cure col ds. nor do they shonen the course of the disew;e. 19 TIM: mllihistullline~ abo are of lillie or no value in diseases such PS ~yste mi c anaphylllXi s and bronchial asthma. in which autOl,!oids other than histamine are imporlalll.' A number of the antihistamines. particularly the phenothi azines and ami_ll.:yl ~thcrs. have anticmetic actions and thus may be useful in the trcaUTlellI of nausea. ,omiti"g. and motion s.ic1.:1ICS$.'1. 14 Also. tOOse agents thai produce pronounced sedauon havc application as nonjlll:$C1iption sl~ping aids.. II. I" !>e"eral oflhe phel10lhiazines ha ve limited use in Parkinson lile syndroull'!i lIS II. result of their ability to bloc!; central muscarinic receptors.tl. 19 And . a number of alllihistamiocs. iociliding pronletha1.i1lC. pyrilamine. tri pelennamine and diphenhydram ine. display local anesthetic activity that may be tnerapcuricaHy useful. Zoi As the gencr.l pharmocological profiles ubo,'c suggest. most ,mtihbtamines cuu intcnlCt with a variety of neutotrallSmiller receptors and other biomacromolcculat ta.rgets. This is most evident among the first -generation arenlS. many of which fUI"ICtion as antagonists al muscarinic receptOl'S and. 10 a lesser extent. adn:nergic. serotooergic. and dopamine receptors.l~ II. 1 Although some of these non-Iarg~ -m:cp 9 tor interactions may h:1\"e !iOIIIC therapeutic value (as dt .... cussed abo,c). more frequ~ntly they am manifested as ad verse reaction~ that limit drug use . This iii particularly true or the peripherM anticholinergic cffects produced by Ihc.r,c dro&S and of intemctions with a number of neurolransmiller system s in the CNS Ihat resul t in sedation. fatiguc. and diu.iness.'''' II. I~ TIM: primary objecuvc of antihistamine research over the past 10 to 15 ycars has centered on de"eloping new drugs with higher selectiVIty fOf HI receplOl'5and tacting undesira ble CNS action. TIle: pronounced sedalive effects of some of the first-generation agents wcre attributed 10 the abIlity of these drop to penetrnt~ tlx: blood- brain barrier (BBH ) because of lheir lipophilic nature and then block ~,tbial H I m:cpl~ and pot;sibly other receprors.'" Thus research cfforts wcre initiuled to design 1lO"cI antihistamines wilh reduced ability 10 penetrnte the eNS and decreased affinity for central histamine m:cptors.1lte.r,c cfforts led 10 the inll"OdUClioo of the sccondgcnerntion antihistam ines. ",hich are nonsedating and have lillie antagonist activity at olher llCurotTllnsmillcr m:~ ptors at therapeutic cOilCcnlrDlions. The ph.armacological prupenics of these agen ts are discussed in ntOre detail below. Surprisingly little information is available concerning the phaonarotinr:tlC and biodisposition profiles of the first -generation antihistamines..lJ Generally. the compounds ate orally active and well absorbed. but oral bio:... ailability may be limited by first -pass metabolism. TIw: metabolilCli formed depend on drog stltlClu\"t' to ~ large t)l t( nl but commonly involve the teniary amino moiety. Thi s functionality may be

subjeCt to ~uccess.i\l' O. datlVl' N-dcalkylalJon. dcamination. U and amino acid conjugation of the resuhant lICid. 1lte amme group may 1110;0 undergo N-oxidation. which mlly be reversibil'. or direct glucuronide conjugation. FiISl -lIel1o!nllion agents with unsubstituted and activated aromatlC nngs (phenothtal.mtS) may undergo aromatIC hydroxylanon 10 yield phcllOl s. which may be di'l1in~lcd as conjugule..~.lJ More deta,1ed ph:tnT\lOCOl.;incl ic data are available for the seco.1Cl-l!cnern tlon IIlents and are il'lCtuded in the l1'lOI1C)graphs thai follow. The H I :mtugoni~IS display II variety nf s'gnilicant dru g Imeractiom ... hen eoaodmmislered with OIher thcr.!pCutic agents. For ('JI.umplt. MAO inhibit~ prolong and intl'nsify tnc nntichohnergic action ~ of the I1l1t ihiSlamil1(':~. '''' I" I lJ Also. the set\;lli vc effect_~ of these IIgents may potcntiute the depn::s..o;:am 8Cm lIy of barbllunllcs. akohol, narcocic analge 5ic~, and ochct- depressums. Rccemly. il was discoverW that )Cvtntl of the <;ond-generu tion anuh ismmincs may prodlK.'(: life-threatening arrhy thmias ",hen coadministered wilh drug~ that inhlbtt their meubolism .I~. II Thc:.'iC internetiOlls are dl.'ICUs....ro it1 ItlOfl: del.!.il in lhe ~Iion~ below.

Flrst-G.n.,Mktn CIas_

H~~fst

Drvg

AMtN QALKYL ETHERS (rTHANOLAMI NES)

1lte aminooJl)-1ether atlt 'hl~U1millCll arc characterized by the

presence of a C HO rormecting moiety ( X ) and II two- or thn:e-cnrbon alom cham us the linling moiety hetween the ley diaryl and teniary ammo gl'Ollp!i ( Fig. 21-6). Most COin' pounds in th,~ ~es an: SI mple N.N-dimeth)-ltthanolamme denvauves DI1Cl are so class,rted m a number of tcxts. C lemastine and dipllenylpyl"Jline differ from this basic ~tn,clllr.!.1 pattern, it1 tltalthe basic nit~cn moicty and at least!X'n of lhe rnroon ch;lIn art' pan of a hctl'rocyclic ring system and there are Ihree carbon aloms between the o~ygen and nitrogcn atoms. n.e ~i mple diphenyl dcrwati\'e diphenhydramine w~ the first di lllcall y useful ",cmber Qrtheclhanolamine series and serves as the proUlI:YPC:. Other thcrnp.!utically useful dcnvath'es of diphenhydnunine ha\'e been obmit1ed by (H'M substi IUtll.!f1 of methyl ( methyldlphenhydrnmine). methoxy (nledrylamine ), c hloro (chlorodiphenhydrnmloc). 01" bromo (brotnodiphenh)'dramine) on OIIC of the phenyl rings. These denvPli\'e s reponoo l)' ltave bener therupeutic profiles than diphenhydramine because of redoccd IIII\'ef'!;(l effec:l$.u Replacement of one of lhe phenyl rings of the diphenhy. dmmine ... ith a 2-pyridyl {(roup. liS m doxylamine and carbi .

no18mioc. enhances atluhisuurumc IICtlVlty. TItc$e pounds dis play 0I'Il1 annh lstaminic IC'IIYllies 40 and 2 gre3ler, respth'ely,lhan diphenltydmmine in aItunab-' As :t result of an asymmetrically substituted benzyl;'; bon. I006I 0( the amiooallyl ethers arc opK'ally ac(I\'e, studi es indlcale thallhe Ind,vidual l'nanhOlTlefS dlff~ \I cantly in Ilnl,histumill ic acti vity, with activity res,ding 1ft' dominantly in the S enantiomer. l l 1lte diaryl tertial)' :tlTunoalkyl ether structure tlW le1i1.l'$ thc!se compounds also SC:I"YC5 a5 a phannacopbon: IImuscarinic receptors. As n result. the drugs in th.i~ ~ poso;css signirlCunl anti.cholincrgic activity . ... hich 1111) If. h:mce the H ,-blocking ac:11011 011 CJlllCnllC STCUOll~_ siness IS a Side effecl common to lhe teniary arrul'lOlll., etheN. presumably a~ II resu lt of the ability of thc;t ("(80 pounds to penetl1lte rite BBB and occupy centnl H, Ifccplon. Although this SIde effec:t IS exploited In O>'ff counlcr (OTC) slccpi ng aids. it may Interfere "lIh lhc manee of I a.~h requ iri ng menta l alcrlr>i:SS. ,.. 19 The it qOt'ocy of G I side effecb in thi~ series of anlihiswnrm relati~cly low. oomp:u'al .... ilh the cthylcntdiamiroe mines.' 1.. ,~ In spite of lhei r Cltct1sive uS(' . j)hannacokinctk d.JD this series of oompollnd~ are relatively limited. Must n. ~ Q( Ihis 'iCries appart'ntly are eJllcnsi\<ely ~ pathways including N -o~ida\ion and SUCCC$5lve Ol'''~ Nalkylalion followed b{; llIT1ino add conjugatiOn d relIuttant acid metabolile5.

'*

with phy sicochemical propenies. 1lte structures I I data. and dosage foml in formation ure gnphs thaI follow .

::~~~~:~:~::

pK. value of 9. and II about 5. ';;00" W'I t i l ; ' , , " " ' "

hibilS antidyst.:mctic. antiemetic . anhlussh~. an(! plOpcnies. II is used in OTC slet>p-llid prodllCU. la dose mnge of25 10400 mg. diphenhydl1lmine i~ active H, antagonist; il ha~ anticholil1o!tglC and
II:

, alter the_ i " ::,~,; ~:.:::;',:;=~::: ,;~ C";~~~ not

the u," icholinergic action. As an antihistamin;e as"nt. mended in various allergic as an antispasmodic . It IS temlly in the treatlllC'nI of urticariu. seasonal fever). and some derTrultoscs. The I~t i5 drowsiness.. and the concurrent and ocher CNS dcpressnntJ should be a,oided.
U-..al adull d()&c: On!. 2$-SO mx: 1M or IV. Io-~ III ~ forms: c ap""le!., eh~lT. J)'IUp.~ . nJ1IOi

A"

CH,z -

CHl -

,
/

Figu re 21 - 6 General

StruClur~

of tM iHI'IInOalkyl el~

ooeo

BloolOOdipl ...."CII.. ' ... Hydood .... k1e

::~~~~~:~:~i~u~s:P:.:~:1:i'"~~~~8i<~h:I:":~rothw~PhYllinme
sail of 1
I

8-chlorothcoptlyllinc lamine compound I powder Ihm is in water and freely soluble in alcohol lind

DIIl~nhydnnate (-cc Structure

be low) is recommended for l1.'lu!oCa of molion ~ick nc,~s lind for hypcremeliis gravi of pn'gnancy). For the prc~cmion of molion dose should bc taL.en al lea~1 one half hour the mp. TIie emil ions li sted for dip~nhy ob6I: ....ed.

Doxy/limine SuccJnilte. USP. The acid succinate salt (bisuccmate) of doxylamine:. 2-1u-12-(dimethyl:muoo)et:hoxyl-(\'-mc1hyl~nl,.yl lpyridinc bisuccinale (Decapryn Succi nate). i~ a white 10 creamy.w hite powder with a eharocteristic odor. II is soluble in W al('r (1 : 1). alcohol (1 :2). IlIld chloroform (I :2). A 1% soiUlion h:I~ a pH of about S. I)oxylamine succi nate is comparable in potency 10 di phenhydramine. h is a good nighllirroe hypnotic, compared with SObartmal.l3 Concurren! use of alcohol IlIld otho:r CNS dC'pm;qnls should be avoided.
UluaJ adult doJc: Oral. 12.j-2!'i '''g/4--6 houn

nuuae r _ Syrup IiPlJ tabku

l.w Iduh dose: Onl. ~IOO "'IV.! 110.. ,..,; 1M ()r IV ,!IO 111&1 hoors; AlClal. 100 "'I '1.11. or b.i.1i [lo " form~; Elmr. ),rup. UIbIct... onj<-l;tlOll. 51'~lones

I Hydrochloride), wllile \0 crystalthai is freely 'iOluble to waler and in alcohol. I ' 10 d.pilenhydr"mine. bromooiphcnhydrarnine is lipid so luble a",) was tWice as effective in protecting pigs against the lethal effects of hista mine aerosols.
t .....1 adull do!oe: 0r:I1 . 2$ mgl"- 6 hou" Do<:lgtc fOfTlH eap..lIlei and ch~lr

USP. The oily. lipid-~luble free base of carbino.r.amine is nvui lable as lhe biuer bimakate !!-alt. (d. J)-2-{p-chloru-....12-(dimclhylamino)elhoxy}-

CiJrb;no.ami,,~ Ma/eat~.

CHOCH~~ ~

" I

CO

e
N N

Ell

I CO<,

bnzyl]pyridine bim.lllealC: (aistin). a while cryslalline pow_ der that is v~ry soluble in water and freely soluble in alcohol and in chloroform. 11w:: pH of a 1'1. !iOlution is btwc:c:n 4.6 and j . 1. CarbioollamillC is Q poIent antih istami nic alld 15 available as the racemic milllun:. Carbioollamine differs slfU(:turaily from ch lorphc:nimmineooly in having an ollygen atom sepamte the asymmetric carbon atom from the aminoc:thyl side chain. The man: active kl'O isomer of earbiooxamine lias tnc (5) abliolute configuration:!!> and can be superi m~ on the more active d~(tro isomc:T (S CC)nfiguration I) or ch Iorpn.:,n i ram inc:.
UsuaI.cIuh dose: Oral. 4-8 nil .i.d . or q,id. ~ge fomu;; Elillir and IlbIc:c!;

OiphenylpyraJine HydfOChlo'~. USP. Dipht:o)'lp),," aline hydrochloride. 4-(diphcnylmetooxy}-lmetI\}IPIPf'I\' dine hydrochloride ( Hispril. Diafen ) occurs as a whllt If slightly orr-whil~ crystalline powder Ihat is soluble in . 'a t or alcohol. Diphenylpyl'ltlinc is structurally related to Iiphcnhydrtll1ine wilh the aminool kyl side chain illOOipOta4 in a piperidine ring. It is I poIent antihistaminic. ad. usual dose is 2 IIlg ) or 4 times daily . 1bc hydrochlondril avai lable as 5- mg sustainedrelease capsules.
U,UlI wluh do!c:;

Oral. oS 1BJ112 hours

I)oqge forms.: B.k:ndn\re1c:ase C<IpS<IIc:s

'!

."
Co.~..<_,

CHCOOH CHCOOH

.. . . .

UI'''lI'

ETHYlENEOIAMINES

C/"mastln" Fumaratfl', USP. Dextrorotatory cIc01I1.~ tine. 2-(2-( 1-(4-chlorophcnyl}-I -phc:nylctho.1.yJethyl] - I mcthylpyrrol idlllC hydrogen fumamte ( 1: I ) (Tavis!), ha.~ Iwo chiraJ centers. each of .... hich is o f the (R) absolute configuration. A comparison of the acti vities of the Intipodc:! indicates thM the asynllllctric ccnter close to the. si de chain nitrogen is of Ic:s$c:r importanCe to anlihiswninic activity. I) Thi s member of the ethanolamine series is characteri~ed by a long dumion of action, wilh an activity that n:aches a maximum in j 10 7110urs lind persi'US for 10 lO 12 IIours. 1t is well absorbed when administered oml ly, and it is excreted primarily in the urine:. The side effects arc those usually encountered with this sc:m of antihistamines. Clc:maslin.c is closely n:lated tochIOl'phcooxaminc:, which is used for ils centr.u choI inc:rpc-blocldng ICti>ily. Thc:n:fore. it is not surprising that clcmastine: has significant antimu scllrinic activity.
U...-I ....11 dose: Ontl. 1.34 m, b.Ld. or 2.68 m, q.d. 10 t.i.1!. Dosage (orn'5: Syrup.oo IlIbIets

The ethylenediamine antihistamines are Cluu1lc:trril="~";,;;* presence of a ni lrog~ n CQIInccting atom (X) and a IV;~
atom c hain as the linkini: moiety bct .... eenthe: key diaryl. tc:nillf)' amino moieties (Rg. 21 -7). All compounds III series are simple diarylc lh ylenc:diamines except antllOUt. in which the terminal amine and II portion of !be ",'" chain are included as part of an imidawline ring 8 ecause il differs significantly in ilS pharmacological iW" file. antawline is 001 always clusiftc:d as an r1h)!r.Iamine:. dc:rivativ~. Phc:nbc:nl.lmine: was the first clinically useful mc::tMa1ll this cla.~ and served as the proIotypc: for the of II'lOIl: dfCC1ivt: derivati ves. Replacement of Illc: moiety of phc:nhcn7.aminc with II 2-pyridyl tripelennamine. a significantly more effectivc ceptOf blocker.lJ SUbl;titut}on of I pam
~

the bnzyl group of tripelennamine I group provided mclhapyrilenc. and replacc:nwmt namine's 2-pyridyl BrouP wilh a pyrimidinyJ wilh p-mctooxy substitution) yielded thonzylanuJll'. which function as poIenl H I-receptor antagoni~IS.D In all of these: COflipounds the aliphatic or termmal_ group is signi ficanlly more basic than the: nil~ bonded 10 the diary l moiety: the I diaryl nitmgcn are dc1ocali7.cd by the

COOH

Figure 21 - 7 General Wucture of If1Il' e

" ,.

Y'-

!e$Uham ~lICtlOI'I in eiltorl dtnsity on norrogen dccn:ases lmicil)'. Thus the aliphatic lUIlino group In the elhylene<iI.unes i~ ~umciently basic (Of the formahon of phannaceuci

ho"':Ier. and may impair the abililY 10 perform casu requiring ak:rtneu. n.c: coocum:m use of alcoholic beleraacs should be Dloidcd.
U~ual Mluh OOK: Onolt~hlcl."
n:k:a~,

tilly w;cful .wttK The c:l!7knediamine;; were among lhe fin<1 useful ami hisIlmines. l1Iey are highly cff~~Ii\'e HI mnagonists. but lhey IIso di~lay a re tall,ely high f~uency of eNS depres<.ant
- ' GI ~dc effects. ,.. 11lc anlichollrlCqlic and anllcmclic Iflions of these compound. are I't'lath-e ly low. CQmparN

25- SO mgl4-6

hoo",;

u leJ\ikd

tOO mg18 1 2 il<>ulll I>.Jsa&e (OI'ms: Tablds. ulCnded-n:IeMC: tablel. The Oily free ba.-.e of pyrilaliline i, avuillible as the add IIIlIlcme <;.all. pyri lamine l11aleale. 2112( duul'lh y Ian II no)e th yll (p- nlel 00 ~) benl'y I)anll 00 1pyridme nlal1'3I1' (1:1). mep)ramll'le. which is a white crystalline powder ",lIh II fUII11 odor and a blllt'r. sahne taste. The: salt " wluble in WaleI' (1:0.4) and frecly soluble In alrohol. A 10% soJlI!ion h~s a pit ofapproxllnatdy 5. AI a pH 0(7.5 or !Ibo~e. the oi ly riff base: begins to pm:ipit~I': . Pyri lallune differs ~ltUCtur.llly from tripelennamine by ha~jng a mclooJlOY group In the pI"ll position of the ben/yl radical . It differs from II~ mon: tOXIC and less potenl precursor phenbenwmine (Antergan) by h1l\ Int! 11 2-pyridyl group on lhe ni ll'Ogen alOin in pl ace of ~ pJlI."llyl Sroup. Clinically. pyrilanlll1C and tripelennamine ure comldered altlOllg lhe less poIent aIlllhist3mil1lcs. n,c,y are hlahly pol('I1t, howe, cr. in anll' gt)l!il ing hl>lamlne induced ConllllC110m of aUlIlC'a pig ileum." 8ecau'iC' of the pTOOOlln.ccd local nlleSthclie oction. the drug shou ld no! be che"OO. bultulen whh food.
.... 11~: <AI. 2S-SO mgl6-8 OtJSllge forlllS: T~bkl.
U~ ~

'nh those of most Oilier classical amihi~llU1line.'. The plpern11111:- and plw:nOlhiazinc-type anti hi ,mminc' 11.10;0 oomain Ihe
M)knediamine moiety. hut thcseagcnts an: discussed scpa~y because they exhibll ~ignificanlly different pmrmacobp:aI propcrtie.~. !kwu\"dy little infonnalioo is available concerning the pa-nlactlkmcti~ of thi~ 'iCries compound~. Tripelcnnais nlClabolized in humans Nglucull)/lidalion. N

Pyrilamine Maleate, US,..

,"" . It -

fonns of the marlele<! ethylenediallllllc anhhisuunincs. along ,d,ll physicochemical proper basic tlM:rupeutic !ICIlvit)' profiles. and dosage form in bnwion. ~re pro\'ided in tIM: monoglllphs below.

rtiprlennamine Citrate. US,..

n.c:

oily free

oo<;e of

citrate, 2-1 benl.~112-(d illlec hy lam i l'lO }ethyIJ(1 :1), PBZ (Pyribcnl.:llllir.e Ci trute ), the less. bilter nlOOocitrute \311. "hich is a powder freely soluble in WaleI' lind in ak:oh;lS u pH of 4.2.5. For (It'lll administr:uion lhe l."i tr.l.1e sail is It'~s billeT and Ihu~ Becau<;c of tIM: differthe doses o f Ihe I\lrO 51111$ mu.t t to20mg

IlMW aIluh dooc: Onl. 25 - j() m&l4-6 hou",

Do!;oge

fOl'm~:

Elixir

Pyrilamlr. Maleate

T~

Citrale or

He!

""rlt'nnamine

Tripelcnnahydroch loride is II "hilt' crysta lline po"'der lh:it dark sIo ... ly on e xposure to lill hl. The sa lt i~ :.olubl e in wuter An) and in alcohol (I :6). II has II pK. of about 9. and II 'solution Iw II pH of aboul 5.5. I . che fiN cthylenetliamille dc\cloped In Iabonuories. is ....ell absorbed when gi~en or.ally. of c linical expcricllCt'. il upPCUI'li to be as eff~-..:. lIS diphenhydrnmine und may ha~e the oovanUige of IIld less severe side n:aclioni. Oro" ~iness may occur.

Hydnxhlorirk,

US".

The oil) free oo<;e 1\ available liS the biner-taM lng monoh)drochlondc salt. melhapyrilenc hydrochlonde, 2-IIZ-idimelhy lamioo)clhyll 2thienylamioo lpyrilline 1lI0nohyllroch ioride (HiSllldyl ). II i~ 11 white ef)'~1~lIinc po"dcr that is soluble in WOller (I :0.5). In alcohol 11 :5). and in ehlorofonn 11;3). lIS solutions hal'e I pH of aboul 5.5. It d.ffers ~ttuClur.llly frum Iripc~nnamll1e in ha~ i nB _ 2-thenyl (thiophene-2mcthylene) group in place of the ben!.yl group. The thiophene ring is cOII~illered 1...0Merle wilh the bcnl.Cnc nng. and 11M: l'iO!'ten,:~ e'{hlbl t sinillar !ICIivily. A study of lhe wild-state conformation of methapyrik:ne hyllrochlOlide ~wed thai the "rIIU conformation IS preferred for the IWO eth~Jcnediaminc nllrosen atoms. The Food and [)rug AdnllllIstrution decl:ircd IIlC'lhapyri1cnl' Upotential carcinogen in 1979. WId all prodUCb containing il Il:... e been recalled.

Melhapyrilene Hydrochloride.

,
\ !

PIPERAZlN ES (CYClIZI NES) The pipnuines or cycJll.ines can al'lO be coosidcred eth,~
C'nediamioe dcrivlIlh 'es or cyclic elhylene(liamilles (~ l'ine\); in Ihi\ series. OOwC'vC'r. the t'Ol1tledil1g moiety (Xlii aCHN grwp. and thecarbon chain. tcnninal amine fuDCliol ality. and the nitrogC'11 atOOl of the connecting poop art pan of I Plpa1lzioe moIClY (Fig. 2 18). BOth nitrogt1l in the.'iC compounds are aliphatic lIlld thus di~play rompn ble ba~icitiC'~ . 1lIe primary 5UlJctuml differencC's "'ithin ch~ series in\'oIve the nature of the P(If"(J :lTOITIatic ring sub!.w_ ( H or 0) and. more l111pOl'llllltly. the nature of the ImIBIII pipc:ral.ioe nill"Oge:n surn.tilllent. 1lle pipcmjl'lCS arc rl'lOdC'ralely ~Itent :mtihistanllll>.' with a low iocidcnce of drow~ines,~.l" 19. II A ..... aml~ Ill' the possibility of 5QnK' dulling of mc:ntal alennc:ss i5I1dn5Cd. holOoever. The activity of the pipcruine-type antihi I~ chaructcri7ed by a slow on.';CI and long durallon of artu. These agem\ exhibit pcriphcml and cemral antimu.<.eamttt; activi ty. which m.ay be n:spon~ible for the amiemcticlll anti\'enigu effects. '" I. The age:nlS diminish \rs!lbubr.ulation and may act QIllhe medullary chelTll')Te(:eplor IfIWI zone. Thus as a group. these agcnt~ are prob;tbly Il"IOI\' ysdil a.~ antienlelics and ant inau..eants and in the ~aUnL"nt of non sickncs~. Some memben; ofth" series ha\e uhiblted lliIl'OIII lIntogenic poItntiaJ. inducing a number of malfonnatKW. r'.lts. Nort:hlorcycliline, p metabolite of the.'\e P!perilIleI, was JlfOPO'ied as respollsible for the terotogenic eff~" the pan: nt drugs. a MeUibolic studies in this series of oonipoulllb I\a'e" cused primPri ly on cYl.'lil.ine and chlorcycli/Jne, and ~ compound~ unticrgo similar biotrlws formatiOl1. The (lIl1U) pathwuy. In\,ol>'e N-oxidation and N-dcmethylatlOll.-' both of these meUlbQIilC!l are devoid of antihist3mlnic z. tiviIY .l.l The structures ofthc marketed ~all form~oflhe:pipm.t* unti histmnines. along with physicochemical propcnteS.b therapeuti c acli vity profile ... and dosage form infIXI t are provided in tbe monographs below.

Me!hapyrIene tt,drochIo<ode

ThonzyfiJmlne Hydrochloride. "Thonlylamine hyd rochloride. 2[ [2 _(d iIllClhy lami oo)elhyl[ (J1-mcthoxybclUyl) amioojpyrimidin.e hydrochloride. is II II hile cl)'~ulliioo powder soluble HI waler (I : I). in alcohol ( I :6). and ill chloroform ( 1:4). A 2'1 aqueous 'IOhm on has a pH of 5.5. 11 is similar in lICtivily 10 Tripelennamine but ;5 cluimed 10 be Ic.~s tollie. The usual dose is 50 mil up LO 4 limes daily. II is ~vailable in cenain wmbi nalion pmdOClS.
CH~CHW HCl

ThonlyIaInone Hydfoct1lo!lde

Antazollne Phosphate.

Anuuoline phosphate. 2-[(N-

bcnz} lani lioo}mcthyIJ-2-imida:roline dih)'drogcn phosphate. occurs as a bUleT, while to off-white cry!l.I:J.llioe powder that 1~ soluble in willer. It has I p K. of 10.0, and II 21k soluti()l1 has a pll or noom 4.5. Anuvol ine. Uke the el hylencdiarni roe.~. contai ns an N-bcnly lanilino group linlced 10 a bask nitrogen

through a IWtX'arboo chain. Antarohn.e is less ani\'c than most or !he Oilier amihiSlaminie droS5. but it is cl\ar.lcteri zrd by the lack of local initlltion. TIle more <;oluble phosphate salt ii appl ied topically to the: eye in a 0.591:- solution. The less soluble hydrochloride
is gh'en orally. In addit;QIl to ils use as lUI antihistamine. amawlil'lC has more than twi~ the local IIIK:WleUC poIency of procahle and al<.() e,;hibits anticholi nergic actions.

Cyclizine Hydrochloride. USP. Cyclizinc hydrodtJo. ride, l-{diphc:nylmethyl}-4-mcth}'lpiperuzine ~ chloride (Marezinc). occurs as a lightsensm\e. crystallme ]101Oo'der .... ith I bitter wte. II is sli&hll~

" --I

,
I CH.
' -eM,

'I
HJ'O.
CH -

'/

,
H

,/
\

I
X

\, -, /

Figure 21-8 General struclUfe of the

Plptl'RrItS.

..... aler (I: 115). in alcohol (I: I 15). and in chlorororm (I: lS). IllS used primarily in lhe propI'Iyla:llls and treatment of IIIOlIon sickness. The lactate SIlll (Cyclizine Lact.ale Injec DOD. USP) is used for in lTal1luscular injeclion bc:c-1lU~ of the bmlled w:lter solubi lity of the hydrochloride . l"he injection Wluld be stoted in a cold place because if il i, Sloted PI room tcmpcruture for several months. a $Iighl yellow linl may develop. Th is does nOl indicale a loss in biologic pothi ..

lv,
1.#'/

/ A

CH-CHa-CHa- N

'A'

Flgur.21 - ' Gtflefal structure of tht> propylimlnl!S_

leney.

"'''l na
.~

Doaae

U~al-'ult~: Oral. foom; Tlble!~

SO mg/4-6 houn: 1M. SO m&l4-6 hour$ ( HO) and injoxtiI)Q (I:ooctate)

or
~'
Ml~

-"\ /\ ~"----'1!J}-CH- "0 -<><,

. ..,

~d

MecJiz/ne Hydrochloride. USP. Meclilinc h)'drochloride. l.(p<hloro-a-phenylbenzyl)-4-(m.me lhylbe.ll7yl)pi perazine dihydrochloride monohydrale (BonillC. Antiven). is a IIwdess . ... hile or sbghlly yello .... ish crystalline pm"dcr that is pnctically insoluble in water ( I: 1.000). II diffen from chJo;yclizine in having an Nm-methylbe:m;yl group m place of the N-mcthyl gl'Ollp. Although it is a modcnllcl y potenl anti hiSlaminic. mcclizine is used primarily as an antinauseant in the pn:venuon and treatment of motion SlC~ncS!. and in !hoe lreotment of nausea and vomi ti ng assoc-iatw with ver1igo and ndiauon ~icknes~.
Usuailldult d!;>8c; Ck1Il. 15-SO ms 1JooIl_le (orTruI ; Tabletl and chewable tablelS

l im

J~er
"~
~.

r"

'"

Chlorcyclizirte: ~.wuchloride. 1-{p<hloro-a-pbenylbenzyl}-4-mclhylpiperanne monohydrochloridc. a li&ht -scn~itive. whi te CfY5ulline pooodcr." soluble In water ( 1:2). in al~-ohol (I:I I).:ind in dluoform ( 1:4). A 1% solution has pH belwccn 4.8 and

ChIorcycIizlnf! Hydrochloritk. USP.

,.,., , od

...~

i ro-

SJ.
o.subsmuuon or substitution of halogen in the 2 or J ~lUon of either of tnc be!17.hydryl rings results in II. ml.lCh Inl potent compound. Chloo:yclirinc is indICated in the l)1IIIltomal1c relief o f Ill1icaria. hay fe~er. and cc nDin Other Ilicrgic conditions.

Bucfizine Hydrochloritk, USP. Buclilirte: hydrochloride. I-(p It rtbu ty Iben zy I)-4-{p<hloro-a-phcn y lbelli'.Y pl)pi erazine dihydrochloridc ( 8 ucladin-S). occurs as a .... hlle 10 slightly yello .... cryslallme po ....deI' that is insoluble in Wlter. The highly liJlld-OIlible buchrine has CNS deprcuant. anti emelic. and II.nlihistaminic jJiOputics. 1lIe sail i5 a\'llilable in 5O--mg I4blus for oral administr.Uion. l"he usWlI ~ 15 50 mg 30 minutes before travel and is reJ)C':ltW in " to 6 hours as needed.
Uluaillduir 00..:: ()n,1. SO rngI4-6 hours DoI.age forms: Tablelli
PRO PYLAMIN ES (M O N OA MINOPROPYl DE RI VATIVES)

Be

.0,~

><eo

hile

01,

llle prof!ylamine antihistamines are chamcteri1.ed structurally by WI spJ or $p2 carbon connecting atom with. casbon chain .of two addilional carbons linking the key ten iary amino and dlaryl pltarmacophore rno~ (Fig. 2 19). Those propylamincs .... ilh. s.atunlted carbon COIIOCCIin& moiety arc commonly ref~ tQas thepMlliraminLI. All of the pbemramines consist of II. phenyl and a 2-pyridyl aryl group and a lenni nal dimethylanulI() mQiety. Tbese compounds differ only in the phenyl substituent althe para posu ion- U (pIle-

co-

CH-N

/\ "--I

N -CH,--<,

><eo

>--- Cti -

"----I

r \ - ~, ---<
N

'}--C-CH,

, He'

b..,

CI (cIlJorphenirnminc). all<I Sr (bromphenirnnunc). n.e hal~naICd phemnlmllles a~ sigrllf"antly more polen! (20 to 50 times) and have Dlonger durntion of action.1) All pncnirnmines are chirol molecules. and the h;tlogc:nsubstituted dcnvalivcs ha~'e been resolved by nYMali ilalioo of salts formed .... nll d-lIUlanc acid. Amihis13l1lmic act;'il)' ~1dc:s almost e,.clusivdy in the S Slereoi'>Omcrs. u The prop)'lar11joe,~ with an ullsalunued OOI1!leCling moiety
nlr~miN:).

40 0113 liO"oCS d:llly. II is available in cenain rombi

products.

iroclulle the opc!n dcrivuti ves pyrrobutami nc and triprolidine and lhe cyc lic ~nalogues dimcthindcllc and phcnind;Jminc.
In the opcn.chain l'IUPy l::unines. II coplanar aromatic double bond system appcllf1 to be lin important (DClOI" for l,"t ih, stamlnic activity. The pyrrohdmo gll)\lp of these compounds i~ the side chai n Icmary amine Ihat impartS grealc~1 antihistaminic activit ),. The confOl'lnalionnJ rigidity of the unsatutated propylamines has pro' ided a useful modcllodclcnnillC dl lances bet ..... een the key diaryl and tertiary p/larmaco>-~ moieties in 1I ,-=PIor antagonists. a dlSlanc.: of 5 to 6 A. The anlihiMamillC!l in Ihis group arc nnlOng the llIost HoCIh'c II , antagonists. 1l1e agentS in Ihis cllI.~s also produce less sedalioo ,han the OIher cla!iSkal antihistamines (yci a si,n,flCant proportion or pallcnl~ do cxpericnc.: thi s cffect) and ha,'c lillie an!lemel>C aclioo. They do. howcver. uhlbi! significanl antichohnergic acu ~ ity. albei' less rhan rhe ummoalkyl clllers and phcnothiUJ.iI1CS.'" 19.2) In the prop)lamine series. the phannacokinclics of chlol'-phcniraminc have ~n ~tudim roost e.JO:ten\ively to humans.n Oral blOluilability ,s relativcly low (30 to .5()'1,) and may be luniled try fil'!ltp:1S1l melabolism. The primary IIIClabolilcs for Ihi~ compound lind other meml:lcr< of lhl~ S('ric.~ are the mOIlO- and di-N-dcalkylalion products. Compielc oJlidation of the lenninal amino moiety followed by glycine conjugation !las abo ~n n.oponm for brompheniramine. Chlorphcnlraminc plasma ruM-lives rungc from aOOuI 12 hOlll'llto 28 hours. depending 00 the: route of administrJtion (oral ~l'l'!IUS IV) .lJ The struclUrc~ of the marlo:.ctl'd salt forllls of lhe propylamine anlihistaffimcs. along with physicochemica l propcrues, basic therapeutic acti~ity profiles. and do\agc form information. arc pru.ided in the: monographs below.

Chlorphenlramine Maleate, USP. Chl~ml'll1llll: maleate. {j:)2-(p-ch loro--a-12 -duflCl lIy lami no)C'1 lIy1)b=)if pyridine bimaleate (Oilor-TriOielon). is II " 'hue crystalIiII po ... def lhat is !ioOluble in water (I:3.4). In alcohol (l1Ot. and in chloroform (I: I 0). II has a pK. of9.2. and an ~ ilQlutioo ha~ II pll between 4 and 5. Chlorination of pt.. uir mine in the 1""0 positioo of the phenyl nng i~ polency I().fold wllh no ~iablc change In toxicity. ~ of the antihl staminic acti,-ily resides ... ith the dUlro -o;;~ (.sec de.\chlnrphcni ruminc below). The usuol dose IS 2 to J mg 3 or 4 Innes a day. It has :1 half-life or 12 to 15 hotn
USUill adult tlosc:

Oosa", fonn~; E."o::ndedrek~sc: (".op:wk-;. ')rup.13bi&. ble I.;Ibl<:!>:. utcndal reic.... tablets. in,ICCIIOfI

Onl."IV. cw sc. ""''' -6 1IIJI8- 12 houn; 1M.

"""IS; e,,~nded ldetie.

~-40"'I

.~

Phenlramlne Maleate. Pheni rumine milleate. 2-[ 0'-[2di IIIclhylamillOCthyl )bcn1yl )pyridine birnaleale (Trl melOn. Inhiston). is a while ery~tal1mc powder. wi th a f"illl amineh~e odor. Il\.:It is 50Iuble in watcr (I :5) and \ cry soluble in aloohol. Th is drug is the least potenl member of the /\Cries and i, mru1.elw as the rucem3le. lllc usual adult dose is 20 to

De" I .... ~ . . . . .' ....

Httw.

Dexchlorphen;r.tm;ne Maleate. USP. o..-.. dt..,~ niruminc (Polatuminc) i, the de; lImrotatory cnantiornrrd l

In vitro and In ~I YO studie!; of the enuntiomorphs of chlorphenimlnin.c sltowed lhat the IIntihlSUl.minie activity e~ I~B predominantly in the ((l'.lIrQ isomcr. As me ntioned above. thoc dutfQ iSOlller lias the (5) coofigur~tion.n hoch IS supcrimpos:ablc oo tlte (5) ~)!1figuralion of the ~ ICU'~ le,orotatory elklnuOfllOll'h of carbioo.\llmme
e ....... ..Jul!
~.

rhlorphcnir~mlne.

Or-al. 2 m !.i.d...... 4i.d.

tabk:u. UIC,Idedn::tc;w: ,able,s

Dou,e room:

S~rup.

powder Ihal is soluble to the u.em of 100.n warm "<Iter. I'yrrobul:unine was invcSllgmed origina ll y u.~ the hydrochloride salt. bul the diphosphate was absorbed nlOre readily and coouplelely. C liniclII stlld,es indic-.Ilc lhat 1\ is long aeung . wllh II rompaJUndy slow onset of IICllon. The feeble anlih.WlffillllC propenlel of sc,'eraJ analogues point to the ,mportance of having a planar ArC ",CH-CII : N IInit and a pyrrolidulO group as the sule ch~in tenilll)' anu ne. '

Ilion

8romphe,,/ramlne MaleiJte, USP. Bromploclliramine maleate. ( + )2-jp-bromo-cr-12-(dullcthylanlllMl}ethyl )helllyl)pyndme bimalcate (Dimctllne). differs (rum chlorphcnirm1;ne by the substit ution of a bromine atOtll fOf lhe chlorine MOm. Its 1ICI10I1~ and uses an: h~e tho!;e of chlorphcni rullune. It has II half-life or 25 hoo~. ~hich is almosltw ice lhilt of thlorpllcn i ra mJ ne .
U.wal adul. oo.e: Oral. 4 lllll.i II ..... 'I.I.d.; e~ lcndtd-",Ie_. 8-12 'n&l8-12 houn.: 1M, IV, ..... SC, 10 """-12 hwo. Do< V form, : Eh~or. Iab~. u.cno.kd.",1eao;e i8bkls. In~

00"

Triprolldine Hydro<hloride, USP. Tnprulidine hydroch lorio.::, (E)- 2 -13( I-p~rrol.d inyl}- I-p-Iol y Ipropenyl) pyri dine monohydrochloride monohydrate (Aclidil). occur; as I ,,'hite cryStalli ne 1lO,,(\er \11th roo more than I slighl. bul unplcaomnl. odor. It is soluble III water and in alcohol. Ifld il.~ wlutions arc alkaline 1 litmus. 0 The lII."Ii~lIy is confined mninl y 10 the gCOlI1oClriC isomer in \lhich the pyrrolidinornethyl group is IrtlnlJ 1 the 2-pyridyl 0 group. Phmnaeologicnl ~lud lCSN conlinn .he high activily ortnproltdJllc and the supcnorlly of (1:) ove!'" C(Jn'e$ponding iZ) i\OlllCr'I as H . arnagOfilslL AI guinea pig ileum sites. the affinity of triprolidine (Of II ! receptors was II"IOI'e than 1.000 tlllOC~ lhe IIffinily of it., (l) partner. 111C n:lutive potcncy of uiprolidinc is of the saliOC ordeT as thai of dexchlorphcnir.lmulC. The pcuk effect occurs about 3.5 hool1lllftfr oral adrui nl~tl1ltion. and the duration of cffecl ;$ about 12 hours.

- - CHC~(C~

."

CHCOOH

CHCOOH

He'

,,4

Oubromphe"lramine MaleiJte, USP. Li ke .he chlor. congellCT. the anlihistaminic actIvity of brumphenira .me uiSt5 predorlllD3.nlly in the dn:lro iSOllocr. de ... brom pb:nJl'aIllillC maleate (DiOlllCr). and is of eOtllp;uabie

'I

"

-,.

I'yrrobutiJmine Phosphare. PyrrobutumlOc phosjNte. {E)- I-r 4 _( 4-ch lorophc:nyl)-3-llhenyl -2-butcnyllpyrrolidinc: diphosphale (Pyroni I). OCI.!urs as a \lhite f:rySlalline

Phenlndamlne riJrtrate, USP. Phenindum.nt tartmle. 2.3.4.9tC:lrJhydro-2"lCthyl9 phcnyl- I /IindcrooI2, l-clpyr-

td"..e b11artr.l~, occurs :t'i a CTe2my-whue powder, usually ... ilh. famt odor and sparingly 50Iubie m watl:\" (\ :40). A 2l1: aqueoui 5OIution has a pH of .boul 3 ..5. It I~ II1O!iiI stable In the pH range of 3.5 to .5.0 and is unstable in 501utioos rX pH 1 01" higher. OllO.idiri ng subUllnCC..\ 01" htal. may cause ison..enzalion to an inact i ~'e fonn. Structurally. phtni ndamioo can be n:1I~rded as an unsaturated propylamioo derivative. in that the rigid ring system contain~ u di~IOf\cd. Irfm.~ alkene. Like the. other commonly used anti hi~lamines. it may proUl.ICC drowsiness and sleepiness; It may also cause a rniklly stimulllllng oction in some lO pauenls and Hlsomnia when t.a1en just bcfOfC bedtime.
UMW oduh <b.c : 0naI. 25 mJ!4-6 hou ...

f igure 21 - 10 Goenefal structure of lhe pOenotliJollltlff

oo.aae (orma.: T:abIcu

y'

"-

I
/

"

.0

Phettifldeil"" T....1Ii
Dimeth lndene Maleate. DimethlndcllC maleate. ( :!: )2-[1- [2-[ 2.dimethy lamiflO)clhyl [indcn. 3yllethyl)pyri dioo bi ma leate ( I : 1) (Fortlist al Male ale), occurs liS a whi,,: 1 off. white cryst all ine powder thai hM II chatllcteristic odor 0 and is spari ngly soluble in watcr. This potent antihistllminic agcnt may be coosidcred a derivuth'e of the un~lIlrlned propylannnc:s. The: principal side effect is SOI"'C sro;IIion Of drowsiness. The IIlltihistamime actlvi ly resides mainly in lhe I !c\orotlltory iSOlTlCT. '
./ CHpizHlCH.,)z

CHCOOH

r'/

CHCOOH

II

or c..,
N

'/

PHENOTH IA.ZINES

!kglnning in the mid I9-W!;. sc\enl anllhlSlaminic druJ!!> I\a\'c ~n dl;;C;O\'em:l 115 a result of bndging Iht ary l uni!!; of .gcflts rt:latcd to the ethylenedianlll1Cli. The search for effecu lc antimalarials led to lhe ",.cst'j!atioo phenothi :iI.lOO \kri vali\'cs in which the bndging mllty is ~ulfur. Sub$C'I ucnl tcsting found th at the phcnoth1ilwlC cllISS of drugs had not only antihisl3mi ni..:: actl"Ity bul plo;o a p1wm3OOl1l$ I'

cal profile of ItS o ... n, COIIsi<k:r.lbly different from 111M orlk cthylencdiamllleS (Fig. 2110). Thus brgan the moflk useful p>~hoIherapcutlc agmt.14. 'I The phcnothilll.iOO den. ali\cs lhat di~play lhtraptll~ uscful anuhlSlan" mc action' conU1in a t..o- Of three .... tu.. br1mchcd al l yl cham bet" 'cxn the nng ~yw:m and t~ nitrogen atom . Thl~ d iffers signifiClml l), from the ~1d1Olht azioo amip<;ychntlc ...eries in ... h,ch an unbntnchW I"1l'!" chain is requ ired. The phcOOlhia/:i1lCli .. ilh a IhreNarIni bridge bel ... cen nitrogen aloms arc more potent In ~il/{l. AI,,). unlite the phtnOlh iaziJlc anlip<;ychotic~. the httcroq clic ring of the antihistamines i~ un~ubsmulcd. t' n..c cnantiomeN of promethazme hale been ~\~MiI havc similar antlhlstaminic and other phannacok)JiClI PIliP" eml'S as \k~bcd below. 12 This is in contra<it "lib ~ of ~lUdle~ of ttoe phtninmincs and carblno.umiRC' a. pounds in ... hteh the (himl center IS clO'iCT 10 tht fcature the moleculc. Asymrneuy apJIC'at\ 10 luI'!: Ie-. Innuence on anllltl\tammic oct.ivity " 'hen the clliral 1ie~ ncar Iht pru;m"ely charged si<k:-cham nilrtJS('" ProntCtru.l.ine. ttoe parent member of this serics. i~ moob atcly potcnt by pre....cnt ~landarUs. with prolonged IlcbOllIlll I'roootJllCcd sedative "ide errect ~. In iKldilion 10 liS anuhiu. minie action, il is a potent amiclllelic. antichohnergit.1IId sedati ng agent :Ind ~ignificantly potentlote<i lhe IICtion of. algeSIC and ocdalive drugS. I9 The other members of t/ul!ll:" ries dt<play a ~i milar pharmacol~ieal profi!c anti thultu! cau'>C dro"'~lncSli and impair the nbllity 10 pc:rfot!ll till, rcqulnng alen~. Also. OOIICurrent admimSlration of hohc be,'eroga and other eNS depJeli~nts wllh" ~ LhiazmeJ should be a\oidcd.'4 In general. lhe co of !cnlllhtnin, of the SIde chain and ~ubsUlunon of h grDlllb in lhe 2 position of the IlromatlC nng resul\) III pound~ II nh dI.'CT"Cased Ilnllhistanun ic 1IC1i\ ity and i I'!'yctootherupcuue propeme~. Ai iOOugh fcw phannacolincllc dala ItfC lI\ Pliable fOl !lor: phcnothiallnc antihistamines. tile !l\C,aboli... m of ti"e cloltt ~truc'ur~l anologuc pronIClhaJ.ine has Dc:cn ~tu(hcd in 1ft. tail .ll This compound mi<k:rgoes mono- mKI di~-dt~l;' :111011. sulfur OXidation. aromallc OXld;IIIOII I I the 3 poIol~ to yield ttoe phenol. and N-oxidation. A !lumber of metabolites. paniculurly lhe phcflOl. rna) yield gIUC;";" conjugates II is c~pccted thw. the phcnothlv.iroe anti . nllnc:~ .... oold d"pl:!.y Mmilar metabolic profiles.

or

;"";':It;

or

Prometha:tine Hydrochloride, USP. h)drochlondc, {:t:)1 ()..[2-(dimcthylamlflO)propyll allllC monohydrochloridc {Phenergan l. occurs as I .. hUe. faint.yellow c!),SllIlline powder that is \'cry IIOluble ID ~ . .

III hoi DbsoIUl~ alcohol. urN.! In (hloroflmn. 11$ IIlll!L'OUS solu IIOlU ~ shghlly lICid to litlllus.
t,;...., adult tto:w: 0.:.1 . ' 2.S mgf4 6 htJur.; or 2S me 'I.d_; 1M or IV. 12.S-2S mg/4- 6 houn< IN,.a~e ronn~: Syrup, 1IIbI~1'. mj-lion. ~U(lpOliitl>lie.<

Methdila::ine Hydrochloride. USP. Methdllv.inc hydrochloride. I0..[ Cl -mcthyl-3-pyrroll,bn) l)methyl [phcnothl v_lire lnonohydrochlorilk (Tacaryl I-I)drochlonlle ). al"" occurs liS a lighHon cI)'~talltnc powder wnh w_light char",temlie odor. Tire ..air ;. free l)' soluble in W;l.tCf and In alcohol . how!'\!'r. The octivit)' i. lile that of I11cthdila/JIII'. and II IS ildmmi'lcrN cnlly for Irs anhprurrhc effl'Cl. DIBENZOCYClOHEPTENES AND DIBENZOCYCLOHEPTANES

' ''--/:;---0

The dibenwcydoheptcnc and dibenlOC)'dohcptonc anllhi ,lamiJlC ' may be regarded as pilcnOlhiatine analogue.. In whit:h rhe 'iUlfur IIlom has bct:n rcplocctJ by an i'OMCric ~in}'1 group (cyproheptadine) or ;I. ~arunllctJ cthyl bridge (anlta dirre). IIlid the nng nil~cn has bn rrplaccd h)' an .pl carbon atom (Fig. 21 - 11 ). l1lc rwo members uf Ihi. sene, are closely relaled '" ,tructurr; azaladlnc I' an :I1.l1 (pyridyl) isoslere of cypmhcpllldll1C 111 \lhich the IO.II-doublc bond i~ rNliCed. The propI't1ICS o f each agent w-e derolled In Itre monogrJph~ below. C)'proOcpta d ine hydrochloride . "-(511-dlbenzo[a.d !-cydohcpten-S-yli dene)-Imc:th)' lpipendinc h~drochloride sc"luihydrntc: (Perioctin). IS slightly );Oluble in water and sparingly IoOluble rn Cyprohc:ptudlllc po55C:s~cs both :mnh!,taminc: :rnd antl"!:l'OIonin activity alN.! i, uo;ed 11., lin antipruntic agcnt. Scd:mon is rbe most prominc:nl silk c:ffCl.1. and this is ur.ually brief. dl~nng after J ot 4 day~ of 're~IJIlC'1lt. U,uaJ atlult

Trimepr.wllC tartl'lltc: . , t ) I0- [3 . {d IIncl h} Iam illo) -2 -methyl propyl! pile: r.oth IalUl!: W1!11C: (Tc:rnanl). occurs as It while to offwhite c rySlllllinc J!O"der lhal is fn.-cly SQlublc in \I'aler lind 500IubJc in IIkohol. Ib .....hi5Iaminit; action i~ reported 10 be from 1.5 to S times m. of promcthazlne. CIII11<:31 Studies ha\'c: shown II has a pronoooced 8Illipruritic llCIion. TIllS acrion OIay be unrelated illns hiSlalnine-antagooiling propct1ie~.

TritnepriUin~

Tartra t~.

USP.

Cyproheptadine Hydrochloride. USP.

lwa! adult dok-: Or.ll, 2.5 mll'l_i_ d.

~

r<ll"lm : Syrup;ond r."'''tlI

,"""".
COO

/'

I
"

;/

I
CHOH

CH:zCHC~(C~12

Do>.aac

oo.c. Oml. 4 m. I'-d or 'I i,d.

rorrrn Syrup and tlhkl>

I CH,

CHOH

COOH

-\

---,",

/-"~

",",

Tline", azIne Tartra~

MethdilatillC'. IO-HI -mclh}' I-3p)'rmlidiny l)llIclhyl!phenor hilll.ioc (Tacaryl). occurs as II Iic/tHan cryst:dllllc powder thaI has a characteristic odor al .. pncllcally 1n.""luhk: in w3ter. Methdiluinc. as the Me bast, is used In c hewdblc: lablc:ls because its low solubil Iy In \';"lt1~r ronlribules 10 Il' tll$le1cssnes.~, Some local ancs \W)I~ of lIM: buccal mucosa may be cxperic'l<.;cd if 11M: table t .drA"Cd and not swal lolOoed promptly.

/MflKlilazi~.

USP.

"-

""
C",

HOI

" "v;/~"

.""

A/aladinc: tOOkal!'. 6.1 1dl h ydro- I 1-( l-mcthyt-4 prpc:ndytillene)-SII-benw-[S,6 \Cyclohcpta!I.2blpyridint: male:ue (I :2) (Optrminc). is a potc:nt. Iongacting anlihiSlam;lIlc \lllh anllJ>('rolonin llCIi~ Ily. In c:arly rc.rrnt:. lIl..iltudll1C exhlblled nrorc than 311nle' lhe poIeocy of c hlOfphc:ninllnillC III rhe i..olalL-u gUloca pi, i ICUlilloCTt:en and more Ihan 7 times the oral poteJlCy of chlorphcnirnOll11C in protC'CUOll of guinea pigs against II double lethal do!ie of mtm,enou~ly udmimstc~ histamine. ') The

A::atadine Ma leate>, USP.

Figure 21 - 11 Gemorill $\ructure of the dibenzocydohep-

teoes and dlbenzocydOOepta!leS.

llsual dosage is I to 2 nlg twice daily. A7.aladi!1t' is available in I-mg tablets.

U,,,,,I &dull
I)a;.:,j~

oo.e: Oral,

1-2 mg h.i.d .

fOl1115 Tabkts

---,
,
I CH,

/
II
CHCOOH

rttCplor antagooi~s with rdatiH:I), high pou:ncy. MOIl 4 these ~'()mpounds also produce prolonged antihistrumnlCcf. feelS as a result of slow dissociation from Ii , ra:cpIOn-' lhe formation of aclive ITIelaboiiles ",uh similar Ita,*, binding profilC5. I~ 1be second-generation agcnt~ hnV( I,a affimty for muscarinie. lIdrencrg;c., or stl'OlonelJlC nn(U1 and. therefore, di~play II tower incidence of side effect!, aQO.. i,led With anlagoni~m al these ~or.;;. T1v::ir afflDibel; for these receptors vary OI11Cwhat. as indicated in the me.> graphs below. Pemaj1li fflOSl imponam ly. all of these rof. pounds lock seliat;ns effects al tlltrapeutic cono:;eMl_ bccaLISC of poor eNS penetration and, J>OI'sibly, lo .... errc!l{ finities for central histaminic.''' c holillef1!lC, and whu",p: reccptors. The first mcrnber~ of ,hiS anli histamlne subcJ-. introduced in tilt United States induded tmcnadilll: lSI'dane) and astemizole ( H i~manal) (Fig. 21-12). AltIIo!IP these o:;ompoonds offered scI'era] IIdvllllluges over thc:d. . cal uo lihiSlUmines. widespn:1Id usc n:~aled ~ therapeulic limi'ut ion~. I1lO'>t notably the ability to pnxb::r life-'h~lening arrhythmias "'hen used concUtm\lJ) ... drugs thot inhibit their rnctaboli sm. Thi s drug imC11ldIOl! lilt been I1lO'>t evident wi th the imi<!alD1e 1I1l1ifungals (kctoa zoic. itl3COnDl.oJc:. and nUC()f1Dl.ole) and the 11\IM01..-b (erythromycin. clnrilhromydn). "'hieh inhibit the IIItlJlto. lism of terfenadioe and astcmi7.oIe arid thus elcvalt of the parent drug~. which an: proarmythrnic." As I rtIIIl of lhese ooncem.~. both lISIeml7.o~ and tcrfcnadinc: have twithdrawn from lhe U. S. market. Subsequent researtlt d fons focused on the de"clopmcnt of serond-llenmMio." Ilisln mincs thaI maintained lhc ~iml recq:Mor-bindilll'" files of I5temizole and tcrfcnadinc but "'ere dnllid " proarrfl)thmic toxicity. These cffotts led to the introduc!iol of fcxofcnadioe. 10000Iadioe, cetiri7.ioe , arid acrivaslIne._ described in the molfM>Srnphs helow.

00_"

CHCOOH
~Ko 'emJdine Hydrochloride. Fcxofenadine ~ chloride. ( .:t H -I l-hydroJ{y-4-I4-(hydroJ{yd iphcnylmtlh)t~

SecandCen...atlon ..... Ant.onlst D.a.

asses
The second-generation anlihislamillC1l are more si milar pharmacologkally than structurally. As dil'oCussed above in this chapter, Ihcse compounds ..... err Oevtloped as sckclivc HI-

d;~. T"'"'"';;;~~0,~~:~(;~,r~;~ ~~~~~~ '

butyropnenone ence of "" Ii
OH

I-piperinyl fb\Jtyl-IJ.o--dimclhylhen7.cncact"tic kid ( gra), OCl:urs as II while to off-wllile crystalline po.,,,irr II1II is flttly soluble in mc:tllanol and ethanol. sl ightly toIubk I chl0r0fonn and water. and insoluble in ileUM. llu! pourld is mar1\eted lIS a f1ICCmate and exists &.'l ~""Ium. in aqueous media at physiological pH. Fe~orenadine is Dprimary o~idal i ~e melaboille Of~rff"

OH

\ /,

I C

/
N-

CHzCH:CH:!CH - - {

'/ '\
-

CH1

)--C -

CIi:!

I COOH

" .--::

He<.

OIa pkr 21 HiJf(1,."~t "lid A,,,,hiJlllmin/r AgMIS

113

of
cf-

CH,

,~-

"'"

-+-CH,

liit

.~

t ie'

,.~

om-

I~

ar

rgic

las~

o"

Sol-

,-

l5Si of

rue<

""

,,"

fIgu,. 21 - 12 StructUIe5 of

!fr!en.ldifl(' and astemilOle

diplltp)'lmethylp.pe:ridine IllOIcty analogous to th:u found in

lilt piperazine ~n'ihjst amioes . Terfenadine i~ II sd ecti vc, Ion,acling (>12 hours) HI amugoois( with linle affinil,. for ~nic. 6efU(OrIergic, or ~nergk reccptoo;. 1be hista-

Unlike its parem drug. (01)' 5'1> of the lOIal dose of fexofenlldine is metabolir.ed. TlIc. remainder is excreted in II!(' bile 1100 urine; the mean elimination half-life is llbout 14
houl5.lf>. 17

~ptor

affinity of this

COITIpOIInd

is belie"ed to be
U.u..al adult doM;e: Oral. 60

~~ Iyl}-

\11c-

kin m

,"",

."

,-

rtI*tI primarily 10 the pic&CllCe of the dip/lcnylmethy lpiperlime moiety. The prolonged action TCsulls from very slow ~ialion from these receptors. II Tht: lack ofanticholincrp:. .nncrgie. or krolOl1ergic IIClioru; appears to be Holed 10 !be ~llCe of the N-phcnylootanol substituent. This IIIbsullltnl also limits distribution of terfenadine 10 the CNS,'" JJ Terfenpdine undergQe!l ~ignifiellnl firsT-pass me.. lIboIisrn, with the predominant nw:o.llIbohte being fuofcna . In active metabolite miu ll ing from nltlll)'t group oxi....... When druss that inhibit this tnlI1fomlluion. such as lnuduole anlifungals and rIllICrolides. Il/'e used COlI(!urmuly. terfcnadine levels may rise to toxic level s. resulting potentially fDtal heart rhythm problems. TlIc. observation . . fuofenadine dlspla)'$ antihistalllinic activity companl~ with that of tcrfenadine but is less cardiOlo,lic led to its i!r.e!npmcnt as an alternative to terfenadlne for the relief 0{ ~ symptoms of SCll'iOfIal allergies. J6 Fu()/'C'1Iadine i5 selective peripheral H I- receptor blocker _like terfenadlne. produces noclinically 5ignificam ami I.tohnergic effects or ai -adrenergic =pIor blockade al tlmpeutic dolies. No sedative or other e NS effects have )em repol1ed for this dru g. and animal studies indkale that klofenadine does not cross the 888 . In "jtro ~udies also ....-Sllhal unlike terfenadine. fexofenadine does not block jum channels in cafdioc)'te5. Funl!('lltl()I'e. in drug inII'IIClion studies no prolongation of the QTc interval or reIIIIlI bean rftythm abnonnalities .... en: detected when (u okaiine was administcm;l concurrently with erythromycin i.ttot'ona7.ole. If>. )1 Ihofenadinc: is nlpidly lIbsorbed after oral adminislnl.~.~producing peak serum concentr.ll.ions in about 2.5 ,. Ftxofenadine is W to 70'1> plasma prot:ein bound.

Dosage form: Clpsutes

rn, b.l.d.

LontMii M . USP. LoratlKIine. 4-(8< hloro-5,6-(!ihydro] I H-belUO/ 5.6J<yclohepta[ I ,2bJpyridinll-ylidene- 1< lIf boxylic acid ethy l es~cr, is a whue to off white: powder nOi soluble in waler but very soluble in 1ICC10IlC. alcohols. lind chlorororm.

Lomtadine is siructurally related !O the ant ihi stamines v .a ~adine aoo cyproheptadine. It diffcrs from u.lIllldiroe. in 111':11 a neutral carbam:lte group has tq>I~ the basic tMlaty

amino moiety. and n phenyl ri ng II:.... been ~ub,!i !uh:d wilh a chlorine Mlom. 111c replaccmcnt of !he: baSIC group .... ilh I nculml fuoclionalily is belie\ed 10 pre.-.erye nn lih i\larninic action ... hdc reducing CNS effects. Loouadme is also S!I\IC tUrdUy rdated 1 a number of uicyclie anlitkprc:s.~nls. II>. Nt 0 LcM-Jludine i~ p seleclivc pcriphcrnl H I amagoniSI Wllh a rc:cepiorbinding profile lile that of !he: otht:r members of Ihis ~nc<i_ Cl~~pllhal it has more: anll"Crotoocrgic acti'lIY. Thus ;1 produces no ubSlamial CNS or autonomic siOe cffccts. l.or.atadme displays potency COOlpanlblc with lhat of IlSlcmiJ.ole and greatcr Ihan Ihal of Icrfcnadine. II>. " Loruuldine is rapidly absortJed aflcr oral lidm inislrnrion. producing pc-ak plasma levcls in aboul 1.5 hours. Thl\ drug is eXlcnsil'cly IlIClaboliu,d. pnmruily 10 the: descarboclhuxy nlCtaoolite. which retains SOUle Mlihistaminic activity . Both parent drug and melllbohlC have climmation half-lI\'c\ ranging from 8 to 15 hourll. The IlIClaooHle is excreted re:nall y a.~ 11 COl1jugate.
U.u~1

cause the drug i. primarily climinmcd by n rCJlal route. it! adverse reac:uOfIJ may be morc pronounced in IIldil'ldllllsuffering from n:nal in)uflieiency. No canhotOlic crrr(\l. socII as QT prolongatioo. lire oo\CI"\'ed ..... 1111 lhe new dna, when used II liS recommended or higher doses or ""hen coadmini~tered with imidalolc antifungal, and macrnl..r antibiotics. Other lypic~1 drug intel".lCtions of II , antihillamines. ho"'cH"r. :Ipply 10 cctirizlne. Concurrem use offill drug .... Ilh alcohol and otocr eNS depressants .\houkl lit

nuided.'.-t)
Dose-proportIOnal C-. 1 'lIllI(:<; are ochle\cd wuh", I bow of or..1 administration of eehri zinc . Food slow\ the M c( cetiri/jne absorption bul docs not affect ttle O\'craJl CJ.ICIL Comistent with the polar nature of th'$ carbo"y"e 1(:113 dnaless Ihan 10% of pc:;.l plasma le\cl\ have been measum!!lI the brain. Cetiril.ine is not e.n en si\'cly Rletaboliud. ... nlOfe than 70% of a 100IIIg oral dose i~ e~crcted In the . . (:>80% a,\ unchanged drug) and 10% i~ recovered In !lit feces. 111c drug I~ highly prOIem bound (93%) and ila6a tcrminnl hnlf-I ife of 8.3 hours. The elcarlmce of ccurizult .. reduced in clderly ~ubjL"cb and in n:nall y and hcp.llicall) impaired palienl~.401
U~1,l;I1

oouil dow: 0.-...1. to- 4O niB da,ly

Cetirizine. US,.. Ccliril.ine. 12-14-1(4~hlorophcnyll phenyhncthyIJ-I-pipcrozinyl \ClOOXY\lICClic acid (Zynec). i~ a racemic compound available a, a whitc eryslalline powder that is waleI' sol ublc. CCliri zine is lhe primary acid metabolite of hydroxYline. resulung from compklC oxKlariOfi of lhe primary alcohol lnoicty. Th is compound is 't.WlllcriOIllC and relali l'cly polar and thus does not pcnetnlle the IJOB readi ly. Before its inttoducuon in !he: United Slale.~. ct:lirizinc was 0fJC of the most widely prc'<lcnbcd II, antihi~laminc' in Europe. It i. highly selecliye in ,,~ interactioo wilh variOu< hormonal binding 5IIM and highly potcnt (:>:> terfenadine) as ... elJ ...... ~ 1 1lle udvantuscs or Ihi. compound appeur 10 be onee-daily dosing. npid onset of aaivily. minimal CNS effecUl. and a rack of , li nically ,ignHieant effeelS o n cardiac rh)thm ..... IK-n adminiqered ..... Ilh imid:l1.ole aUlifungal, and macrolide anti biotics. The OMc:t of actIOn is within 20 10 60 minutes in most pallents. Cetiril.ine produces qualnativcl y diffcn:nt effects on pc<iyehonlOlor and psychophy~icaJ function, from the first -generatJon amih,slamines. The most common adverse: reaction associaled wllh ectlnlJne l~ dose-related somnolence. ho .... c\er. so patients should be advi~ that cetiriline may mterfere wnh lhe pc-rform;m,e of cenain psychomolor and psy,hophysiealllClivi ties Other effccl ~ of thi~ drug 111elude fatigue. dry mouth. ph.lrynSiti<. and diuiness. Be-

H(lult ~; Oml. ~ form. T~blrt'

10 m& lI.d.

AulvimiM, USP.

Acri'a:sline. USP. (l:-.t.)-3-I6-{H" me th ~ Iphenyl)-3-( I_p)'rmhdm yl }- I- pmpc rty 1-2- pyflliD) It 2-propenoic acid {Scmpn::A). is a fhcd-eombnllllion P'''' Oflhe anuhislamlne acrival;line (8 mg) wilh!he ~ pliCudocphc:drine (60 mg). Acma..line is an odorIm. to 1'1Ile-cream cry~talli ne powder thaI is solu hle in cfIkw. form lU1d alcohol and slightly soluble in walet'. Aerivastme is un analoguc of tnprohdl ne COnIalnlll,l! a c.bo"yethenyl molely at the 6 position of the pyrid)1 r-., Aeriv1lStine show, anlihblaminic poIeocy and dtorllO III action conlpllrdble 1 lhose of trlprolJdlne. Unh~(' mprol 0 dine. acrivastine does not display Significant antM:.~~: activity at thc:rdpc:utic conet'ntl'llt,ons. Also. the __' polarity of Ihis OOlnpotJlld rcsultiug from carbo~)ettw:. \ub-itltulion limits 66B penetl'lllJoo. and Ihus. thil< ..,;,.... producc:s less scdauon than triprolidine. .a.J Limited phammcokirn:tic data arc Dyuiluble for tlu! pound. Orally adnHni~ered drug has a half-life ofatxMit I hourll nnd II lotal body deul1lI'K:c of 44 mUm;n per q. TIr mean peak plasma CQIll'enlrutions an: rcportl'd 10 ''WI

OH

JII:, II.. '

.idr:ly. and the drug 1Ippc'lIrs to 1XIl<'lfUlc the eNS poorl y.

;jdual,

n.: metabolic fale of acrivllSlIJ1e has no! been reportoo.

.,c

ffC(:b. " dru~

Jen CO-

:rolitJc: IIhl'taof th"

\,lId be

nile of

II"""

C1tcllI.

inhIbit the chenlQl;u.i( or toSlnophi l~ at lhe sile or appli calion (i.e .. oculal" tissuc). In lung tissue:. pretrratnlent willi the m3.S1 cell stabi lizers cromolyn and Iledocromi l blocks the immedtatC' and dc:layed brollclloconS(rictiv( n:attions Ind uced b) lhe inhalation of anligcns. These drugs also aUcnuIIIC lhe broncho!'pasm associated Wllh nercisc. cold air. en vlronmcl1l.llll pollutwlls, and ccnam drugs (aspirin). lbe mast cellSlablli7.ct'"!l do not b,a\'C' inillnsic bronchodilalor. anhhl" lamine. anticholinergic. vl\SOOOl'L'triclor, or gluCOCOI1ICOId acti~ny aoo, ",hen dt-Ij\'ered by mhalation at the ra"OIT\' mcnded 00sc. b.a,co no known ther~pcutic 'ysle mic act" ny. The Slll.lCWres, chemical propenies. pharmacological profiles. ~nd dosage d;lIa for these agems are provided in the monogrnphs below.

al~

'"~ In the
I

..."" ,
1-(4-

""

OCH,
0

OOOH

,,-

I
o

:/

/ 0 "

u-J IlduJI 00;0.>; Oral. II or 60 mg l.i.d.1U IItd. ~ fann; Tablet!;

OC.,

INHIBITION OF HISTAMINE RELEASE: MAST

all STABILIZERS
a car
nnll_

"

The discovery of the brorn:h.odilaling :W:ljyity of the [\~lUrnl pn;duct klieU in led 10 tile development of the bi'i(chrOfTlOnes) erompoonds thaI ~I:lblhle mast cells and inhLbillhe n:lc3..<;e aflu.umilll' and Oilier medial()l'1i of innammalion. The first t 'npI'llIically slgrllfkant member 0{ thl~ cla.~$ ......s Cl'Of1'lOo \Odium.lG," Further resean:h lalte!!ng mon: crrecuvc . . , Jr.ijjhed In the Introduction of nedocromil, followed ~nlly by JlC'mirolast and lodo.um ide. GcM'r.tlly, the
5tabili l.ers inhibit activDtion of. and IlloC'd imor n:. leN frum. a variety of inflummalOfy cell types U.~SOCiu led 11111 :allergy and a..~Ih.ma. including co.inophi 1 ncutrophils. .1. _mpbagcs. masl ~"II~. nlOllOC)le~. and platckls. In addi 10 lIistamine. Ihe'>C drugs inhibn lhe rdca.'>C of IculcoItIa (C4. D4. &II and ~lIglandins. In ~Ilro !<ludic_ sug!lIM Ihe5e drug~ indIrectly inhi bit calcium Io n cnlfy into ~ cell and Illal IlIi) action PfC\'cnls rne<lllltor rclc~. lI.Jditioo to their lrorollllor n:leasc: . some o f thc....e drugs
~II

".,

Cromolyn Sodium. USP. Crornolyn sodium. disodium I .3 - bi) (2 cnrboxychromon - 5 - yloly ) -2 hydm~ypr<lfXlllC (InIal ). is a h} groscoplc, while. hydnlled cT)".mlline powder III;lt i_ !>OI uble in wmer ( I: I 0), II IS tasteless at first but leaves II very . 1;81111'1 bitter aftenaste. The pK. of cromoJyn is 2.0. It is avwl..ablc lIS a sol ution for. I1<'bulizer. an a.erosol sproy . II nasai.o;olutiott. an ophthalmIC solution. tIIld:tll oral concen Irate NebuhJ.(d and aeroool (I",nol}n h used for prophylactIC managcmcnl of broochial asthma and pn:vention of exm:lseindoced broncllO'ipasm. Cromoiyn nasal solution is used for the: pn:vem ion and tn:atment of allergic rhinitis. and oral COIICcnU11le is used to tn-a! tile III Slnmini c sy mptom s of maslocylo~is (diarrhea. Oust\ing. headaches, vomi ting. unicaria. abdominal pain. nausca. and ncllmg). [n the trraune m of asthma. cromolyn cfficacy is manifc~ted by decn-ascd se\u it '1 of elinK-al s} mptOltlS. or need for CottComilant lherapy. or both. Long-teon \1St IS Jusllfied if the drug sIgnificantly rrouce5 the St'\'cnty of asthma symptoms: pc'onit~ 11 signilicllm n-doction m. or eliminatioo of. ~teroid dosage: or 1111-

/'

/ 0,

'"

I
o

pro'e$ mana!crt'l('nt of those ",110 havc intolcrable side cffects 10 sympathomirt'l('tjc agents or mcdl)lxanthines. For ch",noIyn to be cifCC'live. II must be adnllntstcl"(!(! at 'east 30 mUlwcs prior 10 antigen ch:allengc and administered III ~gu 'ar nllerva's (seedosong onfotmalion be'ow). O"erustof cmlnolyn I'eliults on tolerance. Uj.WIllidull do!.e: NeblMlcr ooIuhon, 20 nla I.\haled q l.d. Aero8Ol. 2 nlelCm! sprays inhaled q.l.d. Inlr:t.I\ll~. S.l nil (I)OC ,",,!em! !pray) in ~,",h OOSInl t.i.d. or Ip.d al "'aular illlCf\al. Ophthalmic. 1 drop of a 2-4'1 \l)IulIQll q.id. 10 6 limes dally Oral.::! ImpuJcsq-id. lO m.IIUln bc(~ _als and 1\ bcdu_ Ncdocromil sodium. diSC dlum 9-cthy l-6.9-dihydr0-4.6-dIO\o-IO-prof)y'-4H-pyraJlO lJ.2_glquinolinc_2.8-dicarto~)"late (Tilade), IS lwai'able as an aerosol in :I mclercd-dosc inhaler. NeOOcromi l is struclUr~lIy rdlUed 10 emmolyn and displays similar. but broader. phannacologicalllCtions. Nedocronul is ondiemed for maimenancc IhCOlp)' in too management of pollients wi th mild to-modcnlle bronchial asthma . It was developed in II. scan:h for a compound with a better biological profile than cromolyn. whiCh ha~ limitations in the t~atmcm of cenain palients. such lIoS the dderly asth matie paticnt and palients With Intrinsic asthma. Cromolyn I ~ more effecti"c in stabilizing connecti.c IIS.~lM! mast cclls than mucosal masl cells. and since release of mediatCotS from m3.St eelh in the lung IS an important eomponent of inflammation and bronchia.! hl'JX'rreaclIvit)" III asthmatIC pallents, an agent with greater cffCC1S on mucosal milSl cclls was de$Inble. Avai lllbk data 5ugge<t that ncdocromil. although ha, ing profile of activit)" likc that of CfOllIolyn. i~ mon: effective in stabi lizing nmcosal mast C<'lIs.~'

llIc :lntia'>lhmalle cffCCb' of ncdocronlll OllIy al'\O in.1IIY!: inhibition of uon rdlellcs. Axon refle'l'lI may be prodIm! by brady"m," m the pre<ocnce of dan~c 10 the 'Ii"'MIl' epathelium. mulling '" ~Ic.sc of oocnsory neuropcptidt'J ,. . stance P. neurokinin A). "'hieh can produce bronchocoISlricuon and edenta. /'Iedocromil 15 more cffectlve m. cromolyn on 1"C,'crsing bradykinon.indU<.'Cd and neurol\llll A_IIl(illCed bronclloronStriction in hurnan ~.
U~unl aduh do': tntrllnasat . t4 mg U... O inll:t.t~l;om) q.tA.

regut..- m!erval.

Nedocromil Sodium. USP.

The only sicruf~ ~lructUI'1lJly ~imilant )' between lodoxamldc and uIXlloI,. and ncJocronlllls the prcs.ence oft"'o acidic groups. 1.oIk. amide tromcihanllne. ,v.W-(2<hkJro.5-cyaoo-m-phen)iea' diolllmic acid (A'onllde). IS a ",hile cl)stalhne . "'Oller ble powder, It is aHlilabie as a 0.1-:' solution. With milllhter conllllmng 1.78 mg of iodonmldc tll)TTlClbamlll( equivalent to I mg of lodo' amidc. llIc wlution tlte pt\'.w .... athc ben1.alkonlunl chlonde ,O.OO7'J)as wei as mannitol. hydrox yprop) I IIlCthy lcel1u lose . ..:xIwm Claw, citric add. CdetD di;.odiuf\l. t)'lo~ apol. hydrochloric DI tC :mcVor sodlUl n hydroxide (to adju<t pll ). and purified ... lIIt! Lodollamidc is Ind lC~lcd in the tn:;umclll of the ocu&. di);()f"(\ers inc luding ,cmallcroloconjuncll vi tiS. "emal cutJuncllvlIIS. IIJ1<I "emal ker1llitis.~ 1l1e doo;c for adull$_ children older than 2 ycan of agc 1 I to 2 drop. in rd 5 affected eyc " timc~ daily for up tu 3 loonthS The f~ucntl)" reponed ocular :;I(hcl"lC CllJX'riencc:s Wert II .slent bumlllg. stlllglllg. or diSCUlufOl1 on In5lillall0ll.

Lodo..mi~ Trometham;ne.

COIlI"-

, ,____ ,coo

Na'

ola~t can be coosidt-red lin analogue of one ponlOll of tit cronlOl)'n structure in ",hich lite CIIrbo~)"1 group hal Imt replaced ",ilh an i..osterk tetral.olc IllOlety. Pemirola~l poe. slum. 9'!\"Icthy l-J-( III_tctnuol_S_y1j -4/f pyridoll .2./I"!PJTI' llIidin-4-one pota.sill m CAlamast). i~ a yello .... wDtcr-soIIbk powder. The commercial ~paration i~ avai lable:li' 0 l~ ~tcrile ophthalmiC !oQlutlon for to(>1ClI1 oonllllistratlOlllO" eyes. Each millill terofthis solution contains 1.0 mgof~ irolast pota~Slum. ali ,,"cll as tbc Jl'!"l"'oC .... '3U\C laural",:-' chloride to.OO.5CJ,). and glycerin. phO!.phatc buffer). and dium hydroxide to maJnlD.in a solution pl-l of 8.0. The,. lion h.as an O'>l11oolality of appro~imatcly 24() mOsrnIL 11rr recommended dose IS one 10 two drops IIl~lIlIed Into affected eyc" tiltlCl; a day. This drug prodUCt is for caIa administration only ~nd not for injection Of oral Ufoe. I'tm1

Pe-m;rolast Potassium Ophthalmic Solution.

rn.

N,
NO

/'

/N

I
OH

e><","

"'-

I HOCH2-C-N~ I
eN","

CN

IN 5OIUlloo should be. used ","h cauT during pregnancy ion .... hlle pursing , SInce its ~fcty has IlOl been STudIed undcr 1hesC' c, rcuntsTances,~7

o
/'

H-

1 \\
/ " ' - H/

"/'
a

I
\

"N
/0
N

e ,e

~/

---ANTIHISTAMINE DEVELOPMENTS: " DUAL-ACTING" ANTIHISTAMINES

m.o. p;asl dix'adc Tncre has bttn oonsidcrublc mTCres! in
de\'elopmcnt of novel am ihisTaminic compounds .... iTh lIlC!Ch:misms of acTion ltIc1uding H I-ICI."CpTor ~nl ago ,,::~~m3S1 cell ~labilil3Tion. Cum:nTly avail~ble drugs ~ such dual anTihisTam;nic acuons lndude a1.t'las T oufen. Thes.c compounds ctmTain T basIC he ..,~""ho,. TO produce relat ively So!It.~Tive hi ~TA millC aIIlaiooism (diarylalkylamines) as ....ell as inhibition rdea.o;c of hi>tamine and Olht;:r mcdialors (e.g .. ~~."" and PAf) from nUlSt cells in"oh'ed III The responSo!. In vjlm siudies sugge.'1 th:lI Thc<e com.~~. 1I~ ~a.-.e CherTIQIlU.iS and acm'alion of eQSmo.... uJa.~ine lind " elOlifen cUlTl'nlly IU"C indicaled fOl'" I of ilchlng of The eye associ aTed ",jlh allergic . I 11M:ir unTiailergy IlCT ions occur wilhin minaflrr IIdmin;str.ltion and may peNiq fOl'" up to II The Struclures. chemical plOpeMle~. plwmacoloilca l ...... and dosage daTa fo r these agenls arc provided in monogruphs below.

11M: n:coonmended dose of :uela"i"e ~ol u!rOll i~ ollC' drop Insu lled imoeach affecTOOC}e I"'ice a day . Thi~ drog pmdllct j~ for ocular adminl.'lru!r()n o nl y and nOl ("r inject ion or oml u;.e. Absorpt ion of ul,c lasline folio", mg ocular atinllnlslra t].on i~ rclatl\"el) low (I..~~ than 1 ng/mL). A~d drug undergoes c.\lcn~i,e o.idali,,: N-dcmcThylllTion by C~ to chrome 1 '-450. and the parent dru g ~rnl mct uboHle an: diminaTed primurily in tnc fece~. TIle most frequcntly reported IIdversc reaction .. arc trun,jen, e} e bumin~ 01'" slrngmg. headlldlC.~, ~nd bi tter !.:lStc. A7.tla""~ ..olullOn .. Ilou ld be USl.--d ... ith ca ution duri ng prcgn;mcy or ",'hile nu,",,;ng. ~lIIce il ~ 8Mct) ha .. nOl been 'ludled under 1hc..'IC cin:um~/UICC.~.-'II KetOl ifen fumamte. 4 l - mc thyl-4- pipcridyl iderle )-4If-bcnlU( 4.51 cyelohcplu( 1.2-blthiophcn-10f1)If)-onc h) d rogen fumarate (ladiIOl'"). is a line crysllll hne po .....der. KClOIrfcn " ~ "ctolhio phene ISOStere anulOl;l.Ie of the diben~(">Cyclohcplulle untihistamines. The o;oluliof\ COnTains 0.345 mg of ketolifen fumarnte. which i, equivalenT Itl 0.25 11111- of kelOlifen. The o;,;.lu,ioo also contains lhe prescr.'at i\e bcn/.:ll J.:OtllulI\ chloride (O.OI 'J) as ... ell a, glycerol. ~l(Jium hydro~i dc lindlOI'" hydrochlo ric acid (to adJUST pll). und p-unlied waTer. It has a pH of 4.4 to 5.8 and an onlOlahl) of 210 T 300 niOsml O

Keto tifen Fumarate Ophthalmic Solution.

-r

'.

o
)--.

Hydrochloride
I

Solu tion. )- I-(211)- phlhalazinollC. 4-[ (+-

Oph thalm ic

I,,;

propylene

in ",mer. soluble in

'"

"'"

. HOOC>==<.H
N

iiI ' alClasTine hydrochlotide equivaJ.:nllo . the preservative bcn1..uIJ.:onium inactive ingredients Including di~

COOH

I CH,

i hydl'O~ ypropylmethykellulose. SQr. wlulion. sodIum hydro.dde. and water for injection. has a pH of appro'(imaltly 5.0 to 6.5 and an approxinllltciy 271 to 312 n)())nV1..

The recommended dose of "etOlifen solutiOll is one drop insulled mto ..ach affected eye e"ery 8 to 12 hount The most frequenTly reported adverse reactions an: conjunctival

injection....."'taches. and rhinitis. This drug product is for CX'ular admimstration only and DOl for injection or on! use. Keloofen 5OIution should be used with caution during pregnaney or while nursing. since its safety has 001 been stud ied under these circumstaoces,""

HISTAMINE H2 ANTAGONISTS
Drugs ....hose pharmacological action primari ly invoh'c$ antagonism of the action of hi'ilaJlline al ilS H2 ~plors find therapt"ulic applicntion in the U"ealment of acid peptic disorders rang;n&: from hcal'lbum to pept ic ulcer disease. Zol linger-Ellison syndrome. gllStroeSOphagcaJ reflu disease (GER D). acute stJ'eS Llkers, and erosions.:IO. 51

acid and proloolytie pepsin enzyme.~ . .."hose fornwion i!; faciliwcd by the klw gastric pH, is generally assumed 10 lit required (or the hydrol ysis of proteins and other foods. The acid secretory unit of the gasulc mucosa is the parieaI (oxyntic) ce ll , Parietal cells contain a hydrogen ion pump, a unique: H,O ~ IK -ATPase: system tnat !iC!C'Tetes H,O - ill exchange for the uplake of K ~ ion . Miction of J6d .., gastric ~etaJ (oxyntic) cells is regul:uc:d by the actic:a of various mediators at n::cc:plor> located on the basoiatml mc:mbr.lIle, inc:luding hi ~tamine 8goni~m of HI n::ttptrn (cellular), gaslrin activit), al G rettplOt'!i (blood). and 1Ca)'~ choline (ACh) at M l mU!ICannic rc:cepiOB (neuronal ) (fit: 2 1.1 3).

P.ptlc Uk ... DI.....D

Peptide ulcer disease ( PUD) is a gruup of uptXl' GI In;! disordc:n thai result fmlll 1m.: erosive aclion of acid and pepsin . Duodenal ulccr(DU) and gastric u1cer (GU) pre the nul common fonns.. although PUD may occur in lhe e w . or small inlestine. FactOl"ll involved III lhe pathogenc:si~_

Peptk Add s.cretlon

A chamclerislK; fcall.m:: of the IlUImmalian stomach j~ its ability 10 !lCe.cle acid as pan of ils i n~'oI"cmcm in digesting food for absorpIion loter in lhe intestine. The ~ of

""
G lEUio,

~
~

" " '.

t ,"'.,
'.
~~-----~
'

"
co

. --.t (Ca:~----------_
--EB

--

,-

Ell
.

-- '-- '-"''oN I ~p I---~--" "- /

'"
. ~

--------.. ,., /

'\
00,0.

W IK',

5
,. G

Ell

"""

...

eo,

"'ad oIdonIc

.....

GulrIo

."
Ellao,,'. 0tI
Fig ure 21 - 13 Ilo.. nona]
~~1lOn

of clCod secretIOn by Pilnetal cells.

1tCUm:nceuf PUD include h)'pel>eCretion of IIdd and pepsin MId 01 mfectlon by Ht'lirobarlt'r pylori. a Gram-negati\'e 5plf31 bacterium. H. pylori h:ls been found in "inuaJly all paticnl5 with DU and appro;dmau~ly 75% of patients with GU. Some mk flC'looo as ....... iated with t'eCUm!1'ICe or PUD Include cigarelle sn)(ll;i ng. chronic use of ulcerogenic drugs le.lI .. nonsteroidal Imi-infl<lll1malory drugs I NSAIDsIJ. male ~. age. alrohol consump(ion. emolional strcu. and famdy history . The pIs of PUD thc:r.tpy are 10 pronxMe healing. relieve pIlIL. and prevmtulccr compiications and t'eCum:/ICe5. Medio:alion, used \0 heal or reduce ulcer recurreoce inc lude :tn t1Cids. hiwuniroe Hr I'CCeptor anl1lgonim. proICClh'e mucosal Iwliel'5. proton pump inhibilors. prostaglandins. and bis BIIh ,\:lIlt and anti biotic combination,.

Sbucblr.' O.rf_.tI_ A review of the characterization and development of hi stamiroe 1l 2-rcccptor anHl.gonists reveals a classic medk inal chemistry approach 10 problem wl,ing." Structural e\oIulion of the fin;t disco\'t~red. clinicall), useful II I amagon;". ci lllelidinc. Is dcpickd in Figure 21- 14. Methy latioro of the S posItion of the imidazole heterocycle of hi stamme pmduces II selective agonist :It atrial his/amine reccplOl'S (Il l)' 111e guanhlino all3logue of hist:lmine pos ... s$C"S ....cak anlagoniS! acli";I), 10 the kid-secretory aclions of histamine. Increasing the length of the sidc chain from t,,o 10 four CIII'boos. coupled wilh replacement of the !iIroIlgly ~lC guanidino ,roup by the neutr.ll methyl Ihiourea function. leads 10 burimamidc. the fint anlogon;SI 10 be developed lacki ng detectable agoni51 activily In laboratOf)' assays. TIll'

STRUCTVRE-ACTMTY RELATIONSHIP

smUCTURE

s.MeIhyI/lIStaml....: Ht > H,
.......n

NH- C - NHa

NN

"

CH ,cH2- NH -C- NHC~

1IurimtunoOt. Ful HI .,'It..,,0,,1.. low poIeney. poor oral bioBvaUabiIity

"
S

~FulHz~

higher potency. Impfthlld 01'81

bIu6vaiIabIiIy. IO;OXic (.,.....)

",C
"=="

C!metidi,.: Full Hz.nI~ hghM ~I.rq> high or.w blu6oh' 1111. low IOidotv

~S

fHPiz -

NH -

C-

NHCH,

W
"CN

Figu re 21- 14 Structural demaloon 01 hiStam,ne HI anLlgOOislS

low poIene), of burimamidc is postu lm~-d to be n:: lated 10 its 1'II)<]ba.~ie. e leetrolHe lcm.ing side chai n. which fa vors the nonph~nnatoplloric N- H imidazole wutomer over the basic. electronwi thdrawing side chain in histamine. which p,,:domimtntl), presents the hi gllcramnity N ' H imida7,ole tautorner to the reccplor. Insertion of an clcctrollCgat; ve thi{)Cther fUlletion in the side chain in place of II mclhylcllC gToo p (a\'or, the N' tilutomer. ami introducti on of the 5methyl group fa,QI'S 1i;:-f'CCeplur 'iC lee ti vity and leads 10 mcti3rnidc. II Hl bloc ker of higher poIency and orJ I bioavailability than burimamidc. Toxicity associated with the thioufl!n strucw ral fC3tUfl! is e liminated by replaci ng the thiourea ~ulfur wi th a cYllnoi mi no function 10 produce cimetidillC. Introduction of cimctidioc into human medicinc n.:'cak-d an effecti\'c gastric anl i ~l"crclOry age nt tha t promotc~ the healing of dllO<knal ulcers. Cimet idillC is nOi withou t anum ber of limi tat ions. however. BL"Cause it is short acting. it requ ires a frequent dosing <l;hedulc in hnmans. and in addi tion. ils '\Clecli " ity is poor. Cimctidirll." has antiandrogcnic activi ty. which can lead 10 gyneeoma,tia. and it inhibits the cytochrome P450 mb.edfunction oxygenase-metabolizing enzyme sYStem in the liH:r. an action thm poIcnriatcs the effects of drugs wOOsc clearJoce also depe nds on biOlrJns fomlation by thi s system. Ci mctidi ne also causes confu siona l States in l>UIll<! elderly paticnt,. Sub>Cllucnt develop me nt of additional drugs of this class indicates that a great dea l of ' tlwlUral lati tude is ~vai l able in the design of H: anragon;,rs (Table 21.1 ).~ Exmninntion of the structum l fcarure~ of H: antagon iSl~ th~t cank' aftcr cimetidine confi rm s th at the imidazole rin g of histamine is noI T(.tJui red rOt" competitive antbgonism of ' histamine m H ~ receptors. Othe r heterocycles may be used and may. in fact. en haocc both potency aoo se lcctivi ty of Hrl'lX-eptor rullagunhm. If tlle imi d.ll7.0le ring is u<ocd, however.the N'H tautomcr shoo ld be the predominant sIX'eies fur maximal Hl-an t:lgoni,t octivity. The elec troni c effect, uf the ring ~ub~ti tucnts bnd sidc-chain Slnu:;turnl featurc.s detcnnine the t ~utomerism . Separation uf the ring 'lnd the nitr'Og.m group with the equlValent of a fourcatOOn chain appears to be necessary for optimal ant3gunist acti vi ty. The iso~teric Ihiocther link i~ present in the fou r agents currently markcK-d in the Unit~d S tutes. The tennina l nit rogen-con-

taining fuoctiona lity should be a polar. nonbasic substituelll for m:uimal an13gonist acti vity. Groups thm an: positivdJ charged at physiological pH appear to CQIlfer agonist ac1il' ity. In gCrll."ral. antagoni st activity varies inverse ly with lilt hydrophilic character of the nitrogcn group. The hydrophilic: group. 1. Idiuminoni trl)Cthene. found in mnitidine and n~. idine is an c~cepr:ion. however: it is much more active m. is predicted by relativc so lubil ity cft'c<:ts. C imetidine. N""cyaJl()-Nmeth)'J," , 12-1 15- methy l imidazoI4-yl )methyl Ithio Icthyl l guanidinr (Tagamct). is a colorlc~s crysta l! inc sol id that is ) lightly. blc in watcr ( 1.14% at 37"C). 'The solubi lity is greatly. creased by the OOdition of dilute ucid 10 protonatc the imidal olc ring (apparent p~ of6.8). At pH 7.!lq ueou s soIUIII.1II are ,tabl e fur at least 7 days. C imetidinc is a re lutivel y h)drophilic molccule with an octanoVwater panitiun ~Xleff!CieII of 2.5.
C~~~NH

Cimetidine, USP.

C-

NHCH:t

II

""'

Cimetidina

Cimctidine n..-duces the hepatic metaboli sm of dru~ Iijo. transfomted by the cytochrome! 1'.450 mixedoxidase S)" tem. delaying cli minatiun and increasing serum le\l:k d these: drugs. COllComirantthcrapy of patients with cimetldinr and drugs lllt'tal)uli7.cd by hepatic microsomal cn1.yn~par liculaT ly those of low therapeu ti c ratio or in paticoo 1I'JIIr renal or hepatic impairment. may require dos.agc atlJu!unM. Table 2].2 provides a compilation of drugs \\husc corn_ tion therapy with ci me' idine may irlCf\':ase their ph;trmacolog ical effccls or toxici ty. Antacids interfere with cirne1idlllt absorption and ~hou ld be adm inistered at lcast I hoor hef(E (]I'" after a cimctidine dose. Ci metid inc has a weak :tntiandrogcnic effect. G)'1'IeCQDll\tia may occur in paticnts In:atcd fOl' I month 01' mort. Cirnc tidine e~hibilS high om l il and a plasma half_lire of about 2 hours.

_',i,

TABLE 21-1

Currently Av",il .. ble H. AntagonIsts

0.",1
Ret"'tl". Pote"cy BI""",lt",blltty

DoH

Ci....,.W; ..

,
<l

6l-?8
.17 ....l j

""
"
"

Metabolism. El'IZ)'me

Me t",bollqd Met",botites Sutf".id.>,

['M03

-2>

""

Route of Etimln..tion

h)'dn>.<ym<th)t Fa,,,,,,,d;,,.
'1"./Id,rc
R"""jdi ...

"

FM03:

'"

S.(l.ldo N,.rn<>n<Jik,;mI;1nyt.
,~'" NOlilk. N<hrn<thyt .. lfOJ.idr:

,
,

-'" -n -'"

.. ,..
".
l ....11
J4-:!6

Clttarlld

.....

,"'-'

Rc~.t
,~,

,~ .

:!OlIO. <!wop. JI>.

TABLE 21-2 Cl"..tidiM Drug Inter.ctions

-~,

Meb

calm..
Calc.,..,. """,,nel bioct.:r<
Ccl!oullUrpn<
('1oklnl<;jU(nt

M""""""" """",,jJll_
-,~

.....

5<01(",,) t.....

'hm...

r.

" ~ ,"_
"--''''''.".JIloI
F,.. 11",_.. U2-. . . . . . . . . ~ JOr<

l.ato<l.1oI

....

QuuUdinc
Quinn",

.........."

f'wwJe""''''

Ttoe''loh)H,..., Tn.num... T",,~dk ... ~ .. nu. VllpoUIC lelJ

Won..,n
;
1_"'I.-.MO.f.........

II ~ t..s.~Dnlf:FiRoo""'C

:01

II ~IIJ.I and hc,opailO;- impai mlent and in the elderly. Approxi lIUk'ly .l(} to 4Q'l. of a ei mcudille dose IS Illl:tabohl.cd (SOJ.!dahon. 'sCH) hydroxyJalion). and the parent drug and metabolilcs an: o;-Iiminatcd primarily by renal e;ccrt: til)l1 .
lj'uII a.luh
I)uo(len~J
tIr~1

abtllty). The drug IS clUllmatcd by Il'nal (65 10 70'1 and mctabolic (30 to 35%) mtltcs . FamOlldioe 5l1Jro~uk i~ the only nll:l.Dbolite identified In hlllJUlns. lltc: effects of food or antacid on the bi(Nl~ailabl lt ty of farnot idinc are 001 clinically si,g nificanl.
U~ual adult OI"~I ~nal uk:C'r. T",,,~"! ~.

dose:

uker. T"'''''""nl doM:. 800- 1.200 ml: q.d. to q_Ld. '0\ ilh "",all anoJ at be.:It",~; n... in~na~ dQ!.c. 400 m& q.d. Bcnl,n I;!."ric ukcr 800- 1.200 m, q.d I" q id_ 1I)p""""n:tQf)' C()ndilion: 1.200-2.400 "'II q 1.d. Ikanbum 200 mil (2 OTC lablcu) up 10 I'''~ dail) l:5IIal prol~loo; dow: 0r:aI. 20-40 IllS (bIw) pet ~Ilosnotll of hody "r1Ih1 q.i_d. .. lib """"~ and at bo:dunw: fOOll!o ; TabIcl (200. 1OO. 400. 800 mt). loquld (300 "'1":1 rnL~ InJr<1lon (300 mgll and SO mi.)

oo..e:

0...
!he

40 "'i !I.d. 10 b_Id. It bro tmll': ma,ntenance~. 20 nq; q d. I! 1 ""111",,, IleOli" pstnc u~r 40 ml q.d. lIypc:~rt1Of)I condmun. 80-640..., q_I.d. IkrU1bum JO ml r I OTe Wllc!J fot n:hcf Of 1 Iloor before "",aI f.". pn:''C'Duon Do:!.a~ fOl'!m ; Tablet ( 20 Ind 40 "'I). onI !oU'i"<'Mlon (40 mgl.'l mU. ,nJl'Clion r iO mgmL)

'.rnol;di~.

Famolidioe. N'(II'I1;lIO\ul (onyl)3 11121 (di~mlnomethykne I-amino J-4thl uolyIJmcthyIJthiul pupllillmdamide ( Pcpcid). "'hieh u<es IIthi u/ole bioi'"~tc~ ;midJl.Olc hetcrocycle. is a white II. pu leyell ow erys IlIhllC compound th ~t is \'cry ~Iight l y \Oluble in ",a ter and pnctrc~lJy m~oluhle in eth:mol

USP.

Ran/tidifle, USP. Ramr ldi ne. N-12-IIIS-l dimclhylllmino ) mcthy l )-2 -fllrdll}I)methyi JUliOIcthyll'N' - lllethyl -2nilro-I, l-elhencdiumine (7..11ntac). is an amillilillkyJ fur~n de ri vulivc .... ,th pK. I'allll:~ of 2.7 (side chain) and 8.2 (di nlCl h yilimino). II is n while 'IOlid, The hydrochloride sail i_ highly soluble in Wilier.

Fao notid1r.

Fwotidme IS a C'O!npetlri\c in hlbttor of hi~ramine H ! reo tq'll0I"i and inhibits basal:md noelurnal ga\tnc secretion as ~rll !Iii 'iI.'CMitlol1 ~l i rl1ularcd by food and pentagustri n. Its <wr~ntl~hcling ind ications art: for the , horl ' leron rtClltfllCot ddOO(lc:n~1 and benign gastric ulcers. GERD. p.ltlooh.gicaJ It)pmecrt:tory cOlldi lions (e.g.. Zullingcr-Eliison 5yn~). and hcartbum IOTC only). \0 l'lt<;l:\ of gyrlCl.'Ulnasria. Hlcrea~ pmloclin lel el~. or have been repor1l'd. e"~ n at the higher dosage \ u.<;ed tn patients with patholosrcal hypcl'5ecll'lOI)' con_~ . SnothClo Wl lh fJ11IoOIidmc III hUman). in animal Is...nd In " ilro ha>'e ~' n no SIS"lflC<dlll mtcrfereott till' dl!;posi lion of compound;, ntelaboli~ed by lhe he""cro50Illal e117.YnteS (e.g" cylochtufrlC P-450 s)'slem). flmohdme I~ Iflcomplctely abwtbcd (40 10 4,S% bio:lI'a.1

..<tto<;

Bioa .. allab llily of an oral dose of noni tidinc is about 50 to 6()';f and is 001 "Snrficantly affected by ttoe p""'SI!lIce of food. Some alllad tis rnay red,oce r:tniridinc Qbsorplloll and ~ould not be taken wilhin I hour or adminisltlilion of the H ~- blocker. 1loc plasma hal f-l ife of lhe drug is 2 10 3 hours. and il i$ eXCl1':tcd along with its mcUlboliteli in the unne. ThI'l.'C mclabolllCII. tlmllidine N-()xidc. tlmiudine S-oxidc . and de$methyl ranitidi lle. hale been identified. Ran iudlnc is only a \leal; inh ibitor of the hIopauc cylochronte P450 mi.( cdfuncIIOil o,id.asc ~ySlem In addition 10 bemg gvaolOlbie In a ..an ely of dosage forms as the hydrochloride sail. raniudinc is . 1 al'aiilblc II.'! I $0 bismuth citra;e saIl for use with lhe macrolide anllblOllC clar ithromycln In treating pal1ems ..jlh an !!Clive duodenal UlcCT

lISSOCilited .... lth II.lIy/llri infl'Ctioo. Eradiclltion of /I'lIyitJrl reduces the risk of duodenal ulcer recurTCnce.
U~ ...llO(\ull

Duodmalllla:r: Trealmcnl oo..e. 200-3.000 rna ".d to bld.~ INIm""nant."C~. ISO mll " .d. Benig.n gasUK: ulcer: 300 rnl ".d. H)penuClory rondU,Ol" )(Xl6.000 m& ! 0<' IlIOn: Un"'-~ daily Ousogc form,: Tallld~ ( ISO and 300 ms of HO 1i111I). ")"'P (U mglmL .. HCI ",II ). injtion C and 2S nLglmL. II O.oS 110 sail,

on.l

~:

Nizatldlne. Ni/..lltidine. N- [ 2-[ [ [2 -[( dimcthylami no) melh)' I J-4 -lhull.oI),1Jmethyl Jth io JethyI IN'_n~th )'1 2ni tr0Ll ~thenedillmtne (AJIOid). IS an olT-white to bulT crysUll hne solid th:u is soluble in water. " lcoilOl. and ehlol"l)fomL. 11Lcl pK"Il of the. drug In witter are 2. 1 (side chain) and 6.8 (di_
mcthyl~mino).

NiJ..IItidinc h3~ e~ce l k:m orol bto~l\'ailabih l y (>90%). The c ffe<:ts of antactds or food on it, btoo.vailllbility are not cl ini clIlIy significant. The cli(llilUltion half-life is I to 2 hours. It is ncrcted primari ly in the urine (9l)Il.) and mostly lIS unch;uLl:ed drug (60%). Mctabolites include ni7..andll~ ~ulr ox it.lc (6%). N-dcsrncthylnlllllidinc (7%). and m/..lltillirw: Nr oxide (dimcthylaminon~lhyl fUI"ICtion). Nilatidinc has no demoosullble amiandrogcnic action or mhibltory clTecllO on cytoc hrome 1'-4SO1 mkcli drug-n:l ~boliling cnlyn: systcm. Usual tLduh onl
dQ(,e:

I)!.K);knaJ u~

Trul ment dole. JOO mil q.d. to b.i.d.; lnaintcNlIIU de-. I SO IIlI lI.d. Hypm;ccm.-yo.:ond,uon; ISO m& b.l.d. Ooug~ form~ : Cap!iub (ISO and 300 m~)

llLCIoC compounll .. wcre sub<.equ.cntly convcned to sulfo~tde derivativ(:5 ..... hich uhibited highl) potent. Irre\'elSlbIc Inti bitioo of thoc proton pump. 1lle benl.Jlnidu.oIe PJ>ls are prodrugs Ihal are rapidly coo"cncd 10 ~ ~ulfcnalnidc '"termedi ate in the hlahly acKiic envII'Oflrnent of gastnc pariffill tdl!;.. The .....eally basic bcnllmidamle PPls accumulate," !be.< 3(:llIic oompanmcms on the luminal Side of lhe tubu, C5101'noll canalicu lar Structures of the paflctal cells. The bellllmj. dai.ole PPls are chemically ooo"ened by acid to a sulfag. mide intennediatllthat inhibt15 lhe proton pump via CO\alent interaction .... ith rystelllt residues (813 or 822) of thr ptIIqI H f K -ATI>a.~ (Fia. 2 I -15 ).~ The IICKi IlIIlLlity of the beaz lIuidll?ole PJ>ls dictates tltutthcse drugs mu,1 be fonnulaud as delayed-release. tmeOc-coated g.ranular dosIIge forms. The PPIs an: nLOfe crfecll"e in lhe short leon than \be' Hrblockers in healing duodenal ulcers and eros,,c e.~.a and can heal esophagitis n:mtant to treatment with the H:blockers. H In addition. the benztnndal,oIe PPI ~ h3\"C amiacrobilll oct,vlty against H. II"/ori and thus possess dfKa"} in treating gm.lrie ulcers or wi lh one or moOre antimlcrobioil~ In eradicating infection by Ih i~ org.mism. Four bcnltmMlt101~ PPI~ are cUrTently appro\ ed for m;tr\:etlng III thr: Umkll States (Table 21-3). Ad"ersc effecl profiles of the \:tn(lII PPI , are difficult to compare becau<.c: comparomc dnllCli trl~ls do nO! usually Include sufflClcm tndl\iduals In lIfool re liable conctuslon~. Rclallvct) early In il~ lIIarlclIRa. tIte use of Offiepra7.ok: ..... as as'iOCiated ..... ilh the OCCUIICliCt! ci diarrhea. headache . and rashes; longer-tcrnL npcncna: iILF' g...sts. howe\ ... r. that the.~ a(herse re~ponses ~rc 1llIl:. SlIT. larl), charucteri7.allOfI of ad\'tne reactIon profiles of (lIa I'Pls must await nW>re Il.'(tensi,e use III pallents. The PPls are elnllmoted olmosl coti l'd y by rapid n~ 11'>ffi to inactive or less active metabolltcs (Fig. 21.161" Vinuall)' 00 unchanged drug ,s ucretcd In the unlit ... fe<:es. Thc cylochrome P-4.so cn7ymc syslcm is pnnurity L1wolved in PPI mctabol i,m and ClLn be the soun't ci drug-druS inleractions for the. PJ>ls. Inhibillon of onlal/l( metabolism byomepralole (but I1OIcsoo~pra7.Qle) is ~ sible for prolonging the clcar.ance of benwdhlZcpl~. piEn)toin. and warfarin. LanlqlfUOle dt:crcases thoop/l)u.. conccntr.nioo slt gluly and may decn::asc the cfflCllCY cI tnt conLJ"lICCp:ives. Pantopralole arid rabcpml.Olc appe:t11O ~ free of thc$.e intenICUons. Funhct. the profound and I:s.>ting Inhibition of gllStric acid secretion by the PPh 11\1)' interfere ..... ith the biO/ivailabilily of drug~ "hcn gastnc rH i~ 1111 imponant detemunant. such as the lI7.ole antlf. (e.g .. ketOCOlla7.olc)_ ampicil lin. iron saIlS. digoxin .1Id"" lIocobalamin. 5-m... t hoxy-2-{(4-methol~ 3.5-dimct h), I-2- pyridinyllntc:lhyl)sulfinyl )IH-beIV1I1_ 1.Q1c (Losee). is a .... hite 10 offwhile crystall ine jlO'/I,Jet .... "cry slighl solubihl Y III Water. OmeptW-Olc is an t"ol1lpound (pyridine N. pK. 4. 13; benl.i nlid:llole NIl. pI;, 1.68), and consi~lcnt with the PfUfIO'td mechanism of . of the substituted bern:inudaloles. it i~ ackl labik. lkat. the omtprlll.ole product is formulated as delayedR' capsules ool1lainil1 11 emeric-lXtaICd granulc~_ ~ ~h!.cillil: bi04l\.-"lIilab,h ly of QI"lIlly .tministercd omcpnzole IS :10 II 40% related to substantial first-pass btOlroru;;form3lKllL l1tr drug has a plasma half-life of about I hour MOSt I~ of an or l dose of o""'pra1.o1e is ClIOcretcd in thr: 1IIl1Jr. .. mctabollte!i '" ith .Mignificant antisccretory acti\lty. Thr
Omepr~zc.. On~pr3lolc.

ou. . .. Antlulcet' Thet'illpl_

PROTON PUMP INHI BITORS

1lle final Sltp m acid <;ecreuon m the parietal cell is the

("pumping") of prolOl1S. The mcmhrone pump. an H '/K' -ATPase. tamlyles the uchange of hydrogen lOllS for potassium ions. InhibitIOn of thiS proton pump ICti beyond the si le of aellOIl of second me:sscngclS (e.g .. Cal' and cA MP) anll is independenl of the action of secretogogLJeS hIstamine:. glblnn.andacetylcholllle. Thus.lIC'id pumpmhlbitOfli block basal and sti mulated secretion. In 1972. II group of S .... edish mcdicinal chcmist~ d i'ii.'QYered th;u ccnain p)ndyln~th)'1 ben1jmidalOle su lfides .....ere octive proton pump B '/K -ATPase: IIIhibilOrJ (PJ>ls)."
c~ lru ~ion

"-N

H(....)

NN

'\

f'tgute 21 - 15 Mechafll5lTl of "",on of PPIs

"I

TAllf 21 - 3

ProtOll Pump Inhibi tors Mart.ted In the United States

Omepo-POIe .... nsopruol.

Irodiation
()e

ft' ""...

&o.M~Jh'

....

_knlil ",,10m

I,

, , , , , ,

, , , , , ,

Ita"""azole Sodium

flC,.,..prazole
Magn.slum

CVP2C19

y:;:-,-/,,)L
II
o

'.

I
N
N

\H

CYpZCIg

II s II
0

...

SuHi(ie

figure 21 - 16 MetabolIC ITiJI\sforrmt'ons of benzimidazole PPIs

mary metabolites of Otncpn!1.ok an: Shydro~ymcpniZOle (cytochrome P-4SO ICY?] isozyme 2C19) and omc:pnu.ole sul fone (CY P 3A4). 1'he anlise<:relOry actions of o rneprazole pel'5isl for24 1 12 hours. long after lhedrug has disappeared 0 from plasma. whIch is consiStent ""ilb its suges.ed mechanism oracllon Involving irm\'el'llible inhibition of !be procoo pump H +IK + A.TPnse ..w

sium lrihydrate ( Ncxium ). is the 5 enanllomcr of oow:ptJo zo ic:. The benldmi d:u:ole PI>I ~ contai n a chiml sul fur . . that forms un cnantiomeric pai r Ihat is stable and insolulJlr under standard conditiom. The S isomer of QOl('prnok III slightly greater PPI acti vity. and il5 imnnsic clemntt. appro_imate]y 3 IH~ lower than that of R 0II1qIrlIl0IeU' versus 43 ,",Um in). 1be loweT deamnce or ~ is rel oted to slower metabolic c leam ncc by the cyp 2C1~ isozyme. Although RoIDCpr1I7.ole is primarily tnmsfa!l to the 5hydro_y meillbolitc. the S isomer is metaboIlltd" O-demelhylation and w lro:u dation. .... hich conuibu~ to intrinsic clcarano:e.
Usual lIduh do/;e:

Omeprnzole j, approved for the treatment and redUCI;Ofl of nsk ofrecum:nccof duodenal uker. GERD. gD5ttie uker, and pathological hyper<;eerttOl'}' conditions.
Usual idull doM:, Oral. 20 rna q .d.

esopha"ti!l: H~al'nll dose: 20 or 4() nil q.d.. f.. 4--1 ""etU; ..... n.clLlllCc do/;e: 20 ma q.d. Trc:ltmml of GERO: 20 m& q.d for " ...La; H. pyI/m tradOCIUon: 40 rna q.d for 10 da)'$ L n" t 7 ... i,I! lIIIlO~kLlhn (I I b.Ld. for 10 day,) and clamhnlCjUC (SOO mil b.L for 10 daylO ) .d. ~e form : On.l: o.layal rc:1etic ~IQ. 20 or 40 m& 01 ....... ,.,,.. (prnmI IS 21J mil or 44.3 mil esomepniole u,hythle ) as en'o:ric:~ pelleu

Eros,~e

Dosage

(Of11l; Dda~"'ka~

cap;ules colllaining 20 ml of

omeprazoie In enlCflC<OIlcd 1"'''''1es

Esomepr~zok

Magnesium.

Esomcpnzole magne-

sium. S-bis(5-OIclhox y-2-[(S)-I ("'melooJ.'I-3.S~imethy l2 pyridi nyl)melllyl)suifi nyl [_1Hbcnzimidv .ol"- I -yl) magne-

Lansoprazole. La nsoprozole. 211l3mclhyl-4-(2.U Iri f1uoroetho... y )- 2 pyridy l l methyl ]SlJlfi nyl]ben71 (Prevacid ). is . ...hit~ 7 bro .... nlsb .... hite. odoriess 0 po ....der that 7 prac tically ,nsoluble in ..... ter. S is ~ weak. base ( pyridine: N. pK.4.01) and I weak acid! imidazole N- II. pK. 1.411). t.ike ~<.u,,'<. '.".P~"

N-

I' \
Mi' 3H,o
N

'--':::V/'o-...~~

,
rsatoually I prodrug lhal. in the .ddic bioplwe of ,he pari &led!. forms an acth'c metaboliTe Ihal im:ve~ibl)' inleracls "'th the wgel ATPase of the pump. Lansopruole DlUst be Ero.o"C C*lphagllis: 30 mg ZoIlinger-mh_ llyndrome: 60 m, NSAIDioolKni pMnc uken.: In:lllmcni and Pft'~Cnllon Douae form: ""1.ycd"'Lra.~ o;apsule'l C'Qlllainlol 15 and 30 m8 of lansopra;o.ole in enlcrk-coouxl gr~nub

fonnola\Cd IS encapsulated c:nlmc-roated granules (Of" (11111 idnllnisull1ion to protect the drug rrom the acidic environ-.enI of the stomach.

Sodium. The acth'c ingn::dirnl in I'n>lon ix (panfOfll"llWIc sodium ) is a SUbsliluli bcnnmidazok. sodium S-( di n lJ()fllI1ldhox y)- 2 -I I(3. 4-di mel OOX Y -pyn(h-2
ny l)mcthylislilliny l l- I H-bcnl.irnid:u,ole SC!;4juihydnllc ( 1.5 U:O). a compound .... ith a molC(:ular weighl of 432.4. 'The

P~n topr.zo/e

CH,
Cf~H.p

"D!~prn.

..-< I II N

/'

bcnzimiduoks have .. eakly basic (pyridll'lc N. pK. 3.96)

and acidic (benlimida7.oIe N- H. pK. 0.89) prupenic$. ,,'hkh facillwc their formulaliQn as uhsor alkaline mlItaWs (Fi,. 21 - 17). Pan lopr.a:wle sodium scsquihydrale is a white [0 offwhitc crySlallinc powder and i~ ractmk. Palltopnu.olc 'IQdium scsquihydrau: is rreely soluble In water. "cry slia.1111y soluble in pho~phale buffer at pH 7.4 . Wld proctically insoluble in ,,hexane. Tbt stabi lit), of the compound in aqu.eoo, solut ion is pH dcpcndcm ; the rate of degrndmion increa.'iCli withdccreasin, pi!. At ambicnllcmpcr.ltun:. thedc:,rad:uiOil half-life is approKimald), 2.8 houn: al pH S.O and approxi mately 220 houn: PI pH 7.8. The: ab!lol'ption of pantopra~.olc is rapid (C_. of 25 j.lg/ mL. T",.. -2.5 houn:) after single or multiple ora l40-mg doses. Pantoprw.ole is well absorbed (-71% bioavailabilit)'). Administration or pantoprll1.Q1c ... ith food ma), dda)' its ab5orption but does TKlI alter it~ bioovai Illblllt)'. P"Jnlopru7.0le

\.r alom
~solublc: role ha.~
~,

10ie (l ~

;prvolc 2CI9
pOI ...cd

the faSling Slate. about ~ o f a dose of lansoprnzole ImstIS -~ or omepra~ole) Il'aches the s),stemic circulalIOI, .. here it is 97% bouod 10 plasma proIdns. The drug is .ulloli/.c:d in lhe: liver (sulfone IUId hydroxy nlClabolites) - ' UCll'ted in bile and urine. with a plasma half life of

I~

Ilud by
IIC lillie

about I j hours.. 100

WuaI aduh dooic: Daily 0011 oo.e lIdmini~en:d bc:f..-....: bn:al;fasl OuocIcnal uker. IS rna once dally

r(lO""

II

,om

.,

2.2.2
azoic ul1ine

((ben7-

~I

N A N
\
H

"',
+ 113'

/'

I
R ,"'-0-

N ' sA N
II
0

uolel>

Flgur.21 - 17 IoniU!1Ofl of beI1nmodazole PI'Is.

i ~ distnbu led mall1ly in extrncel1u Inr fluid.

1110: -.crull! protei n

bulduig of pamopr.u.oIe is about 9tI'l. primanly to albumill. Pamopnawle is ulcn~l\cly metabohf.M in Tbe It' er through tbe CYP sySiem. IncludillIJ O demc:th)lation (CV P 2CI9). wllh ,ubscquenl ~ul fation. Other metabolic palhwa) s Include sulfur oxidation b) CV P 3A4. Tiw:re is no e~ idcncc Ihat any of the panlOprlllOle n1ol:IuOOlitcs It;l,c Signifiealll pharmacologit-JI activity . Al'f"UlIimatcly 71 % of a dose of pantopra 1-01e IS UCll'lcd ill the unne. ",'IIh 18<;1 clIcrelcd In the feces througll blli:try t'\CIl'UOI1 .
OCN,

-0.. ./ '"\\"
U~u~1

o II

"'.
e

wdi tun is forrnu lbtcd as enlenc-coated.dtIQ),ed-re .... ase tablets to allow the drug to pas~ thl'Ollgb W SlOmacn 1".:I311\-.:Iy Inlact. Aft~rOnlI admml ~trdhon of20mc. pC'u plasma I;Qf"ICentnllions (C_) oceurover 3 range 0(10 1 5.0 hour.> (T ..... ), A~l ute bloovailabili ty for 2().1IC 0 orol tablet of mbcprnzolc (vel"'us IV admUli~lrJlion ) 15" pro~ imalcly 52~. The plasma ha lf-life ofrnbeprawk r1n&t' from I 102 hours. l1Ic effects of food on the absorptlOllll rnbepBZOlc Iia\'e not !:Ieen C\QluaIM . Rabeprarolc is 96..J'f bound to humall plasma protci llS. Rabcpr.u.ole IS e~lC1lSivd}' mclaboli;ed ill the liver. The thll)etiler alld sulfooe are pri mary metabolites mea.~ured in human pl".~ma resultilll from CY P 3A OXidaTion. Additionally. desmethyl Tabq:rawk is formed via the actlOli of CYP 2C 19. Appnuillllldy 90% of tbe drug is eliminated In the urine. primarily .. tbtoether carboxylic acid and ns glucuronide and 11le1'tlIj)IIn acid metabolites. The remai nder of The dose I~ reco"cmj ill the feces. Total rorovery of radioactil'ity w,,' 99.SIi. M unctlanged rnbepralole WIIS ~\'e:d in tbe unne or r('('Q.
Ui-IW "ult 00..:, Oral. 20 "'I once dad) (duodenal aim 1or4 ..."ttlu;~ CMI"e or Ukel1llh'c GERO for4- 8 "'ccll); ~ hYI"'r.;c<;rcIO!}' disortlcfs. 60 nog OOCe dally IIlmod III 1rnl~1,,'um of 120 mWda~ I.)o<.all" form; :ro.mg dclayl re~_ \lIbIels uf Ihr ",I

RHbcpr.L'.oI~

....

a.jull ~ ~ Eros" ... cMlph~lIlli ) :iSsociulI:d with GERO: 40 mMq.d. for ,..;8 ...h~ if not huled ~fl".. II ..-eeu of lrealmelll. an addmonal , .... 1: course rna) ~ 1.'OII:'i,detuI Lon'1nI!1 UUlmcrK of ~"e ~IUS .1Id OERO: IV treatn",1M cl ~"c ~I~' U an ahcm:tl"e 10 conllnuW orul lher~p) . 40 rng q.d. by infu,;.ion for 7-10 daYi Silo.",..,,", ununcon (7 10 10 day,,) UI GEIIO T"'~["",11I or p:i1holoaic;ll hypt rn:lory Condillon. ~~i. .I<)d ""th7..o1hnpFJIt,;on Jylldronw:' Dell)td-rcka..., \.able( for oral "mln,,,ulIIion: tach I~blet ,"""~,n, 4S.1 mll of pIIntopmwk '>Od,um ~u lhy dl'llle {equlvalenl to 4(1 mil p:intupr~l.Ok) l'rolO"'~ I. V fTttu-(iJ"itd PO""<.\er for ,nJuoo C(ju"'aknl 10
PruIoni~:

CHEMICAL COMPLEXATION

TIIC sul fate eSICI1l and sul fUllate dcrivativCli of polySiC\.'ba.

rides lUld lignin form chemical C011lpIC~Cli ..... ith che enz~_ pcpsin. l1tesc rornplcxes ha~e no proteolyllc acu ,ily_ Because poI y.sulfalcs and polysulfonatcs IIR: POO,IY:::: from the Gl truet. spc:cific chemical complexa llOll appuh 1 be " desirJbl~ mechani sm of peps in illhibiuon. Unrona0 nalel y. these polymers lire alw potent ant k'oo.!:u lants, 1be POPCIUes of chemical romplcnlion and ani;" I lant action are separ~ble by stT\lclurlll "malion. In a UD .... ,son of selected sulfated 'i-OCCharidcs of increllSlllg ou"m of monosaccharide unils. from disocchnrides thl'Ollgh MD derived polYS/ICcharides of dlfferillg mol ecular size. lint conclusions are supponcd by the dala: (a/the ant ~bIt :lell vily of ~u lfated saccharide is positively relaltd 10 IIl(lkc. ular si!.e, (hi IInlicoalulanl kll" li y is ab'lcnt 10 the d~ ride~, and (('I the inhibi tion of pcJ')in acti~il y and the~ tion 3ga in ~1 experimentally induced ulccnuion dcjX'od (II the degree of 5ulfat ion ~nd not o n mQlecu lnr size. l1Ic read ily a,"i lable d isaccharide SUCI"O!iC has been to !Ie\clop a useful antiulcer agenL sucrnlfale. Sucralfa!e. Sucralfate. 3.4.5.6-lelrn-(polyhydru~~ llIi nu m)-0"1l- g Iucopyrn no~ y I ~u Ifate 2.3 .4.5- tcUll( poIyb). d roxya lumll1urn}-,8--o-fructoruraroosidc w lfalc (Caraf*la the aluminum hydroxidt complex of lhe octas.ulf.te bU CI"O!iC. It is practically msoluble 10 waler and ooIubk I strong acids and m<>es. It has a pl(. ,'aluc bet ... ceo 0.43 .!

~form:

40 mlllW'l","",okbtal

Rabeprazole Sodium. Rabepral.olc sodIUm . 2-1114-13melho~)'propo~y )-3-mclhyl-2 pyri dmyl lrncth yl l ~u Ifinyl]1 lI-benJ.imida!.olc sodium sai l (Aciphcx). i~ a substituted benllmida701e wuh II mola:ula.r .... tight of 38 1 43. Rnbcpra zoic >Odium '~ a .... h, le 1 slightly yc llowi stH\ hilI.' ~I id. It is 0 ,'('f)' Mll uble ill water and melhanol. f":ely soluble in ctliaool. chl oroform. and ethy l acetate. and illsolublc in elher and II hexulle. Rabc pral.Olc i ~ a .... eul: ba.-.c (pyridi ne N. pK. 4.90) and a ....eal: acid (bcnzill1 ida7.ole N-II. pK. 1.(1) .

nlff.

N ,

1.19.

Sucrllifate is minimally absorbed from [he thus e~CI1S il~ antiulcer effecl throul h locall1llher thIa ,!' tcmle action. II has negligible acidneUlrlIril.ing or capacily in therupcUIlC doses. Its mechani sm of action ha.~ 001 beell eslabhshed. susgesl that sucru lfalc binds pll'fcreOlially 10 the ulm.

or tnl'1.

----------------------------10 (onn a proIcl.:m'c barri~r Ilial prevt'ntS exposure of the lesion \0 add and pepsin. In addilJon. II :otborbli pc'psin and bile $alIS. Either would be very deslrublc modes of action .

"-

pro1ccthe IIClions an: propo54!d 10 be related to inc~ascs in G l mocuJ and biearbonate !iCCTelIOfI. i~ilI'C-~ In mucosal blood flow, and/or prel'c ntion of back diffusion of H)O+ 11110 the gastric mUCOSll. o1

". or ""
,

""'"
OR

I [""CHI. lHA I~ ,I ""I

!1 81010..-.l Y 2210 31)

>-

" ~~

The producllabcling Slale~ Ih:1I Inc simull:meous IIdrnini ~ nllon of sUoCralftlle rna)' mluce the bioa~Dilal>ili' y of cCrlain .nlS (t.g,. letr:loC)cill1e. pkn)'toin. dlj!oJlin. or clI1lCudinc). 11 funhef- n:commcrKls reslOl'"Jlion of bioavwlabi lily by !it'paIJUn& adnHnj~U1l1iOll of these agems from lh:1I of sucralfalc by 2 hours. Presulllllbly. sU C'l1Ilfule blllds these agents in the G! lr:t\-1 . The I00I\1 frequently ft'portl'd adverse I'l'at'lioo 10 ~ucr.al hie I~ conSllpauon (2.2'1). Antacids may be pn'.'\Cribcd as -.led bul shoold 1M)! be la~cn "" dun one-balf hoor before

HO

OH
"'I>~(":I

OIlfitr wcnMale.
I).ual oouh 00...,: Orut. I I II "d. on an empty mlln:..:h

IA, ... form ,_,

~lIC11I l r.(C

ubkb

PROSTAGlANDINS

M lo;.oprostol i, rapidly absorbed follOWing 01111 OOnll",slration and undergoes rapid dec;,SlerificlltK)ll to thl: pharmacolos ically acti"e fr~-e acid wi lh a lenninnl halfllfe of 20 to 4() mlllutes.O! Misoproswl is commonly u~ to prc:H'm NSAIJ).lIidueed gastric: ulca"!! in patients at high nsk of complications from a gaslric ulcer. such QS elderly patients and patiems with a history of ulcer. MisotJ'l'U'tol /l:I~ lliso btcn used In I~atins duodenal ulcer.;; unrcsponsil'e to h,Stamllle HI anlllgoni~lS; .he drug does not pn:~ent duodenal uieer.;;. howe, cr. in patients tak"ng N5AIDS. Mi~tol ean eausc mll1Carriagc, often associaled ""th potentially dangerou.~ hlceding. uloUal adult doooe: Oral. 200 I'flllj.d .... nh food iJooIllc form: 100. :and 200-1'& 1.IOIlku;

n.: pmoilDglandms an: endogenous 2(k,aroon

un-aluralcd filly lI(:ids bios)'nllw:ucatly dc:ri~ct! from arachidonic lICit!. TW!.e booactJ\c su~llIl~ and their synthetic dcn~an\l~~ 111\( been of ronsidc:fl1ble ~~an;h and de~eJopment inlc:re>t potential therapeutic agents bc:~ause ..f their wide_prcoo ~~ical and plwmaoologlCal actions on the cardiovas ~}.tem, G l smooth muscle, the ~protIucti\'e sy~lem. I\tl'VOUS ~}stcm. platckts. kidney, the c)e, elc.ft! I'rosID' (llD:hns of the E. F. and I sene~ are round in Slgnifieanl roIICI:ntrauons throughout the Gl tmel . 11le GI :Ietions of _ prostaglandins include inlllbiuon of b;asal and '\Iullulaled JNfIC acid and pt"p!oin ...... ,etion In addJlH)f1 to pol!lention d.ukcrogen or ImlanHnducctl gro'~ l!lucO\UI ie.ions uf Ihe --..:h and in,\:Stllle (temll.'d nUJllrolf"<lIon). The pmo;la&finllns can both stuuulate (PGF,) and mhlbn (PGEs and PGb) lI1,cstmal smooth musc le comrJClihty and accul1luluoffhud and electml)'te~ in the gUllumen (PGEs). 1ller~ p!"IIIlC )pplkation "f thl: natural prmtuglandms in the t~al JIenI of GI tli~ers is hindered by their lack of lcal select" lIy ooupled wnh I lessthan.QJl4l . . boodlSpoIiition profile. MIS<JproSlol. (j:}-methyl Ilu. l 6-dlhy """) I6-mct hyl 90~opro'\l - 1 3t:-cn-l-ome. is a scmisyn dtri~lui'e ofPGE , thaI dc:ril'~ <;orne pharmacological ftroVlty liS "ell as enhanced blostablhty from ilS 16.m)I. 16hydroxy ~lruCturo.l features. Mi~tol c . hibits ~ory and eytoproteclant erfee1~ chamcterisllc 'IItbr rutural ptoStaslandm~ and has a ,herapeuticaJly octqUbIe biodisposilion profile. Although the anlisecrelory :b 0( mlsoprostol are lhought to be ~laled to lIS !lgOfllS' a;UOOS lit parietal cell prostaglandin receptO/"li, it ~ cyto-

HISTAMINE H)-RECEPTOR LlGANDSU' 54

I lj'lIll11ine HJ r~'Ceptors are members o( the G protcin -cou
pled receptor famll), In~olled in the ~gulaliOflofneurotnutS miller release In both cenlnll and penpheral ne urons. The. eDNA (Of the human hblPlliine I I , reccpcor encodes a 44SamHloacid prorem lhal. "hen recombHl:uttly exprused. couples to Inhibition of adenylate cyclase:. pol!~umably through G(ri . The histamine H,-l"eCcptor mRNA is highly expressed in cemral nervous tissues. Hl stamill(' H} hctellJol"eCq)tors have been identified in ~\onlach. lung. and cardiac lisslll:~ of animal,. Pm;ynapcie II , receptors ha"e btcn Implicated in regulaung Il('urotransnnller ~leasc from hl)twnLnergk. noradrencrgic. ciop.1mi ncrgic. cholmergic. S(:rotoninergic. and pt"ptidt-rgie neurons. The potential ther1ljlCutlC roles of hi~lamioe Il r leptor antagonists 111 the eNS ha"e been ev~luoted 111 modcl~ of Icru-nin~ and memory impairment. ollentioo-tkficll "yperacli~Jly t!I..order. obeSIty. and epilepsy. Studies of the ~gu lallon of Innanlm3tory proce~. sa'll"Oprotcction, and card iov~u lar functioo 5u~gest !leVmtl therapeutic possibthlle5 for penpherally acting hiStamine H )recepcor agoni~ts. As yet. no ",'!amine Ill-receptor ligunds lIal'e been appnJ\'w for marketing in the Unned Stales.. l'oten! Ih agon l5tS (I- g. 21-111) are obtained by SImple l modifications of thl: hisllIminc molecule . The imidazole ring is a common slnoctur.d rCaiUTe in ollllOSl all H} agool<;b. MethylalJon of lhe aminoe,hyl sideclmin ofhi~lamine favors

M!i:oprostol.

HO - {

H ,c

-\

:.,

/,

HN
II

NH

'--- 90
\

'\
N

N H,

NH

Figure 21 - 18 Hrstamll'l(> H,rreceptOf agornsts.

s II
NCNH

/
C~npu:lI)iI

HO ,
tiN

o~

N N

'\

>-- (CHzI2 ~\
N

I
'-~~~

) -,(CH,),NHCCCH, - (

II

'/

II o

GR 175737

Figure 21 - 19 Histam lf'\e Hr receptor arllagol1lS15

Chapler 2 1 11I.'l</JfIllit' UN1 Alllihu,umml(" ",(""'1 H,ICt"'i,y. hllrotlUCIion of one or IWO IllClhylllrutJP!> U) g h 'c .... mcth)lhi~tamioc and o.rr-<limcth}lhISiamioc yields potem H, agonists that!ihow lillie ~lccli vllY among the three hbt:tmu'IC TCCepIOI'i. TIle illCrcused potency of cr-11lC,hyl-hiMa I!1IIlC is a.'iCnbcd nlmos, complelely 10 , tS II' i5QIlll'r ( H J H , mlO" 11). The clinical u5C.of Ra-lTIClh yJhi~mlllc i~rom p:oo:tuscd by r~p,d ("" iabolism by hi~u,m'IlCN-mclhyltraru. d Itnsc. Alomclhinc dcn\al,vcs of Ra-,nclhylhlslllnlloc l!a,'c been deve loped and shown 10 pos~~s anti-inflmnma lOry and nrllinockeptive properties. Other H ) ag(wml~ indlldr the i"OlhlOUrca den"al ive, ilTlCl lI , a highly sckcu le. rull agonist Ihal IS IltOf"l: poIenl than R cr-nlClhyl hi , laminc. Alhird Iype of II , agoni SI is immcpip ..... hi ch may be OOIt"idutd a.~ a h i~l:ul1ine analogue wilh an clonghlcd nod cyclil.cd \Ide cluin. Immc pi p is boIh a highly sckctile and potent hal'c been dcscnbcd . AnI3goni" silldic~ ha ve prescllCC of Ii \n."<:cp klr .... btypes. In genel'1ll , anlagooisl Sl ruclUrcs conform 10 lhe fol\oll'ing gel1Cl1ll ~nlnlion;'"

729

12 P<lIma. (L Nllllnllty a ia bodJ It' III II"""" , 'i,1> ... M led.) II ....... 01 "",ponY,,, "'-'-"""IY. ...... 1M 1'..... Von.. SJIf."F'.v...... 1'111, II JIll. 1.1 Iklot. C. II. tI 01. 1. .... y.lol (I"""",.! tl2:m. l<nl 14 F.......,au. L.llIMl IIovtl. 0 " AIrlI. 1M. l'hIrmw:<.dyn. 461lM. 1913 I ~ C.. y. It I Cbmu;uy 01 ..c11I 1 hllwn, .....' .. _Ib. In It"" ... c So ..... M OIl ~ Ibo..... 01 t::'~ l'Iw1NCoII>(y 01, 1&12. Nn. VorL. ~.y.n.c. 1978. p. I" I~ . ..... " D T Itnliallt, p'" In lIu..... A led.l, ,,~.RII Che"""'y. 11\1 cd. N .... Y<ri:. Wi~ InIefK"'....,... 1Y1\J. r 16-13, 17 VoIon.O M k<pt""'" hi""m"le. In ScI_"'''. M (N ~ H,_ "".... _ .......oIIr.um._ New yen. ............. Pia<. I97J. p. 3. II. Mocha" 5.1 .... M ~ _ A _ A a ....... yoflftti ...>WIIWII<_ In Iloclwo, Sil .... M (ed_) IlM<Jboo' 01 r. ...........taI~, ,," III!. N<\w Vnd. Spn..,...Y.."". 1'118. p.lS!, 19 8icl. J II.. Ind M""in. V C , 0.-&"'"'' oyn""',,, ........ ~ uf "" ... ...... p.. I. Goukl. R. F. (N , ~ '''''1 Oootu>ny. Ad>.....,.,. I. t'h.:mllU) Sene. .... 1011. W.Un ....... OC. Al,oc,"''' Chei1111;21 Sodroy. 1'111.

"".'.'1 _ _

.,.1Il>,

H,I&OO'51. A largc number of II ,

anlagoms~ ~uggeslcd Ihe

;!(!.

R .. A... J .... y... ~ IU.s86. 1948. 21 Ln. T M ... at Itnn. N V Acad. Sci 'I9"l1l, 1962. 22. A.tI. A S 1' ........ Sch,k1. II O. II. J """',,"""" t'h.:''''M~. 2l: 4H.

." AMqu.".
,....

11le heterocycle componcnl of Ih ,\ grl1C'ral stroclllre is ~ CQf1llllonly D 4-nlOllO>lIbstilulrd irnid:llole or bI01SOSI me eq uiva lcnt , Chai ns A and 11 can be of va rious SI/UC\tJ res .... lengths. and there j, also wide 1:1111001: in !he $truc11l1'1l1 .renll'tlls ror lhe polar );l'OlIp. II nlogen:ued phenyl. C)"doalkyl. and hclCfQal)"1 ~lruCIUrcs ate IIsually found for till: lipophilic iI'IOiNy (Fig. 2 1- 19). Thioper ,unidc wa.~ lhe pot!'n( II , amagon,,' (0 be ~hed. This agen! enhlloccs arousal and/or ~ igl lnm pat. ICIlISIn ado!.c-dependent fllShlon in amma]~. suggesting posIi>k IISC o r CNSlW:ti ng Ii) 3ntllgoni)ls 1n u'Cllling ~Iccp dis onlc:rs Ch3l1lCICrizcd by cxcc~~jvc tloYlimc ~IL-cp, sud1 as un:otepliy. Other II ,anl:lgooi q struclU res are silo\\. n be lo ...... .lltluding lhe: n:lIl1r.d product verong3nll nc, isolaled fron, a Ita sponge.

2J 1It.d. J W ... ,, N"""" 216 1115. 1912, 2-1 MOlder. 0 K, llo ..... M . _ Snel. E. Eo J Am.. 0....

s....

76.

!>II. 1954
l!I. """"Y." k W .. -.F C.....,., . J. A 0 , J It"", I'IIY'i<.>! 'H~I. 1956:lh Sclla)",. k W 8""'ne". of h..u:.""" In ROC ... " S.h ... M Icd.). 1l_lhoUI. 01 ""pon-.I ~J. rot 11112. New Yorl. Spnafcr.V...... 1971. p. 109 21. \\. m<nf',-.t. II Hi""",.", "'.....bo" ... aad u,~_. In II",""". S.ln. M (<<1.1 IIIIIklbouL oI E.o.l'""mcttW 1'harmIoooIocY. .,II IRa New V, ...... Sprillll.. Ynl'g. 191~. p. 131 211 G.... lhn. e lI .. and~ .. M E.(ed ~yof l">Ui>U .. Rccep....., 1I<u.td. U. K. wnp.. 1981. 2\1 "'--db .... 1 S . _Gro>,m," M 1.1.r.TbonJSy...,oo....... II,... "'... 112lIepIOI Ant&fOiM"' a",...,.) IInllllf ...... O_wl.... c;a.. 1I.,.tUa".... y 101j!):.u'l. I'1IM lO, ~I ... W W 1I.>la,n, .. and Shydn")lrypt;aml"" !!oen),...ul ODd Uk ......... ",,"' .. In G.I""". A G .. Clo<>.linM. L S . RaJI. T w.. -' 104_, " I"'), Good_ - ' 001.... Tk P' ""'. . ...".. S oI'Jbrnrcuin ,'" OIl. fk", ym... ",...... Ibn. 1985. p.1m 31 ... den 1111M., " O~ - ' I.oct\. Il.. J Coo"'"'",.., ...... """,""",,"1"'" """',on""" In Ro<ba S. I... M. (<!d). Il ondbo>O<. oIl..>"".;n .. "",1 I'h",.."",.y. ,,". 1111':. N<!... Yorl. Spnnl""Verlq. 1'1I~. p 31) 11. NMa. W T ,ond R~U ... R. " : StnIctun!...., .-\ry ...."""'HC. 01111 'a............. _ ... I. lIod.... Sitn . M. (ed ~ I~. ,oft::"peri '''' aJ~. YOI. IfIn. New y.,.-t.Sjoco..,.... Vnl ... 1978. II 215, )1 G...II, e ll A",", Rep Med Ole",. 14'91. 1979 14 Sjotjo'>i, F . and , .",... L Cion. f'tIarmI<uI. lbef 8.t8, 1961. l' 8anluh. V . eI": 1. Mal. Chc:m I" 8~, 1'111 :WO. Shafi..,. It . .., HiJc. G. J Mal. a..m. .2:2M. 1M II N<obb, W L ond Blaniun. C 0 : I. """"". Sc. ~II~. 1l1l>I J" ToWy. L . tI 01 . AC\O. Onm. Itl"loll. Sc,- fl ...... ' 9:213. I ~j9 39 I""". k. R. ~ .. nh. F. M . and K S. I Phono. ~ ;z.,;

n",

REFERENCES
Qonil.on. J (': lI,wamo .... ind)l.Jn'.. i-hydru.ylf)p ,,, .... .., thcu _. u III 00_. A . 0 . lIall. T w .. N_ A . S .., 11)100, P

,.... ),0000I ...... _

G.I""", , Tk

II,,,. (ofn....

1 ~ ..... It 1: . _ Sau .... M f>ms. 1 !).nat. G J. o-I~". C II~ '"

pM ..... Sih od~... VOl\, 1'<"..."",. 1Il'.10.

I C..,. A f Tk S"'"" 1'-. Mcdl<OiIal ChtwIhiU)" 1)o>,)iiIinrtn<: ~<of"""""""'>CaIR ...cC '. New V....... I'Icnwn "".... l<)oj). Cblp. II TX. II. 0 1.Joi"<Its. I ~....... It 1I.".".... :ond Inl1.""":o,...., . .......

9OS--9Oi.

1 91~

p.....,.,,,

p. j7S. Dnli II .. W:3'. 1....,12 M I' J Med Oitm 18

$<"'.

,n

W. 1'11). 40 K,...,. C T O. Wea' ... S II~ .... NIITUd. SA: J """"-vI. e.p. lbef l~lWI. 19M.

"1 Cn.p.

I~ "

1 .. ..-:

6It~,.

1'J.l.8

I
I

u-.
II

-,

19\16, Ooac> I I. P 1. ..-. fL' H._... .., I" n - - A ....... n. II 0 1.'1'" 1!I'JoI. CIoap. U. II JJ lid!. S. L (i .... ll1n. C II .. T,mmemoan. 11...0 . 1 I'IIoroII<QI II ... "Ii: W _278.1\f')7 T_ " ,UI1. II ' Trcndo............,.,. S<i, IH'_7. 19',12Bri<IIL N J M T""""'~. s.:.~ 119- 10. 1\191 II.. T",... " II . _ W _ T T ..... -....:.~. ScI. :tB31-l19.200 t l,b.IIn .... '. e . and 1'''1'1. W A .. COlabuI"", <of 1I .... m,ne In U>nils. 8. (td .l. Ill,.."""" :ond lI"I",i.. Itnl.O&t)O\"'" II.......,. .. 0(' bpcn -..I """'.........., . 01 97. New V...... Spnqc<VerI. . 1\191.

".n.

"2, LIorHuu. S W.. Nd",,,,, Wit . and Gay. I~ N J, 1t1l<1JY 22 19. !'Ij I "1 Vill.ni. I' J ... 01. J Med a...n. I"j(). 1~72. .u IMai 0. e..,....,.y. SoW_ It Mol........... lI<dfonL. MAo f.,.,...e""P'>" _ . !'In ., Joh"""", P C .. Ooll<>pe. I!.. """ T""p!e. D L AruIoo. 1Iql. Mal. QIc",. IU1. 198.2. 0/6, CaJd".II.D. R . V<nn.P .. II:I" " 'ich.v"",,.. k .tlalltm J Ophihal. 1iW>I. I IH.Jl bJl,lll'T.!. "', T..... M I"".. Todoy 21_211-1 1. 1'192. oIl. ~kT",,"". D. _ M Orup .lIIn.~800. L9f19 "9. Man.n. U~ aad lloo-. Il Itn.........'ocIf"""""".21:71O 111. 1m. I"kln,;on. M .. ...... Bun .... ME.: N. 1' ....., J Mtd. )D 1612- 1680.

S<n:.n."

so

' I Ft:klman.M , ond8-unoll.M 1' ; 1" E.!o&I J Mo:d.32Jll'9- 1l55. _

""" ,,.,.

S2 SoI~ 1>_ H.. N EDtL J Mt<I. )22:909~916. 1990. '3 BLod:. J s.:- Z4U86 ...... 9). 1989 '" !In....... R. T . Jod. 0 .. -.I Pnoc, 8 . I Treoodo"'.
J10-3 D . 1981

uL ScI. 2:

"~"""""",,,. p~ andJ......-.U.: ScMd.J OM ........ eroI ~s.appL 10Il): 1'~22. 19M. $tI IItooer.R "~ ColJ" P W~ Md'-. P II ....... Ikp. Mecl.O""O'

22;1 91. 1m n. ~. M J. S., Go, 4'}:)O\1-310. 200151. Mey.... U. A., y .... J RIOI 101.0. 69'201- 209.1996. 59 l.&mp.l; 'll. T. A.. o..ellOl, D II.~, 1.. J . and Q . It; DlC P 24 '
60. 6L. 62
6,l
/i;I

II}9(I S~OiM'. C 101 .. and "aukb.. D . Dno,. 41b10' ...... 31. 1992. """'''''' ... S. J.. and "".. h~. W .: Oi Oi Sci 11 :1:>-19, 19&6. Monk. I. P.. -.I Oiooold. S. P Dno,. )):1 _:10. 1987 Leuto. II .. _ T~M " , . H i'nJt. Ret. 39127. 1992-

39J~4Ol.

'''"1.0.

.. lOn.
R"<I,,,
~

pp. 5il...

I'l1011 .... I. 0 .. Ali. S 104.. Y- . S 1-. ud Tedford, C E.: A__ Rep. Mal. Cbmo ));) 1--40. 1991. M s..t.. H. ....... X~ .............. J.104~ C'I .. BIOOfJ.M .... Cllan.Lca.

Dru,

~f;,;;;;.(al.J: H,,ami... [I &DC! .""h,...,..n..:.. In H'"I...... " I' f'IoonnKoIot1. Y<lI. 11111. Ne,. yon., 51" C .\1
Schxlwf. M (rd J: H, .. "'. _ utilouwm.... In I"",. 000< I ~ c... ,~ 0I~ . . n ...."'.. IICO. >I. 7. . ..... I Nt> YotIc. plO ........ 197). S;PI'Y. H W J.\MA 22l92. 19IJ ~. J H ~ ..... diO<J<don- prpIlC u~ !ho __ II RuIKA. A. A. (H .). S.M,h rar N"", Dnop. Modkin&l R...1Irlo Saooo, .01. 6 Nnr Yon. Man:cl Dc~k... 1972. p. I I' ..n <In- Goot. 11 . rod Timme""",,. It.. s.ltive 1Ipn<h .. ooolI to ..... h.. Ulml"" ""'~"""". F,ur J. 104"'. Ch<m. 35:'_20. 2000

' .lOlI _lOl6. 19I18.

SelECTED READING
8.... P 0 ....... ..00;' lCIay oond """u~
II&~_

Ad., Dno, Ro. ':206,

1Ie,,,,,,, 104 A. lIi.wnl"". I.. Rolo ,n Phyi-lOloaiod and rao"""'akol ProceloOet. MOiOOI' Allt'~. vol I). No... Yon . S. K........ 1978.

""

22

Analgesic Agents
ROBERT E WILLETTE The SU"Usslt 10 rellC'l: pam beg:."" nh the ongin ofhumanny. Arteient writings. both <;crious and fanciful. Ikalt with >tCTet remedies. religious rituals, Hnd other method~ of pai" relief. Sktwly. the pn:M:"t modenl em of synthetic analgesic~ flo/,ed. An llntllgt'5lC may be defined as a drug bring in g about lIlo;.en~ibili')' to paUl without l~ of eonscioo.'IM'SIl. Oht d)"loologieal1y corroen lerm ll/llllgt'fie ma), be used in ptaa, of lhe incOlI" t but popular lllla/gt'sic, but the laller ,,1ISld almost uni'"CBally.) Tainter l has divided the hi~1OI")' of Wlalgcsic drug_ into four major era~. namely :
I The pcmlll of Iltscovery aIllI

1 ...;,ulJon of pure planl rnnc,pie1 (e.l .. alkaloidsl fmm the: n.illu raj """1"Cn and the.r idcnt,roaotioo ... ,1It analgesoc lOCIion ~. O'...,I...puk'" m.,..anoc chernlS!ry and lhe fim s)"nthrtoc .... tge~

....

U~

of

nmur~lly

Ol:.:umna piuni

~ O"""'~n'

m modern phaImaooIog..,] ItehnlqllO, ma~'"1: II'JO",blc 10 undrnal.c yS!e.natlC 1l'SU", Qf new AILlII~~

A IlCW era has en~rgcd will! the: di!;covt"ry of opiQid recel~ lOI$.nd endogenOllS chemicals tlull lIave aflulgc'Iic activit),. The isolation of morphlllC from opiuOl by Scr10mer, in 1110.1, and the discovery of Its analgesic :JC1ivily (he named __ rplune ariel" the Grcd. god of dn::uns. MOI'pheus) I15hern! in the second tn. II contmues today only on 11 MnaJl teak. WOhler hllrodu(:N the third era indil'l:Clly "'Ill! hiS

\)1IIhesis ofuR:a in 1828. lie sho"'ed liml chemical ~ynlhc~l~ oou.1d be used !O make ~nd produce drugs. In the third era. !be lillil ~ylllhetic analgesics used in medidroe "'en: the SlIH
C)l;dec<;, originally Found in nmure (me thyl salicylate. su lkin)

-' then ~ynlhesizcd by chemists. Other early synlhesi/.cd ~p ....~ acetJiJ1il id ( 18116), phenacetin ( 1!!S7). and aspinn !1m). These carly djsco'ene~ ... en: tnc pnnc:ipdl clHItnbtJlIonS duI f.ekiunlil nlOlkm methodsofpharmacollllicaltCSh l\g
...Itd thl' (ounh era. TIle effects

of small structural modi

IIClIbOIIS OfSylllliellc molecules then could be assessed accu. .I)' by phannaroioglCal Hlcans. This penniued s),Memutic
of the relationship of structure In acti vit), during this n The development of lhese phannocological tc~'ing pro~,coupled with the fonunous disco~ery ofHlcperidulC by Eisleb IIfKI Schaumann.1 nlOlde possible II period of rapId Ihks LA the.> de"e1op"Il'Ol or poIe"t analgesiCs.
~udy

PAIN
to 1dIt.'c pain of a wide!UTll)' of causes and mech:rnisms. I'ain

Tbc: priltiPry use of Ihe drugs eovered in Ihis ch:lpl er

i~

is tIM! most common eomplaint for which patiem" sed; treat ment. F()I" various reasons. ho""e"cr, iocludiJlj; polities and luck of tmining and ignor:mce. pain is !lOt well managed: less th~n half of th~ ..... "h pain IIlll adequately treated. This is primarily due to a fear of addiction, whkh often limits the proper use of the mm:OI ic or opiOid class of analgcslC<. and lack or U"lUnlng of health c~ prufC$ionals. To under~tand 00..... and when this broad cl~ of drugs is and should be used in the manageme"t of pain requires a bricf review of pain. P-din has been classified into the following t)'pe~: phySKr IQllical. inflamnullory. and neuropathie . The fiN is the most common, forc~umple, touching I hot object or geuing a eut. Inflammatory pain can be millll.ted In a .... ide urict), Qfway~ such as Inflion and tissue lIIJUry. The 101)01. type is due to mjury to the periphcr.!.1 or eentrol nervous sy"'cm (CNS). Within these claS5eS of pain lhere arc dlffcrent Ie,els ofp;un or categories of pain. 1llese include: kute. chromc. cancer. arthropathy (e.g .. anhritis). viseeml. neuropathic, atld diahctic pain. A <;("p:lmtc catc!;Qf)' Ii> /eI."Qgn;/.ed for acqUired i Inmuoodeficicnc), ~ytldrome (A IDS) beeau'iC of it.~ di sseminll.ted nature. Clearly. these all require different appro;lChe~ to pai" managcment . In the follo .... '"g sectiOllS of this chapter. l\e\'eml classes of ""inre l ie~ing drugs are desenbcd. The three major classes Qf drug~ used to manage pain are optOlds. nons.temi dal anti-inflammatory agentS. and acetammophen. A newl) emergmg class, kJl()",n as tlIltIlgt'5ir udJUIllnfl'. is not covered here . Of these drug ClllSIiCS, the historically lInponant group of drugs in the opioid cla..s ha_~ been the most problematic for usc in the proper management of pain. The term 0llia/lhobil/ ""lIlI coined to describe the I'l' luctance of phYMc.ans to prescribe opioid drop in OOequatc anJOUnts or for loog enoollh periods. As early as the 1970,.. the Nallonal In~ltute~ of Hc.al th fomM'd a COOlm lUC(", :u the requesl of the president . \Q \II\'csugate thcroptes for rare di.se~,. but the initial focus was on l);'Iin m::tJlpgement. l1Icre was poilllcal pressure \Q approve the: usc of heroin fOl" pam. under the miSlaken impres~iOll that a more potelll dru g wu.., needed. after se"eml Mudies sllowl-d poor pain management. l1Ic cOllillliul'C found that too problem was a lack of tmming of physJci311S in ""in ntal1-1b,<,nlC"t Ufld miSCOfK'epllons aboul the use of QIlioWs and addlCllon. I UnfOrtunatcly, the problem coollnued through the end of the 200 ~nlury and into the 21S!. O\"('r the past few ycars. major rutuon.al nlC(hcal groups, state me.:ilcal boanIs.. and phannDol.'ClIIlCal groups ha"e fonnulalcd guidelines dim:ted at improving pain thempy. Pharmaclst ~ and ocher health profCSl\ion~ls must clearl), m:oS" lle the a(l,'ances in pain lIIanagenll'nt and the adyantagcs and hmltallQns of the var-

73J

iQuJ drugs. For furthC'r mformation on pain and lIS m:m;lgc-

ment. refcr to number of anicll'$ and Amcric:m Pharnta<:eutieal A~-.ociation eont;llIlillg educulion progf'llOlS.' 1 The OOIIsidcnition of naUlrally occurring and synthetic:muJlcsics is facililated greatly by dividing them into two gTOOps: (a) moI']Ihine and rel:ued OOffip:lUndS lind (b) the antipyretic aoo 3nti-innammatory analgesic5. AI~. numcrous drugs lhat posscss distinctive phanruooological ac:u_iucs in other areas .Iso pos..<;css analgesic propenieli lind an: used lIS analgesIC adjuvants. The analgesic propeny exened may be a direct effe.;:t or may be indirect. but it b subsidi:11')' to ~ OIber, more profIOUnccd effect. SonIC ex3mple~ of these. "hich arc discussed clsc"here in thi ~ ICllI. an:~ uves (e.g .. barbilurates). muscle rd3ums (e.g .. mephcne~lIl. lIIelhocarbamol). and tranqu ilil.crli (e.g.. meprobamatc). TlIesc drugs arc not considered in this chapter.

a valu~hle cXpI:Ctor.lIlt action thai is superior 10 lI.of morphme. Two basic types of structures an: rccognllOO amon, tht opium alk~loKb. the: phl"lwII/lft'nt' (morphine It)'pe and tht Iwn;;,v/LSOquinol/l1t' (p;cpa"crine) type {~ stL'Ul.1uresl.
C.\en~

....... CH 3

RO

(Mor~. R '" R' - HI

..........,

...

H,CO y

" /'....
CH,

MORPHINE AND RELATED COMPOUNDS

Historical P..-sp active 1be discovery of morphine carly in the 19th century and the
demonstration of i15 potent anal~ie prupenie~ led directly to the scarch similat' drugs from plant ~I'C('S. In tnbutc 10 the remarhble po(cllCy and IloCtioll of morphine. it and codeine ltave remained alone as outstanding and indispen~a ble anal~1C!l from a plant source. Only Since 19)8 havc synthetic COfllp:lUnds ri"aling morphine in 11.<; action been found. although man y earlier synthetic changcs llIade on morphine itself gave Illore elTOC1i\'c agcnt.'I. ModifICations of the morphine molecule are ooruidcred under the follow ing headings:

ror

8enzyIosoQuonoI Type
(P8P8\ !lL'or>II)

The pharnlacological action~ of the: two Iypes of.lhkO are dissimilar. The nlOrphillC group acts prioclpaliy IlII tk eNS as a depressant lind stimulanl ; the papa_mne ~
has liliJeeffOC1 on the IICfVQtlSSY!.CIlI bot a mari.:ed anti,noodle action on smooth muscle. ClinICally. tilt' ~ action of the morphine group is ,he most uscfu l ~, te'iuhing in i ncrcased tolerance 10 pain. II sk.'<'py f~linJ. I Io....cr perNption of Cltem:d Slimuh. and II feehng o(.dbeing (euphoria). Respli'luOI')' deprc.\Sion. centnll in on is perhaps the most scrious objection to this ty~or al . . . IS)de from its tendency to causc Iddiction. The: !>IimuiaLf action is well illustrated by the con"uJsioll~ produmill,cenain mcmbers of thiS gTOOp (e.g .. thebamc). Before 1929. die dcri\Pli,cs of lnorphine thaI "'ere nudr primarily I\$ulted from ~imple c hanges on the: moItatk, 'iUCh IS esterincation of the phenolic andr'or ak. ohohc h)," " xyl groups. etherification of the phenolic hydrox)1 ~ and ~imilar minor changes. The net result was the di"".., of somc compounds", IIh grealCT activity Ihan morphine IiLl also With grealCr toxICity and addiction potential. No potJllds were fouod that completely lacked lhe: addktion bil itic s of lIlorphmc. tcrnl m!d;cr;w, linbillil' or tbt ~ renal tcrnl dl'lH'ndiocr Imbilill. as used In thi~ indkates the ability of a substance to toler.mcc and phy~('I1 dependence and/or to wppm. morphine ab~' inence syndrome aftcr withdrdwal of ___ phille from liddicts.) Some of the ~'()IIlpounds on common USC' before J929 h~ted In Tahle 22-ltogethcr wilh '>01flC dueed. All havc the common morphine

I. Early

c~

on mOlp/llne: bc:f\n the

wor~

of Small. fAly .

and !he,r OO "OIkeB

2. Chanp on morphine: imtiated In 1929 by Small. Eddy. 100 WWort:CIlL' u.-.deTlhe luspif;eo; of the Cun'tllmee un Drug Addlc tion of tht. Nltlonal RetiC.n:h Council and cx",,,dool! 1 die pru0
notti~

J. ReKmh 'nIU~ by Eo5kb and Sdl;!UlllilIIn' in 19J8. ",ith the:u d'~ny 01 the: poi"nt analgesic IIClion of mqJCridine: coon
pound thlM departs radically from the typical 11101 phine moleculc

4. Re5CUCh IllI\ia!ed by (;0, ...". in 1946. leading '0 ,lor SOC<'C'~ful $ynLhcsis of lhe 1l1OI ...'unan group or 1Il31 C'ic!.
EARLY MORPHINE MOOlflCATIO NS

Morphine is obtained from opium. which is the panly dnl-d Iutell from incised unripe capsulc..~ of p(1fXll'rr S()mni/"rum . Opium contai ns numerous alJ,:aloid~ (lIS mccon~ltc~ and slIlfate5). of which morphine. codeine. noscapine (narcotine). and papaverine arc therapeutically the Il1O:!it important. Thebaine. "hich has COIlvulsam propenies. is an import:'"t sian ing material for many othcr drug$. Other opium alkilioids. ~l.ICh as narceine. ha,'c ~n tested medicinally but are 1104 of areat importanCe. The action of opium is priocipaJly due to liS morphine COIltem. AJ on analgesic . opium i~ 001 ru. effective as 'llOfJIhinc because of ils ~Iower absorpt ion. but it has. grealer conslipating action and. thus. is beller wited for antidiarrheal prepara60ns (e.l .. ptregoric). Opium, 8!1 constituent of DoVCTS powders and Brown Mixture . also

nloe

morphine. "hldl al..o ~ born obtained surv;"ed as II good analgesiC and cough dcpress.:lnl.

Cba plf r 22

AIOUI~slC Apllfl

733

""" ,'"

TABLE 22- 1

Synthetic Oa rlv . llves of Morphine

C6 oJidi1.ed congcoc~. dihydmrnorphinonc (h) drornorphollC) and dihydrocotlcll1Qne (hydrocodonc), Dcri~alh'cs of

the last two compounds that po!'iscss a hydro~yl Group in position 14 are dlhyUrohydroxymorphinone. or oxymorphone. aJKI dihydrohydroxycodclnone. Of w;ycodone. These are the pnncipal compounds Ihlll cHhcr had been on the mar lCl Of had beton prepared before the studies of Small. Eddy . and t"Owor\.;ers. To this lime. Il(l really ~)"lcrnalic effort had been made 10 InvcslIgmc the slnJclure-GCli yi l)' relalion~h ip" in the molecule. and only the easi ly changed periphcl'lll groups had been modified. 1lle on ly exception is oxymorphone. Introduced In the Un ited Slal in 1959 but menliQncod
here becau<;c

I "'"

Compourtd ,., cpr/elMy

N.I"..

R'

.'
,.,. I

it ob,iously is closely related 1 0

o~ycOodlJnc,.

"
01, H

,c
M ORPHINE M OD IFICATIONS INITIATED BY TH E RESEARCH O f SM A LL A ND EDDY

s.om. ..........
" 11*'.

MM;...,.." 10".". ,

u, ...........

c,.tt.

1-1

0ilI1PII .... .......,

-US)
2C

"';.alg'", \POI obI.od on

<ll(h

...

,,"" ,.

DI

"

..,. .;

pdId

~p

~"'

........ ....".'

-~ "'dlpu-

-2C_

~"y.

11,\. a
ij!Ul , }old.

C/Io:r'Opl_

.. cll-

--"
"...... 000 ..1
01. 00

.... I0" ~

00)

s.m. .. 01

..

..,...o

ilaot

'by
Il!t,o),," .....

._--

""'"
~

cuL e.

"
1-1

""' ""p,
but lia-

'''' 10m.
pre text,

01,"'"' .........

....... In

--.
".,. ... ...... n.
.Ith lhe: eom:;.ponding ethyl ether ..... hich has found li S prin cipal application III ophthalmology. The wacelyl de:ri\'ative oCmorphllle. heroin, has bc:en known for a long ti me: it has llfen banished for years from IhI: Unlled SI.tlles and is bei ng IStd kss in other countri~. II is the: most wiocly used iIliei l ~ among n3tOOlic addlCU, Among the: reduced compgunds are dihydromorptslllC and dihydrorodcIDe and thei r

"I"C
~.

"'"

,=
., ~

.,""0' "
~hcr

",'"

The .~o ..... ed pur"f'IM of Srn.all. Eddy. and ooworters l in 1929 was to approach. the morph llWl problem from the sundpoint lhat Itml,hl be: possible 10 stp.1r.ue chemically lhe addictive propeny of morphine from liS 1,lIhc:r. mon: SoIIluuu')' altnbule!o, or if Ihat was not po!>SIble. il might be: pos.~ible to find other synl hetic rnoh"cules ~hhout ctli~ unde~ir~ble propeny. Pr0ceeding on these aSsumptions. these wortcrs first exnm .. Jed lhe morphine: molecule exhaustively. A~ a staning poim , morplunc: offered lhe advantages of ready availabiht)', pro~'en po!cncy, and ease of alter:uioo. In addition to its addlClIve lendency, they hoped Ihal other lIabllilies (e.g .. resptllltOl')' depression. emcllc propcnlcs. and glL'itromtc\ti nlll llllct .tInd circu lalOf)' di5t urbance~) cou ld be minimil.ed or abolished as well. Because: early modificlitiolls of morphmc (e.g .. acetylation or alky lauon of hydro;o;yts ~nd qu:ucnlll1llion of the: nitrogen ) caused vanations In the addICtive p0tency, they felt that the physiological errects of morphine could be relaled, at leas! In pan, 10 lhe peripheral groops. It ..... as nOl known if the acllonsofmorplllllC "'ere primarily H fuoclion of the peripheral groups or of the slnictural skele too . Thi~ did not mailer. however. because nHldificatioo of the: group" ..... ould alter activity III either case. ~ gt'OUp!o and lhe dTlS on acU\ Ily by modifyin, !hem an: IiSlcd In T able 22-2.. 'The results of these and earher studies ha\'C not always shown the: dflS of simple modifications IHl the analgesiC action of morphme quantitatively, but they do indicate the direction in which the activity i~ l i ~ely 10 go. The slUdic.~ are far ll101'e comprehensive thall Table 22-2 indicates. and \he conclusions usually depend on more than Ollt p.11r of compounds. Unfonunatc:ly . lhese: sIudICS on mor piu ne did not eliminate the addictIOn potential from lhese compounds, In fact, the studies suggested that any moolfiQl uon thai iocreascd thoc analgesic activit y caused II concomi tanl increase: ill addictioll liubility. The second pltase: of the: st udics' dealt with 11M: attempted syntIM:sis of substances ..... ith central ~oti C and. especially. analgesic action. The mOfplunc molecule rorual1\s certam wel1-<k'finc:d types of chemical suuctUR:$. Among these: ~ the phenanthrene nucleus. 11M: dibe:n:wfurun nl,lClellS, and, as a variant of tIM: laller, earnal.oic. 11lcse ~ynthc:tie studie~. ultiKJugh extensive and IIllCrt:Sli ng. provided 110 significant fil\ding~ and are not discussed funher in Ihi s text . One of lhe: more u.cful results of the: III~eSligations was lhe !ynthe<;ls of S-nlClhyldihydromorplullOl'le (Table 22- 1), who!;e nlCthyl subslittll:1l1 .... 11.\ originally u.~igned 10 position

TABLE 22- 2

So~

Stn>dur,,' Re l"tionships in th4' Morphine Mole<ule

I'eriplMril' Groups of

_..,.IM

M odiflutlon (On MOI'J)hJ ne

UflKU on A,."IgHi< ActIvity (Morphine or AnOther Compound

Un"" QthefWiH Indiuled)

iI. lndiciOled 100)

PIwde 'l'O<YI

.) -OH --OC.H, le1t>ft, ... "; 1

-OH--OCH~bots

" " "'" ".

13

-OH --OCH , \lIe1 .. o.:odB '18) -OH - -OCOCH, -OH - -0 (lNJiphnor.' -OH - _0 (Ooi'o, ... ", to dt:Iro-CIrl-=Okifi'.COJI iii 10 OtrydoociOdl ..... ) -01-1 - -H (dor1ydooo'I(IO"'..... 10 (1oI"oy(tOO II )'Y
INJipl. . .O,

-OIi--~i!,.

"......

-....,

"" (o.n.,do .. '.............. c:totI)'d'o no,..._ o. 600 "

390 CDoI:troc'X'E
let..,. dtryIlt,> ,."..,.,..

looo iDfIoornoophooevs.

OoIIro,d ?'<JfI'O'JA_-oI
....
1$"1111.,0,. d F7011)1 , ......... J

=C-O-CH---C-OH HCH-

.- ... -. -

to \e1t8ol'>tOo1! 1000jffOpI_) -CH =-=CH - - - CH,Ct-t.-!dnyooomolplvw)

,-"""'""

1000000~pN1e-O

".

-CH=CH---Oi,Cl-i.-{codl .. 10 ~oc:O(a "leJ

, ,./CH, /N-CH. /N, ()CH,

010. og 01 nIIrogeti tong (morphmev..l

Chaptn II

NoaI~ ~u

735

TABLE 22- 1--COI'1tmued

..... -:7

SoCt'1uhQn o!
-NH~

-OQl'-lli (&1 ~ I) -OH (at ~ 1. tI'I dohydtOIIQl))lD:Jne) -OH /aI pos""" I. n doh\O' OdE 'IOI'It1 -Cti~ (at POSd...., 51 -C>l J (at jlOUlOI1 611 ~OIUjA" ",)

ImoeI ~ _/X*IIIII'I2)

Mar1o.ed dllctea)ll

1'1 ~

2SO (Clto)(o,,'Uj)5"W"oOtle "" (IIIyOlupi ... ",1

(DII'I)O( ..

'"

" S30

',.O.....

~0d0'lit)

33 [1:lIt!yQ .. ,opi ""

5-~olopi.",)

.90 {(lh,<IoMa-I'.. ocr....O ....

"""m'
7. ,0 Although il pos.so.s.ed addiction liabi lities. il was a very
poIenl analgesic wilh a minimum of tiM: undesirable side dfecls of morphine. such as emetic act ion and menial du ll111'''5. Later. liM: high alllligesic activity tkmonSlraled by mor ph,ne coogcrlCrlI in ",hieh lhe alicyclic ring is either reduced or methylulcd (or both) und the alcoholic hydro~yl III positIOn 6 is absent prompted the synthesis of relaJed compou nds possessing lhese feawres. lllcse mclude 6-nlCthyldlhydromorphioo and its dchydr.lloo analogue 6-methyl-.d"-dcsoxyJllQfPhine or methylde.sorphine. I I both of which have high potet1Cy. ALo;o of inlerel'l were the compounds mOfphillOoe; 6-melhylnlOfJlhlne; and 6-melhyl-7-hydrox~-. 6-methyl-. tIld 6-melhyleoc:dihydrodesoJlymorphine. l2. ) In analgesic tn i\il) in mice. the laSI-namcd compound Willi 82 li mes more potent. mi ll igram for milligram. Ihan morphine. 115 lherapeulic lode)! (Tbol .... as 22 times lhat 0( morphine. ,. The siructure-actil'ity relationships of 14-hydroxymorplHne denv8tivell have been revie .....ed.- and several re lated compounds llief"C synthcsi7.ed.'} Ofthcse. the dihydrodesollY COIupoonds possn..'oCd lhe mosI analgesic ~IlV'ly. I\I.<;(). esl(fS of 14-hydro,ycodclne derivati~'es have shown very high .:tlvlty.'" For uample. in nllS. 14-cinnamyloxycodcinonc was I times more lICIive lhan lOOfl)hine. In 1963. !kntley and Hardy" reponed the synt~is of a nolel '>('ncs of poteru analgesics deril'ed from the opium Ilbioid theh.1inc:. In rots. lhe moSt acti ve nICmbcn of tile ~ f l. R, - H. Rz - CH J RJ - isoamyl; and 1. R, COCII]. R ~ - C H), RJ - n-CJ H7) \l,ere se:\'eralthoo~and hmes SU"Oi1gcr th:m morphine. I' TllC5C conlpounds e:oo:hibued maded dlfference.~ in activity of optical isolllCrlI. as .....ell a'!I other ,meresl;ng sFnICl ural effects. 11 was postu laled lhallhe ii"iOrt rigid molecular StRICture might allow them to fi t lhe Il'ttptor surfoce beuer. Extensivc SUUClunl and pharmacological sludics hn,"e been reponed.I'I SonIC of liIe N-cycloIWOP) lmelhyl compounds are lne It"II)St potenl aningonislS yet tIi(x)\'ered and ha,-e been studied 'o'er)' intensi vely.

s:o (On;dood

~~~)

-}ii'opi.",.o""

S.metl'rJleo -*#00 II "J"'U~I

Tuble 22-2. replllCelllCnl of tile N-nxthyl group in morphine by larget" alkyl groupti nOl only lowCfS analgesic act;vit)" but also confcrs morpIlineantagoolslrc propcn ies on lhe ,nolecole (discussed below). In dll~ oontra~t to Ihls effOCl, tile N-phenelhyl dcnvltil'e has 14 limes the analgc:sic activity of morphine. Thi s enhancemenl of IICtivity by N-anllkyl groups has wide apphcalron. as IS shown be low. Some of llie morphine iI./IlDgonifolS. such lIS nalorphine. are also strong analgesics.:O TIle Similarity of lhe ethylemc double bond and the cyclop"",yl group has prompted the syntiM:sis of N-cydopropylrnc:thyl deril,ath'es of morptlillC and ilS delivau"e~.~ ' Thl~ ~Ubslrtu.elll usually confcrs IFroIlg nan:OIic anugoniSlic aCllvily. Wllh vanable effeCb on anal. gesic potency. ~ dih~dronormorphirooroc derllatll'e has only moderale unalgesic octivity.
In

As indicated

MOR PH INE MODIFICATIO NS INmATEO BY THE RESEARCH Of EISLEB AND SCHAUMANN

In 1938. Eisleb and Schaumllnll! reported the: fortu,tQUs dJ.)cover)' that a 5imple piperidine derivative. now kno"',n as meperidillt. possessed analgesic acli~it y.11 was p!q)Irod as an antispasmodic. a prupeny it also possesses. As liM: Slot)' is told. during the pharmacological testing of IlIcpend./lC In mice. it ..... as <Jb,;co'ed 10 cause: lhe peculiar erecllon of lhe latl known IIli lhe Strnub reaction, 8ause this reklJon IS characteristic ofmofphine and ils dcrivlltilcs. tile compound then was lested for analgesic propen les und found 10 be aboul one fifth as actil'e as morphine. This findinG led not only to the di'\Covery of an octivc IInalgc~rc. but far more imponam. it SII mu lated re.sc:an::h. The ~Iatus of rescan:h on analgesic compounds wuh IlII octiv"y cornparubk 10 that of morphine ..... as at a Juw ebb in 1938. Many felt Ihal potent compounds could not be prepared. unless tiM:y were "ery elOiSely related stnlClllrally to nJOlllhinc. The dcmonstr.U.ion of high potency in II ~y nthetlC COITlpound thul was relalcd only distantly 10 morphine. ho .... c~er. spurred lhe efforts of vinous research groups.l2. U The first efforts, n3Iur~lly. were made on the mt:pcmlineIype molecule in an allempt to cnhm"K:e iu. acllvilY furthc:r. It was found tilal replacelllCnt of the 4-pIlcnyl group by hy drogen. al kyl. OIher aryl. aralkyl. lind hetell)l:ychc groups reduced analgesic K tivity. r lllCCnl!'lIt of lhe pheny l and ester

N-CH 3

R,O

Croulb' III ihc 4 posllion of I-mcthylpiperidine abo gll\e optimum IlCtivily. Severnl modificalions of this fundnrllcnwl

SltUClure

hsted In Table 22-3. Among the simplest changes soo.... n 10 increase activily
IUe

is the inscnion of lin m-hydroxyl group OIl the phenyl ring.

in ihc same rellilhe posilion as in morphine. The dflX'! i~ more pro!IO\lllCW on tile keto C'OITlpound (Table 223. A 4) than on mcperidine (A-I). KClobcmidone i. cqulvblcnllO morphine in acd vity and .... as once' widely u!;C'(!. More significantly. Jensen et 111.' dlsco~'ered thallqllact
II

i~

TA8lE 22-3

Compound$ Related to Meperidine

,....""

StruCtl....

.. .., ,. ,., ..

" -c,...

-CCX)C,H.

"

" -CH,CH.-CHP. -CH.CH.-CH,CH,-

-D<,

.
"

No(if Any)

_dine

"

-00-CoH. -C,.H.

-cooc......
-COOCH1CH.,il

-"',
-<><, -D<,

8: ..,.,. ..

PI_-

-c-c"x.
0

"

..
"

" "

-oOH
-CoH,

-C-C.H.
0

-CH.CI1,-CHp-i,-

-D<,

","()I)IOI""".

-O-C-C,H.
0

"

-D<,

,. ,

-c.H ,
-c.",

-O-C-C,H.
0

'"' -CH.&-CH.CH-

-CH~

....... Bool.,.oone
~

, .
"

-O-C-~.

1'"

-0i,tA." CH,J

r... _ _

...
"'.11
... 1:1

"

-CoHo -C,.H

-COOC,H, -COOC,H.

-CHlCH.-

-CH,CH.Co".

P! ~.

-CH,CH.-CH,cH.-CH,CH.-

-CH,c;.,.-Q-NH.
-(CH.I,-NH-C.H, -""",,c>GH,

-P iO<Io ..

" "
M

-o.H,
-o.Ho

-cooc......
-o - C-C......
0

I O-C-C.Ho
0

""

."

"

-c,",

-COOC,H.

-CH.CH,-

-CHICH ,.c(c,,1-1,; I, I
ON

TABLE 22-l-<onMUfd

Com~~~rocI

StNC'lu"

'"

-C.H,p-Ci

"

" -OH
-COOC,l1,

.
-CH,<:H,CICoH,), CN!Oi I

Analgesic

-o-t,CIi,-

...
'"
'"

-Uo:Jl_....

N_ (If Any)

(Meperidine . 11

""""
"""
,

-0.><
-c,H,

-CH,CH~,-

-O-f,H
0 0

-OH,

-0<OH,

-"".
-CH,Oi,c.H.

"""'......

"

_H

-1<I-cc,H,

o,H,
0

"

-CH.c;H,-

'

.....
lf13" 19M

...
,..

."

-COOCH.,

-N-CC,l1,

0,".

-Ct<~,~,

-CHP"..c.H

Kill of the carbethoxyl group in mcperidille by ocyloxy( JIlIIPS ga\'e bell,"," analgcMc, ItS ...1.'11115 ~pasmolytlc, IICU~lty, The "t1':\'~" ('Stl.'r of m<'peridml.', thl.' proplonoxy com (Wild (A.()). was Ille most acth'c, being 5 time~ ItS acti ve II mcperidillC , Tl1c:se rindlnj;.S -.01:1'1: validated and upandcd by l.I.'e ct al .l ' ~ In anl.'l lell'livl.' st udy of iWructur.aIIl1000Il'ic:tuoru; of meperidine , Jan ssen and &kIy:!'> euncltKb1 tllal IbtproplOflOxy eompound~ we ..... always more IICli ve, usuftlly Ibotu Iwofold. n:sardlelo~ of what group was allochcd to thl.' . ,...n. Ue '0 had ])OI>lul:lled thai the.' ronligur.atiOfl or the proplo~)' derivalive (A-6) more closely rC'Io!mbled Ihal or moI'pIu~. wilh the 1.'~ler chanl laking a POSLiiOfl suni lai' 10 that attuptcd b) C6 and C1 In llIOI'JIhine, His spl.'("U lations were ~0Il space modclsand certainly did not renect the actual n::..rormation of the IlQn n gid mcpendmc, He did arrive alihi.' (Oilee! a.<;sumption, ho ... evcr, thallnlroduction of a rJJCthyl poop Into posJllon3 Ortlle piperidmc nng in Inc jlf'OpiorK)\y roalllOOnd wtJUld yicld 1"'0 bomer'S. one .... ith octi vity ap f'\I.\lmaling Ihm o r desomorphine and Ihe olher wi lh lc~~ .:tI\ity, One of the IWO dlaslerwisomcf5 (A1 ). bctaprodmc. .. achvll y in mice about 9 umc~ that of morpttillC and )u~ thai of A.(). Becken et al." have C'Stahlished that .1 II the cis (mcthyllpht-ny1) form, lbe Iron,' form. alpbuporo_, i1 1wicc as octivc as nw::>rphinc. RI.'S(llution of tile race _"ihovo'~ Ihat one enanllomer ha ~ the prcdommant acu~ In Iwmam. howcver. lhe sharp diffcrence~ in analge.~1C poleI)(")' art' rIO! so nlar ~cd , lbe /rI1/I,f fOlllt is nlarketell as k racemate, The ~igniriem'll:c of the 3-methyl ha~ been 01 :::~, to discrlminalion of the enallllouopic edges of IhellC Qcuk!s by the receptor. nns 15 CH'n more dramatic m _ ]allyl and 3-propyl isolilers. for .... hic h lhe Qo/rlms fonus I\' tOOSidc:rubly more 10e ,8 isolltcriO. IIxbc:umg I art': rIO! loicr:lled in the alial . I 3-ethyll<;(}flICn. are nearly equal.n ;l(t.vlly,

funher indlcau ng that t.... o or fewl.'l"carbons are more accept able In the.' drug - receptor Interaction >!' 11 A ~mall subll(itllCnt. soch It:> ITlCthyl. 81lachcd 1 the nitro0 gen had sccmed to be opt imal for ullu l ge~ic aclivity, Thi, .... as believed to be true rIO! only for lhe nICpendine scnc~ of compounds but also for .11 the OIhcr type!; , It IS I'MJW .... ell establisho.'d l/l:tl replaccment of lhe mcthyl grouj! b) "anous ar~l kyl groups can increasc ac tivi ty markc:dl~, A few e~ amplcs of this type of compou nd m the meperidine series are !>hoWl' III Tabie 22-)_ Thc pIlcllClhyJ derivatlvc (A9) is about 3 li mes as lIellVC as meperidlllC (A I ) , The: p amillQ congener. an ileridine (A- IO), is about 4 times ilion: acli \'c, Pim inodinc: . the pIlcnylaminopropy l dc:riVIl1;"c (A . II ). has 55 times the actl~ ily of meperidine m ruts and is about 5 li mc.~ liS cffectl ve in humans I1!l an llllalge.~ic." The JTi()!,t :lCli \'e IIlcperi ll inC' lypc compounds, 10 dale. a ..... the propionOly dcrivali ~c (A 12).... hich is nearly 2,000 t imc:~ as acti"IC as meperidine. and the N.phcflt:th)' 1 3nalogueofbct~;ne, .... hich '-~ 0" 1.'1' 2,~ timc.~ as IICIl\C as lIIorplllne ,l Diphc no~ylatc (Al l), II struclurn I hybrid or nlCperidinc und nteth adooe types, lacks analgesic lICuvlly. although il reponedly supp..:s:>es the nw::>rphinc 1IbstillClK'e syndrome in lIIorphme addicl.~ , 'S,:II> It IS quu .. cffcclhe as an inle~innl spasmolytiC and i~ used fOl" the tfCalnlCIII of diarrhcli (Lomolil). Several other Ocri'al;"c~ or it have bttn iWu(hl-d, jJ The: re lated p . ehloro analoguc. loperamidc (A- 14). bmds 10 opl~tc reccp10<'\ in lhe bram bul does 001 pellClr~lc the blood - broin barricr enough to producc analgesla,l~ Anotller way to modify the struelure of mepc:ndiflt: ... ith f~\OI'"~ble Il'SIJ lts was to cnlarge the p.peodine nnli: 10 the 5e\'cn'lllCmbcn:d heAllhydrwtll.'pllle (or hc:.anIClhylcna . mlllc) ring. As was INC in IIIC piperidme series. the mOM acti ve compound is lhe one cont.:lining a melh)'1 group on posilion ) " fl he"og adjacenl 1 lhe quatcrnary carbon atom 0 in Ihe propiono~y dcrival;'c, Il'Ial is. I ,)-dimeth) I..... phenyl

1 whIch the name pmllf'p, 0 raz;",. was given. In the study by Eddy and coworkers. cited aOO,c. INohcptuinc was one of the more active anal~jcs included and had oneof the highest addICtion liabilities. The higher ring homologue 0( meperidine. ethoi1eplllJ'jne. was on the market. Although originally thought to be lnacti\c. >0 it is Ie5s active than codeine as an ~nalge&ie in humans but is ffl!e of addiction liabi lity wtd has low incidence of ..de effct:1s ..oo It is 00 longer available. Controction of the piperidine ring to the fi ve-membered pyrrolidine ring was also SUC'Ce.~sful. The lower ring homo logue or ~Iph:lprodine, prodilidme (A- 16). i~ an eff1l\'e analgesic; a dose of 100 rng IS equivakntto 30 rng of 00Ikine. but because of its potenti al abuse liability. it was nevcr rnat1r;cted. ' A more unusual modification of lhe mepcridiroe structure is foulld in fentany l (A- 11). in which thephcnyl ~ l1d the lICyl groops art' S('par3ted fl"Qlll the ring by a nitl'Ol!en. It is 11 powerful analgesic. 50 \.lme5 stronger than morphine in humans. wit h mini mal side effects:! I ~ shON durntilJll of IICt ion makes it well suited for usc in anesthesia:) It is rl1:lrketed for this purpose in combinat ion with a neurolepltc. druperidol . The 6${-)-3-methyl analogue wi th an ester group at the ~ posi tion. lil e mqlC. idine (A - IS). was 8.400 ti rncs Il"IOf'e potent than morphine as an analgesic. In additiofl. it has the highes t bi ndi ng affinit y to isolated opillte ~eptors or ;,11 compounds tested .... Fenlllnyl wtd its 3-methyl and rr-methyl analogues have found their way into the illicit drug rl1:lrket and are sold as substi tutes for heroin. Il.ecause of their extrerne poIt'ocy. they ha,e caused many deaths. When the nitrogen ring of morphine is opened. as in the fonno ti on of morphimethines. the analgesic llCtivity is \ rrtWllly abol ished. On t h i~ basi~. predicting ..... he lilCr a oorn pou nd would or would not have lC'\ivity without the mtrogen in a ri ng wOll ld favor a luck of activi ty or. at best. low acli"it y. TIle first report indicat ing thut this was a false IISsumptiofl was based on the initial ...-ort 0( Bockmuehl and Ehrhart .... in which they claimed that the type of ~ompound represented by 8 -1 in Tuble 22-4 possessed both analge~lc and spasmolytic 1)l0JIC11ies. TIle lioeclist laboratories in Ger many fol lowed up this lead dun ng World War II by pn:p:tring the ketC,lor1eli corresponding to these Cltoters. Some of the compounds they prepared wi th high III:ti vity are lept~nted by fonnulas 8 -2 through 8 -1. Compound 8 -2 i~ the we ll know n methado ne. In the meperidine and bemi dom:. types. the irlltodl.lCtion 0( m_hydrolyl group in the phen)'1 ring brought about slightly \0 mar~ edJy increased activity. wlw.!reas the same operation wi th the methadone-type compound martedJy decll'ased llCtion. Phc nadolone: ( 8 -S). the morphoIine analogue of methadone. was nurleted in Englund. n.e piperidi oo ana logue. di panollC. was once under study In this eounlf)' aft~ ~fu l results in England. Methadone ......5 first brought to the attention 0( A.merican phlll1l1UCisls. chem i sL~. lind allied wOlters by the Kleidell'r I"C'port. ' und by the early reporlll of Soon and Chen...... . 1 Since then. nluch work has ~n done on this compound. its isomer isomet hadone. and related com pounds. The n:por1 by Eddy. Touchberry. and Licbeli llan'" <.'O,e'" most of the points eoncernlng the struct u~act i, ity relut ionshi lX 0( me thaool'lC'. The ttl'/} i:wmer ( 0 -3) of nlCthadone ( 0 -2) and the lem isomer of isomethadone ( 8 -4 ) are twice-as cffecth'e as thei r racemic mi~ tures. Also. all Struclu~ derivatives of

4-propiono~yhc~ahydrool.cpillt.

methadone demon,trale greater IlCtlvit) than the cor It'poOOing structural derivatives of io;omcthadone . In OIller ... ord!. the supenority of methadone O'oer Il\Omethudone loalllllll hold. e,'en through tllc denvatl\cs. Cornersc:ly. the mttIIadone serie.~ of compounds was 3lw~ys more tox ic than the
i_t~ group.

MOR' e~ten~i~e pemlUtUIlOlls. such as replocing tile: rroponyl group (R, in 0 -2) by hydrogcn. hydro~yl. Of IICCto~)~ dt:cn-ased acti~ity. In a !ot'ries of amide analogues of IIJ<Ihr done. Janssen and JlIgencau~-j synthesi~ed rocctnOl'allllt (B- 12). which is more act i~e than methadone. The (6) is0mer. \kltl"OmOl'Umide (8 -13). is the lICIive i<;orncr and_ been rrt;Irkcted. A few of the OIher Ill(Xhrl4"atlOflS lhat bne been ~urried out and thei r effect on Qnalgc~ic acti> Ily n:13I11t 10 methadone are described in Table 22-4. whIch incluib most of the IDCthadone congene'" thaI are or were on III! market. Much dcviutiOll i" StruclO rc from tlw.!sc eurnpk'l will rt!iult in varying degn:cs of loss of iICU' ny. Panieular attenllon should be paid to the t.,...o jbaI,1 groups in methadone and the sharply de<:reased acllOO mull ing from removal of one of them. It is believed tII3I liE second phenyl reSIdue hell"" to lod the - COC11I, pQIp of methadone in 3 posillon to simulate the alicychc nn,g 01 morphine. C\'l'n though the propionyl group is not par1ItIIInrly rigid. In thIS connection. 110\\ e\ er. the compotllld .lIt. n flI'Opionoxy group III place of tile p~illflyl group (R, . 8 -2) lacks ~ign i ficant analgesic action. ' In direcl ~ wi th thi~ is (6)-propo~yphcne (S - 14). ... hlCh is 11 pfOpIOIlOl) deri ~ athc with one o f the phen)'1 groops replaced bl 1M 1.yl group. In addition. it is an analogue of isomethadone(B4), makmg it an eJ1.ccplKln to the rule. Thi~ compound I> lower than codeine In analgesic activity. poIi.'lCSSCli ftll oitIt effects. and has a li mited addiction liability.'l Repl","." E' of the dimethylamino group III (6)-pmpolyphene ....,tll I P!". rolidyl grou p gives a compound that is nearly thm:-fOlril as active as methadone: urI(! posseSIoC!i morphillC like rroper ties. TIM: lel'O Isomer of alphacctyhnc:thadol (8 -9 ). u..1 as LAA M.has been rl1:ll"keted as a long-acting Mtbscmltdl' me thadone in the tn:atnlCnt of addICts."

MORPHtNE MODIFICATIONS INITIATED BY GREWE

Grewe. in 1946. approaclw.!d the probkm of synl heticanal!C' sics from QOO(her dirt'(1ion ... ben he synthesi~ed IIr 11l".lCyclic compound that he fiP.Ot Il:Imed mOfpllau and tbeI revised to N-melhy lillorphi nan. The rclution~hip of thi' rollpound to morpllllle is ob,ious.

.
,
3

16

N- N-CH 3

,~

" "'-J.
S-

,.

,
II

N~ptwIarr

N-Mcth),lmorphinarl diffCl"; fl"Qlll the morphine noclm. IIIC~ ing lhe ether bridge bet\\ccn C-4 and CoS. Thi\ C(Do pou nd poo;scs.<;eN u high degree of Ilnlllgc\ic actiyity. .. 1Id ~uggest.. thaI lhe ether bridge is not essential. The3-h) .... deri vative of N-methylmorphman (racemorpll.:m) ....lI~o.dIr mllr~et and had un i ntelL~ity and dur.uion of action that rl etc de" that or morphine. TIM: original roccll1()l'Jlhan ......

t:\pon!J-

.. ord~_

TABLE 22--4

Compounds Related to Me thadone

A...... AI

eeITb to methahan the

R . . . R. /

C'

e propiCCto).),L. fmethaor.umde (6) iso:and has \:It ha,t

relllu~e

,_. .,nd " " ,. -c.H -c. H, .,

po

StNCtUAI

-COO-AI<yl

"

- OiJOi~N(CI-t,),

"'M -t 1Co'MI

ItonMr,

Salt
no

MI1g6lc ActMty (Methadon 11

-C.H.

-C.H

Incl udc~

' o n the ~lImples

.,

-W-CtHl 0

-CHJCHN(CH:aI,

I:tl-HCI

'"

&.,
-CHCH,N10i:a)'
IA\o .. Q'MI .... , Ior'MI

"

s.n. .. ,,8-2
-C.H~

-c.H,

phen)'1

-A-CoHo

I1 re~ult-C.H~

&..
-CHP.NICH~ll

,.""
1'1' )-HO

I-l-Bowtnwt

" '"
0" 080

that the H\ group e ring of parucuund Wllh p( R , in eont ... ,I,\1 Pionoxy )' II ben done: (BpotJnd is

-c.Hs

-i-C~'

NoImoMIlI1done

..
o.

-C.Hs

- c. H,

-K-C,H,

-e><tq
-CHPI.{)
-CHt~'--}
-CH,..cHN!CH.',

00I*l0r.

-C.H.

-c.H

-C-C,H,

few

~I<k

(lCemenl

1 a PYTm
known mule for

:-fOllnhs

: pr'OPCT-

.. ..
."

tie ....., .-

030

-c.H
-e.Hs

-c.H

-i-C,H.
0

"

f'honw:'c;wouI.

('1'H<:l

..
"
"
025

-CoH

-C><C....
0

~~,

~-fH'

ewo.U:ll

1I,(:t1-HO

&.,

5arT4 at In 9-9

BeI~'oetr6jol

Jf,\t.)HCt

: analgethe: td IIld then

his com-

." ." ." ...

Illi

-c.Hs

-c.H,
-c.H

-~H.

-CH~Oi,N '-_}

"

O!!WllP'18IyI bl.Cy-

-c.Hs

-c-{J
~

-CHCHaN'b !H.

FIa;e,QIII''Ide

1+)-8IIse

'--I
Qeoltrcmoramoo

"

-c.

Same as
H

fl

6-12

-Oi,c.H,

O-W-c,H
0

-CHCH~CH,~

",...-,p

(+ )-E\ate 1+l-HC1

&..

"

021

dcl.l~ III
i~

com-

" v.hlCh ,/droxyl

SOIl 1i1c

that exwlL~

Ill-

the h),dmbromide and was the: (dJ), or ... .lCCmic. jgm as ob\a,ntd by \yntheSIS. Realizing thai 11K: L e"orota~ form of raceIllO(p/lan was lhe analgesically ath\'c poe... of the I1ICemate. the munufucturrr resolval thc (til) form -.I marketed the 10'0 form as the: wtnItC salt (levorphanol)_ The du/m form has found use lIS II coug h suppressant (!iCe

t'OOllI,.'td

dc:JItrolllctl!orphan ), The etOer.; and ac),lalc:d denvall\'CS of the J - hydro~)' 1 fonn al.-.o exhibit consider-tble activity, The 2- and "' -hydroxyl lsonlcn are. not uneJ(~1c:dly. without v~lue lIS analgesics. Likew ise. the N-c:thyl deriva'I"e lacks ac1lvi t)', and the N-al l) I compound. Ic:vlIlIOI'phlln. is a potent morphine antagOl1iSl.

Eddy el al.J.o rcporti'd on an e~lcn,ive ~ries of N-amll)'lmol'ptliRan dcM\alj\'C~s. 11le effeC'l of the N-arnlky l ~ub Slitation .....as more dramal;" In rhis S('ries ttuan il 1'11Ili for morphine or IIIcperidmc. 11le Npllcncthyl alld N-'1wmnophc:octhyl analosue~ of levorphanol an: about 3 and I g limes ~ actjn~. n.:specll\'r'ly. than the parent l'()lllpound In analgesic ncu~l\y in [",ce, The most potC11t JllI'mbcr of the SUlci was the N-p.rurylethyt analOj'!uc. "'hith was nearly JO tmw:s as acUH~ as \e\'orphanol or 160 Innes 115 acti\'c a~ rnorphirtc . "The Nl\Cctophcoone analogue, levophenacylmorphan. W,,-( once under clenlelll m,'e~ligalion. III mICe. i. is about 30 !l1I1CS Ill(lI'e acthe th.an 1I10'ptUIIC. and In human~ a 2-",g dose i~ "-'qui"alenl 10 10 1111: of morphine in its analgesIC ~ponSl'.1j II ha..\. much lo wer physicaL-dcpendcoce liabil I!) than morphlllC. The N-cyclopropylrnclhyl dcrh'ulivc o f 3-h)droxymorphman (cydorphao) was reported \0 br II poIen\ morphine anllljlool \l. capabk of p!ttipitarlllg IllOfP/lllle wllhdmwal sy mptoms in lKkhcled mon~eys. rndicaling rhal ir is nona<!dicling . ZI Clinical studies have indicated thar it is about 20 ImleS stronger IlwllllOfP/lme as an aoolgt~ile. but il has some undes ir-.lhlc side cffects. primanly halll.lCinalOl)'. The N. cydobutyl derivali'e. burorphanol. possesses mixed agonisl- ama800i'i-l propcnies. howelcr. and has been markcled as u potent analgesIC. Since removal of the: ether bridge and all rhe peripheral glUUpi III the ahcycllC ring in morphine did 1101 destroy ItS analgesic action. Ma) el al."" synlMsi~ a <.erie.~ of COOl' pounds in which the alicyc lic ring wus replaced by one or 1"'0 n10ethyl group!'. 1lIe.\oC are ~nnwn as ~n;:pnwrpluln rh rim',....s or. more C<lITttrly .INII::.tI::JKinu. They may be repn:scntcd by the following fonllula:

withdrawal symptoms. Furttlcr dlffertnce~ 111 rrop;:rti~ an' found between the enanrionll.'I'S o f,he cis ;"OIlIcr. The ( +) isomer has weat analgesic acti "ity. but a hi gh physiorl-dr pendcnce CllPOlCtty. 11K: (-) r!\Omer I~ a ~t ronger llnalCOK. .... Hnoulthe dcpcndcnceelipacHy. and JlO'SoI"~S<"' IlIltagon,Wc actll'lty.Ji The same i~ tlUl" of the 5.9<diet hyl and 9-t1h)~ 5 phcnyl dcnvatlles. 'The (-) Im,rs-5.9-dlcthyl IJoOma' iIi Similar. uccpl it has 11{) :lllIallUllblie propertlC-~. This de_ strotl'S rh.at it IS P'.,ble to dll'orcr analgesic 1IC1I~ lty COIlIJI'r rabl .. to Ihal of mOI'phlllC from add'Clion poIenllal. Th:M ,\'merhyl compounds hav.. shown IIlltagoni <lic propenltf ~ of greal mttrest as .... el1 . 'The mo>-I potent of \ ' - h till hen7.omOl'phan with an <l'-mcthyl and ,8-J-{nohcplyl Jr'OIII at position 9. '!be (-) isomer shows gremer antagolllS!ic K u\'i ty !ban naloxone and is ~IIII 3 IJines more poten! riIII morph ine a. un analgesic ......

CH,

",I

(e-I

"

/J .... ' ... tu..J

/R,

,..--(!",,", , HC
-'cH,
CH,
RI }CH1

"

The Irimclh)'1 compound (II. H, _ Hl - CII ) l is abou, 3 limes more potent than the dinlClhyl (II. H, - H. Hz _ C H]). The N-ptw:nclhyl derivative" have ulmosl 20 limes lhe analgesic aclhity of Ihe ~poodi ng N-m-clhyl t"Olll ' poulllb. Aga;n. the more poIent was the one containing the two ring mc:rh)'l ~ (II. R, _ CH l Rl - C HzCH 2C,Hj ). DemCCllli7..l11iOll proved the /t,'O isomer o r Ihis compound 1 be 0 nlOre ilCll\'e. bem, about 20 limes as potent as morphine in micc. The (::!:) fotm. phcnawcIIM!. was on the mmkel but was renlOl'oo in favor of pcnlll1.ocine. May ct al . S1 delnonstruted an extremely ~ignificant differ_ ence between the two isomeric "' mcthyl henlomorphans in which the al\:yl in the 5 position is n-prop)'1 (R , ) ~nd the al~yl in the 9 p!)Sltion i~ nrthy! (R 2J. Tlit!oC hal'e been tcrmed the (> and the fJisonM!r and howe lhe groups oriented as indicated. lllC: isomer with too nlky! ('is to illC: phenyl JII)l;VS~S analgesic act;llty (i n rnlce) cqualto thar of morphine but hti little or no capacity 10 su~ wlIhdl'llwal sy mptom~ in addictcd monkeys. On the OItlcr hand. thctnll1s i.'lOlllCr has one of the highest ana!J;C!;k potencies among rhe ben1.0m0rph:in5. bul il is qu ite able 10 ~uP\l'R'S!i morphlllC

An exrensi"e seric., of the an tagoll l'I-IYpe anJlgeslCll" the bcnromorphans was reponcd. 1iII Of these. pclllnoc. (II. R, - CII.. R, - CH~H - C(CH,h) and C)'clazut_ ( II. R, - C HJ R2 _ C lI z-cydopropyl ) ha\ e been the moll ;ntel'e5li ng. ~ntazocil\C ha.~ about half the analgesIC" DClII"f) of morphine. with a 10.... ("1' Incidence of Mdc efTtcU. ' ~ addiction liubllrty ,s much loll er. appmximatlllilihal P( propoxypoollC .t>l It is currently available In parcnlcrnl and l<INd form. Cyclat.oclllC I~ a!ilmn~ R1orphn1oe antagonLst. ...... about 10 tinlC$ the analge~ic acti~lty of morphlllr.'-1 1t UL illvestigaled as an analgesic and for too rrcallne:nl of hi:roirr addi" tton. but LI w .... IIe\'CT mar1eted bec:au~ of halhK'atOl)' ~uJe effects. As rnemiuncd abcl\'\:. rcplacelllCnl of the "'-mcrh} I gr'tqI 111 ItlOI"phme by larg("1' alkyl g lUUp' lowered analgc>.oo.; k'\il ity. In addi"OI'I. these compounds coun teracted the efftd~ morphillC und oIher morphine- like analgesics and an: d. kno.... n as nm'{'(/fic amll.~on;,U. The I'CI'C"1'Sa1 of IIrthil) if ~ase~ from elh)'l. to propyl. to allyl ..... uh the e)'cloprOjijI mClhyl usually being ma~ i l11111. Thi ~ propen) was tlUe" on ly for motphlllC buL also for {)(her .nalgcsic~. N-AII)'lrIornlOl'ptnne (nalOfptnne:) ... a~ the first of the~ bur bel: of side etTl'Cts wa., t:r.~en off the R1:r.rk el. Le ~aIlOf]lh:ul. tk CQlTCSpondllll! allyl analogue or 1c,orphanol. ruLiooOlie I\allylnoroxymorpbonel. :r.nd nallrexone: (N-cyckJj'up)1 oxymorphonc) nrc too lhn:e narcot ic antagonbts 1\0\1 on tilmarket. Naloxone and nal lrcxOOC' appear 10 be purt"~ nr"'~ with no morphllle- or nakKphllle- lr~e effects. Tk)' block rhe effccts or otoor antagonists. These drug~ an: to pl'Clent, dlillmbh. or abo!r\1! many o f the IICtlOlb side effcas encountered .... lIh the LI:u'OOlIC analgesics. of thc!ic ~rc respirnlory and eLrculmory dcpres"OfI. at " ' . nausea. drow~illCss. anaJge,\ia. and hyperg lycemoa. The). !houghl ro act by cOOlpetlng With the analge>.re ~~ for attachmcnt at liS. or a closely related. receptor s.rl~ TIt OOscrnlion thai SOIne: nareotlC ant.agorllSlS thai lad IIIrX lion liabil ity :11\. also ~trong IInalgesK-~ spuiTC..:! ~~

(J.

,mae."l In them. lhc N-cyclopropylmelhyJ compounds mentioned are.he nl(K1 pmen! aJ1lagoni51~ btH appear 10 pr0duce psychotomimetIC effecls lind may IIOl be useful as anal~ One of these, bu~lKJIllhll1c. has shown In InterestInll ~tudy profile. howe'cr, and tm.~ been inlrod~ in Europe and in the U",I~ Slates as II potent anall!:~."" II IS being InirudOttd as a U'ealmcnl for Ml'C(J(ic addicts '" IO\ICI tn:auncnt program. Omce Based Opioid Treatment \080'1). provided by private physicians rather than formal In'.lIncnl chnics.1>l 0Iher efforts have been under ""lI)' 10 develop narrol K: OWIugonhts Ihal call be used to trcal narcotic addiction."" The cootinuQ\ls admiolstMion of an antagonist will block
ft eupt...... 'c e(rtt1~ of heroin, t~by aidmg rchabililation II an addict. The e),eloprop)lmeth),1 de:nvative of naloxone. aaitrellone. II1ls been marl.:eteu for Ihis purpose. The oral dose of 100 10 150 mg 3 times. ",,1.: sufftces to blod. ,"ernl u~U<l1 doses of herom.~7 Longleling prepar3lioru
11= once alSQ un!lcr .lUuy." Much re<oean'h. other than lhal ckscri!led above, has been
QI'htd OUI

been qucstioned.7'1 Additional ~t udi C5 ind ll'at e that deall.:)'l ation does OC(:ur in the br.lin. although il.'i ellOCt role is rKlI clear.'" It is clea... from the N-aralkyl ckl'iVIUVes di~ssN above. that a small group is IIQI ne<:Cssary. Several c~cc ptions \0 the sa:<:Mld fealure ha.c been synthesized. In these senes. the centntl carbon atom has bren replaced by I teMU"), nitrogen. They Ire related 10 methadone and have the following siructures:

, "

by the ~y5lematic dissection of morphHle 10 gIve It>ern! imereslins frosmenls. The~ approochd have nOl yel producl!!! imponaJ1l analgesics and SO are not di SCussed in IIa chapler. The imcrcstoo rcllder may find key 10 this bImlure. oo..e,-cr. in the excellcn! revie",s of Eddy.' Bergel m Morrisoo. 21 ami Lee:'"

O,N

SbbLtllre- ActIvlty Relationships

x-tnl fCl'ie"" on the rclation)hip belween chemical Strue_ and ;malgesic OJCtion hal e been j)Ilblished.9. .09 1'1 Only iIIe IIllIJO" cOIIClusionl ~ consldo;nd here, and the readet- is II1tli toconsul! lhese TeView5 for more complele uiscussion at the: 'lUbja:t. From the tune Small et al . ~taned the-ir Mutlies on the mphillC nucleus to the present. t!leTt ha ~ been much light Ibcd on the SITUCturol fcmures connected with mo,phillCanalgesIC 1ICtion. In a vcry thorough Study made for the tMet! NationsCommi\sioo on N:m:oIia; in 1955. BllIfflden ,. aI.lOII foond Ih~1 lhe features possessed by all I.:lIQwn mor_Ii~e unulgesics were as follows:
1 II IrIWfy n!t~n. ">lh ,he ,roup on the nItrogen bl:1n1 rela U\~Jy .mall 1 A""nlral ~arbon ~Iom. of ",11",,11 nQOC of !he vakrw;e:, I. con IIK1Cd .. ,,'" hy~cn ~ It pbetI}I,tu.lp Of a Group ,5QS1mc .... ph(nyl, ",'hich .. cOlIIDMtoJw rhe ""nlrul cartxJn atom I A , .. u-cwbon cOOin st'pW3IlIIJ ,he cenual cubon 110m from

,'h

.., IIItroam

few

ma~Im:>I IICII\Illy

The above di'>Cu\sion ~ho"'s thaI several exceplions 10 rencrallJAlliolls e~ l"c in the SlnJCIUres of compounds !ul'e been sy ntht$il,ed in the past 5CI'eral yeal'1l. Eddy d~'iCUS5Cd the IIll>1'l: ,ignificant exceptions. Relative co It fll'Sl feature mentioned. e~tensile studies of the action .... " ... I"';lIIe have sho..... n thaI it ~~ analgesic acti vtIuI approllimates that of morphine. In humans. it is about founh a~ !!Ctive as morphine ",hen tldministert.'d intray. but il .... as shghtly ItlpeOor to morphine ",hen III i~ lDtl'llCiSlt'mall{.- On the has's of the IaSI-mencffect, Beckeu ct al. ' poslulated th~t N-deall.:ylation I51CJl in the ~hanis.m of ItIIalgesic action. This has

Diampromide: (III) and 'IS related anili~ ha"e potencies thai ~ comparable ",ith those of morphllle;" they hal'e sho"n addiction liabilit y. however. and ha ve no! aPPC;lfl!d on the marleet. The closely relatcd cyclIC dmvati~e fentanyl (Table 22-3, A- I7) is used in wrgery. The bc:nzimidalo!es. such as etonita7.e1lC (IV). are very potent analge~icl< 001 show the highest addIction liabilities yel enoountered.lll, IJ Po&ibly an uception 10 fealure 3. and tbe only oroe that has been enooumered. may be tbe cydohc~yl analogue of A-6 (Table 22-3). which has significanl activity. &Idy" mentions IWO possible uceptions 10 femure " in ;I(lJ1l1Oll to fentanyl . The many sludies on moleculcs of varying type, that possess analgesic octivity revcaled thm octi,ily was a.~wciatcd not only ",ith cenain struclUral realWl'~ but liso ",ith the siu and the shapeofthe molecule. The hypothesi~ of Beckett and Cnsy"" has dominated thinking fo, <;c!lerol years in the area of stereochemicml specifici ty of the5C molecules. They in iliolly noted lhat the ITl(II'e octil"c cnantiomcl'5 of the metha_ done- and thiambulene-type anal gesics "cre related conligurationally to (H}-alanillC. This ~u88c~ted 10 them that a stcreosclecti\'e fit at a Il'\:cptor could be \11lo1l'ed in an:llgesic activity. To ckplct lhe dImension s of an analgesic Il'\:epllll', they selected morphine {becau5C of ih '>CIllJ ri gidi ty ~nd hi gh activity} to provide: them wilh lDfOl'lnalion on a complementary receptor. The features thoughl 10 be es~ntial for proper receptor fit ....cre
I . A basI('
=~1lI'
ccn~

able: to USOClale "',lh an

;u)tOmC

Sl\c on the

surflf;'C

-:::,brl

2.

i"- .-an lief Waals bondmllO. n;O surface on 1[1(' IC:CCptol' " Ie
to ",Inforce

Anal atonllllk 51IUC1Urc. coptalllU' ""Ih t[l(' ba>K: cenlcr. allow -

tne _'" bond

p<O)IlIIg hydnxarbol1 mo'c:lY room,ng GfflmCtric pilllcm w;Ih 1[1(' bo..~k ~f"I"" ~nd
SlnICIun:

J . A sIluai>ty

f'OSn~

Ihrcc.-Ui""'n~ional

the f1a1 aroman!:

742

w,.:- oNi Gmvld', Te..tbooI. O/DrlIIII,r MrJrri1Wll """ I'hamloa..,wa/ C"'mwrv

H H

TIlese features were se lected, D lllOng other reasons. be cause they !lit present in N- nlCthylmorphinan. which may be looked 011 WI a . 'stripped do ..... n morptllllC (i.e... mO(ptlll1ll Without the characteristic penpheral groups lexcq>l for the basic center I). S, nee N-mcthylmorphman posses!led substanlialllCtivity of the morplline type. tllese three features were comidl'm:i tile fundamental t)nC~ determining a.cliv ity. and tile penptllC,lll groups of ltlOi'phinc ..ere coo.siden:d to essentially modulate the acti vity. In acronI ..... ith tile f~golng po5tulate.~, Socketl and Casy3"' proposed a com,l!k nlCntary receptor site (Fig. 22- 1) lind suggested ways .... in wllich the kllOwn aclive molecule~ coold be lldapted to il. After their mi lial postulates. natural (~).morphine was shown to be reb ted oonligurnlioo ally to mclh3done Dnd Uliambtitene... lI ich lent ... elght to the hypothe.>is. Fundamental 10 the,r proposal WlI,~ thai slICh a n.'cep'or was eSsenti1.lIy inl1 ex ible LInd that 1 loc k-and- key. type situatioo existed. S ubsequcml y, the unnaturnl ( + ). I00I'ptune ...'as symhc!iizai and shown to be inactive.'? Although the f~going lIy~is appeared to fil the facts qUIte well and was a useful hypothesis for 5e\"(.'rnl years. it IIOW appears thut certain anoma lies ex ist that canrlOt be accom modated by it. For C1;a mple. tile more IlCti ve enami orner of tr-metlllldol is rIOt relined oonfigur~tionall y to (R}alamne. in COIllnSt with the methadone and Ihiambutenc !;C'rleJ;. This i~ alS() lrue for the earbelhox y analoguc of methadone (V) and for d,ampromide (III) and its nnalogucs. AnOIher factor that was implicIt in COfI~idering a proper receptor fi l for the motpItlnc molecule and lIS congeners WIIS Ihal the phen)'1 rinS allhc 4 position oflhe piperid ine moiety shoold be III the ax ial orientation for muimum acli,uy. llIe fael that suucture VI hal; only an equalorial phen)'1 group. ),et possesses acu vity equal to tlllli of morphinc ..... oold seem to ca.'1 doubt on tllc necessity for nllial oricntation n.~ 11 receptorfit requirement .

OH
(Pkw~"h.~.

Figure 22 - 1 Dlagrdm of the surface of the analQi'5IC rKfIIo tor !ilte WIth !he COilesponci'ng Iowef !>UrfdCe of the drug rule The Ulri!'NI,rTll'flSIOIlal fe.aturf'S of !he molecule /lie VIOWl by the bonds. - . - - -. and - -. wtnch represent III front rI, berllnd, and III the plane 01 the paper. r~trvely (from Go,r. ley. 0 R. H Prog Drug Res 736. 1964 ]

Q Forx:.
C

'

2Hs

the hypothesiS cnn be applied to the IllCthaOOl iUlOIll.Ily I illustr:ucd in Figure 22-2. After considering acti,ity changes in .ariOllS stru<:ttnI types (i.e .. mcthndoncs. mepen dil"ll;'S. prodHlCS) as rel*<l to the ideutl1 y of the N-suill;utocnt. Portoghcse iI01td certain 5en es. when identICal changes in Nsubl.mucntS.m made. there was p;irallch~m In the direcnon of attivlIJ". whereas in others there appeared to be nonl)aJ"lll lelism.1k has int el pi t ied poarallcJisiIl and nonparallcliSiIl. rtsptill}. as being doe to similar and dissimilar iIlodes of bUII;b,.. Vie....ed by this hypothc!il~. although analgcsi(: ~ must slill be boulld in a fairly pt=ise manner. the ~ of binding is hberalized. in thal li response llIay be obtauIN by two different mo!ccul e~ bindiug Merwsclet1ively In t-.u different precise modes at tIM: same receptor. A ..chemair; representatioo of soch different possible bmdinJ 1n(IIb. sho.... n ill Figure 22-3. Thi. representation .... ,11 aid in ,. izing the ulCuni ng of s;"'lla~ and dissimilar bindingllllllh If two different ::molgcslophorcs (the analgeSic II1OIa:ult

m.

CHaCH- N,

/CH,

I CH,

CH,

In vicw of the difficu lty of accepting Ucc kclI 3nd Casy's hypothesis lIS a cou~elC piclure of analgesic -receptor i nt~ adion. Porioghese 9(l1w offerai an altem&ti"e hypolhe.... .'1. This hypothc!iis is based. III pan. 00 the established abi llIy of enzynlC$ and OIher types of macromolecules to undergo coofO<llluliona l change~'" 9l Oft imeMlCtion with small nlOlecules (substrates or drugs). llIe fact that config unlllooally unrelated analgCSlcs can bind and exert activity is Int~rpreted 1$ lIlCalllng that more than one mode of binding mny be possible al the same Icceptor. Such di fferent modes of bindi ng may be due to differences in pDSuional or conformational interactions with the receptor. llIe man!)Cr in whi ch

{' o
H

....
W
(6RI

W
(65)

Figure 22-2 Hlustrallon of how d,lfere<'lt poI.tr 91"0'.411 analgl'SlC molecules IT\it)' YLISe IOYefSI()fI In ~ conhgur scolectMty of an analgl'SlC rfCeptOf A hydr !'I'KlIety. deooted by X aod Y. rep!"esellts ol SIte tNt IS of bem9 hydrogen bonded

... ,

,
I

-- -

/
/

,,

,,
\ I
I \
\
/

al!iO no useful drug5 developed 10 time thai are sele<:1;'c for

I) re1:cptOf1.

\
\
\

0
\

Anothoer bighl y importnnt development in ~ll\ICltJre-lIC1 i v it)' C(ln"Clations is the development of hIghly 1lC11l"C analgesics from theN-aUyl-type dcriva!ives thai lu're once thought 10 be only morphine anlagolllSlS and devoid of analgesic

...

, ,
\
\

piopenlCS. SerendipilY,Jlaycd a major role In Ihl~ disco,'cry: Lasagna und 8 eecher. in lIuempting 10 find some "itk:ar'

J ,

,,

figure 22 - 3 Schematic l!lustrallOll 01 two di fferent moIecuW modes of b,ndlng to a recl'Ptor lB. protonated nitrogen. Q an Nsubstltuent The anIOnIC ~Ies ~ directly benNth the p-tII\iIted nrtrogen

----

I
/

ralio of arllagon;st {N-allylnomlorphiBC. nalorphine ) 1 anal0 gaic (morphine) 10 maintain the desinable efftcl~ of morphine .... hile minimizing the uOOesil1lblc oocs. dillCOVcn:U WI oalorphmc IUS, milhgr,lm for milligram. lIS potent an analgesIC as morphine. UnfOl"lunalcly. I\.;Ilorphme has depC'rsonahzing and psycholomimeuc propenies thai pn:cJude ils use clinically as a pain reliever. The discovery ltd. however. 10 the development of re luted derivati yes ~ueh as pentazocine and cychaocine. PentlllOCine has achieved some succcs.' in providing an analgesic with 10"" addICtion potential. although it is 001 tOlally free or some of !he other iide effects o f morphine. lbc pauem of activity in these and other Nallyl and Neyc lopropylmethyl derivat ives indil:ates that most poten t antagoni~ts p!l!;5eSS psychotomimetic activity. ""hereas the weak antagoni~ts do Il0l. It is ff{)ln Ihis laner group th.:lt usefu l analgesics. sueh a.~ penta7-ocine. bulorpha001. and nalbuphine. ha'e beeR foooo. lbc laller two posseD N-cydobutylRlt:thyt groups. What 5ttUCturaJ features arc ll5S(rialed 1"lth anlllgonlSllike acuvlty h uncertain. lbc N-oUyl and dlmethy lallyl suI>stituen t doe5 IlOl always confer antagonist propen ies. This is true in tilt: meperi dine and tlle~inol seri es. Demonstration of ~ntal!onist- l ike properties by lipeeifie isomcflI of N-methyl benzomorphans has r.1I~d stilt funherspcculaIiOfl. "The exact meclwlIsms by .... hieh morphine and the: nartOlic antagonists ac:1 arc IlOl dear. and much re'iCarch is procntly belllg carried OIl. Publi.shed ~1 ieWS and sym.pol'ia nu~ be consulted for funher dl~USSIORS of the.'iC tOPICS.""" on_ A funher problem al'iO is demonstmtcd in the tesliR!! for analgesic IICtivity. The analgesic activity of the IIlltagonists was not II.ppafCnt from IiOlinal testing: it was ~r.ed ooly in humans. Screening in animals can be u<oetl to assess the antagonI stIC lIdion. which IIldiroctly indicales possible analge.~ie propc"nies in human~.loo It has been customary in the area of analgesic agents to mlributc differtoces in tlleir activi ties to structumlly Il'latcd diffen:l1Ce~ in their reccptor intcrnctions. This rather uniller~I prolCliee C(lntinues in spile of early ""lIfnings aoo recent finding.. II now appears clear that much o f the diffen:nce in Idative analgesic potencies can be ;tCOOUnted for on the: basiS of phann81"Ok inetic or distribution propcnies." For eumple. a definile col lcl nti on was foooo bet"'C('n the pani. tion coefficien ts and Ihe int rJvenous analgesic wlt a for 17 agentS or widely varying structures. IOI Usual test mcthod.~ do not bel p distinguish whIch structural features an: related 1 receptOl'S and .... hich to dhtribution pheOOlllt:na.. Stooies 0 directed toward diSllllC1ion ha'e u">Cd the measurement or :v:tual booin and pla.~ma levels 1 IOJ or dIrect injection into m. the Ventricu lar an:a. 1DI the 11l('a.~urement of iOf1 il.acion poten ti~ls and p;ln itioll coefficients. ,1>1 and the appl icat ion of Ill(}lecu lar omital theories and quantum mechanics .... '113--1'" 11lcse an: providing valU:lble insight into designing of new and more ~uccc:ssful agents. All or the foregoing ",or1r; hadstrongly suggested !he exi5-

Y"
IIIlnus the N_~ubsti t ucnt. I.e .. that ponion of the molecule Nt ghcs the chamcterislic pnalgesie response) bearing idmIical N-subsmuems arc POSltlOlit:d on !he receptor surface such that the N-$Ubs\itucnt OttUpies essentially the _ posllion . \imilar pharmacological response may be lfIIicipated. Thus. as one: procd$ from ooe N-~ubsllt uent k) another. the respoII!oe sltoo ld likewise chan ge. resulting in paraJ lel i~m of effect. On the other hand. if two different wlgc.'iophllre~ an: bound to the receptor such thai the NIUbWtucnts are not arranged identically. ooe may anticipate ~nlical re~pon5Cllto ehanglnJlhe N-substi tucnt (i .e . a aotopanIllel response). lbc preceding SliltemenlS. as wel l as ~ diagrnm. do not imply thaI the an~lgesiophore ~eSSllr ill 111111 be bound in the iucntieal position within a scnes. They do SUl!ge~t. however. that in series with IX'mllel activitIeS, the paio; being compared will be bouod identicall y w prodllCC the parullel errOCI. Interesllngly ..... hen binding 10k< arc similar. Ponoghcse has been able to demoostmtc lilt ulSlencc of. linear free-energy n:latiOO5hip. 11lcrr is .00 the posSibility thaI more Ihan one l"a"Cptor is involved. Considerable e~idence now demomtrates that multiple!'Ccrptors uist. Manin has characteri7.cd anolI named the'\C by II:SpOIISeS to probe molecule~: ,... (m u) receplOI"" for morpbine-specific effecls. B (de lta ) for cycla7.ocine. and I< !bppit) ror kelocyel:u:oci ne.~) A. dlffcrt:Ol designation for tIK5c n:cC'ptOl"". based on pt\annacotogical criteria. is QP3. OPI. and n:spettil"cly. Various combinat ions of these II different t"'-'ues t"OUld be re~pon~ib le for the varying ef-

,I in

,m! d"

\'cre lily.

Ho

'ely. ing. ules

,""" '". .alle

L1al-

~~

15 IS

des. cult

"

on.

rr<:~ ~rved '104. !I

Thb di'CQ,,:ry has scimulated much research into the tnCCh for drugs that halle Seleclll'lIy for ~ingle reccptors. 1k nalUral opiates and ,"dated synthetic opioids have pretminalllty ,.. ret:c-ptor a.goni~1 activi ty. with morphine and l1li001" ana logues showing 10 to 20 Ulnes the selecti Y y over ll lite tlIher I"CCcptors. Other ana l ge.~ie dl'\l~s havl: show n even IIJber ratios. The antagonists ,how lower sekxtivity. Drugs nil lugh I( receptor affi nity hal"C high anaJg~e aclil"ity. iIo:k many or the opioid side effects. but have 001 been useful Wnn<e or dyspOOnc and hallocinogenic effects. Then: an:

tenet: of ~pecirlC bllldmg SI tes or rrapfO" in brain:md other tLSSIK TIle dcmonstratLoo of the hilh sterie :md structural ~pec,flClly in the: 3Ctioo of the: opiates and their .... 1a~iSl5 led IllanY Hlvl:$ligatln tu sc:arch for soch receptors. oa. ,0\1 Thus in 1971. GoId:.!ein and oowor kel'5 dcmooSlraled ste~ ~ific binding In br in homogenatei.'11 This Wa5 quick ly .. folloll'ed by rofiocmclI\S and furt lle!' discovenc:s by Simon. T erc nius. and Pert and Snyder. 111 - III 'These receptor-binding studies have now become a rout ine assay for examinillg sirucmrc-3Cti vily relationshi p", In addition 1 0lhe b, nd ing studies. eoosidcrable anent ion eootlnucd 00 the use of in vitro mo dels. in panieular the i~ated guinea pig ileum . 1111 jtjunum. and ,oousc vas deferens."~ Wh,le working .... ith these ~Iions, Hughes was lhe first 10 discoH'" the ex iSlence of .... tndogenous factor from p.g brains lhat ~ op.ate-like plIOp,,'ic:s. nilS faclor. gi\'en the nallle rnkpllaUn, consisted of IW O pelllapcpudc~ culled mrlllQnitW-, or fNtenkrphalin. and Ir,. cinr-, or Irurnuphillin. ~ t .... o cnl ephalins ha\'e Mlir.;equently been sho.... n 10 e~iSl in all animals. ioc.ludinf. humans. and 10 po'>scss all mOfphine-lit.:e properties. I 711~ l1lcy c;c.ist as segments ufa pitui tary hormone. the 91-amino acid ,8-1 ipotropin ..... hi eh is c lc~\'cd selectively to release specific segmcnl~ that have now been found 1 have functions 0 ..... ilhin the body. 1111,1 5. scgme:m 61 1065 is ntelCnktphali n. 61 1 076 is a--c:ndorphi n. 61to 771s r-endorphin, and. probably the most important. 61 to 9 1 .s ,8-endol'phin.

lishc:d an tJL,te:nsi\e listing of nan:ot i~ of cUm'nt Intcmt. the drug tMlde. This liSting is moch more: t\tensl''c: . . tho: folio .... ing monogmphs CO\'ering co:npounds primml) 1/ interest 1 American pharmaciSb. 0

'1'. ""

tl 1'11."

... no (I', 010. ~ , ""g

(n.

GO,

" Q

Ptc ... ~ ' ..

.
I

,_ 577'''?'t.
I . 'Ir

'e.

'1, ....

w.o

00, O'AT .......... ' Ir ott

.,~/:to

.... ".. . .,..-l-OO;.,.~ ,,.,_.c> ...... ~ ::

MorpMM. Morphme was i'iOluled fln.t III IS03 by [k. rQSnt. bu lthe e:redit for isolalion gencl1llly gOt's 1 Scrtdnla 0 (IS03). who li rst called attention to too ba~1C proPCTtlCHi this alkaloid. Morph ine, incidentall y. was too 1in.1 plant isolated and recognil.ed as such. Although 1I11en"ve motm wa~ earried out on the Strotturc of morphine. II w..~ in 191j Ihat Gu lland and Robi nson l2\) posIu lmed Ihe eUl"mltly Ecepled formula. The lotal synthes,s of mOl'phl1lCl fin:olly ... e:ffected by Gales and Tschudi l:., III III 1952, CQllIi tho: Gulland and Robinson fonnul:L MorphillCl .s obtained only fronl the opium popp)." PO''''' w mni!,.,.um. eilher from optum, the I'c:.~.n ol;uu>ed '" lancing the unripe pod, 01' from poppy \tf1lW. ~ ~tn P"I cess is favored. as it helps 10 eli minale Il lIcII opium m. which heroin is readily produced. Morph ine occurs in opiIM in amounts varying from 5 10 20% (USI' requires root ~ Ihnn 9 .5%). 11 is isolated by vnriOlJ~ melhods. bill tilt: ftlll step is usually too precipitation of morpltinc from un IL:Id. soluti on by use of excess ammon ia. 11\C (lfec lpilDted IID' pltinc then i~ rc:crystallized from boiling ~Icohol. The free alkaloid occurs as le~oro\.Illory. oc.Ior1c:\.,\.,_. needle-tile cl)'stals posstsslllg a blUtr ta-,te. It .~ a1mo11 soluble .n water( I :5,000, I : 1.1 00 al the boiling pOIUI~ (I :6.250), or e:hloroform ( I : 1.220)_ It ,~ somewhat I1\OIt uble: in ethyl alcohol (1:2 10.1:98 al boiling potntJ. ~ Slll thai in this chllple:r, a solubility or 1:5,000 ind..::t11:S dull g is soluble: to 5.000 mL of tho: so!\'e:nI :It 2.'i"C. Solubi1ltltt't I other temperatures are 50 ind icated.) ~u.'iC of the pIr hydroxyl group, it is n:adi ly soluble in soluuoos of alUli alkal ine ear1h mcl.ll.l hydroxides.

'*

" -tIOtft

EI+ ,Ill'
llW..a.-GItI-L... ' I'

,,~."'".'.,_.c>.:.J. I
I

~. ~

..

"Thto L.. PI. l,' "'"'" ... 1.\ .........

_lYM-rH-I" GI, 0'. OH

~. ,,,En,:kt+pltin. !lAd ........ EnIo.IIII 1in Aela!ior<o"

"

The laSt of lhe:se' endorphins (~hon for I'ndogenous mar I'hi,,~) 1lI1.~ 20 times the analgesic patenI,:)' of morphitw: when Injectl-d into rat brain. 1lw:se subsluoc.e5 can also produce toltrance and dt'pendcnce, C learly. all o f thc5c tcchniques will lead to ntW oonctpl$ and undtrslandi ng of the procc W' of analgesia. toler.mce, and lkpendence. It is hoped thaI learni ng how these: mechanisms operate: will aid in tho: design and development of btlter analgesics.

II soluble sa lts with mosl acids, : . is so poorly wlu ble in for most uses. Nume:rous salt! h3~e ~n ones in use: arc principally the sulfale: nnd. to a the hydrochloride. Many wri ters have poi nlcd ()UI tho: " indl ~penSllbk" lure of morphine. based on liS patenl analgesic to..... ard all types of pain, It is properly termed I PIlI uooISI'sic. Bau.<>e il causes addicuon so readi ly, hovt~ il should be used only ..... hen OIbc:rpolO,rel lC~.n, dl\lp 1"'1 inadequate. It controls pain caused by serious inJ\U). pl !l.~ms. migraine, ple:urisy, biliary and re nal CoIic.lnd;;~ me:rous other condilions. It is oflen ndmmi ste:n:d as a emti ve scdat h 'c, loge loor " 'ilh alropine: 1 control stertt 0 With scopol amine . it is given to obluin the ~alled t.. t1i;r sltep, This effect i$ used in obsletrics. but c:trc IS nttdroJ Pf"Cvenl rcspiralOl')' depression in the fe:lu. ~ toxic ties of morphitw: arc much more evidenl in young and people.

P ....In Gentral Cireular No. 253, Mal'I:h 10,1960. the Treasury Department, Bureau of Narcolici. Washinglon, DC, pub-

Morph/M Hydnxhlori~. Morphll1Cl may be prepared by neuU"alizing a hot aql,lCQU' of morphine .... ith diluted hydrochloroc acid and tl1ltinlthe resultant solution 10 crystllli1.aUOl'l commereial ly av:tilable, II occurs as sil ky, ..... hile.

,,""
il)'

,"'"f "

we.lks.

itS

"Ub.CllI mas'iCli. or D~ a

\0,

hue cry>.llllhne powder.

, Ik,urncr ies of

""arch

,"'"'

The h) drochlondc i. <;()/ublc In .... ater ( I : 17 .S, I :0 .5 at boll"" prnnt). alcohol (I :52. 1:46 al 60). or glrecon. but il is 1Q(11C'Jily illl;Oluble ill elher Of chloroform. Solutions ha\'C I pH of approXUllalcJy 4.111l'1d may be ,!mlilled by bollmg. 11) uses ~ the !lame lIS those of morphine. The usual orol "';!5ubcutal'll'OllS dose is 15 mg e~ery 4 houl'll as needed, '111111 ~ ~uillleslcd runge o f 8 10 20 mg.
Morphine Sulfa te, U5P. M01'philM! ~ulfalc is p"'pared In.he foamc mnnner as ,he hydruchlonlk (i.e . by neutrnhzing morphine I'.ith dilul~'(l sulfuric acid). 11 occun as feathery. "Ik) ..... h'le cry<11I1", as cubical mas!oC~ of crySlals. or as a .h,lt crystalline po,,dcr. Ahhoogh 1\ i~ II (airly ~t:lble !>all, \oo.e<. ,",uteI' of h)drntion IIIId darlen) Of! e~posure 10 3Jr al ri ght II i~ SQluble in ",'lI[er (116. I I II !!(fl. poorly tOIubIe In alcohol 0 :570. 1:240 at 60"). and insoluble in cttloroform or ether. AqllC.'Olls solutions han' a pH of aboul U 2nd may be ~lerili7.ro by healing in an autoclaV1: . Thi' common morphine sal! i~ used WIdely in England. IIId roow in the United Stale.~. by ordl admlni'trdtion for the INnagemem of pam in cancer patienlS. [I h:IS 1:lrgety replact1l Bromplon's mill.lI,m: Of coc ~t uit. a combination of bl-roin and ~"OCaine in chloroform wnter. Illthc United States. thl~ prcparnlion has become Imstakcnly popu lue. suboilituting lIIOfJ'hine , ulfale for lhe: heroin . Morool ... r. Twycm8S has II.h 1'\Cd lnat the stimulant cexalne is COIltr1l1ndicaled because illlcrfcre, IO.-ith sleep. III and liS original U\.C was for cough II tuberculosis p.ltIenls. Morphme sulfate IS a\l1lilable in a taricfy of dosage fOllTL'i: tablel~. oral 'iOIut,Ofl. parenlcnlli . lIIjlpIJ&"one~. and COIltrolled relea.sc tablel$ ( MS Conlin) IIId ClIl"'ulc' (Katlian).

1925
,.~

1)' IIC-

mung

y. Po

ofa<pmn and ~-odt-"IC DoCt addiu\"cly as amdgc<lC!i. however. thus givlllg WIne !\UI)JIOIt to lhe oommoo prot"hCl:' of combtnmg lbe t .....o drugs . COlkme iu. a reputallOO as an antilusslI"C:. Ueprt!l$IMgth.c cough reikl( . and I~ u~ 1M many cough pn:pamhoo!>.. 11 15 one of the mosl widely used morphineli~e analgesics. It is ooru;idcnbly IeSll addicting than morphine. and 111 Ihe u~ual doses. =pimtory de~s~ion IS negllgiblc. although nn oral dose of 60 mg eaU:lt'8 such depression in a normal penon. 11-1 uch of cOlkine'S reputalion as an unti tussive probably rests on subject"'e impressiOils Illtllt::r Ihan OIl objc:<:\ivc ~lUdies. The a~erage 5 mL dose: contains 10 mg t)f code Ine. Sc~enlll cough preparations COIltaining ~iuc are avallablc. wllh some tN.I may be sold ovCr-lhc-OOtlnter as e:>. ...mpt natl:otic ~paratl()Os. Abu,<, or mIsuse of these preparalions. how ever, has led many '>Ial~ to plnce them on f}I"~IIpt.IOII-only status.

"" b, :r proI from

opium

ot le~~

e final
oc id

<II

d mOl"'

.,,01~

",h,tc. lOSt In). etner

(Note

Codeine Phosp hate, U5P. COlkine phosphate rna) be prepared by neutmli",-ing codeine with phosphoric acId and precipitating the -;;,It frolll aqueoti) solution WIth alcohol. Codeine phm;phale occurs as rine. needlc-shapcd. IOohite cry~lnl , or as a ""hite cry,tnlline powder. II IS e m\lI"CliCent and is sen~ithe to light . It is freely soluble ill water (I :2.5. 1:0.5 al 80") but 1e~s SOl ubl e in alcohol (1 :325. I: 125 at boiling point ). Solutions may be slerilil.ro by IXIlIIOg. Becau"C of il) hi gh .-...>!ubihty in water. compared wllh the ~ul. fate. thi ~ saIl 1\ u,<,d .... idely. It is often the only QJt 0( codeine stocked by pharmacies and is dispensed. riply or "'rongly. on all prcscriptiom calling for either !he sulfate or
the phosphale.

that I htlCS al henolic J Lnli or

; water !IC itself ed form 001 the r e~tent.

Cod.iM, U5P. COlkine i, an alkal oid that Ot;t;un natuIIIIly in opium. but tilt:: atnoum prcllCnt i, nsually too small
~

Codeine 5ulfat e, U5P. CodeHIe <u lfatc is prepared by neutnllli7.101! an aqueous suspension of codeine ",ith dIluted sulfuric acid and then effccting cl)'51a llil.ation. It occun as
while crystals. usually I1CL-dlelike. or lI$ a "hite crystalline powder. '1'he _all is cfOt)res';cm and lighl scnsitile. It i~ so lu ble in water ( I:30. I :6.5 at 80"). much less soluble in alcohol ( I : 1,280). and insoluble III ether or ch lorofonn. Th is sa lt of codeiuc is prescnbcd frequently but is IIOl as wl1Dble as !he phosphate for liquid prcparation.~. Solutions of the .sulrate and the phosphate are it1COO1patible " 'Ith alkaloidal reagent!; and alkaJulC substal1CC!l.

be of commerci al imponan<.'C. ConSjuently. most com-

tnrn'ial codeme is prepared from morphine by fTlCthylating the phenolic hydro:>. yl group. The mcth}lation methods make
rcll.genls such as diawnl('tMne. dHlIcthyl sulfate. and 1IIf:Ih)1 iodide. NelOoer mcthod.~ arc based on ilS synthesis from theb:lIne. "hich makcs it pos~iblc to use PopQ\~' brocfrlllilln as a n:ltural souree (see abo\e). II OCCU" as le\orotaIory. colorless. e~nt cryslIIls Of U I "lute crystalline powder. II is light :It'nsili>o:. Codeine .. ~Ightly ~uble in waler ( I: 120) and sparingly soluble. in . . . (I :50). II is freely soluble in alcohol (I :2) and vel)' IOOIbIe in chloroform (1:0.5). Codeine is a monoacidic base lid rt:KlIIy forms salts with acids, WIth the mos t Imponant bnnlthe sulfate and the phosphate. The acetale and methylbromide denvati\es ha vl: been used 10 a limited e~lent in ~gh pn:p.lmtions. The general pharmacologic"1 action of codeine is ~imilar II thai of morphinc. but as indicated nlx"c. " does not pos1m the same analgesic (JO(cney. Studies u"hcale that a dose 01 JO 10 120 IlIg of codeine IS considerably less cfficicnl PftRkraUy than 10 mg of morphine. and the lI.'iual side c&cb of nlOl"phine-rcspu'atory dcpieMion. constipation. ~.I-.a. and such-occur. Codc U IS less eff1i\'O: orally IC *m partntCTlllly. and Houde and WailensteIM 110I stilled tnat I dose of)2 mg of codeme is about 115 effo:cU\e as 650 mg !If til'lnn 1M rclieving terminal clncer pain. Combinations
lie of

"c" na-

"OpCnle~

Mf"l"OIic

p" e~er.

&5 prt)\C

".~

and nu-

.preop-

C"rtlions.

I twilight

Diace tylmorphine Hydroch loride. Although dlacetylmorphluc h)dnxhloride. heroin hydrochloride. diamorphlUC hydrochloride. heroin. is 2 to 3 tinlC..~ moo: (JO(ent th:m morphine as an analgc.<ic. lUi sale and Ulol.' ;m, prohlbl1ed III the United Slme~ Ix.~nuse o f its imense addlclion hability. II is avail able in some European countries. wherc it has a
limited use as (In IImi1U~~h'e and as an analgesic in tenninal cancer patients. Because of il\ s nperior so lubIlity over morphine su lfatc . arguments Iu"'e been raised for ilS IvaI lability . The OIh.er lnorc potent annlge~ics described he:re ha\"e. how. ever. significant advantages in being more stable and longcr (!Cling. It rclllains one of the most " 'Idely used nan;:o(ics for illicit pu~ and pbccs major economic bunltn~ on society.

lCCded to

proper-

, and old

xhlonde

tSpCnSHJII

nCOl"lCCn-

no longer

Hydromorphone.

pistcning

Hydmmorph(me. dlhydromorplu none. a syntheUc deriVQt,,c of morphine. is prepared by titc

catal),tic hydrogenation and de:hydroge rlluion of nKll'ph ine uOOcr acidic tonditilHlS. using 3 large CJ(<:e.~ of plat inum or pall3dium. lbc fr base is similar in properties 10 morphine. Ixing slightly soluble in watcr. freely &oluble in 31cohol. and I'ery soluble In chloroform. Th,s compound. of Gennan origin. 100m mlrOduced in 1926. h ,s a substillllC fOl' morphille (5 times as poIent) but has approxunately equal addicting Iilopc:nic:s and a shoner duratIon of action. It pt..... se$Ses the a!hlIJlta!.~ m 'er mOfpbine or gIving Ic:s.s daYIllTlC sedat ion or drowsiness . It is II potent antitUSSIve and IS onen used for coughs that arc: dIfficult to conlfOi.

plastic di sc:ase.~. and {)(her IYpes of palO thai respond 10 IIU phlne:. Because of the n)l of addiction. II should nO( be uiaI for relief of minor pains that can be controlled .... 'th ~ It has poor anttlussive lIdivl' y and ,s not used as I OOIP SUpptCSSUllt. II mlty be administered orally. parenterally (;. UlIvel1Ol.lsLy , iotramusculnrly. or SU\)clltanc()u,.. ly). Of~. arid for thoo.'se pulposc:'> is supplied as I soIuuon fOl'in.ifttn (1.0 and I.j mglmL) and in supposi torie~ (5 mg). Nalbuphine hydnxiIIDride . N-cyclobutylmclhyl - l4-hyuroxy -N-nortlihydrolllOr(ilinone h~drochloride (Nuooin). N-cyc1nbutylmcthylnorolJ n1OTphone h}drochloride . II as imroduced in 1919 a" I ~ analgesic of lhe agOl1is( -amagoni~t Iype , WIth Lmle to. abuse liability. It is 3 SOfflC ... hat Ics~ potent analgc:sK IIu. lIS parent o.\}morphonc: but shares some of the anlJl properties of the c1o!lely reLated, bul pure, "ntagoni~1S tWA one and nattn:~one. N~lbupl1,ne: h)drochloride OCCU~ 1M lI'hile 10 off-white crystalline: powder that is soLuble in " . and ~paringly soluble in alcohol. [I is prc:pan:d frum cyckllt. tylmethyl bromide und noro~ycodonc foUowro by Clcll of the O mclh)'1 group. This :Illalgc:sic sho .... s a "ery t:1pld onSCt .... ilh a dUraD of x.ion of up to 6 houl'$. It has relati "ely low abuse li;abilirl judged to be Icss .halllll:ot of code ine alld propoxyphene. TIlt injccuon is, therefore . aV3ilabie IIlthoul narcO(I~ ~"" although caution is urged for longternl admini.1nIIinI use in emotionally di~lurbc:d pallenl.~ . Abrupt di'>COlllu", lion after prolonged u.-c has gi"en rise to .... jthdr.l.... ~!.i Usual ~ cause: respiratory depression cOnlp;u3bk of morphine, but no fUl1hcr decrease is secn II IIh hl~ doses. II has fCller cardiac effects than penla;rocUll'.Id t. torphanol . 'The mosl f~uent adverse effec. is ~llon." as wilh I~t olhcr eNS depressantS Arid an3lScsi(;J. ~ should be urged .... hen 1\ is administered to ambullllllr} jilt tienls who may need to drive a car or opcr~te II1IIChinctJ Nalbuphinc: iii murl.etcd as an m,ICCtablc: (10 anti 20 mL). 'The usual dose is 10 ms administered sulx:u. inlrJmu.'>Cularly. 01' inlravcnow;ly at 3- to 6hour i~ wi th a ma.~imal dally dose of 160 mg.
NlJ lbuphi~ Hydrochlo~.

Hydromorphone Hydrochloride, USP. Hydromof phone hydrochloride:. dihydl'OOlOl'phinooc hydrochloride (Dilaudld). occurs as II light -sensitivc. whitc crystalline: powder that i~ frecly soluble in water (I :3). $paringly soluble in alcohol. and practically insoluble in etilc:r. II is used in about oneflfth the dose: or morphine for any of the mdiclltions of morphine. It IS avaIlable: In tablel. liquid. parenter.l.\. and supp06itory dcMge forms . The dosc: is I 10 8 111g. Hydrocodone Bitartrate, USP. Hydrocodone bi lM(t:1le, dihydrooodeinone bilanrole (Dicodid. Codone). i$ prepared by the: calalytic ream:mgemcnl of c()o(ko,ine or by hy drolYl.lI1g dlhydnxhcbaine: . It occurs as fine .... hilt cryslals 01' as a IIhile erySlalline: po... der. [I is soluble in waler (I : 16). slightly soluble in alcohol, arid Insoluble in elher. It forms ocidic solUlion~ and is affected by light. The: hydrochloride is also alaBable. Hydrorodone has a phannacological action midway betwccn lOOse of codeine and morphine. lIilh 15 mg being equivalent to 10 mg of morphine in analgesic puwer. AI though it possesses more addiction Imbillly tha.n oodc:ine. 1\ reporlcdly gll'es 00 evidence of dependence or addiction .... ith long-term usc:. Il~ principal advanwge is In the lo .... er frequency of ~ide effecls encountered With I\S uSC: . It is more effC!t1.ile than oodc:ine as un Iltltitussive and is used primarily rOl' this purpose [I is on tile market in many cough preparations. as well a~ en lab let and p;utfller.l.1 forms. II has also ~n marketed in an ion-exehan!J!e resin oornplCll form under the trade nall~ of Tussioncx. 'The complex release~ lhe: drug 3t 11 su_mined rJle mid i~ ~id to produce' effectil'e cough SUppreSSIon ovcr a 10- 10 12-hour period. Hydrocodone i~ also marketed in combination with ocetammophe:n (e.g .. HydrOo.."et. Vicodin, Lottab. and Zydone) and with homalropine as I lycodan. Although this drug found e~ te/lSil'e use in anl i tussive fonnulaliuns for many yeaTll. it ha.~ bc:c:u plocc:d under I~ SlnnlC'nl n:m:OhC regUlations. Oxymorphone Hydrochloride, USP. O~yrnorphone hydrochlonde, (- )- 1 4-hydro~ydlhydrotnorpll1none hydrochloride ( Numorphan), introduced in 1959. is prepared by deal'age of tilc: oom:sponding c()o(ko,ine derival1'e. It is used as the hyJ.lrochlonde 511lt ..... hich occurs as a while erytal1ine IJO"'der freely soluble in water and sparingly soluble in alcohol. In humun.~. o~ymorphone i~ as effective lIS morp~lInoe in one-eighth to one-tenlh the: dosage. with ~ duralion am a slightly lower frequency of side cfft!Cts. ~ [I has high ad dicuon liabllilY. It is used for the wnc purposeJIIS morphine. weh as control or postopc:~t;"e pain. pain of advallCCd noo-

to.

Oxycodone Hydrochloride. Oxycodonc hY ~';.: ride. d;hydrohydro~ycOOeinooe h)drochloride. i~ pr by the elllltlYlic redue.ion of hydroxycodcmone pt't'p.1Il'd hydroscn peroxide: (in acetic acid) oxidation of tloc! ThIs derivative of morphine OC'CUTll u a ... lUte powder (hat is soluble in .... ater ( I : 10) or alcohol solutions nlay be s lcrili7.l'<1 by bolling. Although is ahTIOlI' as likely 10 cause addictlOll as morphilll'. II is in the Uniled Stal~ in Pcrrodan and SCI'eral othc'r "",In in combination with aspirin or ocelamirlllpol':n. II IS used as a sed3ti"e. all an3lgesic. and I II<VI:Otk depress the cough renex . it is uscc.l111 3- 105-mg as an alUlI~sie in j- 10 l().mg ~. FOI' SC''m dosc: of 20 mg is ghen I marketed as cOl11rullcd-~ ICllse tahletJ.

:~,h;::;~:::;'

, II.

p'm.
I

in,ICC1 the rni:lture. Several overdose deaths frum this practice . leading to tighter conlrols ability.

~~~~-----------------------------------

.,,.,,
:0 mor-

Jdeme

coug h JI)' (in-

tetlilly.

f.iection
rochlonorphl'
lOr{>~y'

Dihydru.'OCkme IS oblimed by the reduction ofoodemc. 111c bnantlllc sail occurs III ... lIite cry51als Ilial are 'IOIuble in Wilier (1;4.5) and only IJighl ly soluble 11\ aloohol. Subcut:mewsly, II dose of 30 mg of this dru g is .lnlOSt equivalent 10 10 nil! of morph.ine Ill; III IIII3.lgesM:. \\ ill! fasler OII)C\ and negligible ~ide efrecu,. It lias addicuon liabdlty. II is available m oornbinalioo wilh
tifIInn or atellimmophen (ur pam.

Pihydrocodei~

Bitartra te.

Nom!tHphil'H!!. Normorphlllc may be prepared by N-deIIleIhylalion or IllOrphirlC. ,2<> I n h.uman~. by nonllal routes of adnllPI'\tr;lhon. it is about one fourth liS :lethe liS morphine
in producing IInalge.~ia btH hIlS II much lower physical !lepenikll(e capacity. Its lmulgesic e/Teets are nearly equal by the lIIlr1I>'('nlricu lllr 11)1.11<:. It doc5 IIQI ~j)ow the ).00.111;'11.' effects !If lTIOI'phine in single doses but does so curl\ulati.'ely. Normmplunc supprc~sc.~ tnc 'fIOIllhllle abstinence ~yndrorne in "dieb. but after itS withdrawal. it giH!s a 5Jow onseI and II Plrld form of the abstrllCoce syndrome. Ill . :It II was IJI1Ce considered for posSli>le use in the trelillTlent of narcotic adlIktioo. but it lia~ no current usc.

\ poIeu!

e \0 no >ic than
IagOfli~1

II LS light 5o:n5iu'e and turns green on exposure to air Ind hght. It is sparingly soluble in water ( I :50. 1:20 at 80") and in IIlcohol (I :50) and is very s lightly soluble in ether or chloroform. Solutions an: neutral 10 litmus. '1l1C change in structure from morphine to IlpomorphillC profoundly changes ilS ph~siological llCtion. The ctnlral depn:r>Sant effects of morphine arc: much lcSlI }ho,lOIlnccd. lind lhe stimulant effects are enhanced greatly. thereby producing e!lle!lis b) II purely centrdl ITlIlChamsm. It is adnllnistero:d SIlixulaneously 10 obtain emesis. It is ineffo:ctive orally. Apomorphine is one of the most effective. prompl (10 10 15 minutes). and safe en-.ctic~ in use today. Care should be cllerdS\.'(I in ilS use. howe~er, because it may be deP1'USIl1ll ill ulrelldy-dl:pres~ patients. It is cu m:ntly classified as lin "Of'JIhan drug" for U!iC in Parkin son's disease.

~ nalo~

u..... as

II

III "'Pier

)dobu1cavage

:Juration iabllity. !ne, TIle

;of1\rol~.

1'Illon or onunua al ~ij!n~,

Opium. An u tnlCt of opium. I;()nlaining a millture of the wl-al alkaloids of opium. is avuilable as all alcoholic IqUCOUS soluliorl. II i~ available lb Dwdom,ed Opium Tinelire (I S mg/mL of morphine base) and Paregoric (2 mg/mL allllOlJlhine bII...e). ~ ;u-e 11.-' primarily for the treatment al diafThea.
T I"Jmadol hydrochloride. ( !: Kis2- [(dill-.cthylamillO)n-.cthyl ] I-(mn-.clhoxyphcny l) C)dohellanol hydrochloride (UItI"Jm). repn:.o;ent~ a frogment f1f codelne 's structure . consisting of the phenyl and cyclolIoaM ring.~. The drug posses.o;es opioid activity but lias (XM"lII1aJb'fS.K: 1Ie"";'Y Ih~t;$ 1>(1( .... e~ by naloxone. TIle \N'CLpal effect i~ annbulcd to the O-demcthylated metabofitt, .... hich is 6lin-.es nl(R potent than the parent compound. III ob$crvation consistent with the diffcrcl'lC~ bet ... ttn coHIe nnd morphine. It produces 5ignifkan lly lower rnortiline-like sid.: effects. It is available in tablel form for use in rnoderate-to-~vere pain in a do!oe of SO 10 100 mg every 4 10 6 hour; and in combination (31.5 mg) with :lCctaminophen 11.1tnlCet) for shon-term ITlllnagement of llCute pain.

k 10 th~1

It higher

r'-'fmldof Hydrochloride.

....,

ulld bu lion. lind , caut loll ",.

;hlJlCry.

120 mp I1COOsly.
ntervlll~.

droch loJll'l!parcd

pored by

thebaine. l'sUlllill('

Aqueou~

this drug II i, "!)Id products

Apomorphin@ Hydrochloride. USP. When morphine CI" morphine h)drochloride is heated at 14(f under pressure 11th ~rong (3S'H) hydructlloric acid. it lose, a molecule of _iller and ~ ields a compound kllO ... n a5 apomorphine .

CH,

allie, To Joses and e pam. a or is al!.O

1010160

'"
HO
The hydrochloride
i~

ely. t~ II'\Ig use .... lems. lind

re:~"lted

OH

Meperid;rte Hydrochlorick, USP. Meperidine hydrochloride. ethyl l-methyl-4-phenylisonipecotate hydrochloride. ethyl l -melhyl-4-pht:nyl-4-pipo:ridintearbo,\ yllte hy drochloride (Dt-meml Hydrochloride). is a fine ..... hlte. odorless cry~talline powder that is .ery soluble in wattr. soluble in alcohol. and sparing ly soluble in ether. It is stable in the air al ordinlll')' temperature:, ond its aqueous 'IOlutiOl1 is J\OI dL,,"'OIl1~ by a short period of boiling. lbe free ba..;e 1II11y be made: by healllli benzyl cyanide with bis(,Bchloroo:thyl}mcth) lamine. hydroly(lIIg to the oorTCSpOndlllg acid and elIterifying lhc lauer wilh ethyl akohol.1 Meperidine first was synthesil..ed 10 study its spasmoly tic ch:intot1er, but il was found 10 have far greater analgesIC proprnit'.\. The spasmolysis is primanly due to a direcl papaverine-like depression of smooth IItuo;c le and. IIlso. to some action on para... ~mpat hclic nerve endinl!~. [n therapeutic doses. it e,\crb an analgesic effecl thai 1;1!lI bctwel:n those of n>Or_ phine and codeine. but it sho .... s lillIe tendency toward hyp_i$. II h indie-ated fOf" the ...,Iief of pain in 1nO:!;' p:.uent~ for .. nom morphine and OIhcr alkalotds of ClpLum genemlly are used. btu u IS especially ,aluable ... hen lhc pain is due to sJXlStic conditions of inld;line. uterus, bladder. bronchi. und loO (011. It~ mosl important U'<C !iCCms to be in IcssminS the severit~ of labor pains in obstctrics and, witli barbiturates or lranquili lers. producing amnesia in labor. In labor. a dose of 100 IlIg h injected imromuscularly as SOOI'I as conlfllCtio'lS occur regu larly. and a second dose may be ghen after 30 minutcs if labor is I'1IpLd or if the cervi .. is thin and diluted (2::2 to 3 em). A ,hird ~ may be necessary an hour or t .... o later. and at this stage a barblturole may be administcred 1111 small dose to ensure adequate umnesia forseven:tl hour;. ~Icpcridine possesses oo(he-IIOI1 liability. Psychic deptndclll.~ de'elops in individuals ... ho cxperieoce euphoria lasling for an hour or more . The de velopment of toleruoce has been observed. and nlCperidine co n be subslitoted successfully fOf' morphine in addicts ...110 a..., being treated by g!"lld. ual withdrawal. Funhcl1I1(lI'O!. mild w1lhdl1lwal symptoms Mve been notcd in CC:rtaill pen;ons ..... 00 hal'e bocome purposely addicted to mepc.idine. The possibility of depen dence is gn"'3t enough to put II under the federal narcotic 1 ..... ~. It i~ available in Qf:IIJiquld, tablet. and parenteral dos3 age forT1ls. AlphiJProdlfle Hydrochloride, USP. Alph:tprodine hydrochlonde. (-::!: )- 1.3-dimethyl-4-phcnyl-4-pipcridinol pro-

heiuvall-

odorless and occun; as minUic. glistrlUng, ... hire or g.rayi~h white crystal~ or ~~ a white powder.

148

\lid.wn IJItd

Gjn'UlJ '~

TUIOOoIt

of Or&anic ,lfro;..;",,! a"u !'harwt(l('rHlira!

CMmmn'

panoolt h)drochlonde. ;s P<'Cpartd by the method ofZleT1ng and Lec:.I:!'I1t OCCUN:I-~ a while crystallme powder that is freely !iOhlble ill water. alcohol. undchloroform oot insoluble 111 tiller. 11Ie compoulld is 1111 effec:ttve an.31ge;lc. ~imll;u- 10 mcperidine:. and of ~pecial value tn ~tetric IInalgestU. II appear.! \0 be quite ~fe for U'lt in Ihts capactty. cau~inJ lillle or no IT~pirutory depression 111 either nxMher or felus. It IS currently not marl.::eted in lhe United Siaies.

USP. Anileridtnt. ethyl I-(p-aminophe ncthyIHphC'nylison;pe<:otale (Leri line). is pR"pared by lhe method ofWeijhml 1:1 al . t lO It OCCUN M It while to ydlow.sh white cry'>l3l1ine powder that is fn:ely soluble in a1coool but only very slighlly soluble an Wilier. It is OXidized on upostilT 10 air aod light . The inJ~"Ctlon is prepared by di~solving the frtt b.:lse in phosphoric !lCid sollilion. Anileridine is mOlT llCl;\'C than meperidine and has the same u!>Cfulness and hmi tutions. Ils dependence capacity is less. and il i ~ considercll II willlble subsutute for meperidine. [I is currt'ntly nul markcted in the Unilcll SIUU:S. Ani/eridine Hydrochloride, USP. Anilerillinc h)drochloride. elhyl 1(JImninophc:llClhyl)-4 phenyl isonipo'1:otutc dihydrochlorilk (Lcritine Ilydrochionde). is pn:pared as cited for alli1eridine. cxcept thaI it IS convcned to the dlhydrochloride by CQI1\'clltiooal procedurt." It ocellrs as a whitc or nearly I'. IUle . CT)'~lallil1C odorless powder that is SllIble in air. It is freely soluble in wmer. sparingly Mllublc io alcohol. and practically insoluble in f1ht:r Ind chlorofonn. Thi ~ salt ha~ tile same octil'ilY as unileridine. It is currently 001 marketed in tIM! Uniled Stmes. Hy drochloride. USP. Dlphenu~ylme hydrochloride. ethyl 1(3-cyano- 3.3diphcn)'lpropyl)-4phcnylt~ipecolale mooohyliroch ioritie (LooIOtII . Lonox . Loge" . !..omallllle). occuno as a while . odorle,s..~lihlly wilteT' ''I>\uble powder wilh nodiMinguishiog IlLSte. Although Ihis dnJg has a ~lrOng ~lnlCHlmllT[ulloo"hip tu the meperi dine-type analgesic , it Ius \ 'cry little. if any. sllCh oct.\ ity Itself. l\li most pronounced acti\."lty is ils ability to inhIbit t.'(ce~~he gastrointc ~tinal moti lity. an llCtivity reminiscent of the constip;lIing sICk l'ffcn of morphine .\litlf. In\'CSliga IQI'S have demonstrated lhe possibihlY of addictioo .J , )6 particularly with large doses. but vinually III sllldies using on.linllry dosage !clels show nonaddictlOO. Its safety is n:~led in i\li classification as lin ucmpt narcotic . wilh tile waming. howe\er. lhal il rna) be habit fonnmg. TQ dIscourage possible :tbu~ Qf the drug. the comnlCrcial prodllCt (LomOlil) once contained a subtherapcuti c dose (2j J.lg) of alropine ~1I[fale 10 each 2.j mg tablet and in each j mL of the IlQuKi. which contaillS II liko;l amount of Ihe drug . II I ~ mdicaled m the QI'lII t,,"al!1lCnl of diarrhea resulting from a variety of C lIU-.es, The uSllal illil;;11 adllh dose is j mg 3 or 4 li~ a day . with the maintenance dose usually substantIally lower and indt vidlllll1y determined. Appropri lite dosage schedules for chi Idrcll nre available in the munu' factulTr' s lilcratulT. The incidence or side eHeels is IQw. but 11M! drug should be used with ealllion. if II aU. in patients with impairell IM!pallC funcllon. Similarly. paliellts taking batbitur.llcs con cumnlly wilh the Ilrug ~1l(JIlld be observed car'l:fully, in view of ""pons of b;u'billll'lllt to.dC.ly uodu lhese circums.t:l.llces.
Diph~no1tyla t~

An i/erid;n ~,

Loperamidc~)Go l operilmide Hydrochloride, USP. chiondc. 4-(4-chloropheny l }-4-lIydro~ y N.N-d. IMlh)I_ d iphcn yl l -p Iperid incbu um:IDl idc . 4.(4.JI--chlorophtn) 1-+ hydrox)'pi pendi 00)- N.N -d ImC1h)' I 2.2-d IpIlen) Ibut)'JWIIICk hydroclll(rnc ( [mOOium ). II hybrid of a nlClhadone U lc" nlCperidine molecule. is c losely rdated 10 diphcn'u)bIc btl is n1()rC "Pt'Cific. lillMe poICni. and longer acu",. II d . WI anudiarrllcal by g direct effect on too c ircul~r and \onJ!Iadin:al IIItestinal mliSC Ies. Afler or.al adminlstlauon n ~ peal. blood le"cI, Within 4 houN and has a \'cry long pp.'_ half life (4{I hours). Tolerune e to its effecls has not Ixa observed. 1)1 Allhough It has li ho..... n mlllmllil eNS rirtdt il has bc(,u controlled IInder s\:hedll[c V. LopeI'1lll1><Jt a IIY1lilablc as 2 mg capsule ~ (l.operantidc hydrochloodc llP' sull$. US!') for t~3t"lCm of acute and chrome dlarrhea.ltt\- ommendcd dosage i~ 4 mg initial1y. with 2 IIIg aflfl'w loose 51001 for a rna.( imllrn of 16 mg/day.

ElhollCptUine crlnllc. hexah yllro- Intcl h~ 1-4- pheo)'1 1, 1-IIl.cpi ne4-carbo~y,* II rule. l nlCthyl-4-carbctho~y-4-phenylhaamethylenlm. cilrutC (Zactane Citrate ). i~ cffccll\'e 0I"J.11 )' Igamst pain in doses of j() to 100 mg. WIth nllmlnal side ~h Pa~nleraJ adllllOl Slrution is limited because of centra! IIlIIIf[aung eff~IS. [I appean to have no lKkll ctioo hablLny." tox ic ~action , have occurred with larll~ doSt'~. A doubkblond '>Iudy III hum. 1M ruted 100 rng of the h)'drochlonoJr equivlliem 10 30 mg of codeine and found thattheaddiuOId 600 log of Il.<pirin increased IInlllgcsic effcclt\'CfItM 10 II ano4hcr study. II dose of 150 mg WlIS found equal to ~ of propoxypllcllt:. with both beller lhun plllCcbo,l)! 11,. OI'ICC: available as a 75 m, tablet and III combmallort. 600 lllg of aspirin (Zacurin).

Ethoheptil~Jne

Citra te.

Fentanyl Citrate, USP. Fentan)'1 citrate. N.J. I ctllY1-4_pi fJ"rid y[)propi ooani [ide e . trllle (Su bli mau J. as I crystalhne po.. dcr w1uble in WlIlcr { [:401.00 and simringly soluble in chlorofonn. Th.s n-Qvcl 3Illlidt .. ri\'alh c ha~ analgesic activil)' j() time~ lhal of mOfp!utU humuns!l lt hIlS II very rapid on'iCl (4 mm)and WIort of action. Side effecls ~in1i1ar to Ihose of other polen! 1WIrcsics are conuoon. panicu[arly respinuory lit".. "'. brndyeurdiu. It i ~ lI~d primarily PS an adjuncl to a For U :ti. neurolcpumalgl$ic In surgery. it is SC eombmalion wilh the ncuroleptlc droperidol (InnQ'iar), k also availabl e liS II transdcnnal release Sy!it~ m 3110tal dose Ie,'cls r.angina from to 100 m!) for mcnt of chronic pmn. [t ha~ dcfJ"ndencc li ability.

:ro

.,lJbII!r. (Ou"",.

AIf~nta nil

N r I
[;

'1 I to fcmanyl , lt i used as primary ancstht:lit: or as an the i . or ant'. thesip. II has tile ~~ . alld .. ide errecl ~ a.~ fen!allyl. It is available II' an (0.5 OIg1mL). Remifentlml

1dn)o-

(1" fl-

WUttural analogue or fcnlan)!. h.u similar plOpCllles and is also used in an.e.~thcsia. II is ayai lable lIS an injeo:\ion (I mgt

'1l4milk e lind e btu

"'-I.
Sufemanil citnlte. N-I4-(n'l('lho"y_ meth) I) 1- 12 -( 2- ullenyl )ethyl !-4 piperidy IJpropionamhdc. mnue (SufenID II ~Iructural unalogllt of fernany!. has simi). III' properties and i\ also used in llnes~ia.. II is ayailable Man injcclion (0.05 mglmL).
Sufent~flil Citr~te.

e'S

as

'i ,lu acnes a.'nl<l

I~

","" focts_
''J'
Reccach

Klc

ethy l ci l"nllnt rille fftc;ts.

~tlnlU

'1, hut

oubkde "lit OOnof J."" In ~5 illS

II \',1..\

1 "'llh

.plle n~'(:u'"

thanol ok doIiI1C' in )rULion nall!cnand

jhc~ia_

!ble In ). It i_ IIt'lc. mage

Hydrochloride, USP. Methadone hydrorblorKk. 6-(Dimethylamino)-4A-diphcnyl-3-lWi'ptanOnt hy_hood<: (Dolophine Hydrochloride). occurs as a biller. ,h,le cry~tall i ne powder. It is <,(Ilublc in water. free ly soluble . alcohol aml chloroform. and inwlub1e inetller. Melhadone slnthesi;tCd In several wlys . The method of Easton CI .' ) b nOleworthy . in thai il avoids the formation of the roubIel;ome iwrneric ,nlemlt<hate arninonnriICli .... I U The I113.lgesk effcct and OIocr morphine-like propcnic~ an:: exlIib!tcd chicny by the ( -) fOIllI. Aquoous 'lQluliOlls are siable lid mal be sieri li1.ld by heat for 'Otramu>cular and imravelOllS U!it . Like all amine SIlIt~. il is inconlp;!tible "' ith alkali and salIS of heavy mela15. It is !IiOII'I('",hal imUlling v.-toen ..jected suhi:utnneoo.ly. The toxicilY of methadone is J to 10 limes thai of mor pIn~. bul ils analgesIC elTect i~ IWice lhlIt of morphine and I(\UI1lc:!Ithat ofmeperidinc. II has been placed under federal lIIt'OIic eOlllrol becau!oe of;15 high addic'IIon habilny. Melh1IIone;~ a ~I cfrcclive :ma 'Se.~ic. u~ ,0 alleviate 11I0ny !)'~ of pain. It can repltlCl! morphine: for the re lief of with....-aI 5ymploms. It prodlltll'> les~ sedatioo and na~is dLm lllOI'pbinll and 3ppeW'!l to Iull'e fewer \ide reactions in !midden pauenlS. Melhadone i~ especially "aluable in JpIIiITI of the unnary blllddc:r 3nd in IIWi' suppn:ssion of the cwgh rene~ .. ThI: /,,'0 iSQmer. leyalK)l1C'. reponedly does not produce IIIphoria or OIlier morphine- Ii ke sensutions and has been adlOCated for the trealrnem of addictS.'J.! MClhadone iHelr is llkllqu,'e eXlen,;\ely in addict m:alment. although not wilh*101111: controvcrsy."l It ~upprcsses withdrawal elTcclS ., is "'idely used 10 maintain former heroin addictS during tis rrnabililation . Large ckKcs nre often used to "block" .. effCCIS of heroin dun ng treatnlCnl. 11le use of methadOlle ftaung addlCIS i~ ~ubjeclto Food nnd l>rug AdminiSlra... (AM) regulation s th;!t requ ire special regislrJtiOll of ,t:)~ans and dispensc:n. Melhadone is avai lable for use III analgesic. however. under the: usupl nan:OIi c require-

Ifkoth~dofle

by il!i demelhylalion lhe dinor IlIctabolile. which has simi lar Pf'OIX'"ies.';e.. ,'1 Beclluse of the need toadmini sler melhaOOoe daily. which tlloonvenienct's the maimen!lllcc flIltienl and leads 10 Wicil diversioo. the loog-acling LAAM II--'U act"'ely In'eStip,ed as an adWc:1-maintellllJ'lCe d1\lg 10 replace melhadone. Generally. !Ill 80- to 1000nlg dose 3 times a ",eek $uffices for roul lne: maintenance.'!. n. ~ f1)A ~ approled the dNg for use. and it i_~ mlln-eled as ORLAAM in solution form ( 10 mg/mL). By I~w. il can be dispensed only by treatment programs ccmfied by the Dcpanmcnt or Health and Human Serviccs' Sub~:tance Abu<:e and MenUlI llealth Service:!> Administnlllon and regislcrro v.-ilh the Drug EnrOl cemenl Ad miniSirutiOll. [tllISQ carrics a warning about pos,lble serious CardUlC IIrrhYlhmia. 11le ncc:tnate of the nontlCtaboJitt. \lOraeylnlClhadoi. was once snldied in the clmic as a pOIential IIl1alg0.:51<:. I '"

Thi ~

,s funher accentuated

,0

PropoKYphefle Hydrochloride, USP. Propo~yphcne hydrochloridt:. (2S.3RH + )-4(dimelh)'lam ino)-3-meth~l1.2-diphcnyl-2-bulaool propill1OOte hydrochlonde (Darvon. DoIene:. Douphcne). was introdueuJ into therapy in 1951. It mal. be prepared hy the method of Pohland and Sulliyan . 1 It occurs a~ II biuer. white crystalline powder th.~1 is frec:ly 50Iuble in Wilier. soluble in alrohol . chloroform. and acelOnc:. bul praclically illwluble in bc:nl.cne and elher. It is lhe a-( +) i-SOl1lCr. the 07-( -) isomer and ,B diascereoisorners are far less polenl in analgesic acl iyity. The rr-( - ) isomer. I~l'(.>.. propoxyphenc:. is an effC:Cli~e !IIltitussi,'e (sc:c: below). In analgc:sic polc:ncy. p!'Op(U:YP"tne is DpproliimalCly equal 10 codeine: phosphute and has a lower frequency of side effects. II has no antidiarrioc:al. antitussive. or IIllipyrelic effcci. thus dilTering fmm mos! analge\ie agenlS. It can suppress the morphine absti nence syndrome in addicts bu, has shollin a low levC'l of abu.-.e because of il.s 1000ielly. It is not very effective in deep pain and apPears 1 be no more elTec0 live in minor pain than aspirin. Its wid!:~pI'ead U'iC' in denIal pain 5eCm!I justified. since aspirin is reponed 10 be rei"" \.t!y ine:ffccti yeoIt has been classified as a narcOlic and controlled under federal law. It does gi"'1e some euphoria in high do!;es and lias been abused. It has been rc:sporu;ible for numerous oyerdosage deaths. Refilling the ~scrif1l;on should be avoided if mi~u<;c: is wspeclcd. It is al'1lilable in sel eral combination product~ with I,spirin or lICo.:IamillQPhen (e.s .. Wyges ie) . PropoxypMne Napsylate, USP. Propoli ypherM: napsylate , ( + )-a-4-dimethylamino-3-nlCthyl - I.2-dlphenyl2. butanol propanoate (ester) 2- naphlhyl e ~sulfonale (~ lt l (Darvon-Nl. ii very slightly soluble in water. but soluble: in alcohol. ehloroform. aml ~Ione. The napsylate salt of propoxyphene was introdut.'W shortly before the PlItcnt on Darvon upired. The insoluble sal, form is clallTlCd to be less prune to aooJ;e because il canllOl be readily dissolved for injection and. OIl oral administralion. gives a slo....er. less pronounced peak blood le .. el. Bccause of its mi ld narcOtie-like propenies. it lI--aJ once invC:SlIgated ... an ~ict-maintenanct' drug to be used III place of rneth:ldooe. It was hoped thDl it would provide casier withdrawal and sen.-e as an addk'1-di:loxifl('atioo drug. Unfonunately. to.llc:1ty al higher doses has h mited Ihl s opplK:a-

oridc.
~h ~"

Itvomethadyl Acetate
I

pottnt ncl In JIC" iC\ cehon

. occurs as a of ( + )-mtthadonc: ~ylatioo. Of the four possible methadol ,somers. isomer LAI\M has the unique (.:hllOll.:te ristic of I lI.'lfCOlic effen... EJtlCnsjve rntU,OO!lave Wown thallhis i~ dllt 10 ils N-dc: nlCthyl (- )-a-acc:lylnormethadoJ. which is more pOIent Illi p.1Il'nl. LAAM. and posM'SliCS ~ l(H1g h.tlf-life.' ''' by

.,dro/ipe n ..'a). a

11011_

It,s I\lUlablc in oombin.:uion with DCClamioophen (Propacet. D3r\lOCd -N).

Levorphanol Tartrate. USP. Gre..... e made: the basic "1ud,c:s In the syn1hesi~ of compoundi of the type of levorphanol larmlle. (-)-3-hydroxy-N-methylmorphnt:ln bitartnlle (Lc~()-Dromoran). as mentioned pbove. Schnider and Grilussner ~ynlhesi1.ed the hydroxymorphi nllllS. including the 3-hydroxyl derivativc. by Similar mcthods . The racemic 3-hydro.\ y_N ,ncthylmorphinnn hydrobromide (rneemorphllll. (j: )-I)romorJ.n) ..... as the original form in which this poIent analgcsic wa., i ntroduc~. Thi s drug is prepared by ~Iution of racelTl(Jl"phan. TIle le.'O compound is avai lable In Eurupt' under the original lIame. Dromol"lln. As the lartrate. " occurs in the form of coIorkss crystals. 1lJe !.all is 5panngly 5OIuble: in "'3ter ( 1:60) and is insoluble in elller. 1lJe drog is used for the relief of !!evere pain and is ill many re~s similar ill its aclions to morphinc. aCC"plthal it is 6 1 8 times as potellL TIle addictioo liability of levorpha0 001 is as great as thllt of morphine and, for that reason, caulion shou ld be observed in its usc. It is claimed that the ga~troj,lh.;.\ti"al effccts of Ihis compound arc significan ll y lower th an those e.\perienced with morphine. Nalo.\one is pn effcclLvc an ti dote fOf overdo_\.IIge. Lcvorphallol is useful for reheving seven: pain origin uting from a multiplicity of C'J.u-c_ (e.g .. inoper.lble IUmot""$. severe tt1lllllUl, renal colic. bil iM)" oohe). In orller words. it has the sanlC fIlnge of usefulne~~ as morphine and is conside~ an acellent sub:5tilute. It i, supplied in ampuls. in mult,dose ~ials, and asoral tablets (2 lI1i), The drog re<[uiI"CS a rwrotic form.
8u torphanol tllftrnle. 17(c~lobut yl-melh yl)lIlOI]lhi nan-3, 14-<1101 1>-(- )-tartrale. (-)N -cyclobut y hnelh y 1 3. 14-di hydro.\)' nH.Jlllh inan bi IlIf1rnle (Stadol). II potcnl analgCliic. occurs as ~ white crystalline powder wluble in wnler and sparing ly sol uble in alcohol. II I~ prcpan.-d from the dlhydro~y-N- nonnorphinan obtained by" mooific31ioo oftht Grewe 5yn thcsi~. It is lhecydobutyl an:tIoglJe of levorphanol pm! levallorphnn, and is as potcnt an analgesic as the foonc:r and a .sonlC .. halless active anlllgonl,\1 than the laltef.

and on the hellf1 ..ort.load. It should thus be used '" IIh CWo lion and only with patients hYpc:niCruiiu>'e 10 .. far the lrCalmenl of myocardial inr:on:tioo or other caninK ~ krm. Other ad~erse effects include a high ,nc.dence ofoela tion and, le:ss frequently. nausea.. headacbc, vc.-n,co. and W:. l,ines$.'1 It 15 available as ~ parentc.-raJ for intramuscular and II\U"aI'rnous adminiS\fIlliOn in II dose of I or 2 mg e>el) 3 til 4 hours. with II nlll.\imal single dose: of 4 mg. It is al-.o DvailJblt as a na5ll1 sprny (Stadol NS ).

""pi".

8Uforphanol Tartrate, USP.

8uprenorphine Hydro<hloride. BUprcnorphlllC~' drochlotide . 2 1~yc.-lopropyl-7 a-[(S)- I hydro.\y I.2l..... melhylpiopyI1 -6. 14 _ endo-elhano - 6, 7.8. 14 - letrah)okoIIipavine hydrochloride (8uprcnex). IS a rwpidly aCIIIII. a. tnllly leling anaIgesie in lhe agonist - aolagOlIlWl cla.\f.. III> about JO tllnes more potent than morphine . It is .,..bIIk for IlUung modernte-t()-'ie\ere pain as a parenlc.-1'lI1 for intrJ. muscular or ;ntt1lVeIlOllS administration In :\ dose 0(0.3l1li every 6 houl$.. After several years of in>'estigalion for u<;c in trealllll lIPoid addielioo . buprcnorphine, alone or in combi nation "0 na l o~one. has bcef\ approved for use in :I highly rtgulMd treatment program called OjJict' B<I:'eJ O"ioiil Trro,.".. (OBOT). Under fedenlilegisl:uion. the Substllnce A _ _ MenIal Health Administrations Center for Drul Abw T reatment has established crileria and trnin.~ prOJrllml" priYllte physicians to admilllSiet" these 5pCC.al ~JC ~ to opioid addicts. TIle intenl of the PfOl!t1lm IS 10 m.ole_ rnent available 1 pcrsoru; woo are nO! IIlely \0 M'(~ ca0 ment in traditiona l IreDllnent clinics. such as adok"'~. ,,,, execulheli, and the Io l e.

Dezoclnfl.

De1.ocine. (-)- I 3,B-amino-5.6.7,8.9, 10.11G.

12-oct:lhydm-5a-mc: th yl-5. I 1_mc:lhanobenJ.(lcydOlkcI'll-J. 01(Dal gan). i~ n synthetic agon ist-llmagoni~t analgC'>II'. 1II an unusual ~troeture. II is similar to morphine in WINpotency und durJ.tion. It produccs fe"'c." side effect'" du>: ..
ilS amagoni~t actl~lty. wllb Icpofted mmimal ~ capacity. It is available: for lreating modcr~te-lo-!;C'm' ~ as a parenteral for IIItnimuscular or intrn>ellOlls ~",imltlJ lioo in a dose of 5 1 020 mg c'ery 3 to 6 houn.

, ,

HO
The on<;et and dumtion of action of the drog are comparable to tho<;e of lIlorphine, but it has the ad~antages of sho ..... ing a maximal ceil ing effect on respiratory depression and a areatly reduced abuse liability. 1lJe injec1al>lc form was marketed without narcOlK: controls: thiS product w~5 oonsidered for plxement in Schedule: IV . however. because or tq)OI1ed m,susc: InU lack of rccognllJon of its potenual abuse habdity. TIle drug ha~ alw been used illegally for \loping racehoric:s. 8utorphanol shareli the alh"elK hemodynamic effectS of pentll7.ocine, cau~ing illCl"eased ~ure in spedrlC lIfteries

Na/buphlM Hydnxhloride. Nalbuphll!e h)dro:tIk ride, 17 -{cydooutylmethyl)-Ua-cpoJ.ymorphl .....1.M 14-triol hydrochloride (Nubai n). is a COfllbinauon oflht(lt~ morphine nucleus and the nitrogen substitll('n t of buttqJIt11(11. [t is a potent unalgesie of the agomst- anlagoni>l tV.~ si milar 10 morphine in potency but with an abuo;e pot(1Ii ruted less Ih;mthDl of codeine. II ;s useful in tre,llIn& rno.leI ate t()-scvcre pain and is !Ivailablc for parcllterJI usc "ltllI USllal dose of to mli10 kg cvcry 3 to 6 houfli. Pentazocine, USP. Ptnuazocinc. 1.2j.4,S,6-hrut,. droc.-Is-6, I I -dimethyl - ].(3-methyl -2-butet1)"I}-2.6-td ano3 btn1.....ocin-8--ol, cis- 2 -dimethy lall y 1-5,9-d1 mediI'! hydroxy-6.7.bell/.otTU"phan (Tal ... in). occurs ~ I .. crysllll hne powder Ihai 15 insoluble: in water and"~::: soluble in alcohol. It forms a poorty soluble: h)iJ salt. but is ~adi l y !iOluble as the l;lCtatl'.

, , ,

< p

", h

" "

p'

"

Chaptu 22 1t .... /~.$ic A~NS

757

,
,

J>t,nllu.ocinc: in a p;an'l1u.'ml do'-C of 30 mg or an or,,1 do:se of SO mg is about as effective us 10 mg of morphine in most pa! ienL~. There is some e~idcncc Ihal th-c :lI1nlgesic IIClioo tl'\ides princip;aU} in th-c (-) i'o()tllI.'r. and a dose of 25 m~ IS ilpprOx unalcly equi,nlem 10 10 mg o r morphinc: sulf~tc. Orcasionnlty. doo;etof 40 to 60 mg may be rm1nred PentalI)Qne'~ plasnl:l half-life IS about 3.5 hours.. tO Allhe 1 0000CI'" dosage levels, it appem; to be .....elltolerated. although JOmC tabllon occu~ In about one third of pel"!KJrl~ rei~mg it_ The incidence of other IllOI"phlllc-lilc side effects is as high a with morphine lind OIher narcotic Wlalge<iej. In paticnt5 .110 ht,,"c beel1 n.'eeivlflg other narcot ic annlgesics. lnrge ~s of pentazocine may precipit ate wilhdmw ~ 1 sym ptoms. 115bow5 an equi,alent or gn'ater respiratory depre..slUlt acu'lIy. J'enta1ocine has gi'en nse to a few CI.)('.S of possible drptndence. It has been placed under control. and it5 abuse poImuaJ should be n'coglllzoo :and close Sllpet"'ISlon of ilS N mamtained. Le,aJlorplmn cannot !"eler.se lIS effects. although naloxQrk' can. !llld nlC"thyl phcn idate is recommended M an 3ntidOie for o,~ge or excessive rt'ipimtory

of unde~ir.lble ~ycbotic effecls. Bc:cauloC of these propenic\ arid the avatlnbilny of allemate antagooists. it ~as withdrn ... n from the mar kel.

t._

Leviillorphan Tartriire, USP. Levallorphan tmmte. 17-(2-jliotlCnyll-morphin.:m-3-o1 lanr.ltc:. (- )-N-ally l-3-hydroxymorplu nan bllllrtnlte (Lorl"an). occurs 115 a ~hl1c or practical ly white. odorless crysUllllne po~der. It is soluble in " 'atCl'" ( I:20). q>anngly ooiubk m alcohol ( I:(0). :and practically insoluble in chloroform arid cthcr. Lelallorpban resembles nlliorphinc in ib phannacological aclion arid is abou t 5 t itnc~ more effective as a narcolic am agoni,t. It wu~ uo;cJul in combination wilh analgc.~ic~ such as meperidine. alphaprodine. and IeYorphanol to preyent the n'spimlory depression usually as..soeiated with these drugs. It i~ 00 looger marl eted.

Nilrcotic Antagonists
Naloxone Hydrochloride, USP. Nalo~onc hydrochloride:. 4 .S-epoxy-3.14-dih)dro~y-17 (2-propenyl )morphman6-one hydrochl oride. N-ally l 14-hydro~ynordihydmnlorplu none hydrochloride (Narcan). NallylnoroxyrHorphorlt: hydrochlonde. is presently on the market as tbeagent or choice for tn'ating narcotic ()\ erdos.age. It laeb not only the analgesic activi ty sIIo ... n by other antagonists, but also all o r the 0Iher Igooist rffed.'l. It is alntO!ll 7 limes more IICti'e th;an nalOl"pi1ine 111 Intagoniling the effech or morphine. It shows 00 wi thdl1lwal effects after Iong-tenn IId.rn inistr.ltion. Tllc: dUratiOiI of IICtiOll is uOOuI 4 hooOl. It ... a~ brie n y investigated for the treatl1lCn t of IlC"ro in addiction. With adequale duse~ of nalo~CMlC, the add ict docs not ra:eivr any effect fmm heroin. 11 is glYen to Ill! addlCl only after a detoxificatioo period. IIlI )ung-tenn u(' rulnes$ is cum::ntly limited because its short durntioon or action reqUI~ large oml doses. Longacung. alternati ve antagoni.'its arc: alailable (fable 22-5).
Cycfa~o<lne. CyclllZOCine. 3-(cydoprop}hncthyl)-I.2,). 4, 5. 6-he X~ hydru-6. I I-<li nlCt hy 1-2 .6-me thallo-3 -bcnz.azocHI-

J-

de:~l'sion.

Ptntalucine as the I ~tutc is availab le in injccdon fOflll l'OIIIli ni ng the base equ llalcnt of JO mglmL. btlffcred!O pH ~ 10 S. It M10uld not be nllxoo ...,ith barbiturate!>. Tablets of ~ mg (as the h}drochlonde In oombinaoon ","h naloronc 10 prevent abuse) are ayallable for oral IId.lm nistrallon. II is 100 Ivallable in oombinat1Oll with aspirin (Tal ..... in Comp,xnd) ~nd ""h ocrtarnmophr n (T alaccn). Mcthoirimepr.ume. (-)IO13(d i mcthy l ~ l nino)-2-me t hylpmpyl )-2-mel hO~Yflhc no lItwinc (Levoproll"lC"l. a pllcoot hia.l.i ftC derivative: close ly reIIttd 10 chlorpronullIllC. fI'OSsesse~ strong analgesic acll~it y. r\D IIItramuscular dose or IS to 20 mg i, equal 10 10 mg or . . plune in human~. It h;asnot shoown anydc'pcndcnce liabilIIY MId appc:u'i not to produce respiratory depression. Tllc: IWISI frequent side effccl'l an: simIlar 10 those: of phcllOihiiiiII(' trnnqui lil.rrs. namc:iy, IICXbtion and orthostatic hypoem,ion. 1llCSe often n:su It in diu. ness and faim ing. Ii nli ti ng tie mil: of nlC"lhotrimeprMi nc to non:.mbuI Hlory p<1tic nts. It *'uld be used with caution along wilh antihypcncnsiYe5. IIJOpine. and ()Iller scd:.t;'cs. It shows ~me advantage in JIIIImlS ror whom addlCtlOO and respirntOf)' depression are
probIem~ I'"

M/!!ho/rimepraline, USP.

l-

..,

I"

.m n-

", <

11-01. ds-2-cyciopropy lmethyl-5.9di mClhyl-2 -hyuro~ y-6. 7bcn7..omorphan, is a poI~nl narcotic antagOlli)t that has sIIo ... n analgcslc activity in humans In I-mil OOloCS. It once: was inlestipled as a clinical analgesic . It doe!; possess hallucinogenic \tde erfects at tugherdose'i. ~hich limited Its userulncssllS!IIl analgesic. II W8.\ jtudied lile naloxooe in the treatment of Dan:otIC addiction. Voluntary trralmc:nt wnh cyclazocine deplwes addicts of the cuphorollenic cffccts of beroin. lis depel1d.:oce liabili lY i~ I()~'cr, and the effect.> of wi thdmwal develop nWJre slowly au<.l Un' nHlder. Toler.mec devclops to tile side cffecls of cyeill1.I)C lne. but not to ih ant:lgOlliSl effccts. I' 1 The rffecb are lonl1la.\ling and are nOl reversed by other antagonist.> such I i nalorplline . It ha.~ not
~n mar~etC(i.

!'> ,.-

"-

..n::otk "-u gonlsls

/l.llorphlne Hydrochloride. USP. Na lorph ine hydrochloride. N-allylnormorphme hydrochluride. mlly be pre pam! according to the method of Weijhltd and Erid.....o n. 12tI h OXCUI"li in the form of " hite ()f" prnctically while crystals IbII ~Iov. l y darl:cn 00 e~po.o.ure to nir nnd light. h i~ f~ly Vlluble In walCl'" (I :8). <>pann8ly soluble in alcohol ( I :35). aI almost insoluble in chklroform and cther. 1be phenolIC Itj*olyl group conrel"li "'lIter <olubili ty In the presl'oce of filed allali . Aqueou.~ ooiuhons of the salt are acid, wi th a pl1 of fibout S. l\~lOIphine has II direct 3ntagonistlc e ffect aga mS! morFltJJlc. meperid ine. nlClhadt)l1C. lind levorphano l. It has lill ie .agonistic effect to"'ard barbi turatc or ge nel'lll anestheti<;: *tnsS.on. ho ....e\er. It h;a~ Strong analgc,~ic propenies. btlt ii l'Ol aoccptable for ~h u<.<: owing to the high Hlcidencc

h,-

aliS.

"",

~,-

,h. 2'hlle

~,

Nafrrexone.

Igly

no"

17(eydop!opylmcthyIH's a-cpo~ y-3.14-dlh)dro~)"morplllnan-6-ooc. N-cyeloprop} lmethyl-l4-h~dro~)"oordi hydrol1lorphlnonc. N-cyelopropyl nICthylnoroxymorphone (ReVin. Depade), a naloxone nna logue. h.1S been mmtetoo a.~ the pn'ferred agcnt for tn:ating rOlTner oplDte 1Iddk.1S. Orul doses of.so mg daily or 100 IIIg 3 times weekly suffice to blncl or protC<1a patient rrom

Naltrexooe.

TABLE 22- 5

l'Iap/ef..y ~me
LAooI')pI_lliOIti'... Nf

Narcotic Antagonists
Uwal Preparationl
~pI_l

Uwal Adult Dose

N 1 '"IiI. Iq: Efled _
aI
10- 10 15-llVIlIAe ont ...... ~

.....

Dose

taIIl_

Lorl8n

ro,&C1l(n, NF

500 ,,1J-2 mg.

1q:Eled. ~ III)(SIIW'/

_.
at

u'" n',

N+ ..... Ilydo:l ... odIt

"",,,,,usp

f'8renlertol. 4OO"'1iI

I .... m~ 2- 10 3-onrue inllIfY8II.

OC&-Olmgn 1lf)OOIf" 10 II Inpr.. ory dep 11)\ 001 "",_Uti

'*'

the ~ffects of herom. Its mctabolism. I" . I"" pharrnacoki nelics,''\(! and phannllCologyl' l have been studied inrensely bccnu"Cofthe tremendous gO"emmenlal inlerest in developing new agents for the treatment of addiction. ' It is nvailable os 50-ml! tahlets (ReVial for U'C in treating narcOlicaddlCtion. It has also shown promise for suppres.~ing eranng in Lhe LrtatmC'nt or alrohoilsm and is available fOl" thatll<;C. Sustluncdreic:asc or tlcpot dosage forms of naltre ... , one were once invc.'i.ligated to avoid Lhe recummL dcci~ion on the p:lrt o( the foroner addu:t of .... hether a prutectlilg ~ of anlilgoni'l is needed ... " l

ues of the I'13rcOlIC agents Some of these: OCt In

I~'"

NlJimefeM Hydrochloride. Nalmefene hydrochlOf1de, 11 ' ( cyclopn.>py ImClhy I) 4 ,S ","e POllY 6 meth y Ie ne morphl nan), 14-diol hydrochloride (Re~eJ,), is the f>.nICthylenc an alOlI.le of nalOllOllC. It is the latest pure antagonist to be introduced for use in revcrsing the effects of oploid agOI'll IS. It is longer acting than naltrellOfie and is used for lhe ,oonc Lndicatll)l1S. It is Ivai lable 15 an mjection (0. 1 and 1.0 mg/mL).

a/Mrs.

Sc''eI'1I1OIhernatOOlic antagonises Iut\t betn In\'i:Sligated (e.g .. dipreiKKph lOO1S] and o~Llorphan).I~

ANTITUSSIVE AGENTS
Cough is a protecti'c, physiological relkx Ihat occurs in he~.lth as well as in dlo;casc, IL IS \.ery widespread and com monly ignored as a mild symptom, In many condilions, Imw, e\'n , It is dc.\lnIDle 10 take me3.~ures to !"Wuce C'.I'.~'eSsl\e coughing, Many etiological faclOl"$ cause thl~ refle~, and when a cough has been presenl for an e~tellded period or lC('ompanlCS any unusual symptOOls, the pC'l'SOO should be referred to a physician. Cough prt'p:lrJtions art' widely :Khcr tised and often sold ind iSl,!rionillalciy: the: phannacist must warn the public of the inherenl dange"'. Among the agents used in the symptomatIC COIl\ll)1 of coug,h are IllOS(: thai act by depressing tile ~"OUgh center 1 0catC'd In lhe medulla . 'I'IK!sc havc been temlC'd anodyn~s, cough JUppUSJlIIUS. and an,rlllly aCling anll'USS,.C's, Until l"C(:C'ntly, the OIlly eff~'Ctive dfLIgs in thi~ areu were n"rt'01 IC analgesic ttgenlS. 1be InOI'e imponant and widely used ones 31'C morphine. hydrolllOl"phone, codc'inc, hydrocodonc, meth adone, and Icvorphanol, wh kh are di scussed abovC'. In ~nl years. several compounds hnc been symhesi1.ed tIt"t possess amitussh'e octivity wilhoot the addiction liablli,

manner through II central effect. In a hypothesis for lhe iaiIJI. lion of IIIe OOtLgh refle)(, Salem and Aviado l),l prnpo!>nl tbI bronchoddataliOll IS an Imponanl nM:ehanosm for the rdd of eoug,h. Their hypothesis suggests that Irritation of mucosa initially causes bnJ.n,choconstrictionthat on tUllln cites 11M: rough receptors, Clt.appcl and ~0Il Sccm:um lJ6 ha\c poontcd out t/u( IDO(I :U1tilussivc.~ of this type fBIl into IWO ~truetural groups.1lo: larger group ha.._ structures that bear a n..-..cmblancc to'''''' tk1ne. Thc Ollll::r group has large, bulky SUbstilucnlS 1111 doe aci d ponion of an estcr. u,ually connected by means QlI long, c\hn<Ofltllining chairo to. Ir:nwry amlllo group. 'nil OOIable CllCCplJonS arc benLonalale and ~;um di~~ Noscapinc cou l<.l be conSidc:red as be longong to (he fa !roup. Many of the OOtLgh prep~ra(ions sold cootalll '"Ini:M ingredients in nddllion to the prunary aniilLissive .~cnt llIr more Importani ones irocl udc: antihIS(3J11I lies., useful ";,;,.... .. cause of the cough is allergic, although somo: llnuhl", drugs (e.II .. diphenhydramine) hQ"e II central anlltu.. ~m:a lion as ....cll: symp:lthomimctics, which are quite dftr.c owing 10 their brooohodil3tory acthny. the IJII,)\t ~. being ephedrine, melhamphetl1mine, phcro).]~ homwrylarnine, isoproterenol, and io;ooct)lnmi~: JWIS!' pathol)'lics, ..... hich help 10 dry sc:cnotionJ. in the upper",;" lory passages; nnd expt'Ctorants. It is 001 koo ... n If drugs potentiate the an tit ussive action. but they uiwll). considered adju"ant therupy_ The more important Ihfo this class are discussed on till:: following .;ection. For uhauslJvc covel1lgc of the ficld, tlIC reader is urged to SIIlt the cllccl1cnt review of Chappel and von SC'c~

Prod"as
Some of the narcotic antitussivc produCb an: " : : above With the nllTC(O(ic analge .. ics. Others are iii below (Table 226 ).

Noscapine, U5P, NO!I<:npine, (- )-n:ut:Olinc Plnc), ~n opium alkaloid. was isolaled in 1817 by It is isolalC'd rdthcr easily '~,.ru", It ma~cs up 0.75 to 9% of opium. i unique antitussi\e poopcrties, the name of this changed from narcotine to noscaplnc, It ..... as /'e1Ilid would not meet ..... ith wKlcspread name ......~s associated with the name IWscapinr: .... as probably "I:-lectcd

from

TABU 221

Antitu uive Agen ts

Ha ....
lkuaI Adutt DoH
1~-30

,., L"

~'--'Y N _

"' .... f.tiom

OoittIOj.dQ~.'

hyO>ot.wo'oOe. US!'

o.tio ,..., .. pI.., ~o;b""loo:Ie

tyn,QUSP
l.tI\

rroQCIlOqoj

t.. _'!4XI'JIlIe., neJ)6J11,1le. USP

Iliathat

Ib, '

,t>opo.yQI.,_,,1fI ~a .. usp

~a

50-100 mg 01
le.<lpropo>l)plWIUII, I I ' "
~e,~ ' l'Ou's

l\IIPIi(klle

OI'aI ....,..,. I ~. USP &wuona!aI, ~ IISP

100 mg Id

,.lllf
~lJ<;ICd

chef

,'"
ex-

1M the name of ( ::!: } nal\;Qtinc, namcly. snoKopm~. I''U once Dvailable in various rou&h preparnnoo~.

~,

Th<

,,'" of'
Th< nau:.

elhu-

fiN

, ,'"
~pira

",",'

Th<

iT llniC

oc

IC1.l\'''-

. -.cfu l

nlmc.

l'iym-

I) all'
Ig~

, COIlm.l~

.. -

Outromethorphan Hydrobromide, USP. Dcx\fl)mrthorphan hydrobromidc. (+ )-1- mcthoxy- 17-mclhyl91l,13/)",14<1"-morphinan hydrobromide ( Romil ur), is 1he 0mc1hylutt..1 (+ } form of ra..:emorphnn left prIer Ihe 1"e,<,()lutI(JIl na:ess.ary in 100 prepal1llion of levorphallol. II occun; prJ<.:ticall y ..... hile crystals or as a cry<tllltinc powder ...,im ,filmt odor. II is sparingly solub~ in water (1:65). freely .:liable In alcohol and chlorofOO11. aoo ,o!ioOlob1e io eHler. II POS~~!iCS the amitussivc proptrl ic.~ of codeine, without analgcs;, add'CI;'C. cenlrnl deprcs!WlI . and OOIISlipatin8 fmur'n. Tcn 18JlI;gram~ is SUI!:~led 115 equivalent 10 a 15II dose 0{ codeiroc: in amitusshc cffeCI. It afTord.~ all oppor. billY to OOIC the specificity exhtbited by very closely relatW -oIecuti. IleTC. the (+) and (- ) fonns boIh rnu~t al1loch 10 Im"flWI"lI ~slblc for Inc: suppression Or tlle cough rdlu.. '- the (+) form i~ apparently in U SlcriC relmionship thai !tlude~ anachi ng to tlte receptors involved in analgesic, OOIIllipalivc. addictive. and other :tClions exhibi ted by thc I) form . II has Illfge ly replaced many older amhus~ivc.~. Itludmgcodcinc. in prescription and nonprescription cough JIItp.llllUom.
~CHNtafE'. US!'. BcnlonalalC. 2.5.8.1 1. 14. 17,20.23. ~.\aocbCOSall<28y l p-(butywni roo>ben"l.oou: (Tcs-

a low fnoquency of 5idc cffoctll. It is available as a pediatric suspenSion (2.5 mgf5 mL) or as capsules (20 mg. Cophcroc: X ), In "lIfious combmations with ant ihistamines and dccongcSIIUIIS. The tannale is al'>O a"ai lablc ( Rynatu\S) a~ a 6O-mg tablet and is !lUid to give a more soslaincd action.

aoo

ANTI INFLAMMATORY ANALGESICS

The early growth of the amiinflammatory analgc<;ic group was related close ly to the belief that lowering Of "curi ng" fC"cr ..-as iIfI end in ilSelf. Drugs that induced. drop In Icmper.llure in rn~rish conditions were oonsido::red quite val uabl~ and .. ~re sought cagroy. The decliroc: of intCft$1 In the!.e drugs COIncided rnore or Ics$ with the reali7.atioo that f",ver was an OUlwatU Sy18p1OO1 of some OIhoer, more. funda mental ailment . During the usc: of the sevcn! amip)'lt'tics. howcver. SOllie were noted 10 be c~cc llem llIIalg1cs for the reli~f of minor ao.:hcs and pains. Thc.~ dru gs have survived to lhe present Iime on the basis of the analgic, mther than the ami pylt' tic. effect Ahhough these drugs are Still widely used for the alley iation of minor aches and pains. thcy life also u!!oed utensh'cly in the symplom:llic treatnlent of rheumatic fe"cr, rheumatoid arthritis (RA ). and OSIeow1hritl~ (OA). The dramatic cffect of salicylatcs in reducing the inflammatory effect!; o f rheumatIC fevcr is lime honomd. and c,'en with the deyclopn"ICnt o f the OOftic05teroids, these drugs alt' sll ll of great ''alue In this 1t'spct1. TlIc: steroids arc reportedly no ....ore cffcclI\'e than the salicylates in pnlvcntingthe cardiac complications of rheumatic fever.,n The anallle~ic drugs Ihat fall into this category have been disclaimcd by some lIS not deservi ng the Icrm a"al~sic be cau.'\C of their low activi ty in comparison with the morphinetype l'"Ompoum1 ~. Indeed. Foumcao has suggested the name ullluigics 10 designate this genera l category and. in this way. 10 cmphasi/.e the distilICtion from the narcotic or so-called true analgesics. " ""0 of the principal features diSiinguishing lhese analgesics from the narcotic analgcsics are the low acti~lIy for a givcn dose (which is 001 increased significarnly at a higher lIosagc) and the lack of addiction potcnilal. Research has intensified in an effort to find roc:w nonsteroi dal antI-Inflammatory drugs ( NSAIDs). Long-term tllctapy with the cunicosleroids is often accompanied by "anousside effects. Efforts to dif,C(l,'('f" new agents ha"e been limited, for the most pan, to ~t ruc tu r.d unalogucs of acttve com

In

;us'>fiI

;ussetl

u~sca

)iqUCI_ tctiOfJ

....). introduced in 1956. is a pale ycllow. viscous liquid _~ublc In water and sol ublc m n~t ocganic soI,ents. It .cfIC'miclilly rdated to p-aminobcnlOOtc local aocsthetlCS. 1\CqlItMtthe aminook:ohol group has been replllCCd by a n}lnted polyethylene lll)'col group. 8eruOllJ tale reponed l), POS'iC.'iSCS both penphcml nnd ccnmllKt" ity in producing its antilU~~i\'c effl.'Ct. [I loOmchow ~ods the s tretch f\. cpton; thought to be responsib le for ~ ~"'. Climcally. il i~ IIOt a~ effccti,'c II.~ codcine. hut it pruJocc~ fill" fewcr side effects and has vcry low to xicity. It ulailable in IQO.mg cap<;ulc.~ ("pcrks").
c.bE'taPfmtane Citr.JtE'. Carbdapentane ctU"Dt~. 2-[2t6af1yllnuroo)-ethoxylcthyl l -phcnylcyclopcntafltt"uOOx CUratc. is I "'hite. odor\cM crystalline pov.der Ihat is lItdy soluble in water ( I : I). 5lightl) soluble m alcohol. lind .oo.bIc: in cI ~r. II is It'ponooly C(ju i ~aklll 10 codciroc: as .,,"tussivc. Introduced in 19.56. it h "" clltolerntcd has

,of il\
id "'3-\ thaI il
lIS Ih

". Th<

- "'

aoo

pounds owing hl a lack of knowledge about the:: causes and mechanisms of inflammatoty di-.ell.o;e~. I~ Although se\'en,ll new agents ha\e been mtroduced for use in RA. aspinn rem:l.lru. one or the:: most wideL)' used drugs for thIS PUrpD"C. It also protects aguinst myocardial in farction). A .signi rlCant stimulu) to this se:irch was the:: observauon that prostaJ!andins pl~y a major rule in the mnamm3101'}' prt)CUSeS. ' Drugs such as aspirin and IIldomcthacin inhibit prostaglandin syl1lhcsi~ in !'Cveml lissues.'f>Il I'unhe::rmore. almost all clll.'>c'~ of NSAI Ds strongly inhibit the:: con'e.,;ion of aruchidonlC acid into prostaglandin E! (PGE l ). 1 IfIJ Thi~ 1>1. occurs al the SllIlIe of eor"ersioo of IU'lIChidonlC acid. re o Ica~d by the IICtion of pllosphohpase A 01'1 damaged li),ues. by prostaglllJldm H! syntheUl.<e. IM)W clllled ('\,c!oo:ngenllse. to the cyclIC eooopClo~ides PGG ) and PGIh, ~ are known to cau'ie vasocon~lrictioo and pam. 1'hey. in tum. are CQIlvened in part 10 PCE) and I'(i Fl .... which can cause pnin and \asod,ilaUltion. Thi ' effect of the NSAIIA. parallels tnclr relati\'e poIency in various te"lS and is SlereospecirlC. ' ~1 The search for specirlC inhibitOl' of eydooxygenasc: has opened a new area of research in Ihis field. 111is enzyme OCClll1 in two fornls, cydooxygenase I (COX - I ) and cydooxygenasc: 2 (COX-2J. COX - I 15 a eonslllllti"e enl.yme and plays a role III the pnxlUClion of essential prostaglandms. Inhi bitiun of this cn;r;ynlC by all tnc older. nonsell:cti"e NSAID, is primarily re.-.ponsible for a number of their , Ide effccts.. The COX-2 e1l1yme i, induced in respon.'iC to the releHe of !;e,'ernl proilifiammatOl')' mediator.;. leading to the inflmnrnaloty response and pain. Thus. there wll.~ all :K:tive search fo.-specific inhibitor.; of the COX-2enzymc. Thig h.1S bccll5UCCes~ful"" l!h In..- approval of three COX -l inhibitOf'l. di.\Cus.scU below. Even with the significant Hdvance~ achieved in tile discov ery ofoew arid more specirlC NSAIDl.. they all ha\'e 11 ceiling effea 0<1 their ahlllly to ...,lIe,e all pam. It is bel,.'o ming CQIIlmon prolCtice to usc combinations of the optOld drog.~ ",i1h NSAIDti 10 treat severe and intractuble pain. ThC!5oC drugs are considered below ill lheir various ch<.'mica l clIl egories.

S.lIcyllc Add Ded\taU.. .

HIS/onealiy. the salicylales .... ere among the fjr;t of this group to ..clue~ recognitioo Illl analgesics. l.en.Ju \. 111 1827. Isolated salkm. IlJId ?ina. 111 18311. prepared iIIllCylic acid. Afler lhese dio;co'crics. Cahours ( 1844) obtained salicylic acid from oi l of wintcrgreen (methyl ~al icylate ). and Kolbe and Lautem1.;l/l/1 ( 1860) prepared II synthetically frol1l phenol. Sod, um salicylHle was introduced in 1875 b) 8ll\'~. follo ..... ed by Inc introduction of phel\~l salicylatc by Nelld,i in 18116. Aspirin. or acet)'lsalicylic acid . wa~ first prepared In 18.53 by Gerhardt but remained obscure until Felix Hoffm:mn disco, ered Its phannacological activities in 1899. It WlIS tested and introduced into medicine by [)reser. who naIllcd it aspIrin by tllking the /I from lICetyl arid adding it to spirin. an old name for salicylic or $pIrie acid. dcri"ed from liS n.1turnl SOIlrce of spirea pbnt5. The phamlacology of the s..llicylatcs and rda tL-u COIIIpound~ bas been reviewed eX len sively by Smith.'h) I.... Salieyl.1CS. in geller:al. nat their antipyretic action in febrile (XItients by increasi ng heat eliminat iOO of the body \"ih the mobilil.ll1 ion of w"ter lmd consequ('.," dilution of the blood. This brings about perspirntion. cau~ing CUIJirH..'Ol.IS di latal ioo.

Thi s does not (A'(.'ur with nonnal temper.ltures . The antil')' 1K: relic atld al1alge~ic actions arc bel ic\'ed to occur in 1 bypothalamIC lIfN of the bnun. Some thlll~ lhal the sal ic) bb exert their analgesia by their effect un ... atl.'1" balance. rcO.:. ing Ihe etkoUla usually ass.ociated with arthrJlglIlS. Asp.. is partI cularly efft'Ctive for thi s. r'Ol'" PII interesting ;IrolIIII( of the history (If aspirin and a discu..~sion of il s medwu~ of action. the reader should (.'OIISlilt an article by CoIllCI". as well as tile rt:views by Smilh ' 6J . I,.. alld by Nicknnderet at IfIJ The possibility of hypoprothrombinemia and COIIOOmIIR capIllary hiredlllg m conjunct,oo with loalleylate IIdrniJmlg. tion accounts for the inclusiOll of menadione rn some salie) Illie formulat iom. There. i ~ 'iOme doubt . ho ... ever. about Ih:' necessity for this ,ncasure. A mon: serious aspect of .o;afll."}' late medication is the po:s..~ibjlity of Inducing hellJoill ,. from dln:e\ irrimlh'e conme t ",ith the:: mucosa. AIVlIrel aI S"mmer..kill have pointed OUt a definne rdlltiomlup~ t ...een salicy latc COI1.'iumpiion aoo mass.,e ga.'ltl'OlPI.... II hemorrhage fronl peptic llICC'l'.' .... Bar..ger and Duthte"' . an ~~tensive ~t\ldy found. h(l ..... e~er. no danger of ;n(Jta;aj anemia or development of peptic llker. ~ards IIlIIt uvy 'M used r.rodiolabded .roo and dclTlOllSlrJted th:lt bImIIIlg does occur following admll1lS1.ratJOII or ~nn. 1br r#fects vaned "' nh the fomlUlallon . Davcnpon ' sugges","" back diffusion or acid from the ,tomach is I1:Spomlbie fa' capillary ~ . Becau!5oC of these ehanrctcris(ics of aspinn .t ~ 11m e~ Iensivc:Jy studied as an amnhrombOllc agenl In the!ml' menl and prel'ention uf elinic~1 Ihrul11bosi~.''10 III II iii thought to llet by itS selecu~ actron on the ~)"nthtsH d the:: prosUlglandl11relllled lhromboxane Al aoo proe;catyck which are the coonterbal"IICing factors invol,W in piJIdlI aggregation alld an: released when tissue is injull.'li II ~ umque from the other NSAIO$. in that it Im:venihly ui._ the eyclooAygenase enl;~nll:5 by acet~la"oo. Aspin._ now been approved ror the prevenuon of trnnSK.'ntlsd.... alillC u. ind icators of an unpending ~trol;e.1'7l 1'he !>:llicylatC'l are n:.Milly absorbed from the Slomx:h .. the small intestine and dcpeoo strongly on the pH u til med,a. Absorphon slows considernbly as Inc pH fI5C:Ii ( _ alkaline) because of the acidic nature of these COIHporrMI and the:: roe.;essity for the.- pI"e'iCl1CC of undi>sociated llIoletaD for absorption through the lipoidal mclllbnne oftheSlonai and illC intestine~. 11Ien:fon:. buffenng a!!:cnt<. IIdntilli~ III the <>ame lime in ut"t'ssil,. amouru~ tkx:rease the rau r:I absorption. In ~llIall quanutics. tlleir pnncipal e(ft l1li) k '0 aid in the di~pel'l>ion o f the salieylme into firre partich. Thi s would help 10 increase ~b:.orption alld decn:~>c tht~ sibility of ga~trie irritation by Ihe :K:CUntU lation of la.rge part> d es of the UllIh s.o;olved acid and thelf a<lhc<;iooto tire mocO!kl. Levy and Haya ll ' ha" e showlilhatlhc ru le of a~pirin nnd the inddence of gaMrlc di~tress "lit I function of the dlssolutioo mte uf ilS particular A more rapid dissolution nile of calc.um arid buITertd wa~ believed to ao:coont for faster aMorptIOl1. "Tb;y demonstraled ~ignlr;cant variat ions '" di~solullon I*' j diffen:m nationally distributed br.u1(h uf piarn 3>p1nn litlets. Thi~ may account for some of the conflicti", and opinions CQnce:ming the relati'e :khantagcs oI'pbiI_ buffered aspln n tablelS. Ueherman et al.'l~ ha,'e aho:;';;; that buffering i~ effeclive III misirll; the blood levcl.ol

douge,"" ..

jpy. 'PO,,~

rin. A nlca.~Iln: of Ihe :mlinn~,cty effect of a'pinn b) rncan~ of electroencephulogr.ulIs (EEG,) fouIIll diffcrenl;c~ beIIIo-e<'n buffered. brand name. anll gelleric aspirin prcp.1l'l1'

due)lnn

uons. '1S
PotcnllUIIQIl of w")Jate acU'H> by <imul lanoow Idmin'SUlIUQIl of p-ammobenl.ok aclll or itS salls has been the basi~ for the intrOOuctiOll of numerous product ~ of th,s kmd. Salas.\,1 :md ooworkcN ha\(': shown Ih:1l this effect" llue 10 !he Inhibition of both !!oIIlicylulc ilIetabolism pnd excretion In the UIlI1<.'.I70 Th.s effect ha~ been prolled amply. providell Wtlhe r.tlloof2-1 g of p-aminubcn/oic acllllo) g of salicylaIe pel'" day I_ obsc-"ed. There is 00 strong ellidence. 00"" t'o'lT. to sulbtant,ate an) ~ignlrtealll elelllilian of pla~n\a sah q latc le\'e!, ",hen IC!>Ii II-anunobcnwie ac id is ustd. The derivati,'cs of salicylic acid are of two types II :lnll II (a and b) I:

00",
i Snl~

r. I~' e r ~t

ltanl
",ro-

JicyII the . licy"bage

"",,

In wlulion. IXlrticularly 111 thoc prclicllCe of sodiu m bitar bonulC. Ihe salt will dnrkcn on standing (Ioee sa licylic acid). Thi~ d ..u1..emng may be Icssetw:d by the lI4klilion of sodi um sulfite or '\Odium blsulfile. Also. use of recently boiled dis lilIed "'altl' and dif,pC'flSing m amm-CQ1orcd bOllks Ies~ color change. Sodium &alicylale forms ~ eutectic mixture "'lib unllpyrine and produces a " iokl color.t tion with iron or lIS ..alcs. Solulion~ of the compound mu'" be neut ....11 or ~ Ii ghtly basic 10 prellcnt pl"l.><:ipilulion of free salicylic ockl. The USP salt forms nculr1ll or acid SOluliOM. howe,cr. llus ~t is the one of choice for .)IIlicylate medication and usually IS oommiqefl'd Wi th sodium biearbonate 10 lesscn gamlCdlstress. or it is admim<t<,rcd in enleric<ooted labletS. The Ullt of $Odium blearbori3te '11 IS ill adVised bccau~ il tk:en::ases the plasmn Ic~cl~ of salicyl aT c aoll Incn::ase.~ the ueretion of free sa licyl!lle in the urine.

,Slinal , ..1 in

, "'-

lind

)Iced

he ef

Sodium Th;osaJjCY//lt~. Sodium thiO"lllicylatc (Rut)laIC) is the ~ulfur or Ib,o analogue of .;odium salicylate. It is more soluble and beuer abso.-bed. Ihu< allowlllg lower dosngC'i . It is reI.'Ommendcd for gout. rheumatic feller. and mUliCul~r pain" in dO!tC~ of 100 10 150 mg t\'ery 3 10 6 hours for:2 day~. and then 100 mg once or Iwicc dJily. It is a,'ai l able only for injection . Magnesium SaUCY/lite, USP. Magnesium salicylate (MobIdm, MagaR) IS a .;odlUmfree saJiC)latc prtp.1l'l1tion (or u<;c .... hen sodium intake is restricted. It IS claimed 10 produce Ic.~s gll.~troinlcst i nDl u~l. '!be dosage nnll indications al\' the .'\.IIll1oC as tbose' for .;odium sal iC) late.
SaIicy1l1t~. e~Ifl'~ly ~Iuble III

tS lholt .k for

been In::llt 11 is :sis of ::)"clin. ,laW'kt I. II I~ nh,b.I'i in hs :hcmic

,.
T)pt I rt'p1\':'cnlJi t/1o!.t lhat art' formed by modIfying The ...ton,,)1 group k -i! >.::Ills. e<;leTS. or amides ). Type' II (a and

Choline

tell 1100

Ieculc~ 1umaeh rate of

,'""""",

of""

bl rerreq:m_ thOst; Ihal are deri.ed by wlxtnution on the b)ilio"yl group of salicyl ic acid. 11,e deri\"atilll:.~ of ~lllic) IiI.' kid were introduced in an ~Ucml" to prevenl the gastne 1!'mJllom~ 1100 the unde"mblc tasle inherent in lhe ~'O<I1mon \IIts of .... he) lie acid. MO!'l hydrolysis o rtype I \.:IJ.:c, place in the inTbllOc. and IOOSt oflne type II rompoooos IIrtllbwrbtd _hangell inlo lhe blootlSl~am (see aspirin).
COMPOUNDS OF TYPE t
'fhto all.:yl noo at) I esters of -.alie) lie acid (Iype I) al\' u<ied

Cboline salicylate (AnhfOlWl) is walti' and i< awilable as I fla,Of\"d liqUid. It i~ daimed to be absorbed IllOfl' nlpldly than aspinn. gilling fn~ter pcllk blood le'cls. It is u.sed when ~lieylates are indkalcd in a reoon1l11c n(\ed llo!".(\ of 870 l11g 10 1.74 g 4 111nt~ daily. II i~ also allailable III combmation with magne Siunt Q]ic)latc (Trili..atc, TrtCOI>al). AmmOfllum.1ithium. and stronlium sail!; of sal icylic oclll bave alU) found uSC:. They orfer 00 distinct adllan lage o,'cr sodium So1licylaTc .
SALOL PRINCIPLE

Others.

l;~temJ

article~

~y ""

the pus. ~ p:1rti~ ga_tnc sorption .. en:: II ~ furm, I a.'p, nn ley al'iO mtes of irlO tllb-

rlkmally. prinlar; I) a~ counterimlwlIs. IIoherc nK"'t of Them f t "'ell aboiorbcd through lhe ~m. This lype of 'otnpouoo .. ofhllie .ulue as an analgesk. A fe ... inorganiC ~ahl'}lates lrI: u;.cd IntemallywlM-n lhe cffect of the 'lllicyime ;011 is 1IIIendl:ll. Thco;(: eotnpounds ,ary In tlM-ir Im tat iOll of Ill!' It\1IlllCb. To pre' Col the developmem of pin~ or red color IUOO III the product. contacT with l1"On should be a,OIdcd in dletr manuf.lClur<' . Sod,u1ll r.alie) late lIIay be pn::. para] b) the reaction. III nqucou~ wlUI;OIl, bcl... ecn I mole rrh of SII hcyli~ acid and SOtlium b.carOOoutc; ellapurJting 10 dryne_s ) iclds the white ~nh . Generally. Ihe Slii t has II putl..JsIt tinge Of is II white microcry_lalline powder. II I~ OtbkU or has a famt.chantctensllcodor. and ,I has II swcct. AIlIII'tll..'-Ie It I. affected by light. 11te CQlnpount.l " soluble: "-:l1er (I; I ). alcohol (I: I 0). and glycerin ( 1:4 J.

Sodium Salicylate, USP.

reporh

IIam aoo O sbov.-n \ of n~pl -

Neocltt ",troduccd salol III 1886 and so ~llIed to the lOCiencc of thera.P) the "~alol principle." In Sllioi. twO loxic sub!otance~ (pheool and 'i.:lhql ic acid) were r.:otTIbincd into an eSler IhatluJ.:cn intemall) slowly hydrolYl.es in lhe intesline to gi.e the antiscpt ic acliOll of its componenls. This Iype of cMcr is fl'fem:d to a~ afull salol or /rue $0101 when both oonlponcnt, of lhe e,ler are acti ve compounds. Examples art guaJllcol benloole. P.naphthol btnw:l1e. and salol. 11Ie ~01 principle can be applied to esters '" IIobkh onJy the nlrohol or lhe acid is the loxk. act,\'e or c:orT'O:'ll\'c poniQll; Ihi~ Iype: 1 eallcll a I,w/in/ 1/01. ExQmples of vanial sulols 5 That contain an 1K1i.c acill are ethy l sa licylnt e and methyl \.8.hcylalc. Examples of panial salois Ibm conlain an aclive phcoolare creosote carbonate. thymol carbonale. and guaia col carbonate. Ahhou,h many salol-type compounds ha\e be<:n pfl'pared and uSCll to $Of1It u teRI. none IS pn::sc:ntly

valuabk agcm.'l.

In

1hl'l'1Ipelltic5. and all are wrpassnJ by 0I:hl'r

Phenyl Salicylate. Phenyl salicylate. 11..1101. occurs as fine" hite cry'laJs or a "hile crystalline powOcr with II characterist ic taste and a faint. aromatic odor. It is insoluble in water (I:6.700). slightly soluble in gJ)cerin. lind soluble in alooOol (1 :6). ether. ch loroform. acetone. or fil(ed and vola tik oils. Damp Of eutectic milltUn::!i form readily "ilh many organic material\. suc h us thymol. mcnthol. camphor.chloml h)dmtc.:and phenol. Salol is sold In combination with methl'nanlirlC WId atropine aU':IIJoids a ~ a uri nary \r",lCt lim iscptic and :malge~1c (c.g .. Prosed/OS. Trac Tabs. Urised and others). ~101 is insohlbk' In gastrH: j uice but i~ s lo" Iy hydrolYl.ed in the inte~tll1C il110 phenol and salicylic acid. Beca usc of thi, propcny. oouplcd wIth 115 low melting POIn! (41 to 4 J~). it has been u!;ed in the past as an enteric t'()ating fur tablets and cap'uk's. It is IKM effICient a. an enteric.eoating material. howcvcr. and its IISC has been superseded by more effteti\e materials. II ha~ u l ~o "'.e n used extl""mull)' as a su n filter (10% ointmc:m) for .wnburn p!"e\ emion (Raydi.'nn). SiJlicyliJmide. Salicylamide. Q- hyUrollybtn1.amide. is a dcriYat"c of s:alicylie acid that has bccn "nown for allllO"t a eemuT)'. It I~ rea<hly Pf\'pal1.'d from s.alicyl chloride and ammonill. The compound occu~ as a nearly odorless. "hi te crystalline powder. II is fairly ",able to hl'at. light. and moisture . It is sla ghtly soluble in water (1:500); loOl ublc in hOi water. alcohol ( 1:15). and prI)JI)lenc glycol; and sparingly wluble in chloroform and ether. It i~ freely soluble in wlutioll$ of alkalies. In alkaline ~olution with S()(hum carbonate or triethanolanllne. decompo!iillon t llke~ place. resulting in a yd low to I1.'d precipitate.

Aspirin. USP. Mpinn. IICClylsalK:ylic acid (Aspro. E".ftI. pinn ). .....as Introduced into med ICIne by l)rescr in 1899. ~ is prepared by treat ing s:tlicyl ic 1IC1U. \\ hich ,,' DS first prep.vcd by Kolbe in 1874. with ~tic anhydride. Thehydrop:a atom of the: hydrollyl group in o;alic-ylic aciu is replXt'd II:< the IlCetyl group; Ihi~ al'oO may be lK:complished by osilll acetyl chloride ,,"h salicylic Kid or ketcnc "ith salie)bc acid.

S-tC'~

SalicylanllUc reponedly ellcns II modcrntely quicler and deeper analgesic effl.'Cl than aspirin. I...oog-term studlC:S on rnts re\'caled 1\0 untoward symptomatic or physiological reo acuon~. Its me tabolism diffel'll from that of ottt..'r ~11ic(lk rompound:s. :and il 15 1101 h)'drolyzcd to salicylic adu . I'" Its :malgc~1C I1J1d IU1\ ipyretlC acti vity is probably no greater Ih:II1 that of aspirin. anu possibly less. It can be u'l:d in pluce of $illicylllcs. /\w.o.cIer. and i~ particularly u'iCful for patients with II OcI1"lQl\,trarcd sensiuYlly to 5IItkylates. It is excreted much more rJPluly than other salicylate:.. which probably IICCOOnl.'l for li S lower tOKici ly and. thus. does IKM permit high blood lelcls. The dose for si mple IInalge!lK: effect may \'ary from 300 mg 10 I g administered J timc.~ dai ly; but for rheumatic condllion,. the dose may be increased to 2 \0 4 g 3 umes a day. OL~tric intoler.lllce may limilthe dosage. howevcr. The usual periOO of the hightr dosage should not I':lceed J to 6 days. It is available in '\Clernl combination product ~ (e.g . SalCIO. Be Po,,der).

Aspirin Ou~ II~ "hite C'T)'stals or as a "'hi te cry.sWJlnt po .....der. II i~ slight ly solublc ill water (I :300) an(! jOjubir in alcohol ( I :5). ch loroform ( I: 17). and ether ( I :15). Abo. it diSj;()l\'cs casily in glycerin. Aqueou, solubility may bt iracn'.ascd by using OCI'tate~ Of cltrntts of allaJi metal .. Iithoogh the\C are said 10 de~ompo'\C it ~ I{)wly. It I~ lIabit II dry air. but in tnc prescl1Cl' of rooi~tun'. it slowly h)'Urot)~ illto IICt'tic and salicy lic :loCids. Salicylic :lCid will cf)!Dllllf om ..... hen all aqUCOOh solution of a.spirln and SOlllum h),Jro\ ide is boiled and then acidirtcd. Aspirin Itself i.s aciuic enough 10 produce ~fft'f\rscna with carbonate.~ undo in the pn-scnce of ioo;dc~. 10 C"lIII\t the slow hberal;on of iodUlC. In lhe prescOC\' of 1I~ hydro~;de~ and rnrbon3tes. it decompo5C'. allhough it ~ form salt. with alkaline mClals and alkaline eanh m:u.l~ The ~11CI' of salicyliC" add. formed on hydmly)i;.1III)' be confinned by the formmiOfl of a violet t"Olor on the:aH tioo of ferric chloride solution. Aspirin is IKM hydroly~ed :appriably on contKl .... wenl...!y adu digcst"'e nUld . of the <Iomach but. 011 lXI' into the intcstine. I~ subjccted to some h)Jrolyw,- Moot 01 it is absorbed uracoongcd. ho\\enr. Garreu t7S has:r;aibellf the gastric l1lucosul irritat iOIl of aspIrin to s.a li cy lic..-id fa.. mation. the r\lItul'1ll aciUl1Y of aspirin. or the ad/Ic:'>IOIIlII undisso,,'ed aspinn to the mlK.""O'o.:l. Hc has also I~q!(l'd thm the rlOflllCidic IlfIhyuridc of aspirin is }upenor for or.tl administl"lltion. Oa\"enponlfl'l collcludo.. thai. aspnn'" ... mUC05al cell pemll'ubilily. aIl0"1111 bad diffusion of ach aciU. which damages the c3pil larie.~. A number of prop1 elluics (c .g.. Buff~rill) usc compounds s~ h 11.'> sodium baa! bonute. ulumimllu g!ycinate. ~iunl citrate. aJunn. hydrollide. or mal;nesium tri.ilicllll: to counlcractl"'~":: pmpc:ny. One of the benCT antocids is ulhydro~~l11 amin03Cetul~. USP. Aspirin is urlll . nally cff(.'C1.ilc ",In pt scribed with calcium glutamal~ . The more "able. IIOIIl/TUI calcium :acetylsalicylate is formnJ. and the glutJma1e".. (glutamic add) muinta;n, a pH of 3.510 5. t>refernbly . df) dosage forms (i.e .. tablets. capsuIc!.. po.nlers) should be used. ~inc\' asplnn " some .. hat '".''': in aquC()U~ medill. In tablet prepanl1ions. the use a(': washed Ulk impm\'CS the ~tabi lity ofaspinn.n" AI~ .... has been found 10 break do .... n in the pre"C.'OC\' ofphrn)'~ rine hydrochloride:. llIU A.pirin in IIqlleou~ medl3 .. ill .,

almo<;! CQIllpictel) In Ie,,, than I week:: -oIUlions mde .... ,Ih alcohol or gl)!;'erin do not derompose as quid,;!),. Citnll~ n"lard hydr()ly~ls on'Y ~hghlJy. Some studies hnvc nlicalro thaI SUC~ lends 10 inhibit hydrolysis. A study III aqueous "",pilin su<;pensions indicated thaI wrbitol el~5 I pronounced <>tllbil i1jng effect " Stable liqUId PfCpoIratloos f t 1\"3rlable that usc Iri:lCe1l1l. propylene: glyoo1. or a polycthykne 81)'001. A)pirin lends il5C lr readily 10 combInation "llh mally OIlier wb<;tance, bullend, 10 sof1rn atld become iWnp wilh IllCthenamine. aminopyrine. salol. ~nllpl'rinc. phmoI. 01" :llX'lalulid. A.pirin j, one o f the mo,' .... idel)' usW compounds in dImIpy and, for many yean!, was 1101 associau.'d with untoun] dfa:b. Allerllic 1'\'3(:lioo<; 10 aspinn arc now obscoaJ mmmonly. A<;lhrna wid unu,'ana :11\: the mO~1 common man QMlion_ and. when lhey occur. lIrc" (ll1rt'ftlC'ly acute and dlfflcult 10 n:lic\"l~:. Llle: sodium s.1hcyl:ne. aspiri n cauo;ed rongmilal malforrnauons w~n adnunlQcred to mice. Ie l'rT!rtauncnt willi <.Olliulll 1 X'lllomam.lal or clllorproma/i nc '"p1lflCamly lo"'crtd lhese elTI).'11 Similar efrC'rls lla\C bmi Dllnbuled 10 I ~ con~umpiiOfl of a.~pirin by women. and II> U'iI: during prej;nancy should be 3voided. Other studle~. _"e\er, fount! no unloward effe<:ts. The reader i~ urged 10 QIIISIlh the ucctlenl rt\Iew by Smitll for an ao:count or the JNrmxologlcal aspech of a~pinn.lbl, I... Prxtical!y all ..alts of a)pirin. except those of aluminum _ co.ldum. are un~t able (or ph ann:ICeulicnl usc. Thcse -ults .lpptar tu have fewer undesirable \ iOc: tff~~ and to illduct INlge!>la (aSltr Iban aspirin. A limed-release pn:paralion of apirin I~ 3\ailablc:. II doe< IKM appear 10 offer any advan 0\'('1" hpirin. except for bedtime dosage. A~pirin ;$ u.scd all an ant ipyretic. :uualgesic. and antirbc:u~.;" usnal!) m powder. capsule. )llpposilory. or IIlblcI n. liS use in meum:u ism lias been re\"ic .... ed. and " is IqlOrItdly lhe drug of choice Ol'er all OIher salicylate dcrivaD'"t!i.ta. ,-, 'There is 50~ aneslhetic acdon when applied b;.tI1y. especially In po .... dc:r form in tonsillitis or pharyng i1iI. and in ointment form for skm "cbing alld ca1ain skin ~.In lite u~ual 00sc. 5210 75"" isncreted in the urine . ,-.iou, forlll$. in a period of 15 10 JOhours, Alkllb..:~iu is !tbel'W 10 be due to lbe: unhydrolp.cd acetylsalicylic acid IIIOkcule.'6.1 'M A 1ow4o..uge form of a~pirin. 8 I mg. Iuil'ulcnl IU Ihe 6lw: recommcnded for infants (Ine baby aspirin"). i~ fCC-.:nded as a dally dose for mdll,idual~ .... ho arc m c"en I Joy, cardiovascular ri;J.. Sc,'CfII I large 5lut1iC$ foooo Ihat low ~ of fI."pirin reduce<; lhe number of heart allack~ thrombotic Slruke~. OIher 'iallcylalc~ and NSA IDs lIa"e III sllo..... n Similar efreclS. In f~. Ike NSA IOs can interfere 1i1t1 uptrin's card,ovascul;u- benefits. alld they should not , . " ,.. Yo !lhm 12 hoo~ of e;ICh other.
~fle

Dff/un/Ja/. O.er IIw: years. sever.1 lIundred analogue! of.,pirin ha"e bn made and lCS{cd tn prodoce acompound Ihal ",'as more potent. wall loogcr ocling. and had less gll'ltrlc ini lalloo . By the Inlroduclion of D hydrophobiC group in lhe 5 posilion. dinunisaJ. 5(2.4-dinuoropbe:nyl)l!;tlic)'IIc acid. 2' ,4' -dlfluoro-4-h)"droxy-3-blphcny1carboxylic lIC id ( Dolobid). appcaN 1 meet lhese cri leria. III animal te'itS. il is 0 at least " limC$ II1Of"C potent. III humans , it appears to be about t.... ice fl.. tffeclivc, witb IWicc tile: dural ion. 190 Like other aryl acids. 11 is highly boulld 10 plasma protein D. ils deacy laled melabol ile . II is markeled in lablcts (250 and SOO mil ) fOf treating mlld-to-rnodc:r:lIe pain and RA and OA.

"Aryl. Ilttiranllk Acids

One: of lhe carly advancC$ in the ~arch for nonnarootic analgcsi(."S ",~.as centered in lhe N-arylanlhf';lnllic acids. TIlcir OUIstanding charJoCteri\lIc is Ihal they are pnmanly NSAII>;. and sccoodanly. some IlO"ses~ an nlg!:>;ic propc nics.

Mefenamic Acid. Mefenamic ocid. N-2.3-xylylanthf';Inilie acid (Pon5tcJ). OCCUl'S as an off .... hlle Cl'}'stalline powder that i ~ insol uble in waler and s lightly );()Iuble in alcohol. II 1lPPC:trs 10 be the: !irsl genuine: amiphloglQIC analgesic d l;;(:o\,ered ,incc ummopyrine. Because it is believed lhal aspirin and aminopyrine: o ....e !heIr geoer.al purpose analgesIC cmeacy to a combinalion of periphc:ml and centml cffects. 191 a .... ide variety of arylanlhranil ic ocids .... ere screened fo.antinockept;,e (annlge.ic) acllvi ly if they showed significant anli-innammatory action. "The combination of lxlth tffe4."1~;s a rarity arllong lhe.<;c CQmpounds. '11K: mechanism of analgesic action i5 believed to be related to lbe: abil"y to block pro5mg!andm symhelase. No reluliolllhip to lipidplasma di~tribution. panll ion cocfflCM:nt. or p ' hlIs bec:n noted. The int .. re~tcd reader. ho .....elcr. will find additional informatioo on anhbradyk ;nin and anti-UV er}'tllCm:l KIt"ilies of lhese compounds. logelher wilh speculalions on a receptor site. In lhe literalure. l :!

(XCOOH
X N
H
(I) (b)

R,

R,

R, .. CH~.)( .. CH R."'H R, .. H. R, .. CF;o X" CH

Sab.alalc. salic)lsahey1ie add (Amillcsic. etc.), i" the eSler formed bcl .....een 1.....0 sahc} lic add ~w'~ 10 .... hlch II i. hydrolyted follo ..... ing absorplion. JtpOrIe-dly causes lC$s gastric upset than aspirin because 01 rtlatllely msoluble in the stollloch and 1~ not pb'iorbed I i1 reaclics tile: small inte.ti llC . L,mited cl inical "" "..-IU suggcIiI thm i1 i. all effective as nspiri n and Ihm rruy llave fe ..... er side effecIS. I" '11K: recommended dose 3"'..5 10 1.000 mg 2 or J l UI1C~ a day . II i~ availab le on ly
~rip!ion.

Mefenamic acid In a t\o$e of 250 mil ," superior to 600 mg of aSpirin as an analgesic. and doubling lbe: dose ~harpl) increase' ils effICacy. 19) A 5100y eXllmimng Ihl ~ drug relat" e 10 gaslroimc,linal bleeding indicated II lo ...... r incidence of Ihi\ side effect tban exhibited by aspirin. ," Dumhe:a. dro .... siness. and headacbe: hale accompanied ils use. '11K: possibility of blood disorders h.a~ prompted limilation of il$ admIMisIrJtiOll 10 7 days. It is not fCCommendcd for children or dunng pregnancy. It has bn approved for usc In lhe: man 3gemc\U of primary dysmenorrhea ( PO) ..... hich i. thoughl 1 be caused b) uces.~i\"e conccnlrolions of prostaglandins 0 and endopl.'ro.~idcs, Medofenamate Sodium. Mt-clofcnam:lle .;odium, ~ dium N-(2.6-dichloro-m -loIy1)an!hf';lnilale. McclonlCTl. 15

aVlUlable in SO- and I OO-mg caPl'ules for use in the ueatrTl('nl of acute and chrome RA. "The most lgnificant side effects art' J!;aslrointe5tinai. including dillrl'llt'll.

---- ~

parent

0.

COO - Na'
Cl
inactive

N
1

CH a

~'3odo m

Arylac:etlc Acid OI!,I".tlves

1l1e arylacetic; add denvau"e group of agenlS ha~ received the most Intensive attention for new dinkal c;andIOOte.s. As a group. they show high analge~1C potency in OOdition to tl1eir am i-in flwnmatOl'y uc;tiv it y.

The parent sulfinyl has a plasma half-hfe of 8 hours.-' that of lhe a\.1ive sulfide metabolile i ~ 16.4 houn. The 11m polar and inacti~c: sulfo~ idc: i~ \'irtually lhe on ly fonn tl' creted. TIle long half-life is due to e~tcnshc: enterohtpatii: recirc:ulatlon. r'loo Only the ~ulfide ~pedrs i nhrbll~ ~Jan. din synthetase in '" ro . Although Ihe'IC fonn~ pre highly ptI),ein bound. the drug doc, nOi aPfl'!ar to affecl bindinr ~ ant ioo;rgulan\.~ Of hypoglyttmic . CoodmlOi ~lrJlion of iI..p. rin is oonlnundicaled becau.'iC il considel1lbly reduces tbe sulfide blood le'el..

Indomethacin, USP. Indomcthacin. l -fp-ch loroben. zoyl)-S-rTI('IOOX y. 2 meth y Ii ndole -3-acetk add (I ndoci n). occurs U II pale-yellow,o yellow-tun ~ry~tal h ne powder thm is soluble in ethanol lind acetone ond practk aJly in()luble in water. II is un stable in all.:aJinc solution and ~unlight. It shows polymorplusm: one fonn melLS al about ISS C. and the OIher a, about 162"<:. II may occur as a mi~turt of both forms wilh a rTl('lting runge belween tiles.: mc:l ting points.

CH,

s..oac
Careful monitoring of patient~ ....rlh a history of ..!emil recornnw:ndcd. Ga<;tric blccdlllG. nllusca. dillrmcll. dl1)~pr\~ and other ad"erst: effct:ls have been nOied. but wnh 11O'Io1l' frequency than with aspirin. Sulin4M: i$ recomrnrndrd r.... RA. OA. and anl.:r,IO!>1ng spondylrllS in a ISO- to ~ dose. twice datly. "7. r'M II i< avaIlable as tablcts (ISO . . 200 Illg).

CH,O"",,, __

SillCC ilS inlrodl,u:lion '" 1965. n h.as been widely u~ as an anninflammalory anal~ic in RA. spondyhli.. and OA. and to a lesser extent In gO\lI. Although both liS analgesic and anti _illflarnn13tory IlCti viues lire well established. il uppears 10 be no more effcclive than a~pi rin"' 'The mo<;t f~ucnl side efftt'1S ute gaslric distreSS and headache: , II has also ~n as.socialed with peplic uker:ltion. blood dic;ordcn. and PQS.\ible deaths. The: side drct:ls appear 10 be do'iC relaled and 50rnctimcs can be rninirnil.ed by reducing the dose. It is not I\.comn~nded for use in children be!;"ause of possible iOlerfe~oce with resiSiaoce 1 mfection. 0 LIke many O(hcr acidic compound~. il cireu lale5 bound to blood proIein. Ihus requiring caUllon in the: concurrent u>e of O(htr protein-bindinG drug.~. In~rnerhllCin is ~oommended only for pat icnt ~ .. ho cannol tolenlle a.~pirin and in place of phenylbutazone in Iong-Ierm therapy. for .. hictt it appears to be: less ha7..:ut1ous Ihan oonicosteroids or phocnylbutuone.

Tolmetin Sodium, USP. ToImctin sodium. I -~~ S-(p-toluoyl)pyrrole-2-acetale dlh) dralt sodium. McNB9I (Toleclin). is an arylacetic acid derivative wnh a pynolt .. the: aryl group. This drug is absorbed rapidly ..... ith Ilfllth'ely 'han plasma halr-Irfe ( I hour). I, i~ rt'CQmlllC'ndtd ' " u>e in the: managemc:nt of IICUtc: ano.I chromc RA. It Wm similar. bulles$ frequent. ad'erse effects .... rlh a~pinn. 1tdDI:J oot potentrole coomarin1 il.:e drug~ nor altcr tile blood !em. of su ](on ylureas or insulin. Like OIller drugS in thi~ it inhibits prtJl:ilaglandin synthetase and Jowen J'GE levels.

c_

"

>-~4CH'COO "'.
CH,
TotmcI.. fur .....: R, -Cl-t 3 R._H R, - a R. - CI-t.
1

OR,

Sulindlllc. USP. Sulindac. (Z}-S-fluoro-2-mC:lhyl-l-ll/l' (methy l>ulfinyllphe:n) llmethylene 1 1H-indenc-3-acetic add (Qinoril). O'Uf'S as yellow !;"r)'stal ~ 'iOIuble in alkaline: but in()luble in ocidic solutions. The: drug n:aclle~ ~I.: blood Ie\'ds within 2 10 4 hoon and undergoes u complicated. reversible metaboli m a$ follow~ :

Available as tahlelS (200 and 600 mg l and a capsulel mg). a drn.c: of 400 mg 3 limes daily . with a mallmUlllrl 2.000 mg. is recommended. Cl inical trial s indicate I daily dose or 1.200 mg IS COIn(XIr:lble 10 relref 10 19 I' aspinn and ISO Illg or indomethacin per day.I'"

Ibuprofen, USP. lbuprorcn. 2-{4-isobul) lphenyl~ onic add (MOIrin. Ad"i!. N oprin ). '" a.< introdu.:ed rnrodili-


cal pncllce follow Ill! Ulen~I'C clinical lnilis. IIllppears to be rompaf"~blc 10 a.~pirin In the treatment of RA ..... llh 11 10....a" llIo.:M.lcncc: of ~1(Jc: effCCb. lIll It has abo been appro"ed f(M" uoc in PD. gastrointestinal bleeding. ulce". dyspcp;.ia. naU'i('a, ,lceplness. and dil.lioe~s reponed hI a lowcr incidence than wilh aspirin. II inhIbits ~Iagland," ~)nll!elase. =

~, ./CHCH,
CH,

-0-

R
1 CHCO~ H

CH,

COO

lbufenac R _ H

lbJpIoIen R. CH 3

0-0,
FlIlOIllolen

In Ihi~ serkll uf l'UTllpoonds. poIeocy wa~ cnhaocoo by irnrodUCIion of the a-methyl group on the aceuc acid moicty. 1k pn'('UJ":\OI" lbufcnac (R = II ). wluch WIlS abandoned (1'/11"1 to hepatOlo~lcity. WIlS less potent. Moo,er, the 111;DI'II) ~Idc!; In the.> (SH +) isomer. IlOl on ly In ibuprofen Iu throughoollhe lU)1occtie acid series.. Funhermor\", lhese IWlIllCl . an' lhe more potenl inhibll00i of IJ'I"Of'laglandin syn1Iicwc. IOI The recommended dos.age i~ 400 mi. Ibuprofen II aOO '"'ailable o.er-ll!eo(.'OOnter IlS 2(X).mg IIlblels.
(+ ~mel hoxy-a-mcthyl acid (Anaprox. Naprosyn). oceol"" as ,,1Iill:" 10 off-lIhi lc cry~l al' lhal an: ~paringl)' sol ubl e in acidic )<~u1ion" fl\.'(:l), wl uble in alkaline M)lulion', and highly "","ble in org.mic ()I" lip id-like solutions. Afler ornl OOl11ini,1Dl1On. II i~ well abwl"bed. giving peal. blood lelcls in 2 10 'boul"'l and a halflife of 13 houn>. A ~Iead)'-"-Dlc blood k-el is usua ll) IIChle,ed afler fOOT 1 fil'e dose~. Nilproxen 0 110 ,~ hl",ly !'fOIcm bound lUld d isplaces most !'fOIdnbotIrIddrul-t. ~ oflhese mUSI be adjusted lICConlingly.
~)Cell. U5P. ~'JI3rhlh~lcncacelic Napro~en.

Alailable a. capsults (200 and 300 mg l and t.ablels (600 mg), i[ is rt(."OIllmentJc:d for RA and 01'1 in divided doses 4 times a day for. maximum of 3.200 mg/day. It shou ld be la}..en al leasl 30 llIinute5 before or 2 houn; afler meills. II i~ nO! yel recomroentJc:d for lhe managemcnl of acme "8,,-,upt. ~ of 2.4 I per da), are ~"On\p;ulIble 10 3.9 g pcr da)' of Il.~p!rin 111 anhrillS. For pain rehe f. 400 1118 gave resul ls ~imilar [0 650 IlIg of aspinn .n
K e ropro fell. Keloprofen. 3-be 11/0)' I a-I11C Ih)' Ibe nl.C ncacelic aci d, m-ben/o)'l hydr~lrop ic acid (Ontdis). is closel)' relaled 10 fcnoprofcn in SINClure. propenies. and indicalions. II has a low incidefl\.'C: of side effects and ha~ been approved flH" OIer lhc~"()tJmer!la1e (Ontd i$ KT, AClrQI1) . It is avail able as capsules and lablcts (25 and.50 !IIg). wilh a recomme l1ded daily dose of ISO 10 300 mg dl~idcd inlo Ihree or foor doscs. It j, also availlible a.~ ulendedrele&)e eapsulc$ ( 100. 1.50. and 200 mg).

~
CH,OA./ ",r
~arroxen

CH,
COOH

is n.~ommcndcd for U.'iC in rhcunlUloi d and Ulyanhrili,. II ~how~ good analgesic oclivi l)'-400 I1 lg romp;!mbk 10 7~ 10 150 mg of 01"".1] mependinc and ~upe 10 65 mg of propoxyphene and 32S IlIg of aspirin plus III; of codelnc. A 220- 10 3JO..mg dose I~ CQfIlp;ullblt 1 0 mg of aspirin alone. II reportedly product'~ di7.1joc~s. "ness. and nause:!. ..... ilh infrequent mennon ofgaslroil1UlIC1 Imllllioll. lil.:e aspi ri n. il inhlbil' pro:slllgiandin -.e and prolongs blood-clotting time. II i~ IlOl n:.:omfor pregnalll ()I" ]octalmg wOll~n or children under 1>1 It IS .1'10 a\lulablc O"er-Ihc-coumer as 200-mg lablCl.
,lJtle ).

Ffurblproff!n, USP. Flurblprofen. (+ r2-(2- n"", 0 'I biphen)I)'l)prupionic acid (A nsaid. Ocurtn ). is another hydrotropic acid analogue: Ihat is used in lhe IIClIte (M" longlerm managemcm of RA and OA. It i lI"ai lable as lablclS (50 and 100 rng). with a ft'COrnmcndcd dose of 200 10 300 mg divided inlo 2, 3, or 4 tirnc.~ dai ly. Ok/o(enac Pora$$ium alld Sodium. Oic lofcnac s0dium. sodium IcH2 .6-dlchloro.amlioo)phcnyl]acel:lle (Voll:Irm). is indicaled f{)l" short and Ionil-Ierm trralmcnt of RA. OA. and aol.:ylosing ~pood)' l lIis. The potaSsium ... 11 (Calaflam ). whIch is faslcr acllng. i~ ,ndkaled for lhe managemenl of acute pam and PD. The sodium salt is available as de layed-release lablctJi (25,.50. 75. and 100 mg). with a ft'COllIroended daily dose of 100 10 200 IlIg in di" ided do<oes. TlIe poIassium salt is available IlS a lablet (50 mg) ...... ilh a recommcntJc:d dose of SO mg J ti mes dai ly. Nabumetone. NabullIclone.4-(6-melhoxy-2-nnphlhy lr 2-bulaoone (Relafen). :;e\"l'cs a~ a prodrug 1 its aCli vc I1lClab0 ollte. 6melhox y2naphlhy lacclic acid. Lil.:e the other aryll celie acid drugs, II IS u ..... d in short- or lOIlglcrm managen~n1 of RA and OA. It is a\ailable as tablelS (500 and 7.50 mg). "i th a recommended ~ingle daily dose of 1.000 mg. Ketorofac Ttomf!rhami~. Kelorolac Immethamine, ( ~ )-benwy l2.3--dlh)dro-llI-pyrrohzlIlc- l -carbox)'11C acid cornpoond with 2anu no-2-( h),tlrmymclhy l)-I.3_propanc_

Fcnoprofcn calci um . q. <";"~;"","ii' add di hydnHc calcium a while crystall ine powder Ihm i~ slighlly 111 lI'hter, soluble in alcohol. and m'iOluble in ben I peal blood k.\els a plasma halflife (3 I"IouB). protein bound h ~t the other IIC) IIIct'IIC acitloi. and rlt\'ded .. hen it is "sed ooocum:ntly with hydan \.UlfonamitJc:t. and ~ulfOlly lorellS. It shat\-s many of effects common 10 this group of dtup.. .... ith

diol (T<lI1K\QI). is :I poIent NSAID unalgc"H: ind>c:utd for the trratllXnt of IIlOd!'rately se~el\", acute pain. Ikcau:sc: of number of potentiltl ,ide: effects. ,t\ Idmini~lratiQn should 001 uCd 5 days. Trralntmt j. l151Jally imu:ued by imra,e noo~ mg) or inlramu~ular (60 mg) oomm,'Ir.mon. wilh analge"u malOtailled by imh:ll oml do!se.. of 20 or 30 mg. 0 fullo .. ed by 10 mg ncry 4 1 6 hour:;.

no

Etodofilc. Elodol:K:, 1,8-dkthyl-I.3.4.9-telrahydmpy_ r.moJ 3.4-bJiooole-l-acclie acid (Lodll1e}, pos.'\Csses an in_ dole nng as the aryl portion of thi~ group of NSAID drug~. II ~hare\ m!U1) ofthc J"'IUPCnic~ o(Thi~ group and is indicated for 5hon- and long-Ienn mallagemcnl of pain and OA. Jt IS .nailabk: u cap-.ules (200 pnd 300 11Ig). tablets (400 and 500 mg) and ellclXkd-l\"lca'iC lableh (400. 500. and 600 mg).... uh a rerommmdaJ dally c.Iolie of 800- to 1.200.mg
In dl\it!cd~.

Rofecolf ib. RofOC()JO ib. 4-14-< nlCthy Isulli ny IIp! Kn) If.}. phcnyl -2(511)-fur.mone (Vion). is a COX-2 mhibltor .... grcalC!f poIcllCY and a longer halflifc than cclccolib (l1 vcrsus II hours). It is apprmtd for u~ in OA, acu'e pala.. and I'D. wilh ~ dcKe of 12.5 mglday and a ma~imum ol ~ mglday for OA. and a si ngle dose of.so mg dally fa"( 'I mended for a ma.\imum of S day, for acute pmn and PO k i~ a... allublc U~ .ablcl~ ( 12.5_ 25. und 50 mg) lind ~U'PCIl\1OIJ (12.5 and 25 mgtml.). Valdecolflb. Introduced in laiC 2OUI. the COX -2 inhIhtlor ..... Idcco~ib_ 4-15-mc.hyl-3-phcn) lisollat.ol-4- yIJtft. l.cncsulfOlUlmide (Bextra). Iud lhe \lime appro\'ed uses. celcco~lb and rofoc()llib. ",ith a rerommendc:d dose oliO mglday for RA and OA and 40 mg for PD. It is a,-":* as 10- and 20-mg tabletJi. Sc\'CTIIJ other COX-2 eru:ymc: IIIhibuOl"'l are under inVCSli!alion lind clinical .rials. IOCIlUltc .he highly specifIC' ClorieQ~.b and the parenterdJ pareawIt.

4 .5 dlphc ny I 2-o.\uolc propio-nic acid (D:lypro). differ; frrlm 11M: other members of this group m being an arylprop,onlc acid derlvallve. II 5hare.~ The !'lime propcnie~ aod \idc eff..-cl' of Olher memhcrs in Ihis group. II i\ imJkatcd for the ~hon und long-teml mnnagemCn! of OA and II.A . admmislncd II, a slIlglc 1.200-mg Uo.)'o(' It i, uvailable a' 6O()..mg el'llle , Ptrol.cam. 4-bydro~y-2-mClhyl-N-2pynd)I2H-l.2benl.othiaLlne-3-c:IrOOJOmnde 1.I-diollide (Fddcnel. rrpresc:n.~ p clH"~ of kid,c mhibltON of proo;tUglandin ~nthcta'IC. althour.h it tklC\ not arllagoolzc POE, dutttly. nll~ drug.s \cry long acting. w,th \I plasma h<l.lflifc of SO hou~. thu~ "",,ulring a dose of only 20 to JO mg oncc dai ly. It" reponcd to ,1\-C re-.ult, ~,mill'r 10 Ihose frum 25 mg of indome.l\acm or 400 mg of ibuprofen 3 'imes a day. l'I'O< MI
PiroxiCiJm, VSf'.

oIfilproz.;n.

O~ 3 pro1J n.

Aniline and p-Amlnophenol DerIvatives The introduelion of ani li ne deri ... ath'es ll~ anulge$ies b bticd
on .he discu\cry by Cahn ~oo Hepp. in 1886_ .hal ~nilil'll: (C I ) and acetani lid (C-2) (Table 227) both ha\c anllp~rc.ie propenies. The origin of this group from anilJar ha, led .0 their bdng !.'plled "cool 'ar unal,e~in." A;';;;,o was inlroduced by the'IC won:l'rs bl-causc of the I.novo n\01i!: ily of aniline i.self. Aniline bring.~ aboul the fOllNlK>n III me.hemoglobin. a form of hemoglobin tlllil cannot fulll.'lD as an QJ,ygcn carrier. 11Ie acyl den\D.i\cs of ;1I1Jh~ ~~ thought to e~cn their analgesic and an.ip),n:lic effect> bJ fiN bell'll hydrolp:ed 10 anihne and.he oorrt'Spolw.hn, aflC!f ..... hlch lhe aniline was oxidu.cd 10 p -llminop/'lCnol (e ). This.\ lhen e.\creted in combi nallon ",ilh glut'llrutUlClII' ~ulfuric lICid 1bc IIniline derivallves do not appear to act on tilt !nil cone~: Ihe pain Impulse Hppeani '0 be interecp4cd III t!tc hypolhalAmus. ",herei n alJ;O lies .he .hcnllorcgu lutOl)' ttnta" of the body. II j, not cleur if thi' i, the , lie of .heir IK'!iIIl} bl-cau;.o: most c" idcnce \uggc,' <' that they IICl ~t pcnp/lml IhemlOCcp401"'1_ TIley are efftttivc in re.urning fe\'cruh ild vidl.lal\ .0 normal .cmperaturr. Normal body.crnpc13lum are not afftttcd by the admini~ra"on of I~ t/Jugs. II .he anl1pyrr.jc analgesic group. the amhnc: denl-lIuI'CS lill ie ifany unti-inflammatory act;"ity. Table 227 ~how~ some of the types of IInil ,ne OenI1t'l"C1 thai hnc been made and tC"led in the pa.~t. In gc"tlal.7~; IYpe of ~lIb<;U\Ullon on the amino group Ihm reduces IISD ily also lowe", its physiological IICli~i.y. Acylalion ~ .ype of ~lIbstituliOll that accontpl i'hc\ this effect. A:laIUli,I (C2) ilelf. althoogh .he best of Ihe acylm~'(! denlalil('\" 101l1C in large dosc.~. bu. when administered in anal~ doses. il is probably wilhOll' signl ficanl harm . FOI11W'l (C-4) i~ rclldily hydrotYled and tOO irriTant. n.e h,ghrr_ oIogucs of acetanilid arc less solublc and. 1h<'l\"rm_ KII\C and Ic<;s toxic. 1110se derhed from arom~IIC~. (e.g., CoS) are ... inl.lally ",ithou. anal,CSic and anup) cffects. One of.hc-oc. salicylanilide (C-6). i, u~ IU. <:ide and antimildew agenl. Exalgin (C-7) is too IQ"'. 1lic hydro.~yIDled ani lines (II. m, pJ. beller ~no .. n ~ nminophcool5. arc ronsidcrably less to~ic than aniIUlt. pam compound (C3) is of panic:ulllf totCI\""l rfOlll

po.ien.

NH-()
1\
S.N, N

CH,

o O;'P.ro"~.(.,,
Melolficam. Like pim~iClm in ~truc.urr. mcloxi~. 4hydrol y. 2 methyl.N.(5.mclhyl-2-thlllLoyl)-21f-1.2-ben~o thiazmc-3-carboxumide I.l-dioxldc (1\IOOle). is also indio entC(! for u~ in OA. II nt'IQ hu~ a relmiH'ly long halflife of ]5 10 20 hours. AV:liluble a~ II 7.5-mg table .he rccom nl<!ndcd do'iC i~ 7.5 109/day. "'"h II maximum of 15 mg/duy .

Cefecolfib. n.e lirst of the COX-2 inhibllordrugs to be mmc.cd. cclccox ib. 4-[5-< 4-nlCth) Ipncnyl )- J(.rifll1OlY>phe. n)' J)-IU-pYTluol-I-yllhenr.cllC\ulfonamide (Cclebrcx). has been appro\ed for U'IC In II.A and OA. "'lib a dose of 100 or 200 mg t... icc I day for RA and 200 mg/day for OA in a smgle dose of 200 mg or 100 ml twice a day. 11 has also been approved for redllCing the numherof tKk:oomatOUS colom:uti polyps in familial adenomatou\ polyposis (FAP). It is a\'ailablc as 100- and 200.mg tablets.

slandpoinlS: 1lartll'ly. II i\ !he melabolic: product of aniline:. and il is lhe lea,t todc of the thR'e possible aminopheook It ul)(l pQS\OSeS It strong amipyretic and analgc~k action. It is too to~ic to !tI.'rYC as 11 drug. howe,er. and lherefore, numerou s modificat ions were auempted. One of the fir$! WlIS the acelyllition of the amirIC group 10 provide "'acctylp' amillOphc:noI (~aminophc:n) (C-II). a product Ih:1I rt:lained a good nlo('3.lOUre of t/1o(' desired acthillClO. Another approach 10 !hedetO~lrlCllllon of p'aminopheool I'''as the etherification mthe pheoolic group. 1be best koo.... n oftne..e arc lUIisidine (C-9) WIll pl\CllClidirIC (C-I 0), which are the methy l and ethyl ether>. re~pc:ct hely. A free amino group in these compounds however. ahhough promoting a strong nn tipyrelic action. WIIS also conducive lcJ methemoglobin formAtion. The only exceptions 10 tllis wert: oompou nds in wllich a carboxy l group or sulfonic acid group had bttn subslitlued on tile benzene nuckus. In tlie...e compounds. ho ..:eler. the: anl ipy, retic efftet also 11:1(1 disappeared. These OOflsider.llioru; led to the preparnlloo of the alk)'1 ethers of Nacetylp' aminoplx:ool. of ... lIkh the ethyl elller wa.~ the best and is ~nown as phen:lcc:tin (C I I ). 1be methyl and propyl homologues ... ere undcsiruble from the standpoim of causing enlo(' si~. ~lil'at ion, lI illre!oi~. and utileI' r<:actiOlls. Alkylation of the nilrogen with II methyl group potemilltc~ the: analgc~ic action bul. unfonunlItely. ha.s a lIighly im tDnl action on mu cous membrallC$. The p/Wi'nacclin moIteule has been modtfied by changi ng the IIC)'I group on the: nitrogen. with somctimes beneficial resu lts. Among these 3re lactylphe[1o('lidm (C- 12). phenocoll (C-13). and kl'}ofine (C- 14). None: of thc...e. ho ....ever. is in current uS/'. C llanging tllc ct/ler grou p of phenacctin to an acyl type of Ikril'~ t il'e ha~ not al .... ays been succcs~fll i . p. Aceto.'( yacet anil id (C- l' ) h.a.~ about the sartll' activilY and d isadvanlages as the flU phenol. The ~icyl este r (CJ6). however. e.'( hlbits dimi nished tO~lCtly:md if'ICKascd anti pyretic activity. Pertonal (C 17) i~ a $OOlC .... hat dtffen:nI type in ... hicll glycol lias been I.lo;ed 10 ettWi'rify !he pheroohc hydroxyl group. II is I'ery s imilar to pl!cnllCetin. None: of these is currenl ly on lhe markel. ReI3ti"c to the fme in human~ of the '{'pes of compound~ jU~1 discussed, Brodie and A.'(eirod 1 to_l t point out that acetanilid and phenacelin arc met:lbolil..e<l by two different routes. ACdani lid is lIlelllboliud primartly 10 "'acetylpoaminophc:noI and acetaminophen and only a small amoum 10 aniline . ... hich they sho ... ed to be the precursor of phen)'llIydroxylllrtllne. the OOfllpound rt:spoosible for methemoglobm form:lIioo. Pbel1aC'etin is mostly deethyloted loacclamin ophcn ..... hereas a ~rnall amounl is OOIIvened by OcacetylatiOl1 lop-phenetidi ne. also responsible for melhemoglobin formation. With bolh ocewnili d 3nd pi1enllCetin. the mcwbo lilc lII."etDminophen is hoc:l ie\'cd 10 be responsible for the aMlgesic act;"ity. Becau<;e of the lO~ici t y described abo\e. both :m: no longer a'81Iable. replaced primarily by acctaminophen. AcetamInophen. NAcetylp Ace faminophen, USP. aminopherool. 4-hydroKyacetanilide. APA P ( PlIrnIdo. Tempro. Tylenol. ele.). may be prepared by reduction of p-ni trophellQl in glaci al ocetie ac id. acetylation of p . aminophenol with acc:tic an llydride or ketene. or from plIydroxy-acelophenone hydrazone. II occurs as a wll ite. odorless. slightly biller cryqalline powder. It is slighcly soluble

tn ....ater and ether I1lllI is !oOIuble in boiling wafer (J;20l ak'Ohol (I : 10). and sodium hydro~idc T.S. Acet:tIlIlIlOpBen has analge~ic and ami pyretic aclJ\'IIIt:1 cornparnblc to tlJ.osc of acetanilid and is used in the SImI: condi tions. It exen~ il s effL'\:t~ by jnllibiling the eyelool)gena.o.e enl,Yrtll' centrally but ha~ vcry liule effcct pmp/la. nlly. Although il possesse, the 'lillie lo~ic effects as ac\'IWhd. they occur less frequently and are less S/'I'cre; IhmfOlf, il is oonsidered safer. Selentl prec-..Iution5 should be rttOJ ni1.ed. bo ... e,er. including 001 10 e'l:"d the reCOllunendnl lIol.ages and the: nsk of livcr tOKtcil) in chronic alooholn It IS available in S/'\'erul nonpre!\Criptiotl forms and. 11'10, is marketcd in combinatIon willi ~spiri n and caffeine (Ela dri n. Vanquish).

Pyrazolone and Pyra zolldlnedione Derivatives

The ~mple doubly unsaturated compound contalnl~' \1Iv ni lm&eTi and tllm: clUbon atoms in the nng ..... uh lhe mtllJlCl Ptoms ndgllboring. is known lIS p.-rn::.ol~. The reduI:1d prodUCI~. n~rncd as are other ri "I:s uftile ;tUHlIS. are p:lral(Iline and pyruzol idine. Sel'cral pyru7.0line ~ubslitutlon pn'duct< urt' used in medicinc . Many of thc'IC arc dcrt>'all.n d 5pyrnl.Olune. Some cun be relaled 10 J.5 pynuolidinal~

( ) C'N-H ( 'N -H I I I H H H
pY"'~

Pyrazon

' MW o
H

I2N-H

~-H OAN~ N I
H

Pyr"""."'v. .. o

Ludwig Knorr. a pupil of Emi l Fi~her .... htk scam....: for antipyrellcs of the quinolllle type, in 18840 dLIro', Ui4 the 'pym7.olorte now koo .... n as mrlipyrint!. Tht S di!;(Olel)' initiated the beginnings of the great German drug ulllulll)' ttuu domi nated the field for about 40 yC3J!i. KIlOIT. all al firsl mistakenly bclie~ing Ihat he lIad a quioohllNyp' OOflrpound. soon recOgnl1.ed IIt< crT\)!". and the coo,.. I .... as mlctpreted correctly as a pyra1.olone. Witlun 2 len t/1o(' arntlg~ic propc'nlcs of thiS compound became: when fnl'OnIble rcpor1s began 10 appe3T in the hlet", particularly wi th refcrence: 10 liS use til headaches and n.:rnIgi:as. Since then. it lias rt:tuined some o f ils populartt~ II_ an alge~ic, nhtlougll it~ uw as UII antipyretic lias dccliid steadi ly. Sioct! its introduction inlo mcdicine. lhere In been more tllan 1.000 compollnds made in an efTon 10" others .... ilh more potent atlalge~ic action combined to.'(ici t)'. Many modificallons of the: basic COOIpOIInd been made. The few denl'lttt,-es :and modificallQllil marlet:art: listed in Tables 228 and 229. !'hen)1 alr hougll aMlgesic ibC"lf, wll.~ origmallydc:'clopc:du . ... bilizC1' for IBe insoluble am illQpyonc. II is now belli( for tBe relief of many form~ of llrlhrili s. in .. hich;'d it 111 0;0 relIuces s.... elling and ~pa!i11l by an antitnnam~ IICtion .

"',m

01"

1:201.
,,!Uco~

'AILE 22--8

Derivatives of 5P')',.azol.

~~

00')'-

,,"'" 'i " ."'. R

E><~.

iphcr;elani "Cfore, l'l'Cog-

,-....... ""P .'vyN_

SI, UClu,.

..... --~

" -0,,,

-CHJ

"

-CH,

"

. -H
-NlCH J ),
-NCH~SOJNa

..... iI4 ....

18 1.... 0

lrogen iucl ion

"""'j ...

-C,Hs -CH, -CH,

-C;H, -CH,
-CH,

,,""'...,..0.

tH,

t)'rtllo-

.I prod hco, of

~lione.

~ t':':':'h ~: f;
'''>
liSt!)'
neur~l

"':~

Anli pyrine, 2.3dunethyl- I-phe ny lJ.p)'nlI.01o n-5-one, phcnm-.onc:. wa~ onco of Inc Ii/"lil Ullportalll mup 1 be made ( L887) ~yJl!he:lical1y. Anlipyn ne and maoy 0 rrL1led rompound\ are Pf'Cpared by IIle condenl,lltion of hychi'l'll" drnvall\'cos with \ari0U5 COMel1i. Anllpynnc llse lf is pn-p.vtd by lbe lICtioo of colh) I ..COIOXrtatc on phcnylhydnllW and MJbscquent methylation. It con~ISIS of colorkss. odorle~. ery\{als or .... hi le powdo:r. "'lIh a ~lightly bincor 1.:I$le. It i\ vcor)' ~I uble in "'3Ier. alrohoI. orchlorofonn and k~~ so In coiller. lt~ aquCOUll so luuoa is ncutro l 10 litmus papcor. II IS NSK' in n:ll ure, ho\I-'ever. "iucilis due pnmarily to the nllrogen al posi tion 2. Locally. ant ipyrine CXCI1S a paml)'lie IlClion on the "",nsory md the motor nerve~. resulting in some :ll1cS lhe~ia and vasotI"I.'ilrictIOll, and il also c:c:cns " (.:cbl e ami'lCptic cffect. SysImIlCally, it causes results thai lire \'ery similar to those of 1imI001id. all hough lhey are uSllal Iy more raPId. [I is readily iIk.bed arter oral admini~r.lIion. circulal~ freely. and is nm'trochicny by lhe kidncy( ..... ithoul having been changed dlemlCally. Any abnormal tempc.-ature IS reducal rapidly
AIIfipy,;ne, USP.

hy an unkno..... n mcochani~m. usuall)' allrilltued 10 an coffect on lhe: seroton in-mediated thermal regulatO!)' center of the: nen'OIlS sy~tem. It h.,~ gn:aler anli -i nnammmory actl\lIy Ihan aspirin. phcnylbtHllJ.one. and mdomethacin. It also Ie cons pcorct'plion to pai n of ttrlilin Iypcos. "'i!houl any aherntion in econlro) 01" mOior fUllClions.. .... hich diffc/"li from the: effect!! of rnorphi nc oVcry oflen it produccos unpltasMl and p!lS.\oibty alanning ,~ymptom~. eve n in small or moderatc doseI;. These nre giddiness. drow~i ness, cyanosis. greal reduct ion in tcmpcor:uure. coldne~s in lhe:: e:C:lremitics, tremor, ~ .... coali nll. and morbilliform or erythc:matous erup4100S: \cry large ~~ producoe asphpia. eptlcoplie coovulsions. and colLapse. Trelllmr-nt for MlCh umoward reaclions mllS! be symplom:l1ic. II is prob.1bly kss hkdy 10 prod~ collalXC' th:ln attIlUlliid and is 110( kl1o(nl'n to cause tnc granulocytOp!:nia Ih:lt somc1imc:s rol lows amlOopyrine. l1lc ~al SIICcesS or antJpyrilX' in .tS early )coalS led 10 the IOlroduetJon of a grraJ. many <krivllthes. cospeclally sailS with a "arielY o f acids, but none or Ihnco ha~ any ad"an lage O\'cr lbe parenl compound. Its use is lim ill"l1 10 a com bmation ..... ith ben /.ocainc as nn coar drop. Other dru gs .n Ih,s group. ..... hich ont'C irIC luded 9mill(lpyrine. pheny lbul a1.olll!. 3M O~ yphcon bulaWllC. are no longer marketed. 11le phamuv:ology or lhese and ot her :malO@ ues has been TC\ iC"'cd (>.'(tCO"sivcly.!I . l

REfERENCES
t T..""". M L """ ,.. Y. Aad. Sa.. 5U. 19-1-11 2, EiIJtb. 0 .:1$.;... _ . 0 .. Obdo Mod, .... ""loonNhr 115967. 1931. 1. u. S, ~ of Ht:oJill. 1'0',1(_. n.. C""""'l1 on ""'... TI... fut: Poi. ond ou.-fon. kJ .... ........... l ""'lf. 1m 4 w.II' ....... ,1.1 .. 1("".....1.. E. A. lind All""". S P J Mod. Chem. 4:!; 10101. 1\199.

,"t"'"

E.heM __

It"'"'"

1 _,,,,,,,,

5, BOIOQIni. A. tl. ~.I JAm. ''Iwm A,""", 39 5'8, 1999 6. An"'n<aII 1'II~"!kol A"""UhOll. 1'!Iannx..... ItC'flQ.".bolouc.
in M..... ,,,, Opioid" A R.."",~ 1'0'111",100. DC. A"",""'on 1'I\;Ir. 1O.,,,,u,1nI1 A.W>C I...... 2002 . 7, A.........,." Phar~;':"1 Auoc;,n...: Achie"n, ()pI."....1 11",. II"'''' I", OuIComeo. ".m NonpR-><npllon A""I, ..... W..... nl ...... !lC.
8 Small. L F. bkty. ~ 8 .. MO>CfI;'. E.. ond H.mmtl;h"".. C. K.: SlIidIn 011 Onot AddICt ...... SIoppI. 131110 .... P\IbI", lieallfl lttpon>..
""""""'" I'IwmaceuIicaI AM<l<1MiM. 1996

ww.."""". DC. $upon".,. I ..I of~ .... u. S ~ 1'nrII.", om.,.. 1938. 9. EdfJy. N 8 . Iblt.dl. H . ond 8."" I ... 0 J. 81111 WHO 14 1H

,,,.

TAILE

22~9

Derivatives of ] ,5' P')'rlllolidinedione

I L V S Pale1II 2.l31.5JI <-....10. Abwr. '21)808. I~, 12. 1Upopon. 11 . H........ D ILInd 1t";<I. II Ill. J Ora.. 0..... , 22 148<1.
1~7

10 Soort. 0. Ind II ...... L.; JAm. Oocm So<. 7' . '71, 19'11

ly 11' an kcli ncd re have

IJ. Owodl\a. ,1.1 S.. ltopOp:>f1. II J A... a..m. Soc- 7'l'7)0. 1957 14 0.."11, It , and 1111100. II W.: J 1'IIormornI. E.o.p lbtt 124 ~,. 19'8 I' , Sol I . Tot."II, II , ond K",,*y.. hi. S. J Phot ... . Jpn.I!4280.
I~,

I 10

lind
17 18 It :!O.
21 22. 2.1

M ud"l.

",nh Ico~\ nd ha\CO

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SELECTED READING
A",",icln CIcn, ...1S<IC'ely: 1'11'>1 Nillinoul MCilk:loW Chomiorry S~m",," ';um. C'~umbus. 0 11, Amtri<'an Choma! S<lCicly. 19048. pp. 1$--'19. A_y""",,, C<>del ... ond Cenaln Od.., AnalF"""'" A",,,,,,.. vc: """"', A He, ...... , IUltny. NI. Men:llt Co.. 1970. Nt.... ~ ...... Ilonu. l.. S : N.-row WUi'"w'" l'II4- I>no, lin. 8,262.
Am ..... ,Mmelli. E.: Inn.mm.t_ ""'i.nflMlm ' , ~Ib. Nr ... Y...... Sp:tnIm. 1<,171 Ib,"'"" . II II Mutphlnc:-lile .... l~."". In Introd",,_ lei Cloen, .. alPIIat """""'-'IY Nt... ~'od. Jolin Wtlry &. Son . 195~. pp. 39- 56Bk .. ~ A. It.. and C y. A. I' The .. ..;11 """ tlr."kIpo ...... ollNJ,."ic ...",... I'roJ. M .... Ctctn. 2.43-17,1963 1ktIJ......... \' .. 1' -.... 5.. .... Aqrn-ali. L Kidrcy loti. IJ 107. 1m V. "",,",I - I. S .. ... AJoterv:aII. L S<itnct ~119. 1m BcrJeI. f . .wI Mom-. A L 0 It"". (LlrId.. 2;349. I'MII. 11..... . F M.. ... II. Am N V AnIII. <;C,. 86JIO. 1%0 Run .... I J . and Allen. G I). I. Mo<IeIl. W (od.) 01 ~ 1970 197 1. St. Looj " C. V. ~IWI. 1970. p 210. 11........... 0 , J . bid). N B.. and I b ll"",,,'" H. BellI. W HO 13937. l~~ Br.ouck. M C~ eI aI. ~.,.,.,.: An~. No." V""Pmo ... 1973 Bra ......... T I'!W-uchr-. Thto-. IZU. 19)(> B"",.... I) M . """ fbnl). T, L D. J 1'Nomat'oI, Cleoid'" \~. 17. 1961. C... y. A F I'mI. Mod Chc-ta 1,~N-l84, 1970 Chappel. C I. ond ''011 s..cm.nn . C I'mI. MCiI, Clem. \ ~ _ 14~ . 11163. a..n. K K" l'IIy.""",klll Ind I'I"""IXllIoS",,1 """k an"""I. 1""' ucJ,"11 melho,j, ,of c'II .... 00.. u( .""1 ....10 ,"*"nl>. I , Am. PIland. A""",. Sd. &I.lB51. 19-19 a.-.. D 11 Nan:oc", Ilnop: 0 _1It"""'" PI.. ",,",<>Iot1 Nt.- Vorl.. 1971, C..." ..... P W. /\nu,,....; ..,.. In 1ko'Jtl. A (.... ~ ~1edM: ... Clemo,">,. 3ni oil N"", V....... Yo '.., . [nlCnC ....... 1970. PI' '" I - 1)6.1 CO)'iI'<. W l' N~ . ... i;nlhmmaklO) ,/')'r<tiQ. In Ru'l<". A (....). MOIl~""r a..,,,,,,,),. 3td od. "'''''' 1-'(10\. WileyInt.,....; ........ 1970. PI' 9~.1-9n doSt., .. ".. G, ICiI.): Analg""",. Ne", YM. Ac:a.kn,,,, - . I%S, Eddy. N II Chcttoo<:I1 ..........,., ""'" 1(. . . . of ...""'"...I, le .onaI~ """ .... od ' ''to- ,,"'.,. a..m. I..... )~) loI()~. 195\1,

".,

I!nw>.-.

DnI,.

m.

"'' ' ..,.1<

Ito.'""

""'ff....

'.1 ,

I'k'"'''' ,_.

a'''''"'''' ....

DlnIw. S D. eI.1 C;...,. '\al II". Rq'1do It. O C_ M.... II",. o,..m.

"n

o,..~ 5;IM. ~ ~S4. 197&.

,m

P Ady.N 8

H.h:Io. lI~.wI lInoondm.o.l

Bull .... ,1014 J51...aoZ.

""

F.4kIy.

8 . 1I.n.oll.

II ~."" R~.

0 I Bull. WHO

\7~-86J.

19'17

h .....

It P PnIJ PIwrm. Itd.n. 1m

110:,,,,,, ..., ..... ' A"''''....'II3I''' . . ., A",

190~411

I""P.

Ftl~ ......

J~""" 1I11)<II. G.

Cbenlio:al Socid).

E . AIIII,...,.-" A A"'l\;y ........... In A,,,,,, or.., M"<IH:; ... I CIotml"". vol. I. Ne .. vort. JolIn
I. Mni kl

\l,'1~.tSoo.I~I . 1'I'

GuId. " .""" C.II.II, M Ani

~, L Anlip)'n ... CT. H~_. 19'00

246m, 1%3
..... "'"' Il.......

1'00........,.
s........

A Cn'ocaIlIl ...... rar>hor R...... Neoo tl",..,...

0...... M Ao:d>II<lo<! A CnlKal

".., II

H,I_,.,. 19-it> Ikl1crbioch. I , 5<1000" .... 0, ~. II .

a,b!""""""" fb"

cr.

I............... A. L Maj, L L ...... L J AoWJtrt"" In 1I<qa. A. led). Mo:doanaI C'IottnoAry. JnI cd. "'"' Vorl.. W... ).I"k ......... . 1'110. PI'. n17 - 1.''10 1_-. P A_I. Syog/kU<: AMI,.........., I ')o''''''''Y~''''''_ ~ Von. ~""'" "'-. 1960 JlIK... n. 1' A. L ........ oIrt Ii)'t'k..... C. A M In Rurter. A. Icd.). PntM'
Aff~ .. ~

....... "'"

<t" N... Von. .A...I,..k" S)n'httor M'''JlII''....'' ondl>.l.Ron'"",,,fl'h,,,,,.,

Sao,.,.

Mon, .. W fl. "11,.,..0<0' l'h:.m"""". fI ..... I\I:.IM ~~ I . I'lLI). M..lkI. L. 8 .. """ WOOlb. I~ A ' Anal"', ....... """icL...... f'NI ""'" In51!16 21>7, I9tiJ ,\W Lrn. 6,n. 19M ~"", .. PurI~, p S; So,c"tcl.. ",io:aI ,.,.",.. ... ''''''' ..... ~u...:\_-.m ole<l ...II! """""'" ..... &<"or. J 1'Iwrn. S<1 ~5:!lM. 19t06, I' S. ~I""" "''''ptplkIo> "",toid ""'''I'''',-u.. IIMI'. "Icd.l, 1I0ndb0. . of E>.pen ........1 l'Ioartn>ooIofy 0pIIIHh I. 00(. 1I)Ii 1 IIt.ti... $pr\IIIC'Vertaa. 199) .u.y.....w.. A K....... b'i'>lt L 0 ~""""''''' .... Allied.,.,.,. T _ U""m.~y "" T.,..,." """'" 19';1. II .. IIIIdA'!oil<>. I> M ""luu'""_A&nt"-'oI. 1 'C Soct.17

Oro.'"

'n

I~pmon

1",.m;olicln;aJ F.JIC)"<kopcd .. of ~ lind Th<",!,<Iit"" ()o. [ON. ~r","~", l're.... 1970. 5<_. R. A .. on.! M. W . A';urlbmmatQr) A...... II<

!he C.nU'al I'<:I'YOIU Sy~.m, Ji;<,..- V... l . "'.....1 Ild.......

~ ~

1\Ii!oII. PI' !3 S~ I... .... L "Th< <1,111<01 .vaI. ."",

1647 8.1. Qo6.I ...... L """'~ 8 F>.1oo1 '*"""'- od*<l '" ,,,.0 . ..... In AiIIrnnII . ,,101 0.......... s..:,,'y Mcdlc,,,,, ChonI,,..., .01. I. Ntw VIri.. ""'n Wllry II!. s.-. ''l'il, rP 438 oI(l6

......,.,......... """01

... tu ........., .......

1'174 Shm. T V ~, ....... ...--.daI .... Clkm. I.. LI. I I 4(:(1. 1'172. S"OOIl. .1 .. and O_nl. T . L: 0p;00J ,"" ...... n"""I'IICM) 1.1 Jl'!nr"""KlIi, """ <"'m",IlI ~""""-"",1.:01"" "'" bond, .... ","," ,.tblt, A (cd.). H.....bool. of F j'<f\ ....n... ~1o&Y Opooodt L .... .... IIMIl Betl,n. Sp'n,a-V...... 1991 Sn)'<kl.S H ap-,<I_."""1f\I........ "P. . Sd.A .... 2J7.~!'I.

V""'- AcaoIonooo<:

Whil_""''''.
~

,.lIanwnMory._ .,,,...

~.

Om.

T _.. L......I C",,"" Rn. 18t77. I'l7S Wlndn-. C , A. Non.oImIo<I .."j .inflan\malory ,*,,1).
1J9 ~ 2(ll , I ~

"""

DniI R- Il

23

Steroid Hormones and Therapeutically Related Compounds

PHILJP J. PROTEAU
SInoid horrnonc~ and related products n:pn:senl one of !he .os! ...,idel), II!led classc~ of IhcmpeUIH:: ag~"b. These drugs are ~scd primaril y in bir1h control, honlloncn:placerncm lknpy H1RT). mnllmnlalory condmon, and cancer 111:81menlo MO~1 of thc'iC agem~ are chcrmcully based 00 a col1lIlOO 5UUClUI1Il b;Jclbone. the steroid baclbooc. Although lhI:y ~han: a common slIuc lUrdl foondauun. the van at ions .. the ~lrucl Un:s provide spe<:iricily for the unique molecular IIIJCU. Five gcnerul group!i o f steroid honllOIlC$ are di soos~: estrogens, progeslil~~. androgens. glucol.:uniooids. IIId mm"'I1IJocorti~'Oitb. TIle SlrocluraJ b.:l~ for the drfferroeI'.' in actions and the various lhcflIJX:ullC U~ for these COO1pound~ nn:' ellplon.'d. Several review artH::~ and tulS p!O\'ide e~cdlcnl cO\cra~e or the pharmacolog y and chcmbII}"

STEROID NOM ENCLATURE, STEREOCHEMISTRY, AND NUMBERING

shown In hgun: 23-1. nearly all ~Ieroids an: named as deri\'aU\'C'S of ehQle'tane, :mdro~t:me, pregn:IlIe, or e$If.me, The siandard s),'lc m of numbering i~ ill u,lr.ned With 5(I,dl(:>k-Sl:me. The ah,olulc \1('reochC'm"lry of tile m()lccur(' and an)' sub stilucnls i~ shnll n with !oOtid {fJ) and d:I!>hed (a) bond~. M051 carbons ha\e one {J bond and one a bone!. wilh tile {J bontI l)'in~ clO!>Cr to the " I..,.," Of CIII and CI9 melhyl ~Klo: of the molccule. 80th a and (J sllh~hluenl\ ilia), be a:\lol <It cqumonal. 1111' s)'~t~m of dc)lgnolmg )lereoc/w.'miSlry can besl be IlIu~lr.m~d b)' u..e of 5a-androslalle (Fig. 23-2).
A~

uf steroid

IIOI'l11000(;S.

." .
Iii

Su-crrl

1_

",

"......,.

EMil, III 01 COi .. ,iOI'I W1d SY'h" ... k Namn

>.,c

>.,c""

"
I~EslrIdol

"
(EIlra- I.3.5(10.... _. 3.17II-ddJ

o
( 17 .21 'Oihydto~~_
3, n.20-~ WeI

COili8ol1e

(I~Hpo"Y"o,,*~--.3-ooe1

T """'*Orte

767

OH

o
TH\O$1erone

l .1

ffP
CH '

""'

H JG
H

;f
H

5u.8o-Andro$Iane

",.Figure 13- 4 AllematJve trpfl!'5oMtallOOS of Sle<oods. nomenclature 1 indicale the backbone ~u:rrochcmtSU')' tJr. 0 t" ...e n ring!> . For e~amplc, Sa slcroid~ nrc All! mrllS. l1li 5IJ Slcroid~ ure AlB d:t. The l~nllS n'lt ~nd lilt/I m uwd Dnul()gou~ ly 10 Irmr.! and .# for indicuti ng stereochcnll. Il)' I bood~ conn.:cting ring' (....g .. the C9:CIO borKlthat COIIntm nngs A and e), The u<;e Oflhcsc terms is indicated In FlJIK 23-2. The lJ'OI'Iu ion of double bonds can be dc)lgnw.ed In an)m the \ 'IUlQU) ways shown below. Double bond~ from a ~ go tov.ani C9 or el4, lIod lOOse from 00 may 10 1 0--..1 e21 or C22. In such ca>oes. both carbons are indlcalal. lhe name if the double bond 1 not between ~ 5 numbered e:ubon~ (e.g .. S.... androsl-S( 14}cnc or 5.... J~' .. and~I CBC: sec Fig. 133). ~ pnnclples of modem .. roid 11Omeoclaltlre are applied to nllmlng ;;e,cn.1 COII.,1Ct steroId drugs shown 111 Figure 23-1. Such ,,:{)m nlOll names as 1~51a.<lrn"'r and rom.flmt ~ ob\'iou~ l y rIlucheasiertousc lh~111 hc long sy~ lcmauc ~ Suhstiwcll1s I11U~t ulways hal'e thei r pill'illon and Slem> che ntlSl!)' clearly indicated. oowe\er. ",hen common_ are used (e,g .. 17 a-mclhyllest.osterone. 9 .... n Uoro.:orIL!oOD:l Steroid dro'o\ ings sometirt"leS appear v.'ilh III~ dr.ln .. stead of methy ls (C H,), arKl backbone slerrochemlW)' I>C indicated unk-Sll il diffen from lhat of SrI'-:mdrost;utr jft: 23-4). Th i\ manner of repKSCl'lllllion should onl) ~ when there j. no ambiguity in the implied ~I~reochanl~

Figure 23 - 2 SterOId

nomendil1ure -~It'feochemIStry.

The slerrocnemislry of the B 31 C5 i~ al"'ays indicated III the: name. Tbe Slcrrochcmi~lry of the ocher H :noms i~ not ind icated unless it di fTer!l frum 5ll'-(:hc)leS(ane. OIanging the stereochc:mbtry of tmy or the ring jUIK1ure Of badbooe carooos (~ho"'''n in Fig. 231 "'nh II MaY)' 1irk 00 5M:holesUlnt) grc:llly changes the shape of !he: 'Ianid. as secn in Ihc: examples of 5ll'.8a-androManc and 5,8-andlU!iumc (Fig. 23 2). Because of the immense effect that "OOcl.bont' ~tereo CheJllI ~ ry 11M on the slmpeofthc molecule. the Imemanonal Umon of Pure and Applied Cheml~lry (IU PA C) rul c~~ strongly Il.'C()mmend lhall hc slcreochemislly:1I all backbooe carboo s be c leady ~ho" n. 1l!.11 is, all hydrogen s oln ng the b'lCkbonc should be drawn . Wilen the SlereQChcrni~try b not known. a WDvy li ne is u)oC(i in the drawing, and the G",d, kiter xi ({) is used in the name InSlelld of (l' or p. M elhyl~ 1m! explici tly indiratoo a.~ CH). 'The terms cis :md lrom arc occasionally used in steroid

STEROID BIOSYNTHESIS
5-AOOroslene or ,1sAndr()$tene or
H
5<:l Andr()$l~"""

or

Andfosls-e ....

5o.,1I.And<ostene

5o-Ao'doo.HI(14r- or
50",,1(' ' I_AndroeIene

Figure 23 - 3 SIt'fOO nomendalUre-doubll." boods.

Steroid humlone~ in mammals an: bio:;) nth ....,''-oo fmen t:IIole$tl.'ro l. which in 111m ;s made in '1;'10 from 1J,:etyl-1:OCnly. A (llCctylCoA) 'lin the n1l.""alonate pathway. Although Illmun_ do obtain approximately 300 mg of cholc~tMll per day in tnel r diets. a g!"Ca ter amount (about I II) is b!oI;y si~ed per day. A schematIC ootlilli' orthese bi(5)ntlll-llC~ way' I' <,.ho"'n in Fi gure 23-S. eonvenlOll of cholesterol 10 prellneoolone I' the IIm8 Mep in steroid hormone bi05)"nlhc~is, II is not dJe malic lr,llt5fOOlllltioo 1t,,('lf that i< Tate limihng. the ITansloculion of coolc<;terol 1 lhe InBCr mil 0 membrane of .... eroi d-\ynt hesi7j ng cc lb is nile IImllr.. ' 4 l ey prot(1Il 1n1'01\'N! in the tmn$IOC ahon is the S~1'l.II

Q.' ale<Ol

"
"","'-""'/'
1

.00
' 7~~

3111'50

HO,A../~

" "
P'OfII'S\eI"",

171l-Hydro..,pregnenoiDnII

IPOijlii,1in1

1"'''''w",,'.'"" I 2 ."" 1
";; 0

I 21 ,..,= / ... 1.,." HE

00 HO 0..,.._ .00

0''''-''':'- "

HO
(OHEA)

"
,

" "
AIdlllucone [mlneralocoftk:old]

HyOro!:ornone (oortieoI)

DtI'rydo 00fj .-.:Iootl..,,_

[glL'OOCorticokf)

",C
o
11111150

, HSO

" "
1

"" "1 ,

",,0

Ahdoosleriedione

",,00

figure 23 - 5 OUtlli'lE! of the biosynthesis of 51efOid hor''''ifS J/3-HSD. 3,B-hydr02;

"

lIt.OId

dehyd~.l

"
rI~!

...........
Ew""
precUrMlf o(the steroIds. TIlls enqme medlhle~ a three-stcp pfOCc..~~ invoh'cd In the oxidmh'c metabolism of thc si de chain. Socct'S.'ii\e hy droxylatlons at C20 and 02 are follOlled by oxidalh'e cleauge of the C20--C22 boott proyid ing pregf\CooIonc. rn,goeoolooc: can be either directly cooverted mlo progestcrone or modified for 5yn the~is of glucoc:OI1icoids. Clilrogcns. aud nndrogcns. lotroduct ion of unsawrntion inlo the A ring lead~ tOlhe formation of proces. u:rone. Specifically. oXJ(\auon of the alcohol at CliO the ketone provides a suilslrale in lI'hlch 1 omeril.lItion of the . .J~'~ double bond to the .J~" double bond is facilitated. Thl5 tntil~formation is med iuted by a bifuoclion31 cnlyme . 3~ hydroxysleroid dchydrogenao;e/.J~ oomel1lse (3~H SD).

l5ol!'MfolSt'; 17p-HSD, l1p.hy-

oxyslefOld detlydrogenase.

[anDrogen]

,~Regulator)'

proIein (StA R). Defts in lhe StA R gene

bd locongcniml lipOId adrenal hyperpla~u., a rnrc oond.uon lIW~ed by a deficiency of adrenal and gonadal steroid horelt7.)'lT~ io\'ohcd In lhe tran~rormaliOf\or choblerol to lhe hoononcs are rNinly C)'lochromes P-4 50 aoo drlJ)'drogenases. The m:un rnule~ of biosymhesis or llle hor-

_ ..,,The

!ll()l'l(5 are depiCled 111 Fi gure 23-5. Emoolol. tC\IOSlerone. puge,lcl'UllC. :11<101>1<:1"00(', nnd hydrocortisooc arc repreM'nIlIha of the disllnct steroid rtteptOf ligand, thaI are sllo~ n. Purther metabolic f:Ma of these compounds arc prcscnlc:d mder the specifIC structural c1a,s. An enfy.ne denoted c),lochrorlle P450"", (sec for side main ck::I\'<!b'C) mcd.:ues the c leavage o f the C I7 side cham III the I) nng of the stemllO pronde prt'gnenolone. the C2 L

This cn:cyme can -..:1 011

SC'\'er~1

3-o15-c'roe stcrozds In addi.

11011 to pregnenolone. Hydroltylatloo at CI7 pro~ides the prttursorfor both sex steroid hoonooes and glucoconicoids. C~ tochrome P-lSOcl 7 hydroxylatC:5 pregnenolone and progt:Su."ronc to pro"lde The corresponding 17a-hydrox),latcd compounds. 17a-Hydroxypregncoolonc can be converted 10 1 7a-h~droxyprol..c:steronc by 3,8-II SO. Cytochrome P450.::17 i~ also a bifullCliOllaI enlynlt'. wHh lyase activity In addiuon to the hydro~ylase action . The Cl 7.20 lyase activity is crucial for the formation of the ~ hormones. The lyase o~idali"dy removes lhe IWO carbons III CI7 .. pro\iding lhe CI7 ketone. In The case of l7a-hydro~yprt'gneoolone .. the prodUCll S dchydroc:piandrosTeronc (DIlEA ). lf l7a- hydro~ ),progC:5lcronc is The SUbSlrllTe for the lyaM:. androstenedione rt'sulis. TIll' con\'ersion of l7a-h ydro~)'progeslerone TO an drostenedione is limiTed in humans .. although in OIbt-r species Thi S IS an ImportanT paThway. DHEA IS con,'encd TO androSTenedione b) The action o f J,8- HSO. Androstenedione can Clther be: con"cned to tcstosterone b)' the acuon of 17,8h)dro~yqcroid dehydrogenase ( I7,8-HSDJ or he It:lns formc."() 1010 eslrone by aromatilsc .. a uniqllC cyTochrome p450 that arornatius ,...., A ring of eenai n stcroid PfeClIr.;or!l. Tc..~loslcrol'le is IU'Qmatil.ed 10 17,8-e1;tradiol by \...., same c n ,yme. I7,8- HSD acts on estrone to fonn l7,8-e~Tradiol. If lestoST erone i ~ acted on by 5a-reductasc.. 5a-dihydrotestosteron,e (DIIT) .. 1111 andl'O!;en imponant in t"'" prostate is produced. TIle major roule 10 glllCoconkQid) diverge1' ilt 17a-h),_ droxy~goenokJnc,. Inslead of oxiwni-'e cleavage lit Cl7 .. 3,8- HSD acu on this substTllte 10 pru~ide l7a-h)'dro~ypro gest('J'(J<le. Sma.llamounts of l7a-h>droxyprogcsterooe can be produced directly from progoteronc. although this is not a majorpalhv;ay in humans. Sequential action or2l-hydro~ ) lone (Cyp21 J and I I ,8-hydro~ )'Iase (Cyp [ [ 8 [ I provide hydroo:.:onisone .. the key glucoooniooid in humans. If PfOiIeSlcrooe is directly acted on by 2 1 - h)dro~)lase (Cyp21) .. ll-deo.xyron icostcronc: IS produced. a precursor to lhe mincTlllocortiroid aldosterone. In tiSSU v; here aldosT e!> erolle is ,)mhesized. the mullifunctional enz)'nlC aldosterone \ynthaloC (Cypl 182) nlCdiHlc~ (he hydroxylation at Cil as well ~ the two-stcp o~ idation ofC I8to an aldehyde. prol id mg aldo!;T erone. v;hich exi~T ~ prcdonnnantly in the c)'clk hcml~lal form.

TABU 2)-1

Solubillt ieJ of Steroid J

Solubility (91100 ml)
CHe t,
EtO M

Cbdc"crul
T~_

~2

11

T._~""",

prI.lpion.>I<O

OdI)dwrholor or1II
~...tioI

- .. -.- ., " '''''''''''

""""" '"""""""'"
It)'dtu.;.;JrJ._
M

., "

'"

" "
" ,

I),))

0.01

'"

~ ),1>1'().

oaII

lI)olro<vn_
II)~

"""'*
SaPO. J;I,\,

1'mIn.1iQIune PrnlnllOk_ .... "'1* Prnlnl""""'" ~IPO. ,..,11

" '''''''- " O. " " "

0.'

.. ,

,., "

0",

--'"
,~-

..... .....

... '"",'
,~

'"-

0",

,.....
"

"

CHEMICAL AND PHYSICAL PROPERTIES OF STEROIDS

With fev; exceptions. the S1eroilb lire white crystalline solids. 1"hey may be in the fonn of needles .. leaflets .. pl3ldeTs .. or amorphous panicles .. dependini o n the paniculllI compound. the so lvent u-cd In crysllllli1J1tion, and the skill and luck of the C'hc m i~l . As the steroids hale 17 or morecurbon lIcoms. it is not \urpri ~i ng th31 lhocy lend to be waler inso luble. Addition of h)'drox)'l or OIher pollir groups (or decreasing C'lU'bons) lIIereases wllter solubility slightly. lIS expected. Salts are the most watcr soluble. Ex amplCli ~re soov;n in T ab le 23- 1.

v;'alcr SOluble by malin, suitable e,tcr deri,'al, .~~ of h)~ X) I groups. Dcri\all\'es \\ ith iocre35Cd lipid solubillt) 1ft ofT made to decrease the rute of rclcao;,c o r the drug (1'01 en intromu)o(,,,lar IDJecUOll ~1Ie!> (I ,e ... 10 depot prcparatiODH More IIpld \Oiuble dcrivatin!s al~ ha,c Impro.cd ~~In" sorption JNopc!ItleS and t hu~ arc: prcfaRd fOl'dcnn;uolop.:<tl preparatloos Dcri ~nt h'e~ wllh incn:aloCd \\ liter sotubilltl _ needed for Intra.cnous preparation s. S,oce h)drolpJ"I ellZ)'ll'ICll are found throughout mammalian cells. ~i.1lly III the h~er.. con,enmg hydro~yl groups to estcn ~ JlOIIoI~ nlficantly modify the acti\'i ly of most conlpound~. Some steroid~ (e .g... estradiol. prog esterone. 1111<.1 tel.!~ one) lire pan icularl)' susceptible 10 rapid I1let3!)oli,m od'ief absorption or ropld inacti\ation in the gaSlroml~IIl.l11llr.1 before abl.orpt ion. These inacti\'allon procc:sscs limn the: ct fecti\'cllC'is of these bormoncs as orally o. Dllable ~ .. though micronll.cd fonns of cstratlio1 and ~enn:_ a"ui lllble for oral adm inistrat,oo. ~Tin1('S ... jlmplect.:. ica! modirlCatlon can dccrt'3Se tbt- mtt 0( Il\;IC'\i'~UOllIlld. lhereby .. IOCrt'aR the drug' s half-h fe or male it ~bk: " be taken ornlly. Examples o f l'Om mon chemical modlficallOlI~ ~ Illit. T rated in Fig ure 23-6. Drul!~ such as te5tOSTeroncn",I~1 prop/OI1(11t (c ),pionate) and mclhy lpredni<;()lonc "odium '" cinaT :1 prodmg$ thut requirt' hydrol)s;\ to reka51: dIo e rt' acti"e hormone in the bod)'.

STEROID HORMONE RE CEPTORS

Stcroid hornlOllCS regulale Tissue-specIfIC gene uPIT' TllC indl~odual bormoncs exhibitA!ffillrbble 1I,;,ue ~ ity .. e .en though Their STrOCtur.ll difference, an: rdJIn minor. Estroge ns soch as eslradiol II1('I1"3.<;e utcOne cdl li ferution. for uamp!e. but not prostate t1:11 proll~"",

CHANGES TO MODIFY PHARMACOKINETIC PROPERTIES OF STEROIDS

As v; Ith many OIher compounds tkscribed In PR'vious chapters. the STeroids can be made more lipid <;()Iublc or more

Ch~pl<'r

2J SlutJiJ 1/'!ml/JIltJ ",,,/

The"'l~UI;mtl,.

Rt laltd C"'''l'lJImds

771

1 ''''''ea:;o I ipit! $n!ybllitv (Slower rat& 01 release lor dI!pOI preparalion ; inctl!ilS8 skln abaorplion)
0 ",C 0

,
H

",C 0
b

H '-'

,
H

(1M doH: 16-25 "'II 2-.1 tlmeslW&ak)

TIISlOSletOllll C)clopeo1ty\pto1l1onata'

(Testosterone cyp;on.ta; 1M dose : 200400 "'II e....-y 4 weeks)

HO
H,c

H,C
H

J OH

OH
HO

,
F

-OH

",C
~

H
,

CH, -O,!. 0 CH3 H

0 Triarnclnoklnoe

Triamc.nolone Acetorride (Increased!Oplcal actMty)

o
H,C

OH

HO'y"'l--\
H

H
,

--,
CH,

"'.
Mothylprednisolontl SOOium SOJeeinate (Sultici&nlly wahl.soIubIe lor IV)

CH,

Meltlyipredlllsoione
(Not watersoIuble)

3. Deaeast Inec!ivlllion H,c

H'<;

OH

,
H

--.
GIIr.:l

-CH,

H,C

H H

O'~

, H

And,oslenediooe
(Reduced ectMty I9IaIive 10 .BSIOS.8lOtl!!!)

Testosterone (Nol orally ac1i,..)

to

17 a Moltlyltu.osterooe (Otally acti,.. - 17 OXidBUon no! possjble)

Figure 23 - 6 Common sterOid modllKollJO<lS

ollter therolpeutIC utili!)' ',prodrug

testosterone do the rc'cl'SI:. but neither IlUI' I'st~cns aff(X"t stomach epi thelium. The sell'eti\"ity is the presence of se leelhe steroid receptors in indi vidual tisstles. This s!ioo proQ\'ervicw of qeroid honnonc receptors and their action. ,1 ' ~ ,temid receptors themselves are key players in gene . but many other proteins are ;n"ol '00 ;n thi s proproteins. fOf example. he lp fold lhe recepllll" illl lhe proper thr~-edi mcnsional shnpc fill" billding
:b

such

the steroid ligand. Toge ther. the steroid honnorte receptor and as..wc iated protcin$ ( Fig. 23-7) make up the mmun: n:te pllll" compicx. Once the ligand is bound to the n:ccptor. the chapcrunc pn)teins dis-weiate, and the recCplOfS di Illcril.e :md arc postltlmslut ionaiJy modified. typically by pho... phoryl31i Ofl. Some of the sieroid receptor-ligalld complexes must be tr~nspork'd into the l1ucleus prior to illler:K;lion with DNA. 1he acti"~ led r~plor_lig:lOd ~omplcx binds 10 u rgel DNA. alld various ~oacliva\o!1! Of corcprcsson; arc rl."cruiled to the DNA - receptor eomple~ . Tr:.l!!scriplion (or reprcssilHl

ER"

115 2!0 3 10

<I

"

'T'~

'"'

ER,
PR,

1 -

AA

( (

GR

MR

Figure 2l - 1 funcllOOoll doma,r.s of the sterood horlllOllr (~ ceptors AJ{ otnd!ogen leceptOf, fR. l'Suogt'n (I'(eptor. (ocortlcOKI receptor. MR. mlneralocorllcood receptor. n ~

GR..

progesterone receptor

Ilk: ..arne. btu Ilk: flumlk:r of auun(l :>('1<1, for e.w:h rtetpb' \me,

23- 7 Ueneroc structur~1 ITl()(!eI 01 a ~Itfotd hofmone-receplor {ompt~~ and I ~ actrvOlt,on lor gene tf.1nscrophon. AT, I'lfstooeacetylua~'erilS@. CA. roact,vator, CC {ochapefooe; HSP. Ileal YlOCl: protem; SHR, 51E'f01d horrTlOl'll' receptor

F;gu~

G.wTL

I ,v.'t'",,,,,,,il' 'AlB", J,<mam Onu lhe ',cfOld

1.pWrro.~~

ha., bound 10 the 'iUJCl l\coc(,l. th,. 00111;1'" la!;ocalled ., H m,mu/m,,' Jm"'''''i ...."v:.'e' ,he ho.)f"""'" ~'pon"'. adJ~nl to 11>0: lent'" 1).., ~ n:<op'on,.e ckment>.., lhe I)SA ildJOICCIII 11111\( I~CI ~cnc They .....,.,""n ah:. 11. I)! b"""'r:uI DNA ""I"e""'" amI con,,,, o( I... " "half "In
IlI:It"'" ""1"""'1c:d II) 'an~"k 'p.>o;~1 In the nl"tar..,,:~ IlonIM"1C =qliu, ~omrlc ~c- ""I'I ,,-, dm"""; 1hr dlll.."t lUll' "II"", a".,, to bnllI IIdlf ,Ue,. 1l\t, nUdC<MI""~~; and _p.oc;ng beI ..""n lhe 11:111 ,,(C, an: c''nll~1 (Hrlnc lfI"Cdi"" 0(,1\( ',-,",lU.' ""n>ld IIoo"on. Aflef 1hrduDcr "'Ill all pnH~II" IlaH ha:n ",auu<'Il 10 .. 11~ Ol\A Irnn...."phon .. In"'alcd 2. (),vAlhnJ"" /"'C") do"'''''' Th" ~h..n >oecIKln " nIIdr lip abuut b5 anion" ...,d, . ()f~"nl/cd IIIlu 1"0 fHIC "flFer ~f, are lmp',"~1I1 fur =~.1II 11U11 and hind'''1l1U 11>0: 1)<.'\ clcmc-nb. TIlt ~Ino; fine."" '"'" al ... ~"1)Ic for of ,he ",cq>lOl'. .1 H"'~.. , " /) " J ,k"'klll! " h" ':lll.hk h,,~~...- "'I!'on "J"IIeM' ION

of Irllllscriptron ) OO:;C UI":'> .... h,"" all 01 I~ n~"cc''''lT)' :USOCIO'CU

proICln5 have !.>cen .... -cnlllcd to the DNA -n:ccph"' COlnl)lc~ .

"'pl, ...

"""""'>1)'

,""'ric,.,.

""mrle,.

Stnacture of Steroid Hormone Rec:eptors

Tbc complcnK'nlary DNA _ (eDNA,) of all Ilk' majOr ~[eroitl honnone receplOf\ 1I~\f,' t>..."tm c1()rllxl. lp\ln~ Inc romplete WlUOO acid sequcoce o f cac ho Ahhou!1h the whole three dl ntensional ~Ul'Clllre of a '>l\...-oid 1I000noll(' receptor ha_ 001 been frOl wd ($IruclUrc_ or the ligmldb,"dllll! domain,. "f the cstrogen. aodrogen. and progc.u:ron!." m:cptor. howe been chlcrdau:d: sec belo ....' in Ihl' <.ecllon ). the ruocliOllJI rok of each part j . well klltlwn ('l'C Fig_ :!3_1I ),1 The urg;",,~alion of tile domain!> for all L)~' of ~lcrol'.1 h....rmonc n:ccpl~ i,

"""Ie...- lo,;"hf-'lIOn aoo '''-''''''P1n I~ "r Iht 'tcro..J- r~c.pl"r .vmrk:, Inl" II\( nu,lcu,.
,n,ot. cd ",,"

CIrr",'..oI 1t~""Jb",J,,,( '/"'E" J '}'""mll/ 1./1/)) . The: C mlllal ,,,,,100.,.. abolll 2:10 ~m,oo lII:Kh. llu1_ .he "clUlIJ IlonnoncllmJ'"r '''e aoo ,. al'" In,,,hN

dom,,"

~a'IllJcI"'''(k "1 Ir~n""npllo":11 "",mal"," . n.>ccplOI' '"

oon. bond'll$ to chapiO""'"

""""" <;;1_
r~JlIQ.>m,

proICln~ (u'scu .. ...:d bdo.. ).:and. In

sehe~

,"." krw;.n,") pafllcul:or ,erie,.

structure of Ste; oid Hoe ... 0_ Receptor c.mpteJl."

SItroId hormone:

-..e rect'plor
I:fI)IIC

m:cploroomple.l~ include: ,he slen:J1d MrlIS well ai OIhcr (lfOlC I n.~. predormn..amly chap-

(heat . hock) prolcin$, cochopcroncs. ~nd inununophihnt (Pi S. 2J-7).~ 9 Thei r rule is 10 "chaperone" the correct confonnallon lind folding of complc.l procdns. which is

OOII:rwise much nM.ll"e difficull llS tempernt ures increase. AI fIOI'Illal phy~lOlogical temperatures. the chaperone proIcios .wi! ,he prupt'r folding of large proteins such a~ steroid 1moonen..'CCpI()f$. The individual comporocnlS vary dcpclldIII 1)11 the Iype o f ~eroid hormone n::ceptor Withoot the
d\opefQIl(5.

hale al..o pro~itkd IInportant infonnauon. Although the eonformatlon\ of ngld molecules in el)~lah and their pn:rCfRd COf1fom13liQn~ in ~ullon ... IIh receptOl"' ean difter. II'~ nowelcar from xraycrysuJlography 51u<hes of'tctO,ds, pt"OlItllglandllls, th)nlld compouoolo. and many other drug classes Ihat 'hI' ttehnlquc ean be a po ... erful tool III urw,ler standing drug OCI,OO and ,n designing new drul!,19:1 TIle relation~h,p i, sll~IShlfllfWartl Steruid drug~ usuall) do not have a eharge lind. a, II n:.,ult. are held [() their recc ptoo by relmively we:lk forces of uUrac::lion. TIll: 'lime is true for steroid molecule~ a.~ they 'pack" into cry,'als. In both e,em~, lhe bnldilll! t'ocr1!Y is tOO sm:dlto hold any but lowenergy COOfUfnlUlioo~. ln ~hon. the ~croid eonformatlon 0bserved III stel"Old el)').[al~ often i~ the sallie or vel)' slm,lar to lhat at the R.'CCptUf
ESTROGEN RECEPTORS

the steroid honnoncbindinl! ,lie on!he IU't'plOf not have the proper folding 100 l"OOromunon for Opll-

m!

~d

bulding.

Once the steroid hOlTllOOe binds 10 the ra.'I.'plOI', a conforl1li110031 change of ,he ~plOr oceUI">. and the mature ,.... cqxor romplC\ di5sociales ( Fig. 23-1) , The I'CCCplOI", di1IIm/.ed. phol.phoryl:ucd. and trunsported into the nudel/s. .r nete~!>.1ry. The re. the zi nc li nger<; on the stero id homlone rtetplOf bi ntl 10 the target gene{sj III the DNA. Addl1ional proteinS an: rteru ited to the receptor- DNA cOf1lple~ prior 10 initiation or n:PfI!.~sion of tr,rn..rn ption. 10 l1le.'oC Ilddilional fifOICms include COOCI;V"'.I1Or<; or C()n:pre.'I.0\0tlI and hi51 00e a:tl)lln"l~rerases. T ypically. the reccptor- DNA -cooctivatlIf ~'OI1lplex displays hl)l()l"lt' lICC(y ltr.ln~fer.l.. action ..... hlCh ~ rrb.,~ lhe chromatin Siruclun:. allo .... i n~ bind;nJ of RNA pol) meta<.(' II and the Qlb6equcnt lI1itlation of 1r:m ..mptlOn_ Ifron:pressors are recn med tothe conlplcx, dc:lCClylatlOll of histone complex is fxililatoo. pre,enu ng Ir~n~ pl ion.
XRAY CRYSTAUOGRAPHY A ND STEROID FIT AT THE NfCEPTOR
A~ n)emioned above. xmy Mructures have t'M,,'e n Mllvcd for

11Ic..... are 1.... 0 dl~l lOcl e,trogen nxeptOD (ER,). c'tTOllen T\:t"\'ptor a (EK.. ) lind e~trollell receptor P t ER~ ..... hlch an:

encoded by dil"ferenl geoc,,!J The ERs hale di"incl ti~~uc dislributlons and can ha'e distinct aclionS on the tllrge1 g"ocs . ER" can be fOllnd in high abundance III the uterus, ,aginu, IUI<.I ()~'Irie~. ," \\dl :I' in lhe bre'l,I, the hypollmla mus. en<.lothehal cell~. lind va,,"ular smooth Inu,,"le. ER/I is fOllOO in greall:~t abtllKlancc m lhe o,aries 3nd the prolotate, cula with reduced occurrence In lhe lungs. br.llll. and ture.:!..! Although many hg;uKl~ bloo With ,1I11i1;u .Iffinlt~ to both ra:eptor ~ubt)pes. loOmc hllands an: sclecule for one or the other rc.:eptor.~ ~ ERs have rec:ei,ed C\tenM~e m,esllgatl()n. IV date . and allhough much ha;, been leamc:d about how lhe ERs fUIK11011 ... hen bouootv agutllsts or an llIgortlsb. new in~lghb an: (."OOlinually bemg galllc:d.- 10

''I..

PROGESTERONE RECEPTORS

die liga ndbindlng doma ins o f ~ver.ll o f the stero id honoolle rtCtpton. 11M:: structures for the l i~and.bindlllil dom ui n, for tstrog<'n re<:cplon a and p. II ~ J the prtlgt:)leronc R:CC'p... " and the aOOTQj!cn receplor lj ha'c all b..'Cn dclennilled. IIomok!gy Inodehnll ~lrocIU""'S for the glucot"Ol1icoid and .ncralocOflicoid recepton havc been en:atc:d b.::i'>Cd on the l'ogc:Slcronc lruclure.'" II

n.e xray el)'<;tlll SlntClUres of lhe cstTQj!en, progc~tcrooe.

~1I:roids

The prog,,-,tCI'QI)e rec:epto, can 01..0 be found III t .... o f<)l1ns. bUI th~ are denIed frum a single gcnc, Pit ... ha~ had 1M amino acld~ InmClllcd from the N lerminus of P it II. pmvidlnl1 a receptor that has different in teracti01l' with larget genc~ aoo associuted pro!ei n~. PR.. mamly mediatc, the ~tlmula 1 01)' ocliulIS of proge'terone. PR .. act~ a.~ a lrJn..criplional inhlbllor of eSlrogen. aoo~en. glucoc~xucOld. nuneralocorlicoid. and PRo receptOl'll.1 These d,fferentlal acuon~ an: belie' ed to be dul' to int('fllCtion~ .... tth d,fferent eOO<."1i,al~ and oore~. TIle DNA and ligandblndm, domalll~ for lhe IWO rectptON art idenlU;-al.
A NDROGEN, GLUCOCORTICOID, ANO M INERALOCORnCOID RECEPTORS

MIl androgen reccptOD ha\c revealc:d 11 ~ey dlfferellcc that Dds w the unique ligand specirlCll Y of the c~trogen re<:ep1IJn.11. Ij In the region of the ligandbindu!8 domain, where

binds. are key rel>iducs that blntl 10 Eltller the phenoli\: A ring of eS lrogen~ Of the enone A ring rI proge,lerone Of te~'ostel'Qne. In the CIt..'oC of Ihe e..~l rogen IeCl:ptor. gl utamme arid argi nine residues arc irnport ant in a ~~~enb(mtling ne twori: tlult invol ~es the phenolIC hydro 1)1 In coo' rm.I IO this ~tructur arrnngcmcnt. the progc'Ster .al .nd IIJ1drogcn receptors ha,c glu tantlllc and arginine tt:wJucs that hydrogen bond 1 ,he A-fing c~ of JII"OgoK0 ""..: IIJ1d tcstosterone . The ehange from glutamate. a h),..... nbonJ acceptor. 10 gl ul WlIioc. a hydrot!:enbond donor. Imlleal for !he discrim ination bel ..... een cslTQj!ens aoo other IIrIOId hormones. n.e :>'ray ery~tal ,ttoctun:) of the 'teroid honnorlC!; them

be A ring of

'*'

The androgen. glucoc:on'(''Old. and mllleraloe<iM lCOId receptors an: presem 111 only a 'ingle form. Onl) one genc lind onc protein are kno ..... n for ea..'h receptor. Mutalll forms of the androgen" and gh.... 'OCOfIicoid\! n:ceplON an: ~no .... n, wid e' Illenee i~ n[(M,mting that ..ollie of the~ mutant recqIIon an: as.'loc,ated .... I'h d,sco:lSC states.

GnRH AND GONADOTROPINS

1be gonadotropll1s lire peptide_ thai ha'e a clO!oC fuoctiOlUlI

rellllion~h ip to the e"rogen~. progestcmne,

and tCSIrn.teronc.

iftcd dccof!Cptide (10 affilOO acids): l"YroGl uIII~Trp-Xf Tyr.(Jly LeuArg I'roGly Nll j The P)roglulamalc al !hi: 1'1 lerminus and lhe Ctcmli IIPI amide lINingmID Ihi~ JX1llid!' from unnMxhrted dccapeplitb. Analogue~ ofGnRlllh3IlR u~:d lhel'oIpcuticall) ao: co'ereti in Chapter 25.

Pltuit.,., CGnadoboplns: LH and FSH

The piLU ll ary gon:!dOlropin, 1.11 and I'S II. ,heir mucturn, genc,," n:ceplors. bIOlogical rule,. and their regUlation I. dulling by IlCgull\"(." feedbacL actioos or steroill OOU ....k>l h:l\e been 'ilullied InlenSt.ely." J.I FSIt. LH. WId CG~. glycopepllllc lIimeN wilh the ,ame (l subunit bUI lIi lTl."frII

fJ subunit~.

They arc clilled gonadOll1l1';1IS because of their acti()ll~ on the gonads. As ~hown in Figure~ 239 through 23" . lhey con trol ovulation. ~pcrrnatogcnesis. and lIc,clopmcnl of ~~ organs. and Iht:y nlaimain ("Il"egnancy. An addnional pcpll&::. gonadotropinreleasing homlOllC (GnRH). rt'gulales release of 1iH; gOlladoLropin~. Includcll in Ihi, group ;lre the fol lowing: ~lnrelca..lnl! honnone (Gn RH) LUleinl,.ing ho,nll>OO (LIt) FoIlidc"lmul~ltnl hormone (FS H) CbonOOIf; ~ropin rCG; hCC .5 hunWl ~rortn). 3 III)topcpude produced by lhe p:oanla. ll~ pharm:ocologlf;al """,ions an: c.s,;cnlially lhe 0Iart1e ~ lhose of Li t

In female~, LH and FSH rc&ulate tbe ITiCn>tru;d cyck (<a: Figs. 239 lind 2311). Al ,he ,tan or Ike cycle. plasma co-ccnll1llioft., of cSll1ldiol and OIlw:r estrogens ( Fig. 23 I I) anrJ progt."Slerune a", low, FSH and UI sum ulale "C,.er.tI O\~ folheles enlarge and begm de\"ClOPUlB more I1Iptlily ~ othe",. A ncr a few days, only one follicle toon l mues dc"cilvIIlg 10 the release of I mature O'UIll. The gl'oIllu losa all. 01 lhe matunng rollicle~ begin ~O:ling c.\trogens. IIhlCfl IbeI callsc 1hc utcrine cnuomelrlum 10 lhic\..en. Vaginal:tlld an cal j;CCretions iocll'lI5C. Gon;o(louopin" and CM~cn rm lhelr ma U;II11um pI:L~nla cooccnlr.luons at aboul day I~ aI lhe cycle. The release III U I cause~ dLC folhd~ 10 . . . open. relensing a mature OVUIIl. Under lbe ~llInulaiion d LH. tbe folltele changC) mlO lhe oorpu~ IUleum, .. hleh secreting pt"OgC!ilemnc as well as estrogen. The inc",ascd concemrauon, or eSI~cns and j"ll\lgC>Ier. one regu b le lhe hypolhalnmu~ ant.llhc: amerior jlIlUItar}'" a rC('dback inhibillOO proce" thai decreases GnR II. Ul._ FS. I pnxiuchon. The resuh 1\ 1M, funher OVUlal1(lf1 is ~ Ilcll. As described below in 1111' ehnpter. ,his is the pn~ n1CCh:uti~m by IIhleh sterood birth conn'Ol prodUCtS InI'ubot

,0

o,olalion.
If renilll.~lion OOcs nOl occur by aboUI lIay 25. lhe CQ1M lu,cum begins 1 degencrnte, ~k111 inl! (k,wn its producl1orl ct 0

C.... N
The hypothalamu s n:lcase~ Gn RH. a pcplillc 111111 stimulule..~ the anlerior pilllllat)' 1 SC'CR:lc LH and FSH In males and 0 females. TIus pcphde control" and regul:ttC!i boI:h male and rCllmle reproduction (Figs. 239 and 23- 10). GnR H b a rllod

"-"'"""

Ntleo ...
,,,,/

I ......,

""""

,
'"

. ----- E1I.0(I00I

,,

,'I,, ,, , ,, ,, , ,

A.'. ' .... , ____ _ LH

SH

"---. U<

CT'jM

"---.

~~~I I
$e)c

1 1 4 11

21
~. .

OwaclOl.ltCS Figure 23 - 10 Regul.ltJoo of 5pe(malogeoeSlS.

TMlO$Ierone

Figure 23 - 11 Hofmooe changes In thfo normal

"'"

""

rp-So!re at the peptide: thm are

u<:tu res. ion (in

~)

j are

all

,rferenl

of estrugen~ and progesterone beJme too low 10 rn.:untllin the vascu iari/.atioo of the endoIIltlfi1lm, and menstruallon results . The pharmacological lICu on~ of hCG are csSC'nUIl!y the ""me as those of LH . In f(' rnales during prt"gn:mcy, the hCG secreted by the pl ~nta m.1intarns the l"OrpUS luteum to con tmue secreli on of e~trogen and vrogeMeronc. thus inhibiting O'oulauon and men'\UUalion. In males (Fig. 2)- IO), 1.H Mirnulatcs teslO~lerone ~y01 he ~i.s by tn.e tesIC~ , lind logether. te~toslcronc and Lli pronMJIe sprnn:llogenesis (spenn produClton) and dc\"Clopmc:nt orthe te.,Ic<;. Tcw>sterone is ul'\('l essenl i31 for Ucve lopment of sec ooda.ry su ch.:\rolCteri"llcs in males. FS H su mulates produc11011 of protcin s and nUlnems ~uin:d for sperm maturuuon.

hormones.11leconccntr.uion~

wl1h les~ lICt lVl1 y for estrtJOC, lind Ihe leasl IICIt \'l1y wilh es Inol . Thi s r.lngc of octiv"y par.111e1s the affinlt), of thclie eSirogen5 for the ER.lI> but the in "i,o achvllle~ of these: compounds urc al so affected by inlerconver.>ions between octi"e and In.:ICU'e metabolites.

BIOSYNTHESIS
The estrogens arc synthesil.ed by IIle acuon of the enl)'tne atOOlatuse on undlU!>lencdione or testosterone (Fig. 23-,5). T1Iey are normally produced In relall\ely large quan1Hld In the o\'lIries und plucenla. in lower amouOlS in tile . 11:11 glands. and in trace quanlLlics In the: testes. In postmenopau. sal womcn. I1100St estrogens are synlhesi/.cd In ad ipose tissue WId other LlOIlOvarian site~ . About SO to 3.50 ,uglday of CSlnI' diol are prodllCed by the ovanes (t'Spccililly the OOfllUS lu teum) during tile menMrua l C)'ele. Du ri ng the lirs! months o f pregnancy. tn.e corptJ) luteum produces larger :unoullIs of t'Stradiol and other estrogen~: the ploccOla produces IOOlot of the circulating hormone in laiC pregnancy. During preg . nancy. IIle estrogen blood lenls an: up to 1.000 hl1lC~ higher thlln dunng the mcn~lnml c~cle.

yde (sec alia con _III and o,tltian dly than

SE)( HORM ONES

Althoug h tile estrogens and progCSlc.orone are usually called female sex hormones Ulld 1I.',lo,tcrone is cu lled II ma lc se~ bormont-. all o f these steroid, are biOl!lynthcl;itC'd In both oWr$ and females. For eXllmple. eXHlL1i nat ion of tile hiosyn \hellc pathway in Fig ure 23,5 re\'eals that pt'OI!eslC1OrIC ii(O'CS lIS IL bios~mheuc precursor 10 h.)drooonl.-.one and 01 (Io;teronc lind. 10 a les,.., r e)( le01. h) te.~ I ""terollC :md the ~ns. TestOlltcronc i, one of the: pt'CCursors of the t'StroJI'IIS. Tllc estrogcn.~ :tlld progC.'oteronc are produced III much iMger amounl S III females, ho"'eve r. lIS i~ te!;tOStero-nc in maJcs. These hormones ploy profound rolcs in n:prodUCIron, In lhe menstrual c)'cle. and in givin g women ond men Ihei r dllrllCleri~tic physicol differcoct:ll. Sc'-el1l1 modified 'teroidal compounds. D) well as some lIOO<;t.:rol d~ 1 com pounds. hllve e._troic nic acli\'ity. A large IlImbc r of 5yntheuc I,N' -.emis)nthetk 5tero-ids ..... ilh biological I(\,,'I U ~'m i llll" to those of ~(erone hal'C been made. CS and these are con Linonl)' called p r QgCSlI1lS. Although tile es qen5 and progestins hale had lheir most exten~,ve u.>c as 'hcmk~1 contr~ccptj\'e agen ls for women and in HRT.tiK:lr .tdc' spectOlm of :Jeuvl ty has g'l en them 0 d"'el1m y of thenpelitic uses in women Il.~ well as H few usc:, m men . Testosterone has t"o primary kinds of acli\'it~~- lIndrora"c (pronMJIing male phy~ical charactmstics) and anabolic IlIIIIsclc bui lding). Many synthetic and !;C rn isynlhetic nndroCtllic ~nd tlnabolic steroids ha"e been prt"pared. Dc.<.pi1C ro:ro. to prt'patC )('1ec1"'e anabolic IIgenls (e.g.. for usc: III lILllng ra.."ery front debi litat ing illne)s or surgery), all . 'an aboIic"' steroid, hale andrOf:enic effectS. lllc androgenic ICCnt5 are mamly used In males. bul lhey do ha\'c .!>Ome 1hmIpcUtK: usc:fulllCS5 m women (e.g .. in the palliation of cawn sex org an cancers). In 5umrLllIfY. IIl though many !.eX honnonc prodllCts ha\'e fttr greatest ther.lpcuttc usc., in either women I,N' men. ..MI) all hne some uses in both sexes. !IIc\'enhcless. the ltJhc-r CQIlt"entndion) of C"troge ns .1nd progcsterone in lonlCH and of testosterone m men cause the dcvelopnxnt of the complememary reproducti\'c syStems and char3CteriM ic pr,-l-icaI dlffen:1ICC!> of women ILtId men.

bciop-

ce lls of ieh then 1<.1 cervi

~~ h

METABOlISM OF ESTROGENS

I~ .0

14 of brcal.. alton 01 h bcgin~

Thc metabolism of ILlLtural e!\lr08ens has been R:'"icwed

17

In

l>(!e~ ler

lit:uy b)' Lit lind l'lOh'DI'rtnl.lry mhlb" t nrpu" ~tion of

cr

dct:li l. 1bc Ihree pnm:ll) c.,tmgens In women are 17,8e,lradio !. CSU"OI1C. lind est riol ( 16a.17,8-e!iuiol). Although 17,8-estradiol IS prodoccd III !he greatest Ilmounb. II is quickly o~idi t.cd (~ Fi g. 23-12) \0 estrone. the eslrogen fou nd in highest conccnlnlion III the plasma. &trone. In tum. IS con\,erted 10 estnol, IIle major estrogen found III human urine, by hydro~~I:lIIoo at C I6 (to pro\'ide the 16!lhydmxy1) and rcduclLon of tile CI7 I..etonc (l7.8-h~dro~)'I). E.~t!lldiol can Dbo be direct ly convened to estri ol. In lhe human placenta, the nlOSt abundant estrogen synthesi/.ed is estriol. In both pregnant ond nonprt'gn:lIlt \lomen , howel'ct. lhe thn:c: primary estrogens are al so mctllboli1.ed to ~rnall amounts of other deri\'atin~;s (e.g .. 2 h.)droxycstronc , 2 met ho):~eStrollC. 4-h}droxye~t(onc, and 16P.h)drl))(y- 17,8e5Iradlol). Onl ~ ILbout .50% of thera~ulLcally administered eslrogens (and their variOO5 mct.1boltte~) an: excreled III IIle un ne during tile fi r.>t 24 hours. Thc remainder are excreted into the: bile and reabsorbed: cons.cquently. r;e"('IlI1 days are required for complete ncrct,on of II gl,en dm.e . Conjugation appean; to be ,'cry important in estrogen ttllJlspor! and mctaboll~m. Although the estrogens an: uncon jug.1lcd in the ovarie~. significant UlllOllnts of conjugated e~trogcns may pn:dominate in the plasma and other 1t!>Sue!-. Most oflhe~)<lJugation lakes place In the liver. Tllc ""mary e'll'Ogen conjuG at~s round In pl ao;ma and urine lire glucuron idti and i\Ulfates. As ,sodIum salts. they are quitc ",ater solu ble. The sodlumglucuronidcof~triol and IIlesodium ~ulfate e~ter of estfUflC are ~ho"'n 10 Figu~ 2)-12.

BIOLOGICAL ACTIVlTIES Of ESTROGENS

In addilion 10 havi ng imponanl role~ in the: nK'n"rual cycle (described above). !he estrogens and. to a 1~5Cf extent. progcslefQneaI"C- largel)' n:sponsible for the development of sec ondary !>eX ch:lrncteri~tics In women HI pul:lcny. Tile estrogens cause a proIiferatioo o f the btcus. ductile system. and proges terone stimulalC1l development of the aiveolll!" system.

ENDOGENOUS ESTROGENS
T1IC 3Ctive endoi;e nous e~lroge ns are estradIOl. estrone. and MIi:II. Esumirol pro\'l~ lhe gn:att'S1 estrogenic octimy.

"",0

- -.

"

No' '0-$- 0 '

o .
o

~~"'':;')

SOdiU'" Sullat' Eal..

!
/'.
"",OH -OH

I
OH

or Estrone

~~~,"A/

/'.

"'<; 0

y<-:". " ;

I
,

OH

HO

" "

"

o~"HO
HO

"

SocNn GIooutonode 01 EstrIOl Figur. 2] - 12 Metabolites 01 11P'f!Sl1adlQl and eslrooe.

The cSll'Oj;ens also stimulate the o;Ie\'C'lopmenl of lipid and ot~ tissues lh::n conlribUle 10 breast ~hape lind fuoction.
Pituitary hormones and !)Iher hormones are also involved. Fluid retention in ,00 breasts durinG the later stages of the mcn'lrual C")clc i~ a COnlmon CIT1 of the estrogens. The cslroccns dm:cd), "l1mulale the ,ro.... lh and dc.clopmen! of the \'a!!ina. "tCIll_. and fallopian lUbes and. in combinmion wilh Olher hormones, playa primary role in 'il,'xua] 1lJUUy.1 and in prodocing lhe body comours of the mature .....oman. Pigmenl:llion of the nipplcs and gcnilalli.lSllCs and gro... th stimulation of pubic and undcrann h:ur (possibly with the help of small amounts of ICS\O"[crone) arc OIlier results of C5lrogcn act ion. TIle: physiological changes at menop;ause cmphaSWl the tmponam rolc~ of csU'Of:C'ns in the )'otmg \o.OITllln, Breo1l.t and reprodLICll\'e tissue~ IItrophy, the slm loses some of its suppleness, coron ary atilel'OliClcl'05is and gout become pou:mial heahh problems for the firstt i(1le, aAd t~ bolles begin 1 lose dcn~lty because of decreased mineral COlltcnt. 0

pounds, Because of rupld metaboh~m, eStnldlol Illdf 1m poor 0011 biool'llllaDility, The adduion of a 17a-alk) I I'OIf 1 t~ eSlru<hol structure blocks o,idalion to c~t ~ Ettun,1 0 eMradiol is therefore " .... ry cffl"Clh'c 0r0lly, "hen:.. ~ dtrablll itself is noI. Most of the therapeutic-ally lI~flll slmlIdaJ r.tl'01;cns an: produttd semi~)'nthetit"aJJy from natural ptmI'. SOIll slIt"h a~ dlosl!cnm. II plant sterol.

Steroidal Estrogens- Conjugated I s trogens, I s teli/ied

Estrogens, Conjugated e<;trogen~ (sometllne;; caIkd equine estrogens) are e .. tradlol-related metabolites onpmil) obtained from tl~ uri lit" of hON:S, eSpel:iuJ1y pregn;ull n1J(e\. ?remann, the mlljorOOlljug~ted estrogen product OIIthclNr' leI. is a mi,. ture of nu~rous components that is Silil 01tamed from man: urine , F.quine e..'>Irogens an: laIllel) _. tures of estl'OOe o;odium sulfate and t"qulllll sodIum !oI.I1I LillIe or no equ ilin and equilenin a~ produad In hUiNIII1ltc sulfate groups must be removed nlCtabolically 10 !tit. the ac1i,'e estl'Oiens. C0I1JUgilted estrogens that dcn\~ ell:" ;"dy from plant prUI'SOI'!l an: abo on the: market EsttrIfied estrogen~ are also mainl) a combimlUon of e$tlUllr \0dium sulfate pnd equilin sodium sulfate. but in a dlffma ratio than in t'OOjugnted estrogens. The esterifoed e~UOl;t an: now prepared uc1usi"dy from plant sterols.
At first glllnce, It IfUPI be l urprising that nonsteroidal molecules such ali dlcth}1id-

STRUavRAl CLASSES- ~ STROG ~ NS

As shown in FIgure 23-13. there an: thrtt structural classes of estrogens: steroidal e'itrogens, dJethyl~ulbestrol and dcTi" ali,'es. and p/lytotStrogens. (Each clau is .sununarbed in the ",-'Ctions th~t follow,) 'The steroidal estrogens include the ruuur.dly occurring cstrollens fouAd in humans and other mammals. as well as semisynthetic derivoth 'es of these oom-

Diethylstilbestrol Derivatives,

btsuol (DES ) COIl ld tUlle the same :!C.. v,ly U) c\lradiol Of OIhcr e.'itrogcns. D I~ can be vi ... ~cd. howe'~. a.~ a form of t>tnIdlol "Jlh nn", B and C open and II ~Ix-(;arboo ri nlj. D. The act ,v't)' of DES IInalollucs was explained in 1946. It "'3~ proposed thai the di,mnce cn the tWO DES phenol Ott groups was the l'1IlTlC a~ the 3-0 H to 17-0 H di~tance o f t"lradiol; therefore. they cou Ld boIh fit the 5ame ~eplor. Modem ~ . hcll'\al chelllislS t\aI'C shown the O Il to.()H dis~ 'obc:lCluall) 12.1 Ai nD ESand IO.9Ai n c~uahoi. In IQUfflUS wlulion. ho .... clcr. estradiol has ' .... 0 WOlter molenoks hydrogen-bonded to [he 17-OH. If one or ille ..... 0 WIlier molecules i~ iocluded in the dlSlallCc measurement. there i~ I prrf1 fit "";lh the two 0 11 groups of DES (Fig. 23- 14).

bill SOliI(' ' nl" cshgatOfli Pfl.IPUSC Ih:U the f'C('~p:or may be fkJ. lblc ~nough to acrommod;)te "lU) m, distances between the
t"' O h),drox ), ls. Th is poim about ~sll"Ogens needmg a phc,lOlk ring for high-affinit), bindi ng 10 the ER is critical. St~mid~ ,," ilh a phcoolic A ri ng and rdmo:d phenolic compounds lack high-offinil), binding 10 the other !il.l'mid hork~)'

be,,, . .

I1lOIlC'!

receptors.

that \lnl er may ha ve an impotlunr role for rsundiol in ib rccc[)Ior sile. It is !lOW ge ...... r~l1y IIcceplcd th:llihe es trogens mu ~t hale a phenolic moiety for binding,

Thi~ sUllg~ts

Thousands of DES analogues .... ~n- ~} m hcsrzed. and from them emcr,ed manyproducl~. IIlCludm, dieneslrol and bmztSlrol. As long as the OH u~O H dIStance n-l1uion~lIp is "_".~;,,, ' signiflC3l11 tslro&emc act;"il), is usually found den"ali'e. Without the centr.11 double bond lind t"'o ethy l or otheT aU.:)'1 groups. the molecule lo ....s all ,IS rigidi ty and shape. the O Hto O H di 'lance i~ not fixed. and octivity is aboli shed. Reductioo of lhe double bond o r DES n-sul l~ in twO diaslen:ome1"5 of hexe~lrol . ll1e mew form ,~

-OH

HO

(Ont. topical)

"...

Ell_to< 1M

h~

E1trfldlol3-b1nro11te Ealrac!io1l7'Y\II!el1lle E"radioll7-cyp1ona1e

o /'0
Cjdopen.\pIoponal8

". " "

,

~'"

-~ "

In) I

'0' 1,,-

...,-

.-.
&

''''
(a)

EIhIny1 Eslrldiol

E~

Eslrldiol J.MeIhy1eIhe<:

.........
".'

~18d

EstrogafW:

~~

$adO.,.

E. _ Sullate
~

(Or" , 1M, IV, ~ ~""'I

(b) Elterffied Eltrogens;

2O-3S~

Sodk.wn EquIn Sullale

pIw roonasll"O\l8l"1ic

''''''

7G-85% Sodium Estrone Sullate 6.5-15% Sodium EQUilIn Suble

~ none:Sl~ compounda

.,,,
",,'
~

cll,l-

o " o-s-o " o

NI'

'o-s-o,"""''--''

'O- S - O" - ' "-''''

...
n-

SodIum Estrooe Sollale

Other MIl ",daNe
~ Estrone

h,
il-

....."
, , " ,"

Sullale

'-----'

Figur.23-13

N<1lUr~1

,lRd synthellt estrogens.

HI H
....",a

" "
",C

"1
oe

50cIium l7o.E.sInodioI Sula\e

0"

"
SOdium
17~ltenin

"""'.,-""''''A
Sodium 17!1-0ihyd0n.>equdentn

"
Sodrum 17j1-Estradlo! SuIIDIe

Su"le

SUU".

"'" I
~

oe

C">

C",
OiemWol

..,

"'"

-0 0

C">

oe

oe

oe

Coume,1rQI

Genliloin

Daldzeln

Figure 2]- 13 Coo","""

active because the OH-w-OH uj,mllt'.:: j, rnumllli lleu. [n the /hrtQ isomer, OOwc\'cr. there is ~tcrk repul,iorl of the IWO ethyl groups. 11M: 1"0 phenol groups fOlate to relic:,'c the repulsion. !he Q U-Io-OH distance i$ changed. and conse quently. the 11r"" iSOfllCr i ~ inach\'C (Fig. 2) 1.5). Phytoestrogefls. s.:,'crnl nalu .... 1 plam ,ubslunces Ihal have gl:fleruJ slNClUrul fcalum. SImilar 10 those of DES and eslnldiol also ha,'c estrogenic effectS and h.me bn lenned phJf~S'1'(,gttU.J'I 'These il'ltludc: genistein, from so}btans

and a spcciC'S of clover; daiul.cm. from soybeans; and coumemol. foum] in cenain
legullle~.

Geni stein and daidtein are

of isonll,ollts. These and OIhcr~ have amifrrum,. acli~il)' In amrnols ..oo Many cl aim s ha\ e been made aOOulllli: bcndici:d c:ffoo~ of coo~umin8 product) ~-OOIIlJnInl! __ _ ph)1oeSlrogelIS. mcluding prI:\enling and lr'C'ahng c;mlio,oI cular di<;casc. reducing poslnJenopausal symptoms. and Fft' '-enliny osl t'Oporosi~. Bt'C~usc of lhe numcrou ~ OIhcr~~ nelliS pr~'iern in mllny of Ihe ~'ommerdal product~ .. as a lacl.. of wcll -dc~igncd ,Iudj e~ 10 le~1 the effcclS 01 phytoe~u\,)geOli thcmsehe,. 00.... C\;"r. j)O!>lhl e lJe"hh til spcciflcall)' due 10 dU"ecl hormonal aclion oflhc ph)' gens :ue uncertam. QuesllOM h",c also been raiJ;cd a possible t Olllnbulioll of pltyloeSirogclls 10 an mOt! d

c~amplell

Hormon@ Replac@fmmt Thf!rapy. Another major use of e!.l.rogens i~ in HRT for postmenopausal women. For this u<;c. a proge.sll n IS onen iocluded to oppose t~ effl.'Cts of estrogc ns on endomelrial tissuc . IRT IS OO\ered ill more depth lalel' In the chapter. TfHtfJl@ntofEstrogen Oefici@nCYFromOvarianFallure or Ahftr Oophorectomy. E.~Irogell therapy. usually ... nh ~ progc~h n , com moo in case, of ovarian f~i1ure and after an oophorectomy. Treatment of Advanced. Inoperable Breast Cancer In M@n and PostfJl@nopalisal Women and of Advanced, E!.lrogens are Inoperable Prostate Canc@r in Men. uscd to tre"t inopemble !)rea_! callcer in mc n and III postmcnopausal women. but estrogen thempy can ac1Ually 5timulale ellisting breast cancC:1li III prc:mcoopaus.ol wOlllt'n . The <;ch.'1:II\C ER modulator tamoxifen i, reponed to hllYC: fCII'er side effects: hence. it is us.uall) preferred. E.'Itrogens ha\e also bc:en used 10 treat ulopemblc pro>.lale cancer. bul Gn R H analogue, aro oow gcnernl1y prefcm=d becau!>C uf fe .... cr unwanted side cffl"('b. Estrogens and Cancer. Many yc:ars of btudy have tim!ly establ i~hed an a"-SOCialioo bctwC\'n estrogen use and Il1Cre3!>Cd ri5~ of brc:aSl cancer TIle n~L IS associated_ ho ... ever, .... 'lh lhe tuning of estrogen exposure:, the cStrogen dose, the length of use. and lhe type of e.-.tTOl!en used.' J A pmient should disclI!lll the plMemial n~Ls o f bll'ast Ca/K'Cr with her (\(x.1(1f caJl' rully before starting c~t rogell therapy. Unoppo:o!Cd esu'Oj;cns ill l-IRT for posTmenopausal " 'omen are ul<.O linked to an locrea.'IC'ti rist.: of cndoml:trial carc moma. IIhich IS the: ba.<lS for mclusioo of a progestin in mmly forms of H RT .... DES Babif!s. Dunng the lale 193(). lhrough the early 1950s. it .... a~ belie\'ed that DES treatmcnt could help "",gnant women .... ho tended to rnbc~rry to ha\'e fullterm pregnancIes. Not (01)' .... as the bo:lief incum:ct. it .... as subsequently reponed tllat !laughl",'" of women .... ho had taken DES during prcgnmlCy ("DES babies", had a high ri,~ of vagm~l. cerolCal. and uterine abnormahuC5. aloog " lth a low risL of \'aginal clcar cell adenocarcinoma:" Women ~po~ to DES in utero who dc.eloped genitul truet problems ha"e ~ much hll:her nsl. of infenllit ), than UM.lposcd ...onICn .... A longlcnn effeel 00 .... onICn .... ho ... ere trCllled w ith DES during their pregn~ocies i~ a slightly higher nsk or breast c;mccr than foc ",orllCn .... 1\0 were 001 e.lpo!ol.!d. although no Increased ri~~ of o\anan. endomctnal. or otncr canccl'l wa~ obscr>'cd.1
~STROG ~N

Estradiol (H~h - dark lines DES light Iw.. Figure 2] _14 Compute!" ~raplu(S SUpefposltlOO 0 1 emil(H,O), (dork bnes)Wlih DES (light I,nes) (Courtey of M.l!dl.. fo.JndatlOl'l of Buffalo. Inc)

of brei"l cancer. TIle..e concerns. ho ... e.er. are Cl'W':ldiclcd by ~lUdics thm sugGcsi a chel1loprott'Clh'e role for \l,)y products c0fl11lining phytoe~trogclt~ (Ihi ~ COIl ld ....1'11 Irtdue tOlMmoomponenisofthe miAlure). TIle long history IIIII><;0floOY pmduclS In the ... orld and no s lobal eom:lIn ions tilh il'lCn:'ased bro:t!ol caocer ris~, sUgge.~1 Ih~l any conncc!II:II bet" C\'n ph) I~ITOI!ens III general and brea!.l. call1.'Cr i~ '/'I11e small." RI:t't'nl ,ludies ha ve dcmonSlrulcd that genistein (and Iy other ph) toe'trogen~l binds prefrn.-nlially to ERIJ O\'t'r 'J lllc clinical relevance o f Ihl' dlffercoce in binding 6undc.at. bu l it 'ui:llcs.l~ diff~oce~ between the ph)'lOes and dasslcal esl rogen.~ that shoul.J be explored.

THERAPEUTI C USES OF ESTROGENS

A map IISC of C'>"'Ogen~ is for Inhlbitioo

"'()\1Jl~tion.

in combin,ltiOlI " ilh progeslin,. Steroidal bir1h IIItroI agenb CQIIlaining estTOl!cns are d'!lell sscd In the~on dlemical L-ontrna:pllOO laler In Ihl~ chapter.

OH

OH

PRODUCTS

&'Irogcns ore commerC"iaJi y a\'ailable in a ... ide variet), of dosuge fonn:;: oral lablelS. \:ti1nal c~ams and foams. tl1Ul$dcnnal palCheS. and imramu<,Cul3T dul;agc: prcparJtioos. OH
Ita ntroi

OH

7'ht.a-.ome,

AcWe

1nacIw.

Import<tnC~ of (oolOl'lnilll()fl and fI~K:li1y In

""'"

Estradiol, USP. Estradiol. C51ra- l.J.S< IO)-lricM-J, 17 /Jdiol. i~ The most acl1"C of the nalurJI ~le roid e.~trogens. AI thoogh liS 17/J-OH group is vul nc rnbk.to baclerial and enqmal ic oxidauoo to eslrone (Fig. 23- 12). il can be IC111porlU'1l)' protected as an ester or pcrmaneml)' protected by addmg

780

14'11_ /JIJd Glu'Old',

T~xlbotJk .if OrglJlli('

Mtllicim,/ unll PIIi,rn,u<utkal ChtmiJl1'Y

a l 7a-alkyl poop (giving l7a-ethinyl estrudiol and the 3methyl ether. mestranol , the most com monly uS! estrogens in onl cootraceplives). The il'lCTCascd oil solubility of the 3and 17,8-estel1l (relative to e~tradiol) pennits the e"ten; to remaIn in oil'tthe injection ~i te for extended penotls. These

derivati ves illustrnlc the principles of steroid modilieatiou shown in Figure 23-6. Transdc:nnal estrudiol prodOClS avoid lint-pass tnetaOOl ism. allowing Cl>tradiol to be as effective a~ oml estrogens for treating menopausal symptoms. Estradiol itse lf is typically ROt very effective orally because of I'IIpid metabolism. but an oml formulatioo of micronized estr.idiol thaI ,llows more I'IIpid absorpt ion of lhe drug is 3" ailable (Estrace). The commercially available estradiol esters are !he following:
&'100,01 lbcl\l,O;l\e. US P

this product is distiBCI from (not equivulent to) the conjllgated estrogcn~ dcri-cd from mare urine:. The "A" fol~ ing the narne indicatell that this is tile finot approved mi~l\IR of ~ynthetic coojugatcd c:.lrogens. Subsequent S)'ntheuc ~ JUllllled esuugc:n prod ucl$ will be named in ordf,r. witlllbe final descript~ " 8 . C, 0 :' elc. Cenc:su n is upproo.ed for the tn'alrnent of moderate-to-SC:"a1: ,asonlOlor symptOllfl lmd vu lv1U' and vagmal acroph y associated with rm'~ t::.,. uum;u t':~IMOGl~~S. USI'. Esterified estrogens (Esuaub. .... Mme5I ) contain some of the same iu lfme conJugates of~ trogcns prescm in conjugated estrogens. but tlx' ralios III these components and the composi tion of millOf oon~nn o f the products differ. 'These products contain 75 10 83 .sodium estrone sulfatc and 6 to l 5'l> .sodium equilin sulfllt, in such proport ion that the total of the.'iC 2 componcnu IS 90% of the total esu:ri fied estrogens ~'()Iltem. The eskrifltd estrogens find tile same u>es as the conjugat ed est~,
Estriol, USP. E.~triol. eSTra I,3,5(IOj-tri ene-3,16n. J7,. triol. is available for compoundmg into a nUlllberof dllfm. formu lations for U'iC in liRT. IT can be u:oed alone or ill combinatioos with e.'tnidlol ( Bi-E\l:) or I<;th e&Iradiol..t estrone erriEst). Ethinyl Estradiol. USP. 17a-Ethin) 1 c.-tradiolbas tIir great advantage over ()Iller esmodiol products of being otaII)' OClTve. It is equal to estrad ,ol in poIeocy by injection but if, 15 to 20 tillles mort active orully. Thc primary ~ p:llh ror ethin) I estradiol is 2-hydrollylauon by cytOchll:UC 1'-450 i!;(llynlC 3A4 (CYP 3A4). foll owed by COl1I'miOllIO the 2 and l-methyl ethers by catcchol-O-meth )lIr.tnsftolt The 3-methyl ether of ethi ny l estradiol is mestranol. USP. used in or,,1 cOIlTractptiw:s. MeS(ranol is a prodru, tNt. )O-dc methylatoo to lhe active elh inyl estrudiol. An on! dose of about 50 }tg of mestl'llnol ha~ an estroa:;emc""" approll im;uely equivalent to 35 }lg of or,,1 ethin}1 estr.Idid. The demet llyl~lioo is mainly mediated by CYP 2C9." Diethylstilbestrol, USP. Dlethybtilbestrol. (}.<l'dieThJ{. ()-4.41-slilbentdiol. DES. is the most acth'e of tbr 1 1" .... roidal estroge ns (sec under the heading. StOlctuntl CbI ses-ESlrogells, abo"e), having aboul the same ItiCU\il} e estrone when given intl1lmu sculllTly. The cis isomer one-te nth the activit) of the trtuU. This is malnl) due III the improper posi tioni ng and distance (-7A) bel .... h)'drOJ\yls in the cis i:;onter. The Intn1 isomer is ,,'dIabsorbed omlly and mC:lllbol ized slowly and. l~) was a populllT e~troge n ror many medical purposes. ~irubJe side effects h:ll'e 5e"erel), limited its usc . The diptooe. phatc ester, di"ilylmJ~litroJ I/ipIJ(lspilmt'. USP. II'll for intTllvenous usc. i~ used ()I1ly for canceT of the ~ Card iovascu lar tOll iC il y iBC luding deep vein tlvumboiti$" m)'ocanliallnfarction limit it~ usc, OO""c'er... The dipt. phate sall has greal water solubility. as one would pmkI rrom Table 23-1. Prior to the 19105. DES was used eJ.IeI. 5;"cly in low doses as an aid to fallen callIe. but dIo:: 10 I potential link to cancer. il: "'0lS oonntd as an addiu,e il . mal feed. Nott': All stilbene demativf'S, slllCh as DES and d"~. . are light ~nsitive and must be kept in lighH'esistulll cceIllinen;.

EsuaoJ.i<.>l l7.nle..IC, USP EMradioI 11-c)'ptOllMt. USP

El tron., USP. ES!roIle. ) hydrox) estra-l.l,5( I O}-lnen17-one, is less ilCtive than e.>tradiol but lOOfe act ive than its metabolite. estriol. As the sa lt of its 3sulfute ester. estrolle is the primary ingredient in conjugated estrogens, USI'. and e&Ierilied eslrogens, US!'. AhOOugh originallyobtailled from the: urine: of pregnant mares (about 10 mgIL). estrone is now prepared synthetically. P1 P'1!IU'W;o; tlR()'O ~ SUU'Ant (J-SUI.I ox, 1:!IT1U_1.J,5i 10)u lIl:",- 17-o"'II I'II't:IlAZINII SA I.Tj, USP. All the estrone 3-sulfale sahs have the obvious pharmacrutical advantage of in . creased water solubiHly and better oml absorption. Acids OOIWffl the salts to the f~ )-sulfale esters and cause some lIydrolysis of the es ter. This does ROt seem to affect aholorplion adversely. but precipitation of the free SUlfate esters in acidic phannoceutical prepamtion~ shou ld be a,oided. The dibasie piperazine: molecule actS as a buffer. giving it $Olllewhat greater stability. CO!'IJl'GAn:O EnltOtir~..,., US". 1loc term C'lHIju811t~d ~Slro g~ns refers to the mill of sulfate conjugalcs of estrogenic components isolated from prtgnantllWre urine (Prtmarin). These compounds ore also referred to as CEE (conjugated equine estrogens). Conjugated estroge ns contain 50 to 65~ sodium ewone sulf,te und 20 to )5% sodium equ il in sulfate (oosed on the total estrogen cootent ofthc: product). Premarin also conlllins the: sulfate csten o f J7ft'-eStrudiol. J7o-dihydrocqui lin. and l7.8-dih)droequilin, in addition to other minor componc:nl$. Although most cOl1lmooly ustd in BRT to treDI postmenopausal symptoms. The conjugated estrogens are used for the e ntire range of indk,tions described abo,c. except binh control. Sv", IInle CONJL"(]ATW f..... "T1t()GI;/'is, A. Celll'!itin is a millture of nine estrogenic substances (Fig. 23 13): sodi um estrone sulfale, sodium equilin sulfate, .sodium equilenin \ ulfate. s0dium 17a-esu adjol ",Ifate. sodium 17,B-csuadiol sulfate. 0dium J7o-dihydroequilin ",Ifate, sodium J7.8-di hydroequi lin sulfate. sodium J7a-dihydroequilenin sulfate, and sodium 17P-dillydroequilenin sulfatc. These estrogenic substanceS lin: synthesized from soy sterols. The term ,yntMlic has been added before conjugated estrogens to indicaT that e

hti.,

=*

but_

con-

.f~

,,,.

Dierocwul. 4.4'-( L.2-dleth)litkne-l. !~nedi)t)blsphcnol. IS or.atly ac11\t but i~ 001)' currentl)' "aliuble as u topical cream. 'T'he cream I' u'o.Co to ttellt mrnpltic valliniu~.

~J tro/,

USP.

adtiulonal al1cnls Ihm c.. n anlagonll.c Eft, are cIOfll'phellC'. "hlCh is used a~ an ovulation slimu lant. and raloxl fene, which is used for lhe prelcrnion and treatment of oSteoporo!o.;s. Tamo,ifen 3.00 clOlmp/K'ne wcre trachllonall)' called I"SIIY/gell I'C<"C{Jlor (EN) <lIIIIIHolII_IU or Uflfil'_'Irr)gl'lu. Referring 10 the-.c ~'OOlpouOOs IlS ER antagonIsts. howc.er. doe~ 1101 accurately portra)' 110" lhese ConlPOUOO~ ... 000 In .;'0. While canlOl ifen b an ER amagoni,t in breast u<~ue. " ha, agoni~lllI:tion~ on the endomelnum.h.cr. borw.>. and Cardlonlscular 5y~tcm. Because of lhe dl fferenllal agonist IUld an-

Iom~

u'\C.

smcnvE eSTROGeN RECEPTOR MODULATORS AND .\NT1ESTROGe NS

\\lIrre,Is e~trn1:cns hale been \(:ry IInponanl In chcnncal colurnccplion ~nd 11RT, compound, thaI c~n antagoniJe the ER hJ.II.' been of Ilre3t mtereSl for lhe m.'atmenl of estrogendq"ltndml breast ca~rs. Tumor bio~ie~ hUlc ~ho"n ER 10 be present in about 6O',i, of primary bre:t!>t cancels. and IIIOSI an: re~pon';'c 10 e,lrogen blocklldc. Unfortunaldy, II)()';I of the'ie ER-relatro brea~t c~ncc"" also Oclclop re~is ~ to antle,t roen IlIcrup)' wlt hm 5 }'ears. In contr' ~t. on Iy .. ibout 6'l> of nonmalignant brca.~1 li~sucs hale signirlCant ER preo.ent. Three COIllPOUOOS thaI are used clinically for Ntl!cn antagonistllcl1l1n in lhe tre:tllllCnt of breast CUIICer .,. tamo~ifen. tOll'mifclll.'. and fuh c'>lrant (Fig. 2]-16). T"o

atah.

r e~
of

lCrns

8S%

Uate.

n ~ I~

fied

171'renl

tagonl,t effects of Ihco;c tyJICS of compounds on Ihe ER. dependini on the 5p:cifk tissue. u new tenll wa.~ coillCli; stll"l"/.It' t!!/rtJfltll rl'l'tIJlIJr modullllors (SERM~). A SERM i~ a drug that has IIssuC,pecirlC estrogcnic ocll lil),. AI . though mllny compouOOs exhibit SERM act;'il)'. a few agems are antagoniSl.~ m all "'MIe\. 'T'he<.e compouOOs are termed f11llil"51mgt'l' s. and ful\'c~tr:ml IS one eX:Imple (Fig. 23 - 16). TalTl{)~ircn and domipl'l\'ne are oftcn refem:d to in older luernture a\ (lllIitSlrtJglms _

'''" lind
~I

I ,,.,

rail) ut I~

'K>lic

. ,~

~ N_CH,

CH,

I
HO

~'"
I~

/SP. ""

Tamoxi/(in (NoYaIde.,

Zuc:IomIp/lene [CIomtpheoe (CiOOlodJ

rnilttu .. 04 ............. lUdomtphene and ijldOIllIf)I....J

at

b~
~iol
h) 1-

,b
,,,.

1\0.,.

~~tC-

l.......N-CH~

CH,

HO

o d
HO

T()(eI'!lIlena (Fa!IISIOO)

~nt~ : to

....
~.

abuly,

ate.

~I'

w<d ",.

t.uoIo>;iIene (CP-336 t56 )

to;
I
~

~"

1 &

,j'
b

,""

,
FulweblllI. 1C1-182, 780 {F'ei'd: -,

Arzmtlltne (lY'\M181'

Figure 2] - 16 SelectIVe esuogen lea>ptOf modulators (SERMs) and anllt'Strogens_

TUIlIO"fen ha., ~n c~lcnsi~c usc In trealing pnmary bn:asl callCrr!l thai are ER depcrwknl.:I<l.,. For pn"ffiermpau~1 ....omen with mctaSlallC di'iC;&!iC , tamoxlfen is lin lIItn-oath'c and adjuvant wi lli oop/Iore<:lorny, oym;.n IrTadlation. and ma!>(eclomy. TIUl1C))lifcn 11.'>('. ho ....\"\'cr. i5 001 problem free . Tarnoxifen itli:fl:ases the ino:ldcncc of cndometnal pol-

The 051.: of cndolllclnaJ cancer n:wltmg from tamoxifcn is. how

yps, hyperplasia, and carcinoma and uterine
ever, much lower than the "mOOc" but highly si gmficant raiuclions in IOOI'bldi ty :md monalit), of breaSt CllllC('I", n Because of tile increased nsl.: of endometrial cal'lCCf with tWlloxikn therapy. tamoxifen .hootd be: u!;cd to prevent brea>t cancer only in ,",omen al hll!h n~l.:. Women Without

~arcoll1as.

a fumily

hl~tory

of breast cancer or ocher ri5h should nl)!

usc larnoxifen in thi S m:mner. Ralolti fcnc is nllOlher SER/I1. but us profile of lIt'llv;l), differ; from Ihal of mmoxi fcn. Ra loxifcnc is an ER muagoniSl In both breast and endometrial lIS.'Iue. bul has agonist action 00 bone alld aclS as an e~lTOgen agooist in lowering tOlal ehole~terol WKI low-dcnsily lipoprotein (LOL.), 'The wbtle )trucl\Jr:t1 diffel'!'nces betVl'ttn tnc twO drugs undc:rlie tnc di,tinct aclivity proliles.~) 1lIc agonist llCtion on bone ti !>S~ i, the basis for the usc of thiS drug for Irl'ating osteopo\"Ol;1'.

A ley questlOO is why do COll1pound.~ like tamOllifen and rJloxlfene c~hlbi l amngoolst OCIiOO in somc u~ucs. but ago. ni~1 action In other ti_sues? Major dc"dopments in the pasl ',wl'cars arc beginning 10 pro~idc w an~\\er to thi~ question. 1 .l6. 27. '"' Tamo~ifm,~ raloxlfent. and eSlradlol(1 all . billd to the ER at the ~anle 'itc. but their binding Il"lOtlel; arc dlffcl'!'nt. In IIddmoo. cxh Induces a dl<.tinn coofonnation in the trJJI~llCtl vat ion n.-gion of tnc hgalld blndl ng domain. II These unique conformalions dtctme how the l'I'pIor- ligand complu willlntcl"olCl ..... lIh coregul:llor proteins (ooaclIValOl"$ or con.-pn:ssors).!7 [n 3I1ti\sue~. the cstl1ldiol- ER cornple.\ I'!'Cruu~ cooclivalon.. so gcne lr.Im.criptiOl1 is s timulated. In brea~ 1 tis.suc. both I1Il0siFcne- and tamosifcn-bound I'I'CCptOCS pn:\"Cnt tnc a.'>ociation wi th cwcti\"lllocs. but t"Jther recruit l'ore~, so amagon 1 aclion IS obse1'\ed. In uterSt ine tissue. howe"er. the rJloxifenc-ER comp[ex ~ruits oor"'pressors, ..... h.el"Cas the laffiOxifen - ER complex l'I'CTUib a coacll,ator. SRC-I. which \cads to agoniSt &l:lion.'"' An additional fllCtor in"ol,-ed in this ago ni'\! aclion of tamoxifen I' the contC1(t in ..... hich lhe ligandcd receptOt" IIlteT"llCtlo with the '~rl!:e' gene . The liganlle<.l ER can interru.:, directly with DNA or can inleract incilra11 by bemg tethered to OIhoer y tl1ln....::ription factors. When lhe lamoxifen-bound rettptor intcfllClS in a tethered manl1Cr VI ith the turget gellC!lii in ulcrin.e ,issue. the SRC-I ~llvator is l'I'CTUited. alld gene 1t".1D!;cription i, pronlOted. l7 . 'I< A dt'eper u!l(\(or;tanding of how the Itg;mdcd rtteptors intel"3Ct with target genes and thoe ulCCha nisms for I'!'Cruilmem of coregu lmors may help to c~plain thoe phenomenon of i.:lI1lOxifen n:Slstance . whiCh n:.5ulb from i nc~1lSed UI/TlOXlfen agOllism in ~U'i' tissue. n La~fo~ Ifene. ba1.cdo.\ifcne. alld arlo~ifene nrc: sevcral of the IICwer SERr.h thai arc in latc-stage clinical trials (Fig. 23-16). Lnsofoxifenc and b<u.cdoxifenc are being sludied for use in lhe trtal1ne m of O~K'O!lOroSis. while arJo~ifene is being In" esngau~d for ~ast CIlOCef Il"Calmen!. Stl\lC1urally, arl,oxifcnc i~ mo..' ~I milar to 11110,\1 fene. with an ether brldgc. rathoerthan u carbony l bridge. attached to the benl,OIhiophenc con:. Baudoxlfenc uses an indole ring system in place 0{

the benl.othlophenc of tulosifenc. B:utdo.\ifent VI us the I\"su it of a sel't!enlllg pro~rum Ihat ..... kct~'d for compoulllh tIt.II did not S1imulale breaM or Ulennc tissue.)(o l.asofo~iftnc C1Il be \"IC\\ed as a t'OOstr.lJned. SIItul1llet.l 31t.:tloguc of .... hydrm)tamox.ifen. Clomiphene i, WlOIher drug Ihm exhlbit~ antlCSlrotCOx tions, but II is not used for treating brca\l ca\1CCT or oYeoJDIOSIS: I1ItheT. it I~ used for 1I1C1"Ca"ing tl1(' odd., of II soct'tS..t1li pregnancy. Clonuphene' s tncrapeutlc :tJ"IPlicaIlOl1 0.\ an l7'iI" lalion stimu lant l"CSull~ fronl its abllny to ill<'n.-:6C GnRH prodUCllon by the hypothaJ:unu). lltc IllC("hanl,m i~ pn'SUlIIably a blocking of fecdb:tck inhibItion of OVPI")-productIi estrogens (~ ia ER antagonlsm).lltc hypothalamus andpilllltal)' interpret the false: ,,(nal that e'trogen Ic,'ds :In: ]0.and respolld by iocll'lI.'ing thoe productiol1 of CnRK TIle increased GnR H. in tum. leads to incn:a..c:d M:c1"eIion IIlLH and FS H. nlUtuJ'lltion of the 0' anan follicle. and o'ubtu (as described abo"e in tillS chapter. !oCC Fig. 23-9). SUppa! for the fcedbac~ mhibnion mechanism I) provided ~ IeICI with e~pcrin1O!ntal :Ullmals in Vlhich ,lol1liph... ne ha~ nori" fOCI In the lItk.encC of a functioolllg pllllllat) gland. Multiple births occur about 10% of the IImc wJlh p:!UC1J< ta~ins clomiphene. alld binh def"b in 2 1 J'I o{lhr ... 0 borns. Vo.somotor "'hot na"he,"' occur about 10'l III thr time. and abllormul clllurl!:cmcnt of Ihc ovur.cs about I~" Abdominal discomfon should be di'iCus.-ro im~ ..... nh ,he physiCian.

SERM ANO ANTlESTROGEN PROOUCTS Tifmoxifen Citrate, USP. Tamoxif... n. H".{1.2-df. pnenyl-l-but ... nyl)pherKny]N.N-dimclh}lethanamlllt , vadc.x). i~ a tripheny1ethylcnc SERM u~<.Itl) tll'at early aI advanced breast carcinoma in postmenopausal womtII. Tilmoxifen i~ us...'d as adjuvant !rcannem for breast CA/IIl"a. women foUOI",ng 171ll.'o1"IOIll)' and ~a~t ilTadiatil)l\. It Itduco the occul"ll'oce of COIltr-dmer 1 brea>l cancer .. ticnt~ receiving adjuvanllumoxifcn Ihcr py. It i~ alsodfcc.. lIve in the t<emmcm of meta~tUlJe breast C:uterf In women and n1O!n In pn:menop;lu!kl1 WOlllC'n Vllth mtUt!IR breast cancer. tamoxifcn i< an altemml\-c to {~ or ovarian Irradiallon. TaJl)o~lfen ('lion be \I.)C\j pn:''t'i"QIJ' to I"Cduee the incidence of bn.-llSt carK.-.:r in "'omen 11\ risk. Ant~trogenlC and estn:tgcnic ~ide effocts ClUl llitialt hot na~lles. nausea. ,omlhng. platelet ~ue\lon. and til tiems wilh bone tnClaStascs) hypc:alccml(( Lilc ((limplitny\cth}lenc dcn,al;'Cl>. \I ~hou"'J be protected from t. . The major IllC'tilbo!nc of tamoxlfcn I~ N-dc5mc:thYII';';~ fen. VI hieh ll'achCl> k\eb hIgher Ihan tamO.IUIJI ilSelf. Ii IS belie\cd significantly 10 Ihc overall II . tabolitc. 4-hydroxytaloo\lfcn. IS II more than tamo.\ifen . but bccau ...... 11 IS only a IlIn)Oxifen. It probably does not contribute

In,.

"

"";"-, ""

-",~;, ,.

in pharmacologICal Studies of the'iC reccptOl).. concentmllons llfC reduced if coadnllni\t~ WIth a cytochrome P-450 inducer.

Toremifene Cltrat~, USP. ehlorn- 1,2 diphenyl

I: b.",

a~

lhe reund;. thal fene elln

lIydro~y-

rogen :te-

OSleopo-

uccc" rlli s an O'U' w GIIRU

pr'e\IlInproduced arK!l'lI uian' low RH ll1e 00 ofUI (i.ulat ion Suppon d b) '('\1\ a~ 110 e r-

mananllllC (Fareston). differs , 11Wtllrally from tamoll.ifen OIIly b) lIaHng II chloroclhyl group (nuher Ihan an ethyl groop) auachcd Iu the triptM:n}lcthylene st~lUre. As l1ught be upetted. the pham1.lcological acll()ll~ of loremifene lind WftOlI.ifcn are qUlIc ~"mlar, Ton:nl1fclle 1<' .ho II SERM. o.lIh estrogen IIntllgOIliSI OCIIOII in Im:a'd IIMIIC bUl agonist a-tiOQ In lhe endornClnum, on bone tis~Ut', lind on <Cn.J111 lipid profiles. Although 100000ntifenc apPears to rnrry Ies.\ rislo 0( causing endomelnal cancer Ihan lamoxifen. 11' lirnllro II)t In ~'OInpariW11 wilh larno.\ifen R.'qUII'e!> the U~ of caution III evaluall ng the ~afclY profile for LOrI!111i fenc, \7 Torell1ifcne I'1I15ed In tnc lreatlnelll of mctllStatle MIiSt c:u",-""Cr In po..tmenopausal .... omcn.

''''
o,?v 0'

",,0

-I

,
aromalilSe

b pallc nl,

1I"e

ne ... -

'l of the

out 14<), m.,,(\i:lle Iy

1t.I01Ci fene, USP. R:1I0.\ifel1e. [~h)'drnll.) -2-<4-hydroll.)p/lm)I )henJ.o [h[ Ihien 3-yll [4 - [2 - ( I - plpendlny!)etho~ y I phL'nyIJII~lh:molic (E~I~ta), i~ a bentuthiophene deri~DII\'e iN1 d,ffer.; ~ I ighlly from the Ulphcn}lethylelic SER~h. A ley .wuctl.ir:ll diffCf\'ntc i, lhe carbon}1 "hinge" Ihal eonIItCt~ the modIfied pht:nolie side choli n to the ben1.othiopl'lelll! on; ~yMem. TIll s hinb'C i, lhe key Structural clcn~nt Ihal !tads to the di ffering acli01lS lit the ERs. ~, Ralo:\ifene, unlilo:e !iI'IIO\ifcn and [orcmifcJ1oC. ha~ amagO",'1 propertlCS 011 lhe radomctriu", arK! breast U\SIIC arK! IIgomq protJertlC\ on _ and Ihe eartliOlllscular '}~ICIll. '11M: lack of IIgoni,[ on endomclrial h~ ha~ been suggested as a ~a'lOO (Of the lack of cndomelrilll cancer llWlCialoo wilh rJloll.ifcoe R. Ralolifenc is appron:d for the: prelcnu01I WId t~atnlCm i/losleQ()OfO.\is in postll~nop:iu!>al .... omen and b being StudIN for the pr'e"enholl (If brell't canct'r in women al lugll

Figure 2]- 17 Cor'IYenIOI'I of aooroo;Il'I'Ied1l)nl' to f'$1J~ by

AROMATASE INHIBITORS

....uon

111.2-dinc (Nol:arly and -nen Ta:nnccr In

...

'n, 11 reo

:r

In

po"

weffee in botll etastauc rectomy lIali\c1y al IIlgh indudc l( inpa '

1 ,nplle I light
latnOlI.l AO\ifcn
rribute~

FuhC<lmnt.1a-19-1(4.4.S.S.Spenla ~~nl yl)suHinyl jrlO1lyI1eslrJ- I.3.S( 1O) triellc-3. 11 ~ 601 (Fa,lodc:~ I. I) an antag()nl~t S!1\J(.1urally b:lscd on Ille tllradiol ~lruCture. with a long. ~ubslilUtet.l alk}1 chain ru IIChed at the 1 n- po<nion ofllle steroid ~ke1eton. When bound 11;1 the ERs. tllis alk}1 chain IndU(:es a runfonnauon of the ~plor dlstlncti,'e from tllm fonllCd upon e,tradlul 1)1" la.mifen b1rK!ing. ~"eminll aIlOllI~tlllCtlon. Ful>e..tr:lnt i~ a pure anlagolll)t 31 both ER" and I: RJI and an ER dowlI~gula g humul:ue, degradauoo of the ER), eOfllpll'lely lading tile uj!oni,tllCt; vjly th:u i1 secn ... ith lumo~i fcn or ralo~ifcnc, ~ differenl phannacologlcal profile of ful>'e' lrani a llo ... , tht: I1>C of tlli, agenl ill ....omen ... ho hale Iud dll>Ca-,e progn:-;won nf!er prlur anlll!StrogCn Iherupy (I}plca!!y 11I1I101I.ifen), pnl'lding lUI d!temati~e to :uom'l1a~ inh,bilor.;.~

Fvlvestranr. USP.

herme lrogen ollte of II1tly 10

grealer
n~IH' I )

Iln,fe n

.mpm.

Oomiphene Citlilte, USP. Clon uphene Cllr~le. 2-[~ (2cMoro-I.2-diphen}1clhenyl )phellllll. y IN.N-diethylelhanIllUDe (Clolllld). I~ uo;ed as an U~1113110n ~lImulunt '" W(1ltlC'n ~inng pn:gnancy, Ahhoogh early hterdture refel'!l 11;1 clolmphcne 'I' an e<1rogcl1 anlnguni,t, it i, IHore acClr.IItdy a SERM.w Clomiphene I~ chenucall) It miJlturc of i'ltt) geomclric is\)lIlCn.. I.udollliphelll:. the <'it isomcr. and o:ndomirhcoe. the frons isomer. In iUlUnal ~tudle~. lhe>!. I.WIIttI' h.wc dlfferenl esll'Oi!enK- actions in different tissues. Zudomiphc:llc appears 10 have weal. agonisl action. Oil alJ IMiK's ~Iudiro. whereas enclonnphcnc 113!l antagonist 111."~ OIl Ulenne " '~uc. hoI ngO!u .'1 lIC1ion nn bone li~sl.lC .tJ(t Thracllorn; of clonnphc:nc: In human~ an: h~d) a composnc II the octlOllS of the two i,;onlCrs.

Arom:llllSC is a cylochromc P-4.'iQenl.}nlC' complex Ihal emaIpxs the ConlCrs' Uti of :mdrOlotclll.-d,onc to e~tronc and 1c:..~I(}\teTOOl: 10 e~lnl\.lIol (Fig" 23S and 23_111. M 1>' TIM." coml'icJ( i, made up or reduced nil."OIlIlIIlmde lIdcmt1C dlJlucleolidc ph~phJte (NADPH)-cyt()chrumc 1 50 re.... duclMC. and eytOChrorllC P-45O hc:mupfOlem In lhe 1i"1 ''''0 ~Icp-;. the Cl9 methyl is hydroxylaled to CII,OIl. and then 1 an aldehyde: h)drdte form Ihar de:b}'dr:ltc, to J1I'O"idc lhe 0 C 19 aldehyde. In the Iinalllf'Olllati/ation ,1q>, thl' C 19 t'arllon " oJ( ld:ltj.ely elea\ro ttl f'1IT11I1le. " h)dndc <hlf!. proton transfer. and fl\:1: radical p:ilh ....a}s lIa'e hem~. with c-i\ elimination of the I # and 2fJ h)'drugcns. In 1'~lIIl'no p;1usal "'omen. uromatll<C is primarily found In o\anes. but in rKNnlCnupJulolll women. arnmata:.c is largely In muscle and adlpO'oe u\~uc:. As d,<;cuS!ied abo~e wilh SERM ... \OtT1C Iypo of brea\t cance:r are cstrogen de:perKk:m . 8ec:tuse lhe uromma~ 1"C:lI,'lioo is uniql.lo.' in stcroid biosynlhetlC' p:ith ... ays. II ...ould be 31111cipaloo Ihnt nrollMase inhihilor; .... ould be I'Cry spccirlC in theIr eo;trogen biO!.ynlheqs blodu 111i. h.!.~ pnJ"ed 10 be Inll:. und UrttmalJ ..... mhibllors offer D lI)('ful Dppro.1oI.:h 10 decrea.~l ng <"Irogen k"el, UI the lrealment uf e:~If\) .. '(."n tkpcntkm !>rea,1 C:lflcer, Iniually. arom~'3SC inhibitor. ... ere U)('tlll~ ~ondhnc: lhempy ill jl'O'olll1enopau,al WOftlCn who failed 011 talllO, ife n lherapy. RC<..'t'Iu ,tudle~ line: Indi~ated. oowCl'er. lhm lhe newer UWllllltase Inh ,buo" can be u\Cd a~ fiN-line lhempy and lJO'Sibly lor runc:er pr'e'l'nIiOli In pIIticll1S :n hil1h ri.I<.6' AWlllata.'oC' inllibuor.; include botll stcrolJal and nonslerold.l! compound~. Exan1plc~ IIf arom:lIl1Se Inhibilnr; 3f"C.' MIo>oo'n in Fig. 23- J 8. TIlC 1in;1-l1cner!ll iun Ilrom,IIO>C mhlbllOf1i .... en: uminogilltl'lhillude. U IIOIlSll'roidal ~"OI1lpound. and the \IeR.1ld-ba..ed te~loIBCtone. 1"'0 cIJmpotllld, th~l ... en: dc, doped bc:fon: it ... a~ ra:ol!l1ilet.l Ihal lheir effCClIIenc: ....' in bn:a~1 cancer trt'lltnK'nl ... a~ dUI! to aromJlase IIlbibllion ..... Aminoglulc1hunide alw inh'blL' OIilcr P-4so-. m\Ohed In 'teroid IiOmlCHlC bio,ynlhe~i~ . ... hkh IImils ih UM! In brellst c-allCC1' tre:t.tnlCnI . Tllc ne ....er drug~ an: more pOlenl and more ~pe eifie inllib1lors of aroll1al~ lhan the curlier eompourK!s. In addulon I" leslOJactOnc. two other ~leroid analogues have been u~ . A ... ellstu(hahleroid analogue IS4-h)dro~y-

AIr.. (Cytadr&n)

oogI"""'.'.
c
H

coN
u.s.)

OH For.... sr ....

{~)

1M {noI . . . .bIe.,

,-(Arorrph)

VI
CH,
M~ eN

""',lAo.,"""'"J
Figure 23- 18 NOfTI;I\.He II"lhibotoo. androstene ..hone (-I-OII A; forme"'al1C. Lt:maron) ..... hich ha~ been marletcd in the Um tl-d Kingdom SUlCe the <'ally 199(k for ITCatmcnt of breast cancer. Although inmally tnought to be a completely 1\'1.::r;lble inhibitor. il IS now lllO ..... 1I Ihat fOOllestalle i, an enl.ymc octil'uted irrel"en;ible ("\UICldc") inhibitor of art)III(11aSC . A lunilalion For rorill,,~ulIIc is lacl of 0IlI1 alailability. E.o:.cme~tal\e is the latest Mcroidal aromal:l.<,e IlIhlbuor. It i~ allother mcchanismbao;ed inactivator o f aromatasc:. but it i, orally al'ailable and 1\ highly sclccule for aromatasc. Both compounds ren cci minor slIuctur.d modirlCatlons to the lIatur,lI subslnate. ilJlUro-orencdione. The oonsterOldaJ lICOIlUltosc rnhlbll()f!; are cornpe1. lilc inhlbilon.lha.t bind to the Cn~}lIlC lICtlle SIIC by coordinating !he itoo atom present 1M the: ilelno: grutlpofthe P-4SO protein. ASIde: frolll aminoglmcthillllde, the fil"1l1 sck.:tilc arolll<lta."C mhlbltor to be ntartt'led in ttIC Umted Slalc~ ..... as anaslrOlote (An nmlcx) . Ana'li"Ol.ole incOl'pOrnte' a triazole nng inlo its SlI\lCIUn: that can C{)()I"I.linate to the heme iron. Letro7.olc i~ another triazolc-containlng inhibitor thut il :lI,o efFective in lhe 1n:~liIICllt of bn:lbl callCer. Cum:mly available inhib.lors ~uppn:'s plasma cstrogell ICI(:II (e",rad lot. estrone. and eMrorw: ~ulfatc) by I!O to 95%. EPrll('!" arolllalase inhibil()f!;, ,och a" arninoglulcthimide and Ic:SlotactO!le. suppl"e<iiscd plas.ma e.~Irll1:ells to a icMCr e.\lCllt. 1llc: SIde effects often seen .... nh aminogiuletnllll.de bel:ause of :oddillonal inhibnioll of other bo-os)'Qthc:hC enzymes are aloided WIth the IICWest agenl~. 1llc: sc:k:cIlHI)' of these drugs for arorn:llasc: I. qulle high. Al; with the SERMs. these drul!S an,: only cffll\"e when the breast Cill"ICcr ce ll s are "c'IO'llcn rCl.."Cplor (E R) posilil'C," lneanmg thatlhe) respond and proIifcralc In Ihf 1ft' cnce of e~tl"Oien. Arornat.:!.'>I: inhibilor.; can cauM' fetallwll III rrcgnalll W()I1lC1i wid an: then-fore l"Ol1lralndJCltcd. Alklili()llal n(>n~lcroidal inhibll()f!; an: based 00 the fIa. "OIlC ~trociurc. Chrysin is a nav()IlQid nalUnll prodllCl rba ha~ ~romal OSC inhibitory lICtion in I'llro ~.milar 10 lhat d. ilJlli nogl UlClhi nllde.&1 It is iwllllcd From Pllnijlllru rot'lVltI and Olhcr plants. While this compound IS 11()Iusetlthcrapeuli cally :i' an lItUIII<ltll.SC inhibitOl". it has foond IItIl.'wul"oaNr: U!iC as II. nUln lional supplement in comb.n<ltion " 'uh ........ Slcl'Old~ 10 enhance musell' bulldmg and athletIC perkr. mance . The lheor} for usc IS that an arOlnatlbt' In/tIbIIor reduces the l'\Erogenic side effects of androgenic rx. pounds. Although a ,aricty of nUlnl10nal supplc:OXI1l prnrIIII,'IS ~ta"lIng chry'ln arc a,allable. II " unh~dy 111M "t nlfiCalllll.romatasc Inhlbilloo is beill!! athlel'ed in lilo.lbr OI""JI bioovariabilll)' of cbl)~1Il is very low. mainly ~_ of efficrent COlllcr;ion 10 the COITC<;pondl ng alucuronrdc l1li !>Illf"te t"11JUgU1C'. \() the pllbma COIICI'I1I1"311011 fnt ch ry~in " mini111al.~

or

AROMATA5E INHI81TOR PRODUm

Anastrozol f!!, USP. A/UlStro.cote, tr.ll'.tI,tI-tCll'lllllCdrylo 5 -( III-I. 2.4 -lriazol - l -ylmcth)"l)- I ,3-bcnlcncdllkCl;;;;;;;;;;' wa~ lhe fiN specific aroolUt.a"C rnhlbllOf 3ppnn'ed II. Unlled St<lte.~. It t\ mdlcated for first-line lrt"atment of porimenopausal I\"IH1M:n with adlanced or mela>tal1c In~r eer and for sa.'OIld-l.ne trealmenl of posmlCnopausal .... ilh advanced breast cancer .... OO have had diSl'a.o;(' ~ion fol lowingtamOJl.ifcn therapy. An alklltionalilldl"~

,~----------------------

for adju"anl Ire;l1ment of "'omen with c;lfl y breast canccr

",as added in 2002. Pullenls who did no! ~.polld 1 \l1mo~i 0

ftn Ihcropy rorely re~pond 10 anastnu.olt. Alm~tro/.ole reduce, ~rum e~tr.ld iolllpproxilll;lI ely 80% after 14 day< of daily dosing . Due 10 Ull eillninalioll halflife of SO hours. arnl>lrolook is cffeo.:lI'c '" Ith ooce-daily dosIng (I mg). Mclaboh~ln of anaSlrowle mcludcs h)"dro~yla IMlII and glucuromdalion. as well as N-dcalkylllUon to pr0duce triawlc. The met."lbohle<i of 1lIl....' lfOl.Olc are macillt. Allhough anasllmolc can inhibil CYP., lAl. 20.1. and 3A4 With K, "alue;; In the 1 0'" rnicTOmolar rangc. the eonccntra l10ns uf ana~tru7.ole reached under ~taJldanllheropeulk dos109 are much lower. lot) unaMTOloolc ,hou ld lad significam P-4SO imerolCliolls.""

ongmally S} nlhesired :I.' a JlO'>"ble annbolic- Mcrold. consid cring its 't1UClUr~1 similarity !{J ICS1()<;Icrone. l11C key SltuC IUrJllhffen:ncc rrum anabolic ,Ieroid, i, lhe O-ring lactone il1\leOO of thc Iypical cyClO" Cl1tyl ring. Al1ltoogh c-omidcrcd in many tcXl( an aIKlroKen or nnnholk \Icrold (it is a Schedulc III drug because:: of Its cla~"ficallon as an anabolic ~Ie Nld). ICSlolaclOllC lacl.s androgenIC effecl5 in \ I10. [t:. 111.1' 011 is beli!l,ro to be due 1 irfC'e~iblc inhibition of aromatase. 0 It IS a rellillvely .....cak Inhlbuor of aromal3SC. but the 1m::1(1"~Iblc nature of lhe inhrbillon Clln lead 10 prolonged efrccts. lls relali"cly weak inhibition of aromalllSC and ils urKlcslI'llblc dosage !'Ch\.-dulc (S X SO-mg mblets q.i.d. ) gll'c Ih" older agen! only Ii rnuoo use:: in h rca~1 cancer treatll1ent bccau)ojl of bellcr available optiulls.

Ihe pre\clal hann

l elrOlo/e, USP. L..ctm/01c. 4.4' -( I H- I.2.4-tria7.01-I-ylmethyltroc)l:h bcn/-,,"itrilc (Fcmara). is u~ for nllN of lilt _ lIltli.:aII01h .... an:l.l.uwolc. It T\'doce.~ rooccntrnlions of ~ I'!oIrogen< by 75 to 95<:1. '" ilh matHnal SUppre"'~lon ochic"ed '" Ithin 2 10 3 day5 . L..clrololc i~ speci fic for arom:llllSC inhibition. ",ilh no addmonal cffecl~ on adrenal conicoid bi osynthc-~is. CY P, 'A4 IlIld 2A6 lire invulvoo in the mClabolisnl rllcwwlc 1 the major c~rbinolmcl:tbol ite. which i~ inac 0 11''1:. The loss of 11M: tri3l.olc ring. which I' lI1Vuhoo in coordlnalion of lhe heme lton ...'ou ld e.~plai n tIM: loss of ocl;v;Ty. Lcuuwle <;ttongl) mhlblt~ CYP 2A6 in vum ...... uh moder.ue IOOlbition of CYP 2C 19. "The effect of Ihl \ in , Itro inhibition 011 Ihl' phanuocol.incucs of coodmlllt"lered drugs i~ un~nown. Tamoxifen reduccs 11M: le,el~ of 1cITOIO!e significanlly if lhey are used together . .so ~"OmbU1atioo treatment "lIh Ihc-;e agenh is not recommelKlcd .1O [Memestane. USP. E~cmcstallC. 6-me:th),lcnandro:staIA-diellC-3.I7-d lOlle (Al\lfI1aljin), ,~ IIlC Ii"'t ~Icroid-bascd .-orn:ltase Illhibilor appro' 00 for the lfI::alll1cm of breast canm in the Umted Stales. It i~ a mechanism-based inacthator tha irTc,cl1l,bly inhtbllS lhe cnzyll1C. Pllbma ""trogen levels 1ft T\'duced by 85 10 95'" within 2 1 3 days. and effects 0 bst 4 to 5 dJy~. &enlCSl3IlC doe~ 1104 Inhibit wny of the map cylOchromcs 1'-450 and has essent ially no imct3Ction ,,"h sleroid rcccll401"S. with only a "cry wcak affinity for the androgen receptor. The: 17P-hydroAyc~(nlCsl:LIle reduction product. ho"'CH'r. h-l~ much higher affinity for the androg."'n I'(cc[l(or than the parelll (~1I11 Si:"cr:al fold lC'\~ lhan DHT. 0..."'8% for parent \ CfliU~ -30'). for mClabolnc). The c!illlcal IoIgoificance of the amnllY is likely mllllmall:!lx-ause of the low lc'cb or lhe IIlClabolr\c producoo.
Aminoglulelhimidc. 3-(4~inOllhcnyl)-3-clhy l -2.6-pipcridillcdi,-,ne. b maillly u'ied \() m,al Cushing' ~ ,yndromc. a condition of ~drenal slcmid excru. a usc in "'hieh lilt 1'-450_ Inhibition ofthr _ compound IH~pIoned rolher Ihan ib wumal:tse rnhibilion. Ami~lu Irdllnudc is 11 wcak inhlbuor of :u-omalll\ie and ha.~ been used lIICcCSlofully 111 the ueannenl of cSltogen-dependenl breast C2la1". lkcauO\C of lhe de"clopmen! of more: selecli,c amIUUse inhibitors. the usc of amll10glulethlllllde for its ability 10 inhibit atUl1latn-;e i, not ~upponed .

Fotmestane. Formc.~l.anc. 4h)droxyandrost -4 -eroc -3. 17-dlone (L..cntaron). "''lI~ onglnall) belicved 1 be:: a CQfllpel0 it" e mhthllor of aromataSl:. bul later studies delcrnuned 1110 be:: a mcchanlsm-based IrfC' C1"Stblc inacliv3tor of aromar.aSC'. Fonnesllll1C was the fir..l afOnllllllSC' rnhibuor appI"O,ed (or u<.e ill trenting breast cancer in Europe. blll it i~ not avolillblc in Ihe Unitoo Sl:ttcs. II hicks ornlncth ily Hod is used lI" otlcc-e\'cry-2-we<'](s injct:lioo.

Progestlns
ENDOGENOUS PROGESTINS

'The kry endogcnou1 Sltroid hormone that !lets allhe progesICrone I"('Crptor.; is PfU:I1C'>1etor1C. All OIhc::r endot.'Cnou~ Stcroid~ lack ~ign ificllm JlI"Oi;c'lalional OCIion.

BtOSYNTHEStS
Pro&c:)teTOIlC is protloced in IllC ovan es. testcs_ and adrenal gland.~. I\lu~.-h of the proaCstcrone IIrat is symhesized from p!"l:gllCnolonc is immediately coo,'cncd 10 othrr hormonal imcmtcdlalcs and Is not secreted. ~ I"" biosyntheuc pathway (Fill. 23-5). The oorplh lUlcurn secrelt'li the IllO!>I progesteront' . 20 to JO mgtday dun ng lilt' last or "Iulcar' ~Iagc: or tilt nlCn,trual cycle. NOrlllal IIlCn 'iCCretC aboul I to ~ mg of progl!..~lcronc daily.

0100.

Inc naduct lmal 10 mal of

~f14I("u

1\

lerJ.jlCU II -

!Mionable 11l1labolic IC perf01"inhibitor nte ~'Om !em prodf that \11-

METABOLISM OF PROGESTERONE
f'roIlc'lcrone has II ltalf-hrc of only abou l 5 IlII11UI&::f ",hen III.... en orally. bc::cause o r rnptd meillbohsm. ProgCSICTOOc can be:: tmnsrormcd 10 nillny other Meroid hormones (l'lg_ 23-5) and. 111 Ihat sense, ha~ nunlt'rotIs IllCtllbolk products. l11C principal tJ(CrelOry product of pr'I"Jj;eSIe:TOI1C mc::lllboh~m. ho"c'e1". is 5p-pregnollC-3a.20a-dio! :Ind ii_ conjugotes (Fig. 23- 19). The sleps Ihal are invull'oo in Ihc f()f111~tion of this lllC\abolile II'" T\'dl,lCliOll of the C4-5 dooblc bond. ",dOCliul1 of ttw::: C3 l CIOIIC: providing the 3a-ol. and reduction of lhe C20 keloroc. The reduclloo al C5 I11U~1 ['i"t'Ccde lhe T\'duclioo of the C" lclOllt'. but lhe timing or the C20 can \-aty. depending on lhe IISSue. 11 n St1UClural fealure( Ihal can block reduction at C5 or C20 ha,'c greatly illCTCased lire h:Ilf-lh'cs of progcstcfOllC derivatives.

Y beC"llU.'o('

""0. The

onide and n of fTee

Aminogluterhlmide. USP.

ramclhy lttoni lnlc. !etl in lhe 11 of PO,I on:aSl .:all111 p.~lIem\ t pro~re. indkat lOll

BIOLOGICAL ACTIVInES OF THE PROGESTtNS'

Teslolactone. USP. TC~lOloclonc. l3-hydro~y-3-o~o1l.17-scconndrostn-l.4-dlen-17-oie acid 6-1oclone. was
Likc lhe hlrogens. progClolerorlC has u variely of phamnlCl)1 0gK.aloclions. with the m.a ill lnrgcllIs~ues being the uterus.

5j}-RIHlaH 3u1-I50 20(1.1-150

..,""-.+-/
5j}-Pregnane.3u.20s.dIoI (*Pfllgrlane-3a,2Oa-diol)

"

figure 23- 19 Pr(lge$te/OI"Ie metabolism (timing of the redllCtioo Steps can vary). HSD, hyd/o)()'Stt/oId dehydrogenase

breast. and brnin. Proge.~terone decreases the fmjl>C'ocy of the hypothalamic pu lse generator and I ncre~ the ampliwde of LH pulse$ rdease<! from the pitUitary. The actions of prDjl~terone: ill the uterus include de\'eloplnent of the SoCCittOl")l endometrium. When release o f prDjleSlei OiK from the corpus luteum at the end of the menstrual cycle declines. menstruation begi ns. Progesterone also actS to thicken cervical secretions. decreasi ng cervical ~nelration by spenn. ProgesterollC is cri tical for ttlc maintcnance of prtgnancy by SU I~sing mc nr.truation and dt."Creasing uterine conlrnctility. Progesterone has imponam IICtions in ItIc breasl duri ng prt:gnancy. acting in conjunction wit h estrogens to prtp:= for lactalion. A thcrmogenic action is uisoas.sociuted with prosesterone:. Dunng the menstrual cycle, progesterone mediates a slight temperature il'lCfeast near midcycle IUld maintains the inCf"('ased tempemlure until the onset of menstruation. Tbe uact mcd\:In ism for Ihis temperature increase is llQIl:nown. ProgesmOolC: and its mct3bol u~ have additional centr.ll er ft("ts. ""hieh are being actively uplOf"Cd:rl
STRuaURAL CLASSES-PR QGESTINS

a 6-nlCth)"1 group cnhancc:s !IeI;vity:and rtdllC('~ IllCtabo!, ...... Medrolyprogc:sterone lCe'late is a parucularly pcl(cnt pie (Table 232). Duax and coworlers' ~ :!II ha\'e stud.ed the "'ructu~ ~ qUlremc:nts I.Irthe progo;lcrone receptor In detail. They ..... elude thaI the progesterone: 4-en3..()1"1e ring A is ~ key 10 binding but only ""hen it is in a conformation quile dltTcmLl from thDt of testosterone: or the glucocon ..::OIds. 1'hI:u Itview~ contain Stereo drawings Ihm show the required cOllfUl"' mations III three dimensions. Struclural fcalurc~ modif)'I"I the ~tcroid 0 ring arc also imponaru for optimal intcruclimi with ttlc progesterone /l."Ccptor. Two imponam dl'ICo\'eries led 10 the tlevelOpnKrM 01 tile nonCStOSlCrone dcrivatlu$.. One was .he: dlSCOvcry Ih.u 19oorprogestcronc stilt maintained significaru prDjlrsw- I octhity. The 'lCCond was thai I7fl'oall)'n)"1 testOSlttalr (ethlstcrone) had grcatCl" ptUl!estluional than androgc:nl( k' livily. Although the 19-nonestOliteroncs do ha\C :aOOf\lFID' side efft("ts. their prim:uy activity. nelcnhelcss. is piiJiCiU" tional . In lIdditlon 10 cau~ing a ma/hod increase in ~ tional activity. the 17-alkynyl group also blocQ mcutdic or bacterinl o~id.ltion 10 .he com:.~ponding 17-orll'S. TlM. by adding a 17n.. elhi nyl group to lestosterone. one can Ii muJtnneously decrea.~ androgenic oclh ily. promote good progc~ta\i()nnl activity. and ha,c an OI"'oIlly octi\c comJlOli*l as well. Table 23-2 Illustrates the relath'c progcst.lliionli k ti\ ity ofa numberofprogwins. A funher modific:u.ion 10* rIOf1estostcrones yiclds progcstins with minimal andq activllIe'. Changing the alkyl group at CI3 from a ~1. an cthyl grt)llp. l!i in 1e\"OfKlf"gI:SU"C1. reduces the .ndt.... effects ..... hlle m"inUlining the prDjltsUitional effecb.
THERA PEUTIC USES OF PROGESTtNS

u_

Progc5tin thcropy may cau\o(' IIlC"llStrual irregulafltll"S..IUi III spOil ing or anlCnorrhea. Weight gam hnd acne halt bear associaled wi th te.~tostcrone and 19noneslOStcrone.,. logues. in pan because of their slighl undrogcnic etTect\

TABl 21- 2 Comparative Progest at ion. 1 ActivItJ of Selected ProgH tiru;

~tatlv.

Orat Activity

Adi" t,

Proge.<tin) arc compounds with biological aclivities simil ar to those of progesterone. They illClude three structuroll classes: (II) progesterone nnd derivatll~. (b) testosterone and 19-nonestosterooe derivatives. and (e} mi.'iCcllaneous synthetic progestins {Fig. 23-20}. ProgestCfOr\C itself has low oral bioovailability because of poor absorption and almost complcte metabolism in one passage through tlK ]ilcr. A rea-ntly available oroll formulation is micronized progester one in gelatin capsules. The micmnil:ed drug is mIlCh mof'e readily absorbed. allowing orol deli\'cry of progestc:ronc:. cven though the dose must be much higher than a parentcral <lose: to conlpt'fl$a.te for extensive liver metabolism. Adding l7a-acyl groups slows meUibolism of the 2Q...onco. whereas

'' ''-

(nlt\

17 ...l:ihln)II,, _ _
(~Ihil"'runel

11 ,,l;Ih ,") t t9nono>lo"",,,,,,,, (non:! hIndn:ono)

N.-h~1

17 "Hy<lr(l')~""
MNn!')~1IOdII<"

t~"",...

--

.S-,
z..tO

~'"

...,
OJ1
>0

" "

0.. "..

5 ""

. ..

II. A. .. ole

~I< '

I "it ur..:..

"

fiI Ooe

I I 1100

81rth Control. A significam U~ of the progl."Shn as of !he c lrogcns, I~ Inhlbitio" of u\'ul31 ion. SlcroidaJ bln h COII!fOIlI,gents are dbcu~scd In ,he following <.Celion 00 I;hcnlll;al
ronlr.ta:plloo

rrlalf:d mcnstrual

dl~

cauo;e(i by horl11011UI delielelK.'Y

or 111IbaiallCc,
8rNst or Endomet,kJl C.arcinoma, Progc~t l11S can be used for palltau\c tn:aUYlcnl of advullCcd carcmoma of the brea,t or endometrium, These: agents >houkll1Ol bc ued In place' of ~urgcry, I".tdlotion, or chemotherapy, Progestins fo, Premenstrua' Syndrome (PMS), There have bun claims that progt~ttl'Ol'lC may reducc the tffeets of PMS, Conl1nucd anoly~, of V:lriou, studies indi .:aIC, ho",<.'\'o:r, that proge!illOS arc 1101 CffCC1I\C for thl~ usc: ? '

n-

,. nt

."'

",-

Refit/etlon of 1M Risk of Endometrial Oncer From Posf~lJsal Estrogens. As discussed ill the sec tIOn on lhempeut ic use~ of c~lrogeus. '>C\ernl ,wdles Ita ,-c

n!:

....ggr.;loo Iltallhe comblllallOrl of a progO:Slin 1I<;,b an ~~Iro !rn nlay ~ignilkunrly rc(luce the n"k of cndomclrial can<.-..:r .. ~"QfllC1I wang polounc:~usal C'Sirogcn$. 8ecauseoflhls .
I

I<

progc"1n ;$ onen Induded

In

HRT.

19-

la l

Primary and Secondary Amenorrhea imd Functional Utfflne B/Hding Clused by Insufficient Progester0IIe Production or Estrogen - Progesterone /mbitlarn:e. Progestm~ rn.\C been u~d ,'cry rffeai"ely 10 treat primary

PR OGESTt N PRODUCTS

oc-

Ole

ta-

and 'ieCQndary amenorrhea. funclioua.1 uterine bleeding. und

The prog<.')lin~;are prim.arily usa! In 01';11 cootrKl'pt;'-c prod ucts and in homumc replacement regIme n' for ",omcn, They arc :11..0 uloCd to lreat SC\'craJ g)"llCCologieal dl~n ; d)~-

,,,,o

)lic

US.

o<J

I""

oc-

""

aiC

P".'l1 n l.." .....

tt,.o.OJt)'PfOlII sterone Citproele

(H~.geltrooe,

ttyIvIin)

0y
'.>--J .
H

eH,
M I 'OJtJ1lli'OQlll8rone Acetate

M81/11Strol Acetate
(Me~)

(Pr()Y$f" Cyerin)

ElhistllfOOll

""OH

OH
H
' ~H

Figure 23 - 20 Natural and synthetIC pt"ogestlOS.

OH
~'H

NtKgeslrei
(L~tr'l)

NorglslimlUI

OH

DII>gIlUItl

-t Ho

H H

.-

OH

o,~'<i
D<oapirenone (CO<I1j)(lnfW'II Q/ ......1Imin)

Figure 23 - 20 Continued

~IIOIII hea. elldonlCl ri<1'i~.

;lIncl'lOlTbea, and dysfunctional

uterine bleWHI&- E>.lrogcns:arc II,en simuliallC()Usly in most

of these snumioos.

solubility. :0I1ow1ll1: II 10 be ~lo .. l) reka>ed from . ., preparations. as one would predl('t from Rguno 23-6.

USP. Progesterone. prcgn-4-cn-J.20dlone is 50 r..pidl y metabolized lhat il is nOi particularly

Pr~sterone.

effective oruUy. being only onetwelflh liS active as illtrumuscularly. An 0l"Il1 formu lalion of micronized progC!;leronc
(Promeinum) i ~ aVIlII:able. Progesterone gh'cn intramuscularly cun be very iml:!!!"g. A vaginal gel comni ning 4 or 8%

progestel'OOC offers an ailcmalivcdosagc form. I>rogesh:rone was origll1ally obIained from animal ovaries but is now prepan:d synthetically from pl:mt SlCroi precurwrs. lbe difoCC)Y' cry of 19-1lOru:sIOSlCI'OIlO With proscslerone OC l;v;t)' made
,ynthctically modified proges. ins of tremcndoos therupeuuc
UllportllJlCe.

PlogtiICfOnC (and all ocher steroId ~nc3..unes) is light sensll,'c and ~Itoukl be protected from light.
Hydroxyprogesterone C~proate. U5P. liydroxyprogeMeronc e:lproale. 17-hydroxypregn-4-ene-3.20-dionc helIaooat ... is much more III;tlve and longer acting than proge.~ tcrone (su Table 23-2), probably because the l7it ester hinder.; mluction to the 20-01. In OOmtllSI_ h}'droxyprogeslCfone ,t>elf lacl.:~ proge..',ullional :Jetlvity. 1lIc caproate ester is gIVen only Inirnmuscullirly. The ester greatly illCfl'ases oil

MedroxyprogestefOlle Acetilte. U5P. Mtdrol) progesterone acetale. 1 7-accl)'Io\)'OO-fTII:thyr~ 3.2O-dionc (Proler.. ). add~ a 6cr-lnclh~ 1 group 10 the 17n-hydroxYPfogcMerone ~truc1Urc to greatly decn'w ttr rule of reductJon of the 4-cnc-3-onc ~ySlem. ~ 17(}-~~. group also decno:lSeS reducuon of the 20-0ne. similar 10 l7cr-caproate. MedroxyprOj!C!>terone ) is ta'J' IICllve orully (o;ce Table 23-2) and has such a I of action intramuscularly thaI II cnnlIOI be inlramuscularly for InolllUlg many lIlC'nslrual inlramuscul ar formul:mon I~ useful in lhe paillru,,~ ~ menl of advanl,:ed endonl('trial. brea!>l. wid nonal c=i,~. . MPA also ha~ an Imponam role in SCleral bn1h control UCIS (Depo-Prol'cra. Lu nclle). Megestrol Act't~te. U5P. MCgolrol llC\'1:ue. 17~ dmxy-6-melh)'lprcgnn-4.6-diene- ~.2O-dione ace). IS a progestin used pnmanly for the mem of l"CCurrelll. illopernblc. or i
for appetite enhllOCl'mcnl 111 AIDS paueTll.s. oosis for Ihi _ use of nl<;:l!e~lrol is unl'lcar.

Norethindrone, USP, ~ nd Norefhynodrel. USP. Nor ethindrone. 17a-elhm)'I19nortestoslerone. and h~ J "IIC'J l'oOIller. norclhynudfl!l. might uppcar at fiN !llonee to he !ilJbtlc copies of each ocher. Olle would I'l"ed icllh:u lhe J 5I'''' doublc bond ..... Ollld iYlrneri~e in Ihc ~lomllCh'\ ocid 10 the J' pihiliOfl. In {OCI . howe, cr. lhi:: Iwo dru", ,"cre developed \imullollCOUsly and tndependently; henee. neither can be COII$idcred a oopy of the other. FUr1I1ctmore. ~hindronc is Ilboot 10 hmes nWlt'e act;''C than ~hynodn:l (;;cc Tobie 23-2). mdicaunll thai i.;omcriJ.alIOII i, noc lIS facile in \'ivo ZI one mi!lht predict. Allboo!lh lhey arc Ie" ""Ii\e Ihan ~sleronc when !I"'en sllbclllll/1eou~ly. lhey Ilaw lhe Imponan! ad"mmlge of being orall y :Iclivc. l1lc di<;covcry of me poIcnt proge,un IIClivity of 11O-C:lhmyltcstOlolerone lethiMerollC) and 19'norpTOb'e>teronc prc!:Wcd lhe de"clopmc-nJ of Ihc.se poienl progotios. 80th are utally IlCtl\e. "i th me l1a-clhinyl group bloc~mjl oxid;uion 10 the le!.s actil"l: 17-ooc:. The: rich electron den>!ty of lhe clhln)'1 group and the ab.ence of the 19-mcth),1 group g",al l), enllanet' progestin .:\ivity. 80th compoUll(is wert of greal II1lpor1anec as pro~Shn romponcnls of oral COfItrneepl1>e<" aJl hollgh curItnlly. u<.e of nort:t hynodrel i~ nllll imal. Non:thindn:me. USP. and norethIndrone acetalI,'. US I'. ure widely u-.cd for ..111M: usual Imilcutioos of lhe progCqiIL~. a.~ well lIS being oomponc:nts of oral rotllr.ICCpl:i>c:s. Bee-oIus.: thes.: oompoonds retuin kcy features of lhe le,toslerone structllre. inrUling the 17,8-0H.11 is I"lOl \lIrpr1Mng that lhey pos.es.\ !O!Ill' androgenic hide cffeeb. fthynodiol DI.cet.te, USP. Elh)'nodiol di:lCeta!C, 19IDpfI:gn-4-cm-20-)'ne-3,B.11 a-diol diKe!aIC. is u prodrug of IItln:thlndronC_ A combinalion uf hydrolysi~ of boIh esters IIId oxidation of Ihe e3 alcohol 1 lhe ~etonc i~ neccs.\3l")' 0 II proHde tnc full), actl\e progesun?~
Norgestrt"i, USP, ~nd LevollOl"gftstre/, USP. Norges1rtI. ( 1711' H :r )-1 3-clh) 1- 11-h)drox)-IS.19-dlOorpregn-4cn-20-yn-3-0I1C. and Ic~onorgestrcl. (110)-(_)-1 3-clhyl-11b}droxy.18,19dinorprt:gn-4-cn-20-y n-3-on~. have a e l 3 tthyl group in~lead of lhe CI3 met hyl bill ha~e proge.staIIoo.l;I prOPC:lt1C~ ~imilar to those of OOI"Clhindronc. with de In"ased androgenIC dfeels. The elhyl group apparently proIUs unrl\ornble ~tcric IOler.K:II011S ","h tllC aoorogcn 1l'CtJII0I" lhal reduce the affinily oomp;an..-d ,,""h that with Ib.: proge<;(CrotIC rtCcptOf"ll. Norgeslrcl "a racemiC mi,turc. le\"Onorgesm:1 is the slOglc actJ\ e le\(WOIllIory cnam; .lIIIn". Norge,lrel j, u'Cd on ly in oml COfltr.lcepmcs. Le,'O-seslrel is 1ISt.-d in both oral f011lblll:tli(l" bIrth conlrol pOOOCIS und polY11lcric implanl) thm proVIde l'()!1lntCC'plioo krupto5)cal"'o.

Norgestimare. USF'. Norge,"mate. 111a)-11-acetyloxy- 13-cth)'I- IS. 19-tli nur-pn-gn-+cn-2Oyn_ j,ul1i: oXime leyden. Tn Cyelen). i~ u 19nOr1c'lo:o.lcfOfle. 3-oll11lC prodrug Ihnt is or.dly acll\C lind used wllh an c,uogen ill oral comfllCepnve product,. II has minimal androgenIC ach Oll. Norge~u matc is mctabol1l.eU 10 11-<kac.etyllKlfl,"C~ltmme (1lOI\'Igc~lromin) and oorgc"n-el . "hlch pro~lde the progestaInJllal KnOll." Norelgestromin. USP. NOIl'lgeqromln. (111\")-13elhyl- 11- hydroxy - IS.19 -d lll(w-pregn--I -en- 2O-yn - 3 - one. o~ inlC. is Ihc progCStlll cOl1lptlllcm III the cOntraccpt I~C pmch (Onho-Evtll ). First -pas) mC[Qboli~m in the liler is uvoidcd by the trolnsdcnnal applicalion. Ilepalic metaboli\m doe!. occur. howeHor, aocJ norge,.",), an achl'e melabollte. and other h)'drox)latcd and conjugated lIletabolile;. lIT(' r~. Efonogesfrel. USF'. Ewoogesln:1. 11o-l3-eth) 1 -17 hydroxy - II-mc:lh} lcnc-18.19-dlnorprcgn-kn-20)n_.l-one . 3-ketOOc-.og1!.'ilrcl. i, the acuve melabolile of desogc'lrcl It i~ 111;: J)I"()!lc)li n l'Olllllollem in Q llC"cr implunlable CQllltlIceplile "mplanon) and III the v:l~mal colllr.K."eptile ntll: (NuluRing) . Drosplrenone. USP. Orosptrcnone. J..oA~fJ.1/1: 15/j, 16,Bd. melhy~ne-11 tr-pre&n .... -en-2 1.11-earbolac:lont', d.f rcf'l SINeIUmny from all of lhe other COITlmerciall) a' atlable Pf"OIe'lI n)_ lIS ~INelUre i~ sundar 10 lhal or ,ptronoIOCWflC. a minc:TIIlocortieo,d receplor amagom.;t. und dl"Ulipll'l:none doe~ hn~ anlillliner-oIloconieOld oclility lIS well a~ pl"Oll~u.. liooal lIcti~, ty. 11 is also reporlL-d \0 have .;ollie IInliandrogemc cfrecb. 1lIc. SpirolaclOOt: at C 11 and the 1"'0 cycloproP)J ifOUPS lit C6-C7 and Cl5-Cl6cOlllribute 10 lhese umquc actioos. DrospircllO!lC I~ the prugcstln COITlpont.'nt III II 01:111 orall'Ql1lracqxi\c. Y~mln rrimegestone. TrinlCge'tOlIC. 11.8{Sl-lactvy l- l1 nw:th}I":'IJ"3-4.9-dien -3-onc. IS u highly mOllified norprogeslerone i.lcnvative Ihm i~ hemg in\"C'ligau.-d for il\ u~ 111 IIRT and as a COnlfXJllCnl of orol cOnlraceptwl~. The k~y MRlClllrnl dlffen:ncc~ are a 11,B-JacIO}1 group in place ofthc Iypieal lICel)'1 group. a I1a-IIIC'lhyl. and a Ol-CIO double bond. TnmegeSiollC 1ac~, androgenic DCtion and I\ll) lillie to no amlllty ror the e"'TOlen and gluroconi.eold receptor. >1

Medroxy,

!gn-4-encI the bot,ie crca-.e the 7 a-lICetlile ular 10 lhe 'AJ i~ ,cry II: durolUM lllCly used .rden.. "The line Irca l'
IIrci nol1l ~"

_"'Ie

CHEMICAL CONTRACEPTIVE AGENTS

Pulitlcal. cuJluroil. and rc...:un.-heo~1 b~rricf'< hal'e CIIOI"moo)l), complicaled lhe development or oonlnICcpti\e agcnt ~ III modem limes. The re~ic:ws b) Djeras~, .'" IIIItT'IO!" of norcthmdrone. and by I..etIni~r*l arc important readln!!. (Thclr i n.,idcr~ ~iewpollll" of the researeh COITlpt'IIUon during the 1950s and 19601- 1 de\clop sten:Jid prodUl1. IS 0 ..... pa: ially mteresllng., More recent revic,,"\ pt"mide ~IIShtly differt'nl per;pc(111e 011 the overall dc"clormcnt (If uru ' COl1lll1Cepli\'c~." OJ The II\(N notable achicvement ill ,hemical cOlllfllCep"0n came mthe blc 19.so-. und eml) 1964h with lhe de~eIOj"lICnl or or~1 coolrncepli\'C agenls- "the 1'111." SIII~:C lhen. a ~Mi

fltrul prod

17-h}" IIiIC ( Meg. 1,' manallcomelriu l or n U1dicmed liochcmical

lie.

USP. Dc'oOgC'itrl:l. (l1a)-l3-ethyl-ll11M) lene-18.19-dlllorpn:gn-4-en-20-) n-l1-o1 ( Ik.-.ogffi). u 19nortr;s10\0ICronc anal~ue with 1l00d ~Slm act;\1)'. Lilt- lhe otht'r progCSlms. it IS Of"~lIy aclivc and used in rornbinaliOll "ilh un c.~IT01lcn 11\ or.\l COIIltIlCCptl\CS. Desog~n:lls a pnxlrus thaI 11111;;1 be oxid iled 1 lhe 3-01lc 111 vi~o 0 ., hal'e JII"Og~'tal;onal action. CYP!; 2C9 and 2e l 9 have ~ implicaled in lhe inillal h)'dro~yIQIlOO of desollcstrel 110....

~trel.

"I) ufconlroccptive prodllCb ha,c beel1lntrlxlllCcd, mducJ inS hofn\(}ocrdeasini\ intrumerinc de,ices. polymcr im planl\. IIlJcctablc fomlulations. and a IrdnscJemlal palch. AdcJlhooaJly, poIiteoilal cootl"..cCpl he30 and Ilbort lr!ICicm~ Iui'e been de'e~ De)ptte lhe ad,ance:!i m chemical contrAiX"pmc agcnh for ..... onN,'n. no hormonal male contmct'p' ti "r:.~ are currently a~ailablc. altlNJogh IlInlled research In thl' area has been oondllell-d. [n lhe follo"ing pages. each of theloC upproaches 10 dl\!l11kal contJ"lll;cptioll i, di<oCu~>cd. Indi\ !dual cumpound) are dl<oCusscd abo,c "ilh the eSlI"Qgens and progestins.

Ovulation Inhlbftors and Related HOi.iLonal Contr~.ptives

HiSTORy.".....J

barrier for the p;i.~-.allc uf sperm through the CCrvill, 8ccatN pregnancy i~ illlJl'O'>,iblc without ovu lation, howe\~r. lilt contraccpti'c cffects of thick ccnical I1\UCUS or ahn"illioa!l in the lining of the ulerus (to decrease the pmbabililt ql II1lplant1l1ioo of a fenllif.cd o\'um) ""ould appear to be f!Illlt: llCConJary. Nc'enhelcss. OCClI~iollal O'I'ulauon m.lyoctW. and Ihu, the I1ltcruliOlIS of the ccn Ical IlUH:us:and the cJldl). rnetl1um mlly aclually ~I'\"e an impur!a!\l contracepli vc fitnr tiUlI (r:.~pc.'Cially. perhaps. when Ihe p;!tlent for!;tts to tAt one uf the lablet,). l)urillg cumbinat ion drug tn:altllelll W endometrial linmg cJe'clopl' enough for " 111w.Ir.lwal bldial to IX~-ur aboul ... Of' 5 days afler lal..In8 lhe last acti,c tabkI; ur the ~ries ('iCC! Table 23-3).
~ lu" ... II ...... 1<: WI"'.U) Co",,'< \ n o",,- The lnonopkasic combiIlHtions uf a pro~e~tl n lind c~trogCI1 ~ontui n the same altlOlllll ofdrog in each acll\e I~blct (St:e Table 233). A, dl>cull

hi the 1930s. !\eveml l'I.'''Carch grotlPS fournlt h31 injections of proge"'etone mhlbn~od ovulalloo in 1:11', mbbu,. and guinea pigs ....... Kunrok, AllMight. and Sturgis, in the early 194<h, are selM.-'T3l1y credited with lhe COIN..~pI thai ~Irogcns. pr0gesterone, or both could be used 10 pn:"cnt uvulmion in .....'mlCn.1 [n 1965. Pincu ..... repun~-d Ihat progCloteronc gi,e n from da)' 5 to day 25 of the mCllslnml cydc would inhIbit uvulation in "umen. During Ihis tllnc. DJerassi et aJ.\\OofS~nte .. , and Culton 91 ufG. D. Searle and Co. reponed the ~)nthcslsof norethindrone Wlll noretllynodrel . 11w.-se progC)lin) ~ very high progeSlalional and ovulation mhlbnmg activity. Exten)ivc animal and clinical lrials conducted by Pincus. Rock, and Garcia cunfi rmcll. in 1956. that Searle's norethyn odrel and S)'ntcll'S I1OI"Cthindrone wen: cffect1\';: omlation Inhibtt0r5 in ..... omen. In 196(1, Searle rnan.etecJ El1(.w id (a mllltuR:ofnorethynodn:'l and oneMranoI).1UId in 1962. Onho man.etcd Onho Novum (a matun: of norethindrone and nlCStl:lnOI) under C()l1tract with S)nte~. Norethindrone /las remall1l..od the nlO"t e~tcn~ively used progestm 111 oral conlr.lceplllCS. but sevcral othe r u'<Cful agent\ hnve bt:cn <levctoped. Th<:so: are discu~>cd in the sections be low.
THERAPEUTIC ClASSES AND MECHANISM OF ACTIO N

belov. in this chapcer. the trend in pre-criblog has bttn 10"'ani 10"'cr ~s of C)lrogen. As <$Irogen le'"els art Itduced. howe"cr, b~~through blcedlllil lor "spolllns" lbr comt:~ ~n aJlllO) ms ~Ide effect for sonIC patlcnts at earlt" mtdqde. Spotting after midcycle Of ~nlCnOlThca appcan III IJ<! rclulcd 10 tOO lillIe proge,lin relat"'e to Ihe estl"Ol:en. TK bipha,ic and triph:t.'>ic cornbinalton, wen: de"eloped 10 iOl,t these bn:akthroughbleedmg problem, III 100m!: patienl>. C... 10 tile II1II 1,11111 mcn"rual qcl\'. progcstcrone plll.~lna COt>l:C11lr.111IM [X'al; laIc in the cycle, The higher cstroseniprogOielUOl: r.tII early in the eycle i, believed to ;L,,"I in developmcnloflhe enJollletriulll. 11Ie lugllCr progeSlC1'QOC roncentrJIIOO 1M contributes to prollfer.llIon of tile endometnum an,J I~' IUlt "normal" 'olume of mcn~trual 'The birttasic l1li tnph.aslc comb<l1lllonS allempl tu 11I111I'C thiS 'OII"lauoa e~lrogcnl~lIn levels. :md then:by to reduce the ..,. dellCe of spotting 8!1SOC i:ued wilh Io,,dose ~ comhinations. With propel' 'lClection of plllicnl.~. the goal. been achieved: but in other patients, the ill\!idcnce of ~IIlJ has not decleased appreciably.
111 ~1 ,~c ,1<0 Tlll ~1 '~IC (V".1""" . )

,.,,<,,...."...,.. .

now,

Thoe modem hormonal cotUracepti,cs fall into se,er.a.I major clllcgoric5 (Table 2))). each with ,ts own mechanism of COl1tmcCPIl"C action. Individual compound~ an: discussed wuh tile cstrogens and prog~tin5 in the section abo,'e.
Combiniltion T bleu; Mecfutni5m of Action. il AI though, as noted abo'e, Sturgis and Albright m:ogni:tcd in the early 19-IOs that either cMR)gcn~ or progestms cou ld in hibit owlation. il was subse<luently found that ~'(>mbinalions were lu gh ly effective. Sollie problcm~, sueh as breakthrough (mtdcycle) bh:cdll1g. were alloO reduced by lhe use of a CQmbinallon of progeSlln and cstrogen. Although all the cJetaii. of lhe ",()(ess al'\' still not completely understood. it 1\ 110" belie"ed Ih;1I the COOlbin31l0n tabler- ~uppn.:ss the production of LH. FS U. or both by Jl fccdbad.mhibilion proccn l!>Ce Rg . 239). Withoul FSH or LIl , oYulatiun is prevenled. The jlfOCc.,~ i~ )itml~r to the nalurul Inhlbillon of ovulat Ion duri n~ prclln8ocy. cau<;cd by the I'\'le<lloC of c)trogcn~ and progc'itCI"OIlI;: fronl the placcnlll and (1\arie., An ilddJlional effect corne~ fromlhe progcstin causmg Ihe cervical mucus tobecome "ery Ihld, pro,iding a

0 11.... CO~III.\n.....,' r. Tn uun', Chmcal m.dl ... curremly in progress that use a 91-day cycle lIS opposed .. lhe cum ot 21l,day cycle5 typically u'iCd for oral cotrtncq. live~. The monophasic eombin::uions in 1\';stll1g ha,t 1c""Onorgesm'l and elhinyl c.~tr.wiol a~ lhe progeslln ~nd e>I!IJIC' n:~pecli vely. I n~cad of 2 1 day, of horrnooo, fol!O\ir.:t! It) a week of incn tablets. these n:gllllCllIi h:,,"e S4 dall ll"IOneS. follo"ed by a wed. of lIIen t3bleb. TIlC ley dttrG eroce with thi~ appll)IICh I~ thal. the nUlllber of IIlt'nsmul "! clc.~ during tile: year ~'ould be. reduced frolll 12 to 4. If ..00.. to be effective and ~pfc. Ihi, type of product l'Ol.lld a1..,. wt"' lCn to reduce the frequency of cranlps and anemIa ciaK wllh menStruallon. -d

t:~"~"I).:"

1Ior-

HOW SAFE?

The safety oflhc " pill" has b<:cn imesllgated e~1CIISI\dl bc<.au",;: of the widc~pread u-e of lhese drugs in yoong "omen. 0\ cl"JIl. Or.ll conlmccpll "1.'5 ha,'e an c~Ct"11c!I s:.fety profile in healthy, non<;lnoking wOl1len of child-taIn& .~~ Early siudies. based largely 00 theeMIir:r""u thai contained high do-e;s of estrogen . .\J1oo",ed an a1~

 " ,r

TA8LE 21- ]

Comp*rison of 5teJ"Oid Contraceptive Regimens

M ongpo'l.Hk

1. Combination

" ".

F'rndI>cI.o ... ,~1aNt ,~ l' .". ~..s.,. "''f'O''''"I ood moll" no. 2A-.I.o) (/''f.. " ..... '~""",d ....cnI ,non (or Fe" _~, .. , ""*to 1>1" 0 doll""""" n>kIf. 1.11,.., dao!) oil.. (hot 21 <It), <>t' ""... ""*to, 0...." <tI "", .... 1lItoI<1. ~ -",,")Oo'n

<-

BrAnd
Nocon 100
"Ot\"!~,,,,,,,-.

Estrogen
I ....
M<<.I~.

'" "

"

50 1"

1'>"",_)1 I

+~

I~

Ootho-s.wu.. 100

"" ,,-

.'"

:zo. .. U!j(E o.. .... ~S

"'""'n 100 n. '"

~ln5

NOftdIl",.",.,.. I rna N~_I .... I'umlll.o...... I IIIJ

lJb)lKl<hoI

M~.~I'I

M<<.I.-.I. 50 1'1

+.- ((

I "'I

Ed.)'oodi<>! "'-'~. I fill

"~.O,.~IIIJ

,~

.......'
M~~

~.LO''''t
---,~
Jj

llh' nyl ........oot. 50 1'-1 IJh'"yl...........,.. 50 "" &h'")I~.50 ... IJh'~)1 Nndd. 50 1'1 I:Ihlll)'l Nr""*"'. 50 ~ llh,,,)1 e~. 3~ ""
L!h.n)'I ... ~,b"' ..'5 "'. Uh,n)I .. ~5 1>8

x-

n"

,. ,.

Nainyll + N......" 1/3,

Onh,,Nm'lJll1
"-'OIl O~l'

IIJ~

Nt.ombo.oo.lton<. I "" N<lrcchtndrono. I "'I 1".,...,hu,drOtlt. 1 rna

"I'lIWolI.

I"

""""hl"""-.O.5 ~"""-. 0.5

n,. m,
I ...

1Il"~)1 ~"lUIliol.]:!I 1"

"""""

O.Yl~

Ni:r<trulldmnt. O,~ ""

'kln:t/lI1Idr-onr_ 0.4 "'.
~.o.n

0." ....35

.. .

00'

0n00-C)"'...
"""""" 'ill 7..,. .. IillE
V."n",

....
...

1111<)
~

t.o/I)_IOI~.

JS 1'1 '''h,"~1 ntr.Idiol.15 1'1 l ctlll.n}I.<.Inod,oI.}j 1'1 IJhiayl..uado<ol.}j 1" l:monyl~. n 1'1 F n}t a.tndiaI. )5 1" .....
EdIo.~1 Nndd. .IS "" F.lhoIl)I ...,noJoaI. JO III

t:'h,a~I""radi<>l,

F.I/I)_~.I

lul!-

~.3 ....

"" ,. "

1 .<>NIUI21 IYIO I _ n Fe ''IIv) Mk",,,:>I,n ,,, I ,.Y.lO

1 .ow.O!t...w1

'1,_,,,,,,,,,,," 0ftW<". l,~ ....

N,~h'''''''- eewt.

1.5 .... N,~rull<lrunc "'--.:wt. 1.5 ....

F.Iho")1 ~"'. _'I) "" 1.I/Ilnyl~. XlI>8

'''"''''
,~

,= '" ,.
<'~

""""'''" "'...

"'-"

1"'..1"""". 0.) m; ",,.,..,...,1.0.) II\I! 0" "'-'lI<<Ir<"1. O. I:!I n'~ 0.1' 0... .... --'.015...,

[)e,.,,..,.....,.

m,

uh,")1 ~~')O"'8 MI.n)1 Nnodiol.:tO II-i 1..1I,">1."11'<I,0/.:tO OI ~ ~ -'h,n)1 ellr...tlr>l .lO II-! l:thln) 1r<lnMll<)!. :to ..., I.Ih,n)l ... ralouI .10 ILl
&hID)1

1""~1l1'ml

NnIthoI,:to ...

Iccp-

H;en.

d"

..... ,,U,h",

"'~

Le,'On<lfJ<'>''''1. 0, U ....

Ewn}t ....-.<1101 .lO 1'-1

.... ,~O," ...

.... '~Ill .... ....._... 111\''-0.1 "" Le>~I.O'\ ...

Elh,") 1.,..-... 1O ...

Etlu~yl Ntadi<ll3) 01'

,,,"',,)1 atnoJM~. 20 III

IJh,n)l.,.nMloul. 3)"'1

ifrerII 1:)"

""'-

I .........nl(

lno

lo""""n Fe 11"20

,*"",h,ndNne...,..te. I "'I Nomlull<lrunc..",..".,. I

wwo

MiI."''I'''''n r < 1/"20

Norcch,"""""' accule. I

!II,

m.

[d,,")1 ntnwlool. 20 ...

l~hl")1 e.'rIId"~.

20 1"

"'runyl "<lr:od,,~. 20 ""

\110"
,~

2. CombinatIon Blphnlc

PrNucI. "'" ",~.L.bI< ,n 21.". lH .....) d.'!"'"""" ond ",1111 ,.""" '"- taL ... 00 ' 110 ...... ",Io;dulc (l/ 11 <loy. plu, 7 do)-. <tI 00 , .... ,,,","111II>Iob .. ,hot ~,lIoblI\.,. "'0.:"", ~t, ........ ~ 0.-. (l/ k\i,e ubIoI>
'"- .oo.;n.

u\'cly
)!11th)

client

....."
N..- 10111

IIrand

Prot"';n And EsbICIEII

1 .aay,.; NooctboIldr<lnt.0.5 me..md othtn)1 .oInMlooi. 3~ ...

14 da)-. ~~ ( ..... "",,_)1 nIn<lo.~ . .1:!I "'.

bearnmng

rJ"'"

10 ...)-..; Noretho"""--. (u " ". . . . CIhon}1 ......"". U ... 1I dly .. /';,~ru""""", I """ ..... CIlIonyl ""'.......,. H 1"
10 ..."

an .....No\'\Im

1'.""'''' .......... \U "". """ ctII'n) I e..nodooI. )~ ....

((''''''~l

TABL. 23-3 Brand

I/VII 11
~""'''l(

Comparison of Steroid Contr;aceptiltle Reg lmen s-Comml.li!'d Progestin a nd Estrogen

I, .toy, NoJn,obontln_..... ...., .. ho~) .........,.. H ....

21 dal'" D.......II"... (l.I~ ml.""l<l tthinyl .... nd"... 20 ... ~ da)" .;.runyl .,..,...,,.,,. 10 Il'
1<10)' ."'""

J . Comblnation-Trlpkaslc
Prod .........., ... ~ In 11- .. U-4aydJ,prm<" aIId ... flu.. ,",,"y "'. w.o. "n lhe .. me .... hcdulc of 21 <ia) ....... 7 da)'O ..... "'"'" ''''''' ........... "'" oc,I'C I",*" _ ........ n.

_opI=""'......" I),,..,. .....

Brand

Prog utln and EJU"ofIen

1 .Y" ~ ..... 0..'1 ..... onol nt""Y1NndmI .." ""
1110) 'fombo....... Q.n ........1I ""I..w.boI. \~"" 7 110)', Non:tIull<ln>ot. I .......... othlnyl""''''''''','~ .... 7 daly" .. ~""""" O.I~ m., _ .thln)1 .-t!1OdoQl. ,~ ... ~ 7 da),< "<qn.IlIIIMr. o.ll ~ cthIftyl e.IrlOdid. 11 Il'

n.,. """

T,m",,",1

7.y ... ~_.O..~ ..... ..... """"yl NradooL .\~ ". 7 da)'" S..".."""""",,,. 0.1 m~. aIId ..hI") ' <'-!ra<hoi .l.S .... 9 doIy, Norrllull<ln>ot. I ...,.""l<l ..hln}'i _"'*'kII. n ,.,

5 oia)'
6 oia)"

Non:dU.......... O~...,.

u-.-........,...,.,I. IHI'I m,...., .."'nyl _ . :lO '"~

..... ..,.,,,)1.....-. H '"

1 oI.iIy'. 1.c""".....,..,~I. 0,075 Ind rlhln) 1.~~'I. -10 '" 10 dol), ~""",p: ....,~ 0 111 q.. ..., MR,I .,tndII)I, 10 1" 6do1), l.cYoro.~~ OM "". ..Jeth.n)'aInIdoo>L'O ... , 5 oI.iIl'. 1.c'"","F"~1. o.on m,. and .. hln)1 ~. -10 '"

"'I-

10 doy,,0.111 nil- ..-.J rlhinyl .,trWlI,~. 10 1'1 to .... ) .. ~ ......... _ 1. ')(1'1 m ..., orhu1)' .......,..1(1 '"

'''''''''''''fe'In''.

f .... o "P

5 d.o)~ u.-~'L ""I. 0073 ...... .." tIbon)t es&r*bo/, -N) '" 10 dly. O. !~ nil- ..-.J tlhinyl eolr3dio ... l() ' " 5 ""p. Non:th,ndn .... I<"OWI". t ..... ...J OIhin,I ......."hlll. 20 ... ,

"'''''''''ae-1f''.

7 oI.iI,~. ""'-""eIb1 ......... K"CtW. 1 ..... ...., tthut) l ............ XI,..

Q dol).

'OI"CIhI ......... "'tIMC. 1 .... ...., .... ft).ew..wt . .\.1 "'"

. Progutln Only
......." ... 1IIbItI ......... e... h doy'>!
Ih<~.

Brand
Q.JS ....
DIS . .

0.07.1 I~I

B,and

Dosage Cyde

''''m.
IjO
\'(dro,y~ .......... (M " "'~

~''''l'' 3 ~

/)..'Iml. I \ . ,nJl'l''- "'"" 'ft IlrIIOod.

1.1 In,. and <'-!.oJ..t C)'1"",Utlt (I!..'CI. 1"..aj ml.

1'"It"-.....,i....... !.. WI''''''''' '1"liI

c ..,. 28 ttl .10 do)'

B,and
Onbu-[,ra
0'1"'1-~~
t>",,_I~ ...

Dosage Cyde

a... ........II_h

/),02 mI. Clh'''rl

"'l1IlltolJl~

/)071 ..........")1

boo"

....,,"

....,.l It. ~ ....,.1..0. 1 ... .,.~ no '*"~

TABLE 21-1 -Continued

Brand
Ph, .... ...,.,

0""
f'NrNet! ......le1o. ln IIUD
Lc.'OftOIJI"UtI ... Q,... ,_enllll ,y~m
(I.RIS)

lB.",. duIiJo in tUD Ia.... t

~.

6 .1"1 ..",, ~.,...u"'" im.l6 ",.II!,"""'lI".;trti. oil b'" I: ................ _ . h..lly kl\ ....

..

nl1d<,JIe .."..... .....,

~ PO~Y"""'" mol .. "h 68 m,_.~J.

52.n1100.. in LitIS f!rO'ldo:, """"","'q'Cion f~ "" ... S ~ ConttKqlllv~ ~ffICar) Ja.I, f... ~ yean If.h< ,mpl"''''", "'"

m_""

...1 r'd .. a rak of -.0 ,""day

C_"'I.'1't ~ff\Q<y ....... "I' 10 1

~~....

if .... ,mpW'!"

IlOl

urro;r.td

11.1 "" """ ....... "A ...ll, 1 .... <1I"nyJ euradJoIln. lk"bI., IkII)'llIC'n.;

,.,,w rill(

....,'nat n", .. 'n....nt<l f~} ..""...

.........iool, Ihnt 1 .'ed: oiI"\!tfure

I....,,,,,,. uf. ""'" n"l

I . [mal'9anq CDntraceptl"as

......

Brand

0""
O.7S .... ~1
The r,fJ! ~ II Iabk-IJ ....... kl bo-Ull,..... " " " ' . P"I>, ........ ",.n Iowtlo 01 ~. ,'" o<J<ICI """" (! 1 _'""", '" taO.t. !l ......... *-' Tht 11 ... , dole (2 !abk1 """'kl bo- Ull,.ft .. ....-

...... t2 u.blet.) _

""""hit ..

,!!I," n "''''''...... tllloo,,1aItt"'"""'" ""'~: .... be

IIIl"Iden.:e of thromboi:mbolic di'otOL'iC': (blood dou). Mon:

rtttnl .~lUdles havc ,hown a gn-.uly reducoo risk of canJio-

'IItC\IJar cffecl~ with lower cSlrogcn dose.~. Another concern _ been an associmion bc' .... een e.\trogens :tnd iocn::lscd
a.;cr ri~k. Recenl reanaly~i~ of clinical d:l1a sUpporls a

incf\'a<;cd n~1.; of breOL"I cancer in .. omen taking onll 1t'IIIl1ICcptl\C\. hUl lhe ri<;1. ~ubsides wilhin 10 ycal'\ of di sroaIJlIWtion of USC. 91 Th,~ <.mall IIlcreasc III incidcnce of Nta.\I canccr is 001 greatly aff(doo by durruiOll of uSC", dose, al liN usc. Of proge~lin (omponenl. Addilionally. use If en! COIIlflICcpti 'cs lias ,hown a decn:aSl:d ri\k for cndo.cttW and o'arian caoccrs.''' The O\'crnlll\'wits of the.<;c: Studle, havc been Ih~t (/.)!~ IfqIII'llllaJ conlr'..ccptivc products .. i!h their high ~s of "',,",en hm'c bct'n n:UKI,red from Amcrican mar~cts: (b} _romhmauon comrnceptl'~ now markc!ed cOUlain Icss 0050 mg of per dose (see Table 23-)): fe}

~1"l1ly

'":;~~=~ a~aiJ~.blc {'iCC Table ~ h:we bc:t'n idcnlified

I I oml contr'.lCCpt lvc~ (e.g .. -.rim .. uh a hlSlory of lhromboc:mholic discn.~ or other ~'ascular di!lea.loC ...'OInen ..... 11o al\' hc:a~y sn~ers o\"cr Ik.,e of 3~. and ..rOllloCn .. ith a hi.<lOI) of hn:asl c~nccr .kir immcd intc faonily). TIle IIClual meidcnce o f pill ~: .. cllflliO\'ascular deulh fOf nonsmokmg young i, qultc small. and lhe:n: i~ not n widc:~pn:ad link ~_n oml conlrnCepli\'c uSC" a.nd caocc:r. Cigal'l'Uc snloOkincrtasc:~ !he: ri~k of thromboembolic disorders assoor'JI con!raceptivc u<e. so women should be ltd to abstain from smoking .. hllc USHlS oml

Progestin Only (MinipIllJ. Tllc: cSlrogen compOOCfn of sc:qLlt:ntial and combination (111) comraccplI\'c agcnt~ I\as been n:lated 10 'i(lIIle ~idc: effects, .... uh [hromboc:mboli<;m being a conccrn. One: soIulion 10 Ihi~ problcm has been !o devc:Jop rIC'" prodLICI~ ..... lth decn:a'\Cd CSlNgen conle!N. The minipi ll contaim no cs!rogcn :a! aIL Although highc:rdosc:s of progCStln an: known 10 supprt'$S ovulauon. minipil1 ~ of progestin do I10It suffice 10 <uppn:ss o\"ulauon in all .... omen. SonloC smdll!.S ha,c IIldicaled !ilal iocn:asc:d Yisoosily of the ccrvical mucus (or 'penn barriff) could account for much of the oontfllCepll \1' cfft"CI. Low do5c:s of progeslin ha,c also bc:cn found 10 incn:ase: thc "IIC of owm !rnnspon and 10 dISrupt implam~!ion. Then: i\ a ~ probabllily thaI most. or all. of !hese: faclon cOlllri btHe 10 lhe o>'crall COlltracepti,c cffeel of Itle nnnlpiH . The inci _ dence of pregnancy wilh Inc mmipiJI i ~ slighlly hIgher lhan with l'Ombll1miOll products. nhhough still ,cry low .. hen the: minipill is uSC'(! as d,rc:cled . Oepo-Provera. Medroxypmgc~tcrooe IICctate imrumuscular (1M ) injection (Depo.Provcm) pro,ides conu<Il:eptiOll for 3 monthS aflcr a ~inglc lSO-mg 1M dose. Mosl ..'omen cxpc:ncnce '\Ome imgul~r bleeding or 'polling and oftcn cxpc:ric:occ: 'mall .... eigh! gam. Feni lny n:1LIm~ fOl" f1K)S! women within Iix' fir,;t 12 months IlrU:r discontmuance of Dcpo-f'rovcm. COOI(1)(.-cpI IOll typically colltinucs for a fcw wtc:ks beyond the )-month tc:tm. givll1g patiems II shon grace period if the subsc:qucnJ 1M dose: L~ delayed.

.,th

tunelle.

Lunc lLc is a ne ..rer injectablc oontrnceptl\ e for mula!ion that oombillcs the effects of a proac:s!m. medrox)-

pI'Ogt.'let011C acelalc ( MPA). and an CMlUl!en. e~tradiol c)"piOlialC (E2C), nl1~ prodUCI i. lll'iO referred 10 u" MPAlE2C. The CypionalC e~lcr 81 C I7 provide~ a lipophlhc prodrug thaI i~ slo" Iy I'I:lca<oed from Ihe injcctiOll ' 1Ie. pro, iding suslailK'd aclion of thoe eqrog~n component. T he progeslin is alw ~Iowly relca.1oCd from the injection site. The MPAlE2C injeclion is gIVen once a momh in the deltoid. gluteu~ nla.\lRlU'. or Dmcrior thigh.

Transdel'mal Contraceptives. In 200 1. lhe Food and Drug AdRllRi~lralion (FDA) appnJ,ed lhe first Ir.msdcm.al contnlCepii IC patch. Onoo..Evra. The prodllct eonloins norelgC'lronl1ll and cl hinyl e"1I1ldiol. A patc h is IIpplicd once 11 week for ] w~'t: k . followed by a week" Ilh no p.:ltch. "The pregn:mcy rJ le fOf" this product i~ 1 in 100. a lOUt ~imilar 10 Ihal oflcn ob<.er.'ed with oml OOIltllll:cptl\"es. ProgesteroM/UD. The 1 Pl'Olcsllndo'iCSoflhe m;m0" pill '\Cell) to hnc a dil"('Cl c frcci on lhe utelU~ and II!;sociated reproduch'c tmel. "Ther.,(ore. il wou ld !lee", pos.'iible 1 0 lower the proge'hn ~ c,'en nlOl'C if lhe d rug were released in the reprod llcli"e trael it5O!1 F. The I'role,w'<Cn 1U D (l>rogesterone I nt rumcri ne Comru CCpl; IC Sy~Iem, USP) tlas 38 mg of microcf)',Ialline progeslemoe dispersc.-d on ~ilicoo<- oi l T1>c (Ii~pe ..... ion i, conlained In a flex ible polymct' in lhe appf(nomatc . tlapc of a T. The poIymcracHIl$ I membfane to peIllllt65 ~g of progt'Stel'UlW.' 10 be released , lo ... ly mlO the uteJU.' cacti day for I year. The progc,lerune-oolllalRong IUD h:a, h:ld ",orne of the theropeillic probletn~ I) f other IUDs . in,cll,ldin~ a rel alhely low patient eontin uution rute. some <;eptic abortion s. and sonW;': perfOl1ll ion~ of I,ltcru ~ und cervix. Levonorgestrel/feleasing Inrrauterine System (LR/S). Ikcause lhe l'roge~ta'iel1 sy'tem pro"Wed cvitleoet. that a '" ogc:slln'l'I:lcaslllg IIltroulennc: devICe wn~ an effccti\ e 0011tr:lC('pll\e. WlOIl\('r introulennc: S)S1Cm ha!; been Uc\e1Qpt:d wi th I,l~ of . difh:rent progeMin. I\1 lrena is I plastic T -shapcd fmme. wllh lhe stem of the ' T " comainin g 52 mg of le'onorge~trel. The le vOIIOf"geqrel is relealotd ~lo ... ly. at a dose lowe r thall In a pill (lipproximntc ly onc''ieventh slre ngt h). direclly to tl\(' linin g of the I,ltCfll~ . Th is k'lcal re lea.o;e and a~ion of the hormone helps 1 I\'du~-e syStemic proges0 tcrone-I)pe Side effects. The OOI1troccptl'e cffCCli ,encss of this de, ICC la~ls up 10 5 ycars. Mirena acb as a ronlroceptive tn t .... o .... ay~: it thickens the mucus al Inc cerv i:.; . pre,enli ng !ipCrIll fronl gelling tliroullh. and II also thin~ the hnmg of the uterus. preleming implantat ion. In 'iOnIC women it also prelcnts ovulation. An addilional feat ure of the LlU S i~ Ih:"1 IIICn.\1lUul periods arc typically hGhlcrthan u~ual.1b/, LRI S may be uscful to alleli Dl e lhe difficultlCS a~socialed wit h Ilea .. y periods. e,en in patienb .... ho dQ IlOI occd eontraccpl ion. TIlerc IS Ismail chance that tile de,ice may dislodge in the carly monlh, of U'ie. Although the LR IS releases a reduced amount of progeslln. it does slighlly IlICreOISC progeqcrone levels in the bloodMream. Th i~ incrca:.ed proge'i.lcronc: can cau'ie sillc effects inc ludIng headacl\('. wlltcr retention. breast tendcnle~,. or acne. althoug tll hesc lire typically mild. Bleeding prob lems are the 111,,,1 oomlllOIl side cffeel. but this effeci usually cca>c.~ aOcr J to 6 months of U'ie.

/ntrauteriM Ring. A new enll) imo lhe OOIltl'3Cql1llf market is a fluible polymeric ring. appro\lmalel) 2. 1 incilel in diameter. Ihat eontam~ tl(lnoge.slrel and elhmyl cI11"lIIdIoI (N uva Ring). T he n ng h IR'-Cned into the I'agina b)' tilt wom3l1 hc~lf :md rema in. in<;c n cd for 3 .... ce~, ll1e ~jlCII ring i, renlO\oo for I "ec:k 10 allow the mtnslrual pcnod, A new nng is IIlsened I ..... I'CII after remo.a! of the pOor nn&.- TIle ring conlains 11.7 mg of etoooges tR:1 and 2.7 me of ethin) I estradiol. wilh a relea.'ie rotc of 0. 12 m! C'lonop:~ tl'l:lIday and 0.015 mg of Clbinyl ~radjollday. Unli~t phrogm. lhe placement of the ~aglRal ring eOlllrutqllllc 6::. ~ icc is not crilical. Cl inical lriall luggc~t a I to 2'l pt"C11IaIKJ role for WOlllCn u'lng the nng as indica ted. Like othrr 10. monc-based cOntroceptl ve~. the ri ng should nOI be u-.ed '" "omen who hal'c cardio\ a~lIlar dio;ca.o;c. blood Clotl. ot 10 RIOIJe-depcndent brea,t cancer. Women should alM! abIaiI ffOlll ~moking " hile using lhe ring . CONTRACE PTtVE IMPlANTS Norp/ant_ The fin;t IInplanlable eomracepli\c "IS /'irt'. plant. II ~I of six fle.\ible Si la,til' (di ITlCthyl!;i 10.\aneI~\. vinyls ll o.\ 3nc copolymer) cup~ule\ Ih;lt OOlllain le,OJKqe Irel. The capsules implnntcd in the midponion of the uwn anll providtd eontmecplion for lip 10 5 )"ea ..... Cont~!Ki'! efrlCxy ,,a' lery high MIN W(H1 c\periencctl c~ ICn in IIICnSl1U.11 bleed,"!. rang Ing from im-gular C)elc<; to P"" longed bleeding or amcnorrilCa. A problem that aro\C 11 Norplam was tMI rt'1llO\al of lhe product. either at IIr of 5 years. or earli er III p.~lIrntJ, .... bo wished 10!>lop , eontr.ocepllon. often entlliled II som"l;nlC~ paillful '>UIJi<ol procedure. T1tc ,"scnion and remMal procedu1l" J'I'qU~ exlr trJi ni ng of physicians. another featu1l' that reduc1lb1 " de~lrabi ht y of Ihi~ producl. Ahhough Norpl:Ul1 "iI$ I I 1n!1l\C1 Y effeenlc as a OOIllr.occptl\"e, a variel) of legal !~qn public eoncerns.:mIl productioo i ........ cs led the manu(",_ lodlscoollnue produclion of Norplam. Norplam 1l.II"'~ implanuble system thaI had reduced problems "lIh Inltftll~ lind remo\al. Wll$lIppro\ed by the FDA bul ... a~ Il('\tf keled in the Ulliled States. A new Implantable 'ystenl may be a,ailoblc MIl'll in k UnHl-d Sta tes, Implufll'JR i. 11 Single-rod ~y<ile l1l (40 x Z Ihm n:leases etonoge51n:1 (J-kelodc'iOgeslrcl) rJther tli;ut le~onore.stre l in Norplant . The conlmccplilc efficocy i- tip to 3 yean.. With II single rod and II 'pecially de5Igncdapp1ialor ,ystcm, the insertionlrcmollli difficu ll ic. "ilh N.... mould be a\oided. The Implanon ,y~tem h:a~ been u\Oed..: ee~~fu lly III Europe for .;cleml )C3n.

1_

*'

othet' Methods of Chemical

Conb'ac:eption
POSTCOITAL CONTRACEPTIVES
T ... 0 product, ~pecir!Cully de.ignateU for Pll""oLlDI or gt'ncy COIltl'3t::eption h.,,e been appnwoo. Plan B U 51 !0C' doo;c progcst in-only approach .... he1l'a., Pre\en , pNgt51in and an ("noxen Both mU51 be 1:U.t11 \JII\biI;, ~ hourll of unpro1ecled intcTCOUI'iC. followed by another 12 houlll Imer. Some IlKJorlOptl3.ic oral conlrnccptll'~ abo be u'<Cd in a si mil ar fa~hion, A specific drug dill bee n used in t hi~ m:mner is O~r.I1. wtlich l'OmbillCS ~l~ trel (0.5 mg) and elhi n} 1estrudiol (SO ... ~). T.,

Chapltr II Sluoid lIo.-.."s fltuJTNro/Hutu,olly

R~Ia/~

Compowlds

795

.-e lake" .... ,Ihm 72 hours o( UIlprotected IInercoorse 01' (ail lilt of other method. follo ...ed by llllOIner t ... o tablets 12 IIoun later. Some piltienlS c.\ptri(1lCt nauea ..... hkh is usu aUy mIld. The trealmcnl successfully Jlre"enlS pregnancy ,m about 9I}'l> of patients. This trcallnem I~ ;n lended , ho.... tltr. only for ue in soonttrm emt'lllency ).i tuutions.
ABORTIFACIENTS

, ,.
"

, ,.

,.

H lslIJry records many different compounds Ihat huve bee n IIied as aboni facitnts. but m:my of these compounds ulso iIR toxic or mutaj,'<!nic Of cause severe hc mormaging along
.. lth the IOOmon. Severnl thc:rupeuticaJly acceptable abon ifrinlJ. ho~lcr. are culTC"mly available. Two prostaglandnl) hal'e been aPJll'O"cd by ~ FDA to induce secondIn!llrlller abonions. !tOO mifcpristonc: (t.lifcpn:x), a proges "'01 ICplor amagooiSi. is Ivllilable for U'le in the: fiN 49 iII)s of pregnancy (fig . 2)2 1). Prostaglandins F2.. (PG F2.. )!tOO E1 (PG E 2) eoocentnlt ions Ulr.ttast significantly in amnIotic n uid bc:fon: normal labor IIId chlldbinh and are: invol>'ed in stimu lating uterine: con lrICIions. In Dsim i lar fllShion. the prostaglandi n drugs stimu LIte the utcru~ to contrJCI . 11le.'iC CO"lr.>etion s usuall y ~uffice 10 expe l the retu ~ from tile uteru~. Good surgiclll suppor1 is

essential .... ilh Cll bOPlOst and dinoplOstOne beeause 5Ofl"Ie clinicians repon 1 high incidc-nce o f incomplete aboftions that require additional tre:atment. C.. bop....ISl is approved only (Of intrnmuscuillt injc:ction. ""hile dinoprostonc: (prosta glandin E2) is lIvuilable: as a vaginal supposi tOf)'. Both prod ucts are: used fOl' secondtrimester abonioos. Carboprost is a PGFl .. analogue: . Mi(epristone 3CtS directl y by antagoni;(ing the effeelS of progesterone at progcstl:l"Qlle reccplors. as well as indirectly by causing. dccre:lI<;e in progesterone secretion from .he corpus IUleum. These combi ned effects lead to an inc-rease in lhe Ie~el of prostaglandins, which stimulates uterine con tractions. M ifepristont also causes a softeni ng of tM cervill. .... hich aids in c~pu lsion orlhe fertilized ovum. Mifepristone trc:atmenl is follo ...td by the usc: of mis0pr05tol. a prostaglan din E:z analogue:. to ensure: a complete abortion. MifepriSlone also hat lIJI{agonist action at glUl.:ocortiroid rc:ct'pl0f5.

RebItI_ eglltnnptlve Effectiveness of V.rklus Medsad.

Some caut ion is requ ired in inlCll>ICting da13 on the effective ness of contracept i~e methods. Even the "beSt"' ITIclhod can lead 10 pregmmcy if not used oonsislCntly and eOlTCCtly. Even lhe genemlly leasl effcctive melhod is belter than no oontl1lCePli~ 01 all. Table 23-4 ~nlS some doW on numbers of pregnancies per method.

.,.

<. .1

OH

TABLE

.........
v _,
Nurpt.m

2~

Failure Ra t e of Contrace ptive

Woman Y . ...

><q

Tubat bpu""

0'

'm _
CaltIOpi OIIt Tramethao"i .. (Hemllbf,~)

'"

0.115
03

(0.05)'

"'lmQ.m.m LOIJ'C ' k>oo f ,.

lSS-Melhyf-prOSlaglandln Flo

MPA/E2C ,n)CC11Q11

C.. ,.......... (Qb f"nU~cp'm."

o
OH
Prostaij1ancin E~
~one

PJoww,n <only ......."'" (mil

~ I U[)

Ow-<TlUO

1...0,.......

,0InUieIi1lt ~~_

!1m',," I~"

......
" ,-,

.,., ,,.,
(U~3

1"u...R....
TJ2I1odcJ1"l\al f<.I<tIbIJWOO<I ClOrIInC:qIU""
o;~

(PI'OIIIin Ez>

("' ,1h II'"rnUC1IJc:)

-W,\hdr.o .....
Mlfep/islOne (Mitepr8ll: AU--e6)

Condom tferN te} C"dam ('""te)

'-"
~"

,.."

~2t

l't, ioOdo< IIb1mnttoce

'-"
...
I"~

N<> to IIIOCt"""'" IIICIbooJ

- - . . I ... T.-. I C Sot d '. " "C T. d

.'F...

''I1 _'7010 _ _ _ _ V.......... ~

lot

E.

1 '"

H OI . . . . .

R. "- r-..l ~

" "

"Jloo r... _ lot I

I"

I .'

Figure 23-21 AbortlfiKl4!"Ots.

,t, .. "'' M"-.' .. .-w:.. _ ... I'\ot'fl_ _ ..... _ . _ ....... """"' 00,., ......

So .....

"p ........,., ...... - -

combined EstrogenlPloge5tin HlM'm_. Repluemellt T'herapr

Simi lar to the combined c'troge n and progest in oral cOntracepm "CS. rombinallOll e~trogenlprogc~t in prodoct~ are available for use in HRT in .... Ol1lcn. In contrast to the 0r.I1contraccpuvC". in which the c'trogc n ~"Qmponent is alnK)<;t always ethln yl e~t r.Jdioi . the e~trogcn cornpollCnt of HRT prodlOCb i ~ typically conjugated e~trogen~ or otr Jdiol. The proge;oun l"Olnponent for HRT i~ oftcn medro:typrogesterone ocetate or noretIundl"OflC :I\:etate. Table 23-5 lists the currently av- il.. :lble combination produet~. BOIh oml wblct~ and a trnnsdcrmal IXIlch are uo;ed.
TREATMENT OF VASOMOTOR SY MPTOMS OF MENOPAUSE ANO ATROPHIC VAGINInS

POSTMENOPAUSAl ESTROGENS IN lOWERING RISK OF HEART DISEASE'oo

E."trogeM have been very useful III treallng the " hoI flasl1cs" lIS$OCiated ..... ith early IIl<:nop;lUse. as .....ell a~ atrophic vaginiII~ and other vag mal s)'mptonls of inadequate e.trogen produclion. Tile eV;Oc nee th31thcy re~ult in enhaoced mood and improved cognithe fu nction in postI1lCnopausal wome n is k\s c kar. ho..... ner. and more stud ies ilIt Il"ded tt) o;ort out the competing claim, in lhese an:IIs.. ... \01>
OSTEOPOflOSIS PREVENTION AND TREATMENT1'l-"

Osteoporo!>i. is an l'nonnou~ public health problem. rt.'flOOsi bk for apprm.nnately 1.5 million frncture:s in the Uniled SIllIes each yellr. IkcD.lIse (If the prevalence of ostcoporosi~. rspecially m older .... omen. lhe pre\'enl i()ll and lnoatmtnl of Ih,s eorl(h tion M\'C recehed much lInention. Prior" to meoopallS<'. a good diet :lnd exercise are e,..e nlial for youn~ WQI1lt."n. 10 decrca..<;e the risk of osteoporoSis laler In life_ After mel1op~u>c. ~upplcnlt."nt81 c\lrogens ean hD\e m ~i li,'e effcci rclali,e 10 OSk'Opol"()';I~. Estrogen. mainly act by decrcasing bone reWflll.ion. so otrogen~ are bener at pre"en ting boric: loss than re\toring bone IlIa.'S. E~trogcns lul;en gfter mc:~usc (oflen .... "h a ~upplemcntal proge~tin) hu\!!" "'---en unequi,veally shown 10 greall) decrease: the ,ncidence Ilnd ",...,~crily of o., tcopormh. ClIpe.; ially when combined wi lh goc.:! I1Ulrit;lIn and (';tercio;(.". The longlenn use of t.,\lrogens plus 3 progestin for pre'cnllllg OSteOpOl"OSIS should be curefully l"Qn~idered ill light of lhe re~-entl\'sults of a ~ Iudy e~om iOing HRT for lowering the risl; oflK-an disease (see below). Al1cmall'e.~ 10 eSl rogcn~ for tile pre"cnhon of osl~is. such a..~ rulo:tifcne. ~hould IlI~o be considered.

After year; of general recommend~tion~ for lhe bc:ncfttUI U'-C of C"lmgens after n~nop.:IlISC for lowering tilt." risk of heart dlscase:. the lCloultS of a Iong-Ienn qudy ...1I1t tOI'IJII" gated ~';trogcn~ supplemented wilh a proge"in ha ~e mdi ~'llled thai tilt." riSks of Ihi~ gpl'rooch Olu ... e igh the bclltflb.. The Womcn'~ Health Inmnl"e ( WIll) trial ..... hich mdltd O\er 16.000 postn~nopauS31 women between 1993:mJ 1998. "'"lIS lenllinated earl) in 2002 becau.<.e of 1111 Ilnactql11ohly high le,el of ad"erg eFfL-cI ~ n: lati'e \0 lhe benefltl gaill(.'d. With Ions-term u.e {lI\el1lge follow -up of 5.2 )taf\l there .... as a ~ light increasc: m lhe incidence of coronary he3II disea.e.1IS well as 1111 Incrca.-...: III brea~1 can.cer n'k. Althougb there was a s lighl decrease III the ri~1; (If colorrct/ll canccf and fewt'T h.p frac:III~~. the effects on tilt." hean and bruit urglll' ag(l;n'l lhe U!oC of c"trogcns plus a progeslIII for tilpre,cntion of oorooul) hean disease in postfJICl"IOJWIUIi .... o"'en. Al10Ihcr WUl triDI "'lIh ~t~en alone In poo.lnft(lo Imll'lll women ""thoul a UTCIlJ'.' <;Iill in progre~. Thc~ gen-pllll'-proges.ti n trillJ u...ro. ho ..... e\er. only one drug..rpmen 10.625 Illl: of eonJugoted eq uil\C ClItrogens and 2.j q of ntcdrox yprogl!., lemne (l(."clme). 100 care should Ix tM" e~ lending lhe.<.c: n:wJt\ to other regllllcns aoo product>. the \ hor! -Ienn use In the Illanagement o f hot n~~_ OIher POSTI1lCOOpausal 'ymPl(lI11 ~ is ~ti1l appropriule. An altcmall\e 10 eombm atKNI e\lrogenlprogeSUD for HRT ..... nuld be a SIng le compound that lias both NItIgen iC and progeslOgCflic DClions. TiboJooc: (17 tt-h)!Irox)-

'*"

7a-nlelhyl 19-norprcgn-~lOl-en-20-yn-3-one) is >Udl1 compound_ II i~ a synlhetic ~le(Old thai h3~ diH'N: .tiwI

and is used alone in IIRT in Europe as an ahematite 10 ~tandard eSlrogen or e\lrogen-plusprogCSlm lherapy. no. loJlC is awnitinll FDA appro"al for U \.C in HRT and rorunt ing o<>teoporosis. II 1la.\ been Ue..'lCribed as a 1i.'\SUC"JX'CIfx compound ..... "h benefic.al actionS 00 bone. \Dgina. clilrlK' leric ~YI1lP40I\1~. mood. and liC~ ual \le ll -belng but .... 1,. sUmulatlon o fbn:as.t and enOometrinl ussuc. 101 101 T......... has e~trogenic. proge'logc:mc. and weal; andTO@enK." ... _ < Thi s nutgc of I>Clions ha. "'---e n altributed 10 nlCtaoohlC'i rt ubolonc (Fi,. 23-22). TiboJone IS I1lpidly coon'ned to . and 3P. h}dro~ y mcmboJiles as .... ell as n .J' me[3bo1it~. Despile the lack of an A-ring phenol, lhe lI)"drol)" ~ lites b.nd 10 lhe ER .... hile lhe .J' nlCtaboJile bind~ 10 it progc-.:terone and androge n n:cCpION. The absenceohlllllt"

TABU 2l-S Combined PiogestinlEstJ"ogert Hormone Repl",cem e rtt Ther",p), Products (A""'l lable In Tablets or Tr"'rtscHrm",1 Patch)

e,,,ncI
PI.". T. ..,..
F.m ....
........dlo

Prog lltin
M_~p.. '~ .... """", ""m!e.

Estrogen

2.5 "'" ~ m~

Mcdn,,)PCS I hAW ....... ~ ...

CorIJ"pI<!<! ~Iro,,,,... O.6.B "" COO;U'_ ~..crowc-. 0 I>2S ....

N"""h""lrorIC .... CUI~. I ....

Norcth,ndroIoo
"'E~ . o.~

!;ohlo)I ............ ~ "'

me

Onho>-Prd"....
C,'O!tnI'Ilch

N'lI"fOIl"-.OO\l "" NorWIII"If\A!I: """""". 11.14 or O m. .l!l

E._. I ""
h'radK>l. j(l " '
,

t:.m.liul. I

m~

,.p

, ,

....

..

CO<
~'H

CO<
"'=HH

HoC

OH
~ 'H

..0'

r3H

H,c OH .-

figure 2l-21

Tl~.Jnd

Its oliC1M! metabolItes

...libelt"..e

Me\at)()l;te

of endometrial ti~soe has been aunbuted to pn.l1!e.... aa.;tion of the .1' rtl('labolitc. T ioolooc and Ihe 3{Jmetabolite mh, bll c~l rone sul fma.o;e .... tll~ h may uplain I ' of bn:ast li~sue > ,imulmIOll (the deamount . I'o'Quid be a~ailab lc for con i li holone r~dllCes high-dcn til) lipoprotein (IIDL) leve ls. i hm. other POSl1i~c dR"cl~ Ihe [",m,lI Q\'3'iCulnr ~yslem Ihal may be benefICial. II'"

rapid l) c{Hnenoo 10 tcst!)'.tc,,!)n... in many ti<slIi:" Tc<to..tcr one levcis In the pl;lsma of men are 5 10 100 tiniC!> higher tlmn tl\o<.e in the phl-'ln~ of women. Te~to'teronc IS prod u~'cd in Ihe tcstcs in re\por!sc 10 1.11 rclCll$C by the amcnor pilllitnry. as shown in Figure 23lO. Tc~!Ostcrone and DHT inhibit die prodllClion of Lli and FSH by a fecdbaeLil1hihllion process. Thi~ is quite sim il ar 10 the feedback: inhibition by e<;tro~cn\ and Pfogc..,jl1~ 111 FSH ~nd LH production.
Metabolism of Androgens

ANDROGENS 105
hgene .... Andlogens
IlIJd il~ more poIenl n:UUCIiOrl product SO'-D HT in ~il!ni ficanlly greater amOtHlI_ III mDle~ Ih;1I1 remnlell alw product' low 31llOUnlS of thc-.e

hormones. Thc'\e rndogt:l1O\J~ compullnds hnvc

Inl pol1al11 :lClh ilic,,: androgenic IlI:liv ity CpronlOlin s ;;;,,;~~ char.IC teri~ liesl and anabolic oclil'ily (rnu..c leand aooro.u:rIe(honc lite refcm;] \0 as 1111""11(" :. ."",," Illlhough this nomenclature i~ 'IOmc'" hal ml~ and arwlroslcnedione an: bi",)nthl:tic pre the andfOl'!en~ bul l'Ia,e only low affiOlty for the

Testosterone i$ rapidly ron"ened TO 5a- OHT 10 many I1!'i'lue<. by the action of 5 .... reductllsc_ l>epcodmg on the tissue. Ihl~ is eilm 10 acti vate te<lQ)lerone to tile ft"I()n;' potent androgen. m 'IT (e.g .. In the p!lJl'1.ne). or II step 10 the metabolIC l11acl1 "3Iion of th i< m,oJrogcn. ll1c primary route for metabolic inact iva tioo o f l e'to~teronc lind OUT i~ ox idation to the 17 one. l "he 3onc group is aho reduced to Ihe 3a- (majur) nnd J,B-ols (mi nor). The metabo lite< arc ,110"'11 in Fi gure 2323. Androsterone i~ the mDjlM' un n:,ry metabolite and "'~ the first "~ndfOi;cnic 'Ierold io;olatOO. 1l1co;c mct~boIliCS are t:'~crcted ma lDly a.~ the colTl"qJol1ding glucuronide<;, Other minor metabolites ha\'e alw been doetC'C Icd.'<n

Ilicmschcs.'O'>' 1(17 ~forc. OUEA or can l'Ia"e androgenIC acIlOll\. btH (111)' aner I]VO cOI1'ero;ion to tc.\IO"ICrone and DIIT. OHF..A and ~:encthone lItr. howe'er. also pn:eul'liOf' 10 the nltocstfOl'!cnic IIClions may also occur.

~plors

Blohtglcal ActIvities of And.Ggens

T c ....o:ste~ and D~IT c~use pronouneed maso:;:uhnlllng ef fa:lS. c' en In the nlale fetus. The) 1nduce the de" dop mcnt of !he prosTate. pcni~. anoJ re lalcd !lCxual tissues. At pubeny. the sccrctioo of IC~IOMerone b)' the teMC$ iocteJ.es gn:mly.

235. teSIO'iterollC can be \)'mhcsilCd

,I
. IIlne also shown that II ean be biOloynthe\ androst5enc3,B. 17p.diol. a reduction product of

is pomanl)' produced b)' the inICN1tI:aJ cell$ ItSIU. s)'I1Ihc.\w:d largely fl'Qlll chole<;terol made in ~1I1. OUT I~ also secreled by Inc lesIC\. as "'cil as ,.: :"pnld~ 111 Qlner li ssue~. The ovancs and adrenal ~"," OIIEA . .... hich ~an he

r"",,<ro~

leadi ng 1 lin inerea.;c In faciol and body hair. dccpenmg of 0 lhe voicc. increa..:ed pnl4CIO anabolic acti, ity and muscle m~ss. rapid gro .... th ofloog honc..~. and loss of some <;uocula 1lCOO<; fal . SpcrnUitogel1C,i\ begins. and the prostate :md o;cm inal ."\"Sicle8 iocrea.-e in "'-'I" il ),. Sex ua l Ofgal1\ illC'J'l'asc in si7.('. Thc sL.m hecol1lCS thickC!'. and o;c~~ gl .. nd~ m crea.'iC in numbc1". leading 10 IleI1l' In many )OIlMg peopIc The ancirugen.~ 1I1!IQ pta)' importanl mIcs in male p.o;)~bolog) and bclm"ior. In "'OOlCn. te<losteronc plays a ro~ in libido. mood. musck mass and ~tn:n~th. lIS well 11.\ hoIlC den <ily,ulll 10'1

..- 5UO,IJydro'"'08te.one (DHT}

ltoHSO

",,-,,"/ "

"

II
"'<; OH

HO

H Sa AndrOllfl.... 3u, t 1~-dIr.lI

"

o
I) *RI :Iud'"

17li-HSO

~
r'
"'<; 0

1 )5u.'~~Q 2) Jll.-HSO

213aHSO

"",0

Met,aboll1l1'loltestostl'lontn DHT (con,ugates of tht> metabohle art also fOI mt4

Figu.,:u-n .

HSD, hydroxystet'Otd

deI1ydfogen~

Strvdarill Cbls5eS- Anilbollc: Androgl!nk 5'Irolds

:11..;;0 kllOWn as anabolic am.lrosenlc ~lerOld.~ (1\1\5). include all of the thempcullC ugents wooe main OCIJOru;; ~ mediated by the androgen rrttplOO. The inclu ~1011 of boIh ",who/it and (lnd"'/:~f!i(" in rcfcmng 10 lhe..e COlHpound~ reflect. lhe fact that 110 prodUCt~!Ite available In which tile nnabolic pmpi'rtlc~ of androgens can be eP;l!1l1ed front tbe androgenic propcr1les. llIC commonly w.ed AAS Ill' shown In figure 2.124. Sc\erdl I'enl re'IC .... 5 on AA5 have becn published. Hl'I. 110
SEMISYNTHETK ANALOGUES

The

Bndrogen~.

TABLE 2~ A,.,drogens

Androg, ,., lc Activiti" of Some

Compound
T.".~tI7 ~..,Il

Equh"',nllo. IntetNltlOMlI.WI

"

Ep ......,.umn,tI1 ...... )

.., "
O>-~

Becnuo;e tmctcrial and hcp;llk oxidation of tiM: 17.8-h) droxyl 10 lhe 17-one i~ a key component of melabolk inacti,'ation. 17a-lIllyl groups ha,c been added to pre'ent oxidation of the alcohol. E\co though 17a-methyltCSlO:!oleronc is only about ha lf as OCIive as lC"IOSICrollC. II can be I~ken OOIl1y because its hal fl ife I~ longer than thai o f tC.<IQStcrollC'. 17Elhylle.'I!ostcronc has greDily red~ DCti~ny. as shown in Table: 23-6. 111 I\s mentioned abon.lIddition of an o-alk) n) I group provides more progestogenic aclion lhan androgemc lletioo. a1tllough some llel;'uy 31 IIndrogen rt."'Cepwr;; is reo tained. A dl~D(hantage of the l7 .... meth)1 te\l{)Sterone\ 1, hcp:UOlo~i( ,ty. Hepatic di'l!urbancC'~. jaundice (OCCl>Jon ally). lind death (in mre caf,C~ ) may occur. p;u1ieutnrly in the hlJ;h doses often used b) athicles (~ next .foCCIlOO). Table: 236 lUUStr.lte\ !lOme structure~ac,iI' i'y effects of the and1UJ;C'n~. ~lJCh a. lhe greally decreased activlly of the 17""01 isomer of te\tos,cronc. (epitc..~loslerone) . Il lIndred~

17 ... \,."h'h~"""""'" 17 fl 11 '0\lc1h) bndn"'.,.....\to. 17 ~loI 17 .. MCOh)I_Io....u"J..-.17 fkij

llh,I"",,"'.,,_

7tl IllI

AIIIIrou ..., .
1'",.~ .. ft>nC

~J".

17 fI-d>I

A~lo..I7n-diu1

"'"
,~

" " ,ro ""

Andn_ .1/l17 tkhol

AJidroo.une 17 /:I~'I:HIM Andro>.Iane-I 7 or-toI. J..OIIO .1A~.14. 11tkb<>1

~'A""""''''''.\J'I. I1tkhol
A~l.n

1:!()1~
,~

" '"'

..
~

'"

"'" ""
"
TUIOSItIi .....

17o-Me!hyfItiIoIlerone CT-.trwd)

"

(1iIololeSbnj

, 7f!-EII_ Commerotlly AYIIH.1JI,f 110< 1 1njecIIDn): M Also teslO81erone propic)f\(Ue (10< COf'I'IP(IUr'Id)

VO~
T'nll'....... ~1(1

"'"
Melhandroat...alone (o..l\MlOI)

0xyTr... ,......

(~l

r--".-c.-v.-../ . " "

Narodo ........ slllEIII,... COmrnefdaIy A... ~atJla Nencholoo" ~I'

""

FiGur. 23- 24

T~tO'l,r()(\('

and

(o..nltlOlifl)

1,ht\w:: anabolIC androgenIC ste-

NanOr'%flt

o.o:.no.te

'"

"'"
AAS have been sym hc~ilCd :md studied. The pi or many ~ynthetic progr.ull$ wa~ 10 make Mcompound ... po<scsscd I~ IUUholic propcnies or Ic~losterone bu. Id.!'d 1l~ androgenic :Ie.ions. While numcrou . compounds ~ rreJl'lraJ .hal did display ,mprmeU anabollclandrop:!IK nI'ioo; In vnTO. 00 oompouJld~ ~omJllctcly locled !Ill' ~nl(: 3Clion,' III Also, the high anabol ic/androgenic ratios .lid 001 appcar to be maimaincd "hen IhcloC df\lg~ weill used hUn1:m~. l)e~pite tiM: m.any compounds thaI ha\'c been cunmled. Ihe ,truclurc-acti\ ity rdiu iOl1~hips of these drugs ft 001 " 'ell delineated. Many hypolhc:-.e~ huve been made .. ;m mlcmpt 10 su mmarize the Mrucrure-~cliYi l )' re l:llion!luI" Or all .he known :mdrogcn~.'US A, wn h othi:r com fIlUIId.' thm na"c been discussed. hydro~)'1 groups in the Ir\Io.ISICfQlIt'I an: oflen cOIl\ened to the rorn.sponding e5lCn 110 prolong ocli\lty or to provide SOITlC' procecl.OIl from oxida-

(....... ~. o.c.Do;raboI+o)

at d,rrerent

T1suapevtk Uses of Anibbolk And. a .ank

S,,"olds
Tl:r primM) u<;c of AAS i.~ in androgen repl:accmcntlhcropy men. e.ther ~t maturity or in adolescence. The cuusc of

Icstosseronc deflClCncy may be d ther h)pogon31bsm or hypopituitarism. The use of the AAS for the.r anabolIC lICI,vit) or for uses other .han androgen repllliCClI1cnl !las been hmi.ed bttau~ of their mllscuilnif.rng !JCIion~. This has grra.ly limned the.r use in ,",olllen and chi ldren. Although anabolic 111:.'\ ny .s onen needed clinically. none of tile prodUCI ~ presently availab le is free of signilicaIll androgenic side effect~ . The mascu linizing (nndrogcnic) side effe<:ts m female include hin;utislII. uene. oc-.:pcning of the voice. clnorn! enlargemcnt. un.d dcpn:s~iOf1 of the men)!rual C)cle. Fu n hcrmore. AAS ge.lCmUy alter .... rum lipid le\"el~ and incft!~ the probability of a lhcrosdel"O"l~. char..cteristecall y a d,I,Ca....e of men and po.unenopau:W women. The masculrnil.ing effects of the AAS preclude thw UIiC in ITIOSI cin;uIIIWl~ In women. Sccund:u"y treatment of OOYllnced or mel:aS!.au.c breast c:an:lnoma on IiClcclCd p:lhcnb i~ gCllCmlly con"dc~ 10 be the OIlly IndlCallon for large doc.long-tenn androgen therapy in women. In Io,",erdolicli. androgen replacc:mcnt Ihcropy i~ more often be lllg ~'QI1~,d ered for use in IflCnopausal and fXl"tmcnopau'-3l women for [he po!>ithc effccls 011 lIbido. mood. vasomotor sy mplOlIiS.

and mu<ele ma~". all areas oe~ari'clr nfrccroo by decrc~ req()',t/.'rone l(m: l, in aging women. U Andmsens are ul0;0 used 10 relle\'e bone pain a,_SOC I31l'tl "i\h O!Ileoporosl~ and \Olrear cennm aneRtlas, although rhl~ use has great ly dreased baUU..e of lhe a,' ailabi Illy of erythropolelln In a ll C;I.'<:S, u~ of ri>c!oC agenl , requires caution.

In

~h ~,,~~

1.... ~Ase<l r"l (>( coronary d,!,.,a... >lrul~. U .... .uuclCd bk>Ud w"...:I, locn:ased ~oo and antllC1a1 1Lch;!.\lor I~" _

".:oirt

Androgens and Sports

Li .'~r !Un,.,..... pelOO<I' hc~IIS (bl"od_flll<.'d ~y'I'). 1Ir<I ..... Wee /for 17,.o.Ikylated andl"ll!CnI onl), In mtn Toucular IMrophy ,,"h coru.cquenl <Ienlny or doc" rl 'perm counL and al'!lonnal nlOlllll) and mllfJ'hoIoIl
I "1fl"I C1'ICC' Enl;wgnl pnN.II~

"~lCro,d

"'SC''''

'The use of androgens for li>clr anabolic dTts (i>cocc lhoe lerm Ilr!flbfl/ic ~lc""i<b) by athlele, hegan In lhe lale 1940s
and ha" al rime", bc:cn widespread.' " l>rior 10 urine t'Kling n.'q uirelllCnl... it WIi> I':SlUnau:d Ihal up 10 8(n. of COlltpt'lit;"e weight lofter.. and abour 1S4 of profe.. siOIlal fOOlOOIl pla}e .... u'lCd rhe~ drugs, ulOllg with II I ariely of OIher al hlete.~. Illlern31iooal a"3renc s~ of lhe ahu'\C of 'lcmids by lUhletc ... how nero Willi Innited until the 1988 Olympic, .... hen Canllda', Ikn John~ " .., disqu:lhl'ial as the .... lnner of the ,old nlCdal III lite IOOyurd dJ,h for hal mg traces of sianomiol in hi, urine. The shocking disqualil'i(.:aliOll hr()ught the imer narional Imsu.sc of AAS to headlllle, world"i<k . Unfonu nately. ahue of sterOids IS ~1111 a problemall.lllel.ct. of tX)fIlpetlti~e Although nUlnerou~ "uu:lbohc" Ilemids hale bt:en I)nthcsizoo and used/abused by IIlhlctcs, IllOSI hL.eI} all of the androgens h:l\,c bc:cn uo;ed by alhleles in an aUcrnpt ro lin prove Ilrcngth :lnd ;ncTea.c. mU<ele ma:..... In lhe early )ca.-... the 17Q"ulL.yI3Led ~tcroid~ "Ith high anabolic/Jndrogemc ralios in ~lIro were u~ wllh lhe belief that the anabolic prope rtie~ of IheM: drug~ were gn:::ller than I ho~ of orher androgalS '\ICh as Ic..rO!>ICrunc:. Wilh the ban on rhe u-.eof steroids in IfM)<.i ~pons and the prevall'flCe of drug teSilng. hmo'e,er, the 17 a-alkyl:ril'd _tcroid~ ha\'l' fallen out of fa~or becau\oC of lhe r ase of dclunl1lhe~ compountb by mass splrome try. TIus has led toa greater useoflestostemne and irs hlers. :IS "'1'11 as the androgen pm;UI':!oOn undrostencdionc: ("and"'''). andlmtcncdiol, andrmlOnediol. and OHE.A . The belicf i~ tOOL beeau..: lhe.;e 5teroid~ all occur naturally . detecting them ... 111 be Illuch more diffK:ult. While II isrTUe Ihal assay~ for the cnd<>genous _temid, mu't now di!)Crnninale dcliations from norm:ll rnlios. il is JXll>,ible 10 deteci the abuse o r lhe<c compuu,,,h. Elrremally ~upplied resto<;lerone. for ex ample . can be deteeted by a unne te~1 e.\ amin ing lhe rnlio of Ic~to$lerone glueumnidc 10 epite~to'lemne 81 IIl'uron ide. A mtio grealer than 6: I usually indicale.~ abu..: .I I~ Man) Sludie-; hlll e atrentpred to dcrcmune If laL.ing una bolic .. teI'oid~ imp!'O\1':.\ Ulhlctk performance."o. "' Some failed 10 use oonlrol .. (alhletes ""110 tf'Jined in Lin identical m.:lIlner hul did 001 taL.e anabolic steroll.ls). Othe ..... failed to II": placebos in PI lea.~t a _;ngle-blrml TeSe3n:h ~ign (ne ilher lhe: tTealed nor contml group, knowing .... hkh they "ere laking). An addluonal problem with nt:lny of the Sludies ha.s been thaI typie:ll IlIempculic dooIes hll' e been re~ted for lheir anabolic propcf1i~s in cl intenl seuinis, ... hereas LI~hlet~ typIcally u..:c much hll1her dO'>C,,' 10. I, Of lhe studIeS uSing ILt leasl a Mngle-blllld prulixol. some h:lI"e reponed Lllat ana bolie sleroids did increll.;e alhletlc performance.... hereas OIhers fOtllld they did nOi . 11 would be fair to sny. therefore. that the bc:nel'it u( ~nabohe stl'll.'lid~ to alhlelic performaTlC'i: b UTlC'i:rtlUn. 'The ri.h of usm~ these drugs appe:lr to 001wei!;h their unct'"~1tl bc:nefils. A~ ~utnrl1ari1.ed by the FDA.117 the side effects include:

Bn:a.t cnl2f~cmcm In W<lmen Chloral enl~menr I:k.>nl tro" Ih

Bakl~s

D.:cpcncd 1'<lIC~ Bn:lI>I d,m,nUlM)fl

'!Xl""

BIX"Juse of IheM: OlL..,. the Intcrnat,onal Ol)mprc C mitreI' . nUIILCrou~ professional ~pon, OrgJnilminn_,ilIld tbr NatIOnal Colk'giale Alhletlc A~SQClallon (NCAA) "". . all:lnabolrc drugs. Te,tlllg of elile :uh'etcs for pcrf~ enhancing drug) of aU Iypr:~ il comlll<)nplace IXsprlt kllQWn problems with lhe U~ of AAS. howelrr. ~. professional ~pon~ ha,c bc:cn ,low 10 enact le\,,"! forperfClmt:lncc..cl1haocing drugs . As of the summer of 100! MDJOi' League I~~scball .... ~~ l'inah,ing II testing poIi11 u its athlete~. "hile lhe National HocL.ey League Slillladtd a policy on the UloC of anabohc steroids, An additional rj .. L. is associated with o;elf, jnjechon la_ling anaholic steroid prepar-Jlions. The ri.l nf COOlnKt.. hepatilis A,llI':pallll~ c.:lOO human IIllIllUnodeflC1CIIC)' ( HI V) i~ IlK:Te:lsed If ncedl~ u~ for mjC'Clmi <Inoich ~

of",

' hared. ' '.

Anabolic Androgenk Steroid Prod..ns
l1ICrnpeulic U'ieS of the andn)8cn ~ are di<>eus..;eu UOOI e. 17_ ESiers arid 171NIllyi produets are a~'aillible for I railgo' of lhera.peutK: IIse~. These drug~ are contl1ll~ 111 nlen ... ilh pTOStalic carn:cr:.n men or ... OIt1('n ""tbbClll, kidney . or !rl.er I tile androgens ~~;~~':"~~~'i'~'~.~i;:"~~::~:~~' Diahch..... causmg tenlrate the: PClion in some patienr~. :Iud rlle~ mny mterft'ft \\Iilt I~boralory lellS.. r-ent:lle patients mlly del'clop llriJiI'lla sid<: e!Tects. and doc'iors ~hould be "amed lhal some cI cffl'Crs mlly be imversible (e.g" m ice change. ,. All 0/ "an:lbol ie" commerclnlly 31'allablr I
o~androlonc:.

0:::

nnndrolooe) ha,'e 1!r/Altion i~ a act;-e.:IS ooc: .. wid man) ofrhcm arc"j' Ii I may Lnduce ]jler lo~icil) IG patients. All stcroid 4-en 3,01le_ arc lighl senSlti\'e ar.d kt'pl in lighl-re~i~lanl container:.

Testosterone. U5P. ~::'~'::~~:g,,;J:!;::::;: dro),!-4-en-3onc. i~ a naluntll)

III ..umen, II mainly scr\,ew lIS ~ biosymhclic precursor to

eilI3diol bul also has other hormonal effects. II is I1Ipldly

a.~

to felaU\'e!y inactive 17-on.es (see Fig. 23-23). r.o..e\er. pte\cmin, sigl1lflCam 01111 octivily. Tt'StlKteronc II I_ailahle in II Ir.lnsderrnal delivery system (patch). a gel iannu lalion. and as InlplllDlable pell('1s. Testosterone 17p.. ~f5 are aYailable in kmg-a<:ling intl1lmusculardepol p.tpaIIl>OIlS iIIustl1llcd in Figure 2324. including lhe following: Te&lOSIeronc
CYpKlnalC.

KI~boIi~ed

Us p TC"OSle,,,,w: 17,8-<:ydopcntyt.

"""""~ ~nanth31~. US!": TCSII)I>ICronc 17,B-hepu"""'t Tt~cronc T""OMeronc prupoonalc. USP: TCSIOIMrOilC 11,B-pr0pt0n3le Melhylteslostcrone. 17p.. ~dro~y- 1 7-mclhy landrost-4-en-3-00e. is only about half:as KtI\e as lestQStCTOOl:l (inll1lm uscularly). bUI it has the greut af..-anuge of being OI'3l1y acl;'e.
"lhy't~stost~t'OlI~,

in spite or the 17a-ethiny] group. tillS link estrogenic or progestogcnic activity. DanDl.ol has bern called a syntnctic steroid with diverse biological effCClS. 1I9 Dan;uol binds to se~honnooe-bindin8 slobulin (S HBG) and decrease~ the hepatic synthesis of this estradiol and te.\tosterone camero Free testosterone thus iocl'eases. Danazol inhibilS FSH and LH production by ,he hypothalamus and phuitary. It binds 10 progcslerone receptors. glucocorticoid T'C'CCplOrS, androgen receptors. and ERs. Although the exllCt meehallis rn of action is unclear. danarol alters endometrial tissue so th3t it becomes inllCtlve and atrophic. wtl kh allows dana;wl to be an effect;"e lreaunt'nt for endometriosis. Danazol is also used to ,reat heredi tary angioedema and librocystic brca~t discase.

US".

AntIand. agens
A variety of compounds (Fig. 23-25) ha ve been inlensively studied as androgcn receptor anlagon ists. or amiandrogens.'lO. ':1 Antiandrogens are of thel1lJleulie L1SC in treating cood itions of hypenmdrogen ism (e.g . hitsLltism. acute. acne. and premature baldness) or androgen-stimulated ealll:Crs (e.g .. prosullie earcil'lQflU.). The ideal IIl11iandrogen wookJ be oonto~ic. highly IICtiYc, and devoid or any hormonal acti vi ty . Both 'IIcroicbl and nonSteroidal anliandr'ogen~ h:l\'e bren investigated. but only II()nstc-roidaJ anliandrogeM have bren appro\ed for U5C in lhe United S'ales. Cyproterone occUlte. D steroidal antiandmgen. is u.o;cd in Europe. 1ne steroidal antiandrogens typkally ha ye action~ at other slcroid n!ceptOl'!l that limit their use. The IIOII.'>teroidaJ antiandrogens, while lacking honnonal activity. bind with lower affinity '0 the androgfll receptor than the endogCflOLls hormones.
FLUTAMIDE, BICALUTAMtOE, AND NILUTAMIOE

""

Auo"ymesterone.9",flulJro11/J.17IJ.dihydro~y- 17 rnelhylandrosI4-en-3-ooe. i~ a Ilghly potent. OI'3l1y acuye androgcn, aboul 5 to 10 times IIIOIt potent than testosterone. It can be uscd for all the indio discussed aboye. bul ils greal androgenic activity lIB made il uscful pnmarily for lrealmen[ of the androgcndtfkicrl1 lIIale.

flIoq",.sterone, US,..

..non,

IfIfthandrostenolone, US,.. M~eooIone, 17~ ~l y-17lTlC thylundrosta I.4dlcn. 3-orIC. is ornlly acti\'c .0 about equal in potency 10 testOSterone:.
Oxymcl00lnne. 17~hydro~y2 IlI)dro\yml:'hylellC} 17methylandl'OSl3n3-onc. is all" I"O'nI for,he treatment of a variety of anemias.

Oiymetholone, US".

OXindroion., USP.

o~andro~~"'"'::'~~~"ifJ.:h~:):'IndroXY_I7aid ~ the pro--

surgcry. I , or SC\'cre tl1lUmll nod to t protcin .....t.r.Iism a.~sociated wittl1ongterm cooicosteroid uq: . O~

_~;~:";:~~ also used 10 reli cve bone pain occomp.mying It has been u......l '0 1n:llllllcnholle he,,'III,10 and
~yndrome.

SIMIozolol, USP.

SUlOo1.olol. 1 7-,rw:th~I-2'IH-5a-an. i ~ used proph~laclically angIOedema to reduce the

DKanoate, US,., and Nandr%ne Pnen USP. NandrolOlle dccano.lIe. 17~tlydro~y17--decanoalc. h.a.~ bttn used in lhe mancertain ancmia!O. but the availabi lity or has greatly reduced thi~ use. Nandrololle is 17~ hydn)\yestr-4rll3-one 17-(3'

..

US".

Dan:v.nl. 17"'pregllll-2.4-dien-20-ynois II " 'cal. androgen lh;lI.

Three nons,croidal anliandrogens are in clinical L1SC in the United States-flLltamide, bkiliutamidc. and nilutamide (Fig, 23-25). 1llcy an! mainly u.o;cd in the managen~nt of prosta1e CllnCCT. ALltamide was the Ii.... oflhesc compounds approved fOf use by the FDA, 1)11( li yc-r toxicity and lJuicedaily dos.ing offcred room for imp!'O\emenl. It was also de temlincd thai a nlCtabol,'e of flutamide. hydro.... "nu'amide. had grealer "''''ant/rogen acuon Ihan the parent. ij icaJutam_ idc. whIch has greater potency than flutamidc. incOtjlOllltcs a hydro~yl illio its structure at the iIOIlllC rclali~e position :as in hydro.... yflullimide. BlClIlutamide is dosed once a day and tlas ICSli to~icity than flutamide and nilLltamide. making I, a preferred choic~ "hen ini,iating thC'mpy . Proslate cancer is strongly androgen scnsitive. $0 by blocking androgen receptQn>, the cancer can be inhibited or slo,,ed. Studies havc sho.... n tha, these drugs completely in hibit the action of testosterone and other androgens by bind ing to androgen recepcors. In elinical trials when giycn u a si ngle agcnt ror pros!atc cancer. serum tCSlos.terone and es,radiol increasc. But when given in combination with a GnR II agonist. such aJ goscrelin or leuprolide. biealutamide and flutamide do not arrecl Ic~,os.tCronc: suppression, whkh is the I'elul, orGnR H. OnR H asonislS greallydecrea,,:egonadal fUllCtiott - the medical equivalcnt of ca.~tnltioo in men. Thus. [he combi nation of Gn RH with bkal utamide or flu tamide bloch the production of It'Stostcrone in the Ie.~es and androgen receptors in the prostatc.

(",("0 ~y 0

H H~ OH

c ".

Hydroxyflutamide

"'.

"",y C'.
o

NN~ CH,
0

~kC~

Nilulamlde (N llandmn)

"'" r " /--/

"0

"

Antiandrogen Products
F/utilmide. USP. Fhllamidt.2-!l1ethyl-N-H-'Ulru).{lrifluorornClhylJphenyl h)ll)Jlanamidc (Eli lexlI1). is do\cd 3 Ii "'c~ d~lly (250-m); dose; 7S().mlllola] daily dose), A major metabolite of flulamidc. h}urox yflummlde. IS a more poIclll androgen receplor aniagolll<' .han tile p;ln:r11 compound. 111 1~ rncmOOlilc. which i< prt''>C.'1l1 nl 3 milch hlgl!er steadysImI! coo.:emr.llion Ihnll i~ fl ulanude. cmllribUlc.~ a ~ignin cant amount mille anualllirogcn action o flh" drug. A limitmg foctor III lhe use of flU!:lInJdc IS hepalOto\icily In from I 10 5% of patlcnls. AlIhoul!:h toc hepalo(Oxicity \15\1:111)' i< fC\'crsiblc following cc,~mion of m:atrnclll. rnre C3"':S of death a"<oCi:ucd ""ith hepatic fallun: !la'1: been repofll-d !O ~ associalcd with flul3midc therJpy. Dlanhca is 3150 a 11 11111m); ~ide cffl"(;\ Wilh flUUUllidc lher:lpy for some p;lticllls. BiGJ/utamide, USP.

er.il lis,ue, IIlId is Hl,uhL-d 11l:lIfdy In lhe' le<;[O-lemne and other A-nns enone<. The I)JIC i\ IOCllied III lhe pn>'Il!llc gland and teslCS IIIId IS for lhe coo\L~ion of tC,lostcmne 10 DlIT for action. Blocking thi~ "',':'!!~~ ". ~.",,~~.h androgcn OCIII.ln. 'l1Ic pro\id.!s nn ewellI'm h.I lilt.' il DHT al",

fl.lnction~

8icalutamitk. N-4<yano--3-(tnfluoromclhyl~hcnyl3-[ (4-fluorophenyl)sulfoo) I J-2- h)dm ... y2_mClhyl_'lI"opanllullllc \Ca..ooc\). i~ more potent Ihnn flul!lmide and has a rm)(;h longer half-lif(' (.5.9 day~ versu, 6 hour" for h)dmllyflui:lIllldc). ikcallSC of lhe longer half-life. bfcalulanmk is used foc OfI(."C-a-d:iy (50 1118) IrcallTlCnl of IId\"~ru:cd piO';lntc e~nccr. Bicalulamide is uvat lable as II ro~e11lic mi~lUrc, bul bolh an"nal and human ~lUdie.~ '" ilh Ihl' androsen I"C'Cl'piOl" silo", thaI lhe H emmhomcr has higher nffinil)' for lhe androgen rrcclMor than the: S enarlllOlller. m

IkI\tendc t, IICll\'Il~-d by the 10 lhe NADI' COfllCIOC. yicldlllg a plc;( thai i., ollly )IOIo,'y rclea..... from lhe' --d <'111'. prodtK"ilig cssenllally lm:.\cr.iblc 'Y"1e (Fig. 23-27). ) I rcdllcta~e ""!1IpleJ( " 'crr _low (r - 30 d:I),,).

Nilutamlcie. USP. Nilutamidc. 55..dllneth) 1 -3-1" -nllro3-( triflnoromcthy llphenyll-2.4-imidawhdll1t."d iooe. is u-.cd 111 combination wilh \urgi.-al c:Nr.ll iOIl for the trea!menl of melastatic pros!ate cancer. NilutlUnide. "hich ha~ lUt ehnlination half-lifc of appro.l.lIllalcly 40 huu,",. call al'i<J be u-.cd III O<ICl'-da.ly dosing, but II ha~ ~uic effecls that limil .~ usc-\l,ua l di,wrb'lIIcC'I. alrohol inloll'l'l.n(.'e. and allCl);lC jlIlCUI1Hll1ltk

(ProKa!. P'opcoa)

''''''''''''''

Inhibition of

S(t- Red~

5(t"- DHT i~ il1lpor1;!J1! for mamluming pro_Iale funcllIHl In mell. The fOl"malion uf DIIT i, mediated by 5u-rcUuctu'<C, "' lin enzyme Ilkll has ' '''0 dlsllIK:t form~. Iype I and I) pc II. ' .... Thc type I enl.)'me I' loc:ned In lhe Ii\ cr and <;onle penph-

" "

Figure 2]-26 $ll!rOO S..-fl'Wct.lst I

--

~oIT"I05I",""1O
5a-Oo/lydroles!OllIBfOAe (DHT)

o H;;
H

!
H;;
H

~.
H

H", ''""~
0

I
0

'H
H H

OH'
5,,'I! ~ KbOn on testoslerooe and IlI\iIster ThIs '\ChI!me lS ;Jn ~mp(,fl(,ltJon of the Net mtr:l1.Jrusms, bul ,t md~ales that ~ IS bound at the .ct~ SlU! of Sa-fiGurt!

. ....,.. cr'"' I

( H H;;
~

H~ C~

~CH,

,. HH

I H",
H,C

' H

2] - 21 . CompillOSOfl

of

"" CH,

~C..,

NAOPH ... po!>Ittoned closer to C 1 firoasteflde than 10 the norma( (5 of testos...... INding to I!SSer1wlIy IrT~bIe ,nh,..
~.

AH

Flfllt5!e<i1Il

NAOPH Complex

11\'1: in the lrealmc:nt of BPlt. a lower dose fonnulal1oo was studil:d for lreating male pattern baltlnCAA. The lriab "'ere a suca's$. and l'Jopeo::ia (t mglday ) was the re.~uh. Although l"inasteri(\(: pref\'renlil,lly Inh,bil~ Ihe lype II cnqlllc. it is belie,'ed w be the penpherullypc IStr-rroucta-.e lhat is oong targeled for the baltlness tn::lltl1ll:l1I. Dula,lcridc is also bellll; in"csligalcd for tI.'iC ." a batd~) tn::al'J1('nl. Saw palmetto (SUt'lilNI r('/~"S) C'~ltUCt is an herbal prod UCI used to trem BI'H. and ;1 has ~n sU!;j;c\lcd lhat lhe I:ffC'Cl'i call be alirilMilcd to II conSl Ilu..:nt of the UU'OCt wlih Sa-rcduClllSO: inhibit ion, hOi oiller mech:U1iSIlIS have: nl<;(} been propoM!d. IZIl Funher snldies and idcntiflClIIioo ofl spc. l' lfie cofllponc'nt Ihal Inhibi l ~ Str-reduelu.>e are nece~sary.

F'ma.$II: ndc IS 11 rellll ivC'ly selC'CI"'c inhibItor of type II SaII:ductase. Thi s C'nl:ymc is prC'sent in high levels in the prosIo" 'er le"el ~ in otherti~ues. Because of the strong
",pelion 10 the fonllalKm of OIIT in lhe prustat .... it \\'a~ .:ted Ihat ~p.'d fie inhibition or this i<;(}form '" ould yield p.:lItC<.I lherapeuuc effect. MCN"e recenl sHldles s uggl!l,l. w.c\'er. lhal the lype I isofonn lIlay also playa role in of hormone.oepelldem prosIale cliocer. 1Z1 ,,;;; : ;'"";. dual Sa-red uctase mhibitors hllvc been de DutOl<;II:ridl:. a compound recently appron:tI for I"'''", BPH. mhlbil~ both lsoforms of lhe cn7yllle and may found 10 haw superior therapeutic effc:cts oncc il i~ Y used (Fig. 23-26). Dul llSll:ride bean; an aromlllic al mlher lhan the ' butyl amide SI,.~II in fill3S\ '

en.

A <;ero!Id use of finastcntlc i~ in the treatmcnt of malc baldness. Tl1C coove .... ioo of IcstOl\ternne 10 OHT ill yean; tcad$ to thinn ing ofha,r ,n men . Inhibttion this ~on,et"'ion Will C'nvi~ioned as a possible: ooldness """'M After finastcnde was sho ..... n 10 be safe and effC'(:

ADRENAL CORTE X HO RM ONES

EndagenD.. S Cortkosterolds
Tl1C adrenal glands (which tiC just above the lldncy~) li."1l'te .wer 5(} different sterOids. mc1uding prccursol!i for OIher 'lC-

roid Iionnoncs. l 11C mOSt importanl 1>011l\01"\;I1 sieroids pmduced by !he adrenal CQI"Ie.\. Ilo~ver. we aldos!erone and 1drooorIisonc. Ak!Qslcronc IS tile primary ,,",in~raloconi (oi<! in hum-bns (I.e. il causes signiliclUlt llllll retention). Hy. dl"OOOflisonc IS tile primary glucocorticoid 10 humans (i.e. II has 115 primary effeclS on intermediary metabolism). T1le glucocOOicoids hale beconlC very important In modem medkiot. especially ror their IInti-innamllllllory efrects. Aldostcrone: and. to a lesser cxtent. OIhcr mincralocorti roi ds mainmin a eonsmm dectrolyte balance and blood vol .

umc. T1le glucocorticoids halC J..cy rolc.~ in CQIl\rolhllg carbohydrate. protein. and lipid rnetabol i~rn.

.les,HII: l!sh
As sho"'n In IIIe chcme in Figure 23-28. aldostu ....lC - ' hydrocortisone are biosyntllesized from pregnc:nolont through a serics of steps inl"ol ving hydroxyladons at e17, C i l. and C21 thai convert pn:gnc:nolone 10 hydrorortOOl'lt Deficiencies in any or the enl.yrne.~ cause congellllaJ III.ireniI

I
""'" -o,A.A/
p,agnanoIDne

"",-,,~ ~

o,A.~A/
'1'~

1)'11" ' I '

17nHjidoCO*tpiOQeste_

21-1..,40"',1'"

I I

.......... 00

,111 ..

o,A.A~
, \-OeoocyhydnIcoI1l8OfIe

Akioslerone

11,.

..,40",",..

o,"'A~

,. .-7-../ ,.
FIgUl"e 23 - 28 8iOSynthesis 01

t+ydo 00JI1IIone (1;:OftiIOI)

I*O'

C()(usone and dldosterone

lIyperplasi:l. (kf=s In the gene regUlmion. :l'i well as the ~lynle~ 111:11 o:al:1I),7'<: the hydroxylation have be.:n st udied mtcns ..-elyu" III In'esligailln hal'c linked dc:fcclS in par-

OH -OH

IlCUlar gtncs or Sleroid-biOOInIl ~JlCS 10 the pIIliKlphysiology of pallen,s "'It II lhe correspondi ng nletabol it di~ast'_~. I j . 11lN: di'\Oltkn; arc usually caused by an mabilll), of the llin'nal gland, 10 carry 001 11 (J-. 17 ...... or 2 1-hydroJl)'lalions. The n"lOSt common i~ a Jack of 21hydrollylase aclh'i,y .. hKh ",III Td.Uh In ~astd production of hydrowrllsone
and a compensatory incl'ea.;c in odrcOOCOftlcotropic iKJrmooe (ACTH) prOOu.cliOll Fun1w;:II,K , the l\'SulL;J.nl Ilvildupof 17..... hydro\Yproges,cronc: will lead 10 an increase of I~SL()<;lerone. The 2 J-hydmll),lasc is imponwll for the synbJofboth nuneraloconkuids and glocOCQrticoids. When 11,8-11) drollyla"" :oc1.vIIy is low. large .rnourlls of 1 r ~x yronico-Iemnc will be "roduetd. Because ll-doollyconicosIt'(lile is a poeent mincralocQn.iroid. there Yo ill be S)' lIlplOllIS of mlllcralocMlcoid C:)(ce~s, IIlduding hypcrtC'nsioo . When 17 ""hydrm,yla...: accivity is low. lhC're wi II be decrea"l'd proOOttion of le\lOSlC'l'OIlC lind e~Crogen~ as WI'll as hydrocorti Ahhough the !klails an'- I'IOt compleU'ly known. lhe 39tnUlIO acid pcp(ide Aem (cortioolropi n) producC'd by lhc ntrior pnuilnry is nC'Cessary for convC'fSion of cholc.~ ltfOI to f"l'gnenolone. AcrH Bets al the' AcrH ~'CpIor. a G-('fO(C'IM--coopled JtCq>tor Ihal IICIJltalC'$ adC'nylyl cycll-lle', leadmg co Il'ICrca!iCd cA MP level s. Activmion of the ACI'II Icpl~ ha. ~hort- and loog-I&:ml C'ffC'C1S 00 sieroidoj!:enc~ The \hor1-lC'nn pha.1Ie' in ltoh'e$ an Incrc;a~ in lhe )upply 01 cOOkstcrol for u...c by cytochrorne />-450..0. in the formaDOn of pregneoolone. l1lI: long-term effC'Cts are due 10 inan.<oed Iran!Cip(ion of steroidogenic enzymes. In An over;all resuh of ACfH a~tioo is increa~d synlhesis and relel-'IC "h)drooortoollC.llydrocOflisooe chen IICl~ by fttdbock in . ""'lion to ~upPrc.'\ the formatioo of addnional Acrl l. IACTII i~ discussed in more detail in Chapter 25.) Thr rete!l>oC' of tile primary mlneral()COl'1iCQid aJdo!;terone .nds OIl!y slightly o n ACTH. Aldosterone is an acth'e partoflhe angiOlen.in-renin-blood pressure cycle lhaCCOIlblood \oIurllC. A decrea>c in blood volume: Slimulate$ kidneys to <;eerelc the C'nl)'Rle remn. Renin.;n turn. 00I"I ' ICIb angiensinogC'n 1 anglotellsin. \Oohich stimu lates the 0 dm:il corte~ 10 relc!l>oC' aldoliteronc. Aldo:sleT"OOe then (lUI,('!, the kidllCy s to rel3in sodium. nnd blood volulnc in'~.~, When the blood \'olume has increased sufficiently . ImIII productron decreases. UII1II blood volume: drops ngain.
OH

1m:

t t fI-Hyclroxyetioehollnolone

Figull! 23-29

Met.ilboht~

of (Oftrsone and hydrOCOftrsone

cortolooes (200' and 2O/lJ. alld II,8-hydroxyetiocbolunolooe

are ~oll1e of tile millor metabolites of hydrocortisone (Fig.

23-29).

Biological Activities of Mlner.loc:orticoids . nd Glucocorticoid.

1lIC adrenocortical ,tcroid~ pennitthc body to adJu~t to cnviIUfIrIlCnUlJ changes. to Stress. and to changes in lhc diet. A ldo!;teronc and. 10 a I""scr extent. ()(he:r rnincralocortiCOlds nlOintain a eonSlan t electrolyte balance and blood \"oIume. and the glucot'OrIiooids Ioa\ e key roles in controlling carbohydrate. prOIein. and lipod mctabolt~m. AldostC'rone increases !IOdium rubsorption in the kidneys. An il'lCT\'asC' in pla.<;ma sodium e~ntmlion. ,n lum. ""ill lead to incrca~d blood \O!UIIlC. bccau'IC blood \"olu nlC und urinury ucrction of water are din:<:lly rc13lC'd to too plasma sodium roncentrJtion. SimUltaneously. aidostC'I'Ot1C In crea~~ pot;l~siurn ion e~crcl ioo. II-Dw~yCOf1iooslcrone also is quite octile as a millCf'alocorticoid. Similar actions an: uhib,ted \00 ilh h)droI,."OfIisonc ulld corlicostcfOllC. but to a much ~ml\lIe!" degree, Aldostel'Ot1C controls the movement of sodium ions III moOst eplthC'lral structures mvolvC'd in active sodium U'IIn sport. Although aldosterone acts primarily on the: distal 1,'011"oluted tubules of the kidneys. it also act! on the proximal convoluted IUbule~ and collecti ng ducts. Aldosterone controls the tran$pon of <;()(lium in .wcal g lands. small ;lItC'slillC. salivary glands. and the culon. In all of these tissues. aldoste rone enhances the inward now of !IOdlum ions and promotes the OUtward flow or pOIlIS..ium ions.

*'

. ....,alism of Hydrocortisone
H)-drocortisone and conisooe are enzymalically imeR:ooverIDle. and th,,~ one finds ITIC'lI1boliteli with both the II-keto lid the II,8-hydroxy functionality . Most of the melabolic "..,-sY'l occur in tile Ihe!". with the' me:lObolileli ucrcled

. . It

,
d'~

und are the SlIme ,n progesterone ITIC'labo/ism. The 1\000 Il1eUlboilles are tClrohydrocOortisol and le1mhydroand their oonjugull:.~. lbc conol s (200' and 20/lJ.

"The glucoconicoid~ Mve many phy~iological and pharmacologwJI acliol1s. llIcy roIllrol Of innucncc: carbohydrate. proIein. lipid. :and purine metaboli~nl. lbey also Rffect the cartllovllSCu lar and nc:rHltl~ sySlem WId ~Ldetlll muscle. They regulate gro\l; Ih honnone gene expression. III addition. glucoconicoKis h~vc anu-mn:ammaLoty and Immuno.supprc:s!'i\c actions IMt arise through comp lex mechani~ms. G luCQC()l1Jcol!h sumulate glycogen stOl1lie symhcSI.!I by inducing lhe synthesis of glyCQgcn sy11lhase WId ~timulatc glucooeogellCSis In the: Ii_cr. "They Ill"'e II ClII~bol ic effect 011 m liloClc: li~suc. stimulating the fomlation amltnmsamillll1100 (If ammo acid~ into glucu:o;.e precUNlf'S in the 11\ cr. The: catabolic achOllS in Cushing's syndrome are dl'n\Ull.tmtcd by wastm, of lhe tlssue~. oslcopo,)rosi~, lind reduced muscle nUbS . Lipid metabolisnl and S)'nthesis incn::ase siglliflCllnlly m the preserj(:c of glucocol'llcOIds, bul the actions usually Cern 10 depend ()11 the ~ncc of other hormones or CQ faclors. A lacL of adn:nal cortell steroIds al'>O causes depn::~sion. Irritability. and evcn psy~~. n::fkcllng ,ignificllm effects ()11 the cemnl! roen'OUs ~y5Iem.
ANTI-INfLAMM ATORVI'I MMUNOSUPPRESSIVE ACTIO NS Of GLUCOCORTIC040S 1ll- 1J7

mcch:mlsm is not fully undel1ilood but appealS 10 be alkcn::.ase m the binding or acti~lIIion ability of glUlX)C()11icoid. r\.'Cepl:OI' complclles and lhe,r targel or "acti~utor" gmt$. DisruptIon of the translocation of the glucocorticoid ICCCPU 10 Ihe nucJe\l~ h:IS al"!) bcc.'n implicated in gl~ n::siSllInce. ' '

Stnlcbtr,,1 a __: Mlnet'aloc:ortkolch and Clucocorticoids

Medically importam adrenal concx honllOlK'.-~ and syothrat millCl"Illocorticoid.~ and gluc(X.'QI1icoids an:: shown in Fipt 2330. BCl:ause II!II! retcntlOll OCIt\1\y is u~ually u~ the drug~ are cla.....~I flc:d by Ihcir !kilt retention acll~ili~ AJ i ll u~tmted in Figure 23-30. the adrenal concx hormooeun: elas.~ificd by their biological actlvilies into thn'e tlllja" groups.
M INERALOCORTICOIDS

111c:: mlnc:ralocoM1coids

Glucocort lcoidn::ccpIor oomple~c, (!iCe Fig. 23-7) may octi. vatc or repn::'s thc: gc:nc~ to which they aSSOCiate. Repression m parl icul:I( may ha\'e an 1tnporlant role in gl lJoCocorti~-oid anti-mn ammatory actIons. Gtucocorllooids inhibu the trano;cription or gellCS encoding cytokines such lIS intmerooy. lumor necrosis rOCtM-u (T NF-u), lhe intcrlcu kins. 3nd gr.mu locylelnlOllOCy1C ~'Olony-.stimul!lting factor. all factors mvolved in Ihc: immune system and innammalOl')' re SponsL'S.1.1l GllIOOCOrtiooids inh lbil the production and release of other mcdlalON of IJ1nammatioo, "lChlding prostaglandins. 1cuLotnc:lleS.WId histamine. In addition. glu cocon looid~ inhibll the c:<prt',sion or lhe gene ene:oding ~'OI lagena.se. an Important enl)'mc: invoh'ed "'Ilh in n am mation.
RESISTANCE TO GLUCOCORTICOtOS ua - 1oo

Ith chronic inn:unmalOl')' illnesscs such a$ a.\lhma. rheumatoid unhrills. and lupus de~clop n::sistance to the: antHnnammatOl'y effcclS of the glucoconicoids. "The
\I;

A fev. pallents

adrenal COflCX Meroids 1I1d_ logucs with high sah -rctaJJ1l11g activlly. They an: ~!.c.l mainly for treatment of Ad(h'iOl1 '" disclI.<o('. Of prinW)" nal insufficicncy. T he naturally (1C(;urnng hormone aldoskronc: has an 11,8-0U and an 18-CHO lhat naturully bndp: to form a hemiacClai (lill drJwn III Fig. 23-28). Aldos1mft is too upen~h'e to prodUC'C comn!Cll:lall)-: thcref~ oem semisynthetic analogues have taken '" place for I~almcfll of Addi'\Ofl' ~ disc:ase:. Addmg a 9a-nuoro group 10 hydllxu, tisuIK greally il'lCrea.<;('s boIh salt retemion 1lIld aOli-inJbm. matOf}' acti ... "y. DeoXycon..coqCIO.K (l1 . dcOlYl. III _. mediale in the biosynthesi' of aldosteronc. has lo"'Cf nUIlCr:lloconlCOLd acti ... il) thJn ah.lOSlerone (-20-foklJ t. mDy playa role if the IIp-hydroxylase i~ defiei~nt. Deol)' conicoslcrooe i~ not available for therapeulic uses. utCIIS;\'C modifications havc been made to the b.:ts~ 11)-. druc:()t'1;wno: S1roctU~ to alter lhe properties or glutOWIIcoid~. Modifications 11\ all SItes of .hc <,jcroid backbon~ bl\~ bc:~n IrIL-d_ Aside from addmon of a double bond It CI-el the n1()!,t beneficia l cllangc' are made to ring~ B and 0 d the steroid s"eleton WId noll(ication 0( tit( CI 7 ~idc ct.. Table 23-7 summaril.e.~ IIle: relal; ve cffCl:\s of vmoo! \.IIbI.tJt uenl5 sun In commercially available products on 5lI1t n:D liOll and glucoconkoid actl"';'y. TIIC salt-n::t.aininll..,x.
~

TABLE 23- 1

Effects of Substituents on Glucocorti(oid/Miner. hxorti (old Activity (jlycogen Depositi on

Antl-Infl.~~

IiHKb on

Fundlonal (jroup
9, ... Pt"""",

Act ivity
1-tO

Urlftlllry Sodlu""

...",..,
\ -Udl)'<In>
6o-'kt~) 1

'-,
,~

"

...
" t-!
B

2_1
0 4...()..5

'fIn-Hy.Jtmy

Ot-{lZ

n,,lt,drmy
~1 1I)"""y

1_2
~,

,,,k,,,"_ 1910
L......... r - -

M I ILj _1I<>6s.01l ho lhoo . " (<d.) , _ -[ 0

.., 1' .. 2. .lnII. "" ... V<rl. "',...,. I...

".--'

-~

appro)(lIn:ah:ly additi,- . Rlr uample. the 3 + locrell!ie c 1'1 <.lilt retenuon of a 9G'-nuoro group can be ell mtnated by IItI: 3- ckcre.tsc of a lXf.mcthyl.
~

Ione.nd predmSQllC'. A~ \hown in Table 23-8. In IIP.OU matnl.1.ins good tOPICal anll- innamm:lIory actl'lIy. bill II .
dch)drogcnal.e III tilt' 'ltn o"ldi7.c~ an II,8-hydro"yl 10 an II -L.c 10IlC. 1' l For OCII' alion or an I I-one gJoroconicoid ror tOPIcal action, rt'dochOtl at ell .... ould be nc:ccs.ary. 'Thc Ic nc or predm-.olonc lind prcdni~one increases anl; i nnaf1\malory activity abollt foonold and 'Ofllc:whnt dccn::a'<C~ ~lIlt retention. Dlla" and coworL.c:",Zt1 hale .~hown thl lM incrclf'-! in

ooc:s havc little or none_ l1Ic

IIP.h)dro"}'~tCf'Ol"

(jLUCOCORTICOID5 WITH MODERATE-TO-LOW SALT RETENTION

The glucllConlcold~ wIth nKXk-ratc:-to-low $lilt retcntion in_ ,Iude conbOl1e, hydrocortisone, und their l cncs predniso-

O--{~
o

(not commercially av.llabIe)

--o

o~"'::11 0e0>:yCOfllcosterone

(not c:ommett:iaIfy BVMabIe)

2. G' "=",-tiooids With Modara18"'t.ow Salt A.teoIIon

o-{
OR"

C",

' V'' _"\ ""

o'~

HyOoOWiIisooe (R' .. R" .. H) {Of eortIsoI)

E'te f' avaIlable

H)'dtocortr~

Hydtocor1lsone bulepflll.

_.ar.

R'w COCH;,. A'. H

R'o.

COCH~H,

A" COCHtCHaCHl tt,dooc:t:WtiSOf'lll butyfa,,' A'o. H, R"o. OOCHtCH;CH3

R". H Hydfocortilone .....18 R'o. H. R"

o'~
OOC~H,.cH;CH;,

Est ........... . . 21-SaIta .... ftiI<tbhe IR" o. H) ttj(llOWititoloe SOdium PhoIphaIa R' .. ~~- (Na')! Hydfoeortisone SOdhJm SuccInate' A'. OOCHaCH,.c02" Ns'

P,""*" .......... KetIIta' R o. COCH;,

PrednIsolone tebutal. , A o.
OOC~CH;,n

Sarts Ivallable PladnillOlone SOdium Phosphate :

R o. PO," INelt
Priido
'J

Jot... Sodium Succinal8

R . OOCH;,CH,COz Nil"

Pled I __

Figu re 23- 30 Natural and synthetic (OrIl(()Stt'fOlCis.

OR'

OR'

,
,

.............
R' . ,
R' . F

CIobe\IqaI

,-H R' . ,-' R' .

p' ........ "'..

R" . - CH~
R' . Fr. H

R'6 .. - CH:! 1'1 " .. OCOCH:zCHJ

0.._

. . .,
R'.'

... ' ........ o1de

,-, R' .

HalOOetasoi PtOpi"...

R" ... ' CHJ

R1.F
R' .. C<X:CH, 011 Xlide

1'1" .

- CHJ

R' . R" " H

0iI\0IQ0ne 0ia0IItI1e

A '''''"

1'1 " .. OCOCHzCH,

R" .

A' . A . F '

- CH:! R' . R" . COCH:!

,-. R' .. H A'

A'''''
~ . ,

R' . H R '''''.''~~''' ''' . .' "

Methyfpftdni.......

R' . ""' A' . R". H

R' _ R" . H
p,tdo .a.rblltfl

FluocinoIone

A' . R R,6. H .
A' .. R" .. C0Cl-l2~

R,,,,1,, "

,-. R'.F A'

Acto"""

R' .. H (1Iuodnoroide Is 1hIoC21 _ _ )

F\no do .. ooIidoio

R' . ,

R' . ,
1'1'''' 7 .. N
~ . ,

-( 00 0
"O~
"CH,

H "a

,
,

H
" H

" CHJ

Fig ure 23-30 Continued.

octi,,;')' m.:ay be due 10 a c twnge in shape of ring A. Specifi-

cally. analOjlucs

lIC1;vc 1il:u1 hydrorortisooe 3ppar 10 have thei r ring A bent underneath the molecule to much gl'('31cr ('x ten! than hydroconisooe. 'The 11,8-011 of hydruoot1ilUJlle is of major imponallCc in binding [O lhe reccptOl'S. Corlisooe is reduced in vivo 1 yield 0
IllOf'e

tor. A 9",halo substituent also reduces o~id:Uion of~ II OU 1 the inaclh'c II -one. 0

GLUCOCORnCOIDS WITH VERY LITTLE OR NO SAll RETENTION

prednisolone, h:l,'e 100 much

h)'drocon isooe lIS the lCIive agem . TIle iocn:ased activily of 9a--halo derj," ath'es may be due 1 the electronwithdra .... ing 0 induct;,'e effect 011 Inc 11,8-0H. making;\ more acidic and, therefore, bencr able to fom! hydrogen bonds wilh llle fCCeP.

doses ncakd for some several

"'"
I

ToULE 2)-8

Appro.i~te

Relative Actlvltl" of Cortic05teroi~

AIItl-ln'....,..m.tory
Actl .. lty Topical Actl .. ity

Sa INI. lai"' ng Actl .. lty

(quI".'e ,"
Oase/ mg)

M ,..."Ioo;onlroo;,b

AkbI,.mnr

_.
C...;.oo.
Pt , . , .
\""*')1,"

0.2

o..:u )'1'<><111:"""""""
~ lu.,ln)..~If1I>(lllO

HydfI... onl .......

f'Itdo."* -.

...

"

, , , ,

,-1100(10 .......
~luo<, """"""
~l_'_i<,It

',<oQIone

Tnaoro:,..oiooe ......,Ido

, " ,
" '"

11(10'....,

~,unndrtll!li~

. ""''''
"'~
O>ff-lO

>-.,.

.-,

,. " 0' , ,

, " ,

1ItUo1TII""-

"'. ,,,,,......
dccrea~

"'-"" >-.00 .0-"

o o
......

Oi~

"

_ _ ... __ " ,_-'''. ' ' ".n..I. ...

........... ""''"'"''_ .... , _ _ 1110.1<............ '''

I

I """"_ ... ""' .... _

" " _ ..... . 111< ....... "-..............................

_01',... "" ... I ..... ....,.. _ _ '.1 0<1,,,,"".

,..... ~Pooo _

md that greatly

'\alt retelltlon. llIc:y II10dudc 16tr')dro~y; 16a,l7a-kclal: 6tr-mcthyl: :md 16tr- and 16.8.myl. Other M1bSlJluents have been fou nd 1 increase both 0

Me<.hum~ 1Ic1~

Cloconoione po .alate. D. I,+

~limet_.

.... lcr.uc. 0 I II

Jllx"ocortioold and mineraklcorticoid acuv ities: Icoe, 9p:.:.

Ituoro, 9tKhl0r0, lind

21-hydro~y.

As a re~ult of the grem econom ic benefit of havi ng UpoIen i JluIinnal1l1nalory prod uct 011 the marl c!. phumlaceu licul iI\:lnu fachlrefS have mad.! lIu me rous combina,ions of these I II almost e\'ery case II l 6-mcthy l or a (to elimina t" salt l"l'1enlion) lias OC'CII

O,OSt:; FlUOt"inolonc liCemnoJe, 0.025'if: Flutlca'I()IIC proplOl'~IC. O.ODS'}

I[ ydroL-OO".onC

bul) "~IC, 0, 1~

l1 ydrocorll.ol1C ,'alcrnl ~. O .2<:f :>' IOIt1Ctl.!,OllC (Urtll1l(.', 0. 1'I Prcdni<:arb,nc. 0.1'" Tnamo;mo'one IlC"C.'lOO''''', 0.1 'it>
1.0" poIeocy .... IcIomela!lOlle d,prrIflIOIUIc. 0.05'10

IIctlvi.y. llIc: h3.'o resulted ill a n:dundalll amay of anaI I'"th I'ery low salt mention and high antiillflammaacI ivil y,

Dc1;on,de.

D~""

Fl""",""""'" ar ...l>I1I<k. 001\1

Tn:unc,noIone llC"C.'looode c",,,",- 0.1'.l lowrst poIn>l""y Hydmcort,\OI1C. 1O"f H)ilrocortiMlllC, l.S,*,

of these: highly am i inflammatory drul!~ topical potency. As sholl n I" Table 23 100 times more act, I'e lopically than Relalive potency i~ as follow,:
V.-ry h'gh potency

.... ugmc:mcd be!ame!harotlC d,propiollll!( otnlmc:nl, O .OS"" CIobct~ propionate.O.OS""

Dtnorasonc dh,cctalC oinl ment. 0.05'1
H'lh r:w;oIency

AUlCulOCIlIie. 0.1 <J

~~ dI~c

O,"Utlcn!. D.M%
O.~'.l

De!,o"met_,O.2S'.l Dtf1or'uone dl_e acam.

~'UOt"I_ O,~'I.

Ible._ode. 0.1'"

Halobel:asol propIOIIO'lt'. O.OS<;i: TnalllC'nI.IIonc Kelllnide, 0.5'10

Although, a~ shown in Table 238. ooniM>l1C and pmini sone are not aclive wpl cally, mo,. OIher glucocorticoids an: active, Sollll: compounds, such as c looc!Il.')1 and hetamet ha. sonc dipropiona lc. have , tri l,. ing activity topically. Sk in absorption i$ fOl'orcd by increased lipid solubi li ty of the drug , Absorption of topical glucocoo leoids can also be greally affected by the cll ient of skill damage, oooccnll':ltion of lhe gllJCOCOrticoid. cream or OlllUl1cnt base used. and \imllar f~tors. On.- must not as-.\ unlC. Ihcn:forc, from a stud) of Table 238 that , for example,- a O.2jq. cream of pmin:soIone IS necessari ly cuclly equivalent in anti- inflammatory p0tency to 1OJ, h) dll)('oo i~. Never1heles.~, .he table can serve as a prelimll1ary guide, I-llrIhcrmore, particular p;t" CnlS may see m to respond better to one topical antiinnamm~tory

glucocomcoid Ih .. n 10 another. irre.'ipOC1ivc of lhe relative potencies sho ... n in Tahle 23-8.

RISK OF SYSTEMIC ABSORPTION

Tbe topical corticQSu:nmis do IJO( typically C;lUse significant ab'iOl'plion effects ... hen uS/,.'<1 on ~mall areas o f intllCt slin. When these compounds are u.'iCd on larKc llI'I:as of the body. ho ... C 'Cf. ~ ySlcmic absorpuon may occur. especially If the slin is damaged or if occlusive dressings are u<;cd. Up to 2() to 40% of hydrucortisol)e gi vcn recul.lly may alS() he lib-

""""'.

i ha,,'I a.lk Uses .. A" ." C., ....

Mosses."
The adreno<:ortlcal steroids an: used pnmarily for their glucocorticoid cfft'Cts. inc luding ilillnunmuppre~sion. anti -in flamm-atO!')' acti~ lly. !lfId antiallergic acti"ity . 1bc millCr.lll)conicoidJ; arc used only for tre31mcnt of Addlsoos diseasc . Addison 's i,li<ea.sc is c:lUsed by chromc adreno<:onical insufflCicocyand may be due loeither adrenal or IUltcriorpltuiwy failure. T he glucocorticoids an: nl so u""d in the tremment of congcnillll adrenal h)"pnplasias. "The ~ymptom~ of Addison ~ disc:t.'iC iIIustr.l.te the great imponance of the adrenocortical steroids in tite body and. especially. the ImpMarICC of aldoslel'O!lC. "Thcr.c symp'onls include increased loss of body sodium. decreased 1 0SIi of potassium. hypoglycemia . ...eight loss. hypotension . lI'eak nes, . locreaSl:d scnsiu"it y 10 insuIi n. and decreased hpolysis. ~l ydlUC"Ql1isonc: is al!>!} used during postoperuti"c n:co"cry after surgery for Cushmg 's sy ndrome---e1ces..~he adrenal secretion glucoconicoids. Cu~h in gs syndrome can be caused by bilatenaJ adn:nal hyperplru. I:I or adrenal tu/llOfS 3nd i ~ treated by surgical remo val of the tumors or resection of hyperplastic adrenal gland{s). 1bc usc of glucocorticoods during n:co"cry from surgery for Cu~h ing'li syndrome illustmtcs a most impon3nt principIC' of gll.l(.'QCQCticoid ther py: abn.Jpt withdra .... al of gluco.. corticolds may f\"~ult in oorenal iusufficienc)". ~howlllg , Iini. cal symptonls simi lar to those of Addio;on s diseasc . For that re:tson. patients ... Ito hal e been on long-term glucocorucoid lher py IIlu~t have Ihe dQSo.' reduced grodu:tlly . Funhcnnore. .. prolonged tn:atmcnt .... lth glurocor1icooW CDIl cause adrenal suppression. especially during !IIllCS of Stre!iS. The symp'oms an:: ~hl\illlr to those of Cu~hi ng ' s ~yndl"t)me. such as rounding of the (lICe. hypcnen~ion . cOelT\:t. hypokalemi a.. thinnmg of the slin. ostCllpOfU!i IS. diabetes. arK! cven subcapsular calntlICts. 1lte glucocorticoids an:: used in the treatment of collagen ~1I.<;cular discase~ . illdudi ng rheumatoid arthritis and di~'\Cm inated lupus erythematosus. Although there is uSU:tlty prompt remission of redness. s.... ell ing. and Icn<lcnlC!is by the glurucorticoids in mcumatoid arthritis. continued long lenn use m:ty lead to 5Clious ~ystemie fonns of collagen di.seasc. As a result . lhe glucoconicoids ~hould be usc<t in frequemly in rheumatoid arthritis. 1lte glucoconlcOids arc: u~d e~tenslvely topically. OO1lly. and parentcrali y to treal inflammatory corK!ition~. 'I11CY also usually relieve the disoomfooing ~ymptoms of many allergic condltions -imrnclnblc hay fever. cxfoliatilc dcmt.atili~ . gencnaJized eClcn\a, and others. 1lte glucocortit-oids ~ also

used to treat a~thmatic symptoms unrcsponshe 10 btUi..... dtlaton. "They are espttially useful 111 inhaled fonnul." (see .section below). 1111.' glucooon"oids' l~rnphoc)'lopmo. actions make them particularly useful for lI"Catlllelll tI chronic lympllocytic leukemia in cOll1binmlOn " 'nh odII antineoplastic drugs. 1lte lKIn:nocortical steroid) are conlraindicated Ui" be used with gre~t ~aut i(ln in patients wtlo ha,r (Q) pepIII ulcer (in which the steroids may causc hc~llc).lb}1uI disease. I e) infcctions (the glucocorticoids ~~ .. body' s llOIl1lal infection fighting processes). (d ) Il!')'< ( ~incc: beha .. ioral disturbilnces may occur dunlll thcrapy ). Ie) diabetes (the Il lucOCOflicoids I~ase I production. so more insulin may be needed). (fJ g (6 ) OSI~i s . or (h) hcrpe!i simplex 1111.011.101 ~ When administcred topically. the glucocorticoids relat;"ely infrequcnt therupcutic probk-ms. but ~II." flmllrnalOl)' action can ma,k symptoms of Infection. Mal physicians p.-efer 1101 aivoog a topical antiinnamrn:lWl)" roid unlil ufter an mfection is control led with topical_" ics. The immuoosuppressl .. e DCti vity of tile topical gllltl'ltU ticoids can also prelcnt natural pnxesses from ~ infection. Topical steroids actually may al~ cause "";.; SC-~ in SOf11C pallcnts. Finalty. as dio;cuS!iCd abole with the 01111 conll... jt1 steroid honnoncs should not be: used il is absolutely I1CCCSSIIf)' to use '~:~ " ' . durlllg pregnaocy. they should be in Ii intact ~ kin and used for II limiled tin~ .

or

MI".r. kKortkoid .nd GlcccCKOrtkoid Phd.,1s The e:orticoslcroids used III commercial products are
III FigufC.' 23-JO. 23-3 1. and 23-32. The structures Iltu;uathe usual changes (see Fig. 23-6) made to modify to! of the prOOIl<."ts and. lhereforc. their tl~rJpcutic uSC5. ln IW'"

tieular. the 21 -hydro~yl can be COfl\'crted to an ester 10';'. it less water soluble to modif~ absorption or 10 a ~ ester salt or hcmi succinate ester salt to make it ITlIft " ... !iOluble. IlIld apptopnate for intntvenous use. n.c also n:flcct lhe: structure- activity relationship chanJa. eussed abo.e to Increase aI1ti -inflannlkllOl)' acti\"lty Ui I"Icney or dccrc3SC salt retention. Again . patient s who have been on long -tenn COld therapy must Im'e the dose ~lIC'Cd It " criti'1I1 rule lind indications are abo.c

comple:.. and specifIC e:K!h i i Many or the glUOOl."OI1lcoids are avai lable in I age forms. including i and wiutiom. Thcy are t timeJI to I I

""",0

tnt

or to damaged urcas 'i~; ;;';,; can occur. 1lte use ~ increase systemic ~bsorption . ..",:rOC;""'~_ TIle gltJCOOOl"ti~'oids that ~ mainly .~ of the. eye are sho .... n i: ",,;,~ ,.,;,.2;].~ ;1.,,"""," ~3 ,~i", differ structurally from ....

;,;,

Cha pltr l.l Suroid Hormm,u and Thu",,,,utkllily Relmed C/"",""uJdJ"

8 11

HO H,C
H

CH, H

HO
H,c

CM, " OH

v
0
~

HO H,C

CH,

,...........
CM,

0
H,c H H

CH, CH 3 CH3 H,c H,c H H

f-O

CH~I

'On"""'-0

v
0
~

.~

Figl.lre 23 - 31 OphthalmIC gh.u:ocortlCa.ds

,,-

lOleprednOt Et3b0n8te

II)'droxyl is mj~sing frolll OIcdrysonc. fluoromerho]one, and rimc~olooc. while JOIcpredool c13bonmc has a modified ester

.C17 [hal leads [0 rapid degradation upon systemic ab~rp

....

MINERAlOCORTICOIDS

FIIIdrocorti$one Acetilte, USP. Fludroconisone acetile, 21-l\Cetyloxy9!1uoro-l I p.17 -dihydro~ ypregn.+ene-

J1IHIiolM.". 9a -floorohydroconisone (F1 orinc:f Acetale). is used only f(lr the tre atment of Addison's disease and for Il/"b,lion of endogenous adrenocortical seerelions. As
!M\\n in Table 23-8. il has up 10 about 800 limes the miner-

m:onicoid ' i

of hydrocortisone and abou t II times

. llClhily. lis potent activify stimulated the and ,judy of the many fluorinated steroids shown 23-30. Although its gre31 .Io3.h-relaining activi ty \I >C 10 Addi}l1' S disease, it has sufficienl gIOCOOOf IllUl in some Cll.<;C' of Ille disease. addilional need rIOt be pre'\Cribed.
GLUCOCORTICOIDS WITH MOOERATE-TO-lOW SALT RETENTION

Cortisone Acetate, U5P. ConiS(llIC acetate. 21-(acet)]ox y)-l7-hydroxyprcgn-4-t'ne-3.11.20-trionc. is the 21aCCUIle of natur~lIy occurring conisone wi th good systemic unti-innammatory octivity and lowto-modenue salt relen tion activity after ilS in vivo conversion too hydtocQl'\ isone acetate. This conversion is mediated by II ,8-hydroxysteroid dehydrogenase. It is used for the entire spectrum of uStS di scussed alx)\'e under the heading. Therapeutic Uses of Adrenal Cortex Hocmones-collagen diseases. Addison's di se:l1iC. severe shock. allergic condition~. chronic lymphocytic leu kemia. and many other iTKIications. Coniso~ acctatt is relatively ineffective topically. mainly l)ecau!;C it must be reduced in vivo 10 hydroconisont. Its plasma hal f_life is only aboul 30 minutes. compnred with 90 minutes to 3 hours for hyd ro..:ortisone. Prednisolone, USP. Prednbololle. ,dl -hydrocon isone. I 1,8.17 .21-trihydroxypregna-1.4-diellC-3.20dione. has less salt-reteution octivity 1han hydroconison<: (see T able 23-8). but some p;uicnts have more frequently experienced conlpli cations ~uch as gastrie irri tation and peptic ulceTli. Beca use of low mineralocorticoid activity. it cannot be used alone for adrenal insufficiency. Predni'Dlone is available in a vari ety of s.alts and esters to maximize its therapeutic utility (see Fig. 23-30):
Pminisolonc: Prt:<Jnisolooe 1 'rednisolooc l'rednisolonc lII.-Clatc. USf' 121 1Il.'CWe) sodium phosphate. US P (21-wdium pho>phate) sodium 'UI.-cinal . US1' (2!wdi um SUCCIn.:IIC) tebulate. US I' (21'lcbutatc)

Hydrocortisone, U5P.

Hydroconisone.llp.11.21-uiI is Ille primm)' natural gluhunmns. Oespile the large number oof synthetic hydrocortisone. ils eslell>. and ils salls reI I of modem adrenocortical steroid therapy I other glUCl)t'OTlicl)ids I 23-8). It is used for 311 i alxwe. Its esters and sa lts il lustr.l.le I I I modifICat ion 1 modify ptlllnnaco0 u.e shown in Figure 236. The cOlllmereially avail and esters (see Fi g. 23-30) include

HyIlroooni5Of>C IIICttutt. US P (21'IIICe1ate) Hyd",,;onisonc: bultpnue. USP ( 17 bul)'r~tc. 21'prupfonalc) Hydroc..niwolC butyrJle. USI' (n butyratc) Hydrocortisone: cypionatc. USP (21~ypiDlUlte) Hydroronisooc wdium phosphate. USP (21>Odium phosphate) HydrocuniWfle >Odium ~uccinatc. US P {2 1.$Odiullll-UIXinattj Hydlo.:onironc valcrate. USP (t 7"unltc)

Prednisone, USP. Prednisone . .J '~orti sone. 17.2 1-dihyd rox ypregnu- ! .4-diene-3 .1 I .2().lrione, has ~ystcmic IlCt ivil y very simi lar to that of prednisolone. and because of ilS lower .';.alt rclcntion ~ctil'ity. il is often preferred over cortisone or hydrocortisone. Prednisone must 'tic reduced ill vivo to predni'iOlone \0 provide the octivt gluco<:onicoid.
GLUCOCORT!COIDS WITH VERY LITTlE OR NO SALT RETENTION

Most of the key diffcn:TICes between the many glucoconi coids with minima l salt retention (see Fig. 2330) have been

SlI mJllanl.cd m Tables 237 and 23-8. The tremendous thernpcunc aoo. thcre fore. 1'00n1ncrciallinportance of thcs.e drugs ha!; stl mulatod the prolifcratioo of new compounds and their products. Man), cornpound~ also arc avai labJc as !.alts 0.Cl>tcr~ to ~l'C the complclI: !"allge of ~peutic nell ib;l; t)' illustnlled in Figure 23-30. When additional pcn;ncnt informatlO1\ IS a\allal)le. 1\ " g1"en below. lbc syslemtC naml' for each drug IS provided after the common naml'.

Oesoximetasone, USP. Oi:sollHIICtaSOJl(', 9-nuoro--l],B. 2 1.di hydroxy.16(t<mclh)"lpregna-I,4-dicne.3.2o..dione. Ilk cloconolone pi,alate. lacks a C I 7a hydro\yl group in Ib structure. Dexamethasone, USP. OcXlIlllCthasone.9-nuoro-ll,!/. 17.21- trihydroxy I6a--lIll'thy lpregna- I.4-diene-3.20-d...... is the 16a isomcr of betamclhaS01ll'.

AldometasOflf! Oipropionate. USP. AldonlCUISOfIC diproplonate. 7 tM:hloro-ll.8-hydro~y- 1 6(t<methyl 17 .2 1bi~( "OllOpTOpl)llY }-pregllaI.4-dicne3.20-dlOlle (Aclov~le). is one or tbe fc'" commerciall y u'Oed glllCoconicoids that beal'S a halogen ~ubst;loent in the 7a poslUOfI. Amcinonide, USP. Amc iJlOllidl!. 2]..{acetylolly) 16ll. 17 -]cyclopcmylidc:ncbi$CollY )] -9-flooro-1 Ipbydro~ YPR'glIaI ,4-(hene3.2().dione C C)doclll'1 ). 8edomethasone Oipropionate, USP. Heclornct ba ~ dlproplonate. 9~hloro-ll.8-hydlllxy-16.8-ml'thyl 17 ,2 1-bl\( l-oxopropoxy}-pregna- I,4-diene. 3.20-diooe ( Beconase. Vancena,.;e. VlUlCCri l. Q V A R). is uo;ed in nasal ~p"'Jys and aerosol formu lations to treat allergic rhmllis and asthffill (see section below). 8etamethasoM, USP. Bctameth:lsooe. 9- n uoro-llp. 17.2 1 trihydro~) - 16.8-nlCthylpregna I.4-dlcnc - 3. 2O-dione. is a\"111lable a~ a variety of e..~tC1" derivatives.
USP ( l7-valrnlC:) Rct~metl\aw,)ne IICU<lIC. US!' (21 .. wlt) Iktamc:ll\n.wnt sod,um phooophate. US P (215(ld'lIm p/K>sp/>~le ) 8c.-Iamc:th:osont dipllllMooale. US!' (17proplonaJe. 21p"" "...
Rclll~ ,"2kra&e.

Dlflorasone O/acetate, USP. DlnOl1lSOrlC diacetatt.I7, 2 1_bi s(acelylo.ly)60.9-dinuoro-l l,8-hydroxy l6a-medI)l pregnll- I,4d iene J .2().diooc. Flunisolich!, USP. Fluni 'lOlide. 6a-nuoro- l ],6.2 1 ~ drox y. 16a. 17-1 (1 - llICtllylclhylidellC)blS( O.lY)] pregl1.l1 A diene3.2O-dione. (See following section for IISC of nllllJ~ ide in the treatment of alithma.) Fluoonolone Acetonide, USP.

Fluocinolonc.

lintel potent than nuocmolone acetonide In at ItIlSl one ~~ti\"ity assay.

;'';',t

..,

USP.

8uch!sonlde, USP. ll uOcSOll ide. 16...... 17[butylidenebi s(a.lY ) ]-1 I fJ.21-dthydlll.lYPR'&na I.4-diene3.2O-diooe (EntOOOl1 ). In oral capsule'.! i~ used 10 treat CroIln' s disell5C . 1llc affinity for the GR is Ilppro.limalely 200-fald grelller than that af hydroconisone and ISfald greater th~n thaI of pred niso\Qne. Budewmde IS mbn ure of epinlCrs. with the 22R farm ha\"lng Iwice the amnlly for the G R of the S epimer. Th,. glucocorticOId i~ Il\claboli,ed by CV I' 3A4 . and its Ie\'els can be Increased in the pre<oenee of potcnt C YI' 3A4 inh,bltoR. Budesonidc: is also used In an inh~1cd formulation f()T thl: trc:alnlCm of asthma (see below). CJobetasoJ Propionate. USP. Qobelasol propIOnate. 21-chlom9- nuoro-l l.8-hydrolly 16.8-rnethyl17-( ] -a~opro po.l y)-prcg naI.4-dicne3.20-diollc (T cmovmej. C/ocortoJone />iva/ate, USP. Cloclll'101aoc ph'a1ate, 9chl olll21 -(2.2-di methyl I-oxopropo.lY )-6o-nllOro-l l,8-hy dro.ly . 16a.lIIcthylpregna. I.4-diene-3.2().di01IC (Clodennj. along \11th desox imdasone. lacl.s the C17u o.lygen rune tionalhy Ih:1I i~ prescnt In other gluoocorllcoids bul sull reo tam~ good glucocorticoid activity. Oesonich!, USP. De!.on.ide. ] 1,B.21 dlh)droxy-1 6a.17 [( l mct hylclhylidene jblS(O.l y)]preglla- I.4-dltne-3.2O-dione ( lksOwen. Tridesiol).

17-acelate ofnuorornetholone i ~u spen~ion (Flarex).

Flurandrenolich!. USP. 11,8.2 1dihydro.ly - ]6 pregn-4-cneJ .2().dione. I oct. can stick 10 and remou~: a\'oidcd wi th \"esicuhrr or " 1.'"Cpinll Fluticasone

as a ~I.in. >0 it

OIlte (Cutiv31e ). i ~ more sonc in receptor bllldlllS as!.a)$. (See al<;o the lion on inhaled corticuslelllid~.)

Haldnonide.
3.2O-dione ......3.$ tllC Likenwtyafthe topically.

Propionate, USP. 3te. 2 1-chlor0-6a.9-dlnuoro-!" '!~.

Halobet~soJ

1131obciaSOl

Chapter 2J Sum;.1 Homw.,rs wid Thrr{l/I('micl,I/.\ R'/IJltd CU"'pI)ult/ls

813

l Ofepredno / Etabonate, USP. t..o.cprednol embonatc. chlororncthyl 17.,..( (elhoxycarbonyl)o~y I-I l,8-hydroxy-3o~oandmsUl-l.4-djr'ne- 1 7-corbo~ylalc

has 11 modified c3rbo~ylat~ ottilc position rather than !be typical kctOflC functionality. This modification maintains lffin;ty for the glocOC()l'tic{)id ..... 'Ceptor but allows facile meWloIism to inacti,-c nletabolites. Th;~ limits the sys temic 1CI10I'l of the drog. Loteprednol etabonatc is u!'Cd a~ a:n ophthalmic suspension Ihm has greatly ..... '()uced .\ ystcmic oction due: to mpid melllbol i,m to the imlctil'e carbo~ ylate ( Fig. 23-

en

(Alre~.

Loterna~).

m.

Medrysone, USP. Medl')''One.ll,8-hydroxy-6a-rnethylpregn-4-ene-3.20-dionc. is uniquc among thc conicostcmid>. in that it lad.s thc lL~ual 170:.11_diol systcm of the other> (Fig. 23-31). Currently. it is used only for treatment Df innammation of the eyes. Methylprednisolone, USP. Mcthylpredni<olone. IlfJ. 17.21-trihydro-" y-6a-methyl-I.4-prcgnadicne-3.20-diollt'. is Ivailnble unmodified or as ester derivntil'es.
MothylpmlniSQlonc ",,<,Ime. USP M~lhylprt'dn;wlune MXIium ,uccinale. USP

than triamcinolone. The plasnlU half-life is approximately 90 minutcs. although the pl:.sma halfli fc and biological h~lf Jives for glucocorticoids do rlOI cOITe lutc well . 'l11e hexacetonide is slowly converted 10 the accton ide in vivonnd is given only by inlra-anicula.r injection. Onl)' triamcinolone and the diucc\;lte are given ol"~lIy. The acelonide and diacemte may hi! gh'ell by ill1rol-anieular or i ntrJ~ynovinl injection: udditionally. the lIeelOnide may be given by ill1rabursal or. some limes. imrJmuscular or subcutanCQU S injection. A ~ingle inIrJl1lus/:ular dose nf Ihe diucetme or :tl"t:lOnidc may last up to 3 or 4 '\ICt:k~. Plasma Ic\'cls wi th intramuscular doses of the acelOnide are significantly higher thllil with triamcinolone iTself. The acctonide is also used In tn-at usthma lind allergic rhinitis (sc:.'C following S4!'Ction).
INHALED CORTICOSTEROIDS FOR ASTHMA AND ALLERGtC RHINITIS

Mometasone Furoate, USP. MomelDsone furoale. 9.21-dichloro-17 u-[ (2-fumnylcnrbonyl)oxy[-1 I,B-h)'droxyIM-methylprcgna-l.4-dicne-3.l0-dione (Elocon). is a high potency glucocorticoid available in cream. lotion. or oi mment fomlulat;ons fOf lopical u-.t:. In addition. mCNIIClasonc furoate monohydmlc is fonnulutcd in a na~al sprJ.y for treating allergic rhinitis (~e following section). Prednicarbate, USP. Prednicmbate. 17-[(ctho~ycarb OIl} l)ox y [-II,8-hydrox y-21-{ Io~opropo~y )pn:gna-IA -d ienc12Q-diollC. i~ a p..... -dnisolone derivativc wilh a C21 propionate e~ter and a CI 7 clh)'1 curbonate group. It is avail~ble for IIIe only in a 0.1 'l> topical cream. PrednicarWle is n mediumpotency glucocorticoid. R ime){%ne, USP. Rirnexolone. II,B-hydroxy-16lt.l7aoJimcthyl17( l-oxopropyl)andro~ta-I.4-dienc-3-o!le. li ke mWryO\One and fluoromctholone. lacks the C21 hydroxyl lfOOP. In addition. rimcxolone h,,-~ an nddilional methyl VOUP in Ihc 170'1' po~il ion. a ,ite where :1 hydroxyl group is typically found. RimexolOlIC i~ avai lable as U MIspension for ophlhalmic use (Fig. 23-31). T riamcinolone, USP. Triamcinolonc.9- n uoro- llfJ.16lt. 17.21 -lelmhydrox yprcgna-IA-dicne-3.20-dionc.
TnamcinolOfli' aceluni<ll:. USP. Tnamcinolonc- t6a.17-acetoTri3mcioolOl'lC' he~ocetonidc. USI>: TriamcinulUllC lICCIunido 21' 3-(3.3-<.1 i mclh)1 )bmyrnl c I TnamdtIUIUllC dioce1at~_ USI': 16.21-o.~le Triamci nolone :lCClOnide is upproximMcJ)' 8 times l11Qre potenllhan prednisone in animal innammatiOlI model s. Top-nlly applied lriarn<:inolone lICelonide i~ a poIenl anti-infiammalory agent (see Table 23-8). about 10 time.~ more so

,,"

'T'he National A'lhm:l Edu~D!ion and !'n'\'cnlion ProgrJ.ul has providcd recenl rccornmcnd31iuns on the treatment of aSlhma. including a Mrong recunlmenti:uion for Ihe first-li ne U'\e of inhaled cortkosleroids for !iCVere and moderate persistcnt aSlhma in nil age groups. The conicosteroi(!;; cumlllty used in inhaled formnl31il>n~ are all n:1:lthel)' potenilopkaJ conico~tcroids Ihut hal'e Ihe ~dvamage of mpid deactivaTion! inactivation for the portion of Ihe dose Ihat is swallowed . The de"ciopmem of glucocOl1i~oids that are cfliciently inactivated n1el~bolically when ~wa llowed has greally reduced Ihe S)'Slcmic side effects associated with the use of steroids in :tslhmlltn:atrnenl. The older ~'OTIicoo.leroids thal an: u'\ed orally (e.g __ 11lClh)'lprl'dniMllollC. prednisolone. and predni~one) have mueh gn:ater ~yslemic side effecTS. and lheir use should be limited. if possible. Although systemIc ~idc cffccl~ ure ..... 'duced_ lhe)' an: nOI completely elimin31L'd. The side effects can vuI')' \\ ith Ihe sieroid u<ocd and Ihe frequeney of udministmtion. The five glueocon,eoids that an' cUrTcnlly upprol'cd for use in the United Simes for asthma as inhaled formulUlions an: beclomethasone dipropionale. bude~nidc. fluni_olide. n uticu>OlIC propionate. llild lriamcinolone acelOnidc (Fig. 23-32). Mometasone fur(Jatc wiJl likely be added soon f(.lr an a<lhma indication. Ciclesomde i~ the newest glutoconiooid being put:<ucd for usc ;nthe lreatmenl (.If u~thma. Cici~sonide is in pha.-.e HI clinkal trial, and may be available in the United SIHlcS within a few years. Clinical trial, suggest that it !\lay have beller tolcrubilily Ihan ~)me of the cum:ntly uvui lable inhaled steroids. The following ngcnt~ ~rc al.;o available in nasal inhalers for the treJlmem of allergic rll initis. Details are provided below for the mode of metabolic inaclivJlioll involved for tach of these products. Allhoogh all of Iheo;e agents ha~e much lower sy~temic effects than the oral "teroids. o\orlle syslemic effe.::t_. liS mea-,ured by ~uppression of the hypothalamic - pituitary - adrenal {HI' A} axi$. h:l\'(, been observed for thc>c produclS.
GLUCOCORTICOIDS fOR ASTHMA A ND ALLE RGIC RHI NITIS

Beclomethasone Dipropiona te. Scciomelhasone dipropionme (Beclovenl. Becollnsc:. Vanceril. Va:ncena.'IC) (SO l') is rapidly c{)Ilvcncd in the lungs 10 1K-clu1Tletha!iOf1C

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figure 2)- 32 GIIKOC:ortlCOIds u:!.ed to treat asthmil and allergIC rh'rlItiS (SOI'l'l(' 17'lTK)f1()pmpionate ( 17 -8M P), the meTabolite that pro~ide5 the bull of the anti-innllmmatory acti ~it)'. The JlIonopmpionate also ha.!; higher affinit), for lhe G R than either the IIipropionate or beelomethasone. The portion of BDP that is swallowed is rapidl)' h)'dml)'l-W 10 17-8MI', 21 -BMP (which arises b)' I transesterification reactioo from 17. BMP). and beclomc:thasone itself. 'OJ Ikclomettwone has much l e.~s ~ lllroconiCQid lICIivi ty than the monopropionate.'''' Budesooidc (Pul mioon Turbl.lhaier, Rhi nocon) i5 eJltensi~ely metabolit-w in the liver, with 8j to 9Y~, of the orally absorbed drug mc:tmboli7-w by the firs!pas! effect. The major meuobolites ure 6,8-h)'droll)''''ode~ ide ami 16(r-h),drox),predniM)lone , both with less than 1% of the 3t"li ~i t)' of tnc parcm compound. Metabolism involves lhe C YP JA4 en1.)'mc:, so ~"Wdmjnistr.llion of bI."'esooide with a known CYP JA4 inhibitor should be monitored caltfull ),.

ale also used topically)

8udesonide.

humans is the 17~carbollylate deri~athe. As e... pt'(kd.1 charged carbox ylate in ph",e of the nomlalllCelol fUflCtiauJ. il)' III Cl7 gn:at l)' rt"dllC"Cs affini t), for the glue'OfIiroid Ir'cc:ptor (2.000- fold less than the part"nI). and this mttabclnl is esse ntilllly Inactj~e. The metaboli te is formed via the cyp JA4 syste m, i\Qcareshoold be taken ifnul k!lSOl1C ~ is COildminislered with a C YP JA4 inhibitor sucll as L~ namle or ritona~ir. C hn icall)' induced C ushing's syndromr has been observed when inhaled nuticaS(ll1c propiON~lI. admi nisle~ COIlCUrTCTll ly with ritona~ir.t O' Fluticasonc is also a'ailable in an inhaled f()flJlubtioi in combination with tnc long-acting .8.z-agoniSl salmewol (Advair Did.us). Mometasonc fUmlle (Natnex) undergoes eX len~i~e metabolism to multipk metab\). litcs. No major mc:'Iabollte!l arc: delectable in human pi .... after oral adminiSlnllion, but the 6,B-hydrox)" metabolite. tlcteclabte by use o f human liver II1krosoolt'S. Thi s metabolile is formed ~ia the CYP JA4 pathwa),.

Mometasone Furoate.

Fluniso/ide. The portion of a nunisolide (Aero Bid. Nasurel) do!iC\ that is swallowed is rapidl y con~ened to the 6~ h)'drox)' metabolite after first -pasli metabolism in the li ~cr. The 6,B-hydrollY mttabolilc: is approximately as acti~e as hydrocortisonc itse lf. bullnc small amount produc:cd usuall y hIlS limited systemic e ffeclS. Water-wluble coojugate5 are inaclhe. F/uticasone Propionate. The main me tabolile of nUT; casonc: propionate ( Flo~enl, Flonase) found in circulation in

Triamcin%neAcetonide. The three m3in met""'t of triamcinolone acetonide (Azmacor1, Nll.l\OCort) are 6(1-111 droll)'Triamcinoiooe acc:tonide . 2 i .carboxytriamculOkae acetooide, and 6,B-h)"dro~y-2I-carbo~yuillJllcino1on nide. All are much Ie.~s acthe than thc parent COInp: t The: 6~hydroxyi group and the 2 1-clUbo_)' group Iff bI:" 5truc:tural featuru that greatl), reduce ,Iuooconicotd Ida. The incrc:a:;cd waler solubility of these mc:Ulbolitc:$ abo fa. iUlleS more rapid u cretion.

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Acknowledgment
I '/o'OUld like 10 thank Debra PclCrs for assistance with she

illU'lnniOl1 of ~yellll li gures. I would al so lil.e 1 e~ pfcss 0 .,y a]lpliluion 10 Ihe aUl hor.; or various review lItIiclcs on Ibr sieroids. Withoul lhe dedication and han! work o r lOe.'\e _viduals. lhe tiSC mbly or this chapter would have been I much TTlOR: challengi ng llosk.

3S, 1t<l<.,1>,. P. C., Female .... Iumonu and ..,..." In w <>IfT. M (ed:). Bu' ..... ' Mlicln.1 Chrmiotry ..... DruB Di"'<wery. 5,h ..t Ne ... Yorl . .IoIIn wi ~'" S<.onl. ",I 4 1\1\16. pp. 553-587. 16, IIkh. II. L . floch. L it. It. F:. <I aI .' Pnx NOli AcwJ Sd U: S. A 99 ~ ..1U67. 2002. 37. Mon",. C. It Endocn... Ploy........,.. Ne_ York, (hftJrd V.. ,"",,>,
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Moub. Plj ....lI.

74 W)"I' , K . Di"""'J<~. P.. .I0Il<" P.....1 1 MN , /. JHn1>-711O. 12. 21.1 1 13, IInw. M II eu.r Med R... Opnl:95-'IlI. I"'~ 76. Gmlilc. 0 lot.. .........., ... C it . SIwtMda. T,""" 8.d... 0 J J - - - . . .. EoI' T1:oor. 21I7,qfS-1iIIl. 1995 n. K~"",. W. f nru ....... . K. U . 1...... fbr:""I. C.. II2d Knot ..... moe""'. R C"" lrJo."tpuoi\ 'U} I 1.\'1. 1m. 78. Zlunl. I l.<indtcr:. S G . Zhu. V ... II SI...""" M A\1-1>-\ I. :!OlIO 79. o,mu .... c.. Tho PoI" .... .,..C~_. Now y,d. W W Nun, ...

12 1 SinJl:. S M . ~"th ..... S.. and 1.LLI>n<. F: C,,", Mcl. Cka 2112H.lOOO III Mult;ujte. A .. Ku1<)1'<i.y. L . Yoo. 11: T .... II Xnoot., .. 117 12l. 1996. i H I... 11:. Chtto. C. 5' ...... S. M . <1.1 S!croodo &:U-U1. 1"-' 124 J,L1. V and ra.n:n.. T, M De.! rr.tt. RD. a,.. f..!ldo<.--L.\bIo 1~:7<J~. 2001 I~, liarTi ... G S.and Ko,..,h. I . W Con Dp<n. Cho:m K"" 1;!S4 ~
I lli. 8uIL H (i. o.-r...c.hu. \ 1 It.............. 5_ .. aI J "'"-~. . So..- 118lll9- !16.'I. 1\296, 121. S:ecn. w. D.: Ur""'t)' SS, 11-N. ZOOI . Ll:scu<""" 14 128 Go t bcr.G.S~J U,,~, 16J: 1401114 12.2tm 1!9 Sl.....u .... M_ II2d Goninn. It. I) I ~ ........ 0...,.,..., Mol 11 215-229. 200' UO 1'I:sct. 1.1 . D<1bu, .. J ~L MIl S'f'P<II. W (i . IknLo. Roo SI ~IIM.. II2d [)r.lOOpwto.\'. M J lWi.., bdo"" nouI M.. ot: 14(S..,p !I) DOl_ I !OIl!;"'........... Ilil. Ul. Scl:immer. 8 P. - ' Part.er. K. ' Ado ... ,,""'....... utJ ___ ,,,,,,1 ..aenlOd> and me. ')2Ilt:..." INIop; "'" I _, '" ') "'''''m onol ... "1""", <If 00dR-..... ..,..iC.l "',.",.",..,. In I~ J G. UId /.i ,nb,r.!. I_ ~. ltd.. ). (iood nwo ... Gi l""",', "Tho """" "" 1 / 8a,.. ofTh<np: .."" ... ,ut L I ~ cd. N", Vorl:. M<"<lrn IILIl PI" 1679- 1114 Ill.

""

,."

110 1.alnLm". O. Icd.): C~ ThoCboLllLCll C_rel.,.. Fen,ILly 1'1..... , ...... M""",I DoH.... 1%9 81. M....... LV . St, ...1 Cht,n,,"l' r..." 1I~ ... n. V.:. "ni'."'ly Pr ....
C. Awll 0 Tho Pill

""

,."

Nni

,'on.. It-.tom H<lu.....

I~.

_ Ii.

'''' Dac,,.. Vou'etal.J . C. M.",..,Chm,"'"

IIJ Cho<oor. I~ \\ omIiIu(V.I<l<. M....... ~ "~,, VorI:.s,,,,,,,,.t Scbu_. 1\291.

84

M .~.pnce.A

W.<I.I Am. I Ph)"001 119312.1937.

85. Sel) It. T",,"". V.. """ 5/ano. S 1'n1 ,I, Sltnl. 22:7J' - 7010. I'" 1. fI6. l>n""",y. r~ W Am J /'hyLiLOl t:!O;'l1(,. 1937.
117. KILi"InJI... R_ J. COIL"""'", 1.21. 19}1.

~~:::; A . T.,.,.... Ie .....

SaMon, 1 B_hem. pt. """'" "-.

1..c:l, K.no. T .

" v. I..ooUoonl.

M Stl--&SO. 2002.
F.

\'199 16Orl. 2001

s-. e.

An.lri .. F . Cdl Mol. "'f~ Sci .

.v.

'"
" 2.

1! Koo ... M .lAd Chant. L . J ~:..Jriool. 169 0147-431. 200 1 !II S~ I!.M J Endo."1U"~ 16942'} _ 4 _\~.lOOI.

14.l. loU

O1I)( a.-..... K~ V_~w ...... H..,..man.G I _ 109- 16--21. 2IXJ)

N~"''''

0.;' _ .. 1 C ' AnA. N ' " And Sci %6.19-41. 200.2. ...... T K . Soorsa. A R-. C.... ipn. C L ond l.. T It

c.....

1.15.

........,. " ........ Rep

2:l .u~ I~.

2OOl.

G P J 1644J7_445. ~l_ GoleY&. KIJlCh. II: O . _ l.c.o .... 0 ' J ImmuIOOI 169~J.I _~. lOO!. Ileaneboid. J D. 0IIII Dor-. R A Art'll. 0.", MOl . I!a. 290: 41 3..... 19.19911 Foo. K.. C1IcuI\l. II T . TlIwn, II N.... ,,' l>nJ, Me'''' 0."1"". 26:131- U 7. IWS D1 ..}.V...... P T Price. A C. Si ..... , I R ." II H, J Chn I'IwmIotoI 5 I 400-4()11, 200 ' CIe-..e,obc,p. P . (''"'''''"I'', M_. o.....a. I).... al. J I.rca. +l 1~ 1 9:i. 2002

a.

_~ .

Endn.""..,..

24

Prostaglandins, Leukotrienes, and Other Eicosanoids

THOMAS J. HOlMES, JR.
The pros1lIglandins (PGA through PGJ ) are one group of nalUl1llly ocrurring 2O<arbon (pu y acid deriv81mes pr0duced by the o~idnli>'e metabolism o f 5,8.11.14+eicos:lle lrac: noic acid. also called IlfIll'hilllmic IId ri. Dl he r so-ca lled ekosaooids producl'ti in the complex biologk:al oxidation .-.cherne called lhe ItIW:hidonk acid cascade (Figs. 24-13nd 24-2) an: thromlxu.ane Al (TXA1). the leukotricrltS (LKTs A 1 F). and the highly potent anmhrombotlc agent p!USta0 eyelin (PC h). The naming and the numbering of IIie5e 20carbon acids are i ocluded in Figures 24-1 to 24-3. Ahhough eicosanoid-derh'ed agents in current human cJ inicallhcropy an: few. !he promise of future CQnuibutiollj from this an:a IS pn:sumc:d 10 be ~'ery great. This promise stems from the
chatactmlallon of the COleoQnOld ubsumeC'$ but also.m ~ fim to realize the: prufound signirlC'oInce of the andttdooie acid cascade in disea..e procC'S.ws. particularly .nfu/Qmat ion. These individ ua ls firlt pro,'cd that the mechanlw o f the anti-inna"' nllttOl)' action o f aspirin aoo related DOmItroidal anti-in n 1l/llmatory drugs (NSA JDs) ..... u d.i~y~ to their inhibitory dTC'Ct 011 prtI\Iaglandin formation. It_ sho..... n substquently tnatthe analgesIC and anllp)'Ttllc rffllo o f thesr: NSAI Os. as we ll a~ their prou lci:rnm C' and anticolJulunt side cffect~. also rew h frolll their effect 011 ekOliaOOid metabolism (e.g .. mhibition of cyclooxygenases I and ~ ICOX-1 and COX2J). Many boob hnve been published descnbing die' 10k 01 eicosano.d~ in the inflammatory process. the immu/l(' J)~ tcm. curci nogC'lItSis. the cardiovascular ~y'tem, repnxluctllr proces'>C'5, gastnc ulceration. and the centml nel"\'ou~ 5)SItttI (Ke Selected Reading). An Ilnnua! update of rtwarth resuIb in this area has been pubhshed Silla' 1975.A.llraMc j"p"" wgland;'u. ThrombQ,UlMS. uml iLl/twineIII' NeJt'arrl Rtcent research fi ndings in thts area may appear In I ,~ of biochemical and clinic"l jou rnals but un: tile prim3l)' ron cern of t.... o specific joumals: I'roS!ORlullllhu tmd Othtr Upid Ml'diatQrs and ProsfllRlundms. iLulolfieMs, and (, sen/jill FOllv Adtb.

fOCI Ihal intermediates of 1U1IC1l!(lonic acid metabolism play un cSliC nli al modu latory role ill many lIon 11ol and dica'>ere lated cc llui llf proccs.ses. In fllCt. muc h of the pai n, fever, ~ ....c l1ing, na usca, and vomi ting u~sociatoo wi th "Illness:' m g<'1K'f"lI1. ~y l"CSu lls from excessivc prostaglandm production in damaged tiSllllCS,

HISTORY OF DISCOVERY
Early in the past century( 193 I), Kurnol; and Lieb lIOted that human scrn inlll n uid could increasc or dccrea'ie spomo neous muscle cont!lll;tions o f utenne ti\~ue under conlltll1ed conditions,' Th is observed cffe<:t on uterine musculature was be, hel'ed to be induced by nn acidiC ,'asoacti'"e substancC' rOl li it'd in the prostate gland, .... hich was Imer ( 1936) temied l,rmwg/rmJ,'" by von EUler.l Much later (19SOs), it was found thnt the: acidic e~ l r.ICt comlliflotd not one but several ~tructurally n: luu:d prostaglandin ~ubsta nces.llllese materi als subsequently wcore sepamted. purified. lind eharacteri1.oo a~ the prostngJaodins(PG A throogh PGJ). "arying some .... hat in degree of oxygenation and dehydrogenation and markedly in bioiogical llCllvi ty [fab le 24-1). Speci rlC stcn:ochemieal ~ymheses of the prostagl:.mdi os provided access 1 suffic ie nt 0 purified matenal for wide-sca le biologi"al evaiulltion and eoro firnied the structural chantcteriution o f these complex 4 subslnnces. Allhough many Kient islS hUH: eorotributed to refilled characterizat ion of the eicusanoid biosyn thet ic pat hways and the biologica l consequences of this casc ade. the diseerning and pcr.;.istcnt pioneering effoos of Suoe lkrgstrorn. Ek'ngt $amuellson, and John R. Vane were m:ogni/.ed by the award or a shared Nobel Pril~ in MedICine in 1982. 1lIesc scltnt ists IIOt oo lydedicatC'd thtmsell'eJi to the ehtmical and biological

EICOSANOID BIOSYNTHESIS
Prostaglandms and other elCO'OaoolCls are rrodUttd b) Ibr olodati\"e metabolism offree amchidontc acid. Undc:roorwuJ circu mstatlCes. arachidonic acid is not a~ai lable melD lism as it is pre.\C nt !l.<; a coI,juguled t'Omponcm OftM phoIpholipid matril of most cell ular membrane" Rdeasc: ofllff arochidonic acid. which 5ubstquently may be OXldltll mc:taboli1.ed, occur.;. by stimulation of pho\phoh~ IPlA C'nl.yme ac1tvity in response to some trolumatlt CI'C1l! If.,. tissue damage. toxin C'xpo!iure. or hormonal Sllmulanon~ ~ is be lieved that the cli nical antiin flammatory C'ff<'Ct of &htcoconical steroids (i.e .. hydroconisone) i ~ due: to their ahilt to SUpprtiS PLA: actJI'liy I'la hpoconins and thus prt'oUil the rr:!nse of f~ arachidollle acid.' MocJu1;mQn of PU. activity by al ~ ali me tal ion., tOXinS. and vanous t her.lpelll~ agents has become a major focus of biological rtSC'arth tit~ause of the changes in eiCO!>linoid prodUCllon and the drr matic biolo"eal coff<:'C1S acxompany ing PLA l Mimulaliolt II suppression. Although iniually Ii ....-as bellt,'ed that ihL'. n amm8tory mponsc: (swelling. red~, pilm) InS pnkl'

ror

.,8

"

!1

.
,

~.'.~~c._

Cydoo<ygio

77

" OH
o
-"'/~COOH -"'~"~ COOH
OH
<'00,

Figure 24- 1 Cydool()'9l'lld'ie pathway

pall)' due \0 I'CE:. rec~nl inlem;1 has focused on !he interrelaIionships of PGE-type ei~fIOids with PG ll and C)'lo!Jnes, such as imerlculi n- l 3nd imcrleukin-2. in the modul:, oon of inflammatory rrllClions.~ Two different rool('S for o~ygenalion of arachidonic acid taa'e been fined: the cycloo.ygenase path.....y (fig. 24.I) and the 1ipo~ygenase pathway ( Fig. 24-2). The rdalin: r..gnificance or each ofthesc pathway~ l1I~y vary in DpanicuIJ/' tissue or discflsc ~lale. The cyclooxygcnase pathway. so r.llIled because of.he unu sual bicyclic cndopcro~ide (PGG u produced in the first step of the SCtjuence, in' 01"1'5 lhe highly iklt'.()j;pccific additioo of two molecu~ of oxygen \0 the IrlIChidonic acid SUbSlralc. followed by subsequent en/yme-

controLled reammgcmenls 10 produce an 8rrJY of oxygenated

clc~3nold~

with di,crse biologicaloclivilies ( ~Table 24I), The fiN cn~.yme in this p:lthway. I'GII synth ase, is II

llemoprolcin that CatalYles both tile addition of oxygen (to form PG(j~) lind IIIe subscquem n:duclion (peroXMtase acll' il)') of the ' !i-posilion hldroperoJlide 1 the 1S-(S}oJnfigu0 rnlion alcohol (I'G H,). I'G II ~) nthllsc (al<iO called cydo o:ryg"n<Ut<:-1 /COXII or rydow:yg",ul)'t'2 {COX-ll. lind f()l1llerl), I'G J)"Il(/rtUJst) hll~ bcC'n tile focus of intense in\,(lo_ ligalion bttuusc of liS ~el rule lIS tile 1i ....1 en/)'mc in IIIe arachidonic acid casco. It l~ this enzyme In conSlitull'c (COX- I) 01" Inducible (COX-2) form thaI lS susccplible to inhibi,ioo by NSAlDs, lead ing to n:lief of pain. fever. and

o.-j

r,H(lE

HOH
I' 5

HeH

.... ,_.0..-.,. . )
H H

C. lIC,1

I;;'"
HeH

'-'
,."' .... F,IL-IF,)
, ..,' tl,I.fD,J

Figure 24- 2 lJpoxygeonase pdlhway

innallllll:l lion.6. ~ Thb enzyme is nlso inhibited by Ihe .... 1 (Of1~gaJ) fany !ll; i(\s (ei('()Sap<'lItaenoic acid IEPA! all(!
doc'os:Ihc~acooic fi~h

body temperature. ce ntral and peripheral pain rchef.1lIId o.\!. crt':ll.ed vascular pcrlu~ion) ba.o;cd on their tiSSUI"" d i , .

acid IDHA I) found in ccruun oold .... atcr

lions.
The llpoxygenase pathway of arnchidonoc:: .cid lit( ...... li5m (Fig. 24.. 2) prodUl""t""s a vanety of lIC)'clic lipid pcrouh ( llydrosxro~ yekoslllc tr-~cnoi c acids [H r ETE., IJ lU1d l.!rml'll alcohols (hydro~ycK."osmetroenoic acids 11IElTh;[).'1 Although the: spcclrIe biological function of each oflhcse 11"'\' ygcn;l$C':-dc-ri\'ed products is not rompll'tely I.:. oown. tIIC)" .. believed 10 play u mnjor role a.~ chemotachc fllCtOl1I1i111 promote ccll ular mobilizm ioll toward sitl'~ of tlSSIlC InJIII')" III addition. the gllltath i()IIC (GSH) conjugatcs LKT JtIId LKTD. arc jXMent. long-acting broncOOoon'itri<:t<n iNlM rt'lcascd III the lungs dllrillg :iC\'cn: hYPCIXIISIII\ il)' epoo.k. (leOO ll1g to thdr innial deslgnatiun as tJoe:: "slo",-n:artuIf; substan(:CS of anapllylaltis [SRSAsl). B~auo;e of tIIC PI'"" '\tuned benefit of pre\'cn"ng foonation ofLKTs In p;lllefIlS. much research cITon 15 bemg dedicated \0 the til sign and di~\'r-ry of drug.'! tl\U\ might sdCClil el) tnhtbI the ltpoxygenasc pad\way of aruchidonic ocid meuboiNl without affecling lhe cycloo~ygcnasc pathway.... lin. (Zyflo by Abbot;l Laboratone!i ) ~pccifically Inhibtb IIiC ipoxygcnase pathway. 11 has ber-n ~ that 1lSpI1\lI1ty. pcN'n~ilivity 111 ~ll\Ccptible indi vidllals may result from cf. f~l i~cly "~hulli ng down"" lhe cyc loox ygl'nase 11lCUIbtJii,: mute. allowi ng only the biO>ylllJoe::si~ of Ilpol )gCnast pG-

and pro ... ided commercially as nUlrillooal supplemcms. Jeadmg 10 beneficial cardiovacuiar crrecls. lO Thi s enzyme will metabolite 2O-curbon fany acids wilh onc more or Olle less double bond than arnchKlon ic acid. leading 10 prostaglandinS of I'aned degrttS of uns,lIuration {e.g.. I'GE, or PGE}. for I'.hkh lhe ~ubscripl number indica," the flurllber of double bonds in the m()I~'ule)n

II bomeh-point \uhSlrate for !f;jW'Cific clllymes, k:ading 10 the pmdlK"tion of the \'ariou~ proslat:landHl.~. TXA! , 1I,ld PC I:. Even enough most tissues call produce ]'GII: . ,he relative produclion of each of These deri I'cd ekO<;;l noid~ " hi ghly li,sue specific ~l1d may 00 suDjl to secondary modulation by vuriety of cofactors. The completc dWOC"ICmahon of cnlymcs involl'ed In brandieS of the cyci-ooxygcna.'IC palhway I~ currently under .... ay. Spccinc ccUu lar or tis~ue Il'spon\oC..~ to the ckQSanoids IlIlI apparently a fuoclion of available surfa4"C re~:cptor recogni tion ~itOl. 11 The ~'ariel)' of ti..sue rc5ponSCS omcr..ed on eicosanOId CApo!>ure IS Olltllned in Toole 24-1. Noo- hSsue..sclcc th'e mhlbltors of the c)clQ(nyg.:nase pathllay. soch as aspirin. thll~ may c~cn n dher;i ty of therapcullc effects Of side crfec t$ (e.g . dccn:ascd uterine mu'iClc cOIltnll:tion and platelet aggregation. gastric ulcer-.atioo. lOll enng of r-Ir-vatoo

~aglllndjn

''': sc:n'es

a~

-e.

p,~

&'

:'
El'lZ)1l'IatlC Metabolism
Nonenzymatic: OegfadatlOl'l

IH)xlClatrve

PGf,.

",_~;;::::';:::::::i COOH "

lDeg!(KIaIO'I

HO

J -H..o

tC'
"'-.."COOH

R,, _2O
IH.~

o o

N \....l.

R
(UoI.-.)

"

R13-20

Tl'o",.",- "'.
H

H,O

"

OH OH
Pms .. ydo, (PGI.)
&KaIo:PGF ..

figure 24- 3 EocOSoilnood clegrOJdaIJOfl.

TABLE 24-1 Bio l09lal Acti vi ti es Oburved with the Eicosanoids

OlKen/eeI Blologicel Activity
WClIL

,,,,,,\0000I '" pIaI<'ItI ""'...._

"' ... >d&bI"",

InhlNI<>f of hpOly ....

1111"",..". ," pI;Iltkl ~ 8",lChod,bbuoa

SI"",,'" ronor.;1lo)ft ' " ~naI """"'"

nlY"'1o

POE,

Sli""'I~'''' h)' ..... "'I~ ItipOII><

Rtn:aI,~~

aeids and phcoolic anlloudallIs. Imphes !heir AI .. cepublhl)' 10 Influence b)' a "31icly CJlogellOlJ~ly adnums. tered agellis. Ba:aulol;: 11'1OlIt arQInatlC drug IlIOlecuics ulllkflu t>ep;lIic hydroxylation, phenolic Ikri ... al i, e~ of a,hmni~trTd drugs become readily available III vivo. Even mon: direcd). aromatIC ITI()lceulc:s on ;n vi lro ulCubatH:m with mICrosomal PGH synthase will ""-"(M11(' h)dro~yl3ted dutt'lly ~ arnchldonlC !lCid metaooh~m. m Q procco;" labeled c...... ~ ,IfHI." ThL~ coo~idml\'e prtx:es~ Pf'C_umably ()CCUI'S dunlll lhe p!;'ro~ida.-e mnler;l()n of 1 'GG: to PCH!. "hich effc\;. lively mal;es a"ailable a lIOn"fICCifiC oxidlllnil .:qUI'''' llIe COO~ldaUon process has been unplic3ted in the a<:UU, lion of polyc~clic aromatic hydnx:urbons I" rorTl) pro.u_

bo~ylic

"r

carci nogcn~. ~

51.-. . """'.... _~ mu\<:10 (t.IIIInCI_

Pn..,. ,"""",_""I."."",~ (,,,,,, .. '"

K~ _""" '" _"""h ...'"

~],r,..................t.ary

"'V"'"'''''''

... poono I n _

Sum~""'" blul.d<>wn <'If ""'1"" (lu 1."ly",) I n am"'" I.

~-

Iuwulll

I'm.

Su"",11IIe< "","rc ....ooUI m~.d" OOII~ .... _ illlulKo<r '" pIw'" l1l"'I01I0Il
f'cluM

,"""",\;010".

5u"," III&e'> """""... '" Inboblb cell pmI'r.......

TXA ,

" - ,,,,,,,", '''",iI,1e! _ev_

PoIt:m I,.......~ ""'~W 1ow=1, In pi,.,., ....
51,,,,,,. . "''''_ '" AD!' ODII_n (IUIII
~,

'''''''''''''''''0:1",.

LTlh
1.1"(:11>.

I","",.~, .... "'''')It

....

cl .. Udn.. and ..... pt"'"

.s. or Il-HI'Ell!
S (If Il-III'TH

Ski .. "''''''inl "'hll~""" "r ....p")'I.". ~ and proioacoJ cOQlla'''''' of IU''''''' pil ' ................... _10 Cuntra1 .......... P'.......... h)""'1 ""PO 8""",1tooron.t.1<tI.-.. 'a .......... ' Inc~ v_uhl' pom ...... hl)' In .Ul .... pi, >~ln 1."nIOtIICd b) 1'Gb;1 V..w.!.aI"," '" ..... rabbo, .1OIn<: amlblioft

Inlllbol> ,........"... pial....

"'~iol"

"">n.", "<110<)'0 ct.."..,..,,,

nunw. Iou~....,t'"

If"'''''''''

llIe only group of drug, Ilmt has been thorou,hlydln; teril.m for ilS effect on arachidonic acid meuloolism IS dx NSAIDlo. Thl~ larb~ group x ldic. aromatIC moIuk'<.CI ens a dlvet'liC speclrunl of aclivilic_ (mennont:t.I abo;'c) by mhihition of lhe Ii""t en7yme in tile arnchidonic acid ca.<ndt. PCII ~)nthase (also called COX- I and COX-2 ). Such age ... ao;, sall cyl".. acid. phcnylbulv.one. n:tproxen. ~uJi~ . .Ibuprofen prc:sumably ItCt by a compctili, e. rio" cr~lblt inluttition uf ornchidunk ocid uxygenutiun . \1 Aspirin and catllII haJogcnatct.l arom;atic, (including indQmelhacin. flurbipr& fen. and Mecll)f1'tCn) appear tu inhibit I'GH ~ynthll.f:o ill li me-dependent. Ine'Cl"Oible manner." Since Ihls Intlmt< ble inh ibition :tppe:tr; cntical for a\pirin' s sigmfic;rnc dfctt 011 plalC let a~regation and. tJlI'rdon.'. prolollgatnm ofblmling t;nw:, I ~ thil> disc",'cry ha... led clinician. I" f'ttOIlI!IleId lhe daily ron'<umpllon low dust, of asplnn (81111() '" p:ttit'nt~ PI nsl;. roc 1Il)'oc;anlial inrllfCtion (MJ. hean IIIAi.l panicul:trly a o;('C"nd M1. Inlere:;1 iug ly. a,pin n' s primary rolllpctilOt III the COIIl(JI(f' cial analscsic martclplace. accunllnophen. I' a rdthcT~' Inhibl loc "f ar.IChidolllC ;acid OX) gt'u3tion In 'itro.: Thb. fact. is a cliar.)(.'tcnstIC of rc'e .....,ble. IIOrICQI11p!;'tlt,ve. ~ lie ant ioXidant inhibitOr< In gencrnl. 21 Thi~ dctennlil3llo. in cOllCen wi lb its locI;. of in vitro antintfiantnUltOf) a<:Ulti) (while maint:tmmg analgesic and UUllp)retic k111'lly ~I. lenl I" Ihal of the salicy l:t.tes) has led to lhe ~ acetami nophen is nKIrC: active as an inhibitor of q'tioo.y genDsc~ in I he bruin... here pt.-roxidc I,,cls t whicli slIlIlIJlA C)'cloo~ygen:tSC 3oI;11\'IIy) are IO"'er than in mfl~nlal ptri~ eru) joint~ . .. hCTe lipid pero~tdc Ic:\'els an: hIgh. It In &rt. when in I liro CApennw:ntal condul()ns IU'C modified 10 n!duo.y thc so-called pcn:uide tont:. IICctmnllluphen becomes 1fi d. fe<.1he as ',piri n in r~'tlucing at'lloChioonic ocid mctabobun,

"r

"r

" 'ay

lntemlCdmtes,

including

tnc

bronchoconstncl ile

COX-2 INHIBITORS
The newer anti-inflamlnal()l')' COX -2 InhIbitOr< (t .! .. ctIf. roxib, rofeco.\ ib, and \'aldoxlh) are clalnlCd 10 greater mhlbito?; o;ciectivity for lhe IndUCible form ~ cydoo~ygcn ase. 1 Although nO( Ith.\Olutc. thiS .... lUla! pro~ides a potential themp.wtlC advantage by rtdocing effects. ""nicularly ,a.~lric imtaltoo and ulcerllhon.:l tunatdy. this altcred profile of IICII\ uy is not tOl:ally ri.~ fltt 111c manufacturer of rofecoxib ( Vio~x) Ii~ ~..enll)' (AjnI 2002) issued a warning regardin, IIIe u<;e of Ihi~ product_ paltents with a metlical hL'>t()l')' "r ischemic hean dt%

LKT~.I '

DRUG ACTION MEDIATED BY EICOSANOIDS

llIe ubiquuOIls nature "f the elCos:ItlOld-produdng cnlynlC:'l implie. lileir significance in II vnriCly of c ...<cntial cell ular proces!>CS. Additiorndly, the o;en~ili'ily of tlle.o;e en7ymc.~ to >lructurully ~aried hydropOObic materials. panicularty cu-

. w

COX-2 inhibj(~ do no! 5h.J.re the bendicial dreels of aspinn In pn:\enung canho"lIsculat Ibrombollc e\enl~ .

"'Ith their lim ited di~tribulion from thi, s ile of oonnnhlmlIon.lot

I g

DESIGN OF EICOSANOID DRUGS

capilalil.c succe~~ full y Oil the highly polen! biological effecbl o f tN: ~Ilrious eicosaooids to de\ dop IlC'W Iberapc:UIIC agents currellll )' seems an unfulfilkd promise to IIII:dIClnal chcmlq~. Although these n.:lIUrdJ substances an: bithly potent cffcclOfli of ... anous biological fUACliOllS, their use as drugs ha.s oc'('u hampered by scveral raclHrs: (Il) their dlemicaJ oomple.~ily and relath'c Instabihty ... hicb ha ve ~mlled. IQ some uteol, their largt-<;eale production and forlIIulation for eli nical testing: (b) their ~usa:plibiJily to rapid "ldahon (Fig. 2-1.--3) ...... hieh limits their effective b looc-

The ability

DEVELOPMENT OF PROSTACYClIN DERIVED PRODUCTS

10

"

n.e OII!OlI1g dc:,c lopment of potent.

half-hfe: and (e) their abili ty Iu affect divcl1!e li~sll&:s Ipmticul3rly the ga",romlesuMI tract. "'hieh rn.ay lead 1 0 S\'\'m Musca and \om lll11 g) if the)' enler the "ystcnllc dn:ul.1Iion. e,"cn in ) Illal l a nlQtJnts. Caution is alway recOIll' n:ndi!d wuh the uSC: of ~Lagl:mdm analogues in femalcs ri duldhearing Il!;C because of their potential for Induc ini IImnacic rontmcCioo of utenlle llIuscles. possibly leading 10
IIIIKamage_

b~

Sevcrul approoclles howe been used to O'CI"COIlIC tOC!le dimeuillell. Fin;t. 5U\lClll131 analogue!> of particular eicosa1'IOId!. have been ,yn the~il-w tho! are lIIore rc:'I~!1l1ll !U chemi cal and metabolic dc:gradatooo but rnamlain.!oa largccxtem. deslrable b iological3CUvily. Although comnlCrcial producbOIl and formulati on may bc faci li!m ~-d by this approach. biologICal potency of thefoC analogue~ is USU.3l1y reduced by Ie'(fal omers of llIagm!udc:. A 1..0. sy~tcmic side effl"t:ls llIay become troublesome because of broaOer ti~uc dIstribution IJ I resu h of the l~ased biologkal half-lifc. Strucluml alterations of the cicosanoids have bc:cn aimed pnmarily lit rc:ducing or elimmanng the ,cl)' rapid nlCtaboh.ml of these potent sub~t:mces to relull,ely inaeti ve mctaboIItt$ (S Fig. 24.)). Sc\"C"rol analogues are pre"Cnted in T ablc ~~-2 to Iltu,trnte apptOaChe5that ha,e led to poIcmiolty uscful eicosanoid drugs. M cthyJatlO/i U1 the IS or 16 positio n Will dim inatc or reduce oxidalloo of the: essc nllal 15-(S) drohoI mOIety. Estcrification oftlle c:ubo~yhc acid function lIIIIy illTecI formulation or absorption chataeteristic!: o f the: nrosanoid. when:'as estc:rusc enzyme.~ III tile bloodstream or urnteS would be e~pled to rc:gcncl3te the act i~e the rapeu tic 11m! q uic kly. Some~hat ,urprislI1gly. considc:nng the: rrstnctil'e configul3l1ooal rc:quln::nK'nlS at the naturally .)'mmc:tric centen;o II ,aricly o f hydrophobic subStn\lt'nlS lilK:luding phenyl rings) may replace the satUntlL'If alky l cbams. wllh retenllon of hio.'lCli ~ ily, A second major approach haJ bcc:n amK'd iiI dd,,"cring the dcsilttl agent. either D natuml e lOO5allOld or a modified analogue:. 10 Ii locali1-w site of IICtion by I cootrol1ed dc:livery 1IItlbod. 1'Ix: exact method of delh cl)' may vary OC('()I1iml! 10 tile desired sile of :tC1ion (e.g .. utero,. stomach. lung) but ~ included aerosols and locilly applied SUpp06itury. gel rormulahon~. or cyclodc:~ 'rin complucs. l1le I\."t:em commercial devclopment of I'GF-type dc:rivutive.~ for usc in the: ~ 10 lower intraocular pressure (lOP) in Glaucoma (dISt\J~ below under the heading. ProstaGlandins for Ophthal IIIic Use) re lies on their poIentlhernpeulic effects COtJplc:d

effccl,,e. and longacting form s of naturall y oecum ng 1 'G12 i~ Iil1 e)(cellenl iIIu~ tration of stralegles thaI capitaliu on the belK'ficial but !ohon hVed biological effects of eicrn,oooi d dc:ri"Dti ves. pc; II it"Clf i~ cUMntly mar"eted a.~ the M)diurn !\lilt (cpoprostc:nol; Holan by GlaxoSmithKhrIC) for COOtUHIOUS inll1ll\enotb in fu sion in pallenl5 ~ufferi ng from prim :U')' pulmonary hype11cnsion (PPH). llle solullon for IIlfUSIon IS prepared wlthll1 48 houl'5 of expected u.r.e bec au.sc of;1S 11I1111ed chenuca l stability. The poIent , asod ilatory . platelet Ill1liaggregatory eflect and vascular smoot h muscle ami prohfernti'e cffect of this nutura ll y ocC'umng eiCOSlillOld produce II dramallc but shoft lived (half life less Ihwl6 minutes) lher peutic c:ffCC1 III PPII .. patients. Conunuous. ummcmJptc:d adl1llm~! r~tlotl of the dl\ig by portable infuSIOil pump i~ nc:cessary. ho ....e'cr. to prevent ~Ylllptor!lS o f rebound pulmonary h)pent:1lsion. To I:rl.~ure proger U."C of 1I11~ the mpy. it.~ di<!ri bulion is rebmdy restricted.

HO

HO

Thrc:e morc~labk dc:rivati,'cs of !'GIl nre belllg developed to extend the dUT'lllion of acllOll of this drug 10 ImprQ'e Ihe safety and con~<'l1i cl1Ce of PPII tbt:rupy and. perh~ps. broodc:n the thempeuuc ind lCatioos for iL Uj;C. Treprosuml ~ (Remodulln) wilh nn e\tcnded hlf-life ha ~ been de,eloped for l'QIIlinuous subcutlillC'OUS Injc:aion for I'Pll pallelllS. Th i\

j0'---,"

"

HO

HO

, ....u: 24-2
c.ndidat.s

Prostaglandin Analogue s under Investigation as Re ce ptor ligands li nd Future Drug

~\

""

/ \, ,,,

",

~COOCH~

,"-

"" ;;.,
~V
BW24SC:
R ~ II

"'~
BWA 866C: A

~Hl-{

R'.HN~

0\
CO<><

""
' .......
IP. ....:qIIOr hpnd

, ;--",'

He

""

""
o
,

, ....._"'~COOCH3 ce,

"" ,, ,

He

,",=,Av ~' co<><

He f ,

S14S

11'-ro.'Cf'WI'ligmJ

Chwpltr 24 1'",slOg//II"/"u. '~~>frlt~s. and OIMf Eict>ulnoNls

82S

TABLE 24-2-ConrlOUt'd

,-''''I=If'\/"'. COOH

Tf'~ue,*"

bpnd

"
""

Sulprootooe (GIof,1 B...... Dati S...i'.....

1lI' ,"",POur IIR1ZI<l

o.yw~.;

N -~-~

~""""""''''... l

""
U-4ti619
TP .0."""" 1.,..,.;1

HO
method of admimstration all(! lonb>ef half. hfe woold m;u1.;edIy I1Upn')\C rhe convcn~ and s.afety of "prost6Cyciin" t/Imlpy III PPH palien!$. Localized imcnniucnl ~ubculane OIlS admlnlSlrntion of Uniprosl is proposoed for the treatme nt of cnliclll limb ischemIa. Aoocher stable deTi valivc: ofPGI!. iloprost, i~ intclXkd for nasal inhalation 10 provide a direct vasudilalor)' effect on PJlmonary blood vessels and thus dec~ase vllscull1r resi~ \a1K,:e. CUrTcnll), available in Europe. p<llienlS inhale 6 to 8 purr~ of aerosohl.cd iloprosl evcl)' 2 \0 3 hours. Side cffcrls soch as coughing, tw.:adaches. and jaw pain ha~c been re-

0 -

"

~ ,,
"

-, ;,
C",

.""d.

""

""

EICOSANOID RECEPTORS
Aoother approoch \0 developing JlCW therapies ba.~ OIl the known biological activities orthe prosmglaooms !tnd Icukotricnes requires characlenlarion of the nalumlly oceuning tissue r"CI.:Cplors for theM: agents. A thorough knQIOik'dge of the ti~sue distribution (loca lization) of such receplOfS and their biooing charuclcristics " 'ou ld allow the design of receptor-s~ific agonists Of anrll.goni~ts that might IlOI possess the same limitations as the natural eicosaooids bot cou ld affect tissue function nonetheless. An exC('lknl hislOTIClI1 ~riplion of prostanmd receptor isolation and CIlaracIC~ril.:lIion has been published.:!'t and a more rt:Cem review of developments in this rK'1d is a,'ailable. IJ Basically. prosllanoid recepl0f"5 are ldi:mified b) their primary eicosanoid agollist (e .g .. DP. EP. IP. and TP). although subclassification 0( PGE receptors ha.~ been nece.~

C",

""

""

An e\Cn more chemically !tnd biologically Stable dcrivau\e of PGll is bentprost..... hich is being culuated in an oral formulation for the lreaunem of carlystage pulmon~ arlerial h)peT1cnsion lV1 and peripheral Yascular disease. This pI'OSt&Cyciin has been appro"ed for use in Japan oot !lOt yet in the United States.

'\3ry Iq; .. EP, Ep!. EP, and EP~)_ In facl. lhe e.tI,.eoce of sublype< of.he EP , rccepmr (1.:1', .. , EI', ... EP ...... EP 'Il) and TP n:ccplOl" (TP,,_ TPIf) h:a., been proJlO'!ICd. Complete chancI<,ri/.;llioo of r....:eplon (and ~ubt) pe~) locludc's (is~ localil.aUon. bIOlogICal cffec. produced. te rrul:.r slll"al trunsduction nle(!ooni,m. mhlbnor \en"II"ny. protein ~truc1Urc _ and geneh. ongin. Not all rct:c p.ors or \ublypes ba\e been com-

plelely chaTal.1eJllCd in Ih" way, bol significant progress low:.rd this gool h:.s occurrl11 r(:cemly. Table 24-3 indicmes ch.mlcteri~tlcs of.he pn)<;'.JIHlid rt.'CcptOl'll uJ,entifi.-d thus far. Although r<'C<'plor 'tOO ICS ha\ Crequired .he use of nonhu_ man Species (prlllcipally th.c tllOU'C bUI :.1'0 lhe 1111. OOW.
'hL't'p. and rabbit ). a high l:om:lbllOlI of ~tnK1ural oomology of receplOr subtype:.;, betll een spec ie, ( - 8(1 10 9I)q) has been ~f'\'ed. whi le Si ruclullil i1o:K1l(llug} :'lIloog receptOf sub-

I} Pl'\ is relall ' d} 10,," (30 1 SO'l-), All )lfmtanoid 0 oo,,"e'cr. arc belic\'ed belong 10 a "rhodop!;m-I}~" fam.ly of receplors IhaJ. function ,lao G'proICln IfllIIsduction mechanisms. Three gencrnl classes of Old rcccptOl'll arc proposed": (II) cela.unt. 11K'ludlng 01'_ U EP. and II' .... hleb prolllQ(e smoolh muo;cle Il'lu ...... m .,ma; Hllr:w:ell ular cyclic adenosine II (cAMP) levels: (b) contractile. IIlcludmg EP, Fl'. and Tl' .... h,ch promOlc slIloolh muscle cOI1lTllClion ,i:. ClIk:iUlJ1 " mobili/.lll ion: and (r) inhibi)1)I. ~uch as E I' ~ ..... h,ch prt\'~ ~ mOOlh Illu<;c!e cOlllracli on by lowering intrnccl1ularcAMP le\ cls. All hough 51ructural bnd fuocuolI.:ll chnraclffll"'" of )lfmlanOld rec~ p1ocs Ilas pt'mlllled .he i(ienllrK'atlOll" dlff('f{'nhail()Jl of ..cit'Cti\ e receptor ligands (Table 2.... 3, agon .. ts and ama~ol1ls",). o\crl"PPini U'iSUC di5lJl"_

TA8LE 24-3 Receptor

DO'

Pt-ostanoid Rec:eptor Characteristics Principle

I'GD,
8W24SC 8WAMIIC
LI~ndJ

Tlnuel .... ction

lIC'Umfmu ....1r .." ... "'~",

Tr~nJductlon

G_ KnodlO\lI Efft
No!
.~.tI.hlr

t cA \lI'lG<

fmm (lepl<'lft'ltnl..,.e>Y IJcqI illllll<'l1""

'"
EP, h ........1>Ic1

>'G,

Kodne)'lpapolt.y .....

Te."

NoI.,..,l>I>Ic

'"'...... "POF ,; !'GC,

11-pbnI)II'GE,

1_&11>0..........""'""""'"

"""""""'""

_Ie roIIlI'a<loOII
t~AMPIG.
lQo.u,-,",

~Imo.

Bu,""""" fm''''fI''JIIOlJ
POI',.; PGI',

tilm"/impb".:m",,

lFeruI" .......

lOP,

Sull'''''''''''''

G""rocI..,,,...,..,ory G."",*,',Oj"O'OIt<1l".
1I1.rwI1nhibu. """"X'"'"

TNa' hyl'"f1tll>
(P'A

l u.MPIO,

I'yn '8ftl ""'!""'><

101''''1'''''''''
Gc~"'1"l'"

Ent'''''''' I

S,..",If.,'"" rc~
DucI ... ~I.u....

EP,. T cA MPI(l. CP", f oAMPI(l, 0'", TM TcAM PK;"

1:1',

I'GI!,. f'(ih
M ,"""""""

,-"'"

I'IIItnt dIIau.. _ _

K"",")I.1omma1u1

0 ...... l ...............

1IIInIoI"""""'" ....,......
i

'S-~_

.........
T,..",""""

e_,...

""'..,.001
~"".,

E,'u'"

r5 ......".,.,...-...,

lPi ' ...0'''1{;"

LoIoIIWI"'_

C"'P'> "'ounVI.-oIl""
L"~"""""""'_

U_ _

"

, p(jl,

81",",,,p"'"
1 .......iIJt'PI_ "iI
k~ M PIG.

,,"--w_
UItG~I"'Q

e.."....

l lnn.m-.., . .
Tl'~ t.eAMP

""",. TXA, Sol-U

Kidnoy"'/kmM _"""'" (T<;rll; )

faltedt",

Kldnoy/lOFII
A~"1Cln

.,..."

sq.-

Tp. teAMp

Thy"",,,,l , _ r dl)'m<iC)1C'
11~j-,!!to

F""" "......,,) .. s. soo" ...... Y """ I ........... , f ! ...) ... ~ Ik> 1'\1

IWI

.d common <Ignallram;dll("hon n.... -ch:mbms prt''''llt fQrtll1..,.,obsIOIClcs to the: de,clop",enl of <pOCirlC phamJaColog ICaJ ihe!1lp!cs.

Prostaglandin E USP. PGE,. alpro:.tooll (ProsJ.on VR Pedialnc). is a naturally OC'("urring pro;taglandin that lias found partlculur usc on ma,nrainmg If patent (opened) dll("lus ancrio<;us in inrMt. with ~'{)i1gcnital def1:Cts thm restrict pulI1l()nary or "ystcmic blood now.

EKOSANOIDS APPROVED FOR HUMAN filNICAl USE

I'ro$taglandin Fz... PG I;~ ... dllloprost (Prml1n F2 Alpha ). is a natural]) occumng prostaglandin that lias ada;~"~d Inlra-anlluoh cally 10 induce labor or abor1,oo .,tll,n the fir;t trimester.

COOH

""

""

"".::
Th,~

""

product. which WIIS ,upplicd as a solution uf Inc r(mI:tllarnillC sal t (5 mglmL) fot dll\!et adminj'tf"~t jon. j, "~:~~;:~, III the United Slalc< for human uSC: bu, ~ for .. ctcrinal) U!>C as dr..cribcd rlSCllhere

l'GE!. dlll(}J)l'"l)!;ICtIlC (J>ro<;t,n El Ceroldll,. is a natural!) oc.urring prostaglandin thm I ~ :Id IIIInlltered in a .' ingle dose of 20 mg by vaginlll SUppo~lIory III Induce labor or aborlion.

~taglandln E~

COOH

""

Alprost:ldil must Ill: :ldministcrcd lmf"Jvcnoosly continually at a Me of allpro~im~tely 0.1 J.lglkg pcr minute to tcmporarily m<lllll;l ln the patent) of Ihc ductus arteri(f<;us until correcthc :.urj;i:i")' can Ill: performed. Up to 80% of circulating IIlprustadil may Ill: metaboli,ed III II ~ingle pa ll1rotlgll the lungs. l1ecause aprlCa oo:.'\:UI)' III 10 to 12% of neonates Willi congcnital Marl defects. Ihi , product shou ld he admin i,tcn.'tl only lIhen ventilatory a~ .. i,t:mce i~ immediIItely IIlallaNc. Othcr common ly ob""r.cd ~ide effects include decreased arlerial blood prc~~ure (lOo llicll ~00u1d be monitored during infu_ion). inhibued platelel aggregation ( ... hi ch might aggravale blccdmg tendeocie~). and diarrhea. Proshn VR f>cd'3tnc is provided as a sterile solution III a~ IUle alcohol (0.5 m&lmLJ thai must be diluted in <mIme or dc~trose ~Iutioo before: intTa'coou~ oomilllstration. A lipoWIllal prepaf"Jlioo i, 1l\"1lilll.blc (Lipuwmc Coolpany) to C~ tend the biological half_life or,hc acthe pro~tllglandin. l\lpnNlldil (CavcrJt-ct) i~ lIJ'iO avallnble in glns\ vials for reconstitution tu provide 1.0 mL of solul1on containing either 10 or 20 J.lg./IlIL for interl:lI\ernos.aJ pt'llI le injection to dbg n05C or WI ,rtl erecnle dy~ruIICl ion in ccrlain CII;;e~ of impotencc. A un:1hrnl sUPJlO!'itory is also a' allablc~ tll ,~ tllcrnpculic usc ha.~ been all but climinat.'(\. ho ....evcr. b) the ;nailabilily of orally IldminiSlcred Viagra.

""

CMbop#ost Trometham;ne. Carboproq tromct h~nllne. 1~S).metllyl PGF20 ( lk- mal)atc). is a prosIaglandlll den>lItlul Ms been modified tu pre>cnl metabolic o~ idat,on IS-poslllon alcohol fUIICI1011.

Prostaglandin E r CyclodeJ(trin. The cyc lrc polySIIC ' dlUridc complex of I'GE, (VasoptOSt ) i~ available a, lin orphan drug for thoc trl:lI\mcnt of .\Cvcre pcriphcrJI IIncnai oc clusive disca.\.C ... hen gruft, or angioplasty arc rIOt irKlicatcd. CyckxkAtrin coll1pl~allon is used 10 enhance II'<1ter solubility and rrduce f"Jpid metabolic inar;tivahon. MiJopt"OJtof. M'.sopro!'lol. 16-\ H,S)-mcthyl 1()"h)"dro~y PGE , I1lCtllyl e,~cr (C)" tOlCC). is a mothfk'tl pi"OStagl:md1ll analogue thai ~llow~ ])Otcm gastric lmt i-ecrt:tory and gH~t ro prolrtli vc effects IOollcn ndministcn.:d ullllly.

nus denvali,c

is adrn inbtc ....:d

,II

I I po!>tpanU11l hemolThage.

a dose: ()f 2.'iO J.lg by to mncl io-

""

Misoprostol is adminJ_lercd OI'"3l1y IIIt.,blel form in 3 dose

of 100 to 200 #14 times a day to prevent gastric ulcel1ltion in sujttplible individuals who are taking NSA I ~. Misopmstol is combined wi th the NSAlDdiclofenac in an analgesic prodUCt (A rthrolec by Phannacil) that is potentially safe for long-term anllanhritK: therapy. This ~llIg1andin denvIIlive should be avoided by pregnant women because of its potential 10 induce abortion. In fact, the combined use of intramuscular methoi.n:ute and iml'llvagilllll misoprostol ha.~ hccn claimed to be a safe and effCClhe. noninvash'e method for the If:nnilllllion of early prrgnancy.JCl

Travoprort. Tnwoprost tTra .. atun) i~ supplied as 12J. mL steri le O.()().I% ophthalmic solut ion in a 3.5-ml. rottainer. Tn"opll)'>t is claimed 10 be tnc, fIlU'it ~ent and FP specifl(: analogue in this product clltegory.' CaUtlonl:and ~Ide efft'Cb arc: Similar to lhose g"en aoo'....

PROSTAGLANDINS FOR OPHTHALMIC USE

Sevenl prostaglandin analogues M\e recemly come tQ market for the treatment of openangle glaucoma or ocular hypcncnsion in pMicnts who ha\'e not benefited from other avai llib le therapies. 1'he.<>e produets are marketed as sterile solutions for usc in the eye (as indicated below). Each of the.<>e agent s is prt'sumcd to lower lOP by stimulation of FP ICUplOI"li tQ open the uveoscleraJ pathway, thus increasing aqueous humor outflow. Commonly occuning side effects n:lX'f'led for this prodUCt group include oonjullClh'al hyperemia, IIlcn:ased pigmentation and gro"'-1h of eyelashes. ocu lar prurituS, and increased pigmcnllltion Qf the iris and eyelid . Contact lenses should be removed during and after (15 min utes) adminir.tl1ltion of these prodUCts.

0 -1
HO

Unoprortone. UnoproslOOC t Rcscul;t) is ~upphcd II" o.I 5% steri Ie ophlhalmic solution. Unopro~tOtlC is some'll~ unusual. in that it is a ~noid (22-cllrbon alom ) PGf, analogue marlctcd as [hi: i~propyl eSler. The n31 lll1ll IlpnlOition alcohol i. o:u dlzed to the ketQll(' . lIS ..... ould be e;l' pected 10 occur in vi\o . Caul ;OIlS and ~ Ide effecls an: "rmt. tQ those gh'C'1I aOO\e .

8imatoprort. Bim:uoptOSt (Lum igan ) is ~upp1ied as a sterile 0.03% ophthalmic solution in 2.5- and .5.O-mL si~ClI. 11Ic recom mended ~ge of bimatoprosl is limited to one drop inlQ the affected eye once dlIily in the e'eni ng. Increased use may dccn:use il$ beneficial effect. If u<;cd concum:ntly with other lOP-lowering drugs, a waiting period of.5 rninutC5 should :;cparale admlniSlJ'ations.

VTERINARY USES OF PROSTANOIDS

SlI'Ice McCllICken and CI.IWoBers demooSlfaled th.lI POF w.:!S as a honnonc in shi:c~ '" induce dlsmtC'sration of dIr corpus luteum (1uteolysis).- : salts o f this pm;uaglaodlD.t a variety of analogues have been marketed 10 induce or s)'J' cheonll.e C$trus in breed unim:tls. This ptOCCdure fieial insemi nation of many animals during one il\5ellll_, period. The following t,,o products are currently .\'lIi1lblr for this JlUrpoIioC.

V"'------{1
-

at""', ....

t..timoprost Latanoprosl (Xalatan) is ovai lable as a 0.005'1> slerile ophthalmk solution in a 2.5-mL dispen:;cr bottle. Latunoprost is al so marketed as 1\ combination ophthalmic product with the ,8-ldn:ncrgie blocking agclM till 101.. which apparently enhullCClI lOP-lowering by decreasing the production of JqUCQUs humor. Cautions and side effect.s IlfC' simi lar to lOOse for other ophthalm ic prostonoids.

C/opror teno/ Sodium. Cloprostenol sodium (&tnimate) is available as the sodium salt from Sayer A&ricuIIuQI Di vi~ion or Bayvet Division of Miles Laborntory asan. (IUS ~ulion containing 2.'iO mglmL

,
"

HO

,, ,

HO

HO

DiIIoproJt

Trimet~mirte.

OmoprOSI

Inrllcth:allune

luU:tl)'.c) mar~(led by Up.tOOn (.elconary) I" a pllbaliD:td aqueous 'iOIIU>OI'l of the IrimcthylammOlllum sail of

PGF.... (S.O mglmL).

23. ........... T I).Goul_~ f ~ v..,...."'. Lttol' rro.-. NOlL A.od. Sc, lJ S A. 967563 - 7~. I9W :M ~ R~ ~. L IIarJn. AS. tt.1e ~ 1011 2W_2U 2001 l!I A .... I HeaI.h'1)", I'!>or-. S' 9'/f1MMl 9fl,2. 199b. 26. hu.o. CD . Scion... , S. M...... h. S .. .. . t llatt S/iblil MS. 2001 n. NAp) ... S . Shim",.. '1' . SMoh. T. tt aI linn fI1J40-JoIS. 2002 lB. I.k<''''. M M<nnd. S .. ~. R. tt 01' C"""l.oIi<xo 102426-411.

EI(QSANOIDS IN CUNICAL DEVELOPMENT f OR HUMAN TREATMENT

\umtrotJ, pm~laglandin analog\leS are under invCSllllmtOn btlle treatmenl of human discasc~ (sec Table 24 2). Effons nbl:mg foclI~ QI'Ilhe an:asof gaSlroproll."diQl'l for anhu lm tb::flIP)'. fertlhly c:ootrol. lhe u.c,nlQpment of Ihromoo~11CS fc.g .. JIfO!itxychll or Ihromooxanc synlhellbe mhlbl1m) 10 treal cerebrovascular 01' (:(It"{)IUU")' ancry diseases. and

19 C...."""'. It. A. S"",h. W L . and N"",m,Y". S" l'honn..:oI. It

2()j_~29 .

"'"'.

01()

1m J(l lI"",l_ho. R V til 1.",1, J MI 33U17- S40. 1'H5 3 I SIoAnf."" A .. 1)0, ... T. L" ..... W,IIWn>.. G. W.: I. Ph>rm. 1'h3n,,:.o.. ~ ... 51 :685- 6'loI.lm .12. l>t,'C""'t .... J. A ., " al N",",c 138, 129. IY72.

SElEaED READ ING

R..Ic-y. J M 1 r<L~ ,,",","-1miI, . ~.-I l.Ipo."'.' N".. von. 8 ..... D. G.

PIeroum 1'm4.

tie deH:lopmenl of allliasthmallCJ Ihrough lnodulatloo of lilt hpo~)"I~cn:hC palhway. FUlure applicallOO of cicmal\Old~ 10 !he treatment of cancer. hYlX"nension. 01' Immune ~)')lem

a....n.

and IIInr ..... ,1IfWnm>IIuy _" . bn. ""'" Mni. Chmo. 2'l1 -f)~. l'Hl R. I( (od); II.."" Hforu <If I ,,.,, """ FIOh Od. So. 101m '
1(11'>

).Upo:.)"~" "' 5'

I""

......

JtionIers cannot be ruled OIl!. holt,e\"cr. Thus. although

progre!>~ hll.~ bt<'n ~Jow. the C:XP.l!ldcd U'>C of eicos:\noiru. or . rK'QSlIooid onalogues U lhernpcutic age!)ls in the fulure i~

alnJO<!t ensured.
REF ERENCES
I l( ...nuL. It.. - ' Ucb. C Pru.. 5. Eo,. 81<11 2826&, III!! 1 ... ' ''''"'". LI. IS ; J "")"101 lLond.1 81;1 U . 19)7 ) ~ S.. tt aL IIcta Chern. s..-d. 1f)~L 1%2 4 " .."Obou. I( C .. - ' ~" "'- In w,n ... A L Itd. ~ 11_"", "'~ ~ ... -.lIU:a....JUpock..0I1 . ponR Doxa ...... A .. CRC ........ 1\1111. pp. I- II. ~ ~""''fI. II L 8l1o:h-cll. G. L MMl Snulh. 0 L la .... ,Ill .. A. L (r<LI, fiN.... ' of ,-",,~ 7 ",I. !'m+IW.....'... MIl ReJ.ud Upodo . ..... II Il<>clIlakJII. 1'1... CRC rm... 19It9. 1"1'. . 1$-16 ~ 1'InoblIn, M 1.. l)oy. R. O .. -..d V., """ II .... W I:l : AJ(''''' """",, 'I ,CI45 ("1'9. 1994 1 T.... A.-I_. -.I Kol""",... R. I . """,-,,1.00.'" o."", I.lpo.! Mtd,.,,,,,

""" f......J'-J. ARTS Himl<docal PuhI ....... """ Postnbu ........ 1\lIN C<ohc-n. M M (rd,) H. ..,,,,aI ""-:1_ ... >111 """",,,,Iand,n.. ,01. I n 2. IJ<x:;a 1ta10r0. 1'1.. CIIC I'm ... 19M. I ~8b. Dunn. M. I .. I'llJUnO. C 0IId Ci"", ... Ci A lni>.)' lIe.w .~. Ad. u.p, MI lIi<>1l!19.1-421 . 19lI9 t\dq.'i .... 1.. 10.. and l(indahl. 1I (<<I ... ; ~Ilnd,n. ,n An, .... l lIeprud"". lion No ... York . fJ .. v..... 1'1801 " ......... i...... M_ Iho'o,..-.I 11<1"11>.. MMl m ...... >ItI>.." 1<1I0I0 '" I'G.I, and ",laII compound>; ... upoJai" l'ro>IIabrwlon' 1""",~<JI ~....... r ....') /\cod. ' 7: 1 12.19'12 Gry, ..... :s&.>. 11 I . MMl S&oo:L. 0 (td/..J """,-,) 01,,, MMl I.. SlobIt An.aIoJI\It

()oy&Jewsl .. II L SI:Cm.Jok. A., _

lkip.,... ""' .. VorL. SI""nrer' V""" 19117

&l:Ht2S-1 . 2O.XI
I Smoth. W I " """ 0.""1. I) L: Adv In.. """",, 102:1&7 215. 1\1%, . YaM. J R.. 1:l.~~Ie. Y. S .. .....t Botunl. II. M Anno. R.~ l'IIamuo..'UI Tu,iroI \II Y7 - I:!II. 19'Jlt I . " W l' M """",, !MIdi ... tzut.,. F "'.... I'-IY lie"" 11.1 .. IU 126. 2000 I ~-.ya. S. Y.. ..... WIItLIIbi. f PIIj'W lie' "N: 11~1 1126. 1999 11 K...... \I .... ><Iq.!MId, ... 0!lI<.- I~ ~ ........ '" f)l255 -270. :!001 1 1IdI. 1I L . 500"",""" I 8 .. _ I...,... R. R ....... Rep MI. Oem J!"I - IOO,I9'97 J.I 5.o<m.~~. A Alto< ~a " ...ob>'_ u..I.ue II.. 12

Su,._

a,1U('&! T ........ ~ Vorl. "-..,,, - . 1'ilIU. Hill .... " C 1. A,huo",Q h. " .111""'............. l-t 8aokln. ~nl' od ..,.... I91J7 - 1981l ~ w 1' M_ MMl Snulh. W I .ltdo.l """'0;1 _ ... _ ........-fI~ "k .... . '..,.. MnJoodo w yrnol. i6 I _~. 19f1,2.. Ld..-. A 101 .. MMl Gee. M " Ird\..); I""",~",ic: " '" ~g" MId pu1111<lfWJ' funnlOll. ..... ('1,n 8iol. II~ 1~ 1 -270. 1'IllS Pat: ... A"" .... C. R ~b." "I'<'ua of 1I"J"'lOi;1md.... oroJ ",I:.Itd prud""',, I" s.m .... I _. 8 .. nd r .. >ieItJ. R (<d.J; Ad. PrniIaSI.oo," fhrom. bo ..... I...... kue It" 1~. I .. SM . I~!19 Ru",fon1 K. I) : AIMI. lnl1.m"....", and An!;-Rhcumol'" Dn.op. mI,. I 1. Bo<:>o R."",. I'L. CIIC ...",... 1\l8.S II ...... ,,""'. H J.. and V_. I R ,td:< I' Synll...... InII,bo\oro, Nt... V<rl. Ro .... Pfc:. ... \974 1I<>b<1l. I . I ..t.~ lA\Iloo-....... and I. "",.)~ Am>\mlaID. 0 ........

..... ..c;,tr. J. C

(""",~

I,"->d.-

"""""land,n

E.; ke\-. II"",,,,, .... To ....:01 .~ I.IS. 1984 I. Robn1 ..... I G C . eo. III . Cancft Res. U476. 19fI,J n '--k. W 1'.. M . Ir .. T","'" P1wmaroI s... 178. 19M1 II Rome, I II . n L.ands. W 1' M. I'ro<-. 1' .. 1 1\( .... Sc. L S ... ..

I~ ~brnen. L I . - ' ~]," T

'"

191. 1994

11"""..... T ~ ond .... Sl, ... Rooo " - . R.. ekC ........ 1'190 Schrur. 1( . - ' S,,,,,..,... H I.u..): Pn.,,,,I_~ ,d CliftlCal 11........11 C.-.lOO"o..,,;ular S)'........ o/. JOI . Non> Von. Abo 11 I~ .... 1919 S,""Jt""',Iol.. .... P K,f... R It . MMl 101 ....... 11 t:. HeaIdo BJ.n. 011'1;)1,.... _ _ Fony ~ ... 5eal"<>Od .. Ncv. V.. k. A, - I Inl<" Pm... 1986. Soamhy. M. r l<d.): I,,,h Olio on SoU'oU<ln New Vot'L . ..... "..u.nd

"..

....

72 ~%J. I'IU. " Hill" G. A . t1 Ill .: '"",", N>lJ. Acad. Sd. U S. A 114 1417. 19117 1Il11lne1. ... M.. Ind Uno!.. W F M S",,""m . .,.",m;ocnI 11:1307. _
K",II1. F A . t1 Ill.' In Rom".II. P. ltd.}. Pro<.I",IMdI" Synlhc"", 10h0b0....... New OWcai "'pplit;aI:"",,- No" Y...t. . AI ... R. ...... t9l!O. pp. 1J.1l> Cryer. R MMl ""Idona. hi ....... J Mon!. 11)1 'll-4ll . 1991

''''

1"III1er 0..0. II.. ckP..,ItI . ... C .. and I'....."i. R.: k:~. and C-.... New V",t. Rl .... Pre . IYII-I. V...... I 11_. and O Orad) . J (e<k ): Th<rapcu,,,, AI'fIII.... n""",( '"',,.'....... d,"". 8otoI' ... 1!d.....-d """'hl. 19'1), W..kin ... W 0 . """'.-, M Ii.. ...... rkl<ber. I R. (ods.): -,JaroJin. """"",e New Y.. ~. Rl,." I'K.... Willi A I... Ird.), llaoodb<l<:olo. 0( [~ R.I",N Up<d;I. ""'- 11 IIa 11.. 01'. I'L. CRC ha&. tm "lht. U_ N.... z.. and ...... A. (edt,!. 10 B.,........ Pled.). UuloIneno. and ~ '" Ikallh _ Oil '."'. New Tm>th in l.Ipo<1 'k +__ 1Ie\an;~ .01 J. ",*,<1. S 1(....... 1989

......... 'm

,.0,.....--..1

"""""'land,,. ....

1m

2 5

Proteins, Enzymes, and Peptide Hormones

STEPHEN
j.

CUTLfR AND HORACE G. currER

prOlein are made available in lit!- furm of pl'O(cm h~ sales. and thoe.o;e can Ix adnlmi~tcred 10 ,oooce a f.,-onIJk balance. Protcin defielcncies in human ",nrillon an: ~OIllc:tJmo trealed with JlRMCin hydrolysates . The lack of 3!kq1ak ~ tc in may m;ul t froln sc\c:rol condltlon~. bul the IMobIcM no! always c:asy 10 diagno!\e . 11lc deficiency may be ',;. C;"'~'~ msu ffK:ient dietlllY intake. lemporarily "\Creased ... (a~ in pregnancy). Impmred diges tKln or ab5orptlOll, l"tI malfunction. inereu-..cd cU1abolism, or Io-.~ of proI~InI" amino acids (e., .. in fc,c.-s. leuk~mia. hemorrhage. bums. fractures. or shock).

Proteins are e\~miaIIO all living mailer and perfonn nUllIerous funclioru. as cellular compOilents. I'undamc:ntal cellular cvcnb are cauai p-td by pn.lIetn.~ called C'lllymes, whj~ other

proteins serve as urchl1tclurnl COnSl llUCmSof proIoplasm nlld cell membr ne.,,- Mosl Important are tlie classes o fhormonc5 ..
lh.:il arc d,arach,'nzed
IJ$

ptOfCIl\li or proIem-lite tompounds

bl>cause uf (heir polypeplidlc structure. ProICIIl the mlsH essential HI ullder.oumding the mechay. n;snlll of mola'u lar bIOlogy and how (:ellular comJlOlK"llts
participate in physiology. is al St) key to certai n aspects of med,cinal chcmi'<try. An uumlmlllOn ofthcchc:micallllllure of proteins ex plains the actIOn oftho!;c medicinal agents thaI are prote ins Of pfotcin -likc compounds and elucidates (heir physicocnenllcal and biochemical properties. This. in lum. relau:s 10 theIr mechanIsms of lletion. FurthemloOn:. in medICinal Chemistry . drug- n.x:eplOl' Interact ions an: directly reholed to 5truc1tlre- octivity relmionships (SA Rs) and aid in tile PfOU'S~ of nmonal drug de~l,n. Drug reccptOllli are conmlcred to be rnacromola:u le$. some of which appear to be pmteins or protein-hke. R~ombinanl DNA (rONA) technology' has had It dra mr,lic impact 011 our abdny UI produce comple~ proIein~ and polypeptides struclUnllJ y idcmlcal wilh lOOse found in vivo. Many of the endogcllOUs proteUl5 or po/),peptides have eAhib,ted llCurotrlln~milter and hormoftal prop::OlCS thaI regulatc a ,ariely of important physiological proccsse\. rDNAderhed technology prudlK1S cUlTl'ntly bemg II~ an: dIScussed below in tlli s chapleT. Altlt-ough th,~ chapter review~ the medicinal che mi stry of proteins. It Includes sOlTle enlymology. 001 only betause many drug~ affect cnqme systems and vice yeN but also because basic diS(."Q\'.::ri.::s in enqmolol:Y ha\'e been pr.ICtically applied to the '\tutly of drug-receptor interactions. Ht'IICt'. a h:asic introduction to enzyme, is included.

Protein Hydrolysa te. Protem hydrolysale is I . of am ino acids and shorteh,un oligopcplldc.s th.ltltl'csmI the approximate: nUlriti,'c l"quivalent of the CIL<irm. I:.ctall. min. piD5ma. fibnn. or other )uilabk: protem from v.1udt i~ derived by acid. enlyn1-3l1c. or OIher h)drolyuc ...... It mlly be modified by 11lInJaJ removal. and ~tQlllbO![ '-' addilioo of one or more am.ooacids _It maycool1lln de\l/I,)It or another carbohydrate \ullable for ,n1I11\ernn In~~. Not less than SO% uf the tOlal oltrugcn preo;ent I~ In til form of a-amioo nitrogen. It i\ a )cllov. J ~h to red transp;mnt liqu id with a pH of 4107. l'!lf\!nt crnl preparuuon, arc: u<c:d to malnt~'" a po!lu,t ml rogen balance in patients ,,110 e~hibil inu,'rfettnr:c: .l1m "Igestion. digestion, or absorption of food For soch lhe matcrial 10 be lnJeclcd must be nonaollgenic llIII I11III not conlain pyrogens or peptide, or hIgh molecular ... nJIiI Injeclion may ~ult in unlQ"ard effCl1S web a. ""_ vomit ing. fc\'er. vasodtlatalloo. abdomi nal pam. tv.,t.:bq: and convulsions. edema at thoe s ite of inj'liOO. and thrombosis. Somellmc~. tiJe.;e reactlOll) are ~ 10 . quate clcal) line ss or toornpld adminl~lrnIlOll .

PROTEIN HYDROLYSATES
In lhc:rupeutic). agmts affr-cting \'olume and composi tion of body nu.d~ nlcludc vanuu, das.~s o f parenteral prooocts. Ideally. it "ould be desirable to have available parenteral fl uids thai provide adequate calories and important proIems and hpid~ [0 mi 'l1ic. as clo~ety as po!Isible. an appropriate d iet. Unfortun:n dy. this is no! the case. Usually. suffK: ie:nt earboh)drate is admimSierN inU'a\'enously 10 prevent ketosis. and in somc ca)ts. it is 1ICC~r;ary 10 give funher sources of carboh)-dl'1lle by vein to reduce protein waSle. Sources of

AMINO ACID SOLUTIONS

A mioo lICid solutiollS contain a nil ~lure of C-.\SI.'nlial and IIIe~senl ial cryslalline amino acid.. ,,ith 01' without ~kcl!ol}1Ci (e.g .. Al11lllOSyn, ProCalal11'lIC. Travasol. NO\ammel. Although 01'31 siudies ha\'e shown a cumparl son Ixt"~D pr0tein hydrolysates and (ree ImIno acid diets. l proIein It)o;~ sates an: being replaced by crystalline al11ioo acid M'lIti for parentel'lll adminislrnllon bec:lU$C lhe fftc: lUImlO

830

n u"ro more efficIently Ch:ullltc peptides produced by the ~"""""" cleavage of protein hydroly ..mcs. \

PROTEINS AND PROTEIN LlKE COMPOUNDS

In. cltcmislry of proteinS
oompk.l. with many fllCel$ 001 undersl:ood. ProtCIn qructure is usually ..tOOied
j,

10 a grealer e.llenl. In b.o-for the PUIIj()st"~ of Ihi ~ chapter 'iOITIe 0( the .n Important lopic-; are >ullunarif.ed. w ilh emphasis on II'lalll.lll~hlps 10 nte(hcin(lJ chcmistry. Much progre.u hIlS tftn made in underlotanding the more ~opItisti cated fea lurcs a( protein 'IructUrc' and i1~ corrclu t i(HI Wilh physicochemica l ...J btoioglCal propet1ies. Wllh the total syn1he..~i~ of ribo... ka:.c in 1969. ne.. aPf'root'hc$ to the siudy 0( SARs . . - , protellls ha,'e inwh'ed thesynlhesisofmodified pro~~.

~~~::;;1:~;~ chemistry nnd.

"0---

Many types ofrolllpounds IInponanl in medicinal chenn'>11'} ill\' cl:i..,slfii:d SlruclUrally as protClns. including enlYInes. Inligen and !U1\ibotlics. NIIIIICI'OUS hormones are low rela u\,t'lIIolecular"!11;'ss prOl ci ns and so are called simplt pft). /rlllJ. Fundamentall y, all proteill~ Drc l'Ontposcd of onc or iOO!\' polypeptide chams; thllt .". the primary organil.l1tiooal level of proIein structure is the polypeptide (polyam ide) dialn composed uf nalur.tJly QCCurrinll amino acids bonded 10 0fIC: anOIm by amide 1,""agCll (Fig. 25-1). The specifIC ph)-.lCOClk'mical and bIOlogICal pt0pWles of proIeins dc ptnd not only 00 lhe nalUre of the specific amioo acids lind drieir ilCqUC'llCe wnhm the polypeplide chain but ol$(! 011 con fom~lh{)Oa l charactm ... k~,

Confollllatianal
Sbuctu ...
M

~t ......

of P,oteln

stated. the polypeptIde cllIIlO .' cons.dered 10 be the ptl .-y1c,cI of prole," Sln.ICIUIl'. and the foidi og of lhe poly
p:-pude chams into a 5pl:ClfIC oolled S1ructllre " mamtaincd druugh hydrogcnbondmg mte1'llCllOns (intrnnKJI('(:ular) (Fi,. 252). T he folding p:utcm is the secondary level of ~io ,lructure. 11Ie intnllnok..:ubr hydrogen bonds in .()I\e the pal1ially negative ()xy~ens of amide carbonyl poops and the ""l1mJly pt~i t ile hydrogens of the amide 'lH. AdditlOOal faclOl'!l. 'lOCh Q510f1ic bonding between pos-lildy and ncgati,'el) charaal groups and disu lfide bonds, lidp Slabihlc !'OCh folded 'ilructures. Tho: arr.m&elllCnI and mlerfoldlng ohhe coi led chains IIIto layer.! detmnille the lel1iary :,nd higher levels of proIeln IIRlcturt'. Such final l'OI1 formalional charnet!:r is <k:tcnnincd :;',~'::; Iypc.~ uf inlemction. pri m;U11 hydropllobic force.'> y ",me cxtent, hydrogen bonding and ion pai ri ng,~' forces all' Implicatcd in many biological pile aSl>O('ialed with protem >tructurt' and inletaclions.' The chams ( R !:fOIJPI") 0( various amioo acids ha,'C It)lttx:W'bon moieties that an: h) drophoblC. and they h:l\'c to as~illle ","h .. atCT mol('(:uJrt ~",~ are qn:N1gly IS50Cinted through hy 1lrogen "hydropllobic R groups tend 1 get 0 ~ Io.J 000 aOOlhcr, with exclu~ioo of watcr mol('(:ule.~. 1 0 form "bolld ~" between different 'lei:Jnents of the chain or

"
Figure 25- 1 DiagrammatIc representat10A of a fulty ex' tended polypeptide chain With the bond lengths and the bood angles denved from crys\.ill SlllKtures and othef expet.menliil e.oodeno::e. (From COfey. R B.. aoo PauI!r\g. L . Proc R Soc Lond 5ef. 814110. 1953)

".de

between differellt chains. 11Iese arc often lermed hyJror'ho bic bottd.f. hw/m,HII'bir !orcts, or hl'/lropJwbic i"'UI'CIIOIts. The stu dy o r protein structure hll~ rcquin.-d .ev.:rnl phy,i cochemical methods of analysi~.4 Ul tlllviolct ~pcctropho.J... IOOlelry has been applied 10 the assessmcnt of cooforrna tional changes thai proteins Ui'\(ierIlO. Cooformahonal changes COIn be in"CSligated by the direct plotling of the dtfference iO absoi'plioo or the prOIem under "moos .sets of cotidiIlOO~. XrdY an31.\'~ls has been ITlO\t u!idul in lhe elucidation or lhe structures of seve",l proteins (e.g .. myo-II lobulin and lyS(1)'mc). Absolute <k:tcrmi nalKJn~ of confOt'malion and helical eooten! can be made by ~ rny d,ffr.IClioo analysis. Optical rotation of proteins has :II~ been studied

Figure 25- 2 Left-handed and righ I-handed It he,hets The II. and H groups on the ...-carbon atom a<e In !hP correct posIlIOrl Corresponding to the ~nowrr conftguratron of the I-ammo aCIds rn prOlems (From Paulmg, L, and Corey, II. 6 IJnpubilShed d'C1WIngs.)

fruitfully. The specific roIation~ of protcins arc always negali~e. lind cx u'eme changC-' in pU (when the protein is in ~Iution) and condil ions mat promote dcrmturulion (urea s0lutions, increased temperatures) tend to augment the negalive opIkal rotation. Accordingly. it is thoughl that the changes in mlation arc due to conformational changes (i.e .. changes in pr<Mein structure at the secondary and higher levels of OI'IaniUllion). Optical roollory dispersion hu also bttn u<;ed \0 study con fonnatiollal alterations and differC!nces among g lobular proteins. Additionally. circu lar di chroism .ne thodology has bttn invoh'od in struCtural studIes. The shape and the magnitude of rotatory dbper.;ion curves and cireuillf dichroism S{lC'ctra are very sensitive to conformalional alterations; Ihu s, the effttts of enzyme inhibitOlS on conf()l111lltion can be analyzed. Structural studies ha~e included the in,'estigation 0{ the teniary structures 0{ prolcins in high-frequency nuclear magnetic resonance

(N MR).' NM R spectroscopy has be<n of some ~ ill Mudy of i.lIernctiom between drug moleculd alld pro" ~uch a.~ i and others. NMR

ands and housefly brain and torpedo was also used in the dclenninalion of the of !he capsid protein of the ","U" (HIV ).11 ...

F.ct't. Arred:l. . Protein Stnlcblre:

Condition) thai promote the hydrolySIS of a/mile alTect prolein 5t1\lrlUre (set' under tile heading. ""~'"' alxJ\'c). The: ordered cooformalron

Chapt~r

25 f'",UIIU.

E"Unt~t,

""d f'rI'I/dr lI"rINOI,rJ

833

;,. los!. This proc~s. cuslOmarily callct.l dt'IImurrl/l'QlI, in-

unfolding of tile (lQlypeptide elmi n,. loss of tlie nuthe conformmion of tlie protein. and disorganization of Ihe tniilucly Ofdcred SlrucWTe, without tile cleavagc of covalent bond> (e.g .. cooked egg albumin). The Npwre of nalive di!I.Ilfide blmds i~ usually considered a more exten_i,'c and dlaslic ch .. nge Ihan denaturation. Cri teria for tile dclcctioo of denaturation i nv()J\"c detection or previously mas~ ed -S H, imiduolc, 1\ml - NH2 groups: da:rea:.ed solubi lity: inc!\'ased lI.tSCeplibility to t he action of protcolylie cnzymes: decreased dlffu~ion con~Ull1t and increased vi."cosity of protein solulion: 10S$ of enzymatic oclivily if the protein is ~n ~n/yll1e: il!!d modifkalioll of antigenic propcnies.

,oil'~~

b"hydratc .....'Qnlaining conjugaled protein, (c.g .. Ih yrog lobulin). Pho,phoproleins comain phosphate moielies (e.g .. ca>'in ). Lipoproteins are lipid bearing. MClalJoprotei ns have wme bound metal. ChromoprOlcin~, ~uch as liemoglobin or cy tochrome. hal'e Wllte chrou lOphoric moiety,

Propel ties of Proteins Tile cl:mificaliQll in Table 25- I is ba.'>Cd on r.olubility propertic~_ Fibrous protcins are waleI' in.;oluble and highly resistant
to hydrolysi. by proteolytic en7.ymes: the I:ollagclls. elastin'. and ~ ernlins are in (his Class. GlobuJ:lr protein, (albumins. globuli ns. histones. and protallllnt:.S) un: rcl ntively water wluble: lhey are also soluble in aqueous sol utions contain ing salts. I\(-"id~_ bases_ or elhanol. En7.ynJeS. oxygen-carry ing proteins. and protein hormoncs an: globulut proteins. AllOIher important characteristic of proteins is thei r a/l1photeric behavior. [n ;;olulion. proteins migrate in an electric fK: Jd, and the direl:tion and rate of migr tion ute 11 fUlll:l ion .. of the nel clectrical charge of lhe protein mo lecule. ",hich in tum depends on lilt pll of the solut ion. The isodC\:tric point is Ihe pH va lue al which II given protein dot's rlOI migrate in an electric field: il is a CQllslnnt for allY sh'en protein and c:m be: u.et1 as an inde~ of chamcteri7.ation. Proteins differ in r.. tc of migr""on and in Ihcir iSOC'ICl.'tric points. Electrophoretic analysis i~ u-cd 10 delennine purity and fOl" (juao t itatil'e estimation becau:;e prOleins differ in eleetrophorelic mobility al any gil'en pH ." Becausc they are ionic in ~olullon. proteins bind with ca l ion~ and ~ni()lts depending nn lilt pH of Ihe ellvironment, Somelimes, complex salts an: formed. and precipitation ,akes pl ..... e (e,g . trichloroace1ic acid is II p..... --eipita ling agenl for proleins and is used fOf deprotcinizing wlutions). Proteins pm;sess chemi.al propc:n ies char.tcleristic of thei r cOl11ponent functional groups. but in the natile stme. some of Ihese groups are "'buried'- within the teniary protein struclure and may not reKI readily, Ccnain denaturalion procedures can expose the!oC fum:tions and a llow lhem to respond 10 the usual chemica l re~cl1ls (e.g . an e~posed -NHl group can be acetylatcd hy kelene: - C02 1i can be esterific(/ wilh dia~omelhane)_

Purffic:atlon and Classifkatlon

I' I be ~id Ihat it is oldfashioned 10 c lassify pTl)teins :~:;::"::~ to the following syslem. sincc so much progress n made in underslanding protein structure. NCI'cnhcku. all outl in.e of this system of class ification is given be:. nust the l elTl1 ~ u.-ed al"l: SlilI found in lhe pharmaceutkal medicalli lcrature. Table 25-1 illcl udes the classifi.ation char.lCtcri7.atioll of simple proteins. Befon: dass ificaI11III. tilt protein material mUSl be purified as mueh as po_~~i"'hkh is a very I lIl~k, Several cri teria are I includingcry,'al1inily, temperature. o,mot;e pressure

",? prolein, con tai n a nonprOlein , truelur..] com

","" i :lddition to the protei n moiety. where",," simple rwute;n) ~on1ain only Ihe polypeptide ch~in of amino acid :::- NucleoproteinS!ln! conjugated proteins conl aining nuacids as SInK:1U 11l1 componcnL~, Glycoprotein, are car :

TAllE 25-1

Simple (True) Proteins

Char.aeristlu OcCUtTence
EU alhum,n, b.:Wbuntin, inUllI "Ibunt;n. 1<"""';11 01 "heM. 1011""",1". of kJ\l~

OH'

GIoIoul,n,

In,,,*"n~

,n "'ill<'<, .oIuM" ,n d,'ul~ ",II ",*",100.

"'...,,~

c,"",,"'h~

I,,"""bk> ., _or <II" olrohol, .. ~ublt. In ~ <>lrohol. no! """~\ll~ble <;(,Iub\e ooly 1ft J,IUI~ ilCid! "" b;I,..".. roIIlu4bl. S<,luble In ".,.. Of ammon,L "r<HId). 1~oJ, .....

ll<b1'n of pa..I'. ~'h:Ili"" 010.., . ...... m ,lobuli". bcl<>r;lolI>ulln, om"",,, of limo,..!>.. ",y<ln of nt_k:s l'uund "",~ 1n rUn1s (0.J., 01 ".htM. hmloj" 0$ bado), Z,,," 01 "<pm, 11ft! ...afju of 1)0)

,Ii"","

R",nd ""'y in rUn" tf' 1_. ,1"","1" of"'~ _

I'oond
0Il1~ In

ory... ~,n of ri<'t)

the iflC'nn offish ('-1 ....1m; .... r..........1"'''''1

"'" '"OlI S..,luIlI"n ,,-....., but ... in ."'n~""L I'f"dnn"'~llIly ",""". 1>01 coo",loble
Inwtubk> ,n ull

u1oblc

"'\>"""

In

I;etlt'n ofhalr, nail., ,..,d fo",IIoO); C(>!llW<"n at ~urt""'lI,r II$'IOC , <~nndrin 01 (1II1 ,1",." fibrol~ of "I~; and >P!"'Ii- of 1<JIII<IIr<;

CoI_ T.st and Mlst.lI.n us Slpor.tI nd W tiRc.tian M.llu!"h

Proteins respond to the following color teslS: (0) biuret. pink to purple wilh an excess of alkali and a m\;lU amounl of copper sulrute: (b) ninhydrin. a bluc color when boiled with ni nhydri n (triketooydrindene hydrate). which is intensifi~ by the presence of pyridine : (c) Millon' S tC'5t for tYr05ine. I brick-red color or precipitate when boil ed with mercuric niIrate in !til excess of nitric acid: (d) Hopki ns-Cole lest for tryplophan. a violet lone with I 5tllt of glyoxylic acid and stnll ified over sulfuric acid: and (t) xanthopnxeic test. a brilliant OI1ll1ge WIlt when a solulion in concentnued nitric acid is stratified undef ammonia. Almost all ~lIlled alkaloidal reagentS will prttipitate proIeins in slightly acid solution. n.e qualiwive identification of the amino acids found in proteins and other substances has been simplified grelIlly by the application of paper clU'Onllllographic techniques 10 the proper hydrolysste of proteins and related substances. End member degradation techniques for the detection of the sequential arrangements of ille amino acid residues in polypeptides (protei ns. hormones. en7.yme.~. etc.) have been developed to such a high degree with the aid of paper chromatography that very smi ll samples of the polypeptides t an be used. 1bcse techn iques. toeether wit ll statistkal methods. I!a\'e led to the elucidation of the amino acid seqUCnce5 in oxytocin . v~in. in~u1in. hypenensin. glucagon. corticotropins. and others. Ion uchange chromatography Iuu bc:cn appl ied to protein analysis and to the sepamtion of amino acids. The principles ofion uclJange chromatoenphy can be applied to !be design of automatic amino acid analYl.crs with applOpiitlle recording iMtrumc:nlat ion . One- Of two-dImensional thin- laycr clU'Omlllograplly has been used to accompl ish separations tIOI possible: with paper chromatography. AnoIIIer method (or separating amino acids and proteins involves a two-dimensional anal ytical procedu~ thut uses elect rophoresi~ in one dimension and panition chromatogmplly in tile otller. The applicabi lity of HPLC was noted aoo\e.'!. I)

b usually IIIXOllIpanlcd '" nalU~ by elustin and. ~ mucoids such as chondromUCOId.. ... hich enter InIO the pr0duct in a small amount n.e ra ... materials for official gtW.. and that used gener.tlJy for food. arc SkiM of calf Of ~"'1Jr and boots. n.e bones arc lirstln:aled ... i,h hydrochloric ICiiI to remove the calcium compounds and then IU'e dlgfSled ... time for a prolonged period. which M lubili7.C':!I ~ odICf impuri'ic~. The fairly pun: coll agen i~ CXtroctl-d ... ith to water UI a pH of aboul 5.5. and lhe IIIlucou~ solulion ul ge lalin i~ concentm ted. filcered. and cooled to a sliff gd. Calf skin~ are trealed in abot.n the sarne way. but lhose fKD Ilogs IU'e not gi~cn any lime treatment. The product dcrhcnl from an acid-treated precursor is kno.... n as Iype A and n hibits an isoclcclric point beI ....een pH 7 and 9: that for_bidI alkali IS used is known as type B and e~hibits an Isoelec1rK point beI .... cen pH 4.7 and 5. n.e minImum gel SU'Cngtbotr~ c ially is that a I 'l> solution kcp: at O"C for 6 houn . . show no perceptible flow ... hen the contaJl'ocr is In,-emd, Gelatin OCCUfll in shec1s. shreds. flakes. ot roaM po..Jc:r [t is .... lIite or )el1owish. lias a shght but cluiractenSlic 0Ib and taSle. and IS stable in dry air but subject to michJNI dccomprn.ition wilen moist or in SQlutiorl . II is Uisolubk. cold water but swell s aud softens whcn inuncr.lCd andgndtHlly absorbs 5 to 10 times its own .... eight of Water It di. solves in hoi WllteT' to form a oolloidal solution: it also'" solves in acetic acid and in IIot dilule glycenn Gdara comnW)f1ly ;s bleached with sui fur dioxide. oot the lnedialil prodUCt must not h:we o,'er 40 parts pc1" million ul dioxide. A proviso is made. howe\er. for the manu~ of eapsults ot pills. whICh may ha\e cenlned com may contain as much as 0. 15<), sulfurdi-oxidc. and mI) bitt a Iov>w gel strength. Gelatin is used in the prcpar.1tnon iug of tablets. and. with glycerin. as a rie5. It hM also been used as a vchicle when is desired for drugs. When dissolved in waler. the becou'ot's 'IOIIICWhal ~iscous. and in cao;es of sllock. thnr solutions may be used 10 replace the l os~ in blood ,oIun Presently. this replacement is oc~'Ompl ished nlOfe eflk>(lll/) with blood plasma . ... lIleh is safer 10 use . In hen~ conditions. it Is sometimes administered Imra\'efIOU\J) IIincrea.-;c tile clotting of blood or is apphed local l) f(lf_ tnatnl('nt of ....ounds. 'The most important value in thernpy is as an etid) 4gested and adju .... nt food. Noubly. it fllib to pnm;Ie tryptophan and is lM:king in adequate amounts of o\IIef ~ scntial amino acids: approximately 60% or tile acids coosist of glycine and the prohnes. Nevenheless.' supp lemented. it is \'ery useful in variou s forms of m.llmllnlion. gastric hyperacidi ty or ulcer. coovalescencc. and pernl diets of the sick. It is especially uscful in tile pn:panta of modified milk formulas for fceding infants.

:~;:::,:~::::;:

Gelatin. NF. is a protein obtained by the partial hydrolysis ofcollagen. an albuminoid found in bones. skin. tendons. canilage-. hoofs. and other animal tissues. n.e products seem to be of great variety. and from a Itthnical standpoint, !be raw material must be se lected according to tile purpose intended (Table: 25-2). This is bause collagen

Gela tin. NF.

tool":::

TABLE 25-2 Products

Pharmaceutically Important Protein

CIItqory

G<1IItin rn.... .... b'c., USPGnft1G<1ab~ 'P' PI'. pL - _boibk.

USP~

1Mnd<r_c'PP'I"I<"I) LocaIIoe_.,

""""""I0\Il"'" ~ 4Ui""' tabkt "labllll ..-nc; OQ(Itn<lirl& .....

Slurt-

Gelalin film . . .. . able (Gelfilml. is a sterile. nonanugemc. absolbable._. insoluble gclatnn film. 1be gdatin films are ~ II solution of specially prepared gelahn-foonaldeh'J)~"~: binlltion. by spreadnng on plates and drying undcr~ humidity and tempertllure. The film is a~ai lab1c as lip,alow. Ir:Insparent. brittle: slleets 0.076 to 0 .228 mm lhicL,-"'~ though insoluble in water. IIIey become rubbery after ,... , in Wiler fot a fcw minutes.

G~/atin

Film. Absorbable. USP.

Chaptu Z! " ..../t'~" GeI.ltin SpotI~, Absorbable, US,.. Gclalm sponge ..tIsorbabie (Gclfoom. SurgifoomJ is a steri le, absorbable. ";akr insohlblc, gelatmbased spon~e that is a !ighl. nearly .lute, nooelasuc, lOUgh. porous matnJl . II IS stable to dry ~. 01 150'C for" houl3. It absorb$ 50 tin1C5 Its own weight of '41ItCf or 4S lIn1('\ o~ahlled whole blood. 11 is absorbed In 4 10 6 weeks ",hen used a.~ a surgical lopOIlge. When applied topICa lly to comrol capll luI)' bleedmg. It should be moistened wi lh sterile iS040lIic sodium chl ori(le iOIul1on or thrombin sol ullon.
VMOfflS.
~mI)(oJ; ic

It'-,.""", <Jnd Ptpildt HOmtOtlrl

835

order the DNA IlItO !oI.ructurnl units called IIuc/to.lQm(,!J. Be eause of the enormous ,moont of researeh on hlSlones. lhe readeT IS eooouruged 1 evaluate the Selected Reading list 0 provided at the end of Ihls chapler.

ENZYMES
Proteins thai hal'f: eallllytic propenics are e~llL-d ell;:J'mtS (i.e" enzymes hI\: biolo&;cal catal)sts of pl'Olcm nature), SonIC enzynlC.< hal'C full catalytic n:actil'ity peT sc; the'oC IIIC oonsiOi.'red to be ~illlple protein~ because they do rlOI hale a nonproleln mOiety, Other cnz) mc~ IIJ'I: conjugated prolel ns. and the nonproteIn ~truelUral eoulporK'nts arc 1ICCc:ssary fOl' n:acuI'Ily. Decaslonally. enzylTlC.~ requin: metallic i005. Be cause cnl.)'nlCS are prol('u\S 01' cooJuglIlCd proleons. lhe: sen eral review of prolein <;(ruetural slUdies pI'C<;enlcd abole in !his chaptcr (e.g .. protem eonformation and den:lIur"lion) i5 fundamental to the fol lOWing tople~, Coodil;oos that affcct denaturation of pro1ci ns usuall y have an adverse COCCI on lhe act;vily of the cn1yme. Gener:ll en/Ylllol0iY i~ di<;cus;;cd cffecli ...ely in nu nlCl'OU' tandard treatises. and onc of the IIlOSt conc ise dISCUM.,OO.'i appears III the classle wor~ by Feniinand.' ",110 ioclude5 n: ... iew$ of cn/.yrne Struclure lind funclioo. toenergelio. and l ill('tics and appropriate tl lustrallnns II'uh a Iota! of ]7 en zymes selected from the: ~iJ; llIajor elasses. FOI' lIdditionai basic studies of enzymology. the reader should refer 10 thl~ clllssic monograph aud to a eomprehe:nshe rel'lell of thIS topie. 'S

COOl'll (Naja) ~enom wlulioo. from ",hich lhe

and proccolylie prioclple~ hue been relllOled. bas hec:n eredlled wllh ... mues ilause of 115 tO~IIIS (lIId I\a) bttn injtc(l intramuscularly as a nonnarrolie analgesic in do>cs uf 1 mUd:ly. Sna~e I tnom 5OlullOO or the "".Iter moe ('tiin i\ u<oed subcutllJlCOllsly in doslos of 0.4 to 1.0 rnL Ill> , ~mo:stalic III recurrem epista~i~ IIIId thrombol.:ytopenu;: 1JUITI'.lr1l and as a proph)'I~lic b!:fore looth e~trnct ioo and mll'lor ~urSical procedurcs. StypI'cn. from the Rus..'lC:1l Viper, iI. lI>C'd topieu ll y a_ a hemoslu tic 300 as a thrumboplaslic 1genl in Quick's modified cloninglime le~t, VcnApis. the pi.mfied and ,tundardi1J.'d vcnom from bees, is fumished in pduatcd sirenglhs of ]2. SO, and 100 bee'~ling u nit.~, II is IIdnllni,lcn:d topically in IICUle an(l chromc anhnti<. myosi tis. lind neurilis. The frog \ eoolli. eaerulcin. isolall-d from the rec.l~}ed tree "Ru/l'(/lIIis clJllid,)'1U ml mies the effects of cholecy~to lUlln and has been used in radlOgr:lphy procedurr:s to 0011 uacl the gallbladder, In addItion . ..au~aglll(,'. :u1 an\iolyhc, As been i<iOlmcd from ,"" rallido'UJi. Finally. bombcsln. II l~amlllO lIl'ld peptide thai al.>O poI>Y:sy:, anAlO1 ylic propcrbeS, ha ... ~n isolated from the European firebellied frog. Although out a complete list of the peptidc ... Isolated from frogs. tocse provide an insight into the: ancient dcfem.:: meehmisnts these repi iles po!;SCss and Ihe po_sibi lit y of c~pIOlla 1100 for ~uch U>CS us analgctics. a "ti!11icroblld~ (e'p,:eiall y apinst resismnt organisms). ~nd cllrdio"'a'ICu br agents.

rroc

Nu(/eopro tei n$. The nucleoproteins menlloned abole lte found in tile: nuclei and cYloplasm of all et'lls, They cnn br dt'protelllu,ed by selel1lJ melhods. The compounds lhal om.u- in yeaS! are usually treated by gnn(ilng .... ,th a IeI)' dilute MJlution of potassiulli h) droxide. IKkImg plC'rie a.cid in nces~, and ~Ipnaung lhe: nucleiC adds .... nh h)drochlorie K'id, Ie;l\ing the profein in solution. The nucle ic acids an: purirlCd by dis.'IOI",mg in dilute pocaS$;UI11 h~droJ;lde, fiiterml- addifylllS ",ilh a!.'Clic acid. ~nd finally prttlpimhng wuh ,luge excc,s of ethanol. The nuclCQprotclIls ft)und in Ihe nueleu~ of eukaryOlic lis include a variety of en~ymc~. such h~ DNA and RNA polYllleTU.'IC:" (in ... olved III nudeie acid 5ynthe~is). nudeases lil1l'olvOO 111 the hydrolytic cleavage of nuclcOllde bonds). 1SOI11Crusc.~,:utd OlllCrs. The nu<:leus of cUkat)'otic cells also rontaln~ \pccializcd proteins. such as tubulin (inl-ol ... ed In lh: formallon of mitotic spll1dle before mll/)S.IS) and hisIOlIC~_ HlSIOrIC:s are proteins rieh ;n !he basic ammo acid!; argmlne _IY~lne . .... hlCh logcther make up DOe fourth 0( the ammo Kld residues. IIlstDOeS combine "'lIh negau,dy charged 6oublchc:licaJ ONA to form CQmpleJles that ure IlCld torcther by elL-cI~latk Interactions. H I"onc~ package and

Relation of Structure and Function o Koshland 1 hllS reviewed ennr:cpis concerning com: l ;.tion~ of prolein cOllfonnation und L'OIlformmional flc~ibdlly of en:t)uICS with ell~)'nlC cataly,is. Enl.ymes do not uist in; . lially in a coofonnallon eomplenlCnwy 10 that of the: sub\tl'1lte. The \ubstnllc induces the en/yrne 10 as>lJnlC a Lomple mental)' conformation, This is the <;(KIlled indueedfil theory. "There is proof th31 proteins do posse\~ conforn13tional lkJlib,lity and undergo eOllformalional changes under !he influence: of small molecule!i. This does not mean thai all proteins muS! be Ilc~;ble; nor does it mean that oonforma Ilona/ly flc~lble cnzymes must undergo oonfonnallonal chanb't'!l ",ocn inlerJCting wuh all COIllpound~. Funhennon::. a n:gululOI)' compound th~1 i~ not directly involved in the reaction Ci' " c~en eontrol on the reactjl'ity of the enl)'llIe by induci ng confonll:ltional changes (i.e .. by mducing the cnl,)'mc to as.Ullle the ~pccific conformat ion complerncnuuy to lhe: Substnlle), (Conceivably, homlOnes lIS rellU l:uors fUllc, tion accordi ng 10 the foregoing mechanism of affC<,:h nll prolem ~rueture.) So-called Ik:o.ible enzymcs can be di~IOI1ed conformationally by nlOlccules classically ealled ",h,bl/OfJ. Sueh inhibitors can 1nduce the procein 10 undc:rgo conforma uonal changes. disruJMmg thecatal) uc funcuons or the btndillg function of the enzyme. In thi. COllllCCllOn. II IS note IIorthy how the .... on: of Bellcau l7 and the molecular pcnur001;00 Iltcory of drug ;aeuon relate 10 Koshland's ~tudlCS presented above III thiS tCJ;lbool:.

oonli nues 10 SUppol1 the uptanalion of enzyme atalysls 011 the basIS of the acll"C slle (KOClivc center) of ammo acid ~ichM"S, which" oonsidcred to be thaln-lath'ely small regIon of the enzyme's mocromokcular surface in,-oj.cd In catalysis. Within I hi~ ~nc. the enzyme has strategically Jl'O'itioncd (ulM:lional gJl)lJpo; (fl"Qlll the side dl3ins of 11111;1"11) acid units) thai p:utU:ipalc coopc'rJII\-ciy in the entaIylic oclion. 18
Some enzymes have absolute specificity for a single su bMnlle: ol hcl"ll cala l)"/.e a panicular type of reaction Ihnt liar ioos cumpounds undergo. I n the Iuuer, the enzyme is said 1 0 have rt'/(I{;I't' JPiJirir.', Nc"cnhclcs.~. compared wilh odxr
calaly51~.

E,,"k~

cnl.)'mes an: outstanding in their spttificity for

cena," \tIbstr.lles. ,. The ph)'~icaJ. chemical, CQIlfonnaliOtUll, and configurational propcrhes of the ~ub<;mue delennine ils complementarity 10 the enzyme's reaethe eenter. 'flMose f.:K"tOf'$. tiM'f\'fore. detcmllllC v,hClhcr a givcn compound ~tislie~ the sptCl licity of a pai1lcular CIlLYIIlC. Enzyme specIficity must be a fuocnoo of lhe 1l31ure. including cL)flfomlalional and chermcal n:acllvity. of the reacti ve eenler. but \lhen the enz)'1lIC is a coojugulcd protein with a cocn7Yl1lC moiety. lhe nature of Ihe eocn7yme also contribUICS to sp.:cilicity clwracte:nstics. [n ""me instances. the aclive center o r the CI11.y nlC: i~ ;II" pa~mly compkn'K'nlary to the SUm;ll"dt e molecule: in a sll11loed configur.ltion. oorrcsponding to lhe "activaTed " comple~ for the reaction calal)'l.ed by lhi: enl.)'mt. 11te sub~1J'ale molecu[e is at~ted to the en1.Ymc. and the fOtteS or attraCtion c:lu<oe il to LlSSume the ~Inloed stule ..... !lh confOl'mauonal chango lhal favor the cheminl reacuoo: thai is. the ('flZyme dcuc.l'iC'5 the acl i\~dhon cocrgy requiremenl of lhe reacllon to such an C~lenl Ihatlhe reaction ~ ap-

prccillbly fa..\ter than II woukl in lhe lIb..ence of the tnL)'I1l' If ell7.ymes were al ....'ll)'s f;QIf\pktely cumplemc:nlaJ)' III _ lure 10 the <>ubstrates. then no OIher molecule v,'(lUkl be Cl' pccIal 10 compete Sl~:essru [[ )' v".th tiM' su~rate: In (Oinbi nallon ",nh the en7.yme, which III thiS respect \\ould bit s.m.hl.. III behaVIOr to anlil)()(ile:s. Occasu;lII:dly. ltov.T\er. an enzyme comple:memary 10 3 str.lmal $ub!otratc mo~ allracls a molecule re.wrnbli ng the ~trdined substl11lc f!IOk.. cule more SlftJIlgJy: fOf c:tamp!c, the hydrolySIS of bcnwyl tAyrosy lglyl:incamidc i~ pnll:tic:llly inlllblied by WI eqwj amounl of benl.oylo-t)rosylglyclocaJl1tde. TIlls eumpk i). Il,Istrales a type of antimetabolilc acliv"y. Severnl lYpcs or imcl1IC1ion comnbute: lo,he f~fI cnlyme- suhslrale COOlplC:te.s: a"I".lCtion~ belv,CC'n cllarJtd (ionic) ,roups on the protein anti lhe ~ub:.tn.te, h) bondmg. hydrophobic fortt~ (Ihe lendency of h>.Iroc.tu moidies or side chain of anllno acid residue); 10 ... .... " h lhe nonpolar groups orth.- StlDstrate in a Ylaleren,_ nw:nl). and LonOOrt rlJols (induced dipole Intcr.IClionsl Many studies of cn7.ynw: specilicny have: IIIvohal 1"_ lytic cnzymes (prou:ases). Configur:lliooa[ ~pel..'i ficity t'tII lit exemplilied by lhe arninopcJlt ida.1oC that clea\ C~ Lkoc)I,I) cy[g[ yeine bUI doc:~ not uffcci o-Icucy lgl)'cylgl)cinc. !)oAia-nylglycylglycinc is cJca\'cd ~Iowly by thh en~yme T'h:-.e phenomena illustrate the signirlCalll:c of SIr::n.: faclm: 11th: aclive center of ami nOJX,'plida.<;e, tlw: cJOSt'~ 0( al'J'll*1 affC(1s lhe klncllcs or tbe reacllon. One can ea~ily imagr ne how t1ifficult II " 10 Mud\ tit! re:liCuvily of cnlynlCS on a funCllonal group basis ""_ the II-.ecnanism of cn~ylTlC :tenon l ' socoml'lu. r. Nc.ath: Ics.\, the - SH group probably is f(lUrld 111 11I0re el\1)1IW$ a fUIIClional gmup than are the other polar groop!o. In_

E-,

OH H

E-,
0
N"

.. ......
'N'

..

.H

I C- O I
0

E-,

".0

" ......

".
~-E-,

O- C-X

I I

L _ N/
A

..

H-O

L
H+A-C-Nu

--E-,
- N,

O-C-Nu

H- Q

--E-O I

0 U

Figure 25- 3 Proposed geoe.-al.zt'(j mKhdnM'l f01' enzyme-utalyz1!d hydro/y5ls of

o R- ~-X

Figurl! 25-4 Generalized mechamsm of plotea~ catalysis (Adapted from Chem Eng News, Apr. 16, 1979, P 23)

C'III)"1TIl'S (e, g .. urease). lhe less readily al'ailablc S H groups .-c: IlCttSS:II)' for bIOlogICal activu), 1 ~nllOl be delected 1.11(1 by thIl nllropru.~ilk \e.'I.... hlCh is used to dclCCl free ly rellC~\~ SH groups.

A free - 011 ,roup of the tyros)l rt'sltlllC is IICCeSSIU')' for _ .em u), of IX'JI'in. BoIh the - OH of -;erine and 1he lmid~ portlOl1 of hlSl,d,1lC' appear 1 be necessary pans of the 0 ...1,\" center 0( ccn31n hydrolytic e nzyme!;, such a~ trypsin and chymoltyf'!-m , anti rumi~h the eleclrOSlatic forces inwhet! In II profIOS'-'d l11Cchani,m (Fig. 25-3), in whIch E deootc~ cnlYrne lind the 01 her symbols an: IIClf-evident. (AI Itm:uivc nu:chani sm, hal'C be:en proposed;" esterification nl hydrolysj~ were ~lUdied (,Xlcn,ively by M . L. Iknd.:r "~i,,;Jf)lInt(1I "f fire "-"'('riCUII Chemical $lH:U! /Y 79: 1258.
~i

plex IS .wllllli1.ro b)' the s mlUllal"lOOU:'l "Cltchan!lc" of the hfdrogen bond fwm the senne: OAygm to the carbon)'1 0\)" ' gcn o f the substrntc. Tbe intcrlllWl~te lIC)" lated Cnl,)"IDC is ..... riucn ""uh the proIOn on the tmlduo.Jc mtTOl!cn. Tbe deacylauof> relICtIon 10voh'es the loss of thts pos;II\'e charge Sl lUullallCOUSly .,.Ith the auack ofthc nucleophilic reagent (abbreviated Nu, H ). Roberts~ used nlllVgcn- 15 (" N) NMR to ~t l.>l.ly tnc I1k'Chanis!1l of protcase catalySIS. A scnClI)ati<: ,ummary of the generalized me\: hani~m ;$ n.'1)f\'M'llled in Fi gure 25-4. It i~ concl uded that the tertiary N- l nitroj!cn of the hi~t id lllc unn lI<ithin the rtOC1i"e ccnlC"r of the c(1)'l1le deproton:ucs the hydrox)'1 of the neighboring serine unit and simult~I1OO\I'ly the hydroll.)1 o\ygen Clterts a nucleuphilic Bllad.; on the carbonyl carbon of the amide ~ubstnue . :I.S depictcd In the seheml'. /It tetrailcdrul Intrnncdiatf' IS implx:ated. and the carboll.yhllc group of the aspanate unit (!he third functlooal group ..... ithin lhe reaclivc center) siabtlius the Oc\cloptng imida~oIiurn .on by hydrog<: n bonding 1 the N-3 h)drogcn 0 Fi nally. dccomposl1ion of the nnlonlC tetnlhet.lroJ ;ntemlt:d, . alC toward prodUCI formation (amine and acyhn ed sermc) i ~ promoted by pnor protonution of the amide nitrogen by the imidnl.olillm grotlp. A possible oitcmative routC 10 deacyl:llion would ill\Oll'e lhe nucleophilic ulIack of the imid~wle nitrogcn 011 the newly fomlt:d ester linkage of ttJ.e poslulm ed acyllnlCnnedl ate. leading 10 lhe formalion of the ac~ 1 mlld:II.o1c. The Jailer is un.~tablc in water. hydrulyt.mg mpidly 10 gm: the rrodllCl :utd regencr.lted :leth'e Clily me. The re:lellon of an alkyl phosphate in such a ~heml' may be wriucn in nn enllrel), an~logQus fashion. t'lI.ccpt Ih.1l the resulting phosphOl"yluted elt:f.ymc would be less suscepllhle to de:acylalion throuGh nuclroplll lic allock. Tbe d lagrum madc scheme in Figure 2.55 hall been proposed 1 e.\pl~.n 0 the furoction of thoc IleIl Ie th;ol e.~tcr ~i te of p;lpain. Thi ~ c~tcr site is fomlt:d ~nd mai nt ained by the: folding e nergy of thoc enl.)'mc (protein) mok'Cule.

z,,,eogens

IProen.~mes)

: 80:53311. 1958: 82:1900. 1960: S6:37Q.J ..BID, 19641.

M. 810 .... rellewed studies cofK:f'mmg the stl\lClure and ~''''.''rn 01 chylllOtrYP"m I sec: tkcmmlS 1 Chf'miclll Nf'1 ..ria 9:145. 1976].) Thtsc t ..o grouP" (i.c .. -OH and '" Nil) could be located ..cparotc pc'ptidl: chains in the enlYIDC as long as the ,fx: thrf'c dIIDCnslooal structure formed dunng 1II.1i\"aof the lymogen brought them near enough to form a bond. 'The pol:ui:t.ation of the resul ting structure ;"W euu'-C the sc nr>C o~ygcn 10 be the nucleophilic IIgent ullnd s the c!\J"bQnyl fUllCIion o f the ~ubstrule . 11le com-

Zyrnogcns. also called P"Otlt::"\III~S. arc cnl,ynlC precursor;. Thc.soe procnlyn~ Un.' said to be IICtI\atl-d .. ho:-n they III\' tl1ll1sformed 1 lhe f'n1.yml'. ACII \" 0 ation usually ;n voJ\'t";S uta lytic action by liOIl1C proIwlytic en1.)" me . Oc:casionaJly. the activatOf"S ml'rely cff('(1 a n:organu.ation of the Io:-n.ary struc ture (con formation) of the protem so that the group' lII\ohed within the reaethe center m-umc. fUllCIional ( i.e.. unmasked ).
S~nthesls

and

~tlo..

of E....,mes

Exportablc protCInS (c nl.ymc~). suc h as amylase. nbonuclease. chymotryp~m{ogcn). tryp!>in(ogcnj. and ilhlliin.

C~)
H
A
I
A- C- N- R'

'.

K_ , C:~)
.RCOD

Dill synthesized on the ribosomes . They pass a4:r1)SS the mem~ bnme of the endoplasmic n:ticu lum into the cisternae and directly into a smooth vesicular structure. which dfect!; further transportation. They are finally stored in highly concen InIted funn within membrane-bound granules called ~'''IQ g~" grt",uin The ex portable protein conlcnt of zymogen granules may reach a value of 40% of the t01al protcin of the gland cell. In the enzyme sequenccs abo,e. the new ly synl hcsiJ.ed exponable protein (enz)'me) is not free in the cell sap. The stored exportable digestive enzymes are released into 11M: exulICellul;lr milieu and the homlOt1es inlo adjacent capillaries. Release of these proteins is initialed by specific inducers. For e. ample . cholinergic agents (but not t epi nephrine) and Ca~ effect a discharge of amylase. lipa.-;c. orothers into the rm:dium. increased glucose levels sti mulate the secretion of insul in. and SO on. This release o f the reserve enzymes und homlones is complctely indepcndent of the synthetic process. as long as the stores in lhe granules are not depicted. Energy oxidative phosphorylation does not play an important rolc in these releases. Electron microscope studics indicate a fusion of the 1.ymogen gn1l1ule membranc with the cell membrunc so that the gTanule opens directly in to the extracellular lumcn of the gland.

Bes ides the en zy mes mentioned. it contai ns some b')JlSlllllgen ..... hich tun be activated by intestinal enterokillaS(: cb) motrypsinogen. which is convcned by trypsin to chymooyp' sin; lind carboxypepti dase. Pancreatin is used 11Irgely for predigestion or food and Ii:r the preparution of hydrotysUlc~. The ,nluc of it!; ClIl)lIIr::I orally must be very sm all because: they are digested by J'ICt ~in lind acid in the stomach. although some of them !lIlY escape into the intestines without change. Even if the) In: protected by entcric coatings. it is doubtful they could be It gTCat assistance in digestion .

Trypsin Crys tallized, USP. Trypsin crystallized ~, proteolyti c enzyme crySlal lil~d from an e,'ltroct of the rcn::1S gland of the ox. Bas Imm ..~. It occurs as a while ID yellowish white. odorless. crystalline or amOlphous po!I.kr. and 500.000 US P trypsin units are soluble in 10 mLof .. :ur or saline 1'S. Trypsin has been used for sever,1I conditions In wfMch its proteo[ ytic acti\itil!.~ relic\'e cc nain inflammatory SI*I. liquefy tenacious sputum. and so forth. I\ lany side: 1l'attDr, are cncountered. however. particularly when it is usN JlIRI" terally. which mitigate against its use. Pancrelipase, U5P. Pancrelipase (Cot .. ~ym) lias I greater lipolytic iIC1ion than other p.:mcremic en1.yme iJItPi' rJtiOIlS. Helice. it is used 10 help control steatOl'Tbe,IIId. other condit ions in which pancreatic in>ufficiency UlIpIiI the digcstion of fats in the diet. Chymotrypsin, USP. Chymotrypsin (ChyrtWJ IS n trueted from mammalian pancreas and is used in C3WIr.'1 surgery. A dilute solution is u-cd to inigJ te the pilIItfia chamber of tile eye to dissoh'c the linc filan10enlS tlw hold the len,. Dornase Alpha, U5P. Doma.<:: alpha (Pulmoz)me) 11 a highly purilied solution of recombinant human de:(I.t~ nuclease I (rhDNAse). It is indicated for use in cysticfi~ because of its ability to liquefy secretions from the lUIIJ effectively. It accomplishes this by dell"ing lhe extfllCtll. . DNA in purulelll sput um and n:ducing the viscosity 1ndd ti city of lhe secn;tion.
Hyaluronidase for injection (A lida.'iC. Wyda.<;e) j, a ~teri le. dry. soluble ~ product prepared from mammalian testes and cnp;tble ofll) drolY1.ing the mucopolysaccharide hyaluronic acid. It COf. tains not more than 0.23 ~g of tyro~ine for each USP h)aJ. uronidase unit. Hyaluronida).C in solution must be ~0Il'd ill 3 refrigcTlltOl'. Hyalu ronic acid. an essential contpontl1li tissues. limits the spread of flu ids and other exll1ll:eliullr malcrial. and because: the enzyme de~troys this ocid. jn~ fluids and other substances tend to spn:ad fanher II!Id {_ than nonnal wht'n administered wilh this enzyme. H)'1II1W1o idllse may be used to increase the spread and CO!lStqUnl absorption of hypodcrmoclytic solut i"n~; to diffu~ local .. est hetics. especially in nefYt' blocking: and to incn:a~ dill.. Si 011 and ahsorpti(>ll of other injl'{:ted materials.!;UCh I'l ~ cil l in. II also en h:mces local anesthesia in surgery of the e)f

Classification
11lere are various systems for the classi ficution of en;r.yme.\. The Internutional Union of Biochemistry system includes some of the tenninology used in the literature of medicinal chemistry. I1I1d in milny insHmces tile tenn~ lire sci fexplana tory . For example. transferases catalyc transfer of a group (e.g .. methyltransfernse); hydrolases catalyze hydrolysis reat1ions (e.g . eliterases and amidases); and Iyases Clll3 ly.tC non hydrolytic removill of groups. leaving dooble bonds. There are also oxidoreductascs. isomerJscs. and ligases. Olher systems are sometimes used to cl assify and characterizc cnzyrm:s. und the following terms are frequently CJlCountcred: /iptlSt'. ~,,,idllse. fUV/eIlJt'. phosplilltaIt'. kj,wse. $),"Ih~/(lSe, d..hydrog~IIlJSe. oxidast'. and rt!f/UCllISt'.

Proch...:ts
Phannaceuticlllly imponant enzyme products are listed in Table 25-3. Pancreatin, U5P. Pancreatin (Panteric) is a substancc obtained from the fresh pancreas of the hog or the OK and contains a mixture of en7ymcs. principally paJlCreatic amyla.;e (amylopsin). protease. and pancreatic lipase (steapsin). It e011vens not less than ~ times its weight of US P Potil\O Starch Reference Standard into soluble carbohydrates nnd not less than 25 times its weight of casein inlo protroscs. P:tncre~tin of hi gher digestive power may be brought to this Sll1l1danl by admixture wi th lactose:. sucrose: comaining not more than 3.25% o f S1~h. or pancrentin of lower digestive power. Pancreuti n is a cream-colored amorphous powder with a fainl. characteristic. but not offensive. odor. It dissolves slowly bUI incompletely in water and is in;;oluble in alcohol. It aCIS best in ncutml or faintly alkaline media. and excesshc acid or alkali renders it inen. Puncreatin can be prepared by extracting lhe fresh gland with 25% alcohol or with water lind subsequently precipitating with alcohol.

Hyaluronidase for Injection, U5P.

TABLE 25-1

PIMorm.ceutically Impon.nt Enzyme Products

Usual Adult

I'roprietMY
NIl,,",

AppIIuUon

.....

P""':moI,n 1Ihktl..
lJS1'

''''''' youl\ircd,
l'SP
....... I,~USP

Tryl"''' Cf)loIall,"'" lot .. USp

'*".

............ 125,000

USP llllill .. J mL." ..line

'-''''

<if

"."ocl..-e1aWcu..
CSP

u'"

"'"

M_'"

ID 1.OOO--2~.0011 USP
....!> of 1o",>ly,1o
_~.ybd{ft_

f5 ... eb~fUI''''''

....,.. or ....,1.. or 10 bo

1 "110..'" 1ICC'OI'd'''I ......

""""""""'''''
".~

lO .he ........ III"

Ch~l!IOIr)'p<in

r",

~)IK:~n'y"",

q>hth.o!n-.c: >IOlu.1OI\, USP

(fo...

",,"1< Iy,,')

1_2 mL by i";Jillion

.""n,m <If ,he

~-.
1~ISOUlmL

10 Ill< pt>l:lmor

~.""""Ihe iri.... I ;oIu,;'"

PI"
1i)1' ,"'.' ''' f(Jt
H)oI... ',.

~)'tio

...".me

",,",,Hypo;Jllmno<.,...

Sp

1 ..........

=p-.lJSS'
AI.....,
Ii'~

' 'J<>'b<III. USP

.,..,; ,'.,,.
Doo< ..... ~ body ...1.ln . IS-6(IUA.IV_

. ".
I~USP

..,p"

I-H."....
TopoctJ. "'n"ntll~ MAklq.i_il.

'SotllSl'Dlr", ,,,,,,,,,_..r .. , "

IS useful

In slalJCOlT'l:j bau~

it causes a tempomry drop

IDlr.IOCUlar pressure. H;,"';;;';",~~;;idlL<;e is practically II(lm{)xic,

cau~

but caution must in the pn:seroce of infection be(:ause the enlymc a local infcclion !O spread. through the same II shou ld never be injecTed in an infected an:a.
is

and is uSC'd [0 lJ~aI type - ] Gaucher's disease because: us :lbility 1 hydrolylC gJucocerebroside prevc:nts the accumula0 tion of thb lipid In organs and liu~.
Suti/al ns. USP.

SUlilaillS (Travasc) is a proteolytIC en-

:.o:ymt obtained from cu ltures of BaCjl/lI$ $ubll/iJ and used 1 dissolve necroric tissue: occurring in second- and third0
degree bum s as well as bed son:s and ulcer-ned wounds. Many substances all' cQnlrdindicllled during the topi cal use of sm ilains. These inclu(Je delergenl~ and allli-in fecli\"cs [hal denature the enzyme prepanllion. 11tc antibiotics peni cillin. streptomycin. and neomycin do noI. inactivale SUli lains. MaJenide 1IteI&le h also compalible ..... ilh lhe enzyme.

,,,, m,,,,,," by mca~uring

SUbslrJ1C of na the hyaluronior by measuring the reduction in

of sodium or poIl!.ssiuUl 11),ils product in turbid or ~i5COS'1)' units. but nJues arc not the sallie becausc ~ilSure diffcll'nl properties of the cru:ymC".
t
llnigluce,.,~ Injtion. I)'me) is II. form ofhunlan

lmiglucer.ase injection (Cell'-

placent.al g l~ll'brosidasc: from _tieh the ternImal mannosc rcsidue<i have been removed. nib prodoct i~ produced llirough n:c:ombmanl leclmoLogy

Streptokinase. Streptokma.o;c (Kabikina.o;c. Srrepta.o;c) is a catabolic 47,.OO(}.Da protein SCClUai by group C P. hemolytic 5trcplococci. II is a protein with no intrinsic en7.y, maiM: activity. Streplol.innsc activates plasmiMgt'n 10
plasmin. a proteolytic enl.ymc that hydrolyzes fibrin and

promole" lhe di~-.oIulion of lhrombi. Phlsmil'lOgcn is acti "aled ... hen streplo"ma.o;e forms a I: I SlOIchiomeuic tomplu with II. Allergic reacl lons to stTCplol.:ina!oe occur ~om monly beeau'l: of an tibody fomlatloo in individuals treated "' ,Ih i1. rurthermore. lhe II.II1Jbolhe~ mllClivatc 5trql1oLJII&.'le and n.'duce its abl hty 10 prolong thrombin lime. Stn:plokir\;tsc IS indic;ltl for acule myocardial inf;u't"lion , (Of" local perfuion of an occ luded ' elIsel. and before II.IlgtOgtaphy. by inlrJl'enous. intra-arterial. uoo intrtlCoronary adnllniSttlil ion. respecl i,ely. Uro/r.;inasc (AbboLiTUlsc) IS a g l y~osylaled senlY proIeasc: coru;I51ing of 41 I amino acid residllC$. \Iohleh e~ i~l~ n.< I\10'0 polypeptide chuin s C()llIlCCled by a slAgle disulfide bond_ It is illOlall:d from human unne Of" tissue culture of human LidlYy~. The only known subslrute of urokmase I~ pl a;.minogcn. which is IlCtivaled 1 plasmin. a fibrinolytic 0 nll)me. UnhLe su"tplol.:lIlase. uro/r.;inase is a direct activator of plasrmnogen_ UroI.:inasc: is non:mugemc btcaUK il IS an erldogeoo-us clI7.),ne aoo. then:fun:. may be used when streptokina...;e u<.e is nnpossible blx"auo,(' of IlI1libody form.:llion_ It IS oommJ5!ered mlnlH!llOUsly or by lhe immcoronary route. Its indication~ are ~l1nilar to Ihose of Sln:plOkinasc. A/rep/ase. Alteplusc: (Activase) i~ a lissue plasmiootcn IIClil;lIOl" (I- PA) produced by rONA technology. It is a l in gle<harn gl)'coprotein proIease coruhling of 527 amino acid ~ltlueS. Native t-rA is isolatetl from u nlC lanoma cell line. 1lw: singlc-chain molecule is susceptible 10enlymati<; digcslion 10 a two-chalO molecule, in \10 hkh the 1\100 chains remain l;nLed \Ioi,h a di~ulfid<! bond_ BOIh forms oflhc nUli"e I- PA :lR: equipotent m fibrinolytIC" (1Uld plasminogcn-acti"oting) propcrtl1:s. II i~ an e~lnnsic pla~mlllogcn octivalOl" associated II ith vascular endotheliul lissue. which pn:fereluiully rlCli.ate~ plasml110gen bound to librm. The fibrinol)\ic action of ultcplosc (I-PA) is confined 10 th rombi. with nummal syslelllll."" acli"auol1 of pln.~minogen. It is produced comnw:rcially by rONA methods by inscnmg the altep1ase gene (acquired from human melanoma cells) into OVllri!U1 ~"ells o f lhe OIilleliC hanL~ler_ set\'mg as bast cells. 1lw: melanomaderi\'ed a!leplasc: I~ immunologICally and chemICally idenucal with lhe uterillC fonll . Altepla~ is intlicaled for lhe intravenous management of acule myocardial infl1ll:11on.

has bl.-cn reponl-d 10 cau-c allcrgie~ in pcl"loOn~ \\'ho handk it, elIpeciaily lbose \lobo are e~posed 10 mbalalian lIf lilt

POWUcT_
Bromelains (Ananase) is a nlillUn: o(prot('Olyllc C'nJ.ynle$ obIamed from Ihe pineapple plaJ1\. II II proposed fOl" use in lhe U\'alment of <;oft lis.~UC' inflammalllll and edema associattd II> llh truum:ltlC" mjul)', loeahUII flammmion. and poslOpenllive lissue i"Cactlons, The s\\clllllJ that IICC"Ofl1panks inflammation may IX' cauSC'!l by OO:Ilnu of the ti ssue spaces WIth fibnn. If thi~ i ~ true. enough " asc would have to be ubsorlll!d antl reach the tar~el an:a aftc 0131 administnltion 1 acl selcctilC'ly on ~ fibnn. ,.., 0 )et to be: esmblished, lIntl ils efficacy Ib an anti-rnl1:unmalOlJ age", i~ inconclushe. An apparent inhibilion of inlhmrNtion_ howe'er. has been ocnlOn,tf1llcd II>ith Imt:l.llts 1oIIdI .. turpentine and CTOlon oil (granu loma pouch tlXhniqut) ....... anase is available in .5O.000Un;1 lablet~ for 0tU1 USC'. Dilll>la!le (Taka-DlaslU<;e) i\ ocm'C'l! from 1k aclion of a fUllgus. A~rgjllu$ ory:pt' Cohn fAhlbwJ!. ~ rice hulls or .... hc:lt bruno It i~ a yellow. hygro'lCOf'IC. al lasteless powtler thai is freely soluble In "'Dler and cansoltbiliz.e 300 limes ilS weighl of starch In 10 nunutcs. It Il> IIloaI in doses of 0,3 to ].0 g In the ~arne ~ondilion ~ as mAt iiistaS<'. Taka-Diastase i\ combined" Ith alkulic~ as ~n 1Ill&'iJ in Takuyme_ wilh vitanull'l In Taka-Conlbc~, and preparalions.
Dlasr~se.

BromeI./m.

Urokimue.

in.

HORMONES
hormones tliscusscd in Ihl" ch~pter may be: cta:."flQt structurally as polypeplidcs. proIeins. or glycllpl"{llt* 1lw:se hormones inc lude melabolilC'S elabonlled by thr 11,.... lhalamus. pi tuitaI)' glund . pallCrea gnslrolntcSM:r1 IJ1f.1. paralhyrotd gland_ liver, anti kidneys. A oonl('R:be:n~M ~ view of lhe biochemistry of lhese polypcplilks and'" rc laletl honnoncs is beyond the <;cope of thi .. chaptC'r fl. I detailed discussion. the reader \hould refer 10 rbc """ by Wallis el 31.11 and OIher IIIC'r.Iture eiled throoghouE chapter.

n.c

Papain, USP_ '>apain (Papa.<;e). lhe dried antl purirlCtl late~ of the frull of Cur;cQ p"pam L. (Cancaccac). e:m dlgc,t prorem in either acitllC or Ill~aline media; It IS be:St lit 1I pl l be:t\lo-cen 4 and 7 and al 6S to 9O"C. II occurs as light broWnish Il"1Iy 10 ....eakty reddish bro\lo'n gTll.llules Of" a.~ a yellowish IlrdY 10 weakly yellow powder. Ie has a charnclcri ~ tu: odor and laSle and is moomplelely soluble in waler 10 form an opales<:enlsolulron . 1bc commen:ial material is prepared by evaporm in g the juice. botlhe pure enzyme hal; also been prc'pared anti cl)'Slalllled_ln nledll.""lIIe_ il h:lS been u'ied locally in \'ariOll~ conditiOl1~ 5111111ar to those for "'hich pepSIA i~ used. II ha, lhe atlvantage of acti ~ily o'er a wider range of condiuon~. bul II IS oflen much less reliable. Imraperitoneal inSlillauOf1 of a weak solution has been recommentkd to cou nter...:! a tendency 10 develop atlhe~ions after abdommal Silrgc:t"), and several enthu\iaslic reportS have bl.-cn matlc about Ito; value under Ihe>e conditions. Pul);un

Hormones From the Hypotludamus

Spatola provides II.Il ucdlenl, although <;()I1\e1l hal !laird. view on the physiologICal and c hnl cal aspeclS of h) lamic-rekasing bomlOllC'i. u Throoi1h use of thN la mooes. the central ncrvous sy~tem regul3t~ OIbe:r~'" endocrine systems. inc luding the pitUitary. \IohlCh In controls Still other systerm; (e.g.. the Ih)mid). Th)"rolibe:rin (thyrotropin-releaslllg hortnor!e [TRHI the hypothalumic Ilormone responsible rOf the n:~~!if_ pituilary's lhyTOlroplR Thyrotropin "lI mulale5 tbe: ""_ lion or th)'rolillC and liOlhyronl1Y by lhe thyroid. TIlt Ihyroid homl<lOCS. by fl:etlbac~ regulnlion. iutl1blt ofTRHonlhepilUi(31)'. TRHis I I rhat has bc:t:n ehunlCtcnzal as

tilt.,.

namidc:. TRH posse5>t'S ;;,'~:;~;, addition 10 Stimulaung the lhe release of proloclin_ It

Chaptrr 25
1}~1lI dTts tl1:lt h;o;I'C been elaluated for antKlcjn.'\S:Int

l'ml~I1U.

& ;;Y"'''-'' muJ P~plu1~ lI",moor..

841

drImlpeulIC pxenual. but the results of clinical lOt yet COII\idered rooclusile.

S4udi~

arc:

Gonadohbenn, as tile name: imrhes. IS tile padolropm. .cltas.ng ho rmooe (Gn- RHJ. also J.:nown llli lutemizlng horlIIOIIt- releaslng hon1'l()l1l: (LH-RH). Th i ~ hYpol:h.ahmllc de pude stimulates the l\"lease Oof lutein ili ng hunnone (LH ) and follicle-~tln1Ul~hng hormone (l'SII) by the pituitary. LH . R is ron~id<:red tOo be Oof potcntial therJpeutic irnportance H WI the: treatment ofh)'pogOonadOlropic infertili ty in both mu les and fcnml ell,H

tuimry). which originatCJ from the min. aoo the adenohypophySis (anterior pituitary). IIhlCh is dc:nled from t'J'.the lial tiSl;lM:. IU"e the tWOo embryOologicall y :md functionall y different parts of tile pitUitary gland. The 3litnohypophysIS is under the cootrol of bypothalamic regulatory hormone(. and it secretes adrellQCorticotroplC hormone (ACTlI ). growth hormone (G H). LH, FSH. prolactin. and otocn, The neurohypophysis IS responsible: for the storage and secretion Oof the hormOones vasopre.ssin nnd Oo~ytoci n. eOomrolied by nerve impu lses tfUI'c ling from the hypol:halamus.
ADRENOCORTtCOTROPIC HORMONE

(pyro)'GIu
His

10
GIy-NH 2

T",

Pm
"'0

I I

I Se< leu I I 5Tyr_GIy

lut8ll'llllOg tlorl l ......Relaasrog IIorI1"Ol1e
(t.H.~)

A hypothalamic gro\\ th -rc:leasing foctor (G RI- abOo l. ruled ,om atollbcrin. rontinues tOo be under imensi ve irwestj. . lis i(\cnhfication and biological characten7.11tion re tOo be completed. but phy~ iological and clinical data the nistence of hypothalamic control Oof pituitary Oof'iOlllat<Mropin. " ,"'" I_ anotller n,:ry mtC:resl rng hypolhalanllc It ii a u.'tradecapcptide posses.~inll: a drsu lrKlc hnling t .....Oo cy~teine residues. 3 and 14. m the form til 38-me:mber rmg. Somat05taUn suppn:ssc:s .several c:ndomile syMcrn_. It in hibits the re lease uf JOrn~tOotropin and ;;:~r~bY the pnuitary. II also inhibits the .secretion of glucagOon by Ihe pancn:as. Gastrin . pepsin, and 1M"t1ln nrc Intc:.~tinal hOonnOones that are Ii~e ..... i~ alT~tcd ilOomatostotin. The therapeutic potential of '>Omatostatin belo ..... in relation tOo the role Oof glucagun in the [IIIlIoIogy of llum~n dIabetes. OIherll)pxhal;unic hormones include tile lutcinlzing

nor-

hormone

foctor (CRf), mclanot (MRF), and merelea'\C-onhiblling factor

AI the foregOoong dIscussion illustralcs. the hypotha hullIc Ntlx:nnc ~)"tel1l perfOomlS mllny cssen tial function~ alTt.. OIherendocrme ~ystCn1s. [n turn. the thalamu s and rotIe~ tl('I1 control Oon lhe secre1ion Oof these (hypothalnonic ) faccOomplete re view of thh flt ld i~ beyond 1he scope Oof the intcre'tl-d reader ~hou ld refer tOo tbe litera -

ACTH (adreIlQCOomcotropin. cortICotropin) is a n1edlei nal agenl that bas been the ~ter Oof much research, In the tate 1950s, its st.n.ICture ""ali elucidated. nnd the tOlal sy nthesis was accomplished mtlle 1960s. Related peptidcs also hlwe been synthesi:ec:d. and somc of theo;c possess SImilar physIOlogical action. Human ACTII h<IS 39 amino acid uni l~ Within the: polypeptide ebuin. SA R studies of ACTU:IoI ~ ..... ed that the COOHterminal ,.t.'quence i.~ not paruculariy important for biOological actl vity. Removul ufthe N l lrtcmlinal ~mino ocid re~ults in cOompletc loss of steroidogeni c IICtiv it y. Full :!Ctivity has been reported fOor synthttic peptidc:s con taining tht firs1 20 amino acids. A peptide containing 24 urn ino acid~ has full M~roidogc nic activity. without allergeniC reactiOons. This is of prxtit'al IMIponaoce bccauo;e natural ACTH preparations j;()I1l('tlftlCS prodUt'e clinically dangerou~ allergic reacttons. Conicotropin uen_~ it s mapactiOli on the adrenal cortex. promoting steroid syn lhe$is by stimulating the fOorm'llion uf pregneoolone from cholesterol. U An internction betwccn ACTH and specific recepton IS implICated in the mechamsm leading 10 slI mulation uf Itdcnylu\e cyclase and accrkrat ion Oof steroid production. The nltc lunlt ing step in tilt bi(5)' n thesis Oof steroIds from cholesterol is the Ooxidati\'c deavagc o f the side chain Oof cholesterol. wbich re~u lts 1M the formation of prcgncoolOone. Thi s mtc- limiting ~tep is regu lmcd by cycl ic adenosine l1\{)rlOph()l;pllate (cA M P). COorticUlropin , through cAM P. stimul ales the biosyntlltsis of steroids from cholesterol by increasing the availability of fn.'C chole,terol. This involl'cs IIClivalion Oof cholesterol esterase by pOosphorylation. Conicotropin also Stimulates the uptake u f cboles_ terol from plasma lipoprotc ins. Other bIOChemical effts e~med by ACfII melude st imu latioo o f phosphorylase IUld bydroxylase acti\itJC!l. Gtycol)'sis also i~ increased by this honnonc:. Enlyme: systems that cataJy.r.e processes rnvOohtng the production Oofreduced nicotinamide adenine dinucleuudc phosphate (NA OP lij IU"e also stimU lated . (NA DPH is req uired by the steroid hydro~ yl ation s tb~tIQJ.:e place: in the 00\'1'1";\11 tran~ fonnation of d1Qle~terOoI tOo hydrocoo isonc. the m~jor g[ucocurt icOoid bonnOonc.) Phannacc utically import unt ACTH products lire l i~ted in Tabl e 25-4.

'"

NJ::..N I..N N J- >

major role I In regu latmg actiHty mdocnne orgaru;. mcluding the adren~1 cortex. the ""';", alld the thyroid. The neurohypophysis (posterior pi-

~::~~~:~~:i~:":~"hypophy~iS' i~ located at thestalk. to the hy~halamu5 by II base

i

TABLE 25-4 Phannac8utically Important ACTH Products

..-

"".plrltlon PliOIpri<ItMY
catl1lO<Y
AdrI'nooort...:OI"'1"" ..."""""'.
~I
",(bol.'"

Usual Aduh DoW

A .... <M<:(JO'lCOlIl'OpOe """"""": ~I. 20 l'''!'un''~ ~Hl.

Osuall'wdiltric

Dos"
... ~""Kotropi<:

C"""""",,"n

C_""""USP ,",..,...,...
k.

,.,..,00... US!'

.,1

w:nIid (."".
di C '"..

.4c"',

Ado .. oo.;on .... "uUld (Md .. ~),.. ,"'aI,lIll'SP q ,,<I,

""'I> DIac_i<IOd(Woc

,.0".,.1

' ""

.... -NrIt,f'WI.
Cl""'~'"

' ..... fI"'dc...:y l: rapid IN_1M.,.. . IV. H USP uni" . ... 1111 blood .....,",1" I hour. -.Jrcn<oronoc.1 ,. UId .... ,pIIl IV iaflnlOll. ! j U ioo j(l(\-I.ooo .. l.oIj~ .~_ I"F""" oYcT. pcnod 01 ......... "" """" .... l ""'"""vc da>. .. ,Ih 24-hou, U"IM: oollcrllQn eacll day

--,-

-to---1IO Ulda).
infi.oo'nrnMlory I.

f'ln:n" ...I, U lJi\1 " ......... or 12.5 UIm' 01

00dy

d...,

Du ...... ",otol

-r..... ,,",4

""'''''''

... <In:IIOC<,,,'':<Il1tIpoC hur_~

. ' ..nlOn...." ........ \IM. '''~I. "o'ShlOloI", ""'(~

''')1-. USP
&1

AdrcnoconlOOlropir: hcJnnoac. 1M .. SC.4()..ItJ U cVCf)' 24-11 houn; I V infu_~U .. 300 mI.."

j ' l .~on-

............"""'~""III. OJ '''''' """""""

....... me.....:'1

.. ,.,""", pcnod. '1.<1.

"'JC"'lIOII ,"-nI oYcT

"'dmK>alnK:al'1M <Md(.."I. U , or SC. 4IJ.4U) ,nfbnu""""Y):

'n

,..-

251)1m; of box!> ....

U.\.a 0( bn.:t) . . . . .

~"Ct)' 2.1-72 ...... ". IV Infu_, ~ t; 3OOml. oI~.d.. """,

"'FIiM" ......... cr .. ~,

".,... Do.....,wc II<i

""",,,.,, by<lru.....

loI""'"
AdmIoo.~

"*,rr",,,,,,,yl: 1\1. 4(l U b",<1 <II' _ II ofl ........ j.O'vc dayi ...11h unne roilt<tlon ~.h day
"''''w"",,~ _ IM_
-'I)..toO

'"

I~ICIII

110m...... ..m:.oc.onuol . . . .' (onI''nI~):d,"-ic

""',M;". <

.......-.USP C""''''I''''~ 1.1","

lid (adrchO<'O'lJ<oI

In.., ..' kicnc,)

"",,-icc """Ur

1IIlOf>:oJ \Q . 8. ,,,",, 72 ....... _ mlu.."" .... "" ..... '"JC"I.11OO ""',ulter; nWnlnO....,.,. 20 Uldoy

UIdo). illCml"",

C...y........
1
C'Ur1filly"
n ...

~'"

aod (.1 ......... U<lOI

,_

... Jrcnorur\lcII.....uid 4.... ' onfbo n,lIf)') 1.l.I. "",..... 0lI):(:,O l.LIoioy ",,,,,... ,,.. -.vallO 4R. d>on 72 1\oUA; mIutt ...... prr Injo.:ti(>n l~, ma,,"''''''''"T-. 20 UJday II> 1 1C\O w~I) .. Do.,- aod (odronoc:oruo:al ~): 1.l.I.-40U .... _II ..t 2 WCCftW"" 2'""'" pmod> 1M or IV.l.loO ~S

i"><1 fr"':"''''-'-)
,rUII",

n.i...... IJ't"'" "'."

.... omlOl;

..

"Sco:USPOII"'''~'''L.lt

CCHficotropin InjKtion. US!'. Adn:nocorllcotropin in, jcc!lOn (Acn1 injection. Acthnr) is a steri le prcparJlion of (he principle or principles dcrin-d from (he anterior lobe of lhe pn uilary of mammals used for food by humans. II occu~ as II oolorless Of light SlI1l .... -colored liquid or a soluble. lIJn()f"' phous sohd by drylOg such liquid ho m [nc froull Siale. II c~ert.~ a tropic ,nnucncc: on lhe adrenal cortc>!. 1l1C solulOOIl lIa~ a pH runge of 3.0 to 7.0 and is usc(] for ilN adrcnoconicolropic :>(.1;\'hy. Repository Corticotropin InjKtion. USP. rilied (ACTII,80. cortiCQ(roplll gel. purified
ACTH po~,"or1 i!,!otroplll )

is con icotl'Oplll in II solultoo of parually hydrolyad gt~ to be u..etl imr:lI11uscularly for a more unironn and rnaimcnan~ of ~clivily .

Sterile Corticotropin Zinc HydroKlrk SIISpf'IWIWlO US!'. SI<:nlc coo iOOlropm zinc hydro~,dc SII:SptII!IIII II ~1t'fi]C ~u~pension of corticolropin. adsorbed on nnr:- II, dro~idc. whi!,!h contain~ no lC)s lhan 4S :llld no nKe .... SS ....g of ,.Inc for cach 20 USP OOI1I00tr0p0n Ullll5.. of its prolonged IICllvity due 10 slow release of ron' an inil;al (Jose, of 40 US P unlbean be adminiSlC!N

cularly, follov.'ed by a maintenanee dose of 20 unilS 2 or 3 ti~ a week,

's.,
T~

I
I

Val 20-Lys

Pro

Val

Phe

tropin, is derived from a larger peptide precursor. proopiomcianocortin ( POMC). Some im portant endocrinological correlations include inhibi tory IICtions of hydrocorti5011e on the r.ecretion of MSH and the inhibitory effects of epinephrine and IJOfcpinephrine on MS H acti on.
LlPOTROPINS (ENKEPHALINS AND ENDORPHINS)

Se<
Mol

Arg Arg

I I I

Tyr
Pro
Asn2~

I I I

Gi,

I I I

I L""

5Glu

l ys

H"

l~!5 ~
G~

~ 35
>'J.

P'o

I I

eI.
I "'9
Tyr

I
I

Aia
Glu

I
I

Val

Pro

Asp

I
I

G',
AJa

I I

Opiates. such as opium and morphine. ha\"e been known for cenluries as substances thaI relieve pain and suffering. NeuropharmocologistS ha ve theori1.ed that opiateS internet with rrceptors in the brain that are affected by endogenous substances that function as regulatOl1! of pain perception. The important breakthrough came in 1975. with the iso lalion of twO peptidcs with opiate-li~e activ ily20 from pil!: braios. Thesc n:laled penlapcplides. ca lled methionine-enkephalin (metenkephalin) and Icucine-enkcphalin (leuenkcphalin). are abundant in ccrtllin IlCrve tenninals and have been foond in the pituitary gland.

!oG~_lYS

GlnlO- Ser

' T~

' T~

Cotlicoltopon

CO!>yntropin (Comusyn) i ~ n s ymhetic ptptide containing the fi rst 24 am ino acids of natural corticotropin, Cusyntropin is used as a diagll()!;tic agent to test fOT mnal conical deficiency. Plasma hydrocortiSOlli: conce nl!3Iion is determined before and 30 minutes after the admini>lrJtion of 250 ~I! of cO!>yntropin. Mosl nonnal respon ses ItSUtc in an appro~imale doubling of the basal hydrocorti , ~. COflCenlr.uion in 30 10 60 minmes. If the responsc is !Ill! nonnal , adrenal insufficiency is indi cated. Such udrcnal iIrs~fficiency could be due to " ither adrenal or pituitary malfUllC1ion. and furthcr lest in g is required to dist in guish be !uoen the two. Cosyntropin (250 ~g infused within" to 8 ; . (80 to 120 Ulday for 3 to " days) is i t with functional adrenal ti ssue shou ld i dosage. Paliems who respond accordingly of hypopituitarism.' the I 'n be by other tests for il Ii ; n who or no response.

(osyntropin,

5Met
'T~

eI. I
I I I I Ly. I

G,
I

oJ,

IMe!IEnkephalin

l LeujEMep"IaIf1

'L""
II.

eI. I
I I

G, I G,
I

As n20 -AJa

G, G,
Phe
5 Me!

Phe

CorticOTelin. Corticorelin (Acthrel) is a synthetic peptide thm may be used as un injectable in the dctenninalion I i responsiveness. It possesses tho: omino acid scin corti cotropi n-releasing hormone that is re'f'OIlsible rOf" ~timulating lhe releasc of ACfH.
t.4HANOTROPINS (MELANOCYTE -STIMULATING OORMONE)

I I Tl" I Se, I
G,

I L"" I Tl" I Val 'S I L" I

P'o

"'""
I H" I L,.. I Ly. I I
Ala

L,.. I I

'I"

lOSer-Gin

I I L,.. Tl" I I

G, ~

Glo
/I EI'.:bp/"oiol (_spl

M elanocyte-stimulating honnone ( MS H) is elaborated by ;ntennedinte lobe of the pituitary gland and regulates of s~ i n in Ii,h. al11ph ib;an~. and. to a lesser t. humans. Altered sccn:tion of MS H has been impl; cau sing chJnges in s~in pig.menllltion during the I I . The Iwo major types of melaredcri\"ed from ACfH and n. a- MSH con lai ns IIw: same amino , 13 amino acids of ACfH: ,8-MSH 18 amilM) acid residues. A Ihird melanOlropi n. l"me laoo-

An examination of the structures of enkephalins revealed lhal !hi:: amino acid sequence of metenkephalin was identical wim the sequence of residues 61 to 65 of ,8-lipotropin (,8LPH). a larger peptide found in !he pilOitary gland. Thi s discowry suggcsted that ,8-LPH might be a pn:cursor for OTher larger peptides containing the melenkephalin sequence. Soon afler the structural relationship between fJLPH and melcnkcphalin was established. longer pept;dcs. called t!JIdorph;'u. were isol aled from lhe inlenne<liatc lobe

of the pllUllaI)' glund. Thccndorphins (a. /Land iloomainrd the nll'tcllkcphahll amino lICid <rquencc aoo possessed mor phi ne llke octh'il y.:7 The IOllgc.\1 of !I1C,loC peptid.es. f3-endorphin. a 3 1 ~ due peptide (residues 61 109 1 of P.I.PI~ ). is aOOut20lo50t llnes more potent lhan morphine as an anaI;c SIC und has II oonsiderobly Iooger duration of action than enktphalins. Numcl'OIls enl..eph alin anulogut"lo und derh"u tives ha\'C been prepared. and lhe lr biological IICtiv;l), has been c\ahmed. Like morphine . .8-endorphin and lhe cnkc phalms can illduce Iolernocc and dependence. In addition to lhe cn ~ ephal in s lind cndorphins. <rvernl other opioid peptl<kS have bern clI.tlllCled from pilui laty. adrenal, alld nCTI" OIIS lissue. includil\i: dynorphlltll and !leOendorphiM. The pepl ides P.LPII. ACTB. aoo ,..MSH are derived from tllC same precursor. POMC. The endorphins and clll ephalins hal'e a .... Ide range of biolo&ical effects. and most of lheir :.c1ions are in the ~'Cntrlll nervous systcm. Tbcir aclions include inhlbluon of rele~ of d~mine in br.lin tissue and inhibi ti on of release of ace ly1choline from rtcummu>cular junction~. The role of cndor pnill and cn~cphalins ru. inhlbilOl) lIl'urotran~miuers agrees well ..... lIh the observed biological cffects of Ihc!;e peptide5 in lowering res pon se 1\1 pain and othcr sti muli. Thc role of endorphins und cnkephahns as neurotl"lln~l1liuers and IleUromodulators. ..... ith emphasi~ on m:cplor imef3f.1lons. has been revlC\lcd. 2I A lso. 'iCC Chapter 22. Anal gesic Agems. in this tcUbook .
GROWTH HORMONE (SOMATOTROPIN)

denIed GH and recootbinant somatotropin by additm. fI an e~tra amllM,) acid. mcthKJIline. Ikcau!.e of its '1na:ID~ difference fmm the nalullIl G H. p:lllem _ reccl ~IIlS sotnalltlll may develop antibodics . ..... hkh nUlY result in a dec=scd response 10 il. Som3trem i ~ oommi stered i mr3Il1 ucubrI~ or subeut3lll'Ol1Sly. and the: therapy i. contlllued as lon! .. \hi: palient respond,. unti l the pmicm reaches mature IIIIDIt l1Cight. or unt il the epiphy'iC:'s close. The dosage IlInge i\ O,QS to 0. 1 IU.

Soma rropin (rONA Origin). Somatropin for in~ ( ll umatrope) I~ a naluml sequclla: human G li of rONA ungill. Its COfllj)Ololtion and o;equcnce of amino acid, are iIbIJ. cal \1 1th those o rhum.:m G tt of pi tuitary origm. lt is IIII10tutft tered intmmuscul arly or subcutaneously . The (Image nIIItt is 0.05 to 0.1 IU.
PROlACTIN

Prol:lCtin (PRL). II hormone secreted by the antenOl"]lIIIIItary. was dlSCOI'cred in 1928. It IS a 198residllC pol)lltplJt ..... ith gt rteral Slruclural features si mi l~r 10 lhose of Gil. I'll ~ti n1U l:ltcs lactlLti()n of patturition.

Gap'd1tbGplc Hasm _ _
The IWO principal gonadotropins elulloratcd by tile adtnob) pophys is are FSH and L~1. LH i~ al "" known as IlIImlll..ul/,sflmw/llIjfl8 Iw""'",~. The g<lf1lIdotmpins a~ thyrotropin form the Incomplete glycoprotei n group""" monCN . FSH and LH may bc produced by 3 slIlgle cdl. W gonadolroph. The secretion o f FSII and LH is controlkd_ the hypothalamus . ..... h,ch produces LH RH. LH RH_ laiC' the secretion of both FSH and Lli . although ilS c:fft\21 on the !-Cerction of LH ~re nlOfe pronounced.
FOlLlCLESTIMUlAnNG HORMONE

Gil I ~ a 19 1residue polypep!idc elabOr.lted by the antenor pituitary. The amino ocid sequence of GH has been deter. mined. and eomparij;()tt .... itll gm\lth honnooe.~ of different spccie~ has re\ealed eonsiderable structural ~arialion.19 In addition, the structure and prupertit'5 of human G H h~\e been rel'iewed.XI The major biologieal :.c1ion of G U i ~ to promote overall somatic growth. Def>ciency in the secretion of this hormone can cause dwarfi sm. and an o\-erprodUC1ion or thi S hormone eall cause acromegaly and giantism . Secretion of thi ~ I\or. monc is ~timulall-d by growth honnooe- n:lcasing hormone (GHRH), a 4--I residue polypeptide <ecreted by the hypothalamus. Secretion o f Gil i~ inhibited by );Om~tOlotalin . GH Sl.i mulal e~ prolein sy mhe!;i s. both in the ~ kelet al nlU~' cles ami in the Iher. In the liver. GH stimulatC$ uptake of anulM,)add~ and promotes the: symhc~i~ ofall rorms of RNA . It stmlUlates glucagon -;ecr"l:tion by the pancl'l:as. increasc~ sy nthesis of glycogen in muscles. uugment ~ the: rckase of faUy acids from adipose ti~sue . and hlCrease, Olot~":lIl'sk It al50 CDLI'it"!> xute hyposl)cemia rollo\l" by cle"ated blood ed ghK.'1N: cOllCelll r.II'OIl and. perhllps. ;Iyoosuria. G il ha.~ bee n rccogni,.cd us an effective Il'plaeement ther apy for G IIdeficient child ren. The: su pply of G U. howe\cr. was "ery hmned because U~ SO!Jrtt II'lI;S the p1\uilury glands of human cada\en. and se\'er~1 reporu of dealhs in children with Cn:u tlfeJdtJ;lkoh di-.ea."\e (1.';11.1'00 by viral contmnina tion of G H) halted the dl~tribution of G il In 1977. Both of thc'iC:' problenlS were 5Oh'Cd ..... ith the applicauon or rONA technology in the comnlCre;al producliun of liQmatrem alld MHnmropin.

FSH prom(J(es the dcl e loprnent of o~aTlali fol lic le~ t o _ rity a~ II"CJ! a.. ~pennalOgelll'sis ;n test icular tI S!o,~~ ".'.' . gl)CQprotem. and the clirboh ydlll te component I~ to be associated with its IlCliI'lIy.
LUTEINIZtNG HORMONE

Lli i' anofher Ilyooprolein It aclS after the maturi~I"" of FSH on ovarian follide~. st imulme, prodUChon of eozro gens. and tr'Jn,ft)f11lS the foll icles into corpora IUlea. LH IlCtS III the male: to stlmulute the u:)dil! cells thal
te_ ~tc runc . "

MENOTROPtN5

Somalrem (Syslemicj. Somatn:m (Procropm) IS:l biosy nthetic form of human GU that d iffel') from the pitUitary

PIllUlar)' hormooe.~ prepared from the uriIlL"' of "'....._ .. sal women whose o"ariull MSue does nof respond tQ! tropin are available for medicinal U!>e a~ the prod-uc;t mautroplllS ( Pc:rgonal). The latter ba.~ FSll and LH I XU, " l' in II I: I mt io. Menotropins are u!.eful in till' ~ of unovular women ..... hoM:. ovarie~ re~pond to prtUIt!ry P' nlldtltropins btli who ha l'e 1\ gonadotropin <kr..:itnc)' ' : : by cuher pituitary Or' hypoth:.... llmus malfunction . .,;~ nll'nOirupin ~ are admin istered imrnmu_~ lar1y III an

Chaptu lS I'rorems. & :... ,.,..1. urnJ I'rplid~ lIonr..:mn

84S

dose of 75 IU of FSH and 75 IU of LH dally for 9 to 12 41)1. follov.td by 10.000 IU of chorionic I!onadotropin I 41y .fter the last dose' of lTII'ootropins.

'.,.
cJ,
I
I I

T1t,.Ob opln
The tllyrolropic horTnone. also ca lltd tilyrolropin and Ihyroid-Jlirnu/lllmg homwnt (TSH ). is 3 gl)'coprolcin coni~t iDf: of IWO polypeptide chain~, Thi s hOnTlOOe pro1l10tc~ produl:lion of thyroid hormones by aff<:Cting the kinetk~ of the nw:ch:mism by whICh the thyroid cOflCemrtn es iodide ions from thl' bloodstream. thereby promoIing incorporation of !be halogen mto the thymid hOf'moncs and release of hor _s by the th)'mid. TStl (Th)'ropar) appears to be a glycoprotein (rel:l1i,'e ....... c<llar ma.u IM,126.000 to 30.000) conlOllninl! ,Iocos...nc. galaccos:tfmne. mannose. and flJCOSC!. whose homogelledy is yel to be estabh~hed. It is produced by tile b.:Isophil cdl. of lhe aniMO!' lobe of the pilllitary gtand, TS H enten; tilt m ru lanon fmlll the pi tuitary. pn"sumably trll"en;inl! cell IIITIlbnmes in the proce~s. After ClIogCnou~ admini stration. iI is widely distributed and di'\tlppca .... 'cry ...~pidly from CII'Culation. Sume evidence suggests that the thyroid may iluTtdy inoctivate some of the TSH by an oxidation nltthamm IImt may involve iodine. TS H thus inactivated can be =ctj''IIted by CCf111in reducing agents. TS ~I regulates the I by the thyroid gland of Ihym~ine. which stimuthe mttabolic rJIC , Thyroxine feedback n1hani ~ms the production of TSH by the pituitary gland.
that leads to hypothy. I can be distinllul~hcd by the adminisu'lltion or TSH t to the uplake of rndioiodine Of' lneie\'3te the blood or pla~ma prOlcin-boulld iodille (PBI) COO~UCllce of enhHnced secretion of hormonal iodine n1tyro~ine). Interest logly. tna.~sh'e ~ ofyitllmi n A inhibit o;ecrction of TSII . i ;s used lIS u di~gllostic and 'iCCoodary hypo. Its u<;c in h)'jXllhyroidism eaused by pituitary ;~oc, has linmed application: other form_ of treatment preferable ,

c,.-S-S-c,.
Lys
~Asn

Sel
Thr

I I

I
"""
Ptle

I
Phe I Thr'll

I
I

TIp

lys

Sao ,)$!'"

A pGIO.erful new synthetic peptIde that mimics the :IC1IO/l of ~oslal in. OCIreoude acetate (Sandosmtin ). is appro,'td by the Food and Drug Admimslnllion (FDA ) for the treat lI~nl of ccnain rnrc forms of int(\linal endocrine C31l1.'('flI. ~uch as malil10ant cllrciooid IUmors and vasoactive intestina l peplide-secreting tUlllOB (V II'omas). Octn:otidc acetate is indicated for long-t~ml t n:3tment of 'iCVere diarrhea IIs.~oci llled with these c~rci nomns ,

Placental HOiiltDn. .
HUMAN CHORIONIC GONADOTROPIN

Buman chorionic I!onadotropin (hCG ) is a gl)'coprotem sy,. thesi/.ed by the placenta. Esut),ens stimulate tbe anterior pituitary 10 produce pI~nlotropin. which in tum ~umulates hCG synthesis and secretion. hCG i~ produced pnmarily during the first lrimester of pn::grnmcy. It e~eftS effects tlult are similll/' to those of piwnary UI. hCG is used therapeutically in the management of cryplOf'chidism in prrpubcrtal ooys , It also is used in women in conjunction with menolropi ns 10 inducc ovulat ion when the endogenous availability or gonlKlOlropin h not normal.
HUMAN PLACENTAL LACTOGEN

at Istatin

"::~;~:;: .~~.:'ii,.~~~::, III the hypothalamus. It is elabby tbe fj cells of the pancreas and el",whcre In the I i is an oligopcptide (1 4 amioo acid res;and is referred to as wmllll!lrQ{lin ,-,'It!//5f!-lnllihmng (SR IF ).

Human placental lactogen (hI'L) aJ.o ;s caJltd human choriomamnwlfflpi" and c/l(lriQll ic gro".-til-lwmlOM proilJ(',ill, This honnooe uet1s nutlll.'fOUS actions. In addition to mamlTlOlroplc and loctotropie errl'CllI. it Uf!ns '>Omatotropic and lutrotropic actions. It i~ a protein composed of 191 amino acid unilliin a single-peptide chlli n with 110.0 disulJide bridges.:J hPL rcsc:mble~ human somatotropin.

0;;,

N."rohypophyse_1 HDr.. _

. . (Oxytocin,

V_sopr. .5Inl
The posteriOf' pit uitary (ncurohypophysis) is the SOUn:l' of vas0pres5in. oxytocin. a- and ,8-M511. and coherin. TIle synthesis. transport. and relea.'ie of these horrnones ha~e bn reviewtd by BrownslClI1. '~ VlISOpITssin and oxylocm IITC
synthesiztd and relea5i!d by IICUrons or the h)'poth.l:unic- neuroh)'pophy~al 5y5tem. ~ pcptirk hormones. and thei r respecti"e neurophYli;n carrier proteins. are synthesiztd as slrUCIunil components of separate precun;or pr0teins. and these proteins appeat' to be p;:u1iaJly rkgrnded mto

:"'!CJ'd

!~,~":pn~.m~~'~"~X~:'~'"~"i;iS inhIbiting the releao;e oftheilreleasethe Somlltost:l1in also suppre\!>C'$ G from of

. Jt e-auses a decrease in both cAMP eyclase acti.-ity, It also inhibits calcium mnUA mlO prtuitary cells and S-UPP' ,se, Illucose pancn::lIic insu lm secretion by acti.-ating and de3e'lipota.S\lUm ion and calcium ion permeability. rcs.pcc'The clienllSlry. SARs. and potenlial chnical applle.Im,'e bren rel'1elO.ed. n. 11 I

~maller

btoact'l'e

ptpll~ In

tIM: CQIIrsc of InlIl5po1't along

the

a~on,

hormone (ADH ). Th .. hormone can c:ffC'Cl gtaded ~ 11\ the permeability of the d' Slal portl(lf1 of the rnarrunalIa

GIy(NH l

NH,

I la, I
I

I "'g
NH ~

GIy(NH 1 )

Pro

. I

Pro

I
I

eysSS"",,
Tyr
lie

, I

eysSs<::y.
Tyr
!'he

I I

Asn~

I I

I I

Asn ~ G~

I I

GIn

""'~

VaKlpt_

The StruClures of\'a~~i" and o~y\Ocin hal'e ~n chlciliated. and thc:lsc ptpudc:s hal'e b'n ~)'nthesiud. Acu.t:llIy, thl\.'e dosely r.:latc:d oonaptptidcs have been ;wlatc:d from mlU1l1na1i;1Il pc)lo.t~rior pituit~ry: oxytocin and ~rgininc vaS(}JIfC"'~m from mosl mammals lind ly~ioc: vllJ;O!)re.s.~i n flUlu p'g~ The: \ilsopn:ssin~ d,ner from one: aOOliter in the MhiK of the eighth ammo acid rc:o;idue: arg'nlne and lysine. rc:spc:ctilely. OxylOCllt has Icucin.: at posi tion 8 and its third amino acid i~ isoleucine insteatl of phcnylalllI1;OC:. Several analogue~ of l'lI"llfl'"I:Ssin hale been S) nthc~iled and their lII1udi "retlc a<:lil-ity evaluated. l)esmopre.. ~slu. 1-Uc.'I:IlIuno-8-argi nille-\asopn;:~sin. i~ a "yntlM:tic derivlluve of vasopressi n. II is a longer-acti ng and nlOre poIent antidiurelic th:U1 vasopre.~ ~i ll, with much less pressor activity. t:lesmoprc:ssi n is much rrIOI\: resistant to the actions of pcpI idascs becuuse of the dcami nallOll 311'0"ill00 I. which accoums for its longer durdtion of actioo. The ,uD<;litution of 0- for ..... argioinc: in posilion II acCOU1l1lo fOl'" it$ sharply lo..... er vasoconstnctive effecl"V~,'n also is ~llI)wn a.~ the pi/u,/(/ry (Jnlid,uretic

nephron to waler. resulting ill either conSl>rvatl(}ll or ~"rt tiOil of water: Ihus. it nlOdulntCl. Ihe renallubular re~ tioo of ....<ller. ADH ha.o. been sho .... 'n to increase cAMP P"'" duchOO in seHr.a.l ti~ll~s. T1Iroph)"lhnc. v.hkh I.... eo cA MI> by inh,biting the en/ymc [pOOspht)(h~~h:l1IloCl tha cUlaly/.e its hydrolysis. causes pcmlCabihty chan~c .. >im.iIr to lhose c:au'\Cd by A mI. C)dli: AM I> also CffCClli SIlIllIaptrmeability changes: IK"nce. it is ~u~esh'd that cA.\lP. involved in the nlCl: hani~m or OCliOil of ADH , lb: oon~nal :w:t;ons of ~ asopre<;~in mcludc Il~ u _ strictOI'" effects and neurotmn.m,lIt'1" action < in I~ mHnII nervOO$ syStem. such liS rc:gullillon 0( ACTI-I 5mion. tr eutation. and body tempemture. AD H is thenlptuticaUy useful in the lrealment ofd,attt. insipidus or pituiUU)' origin, It also ha..< been u..<oed to ItJ~ intestinal paresiS and distenuon. Oxytocin is IIppropriately named on the: ba.~is 0( its 01)111eil.! IICtion. O)lytocin ~)lC'J1S Slimulllnl ("ffccls on the ~ muscle of the uterus and nt.ammary gland and has effecl on .-ascu lar smooth muscle " hen admini stc:ml i. do!;es. II is cOII<idered the drug of chOIce to IIldoce 1Ibcr. particularly in ca-.c:s o r intrupartulIl hypoton~ incnlll. 01)"," ein also is u-.c:d III ille"tablc or HlCtxnplc:tC aoorllOli. the 20th wt:c:k of gc:stlIuon. It also may be used 10 pmai' or CQnlro l hemnrrlmge and 1 correct uterine hypolODlCl), 0 In some ca ...... o)l),\ocin i~ used 1 promot e milk, 0 .:i;;;;'~"'~' actS by OOlItl1lCl.mg the myoc:pithe:hum of lhe , glands. O)lytocin is usually ildmini~lcl\.'"ti p:1r"c:nlerally 11)". tfllvenous infu)ion. intr.l'cliouS ,nJection. or inlnanl\lSi,...u injection. Oxytocin C"i tfllte buccal t"hlels an: 111'10 31'aibNo bul the nlleof absofption" unpre<hclublc. and buccal_ istnllion is Jess precise. TopICal administflltlon ( na~1 ~

""In_

TABLE 25-5
.....,..ration

Neurohypophyt;eal Honnones; PhannltCe...tIQIII Products

PropriefM)' Name

Us,,",,1 Adult DOH

1M. 3-10 U aIItr III pbo..... UI; IV, ,nmalty 1>0 IIIOt<" IlIan 1~2 mOl"" ....... h..,...."wod ~'tt)' I~)(t

O>.)k.O:'" illl"'llI.III. t:SP Piwf"l... S.'n/<X,,,,,,,

"'' '>"ft)'

1111_" utUl1JItfIboll_lmll
....mpl"lQr ...........

<h) .... '" ...... ...auoon. l 'SI'

.I\...~

I !ofn)' or J ~

'0 I Of OOdInooonl. 2-3 n,",,,1<"> lief"", '. """1 01

POI"'.,.'" Slmle . "'""Jft>"" ..........

"'I ... ~

V......,._

"'1"'-. USt'
"",NI,"",,,,, p<NMOI'
pin'lW} hot, ......

tM 01 SC.1j...10 U u.d orq j ......

-,.,

tM crSC,l~HlllUL ... q.iI a

-..,
~

p,,":1.''''
f)D.1I'P

t~ln

......a ....111"'"

.:<tI'e

...... IWIU .... 'kp<NIC<T ..... ""ui",,>, hoo '....10

1\."'Id,~"'k

M ."""o......, ,"'......1. Z-4lLf/d1y....

"lIlIledo>< !If in 2-3 d,,,1W \koso

\I~f'~<.!.~~"*\r ""Ihl pl'I" III) .w ~~

",. ..."'y lor ,n 2_1

di.Nlt<I~

1>n""lP"'>"''' ..:flOI'e
()I)A IP,

PC'

'-~

pllUtlolt)' ~
,

.,!(II

IV or $C. 2-4 ........ ~ .......Iy I~ 1 d.. ldod .s..- in ~ "",",in,,,,

.\t-....
.. . ... -. lOki

-.

IV, 3 .. IlL. ",. tnly.1O II O,9'l ...".,"'" ~nlondo kO.....-.. l'SI'

2 or 3 minutes tlefOf'!: nu ..... lng 1 promote mll~ ejection is 0 KlmCtin~ rec()mmclldoo. 'I Sec Table 25-5 (Of" prodUCI It,Img. OA)tocin injection is a ~terile K/lUtlon In ""aler for injection of o.\ytodc principle prepared by 'ynlhe~l~ or obtamed from the l"IO'ierior lobe of the pitui wy of healthy. dollle_lic "",mab used for food by humun s. The pH is 2.5 10 4.5; e~l)l r.uion d~tc. J )CUrlI. O~)tocin pn:p;lmlions are widely used wilh or wilhout 1I11111000my to induce and stll11u lale labor. Although injtClion i~ the usual route of adnnniStr.l.tion. the sublingual route is e~I",mcly effective. Subl Inguul and mtmnasal !ipf"".ly (OJ. ytG,In Nasal Solution. US!') roules of admini~Imlion al'>O will !oUmul:Ue 111i1~ letdown.

diuretics for uo;c. in children. It i~ mdicated in the nmnagemen! of lemporory polydi psia lind polyuria associalcd ",ith tmunta 1 or surgery in. the pi1 uitary fCgion. 0.
p~tk

Oqtocin Injtion, USP.

HOitlbones

Relahonship!l between hpid and glucose k\< III the blood e1s and lhe genentl dl..ordcrs of lipid mClabolism found in diabetic subjecL~ h\'c rece ived thc allcmion of many chcllli,t~ and eli nidans. T o undl!rsland diabete~ mell ilu~. it s complications. and its lreatmc:nl. one has to begin ""ilh lhe ba.,ic hiochemistry of lhe p;ll1CfC:tS and the way~ c-.trbohydmle.." :tf'l: rorrelaled with lipid and protem Inctaboh "m. The pancreti productS insulin. IS well as glucagon; ,B-cell~ secrete in\Ulm and a-cells se... ete glucagon. hlliulon i~ con~iden,od first.
INSULIN

VlSopn!uin Injection, USP. Vasopressin injection (Pi~sin) i. a sterile oolulloo of the water-'>Olubk: preMO!" prinCIple of the poslt'rior lobe of the: pituitary o f healthy. domOltIC ""mals used for food by humans: ilal!iO may be preparro by ')'mhesi~. Each mllhllter possesses a ~IKY .acti vlly equlllO 20 US!' po!>leri{)f pttuilury Unil$: expimtion date. 3
)caJ"S.

tannate (Pitl"CS.'illl Tannate) is a "" ater-ill!>Olubie tannale of vas.opn:ssin adrnm1\oICffiJ IIltramuJioCularty ( 1.5 10 5 pre$.<iOf unilS dally) ru.. Its prolonged dumllon of octioo by the slow release: of ~asopn:.s SID. II i~ Pllrticularly usefu l for p3tiems who have diabetC$ in.lipiduR. but il ~hould llC\er be u-ed inlm~enously.

V.sopn!uln

Tiln~t..

Vasopn:~sin

FeJ yprcS~1 n. 2-1.' phcn yla Ian I rIC- S-1.-Iys Ine:

,..~ .~:~;,~,'relall,"rl) low amidlurellc IICt i ~ily and lillk IC" . II h.as considcmble pt"eS.'iOf (i.e . Ya.soeonacti \'ily. "" hlch dl ffcrs frum lhat of cpinephrine (i.e . ca pillary constriction in lhe inlClitinc illowers the \ena portlle. wliclTa.'l epinephrine mise-; the i pressure). FeI)'~\~," also causes irocrra..w renal flo", III the cal. ""he~as eplncpbrinc bnngs about a flow, FcI)"pres.~in I~:S limes TIlOI'e effective YIl'>Opl"essot Ihan i~ 1)'slne: \'asopre~in and is reoom surgel) to minlmiu blood flow. cspecially in 01 '1 and g)'TIL'C()logy.

Inc

-:::':.1,;'"

~'~" i~ s)'nlheuc S-I.I)',,1ll' ~asopres

10 ADH. The lys lIle analogue: is <.table. and it is absorbed rnpidly from lhe usaIIIlIlCm.1. Lypre~sln (Di~pid) i~ ph.1mmcrutically aYailas a topical '>Oluti()". sprny . .so pre~1KY unils (ISS p.g)/ 5rIlL container;. Usual dosage. topical (i ntr.... msal). GIlt or more spm)'~ applied to one or both I1(l('itrils one or daily.

~ul1Jlar

.;.; ",mo:,

Of"fmopn!ss;n Acetate. ~~In ocrlate DOA VP. Slunate) is synthellC l-des.amino-8!)-argininc vaIlS efficacy. CJ)C of admini~trntion (intmnasa l). action, and lac~ of ~ide cffects make it the tbe tf'l:anllc nl of ce."tral diabetes insipidus. be adnlllllStered inlmmu~ul(U"ly or immveh i~ prefrrred to Hlsopre"sin onjecllon and IlnLI anti-

One of the major triumphs of the 20th century occurred III 1922. wh'm Banting and Besl ~traned insulin from dot! p;lrlCIUS..l-I Ad"al"lCeS In the biochemi~try of insultn ha\"e been re'ie...ed wllh emphasis 00 proinMl lin hiOl nlhe,is. convCl'lIiou of proinsul in to insuli n. insu lin secretion. insulin recePtors. rnclaboli~m. cffecl~ b)' sulfon),lun:as. ami so on.J! \II lu\ulin is ~)"nlhe\i:.ted by the "leI ,B-eclls from a Singlechain. 86-amlno-acid polypeplidc pn.."Cun.nr. prOlU$ulin." Prolnsu lin it.>elf IS .~)'nthe.."i7.ed in lhe polyribooomes of the rough endoplasmic reticulum of the P.ce.lIs frum ~n cvcn larger polypeplide pn."Curwr. prcproiu~ulin. The B ch:lin of preproinsu lin is c~lended al tilt: N 111'Icmlinus by at lcast 23 amino acids. Proinsulin then tm\eI'SC:S lhe Golgi apparatus and entel'll the SIOr.tge gmnules. where the con\CNion to insulin OCCUfli. The subsequent proteolytic con\Cl).lon of promsulin to insulin is iICCUIIlpltshcd by lhe removal ohhe Arg -A'll ~si due at po!>ilions 31 nnd J2 and the Arg- Lys residue at po~i tions 64 and 65 by an endopeplida.<;e that re;.erllblc... II)'psin in it s 5peci rK:lly arid IIlhiol-acllv3tcd carbo~ypeplldasc: BIt~e enzymc:.-"l The actions of these protl-oJ)UC cnl;)'nlCS 00 prolllsulin result in the fonHalion of c:quimoilif quantities of msulm and the: connecting C-peptide. The moulting insulin molecule consists of chains A lind B. wilh 21 nnd 31 amino acid re5idues. respecti ,'cly. 'The chai ns arc COt" ....>ctcd by 1...0 disu lfide linkages. with an additional disulfide lin~age wlthm cham A (Fig. 25-6). The three-dimc nsional s.tnK:lure of' insultn ""'"lIS drtemllnc:d by x-rdy anaIY\I\ of 'ingle cryst:ll ~. l"hco;c. ~1Udles demonSlnlled lhat the: high blooctiyity of in ~ulin depends on the int egrity of thc overull confonnation. The biologically 3(.tlVC form of the hormoue is thought to he the: niOllOtJICr. The reccptor-bindlng region consisis of A-I GI)'. A-4 Glu. A-5 Gin. A-19Tyr. A-21 Asn. 8-12 Val. 8-16 Tyr. 8-2-' I'he. and 8 -26 Tyr. Thc three-dnnensional cry5uIl ~tnJClure appea .... lo be COIlSCI"\'ed in oolulion and dunnll,ls ra"eplor lnter.K:tion. Thc amino acid !iCquence of lIl~ul i ns from \'ariou~ annnal species has been e~amined.j~ Dctath ur t!lesc are "hown in T able 25-6. It is apparent frum the unalysis that frt.'qucnt changcs in <;equence occur wilhm the Interehain disulfide ring (positions 8. 9. and 10). The bomKlOaI SC<juencc for porcine insu lin is the elOSCIit to that of htJlllatls. d,rrering

PROINSUUN

C-PEPTIOE

Figure 25- 6 Convers.tOO of PfOOlol.o IMui,n

TA8LE 2 5-6

So m e Seque nce Differe nces in Ins ulins o f Va rious Species

Sped ...

AClYln

...
CO<

Itu......

a..w..

.....,
It......

'"'

'" '", G'

Gly, Gly.

"" ""
AI.

..
SSSS-

""'

A<.

0<,

'".

'" G<,

"" "" "" "" ""

Gly. Gly

,.. ,,' ,,'

" ,..

-,

, ""'" "
"" "" "" '" ,,.. '''' '0
l),. l)l,
1,) .

It..,

G<,

,"or

rn,

"" ..

"" ...

.,.

Ly .
C~ C~

,.. ,..

.. ....
...

".
I .)~

C,'

s." Il<l........ " h ........ ""' .............. for CoIIo" I',,,,,iuo ~ .. A

<""'.

""

.. ... ... ... .'" . .. ..

Chapler 25 I'rfJ/dns. Em;ymrJ. nnd only by che ~ubscicU!ion of an alanine residue at che COO Hccnninus of che S chain . Poo::ine insuli n. cherefore. is a good r.urting mmerial for che sy nthe,b of human insulin. Insulin composes I % of p:lncre-mie ti ss uc. and secretory ~crn gro nules ~'Q'lIain nbOtH 10% insulin . These gronules fuse wilh che cell nJC:mbr~r>C wilh simuhnoeous liberalion of equinwlar amouncs of in sul in and che C -pcpcide. In sulin e nlaS che ponal vei n. nnd ltixlU! m, is removed in ics first passage lhrough the liver. Thc Jllasma half-life of insulin is IJIIIIUximacdy 4 minuces. compared wilh 30 minuees for che CPl'pcide. Usunlly. e)!ogellOOs insulin is weatly uncigenk . Insulin 1IIIibodies have been ohsc,..,cd to neulrali1;e Ihe hypoglycemIC effect of injectc-d insu lin . The ;mti body-binding si les on insulin an: quite diffcrenl from the si tes involved in binding of insulin with its recepl on;.~ ' Regulation of insulin sccn:lion is affecled by numcrous faclOfS. soch as food. Ilormollal und neuronal st imuli. and i<lnic mechallisms.2 In humans. the principal subscrate thac lIimulales the re lease of insu Ii n from the islet .8-cell~ is glu ~. In addition to glucose. other substra tes (e.g., amino acids, fm: fally adds. and kelone bodies) also can sti mulatc insulin secre tion directly . Sccrclin and ACTH can directly IIlmulatc in~ulin $Ccretion . Glucagon and otlK'r ~ Iaced peptioks can ino;rease the se<:reti on of insulin. whereas somatoltatin inhibits its secretion. Autonomic llCuronal mech:mi sms al50 pl oy an imponam role in regulating insulin releasc. In che sy mpatlK'lic nervou s Iystem. a-adrencrgic agon ists inhibit in sulin release, .hereas .8-adrenergic agonists slimulate the releasc of insulin. [n the parasympatheti c IlCrvOu~ syste m. cholinomimetic ilrullS stimulate insulin release:. Clinical"' insolin Ihal tms been crystullized 5 limcs and thttt subjected \0 countcrcu~nt dislributi(H1 (2-butanol: I % ilichloroocetic acid in WlltCr) yields about 9()<,l, insulin A. . ith ~nryi ng amounts of insulin B together with other minor romponeJ1ls. A and B differ by un amide groop and hn~e tile !::lOle activity. EnrJ_member analysis, sedimentation. nnd iliffusion ~lUdi es indicnte [tn M. of about 6.000. TIle value rl12.())O M, for insulin oontnin ing Ir.,ICC amoun ts of :d nc lobcIint.'tI by physical metlKxbi) is prob~bly a bimolecular lIWCialion product through the aid of zinc. Insulin was lhe ftnt protein for which a com plete amino acid sequence was determined. Tile extcnsive studies of S;mgel"J and otOers !lucidated tOe amino acid sequence and Structure of insulin . Katsoyallnis.... and others followed with the synthesis of A and B chains of hum;m. bovi ne. and >.hcep insul in. 1lIe A and B clmins were combined to form insulin in 60 to 8Q<l, ) . with a specific activity comparable to that of the

Prp'i,l~ Hormoor~

849

"~rnJ tOlal synthes is ofhulI1an in solin Wll.~ reponed by Rit"""""~. The

11:1 el al.~ llM:sc wor~ers sc lectively syntlK'sized the final llOlecule . cross-linked by disulfide (-5-5-) In mnging between 40 and 50%. whereas carI ti methods invol ved mndom combinatio n of scpA :lIId B ch:lins of tlK' molecule. technology has been :lpplied wccwfully in !he of human in.ulin on a commercial scale. Human is producc-d in geneti cally engineered Escherichia Eli Lilly and Co .. in cOCJpCration wilh Gencmech. marketing rONA..(\eri\c-d human insulin (Humul in) . There are two available methuols of applying rONA ,"I,~ in tile proouct ion of human insulin. The earlier

"d.",;.""

methoo invol ved inscnion of genes. for production of either the A or the B chain of the insulin molecule. inlo a special wain of 1:. (vii ( KI2) and subsequently combinin g the two chains chemically to producc lUI insulin !hac is structurnlly nnd chemically identical with pancreatic human insulin. The second, and mon: recent. me!hod involves the insenion of genes for the entire proinsulin molecule into special F... coli cells that ~ then grown in fermentation process. The coom:cting C-peptide is then enzymatically cleaved from proinsulin to produce human insulin.47 Human insulin produced by rONA technology is less antigenic th;m chat from animal sources. Although insulin is readily available from nalurnl sources (e.g .. porcine and bovine p;:tncrcatic li ss ue), partial syntheses and molecular modifications have been developed as the b<lSi s for SAR studies. Such sludics have shown that amino acid units cannot be removed from tbe insulin peptide chain A withO\lt significant loss of hormonal IICtivity. Sevef'JI amino acids of chain S . however, are not considered essen tial for activity . Up to the first six and the lust!hrec amino acid uniL~ can be removed without significant decrease in acthity.21 T wo insu lin analogues, which differ from the parent Ilormone in that the NH r tenninus of chain A (A ') glycine has been replaced by 1,- and l)-alanine. respectively, have been synthesi~ed by CO$matos et a1. 411 for SAR studies. The relativc potcno;i cs of the I, IUld 0 analogues reveal intere sting SARs. The 1.- and l)-ailinine analogues are 9.4 and 95%, respectively, as potent as insulin in glucose oxidation. The relative binding affini ly 10 isolated fat cells is reponed to be approximately 10% fOf the 1.- and 100% for the 0 analoguc. Apparently. substitution on the a carbon of A' glycinc of insulin with 0 methyl in a particularconfigurotion interferes wilh the binding; hence. the resulting analogue (!hat of 1.alanine) is much less acti ve. Mcthyl substitution in the opposite configurlllion affects neither the binding nor tlK' bioactivity. Molecul ar mooificDlions of insulin on lhe amino groups appear to reduce bio.'K:livity, bUI modifications of che camino group of lysi ne number 29 on chain B (B-29) may yie ld aclive analogues. Accordingly. Muy ct al.'" symhcsized N- c-( + )-biotinyl insulill. which was equipotenl wilh natur:J1 insuli n. Complexes of th is biotinyl-in sul in derivative with avidin also were prepared and evaluated biologically; these complexes showed a potency decrease to 5% of chat of insulin. Such romplelles conjugaced with ferritin arc ex pected to be usc ful in the de~elopment of electron microscope stains of insulin re<.:eptors. Alterntion in tile teninry structure of insulin appears to dl1l5tically reduce biological activity as well as re<.:eptor binding. The three-dimensional structure provided by x-my crystallography of !he in.wlin monomer has revealed an exposed hydrophobic face that is !hO\l~t to be invol~ed di rectly in interacting with the receptor. Thus. loss of biological activity in in sulin dcri~atives, produced by chemical modification. can be inte~tetl in terlllS of oo\'ersc:ly affect ing thi s hydrophobic region. Also. species variation in this hydrophobic region is very unusual . Insulin is inactivated in vivo by (aJ an immunochcm ical system in the blood of insulin-trealed patients. (b) reduction of disulfide bonds (prob.lbly by glutath ione). and (c) insu linase (a proceo[ytic enzyme) tltat occurs in liver. Pepsin and chymotrypsi n hydrol)"l.c some peptide bonds thaI Icad to

inacll\"lItion. Insulin is Inactlvaled b)' reducing agen!!; such as \Odium bisul file. sulfurous acid. and h}'dWjlen. Ad\ances in the area of msulln s molecular mechanisms have been re ... lell'ed ...."., 11 with emph:llois on Il."CCptor inter. IICtiom., effect OIl membrane ~trut1ure.nd fuoclloos. effrtts on enzymes. and the role of second mc:MCngers. 11le ins.ulin rc=ptor is believed 10 be a glycoprotein C'Offiple:c. with a high Mr. The receptor i~ thQllghtto conSISI of four subunit.: IWO idcmical a uni1.~ with lUI M, of about 130,000 Da :md I"Xl idcmi<::al {J units wit h an M, of 95.000 Oa. jointd togcther b)' di~ulfide booos. The l> subunits are pOmari ly respon~ible for binding insulin 10 its I'l.--ceptor. and the {J ~ubunih arc thought 10 possess mtnnsic pmlcin kin:lsc activity that is stnnulatcd b)' insulin The pnmllf)' effect of insul in ma)' be II kin:.se ~imulDtion leading 10 phosphutyhuion o r lhe ~ep lor as wl'll lIS othe:r inlracellular pnxems.':' 'J Addi tionally. insultn blllding to its receptors mOl)' Inull III the generalion of a o;.oJuble i n~ellular second nl('S.<;cni;<.'r (possibly a peptide) that ma)' mediate 50me insulin :.t1i~ lI)' relallng 1 octh'allon 0 of enzymes StICh as p),rovme deh)drogenllsc and glycogen s)'nthelasc. The insulin- reccplorcumplex hc<:OIllC$ internal. i/,ed lind may scrve as II "chide for Ir~ nsIOC:l1Ing insulin 1 0 lhe l),s(JSOlites. in "' hich il ma), be broken down and rec)'cled bad 10 lhe plasma membrane. The hal f life of insulin i. aboul 10 houl1l. The binding of im.uli!! 10 iL~ targcl li'Sue i~ dclennined b)' .'ioCIernl faclors. The IIumher of receptors in the larget li ssue and cheir affinity for in)ulill are t"'O imporuutl delermi . IIIUltS.1'he.IoC faclor.. vary ~ubstrutltalJ)' from lissue to li5SUC: . AllOIher importltnl coosideration is lhe: concentration of insu lin it!ielf. E1evalcd lelel. of circu lating insuhn Uecrease the: number of ins.ulin reptors on largct cdl surfllttS and vice I Ocher foctON that affect in,ulin blllodmg to il~ receptor.. Illclude pH. lempenalure. ntcmbrnoe lipid composilion. and ionIC ~trcngth.!llt is conceivllble. tJlerefore. tllat conditiOlls associated with insulin re.\islul'ICc. ~uch as obesit), al'ld Iype I and I)'pe II diabetes m.::l lilUs. could be c~uscd b), a ltered n:\:eptor kina.e ocli'll), or i11lp.1ircd I:encration of seeond llteS...engel1l (Iow -M, peptides), increased ocgnadalion of lhe mc~S('ngcr. or fe",er SU~lfIl l e.s (en,ynte~ invoJ-cd in mela bollC aclhny) for lbe messenger or m:cptor kina>eY

"'!'Sa.

Met.,bolic Effects of Inlulin. Insuli!! lias pronounced effects on lhe: melaboli'm of carbohydrulC'S. lipids.. and procein~.}! The major ti ~sues affecled b)' insulin are muscle (cardiac and st eletal), adipose tiSSue. and li'er. Tltc kidne)' is much less respOl1~ilc. und Ilthers (c.g .. brain ti5SUC and red blood cells) do IlOI ItSpond III all. 11M: acliOIls of insu lin are highl), complex and diveflie_ Becau'iC mall)' of the aclions of insulin lire lTICdialcd b)' l<CCond n1C~scnl!ers. il is difficult 10 di~lingu ish betwcen ilN prim,1ry :tlld secondary act iol1$. In mu~cle und adipcr.e tbMIt:. insult n promotes lr.msport of glucos<: mad other 1 11()I"I()SOCchari(lc. ilCTUSS I.:cll mem' blllnes: it also facilitale, trlln,port of amino acids, potll.~sium IOnS, nucleosides, und IoniC phosph~le. Ins ulin also aclil'ales cenain enzymes-kina.'iC!i and gl)'l.'OgCt1SYlllbeUISC in mu.~ de and adipose IL~$ue. In adipuo;e tissue . msulan decreases lhe relea>e of fall), acid~ Induced by epilll.,mrine or glucagon. cAM I' promotes fau), acid release from adipose tissue: there fore. it IS possible lhal 1I15ulin det:reasc~ fall)' acid relea...e b)' reducing tiS.MIt: ICI'e!s of eAM P. InSl.l lm al~ raciliulcs the incOtlJOi311on of intmceltu lar amioo IIdd~ into prOlell1.

Insulin is bellel'ed 1 innuclK'C prote in s)'!!thcsui lilt 0 nbosomal le.el in larious ti~sue~,lf> In ~J.elc1al muscles. sulan predormrnmtl )' stimulat.. ~ tr:mslahOl1 b)' I~I"''' rate of imtiation of protcin ~)'n lll<"sis and lhe number rI I'll:. SQlllN. In lhe Iher. tbe predOlTlinant effecl IS on InIII!mp' 1100. In cardiac mu~le$. insultn i~ behel'cd 1 ~ 0 t'lIte of protein degl1lwllion. In the It vcr. there is no b.arrier 10 the traJ"pon of FIICO't in to tcll~: ncvenheless. insulin i Jlnu..,n~:es li~ ... r nil'tnbollSll. decrca,ing gluc~ outpUI. decreasing ure:1 J}rOductlon. K>o' cring tAM!' lele l~. and ioc1\'a.ing potass ium and pbos.pwr uplake . 11te lower tAMP lel'el, ltSult III decreased lCIild} of gl )~'Ogen pho~photy la>e. k:KllIIg 10 dllllll1l"hed SJ~ breakdo",n and increased acliv,,), of glycogen ~y~ It appcan. Ih:1I insulin "aduce~ speclriC hepatIC CIlI) Inl'ohcd m glycolysis. ",'hile mhiblltng gJ;';"';';; cn .. ymes. Thus. insulin pronlOlC( glucoeoe u~ glycol)'sis b)' locreasmg the s)'nthe<l ~ of glucutilutlt pho<phorl'\lClo~ina!lC. and P),NI'3Ie ~inase. In~n ltn~~~ the: IIvallabtlily of glucose: from gluCOllCOJ!enesi, by ~ pre..~~mg pyN\ale cnrOO.l.yla.-.e, phosphilellOlp)'ru~1II: c.. box)'kinase. frucloso.::I.6--dipho!.phaln.'Ie. nnd SIIJCOiMl. phOSlmalu.e . Insulin'~ cffects <)II lipid mctnboli~m "Iso nre imporua In adipose ti\~uc. il hns an antilipol)'lic lICliOIl (i.e .. an dl'a:t oppo'lI1g the brealdown of fall) acid lrigl)'eerid<"\). It II/tg decreases lhe ~ul'pl)' o f gl)'cerol lo III<" lil't:r. Thus. aI!Ift IWO slle~. insulin decreases the: uI'ailabi hi)' of prectINII\ fir lhe f(nnallun of triglyccrides. I n~u]jn i) nece~ rOf aclilatioll and ~}nthe<;is of lipoprotein lipase.~, CIll)lIOlfsponslbk. for Io"'t'nng ICry lo",,-density llpoprotcln (V.CLDI. ... and chy lomicrons III peripheral tis..~ue. Otber cITern~. '1Il11ulatioli of lhe s)'nthesis or fall), acids ( hpogennul" lhe I,,-cr. Oinbetes mellilus is a ~)'S1emk disease cilused by I tkerease in the sa:retion of insulin or reduced senSI\l~1I) G' respol\~i ~cllCss 10 insulin by targel II~Sue [insultn rettp!oI' acl ivil)'). Tlte disease i~ char.acccri1_ b)' hypL'rglyctmll..~ ed perlipidcmia. :md hypenlminoacidemio. I>iabcte> mcliJtII frequenll)' is Ilssocialcd with lhe: dcldopntcnl of micro-a.! lIlacn.w asculllr t.li'\Cases. l'Ieuropm hy. and uthc:ro:lc:""'. Vanous t)'Pt'" of diabeles 11:"'e been rI.-C~",1.ed lild c ., ried III1d their p:!thoph)'~ioIogy di..cu.~sed. 1 The tWO map t)pes diabelcs em type I. insuh~ denl diabelcs melilMi ( II>OM), and I)'pe II. non,mII,.... pendenl diabetes mell ilus (I'I IOOM ). Type: I diabtt~ ( known as JUlcnile-onst:1 diabetnl is charoclen1_ by.tItn1 suuclion of pa ..... reatic {J-eells. ltSuhing in _ dcflCim.,), IIlsuitn secretiOIl. Autoimmune eomplexcs IIIld ,.,~ bf,( been mentioned a~ 111'0 po'isible eause~ of,(kell de'ltu.U Gencmll),. in t)'pe I diabel<'S. rcccptur sen.ilivlI)' 10 ilNll. " l10t di.'Crca'<Cd. Type II diabele~. abo known us llduh di:lbclc~. is characterized primaril), b), insultn ~ptor tiefeelS or po,tin,ulin receptor dc:fccl$. 'n lC.'re i~ 110 de<l!U(bqi of p.cells. aoo insul in <;eeretion is relativel), 1lOIl11a1. In lUiil)" ho"clcr. the 111'0 t)'pes of diabete~ .how a con..."", overlap of clllllCal fealUres.~7 Diabetes mcllilU ~ i ~ as'>OCialcd ""ith both (da.mage 10 smaller Ienels. e.g., the: e)'e~ and kid:ne)1 1Il1lCfOOligiopalb), (da magc to larger Ic:sscl. I::.g .. I~ l'OI'lis). Hyperlipidemia (charocterilcd b)' an IlICreailr CO<lC'Cntr:tlinn of lapoptOieill~ such Il.~ VLOL .~::::::: densit)' lipoprotein III>LI. and LOL) h3~ been il

*'

or

II1KTOIIn,,,,'".

greater ~abitny thnn acidic solutioos; neutral insulin 501uIKIrul maintain nearly full polency when stored up to 18 months at 5 and 2S'C. As llOted In Table 'B-7, the varioos preparatioos differ in onset and dunuion of lIC tioo. A major disad\:J.nUlge o f ~gular insulin ill ill! short dunmon of action (5 to 7 hou rs) . .... hich neces~IUlte_~ ,b admlni ~lrulion scvenll limes dally. Many "\tempts ha,'e been m."Ide to prolong the duration of action of insulin, for example. development of insulin forms Icss .... ater soluble than the lIigbly soluble (in body nuids) regular insulin. ProUUJ"1I1lC insuli n prepannions proved to be less soluble and less readily abstHbed from body ti~ue. ProtamillC l.inc insulin (P'[;I) suspensions were even lonF acting (36 hours) than prownine insulin; these lire prepared by mi~ ing in sulin. prolamine. and line chloride with a buffered solution. The regular insulinIPZl rutios in ehnica lly useful preparation~ range from 2:1 to 4: 1. lsophane insulin suspension incorporal~s some of lhe quali t~ of regular insul in injection and is usually long act ing eflOOgh (although noc lIS much as PZI) to protect the patienl from one day 10 the nell! (the term isophane is derh'ed frum the Greek iso and p/llme. meaning equal and appear ance, rcspeclhdy). lsophane insulin is prepared by clUl: ful COIltrol of the protamioelinsutin ratio and the fOrrn.Jtion of a crysullline enlily COIltaining sloichiometric al11oont~ uf in . sulin and protamine. Osophane in sulin also is koown u NPfI: the N indicatCli ncull1l1 pH. the P Munds for prolamine. and tlic H for Hegedom. the devdopcorof the product.) NPH insulin ha~ a quicker onset an<! a shorter duration of action (28 hours) than PZI. NPU is gh'en in si ngle morning doses and normally uhibi\s greater achvily during IJM:o day than

III night. NPH and regular Insulin can be combined oon\~ itntly ond effectively for many p;;Itienls with dillbcte5. l1w: posology of various insulin prrparations is SUII1IIItri"f.Cd in Table 257. A major concern with PZI and NPII in~ulin s is IJM:o poIC& tial antigenicity of protamine (obIalllc:d from fish). ThiS co. cern led to the de\'colopmC'nt of lconte insuli ns. By varying llIf amoun ts of excess line. by using an acetate buffer (iMlead fA phospiulIU). lind by adjusting the pI!. twO types of lentc i!lSltlin wcrt prepaTC'd. At high concentrations of J:inc. a micrOerysta llirlC form pn!cipit~tes ~nd IS called U/lro/trltC'. llJ. tr.Ilente insulin is relath<e ly insoluble and has 0 slo ...erODSd lind a longer duration of IIChon than PlI. At relati~ly II;!. 7.inc roocentration. lin amorphou s form predpilatt'S JDd iI; cnlkd Jemilenle insulin . TIle lalltt is more soluble and hII a quicker ooset and II soone r duration uf action than n:glll. insulins. A thinttypc: of insulin suspcnsioo. lente insu~n. tI a 70 :30 miAM'e of uhrnl ente and semilente IIIsuliM. U. insul in has a rapid onset and an intermediate dul'llltlOO (j action (comparuble to that of NPH insultn). Lente Insula are chemically incompatib le with the I'll lind NPII msWill! because of the different buffer sy~em used in the pie........ of these insulins (an lK"etate buffer is used in !ente insullllS and a phosphate buffer is used in I'll and NPH insuhlln l>osage and SOUr"Cej; are ~um marbkd in Table 258. AddillOnally. regular insulin will remain flUoI acting..ne. combined .... uh NPII but not when added to Icnte. 1lIt np6 action of regular insulin is neutrnJi~ed by the excess ~ prtselll in lenlC' insulin.'" Similar prodl.lC1S~1 00/IUIUIiIt: rDNA-derived human insulin (i nstead of the OOVHlt . . poreine-deri\ed insuhn) are al"llilable.

TABLE 25-8

Dosag. and SoLin:. of Insulin PT. parll lions

UswII Adult DoH"
IJ-4I) ... .u.;I,

USf't ..... Un~

VtOO llUucI I*'iltd b<d. porl ....... r"'" port;

bOof,)rlI/>(lIc ,"",,,,,,,,, ","",)'I'Ibotl< ""~

/)10M", lIypcr,I)'I'I'mla, SC <I~ tI)" pby>ocwIl~:\O .... Itn tiffin IP ,';'d. IV 1I_._ l 1

mraI."

I....,...... in.uti.. I.....lm'

""",,,,,,<111 (NI'1l

U se ......rKd pod.
IJ~

"".1,

U-400 ""ud., beef. p,onfood bed. p..ri; .......1lI

plfl. bM ..,."ihru.: h _ ; ..m.. ~!UhotiI: '"'"
U-100: ......

$C. a..1hn>e:1I:d by p\l~, ... q.~. )(klJ-::~ btl,.., \:IrUI..r...; .. odJiuooW doM

'" '1..,....,- __ .,,..r(ll'_;

....... \t)

t~inlllhnlll""""",~,

ODd ,,,,,,Ion
III>II\ln)

'ru""" IllI'JI.)

r"'" pOrt; ~JIlhrli< /ro0Ulll

SC... dol"e(kd by ph)')IC'''' q .d. tS-lil bc'f"", "' ..... ,a<1, III' ~

=_

tori""
r

btflll\' "",aiIII'. It,

Ill\IIItII U/IC """""''''''' ( ' -

lI-4II ""led. U- tOO m....t. beef. pun,"'<I beef. ...... rood pol<t: """)nthtlic """'"". ,ot-nUJynlhclK: hum..
U-40m .......

st... d......'Ied hy pIIySOo-..... q-<l 30-60 III~:'"

bcf"", tonl<f.." _ OIJoIulor>oI .... .., ..
...... , r ')lOr_p.neoil aI 1I $C. aHIo,..."ed lIy ph)"$ICIMI. 1(.<1

Ixr,.., ..... or """"me

.,.._lO.,;...
JO-.6O _ _

b!....x.l '",utin """ w.pc","",

(lJ1ln1cnlc in",ton)

U tOO mi.....J beef. punfitd beef

btf.... ""'ok/",'
$C . ... dU..., ..... lIyphyoiciOll.qd. "l--6O.~_ btf..........ak/;IIoI. on idIo...,.,.t 00\0l1\li) to:

""""'" ,no.uhn li"", "'"""",,",,,

(S<m,,,,",,,, , ..... Ion)

U-4O mued. u tOO mu.ed beef. punfitd port.

U~

'u, ,,'} t.. IOmIe pol...... "",... \0

bdu~aU"'l

""""""'" __ I_Ua ~

(PZt tn",hn)
"5 usr DI c:o.

, ""ucI.

to: lin meal (II' btIIIl"'" $C, .. dtro<Vd by ..,...~""'."". q.d. )0..60 _ .

sc..

,Illy

aw,. I

;or"""".,.

Chap ter 25 Progress in nlternuth'e routes of delivery of insu lin has been pI'Ompied by prolliems associated with conventional IIlsulin thempy. mentioned above. First. various typc$ of el~trorl1echankal devices (in fu~ion pumps) have been developed wilh the aim of =lucing nuclUations in blood glucose levels associated with conventional insulin therapy (wbeutaneotJs injections).1lw:se continuous-infusion pumps are either close-loop or open-loop systems. The ullimate gool of research in this area is to develop II rel iable implantable (miniature) device for long-te rm use thnt would e liminnle the JleCd for daily administration and moni toring of blood glucose levels. The second area of research studio allema live routes of administrntioo such as omJ. nasal. and rectal. Pn:liminary results indicate that absorption of insulin at these Sties is not uniform and is unpredictable. The third approach to correcting the problems of con"entional insulin ther.lPy is to ~u pplemcnt the defecti ve p.1ncrellS by transplantation wrth a normally function ing pancreas from an appropriate donor. The major problem with this approach is rejection of the don-or paocreas by the recipient. as well as problems associ3led with the draining of exocrine enzymes. A modi fied procedure transpl an ts only viable pancreatic islet cell s or fetal or 1lC0Data i pancreas. The possibility remains. however. that in type I diabetes. the newly trnnsplantcd pMcreatic j3cells could be de5troyed by thc same autoimmune process that caused the d1!;'l'ase in thc fi rst place.
suppre~sed.

PrOl~;ns. n~mn.

and

P~plld~ I/"mlim~_.

853

GlUCAGON
Glucagon, USP. Tho: hyperg lycemic-glycogenolytic lIormone elaborated by the a ce ll s of the pancreas is !cnown IS glucagon. It contains 29 amino acid re~idues in the sequence shown. Glucagon has been isolated from the amorphous fraction of a commerc ial irusulin sa mple (4% glucagon).

'His
S!r
Gin Gly

Gln 20 -Asp

I I I

Ala
Arg Arg

I I I I

Phe
Val Gin
Tyr~5

I I I I

5Thr

Ser

I Ptte I Thr I Ser I

I

Asp'5

leu

Asp

I leu I Tyr I
Lys

I Met I Asn I
Thr

'O Tyr-Ser
G>1("~

Anemion has been focused on g lucagon as a foctor in the pathology of human diabetes. According to Ungcr et al ../02 the following observat ions ~uppon thi s implication of gluea~: e leva ted glucagon blood levels ( hyperglucagonemia) have been ob5CTVed in association with every type of hyper!lycemia: when SlXretion of both glucagon and insu lin is

hyperglycemia is not obser.ed unl ess tlte gluc agon levels are restored to nonnal by the adminiStrlltiO of Il glucagon: the somatosUitin-induccd suppression of glucagon release in diabetic animals and hum ans restores blood sugar leve ls to normal and alleviatcs cenain other sympiOll1s of diabetes. Unger el aLf>.l propose that although the major role of insulin is regul at ion of the transfer of glucose from the blood 10 storage in in sulin-responsive tissues (e.g .. liver. fat, and musc le). thtl role of glucagon i ~ regulation of the li ver-mediated mobilil.ation of stored gl ucose. 1he principal con$Cquence of hi gh concentrations of glucagon is livermediatcd release into the blood of abnormally hi gh concen trati ons of glucose. thereby causing persistent hyperglycemia. Thi s in dicates that a relati ve c ~cess of glucagon is an essentia l factor in the development of diabetes. Glucagon' S solubility ;s 50 I'gfmL in most buffeMl between pH 3.5 and 8.5. It is so lubl e. I to 10 mgfmL. in the pH r~nges 2.5 to 3.0 and 9.0 to 9.5. Solutions of 200 I'g/ mL at pH 2.5 to 3.0 are slable for at least several months at 4"C if stcri le. los.~ of activity by fibril formation occurs readily at hi gh concentrat ions of glucagon at room tempera ture or above at pU 2.5. The isoelectrie point appears to be at pH 7.5 to 8.5. Because it has been isolated from commercial insulin. its stabil ity propenies shou ld be eonlparable to lhose of insulin . As with insulin and some of the other polypeptide hormones. glucagon-sensi tive reeepior sites in larget ce ll s bind glucagon. Thi s hormone-rece ptor interaction leads to acti vation of membrane adenylate cyclase. which catal yzes cA MP formation. Thus. intracellular eAMP l eve l~ are ell" vated. The mode of action of glu,agon in g l y~)j;cnol ysis i~ basically the same as the mechanism of epinephrine (i.e.. stimulatio n of adenylate cyclase). SuDse'luently. the incrense in cA MP activates the protein kinase that catalyzes phosphorylution of phosphorylase kina.<;e to phosphophosphory 11L<;e kinase . The laner is necessary for the acti vation of phosphorylase to form phosphorylase u. Fin Rlly. phosphoryl ase II catalylCs glycogenolysis. which i~ the basis for the hyper glycemic IlCtion of glucagon. Although both glucagon and epinephrine exen hyperg lycemic action through cAMP. gl ucagon affecls liver celis and epinephri ne affects both muscle and liver cells. Falnf>.! reviewed the many phenomena a~SQCiated with hormone~, membranes. and cyclic nuclcotides. including severa l f!ICtol'S that activate glycogen phosphorylase in rat li ver. 1hese factors involve not only glucagon but also vasoprcs.~in und lite catecholamines. Glucagon and j3-catccholamines mediate their effects on glycogen phosphorylase through cAMP but may involve otilcr factors us well. Glucagon exens other bioo::hemical effccts. Gluconeogenes is in the liver is st imulat ed by glucagon. and thi s is 1ICCompanied by en h\lflCed urea fomlation. Glucagon inhibits the incOl'pOl1ltion of amino acids into li ver proteins. Fally add syn thes is is dcereased by glucagon. Cholesterol fomlation is also reduced. Glucagon activates li ver lipases. however. and stimu lates ketogenesis. Ultimately. the avail ability of fatty acids from liver triglycerides is elevated. fauy acid o~idation increases acetylCoA and other acy lCoAs. and ketoge nesis is promoted. As glucagon effects elevation of c AMP levels. release of glycerol and froe fatty acids from adipose tissue also is increased.

Glucagon. whose reiulatory effect on carbohydrate and fally acid metabolism is ..... 1.'11 understood. is lhcrJpeUlically importlult. It IS ~111,endcd for the treatment of SC\'~ hYJ'Olllyccmlc reactions caused by the IIdministrauon of in sui In 10 diabetIC or psychiatric patients. Of course. this treatment i~ effective only \\<hen ~patk glycogen is available. Nausea and \"omitJQg an: the most frequcmly cllOOUnkred reactions to glucagon. Usual doI;e: parenlel1l.l. adU lts. SOO pg to I "'g (0.5 to I unit). repc:atcd in 10 minules if ..........sary: pediatrk , 25 pg/ ki of body ... elght. repeated In 20 minutes if necessary.

C: b"oi",,"tinal

HlllliilOnes

There is a formidable alT,ly of polypeptide hormones of the ga'lrointestm~1 lmet that ;llCltldes .<;ceretin, pancTCO7,ymin--tliolecySlokmin.gaSlrin. nlOlilin. ocurotensin. "asoKtive imesunal pr-ptide. 50m:llostaUn. and otM-l"li. The bio~ynthesis, chemistry. 'lCCretiOl1. and IICtionS of these hormones have been reviewed.tooI
GASTRIN

is a 17re.,idue pol)'pr-ptidc isolated from the untr1l1 mUOOl>a. It was isolated originally in IWO different foons. In one of the forms. the tyrosine residue in pot;ition 12 is sulfuted. Both (Ofm s are biologICally &Ctiv... Otolmergic response 10 tlw:: pre.'\ence of food in the ga~trointesTinal tract provides the stimulus for gaslrin <;ccretion. The lowering of pB in the ~Iom&eh inhibits the <;CCn:l1on of gastnn. n.e effects of struclUl'l1l rnodificlil ion of gaslrin on ga'tric acid SCCreI.ioo MVC been reviewed.'" These SlU(hes re~ealed that lhe four residues at the COO l l terminus retain SignifICant biologICal &elivity and IMt The aspanalC fCsidue IS the: IIlOSl critical for activi ly. The most importanl action of gastrin is to stimulate lhe sccfCtion of iastric acid lIod pcpsm. OIhc:r IICII()IlS of gU51nn include increilSW secretion of pancreatic en/y IiIeS: contr- tiol1 of slnooIh lIlusclcs: ..... ater lind elt. tm..... ..... Iy te secrelion by the stomach and pancrea.~: ..... atl'l'" and elec trolyte. abSorpllon by the: small inte$linc: and sccretion 0( insultn. glucagon. and somatostatin. A syn lheuc penta pr-ptide deri vpthe. pentagastrin. is currently used as a gastric acid secretllgoguc.

Ga~lri n

the phySiological and pharmacological peopernel oftht gllStrins. illCluding stimulation of gll.Stric secrelion. prp!>IR secretion. gal,tric lnOOlily. pancrealic secn'tioo of water am bIcarbonate. pancreatic enlyme~clCtiOl1 . biliary fIow-' bkurbonuteOtHpul. imrin)lc factor ~retion. and conuactiDa of the gallbladder. PcntagaShin is Indicated!lS:II diagnostic ag..-nttoe\-."'gastric acid secrelory function. and it I~ uscful In I...... for anacidity in pat icnt s ..... ith su<;pcctcd pernicious ar.cmi&. atrophic gastritis or llU51ric carcil"ll.ll1lll. hypen;ecretion In ~ poc1cd duodenal ulcer or postopc:l1It;"e "Ionkll ulccB. - ' Zol linger-Ellison tumor. Penlagastrin is usually adminislcred subcutaneously: ~ optimal dose is 6 ~g/lg. GU5Iric acid sccreiiOl1 be~m... ptoxinlillcly 10 mlnutcs anCT admim$.lnllion. and pcU: Itsponscs usuall y occur \\<Ithin 20 to 30 minutes. The uillll duradon or lICtion is from 60 10 80 minUles. PcnlJp>1JUI nas a relativ.. ly sOOn plasma halflir... perhaps ~ !MilO minutes. The availuble Uata from metaboltc Siudict IndICa thaI pentagastrin is ;nacliv3led by the liver. kidney. and lI5SIK'S of Ill.- upper intestine. Contramdlc:luons 'llCludc hypersensitivity or KlIOf). crusy 10 pentagastrin. It should be used with caullon In petienls with pancreatic. hepatic. Of bi liary disease.
SECRETI N

ha~e

Secret,n is 11 21amiroo-lICid polypeptide thut is strut1ural1) similar 10 glucagon. The presence of acid in tllc- smalllnlnline is the n~t imponunt pnYiiologlcal sumulus for thr CTt'tion of secretin. 1l1oe pnmUl")' action of secretin is ('" ~ CTCahc acinar cells thaI Tl:gulate the secretion of "'";lIef.:l bicarbOilalc. Secretin ~150 promotes the <;CCn:tion 0( 1*1' cn:UllC enzymes. 10 a le~scr extcnt. &.--cretlll inhibits the Ie lease of gastrin 1Uld. IheTl:foTl:. gastric acid. It also incrwes stomach-emptymg time by redu-cmg the COmlliCliOIl 0( d:te p) loric sphincter.tooI

HIS

Gln~-Arg

Ala- TyrS03H
(pyro)lGlu GlulO Glu

I I

GIy
Trp

"'" G,
I I I
Th'

+
Th<

Leu

I I I

Leu

I I

"0
Ala

Lou
Gin

G, I
I I

Set-Aspl~

GlylS
Leu
VaI-NH2

I Pm GIu I I
Trp

Glu

I Met" I
Asp

?he

Alg

I I

l>Mel-Giu

PheNH 2

50,
Gly
IOLeu

I I

L1"
Arg 5 F"\ItI1l

Pcntagastnn (Pcptnlon). a physiolOllIcal glStric ac,d se<:retaiog~. is the synthetic pi'ntapcptide lox deri VPI i ve N.,. bUI Y ycarbot' yl {J-a Ian y I L-t rypt0llh yl.l.methlOnyl-L-ISp;utyl-t.. phenylalanyl anude. It COIltains tnc COOH-tenninal letr.lpeptide an"de (H Try MCI Asp PIle N H1) ..... h,ch is considered 10 be the active f:ent(r of tilc nalUml gastrins. Act-olingly. pentagastrin appears to

Pen tagastrin.

I -5ef I

CHOlECYSTOKI NtN - PANCREOZYMIN

It ..... as thought onginall y thai cholec)'5toklnin and ~"I"" zymin .....cre t\\,"o diffcrenl hormones. Cholecystlltimn UI

be responsible for comracuon of lhe g~lIbIOOdcr. .-~as pancreOl:ymm I\,as belioeled 10 Indoce $eCretiOO of pancreauc cn1ynll'.~. It i~ now dear lhal both I ICllons an: caused by I smgle 33-residue poIypc:pude. referred to IS rhol'l.(fo/l."''''-I'f",('u":)rni,, (CCK-PZ). CCK-PZ is '-Ccrell-d In lhe blood m respon~ 1 the Pf\'<.en.ce of food m 0 !he duodenum. espa: iully long-chain rauy l1C id~. llIc file COOHlcrmi nlll amino acid residues 31'e idcmiclll .... Ith tOOse In sastl'in, The COQ II .lermi nal oclapeplide remins full uc li v_ ny or the p.1renl hormone. thoughl
IQ

'"" J,

Lys20- lys
Val

I
I

Try

I
I

I Met I 5Val Gifl I I

PM

"'I" "t'
I
Th'

.AJa

Leu

\ys [ Ala [

HIS~-Arg

Lys'S

I Asn I Ser l!~ [

lie

[ Ser [ 5G1y

Pro

Set [ Pro [ Asp [ Leu

Ser's

[ Ser [ Asp [ Arg 25

Asp

[ lIe

Arg

leu

"'I" I ..., A<.

IOTyr_ Thr

I I

lou

AM

Arg
Val

[
[

[
[ [

I
I I

va. ........ lnlestnlll f'eptode

the duodenum. Motilin inhibit~ gastric rnoIOI' delays ga~lrIc emptying.

NEUROTE NSIN

1IC11~lty

aud

Gin

Ser
Mel

I I

Tyr-S0 3 H

letJ
Asn

Met
GIy

Asp

1011e - Lys
0-.''

Trp:lO-Met
)'$.-L.......

The OClllpc:pude is found in the gut as ",'CII .. rhe cemr.1I ' .m'ous ~y!item. SAIU of chokcyslol.;lIlIn kale been reIIC",'cd.t><
nirlC~nI

Ncurotensin I~ a 13-arnino-aeid peptide. first isolHlcd from bovine hypothalattllls. II has now been idcnlified in lhe inte~ linallract. llIc tleal IlIl.1OO11:1 oon tains 90% of the tOlal Ileum lensin or lhe body. II i~ imphcaled as II relea~lIlg raclOl' for '-CI'eral adenoh)pophy .... al hormones. It causes ,lbOdilllllllion. iocrea.ses I'aSCU1I1f JlC'llt"Il'abJllty. and inc-rea!oeS ~tron c;ecrelion. II decrease, c;ecrelloo or 13.~tric acid and litcrin .

n.e COOH.ICI1ninal ocrapeptlde is prc-.~m in ~ig

oollCCnlrnlions in li>c (('nlr.d nervou~ ~ySl em. l l~ po'>' wbk IICliom here. lhe lherapeul ie implklllion ~ in lhe tlta1l111:nl of I'arkin s,)n'~ disease and schil.ophn:niu. and ilS SAR h~ve been rtviel>.cd,""
VASOACTIVE INTESTINAL PEPTIDE

Para thJ'rDid Hormone

Th is hormone tS u Imear polypeptide containing 801 ammo acid n:sidues. SAR s ludi(!.~b7 ofbo~ine "'1r~lhyn)id hormone revealed Ihm the biological activlly is retained by :m Nl lr lerminal fragmen! consi,ting of 8 amino acid residues, II regul~tes the coneCnlmliOO of cak.um ion in lhe pla.ma within Inc normal ronge. III SpltC of \'arimioos in cakium lntale, e~Cl'I:tton . and arnabolism 11110 ~ . Also. ror thi~ honnone. cA MP.\ implicaled as a ~ mcs..o;en~er. ParaIhyroid hormone IICItVlile\ adcn)lale eycla!ie in renal arid skelelal cells. aod thiS efft'C1 promoles forrn:llloo of cAMP from ATP. llIc cAMl' tocre~ the synthesis and relea~ of lhe lySO<;Om~1 enqnlC' nccessal") for lhe mobilization (If calci um frt)1lI bone.

V.....,ive Inr.,hnal peptide (V IP) is widely dtSlribuh:d in !he body and i~ beliel'ed 10 occur throughou rrhe gll.$lrolnl('j;.. ooallract. 1t is a 28n:siduc polypeptule wllh sllUCtur 1 ~tml lInucs 1 sc:creun and glucagon. II cauSC'li va,lodilalauoo and 0 ..-ruse. canh ac oonlr:IClibil ity. V IP ~lImulatc, bicarbonate 'IrCIl'tion. relllXe~ lastroinle5linal and OIher smooth musc les. ~Imu)ales glyoogene~is. inhibi lll gastric acid S!:Cl'Ction. and Rlmulate~ insulin secretion, Its honnona l and neurotransmilIff role ha~ been inVl:SliglllCd. M

GASTRIC IN HIBITORY PEPTI DE

G~rk

in hibitory peptide (G 11') is a 43-amino-acid polypeptIIk isolated from the dlK)dcnum. Secrelion of Gi l' imo lhe blood" s1IInu l:iled by food. The prllll:lry IIClion of G IP is dribltion of gastnc acid secrelioo. Dlhcr aclion~ include IlImulallOll onnsu lin mid glucllgon ~ion and ~u mullliion af IIIIc<iunal c;ecf('lion.'"
IdQTlUN

Parathyroid loje<tioo, USP. l'arnthyroid injt'Ctiott has been used ti>cr.'peulicnll y as an Ilfllihypocakemk agenl fOf the temporary comrol of lel:lny in ocule hypopaml hyroldl~m .
CALCITONIN

22-re!.iduc polyp..,1>Iidc if>Olated from lhe doodc.n. Ib secretioo IS slll11ulaled by lhe presence of acitl in

~hn I~ It

Calcitonin (lhyrocalc.tonln) i~ a 32-amirl()-ocid polypep4u.Ie hormone ~ed by ",1mfolhcular <:c:n~ of the Ihyl'Old glands in m.pon,;e 10 hypocal<:c:rma. The enure 32-n:slduc peptide appeaN 10 he reqUired for lICIivily. because smaller frngmellIs arc IOIall) inoch le. CoonnlOl1 slructural feature!. o f CalcitOOIll lsolaled from d.fferent species are a COOll lermmal prohn:l!lude. a disulfide bond betwccn l"C!'idues I

and 7 ~tthc NH~ lenn IllU~. und:l cllain length of 32 Il':siduo. Clllcnumn tnhibits calcium 1l!SOfJl1.ion from bone. cau~ing hypocalcemia. wltll parallel t"hange5 In plasma phosp/1alc concentration. In generdJ. cak:itonin IlCgales tnc osteolytic effeclS of par.lIh)'roKi hormooc . l1le poIentiallhcropt"uue uses of ca\f:l loflln all': In the trralment of hypcrpar.llhyroidl'nl. O'iIeoporom and other bone tlisordcl'1l, hypercalcemia of malignancy. and IdlOpalhi<: hypercalcemia.

'Asp Phe- HIS

Alg Val

I I I

Pro

I I I

Leu '0 Val

I I I

tl" 2-Globuhn

HIs

Ser

Tyr-Ile~

ICyS-S-S-CyS-Met
~

I I

lhr
5ef S
Leu

I I

Leu

I I

GIn- Thrl~

Asn

GIy 10 Pro
TlY
Tyr

Ala

'.J" '"
Va!

-IlTe-His

I I

Phe-HIS
Pro
HIS

Leu>O

Phe
Tty

I
lie

Gly

Tyr-r!e 5

Gin
Asp'~

I Tty I I I

Phe

I I Hls lO Val I I
Lys

........ ' I.e,

Alg Pro

Gty)(l
Ala
PrO-NH 1

'Asp Phe

I I

I I

I
I

I
I

Phe-Asn

Val

Tyr-tle ~

Hls

Anglotenslns
of angiotcnsin) in the pla)nJ<l I~ initialed by the catalytIC actlOfl of Il':nm (ill pcpti~ clabonlled by tnc kidncy~) on aogiutCflSll1Oi:Cn. an a-globuhn produced by the li ver IIlKl found in lhe plasma. 'J"he h)dmlytk action of Il':nin on angl()lensiOOj!en YK:lds angiotensin I, 11 c.k.-capeptlde con)istlnll of 100 firsl 10 R:Mducs of the NHII"ml;nal segmcnl of angiotensillOllcn. AI1~W)lcnsm I has "'ea" phnnnucological acll~uy. It is COIIvet1ed 10 lIngiotensin II . an octapeptide. by the 1'.11:11)"111; acllOflS of angioten~in-(."(lIl\enmg enzyme (ACE). Angluttnsm II I) a hIghly atll'e peptide and .s h) drolyled loangioten~m Ill. a heptapepude. by an aminopeplida.->c. AnlliotcllSln III rculln~ most of lhe pharm3COIogkai acti ... ity of its pre<:UfMII". runher dcgrnd;ltion of angiotensin III lenth to phamUlcologicall~ inactive peplide fmgments. Angiotensin II i~ 100 most aclh'c fonn: hence. it is the nlOSl ,""CSllgated angiOlcnsin for phal1l1acological action and SARs. 'The IWO primary actions of angIotensin 11 all: \a..'iOCOIlSlricllon :md slImulatlon of ~ynthe, i.~ and secretion of aldo-;tcror>e by the adrenal corte~. BOIh of these OCI.ons lead to hypct1ension. Mech;," i~llIs and ~iles uf :lClion Ilf :mgiOlcn~in agoni.ts and antagoniQs in terms of bioloskal act i \il~ and receptor mtcmctions have been Il:vleww. 6IJ Alkhllonally. \."OIllpounds that Inhlbu ACE ha,'e found IhcrnpcullC use ~ &nllhypcrtcn~i' e agenll' (e.g.. eapcopn1). 'J"he ~ymhcsis and the bIOlogical 1IC1I~lt~ of .sevcro] ACE InhlbnOf'l !l:ne been rC\lewed."* Funher, lhe agents 11)("0.1 1 target thiS cnlymc arc dl"l'u\"ed 0 in Ihe cardiovllsculur section of thi~ IC~lbook.

l1le

syn1hc~IS

oClapeptioJc) und has twice lhe prc~sor activity of .... glutens;n II. II is phannaceutical1y available as :I lyophililC'II po",dcr for injection (0.5 10 2.5 rna diluted in SOO mL d ,hum chloride injeCtion or 50;. deX11"OSC for injecllOn! 10 be admimstercd by continuoos inru~ion . The pressor e(ft of angiotensin is due 1 an in<:ll:asc in peripheral 1"eS1 0 S!3IlI:e; it \.-.:m~lrictS Il:siSllln<:e vessels bUI has linle or 110 stimulllln, aclion on the heart uud linle cffe<:1 on lhe capacitance \eli'iell Angiotensin 1Iu.~ been used as an adjullcl in varioo~ hypoctllsh'c states. 11 is maUlty useful in controlling acUIC h)'~ sion during adnllni<tralion of generdlllllC)thctKs th.Jt sen,, Iii.!: the hean 10 the effCClS of C3te<:tIolamillCs.

tcn~in

-~"

PI.liII.klnl".
Bradykinin and kallidin an: potent vasodilmors and h~poIen ~h'e agents thai have diffcll:nl peptide \tnJClures: bradyklrun is a oonapcptide. ",hercas kallidin is a Ikcapcptidc. Kallidin i~ I~~yl-bmdykinin: that is. it has an addltionallyslI1c allhr NHl tcrminu~ of the cham. 'J"hesc tWO compounds are!ll.1lf:k n\'ailab1c rrom kmloogen. a blood globulin. on h}"droI)~ Trypsin. pl asmin, or the protC3!>C of ec nain snake VCTlOmIi call calal~7-'" Ihe hydrolysi~ of kininogen. Alg ILys Alg lO

'IV,
I

PIle

Alg

PIle

P<o

Angioten$in Amide. AnglOtaNn amHk (I-Iypertensin) is a 5ynthetiC polypcpude ( l _l_llSp3nglnyl_5_l_~alinc anglO-

GIy-Phe
&~

I Pro I I Pco Ser I I 5

'GJy- PIle
K r' ch

I Pro I Pro I

I Pro I Ser I

Br..dyltinin is QM of the mOist powerful vasodilaton; known: O.Oj 100.j flg/lcg inlnm:nously can Oecrease blood IftSsu~ in all mammals inY~I;gated 8() far. Although the lumns pcr se lin:: not used as medicinals. b lhl.n::m e/Uyme prepal1l1ions ttw n::ieasc bradykimn from the lnactl\e precursor have been used 111 the tfCItmenl of Rlynaud' 5 dl<;CaJC. dau<hullon, and cin.:u l:1lory diseases of the eyegroulKb. (KIIllIlr"t'mJ is the leml used to designate !he group of proteQl)"ue enqffieS lhat eamly.re the hydrolysis of I.minogcn. forrmng br:wJykillin.) trients_ o'yg('n. carbon dioxide. wa-,te prodUCI~ of metabolism. bolTcr ~ystellls. antlbOOil:$, cn,-ytn('s. and hormones). il~ chemistry i~ I'Cry complet. G!l)!;sly, approxllllutcly 45~ consists of the formed detn('llts th:1l can be scparnted by centrifugation, and of these. only 0.2% are IMher titan erythrocytcs. 1lIe 5j<J, of n::nlOled plusma cont:IIOS approxlnwely 8.., solids. of wllicll a small portion (less 111M 1%) can be n:molet! by clotllng to produce defibrirnlted plasma. called H'rJlm . Serum conuuns inorganic and organic compounds. but the total solids are cllicf1y protein, mostly albumin. and Ihc rest nearly all globulin. The plasma conUU05 the protcm liboroogcn. wlloch h COlwerted by coogulation to insoluble fibrin . "The separated scRIm has an UcefiS or the clolling agcnt tllrombin. Serum globulinS can be 'iC"p;lI1lIed by ela::~l~ Into Q'-_ ~, ~nd )'"globulin~_ wllkh CQntam most of tho: antibod ies. lhe immunological 1I11portaoc'C of gJobulin~ is well l:nown. Many closses and group!> of Immunoglobuhn~ are produced m response to antigen,; or cI'en to a single antigen. lhe specificity of anllbodies lias been studied from vlIfiO\ls point~ of vicw. and Richords Ct a1. " lIave suggested that even though immune scrJ appear 10 be highly \peeific for anl igen bi nding_ individual imlllunogklbulins may nOi only internct witll severnl st nlctllrnlly divcr-e delenninunt s. but may bind such diverse detcrminants \0 diffcrent ~i te~ wilil in lhe combi ning Il'gion . The importance Qfthe blood coagulmion proces~ has been obviou~ for II long time . COligulation mcciulnismj are covered in !\Cveral biochemiqry le~ts (~e ra:ommendcd readings). so II brief summary suffices here. The ret]Ulred lllne for blood clotting is normally 5 minutcs, and any prolongation beyond 10 minutes is coru;idcRd aboormal. Thrombin, the enzyme responsible for the calaly5is of fibon formation. ofiginlltes from the inacme zymogen prothrombm~ the proIhrombin- tltrombm transformation depends on calci um ions and thromboplastin_ The fibrmogen- fibnn I'NCtlOn catalyzed by Ihrombin involves protcol)1ie cleavage /panialllydrolysis). polymenLolion or the librin nlOllOll1Crs from the precedmgstep. and actual clOlung/hard clot formation). The final process forming the hard dIM OCCUB m the ~nce or cakium ions and the en'-yme libonasc.

SU8STANCE P Substance P is a polypeptllk OOflsisting of II amino acid lWduc~. II lias been Implkated in the tl1lllSmMion of "painfur' sensory mformalion through the ~na1 coni 10 higher crnters in the centr.ll neo'ous ~ystcm. _71 Subslance P ;s localized in the primary afierent sensory fibers. OIher phar maoologkal elTccts an:: vasodilatation. stimulallon of smooth muscles. stimulation of ..ahvllry secretion, and diuresis. In adLIi tion. this neuropcptidc contribulCS 10 ~me innammll\Of)' re~ponses . Approximlltely 50% of ,he known neuropepuJo an:: symhesized as biologically inactive glycineextended pn:cu~ Illat require a emboxy-terminal ~lIrnnslat ioun l mn idation for biological !!Ctivity. AmidaliOll enl.ymes an:: n::spu-nsible for the conl'cTllion of the carboxyl group of the ncuropcptidc 10 the corresponding amide group and include the twO :unidating enlYtn('s pcptidylglycinc o -monooxygCIl:ISC ( PAM ) and pcptidylamiooglycolate lyase (PG L), wllicll work sequcntially to produce !he inflammatory ncuropcpt.idc Substance I' from an inactive precursor ptpIide. Moch rnean;1I is belDg performed to exploit this mechamsm of lDflammation.

MeI -N H2

'A.g

leu"
GIy
Phe
Phe

"'I0
lys
Pro

I
I

5G1n-Gln

........ ,

I I

I I

Thyro.kJ .... lln

Thyroglobulin, a glycoprOlcin. IS composed of scvernl pcptide cllains; it also contains 0.5 to I ~ iodine and 8 to I()% carbohydrntc in tile form of twO types or poly5llCc haride. The form;,tion or thyroglobu lin is regulated by TS ll Th yroglobulin ha~ no ltorrn()l1ul propcrtie:l. [I mu~t be hydrolyzed to n: lcasc the lIonnonallodotllyrouines thyroxinc and liOlllyronine (see '1'hyroid Ilormones" in Chapter 19).

Thrombin, USP. Thrombin I~ D Steri le protem ~ubslance pn::pared from prothrombm of OOI'ine origm. It IS u);Cd as a lopical hemostatic bccau.<;c II can clot blood. plasma. or II solution of fibrioollen lI.-;tOOuI addition of OIher ~ub5tances. Thrombin al.'iO may initiale dOlting II.-hen combmcd witll gelaliu sponge or fibrin fOllin. For clI temal usc it is opplied topically 10 lhe wound. as a solution containing 100 to 2.000 NIH unitslmL in sodium chl oride irrigalion or bte-rile wlilcr for injection or as a dry po.... der.

Hemoglobin
ErythrocytCll contain 32 to 5j% llemoglobln, aboot 60% water. and the rest as "rollla_ Slrolllo c:tn ~ obtamcd. aftd hemolysis of the corpuscles by dilution. througllthe IHOCd.! of centrifuging and consists of Icclthln_ cholesterol. inorganic salts. and a protcin_ stromann . lcmolysis of the cor puscles. or "laking" lIS II '5 'l()mc:llmtS called. may be brought about b) hypotomc solUIiOIl. by fat .'iOlvents, by bile

BLOOD PROTEINS
The blood is tile trnnsporl system of !he organism and lhus
pt'rforms important distnbutive functions, Conskkring !he multitude of matenais trnnsported by the blood (e.g .. nu-

858

",ill"" W1d G/wflld'J Tt..rOOok 'if Orlf<lnic M~dic",,,1 ""'/ PMmwct'OIrkal CM"lIJrry

salts that dissolve ,he lecithin. hy soaps or altalic~. by ~po mns, by immune hemolysins. and by hemolytic sera. such as those from snate venom and numerou~ bacterial products. He~lobin (lIb) is conjugated proIein; the prostMIic group heme (hematin) and the protein (,lobm). whIch is romposed of four polypeptide chains. an: usually in ldemical pmrs. The toIal M, is about 66.000, inc ludi ng foor heme molecules. The molecule has 1lIl uis of synlmetry and. therefore, is composed of ide mica I halves ",ith an overall ellipsoid shape of the dimensions 55 x SS x 10 A. Iron in the lleme o r hemoglobin (ferT'Clhc:mo,lobin). is 111 the fCTT'Ollfl SoIate and can combine re"ersibly with oltyge n to function as a tr.lnsporter of oltygcn.
lib ... O. - {h)'hemoaJobIn
( Il~)

In th is process. the fomration of a Mable oltygen complelt. the iron rermins in the fermus form becau!iC tile heme moiety li es wi thin n cover of hydropl'lobic groups of the IIlobi n, Both lib and 0 1 are magnetic ..... hereas U bO~ i5 diamagnetic because the unpaired electrons in both molCCIIIe!; ha'e become paired. When oltidiled to the ferric $tate (methemoglobin or ferrihemoglobin). this fuoction is lost. Carbon mOrM>ltide combil1C'j ",iTh hemoglobin to fonn carboJtyhemoglobin (carbonrnonolt)'lIemoglobin) to inact""aTc il. The sh:reochemislry of the olt)'genation of IIellloglobin is very complelt. and il has been Investigated to ~ I:\lent. Some evidence from x-ray crystallographic studies rcvcal~ that the oonfoonatioos of the a and pchatns are altem! ... hen their heme moieTies oomplelt with oltygcn. thus pffimOting oomplc:ul101l with oltygcn. IT is assumed that hemoslobin CHn ell ist in two form~. the rel ative posiTion of the subunits in each form being different In the deollY form. "and P subunits are bound to each OIlier by ionic bonds in a compacl tructure that is Ies!i reactive toward o~ygen than is the ocy form, Some ionic bonds are cleaved In the Olty fonn. relaxing the coofonnatioo. The laller ooofofmat ion is more rcact ive to oxygen.

listed in Table 259. There an: 14 approval applrcal~ pending at the FDA and 49 in the third and final sage ri cli mcal testing. A detailed diSCU SSIon of the various pr0cesses and methodologies involved in biotechnology and 1M wide nrrny of biotechnology-dtri\'ed pharmaceutical pr0ducts is beyond the scope: of this chapter and is co\'crtd rn Chapter 6. ThcTC are a number of n:fercnce OU11%S71. 7J_11 avai lable. Since the emphasis In 'his c hapter IS 0<1 procein!. pcpI.Idts. and en/_ymc~. the discussion ofbiOlcchnology processcsaru product~ is lim ited to these lopics. Tbc various biotoclmlogydcriled products7~ include cn7yme~, rcceplOfli. hor mones and VOWlh fllClOf'li. cytotillC!l. vaccines. monoclorlal antibothes. and nucleic acids (gene.~ and antisensc RNA). Biotechnology technillUC!S an: CQIl.I.\.(Intly changi ng and 9 panding: howe"cr, tile IWO primary technlquc.~ ~lSibk for the development of most of the prodUCt'! an: rONA ted\nology and monoclonal amillody technology. Tbc empluY:! in this chapttr is on rONA technology Dnd products denl'M from th is tcchrM>logy. The monoclonal antIbody technolo[) and resul ting products are di \Cussed elscwhere in thI S bed. Ex.cellcnt refe~7I. 79 are available for review. Thr: following discussion of r[)NA technology assunICS that die n:ader has thorough comprehension of the normal pnxm of gCllCtic c~pression In hunlll11 cells ( i.c .. replication. InnSCriptlOrl, and \r.Inslation). A number of biochemistry laT book.~ are D~ailable for review.

rGNA Technology
rONA technology frequently !las beo:n refcm:d to as Itnnrr cIIgintl'rjllg or gt1le cllllting . A comprehensi\'e discu\$iorr of tM process and apphCll.tion of rONA techrM>logy is'llilable in seveml good rcview5. tl. 7~ n The L'{JlICept of SCnetic: engineering is based OIl the fact tliat the genetl(' material (DNA) in aU livi ng organi.~!1Is is made of the same row buikling blocks.. thai i ~. four different deoxymOrlonudco tides . Therefore. gl.'l1etie material from one organism arcdl may beoombined wi th the genetic material of another OlJIIII~m or cell. Since e"ery s mgle protein. reglUllles5 01 in MlUrce. is produced as a result of c\pn!S.lion of a specifIC gene coding for II , the application of this technology in tk mass productioo of dc ~jred human proteins is obvil)l.l$. A number of human disea~ are caused by dcfiC!Cnc~ of desired proteins or peptides. For example. i nsul in dcficlCllC) is a major causc of diabcte:lo, and human gro ...th hu" .... ddiclcncy causes dwarfism, [f a human gene cod'"g far I deficient proccin i. idenufied and ,solau:d. lhen it may bt combined ... ith fa~t-repl icating. nonchromosomal bactmaI DNA (i.e., plasmid9. The recombined DN A is placed I.:i into the bacteria. which then arc grown 111 idea l mediL Tht plasnuds replicate and the genes within T plasmid lie o he p",ssed. including the human gene_ resultlllg In I~ quatities of the desired human protein. The major Steps In a typical rONA p!occss UKd In l:OIIIrncreial scale synthesis of human pTOleins Il1'e dicu~ below ai>d ~ummari7.cd 111 Fig. 251. 1. ldenurraillon and I!oObIJOO 0( the l1uclrotJ<ie ~""'T. of ~ desirW rsoIaung and dc:Iermmln, " c.tpressed by the Bcne and tlrcn tide KqlICI1CU fur the ror=pondm,

IMPACT OF BIOTECHNOLOGY ON THE DEVELOPMENT AND COMMERCIAL PRODUCTION OF PROTEINS AND PEPTIDES AS PHARMACEUTICAL PRODUCTS
Qvcrthe past decade and a half. far-reaching and revolutionary bn:atthroughs in molecular biology, especially research involving genc manipul ations (i.e .. geneT engineering). ic ha,'e led the way in the de"elopment of new bIOtechrM>logy<.Icrived products for the treatment of disea.o;es. The term biofh~mp}' has been coined to describe the clinical and diagnostic use of biotechnology-dcri"ed products. Genernlty. these products are proteins, peptidcs. or nucleic acids thai an: stnlcturnlly and/or functionally similar to naltJndly occulTing biomolecules. The large-\Calc produclioo of these comple~ biol1lolecule.s was beyond the eapabi hlies of traditional pharmaceutical technologies. According to the 1995 survey7' conducted by the Ph~utleal Rese3reh and Manufacturersof America. there arecurrtmly I'l1Orc than 2JObiotechrM>l ogy..(\eO'ed products in various stage!; of development and 24 approved biotechnnlogy--dcrived products available in the mastet. The cum:ntly approved btotechrM>logy products an:

.....

TABU: :ZS-9

Approved BiotllKhnology of Drugs lind VlIIinoes

(mllelltlon (Ollt. of U. 5. Approvllt)

-.8'1"'

~,~

IaIcrfenln . - 1 b

).1............ 01 chrQoI;c, (OCC ...... , 1'iI\101

...-oon- o1t>cMe

"'he plio<. "",lmbl .."

IlIIrrlcllIII &,,(' Xl (Nt ... 8,.",..d .. Nl!

...Ifuon N 1aIctf...... oIr.nJ (in........,.,)

WI

i\nIc ..)'OL-.dlaIlnf...."ldI (No'Gulk. 198?); '"""'" ......."" ",,1->, <1tIbo!i.., U"nr: 19\10) c;"",W .. oru (o ......., 1m)

,='......

InIUf. . . b.,u. I b. ,.. "b'lIoOll

a..tc:x ................. CW").... Nil

Ch"",,' (Em<ry'1JIe. C"')
(kn'y .... (C~,
M ... 1

11Ill&1-"'''' foo injec1iM hnOOllbi_ """'ltbiuojd ) [71"'I1a Iltl'""',", 8 Vllttlne (' ..... ' obr_)
[poctHl alf. (rEPaI

S",oaWUinc 8a:c1lano"
(""10<'0 I"",.. PAl

""IOICfi'" (TIIOOsand ()oIo;o. CAl

Trn" ....... 0( ...."" ..-.oI&Od ..."h Chroili( ~<lal flil,,",. IOldlldull "">tm.... eli.I1M..-J IKlI 00 dioly~. and 0lII:!IPi0 101 R&'<w..-_,<4. 11I" 1iIf~ I*IoIU tJ ... 1989); ~_.. ot by clk"~"j"",'ln ~ _J"1oid "",h.""","", iApiJ 1991)

-..... "*"""

",ib

",,," alfol,"I'(h [poetic

T~~lmtnI

"""'''''''

_lin I ..... ...

Ell UUy" Clndi.ilap"h .. IN)

."""'. i.ONA "",,1'1) .... Inp:I;'"

''''''101)'0'I00<I "",6P\.11f1<'" (Apnl 19\1)) It ....... Jl'<i""lh 100111100< .(ldOfl<Y In (hil.ln'c (Matth 1911)

of _mi. """,i.tro wilh ctlrom< moaI f.. I~. Inciudilll]>llioma on chalyw _ noI "" dill,.. ........ , 'In ktoo'or. ..... ttl " W..:wd . - ,.. {o.c ........ 19'101; Ii'" ... 0( _mi' """'"'" '" d"'lioCld>t,opy ''1*10'lI0 .. ,,*,

H.IOI... ,.....Io .. (rOSA

01'1".,

0- LOU 10t10bu 19I1)

lull')' .,.11 "'ul.<eml. (June 19B6~, ",,,,..1" ..... 0 _ 1918); AIOS-ftIOltd KOJlOI'l ', /.111(0)1,11 (Noooomher 1988); """",,u!OO C IF\:bo j' , I'I+\I(), hepoto!1I 8 (July 1m) T~.......... 0( 1 ",opt",iI ... (Fi:bo j' ) 1991) ..

....r"."..lf.2b (~ .. 1 nanO)

,-..
~(,

~III"

r..,,1)I' (m:nmbinao1')

... m""",*, buM """""'" It_pl....,"..

(MMrlII991)

OklO..:!' ,apr...... <d ' .. =opt>lioo (1'ebn1oor)o 1991); or 11"nwmlW

~on!il'itoo

"""""-""J

(JUlIO I?\I'); (h''Otlie

,!

0(

ic: """"

",veK IItUlropenlO (Dealllber 190M)

-Oc.uS<h" CIlIOV Mo."

L w'>-COO

Growd'I (oilu.... thiklmo .... 00 thron", .....1 _1r"'imty, ...,..l11l... ,_.. '............ y .. ch,idmI (Morell I~)

CYI'O(lI,N" (f'rincClOO'i. NI)

Onho 8ioo:dt' (Ibnun. NJ)

De\c(~on. ,,~

""" follo;'rwup of coIom:uoI .00 nv..... n <:ancerl\Dc<.'embe, 19\12)

ORrnoctONe OIIT )

tk_CfAI of ~ bdnc)' "''1''*011 ~;":'1OI'i

"""""~In

... 1dt>J<\o~ln 1..... r1.ukm-l) 5omOIrtm

19116); ~...,""'01""" MIl I,,,,,, Inmfi'/AnI (June 199'1 Renal 001( """"""'"" it-by 19921
(Juno

"'JCCI-

rut

Ial,.._

Gt .... ,",h" (San Francolo<'O. CAl

Pulmoq'iiIe ON ...... (d<!m:.o", al ..... )

GmmIc<'h" (San m...:11itO, CA)

S..1ti' lleahho:udlll''-l o;'1<lon
10

Cyst'" ntwo,;. (Ow:lobi:, 199)1

Ik"""lhIH. A (0..:._ 1!l92)

RECOMEIIN ... tt ....... lu""IooI'" f_,":O)I~II."' HI'I

.Ie. CAl

0....1Q I.......... (C.ub.....,. MA)

TABLE :ZS-9

Approved Biotechnology of Drugs and Vai ne J-Con tinut!'d Cornpeny

Indiuot lon (Dllte o f

I"roch.Kt N _

u. S. Appro~lIl)

RtcQ\l01VAX 110

11"1""'1" 0

~""""j

Ilui) 19861

.......

Ilcl""'" B _""... ("""""";IWII~ MSO

c........... (Mal"",,. I'M

Ell 1.iJ1y" " ... , Cr>t ... IS)
Ant,pt"tWl ,....

,oIJ"" 01 blood dot>

1101'''''''1/\ I... R.-.:ho." IN ...... y. Nil

UloUI>I>c> 1'H41 It.ll)' n.1I Ioul.cm .. 11_ 1'i801, AlDS ,,.!.W

KapoI.i'. '4II't00\li (N"IWffI'Ibt< 191!g)

flmo:). (&/ isotJling Lilli: mKNA and di:lenuonona: U nuckide .. ~uc...:e, and (r/ " sing DN A Inobe:l 10 "fi,1> 001" the de""", sene from lhe: ICoomk libnry (<<lIul>< DNA chopped up inlO ~Smtnts 10.000 10 20.000 nuckidei Ion,). l. Con~lI\lC .. na rONA , On<e lAc dcsjml hllnw> lene iJ lIkru.lronl and iSQI.lw. il IS m:on\blnnl Will> ICIk'S Dr m'CrobiJI lis lhat
are blnwn 10 1Ia\'e rapKll1lle!l of all dI Yi~lon. TI) IIC<:QIlIplhh

)<.

I.. ~"
_~IOI

b'O'<I;n., f'tJ/tV(i()l1 ~todtJn..dnMJ ..-e useoJ. (). fr 100 different v,,"allOOi of Ihcsoe hydrol)'lic ft1)"me< , " 'hlcl> llel like 'iC IS"<JI"S '" hydml )'7inlllhe ~phudie<ta bonds of DNA I I ~ f .. ila (Lc .. nlJC~j<k ~lJClJ.YIiltR lC aV1l']abIc. The Il!le o f Jpec.roc restnt110n Cldo:NlUC~ bold! to obtaon lhe hullWl gt'ne ~nd to opI'n ~IU. on lAc nucrd;uI gertc a llows casy fonnall()ll or lhe lI)brid (reromb,nnI) ON~ molecule bau>e of lhe "Slicky" ro.b on Iloo4h gt'neJ, ThI: o:<Ii!. of the I>Urn;HI ,COl' and lAc mkrobuJ DNA "cww ~ .oJhoed" together by COI.)n'Ies I.n(rAn IU DNA Ji6i'MJ, The hIl .... 1tMI are placed in ~pec.rlC Localions on IhI: ml~robill DNA 'Ilif' 10 cn.ure C1pres~oon of the hum..n IItrtc "hen IhI: nurnJbiIoj celli donuc. Plasmids aft: lhe IU(lI;I ronmlOlll)' u;cd nuaolwl DNA n.c..c ulrxllrorroooliomal cur"l ... DNAs pendenlly or!hl: ~I>~ and Ill' much smallel' lIIan rbr<> mo"omal DNA. I'l asmid. all' ca')" lO II\\Inipulale and Ill' cOMIdo <:lTd c~"",lknL \el"\Of1 10 carry '"un"" IC'OI'S. Other m.. ,o1wI

lhi$ lillo~. ~al tlLl.)"",,"

"'pi""''''

(~H~)
><
DNA

04_
... I I

. ~;~'~'~-:,~,':"':>io. ~
'iI
..

h_

P''' "..,
--

ytt>I "",U5. \fammaloan lit.. Ad!. ChH1l'!Oe iiamsla' 0' ary edl", IIf"C useoJ ",hen gl)'CO'yl;oOOll .,... rDNA. lkmcd proIcon i, ~senual for blDlOiical kll"I.Y (c.J. C1')11>""", .."'n). NO/1/TIammali211 celli cannot I:1 )C/lIylllc ......
cc1~

....w as '-t~ _

,,*,~I

i'>POiwl 'rOfIA

9I ~

.... '7' ..

""

(o ~ )

-.If" 1
&.1 ... _

eM

lein ... 3, Oonin.: n.: carryon, lhe rc:coolboned human Fot Iff ,hen allolO'w 10 lIrow in appropri ate mnI... Althe lit. 0;10 , lAc rl) NA Il'ph,al~$ and e~rr""s il~ prodUCts. loc1udoilll till hui1Wl prole," n ... ell as lhe norm:d bacttrial proItia 4. bol /lilton:md pIIn rOCal>Oll of rDNA-dm,ed protein From ... ~1 miJ.mn: conulin.ng b.:ICnal proteins. 11 ~ che micals U>ed in pn:pnringl he media. el~. iwlali nllnd punf}. in, 'hc de!iirW hu"""" prutc'ln IS a Ib.unlln, IN indeed. TM wit m:ju,~ ~oplm.tkatwlwl~uOll .echn"lues. such. C'-I I I j fillnollOlls. 1'R"'1p!lalions. and HPLC. ~ pnmary pi.,.. .... punficlllion pmc:_ IS II) ensull' lIIal IIIi:: proce," 1$OI:tICd d 1l'1 11II" IIIIi: btologiclll aclivilY o f lhe " allye proIein in the bod:o. n.: r" NA-dm,w proIcon is then fi;ll'Tlllllalcd imo. p/Iaol..... icII producI lhat il Kable dunn, Imlo,portltion. 51.,..." admoni~l"mon 10 a pMocnl,

""'"l'

des,,,,,,

p,rofy po I

BIOTECHNOLOGY-DERIVED PHARMACEUTICAL PRODUCTS

Tbc 1.....0 dozen I-1>A ,appro\ed bilMe'ChoolOj!y:\k",cd pIur.
rnacclilicaJ prod llCls are listed in T able 259. l1tere are_

Fig u re :Z 5-7 Summary 0 1 <1 typICal rONA proc~s used 11'1 the comme'l'oaktale productlOO of human protetns.

Chapt t r 15 1'''''''/111. IA:,>'",..s. than 200 0I1ler produds In ~~rious stages of de,eklpl1ll.'nt.l~ The FDA-appro.ed prodllCb faJ l 1000000Iy mto fi,"e nlaJor a1egoric's: enlymes. tlunnufIc:s. Iymphoit; illdo. hcmatopoi(hC foct"". and biologic.I~. A detailed di!iCu.'~sion of all 0( these products IS beyond the scope of Ihis chapter. SUlCeIOOIit of the<>e product.\ art' proteins or pcphdeS. cursory cv;lIuatlon of them and their u$es~ follows.

",ull)~pr"h- II/J""''''~J

861

'ersc effects illtlude dll.l.incSlO, head:tChe. abdonllllilli discoolfon. nausea. and r<1sh.

ro NA-DERIVED HORMONES

The rDNA-deri,ed hornlOlll."" IIlClude III.'itJ lin human IIIJCClion US!' OIumulUl R. Nowlin R. Velo~ul lll Human).
growlh hormone (wlIl;tlorropin: lIunl~lrope). and SOmall"( m (Protropin). All of Ihe~ p!"ooucts. as we ll as other product~ conlai ning humnn in~ulin. are di~us.o;cd abo~c in thi' chapler.

rO NA-DERIVED ENZYMES
Altepl;ue, Recombinan t. Alleplase (ActivIIsc) was dist'u~sed abo\c in thi~ chapler. Alpha. Dornase alpha. rhl)NA<>e (I>olmolymc). is a mucolytic cru:yme idcmical wnh the nmural hUrrnln DNAo;e and b u<;ed in the trc:wneUl of cyMic fibrosis. Pallcnts ~lIh cy~tic fibrosis surfcr fmlll decrt'a.~ pulmonary fu"'-1)()11 and infect ions cau.o;ed by !he 'iCCrt'lion of thicl.: mucus. Protcin~ contained in the mucus an: bound 10 Cll tl'llcellular DNA. produced as a msult of !;Il<lnlegrutionof baclena In the lungs. This cn7.Ymc is invol vcd in cleaving clliraeclluku DNA and separ:ucs DNA from prOleul~. allowing proteolytk ell/Yllle" to brt:ak down protein~ lind lhus decrca!oC the \'i-o;cosity of muc us in the lungs.- I I'rolehls bound 10 cX Iracc:llulW" DNA are IlOl suo;cepliblc to proiL'Olytic cnlyme~.1l Doma.o;e alpha is a glycoprotein comaining 260 amino lICids Ihll is coollTlCTCialiy produced in genelically engillOl'red Ollnco;e hllmster 0\'111)' cells.. Dom:ase 1I1pha. i~ Indicated for !he trt'atmenl of Cy'ilIC fibrO!iis in coojulltlion with other Iyailable thcn!.pte'. such as IIIUbiOheil- bronchodilalor;. :IIId conico..lcroids. Adull doIi i~ 2.5 mg intlaJcd once daily. administered yill a rccomnw:nded uebuli7.u. Domasc: alpha shoold 001 be: lIJi.~ecJ or lliluled wllh OIlier agems in the ncbuluer bccau.o;c of the jIOSSlbiluy of ad\'erse physicochemical changes rhlll mayaffect IICtlYiry. Common ad,'crse eJf<-'C1S jlltlude wre thro;lr. hoarserlt:.~~. and fflCiul edema. Imiglucerase. Irniglucernse (Cere1ynlC)!IO i~ a glyrojlI'TlIeln conlDi nmg 497 amino ilCid ~idul!!l and is N-glycoJ)lafed at fOllr different positions. It is an analogue of rhe IIIItUra[ human cn/ymc ,B-g1uco~:crt'broslda(' and conlllins a"glmnc at position 495 in'\lcad of the hisudmc in the narurnl rn)mc. II IS comnlC'rt'laily produc:cd in SCllCliclllly engiILCled Olincsc iumS'r 0\'111)' cclls. 1..,I;.e the narural cnlyme. Imiglucer.lsc Calalp.e5 tile hydrolY'I' of gluooccrt'ilrosilk. D glycolipid. 10 g l~ :md mamide whhin the lySO"OIIlC5 of phagoc)ric eel ... G:luchers disca~ is caused by II ck'ficicncy of thi ~ en7ymc. ",hi,-h re.~u!rs in lhe accumulalion of gluCOt:1!rcbroslde wilhin u.ssuc mocrophages. The glycolipid-engorged macroph:rgcs In: kll(lwn ns Gtwr/.t!r ufl5 and are re~pollsible for IIle I1Umerou~ clinICal manifestation s of Gaucher, discaS('. The common clinical mllnifestalions of Gaucher~ dl-.ease are It~en: 4/lCmia. thrombocytopenia. and skel ctal cornplicaIlDnS thaI Inc lude O!>lconc:crosis and os.tcopcnia. Inutllucerao;e i, Indicated for the long_term rt'placement therapy of Gauchn-'s disease. It is adnlinislcred mlra\"t~ _sly nt an inuial dose of 2.5 to 60 U/l;g. mfused o'rr I 10 2 hours. This tkKc: is usually rt'pealed Cycry 2 weeks. Both !he dose and the frcqucllCy 0( adllllni)lrntion lIlay be >'lnw. oo-.e.cr. depending 011 the !\'Spon\(." Cormnon adDo'mm~

rO NA-DERIVED CYTOKINES
Interferon,.- Interferons rut natuml !lyropttMcUl5 pr0duced by \,Irtually all eu~al) otiC cells: they posse"! immuTl()o rnodulanng. anh~inal. and C)tOloxie octhjtlc>'. This rMlIly of glycoprorelns i~ produc:cd by cells In re5pOIlS!: 10 a Wide rdnge of ~t jmuh .'" In hunl:ln.~. Interferon.., bind to t"('lIular receptor;. ~hich Icad~ to the: synthesis of o,'er a (x)l.en pr0teins lhat contribute to ' Iral re.~istance. The Inlivlnll cfrecl ~ of inrerferom may be cuu..ed by Inhibition of the synti'le5i' of \iral mRNA or protc1"" or prevention of \'iml pt:nctrnriOll or ullCooting. u lito IJao;cd o n lheir runigcn1c sublypc~. rhe inlcrferons arc cllI,~ified inw three major gmups: fr. p. ~nd y. II- Interferon and ,B-inlerfcron are produced by 'Inually all cells in response to a vlm l mfCClion and \'arious OIh1:<:r ~imuli. ,..Inteneron is produc:cd specifically by lhe T lym phocytes and the n:uurJl killtr ct'1I~. ,.. Inu:rferon.( ha'e grt':ucr immunon:gul~tOl)'. btu lower antivllnl. effecls than <1"- or ,B-mterferons..... MOl\' than 12 subspecies of D-mterfcrons. I ,B-imcrferon. and 2 ,..interferons an: known 10 exisr . In it'nerol. the lI1[erferoos are g/}ooproIcins conSiSting of 165 to 166 amioo ocld re~,dllCS. 1l1cre arc four rDNA-derived tl'-inrcrfewm u'aI/able for clinical use aruond [he world and thrt'c available in the Unired Srares (descrihcd below). All <1"-imerfcron~ e~ hibit ami\'iml and amiprohfern_ ri.\'e acthity, enhollCe phagocyrk activity. and augmcnt .' p"c,fic cylOlO~lcity of IYl1lphoc)tes fOf cenain larget cclb.11 most co.'nmon ad'cr;e dfecls of <1"- and P.imerfefOl1~ IlICludc flo-lilt Symploms. bone marTOW 5Upprc!i5ioo. JIeU1"OI~~ic cffects. lIypocakcnua. aJ)()fl:xia and odIC'r g!l.(truinrestmal symptom . and .. eight loss.

!he

Interleron Alfa-2.. Recombinant. ImcrfC'roJl alfa-2a. rt'COlllbmam (RofcfOfl). IS produced from genetically engi_ neered E. coli and oomams 165 amllO acid residlK'S. At posilion 23. illlcrferon al fa-2a has a Jy~inc residue. 1bc pharmaceutical product contalll ~ a ~j ngle a-imerferon sutNypr. A murine monoclonal mll iOOdy is uSl.'d during purification by affinity chrommoJ1ruphy.lntcrferoo aJfa-2a is us..'ll in the lremnlenr of hairy ~.... II leu kemia lind acquired illlmuJlOdcfi _ clency syndrome (A I[)S~rt'I~led K~poloi~ !r.m:oma. II i\ all5Ortlc:d ~"('II after imnlITlu<.CUlar or intra\'enous admmislntion and ha~ a half-life: of 5 to 7 hours ... ~n admini~t(red by tnc inlramu.'it:U lar roule. 11lc \OIuuon .should be ~tort.o() in lhe refrigcr:Uor at 3b 10 46"F and !JIould 001 be fTOl.tn or shaken. Intfuferon Affa-2b, RK ombinant. Interferon alfa_2b. ~'OfTIbinal1l ( Imron A ). al.'lO coorains a "ingle .'itJbt)'pe of <1"Interferon. It i~ a gly~-oprotcin containing 165 amino acid

and is cOlllmcrciolly produced frolll ~e rIClically engll'leered . ('Oli. It differs frolll intcrferon lllfa-2b in JlOSSC's, IIIg an !U1:lIIl1lC rc~idue at position 23. 11 is used in the lrcatment of h:llry cell leulemla. condyloma acunllnala (genlla] wIu1s). A IDS-rc latcd Karxl!ol 's ..an::ol11a. hepmius C. and hepa1iti~ B II i\ admiRlMcn:d inlr.lmuM:u13rl y or ~ubcutane_ ou~ly .... "h a hal f- hfe of 2 1 3 tlQurr. anti ... ia mtt:l\enou ~ 0 infusion Wilh a half-life of 8 hours. TIle rttons11Iutcd solu' tioll i~ ~tabl e for I month .... hen Slon.d at a lcmpcrnture of 361046F

re.~idue~

Intf!!rff!!ron Alfa-n3 (in/Ktlon). lmcrferon nlfa -n3 (A lferon N) is a Jkllyclonal mixture of up to 14 natural ainterferon ~ublype!o anti eOlltalllS 166 amino acid re.~idul-~ lIS commercial produclion in_olveli induc uon of pooled units of tlUman leutOC}les with an Ill' ian I'lruS (Scndai virus). 11le purification ~~ ml'oll'CS immunoaffinity and 1iItta/10JI chromat0l!raphy . 11 IS indicaled priman ly by mtr.dc~ionaJ injection for the trcatment of genillli wans. TIle '\Olu lion ~tlQukl be ~torcd at u te mperaHlre of 36 to 46F and ihoIlld not be shJlen. Interff!!ron Beta- lb. rKombinant. Interferon belu- I b. recombll1;lnl (Beta.- cron), ha.~ bi<llo&ical e/Teds simil llf to Ihose of nnluml ,8-imcrferon lmd rt-imcrferon,. 'The nntllrdl ,8-interferon is a i lycoproll:in containi ni 166 amino ocid residues. 'JOe rONA rrudUCl diff.-n from lhe natuml form. in that" is not &lycosyI3u~d. il lacks the 3ntlrlO-t('rmullIl methionine. and it hIlS seril1C in the pl ace of mcthiolline Ht position l7. u Jt b lise<! for a wide vanety of indications via IIllravellOUs, intmmuscllillf. \ubculancous. mlrnthecal. and Imrnle~i(,"al rout('\. Its primary ind ication is for the prevention of e,acc-rbation~ ill paticnts suffcrini from relapsing! remillmg mUltiple <dl'T'OSis. Recommended ~iC is 8 mil lion units. adminlstcred subcut(lI1eoosty. e,('ry Olller dJY . It also is IIldieuted in the trI:utmcm of malignant glioma lind malignant melanoma. RecOl1lnlCndcd temperuHlre for ~tor age i~ 36 1 46 "F .and unu;.ed feCOIlst ltlited solution ~hould 0 be di'-CJrUed. Aldeslfi!Ukin. AloJeslclilin. illlcrlcutin-l (1'ruIeuIan).110 IS an rDNA-deriH:d lympOOkirIC thaI differ; structurally from native Inter1eukin-2 OL-2) bUI hilS biological act ivity Mmilar 1 lhal of the natural lymphoitinc." NatumllL-2 i~ 0 prodoced pn~ril y by the peripheral blood l ymphoC)te~ and contains 133 amino acid I'bidue~. The imll1111l0rejllllutory effects of aldcs1euki n IIlClude enhancing mi tOiencsis of lymphocytes. ~timlilahn! the J!fOII th of 1L-2-dependent ce ll lirICs. enhancing cYIOloxlcny of lymphoc)'te~. mdu cing Iymphotine-lICtil'ated killcr (LA K) L"Clls and natuml killer (N K) cells. and inducing interferon-y prodUClion. Thcel<act nlCChanism of lile antllllmor acti"'lty of alUe<!eut in in humans is unknown . 'The rONA PI'OC('l\S inloll'e$ ieneljea1ly engineered E. culi (p BR 322 pl asmids). 'The gene for IL-2 was synlhew.ed after fir;t i'\OI;l\lni and idenhfYlng the mRNA from lhe human lurkat cell line and then preparing the complementary DNA (eDNA) , 'JOe IL-2 iene "as gCTICl1e.lIy engl~red before it was hybnd'1.ed InlO pBR 322 plasmid. Funhcr manIpulation of the hybridlled plasmid resul\('d III the production of a modified IL-2. alde!;leulm.'IO Alde:sleutin diffcr!! ~trucHlr-

ally from the n.1l;'c 1L-2 in that the former is not il)'COS)Iuted . illach too N-temlinul alanine resiJJuc. alld it has serine in the place of cysteine at position 125. NoncOIalent. moIetular aggregollon of aldcsleuk.n is diffetcnt IL-llIIII the former c\ists as II microaggreg:ate of 27 molecules. 1lIe pnmary indication for al(\eslculin is in the 1tea1lnt:11I of adult mt'I:.sI.atK' 1\'11:1] Clll'CHloma. It is administered III Inlr'dvenous Infus ion In doses of 10,000 to ~.OOO U/lqt;ro"tI') 8 hours for 12 days . It is primarily metabol i1 by thtttd.ed ne)'s. with no actil'e form found in the urine. Aldeslall:ut CJlISeS sc:rious acherse ('/TCCtS m pallents. including fele!'. hypotcnsion. pul monary congestion and dyspnea. coma.liUtrointestinal bleeding. respirutory failure. rC11;l1 failure. ar' rhythmias, sc:ilUl"eS, and death.

rrom

rONA-DERIVED HEMATOPOIETIC fACTORS

Hematopoietic gro .... th foccOlll are glycoprotems pnxkIcaI by a number of pcriphcnll and marrow celLs. M ~ lhan 200 billiOll blood cells are prodoced cach dol)': and the hel'llolt~ poIelic fltCt{)13. alonl: with other Iymphopoielic facton sucb IilS the stem cell factor and the interleukin s. are invoh'cd_ lhe prol ifer~tion. differentiation. and malUmtion of ~ariout Iypes of blood cell~ derived from the plul1pO!cnl !il('m ctlb.

Erythropoif!!tin ..cI Erythropoictin IS II heavil)' gl)'COiyl aled prole:in containing 166 amino acid residues. It is producal primarily by lhe peritubular cells in the COI'\U of dIr kidncy. and lip to 15~ is produced in the liver. II is 1M principal hormone res ponsible for Slimulutinll the productiOll of red blood cells from erythroid prog('nitOf cell ~. Cf)'throC)'tll burst-formini units. and erythrocyte roiony-f(lf1lll"l unil5.9' Small amOllIllS of erythropoietIn are detect:tt* .. the plasma; OO .... e'cr. moSt of the hormone is r.rclcd b)the kidneys III response to hypoxia or IllICmi.a. ,,'hen lc~t\I of the hormone can rise more than 1000 fold. Dc:crca.<:ed erylhropoielin prodUC!ion is one of ~\m! potenlial causes of anemia of chronic rcnal disease. Other causes of ancmia of chronic renal diS('8Se include infcctlOll or inflammatory condltion in the tidneyl. iron dc'rlCif:llC)'. marrow damage. alld .-itami n or minerdl deficicney. Regard le"5 of the underlying disca$C cau,ini renal fallurc. cl)'dtr\). polClin Ie\el s decR'a.'iC in patkots with renal flJlure. UIIlil rONA t~'Chnology W3, used to produce conuncreial ql,l,lll. lities of erythropoietin. It was obtained from the III'UIe 01 patients !MIffc:ring from !;evere aplastic anemia. 1111$ proc:ea of obtaining natural honnone was costly anti UnlC-ct)II$UIaing and produced only small qllbnlities Orlhe hOl'll'lOne. Epoetin AlfiJ. Epoetin !llfa. rEPO (Epogcn . PlOCiit~ ~ the rccombinDnt humun crylhropoietin proJJUCl'd in ClllllCIC hamster Ol'llry cell ~ into which the human eryth."!ticua iene has been inS('ned. l1Ie.se mammahan cells gI)'COS)YIt lhe prolein in J nlllnllC:r simi lar to lhat observed in hUIIIIII ce lls. 9l Epoetin alfa is indicated in ;anc,mic patients with d ......; I\'nal failure. incilldlll& bOIh those wno requirc rcgul." nlysis and those who do not . Epoctin alfa is al so IndiCllltll m aJlCmia associated with AIDS. treatmt'nt of AIDS .. lilt lidoludine . frequcnl blood donations. and neopIa.'iCX: JL. ('ases. II IS illdicated 1 prevenl anemia in patients .... 110 <D0 nate blood prior to sUl'J!cry for futnre 3ucoiosous tr1lMfaOOlli

Chapin' 15 Pmuun. f:"~\""'~, ",wi /'rplllit II'~

863

.-110 reduce the 1II."Cd for repeated maintcmlllce tran~fu ~u 'The hormone is available as an isotonic buffered loOIuhon.. ~hieh is lIdminiSlen:d by the Intra,'enous roote. The wluhon should no! be frwen or shalen and IS ston:d II 36 to 4(i"F.

.DNAOERIVED MtSCELLANEOUS PROOUCTS

CoIony.Stimulating F.ctof$.- Coiony-uimulating fae m II/'e natural glyt'Opl"CKdn) prOOlK'eiI in lymphocytes and
monocytes. Thcl;c factors bind 10 ,-e ll -surface rccepwfs of bem:ltopoietic ~njtor cetls and stimulate proliferation. lifftrenfia.uon. and maturation of these cells Into recogni/' able !U.ll1,R blood cetls.lll Colonystimu lating factors productd by rONA technology have the -.amI' biological activity I!I the n.llUral hormones. Curremly, lhere are IWO colon} lI1I!IUlaonl factors commercially produced by rONA IccllooIog) . These products are discussed below. Filgrostim. rG ,CS F (Neupogen). i~ n 175I18ino-acid polypcp:ide prodlll'fil in gefll'ticarty engineered E. coli celb OOIllllinmg the human grnnulocyte roIonystimu laulli factor (G-CSF) gene. FilgraSllm differs from the natural hormone in Ihm the fornler is not glyct;"yluted and con ~ .n additional methionillC groop at lhe N tenninu~, II'luch Ii ~med necessary for expression of lhe gene in roli. Filptium specificalJy stimu lates the proltferation anti malumuon of neulrophi I granulocytes anti. hellCC. is oonsid atd lineage specific. Accepted mdications for Iilgrosum mcbIo.o thE follow in,: fuJ \0 deereao;e the incidcnc.c of febri Ie ~nla in pottienls ~ith nonmyclOld malignancies ~ho ntt .. e m}elosuppressive chenlOl hel"'.lpeutic agcnts, thus lowmnglhe irICidtnce of infection~ in these patient~: (b) 10 lIXCic:nlle m~elOld rtCo>'cry in palicnts undl:rgoinll 3utol0psbone marrow Inlnsplanl.:uion: and (ej in AIDS patient). 1O~.:ase the irICidtnce of neutropenta callsed by the dl ,. we Itself or by drugs used to trem the dio;e:IC. The usuul lUrIing daR for filgrdstim is 5 ~Kfkg per day in patients 1m nonmydoid cancer ""00 receive m)elosu~s .. e dIemoIher.lpy. Filgruum solulioo ~hou ld IX' )torcd at 36 10 460f and ISed within 24 hoon; of prepar:llion. The ,,<,Iution should not be !JIaken or allowed 10 fn."C1.e. Any solution left lit room dIpCf1ture for n)()lt than 6 houl'lO fohould be diM'arded. 1'hr; - ' frequent adverse effects of filgrnstim are medullary booe pain, IIl1hralgia. and myalgia.

Anllhemophillc factor tfac10r VlJI ) (IIumaIC'P, HenlOphil M. Koolc 1-11', Monodatc P) I~ a glycoprotem fooud III human pla~mll and u ncces-.ary cofactor m the blood-dotllng mec:h:mi.lII. Tili. hlgh,molecu lar-.. eipl glyc:oprolein /1.:t., a t'omplo: ~ ;;truclllfC with SC' ernl romponents (su/:X:ofoctors).'" TIle commen:ially a\'U1lable L'Onct'ntratcs dc:med from blood colledcd from volunteer donors by the American Red Cros.~ Blood Ser. ices are used primarily for lhe trcalrncnt of pallents with hemophilia A. Since the COIllmen:ially I\ailablc prodocb arc purirled con ccntrntcsdcrived from hlood pooled from millions of donors. the major prcc:llltion~ In uSIng tho: pruducts relutc: to Irdn'mi.sion o( \ iruSC'i. ~uch as hc:p;ltiti~ virus. herpcs\ irus. and HIV. Thl~ major problem ha.~ been alle\jated.. moslly be calise of the de,-e1opnlCnt anti nl3l'lcling of rONA-dcI'hed ~nuhern()philic factors, AnliilcnlOphlllC factor (recombUllInl). rAIIF (KoGENale, Hehnle). I~ an rDNA -deI';.cd f.ctor Vllt e.xpres.'>ed in ~ncllCllly engl' ncc.red baby ham"er kldllCY ccll~,"" KoGENate has the ~anw= biologicalllCti~ity II.~ the human pl.tsnmdtrived antiilcmophilic faclor (pdAIIF). 'The punfielll}on proce.\) for rAIlF inc ludc::!l nmoodonal antibody Immunoaflinlty c hromatogl'll' phy 10 relllO\e any proIein COOUlmlllantll. rA liF is indkated for the tt!'ll\mel1l of hemophilia A anll is adrninl"ered by lhe intl'll\cnou. roule . I'atlents suffering (rom hemophilia A uhibit a deerea$<' in the .ch\il) or plasrn:t clotllng factor VIII . 11l1s prodUCI lemporanly prevents bleedlllg epI.,;ock, In hemophillllC~ and may be used 10 prevenl exccsshc bleeding du ring surgical proccdurl"S in IlleloC p;llients. A major 1Ill\'antaGc of lhe r A IIF o~er the nalUrol rllClor VlIl is thl.' lack or \ 11lI) in the product, rAHF docs IK)I contain von WiUebrond '\ (lICIor: therefort'. II b J10I indicated in lhe treatmenl of 'on Wilkbrnnd's diloCa<;c. Patient~ receiving rA liF should IX' momlort'd earcfully for the dc\e1opnw=nt of' antlbodic\ . 810clate i~ an rDNAdcri,ed factor VIII c~prK\Cd in genetically engineered OIillC)C hamster OVllf) cells. It h:ts lbe SlIlIIe blologkHllICtj\lty as pdAHF and is 'IrtlCtulllUy simi lar. Its irldiclllion~ and odn'T"i(' effccts arc sinll illf to those for KoGENatc.
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~th

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60 M..-u. A. C: Am. Sd. 67:42!. 1m 61. l 'SI' 0 1. Dru, Inf.,........,., ft. !he llellth C.... l 12ndN. ROt:~.,I". MD. U. $ ~ ... C......- . :!t'Ir.... 17(11 -1710 U UnitT. K. I . cI" SduO(e 1118'92]. 1975 6.1 " .. n. J. N R.... '" R,,&n. s.", A 6.1. 1978 M ...... " ... M, II" ...dLS L . -.l1'I)"".K. W l'helhodK'lUOII)'of* 1 \ .. I'tlIyp<p>de Ikw". .. CIoKIoNof. U, K . Jolon .... ,Ie)' &! PI'- l lS-33', 16, moun. PC . """ Son<I>erJ. II E.: An ... Ilq>. MN Chnn III

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s....

An ,...,.,.....,..,.,

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1'.n....."OOJ CI,ff.. NJ. ~1tt Ibl1. 197~

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M"..o,1onaI Anub<>ilit." PnlOCl'" AppI ..... _ .. Neo. YorL ......... W,Iey.l: Som. 19'n.

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I'HI'!.

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Hill 1%9

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26

Vitamins and Related Compounds

GUSTAVO R. ORTEGA, MICHAEL J. DEIM lING, JAIME N, DELGADO'
Vimmins traditionally have been considered 10 bI! "acces sory food factors." Generally. vitamins arc: among those nutrients that the human OIl1!lI1 ism canllQt synthesi7.c from

OIher die\ary component:;. Together with ~rtajn amino acids

(i.e., essential ami no acids), the vitamins consti tute a lolal

of 24 organic compounds that have been charuclerized as

dictari1yessential. ' Many vitamins fUllCtion biochemically

as precursors in Ihe synthesis of coef17.ymes necessary in human mctubolism; thus. vitamins perfo"" essential fune
lions. When they are not available in approprimc amOUnls.

the consequences may lead 10 serious disease stales.

Although there ure rel:uively few lher~pcu[k indications for ";!.amin pharmaceutical prepa .... tions. d iseases CJuS! by certain vitami n dcficiencie$ do 1"CS(lQ1Id favorably co vi twllin therapy_ Additionally_ there are products illdicated fOf prophylactic use as dietary supplcrncnts. An optimal diet provides all of the necessary nutrients: in some caSt's of increased demands. however. vitamin and mineral supplementation is rccommended. 2 Two organizatioru provide guidelines for dail y vi tamin inlake in Ihe UniTed States. The fin>t, Ihe Food and Drug Administration (FDA). regulates the labeling of foods witb respect to their nutritional contem. including vitamins. l1Je current labe ling requirentents for vitamins. established following the Dictary Supplement Health and Education ACI (OS HEA) of 1994 and published in the Code of Federal Regulations {CFR) ,l requires that the vitami n content of food be li~ted as a percentage of the daily value (OV). The daily value for nutrients i$ detemlined by using the daily n:fen:nce value (DR V) if the nu trient is a source of energy. such as protein. carbohydrales. and fall.. or by using the reCereoce daily intake (ROI ) for vitamins and minerals. The RDI n:places tile prev iously used term, U. S. RDA (recommended daily a1towancc). to prevent confusion wi th the RI)As publi shed by the National Academy of Sciences. 1ltc ROl s for each of the vitamins as publiShed in the CFR are the same as the values used under the older term. ROAs . 1ltc OV for each of lbe vi tamins (Table 26-1) is based Of] a 2.000-caJorie diet. and the %OV that is placed on the food label is determined by dividing tile conte01 of olle serving of the food by Ihe OV and upressing the result as a pen:entage. The second organi7..ation that provides nutritiOf]DI guidelines is the NutriTiOf] Board of the Nalional Academy of Sciences. Institute of Medicine, Their guidelines arc published in the form of dietary reference intakes (OR is). which inc lude several ways of evalu atin g the proper intake of vilamins and mineral s. su<.:h as the estimated average requirement (EAR). recommended diel ary allowance (RDA ). ade-

quale inwke (A I). and tolerable uppt:r intake leyel (UL). Generally. the RDA is the most specific recommendation of the recommended daily intake. with tnc A I used jf not enough data e.tist to support determination of a RnA . Tabl~ 26-2 contains the CUrTenT dietary ORi s. in terms of the RDA (w hen available) or the A I (when the RDA is not available) for the vitamins covered in thi ~ chapler. The medicinal chemistry of vitamins is fundamental IlOl only 10 the lhernpcutics of nutritional problems but aIJ;o w the understanding oflhe biochemical actions of other medicinal agents that di rectly 01" indirectly affect the metabolic function s of vi tamins and COCnf.yme.~. Accordingly. this chapter ineludes a brief summary of the basic biochemlSUY of vitamins. struCTure- activity relationships. physicochemical properties and some stability considerations. nutritioml and therapcuti<.: applications. and brief characterizations of representative phamlaceutical products_ In 1912. Fu nk" described a sub,tlll1Ce. present in rice pol. ishings and in foods. that cured polyneuritis in birds and beriberi in humans. This substance was referred 10 as "UWI" ine becnuse it was characteriud as an amine and as! yital nutritional component. After other food fllCTor.> wen: OOIo:d to be viTnl nutritional components that were not amines and did not even contain nitrogen.' Drummond suggested the modification thaT led to the tern} "illlm;". McCollum and

TABU: 26-1 Daily Values of the Vitamins Used in Food Labeling

Viu m ;n
Vitamin A Vil.min C Viwnrn 0 Vi .. mm I! V,l;lmrn K Thr"";n

Da ily Va l...

3.00J It!'

., ..

""'" "''" "'"

"mo
1.5 "" 1.7 ""

lIibon.vin
!'OUlCIn

V,"";n 110

""Iale Viwnrn 8" Iho"n l'anmtl,,;nic .<id

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JOO",
IOml

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1m.

866

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~

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I~

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u

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."
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DaVIS'" 1 delicribcd a lipid -so luble esscmial food faclOr in buuerfat aOOegg yol~, and 2 year:s later. reference Wa.'l made 10 I wiler-soluble factor in .... Ileal gcnn. Thus. the tm11sfillJolublt A and ....U/ers<>l"blr 8. respectively. were applic(l \0 Lhese rood factOK Sma.' tl\cn, m;\/ly OIher diellll"y componenlS have been discovered 10 be eSSf'Dliul nutritional COInpoI"II.'nlS (i.e" \itamins). It is lraditional lo classify these com pounds as either hpid-soluble or water-soluble vimmms. This classilicalion is convenicm bccllUSf' mcmben o f each c.uegory pololoC'SS important propcnie5 in common.

Vlumln As
VilnmlO A wa.~ first n:cognil.cd as a 'tlamin by McCollum and Oavi ~&.1 In 1913 10 1915. but studtcs of thc mok.'cuJlI/" ITlI:chanis m of action of retinol in the visu..al pnxeM wen: nOl signilica/llly productive unlil 1961IIo 1972. Thc mechanism of aclion of vit3min A in phy~ioiosicai j>ioc... s l"$ other lhan vision has bun vcry dlfficui! to study. AdvullCCS in rnolc.::u lar biology hn\c. Ilo wevcr, Slarlc(i to idenlify Ille rolc of retinolds in bone growth. reproduclloo. embryonic devd opment. protein synthesi ~. speml production, 1100 OOI1lrol and differenlinltOn o f cpitlJclillltissues. Thi \ has led co lhe "I.lggesllon lhal vitamin A hao:; oormone-Jike proper1ies. "There is convincing evidcllC~ th3t vitamin A perfomls an imponant funcllon in !he binsynthesis or glycopro!eins and in sugar transfer rea(.'tion~ in mnmmalian membral"ll.'S. Investigations on chI.' mechanism ofthi! action were stymied by difficulties in clearly delining!he biochemtcally acli ve form of!he vilamins. wl1ctller il i~ all-trllIIs-relinol or relillOic acid. This question was reviewed comprehens;\ely by Chytil atMi Ong. Mosl. if nOl all, 'ilnmin A lICItOOS in development. differentiation , and metabol ism arc mediated Ihrough nucleat receptors that bind 10 l'\"lino1c :acid. IO

LIPID-SOLUBLE VITAMINS
The lipid-soluble ~ilunJins include ~i!1lmin~ A. O. E. lind K. These compounds JIllSSe$s other characteristics In common besidt\ ~Iubihly. They are u~ually associ alcd wllh tile lipids In foods and an: ab50rbed from the intestine ",ilh thel.e di euty lipids. 11K' lipid-soluble \ilnmms an: stored in the liver lOd. thus. cOIl'<Cr.'ed by the Ofganl ~m. whereas scorn!:e of ibe water-soluble vilnmins IS uwally 001 significant.

TABLE 26-1

Weight Equal to 1 IU

USP Units per Gra", of Selected Retinoid,

TABLE 264
R.tlnold

Ret inoid
AlI,,..,.MdI(lI

'''11-,-..1'<'1I/l0l o.:ttIk
AU .,rut\f .... , ~ ptI.pooalt

"Hot o
0"9
01'

""

AII- ........ -I'<'lIIIOI

N.... "tam'a A
~"'''- Ret,,101
~

1.1q(l.000
b).t.(Ql

,""

'"

...

AII'--.,....... ~ ,,1""lR"

tI-C_OI

"

.13, Do ......_"",..,.

,"",,"

9.11 Do .....-rru ....

AU. "'11""""ln" , t..u-1lnIMI

67'1.000
.1.\Jj()JlOO

The term I'itamrn A currently is applied to compound'! pllsscs~inl! biological llctivity li~e Ih~t of retinol . The tern] I';wmin A / refers to allfrons-retinol . The lenn refinoill is applied to retinol and ib naturally occurring derh'lltil'cs plu$ ~)'olheiic alUllogues. wInch need no! hale vitamin A :ICI. vii),. Vitamin A activi ty is e~f!ressed as USP unit-. International units (IU). retinol equivalents (RE), ~nd ,8-c~tOICIlC equ ivalents. The USP units and IU an: equivalent. Euch unL! expre.~SC'S the 3Clivity of 0.3 II-g of all-mlltl'-retinnl. Thu~. I Illg of nllmms-retinol hns the :lClivi!), o f 3.3)3 units. Other equivalems nrc listed in Table 26-3. One RE rcpre5Cnls the biQk)gicaJ DCtlllty of I 11-& of all-Inms-reuool. 6 pI{. of fjClm:)(enl'. and 12 II-g of miled dietary carotellQlds. The RE is used to :onvert all dietary sourees o f vitllmin A inlo a single unll for easy comparison, II The SI~hemi5lf) of ~itamjn A and related compounds I~ complex. and a complete stereochemical aOlllysis is be yond 100 !\COpe of thi~ chnptcf. A brief summary of some qcreochemical fenlurcs IS pn:s.::nlcd here lI$ the basis for the Charnctcn7.a1l0rl of lhe biochemICal acuon~ ellcned by thIS ,ltamin. The study ofthc StnlClUruJ relationshiP<' among vitamin A and it~ sten:oi'\Omcrs has been complicated by the common lis.:: of '\C"eraloumberiog systems. as shown below. The first nllm~ring syStem (A) is the one currently recQm mended by the Intcmal10nal Union of Pure and Applied Chemistry (IU PAC). 11te second ~yslcm (8 ) plllCe~ emphasis on the conjugnted 1r ,y~lcm. while the third (C) is used by the USP D.cllom./)'ojUSAN Wid 'IIIcmtltionll' Drug NI'mes.
, 2 3

9-oj>.RtbIIIII ~., .\. 01 ......-"",,,..

~. I I,Do ........

\llO.ooo ."
~,

= ...

11,6111,000

... ...

ity l1 of the t'\Omers of ~;tamin A acetate. in terms of USP un its per grnm. 1U"C listed In Table 26-4. Di 'ireg:trding SjCRl)chemical vllliations. !iC~eral compounds with Structureccr respondin, to vitamin A. iUi ethers. and ilS e~lcrs have bttII (!I"epnred. I - 16 These compounds l\.'! well as synthetic \"it~mln A acid possess biological acti vily. DIetary vitamin A ;$ obtained ClIclusi\"ely from foods of animal origin as reti nyl eSlers. The prov;tamlO carolenoilb are obtained from plant and dniry IIOUrces. The highelt sources of Mtural vitamin A IIIl: fish th'u OIls.... hich VIr) greatly in thcconlent ofthis ~ itamin(fable 26-5). MOSt bl"a oils contain vitllmin A and ReOvitllmin A in lhe 11ItlO (1(2I. Vitamin A occurs free mid combined as the biologically active eSle~. chieny of p.almitic and somt: mynsuc and dode canoic acids. It is also found ill tht: Im~rs of ammal!;.~ dally those that are herbiVorouS. Mdt and eggs 11ft: r .... SOUrt'Cll of Ih i~ vitamin .

,
Neovrtamlll A 15 ( ll -tT\Oflo-ClS-ret,noIj

-.::::

-.::::

-.::::

'<:::

'<::: ~ ...

S_A

The li\"e~ of fr~walcr fish COlltll;n vitamin h)'droretioolj.

A~

(3.<kIt-

TABU 26-5

Vita ",In A Content of Some Fish Lw.r

SysIafJ1 B

7-.;;:.8 -.;;:.'

Oils

' ,,<:::'

OH

..

"~
II.....

........
Animal
I/'PI'OI"''''''' o\t,.,....~ .....
1'~"""""1'h

~"'"

SystemC

1I~llbu,-

P.n:II11101"p11. to ....

fiJ/II:'lmIAN

For StehC reasun..~. the number of isontnS o f vi[amll\ A most likely 1 occur ie tunited. These are aU-lmns. 9-cis. 0 I )-ds. and lhe 9. I 3-di-ds. A ci:r Imkage !ltl\ouble bond 7 or II cncotlnt~rs steric hindrance. The II -cis isomer i ~ t''''!Sted as \Io'cll as bent at this linl.age: Ilevel1hcieb. this IS the only isomer that is llCm'e in 'Ision. The biological acti ~-

.... ,<)
ShIri., I,,..

""'" "'.. "",,"

2S_-...o ,'-'"

o.r..~. ~'I''''''''''
If~ ...~'''''''IU lind ",her ,*""i~

SIwL Ii ...
8\1rb(Jt. I, ... C'<>d,h..

Lt>fI> _~to...

.'"

..

A2 (all-trans) 3.4- Dehydroretmol or Oehydrore tirlol

V~!lmm

Dietary rennyl estcrs are hydrol)'l.cd in the intc\t uml lumen by vmOlls hy.:lrol3se:s. The n:tinol is .bsori:Jcd Intu the emeroc}lC:S by facilit.:Ued diffusion in normal concentl'1ltKln~. At ph3l'1l1llCOlogkai ~. ho ...e~'er. rennul can be absorbed by passi~'e diffu~ion.17 Within the> c:nterocytCl>. the: reti nol is 1.'~leriried by IWO enzyme~. acylcoenlYmc A (CoA): relinol acy ltransfcrd.\C (A RAT) and ledthin:rctinal acyltransferoiSC (LR AT ). LRAT eSleri fies ret inol bound 1 an 0 tntll\(:ellu lnr protein. cellular retinol-binding protein Iype 11 (CRBP 111 1). while ARAT can esterify unbound relinol. II lias been ~ thaI LRAT estenfiCl> refinol at normal doses. "hlle ARA T est",rifics exccss retinol. II TIle n:tinyL estCT!i an: iltCOipClIaled inlo ehylomif:ror1~. ... hlch In tum enler the I}mph. Once in lhe generoll circuln111,11'1. chylomicrons are con"ened into chylumicron n:111nami, ... hich an: cleared primarily by Ihe liver. As lhe C\tcrs cn t",r Ih", hcpalocyles, they un: h}droIYl~'d. III It"" elidaplllSmic n:ticulum. lhe n:tinol i~ bound 10 retinol-bim!tng proIein (RBP). Th is com ple.\ i,~ released into lhe bLood or tnmsfelT'Cd to liver stellate ec:11.~ for storng"" Wimm the ~Icl lale eells. tlK' retinol is bound to C RBP(I ) and esterified for WJrlIgC b) ARAT :rnd LRAT, Slellatc cells contain up 10 95%ofthe li,'er vitamin A bton:S, TIle RBP- n:nnol conlplu J't'leased into !he gcnel'lll circululion from hcpalOC}le~ or slel late cells, In tum. is bound to trolnsthyn:tin (TI'R). which pro4ect~ reli nol from nl<:tubo li.ii;1I1 nlHl renal excrction.l ~ ~ ce lluLar uptake o f plasma retiool remaill\ tU be fully urKlerstood. This is further complicuted because: chy loml CI'OiI remllllfllS abo cunuibote reli nol lo the targel ~eJls. The: fate of rell nol after absorptIon .. JU5t bc:g.mmng to be: underJlOOd. RB P and TTR do!'lOl enter tbe: eell , On ent~nng the: cell. the n:ll ool is bound to CRB I,,!) In the cytoplasm. MOI>t U~ contain CRB I,( I) and CR BI,{ Il ). These: intlllCCllular pro4eins function in the tl1ln~por1 und melabolism of n:tl nol and ret inok acid by wlubiliillg tl""lII in aqUl'OU' medlu ~nd presenting the m to the appropriate enzymes while protting them from catabolizing eIl1_YI1Ie~.lU The.<;e proteins also Ii mit the concentration of free n:li nolds wnh in the ~II . CR BP( I) Ttlu latc:s the C:c'i lerification of TtunoL and its oxidallon to n:tinoec 3C1d from retinal. "hlk CRBP( IlJ controls tllC reduclion of retinal 10 rt'Iinoi and It>; Mlbseqoc:nt c:stcnficaIlOO,:1 Reunol is su>ccpuble 1 glucuronide ConjUgatlOll, fol0 Io...cd by cllteroix-palic recycling. [I may be. oxidil.ed tu reu noie lII;:i d by two en1.yrnes. rchnol dchydrogen~ und retmal dehydrogenase, wim the fonller being rate-li mit ing .l ) U n li ~e retinol. retinoic acid has no specific carrie r in the blood. Retinoic lICK! undergoes decarboAyl~lion. fol lowed by glururonidc conj ugation, Normally, no unchanged n:uooll'Ji u creted. Reunal. rc:1inok lICid, and Oihcr metabolites are. 110... e"er. found in the UrillC and fes. Although fish liver oils are used for their vJlamm A CQIltent. purified orroncemrated foom of vitamin A are of gn:at COf1lnlCrcl al signifl(: ance. These are prepared in three ways: fa) supon ificmion of the oil aod concen tration of ttle vitami n A in the nonsaponiliable mnller by soh'ent e:<.tnlCTiOiI. wilh

lhe producI lI'I<Iacled as ~uch: Ib) mokcular di"'llIation of the I1OIIsapomriablc maller. from ... hlCh the ~Ieroh ha,-e been relllOvC'(! by f~t,"g. givi ng a distillate of, itamin A cuntaining I to 2 million IU/g: and I,) subjeclmg the fish l)iI to din:ct lIlolecuhu dl'tiltatlon to recOvct the free vilamin A. vitam in A pall1litatc. and myriSlate. Pull' crystallmc Vllamm A ocrurs as pale yellow plales or crystals, It mt'lb at 63 to 64"C aOO i~ insoluble in ...':tler bul soluble in alcohol. the: usual org~nl(: sohems. and the fixed oib, Jt is unstable in the pre!il:11Ce of light and OK)gen and III oXldl1.cd Oi' readily o~idi1.cd rub and oils, II c~n be protect~'d b) the cxciu"on of 3Jr and light and by the presence of antiOXld~lIt~. Like all ~ubl. tarlCes thaI IIavc a polye rle structure. ~ lIanlin A gives color rc:lIC'lI00\ wnh m:my reagents. mo~t of which are eilher strong add\ or chlorides of pol) ,alem nlelals. An intense blue b obtainetl with \itanun A In dr} chloroform .'iOlUTion on the addlhon of a chloroform solotlOil of :tOhmony trichloride:. 1111s color reaction (Carr- I"nce ll'3Cllon) has been studied ulensI\eI)' and is lhe: ba)1~ of II oolonmt'tric asSoay for vitamin A .21 Vitam in A (all-mm,N ctiIlOlJ is bio<;ynthcsil.<d in animals from plam pigment~ called mru(elwids. which are terpcnes ~'{)mpo>Cd of isopr~noid uni IS. 1'he.<iI;: pigmcms protect plant ~lIs from photoche>mlcal damagt: and trdn~fer nidiant t1) ergy to the pi llnlenh re.~sible for photos}nlhc:sis, Although hundreds of carotenoids ha'e been ldenhfied. only a few function &'I pro\lIllllllll!i.~

, " " " ,.

~ ~

.-<~
~ ~ ~ ~

1 ~l--~

j
~ ~
~

7
~
~

,..c.ro<_
~

l--~

"I

5 C'J UB.,.

OH
~
~ ~ ~ ~ ~ ~ ~

. .1- '<: .
I

Cfyp!o~anlhln

The: pro, lIumin As (~_g .. t', (J-. nnd ".carf)!ene~ and crypIOt3nthin) an: found in deep green. yellow. and ornnge fruit-!> and \egetablC'\. 'uch lIS carrots. 'pi nacho broa:oh. laIc. l"Ol lard and Turnip gtttns, mang~. apricots, IlCCloInnes, pump~ms.. and ~wect potatOei.. TIle carotenoid plimc:nts are used poorly by hull'l<lns. ... hc;o;reas animals differ In their abIlity to usc t.hco;c: comJXIUI\ds, Thc:sc carotcl1Old pigments an: pro"i IIImins A bccauM: lhey are C<mler1ed to the ao:.1ive ~ilD.l1lin A, For cum pie. {J-CnrotCIlC is absorbed Intact by the: ,oleslinal 1I111Cma. thcn cleaved 10 retinal by {J-carotene-15. IS' -diox ygenase ..... hich requires molecular oxygen l~ {J-CUroIclle can

gi~'C n.e 10 ''''0 molecule. or "'Ii nul , w~as I'o,ilh fhe OIheT "

Ihree carotenOids. only one molecule I~ lJO'>.~iblc by Ihls Iran~fOflllllI'on. 1'he"e cart)lcnoids ha.e only one ring (sec formula fot /kamterlC) al the end of lhe poI)'eoo chain. which IS idenlical WII h lhal found in ,8-eUnMcnc und is I\es'IaI)' (ot ,!tamln A lICti," y. Th is acroum~ rot lhe 10.... lICt i ~ ily of ,tkllro\ene. The OOIlJIl8~led double-bond sy'te m~ roond In vilamin A and /karolC"ne an" necessal') rot lICu.ily: ... hen these compounds are pm1 ially (II" OOIllpletely n."IIlM.-ed. lICtivity i\ 1 0SI. The p.KJOOne ring of n:tiool ot IIIe dehydm-P.ionone ring found In dchydroreunol (~ II:!.min A l l IS es~nlial for activity. S:!.lllmtion re~ulb III loss of IM:liviTy. The C$\cr and mClhyl ether!. or vllamin A haH~ a bIOlogICal lICtivily on a molar hasis cq ll~1 10 th~1 of villulUn A. RClirwic acid (vilamin A IIdd) is biologically aclh'c btu i~ not Slorrd in tile li~cr. CamlellOld abSQ'phOO is by pa.'i,i"e diffusion and depends on ab'iOrbablc fals and bile. It i~ 1I~,umcd Ihm one SlKlh of normal diel:ll'}' /karoleot 001 0111) 0Itt Iwelflh 0( the other pnlvillimin A carolenold, i ~ IIbMlfbed. The enlcrocyles 00fl,'el1 IIIe CMOlcncs into reli nol. oot lip 10 20 10 are absorbed unchanged. The intesllnal mucosa i<. the main si le of P.CarolCi"IC Imn~ formacl()f1!'J 10 n:tln:ll. 001 Inc cnl.)~ Ihal C31 a1p.c Inc Ir~,,~f().. m31;on also ocellr in hep'Llic lisstJe. T ....o mt.'Chanisl1ls fOf the cOlwel"ion 10 relinal tlave been ~. Originlll1y. II ... a.~ ~ thai cleavage ot-cllrred cenlral!) by p.caro-Icne-I.5.15'-diollygcna'll:.~ Evideoce Cll ISIS, ho .... e'cr, for peripheru! clca.. agt 10 )'Ield apo-carutin:lls. I'ohlCh can be cornencd further 1 rehnaJ .ll The rcllluJ IhllS formed L re0 S duced to retinol and eslerified before tnleri ng Ihe chylomiCIUIU fur tr.ln<~ fmlll the li'er.

Relinoic acid, Ihe corre'poI!lImg carbo~ylic ucid, promolt"! de"clopment of bone and ~1 lis~ and <,pel III pro1I1lCllon, bul it doe~ not p;inlcip.lle in lhe V!~UlII process. Rctinoic acid j, found in the bile in lhe glucuronide form. Vllamin A IS oficn called lhe gW"'rh "'10111111 becau~ a dcficie",y of il in tile diel causes ee.\SlIlIon of gro .... th In young "'.11'>. A deficiency of .. itamin A b manifesled chiefly

by dc-gcllCTlIliun of the n"ICOU~ 11ll'lLlbmnes Ihroughout tI-t body. This de"enerJlion is n~ pronounced in the eye filii in any other pan of the body ~nd gi'e~ n.e 10 a C'Onthliol knol'on as ",eropluh:!.I",'" In the ean lcr Stages of villlllLD A deficiency, lugJu b"ndlK'S~ (nJc/a/l!p;(I) nl3.Y de\elop. wluch can be cured by v;lnmin A. Nilflrl bU ..d..uJ can be defilltd as lhe LIIabLhty 10 sec III dllll li,hl. /)(Irk lIllI/Pili/ion Of ..I.,wl Ihrt$hold is a mo.t ~LI!tabIt de.~"plion than "i, (/" bllflt/ntS3 in many s.ubclinical Casel I of vitamin A deficiency. "The "ill4ll1lhrtJhoId al lilly IllOmaII is ju~1 that light inlcnsity requi~ 10 elicit :l visua l scnsau",. /)wk fliklpU!/jQ#1 is the change lhal lhoc vi~uaJ IhrcltoId undergoes during a Silly in the: dar\; afler an e~po!oun: 10 lighl. Thi ~ c hange nl3.Y be .. ery greal. Afler (lpolollre of III: tye 10 daylight. D slay of 30 minutes in the tI.tut decn'1:$d the lhre~hoJd by a fuctor of I miliiOil. This phcoomerlOll ,\ used as lhe basis for delecting .ubclimcal casa of 'I13min A defidcl1cy . ThcMl\es\s vary ILl thei. technique. oot es_ tiaJly fhey ""cnsun: 'I~u:ll dan: aUaptntovn aner ex~ 10 bnght light ~nd comP'lre 1\ .... ith the normaJ. U N Advanced dclio.:lClt<:y of viwmin " g .. e~ rlsc to dl)~ and !jCali ~ of the Skin. accompanied by a ICndcnc) '" in(cehon. Char ,lClcristic le\ions of lhoc: hunl1l1l skin (":II!1i!d by vilam'" A deficiency usually ocellr in :.t'lually lTIOIIure ptT'$Ons between the age, of 16 and 30 and not in inflflll. 1lle<;e ~ions appear lirsl on thc pntcrolmcml ~urface or~ Ihigh and lhe poSIerolalCf'JI port/Ofl of lilt upptr fortanm and lntcr sprcad 1 adjacent llreas of the slln. TIlt ItsK.I 0 00Il~1'-I. of plgmenled papoJc.~. up to ~ /Lilli in di:uncter." lhe sitc of lhe hail follicles. Vitamin A rcguhllc\ lhe PCI;"lt ies of O'>leoblasls and o;.ttoclast.~. influcncing the ~ape of lhe bones III the grmr.:,nr animal. The Il'Clh al<;o are afftCled. In ~ Llanlln A. derlCitl") stalCl;. a 10l1g O"ergrol'olh occurs. Ovemo5C.'s of vilDlLLln A in infanl~ for proIongtd periods lead to 11l\'\trsJble ~ in the bones. Inclulling relanlallOtl of growth. premalun: clo sure of lhe epiph)'!i('~. and diffcrencCl; in the lengths ofllw: lower e~lrel11j ti cs. Thus. n clO"C rel:uionship c.\isu bc1"'1 lhe functions of vitamins A and I) n: lmi. c to canilagc. bont\ and letlh.JOThc: tocopl"'loI~ e.ten a sparing and ... hat 10 be D synergistic action" with vimmm A. Blood le"el s of "I!lIm; n A decrease very ~Ju .... ly. !lIId~. creased dark ooaptal101l ,,'a.( ~ed In only 2 0(27 \'Ohmteers (mainlained on a viuIJl1in A- free dlct) alicr 14 monthl, at .... hich lin ... blood le,c!~ had ~Tl'astd from 88 10601111 100 1111. of bloud. Vitamin A perfonns numefOO' biochcmical functions. II pronlOles lhe prodUClloo of mucus by lhe basal etlls of., epitheliu m, .... hereas in ils absencc \;.cr.lhn call be fOlIl"a. Vimmin A performs II (uneliOll in lhe bJosynltiesis of.,)TOgen and some steroid). ~nd increased quantilie! of eQeRl>Q are found in the Ii,'crs of vi tam in-(krlCicnt mts. SiSnifi ClInlly, tnc bc.~t-ln(>wn 1ICt10ll of 'L1amln A ;\ it~ func1io!1 ill the cncmi~t ry of visioo. Il ypervitaminosis A can lead 10 both short- !lnd Iong~ cfrCCIi.'~ ShorH cn n doses or 0 .5 104 million lU can Ie3d. within hours to sc"crnl day,. It) cen lr~1 f\er\'OIIS sy~lcm d reels includlllg increased inll'llCf'.lI1L1l1 prcssure. licadache..l1' rilability. anti ~ilures; gD~t miI1lCSlin~1 effL'Cls includJlIJ nausca. \omiting, lind pain: demlllloloiltC;l1 efftefs !oOdI iIIo dcsIjunmallon: ophthalmic effects ~uch as papilledema. <roo 101Ll3.. and pholOphobia; and li ver damage. MO:!i1 of lhe5t

...,_1

........., ..____________________________________________________-.c' ,.,,..-,.,"',.m;,."';;;;J;r,R,,... ecc........ i>n,E.'o . ,';, ;;;;:;;--.877i'----..

been reported in infants following Creal/nenl ",-jlh large ~ of "lIomln A. but some hnc l'CSul1ed from inge5l1on of rood rkh in Vila/mil A. such lIS ]iH'r. especially from poI..r bears. long-Icon Intale of doses of >'ulIm;n A lower than .he rt'1IClion.
ha~e

"

"

Imalc reqUired (or .hor!-tenn tmieny but ~uJl above thal requirrd by the body can lead 10 1 000gterm efftcts. II'Icluding
the lil: m. liver. cemrul nervous s)"tcm. and bone. Although the amount reqUired .arid. doses 3.lIiow lIS 15.000 IV/d.,)' hal'C Jed 10 some IKlve~ effCl:\s. although higher doses.. generally above" 100,000 IU/day. an: required 10 S alllhc reponed adverse effects. In palien.s .... ith low body "'!'lghl, malnutnlion, or hler or mllIJ dlscase . the do!;c$ ",. quired for longternl adverse effects may be lo ...er Mill. Dermatological ad. CI'C effcclS Include !If} Ing of the ,kin
effect~ 00

and murosa. dermautis. prunlu~. swelling and fi ~surilli of the lips. and homeln1lCS) loss of body IIlllr. I tepUlle effects include hypel1rophy and hyperplasia of IhI= 110 ecll~ (whkh
SlIlrC malmn AI. hcpalomegaly. fibrosis. and cirrllosis.

.... hkh can lead 1 portal hypcneru;ion. ~ile5. and jaundice. 0 Spknomc:galy i~ ~Iso secn. Centml nervous sysu:m effects mcludc: HlCre:a.'\c:d intracranial pressure: (pseudotumor ec:n:bti) lea<1ing 10 hcndache. vl,ual diqurbances (e.g .. diplopi;l). droWSIness. ,onlili ng. KI/,U/'e5. and a bulging fonlanel In infplll~. Finally. pain in the bone olld jl)l nts. with IlC~OIl1pa Rying lendc:mc:u. and reduced bone mmerah1.anon)) have II1so been reponed. TIle terJlogenk effeelS of vitamin A are "Iso well known.Jl. " Intake of !IS little as 10.000 IU/day dUring pregn:mcy may incrrase the nsk of bmh defeets. and the risk locreases with mereasillg IIiUlke of \'immill A_J' 8,nh defecl'l IlIC lude cruniofocial. ~umltuhe. and urogemtal :Uld mu.'iCUJos~elctal uboormalit iu, ,8-CalUlene. in contT1l.~t. is relati-'!:ly nontoxic. After 1 01lgImIl exposure 1 high Ie\ds of ,tkan:llene (30 to 180 mgt 0 day for 13 yean;), ..... hich i, equivnlenllO !iO.OOO to 300.000 IU of vitarnin A, patients ruwe IlOl developed any problems otller Ihan ~kin dIscoloration and aSYl1lplolnatic hypcn:arotot1emia. Futthennorc:. ,8-carotene is noI: teratogenic. llIe most likely meclllilll'iJl1 is the slow rate of convc~ion of ,tkJU'(lltnC: to rrtmol. 11lc molecuhlt meChanism of aclion of vitamin A in lhe: \tSUal piOU:'U has been undc:r lIlve~l1gauon for many yea~, Wald in 196816 alld Monon in 1972.lT chanacteri~ this mtehanism of a.clion, 1llc chemistI')" of \'[sioll wa~ revlewed oomprehcnsi\'c:I)' ill A.croUIIlS (If Cht'mictll Rt'srorc:h ( 1915) by numerous ill\estigator>. These rev~ ..... s include theoreti cal slUdies of the: visual chromophore, cilar.t('teri7.ation of rhodopI;in in synlhell c sys tems. d)'lliImic processes in vc rtebra\e rod \,i.ual pigments and their membl'1lllCS. and the: dypami<:~ of the \'['1.1:11 prOlem opsin."-u Vilamm A (all-trotls-reti nol) undergoes isomemation 1 0 the II ..cjj fomllll the li,er. Thb tl1Ulsformatioll is catalYled by ~ retinol isonltr......c. Subsequclltly. II -('u-reunQI IllIenK:1:$ wllh RBP to form ~ complex thai is unnSporied 1 the: retinal 0 phot~OI' cells. '4h,ch contai n speci fic rcceplOl"S for the R8P- n:tillOl complex. Tlle retina has been eonside/lld" J to be II dooble-scnse organ ill which the rods I\.I'e e~med with colooess \'isior1 1\ low light inlensitlCS and the cones are concerned with color vision lit high light imell..iIlC:S. A dart-adapted. eXCised retina is rose red; '4he-n II IS exposed to light. [I!, color

changcs 10 chamois. to onnge. 1 pale )'ellow: finally, on 0 prolonged irradiation. it become.~ !.'Olorless, 'The contaIn photosensiu\ e \'I$u31 purple (rhodopsl n) ..... hich. '" hen IlCted on by light of a dc:finlle wavelength. i~ convened to \'isual yellow aoo lIlillates 3 senes of chenllcal ,tep!i IIeCCliI\1lI)' 10 vision. Vi~ual purple i. II eonjuglUed c:I.r(M:lIOid pMCIIl .... ilh a relan>e molcculur mass (M,! of about 40.000 and one prosthetic group per molecule. It contains !Ie,'!:n hydrophobic (r'heli~, ..... hICh ~ embedded in the membrane. Short hydrophi lic loops mterconncct the: hehtts and an: eXI'0.scd 1 the 0 aqueou~ envmmment o n ellher side of the Inembnllle. It has WI absorption muimum or about SJO 11m. llIe prosthetiC group is reti nene (neorelinellC b Of' relinal) ...... hich is;o;ned to the protem through a protOllaled Schiff base linkage. The funcllon of reti IlCne in viwal purple is 10 increa.se the ~ion COt'lficicnl in ,';sible light and. thc:reby. sen~itiu the protein, which is dcnalur\.'<.I. Th is proces.~ inillates I series of phy~ical and ehc:nllcal ~teps l...,..ess.a.1)' 1 vision. 1llc pr00 tein il'IClr diffcrs from other prOleiru, in having 11 lower enetgy of activation ...... hich pemlll~ II 10 be dcnmurc:d by 3 qU3m um of ~ isible light, Other proIems R:<juire a qUlUltum of ultraviolel (UV) light to be dcnaturt.'d. The bond between the: pignltnt and the protein is much wcal,;er ..... he-lllhe proIe'n i~ denatun:d Ihall wilen it IS lIall\'e. The dcnl\luration of theproteill is fC,'crsible and tll~es platt I'fIOfe readily in the: dark to gh'e rise ...... hen combined wnh retinene. to "wal purple. The effoctl\'eness of the: spectrum m bicachmg ,isual purple runs rmrly parallel with ils llb!.<"PIioll ~pectruln (!itO nm) and wilh the r.c:nsibi!ily distribution lhe eyc m the spectrunl at low illumilllltions. It has bec:1I calcu lated thaI for a human 10 see a barely pere:epuble flash of lighl. only one molecule of visual purple in each 3 10 14 rod ttlls needs 1 0 be photochemICally transformed in a dar~-ad:tpled eye. The system pos<esses such seMili""y because of biological amplifICation. In ,,;,'0. VIsual purple is re-fonned constantly u_~ it is bleached by lighl, and under CQfltinuoos illumlnallon, an cquilibnum i~ maintained betwcen visual purple, vhua! yellow,:too visual .... hlle. If an anim:tl IS placed III lhe the regenerallon or vI~ual purple !.'O11l inues until II mllXimum concentration is obtained, Visu.:tl purple in the eycs an mlnet anim:l! 11111)' be bleat:hed by hghl and regenerated in the dark an enonnous number of limc:~. In the n:sling SllIte (dark). rod and COlIC nlCmbntne:s ([(hi bit a stead) eleclrical CUlTrnl . llIe membrane allows <;(l(hum ions to entCf fretly through specific channels, A Na '/KATPase: pump mallllalllS the ion gnadlCIIl. llIe clo!iing of the: poi1!$ h)'pcrpol.:ui~e.s lhe membrane and imtiates lhe neu-

,od..

or

dan..

or

ronal response.
The ~ arc ~epl open by bmding 10 cyclIC guanosine monophosphau: (eG MPj.llIe lighHnduced isomeri/Jlllon or n:li llaJ CIlU<e~ a con formallorual change in lbe proIcln pan of rhodopsIn. a<:lr,'ali ng the molecule . One 11(;11 "e rhodopsin acti vates <e\'erul hundred Q-protem molc:coles. called troMducin. (0 pn.)\elll~ ca n bind .... lth guanosine nucleotides.) Acthation of b'lIlIsducin !.'OIIsists of an e1.challgc" of bound gUllflOSine dIphosphate (G OP) for guaoosine triphosphate (GTP ). Activated tl1lflsducrn. ililum. aetivata a phosphodl~terase. which hydrolyzes thousands 01 !.<iMP molecules. llIe decreased coocc:ntralion of cGMP result$ In dosrng of the sodium chanllCls, HydrolYSIS of lransducin-bound GTP to GDI' Inacllvates the: phOIiphodicstel'l1'iC5. The activaled rhodopsin must also

8 72

Wil_ unJ Gum/d', Tnlbook

of O'~UJ"c MttikiMi ,,,,t! 1'I..",nuawl!ctJI CMmi)lry

pre:sel1CC of blue light. Vision continue:s ve:ry we:lI. howt,~. in yello ..... orange. and red light. in .... hlCh no i$OfTlCfl/Ab(ll lakes place. The I I-mono-cis-retinal under 1iw:5e CI~ ~tances is replucw by an active fonn of vilHmi l1 A from 1M bloodlitream.....hlch came: from stores in lhe livrr, ThI: l!lomeri~lion of lrons-vilamin A in lhe body 10 CiJ./rutUvitamin A seems 10 keep pace with lon g-lenl1 procesSt'llRidt as growth. since \'itnmm A, nrovitamm A. and II-nIOIIOcis-retinal are e<jtJally lK:live in groy.th lests III ntl. Tbr sulfhydryl groups (two for each I I -mono-ciHetinal ~ cule iSOlTlel"i1.ed) ellpostd 00 lhe opsin inlliale the IratISnIUsion of impliises in lbe: phenomenon of vision . Research since the mid-1980s has laken vast striOO ia cJetenninmg the moleeulllr n-.echanism of aciion of VIIImiII A. It appears Ihut the vitamin e~ens its biolotlieal fullCtlOl .... ith rcspa:t to de,elopment. diffe:renuauon. and nxtaboIiYro like: a Slc:T'Oid hormoneY--<9 The biologically acti,-c: 5pt(1C$ is belic\'ed to be ~tinok acid. Two inttllCellular retmoic acjd~binding proteins have been isol:ued. CRABI'(I) ... CRABP(II). These: 3ppc:ar to hlIve functions .1lmilar to IboK of the CRBPs . More importantly. severnJ retinoic acid recepiClrS (!tARs) have been iclentlfied: RARa. RARp. and RARy.41 Tbtsc differ in their tissue distribution and the level of eJI~~ during ~'C II de\'elopment and differentiation . Aria hll\dq wi lh retinoic acid, the eornpln binds 10 specific recosmllOI seqUCIlCeS on DNA ( RAREs). lhus influencing the tnnsa1plion o f specific genes. The ultimale biolQgical effC(1S of rtttnoie acid are mcdiated through vQrious prolcins tMt rellliin 10 be identified. Rctinoicb innucnceembryonlc devdupnED. by inhtblling cell proliferation ;and inducing cell differnlD' tion and llpoplosis.:IO A new fpmily of retinoic acid l'Cp!0I'S luis brcn identified." These are called nfinoid X rrpI(KJ. RXRa, RXRp. and RXR y. They have a different O~1Ie distribution from the RARs. The ligand fIJI" RXR hIlS been lOOttified as 9-dJ-reunoic acid. H These: retinoid TtteplOTS must form dimc:rs bef<n ttIrl' intetllCt with RAREs. !tARs mUSI form hetcrodimers WIIb RXRs ...... htreas RXR5 may aJso form homodimers. h lIP" ~ars Ihlat lhe RARE~ for the homodimcrs differ from tho!c for tile heterodimers. This implies that they may IICUVU:: differenl selll of ~nes.'-,)4 RXRs also form heteroduntn with Ihyroid homlOl1e receptors and vitamin 0 11'(C~ increasing their affinity for DNA." Several cnl./,111C:S ...'lIOSt expression dc~nds on RXR have been found. l The able experimental data provide coovil1('ing cvide-na: tIuI these proteins 11/"('. in fact. nuclear rcp!~ bdonginl IOIb: ~teroidJthymid Ilormonc superfamily. They mediate impor tWitaspeclll of vitamin A function. The ex islcnee of pro\elll5 that specificaJly bind retlfloic acid substant iattll the implation of fc!tinoie acid a.~ a phySIOlogICal form of ~ itamln A, Studies have: shown I COI'Telalion belween II diet hl~" {karocene and a reduced risk of cenain QOCC'1S. Se\'e!II reviews of these studiu are II vailo.ble ,.I&. J1

be deaciivated, however. This is lICeompl ished by phosphorylation of opsin by opsin li:inase. Guanylate cyclase replenishe!; the cO M P concentnllion. which reopens the cMnnels. ViStlal purple occurs in all vcncbrates. [t is not distributed evenly o,er the: retma. It is miSSing in the fovea. ;and in the regions outside the fove:a. it~ eoncentnllion undoubtedly increases 10 Illllllimum in the rtgion about off center. corrc:sponding to the high density of rods in Ihis region. Therefore. to see an object best in the dar\(. onc should not look directly lit iL 1lle diagrams represent some of the chanb'e5 that take place in the visual cycle involving the rhodopsin system ill ..... hich the: II -mono-riJ Isomer of vitamin A is functional in tOO aIde-hyde form ....

ur

NH-Lysine

P,oteln

Rhodo,,1In CA ..... 506 nm)

!~11....a.
1
Nam 71 COOWZ

Blthorn,"', sir (A_. S68 I'I1II)

Lurnort\odopIIn ("..,., 491 nm;

~llM~"~
Metamodof w..-... (" ......78 nm)

1
~hO.Jo> H~I

Mom 7 ,"IdOl

!'-_, 380 MI)

SIC_Z

tf1oAut: a" I

.,'IiI-

After the lighl-ClltalY7.ed relICtion. all-Irlll,s-n:!inni is reIc:ased. which in tum is n:dllC! to all-frons-retinol . To be used again by opsin. the all-lron.l'-reUnoi must be con,'eneci to I I-';;I-relinol. [wmeriz.ation occurs in the pigmcnt .. pilbe:lium of the: retina. otj Oxidalion of II --ciJ-rctinol to I I-cilT'Ctlflaldchyde occurs while retinol is bound 10 the protein ccllullll" retinaJdehyde-binding protein (CRALBP) by a micro50mal enzyme in the pigment epithelium..... TIle isomerizat ion of /rIm.s-retinnl may tnke place in the

PRODUCTS
Vita m in A. USf'. Vitamin A (Aqul!.ol A) coOlain$ rtttnol (vitamin A alcohol) Ill'" il$ esters from edlble fany ED (chieny acetie and plllmiti.. acids). whose activity is not!e.than 95"" of the labeled amount; dosage of 0.3 14" vitamin A alcohol (retinol ) equals I USP unil.

Chaptt r 26 Vi/alOli.... Qltd Vitamin A is iooicated only for treatment of vitamin A dtficicocies. Ikcau!.C the vitamin is prevalent in the diet, apccially wilh supplemental ion of mtlk. !his dlliQfller is 11(1( common. II is a.~socialed wilh ct)O(InuXis I~t result in !he malabsorptloo of falS (e.g .. biliary or pancreatIC dlseaSH, ~rue, hepatic drmosi~), Pure vitmnin A has an activity of3.$ million IU/i. Moderate-tu.ma.<.Sive do!Ies of namin A have l)e",n used in prell_ nancy, lactation, acne, lenni nation of colds.. removal of perSIStent folJicula.r hyper\:er:uO&ls of the arms, per.;;~tt'l1t aoo abnormal warts, ooms, aoo calluses, !lAd simtlar conditions. PIiosph,illdes or the tocopherols enhance lhe absorption of vitamin A. Vitamin A applied lopically appean. to rovet1iC the impaiTlTlC'nt of wouoo healing by conicoids, Vi lamin A occurs as a ydlow to red, oily liquid. It is ne.rly odorI~ or hIlS' fiYly odor aoo is unst.ble to .ir 0100 Hllhl. It is insoluble in wate'( or glycerin IlJld is soluble in absolutc alcohol, vcgetable oib, ether, and cillorofonn.
R~llJlrti

Cumpottlldt

873

vcr,

"00

um-

Isolre\lnoln

Tho

~,u

"h

T ho

ok

ru,

,"

min

"oo ism

;ies tOie

'M

...
Ion Ing

R.)

.~

USP. Tretinoin, rel1nolc acid (Reun A), is a ycllow to light'OI'llnge, CT}'lltalline powder. II i~ insoluble in WIlIer and slightly soluble in alcohol .

T~tinoin,

."

np-

'00

OH

di-

Tretinoln Tretinoin, indicated for topical tremillent of acne vulgaris . v.. as inilia lly used systcmically. TIlerupc:utic doses frequently n:<!iulted in hypel"o'illumoosis A, howeye'(. It l.ppCaR 10 e:Ken Its IClion by decreasing the a.dhc'$iOl\ of comoocytes and by locreasing the proliferation of the follicular epilhelium." Tn:ti noin i_~ usu1111y upplioo us :t O.OS,> polyethylene gly_ ~01 (l'EG)-hlI:Wcthanol liquid or a 0.051: hydrophilic cream. Dally application m.ults in inOamm.:uion, erythema. and pot:ling of !he skin. After 3 to 4 weeks, pwitul1U' eruplions may be seen. causing the expul~ion of microoomocloncs. TreauTlCm may lhen be changed to applications every 2 or 3 day~. Bec~use the horny layer i5 thinned, the skin is more su~ptiblc to irritDtion by chemical or physical abuse. Thus, it is recommended Ihat other kerolytic agents (salicylic:, sulfur, resorcinol. benloyl peroxide) be discontmued before beginnmll: trealment wilh tretinoin. Sunscreens labeled SPFI S or hIgher are recOllllIlCndt'd, Unlabeled uses of tretinoin include the treatment of some rorm~ of skin cancer, Iwnellar ichIhYQ$is, Darier's di:;e3SC. and photooging. Photooging of the skin IS lfl3inly !he result of ~ccssi\'e exposure 10 sunlight and is manifc:;tcd by la~. )'ellow, mottled, wrinkled, leathery. rough skin, Once-daily applic:Qtion lias been reponed to aid in the carly stuges of photooging." Tretinoin is believed to exen Ihis oction by its funclion in regulaUI\i ~lthe l ial diffcrentiation, cell di vision, and prlMein synlhesi~, Tennlllauon of treatrncnl, howc"cr, ~11li in n:veru.1 wilhin I year. Tretinoin is believed loexen iIJ antineoplastic: c:lTect by promoting ccllulw- diffc:rcllhation toward nomlal ce ll s.6I

lsotretinoll'l " indicaled for the tremmenl of seven: rt.'C3Icj . trJnt cystic acne. Because of the risks of advcrIiC effctil>, its usc should be rc'Crved for panc:nlJi ",1\0 an: unresponsive to eon'etltional acne thcrapic$. Treatment should be indiHdu. ahud!lAd modified depending on the COI.lIle of the disease, The IIlCChanlSll1 is believed to IIlmll'e inhIbition of sebaceous glalld function and follicular kerntini7.Dlion. lsotTelinoin reduces scbum produelioo. tnc size of the glands, and gland dilTcrentiation. The Intual dose is O,S 1 I m&fk.g daily In 1.....0 divided 0 doses, Absorpllon is rupld. but bioauilability is low (- 2S'I because of dellr.ldauon in the lumen and metaboli sm by the gastrointestinal ntUC:OS3 and the liver on the first pass. The chief metabolite is 4-o~oiSOlrcUnolll. Both 1~linoin and il$ metaboli le arc l'OOJugated to the glucuromde and excreted in the urine and fece!i. 11K' usual toorse of therapy is IS 10 20 ..... cek5. lhe adl'Cn;c effects of iSOlretinoin arc typical of chronic hypervitaminos is A, Because of the high potenual to cause teratogenic effects. isotn:tinoin should be usc:tl Willi t:KtrenlC c:aution in females of childbeanng age. The manufacturer of the drug strongly recommends thai patient!; hale pregnancy Ic:;ts performed before staning thent.py IUld use a form of binh control during thcl'3py . &n:tinale (Tellison) is indicated for !he treauncnt of se"ere I'ttalcllrllm psorlasis, Bec.use of its potentialll(lverse effects, therapy . lIoold be limited 10 diseases that do not respond to standard thcmpies. TIle exact mec:ha . nism of CtrctinalC's action i~ unknown but is believed to result from some of the actions common to lhe retinoids.
Et~tina te.

Ii.

""
ii~
~

en-

,m '"
." <D
n.
lilhat

'P-

Etretlnate Oral bioov:ulahllity of etretlnale is apprOJl.lmately 40'\(>. Mill and lipids increa~ the absorption . EtfCtinatc is coo vened significantly to the free acid on the first pass tllrough the liver. lhe free acid (IICltretin) is also activc , A flcr a single dose, tlte half-life of etn'tinate IS 6 to 13 hoors. but ane'( long-term therapy, the half-lifc is 120 days. E.trehnatC' s h1gh lipid character results in StOfllge in adipose !ISsue, from which il is relea_ slowly. After discontinuation of therapy . '>Cd etn:tinate can be dctected for up to I year. Acitretin ha~ the advantage of a shone'( half life. 2 hou~ after a singll' dose and 5(} houlli after multiple ............ It IS, ho\I'ever, more susceptiblc to OOI1I'ctSion to 13-ds-ctretin. Thu~, 11 appellf5 that the CSler prov1des metabolic stabili ty.

".
" nl

"" ...

'vI ~"""~-"'~""~~""
/-

or

isotretinoin, USP. r~tinoin . Il<is-retll'loic acid (Acculane), is a yellow.orunge 10 Ofllngc. crystalline po .....der, It is insoluble in wale'( and sparingly soluble in alcohol.

The initial d0l>11ge of etrctillale is 0,75 to I mgJkg in di -

Vidal doses. After 8 to 16 wa:ts. a mainlenaI'l ~e of 0.5100.75 mg/kg may be Sla ned. As willi iSOtn:l iooin. U treme caution is needed in lhe ndmi ni Mnuion of elrclin3lc. lbe manuf;tClurer disconti nued Illis product in 1998.

Acit retin. Acitmin (Sorialanc) is a yellow to I"enisllyellow pov.dc:r It IS the act;'e o;pccics of ttretmllte. After absorptioo. ocitrctin IS extenSively nlClaboli7J..'d and also underg~s 1 I)('ril.31ioo 10 its 13cis isomer. Ac ill'Ct in is le!>s <;()I lipid so luble than ell'l:linate and thus is eli miMted fnster by the body. lbe e llnllnatioo half llfe is.50 Iw)urs.

AdfJpalene. Adap.11enc (Differin) IS I ""huc 1 off 0 whilc powder that is ~I ulllc in tctr.tllydrorumn. sparingly soluble in ethanol. and pr.tCtically im;o luble in water. Adapilenc: is applied lIS a 0.1'l- solutioo or gel fOl' lhe trcalnK'lIl of acne vulgaris. The eyes. lips. and mucous membraors shou ld be. Ivoided.

OH

()H

Adapalene

Acitretin AcitretJ n i~ ind icated fOl' the lJutment of se\'cre psorillSis. TIle initial dO!Ic is 2!i to 50 mg In a single dose with food. Because of signifICant variaILon in ph:um:lCOl<;inc:tics and cfficacy. lIo\oe\er. ttJ.c, maintenance dose slw)uld be mdi\'idualIud. Inll ial response may occur in 2 wed:s. but rna,lli mal response requires 2 to 3 month ~. Recause of sig nifican l ad~e~ effe(: l.~ aswciated with ils Uf,('o oci lretin ~hou ld be reserved for patients "'00 do not respond to other Ihcl"llpic~ 01' whose: clinical cooditlon oonll"llindkates the use o f other =almenlS. Concurrent admimstrntioo With ethanol is comrnindkaled because elfC1mate is formed. Because the half-life of eteetinate is much longer. the ICtTOgenlc nsk 10 women i~ significantly irlCrC!\);cd.'" Adapalene is a naphthoic acid dc:rivUII\C. Ihus diffcrinl nwlr;edly from the endogenous ~tinoids. Thi s resu lUi m different abllily 10 bind the many retinotc acid - bindmg prolein. It binds ..... ith RARs but 001 RXRs or C RABPs.&.! ~.

BexfJrot ene. BCJlProceilC (Tw-grctin) i~ a while to oIT""hilc powder that is insolubl e in water and ~lIghtl y soluble in ethanol and "egetable oil. It IS uailablc in 75-mg toft capsules. Be,llarotene has FDA appro\'al for use In the~ ment of cutaneous T-cell lymphoma (CJ'CL) refroctory to atlellSt one prior ~ystcmic therapy . The re<:ommendcd inilial dose is 300 mg/m~ Ibily " 'i lh U meal. Depending on tox icity. tlte dose may be ndjLL~ted up to 400 mg/m l or down by 100 mg/rn 1 or be Icmporuril y sU!lpCnded.

Alitretinoln. AJ ilrelinoln. 9-.-u-rellooic acid (P:mrelin ). is yellow powder that is slightly sol uble In ethanol IUld insoluble in water. Alilreliooln 1~ natumlly occurri ng cn' dogenous rcuooid.

()H

Bexaroteoe iknrotc/IC binds selccll\'eJy with reulIOId X receplors." AC livalHlII of the RXR pathwlY leads to apoptosis and odter cc llul ar acll villes mediated by proteins resulting from gene c,llpressioo. The exact mechanis m in thc treatmc nt or CUIIneous T -cdl lymphoma is not kno .... n. Absorplioo of bellilrOCene i~ cnha.occ:d by fall), meals. tbllS the recommendatioo thaI It be taken .... ith a meal. II is olidi1.e<! by P-4SO isozyme 3A4 (CYP 3A4). but lIS interxlions wl lh CYP 3A4 inhibliotS 01' inducers have 001 bmI studied . Because this drug is administered orall y. it must not be gi\'cn 10 pregnant WUIHen or those expecting 1 0 gCt pl'Ca;nllm. T.3.1aro!cne (Tazor:te) 1 indiCl led fO'" tIr 5 treatmenl of Mable plaque psoriasis. It i~ applied lopic:all)as 1\ 0.05% Of 0.1 % emollient cream. II luis been used on up to 20% of the sk in . As wilh other topi cal retinoid'). cm mUSt be ta kcn to pro4 e<:t eye. mouth. and mucous nxIDImlllcl. and ocelush'e d~.ssmgs should be avoided.

Alitretiooin IS tlidicated fOf the lIl:atmcnt of CUtaneous lesioos in pauenUi witll AIDSrelated Kaposi 's SllR:oma. It is IlOII indIcated "'nen ~ySlcrmc anll- Kaposi ' S san:oma therapy is required. It is IlOII ilidicated 1.5 a syste mic drog. AlitfCIinoin is applied as a 0.1OJ, gcl . Init ial application is twice: daily but may be irlCreaSi ,rad ually to 4 times daily. Application. ho ....e~er. muS( be limited to lhe lesion. Application 10 normal skm and mUC0$3j tissue slw)u ld be avoided. TIle gel ~Id be alJowet.l to dry bd~ dressmg. Ocdo$i"e dtusi ngs Wlu ld noc be used. Unlike its geometric i~r aU Iron$-rcLillQid acid . which binds ooly RAR re<:eplotS. ahtl"Cti OOlll is a ligand (01' h<Mh RAR aod RXR. II hns been called a " pan -agonist:' si nce it binds all retinoid rcceplors. Bcca u'<C of thi s allilny it has been proposed that ailtretinoi n may be more potent and thus more cffe<:tive tRan other rctmoids.o.l

T fJzfJro t.ne.

C hapltr 16 V,w,"illJ IWl Htlowi COIII(1OIU>ds

l"iWm;1I

875

TazarOI8f111 '-~

'<'

TU/..arolcnc is Wl IICCtylenic prodrug. On applicatiQl1, it is rapidly COIl,cnt<! 10 thc IICtive fOfm, ta/.nrolenic acid.~ Although tazarotenic acid can bmd allthro:e RARs. II sholO.'s 5e1C'Cti~IIY for RAR.8 and RAR y. TIle IDIICt"" is lhe primary rccepIor fQUnd ID thecptdermi~.\111 Gene expre$. ~lon then normah1.tS lcrallOocyU: differenlJal ion. produclDlless inflammation and decreasing hnlCrproliftlluion.- TaJ.art)!enic kId IS ret.alned in the skID for up 10 3 mOl1lhs. and ib thempeutic effect COIltlDUCS afler CCSSDtl(ln of therapy."" P.CaroIcnc (Soictene) i~ a red or red dishbrowl\ to ~1Ok:I-brown po,,dcr. II is in.oluble in water iI1Id alcoltol arid sparingly soluble in vcgctnble oil~. It is a naturJ lly ol,:l;:urring carotenoid pigmcnt found in green lind ycllow vegelables. P.Caroiene is indicated for the treatment of erythropoiet ic protoporphyria. It does root provide tOlal proIectlon agalOst lhe sun. but patienu who respond to 115 treatment can remain IB lhe sun lhe !>lime as normal Individuals. Oi'lCQntinuancc of lhe drug resultll in II relWll of hyper;cn si t"ity. P.Carolcne doe!; 001 function as II sunscreen in normal pallent. Ind ~[d I1QI be used as .weh. The dot;agc:. mnge is 30 to 300 mglday m a smgle or dl,oded doric, usually adminis tered with food beeau<;(: il S an... IoOI"pIKln depcnd~ (111 the presence of bi Ie and ab<.orlxtblc:. fal . Most .8-carotene is convened to relinol during absorption. oot the fraction thlll is absorbed is distributed widely und lICCumulales in the skin. The nlelabolie pathway of p.caroil::De is similar 10 that of retinol. Severn[ wccks of therupy are required befon: eooogh IIC(:Umulales in the skin 10 exert pr1lIectlVe effects. Carotel1Q(iennia. a result of OOI,:umulation In the skm. is lhe major side effect. A 'tanning capsule er. COIltaining ,ikarolenc and ewuh:ixanlhin , oowc'< u~ this effecl.

P.Cirotene. USP.

VITAMIN Al
Vitamin Al i~ found in vencmtes thaI li,c or, atlellSt. begm the ir lives in freshwatcr. Vitamin A] e~hibits chemical, phy~iclIl. and biolOflical properties very sim illlJ" to lhose of ' ,lIIm;o A. It has the structuml focml.lla deplcled ubove (sec page 8(9). Vitamin Al has a biological pOIency of I.J mil lion US I' utg. which i~ appro~imalcly 40% of Ihe IIClivity of crys.t.lliline vitllI11in A acetatc.

Vlanlln Os
The rerognlliorl In 191911lat rickets was lhe resu lt of a n\ltriuonal defICiency led to the iso[all()ft of antlrachllic compounds from food products ..... The role of "'n~ht m the Pfe'cnhon o f rickets ..... as llOIed III the sallte time: . 1llc term

IJ " < applied 10 all agent:> ",ilb antirachitic IIcuvny. lIS Severnl compounds lO.ere i$OlatOO, desIgnated 0 ,. O~. tw OJ.0 , was tnc matcrial obtained by imidiallon of yeast ergosterol . This malenallmer was fQUnd 10 be a 1; 1 O1i ." "re of trgQCaJciferoi and lumisterol. O!I puriflC'ation and funner characteri7.lllion, ergocalcIferol (calcIferol) p'l"'ed to poII~s the antirachitic propCl1ies and became: lflOwn as "jl/Un/n 0 1 . Chokcakiferol was designated ,jwm;n D ,. In a classical "len.'IC. vitnrl1in OJ. the form produced in animals. is 001 u true vitamin because it IS produced in the skin from 7-dchydrocholesrcrul by UV nidialion in the range of290 to JOO llm.7II 7-Dehydrocholesterol is prodl.ll:ed from cholCSlerol melabolbm. Only when C);posure to sunlight is madequate does V itamin 0 , become a vnamill in the historical sense. Furtner. vitamin OJ i~ now ielllld,\ II pro,jUlm/n because It reqUires hydroxylation by the Ii>er and the kidney 10 be fully 3I:U'('. Oil UV lmidilltion. 7-dchydrocholeslCTOI is con'crted rapidly to pre,it3min OJ. Previtamm OJ undergoes$lowthermaJ conversion to vitamin Ol and the biologically inactive lumlSterol J and tachysterolJ. Excess exposure increase~ production of the in:ICtivc ~'OmPl)lllids. TIle slow conversion of previtamin 0 , to vitamin OJ cn~ures adequate ~uPJllies when the exposure i, brief. Further. lumi,u:rol and t~chystcrol CIIIl be comertcd blIck to pn::"itumin 0 , and thus scrve a~ a ~loer voi r.711 It mas been e~lInwtOO tluit a 100minUle t'lIposure of jusl the 11I1C(Werc:d hands and face will produoe slifflClem vilamin 0,.71 The meclalll sm :"JlOfIslble for the mol ement of , lIanlln O~ from the slin to the blood is 001 known. In the blood. vitamin OJ is bound primarily to an a protein known as vitamin O- blll(hng proICIll (VDBP). This profcin !iClectlvely remo,cs vitamin OJ from the skin because il has low affinity for 7-tkhydnxholesterul. pn::vhamlll OJ. lumisterol, 1Uld tachysterol. Cholecalciferol (vitumin OJ) does rlOI perform it$ function din.:clly. [t must be transfonncd by the liver nnd the kidney . Tile fit~t step occurs in the liver by the cnzyme vitamin 0 \ 25-hydroxylase. This enzyme con,cns tile provililmin to 25hydroJyvitanun DJ (B-O HDJ). This en:tyme. which require.~ both molecu lar oA~gen and rc:doced niCOlI namide adenillt" dinucleotide phospI!ille (NAOPH). BppearlltO be a C)"tochronJe P-4jQ nlOflOOAygcna!iC 1Uld is found In the endoplasmic fellcululll and the mitochoridria. 1Z The rate of this hydro_ ylDt ion COIn'lates WIth substrate conccntmion.1O The B-OHOJ Ibus fOlIlOtd IS the majtw dlTulaung form of the ~iUlmin bound to VOBP. The circulaling level~ of 15O HD) are proportional to vitamin 0 inlake. Thus plasma le,cls o f B-OHDj are used to indi catc vitamin 0 statUJ.l} The ephllelial cells of the proJimal COIlvoluled IUbul;:.~ COIlvcrt 2501l0 j to lo.25-0 HO, by the enzyme 25-0110 [O'"hydroJylasc. The activity of thi~ mitochonilriul eytochronIC 1'-450 clIl.ynlc is controlled by I a,25-0~I OJ and parathyroid hormone ~s well IIli high COt1Cemralions of ca[cium and phosphate.1\I Cambolism of ,illlmin 0 i~ iniliated by the Cft1.yme vilamin 0 24- h)dro~yllSC, whose upression is "'Imulated by la.25-OHD J il5elf. 24- llydroJ ylDlion is folJo,.ed by O~lda lIOn to the letOlle. Subsequent hydroJylation at C -D leads 10 cleDvage of the ~ide chain. resulung in the bioloj;lcally inactive product ealcilrome IICld. 7J. 7'

876

WiI_ and Cum/d'. Tutbook of O~<Utic Mw;conaIlJIId

PlttJrmucr~lica/

CIIr",wrv

"

" .1";'

"'"

""

c", .

"'"
~I
Vitamin

1-Dehydrocholellerol
PlQYilIImin

'#'

hv;

D;,

co;,....,/'-./'y'C",

--../'~

"'"
Tachysterol:i

Lumisteroi:J

."'

"'"

I I ,c",
CaJe~ediol

c",

~
I I ,cO<,

""'"
.A
HO" '-'/ Cholecalciferol Vltemln D:J

Kidne'i

25- HydloKyvllamln 0 3 (25-HydroxycholecaJeiterol)

1,25-0IhydIOKyvhamln

CaJo,,'"

O:!

(1,25-OihydrOl(yCholecalcllelol)

The need for calcium sti mulates parathyroid hormone se

cretion. Parathyroid hormone. in tum. suppresses tbc 24hydro~ylase and sti mulates the I ahydro~yla!iC system. When phosphute availability is below roonna l. the I a-hy . dro~y lase is sti mulued and !he 24-hydroxylase is sup-

pressed.
As with vitamin A. rTlQIit of the effects of vitamin D in volve D nuc lear receptor. The vi l8min D receptor is a member of the Meroidlthyroid hormone superfamil y of receptors. When la.25-OII D) binds to its ICCCplor, Ihc: oomple~ fanns a heterodimc:r wi th an unoccupied RXR . Th is heterodimer ~ubsequently binds 10 the regul atory regions on specific genes in t.afget tissue. These regions are called "iwmi" 0 raponu eierMnlS ( VDREs) . Tbe binding 10 VDREs can increase or decrease exprcS5ion of genes.1O The proteins thus made Cllrry out the functions of vi tam in D. The physioloaical roleor viUtmin D Is to maintain calcium homeostasis. Phosphate mc:Ulbolism is also affccted. Vita min D accompl ishes ils role by enhancing the absorpIion of calcium and phosphate from the small intestines, promoting their mobilization from bone, and decreasi ng their excretion by !he kklney. Abo involved. are panllhyroid hormone and calcitonin. I a,2S0HD, promotes Cal ~ inte.~tinal absorption and in. creases Cal-> renal reabsorpti on in !he distal tubules and mobilization of Ca z " from bone. The mechanism of lIC1ion pt'OInCIfinll Cal" trnnspon in Ihc: intesti ne: in" ol\'eli formation

of a calciu m-binding protc in . I a,25 0 1\I)j pronlolts availability of !his protein. A calcium-depc:ndenl ATPtit. NI . and the calciu mbinding protei n are necessary for lntesunal Cal' tl"an spoX1. In,2S0 HD J also promote.~ in ttilllw phosphale absorption. l11obiJiLlllion of Cal' pnd ~alc from bone, and renal reabsorption o real .. and phos.plute. lab O HDJ Induce:! the syniMsis of aNa- Pi cotf1lJlSpon," Vitamin D deficiency results in rickets in infants anddul dren !lS result of ilUldequlUc calcifIC ation of bone~ 1~ adults. osltOrTlailtCia rTlQIil often OCCUD during pregnancy MIl lacUltion. Rickets IS rare in the United SUIteS becall'iC of fonifica tion of foods_ Deficiencies in the elderly, howevet. result rrom underexposure to Slmligh!. Uype"'itaminosis 0 a~ntly cannot arise: from eJCtSsive tllposun: to su nllghl but only occu~ following inp tion of larlle qualllitits of sy nthetic vitamin D for ~ l1le umount nect'SSItI")' has hct' n estirnated at SO,lXXI unlls ~ morr in a person with normal parathyroid fuocuon." Thr mechani sm may mvol"e formalion of exccuive lIIIOUntSof the vi tamin D metabol it e 250 HD. Toxic llY invoh'cs denmgcmems of culci um metubol ism. resulting in hypercaletmia and InetJlSUIlic calcificatlOfl of ~ft USSIlt. MO$I pr0blems result fR)fl1 the hypt':rcakemi.a. .... hich Iypically ~ muscular weakness, unOf('xip, nausea, vomiting, and dtpreo sion of the central nervOlJ~ system ( ..... hich can result In com.! and dea!h). In addnion, deposnioo of calcium sall5 tn l1li: kidneys (nepilmcalcinosis) and the tubules (nephroilthD61S1

C .... pter 26 Vi,,,,,,,,..-1Urd HdortJ C""'fI'IJ"IId

877

,,,C", .. -<::.... '

"

"
", . ~

tPl'OYltarnln ~

Erqostero/

Vilamln Dz Ergocalciferol

can kaUlO poIen tially irrevcrsible rena! damuge. Early signs are polyuria and nocturia due 10 damage to the renal concen tratlng mechanism. Ergosterol (precursor of D J ) occurs naturall y in fungi and yeast. Eggs and bulleT contain vitamin OJ (eTgocalciferot) or OJ (cholecalciferol). Mil k and bread are fMi ned With vitamin OJ. Choleca lciferol is found in nsll liver oils. Frjocalciferol (vluomin OJ) is produced in plams front ergosterol on UV Irnodi atlon. Viuomi n D:t is the form mOSt often used in commercial products and to foolfy foods. Al though different in struCture, its bioloaical lC1ivity is COfIlpa IlIble to thaI of vitamin D, and must he biooctivhlcd in n 5imilar fashion. The gastrointestinal ab-sorpt ion oflhe ~ IUlrnin Os requires bile. Vitamin I)J may be absorbed beller than vitamin 0 :. The ~ i twnin Os enter !he circulation through lymph chylOfIlicrons. In the blood they are Il~sociated with vHami n O- bindIng prote in ( VOB I). The 25hydroxylated compounds ure lhe map circuhllinll mclUboJilcs and may be Sloml in fat5 and IlIUSCIe for prolonged penods. 1lle 24-hydroxy meUlbohie!; arc excreted primarily in the bile. Because the vitamin D metabolites are very lipophilic, prolein binding Iw:lps in thelT U'llrlsport in plasma. Protein blllding al"" prolongs the circulatory half-lives by making them less susceptible to he patic melUbol ism and biliary excretion.71 Albumin and lipoproICIIIS also bind vllami n D b UI with lower affinity than VDBP. 1lle ~Itamln Os are Importanl In the thc~utiC$ of hypopamlhyroidism and of vitamin 0 deficiency. Ergocalciferol. cbokcaleifcrol. and dihydrotochysterol are recognilCd by

the USP. AlthoulOh dihydrolllCh),$tcrol has rebliv;:l), weak antirachitic activity. it is dTecuve and fllSler actong In m

creasing serum Cal. concc:ntrnlioos

In

parJlhyroiti defi-

ciency. Di hydrocachyslCrol ha!; II shorter duration of action:

hence. it hali leu polenlial for (ollieil), from hypucalCCllua. Vitami n D receptor.; hllv;: been identified in tissue nQt normally lS!iOCialcd with bone mineral homeo6U1Si5. Bestde1i the inlt'Sline$. kidneys, and OSIcoblasts. vItamin 0 fOCCplOfS have been located in tile panu hyroid glund. the paocrealic islet cells. the m:lmnwy epithe lIUm. and tbe sl.n letlllmocries. This has l'C:Sul u:d HI many mvtsligalioonl u<.es for ... itllmi n D. inc luding suppression of pal1llhyroid hormone and treatment o f colon and breast cancers and psoIiasis. 1O 'These investigational trealffiClIlS require high doses of ~llanlln D. and the re~UIUlnL hypercalcemia and hypm;:lIlciuria limit the use of vitamin 0 natural metabolites. Vitami n D analogues wilh a OC'(:T'ease(! lendency 10 cause hypercalcem ia and h)']>en; alciuria life bei llg (ie\'c1oped and investigated. These ana Iogues have low amnily for VDBP bul retain high afliMy fill' the vi ta min D rco:eplOOi. lO ~ ooly apPllJved U'>e of a vitamin D analogue is ill the treiillment IIf psor1asis wllh calcipotriene.
PR ODUCTS

Ergoca/c/f.roI, USP. One US P or l U of ergocalciferol. (3,8.'sz, 1 E. 22)-9. JO-so..'CocrgoSla-5.1. J0( 19).22-tctmcn 3ol. vitamin Dz. eakiftrol. activated ergusterol. is 0.025 flog of Vllamln OJ. Thus. I flog equals 40 US P unllS. B.. 'Cau~ ergocalciferol is the le;c,\ expensive of the vilamin 0 ana IOKues. it is pre femd. unless the palleTlt camlOl lIC1i\'ate n.

C'""
Kklnov

.AI "CH:2

"'"

HCf'''-/

HO" V 'oH

25-Hyd roxyefqocalcilerol 25-HydrQXyV1larnln D:t

I ,25-Oihydfoxyergoealcilefol 1.25-OihydroxyvlI amm O.z

ErJOCalciferol has a half-life of24 hours (19 1 48 hours) 0 and I durollion of action of up 10 6 mooll15. AfleT oruI or inlrnmuS(:ul;u- admmt~tr;lIion, the onset of action (hypercal cemlD) 1 10 to 24 hours. wilh muimal effects seen 4 weeks $ after dai ly odrninislrlllion. Aftcr IrTadiat;on, the steroid undergoes fission of ring 8 : Ihcrcfon:, It IS kl'lO .... n as a secOSlCrold. This is indlCalcd in !he: name by the "9.1O-!iCCO' ponlOO. The "ergOSIll " portion ind icate, lhe presence of 28 atoms in the carbon skeleton. The hl~lory and prepamtion of Ihi' vitamin an: described above. Villlmin D~ is a white. odorlesscrysllIliine compound Ih:U is soluble In fats lind in the usual organic soheOls. in cluding alcohol. II is insoluble In water. Vilanun ~ is oxidized slowly in oih by o~ygen from the air. probably through the fill pero~idcs that are formed. Vitamm A is much II.'.~s stable under the .lune condiliOllll.

in mobi liLing calcium. Thus, 1\ is used In hypoparathy roi<hsm. After or;tl adminl~tr:lIIon, the OII>et of action is seen .... uhl" houl'li. This fasl OOS(:I of acllOlI IS an advantage of this Maximal activity j~ '\Cell in 2 weds after dally adminlstlll' tion. I l~ duration of action is 2 weeks. Olhydrotachyslerol is act.ivalcd by hepatk enl.YIllCli to IU lS-hydro'\ ylated melabolite. It does IlOl requIre renal act""1tion. ror the hydro~)' on ring A occupies the samc POSIlIOll asth"t ohlle I -hydroxyl in the activated forms of the vitamin Os. lS-~I )droxydlhydJ"(ItaChY"lerol l has \\'ellk ant intdllltC aclivi'Y. but il is more important bone-nw)bIlLl.lng agetlf and i~ more errt:ell\C than dihydrotachysterol ,. Also, It I) more effe<.1ive in incre~_,illg mtestinal caiclum trullSpon and bone mobilil.alion in thyroparulhyroidectomif.cd nus. II!; IC livit), suggests that II may be the drug of choice in thl'!mI' mem uf hypopantth)roidism and simil:u- bone diseases.'"

dru,.

Cholecalciferol, USP. Cholecalciferol, {Jp.sZ,7F.}9.1 O-.-.ecocholesta 5,7. I 0( 19)-lrien 3-o1. ~itall1in OJ. acli vated 7-dehyd,ocholesterol. occurs H while odorless crystals that are soluble in flllty oils. alcohol, and many organic solvcntli. It is insoluble in waleI'. Vi tamin OJ alSQ ocrurs in tuna and halibut liver oils. It has lhe smue activity as vilmnin Oz in roIlS but is ~ effeclive in the chick: both vitami ns. oo\\e\er. ha\'e equal acllvily in humam. Vitamin O J exhibits Stablilly CQ01parmle 10 that of vitamin Ih. Epimeri~l ion of tho.: hydm~yl at C 3 in vitamin 0 1 or 0 \ or comersiun of the hydroxyl at C-3 to It ~etooc group greatly dimin ishes the acti\;IY bill does not CQ01pleld)' destro) il . Elhers and esters that eannot be clea\'cd In the body ha'< 110' IUlmin D ocll~ity. I n"e~ion of the h~drogen at C9 e In ergo,terol and other 7-dehydrostcrols prevenl~ the normpl COUI'SC of irradialion. Dihydro tachysterol. USP. Tachysterol (represented below) is a b),-producl of ergosterol irradialion. Rcduclion of IlIChysterol led to dlhydrotachy~tcro1. (3fJ.!J.7 E, IOa.22)9.10-cTg0lltaS. 7,22-lrien-301. dih)'dJ"(ItaChymroh, dichy~t croI. DIIT, Dihydrotachysterol occurs as colorless or white crystals or Ii white, cr)513l1ine odorlells powder. It is soluble in alcohol, freely "Olub1c in ch loroform. sp.lringly soluble in vegetable oils, and practically iusolublc in wllter. Dib)'dl'Otachyslerol ha.\ slight anlirachi lie activity. It Increa.'lCS lhe calciu m concc:ntr.Ulon in the blood. an effcct for .... hid Ull.:hysterol is only one tenlh as aclive. In high doses, dih)drotochysterol is more effective than tho.: other IlnaloguCII

Calcifed /ol. USP. Calcircdiol. (3.B,5Z.7t.l9,10-~ eoole.sta-S. 7. J0( 19)-lrien-J.2S-diol. lS-h)"drox ycoolecalctf. erol.25 hydro~y\ilamlll 0, occur;:iS a \\hLICl po\\dc:r. 11 II prnclically insoluble m \\ater and sensuive to light and hnL The half-life of calcifediol is 16 day s (10 10 22 day,). IIi onset of action occur; within 2 10 6 hour;. and its duratlOll of action is IS 10 20 days. Calclfcdiol is Indlt:llcd for pallenls ~ivlng 1000g1(fIII renal dIalysis. Calcitriol. Calcllnol. (la.Jp.SZ,7)-9.10secochoksu5.7.10( 19)-1rien- I.3.25-lriol, 1,2!Jdthydro'ycholecalcifrnt 1.25-dlhydroxyvitamin O J OCCUt"!i a.~ rolorles~ crystals th3t arc Insoluble in water. 8 ecause culcitriol does not ~In: activation, increa><.>ct calcium abSOl"plion i~ seen within 2 hours or administtnlKln . h~ half-life is J 10 8 hours. and II> dUr1llion of action is I to 2 days. Cakitfiol is the most acli'e form of Vitam in OJ. It IS Indt cared in patients woo an: receiving long-ttrm renal dial)si5 or who cannot properly meluboli1.c erglX."slciferol. Cakipotriene. Caicipolrienc. (laJ,B.5Z 7 .22.2& 24-cyciopropyJ9. JO-sccochola!J, 7, I 0( 19).22 tctrnenc rJ, 24-triol , calcipolriol (Dovoll('~), is a synthetic vitamin 0, analogue iudicaled ror topical application 11\ the ~ of moderate plaque psoria~is. It has the 5Drne affinity fortbt villlmin D n.-.::eptor as calellnol . but ils e(f1 on c:Uc1W1l metabuli sm is 100 to 200 t ime~ I.::ss. CalclpotriellC inhLbtb epidennaJ cell proliferation and enhances cell diffcrenu.

I
Dihydrotachysterol

"""

25-HydrOllydihydrOlaehysterol

Cha pler 2Ci tlOO. lt rcducc.s ccll numbers and total DNA contcnt."'" Anti proIifffilU\c cffects are caused by a reduction in !he mRNA lel'els of a cellular QflCogcllC associated with prolifcrallon, cm\'(". The IfKIClw1i~m resulting in diffcrtnlialion changes I~ notC(lmplelciy known but InI'OI\'CS lhe secondary messen ~rs inosilol lriphOsp/late (IP)} and diacylglycerol ( DAG ).7'O

Vi_'~ tJnJ

Rrmlt"d Comp<JIIIIdJ

879

unde rgoing chronic rrnal dIalysis. III1Dl1 II Jov,er incidence 0( hypercalcemia and hypcrpho;;phau:mla Ihan ealcilriol ."l

I _ "'"
..,.. ()H

Cak;lpolrlenl

Doxerc.lciferol. DoxercalciferoJ, ( I a.J,B,5Z 1,22)9. I().SC'OOl"rgosta5.7 .10( 19).22tetrxne- [.3-<1iol. I a-hydro~y ergocalciferol, I cr.hydro~yviulmin DJ (Ucclorol). is a color less crystalline compound soluble in oib and organic 101 1"ttItJ btll relalllcly in~lubk: in w~ter. Doxerculciferol is mdicalw for the reducllon of elevated intact pan.thyroid hormooc (i,'nll m the management of IeCOndary h~pul ... rathy It)ldism in pallems underlIQing chronic renal dialysis.

Paricalcilol is p calcitriol analogue inlended for IDlral'eoous II.'\C . The reromm:ndcd initial dosc: IS O.~ 10 0, I f'g/ kg lIS a bolus d05e during dialysis, T he dose may be gil'en 00 more oflen than every other day . TIle gool of therapy i~ 10 lower iPnl levels 1 no more than 1.5 10 3 lime~ lhe 0 noourc:mK: upper normal limit , Thc dose: may be increa<;ai by 2 to 4 f'1! 31 2 to 4-wttL intervals.

Vltit",ln E
Since the early 1920s. il 11a.~ been koown thaI ruts fed on ly C(lw's milk eannoc produce offspnng. The pnoclpk from wheal geml thaI CDn reclify Ihis dcfic lel"ICY in both male and female rats was named I'ifllmin 1::. When lhe compound known as vitamin E was iso lated In 1936. it was named tocopherol. Since then. several other c losdy related com pounds nave been dlSl:m'ered from llaturnl SOUI'C<'S. and lIDS famity of natural products look Ihe generic name 1,}f'tJpll'

,roIJ,
TIle tocopherols arc: espc-cially abundant in "heal genn. rice germ. com germ, other seed germs. lettuce. soya , and oouonr,ecd oil. All grocn plants conlain some locopherols. and there is eVIdence thaI some g.recn leafy vegClabl~ and rose hips conlain more than wheat germ. II is probabl y 5)"nthr:srted by lea ves and Inlnslocaled 10 lhe seed s. All four locopherols have been found in ",heal geml oi l; cr-, ~. bnd l'"tocopherols nave been found in oouonseed OIl. Com oil contain5 prcdomin31111~ l'"locopherol and thus fumi shes a ation of this difficult mcmhetconvenient source for lhe isoL of !he lorophcroIS to prepare, oS-Tocopherol is 3()0% of 100 mixed tocopherols of soya bean oi l. Several tooopOcro{$ na,'c been lsolalcd. Some ha~e lhe 4',g'.12'trim:thyltridecyl...a IUniled ~idc chain; otltcrs have uru.aturalion in lhe side cnai n. It has been suggested thai lhese poJ)'UnsalUralcd lOools be nama:! "' IOCOIncnols."' The be.~t known is ' ''"tocopherol (vi lamin E), which has the Jlreatest biologK:al activity. TItc ba.'\C Sin.IC!Urt, I"Cpn"!ol'nled below. shows Ihat the tocopherols are mClhyl subsliIUl~-d 10001 de rivali vcs: a-tocopherol is 5.7 .8 trintethyIIOCOI: ~Iocopherol is S.8-dimcthyllocol; the ,.. compound is 7,8-du1lelhyllocol; and S-tocophcrol is 8 ntelhyltocol . The locotricnols have similar subSlitucnlS. Nlllural a-( +)-I0C()J!her0I has the 0011 figuration 2R,4'R,g'R, l1te naluml tOCOlnenols hal'e a 2R.3t-.:7'1:: configuration. 'Ibe locopherols arc. dilcrpenoid nalural products bi()5:yn\hesi1.ed from a C"O!1lbanalion of fOOf i~oprenoid unils; gcrnnylgemnyl pyrophOliphale IS the key intermediate that 1eaW; to lhese compound~.u

"",''-A""
Doxercalciflrol Following p~nJlnte.~inal absorpIion after oral adminis tr.lUOO, doxercaldferol is activaled in the liver to la.25(OHh D1, The activation does not require involvement II the kidney, Being a prodrug, doxercaldferol docs not ttlmulatc the absorpllon of dietary ca lcium and phosphoTIle mean halflire In healthy \oIUnlttrli is approxi malely 32 to 37 hours, ..... hich is si milar to the hblflire in pIlienl! ..... ith endstage renal disease. u The dose mu!.t be mdividuaJized fo.- each patient. TIle 1011 i~ 10 1 'er hlood il''TH into the ISO to 300 pglmL range . 0" The m:ommcndtd Inilial dose is 10 f'i: 3 limes weekly. ~ministercd at dloJ~sis. If lhe IPTlI levels are not lowered by 50% lind {ail to reach the indicated range. the dose: may be Increased by 2.5 pg e\t:ry 8 "CC'ks. The maJIinlal recom mtnded dose is 60 .... gfweek.

1Ui..'

'Iricalcltol.

Pariealcitol. ( I /I,3{J,j'Z. 1 E.22E}-19 00f 9, IO-sccocrgosta-S, 7,22lriene I.3 .25triol (Zemplar). is I .h.ue powder. Paricalcitol is indicated for lhe prevcntion IIId treatm:nt of SCCQlKlary hypelp.nnhyroidbm in palient!

 a-Tocopherol

. ""

" a-Toooottienol ~
tl-TOCOPfle fOI

'" '" -

,
~Tocopherol

~ Toootdenol

-Tocopherol

"" , "" , "" ""

, ""

y-Tocopherol

"" "" ""

'" , ""
,

y-Tocotnenol

'" 6-Tocopherol "" '" "" "" """"

~-Tocopherol

&-TOCOIrienol

'" "" "" "" ""

1]- Tocopherol

TIle tocopherols and thrir acetates lite light yellow. vi$COOS, odorless oill th.:at hllve an insipid liSle. They ~ 'nwluble in waler and soluble in alcohol. organic solvents. and filled oils. The acid succi nateestcl'$lI/'e while powders insol uble in water and soluble in elhanol and \'egetable oils. TGcuplk!lQls are sUlble in air fOf reasonable periods but are oxidized slowly by air. Thcy are oxidilCd readi ly by fCTric ,\alt), mild oxidizing agents. and air in the presence of alkali .

1bey arc inactivated rapidly by exposure to UV light:

Irnce.~

noI

1111 s.amples behave alike in this reSpect. however. because

of impurities apparently greatly affect the: rate of oxi dation. Tocopherols lIave antioxidant propcnics for fixed oil$ in the follo"'ing decreasinll order of effectiveness: .t "1.

ols aredcslroyed by the accumulating fat peroxides that they decompose. They are added to Light Mineral Oil NF and Mincral Oil US P because of their anlioxKbnt property. To.
cophclols can be COlwcrted to acetates and bcntOp'es. which are oils as acth'c as the pan:nt compounds but IIlOI"e stable toward oxidaliQn. (+}oa- Tocopherol is aOOut 1.36 times al effectivc as ()ll'-Iocopherol in ral amisterilily bioassay!. ~ Tocopherol is about half as active as il""tocopherol. and the ,.. and oS-tooopherols arc only 11100 tirtl('s as IlCtivc as a-tocophcrol. The cstCf'lll o f tocopherol (C.I., acetat c. propionate. and butyrate) are more active than the paten! compound.- This is also trut of the phosphoric acid ester of ( )-oS-toc:()phcrol when it is administered parenter~Jly.1l The ethef'lll of the tocopherols arc inactive. Oxidation of the toropberols 10 their C()ITCsponding quinones also leads to inactive compounds. Re. piacertl('m of the meth)"1 groups by ethyl groups decreases lCIivity. The imrodut1ion ofadouble bond in the 3.4 position 0( a-tocopherol reduces its activity by about two thirds. Reduction 0( the size of the lon'lllkyl side chain Of the intro-dtlClion of doublc bonds in thi s side chain markedly reduees activity. Vitamin E activity c utrently is u~sed in terms

/1. and a." In the proce.'is of acti ng as anliOll idallls. looopt.c,r

of the a-( + Hooophcrol etjuh'lllems based on the fOl1llrf USP units and mass listed in Table 26-6. One f~ USP unit Is equal to one (Ohllet IU. Vitamin E. US P. may COIISIll of ( + )- or ( :!: )-<1'-IOCopht:roJs or their acewlCS Of !AA"CII\Ml'S, 96.0 to 102.0'1\ pure. (-)- <1'-Tocophcrol is absort:Icd from the gut nMn~} than the (+ }oform ; ab5orplion o f the mixture of (+)- II1II (-)-a-tocopherol. however. Wit.. considerably highl:'r C _ _ 55"') than that e~pttted from the data obtained after Ildministratioo or the si ngle compound s. As doses incrtllSC. tbe fraction absorbctl decreases. No marked diffcleOCCli "'en: noted in the distribution in various tisslies 000 the mClnbolic degnKIation or (+}o ami (-)-t:r-tocop/ll:rols." The li_Cf 1$

TABLE 26-6 Rellti.,. Potenc:tn: of V.rl_ Commerd.1 Forms of Viumin E

.....,
" " '"

I'uk .. )'(,~ (.. " .... USP ""","I of I...,

(~) .....T"'''ph.. uI

(~ ~ ....T'...

".'v:"" .........,
..16.w<nfWc

(~~ .....T~

(+). ...
(~

(+

r.... T<K""...... ~ ..od .....,tn_

r... T,iC(lj~"'oI w:nat~

T""'.,:...o1

'"
,~

1'IIIc&-y (In ........ d(+~ ..... t.u.nl])ot t!lll (+ Ht-T ocqJI .. 'uI .... _

'" '"
061
,~

(+,....T".....,1I.. 01 ond.,.,...,
(:::Ht- T............'"
, "',.... T....tlj~ ..''''
".,

'" '"

--------------------- ....
an Imponanl sloragc ~i le. Mo;;t of the gaslroinlestinal al>5OI'pIU.XI of ~itamin E oa:un! through rhe mucosa and the I)<lllphatic system. Bile perl'omu WI important funcllon in promotmlllOCophcrol absorpl ion. lltc ester deri ~:ul\'es are hydrolyzed by pancrealic enlymell before absorption. AIllIoogh hydrolysIs of llle e~teri. not required. it does improve absorpIion. Vi tamin E prql3fi1tiOOli are absorbed better from tK/1ICOU~ solutions Ihan from oily solution~. ""Tocopherol and ,..toooplKrol are absorbed from lhe InleSlLnes and dlslributed 10 the liver equally ..... ell. ,...T ocopherol is secreled pnmarily inlo !he bile. ho ...evcr, .... hile a -looop/lcrol cmers lnecircuiation .... here il i~ fOllnd in mIlCh hlgber levels than ,..tocopherol. even though lhe laller preUominulO!!; in the diet. This dlffereoce is attributed to II Ih'er cytosohc binding pr0tem t h~1 i~ M:lt:clive for a-Iocopherol . 1'he tocopherols in lymph an: 1l~5OClated wllh ch)'lonllcrons and \ery_ lo ..... -dcn~ity lipoproteins (V LOLs). Circu lal Ing tocopherols an: also a..,~inled mainly ..... ilh the blood Iow-dcnsily lipoproll:ins (LOLs). The locopherols are readily and reversibly bound to most rissue . including adipose: tissue:. and Lhe ~lIamin is thus stored. The: vi tamm is c;QOCClllraled in membt".mc SIf\lctUres. such lIS mi t()l;:hondria, endopW.Imc rellculum. and nuclcru- and plll~ma nlemoolJ)es. Vitamin E i~ met~OOIilcd primarily to tocopOcronic acid and its ,..lactOllC, folIOl'.. ed by glucuromde conjugation. lltc lennimli methyl group i~ o"idiled 10 a carbolyJic acid and !ohortcned by ,lKmdation to producc locopheronic llcid. TIle chroman rinl!: b hytirolp.cd to a quinone: ..... hlch SUMequcnlly is n..'duced 10 a hydroquinon.c. Nucleophi lic ~uack by. hydrolyl UIlthc carbonyl ~Ide chain prodUCC's tocophcronoloclonc. TItcse metabolites an: e,cfleted in the bile, Vl tamm E may undergo SoOme enterohcpauc cm:u lat ion . creatine k.inase and li\'CT Kanrhlne oKidasc. Vnamm E deficiency Icads to an IIlCreasc in the turnover of creatine kinase. Vitamin E..oeficic:nt animals also exh,b,t Incfleased liver xamhine o"idast: octiv,ty. which IS due to IncrellliCd de novo synthesIS." Although il has been dirrlCult to e.Qabh!Jt clinical 00ITelates or vitamm E deficiency in humuns, Hieri and Fam:Il"" ha"e summarized some useful genef'l.lizauoos and conclusion,_ The.-.e worlers noted that the: infunt. c!.pecially the premature infant. is suscepti ble to tocopherol deficiency because of ineffective transfer of the vitamm from plact:nta to fetus and that grt')'4'!h In mfant~ reqUires greater avail abil ity of the vitamin . In adults. the tocopOcroi ~t11r.lgc depoiS pr0VIde adequate availability that IS not reudily depleted. but inles!iTllll malai)!;(ll'phon Iyndromes. ...... hen pcr:;;istent. can lead to depletion of the storage depots. Children with cy~c fibrosis suffer from severe, itamin E deficiency caused by mnlnbsorption. Tropical sprue. celiac discllSC. gastrointestinal resections.. hepatic cirrhosis. bil iary ob$trucrion. and nccsslv'e ingestion of minenal oi l may aboO cause Iongterm malabsorption . Vitamin E therapeutIC indications include the chnlCal conditions charnctcnl.ed by low SCf\l1ll tocopherol Icvels and increased fragi lit), of red blood cells to h}drogen perox ide or cQl1(/ilions that require lIddil ional amounts. The:. lauer can be e1empl ,rted hy IndiVidual!.... 110 consume CKCClIsive amounts of polyunsaturated fally acids (more than 20 glday mcr normal diet).90 It has bun cLaimed that vitamin E coold be oflhc:rapculic benefit in i-.chemic hean dl'iCase. oot evidence against. this claim conlinues 10 accumulate. II has also been sugge~ted that ll1('g~s of tocopheroL be used in the !reaunent of pt'riphc:rul vllSClJ llU' disease Wllh intermillenL cl audication. Although sonw: studies slipporithis propo!i.3l. C1pcns 111 the rlCld Siale thlll f.. nher clinical studic~ are necessary 10 make a dcfinillv'e recommendation. Ne\mhelCS5. It conllnuc:.\ tl) be popular and cOlltro\'cn.ial to consider the benerlCial d {eclll of vi lam;n E and other vilWllins In large (nlega) dietary suppleme ms, and invesrigat ions of megaviUlmin E thempy for cardiovasculhr disc:ase eonllnue 10 appear 111 the hrcrature.1I9 TIle eminent vit amin blOChemisl It J. Willillms has empl\asil.ed that

, ,

, , , ,

Tocoptoaronic acid

Tocopheronolactone

For decade.-.. then: has been significant interest in i Ilvl!.."i lating rhoc biochcnllcal functions of \'l lamin E. bul it 1$ ~I ,II d,meull to nplain m:lIly of thc biochelnical dernn~cmcnts rauKd by vitamin E dcrlCicncy In ummals. There seem, 10 be generaL ugrt't'lnt'nt that one of the primary metabol ic filoctions 0( the vilamin I~ ptl:\'enling tile OX Idation of lipid~. panicularly unSilrurnted fally acKb. This antioddant runcl/(1li does not. however. ex plain all of the biochemical abllorrnahties cauS('(! by \'i tamin E deJiciency . MI)feO\er. vllamin E is nor the o nly in \'l~O antio~;dal1l. Two elt1ynle ~ystems.. Ilutathione reduct~ and o-phenylenedianullC pertmdasc. 1150 function ;n this capacity.... It 1Ia.~ been postulated that \ itanun E has a role in the ~glliation of protein ~ynthesi~, Other actions of th is ".,tarmn have also been inve'llgated. for example. effecl!, o n muscle

!I\ipocI pe.OXldatlOll. the fOO'1l'\aton 01 r..rmfut pe.~ I.om tM IIlteractlOll bet ... een o>eygt't1 and highly urnaturated fau (poIyunsatlllitffi needs to be cont.oiIed ~ the ~ 80ttt O>eygt't1 and the poIyurn.flu'aled hpods aft! essen",,1 to 0Uf wstrna. but " the pl'O!ectlOlllg lISt petO,dall()1l1$ IfI(I(\eqUilte. senous damage 10 varIOUS body pl'ottlns may result. V,tarrwl E IS thought to be the leading agent lor the p<tvefltlOll 01 per~idallOllllnd tM free r.wlK;al p<od1icloon that 1$ awx.... ted both With 1\ and With rilCNtoon. I....
Willi!ml5 also noted tnat although ClI.at't mecnani~n1!l of 111-11011 or 1hc:.'IC anlio~idant.~ are nor yet known .
[p)fCMdlng plenty of Vltarrrn [Mid olSCorix acid {both

harmlel.s antiol<.doW1~ IS indrc.ned as a ~ means of prcYenl>ng premature' I9'T'I9. e5ptOillly If 00f!'~ diet is nch In potyunsaturali'd acids
Consillcring the foregoing implicalion of unneces.Glry per_ o"ldalion of uns.atur.lled lipids. II is in tel'CSling that atherosclerosis appc:OII"S to be due to a derlCkncy of prmtacyclin.

............

which IS caused by inhibition or pr05tacyciin 5)'nthelllsc by lipid peroxide$ or by fTtt radicals thatll likely to be generated during hyperlipidemia. Although no dirttl evidence indicate! thaI In cxperimentnl or hum:m atherosckro5:i~. lipid peroxidaJion is the earliest sign of the disease stalc. lipid peroxides have been found in ancries from atherosclerotic patients and in ceroid athorromatic plaqllt'S. and at the &arne time, hardly an~ prostacyclin is geoenttc:d in human aIheromatic plaques. Vitamin E used in high dose~. as high a~ 3,200 mg/day. has a prove:n record of safety.Jl A ~.aric:ty of n:poI'1s, lTllUly single: case reports Of uncootrolle:d studies. have SUggc!lIc:d adverse effc:ctll such as inlc:rfen:nce: with clotting, weakness. decreased thyroid hormone: levels. and gastrointestinal upset. 1lle importance o f lhese b unknown . The only noIable adverse: e(feelS have occulTed in premalure infants given large c:Io5eli of this vitamin. Hepatotoxicities Ilave: been seen in prr;nUllUre infants of less than 1,500 g birth weight given vitamin E intnlvel'lQU.Sly. and the incideocc of necrotiling enterocolitis and sepsis increasc:d under similar condllions following oral or intr.lvcllOl.ls dosing.

TABLE 26-7 raad

Vitamin

II(

Conte nt
$1.100 SI

of S. lected Foods

Blocm!. Rru, .. t.~ CoI tn ... ,CIurat

c-..~

,.,

-.... ,-, ""'" _.

W..."'..,..

C~ ... ho(oo

T ./l'up ......

"" '" '" '" '" ,'" ,., "" "" ""

100

Lipid.free diet research by Henri],; Dam staninll in 1929 resulted in lhe discovery of an anlihernorrhagic factor thlll was named I'iramin K (from the German word Koogul(J/il}fl). Along with the worlc of Edward /I. , Dolsy , the structure or vitlnlln K was dc:tcnninc:d in 1931 as shown below. For their work. Dam and Doily sh~ the 1943 Nobel Prize in lllI!dM:ine. The lerm l'ilUmin K was applic:d 10 lhe vitamin isolated from alfalf .. and a similar principle from fish meal wllS named I'illlmin K1 , VltIlmin KJ nefers to a !>Cries of Corllpounds called the fMtwquinonf's, 1besc: Ilave a longer side chain with more unsatunnion. This side chain may be com posW of I to 13 isopn:nyl units. The most common are depICted below.

Animals depend on tllO sources for their intake of Ibll vilamin, dietary and bacterial syntlM:sis. Table '26-7 liStS . cc:llc:nt ..ources of "itamin K I . Noturul Kl occurs Ill! a mlnJ isomer and has an R .R.f. configuration. 'rlIe sy nthetic, commefdally available form i5 I mi.lture of cis and /I'OIIS 15Orl1Ct'S. with no more IhII 20% ciJ. Vitamin K J is ~ynlhc:~i/.td by the inte~linal fkn. especially by Gram'JlO';live bacteria, It i~ not Ivai lllblc: rommercially. Numerous COll1pound~ bave beente.,ted for their nnlihcmon1I:Igic activily, and significant btotogieal activity i5 IJIIIIi. rested in compounds with the: following struc:hlne
R

Y B", ..

R'

'-"" "-"-"'-~ ",,,-,,,,,,,C",

KI Phytooadione (2_Malhyl_3-phytyl_I.4-naphthoqulnona)
V~amin

""'

,,

"I""'
n.4 .Vitamin n 5 .Vitamln
~(30) ~(35l

'r
"

t..,

Menaqulnone-6 Menaqulnone-7

MIIJlY other closely relnted compoundS possess vhamin K activity (e.g . mentldionc 12-mc:thyl-1.4-naphtOOquinonc] is as acl i~e!lS viuunin K on I molar basis). 1lte synthetic compounds menadione and mc:nadiol are refelTed 10 as viwmi1lJ KJ and K4> respec1ively. Vitamin K is a naphthoquinone derivative COlluUning diterpcnoid units biosynthes ized by the intc:rmcdiate geranylpyrophosphale. 'H

RIIli A iI; aromatIC 01' hydro.1rom.:1tlC Ron, 1\ is Il()( 5ubS\ltutcd, Rina 8 il II/'OIIwic or lIydrl);jron\;lIl~. R IS 011. CO, OR. OAc (ihI: R ,n OR ,~ rneth,.-I 01' tth)l~ ~. R';s mellI)' I. 6. RN i~ II. JulfonlC add, di~th,.-"'n;"", 01' an atLyl groupronUia'ng to 01' man: carbon atOrM. A double bond in die fJ. tpnilhOa of this alkyl group enhances ~ency ; if llIe double bond ~ funhrr rem.;....:d. It Ucr\S no rff..,L I~noid I,/'OUP' f t an than lua;gbt chairu. In !he .. tamon KltJIIItype.-. poonru. tIIc: 6'.7' -uIQIIIH'/s, i~r i, ~'gn;r;cantty ~ Iml'! than the &ILmllu, or me tS'.I9'moncH"u- ilOnlCf 111" .... also true of the v,tamln K;Y.lO!lwprellOlos~. A votamom K,;, iJO!nnol",ue II.... 20'11 more acli"r than v,larnin Kim, 7. R- is II. 00, NH~, CO, OK. Ac (!he R on OR j, nw:diylll' ethyl).

I. 2. 3. 4.

"(f..,,,,.,,

Decreased anhhc:morrhagic &Clivity is obtalnN " 'hen

I. Ring A iJ su/:Io.htulro, 2, R' ill.,. &IJo;)tlllOOP larter than a meth) l. ). RN i, a hydroxylgroop. 4 R" conllionll hydtmylllIOOp in a side chain

If nn, A 15 benzeooid. tbe introdoclion of su lfur m place of. -CH -CH- in this ring in 2melhylnaplllOOquinooe penOll.'> lbe retenlJon of some antihcmotrhagic IICli~ily . This might indICate thai In the processof ucnma ,"1Iamln K acti~. ity. lbe bcnnoid end orthe molecule must fit imo a pod.et carefully tail~d to it. That the OIhct cnd is not so clo!icly surrounded IS shown by the retenuon ofoctlvny on changing the alkyl group in tile 2 position. Although marked umihcmon1tagic activity is found in nlany nuptnhoquinollc compourKl.'!. these compounds mlly De convened in the body to a vitamin KI type compound. The e5tef5 of the hydroquinoncs may be hydrolyl.W. and the fCS()lhlli hydroquiuonc may be OJlidized 10 the quinone. The mcthyltclralones. which are \'cry active. could be dehydrogenated totbe methylnaphthols. which arc hydro'\yIMw. and the lallcr product cooI'ened to the bioloicaUy equivalent qumonc . Compounds ..... ith a dihydrobcnunold ring (e.g .. S.8-(hhydrovilamm K ,) appcarto be modcrntclyeas.ilydthy. drogcnaled. I' hcrc.u the corrcsponding lctrahydrides arc reo ~1.Ianl 10 sl.lCh change. Vitamins K, and K2 are absotbcd by an OClll'C process m thc proxImal small mtestines. Bi le of norOUlI oomposit ion is necessary to fadH'1I1e the absorption. The bile componem priocijXIlly concerned in the absorplion and tran spon of fatsoluble vitamin K from .he digestive .raet is thought to be deoxycholic acid. The molecular oompound of vitamin K ""th deo'\y~holic acid was cffectivc on 01111 administr.uion 10 ral\ with biliary fistula. Vitamin K is absorbed through tbr lymph In chylomicmns. It is transported 10 lhe liver. ",1Iefe il i5 concentr:ued. but no sigmficant 5tOnlgc occurs. 'The entire metabol ic pathway of \lilllmin K ha$ no( ~n elucidated. 'The major urinary mellbohtcs. howc\ler, are glu.;uromdc cooJugatc\ of carbo~ylic acids den~ed from shonemng of the side chai n. High fecal concentrouonl are proba. bly due to bacterial synthesis, The accepted mechanism for vi tamin K i~ to function lIS I cofactor in the posurnnslation31 5ynthcsi~ of '}'-Carboxyl-glulamic acid (Gla) from glutamic acid residues."'" The dis.covery of Gla in 1974111. 911 clarified lhe mechanism of li lamin K and led 1 the idemificalion of additional vi.amin 0 K- depentk-nt proteins. 'The only known function of ~itamin K in mammals is 10 mainlain adequate len'ls of vitwnin K- dependcnt proICIn!l inl'o!>'cd in coagulation. These in dude prothrombin (factOf' II). factor VII (proconvcnin). fac tor IX (auloprothrombin 11). factOf' X (StuanProwcr factor). IOd proccins C. S. and Z. Prothrombm and factors VIl, IX. IOd X promote wagulalion. while pro!eins C and Shave anucoagulant !ICIivily. The function of proIcin Z is 001
~no".. n.

[t follow5 Ihal IIny condition .hat does nOl permit full use o(the untihemorrhagk: agcnl~ or the produc.ion ofprothrom bin would Icpd 10 increased clouing time or hemorrhagic disorders. Some of lhese conditions are fa) faulty absorption caused by severa.l disorders (c.g .. obstruCtive jaundicc. bi[i W)' fistulll.<. inte5tinal polyposis. chronic uk:cra.tive colilis. mtestmal fistula. intestinal obstruction. and sprue): (b) dam. qed Ji\crs or primary hejXIlk: disease!! (c., .. almphy. cirrhosis. or chronic hepatitis): (e) insufficient anM)Unl/l of bole or abnom~1 bile in the intest inal IfaCt: and (d) insufficient amounts of vlllnlln K. Prochrornbin and f!lClors VII . IX. and X panlCljXllC in the cascade of reactions leading to fibrin clOl formation. Protein

C exerts Its annwagulanl effecl by inactivatmg acuI'au:d factors V. and VIII ." Protcm C is first activaled by pr0thrombin. This ICti vation require$ I cd l JlJrfacc rttcptor. Ihrombomodulin. calcium. and protcm S. Protem C Ilso m creases fibrinolysis by inactivating the major mhlbllor of tissue plasmmogen act, vatOf'. 100 Protcin S funclLon~ a~ 1I cofactor in .he protcin C inactivation of activated f:IiCIOf' V. and VIII,. 1'ror.~ln S is found in the plasma und is bound 10 C4b-binding protein. an inhibitor in lhe complemcnt sys tem. '01 Protein S is also a cofactor in prolein C fibrirlOlysi~. All of the.o;e proteins are symhesiud in lhe liI'er. and they have considerable structural homology. All COOlam 10 10 12 Gla residucs.'Ol.!OJ TIM: wagulution acti vity is proponional to tbe number of Gla rcsiducs present. For example. pr0thrombin has 10 Gla residues. l..o&s of jUSttll'O residues de creases ICtivity by 80'1>.'0) This system reqUlre$ rcducal vitamin K (a hydroqumonc. KH 2). carbon dioxide. ~nd molecular oxygen. Although lhe reaction docs nOi require ATP. it uses !he erocrgy frorn.he o~idation of KH: to execule the cl\Tboxylltion of glutamic acid. 1001 The carboxylase must create a casbanion by CJlttxt ing a proton from the glu tamale )'-Carbon. This requires a base with a pK. of 26 to 28. The anion orlhc hydroqu inone. however. has a pK. of only about 9. A propo.o;ed tnechanbm for the above cllrboxylBhon cre ates such II base: from vitamin K. 10:1. >01> Vitomm K IS reduced 10 its hydroquinone form (vitamin KH 1). Molecular oxygen is inoorporated into the conjugate Kid form or vitamin KH: to form a pcroxy anlOll. I'hich subscqllCntly forms p d,oJle tanc intermediate. The peroxy bond is cleaved by lhe adJII' cenl coolate anIon to produce an intermediale suffICiently basic to deprolonate the cr-carbon . ExlnlCtionofthe proton allow~ tbe catbo~yla.\.e 10 carbox ylall: lhe glutamate reSidue. The vitami n K imermedlu.e is convcned to vitamin K ox ide. which must be reduced back to vitamin K. Vitamin K ox ide is recycled back 10 vitamin K by vilamin K cpoxide reductase an-d vi tamin K quinone reductase. BOIh of these enzymes arc dilhiol dependcm and are inhibited by the 4hydroxycouman n anticoagulunls . All vitamin K-dependent proteins contain Gla residuc~. Vitamin K thus panicipatcs in lhe formation of specific ycarboxylglutamk: aci d Ca .2.b1nding SIICS on the vllanun K-dependcnl protcins. Funhcr. the Gla residues are found in essentially the saIAC region. near the amino lerm lnus. and this region is called lhe Gk, domaill. '07 These Gla re$idue$ function a.~ ion brid~ linking the blood-cIOiting ~Cln 10 phospholipids on cndOlht-liai cells and platelcts.' The I'itamin K-dependem carbo~ylllSC system is located on the cndoplasmic reticulum. It Binding '0 rncmbrone surfaces is criti~al in lhe IIClivalion of thesc: proteins.'011 The discovery ofGla nOl only clarified the biochemic:.! mechanism of vitamin K bu. also resulted in thc isola li on of sevellli nonhclX'tic vitam in K-dependent proteins: OI>leocalcin, matrill Gta proIein. Ga.~. PRGP I and I' RGI' 2. Os u:ocalcin is synthesiud in the OiSteoplasl and odonlOblasts. 115 expression is rejulaled by Icr.2S-dihydro,\yvi':tm1O 0 '09 and retinolC acid. I 0 Studies on O!>lcocalcin-dcflCoent mICe indicale that OSIcoulclO IS a ncgauve regulalor ofbonc fOfmalion via an unknown mcchanJJT1 but docs not alter bone resorption or mincraliJ.IIlion. I I I Matrix Gla prOIcin IS found in bone. canilagc. and sofl li~ . 115 synthesis is rel!uhued by I a.2S-dihydroxyvitamin OJ and reliooic add. and iI

inhibits soft tl S~ue calcification.ll~ Gas6 i( encoded hy growth :lm.'Sl -specir~ gene 6.1l!ld H conlalns 10 10 I I Gla ~Id~"" It i~ in , olvcd in cell prohfer:ttloo regulat.oo through an unknown mechanhm . The phY5iolog.cal roles of three other Gla-contllining prOleins remain unknown . Nephroc,lIcin has been .wlal~'tI from renal 1Is...~ue.II" whi le plaque Gla pro:.n has been isolalcd from alilerosclerollc plaque. IU The ble~1 Gla-comaming protem~ h.a.c .... ide " 5' ~ue distribution and ure rich in proline n"sidues: thus they ha.c bc<"n named proline-rich Gill protcins {I'RGP I and PRGP 2)11& Phytonadione: is con,idc:n"d n"lative ly nontOltM: even al high dosc.~. Rare ca-.es of hemolytic anemia l\:I,c been reo ported. and the mllnufacturer has reponed llnaphylactic reac tion~ following usc of the injecll\blc producl. Menadiooe , in contfllSt. can produce hemolytic anemia. hyperbilirubinemia. Il!ld kcrnicterus In ne ... boms. especially prt'mature i nfanl~. In addition. menadione: can cause hemolytic anemia in patient~ wilh g ll~ose..().p~phatc dch ydrogenase defic iency. 117 -119
PflODUm

PhylOnadl()ne. 2tllClhy l-3-pI1ytyl- J.4-nllphthoquinone. vitam in KI (Mcph ylon. AquaMEPIIYTON ). is a clear. yellow. very viscous. odorlesli Of ncarly odorless liquid. ~ Vitamin K I is a yellow crystal line solid that melts at 69"C. It is insol uble in water. slightly

Phyton~dion~,

USP.

soluble in alcohol. and soluble III "cgcllblc oils aoo in the usual fal sohmts. h is unstablc lo ....ard li ght. OltidallOl. strong acids. and ha logens. It can be redoced casi ly 10 do: correspondi ng hydroqUlnone. whkh in tum can beesterirlnl The Iherapeutic u~ of vimmin K as It S~~I C nll C hemO$L3lK; agcnl i~ based 011 the critit'al function Ihat the ~ nami n per. forTll~ in blood cOAgulauoo. Vilanun K I (phytonadllltll:) it. cffccti~c both In the treatment of hypoprothrombinrmia caused by dictary dcficiC'I"ICY (If tile vitamin or mulabsofrt~ and in the bleedi,,!: cauo;cd by lII1ll amicoagu l:UlI' (e.g. tOIImadill derivati ves). l"hylooooionc ellel"lS I'f'UInpl and pr0longed AClioo. It can be admini~tertd orally. SuOClltancQlljJ). or inlrumuscularly: in cmergcncics il can be Knen by$lool. intru"cnous injlion. Vitamin K is adm ini\lcred in cOltiuneuon with blkult...or thcirdcrival i~es III prtoper.ll"e and postopc.,.II ,cjallndlMl patkms 10 bring about and malnl8m a normal pnxhlOllobia leycl in the blood. rn the average Infant. lhe binh vallltS Ii prothrombin comeRI are adequme. bul dunng the: fi~ f~ .. days of life. lhey appear 1 faU r.lpidly . e,cn dangtrtJll.\lt 0 low. and then slo",ly fn'u,cr spontanoously . 11l1s trlInSIlliJI period was and is cnt lcal becau~ of the numerous SI1~ 0( hemorrhagic mun l fe~tulions. Ir.lummic Of spomuneom. lIIolI may pro"c serioos if nOl fllhtl . Thl \ condition I, no ... IXJIl$ld. ecru It Iype of ahmtnu.ry vitanlitl K derlCienc) _The SflOIU" neflU S rttO, ery is perhaps dll(' to establishme nt of an IIIIC\-

.-"NM"""'M_

--

Clla pttr 26 !/i""";M tJftJ RrlmN Compound! can SYIIll\esiU! vitamin K .fler inges!ion of food. Oral adnllm)tnlnon of v;I:1min K. however, effects prompl I'N'Overy. Vnanlln K, idS more rnpidly(effecl on prothrombin lime) !han IIlI.'nadione. wnhln 2 hours .fter InU1lVtOOUS administrauon . No difference. howe\'Cr. coukl be dc:1ted .ner 2 hours. 'lO l11e menadiooes are much I~ active tllan vitamin K I in rKlflllulil.i ng the prolonged bloodo(:louing tinlC5 cuused by dicumurol and n:lated drugS.'lO Vitumin K I is tlte drug of cholcr for humans becau!;e of Its low toxicity. Its duration of action i ~ longer Ihnn 111.11 of menadione IUld its tlerivuti vcs. Vitam;n K ~ll()Uld nOI be administered to patients reiving ,,'arflll'in or coumann anliCQagulunlS. Vilan"n K can be used 10 diagnose liver function :IcrU ralely. InLnlnlll'OCutar injcClion of 2 mg of 2-lIlI.'lhyl-I,4naphthoquinone eliclt.s a response in prothrombin index m p;Kients wl thj:lundice of extr:lhepalk origin bul not in tOOse .... ith pUndlCC of Intrnhepatic origm (e.g .. citrho:;i!). unal

88S

non th...

Merodione !IOtiium bisulfate occurs a.<; a "hi Ie. eryslllUIIK: . odorless po ....der. One ,",m of it di~soh'CS in about 2 mL of water. and it 15 sli ght ly soluble III alcohol. It decomposes on the presence of albli to hherau: lhe free quinone.

Menadiol Sodium O{phosphat~. U5P. Menadiul sodJUm diphosphate . tetrawdium 2-mc:thyl-I.4-naphthalenediul bi s{d ihydrogcn phosphme). Tetlllsodiurn 2-rncthyhmphthohydroquinorle diphol;phnl e. li t:lmin K.. i~ a while hygroscopic powder. vcry soluble III water. giving ~olu liOlt , with a pH or 7 to 9. It i5 avai lable in ~mpuls for use subcutaneous ly. imnullusculurly. or intravenously and ill tablets f')f oral admin istnllion. Unlike the OIher vitamin K analogues. menadiol'" oral .bwrption does IlOl depend on the presence of bile. Once absorbed . il i, con\'encd to menadiooc.

U5P. MenooiorlC'. 2-mr:thyH .4-nuphthoqUinone. menaphthone. vitamin K ,. can lit' prepared readi ly by the oxidation of 2-mc:t hytnaphlhatcne with chromic acid. It is a bright yellow, crystalline powder and is lK:arly odorbs. 11 is IIffected by sunl igh\. MemuliOIK: is praclicully insoluble in water: il i~ soluble in vegemble oil ~. lind I g of it is soluble in aboul 60 rnL of alcohol. l11e US I'INF caulions !Ilat menadione po..... tler is irritating to the respinllory tract IIIId the slton :and that an alcoholic solution !u.s veskant propertiCS.

~nadion~.

M_Nl~

SodIum Olphosph.,_

"

On a moIefor-mole basis, menadione IS equal to ~;tamin " , in acll\lly and can lit' used as a complete SUbsTitute for !Ilis vi Tamm. It is effecti"e OnIlly. intflweoously, and intramuscuillfly. Oral absorption occurs in the distal small int~ U~ and the colon. If gh'en orally to pallents with biliary obmuctlon. bile 1>alts or their equivalent ohould be adminislered slmuhuJlCOU ~ ly to racilitate abwrplion. It can be ad ministered illll1lmuscularly in oil when the p11lient e:lllllOl lolenne an oral product or has a biliary obstruction or when a prolonged effect is desired. Carbon-14- labeled menadiol diace[lUe in small phy siological doses i~ convenoo in vivo [0 vilOmi n Kl(lOJo and the side c!u.ln probably origin:lles from mevalonk acid. This suggests that mc:nadKme may be an intermediate ora provitamin K.llII Menathonc in oil is J times more effecti\e than I menadione suspension III water. More of mcrodionc tnan or~ita.min K, is abwrbcd Oflllly. but 38% of menadione is exeretoo by tile kidney in 24 hours..... hereas on ly very small amounL~ of ,'lIamlll K, are ueI"Ctcd by thi s route on 24 hours. In nlts. menadione on pan is n:duccd to the hydroquinOIK: ~nd exeret~-d as the ghu.:umnidc (19%) and the sulfate (9.3%).

Mcnadi one bi suirotc lind mcn:K.Iiol dipho>phate produce hemolytic symptoons (reticu locyll~i~. i11Cre;J.~ in Heinl. bodies) in lK: .... bom. premature infants when given in t"ceo;si\c doses (1Il()fe t!u.n 5 to 10 mglli). In severe case-.. o.en Ix-:moI)'tic IlrICnll3 .... lIh hemoglobinuria may occur. The increased red ceJllx'cakdown may lead to hyperbilil"\Jbintlllla IUld kemiClt.'1"\IlI. lkse compounds may also mterfere "'Ith bile pogment secretion. Ne .... bom~ ..... iLh a cong<:nital defect of glucQ!;C-6phosphatc dehydrogenase can react wllh se\'erc hemolySI\. even 10 small doses of menad ione derivati'e~. Small nonhemolyzing doses. ho\\,eler. can be: used In the lK:\\bom. anti a combination wilh vitamin E i~ not considered t.'iSCntiaI. 121

WATER -SOLUBLE VITAMINS

Although the: Iv:ner-soluble vllamins arc SlruclUrally di\'\~r.;o:. they IU"C pul in a gtllt'l1l1 class to di~t;nguish them rrom the lipid-soluble vitamins. Thb cla.<iS includes thl' 8 -comple ... vi tamins and ascorbtc acid (~'llIIllin C). n.e term 8-nJmpla ";lamiru usually refers to thmmlne. ribona~in. pyndoAine. nicOlinic add. pantothenic acid. biotin. eyanocobalamm. and folk acid. Dictary deflCiellCi<'lI of any of the 8 'lIamm~ commonly are eontp1kalcd by deficiencies of another membtr(~) of the group. !IO treallnent with B-complcA prepara ti ons is usually lndicalt-d.

Menadione Sodium Bisulfate. MenadiolK: ~ium bisulfate. 2_ll)elhyl_1.4_naphthoquinone !IOtiium bisulfite. is prc:1l.,n:d by adding a solution or !IOtiium bisulflte 10 mena-

"1111- line (VI-amln &,)

Thi wnine .... as the first water-soluble vitamin to be discov ered (1926). but the complete determination or it) structure and synthesIS "',as 001 accomphshed unti l 1936.
OH

dione.

Many n:lluflIl foods provide adequale arrlOUnlll of this vita min. The geon of cereals, brans. egg yolks. yeast extnICIs. pea..~. beans. and nulS usually provide enough Ihiamine 1 0 SIllisfy adult requiremenlll. The requirement for thiamine is related directly to ca loric intak.e. 0.2 100.3 ntgll.OOO calories. It is not economically practical to isoillte the c!),stalline vitamin from natural sources on a commercial scale. socom men;Illlly flvailable thiamine is prepared synlhetically. Thianune i1 sy nthcsrled biologically from the pyrimidine ck-riv,lIi Ie 4-fIIIlino-Sh ydro~ymcthyl 2 - mcthyl pyrimidine me1l1ylpyrimidine and S-(8hydro~yelhyl)-4-mcthylthia zole. These 1.... 0 pre<:ursors areCOllvened 10 phos.phale derivalives under kinllK calalysis. which requires ATP. The respective phosphote derivatives the n intcractto fonn thiamine phosphalc in a reaction catalY7.ed by thiamine phosphole pyropho6pho1'ylas.e. In higher mammalian organisms. thiamine;1> transformed to the ooenzyme Ihiamine pyrophos.p/lllle by dirttl P)'ro-phosphate lransfer from ATP. This ooenzyme performs important metabolic functions. for example, as cocarboxylase in thoe decatboxyhllion of a-kelo acids (such as pyrul'ale 10 fonn acetyl-CoA) and in Ifllnsketolases (such as use of penlose5 in lhe hexose monophosphale 5hunl ).

O:<ythiamine and neop)'n!hillllline are anu\nUlmns u:lCd in the sludyofthc defi ciency Male. OI)'lhiamlne IJ. comprtilive inhibitor of thnmllllC pyrophosphate. Neopynlhillmlilt inhibits the pyrophosphorylallon of thiamine.
","-...-"

n r OCtr
OM

OH

O!cythlam1ne

C",

""'Yo'\--""' , ~ N~~
A

OH

NlIopyl ithlamine
PRODU~

"'

In the decarboxylalion of pyruvate. lhe coenzyme interacts .... illl pyruvic Kid 10 fonn so-ca lled aclive aldehyde. as sllown below. The actil'e aldehyde inlermediate lhen interactS with !hi. Odic acid 10 form IICClyl-thioclale. ",hich is responsible for IICCtylating CoASH 10 form acetyl-CoA. In defICiency Stale$. the oxidation of a-keto acids ill ~ased. resulling in increa.sed pyn!vl1te IcH:ls in the blood. Thiamine hydrochlori(\c is Slable in acid but unstable in aqueous solutions with a pH I1bove S. Under the5e condi tions. it undergoes decomposition and inoctil'ution. Exposure or thiamine to the atmosphere or to oxidizing reagent s such as hydrogen pcroxi(\c. permangunale. or alkaline potaSsium ferricyanide oxidius it readily to thiochrome. shown below. Thiocllrorne exhibits a vivid blue nuorescence: hence. !his reaction is the basi! for the qlUlJlutalive fluorometric: auay of thiamine in the: USP.

Thi.mlne Hydrodllorlde. USP. Thiamine h).!rocfIb. ride. thiamine monohydrochlOllde. thianllne ehloride. 1'\11min 8 1 hydrochlOOdc . vitamin 8 t. aneurine hydroclllon.k. occu~ as small whi te crystals or lIS a crySlalline powdrr II has a slight. ehamclerislic yeast-li ke odor. The unh)droJl prQIJUCt. when e xposed 10 air. rapidly ub~rbs Uboul 4~ cI water. One gram is soluble in I mL of wUler and in aIxMII 100 mL of alcobo1. It " :.oluble in glycerin . An aq~ solution. I :20. has. pH of 3. Aqueous solutions 1:100 IIIIt a pH of 2.7 1 3.4. Th ianl ine h.aS pK. values of 4.8 and 9.0. 0 Thiamine hydrochlOl'lde is sc:nsitil'e 10 allah . The -.kIi1lOl of 3 moles of sodium hydro~ide per mole ofthiamll1e h)(ko. c hloride givcs lhe reaction snown on page 887. Thiamine hydrochlorilk abwrption is sodium dcJXndeN; thu s. SlItul1l tion limits absorption 10 8 10 15 mg daily. AI>sorption is decreased in alcoholism and cirrhosis. Food 1/. feelS the rate. but not the anlQUlll. absorbed. After Ib"0lplulII. thiamine hydrochlorick- is di stributed to all lissues. l'hM it limited storage or the l'i(JlIrun in the body (aboul 30 I1IIl Normally. little or no thiamll1e II c ~cn:ted in lbe unne.. U doses exceed physiological needs after body M (R$ ~ Sa&iIruted. howeler. thiami ne can be found in the urine II) P)Timj. dine or as the uncllangcd compound . Severe thiamine deficiency is called INribni. The map orgllns affecled lire: lhe nervous systcm ( in d!)' berihen l. tilt cardiO~ lISCu lar syslem (in WCI beriberi). and the gaslroin~ti nal tracl. Th iamine adminiStration TC\erses the ga~lrotntc:!ll nal and canUol'lISCular s)mptoms. 1be neurological ~ may be pennanent. ho"'eler. if lhe deficiency lias beat if_ere or or long durnuOIl. Thiamine h)drochloride is indir;abl

OH

OM _

. '\-

 a
Thiamine Hydrochloride

""
Thiochrome

""

~, OH

lNiOOH "

"" 2 N.eCl

.. the treauncnl or prophylnis of thiamine defICiencies. Di mry dcl'icieocie$ are I1IJ"C in the United SWell: altoholism I$lhe " lOSt commoo ,1luse o r the disease. Alcohol ic~ have

poor dietary habi ts (deficient diel). and alcohol in terferes w,1lI absorption of the viUlmi n. Tluamine dosageof5 mglday f0l'4105 v.eeks has 1't'5ulled in headllChe, insomnia. irritability. incn:ased hean rule. and weaknen. [n addition. lhiurnill(: clln Cau'II: unaphylllClic reactions foliOlOo'ing parenter:U use,lll
Thiamine Monon/t ra te, US,.. Th iamine mononi l ra le. thwnine nimuc, vitamin B, mononi lralc. is a colorlt'..~s compound. II is soluble in water ( I :35) and slightly soluble in 1IroboI; 2% aq~OUIi w lulions I!a\'e II pI! of 6,010 7. 1. This iIll i~ more stable than lhe chloride hydl"()Chloridt: in the dry S1m. less hyg~ic. and recommended for multivitami n p!qXInlUOrlS and wrichlTl('n l or floor ffil'{H.

N~N ___ SH

o
Coenzyme A This vi lamin is synlhesi7.ro by IIIO!iI grecn planUl and microorganisms. The precUtsOf1 are ,)"ketoiSQ"almc acid and ,B.alanine. 1 The laller originates from the decarbmyllilion of aspartic aci d. ,.. KC1oiSQvaleric ocid is converted to ketopantoic acid by ~ N O- methylenetetrnhydrofolic acid: then. on reduction. pantoic acid is fo....ed. Finally. panloie acid and P. alanine react by amide formation to form pantothenic aci d. 11M: metabolic functions of pantOlhenic acid in human biochemi st!)' an: mediated through the ~ynthcsis of CoA. Pantothenic acid i~ D ~truCiural component of CoA. IIhich i~ neces\1lf)' for many imponant metabolic processes. Pantothenic acid is incorporatoo in lo CoA by a sencs of th'e en/.yme<lltalyzed rcaction~. CoA is 11'1"0"'00 in the activation of folly acKls hefon: .8-o~i dation. which n:quire.~ A TP to form the respective fauy acyl -CoA derivatives. Pantothe nic acid also part icipates in fany acid ,tkIx idalion in the firWII step. forming lICCIyl-CoA. Aceryl-CoA is also fo..lloo from pyruY3te decarboxylation. in which CoA partk ipate~ with thiamine pyrophosphate and lipoic acid. tWO other important cocn7.ymes, Thiamine pyr0ph0t5p/'w:ile is the aclUal decarbo~ylati ng cocll7.yme WI funclions with lipoIC acid 10 form acetyldihydrotipoic aci d from pyro va te decarbo:tyl alion. CoA then acceptS the acetyl group from IICCI)"klih)"drolipoic acid to form lICCIy l-CoA. Acetyl-CoA is an lICCIyl donor in many proce5SC'S and i, the precursor in Imporlam biosynthe~s (e .g . those of fany acids, steroids. porphyrins. and acelylcholine). O inical eases of panl~nic acid deficiency develop f':Il"ely. unl~ they arise in combination with deficiencies of lhe other B vitamins.} Accordingly. panlothenic acid is usually included in mult ivi tamin pn:parations. The calc ium salt il commonly used in pnarmaceutkal pn:parations. Panlhenol. the alcohol dC'rivat[.'e , is also commonly used.

P tothenlc: Adds During the 1930s. R. J. Wilham.~ and his collaborators reoog.

.,w from the Greck. meaning

~. i$Olalro. and ~ynthcsi/,cd panlOlhe nic acid . Bteause ItS occurrence is 50 widespread. it wa.~ cu lled fHllllOllI~lIit:

" from everywhere."

Pantothenic acid 1Ill~ also been ca llo!d ,tlUmill 8,. E~cel of the vitamin are liver. eggs.. and cereals. It is holle'er. in the form ofCoA. Thi s coenzyme cannot directly from the gut. Ahhoogh no uperimems conducted i n hu mllrl~. ~tudies on :mimuls indicate iw the cocn,21JlC musl be hydrolyzed 10 panthenene and pantothenate. which are absorbed hy pas.~ve diffusion. Human inteStinal cell s coolain enzymes thai can hydrolyze IbI: cocn/)'me . Pantothenate is the mlljor form circulati ng in tbt; blood and is absol'bed by individual cells. Once inside IIIe co:U. CoA is s),ntheloi1.ed.

PRooum
Pantothenk Acid. PlllltOlhenic acid. vitam in B,. OCClirs b a villCOO\ hygroscopic oi l. freely soluble in water but un'<table to hoem , acid. and all.li. Bccau~ of this instability. the calcium SIll! i~ used contmcrdally. Pantothenic acill and its deri~at ives h:ave essentiall y no pharmacological *-'1ions per 1oC. 1kcau.'iC of the ubiqu itoos nature of the ~lIamin. dcrK:iency stales usually do not dc~dop. lllcy hu\e been produced by use of synthetic d iel~ de~oid of the vllamin or by use of a vi tami n antagon ist. w- Mclhylpanlothenic acid has produced fu tilluc. hcaduchc. pareSthesia of the hands and feel, cardiovascular instobil ily. :md gastrOlnlc.~li nal probknts.
H

Dexpanrhenol, USP. Dexpanthenol oe~urs as a sh,,"ly hygroscopic. viscous oil frcc:ly wluble III waler and akdd. It is the dexlrorotatory alcohol dcriYllli'e of pantOlhenl( Irid and is cOIwtfted n:adlly in vivo to the acid form.

,oas

Dtxpantncool and the rolCemic lllixlIIn: are used in !hi' U'eatnlotn l of paralytic ileus und postoperat ive distentkln. DeJcpautheool in combination ",im choline is used to n:htH retention.

N~,,"

NicotInk Add
N icOlinic acid (niacin) .... as prt'pared Ii r~1 by oxidalion oi the alkaloid nicotine. bul not until 1913 ...as it isolated fro. yeast and recognized \loS an essential food factor (lICe the stn>eturn). In 1934- 1935. nicotinamide was obtained f..the hydrolysis of a COCn7.ynlC ilOlatcd from hone red bIootf cells. This coenzyme .... as I;ncr named CQtm,""'C III11ld il oow more common ly called niC OIilNlmiuc udcninc d;nurlfo. ,idc phosphmc (NADI'J.

PantOlhenlC acid and illl dt."';yalivcs are readily absorbed ~nd wide ly distributed. The h'ghest ~'oncentrations are found in the lIyer. oon:1lII1 glands. heart. und kidneys. Pa ntOthenic ac-id apparently undergoes liule if any metabolism: the amount elimmated apprmum:lles the amount conwmcd. Aboul 7O'l- of a dose is ('Iunmated Unciwl,cd in the urinc. and the remallKkr IS ellllllll3ted in the ftcts. 1'hI' only official indical10n for pantOthenic acid is in the prcvcnlioll 01' tn:atment of vitnmin B dciicielK:iC!;. Because a deficiency of a liinglc B vitam in is rurc. it is commonly formu laled in multivitamin prt'patalions or B-compleil prep:1l'lltions.

OH

Calcium Pan to thenate. USP. Calcium pantothcnlltc. calcium o-panIOlhen:llc. is a "lightly hygroscopic. while. odorless. bincr powder that i~ stable in air. It is insoluble in IlkohoI and IOhlble 1:3 In "'Dler. aqutOUS IOlulions have a pH of aboul 9 and j er]o _ +25 to +27.5". AUloelaving ~alcium p:lnHlthenate al 12O"C for 20 minutcs mill' cau<;e 10 10 30% Oc:~'Omposi l iun. Some of the phQ~phu tes of pantothenic \lodd Ih,u ()(:Cur ntlturally in coenzyulots are 'l uite stable 10 both acid and alkali. even on healing. III

, Calcium Pantothenate

" "'-'"YO cr

Racemic Calcium Pan to thenate. USP. Racemic cal cium pantothenate provides a more ecoflOlnical sourcc of Ihis vitamin . OIlter than containing Il()I less lhan 45% of the deX lrorot:ltOl')' biologically active form. its pilOpen ics 1m VCI)' Simi lar 10 Ihosc of C1Ikium pantOihellJlte. US P. Pan thenol, USP. I>anthcnol. the IllCenliC alcohol analogll(' of panlothenic acid, uhibits both qual ilativcly and quantitati\'ely the viwnin :ICIiyily of panuxhcnic Kid. It is considerably more IUlbk than pan lOlhenic IICid in soIulions .... ,th pH \Illues of 3 to 5 bul o f about equal sUlbilily Ilt pH 6 to 8. It appc:ml 10 be absomtd more n:adi ly from the gu t. pani.:ularly In tl'lc prescnce of food_

of lhis vi tamin Include pork. Iamb. aid bee f livers: hog kidneys : yeaslll: pork: beef long~ ; hean!. lean me31ll: wheal &enn : pe:tnut meal: and grccn pta~. Nicoti nic acid can be synthemed by almosl all plant!J and l1lirnals. T I)'Jltophan can be metllboliled 10 nicoume I0Il nuckolide in animals. bul the C'fficlel1CY of lhis mulllSlql pI'OCClIS Yarlcs from species to species. Plams and many l1licroorganiSllls symllcs.izc this viwmin Ihrough al!ctn.1lilo'C routes by use of aspan ic add. In the human. nicot inic acid n:acts ""Ih S-phosphorioo.)" I-pyrophosphate 10 roml nlcOlinic acid moootlllCltoto:k. .... hich!hen reacts with AT!' 10 produce: dc:wrtioo.NADitllc inlc mlCd iate dinoc leotide .... im !he nicotinic acid lIlOItIy~ Finally. the loltcr intcmlCdimc is coove rted to NAD (on", nal ly called coen:.)/Ilt I) by LflInsfomulIion of lhe carbox)l orthe nicolinic acid moiety to the amide by glulamlilt n. final step is cataJylCd by NAD syntbetase: NADP IS . . . doced from NAD by An> under kinase catalysis.'
'IQIII'CCS

"""""" Generous

"",,0

A . H .. ~ ..... Ie dino.l(**"t R .. POt.. NICOli".";,,. . . . . ,., ciQl(ltoIIidIo pI"*'* III

NA 0 IUld NA DI' 3I'C o~idil.ing cQenlynlC!! for many ( _ than 200) dehydrogenao;es. Sonle dc:hydrogenascs

C-NH

,a

, ,

..0"

NAC"

OH,

..0

H 0"

o
C-NH2

II

y N"
fig ... ,.. 26- 1 GeMralized rep-

resenlallOn 01 &.eo hydnde \t3llSfer

""'~
NAD. OIhcrs m:juire NADP. and some rUI1I.- .ion with either. 1 The genmaJlJ:ed rtpr~~mll!ion in Figure 2~ I ilLu~;!r'Jles the
(unchon of ~ COC'nl.ymtli in metabolic oxidations and reductions. The abbn:viation INAD 'I emphasi~e., the dectroplllllcH)' of the pyridine ~ moiety (" hieh is the center tL reactivity) and the suhslnuC design:tted

"""""" ,
AtdOCl

accc:pt0f3. and NADH and NADPH an:' lIydnde donors. AI thougllthi, is SImplistic representation. it sholl; s the dyna mism of the oxidauoo- redllC1ion reactioos effected by these coenzyme~ under appropriate dehydrogenase: ca talysIs. AI ternatively. the reduced coenl.ynlC5 may be used in ATP production through tile electrootrnnspon system.

COIIld be I pnm3l)' or serondary alcohol. Arroll II in Figure 26-1 5)'rnboh/e5 the function of NAD as oxidant in the hydnde trallsfer from the SUbsll1llC 1 the coenzyme, forming 0 NAIJII. ~d CQtfU.ymc. The hydroxyl of the sumlr.lIC: is IISu.tlUed :b undergoing deprotOfUllion roroccrted ly by fllMr \\'lll('r or the p)"ridinc niuugc: n of NADII. Arrow b
.m",s COOCCI100 fOrm;Jlioo of the clIIbon)'1 ~-bond of the olid:alion product. Arro ... C" syrnbohlc5 the rt\'c:rse hydride lrnI~fcr from reduced coen;t;yme. NADIi. to the carbonyl ClII'bon; and coocenedly. as the carbonyl oxygen undergoeS rroconnlion. the re<iucli on of the carbonyl group fonns the com!~ponding olcoho1. 11,"$. NAD and NA DP are hydride

0;"
Elhanal ChEIa.lion II Schematlcdy llustnlted

"

e llow
;IS

As noted above . nicotinic acid (also known

"'(lein 10

a void confusion .... i'h nicOll ne) can be made avai lable in nu cleotide form from lhe amino x id tryptophan. II has been esti mot ed thol a dosage of 60 mg of tryptophan equals tlull of I mg of niCOlinlC acid. Conli!.'t[uenlly. humans and Oilier mammal s can symhcsile the vi tam in. provided Ihere is ap. propriale dielary uvui lability of Iryptophan. (Thu s. nicOIi nic

,
.. ' l .....' " , 2 . ...

acid i~ not 11 true vitamin by the dassic definition of the temtj

Like nikin. niacinamide is Indicated m the tn:aln1Cnt IDd

pre\'ention of ddicicncy 5tatcs. Unlike niacin . niacinarm-k has no vasodilatory effect, whiCh may be of thel'llpcutic imponancc for compliance reasons. Niacinamide: has nodfta on triglycerides and lipoproteins. This product is formulatal with potassium iodide and used as an iodine 5upplemcllL Niacinamide hydrochloride is alSQ available. It i s _ stable in solution and more compatible ""ilh thiamine cI\Ioo ride in wlution .

PRODUCTS USP. Niacin. nicotinic acid, Jpyridine carbox ylic acid. "itamin OJ. (X."Curs as ..... hite crystab or lIS a cryStal line !X'1r.der. It is odor~s or may ~\'e a shght odoc'. One grom of nicotIniC acid di~sol~es in 60 mL of watcr. It is freely soluble in boiling water. boiling alcohol. and solutions of alkah hydrodde~ and catbooates bot is almost insoluble in ether. A I'l> aqueous solutiOll has a pH of 6. Nicotinic acid has a pI(. of 4 .g~. Nicotinic ncid is stable under normal stornge cooditions. It sublimes wilhout decompositiOll. Serious derlCiency of niacin or tryptophan may lead to pellagra (from the Imlian, ~II" Ilaro. for "rough skin "). The major systems affected are Ihe gastrointestinal tract (diarrhc'a. enteritis. SlIMmltitis). the skin (dermatitis). and the central 1'ICTV000S system (hradochr. dizziness. depression). Se\ere ca.'ie.'l may result in delusions. hallucinations. and (kon1('nlia. In the United Stales. pclla1!r.I hIlS become rare because flour is wpplemcnted ","11 nicollnlc acid. Chronic aJcohoti~m is the chicf cause of pellagm and is associated ..... ith multiple vitamin deficicllCy. The symptoms of pcllagru an: completciy revcrsed by niacin: thcref~ . it is indicated for the treatment and prt\'emion of the defICiency. Adverse effect~ of ni!lein are most COlllmonly ~n when thi s vitamin is u'\td at phan1UlCological doses abovc I gfday in the (realment of dyshpidemiL Notable adverse effecl'! ndude noshmg due 10 vasodilatation: dermatological cf fects iucluding dry skin prurilllS nnd hyperterntosi~: gastrointestinal effects includin& peptic ulcer. stomach pain. nau sea. and dlarrilc:tt; ckvations in serum uric acid and glucose; and hoeP.1l0l0licity. m . llol Niacin (but not niacinamide) is ulso indicated in hyperl ipidemia to Iov.'cr triglyccndes and cholesterol. Triglycerides. VLDu, and LOLs are mjuced; HDLs are Increased. 1lIe eloct ml"Chani~m is not known. Because niacin al high doses ha~ a direct va!lOdiiatory effect bel ieved to be mediated throogh the prostaglandins, the dose required (I to J g 3 times dally) oftcn limits thoe usefulness. Niacin is absorbed readily from the gastrointesti nal t11lCl and distributed widely. At physiological doses, lillie niacin is excreted unchanged. Most is excreted 115 Nmethylniacin or The glycine COfljugatc (nicoununc acid). After admi ni ~tra tion of large tlo!Ics. ni!lein can be found in the urine un ch.lnged. USP. Nluciuamide. nicotina mide, nicotinic acid amide. is prt'pIlrtd by the amidatlon of esters of nicOIinic acid or by passing ammonia Sas imo nicounic acid at J2O"C. NicOlinamide Is a while crystalline po .... der that is odorless. or nearly so. and biller. Olle gram is soluble in about I mL of .... ater. I .S mL of alcohol. and about 10 mL 0( glycenn. Aqueous lIQlutions arc neutrnl to litmus. For occum:nce. 1IC1i0Il, and uses. sec nlOOf;n ic ueid. Niuei n:unide has pI(. villues of 0.5 and 3.3S.
Niaclfl~ mick. Ni~,Jn.

Alboflavln (Vitamin B 3 J
Although crystalline ribollav;n was IKlI isolated until ;., interest in this compound as a pigment dates back 1(1 .'.: in connection with the color in the whey of milk. In

ribona~in was i"Olated as It from yeast by WarbtJrg and ydlo... (),fidarion !ermenl.

~'~:::'~~":;~:':.~ ~I i

~~C ~

"""" '"
Ribolla\'ln is synthesized bb:,;~01:~',:~:''':':;::,:::!!~; bacteria and fungi. .... Ithough y' t !.Iairy products. legu mes. 1 meats an: the major SOlutes the diet. The preeursor is a guanosine phosphalC "'::':':";: oot the e.o;act synthetic stepS leading to the vitamin understood completely. In higher mammal s. ribonavin I~ absorbed n:adi ly till: intestines and distributed to all tissues. ';;:~~: In the bll)Synthcsis Qfthe cocn1.ymes navin n (FMN) and navin 3dcnine dinocleotidc (FAD). The bulic functions oithis vitami n invol"e ~~~~:~o,:~: which par1icipate in numerous "ital ( processcs. FMN (ribon3vin S'pho:sphatc) is producal The vitamin and ATP by lla\'okinase cllt aJysi~. Thl ~ be inhibited by phenothia7jncs and 1M tricyclic s.mlS. FAD origmates from an FMN and An> involvt:.'!\ reversible dinucleotide fonnatiOll I vin nucleotide pyrophosphorylase. These c:ocnxymes lion in combination With sevcrnl en7ymes ro,~",".-'" lyrne complexes. o ften cha11lCleril.ed a.~j1a1oprotti/U.

..

as

EII

Nicotlll31e

Niootlnamde

Ftavin Mononucteotlde

Chwptu 26 VilOmiJIs WId

Rtllll~

CDm{JOfUIIh

89 1

lumichrome

OH

fiavoproteins function in aerobic or anaerobic cood,tionli as o~idases and dchydrogcnasc..~. 8:.amplcs include r;lucose o"idasc, xanthine o"ldase. cytochrome reductase. and acy lCoA dehydrogena.-c , The riboflavin moiety of the complex is coo~idcred a hydrogcn' lrnnspon ing agcnt (carrier) functioning as a hydrogen acceptor: the hydrogen d0nors may be NA I)H , NA[)I'H, or some suitable su bSlr~te. The isoallon;tine rings accept twO hydridcutcpwi!;C to fonn the di hydroribo fiavin deri vat i~e ,

"
QII"1d Speclll

y O

1llc vitamin is commercially .vailable 15 nboO.vm. riboflavin .'i-phosphate. and riboflavin 5phl)5phate sodIUm. "The phosp/late esters a~ usaj comn.... dally on ly in multivitamin preparations. and they ~ hydrolyltd before aMorpI:ton occurs.. Absorption (,IIIXUQ through an active transport S)'$tem in \\'hich riboflavin i5 phosphorylated by the intestinal mu cosa during absol'ptton. Fuod and bile enhallCC absorpt.on. Riboflavin is distributed widely in the body, with limited Sl0rt'5 in the Ih er. spleen. hean. and kidneys. Con\ersion to FA D occurs primari ly in the liver. FMN . nd FAD circulate primarily protein bou nd. Only small amooms ( -lJ'l,) ~ excreted in the urine uncllanged. Larger alJl(Mlms can be found after adm inistr3tion of large doses, Severe riboflavin defidency is known as uriboj1(JI'inosis. Its major S)'mplOms include cheilosis. IiCborrhcic dcooatiti s. and vasculariUltion of lhe cornea. Ariboflavinosis occurs in chronic alcoholism in combi nation with other vi lBmin defi cie ncies. It has also resulted from phenothill1.ine, lricyclic IlfItidcpn::s~anl, and probenecid thcrupy. Riboflavin hM no pharmacological action and is relatively nonto~ic. 1be on ly approved indicalion is in the 1tealmc nt and preventioo of aribofla vinosis.

P"ldoxl_
PRODUCTS
Ribof la",;n, US" . Rlboflav,", loctofla\i n, vi lamin B~. Vlwmn G. is a yellow to orange-ydlow, crylitlllline pov.'dcr '''1m. slight odor. It is soluble in WAter 1:3.000 10 1:20.000 mL '11m the ~ariall()l1 in ~Iubili ly bemg due to diffelcnc::es ID internal cryStalline ~lIUCl u~. but il is IT1(l('e !IOluble in an OOtonic so!utton of ~lium chloride. A salUrutcd aqueous solution has a pH 0(6. R lbofla~m ha$ a pI{" of 10.5, It is less soluble in Ilkoholand insoluble in et~r 01' chloruform, Benzyl alcohol (3% ), gennsic acid (3%). urea in varying IIIlOUnIS, and niacmamlde a~ used to solubil i1-t riboflavin ... hen relacively high concentrations orit a~ needed for par rntcr.lI solutions. Gentisic cmlU'lOl amide and sodium 3hy dro~y2 nnphthoate al<o 5OIubi lil.c ribonavin effective ly. When dry , ribonav;n i~ not affected appreciably by diffused light: it dcteriorute.~, howe~cr. in 5OIUliOl1 in the pre$rncc of light. This dcterionnion i< "ery rupid in the presence of alkalies, producin& lumi flavillc. Thi ~ delerioral ion may be retarded by bufferin& on the acid side. bill under acid rondilions, light can produce lumichrome. Neilher of tllese decomposi tion product$ possesses biological activity.
[n 1935. the term I'i/(lmin 8 6 was applied 10 lhe principle

l umillavine

that cum! demwitis in rats fed a viwninfrte diet supple mented ..... i!h Ihiamine and riboflavin. Three years later, vita min B&was isolated from rice paste and yean In 1935. P. Gyorgy showed that rut pell agra was not the URIC as human pellagn ootmat it rescombled a panicular disease of infancy known as "pink disease" or acnxIynia. This rat acrodynia is chal'llC1erizeti by a symmetric dtnnatO$is affecting first the paws and the ti ps of the ean and the nose , 1bese an:as become swollen. m!. and edcmatoo$. whh ulcers dt"eloping freq uently arou nd the snoot and on the tongue , Thickem"i and scali ng of the can an: noted. and there is weight loss: fawities occur I to 3 \\'ccks after the lIppe~ of the symptoms. Gyorgy was .ble to cure !bese cooditions with II supplement obtaillCd from yeast. which he ea lled "/tlm' /n HI>- [n 1938. this factor was isolatcd from rice pastc and yellSt in a crystalline form in a number of laboratories, A single dose of about 100 ~g prod~ced heaJing in 14 days in a rut wilh severe vitamin B& dcliciency symptoms. Chemical tests, elcctromelric titmtlon detcnninations. and absorption speclrum ~tudics gave c lues 10 its composition. n.esc were substantiated by lhe syn thesis of vitamin B~ ( 1938 and 1939). Two additional che mical forms. pyrido~.1 (an aldehyde) and pyridoumine (a pri mary amine). have been isolated from nalum sou~es. 11lcse thrte compounds are interrelated metabolically and fu nclionally. "The interconversi()fl between the di fferent fOl'ms is snown below, Gyorgy proposed the term pyrid()xiflt for the original compound isolaled. Soon it became synonymous wim "ir(l' mill Br.. In 1960. IUPAC recommended usi ng the teoo pyri-

AIcW>,..,. 0'---:1.-.," ~FAO00

~~
H ,

f')'io~;,~""

;;1

pt........, , ' .

f')'ido..alkJoaMj_
AlP

Pyrido'"

PyriOOIUImine

00

~ct if '0.
H.c"

~O
if '0

..,.. """"'''''''1
H'.c"

NH2

~O
0- '0

Pyridoxal-5-phosphate

Pyridoxamine-5-ptIosp" :.:

11 gtnenC descripror for 1111 forms of the ";1:1I11In mnd p}'ridoxol as Inc uivial flanlC for the Illooho1 furm 0( the vitamin. In 1973, IUPAC rev ised its ~ommendalions. i're.Kmly. the term ";Ulm", 8" is the appro_cd ~'lCnp!or fOf' aU forms of lhe vllamin. and the term p)'ridl}.tj,,~ ",fef'S 10 the alcohol foml. TIlC tcmlplridox.ol is no loogcr recommended. lUPAC fl,lrthc::r recommends thaI the pho!;phatc ('Siers be caned /I>'rlcln.fim ,'phIMp/Wlt. pyrido.wl 5' -pho$f/luUt, I1l1d p.l'rido.mmi~ J'.phoIphllll'. TlleSC' may be abbreviated 1 0 p)'rido.xmt j ' P. P)ridO.flllf'P, elc..... hen J>O ambiguity
IInS<eS.

dtt~in~ !Ill

Pyrido""" is available from ... hole-gnlin ccn:alJ. peanuts. com, meal. poultry, and fish. Up to 40% of the vi tamin may
be destroyed. ho"c\cr, durin, rooking. Food .;ou~s contIIm all three fonns. cither in their fltt form or phosphory-

lated. Plnnls comain prillmrily pyridoxol arK! pyridoxamine.

..... hile annnal ~rces provide chien) pyridoxal. M:lnY plantJ also cuntam a glycoside of pyridoxol. \\hkh is in.;ludc:d in \'hllmin C()fUenl delenninalioru. Although this conjug:ale is absorlled. it is rlOI used well.' This may explai n rhe lower bioava.ilability of the vitamin from plam s.ourl:e..~ than frum ammal source).
00

v"' ....~o....&,
, HO

0-

Coo JOH

5~1Il--0-Gtycolpyrano.y.) Pyrloo~oI
Vitamin 8 6 is absorbed via passive diffusion. chien y in the jejunum. and tran,poned to the livcr. ~ liver i~ II major orpn ofstOr.llle (16 10 27 mil). metabolism. and inlcroonvcr~ion between the 1hrcc form~. Excess 8 6 is ox idil.ed to 4_ pyridoxic !>Cid. This !>Cid is the primary fonn fourK! in lhe urine. accounting for up to 6Q'9I, of ingested vilamin BIoIn the Iivcr.1I11 three fOl'1l1llIlfe com'cned to pyridoxal.5phosphatc. which circulatcs in the blood boIlrK! 10 albumin.

Before cntry imo ~'CII~. til<! phosphate must be dephosphory: b tcd. Inside the cells. pyridoxal kinase rephosphorylatcs dIr vi mmin. This kina'>C is fourK! in many cell types. ahhouglt other enlYIllCli Invuh'ed in the irneI"Colwersions are oot elF pres.'itd in all cells. ' l j Aithouglliarge amounts orlhe \ltaJrul are fourK! in the liver. the mU <c les comam higher aroounu in the form of Illyt~en phospOory1a..loC:. 11:6 This ,namIB 8" i~ 110( readily Dvai lahle. ooleH'r. during deficiency stalt).'2! Pyridoxal 5-pllOliphate is u coenl.yme 111. 1:1'11 tll:lt pctfortDl many ,itat functions In human mc:laboh_m. It flillCtlOM 11 the u1Ulswnirllllions arK! d..-earboxylations thai IImlllo.:KI! gt'nernlly undergo. For u:lmple. it fuoctlOlt$ II!; a COIl"WISImin:asc in tile tran5JIrnination of alamne tu form p)"ru~ic IC1d and & codecllftKuylase in the decarboxylation of ~ 10 form dopamine. Other biologICal transfonnatlom'n., iii amino acids in which pyrido~al cun function are racernll.l: lion. elimination of the Il'-hydrogen togetllerwith 11 ,8-su~: IIcnt (i.e .. O H or SII) or a ,..~ubslltuent. and probably the l"C,ersible dea"age of ,B-hydroxyantino ac-ids to glycine IIIId carbonyl compounds. An clcclrol1leric displocenlCnt of electrons from bondill. h. or e (sec dtagr:un below) would result In the rde;L~ Ill. COlion (II . R'. or COOl!) and. sub!.cquc ntly. lead to the 1110: ety or readioos ~I'\ed with pyridoxal. 1lIe eAlentlO .. lid one of these displacements predominates o~er others drpends on the structureof ille amino acid and the el1vironmtlll (p H. solvent. calilyslS. rnl.ymes. and $UCh): When thIS ~ anism appl ies in vivo. the pyrido.~al component is linl;N 10 the en/ymc: through (he phosphaie of the hydroxymclh)1 grooop. Metals soch as iron and :aluminum ... hich mnrkedly ClIiI Iy/.e nonenzymalic trnn<;.aminations m >jlro. probably do !III by promuting formati on of lhe SchilT base 1IrK! maintJ.milll planarity of the oonju/!aled system through chelme ring famotion. which reqUII"C! the presence of tile phenolIC sroop. This chelated metal ion also providt:~ an additiooal clectroll-

n-c- q
~

,0

~
~

,
b

<>-1 ,0

<>-9 "<5'-

,
-I H
P.-t'.,0
C",

~-

\(
'\-00,

;}heterocyclic nitrogen atom (or nitro group). thereby increasing the electron displacemcnL~ from the a-carbon alUm lIS shown above. Certain hydrnzine derivatives. wilen administered therapeutically (e.g., isonialid). can induce a deficiency of the roen7.yme (pyridoxal 5-phosphalc) by inactivation through the mechanism of lIydrawne fonnation with the aldehyde fUllctional group. AllOIhcr hydrvinc: derivative. hydr~hl7.ine. ~hcn adminj~lered in high dor.es 10 control hypenc:nsion. call cause simi lar Bb dcficicJlCY. conceivably through a similar nle(:hanism in~olving hydrazone formation. Hypochromic anemias caused by rami liar-lYpe pyridoxine depelKkncy respond [0 pyridoxine thempy . Similarly. this I'ilamin has been useful in the tre atment of hypochromic or megaloblastic anem ias mal Ill'e nOI due 1 iron deficiency 0 i\J\d do not respond to other hemalOpoietic agents.: A review by Ro'IC'JO S"lInmuri7.es studies on lhe effts of certain hormones on vitamin B~ nutrition in humans. on !be biochemical interrelationship between steroid Ilonnones :tnd pyridoxal phospll:.te-dependent CIU.ymes, and on the role of vitamin 8 0 in regulating llypothalamus- pilUitary func tions, Some of these studies have impol1ant clinical implications, The use of estrogencontaining 01111 tomruccptives has been investignted as a factor leading to an abnorm ality of tryptoplmn mellibolism. This abnormality resembles dietary "itamin 8 6 dC' ri cicncy and responds favorably to treatment with . he vitamin . For some lime. there Ilas been clinica l Interest in the relationship betwecn certain hormones ~nd ~itamin Bb function because abnormal urinary excretion of trYpiophan ,nctaboJitcs was observed during pregnancy and in pmicnrs with hypcnhyroidism , Es trogens and tryplOphan me mbolism have been Mudied because estrogen admi nistmtion occasionally leads to the ~xcretion of ~bnonnally large amOU11lS of xanthurenic acid, metabolic product of tryptophan. Thi s mel~bolic malfunc

1:7t. "
+ "0 0
~

tion has been related 10 the inhibitory effect of estrogen sui fate conjugates on anothl::r pathway of Iryptophan metabolism - the tr.lns.aminmion of kynurenine from tryp{Oph~n . Consequently. xanthurenic add fonnation appcan to be lib-normal ly high because of this estrogen effect or 8 6 defi ciency. In vitro studies have been conducted to dC'tennine . he ef fect of estrogens on kynurenine aminOlmnsfernse. which cat alp.ts the B6 -dependent transamination of kynurenine to kynurenic ncid. Some estrogen conjugates (e.g .. estradiol disulfate and diethylstilbeslI'Ol sulfate) intcrfcre with thi ~ tron~amination, apparently by re"ersible inhibi ti on of the aminOlransferosc apoenzyme, Apparently. thl:: estrogen sui fate competes with pyridoxal 5phosphate for interaction with the apoenzyme. In contrast, free estrodiol and estrone do nOl posseSl> this inhibitory property. Some women suffer from n~ntal deprcssiOll when taking estrogen-containing orol cuntrd~'(:ptivcs. and thi s depre.~sion could be due to another malfunction in tryPlophan metabolism. leading to 5hydroxyttyptamine (serotonin). Some evi dence indicates that the decarboxylaliOtl of 5hydl'Ox ytryptQphall is inhibited (in "itl'O) by estrogen conjugates competing with pyridoxal phosphate for thl:: decnrbo~ylllSC apoenzyme, Other endocrine systems are interrelmed. Both conkoste roids and thyroid honnone,~ may increase the requirement for pyridoxine and affcct pyridoxal 5phosph01e-dcpendent metabolic processes. Moreovcr, there appear to be associations between vitamin B~ and nnterior pituitary honnones that seem 10 involve the. hypothalamus. 5hydroxylrypta mine, and dopaminc. The latter two neurotronsmillers are synthesi7.ed by metabolic processes that require pyridoxal 5phosphate. Imerestingly. studies lIa~e sllown thaI vimmin Bt.- in tum, innuencc:tl the fUllCtion of stel'Oid honnones.l.S Pyridoxnl 5phosphate hinds to lysine residues on the steroid receptOl'S.

_ """"'" "'" 0''''.......

AIdeh)'dtl

.. NAO

~I>ydrooona ..

Pridoxlne

--

Pyrido.....,.
Py,..., t kinase
ATP

R PIlD89heIUl

NH2

~o
0"0

Pyridoxamine

SilI_

as a gcnerx- descriplor for all forms of the vitamin and pHidQxlJ/ as the trivial n/llne for the alcohol form of ,he vl1.lunin. In 1973, IUPAC revised Its ~J1lendauons. Presently, the term "imm;" 8 a is the approl'ed descriptor for ,II forms of the: ,immin. ~nd the term I'yritli.lxi,,<, refers to lhe alcohol form. 1lIe lcrmp)'rido.lm is no longerrecomn""ndcd. IUPAC further re(:omrnend$ !hm the phospMtc esters be called pyrillQ.ri,,~ Spho.rpho.lt'. pyridc.(ol j"phQ$lmalt, and pl'rido.mmint' 5'-"lwsphmr. 1llese may be abbreviat ed 10
Iloxj,,~

pyridQxmt' S'

-Po pJrillatme-P. etc .... hen 00 ambiguity

arises,
PyridoJlOinc is availuble frolll whole-,rJin cereals. peanu ts. com. meal. poultry. and fish. Up 10 40% of the vitamin may be destroyed. hol'Clcr. during cookin8. Food o;oun:dl cuntain 1111 lhlt'e forms. dther In their free form or phosphoryhlled. f>Jams contain primoril y pyridoxol and pyridoxamine. .... hilt animal sources provide chiefly pyridouJ. Many plants also ~>t)nl 3in ~ glycoside of pyridoxol. which is inc luded in "i,amln cootcnt determinations. Although this conjugate is ubsofbo:d. it IS IlOI used wdl. ~ Thi~ may explain the klwer Irioavailability of the vitumin frum planl sources than (rom 3nimlll wurcc:s.
OH OH OH

5-~~IYCOaPYfanosyl) Pyrldoxol
Vitamin B~ is obsomoo via passive diffusion. chieO y in the jt'junum, :II1d transported to lhe liver. The: liver is a majocorgan of Storage (1610 27 mS). ntetabolism. and interronveTsion betwet':n the three forms. Excess B~ is oxidized to 4 p)'ridoxic acid. This acid is lhe primary form found in the urine. accounting for up 10 60% of ingesled ~ilU lllln B~. In the IheT. all tiutt fOlmS are COO\'erled to p)'ridoxal 5phosphute. which circulates in the blood bound 10 albumin .

Befon: entry into cells. the phosphate must be cIc:~. lated.lnside the t"etls. pyridoxpl kinase ~phosphorylalestht vitamin. Thi s kil\llSe is found in many cell types. uhhoup other enzymes involved III the interconver$ioru aI"e not n p~.ssW in all cells. 'u Although large amounts of the vitarni~ are found in the Iher. the muscle, conlam higher arnIlUIII.I in lhe fonn of glycogen phosphol"ylusc.':ZII> This vitamIn 80 is nQI ~adily avullable. ho .. ner. dunngdeficiency sules. 1TI Pyridoxal 5phosphate is a coen/ynle I~. '19 that perfOlllli many vilal functions in human metabolism. II fUOCliOlll ~ the trnnsammations and decarboxylmions thaI amlllo aclCh gencnal1y ulldergo. For eumple, il funclioos lIS a OOIfl\1\samJ' nase In the lI'11l1saminauOIl of alanine to fonn pyf\l\lc ICId and u a eudecarbox yla~ in the Oi:cllfbox)'lD.lion of dopa ICI form dopamine. 0Iher biological trlnsfonn:IIlOlls :" 11:1 ci ' amino acids in wh Ich pyridoxal can function are nlCelTilntion. Chmmalion of the a-hydrogcn together with a ,B-sumut uent (i.e .. 0 11 or SH) or a ,..wb$tnu~nI. and probably th: !'C\t'TSible elea\'lI8c of ,B-hydroxyarnioo Kids 10 Glycine . . carbon),1 compounds. An eleclromeric displacemem of electron~ from 1:IoIxb a. b. or c (see diagnam below) wou ld ~II in !he ~leasc cil c:II;on (H. R'. or COOH) and. sub.equently. lead 10 II\( van ely of ~actlons obsCl ,'Cd with pyridoxal. The: CJ.lent IQ.,.iIIdt one of these di~placemcnts pmrominatcs over othel'! titpend~ 00 !he structu~oflhe amino acid and the en\'iron_ (pH. ~ol~cnl. calaly~ts. en/) 1nC5. and sueh). When thI SItIC'dIanism applies in vho. the p),ridoxal component is hnlt(! III the en/)'mt through tile: phosphate or tile: h)droxymrtlt)l group. Metals such lIS iron and aluminum. which markedly c:uIy/_e nonen/,ymatic ttalls:aminmions in vitm. probably do 10 by protllOling fonn:llion of !he SchilT base and m:ullWllilJ planari ty of the conjugulcd system Ihrough clle:lalc nng ((I'. m:llion. which rtquill's the prt'SI:t1Ce of the pht:noIic poop This chelaled metal ion also provides an addniooai ebb..

------------------------------------------.....

heterocyclic nUl'Ogen alom (or nuro group), \hercl>y increasmg the clecuoo displacemcnts from the a<lImon atom as
!hown above. Certain hydrazine derh'ative$. when admini~cn:d therapnIlicaJly (e.g .. isoniv.id). can induce a defIciency of the
coen~yme (pyndo~ul S-phosphale) by inactivation through ~ mecturnism of hydl'1lZOl1C formation wilh the aldehyde

functiQnal group. Anodw:r hydr.QlOc dcrivuti\'c, hydl'1llarine, ... hen administered in high doses to COIltroi hypc:rttll~ioo, can nuse si milll1 8 b deficiency, conceivably through a similar

IRel.'hanism involving hydrazone fOl'lTWion.

Hypochromic ancmia~ caused by familiartype: pyrido~ine dependency respond to pyrido~inc thempy. Similarly. this vitamin has bftn useful in the t!'eatmen! of hypochromic or II"It'ploblastic antmias that are no! due to iron deficiency and do 001 mopond to uthcr hernatopoietic agents,] A review by Rose'.lO summari1.<!S studie.~ on Ihe effects 0( cermin hormorles 00 villlmin Bb Munition in humans. on the biochemical intClTelation~ip between steroid hormones IIIId pyridoxal phosphale-dcpendcnl cnzymes, and on the mle of vitumin 8~ in regulating hypothalamus- pituitary funcDOI1~. Some of these studu:s I!.a"e important clinical implica1IOIl5. TIle use of e!itrogcn-containlllg ora! con~i ves has been in\'~stigated as a fnctor leading to an abnomlality of II'yptoph:1Il metabolism. This aboormalily resembles dietary "itamln 8 6 deftciency and responds favorably to tn:atme:nt with the vitamin . For some ti lne. there h:l been clinical in\cre~t in the relatiomhip between certain hormones and vitamin 8~ fullC1ion because: abnO'1IIa l urinary e:tcretion of tryptophan metabolites was obser\'ed dunna ~gnaney and III p:Uicnls wilh hyperthyroi dism. Estrogem. and tryptophan me:lDbolism M\'C been studied bec~use: cstmg<'n adnllnistration occasionally leads to the excretion of abroormaHy large UlllOUnts of unthurenic acid. a metabolic prodoct of trypmphan. This metabolic ma/fune-

tion has been related \0 the inhibitory effect of esuugen sul(me conjugates on another pathway of tryptophan metabolism - the tnm.wnination of kynurenine from tryptophan. Consequently, lIInthurenic acid formation appean to be abi\OrmlIlIy high because: of this e~trogen effect or B6 deftClency. In vitro Studies have been conducted to detenninc the cffeet of estrogens on ltynurenioe amjnotnm.~rera.'ic, which cat alyzes the 8~-dcpendent transaminalion of kynurenine to kynurenic lICid. Some: estrogen conjugates (e.g .. estradiol disulfalC and diethylstilbestrol sulfate) interfere with this transamination. apparently by rt:versible inhibition of the aminotrnnsfernse: apoenzyme. Apparently. the estrogen su lfate cornpetC5 with pyridoxal .:I-phosphate for intel1lC(ion ..... ith the apo!'n~yme:. In contnl$t, free estradioL and ~lrone do not possess thi s inhibitory property, Some wome:n suffer from mental depn:~sion when lDking estrogen-containing oral contntcc:ptives. and this depw.sion rouLd be due 1 another malrullC1ion ill tryplophan metabo0 L ism. leading to .:I -hydrox ytryptumirte (serotonin). Some: evidence indicate!! thut the decarboxylation of.:l-hydroxytryptophan is inhibited (in vi tro) by t:W'Ogen oonjug~tC5 competing with pyridoxal phosphate for the decarboxylase apoen1.ymc:. Other endocrine systems arc interrelated. Both corticosteroids and thyroid hormones may increase the: requiremellt for pyridoxine and affect pyridoxal .:I-ph05:phate-depcndcnt metabolic processes. Moreover, there appear to be a~socia tions betl'l.'een vitami n 8 0 and anterior pituitary hormones tllal seem to involve the hypothalamus. S-hydroxytrypta mine, and dopamine, 11Ic latter 110'0 neurotrnnsmittet1 are ,ynthe.~iud by metabolic proc.... se. that require pyridolUll Sphosphate. Inten:stingly. studies nne ~hown thut vitamin B... in tum. in nue neC!l the function of Meroid hormones ,lS Pyrido~aL pIloI;phatc binds 10 lysine residues on the steroid receptors.

s-

It hill! been proposed lhal lhe Jysule residues are found at the sue 1O'hen: lhe steroid binds to the reccp:or and where the ltiOCp:or bind~ DNA,In Thus, pyrido,lal5-phosphalc deCll'a.o;cs the number of m:ept"" able to bind wilh the steroids and the number of steroid-KttptOf complc.\es binding 10 DNA, TIle o\'erall result is decrea5di e.\Pf'ession of DNA, PRODUaS Pyrido.l ine hydro-chloride, 5- hydroxy -6-melh yl-3,4- py ridi rlCdi methanol hydruchJonde, vilamin 8 6 hydrochloride , mt anlidermatitis faclor, is II white, odorless, cry~talline substance that is soluble 1:5 In Willer and I: 100 In aloohol and Insoluble in elher, It IS relath'dy Mable 10 light and air in the solid form and in add 'iOlulions al II pH no gR:atcr lhan 5, II which pH il can be lIutocla\,cd al 15 poundS:lt 12ifC for 20 10 30 minuteS, Pyrido~lIle is unSlable IOlIen il'11ldiatcd in aqueous soIulions lit p l l 6.8 or abcwc. It is ol(idiJ.cd readi Iy by hydrogen perox ide and OI:her oxidizing aSCnl~, Pyrido.linc i5 as smble in mi.lcd vitamin preparmi<)Os as ribonavin nnd nic()(inic acid, A I <;f aqucoos solution ha.~ a pH of 3. The pK. 1 values for pyridoxi nc, pyridoxal , und pyridoxnmine are 5.00. 4.22. and 3.40. respectively. lind lheir pKol values are 8.96, 8.68, and

Pyridoxine Hydrochloride, USP,

system neurohonoooe .,-.amioobutync lIICid (GA BA). (filii! glutamk lIICid decarboxylation ..... hich i5 effected by the: cocnl.ymt pyridoxal 5phosphatt. Pyridoxine hydrochloride is indICated in the trealmt:ntilld prevenllon orvitamm deficiency. It I~ al~ appro"ed forcmcurrent adminiSlnllion ",ith isonia:t.id llIld cyclosc:nnc 10 decrease thei r toxicity , COtlCUrrcnl iKIministrulion of p)'ridolinc hydrochloride and levodopa is 1101 recommended, TIlt dtcarOO.\ylnt ion of levodopato dopaminc in the penphery is increased by pyridoxine. so Itmllcss IcVoOOp.11l'achcs tbe centrol 1 1Cn."005 system. Peripheral neuropathy can occur following m@csllOli of high doses of pyridoltine, Doses of 2 g/day can pn:odta ~thesia lind alter ptXlpiiocep:ion ,1 \I SonIC studies q. gcst the dose mjuin:d may be as low as .'i(I to SOO 1JII/ day , Symptoms may IICtually incrc:lSe for 5e\'t:r.Il weeuafla dbconlinuing pyrido~illC. a phcl'lOml'nOfl called OOIlJl'IIJIJ.!

Cob _I _II 11_

Vitamin B 11. cyanocobalamin. occurs in nature Ill! a roflltlOl' that originally "'as isolaled as cyunoc"Ob:llllluin and \ ltarru~ 11 1211 (hydroxocohallUnin). In April 1948, R it"~ cs et al 1\1 <1\ isol1Ued from Clinically activc livcr fractions, minulC anlOU nts of a red crys\lIliine ~'ompound that W.lS 1I1'W lughlt effcctive in promoIing the growlh of I-tKw/x'ClIIUJ 1/JdIJ. This compound was called I'irami" H'1- II.nd III single: dolo as small as 3 1 6 ~S' it produced posilll'c ilcmalokJpati 0 activity in patients "'ith addisonian pemlcious antU E~," lIa, !knee Indicates thaI its 3C'Iivily IS comparnble IOlth 1h:M of CaSlk's utriTl!ic f;actor and that il can be stored III the hvn. Vilamin B u is found in eommen: ial fC~nlJlllon ~ cases of antibiotics, soch a~ lhost o r S'"pltJfIl)'UJ S, Q/t'I'(jCt'U,J, S. uureojucll'llJ, sewagc. nlllllrgamle. and odJ. crs, SonIC: of these fC"llCntation s furnish a commm:i& s.ource of vitamin B i l Exce lleot dietary SOlIrce~ are nan. egg~, seafood, dairy, and fermented prodllCl~, Ix no,'o ')11" tlN.!.~is of vitllmin B IZ. however. is restricted 10 mic1\lOlP" nisms, Animals depend o n inttstinal flora synthesis or, &I in hU1l1llns, consumption of products from Wlima] that 1la>"C already obtained vi tamin B ,~, The only dtclary plan! pr(MI.

8,05.

rc.~~tively.

Pymlo.line dcficicncie. hnc bc.'Cn ~Iudied by the usc of :lntivilamms soch as 4-dcso~ypyridoxaJ. As wilh the ()(her 8 \ Ilanli ns. diclal')' deficiencies an: I'1.Il' and are associated main ly ... ilh alooholism. The sy mptoms involvc the skin. ncn-ous systcm, and tf)thropoicsi,.

'''$lou.

4-Desoxypyrldo.,! Because of ioadequate diets, Kimel in fants suffer from scvere vitamin 8 6 deficiencie$ that can Icad 10 cpi lepsy-li t t t"oovulsive M'izu!\'.'i, and the convul~ions can be COfllrol1ed by trealmeot "'ith pyrido~me. I The l"UllVulsions arc bel ieved to be dill: to belo",normalavallllbihty of the centrlll IICn."OUS

R.

-CHa

Hydtoxycobalamin M&thyleobatamlll Adenosylcobalamill (Vitamin BI2 coenzyme)

R,. -OH

IICtS

COIlIDIDlng the v;r.mm are legumes. because of wlr

qmblo.o>Is with mk"roorganjsnl~. Ikcausc dietary vitamlJl Su is protei n bound, the lirst lIep in absorption is il~ I'I:lc~ISC in the ~Iomach. I(clcpsc is enhanced by gaslnc pH and plmcrcalK: protcases. llIe freed vitamin i5 bound immediately to a glycopmtein. the inlrlmic /,1"', SCCR:u:d by pancml ccll~ of the gastric nulCosa. The ' iwnin a u-intri nsic factor complex is ~ed 10 the InlaUIIC:S, II-here it bulds With rteepl~ in !be ileum. Absorpuon Ii m;unly by an :len,'c PO IXCI\J... tlleh can be salUtlUed by 1.5 10 3 ~g of, iUt/mll BIl _fuccss amountS may be absorocd
pas.~I \cly.

'n the intesti nal cetl~. the comple)!. iq broken 1100 "hamin H'l is abSOl'bc:d into the blood. wllere it bi nds 10 tnlnscooolamin II , 11 ,8-globu lin, for distribution. In the liver. the vi la min is ronlerted 10 the :.clive form (IrId Slon:d lIS such. Up .. ~ of rhe vitamin (j 10 I J Illg) iJ 51on:d in rhe Im:l". Vltamm 8 ,~ i~ ncrcted through the bile and undergoes ex!mS11"C reabsorption . In the bio<;ynlhcs.is ohhe coen7ymcs ''' dcrivro from \ '112' mm B ,~_ cobalt is reduced from a tri\'lIknt to II IllOIlOvu lcnt ilaIe btfore the organic anionic ligands are au.ached 10 the \lI1II:turc, TIle IWO types of ~"OOOm idc thin patlicip~u:. as OO('nl.Yme,~ in human metabolism arc the adcnosylcobamide, :and the n1<"1hylcobamides. The:'\C coenl'.ymes perform \'ital fUllClJons III nlCthylmalooatc_suceln:lIe isomeri/.alioon nnd in .:Ih)lation of tlOlllOCy~teitIC 10 mcthioniroe. Meth)'Jcob;tlarmn Iii Inc m:ljor form of the coenzyme In Ibr plasma, and ~.'Olyalknosyk:obalamiroe i5 the major Iortn in the Ii\'cr and Olhi.'rhSwes. The enzymc ~y~tem nlCth)llMlooyl-CoA mutase requ il\"S 5'-dcoxyadcnosylcobamiLIc:: thi~ enzyme s)'tern cDt ol)"u~ the IIlCt hylmnlonyl-CoA l ilII.formation to ~llcciny l CoA, which is the nmjor path wny Ii propiony l.coA me[Qbol i~m , Propionyl-CoA from lipid IIIIrI3bohsm must be proces".ro through thi$ pathway by socOII}I.coA to enter tiIC Krebs citric acid cycle 1 be either 0 lQII\"CTted 10 l""OlUlJ.oacetate. leading to gtUCOfleOgene.m, or O\!diud lIerobically 10 COl. With production of ATV. The: 1IICIh)'I~tlOl1 of homocysteine 10 form mcthiomne requil"Cll 1!tIh) Icobalami n lind, S clllaly.ud by a transnlCthylll~ Ihm abo requires ~-methyltel rnhydrofol ic acid lI,id reduced fAI),' \<' '" dt: rlcicncy of vit ~mm 8 '1 Icads to ancnna. Pernicious wmla i. due 10 II Lack of the intrill.~ic factor. TIle symptoms 1I\0"e y~lcms that 1!a,'C rnpidly d;"iding cell~ and the ncros ~y~tem. Herben and re ... iewed the biochemical .Ies of "itamin 8 u :md folic acid ,n hen13l0p0iesis and IIIIII:'J cellularde"elopment 1l1Cy cn'phasil.!: Ihat "'tam,n it ,: folic acid ~ csscntlal for normal growth and proliferalIOn of all hUm:ln ce lls. Vitan"n H 1 also fUIICliolls to muin1 throughoul the IICrvQ\IS sysle m. Deficiency of

caused by below-normal transform:allon of ~-lIIC1hyltclnlhy drofolic acid 10 tctrnhydrofolic lICid (TUFA) by the Budependent hoIlMXy~lCillC rnethyltrunsferuse reaction and defecti ve cellular uptoke of 5-methyl.THFA in viUllnin Hll derlCiency . Thi s 1IO<lIl1ed mcthyl-TIIFA trup hypothesis seems to rdlionali'U a mechanism for the: pathogcnesis of rnegaloblastlC IIncmia in vitamin 8 11 derlClcncy. and ;n\,es\l 8atiom conlmlle to provide cvidence that supportS this 111tionali1..lllion. Uigh dosesofvltamm B,! are not ASSOCiated wilh toxic ity. Ran: anaphylactic rellCtiom and m,ld dlllrrhca ha,'c occurred. although "itamm B 'ltheruPy has in\'ol\'ro advcrse: events thai resu It mon: from problems wi th 1'C<>oIuI ioo of the disease being treated (usually megaloblastic anemia) than from tile high doses of B ' l u..ro. For uample. after Bu therapy for nlCgaloblast ic aroemia, serious hypolullemia hal; resulted from incn"a.scd po:XJmill m mjuirernents for erythropolesis.,Jf;
PR QOUm

/)as',.

,,::,:::;:::.~'D::~~'
~

to IIlCialoblasti<: allcmia invol"i ng synthc~is, Interference with DN A lyn. ll'.'iullS in the inabilIty of cells to malure properly. arc read,ly re"er'icd by viuumn B ' I supple; the nc ....c lb'TlIII:c. howc.,"Cr. is im:vef1\,ble. It hal; pooulated that the i I frotn low

Cyanocobalamin, USP. Cyal)ocobal~ll1;n, vitllm;n H, :. is a oo"'d t-containing substance usuully produl..:d by the growth of sui table org.:misnlS or obtllined from li'cr. It occurs as dark red crystal s or an amorphoos orcry_tallinc powder. 'The ~nhydrous form is very hygroscopie:md rna)' absorb aboul 12<t wuter. One grunt is soluble in about 80 mL of water. It i~ r.olilble in alcohol but ,"~ublc III chJorofonn and in ether. Vi tamin 8 '1 IIN:S about 1.5'10 or ilS activny pt'T day when stored at room temperature in the presence of a!oOOl'bic acid: ~ilamin B tl'b ( h)'dro~ooob.'lamin ) is very unstable (completely imlCtivntl'tl in I day). This I~s ; n ac tivity is accompanied by relcase of oob:tlt and a I~s of color. The: gn"3tc:r stability uf vitamin 8 u is attributed 10 the ,"creased stnngth of the bond between cobalt arid the ben~imida7.o1e nitrosen by cyamde. Unuw~1 resonance energy is Imputed to the: c~ ball-cyanlde conlplex, g;~ing 11 pos,li'e charge 1 lhe cobalt 0 atom and. thereby. strengtlicnmg the: Co-N bond. The JlI"O'" tectivc IIClion of cenain liver ('.I:lracL~ of v"am;n B ,l'b toward ascorbic ac id lind its ~ium salt ,s. no doubt. due to the presence of copper :Iud iron, Iron salt ~ pI'IHect vitamin B ,l'b in 0.00 I 'l! oonccntnll ioo. Cllla lysis of the O!{idalive destruction of ascorbme by Iron is \\"ell kno", n. 01\ exposure 1 air. 0 liver extnll,:ts conl2ining 8 1! 1~ Il105t of the 8 ,! acti>'ity in ) months. 1l1C rIlOSI fa"Of1Ible pH for a m,xture of cyanocobalamin and ascorbic acid appears 1 bt 6to 7. NillCtnamide 0 can 5tabil ru aqllCOUS pat\"1ltcr.u solulI(lns of cyanocobalamin and folic acid al II pll of 6 to 6.5; it IS. lIov.c'cr. unstable in B ..complc;o; sol ut ion. Cyanocobalamin IS 5table in solutions of sorbitol and glycerin but IlOl in dc!{tros<: or sucrose. AqUOOlls solutions of vitamin B ' 1 are sUi blc to 3utocluving for 15 minutes at 121 "C. It is almost ~"Omplctcly matti,'uted ia 95 hour) by 0 .0 15 N sodium hyumx,de or 0.01 N hydrochloric acid. Cyanocobalamin is rtl(N slahle al pl l 4.~ 1 ~.O 0 arid IS Slable III ..... ide variely of Mllvcnu. Hydroxocobalamin, USP. Hydroxocobalnmin. cobinmnide di hydroxide. dihydrogcn pho!;l"une (c~tcr) mono(in ncr sa il). )' -eliter wi th 5,6-di nlCrhyl - I-ll-n- riborllmllOsylben7imidal.Ole, vitumi n B 'l'" is cyH nocobalumi n in which the CN group is ~placcd by pn 0 11 group, It occurs as lbrk

II has been postu lated Ihat itmn h condil ionc:d folic acid deficiency

red crysulsor a red CT)'$UIlhne powder that is sparingly soluble in water or akohollll1d practically msoluble in the usual orpnic solvents. Under the usual condil1011s. in the absence of cyanide. ions, only the hydro.o form of cobalamin is i50Ialed from naturoll SOUI'ttll. It has good depol pt'l)pf:nies but i~ less ~table than cyanocobalamm.

Cyanocobalamin Radioactive Cobalt (SlCo) Capsules, USP. Cyanocobalamin 57eu capsu les comain cyanocobal amin in .... hich some of lhe rnole<:ules contilin radioacti\'e cabal! (,leo), Each micrognarn of this cyanocobalamin prepanllion has a specific activity of not less than 0.02 MBq (0.5 JtCi). '11M: USP cautions that in mal,;ing dosage caJcula tions one shoo ld correct for r:rodiOOClive decay. '11M: rodiooc th'e halflife of n Co is 170 days. Cyanocobalamin n Co Solution, USP. Cyanocobalamin '1CO solution has the same potency, dosage. and use as described underCyanorobalamin Radioacth~ Cobalt ('7CO) Capsulcs. US P. It is a dear. colorless to pink solu tion that has a pl l I1\J1ge of 4.0 10 5.5. Cyanocobalamin Radioactive Cobalt (GCo) Capsules, USP. Cyanocoballimin ~o capsu les are the couJ1lerpan of cyanocobalami n n eo capwlcs in potency. dosage. and usc. 'I1M:y differ only in radioactive half life. ..... hich is 5.27 yeaB.

tain 1010 2O,..g of cyanocobalamin letivity per mL liver UlrJCI contains 2 .ul: of activily per mL Vitamm 8 11 with intrinsic (octor is. mlXlure .... ~po tency is uprcssed in temu of onaJ unil5 of hematopoildi<: actiVity. One unit has no ITIOI"e than 15.ug of cyal\OCoOalllllllfl lIC1ivity. '11M: intrinsic factor is obtained from dried hos SIOI'JIo leh. pylorus. or- duodenum. One unit contains not II'IIR m. 300 mg of dried product.

au

Folic Add
In lhe early 1940s. R. J . Williams et al. l)9. lOll used 1M lena foUr: acid in referring 10 a vitamin occurring in Ical'n '" folia.ge of spinach. from the Latin for lcaf (folium), Pm1ou.~ly. it was calted \'ilOmill M and 1';lOnr;1I 80. Since folic acid has been found in .... hey. mushrooms. 1I\'.)UIl, bone m:uTO ...... SO)'beans. and fish meal. all of .. hich an: 0 cdlc nt dietary sources, n.c Sll'IX:ture (sec dragram) hubmt proved by ~ynt hesis in many laborntones (e.g .. see Wilier
Ct al .I~ I . I~l).

*'

OH

OH

Cyanocobalamin Radioactive Cobalt (GCo) Solution, U5P. Cyanocobahll111n 110(:0 ldution hili the same p0tency. dQsage. and usc as c;yanocob.alamin 110(:0 capsules. II is a dear. colorless tu pink solution ..... ith a pH runge of 4.0 to 5.5. These four prepannion\ must be labeled "Caution - Ra dioacti\'c Matcrial" and "00 not usc tlfter 6 months frotl! dare of ~tandardi1.alion , ,. Cobalamin Con,ent~te. USP. Cobalamin ~n Ime, dcrh~ from cultures of StrtPfomyr:~S spp. or- of other oobalaminproducing microorgani~ms. conwns 500 ~ of cobalamin per gram of concemrate, A cyanocobahlmin-7jnc \.aIlnnte complell Clll1 be used as a repll!litory form for- the slow release of cyanocobalamin when it is administered by mjection. Commercial prodUCIS contaming !i\'CfUITaCt for onl and parenteral use arc a\'ailable. Lher utracl is assayed 10 con

Folic add is ptcridinc derivative (rings A and B comIIlute the pteridine heterocyclic system ) synthesi7.ed b) t.v. ria from GTP. paminobenzoic acid. IlI1d gJutilmic Kid. N COfdingly. the structure of folic acid i\ oompo6ed of dim moieties: the pteridine moiety derived from GTP. !be paminobcnloic acid moiety. and the glutamic acid (Antibacterial SUlfunamidcs [see Chapter 8J p aminobcnroic ~cid Bfld. thereby. imerfere folic acid liymhesis.) Humans cannot synthe ii( add. In lhe human. dictary folic acid muSt call y to TI-I FA to uen its vital bIOChemical actions. reaction. which ~s through the inleiilJedrBte . folic acid. is eatalyud by a reductase. system has been implicated as \ teps- folic acid reduction and ',_,,.;, ;~ .~,,;;,, '11M: coc:m:yme T HFA is convened '.' .. mulation of the N IO andlor N-5 nitrogen.

I
H ...

--"0
FOlic Acid TetrahydroloUc Aeld

o '"

Chaplt r l6i Vi""";'" WId Rt/(Jlrd C~

897

'fbe!ie coenzymes derived from folic acid pan icip:ue in

many impoJUlnt Il'actions.. including COlwersioo ofhomocys. 11':."", to mettllonine. synthesis of glyd"", from 5I':Tine. purine synthes.s (C-2 1100 C-8). and h.... idi"", IDCUlOOhsm.

""'yN , N_

I
H

i\ "
/ N

H
N
OH

OH

fi

iIII':. This deleteriOU.'l effect may be largely overoome by in. clusion of approllimately 7O'k wgar in the millture. Folic acKl in foods is deslroyed more readily by cooking Ihan an: the other waier-sol uble vitamins. ~ IOS$C$ range from 46~ in lulJibut 10 9S'lo in pork chops and from 69% in cauliflower to 97'1> in carrotS. Folic acid occurs in ,he Iliet as pteroylpolyglutllmates thaI mUSI be hydroly1.cd to the monoglutamates before absorption. The hydrolysis is cal ul ylCll by pteroyly-g lutumy l carboxy-peptidase. fouoo in the membrane of the intestinal mu cosa. The monoglutrunate5 an: absorbed lICIively io the jejuoum lind upper duodenum . This absorptioo is pll seMitive and is facilitated by the slightly acidic coodi,iom fouod in these regiOO5. 1lIC vitamin is transported as mooogluta males bound to album.n.

N5

,ysMettlet~ acid NS - CliO ,ys.Formyltetratytdrololic acid (Iolinic acid) Nl0 -CliO N1 Q. Formyltetrahydrofolic acid W'O _CH_ N'S-lQ.Metheny!letrahydrololic acid N!o-I O -CK,r- N'S- l Q. Methylenetetrahydrofolic acid N5 -CH: ~ r/-i.Formiminotetrahydrololic acid N5 -CH,z-OH f-IS. HydroxyIetrahydrofolic acid

- %

""'Y'l" " - "~ H"'y,N

i)nli1esis rti.juires N' .N, o-methyle ne-T HFA w; tnc methylat IIlJ C()C"nqnll': Il'spomible for cooverting uriuylk acid to th)' mid}lic acid. Interestingly, SOlIII': folic acid anl:tZon iS!s neful in cancer chelllOlherapy (e.g .. metho!n-xa!e I!;ee Chapter 12J) Imerfell'- with DNA synt~is by inhibiling this ftthyllilioo step. "l There is a fuooanll':nlal rdationship between folic add lI'ICIabolism IllMI vitamin Bu. llII': reduclion of mcthyk-III':mFA 10 S-tnI':Ihyl-THFA is bscntially irreversible: heoce , thtre is only one pathway for the I'CBCflCnIlioo ofTIiFA fltH11 SmclhylTI IFA. THFA is regeneT1ltcd by lhe B l1 -dependent IIlClhylgroup Imnsfer from S-melhyl-TIWA \0 homocyste1M. This bi ochemical interre lationship has bceo implicated IIIthc c,iol08Y 0( megaloblastic anemia (see com:sponding di'ICus.... on ulldcr vitamin B I1 1 )6).

The most critical' 'onc-carbon" transfer involved in DNA

n I Pteroylglutamic acid o 6. Pteroylpolyglutamic acid Although the mucosa in these regions pO..'SM dlhydrofolate reductue. moS! rrouclioo aod methylatioll occur In the liver. TI-IF A .s diSlributaJ 10 aJl lissues. where it is siored as polyglutamatl':5. The N'.mcthyl derivati,'e is the roam transpor1 asid storage fonn in the body. 1lIC body 51~S 5 to 10 mg. approxinmtcly 5O'l> in the liver. 1lIC major elimination pathway for the vilamin is bil iary c~cl'Clioo :t5 the N'-methyl derivlltive. Elltensive reabsorptioo occu~. Only lrac:e amounts ure found in the urine. Large doses thut exceed the lUbular reabSOrpiion limil . however, resul! in subs1Dntial arnOllnls io the urine. As with vilamin 8 1:. folic acid defICiencies m.ainly result from malabsol'ptioo or alooholism. No neurological abnormalit>es are aSJocialed with folic acid defICiency. llII': resulling mcgalob'lLStic anemia is indistinguishable from that uused by vit3min Hu because both vitamins are in\'olved in the c rilical biochemical step. Folic acid can CUllect the anemia caused by vitamin 8 11 deficiency. but it has- no effecl 00 the neurological damage. Thus, oo ly small amounts Ire foond in over-the-counler preparatioos. Folic acid !MIministcred to healthy !MIu Its in a daily do!;e of IS mg for I month rt'Sul1ed in gastrointeslinal disturbances (inc luding anOl"ell ia, nausea and pain) aod ccntr:ll nervou s syste m effe<:IS (inc luding sleep d isturbances. vivid dreams. malaise. irrilability and increased I':llcitabi lily),I .. leucovorin C.,clum, USP. Leocovorin calcium. ,\14. I I (2-amino-'-formyll.4.S.6. 7.8-hexahydr0-4-0ll0-6-pterid inyt)mclhyl laminolbenl.oyt '-L-glutamic acid, calcium $lilt. cakium S-formyl-S.6.7.8-tttrahydrofolate. calcium fol inatc. QC!CUTll 11$ I yellowish-whilc or yellow, odorless. microcry5wlilll': powder that .s insolu ble in alcohol asid \'ery lioIuble in Wiler.

PRooum
folic Add, USP. Folic acid. N-III(2-amJn0-4-hydrollY6--p\eodinyl}methyllaminolben7.oyllglutamic acid. pu:roylJlut.am.ic acid (FoIlICine. Folvile). occurs as a yellow or ydIo\o,',$h-onmge powder that b only slightly soluble in waler II m"IOO nil ). II i~ insoluble io tnc rommoo organ ic sol 1"t1llS. The sodium salt is soluble ( I :66) in water. Aqueous lOIutions of folic lICid or ilS sodium salt are stltb1c to ollygen of the air. even on prolong~'d sta nd ing. These ItOlutions Clln be 51crililell by autoclaving m II pressure of IS pounds in the usual maJllIer. Foli c add in the dry $Il1te and in very dilute solutiolU is decomposell readily by sunlight or UV qht. Ahhough folic acid is unstable in acid solutions. par1icvIIrIy bc:1ow a pH Qf 6, the pn-sc:nce of hver tlllractS has I Ilabililing effect I t Io.....er p H levels than an: otherwi~ possible. lroo sailS do not materially affect the Mlbi lily o f folic arid SOluIIOOS. 1lII': water-soluble v ilamlns that h.we a deleImOUS effecl on folic lICid are (i n descending order of effecbl'encss) as follows: riboflavin. th,amine hydnxhlolide . ~IC acid. nilldA1l1nide. pantothenic ac id. and pyridox-

4. 1. and the C-2 hydroxyl ha~ u pK. of 11.6. The monobasic Siium salt i~ the lISIJul salt form (q~ .. Sotbunt A.w:ubaie. USP).

Ascorbic AcId

TIlls prod1.lct is used in chemotherapy ooncum:ntly with

dihydrofolatc redllCt8SC Inhibitors to pJt:,tnl da.rnage to I\QI"mill cc ll~. It is IlOl indic~ted for use in folle acid ddicicncics. AK_bkAdd
The historical s'gnlficance of vitami n C .... as summaril.ed eloquently by the eminent medicinal chemist and ph.:lnnociSl Profcssor Ole Gisvold. and the follo .... ing direct quotation from the 7th edition of this textbook is an apptoprime inlro-duclion to the significancc of asrorbic acid in ITI/..'dicinal cht:misu ), and basic biochemistry:
The d~~ S<:\I<VY. who(h now IS ~no.n its a COfld,hoo due 1 0 a defodency of ast:orboc itOd In the doet.. has consoderable Iustonc:iII ~ 'O!> for III the war bet"tE01 Sweden .md RIJSW (most h~eIy lhe march of Charles X1t mlO !he Ukraone in the ........ ler of t 708- 1709) alrOO'!iI ,H 0/ the sokf:.s of !he S"etlosh army ~ ncapKltilted by ~ But further plogress of the ~ was slOWit<l by lea plepared from plnC l1eedles 11M! IrOQUOIS Indians cored Mcques CartI(O"'s men on !hi' -'teo" of 15]5-1 536 on Quebec by 9Mng them a lea bf'!lo'Ied from an e'o'C<greeo lree Many of Ch<lmpl.l:ns men died of scurvy wken they wmte<ed r.ear the _ ~ in 1608-1609 0unI"0g the long ~ of ~ , ngrad. ""~ of Vltam,n C made ,tseIf p;tItKUlarly Ielt, and a deroCllon made Irom pone needles pI;rJed an important role In the prt<fnllon of scurvy. It 15 some"tt.al common k~ thaI sa,1orl. 00 long YQY~ at wa _c sut,!CI to the raY~ of s.a.or.y The 811IM used supploe of Iimts to prt'o'tI'lt thIS.

_,,,*,.

.00 the !oil ..s often wefC refEm'd to as "."tlS." fioIst and froloch. ' .. in 1907. f,rst ~traled that SC\If'o'Y could be ploduced 11\ gulnN pogs A comparable condil>Oll camot be ploduced WI rats Although Wauogtl and K,ng,47-'n (19]2) isolated aystail'nt' VIIItit1 C Irom!croon JUOC:c and showed It 1 be the 0 MltoscorbutJc factor of Iemoo JUlCc. Szent.G)'Or9yI'U had lsolated the same !.Ubs\(lnu from peppef11t1 t918. m connectior1 With Ills booIoo;JOC.JI OlIId3tlOll-redvctlon lIudoes At the tome. he faded 10 u:"'O!JIWlII!:IS Vltamtn plope<IMIS.oo r~ 11 as a hnUfOlllC ac>d bec.ause some of ,ts pr~MIS resembled ~ of wgiII adds. H,rst et.JI '$00 SU9gested thaI ~ COI'It formula !ohouId be OI'IC of a Wl"MIS of powbIe lautornenc ISOIN'fS and offered b.:tsoc proof that the formw now generally accepted Is COnK! The first srnthesrs of la:;corboc aod (VltiIIrWI C) _ announced iIImost Slmul~ by fWwonh et at.'" and Rttctlsl(lO'M on 1933. Sincc INt tome. iSCOfb< aod has been syfIlhe\.lze<l ,n a nUll**' of different ways

Asrorbic ac id can be synlhcsiLCd by nearly aJl liI'ing (1". ganisnts. pl ants, and animals: but primates. Gui nea pigs. b'lh, and some other species CUno1(1I prOO\)('"e this vilamin. Thr: consensus is that orgllRi:sms lhat cannot synthesize ascorllit" acid lack the livcr microsomal cnzyme l.-Gulooolaclooe~, dasc, which cutafyt.c;ol lhe u:nninal stcp of the biO!Oynlhttio: process. SaIO und Utknrriend"J SUllimarized sciidie! oflbe biosynthesis of lISOOrbic acid in manlOmls lind the bioctv:mi u land l!:eOClH:: basis for the illCap;ohihty o f o;omc specIeS tg synlhcsile the V itamin. Because humans are olle of the b animal species tMt canllOl syn thcsil.c pscorbic acid. Ihe VIanun has 1 be Ivailable 115 a dietary co.-npollcnl. 0 A"",lf'hic acid performs Important nlembolic rUnctlOllS.1I evidenced by tile scvere manife$lation~ of ilS dclicocllCY ID human~ This vitamin is ;n'ol,oo In metabolic b)drm.)" l ion~ in numerous Important metabolic ptQ(:esSC!i (e.g.. tilt ~ynthcsis of sleroids and of neurotr.uosrniueOi and in coll~ lind drull metabolism). AscorbIC acid has also bn ,mplicated as imponanl in other cntical OXld:ll ion-n:duchOl1 flIlI' ~\oelI in human metabolism. 1 Although p.'\Corbic acid is an effcc1l\'c reducing agetltlnl antioxidant. the biochemicul functlOlls of thi~ \"iUlllim art IlOl ":el1 UIKkNood. It is eontro\"crslulto t'Ol1sldcr ~ ucid an Ilnti ~i ....' l agent. but some scientists lIrJIIC' tha a~'OI"bic lICiti I~ an effective cure or pn,wentut;\"1! of "rom0"1011 COIds:"-"'. I'" One sUldy provides some: evidcnct IhIt IIsrortll C acitl appcalll 10 help the l'W"gumsm I"C'CO\"CT no. viral infeclioll s throogh an indirect mcchanism on the body'~ immune system. IOO ASCOfbic acid h.:os also t'eCC1,ed aI1rlIlioI ns a possible pnticanccr agent. In cell culture Sluo.f'o. ascorbiC acid, both alone and in t'OlllbinaliOIl \lith coppa ions.;~ selecti"ely toxic 1 melunoma cancer cells.'' 0
PRODUCT'S

Ascorbic Ad d, USP. ".;corbie acid, ,,tamin C. Lasc<lI"bic lICK! (CeVillllllK: Acid. Cebione). occurs us \I hlte Of
sl ightl y yellow crySlal~ or poII'tkr. II is odorIc3s .1Id. 01\ exposure 1 light. gmdu ully durl.ens. One gl1UII diSiOlvn m 0 aboot 3 mL of waler and in aboot 30 mL of alcohol. A I' aqueou~ solution h:os a pH of 2. 7. Aqueous solutions an: .,. vel)' stablc. 11te ascorbic acid in slICh pll'parations unJa-Ilocs oxidation. p;onicuilltly under aeroble conditiOlL'l. lion to dchydroa-;corbic ac,d I~ folloll'oo by hydrol)toc dell' age of the loclOflC'. l10c effect of pH on the IICfObic degradatioo of lISCorbic acid aqueous solulions has beat ~tud;ed hy I'lIrious ;n'eMigators. Rogt:1"S and YOCCMll('tU' found IMt the degradation rate <bows a ma~imum ~. pH 4 and a minimum ntar pH 5.6. Funhcr. if a prcpafllllOll II ascorbic add .... l1h un initinl pit between 5 and 5.6 tlcvr~

ax...

This vilamin i~ now bcllerknown a.~ lIM:orbie add bccuusc of liS acidIC charneler und its dfe<:li\"t'I~s in the trcutmCnt MU ~~enl ion of lI(:u"-q. The acidic cMrncter is due 10 the IwocrtOlic hydfU~yls: the C-3 hydro~yl has u pI(. "lIlue of

----------------------------......
..:idllr on ~I(ll1lgr. the rule of degradalioo will IllCl\'ase as !be pH decrta"CS; hence .., mitial pH inlhe range of S.6 10 615 " ..commended.

o
OH

Sodium Ascorbale

Dehydro8!lcorbic Add

2.3-0lkelo-l.gu~Acid

I)ietary sources of lISC()I'bie acid iocludc ciu\Js fruiTS. tom~ and potaloe~. Allhoullh lhe sources 0{ some commm:ml products are rose hips and citrus f!\lilli. most ascOfbic acid i\ prt'parcd s)'mheucally. A<;OOri,ic a.cld I~ readIly absorbed by an !!Clive process.
Large dose.s can $a lurute this system. limiting the amount) absorbed. Once absori:lcd. il is distributed to allliS!i~ . The ~Ltamln i5 mClabohl.oo to ()~I, lic acid before e.,crclioo. Asrorbic 3('id-2-sulfalc is also a melabolite (wild in tho" llrilll'. Large doses result In the c~crelion of subs,urniaJ lIIlOUn\ll of uochanged ascorb ic acid. The resull1lm KidilicalIOIIolthe urine: is the basis for mOM ofllle ,-i"'m;n'5 a(l,'crse

A<oeorilyl palmltatc. ascorilic add palmitate (ester). is tIM! C-6 palmitic acid e.-.ler of a..;corbic rocid. II oceu~ lIS a while 10 yello .... i.5h-", hite po'o"der lhal is v('1)' slightl y soluble in water and in vegetable oils. h i~ freely soluble In alcohol. A'iC(lrbk acid has antioxidant properties and i~. very effectlle synergist for tlte phenolic antio~idant~ such :u propylgallatc. hydroquinone, catccbol , and nordlhydroguaiarelic acid, .... hen they are used 10 inh Ibit o~idalive roncidity in fats, oils, and OIlter lipid~. wng-chaln. f:llly acid estCfl> of ascorbic acid are more soluble and more wllable for use .... lIh liPIds than is a'>COrtlic lICld.
AscorlJyl Palmi tate. NF.

Biotin
Biotin Wltll discovered. isolated. and identified structurally in lhe 1930s, Prc~iously. il wa~ kno.... n also ali "Itamin H. Since lhen. II hDS been llIXed that small amounlS of biOlin can be delected In al~t Pit higher animals. 'The D isomer POS'\C:'SSCS all of the acll~ lty. 111c highest cooccntratioos h 31'C been found in liver. kiUney. eggs. Hnd yea.,t. as a WHlcr insoluble complex. Cooslderable qU3lllitic:s are found both fn-e and in lhe OOfl1plex form in v('gctables, grJins, and nUIS. Alfalfa. string beans. spin.xh. ~nd gnbs are fair SOUfl."CS of tlus vitamm.
H

tffoClS.
HIgh do!; of vl1amin C (ascorbic acid) can lead to renal. bonoe, henuilological and gastrointestinal cffectJ. ll Renal calculi due to u.talate or umte resu II from enhanced renal C\CI\'IlOII of these eompounds In the presc!1lI,.'e of high dose<; of _iwmin C. lnl"fl:uscd rdca\.C of calcium and phosphorus from bone h:we bttn ~ed. liematologieal effcclS inrluOr u"!Creased absorplion of noollemc Iron " 'i thout sign ili -

in tOllil body itOll stOl\"ll, Diarrhea. lil;ely reatJung from an osmQIic effect. has ba:n reponed following largedoscs. nnd ascorbic acid tablets Ihat lodge in the: cWpItagus ean c:luse 10C'.I1 CfO!,lOII. FinnUy. a.<iOOfbic acid has ba:n dlQlln 10 interfere \\-lIh;1 number of labor,ltOl)' tests because of ilS ability 10 OCt a, a reducing agent and Interfere with colorllllcuic redoA assays. 1lJe ~ilnlllln is indicated fIJI' Ihe lreatlllcnt nnd prevcntion of:l5COrbic acid defICiency. Ahhoogh scurvy CUTS infrequently. II IS ~n in the elderly. infants. jllcoOol ic~. and drug lISen. A>oorbic ac-id (btH IlIX the !!Odium "1111) frequenlly is adnllm~l~ 1I'lth mctllenaminc 10 improve IIIe effccth'cncss of this umibacteria l agent. Bccau'iC ascorbic acid increase$ troll cl1elatioo by deferoAamll'le. il is med in the tn-annent III chlQIIIC Iron toxicity. It is also a useful adjunct in lhe Imtmc:m of memcnJOllloolncmia.
ASl.wbie acid inJCClion is. stcrile 'iOluuoo of sodium II!iCOrbate Ihal has a pH of 5.5 In 7.0. It is Jl<"Cp;lred from ascorbie acid with lilt aid of oodium hyllro~iIk, 'iOdium cwnon:ue. or 'iOdium bicarbonIt lIIay be USI..'\l fOf' intravenous injt-ction: ll'iCOrbic a.::id is too rocidic for thIS purpo:oe.
AxorlNc Acid InjectJon. USP.

taIIl i~ase~

Jl.

BIotin

.e

Microorganisms synthesu.e bioton fmm the faUy xld oleic acid. 1lJC bio-,ynllM!lic pnx:ess in voh'cs nuolC:rous comple~ ~actions that renwn to be belter undcNood. The 1ina.1 reaclion ;; ICP rrquire!l fomlf.tion of Ihe ~ulfllr heterocycle. but the _rce of the sulfur i~ not yet known. Although this vitamin i, I;noll n 10 perform essential meta_ bol ic fllnctions in Iix- human, the mllllm~1 nutritional reqOlretllt:nt Ita!; not het::n established bc:cauo;e n ha~ ba:n dimcull 10 quanufy the amOllnt~ of the villlJmn mndc available by intestinal microorganisms. Nevcnhdess. delicleocy SlllteS may dc"elop us II result of prolonged reeding of large quamities of ,...IW cgg white. R~w egg lI'bite' contains aviUin. II proIcin that complexes biol:in and minimi7.t"S tiS ab5orpt:ion from the ga,lrointestin:lllmct, The symp!oms Qf biOlin delicit'IlCY include di.'ml:llitis. hypcre'twill. and glo$.oiilis. Biotin pcrfonn~ ~llal n"!Ctabolic runclions in ImportUllt carboxylution processe.~ in lhe rorm Qf carbo~ybiot.i n . II hirh is in combin:uion with a carlJoAylase, as Itpoacnted below.
Hlolln-enqme + HCOJ
.-""-

r'

Sodium Ascorbate. USP. Sodium a...;oorbate IS a "'hite crystalline powder Ihat i~ 'iOlub le I : 1.3 in waler lind Inwillbic III alcohol.

CO:! - btot,n- C1I/)'nle + ADF' + PI

TIle ()~ygen for AT!> cleavage is deril'ed from bicarbonate and appcafll 1/1 the Pi.

Jl.

Inosi tol IS OIl(' of mne diffc~nt cis mills ;<;()I1J('r.: orhcuhydro:c.)c)'c1ohcAane and is us.ually ~~slguro the follov.I'" configul'llt ion:

s.A./'./' Et"fI'OV o CO:rBlotln Enzyme

" uritied prcpamtiOlls (If
~el)'I -CoA curbo~)'lasc syn lhc.~is

OH OH Inositol
InO'I,ol ha, bo.'Cn found in mosl pl:un aud IIrllmaJ h'loUh. II h:t.~ been i.;oll,tOO from ce~al g ..~ins. other planl part!. cgg~. blood. nllll;. li'cr. bmin. lldllCY. hean mu<;cle. IItd other .'.OI,lrttJ;. TIle CQf1CCntralion of 100-.1101 m Ic:r.,es mI[~ II maJlimum ~hortly before,he fruit ripc:n~. Good 'oOU1ttS of thi~ faclor are fruilS. especially citru\ frulIS. IM and l'I:n:.a! gnun$. irlO';itol QCCU,"", rrc:c: and combined In n;r,tu~ In pLaDb. it i, present chlcfly as the "'elllllO",n ph)tic acid. "'hi~b I' ;OO'> iIOI he. p/losph:l1c. 11 is al<,() present in the: ~ph:rtidc u fmellon of soJbcan II~ II glyroside. In antmal~. mu.:h of II occur.: fl\.' e.' Il}()Sitol III thc fonn of phOSpilOtnO\>IIItk\ IS alnmst as "' idely distributed as in,)'\ilol. and S(1IlJ(' of thew fom)~ ure murc! acti"e metabolically. PtHJ!lplmtldyJtuoslioi (tnonophosphoinosi lidc) is tl>c 111U" Widely di~' ribuled of the: int"1I 1dc~. and lhe ,-,hic:f fatty acid re.\ldue I~ ~teanc actd. Pho~pholllO!t.itido l!C,,c as 'to .... ge forms for 'I:COrKl:try nlC,sengCf'\ . P'I10.. pholllosilide, cornpoO/ll (HlIy a nunor frz tion (2-8~) of the lipids in ccll membranes. ~t they can ~ com ened to "I le:bl three inl ..~llular mcs..-.engcr moluk-<. umchidonic add. IlI(,iloi IA.S-trisphosphate ( IP , I. and Ildiacylglyceml (DAG). The funetioru: of arachidonic kill deri, ali 1t"S are discussed III Chaplcr 24 . II' I releases mtfllttl1lJlar calcium. and DAG IS an c\scnnal cofuctor In litt lICIl'-" lion of protein kina.o;e C. IM birlding of many different hormones. ncurotrnmmlt tel"<. lind growlh fuctor.; ttl the cell surface reluh~ in acu* tioo of till: 1 yp/losphoinosilide receptor ~ystc m . 1111> 8inwflj! 101 10 Ihe ~pcd lic llX't'j)l or a.:.:tivaIC. lhe elrt)'me phospholip.:t.~ C ihrough 1he imennediacy of a G pmlcln. PhO'phoitp:t'C C con, en ~ phO'\phaltdy1iflO"ilOI4.S-bl~ph<1,phalc (1'11':) inw II', and DAG. IPJ relc:a!iC!ii cakium Ion. '" hleh In tum affrru many cellular responses in the: target cells. IP J I~ al\,() colwenoo to inositol I J.4.S-tetmki~ (W.). 11'. al\O aclS a.~ an IIlt .. ~lIular nll:~<.e:"gcr. rtsulllaat III an tnflu~ of ~xl~lJ ullll" calcium. II'. is COO\Med It:I 11',0.3.4). "hich IS dephosphorylalCd ~tCP""lse 10 'Il0l>1''' lA-diphosphate. Inositol Iphosphate. then InositOl. Tbr 111O<itol IS then incOfporutcd Into DAG to form phosphatKl)l i~itol (1 ). 1'1 il setjllCntially phosphoryl~tcd to form plio!'1 phUl idylillOSil<)14-phosph~tc (l'II' )ano I'I Pl . 11lt~ DAG relca~d has M:~el"dl ~.~;ble fates. It c~n bt convened to PI. DS mcntioned. or il can be hydroly/.c:d furtlttl 10 ~Icu-.e the W1lChidonic acid oomponcIII. DAG in ~onJunc lion with calcium ion sl i mulatc~ prOIeln kma>e C By ~ phorylating protems. klnase~ regulale IlHUlY l'Cllular actin lies. c)'de IS complcted b) the phosphor)"lauonofDAG 10 p/loJ<ipliatidie ac>d. ",hie" in tum is conl'cnod to PI Tbr complc:te ~ystem R:maHl!> to be fully undeNood. Cyclic pipsphoinositol deri .. ati, t"S appear al<o to be secondary ~ gCN. 111051101 is a growlh factor for II "'Ide: I'lU'lCIy n(IIu_ cell Itnc~ III II~~UC: cu huR:. It is consideR:<! a ch.:nllClem\K

comuin

bioti n (1 mole of biori n per )SO,ooo g of prolein renzyme D.

It cmalyres the first step in pulmitate
CU,COSCoA

as follo",s:

Hoo, + A11'

~.

OOCCIl,COSCoA + "DP + '"

B'OI;n also appears to be ~'IOCialed ,ntunald), in carboxylauOfl by P.methylerotonyl-CoA carboxylUSC'. propiOllyl CoA c;ubollylasc:. pyruvate carboxylase. and methyl malon) iOllUlacetic transcarboxylllSC. BIOI ;n is also joined in an amide linkage to the c-amino

JfOUP of n Iysil'le rt~idue of carbmny1 phosphate synthetase (CI'S ) 10 form biotin- CPS. "'hleh p.lrticipalcs with two
ATl's, HCOJ ,and glutamine in Ihe syn thesis of carbamyl plio!.ph:,l!c. This takes place stcl)wi-.c as follows:
1 RiOl'" CPS + ,0.11' + llCO, - carbol'lic ~c mnhydnde blOlin-CPS (CPA biotin - CPS) + ADP 2. CPA btot,n-CPS - OOC- btoIm-CI'S + Pi J. OOC- bioon-CPS + 'lu .... m"''' _ II ,NOC_blOun---cPS + ATl' - biOl,n-CPS + urblom)'1 phospft..lC + ADP

Carbamyl phosphate can participate m ammo add ntetabohsm and some ntIClo;:ic acid synl~ Biolln is absorbed ~adily from the glllitrointcstinal traci. The body appe:m unable to bn:al; the fusc:d IIllidazolidme and tetrahydrothiophene ring sy~tem_ Biotin appe~ in the urine. predominant ly!l.~ the uJlCh~ulged molecule . Only ~maJi amou nts of lhe mctabolile~ biotin ~lIl fox ide nnd bisoorbiotin nppear in the urine.

n..e

MISCELLANEOUS CONSIDERATIONS
Some dietary componentJ; arc dirrlCUlt to ch.aructcril.e as es$Cnual nUlnuonal fac~ in human ITlCtabol ism bc:eau.se lhe: orxanism C;lJl produce tbtse rompound~ from otl'ltr dietary componenls. (Consider Vltamm D and nicotinic acid. which a~ discussed above.) Vitamin D and nicotinic ocid. Ilow. evcr. gcnemJly are conside~d among the cla.'iSic viwmins. Moroo~er. thcre is 00 clear consensus 011 the nccessity for inositol. clloline. :md wuminOben7.oic acid. Ne~erthcll\~. such dietary compo!lCnts do perform imponant mctubol ic funcliuru;; hence. a brief charactcril.ption of thel.c follows. Inosi tol. Inosi tol. 1.2.3.5-'mll.l-4.6-cyclollcxancbcxol. ;-mOl>ilol. meso-inosi tol (lPI)'()o ioositol. ITIQIlse antiaJopccia factor). is prepared from nalUral sourttS such as com steep hqUOl"li IUld is available in limited commercial qUlllltities. It is a ",hite crystalline po"'lder thai t.S soluble In water 1:6 and in dilute akohol. It is slightly soluble 111 llioohol. the usual organic solvenlS. and fixed oi ls. It I~ stable under normal storage conditions.

n..e

~.
o
'0

"" ",--,:""",::,!,.,,,"" .
Inositol Trlsph05phal8

..-/

"",,":"" ,,~

''

Phosphalidyllnosilol Plf\

~ t..d

~.
OIacylglyceroi DAG

romponcnt of seminal nuid. and the oontem is an indc:\ of the <.ecretory activ ,ty of the S('minal vcsk1e5. EVJ(Jc:~ IS w:cum ulatlng tNt inosi tol will reduce elcuted blood cholesterol Ic,el,. llus In tum may pre'ent or mitigate cholesterol depositions in the intima of blood vcssel~ In humans and unimal- artd. lhereforc. be of value in athrrosclcrosis. I!lOSitol has also been con~ idercd a lipotropic agent. BecDuse humnns can ~ynthc~i~c inosi tul. Ihe I ..:ed for l 1I!lII a nutritiOilal reqUlreinen t has not hccn proved.
An adequate diet should provide the methiOnine neccss:uy for normal metabolism in the human. \lethJonlne is considered an cssenhal amlllo add In human~. It I~ the precursor '" the blllllynthcsis of 5-adeoos.ylmcthJOninc . ~hich is an important methylaung coenzyme involved In a variety o f methylmions (e.g .. N-methy latiotl of roorcpi ncphrine to form epinephrine and O-methyl;uion of cotc cholamu~s catalyzed by clltcchl)l-O-mcthyltrunsferJ. es). Adcnosylrnethionine alo;o part icipates in the nlCthylauOII of (Iho.<;phatldylcdllloolami nc to fonn phosphatidylcholine, but this pathll<"y is not efficient enough to provide all of the dIohnc: required by higher animals; he~. adequatc dielllr)' .'lUlabtiny of choline is necessary.l
Methlorti ne. USP.

1lIc therapeutic uses of choliTM: depcnd on its physiological fullCIions. Because il is involved In !he formation of plasma phospholipids. it is used as a lipotropic agent 1 alle0 viate fauy infil tration of the li ver, ciTTho!.i5. It has been ustd-, in large ~. In certain anlnll I1Cf'\'OUS system disonkni (e.g., tardive dyskinesia. presenile dcmcmia) OC"(;Iuse it is II ",...:cu.-or of acetylcholine. Choline also serves liS a fIlC'lhyl do""r in .' i01l1e n:actions aflcr it is con verted 10 betaine.

p AminoMnzo/c Add, USP. p-Aminoben7.(1ic acid (PA BA) has been rtlC'nliooed as a bt05ynlhe:hc component of folic add In bacteria. but higher m..mmahan orgam'ims canoot synlhesilJ' folic add frOoII1 ils precurson. Ne,'C'ftheless, PABA appears to pcrform cenain metabolic fullClions iJl some animals. In the catty 19S(k, PABA was "potted 1 0 be an e..~scntial factor in the I1(JI'm.aI growth and life of the chick..

~:
p-Aminobenlole Acid Since these original dc,'clopmems in mis r~ld. "arious claims l67 ha ve been made for the chromotrichial value of PABA in rats. Ink~. chicks. minkli, and humuns. The problem of nutrit iona l achromotrichia is a CQm ]'lle~ ooe thaI moy in " olve several vilamin or vitamin - li~c factors WId is comp li cated by the syn lhesis and absorption from the in testitlal tract of several factors produced by baeteri . PABA is a wllile. crysullinc: S UbsUlIICC mal occurs widely in the plant and ammal kingdoms. It occur; both free and combined'" and has been isolated I... from yeast_ of .... hieh it is a naturol const, tllt'nt. It is soluble I: 170 in waler and I: 8 in alcollol and freely soluble in alkal i. PABA is thought 10 playa role in melanin format ion and to innuence or c Ut~IY1.c tyrosine oc1ivity. 171) (t inhibits ox ida tive deS/ruclion of epinc:phrinc: and stilbestrol. coomcraclS the grayi ng of fur attributabl e to hydroqu inonc In ClI1i and mice_ ex hibits IIl1tJsulfanilamide actiVity, lind eoumeracts the toxic effects of cartxu-sone and ocher penta valent phtnylarson:ltes. ,71 When given either parentemlly or in the diet to expcrimen \.:II unimal~. PABA protecl1i thoem ugui nst otherwise fata l 111fect ion s of epidemic or murine typhus. Roc ky Moonmin spotted fever. and Isutsuga mushi disea se. 172 1llcse diseases have been trl:ated cl inically wim mOSt en.cOOlllging results

..,
Methionine
Choline.

OH

Choline is a component of many blOnlCmbnInc!i and plasma phosphoitpid\. Dietary soun= iocludc tU~. fi sh. Ii,tr, mll~_ IIJ1d vegetOibles. "These soon:c:~ provide dIoline primarily as the pltOeophoitpid lecimi n. Lccit hm is bydrolyzed to g lyccropho~pllorykhol ine by the intesti nal murosa hcfore absorption. The liver libcralCS cho linc. Cliolille can be biosyn thc$i7-'ld by humans: consequen tl y. it canIIO! be considered a true "'tannn. B i05ynthesi~ Invo!\'cs methylat ion of ethaoolaminc:. The methyl group" are pro,Ided by methionlnc: or by a reaction in voh'in& vitami n 8 u IIld folic acid. Therdore. dertciencics can occur only if all I11tthyl dooo.-i are e,cludc:d from the diet.

~~"' Choline

r"'

by mamtalmng blood levels of 10 to 20 mgflOO mL for Rocky MOIInla;n spotted fe\'e!" and tStJlsugamushi d isease. The mode: o( octiOfl of PA BA in the tr"l'at.rltnt of these di ~ c:a.o;c:s a ppears 10 be rickellsioslolic ruther than ricl c:tlSicidal, and the immunity mechanisms of lhe hO~1 fina ll y ovcrcumc the infectio n. PABA appem 10 (unction as a eoenlymc In the ron\'c:rsioo of cc:nal n preeurson 10 purines. I?J It ha~ bc:c:n ",,"c:sled as an c:ffeeli \'c StHlSCrn'n asa S<:f. solul ion In SS to 7S'l> eth~1 olcohol on I!'llCl!'S!il\ c: ~un lighl~:<pos.c:d an'as of the sldn. I ~ The historical signlflCllnCl!' of the effeel o( PA BA on the: antimicrobial aetlOll of SlJlfonamidcs and ~ u lrOllc:!i has bn r"l'vicwc:d by Anand . 17 '

bdorf. D. J.," 01, 111_ .\oIL!l'. 1990. '2 ..... 111_ ilty Ril. 199) '.' 0. ..'.... M. I. 8 ....... Il.. Kiuli. M.. ~ ... Blood U.~ 1'1'14 ,. KIIrir. I. M. Uc. J 5 .. GnffiD, T . ...1. Oin. C _ II.., Z::!fl.
H Yu , V C.,., .1: Cell 1>712'1,1991 st., ..... ,lIeu. M D. ~ II.: NUll. II., ~2'Sll. IW-'. " liON. A. C.. - ' Trmu>, M I!. I, AnI. !>oct. "'".... '13 121S. 1991 51 Orf.-. C E.. I!hI<ot. R....... CoUnlclo., H. ""'" 3.-.:19. 1'111 j'\l KI ... "..... A M. It! 01 J A.........'Ml. De'b'" 15.&l6. 19M.

'I. ....... "'r.o

''''.

I:iO
til
62.

W~....

.. ~ JAMA 2j') '27. 1'1116 Loformv"",,!M>od >I: NOdIey. NJ. II",""" ."

S~ ~

,."
~M..- .

if"

..... U, Jaurt>ow>J. A. T..... W P.. It! aI. BIoooI.S lOOl.

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""

$""",.

e.

5. Dnomn ........ J C """,hom, J IHI6(I, 19lO.

t.. McCoIIIlm, Il. V .. """ 1)"'1. M.: J B\oI . Chtm 19:245. 1. McColl"m. t!. V . n<l 0 ..... M.. J 1\\01, ClomI . 21 IN.

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72. Bh.....,haryya. M. II .""" 1><1 . - II F,: Brochern. 8""",) .. 160: . 'X. 19"74 71 lIohck. M F.: J In ..... O<rmat!)[. 77;.SI. 19'8 1. 7~ Mu,ID. G. ~ IL B)f"", V.""" """"- G. S ........ J l'! In.I\liI\l n 1tedoI). G. S_ .... T _ K Y UoodIemuIry ZlI:I76J. I . 'HL l-.n. D II., I .. u 34" I~ - 107. I~ 77, 1>1>..;. 11_, In - - . J. G. MIl ~L E.lodI-~ Coo I "'OI~.Thrf:~"""B .... ",~ IOtd ..... Yorl. McGn .. -Hill. l!II1. CIoap. 62. pp. \71,,174--1 71, Y"", .. A.. Wem..-. A,. Mu ..... II ....... 111Im. J Pfl..,.... Attt. ~n
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nsu.

,,.,

.l """""" Inf.. ..... L 1999

-_: 1 ....... <>1. IIobe C- I.... " , .,.1 \10'

M .".t~

198'J. po I

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Il

~eN.""-

F, !-'IId>. ' L . De, tl

Am. J K....,. Do<. \

IOS.IW7

8.1,.

IlA Od""",,- T A.'" CNIIt. D 1/ G: Ch......uy of 1f Plant MtWrolj"",. $;on Ihndj,CU, I........... -Cooroer. 19\16., p- 2'12 8j. 5~, M A., ~ ".: JAm , CI>om. $01;. 6<':1'869. 1\1+17. IU>. l>omole. V . ~.I HeIY. Oum, ACIlI 22:M. 1939. 17, Kwn: . P.. ..... Bu ......." ... 0 .. Iltl., Ch,m A<IlI 2) .I IJ1, 1...0 8B Wobcr. F. It! aL Bro<btm 8""",). II~ C.............. I~ I~ IW 11'1 Boeri, J 0 ....... Fom:U. P M ViwrI, HonD. 34:31. 1m 9(l 10.-..:_ M. lin' A~ DN. E....""'" Jo.I at " , MA. 1971, 1'1'. 186- 1.'. 91 ",,11;", 11 J :II1_~"""""D' -.~Yorl.P ,. """" . 1'171. p. 148 1)2. \1,',11-'11. J . MJ KalIl&. D. K A Phyo>cian', H......... O'" .. I,,.,lao M ..... Ne...- Coman. CT. K I'\IbI."""", 1m., .. ftI"' ...
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0rJ"''''

s....

e.

Iror (W1htr" '''f........ lO''"1

. ) I...,"'. S: Am ScI. .12;I)i}. 1944 .u "',.,.,. A. 01 01 .. Pri....,pIco 0( B,,,d..,,,,,,">,, /)tl( ft!. New Yorl. McGn ... -lhll. 1971. lIP 1173-1171 4S Bmy. II. J. C........ " J ..J RMo.h. II II I 8d 0... 164 92.11. 1'I8\l 46. s-i. J. C. ad 8,,,,, 'I- 1..: BoopIr) .. Aal711>.l66. 1982.

,">'.....

2111 -)1 L %. E-. C T ~ s..Joo,>L. J A."'" Srouie. J W . J. 8oe1

~7""-47u.. 1975 S ....Ik>.J. ~.'- Pmc . 24'1b:W7~6.1.w.

Fn.nc.-.

a.... 2-.

47. Wolf. (;. J 101,," Ihoc,,"m. U8-I-m, 19'10 48. I><Lllca. L M I'ASI'II J 5:2924-29.1.1. 1991 49 Lbd. M.. """ 0..",...-",. P T ....'h 1I"",,,,,,,.x1 I N!7-4J3. 1\1'91 SQ, GoItanIi. MM. lanIpII. W w. Shall ..... ). I) II 01.1' CIn<I:' lie; 3&:115. I 9%.

97 NMI Acad.S<llJ.SA.71:17'!o-l7J1.JI'1~ 9\1 , NrI",_J 1~.ZY1""'..-"T tt..MKlHov....tJ B J Bolli 0-

1974 'N. 5,""110- J : ThmmIr. 11c"""" 10-109 121. 1\l8oI . 100 Vln \l,>IlerJI1. V W M . ~ .I UIot>J M 444--4S1. 1'lIlS

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lJ1. Scoa.J M. ctol, 1!an<c1 121ol. 19lI1 08. Sbon. It. M (od.): Drut FIru MMI Coo~,_ , _ J. .... ,.ll.2<nl 1)9 W"~""""R.I_ " I Am. Chem.Soc 6J::!2IoI.I941 140. 01 I Am. a...... Sot 66:167. I,,". 1'1 ct 01 , I Am Chrta. 51>;. 70:19. I~
10. ~
,~

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0Dd'l'henp)'. 17111 cd . Wh,~", Sntl()D, Nl. Merd ~""h ........,.,.,.. 1m. pp. 2-'5, o-y Mri"""," Inw. .. rOf V'llUnift A. Vilaml~ K. """nk. 1k>nJn. Cbtom,um. Coppo lo:Ii .... Iron. Man ......... Molybdenum. Nk k"l . S,I-. Von>dIum. ond 7.....,. Food ond Nulriliun 1k>IAl. NlIi<lnlI A<""",,,y of s.:""",", IMlkltle ol Medicine. Ww.i,.,..,... DC. No. IJMaI 2001. loki. 0 .. MMI W .... 0, v ....... tknD. 17;l.~-'1. 19W Kil. T I!.. MMI Sauna. F. M.. $<"""", 112~. 1m AlboddJ. L . ...L N.tr It<-Y. '2:3}-1O. 19M 0. . ..... C!wittoaa. C.: NIIllI'Wt' ..... ,..,. :10"688. 19)1. y. J M.. ..... ~ lAMA VI:6n-6n. 1'J9( 0r0rIY. P v, ....... 110m. 20:600. 1961. C...... S. P~ .. OIl.: ....... J CIiA. Nuu 4S~I. 1981.. Bloc'" A L .... .01 J N_, 1011:670. 1m. S.......,'a. A I!. : ""'l""'" 2;1 15. 1960. ltowa. K ...... Snell. It: J Am. Chetn. 50<" 76;6J1. 1~ R_. D. P.: Vitam. tknD. 36:53. 1971. $<t,aumb'lIJ. It_ tI II.: N En&! J. Mod. 309:445 ........ 8. 1983 Parry. 0 J.. .ond B....x..n. D. E. N~ul'lllotJ 35,1466-1468. 19&5. ItICk... 1' L .. tI ai" SoIeflO<: 107:397. 1948. _ Sm"h. E. 1.., N"",~ 162; 144. 1948. 1!I1l.. B.. tI II. J PIwm. I'\Iarmao:;>I. 1;60. 19019. I ... btlt. V . MMI 0... K. C.: Vil3m. Homo. 304. 1. 1'n6.

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...... s... F-lp. B ..... MeIl. ' 7'''''5. 190'1 S Seier C\I 94 420. 1"'1 ..... Odle'P"'. 1 M N...." 1461J11. 1940. A_ elol 1 A.... CIoem. Sao: 6J:ITII. 190'1. J H. _"bnul ...... C, R.. I. 1'IIao.'" "" &p TlICr, 1

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27

An Introduction to the Medicinal Chemistry of Herbs

JOHN M. BEAlE, JR.

ActXlrding co lhe World Health OrgMizalioo. approximately 8O'.t of tIM: world's populalKJn U5l'S herbal drugs as pan of lhelf oormal health care routine.' 'The Uniled Stales is 00 ClI.ccplion. In the Umted Slales. herbal medicines re~nl the fa..~lesI growing segment of ph:umacy Irade.2 Self medi cation wilh herbs CUIS OCI'O$S all edOC31iooal and affluence le\" eI,. Senior citizens as well as young, hcalth-conscioos pet"IOIls are using herbs at an i~iblc mle. The reasons forherbaJ Ill< are many and ccnainJycannoc be fully enumer ated hen:. Possibly. herbal users desire 10 assume OOfllroi ovtr Iheir own health cml! needs. Perhaps the large. "impersonal" health care ,ystcm is unpalatable \0 many, aIld they tum 10 herbal medicines as an alternative. PUlien1S may feel alicnau:d by increasingly busy pIlysicians who have less time: 10 spend with them. and !hey may tum to helbltJ drugs because lhey fccl that .hey can pin SOInc corum!. Obviously. if poople an: going to lise herbals as pari of their health can: rootine. they mils.! find OUt about !be herbs and whal lhey do. 1llcre is 00 doubl that a definite major '.1or affecting herbal use is ad\'cnlsing ulrgeled \'ery succcssfully to specific populations. such as the yoong professioo:d or the senior cilben, Such IIdvenising is mere pselldoscience. but its flamboyance i5 a big drawing factor. Herbal ad. nflcn ~-on,'ey an alliludc Ih;11 self-medication is ~nre and effCl:tive. and thi~ males people feel good and as if they do not need the physician who JUSt saw them for .'i nllnulcli. l'rople also lend 10 believe Ihal nalural prodU(;l~ are inhen::nll y bener than synthetic drogs. 1llc nalural drogs SOITlC'how con\ilin ,hoe "vilal fOftt" lhat is going to impro"e !beir heallh. This is actually a belief in the VilDlism principle, .. hicl! W(lh1er dispro,'ed in 1828. J Tyler puts this issue intn clear terms: " If it comes in a sIlnnkwrop. safety-sealed bo~. or a boItle with a childproof lid, il is not han'csted freshly from the eanh, It is a manufactured mdustrial product. no mUlier how many fiowel'!i adorn the wr,lppcr. no matter how many li mes the label invokes the word 'nDlure." Cenainly. the COIIt of nledital care cannot be nverlooked wilen con~ideri ng the rca'l(lnS for iIllCrt:'1 in ~ltem ative forms nf medicine. Most herbal medicilM!li nre far less e~pensi\'e lhun prescripcion drogs, There is danger. however. in selfmedicaling with herbal drugli. The old adage thal "he who tries tndiagoose himselfhus a fool for a physician" becomes \'ery Pprupo!i wilh herbll medicine. When pn"SCripcion drugs are di~pcnscd. a patienl has acce.ss 10 the informalion !hat is available from the physician or plwmacis.c. Thi! is oflen not the case with IleTb;iI medicinals. In the United Scates. trainins of he:ahh care profe.~~ional~ in the U.'>e of herbal

drug5 has been nearly IlOOI:lliSlent f(M" years. Henct', hc:rbIl users are left In their n,,'Tl dc"ires regarding dlOlCI:. _tty, and qualily of the herb chosen. Until 1882.s a numbcr nr drug~ were IIlOnOJrIPhed IDlI describtd in The United SWl~S PhtJrmlK~i(J. Gin>eag. f(M" example. was clearly etlarllcl~rized as a dru! and <:wid be labeled and dc.scribtd to patients as weh. Today, thE Fuod and Drug Adminislralion (FDA) nll\ 8in~n&. legally. I "rood for be"eroge U.'>e. " Oulside the Uniled StilI'S, It i!I commnn to find ginseng recommended f()f many diffcltJl medical eoodilions. o Al the lime of lhe 1882 Un;ltd StUltJ /'/mrmllr:opot'ill and imo the early 1900s. plmnnaciMlo 11m wclliruined in the lise. preparnlion. and dispensingofhnblh and MIld advise patients on their herbal ilClection. Tbi~ ft rI()( always the case: today. The CQIlvoluted reglilatory efforts thaI beg:ut In 19061D1 COrltinue todoly are well describtd by Tyler? A group cI herbs had becn gr,lndfathefed against the FetkBl Food. Drug. and Cosmetic Act nr 1938 and the Kefau \er}bm\ amendment! nr 1961. Most purvcy~ or herbs al;~umed IbM these herbs would conti nue 10 be s:clablc wilh the: indicatlOM on the label - in otheT words. marteled IL'i dro8S, 'The B)A dec lared llmt all of these grandfalhel\.-d drugs woold bt mt sidcrcd mbbrnndcd and Subject to confiSCation if any Clall1b of efficacy wert: not in accordance with the evaluatioru rI I of 11 O\'er' lhe<O\Jnlcr (OTC) dru8 evalualion paneb m. had operdled belwecn 1912 and 1990. The nctll!.\ult_1hlt it became possible: to sell herbal drup only ir 00 MlltCmcat> resanlins ptC"enlion or treallTK'nl of a disease Slale "l'fl' 01 the label. 11M: FDA assigned three calegonu IIllO "hIdi herbs were placed. Category I' (effective) contam~ oat, I ~IC:CI fcw herbll drugs. TItese are nlO6tly laxati"" sud!. CDSCma bark and senna leaf (although as Tyler pomll __ prune juicc i5 excluded). Cal~gory II (IInssJe or lneff~b'tl comnined 142 herbs. and catcgory III (in.;urrlCtc:nt ell\leln In judge) contnin~ J 16. As applied tn herbs and. in fact.1bt entire OTC classifICation. the judgment~ nf the FDA b:il,t been hannful und nonsciemific. For lhe most )Xln, herbal manllfacturers decided not \tf fighllhe FDA and merely n:moved the disease- orcundilQspeci fIC information from the labels and contmucd to !d1 lhe herbs as roods or nlltrilional 5upplcnlCn\li, Wilh o:pnI In using herbs as rood addit;"cs. the: FDA has mallltI.1l1~'" list or slIb!itances .. sencrally rt:rognized IS safe" (the: GRAS list ). 11M: list COII\ilins aboul 250 herbs. pnm:mly o:latq to lheir use in 1Je\'enge:s and oooIting and as food I\kIib'"el. 1llc Ii\!, of MI1'liC. contain..i no refereflOOi tn herbs as drup.

In 1990. the NUlnuon Labeling and Education Act required cons,stent. se,cntilica Uy bast'\! labeling on all proo:e.~5ed food~. Hcrblll me:dieines W(':TC still left in 1111100. Finally. in I~ . [nc Dielaf)' Safety Health ~nd Education Act u}fluded herbal mc:d,C,1lCli In the delinitlon of drcuu')' wpplen1Cms. The oct cn,ure$ consumers' OCCt'5S to SUPI)lemcnls on the llI;[r\:et ~ long as they are safe. aod it allows structure and f\llM,:tlOO claims on tnc label. De<plle all of these legi\lath'e efforts. herbal droSS ha ve been relegau:d to the gl'Oc:cry she lf as diclwy supplements. Tht:y are sold with linle or no instruction. and the public has no way of ascertaintng purity. Slandardil..i1Uon. or leg[hm.'ICy of the use for whICh lhe product i~ .w ld . Indeed. lhere is more information on lhe label of a lUbe of lOO1hpaste than on II bottle o f IIll herbal drug. Herbal manufactunng eonlpanU:i are m.1ltng efforts to impro"e produets ak," !! lhese lines. bul tnere i ~ a long way to ~o. Until le'ting can be done to pro"e thai herbs art sofe and Cffttli,I' . they will probably remain in their pre:scnt cir
tumstance~ .

111 a gl\'en herb can he idcnl1fied. bul then:: lI1lIy be no obvIOUS way 10 corrclutc chem ica l structure ",i.h function. Orten. IIS5eSSInent of slructlire- fullCllon n:lationships with herbal productS invohC':$ a 101 of gtJe$SmS.

WHAT IS AN HERB?
An herb is a subsiaocc of plant origin that . :cording to one's desires. can be u..ro for culinwy (W med, clnal PUrpo5C':S. Obviousl)'. some are more 5uited to culinary than medicinal uses. but mll"t herbal substances have some: identifiable me:dicHml usc. As Itl(':ntIOl1l.'\! in the pre,iou~ !Ction . typical herb may contain OOUIlS of different oompounds. so II has rarely been advantagcou.~ to separate an herb IntO its componelll patu. In foct. doing 'W may completely inoctr valC the drug. In an herbal mIxture. 'iOI1lC ctJornpounds can reinfOor'C(': othcf'l; and vice versa. 11 i~ im~s ,ble to prcdk1 ... mll will happen . In relatively few cases h~s the active ingredient of an herb been isolaled. characteri/_ thorooghly. and tesled ed for acti\II ). We an: left ..... ith a situat lOJ1 in "h,ch herb!l are used in ~rod.e form as po ... 'del'$. nUldcxttllCh , lind lellS. T1Jc above should not be rnisconslruc:d to mean lhat analy~iJ of herb components is useless. On the COl1lrdry. it is t'5S('nlial but JUSI is not done often cl1OUgh.

,4

For many years. medi ci nal chemistry was paired with a

Kienee calk'd phllm.#cogntISY. 10 a CO\II"'IC of study of plants with medicinal uses and analytiC:l.ltcchni'lues for detecting ICIt\e ingredien ts. PhannllCQgnosy ""~S 110 important science becuuse many of the pharmaceuticals u<;ed in the treatmcnt of di~ase are disoo,erett through the study o r ethnobolanical !tack and hwonatUf)' re<;call;'h. This CQ\lfSe of slUd y gal'e phamulcists the training rcquired 10 und.er;tand. rL'COmmcnd. and coun~1 on he~. Today. ~y is no longer rrqllu~d in loost school~. and most prncllCing phannacists and phy<ieians have liule und.eNanding of herbs. Medicinal herbs are unlike an),thing else that appean in \be ehaptel'$ or this book. Although they are unquestronably drogs (a fact Ihal many $tIlers of herbs will di~pUle). lhey are noI pun: SUbsIOIICCli . Indeed. most herbal preparations ronlain mmy differenl constituents. Ephcdnr. complex. or Mu huol1g. i5 a sympalhomHnet lC i.h.al contains Ii\ e or six d,fferent P.phcnethyillminc dcriv31il'cs. At least one of Ihe<;c. (+ )- norpscudQCphedrine. is a Schedule IV com pound. The alkaloid content II_II "aries ... ldely In comlTlCl"cial ephl..'dr~-containi ng prcpanalions. In one study, for ooe single product. lot -Io- lot vuriations in the content of (-)qlhedrine. (+)-pseudoepbedrine. and (-}- meth)'lcphedrine u~ ISO. 250. and J,()(X)<'.t. fCSpectively. " TotDI alkalOid OOIltent among 20 products r~ngcd from 0.0 10 18.S mgt rhage unit. and discrepancies were e~hibi ted betv.tcn the b,l:Kk'd contenl$ and acrual n}fasuf'('ltl(':nl5. u Another <lUdy lHSa~ed 9 productS and found Ihm tOial alkaloid lel'el ~ nansed from 0.3 to 56 mglg of ephedra. IJ Unlrke the , nuation .. ith ephcd.rn. in many cases we simply hal'e no idea what the components do. ~ con\.l uuc:ms of somc herbal drugs .o;C('lI1 to wort: synergistically and cannot be SCpar.lted without loss of activily of the prcpannion. Herbal preparations are 11\00st orten used u crude mi)lturcs and III'Il not standardilcd or analy-t.ed foc the content of the actil'e principlc(~). HelX'C. lhe chemistry or medicinal herbs cannot be treated m the same "'a) Its that of. say. a pure anublotic or D calcIum channel blocker. The med icinal dtc:mistry of the. actions. internet ions. mid side effects of hrrbal productS is comple)l IUId diffICult to assess clmically and dlc:miC:l.lly. Frequentl y. some of the compou nds present

HERBAL PURITY AND STANDARDIZATION

In the Umted SlalCl>. the issues of herbal punt) and adultt'ra tion h:!1'C beC'I1 IlCglected ror ),eitl'1. Because herbs are not regu IMed in the United Stutes the SIUlIC way they are in (tIher COUnll1ti. the: pressure to ensure lot-ro.lot standanh /,ation and lOM:Ttcn out plant adultt:r.ll1l5has been less thanopllmal . InstallCt's have been reponed in the literature ll in which several bottles or an herb purchased in the SlIme: location pos. sessed different C<)l'lttnt1'Ul1011S of active ingredienL Ephedra. and gm<;tng an: l10Iable examples. AllOlhcr example is echi nacea. This herb is occa.,ionall y adUltCllIted with a pllll1t thaI loou vcry si nular to &hilJlKWJ /lnguSlifolw but has none: of the at1,;"lly of echinacea. Pllll1t pan~ Insect pIIltS. \Oil. etc. ca n nil be adullernnts. Fonunmely. pre,sure on the herbproducing industry has caused a markedly increased effOf1 to K1l:Cn and siandanlia herbs for tntdc . I'o!;~ibly. "mple high-performance li'luJd chromatognaphy ( ~[PLC) n~thotls cou ld be used to verify the hcrb'~ '1uaJity if the: time were taken to obwin them. A chromatogram l-oold be supplied to the purchaser to '\how the purity of the herb. Nevcnhelcs-. remember th31 an herb is a crude material containing multiple phannacologically oclil'e compounds.

AN HERB IS A DRUG
Despite the regulations. an herbal preparotion possesses the pwpcnir:s of a drug. alheit a mild one til many cases, and should be treated u such. II is pharmaooloJically act,,e. It inll'1'11Cts ..... ilh prt.SCTipl1on drug . It affects the health of the

person laking it. Advenisersoflcn 10111 herbs as "nond rugs" ,n an allernpllo Iu~ ronsuntl'f1i. Ph:lmH'ci ~[); )hoold be cogR'lant of lhe truth that Ilerbs are real drugs and Ihott their pallents may be sc:lf-medicuuna .... uh !hem. Thi~ Pf*:uce nlll)' affect the OIIICQ1lIe of IlH:rapy .. ilh prncnpl'on drugs. For uarnple. suppme a patient is 5tabilized on Coum:wJin and starts to tll~e ginkgo. Ginkgo affects platclct-aclivming fllCtor (PAF)" and can effeclivdy cause an o\'el'Clo5e effect w,lh Coumadm, and the patient can bleed Or,!i-llppose a pahen! takinJl a ITlOI1tXlmioe O\K1aSC mhib,tor (MAOI) decideli lo take SI. Sohn's "'~ ; the pallent may ha\e a toxic reaction.'1> Because phammciSls oftcn do noI sec ",hat their patients are buying. thi~ is a complel< problem. The herbal drucs i\'uilable to CQIlSUrllcrs an: far tOO nuI11I:rous 10 discuss in this chapter. This seclion f"l,!5Cnts a few of the more commonl)' used herbs along ""th the,r chemistry. Infonnntion on other herbs cnn cnsil)' be: found in the litenllurc.

TYPES OF HERBS
Echln.c
The medicinal herb that we call n:hinact'a. or the purple
is indigenous 10 the Orent P1ain~ of the Uni led States and. indeed. can be found in much of the Western Hemisphere. The plnn! gets i.... nanle (cooe no .... er) rrotn the narrow nore ..... which project Oownwanl in a conical lllTIIy from. prominent center toward a substantial stem that beaJ"" one. nOWCf". TOlby. the herb I used LIS an ImmuOO/itimulant. 17 lIS a means of lessening the symploms and duratIOn of a cold or the nu. and sometimc~ as a "'ound healer. Recent reports show lhat echinacea is the bcsi-sclhng hcrh in the Uniled States.'! Folklore l ! tell ~ us thai Nillhe Amcrican5 u~d t;clliruJCN ungl4lifuliu to treat superf.cial wound). sna ~eb,te. and the common cold. In the laller part of the 19th century. selliel'll el<changed mformauon about medi cinc~ "'lth the Indians and added echinacca to their o",n phurmat-opocill. &hin~c..-u c~en became one of the first patent nJediclne~. !>Old b)' II huds tcr in Missouri at midcentury. In lhe early 1900s. echinacea ",'a~ introdUl.'\!d. 10 lhe European ronlinrnt. w~ il occupies a special plocc m mcdlCulthemp), . One estimate MJted thai in German)' alone there are 800 echinocca-contamin~ drugs. includmg a number of honKlOp3thic preparations. I Three species arc identified IlS cchinacea;:!O I-A-hmuN!a an _ gUJIi/oIia. . pu/lidtl. alld. . purpura, All are u~ for medicinal purposes. and they have ~imilar l"optnll'S. There arc slight diffen:nc..-) among the spccit:ll with reganlto the anatomical distribution of acti~e oonstilucntS.
COIICflowcr.

cea"; I:.. /1l"flllrta. . unJ:ui/lfvlw. and E. 1N.III,dd. Somt mcdidnal pn:par.ltiuns an: from the roots (all tim..... ~pecte\~ some from the aerial p;:lrtS (t. pllrpurea). and some: from dJr ",hole plant (homropathJc mother tinelUmiof . llnf(lI$lifolM and . pallll/al, !O AlIOlher fat:lor that affl'ClS the cornpostlXll I)r echmocca pn:par::Ulons i~ the way In ..... hich the)' are e,trloctcd, Exprc~!>Cd juices. tea~. hyurookoholtc C'tnICl!i, lrll iIIlCtureo; in alcohol are u...ed. Ill> well as solids. It is ram) possrble 10 obtain reproducibdlly '" the prcparalloo> In 1916. the Nanonal Formulary of the Unued SlaIC!i ltSlal the root5 of both Ii.. tJIrgumfolltJ and E. (Nrl/llia as otr... iaI. and the diqincllon belween the two begall to be forb'Ollell. In about 1950, E, l'urpurM was introduced a" the pl1ltllf) medicinal plant In Europe, Of the tiutt ~ICS. . pall" is the most "iddy culli\'atcd.. the !allesl. and h:b the ~ flowers. Thr~ i~ considered the official prcraraJion In IIIr Uni ted States. 1- ' pur/lJlfta root preparalloos are SOiTlC1ltm ; lIuulternted "'Ith u ~I mtlar-luo~i!lg plam called PIJrthlfllU/II illll'wifolium. HPl.C lmaly"s ,'an em;ll), octect the adullm1100. 21 TIle alll,we show~ how dlffi.;ul! it is to ~tlnr:lard!lr echmacca rrcparatiollS. Addmonaliy. oplmOll~ dIffer about Yo hich plant OOl11po01l('nt ,~ the: be:;t anal) tIcal loI:1nd3nll1l_ tion of the drug, l~hinace~l conl,lin~ a series of phenyl]l1'O]!lnoid glyeosiun. t'Chm~ioc. ~erbascosl(\c. 3nd 6-0<11'fcoyl cchinllCOSidc. ll. 2J Thc\C rompound~ pos~ .. lIlununo<timulahng ;lCti,il),. SOIlIC' arglK: that !he caffco,t glycoside echlrlat:oside should be the Mnndanl, sillCt it i. cuy to detcet and quamllatc ; othc:rs feel that II make!. knit .-.en,;c to ~\Wrdanl i'e the echtnpcea pn:pamtion to II torIIpound that hu, n.) mcdidnal act"ity.

ror

Rll8mr" It

o~

V
RaGhocclI (1.&-)

""""""'" O:ctdOIe R"H Q.ea"8OVI!IIIJOOSe A'.RhilnrotIlItI I1.31o-Caflooylgl.c" Ro.&6-

CHEMISTRV is no doubt that echillllCClt has immullOlllOdulating pmpcnies. cncmistry of the con~tltuents of the plant has been studied e~ten5ivcly. but il is difficult to correlale a major lICtivily with any plant fraction, lndeed, 110 ~mglc componenl appears to be ~ible for lhe actl\ Ity of echirulcea. Slandarduation of echmacea pn:paranons bas also pr1)\'cd to be a problem. The consumer is prrso:ntcd with three potential preparat ions sold under the name "tchina11le~

n.c

fr.octlO/lS of echmaa ha\C been 1'>(Ilnted. ,"", ... 6ing to polanl)' and Mudied for phannacol\J&1C11 0CIJ\"l1)' lilt II1Q<;I polar components. the polysaccharides. )iddcd 1'10 inliliullOSt imu1Jtory poly~lICCharidl.'S, PS I arid PS2.l ~ ~timiliulc phllgocytosis i n \'i~o and If) vitro alld c~use II bur<;! of production of ox),gen rudicnls by nUlCfOfohag~ In a do;.t dependent "'lIy. PS I is I 4-0_noeth)'lglocuronoarabtlll). Yolth II molecular wClght (MWJ of 35,000. PS2 IS an a:d ambinorllallurognloctan with In ll\Crage MW 0( 45.00:1. l.ucnig c:t al. 2' ha\'e sho .... n that differenl ronl:enll:Luons 01 polysacchandc.~ from E, p,,'/Jllfe(1 could ~litl1ulmt tnklV ph~gc.~ to rcle:l'lt tumor /lCUOS" factor-a n NF-al. Thea coruUlucnl~ also acli\'ate B cells and stimulate the pm~IC' tron of mterieuklll-!' Thn:e glycoprote.11IS ha~'e aI!;o beG I~'atcd (hat el<hlb" B-ccll_stirnulating at:ti~lty und Inducr

Se~er.oJ

C haplu 27 All /'lIrod....,1OII '" 1M Mn/in nal

C/" ,,,,;,'1'\"8 /lulu

907

the n:lcast of Imcrleukin-I. TNF a, and Inlerfcl'Ofl (lFN)

from macrophages. both in vitro and in vi\'o.2J Alcoholic tiOClu~ of the aerial pans and roots of hinacca cont:llll caffeic .eid deriyauv~ and lipopllllic. polyacelylcnic compounds. The roots of E. /In,~u.llifoli{j and /HI1litW rontain OJ to 1.7,. echinacosidelfl as !he principal ronjugalc in the plant. Eo (UlgUJfij(1/i(l cootains 1,S-O-dicaf feoyl qU1Il1C ocids (qulIl,e. chlorogcmc. and cynano)n in the mol tissue. allowing di stinction by HPLC. &hinacoside ha.s low hactcriul and viral !lCtivity but does I\QI ~timulote the Immune sy~lcm. The most imponant set of compounds thai M'em 10 be found throulhool the Ilssues of all of the eet'llna-

lelll as indomcthacin.:D The lipophilic fractions, the aJkamides. stimu latc phagocylOSis and inhibit 5-hpoxygclltiC and cycloo~ygcoasc (COX). blocking the inflammatory

proc,,,.

eta species are the 2.J-O-dicaffroyl IlIl'Wic acids. caftark acid and chicorie acid ,lS Chicoric 1cid posseSM:S phagocytic 1
Mll11ulmory octivity in vitro and in ~ivo. while echinacoside Jad:~ thIs actl~ il)'. Chicoric acid also inhibits h)'al umnidase and ~CC1S collagen typc.' III from fnoe rodic:ll degradation.

--

CO<

......
$I.... .-. (Ounc ADd)

.....

c.",,!P..I
0

"\:,
o' ~

It i5 dcar that echm~a can stimulate components oflhe mnate immune system, but no single: component seems 10 be ICspon~ibJc for the effect Echinacca. if takcn at the Oll.<;ct of symptoms of a cold or flu, will lessen tho.:: sevcrity of the disease. It is not ~n1lll('nded that 0fIC usc cehinacca ioniC!" than 1010 14 day,. howc>cr. and pcr.;ons under lhe: ap' of 12 and lOOse ..... ho are immunocompromised should ne,'cr usc this herb.

Fe .rl_
Feverfew. TfI"OCft/UIfI {J(Jrfhf!,,;Utn (L. ) Schull]. Sip.l . is an herb Ihal was u...cd in ant iqui ty to reduce fever and pain. TIM: litcrawl"e is replete with anecdotal cvidencc of the usefulness of the: herb. and ~nt clinical studies !Ia"e added more: suppon. Fe,'crfcw is a membCl" of the :lStcrfdaisy family. llIc plant tissues havc a pungcnt smell and very biucr taste. 'The Ill('dieinal principle of feverfew is (:oncelilratcd in hall)' tri.:.:homcs on the: chI)'5aIlthe:muml i1o:e lea\cs.J1 TIlC plant displ~ys clusters of daisy-likc flowcrs with ycllow ttntcrs and radiating "hllc fl()l1:ts. Rc:cent USC$ of fc>'crfcw arc: for migrJinc and anhrilis. although the indica lloo for anhritis is disputable . 1bc anecdotal evidcocc thai an herb oould sua:c:ssfully ~at acondil;oo soch as migraine headache nalul3lly begged for sorl1e ~ic:ntific proof. Two prospective el inkaJ sludic:s IIs;ng dried whole fever few leaf have been pcrformedl.l "", to assess the value of the herb in migraine. T1ic: IWO tear studies OIl migraine prov;Ocd good supponh'c evidence for lICtiVl ty or the herb agaillSt m;~inc. Both studies ,,ere double blinded. pl:nbo con trol led. gnd standardized on 0.54 m@ panhe:lIOlillc per capsule. In both ludics. the fevcrfew group demonstrated si@nificant dec~ in frequency. scven ly of attacks. and

The Illbmides N from the I"(){)(S and flowers of tmguslifolio and . purpurwl limulatc phagocylmi5 III model animal systcm,_ Tbc:re are p haoil of Ihc$e oompoonds distributed throughout the aerial parts of some chi1lflull species and the roocs of most. One: ~uch compound. echinatcin." display~ ~ialogogue and IfIscct repellenl propC'nies and is belie:>ed 10 be the mam ImmuOOlimulanl in echmacea. Tbc: Illwnides and kctoolkynes::ll lO may >el)' wcll possess IICtivity. One notable: effect is Lhc !illti-inflammatol)' cffcct of II high-molccular-wciahtlllllbinogaJactan thot is about as po-

nausea and vomiung. No OO\'erse effecu ...-crt: obscnied of the oonstcroHlal anti-inflamnuuOly drug fNSA IO) type.

MECHANISM OF ACTION
Fevcrfew Inhibils prostaglandin synthc~I~. but not through 3n effect on COX.'" The he:rb alS() inhibIts lhe synthesis of thl'QmbQ~:me . ~ain by a COX.illdepclldenl mechanism. Addiuomdly. fC"crfew inhibits the syn thc~is of pho!;pholipaile Al in platelets..II>. n preventi ng the liher--IlioJl of ar--IChidonie acid from mcmbrnoe pllospiloJipids for sub!;cqucm convcr;ion to prostaglandins and Ihrombonoe. Fcvcrfew also inhibil ~ the ADP-. collagen-. and thrombin-ind~d~ grt:gation of platelcts. Mlggc>ting th:1I the hcrb ha~ a greater thrombotic effect. In another. similar siudy. dried leaves of fC"erfcw inhibited prostaglandin and thrt)mbQ~!U~ sy nthesis In platclcl:s and inhibitoo plotclc! ~gatlOll mlti:II~'d by AnI' and collagen.'" Surprisingly. this stud) st.o-..ed that fcverfew inhibited the p!:lIelclrdeasc rcacuon by "'hich Inlrucc:llular StOl1lgc granules are rt:lcascd. 19 ~ stor...gc gnll1ules contain serotonm, a positj,'c cffector In migrdine headoche. Some of tile more surpri~j nl findings for fcvcrfcw arc that il appear.; to be a selectivc inhibitor of iruluciblc COX_2.oo and it has clear effects on voscular tone in unim:,1 models. The phlLnnacologically active eon~t ltucnl in feverfew luis typically been eQIIsitlered to be purthenolide,"' an amphiphi lie sc:squiterpcoe lactone that i~ blosymhc:siud from the germocl'llnolidc eauon. Panhenolide I~ ~nt In much greater quanmies than any of the OIhereon~titucnts. and illl ~nce docs 5m toco.. datc with IIctL~ity. alleast In dried lea\es,. Panheoolide is an a-mcthylcoe lactone,": an O'.,8-uns:uuruted nMi1ecu1e that can.serve a.~ an OCplOf III the: Michael reac1lOn. In the Michael rcac\K)l1, a dorIOr nutlcophile such u a thiQl can allack" the acceptOf 10 fonn a covalent adduct. If .,..rthenolide functions thi s way, a biological nutleophile such as II thiol on an enqmc eoo lll be bound. inactivating that enzyme, The likelihood of Ih,s mcch:lIlislII has been sllo..... n by successfully forming adduct ~ with parthenolide ;\SClf in vivo ....... 11le other eOlllpooen\li-canin, (lJleca-

3-1\. Hyd'OXVJl'LI U.,.101k1e nino !.ecOllLllIIlXlrlheno hde. and 3-,8-hydroxyparthenolide-arc pre'iC'J\! in lower concentrnlions."' 1nci. cfftS rl1:ly be Important to the activity of fe\'crfew, Out !.IllS I> impossible to judgc at prestnt. One Mudy that used aneAInC\ of the leaf wilh known par1henolidc content failed to sIlOII' acll~ ily. so qLJeiuoru; still rcma,".

Saint John's Wort

Saint John 's won (Hy~riC'um ~rf(),/jfum) IS II mcdlCio.al herb that has been used since tile tillle of PlIracdsus ( 149J- IS4I ) to treat II variety of psychiatric dl~ Today, lho! herb rt:mains one of the: IJlOt imponunt psy.hotropic drugs in Germany and Western Europe for the tfnl' t1~nt of dcpfC.~sion . anxiety. and ner\oosness.* The: has recently beCQITIC popul;lr among cOIlSu mc!'5 in the Uruted States. The demand for the drug in the United StaltS ~ been fueled by Gennan ~tuditS that reported that St John'l won ..... 3.'1 equierrecti~e with nuo~etine In the trcatmenl of deprt'SSion. Some Imeruting cm:umstances give the herb tlllllall\"The plant t~ I low-growing shrub that gruv.s '" lid In Europtand Western Asia \\'llh yellow n'lWel'S that bloom .rt.lWIII June 24, the trad1lJ'lnai b,rthdate of St. John. If the nO'Wl"Cn IITl: rubbed. a rt.'d pigment is rt:leascd. Thl~ red subsiMlft has tntditionally bec'n associaled with the: blood of St. JdJI rcle~d at his beheading. The medicinal components of SI. Johll '~ won arc den_til frolll the nowerillg toP). A 200 1 study in JAMA, howc,tt. negate.~ uOOut 30 previoosly publ i~hcd trial~ and showed \h.JI SI. John '~ woo failed to improve major depressi"e dl!oOldcr in the fir<;t large-scale. multicenter. randomi,-td. pl~ controlled trial 111 patic-nlll diagnosed WIth major dtpes-.,'t disorder. The herb has definile mild sedan"e effect.'" in 10 )C:tfS of controlled clLnical trials it has pro"ed II!:ff~''t in the trcatmenl of mild depression,

dru,

'> -{ ,

CHEMISTRY'

The red components of Saint John'~ ",on arc the anlhnlcnx derivatives hypericin. prc~nt in about 0.1.5%, and jNIIIIo-

H;; o

,OH
"
"

""./=~

OH
StcotanaparlhellQllde

hypericin . Fla,onoids present are quercelln. hYJll'ro6Jlk. quercitrin. i'lOquercitrin. and rutin . Two C-Clin~ed MIll ins. amentona\one nnd biapigeni n. art present. as II lilt acyl phloroglucinol deri vauve hyperforin. Procyanldm. I dtral na"ontdimcr. adds to the list ofnavones. Some 1(!pCnet and ,,alkanes are ~nt as minoroompotK'.nts. TllC pnm.) acth'e in~di(nts halC lnIditionally bcc:n he:ldto be the: b)ll" ericiOli and the nnonc/OaH)ools. especially the hyptflC1a In fact. the German Commi!>Sion E Monograph 5pC'C1fadlat the herb should be standan:li.r.ed 10 hYP(',lcm oontenl. Despite the cI'idence of cfflCaCY. the: mcchamsm ofartD of 51. John ' i wort rem3lnS unclear. Severol possibiliua Mill!: been put roo. Probabl y the most popular one is the: MA()LI

Chlol'ltr 27 An ImroUuClitHt 10 1M "'~JicilWl CIr",,,'st,y of I/a/Jl'

OH 0

909

OH OH

OH

OH

OH
Rati , <luefl:e~n

R.cH,. Hypericin R.cHPH, Pseudohyperlcin

R-Gal,

RaRha .

Ctlle . lin

R..GIu , IKqJ8fd1t1n
R-flhII.QIu, Rutin

OH
~

0
~

""

"'-<'

HO

'"
"'""""""""
CH,

'" -<'
#

HO
OH OH

'"

'" -<'
0
Biaplgenio

'" -<'

OH
OH

'"
#

OH

OH

OH

H_ "
CH, H,H,

OH

"'"

'" '" "'"

'"
'"
OH

OH

"r CH, CH,

'"

OH

CH,

"'"

""-

H,c

protyilllldir.e

OIme.

OH

COMT hypothesis, According to this hypothesis, 51. John' s won increases the levels of catecholamines at the brain synapses by inhibiting their in~livatioo by oxidative dearnination (MAO!) and by catechol fuoctiooalization (catechol-DmethyllJ'aJl:>ferase ICO MTj),7 Recent studies have shown tllalhypericins possess such activities only at pharmacologically cllcc:ssivc conct:ntl'1ltions. If tnJe, lhese elTecll\ at normal doses are small Dnd do nothing to alleviate depressioo. Other hypotheses sugges! oonllooaJ effects or cffects 00 the dop.Iminergic system , Hyperiorin h3.'; become a candidate for the major antidepressant constituent of 51. John' s Wor!,

supposedly inhihiti!lg serotonin teuptake by elc\'ating free intraccllular sodium. 5t_ 10hn's won also cxhibi ts anti -inl1mnmatOfy and anti , hacterial activity, Repons of anliviral acti vity are unsubstantiated. llIc: main adverse effect with 51. 10hn' s is severe photolOxicity, A sunburn -like conditioo may occur at oonna! dosages. 51, John' s wort shoul d never be laken with MAOl s because of the risk of potentiatioo of the effects. 5dective serotonin reuptake inhibiton. (55R Is) likewise: should nul be: taken with 51. John 's won becuuse oflhe risk of scTOlOnergic syndrome.

".0/1

Dose (capsules standardized 10 0.3% hypericin): 300 mg of 5t:lnd:lrdized e.tract 3 times daily. The FDA considers 51. John's won uns.afe.

Capslc..... (Capulc:ln. Chili Pepper, Ifot Pepp.r)

Pepper planb ha,'C been used for ycars a5 herbal remedies for pain:'" 1llc thernpeuucall y useful pepper plants ~ mcm bers Qf the 5(,/(JnIll:tIJt fumil y. There nrc t WQ primary speclcs whose dried fro it is t"(IInmooly used : C(lpsku," jrlllC:iCCnJ and C. ann"m. Thc actual activc ingn:dient. capsaicin. is extnlCted from an olcorcs.in thai Itp.-e.>cntS up to 1.5% of thoe plant. Two majOf compone nts in the oleoresin (among sever,d) ure capsaicin and 6.7-<1ihydrocapsaici n. Volatile oi ls and vitllmins A and C occur in large quantities. The amQUnt of ascorbic add in the c~psaicin o~in is reportedly 4 to 6 limes that in an oran~oe ."
/C",

applying capsaicin. Cont;:t with muoous membranes and the eyes shookl be a,oided. If COOIlK:! OCCU~. one should .....ash with cool running ..... attT. Capsaicm as the oleoresin is used as a " pcpper spay'" For S<!lf-defenS<!. Sprnyinll into the eyes ChUSCS unmedillt blepharospasm. blindness. and incupaci lation for up to)O minutes.

Carlk
Garli .. (Allium $/I/, ..u",f l is an herbal drug wilh rcrerenc~ to rnrokinal l" O]X'o1ics Ihat date back thousands o()'CIf'; Of all the hcrb:tl remedies a"alhable to COIl\Umen.. pi..: is probably the most eltensh'o:Iy re.o;ean;hed.': P'ubti('llUID about the cffecb und benefits of gorlic occur with great fit quency . Garlk is a bulb. It may be used as Stl(:h. but is typically dried. powdered. and compre-.sed into I tabItt Usually. the tablets are enteric tooted. CHEMISTRY Garlic- u C()f1tains a key COIllponcnl. alliio or S-nlClhylI-C)~ teine sulfolide. Additionally. mcthiin (mcth)<k)'$teinc: suit olide). cycloalliin. several 1'"L-lI lutamyl ,S BIk.yl ~-cyste incs. and alkyl alkanethiosulfinal~ arc preSCnt. The U~ also contain enzyme~ (alliinasc. pero.idasc. myros;rwe~. wellllll additiunal sulfur-coolllining compounds. ajocuc. a.I other minor components. GarlIC itsclf has the highoi.sulfur rontenl of all of thoe Alliunl species. When the garlIC tkM is CTUshcd, the en,ynlC alliiollS<! is ro:leased. and :i/tiln II cOlwencd 10 allicin. Allicin gives garlic its chantcteruuc odor and is belie"ed to be the plwmacologicalty al1h~ iRgn:dient from the herb. Al1iinase will not surviH' the ICidi.: environment of the ~tomach. so emeric-cootoo tablet! .-.:

CH,

c~#

II,

."".
Capsaicin is supplied pharmaceutically as I cream , gel. 01" 100ioo. The first applicll.lioo 0{ the preparolion prodllCts intense p;un and imtDuon :lllhe site of applicalton. bul USU wly 110 ski n reaction occurs. Repeated applications caust desensititation. and eventually analgesic and anti innamma tory effects occur. Stimulation of afferent net'\'e tr:tcts ..auscs a heat <;cnsation. Thcre are se"eral potential explanations for lhoe a1leviati-on of p.1in by capsaicin. 'There is believed to be a compound called JUbSlUnCfI I' Ihlll mcdiutes pai n stimuli (rom the pe. riphery to the spinal cord. One ttOWly is that ..:apsaicin depleltS thoe neuronal suppl or substaoce P so that painstimuti J cannot rea..h the brnin. Addit;<lNlly. tlte mctho~yplleool ponioo of the capsuici n IllOlecule may fit the COX receptor site and inhibit the lipolygenase.nd Cyc lOOlygenase path ways .... Capsaicm IS e~ trc,",cly poterlC. so lopical preparations nrc rompounded in percenlage stre ngths ofO.02~ to O.2~%. l1lc preparati()f1s deplete substance P most effective ly if used 3 to 4 tirnt!l II day . Capsaicin has been suggcsled as a remedy for postStirgical p,am (postamputation and postmasttctomy). posthcrpetic neuralgia. and a "ariety of OIller complel pain si tuatioM. Rel ief nf P'lin may OIXUf liS quick ly as 3 days or may require up to 28 daY5. PatkntJ shookl be mSIru<:led 10 wash their halKk .....elt afttT

II

NH,

"""

OH

"''''

I _,

C)+h

5,

H,C

Garlic Is mosl often studied for its Ii pid lowering and 1IIb thrombotic'" effecl.!l. II .. holestcrol lowering effa:! is .. cD doaImentcd in both animals lind humans. Garlic to.U\ serum cholesterol, lriglyceridcs, and low-dcnslly hpopiM'JI (LDLJ while increasing high-density lipoprolelll (HDL). .Im reported mean reductions of 6'1> 111 tOUI seruOI c~ and IICfo in LDL Methylallyltrisulfide in garlic oil PI*'"

Chaptr r 27 An /",rodUCIi<1II Itl''''' M~dicilll1l uall)' inMIUS AOP-mduccd platekt aggregation,!IIld ajoene inhibi ts plalelet aggregation for shon pc:'riods. Comp;tmi With the statIO drogs. there is a paucity of human researeh data for gllflic. There na\'e been no morbidit)' and llloruhty uudies for garlic. for inSWICe. All that we can reall)' gather from the literature is Ihat there 1IIfJ)' be an effcct on patient hpid profiles. b\u for every positile response, negative one can be found. Garlic is certainly I1Ql harmful and can be used safety il-~ part of II lipid-reduction progrmn. but this should be done under II physician 's super
~ision.

e""ma,,.,, "llItrln

91'

OH

The herb known 1:5 chamomile-" is ~nved frum the plants Mmricuria cho",ollllllfJ (Gemlan, Hungarian. or gen uine chamormfe) and Alllhcmk rwbilu (English, Rom:tn, orcommoo chamomile). Plants from lhc t ..... o genera have similar acti~1I1eS. The medicmal components are obcained from the flowerio& lops. TIle flowers are dried und used for rnatl'M)nule teu and Utl1lC1S. Chamomi le has btc:n u.o;ed medici!lally for lit leust 2.000 years. The Romans used the herb for its medicinal propcrt ie.~, ..... hich they knew were alllispas modie and .~ t i\'e. The herb also has a lonll hi ~tOf)' in the treatment of digest ive and rheumatic disorden . 1lIe IICli~ity of 4.'hllll1Omile h found in a !iii-hi blue essential 011 tMt composn only 0.5% of the flo .... er. The blue color is dll< to duma.o:ulelle. 7..ethyl-I.4-dimethylu.ulcne. This c:vrnpound is actllall)' a by-product of pnxeuing the herb. The major Conlpont:nt of the oil is the scsquitcrpene (-}- obisabolol. Also prcse!ll are apigmi!l, angelic acid.tigbc acid. the terpene precursors (famcsol. nao!idol. and gcnnacnanolIde) coumann, soopoIelln7glocoside, umbel1iferonc, and herniari!l. Much of lhe effect of chamomile IS due to bi..abo101. 8i ~abolol is. highly active anti-inflamnulIOf)' agent in. variety of rodent inflammation and arthritis tesbl . In addition. biS<lbolol ~hortens lhe healing tinll: of hums 1111(1 ulcers ill animal model s. The gll.,II'()inlestinal (G I) IlIItispasmooic propertie~ of bi<;a bolol and its o~ides arc well known . In fact. bisabolol is s:li(l to be u potent a~ papaverine: in tests of mu sc le sp;!~tici ty. 8eside$ bisabolol, the fla~one and CQUtnann colllponents MI'e IlIIIISpMmodic activities. The blue compound cham:uu !ene possesses both an!i inllammatory and antiallergenic oc ti~ities. as do the wmr-soJuble cornponc:lIIS (the flavonoids). Apigenin and lutcolin possess and inflammatory potencies slIntlar 10 that of tndomethacin. 11tcse fla\'onoids possess acidic phenolic lmuPS. a spacer. and an aromatic lnolCt)' that coold fit into the COX receptor. None of these effects IIll'l been uroequivocal1y documented in humans. The essen tial oil po~<csscs low water solubility. but tca~ used over a loog period o f time provide a cumulative tntdid nal effect. Typically, I teaspoon (3 I) of flo .... er head is boilcd in hot water for 15 minuh:S. 4 times a day.

""
DRUG INTERACTIONS

lult "*l

Chamomile contains coumarins and may enhance the effect ofpll'.'iCri ption amicoogulants. The herb is an antispasmodic and slows the motility of the G I trace. This action might dccrtll$!: the absorption of drugs. Chamomi le prepa1lIlions may be adulterated with c llamomile pollen. This may cause allergy. :maphylllXi~, and atopic dermatitis.

IEp d,.
TIle varieties of ephcdnl (I:,jlhwta Sin/Cll, nn-adcIUU. lri/urea. Ma hUlmg. n:llunt.1 ecstas),. ephedrine. IftUba ephe drru) that possess medICinal acti ~il)' grow in Mongol ia or .Iong the Mongolian border region with China. The plam itself, an evergreen with a pine odor, consists of green canelike Structures Wilh smUll , reddish-brown basal kaves. In the full. the canes, root, pod rhi70me are harvested and dried in the. sun. The. dried f11DleriDI furnishes the :Jetive ingredients.
ACTIVITY

""

Ma huang is a sy mp;!lhoOlimetk agen!. The active prtnciples :ll'C ,8-phencthylamillCS. : : r, 11lese agents can stimulate the release of epinephrine and norepinephrine from ne .... e endings. Ma huang is a symp;!lbomimetic stimu lant to the periphery as well as in the: ccntm neni05JS s),stem (CNS). It has positil'e inotropIC and poIiiti\'e chronotropic effects on lhc heart: hence, the herb ma), be danget'05JS to people \\'tlh cardiac discll$!:. The lUllOUnts of cphcdnl-typc compou nd ~ and the relative composi tion differ so widely that it is dim cuI! 10 be certain what one is gening in any given preparution. Ma huang's main active ingredient is the ,8-phcnethylarnifle compound (- )..ephedrine. Plonts grown in China f11uy con tain 0.5 to 2.5% of Ihi s compound . M5lJlY ephedrine congeners are represented in the plant, 5: and many ofthesc posscs.~ considerable phannacological activity. Some are as follows: (- kphedrine, (+}-pselKlocphcdrine. norephedrine. norpseudoephedrine, ephcdroxartc. and pseudocphedruxane.
H

""".

I"" R
'0

ChamtUlrilna

(-)-aalp.boW

(. >PP.u.L.od.<08t

*'.. . . . "",

912

Wi/WIt

(JItd

GumlJ's l'Ulboot ofOr~"k Mtdicmal altd PIt1H1MIt,i/ Ciw'...mry

\'CSted of seeds and skins. anti Ihc: rest of me fruit is UKd 11$ 11 drink or in capsule form. Cranberry juICe has been used for many ycars as a urinary U3Ct disinfectanl. In 1 923.~ I report said lhat lhc: urine of penons who COIIsumed cnnbcny jUlcc became more: acidic. Because In acidIC medium lunders lhe growth of bac1ena. il WII$ thoughl lhat aciUificlluan of tIM: urine inhibited bacterial growth . An analysi s of ctanbcrry juice show~ lhat il eOOlalllS many differtnt eom pournls. C ilric. mal ic, benl.Oic. aml4luinic lICids ore prescntns eurboxylic acid com ponenls. With pK"s of).5 \0 5. lhese compounds should exist in the ionizeu fOl1T1 in lhe urine at p ~l 5.5, thus lowering the pH, We now know Ihat aciUirlCalion of the urine is not !he cnlinl Slory, In fad, urinking Ihc: cocktail does not appreciably acidify !he unlit. Two other C(IIlSUluenlS exist in the juice: manllOllC and a high _moIecular_weight poIysaa:haride."- .M With b.'tcII:N thaI use fimbrial aUhesins in infecting lhe urinary tract. maltnose bmw aoo inhibils adhesion of Ihc: type I mannosescru;;itl\'e fimbriae. while the high-moiecular-" 'clght poIyJllCCharide inhibilS binding of the P-type fimbriae. He:1II%. adhe$ion of many escherichia coli slrains. which causeQ\'er half of all urinary tract infections . is inhibited. This inhibltion has the effect of blockin g infection . Dosage: Drink between 10 anu 16 ounces of juice lially.

.-A", ",-<,
Nofept""O i ..

H,c ..

O"'H
.... 'doep.'Jedo......".

Ma huang 's principal acu"e Ingredient is (-kphedline.

ThIs l'Olnpound is the t"r)"lhro-o( - ) isomer ~ ith Ihc: 2(S).3(R) coofi~ur:ulC)ll. The less poIent (+ )-pseudoeptiedrine has Ihc: ,hrro 2(S).3(5) stlllelUre . Epheurine actS as a mixed agonist on bOlh it and fJ receplors .
PHARMACOLOGICAL EFFECTS

Ephedrine 's llCIions occur through nll~t'u stimulmioo of the a- anu .8-atlrenergie receplOl'l. "fh.c dlllg is a CNS stimu lant Ihal increases the strength anti nile of cardiac COIItraelion. AUdlllOnally. ephednnc: dccrea:ses gllStne l"fI()\ilily, causes I)roochOOilalion. and Sli mulme! perip}.t!1 &1 Ya'iOConstrlClion wllh Ihc: predIcted increase in blood prt'SSUre. The rhT"t"O isome r I + )-pseudocpb.edrine cauSCll sImilar effects but is much ~, poIent lhan (_ )-<:phednnc:. The elalrl1li that epl)edra causes increa.o;ed metabolism and "fat burning" are certainly fal..e, anti t'phedm lacks aoorectk effects. Any report, of successful usc of cpheura preparations in weight IIlI'S prohably rena1 the 'limul unl or "energizing " effect :1I1d uloCreasW physical :leti" HY, In the Unitcu States, epheura has been IISCU as a recreauonal CNS stimulant (natural ecstasy). II. ''''I'/l/lt''1si5 ami tri!urm are typically used in tea.~. The FDA prohibits preparation s .... ,Ih more: than 8 mgfdose anu advises that one should not take an cphedru proUUoCI lTIorc Orten than elet)' 6 00u" anti no mon: than 24 mg/day. EphOOra shook! not be used for mon: than 7 Uays. I:losagd o,'er the recommended wnount may cause stroke. myocardial Inrarclion. seizures. anti death . Ephedra hllS been close ly linked 10 nloCthampi1etamine pr0duction , 110crc arc: nMWemnUS In rlUIny localities to outlaw tIM: IM:rb. Then.- arc: many drug interacllons wilh Ma huang , ,B-Bloderll may enhaoce the \ympalhellc effect and ca use hYJXnension. MAOI ~ may inlcfI\Cl with ephedra to t,:a use hypertensive rrisis. PhenUlhia1.incs might block the a effects of ephedra. cau_ing hypolen sion and IiIchycardia. Simu hane OIlS use of lhcuphylline may cnust GI and CNS effects. In prtgnallCY. ephcdro is :m..oluteiy conlflliridlCaled ( ut~rine Minlulalton). Pcrwn s wilh hean dISCa.o;e. hYJlCncnsion. and diabetes ~houlu not take cphedra,

Clnk. . bll.".
Ginkgo hi/aha (L.), also known lIS the maidenhair or Kew tree, Iw survived essentially unchanged in China for 200 million yeatS,fI(l 'There is a Chinese rroOioograpil dc!;(:rilMJ Ihc: use of ginkgo leavcsdating from 2800 lie. Today. gonqo is ClIitracled by an clIlremely compIClii multiMep process thai concenlrates the llCIi"e constituents and removes the tou:: ginkgolic aciU.M 'The ginkgo extracl is a complex mll!tUnl of both poQanti nonpolar comporll"nlS. 'The mon: polar ff",tCtion contain navoool lind navone glycosides. 'The more nonpolar fraelions conluin some diterpcne lactones. known as a:in~gettn, ginkgolie aciu, anu isoginkgetin. and some intcrcstingcag~ dilerpencs known lIS ginkgolide A. B. C . J. anti M.o.;: Thereis also a 1S-carbon sesqu;terpene (bilooalide) anti OIlM:r ffill'lCI' components. Gmkgo bj/obtJ extrael is prepared by pickl", the leaves. dryi", them. anti constituting lhem into an ~ tone-.... ater extracl that is slIIndatdi.(Cd to coola;n 24". n. vone glyoositlcs and 6'l> terpenes.'"

Gftgc*MA

"

er... b ... y
The cranbelT) plant (VocC/nium mlJCffl("tlrpm!, V.o.x)'coccus. anti V. I'n'rhmcarpumJ IS 11 traJl inl! e"ergrecn that grows pnmanly in aciuic s wamp lUl:aS, The ~hole benics arc: di -

Chllpter 27 All 'II/roducI"'" ro

I~ M<'IiicUUJI C~islrv of Hubs

9B

for diwnlcni of i1lt"00f)' tllal occur With age and Allkime, ' s lIisease. 11lc popular use for the herb is 10 hclp pJ"le Ihml beller uoder SIll'''' and 1 IIlCrease lhe: lcnglll of lIme that 0 ltldenl) can handle memal StreSii. someone (e.g. a S
Ginseng

HJ:'

OH

Glnkgolkle C

Ginkgo biloba produces vlIsodilatillg crfts Oil both the arteriul and venous cu'Culatioo.oo 61 The result IS irocrea.'>ctI tin ue perfu'iion (i.e .. in the peripheral circ ulatioll) alld <XI\<bral blood now, 11M! cxtroct produces arteria l vusodilulation (rodent lnodels). dampens ancriul ~p.bIlC!:r' and decreases capillary pemlCubility. cu pillary frugility. el) throcyte ago gregation. and blood viscOSIty. Then: an: .several possible c\plan;\tion~ for these cffts. One poIisibilily .s Ihlll the rompotmds In Omkgo biloha extract inhibJl pfOSta,lllIIdm arM! llirombr;mme biosynthesis. It has al'iO been speculatcd Ih3t OinkSII biloha elltr.lCt has un Indirect regulatory eff1 on caIhoIamines. Gintgol ide B is reponcdly poIeni tn hlbuor of PAF. II III allY case. lhe effls are due 1 a mixture 0 of tile cOfIsl rlueni S. not II sillg~ one. GinkR" bilolHl has be<:ome popular because of II, Illllalive abi lities 10 irocrclI!ie penpherul and cerebral circulmion. The herb is cul lL'\! 1111 mfapw,ell. <>J a dru g IIiDI hel p~ perM:IIl S handle stress. In the: periphery. the herb h: bee n cOlllpared 10 pelllo., ifyilme. If the propcnics are tlllC. the herb could be used for intennilleni claud icat ion. If cerebntl blood now ~an be lnauscd Wllh Ginkgo bilolHr, the he:rb mlgllt be use ful

Ginseng is the root of the: ~peeICS Pana.r q",nqr/.jolilH. Thl~ fonn is l'OlIIrnon Iy known II) Anleric~n. 0/" Western. ginseng. llIc shape of Ihe root i ~ ImiIOMan! 10 many and may make il highly pril..ed. PIIII(U means " olr ' or man. Sometimes. lhe: root is ~huped lrte the figure of a human. llIc doclnne of sig nalures would say thai tllis root wou ld benefil the wl1o~ penon. AllOIher species of ginseng. P. Sins"'"g. ISCOflll1lOl1ty callcd ASian. or Korean . gmse ng. Chemically. !he 1100'0 species are "cry "milar. MaJor CQmpotlt'nts are n:anled the: gilUt'lIlJ5id"J," TIle chemical COfISlituents o f ginseng an: called /tUUt'lIoJidl!J or fNIIIIl'(',Jid'J. A [Olal of 12 of the:!iC have bt'cn 1-0lalcd but nrc present in ~uch 'iIll:1I1 quantities Ihat purirlCDtlon is diffi cult. Slcrol ~. na~onoi!h. prolein~. and vitamins ( B , B~. B, 2, pantothenic IICld. niacin. and bi<,)li n) all' also components wi th phnnllllCological t1Ctivity. TIle chemi~try of gill' seng gives a good c.'(Hlllplc of how lIifferent compoonds in one herb call hn,'c oppo!iing pIIannacological efft;;,W GinscrKlllide Rh 1 lIClS as p eNS depressant. IlJ1ticonvulSllllt. analgesic. and antlp')'ChoilC. prevent s Stres5 ulce ...... and k eelocr-lles glyrol)'sis and nlJC~ar RNA synthesis. Grnseooside Rg 1 Slimulata; the central nenous sySlem. combat~ fatigue. is hypen.:nslvc. and aggra\'llte Stress ulcer);. Addllionally. gi nscnosilks Rg and Rg-I enhance cardiac performance. whi le Rb deJl'\'.~ses Ihat function. Some of the OIber ginseno~ide:s display allUarmythnue octl\'r ty simil ar 1 that of the 0 ca ldum channel bloct er \.:rnpamil and amiodarorM:. GinSCllg i ~ popularl y belicvr:J to enhancc concemnllion. 0 siamina. alenness, lind the abilit y 1 do work. Longer term use in elderl y 1)lIllenl~ is claimed to enhance " we llbeing: Theil' arc: few data fronl human siudies. Clinical studie S COIlljXlring grn<ocng to placebo on cognitive function tests showed statisticall y i n~ignili calll improvement. Nevathc

HO

o.t< f' '"

OH

OH

'"- , '" , " ""./ . "'-

"/

0<,

HO

A , :j.-/'-./"''''''"'' CH,
H

CH,

CH,

(R)Oins&nOlllOl

less, gin.'iCng IS a popullir herbal product n:commendcd by

lhoe Gemlan Commission E.

MUk TIIbli.
Milk thistle (Silybum mliriClrlltm) IS a member of the Asternceae. a falll ;] Y lhat includc,~ daisies. asters. and 1111511 cs. The plant tla~ a wide range IIfOOOO the world and is found llI .he Medi lelT2nl:an. Europe. North America. South Amer iea. and Austnllia. TlIe seed~ of the milk Ihislle plant ha\~
been used for 2.(I(X) yt:!'" a.~ a hepaloproleclant. ..... 61 Th is uSlIgc can be ItlICed LO tile writings of l'liny the Elder (liD 23-79) in Rome. who reponro thai Inc juice of the plam could be: u.ed for "call)'ing offbik:.' Culpepper in England reponed thlll milk thistle was usefu l in "removing obslruclions of the lI\cr and spleen and aguinst jaundice:'

CHEMISTRY

Mill. thistle contains as an kli \l~ CQIl.~UIUl'nl \ilymari n.... which is IlCtually a mixture of lIuu honlCnc navanollgnans:
silybin (si libinin). ~i lychrisli n . and silydiani n. Silybin i~ the most OC1i,'e hcp;iloproteclant and arujo~idant compound of the mixture. AIJo present in the plant are the f1avanolignans dehydrosilybm. ~ilyandrin. silybinomc. and silyhennin. Other lipidsoluble eompooents are apigenin. silybonol. and linoleic. oleic. myristic. stearic. and palmi tic acids.

,r0-J\',,."

J
""-<,,,,,~

"'''''''''-/'--...-'''''''
Silymarin

.... hose steroid structure ,~nmulatcs both DNA and RNA IyntheSIS. Through these IICt ivities. the rcgenenlli YC c~ity cL the liver is activmed. Si lymarin is reported 10 alter the 01l~ cdr membrane structure of li,er cell~, blocl.ing entrantt of to~ic substances mto the cell. This blocl..age i~ \0 pro. nounccd that il can reduce the death rate fromAmlllllloplloI toMes poi~()nin8. Silymari n's effect can be explained by its Dntio~ idant propcnies: it so::ayengcs fn:e rndicals. By !bit efftet. the le"d of iruraccllular glullIthione rises. becumJlIJ a\'ai labJe for other deto~ifK'ation reactiO/U. Sil)bin inhibit\ cl1 f.)' mes lil e lipo~)genasc.'" bloeli ng pcroxid:uioo o(f;j/\y ocids and mc mbrune li pid damage. Swdics also ~h.uw tIw silymarin protects the Ih'er from amitriptyline. nortriptylillt. earbon tetrachloride, and cj(platin. When tn:ated. J1i11C1Ib wlIh alcoholic cirrhosis sOO ..,..ed increased li\C~r funcuon as measu red by el'll:yllle~. [n palicrus With acute Yiml he~lli ... silymarin shortened treatl1lent time and illlpro"~ a,'part ..1C wninotransferue (AST) and ulamne aminotransfera'IC (A LT) levds. In liver disca.-.e. si lymann appl'~ 10 ha"e un ImlllUi" modulatory effect. llIc: IIC\lvities or ~uperoxidc di~mul3$e' (SOD) and gJutathiOlle peroxidase are increased, \\-hid! probably accounts ror the effect on rl\,"e r.JdicaJs. Silymann, however. hal. lUI I1I1li- inflammatory effect 00 human plMlell!. Si lybln retllrds release of histamIne from human moW cells and inhibits lICliYat iOI1 of T lymphocytes. 1lIc ehcmlcll appear.; capable of reducing the lewis of all immuooglobulin c lll-~ses and enhances the motility of lymphocy\eS. MII~ thIS' lie exlract and its components ha"e shown efficacy In rrnt ing hepatOioxin poisoOing. eirrhosi~. and htpallllS. It .Iso plays 3 role in blood and immunomodulotion and in !trills and biliary fUl\euoo . llIc: oYerall effect is due to the el1 f011 5Ca\enging Pf'O\)enies of flaYllnohgnan,. the enhallC61 rrgenerath'c capacity of the IIYet'. and the aJteration of b,'C!' cell mc:mbmnes that blocks toxin entry.

V.terlan
Valerian (Vo/t'rian(l offjrtnlltis} is found tn tempt'ralt ~ gion~ or NOI'Ih America. Europe. tmd Asi . The dned Ifulome of valerion contains an unpIe3~antsmellinll ~oIatllr oil that is uttributed 10 i<>oyaieric acid. Despite the odor. valerian is a urI' and effecli\'e sleep uid.

MECHANISM OF ACTION
The silymatin complex i~ aptly suited for its hepatoprotec tiye actions.'" Silylllarin undergoes emerohcpatie cycl ing. tnoy ing from imes.tioe 10 liver and concenlr~li ng in liyer ce ll s. Protein 5)'nthesis is induced in the liver by silybin.

CH EMtSTRY
Three classes of compounds ha\'c been Iltl~ed 10 the "CdallVl: propenies o r yalerian. The rhil.Ome OOI1taim. JI1onoterpt'1'It'I

Ch~ I"~r

27 An IntrOOuclio,. 10 II" Mtdlrll1ltl Chrm"""" of U"bs

91 S

arid SC'sqU"crpt:lles (\ okren1c ocid and lIS actlo"y dc:riva 'l~e). lriOOids (ulepolnoates), and pyridine alkaloids ...... 70 -AI present, il L~ not po!o~lble 10 , tble which cla, of compourld ~ is responsible for.he ~all\e actIvI ty. Most l't'SC'MChcn beI~ve that the ~ah:potn();ltc: IS the llelin' component. bu. 'i01lM: ~tlllli~ hllle shown tha. ~ale1'l:1lie ocit:! i~ nlCW'C poIcn!.

OH

the monotcrpcl\C pu1Cg<lI1C.1I The oil also oont3.ms tannins. a-- nnd ,8--pinenes. other terpt!IK'l.longchain alcohol~, piperilenooes, and par:lffin. The toxic!!y o f pennyroyal is believed to be due to the puleil0llC7 1 in the oil. CYlOd.rome P-4~ cataiYI. the me tabolism of pulegone to ylC'kitM tOAic metabolite n!Cnlhofllnn. Possibly, some of the othC'r tcrpenc.~ undc:tgo o_ilb. tll)l1 10 acrj"e mctabohlO as well . Memhofuran. metabolltcs of other tcrpencs. and pulellOllC Itsclf dc:plcte hepallC gluta thlOne, rcsulung in h"cr failure . This .ner;h:mls.\lc hypotllc:sis IS suppor1cd by \hi: fact that administnllion of act'yicys.elne re\erses the toxicity.

CH,

C",
Pennyroya l lias been used as an nbortifndcnt SUlCe Ihe time of Pl iny the Elder.n an insect repdl en t (Ihe terpenes in the oi l halle ci'Il)I1ClIa l li~e propclT ie9. an nid 10 induce menstru ation. and a treatment for the ~ymp' 0n\S of premen~tlllal syrldrome. It has alw been used as a nea repellent on dogs and cats. When used as an abonlfllCient. the dnJg often causes liver failure and helllOl"Thagc. lear.lmg 10 dc:ath. Pl:nny!"Oyai IS 5011lCtinte<> used wuh block cohosh to occcler.!!e the aborti fa eient effect. Coma and dc:ath have been fCported. Penn)'ro),al i~ an enmple of an herb thatlla., no 5afe u~s. 11 shouki not be wid.

, / ' V,OH

HeiLa. Drugs Used In tIM TN_ booe nt.' Cancer

Aqueous and hydroakohollc e~ t r3Cl5 of valerian mducc: the I't'h:asc of 1)111,..ammoblll),ric acid (GA IJA ) from synapto'iOme prcparntion~. 1be eltfllCtS appear 10 ha lle much the .\arne effects as ben/.odia/CI)i"". e~ccp' .hat \'o leriun does not act 00 the Na '/K ' -A TI'use. Valerenie acId mhlbi.s Ihe GABA transar11lnnsc. TIns effect would increase lhe inhibi tory effect of GAllA III lhe eNS. 11Icre i~ no doubt that valerinn i.. \afe and effective U~ 3. .Ieep aid. U\Cd lllupcriy. It is one of the 1l1Ore I\cornrnend able herbs. Dose: 400 10 000 'ng \ tanr.!anlifcr.! c~truct V to I hoor 1 before bedume. Anticancer drugs derilled from biological 'lQUn:es ~ faIrly common arid ore among the n1O!it important in the therapeutIC armamcntanum. Drugs like doxorublCLII. mitOl11ycin C, mithramycin. and bleomycin ha ..e been around for a 1008 time arid have shed much light 00 the tl't'atme m of cancer. Thl't'e pl ant-derived drugs thai ha lle found lheir way through clinical tnals dc:scTlle menuon IIcre. T \\.o of the m~t famou~ arc .. incri,tine arid vinblastine. "llK'..e arc compounr.!s i~<r laler.! from the pcnwinkle pl nnt C(IIhtlflmlh'lI rose"s. The Vinca alkaloids bind lightly to tubulin in cd ls and imerfere with its nonnal function in spindle fommrron. 'nlC Vinca alkaloids make Ihe tubulin less stable. The net result i~ metaphase arreSl or ce ll division. Pac1ituxcl (Taxol) wa~ originall y i'iOlated f!"Om the needles or bark of 11M: Pocific yew . Because it QCCUI"l!i in vanishingly small coocentrnuOll in .he plnnt. a ...,misynlhetic rnethod for its production was dc:~cloped . Tuol binr.is to .ubulin li~e the Vinca alkaloids, but 11 n\dkC's tM tubuhn struetun:: hYPC:NUlble so that it cannot runction. Agoun . he nct result iJ metaphase
~,.

Pennr-yal
Pl:nny!"Oyal (Ifrdt(InI(J plllegro;lu1. Men/hit pultg;llI/I) is an example of an utremely tOAic herb. 1be plant is a member of the ,mm famI ly. Lab,n'ae. The r.lner.!lca\cs arid nowermg tops of the p/;mt coo!!,," from 16 to JO'l> oi l. consisung of

5UCrosc.

aqueous t'XtroctS Jllay CQllUUn 1010 20% gly<:yrrhllJn . When the herb I~ Ingested, the Ink5urui

ConccmrJ\ed

nor.! calalyu the conversion of glycyrrlu7ln mto glycyrr

~ic acid,

the: pharm3l;'ologl(':llly 3Cti~c compound. Glycyrr-

hil.in and glyC)"rrhelk acid possess mild antHnflamlll.llOl} propenu~s.. GI)cyrrhil.in nppears 10 ~u mul~te gastnc mllCll'o !iI'CU()l1. TIllS may be the origin of tile nnuuk:er properIleS of liconcc. Glyeyn1l1l.in and glycyrrilcllc acid do !lO4 tr.1 directly as bteroids. In slead, they potentIate, ruther tlWl mimic. el1d()gcrlOtl~ compounds.

o
HO

".""."
....

, ,

[
Lkotice
When ...c 1I11nk of licorice. we tYPically 111m!. of the popu lar candy. Licorice. howc:\'er, has an imponam hi~lory in herbal medicine. Licorice i5 a perennilll ~hrub thai j\ indi!lenou~ to the t.k dl temmcan and IS culuvatcd in the Middle East. Spain. nonhcm Asia. and tile United Slalc~. The 1110:;1 comInon variety uscd for medicinul pUrpDo.!!$ is GI.W:\frhh/l gllJ' bra var. rypka. Lioorice has been uloCd since Roman times and " -as described in c:irly Oliroese Iritmgs.

CHEMISTRY

Tl1C rooc and mwJoIl1eS of the licorice pllUll comam approxir!latdy 5 to 9'k of 3 stc:roidal glycoside called glvcyrrlli:.u. . In the glyCOj;ide form. glycyrrhl/.in IS ISO UI1ll'$ swocter than sugar. AIS(! present are tnu:rpenOtds. gl~l)!,oi,'. rnanl1Qo:Se. and

Then: i~ 50lne nllcresting folklore rehlling to tIM: uo;c of "<"oriee. Dunng World War II. a DlIIch phy~ician1l !104Ktd that p.'IIem . .... IIh pcp/ic ulcer disease unpro\'ed drunullCaJll .. hen treated WIth a paste cOlllaming 4O'J. lironee eAIJXI. The physician In:nled IIIIIny pallents in thi ~ way, but dun,,! the COll.l"Se of his ",or!.; he noticed that there .... as a sm<M ~idc cffecl from the herb.11 drug. About 2O'k of hiS um p'lliell!) dc\clopcd n reversible edema of the rKC and t\ tn:nlltJe~. SlIlce these original otJsc,rvati()l1S, rnany ",ud~1 h~\'e b..'Cn coOOuch,:d .... ith licoric.: rOOl. The findmgs hlIle remained the sa me : licorice is useful for pep/it ull'('r di;.ca)(':, but potentially <;erious mi ncrnloconieoid side cffects an:: fIO!I~ible (lcthargy. edema. headacne. sod,um lind water I('tcn' liOll. C':!tl"C$.' C':llcrelioo of potassium, and increased blood pressure). Licoricc (':)lens us prorCCll\'C cffe<.1s ()I1111e gasulc mOC'Olil by il1hibmn, twO enzymes. 15-hydro~)'pr0513ghllldm deb) dmgcnasc and .J "-p!'I1Uglandin n:dUCIasc. InhibltlOll 01 these clU.yll'leS cauSC$ theIr SlIb$/r:lles 10 111CITil..<;C In lOlll .... trntlOll. incretiong the icvels of prostaglandliU on the lIMn(; mucosa and eau~ing a cytoprofc:ctI\'C cffc:ct, The acid al'iO inhibliS I I .~h)droxystcroid dehydrogen:lM:," thu . 11'11:11:.... ing the glucocOftlcoid conccntration in mil1oeraloconlCOid responsive tj\i'Ue~, cuu,ing iocreascd sodium retention, potass iwn cxcretion, urtd blood pn:ssun:. In 1he 1%Os. n semisynthetic compound b:l...:d on ~I)c)rr IIctic acid. 4-0'!iuccinylgl)cyrrhclic acid (cW"berlOloIOl1(~ was imroduced in i:umpe. II proved dTeclh'c ogain~l pI'fllK UICCT d iS('3.loC':, but it wll.~ lalcr sho....'n to be infcrior 10 the H.. ll'Cep/or antagoni'ils. LK:orice 1~ al"" an cffecth'e demu lcent, \OOIhm, SOft throat, and is lUI e~ptttOl1l," and rough ~uppn:"'''lUl1. LK"OIlCC.' can cause: M'rious ad\C'r.ie reactIOnS. 'fbc:sI: _ millMlllJCOflicoid effl't.1s (pswdoprinury aidoJlteR)llllollll mUSlk ....cakness. mabdomyolysis. and hcan failun: . Poi.... ing by lirorke i~ insidious. Long-tenn high du!in an: tl

IIrolC: ly IO~ ie. Liroricc can poIcnliak: lhe dlgilalis Il lycosidcs and cause t01'icily. With cMlliovascular agent.'! mat prolong the QT mlen'al. the effects may be additive .

J.! M...,..,. I 1_ IcpI'MUl . S.. MMlM,"' ..... LI It. A '" 0I ... . IN_.91. .
n. Cui ..... II O. J . a ..... N M . M ...)urWd.{J ........ W J . MMI Sz d. S A'""",,", iinz 923. '980. ~ M......j&.A. M~ MMlB .. Iey.1 M """,,:'05-'.1981 )1, M&ht,a.A M ._IlatIcy. J M ....... ,,1 ', ... l.ftokolnonooM<d.
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tcU", <""41Ol1ndt. I...... ,.,.,. L I) . ooood Ih'..... It (.u,..~ . - . of toropc. CIocmi>uy l1l<I 0 ...........1 Ac1 .. n) A"""","" CIoctni

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Plow M*". 51 llU-I6S. 1992. 2L J............ M J 0., Oocm \2, 1640----1641.1%7 29. 8 ...... R.. Ron,ilft'. P.. ond W........ II .. l'hy"","'nu>l'Y 2H.s.M-S08.

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......... '994. p. '09

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JO. II ..... It. EdIi........" Iholo,""" cff_ .... prinapic>., In L.o ... ..... I.. 0 .. ..... a .... It. (".1 l'Ioy"'",o:d ..... '" F..-, CIormosuy ... II"""""", AcU"~y ... oncricIn Oocm""" Socoroy S)......... Se ne .. 1'1""" V"'l. o.ront Unll, ... llY """'. 1998. Po ' !SO, II 8_. II. 1' ............. 8 .........1df..". ..... pru.dptc>., In ....... ,.",. I.. D~ ..... 0-.. II (edl.). PIor-",,,- 01 ~, ~ - ' O~"' . . al AcU"zy. A......cIIII Chet.oeaI Sox"'y S)D.- I".. Se rie!.. New V",l. o.r.... Un .. n~ny"""" 11l9ll. pp. I jj- I ~

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28

Computational Chemistry and Computer-Assisted Drug Design

J. PHILLIP BOWN

1lIe ad"cnt of pow.,rfill and ;rtexperl~i\'e computer.; has re\'olutionil.eti science and medicine. Medicinal chemistry is no exccplion. Today. drug dc'ign n~lhods ure widely used in both industrial and academic Cilvironn\ents. Through the u!\e of computer graphics. ~t ruct ures of organic molecules can be emen:<! into a computer and m~nipulaled in many way~. Computational chern;.try methods are u\.Cd to calculme mu.lecular propcnic~ and gcncnue ph~lmt:lcophore hypolhc..es , Once a ph:lmlucophOf"(' hypothesis has been developed. lllICluml databases (comnl(:J\:i,,1. corpomlc, and/or public) uf three dimcnsiorml (3D) structures can be searched ropidl y ror "hi\s" (i.e .. existing compounds thaI are available with the required functional groups and pcmissible spatia l orientations as defined by the '\earth query), It has become IXlPUlar to can)' out in si lico screening of drug-receptor calldidale inleractions. known as 1';r1Jm/ high-throughput screeni ng (d ITS), for futur\~ de~'elopmenl. The fCalistic g0.11 of ",ITS is to identify poIcntial lead compounds. The drug-receptor fit and predicted physicochemicol prorcrtie~ lire u;.cd to "score" and "mnk compou nds according to penalty functions and information filters (molecular weight. number of hydrogen bonds, hydrophobicity. etc.), Although medicinal chemists have alwllY s be1:n aware of IIbsorption, distribution, metabolism. e limination. and lO:<ici ly (AD MIT or ADM EJ To:<). in recent years, II much more focused approach addres.w~ thc-e is._ue, in the early dc~ign stages. This is logical when one considers the compelling stati stics associated with clinical el'aluations of tile s.afety and cfficliCY of new drugs. Only approximately 20% of oollllXlunds eml'nng cl inical trial s emerge as morkctable drugs. locmascd efforts to de~clop computl'r-based ab.'>Ol"ptioo. distribution. metabolism, and elimination (A DME) models are being pursued aggresively. Many of the I'r~,lir:I;"~ ADME models use '/uantitati,'e structure activity n:lation.~hip!!' (QSAR). In gener-JI. understanding what chemIcal sp::e descriptors are critical for drug lil.:e molecule.~ helps provide insight into tl: design of chl' tnical libraries for biological ev~luation, With the aid of rnoleculor modeliug software. pharmaceutical sc ientists can modi fy the Mructural fea1UfCS of a poIcmilll drug candidate in ~ilico ~nd make predictio!ls about its physicochemical propen ics prior to looor'JIory synthesis. Crystallographic infommtion about lhe re(.'Cptor has allowoo ..dentiSls to usc structure -oosed drug dc5ign approaches wi th tangible ben.cfit~ (i.e .. marketable drugs). GI\'cn tl: difficu Ity in preparing organic compounds. one can immediate ly appreciate the ilO"'cr Ih"t compu terbased method, offer. Obviously, lhe t'Olnputcr-generated models must be IK~Ul"llte enough to give scientists a high degree of confidence in

them. This me~ns thaI the com pUler results muSI be com_ pared wilh e~peri mental data. Regard l es~ of the intellectual appeal of ('Ompuler-lI~sisted drug ,iesign (CA DD). lhe methods must be vali dated for known cases to give confidence in the many ~i\Uation~ when the 11ll'lhods will be applied 10 unknown cases. The inherem differences between a model and r~lIlir)' shQ\Jld always be appreciated, wlH:the r computer s imlli alion ~ are being used for drug design. "cather forecast ing. or et'Onomic prognostication. The obi Iit y to calculate molccular properties. coupled with visuali/ation of moleeular structures. has grcatly bel)Cfited scientists involved in drug diSCovery, Computer models of drug molecules and drug-receptor interactions are commonly found in thc: sciem ific literature. Olle would be hardpressed these day~ to firnl ajoumal devoted to drug diSCQvery withOUt one paper .~howing computer graphi cs representations of drug mok'cuks. Drug-like mulecules can be displayed with molecular su rfoces and eolor-coded au:ording to solvent oct-.:ssibility, e lectrostatic potential,. or other properties. With molccular modeling software. it is easy 10 ~uperimlXlse IWO or more molecules. Evcn ptmrmllCelllical illdustry llmrketing campaign s have brightly colored repre semations of drugs and their molecular surfaces splashed OIt\O magazine ads or swirling across television sc~ns, In the 1980s. skeptic~ oCtile use of computerbased methods for drug discovery often asl.:ed the qucstion: what compounds "'ere designed by molecular modehng metllod~? Few conlineing e~amples could be provided during this period. sincc CADD Ilad only been in existcllCe for a few years, Furthermore. because il is not uncommon for a drug to tal.:e 10 or more years fr0111 the design stage to final approval. too fruits of CADD would not be revealed umil about a decade later. Unquestionably, In;llly of the major ad vances in medicinal chemistry have used mriOltal drug design but withouT computers. In sume respects. the IIUe.'lion regarding CADD success ~tories is fundamcmall)' flawed, in Thm no olle typical! y asl.:s OOW many drugs were de!;iglled by a si ngle scienTific technique (c.g .. nuclear magnetic resonatv;:e lNMRI SfJ(:Clroscopy), The NMR analogy wa.~ the oftenquoted re~lXln.>t: by computational chemists. In reality. drug discovery is so ulldcniably ~'Omplicated that no one si ngle method geller-oIUy can be crediTed for the complete dc5ign of a drug. An arsenal of methods frOlO di\'crse scientific areII-' is brought 1 bear on drug diSCQvery problems. TIM: 0 scientists involved ha\'c 1 interpret the dum. Although mo0 lecular modeling methods are just Mother tool 10 help scicn tisl.~ make infonncd decisions on what lead compound~ to pursue alld whaT stnlctural featureS should be rnodified to

91.

enhance btoioglCliI activity. there is an Inherenl lIppcal IIS5Odated ..... ith \,isuali/,utiOfl and predictions. In the final analysi~. scientists.. not computcrs. "dcsign" drugs. CA DD has IWO fundamental roles to play in drug research: lefUl disl'Ol'ery and InuJ dt'l~lopmerll. OuOIl8 the late 20th ~nlury. there were many case hiSlOo nes of accurale predictions of in vitro biologIcal activity ba.'itd on so-called rllliOltlli urug design aJlllfOKhe~. In the 197Ol;, Corwin Hanseh demon~t.rated tnat simpk- rt'gression swi~ics cou ld be used to COfttlate bioloJlical activity indiIUdy 10 molecular structure through physkal propen io ~uch as hydrophobici ty (log I'). electron ic (u). and slcnc (ET) effects (Chap!eT 2). 'The seminal COIltnbotions of Han-'iCh dcmooSlrnled the povoer of QSA R and he lped 10 usher in the era o f com pule r-based model ing for molecular design. Beginning in the 1980s. there .....ere many reporu or com puler bilset:\ predtChOOS of tn vi tro biolo&ical activi ty. TIlls IS 110( unreasonable. ~ince then: are fe .....er pharmacodynamic and phanll3Cokinetic variables 10 be considered with in vilro testing than wi lh in vivo tc-~Ii ng. 'The use of slructure-ba..'itd design has gro ....n in imponance since the carly 1980s. Today. there are many ex.amples of drug.' on the market or in cliniul tria ls for which COIllputcr-b,lsed melhods. particularly ~truct urebased drug design. have played cenu"dl wle... in thei r developn'lelM. No si ngle chapter can provide all the dellli ied infOffl1lltion necessary to master this specia lty. which ra nges from quan. tum phy~ics t03D iliuabac;c searching. Many of the subtopks discussed hase h3d entire boots or 5('rie' of bool5 Ue\oted to them. and a complete discus..~;on of each topic i~ simply bocyond the scopeofthiHhaptcr and the purpose of thc book. Instelld. the gool of this chapt er is to provide a brief and accurote ovel'\liew of a select Sl'I of compullitiOllOlI chemistry and CADD methods. highlighted wi th examples when ap_ propriate. In SQme cases. the COllCCptS arc simplified or gt:net'1lli/.cd 10 ma ke sense of them in a few pages. but this is done wi thoul SlI(:rifidng accuracy SO thai the interested reader can continue future studies with a solid foundation in the fundamcnlals. Finally. compu ter-based methods do not Il,'plllCe C)(penml'n tal me thods. In rllCL the purpose of CA DI) i~ to aid pharmaceut ical scientists in the discovery proce~s ..... hether thtoogh simple \ 'isualiuuion or the com piC)( formulation o f a pharmacophore model and SllItislical modI'ling.

COMPUTER GRAPHICS AND MOLECULAR VISUALIZATION

Ever since chemist~ have la.vgni1.cd Ihal molecu lcs are made up of atonts, there have bee n cFfons 10 represent 11100 ... lecular structures accuflltely. One of the. first allemp's to de\'elop molecular models can be traced 10 the earty ISOOl> \\-Ilcn John Dalton used \\-'oodcn spheres dri lled wilh holes to accept meta l rod lin kers as representations of at()m s and chemICal bond.o;;. respectivcly. 'The origi nal mechanical mode ls are on display at the London MUSel.lm ofScicnce. l . l Prior to compu ter graphics. the fundamen tal pri nci ples now associated with CA DD (or nlO lecular modeli ng) wen: used for some landmark diSCO\'mes in structural biology. Unqucslionably. one of the most widely n:oognlud scien-

tirlC achie\'ementli WIIS the conSirueUOl1 of a DNA model proposetl by Walson and Crick in 1953.l 1lle structure 1m wi thstood the te~t of time. lelldmg to II shared Nobel I'n..if for Wlltson and Cnck and seu ing the stage for the age of biotechnology. Imllally. crude moOel~ ..... ere crafted from cardboard. Once a beller un.Jc,...tandm, of !he structural 11:. quircments of the nucletc acid~ was de\doped. liMn ami rate physiealmodc ls \\-en: prcpull,'d from IllCtal. OngHl<Il1y. the int"OlTttt tautomeric foml~ of the hell:roqcik ~"'M used. 'The intOl'Tett tautomeric forms did not 10 Illy viable models of DNA. but OI'K.'C Watson and Crick Itanttd lilat the u lder litertlture was in c rror. they had new nuclc" lIICid models prt'pated based 00 the new ~truc1Unal daUi. Willi !he COI'RCt phYSICal mode ls. coupled \\nh their knov.kdgr o f the e~pcnn'lental data aMIOClated With DNA. they "m able to ~'Qilst ruct the double helK:al Structun:" - an e~cdletlt eUlIlple of the po"'er of Tin~enoy sets in the rlghl ItaIIck. 'The modeling pnnciple... used by Wat-on and Cl'd to arrh 'e at the COlTCCI re~ntallOn of I)NA \\-ere prt>lW>l) used by Li nlls Paul ing. who l'Om.'Clly pl'l:dicted that prottin<i wou ld adopi a-helix or .8-shect confomtations.' Pauhng~ pled that solid molet\lJar models " 'ould assm In under standing molceulnr struCIUn:. pan icullU'ly JlI'Ofcm StructllltS Solid mode ls. in which the atomic sizes of the CQlI)tnuall atoms an: designed accul1ltcly to renect the relame sQc:\ (the van der Waals rdtiii). wen: prepared *XOrtlinllO !rtur national Union of Pu re aoo Apphed Chemistry (lUPi\Q guideli IlCli. 11w:se space-filling molecullU' n!Odds. known as C PK models,l' became comnlCrcially avatlabk- . They IIlI'T been used around the world 10 he lp unde,...moo lhe mokaJlaJ shapes of proteins and nucleic acIds :coo theIr tnlet1lClKD ..... ith small drug-li ke molecules. Comlllercially available handheld tncchanlcal modc:ls be came popular after !he impre<,sI\e structural pmIiCliOllI ~ the a-helix and ,8-Shc:t:1 conformations for protein_~. 1\ uD as the double helix for DNA. During th is tunc. bulldin~ [)II the wor!. of earlier gencmtioo).. S ir Derek Bartillt. EmN Elie!. and OIhel'll dcmonstrJted the imponance of conformltional and stereochemical effects for ~mall organic m0lecu les. Medici nal cilCl1t ists u<oed Ihese models and cl11p lncali) Ueri.ed rule~ to develop hypothcse:s for drug - rccq)IOr HIleI" IClioos. Wooden ball-and-~tid: models were used b) hlp school and college Stulients to help ~ 1s.uaIi7.e organIC WI1!C. lUres. Accurate metal Dn-iding and Kendrew ntodcl~ an: ~tiJl uscful. 1. I l1tcse physical ntodels ha\'c the :J(h:cnlalC that medicmal chentistscan bold them. manipulatr them..Mgt a bener feel for the structural ncltibi1lty. NeverthelN.larrt macromolecular models usually had 10 be supported by saf foldi ng. and they were notoriously troublesome 10 modi~ and manipulale. Il1Iagine the diffieu ltlt$ associated ...... modeling the intercalation of ~mall poIennallc.. ~t1'1Jl11111'S into DNA. The DNA structure would have to be cranl.aI open mechanically. and the ~mall potential inlere-;];;;; would ha\'e 10 be inserted aoo manipulated by hand 10 gt the best fi t as detemlined by Visual mlipechon. Manipu lation of computer models i~ much ~uJXrlor lOtbe' use of IrwJitional physical models (as loog as the eil1K>", is flowing). Mathematical mOdelJ using quantum mcch:lruo:l or force field methods (see below) better account for tK inherent nellibi lity of tnolecuks than do hurd 5phere ph)'~ mOOel~. In addition. it is easy 10 ,upcrimpose one or_ molecular models 00 I computer and to color each Slrumrt

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wpar.tld) fot ClISe of vlel'lng. Med,clnal chennsts usc the Mlpmm~ MI'UCIUn:s It) ;denlify the J1CI."t"SSW)' ~I ruclurnl featuTU alkl the 10 urM::ntahon (pharlllac~) respon!>ib1e fOf!he ob!;cocd hlOloglCalllCll\'ily. The display of the lIIult, ple conformaliON "'ail:Lb1e to a , ingle molecule can pro"de ,'aluable mformalK)ll about lhe conformatKHUlI ~p:ICC 3nllable to drug-like mokcules. Rather lhan meaMlnng bond dl~l:Ince~ I'ilh a ,ukr, b Will> dooe years ago wlIh h:mdhdd modd~, it i~ relat ivel), easy to query II compuler-genemted molecular di<,pl:IY. I1l!Cilusc the coordinates fur each atoll' are siored In computer memory. rnpid data retneval i ~ achlc~l'd . Moreolcr. the shape and ~i/.e of a lIIoll!Cular "yMem can be visual iLtd and qualllified. unlih !he $;IU:l110n I' ;Ih handheld model~. I' hen OI1 ly I i$ual in.peclioos arc posSible. Exactly how much energy docs il eOfiI It) rotate tor;;on angle, from one positlOO 10 the lIC~ t " Undcrl;tanding drug ,olunle' aoo molecul:ar silapt', i ~ cnllCally important ",hen dcfil1111g the wmplcmc:ntary (ncgall\e 1'Olumc image) rttcplOl' sua oordcd 10 acrommod:lle lhe drug moleculc. In the IY70s. major !ldl'~ were made by computcr "denllsts bccauo;e of i1lCrea~tng computer ,peed,. I'hich al_ lowed the genemllon "f computcr models ana log,m~ 10 lhe handhl:ld tncchonical models. Int cll:Stin,s ly. the groll- th uf compu tcr gmplllc~ \.Ol!ware was dri vcn by the need 10 ha vc oomputer-lI~si,<,ted design (CAD) tool_ rOl' the airel'llft manu fllCtunng .OOustry. In the early 1980-. wfIware companies emcrged that de\elopcd aud ~d model-bulld",g 5Oftwan:: to the pharmaceutical aoo agrochemical industncs. Today. then: an:: man)' different 5Oftwan:. COIllp.:tnlC\ 111.:11 spcclOh/.e In thl: mle!'1ll;til'e manipu lations of computer-ba.o;cd molecular unl&e~. Ulgh-re~l u\lOl1 computer j!r.lphic<. hnle n:lolunonucd lhe wa)' drug design ;~ carricd OUI , Once ~ 1lI01t!Cular \true ture h.a.~ been eltlerc\l mto a molccular modehng software progr:lm. the stl\l('ture cun be, IC"cd frotn any de.,red per~peCI' I e. The dlhctlml angles can be: rotaled to gc nerate ne" coo fofrnutioM. aoo funt1ional groups c:m be eliminat ed or modified ~ll1lO~1 cffoolessly. A~ i ooieat~-d above. thl: moletulur featUIl:--~ (booo lenglhs. bond angles. tKlIlbondcd di~ tancc.'I., etc.) c.l1l be: calcu lated readi l), from the ~IOnld 3D coord matcs . SignifICant won. by computcr scientb ts ha~ been m,c~tcd into g'~lllg the illu~lon Ihal Il.derinj computcr imagc~ an:: phy~ical3D oOJects. With "f'CClal vicv..ng glasses, 3D computer images ClIl1 be ,-.ceo. Thew an: rela\l\'et) Inexpto~IIC and lead to impreSliil c results. 1'he bo:ISIC odea IS lhat thl: computer generales twocolorcd Im~gc5(most oommooly gnxn and red ) and each "'ructure c~n only be viel'ed by one e)e. Altemati~ely. I'ic" Illg headgear may be worn S tich tru.t cach lens in the g ll1-~>CS I~ ~)'nchrumud ",ilh the t"Ollllllm:r mOlutOl' to open and shul . To gll'C the ,UUSIOl1 of 3D rcpre.-;cntatiOll~. a special optical technique known Jl.~ dcpth cueing is used . In thi ~ method the brJln i" tricked 11110 belie~ing Ihat s lig tlll y dimmcr obJecb are farther awa)' . while brlghter obJccts are closer. Al10Ihcr IIPfJf011Ch i~ to ha~e the molecular structure ~lol' l )' rocl.. bac l.. and fonh. Since the 1'1105. the co:w of hardware has dccrea...cd and lhe power of computer!! has inercascd dramaticall),. 'TlIoese impressi'e hanl"OlIl: achal\CC-~. coupled .... lIh advane~ In !oOft"'are aoo more efficienl algonthnls. hale nlade COInputer-barerJ modeling acccssible to anyone. Alone I1fTlC . CA Do w._ the nclusi,e domai n of looustry and !lOme spe, cl:thud academic laboratories. Exptnsl\e computer gruph-

5=0 ,

,
Corrt.1 pa\JenlS.

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Figure 28- ' DOflolarrmie (Tfl/Opl). the f,rsl fDAappl'IJved drug 10 b@d!>stgr.edbySlr\Kture-basedmethods. is a urborllc anhydrase mhitl'lor Ih/illS used 10 lower ocular prruure ,n glall'

iC!> worhlation~ oommaled. Today. lhe poIIer of pcNHl31 coonpulc,-,,; mala them an apptahng and affordable ahCfT\,:llilc. Many Maooard molecular modeling 5Oft ... at'C padages an: ~ing ported 10 run 011 pt'oooal computers. and IhI: cost of computer graphICS technology i~ decrc:tSing bccau~ of lhe demand of the video gUlIIc man:cl. Molecular ~truct ures clln be reprc).('n tcd in many d, ffcrent wa)'~. depending 011 the propenies one decides 10 highlight. Dor~olamide (Fig. 28- 1) i,~ :I good enmplc of a drug tru.1 in"ol"cd CADD methods In iL~ dcvclopn~m.9 Fi gure 2B2 shows :I sta ndard repre.o;cntati on of dor"lolamide from n molecular modeling soflware p;lClagc. "The atoms can be color-codt-d in ~1If1OU' W"Jys according to tIM: different propenics lhat one might want to highlight. "The representation in Figure 28-2 shows the coonecti l ity of the alon..., in OOrro!amide that olle might use dunng molecular modeling. As l10Ied abol'e. howelcr. II i .. important to know the ~i/.c and ~hapt' of the molecule. V:uiou.~ rcprescntali0l15 an: poss,ble. One;s a CPK solid reprc'ICntlllion. but insight into the alOl1I1C

Figure 28-2 A compull'f-genel'alecl fepresentlltoon of dotroIamidt! (Trusopt) RIIther tNn a ball-/Ind-stid representllllOO, dof2oIamJde IS shown as /I tube representllUOl'l with coIor-coded /110m typeS Tht structure has been f'f'Itfgy mtrutn/2ec1 With Ow MMfF94 force field on the Sybyl (Tnpos. Inc.) moIKuiar lTo!!!1 log software package

922

11',1_, QIlJ v;nvolll', TUIh<HHt. of OTg""''' Mu/jc/fllJllUId PIo""""K'rulICol Chrfl"51f}

connecu vlty h d,fficult w,th opaque surfoces, Aoother C()n\'enient visuali7.:u ion k'Chnique is 10 havc tnc atoms and bonds displayed ~Imullaneously w,th the \'lUl der Waals surface representcd by an even di.,mbution or dots, These doc surfaces lU'e convenient. in thlll the atormc conlM.'Ctivity is sho~'n along wuh the If.... opnale size lind shape of the m0lecular Mlrface, As computer grdphics lechrroology has rm proved. iL hIlS become possible to represent the ~urfllCe as translucent \olume, shown in Figure 28-3, in which the molecular structure appears to be embedded III a clear gclatin materilll. Finally. computer graphics Images of drug -reptor interllClions, WMthtr taken from x-rdy crystal data or in si hco genclll tai, provide insight into the bindlll!: imcrnctiOflll, as shown in Figure 28-4, A full display orall the atomic centers in a protem stRICture gives too much detail. Most commooly. as shown in Fi~ure 28-4, u ribbon structure tr.lCeli lite back bone of the protein main chain. '0 1lIC Richanlsoo approach is another commonly ur.ed dj~pl.y 10 hIghlight serondary structural features. in which cy llllders dcnOfe (> helkes. ar rowsdcnote/hhects. and wilts ure used forcoilsand turnS,'1 Because drug molecules male cont act ~ilh soI"ems lind receptor sites through surface: C()ntacb, it is paramouR! to Illl"e accuTllte methods to re~nt molecular surfoc'es cor m:tly. Algonthms hale been developed for such purposes. and they continl>C to be improved, 1lIC most struightforward w~y 10 repw.tnl a molecular shape is by the S(K'alJed van dcr WaaJ'i surface.; n ~hlCh each oonstiloe:nt :nom contn bUICS Il~ e.tposN surface to the overull molecular surface. Each atOln ;s ussigncd n ~ol ume corre~ponding to its vun de!' Waals radiu~. and only the unlOO of atumie 5phcres con

Figure 28- 4 A (ompulet'-geot'faled rPpI'e!oefItatron 01 th.enothlpyran2~!fOf1amlde boond to the iKtJYe !.Itt 0( Uf banI( anhydrase. Note that the nbbon has been uactd ltvoI.ql the protem backbone. ProtNlS iIIe <0Il'IITl0l'Ity dr5pIayed th6
y

triootes, 11Ic.~ vun .ler Waals surfaces have MlUlli ~:ll:vices and pockets that ellnnot: male contact ~Jlh soIvenl m0lecules, Another surface. known as lite sohent-lICCCSsibk or Connolly ~urface. can be ge nclllted. U T1!e algorithm taUs lite van de!' Wa:.ls surface and rolls a sphere. luill", the ,olume of a water molecule with II l'1Idius of 1,4 ;,., MU_ it, Wherel'cr the sphere makes contact with the origlll:1l 'ilIf. face, new surface is crealed. This e.tJl'lndcd ,urfxe is. nlOt'e !tahsllc representation of \lhat water molecules COlI[Uel. Another simil:lr solvent!I\.'Cessible surface is ~1IO\II'n 16 the let and Richards wrfaee ,ll This surface ;s comtrucled in an analogous ..... y. w llh a spt'1cre rolled O\'er the I'DII do:f Wlt3ls surface, OOttoo boundary is taken as uline conncctlAl the center of mass of the sphere from poinl 10 point Abo. it I) possible 10 cakulale the i'iOl"ent-cxcludc:d surfllCl: 111: polar and nonpolar surface nn:-IIS can be used as QSAR do:5Criptors (Chapter 2). and mllny computet' models for soil. tion use soh 'enta.ccessiblt 'iloIrfacc: an:as (SASA), C(IIIInlOl1ly. the electrostaric density may be dl s pla~rd 011 till:' ~urfllCe of ;[ molecular structu~, providing lin easily f'tt'O!:. 1117.ed color-eodcd grid lluil fllay be u. ..w 10 inrer lhe compIememary birKling f unctfonal groups of tlte pulath'e rectptor,

Figurtl! 28- 3 Ano\hef computer-geoef.ted rept'e!oefItallOl'l of dorzolamide CTrusopt), The mucture M been enefgy rna".. mired WIth the MMFF94 1000ce freld In the Sybyl CTn~ Inc.) moIe<:ul~ modehng ~f\Ware pildage.nd IS drsplayed WIth a ~ Iramloc;ent V1 der Waals surface. Such representatrons have the advillltages of sIlowIng both the atomIC COOnlIvrty of the molecular m""ure and Its 3D shape and
~

COMPUTATIONAL CHEMISTRY OVERVIEW

Colorful molecu lar gmphics Ifnage5 art Nscd on the fOlllld. !ions of compulal lonal chemistry, Computational c~nu~ methods . ... hich may be defined u the use of theory II1II computer technology to cakulate molecular ptopt:nln. ~ widely u>cd in academia and industry to gBm insigh15 1Il10 CQmplex problems. In many cases. CQmputalional ehtmi5il)

Chapter 28 Compu/aIUJIUI' Chemlnry and is used to r.alloo.aJlle eJi perimefll5 lind to help male sense of the 1!Ia.\j \e aillOUnt of dalJl genel1llcd. StICh P'-lIChees Ilfr Important 10 answer the >I-hv of chemICal and btologlClll pilcnomcnL The greatest poIentia.l povler of C(lffiputational clll-mi~try. howe\er. I~ in the domain of makmg p",d'CI'l)II5 poor to upenmental .. ark. Computet eJtperiments are ide ally SUItOO to help answer qucs.uons lhat IU'C dlffkult - and !IIlmetilllC!> imposslbk- IO answer by experimcnl\ alQIIC . Just whUI kind of predictions can be made ? Energy-oosed calcul0l;on5 have been used 10 predict and to understand molecu lar geonrctry. chemica l condition,. chemical reaction pathways, and transi tion Sillies. as we ll as phySical. AD M!!. and biological propertit~. Usually. computer ~imuiatioos arc k:ss CJlpen~lve and rcquire les.s time than carrying oot phy \ ical eJiperiments. In gel1l'r:tl, rotrf/lrlllll;OIIol Chtmrslry n:fers to enl''l)'based methods. CADO IS a moR: all-cncomp.us'"g term. ineluding not only energy-b.tscd calculations but also QSA R. database !!Carching. and phaml3Cophore perception methods. Computational chemistry approachcli can be di vided IntO two brood categories: quantum mechan ics-based and classkal n1C1;hanics-based. The former co~el'!l the areas of semiempirical. ab initio. and density flll\ChOn~1 theory. Till- luner re fers to force field (molecular mechlll1ic~) calculatiom arKI n10lcculllt dynamic~ si rnu lmions. Each nlCthod h.as its Mrengt h~ and wcai;:l)Csse<. and it is imponant to be aware of these. From the proc1ical standpoint of II phanna ccutical o;cicmist .... hiche~er approach gives reliable ans,,'ers In the shortest time i$ typically used. The trick . ob~ioosly. is ~ nowing .. hen IllS appropriate to use one method O\'er another. ThIs undemanding comes in time through prncu~ . just lIS an organic chemi st can "push" electrons to solve or rallonahl.e complCJI ll'actKln mechams.rns almost Ln.~t inc li,ely. The Born-Oppcnhcmrcr theorem L II good staning S 14 poinl. The thcon:m ba.~iclilly stllte.~ thut electfOrul IIK)ve in a ~tatiorlUry fie ld of nuclei : and then:fon:. the e lcctron and nuclear motions can be considered scpal1ltc ly, This appmJli matiOlI h valid in mOl\t cases of interest to medicinal c hemists. ~irlCe on the time ..calc of e lectroo mOlion. the nucki do rKlI 1 001'1,'. The difrcrellCe in speed is a ~-on'iCquence of the differences III nlaSS of the elec\roll and the p:uudcs Wllh," the nucleus. It is analogous to speedboats cireh ng a heavy airen ft carrier. On the ti nrc scale of the speedboats. dunng a boef SlI3pshot of time, the aircraft camer is motion less relame to the lighter craft. These focts. summari1_ in ed the Bom_Oppenlll-lmer theorem. enable soccC5.ful usc of lhe vanou.~ mathematICal models used in quantum mechan ics and fon.--c field-based methods. Qullntum mechmLlcs invo lves optimizi ng the electron dl stribution ~ with in rnok'(ules. Theoretical physicIsts first pmposed the fou ndation s of quan tum mech~n ics in Ihe 1920s.' 3 There were only a few cai'C5 where elOCt so lut ion' e~iMc:d. Mure t ypl~all y, approxi mate IllClhods had to be Uscd. l~ A lthough the theory hlt~ de~'elopcd and improved. greater lit Icmioo bepn to be plllCcd 011 computat ional quantum chem istry '" the 195(k .. hen the first comnrcreiolly available computers .. efC introduced. Once oonlputer5 became ntore uailable 1 the .;cientirlC community. soh 0 problems with computallonal chemistry became realistic. L . II Force field methods, 00 the other hand. ignore the electrOniC distribution and COflCentrute on the motion of nllClci a., if they beh:wed

Coml""~rAnlJld

Drull

IH~illn

913

lile a ball-and-spring model. wllh poIential enl''lY functions used to desenbe the forces hokhng nucki together. 1llesc: melhods we~ sIlo"-n 10 be viable: In the 1 ~. '9 :' For !!Cvel1ll IUWII'>. this ehapter f'XlISts on fortt field fll1her than quantum mechanics methods. First. IOOSI medicinal cl\o;:mlstry appll cahons an: mon: amenable to tlus t~at ment. Second. most ellC:TiY-based methods used in molecular modeli ng soft ware m~ ~ on force fields -fT\ll1l confor mational );e archlng to 5COI'ing fuoctions for drug- receptor fi t ~-and il is critical to ha'l~ a grasp o f the fundamentals. Thi rd . force field methods are COIl~plually easier to under stand. and the mathematics is nOlas complicated. Finally, for large macromolccu lar 5yst.:m5 with solvation. rortt field cakulat ion~ are the on ly prnctical way to proceed. given the diffe~1lCC$ in computer time bet .. een classicalbased and qu:ultum-ba.~ computations.

FORCE FIELD METHODS

Force field method~ an: rKlI a recent development; III foct , they have a long hi\tory. Three independent groups working o n diffcn:nt proh1c1Il~ ~portc:d the first calculations in 1946. LV l L Of th.: three p.1pcrs. lhe dcscriptioo of biphenyl derivati"es uamincd by Frank Ii. Westm-imer mOM effective ly showed how to soln~ a problem convincingly.19 In the early ye1\fli, the force field or molecular mechanics caleulat ioos w~ known u the WUlhe,mu mt'lhod. We.'i-lheimcr is COIl ~idered the fa\hcr of molecular mechanics. Fum: field methods weT(': rKlI actl\'cly de"elopcd um ilthe 1960s and 19705. as commercial computcn ....e~ becoming morecommono A number of academIC n:sc::ln:h groups began to explore force field calculallonsas a w~y to help50l ~e problems of interest. The ,",-estigaliom ranged from small Slr'llined organic structures to protei n si mulations. MOM of the CUTTCnt force fields can tr:liCe thei r TOOlS to rommon soun:es de~cl oped in the 1970s.ll -;t.o Force field ca lculation~ r.:st on the fundamemal COlK'ept that 3 ball-and-spring model may be used to approximate a rnokc u le.~ ~ That is. the stable re lative positioos of the atoms in a mo lecule are II functIOn of through -bond and through-sp;ICC inunctions .... hich may be described by re latively ~i mple m3lhcll13llClll relationships. Tbc compluity of the mathematical equations used to describe the ball and spring mode l is II function of lhe n:tture. size. and shape of the structures. Moreover. the fundamental equatIOns used In force rrclds are mIlCh less complicated than those found III quantum mechanICS. For example. small stmined orgamc molecules require ,reate!" detail than less stroined iyStem~ $uch DS peplides and proteins. Funhcnnorc. it is assumed that lhe total e~rgy of the ,nolccule is a summation of the individua l energy components. as outl ined in EquatKm 28I. In other w()fds. the toto l energy (E,,"oIl is divided inlO eBCrgy components, which are IIttributed to bond ~trctching (~), angle bending (f1.. f.). nonbonded lntcrnctions (Ew torsion inleractions (Eb .). and coupled cnc:rl!y tem lS (E........ _). The CTUU- tams COIllbine t ....o imem' latcd motIOnS (bend-strctch , stretch-stretch. torsion-stn:tch. elc.). The dlvisKln of the total enetgy into terms lIMOCiaicd "'Im dl stonions from equilibrium valllCS is the .... ay mmt chemisu and biologICal scient ists tend to think about ITIOlecules.
t ...,).

tn,

.-

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L I:........

+ }:e.- _

(&1,21\. 1)

In the 1600s, Robefl Hooke, lhe scientilic rival of the famous Sir Isaac Newton (who among his many scientific OOIllributions invcnled the calculus, developed II !heory of gTllllitation. and formulated class;cal mechanlC$). piOposcd that if IllI ideal spoilll wilh an attached mass m wu com preMed or stretched from its equilibrium posillon by an n tcm al force (!'j-,), the ~prinl: w()IJld exefl a reslorin!; force (tJ~ - - h ...,) of equal magnitude Dot in the opposile dircclion of the dislOn ion. This is an example of Nc""ton's thin! law: For ellery &Clion, there is an equal 1100 opposite l1'aclion. For simplicity, it may be assull'lC'd tltat the sprin!; lies along the or uis, where the equilibrium len;th ~ sponds to Xo. The position..fcl may be oonsiderrd the " natuTll.! length .. of the relaxed spring , Figure 285 shows the setup for the classic oneodimcnsional hannonic oscillator. Hooke's law for a oneodimensional oscillulUr oriented along the x axis may be wri llen in mathematical form occord ing to Eq uation 28-2. where x and ,If, PI'C the disloned and the equil i~um posi lions. respectively. (Note that in Equation 282, x is used 10 symbol ize that the displacement is a ,,?=Ior qLllllllity, which al lemath'ely could be repre.<;enled lIS xi, where i is unit lIeclor in the x ui~.) If there an: no frictional fOfttS pteSCTlt. then the kinelic and pocential elle1" aie! are $lid 10 be cOfIun'td. As shown in Equ~lI ion 28-). if we can expreS5 the forte, as the first derillllti\'e of the poccnti al energy. E. with respect to the displaccment, then we h.ave a cOllsel'llBlille sySte m (i.e .. the kinetic and potential energy equal a constant).

on lhe syste m (p05itille) or whe1her the sy'ilem is domg ....'QI'l on the surrouOOlngs (negame). According to Hooke'~ law . the re~tonng fllftt is JIIUIlOI" tional to the displacement - k( I' - .(u). 1lIen:fon,:, !iUb!;mu lion of Equation 282 Into Equation 285 yield, Equ:11I01l 286. Recogni/illg that Ihe 11100; applicd to the sy,tem I~ now the lotul elll'rgy of the ~y'tem. ""c gellerale Equ~tlOll 211.7,

W.j . . . .

._

(P..q.28-41
f _ . dr 1F..q.2II'1

'i'iu)

-I-'[ ~
0

.lDll o Jx

tlf:"._ ... l1i

.li

IF.q.21:61 IEq 28--7)

Tali n8 the integral of Equation 287. ""here the dlspl;K't ment g()('~ from Xu to x, with 11 corrc,ponding energy chang~ 1 to t: gilles Equation 28-8. " dE ~ t ",,)d, I~. 211-81

t, ,

IlItegmllOll of Equation 28-8 ylC lds Equallon 28.9. is the Inttimlion constant.

r,. -

V. ben'

uJ: ...

E. -

f:, _ ~.(.f

t"Y' +

{Eq.2891

t.

f dE

- k(x - ;0)

(li.q. 282) (li.q 28-J)

- _ -F

From elementary physics, the dot product of the fllftt

and dispiacell'lC'nt is defined lIS tile: appl ied ... ork from the surrou nd ings. This e~temal wort is the energy reqUired 10 diston the spri ng, Equation 28-4, An e~tensiOIl of Nc ... ton s third lo w impliell thor tile: spring requires 011 equal amount of work to be restored. Equation 28-5. NOie thai wort is a scalar quanti ty. 1lIe !legalille and positille signs as:~igned to the ..... ork 11'f1ec1 whether the surrouOOing~ are doing ....ort

"

Equution 289 can be ,illlplified by nuting that E1 h lltt energy CQlTCsponding to the di~looed ~pnng at poslllOll I. ... hetllc:r thi ~ i~ slretching or colllprcs.,ioo. 1'he energy f, CIIfl be defined as oul'lero potential cner!:} ... hell x ... "" rel.JIllc to any dislonion, This means thai by our choice of 1m) poccotia l cner~y. the intcgTalion con~tnr" IIIUSI be H'Il), ( O.... hich can dearl) be secn if no di,tortioo. 1 - "'-1 0, occurs. Fin~lIy. Equ~tion 28,10 i, the gcncrnliJw (lI\C. di rnension~1 potcOI ial cnergy function for strelch'"g and t'()lllpres~ion of a ~pring. Note thm lhe ilF. nOl~tion ha, bttn dropped. since t:l i~ defined a~ the I.cro encrl!) p(I!ollion. EquJlioo 28 10 is II quadratic funclion . Figure 28-6 \ho-All the pl04 or /I ~mlp1e quadrullc funcllon wllh
1;' - :!'{~

In)!

IEq 21-1

(0.0)
Figure 28-5 A Simple or.e diml'fl5lOO(I/ IIIilndj.pl'lrlQ (.I' iOOj.) oscillator seMi as , lTIOdei for bond VIbrations.

"-

Figur. 21- 6 A plot ofl(x) _ II nus fuOOIOO. 11\ tht form of Hooke's law. has been applied WCCtiifu11y m force III'Id c.w. (ulatlOOS to model bond diStoruons (suetd1lr19 and compl'l'SSIng).

ll!c d'StOM100 of 11 oned,menslon~1 ball,um.l'llring model along the (aJCi~ can be gener.lli1ed iOlo the 3 D case. .. lIMe In effect .....e hale: replaced x wllh rand.fG wllh '0\hth Equ~lIon 2811. the spnng does IlOI depend 011 being
placed aloog one lUiS; i1 may be onenled in any direcuon. As pointed out IIbme. Equauoo 28 11 is a quadrw:ic: (UrIC lion . used 10 de.'.,,:obe ~I retch ing 1I101ions in 1T10~t of the mac romolecular fom: fields (e.g.. AMBER1'I-.lO and CUARMM Jt ).

_l 2 ...... I'
1bc: tI'i: of II qu~d ml ie CCju~lttln to munic II chemical bond means thai di~tortioo and compression arc equi\ll.lcm in ttrms of an energy penalty. Think about I'.'hat tbe qUuUratl c
Com pre....~i oo lind st retching n:.~ult in ~qual .~ in enc:rlQ'. Thl$ doe. 110( m:Lle sense physlCall). SlOCC for a d iatomic molecule. eompre. ~ioo bon gs the two ... atoms together. while d b tort;on ..ep-lrntes them . It is .....1.'11 Lnov.n that bond diSlOfhOO is anhannooic. \0 Imrnedlalc ly lilt see a nal'. In our modd, which becomes more obVIOU ' In trymg to rcprodu~e bond d"toniolh for ' Imin.cd mo le cub. The energy associmed with bond stretchmg is de"ribed by II M orse e Ul"le. which is Similar to a qu.,dn uic function onl y in the region elo!lc 10 thc ro (F ig. 287). "The rtlativdy nondlstorted bond lengths. I'. hich are eharao::lCri,tic of proteins. faJ! In Ihe region where the MOI"'C and quadrati c fanction~ o l'erlap reJc\Onably I'.ell. Thi s i~ why ~implc quadrntic terms may be arxeptablc as a fif'l\t approxi m1 tiOIl in 1 m,lcromolc:cul.lr calculu lioos. In fuet. give n the compl exity ofR1ltun:. it is n:mariablc that a ~I mplc HooL c', law pcJten hal energy funct ion woris a~ wcll as i, docs. For 'rllnll S ncd orguilic molcculc~. n'lOl"e complex eqU:I imi tions an: usually nece.~sary. MOI"iC cur. elo Iypccall y are 001 u..oo in forcc lield cakulDl iOIl~. One approach 'hili t:llcs imo model
~uggl!l>t ~:

11<.:coonl tbe orlhnnnOlllcity a.'sociatcd With bond ~I retchlng re lies on JIOllrcr SCTleS appro~imallon. 1'h.c Morse cur.e may be Cltpanded in to a power M:ri!'S funchon uruund lhe equillb riu m posilion . Such eJ(pan~ions follow a "" ell-koown mathe matlCal SlTlItqc:m embodtctl In the Taylor M:rie<; e:>.pamion. shown ," Equation 28 I 2. I'.herc the cJlpansion oceUN about the posilion (I, Co mplex cun- cs may be Q.pprodl11l1u:d by power 'iCf'lCS. There an: m:Ln) ad" antagcs ,o ha~'"i I funclion eKpres~lble as (r - I'f. locluding case o r COI11PU1.:l1tOI1 lind ea!oC in tuling den vallvcs. I'.hlch is why a Moo.e curve. I S 001 u'iCd d ll~C1ly vIa force field cakulattOn!>.
fi,$)

}In)

+ fl) I.l IT

u)

EApandlng the Morse cur.c into a TD} lor scril!li u~lng the. formul a outlined in EqUal ion 2812 Ilcner.:ll c. EquHtion 28 13. The fiflit tl'rRl ill the ..... ric~ i~ a con~ant. and thl ~ may be: set equal 10 lero. "The 5CCond ternl in the serics may be recogni1.cd II~ the gradient. which ,'~' ~'d aoo\ c withOOl pronf and <;hown in Equalion 283. i~ defirlCd a' the ncgah\c fon:e for CUI1~r.c:d .yStc lll <'. At the CCjmhbnum bond length. rothe force i~ eq ual to l.cro. which mean_, that the second tcnn is aJ'iO zero , Therdorc. the Ii"'t two tem lS In this ctpansion Iani,h. The fin;t tlOI1 ~ ani~hlng tenn in the scocs is the third term. ""hich is a quadrutic lCflll , equlla1em to Uooke's law, The founh and lifth tl'nn , cOTre<;pOlKl to cubIC and quartic tl'mls. I'('~pect ilc ly. In Equmioo 281:\,

F-

Leo +

t,

t,
f' 'u) t

+-k-~.I

,.
b

, +-,_ c
24

iI'

r"r

,.,',

--

.. , ,, , ,
,~

iI -

II fI fI fI fI

i I i I

, ,,-.__ - '}I'-'or+ 'i ,

_P I
___ C), ' " ' ' ' , '

The highcr lerms elln be cOIl~iden!d cUlTCClion ... to the qulIdnllk tcnn. wInch is only a fiflit approtimatioo to bond di~tOft,OIl . New force OOIISiants. alKl t: l.,J12. C11II be defined. givlltg &Jullt ion 21\ 14, The use of rhe quud TIltie funct ion alone IS ll1Ol'. n II.> the hannomc appnni rn;ttion .

t: *.n

lit - ' '')' +

to 21'

'01'
(1'..' 1,28t 4 )

.. ..........

------ c.- P

I I ..

~_I'\:IL

Bond D'-Uince

figure 28- 7 In forcl' IIE'Id calculatIOnS, d,fll'rrtll iE'l<lls of ~m.J"oos are uSI'd 10 reprodocl' the stre1chm9 and comprt'SSlOfl of c/wmlul bcods The plot s.hows a MorsI' polen \WII _gy l unc\lOfl supermposed With val"LOUS PO/Jef ~Ie'i ............. m.JtlOm (qUoJdfatlC, cubic. and qUoJrtIC fuflClJOf1S) Note lllat ihe boltorm of the curves. repl'l'SI'mmg the bond Ier1gth for roost dbl'mal bonds of Intt'l'E'SI IO medIon<tI chemrSts, almost 0Yeri<Ip e-.1ctIy. Thts nNrIy pt'rlKt fit In the bonding regL()l'L is tilt rN500 Simple hafmoolC functtOnS can be uSI'd 10 ca-k:ulate bond length.s fOf ulUlrained molecular sllUCIures 111 the force flfld method

MMFf9.' .ll Ito dc, eloped by Thomas H~18ren at Merck IS curn-nlly one of the most wKlely slllilnble force field> . II was developed with Ilk.'dlcinal chcmbtry applicalions 111 mind and can be found ,n various molecular mooehng soft ware paa::kage.~. including Syby l (fnpos. fnc.),7 Spartllll (Wa verunction. Inc.)." I'C.... ODEL (Scrtna Software).'" :md f,locroM ode l (SclviXlmger. Inc .j,..o The force lick! I~ robu ~1 und C~11 deal wilh many d,I'C rse funcllonal group~ found 111 drug like moleculCll. giv ing accurate aMWCfll for small molecules as I'. cll as macromolecu les . .... MA~ rilal5 Ihe accuracy of MM )., ... 1 which IS known n~ an excc ll en t "mall Ofganic molecule forl"C field. as well as ~ resul t'; pubh~hcd for MM4401 ~7 MM 3. howc\~r." n:'stricted In ;l~ uscfulness for rncdicinhl c hcmi ~lT)' appli cati o ns be\,'au'\e of limited paramt:ten ZJllion . The MM4 ron:c rlCld. 3 sub<lcqucnt \Cf"Sioo of MM3. ha. tnodific:d potential enc:Tgy functions and an cKpandcd number o f c['()!;Stcnn~.A n lC.<,(' addl ti on~ shou ld make MM4 more lICCurme than il.' ~ MM4 will probably wffer from . hortconllng., slIlIllar to those of

MM1. In terms of its abilny 10 calculate di~crse drug-like structures. because of the: lad.. of paramc:telll. lntcn:stingly, MM4 has yc:t 10 be rc:leased publICly. e\"l~n though il and MMFf9.' ....ere rc:pon,ed in 1996. at the ~me: lime:. in back Io-back public1ltions w.lhln the: 1OIImc: JOtImai ~oIume:. Beeause MM~ IS -0 .... idely Q~ailable. il IS Ill'guably the ~Iandard small molecule fon:e field of cho.ce al Ihls lime:. 'The MM) and M~ IFF".M stretching functions may be: written as OIJtlinc:d in Equation 28 15, .... here: 4r - r - rok"""'h Is the force eonSlal1l parameler. c, is a eonSIat11 used to modify .I............. and 14).9)25 i~ P CQIl\'cn;ion faclOl". Note: that Equation 28-14 and Equalion 28-15 !lit essc:mially tm, sume but wrillen in a different form. EqU31ion 28-15 demands that the: cubic and quanic force constants be scaled quadratic <;Iretehing constants.

H'~

'-)'
H '

c ~;:---! .. " 0
(d-dol

f igu re 28 - 8 To reprodllte the OUI-ofp]ane ber.d1l"9 molIOnS for SP>-hybf)d l~ed atoms. a quadrall( penaltt funcllon ~ uied to coosttam the system to be planar The sp'-hybnCJltd i!llom forms a prOjeCbOll 0010 the pIafle defined by the t/v~ atoms dtrKtly bonded to It For formaldehyde, tilt two H alCltl!< clnd tilt 0 atom defIne a plane Tilt C'l'l IS coostra,neG to br In lhe plane by the ~ of a quadratIC funcuon

1::''':: '"

143.932S *7I.l,Y [I +

(',1"-,, + ~11'YCl
(Ecj.28 15)

Some: force: rlelds usc: an Impn>pc:r tOf'>.lon angk: COOC'qII IQ constram tM Cl'ntral atom of a trigooal ptan:ll" 'nJUp. 1m
the case of formaldehyde (Fig. 28-8). the improper lOOiotI angle may be defined as H-C~-O,p!- II . Note the faJ.1 m. the:re is no e()~alcnt borwJ bct\loec:n the: o)(n~~n an(l h)'LIrogtn; hence, the nU1lle imprope, lon;;on angle . The u>c of an Improper tor~ion IS an iu;~alem malhematil.:al rnelhod and Iw the ...11111: cffe~t of conslTainlOg lhe centrul mom to be In the pll1lle as a fUI"-1ion of (41 - <AJ)!. Atoms hiwe size and shape. With handheld nJec1wl1Cal model~. the: si1.e of an alom is in\anant regunlkss ullb clv:;mic;ll en\ironment. \10 Jxoreas in reaht) the: ,'an der Willis radii bch;J.'e as if they were ;.oft ~phem. r.J.lhe:r than ha1I spheres (i .e .. rIlOI'r hle mar.;hmallo ..... ~ than ",oodc:n billb~ One: ad~antage of using eonlpuler-bucd ellCrgy ea1cul_ is the ability to treat the: ~an dcr Waals r.ldli IIl1J1"e reaJio;tJcaUy by pro~ldlllg greater flexibility than one can OChlCH lIIitlt physical models. Cenainly. this apPrOOCh dlffe" Sll'lIfi eantly from any hart! sphere model. The other I1nporunt nonbonded energy tenn arise) from ~ I cctro>latl~ illltrar;tions. li aving a good cicctrosullie model i~ Irnponant. pmiculbrly \Iohcn one considers the significance of elCClt05l311C forces in drug- reccp4or inll'raclions. EquutlOl1 28- 19 (itscribeli the nnnbooded 1c:nIlS.

Ikndillg struins arc: trc:aled in an arlalogOlJs way in fon:e It field calculations. Any di<;tOftion ,n bond angles rc:sults in a rise: In the energy. The increase: in energy lIs ....... i_ ated wi th angle bending may be treated effectilely with simple quadmtic temlS (F 2816). r:.(IU~llions similar to 28-16 ..q. !lit found in AMBER. CHARMM. and related macromolec ular fom: fields. The use of quadrutic terms is just a fin;t approdmation applicable: to unstrainc:d systems. as seen in the: casc: of bond stretching. ~bny ~mall molecules require more CQmpk-li fUllClion. Equation 28-17 is the: bending fUllClJon used in the: MMFF9J force fidd. Again. one can -'Cc: thai the: first leM is quadratic ..... hiJc: the: secolld term is cubic. 'The laller may be c;:onsidcred a corrc:clion factor.

e-

E..

I '"

, 'l4-J.

(J -

~I

(Eq.28. 16) (F"l.2S-17)

Til keep C,,,rhybridil.cd cenler!II)lanar. a 5pt.'Cial out-ofplane potential energy function is u..oo. This is necessary because: force: fields lire mcchanicllll y bao;ed DIM] do not treat elcclfQfls explicilly. A qmple solution regHrdmg ol.l!-ofplant' bending. found In SQlIlC force fields. makes u.s-c of quadrullc potential fUllClJons. The idea is ~inlple and effc:c11\1': K~p thc:cc:ntral atom planar. For example: and the sake Qf Simpl icity. ronsidcr formaldehyde. Becau;.e by definilion thrtt points define a plane, the IWO hydrogen 1lI011l5 and oxygen alom (boodcd 1 a carbonyl carbon) fQl1T1 a plaoc:. 0 Wllhoul .'ioOme: constrainl. the carbonyl carbon will lend to mo\'e QUt of the: plane defined by the twO hydrogen atoms and the o~ygen atom . The: projeclion of the ClIml)flyl carbon onlO the plallC forms a direcl imuginary linc. as shown in Figure 288. The inclHpOTatiOIl of an energy penalty term using a simple quadrulic fUllclion .... 111 achie\"e Ihe de.~ired purpoo;e of keeping the: C('ntcr atom in the: plane. The highe:r the: oul-of-plane berwJing c;:on5mnl. the less puckering will be obscned. Equauon 28. 18 ~W5 the simple form used. will're kooP is the out-of-plane: bending conSl.lIIlt and d do is the: diSl!UlCe from the proption of the atom Of! tlv:; plane: to the: 1lI0m itse lf:"

E , ""C~[(;:)

I:

-~;:)J+ 4~ (q,;.qj) {~.2I-1

... .. _

. T

....

(d - J"YC

(Eq. 28 18)

'I'lloe fin;t t ..... o tern,s ..... ithin bnclc:tS define: the van cb Waal s I'I'pulmllls, .... hich "ary a~ II,I !. and the LondoIt di!.. pc:fS.10iI .lIn1C1ions. ",hich \'ary u 111"'...... " The comI.&nllJ. is related to the: siu: of the: alOm pair bellli OOMir:kmI. f is the: dl<;tanr;:e betwccn the atom paio;. and CoJ Il'fm to tilt depth of the: pou:nlial energy well. It is based on the l~nnanI Jones 6-12 potcmial. Mnny fon.--e ficld~ use (unclions of !hi. type to dc.~nbe Merie inlemctiolls (Fig. 28-9). Only allllm with a J.4 nonbondcd relationship to Orle arlothl'r (i .c .. lIIilh thru che mical bonds sclX'rating lhem) are "lCluded in thc!c ea1cu lallons. The: bending and stretching tcnns include IJ nonbondcd anra.ctivc and repuhion ":-nns IIl1ph ~ ltly. Hydrogen borwJlIIg may be tll'au-d a.~ a <;peeial siluatKl1 mjuinng a modified l.C"nnard-Jones potential. The _ bonded culculali0n5 ate the: most time: coosullling. paru;1Ilarly If rIlOI'r romplc~ termS !lit SUbsiUUltd for the repubive pmt of the Lennard-Jones 6-12 potenlla!. u fouad III MM3.

urI

Distanc. flStur.21- ' \Nh.en two alOffi I and j ar~ separated by Inf.. Mt d~tal'lCt. thtre art no mteractoons bet"',en lhem. As twO nonbonded atoms approach one anotll@f. two forCH haw! to Ix' consodered Attrac:tiw dtSperSlOl1 foret'S (toodon forct'S) result from the In te-raction 01 instantaneous dipoles on each atom I and J As the nonbonded atoms Continue to approach one another. a repulW(' Interaction ~rm lhe attrllCllYe inter6(tion. and the energy curve nses sharply. The two.-.onbooded atoms can Il!ach an equilibrium posttlOO ..... hert rtPU~ and attractive forces balanct Oofferent mathematICal reiallOflshij have beffi U5ed In lorct field c.aicui<lllOflS 10 reproduc.~ the nonbooded ~Ienc In ler/lCtlOOS.

'The thlfd tenn in Equation 28-19 isCQU lomb'J law. where 111100 fIJ arc: the charges Oft IWO nonbonded atoms i and j. 'The twO charged atomic cenlers arc: not connected via I chcmK:aJ bond and do not have a common smile alom 11HlCIted 10 nloms i and j . In other words. we are talking aboot 1.4 or greater rc:huionships. as shown in Figure 28- 10. 1bc dic leclric constant ( ba~iClllly d:tmpens tIM: chargc -<: harge inlcrnctions and is a function of the solvent . 1llc g rc:alc r the

value of the diC':lectric conSWII_ the Ies.s electrostlltic inlCnlClion uists between the alom pair. In a vacuum. lhe dlClcctne conslanl i! 1.0: in water. the dielOC'lric COI1staf1t is appro"i mately SO. One: of the maJOf bml1ll11ons o ffon:c: rIC\ds Iw to do ,,"Ith the assignmenl of chargcs 10 each alo mic cc:ntC'r. ThC'rc: is no Dlantic charge operalor in qUDnium medla-nlcs. Atomic charges are determ ined quamum mc:chanK:ally by usinG D population analysis. Consequently. there are many wuys charges may be assigned. One popular way is 10 gener~le: un electrostatic potential from hi gh level ab initio calcu l arion~ (discussed below) and then fit the opr:imal point charge distribution on lhe atom~ via lC'ast-squal'e$ methods . nus approach has been used 10 AMBER .lO As discussed ab(we:. ITIOSt force fields assign point charses to atomic centers and usc Coulomb' s law . 'The most notable uteplion is MMl and MMJ; in both YCI'SIOfIS, a dIpole- d,pole scheme for uncharg! molecular SUlICtul'eS is U<;N,~! For systems with a net charge. MMJ introducc:s functions capable: of dealing with the additional charge--charge WId cilarge-dipole interactions. AlthouGh there should be no dif ference between the two electrostatic schemes, ha ~ing di pole- dipole:. charge -charge. ond charge--dipole terms re quires mon: p.1mmeteri1,ution lime . Improved MM2 and MMJ implcmcntotions found in MacroModcl huve eliminaled the dipolc-<hpolc scheme in fa\or of using point charges and Coulomb's law. If the stretching. bending, and nonbonded te rms ,,"ere summed o\'er all appropnale pairwise :l.lom contributioru within I structure. lTWly important cooformauonal effect$ in the simplest. of hydroc1ll'borls wQUld I'IOl Ix' reproduced. For example, Figll1'e 28- 11 shows the ellCl'tl:y (kcaUmoI) \ 'ct'. sus lorsion angle II profile for butane. 'The energy ri.set and falls during the roIatioo Al'QIJoo the central c,.,,-C-.l bond as a function of the relauve position~ of the methyl groop". Thc: peaks on the cur.'c com:~pond 10 ellCTllY maxima. whILe

q
I

r.
'J

,~ ,

J& ,
r

:~
o

, ,

, ,

"

figure 28- 10 Two partHl l1y charged atoms I and j, nol di, rectly connected 10 tac.h Olher or connected to II common atom (1.4-mteracuons or gre<lter). ~~en. an attractlYl! or repulsove electrostatIC InteriKtlOl'l (dependong on the charge) on each other A Coulomb potenu.1 energy lunctlOfl is the most cornmon wi1'/ U5ed In !Of" fl(ld methods to calculat~ the charge-<hargt' eIKtr05tallC rot'fgy Coulomb'~ law is U5ed In 'o'Irtually all IOfce lie-Ids WIth the txaptlOfl'l 01 the ongmat MM2 and MMl codes.. MM2" and MMl o, tmpIo,ed ver'SIOOS 01 theorlStlf'l(ll IOUIld In the pofJ(JI rnoIKuIar modt/ll1g softwate ptOtJrMn M.lcroModfI d!.eloped by Clark SIi" ,Jfld UioI!' cNrge-char~

I0.' .,

codes._

1I1/f!fKtJOn /t'fms.

Dilled",' Angle Figure 28 - 1 1 PoII'flu.1 energy lot butant' The _gy (kcaU mol) IS pioll@donther iIlUS ~ the tOfSlOfl anglt C...,-CopT Cop.I<...J- whICh IS pIonl!d Ofl /he If iIJUS ~ <If( /hre( ~ Tnt twO ~ conformers are hoght< Ifl _gy INn !he MIll con/ollllN by i1pplI(IffliIleIy 0 9 kc.Jllmol.

'"

,.,

'"

'"

!he 1:llIey5 correspond 1 enC'rg)' mmin\3. For bucme. lhere 0 ~ IWO dlffcl"I:nt types of mmim:l ooe i~ for the IUI,I bullll1C confOlTl13hon. and lhe OIher t~o <';uIC,;.pond 1 !he gaudf' 0 bul:l"" oonformatio.u. The tlnli conformation is lhe global mlnllnum. meaning il halO lhe abiollitc 1000C'St clIC'fly of tnc: lruee pos.~lble low-f!ncrg)' t'OOfonnallons, The dlffcr'l'llt'eS in the conformational CTlCrglCi; camilli be Munbutcd 10 ,ICOC internelioth alone. Structllrc:~ with III011! than one roI;ltable bond have multi ple l11\n;nm avai lllh1e. Knowi ng the pcnnis~ih le cOIlformMioll avail able to drog-Itke molecules is impot'l,ll1\ for de.~ign purpose$. It turns OOt that allOl her nonmeehalilcal effect i~ needed to reproduce the poIenliaJ e""IllY eUI'Ve for butane alM.l OIher strutlun,;. II h3.\ long been koown dUll II reqUIlt" energy for rotation :lOOut single bond~. One of the fil'5t conformallomll effecl~ pre<;cnle(] III organic chemistry Cf)Ur<ai invol\'l~s!he falorable II-C ..."C...,-H torsiona l oncnt:lllOllS foretMoc. The torSion .ngles are either lif'lf'll or sll'g'tf'rt'd. In 1891. 81 <iChoff propo<ed that eth:tne hM a p,den.'nce for a sta)1gcred oonformalion and tbe rOlauon III !>\lll.'llllltcd elhnne:s was re'lncted.H-~ The IMI stene inlerneliOils ulone cannol e~pll\1l1 the erterg}' d iffcrt'I1I."C. If resmcted rotalion was con~idcred. I'i t7.er demon ~t mk'd Ihut 100 ca lcu l:tled ;lIId observed CnlrtJPICS fur ellmne were identica l. "" ~7 The .1'l/Il:l:ercd COIIformation. ~'here the C"",- II hom" are not aligned. i~ preferred iJause the electron dcnsitt<!s in each bond lire as far apan ru. possible. Thi s ell('lllcllcally prefelTt'd onenHuioo is reproduced by quantum mo:cMnlC~ cDleulauon~. but force: field calculalioos nd \01111: eqU I ~aknt fUII('tioo. Since declTOII\ un: I'lOl treated e~plici tl)' bul are t"':lIed indirectly "ia cl:ls\;cal poIenliul I:lIergy fullCtioru.. For other 'l3lUrnted hydrocarbons. the potenual ell('rgy tcmlS are JU.'I utellslOOS of the fundamelltal ethane cur.e ~lIh OIher nonbondcd leml' supcrimpo;.ed, :.ccording to Equation 28-1. In wme CII'SCS. the energy required to rotate aboul ~ Inglc bonds is 100 great. loding MruclUl'CS into chinal confurmahon~ (utrupi<>omcN ). ClinSlie and Kenller first dcn\("I~If11lcd rt:smcled rotation ill 1922 b)' re.solvin)1 2.2' -dilli trurhcnyJ.6,6' dicarbo~ylic acid illlo optically activc iSOlllers.' A ,,"Iulioo successfully implemented 10 reproollce tile ethall(' phel1Qmena. :/,S well as other efftct~. wll.~ acoompll\.hed ~ 1111 the Introdu.. ion of a tl'Ufll.'Dled FolIner serics.~ 01) .... AhlM>ugh C<rl-C..,-C...,-C....' ~nd II-C...,.C.,-H dihedrnl nngk:!l prcfer to be ~taggcred, '10111(' torsilMl combi naliQns prder 10 be tclipsed_~1 Molccul3J' orbItal theory has bttn u<;cd 10 explam the undc:rI )'i ng ctlCmlCllI rea.'iOrI"- Carbonyl o~ygen\ prefer 10 eclip;e III(' Il' hydrogen, or a carbons of

'\

f
,
\./

"

aD

100

120

1010

leo

I.

Olhedral Angt.

f igure 28- 12 A plot of EquatIOn 28-20 wllh VI VI and V] 15 a poSItNe numbe< Note thallh15 curve M thfffiOld symmetry. The thud Iei'm In Equataon 28-20 IS used to,~ dote ethaneII~l' torwn profiles about SIngle borl(b,

II I.~ illu>l mlive to 1001. at each oflhc three lenn~ in F4JII" tiOlT 28-20 fur Ufull ~ppreci allun of how a thn:c-tcnn I'oum series cun be II~ to affect ConformallOOalequilihnl flip!' 28-12 show, the plot of energy wrsus d ihedral angk It)(JlOI ",ilh lhe V, and V1 constants \l:t 10 7.cro. and V, 1Wip:d a poIiime value. The eur.e has threefold s~mlllCll'}. 'lk rna,,; Ullll occur lit (hhedrnJ angles of 0". 120". and 2~; tItr nHAlma occur at dihcdr.l l angles of 60". 180". 100". .00 J6II Inspecllon of Figure 28-12 shows lhe-' ~lInt lanty bet'lltell ~ and IhI:' ethane lorsioo cur.c. COIl<;eqlJelltly. the thlllilCl"ll descnbc:s lhe ethall(' effect ~'ithout rrsonmg to an)' cllJcuJauons. If Ihe V I and V, lerms are sellO ...... rtJ, plotting the ~ len1l ~hown III !'Igufe 28- 13. woore V1 is a,slgncti a IJIl'lil.r value in Ihe lroncalcd Fouri er series. re~cal.\ It~ ph)SlI:,u ~ ignifi cunt"C. There are Illinima ~I 0". 18(f. and 360' WIll m:lXilllU at 90'" ond 270". Therrforc. lhe SoCCOtWl tenn In ~

pll.) I groupll (O'l'l=C-r:-C... ,.1I or O'rl-C'l"l-C""J-CopJ)' !Uld the ac),1 o~)'gens of ""leN prefer to ha\e the O-R gI'Otlps
aligned wilh Ihc C -0 bond (0",2 - C""I-O ...rC'l'l)' These bund aliglllncnt c lTect~ are reproduced UdcqUDldy ill force field calcu lalio ns usi IIg a IhreeleRn trollcllted Fourier series (Eq. 28-10). Essentially. Ihis torsion fUllclioo introduces qll:mlum nwchanical e ffects illto II elas<ical ball -and-spring ~)'stem, ",hieh trnnsfonns our modcllnlo u much more pow. erfu l l()()l. wl lh a fraction of the: eompu ter COSts in tcmlS o r CPU cycles compared wllh u~ing qu:ullum chemical ulculauon~.

f
o 20 00 eo eo '00 120 1* ,. ,.

Dihedral Angle

" . . . . ..

~I (I

- ~I+

,. ,

. ' \I

cO!o2401

+ 2 ( I + cos341)
(Eq. 2&-20)

'.

FigurI28- 1l . A plot of Equa!JOn 28-20Wl!h V, .VI and VI IS a poSItNe IllImbeI Note thai th6 curve has ~Iry The second 1I!n III Equataon 28-20 IS used to I'PfO' duce ethylene ! ~e tOO'SlOO !)follies abolIt double bonds

an example of a fUllCtion.fix). with [1'>'0 minim~ lind [1'>0 maxima. Typically molecular strocture is eruered into II molecu. lar modeling softw~ package by template fl'llgments or through a skctching mode. It is also possible to download StfllClUre5 from sttuctural databases. Slructures mul! or do...nloadcd do not have an optimum geometry based on the force field potential energy equations; i.c . they are not occupying the lowest energy state in V9(;I,I(). Minimil.a1 ion algori thms are wri tten to take a starting Mructure and mini min the energy. which Il'IInslates lnlo lhe structure dropping inlo the nearest potential energy .... ell on the confonn:monal hyperttll'rgy surface. The more complex the 5UlIClure. IlJiUally the more minima are available in confonnallOrlal space. Butatll' . simple hydrocarbon. i! an mfotmati\'e examplc. II has Ihree minima available. Energy mi nimil.allon reqUlTl'..~ a series of itel'lltions because of the nonlinear nalure o f the force. fltld potcntial cocrgy functlon s. The: ge nerul Slr.llagl'm is to tra.nsfonn the full nonlinear optim ization InlO a scriesof 10caI iterative linearizations. and this approach works well. Atoms wi th in a molecular structlll"l' are 1l1O\'ed in ~maJl stcps in the dirKlion that results in a decrease in the clICrgy of the 5ystcm. The Sill' and direction ofthe stcp!! are determined by the specifIC method being used. based on &julltion 2113. and illustrated for a one-dimensiOllal case in Figure 28 Geometry optimizalion may be divided inlo t .... o bro3d catcpes: fit"Sl:-order nltlhods and sccond-ordC'r methods. The formcr uSC'S filiI derivauves to dclennirIC the Stl'P sil.e and direction. whllc the laller uses both first and second derivativC$. First-oroer methods indude !lU!f'PI'JI dl'$cf'nI (S O) and cOlljllBflIl' Brodil'n' (CG). ThI' sccond-orikr method discussed be low is known a.~ the Newton Raphson (N R) geometry oplimiution DpproilCh; there lire many VanDtions of this method. Again. the concepts of minimi1.ing a function arc not rlCw; they ..... ere devcloped yeafll ago. (TI-oe "Ncwton " in Ncwlon- Raphson is Sir I ~ Ne"'tOrl.) The immediate gool of an energy minimization is finding II sui table displacement 6... ... hich. as stated aoove, is opposite to the potential erlCrgy gradient. In other words. the atoms are 1I1(l\'ed in the direction of the forces. The displaccolCnt is

adtk.>d 10 the coordinates at each ,tcp and i~ upd;:ltW by I quick recalculation of the force field tOlal encrg} . SO is the ~nnplc\t approach." ' " The SIC'p size In SD 4\, I~ simply takl'n as a scaled negau\'c gl'ildil'nt as sho .. n In Equallon 28-22. where: V (del). a vector opemtor. 1\ the endicnt &s defined by EqWluon 28-23 and A is a scahng c:omtIIII TIle SD olgori ll\m i$ inefficient \\.-hen the potcnll~l C'ntfI) cun'e IS not \'cry stp. So as the nunimum is Ipproachtd whcrc tiM: sloJIC of the eurve is nailer. SO algorithms baoonlt ",efficient compared wilh OIher mcthixb;.

S. - - AI ....;:.....)

'. ,. ,.) (
];/ + ;r.. J + d: '

(Eq. 2J.2]f

The CG method. outlined in Equalion 2824, 1\ ..... Ilkl) uo;cd ..... - 67 It SIVCIi bellcr con\'cq;encc than SO algonthms.. As the name implies. the previou~ ~tcp ~ile along ..... ill, tilt
current gradient 3!i (\ctermined by the tOlal fon..-e field C'1X'f!) is used to dctl'rmine [he ncxt s.tep sil.c. An additional selling faclor c is found 10 impw\e re:~ults.
r~

.. _ r.

+ C&.

l1Ie Newton Rap!uoo method uses infomUluon obIanv:d by takmg the 1i"1 and o;ccood dcrivati\c:s of the energy "it./l
respect 10 the coordinates.::' a.I The combinat ion ofboth

...

fir<J

om! second dcri\'all\es proVides a powerful method 10 locale minima.. This may be a lirnc-coroSlJIllinJ; prt.lCCSlI beau!!!: o f the m:ll ri~ In:mi pulations Ihal mll~t be tmdena~cn for a 3N system. where N is the number of atom!!.. In EquatIOl"l 28-25. VI is the dot product of'" muillplied by iL..cIf. NrM that 9 2 IS a scalar operator.

&. .. -

~4"'F.)

(ilq28-ZS1

NOlle of the g<'(>l11elry oplll11 il.llliOn method. dr ..cu.<,(II,I finds the global minimum.

CONFORMATIONAL SEARCHING
As Indicated aoo,'c. it i~ important to be able 11) ~,pIott conformational space to (\ctermmc .. hat arrangemenb IX atOlTlS (confonnations) are encrgl'tically fe3.~ible. Ob<;c"'ed physical propertlCS (e.g . hcat~ of forma lion) ~ MaU~u,,;1l a\'eragCli of all the cOllfomlation~ a\ailublc. Most org~nlC molecule~ have mulriple cnergy minllna. In the use of druJ design, it may be imponanl to sample lhe possible number of confonn3t ions a drug molecule c:m adopt. U<iU<lUy. adru, III the drog- reccptor complex adopt~ a biQOClil~ ('t)tI/0fJfIIJlion thaI diffe .... from any of the local nun im:1 or the global minn1\um. From the analysi~ many lI'ad and drug PlII'I. the avrnr.gc drug-like moleculc has more degrees offn:cdom (i.c.. is more nexiblc) than Icadhle compounds. Iml wly. this lIlay seem coun1l.";nluiti\,l'. since the mi~sion of a drug i.to ha\'e it. functional groups bind to complementary funo;.. tion.1 groups of the receptor. It tum~ out that a nnlble dnr~ i. superior to one ..... llh a locked con formation becaU5e tilt nacr oOl'ntalion in a conf()rm:ltlon.ally con_trained looIuk

Slcpslu _ - VI:

or

Dlalllnu

figure 28- 16 The directIOn of t~ Stl'P Silt' In an energy minimizatIOn IS toward the ITIItllmtlm ~

may not be opIinkll for mlel1lCUOll~ wilh the la.oeptor. More0\ er. the poIellual .\U periority of a Oedble druB can be under!oIood when one consider. that both rcttplOr and small nlOlerule mu.~1 mold thems.ches to form the druB-receptor cOI1rplu. A flex.ble drug can contort n<;e lf more ea..lly to n:ach the blllding pocket and then adjUSt Itself acconlillBly It) form the necc~'ilU)' intel1lCtions. A rig.d drug with us functional groups locked inlO place may be nK!' lunlled .n 11.~ ability to get to the larget ite and. once thcre. to prn;iuon Ilsclf correctl y. Of L'OUT"C. based on Ihe Ko<;hlund induced fit hypolhesis, It is known that both small moittule\ and matromolecules IItIJUSt 11Ierru<:I\'c:Il 10 form protein - ligand oomplcxl:.\. Before eonfomtatl{)llal searching is dl'iCussed III any debil, It is critic:l11O have a common ~ocabu lary. The: tenns ron/"nnl'f and nHt/ormD,ion can be: defined III refen:1'ICe 10 lhe: butane poIenual energy CUI'\'e (Fig. 28-11). 'fhcre lire an mfimte number of conformations on lhe CUl'\e. s.nce the dNance bct",ecn an) t .... o poinl'l on any cun'c may be as small us de:\Ir~1. Conformations refer 10 00111 maxima and minima and all positions 111 betv,'ccn. A cfJlrjonnu. on the other hand, refcl'\ to the confonnation at the bottom of the poIem.a l energy well. wllich is a minimum. Looking al the sirnple case of bumne, it is casily seen Ihm tllcre are three poIcnulll energy wells. Every molcculur ~tmcture has D gJobul minimum, tile absolute lowest ellcrgy, but then: an: mall)' minun:t. For butane. tiN: global minimum corrc~ponds \0 tile filiI; con former. One speaks of ellC'rgy minlmiution. not energy opIimi:r.ation (discussed abo\e). becau.<;e tnc patential energy functIOns are being mrnmlf/.ed. not the geotne11)1. G~lry olmmiZlllioo is tile equl\alem reml. for the StruCture .\beingopllmi:edllttonling to the fom: fiddequaIJI)!I~,

hcxanol. an (rronrou~ ansIIoer would J'('sul l. lllc: right way 10 do the calculations is 10 Iool.: at all possible :u;ial and equatorial CQIlfoon:uions. With c)clohexanol. Ihl S is not dif ficu lt andean be done by manually ahering the onenlalion of the OH ifOUP. For more romplell structures. conform:monal

searct.ing

mutlnc~ mu~1

be used.
r~

rjRT

",

I"

PI - '" n, .. "," , - >,IlIT L.J LJI'

Tobie 28-1 _IM,)IIS tile three pos~iblc axial and Cilualorial confomlalions. SUblilulion in Equat ion 2827 gcnt:r.lIc~ tile calculated rulio of each confomxr. Because MMf'l'94 was parameterized 10 reproduce Ihe quantum mechanical calculations. il Ii IIlustrntl\t 1 loot al the ,,11;0 calculated wilh 0 MMFF9.$. The BoIl7.m:mn-a>erogcd di<;Uibulion may then be compared willi the cllpenmental U:u.a as ,",elllb the othct' force. flCld resu lu. Equ:l1ion 2828 outhnes the pi occdures for calculating the deOOlllinalOf m EqU3Uon 28-27. NIMC lilal in Table 281, entries I and 2 (15 10.(11 as 4 and 5) are equwalem in energy. with relali_e confonnallonal ClI('rgies of 0.000 leal/roo and -0323 kcal/mol. r<'~pccti\cly. Consequemly. the frequency factor i~ 2 for both caj;e~. 11le ,u rnmation of Equation 2828 is shown in Eqll:ltiOl1 28-29 10 be 4.0:)7.
tA> ..! '"'

(2)rii"" + (I)I' ..

.,,,.,

-8, ...

oo.

Cl).. ~ "'.

<II!,

(1],.. .....

lOll

IEq 211.28!

D. . """' .. 2.00 + O.71~ + 1160

+ 0.182 .. 4.OS7 (Eq 2829!
The rullO for cacll enuy in Table 28-1 can be: cakullltl by usmg Equatioo 28-27. II is more In!Crestlllg to i0oi. at tnc ~ummation of tile: total calcu lated equ3tonal n~",us total axial cyck.hcxanol ConfOll1l3I100S ...... bich. on a pt:reentagc ba.~is. i ~ calcu lptoo by Equat ions 28-30 and 28-3 I. MMFP94
resulL~ give approximately 67<;t. equmoriul und 33% axii'!,

to explore conform!llional space? Fir;t. lli d.>cu~scd ab(m:. energy minimi1Jltion alJ:Oflthm~ In: d.:;~Igood to <.eek the nearest minimum 10 tile 'tan; ng pG'iluon. So for butane. if we had an inilial input geometry in "'lIkh the C"",-C'fI)-C'pJ-C."J dihedrnillugle W:l~ 90". the IlIolccu lar structure wou ld be energy rninimi/.ed to tile lIf1urhe conformer. If we ~tarled on the ottII:f side: of the 120" balTler..... lIere the C ....'-C..,J-C.... dihedral angle was; 1.50". tnc molecular structure would be energy mJlllmi7.cd to the fJl1Ii conformer. Sc:cond. some conformalJons are Itl()I1l nnpor1alllthan otheTs. llmd. as noted abo\'e. many physinl problems are a conseqUCfICC of a st;mstieal Il\ema:e of the COIlformerll pre'i('()l. Founh. ha\'ing II oonforrn;allonal searrll algornhm i\ a cllc:ck again~t hal'ing bia.~ SlnJClU/ll1 data. In tile: cll..~ butaoc:. if ooly llnti butaoc: were known. tllc:rc: would be a lor of infonnation mis.~ing . 1lle majority of druglike molecule.~ ~re structu/llll y more complel tllan butllllC. but thi, hydrocarbon i~ a slra ight for..... ard c~lImple. 11le InlllOr1aoce of knowing a~ai lable confomlallons for property predictions can be illu.tmted by loot ing ut ~lIbsti lUIed eyclohc~une. For cyclohcxanol. tile !l~ial :equmorial ratio i, de:ri~cd by u~ing Bolumann stotistks to calcu late the rallO. Equatioo 28-27 show~ tile: 801wnann equotioo . .. here PJ is the probability of findrng one conformation.}i ~. frequellCy factor .ndicating the del/eneracy of lhe c~y. ~ i~ tlte relat.\c energy (kcal/mol), It is the gas COIlstant ICl.O I99 kcal/mol-K). and Tis the tempetlltun: (K). For room k'rnpt'rorure calruluuOIl$. the product NT is O,l9 kcaUmol. If one 1001 . swgle L'OIIfomralion of lUlI,l cyc/ohexWlOI and rompared it wllh a single oonforrn;ation of equatonal c)'t lonc<:e.i!.at)'

Wily is II

,c"".

or

This is in close ag reement .... ith the Hanree-Fock (HF) 63 I G(d) quanlLllll IlIech:tnicol calcu lations or 66'1 IUIIlurial and 34% ax.al ..... hich I~ m reasonable al/rc:t'ment ..... ;tll expel" imental dati. The c.tlcu!ated percentages wnll MMJ an: 82'l IuatOl'l,1 and 18~ IIlia!. .... lIlle the calculated percentages with the Triptll'i force rlCld yield 46% equatonal and S4'l Il1lal. In genenl. the Tripoli force field IS quaJrtah\e (at best) and does nOl ghoe panicularly good CAe"!y \1I Iul:.'. so one must be caut ioo ~ when tryi ng to make accuralc pn:dICIIOIU ~ing force field ItlCthod~.

.
p ..... )( l(l(fl. ..

L ,. . ...B'~""''''---o= L r... ",,-r

-'1'"

(1fX)q,)

","",,---

---"'""'---,-=

.. . .
L /. .

~ r
( 1()(Y.l.)
!.;aT

['",';,0.":"

TABLE 28-1 Three Axial and Three Equatorial ConformatlOr\$ of Cycloh. . .nol With Th.ir Relatin Energies Calculated Using Force Field (MMFF94, MMl , rripos) and Ab Initio Quantum Medla nia (6-l 1G(d.p) or 6-ltG'
No.

Confo.. ". r
H

MM'

5,byl
0.129

MMFF

0"

0."

"' 0"
0..

~O H
I ~O
0
H

...
09.t2
08~

.,,'
0063

0. .

,
,

0_ 199 OJ2J

0.200
o.2 ~ J

OM

, ,

cd
,,., .

c:d

0.8l4

0."

0.J2J

.,~

..

;]

2.6.H

O.~I

1 011

!'(IJ ~

"~'18~
O.~

4t>.l '~~_I 0<

/:17.0 3,10 0.42

66_2:n~

0,",

The goal 0{ cooform:lUonal ""arching is 10 lind all possible ~Dl ues of the lliiM:dml angles that could be: assigned to each rotatable borwJ in 1I molecular MruCIUIl.'. Conformational sc:an:hing may be dlvidell IntO t ....o geocl1l1 ClIlegones; rys "millie and IIOI'IS1'SleIMlic ""3ITh ing. As lbe name implics. 0 syslematic searching uses methods thai an:: I!:uamnlccd 1 lind al l minima within the defined '<earch paf'JJllCten;. whilc l'IOOSy~em.alic searching uSt'S stallsucal approaches. SystC' m atic searching includes grill scarching. tOl"$ion drivmg. and cons.tflllned j;('arching. Nonsys.temauc s.carching inc ludes dynamics, stochast~ (randum). and distance geometry, Syslcllwic sclU'Chi ng has bn described as an c)(hausti\'c samplin g of confonn;IIiooal space.... ~ but the success is a funclioo of the numbeT of incre me nts used tll plore each rotatable dihetlrnl nngle. No con formation "'Ill be ovcr' looked ( u nlC!l>.~ the search pammc lC1'!l are not ~lIIali el1<)Ugh). A simple: anal~y should nwe thIS de...-. Imagine waf .. ing alung n pa\'cd hi ghwDy blindfolded (001 recommended) with the goal 0{ d lsco\'ering all pos~ible potholes. The numbcr of po!hole~ lho,t may be locaiCd is a ful\C1lO11 of the Step siT.c Bnd the diwmce tra\c kd. 'The 10llger the gait. too faster one trn>ds down the road. OOt w;th a ~ probabili ty 0{ lirld ing all tbe pothol es. S~stemat ic sea!'l:hing gcnernlly ca n001 handle: sohem ... and the method IS oo ly amenable to ~arc hing fcwcr Ihan 10 dihedral ang lc,~, becau<;e of the c)( poncnlla. cxploo;ion of ~sible conformations tnal results (!lee Equat ioo 2-30 III Chapter 2). Large amounts 0{ computer li lll(' arc c)(pended bec~use ~\1lall d ihedrnl angle inere mc:111S nre required for eac h rotatable: bond. In grid sea!'l:hing (GS), each tOfSioo Dngle is examined, but the structu re is 001 subJCCtcd to grome:try optimiuuon.

According to Equalloo 230. the number of cllnfonnatioa> geocrated rise!! exponentially wllh the: number of I:Jonch rolilted, Torsion anGlc driving ;s GS ..... hile the reS! uf lilt stt'\lClure ( .... ith the C~CCplJ()I1 of the 1 011 bemj; ~y\lemau 01'51 ca lly rotat ed) i ~ ellCrgy nunnniled. Many pmgnuTlS have tI1is fealure, arid accurate conformallooal enr:rgino arc obtained with lhe minimi/,lllhm. NoosyslCmalJc <;earchmg typ~lIl1y is II'IOre U itable for larger molecules. and "o1\'~ nlS may be Included."'" 11 In p cr.lI. lnofe time is tle(.~ to apply b!lItistical analy~ for the ' completencs.~ of a <;earch, Although 5tOrna>lIc searches ore use ful, lhere is an mhercm incomplctencss 10 them. SUlChastic searching can use either internal or cant SlHn coonlinat cs, From a Maili ng lo"'-cnergy cOli fomlalJort. the carlcsian cootdll1atr:.~ are random iled with a " ~ ic"''' If the rnndomi1,l11100 i~ not large enough. the stl\l!,'ture "10 return to il5 SIllrting poinu;, TO() large 0 perturbatiOll gener ales unrealistIc high-cnefi)' CQIIfQl'm;lliQnS. 1ltc rnndumiltd geomet ry is energy min imized wilh II force field, lind tht newly gencnted structure is CQIIlpared ",ilh the oof,1III structure according Illtnc Mctrupoli s al gorit hm (MAj. 7 Tht Cllnenl conformation is CQIIlparcd wlih the newly sentraltd ooc. If the eocrgy or the 11C... ly gencruled cooformallOB Io....cr th:m the enc!iy of tnc original coufonnntion. the new one i~ accepted , If the ocw ronfonnatlOQ M \ higher C'IICfJ). there i~ a slllt i~lical chauce: 1 may al;.() be rellllned. In Ihll 1 lCCond case," Solumann factor is calculaled (Equation 28 27). w h,ch ;s then t'omparcd With a fUlldom numbcrbc:tIl\'Clt o and I . If the BohzlTWln factor i~ k:Sll than lhe rundoml) genera ted number. the collformallOll 11 accepted; OIhroo~. il is rcjected.

With allmelhods.there aJt~rengths and linliUllions. Conform:uu)nal sean:hlng is 110 uttpli()ll. A comparison of the methods Wa5 carried out on cyclohr:ptadecane In an effort lO find OUt .... hat cooformations IU"e signiflCllntly popuhlled at room tem~rature or wlthan. say 3 kcallmol of the ,Iobal minimum?" -' The luthor.; reached the following oooclu ~ions: (a/the effecti~eoe.'>S of the seareh appears to depend hIghly on the method used. and (bl exccpt for distance geometry. all methods could locate the giobJI minimum: none of the lflelhods found all 262 low-en.::rgy eonfornmtions in II smgle search. l1eeause oftl'le importUIICeofeonformnlional searching. newer algonthrns have been developed since this benchmark study. The Confort algorithm. deleloped in the IJbontory of Robert Peatllll:lll. performs a systematic search over all pos~bIeCOl\1b,"atiom of " worthy dihl;:dral angle ranges" rather than ('~hln, o.er all JlOS$ible combinations of dihedral angles per~. Very fast partial opllmillitiOl'lll are carried out for each such combinatioo of dihedrul angle ranges. Each of the tlX'iion runges generuted by Cooforl brackets II single Ioi:al minimum and is fonowed by energy minimization. Al thouGh suI! of exponcl1lial Older. the number of increments used per meor is typically between 2 and 4. thercby making the COllfort algorithm extremely fast and enabling its use for s.earchin g rings und ring systems in addition to acyclic substructures. 7~ Methods have been devised that alter the potential enet'lly hyperlipace... hich have been u<;eful in locatinl the global mimmum. Sccond-derivllll'e informillion. di('U5sed above. mdicates the eUf"ature of the energy surface.... hich may be nallcned or inflated. depending on whether the surface has I posiu"e eUf"amre (negati"e seoood derivative) or negative CUf"aIU~ (ptl6ime second derivati.'e). respectively.1J Genetic algorithms (GAs) bave become popular for many applications in ..dena:. including the detenninfltion of pos~i ble eonfonlln1 ion~.1b The widc~pread use of GAs may be attrihuted 10 their robust lIalUre. 5implici ty . and computa tionnl effidency. One u[lpf'OaCh 10 lhe stochastic s.ampling of the coofOfmlltional encrgy hypcr:surface uses a GA with a fitl1(':$$ function lhlll attempts to 5Ciecl dihedral angle values 1e:Jdlng to low-energy COO fOi IiICl5 and. possibly. ,imul\JIneOLI.'ily altenlpt5 to !i('it dihedralangk values rorrespondi ng to "d,,'ctSe" conformations. Although GA-oo.o;ed search resull$ are incomplete. the ellt:,,&ies used 10 "5OOI'e" various conformation .. are C'8kulated in an appropriate fashion .7" Another stochastic approach involve!llhe "poling" I lgon!hlll ." wh,ch loculI$ minilll:l and artificially increases the conformational enl.'rgy hyperspace until there are no minima at thaI locatiOll. The name: is derived from lhe ana lOlY of I;terully pl:lCing a pole in the energy well and pulling up the surface around the pole. like raising a circus tent. All methods thut involve re... h.aping the potential ene!ly hypersurface suffer from alterations to the surface beillg explored. The mifIClal illCT'C':ase in the ~XlI1fonnalional energy hypersurface ncarcach 1 0we1lCT1lY confonnatiOIl ensum that nearby ron fonnllllOllS \10 III IlOl be sc:1ted. Although this approach is much faster than GA-bascd approaches. poling algorithms III'C oflen IeS!I reliable. 'They fuilt() find 1o... -encrIY conformatioos because. the conform:uions selected are based on artlflClnlly penurbl:d vllues of the conformatiooal energy.

MOLECULAR DYNAMICS SIMULATIONS

The molecularcoofi,u~tion it a funcliOll of ti me_MoIecul:ar syste:ms are not stationary ; molecules vibrate. rotate. and tumble. Force flCld ealculauOI'Ill and the pmpenlcs predICted by them an: based 011 a ~auOl1llf)' mode l. What ,s needed IS some way to predici what l1lOIions the atoms within a moleeu Ie will undergo Qt VQriou~ temJll!ralUre~. Molecular dynamic.~ (MO) simulatiolls use classical mechanics- force field methods- to study the atomic and molecular motions 10 predict macroscopic propeniell.1J MD simulatioos iulYe the potential 10 ",,'eal importanl insights into drul - reccplor intcroctioos. but some:. Import~1lI assumptiOlls should be re~ic ..,c:d:
l. Molecular.~ obr.y clawcal mtClwtlCS. 2. The: r.... cc:s .cll1II un e:ach .tom are equal 10 ,he ~IVC ,""",cnl of the poIelMlai UiCIIY_ J. The potentIal UIC'lY may I:i>L cakul.to:d from rOftt r.cldl.. 4. The: lnI(lCf1Itu~ is I.op:,fuonal ,o,he ,-.:IOOly. ~. The: time "'engc .. equal to the cl\j;Cl11ble .''Cf3Ie. " 'hlCh i ~ known ... the c'lod,,, hypochc.... ' ,

In applying clas.,ical mcchllnlc.~ to Sitllu lale molecular molioo. it is necessary to use Ne:wtoo's laws of 11100ioo. The three laws are SUmmllriled below: 1. Uzw of in~rOO" A body ~y. In mollon or at n:st unlcsa k'to:d on by ..... 1~1Ik ron:a 2. F..,.oo""'~"JI lkji"",.", offo"'~: !RaM X :aoceler.lllon.

C 28m Eq

J . lAw l1{oc,/cfI - mN:1w..: For ~

~Ie telCUOll.

iICllOO.

there ~ an ~ 1M

F,~

F _ _ - F,..., ,

CEq. 21133)

Using Equat ion 28-32 lIS the btani ng point. the ma,s //I may be eliminHlcd Hnd integraled with respect ,0 time' 1Ie cord in, to Equation 2834 to live Equatioo 2835 ... here " is the velOl:ity and C IS the intcgratlon constant. It is a simple: mailer to detcrmine the inte&rnllOn constant. At the imtial time. '1 - 'I ... hleh mean that II~ .. O. 11lerefO'. the integration constant must equal the millal velocity ( C - ,~o).

;p j"; dr .. jd;
<II ..

adl

(Eq 28-34)
"II

_
I' -

_
a {l, - I,}

.
+ C - Q.1.o +
(Eq. 283S)

Inte:gnllioo of Equalion 28 35 provides the distance Q par. ticle has tra veled from it.~ initial posi lioo ; at time I to lIS new position ",I + 0.1) al f + ~I (Eq. 28 36).

;{I + ~'l ..

, i

,+ "~I

(Eq, 28-36)

Equations 28-3~ and 28-36 are known n Newton's equa tions of motion. MD simulDt ioos apply these IWO equatIOnS to all the aloms in a molecular stnx:lure . Acron1lnl! to lhe lr::inetic-moIecular tt.eoocm. the killt:tic ellCfJY is POIlOItional to the lemperalure. This remarlr;abl~ ~laIionshlp IS shown in Equation 28-37 without dcrivallOll. where His the number of molecules. Ii is the 801t:tmann constant. and Tis the ahl;o-

lule: lcmpcr.uurc, EquatiOIl 28-3 7 COIlr.eCIS c1 aS~ l cal pllysic~ to statistical mccMmC'o. oosic ic.k'a behind MD .... mula tiom is 10 i nlIQduce Ileal 111\0 tile sy~lcm and adJust tile veloc lUes 10 m':lIntllin the tcmperoture. The forces on the atoms CIlIl be eakul.. ted IO.-ith II fon:c fi eld . Orw;e the forces I!f"e ],;nolO.-n. based on Ne'''o,'-s cekbr.ued second la'" (Eq. 28 32). the lIO::cderJtiom can be eu kullltcd . UsinS Ihe la"" s of n)()lion (Eq. 28J511nd 28-36), lhe \'clOC1lJCS and new positions can be caku lulcd. This procedure is repe al ed fO( tile durJllon of the sim ulation.

n.c

,,
l.

",I

L '2 ...,{ ~r "" '2 "'AT

f&!

28-37)

The fUlldtllllcntal steps in a MD Simullliion mlly be summarized:

f..nerr.Y mJnimiulIon

2. 'kalin, 3. P-'!ulh/:nlion 4. ProdUClion ruRS S. An;I'y~il

It is in fol1l1uli \c 10 rc~lew "Ollie of tile information n:gurd Ing MD lune steps. It has ~n learned that the beo.t time ~tep ~hould be III OIh of lhc ipr.llest frequency in the systcrn. 1be laI"J!e\t frequency is associ:llcd ..... ith bond vibr.llioo.~. T he largcst fl\.'quency (.'...... - 10 1 sec I) inyolves C- I-! bonds. Because lhe largest frequency i~ IIl"crscly propor. tional to the penod of oscillatlOll. lhe I1me Stcp ~t i ~ usually 10 11 sec or I f). Longer Slmul:uiOl1times mil)' be achin'od by a foclor uf 2 or 3 if the C H bond vibrntions un: eonstrninai The S~IAKE algorithm "'3S de\'elopt:d .... hereby constraints are placed on the ~Ibrullons of C- II bonds.7<I When calculallng protein SllUCtU Il'S. one muSt M ve II good solyation model. Rt:cau'C W ilier play~ II crillca l role in enl.)' nlc: reactiotts and st3bilw ng proIClllS. 1\ is Important to M ve cffC\:li ve ways to mo&:l wllter. [n the struclure based destgn of human immunoderw;ic'ncy vilU5 (H IV) inhibit0f'5. for eurnple. the pre.sc nce of a single waler molc:cule in the bmding cln ity was effc:cth'cly exploited in Slruclurc bascd drug design. 1lIcrc urc e.<sentmlly two ways to inc lude: soI\'enl In MO si mulatIOn' ; (o ) CQIIlinuum sol\'elll I"IlOdtls and (b ) explicit w lvmion model s. In principle. lhe lOIter shoo ld gJ\ e froon' ~urn\l: protein si mulati ons. but II depends highly OIl the lOo'aler model u'>ed. The: simplest CQlltlnuum solvenl model Si mply OOJUSIS the dielectric ~unStunt to equal the medium dlelcctric. An lipproxlmallOll IO.-idcly used In MO si mulallollS b kno ....n 3S the di stancedependent dielectric constnnt . hI thi s approach, the dielectric constant is sct equal 10 the disllllICe a.~ shew. n in Equation 2838. The clectnll'lallC energy " now proportional to Itr rJthcf than Ilf. When this was firsl proposed. the ldi:ll was to hclp reduce C PU lime , The rnlionali1.allOll is thal the charges on t ....o nonboodc:d alOlllS in a macromolecule arc scparJl 00 by the protein. IO.-h ich should rc:dUI% the imerncuon lemls. llItls, the inlCfXtlon ellt'~y shotJld filII off flL~ler ullln Il r bccau'IC the charges arc mas~etI .

widel y used wmer soh'em mode ls un: SPC' I and T1P3p ll In the former, the oxygen !ltorn hllli !l charge of -0.82, and the hydrogens hll"C II c!large of 0.4 I . The: H-O H IlI1gle I~ l09S. and the O -H bond lenglh is 1.0 A. In the lauer. tile oxygen Dtom hM ~ charlie of - 0.83<1. and the hydlollu6 M\e 11 c~e of 0.417. The: H-O-H angle is IOU". and the: OU bond length is 0.957 To noid potential ..... ~tcr-vllCuum mterfllCC problcmslhat might an..e In \I MO ~ imulation. periodic boundary cooditi<K1s art: OOll1111011ly u.'iCd.-) BlIliically. II protein is sur roundc:d by II rectangulnr hox of .....ater '" ith II defined number of water structUJ"e$. This .... uler box is then surrountlc:d 01\ each bee by llnothe r w-.ucr box. When the: MO simulaua. is bemg curried oul ...... ater ncat the edges of the locnlral hoI containing the protein mlly lell\'e and be rcpI:rced ....-uh I watcr comi"g from the '" Dtcr box on the opposite side, TIu. proccdure ensures that the IO.-aters Inside the central ....-ala box reffillill con~tant. The lo ng-mnge forcc:!l found III the nonbondcd Itm1S d Eql1:llion 28-19 pre-.e nt some uniq ue diffi('ulucs fOf I MD s imulation. Ca1culallnllt~ e1lCrgy Icml~ I~ CPU il1lcnsi_c One early solution WIIS to impose 8- to 10- cutoffl. Al though t hl ~ saved dr:llnallclll1y on the simulalloo II~ unrealistic proiel" structUIl'S resUI1L-d after long runs. 'I'bm were se_ ern l poIentlUl wort.;:uound~, tocludl ng longt'r cutoff. and updating these illlenlCliorl~ bt:yond Ihe stMndllrd cutoff les..~ frequentl y .... A vcry IIUtae::\IIC approach to circum''aiI this problem altogether, proposed by Darden. York. Jlnd Ptd eriCn. u!>l':d tile pllrllcle nlCSh E .... llid (PME ) method." Fn:c cnclty penurbatioll (FEP) culcu llltionsll6, 11 1110111' di rect ,l.~G COIl1p;iri'lOlIS bet .....een I dlllg 0 th31 blnth to I pl'(lU:lIl P to fonllthe drug- prolein complex 0 1' and .SIJUo;;. tum! analogue 0' and the SlIme proIelll I' (sec fig. 28-17. .... Ioch depicts the free encrgy pt:nurootiOIl cycle). OeICTTIUn ing the frec energies of binding, ~G , and ~Gz, c.~ pmmrtl' tally Clll1 be difficult and hnle conwmin&_ Conlcning 0 into 0 '. ~ GJ. and D-P Into 0 '-1'. 4G~. l~ C\pcrimcntally f!CIItioos. Such conversions .... ould lllllount to alchemy. The coo'er~ions can. ho .... eler. be camed out III MIICO.

D"

...
n..

r.,.

D' + P

"':::::'-~I D '-P

loG,

'-..

"', ... L41fl\,c~v .. L4 ...c~ -""-'" '-I

'" '"

'"

(hi

21138)

The OI lier approach is to trem lhe solvelll e~phcitly. There are a number of ....alcr models p\":ailnble.1ll T .... o of the IlIOSt

figure 28-17 free enefgy perturbatlOll (FEP) caIoA.t~ take iMivanl.19l' of a therrnodynanoc c:ycle Here, the top FN(. IKJtl shows a drug D combinlll9 WIth pl"Otell"l P 10 form IN drug-pI"Olelll wmpIex o-PWlth a Iree ener9)l change ~G, bonom rHd'iOn ~ ilnCllher drug 0' comt.n.ng Wlt/1 ~ KlenllC3l proteltl P to 101m a second dlug-protem complex 0'P WIth a Iree energy ctwnge .lG1 , Both of these ~aIy ~ Sl'fVable reac;llOOs ~ave a IrE!' ener!ly change, .lG, ,)S<OO.ltec! Wllh them ~ Iree eneogy difference betweef1 the IW\I drug-protein reiKtJOns rs .llG .lGJ - AG 1 " :01'1;11119 10 1M 11m law of thermodynarnK:s (conwrvatlOl"l 01 energy!lwl, the r~,tlOUs c~ . .lGJ and .lG... must be r""'t~ experrmenlal .uG

10"

In a 11K,,"odynamlC cycle. Eljuauoo 28-39 mUlA hokllls lhe: energy diffc:rc:~ Ikpend only 011 Inc tnilktl and final SlalC!. Sub/meling .101 and .lG I (rom both sidc:~ of Equalloo 28-39 prol'ldes the: remT'dnged Equa\i0028-40. Rccogllll.ing Ihal.16.G .. .1C1 6.C" EquDli0028-40can be:simphfied 10 gi I~ EqualiQn 2R-lI . Thi~ rt'markDble rel;u.onship. takmg adYantage of Ihc: lhe:rmod),namIC cycle. indical~ thai the frt'C eoergy differc:occ:!i based on III ~ilico alclKmy must be: eqUlvalc:nl 10 the upenmcntnl .16.G. 'The: melhod has bc:c:n u$Cd to calcu late and comp:tte the bllldin! encrries for many different drug-pmlem cOInpleAc. Although lhe: npproach II in ielleclullily Slimu la""g. 11 rt'qu ires ~ignifican\ computer fC'iOtlrees.
IlGl - ')'G,

QUANTUM MECHANICS
Ooe of the grent Ih~'Of'Ctical accomplishments of the 20th ccntury .... a\ the development of qU1lnlum mechaniI:S." The phi lo!>Ophi~al illlcrprelaliollS of quantum nll.-chani~~ lI1ay he comidered weird from the ~talldpoillt of our practical everyday eApc:ricnee, in lhe macroscopic Vlurld. Nelcrthek,s. the applications of quantum mechanics 10 I:he:mical bonding hale changed the: VI ay l:he:misl' Ihml. about molCC1.llar st1\lC ture~ and hall: made: chemi,tr)' u \tJbdi\Ciphne of phys ics. MlIIIy uneAplamed che:nucal effech may be undcrMood in lhe conlext of molecular orbilal (MO) calculallon~. For ('J.ample . the nnomcric effect S<!en in carbohydrate clocmbtry cnn be ration~liJcd as n eombinaliOfl of MO intcrndions and eiectrostntic effecls, Although chemi,!., lil.e to follow the ellampie of G. N. Lcwb and VI'rile ~ unphfied mokculur structures (Lc .... i~ slroctures). molecules an: renlly nock. embedded in a sca of dcc::trons. It I S reular~ablc: that <;0 man) organic )troCIUrt~ can be reprrsc:nted. alo a fillil :lpprO~irna lioo. by localil.rd chc nncal bonds and lone pnit!i of electrons. As nny ~t ude," going through a COOI'SC in organk che:nll ~lry cnn Uliest. chernkul reactivity and physical propertie\ lIIay be: c~pIDincd, i 11 many si lllatioos. by e~tclllll11g our simplifird bonding eOllCc pi' to ,nclude rc..ormnce and elccuun dcloclll i/.alion. 8L'('au~ most drogs (or organic rnok-cuks) and lheir Irlter.rdioos VI IIh rnacl'OlooieculcI ~ responSible for lhe: ob!ie(\'ed biologIcal effcc!.'! called " drug oclioo:' il is qurle l'Ci1'iOIIable 10 u-.e thcor\.'1ical 0\10 I1l('thod, to understand l'Iectror. distnbullOllll and predict phYSiCal properties of drug-li l.t structures. The only .... ay Ihi~ CUll be: achlCled " through lhe: UltC of quantum Chc'lIIs.Lry. sillCt' force flC'kl methods do not explicitly treat electron~. The hi~t Ol'}' of quantum rn..'('hani c.~. ""hile faSl:inaling. is too lengthy !O di~u.'\S here. as is n full dc"elopmcnt of the theory, The: &001 of thi' I:hapler i~ to p"'.... nt the ooocc:pb SUC("inctly for rt'atlc .... ",ho hal e nelcr tal.en courses in ph) sical chemlslI)'. VI here lhc:sc' topics arc: more fuJly dcl eloped. 'The emphasis i\ 011 follo...-ing the losie:!1 ortI.!r of oonceptS. not 001hc: mathocmntical details ..... h,eh n1t'1I1 <;OUIt' relaIlOl" 1S shIps hUI e been simplified. Wilh the fundnment:rl s p!l'.'!iCn\ed be:lo ..... il i~ possible to undersland the impacl qu:ur!llm 1T1<'I:hanics has. antl willl'OJ1Iinue to halt. 0', mcdicinal l:henmIt)' . The sect io ns Ihat follow cootnin refcrences to quantum mechanical applK:ntioos in CADD. We ~t:u1 .... llh the contributions of M:u I'lanel.. AI tire begmning oflhe: 20Ih ocntury. phy~Ic' 1Ia.<i m n Lt"""CIICal criSIS, It IIIIS belle,'ed that NeVlIQfl. equulloos :utd Muwdl' ~ eleclromagnetlc lheory eould eAplam all nalUl'1I.l ptrc:.. nomcnu. bul lhe: application of these: cla~sica l nlir.:uucs IIK!thods to the emission of clectromagnelic r~diation from p!!rfel:t "bllld: bodics" did not correJllle .... ith clIpcril11Cnl. In the theorelical t rentllloCIIL~. the rudlOtioll W/tl, IISsumed to re:;ult from the: microscopic oscillalOfS. wKllhe inescapablc conelus>O<l of classical mechanic5 was that u CQI1tinuoth runge of enc:ra1C'S was DI'ailabie to the OSCillnlOl'. Planel. slIggested in 1900 thallhe eoerg} associated With oscillalCW'S II'U a fUOC'lioo of inlegr,,1 wIlles o f quanta (Eq. 28-4). Vlhe:~ f. is the erle'l!Y of lhe oscillator. h IS l'r:lnc~'5 ConSUlTH (6.626 X 10 l.j J -SC(:). lind II is the frequency. The sliggeslion VI'Orked, bUI many Sl:icmiSis of thllt pc:nod thought this solulion was simply n Illn!hemnlicnl trkk. becnuse: tire Iogicul

+ dG,

(Eq. 21139)

.1G, - .1G, -

,lv,

(bj 211-40)

.).G, - .1G,

(&1.

28-11 )

Anochcr npplicauOIl of .merclA 10 medicinal chemist) in mh..:s lhe: thermod),nalllic penurbutio11 I:)'dc applied 10 ~Ia twe prupcny c:lkulations. For eJ.umpk:. directly cnlcllilltmg tlK IOlvauon of a 5111011 drug R.'IIuircs utensile simulatioo times, The d rug ha~ to Imnsfer from in vacuo into 1111 uqueous enl ironment. ThiS trun~fcr frolllthe gns phase: 10 the l\(lueoos phase: IS CPU intcnsile. given thai lhe solvent t1us to be reorganized to accommodate the solute. Calculating a sc:cond drug analogue II ill invohe II Similar poOC.,S!i. Mal.ing lise: of IhernloOdynamic cycle. ho...-elcr, can c.'IpedJle the procc:!ilI (analogoW 10 the above dl>ClIssion for the: drug- protein binding). TIrere ute 110'0 t}lpes of mOllon (hannonK: and stochustlCl thm may be siodied by MD simullltiQn~. Ifllnllom r: siml/II/' liolls refer to o!ICiJl:11 ions ncnr equi librium (i.e .. near the min IlIIum of a pll(cnl inl energy II ell). SIQt:hllSlic refet!i t(, SI11IUia lioo~ Ihal Ic:ad from 011( local minimum 1 another loenl 0 nnnnnum. From a harmonic OI'Cillmor.lhe frcqUO!:ocle\ may be caJculatrd occording 10 Equa!ion 28-42 ..... here k is lhe: stretching comllln! and m is the 1n35\. Exlending lhe: conccpt from II ~lDglc 11Iass held to a surface by n spring 10 N pnl1icles r.:quires un eXlension of lhe Taylor series expan)iOfl (Eq. 2813) \0 II m~lri~ fonnululioll of partin] ..cco11d deril' ~li I'es. f:.ach rnode has as.socialed il5 own fun.-e constant. f rt'qucncy. lU1d 3N ll']auI'e dlspl:icenloC11IS , TIre norm:1I mode~ are asSigned 10 the: experimental 1M or Raman spectrum.

MD simulalions hal'e Ilcen npplicd 11.1 gcncrute new CQnfonllmiOI1~.l'. 88 TIle oo\ic ide:1 is to itdd ClIO\lllb IJrermJ] entrgy (through high tempc:rutures) and calTY out the ~i lllu latiQns looli: ellO\lgh ror rhe molcculur systems to OIerrome conformational barric,," After the: simulalions are com pleled. the: lrujeclory Clln be relleVled. 100 lemptnllure of rile syqe m caro be eook'd OOVl'n to sample poIential new conformations. MO ~Irnulations are ) uit:rble for larger molecules. and soh'cm may be irocJuOed. No sUill., ticnl or gt'Ometrical means Ilrt' u-.ed to deterrn; nc their ~'OI11pleteOC!os. In 1.'C'lCrul, M0 NinrulHliQn~ are 1104 us cfIkicnt as stochaSlic or dbumce gc:omcll)' methods.

meant th:u encfJ!Y was available only in discrete quantum vallK'li and was not cominuou5.

e~ums,on

and lowcr-case chi, )(, is used for I is dcfillcd below.)

~pin

orbital, which

e _ Ir.

(Eq. 28-4)

"The quantum Idea was used by Emstein to uplain the photoelcctl"lt: effC!C1. When metal surf....-es are ~ubjected in vacuo (0 dectromagnc1ic radimion of ~flC frequencies;. elecuOll$ are released. "The phenomenon could not be expl:nncd by classical mechanics. EiIlS.ein used the: quantum COf..... pllO ~uggest that eleCltumagnetic r..l(liation WIIS simply a stream of photons where Equation 28-43 C()ITeCIly defined the cnoergy. Using this quamum idea. Einstein fomlUlated a relationship (Eq . 28-44) be, ..ttn the: incident dectromag noetic rudiution and the e~petled electrons. Ei nstein's work supported the Planck quamum theory. In this equation. C/I is called the work function. which is the minimum energy rw:ssmy to eject eLectrons frorn the nM:ull surface.. SonM: simpJc deduction , howing tfmt the: kinctic energy mV'-f2 CIUlIlOf be lero, reqUIr<:S that !II - IIIIQ: therefore . Vo iJ the minimum fl\."'qUC:ocy allowed. (lnterc.~ting ly. Ein~tein won the Nobel Prile for his COIItributions 10 undenumding the photoelectric effect and related mailers rdther than for hi s theory of rclat i~"y.)
II. - 4> -

..'. if' if' if' ) (h'- + "Ji'- + d? "',(.o.y,:) + ~ j

Equation 28-46 can be
arr~nged

(F. - lfl.,,v.y.:) - 0

(F.q. 21-t1tJ

'0give &luation 28-47.

UM-<.y.:) - E....u,''':1

~ if' if' if' s.?IfI\h'- + dY- + d? ) ~...".,:) +

{Eq.2$-471
A more ~ompacl (and pemaps less offens,ve, form of the SchrOdingcr equation is ghen by Equ~lion 28-4$. "hen:
If

- 8:;;:Zm

h1Vl + U(....y.z). ~I~undcrsloodtobea f\IDt. '

, 2/11VJ

(Eq . 28-44)

Bause light hal; particle-like characteristics. de Broglie argued that e lectrons shou ld therefore uhibit wa\e like char..lCleristics. This is odd because il defll'5 our macroscopic experiences. "The wave-like charncler c~isu for all objccts. but only manifests Itself- for all pncuclil purposd- with microsropic panicles (e.g .. electrons). The de Broglie relationshIp (Eq. 28-45) quantifies the wave-like ",,,,,,,,tlies tM\ 1I11mCr exhibiu, where A is the ,,avekngth , h is Planck'~ COIIstant. :lI1d m'; is the momentum (mass X velocity). Clearly, the relalionship soows thaI for tiny masses, the wive IMOp...1y o f maner is $igniflCllIlt, whel"Cll!l for large objects, the: wave-like character is vanishi ngly sma IL .
A --

tion of the x.y.: coordinates, and Vl " 'as defined earlicT ill Equation 28-26. (Ii is 001 necessary to demand that ~ be. function of cartesian ~oordin;lIes. "The cholcc of the cooru.. Mit system may be dictated by till' nature of the p'obkm being solved, In other wortis, it may be eas,er tl) soh~ I problem within D diff~m referrnce frame . II\" may be I function of sphcri~al polar, plane polar. or cyhndncal nates or of other COOfdinate systems. For example, dUU(JI to the hydrogt;.n mom in~ol ~es the U'lt of ~pI1encal pobr COOfdin\lIes .) H is the hamiltonian opentOl", ",tuch i$ tW quantu m mechnnlcal equivalenl of the class ical mecharua formulation H - T + U, ""here T is the linctk mellY lid U is Ihe potential energy. Note the siml larillcs be1",ct!I the classic.1and quantum mechanical formulationoflhelwtil tonian.

ctXlI"

it"", ... F..I/l.o

{I;q 28-1$1

Equation 2g-48 is the SchrOdinger equation fOf si~k particle, For the application of quantum mc."Chanin 10 mcdi.:. inal chemimy. it is necessary 10 thinl; in u:mlS I)r elcctn:lM moving around nuclei , "The SchrOdingcrequalion canbtt'QIIvened into a multiatom problem. given by Equati0f128-4~ III Equation 28-49. the ham,ltonlan is
H -

.,

C 28-45) Eq.

. ' L... ~VJ + LiLit=J 'C'C" - h. 'C'

I , /'"

At this point in 20th century sciel11,.'c. it was becoming IICCCpled that matter had both wavc.like and panicle-like charnclerislics. Depending on the: experime ntal setup. Ihese seemingly rontnKlictory pr""",rties could be observed_ If mailer has wa\e like properties, then there hud to exist some gc"ncmlly dcscripli\'e wne equation. It was ENoln Schrtldingcr who recognilO!d that standing waves with imposed boundary conditions yielded sets of integers. which would be con sistent with spectroscopi c observations." -'" Hc developed the now falTlOU5 Schrlldingcr WlI\e equation (Eq . 2g-46) for. single pan icle such as an electroo in a 3D box. Thil equalion is linear ( nM:lIl1i", the wave function is raised to a power greater than I). !iCCond -ordcr differenlial equalion (meaning second derivathes are invohed). where E is the Iota! energy of the: system, U is the pofential energy, and ~,(.r.y.:) is the ele<1TOl1ic wive function. (Different symbols are used rouTinely in the HterulUre when discussing wave functions. In this cll.lJlIer, Joy,er--case psi . .". and uppercase ~. ' I', are used to <lenulc the wave fuoctions for a smgle partICle or II mulliparticle system, rnpectivcly. Also, Iower-casc phi. ~ is used 10 represent atomic orbilals.

The first term (k,netk energy) is a summation O'oer all. particles in the molecule , "The scwnd term ("",ential eMIlyl uses Coulomb's law .0 calculate the Inlenc1Wn bmofCII every pair of partkJcs in the molecule , wlM:re t , and t , ~ the ~harges on p:lrt ides i and j. For elcctroM. the dur!e & - e. while the charge for a nuclcus is ~. whcrt Z i. the atomi~ number. The SIImmalion notation; <J for the IIIdIct\ means tfml one does 001 doublecount pairwist inleracti;c , terms in the summation (e .g_ t~J _ t /i and should OIly lIppear in the potential energy term once). The denomil'lMolr I'~I in lhe second term is the distance between parllc les i_ j . 1'01 is understood 10 be the electronic wale fuocUII! rtf a many-atom sySlem.

,., ,

Originalty. '" was lhought to be aphysical wave th3! .. ", propagated through space, Today. qt- is TOOR: ",open) preted, from the work of Bom who firsl made the ~opl'l' &5 being pi opot tionaJ to the pi obability of finding a pamo;lC in a small \< olumc element dr, .. here dr - /hd,d:. In tbr more gellenl case. lhe probability is rqlf'Cstnted by "';t.

1"

.. hen: ~ is multIplied by the: compleJl conjugate W. The complex conjugate III 1"IeceS!>Ilry. in that the WaH! function maycontam imagmary numbers. Because w"wdT represenl!l the: probabi lity for a small volume elel1lent. it is possible 1 0 such thai the tnccgral o'er all space is uMy define if'V;,W....h - I) Ihrough lhe: appiOphate choICe of cocfficic:nts. TIle in legrdl ~ymbol is l1Iore cOlllplic:ued tiuln il rnay appear. It really ~pans all of cooniin3tc spatt. so for cartesian coordin.ates. the rang\' goes from negatilc 10 poslU ve infinity for each of the three.1". y. anti: oooedinatcs. This means thai Equ~tion 28-49 is deceptt'e. si nce it involves solvlnK I triple 101eKrnl, flf'I':,(J..)'.z)'V(.I.)'.::)d.rdyd:. To be an "accept ~ble" the:re are ceruUn conditions lhat are required;

Ano!her consequcnce of the Pauli e~clusion pl'llIClpie is that the spm Of'bital IS a prodOCI of a spIItlal functl(lll .. and a spin function a or {J (Equation 28-~!i2).

"'01

"

"'01.

I "., w.we lIquali"n mu,.. be ...ellbt-h~'eIl rruur..markally. 2. 1M t(IYalion muSt be conunllOUlo function .... I"ch boo,,,,, zero .II infinlty_ 3. "The .... ve """ ....... muSi be IInlic ,-.J1ICd

The antisymmttrH;: wave function. shown in Equation 2851. is 0 more compact way of writing a Slater deh.'flllinant C 28-53). In a Slater determiOlll1\. an exchange: ofony twO Eq. rows or columns results in the same wlI,e function multiplied by - I. This IS another stotement of the Paull nclusion principle. The columns in Equation 28-53 un: the si nllie electron wave functionJ. Equmion 28-53. however. i~ only an approxunation. SUlCe the electrons are independent of ont another and then:fore not correlated This oom:lallon pr0blem reveil is itself when calculating the encrgie.~ and is discussed below.

-!

1M..y..:Ju
oM-<..:$

Equalion 28-49 IS a complell equat;OIl. even in the sim plest of namples. It must be applied to e'cry clectron in a rno/e('ule or molecular ~yslem undc:r examilUllion. The SchrOdingcrequMion has UlICt SOIUliull~ for only a few si mple cascs (c.g .. a panicle in a boll. a panicle on a ring. the harmolllc oscillalor. the rigid fOIOf. the hydrogen atom. Ihc hydrogen molecule Ion). Each e:JIample liSTed build~ on the preVIOUS one.\ but gcts more mathematically challenging. Solution of the nonrelativhtic $chri}dinger equatIOn for the h)drogen lIlom Yields the sel of quantum number" n, I, and '" famililll" fronl genernl chemislry . The spm quantum number s is IlOl Olle Ihal conICs from the SchrOdinKcr IreatnlCOI. It rna)' be addc:tJ in an ad hoc fashi on. using lhe magnel1c quantum number m as I gUI&. The founh qUlIn tum number does. ho .... e,cr. natunlily anSI: from an altental;,e rnalhematical devclopment of quumum mechanICS liult is fomlu laled by using matri~ methods.~~ Laler II was ~hown thaI both Ihc lI"a~ WId matrix approaches an: equivaltlll,~"" ExIleISOlulions 1 drug-li le moleeule!;. whether by WI>e or matr1l1 0 quantum meehallic~. are impos...ible. Nevt'nh('/ess, some !.implifying :l.\sutl1ptions MI'e been de'eloped o~cr the )'Clll"S. beginning Ul the 1950s .... hen OOfllPlllen made approxim:IIC o;QJUtlOrlS feasible:. that re<iull in good electron-based models. EqUation 28-49 may be arrnnged to give qualion 28-50 by mtlhtplying both sides of the cqualion by f'I'~ and lhen iOI~lIlg for lhe: ellCfJ!.y of the \yslcm E. If the W function .. is rlOI"maJiud. meaniog it has been sculed ~uch Ihat f"'~~,.d;., - I. the denominator is unity.
f: -

-w;,

x,{I)

Xii,

X,(2) X,(2)

);,(N)

);iM

X.,.cl) x....c2) ; X.,4N)

(&j. 28-53)

Usually. lhe spali al function 1/1 is conslmeted from the summation of onc-cli:clron spatial orbil~l~ (aTomic orbitals) 6. "nown as the basis 51:1. used 10 construct a MO. Thls approach is known as lhe: LCAO method (linear l'Qt11b,nation of atomic orbitals).17. II It is an appro1lnlahon of lhe accurotc many-clcctron wave function ( F-'I. 28-54). The !l.lomic The: orbital contributions are welghled by coefficienls summalion is troncated. so the "function is not cornpkle. which has consequences when .olving for E.

c,.

CEq. 2854)
The energy of lhe system e is a function of 1/1. The vuria tionaltheon:m" is IUl importllnt 8ta"inK POint in conlputationaJ quantum chemistry. It states !hat the: calculated energy of the system is always going 10 be greater than or equal 10 the true experimenllli cnergy (Eq. 28-5S). For the calculuted and troe enc:rgies 10 be equal, Ihc W function mu).l be eJIact. Exoct ... ave runclions lite not possible for molecular woc lUres. since the", 1lI'C an inlinile serie5 of atomic orbitals. described 1100'e. Therefore. every sel/X:lion for '" will ,!,>enctme a trial wa,'e function. 'V...... and the varialional thooiem demands mat the energy will always be higher than the uue energy. A! "'...... approaches the true wave function 'It. the energy becomes lower and lo ...cr. approaching lhe true experimenlJll energy e.

/'I' .."'.,dr

;.!Nt.lIlT

W"I. 285O)

~:...if'II .....'lT

For a ma ny..e ICClrDl1 system. the Hanrtt -Fod: wave function Wilt'. delined as the product of spm orbitals "Xl as OIItlmed m EquatIOn 28-S I. \I here A(II) is 11.0 IInlisymmetrizc:r for the eleclrons. pro~idi.'S good nn~wers.'" Thi~ is the stan . ing point for eilhcr semiemptrical or ah inllio theory. II is necessary to N,e ,4(11) 10 m~le lhe .... 3'e fUnc1ion anllsymmetric. Ihus obeying the Pauh e~clll.'ilon pnnciple. which .~serts Ihm two eleelron~ cannOt be in Ihe SlIme quantum Wile.

ij.!...I/f...,dr

i!:C-

fEq. 28-551

Solutions to the SchrOdingercquation for druglil;e molecules may be obtained by making appro~irnallons and simplifymg assumptions. There are three basic divis,ons of computational quanlum chemiSlry caJcu lation~: fa) semiempiricaJ. (b) ab initio. and (e) density functiooal thooiy (OFT). Early efrorts by Pople and cowor];tN produced a method called CNOO (complete Ilcgleet or dirfcn:ntial overlap).lIe-l(Il ln general. the semiempirical upproach eliminates Integrals lhat are tO(l complicated 10 solve analytically. (TIli!

is an Interesting concept in higher math: if the term is tOO hard to IiOhe. discard n.) In their place. appropriate fact~ (COOSllUlb IIJld equationsl an: mlrOduttd to compensate . For IUnately. the Integrab eliminated on the semlcmpirical approach glle n:latj\'ely Srll;IJI \alun if sohc:d. Equation 28 56 ~how~ the mmt complic~ted type of tntegraJ~ that an: removed In the scmiemplrical model They an: ~nown as tWQelcetron Integl'llls, when: I lind 2 repre5Cnl the 11'0'0 elcetron~. ~pannmg four alomlC centcr<; I. j. ~. I.

l'Ile extcnsh'c cffans of Dewar resulted in a series of reasonably accUr'.I1c .scmicmpiriclll models: MINIX> (modified mtcrmc:dialc ncglcci of Jiffcrenual U\lap).IO I. loa The: third \'CJ'!iioo 10 thiS 5a1C'\. MINDOI3, I~ 1 ga\'e muo:h im(PI proved resulls. The prognun alJoo,.ed OI1:t1lic lind medicinal chenltst~ tQ apply dectron bascd calculations to divcrK cumpound.. l'Ile al":lllabllUy of MINDOI3 helped make computational chemistry accessible to experimental ists. lbe MNDO (moderate "eglcet of <lifferermal overlap) modd. 1111--11 1 aner son..:: modifications of the obser-.'ed 5Y5' Icmalic CITOI'i. scr-.'cd lIS lhe Ixtsi~ for Ille AM I (AuStin n1Cthod 1)."$ Stew.!l1 took the AM I model and introduced aulomated panllnetcrization H."Chnl4uc$ with a diffcrem pa rarnetcri/Alioo phil~lthan o..,war. The remit was PM 3 (paramcter method 3). I TllocK are kno\\'n strenglh~ and \\ca~IM:s.'ICS of each semi ' emptrical method. The AM I and PM3 IllOdels only Include s- and p-functiOflS. \\hich limns the,r usefulness for most elemenb of the periodic cable that reqUIre d-omitals, Many of these elements. however. are not t)'pically fouoo III most drug ll~e molecules. Mon: f'ttCllt IIdvances with MNDOId include the iocurporation of d-functions in the NODO (neglcel of diatormc diffcrential Q\erlap) nuxlel.ll .. ll~ Extcn$ive use has been made of semicmplrical methods in drug dcsill n. l3I. m CnleulntlOns I)f thl: highest occupied MO ~nd loweM ut1()Ccupied MO ( HOMO/LUMO) energies for II series of oclive and inacth'e compounds have been used II.~ dC.'iCriptOOi for QSAR. AM I. for eumplt. has recently been used to lIevelop a predictive AOME model for P-450 OXidation of drugs. which is dB.cussed below. The rnorr mathemat,cally rigOf'QU!; ab mill() cakulauuns. a.\ the name implies ("from first pnnctpl~" ). do not WlC paramcters 10 the SIII1~ way as lhe scnllempinclll models.~ Unh~e semiempiricaJ calculations. no classes of integrals. are eliminated. Ab illitio methods hal-e. howe\er. a number of appro~mlll"ons. Aside from truncated basiS sets. in ",hich the COOsHmts ha\e beell adJus.ted to gl'c the optimal Ixtsis sel. one of the nlOSl nOlcwonhy ~ppro\ima\lOns involves the funct ional form of Ihc WRve fUJlCtion q,. Solving tlIc Schrildmgcr equmion for the hydrogen atom produces the f~nn liar hydrogenic orbitals. which Clln be approximated by Sillier type (Sn functions. Both are exponential functions h:1\'ing the form e -.. 01"'. where, is the t:\ponential coeffiCient and w is a functioo of the electronic and nuclear positions r. Soh'lIlg inlegr.als ..... hlch are products of exponential functions. can be CPU mlellsive Boys proposed Ihal gau..... 51an type (GT) funcliOflS uf the form e ,"01'1 could be substituted for ST functiOflS. IU The theorehcal community did noI.1I1l1nedi:l.lely embnice the idea until ]>QpIe demonstr"ted cOflvulCingly that a lincarcomblnatlOll uf GT functions could

m1l11lC ST fun.ct,ons Il'asooably \\eli. U~lIlg three GT rune tlOllS for e~cry ST functKmgave rise to a popular bas~!d kllO\\'ll ilS ST().3G, and many calculatlon!i wue rricd 011: by using thi~ mlRunaJ basiS seL STO-3G means thrtt. GT funclloos are u!oCd to ",produce evet)' ST functlOll.1!l ! Puple uoo I.'()worl;.cr5 dlsco\'CJed that mon: e~'ens l,'e c0mbinations ofGT funclloos improved the accuracy ofab inl\J;l cakulauOfl~ . The next advl1l1Ce was :til attempt to give grc:1ItI' nexibility 10 lhol ab inilio model s. By ~pllltinl! the GT (unc tions used tn describe lhe valeocc sl1(:11 clcctrolls into 1"'0 ~p:t.rnte functioo~. beller agreement between experiment and caiculallOOs was achicved. This method is Imo"'" l1li splil-Ievel basis SCt$ and is mon: ume consumlng_I'or ~xam pic. 3-21G b;iSI~ set) qu!Cldy Il'placed ST0-3G U7 1 The: !'f symbohsm 3-21G means that the imler core or non,alera' electrons ;on: descnbed by three GT funchons. and the 0UICf ~hell or \aJcnce eleclmlllli ~ broken il1lo an IIlner and 0UIn set. lbe lIlJM:r set i .. ~ilnulated by tWO GT functiom. .... lule lhe outer set is ~imulated by one GT funcllOO . EquatlOl1 2&. 57 sho\\ $ the upan~lOn of the atomic orbttals mlo GT fune lIon~ II!, ",here al "'pre..ent fixed coefncienb.

,. ,
Addltion:,1 ba~i~ sets rTUly be added to tile ~pln- le,el for mulatloos to achie\e greater accUf3Cy. TheK adWuON.i funetions are ~lIown as polarization functioos . l'ore:wnplc. 6-31 (;(d ). fomlerly teprestllled as 6-3 I G . has o,ct of dif, fuse d-oml tals adc.led to the heavy atoms (nonh)doq;tII atoms). I'I). " ~ In llnothoer uumple, 6-31 GCd.p). fOilllftly known lIS 6-3 1G". hll$ II !OCt of d-orbital~ a&.Ietl 10 tad! beavy atom. as in 6-31G(d ). in addniOfl to a sel 0( three po orbitals for all the hydrogens. IJJ The IlClIt \en'l uf apprmi matioo divide!' lhe .-alenee elooro", inlO three (>eh of GT functions (e.g .. 6-31IG ). I}oO An a(kh!looul SCt ofvcry dIffuse: funclion" cun be added 1 the model to help calculate roep 0 li,-ciy charged species or hydrogen bolllJing. denoted by Ihe plu s ~ign in the e"amplcs 63 1 + G(d.p) and (). 311 +G(d .PI.m I"., An ilCrtlti.e iOOlutiOfl of the Hartree Fock Rootllaan I:qUJ !lOll! is requiR:d for semK'mpiricaJ and all iniuo quanrum cbemleal calculatlon~. I)7. I "" lbc: approach i~ abo callft! tb: ,,,,If-C'Ollsistent field (SCf) IIpproach. In SCF calculatlOR\, each sillgle electron' , positiun in space IS optlmlled in tb: cloonc field of all the other electrons. Thl~ ptOttdurt tl I'!'pealed unlll all lhe electroo posilion ~ M' e beocn npllIm/td. and there IS no further significant drop III enerar IhrouP lhe adJuSllncl1l of the electron positions. lhrtreeFock (H~l calC'ulntion~ gi\c good resulL~. lbe bcw:r the b~IS 'itt. tb: luwcr the CI1I:'1l1Y according to the variational theorem, Thrn contes a point of dimini~hillg returns. huwc\er. in thai lhe: crlergy appruoches a limit known as the Hunree-Fod hlllll, No further ooJllstment in the basis !OCt breaks thi S barril:l'. lbc: H w1ree Foc~ limil ocrUI'l' because the eltron mota is comlated. aoo this is not accoullted for in a ~inGIc: SI~\eI dctermmanl. Thai ' So the adjustmc:nt of one electron aITo:cb the pos.UOfl of the other electrons. and thi s is not fully talCII onto accounl by the SCF approach. Tu circum'cllt not Wlna: electron com:latlOll into account, postSCF calculJtlOlll mu't be used in the fonn of coofigur:ltion IIltCDCIIOl1 Of ~rturblllioo rncthods.

Ctuop. ~r

211 Compwmru",,,/ Clwmi.<rry ami ConrPIIIUAssislt'd DflIg INsig..

939

Twsao commonly used poslSCF (or postHartree-Foc:k) methods arc used: configurntion imeraction and perturb3tion II1cthods. r"'-I~. In the former. the w:t\e funClion is a summa tion of other HartrecFock determinants. This is analogous 10 exciting elcctrons to higher energy orbiwl s. In the laller. as rhe name implies. a perturbation is added 10 the Hartree Fock hamiltonian. MIJller Ples)ot1 perturbation rheory (M P2. MP3) is nO! a variational approach. so il is possible 10 ca lcu late an energy lower than the tnJC value. There an: noquanlum mechanical charge operators. Thus. charges an: tkteml ined on the basis uf a populalion analysis. The electron den)ity p(r) is calculated and div ided between It.e :uoms of a molceulc. The diflicuhy. however. is in deter mining how ro a.~sign Shared dccrron densi ly between IWO atoms i andj ofdifl"erent electmncgativi.y. ln the:: Mulliken popu lation analysis.' ~ thc shared elec.ron density is divided evenly betl'>cen monlS i and j. regartlless of .he elecrronega tivity. Th is. of course, is unR'alistic but rt'main.~ a useful technique. OIller electron popnlnlion analyses have become increasingly [lOJl\Ilar oyer the years. As discussed abc... e::. fining charges to electron densi.ie~ is a way \0 gct rl10re realiSli c alomic charges. With !he el~ctTOn dcnsity distributed throughout a ,oole::cular structure. according to an ad hoc populwion analysis. it i~ possible 10 gellCnlle dipole moments ~nd color-code the electrostatic potential on molL'Cular surfaces. The eiloctrosllllic potcntial may be u>c:ful in devel. oping a ))hnrmaeophorc and deciding wh:tl properties a reo ceptor mu~t have. Density functional theOf)' ( OFT) has been used i~as ingly o\'er the ycars.'''b OfT h~.~ a radically diffe::n:llt up proach thanth:11 in Iile. prel.."Cding discussion on semientpirical and ab initio methods and may be more easily understood. In the DFf fomlu lation. Kohn S ham t'qu 3tions. I'ketTOn corre lation i. bu ilrin. '~1 Thi~ mean s Ihat Off rivals postSCF calcul:ltion~ for accurucy. Rut her Ihan de~1 ing with the muhielectron Wave:: function. the I'ke tmn density is used dirccrly. A\'Cording to the Kuhn Hohenberg thL,orem.' .... Ihc energy b minimi7.Cd when the calculated ami true electron densities nre equal. DFT calcuilltions rival the accuracy of stnnd~rd post HartreeFock method.~ . Of pr.ICtica l impor tance to medicinnl chernisb interes ted ill studying drug like molecular SiructuI"CS with quantumbased e::nergy calcula tions. then: is a signi r,c;lIlt n:ducrion in Ihl' C PU lime. Thu s. DFT is an altr~C1ive altentati"e. For eumple. the C PU rime required to complclc HnrtreeFock calculations, whkh of \"OUrse is n function of the nUll1m'r of electron" in the "ystem beiug examined. is proportiomll to tIK: num ber o f eleclrons ruiscd to the fourth power. DFT cakulatious. however. also a function of the number of elec.rons in the system. are proporti0fl1l1 to tbe lIumocr of eleclrons miscd 10 Ihe third power.

spectroscopy rcchniques. stnK:.ure-based drug design me.h ods may be appropri ate. ("1l1 lerro s/n,clurebustd drug design refers to the fuet that experimenlol stnK:lu rul data of the macromolecule oflhe drug-receptor complex is in volved in the modeling process expl icitly.) The xmy stnJCrures of a receptor and ligand receptor complex provide information about .he binding mode of the ligand. If avai lable. mult iple xroy 5.ruclUres with different ligands provide greater insight into the steric and electrostatic tolernnces of the binding cay ity. Using sophisticured molcr:.:ular modeling software. the ligand is modified StrucluraJly in silico to achieve a belief fit between the compicmentlll')' binding sites and molecular Yolu rnes. The small molcr:.:u1e typically is clipped out of the ligand- receptor complex altogether. and new molecular structures are docked into the binding site . Ii is 110 coincidellt"e thai structurebased model ing be gan to be applied more frequentl y in tile mid19SOs. The exponential explo~ion of protein 3D s.fOcturJI information I.... (Fig. 28 18). which wa.~ made possible by cloning techniques. made: it possible:: to have macromolecu lar struclUral data. The 00 vant:es in a seemingly unre lated field hDye helped 10 usher in the alle of slruclurcb<lSCd drug design by making proteins uvailable in larger quantities for xray siudies. If SCant structuml information abour the receptor is klIOwn. which is mo.t commonly the si tuation confronting medicinal chemists, a more indirecl approach is required. This second approach has been characterized as pharroacuphon: mapping or pharmarophore perception. UO"1l1 cri ti cal functional groups and their 3D spatial orientlltions may be perceived by examining all molecular Mructures thar induce biological :tC.ivilies. A compnrison of acli ye \'ersus inactive compounds helps to undersUUid the slruclUml and conforma tional requirements of a drug candidate. Once a model has bt.oen deyeloped. a 3D search query can be submitted to 3D databases. The goal of using a 3D database is to find existing structures that mcctlhe constrai ms of the query for immedi . ute bio log icol eval uat ions. !hus avoiding synthesis. If the: retrieved compounds show activity. they can serve as lead structures for further stroctu ml refinements.

o.p.

,-

STRUCTUREBASED DRUG DESIGN AND PHARMACQPHQRE PERCEPTION

lbc choice (If CADO mcthodo. !llat mny be applied
drug design depend.5 highl y on the a\'ailabil iry of the rece.ptor infonnntion. If the receptor $l ructure:: ha, ocen charncteri ~.ed by eitber hi gh.~"J llltion xmy crystallography or NMR
to

Figure 28- 18 The growlh of a 30 struclural prOtem data base IS exponential. The avai lability of structural mformat!Oll in the Protem Data Bank has helped fuel .he growth and success of slructu re-based drug dl'SK}n Values are as of May 9, 200].

Fig ure 28- 19 Thf~ compcu1(ls dfll9f"'d tJr Beddl'1I and coworkers 1 mimIC the biridq) 0 of 2,3-dIphosphoglytl'latl' (DPG) (2) to ~ globrn.

The cOO<:cpb or sl l'IKCtureba.<;ed or I\"Ceptorba.o;ed drug dcsi&" predate the use of computers. lkddeU and cowort.ers arc credi ted In 1916 wllh SlIl"CCSsfuUy prrdictin8 compounds
that billd 10 human hemoglobin. UI Although I)()I , m etly a

drug -lttCplor interaction. the approach demonstrated the feasibility of molecular modeling 3ppllcd to drug design. The goal or ''-''ir study Wali 10 exploit the known binding site of the human dco~yhcm()globilllcirumer. 11Ie. lelmmer conSI'iH of four smgle polypeptide chains: two (I' and IWo fJ subun its. The small molecu le 2.J-diphosphog lyccr.ue
(DPGj. Z. billds wi th subsequent slabi1il./1lio n of lhe deox)' conformation (Fig. 2819). The binding rt'Su ll s in [he libera tion of oxygen. which i~ readi I)' IlIC3!'iured. Wire molccullU' Illodcl$ of the protein were usa! 10 measure bond distances Qnd inlJ.'racling atoms bclwet'n the protein and Ihe propo$ed SIJ\3U molccuJe.i. Based on the best fil, prediC1ions "'ere made as 10 whkh COOlpoun<lS would bind the best. These early modeling SIOOits suggeMed thai. compoundli 3 - 5 would have ~n affin ity for the 2,3-bindi ng site of humpn IIcmoglobm_ 8ased on the liber-llion of oxygen, it was detenllincd thm the binding affinities corresponded 10 2 .. 5 > 4 > J, The often-dted design of the fir1lt angiotensin<Of1\ert ing enzyme ( ACE) inhibitors by ORdeni and Cu~hman during this time effectivel), demon"tDted the of nle(;ha nism.based and struclI.lre-ba.o;ecJ dl'\lg design. n III The Ondett; :md ClIshnllln approach rt'SUlred in the fin;r marketed ACE mhibilor, cap!OJlI'II. 6 (Fig, 28-20), Man)' other ACE Inhibitors ha,'e been designed usi ng computer-based models,

concer

although not b)' di~ structure -based ,otkling. Sl1~ 10 dme the struCUl1'Ial dclennin:liion uf ACE has not betn ..-romplished. OndeIti and Cushman concc:i\ed of captopril based on a related enzyme, c-.ubo... ypcptidase A. and tbt earlier ..... ports of sucrinic acid inhibilON b)' Wolfenden.'''' Dlhercomputer-b;ased methods Ila\e been used 5ucctssfuJl} in ACE inhibitor design. FOI'CC f ICld eakulation~. oonfllf1lJa ilonal ~hing, and analogue design stnlleg";"s ",e~ II!lfII by Merck scientists to develop mhibil(>l'll, Sci(nli~ls,t Merd have uo;ed s mall molule struc(untl dam (",rn), Ct')'iQIJographic data and NMR SOlution stuuies) coupled wllh coofon-national ITlC'thods to des'gn ronfonnationall)' ~ ACE inhibi tors.' u SHIel' tile 1980s.. then: have bc-en many SUCttSI 510rits using ,tmcture-base<! dl'\lg design. One of the first oonnocing cumples of the combined U),oC of an ",-ra), crystal 'IruClUre and molecular modeling software was ~poI'ttd il 1982.1 36 Again. although this \\,3. not a tl'\le dl'\lg-m:epIOr' inleract ion , lhe wor!.; l!elllonSlrdled rUndamental pnllt'lp!eJ thaI would he applied lalcr, 1l1C ", rny (ry,ta l1ographk coor dinatcs of the L-Ih)'roxine- prcalbu11l111 compound ha,c thret pairs or symmetry-rel;lIed cU"ilies (rig . 28-2 1). It "'as "" liced that one binding pod.et of tile s)"nunetnc pre~bumur

OH

NH,'

'-"', o,' c

Figure 28- 20 Captopril was the succesful outcome of a rattOnal di!'Slgn approach In wnoeh the ~msm of the com",r, $I0I'l of anglOll'OSII'Il to anglOtt'OSUl " was Io::nowo The anglOlenSIll-(Of1vertJng eru:yme tAC E) was assumed to haY! binding uvrtIeS ~milar 10 the koown Hay SlrU(lurl' of c.arbo,;ypepIKlaSol'

,
Flg\.lre28- 21 Thtmoll'(~Hhyro:cml', 1 , bincblopreabl min, , proll!'ln found 11\ blood. Based 0f1 Hay data of th! j lhYfOjOne-pre-albLlmin oomplell., lhe binding alfintty of fl(lIIlI analogues was predICted by USIng mcl~(\.IIar modlll'l9 o!P' proach

dllT1C'r IIlIS urooccuptcd by 1.-lhyrolllllC, 7 (1-'11. 28-22). This u/'IOCCuplCd bllldlll~ pod..et had the pott'nllal to accommodate: II porllOl\ or nell' compound, lI'hlt'h pn:.~umably would result in greatcr binding affinity by incn:&SIIIB the conbC1 bt'tlleen the an dt'r Waals $urfilC($ In this IK.>mlOlle- l"fOIt'in
complc~

()H

The !!odcnti~t~ u.'iCd a gUiding hypothc~l s that lilt' "ught_ oc:"s of fit" bctlleen the compulcr-gcnerlll~-d cOlllplcnlo!ntary molecular ~urfaces of the ligand and prealbUln;n would 001'relate 10 enhaoccd bmdi nil affinit;c~. 11Iey modeled the nK)locular ~urf;lCe interaction) with the MS proJrum on an Evans and Sutocrland PS2 Ill".iphic~ SUIllon , Wilh avai lable mode linB soft ..... lIJ'('. the UCSF (U niven;il y of California at San Fnocl~o) sdenll~Ul stnppcd I.-lhyroxlne frol11ihe billd. mg \ile and docked various n:aphthalcnc-based Structures with different subslitution p:utnns. slKw. n in Fi ,un: 28-23. 1llc: modeling ~tudlCS were carried out lIiti10ut the aid of force field refintlntnl. After modeling a dlu:1"ie o,ct of an:a. logues, the SCICnlISl~ concluded Ihat at leaS! Ihree of the four outcr binding poci.:etS nccdcd 10 be filled. Four thyroid I'Iormooo analogues (Struclures 8- 11 ) wcn: ran~ed ba<ed on vi~ual in'pt'Clion u~ing lheir complementarity of fit hypothe~is, StnlClUn: II did nOI present tmy bad contnet- , wh ile II had some obv iou~ly Ixl(! surface contacts, Slructure!. 9 arid I (I appeared to h,we etjually good nMlleeular Mlrface interaclions, Oroce the compounds wen: mflkcd (8 :> I} ... 10 > I I), lhelr birldinl! affini lies .....ere determined. The bfndml! dam wen: ~'OIISIMenl lI'im the prcdicllOll>, c".'Cpt Structures 9 and 10 IIcre rMJI equivalent. Closer lJupcction I'\'I"Caled Wli the phenoliC hydl'O..l}1 group of 10 had a beucr ~urfacc fil and is In clusc pru~lmny to Scr- 117C and Thr II9C. thus providing additional binding intc:l".tt'tion~ rMJI avai lable 10 , _

co,

()H

,",'

co,

Figure 28- 21 USing moIe<ul<tr modeling melllol;h, foor l-\hyrOl(Jne <tna~ues we+'e piechcted to have good bmcllng afflnlty ,8 > 9 ... 10 > 11) 1 piealbum,n 0

"

"

f'tgure 2'- 22 The bpl'rimental Hay aystal Slfl.I(lure of prNIbumIn WIth boond H llyroxrne Pre.llbumtn IS a lets.wner With fOOf odenllCal subun.~ A. B. C. and 0 The foor rdenlICal subunrls forma channel Wllh two bound l- I~ rnoIKufes. The bonding sot~ have a (l .u.s of symmetry

Pn::sumably. lhe addlttOrlallntCTIlCtiOf\$ lI'OUk! ha.'e been (\('. IOCted .. ilh force lick! call'ulation~. In 1985, scienll\tS al BUJTOUghs Wcllcome (United StalCj;) and the Wclk:ome Re'ICarctl Laboralories (England) reponl.'d some of their CADD c:ffon~ for the ~iclion of dihydrofo. late n:ductast' ( OIlI'R) 1nhlbiIOf'"I ~ DIIFR is an cXl:c llem larget, sincc thi S crl/Yllle pathwuy i~ the only k:nOl\ n de no,'u ~y nthClic route to j)rep~n: thymine in ,'ivo. Thyrmllt.'. of coun;c. is onc of Ihe four nucleic acid~ of DNA. For many yeaN DHFR had been II popular drull larget for medICinal chemists. SignifICartl dru, dc:siJllI activity using lhe pn:vlliling principlell of mcdiCtn~1 chentiM!), II~~ lIS.'iOCililed ..... lIh the (\(" 'elopmcnl of 0111'11. inhibitOr'S for IUllllxictmal and antitumor llgents. Mcthotrex~lc (MTX ). 12. and trirnclOOprim [TMf'). 13. are I!ood Inhibilors of OHFR. Fi,ure 28. 24 oJiows the obI IOUI s1rucllll"JI 5i milantic:s of MTX and folic acid. 14. O'"Cr the yeal'!l, 111t'ro ll y lhousands of inhihitonl or 01 WR were prepart:d on the 00) . \ of nledicinal chemlM!)' Imullion preceding the structul\.'-bascd cfrons. A serie~ of)' -carlJl.nyalkox y anulo811C~ ofTMP WCI'l! dc~igncd based on nMllecuiar models of the l;."scJrrrichill roli DHFR _MTX cOlllplc~ , The designed TM I' analogues had up 10 a 55-fold hIgher enzymc affinily than 'I'MI' itself. Kuyper and coworkt'n; noticed lhnl in the roh DlIFR - MTX comp1c~, the a- and ~arbo~)1 groupo: formed ionic intcr.IClions II ith lhe I!UlUIldl nium group of ArS-57 and the anllnoallyl \ idc' chain of Lys-32. 1\.'\j)l.'ClII'cly. Tl\(' ~rvlUioo thallhere was II pos5ible thml ionic interactIOn WIth Arg52 'llJlIgested thaI TM P anaJogUl."\. lI.th judiciously scilcd carboll, laIC poops. coold rnlt'rocl IWllh one Of ITJOf\' of lheM: complementary resrdues. The IIJ1,:llogllC ... ilh lhe cllrbo, ylllle ell iended by five methylenr: unns,

e.

"
H~ J.:.N I
, . ~~"'~~ OC",

OC~

Flgur. 28- 26 Soaqulr'YVlr (Fortovase. InYlfase). 15. WoiIS IIlf first HIV-1 protease Inhll)ltOf des4goed WIth SlrUCtur~ CADD methods to receive FOA apj)fova! Here saqUIn.JW IS 5hown rnsrde the binding (<WIly of HN-\.

OCH.

"

was the m v proIease. The enzyme is one "f the: prolfllll coded by tile HIV gelK)me. and 1\ is expressed as pan oflfrt
reproductive cycle or tile virus. Tile x-ray crystal stNdtlll' for HI V protease hWi been available for well over Bdc!::Idr: now, and it is classified as an aspanyl protease. since thtn are ac1iyc asparuue residue.~ prescnt. III V proreasc I~ u)'lIImetric dimer. lbeTe are 99 amHlO acid residUC'> In edr 1l1OIIOO1CI". The binding cavity can be seen dearly in ....iJlllf

Figore 28- 24 Dlhydrofolate reduct3Se (OHfR) ~ been a populclf 1iifge1 for drug design. ~holre)((lte (MTX), 12. afld

"

2826.
In the IDle 1990s. seyer.1 H IV-I proIease inhIbitors "'"CfC introduced inlO the: market that ....at designed u:sing 1111(lure-based methods (Fig. 28_27).'.H.. 139 llolTmann _La Rodlt scienliSIS used modeling methods to desig n S:lquina,'u 'flO (Fonovast, hwira.o;e ) 15. which was the fil'$! protease in/ubilor 10 be appro,ed. The drug was \1lade a vailable In JUIII: 1995 through a cOfnpassionlUe treatment program. ID\'1I_ was giycn Food and Drug Administflliion (FDA) appro,A. Ottember 1995. and FonOVIiSC .... as appro'w in NOlcmbrr 1997. hld inavir (Cnxi~an). 16. W1IS dc"e1opa.i by MtTtt ' ' scientists and gi~en qu~1t approval in only 42 days in M.m::It 1996. In March 1996. Abbotl re(;elvcd approval for Rnonayir'f<! (Norvir). 17. The following year. March 1997. Agouron rttei~w final Bpprovul for Nelfinavir 'fll (Vnpi). 18. Each Qf these drug. designed using 5tfUCtwt. basrd methods. represtllt$ major lriumphs of CADI) Agouron originally was a cQmpany foonded. like V~l..(r. the premise thIU SUUClure-based drug design is an elTct\11'C approICh for drug discovery. Amprenllyir (Age.rcflllili. " deve loped al Venex. WIIS "ven FDA approval 11\ Apnll999. The abilily tQ collect rapid x-r... y crystalJ"gruph~ dat. aI lowed scientists 31 PharTTUICia & Upjohn to use ,trur:tun

lnmelhopnm (TMP), U , resemble folIC aclCl, 14, the natural substrate.

shown in Agure 28-25. was found to nave the opIimal binding. Much of lhe uperimenlal bindinll data ..'en: consistent with the molecular nlOdeling studit'S lind the sub$equem Slruclur"J datil. Although all the observution) ~'()IJld not be explnincd. Ihis wort rl'~>oCnts one of the first successful Siruclllreooscd drug de,~ign approacllcs . 'There is 3 growing body of successful eKomples using

drug design approaches. Today, many of these Ita,-", re.whed in approved drugs. 'These methods are applied widely when IllipiopriaJe experimental dala are available. Struclure-Nscd drug design is now consKkn:d a standard approach 10 drug design. ai>d the question posed early can be answered wilh specific cumples. In the 191ID>. the target cnlymc for Inhibitor design was DHFR. as di'\eu,sed above. In the 1990s, the larget cn~yme

S/ructureba~

''''
Figu re 28- 25 WIth the atd of xray data and molecular mo(le-Im!!_ SCe'1l!Sts designed tnmethopnm (TMP). 13. ana~ues that had up to SS-fold h.gher enzyrTM! afllnity thaf1 the parenl InhIbitor

'H,
OCH.

IA

oc,," OCHo

>

"

VQJ--OH"",
CQNN+8u 0

"

"

"

"

fIgure 28-21 TI'K> SIlt HIVl proteMe IIlNbllors grven fDA i!ppfoval b@1 ...lI'tn 1994,nd 1999 wei. ,designed by USIng suuctuce-bilsed drug dnlgn methods.

"

based methods . 1llc rt'~ullif\g compound lipomBv;r. 20. is a Mnal1 nonpcplidit' inhibitor In;., rna) won be a",,,ilable.'1><
lillil drug designed wilh structure-ba.<;ed I1lClhods 10 rench the rn~rkel was dorJ(llamide~' '''' (Trusopl ). I. Ab ini tio calcu lalion.~ and modeling methods wen: used 10 predict SUbslillUion patlem~. Aflel' II declldc: of ~arch and development III M en:k. (\(riola,mlle W:l$ gin'n fl)A approval in I~;cembcr 1994 and intmduccd into the market In the sum-

n.e

figure 28- 28 DorzoIamide (Tru<iOpt), 1, also iI (onSI,tL>ef1t of Cosopt. was the f!f';\ dUlg desf9nI WIth structure-based (ADD methock to become oommel'oaIty available "11(-927, 21, IS a clost structural 'r'I<1logl.1!! and W~ the f,tSt carbonl( iIflhydrase Inhlbilor 10 Iowef ,ntraocular pressure In glaucoma palotnts.

"

merof 199'. Doriolamldc I~ IInefTccu~c camornc anhydrase' Inhibitor uM:<! \0 reduce inhaocular ~ure$ thai occur in glnuooma palieols. [, i~ e~l~mdy effective. Inhibition uf curbonlc unhydrn5e results in n:duced biclU'bonate formation in lheeye. which has the bcnc:licial effect of\Qweri ng sodium ions with the subsequcnt reduction offluid secretions, Mere!.. had been woning on vnrioo~ lead thlcnothiopymn-2-sulfonamities by dlwc loping model s a/ld linlllllthe:m Inlll cl~tron density difference maps of carbonic anhydm5e. The lint car bonic anhydrase inhibitor to lower IntrooculllJ" pn:s~un: in glaucoma patkms ",a~ MK927. 21.'fIoO I'hkh IS a close , tructurnl analogue of the: compound fimilly approved (Fig. 211-28). AnollleT successfu l IIdvllnce in liler.. peutic~ In~olved 3 combination of x-ray crystallographiC studies and molecular shape analysis (MSA jlo prod\ICC tIoocpezil .... (Ariccpl), 22 ' (Fig. 2829). Donepel.ll i~ a potent lK:ety1choline~ternse (AChEj inhibitor used in p..1lients wilh AI:dlcimcr's disease to help SUl\C off the 1 of cogniliveablitlles. DockIng )Imu0m; I:llIons of doncpe:.til suggested that the drug does IlOIl1Ctually bmd to the AOIE ac1i\'c site but mlher Inside the long cha/lnc:1 leading 10 the octi\'e ~i lc in a light, narrow region. In nddition to the !ttructure-ba-..w ITII.Idcling studies, 3DQSA R studies WCT"C carried out I15mg S('l1l1empirical de.lCriplOfS.

Figure 28- 29

d,_

(AII(ept), 22, IU pCII~1 oKelykhohrll!'$t('fa5e (AChE) Intubtor IMd 11'\ tile !'e.llmen! 01 AlzhetmeI's

Oonepe~d

"

The pharmacophon: Cl)IlCCpI plays It centrol mle in druG dellgn. 'The ph~. fil"$t proposed In thee:I.I)' 1900s by Paul Ehrhch. may bedcfined as the 3D ll/lllJ1gt'mcnloflhe csscrllla l functional Groups ncCCSSllry 10 c~usc the biological Il'~, The dcfin iuon only a,slImes that it is nccc\sary for a dru! to pm.cnl ill> pt\IflCrly oriClllcd functional groups

complementary amino acid residues. AI. though the idea may bewnlC" hal simpl isuc. sillCc It ignore\ uphci! cons,,:lenlLion of the ,llQIecu lar structure that COl"rectly onCnlS rhe functiOflal groups, lhe idea ha.~ withstood the test of rime :as a fit)\ appro~jm:uion fOf a model of
drug -~plor mtcnICtion~.

to rhe

n:<:Cplor'~

Prior \0 the ex plosion of struclural data now available 10

mcdiclllal chem ists mlly u;c 3D structures of proteins. \)'ptc'llily on!) mdll'CC:1 information about the nalUre of the recepmr ",a_~ n'ltllab le. The most tommOI1 $i tuallol1 fated by medlClrn.L chemists was II 50encs o f active and inactive rompoullolh The faa that t~ "'liS rI() Mructure of the drug boun<l to its n::IXIMor mchnt tlmt drug design had to follow II Jlf'OCo:dure of romparing the cfficat:y of compoundq and dctenJulling v.hlch fu octiQnal groups ~ imponant and ", hl ch fuoctioool groups "'ere 001 . The OCh ve analogue upproa(:h. oJevdQllCd by GarL and Mar.;haLl. ""as one of the earl ~1 CADD pharmacophore pmcooUI1:.\.I&I-I .... The approach aVOId, having 10"'"OtT)' cxecs,h'eLy aboul the wbtle ~lICrl:y differences Dctwccn oonforIIl:1.lIon .... S)'stemalk conformallo nal sean:hmg b IlJIPhed 10 W-.erics of biologicalLy IlCh \\~ and Inactive rompoonds. The ccnl nll ioca i\ that l!>ere .s a linuled SCI of conformations that all acli,'c compoond (Wi th approprialt functional groups) ma)' adopt. BIOLogIcal inocu\"lIy I~ assumed. as a tirst apprOllunalioo. 10 re,u lt fTOfI! Ihe competition between .mall moIccu les and rhe rccePlor foroccup;ltion of the same phySical <;pacc Usually. lhe most ngld structun:: I~ tonsldcrcd first. Sub<icquen t ,ystcmatk searches ure ca rried out on lhe TCIn.:1ll11ng acl1,c molecu lar stnK.1ure,. It is pos~blc to add iiCrttning filtcn. to Ch nllOldC urtaclXplablc conforma tlOnS; for namplc. computcrgcncrutcd structures mUSt be ablc to IoIdopt ronfonnal.on. simi lar to thol;c availablc to the prn ioos loolecular ~tructures and 001 be outside a specirled relative cncrgy range. At the cOrlClu~jon of the process. a ,olume may be genenl!oo rcpn:scntlllg the union of all available I;OIIfonn::mons for the biolog1t;all) acu.'e compounds. This " active' ~olu me 11111)' be used to glean information about the n:ctplor site. II is possible 10 gellcr-lle an "inacIIIC ,olume a s ....cll .... hi.ch b the tl.'glOlI III 3D spai..-c that should not Dc used to !)\u~e molecular modifications. Ellalnln;mon of a IiCric.~ of acti vc lind inactivc cornpound~ pro"ldes .mponam structur.l1 infonTUlIion lnal is used to de-

woo

vclop a pharrnacophorc hypothesi S. Once a phamlaoophm ;~ de\'c loped.; t is pos.,ibLc 10 -.:areh 3D ~lruclUral dal.lbu'ie$. "The firsl 3D >e:archlllg 5Oftw~ ... as dc\'eloped lOhou~ by pharmattllllcal frnns 10 mille lhe cOfllOlate 3D w talMws (A I..A DDl N.I711 dcvclopc:d m Abbott. ~nd 3DSEARCH."1 de\eloped III Lcdcrlc:).1bc con~truction of 3D dataoo~ "'. made ~sible by 5Oft ...":lft" ~uch as CONCORD m aod COR INA I J thot :.lJowed rapi d I!cncmtiOfl uf 3D ~Iruchlres from 20 ~t1\K.1.un:s. CONCORD ha.~ becomc the standard progrun used for the crcahon of 3D structure\ from 21 Input. It is ) impoftam III 3D scarches to lICrount for structur,d n~)(ibihly. Then: an: e!l'OCntially three: "'DyS this may be ochie_ed: (A) Moring multiple conformations in the wubasc itself; (bj de veloping spcciuli7-OO '1uerie~; and (e) generating confOl'l1lltiQn, durinl! the search qucry. The frn.1 idea reqUIn:~ that .IL conformatiOll~ for c"cry moltcul:u- Sll\K"lun: be stored in I 3D dutubase, Thb approach is 001 prllClical. Although the second approach i) appealing. it requires the iiCienliSlto oksign the ql.K."1)' apPfOpflalely. The thllll approach sccm; 10 S(lhe the problem. lIIa~mUt;h a~ only one (or a fcw)conformauon lK:cds to be stored and adjusted IU nmteh the p/Iartnacophon: ..earch qucry. Today. then: ure ~'eral comrnnc" pt"Ugtams aVllilablt for 3D dataOOsc and phanllaoophort 'ioellrehing. Goodfonl proposed tnat a gnd of te'" points cnvclopllJ a 1lI0h:cur~r structure could he uwd to calculatc favcnbk illlcractions (initially with 6- 12 nonbonded. clc:ctro6lllUC. and hydrogenbondins potcntlal energy funchonS) btt"'mI il and a t~r8cl receptor. The prof TUm GRID"~ .... as:Ul u'lk'r esting inoo\'ation. The IX>CK17., 11~ IJrogtam enn be con~ ered the fir.;t ...rtual hIgh-throughput scn:cnmg soft"'II:. "The goal was 10 allow prescrccning of oompoond., IhiII could bind to an :IC\lve ~i tc. A seric~ of moleeulur struclUrt~ C~ be evaluated for their fit into a rccePlOl" by U'iC of!iOOrilll functions. An carl)' Mud), using a-chyrnotrypsm ranJ,;ec! <co ernl known inh,bilon; m tile lOp to structures. ba...ed OlIlht scoring fu nctions used to e\'alualc the binding porellti;<l.r1' AOOIhcr early academic 3D 'iCan:hlllg program ...-as CA VEAT. " I'rcdiC!h'C pharmarophorc modcl~ can be gCllCrJtec! h;t'\Cd 01"1 3D-QSAR analyso.. Hansch demonstrated lhe mlllno.. <Jf QSAR ,I'N In the 1970s. m~ny 51Udlcs were unden~len III mfer bIOlogical acll\Ily on the ba.~i~ of ph),sical propcnic1 o f a moJeculc. The method remains useful and pr1)\.1dt<, ,;do. able mfOftllutwlI.I\IO Richard Cramer developed a popvl;v program invol\"ing a comparative molecular field 31111)'11 (CoM FA ). III The basiC idea IS to probe. moIc:cular r.lf\ICIIft for ~t eric and cil-.::tl"Q!ilatic interactions directly. and then p "rate a Q SA R cqU3lioo ba....,d on these 1II01 l:u- dcscnptoo. ccu usinll panml least Sl.[UIllt5 (PLS). The .alldny of the 1,IUdd can be predi cted.

PREDICTIVE ADME
"The ulumate gool ofCADD I~ toundc:r;tillld at the moImrJ. It'vd Ihc ooml,le~ rCl3tionshlJ)S bct ...t'Cn a di-casc-e;w."11f tllTgC! (nlllCromolc:cule) and a drug-I il.e looleculc: !iO tJg[ m;. abk: predicti ons can be made 10 enhance molecular intent: tion . Olher IllIpontlnt ph:umaookinel ic facton; are crill';;ol ho... e,C1". for an cffecti." 1/1(."r'llpeUti.c medicine. Es-~I~

potency .wlubllily. and permt"abi lity are the only three phys ical ,unabl~ that can be ooLUSted to enh.:lncc: 1he Xlivi t)' of potential ()r.I1 mc:..Jical ioru. I Lipl n5ki h~ .u"e~lcd "poor absorption or pcml("allOll is lilely .... !'k:n the molecule ha.. nIOn: than one of the follu..... ing I~opc:nics :
I. MOl\' IIwl ~ h)'dn'fC'n bo..d Iloroln 2. MOl\' lhan 10 h)1irogm hun<! arpIOD

e,"troos ~ in,oh cd) ..... ereeanicdout on a Cries of known drugs. The activity. defined as lhe AM I H-lltom lIbstMlC'UOIl. is modeled OIl the presence Of abstocc of chem ical descnp,~ .

, G..... OI~r 11\.111

mola... l:u- welghl

4. Grealer tl\.ln

cooup"lcd lOll I'

Medical prufcs.'iona)~ must be aware of drug- drug inler:acliulls. Ik,:auo;e a signi ficun! numbcT of drugs are met!lholi700 by the c~tochromc P-450(CVP), it bchoo'cs medicinal chemi~ts to coo"lder this o)l;id;l1;ve pathway in lhe design ....... I:$!!, Trugic coosequences of drug - drug and rood-drug onlcr,1("lion~ il:Ile ~ulted in t .... o FDAapprulOO drugs, mi bcfr.tdll (Po!oicor), lJ, and lerfenadme (SeJdane). l-I, bell1g rcmo,ed from the lIkIn.cl in recenl yea ..... M,bcfradil and Icrfenail.lIl(" ;Ire sho ..... n in Figure 28-30, Each drug l\."qUlred P..J5(J for pIt;1!iC I metabolbm . A more recem prl-oic'ti"e model for eVI' 3A4 Illl:tllboll~m has been reponed. I.' The method re l ie~ on I'LS. but one of the dc-.criplOf'l! i, b.lsed on AM I-l;:'kuluced hydrogen ab ~tr;JClion , There are !oC"cr,d assumplions: ra) CV P lA4 su, crptibihty i~ a function of lhe electronic environmcm around tbt h~Jrogcn thaI i, abstracted. (b) Abslr.oction of the hy drulen ~tom 15 the r.ll.c-detcmlining 5lep. (e) The drug being IIIClabohud tumbles freely in the acll"C SlIe of the en7ymc: unulthc n1Ol>1 aclive h)drogcn i$ avai l!lble. AMI c:akulu~ (U\lI1g II procedure to accounl for lhe (II('t thllt unpaired

O',er the nex t decade. in 5i lico "",peily and toxicity pre _ dicllom will Increase. As the predicth'e mtth.ods become more reliable and robust, they will be included increasingly in the ininal drug de~i&n process ruther than being an afterthought. Thcre are muny other CA DD sue<:ess stories. AI though drog discovery Is a compl ex process, in the futun:. a.~ our undcflltanding of drug lICtiOll incn:UC!I. a growing number of therupcutically crfective drugs will be designed Wii ng computcrb;ts.ed methods.

Acknowledgment
1lIe authol' at"tnowledg." Tedman Ehlers, "'00 prepared many of the figures for this chapter. and Mark Volmer, who provided valuable lrumuscripl IlSsistance.

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I"

"I

QuaM. SUucI. "".. lie ... 5-1'9. 191\6, 71J f'tr&u_. D.. and R.b..-. D, J ,: J A... , Clcm, So<. III AJ 7I ,19119 " . 0 -. 0 .. (;1I"da. W. """ StiU. W. C.: J. Am. Chem. 50<. III :4J7'I.

12
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o.-,um

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,7

121 K...-. LS

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In. 8oyo. 5" Prot. II Soc: I.ondon. s.,- A mSo!~ . 1950 123 , II. "", , W L Sle..-.". R, tI.nd ~k. J. A,: J a..m. I'IlJ' 2M7, 19(:,9 IlA I Idn, W J, Dotdlr d. R. Slo< ..... II F. .... I'IIpk. 1 A '''''_ ... Ploys. $2.nM. 1970

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126. I'Ietro, W . , Bblnxl. F.. S, Hoou~ R. F, Ir . .. aI. I"",.. Chern. 2(t )MO. 1911 121. B,.U.,..I 5...1'IlpIt. J "',Md IItlw. W I J.... m.O".. 50< .102;

9)11. 1\lI!IO 121. GonloIL. M S .. B,llkIty. J S .. I'IlpIt. I A .. ...1. J "'m. Ctort.. Soc. 100127'17. 1912. 129. Oobbo.. K. 0 .. and II"""'. W L I C..... pal. Ole .., 7:359. 1986. I.JO. l lehrt. W J. DiI<hr ld. It. and PopIc. J .... I Chtm. PhY' . .)(j .. 22!11. 1972. 1)1 IIlnkley. I . S .. and PQpk. J A.: J. Chtn!. Phyl. 66:119.1971. H2. F.-I. M. M. F'ietru, W 1.. Hrhrr. W J.... aI. I . OIem. PhY'. 77,
~. 1981. Ul, Car1 .. n. Nit a...n.. Phy... L.". ~ I ,19l. 1977 1).4 ~. 11... F"",h. M J.. _ Pqok. 1 A. J OIem. Ph,. .. 72.:'2.

156. 1Ibnc). 1 M .. l<qt"""" F ~C~ C""""Iy. M. L.ecai J Mcd a..... 2jru.I9112. In Kun"'''' 1.. r . ItOl". 8 , Ban ..n. 0 P . ec aI~ J Mod. CIoaa. 1II E. 1915 us. V...."., J P. and COfLdra. J H. 0..,. Do",o'~L') Today L !6I. 1991. Truwlutuon Reo. " I!!. 1999 159. KlihMoyi. H. I . lepOOf .... ' 1tI. PM ... aI J Mod. 160. Ghooh. A. K.. ~ W J.. ,,Chtm 37:2506. 19901 16 1. Done)-. B 0 ,. lc.. R. R. II .. M<:DIiII,d. S 1.. ... 01. I MnI a..:m.

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19904 162. K.mpI'. 0 J.. Stlam. II. 1_. M;on.Io. K. C...1 aI ; J, M....
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1.\5, Clad. T .. o...o_u... J... Sp... ,....t. G. W .. ..... Sd>kya-. P w. 11... I . C"""",~ ' ;:?90'. 19\U 1.16. F........ J.A..flJple. M 1.. _ BIIIlk,-. J S. J CIocm 1'IIys.1IO:.l265. In. lIat1Nt. D. It. I'ru<' CamIItMJ&t s... :M. 10:5. 1928. 131 Itood toft. C C. I . ~. Mod. lJ:69. I~I 139. 11111. O. G. Pnx II;. Soc. 1.oro.Ion. s.r ... 205;5<11. 195 1. l.co. MIOI\er. C.. and~. M. S. 1'IIys. Itc>,. 04(,.611. 19,) . lU Pq>I<. I A.. BlIIlloy. J S.. and Sto:acr. It I... J Qu .... um Chtm. Symp 10'1 . 1976 , 141. Pork. J A.. Sto:Jer. R.. and Kri""'an. It In . J QuOJllum Cben.. S)'n1p. 11149. 1917. 14), Kri.hlWl. 11: . and Puplt. 1. A. 1m. I. Qu""'um C'bcm 1' 091. 1978 I" 5"....... II B J Ootm. I'IIY" 17:3676. Inl. IU M.IM. R. S J a..: .... 1'111" U:18lJ, 195) 01 A _ and l"ft P..-r, R. 0 and V..... W~ Denw'y F""",,,,,,,,, MolItarIes O.fuRI. Od<>nl U",~y~... 1919 1'7 K.... W.. _Slwn.1..1. 1'IIy... It." AI4frIIH. I96$ 141 I..,.", ..... , . P.. """ K-. w~ I"Ityo. Rn- BI:l6.8M. 196-1 149 Buu" . 11 M . ........ ~.z. aI. n.."""",nlllllaa.k. N""L R.... :!I;m. MOO. IlO, GIIoort. O. "(cd.): PI.- ."....I'em!ptool. o."'lopoi.' 4.1nd U.. ~~~ IULB~sm....L-o.lolIa.CA.I".. " ..i<oooaI Un'Vft'Oily ...... XIOO. "I IIMokII. C R.. Goo./fooJ. P J .. F E..fl aI II, J I'hanno. col. ~7201. 1'176. 1)2. Cu>hn...,. D. W.. CJo,r,.ooJ. II. S .. S.OO. fl. I' . ...., 0"11.-.. ;. M A ' llio<""n>I",}, l{d4So1. 1977. IH Ondr,,;. M A. and C\oslin~. 0 w. cite Cril It.v 1I"",""m. 16; 181. 19M4 IS( II~ 1.. 0 .. ond WDlf......... R. I 81oc""m . UH)(lti. 1'172. ISS. ~. E. I). Ibrm. E. E.. Au..-. S 0 .. .. ai, I MI Chon>. 29; 151. 1936.

,,.,

166.

601. 1998 KaIdor. S. W .. Kall"" V J.. OIiYia. I. F.. II. eo al. J Med C'bcm ...:l:)97'J. I\I97. Thai,.;.....,.. S. ond SlRlIobo<II. I. W B""""'y ...... 51. R 1\199 B...... ; ... J. J . PooiIoceIlo, G. S .. Andoenon. P S .. .. II I MnI. 32.-2$10. 1919 K.o.-al ..... Y.. 1...-. A.. K.o ..-,,;. T.. .. aI~ 8""",. Med. Oomo.'

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14:'\1. 19'J6. 167. Ma-Wll. G 1I:. .Iii'OJ~. I , Top Mol """ 115. 1986. 161. Mar>hall G R_ "-'. R"" _ _ TCWoOOI. n 193. 1917 169. ~. D . I'I.,...".C B . M___ I.. and Ma"h&lI.G 11..;1 C""IjI"~ Aided M... Da. I t. 1911 110. v. Onr. J. H .. Wei."". D. """ MaruIl. Y. C ,: I Aided

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17 1. Shtridofo. R. P.. Nilabnw!. 11: .. R.....1ikn. A, III ... 01. J. a..:m. Iftr. Sci . 29:2Sj. 19!19 172. ~arI""", R. """m. ~I" Auw..""ed N..... 2:1. 1m 17). Hiller. C. and GaMcipr. I .: Ein MDld~I""~~"<lc-n In (J....,;Jer. J. (<<I,). S<J/l .."""f. ...... id lu"' In "'" 0 .. 10 . Sprinaor.lm, 174. Goudfool. P J J MI, a.. .... 2/1;84\1. 1\185 175. Dc.lJ..-Ioi.. 11.. 1_ Sho(oi \Pn. k . Po. .'kibeI. G. L ... ai' 1 Mcd Chern

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11'722.19118. 17(> KJULU. I. 0 Scooence 157 1078. 199Z. In. s...-.L K 0 .. I ..... .:1 Cuy. M. T............. C"'I M.dlGllo1 HIl. 1990. 17'. BIftIm. P.. Shea. G T.. T.lfer. S. L Ind Wt' ,,= S' CAVF..AT' A 1''''1'_ '" r""' li......... ~-'.....,.. 01 hd< ,;nJly .... ,~ _I" ..... I" ROOrN. S. M ted.), ~10::01<0:\0'" 11:.............., CIocmoca/...., 8 00qoca/ PhAt Ll' 1t. ~. Royal Soclei)' 01 ~. 1m. pp. 81, 1'#6. 119. 11>110<11. C : An: Ita. 2:Ul. 1969 ISO. H.....,1o. C .. Md Leo. A. Eoplon.,. QSAR: F'I..<lamenlab ..... Af'I'I'. ....1..... ' ,n Chcm''''Y MId tl ooIoaY Waohl"""", IX. A"k'I.... a..:m. oca/ Sudeoy. I~. I ~ I Cnonoor. R. D.. m . PlIII"""". I) 1i .llId Dunce. J. D.; J. A.... OIem. 500, IIf):moJ. 1m 112. UpollSli. C. A_. ~ F.. Do,n,ny. 0 W.. """ lullC)'. P J Ad . !)no, o.l..'<I)'~, 2:):3. 1\197. Ill. S 8 . Sbtio.1.. Q, Walker. M. J .. and SIomdan.II .. J 1041 Oarm, 46: BJO, MOl

BmI..,..

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So.

P PE

N D

Calculated Log P, Log D, and pKa

The log P. Jog 0 at pH 7, and pK. values an: from Chemical

AbstrllCIS ~rvice. American Chemical Sockty,

CQlumbu~.

OH. 2003. and were calcu lated by IIsing Advanced Chemi~ try Development (ACD) Software Solaris V4.67. The pK. vaJI.lC'5 life for !he lnost ncidic HA add and IIIOSI weakly acidic BU ' gfOOp!IO.1lle lalter repfest'nllhe most bask nilrogen. Keep in mind that pI(., values for I IA aci ds Ihal e~cced 10 10 11 rtl('an thai there will ~ lillie. if any , anionic C()Iuri

OOlioo in the pH n111gCS used in pharmaceutical fonllul&lIOO1> and 111 ph ysiological pH rungt'S. Similarly. for a H ' 1ICir.k. there will be li ll ie, if an)" ('minnie comribulioo for pK, >ilUC$ below 2 \0 3. Bc:cau"C ChemIcal AbslraclS doe. IlOI 11:pon calcu lated physicochemical values for ionl(cd compoond~ including saIlS and qU!llcm:If)' anulJ(JnIUIII compound~. tile log P values in thl~ aJ11lCrKh~ ure fol'll'll: WIionized form .

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!ISS

CompauMt

...,..'
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1,7~

logDU

ph'

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"".0.
III..... " 1b"""'11III1IO
RlumpUn

....
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Log D a t

p"
HA
II 41

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""""'~ ICCIaII: 1'fuIn........... Icbu_

H'
1176
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., M

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79}
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947

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12.20

I'l(bt,,,",,'kI

'.00
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Procao"".. Hlo

0.12

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1130

191 171

p,'*"'".. l I.....
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""+

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.., .., .
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". ,. ... '"

..",
-,~

on

'" ,." ,,,

1.13

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2.Ob

'" . ...
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3.01

H6
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S;m.~ln

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1.41

982
HI

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Propo>.yph.... Plopo ..... uI
1'ro\'1~11

4.16
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l.'~

'3.2
13.49 IIUO 13.14

..
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_...... ""- .... ,..,...,.

"-'
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Protnpl)l"..

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10 1>1

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467 O.ll
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1091

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112

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4.67 1112

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- 1.61

5' _

3.12

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,,,, ,.., "" ""

4.13

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261
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11111

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3.87
1.82
D~ D~
,~

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1'N
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C,lu'1\lIpl1

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'" ,...,

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s..-udi...

'H
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Bl 0..91
1~5

." ." '" "" ".

9."
2.21

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-OYI

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."

HZ
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216
~90

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1.1..0:5

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b .... ,1

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~_97

Hl
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ItnnifoMUllll itopq)ulldo

Itea,. ...

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3_12

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Sulf..,<Umi<k Swl f

",,I,,,,,,..

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3.18 Ul

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BI

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91.1

Sulf."",i ...

.,,,
O.M
1.01

2.14 0,74

6.16

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l.78

113

2.88

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131

110

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....
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11.95

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LIZ
11J 0.-"1

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T"""'~,f.n

, .00

TorB>wk:<.m
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,."
,

1.\lfI

11......".,," \I,f.oocon R,I."",,"

IIor_mll'"

-468 -J.Q7 049

,~

1.ZA 6.22
ll9

R,"""'"
Rl ....,""'-

~'IDII

It;,.ato.

,m ,,.
1.8~

".
1.61

-1.7,
1.15

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11.11

."

T.,""""lIm

'm

'cl_ T.,...,..
T"""'o!olde

T"S-' .. rod

''" ". .'" ,>0

.20
-S,611
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, 10

10.011

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112
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"...

... ... ... .'" ,... ,. ,.,

4.n

'.OJ

1,14

l.ll

lUI

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4 .21

r ...""",tdc

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7.91

T_O\-II d,......,..~
T .....06in T......."..

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'" -,'" ".

(C:

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....
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Two',.,...
T~......

""
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.... ,..
T""' ......,
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log D.t phl

HA

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11

l.T.!
141
b,~j

110
O..~7

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Te<IOII"" .... ClIoo".'e T.............- ........bw

Tnch"'"""" .........

101

1.0J

T......::a....
T.......)dnMoi,...
1'he<Jph)lhM

,.9
I II
O.ru

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Hl

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1, ~ .1

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10A~

..... Tnn"",p.""'"
Tn.:h~"""""'h<
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7.12

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1.67
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II

!116

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T"n~n<l,,'" Tn""~)pho"Ol) I

0,01

,,. ""

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Tnmclhadk ....
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110

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109

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,,"'..,.

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1>11

7.76

Tnmrtt.lpnm
Tnmcl'~"'"

""
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1.15
219 H8

-n...b,flt
l icatc~l;n

lkko, ",.., ToI.........., K>J

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1
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Trim,I'""""" T"" ........ T,.,.,..,.odI ... TruI<an<I<Mn)c,n

TfO!lIC",,~d<

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T orufih>n

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2~ I

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101))

1078

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V, ....... lh,,"'

4U

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720

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3.72 U7
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11.72

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2,61

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INDEX

,
Abh<ol\l.a~

SN Urulo_
\lUI
~

,,"'"' ........1IIbm. (01 ........ II)'

-r i...a.caw, II,"""" ~ fulto-d b)'

,M "",-=--.-..
"'dap,"

DRop _

1, _ _ ell< ....., . ..

Al!o:i .."..., 1110. 6J,4,!ItO Abolcct. SN .............,. 1\

... b ,lUI",

"''''') l-CoA. H3. 5.14. 5So1f mt\MloI, ..... In AmJI ..... IIadoI ..,.,w -........ uf, I HI
~,_

At)1~0C}1'"

Ab<on'r.......... 19"1 ... Mul< .d"",,~, 220 ... camo....61! """""'"' !iN I""....""'n ACE. St't' .........-,.......,.......'" at).... ..... d ....... 3+1 'W5. 'Wjf
"'CE,~

oclll $H AJpnn Achromy<:'" .w TetrllCy<:hnc

till
(~",L<tdJ.

.n....., \/."",,) I"...:"""""'.....

St't' O""l"n hy<lndlm.lo ... tbpliI., i""""",'). 2OD. 200t

\'II, 124

Midi". 9_17
15- II>. IIlI

"'-'

ddiM''''' of, 9 ~ ... 0jAc' flI. 101

"".'.kop,. pmJoui fum"

,~ ,t(. 1).10 ,t(. 6M>-M~.

M7f. M71

kJNC r.lf'III 01. " pI! ufo

IIA ( ... """It'd~ "

16. ItII

""'Iluiar ,..." ....... !01. 208 ""'"'-"''''''...... 7611. 76l. C!

..-bodonoo: ""jd """"""'- ......

au

PI4<lf. 11-14, 14. ......... Ih 0Jf. II 14

""oj ...... ~,

""k."""'" ,,(. 11

16. ISf. 'Ill

-.,t..o>i"" aI """"" aI. 1121

nIrIabo;oI,,,,, ai, w.-'.III.

112. 111. 120

()I~

~mi.Jo.

AceI.on'hd. 7100. 7611. 761 foOl. fi04f. bOj. """".... am ..... MI. W1 670

J ""1<1 ...., rno.~ ..... 11-1J. J21 <lirn."l_ ufo t.l Acod-conJ~IP" "''''. ~ -II A~Iph<, IW~ ~ ><l/J,"m
AOII"," *74 .... r!J(c ufo "
~""jl)Cln

....... Iv .. ,t(, Ill. IOJ -I~ A<ttophcfoo_. moIabQI ..... 01. IOJ

"""'e. h._<Of.Il~

"",\I,,,,, 420

Adopt' ...... 9n ....... ",..,., hobolity. 7_12 d,~__ 110 ... dooo..... )'P<>p/ly .... IW I Adr""",,,.,... .trq>-I"""'"'~'" "V""' ~ fIlI Adr",,..;"" 176. 4m. 4011 "droM...... oiean" ... ~ ial!ibooon.. 0108 A.dcauI.o ... ~ ("Mn ~'I,"l "' .......... oronck ..Ia...- . 6U-~, wr s.."'dnMyl"",,'..,,... ISAM). ItO """h).1Oft. I ~. 1261 Adtn)I." "yd.... , ~~.J "DMhT I'''lp<n;''' okfinol"'" aI.~. 60 ioIp-dIroooJlopM ........... lOr. S<I l...... rM. Itul< aI F"., f.".~. Sot ~ 01. 9-W "'" ,,( M."tlmbo1Wll oint ... 17' , inu.1 (I" "hc", ""_"'.... ro<, ", '119 A<W ... I~, 1IormoiIo.. 1101- 81'. St't' <JIlt} GIu<n_io;olio.II'J. M'~'I

"'<kI,,,..',

oro.bo"'' ' ' "..

....... ,h.... 67&. Su..., ,:,-".,.

762 A<:nmyotil) I ,00,um \lOll" 5511 """'.... yt'fttnyl""""\U)', :uo 2Am)..........n....... l"A~l

",~)'."""',Iid. 7611.

A. 416 Ada","", .... 41b ""IuI",".~ d'l"'optOO.rc. !IOMf. "12

............ 4'

""",,,,))y ""un.. 6S2--M1

""foml .... of.

".'M Sa6

n ..

Ado .... , $H A,-k."",.""", d'r""I""".'c ",,,,,,,ntI ""m ...,'Y. 200. :!OOI

12~.

'ynlp.:llllolyl..,..524 ,).,r.pathom,,,,,,,,,",. ~U
A<h<"""".I>Ioc~ ,",

' ......... 01.%

~"io<)'

af. 11S-116

A<eI)IaI;'" in
12.)(

dnoa

meIabo>I ....... 121

""m_.
11 _
A.c1 .... ,

Aafu.ml'~ 'Y~' StY

,mmull<l<l<r",iorn.:'J .......

...... Sl .. , MI 6!ll
'2!1.
5-11

7 1 4,JI~

......,,"'.... ~ntn. '2" "",",ynlhosu d. ~l-' ~24f

Arn.J)nia. 8')1

propen .... nt. 'l-'

f ....... '''' f, ,,,,,d..... of..., '27-'28
'2~

"""all"","", d,ff........... , in. 124 A<eI) t..IlooI po/)"""'JlIii.n,. I U_124 A<eI)lo:hIiI,'" IACh~ S4iI _ f...._ <Of, \-I-lS. ).1(. ~~, .,.w.

ACnl S.., Adml<'''''''''''''1'OJHC "".mone IAcrll1 Amleo. SN 11 .,.,..1<>1)' a,.h<tKn'Jlln

J"III.""" ,..00_"",_. ,
DDU()II\IOIClot.

IO"I ... .....,~ ... by.,1Mi '"- W( h)llrol~. aI. !WI1-StU. 5(>11. ~f. S630 .........,n", ..... 1*". and. ~so. ~'I. '52. "7_~'!I. 557f. 557,
If......... " ..... ""'"

s... CMI<tm,.... ,n"..,....., Arnl.!1J<".'1 .... &.It 11-121 ActhJl:I. s... Con;."",h"
AClO<i ,' S-c T"",Plid .... hydnl<hlolO'"

-s,~

...)mp:tlbom,"""IC>.'32 1IJIlak ..... 1IIdaIw>I...n aI.

... ok ... ,." "pI<ir
G , H\I-~

,~_,n.'261

.OId">.

')9..:1-10

11.54,)46
A","ncr,;,;
~t'flI<X;

... ce'nm"' .... Su Inl.rr."", ,lmm;olb

......""""')'00 Ct. 414, 41'. C .. 41 ~ AcI,nom)"", D. 414. 4"

S4I. M

"I, 552.

S*o-.lU. W( 0..... "'''' ofT.., aI. 587-588 . .wo p/wTnxeulic111. '511

557-~5l. ~,7f.,,7t.

A.c1.nomyc,"

4 ~ I--4U

G.'27 '28 11. '28

....,'''''''''yc..... .lOOI, 4 14--41'. 421-<lU

Arnon "",,,,,,ai. 6110 ()81. 683

A<h<.....pc """Ianto. A<h<....pc .y... m ","~ 649-~

A","""""",",oo"l';"
~,

~,.e"yaf.

16\1-170. I?OI 52"

r<tn..o 01. 5~)f. '54. (083

"on.",...

...... 01. 'SM. ,5-1

......"..,,-oc,.. " Y rel .." ..-too", r.... _'57-'58

........... <Of.,jO .yultor... </., 553- S'W. '.nf, ""f

H1f. 'Sotf. S6Il-.w.I .w.11 ........ aI. .w.1 . StU . .w.11. ~f. !I$lt ~t.o_ ai, SbIL .w.u ..""" .... "'" 01. S6t<f. 56'l "".. l"' ....... " ... ~ .w.}_S69. StiJI

"'Cd)''''''''''''''''''''''

A<eI) "'..., .... oll.ltJndt. "8 ... crt)"'''''h .... o...:"l"o<, 5-I9-Sj(}. bII4 6115 i"'Chll~ S4~. ,~.,-"".

AI'.pl_ ... "'''''' ~ ... 0JIPUI'Ch. 9-W Act,,',11&. Su IklmIooot ~ ... lhefapr AI"-"'~ lfI'rO"a'>lhk ""'tI>tIH"'. 'N """,., , ......... """"'~ .. flOl - W!. 602f .......,.... Su Piochw.-

lion,,,,,.. ("'C'T1Il.lIO.:I.

bi<>l<>sical ""u",;.". nt. 841

"'""" pms.c, ........1111. :WI. 2011

"")<'1<,,, 171 Aq-. J06
A<:) 100. o6op<

"'' ' ' 'IIC, S Qu,"aI'IlI tly<lruohloriJo:

,"',iii.... .108

.......""')'0'"

SN I)o,""""',n Adri""'l"'n<,il. 4 16 Ad,,1 Su lboopn,("" Am.Bid. SN Flu"'....... Ano<pooil. St't' PuI).... ).... 8 ....tf_
Afr",,"y ".,.

>t/1iCNn:-""'''''y .....""''''0fI' rOl. IJ,j I

bydroron' ...... 806 proo;IIocI>.. 1-12- lIU. 1-i!1

n.

inll''"'......

"',"1. s.r.. N,(nI,,,,,,,,

"'<Iapoleno. 874

... n......." B,. il<r ......"'nos""icMy aI. 7() -n

"

'''/lIfIh)'............ ,"'.-ow.

958

Indv.

Africa 260 Mruo. S o..ymewoli ...

.In,"...a...e...

AI~II ....,

Afn ..... Su ,,4 + Aru.. Su T<lIrWlaIc

A... """

l-PseuJc,.'."'.........i... ",,,....,.i,,,, ..... 12f>..128

Apa. iF Su A .."'........ AgJ\Ii''-' iii Un" ..... ""'P' ..... , ~ A""'po ..... ptrJOnD. 173 A,ly""'''''' ~ 17
A ...... in~.48!1

AiDS SN Ii...... _ ..oi<r........ '

A~"Ie"'" bydroohlon<lo: SH

hldrochlorido AIaoowl. SH Pomirolafl potaw"'" .,.,tu.hIlmoc Altt.mycin. SH Albmdalole. 2(16

Albumlnh~

-,...-

y .....

"' ,

bOom.Iun,,,,.197 by conJ ...... odditiof\. 397 ""ron""", or. 394 by f_ ..tint ",..,""'.. m .....:hoP>_ vi. J904-.39t.l\I6f-J99f r- ..... ..,.,. ill, 394 AIl~lbrnl)'klIInottIy~ ..... ch_. W A I ~111L Sn F.. orcrudl ... AllerJ'" all- SIS

m-J98. J96-J99f

8."".kIt ..

...

rttllI"'I.

"""",10,

82O--8l I

",~ .... )2j '0 con,,,,,, "",nlS. ~8 I

"",'<Jbox,. -">IIiurn

1J1I

AJ""" _ h '" ro. 6 _ hi..... Sl31 AIbutcrol. S16 AkOOoI.,219.220 ddly<hil. 120
,nholo I(f

10 local anco.thcbcI. 6B9-690 III penic,lIi .... )(lII-109 ",1/,_ .tut".... (ptIic). 91G--91 1 AI"""",,,,,,. 01(11, 4 14 AtIorOO!h,n, bo .... 68() AIJ)1mnnc .. t.funpll. lJ8_l.J9 AUyl dtIoride. .... tCII)' Ill. t 11_ 119
AlIlh""",Oji)~.""'-'_

Amolll) ..... 001-. IJO-Il I A"" ... h ..... ~ bleD. 319-Wo. WO-W A"".....,...... ClMu. 5112 - S8J Am.nt;JolIcahotl. ~8J-5:U Am,nI)ai~)1 CIhtr>. 701-7()I Amo...... ...... 3&.f-ID ,..A".. dx.~ I<"id (PAIIA~ 901 we ''''' ..... IlI. 112. Illf ;n AlkylOl~ prtpU1iIKIIIl. n5 y-AnllllOlI.uyTic ocid. ~8S.'19 .oc..... f.,. $A> _ GABA... """'I".... """""Il~ 78-'. 7&.fr. A""nost,--...... 3J4-)4 I d ...... 'wy <01. 33' of ... _ of .10), )(12. 33' n.... <Aut _ _ .... lll-J16

tIICdwi,,,,,

,.--y1lo..,,1I)' _
.ptru'UItt

for. U7

tiI<It df..... of.)", )37-3J.B

~-"'''''Y 1'danoII>hIp< vi. 116-l)7

<If "'''';'1 fA. 13!

}oI I

Alomide. Sn loIku.amtdc

00.

~..,IMtd.

lU

mechoni .... 1lI ..1iou (1/, 6S-I AIcdIoI dehl .........-.. 101 AIroIIoi pmon.-1IcIy. r", pnx\n>&" 144_149,
I Uf-I~9f

Alpho>-odrc .... lic r=plOI" titltqon;w" 5l\l-SoIO AJpNcci)lrncv..doi. 738. 7l1lt Alphq ... S B..-dine. Alpt.a.p""",k em,,"",,, $6 Alphopoodinc. 1,l6t. 1)1. 141_148
AJphauIorIt .fBI!

""".d ........

of. 77

~of.3ll

IJl>e' aI. ))7-l41.

.B-A""~,

501-S02 p-Am,nopI><noI. 761 762 AINnIIpIcnob. 760-162. 7611 A" .............. 76lI. 163
AmillllAlityblo ....,.,.... 2j6..~1 p-AlrUnoWoql", otic! (PAS). U4. Z~

mo<aboIi"" Ill. In. IUf

.... 60'1 Anttlripl)liK. SI7
A~ .... I

'''''k MIi-W""',,-e 1IfC'II" ~ 19--220 ......... .. .,-.".... """,';Ii,,,,,,

1l1.lCu:unldallon of, III
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A .......'iN I'Ip:<"unwn brurnMle

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~),~7S-119.~79f

_ .... c/.I~ A,"'-'t, .. h)dru<hlonde opIo:IW""" ............

AI"""",*, ''''1''''1')'1 .......... 220 AI>""t".M2 Amltrum)<"". 132 A/h ,111ft. >pI",m c/ """v"y .... JOII I\,""""on .>;.y rri.mcinolonc ,a".,,<1< A""~k ... n,,d Srr C. Ioroai'OOin ...
AIO '''''''''''' .... , mttiOh<>Il"" ,rI, 107-t08

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....,.......icn...,. b1l An""h"'~ SH PIpeR"'"

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Ikn='ryL ~ l);p/ItBh,""""' ... Ikn;Jnom) ........ 2-tC>

Ilttwqtnlll)~lIkIndo.

AMlin .... " ~ CboI,,,, ..I.qlale AJ}'IOlIc 1S11-760 N.AI}I.",h ... linM: ,,Id . 1S4_7Sg AI')'k,.')'prupontJIIn" ..... 1J 2

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Iim"alloolu", rhlon<l<. 22$ 1Irn,.... ,lid.7blt lIm,,,,,,,,,,,,,,".740

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palmllM. II9'l AoendI . ~ A"",,-r""" IA ........""...... 421-'129. 411 A'I""'" 15-1 Ul .....1IIw..,........ IO'J, 1I!2
canl .. IjIO ......'~," cfl<d> 0(, 1(rI, h)'1'<f"C1'''''''') "'- 8:10 8:1
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a.:.n ...., prnIIlII pump mhibol<lO. 722

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iknI"",..,,,,,,,, w .....,,... 489 Ikn,""''''......... 4118.....,.1

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A''',,''I<>Io. 712. 7111

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AI"'" S Loo"'qIIm "' ............... bl>l

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Aul'P' .... nJ 576..
~nf

11""'_ o.",r",.""" Sci",,,.,. (...- "ru..n. ~1 ..\()8I 3701

II.......... "''"''..... $N MnJunltafl' lIr brurtto<I<

01,.,.,..'.........

b\IO.b9.I. b9IL b92f. b9'(

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Ih.bol ....'".. 49.1

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.. anllron'ul ...... !\04

lien""""""", drn'~.", 140 Rm....-,lSJ lIrn'uI ...p)"'.... 0.<1""1<""'''1 of. 74. 7~f
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A""PI'" .....,........ .. k"''''

676 677

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Ikn,yl aI......ooI. 229

N.lkn')I."'''I..wn ...... metMtoI"", c/. 89

l\enIyl brnI ........ l6II

"'"'_'" S o.,IIIanM_""IL. A...d.<odt .... 2'*1'1

A""""", ..:01 ~ "",-}<.I. A .........) .. " 1t)~h6ondr SH

~ I.....",.IUI'I bronude

.crunurc-""''';') re"'"""",p" r....491-'l'/4 .",.,:,"'" <rI, 493-'1'/4 Ihto.... ...If... Jl,l. 481
~'I. 9~17

l\enIyl dklndo. ""'''''' Y0(, 111-119 1Im,)'lf.."",,,il.... .\(19. 310. ~ . ~~ _

Dqlodtl ~,drorhIondr. b.l2 iIenpn.>ol. ~25 ikf....... 880-U7

0>I0n0In<),11M hyO'o<llkI>d< "','''_ _ _ ')-'em. SU. SSt>, bN

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<""'M .... 9 I I

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A,~ ..... ~7

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II,.",

1Iclad,,,,, ~ ""Jdune.IIlil,,,,
geuo "'" ...""'. protCId. IH. INf Ikt:ogon . Su lie"' .... ""'"...,. 1I0'''.BOIIt. ~Il

1kIam)1..... _.1J9t

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7700

A,looulf... , $N ~ A . - . S" 1"lcrf...o.. btI.11

f""b,,". 227

A,optll. S", Cd"""", A~I.I <"",(,...... ;..,.. 'Il l. 912\ A,1d $N "'".......' ... A"*,,,-b19 A"" b19. 619f. bal A ... h,Uod. b79 A,,, Itlondna. 619 619f
" ' _. $H " " - }"-~Ildi .... .Q. ~
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II.,,, .........o;..~ Mer"""", II.~ ..... Su Cema><OIln BI~" 2j()2. ,"'" ",furti""",

1I... h,jm.ob.1119 11 ....." ...,1>. 1911

>I~""'I" , of.

i:klill...

Iku~ NPO ... I, .... lIbihly ~-., Srr SotaioI

'iIIo"'............... ooI .... li'y C/. 7701

of. 7101

Iku'pon",k .".,.,,-. 456

"'''''''um

1I.)p""" ,...... N,trtn<lip""" 8ondru,' ...... 781f. 781 8 cdl .. lOO. ~2 !OJ
.. ___ >pb<Uc. 440. oWl II('"U .w C........."'" II(' ...... <1 ~ SaIicy_ 11... 1 ,moll. IN
1I~~.11I2.114,

BCO '_~"", 2'4

i:kt>pul..... 7.161. 7J7 8nmtrun . .w lltIcrlorron b<u lb BtuwIoI. W. '-'5. S4$f 8c\Nrotdooi ~"1uoioIe. !160 1\cIopI'" SN l\c1u ....
I k , _ . 4.lO, 412, 114 Ik~""-!in V _ i b 8i1 "" ..... lS-I6. Illi 8, .......III.)IB

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A"", " . 411 "'''''"'''....... Itaar. 71'_71~

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a...,... s..- C\onI!Irum~.

8ica1l11anUdo. 01. 1101-801. !IOlf OJ; lII'l'ne<>Jll.wJo, 434 Bocillon. J,r 1\:o.,.,mQ (l bmttlhofl<! RoCNU. ~ fI,r:.>l. SH f:>tnoI Bill' ........ 2l6 Bolam!. Sn Metnr_

Wtral HO. }41. 730 HIB"" Iaorc~~""oe. rnc:uboI .... 1'1.

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lliood - braia bom,
~

C'W\Iioole~IV'.

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2:>9 Buty!)'I<"'",,,, .... (BuOtH S60-561. ~II BW24K:. W!41 IIWA 1IIo8C, 8~41

1I , ~ ylponbm.

1I.ljnabon.
8 illnci<lr..

mctaboh~

of. 114--115

!iN Pru:oquanoel

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BIoooI '" tlnl"OII 01 642-64~. !\4Jf60/.5f Rlood proI<,n'. 857lI58 8MYl1067, 4:!O Boa"""",a de...., .... In" 11!io1lllOn.1

8,,,,,,... '8. 61

811" 55,."_.828

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Calo;,fcd~~,

8..... "" rooIfOl'tlWlorl. 9.lO 8 "", . SH A~hc f __ .

878

C.kljiCAlklk.871 .. *19

8";"ronn.olC, I'll 192 8 ....... ,.1 """mioool .''''''U'''' 1IIMi. 17 _l l. 2i. 31-41 ~cuorrlC"'" and. 11 -21. 18f. I<H Bi<>Iop'U '""'tpOIlO ..... :!9 I'bf'IJI"C modiflUl>, ''''''''~~IWII.

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bioiafonJlllia .... I'l l -In dono.., 1ft, 16-1. lot>-l68 of, 160. 161f

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194

dl:v<""".",,,,

<lkml>lry.30 1ktIv_ - - - . 9JI Ikto,tbw.!n. Il' S"" d.. 29 n. lit. nr, 33r bn: r..kI taIcu ....... rOO", 'PJ-9::9 hy"""""""'. Ill i "~"" "'" of, St, Mol ..... l.. mo.It:l;n. Boot"" St, \Iccli""" h)droclIkIridt: Born.()ppt ....., ...... tit ""~ 923 1I<utu",,1 Su Ho:rt>ol mcd", , ~ 8<wo,,-'.~, oS%.

Clk"""',,. 1155-856
818 c.k11lllL ' " 'IIItIItn 0 ~ '73-176 C.Ic,um cl>;mncL bloc ........ to..'7-4J! ..... iorrl\~'hm;,.>. 6:>9. 6ltK. 617 fi"'~ 6::9t onc:ehan,,", ctlCl"'" 01, 6<!8_6.'9 ><C1lIICl.Jtnrr.ot,...... 62'1t 1YI"" col, ~-6)1
Ito
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BR. 17

C.Io."!",," 100('1 ,a mu ..1e """~ 62J-4:!'

62-1r.I>.'7 6!11 pruprnko col, (>27-628 ........ ~ 617 628 CoInu", iOa dgruoel" 6.1l. 621(, t.II~ SN . .

DNA uptb."", in. 161- 16l! DNA b)bhclono_ 1ft, 166 OSA 1;'-' In, 16S

I)NA mom-ny~ In. 1'.I2- I~l ONA ~ 16B-ltI'J. 16\11' i. dnit .......,......... 160-162 l62f. 169_172 170-172 enry_ hrtnucc ... Hy ..... 1119-170. 170 "'ii,n! in. 11'19 fl ... ,. , , ...,1miqIon 01, 1(1)-1(,.1 . . . e>prnl"'" 167_ 168 ..... ""''''I')' ill. 1901 .. netic COIJ'<>Ceri.,. ... 162-I M .....- lib<".oneo. .... 164. 1M! 1"OttIlOl in. 191 -193 h)boio~ , ..xl '1 .... ill. 187-IW. Inf

_"In ..

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hi'" . ."_". . ''''lOp< .y_.1l,

'nra'V""" of. 160
'_01.160

Rnodyk,n ,n. 8~-lI57 ,. blood pre ...... ~,w.ItIIII . W - M5. f>4..If II"".............,,'eI)' .... lSI. ISIf !I,ea;.! ...""., ........... r..., 719. ru hvt ' _k <kpa I .y 01. 4J,)-".14, 7Bl. 793 PfOIe>I"'O' (Jr, 7~7

1 d,.n".!> 001
1<OI)lo.iIoIllIC &lid. 6Il C.l<tum I'"".otI .. , _, S88 C.hdk.mi<L ... 421 cAMP. Sj l. '53 I...,.""" ....... ",to .... 62J C"""""h, !iN Altmtll'll<l\lOb cAMP ~ jCRE). 1ft IlI\IJ OI<1ftfIt .. ,. 111. 171(

1In:\lti.... :>tv Tub.tllt""

B~y""'" ....ybte

phaoa., .... ocaI prooIuct> frl)Ql. &WI - 8M<.

""*'" .) ......~ IlL 164. 1611

proIOOmia. ill. Ill) ""'<1*'1 hc:"""'IIC't~

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16'J

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Ie ,Ie,,,,,...

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C~

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m
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<"""''''1

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and. 169-110. 1701

8 ........ru.4I.. 'Y .....Jr)', 9

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8""lod.aS SN 8"".", ... bydroch"""'" BIICIt,j ... h~olrui:bl ... tdc:. 707
B _, 809c. 112. 114,
B~_.
~14(

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in, 1(>j- Ib6, l(,(,f B.... ' ... 899-900 B_d."".._. SN l>ni. mc-.il"" Biporillell h~<lrucbl<.>ndo', BIIIII , ....... SN C_a:.pu,'.. a..""",it,l,_ 672 8i.. N...... n~hyl..ro mclab<tl"e of a(+
VIOn

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6 10-6U. 6 11(, 620

"....11&." ,....

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~

Bun .. x. Sn lIu..... ",,"'" EkutoIoI. .......001..... 01. 10$( lIupovacauc. 6711. 690-69J. 6921

fw. 1101-102. 1IO:!f

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81...."..,..,.. ~. 8nhklooi , ~

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S45f

8ulft""" !iN Rulftr<lfp/l ''''' 8ulftnorphi"., 7' 1. 7j(} B..,.",..,.. '20 Buri .... mtck. 71'l_720. 719f B\II'1'I6. SH Bu ............. B\I5I*. s.r

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407 , ~ IJ .............. U6-1".

Bni_, SN BOINonoI
B, .... 5)7 D,....,. \e>I. 8}4

S""I"""""'2O

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B......
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SN B~ .....If_

lIu..oIf.... .It01 lllIIabMtollllloOdtu .... ~94. 4941 8ul .....;1k ,uiph.o"'. tWQ...ffl\ 6911 Bu ........ 824'

~,.'irr C"",...,..I

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a .......ycon .... f;uo:. 41 7_119, U J 81<xodr~n Str Ti ........~

SoII-~

B" ......""'... 7flJ1

!I",~ $W.u m. St~ lIuI_1II1 .."j,um BItIO<1JftIIil)Ie _ . U 1_2' 2

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C..,....".,

C&j'>ai<'",910

1"""""" 191

col, 1s.

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Cap>ICUIn. 910 CapIopriI. 64~. f>.I6f des;," of. !)4()
s.,~ Sucnl(,",~

963

c....rl!~

Carb;oc<phc ...... )~7

C&rha<II<>I. ~~ - :5M. 562 Cartwna.."".nc. W6 ootlvc .... t:.boIl10!0 of. 1 3~I 1JIOl;aboI.. ", of. 7S. I~ Cart.mKlc: I""""'KIc: IO.Ipk"aI ""'un"". 223 CIIIi>am}I"N oIroI>ol 4~--4% Cort>arnyl ~. 900 C~m . 316- 318 Inve>li~"';""" I. 3 I 8 C..n..."'ill ,n di""'ium . '09<. 31~. ~, ..I",
1'o0"'lIli ...... )

meIIIboIi..., of. 1~ ~m of ,ct"'''Y of. J07 _308 Corbtn",,1Ii1l ind:aoyl .o.l,U"'. J09I. ] 1) _314 CorbtniUln ion ... 395 CI m...IIfIC".nI .... ell",rc. 75J C.""noumlnc .... k=. 102. 703 _10-1 Clrbocainc. ~ ~I<pivaco.illt Clrbo/IyW,los, rom/)In."",.' ~)n''''''i. of. 4 7.

1"""'''''1. 81S In ,,"""," A .ymk'is. 1169-870 8.mml -C_ .... 1169- 870 CIroI"ooids. 1169-870. ~ a/", ViWllIn A ."..,."."'" of. 870 rood >OIl=- of. 869 'tnI<lU"'- acli',ly rcl'lio...llI~ ror. 869-870 In ' ;Iam", A . yn<ho.l" 1169_810 CIIICOIoI. 543. s.t4r CortmI. Sn CaouoIoI C.,.,odilol. 546. S46f C ...oo.~ .'f UlCllutamldo Cwnom. SH DieMon"" CIII.,.".;': 4S11 C.wy ..... n/l mal"'. 835-&37. 836(. U7( ClIIopra. Su CIoni<li .. hydrochloride C",,,,tootln"_ 524_s.t7. Sn ,,/m Atlrtlltli'"

C<f,il. SH tefl'",,",1 C<lebru. oS C<,..,.,,,b C.In:<>.ib, 760. 822-K23 ...... bol"m of. Celeu. Ciulopr1lm C.l1 cycle. 391 . 19If

s...

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boooynd'''''' nl. 5H-5~. 524( drug. off.... ,nl . 528 prop:nieJ nl. SN
"","pion. (Of.
Sn - ~28

......""'""""",." "".pwr. ond,

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CaIt:lollC """,. 211. 221 c,'",,,,,'me,,, of. 14_ " ,8-C.rboIi ...... 489 CarbQnic llIh~. 1m rcn.1l oOO,"m Iran,porI. .l8. ~9~( CarbQn", ... hyd~ inh,blloln. 603- 605. fI(JoI f "..,...-allons <>1". 619 Carbonyl p<omoi<" ... 15(1..132. 151( CatbopI.nn. 428. 431 CartIopro>! trumelIIominc. 79S. 19K 827 Corbo.ide. 220 ..,-Corbo'yl - ,Iu",,,,,,, add. IlllJ - lI84 Clrbo>.)lic ""id C(lnJUI"ioo or. 117 ~ic< <>1".144-149. 145r_ 149f ",.. prodrul" 144 _ 149. 145(- 1491"
c.r.:~;';'''Y

II sympalOOmlmcti.s. HZ "",.I>e onoJ TrIl"Iabt>Il>m of. R'I- S27. 526f C.. ",II<>I Omr"'} ~ nn. r...... (COMl).
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,11"0 01. 524 "''''

>I<nJi" I>rd

of. <lrup Iffc.-hn,. 529

Collmodi.IN immunily. 202_203 Coli "",,,,!nne.:in Mo~.) Cellular lIIIi' ..... ift "acci.. prod""tiun. 207 C.ll"l", immuni,y. 200 Cell"].. retlno!boodlns p"'om (CRB!'). lI6'} Celonlln. Su t.-k\h'lllxlmide Cene>lin.!iN E>.troecn(J) c"nlr,,1 dncma. 162 Ccnl..t nctVOW $~OIom. S48.. 679 Cen",,' .... ' ..,.11 '~l1.rn tIqn< .... ~ 4M - XlIl IlUkon.,uljaRU/""iepi,.".ltl. 485. SOl- 508 "'''I'''yohollCl. 485. 4%-503 In.iol~UcI. wdaI,,,,,, and hyp""u<>. 485-496 ren<nJ one>thclica. 48S. 488 .,......';,,'" of. ~M CcnuaJ ......."". o)"lom "'mul ...... 510-S22 ",,1"""."I. 520-521 IhmylarnlllO h111
.ympalhomilllClicl. 510. 512- 51 4. 51 !f d's"",i.u.., .,.nlll. 522 .... Ihyb.nlh, ..... SlI - 512 Centnl .ymp;olbom,rncti<; ag ....... 510~12 _ ~1 . ~12f Ccphadn .... 32Ot. 325 _326. 3261 C<fIhaIu.In. 32Ot. 325. 3261 CcpluJoridi,.,. 324
C~...-..b.322 ~""

Cell de. ,h. p' .... ' .."mcd. 19O-19!

an'ide"'.....n,.. ~1 (-.:I2U

52()f

CI ,..,II<>I, ..... lnyl.l"'" of. 125 ~ 126 Conon;';' dl"" 2n- 22B Calion", ..,'(Klan,.. 22.. _221 Ca.";""" ~ AI".....adil CC 106.'1. 420. 421( cDNA. in """",,,,1111.,,;.1 <hom:i"ry. 49 "DNA ',,,,.....,,. 1M. 1M, C EAs.:In. Sn An:;"ultl<l<Nb Cmione. ~ A""""", ..1Il CIot. ~ e.r..do, Ct<In. SH Ctftibo".n CNU . Su Lornu";"" Criado... 3201. J2f>- 3:!7. ~26r Criadm,,1. 3ZOo. 326. )2 .... Criodyl.!iN C .."...pirin Cd.lIWldolt n.f.,o. nil. 3260. 328 Cof""hn. 3211. H4. )21_328. 3271 Cd."."",. ]]J e.thi ..... nOt. 3261. )31 Cof"",';u,>Ic SOoJjum. 1221. 326<. 3.10 Cdtlbid. Su Cdopc-ra:rone lIOd,u", CdonKid wdiwn. )21,. )2 ..... )28 CdllJl<fUOn< """'Urn. 3l1l. 324. J~. J261. Cef""",i<lt. 3211. 1261. 328_329 Ccfotan. ~ CcfuleWl dioodium C"fOlUm'" """'Urn. 32 11 . JUt. 3)1 C~(_ di",.hurn. 322 . 3260. 329 - 3JO c~ro:uun. 324 c"r<>l"in ood,unt. 3221. J26t. 32'1 Cc(pi"", ... 3)2- 333 C"(pocIo..",,, pro.~' I . 32fl1. 323. 3261. 3JO_3J I doubJe..e8Itr form nl. 14 7. 14~r hydrolY'i' of. 147. 147f ccrprorJl. 3201. 326<. 327 C~f""" s." Cor"."""" C"ftlUiili"., $OdIUm. n h. 326<. 332 C~flib.""n. 332 Ccfl,~, ~ Cdu",.""" "<111 C"lii,,,,,,,,,, ",-.l'dm. n il. 3261. 33 I Cdlrin""" dildmm. )21 ~ 3261. )3 1- 3J2 Cduro,''''' uttil. J21~ l23. 126t. 3.10 obJlIk-n",. forn' <>1". 147. 148f Criu",.i"", oodlUno.. 3211. 326<. ))0

c::cNU. j q """"',,,""

C<p/Ul<>I.porin,- 318- 334 ..it! ...,.iOlln of. 3261

olalb'""n B,. 76_11 ol .... i,Ja. \16 of ..."""'''' Irnllle>. 9.1 Canlt-.... SH Nkanl,pinc h)"drochlon .... Card,,,, 3tI'h) ,hm:i ..<.. ~}.I - 636 C..nIn.:: '1c<1nlJIh)'",)IoU. 635. 6J5r Canli ... , I)"c",i<ks. 655~1 Canli ... m_onn", "I~Qolo. 551
F ..()'lhn'yl tttranltn'c. dil.,N (:;,n6""""". ~ Quinldi... pco!ypl ....Uf\J03k C........... IecI" .8-bIocLo... S43-546 Canl.,'";l$<ular "'...... 622 - 614 C...ail.te.
s.,~

",

m. do>;",.""",no ,m 0-<:_,,,,,. lI69_ 870

Inli"8"0;0)" 622- ()27 .n';arrll)1hmic.,.634_642 In'ictt:uIlu\U.6/iJ - 6611 an"hYl'"""n,,,.., .. MZ- 6!l7 .nt'hpo .... mic .. 657-661 ..,,,th)mod aacn ... 671---fl74 Ihyl'Old ",""",,_ 673 ..ooiIOlQ<'>. 622- 634 CanJio,__ ut... d"..... .. ()21- 623. 62.lf Cattlim. Sn Diltiu.tm c.dwa. !in D<I>~l n c..ril<lpf1.lllol. 496 C.",,,,,omY<ln. 41~ Cotmu,,,ne. 401 nl. 39;1. J96( c:aromc.:. SH t .........

ad"<1'SC ",OCUon. 10. 3~ 311. 3261 cau.::II<>I.("(IIII.O.lnln,. J)3 ola<<lr",.uon nl. 32~ .... 8ndauon 01. )19- 322. JDr dl>C<l".ry and do,.loprto:m ol. J 19 dru, i .... ""'...,... wi"'. 3~ fl ... 8"nrnuon. 3~. 3261 (oonhSC"""''''''' 32S. 3261 (u,"'" dcvelopmc.m (Of. 331-3:l-1 hlS' on<al pt"l'SpO<ti"I! un. 318 - 319 ,8-la<tllIW<! ""'~ of. JU- Jl5. 31M ,8-lactaon nl. 322 """,han,<m Ill" "",ioo ol. :lOOt MTT"""p. -.I .".. ...... 1JOnS 10. 3~ IlOt'k' .. Wure- for. 319 onl. 32Ot. 322_3D. 3261 pll<"nICrai. l2Ol_l21~ lD. l261 J'I"OdnI. (onn, <>1". 141. I-I-8f pro.ei" bindln, ol. 3261 ",,..on::h dlre<,""" ( <Jr. 333- 3.14 ...,ondl"k ..""". 325, 3261 ""m"yntho: 'ic. ll9 'flKlnJm of acI"ily of. J21. 1261 I"il~ ",l:o/ion.hlp' fOf. 319 """,11Jte of. 32Ot _3221 thinlI~.....oo... 325. 32bt 'J'P<'" of. 32S_ )34 C."molothln. 3201. lH. 3:u.t. 327. 3211 C~Y<';"', 329. 3JO Cephalnn oodium. lWi. 326<. 328 C."nnod"",.3D Cen",;" in o:ombinatorial <bcml>lry. ~9.

"'''(*UIlomonal.

......,W"e-..

fJ-C_nc. 809_870. !in alS<) Vit:unin A o~,.., C/. 871 foo.! """",., ol. 81>\1- 870

..

C_.~

C.... 'asI .... n. MJ Ctnlbidi .... Sn o.uMr'Ubo<"in

lit""'. ..... SN "

Inti.,,,,,,,~

964

'''''''
SN(]e .......... CItIorp/>fft ........ 1I<.7OII .........,"" aI. 101. 114

ea......

C.... ."LSN~~E, C...",,1do SN N",kNmKlo COSl ..... ,nfCS1"ioou. 26;1_216

CllIorfII1otno<nn .....

_ i..., ufo 92

C'bo<>cwooc ~ prol&:Izn. 10 Chn_ r...... """"""'" 185

Chron ....... lIJIhr

Chlorpromll>i"". 498-4.;9. 4991

C.. ) Ipynchouum <:hIondc. ll6 C,.._ "" .... !iN Aiwo ..... odd ct1MI'. in .. ' ........ Iu....... 264f.

C"',,"'.... 71 "

....

o..non', >ImC pan........ (~~ 21

CIIoI01'''I .,.".~ 463 0..""",1 bond>. 29 3 1. 31~ 331.)4f r""" flrid abo ........ for. 9ll-9N 0Iem0nl """""" .., ........ SN C_, ....... _ O>tmlnl ~ ,.,lKk,"I method. r.,... 39-40. S, $6,9.J1)-9JJ Cbe!lllC'lI d'''''''''1
ddi"'1QII <Jl.61 QUMl,I'\nIIOII of. -58

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'-"oU"", aI. II. 904

octi.., nl<tlbillitell ufo 13~ ......tIuI"m aI. 71. II$. .,

affinity. 171 I'<'f'I07 ,ocI"",- n in ".,~"''''''orial <hemmE)'. 51 izIIh-pa1.. " II'I."d. 'I. 1J1
"-c~8J.I

'7..,

Cl10IccaIcifauL IH. rn 1""'"1"'.. af. 87~ Cd )'>Iopphy.4N-4SO Ckloq.obn ....'" .."")'''''. (CCK. ... L).

O1H>rcctrw:y<h .... h)'<lro<:hkln<k. ~ 011onba1 ........ 109. 607-6lO. 607f. 6091. 6191 CbIorTn..-.. ChIorp/1ennall.. ~y . 19-40

J.4".

~ }4

s....

,100.

"'p""'nlJ<ol nuod. jJ Chrom", pIooIphazc p 32. #I...wS o.n..-)'<"ft. 411 ~"'all .... 1M o.y.ift. 1114. 18>Ef Cloyloo'ImJIl'. 161_168. 869

Cboicn

CbrmN;aJ 1,lnria. 43 ,.,neli<". 4], .w r rni"PlR'. 41, 014' ClIctmnl ... nottura "H ' ........ of s..~ ell""oicll .....7

IE

lInI. ,.... "''''" ,nl<:fll<II"... and. ) 1-41 moll"l. nl S M"I..:ul>t "O<>dthn~ ploy"""",,, 1I<.""y and. 11_21. llI. 31 -4 1 !iN III"" ON. '",pCb '~
~f........".!OO
o..,,,,,,~

pn><lruJ. i.... I ~ I S'I ..... 'r'f'" dthVft)' of. !"-I59 Oud"""" no:r.fte, ll l. 2121 CIIoh "'11"", 910 OIimcric lIIIiOOdIO, II!9 Chimeric pnlle.n .. 168-1 69 In dnI. . .'"'M .... 172 00-.1_ Su a.l lydnuyqu, ...i..
Chlolnl hydra:. 4116

........ "" 1c."do aI s.... flYI""I'P<"" ...... '.. nu. in 1'1*1 '''''" .......... l.l l. liN .... uIIol~y aI. 7701 OItruid 'yn"""'" from. 768-170. 7tJH QIoI.,styraml ... "",,".6(,0-66 1 0>01, .... 90 1 0>01, ... .mylnMre.- (o..\T). SH-S54. 'nf.5SoH ChoI''''rpc """'~'11.1 .",nl" 548. '12-S8f> am,,,,,,,k:""'~ CIoiCn. '79-532 amUlOUc:dlol..".,.. S3l_$IIJ ...... 1 oIlOlk. $IIJ-'a.t """........... SU-SM ""U~ eIl!>.". '73-'74 "mcl<lk of. 571-"~ dru. prudu<t ..

COO~"'"

"'-'" 212,. 214-215 """"II<.

('II)",", s... O1Y"""Yf"In CloY'''''''),,",''' 831. 8J91 c;bolim.S S u-... <lin

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kl'"

Ci<klprm '~.m' .... !}4-ll!l CIde>.. S Olulal'aklchyde CIIIofOvu.318-379 Ciprt!OC .............' Ii., *~_ Cib",n.im'pcncm.317 318
Cimclid'lI<, 7 19.

.... III

........... ,""'",..99. 101 Ci.Jl<l<: ...... 67&. 6'JO- Ii9J. 6921 Ci,or!- I a1bo1oi<h.. lI6-lI7. lS6(
Cin<MI" ..... 116 Cinob;oc. s..~ Ci"e,"""i"

"!If.120_721. 7201. 721t

C,""""";". ~48-2S0 C.proI1o.uoclfL UR. Uk U9-2j() (II iwmtB. 31_12

C'ope. s.... Insul,n J'!/1 ....
CilJlopo .... "9 Ci"'''''''''''' f...... 410 CiSfll.un. ~)(l ...U 1

ont,.,

"'_586 iA<IicMrn rw. "4 mua:II..........

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SRS - S36

myllrilllk: cffu 01. '7J _514 ~ a1U1Q1<h _ """""""". """79

.......

...... i ... nlClobohla 01. 1351 metoboI..... d. IOJ CbbW10b00c,I. ,j()()-401 CIllonm' ........ '.. 604f
Chknn~'...,~"'

Oln><'uno ufo j1'

.ylllheli<. '19-582

'"

h"" for. ,72-,n.

Ihcnpcuhc

1<1.....

01. 'n-SN

CbIoran'f!htru<'Ol. 3001. J6n.-361

......i .... .". 101-103. 107. 112-114 .. prodru,. 4_' . 142. 14M """"'lory c/. 4 1>"" of. ..
.....btl,'y.,/.4

.... .IO(j....4O I

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1"",1""""
5S6(,

o""l1 ...... po block, .......... SolI. '12_5Sb 01'011""'1'" =q>I{)I' ,,~_sn bIoc~' ........ Sit)..'89 ........ , . ",- bIoc~ , ..... _ SI9- S9S

on,",,,,,"".

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S~

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Oonlhroonyci ... 3S1-1~2 a-,nc..... 1'''-''1'..... 2"_2& o.""I"".,c "10~","hn. )16 O.vul."",c P"'"""um. '16 o..-utano,<,..",...,ilhn. J Ie o..~", ""Id.. lIS. Jut. 316 O'ys.. .. COIIIml ........ 4n Clcav.,. "' .... romb",acorial" .,. 49,6\ C1<:~ne fumaraoe. 701. 704 C1< .... s.... O,lIIbmyri. h~

ctar....... s... ecfo... '.... oodium

Cladnbo .... oIOS. 4 12

w-."

S!I~

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Chloramphtnicol polmll:l~. :161

.. I'f'ldtq.

4 _'

0001"""", I'ICW'OI:heoniwy.553_554 OId-.."'''''c ... _ 'Jnm...S!lS-n2.

0Il0l' ...._ ,nloibltO<l. S60-~ 'fn"mo,b1c.567 m ~eNbie. SIiO -S67 a..I,""'I'" ,eu ..... 548- 553 lCeIyld."liOlC <W",,,,,

ChoI' ...... '''' ... " .... 548

CIIknrnp><norol ""',,,,n .IU<C1n:11C. 161 <''II1''''''yclil' llO- h~h1oridr. 10&. 701 ChIonltw-poudo hydroi:hltriclo. 48\1. 490
CNoIfaMl,IlO- &h>c~ II'. ~127 C111oru\.JOI:d ~i<..sc:.. ~ 1IItUboIi>m MMl.
Cblm ..........n.'IIIn'l""ollCides. ~2]
~n4

""

Ck<>c'n l'ho$ptI>IC. s.... C1l11damyCl" pIIooph_ OidinoUIII broonuIr. 0,_)'<'1" hydrocl\lond<. 354 OIlNbmy<'" pili"" .... hydrodllorido. m 0 ,_)"1,, J>hosI1haI 3.'1$

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-....... ~-,~. nl f.!lS2( _ " " '. S4&-5:!O. 54\1f. 5490 Old ......'" ",5-3~ 555(. 5551. iS6f. SS60 ChoI, ........ 155 ~" onloohol<lf>. 563- 569. st.lI

Cb1m::JllonMol. 229
Cb~.n2

Chlorodip/><nhydnml"".702 0.100:II'...... ufo lOJ ,...op"....yknl>l.121

meIaboI,,,,,,
s....

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00<1<",,_s.... ClooonoIone povabl<

Oufo>;im' ..... 157
CloIibnlC.6.'!9

O ,"'n s.... C&Ibo ..... am .... nu.1<..., Clobcnpnnl. nl~ 719. 7291" C1obeIaoIII propi<II\ICc. Dr. 1!091. II 2 ~ PO'~'''' 812

(lIbom)ttIJ._ ~ ~.!2I

CboI_~~J

Chkll'QJlrlX.'1I< h)<lru.:fllontl 6'10 69}.691' ChkJrooctuoIl<. ~S7_1IlI. 2!l1f. 295, C1IIoroIhauJde.I!(Ij;-6lO. 606l. 6Ok. 1>19
~n

pbo>phor)lo1"", 01. 568. S6IIf ",,,,Uval...,., of. :l68f. Mh

...."t metJboI_ uf. Il~ ........... ,"" 01. 109 Clam"'. S CIooruphcnc ......

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oan.-. 49S-'9f>

ChoIo>.I7I. S Ou...,.hYr<>IJa <Cdi ...

s.... ChoI,_,ic bIo<kin,

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m<Ubol..."

o."""IItnuitnlC. 181. 7'Il1f. 7'Il2.7IJ CIomipraml ... hydrocIIlondo. 517

01. 101

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Clooo..lo ...
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965

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c........-c~.

s.... Fmun;n"""

Ol. 1004,,,,, 01. 70 Ckwt", 164. 166- 168. Iki(I s"...tJtJ

Ih,_'IIoooIoJY; R"""",b"wlI ON ...

IIJI!'Ik..iorKoi. 1M- 168 cON'" libe.ie. ill. lbo!. 1601,

'''''lIIw>k!ir

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..... _

UN ... I; ......... 16oi-IM f~ Ul0 '10'1. 1M- I"". 1/:11. lib ....... 164. 1601. .........,. ... 7!11, 161. 167, _ ttli. in. 166

01. 1601. 164f ....... iOnaI. 167. 11>7,

1"'>',.... " In. IIlIl

COlrlbo .......... 26-27. ~}_IIo} ....1)tJClIl.rdmiq.... in.. ~1 _'2 Iq:IlH"'" .... <dK)O'l i n. 3(1 carboIIyolm<ll In. 47. .. 1f chruma,~y irl. SI d ........ ~..~Iono on. 49. 61 dooon\'lll~'_ '1'1 . !to. 271, 61 do"" ...... 'klll of. 43 ...... -101.1: moIo:ado ' ... -'6----018. 4. ~1f of. SB- 60 r_~,,,,,,".. iOI UI' OOCIIOIO in. 49. XI( I'l"l 01. 43 bonI<>Itt:Y ~'''' 1 ~ ft. 'nfrared J90<'''''''''''PY on. ~1

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920-91:t. 911 _911.

..... fonn>, ..-...I.......ctIont; ,II. 930--933

,ewictioo

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n....'''e """"",,,1111;"" ,no 30

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lead oI"",' u,... in. 59-60. 591. 61 62 hblonb in.:!()..27 drt1ru,,,,,, of. 61 ....,p of. 5S- SB

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cq.".de. 607- MO, W7f. 6O'}t. 619

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dopIh ""'.... iL 1121 de>-~loJIm<nr d . 920--~21 irnc-ta<'ioo. ond. Il0l4_9015 (inrI_food 'n",,,,,"k><I> _ 1J4.1_9015 "Hn,mw.i"" in. 9l'1 - 9.1O. 934 lIf. 9l9 _ 944 f~ field lIC,htoh 'n.. 923 929. s". 1'110 f<>r<oe field .....101>

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y ...

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C\urplclln s". (hfch~ ..... >d,om CloIrinwole. 240-241 CIoI.,n &T C""Iy11liQo Clou,;lhll !Odoum.109I. 31 1 CIu>:ap... soo. S02 Cl<u..,1 !iN C1oaprrl< CloIMn.,.,....~. 61 CSOO , ... ,11Ud. 931- 938 C",MlMio. 6(i.I--(j61. I" """,,,",,,,,... of. 66;1. 66;1'. &8l

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I"... <!\oun ""*""1<> iD. 4)-46 hnlm .... 48 ....9. 4M. 62 LipomJ.i Rul< of Fi'e in. 40. " "..... ....a ..... by ... 51-52 ~ i . '.I. ~'f M.mfltld .ynllkoo. In. 43. 44(. 4M """,.,.,...", "".." nl .... 47 ...,,"..1 P"'J<IUo: .. In. 47....48. '7(

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n .........Ik1IC~..,..."..., ~ In. "" onc-tcad onr"""",,'C'O'J-"d ')ft""" .. 'n..

'" lead ....".eI) _ 920 "......,~w d) "-oic. """,I """, ......l3 -9.15 ............... 1'rICIIItl.... 1120-911. "'l lf. 92..">( SN Ill'" MoIoo.:ublr ....,...10 ... "'..... iew d . 'U9 920 p!o;onnaco.,to< ... <otIOqlI I '>'U pted":li'' "'U.\ Ul <U4 945 quan'"m m,.:h:.on,u .... "'11,\0 in. 923. 935_9l9 "'"';~'ns ,. !iN Scm:n,... ..,1IUCIIIpU'1<al1llttlM>d> ' 937_9l,1l ~b.vd. S~. '-')9 '>'U 3D ill. 911 VI""''' ........ ill. 921 C"......""""""",,, . 921- 922. 911f. 9221" SN ,,/-'" CumpulCt' ........, h i ' ... ,... CO~lT (<:a,,,,,hol .O .nc.h) II-' .... r.... ;e~

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'ft.

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115 - 126.526- n7 Com'b.III6-L81

Conn. 871. 872 C""fi ...... _ ,rMna<"III)II ntortIoQdo.. 939 c..,rotlRllional 01 ....... ' ..... 39-40 c""r.. , ",,"NIl Ik .. bol~f. J.I- J~ . 14f. 91().-91 1

.....,.,..., pOOl,. in. -SI. 61

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016..48. 30. 62

(,obIl ..."... 1194-896

~of.m

fol", IC1d ....aboli .... -'- 896 897

~M_896

P"1**k itt. 43-106, 451. 6J

.ur. 45r

Cubno _ _ """,...... Hl5 Coool .... dno. o/'.bu~. 520. 522 ..' Ioo:0I~. 676. 671. 6nr. 671. 690
me\lIboI, .... of. I~ Cook' .... 1.12-733. 7l~. nl. 745 .v, h.""" of. 17. 126. 129

"",,,,i.y

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C.....,...

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,.",,.,
.~

S " . : _ 179..10. 02-03. ts9r.. 86.l SAR w,th NMR. 5 1 $alumomatr ptPldetlclo:. 19'.8591

S-"'......... 1I03 SnnoA,n. 6\PO

",",O",IIm.7MS- 719 s... 0Ift0i<h.. bi<loy""""'" uf. 168-17(). 769f SiIroauainuw. S.;U". rn.aJ.ia __ lSl SKic (ff""". 9

otr_.

'I'

SoI,--.., i. """""""11)'''''''''' ....:1 __

Sorn.. !in C.,.,~ SomaiK: ",,11 . rnmJUlb :n. 19-4 SolI s...r-.I,beril!. 8-' r

SuI,.",""",..:bk'

'."f....,,, 922

-'"
ScInrInr..
j

SH~

S,pal ,......,h';05011 ..... illo,.".., 43X-WO

SCF ... ,iw>d. 9)8 SCII 5988-1. 244 S<~"'.4 .... , ~911
I

S.;I'rlld i,,, WIOV1! 936-9)7 Soh....,., ttlL 619. b79f sru.:;p.pily, 45*--160. ~SSf. ~~ So"",11Mln C'aIIIO<a. 45'-460. 4' f. ~YH Soim,IIIt"'" rro>,m"y .... y, in h'll:_"'''''' """""nina. Sol. Solr SC',' ........ "'. SMpobm.n< 1Iytlrtobrornid. '7B SC~'n . Sn a! .... Con,pu""."':cd drua

70-" !I""""'.

Stldnutil. ........ oe. PJI, n.D $i!""""",,. Sff SdVft JUlfadoazr ... 5,1_ .. lfadia>;l,.., 279. St~ ,,/:10 Sulf.... midu IPIIlical;'" for. l?Ot

s.:..n...., ...........

SomltlKPrrin. 841. 845 Somooutrnpil!. a+I

S.." " ".""'" "'~-onbiba"", (>COol (SRJf),

Si/""- _ ....... '00 ( ... I~ lluotlr). 91~ Si .... la.." y ," ,4 . j6, H.

$,,.,,.,.. """,,,ns. ~3! s.m._in. 66)

Som:otf'<m. 177.844. H59t SclmaIrupuI (<II ......-, &4-1. 8:wt 5Ofbic: .. Pd. 2]0 SOfbi: .. re Sff I.ooorbid;: Il:a,tnrc. IlPIIIICd .son-. SN Ac-iounln & ..101. 54). 5-14(, loU Sourb A"""","" o.Icqlana "lck,.,.... :1(;(1 Spwn.,.....ill. 2!!2 s,.n..... !W Proman"" SpotuJ - '''1'' _hrp... "H!~ - .... 'Y"'Ioc:" .. -14. 61 Spa!:.olly odoft'"""'" ')'Il!loc:" 27 Spoc... Iliff............ dnaJ " ,_ _

."

'77_ ',.

Si_.... Sn Do;r.qpuo ~ydovo:""'" SinSIc p/o<Jwn omc.""" rooolf'lllOd \OnIOff3IIhy (SI'liCT), '58-460. I06OI"
$ .......".. 35-36. 371

Si""""';n ..If..., 3-41

ttI-.

"'p

:1""'"<:.,...,.... .J112-)9.I .JIIM

tl-S''''''5CmI. 66 1 S!;,n Inf=ooou. fullpl. 231. 2311 .; ~ ~ for. 23J- ill

Shorer dcrcrm"' ..... 937 SI.,., oy~ fu",:",,,,,, 937 Slcqroq ""' ........ 260
Slcqo-"...,....".",......... 411 SIow . ..... ,, .. w .... oIonapII)h.... .,in (SS RA.I.820 Smail..,.. ' '''''''''. 109 Smol ..... dno& Pn<laboIIJIIl __ III
Sna~~

us.

...."'.PO'ed. I
bioIechnolGcr II!. 1"JO-I7l. Inf
...-.,... c"I" .".. __ 1?Q...171. 170t ",p.IIrroor"""". 26--n. -10. 401". 41. 'l-Sol. Solf.944 fOf . 3901 ""man.'.".,.,,<OIony _ f""""'!
~I _ l

"'f.

.''''Y

12!l" I19

-,.....,.,.. dol. . .. 56 '" Sca.I,

..,ponn '"'" i ... 171_ 172 vin ...1 (.n "I:co). 5-1- ", ~ 419, 919 ., ",ahmodell fOf.J9-4

............ S3' Sodium...PUIl ...~;"" 01.

j\l({--toOOI'

ScbItroi St, Fiu",mide Sccobor!IiIal. ".,.,. . .;.... ttl. 76, 17. KI S utwoboral oodirr ... $~ '9S Se<;onaI. SH s.-.:ob..b"lIl >OIL.", s.-.:G<Idwy rna>P. ~"II')". 32

.................., .. 171, In. "2

SmJ . JS.l Sa:uaJ s..r Acebu!olol Scda!iou. Sn "'""ioI)1i... h)"""';'" IIOd

s.......... 303-~
Scklane. Sn T.-rf~n."lI .... SCk'<"t: ... ...."..n ~ modulJoron (SER""~ 21-29. 29f. 711 - m. 78lf """,iw""IIfOn'. 1<\,.." 01. 29 Sclt<live ~""""in ... """w inlri." ........
'11-'20 ScIocto 1O>Jc>Iy.217 Sclf CONPilknr r..1d (SO') rnnhod. 9.1

_.u

W/- 601 Sodoum 4-...........1ocylMc. 256-257 Sodium ooniimony , IOIConaIe. 263~ 264 Sod:wm .....1 - :c. 1199 Sod,um betrloIl 229 Sochum "tfW) laIC. 2.lJ Sod i. ", o<tuik'ni M.: . ",,,,Ct... ufo 777( Sodoum ..." ... wlflllC. MnIO:, ..... ttl. 7771 Soch,,", iodide I Ill . 444. "5 Sodi"", iOOi"" ~ ... , 4b9 Sodiu", iodi ... ,oral "']u:i<onIc"I""lc. <1609 Sod,um MIn duNe... 681 . 1182-M3. 682f SH
alJ6 Ion .... " ... Sod,u", nirti,.,

Sl*t&I.oIc. St, ~ SI*,j""",yd" . lJ5. 341 Sl*troiAd. St, lIacanrpoc:II.11 S ........ ,.,..,.'.."'b). '" UHD"""'" ok

Sp"dfk immu ... ,lobuli ... 207 SPF.cT ( .. ",110 pIoooo:.t MIl""'" ~ "".......y). 438-460, 4fIOf

n ,"""

e>.

Spof"'""'l'nesi...., ulal;"" 01. 77 ~. 714f spo""r...u..:.... 687. SH _ laI

"

SClf...........ol. In i_lPP'I. &!II ~ U2. W. Scm,"u Sn Aai ....."" Sc"-",. Oumeric: Su o..:blUmab Scru SH O u,,opam s.. ..",1. SH Mctoridui"" bcs) ..... Sc :",,,,,. Su SrrI ...... roI Snomy<in. Su Cydo."ri .. SttoQIorl Sa Q """"p'" Sc, pi i _ y. 200 Sc,. H!.SNReK, pi ... ScrJKM.66S 519 50-- 151

s...u....

Sodium ni!lOJA'!l-Sidc, rU4 Soott .... PAS. 156-257 Sod".", pboopNrre P 32. U4. "5 Sod,um"""''''um pump. 682--6113. t\32f Sod,,,,,, pr<>pi<lnare. 229 Sorlr .... woe)..,.. 75' Sorl m "000c"''''' W", 263-2601 Sod,um Sul"",yrl. Sn Sulr~KIc " :hu", .. Sod"....... lr~ ,.;1"....,.1 (Of, 27Qt So,t""" thoo<aIi<y ..... 753 SoIl '"'PO 14 2 St>kmurro SfIIP 910 ""I................... IIOd ............ 'U-'79 &1'10,,.., SH .8-C_ SoIid-pIwc .yndln... "6...019.

s.... N;,.........rula"""

Spo ......... or:tono.. 616-617. 6161". 6lO. 115 utrwonal .. livily ttl. 619 Spo~hydro<hkrnolluazode. 6.20 Sph: ,PIIJmi )'IlI ........ 4J .wf. 62 sp,r .k,.,l Moi:o ..r}., 9].1 Sj:cro :" Sff lb... I ..... SQ-l9S48. B2.&o Sq ...1mc epuJdor,.,. 238- lJ9. 2J'If SItS..... &20 St ~ Sn 8 .... 1 .... IMbate . StamlOlol.799f.801 Stapbcillill. SH M.thlcillin oOO,wm Star1... Sn NMqI,nidoe StAII ....... 768 Statbrnol<inosii. ~n SI.Mi..ical rnotlouoh. i ......, 00; .... 17 26
S~4)

51""'.. 219

...........

Solid

Scrmol,,..,

SoIubolriy

'" "Ai.

"""""_urial.

S .. ,"":""- JlI S""pW de",.n: opproor:h. 930 S""" ""II 177. l7If. 1'i7. 1911" Src,..w:l5CMoWy ttl dno& rn<tabt>I.1lII. 1.12- 134 01 d"'I-m;-cpwr in...-.ctk>o&. 11 - 34
S~

~.'1""!>. ~9.

63

bookie""" or:trVlIy PJI.lS-J1.

10J

ttl. '2- 53. ~2r. 52L 6 1

s.......It,,oty. J5.
prudtott.
1J2 ~ 133

35f. J6I

lopod. 5 pi(. WId. 17

............ U2

'","$

987

s..J-. 2IS-ll3, 2II1t cmlialuoo 1If. 21S. ZIii!

cff..-uot<>e<> 1If. nt.lualWn 1If. 219

s..ca...", aIm. ... prodru", 147-1 49. 1~

S""-'Clnlmi<\e1.. S05-j(l6 one5al:ooJll..-n 01. 109 Su=n)"'h0>4I .... dIIori<.Ir. ,IB_595 SuaooInL 5 SlOCClnyklloli... oIoloride

-"mIt ... _ q , .., Iz)'dzw;Ido I 1012-40 .-11 SomIe ...... c ..... IM~ ",I ~

ror. 221 JImIo ...."""', .....rw. 159

,I " I <IXff"'"",,

"opt>'" IIf.II9
.... u,

f""""l11"",, 1Ji. 275-m IooaIflirc 01. 2761 illdlclli(w for.~. 27Q5

=-tc~~~~

Suf. 17 , ClIntc. n9 Sulw. SoN ,.;loo4di"' .... Sult.:lam. 31'.316

S~lbKtam""""""llh".

...

for

l",eo"naIll1~

219

,.w' _

*",~_

,_

sz

Szcn~QII/)ft. 211i! od(7~ 767_"~

1IImzIl.8OJ-'U
.oI!o!jr

ll6 Su~ nitrate. 242 Sulf~ 2u.. s.... "''''' S~lfonamkleo. Sulf~ ,bello"". 218. SoN 77hD SuIf.c"I"",pyndlnl... 276. s", . . . SUlf'l"' ........ Sulfldian"". 276l. 277 SN Q/sq Sulfooanooillel S~lfldi.ui ........ hlm. 277. Sa 5ulfOllImiob SulflodoJ.i .... 27tM

adz":

...7 . 1If. 7M_nu, 7(IK 1103-115

.......-.

......

,...... t.Mlon of. 212-274 ....,-..",of .. _0I".270=171. 2711_27.l( "",,'bQlluro of. Ill. 12Jf. 269. 27. 215 1E"'obo.J ... 1'7E'~ ..... 275 miud. Zn-278 11011",1",1.,,,,,, (or. 269. 271(
~".27g-279
~ow.269

"'

",,,,Iou, f""'" or. 269. m ,.-000'" ",.111..,. of. 27'. 215

..... rf't'u of. 215

PK. ........ for. 169-270. 274. 274,

I 1" 1.wun: ror, 71>7_768. 767(. 768r 'u .01.767. 16n 0'I...-.'!CWof.161-16I ;1 01. noodir ' _ 01. ....

5p:<Mim 0( 1<1"'" of. 27. -272 ..""', ..... _I('I\.;,y ",tati"''''''11'' foo. 275 """"' ''" <11'. 21lf 1iJpbI. 'Ut9. 278----m """eur of. In. 214. 275

n"...... 01, 1~8. 1m. 7m 171 f pood.." r

no.

-",w"",

no.

So.oIr-.179-l8O Sulf..,....... (0611-670

Sulfllale. InditlbOll' for. 2X. Suit_rot. 171'. 176. s... aLw Sulft)lWllid<b onetaboIi.", 01.122. IHf SUlf"""""'.... 21)-276. 176t. Su SlIif"""",",",, Soolf............... 27tM. In. SN ""'" SoIlfoownioln .....-..... 7Ii, Ill. 12Jf Sulfll'll<lllo.."oIc ond ui"""""""m. $H TrimalIQpri m.,~lfOil1<lhooo"."" SUlf.."idodll).ooi ........... bo/i.'" c/. 11)1 ,S,Su1'''''''')' I 2-1_)-ami .........,., ..,ioI .........."-610-6IJ So.oIf.."y.... SN M.r...... _ Sulf...;........... l69. 271r SNoW
"""+~ 01. 90( 5ul('ridv..... , .,... I~i,m 01. 99. 100 Sulfu, "",~IWtl. 394 Sulo"",,".758 1<1,,', 1I'IC7Ibo$'1<'> 1Ji. 1351 mctabot ..... or. 1011. 143. I ..... f poWno. room or. 14.1. I#f Sun)'k<oCl. (JuontnC, s.... ~11..,mab ~"'U"" n~ ... tl."'liOT7)SniptIy. ill o:ombiIIIIon.ll chorniWy, ~ 1
Su~_"'~~76

....

JII".lII'W"'. 7U-139 1'0 ..... 100 ol. 710. 7101

II 1 HiE) 01. 7X. I ,<.1 aoi.lOyof,16J-768. 767'. 768f

"'*'

I 1_ ....... 716.. mf-71lf .1 ....."'. p)ndo.o.i ... __ 893.894 S , ' ''-- """......,.. (SlAR)
S

"Ii
o

m. 77U rypa 01. 77.1 S" L. IIInaboIowzz of. n s..- ~"" ocIFIII<Gft 0(.

Sw90d or<qI7or cumpl,,, ... """"""" 01. 77l Szaaid 1DCqiI0I'1. 77Q_77~. 77If

""

"""'1.

De;n........ Sup,... Sir err... l.... SuPf""'_. 12Sc

S.......,...

SI~

I.. ' 510-'22

, " 1 I' w.loI-.935 $Eo 11!iH """'. o..ln)I",~"n.ll SIoJQo .... !iN Amyb:oI ... SIolil SN klo."oriih"" STl". Aklobdi"" 01". 91 'Ilr-. oIoffnmca. ia <WtI "",,>h,'" ii. 121--129 SnoIo 17 ..... 7 $zo I =. Sir SU ........ uwe Szz"*'''E''. B)9_&40 $'171 ~~,..,.n ~uto.mololos 1(1i"ily C/, 2j.I do--..y C/. 299. 3:W_1l5 Szo I -I?<la ""rw. 3J7-33B $zo'I' ... it.. 3&1-.161 SI"I ....... ~2Il Col Szooo 89 dIloridr .u.a. 404$ SZno<\oore-.ICIl'iI)' ,.1"",,,,"'$1. 1~23. 3I-JIl. SH aI*, OSAR wdin tJNI if>HVk

IIIImXom:uiar 1<11"1)' 7Ii. lSoI ....ubo$iom 1If. 122. l2Jf Sui/..... I.mlilel. 269 ay.wlurilond. 274 mo.oI ",.it,,) or. 274 Sulf...,-...tt..lTI. SN ... Sulf<lillirllMb ....*'Xli,- or. Ill, Inf SUlfHal ........ 279. SN Q/sq SllIfOllllFOidn .........,-..,. ill, 130. 151f mmbo$,unof.I07_101l Sui/Me cyd"".Mnn,. 447 SUlfal.... C<)O\jU,"lion <11'. I 14f. 115-116 SuIfIlLHIII, J:W $o.lf-.. Srr sur........1 .iWIe Sulr~ IW"'.... I<711 7Ii. 114 SllIr""' ...... 276. 271Jl. s",...,
mctaboIi .... 1Ji. 122. l2Jf sulr........... JoCeIyl, 276, SN oW Sulfoo:.m;u... SUlfi .... aroIe di<il.miow. 276. 27'. Su ul
S"'/~

""........

s...-.mon """urn
I7lllno:qoINoc . . . ~:lO. ..... 7 .....;p.-"" .... 264 Sw-f1CWlU. CWOII"'. :!2~_227
Sw-pron. s.... 4l",..bkJoopbc ... SU'IIif.,.,.,. SN OeI.h_"I"'I'I' Surital Sulhm. Su Thwnyla! oocllum S""""",ul Su Tnmopnmo ... nWt~ SuMi .... SN Sotcillillo. &J9 S)'mm......1 Amoo lid, .. S)onpadIo71IC ...., ...... muLtl"", 01. S86-SBJ S)~it """'ou~ ')'>Iem. S4I

Et."'.....

s....

Sympalbot~. ~2~ Sy",,,,,,''''>''';'''''';, 71i~n! .. ~ 10. 52~.

~.51~511-514.512f

530.']9.

~';'" 5II,,1 -toe.at dru, obijll, 55. 939_144

51)...... s.... S .......... ' ... Id $ _'I in,..-ooa. dno. Iliwl.......... ..t

.I.
., ..

"".......

direal< .. n.. 5JO.-532 ..............oe I"'<IN...." ..."'. 531-5ll ,84dmI<op: 1.... '.I6-U7 drul;onxtun .. 532_539 dual ... ond /l-IAJtt""'lic: ~ ...,..,....

'"

."";Mot ...

"',..,...I.. .-uy 1If. 530. 5]1

.".... dio.~,.""""" U7-5)I
"".~_. 531-539

Sulf_1deo. 268-280

S...... "'),..... 2J1 .= $.1

SzobwI",,",U

4f,5-6

.,n",,," 'I('n ll) 1JO-Ul.5.!Of

'"

~Ltli"dl"",

for.

s....F 'M)ICIIJMe 5,1 " -" P. U7

I~of.

s.
5

26-27

..Itctioo 01. 2l-2l.131

1M< ...........lb"I1) . 1)2

-..,."

Ii.... _~""UliOiI. izo ~_""'._.. _..,.

obaoobtoble ........ Q&. 21tM .... hDe-...... ,i7Ied. l69 far Ioumi. 278-279 .w... rK'lIU"" of. l69 di __'eI}' .wi de,'cklpmtn, 1Ji. 269 7h>uibuuozl of. 274_27$ "'...,.;.,., 1Ji. 21~. 275 f.,.. .".."'y..... ond. 270_27 . 21lf-213f f...... mlutIMC ...... ""'" ond. 275

Syn2869. 245

S)'.,.... 680.

680(.

68J

Synaptic- dd\. 680. 6IIOf Syotapti< k"""', "79. 6791' SYIIdll. Sn Qo.lnu"....ulHlalf""" ... "
5)1'" Mill";' JII~.1'9

S)'1UC7riil. $H Rnlo~w 5y""" IoII, (0611

988

1"*-<

5y............. ibioc1cnll

5, ' od!ift: l.e""h)'.... ..., ~"'" Sy.-:_, S 0.)1<'<'" m)rt_" 0')1<1<' 1'1
""",1 ""''''''''' T

'"i:""'''' Z47~1U

To",p'" Str A """"."p.... n T....".I s..,. I"""') Iprupon T""''''jAa",,11I4 To ..... 51'. O" ...f..,,,'" hyoln:.:hkondo: T.... po)U,\o, 421o---1H
T""""",,,,!ift: A....,.,. T"",,1m. Srf! &Ia .........'"'" I.'IIknk

TO<aI)I. ~ Mnhd,I"';~ Tochyph)'-' ... ~

Tom ... ~)"JroclII""oio, ~ 7 Todalaf,l, "Un"lM of, N, lOr l'afl '. ~ (f:,~ 21 T I' .w:L, !ift: C; ..... oJ ....

*""

T......'"

T.1lIIIGe1 """" ... ,n <"""""",,,,,al T.. " SH 1)",110)"",_ T.,....,I s..,. 1)dIo)1"".,....
&. r""..,...,010 T.....,.., ... ~_.s4I, Srli. Terw<lI:Iu h)"dn>doloon<k. ~~
TO<bo".ft ... h)oIm<hk>n<J.,

<lo:nIl>!l)',

49

l\IuInl 1Ik"lhod.. '''' ,~,."bI"._.1 1 ,tnnM.

~1 ~j, ~11,

S2,

, 'emulOhllC,3.\fo
mmt.::.I .... of, $7, II~,
T~,1:I~

T"'-'........ 1_""' ..._

T....",.,f... , 4)3, 4'to, 781 -781, 7811 """,,,~oni" .. """, ,~. ~

ToIl""",,),,' II<, ~17 T.I",,". ,.,.." I't...u"-",,,..

126

.....u.hoI,..., "', ~

T .......

T<m"~

"""n, 54l ...

T.,I,n:od,,",, 712-71 \ 7 ( .If, '~3 T......... I touo_ 679. 10M T'".IIY",. Sw (h)",,,_,,)<:""" h)JruchIorodo T~I;oc ........ T.......",. SH Ikn>.-.

T.""'''''.....

p."'I>r~'~'" (f.,nfnrJ, '107.'1(18

T - "' " ret SH &'_IIC TlItr.WIIC, ......001.. '" of, 1m T.,,>I ,...... C'kma,,, ... '~"U/\lI" TLWI. ,.......... IM....,I T.."..,... .'!<orr o......,..ul T.)1oo' oerio ,,,0""'''', 9Z5

T.,.m,........ &

Tandoml, 7b.3l fiparoI<, !ift: M<tIu ...... ok T"P"', ..... uUo"",~ ..... !tH .!M 'flarJ<!<od, S To"'''pl""io
...,*<1<

TNUbo:sOEw:. ~31>. 71\. 1Mf, 7115 I ...." ....1pl. .. oe, ~34 T .. booI<.ot;iulll.'l"1t)' , m, 'NIl! boQ,)n ........ of, ltJ'1(, no, n'f, n3, <t""'''K'' III to ......... iaI, l~J, 7Uf

,,,,,,,I'IlIII'

......,. ..... 0(,

N7

~ of, 799f. Il00-801 oolublj,,} "I'. 7700

""""urr-II.'I''''Y ",1,u;",o<l,,1" fOf, 798- 711'1,

T",,,,,,,,,,,,,, C)<iop<N) I"""",.

,..,

, ,,,",,,,,,",

T_,874 ~7~ Tlllod,mc: Sa C'"f\abJ,,, ........ i..... Ta>toboor'.m, j13, 116 r .....-um J'll""fI"'lhn, J 16 T.......,. !ift: Tv .......... . arc Sff-T",.-h... ~"m T ...,11>;, 200, ~2 ~ I bdp, 200 ~ Tn '-&>' In ''''''bI ......... ')"""" ..,""', 4~f,
~

,M.771'
T~ "Y'I"'..... ?W, T~'("',,,,,,,, onlMn>l",

1101

............'" 77l f

'NIl,!I01

T""' ......"'" propio_ .. """.... opIa<Ioe, ~\.I ,,~"blh'y of, 7701

T,"""-'<I, ~ 17...M.' h)'I"""""....... T... >d ... ",Il'<tion , :2 2-23, 1'-. :16-27 Ttullor.. ""<*I, 2121. 21', 21S

Tod...,,"m II""mo" owq.Md,:I(>\ ~ rooh"""utn .(bum,n ""II",~ '")rt"on. rI6-I Toc"""uum II.... n.m in)rt'M>II.:lb.l
T...,*,..

T= .... ~"'. SH "Ioio.ku~'n

,,,,m...,odo. rI6-I

WG-6'l\ 6'l1! 1-1,7.-Tou-.hl"',,'hbrnl ....p..Ji<u ,n ilii'iii00i;,,,, of, 71.101 T.,rxY""nchl, 341 - 1-19
T,,~.

(Tee" I,

T"d u..... boci.... ,n)rt'M ..... :II>' T""h..."u",!lq'n<:JI1oio in)"<'l""', rIM T""t-uu", di..,{""'d .n)rt1~"', rIM--16S
T ""","",...... ~J'"

""""""'*;"" 0(, 1-12 In.:tI... ......, 342

~

, ho::lItt> of, 34~ _.~,U <1..... ,>11)',,(, \.II

Thr..."bollloOOI,,,, b65
10M, ()64f, 11M, 'IbronIbI>uII< " " 1166->7, &:!O, IUr. Thym,nc1r<4 _h, 4 10
~,n, b/)J,

T""""",,,",,

~ "'J"''-'"",,:IM T"" ....... U/Il mo:nL>l1oio 'n....."'''"',,If>~

'"JOCb<WI. #>j

T"" ......."'" ... ""'" .. 466 T... b..n,~", 1-r<1 ~." ... , :162--167 T "'.n.u~", hIood ~1"l"toIot<"." 466 T............"'"...,..,"" ,n)rt"'''' 466 T""hl'l"'"'", ood,um "..,,,,,hnet.,,,, 4llf>----.467 r .... InjtiOII.. 4(07 T.........."'" ...If.. ,0I1ood 'n)rt1_, ~7 Tbn<I,un, 1CtRlf,.. mon ,")"<'loon.:I67

)rtI''''''

"'"

0/, "'~ mOCT<Jl>W ~ 10, 34l pit, 'al .... , 141, 341r .....' 1-13 prudnIa ""'" 0/, 1.t9 1501' prup<1'1"" <I, J44 1-I3,.):IS. <p<aruan o( ""''' uy 0(, '\,41 _)44 ........,hnru,,",o/, '\,41 , l4Zl """,,,,,, . 1ICti"iIy ",101-"11'" f ,)44 -.):15,
......_ .... 0(11.'10

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