Clinical Pharmacology Made Incredibly

Easy!
3rd Edition

2009
Li ppi ncott Wi l l i ams & Wi l ki ns
Phi l adel phi a
323 Nor r i stown Road, Sui te 200, Ambl er, PA 19002-2756
978-0-7817-8938-7
0-7817-8938-9

The cl i ni cal tr eatments descr i bed and r ecommended i n thi s

publ i cati on ar e based on r esear ch and consul tati on wi th nur si ng,
medi cal , and l egal author i ti es. To the best of our knowl edge, these
pr ocedur es r efl ect cur r entl y accepted practi ce. Never thel ess, they
cant be consi der ed absol ute and uni ver sal r ecommendati ons. For
i ndi vi dual appl i cati ons, al l r ecommendati ons must be consi der ed i n
l i ght of the pati ents cl i ni cal condi ti on and, befor e admi ni strati on of
new or i nfr equentl y used dr ugs, i n l i ght of the l atest package-i nser t
i nfor mati on. The author s and publ i sher di scl ai m any r esponsi bi l i ty
for any adver se effects r esul ti ng fr om the suggested pr ocedur es,
fr om any undetected er r or s, or fr om the r eader s mi sunder standi ng
of the text.
2009 by Li ppi ncott Wi l l i ams & Wi l ki ns. Al l r i ghts r eser ved. Thi s
book i s pr otected by copyr i ght. No par t of i t may be r epr oduced,
stor ed i n a r etr i eval system, or transmi tted, i n any for m or by any
meansel ectr oni c, mechani cal , photocopy, r ecor di ng, or
other wi sewi thout pr i or wr i tten per mi ssi on of the publ i sher, except
for br i ef quotati ons embodi ed i n cr i ti cal ar ti cl es and r evi ews and
testi ng and eval uati on mater i al s pr ovi ded by publ i sher to
i nstr uctor s whose school s have adopted i ts accompanyi ng textbook.
Pr i nted i n the Uni ted States of Amer i ca. For i nfor mati on, wr i te
Li ppi ncott Wi l l i ams & Wi l ki ns, 323 Nor r i stown Road, Sui te 200,
Ambl er, PA 19002-2756.
CPIE3E010608
Staff
Executive Publisher
Judi th A. Schi l l i ng McCann, RN, MSN
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A rt Director
Mar y Ludwi cki
Clinical Project Manager
Jenni fer Meyer i ng, RN, BSN, MS, CCRN
Editors
Mar gar et Eckman, Di ane Labus
Copy Editors
Ki mber l y Bi l otta (super vi sor ), Jane Bradfor d, Shana Har r i ngton, Li sa
Stocksl ager, Dor othy P. Ter r y, Pamel a Wi ngr od
Designer
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Illustrator
Bot Roda
Digital Composition Services
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Editorial A ssistants
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Indexer
Bar bara Hodgson
Library of Congress Cataloging-in-Publication Data
Cl i ni cal phar macol ogy made i ncr edi bl y easy!. 3r d ed.
p.; cm.
 Incl udes bi bl i ographi cal r efer ences and i ndex.
1. Cl i ni cal phar macol ogy Outl i nes, syl l abi , etc.
I. Li ppi ncott Wi l l i ams & Wi l ki ns.
[DNLM: 1. Phar macol ogy, Cl i ni cal methods Handbooks. 2.
Dr ug Therapy Handbooks. 3. Phar maceuti cal Pr eparati ons
Handbooks. QV 39 C6417 2008]
RM301.28.C556 2008
615.1dc22
ISBN-13: 978-0-7817-8938-7 (al k. paper )
ISBN-10: 0-7817-8938-9 (al k. paper ) 2008009967

Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns
Front of Book
Author s
Not another bor i ng for ewor d
Table of Contents
1 F undamental s of cl i ni cal phar macol ogy
2 Autonomi c ner vous system dr ugs
3 Neur ol ogi c and neur omuscul ar dr ugs
4 Pai n medi cati ons
5 Car di ovascul ar dr ugs
6 Hematol ogi c dr ugs
7 Respi rator y dr ugs
8 G astr oi ntesti nal dr ugs
9 G eni tour i nar y dr ugs
10 Anti -i nfecti ve dr ugs
11 Anti -i nfl ammator y, anti -al l er gy, and i mmunosuppr essant
dr ugs
12 Psychotr opi c dr ugs
13 Endocr i ne dr ugs
14 Dr ugs for fl ui d and el ectr ol yte bal ance
15 Anti neopl asti c dr ugs
Back of Book
End Matter

Appendices, references, and index

Other major dr ugs
Vacci nes and tr eatment for bi ol ogi cal weapons exposur e
Tr eatment and anti dotes for chemi cal weapons exposur e
Her bal dr ugs
End Matter
Sel ected r efer ences
Index
A B C D E F G H
IJ K L M N O P
Q R S T U V W X
Y Z
 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

Contributors and consultants

Tricia M. Berry PharmD, BCPS
Associ ate Pr ofessor of Phar macy Practi ce
St. Louis College of Phar macy

Victor Cohen BS, PharmD, BCPS

Assi stant Pr ofessor of Phar macy Practi ce
Ar nold & Mar ie Schwar tz College of Phar macy & Health Sciences
Clinical Phar macy Manager & Residency Pr ogr am Dir ector
Maimonides Medical Center Br ooklyn, N.Y.

Jason C. Cooper PharmD

Cl i ni cal Speci al i st, MUSC Dr ug Infor mati on Center
Medical Univer sity of South Car olina Char leston

Michele A . Danish PharmD, RPH

Phar macy Cl i ni cal Manager
St. Joseph Health Ser vices Nor th Pr ovidence, R.I.

Glen E. Farr PharmD

Pr ofessor of Cl i ni cal Phar macy & Associ ate Dean
Univer sity of Tennessee College of Phar macy Knoxville

Tatyana Gurvich PharmD

Cl i ni cal Phar macol ogi st
G lendale (Calif.) Adventist F amily Pr actice Residency Pr ogr am

Catherine A . Heyneman PharmD, MS, A NP

Associ ate Pr ofessor of Phar macy Practi ce
Idaho State Univer sity College of Phar macy Pocatello
Samantha P. Jellinek PharmD, BCPS
Cl i ni cal Phar macy Manager for Medi cati on Reconci l i ati on & Safety
Clinical Coor dinator , Phar macy Pr actice Residency Pr ogr am
Maimonides Medical Center Br ooklyn, N.Y.

Christine K. ONeil PharmD, BCPS, CGP, FCCP

Pr ofessor of Phar macy Practi ce
Duquesne Univer sity Mylan School of Phar macy Pittsbur gh

Jean Scholtz PharmD, BCPS, FA SHP

Associ ate Pr ofessor
Depar tment of Phar macy Pr actice and Phar macy Administr ation
Univer sity of the Sciences in Philadelphia

A nthony P. Sorrentino PharmD

Assi stant Pr ofessor of Cl i ni cal Phar macy
Philadelphia College of Phar macy Univer sity of the Sciences in
Philadelphia

Suzzanne Tairu PharmD

Cl i ni cal Speci al i st
The Medical Affair s Company/Consultant for Pfiz er Kennesaw, Calif.

Karen Jo Tietze BS, PharmD

Pr ofessor of Cl i ni cal Phar macy
Philadelphia College of Phar macy Univer sity of the Sciences in
Philadelphia

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

Not another boring foreword

If your e l i ke me, your e too busy car i ng for your pati ents to wade
thr ough a for ewor d that uses pr etenti ous ter ms and umpteen dul l
paragraphs to get to the poi nt. So l ets cut r i ght to the chase!
Her es why thi s book i s so ter r i fi c:

It wi l l teach you al l the i mpor tant thi ngs you need to know
about cl i ni cal phar macol ogy. (And i t wi l l l eave out al l the fl uff
that wastes your ti me.)
It wi l l hel p you r emember what youve l ear ned.
It wi l l make you smi l e as i t enhances your knowl edge and
ski l l s.

Dont bel i eve me? Tr y these r ecur r i ng l ogos on for si ze:

Now I get it! i l l ustrates nor mal physi ol ogy and the physi ol ogy
of dr ug acti ons.

War ning! al er ts you to potenti al l y danger ous adver se

r eacti ons.

Yea or nay? sor ts thr ough cur r ent i ssues r el ated to dr ug

r i sks and benefi ts.
 Safe and sound expl ai ns how to admi ni ster medi cati ons
safel y.

Memor y jogger r ei nfor ces l ear ni ng thr ough easy-to-r emember

mnemoni cs.

See? I tol d you! And thats not al l . Look for me and my fr i ends i n
the mar gi ns thr oughout thi s book. Wel l be ther e to expl ai n key
concepts, pr ovi de i mpor tant car e r emi nder s, and offer r eassurance.
Oh, and i f you dont mi nd, wel l be spi ci ng up the pages wi th a bi t of
humor al ong the way, to teach and enter tai n i n a way that no other
r esour ce can.
I hope you fi nd thi s book hel pful . Best of l uck thr oughout your
car eer !

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

1
Fundamentals of clinical pharmacology

Just the facts

In thi s chapter, youl l l ear n:

phar macol ogy basi cs

r outes by whi ch dr ugs ar e admi ni ster ed
key concepts of phar macoki neti cs
key concepts of phar macodynami cs
key concepts of phar macotherapeuti cs
key types of dr ug i nteracti ons and adver se r eacti ons.

Pharmacology basics
Thi s chapter focuses on the fundamental pr i nci pl es of phar macol ogy.
It di scusses basi c i nfor mati on, such as how dr ugs ar e named and
how theyr e cr eated. It al so di scusses the di ffer ent r outes by whi ch
dr ugs can be admi ni ster ed.
Kinetics, dynamics, therapeutics
Thi s chapter al so di scusses what happens when a dr ug enter s the
body. Thi s i nvol ves thr ee mai n ar eas:

phar macoki neti cs (the absor pti on, di str i buti on, metabol i sm,
and excr eti on of a dr ug)
phar macodynami cs (the bi ochemi cal and physi cal effects of
dr ugs and the mechani sms of dr ug acti ons)
phar macotherapeuti cs (the use of dr ugs to pr event and tr eat
di seases).

In addi ti on, the chapter pr ovi des an i ntr oducti on to dr ug

i nteracti ons and adver se dr ug r eacti ons.

Whats in a name?
Dr ugs have a speci fi c ki nd of nomencl atur ethat i s, a dr ug can go by
thr ee di ffer ent names:

The chemical name i s a sci enti fi c name that pr eci sel y descr i bes
i ts atomi c and mol ecul ar str uctur e.
The gener ic, or nonpr opr i etar y, name i s an abbr evi ati on of the
chemi cal name.
The tr ade name (al so known as the br and name or pr opr ietar y
name) i s sel ected by the dr ug company sel l i ng the pr oduct.
Trade names ar e pr otected by copyr i ght. The symbol after the
trade name i ndi cates that the name i s r egi ster ed by and
 r estr i cted to the dr ug manufactur er.

To avoi d confusi on, i ts best to use a dr ugs gener i c name because

any one dr ug can have a number of trade names.
In 1962, the federal gover nment mandated the use of offi ci al names
so that onl y one offi ci al name woul d r epr esent each dr ug. The
offi ci al names ar e l i sted i n the United States Phar macopeia and
National F or mular y.

Family ties
Dr ugs that shar e si mi l ar character i sti cs ar e gr ouped together as a
phar macologic class (or fami l y). beta-adr ener gi c bl ocker s ar e an
exampl e of a phar macol ogi c cl ass.
The ther apeutic class gr oups dr ugs by therapeuti c use.
Anti hyper tensi ves ar e an exampl e of a therapeuti c cl ass.

Where drugs come from

Tradi ti onal l y, dr ugs wer e der i ved fr om natur al sour ces, such as:

pl ants
ani mal s
mi neral s.

Today, however, l aborator y r esear cher s use tradi ti onal knowl edge,
al ong wi th chemi cal sci ence, to devel op synthetic dr ug sour ces. One
advantage of chemi cal l y devel oped dr ugs i s that theyr e fr ee fr om
the i mpur i ti es found i n natural substances.
In addi ti on, r esear cher s and dr ug devel oper s can mani pul ate the
mol ecul ar str uctur e of substances such as anti bi oti cs so that a sl i ght
change i n the chemi cal str uctur e makes the dr ug effecti ve agai nst
di ffer ent or gani sms. The fi r st-, second-, thi r d-, and four th-
generati on cephal ospor i ns ar e an exampl e.

Old-fashioned medicine
The ear l i est dr ug concocti ons fr om pl ants used ever ythi ng: the
l eaves, r oots, bul b, stem, seeds, buds, and bl ossoms. Subsequentl y,
har mful substances often found thei r way i nto the mi xtur e.
As the under standi ng of pl ants as dr ug sour ces became mor e
sophi sti cated, r esear cher s sought to i sol ate and i ntensi fy active
components whi l e avoi di ng har mful ones.

Power plant
The acti ve components consi st of several types and var y i n
character and effect:

Alkaloids, the most acti ve component i n pl ants, r eact wi th aci ds

to for m a sal t that can di ssol ve mor e r eadi l y i n body fl ui ds. The
names of al kal oi ds and thei r sal ts usual l y end i n -i ne.
Exampl es i ncl ude atr opi ne, caffei ne, and ni coti ne.
 G lycosides ar e al so acti ve components found i n pl ants. Names of
gl ycosi des usual l y end i n -i n such as di goxi n.
G ums consti tute another gr oup of acti ve components. G ums gi ve
pr oducts the abi l i ty to attract and hol d water. Exampl es i ncl ude
seaweed extracti ons and seeds wi th star ch.
Resins, of whi ch the chi ef sour ce i s pi ne tr ee sap, commonl y act
as l ocal i r r i tants or as l axati ves.
Oils, thi ck and someti mes gr easy l i qui ds, ar e cl assi fi ed as
vol ati l e or fi xed. Exampl es of vol ati l e oi l s, whi ch r eadi l y
evaporate, i ncl ude pepper mi nt, spear mi nt, and juni per. F i xed
oi l s, whi ch ar ent easi l y evaporated, i ncl ude castor oi l and ol i ve
oi l .

Animal magnetism
The body fl ui ds or gl ands of ani mal s can al so be dr ug sour ces. The
dr ugs obtai ned fr om ani mal sour ces i ncl ude:

hor mones such as i nsul i n

oils and fats (usual l y fi xed) such as cod-l i ver oi l
enz ymes, whi ch ar e pr oduced by l i vi ng cel l s and act as catal ysts,
such as pancr eati n and pepsi n
vaccines, whi ch ar e suspensi ons of ki l l ed, modi fi ed, or
attenuated mi cr oor gani sms. (See Ol d McDonal d had a phar m,
page 4.)

Mineral springs
Metal l i c and nonmetal l i c mi neral s pr ovi de var i ous i nor gani c
mater i al s not avai l abl e fr om pl ants or ani mal s. The mi neral sour ces
ar e used as they occur i n natur e or ar e combi ned wi th other
i ngr edi ents. Exampl es of dr ugs that contai n mi neral s ar e i r on,
i odi ne, and Epsom sal ts.

Down to DNA
Today, most dr ugs ar e pr oduced i n l aborator i es and can be:
 natural (fr om ani mal , pl ant, or mi neral sour ces)
syntheti c.

Old McDonald had a pharm

In the near futur e, tradi ti onal bar nyar d ani mal s mi ght al so be
smal l , or gani c phar maceuti cal factor i es. Some ani mal s have
al r eady been geneti cal l y al ter ed to pr oduce phar maceuti cal s, and
thei r pr oducts ar e bei ng tested by the Food and Dr ug
Admi ni strati on. Her e ar e a few exampl es of the possi bi l i ti es:

a cow that pr oduces mi l k contai ni ng l actofer r i n, whi ch can be

used to tr eat human i nfecti ons
a goat that pr oduces mi l k contai ni ng anti thr ombi n III, whi ch
can hel p pr event bl ood cl otti ng i n humans
a sheep that pr oduces mi l k contai ni ng al pha1 -anti tr ypsi n,
whi ch i s used to tr eat cysti c fi br osi s.

Exampl es of dr ugs pr oduced i n the l aborator y i ncl ude thyr oi d

hor mone (natural ) and rani ti di ne (syntheti c).
Recombi nant deoxyr i bonucl ei c aci d r esear ch has l ed to other
chemi cal sour ces of or gani c compounds. For exampl e, the r eor der i ng
of geneti c i nfor mati on has enabl ed sci enti sts to devel op bacter i a
that pr oduce i nsul i n for humans.
How drugs are administered
A dr ugs admi ni strati on r oute i nfl uences the quanti ty gi ven and the
rate at whi ch the dr ug i s absor bed and di str i buted. These var i abl es
affect the dr ugs acti on and the pati ents r esponse.
Routes of admi ni strati on i ncl ude:

buccal, sublingual, tr anslingual: cer tai n dr ugs ar e gi ven buccal l y

(i n the pouch between the cheek and gum), subl i ngual l y (under
the tongue), or transl i ngual l y (on the tongue) to speed thei r
absor pti on or to pr event thei r destr ucti on or transfor mati on i n
the stomach or smal l i ntesti ne
gastr ic: thi s r oute al l ows di r ect i nsti l l ati on of medi cati on i nto
the G I system of pati ents who cant i ngest the dr ug oral l y
intr ader mal: substances ar e i njected i nto the ski n (der mi s); thi s
r oute i s used mai nl y for di agnosti c pur poses when testi ng for
al l er gi es or tuber cul osi s
intr amuscular : thi s r oute al l ows dr ugs to be i njected di r ectl y i nto
var i ous muscl e gr oups at var yi ng ti ssue depths; i ts used to gi ve
aqueous suspensi ons and sol uti ons i n oi l , i mmuni z ati ons, and
medi cati ons that ar ent avai l abl e i n oral for m

Streaming in
intr avenous: the I.V. r oute al l ows i njecti on of substances (dr ugs,
fl ui ds, bl ood or bl ood pr oducts, and di agnosti c contrast agents)
di r ectl y i nto the bl oodstr eam thr ough a vei n; admi ni strati on can
range fr om a si ngl e dose to an ongoi ng i nfusi on del i ver ed wi th
gr eat pr eci si on
or al: thi s i s usual l y the safest, most conveni ent, and l east
expensi ve r oute; dr ugs ar e admi ni ster ed to pati ents who ar e
consci ous and can swal l ow
r ectal and vaginal: supposi tor i es, oi ntments, cr eams, gel s, and
tabl ets may be i nsti l l ed i nto the r ectum or vagi na to tr eat l ocal
i r r i tati on or i nfecti on; some dr ugs appl i ed to the mucosa of the
r ectum or vagi na can be absor bed systemi cal l y
r espir ator y: dr ugs that ar e avai l abl e as gases can be
 admi ni ster ed i nto the r espi rator y system; dr ugs gi ven by
i nhal ati on ar e rapi dl y absor bed, and medi cati ons gi ven by such
devi ces as the meter ed-dose i nhal er can be sel f-admi ni ster ed, or
dr ugs can be admi ni ster ed di r ectl y i nto the l ungs thr ough an
endotracheal tube i n emer gency si tuati ons
subcutaneous (subQ): wi th the subQ r oute, smal l amounts of a
dr ug ar e i njected beneath the der mi s and i nto the subcutaneous
ti ssue, usual l y i n the pati ents upper ar m, thi gh, or abdomen
topical: thi s r oute i s used to del i ver a dr ug thr ough the ski n or a
mucous membrane; i ts used for most der matol ogi c, ophthal mi c,
oti c, and nasal pr eparati ons.

Dr ugs may al so be gi ven as speci al i zed i nfusi ons i njected di r ectl y

i nto a speci fi c si te i n the pati ents body, such as an epi dural
i nfusi on (i nto the epi dural space), i ntrathecal i nfusi on (i nto the
cer ebr ospi nal fl ui d), i ntrapl eural i nfusi on (i nto the pl eural cavi ty),
i ntraper i toneal i nfusi on (i nto the per i toneal cavi ty), i ntraosseous
i nfusi on (i nto the r i ch vascul ar networ k of a l ong bone), and i ntra-
ar ti cul ar i nfusi on (i nto a joi nt).

New drug development

In the past, dr ugs wer e found by tr i al and er r or. Now theyr e
devel oped pr i mar i l y by systemati c sci enti fi c r esear ch. The Food and
Dr ug Admi ni strati on (F DA) car eful l y moni tor s new dr ug
devel opment, whi ch can take many year s to compl ete.
Onl y after r evi ewi ng extensi ve ani mal studi es and data on the
safety and effecti veness of the pr oposed dr ug wi l l the F DA appr ove
an appl i cati on for an i nvesti gati onal new dr ug (IND). (See Phases of
new dr ug devel opment, page 6.)

Phases of new drug development

When the Food and Dr ug Admi ni strati on (F DA) appr oves the
appl i cati on for an i nvesti gati onal new dr ug, the dr ug must
under go cl i ni cal eval uati on i nvol vi ng human subjects. Thi s cl i ni cal
eval uati on i s di vi ded i nto four phases:
Phase I
The dr ug i s tested on heal thy vol unteer s i n phase I.
Phase II
Phase II i nvol ves tr i al s wi th peopl e who have the di sease for
 whi ch the dr ug i s thought to be effecti ve.
Phase III
Lar ge number s of pati ents i n medi cal r esear ch center s r ecei ve the
dr ug i n phase III. Thi s l ar ger sampl i ng pr ovi des i nfor mati on about
i nfr equent or rar e adver se effects. The F DA wi l l appr ove a new
dr ug appl i cati on i f phase III studi es ar e sati sfactor y.
Phase IV
Phase IV i s vol untar y and i nvol ves postmar ket sur vei l l ance of the
dr ugs therapeuti c effects at the compl eti on of phase III. The
phar maceuti cal company r ecei ves r epor ts fr om doctor s and other
heal th car e pr ofessi onal s about the therapeuti c r esul ts and
adver se effects of the dr ug. Some medi cati ons, for exampl e, have
been found to be toxi c and have been r emoved fr om the mar ket
after thei r i ni ti al r el ease.

Exceptions to the rule

Al though most INDs under go al l four phases of cl i ni cal eval uati on
mandated by the F DA, some can r ecei ve expedi ted appr oval . For
exampl e, because of the publ i c heal th thr eat posed by acqui r ed
i mmunodefi ci ency syndr ome (AIDS), the F DA and dr ug compani es
have agr eed to shor ten the IND appr oval pr ocess for dr ugs to tr eat
the di sease. Thi s al l ows doctor s to gi ve qual i fi ed AIDS pati ents
tr eatment INDs, whi ch ar ent yet appr oved by the F DA.
Sponsor s of dr ugs that r each phase II or III cl i ni cal tr i al s can appl y
for F DA appr oval of tr eatment IND status. When the IND i s
appr oved, the sponsor suppl i es the dr ug to doctor s whose pati ents
meet appr opr i ate cr i ter i a.
Despi te the extensi ve testi ng and devel opment that al l dr ugs go
thr ough, ser i ous adver se r eacti ons may occasi onal l y occur, even
though they wer ent di scover ed dur i ng cl i ni cal tr i al s. Its al so
possi bl e that dr ug i nteracti ons ar ent di scover ed unti l after cl i ni cal
tr i al s have concl uded and the dr ug has been appr oved. The F DA has
pr ocedur es i n pl ace for r epor ti ng adver se events and other pr obl ems
to hel p track the safety of dr ugs. (See Repor ti ng to the F DA.)

Safe and sound

Reporting to the FDA
The Food and Dr ug Admi ni strati on (F DA) compi l es and
tracks i nfor mati on r el ated to pr obl ems associ ated wi th dr ugs
 under i ts r egul ati on. Compl ete a MedWatch for m and send i t to
the F DA i f you suspect an F DA-r egul ated dr ug i s r esponsi bl e for a
pati ents:

death
l i fe-thr eateni ng i l l ness
pr ol onged or i ni ti al hospi tal i z ati on
di sabi l i ty
congeni tal anomal y
need for medi cal or sur gi cal i nter venti on to pr event a
per manent i mpai r ment.

Pharmacokinetics
Ki neti cs r efer s to movement. Phar macoki neti cs deal s wi th a dr ugs
acti ons as i t moves thr ough the body. Ther efor e, phar macoki neti cs
di scusses how a dr ug i s:

absor bed (taken i nto the body)

di str i buted (moved i nto var i ous ti ssues)
metabol i zed (changed i nto a for m that can be excr eted)
excr eted (r emoved fr om the body).

Thi s branch of phar macol ogy i s al so concer ned wi th a dr ugs onset

of acti on, peak concentrati on l evel , and durati on of acti on.

Absorption
Dr ug absor pti on cover s a dr ugs pr ogr ess fr om the ti me i ts
admi ni ster ed, thr ough i ts passage to the ti ssues, unti l i t r eaches
systemi c ci r cul ati on.
On a cel l ul ar l evel , dr ugs ar e absor bed by several meanspr i mar i l y
thr ough acti ve or passi ve transpor t.
The lazy way
Passive tr anspor t r equi r es no cel l ul ar ener gy because di ffusi on
al l ows the dr ug to move fr om an ar ea of hi gher concentrati on to one
of l ower concentrati on. Passi ve transpor t occur s when smal l
mol ecul es di ffuse acr oss membranes and stops when dr ug
concentrati on on both si des of the membrane i s equal .

Using muscle
Active tr anspor t r equi r es cel l ul ar ener gy to move the dr ug fr om an
ar ea of l ower concentrati on to one of hi gher concentrati on. Acti ve
transpor t i s used to absor b el ectr ol ytes, such as sodi um and
potassi um, as wel l as some dr ugs such as l evodopa.
Taking a bite
Pinocytosis i s a uni que for m of acti ve transpor t that occur s when a
cel l engul fs a dr ug par ti cl e. Pi nocytosi s i s commonl y empl oyed to
transpor t fat-sol ubl e vi tami ns (vi tami ns A, D, E, and K).

Watch the speed limit!

If onl y a few cel l s separate the acti ve dr ug fr om the systemi c
ci r cul ati on, absor pti on wi l l occur rapi dl y and the dr ug wi l l qui ckl y
r each therapeuti c l evel s i n the body. Typi cal l y, absor pti on occur s
wi thi n seconds or mi nutes when a dr ug i s admi ni ster ed subl i ngual l y,
I.V., or by i nhal ati on.

Not so fast
Absor pti on occur s at a sl ower rate when dr ugs ar e admi ni ster ed by
the oral , I.M., or subQ r outes because the compl ex membrane
systems of G I mucosal l ayer s, muscl e, and ski n del ay dr ug passage.

At a snails pace
At the sl owest absor pti on rates, dr ugs can take several hour s or
days to r each peak concentrati on l evel s. A sl ow rate usual l y occur s
wi th r ectal l y admi ni ster ed or sustai ned-r el ease dr ugs.

Not enough time

Other factor s can affect how qui ckl y a dr ug i s absor bed. For
exampl e, most absor pti on of oral dr ugs occur s i n the smal l
i ntesti ne. If a pati ent has had l ar ge secti ons of the smal l i ntesti ne
sur gi cal l y r emoved, dr ug absor pti on decr eases because of the
r educed sur face ar ea and the r educed ti me that the dr ug i s i n the
i ntesti ne.

Look to the liver

Dr ugs absor bed by the smal l i ntesti ne ar e transpor ted to the l i ver
befor e bei ng ci r cul ated to the r est of the body. The l i ver may
metabol i ze much of the dr ug befor e i t enter s the ci r cul ati on. Thi s
mechani sm i s r efer r ed to as the fir st-pass effect. Li ver metabol i sm
may i nacti vate the dr ug; i f so, the fi r st-pass effect l ower s the
amount of acti ve dr ug r el eased i nto the systemi c ci r cul ati on.
Ther efor e, hi gher dr ug dosages must be admi ni ster ed to achi eve the
desi r ed effect.

More blood, more absorption

Incr eased bl ood fl ow to an absor pti on si te i mpr oves dr ug absor pti on,
wher eas r educed bl ood fl ow decr eases absor pti on. Mor e rapi d
absor pti on l eads to a qui cker onset of dr ug acti on.
For exampl e, the muscl e ar ea sel ected for I.M. admi ni strati on can
make a di ffer ence i n the dr ug absor pti on rate. Bl ood fl ows faster
thr ough the del toi d muscl e (i n the upper ar m) than thr ough the
gl uteal muscl e (i n the buttocks). The gl uteal muscl e, however, can
accommodate a l ar ger vol ume of dr ug than the del toi d muscl e.

Slowed by pain and stress

Pai n and str ess can decr ease the amount of dr ug absor bed. Thi s may
be due to a change i n bl ood fl ow, r educed movement thr ough the G I
tract, or gastr i c r etenti on tr i gger ed by the autonomi c ner vous
system r esponse to pai n.

High fat doesnt help

Hi gh-fat meal s and sol i d foods sl ow the rate at whi ch contents l eave
the stomach and enter the i ntesti nes, del ayi ng i ntesti nal absor pti on
of a dr ug.

Dosage form factors

Dr ug for mul ati on (such as tabl ets, capsul es, l i qui ds, sustai ned-
r el ease for mul as, i nacti ve i ngr edi ents, and coati ngs) affects the
dr ug absor pti on rate and the ti me needed to r each peak bl ood
concentrati on l evel s.

Absorption increase or decrease?

Combi ni ng one dr ug wi th another dr ug, or wi th food, can cause
i nteracti ons that i ncr ease or decr ease dr ug absor pti on, dependi ng
on the substances i nvol ved.

Distribution
Dr ug di str i buti on i s the pr ocess by whi ch the dr ug i s del i ver ed fr om
the systemi c ci r cul ati on to body ti ssues and fl ui ds. Di str i buti on of
an absor bed dr ug wi thi n the body depends on several factor s:

bl ood fl ow
sol ubi l i ty
pr otei n bi ndi ng.

Quick to the heart

After a dr ug has r eached the bl oodstr eam, i ts di str i buti on i n the
body depends on bl ood fl ow. The dr ug i s qui ckl y di str i buted to
or gans wi th a l ar ge suppl y of bl ood. These or gans i ncl ude the:

hear t
l i ver
ki dneys.

Di str i buti on to other i nter nal or gans, ski n, fat, and muscl e i s
sl ower.

Lucky lipids
The abi l i ty of a dr ug to cr oss a cel l membrane depends on whether
the dr ug i s water or l i pi d (fat) sol ubl e. Li pi d-sol ubl e dr ugs easi l y
cr oss thr ough cel l membranes; water-sol ubl e dr ugs cant.
Li pi d-sol ubl e dr ugs can al so cr oss the bl ood-brai n bar r i er and enter
the brai n.

Free to work
As a dr ug travel s thr ough the body, i t comes i n contact wi th
pr otei ns such as the pl asma pr otei n al bumi n. The dr ug can r emai n
fr ee or bi nd to the pr otei n. The por ti on of a dr ug thats bound to a
pr otei n i s i nacti ve and cant exer t a therapeuti c effect. Onl y the
fr ee, or unbound, por ti on r emai ns acti ve.
A dr ug i s sai d to be hi ghl y pr otei n-bound i f mor e than 80% of the
dr ug i s bound to pr otei n.

Metabolism
Dr ug metabol i sm, or bi otransfor mati on, i s the pr ocess by whi ch the
body changes a dr ug fr om i ts dosage for m to a mor e water-sol ubl e
for m that can then be excr eted. Dr ugs can be metabol i zed i n several
ways:

Most dr ugs ar e metabol i zed i nto i nacti ve metabol i tes (pr oducts
of metabol i sm), whi ch ar e then excr eted.
Other dr ugs ar e conver ted to acti ve metabol i tes, whi ch ar e
 capabl e of exer ti ng thei r own phar macol ogi c acti on. Acti ve
metabol i tes may under go fur ther metabol i sm or may be excr eted
fr om the body unchanged.
Some dr ugs can be admi ni ster ed as i nacti ve dr ugs, cal l ed
pr odr ugs, whi ch dont become acti ve unti l theyr e metabol i zed.

Where metabolism happens

The major i ty of dr ugs ar e metabol i zed by enz ymes i n the l i ver ;
however, metabol i sm can al so occur i n the pl asma, ki dneys, and
membranes of the i ntesti nes. In contrast, some dr ugs i nhi bi t or
compete for enz yme metabol i sm, whi ch can cause the accumul ati on
of dr ugs when theyr e gi ven together. Thi s accumul ati on i ncr eases
the potenti al for an adver se r eacti on or dr ug toxi ci ty.

Conditional considerations
Cer tai n di seases can r educe metabol i sm. These i ncl ude l i ver
di seases such as ci r r hosi s as wel l as hear t fai l ur e, whi ch r educes
ci r cul ati on to the l i ver.

Gene machine
G eneti cs al l ows some peopl e to metabol i ze dr ugs rapi dl y and other s
to metabol i ze them mor e sl owl y.

Stress test
Envi r onment, too, can al ter dr ug metabol i sm. For exampl e, ci gar ette
smoke may affect the rate of metabol i sm of some dr ugs; a str essful
si tuati on or event, such as pr ol onged i l l ness, sur ger y, or i njur y, can
al so change how a per son metabol i zes dr ugs.

The age game

Devel opmental changes can al so affect dr ug metabol i sm. For
i nstance, i nfants have i mmatur e l i ver s that r educe the rate of
metabol i sm, and el der l y pati ents exper i ence a decl i ne i n l i ver si ze,
bl ood fl ow, and enz yme pr oducti on that al so sl ows metabol i sm.

Excretion
Dr ug excr eti on r efer s to the el i mi nati on of dr ugs fr om the body.
Most dr ugs ar e excr eted by the ki dneys and l eave the body thr ough
ur i ne. Dr ugs can al so be excr eted thr ough the l ungs, exocr i ne
(sweat, sal i var y, or mammar y) gl ands, ski n, and i ntesti nal tract.

Half-life = half the drug

The hal f-l i fe of a dr ug i s the ti me i t takes for one-hal f of the dr ug
to be el i mi nated by the body. Factor s that affect a dr ugs hal f-l i fe
i ncl ude i ts rate of absor pti on, metabol i sm, and excr eti on. Knowi ng
how l ong a dr ug r emai ns i n the body hel ps deter mi ne how
fr equentl y i t shoul d be admi ni ster ed.
A dr ug thats gi ven onl y once i s el i mi nated fr om the body al most
compl etel y after four or fi ve hal f-l i ves. A dr ug thats admi ni ster ed
at r egul ar i nter val s, however, r eaches a steady concentrati on (or
steady state) after about four or fi ve hal f-l i ves. Steady state occur s
when the rate of dr ug admi ni strati on equal s the rate of dr ug
excr eti on.

Onset, peak, and duration

In addi ti on to absor pti on, di str i buti on, metabol i sm, and excr eti on,
thr ee other factor s pl ay i mpor tant r ol es i n a dr ugs
phar macoki neti cs:

onset of acti on
peak concentrati on
durati on of acti on.

Lights, camera action!

The onset of acti on r efer s to the ti me i nter val fr om when the dr ug
i s admi ni ster ed to when i ts therapeuti c effect actual l y begi ns. Rate
of onset var i es dependi ng on the r oute of admi ni strati on and other
phar macoki neti c pr oper ti es.

Peak performance
As the body absor bs mor e dr ug, bl ood concentrati on l evel s r i se. The
peak concentrati on l evel i s r eached when the absor pti on rate

equal s the el i mi nati on rate. However, the ti me of peak

concentrati on i snt al ways the ti me of peak r esponse.

Sticking around
The durati on of acti on i s the l ength of ti me the dr ug pr oduces i ts
therapeuti c effect.

Pharmacodynamics
Phar macodynami cs i s the study of the dr ug mechani sms that
pr oduce bi ochemi cal or physi ol ogi c changes i n the body. The
i nteracti on at the cel l ul ar l evel between a dr ug and cel l ul ar
components, such as the compl ex pr otei ns that make up the cel l
membrane, enz ymes, or tar get r eceptor s, r epr esents dr ug acti on.
The r esponse r esul ti ng fr om thi s dr ug acti on i s the dr ug effect.

Its the cell that matters

A dr ug can modi fy cel l functi on or rate of functi on, but i t cant
i mpar t a new functi on to a cel l or to tar get ti ssue. Ther efor e, the
dr ug effect depends on what the cel l i s capabl e of accompl i shi ng.
A dr ug can al ter the tar get cel l s functi on by:

modi fyi ng the cel l s physi cal or chemi cal envi r onment
i nteracti ng wi th a r eceptor (a speci al i zed l ocati on on a cel l
membrane or i nsi de a cel l ).

Agonist drugs
Many dr ugs wor k by sti mul ati ng or bl ocki ng dr ug r eceptor s. A dr ug
attracted to a r eceptor di spl ays an affi ni ty for that r eceptor. When a
dr ug di spl ays an affi ni ty for a r eceptor and sti mul ates i t, the dr ug
acts as an agonist. An agoni st bi nds to the r eceptor and pr oduces a
r esponse. Thi s abi l i ty to i ni ti ate a r esponse after bi ndi ng wi th the
r eceptor i s r efer r ed to as intr insic activity.

Antagonist drugs
If a dr ug has an affi ni ty for a r eceptor but di spl ays l i ttl e or no
i ntr i nsi c acti vi ty, i ts cal l ed an antagonist. An antagoni st pr events a
r esponse fr om occur r i ng.

Reversible or irreversible
Antagoni sts can be competi ti ve or noncompeti ti ve.

A competitive antagonist competes wi th the agoni st for r eceptor

si tes. Because thi s type of antagoni st bi nds r ever si bl y to the
r eceptor si te, admi ni ster i ng l ar ger doses of an agoni st can
over come the antagoni sts effects.

A noncompetitive antagonist bi nds to r eceptor si tes and bl ocks

the effects of the agoni st. Admi ni ster i ng l ar ger doses of the
agoni st cant r ever se the antagoni sts acti on.

Regarding receptors
If a dr ug acts on a var i ety of r eceptor s, i ts sai d to be nonsel ecti ve
and can cause mul ti pl e and wi despr ead effects. In addi ti on, some
r eceptor s ar e cl assi fi ed fur ther by thei r speci fi c effects. For
exampl e, beta r eceptor s typi cal l y pr oduce i ncr eased hear t rate and
br onchi al r el axati on as wel l as other systemi c effects.
Beta r eceptor s, however, can be fur ther di vi ded i nto beta1 r eceptor s
(whi ch act pr i mar i l y on the hear t) and beta2 r eceptor s (whi ch act
pr i mar i l y on smooth muscl es and gl and cel l s).
Potent power
Dr ug potency r efer s to the r el ati ve amount of a dr ug r equi r ed to
pr oduce a desi r ed r esponse. Dr ug potency i s al so used to compar e
two dr ugs. If dr ug X pr oduces the same r esponse as dr ug Y but at a
l ower dose, then dr ug X i s mor e potent than dr ug Y.
As i ts name i mpl i es, a dose-r esponse cur ve i s used to graphi cal l y
r epr esent the r el ati onshi p between the dose of a dr ug and the
r esponse i t pr oduces. (See Dose-r esponse cur ve, page 14.)

Maximum effect
On the dose-r esponse cur ve, a l ow dose usual l y cor r esponds to a
l ow r esponse. At a l ow dose, a dosage i ncr ease pr oduces onl y a
sl i ght i ncr ease i n r esponse. Wi th fur ther dosage i ncr eases, the dr ug
r esponse r i ses mar kedl y. After a cer tai n poi nt, however, an i ncr ease
i n dose yi el ds l i ttl e or no i ncr ease i n r esponse. At thi s poi nt, the
dr ug i s sai d to have r eached maxi mum effecti veness.

Margin of safety
Most dr ugs pr oduce mul ti pl e effects. The r el ati onshi p between a
dr ugs desi r ed therapeuti c effects and i ts adver se effects i s cal l ed
the dr ugs ther apeutic index. Its al so r efer r ed to as i ts mar gin of
safety.
The therapeuti c i ndex usual l y measur es the di ffer ence between:
 an effecti ve dose for 50% of the pati ents tr eated
the mi ni mal dose at whi ch adver se r eacti ons occur.

Narrow index = potential danger

Dr ugs wi th a nar r ow, or l ow, therapeuti c i ndex have a nar r ow
mar gi n of safety. Thi s means that ther es a nar r ow range of safety
between an effecti ve dose and a l ethal one. On the other hand, a
dr ug wi th a hi gh therapeuti c i ndex has a wi de mar gi n of safety and
poses l ess r i sk of toxi c effects.

Now I get it!

Dose-response curve
Thi s graph shows the dose-r esponse cur ve for two di ffer ent
dr ugs. As you can see, at l ow doses of each dr ug, a dosage
i ncr ease r esul ts i n onl y a smal l i ncr ease i n dr ug r esponse (for
exampl e, fr om poi nt A to poi nt B for dr ug X). At hi gher doses, an
i ncr ease i n dosage pr oduces a much gr eater r esponse (fr om poi nt
B to poi nt C). As the dosage conti nues to cl i mb, however, an
i ncr ease i n dosage pr oduces ver y l i ttl e i ncr ease i n r esponse (fr om
poi nt C to poi nt D).
Thi s graph al so shows that dr ug X i s mor e potent than dr ug Y
because i t pr oduces the same r esponse, but at a l ower dose
(compar e poi nt A to poi nt E).
Pharmacotherapeutics
Phar macotherapeuti cs i s the use of dr ugs to tr eat di sease. When
choosi ng a dr ug to tr eat a par ti cul ar condi ti on, heal th car e
pr ovi der s consi der not onl y the dr ugs effecti veness but al so other
factor s such as the type of therapy the pati ent wi l l r ecei ve.

Not all therapy is the same

The type of therapy a pati ent r ecei ves depends on the sever i ty,
ur gency, and pr ognosi s of the pati ents condi ti on and can i ncl ude:

acute ther apy, i f the pati ent i s cr i ti cal l y i l l and r equi r es acute
i ntensi ve therapy
empir ic ther apy, based on practi cal exper i ence rather than on
pur e sci enti fi c data
maintenance ther apy, for pati ents wi th chr oni c condi ti ons that
dont r esol ve

supplemental or r eplacement ther apy, to r epl eni sh or substi tute

for mi ssi ng substances i n the body
suppor tive ther apy, whi ch doesnt tr eat the cause of the di sease
but mai ntai ns other thr eatened body systems unti l the pati ents
condi ti on r esol ves
palliative ther apy, used for end-stage or ter mi nal di seases to
make the pati ent as comfor tabl e as possi bl e.

I can only be myself

A pati ents overal l heal th as wel l as other i ndi vi dual factor s can
al ter that pati ents r esponse to a dr ug. Coi nci di ng medi cal
condi ti ons and per sonal l i festyl e character i sti cs must be consi der ed
when sel ecti ng dr ug therapy. (See Factor s affecti ng a pati ents
r esponse to a dr ug.)

Decreased response
In addi ti on, i ts i mpor tant to r emember that cer tai n dr ugs have a
tendency to cr eate dr ug tol erance and dr ug dependence i n pati ents.
Dr ug toler ance occur s when a pati ent devel ops a decr eased r esponse
to a dr ug over ti me. The pati ent then r equi r es l ar ger doses to
pr oduce the same r esponse.

and increased desire

Tol erance di ffer s fr om dr ug dependence, i n whi ch a pati ent di spl ays
a physi cal or psychol ogi cal need for the dr ug. Physi cal dependence
pr oduces wi thdrawal symptoms when the dr ug i s stopped, wher eas
psychol ogi cal dependence i s based on a desi r e to conti nue taki ng
the dr ug to r el i eve tensi on and avoi d di scomfor t.

Now I get it!

Factors affecting a patients response to a drug
Because no two peopl e ar e al i ke physi ol ogi cal l y or
psychol ogi cal l y, pati ent r esponse to a dr ug can var y gr eatl y,
dependi ng upon such factor s as:

age
car di ovascul ar functi on
di et
di sease
dr ug i nteracti ons
gender
G I functi on
hepati c functi on
i nfecti on
r enal functi on.

Drug interactions
Dr ug i nteracti ons can occur between dr ugs or between dr ugs and
foods. They can i nter fer e wi th the r esul ts of a l aborator y test or
pr oduce physi cal or chemi cal i ncompati bi l i ti es. The mor e dr ugs a
pati ent r ecei ves, the gr eater the chances that a dr ug i nteracti on
wi l l occur.
Potenti al dr ug i nteracti ons i ncl ude:

addi ti ve effects
potenti ati on
 antagoni sti c effects
decr eased or i ncr eased absor pti on
decr eased or i ncr eased metabol i sm and excr eti on.

Memory jogger
When a dr ug i s sai d to be potentiated by another dr ug, the
r esul ts ar e mor e potentthe dr ug goes beyond i ts or i gi nal
potenti al .

Adding it all up
Additive effects can occur when two dr ugs wi th si mi l ar acti ons ar e
admi ni ster ed to a pati ent. The effects ar e equi val ent to the sum of
ei ther dr ugs effects i f i t wer e admi ni ster ed al one i n hi gher doses.
G i vi ng two dr ugs together, such as two anal gesi cs (pai n r el i ever s),
has several potenti al advantages: l ower doses of each dr ug,
decr eased pr obabi l i ty of adver se r eacti ons, and gr eater pai n contr ol
than fr om one dr ug gi ven al one (most l i kel y because of di ffer ent
mechani sms of acti on). Ther es a decr eased r i sk of adver se effects
when gi vi ng two dr ugs for the same condi ti on because the pati ent i s
gi ven l ower doses of each dr ugthe hi gher the dose, the gr eater the
r i sk of adver se effects.

A synergistic situation
A syner gi sti c effect, al so cal l ed potentiation, occur s when two dr ugs
that pr oduce the same effect ar e gi ven together and one dr ug
potenti ates (enhances the effect of ) the other dr ug. Thi s pr oduces
gr eater effects than when each dr ug i s taken al one.

Fighting it out
An antagonistic effect occur s when the combi ned r esponse of two
dr ugs i s l ess than the r esponse pr oduced by ei ther dr ug al one.

An absorbing problem
Two dr ugs gi ven together can change the absor pti on of one or both
of the dr ugs:
 Dr ugs that change the aci di ty of the stomach can affect the
abi l i ty of another dr ug to di ssol ve i n the stomach.
Some dr ugs can i nteract and for m an i nsol ubl e compound that
cant be absor bed.

Someti mes, an absor pti on-r el ated dr ug i nteracti on can be avoi ded
by admi ni ster i ng the dr ugs at l east 2 hour s apar t.

Bound and determined

After a dr ug i s absor bed, the bl ood di str i butes i t thr oughout the
body as a fr ee dr ug or one thats bound to pl asma pr otei n.
When two dr ugs ar e gi ven together, they can compete for pr otei n-
bi ndi ng si tes, l eadi ng to an i ncr ease i n the effects of one dr ug as
that dr ug i s di spl aced fr om the pr otei n and becomes a fr ee, unbound
dr ug.

Toxic waste
Toxi c dr ug l evel s can occur when a dr ugs metabol i sm and excr eti on
ar e i nhi bi ted by another dr ug. Some dr ug i nteracti ons affect
excr eti on onl y.

Back to the lab

Dr ug i nteracti ons can al so al ter l aborator y tests and can pr oduce
changes seen on a pati ents el ectr ocar di ogram.
Menu planning
Interacti ons between dr ugs and food can al ter the therapeuti c
effects of the dr ug. Food can al so al ter the rate and amount of dr ug
absor bed fr om the G I tract, affecti ng bi oavai l abi l i tythe amount of a
dr ug dose thats made avai l abl e to the systemi c ci r cul ati on. Dr ugs
can al so i mpai r vi tami n and mi neral absor pti on.
Some dr ugs sti mul ate enz yme pr oducti on, i ncr easi ng metabol i c
rates and the demand for vi tami ns that ar e enz yme cofactor s (whi ch
must uni te wi th the enz yme i n or der for the enz yme to functi on).
Danger ous i nteracti ons can al so occur. For i nstance, when food that
contai ns Vi tami n K (such as gr een, l eafy vegetabl es) i s eaten by a
per son taki ng war far i n, the dr ugs anti coagul ati on pr oper ti es ar e
decr eased and bl ood cl ots may for m.
G rapefr ui t can i nhi bi t the metabol i sm of cer tai n medi cati ons,
r esul ti ng i n toxi c bl ood l evel s; exampl es i ncl ude fexofenadi ne,
al bendazol e, and ator vastati n. Because of al l the i nteracti ons food
can have wi th dr ug metabol i sm, bei ng awar e of dr ug i nteracti ons i s
essenti al .

Adverse drug reactions

A dr ugs desi r ed effect i s cal l ed the expected ther apeutic r esponse.
An adver se dr ug r eacti on (al so cal l ed a side effect or adver se
effect), on the other hand, i s a har mful , undesi rabl e r esponse.
Adver se dr ug r eacti ons can range fr om mi l d ones that di sappear
when the dr ug i s di sconti nued to debi l i tati ng di seases that become
chr oni c. Adver se r eacti ons can appear shor tl y after star ti ng a new
medi cati on but may become l ess sever e wi th ti me.

Dosage dilemma
Adver se dr ug r eacti ons can be cl assi fi ed as dose-r el ated or pati ent
sensi ti vi tyr el ated. Most adver se dr ug r eacti ons r esul t fr om the
known phar macol ogi c effects of a dr ug and ar e typi cal l y dose-
r el ated. These types of r eacti ons can be pr edi cted i n most cases.
Dose-r el ated r eacti ons i ncl ude:

secondar y effects
hyper suscepti bi l i ty
over dose
i atr ogeni c effects.

Extra effects
A dr ug typi cal l y pr oduces not onl y a major therapeuti c effect but
al so addi ti onal , secondar y effects that can be har mful or benefi ci al .
For exampl e, mor phi ne used for pai n contr ol can l ead to two
undesi rabl e secondar y effects: consti pati on and r espi rator y
depr essi on. Di phenhydrami ne used as an anti hi stami ne pr oduces
sedati on as a secondar y effect and i s someti mes used as a sl eep ai d.
Enhanced action
A pati ent can be hyper suscepti bl e to the phar macol ogi c acti ons of a
dr ug. Such a pati ent exper i ences an excessi ve therapeuti c r esponse
or secondar y effects even when gi ven the usual therapeuti c dose.
Hyper suscepti bi l i ty typi cal l y r esul ts fr om al ter ed phar macoki neti cs
(absor pti on, metabol i sm, and excr eti on), whi ch l eads to hi gher-
than-expected bl ood concentrati on l evel s. Incr eased r eceptor
sensi ti vi ty al so can i ncr ease the pati ents r esponse to therapeuti c or
adver se effects.

Oh nooverdose!
A toxi c dr ug r eacti on can occur when an excessi ve dose i s taken,
ei ther i ntenti onal l y or by acci dent. The r esul t i s an exaggerated
r esponse to the dr ug that can l ead to transi ent changes or mor e
ser i ous r eacti ons, such as r espi rator y depr essi on, car di ovascul ar
col l apse, and even death. To avoi d toxi c r eacti ons, chr oni cal l y i l l or
el der l y pati ents often r ecei ve l ower dr ug doses.

Iatrogenic issues
Some adver se dr ug r eacti ons, known as i atr ogeni c effects, can
mi mi c pathol ogi c di sor der s. For exampl e, such dr ugs as
anti neopl asti cs, aspi r i n, cor ti coster oi ds, and i ndomethaci n
commonl y cause G I i r r i tati on and bl eedi ng. Other exampl es of
i atr ogeni c effects i ncl ude i nduced asthma wi th pr opranol ol , i nduced
nephr i ti s wi th methi ci l l i n, and i nduced deafness wi th gentami ci n.
Youre so sensitive
Pati ent sensi ti vi tyr el ated adver se r eacti ons ar ent as common as
dose-r el ated r eacti ons. Sensi ti vi ty-r el ated r eacti ons r esul t fr om a
pati ents unusual and extr eme sensi ti vi ty to a dr ug. These adver se
r eacti ons ar i se fr om a uni que ti ssue r esponse rather than fr om an
exaggerated phar macol ogi c acti on. Extr eme pati ent sensi ti vi ty can
occur as a dr ug al l er gy or an i di osyncrati c r esponse.

Friend or foe?
A dr ug al l er gy occur s when a pati ents i mmune system i denti fi es a
dr ug, a dr ug metabol i te, or a dr ug contami nant as a danger ous

for ei gn substance that must be neutral i zed or destr oyed. Pr evi ous
exposur e to the dr ug or to one wi th si mi l ar chemi cal character i sti cs
sensi ti zes the pati ents i mmune system, and subsequent exposur e
causes an al l er gi c r eacti on (hyper sensi ti vi ty).
An al l er gi c r eacti on not onl y di r ectl y i njur es cel l s and ti ssues but
al so pr oduces br oader systemi c damage by i ni ti ati ng cel l ul ar r el ease
of vasoacti ve and i nfl ammator y substances.
The al l er gi c r eacti on can var y i n i ntensi ty fr om an i mmedi ate, l i fe-
thr eateni ng anaphyl acti c r eacti on wi th ci r cul ator y col l apse and
swel l i ng of the l ar ynx and br onchi ol es to a mi l d r eacti on wi th a rash
and i tchi ng.

Idiosyncratic response
Some sensi ti vi ty-r el ated adver se r eacti ons dont r esul t fr om
phar macol ogi c pr oper ti es of a dr ug or fr om an al l er gy but ar e
speci fi c to the i ndi vi dual pati ent. These ar e cal l ed idiosyncr atic
r esponses. Some i di osyncrati c r esponses have a geneti c cause.

Quick quiz
1Whi l e teachi ng a pati ent about dr ug therapy for
di abetes, you r evi ew the absor pti on, di str i buti on,
metabol i sm, and excr eti on of i nsul i n and oral
anti di abeti c agents. Whi ch pr i nci pl e of phar macol ogy
ar e you descr i bi ng?
A. Phar macoki neti cs
B. Phar macodynami cs
C. Phar macotherapeuti cs
D. Dr ug potency

2Whi ch type of dr ug therapy i s used for a pati ent who has a

chr oni c condi ti on that cant be cur ed?
A. Empi r i c therapy
B. Acute therapy
C. Mai ntenance therapy
D. Suppl emental therapy

P.
3Whi ch branch of phar macol ogy studi es the way dr ugs wor k i n
l i vi ng or gani sms?
A. Phar macotherapeuti cs
B. Phar macoki neti cs
C. Dr ug i nteracti ons
D. Phar macodynami cs

Scoring
If you answer ed al l thr ee i tems cor r ectl y, excel l ent!
Youve absor bed thi s chapter i n a hur r y.

If you answer ed two i tems cor r ectl y, ter r i fi c! Youve

r eached therapeuti c l evel s of thi s chapter i n a fl ash.

If you answer ed fewer than two i tems cor r ectl y, no need

for concer n. Someti mes food enhances absor pti onso grab
a qui ck snack and come back for a r evi ew.

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

2
Autonomic nervous system drugs

Just the facts

In thi s chapter, youl l r evi ew:

cl asses of dr ugs that affect the autonomi c ner vous system

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se effects of these dr ugs.

Cholinergic drugs
Choliner gic dr ugs pr omote the acti on of the neur otransmi tter
acetylcholine. These dr ugs ar e al so cal l ed par asympathomimetic
dr ugs because they pr oduce effects that i mi tate parasympatheti c
ner ve sti mul ati on.

Mimickers and inhibitors

Ther e ar e two major cl asses of chol i ner gi c dr ugs:

Choliner gic agonists mi mi c the acti on of the neur otransmi tter

acetyl chol i ne.
Anticholinester ase dr ugs wor k by i nhi bi ti ng the destr ucti on of
acetyl chol i ne at the chol i ner gi c r eceptor si tes. (See How
 chol i ner gi c dr ugs wor k, page 22.)

Cholinergic agonists
By di r ectl y sti mul ati ng chol i ner gi c r eceptor s, chol i ner gi c agoni sts
mi mi c the acti on of the neur otransmi tter acetyl chol i ne.
They i ncl ude such dr ugs as:

Now I get it!

How cholinergic drugs work
Chol i ner gi c dr ugs fal l i nto one of two major cl asses:
chol i ner gi c agoni sts and anti chol i nesterase dr ugs. Her es how
these dr ugs achi eve thei r effects.
Cholinergic agonists
When a neur on i n the parasympatheti c ner vous system i s
sti mul ated, the neur otransmi tter acetyl chol i ne i s r el eased.
Acetyl chol i ne cr osses the synapse and i nteracts wi th r eceptor s i n
 an adjacent neur on. Chol i ner gi c agoni sts sti mul ate chol i ner gi c
r eceptor s, mi mi cki ng the acti on of acetyl chol i ne.

Anticholinesterase drugs
After acetyl chol i ne sti mul ates the chol i ner gi c r eceptor, i ts
destr oyed by the enz yme acetyl chol i nesterase. Anti chol i nesterase
dr ugs i nhi bi t acetyl chol i nesterase. As a r esul t, acetyl chol i ne i snt
br oken down and begi ns to accumul ate, l eadi ng to pr ol onged
acetyl chol i ne effects.

bethanechol
car bachol
cevi mel i ne
pi l ocar pi ne.

Pharmacokinetics (how drugs circulate)

The acti on and metabol i sm of chol i ner gi c agoni sts var y wi del y and
depend on the affi ni ty of the i ndi vi dual dr ug for muscar i ni c or
ni coti ni c r eceptor s.

No I.M. or I.V. injections

Chol i ner gi c agoni sts rar el y ar e admi ni ster ed by I.M. or I.V. i njecti on
because theyr e al most i mmedi atel y br oken down by chol i nesterases
i n the i nter sti ti al spaces between ti ssues and i nsi de the bl ood
vessel s. Mor eover, they begi n to wor k rapi dl y and can cause

a chol i ner gi c cr i si s (a dr ug over dose r esul ti ng i n extr eme muscl e

weakness and possi bl y paral ysi s of the muscl es used i n r espi rati on).

Topically, orally, or under the skin

Chol i ner gi c agoni sts ar e usual l y admi ni ster ed:

topi cal l y, wi th eye dr ops

oral l y
by subcutaneous (subQ) i njecti on.

SubQ i njecti ons begi n to wor k mor e rapi dl y than oral doses.

Metabolism and excretion

Al l chol i ner gi c agoni sts ar e metabol i zed by chol i nesterases:

at the muscar i ni c and ni coti ni c r eceptor si tes

i n the pl asma (the l i qui d por ti on of the bl ood)
i n the l i ver.
Al l dr ugs i n thi s cl ass ar e excr eted by the ki dneys.

Pharmacodynamics (how drugs act)

Chol i ner gi c agoni sts wor k by mi mi cki ng the acti on of acetyl chol i ne
on the neur ons i n cer tai n or gans of the body cal l ed tar get or gans.
When they combi ne wi th r eceptor s on the cel l membranes of tar get
or gans, they sti mul ate the muscl e and pr oduce:

sal i vati on
bradycar di a (a sl ow hear t rate)
di l ati on of bl ood vessel s
constr i cti on of the br onchi ol es
i ncr eased acti vi ty of the G I tract
i ncr eased tone and contracti on of the bl adder muscl es
constr i cti on of the pupi l s.

Pharmacotherapeutics (how drugs are used)

Chol i ner gi c agoni sts ar e used to:

tr eat atoni c (weak) bl adder condi ti ons and postoperati ve and

postpar tum ur i ne r etenti on
tr eat G I di sor der s, such as postoperati ve abdomi nal di stenti on
and G I atony
r educe eye pr essur e i n pati ents wi th gl aucoma and dur i ng eye
sur ger y
tr eat sal i var y gl and hypofuncti on caused by radi ati on therapy or
Sjgr ens syndr ome.

Drug interactions
Chol i ner gi c agoni sts have speci fi c i nteracti ons wi th other dr ugs.
Exampl es i ncl ude the fol l owi ng:

Other chol i ner gi c dr ugs, par ti cul ar l y anti chol i nesterase dr ugs
(such as ambenoni um, edr ophoni um, neosti gmi ne,
 physosti gmi ne, and pyr i dosti gmi ne), boost the effects of
chol i ner gi c agoni sts and i ncr ease the r i sk of toxi ci ty.
Chol i ner gi c bl ocki ng dr ugs (such as atr opi ne, bel l adonna,
homatr opi ne, methanthel i ne, methscopol ami ne, pr opanthel i ne,
and scopol ami ne) r educe the effects of chol i ner gi c dr ugs.
Qui ni di ne al so r educes the effecti veness of chol i ner gi c agoni sts.
(See Adver se r eacti ons to chol i ner gi c agoni sts.)

Warning!
Adverse reactions to cholinergic agonists
Because they bi nd wi th r eceptor s i n the parasympatheti c
ner vous system, chol i ner gi c agoni sts can pr oduce adver se effects
i n any or gan i nner vated by the parasympatheti c ner ves.
These adver se effects can i ncl ude:

nausea and vomi ti ng

cramps and di ar r hea
bl ur r ed vi si on
decr eased hear t rate and l ow bl ood pr essur e
shor tness of br eath
ur i nar y fr equency
i ncr eased sal i vati on and sweati ng.

Anticholinesterase drugs
Anticholinester ase dr ugs bl ock the acti on of the enz yme
acetyl chol i nesterase (whi ch br eaks down the neur otransmi tter
acetyl chol i ne) at chol i ner gi c r eceptor si tes, pr eventi ng the
br eakdown of acetyl chol i ne. As acetyl chol i ne bui l ds up, i t conti nues
to sti mul ate the chol i ner gi c r eceptor s. (See One day at a ti me:
Recogni z i ng a toxi c r esponse.)
Anti chol i nesterase dr ugs ar e di vi ded i nto two categor i esr ever si bl e
and i r r ever si bl e.

Yea or nay?
One day at a time: Recognizing a toxic response
Its di ffi cul t to pr edi ct adver se r eacti ons to
 anti chol i nesterase dr ugs i n a pati ent wi th myastheni a gravi s
because the therapeuti c dose var i es fr om day to day. Incr eased
muscl e weakness can r esul t fr om:

r esi stance to the dr ug

r ecei vi ng too l i ttl e of the anti chol i nesterase
r ecei vi ng too much of the anti chol i nesterase.

Enter edrophonium
Deci di ng whether a pati ent i s exper i enci ng a toxi c dr ug r esponse
(too much dr ug) or a myastheni c cr i si s (extr eme muscl e weakness
and sever e r espi rator y di ffi cul ti es) can be di ffi cul t. Edr ophoni um
can be used to di sti ngui sh between a toxi c dr ug r eacti on and a
myastheni c cr i si s. When edr ophoni um i s used, sucti on, oxygen,
mechani cal venti l ati on, and emer gency dr ugs, such as atr opi ne,
must be r eadi l y avai l abl e i n case a chol i ner gi c cr i si s occur s.

These you can reverse

Rever si bl e anti chol i nesterase dr ugs have a shor t durati on of acti on
and i ncl ude:

ambenoni um
demecar i um
donepez i l
edr ophoni um
gal antami ne
guani di ne
neosti gmi ne
physosti gmi ne
pyr i dosti gmi ne
r i vasti gmi ne
tacr i ne.

these you cant

Ir r ever si bl e anti chol i nesterase dr ugs have l ong-l asti ng effects and
ar e used pr i mar i l y as toxi c i nsecti ci des and pesti ci des or as ner ve
gas i n chemi cal war far e. (Pyr i dosti gmi ne enhances the effects of
anti dotes used to counteract ner ve agents.) Onl y one has
therapeuti c useful ness: echothi ophate.

Pharmacokinetics
Her es a br i ef r undown of how anti chol i nesterase dr ugs move
thr ough the body.

Generally GI
Many of the anti chol i nesterase dr ugs ar e r eadi l y absor bed fr om the
G I tract, subcutaneous ti ssue, and mucous membranes.
Because neosti gmi ne i s poor l y absor bed fr om the G I tract, the
pati ent needs a hi gher dose when taki ng thi s dr ug oral l y. Because
the durati on of acti on for an oral dose i s l onger, however, the
pati ent doesnt need to take i t as fr equentl y. When a rapi d effect i s
needed, neosti gmi ne shoul d be gi ven by the I.M. or I.V. r oute.

Distribution
Physosti gmi ne can cr oss the bl ood-brai n bar r i er (a pr otecti ve
bar r i er between the capi l l ar i es and brai n ti ssue that pr events
har mful substances fr om enter i ng the brai n). Donepez i l i s hi ghl y
bound to pl asma pr otei ns, tacr i ne i s about 55% bound, r i vasti gmi ne
i s 40% bound, and gal antami ne i s 18% bound.
Metabolism and excretion
Most anti chol i nesterase dr ugs ar e metabol i zed by enz ymes i n the
pl asma and excr eted i n ur i ne. Donepez i l , gal antami ne, r i vasti gmi ne,
and tacr i ne ar e metabol i zed i n the l i ver.

Pharmacodynamics
Anti chol i nesterase dr ugs pr omote the acti on of acetyl chol i ne at
r eceptor si tes. Dependi ng on the si te and the dr ugs dose and
durati on of acti on, they can pr oduce a sti mul ant or depr essant
effect on chol i ner gi c r eceptor s.

From minutes to weeks

Rever si bl e anti chol i nesterase dr ugs bl ock the br eakdown of
acetyl chol i ne for mi nutes to hour s; i r r ever si bl e anti chol i nesterase
dr ugs do so for days or weeks.

Pharmacotherapeutics
Anti chol i nesterase dr ugs ar e used for a var i ety of therapeuti c
pur poses, i ncl udi ng:

to r educe eye pr essur e i n pati ents wi th gl aucoma and dur i ng eye

sur ger y
 to i ncr ease bl adder tone
to i mpr ove tone and per i stal si s (movement) thr ough the G I tract
i n pati ents wi th r educed moti l i ty or paral yti c i l eus (paral ysi s of
the smal l i ntesti ne)
to pr omote muscl e contracti ons i n pati ents wi th myastheni a
gravi s
to di agnose myastheni a gravi s (neosti gmi ne and edr ophoni um)
as an anti dote to chol i ner gi c bl ocki ng dr ugs (al so cal l ed
anticholiner gic dr ugs), tr i cycl i c anti depr essants, bel l adonna
al kal oi ds, and nar coti cs
to tr eat mi l d to moderate dementi a and enhance cogni ti on i n
pati ents wi th Al z hei mer s di sease (pr i mar i l y donepez i l ,
gal antami ne, r i vasti gmi ne, and tacr i ne).

Drug interactions
These i nteracti ons can occur wi th anti chol i nesterase dr ugs:

Other chol i ner gi c dr ugs, par ti cul ar l y chol i ner gi c agoni sts (such
as bethanechol , car bachol , and pi l ocar pi ne), i ncr ease the r i sk of
a toxi c r eacti on when taken wi th anti chol i nesterase dr ugs.
Car bamazepi ne, dexamethasone, r i fampi n, phenytoi n, and
phenobar bi tal may i ncr ease donepez i l s rate of el i mi nati on.
Ami nogl ycosi de anti bi oti cs, anestheti cs, chol i ner gi c bl ocki ng
dr ugs (such as atr opi ne, bel l adonna, pr opanthel i ne, and
scopol ami ne), magnesi um, cor ti coster oi ds, and anti ar r hythmi c
dr ugs

(such as pr ocai nami de and qui ni di ne) can r educe the effects of
anti chol i nesterase dr ugs and can mask ear l y si gns of a
chol i ner gi c cr i si s. (See Adver se r eacti ons to anti chol i nesterase
dr ugs.)
Other medi cati ons wi th chol i ner gi c-bl ocki ng pr oper ti es, such as
tr i cycl i c anti depr essants, bl adder r el axants, and anti psychoti cs,
can al so counteract the effects of anti chol i nesterase dr ugs.
The effects of tacr i ne, donepez i l , and gal antami ne may be
i ncr eased when these dr ugs ar e combi ned wi th known i nhi bi tor s
of cytochr ome P-450 enz ymes, such as ci meti di ne and
 er ythr omyci n.
Ci gar ette use i ncr eases the cl earance of r i vasti gmi ne.

Warning!
Adverse reactions to anticholinesterase drugs
Most of the adver se r eacti ons caused by anti chol i nesterase
dr ugs r esul t fr om i ncr eased acti on of acetyl chol i ne at r eceptor
si tes.
Adver se r eacti ons associ ated wi th these dr ugs i ncl ude:

car di ac ar r hythmi as
nausea and vomi ti ng
di ar r hea
shor tness of br eath, wheez i ng, or ti ghtness i n the chest
sei z ur es
headache
anor exi a
i nsomni a
pr ur i tus
ur i nar y fr equency and noctur i a.

Cholinergic blocking drugs

Choliner gic blocking dr ugs i nter r upt parasympatheti c ner ve i mpul ses
i n the central and autonomi c ner vous systems. These dr ugs ar e al so
r efer r ed to as anticholiner gic dr ugs because they pr event
acetyl chol i ne fr om sti mul ati ng chol i ner gi c r eceptor s.

Not all receptors are receptive

Chol i ner gi c bl ocki ng dr ugs dont bl ock al l chol i ner gi c r eceptor s, just
the muscar i ni c r eceptor si tes. Muscar i ni c r eceptor s ar e chol i ner gi c
r eceptor s that ar e sti mul ated by the al kal oi d muscar i ne and bl ocked
by atr opi ne.

First come the belladonna alkaloids

The major chol i ner gi c bl ocki ng dr ugs ar e the bel l adonna al kal oi ds:
 atr opi ne (the pr ototype chol i ner gi c bl ocki ng dr ug)
bel l adonna
homatr opi ne
hyoscyami ne sul fate
methscopol ami ne
scopol ami ne.

Next come their synthetic sisters

Syntheti c der i vati ves of these dr ugs (the quater nar y ammoni um
dr ugs) i ncl ude:

gl ycopyr r ol ate
pr opanthel i ne.

And finally the tertiary and quaternary

amines
The ter ti ar y ami nes i ncl ude:

benz tr opi ne
di cycl omi ne
oxybutyni n

tr i hexypheni dyl
tol ter odi ne.

Quater nar y ami nes i ncl ude one dr ug, tr ospi um.
Atr opi ne may al so be used as an anti dote for ner ve agents (See the
appendi x, Vacci nes and anti dotes for bi ol ogi cal and chemi cal
weapons.)

Lets talk about it later

Because benz tr opi ne and tr i hexypheni dyl ar e al most excl usi vel y
tr eatments for Par ki nsons di sease, theyr e di scussed ful l y i n
chapter 3, Neur ol ogi c and neur omuscul ar dr ugs.
Pharmacokinetics
Her es how chol i ner gi c bl ocker s move thr ough the body.

Absorption
The bel l adonna al kal oi ds ar e absor bed fr om the:

eyes
G I tract
mucous membranes
ski n.

The quater nar y ammoni um dr ugs and ter ti ar y and quater nar y
ami nes ar e absor bed pr i mar i l y thr ough the G I tract, al though not as
r eadi l y as the bel l adonna al kal oi ds.

If you want it fast, go I.V.

When admi ni ster ed I.V., chol i ner gi c bl ocker s such as atr opi ne begi n
to wor k i mmedi atel y.

Distribution
The bel l adonna al kal oi ds ar e di str i buted mor e wi del y thr oughout the
body than the quater nar y ammoni um der i vati ves or di cycl omi ne.
The al kal oi ds r eadi l y cr oss the bl ood-brai n bar r i er ; the other
chol i ner gi c bl ocker s dont.
Metabolism and excretion
The bel l adonna al kal oi ds ar e onl y sl i ghtl y to moderatel y pr otei n-
bound. Thi s means that a moderate to hi gh amount of the dr ug i s
acti ve and avai l abl e to pr oduce a therapeuti c r esponse. The
bel l adonna al kal oi ds ar e metabol i zed i n the l i ver and excr eted by
the ki dneys as unchanged dr ug and metabol i tes.
The quater nar y ammoni um dr ugs ar e a bi t mor e compl i cated.
Hydr ol ysi s i s a chemi cal pr ocess wher eby a compound cl eaved i nto
two or mor e si mpl er compounds occur s i n the G I tract and the l i ver ;
the dr ugs ar e excr eted i n feces and ur i ne.

Di cycl omi nes metabol i sm i s unknown, but i ts excr eted equal l y i n

feces and ur i ne.

Pharmacodynamics
Chol i ner gi c bl ocker s can have paradoxi cal effects on the body,
dependi ng on the dosage and the condi ti on bei ng tr eated.

Dual duty
Chol i ner gi c bl ocker s can pr oduce a sti mul ati ng or depr essi ng effect,
dependi ng on the tar get or gan. In the brai n, they do bothl ow dr ug
l evel s sti mul ate, and hi gh dr ug l evel s depr ess.
Conditional considerations
The effects of a dr ug on your pati ent ar e al so deter mi ned by the
pati ents di sor der. Par ki nsons di sease, for exampl e, i s character i zed
by l ow dopami ne l evel s that i ntensi fy the sti mul ati ng effects of
acetyl chol i ne. Chol i ner gi c bl ocker s depr ess thi s effect. In other
di sor der s, however, they sti mul ate the central ner vous system.

Pharmacotherapeutics
Chol i ner gi c bl ocker s ar e often used to tr eat G I di sor der s and
compl i cati ons.

Al l chol i ner gi c bl ocker s ar e used to tr eat spasti c or hyperacti ve

condi ti ons of the G I and ur i nar y tracts because they r el ax
muscl es and decr ease G I secr eti ons. These dr ugs may be used to
r el ax the bl adder and to tr eat ur i nar y i nconti nence. The
quater nar y ammoni um and ami ne compounds such as
pr opanthel i ne ar e the dr ugs of choi ce for these condi ti ons
because they cause fewer adver se r eacti ons than bel l adonna
al kal oi ds.
Bel l adonna al kal oi ds ar e used wi th mor phi ne to tr eat bi l i ar y
col i c (pai n caused by stones i n the bi l e duct).
Chol i ner gi c bl ocki ng dr ugs ar e gi ven by i njecti on befor e such
di agnosti c pr ocedur es as endoscopy and si gmoi doscopy to r el ax
the G I smooth muscl e.

Before surgery
Chol i ner gi c bl ocker s such as atr opi ne ar e gi ven befor e sur ger y to:

r educe oral , gastr i c, and r espi rator y secr eti ons

pr event a dr op i n hear t rate caused by vagal ner ve sti mul ati on
dur i ng anesthesi a.

Brainy belladonna
The bel l adonna al kal oi ds can affect the brai n. For exampl e,
scopol ami ne, gi ven wi th the pai n r el i ever s mor phi ne or meper i di ne,
causes dr owsi ness and amnesi a i n a pati ent havi ng sur ger y. Its al so
used to tr eat moti on si ckness.

Now I get it!

How atropine speeds the heart rate
To under stand how atr opi ne affects the hear t, fi r st consi der
how the hear ts el ectr i cal conducti on system functi ons.
Without the drug
When the neur otransmi tter acetyl chol i ne i s r el eased, the vagus
ner ve sti mul ates the si noatr i al (SA) node (the hear ts pacemaker )
and the atr i oventr i cul ar (AV) node, whi ch contr ol s conducti on
between the atr i a and the ventr i cl es of the hear t. Thi s i nhi bi ts
el ectr i cal conducti on and causes the hear t rate to sl ow down.
With the drug
Atr opi ne, a chol i ner gi c bl ocki ng dr ug, competes wi th acetyl chol i ne
for chol i ner gi c r eceptor si tes on the SA and AV nodes. By bl ocki ng
acetyl chol i ne, atr opi ne speeds up the hear t rate.

Bel l adonna al kal oi ds al so have i mpor tant therapeuti c effects on the

hear t. Atr opi ne i s the dr ug of choi ce to tr eat:

symptomati c si nus bradycar di awhen the hear t beats too sl owl y,

causi ng l ow bl ood pr essur e or di z z i ness (see How atr opi ne
speeds the hear t rate)
ar r hythmi as r esul ti ng fr om the use of anestheti cs, chol i ne
ester s, or succi nyl chol i ne.
An eye on the problem
Chol i ner gi c bl ocker s al so ar e used as cycl opl egi cs. That means that
they:

paral yze the ci l i ar y muscl es of the eye (used for fi ne focusi ng)
al ter the shape of the eye l ens.

Mor eover, chol i ner gi c bl ocker s act as mydr i ati cs to di l ate the pupi l s,
maki ng i t easi er to measur e r efracti ve er r or s dur i ng an eye
exami nati on or to per for m eye sur ger y.

Punishing pesticides
The bel l adonna al kal oi ds, par ti cul ar l y atr opi ne and hyoscyami ne,
ar e effecti ve anti dotes to chol i ner gi c and anti chol i nesterase dr ugs.
Atr opi ne i s the dr ug of choi ce to tr eat poi soni ng fr om
or ganophosphate pesti ci des. Atr opi ne and hyoscyami ne al so
counteract the effects of the neur omuscul ar bl ocki ng dr ugs by
competi ng for the same r eceptor si tes.

Drug interactions
Because chol i ner gi c bl ocker s sl ow the passage of food and dr ugs
thr ough the stomach, dr ugs r emai n i n pr ol onged contact wi th the
mucous membranes of the G I tract. Thi s i ncr eases the amount of
the dr ug thats absor bed and, ther efor e, i ncr eases the r i sk of
adver se effects.

Increased effect
Dr ugs that i ncr ease the effects of chol i ner gi c bl ocker s i ncl ude:

di sopyrami de
anti dyski neti cs such as amantadi ne
anti emeti cs and anti ver ti go dr ugs, such as bucl i z i ne, cycl i z i ne,
mecl i z i ne, and di phenhydrami ne
anti psychoti cs, such as hal oper i dol , phenothi az i nes, and
thi oxanthenes
cycl obenz apr i ne
or phenadr i ne
tr i cycl i c and tetracycl i c anti depr essants.

or decreased effect
Dr ugs that decr ease the effects of chol i ner gi c bl ocker s i ncl ude:

chol i ner gi c agoni sts such as bethanechol

anti chol i nesterase dr ugs, such as neosti gmi ne and
pyr i dosti gmi ne.

Mixing it up some more

Other dr ug i nteracti ons can occur :

The r i sk of di goxi n toxi ci ty i ncr eases when di goxi n i s taken wi th

a chol i ner gi c bl ocker.
Opi ate-l i ke anal gesi cs fur ther sl ow the movement of food and
dr ugs thr ough the G I tract when taken wi th a chol i ner gi c
bl ocker.

The absor pti on of ni tr ogl ycer i n tabl ets pl aced under the tongue
i s r educed when thi s dr ug i s taken wi th a chol i ner gi c bl ocker.
(See Adver se r eacti ons to chol i ner gi c bl ocker s.)

Warning!
Adverse reactions to cholinergic blockers
 Adver se r eacti ons r esul ti ng fr om chol i ner gi c bl ocker s ar e cl osel y
r el ated to the dr ug dose. Wi th these dr ugs, the di ffer ence
between a therapeuti c dose and a toxi c dose i s smal l .
Adver se r eacti ons may i ncl ude:

dr y mouth
r educed br onchi al secr eti ons
i ncr eased hear t rate
decr eased sweati ng.

Adrenergic drugs
Adr ener gic dr ugs ar e al so cal l ed sympathomimetic dr ugs because
they pr oduce effects si mi l ar to those pr oduced by the sympatheti c
ner vous system.

Classified by chemical
Adr ener gi c dr ugs ar e cl assi fi ed i nto two gr oups based on thei r
chemi cal str uctur ecatechol ami nes (natural l y occur r i ng as wel l as
syntheti c) and noncatechol ami nes.

or by action
Adr ener gi c dr ugs ar e al so cl assi fi ed by how they act. They can be:

dir ect-acting, i n whi ch the dr ug acts di r ectl y on the or gan or

ti ssue i nner vated (suppl i ed wi th ner ves or ner ve i mpul ses) by
the sympatheti c ner vous system
indir ect-acting, i n whi ch the dr ug tr i gger s the r el ease of a
neur otransmi tter, usual l y nor epi nephr i ne
dual-acting, i n whi ch the dr ug has both di r ect and i ndi r ect
acti ons. (See Under standi ng adr ener gi cs.)

Memory jogger
A direct-acting dr ug has a di r ect effect on a tar get or gan.
An indirect-acting dr ug tr i gger s a neur otransmi tter that
takes over fr om ther e.
A dual-acting dr ug wor ks both ways.
Which receptor does it affect?
The therapeuti c uses of adr ener gi cscatechol ami nes as wel l as
noncatechol ami nesdepend on whi ch r eceptor s they sti mul ate and to
what degr ee. Adr ener gi c dr ugs can affect:

al pha-adr ener gi c r eceptor s

beta-adr ener gi c r eceptor s
dopami ne r eceptor s.

Mimicking norepinephrine and epinephrine

Most adr ener gi cs pr oduce thei r effects by sti mul ati ng al pha
r eceptor s and beta r eceptor s. These dr ugs mi mi c the acti on of
nor epi nephr i ne and epi nephr i ne.

Doing it like dopamine

Dopami ner gi c dr ugs act pr i mar i l y on r eceptor s i n the sympatheti c
ner vous system sti mul ated by dopami ne.

Now I get it!

Understanding adrenergics
Direct-acting adrenergic action
Di r ect-acti ng adr ener gi cs di r ectl y sti mul ate adr ener gi c r eceptor s.

Indirect-acting adrenergic action

Indi r ect-acti ng adr ener gi cs sti mul ate the r el ease of
nor epi nephr i ne fr om ner ve endi ngs i nto the synapse.
Dual-acting adrenergic action
Dual -acti ng adr ener gi cs sti mul ate both adr ener gi c r eceptor si tes
and the r el ease of nor epi nephr i ne fr om ner ve endi ngs.
Catecholamines
Because of thei r common basi c chemi cal str uctur e, al l
catechol ami nes shar e cer tai n pr oper ti esthey sti mul ate the ner vous
system, constr i ct per i pheral bl ood vessel s, i ncr ease hear t rate, and

di l ate the br onchi . They can be manufactur ed i n the body or i n a

l aborator y. Common catechol ami nes i ncl ude:

dobutami ne
dopami ne
epi nephr i ne, epi nephr i ne bi tar trate, and epi nephr i ne
hydr ochl or i de
nor epi nephr i ne (l evar ter enol )
i sopr oter enol hydr ochl or i de and i sopr oter enol sul fate.
Pharmacokinetics
Catechol ami nes cant be taken oral l y because theyr e destr oyed by
di gesti ve enz ymes. In contrast, when these dr ugs ar e gi ven
subl i ngual l y (under the tongue), theyr e absor bed rapi dl y thr ough
the mucous membranes. Any subl i ngual dr ug not compl etel y
absor bed i s rapi dl y metabol i zed by swal l owed sal i va.

Subcutaneously slow
SubQ absor pti on i s sl owed because catechol ami nes cause the bl ood
vessel s ar ound the i njecti on si te to constr i ct.
I.M. absor pti on i s mor e rapi d because ther es l ess constr i cti on of
l ocal bl ood vessel s.

Distribution and metabolism

Catechol ami nes ar e wi del y di str i buted i n the body. theyr e
metabol i zed and i nacti vated pr edomi nantl y i n the l i ver but can al so
be metabol i zed i n the:

G I tract
l ungs
ki dneys
pl asma
other ti ssues.
Excretion
Catechol ami nes ar e excr eted pr i mar i l y i n ur i ne; however, a smal l
amount of i sopr oter enol i s excr eted i n feces and some epi nephr i ne
i s excr eted i n br east mi l k.

Pharmacodynamics
Catechol ami nes ar e pr i mar i l y di r ect-acti ng. When catechol ami nes
combi ne wi th al pha r eceptor s or beta r eceptor s, they cause ei ther
an exci tator y or an i nhi bi tor y effect. Typi cal l y, acti vati on of al pha
r eceptor s generates an exci tator y r esponse, except for i ntesti nal
r el axati on. Acti vati on of beta r eceptor s typi cal l y pr oduces an
i nhi bi tor y r esponse, except i n hear t cel l s, wher e nor epi nephr i ne
pr oduces exci tator y effects.

Memory jogger
To hel p you r emember the effects of catechol ami nes on al pha
and beta r eceptor s, r emember that A stands for al pha (and
activation, suggesti ng an exci tator y r esponse), and B stands for
beta (or banished, suggesti ng an i nhi bi tor y effect).

How heartening
The cl i ni cal effects of catechol ami nes depend on the dosage and
admi ni strati on r oute. Catechol ami nes ar e potent i notr opesthey
make the hear t contract mor e for ceful l y. As a r esul t, the ventr i cl es
empty mor e compl etel y wi th each hear tbeat, i ncr easi ng the hear ts
wor kl oad and the amount of oxygen i t needs to do thi s har der wor k.

Rapid rates
Catechol ami nes al so pr oduce a posi ti ve chr onotr opi c effect, whi ch
means that they cause the hear t to beat faster. That happens
because the pacemaker cel l s i n the hear ts si noatr i al (SA) node
depol ar i ze at a faster rate. As catechol ami nes cause bl ood vessel s
to constr i ct and bl ood pr essur e to r i se, the hear t rate can fal l as the
body tr i es to compensate for an excessi ve r i se i n bl ood pr essur e.
Fascinating rhythm
Catechol ami nes can cause the Pur ki nje fi ber s (an i ntr i cate web of
fi ber s that car r y el ectr i cal i mpul ses i nto the ventr i cl es) to fi r e
spontaneousl y, possi bl y pr oduci ng abnor mal hear t r hythms, such as
pr ematur e ventr i cul ar contracti ons and fi br i l l ati on. Epi nephr i ne i s
mor e l i kel y than nor epi nephr i ne to pr oduce thi s spontaneous fi r i ng.

Pharmacotherapeutics
The therapeuti c uses of catechol ami nes depend on the par ti cul ar
r eceptor thats acti vated.

Nor epi nephr i ne sti mul ates al pha r eceptor s al most excl usi vel y.
Dobutami ne and i sopr oter enol sti mul ate onl y beta r eceptor s.
Epi nephr i ne sti mul ates both al pha and beta r eceptor s.
Dopami ne acti vates pr i mar i l y dopami ne r eceptor s.

Boosting blood pressure

Catechol ami nes that sti mul ate al pha r eceptor s ar e used to tr eat l ow
bl ood pr essur e (hypotensi on). They general l y wor k best when used
to tr eat hypotensi on caused by:

r el axati on of the bl ood vessel (al so cal l ed a loss of vasomotor

tone)
bl ood l oss (such as fr om hemor r hage).
Restoring rhythm
Catechol ami nes that sti mul ate beta1 r eceptor s ar e used to tr eat:

bradycar di a

hear t bl ock (a del ay or i nter r upti on i n the conducti on of

el ectr i cal i mpul ses between the atr i a and ventr i cl es)
l ow car di ac output.

Its electric
Because theyr e bel i eved to make the hear t mor e r esponsi ve to
defi br i l l ati on (usi ng an el ectr i cal cur r ent to ter mi nate a deadl y
ar r hythmi a), beta1 -adr ener gi c dr ugs ar e used to tr eat:

ventr i cul ar fi br i l l ati on (qui ver i ng of the ventr i cl es, r esul ti ng i n

no pul se)
asystol e (no el ectr i cal acti vi ty i n the hear t)
car di ac ar r est.

Better breathing
Catechol ami nes that exer t beta2 acti vi ty ar e used to tr eat:

acute or chr oni c br onchi al asthma

emphysema
br onchi ti s
acute hyper sensi ti vi ty (al l er gi c) r eacti ons to dr ugs.

Kind to the kidneys

Dopami ne, whi ch sti mul ates the dopami ne r eceptor s, i s used i n l ow
doses to i mpr ove bl ood fl ow to the ki dneys by di l ati ng the r enal
bl ood vessel s.

Synthetic vs. natural

The effects of natural catechol ami nes (those pr oduced by the body)
di ffer somewhat fr om the effects of manufactur ed catechol ami nes.
Manufactur ed catechol ami nes have a shor t durati on of acti on, whi ch
can l i mi t thei r therapeuti c useful ness.

Drug interactions
Dr ug i nteracti ons i nvol vi ng catechol ami nes can be ser i ous, r esul ti ng
i n hypotensi on, hyper tensi on, ar r hythmi as, sei z ur es, and hi gh bl ood
gl ucose l evel s i n di abeti c pati ents.

Al pha-adr ener gi c bl ocker s, such as phentol ami ne, can pr oduce

hypotensi on when taken wi th a catechol ami ne.
Beta-adr ener gi c bl ocker s, such as pr opranol ol , taken wi th a
catechol ami ne can l ead to br onchi al constr i cti on.
Epi nephr i ne may cause hyper gl ycemi a i n di abeti c pati ents
r ecei vi ng the dr ug. These pati ents may r equi r e an i ncr eased
dose of i nsul i n or oral anti di abeti c agents.

Other adr ener gi cs taken wi th a catechol ami ne can pr oduce

addi ti ve, or doubl e, effects, such as hyper tensi on and
ar r hythmi as, as wel l as enhance other adver se effects. Incr eased
r i sk of adver se effects, such as hyper tensi on, may occur when
adr ener gi c dr ugs ar e gi ven wi th other dr ugs that can cause
hyper tensi on.
 Tr i cycl i c anti depr essants taken wi th a catechol ami ne can l ead to
hyper tensi on. (See Adver se r eacti ons to catechol ami nes.)

Warning!
Adverse reactions to catecholamines
Adver se r eacti ons to catechol ami nes can i ncl ude:

r estl essness
asthmati c epi sode
di z z i ness
headache
pal pi tati ons
car di ac ar r hythmi as
hypotensi on
hyper tensi on and hyper tensi ve cr i si s
str oke
angi na
i ncr eased bl ood gl ucose l evel s
ti ssue necr osi s and sl oughi ng (i f a catechol ami ne gi ven I.V.
l eaks i nto sur r oundi ng ti ssue).

Noncatecholamines
Noncatecholamine adr ener gic dr ugs have a var i ety of therapeuti c
uses because of the many effects they can have on the body,
i ncl udi ng:

l ocal or systemi c constr i cti on of bl ood vessel s (phenyl ephr i ne)

nasal and eye decongesti on and di l ati on of the br onchi ol es
(al buter ol , bi tol ter ol , ephedr i ne, for moter ol , i soethar i ne
hydr ochl or i de, i sopr oter enol , l eval buter ol , metapr oter enol ,
pi r buter ol , sal meter ol , and ter butal i ne)
smooth-muscl e r el axati on (ter butal i ne).

Pharmacokinetics
Al though these dr ugs ar e al l excr eted i n ur i ne, theyr e absor bed i n
di ffer ent ways.

Absorption and distribution

Absor pti on of the noncatechol ami nes depends on the admi ni strati on
r oute:

Inhal ed dr ugs, such as al buter ol , ar e absor bed gradual l y fr om

the br onchi and r esul t i n l ower dr ug l evel s i n the body.
Oral dr ugs ar e absor bed wel l fr om the G I tract and ar e
di str i buted wi del y i n body fl ui ds and ti ssues.
Some noncatechol ami nes, such as ephedr i ne, cr oss the bl ood-
brai n bar r i er and can be found i n hi gh concentrati ons i n the
brai n and cer ebr ospi nal fl ui d (fl ui d that moves thr ough and
pr otects the brai n and spi nal canal ).

Metabolism
Noncatechol ami nes ar e metabol i zed and i nacti vated pr i mar i l y i n the
l i ver but al so i n the l ungs, G I tract, and other ti ssues.

Excretion
Noncatechol ami nes and thei r metabol i tes ar e excr eted pr i mar i l y i n
ur i ne. Some, such as i nhal ed al buter ol , ar e excr eted wi thi n 24
hour s; other s, such as oral al buter ol , wi thi n 3 days. Aci di c ur i ne
i ncr eases excr eti on of many noncatechol ami nes; al kal i ne ur i ne
sl ows excr eti on.

Pharmacodynamics
Noncatechol ami nes can be di r ect-acti ng, i ndi r ect-acti ng, or dual -
acti ng (unl i ke catechol ami nes, whi ch ar e pr i mar i l y di r ect-acti ng).

Di r ect-acti ng noncatechol ami nes that sti mul ate al pha r eceptor s
i ncl ude phenyl ephr i ne. Those that sel ecti vel y sti mul ate beta2
r eceptor s i ncl ude al buter ol , i soethar i ne, metapr oter enol , and
ter butal i ne.
Dual -acti ng noncatechol ami nes i ncl ude ephedr i ne.
Pharmacotherapeutics
Noncatechol ami nes sti mul ate the sympatheti c ner vous system,
pr oduci ng a var i ety of effects i n the body. Phenyl ephr i ne, for
exampl e, causes vasoconstr i cti on and i s used to tr eat hypotensi on
i n cases of sever e shock. Ter butal i ne i s used to stop pr eter m l abor.

Warning!
Adverse reactions to noncatecholamines
Adver se r eacti ons to noncatechol ami ne dr ugs may i ncl ude:

headache
r estl essness
anxi ety or euphor i a
i r r i tabi l i ty
tr embl i ng
dr owsi ness or i nsomni a
l i ght-headedness
i ncoher ence
sei z ur es
hyper tensi on or hypotensi on
pal pi tati ons
bradycar di a or tachycar di a
i r r egul ar hear t r hythm
car di ac ar r est
cer ebral hemor r hage
ti ngl i ng or col dness i n the ar ms or l egs
pal l or or fl ushi ng
angi na.

Drug interactions
Her e ar e a few exampl es of dr ugs that i nteract wi th
noncatechol ami nes:

Anestheti cs (general ), cycl opr opane, and hal ogenated

 hydr ocar bons can cause ar r hythmi as. Hypotensi on can al so occur
i f these dr ugs ar e taken wi th noncatechol ami nes that exer t
pr edomi nantl y beta2 acti vi ty, such as ter butal i ne.
Monoami ne oxi dase i nhi bi tor s can cause sever e hyper tensi on and
even death.
Oxytoci c dr ugs that sti mul ate the uter us to contract can be
i nhi bi ted when taken wi th ter butal i ne. When taken wi th other
noncatechol ami nes, oxytoci c dr ugs can cause hyper tensi ve cr i si s
or a str oke.
Tr i cycl i c anti depr essants can cause hyper tensi on and
ar r hythmi as.
Ur i ne al kal i zer s, such as acetazol ami de and sodi um bi car bonate,
sl ow excr eti on of noncatechol ami nes, pr ol ongi ng thei r durati on
of acti on. (See Adver se r eacti ons to noncatechol ami nes.)

Adrenergic blocking drugs

Adr ener gic blocking dr ugs, al so cal l ed sympatholytic dr ugs, ar e used
to di sr upt sympatheti c ner vous system functi on. These dr ugs wor k
by bl ocki ng i mpul se transmi ssi on (and thus sympatheti c ner vous
system sti mul ati on) at adr ener gi c neur ons or adr ener gi c r eceptor
si tes. Thei r acti on at these si tes can be exer ted by:

i nter r upti ng the acti on of adr ener gi c (sympathomi meti c) dr ugs

 r educi ng avai l abl e nor epi nephr i ne
pr eventi ng the acti on of chol i ner gi c dr ugs.

Classified information
Adr ener gi c bl ocki ng dr ugs ar e cl assi fi ed accor di ng to thei r si te of
acti on as:

al pha-adr ener gi c bl ocker s (or alpha blocker s)

beta-adr ener gi c bl ocker s (or beta blocker s).

Alpha-adrenergic blockers
Alpha-adr ener gic blocker s wor k by i nter r upti ng the acti ons of the
catechol ami nes epi nephr i ne and nor epi nephr i ne at al pha r eceptor s.
Thi s r esul ts i n:

r el axati on of the smooth muscl e i n bl ood vessel s

i ncr eased di l ati on of bl ood vessel s
decr eased bl ood pr essur e.

Dr ugs i n thi s cl ass i ncl ude:

al fuzosi n
 er gol oi d mesyl ates
phenoxybenz ami ne
phentol ami ne
prazosi n, doxazosi n, and terazosi n
tamsul osi n.

A mixed bag
Er gotami ne i s a mi xed al pha agoni st and antagoni st; at hi gh doses,
i t acts as an al pha-adr ener gi c bl ocker.

Pharmacokinetics
The acti on of al pha-adr ener gi c bl ocker s i n the body i snt wel l
under stood. Most of these dr ugs ar e absor bed er rati cal l y when
admi ni ster ed oral l y, and mor e rapi dl y and compl etel y when
admi ni ster ed subl i ngual l y. Al pha-adr ener gi c bl ocker s var y
consi derabl y i n

thei r onset of acti on, peak concentrati on l evel s, and durati on of

acti on.

Pharmacodynamics
Al pha-adr ener gi c bl ocker s wor k i n one of two ways:
 They i nter fer e wi th or bl ock the synthesi s, storage, r el ease, and
r euptake of nor epi nephr i ne by neur ons.
They antagoni ze epi nephr i ne, nor epi nephr i ne, or adr ener gi c
(sympathomi meti c) dr ugs at al pha r eceptor si tes.

Not very discriminating

Al pha-adr ener gi c bl ocker s i ncl ude dr ugs that bl ock sti mul ati on of
al pha 1 r eceptor s and that may bl ock al pha2 r eceptor s.

Reducing resistance
Al pha-adr ener gi c bl ocker s occupy al pha r eceptor si tes on the
smooth muscl e of bl ood vessel s. (See How al pha-adr ener gi c bl ocker s
affect per i pheral bl ood vessel s.)
Thi s pr events catechol ami nes fr om occupyi ng and sti mul ati ng the
r eceptor si tes. As a r esul t, bl ood vessel s di l ate, i ncr easi ng l ocal
bl ood fl ow to the ski n and other or gans. The decr eased per i pheral
vascul ar r esi stance (r esi stance to bl ood fl ow) hel ps to decr ease
bl ood pr essur e.

Now I get it!

How alpha-adrenergic blockers affect peripheral
blood vessels
By occupyi ng al pha r eceptor si tes, al pha-adr ener gi c bl ocki ng
dr ugs cause the bl ood vessel wal l s to r el ax. Thi s l eads to di l ati on
of the bl ood vessel s and r educed per i pheral vascul ar r esi stance
(the pr essur e that bl ood must over come as i t fl ows i n a vessel ).

One result: Orthostatic hypotension

These effects can cause or thostati c hypotensi on, a dr op i n bl ood
pr essur e that occur s when changi ng posi ti on fr om l yi ng down to
 standi ng. Redi str i buti on of bl ood to the di l ated bl ood vessel s of
the l egs causes hypotensi on.

Sympathetic response?
The therapeuti c effect of an al pha-adr ener gi c bl ocker depends on
the sympatheti c tone (the state of par ti al constr i cti on of bl ood
vessel s) i n the body befor e the dr ug i s admi ni ster ed. For i nstance,
when the dr ug i s gi ven wi th the pati ent l yi ng down, onl y a smal l
change i n bl ood pr essur e occur s. In thi s posi ti on, the sympatheti c
ner ves r el ease ver y l i ttl e nor epi nephr i ne.

Patient up, pressure down

On the other hand, when a pati ent stands up, nor epi nephr i ne i s
r el eased to constr i ct the vei ns and shoot bl ood back up to the hear t.
If the pati ent r ecei ves an al pha-adr ener gi c bl ocker, however, the
vei ns cant constr i ct and bl ood pool s i n the l egs. Because bl ood
r etur n to the hear t i s r educed, bl ood pr essur e dr ops. Thi s dr op i n
bl ood pr essur e that occur s when a per son stands up i s cal l ed
or thostatic hypotension.
Pharmacotherapeutics
Because al pha-adr ener gi c bl ocker s cause smooth muscl es to r el ax
and bl ood vessel s to di l ate, they i ncr ease l ocal bl ood fl ow to the
ski n and other or gans and r educe bl ood pr essur e. As a r esul t,
theyr e used to tr eat:

beni gn pr ostati c hyper tr ophy

hyper tensi on
per i pheral vascul ar di sor der s (di seases of the bl ood vessel s of
the extr emi ti es), especi al l y those i n whi ch bl ood vessel spasm
causes poor l ocal bl ood fl ow, such as Raynauds di sease
(i nter mi ttent pal l or, cyanosi s, or r edness of fi nger s),
acr ocyanosi s (symmetr i cal mottl ed cyanosi s of the hands and
feet), and fr ostbi te
pheochr omocytoma (a catechol ami ne-secr eti ng tumor that
causes sever e hyper tensi on).
Drug interactions
Many dr ugs i nteract wi th al pha-adr ener gi c bl ocker s, pr oduci ng a
syner gi sti c, or exaggerated, effect. The most ser i ous i nteracti ons
ar e sever e hypotensi on and vascul ar col l apse.
These i nteracti ons can occur when these dr ugs ar e taken wi th
er gol oi d mesyl ates and er gotami ne:

Caffei ne and macr ol i de anti bi oti cs can i ncr ease the effects of
er gotami ne.
Dopami ne i ncr eases the pr essor (r i si ng bl ood pr essur e) effect.

Ni tr ogl ycer i n can pr oduce hypotensi on fr om excessi ve di l ati on of

bl ood vessel s.
Sympathomi meti cs, i ncl udi ng many over-the-counter dr ugs, can
i ncr ease the sti mul ati ng effects on the hear t, possi bl y r esul ti ng
i n hypotensi on wi th r ebound hyper tensi on. (See Adver se
r eacti ons to al pha-adr ener gi c bl ocker s.)

Warning!
Adverse reactions to alpha-adrenergic blockers
Most adver se r eacti ons associ ated wi th al pha-adr ener gi c
bl ocker s ar e caused pr i mar i l y by di l ati on of the bl ood vessel s.
They i ncl ude:
 or thostati c hypotensi on or sever e r ebound hyper tensi on
bradycar di a or tachycar di a
edema
di ffi cul ty br eathi ng
l i ght-headedness
fl ushi ng
ar r hythmi as
angi na
hear t attack
spasm of bl ood vessel s i n the brai n
a shockl i ke state.

Beta-adrenergic blockers
Beta-adr ener gic blocker s, the most wi del y used adr ener gi c bl ocker s,
pr event sti mul ati on of the sympatheti c ner vous system by i nhi bi ti ng
the acti on of catechol ami nes at beta-adr ener gi c r eceptor s.

From not so selective

Beta-adr ener gi c bl ocker s can be sel ecti ve or nonsel ecti ve.
Nonsel ecti ve beta-adr ener gi c bl ocker s affect:

beta 1 r eceptor si tes (l ocated mai nl y i n the hear t)

beta 2 r eceptor si tes (l ocated i n the br onchi , bl ood vessel s, and
uter us).

Nonsel ecti ve beta-adr ener gi c bl ocker s i ncl ude car teol ol , car vedi l ol ,
l abetal ol , l evobunol ol , meti pranol ol , penbutol ol , pi ndol ol , sotal ol ,
nadol ol , pr opranol ol , and ti mol ol . (Car vedi l ol and l abetal ol al so
bl ock al pha1 r eceptor s.)

to highly discriminating
Sel ecti ve beta-adr ener gi c bl ocker s pr i mar i l y affect beta1 -adr ener gi c
si tes. They i ncl ude acebutol ol , atenol ol , betaxol ol , bi sopr ol ol ,
esmol ol , and metopr ol ol .
The not so beta blockers
Some beta-adr ener gi c bl ocker s, such as pi ndol ol and acebutol ol ,
have i ntr i nsi c sympatheti c acti vi ty. Thi s means that i nstead of
attachi ng to beta r eceptor s and bl ocki ng them, these beta-
adr ener gi c bl ocker s attach to beta r eceptor s and sti mul ate them.
These dr ugs ar e someti mes cl assi fi ed as par tial agonists.

Pharmacokinetics
Beta-adr ener gi c bl ocker s ar e usual l y absor bed rapi dl y and wel l fr om
the G I tract and ar e somewhat pr otei n-bound. Food doesnt
i nhi bi tand may even enhancethei r absor pti on. Some beta-
adr ener gi c bl ocker s ar e absor bed mor e compl etel y than other s.

Peak by I.V.
The onset of acti on of beta-adr ener gi c bl ocker s i s pr i mar i l y dose-
and dr ug-dependent. The ti me i t takes to r each peak concentrati on
l evel s depends on the admi ni strati on r oute. Beta-adr ener gi c
bl ocker s gi ven I.V. r each peak l evel s much mor e rapi dl y than those
taken by mouth.

Distribution
Beta-adr ener gi c bl ocker s ar e di str i buted wi del y i n body ti ssues, wi th
the hi ghest concentrati ons found i n the:
 hear t
l i ver
l ungs
sal i va.

Metabolism and excretion

Except for nadol ol and atenol ol , beta-adr ener gi c bl ocker s ar e
metabol i zed i n the l i ver. Theyr e excr eted pr i mar i l y i n ur i ne, ei ther
unchanged or as metabol i tes, but can al so be excr eted i n feces, bi l e
and, to some degr ee, br east mi l k.

Pharmacodynamics
Beta-adr ener gi c bl ocker s have wi despr ead effects i n the body
because they pr oduce thei r bl ocki ng acti on not onl y at adr ener gi c
ner ve endi ngs but al so i n the adr enal medul l a.

A matter of the heart

Effects on the hear t i ncl ude i ncr eased per i pheral vascul ar
r esi stance, decr eased bl ood pr essur e, decr eased for ce of the hear ts
contracti ons, decr eased oxygen consumpti on by the hear t, sl owed
i mpul se conducti on between the atr i a and ventr i cl es, and decr eased
car di ac output (the amount of bl ood the hear t pumps each mi nute).
(See How beta-adr ener gi c bl ocker s wor k.)

Now I get it!

How beta-adrenergic blockers work
By occupyi ng beta r eceptor si tes, beta-adr ener gi c bl ocker s
pr event catechol ami nes (nor epi nephr i ne and epi nephr i ne) fr om
occupyi ng these si tes and exer ti ng thei r sti mul ati ng effects. Thi s
i l l ustrati on shows the effects of beta-adr ener gi c bl ocker s on the
hear t, l ungs, and bl ood vessel s.
Selective and nonselective effects
Some beta-adr ener gi c bl ocker effects depend on whether the dr ug i s
cl assi fi ed as sel ecti ve or nonsel ecti ve.
Sel ecti ve beta-adr ener gi c bl ocker s, whi ch pr efer to bl ock beta1 -
r eceptor si tes, r educe sti mul ati on of the hear t. Theyr e often
r efer r ed to as car dioselective beta-adr ener gic blocker s.

Nonsel ecti ve beta-adr ener gi c bl ocker s, whi ch bl ock both beta1 - and
beta 2 -r eceptor si tes, not onl y r educe sti mul ati on of the hear t but
al so cause the br onchi ol es of the l ungs to constr i ct. For i nstance,
nonsel ecti ve beta-adr ener gi c bl ocker s can cause br onchospasm i n
pati ents wi th chr oni c obstr ucti ve l ung di sease. Thi s adver se effect
i snt seen when car di osel ecti ve dr ugs ar e gi ven at l ower doses.
Pharmacotherapeutics
Beta-adr ener gi c bl ocker s ar e used to tr eat many condi ti ons and ar e
under i nvesti gati on for use i n many mor e. As menti oned pr evi ousl y,
thei r cl i ni cal useful ness i s based l ar gel y (but not excl usi vel y) on
how they affect the hear t. (See Ar e beta-adr ener gi c bl ocker s
under used i n el der l y pati ents?)

Helping the heart

Beta-adr ener gi c bl ocker s can be pr escr i bed after a hear t attack to
pr event another hear t attack or to tr eat:

angi na
hear t fai l ur e
hyper tensi on
car di omyopathy (a di sease of the hear t muscl e)
supraventr i cul ar ar r hythmi as (i r r egul ar hear tbeats that or i gi nate
i n the atr i a, SA node, or atr i oventr i cul ar node).

Yea or nay?
Are beta-adrenergic blockers underused in
elderly patients?
Resear ch has cl ear l y shown that use of beta-adr ener gi c bl ocker s
 after a hear t attack r educes the r i sk of death and another hear t
attack. However, these dr ugs ar ent bei ng pr escr i bed for el der l y
pati ents.
Study findings
One study found that onl y 34% of pati ents wer e pr escr i bed a
beta-adr ener gi c bl ocker after di schar ge fr om the hospi tal
fol l owi ng a hear t attack. Those l east l i kel y to r ecei ve a beta-
adr ener gi c bl ocker i ncl uded ver y si ck pati ents, bl acks, and the
el der l y.
Why?
The chi ef i nvesti gator of a study that l ooked at the use of beta-
adr ener gi c bl ocker s i n the el der l y bel i eves that many doctor s fear
the adver se effects these dr ugs may pr oduce i n ol der pati ents.
However, the study suggested that beta-adr ener gi c bl ocker s ar e
safe for el der l y hear t attack pati ents i f the l owest effecti ve dose
of a sel ecti ve beta-adr ener gi c bl ocker i s pr escr i bed.

Jack of all trades

Beta-adr ener gi c bl ocker s ar e al so used to tr eat:

anxi ety
car di ovascul ar symptoms associ ated wi th thyr otoxi cosi s
(over pr oducti on of thyr oi d hor mones)
essenti al tr emor
mi grai ne headaches
open-angl e gl aucoma
pheochr omocytoma (tumor of the adr enal gl and).

Drug interactions
Many dr ugs can i nteract wi th beta-adr ener gi c bl ocker s to cause
potenti al l y danger ous effects. Some of the most ser i ous effects
i ncl ude car di ac or r espi rator y depr essi on, ar r hythmi as, sever e
br onchospasm, and sever e hypotensi on that can l ead to vascul ar
col l apse. Other i nteracti ons can al so occur :

Incr eased effects or toxi ci ty can occur when ci meti di ne, di goxi n,
 or cal ci um channel bl ocker s (pr i mar i l y verapami l ) ar e taken wi th
beta-adr ener gi c bl ocker s.
Decr eased effects can occur when r i fampi n, antaci ds, cal ci um
sal ts, bar bi turates, or anti -i nfl ammator i es, such as i ndomethaci n
and sal i cyl ates, ar e taken wi th beta-adr ener gi c bl ocker s.
Li docai ne toxi ci ty may occur when l i docai ne i s taken wi th beta-
adr ener gi c bl ocker s.
The r equi r ements for i nsul i n and oral anti di abeti c dr ugs can be
al ter ed when these dr ugs ar e taken wi th beta-adr ener gi c
bl ocker s.
The abi l i ty of theophyl l i ne to pr oduce br onchodi l ati on i s
i mpai r ed by nonsel ecti ve beta-adr ener gi c bl ocker s.
Cl oni di ne taken wi th a nonsel ecti ve beta-adr ener gi c bl ocker can
cause l i fe-thr eateni ng hyper tensi on dur i ng cl oni di ne wi thdrawal .
Sympathomi meti cs taken wi th nonsel ecti ve beta-adr ener gi c
bl ocker s can cause hyper tensi on and r efl ex bradycar di a. (See
Adver se r eacti ons to beta-adr ener gi c bl ocker s.)

Warning!
Adverse reactions to beta-adrenergic blockers
Beta-adr ener gi c bl ocker s general l y cause few adver se
r eacti ons; those that do occur ar e dr ug- or dose-dependent and
i ncl ude:

hypotensi on
bradycar di a
per i pheral vascul ar i nsuffi ci ency
atr i oventr i cul ar bl ock
hear t fai l ur e
fati gue
br onchospasm
di ar r hea or consti pati on
nausea and vomi ti ng
abdomi nal di scomfor t
anor exi a
fl atul ence
rash
 fever wi th sor e thr oat
spasm of the l ar ynx
r espi rator y di str ess (al l er gi c r esponse).

Quick quiz
1Dur i ng bethanechol therapy, whi ch common adver se
r eacti ons shoul d you expect to obser ve?
A. Dr y mouth, fl ushed face, and consti pati on
B. Fasci cul ati ons, dysphagi a, and r espi rator y di str ess
C. Nausea, vomi ti ng, di ar r hea, and i ntesti nal cramps
D. Anor exi a, car di ac ar r hythmi as, fati gue, and br onchospasm

2Catechol ami nes act as potent i notr opes. That means that they:
A. cause the hear t to contract for ceful l y.
B. sl ow the hear t rate.
C. l ower bl ood pr essur e.
D. decr ease ur i nar y output.
P.
3Noncatechol ami nes can i nteract wi th monoami ne oxi dase
i nhi bi tor s to cause:
A. ar r hythmi as.
B. sever e hyper tensi on.
C. sei z ur es.
D. tachycar di a.

4Beta-adr ener gi c bl ocker s have wi despr ead effects because they

pr oduce thei r bl ocki ng acti on i n the:
A. hypothal amus.
B. anter i or pi tui tar y gl and.
C. pi tui tar y gl and.
D. adr enal medul l a.

Scoring
If you answer ed al l four i tems cor r ectl y, fabul ous! Your e
automati c wi th the autonomi c ner vous system.
If you answer ed thr ee i tems cor r ectl y, gr eat! Youve had
nothi ng but posi ti ve i nteracti ons wi th these dr ugs.

If you answer ed fewer than thr ee i tems cor r ectl y, dont

wor r y. Li ke the ner vous system, you have a l ot of
i nfor mati on to coor di nate. Just r evi ew the chapter and
tr y agai n.

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

3
Neurologic and neuromuscular drugs

Just the facts

In thi s chapter, youl l r evi ew:

cl asses of dr ugs used to tr eat neur ol ogi c and neur omuscul ar

di sor der s
uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se effects of these dr ugs.

Skeletal muscle relaxants

Skeletal muscle r elaxants r el i eve muscul oskel etal pai n or spasm and
sever e muscul oskel etal spasti ci ty (sti ff, awkwar d movements).
Theyr e used to tr eat acute, pai nful muscul oskel etal condi ti ons and
the muscl e spasti ci ty associ ated wi th mul ti pl e scl er osi s (MS) (a
pr ogr essi ve demyel i nati on of the whi te matter of the brai n and
spi nal cor d that causes wi despr ead neur ol ogi c dysfuncti on), cer ebral
pal sy (a motor functi on di sor der caused by neur ol ogi c damage),
str oke (r educed oxygen suppl y to the brai n, r esul ti ng i n neur ol ogi c
defi ci ts), and spi nal cor d i njur i es that can r esul t i n paral ysi s or
death.
Thi s chapter di scusses the two mai n cl asses of skel etal muscl e
r el axantscentr ally acting and dir ect-actingas wel l as other
muscl e r el axants.

Cycling problems
Exposur e to sever e col d, l ack of bl ood fl ow to a muscl e, or
over exer ti on can send sensor y i mpul ses fr om the poster i or sensor y
ner ve fi ber s to the spi nal cor d and the hi gher l evel s of the central
ner vous system (CNS). These sensor y i mpul ses can cause a r efl ex
(i nvol untar y) muscl e contracti on or spasm fr om trauma, epi l epsy,
hypocal cemi a (l ow cal ci um l evel s), or muscl e di sor der s.

The muscl e contracti on fur ther sti mul ates the sensor y r eceptor s to
a mor e i ntense contracti on, establ i shi ng a cycl e. Central l y acti ng
muscl e r el axants ar e bel i eved to br eak thi s cycl e by acti ng as CNS
depr essants.
Centrally acting skeletal muscle relaxants
Centr ally acting skeletal muscle r elaxants, whi ch act on the CNS,
ar e used to tr eat acute spasms caused by such condi ti ons as:

anxi ety
i nfl ammati on
pai n
trauma.

For intermittent or chronic spasms

A pati ent wi th i nter mi ttent or chr oni c spasms may r ecei ve
ti z ani di ne.

For acute spasms

A pati ent wi th acute muscl e spasms may r ecei ve one of these dr ugs:

car i sopr odol

chl or zoxazone
cycl obenz apr i ne
metaxal one
methocar bamol
or phenadr i ne
ti z ani di ne.

Pharmacokinetics (how drugs circulate)

Ther es sti l l a l ot we dont know about how central l y acti ng skel etal
muscl e r el axants ci r cul ate wi thi n the body. In general , these dr ugs
ar e absor bed fr om the G I tract, wi del y di str i buted i n the body,
metabol i zed i n the l i ver, and excr eted by the ki dneys.
Cyclobenzaprine sticks around
When these dr ugs ar e admi ni ster ed oral l y, i t can take fr om 30
mi nutes to 1 hour for effects to be achi eved. The durati on of acti on
of most of these dr ugs var i es fr om 4 to 6 hour s; cycl obenz apr i ne
has the l ongest durati on of acti on, at 12 to 25 hour s.

Pharmacodynamics (how drugs act)

The central l y acti ng dr ugs dont r el ax skel etal muscl es di r ectl y or
depr ess neur onal conducti on, neur omuscul ar transmi ssi on, or
muscl e exci tabi l i ty. Al though thei r pr eci se mechani sm of acti on i s
unknown, these dr ugs ar e known to be CNS depr essants. Thei r
muscl e r el axant effects may be r el ated to thei r sedati ve effects.
Pharmacotherapeutics (how drugs are used)
Pati ents r ecei ve central l y acti ng skel etal muscl e r el axants to tr eat
acute, pai nful muscul oskel etal condi ti ons. Theyr e usual l y
pr escr i bed al ong wi th r est and physi cal therapy.

Drug interactions
The central l y acti ng skel etal muscl e r el axants i nteract wi th other
CNS depr essants (i ncl udi ng al cohol , nar coti cs, bar bi turates,
anti convul sants, tr i cycl i c anti depr essants, kava kava, and
anti anxi ety dr ugs), causi ng i ncr eased sedati on, i mpai r ed motor
functi on, and r espi rator y depr essi on. In addi ti on, some of these
dr ugs have other i nteracti ons:

Cycl obenz apr i ne i nteracts wi th monoami ne oxi dase i nhi bi tor s

(MAOIs) and can r esul t i n a hi gh body temperatur e, exci tati on,
and sei z ur es.
Cycl obenz apr i ne can decr ease the anti hyper tensi ve effects of the
bl ood pr essur el ower i ng dr ugs guanethi di ne and cl oni di ne.
Or phenadr i ne and cycl obenz apr i ne someti mes enhance the
effects of chol i ner gi c-bl ocki ng dr ugs.
Methocar bamol can antagoni ze the chol i ner gi c effects of the
anti chol i nesterase dr ugs used to tr eat myastheni a gravi s.
 Or phenadr i ne can r educe the effects of phenothi az i nes.
Or phenadr i ne and pr opoxyphene taken together can cause
addi ti ve CNS effects, i ncl udi ng mental confusi on, anxi ety, and
tr emor s. (See Adver se r eacti ons to central l y acti ng skel etal
muscl e r el axants, page 52.)
Ti z ani di ne combi ned wi th di ur eti cs, central al pha-adr ener gi c
agoni sts, or anti hyper tensi ves may i ncr ease hypotensi ve dr ug
effects. Concur r ent use of ti z ani di ne wi th CNS depr essants may
cause addi ti ve CNS depr essi on. Hor monal contracepti ves may
r educe the cl earance of ti z ani di ne, necessi tati ng a dosage
r educti on.

Warning!
Adverse reactions to centrally acting skeletal
muscle relaxants
A pati ent can devel op physi cal and psychol ogi cal dependence after
l ong-ter m use of these dr ugs. Abr uptl y stoppi ng any of these
dr ugs can cause sever e wi thdrawal symptoms. Other adver se
r eacti ons can al so occur.
Common reactions

Di z z i ness
Dr owsi ness

Occasional reactions

Abdomi nal di str ess

Ataxi a
Consti pati on
Di ar r hea
Hear tbur n
Nausea and vomi ti ng

Severe reactions

Al l er gi c r eacti ons
Ar r hythmi as
 Bradycar di a

Direct-acting skeletal muscle relaxants

Dantr olene i s the most common di r ect-acti ng skel etal muscl e
r el axant. Al though dantr ol ene has a si mi l ar therapeuti c effect to the
central l y acti ng dr ugs, i t wor ks thr ough a di ffer ent mechani sm of
acti on. Because i ts major effect i s on the muscl es, dantr ol ene has a
l ower i nci dence of adver se CNS effects; hi gh therapeuti c doses,
however, ar e toxi c to the l i ver.
Common adver se effects of dantr ol ene i ncl ude dr owsi ness,
di z z i ness, mal ai se, fati gue, and weakness. Mor e ser i ous adver se
effects i ncl ude sei z ur es and hepati ti s. (See Dantr ol ene.)

In the head
Dantr ol ene seems most effecti ve for spasti ci ty of cer ebral or i gi n.
Because i t pr oduces muscl e weakness, dantr ol ene i s of questi onabl e
benefi t i n pati ents wi th bor der l i ne str ength.

Pharmacokinetics
Al though the peak dr ug concentrati on of dantr ol ene usual l y occur s
wi thi n about 5 hour s after i ts i ngested, the pati ent may not noti ce
the therapeuti c benefi t for a week or mor e.

Absorption
Dantr ol ene i s absor bed poor l y fr om the G I tract and i s hi ghl y
pl asma pr otei nbound. Thi s means that onl y a smal l por ti on of the
dr ug i s avai l abl e to pr oduce a therapeuti c effect.
 Safe and sound
Dantrolene
Because of the r i sk of l i ver damage wi th l ong-ter m use of
dantr ol ene, basel i ne l i ver functi on tests shoul d be obtai ned and
therapy shoul d be di sconti nued i f benefi ts ar ent seen i n 45 days.

Metabolism and excretion

Dantr ol ene i s metabol i zed by the l i ver and excr eted i n ur i ne. Its
el i mi nati on hal f-l i fe i n heal thy adul ts i s about 9 hour s. Because
dantr ol ene i s metabol i zed i n the l i ver, i ts hal f-l i fe may be pr ol onged
i n pati ents wi th i mpai r ed l i ver functi on.

Pharmacodynamics
Dantr ol ene i s chemi cal l y and phar macol ogi cal l y unr el ated to the
other skel etal muscl e r el axants.
Dantr ol ene wor ks by acti ng on the muscl e i tsel f. It i nter fer es wi th
cal ci um i on r el ease fr om the sar copl asmi c r eti cul um and weakens
the for ce of contracti ons. At therapeuti c concentrati ons, dantr ol ene
has l i ttl e effect on car di ac or i ntesti nal smooth muscl e.

Pharmacotherapeutics
Dantr ol ene hel ps manage al l types of spasti ci ty but i s most effecti ve
i n pati ents wi th:

cer ebral pal sy

MS
spi nal cor d i njur y
str oke.

Dantr ol ene i s al so used to tr eat and pr event mal i gnant

hyper ther mi a. Thi s rar e but potenti al l y fatal compl i cati on of
anesthesi a i s character i zed by skel etal muscl e r i gi di ty and hi gh
fever. (See How dantr ol ene r educes muscl e r i gi di ty.)

Drug interactions
 CNS depr essants can i ncr ease the depr essi ve effects of
dantr ol ene, r esul ti ng i n sedati on, l ack of coor di nati on, and
r espi rator y depr essi on.
Estr ogens, when gi ven wi th dantr ol ene, can i ncr ease the r i sk of
l i ver toxi ci ty.
I.V. verapami l , when gi ven wi th dantr ol ene, may r esul t i n
car di ovascul ar col l apse; these dr ugs shoul dnt be admi ni ster ed
concur r entl y.
Al cohol may i ncr ease CNS depr essi on when gi ven wi th
dantr ol ene.
Sun exposur e may cause photosensi ti vi ty.

Now I get it!

How dantrolene reduces muscle rigidity
Dantr ol ene appear s to decr ease the number of cal ci um i ons
r el eased fr om the sar copl asmi c r eti cul um (a str uctur e i n muscl e
cel l s that pl ays a r ol e i n muscl e contracti on and r el axati on by
r el easi ng and stor i ng cal ci um). The l ower the cal ci um l evel i n the
muscl e pl asma or myopl asm, the l ess ener gy pr oduced when
cal ci um pr ompts the muscl es acti n and myosi n fi l aments
(r esponsi bl e for muscl e contracti on) to i nteract. Less ener gy
means a weaker muscl e contracti on.
Reducing rigidity, halting hyperthermia
By pr omoti ng muscl e r el axati on, dantr ol ene pr events or r educes
the r i gi di ty that contr i butes to the l i fe-thr eateni ng body
temperatur es of mal i gnant hyper ther mi a.

Other skeletal muscle relaxants

Two other dr ugs used as skel etal muscl e r el axants ar e bacl ofen and
di azepam. Di azepam, however, i s pr i mar i l y an anti anxi ety dr ug.
(See Di azepam as a skel etal muscl e r el axant, page 54.)

Diazepam as a skeletal muscle relaxant

Di azepam i s a benzodi azepi ne dr ug thats used to tr eat acute
muscl e spasms as wel l as spasti ci ty caused by chr oni c di sor der s.
Other uses of di azepam i ncl ude tr eati ng anxi ety, al cohol
wi thdrawal , and sei z ur es. It seems to wor k by pr omoti ng the
 i nhi bi tor y effect of the neur otransmi tter gamma-ami nobutyr i c
aci d on muscl e contracti on.
The negatives: Sedation and tolerance
Di azepam can be used al one or wi th other dr ugs to tr eat
spasti ci ty, especi al l y i n pati ents wi th spi nal cor d l esi ons and,
occasi onal l y, i n pati ents wi th cer ebral pal sy. Its al so hel pful i n
pati ents wi th pai nful , conti nuous muscl e spasms who ar ent too
suscepti bl e to the dr ugs sedati ve effects. Unfor tunatel y,
di azepams use i s l i mi ted by i ts central ner vous system effects
and the tol erance that devel ops wi th pr ol onged use.

Pharmacokinetics
Bacl ofen and di azepam ar e absor bed rapi dl y fr om the G I tract.
Bacl ofen i s di str i buted wi del y (wi th onl y smal l amounts cr ossi ng the
bl ood-brai n bar r i er ), under goes mi ni mal l i ver metabol i sm, and i s
excr eted pr i mar i l y unchanged i n ur i ne.
Di azepam i s metabol i zed i n the l i ver and mostl y excr eted i n the
ur i ne, wi th a smal l amount excr eted i n the feces.

Slow to a stop
It can take fr om hour s to weeks befor e the pati ent noti ces the
benefi ci al effects of bacl ofen. The el i mi nati on hal f-l i fe of bacl ofen i s
2 to 4 hour s. Abr upt wi thdrawal of the dr ug can cause
hal l uci nati ons, sei z ur es, and wor seni ng of spasti ci ty.

Pharmacodynamics
It i snt known exactl y how bacl ofen or di azepam wor ks. Di azepam
pr obabl y depr esses the CNS at the l i mbi c and subcor ti cal l evel s of
the brai n. It suppr esses the spr ead of sei z ur e acti vi ty i n the cor tex,
thal amus, and l i mbi c ar eas.
Bacl ofen i s chemi cal l y si mi l ar to the neur otransmi tter gamma-
ami nobutyr i c aci d (G ABA) and pr obabl y acts i n the spi nal cor d. It
r educes ner ve i mpul ses fr om the spi nal cor d to skel etal muscl e,
decr easi ng the number and sever i ty of muscl e spasms and r educi ng
associ ated pai n.
A choice drug
Because bacl ofen pr oduces l ess sedati on than di azepam and l ess
per i pheral muscl e weakness than dantr ol ene, i ts the dr ug of choi ce
to tr eat spasti ci ty.

Pharmacotherapeutics
Bacl ofens pr i mar y cl i ni cal use i s for parapl egi c or quadr i pl egi c
pati ents wi th spi nal cor d l esi ons, most commonl y caused by MS or
trauma. For these pati ents, bacl ofen si gni fi cantl y r educes the
number and sever i ty of pai nful fl exor spasms. However, i t doesnt
i mpr ove sti ff gai t, manual dexter i ty, or r esi dual muscl e functi on.
Bacl ofen may be admi ni ster ed i ntrathecal l y for pati ents who ar e
unr esponsi ve to oral bacl ofen or who exper i ence i ntol erabl e adver se
r eacti ons. After a posi ti ve r esponse to a bol us dose, an i mpl antabl e
por t for chr oni c therapy i s i nser ted.
Di azepam r el i eves anxi ety, muscl e spasms, and sei z ur es, and i t
i nduces cal mness and sl eep.

Warning!
Adverse reactions to baclofen
Most common

Transi ent dr owsi ness

Less common

Nausea
Fati gue
Ver ti go
Hypotoni a
Muscl e weakness
 Depr essi on
Headache

Drug interactions
Bacl ofen has few dr ug i nteracti ons:

The most si gni fi cant dr ug i nteracti on i s an i ncr ease i n CNS

depr essi on when bacl ofen i s admi ni ster ed wi th other CNS
depr essants, i ncl udi ng al cohol .
Anal gesi a can be pr ol onged when fentanyl and bacl ofen ar e
admi ni ster ed together.
Li thi um car bonate and bacl ofen taken together can aggravate
hyper ki nesi a (an abnor mal i ncr ease i n motor functi on or
acti vi ty).
Tr i cycl i c anti depr essants and bacl ofen taken together can
i ncr ease muscl e r el axati on.
Bacl ofen may i ncr ease bl ood gl ucose l evel s, r esul ti ng i n the
need for i ncr eased doses of oral anti di abeti c agents and i nsul i n.

Intrathecal bacl ofen shoul dnt be di sconti nued abr uptl y because
doi ng so has r esul ted i n hi gh fever, al ter ed mental status,
exaggerated r ebound spasti ci ty, and muscl e r i gi di ty that, i n rar e
cases, has pr ogr essed to r habdomyol ysi s, mul ti pl e or gan system
fai l ur e, and death. (See Adver se r eacti ons to bacl ofen.)

Neuromuscular blocking drugs

Neur omuscular blocking dr ugs r el ax skel etal muscl es by di sr upti ng
the transmi ssi on of ner ve i mpul ses at the motor end pl ate (the
branchi ng ter mi nal s of a motor ner ve axon). (See Motor end pl ate,
page 56.)
Neur omuscul ar bl ocker s have thr ee major cl i ni cal i ndi cati ons:

to r el ax skel etal muscl es dur i ng sur ger y

to r educe the i ntensi ty of muscl e spasms i n dr ug- or
el ectr i cal l y i nduced sei z ur es
 to manage pati ents who ar e fi ghti ng the use of a venti l ator to
hel p wi th br eathi ng.

Now I get it!

Motor end plate
The motor ner ve axon di vi des to for m branchi ng ter mi nal s
cal l ed motor end plates. These ar e enfol ded i n muscl e fi ber s, but
separated fr om the fi ber s by the synapti c cl eft.
Competing with contraction
A sti mul us to the ner ve causes the r el ease of acetyl chol i ne i nto
the synapti c cl eft. Ther e, acetyl chol i ne occupi es r eceptor si tes on
the muscl e cel l membrane, depol ar i z i ng the membrane and
causi ng muscl e contracti on. Neur omuscul ar bl ocki ng agents act at
the motor end pl ate by competi ng wi th acetyl chol i ne for the
r eceptor si tes or by bl ocki ng depol ar i z ati on.

Two main classifications

Ther e ar e two mai n cl asses of natural and syntheti c dr ugs used as
neur omuscul ar bl ocker snondepol ar i z i ng and depol ar i z i ng.

Nondepolarizing blocking drugs

Nondepolar iz ing blocking dr ugs, al so cal l ed competitive or stabiliz ing
dr ugs, ar e der i ved fr om curar e al kal oi ds and syntheti cal l y si mi l ar
compounds. They i ncl ude:

atracur i um
ci satracur i um
pancur oni um
r ocur oni um
vecur oni um.

Pharmacokinetics
Because nondepol ar i z i ng bl ocker s ar e absor bed poor l y fr om the G I
tract, theyr e admi ni ster ed par enteral l y. The I.V. r oute i s pr efer r ed
because the acti on i s mor e pr edi ctabl e.

Distribution
These dr ugs ar e di str i buted rapi dl y thr oughout the body.

Metabolism and excretion

A var i abl e but l ar ge pr opor ti on of the nondepol ar i z i ng dr ugs i s
excr eted unchanged i n ur i ne. Some dr ugs, such as atracur i um,
pancur oni um, and vecur oni um, ar e par ti al l y metabol i zed i n the
l i ver.

Pharmacodynamics
Nondepol ar i z i ng bl ocker s compete wi th acetyl chol i ne at the
chol i ner gi c r eceptor si tes of the skel etal muscl e membrane. Thi s
bl ocks acetyl chol i nes neur otransmi tter acti on, pr eventi ng the
muscl e fr om contracti ng.
The effect can be counteracted by anti chol i nesterase dr ugs, such as
neosti gmi ne and pyr i dosti gmi ne, whi ch i nhi bi t the acti on of
acetyl chol i nesterase, the enz yme that destr oys acetyl chol i ne.

Safe and sound

Using a neuromuscular blocker safely
When usi ng a neur omuscul ar bl ocker, r emember these
i mpor tant poi nts to keep the pati ent safe:
 Emer gency r espi rator y suppor t equi pment (endotracheal
equi pment, venti l ator, oxygen, atr opi ne, edr ophoni um,
epi nephr i ne, and neosti gmi ne) shoul d be i mmedi atel y
avai l abl e.
Dr ug-i nduced neur omuscul ar bl ockade may be r ever sed wi th
an anti chol i nesterase (such as neosti gmi ne or edr ophoni um),
whi ch i s usual l y gi ven wi th an anti chol i ner gi c, such as
atr opi ne.
Sedati ves or general anestheti cs shoul d be admi ni ster ed
befor e neur omuscul ar bl ocker s.

From weakness to paralysis

The i ni ti al muscl e weakness pr oduced by these dr ugs qui ckl y
changes to a fl acci d (l oss of muscl e tone) paral ysi s that affects the
muscl es i n a speci fi c sequence. The fi r st muscl es to exhi bi t fl acci d
paral ysi s ar e those of the eyes, face, and neck. Next, the l i mb,
abdomen, and tr unk muscl es become fl acci d. Lastl y, the i nter costal
muscl es (between the r i bs) and di aphragm (the br eathi ng muscl e)
ar e paral yzed. Recover y fr om the paral ysi s usual l y occur s i n the
r ever se or der.

Conscious and aware

Because these dr ugs dont cr oss the bl ood-brai n bar r i er, the pati ent
r emai ns consci ous and can feel pai n. Even though the pati ent i s
paral yzed, hes awar e of whats happeni ng to hi m and can
exper i ence extr eme anxi ety but cant communi cate hi s feel i ngs. For
thi s r eason, an anal gesi c or anti anxi ety dr ug shoul d be
admi ni ster ed al ong wi th a neur omuscul ar bl ocker. (See Usi ng a
neur omuscul ar bl ocker safel y.)

Pharmacotherapeutics
Nondepol ar i z i ng bl ocker s ar e used for i nter medi ate or pr ol onged
muscl e r el axati on to:

ease the passage of an endotracheal (ET) tube

decr ease the amount of anestheti c r equi r ed dur i ng sur ger y
faci l i tate r eal i gnment of br oken bones and di sl ocated joi nts
paral yze pati ents who need venti l ator y suppor t but who fi ght the
ET tube and venti l ati on
pr event muscl e i njur y dur i ng el ectr oconvul si ve therapy (ECT)
(passi ng an el ectr i c cur r ent thr ough the brai n to tr eat
depr essi on) by r educi ng the i ntensi ty of muscl e spasms.

Drug interactions
These dr ugs al ter the effects of nondepol ar i z i ng neur omuscul ar
bl ocker s:

Ami nogl ycosi de anti bi oti cs and anestheti cs potenti ate or

exaggerate the neur omuscul ar bl ockade.
Dr ugs that al ter the ser um l evel s of the el ectr ol ytes cal ci um,
magnesi um, or potassi um al so al ter the effects of the
 nondepol ar i z i ng bl ocker s.
The anti chol i nesterases (neosti gmi ne, pyr i dosti gmi ne, and
edr ophoni um) antagoni ze nondepol ar i z i ng bl ocker s and ar e used
as anti dotes to them.
Dr ugs that can i ncr ease the i ntensi ty and durati on of paral ysi s
when taken wi th a nondepol ar i z i ng bl ocker i ncl ude i nhal ati on
anestheti cs, ami nogl ycosi des, cl i ndamyci n, pol ymyxi n,
verapami l , qui ni ne der i vati ves, ketami ne, l i thi um, ni trates,
thi az i de di ur eti cs, tetracycl i nes, and magnesi um sal ts.
Dr ugs that can cause decr eased neur omuscul ar bl ockade when
taken wi th a nondepol ar i z i ng bl ocker i ncl ude car bamazepi ne,
hydantoi ns, rani ti di ne, and theophyl l i ne. (See Adver se r eacti ons
to nondepol ar i z i ng bl ocker s.)
Concur r ent use of cor ti coster oi ds may r esul t i n pr ol onged muscl e
weakness.

Warning!
Adverse reactions to nondepolarizing blockers
To all drugs in this class

Apnea
Hypotensi on
Ski n r eacti ons
Br onchospasm
Excessi ve br onchi al and sal i var y secr eti ons

To pancuronium

Tachycar di a
Car di ac ar r hythmi as
Hyper tensi on

Depolarizing blocking drugs

Succinylcholine i s the onl y therapeuti c depol ar i z i ng bl ocki ng dr ug.
Al though i ts si mi l ar to the nondepol ar i z i ng bl ocker s i n i ts
therapeuti c effect, i ts mechani sm of acti on di ffer s. Succi nyl chol i ne
acts l i ke acetyl chol i ne, but i t i snt i nacti vated by chol i nesterase. Its
the dr ug of choi ce when shor t-ter m muscl e r el axati on i s needed.

Pharmacokinetics
Because succi nyl chol i ne i s absor bed poor l y fr om the G I tract, the
pr efer r ed admi ni strati on r oute i s I.V.; the I.M. r oute can be used, i f
necessar y.

Metabolism and excretion

Succi nyl chol i ne i s hydr ol yzed i n the l i ver and pl asma by the enz yme
pseudochol i nesterase, pr oduci ng a metabol i te wi th a
nondepol ar i z i ng bl ocki ng acti on. Succi nyl chol i ne i s excr eted by the
ki dneys, wi th a smal l amount excr eted unchanged.

Pharmacodynamics
After admi ni strati on, succi nyl chol i ne i s rapi dl y metabol i zed, but at a
sl ower rate than acetyl chol i ne. As a r esul t, succi nyl chol i ne r emai ns
attached to r eceptor si tes on the skel etal muscl e membrane for a
l onger per i od of ti me. Thi s pr events r epol ar i z ati on of the motor end
pl ate and r esul ts i n muscl e paral ysi s.

Pharmacotherapeutics
Succi nyl chol i ne i s the dr ug of choi ce for shor t-ter m muscl e
r el axati on, such as dur i ng i ntubati on and ECT.
Drug interactions
The acti on of succi nyl chol i ne i s potenti ated by a number of
anestheti cs and anti bi oti cs. In contrast to thei r i nteracti on wi th
nondepol ar i z i ng bl ocker s, anti chol i nesterases i ncr ease
succi nyl chol i ne bl ockade. (See Adver se r eacti ons to
succi nyl chol i ne.)

Antiparkinsonian drugs
Dr ug therapy i s an i mpor tant par t of the tr eatment for Par ki nsons
di sease, a pr ogr essi ve neur ol ogi c di sor der character i zed by four
car di nal featur es:

muscl e r i gi di ty (i nfl exi bi l i ty)

aki nesi a (l oss of muscl e movement)
tr emor s at r est
di stur bances of postur e and bal ance.

Warning!
Adverse reactions to succinylcholine
The pr i mar y adver se dr ug r eacti ons to succi nyl chol i ne ar e:

pr ol onged apnea
hypotensi on.

Genetics increases the risk

The r i sks associ ated wi th succi nyl chol i ne i ncr ease wi th cer tai n
geneti c pr edi sposi ti ons, such as a l ow pseudochol i nesterase l evel
and the tendency to devel op mal i gnant hyper ther mi a.

A defect in the dopamine pathway

Par ki nsons di sease affects the extrapyrami dal system, whi ch
i nfl uences movement. The extrapyrami dal system i ncl udes the
cor pus str i atum, gl obus pal l i dus, and substanti a ni gra of the brai n.

In Par ki nsons di sease, a dopami ne defi ci ency occur s i n the basal

gangl i a, the dopami ne-r el easi ng pathway that connects the
substanti a ni gra to the cor pus str i atum.

causes an imbalance of neurotransmitters

Reducti on of dopami ne i n the cor pus str i atum upsets the nor mal
bal ance between two neur otransmi tter s, acetyl chol i ne and
dopami ne. Thi s r esul ts i n a r el ati ve excess of acetyl chol i ne. The
excessi ve exci tati on caused by chol i ner gi c acti vi ty cr eates the
movement di sor der s that character i ze Par ki nsons di sease.

Other causes
Par ki nsons di sease can al so r esul t fr om dr ugs, encephal i ti s,
neur otoxi ns, trauma, ar ter i oscl er osi s, or other neur ol ogi c di sor der s
and envi r onmental factor s.

Goals of drug therapy

The goal s of dr ug therapy ar e to pr ovi de r el i ef of symptoms and to
mai ntai n the pati ents i ndependence and mobi l i ty.
Dr ug therapy for Par ki nsons di sease i s ai med at cor r ecti ng the
i mbal ance of neur otransmi tter s by:

i nhi bi ti ng chol i ner gi c effects (wi th anti chol i ner gi c dr ugs)

enhanci ng the effects of dopami ne (wi th dopami ner gi c dr ugs).

Anticholinergic drugs
Anticholiner gic dr ugs ar e someti mes cal l ed par asympatholytic dr ugs
because they i nhi bi t the acti on of acetyl chol i ne at speci al r eceptor s
i n the parasympatheti c ner vous system.
Two classes
Anti chol i ner gi cs used to tr eat Par ki nsons di sease ar e cl assi fi ed i n
two chemi cal categor i es accor di ng to thei r chemi cal str uctur e:

syntheti c ter ti ar y ami nes, such as benz tr opi ne, bi per i den
hydr ochl or i de, bi per i den l actate, pr ocycl i di ne, and
tr i hexypheni dyl
anti hi stami nes (such as di phenhydrami ne) that have
anti chol i ner gi c pr oper ti es, whi ch ar e effecti ve i n tr eati ng the
symptoms of Par ki nsons di sease.

Pharmacokinetics
Typi cal l y, anti chol i ner gi c dr ugs ar e wel l absor bed fr om the G I tract
and cr oss the bl ood-brai n bar r i er to thei r acti on si te i n the brai n.
Most ar e metabol i zed i n the l i ver, at l east par ti al l y, and ar e
excr eted by the ki dneys as metabol i tes and unchanged dr ug. The
exact di str i buti on of these dr ugs i s unknown.

Up to 24 hours
Benz tr opi ne i s a l ong-acti ng dr ug wi th a durati on of up to 24 hour s
i n some pati ents. For most anti chol i ner gi cs, hal f-l i fe i s
undeter mi ned. In addi ti on to the oral r oute, some anti chol i ner gi cs
can al so be gi ven I.M. or I.V.

Pharmacodynamics
Hi gh acetyl chol i ne l evel s pr oduce an exci tator y effect on the CNS,
whi ch can cause a par ki nsoni an tr emor. Pati ents wi th Par ki nsons
di sease take anti chol i ner gi c dr ugs to i nhi bi t the acti on of
acetyl chol i ne at r eceptor si tes i n the CNS and autonomi c ner vous
system, thus r educi ng the tr emor.

Pharmacotherapeutics
Anti chol i ner gi cs ar e used to tr eat al l for ms of Par ki nsons di sease.
Theyr e used most commonl y i n the ear l y stages of Par ki nsons
di sease when symptoms ar e mi l d and dont have a major i mpact on
the pati ents l i festyl e. These dr ugs effecti vel y contr ol si al or r hea
(excessi ve fl ow of sal i va) and ar e about 20% effecti ve i n r educi ng
the i nci dence and sever i ty of aki nesi a and r i gi di ty.

Together or alone
Anti chol i ner gi cs can be used al one or wi th amantadi ne i n the ear l y
stages of Par ki nsons di sease. In addi ti on, anti chol i ner gi cs can be
gi ven wi th l evodopa dur i ng the l ater stages to fur ther r el i eve
symptoms.

Drug interactions
Interacti ons can occur when cer tai n medi cati ons ar e taken wi th
anti chol i ner gi cs:

Amantadi ne can cause i ncr eased anti chol i ner gi c adver se effects.
Absor pti on of l evodopa can be decr eased, whi ch coul d l ead to
wor seni ng of par ki nsoni an si gns and symptoms.
Anti psychoti cs taken wi th anti chol i ner gi cs (such as
phenothi az i nes, thi othi xene, hal oper i dol , and l oxapi ne) decr ease
the effecti veness of both anti chol i ner gi cs and anti psychoti cs. The
i nci dence of anti chol i ner gi c adver se effects can al so be
i ncr eased.
Over-the-counter cough or col d pr eparati ons, di et ai ds, and
anal epti cs (dr ugs used to stay awake) i ncr ease anti chol i ner gi c
effects.
Al cohol i ncr eases CNS depr essi on. (See Adver se r eacti ons to
anti chol i ner gi cs, page 62.)
 Warning!
Adverse reactions to anticholinergics
Mi l d, dose-r el ated adver se r eacti ons ar e seen i n 30% to
50% of pati ents who take anti chol i ner gi cs. Dr y mouth may be a
dose-r el ated r eacti on to tr i hexypheni dyl .
Common reactions

Confusi on
Restl essness
Agi tati on and exci tement
Dr owsi ness or i nsomni a
Tachycar di a and pal pi tati ons
Consti pati on
Nausea and vomi ti ng
Ur i ne r etenti on
Incr eased i ntraocul ar pr essur e, bl ur r ed vi si on, pupi l di l ati on,
and photophobi a

Sensitivity-related reactions

Hi ves
Al l er gi c rash

Reactions in patients older than age 60

Incr eased sensi ti vi ty to anti chol i ner gi cs, r esul ti ng i n

confusi on, agi tati on, hal l uci nati ons, and possi bl y psychoti c
symptoms

Dopaminergic drugs
Dopaminer gic dr ugs i ncl ude several dr ugs that ar e chemi cal l y
unr el ated:

l evodopa, the metabol i c pr ecur sor to dopami ne

car bi dopa-l evodopa, a combi nati on dr ug composed of car bi dopa
 and l evodopa
amantadi ne, an anti vi ral dr ug wi th dopami ner gi c acti vi ty
br omocr i pti ne, an er got-type dopami ne agoni st
r opi ni r ol e and prami pexol e, two non-er got-type dopami ne
agoni sts
sel egi l i ne and rasagi l i ne, type B MAOIs.

Pharmacokinetics
Li ke anti chol i ner gi c dr ugs, dopami ner gi c dr ugs ar e absor bed fr om
the G I tract i nto the bl oodstr eam and ar e del i ver ed to thei r acti on
si te i n the brai n.

Slowing down with food

Absor pti on of l evodopa i s sl owed and r educed when i ts i ngested
wi th food. The body absor bs most l evodopa, car bi dopa-l evodopa,
prami pexol e, or amantadi ne fr om the G I tract after oral
admi ni strati on, but onl y about 28% of br omocr i pti ne. About 73% of
an oral dose of sel egi l i ne i s absor bed. Rasagi l i ne i s rapi dl y absor bed
i nto the bl oodstr eam.

Distribution
Levodopa i s wi del y di str i buted i n body ti ssues, i ncl udi ng the G I
tract, l i ver, pancr eas, ki dneys, sal i var y gl ands, and ski n. Car bi dopa-
l evodopa and prami pexol e ar e al so wi del y di str i buted. Amantadi ne i s
di str i buted i n sal i va, nasal secr eti ons, and br east mi l k.
Br omocr i pti ne and rasagi l i ne ar e hi ghl y pr otei n-bound. The
di str i buti on of sel egi l i ne i s unknown.

Metabolism and excretion

Dopami ner gi c dr ugs ar e metabol i zed extensi vel y i n var i ous ar eas of
the body and el i mi nated by the l i ver, the ki dneys, or both.

Lar ge amounts of l evodopa ar e metabol i zed i n the stomach and

dur i ng the fi r st pass thr ough the l i ver. The dr ug i s metabol i zed
extensi vel y to var i ous compounds that ar e excr eted by the
ki dneys.
 Car bi dopa i snt metabol i zed extensi vel y. The ki dneys excr ete
appr oxi matel y one-thi r d of i t as unchanged dr ug wi thi n 24
hour s.
Amantadi ne, r opi ni r ol e, and prami pexol e ar e excr eted mostl y
unchanged by the ki dneys.
Al most al l of a br omocr i pti ne or rasagi l i ne dose i s metabol i zed
by the l i ver to phar macol ogi cal l y i nacti ve compounds, whi ch ar e
then el i mi nated pr i mar i l y i n feces, wi th onl y a smal l amount
excr eted i n ur i ne.
Sel egi l i ne i s metabol i zed to L-amphetami ne, L-
methamphetami ne, and N-desmethyl depr enyl (the major
metabol i te), whi ch ar e el i mi nated i n ur i ne.

Pharmacodynamics
Dopami ner gi c dr ugs act i n the brai n to i mpr ove motor functi on i n
one of two ways: by i ncr easi ng the dopami ne concentrati on or by
enhanci ng neur otransmi ssi on of dopami ne.

Getting the job done

Levodopa i s i nacti ve unti l i t cr osses the bl ood-brai n bar r i er and i s
conver ted to dopami ne by enz ymes i n the brai n, i ncr easi ng
dopami ne concentrati ons i n the basal gangl i a. Car bi dopa enhances
l evodopas effecti veness by bl ocki ng the per i pheral conver si on of
l evodopa, thus per mi tti ng i ncr eased amounts of l evodopa to be
transpor ted to the brai n.
The other dopami ner gi c dr ugs have var i ous mechani sms of acti on:

Amantadi nes mechani sm of acti on i snt cl ear. Its thought to

r el ease dopami ne fr om i ntact neur ons, but i t may al so have
nondopami ner gi c mechani sms.

Br omocr i pti ne, r opi ni r ol e, and prami pexol e sti mul ate dopami ne
r eceptor s i n the brai n, pr oduci ng effects that ar e si mi l ar to
dopami nes.
Rasagi l i ne has an unknown mechani sm of acti on.
Sel egi l i ne can i ncr ease dopami ner gi c acti vi ty by i nhi bi ti ng type
B MAO acti vi ty or by other mechani sms.

Pharmacotherapeutics
The choi ce of therapy i s hi ghl y i ndi vi dual i zed, dependi ng on the
pati ents symptoms and extent of di sabi l i ty. Pati ents wi th mi l d
Par ki nsons di sease whose mai n symptom i s a tr emor ar e commonl y
gi ven anti chol i ner gi cs or amantadi ne. Sel egi l i ne i s i ndi cated for
extendi ng the durati on of l evodopa by bl ocki ng i ts br eakdown; i t
has al so been used i n the ear l y stages of Par ki nsons di sease
because of i ts neur opr otecti ve pr oper ti es and potenti al to sl ow the
pr ogr essi on of the di sease.
Dopami ner gi c dr ugs ar e usual l y used to tr eat pati ents wi th sever e
Par ki nsons di sease or those who dont r espond to anti chol i ner gi cs
al one. Levodopa i s the most effecti ve dr ug used to tr eat Par ki nsons
di sease; however, i t l oses i ts effecti veness after 3 to 5 year s. (See
Levodopa: Pr os and cons.)

Yea or nay?
Levodopa: Pros and cons
Levodopa i s commonl y used to tr eat Par ki nsons di sease;
however, i ts use i snt wi thout contr over sy. Ini ti al l y, l evodopa i s
ver y effecti ve i n contr ol l i ng symptoms. But after several year s,
the effects of the dr ug someti mes dont l ast as l ong (the wear i ng-
off effect) or l ead to shar p fl uctuati ons i n symptoms (the on-off
phenomenon).
Early vs. late start
Some doctor s feel that l evodopa shoul d be star ted ear l y (when
the di agnosi s i s made) i n l ow doses. Other s bel i eve i t shoul d be
 star ted l ater i n the cour se of the di sease (when symptoms
compr omi se functi on). Advocates of an ear l y star t bel i eve that
fl uctuati ons i n the pati ents r esponse to l evodopa stem fr om the
pr ogr essi on of Par ki nsons di sease and not fr om the effects of
l evodopa.
Some doctor s ar e concer ned that l evodopa accel erates the
pr ogr essi on of Par ki nsons di sease by pr ovi di ng a sour ce of fr ee
radi cal s that contr i bute to the degenerati on of dopami ner gi c
neur ons.

Flurry of fluctuations
When the pati ents r esponse to l evodopa fl uctuates, dosage
adjustments and i ncr eased fr equency of admi ni strati on may be
tr i ed. Al ter nati vel y, adjuncti ve therapy, such as dopami ne agoni sts,
sel egi l i ne, amantadi ne, or catechol -O-methyl transferase (COMT)
i nhi bi tor s, may be added. Contr ol l ed-r el ease for ms of car bi dopa-
l evodopa may be hel pful i n managi ng the wear i ng-off effect (when
l evodopas effects dont l ast as l ong as they used to) or del ayed-
onset motor fl uctuati ons.

Add carbidopa, reduce levodopa

Levodopa i s al most al ways combi ned wi th car bi dopa as the standar d
therapy for Par ki nsons di sease. When these dr ugs ar e gi ven
together, the dosage of l evodopa can be r educed, decr easi ng the
r i sk of G I and car di ovascul ar adver se effects.

Tapered treatment
The dosage of some dopami ner gi c dr ugs, such as amantadi ne,
l evodopa, prami pexol e, and br omocr i pti ne, must be gradual l y
taper ed to avoi d pr eci pi tati ng par ki nsoni an cr i si s (sudden mar ked
cl i ni cal deter i orati on) and possi bl y l i fe-thr eateni ng compl i cati ons,
i ncl udi ng muscl e r i gi di ty, el evated body temperatur e, tachycar di a,
mental changes, and i ncr eased ser um cr eati ne ki nase (r esembl i ng
neur ol epti c mal i gnant syndr ome).

Drug interactions
Ther e ar e a number of dr ug i nteracti ons r el ated to dopami ner gi c
dr ugs, i ncl udi ng some that ar e potenti al l y fatal .
 Levodopas effecti veness may be r educed when used concur r entl y
wi th pyr i doxi ne (vi tami n B6 ), phenytoi n, benzodi azepi nes,
r eser pi ne, or papaver i ne.
MAOIs such as tranyl cypr omi ne i ncr ease the r i sk of hyper tensi ve
cr i si s.
Anti psychoti cs, such as phenothi az i nes, thi othi xene, hal oper i dol ,
and l oxapi ne, can r educe the effecti veness of l evodopa.
Amantadi ne may potenti ate the anti chol i ner gi c adver se effects,
such as confusi on and hal l uci nati ons, of anti chol i ner gi c dr ugs
and r educe the absor pti on of l evodopa.
Meper i di ne taken wi th sel egi l i ne at a hi gher-than-r ecommended
dose can cause a fatal r eacti on. (See Adver se r eacti ons to
dopami ner gi c dr ugs, page 66.)

In some pati ents, l evodopa can pr oduce a si gni fi cant i nteracti on

wi th foods. Di etar y ami no aci ds can decr ease l evodopas
effecti veness by competi ng wi th i t for absor pti on fr om the i ntesti ne
and sl owi ng i ts transpor t to the brai n.

Warning!
Adverse reactions to dopaminergic drugs
Levodopa

Nausea and vomi ti ng

Or thostati c hypotensi on
Anor exi a
Neur ol epti c mal i gnant syndr ome
Ar r hythmi as
Ir r i tabi l i ty
Confusi on

Amantadine

Or thostati c hypotensi on
Consti pati on

Bromocriptine
 Per si stent or thostati c hypotensi on
ventr i cul ar tachycar di a
bradycar di a
wor seni ng angi na

Rasagiline

Hyper tensi ve cr i si s (i f taken wi th tyrami ne-contai ni ng foods)

hal l uci nati ons
F l u syndr ome
Ar thral gi a
Depr essi on

Pramipexole, ropinirole

Or thostati c hypotensi on
di z z i ness
confusi on
i nsomni a

COMT inhibitors
COMT i nhi bi tor s ar e used as adjuncts to l evodopa-car bi dopa therapy
i n managi ng pati ents wi th Par ki nsons di sease who exper i ence the
wear i ng-off effect at the end of a dosi ng i nter val .
Cur r entl y two COMT i nhi bi tor s ar e avai l abl e:

tol capone
entacapone.
Pharmacokinetics
Tol capone and entacapone ar e rapi dl y absor bed i n the G I tract and
have an absol ute bi oavai l abi l i ty of 65% and 35% , r especti vel y. Both
dr ugs ar e hi ghl y bound to al bumi n and ther efor e have l i mi ted
di str i buti on to the ti ssues. Theyr e al most compl etel y metabol i zed i n
the l i ver to i nacti ve metabol i tes and ar e excr eted i n ur i ne.

Pharmacodynamics
Tol capone and entacapone ar e sel ecti ve and r ever si bl e i nhi bi tor s of
COMT, the major metabol i z i ng enz yme for l evodopa, i n the pr esence
of a decar boxyl ase i nhi bi tor such as car bi dopa. Inhi bi ti on of COMT
al ter s the phar macoki neti cs of l evodopa, l eadi ng to sustai ned
pl asma l evel s of thi s dr ug. Thi s r esul ts i n mor e sustai ned
dopami ner gi c sti mul ati on i n the brai n and i mpr ovement i n si gns and
symptoms of Par ki nsons di sease.

Pharmacotherapeutics
Ei ther tol capone or entacapone may be added to the car bi dopa-
l evodopa r egi men of a pati ent who exper i ences wear i ng-off
symptoms at the end of a dosi ng i nter val or random on-off
fl uctuati ons i n r esponse to car bi dopa-l evodopa. COMT i nhi bi tor s
have no anti par ki nsoni an effect when used al one and shoul d al ways
be combi ned wi th car bi dopa-l evodopa. The addi ti on of a COMT
i nhi bi tor often r equi r es a decr ease i n the car bi dopa-l evodopa
dosage, par ti cul ar l y for pati ents r ecei vi ng a l evodopa dose of mor e
than 800 mg.
Slow and steady
Rapi d wi thdrawal of a COMT i nhi bi tor may l ead to par ki nsoni an
cr i si s and may cause a syndr ome of muscl e r i gi di ty, hi gh fever,
tachycar di a, el evated ser um cr eati ne ki nase, and confusi on si mi l ar
to neur ol epti c mal i gnant syndr ome. Al though taper i ng schedul es
havent been eval uated, a sl ow taper i ng of the dosage i s suggested.

Drug interactions
COMT i nhi bi tor s shoul dnt be used concur r entl y wi th Type A
MAOIs but may be used wi th sel egi l i ne.
Because of MAO i nhi bi ti on, COMT i nhi bi tor s shoul dnt be used
wi th l i nezol i d.
Si gni fi cant car di ac effects or ar r hythmi as may r esul t when COMT
i nhi bi tor s ar e combi ned wi th catechol ami ne dr ugs (dopami ne,
dobutami ne, epi nephr i ne, methyl dopa, or nor epi nephr i ne).
Use of COMT i nhi bi tor s wi th CNS depr essants (benzodi azepi nes,
tr i cycl i c anti depr essants, anti psychoti cs, ethanol , opi oi d
anal gesi cs, and other sedati ve hypnoti cs) may cause addi ti ve
CNS effects.
Concur r ent use of entacapone and br omocr i pti ne may cause
fi br oti c compl i cati ons.

Calling an interference
Dr ugs that i nter fer e wi th gl ucur oni dati on (er ythr omyci n,
r i fampi n, chol estyrami ne, and pr obeneci d) may decr ease
entacapone el i mi nati on.
Use of COMT i nhi bi tor s may i ncr ease the r i sk of or thostati c
hypotensi on i n pati ents r ecei vi ng dopami ner gi c therapy.
Tol capone shoul dnt be i ni ti ated i n pati ents wi th evi dence of
l i ver di sease or al ani ne ami notransferase or aspar tate
ami notransferase val ues gr eater than the upper l i mi t of nor mal .
In addi ti on, the pati ent must be advi sed of the r i sks of l i ver
i njur y and must

gi ve wr i tten i nfor med consent befor e r ecei vi ng tol capone. (See

Adver se r eacti ons to COMT i nhi bi tor s.)
 Warning!
Adverse reactions to COMT inhibitors
Catechol -O-methyl transferase (COMT) i nhi bi tor s may
pr oduce acute l i ver fai l ur e, a l i fe-thr eateni ng adver se r eacti on.
Consequentl y, tol capone shoul d be used onl y i n pati ents wi th
Par ki nsons di sease who ar e exper i enci ng fl uctuati ons i n l evodopa
r esponse and ar ent r espondi ng toor ar ent appr opr i ate
candi dates for other adjuncti ve therapi es. Pati ents shoul d be
advi sed of the r i sks of l i ver i njur y and pr ovi de wr i tten i nfor med
consent befor e star ti ng tol capone.
Li ver functi on tests shoul d be obtai ned at the star t of therapy to
pr ovi de a basel i ne and ever y 2 weeks for the fi r st year of
therapy, then ever y 4 weeks for the next 3 months, and ever y 8
weeks ther eafter.
COMT i nhi bi tor s can al so pr oduce these adver se r eacti ons.
Common reactions

Nausea
Dyski nesi a
Di ar r hea
Br own-orange ur i ne di scol orati on (entacapone)
Hyper ki nesi a or hypoki nesi a

Less common reactions

Or thostati c hypotensi on
Syncope
Di z z i ness
Fati gue
Abdomi nal pai n
Consti pati on
Vomi ti ng
Dr y mouth
Back pai n
Di aphor esi s
Anticonvulsant drugs
Anticonvulsant dr ugs i nhi bi t neur omuscul ar transmi ssi on and ar e
pr escr i bed for :

l ong-ter m management of chr oni c epi l epsy (r ecur r ent sei z ur es)
shor t-ter m management of acute i sol ated sei z ur es not caused by
epi l epsy, such as those occur r i ng after trauma or brai n sur ger y.

In addi ti on, some anti convul sants ar e used i n the emer gency
tr eatment of status epi l epti cus (a conti nuous sei z ur e state).
Tr eatment of epi l epsy shoul d begi n wi th a si ngl e dr ug whose dosage
i s i ncr eased unti l sei z ur es ar e contr ol l ed or adver se r eacti ons
become pr obl emati c. G eneral l y, a second al ter nati ve shoul d be tr i ed
as monotherapy befor e combi nati on therapy i s consi der ed. The
choi ce of dr ug tr eatment depends on sei z ur e type, dr ug
character i sti cs, and pati ent pr efer ences.

Major classes
Anti convul sants fal l i nto several major cl asses:

hydantoi ns

bar bi turates
i mi nosti l benes
benzodi azepi nes
car boxyl i c aci d der i vati ves
1-(ami nomethyl ) cycl ohexaneaceti c aci d
phenyl tr i az i nes
car boxami des
sul famate-substi tuted monosacchar i des
succi ni mi des
sul fonami des
pyr r ol i di nes.
Hydantoins
The two most commonl y pr escr i bed anti convul santsphenytoi n and
phenytoi n sodi umbel ong to the hydantoin cl ass. Other hydantoi ns
i ncl ude fosphenytoi n and ethotoi n.

Pharmacokinetics
The phar macoki neti cs of hydantoi ns var y fr om dr ug to dr ug.

Phenytoin fits in slowly

Phenytoi n i s absor bed sl owl y after both oral and I.M.
admi ni strati on. Its di str i buted rapi dl y to al l ti ssues and i s hi ghl y
(90% ) pr otei n-bound. Phenytoi n i s metabol i zed i n the l i ver. Inacti ve
metabol i tes ar e excr eted i n bi l e and then r eabsor bed fr om the G I
tract. Eventual l y, however, theyr e excr eted i n ur i ne.

Fosphenytoin for the short term

Fosphenytoi n i s i ndi cated for shor t-ter m I.M. or I.V. admi ni strati on.
Its wi del y di str i buted thr oughout the body and i s hi ghl y (90% )
pr otei n-bound. Fosphenytoi n i s metabol i zed by the l i ver and
excr eted i n ur i ne.

Talkin ethotoin
Ethotoi n i s r eadi l y absor bed fr om the G I tract and i s metabol i zed by
the l i ver. Extensi vel y pr otei n-bound, ethotoi n i s excr eted i n ur i ne,
pr i mar i l y as metabol i tes.

Pharmacodynamics
In most cases, the hydantoi n anti convul sants stabi l i ze ner ve cel l s to
keep them fr om getti ng over exci ted. Phenytoi n appear s to wor k i n
the motor cor tex of the brai n, wher e i t stops the spr ead of sei z ur e
acti vi ty. The phar macodynami cs of fosphenytoi n and ethotoi n ar e
thought to mi mi c those of phenytoi n. Phenytoi n may al so

be used as an anti ar r hythmi c dr ug to contr ol i r r egul ar hear t

r hythms, wi th pr oper ti es si mi l ar to those of qui ni di ne or
pr ocai nami de, al though thi s use i s decr easi ng.

Pharmacotherapeutics
Because of i ts effecti veness and r el ati vel y l ow toxi ci ty, phenytoi n i s
the most commonl y pr escr i bed anti convul sant. Its one of the dr ugs
of choi ce to tr eat:

compl ex par ti al sei z ur es (al so cal l ed psychomotor or tempor al

lobe seiz ur es)
toni c-cl oni c sei z ur es.

Warning!
Adverse reactions to hydantoins
Adver se r eacti ons to hydantoi ns i ncl ude:

dr owsi ness
ataxi a
i r r i tabi l i ty
headache
r estl essness
nystagmus
di z z i ness and ver ti go
dysar thr i a
nausea and vomi ti ng
abdomi nal pai n
anor exi a
 depr essed atr i al and ventr i cul ar conducti on
ventr i cul ar fi br i l l ati on (i n toxi c states)
bradycar di a, hypotensi on, and car di ac ar r est (wi th I.V.
admi ni strati on)
hyper sensi ti vi ty r eacti ons.

Hydantoi ns (phenytoi n and fosphenytoi n) ar e the l ong-acti ng

anti convul sant of choi ce to tr eat status epi l epti cus after i ni ti al I.V.
benzodi azepi nes.

Resistance is futile
Heal th car e pr ovi der s someti mes pr escr i be phenytoi n and ethotoi n
i n combi nati on wi th other anti convul sants for par ti al and toni c-
cl oni c sei z ur es i n pati ents who ar e r esi stant to or i ntol erant of
other anti convul sants.

Drug interactions
Hydantoi ns i nteract wi th a number of other dr ugs. Her e ar e some
dr ug i nteracti ons of major to moderate cl i ni cal si gni fi cance:

Phenytoi ns effect i s decr eased when i ts taken wi th

phenobar bi tal , di azoxi de, theophyl l i ne, car bamazepi ne, r i fampi n,
antaci ds, or sucral fate.
Phenytoi ns effect and potenti al for toxi ci ty i ncr ease when i ts
taken wi th ci meti di ne, di sul fi ram, fl uconazol e, i soni az i d,
omeprazol e, sul fonami des, oral anti coagul ants, chl orampheni col ,
val pr oi c aci d, or ami odar one.
Enteral tube feedi ngs may i nter fer e wi th the absor pti on of oral
phenytoi n. Stop feedi ngs for 2 hour s befor e and after phenytoi n
admi ni strati on.
The effect of these dr ugs i s decr eased when theyr e taken wi th a
hydantoi n anti convul sant: oral anti coagul ants, anti r etr ovi ral s,
l evodopa, ami odar one, cor ti coster oi ds, doxycycl i ne, methadone,
metyrapone, qui ni di ne, theophyl l i ne, thyr oi d hor mone, hor monal
contracepti ves, val pr oi c aci d, cycl ospor i ne, and car bamazepi ne.
(See Adver se r eacti ons to hydantoi ns.)
Barbiturates
The l ong-acti ng bar bi turate phenobar bi tal was for mer l y one of the
most wi del y used anti convul sants. Its now used l ess fr equentl y

because of i ts sedati ve effects. Phenobar bi tal i s someti mes used for

l ong-ter m tr eatment of epi l epsy and i s pr escr i bed sel ecti vel y to
tr eat status epi l epti cus i f hydantoi ns ar e i neffecti ve.

Other barbiturates
Mephobar bi tal , al so a l ong-acti ng bar bi turate, i s someti mes used as
an anti convul sant. Pr i mi done, whi ch i s cl osel y r el ated chemi cal l y to
the bar bi turates, i s al so used to tr eat chr oni c epi l epsy.

Pharmacokinetics
Each bar bi turate has a sl i ghtl y di ffer ent set of phar macoki neti c
pr oper ti es.

Phenobarbital for the long haul

Phenobar bi tal i s absor bed sl owl y but wel l fr om the G I tract. Peak
pl asma l evel s occur 8 to 12 hour s after a si ngl e dose. The dr ug i s
20% to 45% bound to ser um pr otei ns and to a si mi l ar extent to
other ti ssues, i ncl udi ng the brai n. About 75% of a phenobar bi tal
dose i s metabol i zed by the l i ver, and 25% i s excr eted unchanged i n
ur i ne.

Mephobarbital moves quickly

Al most one-hal f of a mephobar bi tal dose i s absor bed fr om the G I
tract and wel l di str i buted i n body ti ssues. The dr ug i s bound to
ti ssue and pl asma pr otei ns. Mephobar bi tal under goes extensi ve
metabol i sm by the l i ver ; onl y 1% to 2% i s excr eted unchanged i n
ur i ne.

Primidone and protein

Appr oxi matel y 60% to 80% of a pr i mi done dose i s absor bed fr om
the G I tract and di str i buted evenl y among body ti ssues. The dr ug i s
pr otei n-bound to a smal l extent i n the pl asma. Pr i mi done i s
metabol i zed by the l i ver to two acti ve metabol i tes, phenobar bi tal
and phenyl ethyl mal onami de (PEMA). F r om 15% to 25% of pr i mi done
i s excr eted unchanged i n ur i ne, 15% to 25% i s metabol i zed to
phenobar bi tal , and 50% to 70% i s excr eted i n ur i ne as PEMA.
Pr i mi done i s al so secr eted i n br east mi l k.

Pharmacodynamics
Bar bi turates exhi bi t anti convul sant acti on at doses bel ow those that
pr oduce hypnoti c effects. For thi s r eason, they usual l y dont
pr oduce addi cti on when used to tr eat epi l epsy. Bar bi turates el evate
the sei z ur e thr eshol d by decr easi ng postsynapti c exci tati on.

Pharmacotherapeutics
Bar bi turates ar e an effecti ve al ter nati ve therapy for :

par ti al sei z ur es
toni c-cl oni c sei z ur es
febr i l e sei z ur es.

Bar bi turates can be used al one or wi th other anti convul sants. I.V.
phenobar bi tal i s al so used to tr eat status epi l epti cus. The major
di sadvantage of usi ng phenobar bi tal for status epi l epti cus i s that i t
has a del ayed onset of acti on when an i mmedi ate r esponse i s
needed. Bar bi turates ar e i neffecti ve i n tr eati ng absence sei z ur es.

Warning!
Adverse reactions to barbiturates
Adver se r eacti ons to phenobar bi tal and mephobar bi tal
i ncl ude:

dr owsi ness, l ethar gy, and di z z i ness

nystagmus, confusi on, and ataxi a (wi th l ar ge doses)
l ar yngospasm, r espi rator y depr essi on, and hypotensi on (when
admi ni ster ed I.V.).

The same, plus psychoses

Pr i mi done can cause the same central ner vous system and G I
adver se r eacti ons as phenobar bi tal . It can al so cause acute
psychosi s, hai r l oss, i mpotence, and osteomal aci a.
As a group
Al l thr ee bar bi turates can pr oduce a hyper sensi ti vi ty rash, other
 rashes, l upus er ythematosusl i ke syndr ome (an i nfl ammator y
di sor der ), and enl ar ged l ymph nodes.

Consider this
Mephobar bi tal has no advantage over phenobar bi tal and i s used
when the pati ent cant tol erate the adver se effects of phenobar bi tal .
Because of moni tor i ng, costs, and dosi ng fr equency, phenobar bi tal i s
usual l y tr i ed befor e pr i mi done. Pr i mi done may be effecti ve i n
pati ents who fai l to r espond to phenobar bi tal .

Drug interactions
The effects of bar bi turates can be r educed when theyr e taken wi th
r i fampi n. Her e ar e some other dr ug i nteracti ons:

The r i sk of toxi ci ty i ncr eases when phenobar bi tal i s taken wi th

CNS depr essants, val pr oi c aci d, chl orampheni col , fel bamate,
ci meti di ne, or phenytoi n.
The metabol i sm of cor ti coster oi ds, di goxi n, and estr ogens may
be enhanced when these dr ugs ar e taken wi th phenobar bi tal ,
l eadi ng to decr eased effects.
Adver se effects of tr i cycl i c anti depr essants i ncr ease when
theyr e taken wi th bar bi turates.
Eveni ng pr i mr ose oi l may i ncr ease anti convul sant dosage
r equi r ements. (See Adver se r eacti ons to bar bi turates.)
Reduced effects
Bar bi turate use can decr ease the effects of many dr ugs, i ncl udi ng
beta-adr ener gi c bl ocker s, cor ti coster oi ds, di goxi n, estr ogens,
doxycycl i ne, oral anti coagul ants, hor monal contracepti ves,
qui ni di ne, phenothi az i ne, metr oni dazol e, tr i cycl i c anti depr essants,
theophyl l i ne, cycl ospor i ne, car bamazepi ne, fel odi pi ne, and
verapami l .

Iminostilbenes
Car bamaz epine i s the most commonl y used i mi nosti l bene
anti convul sant. It effecti vel y tr eats:

par ti al and general i zed toni c-cl oni c sei z ur es

mi xed sei z ur e types
compl ex par ti al sei z ur es (dr ug of choi ce).

Pharmacokinetics
Car bamazepi ne i s absor bed sl owl y fr om the G I tract and i s
metabol i zed i n the l i ver by the cytochr ome P-450 i sofor m 3A4
(CYP450) and i s excr eted i n ur i ne. Car bamazepi ne i s di str i buted
rapi dl y to al l ti ssues; 75% to 90% i s bound to pl asma pr otei ns. A
smal l amount cr osses the pl acenta, and some i s secr eted i n br east
mi l k. The hal f-l i fe var i es gr eatl y.

Pharmacodynamics
Car bamazepi nes anti convul sant effect i s si mi l ar to that of
phenytoi n. The dr ugs anti convul sant acti on can occur because of i ts
abi l i ty to i nhi bi t the spr ead of sei z ur e acti vi ty or neur omuscul ar
transmi ssi on i n general .

Pharmacotherapeutics
Car bamazepi ne i s the dr ug of choi ce, i n adul ts and chi l dr en, for
tr eati ng:

general i zed toni c-cl oni c sei z ur es

si mpl e and compl ex par ti al sei z ur es.
Car bamazepi ne may wor sen absence or myocl oni c sei z ur es.
However, i t r el i eves pai n when used to tr eat tr i gemi nal neural gi a
(ti c doul our eux, character i zed by excr uci ati ng faci al pai n al ong the
tr i gemi nal ner ve) and may be useful i n tr eati ng sel ecti ve psychi atr i c
di sor der s.

Drug interactions
Car bamazepi ne can r educe the effects of several dr ugs, i ncl udi ng
hal oper i dol , bupr opi on, l amotr i gi ne, tr i cycl i c anti depr essants, oral
anti coagul ants, hor monal contracepti ves, doxycycl i ne, fel bamate,
theophyl l i ne, pr otease i nhi bi tor s, anti psychoti cs, and val pr oi c aci d.
Other dr ug i nteracti ons can al so occur :

Incr eased car bamazepi ne l evel s and toxi ci ty can occur wi th the
use of ci meti di ne, danazol , di l ti azem, er ythr omyci n, i soni az i d,
sel ecti ve ser otoni n r euptake i nhi bi tor s, pr opoxyphene,
ketoconazol e, val pr oi c aci d, and verapami l .

Li thi um and car bamazepi ne taken together i ncr ease the r i sk of

toxi c neur ol ogi c effects.

Confusion alert!
Dont confuse Tegr etol (a brand name for car bamazepi ne) wi th
Toradol (a brand name for ketor ol ac).
 Car bamazepi ne l evel s may be decr eased when taken wi th
bar bi turates, fel bamate, or phenytoi n. (See Adver se r eacti ons to
car bamazepi ne.)
The her bal r emedy pl antai n may i nhi bi t G I absor pti on of
car bamazepi ne.

Warning!
Adverse reactions to carbamazepine
Occasi onal l y, car bamazepi ne can r esul t i n ser i ous
hematol ogi c toxi ci ty. Because car bamazepi ne i s r el ated
str uctural l y to the tr i cycl i c anti depr essants, i t can cause si mi l ar
toxi ci ti es and affect behavi or s and emoti ons.
Hi ves and Stevens-Johnson syndr ome (a potenti al l y fatal
i nfl ammator y di sease) can al so occur. Rash i s the most common
hyper sensi ti vi ty r esponse.

Benzodiazepines
The four benz odiaz epine dr ugs that pr ovi de anti convul sant effects
ar e:

cl onazepam
cl orazepate
di azepam (par enteral for m)
l orazepam. (See Sound-al i kes: Di azepam and l orazepam.)

Only one for ongoing treatment

Onl y cl onazepam i s r ecommended for l ong-ter m tr eatment of
epi l epsy. Di azepam may be used to tr eat status epi l epti cus or, i n
r ectal for m, r epeti ti ve sei z ur es. Lorazepam I.V. i s consi der ed the
dr ug of choi ce for status epi l epti cus. Cl orazepate i s pr escr i bed as an
adjunct i n tr eati ng par ti al sei z ur es.

Safe and sound

Sound-alikes: Diazepam and lorazepam
Be car eful not to confuse the sound-al i ke dr ugs di azepam
and l orazepam. Both dr ugs ar e benzodi azepi nes that can be used
 to tr eat status epi l epti cus. Lorazepam I.V. i s consi der ed the dr ug
of choi ce. Di azepam pr ovi des onl y shor t-ter m effects and i snt
r ecommended for l ong-ter m tr eatment because hi gh ser um
concentrati ons ar e needed to contr ol sei z ur es and l ong-ter m use
can l ead to addi cti on.

Pharmacokinetics
The pati ent can r ecei ve benzodi azepi nes oral l y, par enteral l y or, i n
speci al si tuati ons, r ectal l y (di azepam r ectal gel ).

Absorption and distribution

Benzodi azepi nes ar e absor bed rapi dl y and al most compl etel y fr om
the G I tract but ar e di str i buted at di ffer ent rates. Pr otei n bi ndi ng of
benzodi azepi nes ranges fr om 85% to 90% .

Metabolism and excretion

Benzodi azepi nes ar e metabol i zed i n the l i ver to mul ti pl e metabol i tes
and ar e then excr eted i n ur i ne. They r eadi l y cr oss the pl acenta and
ar e secr eted i n br east mi l k.

Pharmacodynamics
Benzodi azepi nes act as:

anti convul sants

anti anxi ety agents
sedati ve-hypnoti cs
muscl e r el axants.

Thei r mechani sm of acti on i s poor l y under stood.

Pharmacotherapeutics
Each of the benzodi azepi nes can be used i n sl i ghtl y di ffer ent ways.

Absence, atypical, and more

Cl onazepam i s used to tr eat the fol l owi ng types of sei z ur es:
 absence (peti t mal )
atypi cal absence (Lennox-G astaut syndr ome)
atoni c
myocl oni c.

I.V. or with others

Di azepam i snt r ecommended for l ong-ter m tr eatment because of i ts
potenti al for addi cti on and the hi gh ser um concentrati ons r equi r ed
to contr ol sei z ur es.
I.V. l orazepam i s cur r entl y consi der ed the benzodi azepi ne of choi ce
for tr eati ng status epi l epti cus.
I.V. di azepam i s used to contr ol status epi l epti cus. Because
di azepam pr ovi des onl y shor t-ter m effects of l ess than 1 hour, the
pati ent must al so be gi ven a l ong-acti ng anti convul sant, such as
phenytoi n or phenobar bi tal , dur i ng di azepam therapy. Di azepam
r ectal gel i s appr oved

for tr eatment of r epeti ti ve sei z ur es and has r educed the i nci dence
of r ecur r ent sei z ur es i n chi l dr en.
Cl orazepate i s used wi th other dr ugs to tr eat par ti al sei z ur es.

Warning!
Adverse reactions to benzodiazepines
Most common
 Dr owsi ness
Confusi on
Ataxi a
Weakness
Di z z i ness
Nystagmus
Ver ti go
Fai nti ng
Dysar thr i a
Headache
Tr emor
G l assy-eyed appearance

Less common

Depr essi on of the hear t and br eathi ng (wi th hi gh doses and

wi th I.V. di azepam)
Rash and other acute hyper sensi ti vi ty r eacti ons

Drug interactions
When benzodi azepi nes ar e taken wi th CNS depr essants, sedati ves,
ci meti di ne, or hor monal contracepti ves, depr essant effects ar e
enhanced. Thi s can cause motor ski l l i mpai r ment, r espi rator y
depr essi on, excessi ve sedati on, CNS depr essi on, and even death at
hi gh doses. (See Adver se r eacti ons to benzodi azepi nes.)

Carboxylic acid derivatives

Val pr oi c aci d, the most wi del y used car boxyl i c aci d der i vati ve, i s
unr el ated str uctural l y to the other anti convul sants. Val pr oi c aci d i s
al so avai l abl e as:

val pr oate
di val pr oex.

Pharmacokinetics
Val pr oate i s conver ted rapi dl y to val pr oi c aci d i n the stomach.
Di val pr oex i s a pr ecur sor of val pr oi c aci d and separates i nto val pr oi c
aci d i n the G I tract. Val pr oi c aci d i s a hepati c enz yme i nhi bi tor ; i ts
absor bed wel l , i s str ongl y pr otei n-bound, and i s metabol i zed i n the
l i ver. Metabol i tes

and unchanged dr ug ar e excr eted i n ur i ne.

Val pr oi c aci d r eadi l y cr osses the pl acental bar r i er and al so appear s
i n br east mi l k.

Pharmacodynamics
The mechani sm of acti on for val pr oi c aci d r emai ns unknown. The
dr ug i s thought to i ncr ease l evel s of G ABA, an i nhi bi tor y
neur otransmi tter, and to have a di r ect membrane-stabi l i z i ng effect.

Pharmacotherapeutics
Val pr oi c aci d i s pr escr i bed for l ong-ter m tr eatment of:

absence sei z ur es
myocl oni c sei z ur es
toni c-cl oni c sei z ur es
par ti al sei z ur es.

Val pr oi c aci d may al so be useful for neonatal sei z ur es.

Drug interactions
Val pr oi c aci d must be used cauti ousl y i n chi l dr en under 2 year s ol d,
par ti cul ar l y those r ecei vi ng mul ti pl e anti convul sants and those wi th
congeni tal metabol i c di sor der s, sever e sei z ur es wi th mental
r etar dati on, or or gani c brai n di sease. In these pati ents, val pr oi c
aci d car r i es a r i sk of potenti al l y fatal l i ver toxi ci ty (pr i mar i l y i n the
fi r st 6 months of tr eatment).
Thi s r i sk l i mi ts i ts use as a dr ug of choi ce for sei z ur e di sor der s.
However, whi l e i ts a r i sk for al l pati ents, the r i sk decr eases wi th
age. Cauti on shoul d al so be taken wi th pati ents wi th hepati c
di sease.
Valproic warnings
These ar e the most si gni fi cant dr ug i nteracti ons associ ated wi th
val pr oi c aci d:

Ci meti di ne, aspi r i n, er ythr omyci n, and fel bamate may i ncr ease
l evel s of val pr oi c aci d.
Car bamazepi ne, l amotr i gi ne, phenobar bi tal , pr i mi done,
phenytoi n, and r i fampi n may decr ease l evel s of val pr oi c aci d.
Val pr oi c aci d may decr ease the effects of fel bamate,
phenobar bi tal , pr i mi done, benzodi azepi nes, CNS depr essants,
war far i n, and z i dovudi ne. (See Adver se r eacti ons to val pr oi c
aci d, page 78.)

Warning!
Adverse reactions to valproic acid
Because rar e, but deadl y, l i ver toxi ci ty has occur r ed wi th
val pr oi c aci d, i t shoul d be used wi th cauti on i n pati ents who have
a hi stor y of hepati c di sease. Chi l dr en younger than age 2 have a
hi gh r i sk of devel opi ng hepatotoxi ci ty.
Most other adver se r eacti ons ar e tol erabl e and dose-r el ated.
These i ncl ude:

nausea and vomi ti ng

di ar r hea
 consti pati on
sedati on
di z z i ness
ataxi a
headache
muscl e weakness
i ncr eased bl ood ammoni a l evel .

1-(aminomethyl) cyclohexaneacetic acid

The 1-(ami nomethyl ) cycl ohexaneaceti c aci d cl ass i ncl udes the dr ug
gabapenti n, whi ch was desi gned to be a G ABA agoni st, al though i ts
exact mechani sm of acti on i s unknown.
G abapenti n i s appr oved as adjuncti ve therapy for par ti al sei z ur es i n
adul ts and i n chi l dr en ages 3 and ol der wi th epi l epsy. It has al so
been used to tr eat pai n, tr emor associ ated wi th MS, bi pol ar
di sor der, and Par ki nsons di sease as wel l as to pr event mi grai nes.

Pharmacokinetics
G abapenti n i s r eadi l y absor bed i n the G I tract. Because of thi s
acti ve-transpor t mechani sm, the dr ugs bi oavai l abi l i ty may decr ease
as the dosage i ncr eases. G abapenti n i snt metabol i zed; i ts excr eted
excl usi vel y by the ki dneys.

Pharmacodynamics
G abapenti ns exact mechani sm of acti on i s unknown. The dr ug
doesnt appear to act at the G ABA r eceptor, affect G ABA uptake, or
i nter fer e wi th G ABA transami nase. Instead, gabapenti n appear s to
bi nd to a car r i er pr otei n and act at a uni que r eceptor i n the brai n,
r esul ti ng i n el evated G ABA l evel s i n the brai n.

Pharmacotherapeutics
G abapenti n i s used as adjuncti ve therapy for par ti al and secondar i l y
general i zed sei z ur es i n adul ts and chi l dr en ages 3 and ol der. It al so
seems to be effecti ve as monotherapy al though i t i snt F DA-
appr oved for that pur pose.
Drug interactions
Li ke car bamazepi ne, gabapenti n may wor sen myocl oni c sei z ur es.
G abapenti n doesnt i nduce or i nhi bi t hepati c enz ymes, so i t causes
ver y few dr ug i nteracti ons and doesnt affect the metabol i sm of
other anti convul sants. Antaci ds and ci meti di ne may affect
gabapenti n concentrati on.
Pati ents wi th r enal i mpai r ment (cr eati ni ne cl earance l ess than 60
ml /mi nute) r equi r e a dosage r educti on. (See Adver se r eacti ons to
gabapenti n.)

Warning!
Adverse reactions to gabapentin
Common adver se r eacti ons to gabapenti n i ncl ude:

fati gue
somnol ence
di z z i ness
ataxi a
l eukopeni a.

Less common adver se r eacti ons i ncl ude:

edema
wei ght gai n
hosti l i ty
emoti onal l abi l i ty
nausea and vomi ti ng
br onchi ti s
vi ral i nfecti on
fever
nystagmus
r hi ni ti s
di pl opi a
tr emor.
Phenyltriazines
The phenyl tr i az i ne l amotr i gi ne i s chemi cal l y unr el ated to other
anti convul sants. Thi s dr ug i s F DA-appr oved as adjuncti ve therapy
for adul ts who have par ti al sei z ur es and for chi l dr en ol der than age
2 who have general i zed sei z ur es or Lennox-G astaut syndr ome. It
may al so be used as monotherapy for par ti al sei z ur es i n adul ts after
a hepati c enz ymei nduci ng anti convul sant has been di sconti nued.

Pharmacokinetics
Lamotr i gi ne i s rapi dl y and wel l absor bed. Its metabol i zed by the
l i ver and excr eted by the ki dneys. Cl earance i s i ncr eased i n the
pr esence of other enz yme-i nduci ng anti convul sants. Lamotr i gi ne
i snt si gni fi cantl y bound to pl asma pr otei ns.

Pharmacodynamics
Lamotr i gi nes pr eci se mechani sm of acti on i s unknown, but the dr ug
i s thought to bl ock vol tage-sensi ti ve sodi um channel s, thus
i nhi bi ti ng the r el ease of the exci tator y neur otransmi tter s gl utamate
and aspar tate.

Pharmacotherapeutics
Lamotr i gi ne pr events par ti al sei z ur e acti vi ty. In addi ti on,
l amotr i gi ne appear s to be effecti ve for many types of general i zed
sei z ur es. However i t can wor sen myocl oni c sei z ur es.
The dr ug may al so l ead to i mpr ovement i n the pati ents mood.

Drug interactions
Lamotr i gi nes effects may be decr eased i f the dr ug i s gi ven wi th
car bamazepi ne, phenytoi n, phenobar bi tal , pr i mi done, or
acetami nophen.
Lamotr i gi ne may pr oduce addi ti ve effects when combi ned wi th
fol ate i nhi bi tor s.
Val pr oi c aci d may decr ease l amotr i gi ne cl earance and i ncr ease
the steady-state l evel and effects of l amotr i gi ne. (See Adver se
r eacti ons to l amotr i gi ne.)

Warning!
Adverse reactions to lamotrigine
Adver se r eacti ons to l amotr i gi ne commonl y i ncl ude:

di z z i ness
ataxi a
somnol ence
headache
di pl opi a
nausea
vomi ti ng
rash.

Several types of rash, i ncl udi ng Stevens-Johnson syndr ome, may

occur wi th use of thi s dr ug. A general i zed, er ythematous,
mor bi l l i for m rash may appear i n the fi r st 3 to 4 weeks of therapy;
i ts usual l y mi l d to moderate, but i t may be sever e.
Lamotr i gi ne now car r i es a bl ack box war ni ng r egar di ng the rash,
and the manufactur er r ecommends di sconti nui ng the dr ug at the
fi r st si gn of rash. The r i sk of rash may be i ncr eased by star ti ng at
hi gh doses, by rapi dl y i ncr easi ng doses, or by usi ng val pr oate
concur r entl y.

Carboxamides
Oxcar bazepi ne, a car boxami de, i s chemi cal l y si mi l ar to
car bamazepi ne but causes l ess i nducti on of hepati c enz ymes.
Oxcar bazepi ne i s a pr odr ug. Its useful as adjuncti ve therapy or
monotherapy for adul ts wi th par ti al sei z ur es and as adjuncti ve
therapy for chi l dr en wi th par ti al sei z ur es.

Pharmacokinetics
Oxcar bazepi ne i s compl etel y absor bed and extensi vel y metabol i zed
by hepati c enz ymes to the 10-monohydr oxy metabol i te (MHD) thats
r esponsi bl e for i ts phar macol ogi c acti vi ty. MHD i s excr eted pr i mar i l y
by the ki dneys.

9 hours in half
The hal f-l i fe of MHD i s about 9 hour s. Unl i ke car bamazepi ne,
oxcar bazepi ne doesnt i nduce i ts own metabol i sm.

Pharmacodynamics
The pr eci se mechani sm of acti on of oxcar bazepi ne and i ts
metabol i te MHD i s unknown, but anti sei z ur e acti vi ty i s thought to
occur thr ough bl ockade of sodi um-sensi ti ve channel s, whi ch
pr events sei z ur e spr ead i n the brai n.

Pharmacotherapeutics
Oxcar bazepi ne i s F DA-appr oved as adjuncti ve therapy for par ti al
sei z ur es i n adul ts and chi l dr en ol der than age 4 and as
monotherapy for adul ts.
As wi th car bamazepi ne, i ts al so effecti ve for general i zed sei z ur es
but may wor sen myocl oni c and absence sei z ur es.

Drug interactions
Car bamazepi ne, phenytoi n, phenobar bi tal , val pr oi c aci d, and
verapami l may decr ease the l evel s of oxcar bazepi nes acti ve
metabol i te MHD.
Pill worries
Oxcar bazepi ne may decr ease the effecti veness of hor monal
contracepti ves and fel odi pi ne.
Dosage r educti ons ar e necessar y for pati ents wi th r enal
i mpai r ment (cr eati ni ne cl earance l ess than 30 ml /mi nute) and
those at r i sk for r enal i mpai r ment, such as el der l y pati ents. (See
Adver se r eacti ons to oxcar bazepi ne.)

Warning!
Adverse reactions to oxcarbazepine
About 20% to 30% of pati ents who have had an al l er gi c
r eacti on to car bamazepi ne wi l l exper i ence a hyper sensi ti vi ty
r eacti on to oxcar bazepi ne.
Common reactions

Somnol ence
Di z z i ness
Di pl opi a
Ataxi a
Nausea and vomi ti ng
Abnor mal gai t
Tr emor
Aggravated sei z ur es
Rectal bl eedi ng
 Less common reactions

Agi tati on
Confusi on
Hypotensi on
Hyponatr emi a
Rhi ni ti s
Speech di sor der
Back pai n
Upper r espi rator y tract i nfecti on

Sulfamate-substituted monosaccharides
Topi ramate, a sul famate-substi tuted monosacchar i de, i s one of the
newer anti convul sants avai l abl e.

Pharmacokinetics
Topi ramate i s absor bed rapi dl y and i s par ti al l y metabol i zed i n the
l i ver and excr eted mostl y unchanged i n ur i ne.

Pharmacodynamics
Topi ramate i s bel i eved to act by bl ocki ng vol tage-dependent sodi um
channel s, enhanci ng acti vi ty of the G ABA r eceptor s, and
antagoni z i ng gl utamate r eceptor s.

Pharmacotherapeutics
Topi ramate i s appr oved as adjuncti ve therapy for par ti al and
pr i mar y general i zed toni c-cl oni c sei z ur es i n adul ts and chi l dr en
ol der than age 2 and for chi l dr en wi th Lennox-G astaut syndr ome. It
may al so pr ove benefi ci al for other types of sei z ur es and as
monotherapy.

Drug interactions
Car bamazepi ne, phenytoi n, and val pr oi c aci d may cause
decr eased topi ramate l evel s.
 Topi ramate may decr ease the effecti veness of hor monal
contracepti ves and decr ease val pr oi c aci d l evel s.
CNS depr essants may cause addi ti ve CNS effect when combi ned
wi th topi ramate.

50% off
For r enal l y i mpai r ed pati ents (cr eati ni ne cl earance l ess than 70
ml /mi nute), the topi ramate dosage shoul d be r educed by 50% .
(See Adver se r eacti ons to topi ramate.)

Warning!
Adverse reactions to topiramate
Psychomotor sl owi ng, wor d-fi ndi ng di ffi cul ty, i mpai r ed
concentrati on, and memor y i mpai r ment ar e common r eacti ons
that may r equi r e stoppi ng topi ramate. Low star ti ng doses and
sl ow dosage ti trati on may mi ni mi ze these effects.
Other common adver se r eacti ons i ncl ude:

dr owsi ness
di z z i ness
headache
ataxi a
ner vousness
confusi on
par esthesi a
wei ght gai n
di pl opi a.

Ser i ous but i nfr equent adver se r eacti ons i ncl ude:

secondar y angl ecl osur e gl aucoma

l i ver fai l ur e
decr eased sweati ng
hyper ther mi a
heat str oke
r enal cal cul i .
Succinimides
The succi ni mi des, ethosuxi mi de and methsuxi mi de, ar e used to
manage absence sei z ur es. Ethosuxi mi de i s consi der ed the dr ug of
choi ce for absence sei z ur es.

Pharmacokinetics
The succi ni mi des ar e r eadi l y absor bed fr om the G I tract and
metabol i zed i n the l i ver and excr eted i n ur i ne. Metabol i tes ar e
bel i eved

to be i nacti ve. The el i mi nati on hal f-l i fe of ethosuxi mi de i s about 60

hour s i n adul ts and 30 hour s i n chi l dr en.

Pharmacodynamics
Ethosuxi mi des exact mechani sm of acti on i s unknown. Its thought
to i nhi bi t an enz yme necessar y for the for mati on of gamma-
hydr oxybutyrate, whi ch has been associ ated wi th the i nducti on of
absence sei z ur es.

Pharmacotherapeutics
In addi ti on to bei ng the dr ug of choi ce for tr eati ng absence
sei z ur es, ethosuxi mi de may al so be used i n combi nati on wi th
val pr oi c aci d for har d-to-contr ol absence sei z ur es.

Drug interactions
Ethosuxi mi de i snt pr otei n-bound, so di spl acement r eacti ons cant
occur. Car bamazepi ne may i nduce the metabol i sm of ethosuxi mi de.
Val pr oi c aci d may i nhi bi t the metabol i sm of ethosuxi mi de onl y i f the
metabol i sm i s near saturati on. (See Adver se r eacti ons to
succi ni mi des.)

Warning!
Adverse reactions to succinimides
Ethosuxi mi de i s general l y wel l tol erated. The most common
adver se effects (occur r i ng i n up to 40% of pati ents) ar e nausea
and vomi ti ng. Other common adver se effects i ncl ude:
 dr owsi ness and fati gue
l ethar gy
di z z i ness
hi ccups
headaches
mood changes.

Rar el y, bl ood dyscrasi as, rashes (i ncl udi ng Stevens-Johnson

syndr ome and er ythema mul ti for me), l upus-l i ke syndr ome, and
psychoti c behavi or s can occur.

Sulfonamides
Zoni sami de, a sul fonami de, i s appr oved as adjuncti ve tr eatment for
par ti al sei z ur es i n adul ts.

Pharmacokinetics
Zoni sami de i s absor bed r el ati vel y rapi dl y, wi th peak concentrati ons
occur r i ng i n 2 to 6 hour s. Zoni sami de i s wi del y di str i buted and i s
extensi vel y bound to er ythr ocytes.
The dr ug i s metabol i zed by the CYP3A4 enz yme i n the l i ver and i s
excr eted i n ur i ne, pr i mar i l y as the par ent dr ug and the gl ucur oni de
metabol i te.

Pharmacodynamics
Zoni sami des pr eci se mechani sm of acti on i s unknown, but i ts
bel i eved to i nvol ve stabi l i z ati on of neur onal membranes and
suppr essi on of neur onal hyper sensi ti vi ty.

Pharmacotherapeutics
Zoni sami de i s appr oved onl y as adjuncti ve therapy for par ti al
sei z ur es i n adul ts, but i t appear s to have a br oad spectr um of
acti vi ty

for other types of sei z ur es (i nfanti l e spasms; myocl oni c,

general i zed, and atypi cal absence sei z ur es).
 Warning!
Adverse reactions to sulfonamides
Common adver se effects of zoni sami de i ncl ude:

somnol ence
di z z i ness
confusi on
anor exi a
nausea
di ar r hea
wei ght l oss
rash.

Sl ow ti trati on of the dosage and admi ni strati on wi th meal s may

decr ease the i nci dence of these adver se effects.
Mor e ser i ous adver se effects associ ated wi th zoni sami de use
i ncl ude:

Stevens-Johnson syndr ome

toxi c epi der mal necr ol ysi s
psychosi s
apl asti c anemi a
agranul ocytosi s.

Ol i gohydr osi s, hyper ther mi a, and heat str oke have been r epor ted
i n chi l dr en. Zoni sami de i s contrai ndi cated i n pati ents wi th an
al l er gy to sul fonami des. Low doses shoul d be i ni ti ated i n el der l y
pati ents because of the possi bi l i ty of r enal i mpai r ment i n thi s
popul ati on.

Drug interactions
Dr ugs that i nduce l i ver enz ymes, such as phenytoi n,
car bamazepi ne, and phenobar bi tal , i ncr ease the metabol i sm and
decr ease the hal f-l i fe of zoni sami de.

Serious serum
 Concur r ent use of zoni sami de wi th dr ugs that i nhi bi t or i nduce
CYP3A4 may i ncr ease or decr ease the ser um concentrati on of
zoni sami de. Zoni sami de i snt an i nducer of CYP3A4, so i ts
unl i kel y to affect other dr ugs metabol i zed by thi s system. (See
Adver se r eacti ons to sul fonami des.)

Pyrrolidines
Leveti racetam, a pyr r ol i di ne der i vati ve, i s a newer anti sei z ur e dr ug
thats chemi cal l y unr el ated to pr evi ousl y avai l abl e anti epi l epti c
dr ugs. Its used as adjuncti ve therapy to tr eat cer tai n types of
par ti al and myocl oni c sei z ur es.

Pharmacokinetics
Leveti racetam i s admi ni ster ed oral l y or I.V. Oral admi ni strati on
r esul ts i n rapi d and ful l absor pti on wi th a 100% bi oavai l abi l i ty. Peak
concentrati ons occur i n about 1 hour. Leveti racetam i snt
extensi vel y metabol i zed; any metabol i tes that ar e pr oduced ar ent
acti ve. The major metabol i c pathway i s enz ymati c hydr ol ysi s, and
metabol i sm doesnt depend on any hepati c cytochr ome P450
i soenz ymes. Leveti racetam i s el i mi nated by r enal excr eti on. The
hal f-l i fe i s about 8 hour s and i s unaffected by dose, r oute of
admi ni strati on, or r epeated admi ni strati on.

Pharmacodynamics
The pr eci se mechani sm of acti on i snt known. The dr ugs
anti epi l epti c effect doesnt appear to i nvol ve known mechani sms
r el ati ng to i nhi bi tor y and exci tator y neur otransmi ssi on.

Pharmacotherapeutics
Leveti racetam has several i ndi cati ons for us, i ncl udi ng:

adjuncti ve therapy for epi l epsy i n adul ts and chi l dr en ol der than
age 4
adjuncti ve tr eatment for myocl oni c sei z ur es i n adul ts and
chi l dr en ol der than age 12
adjuncti ve tr eatment for pr i mar y general i zed toni c-cl oni c
sei z ur es i n adul ts and chi l dr en ol der than age 6.
Drug interactions
Leveti racetam has no known major dr ug i nteracti ons. (See Adver se
r eacti ons to l eveti racetam.)

Warning!
Adverse reactions to levetiracetam
Common adver se r eacti ons to l eveti racetam i ncl ude:

dr owsi ness
di z z i ness
fati gue
astheni a
headache
vomi ti ng.

Less common adver se r eacti ons i ncl ude:

depr essi on
phar yngi ti s
conjuncti vi ti s
mood swi ngs.

Antimigraine drugs
Mi grai ne i s one of the most common pr i mar y headache di sor der s,
affecti ng an esti mated 24 mi l l i on peopl e i n the Uni ted States. An
epi sodi c di sor der, mi grai ne pr oduces a uni l ateral pai n thats
commonl y descr i bed as poundi ng, pul sati ng, or thr obbi ng. It may be
pr eceded by an aura. Other common symptoms ar e sensi ti vi ty to
l i ght or sound, nausea, vomi ti ng, consti pati on, and di ar r hea.
Resear cher s bel i eve that mi grai ne symptoms ar e caused by crani al
vasodi l ati on or the r el ease of vasoacti ve and pr oi nfl ammator y
substances fr om ner ves i n an acti vated tr i gemi nal system.

Attacking aches
Tr eatment of mi grai ne ai ms to al ter an attack once i ts under way
(abor ti ve or symptomati c tr eatment) or to pr event an attack. Choi ce
of therapy depends on the sever i ty, durati on, and fr equency of the
headaches; on the degr ee of di sabi l i ty that the headache cr eates i n
the pati ent; and on pati ent character i sti cs.
Abor ti ve tr eatments may i ncl ude anal gesi cs (aspi r i n and
acetami nophen), nonster oi dal anti -i nfl ammator y dr ugs (NSAIDs),
er gotami ne, 5-hydr oxytr yptami ner gi c (5-HT 1 )-r eceptor agoni sts,
and var i ous mi scel l aneous dr ugs (such as i sometheptene
combi nati ons, i ntranasal butor phanol , metocl oprami de, and
cor ti coster oi ds). Pr ophyl acti c therapy i ncl udes beta-adr ener gi c
bl ocker s, tr i cycl i c anti depr essants, val pr oi c aci d, and NSAIDs, to
name a few.

Memory jogger
How can you tel l i f i ts a mi grai ne or a headache? Look at the
mnemoni c PAIN to see i f the pati ent has these key symptoms:
Ppai n
A aura
Ii r r i tated by l i ght
Nnausea.

5-HT 1 -receptor agonists (triptans)

The 5-HT 1 -r eceptor agoni sts, commonl y known as the tr iptans, ar e
the tr eatment of choi ce for moderate to sever e mi grai ne. They
i ncl ude:
 al motr i ptan
el etr i ptan
fr ovatr i ptan
naratr i ptan
r i z atr i ptan
sumatr i ptan
zol mi tr i ptan. (See Sound-al i kes: Sumatr i ptan and zol mi tr i ptan.)

Pharmacokinetics
When compar i ng the tr i ptans, the key phar macoki neti c featur es ar e
onset of acti on and durati on of acti on. Ri z atr i ptan, sumatr i ptan, and
zol mi tr i ptan have a hal f-l i fe of appr oxi matel y 2 hour s; al motr i ptan
and el etr i ptan have a hal f-l i fe of 3 to 4 hour s; naratr i ptan has a
hal f-l i fe of about 6 hour s; and fr ovatr i ptan has the l ongest hal f-l i fe
(25 hour s) and the most del ayed onset of acti on.

Triptan tablets
Al l of the tr i ptans ar e avai l abl e i n an oral for m. Ri z atr i ptan and
zol mi tr i ptan ar e al so avai l abl e i n rapi d-di ssol ve tabl ets.
Zol mi tr i ptan and sumatr i ptan ar e avai l abl e i n i ntransal for ms.
Sumatr i ptan i s al so avai l abl e as a subcutaneous i njecti on. The
i njectabl e for m of sumatr i ptan has the most rapi d onset of acti on of
al l the tr i ptans.

Safe and sound

Sound-alikes: Sumatriptan and zolmitriptan
Dont confuse the sound-al i ke dr ugs sumatr i ptan and
 zol mi tr i ptan. Both dr ugs ar e used to tr eat acute mi grai nes, but
r ecommended doses ar e si gni fi cantl y di ffer ent.

Pharmacodynamics
Tr i ptans ar e ser otoni n 5-HT 1 -r eceptor agoni sts, whi ch constr i ct the
crani al vessel s, i nhi bi t neur opepti de r el ease, and r educe the
neur ogeni c i nfl ammator y pr ocess transmi ssi on al ong the tr i gemi nal
pathway. These acti ons may abor t or pr ovi de symptomati c r el i ef for
mi grai nes. Asi de fr om r el i evi ng pai n, tr i ptans ar e al so effecti ve i n
contr ol l i ng the nausea and vomi ti ng associ ated wi th mi grai nes.

Pharmacotherapeutics
The choi ce of a tr i ptan depends on pati ent pr efer ences for dosage
for m (i f nausea and vomi ti ng ar e pr esent), pr esence of r ecur r ent
mi grai nes, and for mul ar y r estr i cti ons. A pati ent exper i enci ng
nausea and vomi ti ng may pr efer i njectabl e or i ntranasal
sumatr i ptan. Recur r ent mi grai nes may r espond to tr i ptans wi th a
l onger hal f-l i fe, such as fr ovatr i ptan and naratr i ptan. However,
tr i ptans wi th a l onger hal f-l i fe have a del ayed onset of effect. Two
newer tr i ptans, al motr i ptan and el etr i ptan, have a rapi d onset and
an i nter medi ate hal f-l i fe.

Adverse reactions to 5-HT 1 -receptor agonists

(triptans)
Adver se effects of 5-HT 1 -r eceptor agoni sts i ncl ude:

ti ngl i ng, war m or hot sensati on, or fl ushi ng

nasal and thr oat di scomfor t
vi si on di stur bances
par esthesi a
di z z i ness
fati gue or somnol ence
chest pai n or pr essur e; neck or thr oat pai n; jaw pai n or
pr essur e
weakness
dr y mouth
i ndi gesti on, nausea, sweati ng
 i njecti on si te r eacti on (sumatr i ptan subcutaneousl y)
taste di stur bances (i ntranasal sumatr i ptan).

Ser i ousbut rar e car di ac events, i ncl udi ng acute myocar di al

i nfar cti on, ar r hythmi as, and death, have been r epor ted wi thi n a
few hour s after use of 5-HT 1 -r eceptor agoni sts.

Drug interactions
Tr i ptans have many contrai ndi cati ons and ar ent for use i n pati ents
wi th cer tai n condi ti ons. (See Tr i ptans: Contrai ndi cati ons and
cauti ons, page 88.)
The safety of tr eati ng mor e than thr ee mi grai ne attacks i n a 30-day
per i od wi th tr i ptans hasnt been establ i shed. (See Adver se r eacti ons
to 5-HT 1 -r eceptor agoni sts [tr i ptans].)
In addi ti on:

Tr i ptans shoul dnt be admi ni ster ed wi thi n 24 hour s of another 5-

HT 1 -r eceptor agoni st.
Er gotami ne-contai ni ng and er got-type dr ugs (such as
di hydr oer gotami ne and methyser gi de) shoul dnt be gi ven wi thi n
24 hour s of a 5-HT 1 -r eceptor agoni st because pr ol onged
vasospasti c r eacti ons may occur.
El etr i ptan shoul dnt be used wi thi n at l east 72 hour s of these
potent CYP3A4 i nhi bi tor s: ketoconazol e, i traconazol e,
nefazodone, cl ar i thr omyci n, r i tonavi r, nel fi navi r, and any other
dr ugs that have demonstrated potent CYP3A4 i nhi bi ti on, as
descr i bed i n thei r l abel i ng.
 Safe and sound
Triptans: Contraindications and cautions
Tr i ptans ar e contrai ndi cated for pati ents wi th i schemi c
hear t di sease (such as angi na pector i s, hi stor y of myocar di al
i nfar cti on, or documented si l ent i schemi a) and i n pati ents who
have symptoms or fi ndi ngs consi stent wi th i schemi c hear t di sease,
cor onar y ar ter y vasospasm (i ncl udi ng Pr i nz metal s var i ant
angi na), or other si gni fi cant under l yi ng car di ovascul ar condi ti ons.
Tr i ptans shoul dnt be pr escr i bed for pati ents wi th cer ebr ovascul ar
syndr omes, such as str okes or transi ent i schemi c attacks, or for
pati ents wi th per i pheral vascul ar di sease, i ncl udi ngbut not
l i mi ted toi schemi c bowel di sease. Tr i ptans shoul dnt be gi ven to
pati ents wi th uncontr ol l ed hyper tensi on or wi th hemi pl egi c or
basi l ar mi grai nes.
In addi ti on, tr i ptans ar ent r ecommended for use i n pati ents who
have r i sk factor s for unr ecogni zed cor onar y ar ter y di sease (CAD)
(such as hyper tensi on, hyper chol ester ol emi a, smoki ng, obesi ty,
di abetes, str ong fami l y hi stor y of CAD, bei ng a femal e wi th
sur gi cal or physi ol ogi c menopause, or bei ng a mal e over age 40)
unl ess a car di ovascul ar eval uati on i ndi cates that the pati ent i s
r easonabl y fr ee fr om under l yi ng car di ovascul ar di sease. If a
tr i ptan i s used i n thi s setti ng, the fi r st dose shoul d be
admi ni ster ed i n a doctor s offi ce or other medi cal l y staffed and
equi pped faci l i ty.
Al so, i nter mi ttent, l ong-ter m user s of tr i ptans and those who
have r i sk factor s shoul d under go per i odi c car di ac eval uati on.
Wait two weeks
Al motr i ptan, r i z atr i ptan, sumatr i ptan, and zol mi tr i ptan shoul d
not be used wi th, or wi thi n 2 weeks of di sconti nui ng, an MAOI.
Sel ecti ve ser otoni n r euptake i nhi bi tor s (SSRIs), such as
ci tal opram, fl uoxeti ne, fl uvoxami ne, par oxeti ne, and ser tral i ne,
have, i n rar e cases, caused weakness, hyper r efl exi a, and
i ncoor di nati on when admi ni ster ed wi th a tr i ptan. (Thi s r eacti on
has al so been r epor ted when the appeti te suppr essant
si butrami ne i s used wi th a tr i ptan.) Moni tor the pati ent cl osel y i f
concomi tant tr eatment wi th a tr i ptan and an SSRI i s cl i ni cal l y
war ranted.
The bi oavai l abi l i ty of fr ovatr i ptan i s 30% hi gher i n pati ents
taki ng hor monal contracepti ves.
Pr opranol ol i ncr eases the bi oavai l abi l i ty of zol mi tr i ptan,
r i z atr i ptan, fr ovatr i ptan, and el etr i ptan.

Ergotamine preparations
Er gotami ne and i ts der i vati ves may be used as abor ti ve or
symptomati c therapy for mi grai ne.
Some common pr eparati ons used for mi grai ne i ncl ude:

er gotami ne, avai l abl e i n subl i ngual and oral tabl ets and
supposi tor i es (combi ned wi th caffei ne)
di hydr oer gotami ne, avai l abl e i n i njectabl e and i ntranasal for ms.

Pharmacokinetics
Er gotami ne i s i ncompl etel y absor bed fr om the G I tract. The
i ntranasal for m of di hydr oer gotami ne i s rapi dl y absor bed. Peak
pl asma concentrati on, fol l owi ng subcutaneous i njecti on, i s wi thi n 45
mi nutes, and 90% of the dose i s pl asma pr otei n-bound. Er gotami ne
i s metabol i zed i n the l i ver, and 90% of the metabol i tes ar e excr eted
i n bi l e; traces of unchanged dr ug ar e excr eted i n ur i ne.

Pharmacodynamics
Er gotami ne-der i vati ve anti mi grai ne effects ar e bel i eved to be due to
bl ockade of neur ogeni c i nfl ammati on. They al so act as par ti al
agoni sts or antagoni sts at ser otoni n, dopami ner gi c, and al pha-
adr ener gi c r eceptor s dependi ng on thei r si te. Er gotami ne
pr eparati ons often need to be pr escr i bed wi th anti emeti c
pr eparati ons when used for mi grai ne.
Di hydr oer gotami ne, a hydr ogenated for m of er gotami ne, di ffer s
mai nl y i n degr ee of acti vi ty. It has l ess vasoconstr i cti ve acti on than
er gotami ne and much l ess emeti c potenti al .

Pharmacotherapeutics
Er gotami ne pr eparati ons ar e used to pr event or tr eat vascul ar
headaches, such as mi grai ne, mi grai ne var i ant, and cl uster
headaches. Di hydr oer gotami ne i s used when rapi d contr ol of
mi grai ne i s desi r ed or when other r outes ar e undesi rabl e.

Drug interactions
Pr opranol ol and other beta-adr ener gi c bl ocki ng dr ugs bl ock the
natural pathway for vasodi l ati on i n pati ents r ecei vi ng
er gotami ne pr eparati ons, r esul ti ng i n excessi ve vasoconstr i cti on
and col d extr emi ti es.
 Warning!
Adverse reactions to ergotamine derivatives
Adver se effects of er gotami ne der i vati ves i ncl ude:

nausea and vomi ti ng

numbness
ti ngl i ng
muscl e pai n
l eg weakness
i tchi ng.

Pr ol onged admi ni strati on of er gotami ne der i vati ves may r esul t i n

gangr ene and r ebound headaches. Contrai ndi cati ons to the use of
er gotami ne pr eparati ons i ncl ude cor onar y, cer ebral , or per i pheral
vascul ar di sease; hyper tensi on; and l i ver or ki dney di sease.

Steady, now
Ther e may be an i ncr eased r i sk of weakness, hyper fl exi on, and
i ncoor di nati on when usi ng er gotami ne pr eparati ons wi th SSRIs.
Sumatr i ptan may cause an addi ti ve effect, i ncr easi ng the r i sk of
cor onar y vasospasm. Dont gi ve any er gotami ne pr eparati ons
and tr i ptans wi thi n 24 hour s of each other.
Dr ugs that i nhi bi t the CYP3A4 enz yme (such as er ythr omyci n,
cl ar i thr omyci n, r i tonavi r, nel fi navi r, i ndi navi r, and azol e-
der i vati ve anti fungal agents) may al ter the metabol i sm of
er gotami ne, r esul ti ng i n i ncr eased ser um concentrati ons of
er gotami ne. Thi s i ncr eases the r i sk of vasospasm and cer ebral or
per i pheral i schemi a. These dr ugs shoul dnt be used together.
Vasoconstr i ctor s may cause an addi ti ve effect when gi ven wi th
er gotami ne pr eparati ons, i ncr easi ng the r i sk of hi gh bl ood
pr essur e. (See Adver se r eacti ons to er gotami ne der i vati ves.)
 Quick quiz
1A 15-year-ol d pati ent has a toni c-cl oni c sei z ur e
di sor der and i s pr escr i bed phenytoi n. Whi ch ter m best
descr i bes the absor pti on rate of oral phenytoi n?
A. Rapi d
B. Inter mi ttent
C. Er rati c
D. Sl ow

2An 11-year-ol d pati ent devel ops myocl oni c sei z ur es. Whi ch
potenti al adver se r eacti on makes i t unl i kel y that val pr oate wi l l be
pr escr i bed for thi s pati ent?
A. Li ver toxi ci ty
B. Central ner vous system sedati on
C. Respi rator y depr essi on
D. Renal toxi ci ty

3A 48-year-ol d pati ent has been pr escr i bed tr i hexypheni dyl for
her Par ki nsons di sease. Whi ch adver se r eacti on i s dose-r el ated?
A. Excessi ve sal i vati on
B. Dr y mouth
C. Bradycar di a
D. Nausea

4Whi ch anti par ki nsoni an dr ug i s associ ated wi th the on-off

phenomenon and the wear i ng-off effect?
A. Amantadi ne
B. Benz tr opi ne
C. Levodopa
D. Sel egi l i ne

P.
Scoring
If you answer ed al l four i tems cor r ectl y, mar vel ous!
Your e mi ghty fi ne wi th neur omuscul ar s.

If you answer ed thr ee i tems cor r ectl y, congrats! Your

knowl edge has a rapi d onset and l ong durati on.

If you answer ed fewer than thr ee i tems cor r ectl y, dont

wor r y. G i ve your sel f another dose of the chapter, and
r echeck the r esul ts.

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

4
Pain medications

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs used to contr ol pai n

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and pain control

Dr ugs used to contr ol pai n range fr om mi l d, over-the-counter (OTC)
pr eparati ons such as acetami nophen to potent general anestheti cs.
They i ncl ude:

nonopi oi d anal gesi cs, anti pyr eti cs, and nonster oi dal anti -
i nfl ammator y dr ugs (NSAIDs)
opi oi d agoni st and antagoni st dr ugs
anestheti c dr ugs.
Nonopioid analgesics, antipyretics, and
NSAIDs
Nonopi oi d anal gesi cs, anti pyr eti cs, and NSAIDs ar e a br oad gr oup of
pai n medi cati ons. Theyr e di scussed together because, i n addi ti on to
pai n contr ol , they al so pr oduce anti pyr eti c (fever contr ol ) and anti -
i nfl ammator y effects. These dr ugs may be used al one or i n
combi nati on wi th other medi cati ons. They have a cei l i ng effect
(maxi mum dose above whi ch ther es no added benefi t) and dont
cause physi cal dependence.
The dr ug cl asses i ncl uded i n thi s gr oup ar e:

sal i cyl ates (especi al l y aspi r i n), whi ch ar e wi del y used

the para-ami nophenol der i vati ve acetami nophen

NSAIDs
the ur i nar y tract anal gesi c phenazopyr i di ne.

Salicylates
Salicylates ar e among the most commonl y used pai n medi cati ons.
Theyr e used r egul ar l y to contr ol pai n and r educe fever and
i nfl ammati on.
Cheap, easy, and reliable
Sal i cyl ates usual l y cost l ess than other anal gesi cs and ar e r eadi l y
avai l abl e wi thout a pr escr i pti on. Aspi r i n i s the most commonl y used
sal i cyl ate. Other common sal i cyl ates i ncl ude:

chol i ne magnesi um tr i sal i cyl ate

chol i ne sal i cyl ate
di fl uni sal
sal sal ate
sodi um sal i cyl ate.

Pharmacokinetics (how drugs circulate)

Taken oral l y, sal i cyl ates ar e absor bed par tl y i n the stomach, but
pr i mar i l y i n the upper par t of the smal l i ntesti ne. The pur e and
buffer ed for ms of aspi r i n ar e absor bed r eadi l y, but sustai ned-
r el ease and enter i c-coated sal i cyl ate pr eparati ons ar e absor bed
mor e sl owl y. Food or antaci ds i n the stomach al so del ay absor pti on.
Sal i cyl ates gi ven r ectal l y have a sl ower, mor e er rati c absor pti on.

Distribution, metabolism, and excretion

Sal i cyl ates ar e di str i buted wi del y thr oughout body ti ssues and
fl ui ds, i ncl udi ng br east mi l k. In addi ti on, they easi l y cr oss the
pl acental bar r i er.
The l i ver extensi vel y metabol i zes sal i cyl ates i nto several
metabol i tes. The ki dneys excr ete the metabol i tes al ong wi th some
unchanged dr ug.

Pharmacodynamics (how drugs act)

The di ffer ent effects of sal i cyl ates stem fr om thei r separate
mechani sms of acti on. They r el i eve pai n pr i mar i l y by i nhi bi ti ng the
synthesi s of pr ostagl andi n. (Recal l that pr ostagl andi n i s a chemi cal
medi ator that sensi ti zes ner ve cel l s to pai n.) In addi ti on, they may
al so r educe i nfl ammati on by i nhi bi ti ng the pr ostagl andi n synthesi s
and r el ease that occur s dur i ng i nfl ammati on.

Hot and bothered

Sal i cyl ates r educe fever by sti mul ati ng the hypothal amus, pr oduci ng
di l ati on of the per i pheral bl ood vessel s and i ncr eased sweati ng. Thi s
pr omotes heat l oss thr ough the ski n and cool i ng by evaporati on.
Al so, because pr ostagl andi n E i ncr eases body temperatur e,
i nhi bi ti ng i ts pr oducti on l ower s a fever.
No clots allowed
One sal i cyl ate, aspi r i n, per manentl y i nhi bi ts pl atel et aggr egati on
(the cl umpi ng of pl atel ets to for m a cl ot) by i nter fer i ng wi th the
pr oducti on of a substance cal l ed thr omboxane A2 , necessar y for
pl atel et aggr egati on. Not al l sal i cyl ates have thi s effect. For
exampl e, chol i ne magnesi um doesnt i ncr ease bl eedi ng ti me.

Pharmacotherapeutics (how drugs are used)

Sal i cyl ates ar e used pr i mar i l y to r el i eve pai n and r educe fever.
However, they dont effecti vel y r el i eve vi sceral pai n (pai n fr om the
or gans and smooth muscl e) or sever e pai n fr om trauma.

You give me fever

Sal i cyl ates wont r educe a nor mal body temperatur e. They can
r educe an el evated body temperatur e, and wi l l r el i eve headache and
muscl e ache at the same ti me.

What kind of joint is this?

Sal i cyl ates can pr ovi de consi derabl e r el i ef i n 24 hour s when theyr e
used to r educe i nfl ammati on i n r heumati c fever, r heumatoi d
ar thr i ti s, and osteoar thr i ti s.

Go with the flow

As a r esul t of i ts anti cl otti ng pr oper ti es, aspi r i n can be used to
enhance bl ood fl ow dur i ng myocar di al i nfar cti on (MI) and to pr event
r ecur r ence of MI.
How low can you go?
No matter what the cl i ni cal i ndi cati on, the mai n gui del i ne of
sal i cyl ate therapy i s to use the l owest dose that pr ovi des r el i ef. Thi s
r educes the l i kel i hood of adver se r eacti ons. (See Adver se r eacti ons
to sal i cyl ates.)

Warning!
Adverse reactions to salicylates
The most common adver se r eacti ons to sal i cyl ates i ncl ude
gastr i c di str ess, nausea, vomi ti ng, and bl eedi ng tendenci es. Other
adver se r eacti ons i ncl ude:

hear i ng l oss (when taken for pr ol onged per i ods)

di ar r hea, thi r st, sweati ng, ti nni tus, confusi on, di z z i ness,
i mpai r ed vi si on, and hyper venti l ati on (rapi d br eathi ng)
Reyes syndr ome (when gi ven to chi l dr en wi th chi ckenpox or
fl ul i ke symptoms).

Drug interactions
Because sal i cyl ates ar e hi ghl y pr otei n-bound, they can i nteract wi th
many other pr otei n-bound dr ugs by di spl aci ng those dr ugs fr om
si tes to whi ch they nor mal l y bi nd. Thi s i ncr eases the ser um

concentrati on of the unbound acti ve dr ug, causi ng i ncr eased

phar macol ogi c effects (the unbound dr ug i s sai d to be potentiated).

Safe and sound

Using salicylates safely
Befor e admi ni ster i ng nonster oi dal anti -i nfl ammator y dr ugs
(NSAIDs), be awar e of speci al popul ati on concer ns.
Childr en: Some NSAIDs ar ent r ecommended for use i n chi l dr en.
Elder ly patients: The r i sk of ul cer s i ncr eases wi th age.
Pr egnant women: Di cl ofenac, fl ur bi pr ofen, ketopr ofen, and
napr oxen ar e pr egnancy r i sk categor y B dr ugs. Etodol ac,
ketor ol ac, mel oxi cam, nabumetone, oxapr oz i n, and pi r oxi cam ar e
categor y C dr ugs. Because most NSAIDs appear i n br east mi l k, i ts
best not to use these dr ugs i n br east-feedi ng women.
The fol l owi ng dr ug i nteracti ons may occur :

Oral anti coagul ants, hepar i n, methotr exate, oral anti di abeti c
agents, and i nsul i n ar e among the dr ugs that have an i ncr eased
effect or r i sk of toxi ci ty when taken wi th sal i cyl ates.
Pr obeneci d, sul fi npyrazone, and spi r onol actone may have a
decr eased effect when taken wi th sal i cyl ates.
Cor ti coster oi ds may decr ease pl asma sal i cyl ate l evel s and
i ncr ease the r i sk of ul cer s.
Al kal i ni z i ng dr ugs and antaci ds may r educe sal i cyl ate l evel s.
The anti hyper tensi ve effect of angi otensi n-conver ti ng enz yme
(ACE) i nhi bi tor s and beta-adr ener gi c bl ocker s may be r educed
when these dr ugs ar e combi ned wi th sal i cyl ates.
NSAIDs may have a r educed therapeuti c effect and an i ncr eased
r i sk of G I effects when taken wi th sal i cyl ates. (See Usi ng
sal i cyl ates safel y.)

Acetaminophen
Al though the cl ass of para-ami nophenol der i vati ves i ncl udes two
dr ugsphenaceti n and acetami nophenonl y acetami nophen i s
avai l abl e i n the Uni ted States. Acetaminophen i s an OTC dr ug that
pr oduces anal gesi c and anti pyr eti c effects. It appear s i n many

pr oducts desi gned to r el i eve the pai n and symptoms associ ated wi th
col ds and i nfl uenz a.
Pharmacokinetics
Acetami nophen i s absor bed rapi dl y and compl etel y fr om the G I
tract. Its al so absor bed wel l fr om the mucous membranes of the
r ectum.

Distribution, metabolism, and excretion

Acetami nophen i s di str i buted wi del y i n body fl ui ds and r eadi l y
cr osses the pl acental bar r i er. After acetami nophen i s metabol i zed by
the l i ver, i ts excr eted by the ki dneys and, i n smal l amounts, i n
br east mi l k.

Pharmacodynamics
Acetami nophen r educes pai n and fever, but unl i ke sal i cyl ates, i t
doesnt affect i nfl ammati on or pl atel et functi on. It can cause
anti coagul ati on i n the pati ent taki ng war far i n.

Mystery theater
The pai n-contr ol effects of acetami nophen ar ent wel l under stood.
The dr ug may wor k i n the central ner vous system (CNS) by
i nhi bi ti ng pr ostagl andi n synthesi s and i n the per i pheral ner vous
system i n some unknown way. It r educes fever by acti ng di r ectl y on
the heat-r egul ati ng center i n the hypothal amus.

Pharmacotherapeutics
Acetami nophen i s used to r educe fever and r el i eve headache,
muscl e ache, and general pai n.

Childs play
Acetami nophen i s the dr ug of choi ce to tr eat fever and fl ul i ke
symptoms i n chi l dr en. Addi ti onal l y, the Amer i can Ar thr i ti s
Associ ati on has i ndi cated that acetami nophen i s an effecti ve pai n
r el i ever for some types of ar thr i ti s.
Drug interactions
Acetami nophen can pr oduce the fol l owi ng dr ug i nteracti ons:

The effects of oral anti coagul ants and thr ombol yti c dr ugs may be
sl i ghtl y i ncr eased.
The r i sk of l i ver toxi ci ty i s i ncr eased when l ong-ter m al cohol
use, phenytoi n, bar bi turates, car bamazepi ne, and i soni az i d ar e
combi ned wi th acetami nophen.
The effects of l amotr i gi ne, l oop di ur eti cs, and z i dovudi ne may be
r educed when these dr ugs ar e taken wi th acetami nophen. (See
Adver se r eacti ons to acetami nophen.)

Nonsteroidal anti-inflammatory drugs

As thei r name suggests, nonster oidal anti-inflammator y dr ugs
(NSAIDs), ar e typi cal l y used to combat i nfl ammati on. Thei r anti -
i nfl ammator y acti on equal s that of aspi r i n. They al so have anal gesi c
and anti pyr eti c effects. Unl i ke aspi r i ns effects, the effects of
NSAIDs on pl atel et aggr egati on ar e temporar y.

Picky, picky
Ther e ar e two types of NSAIDs: sel ecti ve and nonsel ecti ve. The
nonsel ecti ve NSAIDs i ncl ude di cl ofenac, etodol ac, fenopr ofen,
fl ur bi pr ofen, i bupr ofen, i ndomethaci n, ketopr ofen, ketor ol ac,
mel oxi cam, nabumetone, napr oxen, oxapr oz i n, pi r oxi cam, and
sul i ndac. The onl y sel ecti ve NSAID avai l abl e on todays mar ket i s
cel ecoxi b. (See Ri sks of usi ng sel ecti ve NSAIDs.)

Pharmacokinetics
Al l NSAIDs (nonsel ecti ve and sel ecti ve) ar e absor bed i n the G I
tract. Theyr e mostl y metabol i zed i n the l i ver and excr eted pr i mar i l y
by the ki dneys.

Pharmacodynamics
Two i soenz ymes of cycl ooxygenase, known as COX-1 and COX-2,
conver t arachi doni c aci d i nto pr ostagl andi ns. The nonsel ecti ve
NSAIDs bl ock both COX-1 and COX-2. Sel ecti ve NSAIDs bl ock onl y
the COX-2 enz yme.

Warning!
Adverse reactions to acetaminophen
Most pati ents tol erate acetami nophen wel l . Unl i ke the
sal i cyl ates, acetami nophen rar el y causes gastr i c i r r i tati on or
bl eedi ng tendenci es.
Acetami nophen may cause sever e l i ver toxi ci ty, and the total
dai l y dose shoul d be moni tor ed. (The total dai l y dose shoul dnt
exceed 4,000 mg/day.)
Other adver se r eacti ons i ncl ude:

ski n rash
hypogl ycemi a
neutr openi a.

Safe and sound

Risks of using selective NSAIDs
Two sel ecti ve nonster oi dal anti -i nfl ammator y dr ugs
(NSAIDs) wer e pul l ed fr om the mar ket after i t was di scover ed
they wer e associ ated wi th an i ncr eased r i sk of hear t attack and
str oke, l eavi ng cel ecoxi b as the onl y avai l abl e dr ug i n i ts cl ass.
Pati ents consi der i ng the use of cel ecoxi b shoul d be car eful l y
scr eened for a hi stor y of cer ebr ovascul ar or car di ovascul ar
di sease and then cl osel y moni tor ed thr oughout tr eatment for
si gns or symptoms of devel opi ng pr obl ems.
 Safe and sound
Using nonselective NSAIDs safely
Befor e admi ni ster i ng nonster oi dal anti -i nfl ammator y dr ugs
(NSAIDs), be awar e of speci al popul ati on concer ns.
Childr en: Some NSAIDs ar ent r ecommended for use i n chi l dr en.
Elder ly patients: The r i sk of ul cer s i ncr eases wi th age.
Pr egnant women: Di cl ofenac, fl ur bi pr ofen, ketopr ofen, and
napr oxen ar e pr egnancy r i sk categor y B dr ugs. Etodol ac,
ketor ol ac, mel oxi cam, nabumetone, oxapr oz i n, and pi r oxi cam ar e
categor y C dr ugs. Because most NSAIDs appear i n br east mi l k, i ts
best not to use these dr ugs i n br east-feedi ng women.

Hard to stomach
The pr ostagl andi ns pr oduced by COX-1 mai ntai n the stomach l i ni ng,
whi l e those pr oduced by COX-2 cause i nfl ammati on. Thats why the
nonsel ecti ve NSAIDs, whi ch i nhi bi t COX-1 al ong wi th COX-2,
commonl y cause G I adver se effects. Sel ecti ve NSAIDs, however,
al l evi ate pai n and i nfl ammati on wi thout causi ng si gni fi cant G I
adver se effects because they i nhi bi t onl y COX-2.

Pharmacotherapeutics
NSAIDs ar e used pr i mar i l y to decr ease i nfl ammati on. Theyr e
secondar i l y used to r el i eve pai n, but ar e sel dom pr escr i bed to
r educe fever. (See Usi ng nonsel ecti ve NSAIDs safel y.)
COX-2 i nhi bi tor s ar e pr i mar i l y used to r el i eve pai n and to decr ease
i nfl ammati on. These dr ugs ar e par ti cul ar l y useful i n the tr eatment
of osteoar thr i ti s, r heumatoi d ar thr i ti s, acute pai n, pr i mar y
dysmenor r hea, and fami l i al adenomatous pol yposi s.

Call and response

The fol l owi ng condi ti ons r espond favorabl y to tr eatment wi th
NSAIDs:

ankyl osi ng spondyl i ti s (an i nfl ammator y joi nt di sease that fi r st

affects the spi ne)
moderate to sever e r heumatoi d ar thr i ti s (an i nfl ammator y
di sease of per i pheral joi nts)
 osteoar thr i ti s (a degenerati ve joi nt di sease) i n the hi p, shoul der,
or other l ar ge joi nts
osteoar thr i ti s accompani ed by i nfl ammati on
acute gouty ar thr i ti s (urate deposi ts i n the joi nts)
dysmenor r hea (pai nful menstr uati on)
mi grai ne headaches
bur si ti s and tendoni ti s
mi l d to moderate pai n.

Warning!
Adverse reactions to nonselective NSAIDs
Nonsel ecti ve nonster oi dal anti -i nfl ammator y dr ugs
(NSAIDs) pr oduce si mi l ar adver se r eacti ons, i ncl udi ng:

abdomi nal pai n, bl eedi ng, anor exi a, di ar r hea, nausea, ul cer s,
and l i ver toxi ci ty
dr owsi ness, headache, di z z i ness, confusi on, ti nni tus, ver ti go,
and depr essi on
bl adder i nfecti on, bl ood i n the ur i ne, and ki dney necr osi s
hyper tensi on, hear t fai l ur e, and pedal edema.

Drug interactions
A wi de var i ety of dr ugs can i nteract wi th NSAIDs, especi al l y wi th
i ndomethaci n, pi r oxi cam, and sul i ndac. Because theyr e hi ghl y
pr otei n-bound, NSAIDs ar e l i kel y to i nteract wi th other pr otei n-
bound dr ugs. Such dr ugs as fl uconazol e, phenobar bi tal , r i fampi n,
r i tonavi r, and sal i cyl ates affect absor pti on of NSAIDs, wher eas
NSAIDs affect the absor pti on of such dr ugs as oral anti coagul ants,
ami nogl ycosi des, ACE i nhi bi tor s, beta-adr ener gi c bl ocker s, di goxi n,
di l anti n, and many other s. (See Adver se r eacti ons to nonsel ecti ve
NSAIDs and Adver se r eactions to COX-2 inhibitor s.)
Because NSAIDs ar e metabol i zed by the l i ver, dr ug-dr ug i nteracti ons
have been i denti fi ed for al l of them. For exampl e, these dr ugs
decr ease the cl earance of l i thi um, whi ch can r esul t i n l i thi um
toxi ci ty. They al so r educe the anti hyper tensi ve effects of ACE
i nhi bi tor s and di ur eti cs.

Warning!
Adverse reactions to COX-2 inhibitors
COX-2 i nhi bi tor s can have the fol l owi ng adver se r eacti ons:

dyspepsi a, nausea, and vomi ti ng

G I ul cer s (to a l esser degr ee than wi th nonsel ecti ve NSAIDs)
hyper tensi on, fl ui d r etenti on, and per i pheral edema
di z z i ness and headache.

COX-2 i nhi bi tor s ar e cl assi fi ed as pr egnancy r i sk categor y C; most

appear i n br east mi l k. As a pr ecauti on, dont use i n br east-
feedi ng women.

Phenazopyridine hydrochloride
Phenaz opyr idine hydr ochlor ide, an azo dye used i n commer ci al
col or i ng, pr oduces a l ocal anal gesi c effect on the ur i nar y tract.

Pharmacokinetics
When taken oral l y, the l i ver metabol i zes 35% of phenazopyr i di ne.
The r emai nder i s excr eted unchanged i n the ur i ne, causi ng the
pati ents ur i ne to tur n an orange or r ed col or.

Pharmacodynamics
Phenazopyr i di ne i s taken oral l y and pr oduces an anal gesi c effect on
the ur i nar y tract usual l y wi thi n 24 to 48 hour s after therapy begi ns.

Phamacotherapeutics
The dr ug i s used to r el i eve such symptoms as pai n, bur i ng, ur gency,
and fr equency associ ated wi th ur i nar y tract i nfecti ons.

Drug interactions
Ther e ar e no l i sted dr ug i nteracti ons wi th phenazopyr i di ne. (See
Adver se r eacti ons to phenazopyr i di ne hydr ochl or i de.)
 Warning!
Adverse reactions to phenazopyridine
hydrochloride
Phenazopyr i di ne hydr o-chl or i de can have cer tai n adver se
r eacti ons.

If the dr ug accumul ates, the pati ents ski n and scl era may
assume a yel l ow ti nge. If thi s occur s, the dr ug may need to be
di sconti nued.
Acute r enal or hepati c fai l ur e may occur.

Opioid agonist and antagonist drugs

The wor d opioid r efer s to der i vati ves of the opi um pl ant or to
syntheti c dr ugs that i mi tate natural nar coti cs. Opi oi d agoni sts (al so
cal l ed nar cotic agonists) i ncl ude opi um der i vati ves and syntheti c
dr ugs wi th si mi l ar pr oper ti es. Theyr e used to r el i eve or decr ease
pai n wi thout causi ng the per son to l ose consci ousness.
Some opi oi d agoni sts may al so have anti tussi ve effects that
suppr ess coughi ng and anti di ar r heal acti ons that can contr ol
di ar r hea.

Anta-dote
Opi oi d antagoni sts ar ent pai n medi cati ons. Instead, they bl ock the
effects of opi oi d agoni sts and ar e used to r ever se adver se dr ug
r eacti ons, such as r espi rator y and CNS depr essi on, pr oduced by
those dr ugs. Unfor tunatel y, by r ever si ng the anal gesi c effect, they
al so cause the pati ents pai n to r ecur.

Having it both ways

Some opi oi d anal gesi cs, cal l ed mixed opioid agonist-antagonists,
have agoni st and antagoni st pr oper ti es. The agoni st component
r el i eves pai n, whi l e the antagoni st component decr eases the r i sk of
toxi ci ty and dr ug dependence. These mi xed opi oi d agoni st-
antagoni sts r educe the r i sk of r espi rator y depr essi on and dr ug
abuse.
Opioid agonists
Opioid agonists i ncl ude:

codei ne
fentanyl
hydr ocodone
hydr omor phone
l evor phanol
meper i di ne
methadone
mor phi ne sul fate (i ncl udi ng mor phi ne sul fate sustai ned-r el ease
tabl ets and i ntensi fi ed oral sol uti on)
oxycodone
oxymor phone
pr opoxyphene
r emi fentani l
sufentani l .

Gold standard
Mor phi ne sul fate i s the standar d agai nst whi ch the effecti veness and
adver se r eacti ons of other pai n medi cati ons ar e measur ed. (See
Usi ng opi oi d agoni sts safel y.)

Pharmacokinetics
A per son may r ecei ve an opi oi d agoni st by any admi ni strati on r oute,
al though i nhal ati on admi ni strati on i s uncommon. Oral doses ar e
absor bed r eadi l y fr om the G I tract; however, transmucosal and
i ntrathecal opi ates ar e faster-acti ng.

Speedy delivery
Opi oi d agoni sts admi ni ster ed I.V. pr ovi de the most rapi d (al most
i mmedi ate) and r el i abl e pai n r el i ef. The subcutaneous (subQ) and
I.M. r outes may r esul t i n del ayed absor pti on, especi al l y i n pati ents
wi th poor ci r cul ati on.

Distribution
Opi oi d agoni sts ar e di str i buted wi del y thr oughout body ti ssues. They
have a r el ati vel y l ow pl asma pr otei n-bi ndi ng capaci ty (30% to
35% ).

Safe and sound

Using opioid agonists safely
Be awar e that mor phi ne sul fate (MSO4 ) can be confused
wi th magnesi um sul fate (MgSO4 ). To avoi d confusi ng the dr ugs,
never use abbr evi ati ons.

Metabolism
Opi oi d agoni sts ar e metabol i zed extensi vel y i n the l i ver. For
exampl e, meper i di ne i s metabol i zed to nor meper i di ne, a toxi c
metabol i te wi th a l onger hal f-l i fe than meper i di ne. Thi s metabol i te
accumul ates i n pati ents wi th r enal fai l ur e and may l ead to CNS
exci tati on and sei z ur es. Admi ni strati on of meper i di ne for mor e than

48 hour s i ncr eases the r i sk of neur otoxi ci ty and sei z ur es fr om

bui l dup of nor meper i di ne.

Excretion
Metabol i tes ar e excr eted by the ki dneys. A smal l amount i s excr eted
i n stool thr ough the bi l i ar y tract.

Pharmacodynamics
Opi oi d agoni sts r educe pai n by bi ndi ng to opi ate r eceptor si tes (mu
r eceptor s and N-methyl -D-aspar tate r eceptor s) i n the per i pheral
ner vous system and the CNS. When these dr ugs sti mul ate the
opi ate r eceptor s, they mi mi c the effects of endor phi ns (natural l y
occur r i ng opi ates that ar e par t of the bodys own pai n r el i ef
system). Thi s r eceptor-si te bi ndi ng pr oduces the therapeuti c effects
of anal gesi a and cough suppr essi on. It al so pr oduces adver se
r eacti ons, such as r espi rator y depr essi on and consti pati on.

Smooth operator
Opi oi d agoni sts, especi al l y mor phi ne, affect the smooth muscl e of
the G I and geni tour i nar y tracts (the or gans of the r epr oducti ve and
ur i nar y systems). Thi s causes contracti on of the bl adder and
ur eter s. It al so sl ows i ntesti nal per i stal si s (r hythmi c contracti ons
that move food al ong the di gesti ve tract), r esul ti ng i n consti pati on,
a common adver se effect of opi ates.

Too much of a good thing

These dr ugs al so cause bl ood vessel s to di l ate, especi al l y i n the
face, head, and neck. In addi ti on, they suppr ess the cough center i n
the brai n, pr oduci ng anti tussi ve effects and causi ng constr i cti on of
the br onchi al muscl es. These effects can pr oduce adver se r eacti ons
i f excessi ve. For exampl e, i f the bl ood vessel s di l ate too much,
hypotensi on can occur.
Pharmacotherapeutics
Opi oi d agoni sts ar e pr escr i bed to r el i eve sever e pai n i n acute,
chr oni c, and ter mi nal i l l nesses. They al so r educe anxi ety befor e a
pati ent r ecei ves anesthesi a and ar e someti mes pr escr i bed to contr ol
di ar r hea and suppr ess coughi ng. (See How opi oi d agoni sts contr ol
pai n, page 104.)
Methadone i s used for temporar y mai ntenance of nar coti c addi cti on.
Other opi oi ds and r emi fentani l ar e used for the i nducti on and
mai ntenance of general anesthesi a.

Now I get it!

How opioid agonists control pain
Opi oi d agoni sts, such as meper i di ne, i nhi bi t pai n
transmi ssi on by mi mi cki ng the bodys natural pai n contr ol
mechani sms.

Where neurons meet

In the dor sal hor n of the spi nal cor d, per i pheral pai n neur ons
meet central ner vous system (CNS) neur ons. At the synapse, the
pai n neur on r el eases substance P (a pai n neur otransmi tter ). Thi s
agent hel ps transfer pai n i mpul ses to the CNS neur ons that car r y
those i mpul ses to the brai n.
Taking up space
In theor y, the spi nal i nter neur ons r espond to sti mul ati on fr om the
descendi ng neur ons of the CNS by r el easi ng endogenous opi ates.
These opi ates bi nd to the per i pheral pai n neur on to i nhi bi t
r el ease of substance P and to r etar d the transmi ssi on of pai n
i mpul ses.
Stopping substance P
Syntheti c opi ates suppl ement thi s pai n-bl ocki ng effect by bi ndi ng
wi th fr ee opi ate r eceptor s to i nhi bi t the r el ease of substance P.
Opi ates al so al ter consci ousness of pai n, but how thi s mechani sm
wor ks r emai ns unknown.
Cardio-assistance
Mor phi ne r el i eves shor tness of br eath i n pati ents wi th pul monar y
edema (fl ui d i n the l ungs) and l eft-si ded hear t fai l ur e (i nabi l i ty of
the hear t to pump enough bl ood to meet the needs of the body). It
does thi s by di l ati ng per i pheral bl ood vessel s, keepi ng mor e bl ood i n
the per i pher y, and decr easi ng car di ac pr el oad.

Warning!
Adverse reactions to opioid agonists
One of the most common adver se r eacti ons to opi oi d
agoni sts i s decr eased rate and depth of br eathi ng that wor sens as
the dose of opi oi d i s i ncr eased. Thi s may cause per i odi c, i r r egul ar
br eathi ng or tr i gger asthmati c attacks i n suscepti bl e pati ents.
Other adver se r eacti ons i ncl ude:

fl ushi ng
or thostati c hypotensi on
pupi l constr i cti on.

Adver se r eacti ons to meper i di ne i ncl ude:

tr emor s
 pal pi tati ons
tachycar di a
del i r i um
sei z ur es.

Drug interactions
The use of opi oi d agoni sts wi th other dr ugs that al so decr ease
r espi rati ons, such as al cohol , sedati ves, hypnoti cs, and
anestheti cs, i ncr eases the pati ents r i sk of sever e r espi rator y
depr essi on.
Taki ng tr i cycl i c anti depr essants, phenothi az i nes, or
anti chol i ner gi cs wi th opi oi d agoni sts may cause sever e
consti pati on and ur i ne r etenti on.
Dr ugs that may affect opi oi d anal gesi c acti vi ty i ncl ude
ami tr i ptyl i ne, di azepam, phenytoi n, pr otease i nhi bi tor s, and
r i fampi n.
Dr ugs that may be affected by opi oi d anal gesi cs i ncl ude
car bamazepi ne, war far i n, beta-adr ener gi c bl ocker s, and cal ci um
channel bl ocker s. (See Adver se r eacti ons to opi oi d agoni sts.)

Mixed opioid agonist-antagonists

Mixed opioid agonist-antagonists attempt to r el i eve pai n whi l e
r educi ng toxi c effects and dependency. The mi xed opi oi d agoni st-
antagoni sts i ncl ude:

bupr enor phi ne

butor phanol
nal buphi ne
pentazoci ne hydr ochl or i de (combi ned wi th pentazoci ne l actate,
nal oxone, aspi r i n, or acetami nophen).

No free ride
Or i gi nal l y, mi xed opi oi d agoni st-antagoni sts appear ed to have l ess
abuse potenti al than the pur e opi oi d agoni sts. However, butor phanol
and pentazoci ne have r epor tedl y caused dependence. Al so,

pati ents wi th chr oni c pai n who ar e taki ng an opi oi d agoni st

shoul dnt take a mi xed opi oi d agoni st-antagoni st wi th i t because of
the r i sk of wi thdrawal symptoms.

Pharmacokinetics
Absor pti on of mi xed opi oi d agoni st-antagoni sts occur s rapi dl y fr om
par enteral si tes. These dr ugs ar e di str i buted to most body ti ssues
and al so cr oss the pl acental bar r i er. Theyr e metabol i zed i n the l i ver
and excr eted pr i mar i l y by the ki dneys, al though mor e than 10% of
a butor phanol dose and a smal l amount of a pentazoci ne dose ar e
excr eted i n stool .

Pharmacodynamics
The exact mechani sm of acti on of the mi xed opi oi d agoni st-
antagoni sts i snt known. However, r esear cher s bel i eve that these
dr ugs weakl y antagoni ze the effects of mor phi ne, meper i di ne, and
other opi ates at one of the opi oi d r eceptor si tes, whi l e exer ti ng
agoni sti c effects at other opi oi d r eceptor si tes.

No rush to go
Bupr enor phi ne bi nds wi th r eceptor s i n the CNS, al ter i ng per cepti on
of and emoti onal r esponse to pai n thr ough an unknown mechani sm.
It seems to r el ease sl owl y fr om bi ndi ng si tes, pr oduci ng a l onger
durati on of acti on than the other dr ugs i n thi s cl ass.

Dont get emotional

The si te of acti on of butor phanol may be opi ate r eceptor s i n the
l i mbi c system (the par t of the brai n i nvol ved i n emoti on).
Li ke pentazoci ne, butor phanol al so acts on pul monar y ci r cul ati on,
i ncr easi ng pul monar y vascul ar r esi stance (the r esi stance i n the
bl ood vessel s of the l ungs that the r i ght ventr i cl e must pump
agai nst). Both dr ugs al so i ncr ease bl ood pr essur e and the wor kl oad
of the hear t.

Pharmacotherapeutics
Mi xed opi oi d agoni st-antagoni sts ar e used as anal gesi a dur i ng
chi l dbi r th and ar e al so admi ni ster ed postoperati vel y.

Independence day
Mi xed opi oi d agoni st-antagoni sts ar e someti mes pr escr i bed i n pl ace
of opi oi d agoni sts because they have a l ower r i sk of dr ug
dependence. Mi xed opi oi d agoni st-antagoni sts ar e al so l ess l i kel y to
cause r espi rator y depr essi on and consti pati on, al though they can

pr oduce some adver se r eacti ons. (See Adver se r eacti ons to opi oi d
agoni st-antagoni sts.)

Warning!
Adverse reactions to opioid agonist-antagonists
 The most common adver se r eacti ons to opi oi d agoni st-antagoni sts
i ncl ude nausea, vomi ti ng, l i ght-headedness, sedati on, and
euphor i a.

Drug interactions
Incr eased CNS depr essi on and an accompanyi ng decr ease i n
r espi rator y rate and depth may r esul t i f mi xed opi oi d agoni st-
antagoni sts ar e admi ni ster ed to pati ents taki ng other CNS
depr essants, such as bar bi turates and al cohol .

Clean and sober?

Pati ents who abuse opi oi ds shoul dnt r ecei ve mi xed opi oi d agoni st-
antagoni sts because these dr ugs can cause symptoms of wi thdrawal .
Mi xed opi oi d agoni st-antagoni sts ar e l i sted as pr egnancy r i sk
categor y C dr ugs; safety and use i n br east-feedi ng women havent
been establ i shed.

Opioid antagonists
Opioid antagonists have a gr eater attracti on for opi ate r eceptor s
than opi oi ds do; however, they dont sti mul ate those r eceptor s. As a
r esul t, opi oi d antagoni sts bl ock the effects of opi oi d dr ugs,
enkephal i ns, and endor phi ns.
Opi oi d antagoni sts i ncl ude:

nal oxone
nal tr exone.

Pharmacokinetics
Nal oxone i s admi ni ster ed I.M., subQ, or I.V. Nal tr exone i s
admi ni ster ed oral l y i n tabl et or l i qui d for m. Both dr ugs ar e
metabol i zed by the l i ver and excr eted by the ki dneys.

Pharmacodynamics
Opi oi d antagoni sts act by occupyi ng opi ate r eceptor si tes, di spl aci ng
opi oi ds attached to opi ate r eceptor s, and pr eventi ng opi oi ds fr om
bi ndi ng at these si tes. Thi s pr ocess, known as competitive inhibition,
effecti vel y bl ocks the effects of opi oi ds.
Pharmacotherapeutics
Nal oxone i s the dr ug of choi ce for managi ng an opi oi d over dose. It
r ever ses r espi rator y depr essi on and sedati on and hel ps stabi l i ze the
pati ents vi tal si gns wi thi n seconds after admi ni strati on.

Managing naltrexone therapy for drug addiction

To pr event acute wi thdrawal dur i ng tr eatment for opi oi d
addi cti on, pl an to use nal tr exone as par t of a compr ehensi ve
r ehabi l i tati on pr ogram. Keep i n mi nd the fol l owi ng gui del i nes:

Dont gi ve nal tr exone unti l a negati ve nal oxone chal l enge test
i s obtai ned.
Dont gi ve nal tr exone to a pati ent whos r ecei vi ng an opi oi d
agoni st, addi cted to an opi oi d agoni st, or i n the acute phase of
opi oi d wi thdrawal because acute wi thdrawal symptoms may
occur or wor sen.
For a pati ent whos addi cted to a shor t-acti ng opi oi d, such as
her oi n or meper i di ne, wai t at l east 7 days after the l ast opi oi d
dose befor e star ti ng nal tr exone.
For a pati ent whos addi cted to a l onger-acti ng opi oi d, such as
methadone, wai t at l east 10 days after the l ast opi oi d dose
befor e star ti ng nal tr exone.
Dur i ng nal tr exone therapy, be al er t for si gns of opi oi d
wi thdrawal , such as dr ug cravi ng, confusi on, dr owsi ness,
vi sual hal l uci nati ons, abdomi nal pai n, vomi ti ng, di ar r hea,
fever, chi l l s, tachypnea, di aphor esi s, sal i vati on, l acr i mati on,
r unny nose, and mydr i asi s.

Nal oxone al so r ever ses the anal gesi c effects of opi oi ds. Ther efor e,
after nal oxone admi ni strati on, the pati ent may compl ai n of pai n or
even exper i ence wi thdrawal symptoms.

Kicking the habit

Nal tr exone i s used al ong wi th psychotherapy or counsel i ng to tr eat
dr ug abuse; however, the r eci pi ent must fi r st have gone thr ough a
detoxi fi cati on pr ogram. Other wi se, i f the pati ent r ecei ves
nal tr exone whi l e he sti l l has opi oi ds i n hi s body, acute wi thdrawal
symptoms may occur. (See Managi ng nal tr exone therapy for dr ug
addi cti on.)

Drug interactions
Nal oxone pr oduces no si gni fi cant dr ug i nteracti ons. Nal tr exone wi l l
cause wi thdrawal symptoms i f gi ven to a pati ent r ecei vi ng an opi oi d
agoni st or to an opi oi d addi ct. (See Adver se r eacti ons to nal oxone
and nal tr exone.)

Warning!
Adverse reactions to naloxone and naltrexone
Nal oxone and nal tr exone pr oduce di ffer ent adver se
r eacti ons.
Naloxone
Nal oxone may cause nausea, vomi ti ng and, occasi onal l y,
hyper tensi on and tachycar di a. An unconsci ous pati ent r etur ned to
consci ousness abr uptl y after nal oxone admi ni strati on may
hyper venti l ate and exper i ence tr emor s.
Naltrexone
Nal tr exone can cause a var i ety of adver se r eacti ons, i ncl udi ng:

edema, hyper tensi on, pal pi tati ons, phl ebi ti s, and shor tness of
br eath
anxi ety, depr essi on, di sor i entati on, di z z i ness, headache, and
ner vousness
anor exi a, di ar r hea or consti pati on, nausea, thi r st, and
vomi ti ng
ur i nar y fr equency
l i ver toxi ci ty.

Anesthetic drugs
Anesthetic dr ugs can be di vi ded i nto thr ee gr oupsgeneral
anestheti cs, l ocal anestheti cs, and topi cal anestheti cs.

Inhale or inject?
G eneral anestheti c dr ugs ar e fur ther subdi vi ded i nto two mai n
types: those gi ven by i nhal ati on and those gi ven i ntravenousl y.
Inhalation anesthetics
Commonl y used general anestheti cs gi ven by i nhal ati on i ncl ude:

desfl urane
enfl urane
hal othane
i sofl urane
ni tr ous oxi de
sevofl urane.

Pharmacokinetics
The absor pti on and el i mi nati on rates of an anestheti c ar e gover ned
by i ts sol ubi l i ty i n bl ood. Inhalation anesthetics enter the bl ood fr om
the l ungs and ar e di str i buted to other ti ssues. Di str i buti on i s most
rapi d to or gans wi th hi gh bl ood fl ow, such as the brai n, l i ver,
ki dneys, and hear t. Inhal ati on anestheti cs ar e el i mi nated pr i mar i l y
by the l ungs; enfl urane, hal othane, and sevofl urane ar e al so
el i mi nated by the l i ver. Metabol i tes ar e excr eted i n the ur i ne.

Pharmacodynamics
Inhal ati on anestheti cs wor k pr i mar i l y by depr essi ng the CNS,
pr oduci ng l oss of consci ousness, l oss of r esponsi veness to sensor y
sti mul ati on (i ncl udi ng pai n), and muscl e r el axati on. They al so affect
other or gan systems.

Pharmacotherapeutics
Inhal ati on anestheti cs ar e used for sur ger y because they offer mor e
pr eci se and rapi d contr ol of depth of anesthesi a than i njecti on
anestheti cs do. These anestheti cs, whi ch ar e l i qui ds at r oom
temperatur e, r equi r e a vapor i zer and speci al del i ver y system for
safe use.
Of the i nhal ati on anestheti cs avai l abl e, desfl urane, i sofl urane, and
ni tr ous oxi de ar e the most commonl y used.
 Safe and sound
Unusual but serious reaction
Mal i gnant hyper ther mi a, character i zed by a sudden and
often l ethal i ncr ease i n body temperatur e, i s a ser i ous and
uncommon r eacti on to i nhal ati on anestheti cs. It occur s i n
geneti cal l y suscepti bl e pati ents onl y and may r esul t fr om a fai l ur e
i n cal ci um uptake by muscl e cel l s. The skel etal muscl e r el axant
dantr ol ene i s used to tr eat thi s condi ti on.

Stop signs
Inhal ati on anestheti cs ar e contrai ndi cated i n the pati ent wi th known
hyper sensi ti vi ty to the dr ug, a l i ver di sor der, or mal i gnant
hyper ther mi a (a potenti al l y fatal compl i cati on of anesthesi a
character i zed by skel etal muscl e r i gi di ty and hi gh fever ). (See
Unusual but ser i ous r eacti on and Adver se r eactions to inhalation
anesthetics, page 110.)

Warning!
Adverse reactions to inhalation anesthetics
The most common adver se r eacti on to i nhal ati on
anestheti cs i s an exaggerated pati ent r esponse to a nor mal dose.
Waking up
After sur ger y, a pati ent may exper i ence r eacti ons si mi l ar to those
seen wi th other central ner vous system depr essants, i ncl udi ng
depr essi on of br eathi ng and ci r cul ati on, confusi on, sedati on,
 nausea, vomi ti ng, ataxi a, and hypother mi a.
It happens with halothane
Rar el y, l i ver necr osi s devel ops several days after hal othane use
and occur s most commonl y wi th mul ti pl e dr ug exposur es.
Symptoms i ncl ude rash, fever, jaundi ce, nausea, vomi ti ng,
eosi nophi l i a, and al terati ons i n l i ver functi on.

Drug interactions
The most i mpor tant dr ug i nteracti ons i nvol vi ng i nhal ati on
anestheti cs occur wi th other CNS, car di ac, or r espi rator y-depr essant
dr ugs. Inhal ati on anestheti cs can cause CNS depr essi on, car di ac
ar r hythmi as, or depr essed r espi rati ons, r esul ti ng i n compr omi sed
pati ent status.

Intravenous anesthetics
Intr avenous anesthetics ar e typi cal l y used when the pati ent r equi r es
general anesthesi a for just a shor t per i od such as dur i ng outpati ent
sur ger y. Theyr e al so used to pr omote rapi d i nducti on of anesthesi a
or to suppl ement i nhal ati on anestheti cs.

Main options
The dr ugs used as i ntravenous anestheti cs ar e:

bar bi turates (methohexi tal , thi opental )

benzodi azepi nes (mi dazol am)
di ssoci ati ves (ketami ne)
hypnoti cs (etomi date, pr opofol )
opi ates (fentanyl , sufentani l ).

Pharmacokinetics
Intravenous anestheti cs ar e l i pi d-sol ubl e and wel l -di str i buted
thr oughout the body, cr ossi ng the pl acental bar r i er and enter i ng
br east mi l k. These dr ugs ar e metabol i zed i n the l i ver and excr eted
i n the ur i ne.
Pharmacodynamics
Opi ates wor k by occupyi ng si tes on speci al i zed r eceptor s scatter ed
thr oughout the CNS and by modi fyi ng the r el ease of
neur otransmi tter s fr om sensor y ner ves enter i ng the CNS. Ketami ne
acts di r ectl y on the cor tex and l i mbi c system of the brai n, pr oduci ng
a pr ofound sense of di ssoci ati on fr om the envi r onment.

Getting sleepy
Bar bi turates, benzodi azepi nes, and etomi date seem to enhance
r esponses to the CNS neur otransmi tter, gamma-ami nobutyr i c aci d.
Thi s i nhi bi ts the brai ns r esponse to sti mul ati on of the r eti cul ar
acti vati ng system, the ar ea of the brai n stem that contr ol s
al er tness. Bar bi turates al so depr ess the exci tabi l i ty of CNS neur ons.

Pharmacotherapeutics
Because of the shor t durati on of acti on of i ntravenous anestheti cs,
theyr e used i n br i ef sur gi cal pr ocedur es such as outpati ent sur ger y.

Going solo
Bar bi turates ar e used al one i n sur ger y that i snt expected to be
pai nful and as adjuncts to other dr ugs i n mor e extensi ve
pr ocedur es. Benzodi azepi nes pr oduce sedati on and amnesi a, but not
pai n r el i ef.
Etomi date i s used to i nduce anesthesi a and to suppl ement l ow-
potency i nhal ati on anestheti cs such as ni tr ous oxi de. The opi ates
pr ovi de pai n r el i ef and suppl ement other anestheti cs.

Drug interactions
I.V. anestheti cs, par ti cul ar l y ketami ne, can pr oduce a var i ety of
dr ug i nteracti ons.

Verapami l enhances the anestheti c effects of etomi date, causi ng

r espi rator y depr essi on and apnea.
Admi ni ster i ng ketami ne together wi th hal othane i ncr eases the
r i sk of hypotensi on and r educes car di ac output (the amount of
bl ood pumped by the hear t each mi nute).
G i vi ng ketami ne and nondepol ar i z i ng dr ugs together i ncr eases
neur omuscul ar effects, r esul ti ng i n pr ol onged r espi rator y
 depr essi on.
Usi ng bar bi turates or opi oi ds wi th ketami ne may pr ol ong
r ecover y ti me after anesthesi a.
Ketami ne pl us theophyl l i ne may pr omote sei z ur es.

Ketami ne and thyr oi d hor mones may cause hyper tensi on and
tachycar di a (rapi d hear t rate). (See Adver se r eacti ons to I.V.
anestheti cs.)

Warning!
Adverse reactions to I.V. anesthetics
Ketamine

Pr ol onged r ecover y
Ir rati onal behavi or
Exci tement
Di sor i entati on
Del i r i um, hal l uci nati ons
Incr eased hear t rate
Hyper tensi on

Propofol

Respi rator y depr essi on

Hi ccups, coughi ng, muscl e-twi tchi ng

Thiopental

Respi rator y depr essi on

Hi ccups, coughi ng, muscl e-twi tchi ng
Depr essed car di ac functi on and per i pheral di l ati on

Etomidate

Hi ccups, coughi ng, muscl e-twi tchi ng

Fentanyl
 Central ner vous system (CNS) and r espi rator y depr essi on
Hypoventi l ati on
Car di ac ar r hythmi as

Midazolam

CNS and r espi rator y depr essi on

Hypotensi on
Di z z i ness

Local anesthetics
Local anesthetics ar e admi ni ster ed to pr event or r el i eve pai n i n a
speci fi c ar ea of the body. In addi ti on, these dr ugs ar e often used as
an al ter nati ve to general anesthesi a for el der l y or debi l i tated
pati ents.

Now I get it!

Amides and esters
Ami de anestheti cs ar e l ocal anestheti cs that have ni tr ogen
as par t of thei r mol ecul ar makeup. They i ncl ude:

bupi vacai ne
l i docai ne
mepi vacai ne
pr i l ocai ne
r opi vacai ne.

Give them oxygen

Ester anestheti cs have oxygen, not ni tr ogen, as par t of thei r
mol ecul ar makeup. They i ncl ude:

chl or opr ocai ne

pr ocai ne
tetracai ne.

Chain gang
Local anestheti cs may be:

ami de dr ugs (wi th ni tr ogen i n the mol ecul ar chai n, such as

bupi vacai ne, l evobupi vacai ne, l i docai ne, mepi vacai ne, pr i l ocai ne,
and r opi vacai ne)
ester dr ugs (wi th oxygen i n the mol ecul ar chai n, such as
chl or opr ocai ne, cocai ne, pr ocai ne, and tetracai ne). (See Ami des
and ester s.)

Pharmacokinetics
Absor pti on of l ocal anestheti cs var i es wi del y, but di str i buti on occur s
thr oughout the body. Ester s and ami des under go di ffer ent types of
metabol i sm, but both yi el d metabol i tes that ar e excr eted i n the
ur i ne.

Now I get it!

Blocking the pain pathways
Ner ve endi ngs transmi t pai n si gnal s thr ough the per i pheral
and central ner vous systems to the brai n. G i vi ng a central ner ve
bl ock can bl ock the si gnal transmi ssi on and r el i eve pai n. The
i l l ustrati on bel ow shows two key poi nts wher e an anestheti c may
be admi ni ster ed to pr oduce a central ner ve bl ock

Pharmacodynamics
Local anestheti cs bl ock ner ve i mpul ses at the poi nt of contact i n al l
ki nds of ner ves. They accumul ate, causi ng the ner ve cel l membrane
to expand. As the membrane expands, the cel l l oses i ts abi l i ty to
depol ar i ze, whi ch i s necessar y for i mpul se transmi ssi on. (See
Bl ocki ng the pai n pathways.)

Pharmacotherapeutics
Local anestheti cs ar e used to pr event and r el i eve pai n fr om medi cal
pr ocedur es, di sease, or i njur y. Local anestheti cs may al so be used
for sever e pai n that topi cal anestheti cs or anal gesi cs cant r el i eve.

Staying local
Local anestheti cs ar e usual l y pr efer r ed to general anestheti cs for
sur ger y i n an el der l y or debi l i tated pati ent or a pati ent wi th a
di sor der that affects r espi rator y functi on, such as chr oni c
obstr ucti ve pul monar y di sease and myastheni a gravi s.

Tighten up
For some pr ocedur es, a l ocal anestheti c i s combi ned wi th a dr ug
that constr i cts bl ood vessel s, such as epi nephr i ne. Vasoconstr i cti on
hel ps contr ol l ocal bl eedi ng and r educes absor pti on of the
anestheti c. Reduced absor pti on pr ol ongs the anestheti cs acti on at
the si te and l i mi ts i ts di str i buti on and CNS effects.

Drug interactions
Local anestheti cs pr oduce few si gni fi cant i nteracti ons wi th other
dr ugs. They can, however, pr oduce adver se r eacti ons. (See Adver se
r eacti ons to l ocal anestheti cs.)

Warning!
Adverse reactions to local anesthetics
Dose-r el ated central ner vous system (CNS) r eacti ons
i ncl ude anxi ety, appr ehensi on, r estl essness, ner vousness,
di sor i entati on, confusi on, di z z i ness, bl ur r ed vi si on, tr emor s,
twi tchi ng, shi ver i ng, and sei z ur es. Dose-r el ated car di ovascul ar
r eacti ons may i ncl ude myocar di al depr essi on, bradycar di a (sl ow
hear t rate), ar r hythmi as, hypotensi on, car di ovascul ar col l apse,
and car di ac ar r est.
All the rest
Local anestheti c sol uti ons that contai n vasoconstr i ctor s such as
epi nephr i ne can al so pr oduce CNS and car di ovascul ar r eacti ons,
i ncl udi ng anxi ety, di z z i ness, headache, r estl essness, tr emor s,
 pal pi tati ons, tachycar di a, angi na, and hyper tensi on.

Topical anesthetics
Topical anesthetics ar e appl i ed di r ectl y to i ntact ski n or mucous
membranes. Al l topi cal anestheti cs ar e used to pr event or r el i eve
mi nor pai n.

All together now

Some i njectabl e l ocal anestheti cs, such as l i docai ne and tetracai ne,
ar e al so topi cal l y effecti ve. In addi ti on, some topi cal anestheti cs,
such as l i docai ne, ar e combi ned i n other pr oducts.

Pharmacokinetics
Topi cal anestheti cs pr oduce l i ttl e systemi c absor pti on, except for the
appl i cati on of cocai ne to mucous membranes. However, systemi c
absor pti on may occur i f the pati ent r ecei ves fr equent or hi gh-dose
appl i cati ons to the eye or l ar ge ar eas of bur ned or i njur ed ski n.
Tetracai ne and other ester s ar e metabol i zed extensi vel y i n the bl ood
and to a l esser extent i n the l i ver. Di bucai ne, l i docai ne, and other
ami des ar e metabol i zed pr i mar i l y i n the l i ver. Both types of topi cal
anestheti cs ar e excr eted i n the ur i ne.

Pharmacodynamics
Benzocai ne, butacai ne, cocai ne, dycl oni ne, and pramoxi ne pr oduce
topi cal anesthesi a by bl ocki ng ner ve i mpul se transmi ssi on. They
accumul ate i n the ner ve cel l membrane, causi ng i t to expand and
l ose i ts abi l i ty to depol ar i ze, thus bl ocki ng i mpul se transmi ssi on.
Di bucai ne, l i docai ne, and tetracai ne may al so bl ock i mpul se
transmi ssi on acr oss the ner ve cel l membranes.

Sensory overload
The ar omati c compounds, such as benz yl al cohol and cl ove oi l ,
appear to sti mul ate ner ve endi ngs. Thi s sti mul ati on causes
counter i r r i tati on that i nter fer es wi th pai n per cepti on.

A chilling ending
Ethyl chl or i de spray super fi ci al l y fr eezes the ti ssue, sti mul ati ng the
col d-sensati on r eceptor s and bl ocki ng the ner ve endi ngs i n the
fr ozen ar ea. Menthol sel ecti vel y sti mul ates the sensor y ner ve
endi ngs for col d, causi ng a cool sensati on and some l ocal pai n r el i ef.

Pharmacotherapeutics
Topi cal anestheti cs ar e used to:

r el i eve or pr event pai n, especi al l y mi nor bur n pai n

r el i eve i tchi ng and i r r i tati on
anestheti ze an ar ea befor e an i njecti on i s gi ven
numb mucosal sur faces befor e a tube, such as a ur i nar y
catheter, i s i nser ted
al l evi ate sor e thr oat or mouth pai n when used i n a spray or
sol uti on.

All eyes and ears

Tetracai ne i s al so used as a topi cal anestheti c for the eye.
Benzocai ne i s used wi th other dr ugs i n several ear pr eparati ons.

Drug interactions
Few i nteracti ons wi th other dr ugs occur wi th topi cal anestheti cs
because they ar ent absor bed wel l i nto the systemi c ci r cul ati on.
(See Adver se r eacti ons to topi cal anestheti cs.)

Warning!
Adverse reactions to topical anesthetics
Topi cal anestheti cs can cause several di ffer ent adver se
r eacti ons.

Benz yl al cohol can cause topi cal r eacti ons such as ski n
i r r i tati on.
Refr i gerants, such as ethyl chl or i de, may pr oduce fr ostbi te
wher e theyve been appl i ed.
Topi cal anestheti cs can cause a hyper sensi ti vi ty r eacti on,
i ncl udi ng a rash, i tchi ng, hi ves, swel l i ng of the mouth and
thr oat, and br eathi ng di ffi cul ty.
 Quick quiz
1How does the topi cal anestheti c benzocai ne r el i eve
sunbur n pai n?
A. It numbs the ski n sur face, decr easi ng the per cepti on
of pai n.
B. It fr eezes the ski n, whi ch pr events ner ve i mpul se
transmi ssi on.
C. It bl ocks ner ve i mpul se transmi ssi on by pr eventi ng ner ve
cel l depol ar i z ati on.
D. It sti mul ates ner ve endi ngs, i nter fer i ng wi th the
per cepti on of pai n.

2Whi ch adver se r eacti on i s a pati ent most l i kel y to exper i ence

postsur ger y after r ecei vi ng general anesthesi a?
A. Nausea and vomi ti ng
B. Sei z ur es
C. Cyanosi s
D. Fever

3Befor e admi ni ster i ng bupr enor phi ne, the nur se asks the pati ent
i f he has used opi ates. Thats because admi ni ster i ng a mi xed
opi oi d agoni st-antagoni st to a pati ent dependent on opi oi d
agoni sts may cause whi ch r eacti on?
A. Hyper sensi ti vi ty r eacti on
B. Wi thdrawal symptoms
C. Ur i nar y i nconti nence
D. Respi rator y depr essi on

P.
4The dr ug commonl y pr escr i bed to tr eat an opi oi d over dose i s:
A. butor phanol .
B. nal oxone.
C. pentazoci ne.
D. ketami ne.

5What ar e the most common adver se r eacti ons to aspi r i n?

A. Incr eased rate and depth of r espi rati ons
 B. Confusi on, sedati on, and hypother mi a
C. Di z z i ness and vi si on changes
D. Nausea, vomi ti ng, and G I di str ess

6Desfl urane i s whi ch type of anestheti c?

A. Opi oi d
B. Local
C. Topi cal
D. G eneral

7Topi cal anestheti cs ar e used:

A. as an al ter nati ve to general anesthesi a for el der l y or
debi l i tated pati ents.
B. to numb mucosal sur faces befor e tube i nser ti on.
C. when anesthesi a i s needed for onl y a shor t per i od.
D. to pr omote rapi d i nducti on of anesthesi a.

P.
Scoring
If you answer ed al l seven i tems cor r ectl y, bravo! Your e a
pai n medi cati on power house.

If you answer ed fi ve or si x i tems cor r ectl y, fabul ous! For

you, thi s chapter was pai nl ess.

If you answer ed fewer than fi ve i tems cor r ectl y, hey,

dont gi ve up! Remember : No pai n, no gai n.

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

5
Cardiovascular drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs used to tr eat car di ovascul ar di sor der s

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and the cardiovascular system

The hear t, ar ter i es, vei ns, and l ymphati cs make up the
car di ovascul ar system. These str uctur es transpor t l i fe-suppor ti ng
oxygen and nutr i ents to cel l s, r emove metabol i c waste pr oducts, and
car r y hor mones fr om one par t of the body to another. Because thi s
system per for ms such vi tal functi ons, a pr obl em wi th the hear t or
bl ood vessel s can ser i ousl y affect a per sons heal th.
Types of dr ugs used to i mpr ove car di ovascul ar functi on i ncl ude:

i notr opi c
anti ar r hythmi c
anti angi nal
anti hyper tensi ve
 di ur eti c
anti l i pemi c.

Inotropics
Inotr opi c dr ugs, such as car di ac gl ycosi des and phosphodi esterase
(PDE) i nhi bi tor s, i ncr ease the for ce of the hear ts contracti ons. In
other wor ds, the dr ugs have whats known as a

positive inotr opic effect. (Inotr opi c means affecti ng the for ce or
ener gy of muscul ar contracti ons.)
Car di ac gl ycosi des al so sl ow the hear t rate (cal l ed a negative
chr onotr opic effect) and sl ow el ectr i cal i mpul se conducti on thr ough
the atr i oventr i cul ar (AV) node (cal l ed a negative dr omotr opic
effect).
Cardiac glycosides
Car diac glycosides ar e a gr oup of dr ugs der i ved fr om di gi tal i s, a
substance that occur s natural l y i n foxgl ove pl ants and i n cer tai n
toads. The most fr equentl y used car di ac gl ycosi de i s digoxin.

Pharmacokinetics (how drugs circulate)

The i ntesti nal absor pti on of di goxi n var i es gr eatl y; the capsul es ar e
absor bed most effi ci entl y, fol l owed by the el i xi r for m, and then
tabl ets. Di goxi n i s di str i buted wi del y thr oughout the body, wi th
hi ghest concentrati ons i n the hear t muscl e, l i ver, and ki dneys.
Di goxi n bi nds poor l y to pl asma pr otei ns.
In most pati ents, a smal l amount of di goxi n i s metabol i zed i n the
l i ver and gut by bacter i a. Thi s effect var i es and may be substanti al
i n some peopl e. Most of the dr ug i s excr eted by the ki dneys as
unchanged dr ug. (See Load that dose.)

Pharmacodynamics (how drugs act)

Di goxi n i s used to tr eat hear t fai l ur e because i t str engthens the
contracti on of the ventr i cl es by boosti ng i ntracel l ul ar cal ci um at the
cel l membrane, enabl i ng str onger hear t contracti ons.
Di goxi n may al so enhance the movement of cal ci um i nto the
myocar di al cel l s and sti mul ate the r el ease, or bl ock the r euptake, of
nor epi nephr i ne at the adr ener gi c ner ve ter mi nal .

Stop that impulse

Di goxi n acts on the central ner vous system (CNS) to sl ow the hear t
rate, thus maki ng i t useful for tr eati ng supraventr i cul ar ar r hythmi as
(abnor mal hear t r hythms that or i gi nate above the bundl e branches
of the hear ts conducti on system), such as atr i al fi br i l l ati on and
atr i al fl utter. It al so i ncr eases the r efractor y per i od (the per i od
when the cel l s of the conducti on system cant conduct an i mpul se).

Load that dose

Because di goxi n has a l ong hal f-l i fe, a l oadi ng dose must be gi ven
to a pati ent who r equi r es i mmedi ate dr ug effects, as i n
supraventr i cul ar ar r hythmi a.
By gi vi ng a l ar ger i ni ti al dose, a mi ni mum effecti ve concentrati on
of the dr ug i n the bl ood may be r eached faster.
 Note: Avoi d gi vi ng a l oadi ng dose to a pati ent wi th hear t fai l ur e
to avoi d toxi ci ty.

Pharmacotherapeutics (how drugs are used)

In addi ti on to tr eati ng hear t fai l ur e and supraventr i cul ar
ar r hythmi as, di goxi n i s used to tr eat par oxysmal atr i al tachycar di a

(an ar r hythmi a mar ked by br i ef per i ods of tachycar di a that

al ter nate wi th br i ef per i ods of si nus r hythm).

Drug interactions
Many dr ugs can i nteract wi th di goxi n.

Antaci ds, bar bi turates, chol estyrami ne r esi n, kaol i n and pecti n,
neomyci n, metocl oprami de, r i fampi n, and sul fasal az i ne r educe
the therapeuti c effects of di goxi n.
Cal ci um pr eparati ons, qui ni di ne, verapami l , cycl ospor i ne,
tetracycl i ne, cl ar i thr omyci n, pr opafenone, ami odar one,
spi r onol actone, hydr oxychl or oqui ne, er ythr omyci n, i traconazol e,
and omeprazol e i ncr ease the r i sk of di goxi n toxi ci ty.
Amphoter i ci n B, potassi um-wasti ng di ur eti cs, and ster oi ds taken
wi th di goxi n may cause hypokal emi a (l ow potassi um l evel s) and
i ncr ease the r i sk of di goxi n toxi ci ty.
Beta-adr ener gi c bl ocker s and cal ci um channel bl ocker s taken
wi th di goxi n may cause an excessi vel y sl ow hear t rate and
ar r hythmi as.
Succi nyl chol i ne and thyr oi d pr eparati ons i ncr ease the r i sk of
ar r hythmi as when theyr e taken wi th di goxi n.
St. Johns wor t, an her bal pr eparati on, can i ncr ease di goxi n
l evel s and r i sk of toxi ci ty.

Di goxi n can al so pr oduce adver se r eacti ons, mostl y i nvol vi ng

di goxi n toxi ci ty. (See Recogni z i ng si gns and symptoms of di goxi n
toxi ci ty, page 122, and Adver se r eactions to car diac glycosides.)

Warning!
Adverse reactions to cardiac glycosides
Because car di ac gl ycosi des have a nar r ow therapeuti c i ndex
(mar gi n of safety), they may pr oduce di goxi n toxi ci ty. To pr event
di goxi n toxi ci ty, the dosage shoul d be i ndi vi dual i zed based on the
pati ents ser um di goxi n concentrati on.
Adver se r eacti ons to di goxi n i ncl ude:

rash
fever
eosi nophi l i a
ar r hythmi as.

Safe and sound

Recognizing signs and symptoms of digoxin
toxicity
Di goxi n toxi ci ty usual l y pr oduces car di ac, gastr oi ntesti nal , and
neur ol ogi c si gns and symptoms. To pr event sever e or even l i fe-
thr eateni ng effects, be pr epar ed to r ecogni ze the si gns and
symptoms l i sted bel ow. Al so assess the pati ent for the most
common ear l y i ndi cator s of toxi ci ty, whi ch ar e usual l y G I-r el ated.
Cardiac

Accel erated juncti onal r hythms

Atr i al tachycar di a wi th atr i oventr i cul ar (AV) bl ock
Second-degr ee AV bl ock (Wenckebach)
Si noatr i al ar r est or bl ock
Thi r d-degr ee AV bl ock (compl ete)
Ventr i cul ar ar r hythmi as

Gastrointestinal

Abdomi nal pai n

Anor exi a
Di ar r hea
Nausea
Vomi ti ng

Neurologic
 Bl ue-yel l ow col or bl i ndness
Bl ur r ed vi si on
Col or ed dots i n vi si on
Coma
Confusi on
Depr essi on
Di sor i entati on
F l i cker i ng l i ghts
Headache
Insomni a
Ir r i tabi l i ty
Lethar gy
Per sonal i ty changes
Psychosi s
Restl essness
Sei z ur es
Whi te hal os on dar k objects

PDE inhibitors
PDE inhibitor s ar e typi cal l y used for shor t-ter m management of
hear t fai l ur e or l ong-ter m management i n pati ents awai ti ng hear t
transpl ant sur ger y. Speci fi c PDE i nhi bi tor s ar e i namr i none and
mi l r i none.

Pharmacokinetics
Admi ni ster ed I.V., i namr i none i s di str i buted rapi dl y, metabol i zed by
the l i ver, and excr eted by the ki dneys. Its rar el y used because
secondar y thr ombocytopeni a may occur as an adver se r eacti on.

Ready for action

Mi l r i none i s al so admi ni ster ed I.V. Its di str i buted rapi dl y and
excr eted by the ki dneys, pr i mar i l y as unchanged dr ug.
 Warning!
Adverse reactions to PDE inhibitors
Adver se r eacti ons to phosphodi esterase (PDE) i nhi bi tor s ar e
uncommon, but the l i kel i hood i ncr eases si gni fi cantl y when a
pati ent i s on pr ol onged therapy.
Adver se r eacti ons may i ncl ude:

ar r hythmi as
nausea and vomi ti ng
headache
fever
chest pai n
hypokal emi a
thr ombocytopeni a (especi al l y wi th i namr i none)
mi l d i ncr ease i n hear t rate.

Pharmacodynamics
PDE i nhi bi tor s i mpr ove car di ac output by str engtheni ng
contracti ons. These dr ugs ar e thought to hel p move cal ci um i nto the
car di ac cel l or to i ncr ease cal ci um storage i n the sar copl asmi c
r eti cul um. By di r ectl y r el axi ng vascul ar smooth muscl e, they al so
decr ease per i pheral vascul ar r esi stance (after l oad) and the amount
of bl ood r etur ni ng to the hear t (pr el oad).

Pharmacotherapeutics
Inamr i none and mi l r i none ar e used to manage hear t fai l ur e i n
pati ents who havent r esponded adequatel y to tr eatment wi th
car di ac gl ycosi des, di ur eti cs, or vasodi l ator s. Pr ol onged use of these
dr ugs may i ncr ease the pati ents r i sk of compl i cati ons and death.
(See Adver se r eacti ons to PDE i nhi bi tor s.)

Drug interactions
PDE i nhi bi tor s may i nteract wi th di sopyrami de, causi ng
hypotensi on.
Because PDE i nhi bi tor s r educe ser um potassi um l evel s, taki ng
them wi th a potassi um-wasti ng di ur eti c may l ead to
 hypokal emi a.

Antiarrhythmic drugs
Antiar r hythmic dr ugs ar e used to tr eat ar r hythmi as, di stur bances of
the nor mal hear t r hythm.

Troublemakers
Unfor tunatel y, many anti ar r hythmi cs ar e al so capabl e of wor seni ng
or causi ng the ver y ar r hythmi as theyr e supposed to tr eat. The
benefi ts need to be wei ghed car eful l y agai nst the r i sks of
anti ar r hythmi c therapy.

A touch of class
Anti ar r hythmi cs ar e categor i zed i nto four cl asses:

I (whi ch i ncl udes cl asses IA, IB, and IC)

II
III
IV.

Cl ass I anti ar r hythmi cs consi st of sodi um channel bl ocker s. Thi s i s

the l ar gest gr oup of anti ar r hythmi cs. Cl ass I agents ar e fr equentl y
subdi vi ded i nto cl asses IA, IB, and IC. One dr ug, adenosi ne (an AV
nodal bl ocki ng agent used to tr eat par oxysmal supraventr i cul ar
tachycar di a), doesnt fal l i nto any of these cl asses.
The mechani sms of acti on of anti ar r hythmi cs var y wi del y, and a few
dr ugs exhi bi t pr oper ti es common to mor e than one cl ass.

Class IA antiarrhythmics
Class IA antiar r hythmics ar e used to tr eat a wi de var i ety of atr i al
and ventr i cul ar ar r hythmi as. Cl ass IA anti ar r hythmi cs i ncl ude:

di sopyrami de
pr ocai nami de
qui ni di ne (sul fate and gl uconate).

Pharmacokinetics
When admi ni ster ed oral l y, cl ass IA dr ugs ar e rapi dl y absor bed and
metabol i zed. Because they wor k so qui ckl y, sustai ned-r el ease for ms
of these dr ugs wer e devel oped to hel p mai ntai n therapeuti c l evel s.
A shot to the head
These dr ugs ar e di str i buted thr ough al l body ti ssues. Qui ni di ne,
however, i s the onl y one that cr osses the bl ood-brai n bar r i er.
Al l cl ass IA anti ar r hythmi cs ar e metabol i zed i n the l i ver and ar e
excr eted unchanged by the ki dneys. Aci di c ur i ne i ncr eases the
excr eti on of qui ni di ne.

Pharmacodynamics
Cl ass IA anti ar r hythmi cs contr ol ar r hythmi as by al ter i ng the
myocar di al cel l membrane and i nter fer i ng wi th autonomi c ner vous
system contr ol of pacemaker cel l s.

No (para)sympathy
Cl ass IA anti ar r hythmi cs al so bl ock parasympatheti c sti mul ati on of
the si noatr i al (SA) and AV nodes. Because sti mul ati on of the
parasympatheti c ner vous system causes the hear t rate to sl ow
down, dr ugs that bl ock the parasympatheti c ner vous system
i ncr ease the conducti on rate of the AV node.

Rhythmic risks
Thi s i ncr ease i n the conducti on rate can pr oduce danger ous
i ncr eases i n the ventr i cul ar hear t rate i f rapi d atr i al acti vi ty i s
pr esent, as i n a pati ent wi th atr i al fi br i l l ati on. In tur n, the
i ncr eased ventr i cul ar hear t rate can offset the abi l i ty of the
anti ar r hythmi cs to conver t atr i al ar r hythmi as to a r egul ar r hythm.

Pharmacotherapeutics
Cl ass IA anti ar r hythmi cs ar e pr escr i bed to tr eat such ar r hythmi as as
pr ematur e ventr i cul ar contracti ons, ventr i cul ar tachycar di a, atr i al
fi br i l l ati on, atr i al fl utter, and par oxysmal atr i al tachycar di a.

Drug interactions
Cl ass IA anti ar r hythmi cs can i nteract wi th other dr ugs:

Di sopyrami de taken wi th macr ol i de anti bi oti cs, such as

cl ar i thr omyci n and er ythr omyci n, i ncr eases the pati ents r i sk of
devel opi ng a pr ol onged QT i nter val . In tur n, thi s may l ead to an
i ncr eased r i sk of ar r hythmi as, especi al l y pol ymor phi c ventr i cul ar
tachycar di a.
Di sopyrami de pl us verapami l may i ncr ease myocar di al depr essi on
and shoul d be avoi ded i n pati ents wi th hear t fai l ur e.
Other anti ar r hythmi cs, such as beta-adr ener gi c bl ocker s,
i ncr ease the r i sk of ar r hythmi as.
Qui ni di ne pl us neur omuscul ar bl ocker s may cause i ncr eased
skel etal muscl e r el axati on.
Qui ni di ne i ncr eases the r i sk of di goxi n toxi ci ty.
Ri fampi n, phenytoi n, and phenobar bi tal can r educe the effects of
qui ni di ne and di sopyrami de.

Warning!
Adverse reactions to class IA antiarrhythmics
Cl ass IA anti ar r hythmi cs, especi al l y qui ni di ne, may pr oduce
G I symptoms, such as di ar r hea, crampi ng, nausea, vomi ti ng,
anor exi a, and a bi tter taste.
 Dramatic irony
Ir oni cal l y, not onl y do cl ass IA anti ar r hythmi cs tr eat ar r hythmi as,
but they can al so i nduce ar r hythmi as, especi al l y conducti on
del ays that may wor sen exi sti ng hear t bl ocks.

G I symptoms ar e a common adver se r eacti on to cl ass IA

anti ar r hythmi cs. (See Adver se r eacti ons to cl ass IA
anti ar r hythmi cs.)

Class IB antiarrhythmics
Cl ass IB anti ar r hythmi cs ar e used for tr eati ng acute ventr i cul ar
ar r hythmi as. They i ncl ude:

l i docai ne
mexi l eti ne.

Pharmacokinetics
Mexi l eti ne i s absor bed fr om the G I tract after oral admi ni strati on.
Li docai ne i s admi ni ster ed I.V. to pr event rapi d metabol i sm by the
l i ver after i t enter s the hepati c por tal ci r cul ati on.

All bound up?

Li docai ne i s di str i buted wi del y thr oughout the body, i ncl udi ng the
brai n. Li docai ne and mexi l eti ne ar e moderatel y bound to pl asma
pr otei ns. (Remember, onl y that por ti on of a dr ug thats unbound can
pr oduce a r esponse.)
Cl ass IB anti ar r hythmi cs ar e metabol i zed i n the l i ver and excr eted
i n ur i ne. Mexi l eti ne al so appear s i n br east mi l k.

Pharmacodynamics
Cl ass IB dr ugs wor k by bl ocki ng the rapi d i nfl ux of sodi um i ons
dur i ng the depol ar i z ati on phase of the hear ts depol ar i z ati on-
r epol ar i z ati on cycl e. Thi s decr eases the r efractor y per i od, whi ch
r educes the r i sk of ar r hythmi a. (See How l i docai ne wor ks.)

Make a IB-line for the ventricle

Because cl ass IB anti ar r hythmi cs especi al l y affect the Pur ki nje
fi ber s (fi ber s i n the conducti ng system of the hear t) and myocar di al
cel l s i n the ventr i cl es, theyr e used to tr eat onl y ventr i cul ar
ar r hythmi as.

Warning!
Adverse reactions to class IB antiarrhythmics
Adver se r eacti ons to cl ass IB anti ar r hythmi cs i ncl ude
dr owsi ness, l i ght-headedness, par esthesi a, sensor y di stur bances,
hypotensi on, and bradycar di a.
Li docai ne toxi ci ty can cause sei z ur es and r espi rator y ar r est.
Adver se r eacti ons to mexi l eti ne i ncl ude hypotensi on,
atr i oventr i cul ar bl ock, bradycar di a, confusi on, ataxi a, and doubl e
vi si on. Mexi l eti ne may al so pr oduce nausea and vomi ti ng.

Pharmacotherapeutics
Cl ass IB anti ar r hythmi cs ar e used to tr eat ventr i cul ar ectopi c beats,
ventr i cul ar tachycar di a, and ventr i cul ar fi br i l l ati on.
Cl ass IB anti ar r hythmi cs ar e usual l y the dr ug of choi ce i n acute
car e because they dont pr oduce i mmedi ate ser i ous adver se
r eacti ons.

Drug interactions
Cl ass IB anti ar r hythmi cs may exhi bi t addi ti ve or antagoni sti c effects
when admi ni ster ed wi th other anti ar r hythmi cs, such as
phenytoi n, pr opranol ol , pr ocai nami de, and qui ni di ne. Other dr ug
i nteracti ons i ncl ude the fol l owi ng:

Now I get it!

How lidocaine works
Li docai ne wor ks i n i njur ed or i schemi c myocar di al cel l s to
r etar d sodi um i nfl ux and r estor e car di ac r hythm. Nor mal l y, the
ventr i cl es contract i n r esponse to i mpul ses fr om the si noatr i al
(SA) node. But when ti ssue damage occur s i n the ventr i cl es,
i schemi c cel l s can cr eate an ectopi c pacemaker, whi ch can tr i gger
ventr i cul ar ar r hythmi as. The i l l ustrati ons bel ow show how these
ar r hythmi as devel op at the cel l ul ar l evel and how l i docai ne
suppr esses them.
Ischemic myocardial cell
Nor mal myocar di al cel l s per mi t a l i mi ted amount of sodi um i ons to
enter, whi ch l eads to contr ol l ed depol ar i z ati on. Ischemi c
myocar di al cel l s al l ow a rapi d i nfusi on of sodi um i ons. Thi s causes
the cel l s to depol ar i ze much mor e qui ckl y than nor mal and then
begi n fi r i ng spontaneousl y. The r esul t: a ventr i cul ar ar r hythmi a.

Ischemic myocardial cell with lidocaine

By sl owi ng sodi ums i nfl ux, l i docai ne rai ses the cel l s el ectr i cal
sti mul ati on thr eshol d (EST). The i ncr eased EST pr ol ongs
depol ar i z ati on i n the i schemi c cel l s and r etur ns contr ol to the SA
node, the hear ts mai n pacemaker.
 Ri fampi n may r educe the effects of mexi l eti ne.
Theophyl l i ne l evel s i ncr ease when gi ven wi th mexi l eti ne.
Use of a beta-adr ener gi c bl ocker or di sopyrami de wi th mexi l eti ne
may r educe the contracti l i ty of the hear t. (See Adver se r eacti ons
to cl ass IB anti ar r hythmi cs.)

Class IC antiarrhythmics
Class IC antiar r hythmics ar e used to tr eat cer tai n sever e, r efractor y
(r esi stant) ventr i cul ar ar r hythmi as. Cl ass IC anti ar r hythmi cs
i ncl ude:

fl ecai ni de
mor i ci z i ne
pr opafenone.

Pharmacokinetics
After oral admi ni strati on, cl ass IC anti ar r hythmi cs ar e absor bed
wel l , di str i buted i n var yi ng degr ees, and pr obabl y metabol i zed by
the l i ver. Theyr e excr eted pr i mar i l y by the ki dneys, except for
pr opafenone, whi ch i s excr eted pr i mar i l y i n stool .

Memory jogger
To r emember the mai n di ffer ences between what Cl ass IA,
Cl ass IB, and Cl ass IC anti ar r hythmi cs do, just thi nk of thei r
 names:
Cl ass IA : A l ter s the myocar di al cel l membrane
Cl ass IB: Bl ocks the rapi d i nfl ux of sodi um i ons
Cl ass IC: sl ows Conducti on

More about moricizine

After oral admi ni strati on, about 38% of mor i ci z i ne i s absor bed. It
under goes extensi ve metabol i sm, wi th l ess than 1% of a dose
excr eted unchanged i n the ur i ne. Mor i ci z i ne i s hi ghl y pr otei n-
bound, l eavi ng onl y a smal l por ti on of the dr ug fr ee to pr oduce i ts
anti ar r hythmi c effect.

Pharmacodynamics
Cl ass IC anti ar r hythmi cs pr i mar i l y sl ow conducti on al ong the hear ts
conducti on system. Mor i ci z i ne decr eases the fast i nwar d cur r ent of
sodi um i ons of the acti on potenti al , depr essi ng the depol ar i z ati on
rate and the effecti ve r efractor y per i od.

Pharmacotherapeutics
Li ke cl ass IB anti ar r hythmi cs, cl ass IC anti ar r hythmi cs ar e used to
tr eat and pr event l i fe-thr eateni ng ventr i cul ar ar r hythmi as. Theyr e
al so used to tr eat supraventr i cul ar ar r hythmi as (abnor mal hear t
r hythms that or i gi nate above the bundl e branches of the hear ts
conducti on system).
F l ecai ni de and pr opafenone may al so be used to pr event par oxysmal
supraventr i cul ar tachycar di a (PSVT) i n pati ents wi thout str uctural
hear t di sease. Mor i ci z i ne i s used to manage l i fe-thr eateni ng
ventr i cul ar ar r hythmi as such as sustai ned ventr i cul ar tachycar di a.

Drug interactions
Cl ass IC anti ar r hythmi cs may exhi bi t addi ti ve effects wi th other
anti ar r hythmi cs. Other i nteracti ons i ncl ude the fol l owi ng:

Warning!
Adverse reactions to class IC antiarrhythmics
Cl ass IC anti ar r hythmi cs can pr oduce ser i ous adver se
r eacti ons, i ncl udi ng the devel opment of new ar r hythmi as and
 aggravati on of exi sti ng ar r hythmi as. Theyr e avoi ded i n pati ents
wi th str uctural hear t defects because of a hi gh i nci dence of
mor tal i ty.
Because pr opafenone has beta-bl ocki ng pr oper ti es, i t may cause
br onchospasm.
Adverse reactions to moricizine
The most ser i ous adver se r eacti on i s the appearance of new
ar r hythmi as or the wor seni ng of an exi sti ng ar r hythmi a.
Other car di ovascul ar adver se r eacti ons i ncl ude pal pi tati ons,
shor tness of br eath, chest pai n, hear t fai l ur e, and car di ac ar r est.
G I adver se r eacti ons i ncl ude abdomi nal pai n, hear tbur n, nausea,
and vomi ti ng.

When used wi th di goxi n, fl ecai ni de and pr opafenone i ncr ease the

r i sk of di goxi n toxi ci ty.
Pr opafenone i ncr eases pl asma concentrati ons of war far i n and
i ncr eases pr othr ombi n ti mes.
Qui ni di ne i ncr eases the effects of pr opafenone.
Ci meti di ne may i ncr ease the pl asma l evel and the r i sk of toxi ci ty
of mor i ci z i ne.
Pr opanol ol or di goxi n gi ven wi th mor i ci z i ne may i ncr ease the PR
i nter val on the el ectr ocar di ogram.
Theophyl l i ne l evel s may be r educed i n a pati ent r ecei vi ng
mor i ci z i ne.
Ri tonavi r i ncr eases the pl asma concentrati on and the effects of
pr opafenone.
Pr opafenone i ncr eases the ser um concentrati on and the effects
of metopr ol ol and pr opranol ol . (See Adver se r eacti ons to cl ass IC
anti ar r hythmi cs.)

Class II antiarrhythmics
Class II antiar r hythmics ar e composed of beta-adr ener gi c
antagoni sts, or beta-adr ener gi c bl ocker s. Beta-adr ender gi c bl ocker s
used as anti ar r hythmi cs i ncl ude:

acebutol ol (not used ver y often)

 esmol ol
pr opranol ol .

Pharmacokinetics
Acebutol ol and pr opranol ol ar e absor bed al most enti r el y fr om the G I
tract after an oral dose. Esmol ol , whi ch can be gi ven onl y by I.V., i s
i mmedi atel y avai l abl e thr oughout the body.

Fat-headed
Acebutol ol and esmol ol have l ow l i pi d sol ubi l i ty. That means that
they cant penetrate the hi ghl y fatty cel l s that act as bar r i er s
between the bl ood and brai n, cal l ed the bl ood-brai n bar r i er.
Pr opranol ol has hi gh l i pi d sol ubi l i ty and r eadi l y cr osses the bl ood-
brai n bar r i er.

No leftovers
Pr opranol ol under goes si gni fi cant fi r st-pass effect, l eavi ng onl y a
smal l por ti on of these dr ugs avai l abl e to r each ci r cul ati on and be
di str i buted to the body.
Esmol ol i s metabol i zed excl usi vel y by r ed bl ood cel l s (RBCs), wi th
onl y 1% excr eted i n ur i ne. Pr opranol ol s metabol i tes ar e excr eted i n
ur i ne.

Pharmacodynamics
Cl ass II anti ar r hythmi cs bl ock beta-adr ener gi c r eceptor si tes i n the
conducti on system of the hear t. As a r esul t, the abi l i ty of the SA
node to fi r e spontaneousl y (automati ci ty) i s sl owed. The abi l i ty of
the AV node and other cel l s to r ecei ve and conduct an el ectr i cal
i mpul se to near by cel l s (conducti vi ty) i s al so r educed.
Cl ass II anti ar r hythmi cs al so r educe the str ength of the hear ts
contracti ons. When the hear t beats l ess for ceful l y, i t doesnt r equi r e
as much oxygen to do i ts wor k.
Pharmacotherapeutics
Cl ass II anti ar r hythmi cs sl ow ventr i cul ar rates i n pati ents wi th
atr i al fl utter, atr i al fi br i l l ati on, and par oxysmal atr i al tachycar di a.

Drug interactions
Cl ass II anti ar r hythmi cs can cause a var i ety of dr ug i nteracti ons:

Admi ni ster i ng these dr ugs wi th phenothi az i nes and other

anti hyper tensi ves i ncr eases the anti hyper tensi ve effect.

When gi ven wi th nonster oi dal anti -i nfl ammator y agents, fl ui d

and water r etenti on may occur, decr easi ng the anti hyper tensi ve
effect.
The effects of sympathomi meti cs may be r educed when taken
wi th cl ass II anti ar r hythmi cs.
Beta-adr ener gi c bl ocker s gi ven wi th verapami l can depr ess the
hear t, causi ng hypotensi on, bradycar di a, AV bl ock, and asystol e.
Beta-adr ener gi c bl ocker s r educe the effects of sul fonyl ur eas.
The r i sk of di goxi n toxi ci ty i ncr eases when di goxi n i s taken wi th
esmol ol . (See Adver se r eacti ons to cl ass II anti ar r hythmi cs.)

Warning!
Adverse reactions to class II antiarrhythmics
 Common adver se r eacti ons i ncl ude:

ar r hythmi as
bradycar di a
hear t fai l ur e
hypotensi on
G I r eacti ons, such as nausea, vomi ti ng, and di ar r hea
br onchoconstr i cti on.

Class III antiarrhythmics

Class III antiar r hythmics ar e used to tr eat ventr i cul ar ar r hythmi as.
The dr ugs i n thi s cl ass ar e ami odar one, dofeti l i de, i buti l i de, and
sotal ol .

Which class are you in?

Sotal ol i s a nonsel ecti ve beta-adr ener gi c bl ocker (cl ass II dr ug) that
al so has cl ass III pr oper ti es. Nonsel ecti ve means that the dr ug
doesnt have a speci fi c affi ni ty for a r eceptor. Al though sotal ol i s a
cl ass II dr ug, i ts cl ass III anti ar r hythmi c effects ar e mor e
pr edomi nant, especi al l y at hi gher doses. Ther efor e, i ts usual l y
l i sted as a cl ass III anti ar r hythmi c.

Pharmacokinetics
The absor pti on of these anti ar r hythmi cs var i es wi del y.

Slow going
After oral admi ni strati on, ami odar one i s absor bed sl owl y at wi del y
var yi ng rates. The dr ug i s di str i buted extensi vel y and accumul ates
i n many si tes, especi al l y i n or gans wi th a r i ch bl ood suppl y and
fatty ti ssue. Its hi ghl y pr otei n-bound i n pl asma, mai nl y to al bumi n.
Dofeti l i de i s ver y wel l absor bed fr om the G I tract, wi th al most 100%
overal l absor pti on. Of that, about 70% i s bound to pl asma pr otei ns.
Ibuti l i de, whi ch i s admi ni ster ed onl y by I.V., has an absor pti on of
100% . Sotal ol s absor pti on i s sl ow and var i es between 60% and
100% , wi th mi ni mal pr otei n-bi ndi ng.

Pharmacodynamics
Al though the exact mechani sm of acti on i snt known, cl ass III
anti ar r hythmi cs ar e thought to suppr ess ar r hythmi as by conver ti ng
a uni di r ecti onal bl ock to a bi di r ecti onal bl ock. Cl ass III
anti ar r hythmi cs have l i ttl e or no effect on depol ar i z ati on. Rather,
these dr ugs sl ow r epol ar i z ati on, pr ol ongi ng the r efractor y per i od
and durati on of the acti on potenti al .

Pharmacotherapeutics
Cl ass III anti ar r hythmi cs ar e used for l i fe-thr eateni ng ar r hythmi as.
Ami odar one i s the fi r st-l i ne dr ug of choi ce for ventr i cul ar
tachycar di a and ventr i cul ar fi br i l l ati on.

Drug interactions
Ami odar one i ncr eases phenytoi n, pr ocai nami de, and qui ni di ne
l evel s.
Ami odar one al so i ncr eases the r i sk of di goxi n toxi ci ty.
Ibuti l i de shoul dnt be admi ni ster ed wi thi n 4 hour s of cl ass I or
other cl ass III anti ar r hythmi cs because i t i ncr eases the potenti al
for a pr ol onged r efractor y per i od.
Dofeti l i de shoul dnt be admi ni ster ed wi th ci meti di ne,
ketoconazol e, megestr ol , pr ochl or peraz i ne, sul famethoxazol e,
tr i methopr i m, or verapami l because of thei r potenti al to i nduce
l i fe-thr eateni ng ar r hythmi as.
Sotal ol shoul dnt be admi ni ster ed wi th dol asetr on or dr oper i dol
because of the i ncr eased r i sk of l i fe-thr eateni ng ar r hythmi as.
Concomi tant use of ami odar one and fl uor oqui nol ones, macr ol i de
anti bi oti cs, and azol e anti fungal s may cause pr ol ongati on of the
QTc i nter val , l eadi ng to car di ac ar r hythmi as, i ncl udi ng tor sades
de poi ntes.
Pressure plunge
Sever e hypotensi on may devel op fr om too-rapi d I.V. admi ni strati on
of ami odar one. (See Adver se r eacti ons to cl ass III anti ar r hythmi cs.)

Warning!
Adverse reactions to class III antiarrhythmics
Adver se r eacti ons to cl ass III anti ar r hythmi cs, especi al l y
ami odar one, var y wi del y and commonl y l ead to dr ug
di sconti nuati on. A common adver se effect i s aggravati on of
ar r hythmi as.
Adverse reactions to amiodarone
Ami odar one may pr oduce hypotensi on, nausea, and anor exi a.
Sever e pul monar y toxi ci ty occur s i n 15% of pati ents and can be
fatal . Vi si on di stur bances and cor neal mi cr odeposi ts may occur.
and ibultilide
Ibuti l i de may cause sustai ned ventr i cul ar tachycar di a,
pr ol ongati on of the QT i nter val , hypotensi on, nausea, and
headache.
and sotalol
Sotal ol may cause atr i oventr i cul ar bl ock, bradycar di a, ventr i cul ar
ar r hythmi as, br onchospasm, and hypotensi on.
Class IV antiarrhythmics
Class IV antiar r hythmics ar e composed of cal ci um channel bl ocker s.
The cal ci um channel bl ocker s verapami l and di l ti azem ar e used to
tr eat supraventr i cul ar ar r hythmi as wi th a rapi d ventr i cul ar r esponse
(rapi d hear t rate i n whi ch the r hythm or i gi nates above the
ventr i cl es).
For a thor ough di scussi on of cal ci um channel bl ocker s and how they
wor k, see Cal ci um channel bl ocker s, page 138.

Adenosine
Adenosine i s an i njectabl e anti ar r hythmi c i ndi cated for acute
tr eatment of PSVT.

Pharmacokinetics
After I.V. admi ni strati on, adenosi ne i s pr obabl y di str i buted rapi dl y
thr oughout the body. Its metabol i zed i nsi de RBCs as wel l as i n
vascul ar endothel i al cel l s.

Pharmacodynamics
Adenosi ne depr esses the pacemaker acti vi ty of the SA node,
r educi ng the hear t rate and the abi l i ty of the AV node to conduct
i mpul ses fr om the atr i a to the ventr i cl es.

Pharmacotherapeutics
Adenosi ne i s especi al l y effecti ve agai nst r eentr y tachycar di as (when
an i mpul se depol ar i zes an ar ea of hear t muscl e, then r etur ns and
r epol ar i zes i t) that i nvol ve the AV node.
No slouch
Adenosi ne al so effecti vel y r esol ves PSVT i n 90% of cases. Its
typi cal l y used to tr eat ar r hythmi as associ ated wi th accessor y bypass
tracts, as i n Wol ff-Par ki nson-Whi te syndr ome (br i ef per i ods of rapi d
hear t rate i n whi ch the r hythm or i gi nates above the ventr i cl e).

Drug interactions
Methyl xanthi nes antagoni ze the effects of adenosi ne, so l ar ger
doses of adenosi ne may be necessar y.
Di pyr i damol e and car bamazepi ne potenti ate the effects of
adenosi ne, so smal l er doses of adenosi ne may be necessar y.

When adenosi ne i s admi ni ster ed wi th car bamazepi ne, ther es an

i ncr eased r i sk of hear t bl ock. (See Adver se r eacti ons to
adenosi ne.)

Antianginal drugs
Al though angi nas car di nal symptom i s chest pai n, the dr ugs used to
tr eat angi na ar ent typi cal l y anal gesi cs.
Instead, antianginal dr ugs tr eat angi na by r educi ng myocar di al
oxygen demand (r educi ng the amount of oxygen the hear t needs to
do i ts wor k), by i ncr easi ng the suppl y of oxygen to the hear t, or
both. (See How anti angi nal dr ugs wor k.)
The thr ee cl asses of anti angi nal dr ugs di scussed i n thi s secti on
i ncl ude:

Warning!
Adverse reactions to adenosine
Common adver se r eacti ons to adenosi ne i ncl ude:

faci al fl ushi ng
shor tness of br eath
dyspnea
chest di scomfor t.

Now I get it!

How antianginal drugs work
Angi na occur s when the cor onar y ar ter i es (the hear ts
pr i mar y sour ce of oxygen) suppl y i nsuffi ci ent oxygen to the
myocar di um. Thi s i ncr eases the hear ts wor kl oad, i ncr easi ng hear t
rate, pr el oad (bl ood vol ume i n the ventr i cl e at the end of
di astol e), after l oad (pr essur e i n the ar ter i es l eadi ng fr om the
ventr i cl e), and for ce of myocar di al contracti l i ty.
Anti angi nal dr ugs (ni trates, beta-adr ener i c bl ocker s, and cal ci um
channel bl ocker s) r el i eve angi na by decr easing one or mor e of
these four factor s. Thi s di agram summar i zes how anti angi nal
dr ugs affect the car di ovascul ar system.
 ni trates (for tr eati ng acute angi na)
beta-adr ener gi c bl ocker s (for l ong-ter m pr eventi on of angi na)
cal ci um channel bl ocker s (used when other dr ugs fai l to pr event
angi na).

Nitrates
Nitr ates ar e the dr ugs of choi ce for r el i evi ng acute angi na. Ni trates
commonl y pr escr i bed to tr eat angi na i ncl ude:

amyl ni tr i te
i sosor bi de di ni trate
i sosor bi de mononi trate
ni tr ogl ycer i n.

Pharmacokinetics
Ni trates can be admi ni ster ed i n a var i ety of ways.

All absorbed
Ni trates gi ven subl i ngual l y (under the tongue), buccal l y (i n the
pocket of the cheek), as chewabl e tabl ets, as l i ngual aer osol s
(sprayed onto or under the tongue), or by i nhal ati on (amyl ni tr i te)
ar e absor bed al most compl etel y because the mucous membranes of
the mouth have a r i ch bl ood suppl y.

Half-absorbed
Swal l owed ni trate capsul es ar e absor bed thr ough the mucous
membranes of the G I tract, and onl y about one-hal f of the dose
enter s ci r cul ati on.
Transder mal ni trates (a patch or oi ntment pl aced on the ski n) ar e
absor bed sl owl y and i n var yi ng amounts, dependi ng on the quanti ty
of dr ug appl i ed, the l ocati on of i ts appl i cati on, the sur face ar ea of
ski n used, and ci r cul ati on to the ski n.

Or no absorption required
I.V. ni tr ogl ycer i n, whi ch doesnt need to be absor bed, goes di r ectl y
i nto ci r cul ati on.

Pharmacodynamics
Ni trates cause the smooth muscl e of the vei ns and, to a l esser
extent, the ar ter i es to r el ax and di l ate. Thi s i s what happens:

When the vei ns di l ate, l ess bl ood r etur ns to the hear t.

Thi s, i n tur n, r educes the amount of bl ood i n the ventr i cl es at
the end of di astol e, when the ventr i cl es ar e ful l . (The vol ume of
bl ood i n the ventr i cl es just befor e contracti on i s cal l ed pr el oad.)
By r educi ng pr el oad, ni trates r educe ventr i cul ar si ze and
ventr i cul ar wal l tensi on (the l eft ventr i cl e doesnt have to
str etch as

much to pump bl ood). Thi s, i n tur n, r educes the oxygen

r equi r ements of the hear t.

Dont fight it
The ar ter i ol es pr ovi de the most r esi stance to the bl ood pumped by
the l eft ventr i cl e (cal l ed per ipher al vascular r esistance). Ni trates
decr ease after l oad by di l ati ng the ar ter i ol es, r educi ng r esi stance,
easi ng the hear ts wor kl oad, and easi ng the demand for oxygen.
Pharmacotherapeutics
Ni trates ar e used to r el i eve and pr event angi na.

For speedy relief

The rapi dl y absor bed ni trates, such as ni tr ogl ycer i n, ar e the dr ugs
of choi ce for r el i ef of acute angi na because:

they have a rapi d onset of acti on

theyr e easy to take
theyr e i nexpensi ve.

Or prevention
Longer-acti ng ni trates, such as the dai l y ni tr ogl ycer i n transder mal
patch, ar e conveni ent and can be used to pr event chr oni c angi na.
Oral ni trates ar e al so used because they sel dom pr oduce ser i ous
adver se r eacti ons.

Warning!
Adverse reactions to nitrates
Most adver se r eacti ons to ni trates r esul t fr om changes i n
the car di ovascul ar system. These r eacti ons usual l y di sappear
when dosage i s r educed.
The three Hs
Headache i s the most common adver se r eacti on. Hypotensi on may
 al so occur, accompani ed by di z z i ness and i ncr eased hear t rate.

Drug interactions
Sever e hypotensi on can r esul t when ni trates i nteract wi th
al cohol .
Er ecti l e dysfuncti on dr ugs shoul dnt be taken wi thi n 24 hour s of
ni trate admi ni strati on because of possi bl e enhanced hypotensi ve
effects.
Absor pti on of subl i ngual ni trates may be del ayed when taken
wi th an anti chol i ner gi c dr ug.
Mar ked or thostati c hypotensi on (a dr op i n bl ood pr essur e when a
per son stands up) wi th l i ght-headedness, fai nti ng, or bl ur r ed
vi si on may occur when cal ci um channel bl ocker s,
anti hyper tensi ves, beta-adr ener gi c bl ocker s, or phenothi az i nes
and ni trates ar e used together. (See Adver se r eacti ons to
ni trates.)

Beta-adrenergic antagonists
Beta-adr ener gic antagonists (al so cal l ed beta blocker s) ar e used for
l ong-ter m pr eventi on of angi na and ar e one of the mai n types of
dr ugs used to tr eat hyper tensi on. Beta-adr ener gi c bl ocker s i ncl ude:

atenol ol
metopr ol ol
nadol ol
pr opranol ol .

Pharmacokinetics
Metopr ol ol and pr opranol ol ar e absor bed al most enti r el y fr om the G I
tract, wher eas l ess than one-hal f the dose of atenol ol or nadol ol i s
absor bed. These beta-adr ener gi c bl ocker s ar e di str i buted wi del y.
Pr opranol ol i s hi ghl y pr otei n-bound; the other beta-adr ener gi c
bl ocker s ar e poor l y pr otei n-bound.
Making an escape
Pr opranol ol and metopr ol ol ar e metabol i zed i n the l i ver, and thei r
metabol i tes ar e excr eted i n ur i ne. Atenol ol and nadol ol ar ent
metabol i zed and ar e excr eted unchanged i n ur i ne and stool .

Pharmacodynamics
Beta-adr ener gi c bl ocker s decr ease bl ood pr essur e and bl ock beta-
adr ener gi c r eceptor si tes i n the hear t muscl e and the conducti on
system. Thi s decr eases the hear t rate and r educes the for ce of the
hear ts contracti ons, r esul ti ng i n a l ower demand for oxygen.

Pharmacotherapeutics
Beta-adr ener gi c bl ocker s ar e i ndi cated for l ong-ter m pr eventi on of
angi na. In acute cor onar y syndr ome, metopr ol ol may be gi ven
i ni ti al l y I.V., and then oral l y. Metopr ol ol may al so be used for hear t
fai l ur e.
Because of thei r abi l i ty to r educe bl ood pr essur e, beta-adr ener gi c
bl ocker s ar e al so fi r st-l i ne therapy for tr eati ng hyper tensi on.

Drug interactions
A number of dr ugs i nteract wi th beta-adr ener gi c bl ocker s.

Antaci ds r educe absor pti on of beta-adr ener gi c bl ocker s.

Nonster oi dal anti -i nfl ammator y dr ugs (NSAIDs) can decr ease the
hypotensi ve effects of beta-adr ener gi c bl ocker s.
 Car di ac gl ycosi des and cal ci um channel bl ocker s can have
negati ve addi cti ve effects on SA or AV node conducti on when
admi ni ster ed wi th a beta-adr ener gi c bl ocker.
Di ur eti cs or other hypotensi ve agents can potenti ate the
hypotensi ve effects of beta-adr ener gi c bl ocker s.
Li docai ne toxi ci ty may occur when l i docai ne i s taken wi th beta-
adr ener gi c bl ocker s.
The r equi r ements for i nsul i n and oral anti di abeti cs can be
al ter ed by beta-adr ener gi c bl ocker s.
The abi l i ty of theophyl l i ne to pr oduce br onchodi l ati on i s
i mpai r ed by nonsel ecti ve beta-adr ener gi c bl ocker s. (See Adver se
r eacti ons to beta-adr ener gi c bl ocker s.)

Warning!
Adverse reactions to beta-adrenergic blockers
Beta-adr ener gi c bl ocker s may cause:

bradycar di a
angi na
fl ui d r etenti on
per i pheral edema
hear t fai l ur e
ar r hythmi as, especi al l y atr i oventr i cul ar bl ock
hypotensi on
di z z i ness
nausea and vomi ti ng
di ar r hea
si gni fi cant constr i cti on of the br onchi ol es.

Quick stop causes concern

Suddenl y stoppi ng a beta-adr ener gi c bl ocker may tr i gger :

angi na
hyper tensi on
ar r hythmi as
acute myocar di al i nfar cti on.
Calcium channel blockers
Calcium channel blocker s ar e commonl y used to pr event angi na that
doesnt r espond to dr ugs i n ei ther of the other anti angi nal cl asses.
Theyr e the dr ug of choi ce to tr eat Pr i nz metal s angi na. As
menti oned ear l i er, several of the cal ci um channel bl ocker s ar e al so
used as anti ar r hythmi cs and to tr eat hyper tensi on. Cal ci um channel
bl ocker s used to tr eat angi na i ncl ude:

aml odi pi ne
di l ti azem
ni car di pi ne
ni fedi pi ne
verapami l .

Now I get it!

How calcium channel blockers work
Cal ci um channel bl ocker s i ncr ease the myocar di al oxygen
suppl y and sl ow the hear t rate. Appar entl y, the dr ugs pr oduce
these effects by bl ocki ng the sl ow cal ci um channel . Thi s acti on
i nhi bi ts the i nfl ux of extracel l ul ar cal ci um i ons acr oss both
myocar di al and vascul ar smooth muscl e cel l membranes. Cal ci um
channel bl ocker s achi eve thi s bl ockade wi thout changi ng ser um
cal ci um concentrati ons.
No calcium = dilation
Thi s cal ci um bl ockade causes the cor onar y ar ter i es (and, to a
l esser extent, the per i pheral ar ter i es and ar ter i ol es) to di l ate,
decr easi ng after l oad and i ncr easi ng myocar di al oxygen suppl y.
Pharmacokinetics
When admi ni ster ed oral l y, cal ci um channel bl ocker s ar e absor bed
qui ckl y and al most compl etel y. Because of the fi r st-pass effect,
however, the bi oavai l abi l i ty of these dr ugs i s much l ower. The
cal ci um channel bl ocker s ar e hi ghl y bound to pl asma pr otei ns.
Gone without a trace
Al l cal ci um channel bl ocker s ar e metabol i zed rapi dl y and al most
compl etel y i n the l i ver.

Pharmacodynamics
Cal ci um channel bl ocker s pr event the passage of cal ci um i ons acr oss
the myocar di al cel l membrane and vascul ar smooth-muscl e

cel l s. Thi s causes di l ati on of the cor onar y and per i pheral ar ter i es,
whi ch decr eases the for ce of the hear ts contracti ons and r educes
the wor kl oad of the hear t.

The relaxation response

Al so, by pr eventi ng ar ter i ol es fr om constr i cti ng, cal ci um channel
bl ocker s r educe after l oad. Decr easi ng after l oad fur ther decr eases
the oxygen demands of the hear t. (See How cal ci um channel
bl ocker s wor k, page 139.)

Rate reductions
Some cal ci um channel bl ocker s (di l ti azem and verapami l ) al so
r educe the hear t rate by sl owi ng conducti on thr ough the SA and AV
nodes. A sl ower hear t rate r educes the hear ts need for addi ti onal
oxygen.

Pharmacotherapeutics
Cal ci um channel bl ocker s ar e used for l ong-ter m pr eventi on of
angi na onl y, not shor t-ter m r el i ef of chest pai n. Cal ci um channel
bl ocker s ar e par ti cul ar l y effecti ve for pr eventi ng Pr i nz metal s
angi na.

Drug interactions
Cal ci um sal ts and vi tami n D r educe the effecti veness of cal ci um
channel bl ocker s.
Nondepol ar i z i ng bl ocki ng dr ugs may have an enhanced muscl e-
r el axant effect when taken wi th cal ci um channel bl ocker s.
Verapami l and di l ti azem i ncr ease the r i sk of di goxi n toxi ci ty,
enhance the acti on of car bamazepi ne, and may cause myocar di al
depr essi on. (See Adver se r eacti ons to cal ci um channel bl ocker s.)

Warning!
Adverse reactions to calcium channel blockers
As wi th other anti angi nal dr ugs, car di ovascul ar r eacti ons
ar e the most common and ser i ous adver se r eacti ons to cal ci um
channel bl ocker s. These i ncl ude or thostati c hypotensi on (a dr op i n
bl ood pr essur e when a per son stands up), hear t fai l ur e, and
hypotensi on. Di l ti azem and verapami l can cause such ar r hythmi as
as bradycar di a, si nus bl ock, and atr i oventr i cul ar bl ock.
Others
Other possi bl e adver se r eacti ons i ncl ude di z z i ness, headache,
fl ushi ng, weakness, and per si stent per i pheral edema.
Antihypertensive drugs
Antihyper tensive dr ugs, whi ch act to r educe bl ood pr essur e, ar e
used to tr eat hyper tensi on, a di sor der character i zed by el evati on i n
systol i c bl ood pr essur e, di astol i c bl ood pr essur e, or both.

Know the program

Tr eatment for hyper tensi on typi cal l y begi ns wi th a thi az i de di ur eti c
or a cal ci um channel bl ocker. (For mor e i nfor mati on, see Cal ci um
channel bl ocker s, page 138.) The pati ent may al so r ecei ve a beta-
adr ener gi c antagoni st, angi otensi n-conver ti ng enz yme (ACE)
i nhi bi tor, or an angi otensi n II r eceptor bl ocker. The choi ce of

these dr ugs depends on whether the pati ent has a compel l i ng

i ndi cati on, such as hear t fai l ur e, hi stor y of an MI, hi gh r i sk of
cor onar y ar ter y di sease (CAD), di abetes, or chr oni c ki dney di sease.
(See Beta-adr ener gi c antagoni sts, page 137.)
Other dr ugs used to tr eat hyper tensi on i ncl ude sympathol yti c dr ugs
(other than beta-adr ener gi c bl ocker s), and vasodi l ator s. At ti mes, a
combi nati on of dr ugs may be used.

Sympatholytic drugs
Sympatholytic dr ugs i ncl ude several di ffer ent types of dr ugs, but al l
r educe bl ood pr essur e by i nhi bi ti ng or bl ocki ng the sympatheti c
ner vous system. Theyr e cl assi fi ed by thei r si te or mechani sm of
acti on and i ncl ude:

central -acti ng sympatheti c ner vous system i nhi bi tor s (cl oni di ne
and methyl dopa)
al pha-adr ener gi c bl ocker s (doxazosi n, phentol ami ne, prazosi n,
and terazosi n)
mi xed al pha- and beta-adr ener gi c bl ocker s (car vedi l ol and
l abetal ol )
nor epi nephr i ne depl etor s (guanadr el , guanethi di ne, and
r eser pi nethese ar e rar el y used).

Pharmacokinetics
Most sympathol yti c dr ugs ar e absor bed wel l fr om the G I tract,
di str i buted wi del y, metabol i zed i n the l i ver, and excr eted pr i mar i l y
i n ur i ne.

Pharmacodynamics
Al l sympathol yti c dr ugs i nhi bi t sti mul ati on of the sympatheti c
ner vous system, causi ng di l ati on of the per i pheral bl ood vessel s or
decr eased car di ac output, ther eby r educi ng bl ood pr essur e.

Pharmacotherapeutics
If bl ood pr essur e fai l s to come under contr ol wi th beta-adr ener gi c
bl ocker s and di ur eti cs, an al pha-adr ener gi c bl ocker, such as
prazosi n, or a mi xed al pha- and beta-adr ener gi c bl ocker, such as
l abetal ol , may be used. If the pati ent fai l s to achi eve the desi r ed
bl ood pr essur e, the physi ci an may add a dr ug fr om a di ffer ent cl ass,
substi tute a dr ug i n the same cl ass, or i ncr ease the dr ug dosage.

Warning!
Adverse reactions to sympatholytics
Alpha-adrenergic blockers

Hypotensi on

Central-acting drugs

Depr essi on
Dr owsi ness
Edema
Li ver dysfuncti on
Numbness, ti ngl i ng
Ver ti go

Guanadrel

Di ffi cul ty br eathi ng

Excessi ve ur i nati on
Fai nti ng
Or thostati c hypotensi on
 Guanethidine

Decr eased hear t contracti l i ty

Di ar r hea
F l ui d r etenti on
Or thostati c hypotensi on

Reserpine

Abdomi nal cramps, di ar r hea

Angi na
Bl ur r ed vi si on
Bradycar di a
Br onchoconstr i cti on
Decr eased l i bi do
Depr essi on
Dr owsi ness
Wei ght gai n
Fati gue
Hypotensi on

Drug interactions
Sympathol yti c dr ugs can cr eate these dr ug i nteracti ons:

Car vedi l ol taken wi th anti di abeti cs may r esul t i n i ncr eased

hypogl ycemi c effect.
Car vedi l ol taken wi th cal ci um channel bl ocker s may r esul t i n
i ncr eased conducti on di stur bances.
Car vedi l ol taken wi th di goxi n may r esul t i n i ncr eased di goxi n
l evel s.
Car vedi l ol taken wi th r i fampi n decr eases car vedi l ol l evel s.
Cl oni di ne pl us tr i cycl i c anti depr essants may i ncr ease bl ood
pr essur e.
Cl oni di ne taken wi th CNS depr essants may wor sen CNS
depr essi on.
 Reser pi ne taken wi th di ur eti cs or other hypotensi ve agents can
i ncr ease the hypotensi ve effects of r eser pi ne.
Reser pi ne taken wi th car di ac gl ycosi des can l ead to car di ac
ar r thymi as.

Sympathol yti c dr ugs can al so pr oduce si gni fi cant adver se r eacti ons.
(See Adver se r eacti ons to sympathol yti cs.)

Vasodilating drugs
Ther e ar e two types of vasodilating dr ugsdi r ect vasodi l ator s and
cal ci um channel bl ocker s. Both types decr ease systol i c and di astol i c
bl ood pr essur e.

Resistance is futile
Dir ect vasodilator s act on ar ter i es, vei ns, or both. They i ncl ude:

di azoxi de
hydral az i ne
mi noxi di l
ni tr opr ussi de.

Hydral az i ne and mi noxi di l ar e usual l y used to tr eat r esi stant or

r efractor y hyper tensi on. Di azoxi de and ni tr opr ussi de ar e r eser ved
for use i n hyper tensi ve cr i si s.

No admittance
Cal ci um channel bl ocker s pr oduce ar ter i ol ar r el axati on by
pr eventi ng the entr y of cal ci um i nto the cel l s. Thi s pr events the
contracti on of vascul ar smooth muscl e. (See Cal ci um channel
bl ocker s, page 138.)

Pharmacokinetics
Most of these dr ugs ar e absor bed rapi dl y and wel l -di str i buted.
Theyr e al l metabol i zed i n the l i ver, and most ar e excr eted by the
ki dneys.

Pharmacodynamics
The di r ect vasodi l ator s r el ax per i pheral vascul ar smooth muscl e,
causi ng the bl ood vessel s to di l ate. The i ncr eased di ameter of the
bl ood vessel s r educes total per i pheral r esi stance, whi ch l ower s
bl ood pr essur e.

Pharmacotherapeutics
Vasodi l ati ng dr ugs ar e rar el y used al one to tr eat hyper tensi on.
Theyr e usual l y combi ned wi th other dr ugs to tr eat the pati ent wi th
moderate to sever e hyper tensi on (hyper tensi ve cr i si s).
Cal ci um channel bl ocker s ar e occasi onal l y used al one to tr eat mi l d
to moderate hyper tensi on.

Warning!
Adverse reactions to direct vasodilators
Di r ect vasodi l ator s commonl y pr oduce adver se r eacti ons
r el ated to r efl ex acti vati on of the sympatheti c ner vous system. As
bl ood pr essur e fal l s, the sympatheti c ner vous system i s
sti mul ated, pr oduci ng compensator y measur es, such as
vasoconstr i cti on and tachycar di a.
Other r eacti ons to sympatheti c sti mul ati on i ncl ude:

pal pi tati ons

angi na
edema
br east tender ness
fati gue
headache
rash
sever e per i car di al effusi on.

Drug interactions
The anti hyper tensi ve effects of hydral az i ne and mi noxi di l ar e
i ncr eased when theyr e gi ven wi th other anti hyper tensi ve dr ugs,
such as methyl dopa or r eser pi ne.
Vasodi l ati ng dr ugs may pr oduce addi ti ve effects when gi ven wi th
ni trates, such as i sosor bi de di ni trate or ni tr ogl ycer i n.
 Few other dr ug i nteracti ons occur wi th vasodi l ati ng dr ugs. (See
Adver se r eacti ons to di r ect vasodi l ator s.)

ACE inhibitors
ACE inhibitor s ar e typi cal l y used when beta-adr ener gi c bl ocker s or
di ur eti cs ar e i neffecti ve. Commonl y pr escr i bed ACE i nhi bi tor s
i ncl ude:

benazepr i l
captopr i l
enal apr i l
enal apr i l at
fosi nopr i l
l i si nopr i l
moexi pr i l
qui napr i l
rami pr i l
trandol apr i l .

Pharmacokinetics
ACE i nhi bi tor s ar e absor bed fr om the G I tract, di str i buted to most
body ti ssues, metabol i zed somewhat i n the l i ver, and excr eted by
the ki dneys. Rami pr i l i s al so excr eted i n stool . Enal apr i l at i s the
onl y ACE i nhi bi tor thats admi ni ster ed I.V.

Pharmacodynamics
ACE i nhi bi tor s r educe bl ood pr essur e by i nter r upti ng the r eni n-
angi otensi n-al doster one system. Nor mal l y, the ki dneys mai ntai n
bl ood pr essur e by r el easi ng the hor mone r eni n. Reni n acts on the
pl asma pr otei n angi otensi nogen to for m angi otensi n I. Angi otensi n I
i s then conver ted to angi otensi n II. Angi otensi n II, a potent
vasoconstr i ctor, i ncr eases per i pheral r esi stance and pr omotes the
excr eti on of al doster one. Al doster one, i n tur n, pr omotes the
r etenti on of sodi um and water, i ncr easi ng the vol ume of bl ood the
hear t needs to pump.

Conversion diversion
ACE i nhi bi tor s pr event the conver si on of angi otensi n I to
angi otensi n II. As angi otensi n II i s r educed, ar ter i ol es di l ate,
r educi ng per i pheral vascul ar r esi stance.

Less water, less work

By r educi ng al doster one secr eti on, ACE i nhi bi tor s pr omote the
excr eti on of sodi um and water, whi ch r educes the amount of bl ood
the hear t needs to pump, ther eby l ower i ng bl ood pr essur e.

Pharmacotherapeutics
ACE i nhi bi tor s may be used al one or wi th another dr ug, such as a
thi az i de di ur eti c, to tr eat hyper tensi on. Cer tai n ACE i nhi bi tor ssuch
as captopr i l , enal apr i l , fosi nopr i l , l i si nopr i l , qui napr i l , rami pr i l , and
trandol apr i l may al so be used to tr eat pati ents wi th hear t fai l ur e or
fol l owi ng MI. Such si tuati ons i ncl ude:

l eft ventr i cul ar systol i c fai l ur e (unl ess contrai ndi cated or
i ntol erant)
l eft ventr i cul ar systol i c dysfuncti on wi thout symptoms of hear t
fai l ur e
 r educi ng mor tal i ty fol l owi ng acute MI (especi al l y i n pati ents wi th
pr i or myocar di al i njur y)
pr eventi ng or del ayi ng the devel opment of l eft ventr i cul ar
di l ati on and over t hear t fai l ur e i n pati ents wi th l eft ventr i cul ar
dysfuncti on (r ecent or r emote)
possi bl e pr oducti on of compl ementar y effects (combi ned wi th
beta-bl ockade)
hi stor y of or pr esent fl ui d r etenti on (combi ned wi th di ur eti cs).

Rami pr i l i s al so i ndi cated to pr event major car di ovascul ar events i n

pati ents wi th a hi stor y of vascul ar di sease or di abetes. Its al so used
to r educe overal l car di ovascul ar r i sk, i ncl udi ng death, nonfatal MI,
nonfatal str oke, and compl i cati ons of di abetes. Captopr i l i s al so
i ndi cated for the l ong-ter m tr eatment of di abeti c neur opathy.

Drug interactions
ACE i nhi bi tor s can cause several di ffer ent types of i nteracti ons wi th
other car di ovascul ar dr ugs. Al l ACE i nhi bi tor s enhance the
hypotensi ve effects of di ur eti cs and other anti hyper tensi ves such as
beta-adr ener gi c bl ocker s. They can al so i ncr ease ser um l i thi um
l evel s, possi bl y r esul ti ng i n l i thi um toxi ci ty.
When ACE i nhi bi tor s ar e used wi th potassi um-spar i ng di ur eti cs,
potassi um suppl ements, or potassi um-contai ni ng sal t substi tutes,
hyper kal emi a may occur.

Warning!
Adverse reactions to ACE inhibitors
Angi otensi n-conver ti ng enz yme (ACE) i nhi bi tor s can
pr oduce these adver se r eacti ons:

headache and fati gue

dr y, nonpr oducti ve, per si stent cough
angi oedema
G I r eacti ons
i ncr eased ser um potassi um concentrati ons
ti ckl i ng i n the thr oat
transi ent el evati ons of bl ood ur ea ni tr ogen and ser um
cr eati ni ne l evel s (i ndi cator s of ki dney functi on).
 Caused by captopril
Captopr i l may cause pr otei n i n the ur i ne, r educed neutr ophi l s and
granul ocytes (a type of whi te bl ood cel l s), rash, l oss of taste,
hypotensi on, or a sever e al l er gi c r eacti on.

Individual items
ACE i nhi bi tor s i nteract wi th many other medi cati ons, pr escr i pti on as
wel l as over-the-counter (OTC). For exampl e, pati ents taki ng ACE
i nhi bi tor s shoul d avoi d taki ng al l NSAIDs. Besi des decr easi ng the
anti hyper tensi ve effect of ACE i nhi bi tor s, NSAIDs may al ter r enal
functi on. Al so, antaci ds may i mpai r the absor pti on of fosi nopr i l , and
qui napr i l may r educe the absor pti on of tetracycl i ne.
A pati ent taki ng ACE i nhi bi tor s shoul dnt take pr escr i pti ons or OTC
medi cati ons or her bal pr oducts wi thout fi r st consul ti ng hi s
physi ci an. (See Adver se r eacti ons to ACE i nhi bi tor s.)

Angiotensin II receptor blockers

Angi otensi n II r eceptor bl ocker s (ARBs) l ower bl ood pr essur e by
bl ocki ng the vasoconstr i cti ve effects of angi otensi n II. Speci fi c
dr ugs i ncl ude:

candesar tan ci l exeti l

epr osar tan
i r besar tan
l osar tan
ol mesar tan
tel mi sar tan
val sar tan.

Warning!
Adverse reactions to ARBs
Adver se r eacti ons to angi otensi n II r eceptor bl ocker s
(ARBs) i ncl ude:

headache and fati gue

 cough and ti ckl i ng i n the thr oat
angi oedema
G I r eacti ons
i ncr eased ser um potassi um l evel
transi ent el evati ons of bl ood ur ea ni tr ogen and ser um
cr eati ni ne l evel s.

Pharmacokinetics
ARBs have var yi ng phar macoki neti c pr oper ti es and al l ar e hi ghl y
bound to pl asma pr otei ns.

Pharmacodynamics
ARBs act by i nter fer i ng wi th the r eni n-angi otensi n-al doster one
system. Speci fi cal l y, these dr ugs bl ock the bi ndi ng of angi otensi n II
to the AT1 r eceptor. Thi s pr events angi otensi n II fr om exer ti ng i ts
vasoconstr i cti ng pr oper ti es and fr om pr omoti ng the excr eti on of
al doster one. Both of these acti ons r esul t i n l ower ed bl ood pr essur e.
ARBs dont i nhi bi t the conver si on of angi otensi n I to angi otensi n II,
nor do they cause a br eakdown i n bradyki ni n (a vasodi l ator ).

Pharmacotherapeutics
ARBs may be used al one or i n combi nati on wi th other dr ugs such as
a di ur eti c. Val sar tan may al so be used as an al ter nati ve to an ACE
i nhi bi tor or for the management of hear t fai l ur e. Because i r besar tan
and l osar tan pr otect the r enal system, theyr e often pr escr i bed for
pati ents wi th type 2 di abetes. Losar tan i s al so used to r educe the
r i sk of str oke i n hi gh-r i sk pati ents wi th hyper tensi on and l eft
ventr i cul ar hyper tr ophy. (See Adver se r eacti ons to ARBs.)

Drug interactions
ARBs can i nteract wi th other dr ugs i n var i ous ways.

When l osar tan i s taken wi th fl uconazol e, an i ncr eased bl ood

l evel of l osar tan may r esul t, l eadi ng to hypotensi on.
NSAIDs r educe the anti hyper tensi ve effects of ARBs.
Ri fampi n may i ncr ease metabol i sm of l osar tan and decr ease i ts
 anti hyper tensi ve effect.

Candesar tan may i ncr ease bl ood l evel s of l i thi um, l eadi ng to
l i thi um toxi ci ty.
When di goxi n i s taken wi th tel mi sar tan, an i ncr eased bl ood l evel
of di goxi n may occur, possi bl y l eadi ng to di goxi n toxi ci ty.
Potassi um suppl ements may i ncr ease the r i sk of hyper kal emi a
when used wi th ARBs.

Antilipemic drugs
Antilipemic dr ugs ar e used to l ower abnor mal l y hi gh bl ood l evel s of
l i pi ds, such as chol ester ol , tr i gl ycer i des, and phosphol i pi ds. The r i sk
of devel opi ng CAD i ncr eases when ser um l i pi d l evel s ar e el evated.
Dr ugs ar e used i n combi nati on wi th l i festyl e changes (such as
pr oper di et, wei ght l oss, and exer ci se) and tr eatment of an
under l yi ng di sor der causi ng the l i pi d abnor mal i ty to hel p l ower l i pi d
l evel s.
The cl asses of anti l i pemi c dr ugs i ncl ude:

bi l e-sequester i ng dr ugs
fi br i c aci d der i vati ves
3-hydr oxy-3-methyl gl utar yl coenz yme A (HMG -CoA) r eductase
i nhi bi tor s
ni coti ni c aci d
chol ester ol absor pti on i nhi bi tor s.

Bile-sequestering drugs
The bile-sequester ing dr ugs ar e chol estyrami ne, col esti pol , and
col esevel am. These dr ugs ar e r esi ns that r emove excess bi l e aci ds
fr om the fat deposi ts under the ski n.

Pharmacokinetics
Bi l e-sequester i ng dr ugs ar ent absor bed fr om the G I tract. Instead,
they r emai n i n the i ntesti ne, wher e they combi ne wi th bi l e aci ds for
about 5 hour s. Eventual l y, theyr e excr eted i n stool .
Pharmacodynamics
The bi l e-sequester i ng dr ugs l ower bl ood l evel s of l ow-densi ty
l i popr otei ns (LDLs). These dr ugs combi ne wi th bi l e aci ds i n the
i ntesti nes to for m an i nsol ubl e compound thats then excr eted i n
stool . The decr easi ng l evel of bi l e aci d i n the gal l bl adder tr i gger s
the l i ver to synthesi ze mor e bi l e aci ds fr om thei r pr ecur sor,
chol ester ol .

Getting out of storage

As chol ester ol l eaves the bl oodstr eam and other storage ar eas to
r epl ace the l ost bi l e aci ds, bl ood chol ester ol l evel s decr ease.
Because the smal l i ntesti ne needs bi l e aci ds to emul si fy l i pi ds and
for m chyl omi cr ons, absor pti on of al l l i pi ds and l i pi d-sol ubl e dr ugs
decr eases unti l the bi l e aci ds ar e r epl aced.

Pharmacotherapeutics
Bi l e-sequester i ng dr ugs ar e the dr ugs of choi ce for tr eati ng type IIa
hyper l i popr otei nemi a (fami l i al hyper chol ester ol emi a) when the
pati ent cant l ower hi s LDL l evel s thr ough di et al one. Pati ents whose
bl ood chol ester ol l evel s pl ace them at a sever e r i sk of CAD wi l l most
l i kel y r equi r e one of these dr ugs i n addi ti on to di etar y changes.

Drug interactions
Bi l e-sequester i ng dr ugs pr oduce the fol l owi ng dr ug i nteracti ons:

They may bi nd wi th aci di c dr ugs i n the G I tract, decr easi ng thei r

absor pti on and effecti veness. Aci di c dr ugs l i kel y to be affected
i ncl ude bar bi turates, phenytoi n, peni ci l l i ns, cephal ospor i ns,
thyr oi d hor mones, thyr oi d der i vati ves, and di goxi n.
Bi l e-sequester i ng dr ugs may decr ease absor pti on of pr opranol ol ,
tetracycl i ne, fur osemi de, peni ci l l i n G , hydr ochl or othi az i de and
gemfi br oz i l .
Bi l e-sequester i ng dr ugs may r educe absor pti on of l i pi d-sol ubl e
vi tami ns, such as vi tami ns A, D, E, and K. Poor absor pti on of
vi tami n K can affect pr othr ombi n ti mes si gni fi cantl y, i ncr easi ng
the r i sk of bl eedi ng. (See Adver se r eacti ons to bi l e-sequester i ng
dr ugs.)
 Warning!
Adverse reactions to bile-sequestering drugs
Shor t-ter m adver se r eacti ons to these dr ugs ar e r el ati vel y
mi l d. Mor e sever e r eacti ons can r esul t fr om l ong-ter m use.
Adver se G I effects wi th l ong-ter m therapy i ncl ude sever e fecal
i mpacti on, vomi ti ng, di ar r hea, and hemor r hoi d i r r i tati on.
Rar el y, pepti c ul cer s and bl eedi ng, gal l stones, and i nfl ammati on
of the gal l bl adder may occur.

Fibric acid derivatives

F ibr ic acid i s pr oduced by several fungi . Two der i vati ves of thi s aci d
ar e fenofi brate and gemfi br oz i l . These dr ugs ar e used to r educe
hi gh tr i gl ycer i de l evel s and, to a l esser extent, hi gh LDL l evel s.

Pharmacokinetics
Fenofi brate and gemfi br oz i l ar e absor bed r eadi l y fr om the G I tract
and ar e hi ghl y pr otei n-bound. Fenofi brate i s hydr ol yzed whi l e
gemfi br oz i l under goes extensi ve metabol i sm i n the l i ver. Both dr ugs
ar e excr eted i n the ur i ne.

Pharmacodynamics
Al though the exact mechani sm of acti on for these dr ugs i snt
known, r esear cher s bel i eve that fi br i c aci d der i vati ves may:

r educe chol ester ol pr oducti on ear l y i n i ts for mati on

 mobi l i ze chol ester ol fr om the ti ssues
i ncr ease chol ester ol excr eti on
decr ease synthesi s and secr eti on of l i popr otei ns
decr ease synthesi s of tr i gl ycer i des.

Power in the blood

G emfi br oz i l pr oduces two other effects:

It i ncr eases hi gh-densi ty l i popr otei n (HDL) l evel s i n the bl ood

(r emember, thi s i s good chol ester ol ).
It i ncr eases the ser ums capaci ty to di ssol ve addi ti onal
chol ester ol .

Pharmacotherapeutics
F i br i c aci d dr ugs ar e used pr i mar i l y to r educe tr i gl ycer i de l evel s,
especi al l y ver y-l ow-densi ty tr i gl ycer i des, and secondar i l y to r educe
bl ood chol ester ol l evel s. Theyr e typi cal l y used to tr eat pati ents
wi th types II, III, IV, and mi l d type V hyper l i popr otei nemi a.

Drug interactions
F i br i c aci d dr ugs may di spl ace aci di c dr ugs, such as bar bi turates,
phenytoi n, thyr oi d der i vati ves, and car di ac gl ycosi des.
The r i sk of bl eedi ng i ncr eases when fi br i c aci d der i vati ves ar e
taken wi th oral anti coagul ants.
F i br i c aci d der i vati ves can l ead to adver se G I effects.
The hypogl ycemi c effects of r epagl i ni de may be i ncr eased and
pr ol onged i f taken wi th gemfi br oz i l .
Use of fi br i c aci d der i vati ves and HMG -CoA r eductase i nhi bi tor s
may i ncr ease the r i sk of r habdomyol ysi s.
HMG-CoA reductase inhibitors
HMG -CoA r eductase inhibitor s (al so known as the statins) l ower l i pi d
l evel s by i nter fer i ng wi th chol ester ol synthesi s. These dr ugs i ncl ude
ator vastati n, fl uvastati n, l ovastati n, pravastati n, r osuvastati n, and
si mvastati n.

Pharmacokinetics
Each dr ug has sl i ghtl y di ffer ent phar macoki neti c pr oper ti es. Wi th
the excepti on of pravastati n, al l ar e hi ghl y bound to pl asma pr otei ns
and under go extensi ve fi r st-pass metabol i sm. However, pl asma
l evel s dont cor r el ate wi th the dr ugs abi l i ti es to l ower chol ester ol .

Pharmacodynamics
HMG -CoA r eductase i nhi bi tor s i nhi bi t the enz yme r esponsi bl e for
the conver si on of HMG -CoA to meval onate, an ear l y step i n the
synthesi s of chol ester ol .

Pharmacotherapeutics
Stati ns ar e used pr i mar i l y to r educe LDL chol ester ol and total bl ood
chol ester ol l evel s. These agents al so pr oduce a mi l d i ncr ease i n HDL
chol ester ol l evel s.
Stati ns ar e used to tr eat pr i mar y hyper chol ester ol emi a (types IIa
and IIb). Because of thei r effect on LDL and total chol ester ol , these
dr ugs ar e al so used to r educe the r i sk of CAD and to pr event MI or
str oke i n pati ents wi th hi gh chol ester ol l evel s.

Drug interactions
Taki ng a stati n dr ug wi th ami odar one, cl ar i thr omyci n,
cycl ospor i ne, er ythr omyci n, fl uconazol e, gemfi br oz i l ,
i traconazol e, ketoconazol e, or ni aci n i ncr eases the r i sk of
myopathy or r habdomyol ysi s (a potenti al l y fatal br eakdown of
skel etal muscl e, causi ng r enal fai l ur e).
Lovastati n, r osuvastati n and si mvastati n may i ncr ease the r i sk of
bl eedi ng when admi ni ster ed wi th war far i n.
Al l of these dr ugs shoul d be admi ni ster ed 1 hour befor e or 4
hour s after the admi ni strati on of bi l e-sequester i ng dr ugs
(chol estyrami ne, col esevel am, and col esti pol ). (See Adver se
r eacti ons to HMG -CoA r eductase i nhi bi tor s.)

Warning!
Adverse reactions to HMG-CoA reductase
inhibitors
HMG -CoA r eductase i nhi bi tor s may al ter l i ver functi on studi es,
i ncr easi ng aspar tate ami notransferase, al ani ne ami notransferase,
al kal i ne phosphatase, and bi l i r ubi n l evel s. Other hepati c effects
may i ncl ude pancr eati ti s, hepati ti s, and ci r r hosi s.
Myal gi a i s the most common muscul oskel etal effect, al though
ar thral gi a and muscl e cramps may al so occur. Myopathy and
r habdomyol ysi s ar e rar e, but potenti al l y sever e, r eacti ons that
may occur wi th these dr ugs.
Possi bl e adver se G I r eacti ons i ncl ude nausea, vomi ti ng, di ar r hea,
abdomi nal pai n, fl atul ence, and consti pati on.

Nicotinic acid
Al so known as niacin, ni coti ni c aci d i s a water-sol ubl e vi tami n that
decr eases chol ester ol , tr i gl ycer i de, and apol i popr otei n B-100 l evel s
and i ncr eases the HDL l evel . The dr ug i s avai l abl e i n i mmedi ate-
r el ease and extended-r el ease tabl ets.
Pharmacokinetics
Ni coti ni c aci d i s rapi dl y and extensi vel y absor bed fol l owi ng oral
admi ni strati on. Its moderatel y bound to pl asma pr otei ns; i ts overal l
bi ndi ng ranges fr om 60% to 70% . The dr ug under goes rapi d
metabol i sm by the l i ver to acti ve and i nacti ve metabol i tes. About
75% of the dr ug i s excr eted i n ur i ne.

Pharmacodynamics
The mechani sm of acti on by whi ch ni coti ni c aci d l ower s tr i gl ycer i de
and apol i popr otei n l evel s i s unknown. However, i t may wor k by
i nhi bi ti ng hepati c synthesi s of l i popr otei ns that contai n
apol i popr otei n B-100, pr omoti ng l i popr otei n l i pase acti vi ty, r educi ng
fr ee fatty aci d mobi l i z ati on fr om adi pose ti ssue, and i ncr easi ng fecal
el i mi nati on of ster ol s.

Pharmacotherapeutics
Ni coti ni c aci d i s usual l y used i n combi nati on wi th other dr ugs to
l ower tr i gl ycer i de l evel s i n pati ents wi th type IV or V hyper l i pi demi a
who ar e at hi gh r i sk for pancr eati ti s and to l ower chol ester ol and
LDL l evel s i n pati ents wi th hyper chol ester ol emi a. It may al so be
used wi th other anti l i pemi cs to boost HDL l evel s.
Ni coti ni c aci d i s contrai ndi cated i n pati ents who ar e hyper sensi ti ve
to ni coti ni c aci d and i n those wi th hepati c dysfuncti on, acti ve pepti c
ul cer di sease, or ar ter i al bl eedi ng.

Warning!
Adverse reactions to nicotinic acid
Hi gh doses of ni coti ni c aci d may pr oduce vasodi l ati on and
cause fl ushi ng. Extendedr el ease for ms tend to pr oduce l ess
sever e vasodi l ati on than i mmedi ate-r el ease for ms do. To hel p
mi ni mi ze fl ushi ng, admi ni ster aspi r i n 30 mi nutes befor e ni coti ni c
aci d, or gi ve the extendedr el ease for m at ni ght.
Ni coti ni c aci d can cause hepatotoxi ci ty; the r i sk of thi s adver se
r eacti on i s gr eater wi th extended-r el ease for ms.
Other adver se r eacti ons i ncl ude nausea, vomi ti ng, di ar r hea, and
epi gastr i c or subster nal pai n.
Drug interactions
Together, ni coti ni c aci d and an HMG -CoA r eductase i nhi bi tor may
i ncr ease the r i sk of myopathy or r habdomyol ysi s.
Bi l e-sequester i ng dr ugs (chol estyrami ne, col esevel am, and
col esti pol ) can bi nd wi th ni coti ni c aci d and decr ease i ts
effecti veness.
When gi ven wi th ni coti ni c aci d, kava may i ncr ease the r i sk of
hepatotoxi ci ty. (See Adver se r eacti ons to ni coti ni c aci d.)

Cholesterol absorption inhibitors

As the name i mpl i es, cholester ol absor ption inhibitor s i nhi bi t the
absor pti on of chol ester ol and r el ated phytoster ol s fr om the
i ntesti ne. Ezeti mi be i s the dr ug i n thi s cl ass.

Pharmacokinetics
Ezeti mi be i s rapi dl y and extensi vel y absor bed fol l owi ng oral
admi ni strati on. Its i s r eadi l y absor bed and i s hi ghl y bound to
pl asma pr otei ns. Its pr i mar i l y metabol i zed i n the smal l i ntesti ne
and excr eted by the l i ver and ki dneys.

Pharmacodynamics
Ezeti mi be r educes bl ood chol ester ol l evel s by i nhi bi ti ng the
absor pti on of chol ester ol by the smal l i ntesti ne. Thi s l eads to a
decr ease i n del i ver y of i ntesti nal chol ester ol to the l i ver, r educi ng
hepati c chol ester ol stor es and i ncr easi ng cl earance fr om the bl ood.

Pharmacotherapeutics
Ezeti mi be may be admi ni ster ed al one or wi th di etar y changes to
tr eat pr i mar y hyper chol ester ol emi a and homoz ygous si toster ol emi a
(her edi tar y hyperabsor pti on of chol ester ol and pl ant ster ol s). The
dr ug i s al so used i n combi nati on wi th HMG -CoA r eductase i nhi bi tor s
to tr eat pr i mar y hyper chol ester ol emi a and homoz ygous fami l i al
hyper chol ester ol emi a.
Ezeti mi be may al so hel p l ower total chol ester ol and LDL chol ester ol ,
and i ncr ease HDL chol ester ol , when maxi mum-dose HMG -CoA
r eductase i nhi bi tor therapy has been i neffecti ve.

Warning!
Adverse reactions to cholesterol absorption
inhibitors
The most common adver se r eacti ons i ncl ude:

fati gue
abdomi nal pai n and di ar r hea
phar yngi ti s and si nusi ti s
ar thral gi a
back pai n
cough.

When these dr ugs ar e gi ven wi th an HMG -CoA r eductase i nhi bi tor,

the most common adver se r eacti ons ar e chest pai n, di z z i ness,
headache, abdomi nal pai n, di ar r hea, phar yngi ti s, si nusi ti s, upper
r espi rator y tract i nfecti on, ar thral gi a, back pai n, and myal gi a.

Drug interactions
Ezeti mi be admi ni ster ed wi th chol estyrami ne may l ead to
decr eased effecti veness of ezeti mi be.
Ezeti mi be admi ni ster ed wi th cycl ospor i ne, fenofi brate, or
gemfi br oz i l l eads to i ncr eased l evel s of ezeti mi be. (See Adver se
r eacti ons to chol ester ol absor pti on i nhi bi tor s.)

Quick quiz
1Tr eatment wi th fenofi brate, a type of fi br i c aci d
der i vati ve, woul d have to pr oceed cauti ousl y i f the
pati ent i s al so r ecei vi ng whi ch dr ug?
A. Peni ci l l i n
B. Thi az i de di ur eti c
C. Di goxi n
D. Oral anti coagul ant
2A pati ent i s taki ng l ovastati n, an HMG -CoA r eductase i nhi bi tor.
Whi ch parameter shoul d the pati ent moni tor per i odi cal l y?
A. Li ver functi on test r esul ts
B. El ectr ol yte l evel s
C. Vi si on testi ng
D. Coagul ati on studi es

3A pati ent di agnosed wi th hyper tensi on i s most l i kel y to be

pr escr i bed whi ch cl ass of dr ugs fi r st?
A. Angi otensi n II r eceptor bl ocker
B. Beta-adr ener gi c bl ocker
C. Cal ci um channel bl ocker
D. Angi otensi n-conver ti ng enz yme i nhi bi tor

4Ni trates ar e the dr ug of choi ce for r el i evi ng acute angi na.

Ni trates wor k by:
A. pr omoti ng vasodi l ati on, r educi ng pr el oad, and i ncr easi ng
after l oad.
B. pr omoti ng vasodi l ati on, r educi ng pr el oad, and r educi ng
after l oad.
C. pr omoti ng vasodi l ati on, i ncr easi ng pr el oad, and i ncr easi ng
after l oad.
D. pr omoti ng vasodi l ati on, i ncr easi ng pr el oad, and r educi ng
after l oad.

P.
Scoring
If you answer ed al l four i tems cor r ectl y, A+! Your e aces
wi th ACE i nhi bi tor s!

If you answer ed thr ee i tems cor r ectl y, cool !

Car di ovascul ar dr ugs ar ent gi vi ng you compl i cati ons.

If you answer ed fewer than thr ee i tems cor r ectl y, stay

mel l ow. Thi s i s a compl ex chapter, and i t mi ght just take
another go.

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

6
Hematologic drugs

Just the facts

cl asses of dr ugs used to tr eat hematol ogi c di sor der s

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and the hematologic system

The hematol ogi c system i ncl udes pl asma (the l i qui d component of
bl ood) and bl ood cel l s, such as r ed bl ood cel l s (RBCs), whi te bl ood
cel l s, and pl atel ets. Types of dr ugs used to tr eat di sor der s of the
hematol ogi c system i ncl ude:

hemati ni c
anti coagul ant
thr ombol yti c.

Hematinic drugs
Hematinic dr ugs pr ovi de essenti al bui l di ng bl ocks for RBC
pr oducti on. They do so by i ncr easi ng hemogl obi n, the necessar y
el ement for oxygen transpor tati on.

Iron, vitamin B1 2 , folic acid

Thi s secti on di scusses hemati ni c dr ugs used to tr eat mi cr ocyti c and
macr ocyti c anemi ai r on, vi tami n B1 2 , and fol i c aci d.
It al so descr i bes the use of er ythr opoi eti n agents to tr eat
nor mocyti c anemi a.

Iron
Ir on pr eparati ons ar e used to tr eat the most common for m of
anemi ai r on defi ci ency anemi a. Ir on pr eparati ons di scussed i n thi s
secti on i ncl ude fer r ous fumarate, fer r ous gl uconate, fer r ous sul fate,
i r on dextran, and sodi um fer r i c gl uconate compl ex.

Pharmacokinetics (how drugs circulate)

Ir on i s absor bed pr i mar i l y fr om the duodenum and upper jejunum of
the i ntesti ne. Di ffer ent i r on for mul ati ons dont var y i n absor pti on,
but they do var y i n the amount of el emental i r on suppl i ed.

Low iron increases absorption

The amount of i r on absor bed depends par ti al l y on the bodys stor es
of i r on. When body stor es ar e l ow or RBC pr oducti on i s accel erated,
i r on absor pti on may i ncr ease by 20% to 30% . On the other hand,
when total i r on stor es ar e l ar ge, the body absor bs onl y about 5% to
10% of the i r on avai l abl e.
Enter i c-coated pr eparati ons decr ease i r on absor pti on because, i n
that for m, i r on i snt r el eased unti l after i t l eaves the duodenum.
The l ymphati c system absor bs the par enteral for m after I.M.
i njecti ons.

Hemoglobin has it
Ir on i s transpor ted by the bl ood and bound to transfer r i n, i ts car r i er
pl asma pr otei n. About 30% of the i r on i s stor ed pr i mar i l y as
hemosi der i n or fer r i ti n i n the r eti cul oendothel i al cel l s of the l i ver,
spl een, and bone mar r ow. About 66% of the total body i r on i s
contai ned i n hemogl obi n. Excess i r on i s excr eted i n ur i ne, stool ,
sweat, and thr ough i ntesti nal cel l -sl oughi ng. It appear s i n br east
mi l k and cr osses the pl acenta.

Pharmacodynamics (how drugs act)

Al though i r on has other r ol es, i ts most i mpor tant r ol e i s the
pr oducti on of hemogl obi n. About 80% of i r on i n the pl asma goes to
the bone mar r ow, wher e i ts used for er ythr opoi esi s (pr oducti on of
RBCs).

Pharmacotherapeutics (how drugs are used)

Oral i r on therapy i s the pr efer r ed r oute for pr eventi ng or tr eati ng
i r on defi ci ency anemi a. Its used to pr event anemi as i n chi l dr en
ages 6 months to 2 year s because thi s i s a per i od of rapi d gr owth
and devel opment. Pr egnant women may need i r on suppl ements to
r epl ace the i r on used by the devel opi ng fetus.
 Warning!
Adverse reactions to iron therapy
The most common adver se r eacti ons to i r on therapy ar e
gastr i c i r r i tati on and consti pati on. Ir on pr eparati ons al so dar ken
stool , and l i qui d pr eparati ons can stai n the teeth.
The most ser i ous r eacti on i s anaphyl axi s, whi ch may occur after
admi ni strati on of par enteral i r on. To guar d agai nst such a
r eacti on, admi ni ster an i ni ti al test dose befor e gi vi ng a ful l -dose
i nfusi on.

Ironclad options
Par enteral i r on therapy i s used for pati ents who cant absor b oral
pr eparati ons, ar ent compl i ant wi th oral therapy, or have bowel
di sor der s (such as ul cerati ve col i ti s or Cr ohns di sease). Pati ents
wi th end-stage r enal di sease who ar e r ecei vi ng hemodi al ysi s may
al so r ecei ve par enteral i r on therapy at the end of thei r di al ysi s
sessi on. Whi l e par enteral i r on therapy cor r ects the i r on stor e
defi ci ency qui ckl y, i t doesnt cor r ect the anemi a any faster than oral
pr eparati ons woul d.
Ir on pr eparati ons avai l abl e for par enteral admi ni strati on ar e i r on
dextran (gi ven by I.M. i njecti on or sl ow, conti nuous I.V. i nfusi on)
and i r on sucr ose. Ir on sucr ose i s used for pati ents on hemodi al ysi s.
(See Testi ng for par enteral i r on sensi ti vi ty.)

Drug interactions
Ir on absor pti on i s r educed by antaci ds as wel l as by such foods as
coffee, tea, eggs, and mi l k. Other dr ug i nteracti ons i nvol vi ng i r on
i ncl ude:

Absor pti on of tetracycl i nes (demecl ocycl i ne, doxycycl i ne,

mi nocycl i ne, oxytetracycl i ne, and tetracycl i ne), methyl dopa,
qui nol ones (ci pr ofl oxaci n, l evofl oxaci n, l omefl oxaci n,
moxi fl oxaci n, nor fl oxaci n, ofl oxaci n, and spar fl oxaci n),
l evothyr oxi ne, and peni ci l l ami ne may be r educed when taken
wi th oral i r on pr eparati ons.
Chol estyrami ne, ci meti di ne, pr oton-pump i nhi bi tor s, and
col esti pol may r educe i r on absor pti on i n the G I tract. (See
Adver se r eacti ons to i r on therapy.)
 Safe and sound
Testing for parenteral iron sensitivity
Par enteral i r on can cause acute hyper sensi ti vi ty r eacti ons,
i ncl udi ng anaphyl axi s, dyspnea, ur ti car i a, other rashes, pr ur i tus,
ar thral gi a, myal gi a, fever, sweati ng, and al l er gi c pur pura. To test
for dr ug sensi ti vi ty and pr event ser i ous r eacti ons, al ways gi ve a
test dose of i r on dextran befor e begi nni ng therapy.
Car eful l y assess the pati ents r esponse to the test dose. If no
adver se r eacti ons occur wi thi n 1 hour, gi ve the total dose. If
adver se r eacti ons occur, noti fy the pr escr i ber i mmedi atel y. To
tr eat anaphyl axi s, keep epi nephr i ne and standar d emer gency
equi pment r eadi l y avai l abl e.

Vitamin B1 2
Vitamin B1 2 pr eparati ons ar e used to tr eat per ni ci ous anemi a.
Common vi tami n B1 2 pr eparati ons i ncl ude cyanocobal ami n and
hydr oxocobal ami n.

Pharmacokinetics
Vi tami n B1 2 i s avai l abl e i n par enteral , oral , and i ntranasal for ms.
For the body to absor b oral for ms of vi tami n B1 2 , the gastr i c mucosa
must secr ete a substance cal l ed intr insic factor. Peopl e who have a
defi ci ency of i ntr i nsi c factor devel op a speci al type of anemi a known
as vitamin B1 2 -deficiency per nicious anemia.

Parenteral possibilities
When cyanocobal ami n i s i njected by the I.M. or subcutaneous
(subQ) r oute, i ts absor bed and bound to transcobal ami n II for
transpor t to the ti ssues. It then travel s vi a the bl oodstr eam to the
l i ver, wher e 90% of the bodys suppl y of vi tami n B1 2 i s stor ed.
Al though hydr oxocobal ami n i s absor bed mor e sl owl y fr om the
i njecti on si te, i ts uptake i n the l i ver may be gr eater than that of
cyanocobal ami n. Hydr oxocobal ami n i s onl y admi ni ster ed I.M.

Most gets lost

Wi th ei ther dr ug, the l i ver sl owl y r el eases vi tami n B1 2 as needed by
the body. About 3 to 8 mcg of vi tami n B1 2 ar e excr eted i n bi l e each
day and then r eabsor bed i n the i l eum. Its al so secr eted i n br east
mi l k dur i ng l actati on.
Wi thi n 48 hour s after a vi tami n B1 2 i njecti on, 50% to 95% of the
dose i s excr eted unchanged i n ur i ne.

Pharmacodynamics
When vi tami n B1 2 i s admi ni ster ed, i t r epl aces vi tami n B1 2 that the
body woul d nor mal l y absor b fr om the di et. Thi s vi tami n i s essenti al
for cel l gr owth and r epl i cati on and for the mai ntenance of myel i n
(ner ve cover i ngs) thr oughout the ner vous system. Vi tami n B1 2 may
al so be i nvol ved i n l i pi d and car bohydrate metabol i sm.

Pharmacotherapeutics
Cyanocobal ami n and hydr oxocobal ami n ar e used to tr eat per ni ci ous
anemi a, a megal obl asti c anemi a character i zed by decr eased gastr i c
pr oducti on of hydr ochl or i c aci d and i ntr i nsi c factor defi ci ency.
Intr i nsi c factor, a substance nor mal l y secr eted by the par i etal cel l s
of the gastr i c mucosa, i s essenti al for vi tami n B1 2 absor pti on.
Intr i nsi c factor defi ci enci es ar e common i n pati ents who have had
total or par ti al gastr ectomi es or total i l eal r esecti on.

Oral vi tami n B1 2 pr eparati ons ar e used to suppl ement nutr i ti onal

defi ci enci es of the vi tami n. The par enteral and i ntranasal
for mul ati ons ar e used to tr eat pati ents wi th per ni ci ous anemi a.

Warning!
Adverse reactions to vitamin B1 2 therapy
No dose-r el ated adver se r eacti ons occur wi th vi tami n B1 2
therapy. However, some rar e r eacti ons may occur when vi tami n
B 1 2 i s admi ni ster ed par enteral l y.
Parenteral problems
Adver se r eacti ons to par enteral admi ni strati on can i ncl ude
hyper sensi ti vi ty r eacti ons that coul d r esul t i n anaphyl axi s and
death, pul monar y edema, hear t fai l ur e, per i pheral vascul ar
thr ombosi s, pol ycythemi a vera, hypokal emi a, i tchi ng, transi ent
rash, hi ves, and mi l d di ar r hea.

Drug interactions
Al cohol , aspi r i n, neomyci n, chl orampheni col , and col chi ci ne may
decr ease the absor pti on of oral cyanocobal ami n. (See Adver se
r eacti ons to vi tami n B1 2 therapy .)

Folic acid
F olic acid i s gi ven to tr eat megal obl asti c anemi a due to fol i c aci d
defi ci ency. Thi s type of anemi a usual l y occur s i n pati ents who have
tr opi cal or nontr opi cal spr ue, al though i t can al so r esul t fr om poor
nutr i ti onal i ntake dur i ng pr egnancy, i nfancy, or chi l dhood.
Pharmacokinetics
Fol i c aci d i s absor bed rapi dl y i n the fi r st thi r d of the smal l i ntesti ne,
di str i buted i nto al l body ti ssues, and metabol i zed i n the l i ver.
Excess fol ate i s excr eted unchanged i n ur i ne, and smal l amounts of
fol i c aci d ar e excr eted i n stool . Fol i c aci d al so appear s i n br east
mi l k. Syntheti c fol i c aci d i s r eadi l y absor bed, even i n mal absor pti on
syndr omes.

Pharmacodynamics
Fol i c aci d i s an essenti al component for nor mal RBC pr oducti on and
gr owth. A defi ci ency i n fol i c aci d r esul ts i n megal obl asti c anemi a
and l ow ser um and RBC fol ate l evel s.

Pharmacotherapeutics
Fol i c aci d i s used to tr eat fol i c aci d defi ci ency. Pati ents who ar e
pr egnant or under goi ng tr eatment for l i ver di sease, hemol yti c
anemi a, al cohol abuse, or ski n or r enal di sor der s typi cal l y need fol i c
aci d suppl ementati on. Ser um fol i c aci d l evel s bel ow 5 ng/ml i ndi cate
fol i c aci d defi ci ency.
Leucovor i n i s a fol i c aci d der i vati ve used to tr eat fol i c aci d
defi ci enci es r esul ti ng fr om admi ni strati on of methotr exate.

Drug interactions
Methotr exate, sul fasal az i ne, hor monal contracepti ves, aspi r i n,
tr i amter ene, pentami di ne, and tr i methopr i m r educe the
effecti veness of fol i c aci d.
In l ar ge doses, fol i c aci d may counteract the effects of
anti convul sants, such as phenytoi n, potenti al l y l eadi ng to
sei z ur es. (See Adver se r eacti ons to fol i c aci d.)

Warning!
Adverse reactions to folic acid
Adver se r eacti ons to fol i c aci d i ncl ude:

er ythema
i tchi ng
 rash
anor exi a and nausea
al ter ed sl eep patter ns
di ffi cul ty concentrati ng
i r r i tabi l i ty
hyperacti vi ty.

Erythropoietin agents
Epoetin alfa and dar bepoetin alfa ar e gl ycopr otei ns that sti mul ate
RBC pr oducti on (er ythr opoi esi s).

Pharmacokinetics
Epoeti n al fa and dar bepoeti n al fa may be gi ven subQ or I.V. After
subQ admi ni strati on, ser um l evel s of epoeti n al fa peak i n 5 to 24
hour s, whi l e ser um l evel s of dar bepoeti n al fa peak i n 24 to 72
hour s.
The ci r cul ati ng hal f-l i fe of epoeti n al fa i s al so shor ter at 4 to 13
hour s, compar ed to 49 hour s for dar bepoeti n al fa. The therapeuti c
effect of these agents l asts for several days after admi ni strati on.

Pharmacodynamics
Epoeti n al fa and dar bepoeti n al fa boost the pr oducti on of
er ythr opoi eti n, thus sti mul ati ng RBC pr oducti on i n bone mar r ow.
Nor mal l y, er ythr opoi eti n i s for med i n the ki dneys i n r esponse to
hypoxi a (r educed oxygen) and anemi a.
Pati ents wi th condi ti ons that decr ease pr oducti on of er ythr opoi eti n
typi cal l y devel op nor mocyti c anemi a. Thi s anemi a can usual l y be
cor r ected after 5 to 6 weeks of tr eatment wi th an er ythr opoi eti n
agent.

Pharmacotherapeutics
Epoeti n al fa i s used to:

tr eat pati ents wi th anemi a associ ated wi th chr oni c r enal fai l ur e
tr eat anemi a associ ated wi th z i dovudi ne therapy i n pati ents wi th
human i mmunodefi ci ency vi r us i nfecti on
tr eat anemi a i n cancer pati ents r ecei vi ng chemotherapy
r educe the need for al l ogeni c bl ood transfusi ons i n sur gi cal
pati ents.

Dar bepoeti n al fa i s used to tr eat anemi a associ ated wi th chr oni c

r enal fai l ur e.

Drug interactions
No known dr ug i nteracti ons exi st wi th ei ther dr ug, al though they
can cause some adver se r eacti ons. (See Adver se r eacti ons to
er ythr opoi eti n agents.)

Warning!
Adverse reactions to erythropoietin agents
Hyper tensi on i s the most common adver se r eacti on. Other
adver se r eacti ons may i ncl ude:

headache
joi nt pai n
nausea
edema
fati gue
di ar r hea
vomi ti ng
chest pai n
ski n r eacti ons at the i njecti on si te
 weakness
di z z i ness.

Anticoagulant drugs
Anticoagulant dr ugs ar e used to r educe the abi l i ty of the bl ood to
cl ot. Major categor i es of anti coagul ants i ncl ude:

hepar i n and i ts der i vati ves

oral anti coagul ants
anti pl atel et dr ugs
di r ect thr ombi n i nhi bi tor s
factor Xa i nhi bi tor dr ugs.

Heparin
Hepar in, pr epar ed commer ci al l y fr om ani mal ti ssue, i s an anti -
thr ombol yti c agent used to tr eat and pr event cl ot for mati on.
Because i t doesnt affect the synthesi s of cl otti ng factor s, hepar i n
cant di ssol ve al r eady-for med cl ots.

Weighty words
The two types of hepar i n ar e unfracti onated hepar i n (UF H) and l ow-
mol ecul ar-wei ght hepar i n (LMWH). LMWHs, such as dal tepar i n,
enoxapar i n, and ti nz apar i n, wer e devel oped to pr event
deep vei n thr ombosi s (DVT) (a bl ood cl ot i n the deep vei ns, usual l y
of the l egs) i n sur gi cal pati ents.

Pharmacokinetics
Because hepar i n i snt absor bed wel l fr om the G I tract, i t must be
admi ni ster ed par enteral l y. UF H i s admi ni ster ed I.V. by conti nuous
i nfusi on or by subQ i njecti on. LMWHs, because of thei r pr ol onged
ci r cul ati ng hal f-l i fe, can be admi ni ster ed once or twi ce dai l y by
subQ i njecti on.
After I.V. admi ni strati on, the di str i buti on of hepar i n i s i mmedi ate;
however, di str i buti on i snt as pr edi ctabl e fol l owi ng subQ i njecti on.

I.M. is out
Hepar i n i snt gi ven I.M. because of the r i sk of l ocal i zed bl eedi ng.
Hepar i n i s metabol i zed i n the l i ver, and i ts metabol i tes ar e excr eted
i n ur i ne.

Pharmacodynamics
Hepar i n pr events the for mati on of new thr ombi . Her es how i t
wor ks:

Hepar i n i nhi bi ts the for mati on of thr ombi n and fi br i n by

acti vati ng anti thr ombi n III.
Anti thr ombi n III then i nacti vates factor s IXa, Xa, XIa, and XIIa
i n the i ntr i nsi c and common pathways. The end r esul t i s
pr eventi on of a stabl e fi br i n cl ot.
In l ow doses, hepar i n i ncr eases the acti vi ty of anti thr ombi n III
agai nst factor Xa and thr ombi n and i nhi bi ts cl ot for mati on.
Much l ar ger doses ar e necessar y to i nhi bi t fi br i n for mati on after
a cl ot has been for med. Thi s r el ati onshi p between dose and
effect i s the rati onal e for usi ng l ow-dose hepar i n to pr event
cl otti ng.
Whol e bl ood cl otti ng ti me, thr ombi n ti me, and par ti al
thr ombopl asti n ti me (PTT) ar e pr ol onged dur i ng hepar i n therapy.
However, these ti mes may be onl y sl i ghtl y pr ol onged wi th l ow or
ul tra-l ow pr eventi ve doses.
Pharmacotherapeutics
Hepar i n may be used i n a number of cl i ni cal si tuati ons to pr event
the for mati on of new cl ots or the extensi on of exi sti ng cl ots. These
si tuati ons i ncl ude:

pr eventi ng or tr eati ng venous thr omboembol i , character i zed by

i nappr opr i ate or excessi ve i ntravascul ar acti vati on of bl ood
cl otti ng

tr eati ng di ssemi nated i ntravascul ar coagul ati on, a compl i cati on

of other di seases, r esul ti ng i n accel erated cl otti ng
tr eati ng ar ter i al cl otti ng and pr eventi ng embol us for mati on i n
pati ents wi th atr i al fi br i l l ati on, an ar r hythmi a i n whi ch
i neffecti ve atr i al contracti ons cause bl ood to pool i n the atr i a,
i ncr easi ng the r i sk of cl ot for mati on
pr eventi ng thr ombus for mati on and pr omoti ng car di ac ci r cul ati on
i n an acute myocar di al i nfar cti on (MI) by pr eventi ng fur ther cl ot
for mati on at the si te of the al r eady for med cl ot.

Safe and sound

Monitoring PTT in heparin therapy
A pati ent r ecei vi ng unfracti onated hepar i n (UF H) therapy
r equi r es cl ose moni tor i ng of hi s par ti al thr ombopl asti n ti me (PTT).
Dosage adjustments, based on the test r esul ts, ar e typi cal l y
necessar y to ensur e therapeuti c effecti veness wi thout i ncr eased
r i sk of bl eedi ng.
 Low-mol ecul ar-wei ght hepar i n (LMWH) therapy doesnt r equi r e
PTT moni tor i ng. Cur r entl y, no l aborator y test exi sts to assess the
effecti veness of LMWH therapy.
Heparin-induced thrombocytopenia
Pl atel et counts shoul d be moni tor ed i n al l pati ents r ecei vi ng
hepar i n therapy. A pati ent who devel ops hepar i n-i nduced
thr ombocytopeni a (HIT) shoul d be swi tched fr om anti coagul ant
therapy to ar gatr oban, bi val i r udi n, or l epi r udi n. These dr ugs ar e
di r ect thr ombi n i nhi bi tor s i ndi cated for use i n the pati ent who
needs anti coagul ati on therapy but has HIT.

Circulate freely
Hepar i n can be used to pr event cl otti ng whenever the pati ents
bl ood must ci r cul ate outsi de the body thr ough a machi ne, such as
the car di opul monar y bypass machi ne or hemodi al ysi s machi ne, and
dur i ng bl ood transfusi ons. (See Moni tor i ng PTT i n hepar i n therapy.)

Youre the one

Hepar i n i s al so useful for pr eventi ng cl otti ng dur i ng i ntra-abdomi nal
or or thopedi c sur ger y. (These types of sur ger i es, i n many cases,
acti vate the coagul ati on mechani sms excessi vel y.) In fact, hepar i n
i s the dr ug of choi ce for or thopedi c sur ger y.

Warning!
Adverse reactions to heparin
One advantage of hepar i n i s that i t pr oduces r el ati vel y few
adver se r eacti ons. Even so, these r eacti ons can usual l y be
pr evented i f the pati ents par ti al thr ombopl asti n ti me i s
mai ntai ned wi thi n the therapeuti c range.
Bl eedi ng, the most common adver se r eacti on, can be r ever sed
easi l y by admi ni ster i ng pr otami ne sul fate, whi ch bi nds to hepar i n
to for m a stabl e sal t.
Other adver se r eacti ons i ncl ude br ui si ng, hematoma for mati on,
necr osi s of ski n or other ti ssue, and thr ombocytopeni a.
Drug interactions
Because hepar i n acts syner gi sti cal l y wi th al l oral anti coagul ants,
the r i sk of bl eedi ng i ncr eases when the pati ent takes both dr ugs
together. The pr othr ombi n ti me and Inter nati onal Nor mal i zed
Rati o (INR), used to moni tor the effects of oral anti coagul ants,
may al so be pr ol onged.
The r i sk of bl eedi ng i ncr eases when the pati ent takes
nonster oi dal anti -i nfl ammator y dr ugs (NSAIDs), i r on dextran,
ci l ostazol , or an anti pl atel et dr ug, such as aspi r i n, cl opi dogr el ,
ti cl opi di ne, or di pyr i damol e, whi l e r ecei vi ng hepar i n.

Another reason to quit

Dr ugs that antagoni ze or i nacti vate hepar i n i ncl ude
anti hi stami nes, cephal ospor i ns, di goxi n, neomyci n, ni coti ne,
ni tr ogl ycer i n, peni ci l l i ns, phenothi az i nes, qui ni di ne, and
tetracycl i ne.
Ni coti ne may i nacti vate hepar i n; ni tr ogl ycer i n may i nhi bi t the
effects of hepar i n.
Admi ni strati on of pr otami ne sul fate and fr esh fr ozen pl asma
counteract the effects of hepar i n. (See Adver se r eacti ons to
hepar i n.)
Oral anticoagulants
The major or al anticoagulant used i n the Uni ted States i s the
coumar i n compound war far i n.

Pharmacokinetics
War far i n i s absor bed rapi dl y and al most compl etel y when i ts taken
oral l y. It bi nds extensi vel y to pl asma al bumi n and i s metabol i zed i n
the l i ver and excr eted i n ur i ne. Al though war far i n i s absor bed
qui ckl y, i ts effects dont occur for about 48 hour s, wi th the ful l
effect taki ng 3 to 4 days.
Because war far i n i s hi ghl y pl asma-pr otei n-bound and i s metabol i zed
by the l i ver, admi ni strati on of war far i n wi th other medi cati ons may
al ter the amount of war far i n i n the body. Thi s may i ncr ease the r i sk
of bl eedi ng or cl otti ng, dependi ng upon the medi cati ons
admi ni ster ed.

Pharmacodynamics
Oral anti coagul ants al ter the abi l i ty of the l i ver to synthesi ze
vi tami n Kdependent cl otti ng factor s, i ncl udi ng pr othr ombi n and
factor s VII, IX, and X. However, cl otti ng factor s al r eady i n the
bl oodstr eam conti nue to coagul ate bl ood unti l they become
depl eted, so anti coagul ati on doesnt begi n i mmedi atel y. (See
Moni tor i ng war far i n l evel s.)
Pharmacotherapeutics
Oral anti coagul ants ar e pr escr i bed to tr eat or pr event
thr omboembol i sm. Pati ents wi th thi s di sor der begi n taki ng the
medi cati on whi l e sti l l r ecei vi ng hepar i n. However, outpati ents at
hi gh r i sk for thr omboembol i sm may begi n oral anti coagul ants
wi thout fi r st r ecei vi ng hepar i n.

Deep in the veins

Oral anti coagul ants ar e al so the dr ugs of choi ce to pr event DVT and
for pati ents wi th pr ostheti c hear t val ves or di seased mi tral val ves.
To decr ease the r i sk of ar ter i al cl otti ng, oral anti coagul ants ar e
someti mes combi ned wi th an anti pl atel et dr ug, such as aspi r i n,
cl opi dogr el , or di pyr i damol e.

Monitoring warfarin levels

Pati ents taki ng war far i n need cl ose moni tor i ng of pr othr ombi n
ti me and Inter nati onal Nor mal i zed Rati os to make sur e they ar e
mai ntai ni ng therapeuti c l evel s of the dr ug. If l aborator y r esul ts
fal l outsi de the accepted range, war far i n dosage shoul d be
adjusted.

Drug interactions
Many pati ents who take oral anti coagul ants al so r ecei ve other
dr ugs, pl aci ng them at r i sk for ser i ous dr ug i nteracti ons.

Many dr ugs, such as hi ghl y pr otei n-bound medi cati ons, i ncr ease
the effects of war far i n, r esul ti ng i n an i ncr eased r i sk of
bl eedi ng. Exampl es i ncl ude acetami nophen, al l opur i nol ,
ami odar one, cephal ospor i ns, ci meti di ne, ci pr ofl oxaci n, cl ofi brate,
danazol , di azoxi de, di sul fi ram, er ythr omyci n, fl uor oqui nol ones,
gl ucagon, hepar i n, i bupr ofen, i soni az i d, ketopr ofen,
methyl thi ouraci l , metr oni dazol e, mi conazol e, neomyci n,
pr opafenone, pr opyl thi ouraci l ,

qui ni di ne, str eptoki nase, sul fonami des, tamoxi fen, tetracycl i nes,
thi az i des, thyr oi d dr ugs, tr i cycl i c anti depr essants, ur oki nase,
and vi tami n E.
Dr ugs metabol i zed by the l i ver may i ncr ease or decr ease the
effecti veness of war far i n. Exampl es i ncl ude bar bi turates,
 car bamazepi ne, cor ti coster oi ds, cor ti cotr opi n, mer captopur i ne,
nafci l l i n, hor monal contracepti ves contai ni ng estr ogen, r i fampi n,
spi r onol actone, sucral fate, and trazodone.
The r i sk of phenytoi n toxi ci ty i ncr eases when phenytoi n i s taken
wi th war far i n, and phenytoi n may i ncr ease or decr ease the
effects of war far i n.

Other i nteracti ons i ncl ude the fol l owi ng:

A di et hi gh i n vi tami n K r educes the effecti veness of war far i n.

Chr oni c al cohol abuse i ncr eases the pati ents r i sk of cl otti ng
whi l e taki ng war far i n. Acute al cohol i ntoxi cati on i ncr eases the
r i sk of bl eedi ng.
Vi tami n K and fr esh fr ozen pl asma r educe the effects of
war far i n. (See Adver se r eacti ons to oral anti coagul ants.)

Warning!
Adverse reactions to oral anticoagulants
The pr i mar y adver se r eacti on to oral anti coagul ant therapy
i s mi nor bl eedi ng. Sever e bl eedi ng can occur, however, wi th the
most common si te bei ng the G I tract. Bl eedi ng i nto the brai n may
be fatal . Br ui ses and hematomas may for m at ar ter i al punctur e
si tes (for exampl e, after a bl ood gas sampl e i s drawn). Necr osi s or
gangr ene of the ski n and other ti ssues can occur.
Quick fix
The effects of oral anti coagul ants can be r ever sed wi th
phytonadi one (vi tami n K1 ).

Antiplatelet drugs
Antiplatelet dr ugs ar e used to pr event ar ter i al thr omboembol i sm,
par ti cul ar l y i n pati ents at r i sk for MI, str oke, and ar ter i oscl er osi s
(har deni ng of the ar ter i es).
Aspi r i n, cl opi dogr el , di pyr i damol e, sul fi npyrazone, and ti cl opi di ne
ar e exampl es of oral anti pl atel et dr ugs. Anti pl atel et dr ugs
admi ni ster ed I.V. i ncl ude abci xi mab, epti fi bati de, and ti r ofi ban.

Pharmacokinetics
When taken oral l y, anti pl atel et dr ugs ar e absor bed ver y qui ckl y and
r each peak concentrati on i n 1 to 2 hour s. Aspi r i n mai ntai ns i ts
anti pl atel et effect for about 10 days, or as l ong as pl atel ets
nor mal l y sur vi ve. The effects of cl opi dogr el l ast about 5 days.
Sul fi npyrazone may r equi r e several days of admi ni strati on befor e i ts
anti pl atel et effects occur.
After I.V. admi ni strati on, anti pl atel et dr ugs ar e qui ckl y di str i buted
thr oughout the body. Theyr e mi ni mal l y metabol i zed and excr eted
unchanged i n ur i ne. The effects of these dr ugs occur wi thi n 15 to 20
mi nutes of admi ni strati on and l ast about 6 to 8 hour s.
El der l y pati ents and pati ents wi th r enal fai l ur e may have decr eased
cl earance of anti pl atel et dr ugs, whi ch woul d pr ol ong the anti pl atel et
effect.

Pharmacodynamics
Anti pl atel et dr ugs i nter fer e wi th pl atel et acti vi ty i n di ffer ent dr ug-
speci fi c and dose-r el ated ways.

Low doses of aspi r i n i nhi bi t cl ot for mati on by bl ocki ng the

synthesi s of pr ostagl andi n, whi ch i n tur n pr events for mati on of
the pl atel et-aggr egati ng substance thr omboxane A2 .
Cl opi dogr el i nhi bi ts pl atel et aggr egati on by i nhi bi ti ng pl atel et-
fi br i nogen bi ndi ng.
I.V. anti pl atel et dr ugs i nhi bi t the gl ycopr otei n IIa-IIIb r eceptor,
whi ch i s the major r eceptor i nvol ved i n pl atel et aggr egati on.
Di pyr i damol e may i nhi bi t pl atel et aggr egati on because i t
i ncr eases adenosi ne, a cor onar y vasodi l ator and pl atel et
aggr egati on i nhi bi tor.
Ti cl opi di ne i nhi bi ts the bi ndi ng of fi br i nogen to pl atel ets dur i ng
the fi r st stage of the cl otti ng cascade.
Sul fi npyrazone i nhi bi ts several pl atel et functi ons. It l engthens
pl atel et sur vi val and pr ol ongs the patency of ar ter i ovenous
shunts used for hemodi al ysi s. A si ngl e dose rapi dl y i nhi bi ts
pl atel et aggr egati on.
Pharmacotherapeutics
Anti pl atel et dr ugs have many di ffer ent uses.

Managing MIs
Aspi r i n i s used i n pati ents who have had a pr evi ous MI or who have
unstabl e angi na to r educe the r i sk of death i n pati ents at hi gh r i sk
for CAD. Its al so pr escr i bed to r educe the r i sk of transi ent i schemi c
attacks (TIAs) (temporar y r educti on i n ci r cul ati on to the brai n).
Cl opi dogr el i s used to r educe the r i sk of str oke or vascul ar death i n
pati ents wi th a hi stor y of a r ecent MI, str oke, or establ i shed
per i pheral ar ter y di sease. Cl opi dogr el i s al so used to hel p tr eat
acute cor onar y syndr omes, especi al l y i n pati ents under goi ng
per cutaneous transl umi nal cor onar y angi opl asty (PTCA) or cor onar y
ar ter y bypass graft.
Epti fi bati de may be used for pati ents wi th acute cor onar y syndr ome
and for those under goi ng per cutaneous cor onar y i nter venti on (PCI).
Abci xi mab may al so be used i n combi nati on wi th PCI. Ti r ofi ban may
be used to tr eat acute cor onar y syndr ome.

Salve for surgery

Di pyr i damol e i s used wi th a coumar i n compound to pr event
thr ombus for mati on after car di ac val ve r epl acement. Di pyr i damol e
may be admi ni ster ed wi th aspi r i n to pr event bl ood cl ots i n

pati ents who have had cor onar y ar ter y bypass grafts (bypass
sur ger y) or pr ostheti c (ar ti fi ci al ) hear t val ves.
 Warning!
Adverse reactions to antiplatelet drugs
Hyper sensi ti vi ty r eacti ons, par ti cul ar l y anaphyl axi s, can
occur. Bl eedi ng i s the most common adver se r eacti on when I.V.
anti pl atel et dr ugs ar e admi ni ster ed.
Aspirin

Stomach pai n
Hear tbur n, nausea
Consti pati on
Bl ood i n stool
Sl i ght gastr i c bl ood l oss

Clopidogrel

Headache
Ski n ul cerati on
Joi nt pai n
F l ul i ke symptoms
Upper r espi rator y tract i nfecti on

Sulfinpyrazone

Abdomi nal di scomfor t

Ticlopidine

Di ar r hea
Nausea
Dyspepsi a
Rash
El evated l i ver functi on test r esul ts
Neutr openi a

Dipyridamole

Headache
Di z z i ness
 Nausea
F l ushi ng
Weakness
Fai nti ng
Mi l d G I di str ess

Circumventing stroke
Ti cl opi di ne i s used to r educe the r i sk of thr omboti c str oke i n hi gh-
r i sk pati ents, such as those wi th a hi stor y of fr equent TIAs or a
pr evi ous thr omboti c str oke.

Drug interactions
Anti pl atel et medi cati ons taken wi th NSAIDs, hepar i n, oral
anti coagul ants, or another anti pl atel et medi cati on i ncr ease the
r i sk of bl eedi ng.
Sul fi npyrazone taken wi th aspi r i n and oral anti coagul ants
i ncr eases the r i sk of bl eedi ng.

Tales of toxicity
Aspi r i n i ncr eases the r i sk of toxi ci ty of methotr exate and
val pr oi c aci d.
Aspi r i n and ti cl opi di ne may r educe the effecti veness of
sul fi npyrazone to r el i eve si gns and symptoms of gout.
Antaci ds may r educe the pl asma l evel s of ti cl opi di ne.

Ci meti di ne i ncr eases the r i sk of ti cl opi di ne toxi ci ty and bl eedi ng.

You just dont know

Because gui del i nes havent been establ i shed for admi ni strati ng
ti cl opi di ne wi th hepar i n, oral anti coagul ants, aspi r i n, or fi br i nol yti c
dr ugs, these dr ugs shoul d be di sconti nued befor e ti cl opi di ne therapy
begi ns. (See Adver se r eacti ons to anti pl atel et dr ugs.)
Direct thrombin inhibitors
Thr ombi n i nhi bi tor s, i ncl udi ng ar gatr oban, bi val i r udi n, and
l epi r udi n, hel p pr event the for mati on of bl ood cl ots.

Pharmacokinetics
Di r ect thr ombi n i nhi bi tor s ar e typi cal l y admi ni ster ed by conti nuous
I.V. i nfusi on. They may al so be gi ven as an i ntra-cor onar y bol us
dur i ng car di ac catheter i z ati on. In that case, the dr ug begi ns acti ng
i n 2 mi nutes, wi th a peak r esponse of 15 mi nutes and a durati on of
2 hour s. After subQ i njecti on, pl asma l evel s peak i n 2 hour s; after
I.V. admi ni strati on, l evel s peak i n l ess than 1 hour.
Effects on PTT become appar ent wi thi n 4 to 5 hour s of
admi ni strati on. In pati ents wi th hepar i n-i nduced thr ombocytopeni a,
pl atel et count r ecover y becomes appar ent wi thi n 3 days.
Ar gatr oban i s metabol i zed by the l i ver and excr eted pr i mar i l y i n
stool . Bi val i r udi n and l epi r udi n ar e metabol i zed by the l i ver and
ki dneys and excr eted i n ur i ne

Pharmacodynamics
Di r ect thr ombi n i nhi bi tor s i nter fer e wi th bl ood cl otti ng by di r ectl y
bl ocki ng al l thr ombi n acti vi ty. These dr ugs offer several advantages
over hepar i n: di r ect thr ombi n i nhi bi tor s act agai nst sol ubl e as wel l
as cl ot-bound thr ombi n (thr ombi n i n cl ots that have al r eady
for med); thei r anti coagul ant effects ar e mor e pr edi ctabl e than those
of hepar i n; and thei r acti ons ar ent i nhi bi ted by the pl atel et r el ease
r eacti on.
The bi ndi ng of the dr ug to thr ombi n i s r ever si bl e.

Pharmacotherapeutics
Admi ni ster ed by I.V. i nfusi on, ar gatr oban and l epi r udi n ar e used to
tr eat hepar i n-i nduced thr ombocytopeni a (HIT). Ar gatr oban may al so
be gi ven wi th aspi r i n to pati ents wi th HIT who ar e under goi ng a
car di ac pr ocedur e, such as PTCA, cor onar y stent pl acement, or
ather ectomy.

Bi val i r udi n has been appr oved for use i n pati ents wi th unstabl e
angi na under goi ng PTCA, and shoul d be used i n conjuncti on wi th
aspi r i n therapy.
Pati ents wi th l i ver dysfuncti on may r equi r e a r educed dose of
ar gatr oban. Al so, the dosage of bi val i r udi n and l epi r udi n may need
to be r educed i n pati ents wi th i mpai r ed r enal functi on.
Use cauti on when admi ni ster i ng a di r ect thr ombi n i nhi bi tor to a
pati ent who has an i ncr eased r i sk of bl eedi ng. Pati ents at gr eatest
r i sk for hemor r hage ar e those wi th sever e hyper tensi on, gastr i c
ul cer s, or hematol ogi c di sor der s associ ated wi th i ncr eased bl eedi ng.
Pati ents r ecei vi ng spi nal anesthesi a or those under goi ng a l umbar
punctur e or havi ng major sur ger y (especi al l y sur ger y of the brai n,
spi nal cor d, or the eye) al so have an i ncr eased r i sk for bl eedi ng.

Drug interactions
Hemor r hage can occur as an adver se r eacti on to di r ect thr ombi n
i nhi bi tor s, so avoi d gi vi ng these dr ugs wi th another dr ug that
may al so i ncr ease the r i sk of bl eedi ng.
Di sconti nue al l par enteral anti coagul ants befor e admi ni ster i ng
ar gatr oban.
Admi ni strati on of ar gatr oban al ong wi th war far i n i ncr eases the
INR.
If the pati ent has r ecei ved hepar i n, al l ow ti me for hepar i ns
effect on PTT to decr ease befor e admi ni ster i ng ar gatr oban. (See
Adver se r eacti ons to bi val i r udi n.)

Warning!
Adverse reactions to bivalirudin
The major adver se r eacti on to bi val i r udi n i s bl eedi ng; major
hemor r hage occur s i nfr equentl y. Other adver se r eacti ons i ncl ude:

i ntracrani al hemor r hage

r etr oper i toneal hemor r hage
nausea, vomi ti ng, abdomi nal cramps, and di ar r hea
headache
hematoma at I.V. i nfusi on si te.

Factor Xa inhibitor drugs

Factor Xa i nhi bi tor dr ugs ar e used to pr event DVT i n pati ents
under goi ng total hi p and knee r epl acement sur ger y or sur ger y to
r epai r a hi p fractur e. The onl y factor Xa i nhi bi tor dr ug used i n the
Uni ted States i s fondapar i nux.

Pharmacokinetics
Admi ni ster ed subQ, fondapar i nux i s absor bed rapi dl y and compl etel y
and i s excr eted pr i mar i l y unchanged i n ur i ne. Its effects peak wi thi n
2 hour s of admi ni strati on and l ast for about 17 to 24 hour s.

Pharmacodynamics
Fondapar i nux bi nds to anti thr ombi n III and gr eatl y i nfl uences the
neutral i z ati on of factor Xa by anti thr ombi n III. Neutral i z ati on of

factor Xa i nter r upts the coagul ati on cascade, ther eby i nhi bi ti ng cl ot
for mati on.

Pharmacotherapeutics
Fondapar i nux i s used onl y to pr event the for mati on of bl ood cl ots.

Drug interactions
Avoi d admi ni ster i ng fondapar i nux wi th another dr ug that may
i ncr ease the r i sk of bl eedi ng. (See Adver se r eacti ons to factor Xa
i nhi bi tor s.)

Warning!
Adverse reactions to factor Xa inhibitors
Adver se r eacti ons that can occur wi th factor Xa i nhi bi tor
therapy i ncl ude:

bl eedi ng
nausea
anemi a
fever
rash
consti pati on
edema.
Thrombolytic drugs
Thr ombolytic dr ugs ar e used to di ssol ve a pr eexi sti ng cl ot or
thr ombus, often i n an acute or emer gency si tuati on. Some of the
thr ombol yti c dr ugs cur r entl y used i ncl ude al tepl ase, r etepl ase,
str eptoki nase, tenectepl ase, and ur oki nase.

Pharmacokinetics
After I.V. or i ntracor onar y admi ni strati on, thr ombol yti c dr ugs ar e
di str i buted i mmedi atel y thr oughout the ci r cul ati on, qui ckl y
acti vati ng pl asmi nogen (a pr ecur sor to pl asmi n, whi ch di ssol ves
fi br i n cl ots).

Blood work
Al tepl ase, r etepl ase, tenectepl ase, and ur oki nase ar e cl ear ed rap-
i dl y fr om ci r cul ati ng pl asma, pr i mar i l y by the l i ver. Str eptoki nase i s
r emoved rapi dl y fr om the ci r cul ati on by anti bodi es and the
r eti cul oendothel i al system (a body system i nvol ved i n defendi ng
agai nst i nfecti on and di sposi ng of pr oducts of cel l br eakdown).
These agents dont appear to cr oss the pl acental bar r i er.

Pharmacodynamics
Thr ombol yti c dr ugs conver t pl asmi nogen to pl asmi n, whi ch l yses
(di ssol ves) thr ombi , fi br i nogen, and other pl asma pr otei ns. (See
How al tepl ase hel ps r estor e ci r cul ati on, page 172.)
Pharmacotherapeutics
Thr ombol yti c dr ugs have a number of uses. Theyr e used to tr eat
cer tai n thr omboembol i c di sor der s (such as acute MI, acute i schemi c
str oke, and per i pheral ar ter y occl usi on) and have al so

been used to di ssol ve thr ombi i n ar ter i ovenous cannul as (used i n

di al ysi s) and I.V. catheter s to r eestabl i sh bl ood fl ow.

Now I get it!

How alteplase helps restore circulation
When a thr ombus for ms i n an ar ter y, i t obstr ucts the bl ood
suppl y, causi ng i schemi a and necr osi s. Al tepl ase can di ssol ve a
thr ombus i n ei ther the cor onar y or pul monar y ar ter y, r estor i ng
the bl ood suppl y to the ar ea beyond the bl ockage.
Obstructed artery
A thr ombus bl ocks bl ood fl ow thr ough the ar ter y, causi ng di stal
i schemi a.
Inside the thrombus
Al tepl ase enter s the thr ombus, whi ch consi sts of pl asmi nogen
bound to fi br i n. Al tepl ase bi nds to the fi br i n-pl asmi nogen
compl ex, conver ti ng the i nacti ve pl asmi nogen i nto acti ve pl asmi n.
Thi s acti ve pl asmi n di gests the fi br i n, di ssol vi ng the thr ombus. As
the thr ombus di ssol ves, bl ood fl ow r esumes.
The sooner the better
Thr ombol yti c dr ugs ar e the dr ugs of choi ce to br eak down newl y
for med thr ombi . They seem most effecti ve when admi ni ster ed wi thi n
6 hour s of the symptoms onset.

Acute MI and others

In addi ti on, each dr ug has speci fi c uses.

Al tepl ase i s used to tr eat acute MI, pul monar y embol i sm, acute
i schemi c str oke, per i pheral ar ter y occl usi on, and to r estor e
patency to cl otted grafts and I.V. access devi ces.
Str eptoki nase i s used to tr eat acute MI, pul monar y embol us, and
DVT.
Retepl ase and tenectepl ase ar e used to tr eat acute MI.
Ur oki nase i s used to tr eat pul monar y embol i sm and cor onar y
ar ter y thr ombosi s and for catheter cl earance.
Drug interactions
Thr ombol yti c dr ugs i nteract wi th hepar i n, oral anti coagul ants,
anti pl atel et dr ugs, and NSAIDs to i ncr ease the pati ents r i sk of
bl eedi ng.
Ami nocapr oi c aci d i nhi bi ts str eptoki nase and can be used to
r ever se i ts fi br i nol yti c effects. (See Adver se r eacti ons to
thr ombol yti c dr ugs.)

Warning!
Adverse reactions to thrombolytic drugs
The major r eacti ons associ ated wi th thr ombol yti c dr ugs ar e
bl eedi ng and al l er gi c r esponses, especi al l y wi th str eptoki nase.

Quick quiz
1A pati ent i s gi ven hepar i n to tr eat thr ombophl ebi ti s. If
the pati ent star ts to bl eed excessi vel y dur i ng hepar i n
therapy, whi ch dr ug i s l i kel y to be pr escr i bed to r ever se
i ts effects?
A. Vi tami n K
B. Factor VIII
C. Ar gatr oban
D. Pr otami ne sul fate

2Why i s hepar i n admi ni ster ed concur r entl y wi th war far i n?

A. War far i ns therapeuti c effects dont occur unti l cl otti ng
factor s ar e depl eted.
B. Hepar i n acti vates war far i n.
C. War far i n and hepar i n have a syner gi sti c effect.
D. Hepar i n hel ps the body absor b war far i n.

P.
3How soon after cyanocobal ami n (vi tami n B1 2 ) therapy i s begun
can a pati ent expect to feel better ?
A. 24 hour s
B. 72 hour s
C. 1 week
 D. 2 weeks

Scoring
If you answer ed al l thr ee i tems cor r ectl y, far out! Your e
hi p to hematol ogi c dr ugs.

If you answer ed two i tems cor r ectl y, thats gr eat! Youve

caught the wave of anti coagul ants.

If you answer ed fewer than two i tems cor r ectl y, pl ay i t

cool . You just mi ght need some ti me to get the bl ood
fl owi ng.

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

7
Respiratory drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs used to tr eat r espi rator y di sor der s

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and the respiratory system

The r espi rator y system, extendi ng fr om the nose to the pul monar y
capi l l ar i es, per for ms the essenti al functi on of gas exchange between
the body and i ts envi r onment. In other wor ds, i t takes i n oxygen
and expel s car bon di oxi de.

Breathe easy
Dr ugs used to i mpr ove r espi rator y symptoms ar e avai l abl e i n
i nhal ati on and systemi c for mul ati ons. These dr ugs i ncl ude:

beta 2 -adr ener gi c agoni sts

anti chol i ner gi cs
cor ti coster oi ds
 l eukotr i ene modi fi er s
mast cel l stabi l i zer s
methyl xanthi nes
monocl onal anti bodi es
expectorants
anti tussi ves
mucol yti cs
decongestants.

Beta 2 -adrenergic agonists

Beta 2 -adr ener gic agonists ar e used to tr eat symptoms associ ated
wi th asthma and chr oni c obstr ucti ve pul monar y di sease (COPD).
Dr ugs i n thi s cl ass can be ei ther shor t-acti ng or l ong-acti ng.

Short-acting beta2 -adrenergic agonists

Shor t-acti ng beta2 -adr ener gi c agoni sts i ncl ude:

al buter ol (systemi c, i nhal ati on)

l eval buter ol (i nhal ati on)
metapr oter enol (i nhal ati on)
 pi r buter ol (i nhal ati on)
ter butal i ne (systemi c).

Long-acting beta2 -adrenergic agonists

Long-acti ng beta2 -adr ener gi c agoni sts i ncl ude:

for moter ol (i nhal ati on)

sal meter ol (i nhal ati on).

Pharmacokinetics (how drugs circulate)

Beta 2 -adr ener gi c agoni sts ar e mi ni mal l y absor bed fr om the G I tract;
i nhal ed for ms exer t thei r effects l ocal l y. After i nhal ati on, beta2 -
adr ener gi c agoni sts appear to be absor bed over several hour s fr om
the r espi rator y tract. These dr ugs dont cr oss the bl ood-brai n
bar r i er ; theyr e extensi vel y metabol i zed i n the l i ver to i nacti ve
compounds and rapi dl y excr eted i n ur i ne and stool .

Pharmacodynamics (how drugs act)

Beta 2 -adr ener gi c agoni sts i ncr ease l evel s of cycl i c adenosi ne
monophosphate by sti mul ati ng the beta2 -adr ener gi c r eceptor s i n the
smooth muscl e, r esul ti ng i n br onchodi l ati on. These dr ugs may l ose
thei r sel ecti vi ty at hi gher doses, whi ch can i ncr ease the r i sk of
toxi ci ty. Inhal ed for ms ar e pr efer r ed because they act l ocal l y i n the
l ungs, r esul ti ng i n fewer adver se r eacti ons than systemi cal l y
absor bed for ms.
Pharmacotherapeutics (how drugs are used)
Shor t-acti ng i nhal ed beta2 -adr ener gi c agoni sts ar e the dr ugs of
choi ce for fast r el i ef of symptoms i n the pati ent wi th asthma.
Theyr e general l y used as needed for asthma (i ncl udi ng exer ci se-
i nduced asthma) and COPD. A pati ent wi th COPD may use them
ar ound-the-cl ock on a speci fi ed schedul e. However, excessi ve use of
a shor t-acti ng beta2 -adr ener gi c

agoni st may i ndi cate poor asthma contr ol , r equi r i ng r eassessment of

the pati ents therapeuti c r egi men.

Safe and sound

Problems with long-acting beta2 -adrenergic
agonists
If a pati ent i s taki ng a l ong-acti ng beta2 -adr ener gi c agoni st, make
sur e that hes usi ng i t onl y as par t of a combi nati on therapy wi th
other medi cati ons such as i nhal ed cor ti coster oi ds. Pati ents who
use l ong-acti ng beta2 -adr ener gi c agoni sts as thei r onl y means of
asthma contr ol ar e at ser i ous r i sk for adver se effects, i ncl udi ng
death.

A good combination
Long-acti ng beta2 -adr ener gi c agoni sts tend to be used wi th
anti i nfl ammator y agents, namel y i nhal ed cor ti coster oi ds, to hel p
contr ol asthma. (See Pr obl ems wi th l ong-acti ng beta2 -adr ener gi c
agoni sts.) Theyr e especi al l y useful for the pati ent wi th noctur nal
asthmati c symptoms. These dr ugs must be admi ni ster ed on a
schedul e. They ar ent used to r el i eve acute symptoms because thei r
onset of acti on i snt fast enough. They al so dont affect the chr oni c
i nfl ammati on associ ated wi th asthma.

Drug interactions
Interacti ons ar e uncommon when usi ng the i nhal ed for ms. Beta-
adr ener gi c bl ocker s decr ease the br onchodi l ati ng effects of beta2 -
adr ener gi c agoni sts. They shoul d be used together cauti ousl y. (See
Adver se r eacti ons to beta2 -adr ener gi c agoni sts.)
 Warning!
Adverse reactions to beta2 -adrenergic agonists
Adver se r eacti ons to shor t-acti ng beta2 -adr ener gi c agoni sts
i ncl ude:

paradoxi cal br onchospasm

tachycar di a
pal pi tati ons
tr emor s
dr y mouth.

Adver se r eacti ons to l ong-acti ng beta2 -adr ener gi c agoni sts

i ncl ude:

br onchospasm
tachycar di a
pal pi tati ons
hyper tensi on
tr emor s.

Anticholinergics
Inhal ed i pratr opi um, an anticholiner gic, i s a br onchodi l ator used
pr i mar i l y i n the pati ent suffer i ng fr om COPD, but i t may al so be
used as an adjunct to beta2 -adr ener gi c agoni sts.

Ipratropium
Ipr atr opium i s the most common anti chol i ner gi c used for r espi rator y
di sor der s.

Pharmacokinetics
Anti chol i ner gi cs ar e mi ni mal l y absor bed fr om the G I tract; they
come i n i nhal ed for ms that exer t thei r effects l ocal l y.

Pharmacodynamics
Ipratr opi um i nhi bi ts muscar i ni c r eceptor s, whi ch r esul ts i n
br onchodi l ati on. Thi s dr ug wor ks by bl ocki ng the parasympatheti c
ner vous system, rather than sti mul ati ng the sympatheti c ner vous
system.

Pharmacotherapeutics
Anti chol i ner gi cs ar e used to r el i eve symptoms i n the pati ent wi th
COPD. Theyr e l ess effecti ve i n l ong-ter m management of the
pati ent wi th asthma; however, they may be used as adjuncti ve
therapy (usual l y i n combi nati on wi th a shor t-acti ng beta2 -
adr ener gi c agoni st on a schedul ed basi s).

Drug interactions
Interacti ons ar e uncommon when usi ng the i nhal ed for ms.
Ipratr opi um shoul d be used cauti ousl y wi th anti muscar i ni c dr ugs
and other anti chol i ner gi cs. (See Adver se r eacti ons to
anti chol i ner gi cs.)

Warning!
Adverse reactions to anticholinergics
The most common adver se r eacti ons to anti chol i ner gi cs
i ncl ude:

ner vousness
tachycar di a
nausea and vomi ti ng
paradoxi cal br onchospasm (wi th excessi ve use)
dr y mouth.

Corticosteroids
Cor ticoster oids ar e anti -i nfl ammator y dr ugs avai l abl e i n i nhal ed and
systemi c for ms for the shor t- and l ong-ter m contr ol of asthma
symptoms. Many pr oducts wi th di ffer i ng potenci es ar e avai l abl e.
Inhal ed cor ti coster oi ds i ncl ude:

becl omethasone di pr opi onate

budesoni de
 fl uni sol i de
fl uti casone
tr i amci nol one acetoni de.

Oral cor ti coster oi ds i ncl ude:

pr edni sol one

pr edni sone.

I.V. cor ti coster oi ds i ncl ude:

hydr ocor ti sone sodi um succi nate

methyl pr edni sol one sodi um succi nate.

Safe and sound

Corticosteroids
These speci al popul ati ons may r equi r e speci al car e when
taki ng cor ti coster oi ds:

Childr en: G r owth shoul d be moni tor ed, especi al l y when theyr e
taki ng systemi c dr ugs or hi gher doses of i nhal ed dr ugs.
Elder ly patients: May benefi t fr om r ecei vi ng dr ugs that pr event
osteopor osi s, such as al endr onate dur i ng therapy wi th
cor ti coster oi ds, especi al l y i f theyr e taki ng hi gher doses of
i nhal ed or systemi c ster oi ds.

Patients with diabetes: May r equi r e cl oser moni tor i ng of thei r

bl ood gl ucose l evel s whi l e on ster oi ds.
Br east-feeding women: Cor ti coster oi d l evel s ar e negl i gi bl e i n
the br east mi l k of mother s who take l ess than 20 mg/day of
oral pr edni sone. The amount found i n br east mi l k can be
mi ni mi zed i f the woman wai ts at l east 4 hour s after taki ng
pr edni sone to br east-feed her i nfant.

Pharmacokinetics
Oral pr edni sone i s r eadi l y absor bed and extensi vel y metabol i zed i n
the l i ver to the acti ve metabol i te pr edni sol one. The I.V. for m has a
rapi d onset. Inhal ed dr ugs ar e mi ni mal l y absor bed, al though
absor pti on i ncr eases as the dosage i s i ncr eased.

Pharmacodynamics
Cor ti coster oi ds wor k by i nhi bi ti ng the pr oducti on of cytoki nes,
l eukotr i enes, and pr ostagl andi ns; the r ecr ui tment of eosi nophi l s;
and the r el ease of other i nfl ammator y medi ator s. They al so affect
other ar eas i n the body, whi ch can cause l ong-ter m adver se
r eacti ons. (See Cor ti coster oi ds.)

Pharmacotherapeutics
Cor ti coster oi ds ar e the most effecti ve dr ugs avai l abl e for the l ong-
ter m tr eatment and pr eventi on of acute asthma attacks.

Inhalation for prevention

Inhal ed cor ti coster oi ds ar e the pr efer r ed dr ugs for pr eventi ng futur e
attacks i n the pati ent wi th mi l d to sever e asthma. Use of i nhal ed
cor ti coster oi ds r educes the need for systemi c ster oi ds i n many
cases, thus r educi ng the pati ents r i sk of devel opi ng ser i ous l ong-
ter m adver se r eacti ons.

Systemic for the serious

Systemi c for ms ar e usual l y r eser ved for moderate to sever e attacks,
but theyr e al so used i n the pati ent wi th mi l der asthma that

fai l s to r espond to other measur es. Systemi c cor ti coster oi ds shoul d

be used at the l owest effecti ve dosage and for the shor test per i od
possi bl e to avoi d adver se r eacti ons.

Drug interactions
Interacti ons ar e uncommon when usi ng i nhal ed for ms.

Hor monal contracepti ves, ketoconazol e, and macr ol i de

anti bi oti cs may i ncr ease the acti vi ty of cor ti coster oi ds i n
general , r esul ti ng i n the need to decr ease the ster oi d dosage.
Bar bi turates, chol estyrami ne, r i fampi n, and phenytoi n may
decr ease the effecti veness of cor ti coster oi ds, r esul ti ng i n the
need to i ncr ease the ster oi d dosage. (See Adver se r eacti ons to
i nhal ed cor ti coster oi ds.)

Warning!
Adverse reactions to inhaled corticosteroids
Adver se r eacti ons to i nhal ed cor ti coster oi ds may i ncl ude:

mouth i r r i tati on
oral candi di asi s
upper r espi rator y tract i nfecti on.

To r educe the r i sk of adver se r eacti ons fr om i nhal ed ster oi ds, the

pati ent shoul d use the l owest possi bl e dosage to mai ntai n contr ol ,
admi ni ster doses usi ng a spacer, and r i nse out hi s mouth after
admi ni strati on.

Leukotriene modifiers
Leukotr iene modifier s ar e used for the pr eventi on and l ong-ter m
contr ol of mi l d asthma.
Leukotr i ene r eceptor antagoni sts i ncl ude:

montel ukast
 z afi r l ukast.

Leukotr i ene for mati on i nhi bi tor s i ncl ude:

z i l euton.

Pharmacokinetics
Montel ukast i s rapi dl y absor bed. Zafi r l ukasts absor pti on i s
decr eased by food, so i t shoul d be gi ven 1 hour befor e or 2 hour s
after meal s.
Al l of the l eukotr i ene modi fi er s ar e hi ghl y pr otei n-bound (mor e than
90% ).

Metabolism and excretion

Zafi r l ukast i s extensi vel y metabol i zed i n the l i ver by the
cytochr ome P450 2C9 (CYP2C9) enz yme i nto i nacti ve metabol i tes
and excr eted pr i mar i l y i n stool . In general , thi s cl ass of dr ugs i s
metabol i zed, i nduced, or i nhi bi ted by the cytochr ome P450 enz yme
system, whi ch i s i mpor tant for establ i shi ng dr ug i nteracti ons.

Caution required
Zi l euton i s contrai ndi cated i n the pati ent wi th acti ve l i ver di sease.
Cl osel y moni tor the pati ent wi th l i ver i mpai r ment whos taki ng
z afi r l ukast for adver se r eacti ons; he may r equi r e a dosage
adjustment. Thi s doesnt appl y for montel ukast.

Pharmacodynamics
Leukotr i enes ar e substances r el eased fr om mast cel l s, eosi nophi l s,
and basophi l s that can cause smooth-muscl e contracti on of the
ai r ways, i ncr eased per meabi l i ty of the vascul atur e, i ncr eased
secr eti ons, and acti vati on of other i nfl ammator y medi ator s.
Leukotr i enes may be i nhi bi ted by two di ffer ent mechani sms. The
l eukotr i ene r eceptor antagoni sts z afi r l ukast and montel ukast
pr event the D4 and E4 l eukotr i enes fr om i nteracti ng wi th thei r
r eceptor s, ther eby bl ocki ng thei r acti on. The l eukotr i ene for mati on
i nhi bi tor z i l euton i nhi bi ts the pr oducti on of 5-l i poxygenase, ther eby
pr eventi ng the for mati on of l eukotr i enes.
Pharmacotherapeutics
Leukotr i ene modi fi er s ar e pr i mar i l y used to pr event and contr ol
asthma attacks i n the pati ent wi th mi l d to moderate di sease.
Montel ukast i s al so i ndi cated for the tr eatment of al l er gi c r hi ni ti s.

Drug interactions
Zafi r l ukast i nhi bi ts CYP2C9 and thus coul d i ncr ease the r i sk of
toxi ci ty i f used wi th phenytoi n or war far i n.
Zafi r l ukast and z i l euton i nhi bi t CYP3A4 and thus coul d i ncr ease
the r i sk of toxi ci ty i f used wi th aml odi pi ne, ator vastati n,
car bamazepi ne, cl ar i thr omyci n, cycl ospor i ne, er ythr omyci n,
hor monal contracepti ves, i traconazol e, ketoconazol e, l ovastati n,
nel fi navi r, ni fedi pi ne, r i tonavi r, ser tral i ne, si mvastati n, or
war far i n.
Zi l euton i nhi bi ts CYP1A2 and thus coul d i ncr ease the r i sk of
toxi ci ty i f used wi th ami tr i ptyl i ne, cl oz api ne, desi prami ne,
fl uvoxami ne, i mi prami ne, theophyl l i ne, or war far i n.

Talkin toxicity
Zafi r l ukast, z i l euton, and montel ukast ar e metabol i zed by
CYP2C9 and thus coul d i ncr ease the r i sk of toxi ci ty i f used wi th
ami odar one, ci meti di ne, fl uconazol e, fl uoxeti ne, fl uvoxami ne,
 i soni az i d, metr oni dazol e, or vor i conazol e. If car bamazepi ne,
phenobar bi tal , phenytoi n, pr i mi done, or r i fampi n i s used wi th
l eukotr i enes, the effecti veness of the l eukotr i enes coul d be
r educed.
Zi l euton and montel ukast ar e metabol i zed by CYP3A4 and thus
coul d i ncr ease the r i sk of toxi ci ty i f used wi th ami odar one,
ci meti di ne, cl ar i thr omyci n, cycl ospor i ne, er ythr omyci n,
fl uoxeti ne, fl uvoxami ne, grapefr ui t jui ce, i traconazol e,
ketoconazol e, metr oni dazol e, or vor i conazol e and coul d r esul t i n
decr eased effecti veness i f used wi th car bamazepi ne, efavi r enz ,
gar l i c suppl ements, modafi ni l , nevi rapi ne, oxcar bazepi ne,
phenobar bi tal , phenytoi n, pr i mi done, r i fabuti n, r i fampi n, or St.
Johns wor t.

Zi l euton i s metabol i zed by CYP1A2 and thus coul d i ncr ease the
r i sk of toxi ci ty i f used wi th ci meti di ne, cl ar i thr omyci n,
er ythr omyci n, fl uvoxami ne, or i soni az i d and coul d r esul t i n
decr eased effecti veness i f used wi th car bamazepi ne,
phenobar bi tal , phenytoi n, pr i mi done, r i fampi n, r i tonavi r, or St.
Johns wor t or i f used by a smoker. (See Adver se r eacti ons to
l eukotr i ene modi fi er s.)

Mast cell stabilizers

Mast cell stabiliz er s ar e used to pr event asthma attacks, especi al l y
i n a chi l d or a pati ent wi th mi l d di sease. Theyr e al so used i n an
adul t or chi l d wi th mi l d to moderate per si stent asthma. Dr ugs i n
thi s cl ass i ncl ude:

cr omol yn
nedocr omi l .

Pharmacokinetics
Mast cel l stabi l i zer s ar e mi ni mal l y absor bed fr om the G I tract;
theyr e avai l abl e i n i nhal ed for ms that exer t thei r effects l ocal l y.

Pharmacodynamics
These dr ugs stabi l i ze the mast cel l membrane, possi bl y by i nhi bi ti ng
cal ci um channel s, thus pr eventi ng the r el ease of i nfl ammator y
medi ator s.

Pharmacotherapeutics
Mast cel l stabi l i zer s ar e used for the pr eventi on and l ong-ter m
contr ol of asthma symptoms. They do thi s by contr ol l i ng the
i nfl ammator y pr ocess.

Warning!
Adverse reactions to leukotriene modifiers
Adver se r eacti ons that may occur wi th l eukotr i ene modi fi er s
i ncl ude:

headache
di z z i ness
nausea and vomi ti ng
myal gi a.

Number 1 for children

Mast cel l stabi l i zer s ar e often used for chi l dr en and pati ents wi th
exer ci se-i nduced asthma.

Warning!
Adverse reactions to mast cell stabilizers
Inhal ed mast cel l stabi l i zer s may cause these adver se
r eacti ons:

phar yngeal and tracheal i r r i tati on

cough
wheez i ng
br onchospasm
headache.

Drug interactions
Interacti ons ar e uncommon when usi ng i nhal ed for ms. (See Adver se
r eacti ons to mast cel l stabi l i zer s.)
Methylxanthines
Methylxanthines, al so cal l ed xanthines, ar e used to tr eat r espi rator y
di sor der s.

Types of methylxanthines
Methyl xanthi nes i ncl ude anhydr ous theophylline and i ts der i vati ve
sal t ami nophyl l i ne.
Theophyl l i ne i s the most commonl y pr escr i bed oral methyl xanthi ne.
Ami nophyl l i ne i s pr efer r ed when an I.V. methyl xanthi ne i s r equi r ed.
Caffei ne i s al so a xanthi ne der i vati ve.

Pharmacokinetics
The phar macoki neti cs of methyl xanthi nes var y accor di ng to whi ch
dr ug the pati ent i s r ecei vi ng, the dosage for m, and the
admi ni strati on r oute.

Absorption
When theophyl l i ne i s gi ven as an oral sol uti on or a rapi d-r el ease
tabl et, i ts absor bed rapi dl y and compl etel y. Hi gh-fat meal s can
i ncr ease theophyl l i ne concentrati ons and the r i sk of toxi ci ty.

Gastric measures
Absor pti on of some of theophyl l i nes sl ow-r el ease for ms depends on
the gastr i c pH. Food can al ter absor pti on. When conver ti ng the
pati ent fr om I.V. ami nophyl l i ne to oral theophyl l i ne, the dosage i s
decr eased by 20% .

Distribution
Theophyl l i ne i s appr oxi matel y 56% pr otei n-bound i n adul ts and
36% pr otei n-bound i n neonates. It r eadi l y cr osses the pl acental
bar r i er and i s secr eted i n br east mi l k. Smoker s and pati ents on
di al ysi s may need hi gher doses.

Metabolism and excretion

Theophyl l i ne i s metabol i zed pr i mar i l y i n the l i ver by the CYP1A2
enz yme. In adul ts and chi l dr en, about 10% of a dose i s excr eted
unchanged i n ur i ne; ther efor e, no dosage adjustment i s r equi r ed i n
pati ents wi th r enal i nsuffi ci ency. El der l y pati ents and those wi th
l i ver dysfuncti on may r equi r e a l ower dose. Because an i nfant has
an i mmatur e l i ver wi th r educed metabol i c functi oni ng, as much as
one-hal f of a dose may be excr eted unchanged i n hi s ur i ne.

Blood levels matter

Theophyl l i ne l evel s must be measur ed to eval uate effi cacy and avoi d
toxi ci ty. The therapeuti c ser um concentrati on i s 10 to 20 mcg/ml
(SI, 44 to 111 mol /L). Level s must be assessed when dr ug therapy
i s i ni ti ated, when the dosage i s changed, and when dr ugs ar e added
or r emoved fr om the pati ents r egi men.

Pharmacodynamics
Methyl xanthi nes act i n many ways.

Relax and breathe deeply

Methyl xanthi nes decr ease ai r way r eacti vi ty and r el i eve
br onchospasm by r el axi ng br onchi al smooth muscl e. Theophyl l i ne i s
bel i eved to i nhi bi t phosphodi esterase, r esul ti ng i n smooth-muscl e
r el axati on, br onchodi l ati on, and decr eased i nfl ammator y medi ator s
(namel y mast cel l s, T cel l s, and eosi nophi l s). Much of theophyl l i nes
toxi ci ty may be due to i ncr eased catechol ami ne r el ease.

A stimulating conversation
In nonr ever si bl e obstr ucti ve ai r way di sease (chr oni c br onchi ti s,
emphysema, and apnea), methyl xanthi nes appear to i ncr ease the
sensi ti vi ty of the brai ns r espi rator y center to car bon di oxi de and to
sti mul ate the r espi rator y dr i ve.

Pumping you up
In chr oni c br onchi ti s and emphysema, these dr ugs r educe fati gue of
the di aphragm, the r espi rator y muscl e that separates the abdomen
fr om the thoraci c cavi ty. They al so i mpr ove ventr i cul ar functi on
and, ther efor e, the hear ts pumpi ng acti on.

Pharmacotherapeutics
Theophyl l i ne and i ts sal ts ar e used as second- or thi r d-l i ne therapy
for the l ong-ter m contr ol and pr eventi on of symptoms r el ated to:

asthma
chr oni c br onchi ti s
emphysema.

Memory jogger
How can you r emember what theophyl l i ne and i ts sal ts ar e
used to tr eat? Si mpl e: Just r emember that you r eal l y need to
ACE thi s one! Its used for l ong-ter m contr ol and pr eventi on of
symptoms r el ated to:
A asthma
Cchr oni c br onchi ti s
Eemphysema.

Useful for neonates?

Theophyl l i ne has been used to tr eat neonatal apnea (per i ods of not
br eathi ng i n the neonate) and has been effecti ve i n r educi ng sever e
br onchospasm i n an i nfant wi th cysti c fi br osi s.

Warning!
Adverse reactions to methylxanthines
Gut reactions
Adver se G I system r eacti ons i ncl ude:

nausea and vomi ti ng

abdomi nal crampi ng
epi gastr i c pai n
anor exi a
di ar r hea.

Nerve racking
Adver se central ner vous system r eacti ons i ncl ude:

headache

i r r i tabi l i ty
r estl essness
anxi ety
i nsomni a
di z z i ness.

Heart of the matter

Adver se car di ovascul ar r eacti ons i ncl ude:

tachycar di a
pal pi tati ons
ar r hythmi as.

Drug interactions
Theophyl l i ne dr ug i nteracti ons occur wi th substances that i nhi bi t or
i nduce the CYP1A2 enz yme. (See Adver se r eacti ons to
methyl xanthi nes.)

Inhi bi tor s of the CYP1A2 enz yme (i ncl udi ng ci meti di ne,
ci pr ofl oxaci n, cl ar i thr omyci n, er ythr omyci n, fl uvoxami ne,
hor monal contracepti ves, i soni az i d, ketoconazol e, ti cl opi di ne,
and z i l euton) decr ease theophyl l i ne metabol i sm, thus i ncr easi ng
i ts ser um l evel as wel l as the r i sk of adver se r eacti ons and
toxi ci ty. The dosage of theophyl l i ne may need to be r educed.
Inducer s of the CYP1A2 enz yme (i ncl udi ng car bamazepi ne,
phenobar bi tal , phenytoi n, r i fampi n, St. Johns wor t, and
char br oi l ed meats) i ncr ease theophyl l i ne metabol i sm, thus
decr easi ng i ts ser um l evel and possi bl y i ts effecti veness. The
dosage of theophyl l i ne may need to be i ncr eased.
Smoki ng ci gar ettes or mar i juana i ncr eases theophyl l i ne
el i mi nati on, thus decr easi ng i ts ser um l evel and effecti veness.
Taki ng adr ener gi c sti mul ants or dr i nki ng beverages that contai n
caffei ne or caffei nel i ke substances may r esul t i n addi ti ve
adver se r eacti ons to theophyl l i ne or si gns and symptoms of
methyl xanthi ne toxi ci ty.
Acti vated char coal may decr ease theophyl l i ne l evel s.
The use of enfl urane or i sofl urane wi th theophyl l i ne or
theophyl l i ne der i vati ves i ncr eases the r i sk of car di ac toxi ci ty.
Theophyl l i ne and i ts der i vati ves may r educe the effects of
l i thi um by i ncr easi ng i ts rate of excr eti on.
Thyr oi d hor mones may r educe theophyl l i ne l evel s; anti thyr oi d
dr ugs may i ncr ease theophyl l i ne l evel s.
Monoclonal antibodies
Monoclonal antibodies, par ti cul ar l y anti -i mmunogl obi n (Ig) E
monocl onal anti bodi es, ar e used i n pati ents wi th moderate-to-
sever e asthma wi th a posi ti ve ski n test and who ar e i nadequatel y
contr ol l ed wi th i nhal ed cor ti coster oi ds. Omal i z umab i s the onl y dr ug
i n thi s cl ass.

Omalizumab
Pharmacokinetics
Omal i z umab i s sl owl y absor bed after subcutaneous i njecti on. Its
metabol i zed by the l i ver, but the rate of metabol i z ati on depends on
IgG cl earance.

Pharmacodynamics
Omal i z umab i nhi bi ts the bi ndi ng of IgE to i ts r eceptor on the mast
cel l and basophi l s. Thi s i n tur ns i nhi bi ts the r el ease of al l er gi c
substances whi ch potenti ate asthma symptoms.

Pharmacotherapeutics
Omal i z umab i s used i n pati ents wi th moderate-to-sever e asthma
wi th a posi ti ve ski n test and i nsuffi ci ent contr ol on i nhal ed
cor ti coster oi ds. Dosi ng for the dr ug i s based on pr etr eatment ser um
IgE l evel s.

Warning!
Adverse reactions to monoclonal antibodies
Adver se r eacti ons to monocl onal anti bodi es i ncl ude:

i njecti on si te r eacti ons

upper r espi rator y tract i nfecti ons
si nusi ti s
headache
phar yngi ti s
al l er gi c r eacti on.

Al l er gi c r eacti ons may be sever e enough to be l i fe-thr eateni ng

and typi cal l y occur wi thi n 2 hour s of admi ni strati on. However, i n
rar e cases, del ayed anaphyl acti c r eacti ons (occur r i ng mor e than
24 hour s after admi ni strati on) may occur.

Drug interactions
No for mal dr ug-i nteracti on studi es have been done. (See Adver se
r eacti ons to monocl onal anti bodi es.)

Expectorants
Expector ants thi n mucus so i ts cl ear ed mor e easi l y out of the
ai r ways. They al so soothe mucous membranes i n the r espi rator y
tract. The r esul t i s a mor e pr oducti ve cough.
Guaifenesin
The most commonl y used expectorant i s guaifenesin.

Pharmacokinetics
G uai fenesi n i s absor bed thr ough the G I tract, metabol i zed by the
l i ver, and excr eted pr i mar i l y by the ki dneys.

Pharmacodynamics
By i ncr easi ng pr oducti on of r espi rator y tract fl ui ds, expectorants
r educe the thi ckness, adhesi veness, and sur face tensi on of mucus,
maki ng i t easi er to cl ear fr om the ai r ways. Expectorants al so
pr ovi de a soothi ng effect on the mucous membranes of the
r espi rator y tract.

Pharmacotherapeutics
G uai fenesi n i s used to r el i eve symptoms due to i neffecti ve,
pr oducti ve coughs fr om many di sor der s, such as:

br onchi al asthma
br onchi ti s
col ds
emphysema
i nfl uenz a
mi nor br onchi al i r r i tati on
si nusi ti s.
 Warning!
Adverse reactions to guaifenesin
Adver se r eacti ons to guai fenesi n i ncl ude:

nausea
vomi ti ng (i f taken i n l ar ge doses)
di ar r hea
abdomi nal pai n
dr owsi ness
headache
hi ves
rash.

Drug interactions
G uai fenesi n i snt known to have speci fi c dr ug i nteracti ons; however,
i t does cause some adver se r eacti ons. (See Adver se r eacti ons to
guai fenesi n.)

Antitussives
Antitussive dr ugs suppr ess or i nhi bi t coughi ng.

Types of antitussives
Anti tussi ves ar e typi cal l y used to tr eat dr y, nonpr oducti ve coughs.
The major anti tussi ves i ncl ude:
 benzonatate
codei ne
dextr omethor phan
hydr ocodone bi tar trate.

Pharmacokinetics
Anti tussi ves ar e absor bed wel l thr ough the G I tract, metabol i zed i n
the l i ver, and excr eted i n ur i ne.

Pharmacodynamics
Anti tussi ves act i n sl i ghtl y di ffer ent ways.

Removing the sensation

Benzonatate acts by anestheti z i ng str etch r eceptor s thr oughout the
br onchi , al veol i , and pl eurae.

Taking direct action

Codei ne, dextr omethor phan, and hydr ocodone suppr ess the cough
r efl ex by di r ect acti on on the cough center i n the medul l a of the
brai n, thus l ower i ng the cough thr eshol d.

Pharmacotherapeutics
The uses of these dr ugs var y sl i ghtl y, but each tr eats a ser i ous,
nonpr oducti ve cough that i nter fer es wi th a pati ents abi l i ty to r est
or car r y out acti vi ti es of dai l y l i vi ng.

Put it to the test

Benzonatate r el i eves cough caused by pneumoni a, br onchi ti s, the
common col d, and chr oni c pul monar y di seases such as emphysema.
It can al so be used dur i ng br onchi al di agnosti c tests, such as
br onchoscopy, when the pati ent must avoi d coughi ng.

Top of the charts

Dextr omethor phan i s the most wi del y used cough suppr essant i n the
Uni ted States and may pr ovi de better anti tussi ve effects than
codei ne. Its popul ar i ty may stem fr om the fact that i t i snt
associ ated

wi th sedati on, r espi rator y depr essi on, or addi cti on at usual doses.

Warning!
Adverse reactions to antitussives
Benzonatate
Benzonatate needs to be swal l owed whol e; chewi ng or cr ushi ng i t
can pr oduce a l ocal anestheti c effect i n the mouth and thr oat,
whi ch can compr omi se the ai r way. These r eacti ons can al so occur
when taki ng benzonatate:

di z z i ness
sedati on
 headache
nasal congesti on
bur ni ng i n the eyes
G I upset or nausea
consti pati on
rash, er upti ons, or i tchi ng
chi l l s
chest numbness.

Opioid antitussives
The most common r eacti ons i ncl ude nausea, vomi ti ng, sedati on,
di z z i ness, and consti pati on. Other r eacti ons i ncl ude:

pupi l constr i cti on

bradycar di a

tachycar di a
hypotensi on
stupor
sei z ur es
ci r cul ator y col l apse
r espi rator y ar r est.

Use opi oi d anti tussi ves cauti ousl y i n the pati ent wi th cur r ent or
pr evi ous opi oi d addi cti on and i n the pati ent wi th a r espi rator y
di sor der, such as asthma or chr oni c obstr ucti ve pul monar y
di sease.

For really tough coughs

The opi oi d anti tussi ves (typi cal l y codei ne and hydr ocodone) ar e
r eser ved for tr eati ng an i ntractabl e cough.

Drug interactions
Anti tussi ves may i nteract wi th other dr ugs.

Codei ne and hydr ocodone may cause exci tati on, an extr emel y
el evated temperatur e, hyper tensi on or hypotensi on, and coma
when taken wi th monoami ne oxi dase i nhi bi tor s (MAOIs).
 Dextr omethor phan use wi th MAOIs may pr oduce exci tati on, an
el evated body temperatur e, hypotensi on, and coma.
Codei ne taken wi th other central ner vous system (CNS)
depr essants, i ncl udi ng al cohol , bar bi turates, phenothi az i nes, and
sedati ve-hypnoti cs, may i ncr ease CNS depr essi on, r esul ti ng i n
dr owsi ness, l ethar gy, stupor, r espi rator y depr essi on, coma, and
even death. (See Adver se r eacti ons to anti tussi ves.)

Mucolytics
Mucolytics act di r ectl y on mucus, br eaki ng down sti cky, thi ck
secr eti ons so that theyr e mor e easi l y el i mi nated.

Acetylcysteine
Acetylcysteine i s the onl y mucol yti c used cl i ni cal l y i n the Uni ted
States for the pati ent wi th abnor mal or thi ck mucus.

Pharmacokinetics
Inhal ed acetyl cystei ne i s absor bed fr om the pul monar y epi thel i um.
When taken oral l y, the dr ug i s absor bed fr om the G I tract.

Metabolism and excretion

Acetyl cystei ne i s metabol i zed i n the l i ver ; i ts excr eti on i s unknown.

Pharmacodynamics
Acetyl cystei ne decr eases the thi ckness of r espi rator y tract
secr eti ons by al ter i ng the mol ecul ar composi ti on of mucus. It al so
i r r i tates the mucosa to sti mul ate cl earance and r estor es
gl utathi one, a substance that pl ays an i mpor tant r ol e i n oxi dati on-
r educti on pr ocesses.

Liver cleaner
G l utathi ones enz ymati c acti on i n the l i ver r educes acetami nophen
toxi ci ty fr om over dose.

Pharmacotherapeutics
Mucol yti cs ar e used wi th other therapi es to tr eat the pati ent wi th
abnor mal or thi ck mucus secr eti ons, such as the pati ent wi th:

atel ectasi s caused by mucus obstr ucti on, as may occur i n

pneumoni a, br onchi ectasi s, or chr oni c br onchi ti s
br onchi ti s
pul monar y compl i cati ons r el ated to cysti c fi br osi s.

Patient preparations
Mucol yti cs may al so be used to pr epar e the pati ent for
br onchography and other br onchi al studi es.

Overdose antidote
Acetyl cystei ne i s the anti dote for acetami nophen over dose.
However, i t doesnt ful l y pr otect agai nst l i ver damage caused by
acetami nophen toxi ci ty.

Drug interactions
Acti vated char coal decr eases acetyl cystei nes effecti veness. When
usi ng acetyl cystei ne to tr eat an acetami nophen over dose, r emove

acti vated char coal fr om the stomach befor e admi ni ster i ng. (See
Adver se r eacti ons to acetyl cystei ne.)

Decongestants
Decongestants may be cl assi fi ed as systemi c or topi cal , dependi ng
on how theyr e admi ni ster ed.

Types of decongestants
As sympathomi meti c dr ugs, systemi c decongestants sti mul ate the
sympatheti c ner vous system to r educe swel l i ng of the r espi rator y
tracts vascul ar networ k. Systemi c decongestants i ncl ude:

ephedr i ne
phenyl ephr i ne
pseudoephedr i ne.

Topical concerns
Topi cal decongestants ar e al so power ful vasoconstr i ctor s. When
appl i ed di r ectl y to swol l en mucous membranes of the nose, they
pr ovi de i mmedi ate r el i ef fr om nasal congesti on. These dr ugs
i ncl ude:

ephedr i ne, epi nephr i ne, and phenyl ephr i ne (sympathomi meti c
ami nes)
naphazol i ne and tetrahydr ozol i ne (i mi dazol i ne der i vati ves of
sympathomi meti c ami nes).

Pharmacokinetics
The phar macoki neti c pr oper ti es of decongestants var y.

Absorbed quickly
When taken oral l y, the systemi c decongestants ar e absor bed r eadi l y
fr om the G I tract and wi del y di str i buted thr oughout the body i nto
var i ous ti ssues and fl ui ds, i ncl udi ng cer ebr ospi nal fl ui d, the
pl acenta, and br east mi l k.

metabolized slowly
Systemi c decongestants ar e sl owl y and i ncompl etel y metabol i zed by
the l i ver and excr eted l ar gel y unchanged i n ur i ne wi thi n 24 hour s of
oral admi ni strati on.
Direct action
Topi cal decongestants act l ocal l y on the al pha r eceptor s of the
vascul ar smooth muscl e i n the nose, causi ng the ar ter i ol es to
constr i ct. As a r esul t of thi s l ocal acti on, absor pti on of the dr ug i s
negl i gi bl e.

Warning!
Adverse reactions to acetylcysteine
Dur i ng admi ni strati on, acetyl cystei ne has a r otten egg
odor that may cause nausea. Wi th pr ol onged or per si stent use,
acetyl cystei ne may pr oduce:

br onchospasm
dr owsi ness
nausea and vomi ti ng
sever e r unny nose
stomati ti s.

Acetyl cystei ne i snt r ecommended for the pati ent wi th asthma

because i t may cause br onchospasm.

Pharmacodynamics
The pr oper ti es of systemi c and topi cal decongestants var y sl i ghtl y.
System(ic) analysis
Systemi c decongestants cause vasoconstr i cti on by sti mul ati ng
al pha-adr ener gi c r eceptor s i n the bl ood vessel s of the body. Thi s
r educes the bl ood suppl y to the nose, whi ch decr eases swel l i ng of
the nasal mucosa. They al so cause contracti on of ur i nar y and G I
sphi ncter s, di l ated pupi l s, and decr eased i nsul i n secr eti on.

Indirect hit
These dr ugs may al so act i ndi r ectl y, causi ng the r el ease of
nor epi nephr i ne fr om storage si tes i n the body, whi ch r esul ts i n
per i pheral vasoconstr i cti on.

On topic(al)
Li ke systemi c decongestants, topi cal decongestants sti mul ate al pha-
adr ener gi c r eceptor s i n the smooth muscl e of nasal bl ood vessel s,
r esul ti ng i n vasoconstr i cti on. The combi nati on of r educed bl ood fl ow
to the nasal mucous membranes and decr eased capi l l ar y
per meabi l i ty r educes swel l i ng. Thi s acti on i mpr oves r espi rati on by
hel pi ng to drai n si nuses, cl ear nasal passages, and open eustachi an
tubes.

Pharmacotherapeutics
Systemi c and topi cal decongestants ar e used to r el i eve the
symptoms of swol l en nasal membranes r esul ti ng fr om:

acute cor yz a (pr ofuse di schar ge fr om the nose)

al l er gi c r hi ni ti s (hay fever )
the common col d
si nusi ti s
vasomotor r hi ni ti s.

Team tactics
Systemi c decongestants ar e commonl y gi ven wi th other dr ugs, such
as anti hi stami nes, anti muscar i ni cs, anti pyr eti c anal gesi cs, and
anti tussi ves.
Advantage, topical
Topi cal decongestants pr ovi de two major advantages over systemi cs:
mi ni mal adver se r eacti ons and rapi d symptom r el i ef.

Drug interactions
Because they pr oduce vasoconstr i cti on, whi ch r educes dr ug
absor pti on, topi cal decongestants sel dom pr oduce dr ug i nteracti ons.

Systemi c decongestants, however, may i nteract wi th other dr ugs.

(See Adver se r eacti ons to decongestants.)

Warning!
Adverse reactions to decongestants
Most adver se r eacti ons to decongestants r esul t fr om central
ner vous system sti mul ati on and i ncl ude:

ner vousness

r estl essness
i nsomni a
nausea
pal pi tati ons
tachycar di a
di ffi cul ty ur i nati ng
el evated bl ood pr essur e.

Systemi c decongestants exacer bate hyper tensi on,

hyper thyr oi di sm, di abetes, beni gn pr ostati c hyper tr ophy,
gl aucoma, and hear t di sease. Theyr e al so secr eted i n br east mi l k
i n a br east-feedi ng woman.
Topical decongestants
The most common adver se r eacti on associ ated wi th pr ol onged use
(mor e than 5 days) of topi cal decongestants i s r ebound nasal
congesti on.
Other r eacti ons i ncl ude:

bur ni ng and sti ngi ng of the nasal mucosa

sneez i ng
 mucosal dr yness or ul cerati on.

Issue of sensitivity
The pati ent whos hyper sensi ti ve to other sympathomi meti c
ami nes may al so be hyper sensi ti ve to decongestants.

Incr eased CNS sti mul ati on may occur when systemi c
decongestants ar e taken wi th other sympathomi meti c dr ugs,
i ncl udi ng epi nephr i ne, nor epi nephr i ne, dopami ne, dobutami ne,
i sopr oter enol , metapr oter enol , ter butal i ne, and phenyl ephr i ne,
and tyrami ne-contai ni ng foods.
Use of systemi c decongestants wi th MAOIs may cause sever e
hyper tensi on or a hyper tensi ve cr i si s, whi ch can be l i fe-
thr eateni ng. These dr ugs shoul dnt be used together.
Al kal i ni z i ng dr ugs may i ncr ease the effects of pseudoephedr i ne
by r educi ng i ts ur i nar y excr eti on.

Quick quiz
1Whi ch adver se r eacti on can occur i f guai fenesi n i s
taken i n l ar ger doses than necessar y?
A. Consti pati on
B. Vomi ti ng
C. Insomni a
D. Di ar r hea

P.
2Whi ch medi cati on shoul d the pati ent avoi d when taki ng
dextr omethor phan?
A. Acetami nophen
B. G uai fenesi n
C. Phenel z i ne
D. Famoti di ne

3Besi des br onchi ti s, acetyl cystei ne may al so be used to tr eat:

A. acetami nophen over dose.
B. sever e r hi nor r hea.
C. stomati ti s.
 D. di ar r hea.

4Whi ch adver se r eacti on most commonl y occur s wi th a

decongestant, such as tetrahydr ozol i ne, especi al l y i f i ts taken
mor e often than r ecommended?
A. Nausea
B. Di z z i ness
C. Di ar r hea
D. Rebound nasal congesti on

Scoring
If you answer ed al l four i tems cor r ectl y, your e sl i cker
than a mucol yti c i n acti on!

If you answer ed thr ee i tems cor r ectl y, your e as r el axed

as br onchi al smooth muscl e on xanthi nes.

If you answer ed fewer than thr ee i tems cor r ectl y, you

may need to cl ear your head wi th a decongestant. Revi ew
the chapter once mor e and tr y agai n!

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

8
Gastrointestinal drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs used to i mpr ove G I functi on

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and the GI system

The G I tract i s basi cal l y a hol l ow, muscul ar tube that begi ns at the
mouth and ends at the anus; i t encompasses the phar ynx,
esophagus, stomach, and the smal l and l ar ge i ntesti nes. Its pr i mar y
functi ons ar e to di gest food and absor b nutr i ents and fl ui ds and
excr ete metabol i c waste.

Getting on tract
Cl asses of dr ugs used to i mpr ove G I functi on i ncl ude:

pepti c ul cer dr ugs

adsor bent, anti fl atul ent, and di gesti ve dr ugs
obesi ty dr ugs
 anti di ar r heal and l axati ve dr ugs
anti emeti c and emeti c dr ugs.

Antiulcer drugs
A peptic ulcer i s a ci r cumscr i bed l esi on that devel ops i n the mucous
membranes of the l ower esophagus, stomach, duodenum, or
jejunum.

Counting causes
The fi ve major causes of pepti c ul cer s ar e:

bacter i al i nfecti on wi th Helicobacter pylor i

the use of nonster oi dal anti -i nfl ammator y dr ugs (NSAIDs)
hyper secr etor y states such as Zol l i nger-El l i son syndr ome (a
condi ti on i n whi ch excessi ve secr eti on of gastr i c aci d causes
pepti c ul cer s)
ci gar ette smoki ng, whi ch causes hyper secr eti on and i mpai r s
ul cer heal i ng
a geneti c pr edi sposi ti on, whi ch accounts for 20% to 50% of
pepti c ul cer s.

Balancing act
Peptic ulcer dr ugs ar e ai med at ei ther eradi cati ng H. pylor i or
r estor i ng the bal ance between aci d and pepsi n secr eti ons and the G I
mucosal defense. These dr ugs i ncl ude:

systemi c anti bi oti cs

antaci ds
Hi stami ne-2 (H2 ) r eceptor antagoni sts
pr oton pump i nhi bi tor s
other pepti c ul cer dr ugs, such as mi sopr ostol and sucral fate.

Systemic antibiotics
H. pylor i i s a gram-negati ve bacter i um thats thought to be a major
causati ve factor i n the for mati on of pepti c ul cer s and gastr i ti s
(i nfl ammati on of the stomach l i ni ng). Eradi cati on of the bacter i a
hel ps to heal ul cer s and decr ease thei r r ecur r ence.

Teamwork is a must
Successful tr eatment i nvol ves the use of two or mor e anti bi oti cs i n
combi nati on wi th other dr ugs such as aci d suppr essants. Systemic
antibiotics used to tr eat H. pylor i i ncl ude:

amoxi ci l l i n
cl ar i thr omyci n
metr oni dazol e
tetracycl i ne.

Pharmacokinetics (how drugs circulate)

Systemi c anti bi oti cs ar e var i abl y absor bed fr om the G I tract.

Dairy delay
Food, especi al l y dai r y pr oducts, decr eases the absor pti on of
tetracycl i ne but doesnt si gni fi cantl y del ay the absor pti on of the
other anti bi oti cs.

Distribution and excretion

Al l of these anti bi oti cs ar e di str i buted wi del y and ar e excr eted
pr i mar i l y i n ur i ne.

Pharmacodynamics (how drugs act)

Anti bi oti cs act by tr eati ng the H. pylor i i nfecti on. Theyr e usual l y
combi ned wi th an H2 -r eceptor antagoni st or a pr oton pump i nhi bi tor
to decr ease stomach aci d and fur ther pr omote heal i ng.

Pharmacotherapeutics (how drugs are used)

They ar e i ndi cated for H. pylor i eradi cati on to r educe the r i sk of a
duodenal ul cer. For thi s r eason they may be used i n conjuncti on
wi th other medi cati ons such as pr oton pump i nhi bi tor s.

Successful strategy
Successful tr eatment pl ans use at l east two anti bi oti cs and a pr oton
pump i nhi bi tor for 14 days and then use a pr oton pump i nhi bi tor for
6 mor e weeks to hel p r educe aci d i n pati ents wi th a pepti c ul cer.

Drug interactions
Tetracycl i ne and metr oni dazol e can i nteract wi th many other
medi cati ons.

Tetracycl i ne i ncr eases di goxi n l evel s.

Metr oni dazol e and tetracycl i ne i ncr ease the r i sk of bl eedi ng
when taken wi th oral anti coagul ants.
Metr oni dazol e can cause a sever e r eacti on when combi ned wi th
al cohol . (See Adver se r eacti ons to anti bi oti cs.)
 Warning!
Adverse reactions to antibiotics
Anti bi oti cs used to i mpr ove G I tract functi on may l ead to
adver se r eacti ons.

Metr oni dazol e, cl ar i thr omyci n, and tetracycl i ne commonl y

cause mi l d G I di stur bances.
Cl ar i thr omyci n and metr oni dazol e may al so pr oduce abnor mal
tastes.
Amoxi ci l l i n may cause di ar r hea.

Antacids
Antacids ar e over-the-counter (OTC) medi cati ons that ar e used as
adjunct therapy to tr eat pepti c ul cer s. They i ncl ude:

al umi num car bonate gel

cal ci um car bonate
magal drate (al umi num-magnesi um compl ex)
magnesi um hydr oxi de and al umi num hydr oxi de
si methi cone.

Pharmacokinetics
Antaci ds wor k l ocal l y i n the stomach by neutral i z i ng gastr i c aci d.
They dont need to be absor bed to tr eat pepti c ul cer s.

Distribution and excretion

Antaci ds ar e di str i buted thr oughout the G I tract and ar e el i mi nated
pr i mar i l y i n stool .

Pharmacodynamics
The aci d-neutral i z i ng acti on of antaci ds r educes the total amount of
aci d i n the G I tract, al l owi ng pepti c ul cer s to heal .
The more it works, the sooner it rests
Pepsi n, one of the stomach secr eti ons, acts mor e effecti vel y when
the stomach i s hi ghl y aci di c; ther efor e, as aci di ty dr ops, pepsi n
acti on i s al so r educed. Contrar y to popul ar bel i ef, antaci ds dont
wor k by coati ng pepti c ul cer s or the l i ni ng of the G I tract.

Warning!
Adverse reactions to antacids
Al l adver se r eacti ons to antaci ds ar e dose r el ated and
i ncl ude:

di ar r hea
consti pati on
el ectr ol yte i mbal ances
al umi num accumul ati on i n ser um.

Pharmacotherapeutics
Antaci ds ar e pr i mar i l y pr escr i bed to r el i eve pai n and ar e used
adjuncti vel y i n pepti c ul cer di sease.

Settling the GI system

Antaci ds al so r el i eve symptoms of aci d i ndi gesti on, hear tbur n,
dyspepsi a (bur ni ng or i ndi gesti on), or gastr oesophageal r efl ux
di sease (G ERD), i n whi ch the contents of the stomach and
duodenum fl ow back i nto the esophagus.

Fighting phosphate
Antaci ds may be used to contr ol hyper phosphatemi a (el evated bl ood
phosphate l evel s) i n ki dney fai l ur e. Because cal ci um bi nds wi th
phosphate i n the G I tract, cal ci um car bonate antaci ds pr event
phosphate absor pti on.
Drug interactions
Al l antaci ds can i nter fer e wi th the absor pti on of oral dr ugs gi ven at
the same ti me. Absor pti on of di goxi n, phenytoi n, ketoconazol e, i r on
sal ts, i soni az i d, qui nol ones, and tetracycl i nes may be r educed i f
taken wi thi n 2 hour s of antaci ds. (See Adver se r eacti ons to
antaci ds.)

H 2 -receptor antagonists
H 2 -r eceptor antagonists ar e commonl y pr escr i bed anti ul cer dr ugs i n
the Uni ted States. They i ncl ude:

ci meti di ne
famoti di ne
ni z ati di ne
rani ti di ne.

Pharmacokinetics
Ci meti di ne, ni z ati di ne, and rani ti di ne ar e absor bed rapi dl y and
compl etel y fr om the G I tract. Famoti di ne i snt compl etel y absor bed.
Antaci ds may r educe the absor pti on of H2 -r eceptor antagoni sts.

Distribution, metabolism, and excretion

H 2 -r eceptor antagoni sts ar e di str i buted wi del y thr oughout the body,
metabol i zed by the l i ver, and excr eted pr i mar i l y i n ur i ne.

Pharmacodynamics
H 2 -r eceptor antagoni sts bl ock hi stami ne fr om sti mul ati ng the aci d-
secr eti ng par i etal cel l s of the stomach.

The acid test

Aci d secr eti on i n the stomach depends on the bi ndi ng of gastr i n,
acetyl chol i ne, and hi stami ne to r eceptor s on the par i etal cel l s. If
the bi ndi ng of one of these substances i s bl ocked, aci d secr eti on i s
r educed. The H2 -r eceptor antagoni sts, by bi ndi ng wi th H2 r eceptor s,
bl ock the acti on of hi stami ne i n the stomach and r educe aci d
secr eti on. (See How H2 -r eceptor antagoni sts wor k, page 200.)

Pharmacotherapeutics
H 2 -r eceptor antagoni sts ar e used therapeuti cal l y to:

pr omote heal i ng of duodenal and gastr i c ul cer s

pr ovi de l ong-ter m tr eatment of pathol ogi c G I hyper secr etor y
condi ti ons such as Zol l i nger-El l i son syndr ome
r educe gastr i c aci d pr oducti on and pr event str ess ul cer s i n the
sever el y i l l pati ent and i n the pati ent wi th r efl ux esophagi ti s or
upper G I bl eedi ng.

Drug interactions
H 2 -r eceptor antagoni sts may i nteract wi th antaci ds and other dr ugs.

Now I get it!

How H2 -receptor antagonists work
These i l l ustrati ons show how hi stami ne-2 (H2) r eceptor
antagoni sts r educe the r el ease of gastr i c aci d.
To sti mul ate gastr i c aci d secr eti on, cer tai n endogenous
substancespr i mar i l y hi stami ne, but al so acetyl chol i ne and
gastr i nattach to r eceptor s on the sur face of par i etal cel l s. These
substances acti vate the enz yme adenyl cycl ase, whi ch conver ts
adenosi ne tr i phosphate (ATP) to the i ntracel l ul ar catal yst cycl i c
adenosi ne monophosphate (cAMP).

The cAMP ul ti matel y sti mul ates pr oton-pump (H/K ATPase)

acti vi ty. The pump catal yzes the exchange of extracel l ul ar
potassi um (K) i ons for i ntracel l ul ar hydr ogen (H) i ons. When the
H+ i ons combi ne wi th extracel l ul ar chl or i de (Cl ) i ons excr eted by
gastr i c cel l s at a di ffer ent si te, the r esul t i s hydr ochl or i c (HCl ), or
gastr i c, aci d.

H2-r eceptor antagoni sts competi ti vel y bi nd to H2-r eceptor si tes

on the sur face of par i etal cel l s and i nhi bi t the common pathway
that hi stami ne and the other substances must travel to sti mul ate
pr oton-pump acti vi ty and pr omote gastr i c aci d secr eti on.
 Antaci ds r educe the absor pti on of ci meti di ne, famoti di ne,
ni z ati di ne, and rani ti di ne.
Ci meti di ne may i ncr ease the bl ood l evel s of oral anti coagul ants,
pr opranol ol (and possi bl y other beta-adr ener gi c bl ocker s),
benzodi azepi nes, tr i cycl i c anti depr essants, theophyl l i ne,
pr ocai nami de, qui ni di ne, l i docai ne, phenytoi n, cal ci um channel
bl ocker s, cycl o-spor i ne, car bamazepi ne, and opi oi d anal gesi cs by
r educi ng thei r metabol i sm i n the l i ver and subsequent excr eti on.
Ci meti di ne taken wi th car musti ne i ncr eases the r i sk of bone
mar r ow toxi ci ty.
Ci meti di ne i nhi bi ts metabol i sm of ethyl al cohol i n the stomach,
r esul ti ng i n hi gher bl ood al cohol l evel s. (See Adver se r eacti ons
to H2 -r eceptor antagoni sts.)

Warning!
Adverse reactions to H2 -receptor antagonists
The use of H2 -r eceptor antagoni sts may l ead to adver se
r eacti ons, especi al l y i n the el der l y pati ent and the pati ent wi th
al ter ed hepati c or r enal functi on.

Ci meti di ne and rani ti di ne may pr oduce headache, di z z i ness,

mal ai se, muscl e pai n, nausea, di ar r hea or consti pati on, rash,
i tchi ng, l oss of sexual desi r e, gynecomasti a (ci meti di ne), and
i mpotence.
Famoti di ne and ni z ati di ne pr oduce few adver se r eacti ons;
head-ache i s the most common, fol l owed by consti pati on or
di ar r hea and rash.

Proton pump inhibitors

Pr oton pump inhibitor s di sr upt chemi cal bi ndi ng i n stomach cel l s to
r educe aci d pr oducti on, l esseni ng i r r i tati on and al l owi ng pepti c
ul cer s to better heal . They i ncl ude:

esomeprazol e
l ansoprazol e
 omeprazol e
pantoprazol e
rabeprazol e.

Pharmacokinetics
Pr oton pump i nhi bi tor s ar e gi ven oral l y i n enter i c-coated for mul as
to bypass the stomach because theyr e hi ghl y unstabl e i n aci d.
When i n the smal l i ntesti ne, they di ssol ve and ar e absor bed rapi dl y.

Metabolism and excretion

These medi cati ons ar e hi ghl y pr otei n-bound and ar e extensi vel y
metabol i zed by the l i ver to i nacti ve compounds and then el i mi nated
i n ur i ne.

Pharmacodynamics
Pr oton pump i nhi bi tor s bl ock the l ast step i n the secr eti on of gastr i c
aci d by combi ni ng wi th hydr ogen, potassi um, and adenosi ne
tr i phosphate i n the par i etal cel l s of the stomach.

Pharmacotherapeutics
Pr oton pump i nhi bi tor s ar e i ndi cated for :

shor t-ter m tr eatment of acti ve gastr i c ul cer s

acti ve duodenal ul cer s

er osi ve esophagi ti s
symptomati c G ERD unr esponsi ve to other therapi es
acti ve pepti c ul cer s associ ated wi th H. pylor i i nfecti on, i n
combi nati on wi th anti bi oti cs
l ong-ter m tr eatment of hyper secr etor y states such as Zol l i nger-
El l i son syndr ome.

Drug interactions
Pr oton pump i nhi bi tor s may i nter fer e wi th the metabol i sm of
di azepam, phenytoi n, and war far i n, causi ng i ncr eased hal f-l i fe and
el evated pl asma l evel s of these dr ugs.

Absorbing talk
Pr oton pump i nhi bi tor s may al so i nter fer e wi th the absor pti on of
dr ugs that depend on gastr i c pH for absor pti on, such as
ketoconazol e, di goxi n, ampi ci l l i n, and i r on sal ts. (See Adver se
r eacti ons to pr oton pump i nhi bi tor s.)

Warning!
Adverse reactions to proton pump inhibitors
Adver se r eacti ons to pr oton pump i nhi bi tor s i ncl ude:

abdomi nal pai n

di ar r hea
nausea and vomi ti ng.

Other antiulcer drugs

Resear ch conti nues on the useful ness of other dr ugs i n tr eati ng
pepti c ul cer di sease. Two other dr ugs cur r entl y i n use ar e:

mi sopr ostol (a syntheti c for m of pr ostagl andi n E1 )

sucral fate.
Pharmacokinetics
Each dr ug has a sl i ghtl y di ffer ent phar macoki neti c pr oper ty.

Absorption, metabolism, and excretion

After an oral dose, mi sopr ostol i s absor bed extensi vel y and rapi dl y.
Its metabol i zed to mi sopr ostol aci d, whi ch i s cl i ni cal l y acti ve,
meani ng that i t can pr oduce a phar macol ogi c effect. Mi sopr ostol aci d
i s hi ghl y pr otei n-bound and i s excr eted pr i mar i l y i n ur i ne.
Sucral fate i s mi ni mal l y absor bed fr om the G I tract and i s excr eted
i n stool .

Pharmacodynamics
The acti ons of these dr ugs var y.

Nay-saying NSAIDs
Mi sopr ostol pr otects agai nst pepti c ul cer s caused by NSAIDs by
r educi ng the secr eti on of gastr i c aci d and boosti ng the pr oducti on of
gastr i c mucus, a natural defense agai nst pepti c ul cer s.

Safe and sound

Dangers of misoprostol use during pregnancy
Use of mi sopr ostol dur i ng pr egnancy can l ead to pr ematur e
bi r th, bi r th defects, or fetal abor ti on. When used after the 8th
week of pr egnancy to i nduce l abor or abor ti on, mi sopr ostol can
cause uter i ne r uptur e as wel l . Mi sopr ostol -i nduced abor ti ons may
be i ncompl ete. For these r easons, the dr ug i s contrai ndi cated for
gastr i c ul cer pr eventi on dur i ng pr egnancy.

Protective paste
Sucral fate wor ks l ocal l y i n the stomach, rapi dl y r eacti ng wi th
hydr ochl or i c aci d to for m a thi ck, pastel i ke substance that adher es
to the gastr i c mucosa and, especi al l y, to ul cer s. By bi ndi ng to the
ul cer si te, sucral fate actual l y pr otects the ul cer fr om the damagi ng
effects of aci d and pepsi n to pr omote heal i ng. Thi s bi ndi ng usual l y
l asts for 6 hour s.
Pharmacotherapeutics
Each of these dr ugs has i ts own therapeuti c use.

Warning!
Adverse reactions to other peptic ulcer drugs
Misoprostol

Di ar r hea (common and usual l y dose-r el ated)

Abdomi nal pai n
G as
Indi gesti on
Nausea and vomi ti ng

Sucralfate

Consti pati on
Nausea and vomi ti ng
Metal l i c taste

Making it less complicated

Mi sopr ostol pr events gastr i c ul cer s caused by NSAIDs i n the pati ent
at hi gh r i sk for compl i cati ons r esul ti ng fr om gastr i c ul cer s. (See
Danger s of mi sopr ostol use dur i ng pr egnancy.)

In the short run

Sucral fate i s used for the shor t-ter m tr eatment (up to 8 weeks) of
duodenal or gastr i c ul cer s and for the pr eventi on of r ecur r ent ul cer s
or str ess ul cer s.

Drug interactions
Mi sopr ostol and sucral fate may i nteract wi th other dr ugs.

Antaci ds may bi nd wi th mi sopr ostol or decr ease i ts absor pti on.

However, thi s effect doesnt appear to be cl i ni cal l y si gni fi cant.
Antaci ds may r educe the bi ndi ng of sucral fate to the gastr i c and
duodenal mucosa, r educi ng i ts effecti veness.
 Ci meti di ne, di goxi n, nor fl oxaci n, phenytoi n, fl uor oqui nol ones,
rani ti di ne, tetracycl i ne, and theophyl l i ne decr ease the
absor pti on of sucral fate. (See Adver se r eacti ons to other pepti c
ul cer dr ugs.)

Adsorbent, antiflatulent, and digestive drugs

Adsor bent, anti fl atul ent, and di gesti ve dr ugs ar e used to fi ght
undesi rabl e toxi ns, aci ds, and gases i n the G I tract, ai di ng heal thy
G I functi on.

Adsorbent drugs
Natural and syntheti c adsor bents ar e pr escr i bed as anti dotes for the
i ngesti on of toxi ns, substances that can l ead to poi soni ng or
over dose.

Charcoal sketch
The most commonl y used cl i ni cal adsor bent i s acti vated char coal , a
bl ack powder r esi due obtai ned fr om the di sti l l ati on of var i ous
or gani c mater i al s.

Pharmacokinetics
Acti vated char coal must be admi ni ster ed soon after toxi c i ngesti on
because i t can bi nd onl y wi th dr ugs or poi sons that havent yet been
absor bed fr om the G I tract.

Vicious cycle
After i ni ti al absor pti on, some poi sons move back i nto the i ntesti nes,
wher e theyr e r eabsor bed. Acti vated char coal may be admi ni ster ed
r epeatedl y to br eak thi s cycl e.

Absorption, metabolism, and excretion

Acti vated char coal , whi ch i snt absor bed or metabol i zed by the body,
i s excr eted unchanged i n stool .

Pharmacodynamics
Because adsor bents attract and bi nd to toxi ns i n the i ntesti ne, they
i nhi bi t toxi ns fr om bei ng absor bed by the G I tract. However, thi s
bi ndi ng doesnt change toxi c effects caused by ear l i er absor pti on of
the poi son.

Pharmacotherapeutics
Acti vated char coal i s a general -pur pose anti dote used for many
types of acute oral poi soni ng. It i snt i ndi cated i n acute poi soni ng
fr om mi neral aci ds, al kal i nes, cyani de, ethanol , methanol , i r on,

l i thi um, sodi um chl or i de al kal i , i nor gani c aci ds, or or gani c sol vents.
It al so shoul dnt be used i n a chi l d whos younger than age 1 year.
In addi ti on, i t shoul dnt be used i n a pati ent who has a r i sk of G I
obstr ucti on, per forati on, or hemor r hage or decr eased or absent
bowel sounds, or who has had r ecent G I sur ger y.

Drug interactions
Acti vated char coal can decr ease absor pti on of oral medi cati ons;
ther efor e, medi cati ons (other than those used to tr eat the i ngested
toxi n) shoul dnt be taken oral l y wi thi n 2 hour s of taki ng the
acti vated char coal . The effecti veness of acti vated char coal may be
decr eased by vomi ti ng i nduced by i pecac syr up. If both dr ugs ar e
used to tr eat oral poi soni ng, acti vated char coal shoul d be used after
vomi ti ng has ceased. (See Adver se r eacti ons to acti vated char coal.)

Warning!
Adverse reactions to activated charcoal
Acti vated char coal tur ns stool s bl ack and may cause
consti pati on.
Teaming up
A l axati ve, such as sor bi tol , usual l y i s gi ven wi th acti vated
char coal to pr event consti pati on and i mpr ove taste.

Antiflatulent drugs
Antiflatulents di sper se gas pockets i n the G I tract. Theyr e avai l abl e
al one or i n combi nati on wi th antaci ds. A major anti fl atul ent dr ug
cur r entl y i n use i s si methi cone.

Pharmacokinetics
Anti fl atul ents ar ent absor bed fr om the G I tract. Theyr e di str i buted
onl y i n the i ntesti nal l umen and ar e el i mi nated i ntact i n stool .

Pharmacodynamics
Anti fl atul ents pr ovi de defoami ng acti on i n the G I tract. By
pr oduci ng a fi l m i n the i ntesti nes, si methi cone di sper ses mucus-
encl osed gas pockets and hel ps pr event thei r for mati on.

Pharmacotherapeutics
Anti fl atul ents ar e pr escr i bed to tr eat condi ti ons i n whi ch excess gas
i s a pr obl em, such as:
 functi onal gastr i c bl oati ng
postoperati ve gaseous bl oati ng
di ver ti cul ar di sease
spasti c or i r r i tabl e col on
ai r swal l owi ng.

Drug interactions
Si methi cone doesnt i nteract si gni fi cantl y wi th other dr ugs and
doesnt cause known adver se r eacti ons.

Digestive drugs
Digestive dr ugs (di gestants) ai d di gesti on i n the pati ent whos
mi ssi ng enz ymes or other substances needed to di gest food.
Di gestants that functi on i n the G I tract, l i ver, and pancr eas i ncl ude:

pancr eati n
pancr el i pase
l i pase
pr otease
amyl ase (pancr eati c enz ymes).
Pharmacokinetics
Di gestants ar ent absor bed; they act l ocal l y i n the G I tract and ar e
excr eted i n stool .

Pharmacodynamics
The acti on of di gestants r esembl es the acti on of the body
substances they r epl ace. Pancr eati c enz ymes r epl ace nor mal
pancr eati c enz ymes. They exer t thei r effect i n the duodenum and
upper jejunum of the upper G I tract.

Warning!
Adverse reactions to digestive drugs
Pancreatic enzymes

Abdomi nal crampi ng

Di ar r hea
Nausea

Breaking it down
These dr ugs contai n tr ypsi n to di gest pr otei ns, amyl ase to di gest
car bohydrates, and l i pase to di gest fats.

Pharmacotherapeutics
Because thei r acti on r esembl es the acti on of the body substances
they r epl ace, each di gestant has i ts own i ndi cati on.

Mirror images
Pancr eati c enz ymes ar e admi ni ster ed to the pati ent wi th i nsuffi ci ent
l evel s of pancr eati c enz ymes, such as the pati ent wi th pancr eati ti s
or cysti c fi br osi s. They may al so be used to tr eat steator r hea
(di sor der of fat metabol i sm character i zed by fatty, foul -smel l i ng
stool ).

Drug interactions
Antaci ds r educe the effects of pancr eati c enz ymes and shoul dnt be
gi ven at the same ti me. Pancr eati c enz ymes may decr ease the
absor pti on of fol i c aci d and i r on. (See Adver se r eacti ons to di gesti ve
dr ugs.)

Obesity drugs
Obesity dr ugs ar e used for pati ents who ar e mor bi dl y obese and
have heal th pr obl ems that ar e l i kel y to i mpr ove wi th wei ght l oss.
Theyr e used i n combi nati on wi th a wei ght management pr ogram
that i ncl udes di et, physi cal acti vi ty, and behavi oral modi fi cati on.
Dr ug therapy shoul d be used to i mpr ove heal th rather than pr omote
cosmeti c wei ght l oss.
Dr ugs for obesi ty fal l i nto two categor i es:

appeti te suppr essants (phenter mi ne and si butrami ne)

fat bl ocker s (or l i stat).

Pharmacokinetics
Si butrami ne i s rapi dl y absor bed fr om the i ntesti nes and rapi dl y
di str i buted to most body ti ssues. Its metabol i zed i n the l i ver and
excr eted i n the ur i ne and feces. Or l i stat i snt absor bed systemi cal l y;
i ts acti on occur s i n the G I tract. Or l i stat i s excr eted i n the feces.

Pharmacodynamics
Appeti te suppr essants i ncr ease the amount of nor epi nephr i ne and
dopami ne i n the brai n, ther eby suppr essi ng the appeti te. The fat-
bl ocki ng dr ug or l i stat bi nds to gastr i c and pancr eati c l i pases i n the
G I tract, maki ng them unavai l abl e to br eak down fats. Thi s bl ocks
absor pti on of 30% of the fat i ngested i n a meal .

Pharmacotherapeutics
Appeti te suppr essants and fat bl ocker s ar e used pr i mar i l y for wei ght
l oss when l osi ng wei ght wi l l i mpr ove the pati ents heal th and
pr event death.
Drug interactions
Obesi ty dr ugs i nteract wi th other dr ugs.

Appeti te suppr essants taken wi th car di ovascul ar sti mul ants may
i ncr ease the r i sk of hyper tensi on and ar r hythmi as.
Appeti te suppr essants taken wi th central ner vous system (CNS)
sti mul ants can cause i ncr eased anxi ety and i nsomni a.
Appeti te suppr essants taken wi th ser otoner gi c dr ugs (i ncl udi ng
fl uoxeti ne, sumatr i ptan, dextr omethor phan, and l i thi um) can
cause agi tati on, confusi on, hypomani a, i mpai r ed coor di nati on,
l oss of consci ousness, nausea, or tachycar di a.

Or l i stat bl ocks the absor pti on of fat-sol ubl e vi tami ns i f taken

together. (See Adver se r eacti ons to obesi ty dr ugs.)

Warning!
Adverse reactions to obesity drugs
Adver se r eacti ons to obesi ty dr ugs i ncl ude the fol l owi ng:
 Phenter mi ne can cause ner vousness, dr y mouth, consti pati on,
and hyper tensi on.
Si butrami ne can cause dr y mouth, headache, i nsomni a,
ner vousness, consti pati on, hyper tensi on, tachycar di a, and
pal pi tati ons.
Or l i stat causes abdomi nal pai n, oi l y spotti ng, fecal ur gency,
fl atul ence wi th di schar ge, fatty stool s, fecal i nconti nence, and
i ncr eased defecati on. These effects usual l y subsi de after a few
weeks.

Antidiarrheal and laxative drugs

Di ar r hea and consti pati on ar e the two major symptoms r el ated to
di stur bances of the l ar ge i ntesti ne.

Is it local?
Antidiar r heals act systemi cal l y or l ocal l y and i ncl ude:

opi oi d-r el ated dr ugs

kaol i n and pecti n
5-HT 3 r eceptor antagoni sts (al osetr on).

Loosen up!
Laxatives sti mul ate defecati on and i ncl ude:

hyper osmol ar dr ugs

di etar y fi ber and r el ated bul k-for mi ng substances
emol l i ents
sti mul ants
l ubr i cants.
Opioid-related drugs
Opioid-r elated dr ugs decr ease per i stal si s (i nvol untar y, pr ogr essi ve,
wavel i ke i ntesti nal movement that pushes fecal matter al ong) i n the
i ntesti nes and i ncl ude:

di phenoxyl ate wi th atr opi ne

l operami de.

Pharmacokinetics
The combi nati on dr ug di phenoxyl ate wi th atr opi ne i s r eadi l y
absor bed fr om the G I tract. However, l operami de i snt absor bed wel l
after oral admi ni strati on.

Distribution, metabolism, and excretion

Both dr ugs ar e di str i buted i n ser um, metabol i zed i n the l i ver, and
excr eted pr i mar i l y i n stool . Di phenoxyl ate wi th atr opi ne i s
metabol i zed to di fenoxi n, i ts bi ol ogi cal l y acti ve major metabol i te.

Pharmacodynamics
Di phenoxyl ate wi th atr opi ne and l operami de sl ow G I moti l i ty by
depr essi ng per i stal si s i n the l ar ge and smal l i ntesti nes. These dr ugs
al so decr ease expul si ve contracti ons thr oughout the col on.
Pharmacotherapeutics
Di phenoxyl ate wi th atr opi ne and l operami de ar e used to tr eat acute,
nonspeci fi c di ar r hea. Loperami de i s used to tr eat chr oni c di ar r hea.

Drug interactions
Di phenoxyl ate wi th atr opi ne and l operami de may enhance the
depr essant effects of bar bi turates, al cohol , opi oi ds, tranqui l i zer s,
and sedati ves. (See Adver se r eacti ons to opi oi d-r el ated dr ugs.)

Warning!
Adverse reactions to opioid-related drugs
Adver se r eacti ons to di phenoxyl ate wi th atr opi ne and
l operami de i ncl ude:

nausea and vomi ti ng

abdomi nal di scomfor t or di stenti on
dr owsi ness
fati gue
central ner vous system depr essi on
tachycar di a (fast hear t rate)
paral yti c i l eus (r educed or absent per i stal si s i n the
i ntesti nes).

Kaolin and pectin

Kaolin and pectin mi xtur es ar e l ocal l y acti ng OTC anti di ar r heal s.
They wor k by adsor bi ng i r r i tants and soothi ng the i ntesti nal
mucosa.
Pharmacokinetics
Kaol i n and pecti n ar ent absor bed and, ther efor e, ar ent di str i buted
thr oughout the body. Theyr e excr eted i n stool .

Pharmacodynamics
Kaol i n and pecti n act as adsor bents, bi ndi ng wi th bacter i a, toxi ns,
and other i r r i tants i n the i ntesti nal mucosa. Pecti n decr eases the pH
i n the i ntesti nal l umen and pr ovi des a soothi ng effect on the
i r r i tated mucosa.

Pharmacotherapeutics
Kaol i n and pecti n ar e used to r el i eve mi l d to moderate acute
di ar r hea. They may al so be used to temporar i l y r el i eve chr oni c
di ar r hea unti l the cause i s deter mi ned and defi ni ti ve tr eatment
begun.

Drug interactions
These anti di ar r heal s can i nter fer e wi th the absor pti on of di goxi n
and other dr ugs by the i ntesti nal mucosa i f admi ni ster ed at the
same ti me. (See Adver se r eacti ons to kaol i n and pecti n.)

Warning!
Adverse reactions to kaolin and pectin
Kaol i n and pecti n mi xtur es cause few adver se r eacti ons.
However, consti pati on may occur, especi al l y i n an el der l y or a
debi l i tated pati ent and wi th over dose or pr ol onged use.
5-HT 3 receptor antagonists
Alosetr on i s a sel ecti ve 5-HT 3 r eceptor antagoni st used for shor t-
ter m tr eatment of women wi th i r r i tabl e bowel syndr ome (IBS) wi th
sever e di ar r hea as the mai n symptom. Thi s dr ug i s avai l abl e onl y
thr ough a r estr i cted mar keti ng pr ogram because of r epor ted ser i ous
G I adver se effects. Onl y pr escr i ber s enr ol l ed i n the pr escr i bi ng
pr ogram for al osetr on may wr i te a pr escr i pti on for i t.

Pharmacokinetics
Al osetr on i s rapi dl y absor bed after oral admi ni strati on and i s
metabol i zed by the cytochr ome P450 pathway.

Pharmacodynamics
Al osetr on i s thought to bl ock ser otoni n i n the G I system, ther eby
r educi ng the abdomi nal crampi ng and di scomfor t, ur gency, and
di ar r hea commonl y associ ated wi th IBS.

Pharmacotherapeutics
Al osetr on i s used for the shor t-ter m tr eatment of a woman wi th IBS
whose pr i mar y symptom i s di ar r hea. The dr ug shoul dnt be taken i f
the pati ent i s consti pated and shoul d be stopped i f consti pati on
devel ops.

Drug interactions
Al osetr on pr oduces a 30% i nhi bi ti on of N-acetyl transferase and
CYP1A2. Al though studi es havent been done, the i nhi bi ti on of N-
acetyl transferase may have cl i ni cal si gni fi cance when al osetr on i s
gi ven wi th such dr ugs as i soni az i d, pr ocai nami de, and hydral -az i ne.
Al osetr on gi ven wi th other dr ugs that decr ease G I moti l i ty coul d
cause consti pati on. (See Adver se r eacti ons to al osetr on.)

Warning!
Adverse reactions to alosetron
Al osetr on can cause ser i ous and someti mes fatal adver se
r eacti ons, such as i schemi c col i ti s, and compl i cati ons of
consti pati on, i ncl udi ng obstr ucti on, per forati on, and toxi c
megacol on.
Elderly patients
 Ol der adul ts may have i ncr eased sensi ti vi ty to al osetr ons effects,
thus i ncr easi ng thei r r i sk of devel opi ng ser i ous consti pati on.
P.

Hyperosmolar laxatives
Hyper osmolar laxatives wor k by drawi ng water i nto the i ntesti ne,
ther eby pr omoti ng bowel di stenti on and per i stal si s. They i ncl ude:

gl ycer i n
l actul ose
sal i ne compounds (magnesi um sal ts, sodi um bi phosphate, sodi um
phosphate, pol yethyl ene gl ycol [PEG ], and el ectr ol ytes).

Pharmacokinetics
The phar macoki neti c pr oper ti es of hyper osmol ar l axati ves var y.

Direct placement
G l ycer i n i s pl aced di r ectl y i nto the col on by enema or supposi tor y
and i snt absor bed systemi cal l y.

Minimal absorption
Lactul ose enter s the G I tract oral l y and i s mi ni mal l y absor bed. As a
r esul t, the dr ug i s di str i buted onl y i n the i ntesti ne. Its metabol i zed
by bacter i a i n the col on and excr eted i n stool .

Introducing ions
After sal i ne compounds ar e i ntr oduced i nto the G I tract oral l y or as
an enema, some of thei r i ons ar e absor bed. Absor bed i ons ar e
excr eted i n ur i ne, the unabsor bed dr ug i n stool .

Pegging PEG
PEG i s a nonabsor babl e sol uti on that acts as an osmoti c dr ug, but
doesnt al ter el ectr ol yte bal ance.

Pharmacodynamics
Hyper osmol ar l axati ves pr oduce a bowel movement by drawi ng
water i nto the i ntesti ne. F l ui d accumul ati on di stends the bowel and
pr omotes per i stal si s, r esul ti ng i n a bowel movement.

Pharmacotherapeutics
The uses of hyper osmol ar l axati ves var y.

G l ycer i n i s hel pful i n bowel r etrai ni ng.

Lactul ose i s used to tr eat consti pati on and to r educe ammoni a
pr oducti on and absor pti on fr om the i ntesti nes i n the pati ent wi th
an el evated ammoni a l evel , as occur s i n ci r r hosi s and l i ver
fai l ur e.
Sal i ne compounds ar e used when pr ompt and compl ete bowel
evacuati on i s r equi r ed.

Warning!
Adverse reactions to hyperosmolar laxatives
Adver se r eacti ons to most hyper osmol ar l axati ves i nvol ve
fl ui d and el ectr ol yte i mbal ances.
Glycerin

Weakness
Fati gue
 Lactulose

Abdomi nal di stenti on and cramps, gas

Nausea and vomi ti ng
Di ar r hea
Hypokal emi a
Hypovol emi a
Incr eased bl ood gl ucose l evel

Saline compounds

Weakness
Lethar gy
Dehydrati on
Hyper natr emi a
Hyper magnesemi a
Hyper phosphatemi a
Hypocal cemi a
Car di ac ar r hythmi as
Shock

Polyethylene glycol

Nausea
Expl osi ve di ar r hea
Bl oati ng

Drug interactions
Hyper osmol ar l axati ves dont i nteract si gni fi cantl y wi th other dr ugs.
However, oral dr ugs gi ven 1 hour befor e admi ni ster i ng PEG have
si gni fi cantl y decr eased absor pti on. (See Adver se r eacti ons to
hyper osmol ar l axati ves.)
Dietary fiber and related bulk-forming
laxatives
A hi gh-fi ber di et i s the most natural way to pr event or tr eat
consti pati on. Dietar y fiber i s the par t of pl ants not di gested i n the
smal l i ntesti ne.

Bulking up
Bulk-for ming laxatives, whi ch r esembl e di etar y fi ber, contai n natural
and semi syntheti c pol ysacchar i des and cel l ul ose. These l axati ves
i ncl ude:

methyl cel l ul ose

pol ycar bophi l
psyl l i um hydr ophi l i c muci l l oi d.

Pharmacokinetics
Di etar y fi ber and bul k-for mi ng l axati ves ar ent absor bed
systemi cal l y. The pol ysacchar i des i n these dr ugs ar e conver ted by
i ntesti nal bacter i al fl ora i nto osmoti cal l y acti ve metabol i tes that
draw water i nto the i ntesti ne.

Excretion
Di etar y fi ber and bul k-for mi ng l axati ves ar e excr eted i n stool .
Pharmacodynamics
Di etar y fi ber and bul k-for mi ng l axati ves i ncr ease stool mass and
water content, pr omoti ng per i stal si s.

Pharmacotherapeutics
Bul k-for mi ng l axati ves ar e used to:

tr eat si mpl e cases of consti pati on, especi al l y consti pati on

r esul ti ng fr om a l ow-fi ber or l ow-fl ui d di et
ai d pati ents r ecover i ng fr om acute myocar di al i nfar cti on (MI) or
cer ebral aneur ysms who need to avoi d Val sal vas maneuver
(for ced expi rati on agai nst a cl osed ai r way) and mai ntai n soft
stool
manage pati ents wi th IBS and di ver ti cul osi s.

Drug interactions
Decr eased absor pti on of di goxi n, war far i n, and sal i cyl ates occur s i f
these dr ugs ar e taken wi thi n 2 hour s of taki ng fi ber or bul k-for mi ng
l axati ves. (See Adver se r eacti ons to di etar y fi ber and r el ated bul k-
for mi ng l axati ves.)

Warning!
Adverse reactions to dietary fiber and related
bulk-forming laxatives
Adver se r eacti ons to di etar y fi ber and r el ated bul k-for mi ng
l axati ves i ncl ude:

gas
abdomi nal ful l ness
i ntesti nal obstr ucti on
fecal i mpacti on (har d stool that cant be r emoved fr om the
r ectum)
esophageal obstr ucti on (i f suffi ci ent l i qui d hasnt been
admi ni ster ed wi th the dr ug)
sever e di ar r hea.
Emollient laxatives
Emollientsal so known as stool softener si ncl ude the cal ci um,
potassi um, and sodi um sal ts of docusate.

Pharmacokinetics
Admi ni ster ed oral l y, emol l i ents ar e absor bed and excr eted thr ough
bi l e i n stool .

Pharmacodynamics
Emol l i ents soften stool and make bowel movements easi er by
emul si fyi ng the fat and water components of stool i n the smal l and
l ar ge i ntesti nes. Thi s deter gent acti on al l ows water and fats to
penetrate stool , maki ng i t softer and easi er to el i mi nate.

Stimulating talk
Emol l i ents al so sti mul ate el ectr ol yte and fl ui d secr eti on fr om
i ntesti nal mucosal cel l s.

Pharmacotherapeutics
Emol l i ents ar e the dr ugs of choi ce for softeni ng stool s i n pati ents
who shoul d avoi d strai ni ng dur i ng a bowel movement, i ncl udi ng
those wi th:

r ecent MI or sur ger y

di sease of the anus or r ectum
i ncr eased i ntracrani al pr essur e (ICP)
her ni as.

Drug interactions
Taki ng oral doses of mi neral oi l wi th oral emol l i ents i ncr eases the
systemi c absor pti on of mi neral oi l and may r esul t i n ti ssue deposi ts
of the oi l .

Proceed with caution

Because emol l i ents may enhance the absor pti on of many oral dr ugs,
dr ugs wi th l ow mar gi ns of safety (nar r ow therapeuti c i ndex) shoul d
be admi ni ster ed cauti ousl y wi th emol l i ents. (See Adver se r eacti ons
to emol l i ent l axati ves.)

Warning!
Adverse reactions to emollient laxatives
Al though adver se r eacti ons to emol l i ents sel dom occur, they
may i ncl ude:

bi tter taste
di ar r hea
thr oat i r r i tati on
mi l d, transi ent abdomi nal crampi ng.

Stimulant laxatives
Stimulant laxatives, al so known as ir r itant cathar tics, i ncl ude:

bi sacodyl
castor oi l
senna.

Pharmacokinetics
Sti mul ant l axati ves ar e mi ni mal l y absor bed and ar e metabol i zed i n
the l i ver. The metabol i tes ar e excr eted i n ur i ne and stool .
Pharmacodynamics
Sti mul ant l axati ves pr omote per i stal si s and pr oduce a bowel
movement by i r r i tati ng the i ntesti nal mucosa or sti mul ati ng ner ve
endi ngs of the i ntesti nal smooth muscl e.

No job is too small

Castor oi l al so i ncr eases per i stal si s i n the smal l i ntesti ne.

Pharmacotherapeutics
Sti mul ant l axati ves ar e the pr efer r ed dr ugs for emptyi ng the bowel
befor e general sur ger y, si gmoi doscopi c or pr octoscopi c pr ocedur es,
and radi ol ogi c pr ocedur es such as bar i um studi es of the G I tract.
Theyr e al so used to tr eat consti pati on caused by pr ol onged bed
r est, neur ol ogi c dysfuncti on of the col on, and consti pati ng dr ugs
such as opi oi ds.

Drug interactions
No si gni fi cant dr ug i nteracti ons occur wi th the sti mul ant l axati ves.
However, because these l axati ves pr oduce i ncr eased i ntesti nal
moti l i ty, they r educe the absor pti on of other oral dr ugs
admi ni ster ed at the same ti me, especi al l y sustai ned-r el ease for ms.
(See Adver se r eacti ons to sti mul ant l axati ves.)

Warning!
Adverse reactions to stimulant laxatives
Adver se r eacti ons to sti mul ant l axati ves i ncl ude:

weakness
nausea
abdomi nal cramps
mi l d i nfl ammati on of the r ectum and anus
ur i ne di scol orati on (wi th senna).

Lubricant laxatives
Mi neral oi l i s the mai n lubr icant laxative cur r entl y i n cl i ni cal use.
Pharmacokinetics
In i ts nonemul si fi ed for m, mi neral oi l i s mi ni mal l y absor bed; the
emul si fi ed for m i s about hal f absor bed. Absor bed mi neral oi l i s
di str i buted to the mesenter i c l ymph nodes, i ntesti nal mucosa, l i ver,
and spl een.

Metabolism and excretion

Mi neral oi l i s metabol i zed by the l i ver and excr eted i n stool .

Pharmacodynamics
Mi neral oi l l ubr i cates stool and the i ntesti nal mucosa and pr events
water r eabsor pti on fr om the bowel l umen. The i ncr eased fl ui d
content of stool i ncr eases per i stal si s. Admi ni strati on by enema al so
pr oduces di stenti on.

Pharmacotherapeutics
Mi neral oi l i s used to tr eat consti pati on and mai ntai n soft stool
when strai ni ng i s contrai ndi cated, such as after a r ecent MI (to
avoi d Val sal vas maneuver ), eye sur ger y (to pr event i ncr eased
pr essur e i n the eye), or cer ebral aneur ysm r epai r (to avoi d
i ncr eased ICP).

Warning!
Adverse reactions to mineral oil
Adver se r eacti ons to mi neral oi l i ncl ude:

nausea and vomi ti ng

di ar r hea
abdomi nal crampi ng.

Impacting impaction
Admi ni ster ed oral l y or by enema, thi s l ubr i cant l axati ve i s al so used
to tr eat the pati ent wi th fecal i mpacti on.

Drug interactions
Mi neral oi l can i nteract wi th other dr ugs.

Mi neral oi l may i mpai r the absor pti on of many oral dr ugs,

i ncl udi ng fat-sol ubl e vi tami ns, hor monal contracepti ves, and
anti -coagul ants.
Mi neral oi l may i nter fer e wi th the anti bacter i al acti vi ty of
nonabsor babl e sul fonami des. To mi ni mi ze dr ug i nteracti ons,
admi ni ster mi neral oi l at l east 2 hour s befor e these medi cati ons.
(See Adver se r eacti ons to mi neral oi l.)

Antiemetic and emetic drugs

Antiemetics and emetics ar e two gr oups of dr ugs wi th opposi ng
acti ons. Anti emeti c dr ugs decr ease nausea, r educi ng the ur ge to
vomi t. Emeti c dr ugs, whi ch ar e der i ved fr om pl ants, pr oduce
vomi ti ng.

Antiemetics
The major anti emeti cs ar e:

anti hi stami nes, i ncl udi ng bucl i z i ne, cycl i z i ne, di menhydr i nate,
di phenhydrami ne, hydr oxyz i ne hydr ochl or i de, hydr oxyz i ne
pamoate, mecl i z i ne, and tr i methobenz ami de
phenothi az i nes, i ncl udi ng chl or pr omaz i ne, per phenaz i ne,
pr ochl or peraz i ne mal eate, pr omethaz i ne, and thi ethyl peraz i ne
mal eate
 ser otoni n 5-HT 3 r eceptor antagoni sts, i ncl udi ng dol asetr on,
grani setr on, and ondansetr on.

Top of the charts

Ondansetr on i s cur r entl y the anti emeti c of choi ce i n the Uni ted
States.

Pharmacokinetics
The phar macoki neti c pr oper ti es of anti emeti cs may var y sl i ghtl y.

Absorption, metabolism, and excretion

Oral anti hi stami ne anti emeti cs ar e absor bed wel l fr om the G I tract
and ar e metabol i zed pr i mar i l y by the l i ver. Thei r i nacti ve
metabol i tes ar e excr eted i n ur i ne.
Phenothi az i ne anti emeti cs and ser otoni n 5-HT 3 r eceptor antagoni sts
ar e absor bed wel l , extensi vel y metabol i zed by the l i ver, and
excr eted i n ur i ne and stool .

Pharmacodynamics
The acti on of anti emeti cs may var y.

Whats going on here?

The mechani sm of acti on that pr oduces the anti emeti c effect of
anti hi stami nes i s uncl ear.

Dont pull the trigger!

Phenothi az i nes pr oduce thei r anti emeti c effect by bl ocki ng the
dopami ner gi c r eceptor s i n the chemor eceptor tr i gger zone i n the
brai n. (Thi s ar ea of the brai n, near the medul l a, sti mul ates the
vomi ti ng center i n the medul l a, causi ng vomi ti ng.) These dr ugs may
al so di r ectl y depr ess the vomi ti ng center.

Stopping serotonin stimulation

The ser otoni n 5-HT 3 r eceptor antagoni sts bl ock ser otoni n
sti mul ati on central l y i n the chemor eceptor tr i gger zone and
per i pheral l y i n the vagal ner ve ter mi nal s, both of whi ch sti mul ate
vomi ti ng.

Pharmacotherapeutics
The uses of anti emeti cs may var y.

Lend me your ear

Anti hi stami nes ar e speci fi cal l y used for nausea and vomi ti ng caused
by i nner ear sti mul ati on. As a consequence, these dr ugs pr event or
tr eat moti on si ckness. They usual l y pr ove most

effecti ve when gi ven befor e acti vi ti es that pr oduce moti on si ckness

and ar e much l ess effecti ve when nausea or vomi ti ng has al r eady
begun.

Other antiemetics
Her e ar e other anti emeti cs cur r entl y i n use.
Scopolamine
Scopol ami ne pr events moti on si ckness, but i ts use i s l i mi ted
because of i ts sedati ve and anti chol i ner gi c effects. One
transder mal pr eparati on, Transder m-Sc p, i s hi ghl y effecti ve
wi thout pr oduci ng the usual adver se effects.
Metoclopramide
Metocl oprami de i s used pr i mar i l y to tr eat G I moti l i ty di sor der s
i ncl udi ng gastr opar esi s i n di abeti c pati ents. Its al so used to
pr event chemotherapy-i nduced nausea and vomi ti ng.
Diphenidol
Di pheni dol i s used to pr event ver ti go (whi r l i ng sensati on) and to
pr event or tr eat general i zed nausea and vomi ti ng. However, i ts
use i s l i mi ted because of the audi tor y and vi sual hal l uci nati ons,
 confusi on, and di sor i entati on that may occur.
Dronabinol
Dr onabi nol , a pur i fi ed der i vati ve of cannabi s, i s a Schedul e II
dr ug (meani ng i t has a hi gh potenti al for abuse) used to tr eat
chemotherapy-i nduced nausea and vomi ti ng i n the pati ent who
doesnt r espond adequatel y to conventi onal anti emeti cs. It has
al so been used to sti mul ate appeti te i n the pati ent wi th acqui r ed
i mmunodefi ci ency syndr ome. However, dr onabi nol can accumul ate
i n the body, and the pati ent can devel op tol erance or physi cal and
psychol ogi cal dependence.

Severe cases
Phenothi az i ne anti emeti cs and ser otoni n 5-HT 3 r eceptor antagoni sts
contr ol sever e nausea and vomi ti ng fr om var i ous causes. Theyr e
used when vomi ti ng becomes sever e and potenti al l y haz ar dous,
such as postsur gi cal or vi ral nausea and vomi ti ng. Both types of
dr ugs ar e al so pr escr i bed to contr ol the nausea and vomi ti ng
r esul ti ng fr om chemotherapy and radi otherapy. (See Other
anti emeti cs.)

Drug interactions
Anti emeti cs may have many si gni fi cant i nteracti ons.

Anti hi stami nes and phenothi az i nes can pr oduce addi ti ve CNS
depr essi on and sedati on when taken wi th CNS depr essants, such
 as bar bi turates, tranqui l i zer s, anti depr essants, al cohol , and
opi oi ds.
Anti hi stami nes can cause addi ti ve anti chol i ner gi c effects, such
as consti pati on, dr y mouth, vi si on pr obl ems, and ur i ne
r etenti on, when taken wi th anti chol i ner gi c dr ugs, i ncl udi ng
tr i cycl i c anti depr essants, phenothi az i nes, and anti par ki nsoni an
dr ugs.

Phenothi az i ne anti emeti cs taken wi th anti chol i ner gi c dr ugs

i ncr ease the anti chol i ner gi c effect and decr ease the anti emeti c
effects.
Dr oper i dol used wi th phenothi az i ne anti emeti cs i ncr eases the
r i sk of extrapyrami dal (abnor mal i nvol untar y movements)
effects. (See Adver se r eacti ons to anti emeti cs.)

Warning!
Adverse reactions to antiemetics
Use of these anti emeti c dr ugs may l ead to adver se
r eacti ons:

Anti hi stami ne and phenothi az i ne anti emeti cs pr oduce

dr owsi ness and someti mes paradoxi cal central ner vous system
(CNS) sti mul ati on.
CNS effects associ ated wi th phenothi az i ne and ser otoni n 5-HT 3
r eceptor antagoni st anti emeti cs i ncl ude confusi on, anxi ety,
euphor i a, agi tati on, depr essi on, headache, i nsomni a,
r estl essness, and weakness.
The anti chol i ner gi c effect of anti emeti cs may cause
consti pati on, dr y mouth and thr oat, pai nful or di ffi cul t
ur i nati on, ur i ne r etenti on, i mpotence, and vi sual and audi tor y
di stur bances.
Phenothi az i ne anti emeti cs commonl y cause hypotensi on and
or thostati c hypotensi on wi th an i ncr eased hear t rate, fai nti ng,
and di z z i ness.

Emetics
Emetics ar e used to i nduce vomi ti ng i n a per son who has i ngested
toxi c substances. Ipecac syr up i s used to i nduce vomi ti ng i n ear l y
management of oral poi nsoni ng or dr ug over dose.

Controversy?
The use of i pecac syr up has become contr over si al , however, because
i t del ays the use of acti vated char coal . Ther es a r i sk of potenti al
abuse by i ndi vi dual s wi th eati ng di sor der s. The Amer i can Academy
of Pedi atr i cs no l onger r ecommends the r outi ne use of i pecac syr up.
The fi r st acti on par ents or car egi ver s shoul d take i f a chi l d has
i ngested a poi sonous substance i s to cal l the poi son contr ol center
and emer gency medi cal ser vi ces.

Pharmacokinetics
Li ttl e i nfor mati on exi sts concer ni ng the absor pti on, di str i buti on, and
excr eti on of i pecac syr up. After admi ni strati on of i pecac syr up,
vomi ti ng occur s wi thi n 10 to 30 mi nutes.

Measuring success
The success of tr eatment i s di r ectl y l i nked to fl ui d i ntake wi th
i pecac admi ni strati on.

Pharmacodynamics
Ipecac syr up i nduces vomi ti ng by sti mul ati ng the vomi ti ng center
l ocated i n the brai ns medul l a.

Pharmacotherapeutics
Ipecac syr up i s used to i nduce vomi ti ng i n the ear l y management of
oral poi soni ng and dr ug over dose i n i ndi vi dual s who ar e ful l y
consci ous. It shoul dnt be used after i ngesti on of petr ol eum
pr oducts, vol ati l e oi l s, or causti c substances, such as l ye, because of
the r i sk of addi ti onal esophageal i njur y or aspi rati on.

Drug interactions
Because i pecac syr up i s used onl y i n acute si tuati ons, dr ug
i nteracti ons rar el y occur. If poi soni ng r esul ts fr om i ngesti on of a
phenothi az i ne, the phenothi az i nes anti emeti c effect may decr ease
the emeti c effect of i pecac syr up. Ipecac syr up shoul dnt be
admi ni ster ed concur r entl y wi th acti vated char coal , whi ch wi l l absor b
and i nacti vate i t. (See Adver se r eacti ons to i pecac syr up.)

Warning!
Adverse reactions to ipecac syrup
Ipecac syr up rar el y pr oduces adver se r eacti ons when used
i n the r ecommended dosages. However, pr ol onged vomi ti ng (for
mor e than 1 hour ) or r epeated vomi ti ng (mor e than si x epi sodes
i n 1 hour ), l ethar gy, and di ar r hea may occur wi th r egul ar dosage
as wel l . Some peopl e ar e ver y sensi ti ve to i pecac syr up.

Quick quiz
1A pati ent i s asked why hes taki ng anti bi oti cs for an
ul cer. The practi ti oner expl ai ns that anti bi oti cs wi l l :
A. destr oy the bacter i a causi ng the ul cer.
B. destr oy the vi r us causi ng the ul cer.
C. pr event i nfecti on fr om enter i ng thr ough open ar eas i n the
gastr i c mucosa.
D. pr event i nfecti on fr om occur r i ng.

2Whats a common adver se r eacti on to mi sopr ostol ?

A. Indi gesti on
B. Consti pati on
 C. Headache
D. Di ar r hea

3How does si methi cone r el i eve gas i n the G I tract?

A. It di sper ses and pr events gas pocket for mati on.
B. It faci l i tates expul si on of gas pockets.
C. It neutral i zes gastr i c contents and r educes gas.
D. It coats and pr otects the l i ni ng of the stomach.

4The anti emeti c dr ug that woul d pr obabl y be best for a pati ent
who exper i ences moti on si ckness on an ai r pl ane i s:
A. chl or pr omaz i ne.
B. dr onabi nol .
C. di menhydr i nate.
D. dol asetr on.

5To pr event a postsur gi cal pati ent fr om strai ni ng dur i ng a bowel

movement, the practi ti oner i s most l i kel y to pr escr i be:
A. docusate.
B. magnesi um ci trate.
C. bi sacodyl .
D. castor oi l .
P.

Scoring
If you answer ed al l fi ve i tems cor r ectl y, wel l done! You
di gested thi s G I i nfor mati on admi rabl y!

If you answer ed four i tems cor r ectl y, keep up the good

wor k (pr eferabl y wi thout emeti cs).

If you answer ed fewer than four i tems cor r ectl y, you may
need extra sti mul ati on. Rer ead thi s chapter and see what
you can do!

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

9
Genitourinary drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs used to tr eat geni tour i nar y (G U) di sor der s

uses and var yi ng acti ons of these dr ugs
absor pti on, di str i buti on, metabol i z ati on, and excr eti on of
these dr ugs
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and the genitourinary system

The G U system consi sts of the r epr oducti ve system (the sex or gans)
and the ur i nar y system, whi ch i ncl udes the ki dneys, ur eter s,
bl adder, and ur ethra. The ki dneys per for m most of the wor k of the
ur i nar y system.

Multitalented
The ki dneys per for m several vi tal tasks, i ncl udi ng:

di sposi ng of wastes and excess i ons i n the for m of ur i ne

fi l ter i ng bl ood, whi ch r egul ates i ts vol ume and chemi cal makeup
hel pi ng to mai ntai n fl ui d, el ectr ol yte, and aci d-base bal ances
pr oduci ng several hor mones and enz ymes
 conver ti ng vi tami n D to a mor e acti ve for m
hel pi ng to r egul ate bl ood pr essur e and vol ume by secr eti ng
r eni n.

Helping hands
Types of dr ugs used to tr eat G U di sor der s i ncl ude:

di ur eti cs
ur i nar y tract anti spasmodi cs
er ecti l e dysfuncti on therapy dr ugs
hor monal contracepti ves.

Diuretics
Di ur eti cs tr i gger the excr eti on of water and el ectr ol ytes fr om the
ki dneys, maki ng these dr ugs a pr i mar y choi ce i n the tr eatment of
r enal di sease, edema, hyper tensi on, and hear t fai l ur e.

Thiazide and thiazide-like diuretics

Der i ved fr om sul fonami des, thi az i de and thi az i de-l i ke di ur eti cs ar e
used to tr eat edema and to pr event the devel opment and r ecur r ence
of r enal cal cul i . Theyr e al so used for such car di ovascul ar di seases
as hyper tensi on and hear t fai l ur e.
Thi az i de di ur eti cs i ncl ude:

bendr ofl umethi az i de

chl or othi az i de
hydr ochl or othi az i de
hydr ofl umethi az i de
methycl othi az i de
pol ythi az i de.

Thi az i de-l i ke di ur eti cs i ncl ude:

chl or thal i done

i ndapami de
metol azone.

Pharmacokinetics (how drugs circulate)

Thi az i de di ur eti cs ar e absor bed rapi dl y but i ncompl etel y fr om the G I
tract after oral admi ni strati on. They cr oss the pl acenta and ar e
secr eted i n br east mi l k. These dr ugs di ffer i n how wel l theyr e
metabol i zed, but al l ar e excr eted pr i mar i l y i n ur i ne.
Thi az i de-l i ke di ur eti cs ar e absor bed fr om the G I tract.
Chl or thal i done i s 90% bound to er ythr ocytes; l i ttl e i s known about
i ts metabol i sm. Indapami de i s di str i buted wi del y i nto body ti ssues
and metabol i zed i n the l i ver. Li ttl e i s al so known about the
metabol i sm of metol azone. Al l of these dr ugs ar e pr i mar i l y excr eted
i n ur i ne.

Pharmacodynamics (how drugs act)

Thi az i de and thi az i de-l i ke di ur eti cs pr omote the excr eti on of water
by pr eventi ng the r eabsor pti on of sodi um i n the ki dneys. As the
ki dneys excr ete the excess sodi um, they excr ete water al ong wi th
i t. These dr ugs al so i ncr ease the excr eti on of chl or i de, potassi um,
and bi car bonate, whi ch can r esul t i n el ectr ol yte i mbal ances. Wi th
l ong-ter m use, thi az i de di ur eti cs al so l ower bl ood pr essur e by
causi ng ar ter i ol ar vasodi l ati on.
Turning down the volume
Ini ti al l y, di ur eti c dr ugs decr ease ci r cul ati ng bl ood vol ume, l eadi ng
to r educed car di ac output. However, i f therapy i s mai ntai ned,
car di ac output stabi l i zes but pl asma fl ui d vol ume decr eases.

Pharmacotherapeutics (how drugs are used)

Thi az i des ar e used for the l ong-ter m tr eatment of hyper tensi on;
theyr e al so used to tr eat edema caused by ki dney or l i ver di sease,
mi l d or moderate hear t fai l ur e, and cor ti coster oi d and estr ogen
therapy. Because these dr ugs decr ease the l evel of cal ci um i n ur i ne,
they may be used al one or wi th other dr ugs to pr event the
devel opment and r ecur r ence of r enal cal cul i .

Pointing out a paradox

In pati ents wi th di abetes i nsi pi dus (a di sor der character i zed by
excessi ve ur i ne pr oducti on and excessi ve thi r st r esul ti ng fr om
r educed secr eti on of anti di ur eti c hor mone), thi az i des paradoxi cal l y
decr ease ur i ne vol ume, possi bl y thr ough sodi um depl eti on and
pl asma vol ume r educti on.

Warning!
Adverse reactions to thiazide and thiazide-like
diuretics
The most common adver se r eacti ons to thi az i de and thi az i de-l i ke
di ur eti cs i ncl ude:

r educed bl ood vol ume

or thostati c hypotensi on
hypokal emi a
hyper gl ycemi a
hyponatr emi a.

Drug interactions
Dr ug i nteracti ons r el ated to thi az i de and thi az i de-l i ke di ur eti cs
r esul t i n al ter ed fl ui d vol ume, bl ood pr essur e, and ser um el ectr ol yte
l evel s:
 These dr ugs may decr ease excr eti on of l i thi um, causi ng l i thi um
toxi ci ty.
Nonster oi dal anti -i nfl ammator y dr ugs, i ncl udi ng cycl ooxygenase-
2 (COX-2) i nhi bi tor s, may r educe the anti hyper tensi ve effect of
these di ur eti cs.
Use of these dr ugs wi th other potassi um-depl eti ng dr ugs and
di goxi n may cause an addi ti ve effect, i ncr easi ng the r i sk of
di goxi n toxi ci ty.
These di ur eti cs may i ncr ease the r esponse to skel etal muscl e
r el axants.
Use of these dr ugs may i ncr ease bl ood gl ucose l evel s, r equi r i ng
hi gher doses of i nsul i n or oral anti di abeti c dr ugs.
These dr ugs may pr oduce addi ti ve hypotensi on when used wi th
anti hyper tensi ves. (See Adver se r eacti ons to thi az i de and
thi az i de-l i ke di ur eti cs.)

Loop diuretics
Loop (hi gh cei l i ng) di ur eti cs ar e hi ghl y potent dr ugs. They i ncl ude
bumetani de, ethacr yni c aci d, and fur osemi de.

Pharmacokinetics
Loop di ur eti cs ar e absor bed wel l i n the G I tract and ar e rapi dl y
di str i buted. These di ur eti cs ar e hi ghl y pr otei n bound. They under go
par ti al or compl ete metabol i sm i n the l i ver, except for fur osemi de,
whi ch i s excr eted pr i mar i l y unchanged. Loop di ur eti cs ar e excr eted
pr i mar i l y by the ki dneys.

Pharmacodynamics
Loop di ur eti cs ar e the most potent di ur eti cs avai l abl e, pr oduci ng the
gr eatest vol ume of di ur esi s (ur i ne pr oducti on). Bumetani dewhi ch i s
40 ti mes mor e potent than fur osemi dei s the shor test-acti ng
di ur eti c. Loop di ur eti cs al so have a hi gh potenti al for causi ng sever e
adver se r eacti ons. (See Loop di ur eti cs war ni ng.)

Warning!
Loop diuretics warning
Loop di ur eti cs, wi th the excepti on of ethacr yni c aci d,
contai n sul fa. A pati ent who has an al l er gy to sul fa may
exper i ence an al l er gi c r eacti on to l oop di ur eti cs. Use wi th
cauti on, and al er t the pati ent to thi s possi bi l i ty.

The scoop on the loop

Loop di ur eti cs r ecei ved thei r name because they act pr i mar i l y on
the thi ck, ascendi ng l oop of Henl e (the par t of the nephr on
r esponsi bl e for concentrati ng ur i ne) to i ncr ease the secr eti on of
sodi um, chl or i de, and water. These dr ugs al so i nhi bi t sodi um,
chl or i de, and water r eabsor pti on i n the pr oxi mal tubul e.

Pharmacotherapeutics
Loop di ur eti cs ar e used to tr eat edema associ ated wi th r enal
di sease, hepati c ci r r hosi s, and hear t fai l ur e, as wel l as to tr eat
hyper tensi on (usual l y wi th a potassi um-spar i ng di ur eti c or
potassi um suppl ement to pr event hypokal emi a).
Ethacr yni c aci d may al so be used for the shor t-ter m management of
asci tes due to mal i gnancy, i di opathi c edema, or l ymphedema.
F ur osemi de may be used wi th manni tol to tr eat cer ebral edema.

Drug interactions
Loop di ur eti cs pr oduce a var i ety of dr ug i nteracti ons:

The r i sk of ototoxi ci ty (damage to the or gans of hear i ng)

 i ncr eases when ami nogl ycosi des and ci spl ati n ar e taken wi th
l oop di ur eti cs (especi al l y wi th hi gh doses of fur osemi de). (See
Adver se r eacti ons to l oop di ur eti cs.)
Loop di ur eti cs r educe the hypogl ycemi c effects of oral
anti di abeti c dr ugs, possi bl y r esul ti ng i n hyper gl ycemi a.
These dr ugs may i ncr ease the r i sk of l i thi um toxi ci ty.
The r i sk of el ectr ol yte i mbal ances that can tr i gger ar r hythmi as
i ncr eases when car di ac gl ycosi des and l oop di ur eti cs ar e taken
together.

Use wi th di goxi n may cause addi ti ve toxi ci ty, i ncr easi ng the r i sk
of di goxi n toxi ci ty and ar r hythmi as.

Warning!
Adverse reactions to loop diuretics
The most common adver se r eacti ons to l oop di ur eti cs
i ncl ude:

fl ui d and el ectr ol yte i mbal ances (i ncl udi ng metabol i c al kal osi s,
hypovol emi a, hypochl or emi a, hypochl or emi c al kal osi s,
hyper gl ycemi a, hyper ur i cemi a, dehydrati on, hyponatr emi a,
hypokal emi a, and hypomagnesemi a)
transi ent deafness
ti nni tus
di ar r hea
nausea
vomi ti ng
abdomi nal pai n
i mpai r ed gl ucose tol erance
der mati ti s
par esthesi a
hepati c dysfuncti on
photosensi ti vi ty
or thostati c hypotensi on.
Potassium-sparing diuretics
Potassi um-spar i ng di ur eti cs have weaker di ur eti c and
anti hyper tensi ve effects than other di ur eti cs but pr ovi de the
advantage of conser vi ng potassi um. These dr ugs i ncl ude ami l or i de,
spi r onol actone, and tr i amter ene.

Pharmacokinetics
Potassi um-spar i ng di ur eti cs ar e onl y avai l abl e oral l y and ar e
absor bed i n the G I tract. Theyr e metabol i zed by the l i ver (except
for ami l or i de, whi ch i snt metabol i zed) and excr eted pr i mar i l y i n
ur i ne.

Pharmacodynamics
The di r ect acti on of potassi um-spar i ng di ur eti cs on the di stal tubul e
of the ki dneys r esul ts i n ur i nar y excr eti on of sodi um, water,
bi car bonate, and cal ci um. The dr ug al so decr eases the excr eti on of
potassi um and hydr ogen i ons. These effects l ead to r educed bl ood
pr essur e and i ncr eased ser um potassi um l evel s.

Compare and contrast

Str uctural l y si mi l ar to al doster one, spi r onol actone acts as an
al doster one antagoni st. Al doster one pr omotes the r etenti on of
sodi um and water and the l oss of potassi um, wher eas spi r onol actone
counteracts these effects by competi ng wi th al doster one for r eceptor
si tes. As a r esul t, sodi um, chl or i de, and water ar e excr eted and
potassi um i s r etai ned.

Pharmacotherapeutics
Potassi um-spar i ng di ur eti cs ar e used to tr eat:

edema
di ur eti c-i nduced hypokal emi a i n pati ents wi th hear t fai l ur e
ci r r hosi s
nephr oti c syndr ome (abnor mal condi ti on of the ki dneys)
hear t fai l ur e
hyper tensi on.
A hairy situation
Spi r onol actone al so i s used to tr eat hyperal doster oni sm (excessi ve
secr eti on of al doster one) and hi r suti sm (excessi ve hai r gr owth),
i ncl udi ng hi r suti sm associ ated wi th Stei n-Leventhal

(pol ycysti c ovar y) syndr ome. Potassi um-spar i ng di ur eti cs ar e

commonl y used wi th other di ur eti cs to potenti ate thei r acti on or
counteract thei r potassi um-wasti ng effects.

Drug interactions
G i vi ng potassi um-spar i ng di ur eti cs wi th potassi um suppl ements or
angi otensi n-conver ti ng enz yme i nhi bi tor s i ncr eases the r i sk of
hyper kal emi a. Concur r ent use of spi r onol actone and di goxi n
i ncr eases the r i sk of di goxi n toxi ci ty. (See Adver se r eacti ons to
potassi um-spar i ng di ur eti cs.)

Warning!
Adverse reactions to potassium-sparing
diuretics
Few adver se dr ug r eacti ons occur wi th potassi um-spar i ng
di ur eti cs. However, thei r potassi um-spar i ng effects can l ead to
hyper kal emi a, especi al l y i f gi ven wi th a potassi um suppl ement or
hi gh-potassi um di et.

Osmotic diuretics
Osmoti c di ur eti cs cause di ur esi s thr ough osmosi s, movi ng fl ui d i nto
the extracel l ul ar spaces. They i ncl ude manni tol and ur ea.

Pharmacokinetics
Admi ni ster ed I.V. for rapi d di str i buti on, osmoti c di ur eti cs ar e fr eel y
fi l ter ed by the gl omer ul i of the ki dneyexcept for manni tol , whi ch i s
onl y sl i ghtl y metabol i zed. Osmoti c di ur eti cs ar e excr eted pr i mar i l y
i n ur i ne.

Pharmacodynamics
Osmoti c di ur eti cs r ecei ve thei r name because they i ncr ease the
osmoti c pr essur e of the gl omer ul ar fi l trate, whi ch i nhi bi ts the
r eabsor pti on of sodi um and water. They cr eate an osmoti c gradi ent
i n the gl omer ul ar fi l trate and the bl ood. In the gl omer ul ar fi l trate,
the gradi ent pr events sodi um and water r eabsor pti on. In the bl ood,
the gradi ent al l ows fl ui d to be drawn fr om the i ntracel l ul ar i nto the
i ntravascul ar spaces.

Pharmacotherapeutics
Osmoti c di ur eti cs ar e used to tr eat acute r enal fai l ur e and cer ebral
edema and to r educe i ntracrani al and i ntraocul ar pr essur e. Manni tol
i s used to pr omote di ur esi s i n acute r enal fai l ur e and to pr omote
ur i nar y excr eti on of toxi c substances.

Drug interactions
Taki ng osmoti c di ur eti cs wi th l i thi um may i ncr ease r enal excr eti on
of l i thi um, whi ch i n tur n decr eases the effecti veness of l i thi um.
Pati ents taki ng both dr ugs r equi r e l i thi um l evel moni tor i ng. (See
Adver se r eacti ons to osmoti c di ur eti cs.)

Warning!
Adverse reactions to osmotic diuretics
Adver se r eacti ons to osmoti c di ur eti cs i ncl ude:

hyponatr emi a
dehydrati on
ci r cul ator y over l oad (fr om osmoti c effects)
thr ombophl ebi ti s or l ocal i r r i tati on at the i nfusi on si te.

Carbonic anhydrase inhibitors

Car boni c anhydrase i nhi bi tor s ar e di ur eti cs that bl ock the acti on of
car boni c anhydrase. They i ncl ude acetazol ami de and
methazol ami de.

Pharmacokinetics
Car boni c anhydrase i nhi bi tor s ar e absor bed thr ough the G I tract.
Some systemi c absor pti on al so occur s after ophthal mi c
admi ni strati on. Theyr e di str i buted i n ti ssues wi th hi gh car boni c
anhydrase content, such as er ythr ocytes, pl asma, ki dneys, eyes,
l i ver, and muscl e. Car boni c anhydrase i nhi bi tor s ar e excr eted by the
ki dneys i n ur i ne.

Pharmacodynamics
In the ki dneys, car boni c anhydrase i nhi bi tor s decr ease the
avai l abi l i ty of hydr ogen i ons, whi ch bl ocks the sodi um-hydr ogen
exchange mechani sms. As a r esul t, ur i nar y excr eti on of sodi um,
potassi um, bi car bonate, and water i ncr eases.

Dont lose your sense of humor

In the eyes, car boni c anhydrase i nhi bi ti on r educes aqueous humor
pr oducti on, whi ch r educes i ntraocul ar pr essur e.

Pharmacotherapeutics
Car boni c anhydrase i nhi bi tor s ar e used for di ur esi s and to tr eat
gl aucoma. Acetazol ami de may al so be used to tr eat epi l epsy and
acute mountai n si ckness.

Drug interactions
Car boni c anhydrase i nhi bi tor s pr oduce a var i ety of dr ug
i nteracti ons:

Sal i cyl ates may cause car boni c anhydrase i nhi bi tor toxi ci ty,
i ncl udi ng central ner vous system depr essi on and metabol i c
aci dosi s.
 Di fl uni sal may i ncr ease i ntraocul ar pr essur e when gi ven wi th a
car boni c anhydrase i nhi bi tor.
Acetazol ami de used concur r entl y wi th cycl ospor i ne may i ncr ease
cycl ospor i ne l evel s and the r i sk of neur otoxi ci ty.
Acetazol ami de used concur r entl y wi th pr i mi done may decr ease
ser um and ur i ne l evel s of pr i mi done. (See Adver se r eacti ons to
car boni c anhydrase i nhi bi tor s.)

Warning!
Adverse reactions to carbonic anhydrase
inhibitors
Adver se r eacti ons to car boni c anhydrase i nhi bi tor s i ncl ude:

hypokal emi a
metabol i c aci dosi s
el ectr ol yte i mbal ances.

Urinary tract antispasmodics

Ur i nar y tract anti spasmodi cs hel p decr ease ur i nar y tract muscl e
spasms. They i ncl ude dar i fenaci n, fl avoxate, oxybutyni n,
sol i fenaci n, tol ter odi ne, and tr ospi um.

Pharmacokinetics
F l avoxate, oxybutyni n, tol ter odi ne, dar i fenaci n, and sol i fenaci n ar e
most often admi ni ster ed oral l y and ar e rapi dl y absor bed. Tr ospi um
i s admi ni ster ed oral l y but i s poor l y absor bed. Oxybutyni n i s al so
avai l abl e as a der mal patch. These dr ugs ar e al l wi del y di str i buted,
metabol i zed i n the l i ver, and excr eted i n ur i ne. Ur i nar y tract
anti spasmodi cs al so cr oss the pl acenta and ar e excr eted i n br east
mi l k.

Pharmacodynamics
Ur i nar y tract anti spasmodi cs r el i eve smooth muscl e spasms by
i nhi bi ti ng parasympatheti c acti vi ty, whi ch causes the detr usor and
ur i nar y muscl es to r el ax. F l avoxate and oxybutyni n al so exhi bi t
many anti chol i ner gi c effects.
Pharmacotherapeutics
Ur i nar y tract anti spasmodi cs ar e used for pati ents wi th overacti ve
bl adder s who have symptoms of ur i nar y fr equency, ur gency, or
i nconti nence.

Now I get it!

How oxybutynin works
When acetyl chol i ne i s r el eased wi thi n the bl adder, i t
attaches to r eceptor s on the sur face of smooth muscl e i n the
bl adder, sti mul ati ng bl adder contracti ons. Oxybutyni n suppr esses
these i nvol untar y contracti ons by bl ocki ng the r el ease of
acetyl chol i ne. Thi s anti chol i ner gi c effect i s what makes
oxybutyni n useful i n the tr eatment of overacti ve bl adder.

Urgent symptoms
Tr ospi um i s al so i ndi cated for pati ents wi th overacti ve bl adder s who
have symptoms of ur ge ur i nar y i nconti nence, and oxybutyni n acts
as an anti spasmodi c for uni nhi bi ted or r efl ex neur ogeni c bl adder.
(See How oxybutyni n wor ks.)

Drug interactions
Ur i nar y tract anti spasmodi cs have few dr ug i nteracti ons:

Use wi th anti chol i ner gi c agents may i ncr ease dr y mouth,

consti pati on, and other anti chol i ner gi c effects. (See Adver se
r eacti ons to ur i nar y tract anti spasmodi cs.)
Ur i nar y tract anti spasmodi cs may decr ease the effecti veness of
phenothi az i nes and hal oper i dol .
Tr ospi um may i nter fer e wi th the el i mi nati on of cer tai n dr ugs
excr eted thr ough the ki dneys (such as di goxi n, metfor mi n, and
vancomyci n), r esul ti ng i n i ncr eased bl ood l evel s of these dr ugs.

Erectile dysfunction therapy drugs

Er ecti l e dysfuncti on therapy dr ugs tr eat peni l e er ecti l e dysfuncti on
that r esul ts fr om a l ack of bl ood fl owi ng thr ough the cor pus
caver nosum. Thi s type of er ecti l e dysfuncti on usual l y stems fr om
vascul ar and neur ol ogi c condi ti ons. Dr ugs used for er ecti l e
dysfuncti on i ncl ude al pr ostadi l , si l denafi l , tadal afi l , and var denafi l .

Warning!
Adverse reactions to urinary tract
antispasmodics
Possi bl e adver se r eacti ons to ur i nar y tract anti spasmodi cs
i ncl ude:

bl ur r ed vi si on
headache
somnol ence
ur i nar y r etenti on
dr y mouth
dyspepsi a
consti pati on
nausea
vomi ti ng
wei ght gai n
pai n
acute and secondar y angl e-cl osur e gl aucoma.

Pharmacokinetics
Er ecti l e dysfuncti on dr ugs ar e wel l absor bed i n the G I tract.
Di str i buti on of these dr ugs i snt known. The major i ty of these
dr ugsi ncl udi ng si l denafi l , tadal afi l , and var denafi l ar e gi ven oral l y,
metabol i zed i n the l i ver, and excr eted i n feces.

An exceptional drug
Al pr ostadi l i s the excepti on: i ts admi ni ster ed di r ectl y i nto the
cor pus caver nosum, metabol i zed i n the l ungs, and excr eted i n ur i ne.

Pharmacodynamics
Si l denafi l , tadal afi l , and var denafi l sel ecti vel y i nhi bi t the
phosphodi esterase type 5 r eceptor s, whi ch causes an i ncr ease i n
bl ood l evel s of ni tr i c oxi de. Thi s i ncr ease i n ni tr i c oxi de l evel s
acti vates the cG MP enz yme, whi ch r el axes smooth muscl es and
al l ows bl ood to fl ow i nto the cor pus caver nosum, causi ng an
er ecti on.
Al pr ostadi l acts l ocal l y, pr omoti ng smooth muscl e r el axati on, whi ch
causes an i ncr ease i n bl ood fl ow to the cor pus caver nosum and
pr oduces an er ecti on.

Warning!
Adverse reactions to erectile dysfunction drugs
Adver se r eacti ons to er ecti l e dysfuncti on dr ugs i ncl ude:

decr eased supi ne bl ood pr essur e and car di ac output

i ncr eased r i sk of car di ovascul ar events, i ncl udi ng myocar di al
i nfar cti on, sudden car di ac death, ventr i cul ar ar r hythmi as,
cer ebr ovascul ar hemor r hage, transi ent i schemi c attack, and
hyper tensi on
headache
di z z i ness
fl ushi ng
dyspepsi a
vi si on changes
pr ol onged er ecti ons (mor e than 4 hour s), whi ch can r esul t i n
i r r ever si bl e damage to er ecti l e ti ssue
peni l e pai n (wi th al pr ostadi l ).

Pharmacotherapeutics
Al pr ostadi l , si l denafi l , tadal afi l , and var denafi l ar e al l used i n the
tr eatment of er ecti l e dysfuncti on. Si l denafi l i s al so i ndi cated for the
tr eatment of pul monar y ar ter i al hyper tensi on.

Drug interactions
Er ecti l e dysfuncti on dr ugs may i nteract wi th other dr ugs i n the
fol l owi ng ways:

Ni trates and al pha-adr ener gi c bl ocker s used i n combi nati on wi th

er ecti l e dysfuncti on dr ugs may cause sever e hypotensi on and
potenti al l y ser i ous car di ac events. (See Adver se r eacti ons to
 er ecti l e dysfuncti on dr ugs.)
Ketoconazol e, i traconazol e, and er ythr omyci n may r esul t i n
i ncr eased l evel s of var denafi l or tadal afi l .
Pr otease i nhi bi tor s, such as i ndi navi r or r i tonavi r, may cause
i ncr eased tadal afi l or var denafi l l evel s.

Hormonal contraceptives
Hor monal contracepti ves i nhi bi t ovul ati on. Contracepti ves typi cal l y
contai n a combi nati on of hor mones. For exampl e, ethi nyl estradi ol
may be combi ned wi th desogestr el , dr ospi r enone, l evonor gestr el ,
nor ethi ndr one, nor gesti mate, or nor gestr el . Al so, mestranol may be
combi ned wi th nor ethi ndr one. Ethi nyl estradi ol or ethynodi ol
di acetate may al so be used al one as a contracepti ve.

Pharmacokinetics
Hor monal contracepti ves ar e absor bed fr om the G I tract and ar e
wi del y di str i buted. Theyr e metabol i zed i n the ki dneys and excr eted
i n ur i ne and feces.

Patch power
Some for ms of hor monal contracepti ves ar e avai l abl e i n a
transder mal patch for m. These contracepti ves ar e absor bed thr ough
the ski n but have the same di str i buti on, metabol i sm, and excr eti on
as oral l y admi ni ster ed contracepti ves.

Pharmacodynamics
The pr i mar y mechani sm of acti on of combi nati on hor monal
contracepti ves (estr ogen and pr ogesti n) i s the suppr essi on of
gonadotr opi ns, whi ch i nhi bi ts ovul ati on. Estr ogen suppr esses
secr eti on of fol l i cl e-sti mul ati ng hor mone, whi ch bl ocks fol l i cul ar
devel opment and ovul ati on. Pr ogesti n suppr esses the secr eti on of
l utei ni z i ng hor mone, whi ch pr events ovul ati on, even i f the fol l i cl e
devel ops. Pr ogesti n al so thi ckens the cer vi cal mucus; thi s i nter fer es
wi th sper m mi grati on and causes endometr i al changes that pr event
i mpl antati on of a fer ti l i zed ovum.

Pharmacotherapeutics
The pr i mar y pur pose for taki ng hor monal contracepti ves i s the
pr eventi on of pr egnancy i n women. The combi nati on of ethi nyl
estradi ol and nor gesti mate i s al so used to tr eat moderate acne i n
femal es younger than age 15.

Drug interactions
Hor monal contracepti ves can i nteract wi th other medi cati ons i n
var i ous ways:

Anti bi oti cs, oxcar bazepi ne, phenobar bi tal , phenytoi n,

topi ramate, and modafi ni l may decr ease the effecti veness of oral
contracepti ves. A pati ent taki ng these dr ugs wi th a hor monal
contracepti ve needs to use a bar r i er contracepti ve.
 Ator vastati n may i ncr ease ser um estr ogen l evel s.
Cycl ospor i n and theophyl l i ne have an i ncr eased r i sk of toxi ci ty
when taken wi th hor monal contracepti ves.
Pr edni sone i ncr eases the therapeuti c and possi bl y toxi c effects
of hor monal contracepti ves. (See Adver se r eacti ons to hor monal
contracepti ves.)
Several her bal medi cati ons can affect ser um l evel s of hor monal
contracepti ves.

Warning!
Adverse reactions to hormonal contraceptives
Potenti al l y ser i ous adver se r eacti ons to hor monal
contracepti ves i ncl ude ar ter i al thr ombosi s, thr ombophl ebi ti s,
pul monar y embol i sm, myocar di al i nfar cti on, cer ebral hemor r hage
or thr ombosi s, hyper tensi on, gal l bl adder di sease, and hepati c
adenomas.
Other adver se r eacti ons i ncl ude:

acne
bl eedi ng or spotti ng between menstr ual per i ods
bl oati ng
br east tender ness or enl ar gement
changes i n l i bi do
di ar r hea
di ffi cul ty wear i ng contact l enses
unusual hai r gr owth
wei ght fl uctuati ons
upset stomach
vomi ti ng.

Quick quiz
1When car i ng for a pati ent taki ng a
hydr ochl or othi az i de, you shoul d moni tor the pati ent
for :
 A. hyper tensi on.
B. hyper natr emi a.
C. hypokal emi a.
D. hypogl ycemi a.

2When teachi ng a pati ent about di ur eti cs, you shoul d tel l hi m to:
A. take the dr ug i n the eveni ng.
B. cal l hi s practi ti oner i f he l oses mor e that 2 l b (0.9 kg) per
day.
C. eat a hi gh-sodi um di et.
D. avoi d sun exposur e for several hour s after taki ng the
medi cati on to pr event a photosensi ti vi ty r eacti on.

3Ur i nar y tract anti spasmodi cs ar e used to tr eat:

A. overacti ve bl adder.
B. er ecti l e dysfuncti on.
C. hyper tensi on.
D. sei z ur es.

4Whi ch dr ug necessi tates use of an addi ti onal for m of

contracepti on for a pati ent taki ng hor monal contracepti ves?
A. Ator vastati n
B. Theophyl l i ne
C. Cycl ospor i ne
D. Anti bi oti cs

P.
Scoring
If you answer ed al l four questi ons cor r ectl y, ter r i fi c!
Ever ythi ngs fl owi ng smoothl y for you when i t comes to
G U dr ugs.

If you answer ed thr ee questi ons cor r ectl y, super ! Your

str eam of knowl edge about G U dr ugs i s i mpr essi ve.

If you answer ed fewer than thr ee questi ons cor r ectl y,

dont spaz out! Rel ax, r evi ew the chapter, and tr y agai n.

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

10
Anti-infective drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs that act as anti -i nfecti ves

the uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Selecting an antimicrobial drug

Sel ecti ng an appr opr i ate anti mi cr obi al dr ug to tr eat a speci fi c
i nfecti on i nvol ves several i mpor tant factor s:

F i r st, the mi cr oor gani sm must be i sol ated and

i denti fi edgeneral l y thr ough gr owi ng a cul tur e.
Then i ts suscepti bi l i ty to var i ous dr ugs must be deter mi ned.
Because cul tur e and sensi ti vi ty r esul ts take 48 hour s, tr eatment
usual l y star ts at assessment and then i s r eeval uated when test
r esul ts ar e obtai ned.
The l ocati on of the i nfecti on must be consi der ed. For therapy to
be effecti ve, an adequate concentrati on of the anti mi cr obi al
must be del i ver ed to the i nfecti on si te.
 Lastl y, the cost of the dr ug must be consi der ed as wel l as i ts
potenti al adver se effects and the possi bi l i ty of pati ent al l er gi es.

Preventing pathogen resistance

The useful ness of anti mi cr obi al dr ugs i s l i mi ted by pathogens that
may devel op r esi stance to a dr ugs acti on.
Resi stance i s the abi l i ty of a mi cr oor gani sm to l i ve and gr ow i n the
pr esence of an anti mi cr obi al dr ug thats ei ther bacter i ostati c
(i nhi bi ts the gr owth or mul ti pl i cati on of bacter i a) or bacter i ci dal

(ki l l s bacter i a). Resi stance usual l y r esul ts fr om geneti c mutati on of

the mi cr oor gani sm. (See The r i se of the r esi stance movement.)

Antibacterial drugs
Antibacter ial dr ugs, al so known as antibiotics (dr ugs that i nhi bi t the
gr owth of bacter i a), ar e used mai nl y to tr eat systemi c (i nvol vi ng
the whol e body rather than a l ocal i zed ar ea) bacter i al i nfecti ons.
The anti bacter i al s i ncl ude:

ami nogl ycosi des

peni ci l l i ns
cephal ospor i ns
tetracycl i nes
l i ncomyci n der i vati ves
macr ol i des
vancomyci n
 car bapenems
monobactams
fl uor oqui nol ones
sul fonami des
ni tr ofurantoi n (ni tr ofuran).

Yea or nay?
The rise of the resistance movement
Indi scr i mi nate use of anti mi cr obi al dr ugs has ser i ous
consequences. Unnecessar y exposur e of or gani sms to these dr ugs
encourages the emer gence of r esi stant strai ns, whi ch ar e l i kel y to
do far mor e damage than thei r pr edecessor s.
Make reservations
The use of anti mi cr obi al dr ugs shoul d be r eser ved for pati ents
wi th i nfecti ons caused by suscepti bl e or gani sms and shoul d be
used i n hi gh enough doses and for an appr opr i ate per i od. New
anti mi cr obi al dr ugs shoul d be r eser ved for sever el y i l l pati ents
wi th ser i ous i nfecti ons that dont r espond to conventi onal dr ugs.

Aminoglycosides
Aminoglycosides pr ovi de effecti ve bacter i ci dal acti vi ty agai nst:

gram-negati ve baci l l i
some aer obi c gram-posi ti ve bacter i a
mycobacter i a
some pr otozoa.

Common aminoglycosides
Ami nogl ycosi des cur r entl y i n use i ncl ude:

ami kaci n sul fate

gentami ci n sul fate
kanamyci n sul fate
neomyci n sul fate
 par omomyci n sul fate
str eptomyci n sul fate
tobramyci n sul fate.

Pharmacokinetics (how drugs circulate)

Because ami nogl ycosi des ar e absor bed poor l y fr om the G I tract,
theyr e usual l y gi ven par enteral l y. After I.V. or I.M. admi ni strati on,
ami nogl ycosi de absor pti on i s rapi d and compl ete.

Distribution
Ami nogl ycosi des ar e di str i buted wi del y i n extracel l ul ar fl ui d. They
r eadi l y cr oss the pl acental bar r i er, but dont cr oss the bl ood-brai n
bar r i er.

Metabolism and excretion

Ami nogl ycosi des ar ent metabol i zed. Theyr e excr eted pr i mar i l y
unchanged by the ki dneys.

Pharmacodynamics (how drugs act)

Ami nogl ycosi des act as bacter i ci dal dr ugs (r emember, thi s means
they ki l l bacter i a) agai nst suscepti bl e or gani sms by bi ndi ng to the
bacter i ums 30S subuni t, a speci fi c r i bosome i n the mi cr oor gani sm,
ther eby i nter r upti ng pr otei n synthesi s and causi ng the bacter i um to
di e.

Rising resistance
Bacter i al r esi stance to ami nogl ycosi des may be r el ated to:

fai l ur e of the dr ug to cr oss the cel l membrane

al ter ed bi ndi ng to r i bosomes
destr ucti on of the dr ug by bacter i al enz ymes.

One-two punch
Some gram-posi ti ve enter ococci r esi st ami nogl ycosi de transpor t
acr oss the cel l membrane. When peni ci l l i n i s used wi th
ami nogl ycosi de therapy, the cel l wal l i s al ter ed, al l owi ng the
ami nogl ycosi de to penetrate the bacter i al cel l .

Pharmacotherapeutics (how drugs are used)

Ami nogl ycosi des ar e most useful i n tr eati ng:

i nfecti ons caused by gram-negati ve baci l l i

ser i ous nosocomi al (hospi tal -acqui r ed) i nfecti ons, such as gram-
negati ve bacter emi a (abnor mal pr esence of mi cr oor gani sms i n
the bl oodstr eam), per i toni ti s (i nfl ammati on of the per i toneum,
the membrane that l i nes the abdomi nal cavi ty), and pneumoni a,
i n cr i ti cal l y i l l pati ents
ur i nar y tract i nfecti ons (UTIs) caused by enter i c baci l l i that ar e
r esi stant to l ess toxi c anti bi oti cs, such as peni ci l l i ns and
cephal ospor i ns
i nfecti ons of the central ner vous system (CNS) and the eye
(tr eated wi th l ocal i nsti l l ati on).

Works well with others

Ami nogl ycosi des ar e used i n combi nati on wi th peni ci l l i ns to tr eat
gram-posi ti ve or gani sms, such as staphyl ococcal or enter ococcal

i nfecti ons. Combi nati on therapy i ncr eases the dr ugs effecti veness.
 Warning!
Adverse reactions to aminoglycosides
Ser i ous adver se r eacti ons l i mi t the use of ami nogl ycosi des.
They i ncl ude:

neur omuscul ar r eacti ons, rangi ng fr om per i pheral ner ve

toxi ci ty to neur omuscul ar bl ockade
ototoxi ci ty
r enal toxi ci ty.

Oral history
Adver se r eacti ons to oral ami nogl ycosi des i ncl ude:

nausea and vomi ti ng

di ar r hea.

Inactive duty
Ami nogl ycosi des ar e i nacti ve agai nst anaer obi c bacter i a.

Role call
Indi vi dual ami nogl ycosi des may have thei r own par ti cul ar
useful ness:

Str eptomyci n i s acti ve agai nst many strai ns of mycobacter i a,

i ncl udi ng Mycobacter ium tuber culosis, and agai nst the gram-
posi ti ve bacter i a Nocar dia and Er ysipelothr ix.
Ami kaci n, gentami ci n, and tobramyci n ar e acti ve agai nst
Acinetobacter , Citr obacter , Enter obacter , Klebsiella, Pr oteus
(i ndol e-posi ti ve and i ndol e-negati ve), Pr ovidencia, Ser r atia,
Escher ichia coli, and Pseudomonas aer uginosa.

Drug interactions
Car beni ci l l i n and ti car ci l l i n r educe the effects of ami kaci n,
gentami ci n, kanamyci n, neomyci n, str eptomyci n, and tobramyci n.
Thi s i s especi al l y tr ue i f the peni ci l l i n and ami nogl ycosi de ar e mi xed
i n the same contai ner or I.V. l i ne.
Putting up a blockade
Ami kaci n, gentami ci n, kanamyci n, neomyci n, str eptomyci n, and
tobramyci n admi ni ster ed wi th neur omuscul ar bl ocker s i ncr ease
neur omuscul ar bl ockade, r esul ti ng i n i ncr eased muscl e r el axati on
and r espi rator y di str ess.

Kidney punch
Toxi ci ty to the ki dneys may r esul t i n r enal fai l ur e; toxi ci ty to the
neur ol ogi c system r esul ts i n per i pheral neur opathy wi th numbness
and ti ngl i ng of the extr emi ti es. The r i sk of r enal toxi ci ty al so
i ncr eases when ami kaci n, gentami ci n, kanamyci n, or tobramyci n i s
taken wi th cycl ospor i ne, amphoter i ci n B, or acycl ovi r.

What? Say that again

The symptoms of ototoxi ci ty (damage to the ear ) caused by
ami nogl ycosi des may be masked by anti emeti c dr ugs. Loop di ur eti cs
taken wi th ami nogl ycosi des i ncr ease the r i sk of ototoxi ci ty. Hear i ng
l oss may occur i n var yi ng degr ees and may be i r r ever si bl e. (See
Adver se r eacti ons to ami nogl ycosi des.)

Penicillins
Penicillins r emai n one of the most i mpor tant and useful
anti bacter i al s, despi te the avai l abi l i ty of numer ous other s. The
peni ci l l i ns can be di vi ded i nto four gr oups:

natural peni ci l l i ns (peni ci l l i n G benz athi ne, peni ci l l i n G

potassi um, peni ci l l i n G pr ocai ne, peni ci l l i n G sodi um, peni ci l l i n V
potassi um)
peni ci l l i nase-r esi stant peni ci l l i ns (di cl oxaci l l i n, nafci l l i n,
oxaci l l i n)
ami nopeni ci l l i ns (amoxi ci l l i n, ampi ci l l i n)
extended-spectr um peni ci l l i ns (car beni ci l l i n, ti car ci l l i n).

Pharmacokinetics
After oral admi ni strati on, peni ci l l i ns ar e absor bed mai nl y i n the
duodenum and the upper jejunum of the smal l i ntesti ne.
Absorb these factors
Absor pti on of oral peni ci l l i n var i es and depends on such factor s as
the:

par ti cul ar peni ci l l i n used

pH of the pati ents stomach and i ntesti ne
pr esence of food i n the G I tract.

Most peni ci l l i ns shoul d be gi ven on an empty stomach (1 hour

befor e or 2 hour s after a meal ) to enhance absor pti on. Peni ci l l i ns
that can be gi ven wi thout r egar d to meal s i ncl ude amoxi ci l l i n,
peni ci l l i n V, and amoxi ci l l i n/cl avul anate potassi um.

Distribution
Peni ci l l i ns ar e di str i buted wi del y to most ar eas of the body,
i ncl udi ng the l ungs, l i ver, ki dneys, muscl e, bone, and pl acenta. Hi gh
concentrati ons al so appear i n ur i ne, maki ng peni ci l l i ns useful i n
tr eati ng UTIs.

Metabolism and excretion

Peni ci l l i ns ar e metabol i zed to a l i mi ted extent i n the l i ver to
i nacti ve metabol i tes and ar e excr eted 60% unchanged by the
ki dneys. Nafci l l i n and oxaci l l i n ar e excr eted i n bi l e.

Pharmacodynamics
Peni ci l l i ns ar e usual l y bacter i ci dal i n acti on. They bi nd r ever si bl y to
several enz ymes outsi de the bacter i al cytopl asmi c membrane.

Playing with PBPs

These enz ymes, known as penicillin-binding pr oteins (PBPs), ar e
i nvol ved i n cel l -wal l synthesi s and cel l di vi si on. Inter fer ence wi th
these pr ocesses i nhi bi ts cel l -wal l synthesi s, causi ng rapi d
destr ucti on of the cel l .

Pharmacotherapeutics
No other cl ass of anti bacter i al dr ugs pr ovi des as wi de a spectr um of
anti mi cr obi al acti vi ty as the peni ci l l i ns. As a cl ass, they cover gram-
posi ti ve, gram-negati ve, and anaer obi c or gani sms, al though speci fi c
peni ci l l i ns ar e mor e effecti ve agai nst speci fi c or gani sms.

Oral vs. I.M. route

Peni ci l l i n i s gi ven by I.M. i njecti on when oral admi ni strati on i s
i nconveni ent or a pati ents compl i ance i s questi onabl e. Because
l ong-acti ng pr eparati ons of peni ci l l i n G (peni ci l l i n G benz athi ne and
peni ci l l i n G pr ocai ne) ar e r el ati vel y i nsol ubl e, they must be
admi ni ster ed by the I.M. r oute.

Drug interactions
Peni ci l l i ns may i nteract wi th var i ous dr ugs.

Pr obeneci d i ncr eases the pl asma concentrati on of peni ci l l i ns.

Peni ci l l i ns r educe tubul ar secr eti on of methotr exate i n the
ki dney, i ncr easi ng the r i sk of methotr exate toxi ci ty.
Tetracycl i nes and chl orampheni col r educe the bacter i ci dal acti on
of peni ci l l i ns.
Neomyci n decr eases the absor pti on of peni ci l l i n V.
The effecti veness of hor monal contracepti ves i s r educed when
theyr e taken wi th peni ci l l i n V or ampi ci l l i n. Be sur e to advi se
the pati ent to use a r el i abl e, al ter nati ve method of contracepti on
i n addi ti on to hor monal contracepti ves dur i ng peni ci l l i n therapy.
Lar ge doses of I.V. peni ci l l i ns can i ncr ease the bl eedi ng r i sk of
anti coagul ants by pr ol ongi ng bl eedi ng ti me. Nafci l l i n and
di cl oxaci l l i n have been i mpl i cated i n war far i n r esi stance.

Acting against aminoglycosides

Hi gh dosages of peni ci l l i n G and extended-spectr um peni ci l l i ns
(car beni ci l l i n and ti car ci l l i n) i nacti vate ami nogl ycosi des. Mor eover,
peni ci l l i ns shoul dnt be mi xed i n the same I.V. sol uti ons wi th
ami nogl ycosi des. (See Adver se r eacti ons to peni ci l l i ns.)

Warning!
Adverse reactions to penicillins
Hyper sensi ti vi ty r eacti ons ar e the major adver se r eacti ons
to peni ci l l i ns. They may i ncl ude:

anaphyl acti c r eacti ons

ser um si ckness (a hyper sensi ti vi ty r eacti on occur r i ng 1 to 2
weeks after i njecti on of a for ei gn ser um)
dr ug fever
var i ous rashes.

Oral penicillins
Adver se G I r eacti ons associ ated wi th oral peni ci l l i ns i ncl ude:

tongue i nfl ammati on

 nausea and vomi ti ng
di ar r hea.

Aminopenicillins and extended-spectrum penicillins

The ami nopeni ci l l i ns and extended-spectr um peni ci l l i ns can
pr oduce pseudomembranous col i ti s (di ar r hea caused by a change
i n the fl ora of the col on or an over gr owth of a toxi npr oduci ng
strai n of Clostr idium difficile).
Oxacillin
Oxaci l l i n therapy may cause l i ver toxi ci ty.

Cephalosporins
Many anti bacter i al dr ugs i ntr oduced for cl i ni cal use i n r ecent year s
have been cephalospor ins.

Through the generations

Cephal ospor i ns ar e gr ouped i nto generati ons accor di ng to thei r
effecti veness agai nst di ffer ent or gani sms, thei r character i sti cs, and
thei r devel opment.

F i r st-generati on cephal ospor i ns i ncl ude cefadr oxi l , cefazol i n

sodi um, and cephal exi n monohydrate.
Second-generati on cephal ospor i ns i ncl ude cefacl or, cefpr oz i l ,
cefoxi ti n, cefur oxi me axeti l , and cefur oxi me sodi um.
Thi r d-generati on cephal ospor i ns i ncl ude cefdi ni r, cefi xi me,
cefotaxi me sodi um, cefpodoxi me pr oxeti l , ceftaz i di me,
cefti buten, and ceftr i axone sodi um.
Four th-generati on cephal ospor i ns i ncl ude cefepi me
hydr ochl or i de.

A sensitive issue
Because peni ci l l i ns and cephal ospor i ns ar e chemi cal l y si mi l ar (they
have whats cal l ed a beta-lactam molecular str uctur e), cr oss-
sensi ti vi ty occur s i n 10% to 15% of pati ents. Thi s means that
someone who has had a r eacti on to peni ci l l i n i s al so at r i sk for a
r eacti on to cephal ospor i ns.
Pharmacokinetics
Many cephal ospor i ns ar e admi ni ster ed par enteral l y because they
ar ent absor bed fr om the G I tract. Some cephal ospor i ns ar e
absor bed fr om the G I tract and can be admi ni ster ed oral l y, but food
usual l y decr eases the absor pti on rate of these oral cephal ospor i ns,
though not the amount absor bed. Two cephal ospor i ns (oral
cefur oxi me and cefpodoxi me) actual l y have i ncr eased absor pti on
when gi ven wi th food.

Distribution
After absor pti on, cephal ospor i ns ar e di str i buted wi del y and r eadi l y
cr oss the pl acenta.

Generational divide
Cefur oxi me (second-generati on) and the thi r d-generati on dr ugs
cefotaxi me, ceftr i axone, and ceftaz i di me cr oss the bl ood-brai n
bar r i er after I.V. or I.M. admi ni strati on. Cefepi me (four th-
generati on) al so cr osses the bl ood-brai n bar r i er, but to what extent
i snt known.

Metabolism
Many cephal ospor i ns ar ent metabol i zed at al l . Cefotaxi me sodi um i s
metabol i zed to the nonacetyl for ms, whi ch pr ovi de l ess anti bacter i al
acti vi ty than the par ent compounds. To a smal l extent, ceftr i axone
i s metabol i zed i n the i ntesti nes to i nacti ve metabol i tes, whi ch ar e
excr eted vi a the bi l i ar y system.
Excretion
Al l cephal ospor i ns ar e excr eted pr i mar i l y unchanged by the ki dneys
wi th the excepti on of ceftr i axone, whi ch i s excr eted i n stool vi a bi l e.

Pharmacodynamics
Li ke peni ci l l i ns, cephal ospor i ns i nhi bi t cel l -wal l synthesi s by bi ndi ng
to the bacter i al enz ymes known as PBPs, l ocated on the cel l
membrane. After the dr ug damages the cel l wal l by bi ndi ng wi th the
PBPs, the bodys natural defense mechani sms destr oy the bacter i a.
(See How cephal ospor i ns attack bacter i a.)

Pharmacotherapeutics
The four generati ons of cephal ospor i ns have par ti cul ar therapeuti c
uses.

F i r st-generati on cephal ospor i ns, whi ch act pr i mar i l y agai nst

gram-posi ti ve or gani sms, may be used as al ter nati ve therapy i n

the pati ent whos al l er gi c to peni ci l l i n, dependi ng on how

sensi ti ve to peni ci l l i n he i s. Theyr e al so used to tr eat
staphyl ococcal and str eptococcal i nfecti ons, i ncl udi ng
pneumoni a, cel l ul i ti s (ski n i nfecti on), and osteomyel i ti s (bone
i nfecti on).

Now I get it!

How cephalosporins attack bacteria
The anti bacter i al acti on of cephal ospor i ns depends on thei r
abi l i ty to penetrate the bacter i al wal l and bi nd wi th pr otei ns on
the cytopl asmi c membrane, as shown bel ow.
Second-generati on cephal ospor i ns act agai nst gram-negati ve
bacter i a. Cefoxi ti n i s the onl y cephal ospor i n effecti ve agai nst
anaer obes (or gani sms that l i ve wi thout oxygen).
Thi r d-generati on cephal ospor i ns, whi ch act pr i mar i l y agai nst
gram-negati ve or gani sms, ar e the dr ugs of choi ce for i nfecti ons
caused by Enter obacter , P. aer uginosa, and anaer obi c or gani sms.
Four th-generati on cephal ospor i ns ar e acti ve agai nst many gram-
posi ti ve and gram-negati ve bacter i a.
 Warning!
Adverse reactions to cephalosporins
Adver se r eacti ons to cephal ospor i ns i ncl ude:

confusi on
sei z ur es
bl eedi ng
nausea
vomi ti ng
di ar r hea.

Ceftr i axone may be associ ated wi th a decr ease i n pr othr ombi n

acti vi ty (pr othr ombi n ti me and par ti al thr ombopl asti n ti me),
l eadi ng to an i ncr eased r i sk of bl eedi ng. Pati ents at r i sk i ncl ude
those wi th r enal i mpai r ment, l i ver di sease, or i mpai r ed vi tami n K
synthesi s or storage.
An issue of sensitivity
Hyper sensi ti vi ty r eacti ons ar e the most common systemi c adver se
r eacti ons to cephal ospor i ns. They i ncl ude:

hi ves
i tchi ng
measl es-type rash
ser um si ckness (r eacti on after i njecti on of a for ei gn ser um
character i zed by edema, fever, hi ves, and i nfl ammati on of the
bl ood vessel s and joi nts)
anaphyl axi s (i n rar e cases).

Drug interactions
The pati ent r ecei vi ng cephal ospor i ns who dr i nks al cohol i c beverages
wi th or up to 72 hour s after taki ng a dose may exper i ence acute
al cohol i ntol erance, wi th such si gns and symptoms as headache,
fl ushi ng, di z z i ness, nausea, vomi ti ng, or abdomi nal cramps wi thi n
30 mi nutes of al cohol i ngesti on. Thi s r eacti on can occur up to 3
days after di sconti nui ng the anti bi oti c. (See Adver se r eacti ons to
cephal ospor i ns.)
In use with uricosurics
Ur i cosur i cs (dr ugs to r el i eve gout), such as pr obeneci d and
sul fi npyrazone, can r educe ki dney excr eti on of some cephal ospor i ns.
Pr obeneci d i s used therapeuti cal l y to i ncr ease and pr ol ong pl asma
cephal ospor i n concentrati ons.
Cephal ospor i ns may al so decr ease estr ogen absor pti on, l eadi ng to
decr eased effi cacy of oral contracepti ves contai ni ng estr ogen and
pr ogester one.

Tetracyclines
Tetr acyclines ar e br oad-spectr um anti bi oti cs. They may be cl assi fi ed
as:

i nter medi ate-acti ng compounds such as demecl ocycl i ne

hydr ochl or i de
l ong-acti ng compounds, such as doxycycl i ne hycl ate and
mi nocycl i ne hydr ochl or i de.

Pharmacokinetics
Tetracycl i nes ar e absor bed fr om the stomach and smal l i ntesti ne
when taken oral l y.
Distribution and excretion
Tetracycl i nes ar e di str i buted wi del y i nto body ti ssues and fl ui ds,
concentrated i n bi l e, and excr eted pr i mar i l y by the ki dneys.
Doxycycl i ne i s al so excr eted i n stool . Mi nocycl i ne under goes
enter ohepati c r eci r cul ati on.

Pharmacodynamics
Al l tetracycl i nes ar e pr i mar i l y bacter i ostati c, meani ng they i nhi bi t
the gr owth or mul ti pl i cati on of bacter i a. They penetrate the
bacter i al cel l by an ener gy-dependent pr ocess. Wi thi n the cel l , they
bi nd pr i mar i l y to a subuni t of the r i bosome, i nhi bi ti ng the pr otei n
synthesi s needed to mai ntai n the bacter i al cel l .

Pharmacotherapeutics
Tetracycl i nes pr ovi de a br oad spectr um of acti vi ty agai nst:

gram-posi ti ve and gram-negati ve aer obi c and anaer obi c bacter i a

spi r ochetes
mycopl asma
r i ckettsi ae
chl amydi ae
some pr otozoa.

Longer equals broader

The l ong-acti ng compounds doxycycl i ne and mi nocycl i ne pr ovi de
mor e acti on agai nst var i ous or gani sms than other tetracycl i nes.

Taking aim
Tetracycl i nes ar e used to tr eat Rocky Mountai n spotted fever, Q
fever, and Lyme di sease. Theyr e the dr ugs of choi ce for tr eati ng
nongonococcal ur ethr i ti s caused by Chlamydia and Ur eaplasma.

Combi nati on therapy wi th a tetracycl i ne and str eptomyci n i s the

most effecti ve tr eatment for br ucel l osi s.

Zit zapper
Tetracycl i nes i n l ow dosages effecti vel y tr eat acne because they can
decr ease the fatty aci d content of sebum.

Drug interactions
Tetracycl i nes can r educe the effecti veness of hor monal
contracepti ves, whi ch may r esul t i n br eakthr ough bl eedi ng or
i neffecti ve contracepti on. The pati ent taki ng hor monal
contracepti ves shoul d use a r el i abl e, secondar y method of
contracepti on. Tetracycl i nes may al so decr ease the bacter i ci dal
acti on of peni ci l l i n.
Other i nteracti ons commonl y affect the abi l i ty of tetracycl i nes to
move thr ough the body.

Al umi num, cal ci um, and magnesi um antaci ds r educe the

absor pti on of oral tetracycl i nes.
Ir on sal ts, bi smuth subsal i cyl ate, and z i nc sul fate r educe the
absor pti on of tetracycl i nes. Reduced absor pti on can be pr evented
by separati ng doses of tetracycl i nes and these agents by 2 to 3
hour s.
Bar bi turates, car bamazepi ne, and phenytoi n i ncr ease the
metabol i sm and r educe the anti bi oti c effect of doxycycl i ne.

Warning!
Adverse reactions to tetracyclines
Tetracycl i nes pr oduce many of the same adver se r eacti ons
as other anti bacter i al s, such as:

super i nfecti on (over gr owth of r esi stant or gani sms)

nausea and vomi ti ng
abdomi nal di str ess and di stenti on
di ar r hea.

Toxicities
Other adver se r eacti ons i ncl ude:

photosensi ti vi ty r eacti ons (r ed rash on ar eas exposed to

sunl i ght)
l i ver toxi ci ty
 r enal toxi ci ty.

Be wary of dairy
These dr ugs, wi th the excepti on of doxycycl i ne and mi nocycl i ne,
may al so i nteract wi th mi l k and mi l k pr oducts, whi ch bi nd wi th the
dr ugs and pr event thei r absor pti on. To pr event decr eased
absor pti on, admi ni ster the tetracycl i ne 1 hour befor e or 2 hour s
after meal s. (See Adver se r eacti ons to tetracycl i nes.)

Lincomycin derivatives
Because of i ts hi gh potenti al for causi ng ser i ous adver se effects,
clindamycin i s another anti bacter i al pr escr i bed onl y when ther es no
therapeuti c al ter nati ve. Its used for many gram-posi ti ve and
anaer obi c or gani sms.

Less from lincomycin

Lincomycin i s l ess effecti ve than cl i ndamyci n and i s rar el y used.
Li ncomyci n shoul dnt be used i n the tr eatment of mi nor i nfecti ons
but woul d be used to tr eat ser i ous r espi rator y or ski n i nfecti ons i n
the pati ent whos al l er gi c to other anti bi oti cs i ndi cated for the
i nfecti on.

Pharmacokinetics
When taken oral l y, cl i ndamyci n i s absor bed wel l and di str i buted
wi del y thr oughout the body. Its metabol i zed by the l i ver and
excr eted by the ki dneys and bi l i ar y pathways. About 20% to 30% of
l i ncomyci n, when taken oral l y, i s absor bed fr om the G I tract; food
del ays i ts absor pti on. Li ncomyci n i s par ti al l y metabol i zed i n the
l i ver and i s excr eted i n the ur i ne, stool , and bi l e.

Pharmacodynamics
Cl i ndamyci n and l i ncomyci n i nhi bi t bacter i al pr otei n synthesi s by
i nhi bi ti ng the bi ndi ng of bacter i al r i bosomes. At therapeuti c
concentrati ons, cl i ndamyci n i s pr i mar i l y bacter i ostati c agai nst most
or gani sms.

Pharmacotherapeutics
Because of thei r potenti al for causi ng ser i ous toxi ci ty and
pseudomembranous col i ti s (character i zed by sever e di ar r hea,
abdomi nal pai n, fever, and mucus and bl ood i n stool ), these dr ugs
ar e l i mi ted to a few cl i ni cal si tuati ons i n whi ch safer al ter nati ve
anti bacter i al s ar ent avai l abl e.

Cl i ndamyci n i s potent agai nst most aer obi c gram-posi ti ve

or gani sms, i ncl udi ng staphyl ococci , str eptococci (except
Enter ococcus faecalis), and pneumococci .
Cl i ndamyci n i s effecti ve agai nst most cl i ni cal l y i mpor tant
anaer obes and i s used pr i mar i l y to tr eat anaer obi c
i ntraabdomi nal , pl eural , or pul monar y i nfecti ons caused by
Bacter oides fr agilis. Its al so used as an al ter nati ve to peni ci l l i n
i n tr eati ng Clostr idium per fr ingens i nfecti ons.
Cl i ndamyci n and l i ncomyci n may be used as al ter nati ves to
peni ci l l i n i n tr eati ng staphyl ococcal i nfecti ons i n a pati ent whos
al l er gi c to peni ci l l i n.

Warning!
Adverse reactions to clindamycin
Pseudomembranous col i ti s may occur wi th cl i ndamyci n. Thi s
syndr ome can be fatal and r equi r es pr ompt di sconti nuati on of the
dr ug as wel l as aggr essi ve fl ui d and el ectr ol yte management.
Al though thi s i s the most ser i ous r eacti on to cl i ndamyci n and
l i mi ts i ts use, other r eacti ons may al so occur, such as:

di ar r hea
stomati ti s (mouth i nfl ammati on)
nausea and vomi ti ng
 hyper sensi ti vi ty r eacti ons.

Drug interactions
Cl i ndamyci n and l i ncomyci n have neur omuscul ar bl ocki ng pr oper ti es
and may enhance the neur omuscul ar bl ocki ng acti on of
neur omuscul ar bl ocker s. Thi s can l ead to pr ofound r espi rator y
depr essi on. (See Adver se r eacti ons to cl i ndamyci n.)

Macrolides
Macr olides ar e used to tr eat a number of common i nfecti ons. They
i ncl ude er ythr omyci n and i ts der i vati ves, such as:

er ythr omyci n estol ate

er ythr omyci n ethyl succi nate

er ythr omyci n l actobi onate

er ythr omyci n stearate.

These arent derivatives

Other macr ol i des i ncl ude:

az i thr omyci n
cl ar i thr omyci n.

Pharmacokinetics
Because er ythr omyci n i s aci d-sensi ti ve, i t must be buffer ed or have
an enter i c coati ng to pr event destr ucti on by gastr i c aci d.
Er ythr omyci n i s absor bed i n the duodenum. Its di str i buted to most
ti ssues and body fl ui ds except, i n most cases, for cer ebr ospi nal fl ui d
(CSF ). However, as a cl ass, macr ol i des can enter the CSF when
meni nges ar e i nfl amed.
Metabolism and excretion
Er ythr omyci n i s metabol i zed by the l i ver and excr eted i n bi l e i n
hi gh concentrati ons; smal l amounts ar e excr eted i n ur i ne. It al so
cr osses the pl acental bar r i er and i s secr eted i n br east mi l k.

Pharmacodynamics
Macr ol i des i nhi bi t r i bonucl ei c aci d (RNA)dependent pr otei n
synthesi s by acti ng on a smal l por ti on of the r i bosome, much l i ke
cl i ndamyci n.

Pharmacotherapeutics
Er ythr omyci n has a range of therapeuti c uses.

It pr ovi des a br oad spectr um of anti mi cr obi al acti vi ty agai nst

gram-posi ti ve and gram-negati ve bacter i a, i ncl udi ng
Mycobacter ium, Tr eponema, Mycoplasma, and Chlamydia.
Its al so effecti ve agai nst pneumococci and gr oup A str eptococci .
Staphylococcus aur eus i s sensi ti ve to er ythr omyci n; however,
r esi stant strai ns may appear dur i ng therapy.
Er ythr omyci n i s the dr ug of choi ce for tr eati ng Mycoplasma
pneumoniae i nfecti ons as wel l as pneumoni a caused by Legionella
pneumophila.
An alternative to penicillin
In the pati ent whos al l er gi c to peni ci l l i n, er ythr omyci n i s effecti ve
for i nfecti ons pr oduced by gr oup A beta-hemol yti c str eptococci or
Str eptococcus pneumoniae. It may al so be used to tr eat gonor r hea
and syphi l i s i n the pati ent who cant tol erate peni ci l l i n G or

the tetracycl i nes. Er ythr omyci n may al so be used to tr eat mi nor

staphyl ococcal i nfecti ons of the ski n.

Ranging far and wide

Az i thr omyci n pr ovi des a br oad spectr um of anti mi cr obi al acti vi ty
agai nst gram-posi ti ve and gram-negati ve bacter i a, i ncl udi ng
Mycobacter ium, S. aur eus, Haemophilus influenz ae, Mor axella
catar r halis, and Chlamydia. Its al so effecti ve agai nst pneumococci
and gr oups C, F, and G str eptococci .

Cl ar i thr omyci n i s a br oad-spectr um anti bacter i al thats acti ve

agai nst gram-posi ti ve aer obes, such as S. aur eus, S. pneumoniae,
and Str eptococcus pyogenes; gram-negati ve aer obes, such as H.
influenz ae and M. catar r halis; and other aer obes such as M.
pneumoniae.
Cl ar i thr omyci n has al so been used i n combi nati on wi th antaci ds,
hi stami ne-2 bl ocker s, and pr oton pump i nhi bi tor s to tr eat
Helicobacter pylor ii nduced duodenal ul cer di sease.

Drug interactions
Macr ol i des may i nteract wi th these dr ugs.
 Er ythr omyci n, az i thr omyci n, and cl ar i thr omyci n can i ncr ease
theophyl l i ne l evel s i n the pati ent r ecei vi ng hi gh dosages of
theophyl l i ne, i ncr easi ng the r i sk of theophyl l i ne toxi ci ty.
Cl ar i thr omyci n may i ncr ease the concentrati on of car bamazepi ne
when used together. (See Adver se r eacti ons to macr ol i des.)

Warning!
Adverse reactions to macrolides
Er ythr omyci n pr oduces few adver se effects, whi ch may
i ncl ude:

epi gastr i c di str ess

nausea and vomi ti ng
di ar r hea (especi al l y wi th l ar ge doses)
rash
fever
eosi nophi l i a (an i ncr ease i n the number of eosi nophi l s, a type
of whi te bl ood cel l )
anaphyl axi s.

Vancomycin
Vancomycin hydr ochlor ide i s used i ncr easi ngl y to tr eat methi ci l l i n-
r esi stant S. aur eus, whi ch has become a major concer n i n the
Uni ted States and other par ts of the wor l d. Because of the
emer gence of vancomyci n-r esi stant enter ococci , vancomyci n must
be used judi ci ousl y. As a r ul e of thumb, i t shoul d be used onl y when
cul tur e and sensi ti vi ty test r esul ts confi r m the need for i t.

Pharmacokinetics
Because vancomyci n i s absor bed poor l y fr om the G I tract, i t must be
gi ven I.V. to tr eat systemi c i nfecti ons. However, an oral for m of
vancomyci n i s used to tr eat pseudomembranous col i ti s. Vancomyci n
di ffuses wel l i nto pl eural (ar ound the l ungs), per i car di al (ar ound the
hear t), synovi al (joi nt), and asci ti c (i n the per i toneal cavi ty) fl ui ds.

No switching!
Remember that I.V. vancomyci n cant be used i n pl ace of oral
vancomyci n and vi ce ver sa. The two for ms ar ent i nter changeabl e.

Metabolism and excretion

The metabol i sm of vancomyci n i s unknown. About 85% of the dose
i s excr eted unchanged i n ur i ne wi thi n 24 hour s. A smal l amount
may be el i mi nated thr ough the l i ver and bi l i ar y tract.

Pharmacodynamics
Vancomyci n i nhi bi ts bacter i al cel l -wal l synthesi s, damagi ng the
bacter i al pl asma membrane. When the bacter i al cel l wal l i s
damaged, the bodys natural defenses can attack the or gani sm.

Pharmacotherapeutics
Vancomyci n i s acti ve agai nst gram-posi ti ve or gani sms, such as S.
aur eus, S. epider midis, S. pyogenes, Enter ococcus, and S.
pneumoniae.

In the I.V. league

I.V. vancomyci n i s the therapy of choi ce for the pati ent wi th a
ser i ous r esi stant staphyl ococcal i nfecti on whos hyper sensi ti ve to
peni ci l l i ns.

Oral history
Oral vancomyci n i s used for the pati ent wi th anti bi oti c-associ ated
Clostr idium difficile col i ti s who cant take or has r esponded poor l y to
metr oni dazol e.

The 1 in the 1-2 punch

Vancomyci n, when used wi th an ami nogl ycosi de, i s al so the
tr eatment of choi ce for E. faecalis endocar di ti s i n the pati ent whos
al l er gi c to peni ci l l i n.

Drug interactions
Vancomyci n may i ncr ease the r i sk of toxi ci ty when admi ni ster ed
wi th other dr ugs toxi c to the ki dneys and or gans of hear i ng, such as
ami nogl ycosi des, amphoter i ci n B, baci traci n, ci spl ati n, col i sti n, and
pol ymyxi n B. (See Adver se r eacti ons to vancomyci n.)

Warning!
Adverse reactions to vancomycin
Adver se r eacti ons to vancomyci n, al though rar e, i ncl ude:

hyper sensi ti vi ty and anaphyl acti c r eacti ons

dr ug fever
eosi nophi l i a (an i ncr eased number of eosi nophi l s, a type of
whi te bl ood cel l [WBC])
neutr openi a (a decr eased number of neutr ophi l s, another type
of WBC)
hear i ng l oss (transi ent or per manent), especi al l y wi th
excessi ve doses (as when i ts gi ven wi th other ototoxi c dr ugs).

Rash behavior
Sever e hypotensi on may occur wi th rapi d I.V. admi ni strati on of
vancomyci n and may be accompani ed by a r ed rash wi th fl at and
rai sed l esi ons on the face, neck, chest, and ar ms (r ed mans
syndr ome).
Dosages of 1 g or l ess shoul d be gi ven over 1 hour, and dosages
of mor e than 1 g shoul d be gi ven over 1 to 2 hour s.

Carbapenems
Car bapenems ar e a cl ass of beta-l actam anti bacter i al s that i ncl udes:

er tapenem
i mi penem-ci l astati n sodi um (a combi nati on dr ug)
mer openem.

The Broadway of antibacterials

The anti bacter i al spectr um of acti vi ty for i mi penem-ci l astati n i s
br oader than that of any other anti bacter i al studi ed to date.
Because of thi s br oad spectr um of acti vi ty, i ts used for ser i ous or
l i fe-thr eateni ng i nfecti on, especi al l y gram-posi ti ve and gram-
negati ve heal th-car e acqui r ed i nfecti ons. Br oad-spectr um
anti bacter i al s cover many or gani sms; nar r ow-spectr um
anti bacter i al s ar e effecti ve agai nst a sel ect few or gani sms.

Pharmacokinetics
The phar macoki neti c pr oper ti es of car bapenems var y sl i ghtl y.

Distribution, metabolism, and excretion

Imi penem must be gi ven wi th ci l astati n because i mi penem al one i s
rapi dl y metabol i zed i n the tubul es of the ki dneys, r ender i ng i t
i neffecti ve. After par enteral admi ni strati on, i mi penem-ci l astati n i s
di str i buted wi del y. Its metabol i zed by several mechani sms and
excr eted pr i mar i l y i n ur i ne.

Er tapenem i s compl etel y absor bed after I.V. admi ni strati on and i s
mor e hi ghl y pr otei n-bound than the other two car bapenems. Its
metabol i zed by hydr ol ysi s and excr eted mai nl y i n ur i ne.

Mostly unchanged
After par enteral admi ni strati on, mer openem i s di str i buted wi del y,
i ncl udi ng to the CNS. Metabol i sm i s i nsi gni fi cant; 70% of the dr ug
i s excr eted unchanged i n ur i ne.

Pharmacodynamics
Imi penem-ci l astati n, er tapenem, and mer openem ar e bacter i ci dal .
They exer t anti bacter i al acti vi ty by i nhi bi ti ng bacter i al cel l -wal l
synthesi s.

Pharmacotherapeutics
Imi penem has the br oadest spectr um of acti vi ty of cur r entl y
avai l abl e beta-l actam anti bi oti cs.

Its effecti ve agai nst aer obi c gram-posi ti ve speci es, such as
Str eptococcus, S. aur eus, and S. epider midis.
It i nhi bi ts most Enter obacter speci es.
It al so i nhi bi ts P. aer uginosa (i ncl udi ng strai ns r esi stant to
pi peraci l l i n and ceftaz i di me) and most anaer obi c speci es,
i ncl udi ng B. fr agilis.

Lone ranger
Imi penem may al so be used al one to tr eat ser i ous heal th-car e
acqui r ed i nfecti ons and i nfecti ons i n i mmunocompr omi sed pati ents
caused by mi xed aer obi c and anaer obi c or gani sms.

Dont forget the other carbapenems

Mer openem i s i ndi cated for the tr eatment of i ntra-abdomi nal
i nfecti ons as wel l as for the management of bacter i al meni ngi ti s
caused by suscepti bl e or gani sms.
Er tapenems spectr um of acti vi ty i ncl udes i ntra-abdomi nal , ski n,
ur i nar y tract, and gynecol ogi c i nfecti ons as wel l as communi ty-
acqui r ed pneumoni as caused by a var i ety of gram-posi ti ve, gram-
negati ve, and anaer obi c or gani sms.

Drug interactions
Car bapenems may i nteract wi th these dr ugs.

Taki ng pr obeneci d wi th i mi penem-ci l astati n i ncr eases the ser um

l evel of ci l astati n, but onl y sl i ghtl y i ncr eases the ser um l evel of
i mi penem.
Pr obeneci d may cause mer openem and er tapenem to accumul ate
to toxi c l evel s.

The combi nati on of i mi penem-ci l astati n and an ami nogl ycosi de

 acts syner gi sti cal l y agai nst E. faecalis, Staphylococcus aur eus
and Lister ia monocytogenes. (See Adver se r eacti ons to
car bapenems.)

Warning!
Adverse reactions to carbapenems
Common adver se r eacti ons to er tapenem, i mi penem-
ci l astati n, and mer openem i ncl ude:

nausea and vomi ti ng

di ar r hea.

If youre sensitive to penicillin

Hyper sensi ti vi ty r eacti ons, such as rashes, may occur, par ti cul ar l y
i n the pati ent wi th a known hyper sensi ti vi ty to peni ci l l i ns.
Kidney conditions
In the pati ent wi th decr eased or i mpai r ed r enal functi on, the
dosage may need to be adjusted.

Monobactams
Az tr eonam i s the fi r st member i n the cl ass of monobactam
anti bi oti cs and the onl y one cur r entl y avai l abl e. Its a syntheti c
monobactam wi th a nar r ow spectr um of acti vi ty that i ncl udes many
gram-negati ve aer obi c bacter i a.

Pharmacokinetics
After par enteral admi ni strati on, az tr eonam i s rapi dl y and
compl etel y absor bed and wi del y di str i buted thr oughout the body.
Its metabol i zed par ti al l y and excr eted pr i mar i l y i n ur i ne as
unchanged dr ug.

Pharmacodynamics
Az tr eonams bacter i ci dal acti vi ty r esul ts fr om i nhi bi ti on of bacter i al
cel l -wal l synthesi s. It bi nds to the PBP-3 of suscepti bl e gram-
negati ve bacter i al cel l s, i nhi bi ti ng cel l -wal l di vi si on and r esul ti ng i n
l ysi s.

Pharmacotherapeutics
Az tr eonam i s i ndi cated i n a range of therapeuti c si tuati ons.

Its effecti ve agai nst a wi de var i ety of gram-negati ve aer obi c

or gani sms, i ncl udi ng P. aer uginosa.
Its effecti ve agai nst most strai ns of the fol l owi ng or gani sms: E.
coli, Enter obacter , Klebsiella pneumoniae, K. oxytoca, Pr oteus
mir abilis, Ser r atia mar cescens, H. influenz ae, and Citr obacter .
Its al so used to tr eat compl i cated and uncompl i cated UTIs,
septi cemi a, and l ower r espi rator y tract, ski n and ski n-str uctur e,
i ntra-abdomi nal , and gynecol ogi c i nfecti ons caused by
suscepti bl e gram-negati ve aer obi c bacter i a.
Its usual l y acti ve agai nst gram-negati ve aer obi c or gani sms that
ar e r esi stant to anti bi oti cs hydr ol yzed by beta-l actamases.
(Beta-l actamase i s an enz yme that makes an anti bi oti c
i neffecti ve.)

It can need help

Az tr eonam shoul dnt be used al one as empi r i c therapy (tr eatment
based on cl i ni cal exper i ence rather than on medi cal data) i n a
ser i ousl y

i l l pati ent who may have a gram-posi ti ve bacter i al i nfecti on or a

mi xed aer obi c-anaer obi c bacter i al i nfecti on.

Drug interactions
Az tr eonam may i nteract wi th several other dr ugs.
 Syner gi sti c or addi ti ve effects occur when az tr eonam i s used
wi th ami nogl ycosi des or other anti bi oti cs, such as cefoperazone,
cefotaxi me, cl i ndamyci n, and pi peraci l l i n.
Potent i nducer s of beta-l actamase pr oducti on (cefoxi ti n,
i mi penem) may i nacti vate az tr eonam. Concomi tant use i snt
r ecommended.
Taki ng az tr eonam wi th cl avul ani c aci dcontai ni ng anti bi oti cs may
pr oduce syner gi sti c or antagoni sti c effects, dependi ng on the
or gani sm i nvol ved. (See Adver se r eacti ons to az tr eonam.)

Warning!
Adverse reactions to aztreonam
Az tr eonam can cause some adver se r eacti ons, i ncl udi ng:

di ar r hea
hyper sensi ti vi ty and ski n r eacti ons
hypotensi on
nausea and vomi ti ng
transi ent el ectr ocar di ogram changes (i ncl udi ng ventr i cul ar
ar r hythmi as)
transi ent i ncr eases i n ser um l i ver enz yme l evel s.

Fluoroquinolones
F luor oquinolones ar e str uctural l y si mi l ar syntheti c anti bi oti cs. They
ar e pr i mar i l y admi ni ster ed to tr eat UTIs, upper r espi rator y tract
i nfecti ons, pneumoni a, and gonor r hea and i ncl ude:

ci pr ofl oxaci n
l evofl oxaci n
moxi fl oxaci n
nor fl oxaci n
ofl oxaci n.

Pharmacokinetics
After oral admi ni strati on, fl uor oqui nol ones ar e absor bed wel l .

Metabolism and excretion

F l uor oqui nol ones ar ent hi ghl y pr otei n-bound, ar e mi ni mal l y
metabol i zed i n the l i ver, and ar e excr eted pr i mar i l y i n ur i ne.

Pharmacodynamics
F l uor oqui nol ones i nter r upt deoxyr i bonucl ei c aci d (DNA) synthesi s
dur i ng bacter i al r epl i cati on by i nhi bi ti ng DNA gyrase, an essenti al
enz yme of r epl i cati ng DNA. As a r esul t, the bacter i a cant
r epr oduce.

Pharmacotherapeutics
F l uor oqui nol ones can be used to tr eat many UTIs. Each dr ug i n thi s
cl ass al so has speci fi c i ndi cati ons.

Ci pr ofl oxaci n i s used to tr eat l ower r espi rator y tract i nfecti ons,
i nfecti ous di ar r hea, and ski n, bone, and joi nt i nfecti ons.
Levofl oxaci n i s i ndi cated for the tr eatment of l ower r espi rator y
tract i nfecti ons, ski n i nfecti ons, and UTIs.
Moxi fl oxaci n i s used to tr eat acute bacter i al si nusi ti s and mi l d to
moderate communi ty-acqui r ed pneumoni a.
Nor fl oxaci n i s used to tr eat UTIs and pr ostati ti s.
Ofl oxaci n i s used to tr eat sel ected sexual l y transmi tted di seases,
l ower r espi rator y tract i nfecti ons, ski n and ski n-str uctur e
i nfecti ons, and pr ostati ti s (i nfl ammati on of the pr ostate gl and).

Warning!
Adverse reactions to fluoroquinolones
F l uor oqui nol ones ar e wel l tol erated by most pati ents, but
some ser i ous adver se effects may occur, i ncl udi ng:

di z z i ness
nausea and vomi ti ng
di ar r hea
abdomi nal pai n.
 Serious reactions
Moderate to sever e phototoxi c r eacti ons have occur r ed wi th di r ect
and i ndi r ect sunl i ght and wi th ar ti fi ci al ul travi ol et l i ghts, wi th and
wi thout sunscr een. Li ght shoul d be avoi ded for several days after
stoppi ng fl uor oqui nol one therapy.

Drug interactions
Several dr ug i nteracti ons may occur wi th the fl uor oqui nol ones.

Admi ni strati on wi th antaci ds that contai n magnesi um or

al umi num hydr oxi de r esul ts i n decr eased absor pti on of the
fl uor oqui nol one.
Some fl uor oqui nol ones, such as ci pr ofl oxaci n, nor fl oxaci n, and
ofl oxaci n, i nteract wi th xanthi ne der i vati ves, such as
ami nophyl l i ne and theophyl l i ne, i ncr easi ng the pl asma
theophyl l i ne l evel and the r i sk of theophyl l i ne toxi ci ty.
G i vi ng ci pr ofl oxaci n or nor fl oxaci n wi th pr obeneci d r esul ts i n
decr eased ki dney el i mi nati on of these fl uor oqui nol ones,
i ncr easi ng thei r ser um l evel s and hal f-l i fe.
Dr ugs that pr ol ong the QT i nter val , such as anti ar r hythmi cs,
shoul d be used cauti ousl y dur i ng moxi fl oxaci n therapy. (See
Adver se r eacti ons to fl uor oqui nol ones.)

Sulfonamides
Sulfonamides wer e the fi r st effecti ve systemi c anti bacter i al dr ugs.
They i ncl ude:

co-tr i moxazol e (sul famethoxazol e and tr i methopr i m)

sul fadi az i ne.

Pharmacokinetics
Most sul fonami des ar e wel l absor bed and wi del y di str i buted i n the
body. Theyr e metabol i zed i n the l i ver to i nacti ve metabol i tes and
excr eted by the ki dneys.

Lots and lots and lots of liquid

Because cr ystal l ur i a and subsequent ki dney stone for mati on may
occur dur i ng the metabol i c excr etor y phase, adequate fl ui d i ntake i s
hi ghl y r ecommended dur i ng sul fonami de therapy. The pati ent taki ng
oral sul fonami des shoul d take the medi cati on wi th 8 oz of

water and shoul d dr i nk pl enty of fl ui ds thr oughout therapy (2 to 3 L

dai l y).

Pharmacodynamics
Sul fonami des ar e bacter i ostati c dr ugs that pr event the gr owth of
mi cr oor gani sms by i nhi bi ti ng fol i c aci d pr oducti on. The decr eased
fol i c aci d synthesi s decr eases the number of bacter i al nucl eoti des
and i nhi bi ts bacter i al gr owth.

Pharmacotherapeutics
Sul fonami des ar e commonl y used to tr eat acute UTIs. Wi th
r ecur r ent or chr oni c UTIs, the i nfecti ng or gani sm may not be
suscepti bl e to sul fonami des. Ther efor e, the choi ce of therapy shoul d
be based on bacter i a suscepti bi l i ty tests.

Infectious behavior
Sul fonami des al so ar e used to tr eat i nfecti ons caused by Nocar dia
aster oides and Toxoplasma gondii. Co-tr i moxazol e (a combi nati on of
a sul fa dr ug and a fol ate antagoni st) i s used for a var i ety of other
i nfecti ons, such as Pneumocystis car inii ( Pneumocystis jir oveci)
pneumoni a, acute oti ti s medi a (due to H. influenz ae and S.
pneumoniae), and acute exacer bati ons of chr oni c br onchi ti s (due to
H. influenz ae and S. pneumoniae). Sul fonami des exhi bi t a wi de
spectr um of acti vi ty agai nst gram-posi ti ve and gram-negati ve
bacter i a.

Drug interactions
Sul fonami des have few si gni fi cant i nteracti ons.

They i ncr ease the hypogl ycemi c effects of the sul fonyl ur eas (oral
anti di abeti c dr ugs), whi ch may decr ease bl ood gl ucose l evel s.
When taken wi th methenami ne, they may l ead to the
devel opment of cr ystal s i n ur i ne.
Co-tr i moxazol e may i ncr ease the anti coagul ant effect of
coumar i n anti coagul ants.
Co-ti moxazol e and methotr exate may cause i ncr eased
methotr exate l evel s and i ncr ease the r i sk of toxi ci ty.
Co-tr i moxazol e pl us cycl ospor i ne i ncr eases the r i sk of ki dney
toxi ci ty. (See Adver se r eacti ons to sul fonami des.)

Warning!
Adverse reactions to sulfonamides
Excessi vel y hi gh doses of l ess water-sol ubl e sul fonami des
can pr oduce cr ystal s i n ur i ne and deposi ts of sul fonami de cr ystal s
i n the r enal tubul es. Thi s compl i cati on i snt a pr obl em wi th the
newer water-sol ubl e sul fonami des. Hyper sensi ti vi ty r eacti ons may
occur and appear to i ncr ease as the dosage i ncr eases.
Is it serum sickness?
A r eacti on that r esembl es ser um si ckness may occur, pr oduci ng
fever, joi nt pai n, hi ves, br onchospasm, and l eukopeni a (r educed
whi te bl ood cel l count).
Photo finish
Sul fonami des can al so pr oduce photosensi ti vi ty r eacti ons.

Nitrofurantoin
Nitr ofur antoin i s used to tr eat acute and chr oni c UTIs. It i snt useful
i n tr eati ng pyel onephr i ti s or per i nephr i c (ar ound the ki dney)
di seases.
Pharmacokinetics
After oral admi ni strati on, ni tr ofurantoi n i s absor bed rapi dl y and wel l
fr om the G I tract. Taki ng the dr ug wi th food enhances i ts
bi oavai l abi l i ty. Its avai l abl e i n a mi cr ocr ystal l i ne for m and a
macr ocr ystal l i ne for m. The mi cr ocr ystal l i ne for m i s absor bed mor e
sl owl y because of sl ower di ssol uti on and thus causes l ess G I
di str ess.

Distribution
The dr ug i s 20% to 60% pr otei n-bound. Ni tr ofurantoi n cr osses the
pl acental bar r i er and i s secr eted i n br east mi l k. Its al so di str i buted
i n bi l e.

Metabolism and excretion

Ni tr ofurantoi n i s par ti al l y metabol i zed by the l i ver, and 30% to 50%
i s excr eted unchanged i n ur i ne.

Pharmacodynamics
Usual l y bacter i ostati c, ni tr ofurantoi n may become bacter i ci dal ,
dependi ng on i ts ur i nar y concentrati on and the suscepti bi l i ty of the
i nfecti ng or gani sm.

Reduces power?
Al though i ts exact mechani sm of acti on i s unknown, ni tr ofurantoi n
appear s to i nhi bi t for mati on of acetyl coenz yme A fr om pyr uvi c aci d,
ther eby i nhi bi ti ng the ener gy pr oducti on of the i nfecti ng or gani sm.
Ni tr ofurantoi n may al so di sr upt bacter i al cel l -wal l for mati on.

Pharmacotherapeutics
Because the absor bed dr ug concentrates i n ur i ne, ni tr ofurantoi n i s
used to tr eat UTIs. It has a hi gher anti bacter i al acti vi ty i n aci d
ur i ne. Ni tr ofurantoi n i snt effecti ve agai nst systemi c bacter i al
i nfecti ons.

Drug interactions
Ni tr ofurantoi n has few si gni fi cant i nteracti ons.
 Pr obeneci d and sul fi npyrazone i nhi bi t the excr eti on of
ni tr ofurantoi n by the ki dneys, r educi ng i ts effi cacy and
i ncr easi ng i ts toxi c potenti al .
Magnesi um sal ts and magnesi um-contai ni ng antaci ds can
decr ease the extent and rate of ni tr ofurantoi n absor pti on.
Ni tr ofurantoi n may decr ease the anti bacter i al acti vi ty of
nor fl oxaci n and nal i di xi c aci d. (See Adver se r eacti ons to
ni tr ofurantoi n.)

Warning!
Adverse reactions to nitrofurantoin
Adver se r eacti ons to ni tr ofurantoi n i ncl ude:

G I i r r i tati on
anor exi a
nausea and vomi ti ng
di ar r hea
dar k yel l ow or br own ur i ne
abdomi nal pai n
chi l l s
fever
joi nt pai n
anaphyl axi s
headache
hyper sensi ti vi ty r eacti ons i nvol vi ng the ski n, l ungs, bl ood, and
l i ver.

Antiviral drugs
Antivir al dr ugs ar e used to pr event or tr eat vi ral i nfecti ons rangi ng
fr om i nfl uenz a to human i mmunodefi ci ency vi r us (HIV). The major
anti vi ral dr ug cl asses used to tr eat systemi c i nfecti ons i ncl ude:

syntheti c nucl eosi des

pyr ophosphate anal ogues
i nfl uenz a A and syncyti al vi r us dr ugs
 nucl eosi de anal ogue r ever se transcr i ptase i nhi bi tor s (NRTIs)
non-nucl eosi de r ever se transcr i ptase i nhi bi tor s (NNRTIs)
nucl eoti de anal ogue r ever se transcr i ptase i nhi bi tor s
pr otease i nhi bi tor s.

Synthetic nucleosides
Synthetic nucleosides ar e a gr oup of dr ugs used to tr eat many vi ral
syndr omes that can occur i n an i mmunocompr omi sed pati ent,

i ncl udi ng her pes si mpl ex vi r us (HSV) and cytomegal ovi r us (CMV).
Dr ugs i n thi s cl ass i ncl ude:

acycl ovi r
famci cl ovi r
ganci cl ovi r
val acycl ovi r
val ganci cl ovi r.

Acycl ovi r sodi um, used to tr eat HSV, i s an effecti ve anti vi ral dr ug
that causes mi ni mal toxi ci ty to cel l s. A der i vati ve of acycl ovi r,
ganci cl ovi r has potent anti vi ral acti vi ty agai nst HSV and CMV.

A prodrug drug
Famci cl ovi r i s used to tr eat acute her pes zoster, geni tal her pes, and
r ecur r ent HSV i nfecti ons i n the HIV-i nfected pati ent. Val acycl ovi r i s
used to tr eat her pes zoster, geni tal her pes, and her pes l abi al i s.
Val ganci cl ovi r i s used to tr eat CMV r eti ni ti s i n the pati ent wi th
acqui r ed i mmunodefi ci ency syndr ome (AIDS).

Pharmacokinetics
Each of these anti vi ral dr ugs travel s i ts own r oute thr ough the body.

Slow by mouth
When gi ven oral l y, acycl ovi r absor pti on i s sl ow and onl y 10% to
30% compl ete. Its di str i buted thr oughout the body and metabol i zed
pr i mar i l y i nsi de the i nfected cel l s; the major i ty of the dr ug i s
excr eted i n ur i ne.

Bound? Not much

Famci cl ovi r i s l ess than 20% bound to pl asma pr otei ns. Its
extensi vel y metabol i zed i n the l i ver and excr eted i n ur i ne.

I.V. only
G anci cl ovi r i s admi ni ster ed I.V. because i ts absor bed poor l y fr om
the G I tract. Mor e than 90% of ganci cl ovi r i snt metabol i zed and i s
excr eted unchanged by the ki dneys.

Metabolic changes
Val acycl ovi r i s conver ted to acycl ovi r dur i ng i ts metabol i sm and has
phar macoki neti c pr oper ti es si mi l ar to those of acycl ovi r.
Val ganci cl ovi r i s metabol i zed i n the i ntesti nal wal l and l i ver to
ganci cl ovi r ; however, i nter changi ng the two dr ugs i snt effecti ve.

Pharmacodynamics
To be effecti ve, acycl ovi r, famci cl ovi r, and ganci cl ovi r must be
metabol i zed to thei r acti ve for m i n cel l s i nfected by HSV.

Presto change-o
Acycl ovi r enter s vi r us-i nfected cel l s, wher e i ts changed thr ough a
ser i es of steps to acycl ovi r tr i phosphate. Acycl ovi r tr i phosphate
i nhi bi ts vi r us-speci fi c DNA pol ymerase, an enz yme necessar y for
vi ral gr owth, thus di sr upti ng vi ral r epl i cati on.
On entr y i nto CMV-i nfected cel l s, ganci cl ovi r i s conver ted to
ganci cl ovi r tr i phosphate, whi ch i s thought to pr oduce i ts anti vi ral
acti vi ty by i nhi bi ti ng vi ral DNA synthesi s.
Famci cl ovi r enter s vi ral cel l s (her pes si mpl ex 1 and 2, var i cel l a
zoster ), wher e i t i nhi bi ts DNA pol ymerase, vi ral DNA synthesi s and,
thus, vi ral r epl i cati on.
Val acycl ovi r rapi dl y conver ts to acycl ovi r ; acycl ovi r then becomes
i ncor porated i nto vi ral DNA and i nhi bi ts vi ral DNA pol ymerase, thus
i nhi bi ti ng vi ral mul ti pl i cati on.
Val ganci cl ovi r i s conver ted to ganci cl ovi r, whi ch i nhi bi ts r epl i cati on
of vi ral DNA synthesi s of CMV.

Pharmacotherapeutics
Acycl ovi r i s used to tr eat i nfecti on caused by her pes vi r uses,
i ncl udi ng HSV types 1 and 2 and the var i cel l a-zoster vi r us. Oral
acycl ovi r i s used pr i mar i l y to tr eat i ni ti al and r ecur r ent HSV type 2
i nfecti ons.
I.V. acycl ovi r i s used to tr eat:

sever e i ni ti al HSV type 2 i nfecti ons i n a pati ent wi th a nor mal

i mmune system
i ni ti al and r ecur r ent ski n and mucous membrane HSV type 1 and
2 i nfecti ons i n an i mmunocompr omi sed pati ent
her pes zoster i nfecti ons (shi ngl es) caused by the var i cel l a-zoster
vi r us i n an i mmunocompr omi sed pati ent
di ssemi nated var i cel l a-zoster vi r us i n an i mmunocompr omi sed
pati ent
var i cel l a i nfecti ons (chi ckenpox) caused by the var i cel l a-zoster
vi r us i n an i mmunocompr omi sed pati ent.

RSVP for CMV

G anci cl ovi r i s used to tr eat CMV r eti ni ti s i n an i mmunocompr omi sed
pati ent, i ncl udi ng a pati ent wi th AIDS or other CMV i nfecti ons such
as encephal i ti s.

If it keeps coming back

Famci cl ovi r i s used to tr eat acute her pes zoster, geni tal her pes, and
r ecur r ent HSV i nfecti ons i n a pati ent wi th HIV.

The valiant vals

Val ganci cl ovi r i s used to tr eat CMV r eti ni ti s, and val acycl ovi r i s
effecti ve agai nst her pes zoster, geni tal her pes, and her pes l abi al i s.

Drug interactions
Syntheti c nucl eosi des may i nteract wi th these dr ugs.

Pr obeneci d r educes ki dney excr eti on and i ncr eases bl ood l evel s
of ganci cl ovi r, val ganci cl ovi r, val acycl ovi r, famci cl ovi r, and
acycl ovi r, i ncr easi ng the r i sk of toxi ci ty.
Taki ng ganci cl ovi r wi th dr ugs that ar e damagi ng to ti ssue cel l s,
such as dapsone, pentami di ne i sethi onate, fl ucytosi ne,
vi ncr i sti ne, vi nbl asti ne, doxor ubi ci n, amphoter i ci n B, and co-
tr i moxazol e, i nhi bi ts r epl i cati on of rapi dl y di vi di ng cel l s i n the
 bone mar r ow, G I tract, ski n, and sper m-pr oduci ng cel l s.
Imi penem-ci l astati n i ncr eases the r i sk of sei z ur es when taken
wi th ganci cl ovi r or val ganci cl ovi r.
Zi dovudi ne i ncr eases the r i sk of granul ocytopeni a (r educed
number of granul ocytes, a type of whi te bl ood cel l ) when taken
wi th ganci cl ovi r. (See Adver se r eacti ons to syntheti c
nucl eosi des.)

Warning!
Adverse reactions to synthetic nucleosides
Tr eatment wi th these dr ugs may l ead to par ti cul ar adver se
r eacti ons.
Acyclovir
Rever si bl e ki dney i mpai r ment may occur wi th rapi d I.V. i njecti on
(l ess than 10 mi nutes) or i nfusi on of acycl ovi r.
Oral history
Common r eacti ons to oral acycl ovi r i ncl ude headache, nausea,
vomi ti ng, and di ar r hea.
Issues of sensitivity
Hyper sensi ti vi ty r eacti ons may occur wi th acycl ovi r.
Ganciclovir
The most common adver se r eacti ons to ganci cl ovi r ar e
granul ocytopeni a and thr ombocytopeni a.
Famciclovir and valacyclovir
Common adver se r eacti ons to famci cl ovi r and val acycl ovi r i ncl ude
headache, nausea, and vomi ti ng.
Valganciclovir
Common adver se r eacti ons to val ganci cl ovi r i ncl ude headache,
i nsomni a, sei z ur es, r eti nal detachment, di ar r hea, nausea,
vomi ti ng, abdomi nal pai n, neutr openi a, anemi a,
thr ombocytopeni a, pancytopeni a, bone mar r ow depr essi on,
apl asti c anemi a, sepsi s, and hyper sensi ti vi ty r eacti ons.

Pyrophosphate analogues
The anti vi ral dr ug foscar net i s used to tr eat CMV r eti ni ti s i n the
pati ent wi th AIDS. Its al so used to tr eat acycl ovi r-r esi stant HSV
i nfecti ons i n the i mmunocompr omi sed pati ent.

Pharmacokinetics
Foscar net i s poor l y bound to pl asma pr otei ns. In pati ents wi th
nor mal ki dney functi on, the major i ty of foscar net i s excr eted
unchanged i n ur i ne.

Pharmacodynamics
Foscar net pr events vi ral r epl i cati on by sel ecti vel y i nhi bi ti ng DNA
pol ymerase.

Pharmacotherapeutics
Foscar nets pr i mar y therapeuti c use i s tr eati ng CMV r eti ni ti s i n the
pati ent wi th AIDS. Its al so used i n combi nati on therapy wi th
ganci cl ovi r for the pati ent who has r el apsed wi th ei ther dr ug.

Drug interactions
Foscar net has few dr ug i nteracti ons.

Foscar net and pentami di ne together i ncr ease the r i sk of

hypocal cemi a (l ow bl ood cal ci um l evel s) and toxi ci ty to the
ki dneys.
The use of foscar net and other dr ugs that al ter ser um cal ci um
l evel s may r esul t i n hypocal cemi a.
Foscar net gi ven wi th ami odar one i ncr eases the r i sk of
car di otoxi ci ty and QT pr ol ongati on.
The r i sk of ki dney i mpai r ment i ncr eases when dr ugs toxi c to the
ki dneys, such as amphoter i ci n B and ami nogl ycosi des, ar e taken
wi th foscar net. Because of the r i sk of ki dney toxi ci ty, the pati ent
shoul d be aggr essi vel y hydrated dur i ng tr eatment. (See Adver se
r eacti ons to foscar net.)

Warning!
Adverse reactions to foscarnet
Adver se r eacti ons to foscar net may i ncl ude:

fati gue, depr essi on, fever, confusi on, headache, numbness and
ti ngl i ng, di z z i ness, and sei z ur es
 nausea and vomi ti ng, di ar r hea, and abdomi nal pai n
granul ocytopeni a, l eukopeni a, and anemi a
i nvol untar y muscl e contracti ons and neur opathy
br eathi ng di ffi cul ti es and coughi ng
rash
al ter ed ki dney functi on
el ectr ol yte di stur bances.

Influenza A and syncytial virus drugs

Amantadine and i ts der i vati ve, r imantadine hydr ochlor ide, ar e used
to pr event or tr eat i nfl uenz a A i nfecti ons. Ribavir in i s used to tr eat
r espi rator y syncyti al vi r us (RSV) i nfecti ons i n chi l dr en.

Breathe in
To tr eat RSV, r i bavi r i n i s admi ni ster ed by aer osol i nhal ati on, usi ng a
smal l -par ti cl e aer osol generator.

Pharmacokinetics
After oral admi ni strati on, amantadi ne and r i mantadi ne ar e wel l
absor bed i n the G I tract and wi del y di str i buted thr oughout the body.
Ri bavi r i n i s admi ni ster ed by nasal or oral i nhal ati on and i s wel l
absor bed. It has a l i mi ted, speci fi c di str i buti on, wi th the hi ghest
concentrati on found i n the r espi rator y tract and i n r ed bl ood cel l s
(RBCs). Ri bavi r i n capsul es ar e rapi dl y absor bed after admi ni strati on
and ar e di str i buted i n pl asma.

Metabolism and excretion

Amantadi ne i s el i mi nated pr i mar i l y i n ur i ne; r i mantadi ne i s
extensi vel y metabol i zed and then excr eted i n ur i ne.
Ri bavi r i n i s metabol i zed i n the l i ver and by RBCs. Its excr eted
pr i mar i l y by the ki dneys, wi th some excr eted i n stool .

Pharmacodynamics
Al though i ts exact mechani sm of acti on i s unknown, amantadi ne
appear s to i nhi bi t an ear l y stage of vi ral r epl i cati on. Ri mantadi ne
i nhi bi ts vi ral RNA and pr otei n synthesi s.
The mechani sm of acti on of r i bavi r i n i snt known compl etel y, but the
dr ugs metabol i tes i nhi bi t vi ral DNA and RNA synthesi s,
subsequentl y hal ti ng vi ral r epl i cati on.

Pharmacotherapeutics
Amantadi ne and r i mantadi ne ar e used to pr event and tr eat
r espi rator y tract i nfecti ons caused by strai ns of the i nfl uenz a A
vi r us. They can r educe the sever i ty and durati on of fever and other
symptoms i n pati ents al r eady i nfected wi th i nfl uenz a A.
Ri bavi r i n, used to tr eat sever e RSV i nfecti on i n chi l dr en, i s al so
used i n adul ts i n combi nati on wi th i nter fer on al fa-2B for tr eatment
of chr oni c hepati ti c C.

Warning!
Adverse reactions to amantadine and
rimantadine
Amantadine
Adver se r eacti ons i ncl ude:

anor exi a
anxi ety
confusi on
depr essi on
di z z i ness
fati gue
for getful ness
hal l uci nati ons
hyper sensi ti vi ty r eacti ons
i nsomni a
i r r i tabi l i ty
nausea
ner vousness
psychosi s.

Rimantadine
Adver se r eacti ons to r i mantadi ne ar e si mi l ar to those for
amantadi ne. However, they tend to be l ess sever e.
In the meantime
These dr ugs al so pr otect the pati ent who has r ecei ved the i nfl uenz a
vacci ne dur i ng the 2 weeks needed for i mmuni ty to devel op as wel l
as the pati ent who cant take the i nfl uenz a vacci ne because of
hyper sensi ti vi ty.

Calming the shakes

Amantadi ne i s al so used to tr eat par ki nsoni sm and dr ug-i nduced
extrapyrami dal r eacti ons (abnor mal i nvol untar y movements).

Drug interactions
Amantadi ne may i nteract wi th some dr ugs. (See Adver se r eacti ons
to amantadi ne and r i mantadi ne, page 265.)

Taki ng anti chol i ner gi cs wi th amantadi ne i ncr eases adver se

anti chol i ner gi c effects.
Amantadi ne gi ven wi th the combi nati on dr ug hydr ochl or othi az i de
and tr i amter ene r esul ts i n decr eased ur i ne excr eti on of
amantadi ne, causi ng i ncr eased amantadi ne l evel s.
Amantadi ne and co-tr i moxazol e l evel s ar e i ncr eased when used
together.

All quiet on the rimantadine front

No cl i ni cal l y si gni fi cant dr ug i nteracti ons have been documented
wi th r i mantadi ne.
Ri bavi r i n has few i nteracti ons wi th other dr ugs.

Ri bavi r i n r educes the anti vi ral acti vi ty of z i dovudi ne, and

concomi tant use of these dr ugs may cause bl ood toxi ci ty.
Taki ng r i bavi r i n and di goxi n can cause di goxi n toxi ci ty,
pr oduci ng such effects as G I di str ess, CNS abnor mal i ti es, and
car di ac ar r hythmi as. (See Adver se r eacti ons to r i bavi r i n.)
 Warning!
Adverse reactions to ribavirin
Adver se r eacti ons to r i bavi r i n i ncl ude:

apnea (l ack of br eathi ng)

car di ac ar r est
hypotensi on
nausea
pneumothorax (ai r i n the pl eural space, causi ng the l ung to
col l apse)
wor seni ng of r espi rator y functi on.

Nucleoside analogue reverse transcriptase

inhibitors
NRTIs ar e used to tr eat the pati ent wi th advanced HIV i nfecti on.
Dr ugs i n thi s cl ass i ncl ude:

abacavi r
di danosi ne
emtr i ci tabi ne
l ami vudi ne
stavudi ne
z i dovudi ne.

First in the fight against AIDS

Zi dovudi ne was the fi r st dr ug to r ecei ve Food and Dr ug
Admi ni strati on (F DA) appr oval for tr eati ng AIDS and AIDS-r el ated
compl ex.

Pharmacokinetics
Each of the NRTIs has i ts own phar macoki neti c pr oper ti es.
Into space
Abacavi r i s rapi dl y and extensi vel y absor bed after oral
admi ni strati on. Its di str i buted i n the extravascul ar space, and
about 50% bi nds wi th pl asma pr otei ns. Abacavi r i s metabol i zed by
the cytosol i c enz ymes and excr eted pr i mar i l y i n ur i ne wi th the
r emai nder excr eted i n stool .
Lami vudi ne and stavudi ne ar e rapi dl y absor bed after admi ni strati on
and ar e excr eted by the ki dneys.
Emtr i ci tabi ne i s rapi dl y and extensi vel y absor bed after oral
admi ni strati on and i s excr eted by the ki dneys.

Buffer needed
Because di danosi ne i s degraded rapi dl y i n gastr i c aci d, di danosi ne
tabl ets and powder contai n a buffer i ng dr ug to i ncr ease pH. The
exact r oute of metabol i sm i snt ful l y under stood. About one-hal f of
an absor bed dose i s excr eted i n ur i ne.

Well absorbed, widely distributed

Zi dovudi ne i s wel l absor bed fr om the G I tract, wi del y di str i buted
thr oughout the body, metabol i zed by the l i ver, and excr eted by the
ki dneys. The dosage may need to be adjusted i n the pati ent wi th
ki dney or l i ver di sease, as i s the case wi th most of the NRTIs.

Pharmacodynamics
NRTIs must under go conver si on to thei r acti ve metabol i tes to
pr oduce thei r acti on.
 Abacavi r i s conver ted to an acti ve metabol i te that i nhi bi ts the
acti vi ty of HIV-1 transcr i ptase by competi ng wi th a natural
component and i ncor porati ng i nto vi ral DNA.
Di danosi ne under goes cel l ul ar enz yme conver si on to i ts acti ve
anti vi ral metabol i te to bl ock HIV r epl i cati on.
Emtr i ci tabi ne i nhi bi ts the enz yme, r ever se transcr i ptase, and
thus i nhi bi ts vi ral DNA r epl i cati on.
Lami vudi ne and stavudi ne ar e conver ted i n the cel l s to thei r
acti ve metabol i tes, whi ch i nhi bi t vi ral DNA r epl i cati on.
Zi dovudi ne i s conver ted by cel l ul ar enz ymes to an acti ve for m,
z i dovudi ne tr i phosphate, whi ch pr events vi ral DNA fr om
r epl i cati ng. (See How z i dovudi ne wor ks, page 268.)

Pharmacotherapeutics
NRTIs ar e used to tr eat HIV and AIDS.

Now I get it!

How zidovudine works
Zi dovudi ne can i nhi bi t r epl i cati on of the human
i mmunodefi ci ency vi r us (HIV). The fi r st two i l l ustrati ons show
how HIV i nvades cel l s and then r epl i cates i tsel f. The bottom
i l l ustrati on shows how z i dovudi ne bl ocks vi ral transfor mati on.
When youre hospitalized
I.V. z i dovudi ne i s used for the hospi tal i zed pati ent who cant take
oral medi cati on. Its al so used to pr event transmi ssi on of HIV fr om
the mother to her fetus and to tr eat AIDS-r el ated dementi a.
Li ke al l dr ugs for HIV i nfecti on, oral z i dovudi ne i s used as par t of a
mul ti dr ug r egi men.

Getting a jump on HIV

Di danosi ne, i n combi nati on wi th other anti r etr ovi ral s (anti vi ral s
used to tr eat HIV i nfecti on), i s an al ter nati ve i ni ti al tr eatment for
HIV i nfecti on.

Part of the combo

Lami vudi ne, stavudi ne, and abacavi r ar e used i n combi nati on wi th
other anti r etr ovi ral s to tr eat HIV i nfecti on. Combivir i s combi nati on
therapy that i ncl udes l ami vudi ne and z i dovudi ne. Tr iz ivir i s
combi nati on therapy that i ncl udes abacavi r, l ami vudi ne, and
z i dovudi ne; i t was appr oved by the F DA i n November 2000 to
si mpl i fy dosi ng i n the tr eatment of HIV.
Emtr i ci tabi ne i s used i n combi nati on wi th other anti r etr ovi ral s to
tr eat HIV i nfecti on.

but be careful here

Because of i nhi bi ti on of phosphor yl ati on (the pr ocess needed to
for m the acti ve DNA-i nhi bi ti ng metabol i te), stavudi ne shoul dnt be
gi ven i n combi nati on wi th z i dovudi ne.

Drug interactions
NRTIs may be r esponsi bl e for many dr ug i nteracti ons.

Potenti al l y fatal l acti c aci dosi s and sever e hepatomegal y wi th

steatosi s have occur r ed i n pati ents taki ng NRTIs al one or wi th
other anti r etr ovi ral s such as tenofovi r. The major i ty of pati ents
wer e women, and obesi ty and pr ol onged NRTI exposur e may be
r i sk factor s.
An i ncr eased r i sk of cel l ul ar and ki dney toxi ci ty occur s when
z i dovudi ne i s taken wi th such dr ugs as dapsone, pentami di ne
i sethi onate, fl ucytosi ne, vi ncr i sti ne, vi nbl asti ne, doxor ubi ci n,
i nter fer on, and ganci cl ovi r.
Taki ng z i dovudi ne wi th pr obeneci d, aspi r i n, acetami nophen,
i ndomethaci n, ci meti di ne, or l orazepam i ncr eases the r i sk of
toxi ci ty of ei ther dr ug.
Zi dovudi ne pl us acycl ovi r may pr oduce pr ofound l ethar gy and
dr owsi ness.
Di danosi ne may r educe the absor pti on of tetracycl i nes,
del avi r di ne, and fl uor oqui nol ones.

Abacavi r l evel s i ncr ease wi th al cohol consumpti on.

 Emtr i ci tabi ne has been studi ed i n combi nati on wi th i ndi navi r,
stavudi ne, famci cl ovi r, and tenofovi r ; ther e wer e no cl i ni cal l y
si gni fi cant dr ug i nteracti ons. (See Adver se r eacti ons to NRTIs.)

Warning!
Adverse reactions to NRTIs
Each of the nucl eosi de r ever se transcr i ptase i nhi bi tor s
(NRTIs) can cause adver se r eacti ons.
Zidovudine

Bl ood-r el ated r eacti ons

Headache and di z z i ness
Muscl e pai n, fever, and rash
Nausea, vomi ti ng, abdomi nal pai n, di ar r hea

Didanosine

Di ar r hea, nausea, vomi ti ng, abdomi nal pai n, consti pati on,
stomati ti s, unusual taste or l oss of taste, dr y mouth,
pancr eati ti s
Headache, per i pheral neur opathy, di z z i ness
Muscl e weakness, rash, i tchi ng, muscl e pai n, hai r l oss

Abacavir

Potenti al l y fatal hyper sensi ti vi ty r eacti ons

Non-nucleoside reverse transcriptase
inhibitors
NNRTIs ar e used i n combi nati on wi th other anti r etr ovi ral s to tr eat
HIV i nfecti on. The thr ee agents i n thi s cl ass i ncl ude:

del avi r di ne
efavi r enz
nevi rapi ne. (See Combi ni ng anti r etr ovi ral dr ugs.)

Pharmacokinetics
Efavi r enz and del avi r di ne ar e hi ghl y pr otei n-bound after absor pti on
and di str i buti on, and nevi rapi ne i s wi del y di str i buted thr oughout the
body. Al l thr ee dr ugs ar e metabol i zed by the cytochr ome P-450 l i ver
enz yme system and excr eted i n ur i ne and stool .

Combining antiretroviral drugs

Monotherapy (usi ng a si ngl e dr ug) i snt r ecommended for human
i mmunodefi ci ency vi r us i nfecti on. For the best r esul ts, a
combi nati on of anti r etr ovi ral agents i s used.

Pharmacodynamics
Nevi rapi ne and del avi r di ne bi nd to the r ever se transcr i ptase
enz yme, pr eventi ng i t fr om exer ti ng i ts effect, and thus pr eventi ng
HIV r epl i cati on. Efavi r enz competes for the enz yme thr ough
noncompeti ti ve i nhi bi ti on.

Pharmacotherapeutics
NNRTIs ar e used i n combi nati on wi th other anti r etr ovi ral s i n HIV
tr eatment; nevi rapi ne i s speci fi cal l y i ndi cated for the pati ent whose
cl i ni cal condi ti on and i mmune status have deter i orated.

Drug interactions
NNRTIs may be r esponsi bl e for many dr ug i nteracti ons.
 Nevi rapi ne may decr ease the acti vi ty of pr otease i nhi bi tor s and
hor monal contracepti ves; these dr ugs shoul dnt be used
together.
Del avi r di ne may i ncr ease l evel s of benzodi azepi nes,
cl ar i thr omyci n, r i fabuti n, saqui navi r, and war far i n; i t may al so
si gni fi cantl y i ncr ease concentrati ons of i ndi navi r, r equi r i ng a
decr ease i n the i ndi navi r dosage.
The i ndi navi r dosage wi l l need to be i ncr eased when gi ven wi th
efavi r enz .
Nevi rapi ne has been associ ated wi th a sever e rash that may be
l i fe-thr eateni ng. If a rash occur s, di sconti nue the dr ug. (See
Adver se r eacti ons to NNRTIs.)

Warning!
Adverse reactions to NNRTIs
Adver se r eacti ons to nonnucl eosi de r ever se transcr i ptase
i nhi bi tor s (NNRTIs) i ncl ude:

headache
di z z i ness
astheni a
nausea and vomi ti ng
di ar r hea
rash.

Nucleotide analogue reverse transcriptase

inhibitors
Nucl eoti de anal ogue r ever se transcr i ptase i nhi bi tor s ar e used i n
combi nati on wi th other anti r etr ovi ral s i n the tr eatment of HIV. The
onl y dr ug i n thi s cl ass to date i s tenofovir , and i t wor ks much l i ke
the NRTIs.
Pharmacokinetics
Tenofovi r i s absor bed much better after a hi gh-fat meal . Its then
di str i buted i n smal l amounts i nto pl asma and ser um pr otei ns.
Metabol i sm i snt thought to be medi ated by cytochr ome P-450 l i ver
enz ymes, and the dr ug i s excr eted by the ki dneys.

Pharmacodynamics
Tenofovi r competes wi th substrates and i s subsequentl y i ncor porated
i nto the DNA chai n, thus hal ti ng HIV r epl i cati on.

Pharmacotherapeutics
Tenofovi r i s used i n combi nati on wi th other dr ugs to tr eat HIV
i nfecti on.

Drug interactions
Tenofovi r may be r esponsi bl e for some dr ug i nteracti ons.

Dr ugs that ar e el i mi nated thr ough the ki dneys or that decr ease
ki dney functi on may i ncr ease l evel s of tenofovi r when gi ven
concur r entl y.
Di danosi ne l evel s i ncr ease when i ts gi ven wi th tenofovi r ; watch
for di danosi ne-based adver se effects.
Potenti al l y fatal l acti c aci dosi s and sever e hepatomegal y wi th
steatosi s have occur r ed i n pati ents taki ng tenofovi r al one or
wi th other anti r etr ovi ral s. The major i ty of pati ents wer e women,
 and obesi ty and pr evi ous NRTI exposur e may be r i sk factor s.
Pati ents wi th pr eexi sti ng l i ver di sease shoul d take thi s dr ug wi th
cauti on. Suspend tr eatment i f hepatotoxi ci ty i s suspected. (See
Adver se r eacti ons to tenofovi r.)

Warning!
Adverse reactions to tenofovir
Adver se r eacti ons to the nucl eoti de anal ogue r ever se
transcr i ptase i nhi bi tor tenofovi r i ncl ude:

nausea and vomi ti ng

di ar r hea
anor exi a
abdomi nal pai n
sever e hepatomegal y (enl ar gement of the l i ver )
l acti c aci dosi s (i ncr eased l acti c aci d pr oducti on i n the bl ood).

Protease inhibitors
Pr otease inhibitor s ar e dr ugs that act agai nst the enz yme HIV
pr otease, pr eventi ng i t fr om di vi di ng a l ar ger vi ral pr ecur sor pr otei n
i nto the acti ve smal l er enz ymes that the HIV vi r us needs to ful l y
matur e. The r esul t i s an i mmatur e, noni nfecti ous cel l . Dr ugs i n thi s
gr oup i ncl ude:

ampr enavi r
ataz anavi r
dar unavi r
fosampr enavi r
i ndi navi r sul fate
l opi navi r and r i tonavi r
nel fi navi r mesyl ate
r i tonavi r
saqui navi r mesyl ate
ti pranavi r.
Pharmacokinetics
Pr otease i nhi bi tor s may have di ffer ent phar macoki neti c pr oper ti es.

Active and inactive

Ampr enavi r i s metabol i zed i n the l i ver to acti ve and i nacti ve
metabol i tes and i s mi ni mal l y excr eted i n ur i ne and stool .
Ataz anavi r i s rapi dl y absor bed and i s metabol i zed i n the l i ver by the
CYP3A. The dr ug i s excr eted mai nl y thr ough stool and ur i ne.
Dar unavi r i s wel l absor bed when taken wi th food and hi ghl y pr otei n-
bound. Its metabol i zed i n the l i ver and excr eted i n stool .
Fosampr enavi r i s wel l absor bed and hi ghl y pr otei n-bound. Its
rapi dl y metabol i zed by CYP3A4 and i t i s unknown how i t i s excr eted.

P-450 at it again
Lopi navi r i s extensi vel y metabol i zed by the l i ver s cytochr ome P-
450 system; r i tonavi r acts as an i nhi bi tor of l opi navi r. Thi s
combi nati on dr ugs anti vi ral acti vi ty i s due to l opi navi r.

Availability unknown
Nel fi navi r s bi oavai l abi l i ty (the degr ee to whi ch i t becomes avai l abl e
to tar get ti ssue after admi ni strati on) i snt deter mi ned. Food
i ncr eases i ts absor pti on. Its hi ghl y pr otei n-bound, metabol i zed i n
the l i ver, and excr eted pr i mar i l y i n stool .
Broken into five
Ri tonavi r i s wel l absor bed, metabol i zed by the l i ver, and br oken
down i nto at l east fi ve metabol i tes. Its mai nl y excr eted i n stool ,
wi th some el i mi nati on thr ough the ki dneys.

and seven
Indi navi r sul fate i s rapi dl y absor bed and moderatel y bound to
pl asma pr otei ns. Its metabol i zed by the l i ver i nto seven
metabol i tes. The dr ug i s excr eted mai nl y i n stool .

Highly bound
Saqui navi r mesyl ate i s poor l y absor bed fr om the G I tract. Its wi del y
di str i buted, hi ghl y bound to pl asma pr otei ns, metabol i zed by the
l i ver, and excr eted mai nl y by the ki dneys.
Ti pranavi r has l i mi ted absor pti on, but i ts bi oavai l abi l i ty i ncr eases
when i ts taken wi th a hi gh-fat meal . Its metabol i zed by the
chr omosome P-450 and excr eted mostl y unchanged i n stool .

Pharmacodynamics
Al l of these dr ugs i nhi bi t the acti vi ty of HIV pr otease and pr event
the cl eavage of vi ral pol ypr otei ns.

Pharmacotherapeutics
Pr otease i nhi bi tor s ar e used i n combi nati on wi th other anti r etr ovi ral
agents for the tr eatment of HIV i nfecti on.

Drug interactions
Pr otease i nhi bi tor s may i nteract wi th many dr ugs. Her e ar e some
common i nteracti ons.

The acti on of saqui navi r may be r educed by phenobar bi tal ,

phenytoi n, dexamethasone, and car bamazepi ne.

Blockers beware!
Ri tonavi r may i ncr ease the effects of al pha-adr ener gi c bl ocker s,
anti ar r hythmi cs, anti depr essants, anti emeti cs, anti fungal s, anti -
l i pemi cs, anti mal ar i al s, anti neopl asti cs, beta-adr ener gi c
bl ocker s, cal ci um channel bl ocker s, ci meti di ne, cor ti coster oi ds,
er ythr o-myci n, i mmunosuppr essants, methyl pheni date,
pentoxi fyl l i ne, phenothi az i nes, and war far i n.
Indi navi r sul fate i nhi bi ts the metabol i sm of mi dazol am and
tr i azol am, i ncr easi ng the r i sk of potenti al l y fatal events such as
car di ac ar r hythmi as.
Di danosi ne decr eases gastr i c absor pti on of i ndi navi r sul fate;
these dr ugs shoul d be admi ni ster ed at l east 1 hour apar t.
Ri fampi n mar kedl y r educes pl asma l evel s of most pr otease
i nhi bi tor s, i ncl udi ng ataz anavi r.
Nel fi navi r may gr eatl y i ncr ease pl asma l evel s of ami odar one,
er got der i vati ves, mi dazol am, r i fabuti n, qui ni di ne, and
tr i azol am.
Lopi navi r and r i tonavi r ar e used i n combi nati on because of thei r
posi ti ve effects on HIV RNA l evel s and CD4 counts. When gi ven
together, r i tonavi r i nhi bi ts the metabol i sm of l opi navi r, l eadi ng
to i ncr eased pl asma l opi navi r l evel s.
Car bamazepi ne, phenobar bi tal , and phenytoi n may r educe the
effecti veness of nel fi navi r.
Pr otease i nhi bi tor s may i ncr ease si l denafi l l evel s, r esul ti ng i n
si l denafi l -associ ated adver se r eacti ons, i ncl udi ng hypotensi on,
vi si on changes, and pr i api sm.
Ataz anavi r shoul dnt be gi ven wi th dr ugs al so metabol i zed by the
CYPA3A pathway, such as HMG -CoA r eductase i nhi bi tor s
(i ncl udi ng l ovastati n, si mvastati n, and ator vastati n). Concur r ent
use may i ncr ease the r i sk of myopathy and r habdomyol ysi s.
Interval issues
Dr ugs that pr ol ong the PR i nter val , such as cal ci um channel
bl ocker s (i ncl udi ng di l ti azem) and beta-adr ener gi c bl ocker s
(i ncl udi ng atenol ol ), shoul d be used cauti ousl y wi th ataz anavi r
because ataz anavi r may al so pr ol ong the PR i nter val .
Ataz anavi r shoul dnt be gi ven wi th benzodi azepi nes, such as
mi dazol am and tr i azol am, because of the potenti al for i ncr eased
sedati on or r espi rator y depr essi on.
Ataz anavi r shoul dnt be gi ven wi th er got der i vati ves, such as
er gotami ne and di hydr oer gotami ne, because of the potenti al for
l i fe-thr eateni ng er got toxi ci ty r esul ti ng i n per i pheral vasospasm
and i schemi a of the extr emi ti es.
St. Johns wor t may r educe pl asma l evel s of ataz anavi r and
dar unavi r.
Ti pranavi r and sul fonyur eas admi ni ster ed together may r esul t i n
hypogl ycemi a.

Indi navi r and r i tonavi r may i ncr ease pl asma nel fi navi r l evel s.
(See Adver se r eacti ons to pr otease i nhi bi tor s.)

Warning!
Adverse reactions to protease inhibitors
These common adver se r eacti ons occur wi th pr otease
i nhi bi tor s:
 abdomi nal di scomfor t
abdomi nal pai n
aci d r egur gi tati on
anor exi a
back pai n
deep vei n thr ombosi s
depr essi on
di ar r hea
di z z i ness
dr y mouth
encephal opathy
fati gue
fl ank pai n
headache
hemor r hagi c col i ti s
hyper chol ester ol emi a
hyper gl ycemi a
hyper tr i gl ycer i demi a
i nsomni a
l eukopeni a
muscl e weakness
nausea and vomi ti ng
neutr openi a
pancr eati ti s
par esthesi s
rash
Stevens-Johnson syndr ome
taste per ver si on

Antitubercular drugs
Antituber cular dr ugs ar e used to tr eat tuber cul osi s (TB), whi ch i s
caused by Mycobacter ium tuber culosis. Not al ways curati ve, these
dr ugs can hal t the pr ogr essi on of a mycobacter i al i nfecti on.

Myco-versatility
These dr ugs al so ar e effecti ve agai nst l ess common mycobacter i al
i nfecti ons caused by M. kansasii, M. avium-intr acellular e, M.
for tuitum, and r el ated or gani sms.

Time consuming
Unl i ke most anti bi oti cs, anti tuber cul ar dr ugs may need to be
admi ni ster ed over many months. Thi s cr eates pr obl ems, such as
pati ent noncompl i ance, the devel opment of bacter i al r esi stance, and
dr ug toxi ci ty. (See Di r ectl y obser vabl e therapy for TB, page 276.)

Yea or nay?
Directly observable therapy for TB
Among i nfecti ous di seases, tuber cul osi s (TB) r emai ns a
fr equent ki l l er wor l dwi de. What makes tr eatment di ffi cul t i s that
i t r equi r es l ong-ter m medi cal therapytypi cal l y for as l ong as 6 to
9 months. The l ong tr eatment per i od commonl y cr eates pr obl ems
wi th pati ent compl i ance (an i nabi l i ty or unwi l l i ngness to fol l ow a
tr eatment pl an), and poor compl i ance contr i butes to r eacti vati on
of the di sease and the devel opment of dr ug-r esi stant TB.
DOT on the spot
Di r ectl y obser vabl e therapy (DOT) was devel oped to combat these
tr eatment i ssues. DOT r equi r es that a heal th car e wor ker obser ve
a pati ent take ever y dose of medi cati on for the durati on of
therapy. A contr over sy exi sts over whether ever y i ndi vi dual wi th
TB shoul d be obser ved (uni ver sal DOT) or whether onl y the
pati ent at r i sk for poor compl i ance shoul d be obser ved (sel ecti ve
DOT).
Who fails to comply?
The pati ent at r i sk for poor compl i ance i ncl udes one wi th a
hi stor y of poor compl i ance or dr ug or al cohol abuse, mental
i l l ness, homel essness, i ncar cerati on, or r esi dence i n a homel ess
shel ter. Some ar eas, such as Mi ssi ssi ppi and New Yor k Ci ty,
practi ce uni ver sal DOT; other ar eas, i ncl udi ng Massachusetts, fi r st
eval uate a pati ents abi l i ty and wi l l i ngness to compl y.

Drug regimens for treating TB

Tradi ti onal l y, i soni az i d, r i fampi n, and ethambutol wer e the
mai nstays of mul ti dr ug TB therapy and successful l y pr evented the
emer gence of dr ug r esi stance.
A new regimen to combat resistance
Because of the cur r ent i nci dence of dr ug-r esi stant TB strai ns, a
four-dr ug r egi men i s now r ecommended for i ni ti al tr eatment:

i soni az i d
r i fampi n
pyraz i nami de
str eptomyci n or ethambutol .

One regimen may succeed another

The anti tuber cul ar r egi men shoul d be modi fi ed i f l ocal testi ng shows
r esi stance to one or mor e of these dr ugs. If l ocal outbr eaks of TB
r esi stant to i soni az i d and r i fampi n ar e occur r i ng i n faci l i ti es (for
exampl e, heal th car e or cor r ecti onal faci l i ti es), then fi ve- or

si x-dr ug r egi mens ar e r ecommended as i ni ti al therapy. (See Other

anti tuber cul ar dr ugs.)

Other antitubercular drugs

Several other dr ugs ar e used as anti tuber cul ar dr ugs i n
combi nati on wi th fi r st-l i ne dr ugs. Because these dr ugs have a
gr eater i nci dence of toxi ci ty, theyr e used pr i mar i l y for the
pati ent whos r esi stant or al l er gi c to l ess toxi c dr ugs.
Fluoroquinolones
F l uor oqui nol ones, such as ci pr ofl oxaci n and ofl oxaci n, ar e
effecti ve agai nst Mycobacter ium tuber culosis. Of these two dr ugs,
ofl oxaci n i s mor e potent and may be an i ni ti al choi ce i n
r etr eatment. These dr ugs ar e admi ni ster ed oral l y and ar e
general l y wel l tol erated. G I adver se r eacti ons ar e most commonl y
r epor ted. However, r esi stance to fl uor oqui nol ones devel ops
rapi dl y when these dr ugs ar e used al one or i n i nsuffi ci ent doses.
Streptomycin
Str eptomyci n was the fi r st dr ug r ecogni zed as effecti ve i n tr eati ng
tuber cul osi s. Str eptomyci n i s admi ni ster ed I.M. onl y. It appear s to
enhance the acti vi ty of oral anti tuber cul ar dr ugs and i s of
gr eatest val ue i n the ear l y weeks to months of therapy. However,
I.M. admi ni strati on l i mi ts i ts useful ness i n l ong-ter m therapy.
 Rapi dl y absor bed fr om the I.M. i njecti on si te, str eptomyci n i s
excr eted pr i mar i l y by the ki dneys as unchanged dr ug. Most
pati ents tol erate str eptomyci n wel l , but those r ecei vi ng l ar ge
doses may exhi bi t ei ghth crani al ner ve toxi ci ty (ototoxi ci ty).

Pharmacokinetics
Most anti tuber cul ar dr ugs ar e admi ni ster ed oral l y. When
admi ni ster ed oral l y, these dr ugs ar e wel l absor bed fr om the G I tract
and wi del y di str i buted thr oughout the body. Theyr e metabol i zed
pr i mar i l y i n the l i ver and excr eted by the ki dneys.

Pharmacodynamics
Anti tuber cul ar dr ugs ar e speci fi c for mycobacter i a. At usual doses,
ethambutol and i soni az i d ar e tuber cul ostati c, meani ng that they
i nhi bi t the gr owth of M. tuber culosis. In contrast, r i fampi n i s
tuber cul oci dal , meani ng that i t destr oys the mycobacter i a. Because
bacter i al r esi stance to i soni az i d and r i fampi n can devel op rapi dl y,
they shoul d al ways be used wi th other anti tuber cul ar dr ugs.

Antireplication station
The exact mechani sm of acti on of ethambutol r emai ns uncl ear, but i t
may be r el ated to i nhi bi ti on of cel l metabol i sm, ar r est of
mul ti pl i cati on, and cel l death. Ethambutol acts onl y agai nst
r epl i cati ng bacter i a.

Breaking down walls

Al though i soni az i ds exact mechani sm of acti on i snt known, the
dr ug i s bel i eved to i nhi bi t the synthesi s of mycol i c aci ds, i mpor tant
components of the mycobacter i um cel l wal l . Thi s i nhi bi ti on di sr upts
the cel l wal l . Onl y r epl i cati ng, not r esti ng, bacter i a appear to be
i nhi bi ted.
Synthesis stopper
Ri fampi n i nhi bi ts RNA synthesi s i n suscepti bl e or gani sms. The dr ug
i s effecti ve pr i mar i l y i n r epl i cati ng bacter i a, but may have some
effect on r esti ng bacter i a as wel l .

Acid based
The exact mechani sm of acti on of pyraz i nami de i snt known, but the
anti mycobacter i al acti vi ty appear s to be l i nked to the dr ugs
conver si on to the acti ve metabol i te pyraz i noi c aci d. Pyraz i noi c aci d,
i n tur n, cr eates an aci di c envi r onment wher e mycobacter i a cant
r epl i cate.

Pharmacotherapeutics
Isoni az i d usual l y i s used wi th ethambutol , r i fampi n, or
pyraz i nami de. Thi s i s because combi nati on therapy for TB and other
mycobacter i al i nfecti ons can pr event or del ay the devel opment of
r esi stance.

In uncomplicated cases
Ethambutol i s used wi th i soni az i d and r i fampi n to tr eat the pati ent
wi th uncompl i cated pul monar y TB. Its al so used to tr eat i nfecti ons
r esul ti ng fr om M. bovis and most strai ns of M. kansasii.

Isolating isoniazid
Al though i soni az i d i s the most i mpor tant dr ug for tr eati ng TB,
bacter i al r esi stance devel ops rapi dl y i f i ts used al one. However,
r esi stance doesnt pose a pr obl em when i soni az i d i s used al one to
pr event TB i n the pati ent who has been exposed to the di sease, and
no evi dence exi sts of cr oss-r esi stance between i soni az i d and other
anti tuber cul ar dr ugs. Isoni az i d i s typi cal l y gi ven oral l y, but may be
gi ven i ntravenousl y, i f necessar y.

Pulmonary power
Ri fampi n i s a fi r st-l i ne dr ug for tr eati ng pul monar y TB wi th other
anti tuber cul ar dr ugs. It combats many gram-posi ti ve and some
gram-negati ve bacter i a, but i s sel dom used for nonmycobacter i al
i nfecti ons because bacter i al r esi stance devel ops rapi dl y. Its used to
tr eat asymptomati c car r i er s of Neisser ia meningitidis when the r i sk
of meni ngi ti s i s hi gh, but i t i snt used to tr eat N. meningitidis

i nfecti ons because of the potenti al for bacter i al r esi stance.

Warning!
Adverse reactions to antitubercular drugs
Her e ar e common adver se r eacti ons to anti tuber cul ar dr ugs.
Ethambutol
Itchi ng, joi nt pai n, G I di str ess, mal ai se, l eukopeni a, headache,
di z z i ness, numbness and ti ngl i ng of the extr emi ti es, opti c
neur i ti s, and confusi on may occur.
Al though rar e, hyper sensi ti vi ty r eacti ons to ethambutol may
pr oduce rash and fever. Anaphyl axi s may al so occur.
Isoniazid
Per i pheral neur opathy i s the most common adver se r eacti on.
Sever e and occasi onal l y fatal hepati ti s associ ated wi th i soni az i d
may occur even many months after tr eatment has stopped. The
pati ent must be moni tor ed car eful l y.
Rifampin
The most common adver se r eacti ons i ncl ude epi gastr i c pai n,
nausea, vomi ti ng, abdomi nal cramps, fl atul ence, anor exi a, and
di ar r hea.
Pyrazinamide
Li ver toxi ci ty i s the major l i mi ti ng adver se r eacti on. G I
di stur bances i ncl ude nausea, vomi ti ng, hyper ur i cemi a, ar thral gi a,
and anor exi a.
On the TB front
Pyraz i nami de i s cur r entl y r ecommended as a fi r st-l i ne TB dr ug i n
combi nati on wi th ethambu-tol , r i fampi n, and i soni az i d. Pyraz i nami de
i s a hi ghl y speci fi c dr ug thats acti ve onl y agai nst M. tuber culosis.
Resi stance to pyraz i nami de may devel op rapi dl y when i ts used
al one.

Drug interactions
Anti tuber cul ar dr ugs may i nteract wi th many other dr ugs. (See
Adver se r eacti ons to anti tuber cul ar dr ugs.)

Cycl oser i ne and ethi onami de may pr oduce addi ti ve CNS effects,
such as dr owsi ness, di z z i ness, headache, l ethar gy, depr essi on,
tr emor, anxi ety, confusi on, and ti nni tus (r i ngi ng i n the ear s),
when admi ni ster ed wi th i soni az i d.
Isoni az i d may i ncr ease l evel s of phenytoi n, car bamazepi ne,
di azepam, ethosuxi mi de, pr i mi done, theophyl l i ne, and war far i n.
When cor ti coster oi ds and i soni az i d ar e taken together, the
effecti veness of i soni az i d i s r educed whi l e the effects of
cor ti coster oi ds ar e i ncr eased.

Isoni az i d may r educe the pl asma l evel s of ketoconazol e,

i traconazol e, and oral anti di abeti c agents.
Oral contracepti ves and r i fampi n taken together may decr ease
 the effecti veness of the oral contracepti ve.
When gi ven together, r i fampi n, i soni az i d, ethi onami de, and
pyraz i nami de i ncr ease the r i sk of hepatotoxi ci ty.
Pyraz i nami de combi ned wi th phenytoi n may i ncr ease phenytoi n
l evel s.

Antimycotic drugs
Antimycotic, or antifungal, dr ugs ar e used to tr eat fungal i nfecti ons.
The major anti fungal dr ug gr oups i ncl ude:

pol yenes
fl uor i nated pyr i mi di ne
i mi dazol e
syntheti c tr i azol es
gl ucan synthesi s i nhi bi tor s
syntheti c al l yl ami ne der i vati ves. (See Other anti mycoti c dr ugs.)

Polyenes
The pol yenes i ncl ude amphoter icin B and nystatin. Amphoter i ci n Bs
potency has made i t the most wi del y used anti mycoti c dr ug for
sever e systemi c fungal i nfecti ons. Its avai l abl e i n several for ms,
i ncl udi ng l i pi d-based pr eparati ons that may decr ease r enal or
systemi c toxi ci ty. Nystati n i s used onl y topi cal l y or oral l y to tr eat
l ocal fungal i nfecti ons because i ts extr emel y toxi c when
admi ni ster ed par enteral l y.

Pharmacokinetics
After I.V. admi ni strati on, amphoter i ci n B i s di str i buted thr oughout
the body and excr eted by the ki dneys. Its metabol i sm i snt wel l
defi ned.
Oral nystati n under goes l i ttl e or no absor pti on, di str i buti on, or
metabol i sm. Its excr eted unchanged i n stool . Topi cal nystati n i snt
absor bed thr ough the ski n or mucous membranes.

Pharmacodynamics
Amphoter i ci n B wor ks by bi ndi ng to ster ol (a l i pi d) i n the fungal cel l
membrane, al ter i ng cel l per meabi l i ty (abi l i ty to al l ow a substance

to pass thr ough) and al l owi ng i ntracel l ul ar components to l eak out.

Other antimycotic drugs

Several other anti mycoti c dr ugs offer al ter nati ve for ms of
tr eatment for topi cal fungal i nfecti ons.
Clotrimazole
An i mi dazol e der i vati ve, cl otr i mazol e i s used:

topi cal l y to tr eat der matophyte and Candida albicans i nfecti ons
oral l y to tr eat oral candi di asi s
vagi nal l y to tr eat vagi nal candi di asi s.

Griseofulvin
G r i seoful vi n i s used to tr eat fungal i nfecti ons of the:

ski n (ti nea cor por i s)

feet (ti nea pedi s)
gr oi n (ti nea cr ur i s)
bear d ar ea of the face and neck (ti nea bar bae)
nai l s (ti nea ungui um)
scal p (ti nea capi ti s).

Long-term treatment
To pr event a r el apse, gr i seoful vi n therapy must conti nue unti l the
fungus i s eradi cated and the i nfected ski n or nai l s ar e r epl aced.
Miconazole
Avai l abl e as mi conazol e or mi conazol e ni trate, thi s i mi dazol e
der i vati ve i s used to tr eat l ocal fungal i nfecti ons, such as vagi nal
and vul var candi di asi s, and topi cal fungal i nfecti ons such as
chr oni c candi di asi s of the ski n and mucous membranes.
Delivery options
Mi conazol e may be admi ni ster ed:

I.V. or i ntrathecal l y (i nto the subarachnoi d space) to tr eat

fungal meni ngi ti s
I.V. or by bl adder i r r i gati on to tr eat fungal bl adder i nfecti ons
 l ocal l y to tr eat vagi nal i nfecti ons
topi cal l y to tr eat topi cal i nfecti ons.

Other topical antimycotic drugs

Ci cl opi r ox ol ami ne, econazol e ni trate, hal opr ogi n, butoconazol e
ni trate, nafti fi ne, ti oconazol e, ter conazol e, tol naftate, butenafi ne,
ter bi nafi ne, sul conazol e, oxi conazol e, cl i oqui nol , tr i aceti n, and
undecyl eni c aci d ar e avai l abl e onl y as topi cal dr ugs.

A license to kill
Amphoter i ci n B usual l y acts as a fungi stati c dr ug (i nhi bi ti ng fungal
gr owth and mul ti pl i cati on), but can become fungi ci dal (destr oyi ng
fungi ) i f i t r eaches hi gh concentrati ons i n the fungi .
Nystati n bi nds to ster ol s i n fungal cel l membranes and al ter s the
per meabi l i ty of the membranes, l eadi ng to l oss of cel l components.
Nystati n can act as a fungi ci dal or fungi stati c dr ug, dependi ng on
the or gani sm pr esent.

Memory jogger
If a dr ug i s fungi ci dal , i t destr oys the fungusci dus i s a Lati n
ter m for ki l l i ng. If i ts fungi stati c, i t pr events fungal gr owth
and mul ti pl i cati onstasi s i s a G r eek ter m for hal ti ng.

Pharmacotherapeutics
Amphoter i ci n B usual l y i s admi ni ster ed to tr eat sever e systemi c
fungal i nfecti ons and meni ngi ti s caused by fungi sensi ti ve to the
dr ug. Its never used for noni nvasi ve for ms of fungal di sease
because i ts hi ghl y toxi c. Its usual l y the dr ug of choi ce for sever e
i nfecti ons caused by Candida, Par acoccidioides br asiliensis,
Blastomyces der matitidis, Coccidioides immitis, Cr yptococcus
neofor mans,

and Spor othr ix schenckii. Its al so effecti ve agai nst Asper gillus
fumigatus, Micr ospor um audouinii, Rhiz opus, Candida glabr ata,
Tr ichophyton, and Rhodotor ula.

Last-ditch effort
Because amphoter i ci n B i s hi ghl y toxi c, i ts use i s l i mi ted to the
pati ent who has a defi ni ti ve di agnosi s of l i fe-thr eateni ng i nfecti on
and i s under cl ose medi cal super vi si on.

Topical concerns
Nystati n i s used pr i mar i l y to tr eat candi dal ski n i nfecti ons. Di ffer ent
for ms of nystati n ar e avai l abl e for tr eati ng di ffer ent types of
candi dal i nfecti ons. Topi cal nystati n i s used to tr eat candi dal ski n or
mucous membrane i nfecti ons, such as oral thr ush, di aper rash,
vagi nal and vul var candi di asi s, and candi di asi s between ski n fol ds.

Oral history
Oral nystati n i s used to tr eat G I i nfecti ons.

Drug interactions
Nystati n doesnt i nteract si gni fi cantl y wi th other dr ugs, but
amphoter i ci n B may have si gni fi cant i nteracti ons wi th many dr ugs.

Because of the syner gi sti c effects between fl ucytosi ne and

amphoter i ci n B, these two dr ugs commonl y ar e combi ned i n
therapy for candi dal or cr yptococcal i nfecti ons, especi al l y for
cr yptococcal meni ngi ti s.
The r i sk of ki dney toxi ci ty i ncr eases when amphoter i ci n B i s
taken wi th ami nogl ycosi des, cycl ospor i ne, or acycl ovi r.
Cor ti coster oi ds, extended-spectr um peni ci l l i ns, and di goxi n may
wor sen the hypokal emi a (l ow bl ood potassi um l evel s) pr oduced
by amphoter i ci n B, possi bl y l eadi ng to hear t pr obl ems. Mor eover,
the r i sk of di goxi n toxi ci ty i s i ncr eased.
Amphoter i ci n B pl us nondepol ar i z i ng skel etal muscl e r el axants
(such as pancur oni um br omi de) i ncr ease muscl e r el axati on.
El ectr ol yte sol uti ons may i nacti vate amphoter i ci n B when di l uted
i n the same sol uti on. Amphoter i ci n B pr eparati ons must be
mi xed wi th dextr ose 5% i n water ; they cant be mi xed wi th
sal i ne sol uti on.
Magnesi um and potassi um l evel s and ki dney functi on must be
moni tor ed fr equentl y i n pati ents r ecei vi ng amphoter i ci n. (See
Adver se r eacti ons to amphoter i ci n B and Adver se r eactions to
nystatin.)
 Warning!
Adverse reactions to nystatin
Reacti ons to nystati n sel dom occur, but hi gh dosages may
pr oduce:

di ar r hea
nausea and vomi ti ng
abdomi nal pai n
a bi tter taste.

It can get under your skin

Topi cal nystati n may al so cause ski n i r r i tati on, and a
hyper sensi ti vi ty r eacti on may occur wi th oral or topi cal
admi ni strati on.

Warning!
Adverse reactions to amphotericin B
Al most al l pati ents r ecei vi ng I.V. amphoter i ci n B,
par ti cul ar l y at the begi nni ng of l ow-dose therapy, exper i ence:

chi l l s
fever
nausea and vomi ti ng
anor exi a
muscl e and joi nt pai n
i ndi gesti on.

Anemia
Most pati ents al so devel op nor mochr omi c (adequate hemogl obi n
i n each r ed bl ood cel l [RBC]) or nor mocyti c anemi a (too few
RBCs) that si gni fi cantl y decr eases the hematocr i t.
Hypomagnesemi a and hypokal emi a may occur, causi ng
el ectr ocar di ographi c changes and r equi r i ng r epl acement
el ectr ol yte therapy.
Kidney concerns
Up to 80% of pati ents may devel op some degr ee of ki dney
toxi ci ty, causi ng the ki dneys to l ose thei r abi l i ty to concentrate
 ur i ne.

Flucytosine
F lucytosine i s the onl y anti metabol i te (a substance that cl osel y
r esembl es one r equi r ed for nor mal physi ol ogi c functi oni ng and that
exer ts i ts effect by i nter fer i ng wi th metabol i sm) that acts as an
anti mycoti c. Its a pur i ne and pyr i mi di ne i nhi bi tor thats used
pr i mar i l y wi th another anti mycoti c dr ug, such as amphoter i ci n B, to
tr eat systemi c fungal i nfecti ons.

Pharmacokinetics
After oral admi ni strati on, fl ucytosi ne i s wel l absor bed fr om the G I
tract and wi del y di str i buted. It under goes l i ttl e metabol i sm and i s
excr eted pr i mar i l y by the ki dneys.

Pharmacodynamics
F l ucytosi ne penetrates fungal cel l s, wher e i ts conver ted to i ts
acti ve metabol i te fl uor ouraci l . F l uor ouraci l then i s i ncor porated i nto
the RNA of the fungal cel l s, al ter i ng thei r pr otei n synthesi s and
causi ng cel l death.

Pharmacotherapeutics
Al though amphoter i ci n B i s effecti ve i n tr eati ng candi dal and
cr yptococcal meni ngi ti s al one, fl ucytosi ne i s gi ven wi th i t to r educe

the dosage and the r i sk of toxi ci ty. Thi s combi nati on therapy i s the
tr eatment of choi ce for cr yptococcal meni ngi ti s.

Standing alone
F l ucytosi ne can be used al one to tr eat candi dal i nfecti ons of the
l ower ur i nar y tract because i t r eaches a hi gh ur i nar y concentrati on.
Its al so effecti ve i n tr eati ng i nfecti ons caused by T. glabr ata,
Phialophor a, Asper gillus, and Cladospor ium.

Drug interactions
Cytarabi ne may antagoni ze the anti fungal acti vi ty of fl ucytosi ne,
possi bl y by competi ti ve i nhi bi ti on. Hematol ogi c, ki dney, and l i ver
functi on must be cl osel y moni tor ed dur i ng fl ucytosi ne therapy
because of the dr ugs ser i ous r i sk of toxi ci ty. (See Adver se r eacti ons
to fl ucytosi ne.)

Warning!
Adverse reactions to flucytosine
F l ucytosi ne may pr oduce unpr edi ctabl e adver se r eacti ons,
i ncl udi ng:

confusi on
headache
dr owsi ness
ver ti go
hal l uci nati ons
di ffi cul ty br eathi ng
r espi rator y ar r est
rash
nausea and vomi ti ng
abdomi nal di stenti on
di ar r hea
anor exi a.

Imidazole
Ketoconaz ole, the most commonl y used i mi dazol e, i s an effecti ve
oral anti mycoti c dr ug wi th a br oad spectr um of acti vi ty.

Pharmacokinetics
When gi ven oral l y, ketoconazol e i s absor bed var i abl y and
di str i buted wi del y. It under goes extensi ve l i ver metabol i sm and i s
excr eted thr ough bi l e and stool .

Pharmacodynamics
Wi thi n the fungal cel l s, ketoconazol e i nter fer es wi th ster ol
synthesi s, damagi ng the cel l membrane and i ncr easi ng i ts
per meabi l i ty. Thi s l eads to a l oss of essenti al i ntracel l ul ar el ements
and i nhi bi ti on of cel l gr owth.
Can inhibit or kill
Ketoconazol e usual l y pr oduces fungi stati c effects, but can al so
pr oduce fungi ci dal effects under cer tai n condi ti ons.

Pharmacotherapeutics
Ketoconazol e i s used to tr eat topi cal and systemi c i nfecti ons caused
by suscepti bl e fungi , whi ch i ncl ude der matophytes and most other
fungi .

Drug interactions
Ketoconazol e may have si gni fi cant i nteracti ons wi th other dr ugs.

Ketoconazol e used wi th dr ugs that decr ease gastr i c aci di ty, such
as ci meti di ne, rani ti di ne, famoti di ne, ni z ati di ne, antaci ds, and
anti chol i ner gi c dr ugs, may decr ease absor pti on of ketoconazol e
and r educe i ts anti mycoti c effects. If the pati ent must take these
dr ugs, del ay admi ni strati on of ketoconazol e by at l east 2 hour s.
Taki ng ketoconazol e wi th phenytoi n may al ter metabol i sm and
i ncr ease bl ood l evel s of both dr ugs.
When taken wi th theophyl l i ne, ketoconazol e may decr ease the
ser um theophyl l i ne l evel .
Usi ng ketoconazol e wi th other l i ver-toxi c dr ugs may i ncr ease the
r i sk of l i ver di sease.
Combi ned wi th cycl ospor i ne therapy, ketoconazol e may i ncr ease
cycl ospor i ne and ser um cr eati ni ne l evel s.
Ketoconazol e i ncr eases the effect of oral anti coagul ants and can
cause hemor r hage.
Ketoconazol e can i nhi bi t the metabol i sm (and possi bl y i ncr ease
l evel s) of qui ni di ne, sul fonyl ur eas, car bamazepi ne, and pr otease
i nhi bi tor s.
Ketoconazol e shoul dnt be gi ven wi th r i fampi n because ser um
ketoconazol e l evel s may decr ease. (See Adver se r eacti ons to
ketoconazol e.)
 Warning!
Adverse reactions to ketoconazole
The most common adver se r eacti ons to ketoconazol e ar e
nausea and vomi ti ng. Less fr equent r eacti ons i ncl ude:

anaphyl axi s
joi nt pai n
chi l l s
fever
r i ngi ng i n the ear s
i mpotence
photophobi a.

Toxic topics
Li ver toxi ci ty i s rar e and r ever si bl e when the dr ug i s stopped.

Synthetic triazoles
The syntheti c tr i azol es i ncl ude:

fl uconazol e
i traconazol e
vor i conazol e.

F luconaz ole bel ongs to a cl ass of syntheti c, br oad-spectr um tr i azol es

and i s al so r efer r ed to as a bistr iaz ole antimycotic dr ug.
Itr aconaz ole and vor iconaz ole al so bel ong to the syntheti c tr i azol e
cl ass of dr ugs. They i nhi bi t the synthesi s of er goster ol , a vi tal
component of fungal cel l membranes.

Pharmacokinetics
After oral admi ni strati on, fl uconazol e i s about 90% absor bed. Its
di str i buted i nto al l body fl ui ds, and mor e than 80% of the dr ug i s
excr eted unchanged i n ur i ne.
Oral bi oavai l abi l i ty i s gr eatest when i traconazol e i s taken wi th food;
vor i conazol e i s mor e effecti ve i f taken 1 hour befor e or after a
meal .
Bound and determined
Itraconazol e and vor i conazol e ar e bound to pl asma pr otei ns and
extensi vel y metabol i zed i n the l i ver i nto a l ar ge number of
metabol i tes. Theyr e mi ni mal l y excr eted i n stool .

Pharmacodynamics
F l uconazol e i nhi bi ts fungal cytochr ome P-450, an enz yme
r esponsi bl e for fungal ster ol synthesi s, causi ng fungal cel l wal l s to
weaken.
Itraconazol e and vor i conazol e i nter fer e wi th fungal cel l -wal l
synthesi s by i nhi bi ti ng the for mati on of er goster ol and i ncr easi ng
cel l -wal l per meabi l i ty, maki ng the fungus suscepti bl e to osmoti c
i nstabi l i ty.

Pharmacotherapeutics
F l uconazol e i s used to tr eat mouth, thr oat, and esophageal
candi di asi s and ser i ous systemi c candi dal i nfecti ons, i ncl udi ng UTIs,
per i toni ti s, and pneumoni a. Its al so used to tr eat cr yptococcal
meni ngi ti s.

Osis, smosis
Itraconazol e i s used to tr eat bl astomycosi s, nonmeni ngeal
hi stopl asmosi s, candi di asi s, asper gi l l osi s, and fungal nai l di sease.
Vor i conazol e i s used to tr eat i nvasi ve asper gi l l osi s and ser i ous
fungal i nfecti ons caused by Scedospor ium apiosper mum and
F usar ium speci es.

Drug interactions
F l uconazol e may have i nteracti ons wi th other dr ugs:

Usi ng fl uconazol e wi th war far i n may i ncr ease the r i sk of

bl eedi ng.
It may i ncr ease l evel s of phenytoi n and cycl ospor i ne.
It may i ncr ease the pl asma l evel s of oral anti di abeti c dr ugs,
such as gl ybur i de, tol butami de, and gl i pi z i de, i ncr easi ng the r i sk
of hypogl ycemi a.
Ri fampi n and ci meti di ne enhance the metabol i sm of fl uconazol e,
r educi ng i ts pl asma l evel .
F l uconazol e may i ncr ease the acti vi ty of z i dovudi ne. (See
Adver se r eacti ons to syntheti c tr i azol es.)

Itraconazol e and vor i conazol e may have these i nteracti ons:

Both may i ncr ease the r i sk of bl eedi ng when combi ned wi th oral
anti coagul ants.
Antaci ds, H2 -r eceptor antagoni sts, phenytoi n, and r i fampi n l ower
pl asma i traconazol e l evel s.

Vor i conazol e may i nhi bi t the metabol i sm of phenytoi n,

benzodi azepi nes, cal ci um channel bl ocker s, sul fonyl ur eas, and
tacr ol i mus.
Vor i conazol e i s contrai ndi cated wi th si r ol i mus and er got
al kal oi ds because vor i conazol e may i ncr ease pl asma l evel s of
si r ol i mus and er gots.
Vor i conazol e i s contrai ndi cated wi th qui ni di ne and pi moz i de
because of the r i sk of pr ol onged QT i nter val and, rar el y,
tor sades de poi ntes.
 Warning!
Adverse reactions to synthetic triazoles
Adver se r eacti ons to fl uconazol e i ncl ude:

abdomi nal pai n

di ar r hea
di z z i ness
headache
el evated l i ver enz yme l evel s
nausea and vomi ti ng
rash.

Adver se r eacti ons to i tracon-azol e i ncl ude:

di z z i ness
headache
hyper tensi on
i mpai r ed l i ver functi on
nausea.

Adver se r eacti ons to vor i con-azol e i ncl ude:

vi si on di stur bances
fever
chi l l s
headache
tachycar di a
nausea and vomi ti ng
rash
el evated l i ver enz yme.

Glucan synthesis inhibitors

Caspofungin i s a dr ug i n a new cl ass of agents known as glucan
synthesis inhibitor s (al so cal l ed echinocandins). Its major use i s i n
the pati ent who hasnt r esponded to other anti fungal therapi es,
such as amphoter i ci n B or i traconazol e.
Pharmacokinetics
After bei ng gi ven i ntravenousl y, caspofungi n i s hi ghl y pr otei n-
bound, wi th l i ttl e di str i buti on i nto RBCs. The dr ug i s sl owl y
metabol i zed and i s excr eted i n ur i ne and stool .

Pharmacodynamics
Caspofungi n i nhi bi ts the synthesi s of beta (1,3) D-gl ucan, an
i ntegral component of the fungal cel l wal l .

Pharmacotherapeutics
Caspofungi n i s used to tr eat i nvasi ve asper gi l l osi s i n the pati ent
who hasnt r esponded to, or cant tol erate, other anti fungal s. It
hasnt been studi ed as an i ni ti al tr eatment for i nvasi ve
asper gi l l osi s.

Drug interactions
Pati ents taki ng caspofungi n and tacr ol i mus may need hi gher
doses of tacr ol i mus because caspofungi n decr eases the bl ood
tacr ol i mus l evel .
Inducer s of dr ug cl earance, such as phenytoi n, car bamazepi ne,
efavi r enz , nevi rapi ne, and nel fi navi r, may l ower caspofungi n
cl earance.
Concur r ent use of caspofungi n and cycl ospor i ne may r esul t i n
 el evated l i ver enz yme l evel s and decr eased caspofungi n
cl earance, so use together i snt r ecommended. (See Adver se
r eacti ons to caspofungi n.)

Warning!
Adverse reactions to caspofungin
Adver se r eacti ons to caspofungi n i ncl ude:

par esthesi a (bur ni ng or pr i ckl i ng sensati on)

tachycar di a (excessi vel y rapi d hear t beat)
tachypnea (excessi vel y rapi d br eathi ng)
nausea and vomi ti ng
di ar r hea
rash
faci al swel l i ng.

Synthetic allylamine derivatives

Ter binafine, the most commonl y used syntheti c al l yl ami ne
der i vati ve, i s an al l yl ami ne anti fungal , whi ch i nhi bi ts fungal cel l
gr owth by i nhi bi ti ng an enz yme r esponsi bl e for the manufactur e of
er goster ol .

Pharmacokinetics
Ter bi nafi ne i s wel l absor bed and di str i buted thr oughout the body,
especi al l y i f taken wi th food. Its extensi vel y metabol i zed; mor e
than two-thi r ds of the dr ug i s excr eted i n ur i ne.

Risk to liver
Rar e cases of l i ver fai l ur e have occur r ed wi th ter bi nafi ne use, even
i n the pati ent wi th no known hi stor y of l i ver di sease. Avoi d usi ng
thi s dr ug i f l i ver di sease i s suspected, and obtai n basel i ne l i ver
enz yme test r esul ts befor e use.

Pharmacodynamics
Ter bi nafi ne i s thought to i nhi bi t squal ene epoxi dase, whi ch bl ocks
the bi osynthesi s of er goster ol , an essenti al component of fungal cel l
membranes.

Pharmacotherapeutics
Thi s dr ug i s used to tr eat ti nea ungui um (fungal i nfecti ons of the
fi nger nai l or toenai l ).

Drug interactions
Ter bi nafi ne cl earance i s decr eased when i ts taken wi th
ci meti di ne and i ncr eased when i ts taken wi th r i fampi n.
Ter bi nafi ne i ncr eases pl asma l evel s of caffei ne and
dextr omethor phan and decr eases l evel s of cycl ospor i ne. (See
Adver se r eacti ons to ter bi nafi ne.)

Warning!
Adverse reactions to terbinafine
Adver se r eacti ons to ter bi nafi ne i ncl ude:

headache
vi sual di stur bances
nausea
di ar r hea
abdomi nal pai n
neutr openi a
Stevens-Johnson syndr ome.

Recombinant human activated protein C

Recombi nant human acti vated pr otei n C (r hAPC) i s a r el ati vel y new
cl ass of dr ug possessi ng anti thr omboti c, anti -i nfl ammator y, and
fi br i nol yti c pr oper ti es. Al though i ts mechani sm of acti on i snt wel l
known, r hACP i s used to tr eat pati ents wi th sever e sepsi s when the
r i sk of death fr om acute or gan dysfuncti on i s extr emel y hi gh.

Drotrecogin alfa
Dr otr ecogin alfa, the fi r st F DA-appr oved r hACP dr ug, i s used to tr eat
sever e sepsi s i n adul t pati ents wi th acute or gan dysfuncti on when
they ar e at r i sk for death.

Pharmacokinetics
After I.V. i nfusi on, dr otr ecogi n al fa achi eves a medi an steady state
l evel i n 2 hour s. Infor mati on about i ts di str i buti on, metabol i sm, and
excr eti on i snt avai l abl e.

Pharmacodynamics
Al though dr otr ecogi n al fas anti -i nfecti ve acti on i snt known, i t may
wor k by pr oduci ng dose-dependent r educti ons i n D-di mer and
i nter l euki n-6. Acti vated pr otei n C exer ts an anti thr omboti c effect by
i nhi bi ti ng factor s Va and VIIIa.

Safe and sound

Contraindications for drotrecogin alfa
Thi s dr ug i s contrai ndi cated i n pati ents who ar e
hyper sensi ti ve to the dr ug or any of i ts components. Its al so
contrai ndi cated i n pati ents wi th acti ve i nter nal bl eedi ng and those
who have had hemor r hagi c str oke i n the past 3 months or
i ntracrani al or i ntraspi nal sur ger y i n the past 2 months. In
addi ti on, the dr ug i s contrai ndi cated i n pati ents wi th sever e head
trauma, trauma wi th i ncr eased r i sk of l i fe-thr eateni ng bl eedi ng,
an epi dural catheter, an i ntracrani al neopl asm or mass l esi on, or
cer ebral her ni ati on.

Warning!
Adverse reactions to drotrecogin alfa
The most common adver se r eacti on to dr otr ecogi n al fa i s
bl eedi ng. Bl eedi ng seen wi th thi s dr ug most often occur s as
ecchymosi s or G I bl eedi ng.

Pharmacotherapeutics
Dr otr ecogi n al fa i s used to tr eat adul ts who have sever e sepsi s
associ ated wi th acute or gan dysfuncti on and who have a hi gh r i sk of
death. The dr ug has anti thr omboti c, anti -i nfl ammator y, and
fi br i nol yti c pr oper ti es.
Drug interactions
Dr otr ecogi n al fa may i nteract wi th another dr ug that affects
hemostasi s, such as an anti coagul ant, anti pl atel et dr ug, or
thr ombol yti c, possi bl y i ncr easi ng the r i sk of bl eedi ng. (See Adver se
r eacti ons to dr otr ecogi n al fa and Contr aindications for dr otr ecogin
alfa.)

Quick quiz
1Whi ch rati onal e best justi fi es admi ni ster i ng di ffer ent
anti tuber cul ar dr ugs concur r entl y i n tr eati ng acti ve
tuber cul osi s?
A. Theyr e second-l i ne dr ugs and effecti ve onl y
together.
B. Ri fampi n i ncr eases the acti vi ty of i soni az i d.
C. Combi nati on therapy can pr event or del ay bacter i al
r esi stance.
D. Si ngl e therapy i snt effecti ve.

2Whi ch adver se r eacti on do most pati ents exper i ence when

r ecei vi ng I.V. amphoter i ci n B?
A. Anur i a
B. Coagul ati on defects
C. Shor tness of br eath
D. Nor mochr omi c or nor mocyti c anemi a

3Whats the I.V. dr ug of choi ce for ser i ous r esi stant

staphyl ococcal i nfecti ons i n the pati ent whos al l er gi c to
peni ci l l i n?
A. Vancomyci n
B. Er ythr omyci n
C. Az i thr omyci n
D. Str eptomyci n

P.
Scoring
If you answer ed al l thr ee i tems cor r ectl y, extraor di nar y!
Your e mor e than a match for unwanted mi cr obes!
If you answer ed two i tems cor r ectl y, congratul ati ons.
Your e wi nni ng the battl e agai nst bacter i a.

If you answer ed fewer than two i tems cor r ectl y, di g i n!

The war wi th dr ugs conti nues for fi ve mor e chapter s!

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

11
Anti-inflammatory, anti-allergy, and
immunosuppressant drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs that modi fy i mmune or i nfl ammator y

r esponses
uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and the immune system

Immune and i nfl ammator y r esponses pr otect the body fr om i nvadi ng
for ei gn substances. These r esponses can be modi fi ed by cer tai n
cl asses of dr ugs:

Anti hi stami nes bl ock the effects of hi stami ne on tar get ti ssues.
Cor ti coster oi ds suppr ess i mmune r esponses and r educe
i nfl ammati on.
Noncor ti coster oi d i mmunosuppr essants pr event r ejecti on of
transpl anted or gans and can be used to tr eat auto i mmune
di sease.
 Ur i cosur i cs pr event or contr ol the fr equency of gouty ar thr i ti s
attacks.

Antihistamines
Antihistamines pr i mar i l y act to bl ock hi stami ne effects that occur i n
an i mmedi ate (type I) hyper sensi ti vi ty r eacti on, commonl y cal l ed an
aller gic r eaction. Theyr e avai l abl e al one or i n combi nati on pr oducts
by pr escr i pti on or over-the-counter.

Histamine-1 receptor antagonists

The ter m antihistamine r efer s to dr ugs that act as hi stami ne-1 (H1 )
r eceptor antagoni sts; that i s, they compete wi th hi stami ne for
bi ndi ng to H1 -r eceptor si tes thr oughout the body. However, they
dont di spl ace hi stami ne al r eady bound to the r eceptor.

Its all about chemistry

Based on chemi cal str uctur e, anti hi stami nes ar e categor i zed i nto
fi ve major cl asses:

Ethanol ami nes i ncl ude cl emasti ne fumarate, di menhydr i nate,

and di phenhydrami ne hydr ochl or i de.
Al kyl ami nes i ncl ude br ompheni rami ne mal eate, chl or pheni r-
ami ne mal eate, and dexchl or pheni rami ne mal eate.
Phenothi az i nes i ncl ude pr omethaz i ne hydr ochl or i de.
Pi per i di nes i ncl ude az atadi ne mal eate, ceti r i z i ne hydr ochl or i de,
cypr oheptadi ne hydr ochl or i de, desl oratadi ne, fexofenadi ne
hydr ochl or i de, l oratadi ne, and mecl i z i ne hydr ochl or i de.
Mi scel l aneous dr ugs, such as hydr oxyz i ne hydr ochl or i de and
hydr oxyz i ne pamoate, al so act as anti hi stami nes.

Pharmacokinetics (how drugs circulate)

H 1 -r eceptor antagoni sts ar e wel l absor bed after oral or par enteral
admi ni strati on. Some can al so be gi ven r ectal l y.

Distribution
Wi th the excepti on of l oratadi ne and desl oratadi ne, anti hi stami nes
ar e di str i buted wi del y thr oughout the body and central ner vous
system (CNS).

Less penetration, fewer effects

Fexofenadi ne, desl oratadi ne, and l oratadi ne, whi ch ar e nonsedati ng
anti hi stami nes, mi ni mal l y penetrate the bl ood-brai n bar r i er so that
l i ttl e of the dr ug i s di str i buted i n the CNS, pr oduci ng fewer effects
ther e than other anti hi stami nes.
 Memory jogger
A nti- i s a fami l i ar pr efi x meani ng opposi ng. Thats exactl y
what antihi stami nes do: They oppose hi stami ne effects (or
al l er gi c r eacti ons).

Metabolism and excretion

Anti hi stami nes ar e metabol i zed by l i ver enz ymes and excr eted i n
ur i ne; smal l amounts appear i n br east mi l k. Fexofenadi ne, mai nl y
excr eted i n stool , i s an excepti on. Ceti r i z i ne under goes l i mi ted
hepati c metabol i sm.

Pharmacodynamics (how drugs act)

H 1 -r eceptor antagoni sts compete wi th hi stami ne for H1 r eceptor s on
effector cel l s (the cel l s that cause al l er gi c symptoms), bl ocki ng
hi stami ne fr om pr oduci ng i ts effects. (See How chl or pheni rami ne
stops an al l er gi c r esponse, page 296.)

Antagonizing tactics
H 1 -r eceptor antagoni sts pr oduce thei r effects by:

bl ocki ng the acti on of hi stami ne on the smal l bl ood vessel s

decr easi ng di l ati on of ar ter i ol es and engor gement of ti ssues
r educi ng the l eakage of pl asma pr otei ns and fl ui ds out of the
capi l l ar i es (capi l l ar y per meabi l i ty), ther eby l esseni ng edema
i nhi bi ti ng most smooth-muscl e r esponses to hi stami ne (i n
par ti cul ar, bl ocki ng the constr i cti on of br onchi al , G I, and
vascul ar smooth muscl e)
r el i evi ng symptoms by acti ng on the ter mi nal ner ve endi ngs i n
the ski n that fl ar e and i tch when sti mul ated by hi stami ne
suppr essi ng adr enal medul l a sti mul ati on, autonomi c gangl i a
sti mul ati on, and exocr i ne gl and secr eti on, such as l acr i mal and
sal i var y secr eti on.
Straight to the head
Several anti hi stami nes have a hi gh affi ni ty for H1 r eceptor s i n the
brai n and ar e used for thei r CNS effects. These dr ugs i ncl ude
di phenhydrami ne, di menhydr i nate, pr omethaz i ne, and var i ous
pi per i di ne der i vati ves.

No stomach for this

H 1 -r eceptor antagoni sts dont affect par i etal cel l secr eti on i n the
stomach because thei r r eceptor s ar e H2 r eceptor s, not H1 .

Pharmacotherapeutics (how drugs are used)

Anti hi stami nes ar e used to tr eat the symptoms of type I
hyper sensi ti vi ty r eacti ons, such as:

al l er gi c r hi ni ti s (r unny nose and i tchy eyes caused by a l ocal

sensi ti vi ty r eacti on)
vasomotor r hi ni ti s (r hi ni ti s not caused by al l er gy or i nfecti on)
al l er gi c conjuncti vi ti s (i nfl ammati on of the membranes of the
eye)

ur ti car i a (hi ves)

angi oedema (submucosal swel l i ng i n the hands, face, and feet).
 Now I get it!
How chlorpheniramine stops an allergic
response
Al though chl or pheni rami ne cant r ever se symptoms of an al l er gi c
r esponse, i t can stop the pr ogr essi on of the r esponse. Her es what
happens.
Release the mediators
When sensi ti zed to an anti gen, a mast cel l r eacts to r epeated
anti gen exposur e by r el easi ng chemi cal medi ator s. One of these
medi ator s, hi stami ne, bi nds to hi stami ne-1 (H1 ) r eceptor s found
on effector cel l s (the cel l s r esponsi bl e for al l er gi c symptoms).
Thi s i ni ti ates the al l er gi c r esponse that affects the r espi rator y,
car di ovascul ar, G I, endocr i ne, and i ntegumentar y systems.
The first one there wins
Chl or pheni rami ne competes wi th hi stami ne for H1 -r eceptor si tes
on the effector cel l s. By attachi ng to these si tes fi r st, the dr ug
pr events mor e hi stami ne fr om bi ndi ng to the effector cel l s.
Not just for allergies
Anti hi stami nes can have other therapeuti c uses:

Many ar e used pr i mar i l y as anti emeti cs (to contr ol nausea and

vomi ti ng).
They can al so be used as adjuncti ve therapy to tr eat an
anaphyl acti c r eacti on after the ser i ous symptoms ar e contr ol l ed.
Di phenhydrami ne can hel p tr eat Par ki nsons di sease and dr ug-
i nduced extrapyrami dal r eacti ons (abnor mal i nvol untar y
movements).
Because of i ts anti ser otoni n qual i ti es, cypr oheptadi ne may be
used to tr eat Cushi ngs di sease, ser otoni n-associ ated di ar r hea,
vascul ar cl uster headaches, and anor exi a ner vosa.

Drug interactions
Anti hi stami nes may i nteract wi th many dr ugs, someti mes wi th l i fe-
thr eateni ng consequences:

They may bl ock or r ever se the vasopr essor effects of

epi nephr i ne, pr oduci ng vasodi l ati on, i ncr eased hear t rate, and
ver y l ow bl ood pr essur e.
They may mask the toxi c si gns and symptoms of ototoxi ci ty (a
detr i mental effect on hear i ng) associ ated wi th ami nogl ycosi des
or l ar ge dosages of sal i cyl ates.
They may i ncr ease the sedati ve and r espi rator y depr essant
effects of CNS depr essants, such as tranqui l i zer s or al cohol .
Loratadi ne may cause ser i ous car di ac effects when taken wi th
macr ol i de anti bi oti cs (such as er ythr omyci n), fl uconazol e,
ketoconazol e, i traconazol e, mi conazol e, ci meti di ne,
ci pr ofl oxaci n, and cl ar i thr omyci n. (See Adver se r eacti ons to
anti hi stami nes.)

Warning!
Adverse reactions to antihistamines
The most common adver se r eacti on to anti hi stami nes (wi th
 the excepti ons of fexofenadi ne and l oratadi ne) i s central ner vous
system (CNS) depr essi on. Other CNS r eacti ons i ncl ude:

di z z i ness
l assi tude and fati gue
di stur bed coor di nati on
muscl e weakness.

Gut reactions
G I r eacti ons may i ncl ude:

epi gastr i c di str ess

l oss of appeti te
nausea and vomi ti ng
consti pati on
di ar r hea
dr yness of the mouth, nose, and thr oat.

They can get the heart racing

Car di ovascul ar r eacti ons may i ncl ude:

hypotensi on
hyper tensi on
rapi d hear t rate
ar r hythmi as.

A sensitive issue
Sensi ti vi ty r eacti ons can al so occur.

Corticosteroids
Cor ticoster oids suppr ess i mmune r esponses and r educe
i nfl ammati on. Theyr e avai l abl e as natural or syntheti c ster oi ds.

Theres no improving on nature

Natural cor ti coster oi ds ar e hor mones pr oduced by the adr enal
cor tex; most cor ti coster oi ds ar e syntheti c for ms of these hor mones.
Natural and syntheti c cor ti coster oi ds ar e cl assi fi ed accor di ng to
thei r bi ol ogi cal acti vi ti es:
 G l ucocor ti coi ds, such as cor ti sone acetate and dexamethasone,
affect car bohydrate and pr otei n metabol i sm.

Mi neral ocor ti coi ds, such as al doster one and fl udr ocor ti sone
acetate, r egul ate el ectr ol yte and water bal ance.

Glucocorticoids
Most glucocor ticoids ar e syntheti c anal ogues of hor mones secr eted
by the adr enal cor tex. They exer t anti -i nfl ammator y, metabol i c, and
i mmunosuppr essant effects. Dr ugs i n thi s cl ass i ncl ude:

becl omethasone
betamethasone
cor ti sone
dexamethasone
hydr ocor ti sone
methyl pr edni sol one
pr edni sol one
pr edni sone
tr i amci nol one.

Pharmacokinetics
G l ucocor ti coi ds ar e wel l absor bed when admi ni ster ed oral l y. After
I.M. admi ni strati on, theyr e absor bed compl etel y.

Distribution
G l ucocor ti coi ds ar e bound to pl asma pr otei ns and di str i buted
thr ough the bl ood.

Metabolism and excretion

G l ucocor ti coi ds ar e metabol i zed i n the l i ver and excr eted by the
ki dneys.
Pharmacodynamics
G l ucocor ti coi ds suppr ess hyper sensi ti vi ty and i mmune r esponses
thr ough a pr ocess that i snt enti r el y under stood. Resear cher s
bel i eve that gl ucocor ti coi ds i nhi bi t i mmune r esponses by:

suppr essi ng or pr eventi ng cel l -medi ated i mmune r eacti ons

r educi ng l evel s of l eukocytes, monocytes, and eosi nophi l s
decr easi ng the bi ndi ng of i mmunogl obul i ns to cel l sur face
r eceptor s
i nhi bi ti ng i nter l euki n synthesi s.

Taking the red (and more) out

G l ucocor ti coi ds suppr ess the r edness, edema, heat, and tender ness
associ ated wi th the i nfl ammator y r esponse. They star t on the
cel l ul ar l evel by stabi l i z i ng the l ysosomal membrane (a str uctur e

wi thi n the cel l that contai ns di gesti ve enz ymes) so that i t doesnt
r el ease i ts stor e of hydr ol yti c enz ymes i nto the cel l s.

Now I get it!

How methylprednisolone works
Ti ssue trauma nor mal l y l eads to ti ssue i r r i tati on, edema,
i nfl ammati on, and pr oducti on of scar ti ssue. Methyl pr edni sol one
 counteracts the i ni ti al effects of ti ssue trauma, pr omoti ng
heal i ng.

No leaks, no drips
As cor ti coster oi ds, gl ucocor ti coi ds pr event the l eakage of pl asma
fr om capi l l ar i es, suppr ess the mi grati on of pol ymor phonucl ear
l eukocytes (cel l s that ki l l and di gest mi cr oor gani sms), and i nhi bi t
phagocytosi s (i ngesti on and destr ucti on).
To ensur e a job wel l done, gl ucocor ti coi ds decr ease anti body
for mati on i n i njur ed or i nfected ti ssues and di sr upt hi stami ne
synthesi s, fi br obl ast devel opment, col l agen deposi ti on, capi l l ar y
di l ati on, and capi l l ar y per meabi l i ty. (See How methyl pr edni sol one
wor ks.)

Warning!
Adverse reactions to cortico-steroids
Cor ti coster oi ds affect al most al l body systems. Thei r
wi despr ead adver se effects i ncl ude:

i nsomni a
i ncr eased sodi um and water r etenti on
i ncr eased potassi um excr eti on
suppr essed i mmune and i nfl ammator y r esponses
 osteopor osi s
i ntesti nal per forati on
pepti c ul cer s
i mpai r ed wound heal i ng.

Diabetes and more

Endocr i ne system r eacti ons may i ncl ude:

di abetes mel l i tus

hyper l i pi demi a
adr enal atr ophy
hypothal ami c-pi tui tar y axi s suppr essi on
cushi ngoi d si gns and symptoms (such as buffal o hump, moon
face, and el evated bl ood gl ucose l evel s).

Pharmacotherapeutics
Besi des thei r use as r epl acement therapy for pati ents wi th
adr enocor ti cal i nsuffi ci ency, gl ucocor ti coi ds ar e pr escr i bed for
i mmunosuppr essi on and r educti on of i nfl ammati on and for thei r
effects on the bl ood and l ymphati c systems.

Drug interactions
Many dr ugs i nteract wi th cor ti coster oi ds:

Ami nogl utethi mi de, bar bi turates, phenytoi n, and r i fampi n may
r educe the effects of cor ti coster oi ds.
Thei r potassi um-wasti ng effects may be enhanced by
amphoter i ci n B, chl or thal i done, ethacr yni c aci d, fur osemi de, and
thi az i de di ur eti cs.
Er ythr omyci n and tr ol eandomyci n may i ncr ease thei r effects by
r educi ng thei r metabol i sm.
They r educe the ser um concentrati on and effects of sal i cyl ates.
The r i sk of pepti c ul cer s associ ated wi th nonster oi dal anti -
i nfl ammator y dr ugs and sal i cyl ates i ncr eases when these agents
ar e taken wi th cor ti coster oi ds.
The r esponse to vacci nes and toxoi ds may be r educed i n a
 pati ent taki ng cor ti coster oi ds.
Estr ogen and hor monal contracepti ves that contai n estr ogen
i ncr ease the effects of cor ti coster oi ds.
The effects of anti di abeti c dr ugs may be r educed, r esul ti ng i n
i ncr eased bl ood gl ucose l evel s. (See Adver se r eacti ons to
cor ti co-ster oi ds.)

Mineralocorticoids
Miner alocor ticoids affect el ectr ol yte and water bal ance. These dr ugs
i ncl ude:

fl udr ocor ti sone acetate, a syntheti c anal ogue of hor mones

secr eted by the adr enal cor tex
al doster one, a natural mi neral ocor ti coi d (the use of whi ch has
been cur tai l ed by hi gh cost and l i mi ted avai l abi l i ty).

Pharmacokinetics
F l udr ocor ti sone acetate i s absor bed wel l and di str i buted to al l par ts
of the body.

Metabolism and excretion

F l udr ocor ti sone acetate i s metabol i zed i n the l i ver to i nacti ve
metabol i tes. The dr ug i s excr eted by the ki dneys, pr i mar i l y as
i nacti ve metabol i tes.

Pharmacodynamics
F l udr ocor ti sone acetate affects fl ui d and el ectr ol yte bal ance by
acti ng on the di stal r enal tubul e to i ncr ease sodi um r eabsor pti on
and potassi um and hydr ogen secr eti on.

Pharmacotherapeutics
F l udr ocor ti sone acetate i s used as r epl acement therapy for pati ents
wi th adr enocor ti cal i nsuffi ci ency (r educed secr eti on of
gl ucocor ti coi ds, mi neral ocor ti coi ds, and andr ogens).
Seasoning reasoning
F l udr ocor ti sone acetate may al so be used to tr eat sal t-l osi ng
congeni tal adr enogeni tal syndr ome (character i zed by a l ack of
cor ti sol and defi ci ent al doster one pr oducti on) after the pati ents
el ectr ol yte bal ance has been r estor ed.

Drug interactions
As i s the case wi th adver se r eacti ons, the dr ug i nteracti ons
associ ated wi th mi neral ocor ti coi ds ar e si mi l ar to those associ ated
wi th gl ucocor ti coi ds.

Other immunosuppressants
Several dr ugs used for thei r i mmunosuppr essant effects i n pati ents
under goi ng al l ograft transpl antati on (transpl antati on between two
peopl e who ar ent i denti cal twi ns) ar e al so used exper i mental l y to
tr eat autoi mmune di seases (di seases r esul ti ng fr om an
i nappr opr i ate i mmune r esponse di r ected agai nst the sel f ). They
i ncl ude:

az athi opr i ne
basi l i xi mab
cycl ospor i ne
 dacl i z umab
l ymphocyte i mmune gl obul i n (ATG [equi ne])
mur omonab-CD3
mycophenol ate mofeti l
si r ol i mus
tacr ol i mus
thymogl obul i n (anti thymocyte gl obul i n [rabbi t]).

Also these
Cycl ophosphami de, cl assi fi ed as an al kyl ati ng dr ug, i s al so used as
an i mmunosuppr essant; however, i ts pr i mar i l y used to tr eat cancer.
Anaki nra i s an i mmunosuppr essant used to tr eat adul ts wi th
moderate to sever e acti ve r heumatoi d ar thr i ti s who havent
r esponded to at l east one di sease-modi fyi ng anti r heumati c dr ug.

Pharmacokinetics
Immunosuppr essants take di ffer ent paths thr ough the body.

Absorption
When admi ni ster ed oral l y, az athi opr i ne and mycophenol ate ar e
r eadi l y absor bed fr om the G I tract, wher eas absor pti on of
cycl ospor i ne, tacr ol i mus, and si r ol i mus i s var i ed and i ncompl ete.

Only I.V.
Anaki nra, ATG , basi l i xi mab, dacl i z umab, mur omonab-CD3, and
thymogl obul i n ar e admi ni ster ed onl y by I.V. i njecti on.

Distribution
The di str i buti on of az athi opr i ne, basi l i xi mab, and dacl i z umab i snt
ful l y under stood. Cycl ospor i ne and mur omonab-CD3 ar e di str i buted
wi del y thr oughout the body. Az athi opr i ne and cycl ospor i ne cr oss the
pl acental bar r i er. The di str i buti on of ATG i snt cl ear, but

i t may appear i n br east mi l k. Di str i buti on of tacr ol i mus depends on

several factor s; 75% to 99% i s pr otei n-bound. Si r ol i mus i s 97%
pr otei n-bound.
Metabolism and excretion
Az athi opr i ne and cycl ospor i ne ar e metabol i zed i n the l i ver.
Mur omonab-CD3 i s consumed by T cel l s ci r cul ati ng i n the bl ood. The
metabol i sm of ATG i s unknown.
Mycophenol ate i s metabol i zed i n the l i ver to mycophenol ate aci d, an
acti ve metabol i te, and then fur ther metabol i zed to an i nacti ve
metabol i te, whi ch i s excr eted i n ur i ne and bi l e. Concentrati ons of
mycophenol ate and acycl ovi r may i ncr ease i n the pr esence of
nephr otoxi ci ty.
Az athi opr i ne, anaki nra, and ATG ar e excr eted i n ur i ne; cycl ospor i ne
i s excr eted pr i nci pal l y i n bi l e. Its unknown how mur omonab-CD3 i s
excr eted.
Tacr ol i mus i s extensi vel y metabol i zed and excr eted pr i mar i l y i n
bi l e; l ess than 1% i s excr eted unchanged i n ur i ne. Si r ol i mus i s
metabol i zed by the mi xed functi on oxi dase system, pr i mar i l y
cytochr ome P-450 (CYP3A4); 91% i s excr eted i n stool and 2.2% i n
ur i ne. Metabol i sm and excr eti on of basi l i xi mab and dacl i z umab
ar ent under stood.

Pharmacodynamics
How cer tai n i mmunosuppr essants achi eve thei r desi r ed effects has
yet to be deter mi ned.

Whats going on here?

The exact mechani sm of acti on of az athi opr i ne, cycl ospor i ne, and
ATG i s unknown, but may be expl ai ned by these theor i es:

Az athi opr i ne antagoni zes metabol i sm of the ami no aci d pur i ne

and, ther efor e, may i nhi bi t r i bonucl ei c aci d and deoxyr i bonucl ei c
aci d str uctur e and synthesi s. It al so may i nhi bi t coenz yme
for mati on and functi on.
Cycl ospor i ne i s thought to i nhi bi t hel per T cel l s and suppr essor T
cel l s.
ATG may el i mi nate anti gen-r eacti ve T cel l s i n the bl ood, al ter T-
cel l functi on, or both.
They do know this much
In pati ents r ecei vi ng ki dney al l ografts, az athi opr i ne suppr esses cel l -
medi ated hyper sensi ti vi ty r eacti ons and pr oduces var i ous
al terati ons i n anti body pr oducti on. Mur omonab-CD3, a monocl onal
anti body, i s under stood to bl ock the functi on of T cel l s.
Anaki nra, basi l i xi mab, and dacl i z umab bl ock the acti vi ty of
i nter l euki n. Mycophenol ate i nhi bi ts r esponses of T and B
l ymphocytes,

suppr esses anti body for mati on by B l ymphocytes, and may i nhi bi t
r ecr ui tment of l eukocytes i nto si tes of i nfl ammati on and graft
r ejecti on.

Yea or nay?
Cyclosporine: Miracle drug or death sentence?
Or gan transpl antati on can save a l i fe. However,
cycl ospor i ne, an i mmunosuppr essant used to r educe the r i sk of
or gan r ejecti on, may al so cause cancer.
Does cyclosporine encourage cells to become
cancerous?
It has l ong been bel i eved that when the i mmune system i s
weakened by i mmunosuppr essants, i t l oses i ts abi l i ty to fi ght and
ki l l cancer ous cel l s. Recent r esear ch suggests that cycl ospor i ne
may al so encourage abnor mal cel l s to become cancer ous and
per haps even gr ow aggr essi vel y. Thi s r esear ch has rai sed concer n
about the use of cycl ospor i ne i n or gan transpl antati on.
 A double-edged sword
However, thi s concer n needs to be bal anced agai nst the l i fe-
thr eateni ng r i sk of or gan r ejecti on. Sci enti sts ar e now l ooki ng for
ways to bl ock thi s tumor-pr omoti ng effect of cycl o-spor i ne.

Si r ol i mus i s an i mmunosuppr essant that i nhi bi ts T-l ymphocyte

acti vati on and pr ol i ferati on that occur i n r esponse to anti geni c and
cytoki ne sti mul ati on; i t al so i nhi bi ts anti body for mati on.

Pharmacotherapeutics
Immunosuppr essants ar e used mai nl y to pr event r ejecti on i n
pati ents who under go or gan transpl antati on. (See Cycl ospor i ne:
Mi racl e dr ug or death sentence?)

Drug interactions
Most dr ug i nteracti ons wi th thi s cl ass of dr ugs i nvol ve other
i mmunosuppr essant and anti -i nfl ammator y dr ugs and var i ous
anti bi oti c and anti mi cr obi al dr ugs. (See Adver se r eacti ons to
noncor ti coster oi d i mmunosuppr essants.)

Al l opur i nol i ncr eases the bl ood l evel s of az athi opr i ne.
Verapami l i ncr eases bl ood l evel s of si r ol i mus.
Vor i conazol e shoul dnt be gi ven wi th si r ol i mus because the
combi nati on i nhi bi ts CYP3A4 enz ymes, r esul ti ng i n i ncr eased
si r ol i mus l evel s.
When mycophenol ate i s taken wi th antaci ds or chol estyrami ne,
mycophenol ate l evel s decr ease.

Coadmi ni strati on of mycophenol ate wi th acycl ovi r, especi al l y i n

pati ents wi th r enal i mpai r ment, may i ncr ease concentrati ons of
both dr ugs.
Cycl ospor i ne l evel s may i ncr ease i f cycl ospor i ne i s taken wi th
ketoconazol e, cal ci um channel bl ocker s, ci meti di ne, anabol i c
ster oi ds, hor monal contracepti ves, er ythr omyci n, or
metocl oprami de.
The r i sk of toxi ci ty to the ki dneys i ncr eases when cycl ospor i ne
or si r ol i mus i s taken wi th acycl ovi r, ami nogl ycosi des, or
amphoter i ci n B.
 Taki ng anaki nra, ATG , basi l i xi mab, cycl ospor i ne, dacl i z umab,
mur omonab-CD3, si r ol i mus, or thymogl obul i n wi th other
i mmunosuppr essants (except cor ti coster oi ds) i ncr eases the r i sk
of i nfecti on and l ymphoma (neopl asm of the l ymph ti ssue;
typi cal l y mal i gnant).
Bar bi turates, r i fampi n, phenytoi n, sul fonami des, and
tr i methopr i m decr ease pl asma cycl ospor i ne and si r ol i mus l evel s.
Ser um di goxi n l evel s may i ncr ease when cycl ospor i ne i s taken
wi th di goxi n.
Anaki nra shoul dnt be gi ven to pati ents wi th acti ve i nfecti ons or
neutr openi a.

Warning!
Adverse reactions to noncorticosteroid
immunosuppressants
Al l noncor ti coster oi d i mmunosuppr essants can cause
hyper sensi ti vi ty r eacti ons. Her e ar e adver se r eacti ons to
i ndi vi dual dr ugs.
Azathioprine

Bone mar r ow suppr essi on

Nausea and vomi ti ng
Li ver toxi ci ty

Cyclosporine

Ki dney toxi ci ty
Hyper kal emi a
Infecti on
Li ver toxi ci ty
Nausea and vomi ti ng

Daclizumab

G I di sor der s
Hyper tensi on
Hypotensi on
Chest pai n
 Tachycar di a
Edema
Dyspnea
Pul monar y edema
Thr ombosi s
Bl eedi ng
Renal tubul ar necr osi s

Lymphocyte immune globulin

Fever and chi l l s

Reduced whi te bl ood cel l (WBC) or pl atel et count
Infecti on
Nausea and vomi ti ng

Muromonab-CD3

Fever and chi l l s

Nausea and vomi ti ng
Tr emor
Pul monar y edema
Infecti on

Mycophenolate mofetil

Nausea
Di ar r hea
Leukopeni a
Headache
Weakness
Ur i nar y fr equency
Leg cramps or pai n
Li ver functi on test r esul t abnor mal i ti es
Rash

Sirolimus

Anemi a
 Thr ombocytopeni a
Hyper l i pi demi a
Hyper tensi on

Tacrolimus

Nausea and vomi ti ng

Di ar r hea
Consti pati on
Tr emor
Leukopeni a
Hyper tensi on
Nephr otoxi ci ty
Hepatotoxi ci ty

Thymoglobulin

Abdomi nal pai n

Di ar r hea
Dyspnea
Fever and chi l l s
Headache
Infecti on
Nausea and vomi ti ng
Reduced WBC or pl atel et count
Systemi c i nfecti ons
Di z z i ness

Uricosurics and other antigout drugs

Ur icosur ics, al ong wi th other anti gout dr ugs, exer t thei r effects
thr ough thei r anti -i nfl ammator y acti ons.

Uricosurics
The two major ur i cosur i cs ar e:
 pr obeneci d
sul fi npyrazone.

Getting the gout out

Ur i cosur i cs act by i ncr easi ng ur i c aci d excr eti on i n ur i ne. The
pr i mar y goal i n usi ng ur i cosur i cs i s to pr event or contr ol the
fr equency of gouty ar thr i ti s attacks.

Pharmacokinetics
Ur i cosur i cs ar e absor bed fr om the G I tract.

Distribution
Di str i buti on of the two dr ugs i s si mi l ar, wi th 75% to 95% of
pr obeneci d and 98% of sul fi npyrazone bei ng pr otei n-bound.

Metabolism and excretion

Metabol i sm of the dr ugs occur s i n the l i ver, and excr eti on i s
pr i mar i l y by the ki dneys. Onl y smal l amounts of these dr ugs ar e
excr eted i n stool .

Pharmacodynamics
Pr obeneci d and sul fi npyrazone r educe the r eabsor pti on of ur i c aci d
at the pr oxi mal convol uted tubul es of the ki dneys. Thi s r esul ts i n
excr eti on of ur i c aci d i n ur i ne, r educi ng ser um urate l evel s.

Pharmacotherapeutics
Pr obeneci d and sul fi npyrazone ar e i ndi cated for the tr eatment of:

chr oni c gouty ar thr i ti s

tophaceous gout (the deposi ti on of tophi or urate cr ystal s under
the ski n and i nto joi nts).

A part-time promoter
Pr obeneci d i s al so used to pr omote ur i c aci d excr eti on i n pati ents
exper i enci ng hyper ur i cemi a.
Substitute when acute
Pr obeneci d and sul fi npyrazone shoul dnt be gi ven dur i ng an acute
gouty attack. If taken at that ti me, these dr ugs pr ol ong
i nfl ammati on. Because these dr ugs may i ncr ease the chance of an
acute gouty attack when therapy begi ns and whenever the ser um
urate l evel changes rapi dl y, col chi ci ne i s admi ni ster ed dur i ng the
fi r st 3 to 6 months of pr obeneci d or sul fi npyrazone therapy.

Drug interactions
Many dr ug i nteracti ons, some potenti al l y ser i ous, can occur wi th
ur i cosur i c dr ugs:

Pr obeneci d si gni fi cantl y i ncr eases or pr ol ongs the effects of

cephal ospor i ns, peni ci l l i ns, and sul fonami des.
Ser um urate l evel s may i ncr ease when pr obeneci d i s taken wi th
anti neopl asti c dr ugs.
Pr obeneci d i ncr eases the ser um concentrati on of dapsone,
ami nosal i cyl i c aci d, and methotr exate, causi ng toxi c r eacti ons.
Sul fi npyrazone i ncr eases the effecti veness of war far i n,
i ncr easi ng the r i sk of bl eedi ng.
Sal i cyl ates r educe the effects of sul fi npyrazone.
Sul fi npyrazone may potenti ate the effects of oral anti di abeti c
dr ugs, i ncr easi ng the r i sk of hypogl ycemi a. (See Adver se
r eacti ons to ur i cosur i cs.)
 Warning!
Adverse reactions to uricosurics
Adver se r eacti ons to ur i cosur i cs i ncl ude ur i c aci d stone
for mati on and bl ood abnor mal i ti es.
Probenecid

Headache
Anor exi a
Nausea and vomi ti ng
Hyper sensi ti vi ty r eacti ons

Sulfinpyrazone

Nausea
Indi gesti on
G I pai n
G I bl ood l oss

Other antigout drugs

Allopur inol i s used to r educe pr oducti on of ur i c aci d, pr eventi ng
gouty attacks, and colchicine i s used to tr eat acute gouty attacks.

Pharmacokinetics
Al l opur i nol and col chi ci ne take somewhat di ffer ent paths thr ough
the body.

All aboard allopurinol

When gi ven oral l y, al l opur i nol i s absor bed fr om the G I tract.
Al l opur i nol and i ts metabol i te oxypur i nol ar e di str i buted thr oughout
the body except i n the brai n, wher e dr ug concentrati ons ar e 50%

of those found i n the r est of the body. Its metabol i zed by the l i ver
and excr eted i n ur i ne.

Following colchicines course

Col chi ci ne i s absor bed fr om the G I tract and i s par ti al l y metabol i zed
i n the l i ver. The dr ug and i ts metabol i tes then r eenter the i ntesti nal
tract thr ough bi l i ar y secr eti ons. After r eabsor pti on fr om the
i ntesti nes, col chi ci ne i s di str i buted to var i ous ti ssues. Its excr eted
pr i mar i l y i n stool and to a l esser degr ee i n ur i ne.

Pharmacodynamics
Al l opur i nol and i ts metabol i te oxypur i nol i nhi bi t xanthi ne oxi dase,
the enz yme r esponsi bl e for the pr oducti on of ur i c aci d. By r educi ng
ur i c aci d for mati on, al l opur i nol el i mi nates the haz ar ds of
hyper ur i cur i a.

Migration control
Col chi ci ne appear s to r educe the i nfl ammator y r esponse to mono-
sodi um urate cr ystal s deposi ted i n joi nt ti ssues. Col chi ci ne may
pr oduce i ts effects by i nhi bi ti ng mi grati on of whi te bl ood cel l s
(WBCs) to the i nfl amed joi nt. Thi s r educes phagocytosi s and l acti c
aci d pr oducti on by WBCs, decr easi ng urate cr ystal deposi ts and
r educi ng i nfl ammati on.

Pharmacotherapeutics
Al l opur i nol tr eats pr i mar y gout, hopeful l y pr eventi ng acute gouty
attacks. It can be pr escr i bed wi th ur i cosur i cs when smal l er dosages
of each dr ug ar e di r ected. Its used to tr eat:

gout or hyper ur i cemi a that may occur wi th bl ood abnor mal i ti es

and dur i ng tr eatment of tumor s or l eukemi a
pr i mar y or secondar y ur i c aci d nephr opathy (wi th or wi thout the
accompanyi ng symptoms of gout)
pati ents who r espond poor l y to maxi mum dosages of ur i cosur i cs
or who have al l er gi c r eacti ons or i ntol erance to ur i cosur i c dr ugs
(i ts al so used to pr event r ecur r ent ur i c aci d stone for mati on).
Acute alert
Col chi ci ne i s used to r el i eve the i nfl ammati on of acute gouty
ar thr i ti s attacks. If gi ven pr omptl y, i ts especi al l y effecti ve i n
r el i evi ng pai n. In addi ti on, gi vi ng col chi ci ne dur i ng the fi r st several
months of al l opur i nol , pr obeneci d, or sul fi npyrazone therapy may
pr event the acute gouty attacks that someti mes accompany the use
of these dr ugs.

Drug interactions
Col chi ci ne doesnt i nteract si gni fi cantl y wi th other dr ugs. When
al l opur i nol i s used wi th other dr ugs, the r esul ti ng i nteracti ons can
be ser i ous:

Al l opur i nol potenti ates the effect of oral anti coagul ants.
Al l opur i nol i ncr eases the ser um concentrati ons of mer capto-
pur i ne and az athi opr i ne, i ncr easi ng the r i sk of toxi ci ty.
Angi otensi n-conver ti ng enz yme i nhi bi tor s i ncr ease the r i sk of
hyper sensi ti vi ty r eacti ons to al l opur i nol .
Al l opur i nol i ncr eases ser um theophyl l i ne l evel s.
The r i sk of bone mar r ow depr essi on i ncr eases when
 cycl ophosphami de i s taken wi th al l opur i nol . (See Adver se
r eacti ons to other anti gout dr ugs.)

Warning!
Adverse reactions to other antigout drugs
Al l opur i nol and col chi -ci ne commonl y cause nausea,
vomi ti ng, di ar r hea, and i nter mi ttent abdomi nal pai n.
Allopurinol
The most common adver se r eacti on to al l o-pur i nol i s a rash.
Colchicine
Pr ol onged admi ni strati on of col chi ci ne may cause bone mar r ow
suppr essi on.

Quick quiz
1How does di phenhydrami ne wor k?
A. It bl ocks pr oducti on of hi stami ne.
B. It pr events bi ndi ng of hi stami ne to r eceptor s.
C. It r ever ses the effects of hi stami ne.
D. It i ncr eases l evel s of hi stami ne.

2Whats the most common adver se r eacti on for most

anti hi stami nes, wi th the excepti ons of fexofenadi ne and
l oratadi ne?
A. Dr ug fever
B. G I di str ess
C. Respi rator y di str ess
D. Sedati on

3Whi ch si gns and symptoms suggest that a pati ent i s

exper i enci ng Cushi ngs syndr ome?
A. Buffal o hump, el evated bl ood gl ucose l evel s, and moon
face
B. Low bl ood pr essur e, rapi d hear t rate, and di ffi cul ty
br eathi ng
C. Low bl ood gl ucose l evel s and r educed pl atel et count
D. Incr eased thi r st, i ncr eased ur i nati on, and i ncr eased
appeti te
 P.

4Whi ch condi ti on i ndi cates that a pati ent i s exper i enci ng an

adver se r eacti on to az athi opr i ne?
A. Ki dney fai l ur e
B. Pepti c ul cer
C. Bone mar r ow suppr essi on
D. Hear t fai l ur e

5Whi ch si gn i s an adver se r eacti on to pr obeneci d?

A. Edema
B. Vomi ti ng
C. Ver ti go
D. Decr eased ur i ne output

Scoring
If you answer ed al l fi ve i tems cor r ectl y, extraor di nar y!
You cer tai nl y ar ent al l er gi c to smar ts!

If you answer ed thr ee or four i tems cor r ectl y,

congratul ati ons! Your e taki ng the sti ng out of l ear ni ng!

If you answer ed fewer than thr ee i tems cor r ectl y, keep

tr yi ng! Wi th conti nued i mpr ovement, the next chapter
shoul d have you feel i ng better !

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

12
Psychotropic drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs that al ter psychogeni c behavi or and pr omote

sl eep
uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and psychiatric disorders

Thi s chapter pr esents dr ugs that ar e used to tr eat var i ous sl eep and
psychogeni c di sor der s, such as anxi ety, depr essi on, and psychoti c
di sor der s.

Sedative and hypnotic drugs

Sedatives r educe anxi ety, tensi on, or exci tement. Some degr ee of
dr owsi ness commonl y accompani es sedati ve use.

Youre getting very sleepy

When gi ven i n l ar ge doses, sedati ves ar e consi der ed hypnoti cs,
whi ch i nduce a state r esembl i ng natural sl eep. The thr ee mai n
cl asses of syntheti c dr ugs used as sedati ves and hypnoti cs ar e:

benzodi azepi nes

bar bi turates
nonbenzodi azepi ne-nonbar bi turate dr ugs.

And if that doesnt put you to sleep

Other sedati ves may i ncl ude sedati ng anti depr essants, such as
trazodone, and over-the-counter sl eep ai ds.

Benzodiazepines
Benz odiaz epines pr oduce many therapeuti c effects, i ncl udi ng:

sedati on befor e anesthesi a

sl eep i nducement
r el i ef of anxi ety and tensi on
skel etal muscl e r el axati on
anti convul sant acti vi ty.

Keep your eye on the hypnotic ones

Benzodi azepi nes ar e used i n var i ous cl i ni cal si tuati ons and exer t
ei ther a pr i mar y or a secondar y sedati ve or hypnoti c effect.
Benzodi azepi nes used pr i mar i l y for thei r sedati ve or hypnoti c
effects i ncl ude:

estazol am
fl urazepam
l orazepam
quazepam
temazepam
tr i azol am.

When some calm is needed

Benzodi azepi nes used pr i mar i l y for the tr eatment of anxi ety
i ncl ude:

al prazol am
chl or di azepoxi de
cl onazepam
cl orazepate
di azepam
l orazepam
oxazepam.

Pharmacokinetics (how drugs circulate)

Benzodi azepi nes ar e absor bed rapi dl y and compl etel y fr om the G I
tract and ar e di str i buted wi del y i n the body. Penetrati on i nto the
brai n al so occur s rapi dl y. Some benzodi azepi nes, such as di aze-pam
and l orazepam, may al so be gi ven par enteral l y.

How fast?
The rate of absor pti on deter mi nes how qui ckl y the dr ug wi l l wor k;
fl urazepam and tr i azol am have the fastest onset.
How long?
The durati on of effect i s deter mi ned by the extent of di str i buti on.
Tr i azol am bi nds qui ckl y to fat and i s wi del y di str i buted; ther efor e, i t
has a shor t durati on of acti on.

Metabolism and excretion

Al l benzodi azepi nes ar e metabol i zed i n the l i ver and excr eted
pr i mar i l y i n ur i ne. Some benzodi azepi nes have acti ve metabol i tes,
whi ch may gi ve these dr ugs a l onger per i od of acti on.

Pharmacodynamics (how drugs act)

Resear cher s bel i eve that benzodi azepi nes wor k by sti mul ati ng
gamma-ami nobutyr i c aci d (G ABA) r eceptor s i n the ascendi ng
r eti cul ar acti vati ng system (RAS) of the brai n. The RAS i s
associ ated wi th wakeful ness and attenti on and i ncl udes the cer ebral
cor tex and l i mbi c, thal ami c, and hypothal ami c l evel s of the central
ner vous system (CNS). (See How benzodi azepi nes wor k, page 314.)

Low will ease your mind

At l ow dosages, benzodi azepi nes decr ease anxi ety by acti ng on the
l i mbi c system and other ar eas of the brai n that hel p r egul ate
emoti onal acti vi ty. The dr ugs can usual l y cal m or sedate the pati ent
wi thout causi ng dr owsi ness.

High will ease you into sleep

At hi gher dosages, benzodi azepi nes i nduce sl eep, pr obabl y because
they depr ess the RAS of the brai n.
Zzzzzzzzzzzz
Benzodi azepi nes i ncr ease total sl eep ti me and r educe the number of
awakeni ngs. In most cases, benzodi azepi nes dont decr ease the ti me
spent i n rapi d-eye-movement (REM) sl eep, the state of sl eep i n
whi ch brai n acti vi ty r esembl es the acti vi ty i t shows when awake;
the bodys muscl es r el ax, and the eyes move rapi dl y. Because
benzodi azepi nes dont decr ease the durati on of REM sl eep, they
have a si gni fi cant advantage over bar bi turates.
Dur i ng each sl eep cycl e the sl eepi ng per son pr ogr esses fr om stage
1, whi ch i s dr owsi ness, to stages 3 and 4, whi ch ar e deep-sl eep
stages. Benzodi azepi nes r educe the amount of ti me spent i n stages
3 and 4. The decr ease i n stage 4 sl eep i s accompani ed by a
r educti on i n ni ghtmar es.

Pharmacotherapeutics (how drugs are used)

Cl i ni cal i ndi cati ons for benzodi azepi nes i ncl ude:

r el axi ng the pati ent dur i ng the day of or befor e sur ger y
tr eati ng i nsomni a
pr oduci ng I.V. anesthesi a
tr eati ng al cohol wi thdrawal symptoms
tr eati ng anxi ety and sei z ur e di sor der s
pr oduci ng skel etal muscl e r el axati on.
 Now I get it!
How benzodiazepines work
These i l l ustrati ons show how benzodi azepi nes wor k at the
cel l ul ar l evel .
Speed and passage
The speed of i mpul ses fr om a pr esynapti c neur on acr oss a synapse
i s i nfl uenced by the number of chl or i de i ons i n the postsynapti c
neur on. The passage of chl or i de i ons i nto the postsynapti c neur on
depends on the i nhi bi tor y neur otransmi tter cal l ed gamma-
aminobutyr ic acid, or G ABA.

It binds
When G ABA i s r el eased fr om the pr esynapti c neur on, i t travel s
acr oss the synapse and bi nds to G ABA r eceptor s on the
postsynapti c neur on. Thi s bi ndi ng opens the chl or i de channel s,
al l owi ng chl or i de i ons to fl ow i nto the postsynapti c neur on and
causi ng the ner ve i mpul ses to sl ow down.

The result is another kind of depression

Benzodi azepi nes bi nd to r eceptor s on or near the G ABA r eceptor,
enhanci ng the effect of G ABA and al l owi ng mor e chl or i de i ons to
fl ow i nto the post-synapti c neur on. Thi s depr esses the ner ve
i mpul ses, causi ng them to sl ow down or stop.
Drug interactions
Except for other CNS depr essants such as al cohol , few dr ugs
i nteract wi th benzodi azepi nes.

Deep sleep
When benzodi azepi nes ar e taken wi th other CNS depr essants
(i ncl udi ng al cohol and anti convul sants), the r esul t i s enhanced
sedati ve and CNS depr essant effects, i ncl udi ng r educed l evel of
consci ousness, r educed muscl e coor di nati on, r espi rator y depr essi on,
and death.

Possible problems with the pill

Hor monal contracepti ves may r educe the metabol i sm of fl uraze pam
hydr ochl or i de, i ncr easi ng the r i sk of toxi ci ty.
Tr i azol am may be affected by i nhi bi tor s of the CYP3A system (such
as er ythr omyci n and ketoconazol e). (See Adver se r eacti ons to
benzodi azepi nes.)

Warning!
Adverse reactions to benzodiazepines
Benzodi azepi nes may cause:

amnesi a
fati gue
muscl e weakness
mouth dr yness
nausea and vomi ti ng
 di z z i ness
ataxi a (i mpai r ed abi l i ty to coor di nate movement).

Getting groggy
Uni ntenti onal dayti me sedati on, hangover effect (r esi dual
dr owsi ness and i mpai r ed r eacti on ti me on awakeni ng), and
r ebound i nsomni a may al so occur.
One more may be one too many
These dr ugs have a potenti al for abuse, tol erance, and physi cal
dependence. Benzodi azepi nes wi th a l ong hal f-l i fe or acti ve
metabol i tes may accumul ate and cause adver se effects i n el der l y
pati ents. In general , l ower star ti ng doses, wi th gradual dosage
i ncr eases, shoul d be used i n el der l y pati ents who ar e taki ng
benzodi azepi nes.

Barbiturates
The major phar macol ogi c acti on of bar bitur ates i s to r educe overal l
CNS al er tness. Bar bi turates used pr i mar i l y as sedati ves and
hypnoti cs i ncl ude:

amobar bi tal
butabar bi tal
mephobar bi tal
pentobar bi tal
phenobar bi tal
secobar bi tal .

On the dose
Low doses of bar bi turates depr ess the sensor y and motor cor tex i n
the brai n, causi ng dr owsi ness. Hi gh doses may cause r espi rator y
depr essi on and death because of thei r abi l i ty to depr ess al l l evel s of
the CNS.

Pharmacokinetics
Bar bi turates ar e wel l absor bed fr om the G I tract, di str i buted rapi dl y,
metabol i zed by the l i ver, and excr eted i n ur i ne.

Pharmacodynamics
As sedati ve-hypnoti cs, bar bi turates depr ess the sensor y cor tex of
the brai n, decr ease motor acti vi ty, al ter cer ebral functi on, and
pr oduce dr owsi ness, sedati on, and hypnosi s.

We interrupt this transmission

These dr ugs appear to act thr oughout the CNS; however, the RAS of
the brai n, whi ch i s r esponsi bl e for wakeful ness, i s a par ti cul ar l y
sensi ti ve si te.

Pharmacotherapeutics
Bar bi turates have many cl i ni cal i ndi cati ons, i ncl udi ng:

dayti me sedati on (for shor t per i ods onl y, typi cal l y l ess than 2
weeks)
hypnoti c effects for pati ents wi th i nsomni a
pr eoperati ve sedati on and anesthesi a
r el i ef of anxi ety
anti convul sant effects.
Popularity plunge
Pati ents devel op tol erance to bar bi turates mor e qui ckl y than to
benzodi azepi nes, and physi cal dependence on bar bi turates

may occur even wi th a smal l dai l y dosage. In compar i son,

benzodi azepi nes ar e r el ati vel y effecti ve and safe and, for these
r easons, have r epl aced bar bi turates as the sedati ves and hypnoti cs
of choi ce.

Drug interactions
Bar bi turates may i nteract wi th many other dr ugs:

They may r educe the effects of beta-adr ener gi c bl ocker s

(metopr ol ol , pr opranol ol ), chl orampheni col , cor ti coster oi ds,
doxycycl i ne, oral anti coagul ants, hor monal contracepti ves,
qui ni di ne, tr i cycl i c anti depr essants (TCAs), metr oni dazol e,
theophyl l i ne, and cycl ospor i ne.
Hydantoi ns, such as phenytoi n, r educe the metabol i sm of
phenobar bi tal , r esul ti ng i n i ncr eased toxi c effects.
Thei r use wi th methoxyfl urane may sti mul ate pr oducti on of
metabol i tes that ar e toxi c to the ki dneys.
Thei r use wi th other CNS depr essants (especi al l y al cohol ) may
 cause excessi ve CNS depr essi on.
Val pr oi c aci d may i ncr ease bar bi turate l evel s.
Monoami ne oxi dase i nhi bi tor s (MAOIs) i nhi bi t the metabol i sm of
bar bi turates, i ncr easi ng thei r sedati ve effects.
When bar bi turates ar e taken wi th acetami nophen, the r i sk of
l i ver toxi ci ty i ncr eases. (See Adver se r eacti ons to bar bi turates.)

Warning!
Adverse reactions to barbiturates
Bar bi turates may have wi despr ead adver se effects.
S.O.S. for CNS
Central ner vous system (CNS) r eacti ons i ncl ude:

dr owsi ness
l ethar gy
headache
depr essi on.

Heart of the matter

Car di ovascul ar and r espi rator y effects i ncl ude:

mi l d bradycar di a
hypotensi on
hypoventi l ati on
spasm of the l ar ynx (voi ce box) and br onchi
r educed rate of br eathi ng
sever e r espi rator y depr essi on.

All the rest

Other r eacti ons i ncl ude:

ver ti go
nausea and vomi ti ng
di ar r hea
epi gastr i c pai n
al l er gi c r eacti ons.
Nonbenzodiazepines-nonbarbiturates
Nonbenz odiaz epine-nonbar bitur ates act as hypnoti cs for tr eatment
of si mpl e i nsomni a. These dr ugs, whi ch offer no speci al advantages
over other sedati ves, i ncl ude:

chl oral hydrate

eszopi cl one
ramel ton
z al epl on
zol pi dem.

Diminishing returns
Chl oral hydrate and z al epl on l ose thei r effecti veness by the end of
the second week. Zol pi dem i s usual l y effecti ve for up to 35 days.
Eszopi cl one and ramel ton ar e appr oved for l ong-ter m tr eatment of
i nsomni a.

Pharmacokinetics
Nonbenzodi azepi nes-nonbar bi turates ar e absor bed rapi dl y fr om the
G I tract, metabol i zed i n the l i ver, and excr eted i n ur i ne.

Safe and sound

Warning about sleep agents
The U.S. Food and Dr ug Admi ni strati on r equi r es that al l
sedati ve-hypnoti c dr ugs i ncl ude a war ni ng on the dr ug l abel about
the r i sk of compl ex sl eep-r el ated behavi or s. Compl ex sl eep-
r el ated behavi or s i ncl ude pr epar i ng and eati ng food, maki ng
phone cal l s, and even dr i vi ng when not ful l y awake, whi l e havi ng
no memor y of the event.

Pharmacodynamics
The mechani sm of acti on for nonbenzodi azepi nes-nonbar bi turates
i snt ful l y known; however, they pr oduce depr essant effects si mi l ar
to bar bi turates.
Pharmacotherapeutics
Nonbenzodi azepi nes-nonbar bi turates ar e typi cal l y used for :

tr eatment of si mpl e i nsomni a

sedati on befor e sur ger y
sedati on befor e EEG studi es.

Drug interactions
When nonbenzodi azepi nes-nonbar bi turates ar e used wi th other CNS
depr essants, addi ti ve CNS depr essi on occur s, r esul ti ng i n
dr owsi ness, r espi rator y depr essi on, stupor, coma, or death. (See
War ni ng about sl eep agents.)

Warning!
Adverse reactions to nonbenzodiazepines-
nonbarbiturates
The most common dose-r el ated adver se r eacti ons i nvol vi ng
nonbenzodi azepi nes-nonbar bi turates i ncl ude:

nausea and vomi ti ng

gastr i c i r r i tati on
hangover effects (possi bl y l eadi ng to r espi rator y depr essi on or
even r espi rator y fai l ur e).

A chlorus of interactions
Chl oral hydrate may i ncr ease the r i sk of bl eedi ng i n pati ents taki ng
oral anti coagul ants. Use wi th I.V. fur osemi de may pr oduce sweati ng,
fl ushi ng, var i abl e bl ood pr essur e, and uneasi ness. (See Adver se
r eacti ons to nonbenzodi azepi nes-nonbar bi turates.)

Antianxiety drugs
Antianxiety dr ugs, al so cal l ed anxiolytics, i ncl ude some of the most
commonl y pr escr i bed dr ugs i n the Uni ted States. They ar e used
pr i mar i l y to tr eat anxi ety di sor der s. The thr ee mai n types of
anti anxi ety dr ugs ar e benzodi azepi nes (di scussed i n a pr evi ous
secti on), bar bi turates (al so di scussed i n a pr evi ous secti on), and
buspi r one.

Buspirone
Buspir one i s the fi r st anti anxi ety dr ug i n a cl ass of dr ugs known as
az aspir odecanedione der ivatives. Thi s dr ugs str uctur e and
mechani sm of acti on di ffer fr om those of other anti anxi ety dr ugs.

Advantage, buspirone
Buspi r one has several advantages, i ncl udi ng:

l ess sedati on
no i ncr ease i n CNS depr essant effects when taken wi th al cohol
or sedati ve-hypnoti cs
l ower abuse potenti al .

Pharmacokinetics
Buspi r one i s absor bed rapi dl y, under goes extensi ve fi r st-pass effect,
and i s metabol i zed i n the l i ver to at l east one acti ve metabol i te.
The dr ug i s el i mi nated i n ur i ne and stool .

Pharmacodynamics
Al though the mechani sm of acti on of buspi r one i snt known, i ts
known that buspi r one doesnt affect G ABA r eceptor s l i ke the
benzodi azepi nes do.

Warning!
Adverse reactions to buspirone
The most common r eacti ons to buspi r one i ncl ude:

di z z i ness
l i ght-headedness
i nsomni a
rapi d hear t rate
pal pi tati ons
headache.
Midbrain modulator
Buspi r one seems to pr oduce var i ous effects i n the mi dbrai n and acts
as a mi dbrai n modul ator, possi bl y due to i ts hi gh affi ni ty for
ser otoni n r eceptor s.

Pharmacotherapeutics
Buspi r one i s used to tr eat general i zed anxi ety states. Pati ents who
havent r ecei ved benzodi azepi nes seem to r espond better to bu-
spi r one.

In case of panic
Because of i ts sl ow onset of acti on, buspi r one i s i neffecti ve when
qui ck r el i ef fr om anxi ety i s needed.

Drug interactions
Unl i ke other anti anxi ety dr ugs, buspi r one doesnt i nteract wi th
al cohol or other CNS depr essants. When buspi r one i s gi ven wi th
MAOIs, hyper tensi ve r eacti ons may occur. (See Adver se r eacti ons to
buspi r one.)

Antidepressant and mood stabilizer drugs

Antidepr essant and mood stabiliz er dr ugs ar e used to tr eat affecti ve
di sor der sdi stur bances i n mood, character i zed by depr essi on or
el ati on.

Pole positions
Uni pol ar di sor der s, character i zed by per i ods of cl i ni cal depr essi on,
ar e tr eated wi th:

sel ecti ve ser otoni n r euptake i nhi bi tor s (SSRIs)

MAOIs
TCAs
mi scel l aneous anti depr essants.

Bi pol ar di sor der s, character i zed by al ter nati ng per i ods of mani c
behavi or and cl i ni cal depr essi on, ar e tr eated wi th l i thi um and
anti convul sant dr ugs.
Other mood stabi l i zer s i ncl ude di val pr oex, car bamazepi ne, and
ol anz api ne.

Putting a new stress on SSRIs

The Food and Dr ug Admi ni strati on appr oved ser tral i ne (Zol oft)
and par oxeti ne (Paxi l ) as the dr ugs of choi ce for tr eati ng
posttraumati c str ess di sor der. In or der for these dr ugs to be used,
the pati ent must have symptoms, such as i ntense fear,
hel pl essness, and hor r or that exi st for at l east 1 month and cause
si gni fi cant i mpai r ed functi oni ng.

Selective serotonin reuptake inhibitors

Devel oped to tr eat depr essi on wi th fewer adver se r eacti ons, SSRIs,
ar e chemi cal l y di ffer ent fr om MAOIs and TCAs. (See Putti ng a new
str ess on SSRIs.)
Some of the SSRIs cur r entl y avai l abl e ar e:

ci tal opram
dul oxeti ne
esci tal opram
fl uoxeti ne
fl uvoxami ne
 par oxeti ne
ser tral i ne
venl afaxi ne. (See Stoppi ng SSRIs.)

Pharmacokinetics
SSRIs ar e absor bed al most compl etel y after oral admi ni strati on and
ar e hi ghl y pr otei n-bound.

Metabolism and excretion

SSRIs ar e pr i mar i l y metabol i zed i n the l i ver and ar e excr eted i n
ur i ne.

Safe and sound

Stopping SSRIs
Abr uptl y stoppi ng sel ecti ve ser otoni n r euptake i nhi bi tor
(SSRI) therapy may r esul t i n SSRI di sconti nuati on syndr ome, wi th
di z z i ness, ver ti go, ataxi a, nausea, vomi ti ng, muscl e pai ns,
fati gue, tr emor, and headache. Psychol ogi cal symptoms, such as
anxi ety, cr yi ng spel l s, i r r i tabi l i ty, feel i ng sad, memor y pr obl ems,
and vi vi d dr eams, may al so occur.
Thi s syndr ome i s mor e common i n SSRIs wi th a shor ter hal f-l i fe,
such as par oxeti ne and venl afaxi ne, and occur s i n up to one-thi r d
of pati ents r ecei vi ng SSRI therapy.
Go slow
Taper i ng the dosage of the dr ug sl owl y over several weeks can
pr event SSRI di sconti nuati on syndr ome. F l uoxeti ne i s the l east
l i kel y to cause thi s pr obl em because of i ts extr emel y l ong hal f-
l i fe. The syndr ome i s sel f-l i mi ti ng (over 2 to 3 weeks wi th
tr eatment).

Pharmacodynamics
SSRIs i nhi bi t the neur onal r euptake of the neur otransmi tter
ser otoni n.

Pharmacotherapeutics
SSRIs ar e used to tr eat the same major depr essi ve epi sodes as TCAs
and have the same degr ee of effecti veness. F l uvoxami ne,
fl uoxeti ne, ser tral i ne, and par oxeti ne ar e al so used to tr eat
obsessi ve-compul si ve di sor der. F l uoxeti ne has al so been appr oved
for the tr eatment of bul i mi a. Par oxeti ne i s al so i ndi cated for soci al
anxi ety di sor der.
Venl afaxi ne i s an anti depr essant dr ug thats chemi cal l y di ffer ent
fr om other anti depr essants and has uni que pr oper ti es i n ter ms of
absor pti on and mechani sm of acti on. It has been par ti cul ar l y
effecti ve i n pati ents wi th ver y sever e depr essi on.

Dont panic, but theres more

SSRIs may al so be useful i n tr eati ng pani c di sor der s, eati ng
di sor der s, per sonal i ty di sor der s, i mpul se contr ol di sor der s, and
anxi ety di sor der s. Several SSRIs ar e appr oved for pr emenstr ual
(dysphor i c) di sor der.

Drug interactions
Dr ug i nteracti ons associ ated wi th SSRIs i nvol ve thei r abi l i ty to
competi ti vel y i nhi bi t a l i ver enz yme thats r esponsi bl e for oxi dati on
of numer ous dr ugs, i ncl udi ng TCAs, car bamazepi ne, metopr ol ol ,

fl ecai ni de, encai ni de, and anti psychoti cs, such as cl oz api ne and
thi or i daz i ne.

Safe and sound

Risks of antidepressants
Studi es have shown a cor r el ati on between taki ng an
anti depr essant and the i ncr eased r i sk of sui ci dal behavi or i n
young adul ts ages 18 to 24. Because of thi s r i sk, the F DA has
mandated a bl ack-box war ni ng (the str ongest war ni ng possi bl e) to
be added to the l abel s of al l anti depr essants, war ni ng
practi ti oner s to eval uate the need for the anti depr essant wi th the
i ncr eased r i sk i t pr esents.

They dont mix with MAOIs

The use of SSRIs wi th MAOIs can cause ser i ous, potenti al l y fatal
r eacti ons. Indi vi dual SSRIs al so have thei r own par ti cul ar
i nteracti ons. (See Adver se r eacti ons to SSRIs.)
 Use of ci tal opram and par oxeti ne wi th war far i n may l ead to
i ncr eased bl eedi ng.
Car bamazepi ne may i ncr ease cl earance of ci tal opram.
F l uoxeti ne i ncr eases the hal f-l i fe of di azepam and di spl aces
hi ghl y pr otei n-bound dr ugs, l eadi ng to toxi ci ty.
F l uvoxami ne use wi th di l ti azem hydr ochl or i de may cause
bradycar di a.
Par oxeti ne shoul dnt be used wi th tr yptophan because thi s
combi nati on can cause headache, nausea, sweati ng, and
di z z i ness.
Par oxeti ne may i ncr ease pr ocycl i di ne l evel s, causi ng i ncr eased
anti chol i ner gi c effects.
Ci meti di ne, phenobar bi tal , and phenytoi n may r educe par oxeti ne
metabol i sm by the l i ver, i ncr easi ng the r i sk of toxi ci ty.
Par oxeti ne and ser tral i ne may i nteract wi th other hi ghl y pr otei n-
bound dr ugs, causi ng adver se r eacti ons to ei ther dr ug. (See
Ri sks of anti depr essants.)

Warning!
Adverse reactions to SSRIs
Anxi ety, i nsomni a, somnol ence, pal pi tati ons, var i ous
rashes, and sexual dysfuncti on (anor gasmi a and del ayed
ejacul ati on) may occur wi th the use of ser otoni n sel ecti ve
r euptake i nhi bi tor s (SSRIs).
Other reactions
Decr eased pl asma gl ucose l evel s can occur wi th fl uoxeti ne.
Or thostati c hypotensi on may occur wi th ci tal opram and
par oxeti ne.

Tricyclic antidepressants
TCAs ar e used to tr eat depr essi on. They i ncl ude:

ami tr i ptyl i ne
amoxapi ne
cl omi prami ne
 desi prami ne
doxepi n

i mi prami ne
nor tr i ptyl i ne
pr otr i ptyl i ne
tr i mi prami ne.

Pharmacokinetics
Al l of the TCAs ar e acti ve phar macol ogi cal l y, and some of thei r
metabol i tes ar e al so acti ve. Theyr e absor bed compl etel y when
taken oral l y but under go fi r st-pass effect.

Distribution, metabolism, and excretion

Wi th fi r st-pass effect, a dr ug passes fr om the G I tract to the l i ver,
wher e i ts par ti al l y metabol i zed befor e enter i ng the ci r cul ati on.
TCAs ar e metabol i zed extensi vel y i n the l i ver and eventual l y
excr eted as i nacti ve compounds (onl y smal l amounts of acti ve dr ug
ar e excr eted) i n ur i ne.

They just melt in fat

The extr eme fat sol ubi l i ty of these dr ugs accounts for thei r wi de
di str i buti on thr oughout the body, sl ow excr eti on, and l ong hal f-
l i ves.

Pharmacodynamics
Resear cher s bel i eve that TCAs i ncr ease the amount of
nor epi nephr i ne, ser otoni n, or both i n the CNS by pr eventi ng thei r
r euptake i nto the storage granul es i n the pr esynapti c ner ves. They
al so bl ock acetyl chol i ne and hi stami ne r eceptor s.

The upside to preventing reuptake

After a neur otransmi tter has per for med i ts job, several fates ar e
possi bl e, i ncl udi ng rapi dl y r eenter i ng the neur on fr om whi ch i t was
r el eased (or r euptake). Pr eventi ng r euptake r esul ts i n i ncr eased
l evel s of these neur otransmi tter s i n the synapses, r el i evi ng
depr essi on.
Pharmacotherapeutics
TCAs ar e used to tr eat epi sodes of major depr essi on. Theyr e
especi al l y effecti ve i n tr eati ng depr essi on of i nsi di ous onset
accompani ed by wei ght l oss, anor exi a, or i nsomni a. Physi cal si gns
and symptoms may r espond after 1 to 2 weeks of therapy;
psychol ogi cal symptoms, after 2 to 4 weeks.

Warning!
Adverse reactions to TCAs
Adver se r eacti ons to TCAs i ncl ude:

or thostati c hypotensi on (a dr op i n bl ood pr essur e on standi ng)

sedati on
jaundi ce
rashes
photosensi ti vi ty r eacti ons
a fi ne r esti ng tr emor
decr eased sexual desi r e
i nhi bi ted ejacul ati on
transi ent eosi nophi l i a
r educed whi te bl ood cel l count
mani c epi sodes (i n pati ents wi th or wi thout bi pol ar di sor der )
exacer bati on of psychoti c symptoms i n suscepti bl e pati ents.

Special effects
Al though rar e, TCA therapy may al so l ead to:

granul ocytopeni a
pal pi tati ons
conducti on del ays
rapi d hear tbeat
i mpai r ed cogni ti on, car di ovascul ar adver se r eacti ons (i n
el der l y pati ents).

Sudden death has occur r ed i n chi l dr en and adol escents taki ng

desi prami ne. For thi s r eason a basel i ne el ectr ocar di ogram i s
r ecommended befor e gi vi ng a TCA to pati ents i n thi s age-gr oup.
Problem patients
TCAs ar e much l ess effecti ve i n pati ents wi th hypochondr i asi s,
atypi cal depr essi on, or depr essi on accompani ed by del usi ons. When
gi ven wi th a mood stabi l i zer, they may be hel pful i n tr eati ng acute
epi sodes of depr essi on i n bi pol ar I di sor der.

Migraines and more

TCAs ar e al so used for pr eventi ng mi grai ne headaches and i n
tr eati ng phobi as (pani c di sor der wi th agoraphobi a), ur i nar y
i nconti nence, attenti on defi ci t di sor der, obsessi ve-compul si ve
di sor der, neur opathi c pai n (chr oni c pai n that can occur wi th
per i pheral neur opathi es, her pes zoster i nfecti ons, traumati c ner ve
i njur i es, and some types of cancer or cancer tr eatments), di abeti c
neur opathy, and enur esi s.

Drug interactions
TCAs i nteract wi th several commonl y used dr ugs:

They i ncr ease the catechol ami ne effects of amphetami nes and
sympathomi meti cs, l eadi ng to hyper tensi on.
Bar bi turates i ncr ease the metabol i sm of TCAs and decr ease thei r
bl ood l evel s.

Ci meti di ne i mpai r s metabol i sm of TCAs by the l i ver, i ncr easi ng

the r i sk of toxi ci ty.
Concur r ent use of TCAs wi th MAOIs may cause an extr emel y
el evated body temperatur e, exci tati on, and sei z ur es.
An i ncr eased anti chol i ner gi c effect, such as dr y mouth, ur i ne
r etenti on, and consti pati on, i s seen when anti chol i ner gi c dr ugs
ar e taken wi th TCAs.
TCAs r educe the anti hyper tensi ve effects of cl oni di ne and
guanethi di ne. (See Adver se r eacti ons to TCAs.)

Monoamine oxidase inhibitors

MAOIs ar e di vi ded i nto two cl assi fi cati ons based on chemi cal
str uctur e:
 hydraz i nes, whi ch i ncl ude phenel z i ne sul fate
nonhydraz i nes, consi sti ng of a si ngl e dr ug, tranyl cypr omi ne
sul fate.

Pharmacokinetics
MAOIs ar e absor bed rapi dl y and compl etel y fr om the G I tract and
ar e metabol i zed i n the l i ver to i nacti ve metabol i tes. These
metabol i tes ar e excr eted mai nl y by the G I tract and, to a l esser
degr ee, by the ki dneys.

Pharmacodynamics
MAOIs appear to wor k by i nhi bi ti ng MAO, an enz yme thats wi del y
di str i buted thr oughout the body and that nor mal l y metabol i zes
many neur otransmi tter s, i ncl udi ng nor epi nephr i ne, dopami ne, and
ser otoni n. Thi s l eaves mor e nor epi nephr i ne, dopami ne, and
ser otoni n avai l abl e to the r eceptor s, ther eby r el i evi ng the
symptoms of depr essi on.

Pharmacotherapeutics
The i ndi cati ons for MAOIs ar e si mi l ar to those for other
anti depr essants. MAOIs ar e par ti cul ar l y effecti ve for tr eati ng pani c
di sor der wi th agoraphobi a, eati ng di sor der s, posttraumati c str ess
di sor der, and pai n di sor der s.
MAOIs may be mor e effecti ve than other anti depr essants i n the
tr eatment of atypi cal depr essi on. Atypi cal depr essi on pr oduces si gns
opposi te to those of typi cal depr essi on. For exampl e, the pati ent
gai ns wei ght, sl eeps mor e, and has a hi gher suscepti bi l i ty to
r ejecti on.

Warning!
Adverse reactions to MAOIs
Adver se r eacti ons to mono-ami ne oxi dase i nhi bi tor s
(MAOIs) i ncl ude:

hyper tensi ve cr i si s (when taken wi th tyrami ne-r i ch foods)

or thostati c hypotensi on
r estl essness
 dr owsi ness
di z z i ness
headache
i nsomni a
consti pati on
anor exi a
nausea and vomi ti ng
weakness
joi nt pai n
dr y mouth
bl ur r ed vi si on
per i pheral edema
ur i ne r etenti on
transi ent i mpotence
rash
ski n and mucous membrane hemor r hage.

Reaction relief
Adver se r eacti ons may be avoi ded by gi vi ng the dr ug i n smal l
di vi ded doses.

It tackles typical depression, too

MAOIs may be used to tr eat typi cal depr essi on r esi stant to other
therapi es or when other therapi es ar e contrai ndi cated. For exampl e,
tranyl cypr omi ne i s the pr efer r ed MAOI for pati ents wi th depr essi on
who have l i ver di sease. Other uses i ncl ude tr eatment for :

phobi c anxi eti es

neur oder mati ti s (an i tchy ski n di sor der seen i n anxi ous, ner vous
peopl e)
hypochondr i asi s (abnor mal concer n about heal th)
r efractor y nar col epsy (sudden sl eep attacks).

Moving from MAOIs

Monoami ne oxi dase i nhi bi tor s (MAOIs) shoul d be di sconti nued 2
weeks befor e star ti ng an al ter nati ve anti depr essant. A 2-week
wai ti ng per i od (5 weeks for fl uoxeti ne) shoul d al so el apse when
di sconti nui ng an anti depr essant and star ti ng an MAOI.

Drug interactions
MAOIs i nteract wi th a wi de var i ety of dr ugs:

Taki ng MAOIs wi th amphetami nes, methyl pheni date, l evodopa,

sympathomi meti cs, and nonamphetami ne appeti te suppr essants
may i ncr ease catechol ami ne r el ease, causi ng hyper tensi ve cr i si s.
Usi ng them wi th fl uoxeti ne, TCAs, ci tal opram, cl omi prami ne,
trazodone, ser tral i ne, par oxeti ne, and fl uvoxami ne may r esul t i n
an el evated body temperatur e, exci tati on, and sei z ur es.
When taken wi th doxapram, MAOIs may cause hyper tensi on and
ar r hythmi as and may i ncr ease the adver se r eacti ons to
doxapram.
MAOIs may enhance the hypogl ycemi c effects of anti di abeti c
dr ugs.
Admi ni ster i ng MAOIs wi th meper i di ne may r esul t i n exci tati on,
hyper tensi on or hypotensi on, extr emel y el evated body
temperatur e, and coma. (See Movi ng fr om MAOIs.)

Forbidden fruit (and other foods)

Cer tai n foods can i nteract wi th MAOIs and pr oduce sever e r eacti ons.
The most ser i ous r eacti ons i nvol ve tyrami ne-r i ch foods, such as r ed
wi nes, aged cheese, and fava beans. Foods wi th moderate tyrami ne
contentsfor exampl e, yogur t and r i pe bananasmay be eaten
occasi onal l y, but wi th car e. (See Adver se r eacti ons to MAOIs.)

Miscellaneous antidepressants
Other antidepr essants i n use today i ncl ude:

mapr oti l i ne and mi r taz api ne, tetracycl i c anti depr essants
bupr opi on, a dopami ne r euptake bl ocki ng agent
venl afaxi ne, a ser otoni n-nor epi nephr i ne r euptake i nhi bi tor
trazodone, a tr i azol opyr i di ne agent
nefazodone, a phenyl pi peraz i ne agent.

Pharmacokinetics
The paths these anti depr essants take thr ough the body may var y:

Mapr oti l i ne and mi r taz api ne ar e absor bed fr om the G I tract,

di str i buted wi del y i n the body, metabol i zed by the l i ver, and
excr eted by the ki dneys.
Bupr opi on i s wel l absor bed fr om the G I tract and metabol i zed by
the l i ver. Its metabol i tes ar e excr eted by the ki dneys. It appear s
to be hi ghl y bound to pl asma pr otei ns.
 Venl afaxi ne i s rapi dl y absor bed after oral admi ni strati on,
par ti al l y bound to pl asma pr otei ns, metabol i zed i n the l i ver, and
excr eted i n ur i ne.
Trazodone i s wel l absor bed fr om the G I tract, di str i buted wi del y
i n the body, and metabol i zed by the l i ver. About 75% i s excr eted
i n ur i ne; the r emai nder i s excr eted i n stool .
Nefazodone i s rapi dl y and compl etel y absor bed but, because of
extensi ve metabol i sm, onl y about 20% of the dr ug i s avai l abl e.
The dr ug i s al most compl etel y bound to pl asma pr otei ns and i s
excr eted i n ur i ne.

Pharmacodynamics
Much about how these dr ugs wor k has yet to be ful l y under stood:

Mapr oti l i ne and mi r taz api ne pr obabl y i ncr ease the amount of
nor epi nephr i ne, ser otoni n, or both i n the CNS by bl ocki ng thei r
r euptake by pr esynapti c neur ons (ner ve ter mi nal s).

Bupr opi on was once thought to i nhi bi t the r euptake of the

neur otransmi tter dopami ne; however, i t mor e l i kel y acts on
nonadr ener gi c r eceptor s.
Venl afaxi ne i s thought to potenti ate neur otransmi tter acti vi ty i n
the CNS by i nhi bi ti ng the neural r euptake of ser otoni n and
nor epi nephr i ne.
Trazodone, al though i ts acti on i s unknown, i s thought to exer t
anti depr essant effects by i nhi bi ti ng the r euptake of
nor epi nephr i ne and ser otoni n i n the pr esynapti c neur ons.
Nefazodones acti on i snt pr eci sel y defi ned. It i nhi bi ts neur onal
uptake of ser otoni n and nor epi nephr i ne. Its al so a ser otoni n
antagoni st, whi ch expl ai ns i ts effecti veness i n tr eati ng anxi ety.

Pharmacotherapeutics
These mi scel l aneous dr ugs ar e al l used to tr eat depr essi on.
Trazodone may al so be effecti ve i n tr eati ng aggr essi ve behavi or and
pani c di sor der.

Drug interactions
Al l of these anti depr essants may have ser i ous, potenti al l y fatal ,
effects when combi ned wi th MAOIs. Each of these dr ugs al so car r i es
i ts own speci fi c r i sks when used wi th other dr ugs:

Mapr oti l i ne and mi r taz api ne i nteract wi th CNS depr essants to

cause an addi ti ve effect.
Bupr opi on combi ned wi th l evodopa, phenothi az i nes, or TCAs
i ncr eases the r i sk of adver se r eacti ons, i ncl udi ng sei z ur es.
Trazodone may i ncr ease ser um l evel s of di goxi n and phenytoi n.
Its use wi th anti hyper tensi ve agents may i ncr ease hypotensi ve
effects. CNS depr essi on may be enhanced i f trazodone i s
admi ni ster ed wi th other CNS depr essants.
Nefazodone may i ncr ease the di goxi n l evel i f admi ni ster ed wi th
di goxi n. It i ncr eases CNS depr essi on when combi ned wi th CNS
depr essants. (See Adver se r eacti ons to mi scel l aneous
anti depr essants.)

Warning!
Adverse reactions to miscellaneous
antidepressants
These anti depr essants may pr oduce var i ous adver se r eacti ons.

Venlafaxine
Maprotiline Mirtazapine Bupropion and
nefazodone

Sei z ur es
Or thostati c
hypotensi on
Tachycar di a
El ectr ocar di ographi c
changes

Tr emor s
Confusi on
Nausea
Consti pati on
 Headache
Confusi on
Tr emor
Agi tati on
Tachycar di a
Anor exi a
Nausea and
vomi ti ng

headache
somnol ence
di z z i ness
nausea

Dr owsi ness
Di z z i ness

Lithium
Lithium car bonate and lithium citr ate ar e used to pr event or tr eat
mani a. The di scover y of l i thi um was a mi l estone i n tr eati ng mani a
and bi pol ar di sor der s.

Pharmacokinetics
When taken oral l y, l i thi um i s absor bed rapi dl y and compl etel y and i s
di str i buted to body ti ssues.

Metabolism and excretion

An acti ve dr ug, l i thi um i snt metabol i zed and i s excr eted fr om the
body unchanged.

Pharmacodynamics
Its theor i zed that i n mani a, the pati ent exper i ences excessi ve
catechol ami ne sti mul ati on. In bi pol ar di sor der, the pati ent i s
affected by swi ngs between the excessi ve catechol ami ne sti mul ati on
of mani a and the di mi ni shed catechol ami ne sti mul ati on of
depr essi on.

Returning to normal
Li thi ums exact mechani sm of acti on i s unknown. It may r egul ate
catechol ami ne r el ease i n the CNS by:

i ncr easi ng nor epi nephr i ne and ser otoni n uptake

r educi ng the r el ease of nor epi nephr i ne fr om the synapti c
vesi cl es (wher e neur otransmi tter s ar e stor ed) i n the pr esynapti c
neur on
i nhi bi ti ng nor epi nephr i nes acti on i n the postsynapti c neur on.

Getting more of the message

Resear cher s ar e al so exami ni ng l i thi ums effects on el ectr ol yte and
i on transpor t. Li thi um may al so modi fy the acti ons of second
messenger s such as cycl i c adenosi ne monophosphate.

Pharmacotherapeutics
Li thi um i s used pr i mar i l y to tr eat acute epi sodes of mani a and to
pr event r el apses of bi pol ar di sor der s.

Under investigation
Other uses of l i thi um bei ng r esear ched i ncl ude pr eventi ng uni pol ar
depr essi on and mi grai ne headaches and tr eati ng depr essi on, al cohol
dependence, anor exi a ner vosa, syndr ome of i nappr opr i ate
anti di ur eti c hor mone, and neutr openi a.

No margin for error

Li thi um has a nar r ow therapeuti c mar gi n of safety. A bl ood l evel
that i s even sl i ghtl y hi gher than the therapeuti c l evel can be
danger ous.

Drug interactions
Ser i ous i nteracti ons wi th other dr ugs can occur because of l i thi ums
nar r ow therapeuti c range:

The r i sk of l i thi um toxi ci ty i ncr eases when l i thi um i s taken wi th

thi az i de and l oop di ur eti cs and nonster oi dal anti -i nfl ammator y
dr ugs.
Admi ni strati on of l i thi um wi th hal oper i dol , phenothi az i nes, or
car bamazepi ne may i ncr ease the r i sk of neur otoxi ci ty.
Li thi um may i ncr ease the hypothyr oi d effects of potassi um
i odi de.
Sodi um bi car bonate may i ncr ease l i thi um excr eti on, r educi ng i ts
effects.
Li thi ums effects ar e r educed when l i thi um i s taken wi th
theophyl l i ne.

Warning!
Adverse reactions to lithium
Common adver se r eacti ons to l i thi um i ncl ude:

r ever si bl e el ectr ocar di ogram changes

thi r st
pol yur i a
el evated whi te bl ood cel l count.

A flood in the blood

El evated toxi c bl ood l evel s of l i thi um may pr oduce:

confusi on
l ethar gy
sl ur r ed speech
i ncr eased r efl ex r eacti ons
sei z ur es.

Take this with a grain (or more) of salt

A pati ent on a sever e sal t-r estr i cted di et i s suscepti bl e to l i thi um
toxi ci ty. On the other hand, an i ncr eased i ntake of sodi um may
r educe the therapeuti c effects of l i thi um. (See Adver se r eacti ons to
l i thi um.)

Antipsychotic drugs
Antipsychotic dr ugs can contr ol psychoti c symptoms, such as
del usi ons and hal l uci nati ons, and thought di sor der s that can occur
wi th schi zophr eni a, mani a, and other psychoses.

By any other name

Dr ugs used to tr eat psychoses have several di ffer ent names,
i ncl udi ng:

anti psychoti c, because they can el i mi nate si gns and symptoms of

psychoses
major tranqui l i zer, because they can cal m an agi tated pati ent
neur ol epti c, because they have an adver se neur obi ol ogi c effect
that causes abnor mal body movements.

Two major groups

Regar dl ess of what theyr e cal l ed, al l anti psychoti c dr ugs bel ong to
one of two major gr oups:

atypi cal anti psychoti cs, whi ch i ncl ude ar i pi prazol e, cl oz a-pi ne,
ol anz api ne, pal i per i done, queti api ne, r i sper i done, and
z i prasi done
typi cal anti psychoti cs, whi ch i ncl ude phenothi az i nes and
nonphenothi az i nes.
Atypical antipsychotics
Atypical antipsychotic dr ugs ar e agents desi gned to tr eat
schi zophr eni a. They i ncl ude ar i pi prazol e, cl oz api ne, ol anz api ne,
pal i per i done, queti api ne, r i sper i done, and z i prasi done.

Pharmacokinetics
Atypi cal anti psychoti cs ar e absor bed after oral admi ni strati on.

Metabolism and excretion

Atypi cal anti psychoti cs ar e metabol i zed by the l i ver. Metabol i tes of
cl oz api ne, ol anz api ne, queti api ne, and z i prasi done ar e i nacti ve,
wher eas r i sper i done and pal i per i done have acti ve metabol i tes.
Theyr e hi ghl y pl asma pr otei n-bound and el i mi nated i n ur i ne, wi th a
smal l por ti on el i mi nated i n stool .

Pharmacodynamics
Atypi cal anti psychoti cs typi cal l y bl ock the dopami ne r eceptor s, but
to a l esser extent than the typi cal anti psychoti cs, r esul ti ng i n far
fewer extrapyrami dal adver se effects. Addi ti onal l y, atypi cal
anti psychoti cs bl ock ser otoni n r eceptor acti vi ty.

Putting it together
These combi ned acti ons account for thei r effecti veness agai nst the
posi ti ve and negati ve symptoms of schi zophr eni a wi th mi ni mal
extrapyrami dal effects.

Pharmacotherapeutics
Atypi cal anti psychoti cs ar e consi der ed the fi r st l i ne of tr eatment for
pati ents wi th schi zophr eni a because of equal or i mpr oved
effecti veness combi ned wi th i mpr oved tol erabi l i ty.

Lower doses do for dementia

Atypi cal anti psychoti cs ar e commonl y used to tr eat behavi oral and
psychoti c symptoms i n pati ents wi th dementi a. Dosages ar e
si gni fi cantl y l ower for these pati ents than for pati ents wi th
schi zophr eni a.
Drug interactions
Dr ugs that al ter the P-450 enz yme system al ter the metabol i sm of
some atypi cal anti psychoti cs.

The straight dopa

Atypi cal anti psychoti cs counteract the effects of l evodopa and other
dopami ne agoni sts. (See Adver se r eacti ons to atypi cal
anti psychoti cs.)

Warning!
Adverse reactions to atypical antipsychotics
Atypi cal anti psychoti cs have fewer extrapyrami dal effects
than typi cal anti -psychoti cs and car r y a mi ni mal r i sk for sei z ur es
(except for cl oz api ne).
Aripiprazole
Ar i pi prazol e i s a newer atypi cal anti psychoti c and may pr oduce
mi l d sedati on.
Clozapine
Cl oz api ne i s associ ated wi th agranul o-cytosi s (an abnor mal
decr ease i n whi te bl ood cel l s). Wei ght gai n i s common, and
sei z ur es may al so occur.
Olanzapine
Ol anz api ne pl aces the pati ent at mi ni mal r i sk for extrapyrami dal
effects. Wei ght gai n i s common.
Quetiapine
Queti api ne i s associ ated wi th sedati on.
Risperidone and paliperidone
Ri sper i done and pal i per i done have a hi gher r i sk of extrapyrami dal
effects than other atypi cal anti psychoti cs, especi al l y when
pr escr i bed at doses at the hi gher range of nor mal .
Ziprasidone
Because z i prasi done may cause el ectr ocar di ogram changes, i ts
usual l y r ecommended as an al ter nati ve therapy onl y after the
pati ent has fai l ed to r espond to other atypi cal anti psychoti cs.

Typical antipsychotics
Typical antipsychotics, whi ch i ncl ude phenothi az i nes and
nonphenothi az i nes, can be br oken down i nto smal l er cl assi fi cati ons.

Different adverse reactions

Many cl i ni ci ans bel i eve that the phenothi az i nes shoul d be tr eated as
thr ee di sti nct dr ug cl asses because of the di ffer ences i n the adver se
r eacti ons they cause:

Al i phati cs pr i mar i l y cause sedati on and anti chol i ner gi c effects.

Theyr e l ow potency dr ugs that i ncl ude chl or pr omaz i ne.
Pi peraz i nes pr i mar i l y cause extrapyrami dal r eacti ons and i ncl ude
fl uphenaz i ne decanoate, fl uphenaz i ne enanthate, fl uphena-z i ne
hydr ochl or i de, per phenaz i ne, and tr i fl uoperaz i ne.
Pi per i di nes pr i mar i l y cause sedati on and anti chol i ner gi c and
car di ac effects; they i ncl ude mesor i daz i ne and thi or i daz i ne.

Different chemical structure

Based on thei r chemi cal str uctur e, nonphenothi az i ne anti psychoti cs
can be di vi ded i nto several dr ug cl asses, i ncl udi ng:

butyr ophenones, such as hal oper i dol and hal oper i dol decanoate
di benzoxazepi nes such as l oxapi ne
di hydr oi ndol ones such as mol i ndone
di phenyl butyl pi per i di nes such as pi moz i de
thi oxanthenes, such as thi othi xene and thi othi xene
hydr ochl or i de.

Pharmacokinetics
Al though phenothi az i nes ar e absor bed er rati cal l y, theyr e ver y l i pi d-
sol ubl e and hi ghl y pr otei n-bound. Ther efor e, theyr e di str i buted to
many ti ssues and ar e hi ghl y concentrated i n the brai n.
Li ke phenothi az i nes, nonphenothi az i nes ar e absor bed er rati cal l y,
ar e l i pi d-sol ubl e, and ar e hi ghl y pr otei n-bound. Theyr e al so
di str i buted thr oughout the ti ssues and ar e hi ghl y concentrated i n
the brai n.
Metabolism and excretion
Al l phenothi az i nes ar e metabol i zed i n the l i ver and excr eted i n
ur i ne and bi l e. Because fatty ti ssues sl owl y r el ease accumul ated
phenothi az i ne metabol i tes i nto the pl asma, phenothi az i nes may
pr oduce effects up to 3 months after theyr e stopped.
Nonphenothi az i nes ar e al so metabol i zed i n the l i ver and excr eted i n
ur i ne and bi l e.

Pharmacodynamics
Al though the mechani sm of acti on of phenothi az i nes i snt ful l y
under stood, r esear cher s bel i eve that these dr ugs wor k by bl ocki ng
postsynapti c dopami ner gi c r eceptor s i n the brai n.
The mechani sm of acti on of nonphenothi az i nes r esembl es that of
phenothi az i nes.

Erecting a blockade
The anti psychoti c effect of phenothi az i nes i s due to r eceptor
bl ockade i n the l i mbi c system. Thei r anti emeti c effect i s due to
r eceptor bl ockade i n the chemor eceptor tr i gger zone l ocated i n the
brai ns medul l a.

Sending a charge
Phenothi az i nes al so sti mul ate the extrapyrami dal system (motor
pathways that connect the cer ebral cor tex wi th the spi nal ner ve
pathways).
Pharmacotherapeutics
Phenothi az i nes ar e used pr i mar i l y to:

tr eat schi zophr eni a

cal m anxi ous or agi tated pati ents
i mpr ove a pati ents thought pr ocesses
al l evi ate del usi ons and hal l uci nati ons.

Working overtime
Other therapeuti c uses have been found for phenothi az i nes:

Theyr e admi ni ster ed to tr eat other psychi atr i c di sor der s, such
as br i ef r eacti ve psychosi s, atypi cal psychosi s, schi zoaffecti ve
psychosi s, auti sm, and major depr essi on wi th psychosi s.
In combi nati on wi th l i thi um, theyr e used i n the tr eatment of
pati ents wi th bi pol ar di sor der, unti l the sl ower-acti ng l i thi um
pr oduces i ts therapeuti c effect.
Theyr e pr escr i bed to qui et mental l y chal l enged chi l dr en and
agi tated ger i atr i c pati ents, par ti cul ar l y those wi th dementi a.
The pr eoperati ve effects of anal gesi cs may be boosted wi th thei r
addi ti on.
Theyr e hel pful i n the management of pai n, anxi ety, and nausea
i n pati ents wi th cancer.
Solo solutions
As a gr oup, nonphenothi az i nes ar e used to tr eat psychoti c
di sor der s. Thi othi xene i s al so used to contr ol acute agi tati on.
Hal oper i dol and pi moz i de may al so be used to tr eat Tour ette
syndr ome.

Drug interactions
Phenothi az i nes i nteract wi th many di ffer ent types of dr ugs and may
have ser i ous effects:

Incr eased CNS depr essant effects, such as stupor, may occur
when phenothi az i nes ar e taken wi th CNS depr essants.
CNS depr essants may r educe phenothi az i ne effecti veness,
r esul ti ng i n i ncr eased psychoti c behavi or or agi tati on.
Taki ng anti chol i ner gi c dr ugs wi th phenothi az i nes may r esul t i n
i ncr eased anti chol i ner gi c effects, such as dr y mouth and
consti pati on. By i ncr easi ng phenothi az i ne metabol i sm,
anti chol i ner gi c dr ugs may al so r educe the anti psychoti c effects
of phenothi az i nes.
Phenothi az i nes may r educe the anti par ki nsoni an effects of
l evodopa.
Concur r ent use wi th l i thi um i ncr eases the r i sk of neur otoxi ci ty.
Concur r ent use wi th dr oper i dol i ncr eases the r i sk of
extrapyrami dal effects.
The thr eshol d for sei z ur es i s l ower ed when phenothi az i nes ar e
used wi th anti convul sants.
Phenothi az i nes may i ncr ease the ser um l evel s of TCAs and beta-
adr ener gi c bl ocker s. Thi or i daz i ne can cause ser i ous, even fatal ,
car di ac ar r hythmi as when combi ned wi th such dr ugs as
fl uvoxami ne, pr opranol ol , pi ndol ol , and fl uoxeti ne that i nhi bi t
the cyto-chr ome P-450 2D6 i soenz yme, or dr ugs known to
pr ol ong the QTc i nter val . (See Adver se r eacti ons to typi cal
anti psychoti cs.)

Warning!
Adverse reactions to typical antipsychotics
 Neur ol ogi c r eacti ons ar e the most common and ser i ous adver se
r eacti ons associ ated wi th phenothi az i nes.
Extrapyramidal symptoms
Extrapyrami dal symptoms (EPS) may appear after the fi r st few
days of therapy; tar di ve dyski nesi a may occur after several year s
of tr eatment.
S.O.S.! Extreme EPS!
Neur ol epti c mal i gnant syndr ome i s a potenti al l y fatal condi ti on
that pr oduces muscl e r i gi di ty, extr eme EPS, sever el y el evated
body temperatur e, hyper tensi on, and rapi d hear t rate. If l eft
untr eated, i t can r esul t i n r espi rator y fai l ur e and car di ovascul ar
col l apse.
Little difference
Most nonphenothi az i nes cause the same adver se r eacti ons as
phenothi az i nes.
Special caution
Anti psychoti cs wi th anti chol i ner gi c pr oper ti es shoul d be avoi ded
i n el der l y pati ents.

Fewer interactions
Nonphenothi az i nes i nteract wi th fewer dr ugs than phenothi az i nes.
Thei r dopami ne-bl ocki ng acti vi ty can i nhi bi t l evodopa and may
cause di sor i entati on i n pati ents r ecei vi ng both medi cati ons. Hal o-
per i dol may boost the effects of l i thi um, pr oduci ng encephal opathy
(brai n dysfuncti on).

Stimulants
Sti mul ants ar e used to tr eat attenti on defi ci t hyperacti vi ty di sor der
(ADHD), a condi ti on character i zed by i nattenti on, i mpul si vi ty, and
hyperacti vi ty. They i ncl ude:

dextr oamphetami ne
l i sdexamfetami ne
methyl pheni date
mi xed amphetami ne sal ts
modafi ni l .
Pharmacokinetics
Sti mul ants ar e wel l absor bed fr om the G I tract and ar e di str i buted
wi del y i n the body. Methyl pheni date under goes si gni fi cant fi r st pass
effect.

Metabolism and excretion

Sti mul ants ar e metabol i zed i n the l i ver and excr eted pr i mar i l y i n
ur i ne.

Pharmacodynamics
These dr ugs ar e bel i eved to wor k by i ncr easi ng l evel s of dopa-mi ne
and nor epi nephr i ne i n one of thr ee ways: by bl ocki ng the r euptake
of dopami ne and nor epi nephr i ne, by enhanci ng the pr esynapti c
r el ease, or by i nhi bi ti ng MAO.

Pharmacotherapeutics
Sti mul ants ar e the tr eatment of choi ce for ADHD. Theyr e hel pful i n
i mpr ovi ng attenti on, l eadi ng to i mpr oved school or wor k
per for mance, and decr easi ng i mpul si vi ty and hyperacti vi ty, i f
pr esent. Pemol i ne, however, i s no l onger a fi r st l i ne choi ce for
tr eatment of ADHD because i t can cause hepatotoxi ci ty.
Dextr oamphetami ne and methyl pheni date ar e al so used i n the
tr eatment of nar col epsy.
 Warning!
Adverse reactions to stimulants
Adver se r eacti ons to sti mul ants ar e l i sted bel ow.
Dextroamphetamine and lisdexamfetamine

Restl essness
Tr emor
Insomni a
Tachycar di a
Pal pi tati ons
Ar r hythmi as
Dr y mouth
Unpl easant taste
Di ar r hea

Methylphenidate

Di z z i ness
Insomni a
Sei z ur es
Pal pi tati ons
Ar r hythmi as
Abdomi nal pai n
Rash
Thr ombocytopeni a

Mixed amphetamine salts

Restl essness
Insomni a
Hyper exci tabi l i ty
Pal pi tati ons
Ar r hythmi as
Tr emor
Abdomi nal pai n
 Dr y mouth
Unpl easant taste

Measure up
Sti mul ants may affect gr owth; chi l dr en shoul d be moni tor ed
cl osel y for hei ght and wei ght changes.
Take a holiday
Dr ug hol i days ar e r ecommended ever y year to assess the
conti nued need for a sti mul ant.

Drug interactions
Methyl pheni date may decr ease the effect of guanethi di ne and
may i ncr ease the effects of TCAs, war far i n, and some
anti convul sant dr ugs.
Sti mul ants shoul dnt be used wi thi n 14 days of di sconti nui ng
therapy wi th an MAOI.
Sti mul ants ar e hi ghl y abused substances, and cl ose moni tor i ng i s
r equi r ed. (See Adver se r eacti ons to sti mul ants.)

Quick quiz
1Whats the di ffer ence between a sedati ve and a
hypnoti c?
A. Sedati ves pr oduce physi cal dependence; hypnoti cs
dont.
B. Sedati ves r educe anxi ety or exci tement; hypnoti cs i nduce
sl eep.
C. Sedati ves r equi r e l ar ger doses than hypnoti cs to pr oduce
desi r ed effects.
D. Sedati ves i ncr ease anxi ety; hypnoti cs r educe anxi ety.

P.
2Wi th the use of the nonbenzodi azepi ne-nonbar bi turate chl oral
hydrate, what adver se r eacti ons ar e most l i kel y?
A. Sever e wi thdrawal symptoms
B. Hyper sensi ti vi ty r eacti ons
C. Car di ac adver se effects
 D. G I symptoms and hangover effects

3Whi ch medi cati on shoul d a pati ent tr eated wi th l i thi um avoi d?

A. Hor monal contracepti ves
B. Loop di ur eti cs
C. Oral anti di abeti c dr ugs
D. Anti hyper tensi ve dr ugs

Scoring
If you answer ed al l thr ee i tems cor r ectl y, extraor di nar y!
You defi ni tel y ar ent psyched out by phar macol ogy!

If you answer ed two i tems cor r ectl y, congratul ati ons!

Your knowl edge shoul d have you feel i ng el ated!

If you answer ed fewer than two i tems cor r ectl y, ther es

no need for anxi ety! By the end of the next chapter,
youl l pr obabl y have your head on strai ght!

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

13
Endocrine drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs that affect the endocr i ne system

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and the endocrine system

The endocr i ne system consi sts of glands, whi ch ar e speci al i zed cel l
cl uster s, and hor mones, the chemi cal transmi tter s secr eted by the
gl ands i n r esponse to sti mul ati on.

Keeping well balanced

Together wi th the central ner vous system, the endocr i ne system
r egul ates and i ntegrates the bodys metabol i c acti vi ti es and
mai ntai ns homeostasi s (the bodys i nter nal equi l i br i um). The dr ug
cl asses that tr eat endocr i ne system di sor der s i ncl ude:

natural hor mones and thei r syntheti c anal ogues

hor monel i ke substances
 dr ugs that sti mul ate or suppr ess hor mone secr eti on.

Antidiabetic drugs and glucagon

Insul i n, a pancr eati c hor mone, and oral anti di abeti c dr ugs ar e
cl assi fi ed as hypoglycemic dr ugs because they l ower bl ood gl ucose
l evel s. G l ucagon, another pancr eati c hor mone, i s cl assi fi ed as a
hyper glycemic dr ug because i t rai ses bl ood gl ucose l evel s.

Sugar surplus
Di abetes mel l i tus, or si mpl y di abetes, i s a chr oni c di sease of i nsul i n
defi ci ency or r esi stance. Its character i zed by di stur bances i n
car bohydrate, pr otei n, and fat metabol i sm. Thi s l eads to el evated
l evel s of the sugar gl ucose i n the body. The di sease appear s i n two
pr i mar y for ms:

type 1, pr evi ousl y r efer r ed to as i nsul i n-dependent di abetes

mel l i tus
type 2, pr evi ousl y r efer r ed to as non-i nsul i n-dependent
di abetes mel l i tus.

Insulin
Pati ents wi th type 1 di abetes r equi r e an exter nal sour ce of insulin to
contr ol bl ood gl ucose l evel s. Insul i n may al so be gi ven to pati ents
wi th type 2 di abetes.
Types of i nsul i n i ncl ude:
 rapi d-acti ng: l i spr o
shor t-acti ng: r egul ar
i nter medi ate-acti ng: NPH
l ong-acti ng: Ul tral ente.

Pharmacokinetics (how drugs circulate)

Insul i n i snt effecti ve when taken oral l y because the G I tract br eaks
down the pr otei n mol ecul e befor e i t r eaches the bl oodstr eam.

Under the skin

Al l i nsul i ns, however, may be gi ven by subcutaneous (subQ)
i njecti on. Absor pti on of subQ i nsul i n var i es accor di ng to the
i njecti on si te, the bl ood suppl y, and degr ee of ti ssue hyper tr ophy at
the i njecti on si te.

In the I.V. league

Regul ar i nsul i n may al so be gi ven by I.V. i nfusi on as wel l as i n
di al ysate fl ui d i nfused i nto the per i toneal cavi ty for pati ents on
per i toneal di al ysi s therapy.

Distribution, metabolism, and excretion

After absor pti on i nto the bl oodstr eam, i nsul i n i s di str i buted
thr oughout the body. Insul i n-r esponsi ve ti ssues ar e l ocated i n the
l i ver, adi pose ti ssue, and muscl e. Insul i n i s metabol i zed pr i mar i l y i n
the l i ver and to a l esser extent i n the ki dneys and muscl e, and i ts
excr eted i n stool and ur i ne.

Now I get it!

How insulin aids glucose uptake
These i l l ustrati ons show how i nsul i n al l ows a cel l to use
gl ucose for ener gy.
G l ucose cant enter the cel l wi thout the ai d of i nsul i n.
 Nor mal l y pr oduced by the beta cel l s of the pancr eas, i nsul i n
bi nds to the r eceptor s on the sur face of the tar get cel l . Insul i n
and i ts r eceptor fi r st move to the i nsi de of the cel l , whi ch
acti vates gl ucose transpor ter channel s to move to the sur face of
the cel l .

These channel s al l ow gl ucose to enter the cel l . The cel l can then
use the gl ucose for metabol i sm.

Pharmacodynamics (how drugs act)

Insul i n i s an anabol i c, or bui l di ng, hor mone that hel ps:
 pr omote storage of gl ucose as gl ycogen
i ncr ease pr otei n and fat synthesi s
sl ow the br eakdown of gl ycogen, pr otei n, and fat
bal ance fl ui ds and el ectr ol ytes.

Insulins special effects

Al though i t has no anti di ur eti c effect, i nsul i n can cor r ect the pol y-
ur i a (excessi ve ur i nati on) and pol ydi psi a (excessi ve thi r st)
associ ated wi th the osmoti c di ur esi s that occur s i n hyper gl ycemi a by
decr easi ng the bl ood gl ucose l evel . Insul i n al so faci l i tates the
movement of potassi um fr om the extracel l ul ar fl ui d i nto the cel l .
(See How i nsul i n ai ds gl ucose uptake.)

Pharmacotherapeutics (how drugs are used)

Insul i n i s i ndi cated for :

type 1 di abetes
type 2 di abetes when other methods of contr ol l i ng bl ood gl ucose
l evel s have fai l ed or ar e contrai ndi cated
type 2 di abetes when bl ood gl ucose l evel s ar e el evated dur i ng
per i ods of emoti onal or physi cal str ess (such as i nfecti on and
sur ger y)
type 2 di abetes when oral anti di abeti c dr ugs ar e contrai ndi cated
because of pr egnancy or hyper sensi ti vi ty
gestati onal di abetes.
When things get complicated
Insul i n i s al so used to tr eat two compl i cati ons of di abetes: di abeti c
ketoaci dosi s, mor e common wi th type 1 di abetes, and hyper osmol ar
hyper gl ycemi c nonketoti c syndr ome, whi ch i s mor e common wi th
type 2 di abetes.

What? But I dont have diabetes

Insul i n i s al so used to tr eat sever e hyper kal emi a (el evated ser um
potassi um l evel s) i n pati ents wi thout di abetes. Potassi um moves
wi th gl ucose fr om the bl oodstr eam i nto the cel l , l ower i ng ser um
potassi um l evel s.

Drug interactions
Some dr ugs i nteract wi th i nsul i n, al ter i ng i ts abi l i ty to decr ease the
bl ood gl ucose l evel ; other dr ugs di r ectl y affect gl ucose l evel s:

Anabol i c ster oi ds, sal i cyl ates, al cohol , and monoami ne oxi dase
i nhi bi tor s (MAOIs) may i ncr ease the hypogl ycemi c effect of
i nsul i n.
Cor ti coster oi ds, sympathomi meti c dr ugs, thi az i de di ur eti cs, and
dextr othyr oxi ne sodi um may r educe the effects of i nsul i n,
r esul ti ng i n hyper gl ycemi a.
Beta-adr ener gi c bl ocker s may pr ol ong the hypogl ycemi c effect of
i nsul i n and may mask si gns and symptoms of hypogl ycemi a. (See
Adver se r eacti ons to i nsul i n.)

Warning!
Adverse reactions to insulin
Adver se r eacti ons to i nsul i n i ncl ude:

hypogl ycemi a (bel ow-nor mal bl ood gl ucose l evel s)

Somogyi effect (hypogl ycemi a fol l owed by r ebound
hyper gl ycemi a)
hyper sensi ti vi ty r eacti ons
l i podystr ophy (di stur bance i n fat deposi ti on)
i nsul i n r esi stance.
Oral antidiabetic drugs
Many types of or al antidiabetic dr ugs ar e appr oved for use i n the
Uni ted States. Types of avai l abl e oral anti di abeti c dr ugs i ncl ude:

fi r st-generati on sul fonyl ur eas, whi ch i ncl ude acetohexami de,

chl or pr opami de, tol az ami de, and tol butami de
second-generati on sul fonyl ur eas, whi ch i ncl ude gl i cl az i de,
gl i pi z i de, gl i mepi r i de, and gl ybur i de.

thi azol i di nedi ones, whi ch i ncl ude pi ogl i tazone and r osi gl i tazone
a bi guani de dr ug, metfor mi n
al pha-gl ucosi dase i nhi bi tor s, whi ch i ncl ude acar bose and mi gl i tol
a megl i ti ni de dr ug, r epagl i ni de
an ami no aci d der i vati ve, nategl i ni de
combi nati on therapi es, whi ch i ncl ude gl i pi z i de and metfor mi n,
gl ybur i de and metfor mi n, and r osi gl i tazone and metfor mi n.

Pharmacokinetics
Oral anti di abeti c dr ugs ar e wel l absor bed fr om the G I tract and
di str i buted vi a the bl oodstr eam thr oughout the body. Because
r epagl i ni de has a shor t durati on of acti on, i ts gi ven befor e meal s.

Metabolism and excretion

Oral anti di abeti c dr ugs ar e metabol i zed pr i mar i l y i n the l i ver and
ar e excr eted mostl y i n ur i ne, wi th some excr eted i n bi l e. G l ybur i de
i s excr eted equal l y i n ur i ne and stool ; r osi gl i tazone and
pi ogl i tazone ar e l ar gel y excr eted i n both.

Pharmacodynamics
Its bel i eved that oral anti di abeti c dr ugs pr oduce acti ons both wi thi n
and outsi de the pancr eas (extrapancr eati c) to r egul ate bl ood
gl ucose.

Pancreas partners
Oral anti di abeti c dr ugs pr obabl y sti mul ate pancr eati c beta cel l s to
r el ease i nsul i n i n a pati ent wi th a mi ni mal l y functi oni ng pancr eas.
Wi thi n a few weeks to a few months of star ti ng sul fonyl ur eas,
pancr eati c i nsul i n secr eti on dr ops to pr etr eatment l evel s, but bl ood
gl ucose l evel s r emai n nor mal or near-nor mal . Most l i kel y, i ts the
acti ons of the oral anti di abeti c agents outsi de of the pancr eas that
mai ntai n thi s gl ucose contr ol .

Working beyond the pancreas

Oral anti di abeti c dr ugs pr ovi de several extrapancr eati c acti ons to
decr ease and contr ol bl ood gl ucose. They can go to wor k i n the l i ver
and decr ease gl ucose pr oducti on (gl uconeogenesi s) ther e. Al so, by
i ncr easi ng the number of i nsul i n r eceptor s i n the per i pheral ti ssues,
they pr ovi de mor e oppor tuni ti es for the cel l s to bi nd suffi ci entl y
wi th i nsul i n, i ni ti ati ng the pr ocess of gl ucose metabol i sm.

Getting in on the action

Other oral anti di abeti c agents pr oduce speci fi c acti ons:

Pi ogl i tazone and r osi gl i tazone i mpr ove i nsul i n sensi ti vi ty and
l ower gl ucose pr oducti on by the l i ver.
Metfor mi n decr eases l i ver pr oducti on and i ntesti nal absor pti on of
gl ucose and i mpr oves i nsul i n sensi ti vi ty.
 Acar bose and mi gl i tol i nhi bi t enz ymes, del ayi ng gl ucose
absor pti on.
Repagl i ni de and nategl i ni de i ncr ease i nsul i n secr eti on.

Pharmacotherapeutics
Oral anti di abeti c dr ugs ar e i ndi cated for pati ents wi th type 2
di abetes i f di et and exer ci se cant contr ol bl ood gl ucose l evel s.
These dr ugs ar ent effecti ve i n pati ents wi th type 1 di abetes
because the pati ents pancr eati c beta cel l s ar ent functi oni ng at a
mi ni mal l evel .

The old 1-2 punch

Combi nati ons of mul ti pl e oral anti di abeti c dr ugs or an oral
anti di abeti c dr ug wi th i nsul i n therapy may be i ndi cated for some
pati ents who dont r espond to ei ther therapy al one. (See Cauti onar y
tal es.)

Drug interactions
Hypogl ycemi a and hyper gl ycemi a ar e the mai n r i sks when oral
anti di abeti c dr ugs i nteract wi th other dr ugs.

Getting too low

Hypogl ycemi a may occur when sul fonyl ur eas ar e combi ned wi th
al cohol , anabol i c ster oi ds, chl orampheni col , ci meti di ne, cl ofi brate,
coumadi n, fl uconazol e, gemfi br oz i l , MAOIs, phenyl butazone,
rani ti di ne, sal i cyl ates, or sul fonami des. It may al so occur when
metfor mi n i s combi ned wi th ci meti di ne, ni fedi pi ne, pr ocai nami de,
rani ti di ne, or vancomyci n. Hypogl ycemi a i s l ess l i kel y to occur when
metfor mi n i s used as a si ngl e agent.

Safe and sound

Cautionary tales
To mai ntai n bl ood gl ucose l evel s as cl ose to nor mal as
possi bl e, pr egnant women shoul d avoi d oral anti di abeti c agents.
Insul i n therapy i s r ecommended i nstead.
Because agi ng i s commonl y associ ated wi th a decl i ne i n ki dney
functi on, and because the ki dneys substanti al l y excr ete
metfor mi n, metfor mi n shoul d be used wi th cauti on i n el der l y
pati ents. Pati ents wi th r enal and hepati c i mpai r ment shoul d al so
avoi d metfor mi n.

Going too high

Hyper gl ycemi a may occur when sul fonyl ur eas ar e taken wi th
cor ti coster oi ds, dextr othyr oxi ne, r i fampi n, sympathomi meti cs, and
thi az i de di ur eti cs.
Because metfor mi n gi ven wi th i odi nated contrast dyes can cause
acute r enal fai l ur e, metfor mi n doses shoul d be wi thhel d i n pati ents
under goi ng pr ocedur es that r equi r e I.V. contrast dye and

not r estar ted for at l east 48 hour s after the pr ocedur e. (See
Adver se r eacti ons to oral anti di abeti c dr ugs.)

Glucagon
G lucagon, a hyper gl ycemi c dr ug that rai ses bl ood gl ucose l evel s, i s
a hor mone nor mal l y pr oduced by the al pha cel l s of the i sl ets of
Langer hans i n the pancr eas. (See How gl ucagon rai ses gl ucose
l evel s, page 346.)

Pharmacokinetics
After subQ, I.M., or I.V. i njecti on, gl ucagon i s absor bed rapi dl y.
G l ucagon i s di str i buted thr oughout the body, al though i ts effect
occur s pr i mar i l y i n the l i ver.

Metabolism and excretion

G l ucagon i s degraded extensi vel y by the l i ver, ki dneys, and pl asma,
and at i ts ti ssue r eceptor si tes i n pl asma membranes. Its r emoved
fr om the body by the l i ver and the ki dneys.

Pharmacodynamics
G l ucagon r egul ates the rate of gl ucose pr oducti on thr ough:

gl ycogenol ysi s, the conver si on of gl ycogen back i nto gl ucose by

the l i ver
gl uconeogenesi s, the for mati on of gl ucose fr om fr ee fatty aci ds
and pr otei ns
l i pol ysi s, the r el ease of fatty aci ds fr om adi pose ti ssue for
conver si on to gl ucose.

Pharmacotherapeutics
G l ucagon i s used for emer gency tr eatment of sever e hypogl ycemi a.
Its al so used dur i ng radi ol ogi c exami nati on of the G I tract to
r educe G I moti l i ty.

Drug interactions
G l ucagon i nteracts adver sel y onl y wi th oral anti coagul ants,
i ncr easi ng the tendency to bl eed. Adver se r eacti ons to gl ucagon ar e
rar e.

Warning!
Adverse reactions to oral antidiabetic drugs
Hypogl ycemi a i s a major adver se r eacti on to oral
anti di abeti c dr ugs, especi al l y when combi nati on therapy i s used.
Her e ar e some common adver se r eacti ons to i ndi vi dual oral
anti di abeti c dr ugs.
Sulfonylureas

nausea
epi gastr i c ful l ness
bl ood abnor mal i ti es
water r etenti on
rash
hyponatr emi a
 photosensi ti vi ty

Metformin

metal l i c taste
nausea and vomi ti ng
abdomi nal di scomfor t

Acarbose

abdomi nal pai n

di ar r hea
F l atul ence

Thiazolidinediones

Wei ght gai n

Swel l i ng

Now I get it!

How glucagon raises glucose levels
When adequate stor es of gl ycogen ar e pr esent, gl ucagon
can rai se gl ucose l evel s i n pati ents wi th sever e hypogl ycemi a.
What happens i s easy to fol l ow:

Ini ti al l y, gl ucagon sti mul ates the for mati on of adenyl ate
cycl ase i n the l i ver cel l .
Adenyl ate cycl ase then conver ts adenosi ne tr i phosphate (ATP)
to cycl i c adenosi ne monophosphate (cAMP).
Thi s pr oduct i ni ti ates a ser i es of r eacti ons that r esul t i n an
acti ve phosphor yl ated gl ucose mol ecul e.
In thi s phosphor yl ated for m, the l ar ge gl ucose mol ecul e cant
pass thr ough the cel l membrane.
Thr ough gl ycogenol ysi s (the br eakdown of gl ycogen, the
stor ed for m of gl ucose), the l i ver r emoves the phosphate
gr oup and al l ows the gl ucose to enter the bl oodstr eam, rai si ng
bl ood gl ucose l evel s for shor t-ter m ener gy needs.
Estrogens
Estr ogens mi mi c the physi ol ogi c effects of natural l y occur r i ng
femal e sex hor mones.

To serve and protect

Estr ogens ar e used to cor r ect estr ogen-defi ci ent states and, al ong
wi th hor monal contracepti ves, pr event pr egnancy.

Natural and synthetic estrogen

Estr ogens that tr eat endocr i ne system di sor der s i ncl ude:

natural pr oducts, such as conjugated estr ogeni c substances,

estradi ol , and estr opi pate
syntheti c estr ogens, such as ester i fi ed estr ogens, estradi ol
cypi onate, estradi ol val erate, and ethi nyl estradi ol .
Pharmacokinetics
Estr ogens ar e wel l absor bed and di str i buted thr oughout the body.
Metabol i sm occur s i n the l i ver, and the metabol i tes ar e excr eted
pr i mar i l y by the ki dneys.

Pharmacodynamics
The exact mechani sm of acti on of estr ogen i snt cl ear l y under stood,
but i ts bel i eved to i ncr ease synthesi s of deoxyr i bonucl ei c aci d,
r i bonucl ei c aci d, and pr otei n i n estr ogen-r esponsi ve ti ssues i n the
femal e br east, ur i nar y tract, and geni tal or gans.

Pharmacotherapeutics
Estr ogens ar e pr escr i bed:

pr i mar i l y for hor mone r epl acement therapy i n postmenopausal

women to r el i eve symptoms caused by l oss of ovar i an functi on
(see Hor mone r epl acement therapy and hear t di sease, page 348)
l ess commonl y for hor monal r epl acement therapy i n women wi th
pr i mar y ovar i an fai l ur e or femal e hypogonadi sm (r educed
hor monal secr eti on by the ovar i es), for pr eventi on and
tr eatment of osteopor osi s i n postmenopausal women, and i n
pati ents who have under gone sur gi cal castrati on
pal l i ati vel y to tr eat advanced, i noperabl e br east cancer i n
postmenopausal women and pr ostate cancer i n men.
 Yea or nay?
Hormone replacement therapy and heart disease
Fol l owi ng a 5-year study, the Womens Heal th Ini ti ati ve
r epor ted i ncr eased r i sks of myocar di al i nfar cti on, str oke, br east
cancer, pul monar y embol i , and deep vei n thr ombosi s i n women
bei ng tr eated wi th conjugated equi ne estr ogens and pr ogester one
as compar ed to those taki ng a pl acebo.
The U.S. Pr eventi ve Ser vi ces Task For ce r ecommends agai nst the
use of estr ogen and pr o-gesti n to pr event cor onar y hear t di sease
i n heal thy women.
What to do?
Because the l ong-ter m safety of shor t-ter m therapy has yet to be
deter mi ned, the Food and Dr ug Admi ni strati on and Amer i can
Col l ege of Obstetr i ci ans and G ynecol ogi sts r ecommend that
women who choose to take hor mone r epl acement therapy for
menopausal symptoms use these dr ugs for the shor test durati on
possi bl e and i n the l owest possi bl e dosages.

Warning!
Adverse reactions to estrogens
Adver se r eacti ons to estr ogens i ncl ude:

hyper tensi on
thr omboembol i sm (bl ood vessel bl ockage caused by a bl ood
cl ot)
thr ombophl ebi ti s (vei n i nfl ammati on associ ated wi th cl ot
for mati on).

Drug interactions
Rel ati vel y few dr ugs i nteract wi th estr ogens:

Estr ogens may decr ease the effects of anti coagul ants, i ncr easi ng
the r i sk of bl ood cl ots.
Anti bi oti cs, bar bi turates, car bamazepi ne, phenytoi n, pr i mi done,
and r i fampi n r educe estr ogen effecti veness.
Estr ogens i nter fer e wi th the absor pti on of di etar y fol i c aci d,
 whi ch may r esul t i n a fol i c aci d defi ci ency. (See Adver se
r eacti ons to estr ogens.)

Pituitary drugs
Pituitar y dr ugs ar e natural or syntheti c hor mones that mi mi c the
hor mones pr oduced by the pi tui tar y gl and. The pi tui tar y dr ugs
consi st of two gr oups:

Anter i or pi tui tar y dr ugs may be used di agnosti cal l y or

therapeuti cal l y to contr ol the functi on of other endocr i ne gl ands,
such as the thyr oi d gl and, adr enal s, ovar i es, and testes.
Poster i or pi tui tar y dr ugs may be used to r egul ate fl ui d vol ume
and sti mul ate smooth-muscl e contracti on i n sel ected cl i ni cal
si tuati ons.

Anterior pituitary drugs

The pr otei n hor mones pr oduced i n the anter i or pi tui tar y gl and
r egul ate gr owth, devel opment, and sexual character i sti cs by
sti mul ati ng the acti ons of other endocr i ne gl ands. Anter ior pituitar y
dr ugs i ncl ude:

adr enocor ti cotr opi cs, whi ch i ncl ude cor ti cotr opi n, cor ti cotr opi n
r eposi tor y, cor ti cotr opi n z i nc hydr oxi de, and cosyntr opi n
somatr em and somatr opi n, gr owth hor mones
 gonadotr opi cs, whi ch i ncl ude chor i oni c gonadotr opi n and
menotr opi ns
thyr otr opi cs, whi ch i ncl ude thyr oi d-sti mul ati ng hor mone,
thyr otr opi n, and pr oti r el i n.

Pharmacokinetics
Anter i or pi tui tar y dr ugs ar ent gi ven oral l y because theyr e
destr oyed i n the G I tract. Some of these hor mones can be
admi ni ster ed topi cal l y, but most r equi r e i njecti on.

Absorption, distribution, and metabolism

Usual l y, natural hor mones ar e absor bed, di str i buted, and
metabol i zed rapi dl y. Some anal ogues, however, ar e absor bed and
metabol i zed mor e sl owl y. Anter i or pi tui tar y hor mone dr ugs ar e
metabol i zed at the r eceptor si te and i n the l i ver and ki dneys. The
hor mones ar e excr eted pr i mar i l y i n ur i ne.

Pharmacodynamics
Anter i or pi tui tar y dr ugs exer t a pr ofound effect on the bodys
gr owth and devel opment. The hypothal amus contr ol s secr eti ons of
the pi tui tar y gl and. In tur n, the pi tui tar y gl and secr etes hor mones
that r egul ate secr eti ons or functi ons of other gl ands.

Concentrate on this formula

The concentrati on of hor mones i n the bl ood hel ps deter mi ne
hor mone pr oducti on rate. Incr eased hor mone l evel s i nhi bi t hor mone
pr oducti on; decr eased l evel s rai se pr oducti on and secr eti on.

Pharmacotherapeutics
Anter i or pi tui tar y hor mone dr ugs ar e used for di agnosti c and
therapeuti c pur poses:

Cor ti cotr opi n and cosyntr opi n ar e used di agnosti cal l y to

di ffer enti ate between pr i mar y and secondar y fai l ur e of the
adr enal cor tex.
Cor ti cotr opi n i s al so used to tr eat adr enal i nsuffi ci ency.
Somatr em i s used to tr eat gr owth hor mone defi ci ency.

Drug interactions
Anter i or pi tui tar y dr ugs i nteract wi th several types of dr ugs:

Admi ni ster i ng i mmuni z ati ons to a per son r ecei vi ng cor ti cotr opi n
i ncr eases the r i sk of neur ol ogi c compl i cati ons and may r educe
the anti body r esponse.
Cor ti cotr opi n r educes sal i cyl ate l evel s.
Enhanced potassi um l oss may occur when di ur eti cs ar e taken
wi th cor ti cotr opi ns.
Bar bi turates, phenytoi n, and r i fampi n i ncr ease the metabol i sm
of cor ti cotr opi n, r educi ng i ts effects.

Estrogen effects
Estr ogen i ncr eases the effect of cor ti cotr opi n.
Taki ng estr ogens, amphetami nes, and l i thi um wi th cosyntr opi n
can al ter r esul ts of adr enal functi on tests.
Concur r ent use of amphetami nes and andr ogens wi th somatr em
may pr omote epi physeal cl osur e (cl osur e of the car ti l agi nous
bone gr owth pl ate).
Concur r ent use of somatr em and cor ti coster oi ds i nhi bi ts the
gr owth-pr omoti ng acti on of somatr em. (See Adver se r eacti ons to
 anter i or pi tui tar y dr ugs.)

Warning!
Adverse reactions to anterior pituitary drugs
The major adver se r eacti ons to pi tui tar y dr ugs ar e
hyper sensi ti vi ty r eacti ons.
Over the long haul
Long-ter m use of cor ti cotr opi n can cause Cushi ngs syndr ome.

Posterior pituitary drugs

Poster ior pituitar y hor mones ar e synthesi zed i n the hypothal amus
and stor ed i n the poster i or pi tui tar y, whi ch, i n tur n, secr etes the
hor mones i nto the bl ood. These dr ugs i ncl ude:

al l for ms of anti di ur eti c hor mone (ADH), such as desmopr essi n

acetate and vasopr essi n
the oxytoci c dr ug oxytoci n.

Pharmacokinetics
Because enz ymes i n the G I tract can destr oy al l pr otei n hor mones,
these dr ugs cant be gi ven oral l y. Poster i or pi tui tar y dr ugs may be
gi ven by i njecti on or i ntranasal spray.

Absorption, distribution, and metabolism

Li ke other natural hor mones, oxytoci c dr ugs ar e usual l y absor bed,
di str i buted, and metabol i zed rapi dl y. Par enteral l y admi ni ster ed
oxytoci n i s absor bed rapi dl y; however, when i ts admi ni ster ed
i ntranasal l y, absor pti on i s er rati c.
Pharmacodynamics
Under neural contr ol , poster i or pi tui tar y hor mones affect:

smooth-muscl e contracti on i n the uter us, bl adder, and G I tract

fl ui d bal ance thr ough ki dney r eabsor pti on of water
bl ood pr essur e thr ough sti mul ati on of the ar ter i al wal l muscl es.

Going to cAMP
ADH i ncr eases cycl i c adenosi ne monophosphate (cAMP), whi ch
i ncr eases the per meabi l i ty of the tubul ar epi thel i um i n the ki dneys,
pr omoti ng r eabsor pti on of water. Hi gh dosages of ADH sti mul ate
contracti on of bl ood vessel s, i ncr easi ng the bl ood pr essur e.
Desmopr essi n r educes di ur esi s and pr omotes cl otti ng by i ncr easi ng
the pl asma l evel of factor VIII (anti hemophi l i c factor ).

Baby talk
In pr egnant women, oxytoci n may sti mul ate uter i ne contracti ons by
i ncr easi ng the per meabi l i ty of uter i ne cel l membranes to sodi um
i ons. It al so can sti mul ate l actati on thr ough i ts effect on mammar y
gl ands.
Pharmacotherapeutics
ADH i s pr escr i bed for hor mone r epl acement therapy i n pati ents wi th
neur ogeni c di abetes i nsi pi dus (an excessi ve l oss of ur i ne caused by
a brai n l esi on or i njur y that i nter fer es wi th ADH synthesi s or
r el ease). However, i t doesnt effecti vel y tr eat nephr ogeni c di abetes
i nsi pi dus (caused by r enal tubul ar r esi stance to ADH).

The ABCs of ADH treatment

Desmopr essi n i s the dr ug of choi ce for chr oni c ADH defi ci ency and i s
admi ni ster ed i ntranasal l y. Its al so i ndi cated for pr i mar y noctur nal
enur esi s. Desmopr essi n has a l ong durati on of acti on and r el ati vel y
few adver se effects.
Shor t-ter m ADH tr eatment i s i ndi cated for pati ents wi th transi ent
di abetes i nsi pi dus after head i njur y or sur ger y; therapy may be
l i fel ong for pati ents wi th i di opathi c hor mone defi ci enci es. Used for
shor t-ter m therapy, vasopr essi n el evates bl ood pr essur e i n pati ents
wi th hypotensi on caused by l ack of vascul ar tone. It al so r el i eves
postoperati ve gaseous di stenti on.

They help with deliveries (before, during,

and after)
Oxytoci cs ar e used to:

i nduce l abor and compl ete i ncompl ete abor ti ons

tr eat pr eecl ampsi a, ecl ampsi a, and pr ematur e r uptur e of
membranes
 contr ol bl eedi ng and uter i ne r el axati on after del i ver y
hasten uter i ne shr i nki ng after del i ver y
sti mul ate l actati on.

Warning!
Adverse reactions to posterior pituitary drugs
Hyper sensi ti vi ty r eacti ons ar e the most common adver se
r eacti ons to poster i or pi tui tar y dr ugs.
Natural ADH
Anaphyl axi s may occur after i njecti on. Natural anti di ur eti c
hor mone (ADH) can al so cause:

r i ngi ng i n the ear s

anxi ety
hyponatr emi a (l ow ser um sodi um l evel s)
pr otei ns i n ur i ne
ecl ampti c attacks
pupi l di l ati on
transi ent edema.

Synthetic ADH
Adver se r eacti ons to syntheti c ADH ar e rar e.

Drug interactions
A var i ety of dr ugs can cause i nteracti ons wi th poster i or pi tui tar y
dr ugs:

Al cohol , demecl ocycl i ne, epi nephr i ne, and l i thi um may decr ease
the ADH acti vi ty of desmopr essi n and vasopr essi n.
Chl or pr opami de, cl ofi brate, car bamazepi ne, and
cycl ophosphami de i ncr ease ADH acti vi ty.
Syner gi sti c effects may occur when bar bi turates or cycl opr opane
anestheti cs ar e used concur r entl y wi th ADH, l eadi ng to cor onar y
i nsuffi ci ency or ar r hythmi as.
Cycl ophosphami de may i ncr ease the effect of oxytoci n.
 Concur r ent use of vasopr essor s (anestheti cs, ephedr i ne,
methoxami ne) and oxytoci n i ncr eases the r i sk of hyper tensi ve
cr i si s and postpar tum r uptur e of cer ebral bl ood vessel s. (See
Adver se r eacti ons to poster i or pi tui tar y dr ugs.)

Thyroid and antithyroid drugs

Thyr oid and antithyr oid dr ugs functi on to cor r ect thyr oi d hor mone
defi ci ency (hypothyr oi di sm) and thyr oi d hor mone excess
(hyper thyr oi di sm).

Thyroid drugs
Thyr oid dr ugs can be natural or syntheti c hor mones and may
contai n tr i i odothyr oni ne (T3 ), thyr oxi ne (T4 ), or both.

All natural
Natural thyr oi d dr ugs ar e made fr om ani mal thyr oi d and i ncl ude:

thyr oi d USP (desi ccated), whi ch contai ns both T3 and T4

thyr ogl obul i n, whi ch al so contai ns both T3 and T4 .

Man-made
Syntheti c thyr oi d dr ugs ar e actual l y the sodi um sal ts of the L-
i somer s of the hor mones. These syntheti c hor mones i ncl ude:

l evothyr oxi ne sodi um, whi ch contai ns T4

l i othyr oni ne sodi um, whi ch contai ns T3
l i otr i x, whi ch contai ns both T3 and T4 .

Pharmacokinetics
Thyr oi d hor mones ar e absor bed var i abl y fr om the G I tract,
di str i buted i n pl asma, and bound to ser um pr otei ns.

Metabolism and excretion

Thyr oi d dr ugs ar e metabol i zed thr ough dei odi nati on, pr i mar i l y i n
the l i ver, and excr eted unchanged i n stool .

Pharmacodynamics
The pr i nci pal phar macol ogi c effect i s an i ncr eased metabol i c rate i n
body ti ssues. Thyr oi d hor mones affect pr otei n and car bohydrate
metabol i sm and sti mul ate pr otei n synthesi s. They pr omote
gl uconeogenesi s (the for mati on of gl ucose fr om fr ee fatty aci ds and
pr otei ns) and i ncr ease the use of gl ycogen stor es.

They get the heart pumping

Thyr oi d hor mones i ncr ease hear t rate and car di ac output (the
amount of bl ood pumped by the hear t each mi nute). They may even
i ncr ease the hear ts sensi ti vi ty to catechol ami nes and i ncr ease the
number of beta-adr ener gi c r eceptor s i n the hear t (sti mul ati on of
beta r eceptor s i n the hear t i ncr eases hear t rate and contracti l i ty).

and the blood flowing

Thyr oi d hor mones may i ncr ease bl ood fl ow to the ki dneys and
i ncr ease the gl omer ul ar fi l trati on rate (the amount of pl asma
fi l ter ed thr ough the ki dney each mi nute) i n hypothyr oi d pati ents,
pr oduci ng di ur esi s.
Pharmacotherapeutics
Thyr oi d dr ugs act as r epl acement or substi tute hor mones i n these
si tuati ons:

to tr eat the many for ms of hypothyr oi di sm

wi th anti thyr oi d dr ugs to pr event goi ter for mati on (an enl ar ged
thyr oi d gl and) and hypothyr oi di sm
to di ffer enti ate between pr i mar y and secondar y hypothyr oi di sm
dur i ng di agnosti c testi ng
to tr eat papi l l ar y or fol l i cul ar thyr oi d car ci noma.

Warning!
Adverse reactions to thyroid drugs
Most adver se r eacti ons to thyr oi d dr ugs r esul t fr om toxi ci ty.
GI impact
Adver se r eacti ons i n the G I system i ncl ude:

di ar r hea
abdomi nal cramps
wei ght l oss
i ncr eased appeti te.

Heart of the matter

 Adver se r eacti ons i n the car di ovascul ar system i ncl ude:

pal pi tati ons

sweati ng
rapi d hear t rate
i ncr eased bl ood pr essur e
angi na
ar r hythmi as.

Toxic topics
G eneral mani festati ons of toxi c doses i ncl ude:

headache
tr emor
i nsomni a
ner vousness
fever
heat i ntol erance
menstr ual i r r egul ar i ti es.

The drug of choice

Levothyr oxi ne i s the dr ug of choi ce for thyr oi d hor mone
r epl acement and thyr oi d-sti mul ati ng hor mone suppr essi on therapy.

Drug interactions
Thyr oi d dr ugs i nteract wi th several common medi cati ons. (See
Adver se r eacti ons to thyr oi d dr ugs.)

They i ncr ease the effects of oral anti coagul ants, i ncr easi ng the
tendency to bl eed.
Chol estyrami ne and col esti pol r educe the absor pti on of thyr oi d
hor mones.
Phenytoi n may di spl ace thyr oxi ne fr om pl asma-bi ndi ng si tes,
temporar i l y i ncr easi ng l evel s of fr ee thyr oxi ne.
Taki ng thyr oi d dr ugs wi th di goxi n may r educe ser um di goxi n
l evel s, i ncr easi ng the r i sk of ar r hythmi as or hear t fai l ur e.
 Car bamazepi ne, phenytoi n, phenobar bi tal , and r i fampi n i ncr ease
metabol i sm of thyr oi d hor mones, r educi ng thei r effecti veness.
Ser um theophyl l i ne l evel s may i ncr ease when theophyl l i ne i s
admi ni ster ed wi th thyr oi d dr ugs.

Antithyroid drugs
A number of dr ugs act as antithyr oid dr ugs, or thyr oid antagonists.
Used for pati ents wi th hyper thyr oi di sm (thyr otoxi cosi s), these dr ugs
i ncl ude:

thi oami des, whi ch i ncl ude pr opyl thi ouraci l and methi mazol e
i odi des, whi ch i ncl ude stabl e i odi ne and radi oacti ve i odi ne.

Pharmacokinetics
Thi oami des and i odi des ar e absor bed thr ough the G I tract,
concentrated i n the thyr oi d, metabol i zed by conjugati on, and
excr eted i n ur i ne.

Pharmacodynamics
Dr ugs used to tr eat hyper thyr oi di sm wor k i n di ffer ent ways.

The antithesis to synthesis

Thi oami des bl ock i odi nes abi l i ty to combi ne wi th tyr osi ne, ther eby
pr eventi ng thyr oi d hor mone synthesi s.

In Wolff (-Chaikoff)s clothing

Stabl e i odi ne i nhi bi ts hor mone synthesi s thr ough the Wol ff-Chai koff
effect, i n whi ch excess i odi ne decr eases the for mati on and r el ease
of thyr oi d hor mone.

Warning: Radioactive material

Radi oacti ve i odi ne r educes hor mone secr eti on by destr oyi ng thyr oi d
ti ssue thr ough i nducti on of acute radi ati on thyr oi di ti s (i nfl ammati on
of the thyr oi d gl and) and chr oni c gradual thyr oi d atr ophy. Acute
radi ati on thyr oi di ti s usual l y occur s 3 to 10 days after admi ni ster i ng
radi oacti ve i odi ne. Chr oni c thyr oi d atr ophy may take several year s
to appear.

Pharmacotherapeutics
Anti thyr oi d dr ugs ar e commonl y used to tr eat hyper thyr oi di sm,
especi al l y i n the for m of G raves di sease (hyper thyr oi di sm caused
by autoi mmuni ty), whi ch accounts for 85% of al l cases.

In case of removal
To tr eat hyper thyr oi di sm, the thyr oi d gl and may be r emoved by
sur ger y or destr oyed by radi ati on. Befor e sur ger y, stabl e i odi ne i s

used to pr epar e the gl and for sur gi cal r emoval by fi r mi ng i t and

decr easi ng i ts vascul ar i ty.
Stabl e i odi ne i s al so used after radi oacti ve i odi ne therapy to contr ol
symptoms of hyper thyr oi di sm whi l e the radi ati on takes effect.

If it gets too severe

Pr opyl thi ouraci l , whi ch l ower s ser um T3 l evel s faster than
methi mazol e, i s usual l y used for rapi d i mpr ovement of sever e
hyper thyr oi di sm.

When taking them for two

Pr opyl thi ouraci l i s pr efer r ed over methi mazol e i n pr egnant women
because i ts rapi d acti on r educes transfer acr oss the pl acental
bar r i er and i t doesnt cause apl asi a cuti s (a sever e ski n di sor der ) i n
the fetus.
Pr opyl thi ouraci l and methi mazol e appear i n br east mi l k, so i ts
r ecommended that mother s taki ng these dr ugs shoul dnt br east-
feed. If a br east-feedi ng woman must take one of these dr ugs,
pr opyl thi ouraci l i s the pr efer r ed dr ug.

One a day keeps the trouble away

Because methi mazol e bl ocks thyr oi d hor mone for mati on for a l onger
ti me, i ts better sui ted for admi ni strati on once per day to pati ents
wi th mi l d to moderate hyper thyr oi di sm. Therapy may conti nue for
12 to 24 months befor e r emi ssi on occur s.

Drug interactions
Iodi de pr eparati ons may r eact syner gi sti cal l y wi th l i thi um, causi ng
hypothyr oi di sm. Other i nteracti ons ar ent cl i ni cal l y si gni fi cant. (See
Adver se r eacti ons to anti thyr oi d dr ugs.)

Warning!
Adverse reactions to antithyroid drugs
The most ser i ous adver se r eacti on to thi oami de therapy i s
granul ocytopeni a. Hyper sensi ti vi ty r eacti ons may al so occur.
In bad taste
The i odi des can cause an unpl easant brassy taste and bur ni ng
sensati on i n the mouth, i ncr eased sal i vati on, and pai nful swel l i ng
of the par oti d gl ands.
Too sensitive
Rar el y, I.V. i odi ne admi ni strati on can cause an acute
hyper sensi ti vi ty r eacti on. Radi oacti ve i odi ne al so can cause a
rar ebut acuter eacti on 3 to 14 days after admi ni strati on.

Quick quiz
1How does i nsul i n l ower the bl ood gl ucose l evel ?
A. It pr events gl ucose absor pti on fr om the G I tract.
B. It i ncr eases gl ucose excr eti on fr om the G I tract.
 C. It i ncr eases gl ucose absor pti on.
D. It pr omotes the transpor t of gl ucose i nto cel l s.

2Why cant gl ucagon be gi ven oral l y?

A. It wor ks too sl owl y when gi ven oral l y.
B. Its destr oyed by the G I tract.
C. Its absor bed unpr edi ctabl y.
D. Its too causti c to the G I tract.

3Whi ch si gns i ndi cate that a pati ent taki ng l evothyr oxi ne i s
exper i enci ng thyr oi d toxi ci ty?
A. Di ar r hea and wei ght l oss
B. Wei ght gai n and consti pati on
C. Sl ow hear t rate and l ow bl ood pr essur e
D. Ir r egul ar hear t rate and l ow bl ood pr essur e

4The poster i or pi tui tar y dr ug used to sti mul ate uter i ne

contracti ons i s:
A. vasopr essi n.
B. oxytoci n.
C. desmopr essi n.
D. estr ogen.

5Estr ogens ar e someti mes pr escr i bed to tr eat whi ch condi ti on i n

men?
A. Renal cancer
B. Testi cul ar cancer
C. Col or ectal cancer
D. Pr ostate cancer

P.
Scoring
If you answer ed al l fi ve i tems cor r ectl y, extraor di nar y!
Your e hyper-knowl edgeabl e about hyper gl ycemi c dr ugs
and mor e!

If you answer ed four i tems cor r ectl y, congratul ati ons! You
have a wel l -bal anced under standi ng of phar macol ogy!
If you answer ed fewer than four i tems cor r ectl y, keep
tr yi ng! You have two mor e Qui ck qui z zes to go!

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

14
Drugs for fluid and electrolyte balance

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs that affect fl ui d and el ectr ol yte bal ance

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and homeostasis

Il l ness can easi l y di stur b the homeostati c mechani sms that hel p
mai ntai n nor mal fl ui d and el ectr ol yte bal ance. Such occur r ences as
l oss of appeti te, medi cati on admi ni strati on, vomi ti ng, di ar r hea,
sur ger y, and di agnosti c tests can al so al ter thi s del i cate bal ance.
For tunatel y, numer ous dr ugs can be used to cor r ect these
i mbal ances and hel p br i ng the body back to homeostasi s.
Electrolyte replacement drugs
An el ectr ol yte i s a compound or el ement that car r i es an el ectr i cal
char ge when di ssol ved i n water. Electr olyte r eplacement dr ugs ar e
i nor gani c or or gani c sal ts that i ncr ease depl eted or defi ci ent
el ectr ol yte l evel s, hel pi ng to mai ntai n homeostasi s, the stabi l i ty of
body fl ui d composi ti on and vol ume. They i ncl ude:

potassi um, the pr i mar y i ntracel l ul ar fl ui d (ICF ) el ectr ol yte

cal ci um, a major extracel l ul ar fl ui d (ECF ) el ectr ol yte
magnesi um, an el ectr ol yte essenti al for homeostasi s found i n
ICF
sodi um, the pr i nci pal el ectr ol yte i n ECF necessar y for
homeostasi s.

Potassium
Potassium i s the major posi ti vel y char ged i on (cati on) i n ICF.
Because the body cant stor e potassi um, adequate amounts must be
i ngested dai l y. If thi s i snt possi bl e, potassi um r epl acement can be
accompl i shed oral l y or I.V. wi th potassi um sal ts, such as:

potassi um acetate
potassi um bi car bonate
 potassi um chl or i de
potassi um gl uconate
potassi um phosphate.

Pharmacokinetics (how drugs circulate)

Oral potassi um i s absor bed r eadi l y fr om the G I tract.

Absorption, metabolism, and excretion

After absor pti on i nto the ECF, al most al l of the potassi um passes
i nto the ICF. Ther e, the enz yme adenosi netr i phosphatase mai ntai ns
the concentrati on of potassi um by pumpi ng sodi um out of the cel l i n
exchange for potassi um.
Nor mal ser um l evel s of potassi um ar e mai ntai ned by the ki dneys,
whi ch excr ete most excess potassi um i ntake. The r est i s excr eted i n
stool and sweat.

Pharmacodynamics (how drugs act)

Potassi um moves qui ckl y i nto ICF to r estor e depl eted potassi um
l evel s and r eestabl i sh bal ance. Its an essenti al el ement i n
deter mi ni ng cel l membrane potenti al and exci tabi l i ty.

Feel nervous about potassium?

Potassi um i s necessar y for pr oper functi oni ng of al l ner ve and
muscl e cel l s and for ner ve i mpul se transmi ssi on. Its al so essenti al
for ti ssue gr owth and r epai r and for mai ntenance of aci d-base
bal ance.

Pharmacotherapeutics (how drugs are used)

Potassi um r epl acement therapy cor r ects hypokal emi a, l ow l evel s of
potassi um i n the bl ood. Hypokal emi a i s a common occur r ence i n
condi ti ons that i ncr ease potassi um excr eti on or depl eti on, such as:

vomi ti ng, di ar r hea, or nasogastr i c sucti on

excessi ve ur i nati on
some ki dney di seases
cysti c fi br osi s
bur ns

excess of anti di ur eti c hor mone or therapy wi th a potassi um-

depl eti ng di ur eti c
l axati ve abuse
al kal osi s
i nsuffi ci ent potassi um i ntake fr om star vati on, anor exi a ner vosa,
al cohol i sm, or cl ay i ngesti on
admi ni strati on of a gl ucocor ti coi d, I.V. amphoter i ci n B, vi tami n
B 1 2 , fol i c aci d, granul ocyte-macr ophage col onysti mul ati ng
factor, or I.V. sol uti ons that contai n i nsuffi ci ent potassi um.

Be still my heart
Potassi um decr eases the toxi c effects of di goxi n. Because potassi um
i nhi bi ts the exci tabi l i ty of the hear t, nor mal potassi um l evel s
moderate the acti on of di goxi n, r educi ng the chances of toxi ci ty.

Drug interactions
Potassi um shoul d be used cauti ousl y i n pati ents r ecei vi ng
potassi um-spar i ng di ur eti cs (such as ami l or i de, spi r onol actone, and
tr i amter ene) or angi otensi n-conver ti ng enz yme i nhi bi tor s (such as
captopr i l , enal apr i l , and l i si nopr i l ) to avoi d hyper kal emi a. (See
Adver se r eacti ons to potassi um.)

Warning!
Adverse reactions to potassium
Most adver se r eacti ons to potassi um ar e r el ated to the
method of admi ni strati on.
Oral history
Oral potassi um someti mes causes nausea, vomi ti ng, abdomi nal
pai n, and di ar r hea. Enter i c-coated tabl ets may cause smal l -bowel
ul cerati on, stenosi s, hemor r hage, and obstr ucti on.
I.V. issues
I.V. i nfusi on of potassi um pr eparati ons can cause pai n at the
i njecti on si te and phl ebi ti s (vei n i nfl ammati on). G i ven rapi dl y,
I.V. admi ni strati on may cause car di ac ar r est. Infusi on of
potassi um i n pati ents wi th decr eased ur i ne pr oducti on i ncr eases
the r i sk of hyper kal emi a.

Calcium
Calcium i s a major cati on i n ECF. Al most al l of the cal ci um i n the
body (99% ) i s stor ed i n bone, wher e i t can be mobi l i zed, i f
necessar y. When di etar y i ntake i snt enough to meet metabol i c
needs, cal ci um stor es i n bone ar e r educed.

Bound, complexed, ionized

Extracel l ul ar cal ci um exi sts i n thr ee for msi ts bound to pl asma
pr otei n (mai nl y al bumi n); compl exed wi th such substances as
phosphate, ci trate, or sul fate; and i oni zed. Ioni zed cal ci um i s the
physi ol ogi cal l y acti ve for m and pl ays a r ol e i n cel l ul ar functi ons.

Salting the body

Chr oni c i nsuffi ci ent cal ci um i ntake can r esul t i n bone
demi neral i z ati on. Cal ci um i s r epl aced oral l y or I.V. wi th cal ci um
sal ts, such as:

cal ci um car bonate

cal ci um chl or i de
cal ci um ci trate
 cal ci um gl ubi onate
cal ci um gl uceptate
cal ci um gl uconate
cal ci um l actate.

Pharmacokinetics
Oral cal ci um i s absor bed r eadi l y fr om the duodenum and pr oxi mal
jejunum. A pH of 5 to 7, parathyr oi d hor mone, and vi tami n D al l ai d
cal ci um absor pti on.

Absorbed with absorption

Absor pti on al so depends on di etar y factor s, such as cal ci um bi ndi ng
to fi ber, phytates, and oxal ates, and on fatty aci ds, wi th whi ch
cal ci um sal ts for m i nsol ubl e soaps.

Distribution and excretion

Cal ci um i s di str i buted pr i mar i l y i n bone. Cal ci um sal ts ar e
el i mi nated unchanged pr i mar i l y i n stool ; the r emai nder i s excr eted
i n ur i ne.

Pharmacodynamics
Cal ci um moves qui ckl y i nto ECF to r estor e cal ci um l evel s and
r eestabl i sh bal ance. Cal ci um has several i mpor tant r ol es i n the
body:

Extracel l ul ar i oni zed cal ci um pl ays an essenti al r ol e i n nor mal

ner ve and muscl e exci tabi l i ty.
Cal ci um i s i ntegral to nor mal functi oni ng of the hear t, ki dneys,
and l ungs, and i t affects the bl ood coagul ati on rate as wel l as
cel l membrane and capi l l ar y per meabi l i ty.
Cal ci um i s a factor i n neur otransmi tter and hor mone acti vi ty,
ami no aci d metabol i sm, vi tami n B1 2 absor pti on, and gastr i n
secr eti on.
Cal ci um pl ays a major r ol e i n nor mal bone and tooth for mati on.
Pharmacotherapeutics
Cal ci um i s hel pful i n tr eati ng magnesi um i ntoxi cati on. It al so hel ps
str engthen myocar di al ti ssue after defi br i l l ati on (el ectr i c shock to
r estor e nor mal hear t r hythm) or a poor r esponse to epi nephr i ne
dur i ng r esusci tati on. Pr egnancy and br east-feedi ng i ncr ease cal ci um
r equi r ements, as do per i ods of bone gr owth dur i ng chi l dhood and
adol escence.

In the I.V. league

The major cl i ni cal i ndi cati on for I.V. cal ci um i s acute hypocal cemi a
(l ow ser um cal ci um l evel s), whi ch necessi tates a rapi d i ncr ease i n
ser um cal ci um l evel s, as i n tetany, car di ac ar r est, vi tami n D
defi ci ency, parathyr oi d sur ger y, and al kal osi s. I.V. cal ci um i s al so
used to pr event a hypocal cemi c r eacti on dur i ng exchange
transfusi ons.

Oral history
Oral cal ci um i s commonl y used to suppl ement a cal ci um-defi ci ent
di et and pr event osteopor osi s. Chr oni c hypocal cemi a fr om such
condi ti ons as chr oni c hypoparathyr oi di sm (a defi ci ency of
parathyr oi d hor mones), osteomal aci a (softeni ng of bones), l ong-
ter m gl ucocor ti coi d therapy, and pl i camyci n and vi tami n D
defi ci ency i s al so tr eated wi th oral cal ci um.

Drug interactions
Cal ci um has few si gni fi cant i nteracti ons wi th other dr ugs.

Pr eparati ons admi ni ster ed wi th di goxi n may cause car di ac

ar r hythmi as.
Cal ci um r epl acement dr ugs may r educe the r esponse to cal ci um
channel bl ocker s.
Cal ci um r epl acements may i nacti vate tetracycl i nes.
Cal ci um suppl ements may decr ease the amount of atenol ol
avai l abl e to the ti ssues, r esul ti ng i n decr eased effecti veness of
the dr ug.
When gi ven i n total par enteral nutr i ti on, cal ci um may r eact wi th
phosphor us pr esent i n the sol uti on to for m i nsol ubl e cal ci um
phosphate granul es, whi ch may fi nd thei r way i nto pul monar y
ar ter i ol es, causi ng embol i and possi bl y death. (See Adver se
r eacti ons to cal ci um.)

Magnesium
Magnesium i s the most abundant cati on i n ICF after potassi um. Its
essenti al i n transmi tti ng ner ve i mpul ses to muscl e and acti vati ng
enz ymes necessar y for car bohydrate and pr otei n metabol i sm. About
65% of al l magnesi um i s i n bone, and 20% i s i n muscl e.

Officiating in the ICF

Magnesi um sti mul ates parathyr oi d hor mone secr eti on, thus
r egul ati ng ICF cal ci um l evel s.

Traffic control
Magnesi um al so ai ds i n cel l metabol i sm and the movement of
sodi um and potassi um acr oss cel l membranes.

Warning!
Adverse reactions to calcium
Cal ci um pr eparati ons may pr oduce hyper cal cemi a (el evated
ser um cal ci um l evel s). Ear l y si gns i ncl ude:

dr owsi ness
l ethar gy
muscl e weakness
headache
consti pati on
metal l i c taste.

Take this to heart

El ectr ocar di ogram changes that occur wi th el evated ser um
cal ci um l evel s i ncl ude a shor tened QT i nter val and hear t bl ock.
Sever e hyper cal cemi a can cause car di ac ar r hythmi as, car di ac
ar r est, and coma.

A run on magnesium
Magnesi um stor es may be depl eted by:

mal absor pti on

chr oni c di ar r hea
pr ol onged tr eatment wi th di ur eti cs

nasogastr i c sucti oni ng

pr ol onged therapy wi th par enteral fl ui ds not contai ni ng
magnesi um
hyperal doster oni sm
hypoparathyr oi di sm or hyper parathyr oi di sm
 excessi ve r el ease of adr enocor ti cal hor mones
acute and chr oni c al cohol consumpti on
dr ugs, such as ci spl ati n, ami nogl ycosi des, cycl ospor i ne, and
amphoter i ci n B.

Restocking the mineral stores

Magnesi um i s typi cal l y r epl aced i n the for m of magnesi um sul fate
when admi ni ster ed I.V. or i n the for m of magnesi um oxi de i f gi ven
oral l y.

Pharmacokinetics
Magnesi um sul fate i s di str i buted wi del y thr oughout the body. I.V.
magnesi um sul fate acts i mmedi atel y, wher eas the dr ug acts wi thi n
30 mi nutes after I.M. admi ni strati on. However, I.M. i njecti ons can
be pai nful , can i nduce scl er osi s, and need to be r epeated fr equentl y.

Metabolism and excretion

Magnesi um sul fate i snt metabol i zed and i s excr eted unchanged i n
ur i ne and stool ; some appear s i n br east mi l k.

Pharmacodynamics
Magnesi um sul fate r epl eni shes and pr events magnesi um
defi ci enci es. It al so pr events or contr ol s sei z ur es by bl ocki ng
neur omuscul ar transmi ssi on.

Pharmacotherapeutics
I.V. magnesi um sul fate i s the dr ug of choi ce for r epl acement
therapy i n symptomati c magnesi um defi ci ency (hypomagnesemi a).
Its wi del y used to tr eat or pr event pr eecl ampti c and ecl ampti c
sei z ur e acti vi ty and i s used to tr eat ventr i cul ar ar r hythmi as such as
tor sades de poi ntes. Its al so used to tr eat sei z ur es, sever e toxe-
mi a, and acute nephr i ti s i n chi l dr en.
Drug interactions
Magnesi um has few si gni fi cant i nteracti ons wi th other dr ugs.

Magnesi um used wi th di goxi n may l ead to hear t bl ock.

Magnesi um sul fate combi ned wi th al cohol , nar coti cs, anti anxi ety
dr ugs, bar bi turates, anti depr essants, hypnoti cs, anti psychoti c
dr ugs, or general anestheti cs may i ncr ease central ner vous
system depr essant effects.

Magnesi um sul fate combi ned wi th succi nyl chol i ne or

tubocurar i ne potenti ates and pr ol ongs the neur omuscul ar
bl ocki ng acti on of these dr ugs. (See Adver se r eacti ons to
magnesi um.)

Warning!
Adverse reactions to magnesium
Adver se r eacti ons to magnesi um sul fate, whi ch can be l i fe-
 thr eateni ng, i ncl ude:

hypotensi on
ci r cul ator y col l apse
fl ushi ng
depr essed r efl exes
r espi rator y paral ysi s
car di ac ar r est.

Sodium
Sodium i s the major cati on i n ECF. Sodi um per for ms many functi ons:

It mai ntai ns the osmoti c pr essur e and concentrati on of ECF,

aci d-base bal ance, and water bal ance.
It contr i butes to ner ve conducti on and neur omuscul ar functi on.
It pl ays a r ol e i n gl andul ar secr eti on.

Dont sweat it
Sodi um r epl acement i s necessar y i n condi ti ons that rapi dl y depl ete
sodi um, such as anor exi a, excessi ve l oss of G I fl ui ds, and excessi ve
per spi rati on. Di ur eti cs and tap water enemas can al so depl ete
sodi um, par ti cul ar l y when fl ui ds ar e r epl aced by pl ai n water.

The salt flats

Sodi um al so can be l ost i n trauma or wound drai nage, adr enal gl and
i nsuffi ci ency, ci r r hosi s of the l i ver wi th asci tes, syndr ome of
i nappr opr i ate anti di ur eti c hor mone, and pr ol onged I.V. i nfusi on of
dextr ose i n water wi thout other sol utes.
Calling all chlorides
Sodi um i s typi cal l y r epl aced i n the for m of sodi um chl or i de.

Pharmacokinetics
Oral and par enteral sodi um chl or i de ar e qui ckl y absor bed and
di str i buted wi del y thr oughout the body.

Metabolism and excretion

Sodi um chl or i de i snt si gni fi cantl y metabol i zed. Its el i mi nated
pr i mar i l y i n ur i ne but al so i n sweat, tear s, and sal i va.

Pharmacodynamics
Sodi um chl or i de sol uti on r epl aces defi ci enci es of the sodi um and
chl or i de i ons i n the bl ood pl asma.

Pharmacotherapeutics
Sodi um chl or i de i s used for water and el ectr ol yte r epl acement i n
pati ents wi th hyponatr emi a fr om el ectr ol yte l oss or sever e sodi um
chl or i de depl eti on.
A welcome infusion
Sever e symptomati c sodi um defi ci ency may be tr eated by I.V.
i nfusi on of a sol uti on contai ni ng sodi um chl or i de.

Drug interactions
No si gni fi cant dr ug i nteracti ons have been r epor ted wi th sodi um
chl or i de. (See Adver se r eacti ons to sodi um.)

Warning!
Adverse reactions to sodium
Adver se r eacti ons to sodi um i ncl ude:

pul monar y edema (i f gi ven too rapi dl y or i n excess)

hyper natr emi a
potassi um l oss.

Alkalinizing and acidifying drugs

Alkaliniz ing and acidifying dr ugs act to cor r ect aci d-base i mbal ances
i n the bl ood. These aci d-base i mbal ances i ncl ude:

metabolic acidosis, a decr eased ser um pH caused by excess

hydr ogen i ons i n the ECF, whi ch i s tr eated wi th al kal i ni z i ng
dr ugs
metabolic alkalosis, an i ncr eased ser um pH caused by excess
bi car bonate i n the ECF, whi ch i s tr eated wi th aci di fyi ng dr ugs.

Odd couple
Al kal i ni z i ng and aci di fyi ng dr ugs have opposi te effects:

An al kal i ni z i ng dr ug wi l l i ncr ease the pH of the bl ood and

decr ease the concentrati on of hydr ogen i ons.
An aci di fyi ng dr ug wi l l decr ease the pH of the bl ood and i ncr ease
the concentrati on of hydr ogen i ons.
Rx for o.d.
Some of these dr ugs al so al ter ur i ne pH, maki ng them useful i n
tr eati ng some ur i nar y tract i nfecti ons and dr ug over doses.

Alkalinizing drugs
Alkaliniz ing dr ugs ar e used to tr eat metabol i c aci dosi s and to
i ncr ease bl ood pH. These i ncl ude:

sodi um bi car bonate

sodi um ci trate
sodi um l actate
tr omethami ne.

Increasing another pH
Sodi um bi car bonate i s al so used to i ncr ease ur i ne pH.

Pharmacokinetics
Al l of the al kal i ni z i ng dr ugs ar e absor bed wel l when gi ven oral l y.

Metabolism and excretion

Sodi um ci trate and sodi um l actate ar e metabol i zed to the acti ve
i ngr edi ent, bi car bonate. Sodi um bi car bonate i snt metabol i zed.
Tr omethami ne under goes l i ttl e or no metabol i sm and i s excr eted
unchanged i n ur i ne.

Pharmacodynamics
Sodi um bi car bonate separates i n the bl ood, pr ovi di ng bi car bonate
i ons that ar e used i n the bl ood buffer system to decr ease the
hydr ogen i on concentrati on and rai se bl ood pH. (Buffer s pr event
extr eme changes i n pH by taki ng or gi vi ng up hydr ogen i ons to
neutral i ze aci ds or bases.) As the bi car bonate i ons ar e excr eted i n
ur i ne, ur i ne pH r i ses. Sodi um ci trate and l actate, after conver si on
to bi car bonate, al kal i ni ze the bl ood and ur i ne i n the same way.
 Memory jogger
Remember : A l ow pH means a sol uti on i s acidic, and a hi gh pH
means i ts alkaline. Ther efor e, to rai se the pH, you use an
alkaliniz ing dr ug and, l i kewi se, to l ower the pH, you use an
acidifying dr ug.

Hitching up with hydrogen

Tr omethami ne acts by combi ni ng wi th hydr ogen i ons to al kal i ni ze
the bl ood; the r esul ti ng tr omethami nehydr ogen i on compl ex i s
excr eted i n ur i ne.

Pharmacotherapeutics
Al kal i ni z i ng dr ugs ar e commonl y used to tr eat metabol i c aci dosi s.
Other uses i ncl ude rai si ng ur i ne pH to hel p r emove cer tai n
substances, such as phenobar bi tal , after an over dose.

Drug interactions
The al kal i ni z i ng dr ugs sodi um bi car bonate, sodi um ci trate, and
sodi um l actate can i nteract wi th a wi de range of dr ugs to i ncr ease
or decr ease thei r phar macol ogi c effects.

They may i ncr ease excr eti on and r educe the effects of
chl or pr opami de, ketoconazol e, l i thi um, and sal i cyl ates.
They may r educe the excr eti on and i ncr ease the effects of
 amphetami nes, fl ecai ni de, qui ni di ne, and pseudoephedr i ne.
The anti bacter i al effects of methenami ne ar e r educed when
taken wi th al kal i ni z i ng dr ugs. (See Adver se r eacti ons to
al kal i ni z i ng dr ugs, page 368.)

Warning!
Adverse reactions to alkalinizing drugs
Adver se r eacti ons to al kal i ni z i ng dr ugs var y.
Sodium bicarbonate

Bi car bonate over dose

Cer ebral dysfuncti on, ti ssue hypoxi a, and l acti c aci dosi s (wi th
rapi d admi ni strati on for di abeti c ketoaci dosi s)
Water r etenti on and edema

Sodium citrate

Metabol i c al kal osi s, tetany, or aggravati on of exi sti ng hear t

di sease (wi th over dose)
Laxati ve effect (wi th oral admi ni strati on)

Sodium lactate

Metabol i c al kal osi s (wi th over dose)

Extravasati on
Water r etenti on or edema (i n pati ent wi th ki dney di sease or
hear t fai l ur e)

Tromethamine

Hypogl ycemi a
Respi rator y depr essi on
Extravasati on
Hyper kal emi a
Toxi c dr ug l evel s (i f gi ven for mor e than 24 hour s)
Acidifying drugs
Acidifying dr ugs ar e used to cor r ect metabol i c al kal osi s. These
i ncl ude:

acetazol ami de (used i n tr eatment of acute mountai n si ckness)

ammoni um chl or i de.

Ascor bi c aci d, al ong wi th ammoni um chl or i de, ser ves as a ur i nar y

aci di fi er.

Pharmacokinetics
The acti on of most aci di fyi ng dr ugs i s i mmedi ate.

Absorption, metabolism, and excretion

Oral l y admi ni ster ed ammoni um chl or i de i s absor bed compl etel y i n 3
to 6 hour s. Its metabol i zed i n the l i ver to for m ur ea, whi ch i s
excr eted by the ki dneys.

Break it down
Acetazol ami de i nhi bi ts the enz yme car boni c anhydrase, whi ch bl ocks
hydr ogen i on secr eti on i n the r enal tubul e, r esul ti ng i n i ncr eased
excr eti on of bi car bonate and a l ower pH. Acetazol ami de al so
aci di fi es ur i ne but may pr oduce metabol i c aci dosi s i n nor mal
pati ents.

Pharmacodynamics
Aci di fyi ng dr ugs have several acti ons:

Ammoni um chl or i de l ower s the bl ood pH after bei ng metabol i zed

to ur ea and to hydr ochl or i c aci d, whi ch pr ovi des hydr ogen i ons
to aci di fy the bl ood or ur i ne.
Ascor bi c aci d di r ectl y aci di fi es ur i ne, pr ovi di ng hydr ogen i ons
and l ower i ng ur i ne pH.
Acetazol ami de i ncr eases the excr eti on of bi car bonate, l ower i ng
bl ood pH.

Pharmacotherapeutics
A pati ent wi th metabol i c al kal osi s r equi r es therapy wi th an
aci di fyi ng dr ug that pr ovi des hydr ogen i ons; such a pati ent may
need chl or i de i on therapy as wel l .

Safe and easy

Most pati ents r ecei ve both types of i ons i n oral or par enteral doses
of ammoni um chl or i de, a safer dr ug thats easy to pr epar e.

Kidney concerns
In pati ents wi th r enal dysfuncti on, acetazol ami de may be i neffecti ve
and cause l oss of potassi um i n ur i ne.

Drug interactions
Aci di fyi ng dr ugs dont cause cl i ni cal l y si gni fi cant dr ug i nteracti ons.
However, concur r ent use of ammoni um chl or i de and spi r onol actone
may cause i ncr eased systemi c aci dosi s. (See Adver se r eacti ons to
aci di fyi ng dr ugs.)

Warning!
Adverse reactions to acidifying drugs
Adver se r eacti ons to aci di fyi ng dr ugs ar e usual l y mi l d, such
as G I di str ess. Over dose may l ead to aci dosi s.
Acetazolamide

Dr owsi ness
Sei z ur es
Anor exi a
Nausea and vomi ti ng
Di ar r hea
Al ter ed taste
Apl asti c anemi a

Ammonium chloride

Metabol i c aci dosi s and l oss of el ectr ol ytes, especi al l y

potassi um (wi th l ar ge doses)

Ascorbic acid

G I di str ess (wi th hi gh doses)

Hemol yti c anemi a (i n a pati ent wi th gl ucose-6-phosphate
dehydr ogenase defi ci ency)
 Quick quiz
1Whi ch dr ug can cause hypokal emi a?
A. Di goxi n
B. Amphoter i ci n B
C. Spi r onol actone
D. Lansoprazol e

2Potassi um shoul d be used cauti ousl y i n pati ents r ecei vi ng:

A. ami l or i de.
B. fur osemi de.
C. di goxi n.
D. ceti r i z i ne.

3How does sodi um bi car bonate cor r ect metabol i c aci dosi s?
A. By l ower i ng bl ood pH after bei ng metabol i zed
B. By i ncr easi ng hydr ogen i on concentrati on
C. By combi ni ng wi th hydr ogen i ons to al kal i ni ze the bl ood
D. By decr easi ng hydr ogen i on concentrati on

Scoring
If you answer ed al l thr ee i tems cor r ectl y, extraor di nar y!
Your e one wel l -bal anced i ndi vi dual !

If you answer ed two i tems cor r ectl y, congratul ati ons!

Your e movi ng cl oser to compl ete har mony!

If you answer ed fewer than two i tems cor r ectl y, keep

tr yi ng! By the end of the book, your e sur e to have al l
your l evel s up!

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

15
Antineoplastic drugs

Just the facts

In thi s chapter, youl l l ear n:

cl asses of dr ugs used to tr eat cancer

uses and var yi ng acti ons of these dr ugs
how these dr ugs ar e absor bed, di str i buted, metabol i zed, and
excr eted
dr ug i nteracti ons and adver se r eacti ons to these dr ugs.

Drugs and cancer

In the 1940s, antineoplastic (chemotherapeuti c) dr ugs wer e
devel oped to tr eat cancer. However, these agents commonl y had
ser i ous adver se effects.

A brighter future
Today, many of these toxi ci ti es can be l essened so they ar ent as
devastati ng to the pati ent. Wi th moder n chemotherapy, chi l dhood
mal i gnanci es, such as acute l ymphobl asti c l eukemi a, and adul t
cancer s, such as testi cul ar cancer, ar e curabl e i n most pati ents. New
therapeuti c strategi es, such as usi ng monocl onal anti bodi es or
tar geti ng speci fi c pr otei ns, ar e fur ther i mpr ovi ng the ti me that a
pati ents cancer can r emai n i n r emi ssi on. In addi ti on, dr ugs such as
i nter fer ons ar e bei ng used to tr eat pati ents wi th cancer.
Alkylating drugs
Alkylating dr ugs, gi ven al one or wi th other dr ugs, effecti vel y act
agai nst var i ous mal i gnant neopl asms. These dr ugs fal l i nto one of
si x cl asses:

ni tr ogen mustar ds
al kyl sul fonates

ni tr osour eas
tr i azenes
ethyl eni mi nes
al kyl ati ng-l i ke dr ugs.

Unfazed at any phase

Al l of these dr ugs pr oduce thei r anti neopl asti c effects by damagi ng
deoxyr i bonucl ei c aci d (DNA). They hal t DNAs r epl i cati on pr ocess by
cr oss-l i nki ng i ts strands so that ami no aci ds dont pai r up cor r ectl y.
Al kyl ati ng dr ugs ar e cel l cycl ephase nonspeci fi c. Thi s means that
thei r al kyl ati ng acti ons may take pl ace at any phase of the cel l
cycl e.

Nitrogen mustards
Nitr ogen mustar ds r epr esent the l ar gest gr oup of al kyl ati ng dr ugs.
They i ncl ude:

chl orambuci l
cycl ophosphami de
estramusti ne
i fosfami de
mechl or ethami ne hydr ochl or i de
mel phal an.

First and fast

Mechl or ethami ne hydr ochl or i de was the fi r st ni tr ogen mustar d
i ntr oduced and i s rapi d-acti ng.
Pharmacokinetics (how drugs circulate)
The absor pti on and di str i buti on of ni tr ogen mustar ds, as wi th most
al kyl ati ng dr ugs, var y wi del y.

Metabolism and excretion

Ni tr ogen mustar ds ar e metabol i zed i n the l i ver and excr eted by the
ki dneys. Mechl or ethami ne under goes metabol i sm so rapi dl y that no
acti ve dr ug r emai ns after a few mi nutes. Most ni tr ogen mustar ds
possess mor e i nter medi ate hal f-l i ves than mechl or eth-ami ne.

Pharmacodynamics (how drugs act)

Ni tr ogen mustar ds for m coval ent bonds wi th DNA mol ecul es i n a
chemi cal r eacti on known as alkylation. Al kyl ated DNA cant r epl i cate
pr oper l y, ther eby r esul ti ng i n cel l death. Unfor tunatel y, cel l s may
devel op r esi stance to the cytotoxi c effects of ni tr ogen mustar ds.
(See How al kyl ati ng dr ugs wor k.)

Now I get it!

How alkylating drugs work
Bifunctional alkylation
Some dr ugs become i nser ted between two base pai r s i n the DNA
chai n, for mi ng an i r r ever si bl e bond between them. Thi s i s cal l ed
bifunctional alkylation; i t causes cytotoxi c effects capabl e of
destr oyi ng or poi soni ng cel l s.
 Monofunctional alkylation
Other dr ugs r eact wi th just one par t of a pai r, separati ng i t fr om
i ts par tner and eventual l y causi ng i t and i ts attached sugar to
br eak away fr om the DNA mol ecul e. Thi s i s cal l ed monofunctional
alkylation; i t eventual l y may cause per manent cel l damage.

Pharmacotherapeutics (how drugs are used)

Because they pr oduce l eukopeni a (r educed number of whi te bl ood
cel l s [WBCs]), the ni tr ogen mustar ds ar e effecti ve i n tr eati ng
mal i gnant neopl asms, such as Hodgki ns di sease (cancer causi ng
pai nl ess enl ar gement of the l ymph nodes, spl een, and l ymphoi d
ti ssues) and l eukemi a (cancer of the bl ood-for mi ng ti ssues), that
can have an associ ated el evated WBC count.

Nitrogen bomb
Ni tr ogen mustar ds al so pr ove effecti ve agai nst mal i gnant l ymphoma
(cancer of the l ymphoi d ti ssue), mul ti pl e myel oma (cancer of the
mar r ow pl asma cel l s), mel anoma (mal i gnancy that ar i ses fr om
mel anocytes), and cancer s of the br east, ovar i es, uter us, l ung,
brai n, testes, bl adder, pr ostate, and stomach.

Drug interactions
Ni tr ogen mustar ds i nteract wi th a wi de var i ety of other dr ugs:

Cal ci um-contai ni ng dr ugs and foods, such as antaci ds and dai r y

pr oducts, r educe absor pti on of estramusti ne.
Cycl ophosphami de taken wi th car di otoxi c dr ugs pr oduces
addi ti ve car di ac effects.
Cycl ophosphami de may r educe ser um di goxi n l evel s.
An i ncr eased r i sk of i fosfami de toxi ci ty exi sts when the dr ug i s
taken wi th al l opur i nol , bar bi turates, chl oral hydrate, or
phenytoi n.
Cor ti coster oi ds r educe the effects of i fosfami de.
The l ung toxi ci ty thr eshol d of car musti ne may be r educed when
taken wi th mel phal an.
Inter fer on al pha may r educe ser um concentrati on of mel phal an.
(See Adver se r eacti ons to ni tr ogen mustar ds.)

Alkyl sulfonates
Busulfan, an alkyl sulfonate, has hi stor i cal l y been used to tr eat
chr oni c myel ogenous l eukemi a, pol ycythemi a vera (i ncr eased r ed
bl ood cel l mass and i ncr eased number of WBCs and pl atel ets), and
other myel opr ol i ferati ve (per tai ni ng to an overacti ve bone mar r ow)
di sor der s. Its al so used for tr eatment of l eukemi a dur i ng bone
mar r ow transpl ant pr ocedur es.

Warning!
Adverse reactions to nitrogen mustards
Many pati ents exper i ence fati gue dur i ng ni tr ogen mustar d
therapy. Other adver se r eacti ons i ncl ude:

sever e l eukopeni a and thr ombocytopeni a

nausea and vomi ti ng
stomati ti s
r ever si bl e hai r l oss
sever e ski n r eacti ons wi th di r ect contact
sever e ti ssue damage, i f extravasati on occur s.

Pharmacokinetics
Busul fan i s rapi dl y wel l absor bed fr om the G I tract. Li ttl e i s known
about i ts di str i buti on.

Metabolism and excretion

Busul fan i s extensi vel y metabol i zed i n the l i ver befor e ur i nar y
excr eti on. Its hal f-l i fe i s 2 to 3 hour s.

Pharmacodynamics
As an al kyl sul fonate, busul fan for ms coval ent bonds wi th the DNA
mol ecul es i n al kyl ati on.

Pharmacotherapeutics
Busul fan pr i mar i l y affects granul ocytes (a type of WBC) and, to a
l esser degr ee, pl atel ets. Because of i ts acti on on granul ocytes, i t
has been used for tr eati ng chr oni c myel ogenous l eukemi a and as
adjunct therapy befor e and after bone mar r ow transpl antati on.

A backup option
Busul fan i s al so effecti ve i n tr eati ng pol ycythemi a vera, al though
other dr ugs ar e usual l y used to tr eat i t because busul fan can cause
sever e myel osuppr essi on (hal ti ng of bone mar r ow functi on).

Drug interactions
Ther es an i ncr eased r i sk of bl eedi ng when busul fan i s taken wi th
anti coagul ants or aspi r i n. Concur r ent use of busul fan and
thi oguani ne may cause l i ver toxi ci ty, esophageal var i ces (enl ar ged,
swol l en vei ns i n the esophagus), or por tal hyper tensi on (i ncr eased
pr essur e i n the por tal vei n of the l i ver ). (See Adver se r eacti ons to
busul fan.)

Warning!
Adverse reactions to busulfan
The major adver se r eacti on to busul fan i s bone mar r ow
suppr essi on, pr oduci ng sever e l eukopeni a, anemi a, and
thr ombocytopeni a (r educed whi te bl ood cel l s, r ed bl ood cel l s, and
pl atel ets, r especti vel y). Thi s r eacti on i s usual l y dose-r el ated and
r ever si bl e.

Nitrosoureas
Nitr osour eas ar e al kyl ati ng agents that wor k by hal ti ng cancer cel l
r epr oducti on. They i ncl ude:

car musti ne
l omusti ne
str eptozoci n.

Pharmacokinetics
When admi ni ster ed topi cal l y to tr eat mycosi s fungoi des (a rar e ski n
mal i gnancy), car musti ne i s 5% to 28% systemi cal l y absor bed. After
oral admi ni strati on, l omusti ne i s absor bed adequatel y, though
i ncompl etel y.

I.V. is the way

Str eptozoci n and car musti ne ar e admi ni ster ed I.V. because theyr e
poor l y absor bed oral l y.
Metabolism and excretion
Ni tr osour eas ar e l i pophi l i c (attracted to fat), di str i buti ng to fatty
ti ssues and cer ebr ospi nal fl ui d. Theyr e metabol i zed extensi vel y
befor e ur i ne excr eti on.

Pharmacodynamics
Dur i ng a pr ocess cal l ed bifunctional alkylation, ni tr osour eas
i nter fer e wi th ami no aci ds, pur i nes, and DNA needed for cancer cel l s
to di vi de, thus hal ti ng thei r r epr oducti on.

Pharmacotherapeutics
The ni tr osour eas ar e hi ghl y l i pi d (fat) sol ubl e, whi ch al l ows them or
thei r metabol i tes to easi l y cr oss the bl ood-brai n bar r i er. Because of
thi s abi l i ty, ni tr osour eas ar e used to tr eat brai n tumor s and
meni ngeal l eukemi as.

Drug interactions
Each of the ni tr osour eas has i ts own i nteracti ons wi th other dr ugs.
Ci meti di ne may i ncr ease car musti nes bone mar r ow toxi ci ty.
Str eptozoci n pr ol ongs the el i mi nati on hal f-l i fe of doxor ubi ci n,
pr ol ongi ng the l eukopeni a and thr ombocytopeni a. (See Adver se
r eacti ons to ni tr osour eas.)

Warning!
Adverse reactions to nitrosoureas
Al l of the ni tr osour eas can pr oduce sever e nausea and
vomi ti ng.
Down to the bone
Car musti ne and l omusti ne pr oduce bone mar r ow suppr essi on that
begi ns 4 to 6 weeks after tr eatment and l asts 1 to 2 weeks.
Kidney concerns
Ki dney toxi ci ty and ki dney fai l ur e may al so occur wi th pati ents
taki ng ni tr osour eas. Hi gh-dose car musti ne may pr oduce r ever si bl e
l i ver toxi ci ty.
Pulmonary problems
Car musti ne may cause l ung toxi ci ty character i zed by l ung
i nfi l trates or fi br osi s (scar r i ng).
Triazenes
Dacar baz ine, a tr iaz ene, functi ons as an al kyl ati ng dr ug after bei ng
acti vated by the l i ver.

Pharmacokinetics
After I.V. i njecti on, dacar baz i ne i s di str i buted thr oughout the body
and metabol i zed i n the l i ver. Wi thi n 6 hour s, 30% to 46% of a dose
i s excr eted by the ki dneys (hal f i s excr eted unchanged, and hal f i s
excr eted as one of the metabol i tes).

Dysfunction junction
In pati ents wi th ki dney or l i ver dysfuncti on, dacar baz i nes hal f-l i fe
may i ncr ease to 7 hour s.

Pharmacodynamics
Dacar baz i ne must fi r st be metabol i zed i n the l i ver to become an
acti ve dr ug. It seems to i nhi bi t r i bonucl ei c aci d (RNA) and pr otei n
synthesi s. Li ke other al kyl ati ng dr ugs, dacar baz i ne i s cel l
cycl enonspeci fi c.

Pharmacotherapeutics
Dacar baz i ne i s used pr i mar i l y to tr eat pati ents wi th mal i gnant
mel anoma but i s al so used wi th other dr ugs to tr eat pati ents wi th
Hodgki ns di sease.

Drug interactions
No si gni fi cant dr ug i nteracti ons have been r epor ted wi th
dacar baz i ne. (See Adver se r eacti ons to tr i azenes.)

Warning!
Adverse reactions to triazenes
Dacar baz i ne use may cause some adver se r eacti ons,
i ncl udi ng:

l eukopeni a
thr ombocytopeni a
nausea and vomi ti ng (whi ch begi n wi thi n 1 to 3 hour s after
 admi ni strati on i n most pati ents and may l ast up to 48 hour s)
phototoxi ci ty
fl ul i ke symptoms
hai r l oss.

Ethylenimines
Thiotepa, an ethylenimine der i vati ve, i s a mul ti functi onal al kyl ati ng
dr ug.

Pharmacokinetics
After I.V. admi ni strati on, thi otepa i s 100% bi oavai l abl e. Si gni fi cant
systemi c absor pti on may occur when thi otepa i s admi ni ster ed i nto
pl eural (ar ound the l ungs) or per i toneal (abdomi nal ) spaces to tr eat
mal i gnant effusi ons or i s i nsti l l ed i nto the bl adder.

Metabolism and excretion

Thi otepa cr osses the bl ood-brai n bar r i er and i s metabol i zed
extensi vel y i n the l i ver. Thi otepa and i ts metabol i tes ar e excr eted i n
ur i ne.

Pharmacodynamics
Thi otepa exer ts i ts cytotoxi c acti vi ty by i nter fer i ng wi th DNA
r epl i cati on and RNA transcr i pti on. Ul ti matel y, i t di sr upts nucl ei c aci d
functi on and causes cel l death.

Pharmacotherapeutics
Thi otepa i s used to tr eat bl adder cancer. Thi s al kyl ati ng dr ug i s al so
pr escr i bed for pal l i ati ve (symptom-r el i ef ) tr eatment of l ymphomas
and ovar i an or br east cancer s.

Wait! Theres more

Thi otepa i s used for the tr eatment of i ntracavi tar y effusi ons
(accumul ati on of fl ui d i n a body cavi ty). It may al so pr ove useful i n
the tr eatment of l ung cancer.

Drug interactions
Thi otepa may i nteract wi th other dr ugs.

Concur r ent use of thi otepa, anti coagul ants, and aspi r i n may
i ncr ease the r i sk of bl eedi ng.
Taki ng thi otepa wi th neur omuscul ar bl ocki ng dr ugs may pr ol ong
muscul ar paral ysi s.

Concur r ent use of thi otepa and other al kyl ati ng dr ugs or
radi ati on therapy may i ntensi fy toxi ci ty rather than enhance the
therapeuti c r esponse.

Itll take your breath away

When used wi th succi nyl chol i ne, thi otepa may cause pr ol onged
r espi rati ons and apnea (per i ods of not br eathi ng). Thi otepa appear s
to i nhi bi t the acti vi ty of chol i nesterase, the enz yme that deacti vates
succi nyl chol i ne. (See Adver se r eacti ons to thi otepa.)

Warning!
Adverse reactions to thiotepa
The major adver se r eacti ons to thi otepa ar e bl ood-r el ated
and i ncl ude l eukopeni a, anemi a, thr ombocytopeni a, and
pancytopeni a (defi ci ency of al l cel l ul ar el ements of the bl ood),
whi ch may be fatal .
Other adver se r eacti ons i ncl ude:

nausea and vomi ti ng (commonl y)

stomati ti s and ul cerati on of the i ntesti nal mucosa (especi al l y
at bone mar r ow transpl antati on doses)
hi ves, rash, and pr ur i tus (occasi onal l y).

Alkylating-like drugs
Car boplatin, cisplatin, and oxaliplatin ar e heavy metal compl exes
that contai n pl ati num. Because thei r acti on r esembl es that of a
bi functi onal al kyl ati ng dr ug, they ar e r efer r ed to as alkylating-like
dr ugs.

Pharmacokinetics
The di str i buti on and metabol i sm of car bopl ati n ar ent defi ned
cl ear l y. After I.V. admi ni strati on, car bopl ati n i s el i mi nated pr i mar i l y
by the ki dneys. The el i mi nati on of car bopl ati n i s bi phasi c. It has an
i ni ti al hal f-l i fe of 1 to 2 hour s and a ter mi nal hal f-l i fe of 2 to 6
hour s. In pati ents wi th decr eased r enal functi on, the ter mi nal hal f-
l i fe of car bopl ati n may l ast fr om 30 to 300 hour s.Oxal i pl ati n i s 70%
to 90% bound to pl asma pr otei ns, and the pr otei n-bi ndi ng i ncr eases
over ti me. Its wi del y di str i buted i nto most body ti ssues and i s
el i mi nated i n phases.

Into the lungs and peritoneum

When admi ni ster ed i ntrapl eural l y (i nto the pl eural space ar ound the
l ung) or i ntraper i toneal l y (i nto the per i toneum), ci spl ati n may
exhi bi t si gni fi cant systemi c absor pti on. Hi ghl y pr otei n bound,
ci spl ati n r eaches hi gh concentrati ons i n the ki dneys, l i ver,
i ntesti nes, and testes but has poor central ner vous system (CNS)
penetrati on. The dr ug under goes some l i ver metabol i sm, fol l owed by
excr eti on thr ough the ki dney.

Going platinum
Pl ati num i s detectabl e i n ti ssue for at l east 4 months after
admi ni strati on.

Pharmacodynamics
Li ke al kyl ati ng dr ugs, car bopl ati n, ci spl ati n, and oxal i pl ati n ar e cel l
cycl enonspeci fi c and i nhi bi t DNA synthesi s. They act l i ke
bi functi onal al kyl ati ng dr ugs by cr oss-l i nki ng strands of DNA and
i nhi bi ti ng DNA synthesi s.

Pharmacotherapeutics
These al kyl ati ng-l i ke dr ugs ar e used i n the tr eatment of several
cancer s.

Car bopl ati n i s used pr i mar i l y to tr eat ovar i an and l ung cancer.
Ci spl ati n i s pr escr i bed to tr eat bl adder and metastati c ovar i an
cancer.
Ci spl ati n i s the dr ug of choi ce to tr eat metastati c testi cul ar
cancer s.
 Ci spl ati n may al so be used to tr eat head, neck, and l ung cancer
(al though these i ndi cati ons ar e cl i ni cal l y accepted, theyr e
cur r entl y unl abel ed uses).
Oxal i pl ati n i s used i n combi nati on wi th other agents to tr eat
col or ectal cancer.

Drug interactions
Al kyl ati ng-l i ke dr ugs i nteract wi th a few other dr ugs:

When car bopl ati n, oxal i pl ati n, or ci spl ati n i s admi ni ster ed wi th
an ami nogl ycosi de, the r i sk of toxi ci ty to the ki dney i ncr eases.
Car bopl ati n or ci spl ati n taken wi th bumetani de, ethacr yni c aci d,
or fur osemi de i ncr eases the r i sk of ototoxi ci ty (damagi ng the
or gans of hear i ng and bal ance).
Ci spl ati n may r educe ser um phenytoi n l evel s. (See Adver se
r eacti ons to al kyl ati ng-l i ke dr ugs.)

Warning!
Adverse reactions to alkylating-like drugs
Al kyl ati ng-l i ke dr ugs pr oduce many of the same adver se
r eacti ons as the al kyl ati ng dr ugs.

Car bopl ati n can pr oduce bone mar r ow suppr essi on.
Ki dney toxi ci ty may occur wi th ci spl ati n, usual l y after mul ti pl e
cour ses of therapy. Car bopl ati n i s l ess toxi c to the ki dneys.
Ci spl ati n pr oduces mar ked nausea and vomi ti ng. Wi th l ong-
ter m ci spl ati n therapy, neur otoxi ci ty can occur. Neur otoxi ci ty
i s l ess common wi th car bopl ati n.
Ti nni tus and hear i ng l oss may occur wi th ci spl ati n and, l ess
commonl y, wi th car bopl ati n.
Oxal i pl ati n may cause anaphyl axi s, anemi a, or i ncr eased r i sk
of bl eedi ng or i nfecti on.

Antimetabolite drugs
Because antimetabolite dr ugs str uctural l y r esembl e DNA base pai r s,
they can become i nvol ved i n pr ocesses associ ated wi th DNA base
pai r sthat i s, the synthesi s of nucl ei c aci ds and pr otei ns.

Getting specific
Anti metabol i tes di ffer suffi ci entl y fr om DNA base pai r s i n how they
i nter fer e wi th thi s synthesi s. Because the anti metabol i tes ar e cel l
cycl especi fi c and pr i mar i l y affect cel l s that acti vel y synthesi ze DNA,
theyr e r efer r ed to as S phasespecific. Nor mal cel l s that ar e
r epr oduci ng acti vel y, as wel l as the cancer cel l s, ar e affected by the
anti metabol i tes.

Each according to its metabolite

These dr ugs ar e subcl assi fi ed accor di ng to the metabol i te affected
and i ncl ude:

fol i c aci d anal ogues

pyr i mi di ne anal ogues
pur i ne anal ogues.

Folic acid analogues

Al though r esear cher s have devel oped many folic acid analogues, the
ear l y compound methotr exate r emai ns the most commonl y used.

Pharmacokinetics
Methotr exate i s wel l absor bed and di str i buted thr oughout the body.
It can accumul ate i n any fl ui d col l ecti on, such as asci tes or pl eural
or per i car di al effusi on, possi bl y r esul ti ng i n pr ol onged el i mi nati on
and hi gher than expected toxi ci ty, especi al l y myel osuppr essi on. At
usual dosages, i t doesnt enter the CNS r eadi l y.

Metabolism and excretion

Al though methotr exate i s metabol i zed par ti al l y, i ts excr eted
pr i mar i l y unchanged i n ur i ne.

A disappearing act
Methotr exate exhi bi ts a thr ee-par t di sappearance fr om pl asma; the
rapi d di str i buti ve phase i s fol l owed by a second phase, whi ch
r efl ects ki dney cl earance. The l ast phase, the ter mi nal hal f-l i fe, i s 3
to 10 hour s for a l ow dose and 8 to 15 hour s for a hi gh dose.

Pharmacodynamics
Methotr exate r ever si bl y i nhi bi ts the acti on of the enz yme
di hydr ofol ate r eductase, ther eby bl ocki ng nor mal fol i c aci d
pr ocessi ng and thus i nhi bi ti ng DNA and RNA synthesi s. The r esul t i s
cel l death. Fol i ni c aci d i s used i n hi gh-dose methotr exate therapy to
hel p pr event cel l death.

Pharmacotherapeutics
Methotr exate i s especi al l y useful i n tr eati ng:

acute l ymphobl asti c l eukemi a (abnor mal gr owth of l ymphocyte

pr ecur sor s, the l ymphobl asts), the most common l eukemi a i n
chi l dr en

acute l ymphocyti c l eukemi a (abnor mal gr owth of l ymphocytes);

methotr exate may be gi ven as tr eatment or pr ophyl axi s for
meni ngeal l eukemi a
CNS di seases (gi ven i ntrathecal l y, or thr ough the spi nal cor d
i nto the subarachnoi d space)
chor i ocar ci noma (cancer that devel ops fr om the chor i oni c
por ti ons of the pr oducts of concepti on)
osteogeni c sar coma (bone cancer )
mal i gnant l ymphomas
 cancer s of the head, neck, bl adder, testi s, and br east.

Unconventional treatment
The dr ug i s al so pr escr i bed i n l ow doses to tr eat such di sor der s as
sever e psor i asi s, graft ver sus host di sease, and r heumatoi d ar thr i ti s
that dont r espond to conventi onal therapy.

Drug interactions
Methotr exate i nteracts wi th several other dr ugs:

Pr obeneci d decr eases methotr exate excr eti on, i ncr easi ng the
r i sk of methotr exate toxi ci ty, i ncl udi ng fati gue, bone mar r ow
suppr essi on, and stomati ti s (mouth i nfl ammati on).
Sal i cyl ates and nonster oi dal anti -i nfl ammator y dr ugs, especi al l y
di cl ofenac, ketopr ofen, i ndomethaci n, and napr oxen, al so
i ncr ease methotr exate toxi ci ty.
Chol estyrami ne r educes absor pti on of methotr exate fr om the G I
tract.
Concur r ent use of al cohol and methotr exate i ncr eases the r i sk of
l i ver toxi ci ty.
Taki ng co-tr i moxazol e wi th methotr exate may pr oduce bl ood cel l
abnor mal i ti es.
Peni ci l l i n decr eases r enal tubul ar secr eti on of methotr exate,
i ncr easi ng the r i sk of methotr exate toxi ci ty. (See Adver se
r eacti ons to methotr exate.)

Warning!
Adverse reactions to methotrexate
Adver se r eacti ons to methotr exate i ncl ude:

bone mar r ow suppr essi on

stomati ti s
pul monar y toxi ci ty, exhi bi ted as pneumoni ti s or pul monar y
fi br osi s
ski n r eacti ons, such as photosensi ti vi ty and hai r l oss.
 Kidney concerns
Wi th hi gh doses, ki dney toxi ci ty can al so occur wi th methotr exate
use. Dur i ng hi gh-dose therapy, l eucovor i n (fol i ni c aci d) may be
used i n a techni que known as leucovor in r escue to mi ni mi ze
adver se r eacti ons.
The spine of the matter
Adver se r eacti ons to i ntrathecal admi ni strati on (thr ough the dura
i nto the subarachnoi d space) of methotr exate may i ncl ude
sei z ur es, paral ysi s, and death. Other l ess sever e adver se
r eacti ons may al so occur, i ncl udi ng headaches, fever, neck
sti ffness, confusi on, and i r r i tabi l i ty.

Pyrimidine analogues
Pyr imidine analogues ar e a di ver se gr oup of dr ugs that i nhi bi t
pr oducti on of pyr i mi di ne nucl eoti des necessar y for DNA synthesi s.
They i ncl ude:

capeci tabi ne
cytarabi ne
fl oxur i di ne
fl uor ouraci l
gemci tabi ne.

Now I get it!

How pyrimidine analogues work
To under stand how pyr i mi di ne anal ogues wor k, i t hel ps to
consi der the basi c str uctur e of deoxyr i bonucl ei c aci d (DNA).
Climbing the ladder to understanding
DNA r esembl es a l adder that has been twi sted. The r ungs of the
l adder consi st of pai r s of ni tr ogenous bases: adeni ne al ways pai r s
wi th thymi ne, and guani ne al ways pai r s wi th cytosi ne. Cytosi ne
and thymi ne ar e pyr i mi di nes; adeni ne and guani ne ar e pur i nes.
One part sugar
The basi c uni t of DNA i s the nucl eoti de. A nucl eoti de i s the
bui l di ng bl ock of nucl ei c aci ds. It consi sts of a sugar, a ni tr ogen-
contai ni ng base, and a phosphate gr oup. Its on these components
 that pyr i mi di ne anal ogues do thei r wor k.
In the guise of a nucleotide
After pyr i mi di ne anal ogues ar e conver ted i nto nucl eoti des, theyr e
i ncor porated i nto DNA, wher e they may i nhi bi t DNA and
r i bonucl ei c aci d synthesi s as wel l as other metabol i c r eacti ons
necessar y for pr oper cel l gr owth.
Li ke most anti neopl asti c dr ugs, pyr i mi di ne anal ogues can cause:

Pharmacokinetics
Because pyr i mi di ne anal ogues ar e poor l y absor bed when theyr e
gi ven oral l y, theyr e usual l y admi ni ster ed by other r outes.

Distribution, metabolism, and excretion

Wi th the excepti on of cytarabi ne, pyr i mi di ne anal ogues ar e wel l
di str i buted thr oughout the body, i ncl udi ng i n cer ebr ospi nal fl ui d
(CSF ). Theyr e metabol i zed extensi vel y i n the l i ver and ar e excr eted
i n ur i ne. Intrathecal cytarabi ne may be gi ven wi th or wi thout
crani al radi ati on to tr eat CNS l eukemi a.

Pharmacodynamics
Pyr i mi di ne anal ogues ki l l cancer cel l s by i nter fer i ng wi th the
natural functi on of pyr i mi di ne nucl eoti des. (See How pyr i mi di ne
anal ogues wor k.)

Pharmacotherapeutics
Pyr i mi di ne anal ogues may be used to tr eat many tumor s. However,
theyr e pr i mar i l y i ndi cated i n the tr eatment of:

acute l eukemi as
G I tract adenocar ci nomas, such as col or ectal , pancr eati c,
esophageal , and stomach adenocar ci nomas

cancer s of the br east and ovar i es

mal i gnant l ymphomas.
 Warning!
Adverse reactions to pyrimidine analogues
Li ke most anti neopl asti c dr ugs, pyr i mi di ne anal ogues can
cause:

fati gue and l ack of ener gy

i nfl ammati on of the mouth, esophagus, and thr oat
bone mar r ow suppr essi on
nausea and anor exi a.

Cytarabine

Sever e cer ebel l ar neur otoxi ci ty

Chemi cal conjuncti vi ti s
Di ar r hea
Fever
Hand-foot syndr ome
Crab er ythema (when hi gh-dose cytarabi ne i s combi ned wi th
conti nuous i nfusi ons of fl uor ouraci l )

Fluorouracil

Di ar r hea
Hai r l oss
Mucosi ti s (when combi ned wi th fol i ni c aci d)

Drug interactions
No si gni fi cant dr ug i nteracti ons occur wi th most of the pyr i mi di ne
anal ogues; however, several dr ug i nteracti ons ar e possi bl e wi th
capeci tabi ne.

Antaci ds, when gi ven wi th capeci tabi ne, may i ncr ease absor pti on
of capeci tabi ne.
Capeci tabi ne can i ncr ease the phar macodynami c effects of
war far i n, ther eby i ncr easi ng the r i sk of bl eedi ng.
Capeci tabi ne may i ncr ease ser um phenytoi n l evel s. (See Adver se
 r eacti ons to pyr i mi di ne anal ogues.)

Purine analogues
Pur ine analogues ar e i ncor porated i nto DNA and RNA, i nter fer i ng
wi th nucl ei c aci d synthesi s and r epl i cati on. They i ncl ude:

fl udarabi ne phosphate
cl adr i bi ne
mer captopur i ne
pentostati n
thi oguani ne.

Pharmacokinetics
The phar macoki neti cs of pur i ne anal ogues ar ent cl ear l y defi ned.
Theyr e l ar gel y metabol i zed i n the l i ver and excr eted i n ur i ne.

Pharmacodynamics
As wi th the other anti metabol i tes, fl udarabi ne, mer captopur i ne, and
thi oguani ne fi r st must be conver ted vi a phosphor yl ati on
(i ntr oducti on to a phosphate) to the nucl eoti de l evel to be acti ve.
The r esul ti ng nucl eoti des ar e then i ncor porated i nto DNA, wher e
they may i nhi bi t DNA and RNA synthesi s as wel l as other metabol i c
r eacti ons necessar y for pr oper cel l gr owth. Cl adr i bi ne r esponds i n a
si mi l ar fashi on.

Analogous to pyrimide analogues

Thi s conver si on to nucl eoti des i s the same pr ocess that pyr i mi di ne
anal ogues go thr ough but, i n thi s case, i ts pur i ne nucl eoti des that
ar e affected. Pur i ne anal ogues ar e cel l cycl especi fi c as wel l ,
exer ti ng thei r effect dur i ng that same S phase.

Death to T cells
Pentostati n i nhi bi ts adenosi ne deami nase (ADA), causi ng an
i ncr ease i n i ntracel l ul ar l evel s of deoxyadenosi ne tr i phosphate. Thi s
l eads to cel l damage and death. The gr eatest acti vi ty of ADA i s i n
cel l s of the l ymphoi d system, especi al l y mal i gnant T cel l s.

Pharmacotherapeutics
Pur i ne anal ogues ar e used to tr eat acute and chr oni c l eukemi as and
may be useful i n the tr eatment of l ymphomas.

Drug interactions
No si gni fi cant i nteracti ons occur wi th cl adr i bi ne or thi oguani ne.

A serious flub with fludarabine

Taki ng fl udarabi ne wi th pentostati n may cause sever e pul monar y
toxi ci ty, whi ch can be fatal .
Taki ng pentostati n wi th al l opur i nol may i ncr ease the r i sk of
rash.
Taki ng pentostati n wi th vi darabi ne may enhance the effect of
vi darabi ne and i ncr ease the r i sk of toxi ci ty.

Warning!
Adverse reactions to purine analogues
Pur i ne anal ogues can cause:

bone mar r ow suppr essi on

nausea and vomi ti ng
 anor exi a
mi l d di ar r hea
stomati ti s
a r i se i n ur i c aci d l evel s.

High-dose horrors
F l udarabi ne, when used at hi gh doses, may cause sever e
neur ol ogi c effects, i ncl udi ng bl i ndness, coma, and death.

Down to the bone

Concomi tant admi ni strati on of mer captopur i ne and al l opur i nol
may i ncr ease bone mar r ow suppr essi on by decr easi ng
mer captopur i ne metabol i sm. (See Adver se r eacti ons to pur i ne
anal ogues.)

Antibiotic antineoplastic drugs

Antibiotic antineoplastic dr ugs ar e anti mi cr obi al pr oducts that
pr oduce tumor i ci dal (tumor-destr oyi ng) effects by bi ndi ng wi th DNA.
These dr ugs i nhi bi t the cel l ul ar pr ocesses of nor mal and mal i gnant
cel l s. They i ncl ude:

anthracycl i nes (daunor ubi ci n, doxor ubi ci n, i dar ubi ci n)

bl eomyci n
dacti nomyci n
mi tomyci n
mi toxantr one.

Pharmacokinetics
Anti bi oti c anti neopl asti c dr ugs ar e usual l y admi ni ster ed I.V.

Direct deliveries
Some dr ugs ar e al so admi ni ster ed di r ectl y i nto the body cavi ty
bei ng tr eated. Bl eomyci n, doxor ubi ci n, and mi tomyci n ar e
someti mes gi ven as topi cal bl adder i nsti l l ati ons, r esul ti ng i n
mi ni mal systemi c absor pti on. When bl eomyci n i s i njected i nto the
pl eural space for mal i gnant effusi ons, up to one-hal f of the dose i s
absor bed systemi cal l y.

Distribution, metabolism, and excretion

Di str i buti on of anti bi oti c anti neopl asti c dr ugs thr oughout the body
var i es; thei r metabol i sm and el i mi nati on al so var y.

Pharmacodynamics
Wi th the excepti on of mi tomyci n, anti bi oti c anti neopl asti c dr ugs
i nter cal ate, or i nser t themsel ves, between adjacent base pai r s of a
DNA mol ecul e, physi cal l y separati ng them.

Taking the extra base

Remember, DNA l ooks l i ke a twi sted l adder wi th the r ungs made up
of pai r s of ni tr ogenous bases. These dr ugs i nser t themsel ves
between those ni tr ogenous bases. Then, when the DNA chai n
r epl i cates, an extra base i s i nser ted opposi te the i nter cal ated
anti bi oti c, r esul ti ng i n a mutant DNA mol ecul e. The overal l effect i s
cel l death.

Clean break
Mi tomyci n i s acti vated i nsi de the cel l to a bi functi onal or even
tr i functi onal al kyl ati ng dr ug. Mi tomyci n pr oduces si ngl e-strand
br eakage of DNA. It al so cr oss-l i nks DNA and i nhi bi ts DNA
synthesi s.

Warning!
Adverse reactions to antibiotic antineoplastic
drugs
The pr i mar y adver se r eacti on to anti bi oti c anti neopl asti c dr ugs i s
bone mar r ow suppr essi on. Ir r ever si bl e car di omyopathy and acute
el ectr ocar di ogram changes can al so occur as wel l as nausea and
vomi ti ng.
Extra steps
An anti hi stami ne and an anti pyr eti c shoul d be gi ven befor e
bl eomyci n to pr event fever and chi l l s. Anaphyl acti c r eacti ons can
 occur i n pati ents r ecei vi ng bl eo-myci n for l ymphoma, so test
doses shoul d be gi ven fi r st.
Seeing colors
Doxor ubi ci n may col or ur i ne r ed; mi toxantr one may col or i t bl ue-
gr een.

Pharmacotherapeutics
Anti bi oti c anti neopl asti c dr ugs act agai nst many cancer s, i ncl udi ng:

acute l eukemi a
br east, ovar i an, bl adder, and l ung cancer
cancer s of the G I tract
chor i ocar ci noma
Ewi ngs sar coma (a mal i gnant tumor that or i gi nates i n bone
mar r ow, typi cal l y i n l ong bones or the pel vi s) and other soft-
ti ssue sar comas
Hodgki ns di sease and mal i gnant l ymphomas
mel anoma
osteogeni c sar coma and r habdomyosar coma (mal i gnant neopl asm
composed of str i ated muscl e cel l s)
squamous cel l car ci noma of the head, neck, and cer vi x
testi cul ar cancer
Wi l ms tumor (a mal i gnant neopl asm of the ki dney, occur r i ng i n
young chi l dr en).

Drug interactions
Anti bi oti c anti neopl asti c dr ugs i nteract wi th many other dr ugs. (See
Adver se r eacti ons to anti bi oti c anti neopl asti c dr ugs.)

Concur r ent therapy wi th fl udarabi ne and i dar ubi ci n i snt

r ecommended because of the r i sk of fatal l ung toxi ci ty.
Bl eomyci n may decr ease ser um di goxi n and ser um phenytoi n
l evel s.
Doxor ubi ci n may r educe ser um di goxi n l evel s.
 Combi nati on chemotherapi es enhance l eukopeni a and
thr ombocytopeni a (r educed number of pl atel ets).
Mi tomyci n pl us vi nca al kal oi ds may cause acute r espi rator y
di str ess.

Hormonal antineoplastic drugs and hormone

modulators
Hor monal antineoplastic dr ugs and hor mone modulator s ar e
pr escr i bed to al ter the gr owth of mal i gnant neopl asms or to manage
and tr eat thei r physi ol ogi c effects.

Hitting them where it hurts

Hor monal therapi es and hor mone modul ator s pr ove effecti ve agai nst
hor mone-dependent tumor s, such as cancer s of the pr os-tate,
br east, and endometr i um. Lymphomas and l eukemi as ar e usual l y
tr eated wi th therapi es that i ncl ude cor ti coster oi ds because of thei r
potenti al for affecti ng l ymphocytes.

Aromatase inhibitors
In postmenopausal women, estr ogen i s pr oduced thr ough ar omatase,
an enz yme that conver ts hor mone pr ecur sor s i nto estr ogen.
Ar omatase inhibitor s pr event andr ogen fr om bei ng conver ted i nto
estr ogen i n postmenopausal women, ther eby bl ocki ng estr ogens
abi l i ty to acti vate cancer cel l s; l i mi ti ng the amount of estr ogen
means that l ess estr ogen i s avai l abl e to r each cancer cel l s and make
them gr ow.
Two types
Ther e ar e two types of ar omatase i nhi bi tor s. Type 1, or ster oidal,
i nhi bi tor s i ncl ude exemestane; type 2, or nonster oidal, i nhi bi tor s
i ncl ude anastr ozol e and l etr ozol e.

Pharmacokinetics
Ar omatase i nhi bi tor s ar e taken oral l y (i n pi l l for m) and ar e usual l y
wel l tol erated. Steady-state pl asma l evel s after dai l y doses ar e
r eached i n 2 to 6 weeks. Inacti ve metabol i tes ar e excr eted i n ur i ne.

Pharmacodynamics
Ar omatase i nhi bi tor s wor k by l ower i ng the bodys pr oducti on of
estr ogen. In about one-hal f of al l pati ents wi th br east cancer, the
tumor s depend on estr ogen to gr ow. Ar omatase i nhi bi tor s ar e used
onl y i n postmenopausal women because they l ower the amount of
estr ogen thats pr oduced outsi de the ovar i es, such as i n muscl e and
fat ti ssue. Because these dr ugs i nduce estr ogen depr i vati on, bone
thi nni ng and osteopor osi s may devel op over ti me.

To reverse or not to reverse: That is the

question
Type 1 i nhi bi tor s, such as exemestane, i r r ever si bl y i nhi bi t the
ar omatase enz yme, wher eas type 2 i nhi bi tor s, such as anastr ozol e,
r ever si bl y i nhi bi t i t. Type 1 ar omatase i nhi bi tor s may sti l l be
effecti ve after a type 2 ar omatase i nhi bi tor has fai l ed.

Memory jogger
Remember : Hor monal -dependent (gender speci fi c) tumor s ar e
tr eated wi th hor monal therapi es; tumor s common to both
gender s ar e tr eated wi th cor ti coster oi ds.

Competitive advantage
Anastr oz al e and l etr ozol e wor k by competi ti vel y bi ndi ng to heme of
the cytochr ome P450 subuni t of ar omatase, l eadi ng to decr eased
l evel s of estr ogen i n al l ti ssues; they dont affect synthesi s of
adr enocor ti coster oi ds, al doster one, or thyr oi d hor mones.
Pharmacotherapeutics
Ar omatase i nhi bi tor s ar e pr i mar i l y used to tr eat postmenopausal
women wi th metastati c br east cancer. They may be admi ni ster ed
al one or wi th other agents such as tamoxi fen.

Drug interactions
Cer tai n dr ugs may decr ease the effecti veness of anastr ozol e,
i ncl udi ng tamoxi fen and estr ogen-contai ni ng dr ugs. (See Adver se
r eacti ons to ar omatase i nhi bi tor s.)

Warning!
Adverse reactions to aromatase inhibitors
Adver se r eacti ons to ar omatase i nhi bi tor s ar e rar e. They
may i ncl ude di z z i ness, mi l d nausea, mi l d muscl e and joi nt aches,
and hot fl ashes.
Occasi onal l y, ar omatase i nhi bi tor s can al so affect chol ester ol
l evel s; anastrazol e may el evate both hi gh-densi ty and l ow-densi ty
l i popr otei n l evel s.

Antiestrogens
Antiestr ogens bi nd to estr ogen r eceptor s and bl ock estr ogen acti on.
The anti estr ogens i ncl ude tamoxifen citr ate, tor emifene citr ate, and
fulvestr ant. Tamoxi fen and tor emi fene ar e nonster oi dal estr ogen
agoni st-antagoni sts, and ful vestrant i s a pur e estr ogen antagoni st.

Pharmacokinetics
After oral admi ni strati on, tamoxi fen i s wel l absor bed and under goes
extensi ve metabol i sm i n the l i ver befor e bei ng excr eted i n stool .
Ser um l evel s of ful vestrant, when gi ven I.M., peak i n 7 to 9 days.
Its hal f-l i fe i s 40 days. Tor emi fene i s wel l absor bed, and absor pti on
i snt i nfl uencd by food.

Pharmacodynamics
The exact anti neopl asti c acti on of these agents i snt known.
However, theyr e known to act as estr ogen antagoni sts. Estr ogen
r eceptor s, found i n the cancer cel l s of one-hal f of pr emenopausal
and thr ee-four ths of postmenopausal women wi th br east cancer,
r espond to estr ogen to i nduce tumor gr owth.
Its bound to inhibit growth
The anti estr ogens ful vestrant, tamoxi fen, and tor emi fene bi nd to
the estr ogen r eceptor s and i nhi bi t estr ogen-medi ated tumor gr owth
i n br east ti ssue. Tamoxi fen may be abl e to do thi s because i t bi nds
to r eceptor s at the nucl ear l evel or because the bi ndi ng r educes the
number of fr ee r eceptor s i n the cytopl asm. Ul ti matel y, DNA
synthesi s and cel l gr owth ar e i nhi bi ted.

Yea or nay?
Who benefits from tamoxifen?
The cur r ent i ndi cati on for the use of tamoxi fen i s based on
the 1998 r esul ts of the Br east Cancer Pr eventi on Tr i al ,
sponsor ed by the Nati onal Cancer Insti tute. Resul ts i ndi cated that
tamoxi fen r educed the rate of br east cancer i n heal thy hi gh-r i sk
women by one-hal f. However, tamoxi fen has ser i ous adver se
effects that i ncl ude potenti al l y fatal bl ood cl ots and uter i ne
cancer. The questi on i s whether these r i sks ar e wor th the benefi ts
i n heal thy women.
The National Cancer Institutes report
To hel p answer thi s questi on, the Nati onal Cancer Insti tute
publ i shed a r epor t i n November of 1999. They concl uded that
most women ol der than age 60 woul d r ecei ve mor e har m than
benefi t fr om tamoxi fen. Even though women younger than age 60
coul d benefi t fr om taki ng tamoxi fen, they wer e sti l l at r i sk unl ess
they had a hyster ectomy, whi ch el i mi nated the r i sk of uter i ne
cancer or wer e i n the ver y hi gh-r i sk gr oup for devel opi ng br east
cancer.
Breaking it down further
The r epor t al so concl uded that the r i sks of tamoxi fen wer e
gr eater than the benefi ts for bl ack women ol der than age 60 and
al most al l other women ol der than age 60 who sti l l had a uter us.
But for ol der women wi thout a uter us and wi th a 3.5% chance of
devel opi ng br east cancer over the next 5 year s, the benefi ts may
outwei gh the r i sks.
NSABP studies update
A r epor t fr om the 2000 annual meeti ng of the Amer i can Soci ety
of Cl i ni cal Oncol ogy, pr esented an anal ysi s of data gather ed fr om
the Nati onal Sur gi cal Adjuvant Br east and Bowel Pr ojects
(NSABPs) ni ne studi es of adjuvant tamoxi fen for br east cancer.
The data anal ysi s i ndi cates that tamoxi fen i s as effecti ve i n Bl ack
women as i n Whi te women i n r educi ng the occur r ence of
contral ateral br east cancer (br east cancer that devel ops i n the
heal thy br east after tr eatment i n the opposi te br east).
Future findings
The Study of Tamoxi fen and Ral oxi fene (STAR), i s a cl i ni cal tr i al
that was conducted to deter mi ne whether ral oxi fene can pr event
br east cancer better and wi th fewer adver se effects than
tamoxi fen. The study began i n 1999 and r ecentl y concl uded. The
r esul ts showed that the ral oxi fem-tr eated gr oup had a l ower
i nci dence of uter i ne cancer and cl otti ng events than the
tamoxi fen gr oup.
Pharmacotherapeutics
Tamoxi fen i s used al one and as adjuvant tr eatment wi th radi ati on
therapy and sur ger y i n women wi th negati ve axi l l ar y l ymph nodes
and i n postmenopausal women wi th posi ti ve axi l l ar y nodes. Its used
for advanced br east cancer i nvol vi ng estr ogen r eceptor posi ti ve
tumor s i n postmenopausal women and may be used i n pal l i ati ve
tr eatment of advanced or metastati c br east cancer thats estr ogen
r eceptor posi ti ve. Tumor s i n postmenopausal women ar e mor e
r esponsi ve to tamoxi fen than those i n pr emenopausal women.
Tamoxi fen may al so be used to r educe the i nci dence of br east
cancer i n women at hi gh r i sk.

Tor emi fene i s used to tr eat metastati c br east cancer i n

postmenopausal women wi th estr ogen r eceptor posi ti ve tumor s.
F ul vestrant i s used i n postmenopausal women wi th r eceptor-posi ti ve
metastati c br east cancer wi th di sease pr ogr essi on after tr eatment
wi th tamoxi fen. (See Who benefi ts fr om tamoxi fen? page 389.)

Drug interactions
Ther e ar e no known dr ug i nteracti ons for ful vestrant. However,
these r eacti ons may occur wi th other anti estr ogens:

Tamoxi fen and tor emi fene i ncr ease the effects of war far i n,
i ncr easi ng the r i sk of bl eedi ng.
Br omocr i pti ne i ncr eases the effects of tamoxi fen.
Dr ugs that i nduce cer tai n l i ver enz ymes, such as phenytoi n,
r i fampi n, and car bamazepi ne, may i ncr ease tamoxi fen
metabol i sm, causi ng decr eased ser um l evel s. (See Adver se
r eacti ons to anti estr ogens.)

Warning!
Adverse reactions to antiestrogens
The most common adver se r eacti ons to anti estr ogens, such
as tamoxi fen, tor emi fene, and ful vestrant, i ncl ude:

hot fl ashes
nausea
 vomi ti ng.

Tamoxifen

Di ar r hea
F l ui d r etenti on
Vagi nal bl eedi ng

Toremifene

Vagi nal di schar ge or bl eedi ng

Edema

Fulvestrant

Di ar r hea
Consti pati on
Abdomi nal pai n
Headache
Backache
Phar yngi ti s

Androgens
The therapeuti cal l y useful andr ogens ar e syntheti c der i vati ves of
natural l y occur r i ng testoster one. They i ncl ude:

fl uoxymester one
testol actone
testoster one enanthate
testoster one pr opi onate.

Pharmacokinetics
The phar macoki neti c pr oper ti es of therapeuti c andr ogens r esembl e
those of natural l y occur r i ng testoster one.
Absorption
The oral andr ogensfl uoxymester one and testol actonear e wel l
absor bed. The par enteral onestestoster one enanthate and
testoster one pr opi onatear e desi gned speci fi cal l y for sl ow absor pti on
after I.M. i njecti on.

Distribution, metabolism, and excretion

Andr ogens ar e wel l di str i buted thr oughout the body, metabol i zed
extensi vel y i n the l i ver, and excr eted i n ur i ne.

Checking the suspension

The durati on of the par enteral for ms i s l onger because the oi l
suspensi on i s absor bed sl owl y. Par enteral andr ogens ar e
admi ni ster ed one to thr ee ti mes per week.

Pharmacodynamics
Andr ogens pr obabl y act by one or mor e mechani sms. They may
r educe the number of pr ol acti n r eceptor s or may bi nd competi ti vel y
to those that ar e avai l abl e.

Keeping its sister hormone in check

Andr ogens may i nhi bi t estr ogen synthesi s or competi ti vel y bi nd at
estr ogen r eceptor s. These acti ons pr event estr ogen fr om affecti ng
estr ogen-sensi ti ve tumor s.

Pharmacotherapeutics
Andr ogens ar e i ndi cated for the pal l i ati ve tr eatment of advanced
br east cancer, par ti cul ar l y i n postmenopausal women wi th bone
metastasi s.

Drug interactions
Andr ogens may al ter dose r equi r ement i n pati ents r ecei vi ng i nsul i n,
oral anti di abeti c dr ugs, or oral anti coagul ants. Taki ng them wi th
dr ugs that ar e toxi c to the l i ver i ncr eases the r i sk of l i ver toxi ci ty.
(See Adver se r eacti ons to andr ogens.)
 Warning!
Adverse reactions to androgens
Nausea and vomi ti ng ar e the most common adver se
r eacti ons to andr ogens. F l ui d r etenti on caused by sodi um
r etenti on may al so occur.
Just for women
Women may devel op:

acne
cl i toral hyper tr ophy
deeper voi ce
i ncr eased faci al and body hai r
i ncr eased sexual desi r e
menstr ual i r r egul ar i ty.

Just for men

Men may exper i ence these effects as a r esul t of conver si on of
ster oi ds to femal e sex hor mone metabol i tes:

gynecomasti a
pr ostati c hyper pl asi a
testi cul ar atr ophy.

Just for kids

Chi l dr en may devel op:

pr ematur e epi physeal cl osur e

secondar y sex character i sti c devel opments (especi al l y i n
boys).

Antiandrogens
Antiandr ogens ar e used as an adjunct therapy wi th gonadotr opi n-
r el easi ng hor mone anal ogues i n tr eati ng advanced pr ostate cancer.
These dr ugs i ncl ude:

fl utami de
 ni l utami de
bi cal utami de.

Pharmacokinetics
After oral admi ni strati on, anti andr ogens ar e absor bed rapi dl y and
compl etel y.

Metabolism and excretion

Anti andr ogens ar e metabol i zed rapi dl y and extensi vel y and excr eted
pr i mar i l y i n ur i ne.

Pharmacodynamics
F l utami de, ni l utami de, and bi cal utami de exer t thei r anti andr ogeni c
acti on by i nhi bi ti ng andr ogen uptake or pr eventi ng andr ogen
bi ndi ng i n cel l nucl ei i n tar get ti ssues.

Pharmacotherapeutics
Anti andr ogens ar e used wi th a gonadotr opi n-r el easi ng hor mone
anal ogue, such as l eupr ol i de, to tr eat metastati c pr ostate cancer.

Special feature: no flareup

Concomi tant admi ni strati on of anti andr ogens and a gonadotr opi n-
r el easi ng hor mone anal ogue may hel p pr event the di sease fl ar e that
occur s when the gonadotr opi n-r el easi ng hor mone anal ogue i s used
al one.
Drug interactions
Anti andr ogens dont i nteract si gni fi cantl y wi th other dr ugs.
However, fl utami de and bi cal utami de may affect pr othr ombi n ti me
(a test to measur e cl otti ng factor s) i n a pati ent r ecei vi ng war far i n.
(See Adver se r eacti ons to anti andr ogens.)

Progestins
Pr ogestins ar e hor mones used to tr eat var i ous for ms of cancer.
These dr ugs i ncl ude:

hydr oxypr ogester one capr oate

medr oxypr ogester one acetate
megestr ol acetate.

Pharmacokinetics
When taken oral l y, megestr ol acetate i s wel l absor bed. After I.M.
i njecti on i n an aqueous or oi l suspensi on, hydr oxypr ogester one
capr oate and medr oxypr ogester one ar e absor bed sl owl y fr om thei r
deposi t si tes.

Warning!
Adverse reactions to antiandrogens
When anti andr ogens ar e used wi th gonadotr opi n-r el easi ng
hor mone anal ogues, the most common adver se r eacti ons ar e:
 hot fl ashes
decr eased sexual desi r e
i mpotence
di ar r hea
nausea
vomi ti ng
br east enl ar gement.

Distribution, metabolism, and excretion

These dr ugs ar e wel l di str i buted thr oughout the body and may
sequester i n fatty ti ssue. Pr ogesti ns ar e metabol i zed i n the l i ver
and excr eted as metabol i tes i n ur i ne.

Pharmacodynamics
The mechani sm of acti on of pr ogesti ns i n tr eati ng tumor s i snt
compl etel y under stood. Resear cher s bel i eve the dr ugs bi nd to a
speci fi c r eceptor to act on hor monal l y sensi ti ve cel l s.

They arent exhibitionists

Because pr ogesti ns dont exhi bi t a cytotoxi c acti vi ty (destr oyi ng or
poi soni ng cel l s), theyr e consi der ed cytostati c (they keep the cel l s
fr om mul ti pl yi ng).

Pharmacotherapeutics
Pr ogesti ns ar e used for the pal l i ati ve tr eatment of advanced
endometr i al , br east, pr ostate, and r enal cancer s. Of these dr ugs,
megestr ol i s used most commonl y.

Drug interactions
No dr ug i nteracti ons have been i denti fi ed for megestr ol . However,
other pr ogesti ns do have si gni fi cant i nteracti ons wi th other dr ugs.

Bar bi turates, car bamazepi ne, and r i fampi n r educe the pr ogesti n
effects of hydr oxypr ogester one.
Hydr oxypr ogester one and medr oxypr ogester one may i nter fer e
 wi th br omocr i pti nes effects, causi ng menstr uati on to stop.
Hydr oxypr ogester one taken wi th dantr ol ene and other l i ver-toxi c
dr ugs i ncr eases the r i sk of l i ver toxi ci ty.
Dose adjustments i n oral anti coagul ants may be needed when
theyr e taken wi th hydr oxypr ogester one.
Ami nogl utethi mi de and r i fampi n may r educe the pr ogesti n
effects of medr oxypr ogester one. (See Adver se r eacti ons to
pr ogesti ns.)

Warning!
Adverse reactions to progestins
Mi l d fl ui d r etenti on i s pr obabl y the most common r eacti on
to pr ogesti ns. Other adver se r eacti ons i ncl ude:

thr omboembol i
br eakthr ough bl eedi ng, spotti ng, and changes i n menstr ual
fl ow
br east tender ness
l i ver functi on abnor mal i ti es.

Oil issues
Pati ents who ar e hyper sensi ti ve to the oi l car r i er used for
i njecti on (usual l y sesame or castor oi l ) may exper i ence a l ocal or
systemi c hyper sensi ti vi ty r eacti on.

Gonadotropin-releasing hormone analogues

G onadotr opin-r eleasing hor mone analogues ar e used for tr eatment
of advanced pr ostate cancer. They i ncl ude:

goser el i n
l eupr ol i de
tr i ptor el i n.

Pharmacokinetics
G oser el i n i s absor bed sl owl y for the fi r st 8 days of therapy and
rapi dl y and conti nuousl y ther eafter. After subcutaneous i njecti on,
l eupr ol i de i s wel l absor bed. Nei ther dr ugs di str i buti on, metabol i sm,
or excr eti on i s defi ned cl ear l y.

Tr i ptor el i n ser um l evel s peak wi thi n 1 week of I.M. i njecti on; the
dr ug r emai ns detectabl e i n ser um for 4 weeks.

Warning!
Adverse reactions to gonadotropin-releasing
hormone analogues
Hot fl ashes, i mpotence, and decr eased sexual desi r e ar e
commonl y r epor ted r eacti ons to gonadotr opi n-r el easi ng hor mone
anal ogues. Other adver se r eacti ons i ncl ude:

per i pheral edema

nausea and vomi ti ng
consti pati on
anor exi a.

Flares and flashes

Di sease symptoms and pai n may wor sen or fl ar e dur i ng the fi r st 2
weeks of goser el i n or l eupr ol i de therapy. The fl ar e can be fatal i n
pati ents wi th bony ver tebral metastasi s.
Tr i ptor el i n may cause hot fl ashes and skel etal pai n. Less
commonl y, i t may cause hyper tensi on, di ar r hea, vomi ti ng, ur i ne
r etenti on, and i mpotence.
Pharmacodynamics
G oser el i n and l eupr ol i de act on the mal es pi tui tar y gl and to
i ncr ease l utei ni z i ng hor mone (LH) secr eti on, whi ch sti mul ates
testoster one pr oducti on. The peak testoster one l evel i s r eached
about 72 hour s after dai l y admi ni strati on.

Running the reverse

Wi th l ong-ter m admi ni strati on, however, goser el i n and l eupr ol i de
i nhi bi t LH r el ease fr om the pi tui tar y and subsequentl y i nhi bi t
testi cul ar r el ease of testoster one. Because pr ostate tumor cel l s ar e
sti mul ated by testoster one, the r educed testoster one l evel i nhi bi ts
tumor gr owth.

Then theres triptorelin

Tr i ptor el i n i s a potent i nhi bi tor of gonadotr opi n secr eti on. After the
fi r st dose, l evel s of LH, fol l i cl e-sti mul ati ng hor mone (F SH),
testoster one, and estradi ol sur ge transi entl y. After l ong-ter m
conti nuous admi ni strati on, LH and F SH secr eti on steadi l y decl i nes
and testi cul ar and ovar i an ster oi d pr oducti on decr eases. In men,
testoster one decl i nes to a l evel typi cal l y seen i n sur gi cal l y castrated
men. As a r esul t, ti ssues and functi ons that depend on these
hor mones become i nacti ve.

Pharmacotherapeutics
G oser el i n, l eupr ol i de, and tr i ptor el i n ar e used for the pal l i ati ve
tr eatment of metastati c pr ostate cancer. The dr ugs l ower the
testoster one l evel wi thout the adver se psychol ogi cal effects of
castrati on or the adver se car di ovascul ar effects of di ethyl sti l bestr ol .

Drug interactions
No dr ug i nteracti ons have been i denti fi ed wi th goser el i n, l eupr ol i de,
or tr i ptor el i n. (See Adver se r eacti ons to gonadotr opi n-r el easi ng
hor mone anal ogues.)

Natural antineoplastic drugs

A subcl ass of anti neopl asti c dr ugs known as natur al pr oducts
i ncl udes:
 vi nca al kal oi ds
podophyl l otoxi ns.

Vinca alkaloids
Vinca alkaloids ar e ni tr ogenous bases der i ved fr om the per i wi nkl e
pl ant. These dr ugs ar e cel l cycl especi fi c for the M phase and
i ncl ude:

vi nbl asti ne
vi ncr i sti ne
vi nor el bi ne.

Pharmacokinetics
After I.V. admi ni strati on, the vi nca al kal oi ds ar e wel l di str i buted
thr oughout the body.

Metabolism and excretion

Vi nca al kal oi ds under go moderate l i ver metabol i sm befor e bei ng
el i mi nated thr ough di ffer ent phases, pr i mar i l y i n stool wi th a smal l
per centage el i mi nated i n ur i ne.

Pharmacodynamics
Vi nca al kal oi ds may di sr upt the nor mal functi on of the mi cr otu-
bul es (str uctur es wi thi n cel l s that ar e associ ated wi th the movement
of DNA) by bi ndi ng to the pr otei n tubul i n i n the mi cr otu-bul es.

Separation anxiety
Wi th the mi cr otubul es unabl e to separate chr omosomes pr oper l y,
the chr omosomes ar e di sper sed thr oughout the cytopl asm or
ar ranged i n unusual gr oupi ngs. As a r esul t, for mati on of the mi toti c
spi ndl e i s pr evented, and the cel l s cant compl ete mi tosi s (cel l
di vi si on).

Under arrest
Cel l di vi si on i s ar r ested i n metaphase, causi ng cel l death.
Ther efor e, vi nca al kal oi ds ar e cel l cycl especi fi c for the M phase.
Inter r upti on of the mi cr otubul e functi on may al so i mpai r some types
of cel l ul ar movement, phagocytosi s (engul fi ng and destr oyi ng mi cr o-
or gani sms and cel l ul ar debr i s), and CNS functi ons.

Pharmacotherapeutics
Vi nca al kal oi ds ar e used i n several therapeuti c si tuati ons:

Vi nbl asti ne i s used to tr eat metastati c testi cul ar cancer,

l ymphomas, Kaposi s sar coma (the most common acqui r ed
i mmunodefi ci ency syndr ome [AIDS]r el ated cancer ),
neur obl astoma (a hi ghl y mal i gnant tumor or i gi nati ng i n the
sympatheti c ner vous system), br east cancer, and
chor i ocar ci noma.
Vi ncr i sti ne i s used i n combi nati on therapy to tr eat Hodgki ns
di sease, non-Hodgki ns l ymphoma, Wi l ms tumor,
r habdomyosar coma, and acute l ymphocyti c l eukemi a.
Vi nor el bi ne i s used to tr eat nonsmal l -cel l l ung cancer. It may
al so be used i n the tr eatment of metastati c br east cancer,
ci spl ati n-r esi stant ovar i an cancer, and Hodgki ns di sease.
Drug interactions
Vi nca al kal oi ds can i nteract wi th other dr ugs.

Er ythr omyci n may i ncr ease the toxi ci ty of vi nbl asti ne.
Vi nbl asti ne decr eases the pl asma l evel s of phenytoi n.
Vi ncr i sti ne r educes the effects of di goxi n.
Asparagi nase decr eases l i ver metabol i sm of vi ncr i sti ne,
i ncr easi ng the r i sk of toxi ci ty.
Cal ci um channel bl ocker s enhance vi ncr i sti ne accumul ati on,
i ncr easi ng the tendency for toxi ci ty. (See Adver se r eacti ons to
vi nca al kal oi ds.)

Warning!
Adverse reactions to vinca alkaloids
Nausea, vomi ti ng, consti pati on, and stomati ti s may occur i n
pati ents taki ng vi nca al kal oi ds. Ti ssue necr osi s may al so occur
wi th extravasati on.
Toxic topics
Vi nbl asti ne and vi nor el bi ne toxi ci ti es occur pr i mar i l y as bone
mar r ow suppr essi on.
Muscle matters
Neur omuscul ar abnor mal i ti es commonl y occur wi th vi ncr i sti ne and
vi nor el bi ne and, occasi onal l y, wi th vi nbl asti ne therapy.
Tumor trouble
Vi nbl asti ne may pr oduce tumor pai n descr i bed as an i ntense
sti ngi ng or bur ni ng i n the tumor bed, wi th an abr upt onset 1 to 3
mi nutes after dr ug admi ni strati on. The pai n usual l y l asts 20
mi nutes to 3 hour s.
Less hair there
Rever si bl e al opeci a occur s i n up to one-hal f of pati ents r ecei vi ng
vi nca al kal oi ds; i ts mor e l i kel y to occur wi th vi ncr i sti ne than wi th
vi nbl asti ne.

Podophyllotoxins
Podophyllotoxins ar e semi syntheti c gl ycosi des that ar e cel l
cycl especi fi c and act dur i ng the G 2 and l ate S phases of the cel l
cycl e. They i ncl ude:

etoposi de
teni posi de.

Outside activities
Etoposi de i s effecti ve i n the tr eatment of testi cul ar cancer, non-
Hodgki ns l ymphoma, l ung cancer, and acute l eukemi a. Teni posi de
has demonstrated some acti vi ty i n tr eati ng Hodgki ns di sease,
l ymphomas, and brai n tumor s.

Pharmacokinetics
When taken oral l y, podophyl l otoxi ns ar e onl y moderatel y absor bed.
Al though the dr ugs ar e wi del y di str i buted thr oughout the body, they
achi eve poor CSF l evel s.

Metabolism and excretion

Podophyl l otoxi ns under go l i ver metabol i sm and ar e excr eted
pr i mar i l y i n ur i ne.

Pharmacodynamics
Al though thei r mechani sm of acti on i snt compl etel y under stood,
podophyl l otoxi ns pr oduce several bi ochemi cal changes i n tumor
cel l s.

Arresting development
At l ow concentrati ons, these dr ugs bl ock cel l s at the l ate S or G 2
phase. At hi gher concentrati ons, they ar r est the cel l s i n the G 2
phase.

Breaking a rung on the ladder

Podophyl l otoxi ns can al so br eak one of the strands of the DNA
mol ecul e and can i nhi bi t nucl eoti de transpor t and i ncor porati on i nto
nucl ei c aci ds.

Pharmacotherapeutics
Etoposi de i s used to tr eat testi cul ar cancer l ymphomas, pr ostate
cancer, and smal l -cel l l ung cancer. Teni posi de i s used to tr eat acute
l ymphobl asti c l eukemi a.

Drug interactions
Podophyl l otoxi ns have few si gni fi cant i nteracti ons wi th other dr ugs.

Etoposi de may i ncr ease the r i sk of bl eedi ng i n a pati ent taki ng

war far i n.
Teni posi de may i ncr ease the cl earance and i ntracel l ul ar l evel s of
methotr exate. (See Adver se r eacti ons to podophyl l otoxi ns.)

Warning!
Adverse reactions to podophyllotoxins
The major i ty of pati ents r ecei vi ng podophyl l otoxi ns
exper i ence hai r l oss. Other adver se r eacti ons i ncl ude:

nausea and vomi ti ng

anor exi a
stomati ti s
bone mar r ow suppr essi on, causi ng l eukopeni a and, l ess
commonl y, thr ombocytopeni a
acute hypotensi on (i f a podophyl l otoxi n i s i nfused too rapi dl y
I.V.).
Monoclonal antibodies
Recombi nant DNA technol ogy has al l owed for the devel opment of
monoclonal antibodies di r ected at such tar gets as other i mmune
cel l s or cancer cel l s. Monocl onal anti bodi es i ncl ude:

al emtuz umab
gemtuz umab ozogami ci n
i br i tumomab ti uxetan
r i tuxi mab
trastuz umab.

Pharmacokinetics
Because of thei r l ar ge pr otei n mol ecul e str uctur e, monocl onal
anti bodi es ar ent absor bed oral l y. They may have a l i mi ted
di str i buti on as wel l as a l ong hal f-l i fe, someti mes measur ed i n
weeks.

Pharmacodynamics
Monocl onal anti bodi es bi nd to tar get r eceptor s or cancer cel l s and
cause tumor death vi a several mechani sms: They may i nduce
pr ogrammed cel l death; they may r ecr ui t other el ements of the
i mmune system to attack the cancer cel l ; or they may del i ver a
dose of a toxi c chemotherapy dr ug (gemtuz umab) or radi ati on
(i br i tumomab) to the tumor si te.

Pharmacotherapeutics
Monocl onal anti bodi es have demonstrated acti vi ty i n both sol i d
tumor s and hematol ogi c mal i gnanci es, such as:

non-Hodgki ns l ymphomar i tuxi mab and i br i tumomab (tar get

CD20 or mal i gnant B l ymphocytes)
chr oni c l ymphocyti c l eukemi aal emtuz umab (tar get CD52 anti gen
or B cel l s)
acute myel oi d l eukemi agemtuz umab (tar get CD33 anti gen i n
 myel oi d l eukemi c cel l s)
br east cancer trastuz umab (tar get HER-2 pr otei n i n br east
cancer cel l s).

Drug interactions
Al though no i nteracti ons have been noted wi th al emtuz umab,
mul ti pl e dr ug i nteracti ons ar e associ ated wi th other monocl onal
anti bodi es.

Ibr i tumomab may i nter fer e wi th the acti ons of such dr ugs as
war far i n, aspi r i n, cl opi dogr el , ti cl opi di ne, nonster oi dal anti -
i nfl ammator y dr ugs, az athi opr i ne, cycl ospor i ne, and
cor ti coster oi ds.
Trastuz umab i ncr eases the car di ac toxi ci ty associ ated wi th
anthracycl i ne admi ni strati on. (See Adver se r eacti ons to
monocl onal anti bodi es.)

Topoisomerase I inhibitors
Topoisomer ase I inhibitor s ar e der i vati ves of camptotheci n and
i nhi bi t the enz yme topoi somerase I. These agents ar e der i ved fr om
a natural l y occur r i ng al kal oi d fr om the Chi nese tr ee Camptotheca
acuminata. Cur r entl y avai l abl e topoi somerase I i nhi bi tor s i ncl ude:

i r i notecan
 topotecan.

Pharmacokinetics
Both i r i notecan and topotecan ar e mi ni mal l y absor bed and must be
gi ven I.V. Ir i notecan under goes metabol i c changes to become the
acti ve metabol i te SN-38. The hal f-l i fe of SN-38 i s about 10 hour s;
SN-38 i s el i mi nated thr ough bi l i ar y excr eti on. Topotecan i s
metabol i zed by the l i ver, al though r enal excr eti on i s a si gni fi cant
path for el i mi nati on.

Pharmacodynamics
Topoi somerase I i nhi bi tor s exer t thei r cytotoxi c effect by i nhi bi ti ng
topoi somerase I enz yme, an essenti al enz yme that medi ates the
r el axati on of super coi l ed DNA.

Warning!
Adverse reactions to monoclonal antibodies
Al l monocl onal anti bodi es ar e associ ated wi th i nfusi on-
r el ated r eacti ons that have occasi onal l y been fatal . These i ncl ude
fever, chi l l s, shor tness of br eath, l ow bl ood pr essur e, and
anaphyl axi s.
In addi ti on, the fol l owi ng adver se r eacti ons can occur :

Al emtuz umab i s associ ated wi th myel osuppr essi on and an

i ncr eased r i sk of oppor tuni sti c i nfecti ons, such as
pneumocysti ti s, pneumoni a, and fungal and vi ral i nfecti ons.
G emtuz umab ozogami ci n i s associ ated wi th si gni fi cant
myel osuppr essi on and l i ver toxi ci ty.
Ibr i tumomab ti uxetan i s associ ated wi th i ncr eased
myel osuppr essi on to r i tuxi mab.

Its all about that DNA

Topoi somerase i nhi bi tor s bi nd to the DNA topoi somerase I compl ex
and pr event r eseal i ng, ther eby causi ng DNA strand br eaks. Thi s
r esul ts i n i mpai r ed DNA synthesi s.

Pharmacotherapeutics
Topoi somerase I i nhi bi tor s act agai nst both sol i d tumor s and
hematol ogi c mal i gnanci es:

Ir i notecan i s used to tr eat col or ectal cancer and smal l -cel l l ung
cancer.

Topotecan i s used to tr eat ovar i an cancer, smal l -cel l l ung cancer,

and acute myel oi d l eukemi a.

Drug interactions
Topoi somerase I i nhi bi tor s, par ti cul ar l y i r i notecan, can i nteract wi th
other dr ugs.

Ketoconazol e si gni fi cantl y i ncr eases SN-38 ser um l evel s, ther eby
i ncr easi ng the r i sk of i r i notecan-associ ated toxi ci ti es.
Ir i notecan when taken wi th di ur eti cs may exacer bate
dehydrati on caused by i r i notecan-i nduced di ar r hea.
Laxati ves taken wi th i r i notecan can i nduce di ar r hea.
Pr ochl or peraz i ne admi ni ster ed wi th i r i notecan can i ncr ease the
i nci dence of extrapyrami dal toxi ci ti es. (See Adver se r eacti ons to
topoi somerase I i nhi bi tor s.)

Targeted therapies
A gr oundbr eaki ng appr oach to anti cancer therapi es i nvol ves
tar geti ng pr otei ns associ ated wi th the gr owth patter ns of speci fi c
types of cancer. Dr ugs used for thi s new appr oach to cancer
tr eatment i ncl ude:

bor tezomi b
gefi ti ni b
i mati ni b.

Pharmacokinetics
Bor tez omib i snt absor bed oral l y and must be gi ven I.V. Its
extensi vel y di str i buted i nto body ti ssues and metabol i zed by the
l i ver.
G efitinib i s avai l abl e i n an oral for m, and about hal f of the dose i s
absor bed. The dr ug i s wi del y di str i buted i n ti ssues. It under goes
hepati c metabol i sm wi th mi ni mal ur i nar y excr eti on.
Imatinib i s al so avai l abl e i n an oral for m and i s al most compl etel y
absor bed. Its 95% bound to pl asma pr otei ns and i s extensi vel y
metabol i zed by the l i ver. The hal f-l i fe of i mati ni b i s about 15 hour s.

Pharmacodynamics
Bor tezomi b i nhi bi ts pr oteosomes, whi ch ar e i nvol ved i n i ntegral
cel l -cycl e functi on and pr omote tumor gr owth. Pr oteol ysi s by
bor tezomi b r esul ts i n di sr upti on of the nor mal homeostati c
mechani sms and l eads to cel l death.

Warning!
Adverse reactions to topoisomerase I inhibitors
Common reactions
The mor e common adver se r eacti ons to topo-i somerase I
i nhi bi tor s, par ti cul ar l y i r i notecan, i ncl ude:

di ar r hea (possi bl y sever e)

abdomi nal cramps
hai r l oss or thi nni ng
i ncr eased sweati ng and pr oducti on of sal i va
nausea, vomi ti ng, and l oss of appeti te
ti r edness
water y eyes.

Additional reactions
Occasi onal l y, these r eacti ons may occur :

mouth sor es and ul cer s

muscl e cramps
rashes, whi ch may be i tchy
si gni fi cant myel osuppr essi on, especi al l y wi th topotecan (rar e)
temporar y effects on l i ver functi on test r esul ts.
Too much of this
G efi ti ni b i nhi bi ts the epi der mal gr owth factor r eceptor-1 tyr osi ne
ki nase, whi ch i s over expr essed i n such cancer s as nonsmal l -cel l
l ung cancer. Thi s i nhi bi ti on bl ocks si gnal i ng pathways for gr owth,
sur vi val , and metastasi s of cancer.

too many of those

In pati ents wi th chr oni c myel oi d l eukemi a, the BCR-ABL pr otei n
sti mul ates other tyr osi ne ki nase pr otei ns, causi ng an abnor mal l y
hi gh pr oducti on of WBCs. Imati ni b bi nds to the adenosi ne
tr i phosphatebi ndi ng domai n of the BCR-ABL pr otei n, effecti vel y
shutti ng down the abnor mal WBC pr oducti on.

Pharmacotherapeutics
Bor tezomi b i s used to tr eat mul ti pl e myel oma that has r el apsed
after standar d chemotherapy.
G efi ti ni b i s used as a si ngl e agent for pati ents wi th nonsmal l -cel l
l ung cancer that hasnt r esponded to two standar d chemotherapy
r egi mens.
Imati ni b i s used to tr eat chr oni c myel oi d l eukemi a, acute l ymphoi d
l eukemi a, and G I stomal tumor s.
Drug interactions
Bor tezomi b, gefi ti ni b, and i mati ni b have been associ ated wi th some
dr ug i nteracti ons.

Bor tezomi b when taken wi th dr ugs that i nhi bi t cytochr ome

CYP3A4 (such as ami odar one, ci meti di ne, er ythr omyci n,
di l ti azem, fl uoxeti ne, verapami l , z afi r l ukast, and z i l euton) or
i nduce cytochr ome CYP3A4 (such as ami odar one, car bamazepi ne,
nevi rapi ne, phenobar bi tal , phenytoi n, and r i fampi n), coul d cause
ei ther toxi ci ti es or r educed effi cacy of these dr ugs.
Bor tezomi b when taken wi th oral hypogl ycemi cs coul d cause
hypogl ycemi a and hyper gl ycemi a i n pati ents wi th di abetes.
Pl asma l evel s of gefi ti ni b and i mati ni b ar e r educed, someti mes
substanti al l y, when these dr ugs ar e gi ven wi th car bamazepi ne,
dexamethasone, phenobar bi tal , phenytoi n, r i fampi n, or St.
Johns wor t.
Hi gh doses of rani ti di ne wi th sodi um bi car bonate when taken
wi th gefi ti ni b r educe gefi ti ni b l evel s.
Admi ni strati on of gefi ti ni b or i mati ni b wi th war far i n causes
el evati ons i n the Inter nati onal Nor mal i zed Rati o, i ncr easi ng the
r i sk of bl eedi ng.
Cl ar i thr omyci n, er ythr omyci n, i traconazol e, and ketoconazol e,
when taken wi th i mati ni bor may i ncr ease i mati ni b pl asma l evel s.

Car bamazepi ne, dexamethasone, phenobar bi tal , phenytoi n, or

r i fampi n gi ven wi th i mati ni b may i ncr ease metabol i sm of
i mati ni b and decr ease i mati ni b l evel .
Imati ni b gi ven wi th si mvastati n i ncr eases si mvastati n l evel s
about thr eefol d.
Imati ni b i ncr eases pl asma l evel s of other CYP3A4-metabol i zed
dr ugs, such as tr i azol o-benzodi azepi nes, cal ci um channel
bl ocker s, and cer tai n HMG -CoA r eductase i nhi bi tor s. (See
Adver se r eacti ons to tar geted therapi es.)

Warning!
Adverse reactions to targeted therapies
Pati ents shoul d avoi d becomi ng pr egnant whi l e taki ng
 bor tezomi b, gefi ti ni b, or i mati ni b because i n ani mal studi es these
dr ugs cr ossed the pl acental bar r i er, causi ng fetal har m and death.
Ther e ar e al so adver se r eacti ons speci fi c to each therapy.
Bortezomib

Fati gue, mal ai se, weakness, nausea, di ar r hea, appeti te l oss,

consti pati on, pyr exi a, and vomi ti ng (most common r eacti ons)
Per i pheral neur opathy, headache, l ow bl ood pr essur e, l i ver
toxi ci ty, thr ombocytopeni a, r enal toxi ci ty, and car di ac toxi ci ty,
such as ar r hythmi as, hear t fai l ur e, myocar di al i schemi a and
i nfar cti on, pul monar y edema, and per i car di al effusi on (l ess
common r eacti ons)

Gefitinib

Rash, di ar r hea, and abnor mal eyel ash gr owth

Lung and l i ver damage

Imatinib

Per i or bi tal and l ower l i mb edema, possi bl y r esul ti ng i n

pul monar y edema, effusi ons, and hear t or r enal fai l ur e
Nausea, vomi ti ng, l i ver functi on abnor mal i ti es, and
myel osuppr essi on (especi al l y neutr openi a and
thr ombocytopeni a)

Unclassifiable antineoplastic drugs

Many other anti neopl asti c dr ugs cant be i ncl uded i n exi sti ng
cl assi fi cati ons. These dr ugs i ncl ude:

ar seni c tr i oxi de
asparagi nases
pr ocar baz i ne
hydr oxyur ea
i nter fer on
al desl euki n
al tr etami ne
 pacl i taxel (taxane)
docetaxel (taxane).

Arsenic trioxide
Ar senic tr ioxide i s a commer ci al l y avai l abl e tr eatment for pati ents
wi th acute pr omyel ocyti c l eukemi a (a rar e for m of acute myel oi d
l eukemi a). Its i ndi cated when standar d therapy has fai l ed.

Pharmacokinetics
Ar seni c tr i oxi de i s admi ni ster ed I.V. because i ts i nadequatel y
absor bed oral l y. The metabol i sm of ar seni c tr i oxi de i nvol ves
r educti on vi a ar senate r eductase, wi th subsequent methyl ati on to
i nacti ve metabol i tes i n ur i ne. Ar seni c i s di str i buted i n the hear t,
l i ver, ki dney, l ung, hai r, and nai l s. (See Pr eventi ng the fatal effects
of ar seni c.)

Pharmacodynamics
Ar seni c tr i oxi de causes DNA fragmentati on.

Pharmacotherapeutics
Ar seni c tr i oxi de i s used to tr eat acute pr omyel ocyti c l eukemi a that
has r el apsed after standar d chemotherapy. Its al so bei ng
i nvesti gated for tr eatment of mul ti pl e myel oma.

Drug interactions
G i vi ng ar seni c tr i oxi de wi th other dr ugs known to pr ol ong the QT
i nter val may i ncr ease the r i sk of car di ac ar r hythmi as. (See Adver se
r eacti ons to ar seni c tr i oxi de.)

Warning!
Adverse reactions to arsenic trioxide
Ar seni c tr i oxi de can cause el ectr ocar di ogram abnor mal i ti es,
whi ch coul d pr ogr ess to l i fe-thr eateni ng car di ac ar r hythmi as.
Other adver se r eacti ons i ncl ude:

anxi ety
di z z i ness
 headache
hypocal cemi a
i nsomni a
l i ver damage
muscl e and bone aches
nausea and vomi ti ng
rash
tr emor.

Safe and sound

Preventing the fatal effects of arsenic
Ar seni c tr i oxi de has been l i nked to acute pr omyel ocyti c
l eukemi a (APL) di ffer enti ati on syndr ome. To pr event i ts l i fe-
thr eateni ng effects, fol l ow these gui del i nes:

Moni tor the pati ent for si gns and symptoms of APL
di ffer enti ati on syndr ome, i ncl udi ng dyspnea, wei ght gai n,
pul monar y i nfi l trates, and pl eural or per i car di al effusi on wi th
or wi thout l eukocytosi s.
If you detect any of these si gns or symptoms, noti fy the
pr escr i ber i mmedi atel y.
Expect to tr eat the syndr ome wi th hi gh doses of
cor ti coster oi ds.

Asparaginases
Aspar aginases ar e cel l cycl especi fi c and act dur i ng the G 1 phase.
They i ncl ude:

asparagi nase
pegaspar gase.

Pharmacokinetics
Asparagi nase i s admi ni ster ed par enteral l y. Its consi der ed 100%
bi oavai l abl e when admi ni ster ed I.V. and about 50% bi oavai l abl e
when admi ni ster ed I.M.

Distribution and metabolism

After admi ni strati on, asparagi nase r emai ns i nsi de the bl ood vessel s,
wi th mi ni mal di str i buti on el sewher e. The metabol i sm of
asparagi nase i s unknown; onl y trace amounts appear i n ur i ne.

Pharmacodynamics
Asparagi nase and pegaspar gase capi tal i ze on the bi ochemi cal
di ffer ences between nor mal cel l s and tumor cel l s.

Tumor cellseat your asparagine or else

Most nor mal cel l s can synthesi ze asparagi ne, but some tumor cel l s
depend on other sour ces of asparagi ne for sur vi val . Asparagi nase
and pegaspar gase hel p to degrade asparagi ne to aspar ti c aci d and
ammoni a. Depr i ved of thei r suppl y of asparagi ne, the tumor cel l s
di e.

Pharmacotherapeutics
Asparagi nase i s used pr i mar i l y i n combi nati on wi th standar d
chemotherapy to i nduce r emi ssi on i n pati ents wi th acute
l ymphocyti c l eukemi a.

Warning!
Adverse reactions to asparaginase drugs
Many pati ents r ecei vi ng asparagi nase and peg-aspar gase
devel op nausea and vomi ti ng. Fever, headache, abdomi nal pai n,
pancr eati ti s, coagul opathy, and l i ver tox-i ci ty may al so occur.
Rising risk
Asparagi nase and peg-aspar gase can cause anaphyl axi s, whi ch i s
mor e l i kel y to occur wi th i nter mi ttent I.V. dosi ng than wi th dai l y
I.V. dosi ng or I.M. i njecti ons. The r i sk of a r eacti on r i ses wi th
each successi ve tr eatment.
Hyper sensi ti vi ty r eacti ons may al so occur.

If allergic
Pegaspar gase i s used to tr eat acute l ymphocyti c l eukemi a i n
pati ents who ar e al l er gi c to the nati ve for m of asparagi nase.
Drug interactions
Asparagi nase dr ugs may i nteract wi th other dr ugs. Asparagi nase and
pegaspar gase may r educe the effecti veness of methotr exate.
Concur r ent use of asparagi nase wi th pr edni sone or vi ncr i sti ne
i ncr eases the r i sk of toxi ci ty. (See Adver se r eacti ons to
asparagi nase dr ugs.)

Procarbazine
Pr ocar baz ine hydr ochlor ide, a methyl hydraz i ne der i vati ve wi th
monoami ne oxi dase i nhi bi tor (MAOI) pr oper ti es, i s used to tr eat
Hodgki ns di sease and pr i mar y and metastati c brai n tumor s.

Pharmacokinetics
After oral admi ni strati on, pr ocar baz i ne i s wel l absor bed. It r eadi l y
cr osses the bl ood-brai n bar r i er and i s wel l di str i buted i nto CSF.

Metabolism and excretion

Pr ocar baz i ne i s metabol i zed rapi dl y i n the l i ver and must be
acti vated metabol i cal l y by mi cr osomal enz ymes. Its excr eted i n
ur i ne, pr i mar i l y as metabol i tes. Respi rator y excr eti on of the dr ug
occur s as methane and car bon di oxi de gas.

Pharmacodynamics
An i ner t dr ug, pr ocar baz i ne must be acti vated metabol i cal l y i n the
l i ver befor e i t can pr oduce var i ous cel l changes. It can cause
chr omosomal damage, suppr ess mi tosi s, and i nhi bi t DNA, RNA, and
pr otei n synthesi s. Cancer cel l s can qui ckl y devel op r esi stance to
pr ocar baz i ne.
Pharmacotherapeutics
Pr ocar baz i ne i s used i n the tr eatment of Hodgki ns di sease,
l ymphoma, and brai n cancer.

Drug interactions
Interacti ons wi th pr ocar baz i ne can be si gni fi cant.

It pr oduces an addi ti ve effect when admi ni ster ed wi th CNS

depr essants.
Taken wi th meper i di ne, i t may r esul t i n sever e hypotensi on and
death.

Warning!
Adverse reactions to procarbazine
Late-onset bone mar r ow suppr essi on i s the most common
dose-l i mi ti ng toxi ci ty associ ated wi th pr ocar baz i ne. Inter sti ti al
pneumoni ti s (l ung i nfl ammati on) and pul monar y fi br osi s
(scar r i ng) may al so occur.
A bad start
Ini ti al pr ocar baz i ne therapy may i nduce fl ul i ke symptoms,
i ncl udi ng fever, chi l l s, sweati ng, l ethar gy, and muscl e pai n.
Gut reactions
G I r eacti ons i ncl ude nausea, vomi ti ng, stomati ti s, and di ar r hea.

Mirroring MAO
Because of pr ocar baz i nes MAOI pr oper ti es, hyper tensi ve r eacti ons
may occur when i ts admi ni ster ed concur r entl y wi th
sympathomi meti cs, anti depr essants, and tyrami ne-r i ch foods. (See
Adver se r eacti ons to pr ocar baz i ne.)

Hydroxyurea
Hydr oxyur ea i s used most commonl y for pati ents wi th chr oni c
myel ogenous l eukemi a.

When your neck is on the line

Hydr oxyur ea i s al so used for sol i d tumor s and head and neck cancer.

Pharmacokinetics
Hydr oxyur ea i s r eadi l y absor bed and wel l di str i buted i nto CSF after
oral admi ni strati on. It r eaches a peak ser um l evel 2 hour s after
admi ni strati on.

Metabolism and excretion

About one-hal f of the dose i s metabol i zed by the l i ver to car bon
di oxi de, whi ch i s excr eted by the l ungs, or to ur ea, whi ch i s
excr eted by the ki dneys. The r emai ni ng one-hal f i s excr eted
unchanged i n ur i ne.

Pharmacodynamics
Hydr oxyur ea exer ts i ts effect by i nhi bi ti ng the enz yme
r i bonucl eoti de r eductase, whi ch i s necessar y for DNA synthesi s.
Divide and conquer
Hydr oxyur ea ki l l s cel l s i n the S phase of the cel l cycl e and hol ds
other cel l s i n the G 1 phase, wher e theyr e most suscepti bl e to
i r radi ati on.

Pharmacotherapeutics
Hydr oxyur ea i s used to tr eat sel ected myel opr ol i ferati ve di sor der s.
It may pr oduce temporar y r emi ssi ons i n some pati ents wi th
metastati c mal i gnant mel anomas as wel l .

Working with radiation

Hydr oxyur ea i s al so used i n combi nati on therapy wi th radi ati on to
tr eat cancer s of the head, neck, and l ungs.

Drug interactions
Cytotoxi c dr ugs and radi ati on therapy enhance the toxi ci ty of
hydr oxyur ea. (See Adver se r eacti ons to hydr oxyur ea.)

Warning!
Adverse reactions to hydroxyurea
Tr eatment wi th hydr oxy-ur ea l eads to few adver se
r eacti ons. Those that do occur i ncl ude:

bone mar r ow suppr essi on

dr owsi ness
headache
nausea and vomi ti ng
ski n rash
anor exi a
el evated ur i c aci d l evel s, whi ch r equi r e some pati ents to take
al l opur i nol to pr event ki dney damage.

Interferons
A fami l y of natural l y occur r i ng gl ycopr otei ns, inter fer ons ar e so
named because of thei r abi l i ty to i nter fer e wi th vi ral r epl i cati on.
These dr ugs exhi bi t anti cancer acti vi ty as wel l as acti vi ty agai nst
condyl omata acumi nata (soft, war tl i ke gr owths on the ski n and
mucous membrane of the geni tal i a caused by a vi r us). The thr ee
types of i nter fer ons ar e:

alfa inter fer ons der i ved fr om l eukocytes

beta inter fer ons der i ved fr om fi br obl asts (connecti ve ti ssue
cel l s)
gamma inter fer ons der i ved fr om fi br obl asts and l ymphocytes.

Pharmacokinetics
After I.M. or subcutaneous admi ni strati on, i nter fer ons ar e usual l y
wel l absor bed. Infor mati on about thei r di str i buti on i s unavai l abl e.

Metabolism and excretion

Al fa i nter fer ons ar e fi l ter ed by the ki dneys, wher e theyr e degraded.
Li ver metabol i sm and bi l i ar y excr eti on of i nter fer ons ar e negl i gi bl e.

Pharmacodynamics
Al though thei r exact mechani sm of acti on i s unknown, i nter fer ons
appear to bi nd to speci fi c membrane r eceptor s on the cel l sur face.
When bound, they i ni ti ate a sequence of i ntracel l ul ar events that
i ncl udes the i nducti on of cer tai n enz ymes.
Running interference
Thi s pr ocess may account for the abi l i ty of i nter fer ons to:

i nhi bi t vi ral r epl i cati on

suppr ess cel l pr ol i ferati on
enhance macr ophage acti vi ty (engul fi ng and destr oyi ng
mi cr oor gani sms and other debr i s)
i ncr ease cytotoxi ci ty of l ymphocytes for tar get cel l s.

Pharmacotherapeutics
Al fa i nter fer ons have shown thei r most pr omi si ng acti vi ty i n
tr eati ng bl ood mal i gnanci es, especi al l y hai r y cel l l eukemi a. Thei r
appr oved i ndi cati ons cur r entl y i ncl ude:

hai r y cel l l eukemi a

AIDS-r el ated Kaposi s sar coma

condyl omata acumi nata.

Interfering in these areas as well

Al fa i nter fer ons al so demonstrate some acti vi ty agai nst chr oni c
myel ogenous l eukemi a, mal i gnant l ymphoma, mul ti pl e myel oma,
mel anoma, and r enal cel l car ci noma.

Drug interactions
Inter fer ons i nteract wi th other dr ugs:

They may enhance the CNS effects of CNS depr essants and
substanti al l y i ncr ease the hal f-l i fe of methyl xanthi nes (i ncl udi ng
theophyl l i ne and ami nophyl l i ne).
Concur r ent use wi th a l i ve vi r us vacci ne may potenti ate
r epl i cati on of the vi r us, i ncr easi ng the adver se effects of the
vacci ne and decr easi ng the pati ents anti body r esponse.
Bone mar r ow suppr essi on may be i ncr eased when an i nter fer on
i s used wi th radi ati on therapy or a dr ug that causes bl ood
 abnor mal i ti es or bone mar r ow suppr essi on.
Al fa i nter fer ons i ncr ease the r i sk of ki dney fai l ur e fr om
i nter l euki n-2. (See Adver se r eacti ons to i nter fer ons.)

Warning!
Adverse reactions to interferons
Bl ood toxi ci ty occur s i n up to one-hal f of pati ents taki ng
i nter fer ons and may pr oduce l eukopeni a, neutr openi a,
thr ombocytopeni a, and anemi a. Adver se G I r eacti ons i ncl ude
anor exi a, nausea, and di ar r hea.
Alfa concerns
The most common adver se r eacti on to al fa i nter fer ons i s the
devel opment of fl ul i ke symptoms, whi ch may pr oduce fever,
fati gue, muscl e pai n, headache, chi l l s, and joi nt pai n.
It catches your breath
Coughi ng, di ffi cul ty br eathi ng, hypotensi on, edema, chest pai n,
and hear t fai l ur e have al so been associ ated wi th i nter fer on
therapy.

Aldesleukin
Aldesleukin i s a human r ecombi nant i nter l euki n-2 der i vati ve thats
used to tr eat metastati c r enal cel l car ci noma.

Pharmacokinetics
After I.V. admi ni strati on of al desl euki n, about 30% i s absor bed i nto
pl asma and about 70% i s absor bed rapi dl y by the l i ver, ki dneys, and
l ungs. The dr ug i s excr eted pr i mar i l y by the ki dneys.

Pharmacodynamics
The exact anti tumor mechani sm of acti on of al desl euki n i s unknown.
The dr ug may sti mul ate an i mmunol ogi c r eacti on agai nst the tumor.

Pharmacotherapeutics
Al desl euki n i s used to tr eat metastati c r enal cel l car ci noma. It may
al so be used i n the tr eatment of Kaposi s sar coma and metastati c
mel anoma.
Drug interactions
Al desl euki n wi l l i nteract wi th other dr ugs.

Concomi tant admi ni strati on of al desl euki n and dr ugs wi th

psychotr opi c pr oper ti es (such as opi oi ds, anal gesi cs, anti emeti cs,
sedati ves, and tranqui l i zer s) may pr oduce addi ti ve CNS effects.
G l ucocor ti coi ds may r educe al desl euki ns anti tumor effects.
Anti hyper tensi ve dr ugs may potenti ate al desl euki ns hypotensi ve
effects.
Concur r ent therapy wi th dr ugs that ar e toxi c to the ki dneys
(such as ami nogl ycosi des), bone mar r ow (such as cytotoxi c
chemotherapy dr ugs), hear t (such as doxor ubi ci n), or l i ver (such
as methotr exate or asparagi nase) may i ncr ease toxi ci ty to these
or gans. (See Adver se r eacti ons to al desl euki n.)

Altretamine
Altr etamine i s a syntheti c cytotoxi c anti neopl asti c dr ug thats used
as pal l i ati ve tr eatment for pati ents wi th ovar i an cancer.

Pharmacokinetics
Al tr etami ne i s wel l absor bed after oral admi ni strati on.

Metabolism and excretion

Al tr etami ne i s metabol i zed extensi vel y i n the l i ver and excr eted by
the l i ver and ki dneys. The par ent compound i s poor l y bound to
pl asma pr otei ns.

Pharmacodynamics
The exact mechani sm of acti on of al tr etami ne i s unknown. However,
i ts metabol i tes ar e al kyl ati ng dr ugs.

Pharmacotherapeutics
Al tr etami ne i s used as pal l i ati ve tr eatment of per si stent or
r ecur r i ng ovar i an cancer after fi r st-l i ne therapy wi th ci spl ati n or an
al kyl ati ng dr ug-based combi nati on.
Drug interactions
Al tr etami ne has a few si gni fi cant i nteracti ons wi th other dr ugs.
Concomi tant therapy wi th ci meti di ne may i ncr ease al tr etami nes
hal f-l i fe, i ncr easi ng the r i sk of al tr etami ne toxi ci ty.

Warning!
Adverse reactions to aldesleukin
Dur i ng cl i ni cal tr i al s, mor e than 15% of pati ents devel oped
adver se r eacti ons to al desl euki n. These i ncl ude:

pul monar y congesti on and di ffi cul ty br eathi ng

anemi a, thr ombocytopeni a, and l eukopeni a
el evated bi l i r ubi n, transami nase, and al kal i ne phosphate
l evel s
hypomagnesemi a and aci dosi s
r educed or absent ur i nar y output
el evated ser um cr eati ni ne l evel
stomati ti s
nausea and vomi ti ng.

Dont mix with MAOI

Use wi th an MAOI may cause sever e or thostati c hypotensi on (a dr op
i n bl ood pr essur e upon r i si ng). (See Adver se r eacti ons to
al tr etami ne.)

Paclitaxel and docetaxel

Antineoplastic dr ugs ar e used to tr eat metastati c ovar i an and br east
cancer after chemotherapy has fai l ed. They i ncl ude:

pacl i taxel
docetaxel .

Pharmacokinetics
After I.V. admi ni strati on, pacl i taxel i s hi ghl y bound to pl asma
pr otei ns. Docetaxel i s admi ni ster ed I.V. wi th a rapi d onset of acti on.

Metabolism and excretion

Pacl i taxel i s metabol i zed pr i mar i l y i n the l i ver wi th a smal l amount
excr eted unchanged i n ur i ne. Docetaxel i s excr eted pr i mar i l y i n
stool .

Pharmacodynamics
Pacl i taxel and docetaxel exer t thei r chemotherapeuti c effect by
di sr upti ng the mi cr otubul e networ k essenti al for mi tosi s and other
vi tal cel l ul ar functi ons.

Pharmacotherapeutics
Pacl i taxel i s used when fi r st-l i ne or subsequent chemotherapy has
fai l ed i n tr eati ng metastati c ovar i an cancer as wel l as metastati c
br east cancer.

Warning!
Adverse reactions to altretamine
Mor e than 10% of pati ents usi ng al tr etami ne i n cl i ni cal
tr i al s exper i enced adver se r eacti ons, such as:

nausea and vomi ti ng

neur otoxi ci ty
per i pheral neur opathy
anemi a.

Bone mar r ow suppr essi on i s al so common.

Head, neck, and below
The taxanes may al so be used for tr eati ng head and neck cancer,
pr ostate cancer, and nonsmal l -cel l l ung cancer. (See Cul tural
consi derati ons wi th docetaxel use.)

Drug interactions
Taxanes may i nteract wi th other dr ugs.

Concomi tant use of pacl i taxel and ci spl ati n may cause addi ti ve
myel osuppr essi ve effects.
Cycl ospor i ne, ketoconazol e, er ythr omyci n, and tr ol eandomyci n
may modi fy the metabol i sm of docetaxel .

Phenytoi n may decr ease pacl i taxel ser um l evel , l eadi ng to a l oss
of effi cacy.
Qui nupr i sti n/dal fopr i sti n may i ncr ease pacl i taxel ser um l evel s,
i ncr easi ng the r i sk of toxi ci ty. (See Adver se r eacti ons to
pacl i taxel and docetaxel.)
 Yea or nay?
Cultural considerations with docetaxel use
Cl i ni cal tr i al s of docetaxel i n Japanese and Amer i can
pati ents wi th br east cancer r eveal ed si gni fi cant di ffer ences i n the
i nci dence of adver se effects between the two cul tur es.
The results
Japanese women wer e mor e l i kel y to devel op thr ombocytopeni a
14.4% ver sus 5.5% . However, the Japanese women i n thi s study
wer e l ess l i kel y than the Amer i can pati ents (6% ver sus 29.1% ) to
devel op many of the other adver se r eacti ons such as
hyper sensi ti vi ty r eacti ons.
Other r esul ts showed fewer i nci dences of fl ui d r etenti on,
neur osensor y effects, muscl e pai n, i nfecti on, and devel opment of
anemi a i n the Japanese pati ents. The study al so i ndi cated that
Japanese pati ents ar e mor e l i kel y to devel op fati gue and
weakness than ar e Amer i can women.
Putting it into a plan
These r esul ts ar e i mpor tant to consi der when car i ng for pati ents
r ecei vi ng docetaxel and can pr ovi de cl ues for devel opi ng a car e
pl an and for knowi ng what adver se r eacti ons to expect.

Warning!
Adverse reactions to paclitaxel and docetaxel
Dur i ng cl i ni cal tr i al s, 25% or hi gher of pati ents exper i enced
these adver se r eacti ons to pacl i taxel :

bone mar r ow suppr essi on

hyper sensi ti vi ty r eacti ons
abnor mal EEG traci ngs
per i pheral neur opathy
muscl e pai n and joi nt pai n
nausea, vomi ti ng, and di ar r hea
mucous membrane i nfl ammati on
hai r l oss.

Docetaxel
Adver se r eacti ons to docetaxel i ncl ude:
 hyper sensi ti vi ty r eacti ons
fl ui d r etenti on
l eukopeni a, neutr openi a, or thr ombocytopeni a
hai r l oss
stomati ti s
numbness and ti ngl i ng
pai n
weakness and fati gue.

Quick quiz
1Whats the major adver se r eacti on thats common to
al l al kyl ati ng dr ugs?
A. Photosensi ti vi ty
B. Ner ve toxi ci ty
C. Car di ac toxi ci ty
D. Bone mar r ow suppr essi on

P.
2The dr ug l i kel y to be admi ni ster ed wi th methotr exate to
mi ni mi ze i ts adver se effects i s:
A. fl uor ouraci l .
B. l eucovor i n.
C. cl adr i bi ne.
D. trastuz umab.

3Befor e admi ni ster i ng bl eomyci n to a pati ent, why shoul d you

admi ni ster an anti hi stami ne and an anti pyr eti c?
A. To pr event fever and chi l l s
B. To pr event anaphyl acti c shock
C. To pr event bone mar r ow suppr essi on
D. To pr event hyper tensi on

Scoring
If you answer ed al l thr ee i tems cor r ectl y, extraor di nar y!
You r eal l y mowed down the mal i gnant neopl asms!
If you answer ed two i tems cor r ectl y, congratul ati ons!
Your e mor e than competent to combat cancer !

If you answer ed fewer than two i tems cor r ectl y, gi ve i t

another shot! Remember, thi s i s your l ast crack at a qui ck
qui z !

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

Other major drugs

OPHTHA LMIC
DRUGS

Drug A ction Treatment uses Ad

A ntiallergic agents

Decr ease To tr eat al l er gi c

Azel asti ne
i r r i tati on conjuncti vi ti s

To tr eat
Cr omol yn seasonal
conjuncti vi ti s

Emedasti ne To tr eat kerati ti s

Ketoti fen

Lodoxami de

Ol opatadi ne

A nesthetics
 To anestheti ze
the cor nea,
al l owi ng
Pr event the appl i cati on of
i ni ti ati on and i nstr uments for
Pr oparacai ne
transmi ssi on of measur i ng
ner ve i mpul ses i ntraocul ar
pr essur e (I0P)
or r emovi ng
for ei gn bodi es

Tetracai ne

To pr epar e for
sutur e r emoval ,
conjuncti val or
cor neal
scrapi ng, and
tear duct
mani pul ati on

Anti -i nfecti ves

To tr eat cor neal

 ul cer s or
conjuncti vi ti s
Ki l l bacter i a or caused by
i nhi bi t gr owth bacter i a,
Ci pr ofl oxaci n
of bacter i a or fungus, or vi r us
vi r uses (each dr ug i s
speci fi c to
par ti cul ar
or gani sms)

Er ythr omyci n

G entami ci n

Levofl oxaci n

Natamyci n

Nor fl oxaci n

Ofl oxaci n

Sul facetami de

Sul fi soxazol e

Tobramyci n

Tr i fl ur i di ne

A nti-
inflammatories

Decr ease
l eukocyte To tr eat
i nfi l i nfi l trati on i nfl ammator y
at di sor der s and
i nfl ammati on hyper sensi ti vi ty-
Ster oidalanti-anti- si tes, causi ng r el ated
inflammator ies r educed ooz i ng condi ti ons of the
of fl ui ds and cor nea, i r i s,
r educed conjuncti va,
edema, scl era, and
r edness, and anter i or uvea
scar r i ng

Dexamethasone

F l uor omethol one

Lotepr ednol

Pr edni sol one

Ri mexol one

To i nhi bi t pupi l
Decr ease constr i cti on
Nonster oidal anti-
i nfl ammati on dur i ng sur ger y
inflammator ies
and i tchi ng (fl ur bi pr ofen
and supr ofen)

To r educe
i tchi ng due to
Di cl ofenac seasonal
al l er gi es
(ketor ol ac)

F l ur bi pr ofen
 To tr eat
Ketor ol ac i nfl ammati on
after sur ger y

Supr ofen

Lubricants

To pr otect
Act as ar ti fi ci al cor nea dur i ng
Methyl cel l ul ose
tear s di agnosti c
pr ocedur es

Pol yvi nyl al cohol Moi sten cor nea

To moi sten
contact l enses

Miotics

To tr eat open-
angl e gl aucoma,
Sti mul ate and acute and
contract the chr oni c angl e-
sphi ncter cl osur e
Car bachol muscl e of the gl aucoma, and
i r i s, cer tai n cases of
constr i cti ng secondar y
the pupi l gl aucoma
r esul ti ng fr om
i ncr eased IOP

Impr ove
Pi l ocar pi ne aqueous
 outfl ow

Mydriatics

To di l ate the
Acton the i r i s
pupi l s for
Di pi vefr i n to di l ate the
i ntraocul ar
pupi l
exami nati ons

Epi nephr i ne

To l ower I0P i n
Hydr oxyamphetami ne Lower I0P pati ents wi th
gl aucoma

Phenyl ephr i ne
Mydriatics and
cycloplegics

Act on the
ci l i ar y body of
the eye to To per for m
paral yze the r efracti ve eye
fi ne-focusi ng exami nati ons i n
Atr opi ne sul fate muscl es chi l dr en befor e
(ther eby and after
pr eventi ng ophthal mi c
accommodati on sur ger y
for near
vi si on)

Cycl opentol ate

hydr ochl or i de

To tr eat
Homatr opi ne condi ti ons
hydr obr omi de i nvol vi ng the
iris

Tr opi cami de

Other drugs to
low er IOP
 May r educe To pr event and
aqueous humor contr ol el evated
for mati on and IOP, chr oni c
Adr ener gic blocker s
sl i ghtl y open-angl e
(topical)
i ncr ease gl aucoma, and
aqueous humor secondar y
outfl ow gl aucoma

Apracl oni di ne

Betaxol ol outfl ow Sl o

Br i moni di ne

Car teol ol

Levobunol ol

Meti pranol ol

Ti mol ol mal eate

Inhi bi t acti on To tr eat chr oni c

of car boni c open angl e
anhydrase, gl aucoma, acute
Car bonic anhydr ase
thus angl e-cl osur e
inhibitor s
decr easi ng epi sodes, and
aqueous humor secondar y
pr oducti on gl aucoma

Hy

Acetazol ami de Le

Br i nzol ami de Na
Dor zol ami de

Reduce vol ume

Osmotic agents To pr epar e for
of vi tr eous H
G lycer in i ntraocul ar sur ger y
humor

To tr eat acute
D
gl aucoma

Isosor bi de Decr ease IOP

Manni tol

Pr ostaglandin
Decr ease IOP To tr eat gl aucoma Ir
analogues

Tea

Bi matopr ost

Latanopr ost

Travopr ost

Unopr ostone

OTIC DRUGS

Treatment A dverse
Drug A ction
uses reactions

A nesthetics
(local)

Ear
i r r i tati on
i tchi ng
Edema
Temporar i l y
 i nter r upt the To Hi ves
Benzocai ne conducti on temporar i l y Maski ng o
of ner ve i m- r el i eve ear the
pul ses pai n symptoms
a
ful mi nati n
mi ddl e ea
i nfecti on

A nti-infectives

Ki l l bacter i a
or i nhi bi t To tr eat
bacter i al oti ti s
gr owth exter na Bur ni ng
Inhi bi t To tr eat Der mati ti
Aceti c aci d
fungal oti ti s medi a Ear i tchi n
gr owth (col i sti n and Hi ves
(aceti c aci d pol ymyxi n B
and bor i c sul fate)
aci d)

Bor i c aci d

Chl orampheni col

Col i sti n sul fate

Neomyci n
sul fate

Pol ymyxi n B
sul fate

A nti-
inflammatories

Inhi bi t
edema,
capi l l ar y
 di l ati on, Maski ng o
fi br i n exacer bat
deposi ti on, of
and under l yi n
To tr eat
phagocyte oti c
i nfl ammator y
and l euko- i nfecti on
Hydr ocor ti sone condi ti ons of
cyte Transi ent
the exter nal
mi grati on l ocal
ear canal
Reduce sti ngi ng o
capi l l ar y and bur ni ng
fi -br obl ast sensati on
pr ol i ferati on,
col -l agen
deposi ti on,
and scar
for mati on

Dexamethasone-
sodi um
phosphate

Cerumenolytics

Reduce
har dened To l oosen
Car bami de Mi l d,
cer u-men by and r emove
per oxi de l ocal i zed
emul si fyi ng cer umen
Tr i ethanol ami ne r edness a
and fr om the ear
pol ypepti de i tchi ng
mechani cal l y canal
l ooseni ng i t

DERMA TOLOGIC
DRUGS

A dverse
Drug A ction Treatment uses
reactions

A nti-infectives
Anti bacter i al s
Azel ai c aci d
Baci traci n
To tr eat
Cl i ndamyci n
i nfecti ons Conta
Er ythr omyci n
caused by der ma
G entami ci n
Ki l l or bacter i a (each Rash
Mafeni de
i nhi bi t the dr ug i s speci fi c Ski n b
Metr oni dazol e
gr owth of to par ti cul ar i tchi ng
Mupi r oci n
bacter i a or gani sms; r ed-ne
Neomyci n
combi nati on Ski n d
Si l ver
pr oducts may Sti ngi
sul fadi az i ne
al so be used)
Sul facetami de
sodi um
Tetracycl i ne

Anti fungal s
Amphoter i ci n B
Butenafi ne
Ci cl opi r ox To tr eat
Cl otr i mazol e Ki l l or i nfecti ons
Econazol e i nhi bi t the caused by fungi
Same
Ketoconazol e gr owth of (each dr ug i s
anti ba
Mi conazol e fungi of speci fi c to
Nafti fi ne bacter i a par ti cul ar or-
Nystati n gani sms)
Oxi conazol e
Sul conazol e
Ter bi nafi ne

Anti vi ral s Inhi bi t the To tr eat her pes

Same
Acycl ovi r gr owth of geni tal i s or
anti ba
Penci cl ovi r her pes vi r us her pes l abi al i s

Al cl ometasone Suppr ess

Betamethasone i nfl ammati on by
di pr opi onate bi ndi ng to To r el i
Cl obetasol i ntracel l ul ar i nfl am
Cl ocor tol one cor ti coster oi d and i t
Desoni de r eceptor s, topi ca
 Desoxi metasone i ni ti ati ng a r espon
Dexamethasone cascade of anti - di sor d
A nti- Di fl orasone i nfl ammator y as ecz
inflammatories di acetate medi ator s psor i a
F l uoci nol one Cause angi oe
F l uoci noni de vasoconstr i cti on contac
F l urandr enol i de i n i nfl amed der ma
F l uti casone ti ssue and pr e- sebor-
Hal ci noni de vent der ma
Hal obetasol macr ophages atopi c
Hydr ocor ti sone and l eukocytes der ma
Mometasone fr om movi ng hi ves
Tr i amci nol one i nto the ar ea
acetoni de

Hair grow th
stimulants

Sti mul ate

hai r gr owth
by causi ng
vasodi l ati on,
whi ch To tr eat mal e F l ui d r
i ncr eases and femal e Rapi d
Mi noxi di l
bl ood fl ow to patter n rate
the ski n bal dness Wei gh
(exact
mecha-ni sm
of acti on i s
unknown)

Topical
antiacne drugs

To tr eat mi l d
acne, oi l y ski n, Bur ni n
and acne Hi ves
Pr oduce vul gar i s (oral Rash
Ker atolytics anti bacter i al anti bi oti c Scal i n
Aci tr eti n effects therapy used as bl i ster
Adapal ene Reduce needed for deep peel i n
Isotr eti noi n i nfl ammati on acne) Ski n d
Taz ar otene Pr oduce To tr eat mi l d Ski n i
Tr eti noi n anti bacter i al acne, oi l y ski n, Super
Counter i r r i tants effects and acne (wi th
Benzoyl per oxi de Reduce vul gar i s (oral use)
i nfl ammati on anti bi oti c
therapy used as Sa
needed for deep ke
acne)

Same
To tr eat mi l d kerato
Anti mi cr obi al s acne, oi l y ski n, Hyper
Pr oduce
Cl i ndamyci n and acne r eacti
anti bacter i al
Doxycycl i ne vul gar i s (oral Candi d
effects
Er ythr omyci n anti bi oti c vagi ni
Reduce
Mi nocycl i ne therapy used as G ram-
i nfl ammati on
Tetracycl i ne needed for deep pustul
acne) fol l i cu
(oral )

Scabicides and
pediculicides

Act on
parasi te
ner ve cel l
membranes Conta
G amma benzene to di sr upt der ma
hexachl or i de the sodi um Hyper
To tr eat scabi es
Li ndane channel r eacti
and l i ce
Mal athi on cur r ent, Respi r
Per methr i n causi ng al l er g
paral ysi s sympt
(some ar e
al so
ovi ci dal )

 Clinical Pharmacology Made Incredibly
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2009 Li ppi ncott Wi l l i ams & Wi l ki ns

Vaccines and treatment for biological

weapons exposure

Li sted her e ar e potenti al l y thr eateni ng bi ol ogi cal (bacter i al and

vi ral ) agents as wel l as tr eatments and vacci nes cur r entl y avai l abl e
for condi ti ons caused by bi ol ogi cal agents.
Impl ement standar d pr ecauti ons for al l cases of suspected exposur e.
For cases of smal l pox, i nsti tute ai r bor ne pr ecauti ons for the
durati on of the i l l ness and unti l al l scabs fa II off. For pneumoni c
pl ague cases, i nsti tute dr opl et pr ecauti ons for 72 hour s after
i ni ti ati on of effecti ve therapy.

Biological agent
Treatment Vaccine
(condition)

Li mi ted suppl y
of an
i nacti vated
cel l -fr ee
pr oduct
avai l abl e;
when used,
Ci pr ofl oxaci n, shor tens
Bacillus
doxycycl i ne, per i od of
anthr acis(anthrax)
peni ci l l i n anti mi cr obi al
pr ophyl axi s
Not
r ecommended
i n absence of
exposur e to
 anthrax

Postexposur e
pr ophyl axi s
Suppor ti ve; may wi th equi ne
r equi r e bot-ul i num
endotracheal anti toxi n
i ntubati on and Botul i num
Clostr idium botulinum mechani cal toxoi d
(botul i sm)Not venti l ati on avai l abl e fr om
contagi ous Passi ve the Cen-ter s
i mmuni z ati on for Di sease
wi th equi ne an- Contr ol and
ti toxi n to l essen Pr eventi on;
ner ve damage r ecombi nant
vacci ne under
devel opment

Vacci nati on
wi th l i ve,
attenuated
G entami ci n or vacci ne
str eptomyci n; cur r entl y
F r ancisella tular ensis
al ter nati vel y, under
(tul ar emi a)Not
doxycycl i ne, i nvesti gati on
contagi ous
chl orampheni col , and r evi ew by
and ci pr ofl oxaci n the Food and
Dr ug
Admi ni strati on
(F DA)

Var iola major (smal l pox) No F DA-

Transmi tted by appr oved
i nhal ati on of ai r anti vi ral Vacci ne
dr opl ets or aer osol s; avai l abl e; avai l abl e as
pati ent most i nfecti ous ci dofovi r may be pr ophyl axi s
fr om onset of therapeuti c i f wi thi n 3 to 4
macul opapul ar rash admi ni s-ter ed 1 days of
thr ough fi r st 7 to 10 to 2 days after exposur e
days exposur e

Vacci nati on no
Str eptomyci n or l onger
Yer sinia pestis (pl ague) gentami ci n; avai l abl e;
Transmi t-ted per son to al ter na-ti vel y, di dnt pr o-tect
per son vi a aer osol doxycycl i ne, agai nst
(pneumoni c pl ague) ci pr ofl oxaci n, or pr i mar y
chl orampheni col pneumoni c
pl ague

 Clinical Pharmacology Made Incredibly
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2009 Li ppi ncott Wi l l i ams & Wi l ki ns

Treatment and antidotes for chemical

weapons exposure

Li sted her e ar e potenti al l y thr eateni ng chemi cal agents, tr eatments

cur r entl y avai l abl e, and anti dotes.
In the event of chemi cal agent exposur e, fol l ow standar d
pr ecauti ons and decontami nati on pr otocol s, such as r emovi ng
cl othi ng and seal i ng i t i n pl asti c bags, i r r i gati ng the eyes, washi ng
ski n and hai r usi ng copi ous water, tr eati ng waste water as needed,
and decontami nati ng the heal th car e faci l i ty accor di ng to the
speci fi c agent i nvol ved.

Chemical agent Treatment A ntidote

Nerve agents Atr opi ne I.M. or

Suppor ti ve car e
Sar i n I.V.
Di azepam or
Soman Pral i doxi me
l orazepam to
Tabun chl or i de I.M. or
pr event sei z ur es
VX I.V.

Cyanides
Cyanogen chl or i de
Hydr ogen cyani de
Suppor ti ve car e
100% oxygen by Amyl ni tr i te vi a
face mask; may i nhal ati on
need en- Sodi um ni tr i te
dotracheal (ET) I.V. and sodi um
i ntubati on wi th thi osul fate I.V.;
100% F IO 2 dosage based on
Acti vated char coal pati ents wei ght
 for consci ous and hemogl obi n
pati ent l evel

No anti dote
Vesicants or avai l abl e for
blister agents Ther mal bur n mus-tar ds or
Lewi si te therapy phosgene oxi me
Mustar d l ewi si te Respi rator y For l ewi si te and
Ni tr ogen mustar d suppor t and eye l ewi si te mustar d
Phosgene oxi me car e mi xtur es: Br i ti sh
Sul fur mustar d Anti -Lewi si te I.M.
(rar el y avai l abl e)

Suppor ti ve car e
Oxygen thera-py;
Pulmonary or
possi bl e ET
choking agents
i ntubati on and
Chl or i ne
mechani cal None
Di phosgene
venti l ati on wi th
Phosgene
posi ti ve-end
Sul fur di oxi de
expi rator y
pr essur e

Ricin (bi otoxi n

Suppor ti ve car e
i sol ated fr om
For i ngesti on, None
castor bean oi l
acti vated char coal
extract)

T-2 mycotoxins
(toxi c compounds
pr o-duced by fungi )
F usar i um
Suppor ti ve
Myr oteci um
Stachybotr ys
Tr i choder ma
Ver ti ci monospor i um
Suppor ti ve car e
For i ngesti on,
acti vated None
char coal
Possi bl e hi gh-
dose ster oi ds

 Clinical Pharmacology Made Incredibly
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Herbal drugs

The fol l owi ng tabl e l i sts some common her bal dr ugs, thei r uses, and
consi derati ons to know when car i ng for pati ents taki ng these dr ugs.

Herbal
Common uses Special considerations
medicine

Oral
The l axati ve acti ons of
Consti pati on al oe may take up to 10
Bowel evacuati on hour s after i ngesti on to
be effecti ve.
Al oe
Topical Moni tor the pati ent for
si gns of dehydrati on;
Mi nor bur ns ger i atr i c pati ents ar e
Ski n i r r i tati on par ti cul ar l y at r i sk.

Oral Peopl e sensi ti ve to

ragweed and
Anxi ety or chr ysanthemums or
r estl essness other s i n the
Di ar r hea Composi tae fami l y may
Moti on si ckness be mor e suscepti bl e to
Indi gesti on contact al l er gi es and
anaphyl axi s.
Topical Pati ents wi th hay fever
Consti pati on or br onchi al asthma
 Infl ammati on caused by pol l ens ar e
Wound heal i ng mor e suscepti bl e to
Cutaneous bur ns anaphyl acti c r eacti ons.
Pr egnant women
Teas shoul dnt use
chamomi l e.
Sedati on Chamomi l e may
Rel axati on enhance
anti coagul ants effect.

Onl y the unsweetened

Pr ophyl axi s for
for m of cranber r y
ur i nar y tract
pr events bacter i a fr om
i nfecti on (UTI)
Cranber r y ad-her i ng to the
Tr eatment of UTI
bl adder wal l and
Pr eventi on of r enal
pr eventi ng or tr eati ng
cal cul i
UTIs

Suppor ti ve therapy
to pr event and Echi nacea i s consi der ed
tr eat common col d suppor ti ve therapy and
Echi nacea and acute and shoul dnt be used i n
chr oni c i nfecti ons pl ace of anti bi oti c
of the upper therapy.
r espi rator y tract

Avoi d usi ng i n pr egnant

pati ents because
fever few i s al so an
abor ti fa-ci ent.
Pr eventi on and Fever few may i ncr ease
tr eatment of the r i sk of abnor mal
mi grai nes and bl eedi ng when
headaches combi ned wi th an
Hot fl ashes anti coagul ant or
Fever few anti pl atel et.
Rheumatoi d
ar thr i ti s Abr uptl y stoppi ng
Asthma fever few may cause
 Menstr ual pr obl ems postfever few
syndr ome i n-vol vi ng
tensi on headaches,
i nsomni a, joi nt
sti ffness and pai n, and
l ethar gy.

Odor of gar l i c may be

appar ent on br eath and
ski n.
G ar l i c may pr ol ong
bl eedi ng ti me i n
Decr ease
pati ents r ecei vi ng
chol ester ol and
anti coagul ants.
tr i gl ycer i de l evel s
Excess raw gar l i c
Pr event
i ntake may i ncr ease
ather oscl er osi s
the r i sk of adver se
G ar l i c Age-r el ated
r eacti ons.
vascul ar changes
G ar l i c shoul dnt be
Pr event G I cancer
used i n pati ents wi th
Coughs, col ds,
di abetes, i nsomni a,
fever s, and sor e
pemphi -gus, or gan
thr oats
transpl ants, or
r heumatoi d ar thr i ti s or
i n those who have r e-
centl y under gone
sur ger y.

G i nger may i ncr ease

Nausea the r i sk of bl eedi ng,
(anti emeti c) br ui si ng, or
Moti on si ckness nosebl eeds.
Mor ni ng si ckness Pr egnant women shoul d
G I upset (col i c, obtai n medi cal advi ce
fl atul ence, i n- befor e usi ng gi nger
G i nger di gesti on) medi ci nal l y.
Hyper chol ester emi a G i nger may i nter fer e
Li ver toxi ci ty wi th the i ntended
Bur ns therapeuti c effects of
Ul cer s cer tai n conventi onal
 Depr essi on dr ugs.

Adver se effects occur

i n l ess than 1% of
pati ents; the most
common i s G I upset.
G i nkgo bi l oba may
potenti ate
anti coagul ants and
Memor y agent
i ncr ease the r i sk of
Al z hei mer s di sease
bl eedi ng.
Mul ti -i nfar ct
G i nkgo extracts ar e
dementi a
consi der ed
G i nkgo Cer ebral
standar di zed i f they
bi l oba i nsuffi ci ency
contai n 24% fl avonoi d
Inter mi ttent
gl ycosi des and 6%
cl audi cati on
ter pene l actones.
Ti nni tus
Sei z ur es have been
Headache
r epor ted i n chi l dr en
after i ngesti on of mor e
then 50 seeds.
Tr eatment shoul d
conti nue for 6 to 8
weeks but for no mor e
than 3 months.

G i nseng may cause

sever e adver se
Fati gue r eacti ons when taken
Impr ove i n l ar ge doses (mor e
concentrati on than 3 g per day for 2
Tr eat year s), such as
ather oscl er osi s i ncr eased motor and
Al so bel i eved to cogni ti ve acti vi ty wi th
G i nseng str engthen the si gni fi cant di ar r hea,
body and i ncr ease ner vousness, i nsomni a,
r esi stance to hy-per tensi on, edema,
di sease after and ski n er upti ons.
si ckness or G i nseng may potenti ate
 weakness anti coagul ants and
i ncr ease the r i sk of
bl eedi ng.

G r een tea contai ns

caffei ne.
Avoi d pr ol onged and
hi gh caffei ne i ntake,
whi ch may cause
Pr event cancer
r estl ess-ness,
Hyper l i pi demi a
i r r i tabi l i ty, i nsomni a,
Ather oscl er osi s
pal pi tati ons, ver ti go,
Dental car i es
headache, and adver se
G r een tea Headaches
G I effects.
Central ner vous
Addi ng mi l k may
system (CNS)
decr ease adver se G I
sti mul ant
effects of gr een tea.
Mi l d di ur eti c
G r een tea may
potenti ate
anti coagul ants and
i ncr ease the r i sk of
bl eedi ng.

Kava i s contrai ndi cated

i n pr egnancy and
l actati on.
Kava shoul dnt be used
i n combi nati on wi th St.
Johns wor t.
Anti anxi ety Kava shoul dnt be
Str ess taken wi th other CNS
Restl essness depr essants,
Sedati on monoami ne oxi dase
Pr omote wound i nhi bi tor s, l evodopa,
Kava heal i ng anti pl atel ets, al cohol ,
Headache or anxi ol yti cs.
Sei z ur e di sor der s Kava can cause
Common col d dr owsi ness and may
Respi rator y i mpai r motor r efl exes
i nfecti ons
 and men-tal acui ty;
advi se the pati ent to
avoi d haz ar dous
acti vi ti es.
Effects shoul d appear
wi thi n 2 days of
i ni ti ati on of therapy.

Effects may take

several weeks;
however, i f no
i mpr ovement occur s
after 4 to 6 weeks,
consi der al ter nati ve
Mi l d to moderate
therapy.
depr essi on
St. Johns wor t
Anxi ety
St. John's i nteracts wi th many
Psychovegetati ve
wor t di ffer ent types of
di sor der s
dr ugs.
Sci ati ca
St. Johns wor t
Vi ral i nfecti ons
shoul dnt be used i n
combi nati on wi th
pr escr i pti on
anti depr essants or
anti anxi ety
medi cati ons.

Vi tex shoul d be taken

i n the mor ni ng wi th
water.
Pr emenstr ual
Vi tex Vi tex i s a ver y sl ow
syndr ome
acti ng substance; i t
may take several cycl es
to see an effect.

Yohi mbi ne may cause

CNS exci tati on,
i ncl udi ng tr emor,
 Impotence (wor ks sl eepl essness, anxi ety,
Yohi mbi ne as an aphr odi si ac) i ncr eased bl ood
pr essur e, and
tachycar di a.
Dont use i n pati ents
wi th r enal or hepati c
i nsuffi ci ency.

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

Selected references
Amer ican Dr ug Index, 50th ed. Phi l adel phi a: Facts and
Compar i sons, 2006.

Amer i can Hospi tal For mul ar y Ser vi ce. AHF S Dr ug Infor mation
2008. Bethesda, Md.: Amer i can Soci ety of Hospi tal Phar maci sts,
2008.

Arana, G .W., et al . Handbook of Psychiatr ic Dr ug Ther apy.

Phi l adel phi a: Li ppi ncott Wi l l i ams and Wi l ki ns, 2006.

Bi sno, A.L. Practi ce G ui del i nes for the Di agnosi s and

Management of Ski n and Soft-ti ssue Infecti ons, Clinical
Infectious Disease 41:1174-78, 2005.

Bur ke, M.B., and Wi l kes, G .M. 2006 Oncology Nur sing Dr ug
Handbook. Sudbur y, Mass.: Jones & Bar tl ett Pubs., Inc., 2006.

Center s for Di sease Contr ol and Pr eventi on. www.cdc.gov

Chong, O.T. An Integrati ve Appr oach to Addr essi ng Cl i ni cal

Issues i n Compl ementar y and Al ter nati ve Medi ci ne i n an
Outpati ent Oncol ogy Center, Clinical Jour nal of Oncology Nur sing
10(1):83-88, Febr uar y 2006.

Chu, E. Physicians Cancer Chemother apy Dr ug Manual 2006.

Sudbur y, Mass.: Jones & Bar tl ett Pubs., Inc., 2008.

G ensur e, R., and Jppner, H. Parathyr oi d Hor mone wi thout

Parathyr oi d G l ands, Endocr inology 146(2):544-46, Febr uar y
2005.

G ol an, D., et al . Pr inciples of Phar macology: The Pathophysiologic

Basis of Dr ug Ther apy, 2nd ed. Phi l adel phi a: Li ppi ncott Wi l l i ams
& Wi l ki ns, 2007.

G uti er r ez , K. Phar macother apeutics: Clinical Reasoning in Pr imar y

Car e, 2nd ed. Phi l adel phi a: W.B. Saunder s Co., 2008.

Houck, P.M., and Bratz l er, D.W. Admi ni strati on of F i r st Hospi tal
Anti bi oti cs for Communi ty-Acqui r ed Pneumoni a: Does Ti mel i ness
Affect Outcomes? Cur r ent Opinion in Infectious Diseases
18(2):151-56, Apr i l 2005.

Kanner, E.M., and Tsai , J.C. Cur r ent and Emer gi ng Medi cal
Therapi es for G l aucoma, Exper t Opinion on Emer ging Dr ugs
10(1):109-18 Febr uar y 2005.

Lippincotts Nur sing Dr ug G uide 2008. Phi l adel phi a: Li ppi ncott
Wi l l i ams & Wi l ki ns, 2008.

Nol an, C.R.Strategi es for Impr ovi ng Long-Ter m Sur vi val i n

Pati ents wi th ESRD, Jour nal of the Amer ican Society of
Nephr ology 16(Suppl 2): S120-S127, November 2005.

Nur sing I.V. Dr ug Handbook, 9th ed. Phi l adel phi a: Li ppi ncott
Wi l l i ams & Wi l ki ns, 2006.

Nur sing2008 Dr ug Handbook, 28th ed. Phi l adel phi a: Li ppi ncott
Wi l l i ams & Wi l ki ns, 2008.

Physicians Desk Refer ence, 58th ed. Montval e, Md.: Thomson

PDR, 2004.

Pr ofessional G uide to Pathophysiology, 2nd ed. Phi l adel phi a:

Li ppi ncott Wi l l i ams & Wi l ki ns, 2007.

Psychophar macology, 2nd ed. Ar l i ngton, Va.: Amer i can Psychi atr i c
Publ i shi ng, Incor porated, 2006.
Roach, S., and Zor ko, B.S. Phar macology for Health Pr ofessionals.
Phi l adel phi a: Li ppi ncott Wi l l i ams & Wi l ki ns, 2006.

Roach, S., and For d, S.M. Intr oductor y Clinical Phar macology, 8th
ed. Phi l adel phi a: Li ppi ncott Wi l l i ams & Wi l ki ns, 2007.

Sal z man, C. Clinical G er iatr ic Psychophar macology, 4th ed.

Phi l adel phi a: Li ppi ncott Wi l l i ams & Wi l ki ns, 2005.

Sande, M.A., and El i opoul os, G . The Sanfor d G uide to HIV/AIDS

Ther apy, 14th ed. Hyde Par k, Vt.: Anti mi cr obi al Therapy, Inc.,
2005.

U.S. Food and Dr ug Admi ni strati on: www.fda.gov

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

A
Abacavi r 266270
Abci xi mab 165169
Absor pti on 79
dr ug i nteracti ons and 16
Acar bose 342345
Acebutol ol 4347 129131
Acetami nophen 9698
nonsel ecti ve, safe use of 99
sel ecti ve, r i sks of usi ng 98
Acetazol ami de 229 368369 416
Aceti c aci d 417
Acetohexami de 342345
Acetyl chol i ne 21 22 23 24 26 27 60 61
Acetyl cystei ne 190191
Aci di fyi ng dr ugs 368369
Aci tr eti n 419
Acti vated char coal 204205 422
Acti ve transpor t 7
Acute therapy 14
Acycl ovi r 260263 418
Adapal ene 419
Addi ti ve effects 16
Adenosi ne 133134
Adr ener gi c bl ocki ng dr ugs 4047
topi cal 416
Adr ener gi c dr ugs 3239
cl assi fyi ng 32
mechani sm of acti on of 33
Adsor bent dr ugs 204205
Adver se dr ug r eacti ons 1719
dose-r el ated 1718
 pati ent sensi ti vi tyr el ated 1819
Agoni st 12
Al buter ol 3739 176177
Al cl ometasone 419
Al desl euki n 408409
Al doster one 301
Al emtuz umab 398399
Al fuzosi n 4043
Al kal i ni z i ng dr ugs 366368
Al kyl ati ng dr ugs 371379
mechani sm of acti on of 373
Al kyl ati ng-l i ke dr ugs 378379
Al kyl sul fonates 374375
Al l opur i nol 307309
Al l yl ami ne der i vati ves, syntheti c 288289
Al motr i ptan 8688
Al oe 423
Al osetr on 210
Al pha-adr ener gi c bl ocker s 4043 141142
mechani sm of acti on of 41
Al prazol am 312313 314 315
Al pr ostadi l 231232
Al tepl ase 171173 172
Al tr etami ne 409410
Al umi num car bonate gel 197198
Al umi num-magnesi um compl ex 197198
Amantadi ne 6266 264266
Ambenoni um 2427
Ami kaci n 238240
Ami l or i de 227228
Ami nogl ycosi des 238240
1-(ami nomethyl ) cycl ohexaneaceti c aci d 7879
Ami nophyl l i ne 183185
Ami odar one 131132
Ami tr i ptyl i ne 322325
Aml odi pi ne 138140
Ammoni um chl or i de 368369
Amobar bi tal 316317
Amoxapi ne 322325
Amoxi ci l l i n 196197 241243
Amphetami ne sal ts, mi xed 336337
Amphoter i ci n B 280283 418
Ampi ci l l i n 241243
Ampr enavi r 272275
Amyl ase 206
Amyl ni tr i te 135136
Anaki nra 302306
Anastr ozol e 387388
Andr ogens 390391
Anestheti c dr ugs 108115
ophthal mi c 414
oti c 417
Angi otensi n-conver ti ng enz yme i nhi bi tor s 144145
Angi otensi n II r eceptor bl ocker s 146147
Ani mal s as dr ug sour ces 3 4
Antaci ds 197198
Antagoni st 12
types of 1213
Antagoni sti c effect 16
Anter i or pi tui tar y dr ugs 349350
Anti acne dr ugs, topi cal 419420
Anti al l er gi c agents as ophthal mi c dr ugs 414
Anti andr ogens 391392
Anti angi nal dr ugs 134140
mechani sm of acti on of 134
Anti anxi ety dr ugs 318319
Anti ar r hythmi c dr ugs 123134
Anti bacter i al dr ugs 238260
der matol ogi c 418
Anti bi oti c anti neopl asti c dr ugs 385386
Anti bi oti cs, systemi c, as gastr oi ntesti nal dr ugs 196197 See also
Anti bacter i al dr ugs
Anti chol i ner gi c dr ugs 2732 6062 177178
Anti chol i nesterase dr ugs 2427
di ffer enti ati ng toxi c r esponse to, fr om myastheni c cr i si s 24
mechani sm of acti on of 22
Anti coagul ant dr ugs 161171
Anti convul sant dr ugs 6885
Anti depr essants 320329
r i sks of 322
Anti di abeti c dr ugs 339345
Anti di ar r heal dr ugs 208210
Anti di ur eti c hor mone 350352
Anti emeti cs 216219
Anti estr ogens 388390
Anti fl atul ent dr ugs 205
Anti fungal dr ugs 280289
der matol ogi c 418
Anti gout dr ugs 306309
Anti hi stami nes 216219 294297

Anti hyper tensi ve dr ugs 140147

Anti -i nfecti ve dr ugs 237290
der matol ogi c 418
ophthal mi c 414
oti c 417
Anti -i nfl ammator i es der matol ogi c 419
ophthal mi c 415
oti c 417
Anti l i pemi c dr ugs 147152
Anti metabol i te dr ugs 379384
Anti mi cr obi al dr ug, sel ecti ng 237
Anti mi grai ne dr ugs 8590
Anti mycoti c dr ugs 280289
Anti neopl asti c dr ugs 371411
uncl assi fi abl e 402411
Anti par ki nsoni an dr ugs 5968
Anti pl atel et dr ugs 165169
Anti psychoti c dr ugs 330336
Anti pyr eti cs 93101
Anti r etr ovi ral dr ugs 266275
Anti thymocyte gl obul i n 302306
Anti thyr oi d dr ugs 355356
Anti tuber cul ar dr ugs 275280
Anti tussi ves 188189
Anti ul cer dr ugs 195203
Anti vi ral dr ugs 260275
der matol ogi c 418
Anxi ol yti cs 318319
Apracl oni di ne 416
Ar gatr oban 169170
Ar i pi prazol e 331332
Ar omatase i nhi bi tor s 387388
Ar seni c tr i oxi de 403
Ascor bi c aci d 368369
Asparagi nases 404
Aspi r i n 9496 166169
Ataz anavi r 272275
Atenol ol 4347 137138
Ator vastati n 149150
Atracur i um 5658
Atr opi ne 2732 30 416
Atypi cal anti psychoti cs 331332
Autonomi c ner vous system dr ugs 2147
Az aspi r odecanedi one der i vati ves 319
Az atadi ne 294295 297
Az athi opr i ne 302306
Azel ai c aci d 418
Azel asti ne 414
Az i thr omyci n 249251
Az tr eonam 255256

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

B
Baci traci n 418
Bacl ofen 5355
Bar bi turates 7072 110112 316317
Basi l i xi mab 302306
Becl omethasone 178180 298300
Bel l adonna 2732
Benazepr i l 144145
Bendr ofl umethi az i de 224225
Benzocai ne 114115 417
Benzodi azepi nes 7476 110112 312313 315
mechani sm of acti on of 314
Benzonatate 188189
Benzoyl per oxi de 420
Benz tr opi ne 2732 6062
Benz yl al cohol 114115
Beta-adr ener gi c bl ocker s 4347 129131 137138
car di osel ecti ve 45
mechani sm of acti on of 45
under use of, i n el der l y pati ents 46
Beta 2 -adr ener gi c agoni sts 176177
Betamethasone 298300
Betaxol ol 4347 416
Bethanechol 2124
Bi cal utami de 391392
Bi l e-sequester i ng dr ugs 147148
Bi matopr ost 416
Bi ol ogi cal weapons exposur e, vacci nes and tr eatment for 421
Bi otransfor mati on See Metabol i sm.
Bi per i den 6062
Bi sacodyl 214215
Bi sopr ol ol 4347
Bi str i azol e anti mycoti c dr ug 285287
Bi tol ter ol 3739
Bi val i r udi n 169170
Bl eomyci n 385386
Bor i c aci d 417
Bor tezomi b 400402
Br i moni di ne 416
Br i nzol ami de 416
Br omocr i pti ne 6266
Br ompheni rami ne 294295 297
Buccal r oute of admi ni strati on 4
Bucl i z i ne 216219
Budesoni de 178180
Bul k-for mi ng l axati ves 212213
Bumetani de 225227
Bupi vacai ne 112114
Bupr enor phi ne 105107
Bupr opi on 327329
Buspi r one 319
Busul fan 374375
Butabar bi tal 316317
Butacai ne 114115
Butenafi ne 281 418
Butoconazol e 281
Butor phanol 105107

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

C
Cal ci um car bonate 197198
Cal ci um channel bl ocker s 138140 142143
mechani sm of acti on of 139
Cal ci um r epl acement 361363
Cancer, dr ugs and 371
Candesar tan ci l exeti l 146147
Capeci tabi ne 381383
Captopr i l 144145
Car bachol 2124 415
Car bamazepi ne 7374
Car bami de per oxi de 417
Car bapenems 253255
Car beni ci l l i n 241243
Car bi dopa-l evodopa 6266
Car boni c anhydrase i nhi bi tor s 229 416
Car bopl ati n 378379
Car boxami des 8081
Car boxyl i c aci d der i vati ves 7678
Car di ac gl ycosi des 120122
Car di ovascul ar dr ugs 119152
Car i sopr odol 5052
Car musti ne 375376
Car teol ol 4347 416
Car vedi l ol 4347 141142
Caspofungi n 287288
Castor oi l 214215
Catechol ami nes 3337

Catechol -O-methyl transferase i nhi bi tor s 6668

Cefacl or 243246
Cefadr oxi l 243246
Cefazol i n 243246
Cefdi ni r 243246
Cefepi me 243246
Cefi xi me 243246
Cefotaxi me 243246
Cefoxi ti n 243246
Cefpodoxi me 243246
Cefpr oz i l 243246
Ceftaz i di me 243246
Cefti buten 243246
Ceftr i axone 243246
Cefur oxi me 243246
Cel ecoxi b 98100
Central -acti ng sympatheti c ner vous system i nhi bi tor s 141142
Central l y acti ng skel etal muscl e r el axants 5052
Central ner ve bl ock 113
Cephal exi n 243246
Cephal ospor i ns 243246
mechani sm of acti on of 245
Cer umenol yti cs 417
Ceti r i z i ne 294295 297
Cevi mel i ne 2124
Chamomi l e 423
Chemi cal weapons exposur e, tr eatment and anti dotes for 422
Chl oral hydrate 317318
Chl orambuci l 372374
Chl orampheni col 417 421
Chl or di azepoxi de 312313 314 315
Chl or opr ocai ne 112114
Chl or othi az i de 224225
Chl or pheni rami ne 294295 296 297
Chl or pr omaz i ne 216219 333336
Chl or pr opami de 342345
Chl or thal i done 224225
Chl or zoxazone 5052
Chol ester ol absor pti on i nhi bi tor s 152
Chol estyrami ne 147148
Chol i ne magnesi um tr i sal i cyl ate 9496
Chol i ner gi c agoni sts 2124
mechani sm of acti on of 22
Chol i ner gi c bl ocki ng dr ugs 2732 6062 177178
Chol i ner gi c dr ugs 2127
mechani sm of acti on of 22
Chol i ne sal i cyl ate 9496
Chor i oni c gonadotr opi n 349350
Ci cl opi r ox 281 418
Ci dofovi r 421
Ci meti di ne 199 200 201
Ci pr ofl oxaci n 256257 277 414 421
Ci satracur i um 5658
Ci spl ati n 378379
Ci tal opram 320322
Cl adr i bi ne 383384
Cl ar i thr omyci n 196197 249251
Cl ass IA anti ar r hythmi cs 124125
Cl ass IB anti ar r hythmi cs 126127
Cl ass IC anti ar r hythmi cs 128129
Cl ass II anti ar r hythmi cs 129131
Cl ass III anti ar r hythmi cs 131132
Cl ass IV anti ar r hythmi cs 133134 See also Cal ci um channel
bl ocker s.
Cl emasti ne 294295 297
Cl i ndamyci n 248249 418 420
Cl i oqui nol 281
Cl obetasol 419
Cl ocor tol one 419
Cl omi prami ne 322325
Cl onazepam 7476 312313 314 315
Cl oni di ne 141142
Cl opi dogr el 165169
Cl orazepate 7476 312313 314 315
Cl otr i mazol e 281 418
Cl ove oi l 114115
Cl oz api ne 331332
Cocai ne 112115
Codei ne 102105 188189
Col chi ci ne 307309
Col esevel am 147148
Col esti pol 147148
Col i sti n sul fate 417
Competi ti ve dr ugs 5658
Competi ti ve i nhi bi ti on 107
Cor ti coster oi ds 178180 297301
speci al popul ati on concer ns and 179
Cor ti cotr opi n 349350
Cor ti cotr opi n r eposi tor y 349350
Cor ti sone 298300
Cosyntr opi n 349350
Co-tr i moxazol e 257259
COX-2 i nhi bi tor s 9899 100 See also Nonster oi dal anti -
i nfl ammator y dr ugs.
Cranber r y 423
Cr omol yn 182 414
Cyanocobal ami n 158159
Cycl i z i ne 216219
Cycl obenz apr i ne 5052
Cycl opentol ate 416
Cycl ophosphami de 302306 372374
Cycl opl egi cs 416
Cycl ospor i ne 302306
Cypr oheptadi ne 294295 297
Cytarabi ne 381383

 Clinical Pharmacology Made Incredibly
Easy!
3rd Edition
2009 Li ppi ncott Wi l l i ams & Wi l ki ns

D
Dacar baz i ne 376377
Dacl i z umab 302306
Dacti nomyci n 385386
Dal tepar i n 161164
Dantr ol ene 5253
Dar bepoeti n al fa 160161
Dar i fenaci n 230231
Dar unavi r 272275
Daunor ubi ci n 385386
Decongestants 191193
Del avi r di ne 270271
Demecar i um 2427
Demecl ocycl i ne 247248
Depol ar i z i ng bl ocki ng dr ugs 5859
Der matol ogi c dr ugs 418420
Desfl urane 109110
Desi prami ne 322325
Desl oratadi ne 294295 297
Desmopr essi n 350352
Desoni de 419
Desoxi metasone 419
Dexamethasone 298300 415 417 419
Dexchl or pheni rami ne 294295 297
Dextr oamphetami ne 336337
Dextr omethor phan 188189
Di azepam 5355 7476 312313 314 315 422
Di azoxi de 142143
Di bucai ne 114115
Di cl ofenac 98100 415
Di cl oxaci l l i n 241243
Di cycl omi ne 2732
Di danosi ne 266270
Di etar y fi ber 212213
Di fl orasone 419
Di fl uni sal 9496
Di gesti ve dr ugs 206
Di goxi n 120122
Di goxi n toxi ci ty, si gns and symptoms of 122
Di hydr oer gotami ne 8990
Di l ti azem 133134 138140
Di menhydr i nate 216219 294295 297
Di phenhydrami ne 6062 216219 294295 297
Di pheni dol 218
Di phenoxyl ate wi th atr opi ne 208209
Di pi vefr i n 415
Di pyr i damol e 165169
Di r ect-acti ng skel etal muscl e r el axants 5253
Di r ectl y obser vabl e therapy 276
Di r ect thr ombi n i nhi bi tor s 169170
Di r ect vasodi l ator s 142143
Di sopyrami de 124125
Di str i buti on 910
dr ug i nteracti ons and 16
Di ur eti cs 224229
Di val pr oex 7678
Dobutami ne 3337
Docetaxel 410411
Docusate sal ts 213214
Dofeti l i de 131132
Dol asetr on 216219
Donepez i l 2427
Dopami ne 3337
Dopami ner gi c dr ugs 6266
Dor zol ami de 416
Dose-r esponse cur ve 13 14
Doxazosi n 4043 141142
Doxepi n 322325
Doxor ubi ci n 385386
Doxycycl i ne 247248 420 421
Dr onabi nol 218
Dr otr ecogi n al fa 289290
Dr ug admi ni strati on r outes 45
effect of, on absor pti on 78
Dr ug al l er gy 1819
Dr ug dependence 15
Dr ug effect 12
Dr ug i nteracti ons 1517
Dr ug nomencl atur e 2
Dr ug potency 13
Dr ug sour ces 24
Dr ug tol erance 15
Dul oxeti ne 320322
Durati on of acti on 12
Dycl oni ne 114115

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E
Echi nacea 423
Echi nocandi ns 287288
Echothi ophate 2427
Econazol e 281 418
Edr ophoni um 2427
toxi c dr ug r esponse ver sus myastheni c cr i si s and 24
Efavi r enz 270271
El ectr ol yte r epl acement dr ugs 359366
El etr i ptan 8688
Emedasti ne 414
Emeti cs 219220
Emol l i ent l axati ves 213214
Empi r i c therapy 14
Emtr i ci tabi ne 266270
Enal apr i l 144145
Enal apr i l at 144145
Endocr i ne dr ugs 339356
Enfl urane 109110
Enoxapar i n 161164
Entacapone 6668
Ephedr i ne 3739 191193
Epi dural i nfusi on 5
Epi nephr i ne 3337 415
Epoeti n al fa 160161
Epr osar tan 146147
Epti fi bati de 165169
Er ecti l e dysfuncti on therapy dr ugs 231232
Er gol oi d mesyl ates 4043
Er gotami ne 4043
Er gotami ne pr eparati ons 8990
Er tapenem 253255
Er ythr omyci n 249251 414 418 420
Er ythr opoi eti n agents 160161
Esci tal opram 320322
Esmol ol 4347 129131
Esomeprazol e 201202
Estazol am 312313 314 315
Estradi ol 347348
Estramusti ne 372374
Estr ogeni c substances, conjugated 347348
Estr ogens 347348
ester i fi ed 347348
Estr opi pate 347348
Eszopi cl one 317318
Ethacr yni c aci d 225227
Ethambutol 276280
Ethi nyl estradi ol 233234 347348
Ethosuxi mi de 8283
Ethotoi n 6970
Ethyl chl or i de 114115
Ethyl eni mi nes 377378
Ethynodi ol di acetate 233234
Etodol ac 98100
Etomi date 110112
Etoposi de 396397
Excr eti on 11
dr ug i nteracti ons and 16
Exemestane 387388
Expected therapeuti c r esponse 17
Expectorants 187
Ezeti mi be 152

 Clinical Pharmacology Made Incredibly
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F
Factor Xa i nhi bi tor dr ugs 170171
Famci cl ovi r 260263
Famoti di ne 199 200 201
Fenofi brate 148149
Fenopr ofen 98100
Fentanyl 102105 110112
Fer r ous fumarate 156157
Fer r ous gl uconate 156157
Fer r ous sul fate 156157
Fever few 423
Fexofenadi ne 294295 297
F i br i c aci d der i vati ves 148149
F i r st-pass effect 8
F l avoxate 230231
F l ecai ni de 128129
F l oxur i di ne 381383
F l uconazol e 285287
F l ucytosi ne 283284
F l udarabi ne 383384

F l udr ocor ti sone 301

F l uni sol i de 178180
F l uoci nol one 419
F l uoci noni de 419
F l uor omethol one 415
F l uor oqui nol ones 256257 277
F l uor ouraci l 381383
F l uoxeti ne 320322
F l uoxymester one 390391
F l uphenaz i ne 333336
F l urandr enol i de 419
F l urazepam 312313 314 315
F l ur bi pr ofen 98100 415
F l utami de 391392
F l uti casone 178180
F l uvastati n 149150
F l uvoxami ne 320322
Fol i c aci d 159160
Fol i c aci d anal ogues 380381
Fondapar i nux 170171
Food, dr ug i nteracti ons and 17
Food and Dr ug Admi ni strati on, new dr ug devel opment and 56
For moter ol 3739 176177
Fosampr enavi r 272275
Foscar net 264
Fosi nopr i l 144145
Fosphenytoi n 6970
F r ovatr i ptan 8688
F ul vestrant 388390
F ur osemi de 225227

 Clinical Pharmacology Made Incredibly
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G
G abapenti n 7879
G al antami ne 2427
G amma benzene hydr ochl or i de 420
G anci cl ovi r 260263
G ar l i c 423
G astr i c r oute of admi ni strati on 4
G astr oi ntesti nal dr ugs 195220
G efi ti ni b 400402
G emci tabi ne 381383
G emfi br oz i l 148149
G emtuz umab ozogami ci n 398399
G eni tour i nar y dr ugs 223234
G entami ci n 238240 414 418 421
G i nger 423424
G i nkgo bi l oba 424
G i nseng 424
G l i cl az i de 342345
G l i mepi r i de 342345
G l i pi z i de 342345
G l ucagon 345 346
G l ucan synthesi s i nhi bi tor s 287288
G l ucocor ti coi ds 298300
G l ybur i de 342345
G l ycer i n 211212 416
G l ycopyr r ol ate 2732
G onadotr opi n-r el easi ng hor mone anal ogues 393395
G oser el i n 393395
G rani setr on 216219
G r een tea 424
G r i seoful vi n 281
G uai fenesi n 187
G uanadr el 141142
G uanethi di ne 141142
G uani di ne 2427

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H
Hai r gr owth sti mul ants 419
Hal ci noni de 419
Hal f-l i fe 11
Hal obetasol 419
Hal oper i dol 333336
Hal opr ogi n 281
Hal othane 109110
Hemati ni c dr ugs 155161
Hematol ogi c dr ugs 155173
Hepar i n 161164
par ti al thr ombopl asti n ti me moni tor i ng and 163
Her bal dr ugs 423424
Hi stami ne-1 r eceptor antagoni sts 294297
Hi stami ne-2 r eceptor antagoni sts 199 201
mechani sm of acti on of 200
HMG -CoA r eductase i nhi bi tor s 149150
Homatr opi ne 2732 416
Homeostasi s, dr ugs and 359
Hor monal anti neopl asti c dr ugs 386395
Hor monal contracepti ves 233234
Hor mone modul ator s 386395
Hor mone r epl acement therapy, hear t di sease and 348
5-HT 1 -r eceptor agoni sts 8688
contrai ndi cati ons to 88
5-HT 3 r eceptor antagoni sts 210
Hydantoi ns 6970
Hydral az i ne 142143
Hydr ochl or othi az i de 224225
Hydr ocodone 102105 188189
Hydr ocor ti sone 178180 298300 417 419
Hydr ofl umethi az i de 224225
Hydr omor phone 102105
Hydr oxocobal ami n 158159
Hydr oxyamphetami ne 415
5-Hydr oxy-3-methyl gl utar yl coenz yme A r eductase i nhi bi tor s 149
150
Hydr oxypr ogester one 392393
Hydr oxyur ea 406
Hydr oxyz i ne 216219 294295 297
Hyoscyami ne sul fate 2732
Hyper gl ycemi c dr ug 345 346
Hyper osmol ar l axati ves 211212
Hyper suscepti bi l i ty 18
Hypogl ycemi c dr ugs 339345

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IJ
Iatr ogeni c effects 18
Ibr i tumomab ti uxetan 398399
Ibupr ofen 98100
Ibuti l i de 131132
Idar ubi ci n 385386
Idi osyncrati c r esponse 19
Ifosfami de 372374
Imati ni b 400402
Imi dazol e 284285
Imi nosti l benes 7374
Imi penem-ci l astati n 253255
Imi prami ne 322325
Immune system dr ugs 293309
Immunosuppr essants 302306
Inamr i none 122123
Indapami de 224225
Indi navi r 272275
Indomethaci n 98100
Infl uenz a A dr ugs 264266
Inhal ati on anestheti cs 109110
Inotr opi cs 119123

Insul i n 340342 341

Inter fer ons 407408
Intra-ar ti cul ar i nfusi on 5
Intrader mal r oute of admi ni strati on 4
Intramuscul ar r oute of admi ni strati on 4 8
Intraocul ar pr essur e, dr ugs to l ower 416
Intraosseous i nfusi on 5
Intraper i toneal i nfusi on 5
Intrapl eural i nfusi on 5
Intrathecal i nfusi on 5
Intravenous anestheti cs 110112
Intravenous r oute of admi ni strati on 5 7
Intr i nsi c acti vi ty 12
Investi gati onal new dr ug, appr oval pr ocess for 56
Ipecac syr up 219220
Ipratr opi um 176177
Ir besar tan 146147
Ir i notecan 399400
Ir on 156157
par enteral , testi ng for sensi ti vi ty to 157
Ir on dextran 156157
Ir r i tant cathar ti cs 214215
Isoethar i ne 3739
Isofl urane 109110
Isoni az i d 276280
Isopr oter enol 3339
Isosor bi de 135136 416
Isotr eti noi n 419
Itraconazol e 285287

 Clinical Pharmacology Made Incredibly
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K
Kanamyci n 238240
Kaol i n and pecti n 209210
Kava 424
Ketami ne 110112
Ketoconazol e 284285 418
Ketopr ofen 98100
Ketor ol ac 98100 415
Ketoti fen 414

 Clinical Pharmacology Made Incredibly
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L
Labetal ol 4347 141142
Lactul ose 211212
Lami vudi ne 266270
Lamotr i gi ne 7980
Lansoprazol e 201202
Latanopr ost 416
Laxati ves 211216
Lepi r udi n 169170
Letr ozol e 387388
Leucovor i n 160
Leukotr i ene modi fi er s 180182
Leupr ol i de 393395
Leval buter ol 3739 176177
Levar ter enol 3337
Leveti racetam 8485
Levobunol ol 4347 416
Levobupi vacai ne 112114
Levodopa 6266
pr os and cons of 64
Levofl oxaci n 256257 414
Levor phanol 102105
Levothyr oxi ne 352354
Li docai ne 112115 126127
mechani sm of acti on of 127
Li ncomyci n der i vati ves 248249
Li ndane 420
Li othyr oni ne 352354
Li otr i x 352354
Li pase 206
Li sdexamfetami ne 336337
Li si nopr i l 144145
Li thi um 329330
Local anestheti cs 112114
Lodoxami de 414
Lomusti ne 375376
Loop di ur eti cs 225227
Loperami de 208209
Lopi navi r 272275
Loratadi ne 294295 297
Lorazepam 7476 312313 314 315 422
Losar tan 146147
Lotepr ednol 415
Lovastati n 149150
Loxapi ne 333336
Lubr i cant l axati ves 215216
Lubr i cants, ophthal mi c 415
Lymphocyte i mmune gl obul i n 302306

 Clinical Pharmacology Made Incredibly
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M
Macr ol i des 249251
Mafeni de 418
Magal drate 197198
Magnesi um hydr oxi de and al umi num hydr oxi de 197198
Magnesi um r epl acement 363365
Magnesi um sal ts 211212
Mai ntenance therapy 14
Mal athi on 420
Manni tol 228 416
Mapr oti l i ne 327329
Mar gi n of safety 13
Mast cel l stabi l i zer s 182
Mechl or ethami ne 372374
Mecl i z i ne 216219 294295 297
Medr oxypr ogester one 392393
Megestr ol 392393
Mel oxi cam 98100
Mel phal an 372374
Menotr opi ns 349350
Menthol 114115
Meper i di ne 102105
Mephobar bi tal 7072 316317
Mepi vacai ne 112114
Mer captopur i ne 383384
Mer openem 253255
Mesor i daz i ne 333336
Mestranol 233234
Metabol i sm 1011
dr ug i nteracti ons and 16 17
Metapr oter enol 3739 176177
Metaxal one 5052
Metfor mi n 342345
Methadone 102105
Methazol ami de 229
Methi mazol e 355356
Methocar bamol 5052
Methohexi tal 110112
Methotr exate 380381
Methscopol ami ne 2732
Methsuxi mi de 8283
Methycl othi az i de 224225
Methyl cel l ul ose 212213 415
Methyl dopa 141142
Methyl pheni date 336337
Methyl pr edni sol one 178180 298300 299

Methyl xanthi nes 183185

Meti pranol ol 4347 416
Metocl oprami de 218
Metol azone 224225
Metopr ol ol 4347 137138
Metr oni dazol e 196197 418
Mexi l eti ne 126127
Mi conazol e 281 418
Mi dazol am 110112
Mi gl i tol 342345
Mi l r i none 122123
Mi neral ocor ti coi ds 301
Mi neral oi l 215216
Mi neral s as dr ug sour ces 3
Mi nocycl i ne 247248 420
Mi noxi di l 142143 419
Mi oti cs 415
Mi r taz api ne 327329
Mi sopr ostol 202203
danger s of usi ng, dur i ng pr egnancy 203
Mi tomyci n 385386
Mi toxantr one 385386
Mi xed al pha- and beta-adr ener gi c bl ocker s 141142
Mi xed opi oi d agoni st-antagoni sts 101 105107
Modafi ni l 336337
Moexi pr i l 144145
Mol i ndone 333336
Mometasone 419
Monoami ne oxi dase i nhi bi tor s 325327
Monobactams 255256
Monocl onal anti bodi es 186187 398399
Montel ukast 180182
Mood stabi l i zer dr ugs 329330
Mor i ci z i ne 128129
Mor phi ne sul fate 102105

Motor end pl ate, neur omuscul ar bl ocki ng dr ugs and 56

Moxi fl oxaci n 256257
Mucol yti cs 189191
Mupi r oci n 418
Mur omonab-CD3 302306
Mycophenol ate mofeti l 302306
Mydr i ati cs 415416

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N
Nabumetone 98100
Nadol ol 4347 137138
Nafci l l i n 241243
Nafti fi ne 281 418
Nal buphi ne 105107
Nal oxone 107108
Nal tr exone 107108
for dr ug addi cti on 108
Napr oxen 98100
Naratr i ptan 8688
Nar coti c agoni sts See Opi oi d agoni sts.
Natamyci n 414
Nategl i ni de 342345
Natural anti neopl asti c dr ugs 395397
Nedocr omi l 182
Nefazodone 327329
Negati ve chr onotr opi c effect 120
Negati ve dr omotr opi c effect 120
Nel fi navi r 272275
Neomyci n 238240 417 418
Neosti gmi ne 2427
Neur omuscul ar bl ocki ng dr ugs 5559
motor end pl ate and 56
safe use of 57
Nevi rapi ne 270271
New dr ug devel opment 56
Ni aci n 150151
Ni car di pi ne 138140
Ni coti ni c aci d 150151
Ni fedi pi ne 138140
Ni l utami de 391392
Ni trates 135136
Ni tr ofurantoi n 259260
Ni tr ogen mustar ds 372374
Ni tr ogl ycer i n 135136
Ni tr opr ussi de 142143
Ni tr osour eas 375376
Ni tr ous oxi de 109110
Ni z ati di ne 199 200 201
Nonbenzodi azepi nes-nonbar bi turates 317318
Noncatechol ami nes 3739
Nondepol ar i z i ng bl ocki ng dr ugs 5658
Non-nucl eosi de r ever se transcr i ptase i nhi bi tor s 270271
Nonopi oi d anal gesi cs 93101
Nonsel ecti ve dr ug 13
Nonster oi dal anti -i nfl ammator y dr ugs 98100
r i sks of usi ng 98
Nor epi nephr i ne 3337
Nor epi nephr i ne depl etor s 141142
Nor fl oxaci n 256257 414
Nor tr i ptyl i ne 322325
Nucl eosi de anal ogue r ever se transcr i ptase i nhi bi tor s 266270
Nucl eosi des, syntheti c 260263
Nucl eoti de anal ogue r ever se transcr i ptase i nhi bi tor s 271272
Nystati n 280282 418

 Clinical Pharmacology Made Incredibly
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O
Obesi ty dr ugs 207208
Ofl oxaci n 256257 277 414
Ol anz api ne 331332
Ol mesar tan 146147
Ol opatadi ne 414
Omal i z umab 186187
Omeprazol e 201202
Ondansetr on 216219
Onset of acti on 11
Ophthal mi c dr ugs 414416
Opi oi d agoni sts 101 102105
pai n contr ol and 104
safe use of 102
Opi oi d antagoni sts 101 107108
Opi oi d-r el ated dr ugs as anti di ar r heal s 208209
Oral anti coagul ants 164166
Oral anti di abeti c dr ugs 342345
Oral r oute of admi ni strati on 5 8
Or l i stat 207208
Or phenadr i ne 5052
Osmoti c agents 416
Osmoti c di ur eti cs 228
Oti c dr ugs 417
Over dose 18
Oxaci l l i n 241243
Oxal i pl ati n 378379
Oxapr oz i n 98100
Oxazepam 312313 314 315
Oxcar bazepi ne 8081
Oxi conazol e 281 418
Oxybutyni n 2732 230231
Oxycodone 102105
Oxymor phone 102105
Oxytoci n 350352

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P
Pacl i taxel 410411
Pai n medi cati ons 93115
Pal i per i done 331332
Pal l i ati ve therapy 15
Pancr eati c enz ymes 206
Pancr eati n 206
Pancr el i pase 206
Pancur oni um 5658
Pantoprazol e 201202
Parasympathol yti c dr ugs 6062
Parasympathomi meti c dr ugs See Chol i ner gi c dr ugs.
Par omomyci n 238240
Par oxeti ne 320322
Par ti al agoni sts 44
Passi ve transpor t 7
Pathogen r esi stance, pr eventi ng 237238
Pati ent sensi ti vi tyr el ated r eacti ons 1819
Pati ents r esponse to dr ug, factor s that affect 15
Peak concentrati on 1112
Pedi cul i ci des 420
Pegaspar gase 404
Penbutol ol 4347
Penci cl ovi r 418
Peni ci l l i n-bi ndi ng pr otei ns 241242
Peni ci l l i ns 241243 421
Pentazoci ne 105107
Pentobar bi tal 316317
Pentostati n 383384
Pepti c ul cer dr ugs 195203
Per i pheral vascul ar r esi stance 136
Per methr i n 420
Per phenaz i ne 216219 333336
Phar macodynami cs 1213 14
Phar macoki neti cs 712
Phar macol ogi c cl ass 2
Phar macotherapeuti cs 1415
Phenazopyr i di ne hydr ochl or i de 100101
Phenel z i ne 325327
Phenobar bi tal 7072 316317
Phenothi az i nes 216219
Phenoxybenz ami ne 4043
Phenter mi ne 207208
Phentol ami ne 4043 141142
Phenyl ephr i ne 3739 191193 415
Phenyl tr i az i nes 7980
Phenytoi n 6970
Phosphodi esterase i nhi bi tor s 122123
Physosti gmi ne 2427
Pi l ocar pi ne 2124 415
Pi moz i de 333336
Pi ndol ol 4347
Pi nocytosi s 7
Pi ogl i tazone 342345
Pi r buter ol 3739 176177
Pi r oxi cam 98100
Pi tui tar y dr ugs 348352
Pl ants as dr ug sour ces 3
Podophyl l otoxi ns 396397
Pol ycar bophi l 212213
Pol yenes 280283
Pol yethyl ene gl ycol 211212
Pol ymyxi n B sul fate 417
Pol ythi az i de 224225
Pol yvi nyl al cohol 415
Posi ti ve i notr opi c effect 119120
Poster i or pi tui tar y dr ugs 350352
Potassi um r epl acement 360361
Potassi um-spar i ng di ur eti cs 227228
Potenti ati on 16
Prami pexol e 6266
Pramoxi ne 114115
Pravastati n 149150
Prazosi n 4043 141142
Pr edni sol one 178180 298300 415
Pr edni sone 178180 298300
Pr i l ocai ne 112114
Pr i mi done 7072
Pr obeneci d 306307
Pr ocai nami de 124125
Pr ocai ne 112114
Pr ocar baz i ne 405
Pr ochl or peraz i ne 216219
Pr ocycl i di ne 6062
Pr odr ug 10
Pr ogesti ns 392393
Pr omethaz i ne 216219 294295 297
Pr opafenone 128129
Pr opanthel i ne 2732
Pr oparacai ne 414
Pr opofol 110112
Pr opoxyphene 102105
Pr opranol ol 4347 129131 137138
Pr opyl thi ouraci l 355356
Pr ostagl andi n anal ogues 416
Pr otease 206
Pr otease i nhi bi tor s 272275
Pr oti r el i n 349350
Pr oton pump i nhi bi tor s 201202
Pr otr i ptyl i ne 322325
Pseudoephedr i ne 191193
Psychotr opi c dr ugs 311337
Psyl l i um hydr ophi l i c muci l l oi d 212213
Pur i ne anal ogues 383384
Pyraz i nami de 276280
Pyr i dosti gmi ne 2427
Pyr i mi di ne anal ogues 381383
mechani sm of acti on of 382
Pyr ophosphate anal ogues 264
Pyr r ol i di nes 8485

 Clinical Pharmacology Made Incredibly
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Q
Quazepam 312313 314 315
Queti api ne 331332
Qui napr i l 144145
Qui ni di ne 124125

 Clinical Pharmacology Made Incredibly
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R
Rabeprazol e 201202
Radi oacti ve i odi ne 355356
Ramel ton 317318
Rami pr i l 144145
Rani ti di ne 199 200 201
Rasagi l i ne 6266
Recombi nant human acti vated pr otei n C 289290
Rectal r oute of admi ni strati on 5
Remi fentani l 102105
Repagl i ni de 342345
Repl acement therapy 15
Reser pi ne 141142
Respi rator y dr ugs 175193
Respi rator y r oute of admi ni strati on 5
Retepl ase 171173

Ri bavi r i n 264266
Ri fampi n 276280
Ri mantadi ne 264266
Ri mexol one 415
Ri sper i done 331332
Ri tonavi r 272275
Ri tuxi mab 398399
Ri vasti gmi ne 2427
Ri z atr i ptan 8688
Rocur oni um 5658
Ropi ni r ol e 6266
Ropi vacai ne 112114
Rosi gl i tazone 342345
Rosuvastati n 149150

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S
Sal i cyl ates 9496
safe use of 96
Sal i ne compounds 211212
Sal meter ol 3739 176177
Sal sal ate 9496
Saqui navi r 272275
Scabi ci des 420
Scopol ami ne 2732 218
Secobar bi tal 316317
Secondar y effects 18
Sedati ve-hypnoti c dr ugs 311318
Sel ecti ve ser otoni n r euptake i nhi bi tor s 320322
di sconti nuati on syndr ome and 321
Sel egi l i ne 6266
Senna 214215
Ser otoni n 5-HT 3 r eceptor antagoni sts 216219
Ser tral i ne 320322
Sevofl urane 109110
Si butrami ne 207208
Si de effects 1719
Si l denafi l 231232
Si l ver sul fadi az i ne 418
Si methi cone 197198 205
Si mvastati n 149150
Si r ol i mus 302306
Skel etal muscl e r el axants 4955
Sl eep agents, war ni ng about 318
Sodi um bi car bonate 366368
Sodi um bi phosphate 211212
Sodi um ci trate 366368
Sodi um fer r i c gl uconate compl ex 156157
Sodi um l actate 366368
Sodi um phosphate 211212
Sodi um r epl acement 365366
Sodi um sal i cyl ate 9496
Sol i fenaci n 230231
Somatr em 349350
Somatr opi n 349350
Sotal ol 4347 131132
Spi r onol actone 227228
St. Johns wor t 424
Stabi l i z i ng dr ugs 5658
Stabl e i odi ne 355356
Stati ns 149150
Stavudi ne 266270
Sti mul ant l axati ves 214215
Sti mul ants 336337
Stool softener s 213214
Str eptoki nase 171173
Str eptomyci n 238240 276280 421
Str eptozoci n 375376
Subcutaneous r oute of admi ni strati on 5 8
Subl i ngual r oute of admi ni strati on 4 7
Succi ni mi des 8283
Succi nyl chol i ne 5859
Sucral fate 202203
Sufentani l 102105 110112
Sul conazol e 281 418
Sul facetami de 414 418
Sul fadi az i ne 257259
Sul famate-substi tuted monosacchar i des 82
Sul famethoxazol e and tr i methopr i m 257259
Sul fi npyrazone 165169 306307
Sul fi soxazol e 414
Sul fonami des 8384 257259
Sul i ndac 98100
Sumatr i ptan 8688
Suppl emental therapy 15
Suppor ti ve therapy 15
Supr ofen 415
Sympathol yti c dr ugs 4047 141142
Sympathomi meti c dr ugs See Adr ener gi c dr ugs.
Syncyti al vi r us dr ugs 264266
Syntheti c dr ug sour ces 2 34

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T
Tacr i ne 2427
Tacr ol i mus 302306
Tadal afi l 231232
Tamoxi fen 388390
r i sks ver sus benefi ts of 389
Tamsul osi n 4043
Tar geted therapi es 400402
Tar get or gans 23
Taz ar otene 419
Tel mi sar tan 146147
Temazepam 312313 314 315
Tenectepl ase 171173
Teni posi de 396397
Tenofovi r 271272
Terazosi n 4043 141142
Ter bi nafi ne 281 288289 418
Ter butal i ne 3739 176177
Ter conazol e 281
Testol actone 390391
Testoster one 390391
Tetracai ne 112115 414
Tetracycl i ne 196197 418 420
Tetracycl i nes 247248
Theophyl l i ne 183185
Therapeuti c cl ass 2
Therapeuti c i ndex 13
Thi az i de and thi az i de-l i ke di ur eti cs 224225
Thi ethyl peraz i ne 216219
Thi oguani ne 383384
Thi opental 110112
Thi or i daz i ne 333336
Thi otepa 377378
Thi othi xene 333336
Thr ombol yti c dr ugs 171173
Thymogl obul i n 302306
Thyr ogl obul i n 352354
Thyr oi d antagoni sts 355356
Thyr oi d dr ugs 352354
Thyr oi d-sti mul ati ng hor mone 349350
Thyr oi d USP (desi ccated) 352354
Thyr otr opi n 349350
Ti car ci l l i n 241243
Ti cl opi di ne 165169
Ti mol ol 4347 416

Ti nz apar i n 161164
Ti oconazol e 281
Ti pranavi r 272275
Ti r ofi ban 165169
Ti z ani di ne 5052
Tobramyci n 238240 414
Tol az ami de 342345
Tol butami de 342345
Tol capone 6668
Tol naftate 281
Tol ter odi ne 2732 230231
Topi cal anestheti cs 114115
Topi cal r oute of admi ni strati on 5
Topi ramate 82
Topoi somerase I i nhi bi tor s 399400
Topotecan 399400
Tor emi fene 388390
Trandol apr i l 144145
Transl i ngual r oute of admi ni strati on 4
Tranyl cypr omi ne 325327
Trastuz umab 398399
Travopr ost 416
Trazodone 327329
Tr eti noi n 419
Tr i aceti n 281
Tr i amci nol one 178180 298300 419
Tr i amter ene 227228
Tr i azenes 376377
Tr i azol am 312313 314 315
Tr i azol es, syntheti c 285287
Tr i cycl i c anti depr essants 322325
Tr i ethanol ami ne pol ypepti de 417
Tr i fl uoperaz i ne 333336
Tr i fl ur i di ne 414
Tr i hexypheni dyl 2732 6062
Tr i methobenz ami de 216219
Tr i mi prami ne 322325
Tr i ptans See 5-HT 1 -r eceptor agoni sts.
Tr i ptor el i n 393395
Tr omethami ne 366368
Tr opi cami de 416
Tr ospi um 230231
Tuber cul osi s di r ectl y obser vabl e therapy for 276
dr ug r egi mens for tr eati ng 276280
Typi cal anti psychoti cs 333336

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U
Undecyl eni c aci d 281
Unfracti onated hepar i n 161164
Unopr ostone 416
Ur ea 228
Ur i cosur i cs 306307
Ur i nar y tract anti spasmodi cs 230231
Ur oki nase 171173

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V
Vagi nal r oute of admi ni strati on 5
Val acycl ovi r 260263
Val ganci cl ovi r 260263
Val pr oate 7678
Val pr oi c aci d 7678
Val sar tan 146147
Vancomyci n 251253
Var denafi l 231232
Vasodi l ati ng dr ugs 142143
Vasopr essi n 350352
Vecur oni um 5658
Venl afaxi ne 320322 327329
Verapami l 133134 138140
Vi nbl asti ne 395396
Vi nca al kal oi ds 395396
Vi ncr i sti ne 395396
Vi nor el bi ne 395396
Vi tami n B1 2 158159
Vi tex 424
Vor i conazol e 285287

 Clinical Pharmacology Made Incredibly
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W
War far i n 164166
moni tor i ng l evel s of 165

 Clinical Pharmacology Made Incredibly
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X
Xanthi nes 183185

 Clinical Pharmacology Made Incredibly
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2009 Li ppi ncott Wi l l i ams & Wi l ki ns

Y
Yohi mbi ne 424

 Clinical Pharmacology Made Incredibly
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Z
Zafi r l ukast 180182
Zal epl on 317318
Zi dovudi ne 266270 268
Zi l euton 180182
Zi prasi done 331332
Zol mi tr i ptan 8688
Zol pi dem 317318
Zoni sami de 8384