USMLE Road Map Pharmacology

A ZUNG
ECOND
ITID
VOR
Contents
PRINC IPLES OF PHARMACOLOGY
I
2
3
4
II
5
6
7
8
9
Introduction to Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Drug Dosing and Prescription Writing . . . . . . . . . . . . . . . . . . . . . . .
3
5
12
17
AUT ONOMIC NERVOUS SYSTEM
Introduction to Autonomic Nervous System Pharmacology

Cholinergic Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cholinergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adrenergic Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ill
C EN T RAL NERVOUS SYSTEM
I0
II
12
13
14
IS
16
17
18
19
Introduction to Central Nervous System Pharmacology . . . . . . . . .

Anxiolytics, Hypnotics, and Sedatives . . . . . . . . . . . . . . . . . . . . . . . .
Ant.ipsychotlcs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Drugs Used to Treat Depression and Mania . . . . . . . . . . . . . . . . . . .
Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Drugs Used to Treat Parkinson s Disease and Other
Movement Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CNS Stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Alcohol and Other Drugs of Abuse . . . . . . . . . . . . . . . . . . . . . . . . . .
Opioid Analgesics and Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . .
IV
CARDIOVASCULAR SYSTEM
20
21
22
23
24
25
26
27
Antihypertensive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Drugs Used to Treat Congestive Heart Failure ....... ........ .
Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Anticoagulant, Fibrinolytic, and Antiplatelet Drugs . . . . . . . . . . . . . .
Antihyperlipidemic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Drugs Used to Treat Anemia .... ........ .............. .... .
23
28
37
45
55
65
67
74
80
87
95
I02
I IS
I 19
125
135
148
161
167
174
179
188
195
xill
xiv
Contents
RESPIRATORY SYSTEM
28
Drugs Used to Treat Asthma. Coughs. and Colds
VI
ENDOCRINE SYSTEM
29
30
31
32
33
34
Hypothalamic and Pituitary Hormones

Thyroid and Antithyroid Drugs
Sex Steroids and Inhibitors
Corticosteroids and Inhibitors
lnsulins and Oral Hypoglycemic Drugs
Drugs That Affect Calcium Homeostasis
VII
MUSCULOSKELETAL SYSTEM
35
36
37
Anti-inflammatory Drugs and Acetaminophen

Drugs Used to Treat Gout
Autocoids and Autocoid Antagonists
VIII
GASTROINTESTINAL SYSTEM
38
Drugs Used to Treat Gastrointestinal Disorders
IX
IMMUNE SYSTEM
39
Antineoplastic Drugs
ANTIMICROBIAL DRUGS
40
41
42
43
44
45
46
47
48
49
50
Introduction to Antimicrobial Drugs

Penicillins
Cephalosporins and Other Cell Wall Synthesis Inhibitors
Protein Synthesis Inhibitors
Quinolones and Drugs Used to Treat Urinary Tract Infections
Folate Antagonists
Antifungal Drugs
Antiprotozoal Drugs
Anthelmintic Drugs
Antiviral Drugs
Drugs Used to Treat Tuberculosis and leprosy
XI
TOXICOLOGY
51
Toxicology
XII
PHARMACOLOGY POWER REVIEW
52
Pharmacology Power Review
0.
0.
20 I
21 I
215
221
229
23S
241
247
255
262
267
277
293
297
303
31 I
320
323
328
335
350
357
369
377
397
Contents
xv
APPENDICES
A
B
C
Index
Sample Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

Recommended Antimicrobial Agents Against Selected Organisms . 454
Comparison of Antimicrobial Spectra . . . . . . . . . . . . . . . . . . . . . . . . 461
469
Section I
Principles of
Pharmacology
Introduction to
Pharmacology
What is pharmacology?
The study of the interaction between

chemicals and living systems
What is a drug?
A drug is broadly defined as any chemical

agent that affects biologic system~.
Name and define the fom

major subdjvisions of
pharmacology.
1. Pharmacokinclics--<lescribes "what
the body does to tht> drug." This
includes topics such as absorption,
distribution, metabolism, and
excre tion or drugs.
2. Pharmacodynamlcs--<lcscribes
"what the drug docs to the body."
Specifically, it deals with the
biochemical and physiological effects
of drugs and their mechanisms of
action.
3. Pharmacothe rap eutics--<lescribes
the use of drugs for the prevention,
diagnosis, and treatment of disease.
4. Toxicology--<lescribes the
undesirable effects of therapeutic
agents, poisons, and pollutants on
biologic systems.
For each of the following

e ndings, name the classificalion of dr ug and give an
example :
-azine
phenothiazine-like anti psychotics (e.g.,

chlorpromazine)
-ane
volatile general anesthetics (e.g.,

halothane)
-azepam
antianxiety drugs (e.g., dia7.epam)

3
Section I I Principles of Pharmacology
-hi tal
barbiturate sedative hypuotic drugs (e.g..

phenobarbital)
-caine
local ant>stht>ti<'s (e.g., ('IXainl'}
-ciiJin
penicillins (e.g.. nafcillin)
-cycline
tetra<.)dine-typ(' antibiotit's (<..g.

do~ycydine)
-olol
13-blockers (e.g.. propranolol)
-opril
ACE inhibitor1. (<-.g. captopril)
-slatin
IIMG-CoA reductase inhibitors (e.g.,

lovastatin)
-zosin
postsynaptic a -receptor blockers (e.g.,

te razosin)
Should trade names be

memorized for the Boards?
~ In the past the Boards have not tested

trade names. It is best to first leam the
generic name. Trade names havl" been
provided only for future reference.
Do I need to know every

characteristic of every drug?
1\o. However, it is absolutely critical that

you at least remember the classilk-ation,
mechanism of action, therapeutic use,
and life threatening or unique adverse
effects of all of tht major drug~.
2
Define pharmacokinetics.
Pharmacokinetics
Pharmacokint'lic~ deS<:ribcs actions of

the body on drugs, including the
principles of dmg absorption,
distribution, biolmmfonnation
(metabolism ), and excretion.
ABSORPTION
De fine absorption.
Absorption i~ the rate at which and e~'tent

to which a drug moves from its site of
adm in istration.
What does the rate and

e fficncy of absorption
depe nd on?
Route of administration
Tlw
intravenous route is 111ost eflcclive.
Blood Oow- ll ighly vascularized organs
such as the small int<'stine haw tJ1e
greatest ab~orbing ;tbility.
Surface area available- Absorption of
a drug~ dirt'ctly proportional to the
surface area availablc.
Solubility of a drug- The ratio of
hydrophilic to lipophilic propertil.'s
(partition coefficie nt) that a dmg
halt will dt>ltrmirw ''hether the dmg
c;m permeate t-ell nwmlmmes.
Drug--<lrug inte ractions- When ~hen

in combination. dnrgs can either
enh<UK'C or inhibit orw another's
ahso'1)lion.
pH- A drug's acidit) or alkalinity affects
its charge. which afTlcts abs0'1)tion.
In what way docs the pH of

a drug affect its charge?
Many drugs are t'itllcr wt'ak acids or weak

hases. Acidic dnr~s ar<> uncha..ged when
prot cmalc~d:
11 Ai1 11 I"
Basic drugs arC' chal'ged >vlwn
protonated:
Bll rt B + II
5
Section 1/ Principles of Pharmacology
How does charge affect a

drug's ability to penneate a
ceU membrane?
Generally, a drug will pa!>~ through cell

membranes more eusily if it is
uncharged. Therefore, the amount of
drug absorbed depends upon its mtio of
charged to unc:harged sp<.'Cies. which is
determined by the ambient pi I at Lhc site
of administration and the pK"" (ncgali'e
log of dissociation constant) of the drug
(FigurP 2-1 ).
Define bioavailability.
The fraction of administered drug that

gains acccs~ to its site of <lction or a
biologic Ouid that allows access to the site
of action
What is the bioavailability

of an intravenously injected
drug?
100%-bccausc all of I he drug enters the

systemic circulation
What is the bioavaiJabiUty

of any drug that is not intravascuJaily injected?
Less than I 00%-becuu~e some of the

drug ma) not be ahsorhed, or it may
become inactintted
What factor!> affect bioavailability?
1. First-pass mctaboli~m
2. All of tlw factors that affect absorption
When pH= pKa

HA= A' and BH+ = B
When pH is less than pKa.

the protonated forms
HA and BH+ predominate.
A
(
pH
pHfK,
JLI
pH< pKa
When pH is greater than pKa.

the deprotonated forms
A- and B predominate.
6I
J
10
11
pKa
Figure 2-1. The distribution of a drug between its ionized and un-Ionized form depends
on the ambient pH and pJ<. of the drug. For illustrative purposes. the drug has been assigned a pJ<. of 6.5. (Redrawn from Mycek MJ. Gertner SB, Perper MM (Harvey RA.
Champe PC, eds]: uppincott's Illustrated Reviews: Pharmacology, 2nd ed. Philadelphia, Uppincott-Raven Publishers. 1997. p 6.)
Chapter 2 f Pharmacokinetics
What factors affect bioavailability?
I. First-pas~ metabolism
2. All of the factors that affect ahsorption
(i.e .. p i I, blood flow , drug soluhilit).
dnag-dlllg interactions. route of
administration)
'W hat is ftst-pass

metabolism ?
Riolransformation that occnrs he fore the

drug reac hes its site of action . It 111ost
commonly occurs in the liver. (For
example, .orally administered
nitroglycerin is said to have a high firstpass llH:.t,aholism because 901Jf of it is
inactivated by the lhcr. lllorphiaw i~
anotla<>r important drug that has a hi~h
first-pas~ metabolism.)
\Vhat arc the ro utes of drug

adminbtnllion?
Alinapntaa)'
Pnrenteral
lnhalatio11
Topic; a!
Tmnsdrnaaal
Subcutaawous
Name the fom typ es of
alime ntary routes of adminis tra tio n and slate the
a d vantage of each.
I. Orai-{'Ommoncst route. Adrmtlal!,es

includt' t-om enience/patient
<:ompliante and the utilil'..<ltion of tlw
\mall intestine. which i~ speciali;ed l<w
absorption because of its lar~e .,u rfacc
art;.t.
2. Bucc;J (between ~urn and cheek~).

1\drYm/age: Allows tlired absorption
into the venous <.:ixculation
:3. Subliugual (under the lon~ue)' itro~ly<erin L~ often given by this
route .. \dmntag,e: Allows the dru~ to
Jraiu into the superior' en:\ C;l\ <1 , thus
b}lX~\in~
hepatic first-pa"
nwtaholism.
<1. Htl'l;\l (:.uppository)-Useful "lwn
tlw cmJ route is tu1availahiP due to
vo a uitin~ or loss of comcious raess.
Adra11iage: Approxi m ate!~ 50% of
drug absorbed Crom the rectaam wi ll
bypa\~ the Li\er.
Name the fo ur pare nteral

routes of a dministration and
s ta te the advantage of e ach.
I. I ntravenons--dircct inject ion into tht

\'<LS<:ular sy,tem. Adcm;tage: l\lost
rapid and potent mode of administration, because 100% of dmg enters
the circulation.
2. Jntramusculur-AdcontageN: Usually
more rapid and complete absorption
than with oral administration.
~1inimizes ha1.ards of intrav<l!>cular
injection.
3. Subcutaneous-Ac/V<mlages: Sam(' as
intramuscular.
-!. lntrathecai-Adranlage l nca.ses of
acute CNS infections or spinal
anesthesia, dngs can be more
effective if injected direct!)' into the
spinal subarachnoid space.
What category of drugs is

commonJy administered by
inhalation?
Pulmonary agents
How are inhaled drugs

administered?
By machine aerosolization or vaporization
When is topical
administration used?
Usually for treatment of localized disease

(e.g., psoriasis, acn<', rye inft>c-tions)
When is lransdermal
ndmirustration used?
For sustained release of a drug-for

example, nicotine patches
DISTRIBUTION
Define distribution.
The process by which a drug leaves the

bloodstream and entt>rs the interstitium
or the cells of tht ti~sucs
By what three bioche mical

mechanisms are drugs
absorbed into cells?
l. Pass ive diffus ion-governed by a

concentration gradient acros~ a
membrane, which makes a drug move
from an area of high <.xmcentmtion to
one of low concentration. It is the
most common mode of drug tnmsport
2. Transport by special carrier
proteins-a form of passive diffusion
that is facilitated by u carrier protein
3. Active lranspo1- transport against a
concentration gradient. The energy for
this mechanism comes from
dephosphorylation of adenosine
triphosphate.
What does distribution

depend upon?
Blood Oow
Capillary permeability- The structure
Chapter 2 I Pharmacokinetics
of capillaries varies depending on the

organ. For example, in the brain the
junction between cells is very tight. In
the liver and spleen, the junction
between em.lothelial cells is wide,
which allows large molecules to pass
through.
Binding to p lasma proteins such as
albumin-This will limit access to
cellular compartments.
Drug sb-uctore-Small Lpophilic
molecules will be able to disttibute to
more compartme nts thru1 will large
polar molecules.
BIOTRANSFORMATION
Why does the body

biotransform d1ugs?
The lipophilic prop erties of drugs tl1at

allow them to pass through cell
membranes hinde r their elimination.
Therefore, drugs rue modified to become
more polar so tl1at elimination can occur
more quickly.
What :ue the two general

sets of modifications that
occw in biotransfonnation?
They are known as phase I and phase 11

reactions.
What happens in a phase I

1eaction?
Lipophilic molecules are converted into

more-polar molecules by introduction of,
or unmasking of, a polar functional group.
What types of phase I

reactions occur?
Oxidation, reduction (dehydrogenation),

and hydrolysis
What happens in phase n

conjugation reactions?
Formation of a covalent linkage between

functional groups on the parent drug and
anotber substrate
Specifically, what substrates

are added in phase II
conjugation reactions?
Glucuronate-Quantitatively, addition of
this substrate constitutes the most
important conjugation reaction.
Acetic acid
Glutathione
Sulfate
In what organ do phase I and

phase n reactions occur?
Primarily in tl1e liver
I0
Whcte do these r e action

o ccrn on a ce llular level?
Pha.~P I reactions Ot'<ur in thf'
Pncloplasmi(' rp!i('ulum.
II rtactions <X.'<.ur in tlw c~imol.
Phu.~e
Wha t factots affect drug

biotnamfonna tion?
Genetic- dilfPrt'll('t>S- Eadt iudi\idual has

a \ ":ll) ing tapat'il) to nwtaholitc a dnu~
through a gi\C>n p<tthwa\ . ( For
exam pit'. some' indi\ iduals ;m \low
ac-t'tylator\ amltlwrd()rt cannot
rapidl) ina<ti\all' dntgs su<.h a'
isoni;vicl. pn)(:ainamid<. ;md
hwlraht7.itw. )
lml~ction of tlw C)1odmmw P-450

intrcas<.
biotransformation
lnhibiti01 1of the tyl<x:hrornc P-150
system-! I' two dmgs or wmpounds
an <.on11Wting li11 tlu acti w sill' of l il t'
same <nzyuw. tlwn ouc of thl' d mgs
will ha\'l' a d<'t'rtas<d rate nl'
l ran~forn lali<m.
DisPaSP, <'S JWC'iall) of th< livcr
Age and gl'nder
sy~lt' ll l-may
Arc the .-ale!> for drug biottamfonnation pre dictable?
Yl'!>.
De fine fint-orde r kine tics.
Prcx.'t'ss h) \\ hid a t~mstant J'<'R't' nlag.>

of ~uhstrate i' nwtaholi/cd p:r unit time.
( For t'\<Unplc T1n ll<'rt'Plll of a l'f'rtain
tlmg [t-oncentration. LOO nw'dL]s
eliminatt'd t'\1'1'\ 2 homs: 2 hour~ latPr.
the c.ou<:cntmti;111 will h~, 00 n).!/UL; in 1
hour~ it will he ') I 1ng/d 1.: ;md 'II on.) Tlw
high<'r the ton<entration of dn1g. the
greater thl' absolnll' HIII01 11 1t of Uf\1~
hiotransfn rnwd or excnl<d 1wr nnil of
time.
D e!>cdbe ze to-orde r kinetics.
PrO(e~s hy '' hith a tmtstnnl tlll10IIllt of

drug is ru<tHholind 1wr nnit of time
In gttwral. dru).(s \\ill he. iuacth at(d

or hiotr;llhlimnl'd att'onling to ou< of
two gt'nf'r.ll dwllll\11'\ prindple\: firslordl'r and z<roordPr kimties.
regardless of lh<' drng <'Olll'tnl ralion. (For

example: If u drug tont<ntration is 100
mj:lfdL and the bod) t':lll remove 5 m)idL
cve1y hour then l hour lalt'r tlw
concentration will ht' 95 m!idL: 2 hours
Chapter 2/ Pharmacokinetics
II
later it will be 90 mg!dL; and so on.)

Alcohol is metabolized according to zeroorder kinetics.
EXCRETION
What is excretion ?
The process by which a drug or

metabolite is removed from the body
What is the difference

between excaetion and
secaetion ?
Excretion is the removal of a drug from

the body.
Secretion occurs when the drug is actively
transported from one compartment
into another. ( For example: Dmgs are
secreted into the renal tubule from the
medullary capillaries.)
What a1e the m ajor 1outes

of excaelioo?
Renal-urine is one of the most common

routes of elimination
Fecal
Respiration-primarily for anesthetic
gases and vapors
Breast milk
Skin
3
Define pha rmacodynamics.
Pharmacodynamics
Ph:u-rnacodynamics clesclibes the actions
of a umg on the body. and includes tltc
principles of receptor interaction),
mechanisms of therapeutic and to\iC
action, and dose-response relationships.
llow is phannacodynamics
related to phannacokinetics?
The phanna<.-<>J..;nPtic processes of

absorption. distribution.
biolran~formation, and excretion
dt>t!'rmine how quickly and to what cxttnt
a drug will apppar at a target site.
Pharmacodynamics concepts explain tit<'
pharmacologieal effects of tlmg~ and thrir
nwchanism of action (Figwe 3-1).
RECEPTOR INTERACTIONS
What is a receptor?
A macromolecule typically made of

proteins that interacts with eithPr an
cndogcnom li!'(and or a drug to rnedialc n
pharmacol o~c or physiologic effcd
What arc the two maio

flmctions of receplors?
1. Ligand binding
2. Activation of an e ffector systPm
(message propagation)
What is an effector?
E!1'ectors transduce drug-receptor

interactions into cellular effects. Tlwre
are four tnxs of well-known effedor
mech,misms:
I . Tnmsmcmbrane-Some ligaml~
such us insulin bind to receptor:. that
haw boUt an extracellular and

inlracf'll ular component. Bindin~ of
tl1c c~tnlt'dlular component sti mulates
tltl' intraedlulnr component. wltidt is
cOt ipled to an enzyme. for example,
tvru\ine kinase.
2. Ligand-gated ion channels- Drugs

bind to tlwse receptor~. which tlwn
12
Chapter 3 I Pharmacodynamics
13
Dose of drug
administered
ABSORPTION
Pharmacokinetics
ELIMINATION
J
Pharmacologic effect
~iJ\.
Toxicity
Pharmacodynamics
Efficacy
Figure 3-1. The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components.
Concentration provides the link between pharmacokinetics and pharm<~codyn<~mics and is
the focus of the target concentration approach to rational dosing. The three primary
processes of pharmacokinetics are absorption. distribution. and elimination. (Redrawn
from Katzung BG: Basic and Oinical Pharmacology. 7th ed. Stamford, CT. Appleton & Lange.
1998, p 35.)
alter the conductance of ions through

the cell membr-ane channels.
Examples of ligand-gated ion channel
drugs are benzodiazepines and
acetylcholine.
3. IntraceUular-Thyroid a11d steroid
hormones bind to nuclear receptors to
form complexes that iutcract with
DNA, which causes changes in gene
expression.
4. Second messenge r system-Drugs
hind to rec:eptors that activate second
messenger systems involving G
proteins (Figure 3-2).
14
Receptors as
Enzymes
Nicotinic
acetylcholine R G Protein-Coupled Receptor systems
Glutamate R
GABAA R
Glycine R
5HT3 serotonin R
Cell
Transmembrane
Effectors
G Proteins
receptors Catalytic Activities
Tyrosine kinases
Growth factor receptors
Regulated by a subunits:
Cytoplasm
Neurotrophic factor receptors
t Adenylyl cyclase,
Tyrosine phosphatases
t Ca2+ currents
Serine/threonine kinases
+
Adenylyl
cyclase,
TBF~-receptor
t K+ currents
Guanylyl cyclase
+Ca2 currents
ANF receptor
t Phospholipase cp
Guanylin receptor
+
Na+tw exchange
Nucleus
Cytosolic
t cGMP
Receptor
Regulation of
-phosphodiesterase
~
transcription
(vision)
Steroids
1~
~
Aetinoids
~
Thyroid hormone
Figure 3-2. Classification of physiological receptors and their relationships to signaling

pathways. (Redrawn from Hardman JG, Limbird LE [eds]: Goodman and Gilman's The Pharmacological Basis o(Therapeutlcs, 9th ed. New York, McGraw-Hill. 1996, p 32. Used with
permission of The McGraw-Hill Companies.)
What are second messenger

systems?
Second messenger systems allow signals

from cell surface receptors to be
conve1ted and amplified into a cellular
response.
What are the three bestknown second messenger

systems, and which enzyme
produces each of them?
1. Cyclic adenosine monophosphate

(cAMP)-produced by adenylate
cyclase
2. Cycllc guanosine rnonophosphate
(cGMP)-produced by guanylate
cyclase
3. Inositol triphosphate ( lP3 )-procluced
by phospholipase C
Chapter 3 I Pharmacodynamics
IS
MECHANISMS OF THERAPEUTIC AND TOX IC ACT ION
What is an agonist?
A drug that binds to and activates
receptors
What is a full agonist?
'W hat a1e partial agonists?
A drug that, when bound t o a receptor,

prod uces 100% of the maximum po~sible
biologic response
Drugs that produce less than 100% of the

maximum possi ble biologic response no
ITI<ltter how high their concenhation
What :-w e a ntagonists?
Drugs that bind to receptors or other

dmgs and iuhibit a Liologie response
What does a compe titive

antagonis t do?
It binds reversibly to the same active site

of an enzyme as an agonist.
How can a compe titive

antagonis t be overcome?
By increasing the concentration of the

tbug (agonist). The maximum efficacy of
the drug w ill not change in the presence
of a competitive antagonist.
What does a n oncompetitive

antagonist do?
It binds irreversibly to a di!Terent site on

Lhe enzyme than the antagonist.
Noncompetitive agonists cannot be
overcome hy increasing concentrations of
the drug.
H ow will the maximwn

efficacy of a dr ug b e
affected by such
noncompe titive antagonists?
Maxim um efficacy will be reduced in the

presence of a noncompetitive antagonist
(Figure 3- 3).
DOSE- RESPONSE RELATIONSHIPS
What is the difference

b etween e fficacy a nd
potency?
Efficacy is the ability to produce a

biologic effect. Potency is re lated to the
a mount of drug uecess:uy to cause a
biologic eflect.
Give an example of efficacy.
If two drugs, drug A and drug B, are both

claimed to reduce a patient's h eart rate by
25%, the n they both have the same
efficacy.
Give an example of potency.
Only l mg of drug A needs to be given to
16

Drug with non-competitive antagonist
'I
Drug concentration
EC 50 for drug alone or

in presence of noncompetitive antagonist
EC50 for drug in presence

of partial agonist
EC 50 for drug in
presence of partial agonist
Figure 3-3. Effects of drug antagonists and partial agonist. EC50 = drug dose that shows
50% of maximal response. (Redrawn from Mycek MJ. Gertner SB. Perpecr MM [Harvey RA.
Champe PC. eds]: Uppincott's Illustrated Reviews: Phormocology, 2nd ed. Philadelphia. Uppincott-Raven Publishers, 1997. p 22.)
a<"hieve a rec..luction in heart ralf', wher<:'a~

10 mg o f' dnag Bare needed. Therefor~>, it
can be inferred that drng A is rnure
pole aat.
Wbati!. K,/
Tlw concentration of dm~ ;ielding 50%

occupanc) of the receptor (dissociation
constant)
What is EC50?
The dmg concentration that produces

509f of the rn:Lximum possible response in
a graded dose-response cun:e (see Figm<>
3-3).
Drug Dosing and

Prescription Writing
DRUG DOSING
What tlwee factors :ue
involved in dete rmining an
a ppmpriute drug dose for a
patie nt?
What is volume of di~bi

bution (Vd)?
l. T)pe of infection or disease

2. Patient variables (l'.g.. weight. li\'t>r or
lddney disease )
:3. Plasma concentration needPd to
achieve efFicacy
The 1pparenl volume into wl lich a drug is

nbk to distribu te
H ow is Vd calculated ?
V,1 = total drug in the body

conc:cntration of the dwg
What is the significance of a

large Vtl?
Based on the equation prest?ntf'd above. a

large\'d si~ifies that most of tlw drug is
being sequestered in some organ or
com p<u'trrw11 t.
What is a mainte nance dose?
A dosfl of a drug given to achieve a

tlwrupcutic plasma concentration ov(r an
e:\tcudcd period of t ime
What is the equa tion for

calculating a maintenance
dose?
\laintenance dose = clearance X d(o',irt>cl

phl,ma concentration
What is important to
tcmc mbc r in pe rforming
Ulis calculation?
What is a loading dose?
plasma
You must be absolutely certain that the
u nits arc correct.
In SC)Il1!-' clinical situations the desirC'd

plasma tonecntration of a drug must bE"
achieved rapiclly. ln these cases a siuglc
loading dose is injected. followed b) a
routine maintenance dose.
17
18
\Vbat ~ the equation for

calculating a loading dose?
Define peal.. and trough

concenlnllions.
Loading clo!>e -
Vd X
desired plasma
COllCl'lltration
Thest arc maximum and minimum

plasma conccutrations, respectively,
which are observed during dosing
intervals.
What variable affects these
concentnltion.'i?
They will fluctuate around the steadyslate plasma concentration (C,.,.).
What i~> the ~teady-state

pla.o;ma concent ration?
The point at which the rate of drug

availability is equal to the rate of dmg
elimination
How doc!> frectuency of

dosing affect the steadystate concentration?
It will not change.
What factors will dosing

frequency affect?
Using smaller doses more frequcutly will

help miuimiz<> swin11;s in drug
concentration (i.e . maximum and
minimum phl.~ma concentrations). See
Figure I L.
How many half-lives arc

requicclto reach steadystate conccnhation?
Approximate!)
What is clearance?
Clearance is defined as the vohune of

plasrrra c:btred of drug per unit of time.
\Vhat is an excretion rate?
The rate at which a drug is eliminated

from the body. which is measured by
cleamnce X plasma c'Oncentration
What i~> a the rape utic index?
The mtio of a dmg's toxic dose to its

thcrapc>ulic dose. A safe drug will have a
high therapeutic index. See Appenwx A
for snmpk problems illustrating these
concPpts.
..t~
half-lives. At 3.3X,
the half-life of the drug will reach 90% of

its ciTec:livr ha.lf-life.
PRESCRIPTION WRITING
Define the following abbreviations:

q
en'')' hour
qhl>
CWI)'
night
Chapter 4 I Drug Dosing and Prescription Writing
'2
:I
:e
.!.
.g
Injection of
2 U of drug
Injection of
1 U of drug
~y
~00}
19
.a
.5
en
'g
c
:I
<
'-continuous infusion of 2 U of drug/day

o~L----------------------------
1
0
Days
!= Rapid Injection of drug

Figure 4-1. Predicted plasma concentration variations of a drug given by Infusion (A).
twice dally injection (8), or once dally Injection (C). Model assumes rapid mixing In a single body compartment and a t 1n of 12 hours.( Redrawn from Mycek MJ, Gertner SB, Perper MM (Harvey RA. Champe PC, eds): Uppincott'slllustrated Reviews: Pharmacology, 2nd ed.
Philadelphia, Lippincott-Raven Publishers, 1997. p 20.)
qd
every day
bid
twice a day
tid
three times a day
qid
four times a day
qos
every night at bedtime
stat
immediately
ac
at meal time
hs
at night
pc
after meal time
20
po
orally
gtt
drops
pm
as needed
qs
quanti!) sufficie nt (i.e.. thC' pharmacist

'"ill dispense the appropriate number of
pills)
How i~ a standard
prescript:ion written?
See Figure 4-2.

The first line contains tlw cln1g name and
dose:
Lasix -10 mg
The second line contains the directions
for use:
Sig: Ttrtb po bid

This line ~tales, ''takl' ouc tahll'l hy mouth
twice a day."
The thlrd line contains the nu mber of
tablets to be dispensed :
#14
Riverside Hospital
1492 Columbus Ave.
Ashtabula, New York
(212) 613-5000
NAME - - - - -- - - - - - - -- - - --
AGE _ _ _ _ __
ADO!lESS _ _ _ _ _ __ _ __ _ __ _ _ _ DATE - - - - - -
T~~P~E~-------------------
REFill --TIMES
PRAC11110NEFI'S SIGNATURE
DEA REG~ - - - - -- - - - - -
Figure 4-2. A sample prescription.
Section II
Autonomic Nervous
System
Introduction to
Autonomic Nervous
System Pharmacology
Name the two branches of

the human ner vous syste m.
l. Central nerYous system

2. PeriphPral nervous system
What are the two sub divisions

of th e perip heral n e rvous
syste m?
1. Somatic ncrvoul. system, which

innervates skeletal mtL~cle
2. Autonomic nervous system (ANS)
What is the a utonomic

system?
A collection of nuclei, cell bodi<>s, ncrves.

ganglia. <uH1 plell.uses that provides
llC I'VOU S
<lll'erent and efferent innervation to

smooth muscle and vis<.'Cral organs of tlw
hody
Wh y is thh
sy~1:em
important?
The A 'S regulates functions that are not

under conscious control, such as blood
prcs:.ure, heart rate, and intestinal
mot-ility. (~Also, ANS drugs lt:WI'
tnld itionally been a favorite topic of
USMLE examiners.)
\Vhat ure the two major

su bdivisions of th e ANS?
l . Sympathetic nervous system

2. Parasrmpathetic nervous <;ystem
\VItal are the anat o mic
Tlw :.ympatbetic n e n ous system
diffe rence!> be tween these

two syste ms?
originates in the thoracolumbar

portion of the spinal cord. The
prcga11glionic neurons are short and
usually synapse somewhere iu
tlw
parave1tehral ganglia (syrnpatlacti\.'

chain). The 71ostganglicmir /It'll rOllS ;ue
long and terminate at the visceral
organs.
The pamsympatbetic ner'Vous syste m

originates (rom cranial nl'JYl' nuelci
Ill \'11, IX. and X. as weiJ '~' tht' third
23
V>
CD
TABLE 5-l. Automatic Nervous System: S~111pathetic vs
Para~) 111pathcti<: Responses
S}11lpat.hetic
a.
=
0
:::J
Parasvmpathetic
)>
Effector Organs"
Eye
Radial muscle (iris)
Circular muscle (iris)
Ciliary muscle
Heart
SA node
A\' node
Contractility
Lung
Bronchial muscle
Blood vessels
Most (except skeletal muscle)
Skeletal muscle
GI (Stomach and Intestine)
Sphincter
~1otility and tone
Heceplor
Response
Rccf'ptor
Response
c:
8:::J
0
;:;
Contraction (wydriasis)
Ql
~2
Relaxation
Contractio n (miosis)
Contraction (accommodation)
~I
~I
~I
iHR
eonduction velocity and automaticity
i force of contraction (atria & ventricles)
J. IIR
J. conduction velocity
J. contractility (atria)
~2
Relaxation (bronchodilation)
a,
Contraction (hronchocomtriction)
~ 13
M3
Constriction
Relaxation
132
o:,
0:,
M3
Constriction (retention )
132
J.
Relaxation (defecation)
motilit) and tone
CD
...c:
~
;;
3
GU
Urinary sphincter
Bladder wall
Uterus, pregnant
Uterus, nonpregnant
Penis, seminal vesicles
Secretory glands
Sweat
Intestinal
Bronchial
Lacrimal
Metabolism
Adrenal med ulla
Kidney
Skeletal muscle
Pancreas (beta cells)
Fat cells
Ctl
132
et1; 13z
132
('(!
Constriction
Relaxation (retention)
Contraction; relaxation
He laxation
Ejaculation
MJ
Rehtxation
Contraction
E rection
M3
5"
a
Q.
a2
Localized secretion
Inhibition
M
M3
M
M
<X I
secretion (moderate)
Generalized secretion
i secretion
i secretion
Profuse secretion
5
::l
>
c
8::l
0
NN
131
132
('(2
133
Secretion of catecholamines
i renin release
Glycogenolysis, i contractility
! insulin release
Lipolysis
The parasympathetics system controls most organs except blood vessels, which are regulated by the sympathetic nervous syste m.
N,. = nicotinic; M = muscarinic receptors
(Adapted from Gallia G, Hann CL, Hewson WH: The Phannacology Companion. Ann Arbor, Ml, Alert & Oriented Publishing Company. 1997. )
i'i'
'"~
c
"'
~
..
..
"
3
-:T
n
0
g
....
"'
26
Section II I Autonomic Nervous System
and fourth sacral spinal roots

(craniosacral origins). The
prcg;tnglionic neurons take a long path
and syuapse onto short postganglionic
nPurons in or near the target organ.
What arc the functions of the

sympathetic nervous system?
The sympathetic nervous system is

nornmlly active, even at rest; however, it
ass lliiH's a dominant role when the body
becomes stressed in some way. For

example, if you sense danger, your heart
rate increase!>, blood pressure rises, eyes
dilate, blood sugar rises. bronchioles
e\11and, and blood flow shifts from the
skin to skeletal muscles.
The sympathetic ne1vous
syslcm prepares you for
"flight 01 llght" situations.
With what rnajo receptos
docs the sympathetic
nervou ~ system work?
Adrenergic receptors-alpha-l (a 1),

alpha-2 (cx 2). beta-1 (j3 1), beta-2 (132 ), and
dopamine recxptors (Table 5-l)
What are the actions of the

parao.ympathctic syste m?
The parasp11pathetic nervous S)stem is

prt'domim~nt under tranquil conditions. It
slows heart rate, lowers blood pressure,
increases intestinal acti,ity, constrict\ the
pnpil~. and empties the urinary bladder.
The parasympathetic neJVous
system is also known as tlte rest ~x,
and digest system.
fiJ:'i
\Vhat eccptors does the

parasympathetic syste m
Cholinf'rgic receptors-muscarinic and

HJ<.'otinic
act upo n ?
How arc the parasympath e tic

and sympa thetic sy~>'tems
elated?
Thc\e two S)Stt'ms oppose each other's

aclions. Tiernember that both S")"Stems
arc work;ng at all times; however, which
sy~tem pretlmninates over an orgm1 will
tlqwnd on the situation. The henrl, for
<>:o.amplc. is predominantly controlled by
the parasympathetic system. except uut!C'I"
~tn.'ss. whtu it is controlled by the
sympatheti<' system.
What arc the two principle

1. ,\(.'etylcholine-cholioer~-,ri<.
ncwotransmitters in the ANS?
transmission
Chapter 5 / Introduction to Autonomic Nervous System Pharmacology
27
2. Norepinephrine-adrenergic
transmission
Which ion is required for the

release of these neurotransmitters from their storage
vesicles?
T he calcium ion (Ca2 +) is required for

the release of most neurotransmitters
from their storage \'esicles.
How do autonomic drugs

function?
At S drugs achieve their effects by acting

as either agonists or antagonists at
cholinergic and adrenergic receptors. The
following four chapters discuss each of
these drug classes in greater detail.
Cholinergic Agonists
What are choline rgic

agonists?
Cholinergic agonists are drugs that mimic

or potentiate the actions of acetylcholine.
What are the two major

families of cholinergic
teceptors?
1. Muscarinic-This receptor family

ean1cd its name because it was first
identified using muscarine, an alkaloid
found in certain poisonous
mushrooms.
2. Nicotinic
What pharmacologic subtypes The re arc several different subtypes of

of muscarinic r eceptors exist? muscarinic receptors, namely, M 1 to M 5
Thty are found in ganglia, smooth
muscle, myocardium, secretory glands,
and the CNS. (~ For the USMLE, it is
not necessary to memorize which subtype
of muscarinic receptors a drug will act
upon.)
Identify the two types of
nicotinic receptors.
Whe re in the body are

choline rgic r eceptors found?
1. Neuronal nicotinic (K , ), located in
autonomic ganglia
2. Muscular uicot.inic (N~.1 ), 1ocated in
tlae nC'uromuscular junction
Prcg;tnglionic fibers of the autonomic
ganglia
Preganglionic fibers that terminate in the
adrenal medulla
Postganglio11ic fibers of the
parasympathetic system
Voluntary muscles of the somatic system
CNS
Sweat gland~ innervated by postgangliunic sympathetic nervous ~ystcm
Se<> Figure 6-1.
What types of choline rgic

agonists a e available for
clinical use?
28
Cholinergic agonisls t:an be divided into

two major groups:
1. Direct-acting agonists chemically
hind with and activate muscarinic and
nicotinic receplors in the body.
Chapter 6 I Cholinergic Agonists
Somatic
Nervous System
Autonomic Nervous System

Sympathetic innervation
of adrenal medulla
$L
Sympathetic
Paresympathetlc
Acelylcholin&
ii!IIWII*'I,-~~
18'/"W~
Acetylcholine
Acetylcholine
iu-
i!.
~N'~cotinlc
~oooptor
....
~
receptor
.g
~ J<icotinio
(no gangha)
receptor
~t-
Adren~medulla
Epinephrine
{released
into lhe blood)
Niootinic
receptor
29
NOleptnephnne
AcetylchOline
....
~
receptor
~
receptor
Acetylcholine
Effector organs
Striated muscle
Figure 6-1 . Sites of action of cholinergic agonists in the autonomic and somatic nervous
systems. (Redrawn from Mycek MJ, Gertner SB, Perper MM [Harvey RA. Champe PC,
eds): Uppincott's Illustrated Reviews: Pharmacology, 2nd ed. Philadelphia. Lippincott-Raven
Publishers, 1997, p 36.)
2. Indirect-acting agonists inhibit the

enzyme ac-etylcholinesterase and
therefore increase the concentration
of acetylcholine within the sym1pse.
DIRECT-ACTING AGONISTS
Give six examples of rurectacting agonists.
l.
2.
3.
4.
Acetylcholine~prototype
Bethanechol
Carbachol
Pilocarpine
5. Methacholine
6. Nicotine (discussed in Chapter 17CNS Stinwlants)
ACETYLCHOLINE
What are the physiologic

actions of acetylcholine?
Acetylcholine affects almost every system

within the body:
Cardiovascular system-It decreases
heart rate, contractility, and blood
pres~ure.
30
Section II/ Autonomic Nervous System
Gasbointestinal system-It increases

motility of the gastrointestinal tract
and bladder.
Pul mona.y system-It increases
secretions of the bronchioles
The eyt.'-lt causes constriction of the
pupilla1y sphincter muscle, which
causes mlosis and accommodation.
Petipheral netvous system-It causes
conhaction of skeletal muscle.
Central netvous system-It affects
nemotransmission.
Endocrine system-It causes release of
epinepluine from the ackenal medulla
(via nicotinic receptor), and it
stimulates sweat gland secretions.
What receptors does

acetylcholine activate?
Bod1 muscarinic and nicotinic
What are the clinical

indications?
Acetylcholine is used to achieve miosis

dming ophthalmic surgery. In general, it
is rarely used because it has widespread
effects and is so rapidly hydrolyzed by
acetylcholinesterase.
What are the adverse

reactions?
The adverse effects result from excessive

generalized cholinergic stimulation. They
include:
D iarrhea and decreased blood pressme
Urination
Miosis
Bronchoconshiction
Excitation of skeletal muscle
Lacrimation
Salivation and sweating
DUMBELS
NOTE: These adverse effects are
typical of all direct and indirect
cholinergic agonists, not just
acetylcholine.
BETHANECHOL (Urecholine)
What type of chemical

compound i'i bethanechol?
A carbamic acid ester
l'fM
\;X,
31
What receptors does it

work on?
Bethancchol works primarily on

muscarinic receptors, but it also has some
mild nicotinic properties.
What are its therapeutic uses?
Bethanechol increases intestinal motility,

especially alter surgery. Because this drug
al~o stimulates the detrusor mnsclc of the
bladder, it is also used to treat urinary
retention.
BBB- Bethanechol stimulates
~
the Bladder and Bowel.
\"X,
What are the adverse e ffects

of bethanccbol administration?
The adverse effects are those that rel.ult

from generalized cholinergic stimulation
(sec above).
CARBACHOL
What type of compound is

carbachol?
A cnrb<Lmic acid ester similar to

heth<lnechol
State its clinical use.
This drug is rarely used in the clinics, but

it can be used for glaucoma and to
stimulate miosis during ophthalmic
surgery.
What receptors does

catbachol work on?
Roth muscarinic and nicotinic receptors
What are iL<> adverse effects?
Those that result from excessive

generalized cholinergic stimulation
PILOCARPINE (Pilocar)
Wha t type of compound is

piloca.-pine?
An alkaloid
What are pilocarpine's

physiologic actions?
Causes miosis and contraction of thE'

ciliary muscle
Decreases heart rate
Causes bronchial smoot!J muscle
contrac.:tion
1ntrt>ases secretions from salivary,
lac:limal, .u1d sweat glands
Is it cleaved by acetylcbolin-
'o, the drug is unaffected by this

enzyme.
estera~e?
32
Sta te the clinical use.
Pilocarpine is extremely good for

stimulatinf!; miosis and opening the
lrah<.c:ular meshwork around the C<Ulal of
Schle111m. Tlterefore, pilocarpine <:an lw
used for the treatment of glancoma.
What eccpto s docs this

cllug work o n?
Primarily muscarinic receptors
What me the a d vctse e ffects?
lJ nlikt' the olhcr direct-acting agonisls

previously discu.sse<l pilocarpine is able
to enter the br.un and cause Cl\S
disturbances such as hallucinations and
tonvulsions, along with generalized
cholinergic stimulation.
METHACHOLINE
\\1hat
is methac ho line used
fm?
Diagnosis of asthma and bronchial

hyp<'ITCaclivity
Wba t receptoas does it

stimula te?
M uscarinic receptors
Wha t me the a d verse effects?
Cener:1lized cholinergic stimulation
INDIRECT-ACTING AGONISTS
Give s ix examples of indirectacting cho linergic agonists.
l.
2.
3.
4.
5.
6.
rso flu rophatc

Echoth iophatl:'
Parathion
0:drophoniu11t
Physostigmine
l\costigmine
How do they work?
By inhibiting the enzyme

acety lcholinC'StC'mse. which is rl:'sponsible
for the hydrolysis of acetylcholine.
Neuronal response to acetylcholine is
thcr<.>fore enhanced.
Which indirect-acting choline tgic agonis ts have the

ability to irreversibly inhibit
acetylcho lineste rase?
Only lhc organophosphates

(isollumphatc, eehothiophale, and
parathion) inevcrsibly inhibit
Why mc p h ysostigmine,
ne ostig m ine, c drophonium,
a nd pyrido~ligmine
considered to be eversible?
Because they do not bind covalently to

acet) kholinesterase
Chapter 6 f Cholinergic Agonists
33
ORGANOPHOSPHATES (ISOFLUROPHATE. ECHOTHIOPHATE,

PARATHION)
Describe the mech anism

of action.
Organophosphates bind covalently to

acetylcholinesterase and can permane ntly
inactivate the enzyme. The eflects of
organophosphates can last as long as a
week, whic h is approximately the time
needed to synthesize a new molecule of'
Is it at all possible to re verse

the effects of organophosphates?
In mos t cases, no. However, if

pralidox.ime (a cholinesterase reactivator)
is given before the organophosphate
binds to acetylcholinesterasE> <md loses
one if its alkyl groups (a process callc>d
aging). then it may he possible for
pralidoxime to remove the
organophosphate from
acetylcholinesterase (Figme 6-2).
What were these drugs used

for in the pa!!1:?
Organophosphates were used in wars as

netve gases. They produce an immense
stimulation at cholinoreccptors
throug hout the body, causing resp iratory
muscle paralysis and convulsions.
What ar e these drugs used

for today?
Isoflurophate and echothiophate are used

occasionally for glaucorna aml
accommodative esotropia.
\>Vhat drug is used to treat

organophosphate poisoning?
Atropine is nsed, along with gastric lavage

and chmcoal
'W hat a1e the toxicities of the

01ganophosphates?
l:i:xcessive cholinergic stimulation
PHYSOSTIGMINE
w hen is physostigmine
administered ?
For glaucoma- second-choice drug after

pilocarpi ne
For overdoses of atropine,
phenotbiazines, and tricyclic
antidepressants
For intestinal ;mel bowel atony
For accommodative esotropia (rarely)
34
Phosphorylation of Enzyme
Enzyme inactivated
Pralidox1me (PAM) can
remove the inhibitor
II
C3 H70 - P- OC3 H7
I
F
Isoflurophate
,..0 - H
Active site of
acetylcholinesterase
Acetylcholinesterase
(irreversibly inactive)
,..0 - H
Acetylcholinesterase
(active)
Figure 6-2. Covalent modification of acetylcholinesterase by isoflurophate. (Redrawn

from Mycek MJ, Gertner SB. Perper MM [Harvey RA, Champe PC. eds]: Upprncott's Illustrated Revrews: Phormocology, Znd ed. Philadelphia, Upptncon-Raven Publishers. 1997, p 43.)
Can physo!.1igmine entet the

CNS?
Yes, because it is a tertiaryamine
State the advetse effects.
Convulsions
Muscle paralysis secondary to
overstimulation
Cataracts
Generalized excessive cholinergic
stimulation
35
NEOSTIGMINE (Prostigmin)
Does this drug enter the
CNS?
No, because it is a polar quaternary

carbamate
Describe the tbempeutic

uses.
Treatment of myasthenia gravis

Treatment of urinary retention and
paralytic ileus
Antidote for nondepolarinzing
neuromuscular blockade such as with
tubocurarine
What is the duration of

action?
Usually 2 to 4 hours
What are the advetse effects?
Excessive cholinergic stimulation
EDROPHONIUM (Enlon)
What is its clinical use?
Edrophonium is similar to neostigmine

except that it is used in the diagnosis of
myasthenia gravis. It is not useful for
maintenance therapy because of its sh01t
duration of action (approximately 5 to 15
minutes). Edropboniurn is also used to
differentiate myasthenia gravis from
cholinergic crisis. Both conditions can
result in muscle weakness; however,
administration of edrophoniurn helps
myasthenia but worsens cholinergic crisis.
What ar.e the adverse effects?
Excessive cholinergic stimulation
PYRIDOSTIGMINE (Mestinon)
What is pyridostigmine's
duration of action?
Very long-usually 3 to 6 hours
36
What is the clinical use?
Because of its long durati<nt of acliou,

pyridostigmin<>. lik< neostigmine. mn I){'
used for long-term lrtatnwnt of
myasthenia gravis.
\Vhal are the adverse effects?
Excessi,c cholinergic stimulation
Cholinergic
Antagonists
What rue cholinergic

antagonists?
Dnags that bind to cholinergic receptors

(muscarinic and/or nicotinic), but do not
trigger the usual intracellular response
Name three subclasses of

choline rgic antagonists.
1. Muscarinic blockers
2. Neuromuscular blocking agentsinhihit the efferent impulses to
skelE>talmuscle via the nicotinic
muscle receptor (NM)
3. Ganglionic blockers- inhibit l11e
nicotinic neuronal receptor (NN) of
both parasympathetic and sympathetic
ganglia
MUSCARINIC ANTAGONISTS
Give six examples of

muscarinic blockers.
l. Atropine (prototype)
2. Scopolamine
3. l lomatropine
4. Cydopentolate
5. Tropicamide
6. Pirenzcpinc
Arc there other drugs that

exhibit antimuscarinic
properties?
Yes-these include tbe anti-Parkinson's

drugs (e.g.. benztroplne), the antidepressants (e.g. Thorazine),
antihistamines (e.g., diphenhydramint),
and anti-asthmatics (e.g., ipratropium),
which are discussed further in later
chaptC'rs.
ATROPI NE
To what family of compounds

does atropine belong?
Atropint <.'Omes f1om the plant Atropa
bellodmmn and is known as a belladonna

alkaloid.
37
38
Section II / Autonomic Nervous System
What is the signi6cance of

the plant's name?
Belladonna in Latin means pretty lady.

During the Roman era the plant was used
to dilate women's pupils. which was
cou~idcrcd to he attractive.
What is atropine's mechanism of action?
lt causes reversible, nonselective

blockadu of muscarinic receptors.
What agent can be used to

counte .-act the effects of
atropine?
High concentrations of acetylcholine or

an equivalent muscarinic agonist
Does this drug cross the

blood-brain barrier?
:>Jo. Atropine docs not readily cross the

blood-hrain barrier.
What arc the phannacologic

actions of atropine?
CNS-At toxic doses can cause restlessness, hallncinations, and delusions

Cardiovascular system-At low doses,
atropine reduces heart rate through
central stimulation of the vagus
nude us. At high doses, atropine blcx:l..s
muscarinic receptors of the heart and
thu~ induces tachycardia.
Gastrointestinal system-Reduces
saliva!} gland secretion and GJ
motility
Pulmonary system-Reduces bronchial
sE-cretions and stinmlates
bronchodilation
Urinary syo;te m-Biocks muscarinic
receptors in the bladder wall, which
re~ults in bladder wall relaxation
Eye-Causes paralysis of the sphincter
muse!..: uf thl.' it C. <mJ l.'iliat) uau~de of
the lens, resultin~ in mydriasis and

cycloplegia.
~l)driasis = d ilation
Sweat glands-Suppresses
\;"',
:;wcating, especially in children
You will more readily remember t ltc
actions of' atropine if you recogni?:e tlmt
blocked cholinergic receptors result in an
unopposed sympathetic response.
List the therapeutic uses of

atropine.
Bradycardia
Mydriasis and cycloplegia-beneficial
Chapter 7 I Cholinergic AntagonistS
39
whf'n a thorough fundus examination

or an a<:curatc refraction i~ required
Casbointestinal and hlaclder spasms
Organophosphatt' poisoning
When is the use of atropine
to effect mydriasis and
cycloplegia contraindicated ?
Do not dilatE> the eyes of a patient who

has narrow-angle glmu.:oma, because this
mar result in an acute crisis due to
closure of the canal of Schlemm.
How long is a tropmes

duation of action ?
Approximately 4 hours, except when it is

placed in tlw eye. where it usually lasts
ahout 14 days
How is a tropine absorbed

a nd excrete d?
It is well absorhed from the

gastrointestinal syst<>m and conjunctival
membrane. It is cxcrctcd through both
hepatic metnholism a11d rclltll AJtralion.
What mc the toxic effects

of this cltug?
Mnemonic:
1'oxic Eff ect:
" 0 1y as a bone"
Dry mouth
Inhibition of ~-weating, " I lot as a hare"
especially in young
childnm
"Hed as a beet"
Tachycardia and
cutaneous
vasodilation
Blurring of vision
Hallucinations <tlld
"Blind as a baf'
" Mad a~ a hatter
delirium
l'fM
\;X,
SCOPOLAMINE
What is the classification of

scopolamine?
LikP atropine, thi~ tln1g b a belladonna

alkaloid.
What is its mechanism of
Nonsclcctivt' <.ompetitive blockade of
a c tion ?
1nuscarini<.:
How is scopolamine used
rct'l'ptor\
PrevPntion of motion
"lotio11 for nwtion"
l'fM
\;X,
thc n1pc utically?
sickness
H ow docs this drug diiTer

from alm pine?
1t has a longer duratioll a<.:tion and

more potent CNS efT<"cts.
\Vhat is scopolamines oute

or administalion?
It is often ~iVP11 transdtrmally.
or
40
Are there any adverse

eiTects?
Yes-similar to tho~c of atropinr:

.. Dry as a bone. red as u L<ct. hot
as a hare. blind as a bat. mad <l~ a
hatter.''
HOMATROPINE, CYCLOPENTOLATE (Cyclogyl).

AND TROPICAMIDE (Mydriacyl)
What a1e the!>e drugs used

for?
In ophthalmolog). the) an !Qven topically

for mydriasis and C)doplef{ia
What are the adverse effects?
Similar to those for atropine but much

uti.h.lcr
PIRENZEPINE
What is it?
A selective M 1 muscarinic inhibitor
How is this drug used?
For treating gastric ulc:crs
Similar to those for alrCipinc
NEUROMUSCULAR BLOCKING AGENTS
Name the two major subdivisions of neuromuscular

agents.
L r\ondcpolarizing blocking agents

2. Depolarizing blocking agents
NONDEPOLARIZING BLOCKING AGENTS
Name four nondepolarizing

agents.
l. Tubocumriru.'-prototypc
2. Pancuronium- longer duration of
action than tubo<-urarinc
3. Atracurium
4. Vecuronium
~'hat is their mechanism of

action?
These drugs competitively block

cholinergic tmnsmission at the nicotinic
receptors by preventing the binding of
acetylcholine to its receptor.
What is the therapeutic use

of these agents?
They are used as adjuvant drugs for

anesthesia-they promote muscle
relaxation.
Are all muscles equally

affected?
No. The muscles of the eye and lace are

affected first, whereas the respiratory
muscles are affected last.
Chapter 7 f Cholinergic Antagonists
What is th e mute of
administration?
41
All neuromuscular junction blockrrs must

be given IV because oral absorption is
poor.
What arc tbc adverse effects?
RronchO<'onstriction and hypotension,

caused by histmuinc rcle<C>c
\Vba t can be used to counte ract tbe effects of thes e drugs?
Because neuromuscular junction blockers

are competitive inhibitors. tludr ad ions
can be reversed with edrophonium or
neostigmine.
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS
Nam e the only depolarizing

ne uromuscular blocking
agent used in the Unite d
States.
What is this drug's mechanism of action?
Succinylcholine
P hase 1- Succinylcholinc binds to the

nicotinic receptor, opens tl~e Na+
channels, and catJses membrane
depolarization. which results in
transient faseiculations . Flaccid
paralysis will follow in a few minutes,
because succinylcholine is resistant to
acetylcholinesterase and will cause
prolonged depolarization of the
membranE'.
Phase ll-Evpntually thr membrane will
at least partially repol:uize. However,
the receptor is now desensitrted to
an:tyld oolint-, I lou~ pn:v~;uliug tloe
formation of further action potentials.

In other words, suc;<:inylcholine is now
acting in a manner similar to
tubocurarine (Pigure 7- 1).
What is the duration of
aclion?
3 to 6 min utes if given as u single dose
What substance metabolizes

succinylcholine?
Plasma cholinestcr;L~e
How is succinylcholine used

clinically?
As an adjuvant to general anesthesia

To facilitate rapid intubation
42
Section 11/ Autonomic Nervous System
Phase r
Membrane depolari7.es. resulting io ao
initial discharge which produces transient
fasciculati ons followed by flaccid paralysis.
'
(!
'
Na
~~('\~
++ +
+ + +
Nicotin ic receptor at
neuromuscular junction
Na+
PhaseD
Membrane repolarizes but receptor is
desensitized to effect of acetylcholine.
Figure 7-1. Mechanism of action of depolarizing neuromuscular agents.(Redrawn from

Mycek MJ. Gertner SB. Perper MM [Harvey RA, Champe PC, eds]: Lippincott's Illustrated
Reviews: Pllormocology, 2nd ed. PI 1ilaudphia, UppincoltRaven Publishers. i997, p 53.)
What are the adverse e ffects?
Bronchoconstriction caused by histamine

release
Hypotension
Arrhythmias
Apnea due to respiratory paralysis
Malign<Ult hyperthennia
How is malignant bypetthennia beate d ?
Dantrolene is used. It blocks the release

of Ca2 + fro m tbe sarcop lasmic re ticulu m,
,,~, ich subsequently reduces skeletal
musde contraction.
Chapter 7 I Cholinergic Antagonists
Do neuromuscular blocking
agents block autonomic
ganglia as weU?
43
ln general, no. The skeletal muscle end

plate and autonomic ganglia use different
subtypes of nicotinic receptors.
Tubocurarine can, however, produce a
small amount of ganglionic blockade.
GANGLIONIC BLOCKERS
Name four ganglionic

blockers.
1.
2.
3.
4.
What exactly do these

drugs do?
Ganglionic inhibitors compete with

acetylcholine to bind with nicotinic
receptors of both parasympathetic and
sympathetic ganglia.
"Vhat is the mechanism of

action?
Ganglionic blockers can be divided into

two groups:
l. Drugs such as nicotine, which initially
stimulate the ganglia and then block
them because of a persistent
depolarization
2. Drugs such as hexamethonium,
mecamylamine, and trimethaphan,
which block ganglia without any prior
stimulation
Describe the physiologic

effects.
The physiologic effects of ganglionic

blockers can be predicted if you
remember which division of the
autonomic nervous system exercises
dominant control of the o~gan in
question :
Heart- Tachycardia results because the
parasympathetic system is nonnally
dominant on the heart.
Arterioles and veins- Vasodilation,
increased peripheral blood
(sympathetic normally dominant)
Eye-Cycloplegia, mydriasis
(parasympathetic normally dominant)
GI system- Reduced motility;
diminished gastric and pancreatic
secretions (parasympathetic normally
dominant)
Nicotine
Hexamethonium
Mecamylamine
Trimethaphan
44
Urinary syste m- Urinary retE-ntion

(parasympathetic nonnally dominant)
Swe at glands-ReducE-d ~weating
(sympathetic nonnally dominant)
What is the the rapeutic use?
Because they lack selectivity. the

ganglionic blocker.; are very rarely used
clinically. In the past. tlll'sc dmg~ were
used in hypertensive emergencies.
What arc the adverse effects?
The toxicities of ganglionic blockers are

identical to their physiologic effects,
which have been described above.
Adrenergic Agonists
Wha t are adrenergic agonists? Drugs or endogenous catecholamines

that activate a ancVor 13 receptors. These
drugs are also knows as
sympalhomim e tics.
How can these substances
be classified ?
According to mechanism of aclion (direct

vs indirect) a~ well as receptor site
specificity (a 1, a 2 13 1. 132)
Num e the impm-tant a selective d ire ct-acting agonists.
Pbeuylcphrinc
Methoxamine
Clonidinc
Melhyldopa
Ide ntify the major {l selective direct-acting agonh-ts.
DobutnmiJte
Isoproterenol
Albuterol
Mctaprotcrcnol
Terbutaliue
List the major a and 13 directacting agoois ts.
Epinephrine
Norepinephrine
Dopamine
Which of the direct-acting

agonists are conside red
catecbolamines?
Epinephrine, norepinephrine.
isoprotere nol, dop<lmine, and dobutamine
Nam e two indirect-acting
Tyramine and amphetamine
adrene rgic agonis ts.

Name two mixed (direct and
indirect) ago n ists.
Ephedrine and metaraminol
DIRECT-ACTING a SELECTIVE RECEPTOR AGONISTS
Where are a 1 and ~

recep tors located?
a 1 receptors are located on the effector

organ's postsynaptic mernbrane.
a 2 rl"Ceptors are predominantly located
on the presynaptic membrane.
.fS
46
PoslS}11aptic a 2 r<'ceptor~ are limited

to the CNS and blood \CSsels.
What physiologic responses
occur whe n <X receptors are
stimulate d?
a 1 stimulation leads to the re lease of

intracellular calcium from the endoplasmic reticulum via inositol
triphosphate (IP3 ). This ll:'ads to vascular
constriction. decreased intc~tinal tone
and motilih , contra('( ion of the bladder"s
internal spi1incter. <'jacul;ttion.
contraction of tht> pr<'gnant utems, and
mydri~is. (Sec Table 5 -1 in Chapter 5lutroductlon to Autonomic Ncrrotn
Syste-m Plw rmnrof<>gy.)
When a 2 presynaptic m e mbrane
receptors arc stimulated. intracellular
cyclic adenosine monophosphatc (cAMP)
production is inhibited. a 2 receptors
function primarily as purl of a negative
feedback loop. When norepinephrine is
released from nerve terminals. some will
circulate back to thC' presynaptic
membrane and bin<.! to the a 2 receptor.
This will subsequently inhibit further
norepinephrine release. Other actions
mediated by a 2 receptors include
increased vagal tone, platelet aggregation,
and suppressed insulin secretion. See
Figure 8-1.
Name the direct-acting

agonists that are selective
for o: 1- and ~-adrenergic
receptors.
a 1 rec:eptors- phenylcphrine and

methoxamine
o.2 receptors-clonidinc:- and methyldopa
(discussed in Chapter 20-Antihypertensive Dnl{!.S)
PHENYLEPHRINE (Nco-Synephrine)
What are phenylephrine's
physiologic actions?
Primarily vasoconstriction. The

subsequent rise in blood pressure also
leads to a reflex bradycardia.
Describe this drug's therapeutic uses.
As a nasal decongestant (primary use)

To treat hypotension
For ocular examinations (mydriasis)
To terminate episodes of paroxysmal
atrial tachycardia (PAT)
Chapter 8 I Adrenergic Agonists
47
~ Receptors
Activation of receptor
decreases production
of cAMP, leading to an
inhibition of furth er
release of norepinephrine
from the neuron.
Membrane ~ D~
phospho ~
inosltldes
-v ca++
IP~
a, Receptors
Activation of receptor
increases production of
diacylglycerol and inositol
triphosphate, leading to
an increase In intracellular
calcium ions.
Figure 8- 1. Second messengers mediate the effects of a receptors. DAG

diacylglycerol: /P Inositol triphosphate. (Redrawn from Mycek MJ, Gertner SB, Perper MM [Harvey RA. Champe PC, eds]: Uppincott's Illustrated Reviews: Pharmacology, 2nd ed. Philadelphia,
lippincott-Raven Publishers. 1997, p 59.)
48
"Vhat arc the adverse effects

associated with phenyle phrine administration?
Rehouud mucosal .swelling and

h) pcrt<.usi\( headache
METHOXAMINE
Whnt eccplos docs

methoxamine w01k on?
As with phcnylepl11inc, methoxamine is

fairly s1wt'i fie for c.x 1 receptors.
Describe the lhe rape utic uses. Treatment of l)poteosion mld PAT
\Vhut mc m e thoxamine's
adver~c cfTcc~?
The ad\'(rsP PITects are similar to tlu~l' of

ph en) lcphrine.
CLONIDINE
Clonidillt' is also cliseussed in Chapter 20-Aillihyperlellsiue Drugs.

What eccptMs does clonidine work on?
Clouidin<' sti mulates cx2 receptors in tlw

CNS. which rC'duces sympathetie uervous
:;ystl~lll outflow from the brain.
D escribe its therapeutic uses.
TreatmC'nt of hypertension
\\ 'ithdrawal from benzodiazepincs and
opiates
TrPatm<>nt of diarrhea in diabetic patients
whn have autonomic neuropalhit>s
What toxicities may patients

exp erie nce while using
clonidiuc?
Sedation
Dry mouth
Sex1 1al dysfmwtim1
Ortho~tatic hypotension
DIRECT-ACTING
When~
a rc the
located?
fl
fl SELECTIVE AGONISTS
receptors
(3 1 receptors are primarily located on tlw

membrane. (3 2 receptors an'
posts)~1aptic
found 0 11 both the pre-m1d posls}1utpt ic

membranes.
What arc the physiologic

esponses once (3 receptors
me stimulated ?
(3 1 stimulation activates adenylate

which oppns calcium channels,
lead in~ to cardiac stimulation with both
incr<'a~ccl inotropic and chronotropic
effects. (3 1 ~timulation also lea<.b tu
imr<a~ed lipolysis. (3 2 receptors work \'ht
adenylatc> cyclase stimulation as well.
c:yda~e.
Chapter 8 I Ad renergic Agonists
49
In this case. howP\t' r, bronc:hial smooth

muscle as well as skeletal IIHI\C'lc
\asctJaturc are dilah:d. Tlw uterus.
ciliaf}. ami dttrusm rnusdts are rehL\ed
ami gluca!!:on nIP<LW b inc:reaSl'U. Both
13 1 a n d 132 receptors produce decreased
intestinal tom and motility (just as the aadn.'ner~c reteptors do) ~te also Table
5 1 in Clwptrr.5-bllmdrU"Iiou to Autorumric Ncrrou.~ Sy\tcru 1'/wnnnrology.
DOBUTAMINE
Wlm t is it ?
A dopamine a n a lo~ue
What ece ptors d oes

dohuta mine act o n ?
Prim<trily f3 1, bnt it clews havt' somv action

un 132 receptors a$ wd l
What ~we the physiologic

c flccts of do buta mine?
Smooth nu tsde rdil\lltion (132)
l nc:n.:ascd heart ratl' and t'tHltnwh li ty (J3 1)
W h a t is d o h u ta mine's the r ap e utic usc?
T reatment o f' un~tab l t (; II F and shock
Wh at is the route of a clminisl mtion?
IV
W h a t are this drug's adverse

e ffects?
Arrh) thmias
Headache
Hypertension
Palpitations
/\Jt~ina
Nausea
ISOPROTEREN OL
Which rece ptors mediate

the e ffects of iso poterenol?
What a 1e its physiologic
actions?
Increase~ cardiovascula r inot ropiC'
anrl
dnonotrop it w~ pon sr (f3 1)

Lowers periphe ml vu~c u l;~r rcs islanc;e
(13.,)
Rda,'I:~S smootlt t nu~c:ks

In wh al cliJ1ical sit ua tions is
it app.-op riate to use io;op roteenol?
(13 2 )
Stimulatiou oflt<'<llt rate in patients

suffcriug fro tn he;~rt blo(k aud
bradycardia
l n the past, ustd for trcatu1e11t of asthma
50
What is the route of adminis lralion?

Wlmt arc the toxicities of
isoprote renol?
1\
\rrll)tlnnhL~
Palpitations
Tachycardia
lleadadH'
ALBUTEROL, METAPROTERENOL, AND TERBUTALINE
What :uc the phannacologic

action'> of these ~ 2 directacting agonist<;?
Stimulatiutl of smooth muscle dil<ltatum

Can stimulate ~ 1 T("<eptors at hi~lwr
dose>s
What i~> the route of adminis tratio n?
Albuterol ami metaproterenol an' usuall)

inhaled. Terbutaline can be given orally
or subc11lancously.
List the lhe ape ulic uses.
TrtatmC'nt of bronchospasm/astl una

Trtatnlt'llt of chronic ohstructiw
pulmonary disease
TrPal nwnt of bronchitis
Tcrhutaline and ritodrine can be U\CU to
reht\ the ut(rus durin~ prPmatun
lahor.
What urc the potential

adverse e ffects of the ~ 2
selecti ve clmgs?
Arrh) thmitt.s
Tachycardia
lleadachc
Nausea and vomiting
DIRECT-ACTING o: AND~ AGONISTS

EPINEPHRINE
Which receptors does

epinephrine act upon?
It stimulates o:1, o:2 , ~ 1 , and ~ 2 receptors.

At low doses epinephrine stimulates ~
receptors and at high doses it stimulates o:
receptors.

responses to epinephrine?
Canliovuscular- increased heart rate ;\nd

contractility; vasoconstriction of
arl!"rioles in the skin, viscem, and
rnucous membranes
Rl'l>piratory- bronchodilation through
activation of~:! receptors
Metabolic-increased glyc."Ogenolysis and
release of glucagon and a dccrea~ed
Chapter 8 I Adrenergic Agonlsts
SI
release of insulin results in

h)perglycemia
What are the therapeutic

uses?
Given for bronchospasm secondary to

acute asthma or anaphylactic shock
Used in anaphyla.,is and cardiac arrest to
increase cardiac electrical actidty
Used in conjunction with local ane~thetics
to prolong effects via vaso<:onstriction
Used to achieve hemostasis
What are epinephrine's

adverse effects?
Cardiac arrhythmias
Hypertension
Palpitations
Dizziness, am.iety, headache
Tre mor
Myocardial infarction due to increased
cardiac work
Pulmonary edema
To what does the term

"epinephrine reversal"
refer?
When epinephrine is administe red alone,

it will cause an increase in systemic blood
pressure because of its a activity. When
given in conjunction with an a blocker
such as phenoxybcnzamine, epinephrine
will cause a decrease in blood pressure
because of its 132 activity. This effect is
knows as epinephrine reversal.
NOREPINEPHRINE (Levophed)
What receptors does norepinephrine stimulate?
a 1, a 2 , and 131 receptors. :-Jorepinephrine

has a stronger affinity for a receptors than
for
J3 receptors.
What are its physiologic

effects?
Vasoconstriction
Reflex bradycardia
What is its therapeutic use?
It is one of the last-line agents in the

treatment of shock.
What are norepinephrine's

adverse effects?
Tissue hypoxia secondary to potent

vasoconstriction
Decreased perfusion to the kidneys
Tissue necrosis due to extravasation
during intravenous administration
Arrhythmias
52
DOPAMINE
Whee is this agonist found?
It is syntltesized in the CNS, sympathetic

ganglia, and adrcuul medulla.
What receplos does

dopamine act on?
a 1 13 1, and 132 It also stiu1ttlates its own

uopamine (0 1 and D~) receptors locat<'d
in the peripheral mesenteric and renal
vascular beds. Dopmnjne receptors are
stimulated at low dose, 13 receptors at
moderate dose, a11d a 1 receptors at
higher doses. Dopamine does not cross
the blood-brain barrier.
'What are dopamine's therapeutic uses?
Treatment of shock-it rruses blood

pressure by stimulating the 13 1
receptors of the heart
Used in acute renal failure to increase
renal blood flow
Treatment of acute congestive heart
failure
How is it administered?
IV
What are dopamine's

adverse effects?
Decreased renal perfusion at rugher
doses
Arrhythmias
Tachycarrua
Hypertension
Tissue necrosis can oc-cur if dopamine
extravasates during infusion.
INDIRECTACTING AGONISTS
TYRAMINE
What is tyramine?
Tyramine is a by-product of tyrosine

rnetabollsm; tyrosine is a precursor to
dopamine, epinephrine, and norepin-
ephline.
What is the mechanism of
action of tyramine?
Tyramine is taken up by sympathetic

neurons, which causes a release of
catechohunines.
Is there a therapeutic use

for tyramine?
No
Chapter 8 I Adrenergic Ago nlsts
h at are tyramine's adverse

cflects?
\ \1
53
It can cause a hype rte nsive em ergency

in pat-ients wht) take MAO inhibiting
drugs since MAO is responsible for the
metaboHsm of tyramine. lt is important to
warn p atients w ho ar e taking MAO
inhibitors not to cat foods with higl t
ty ramine conccutmtions, such as red
wine, b eer , chocolate, <md cheese.
AMPHETAMINE
-what arc its pharmacologic

actions?
It releases stores of norepinephrine and

dopamine. ll can enter the CNS.
When is it appropriate to
adm inister amphetamine?
Amphetamine is used to treat attention

dt>ficit hyperactivity disorder (ADHD)
and mm;olepsy. It is also nst>d for appetite
suppression.
What are the advese e llects?
Psychological and physical de pendence

Psychosis
Confusion
Insomnia
Tleadat:he
Restlcssuess
Palpitations
Tachycardia
I mpole ncf'
MIXED (D I RECT AND INDIRECT) AGONISTS
EPHEDRINE
or
How does ephedrine work?
It stimulates the release

norepinephrine [rom IIC'I'VC terminals. ft
also acts as a direct adrenergic agonist.
W h a t are ephedrine's
therapeutic uses?
Epheclrin t:> is used in the heatment of

urinary incontiJlcnt:e. bronchospasm, and
hypotension.
Arrhythmias
Palpitations
Insomnia
H:1Jett cnsiott
54
Section Il l Autonomic Nervous System
METARAMINOL
Describe this drug's actions.
~letaraminol acts indirectly by releasing

norepinephrine. It can also dirC'ctly
stimulate a receptors
What are its therapeutic

uses?
Treatment of hypotension and

temtination of PAT episodes
Similar to tho~e of norepinephrine
Adrenergic
Antagonists
What arc adrenergic

antagonists?
They are dm~s that hind to adrenergic

receptors hut do not mitiate the usual
intracellular response.
Name the two major subdivisions of this drug class.
1. a hloektrs
2. f3 blocklrs
Is there anothe r class of

adrenetgic antagonists?
Yes- the indirect aurCIWrgic antagonists
a BLOCKERS
Name
~ix
a blockets.
.l. Pn\'losin ( Minip nss)- a 1-mlr<'nergic
sdcctivc. revcrsihle
2. Doxazosin (Canlu ra)
sp]pdi\p .
a 1-atlrcncrgic
rpV('rsihJI'
:3. Tcnvosin (l l}trin)-a 1-adr<'nc>rgic

~elt>(tivP. nwr~ihlt
4. Plwno') bc1wunim (Oihtnl) lin<')nunwlettiw. ine, cr~ibl e

-Rc>llwmher phcno:~.ybcnza minc is
thl' unl~ a -adnnprgi< re<'' ptor
mention~od that is nonreHr,ihlt'
(~ board tpu: ,tion)
5. Yuhimhint'( Ycx~ln )-~-adrcner~ie
sell,<: Ih c, re' ersihle

6. Plwntolaminc ( Rq~ititw )
nonselectil t , rt'' t'rsihle
PRAZOSIN, TERAZOSIN. AND DOXAZOSIN
What is tJ1eir mechanism of

action?
They eompetiti vdy and stll'l'livdy block

a 1-adrenergi< r<><tplor~.
Describe tJ1e physiologic

sequelae of Ot 1 blockade.
Blockade ol' a 1 -adn:ncr~ic rtc:eplors on

vasc1dar smooth 111 11 sclt~ inhibits
c:onstri<:lion ol' arlNiole~ and vci11s.
This results in dccrtasc<.l pcripht>ml
v;Ls<:ular resisl<lllt'l' und a lowC'r blood
pnssun.
55
56
Blockade of a 1-adrenergic receptors in

bladder smooth muscle results in
relaxation and decreased resistance to
urint How.
What a r e the clinicaJ uses?
Treatment of hype1tension
Prevention of u1inaryretention in
patients who have benign pn1slntic
hypertrophy
Are there adverse effects?
Prazosin and stmctural analogues can

cau~c:
Gastrointestinal hnlermotility
Orthostatic hypertension. especially after
the initial dose
Sexual dysfunction. dry mouth, <md

dizzin<ss
PHENOXYBENZAMINE
How does this drug work?
Pheuoxybenzaminc is unique in that it

works by noncompetitively blocking the
a 1 postsynaptic receptor and a 2
preS)113ptic receptors.
Describe the physiologic

lt blocks peripheral vasoconstriction.
aclions of phenoxybenzamine. 1t induces a reflex tachycardia.
H ow is phcnoA')'henzamine
a dmi n istc 1cd?
Orally
What is Lhe duration of

action?
Because it binili covalently to the

receptor, this drng has a very long
duration uf action (approximately 14-48
hours).
D escribe the the rape utic use.
Treatment of patients with

pheochromocytoma-induced
hypertension. Phenoxybenz.amint> is
VE'I')' effective because of its long
<.Juration of action.
Trf'atmrnt of patients with benign
prostatic hyperbophy. Phenoxybenzaminc reduces the size of the
prostate.
Treatment of patients with spinal cord
injuries who may suffer from
hyperreflexia, which results in high
blood pressure. Phcnoxybenzamine

blunts this response.
Chapter 9 I Adrenergic Antagonists
57
Treatment of patients with Raynaucl's

disease
\\!hat are the toxicities asso-
ciated with the use of phenoxyb enzamine?
Orthostatie hypotension
Reflex tachycardia- If severe, it may
induce anginal pain; therefore
phcnoxyben;r.amine is contmindicated
in patients with coronary disease.
Inltibition of ejaculation due to lad. of
smooth muscle contraction in the vas
deferens
YOHIMBINE
What is it?
A selective a 2-rP<'eptor antagonist
Describe the clinical use.
It is someti 111es used to l real impotency

via di rcct penile injection.
PHENTOLAMINE
What is it?
An imidazole derivative
Describe the mechanism of

action.
Reversibly blocks a 1 and a 2 receptors
How is this drug used

clinically?
Because it has a half-life of only 4 hours,

phentolamine is used for the short-term
control of pheochromocytoma-inch Iced
hypertension.
\\!hat i'> the route of

administration?
Nor 1M-poorly absorbed omlly
What are the adverse

e ffects of phentolamine
administration?
Orthostat1c hypotens1on
Gastrointestinal stimulation which may
lead to peptic ulcers
Tachycardia, myocardial infarction, or
<lrrhytlrmias due lo reliex sympathetic
response
~BLOCKERS
now are ~ blockers subclassified?
All of the f3 blockers arc co1npetitjve

antagonists; however, they can be
subgrouped according to tlrrct major
properties:
l. Selectivity of receptor blockade
58
2. Pmstssion of intrinsi<:
'' mpathmnimeti<: adhity
3 Capacit) to block a-adrenPr~it
r<<rptor~
13 1 SELECTIVE BLOCKERS
Name fom selective 13 1
blockers.
I. At1nolol (Tenormin)
2. E~ c llolol (Brt>vibloc)
3. Ac:dmtolol (Sectral)
4 . .Mttoprolol ( Lopressor)
In ~tneml. 13-blockers starting with 1\ or
M are tardtOselectin:.
Is the ir ~ 1 ~electivity
absolute?
What is the main advantage
of 13 1 selectivity?
\Jo. At high doses these dmgs \\ill hlod.
132 I"('C'<ptor<..
Thest dmgs arP sometimes called
card ic>.~dcctive because tJH..Y lack tltl
unwmcted hronchoconstric.:tor and
h~11oglyct'mic d'fects of nonst>lccti\"(
bloC'k<'rs.
What c linical conditions
wananl t he usc of cardio
selective ~ blockers?
Atenuloi-Jl~lwrtension.
myoc<udial
infarction
Esmoloi-Because of its VE'r\ short

duration of action (10 minutes ). it is
mtd when immediatt> f3 blockadt is
tweucd. \uch as for thyroid \torm. It is
onl:v administered lV.
Ac<'ht ctolol-1 I)'llCttensim 1

M<t"oprolol- 1-1 ypertension. .u1ginal pnin.
IIIY<Kardial infm"Ction
NONSELECTIVE 13-ADRENERGIC ANTAGONISTS
Wlml i~ the prototype nonseleclh e ~ blocker?
Propranolol
Name the pharmacologic

actions of nonselective 13
Dcc.rtascd carclia< output and blood
blockc as.
Reduct inn of sinns rate and eon duct ion
pr<S\UJ'l'
througl1 the ahia

PNip lwrnl vasoconshi ction
Hronchocc msl riclion-Rcmcnc bcr, tlw

t'<l rdimelecti\e 13 1 blockers lad. thl'
hrondHwonsliiclive and hypoglyc<>mic
dT<cts of nonselective blo<kcr.-..
Decrt'ased glycogenolysis and glucagon
sccr<>tion
lncre;u.td VLDL and decreased HDL
59
How is propranolol absorbed? This drug is almost completely absorbed

after oral administration, but only
approximately 2.'5% reaches the systemic
circulation because of flrst-pass
metabolism.
What is the site of propranolol's me tabolism?
In what clinical situations
are non.<;electiYe ~ blockers
indicated?
The liver
Hn>ertension
Angina. tachycardia
Arrh)1:hmia
Thyroid storm
Acute panic syndrome
M igraine headache~
Name two other nonselective

antagoni.'its.
Timolol and nadoloi- T hey have

extremely long half-lives (20 hours).
What is the clinical use of

these two drugs?
T reatment of glaucoma They decrease

the production of aqueous humor by the
ciliary body.
What arc the adverse effects

of nonselective ~ blockers?
Bradycardia
Bronchoconstriction--cun result in an
asthmatic attack
May hide waming signs of hypoglycemia
such as tachycardia; therefore, it is
critical to monitor diabetics who are
receiving ~-blockt'rs.
Fatigue
Depression
Sexual dysfunction
~-adrenergic
BLOCKERS W ITH INTRINSIC SYMPATHOMIMETIC ACTIVITY
Name two drugs that are

classified as ~ blocke rs but
also have some ~-agonistic
properties.
Acebutolol and pindolol
Why ae these drugs

conside red to be partial
agonists?
They very mildly sti mulate hoth 1) 1- and

132-adrenergic receptors. However, t heir
intrinsic effect's are not as strong as that
of a fuJJ agonist, such as isoproterenol.
'W hat a1c these two drugs

use d for?
T reatoacut of hypenen~ion in patients

prone to bradycardia
Are the re any advantages to

using these agents?
Acebutolol and pindolol produce

bronchoconstriction only at extremely
60
high doses. The) do nolllldll(:c

bradycardia to tlw dtgre<. that full
antagonists do. and thcv <.ausc vcn

mi11imal disruption of lipid and
C'.Jrbohydmte nwtaholism
~ BLOCKERS WITH
a BLOCKING CAPACITY
Labeta lol
What is thh drug's mechani~m of action?
!'\ons<>INtive 13-hlcKkadc alcmg with

a 1-adrenergic stltctin blockade. wh1ch
result~ in periplwral vascxli latiou rather
than th<' v;Lsoconstriction that cxcnrs \\i th
the ollwr J3 blochrs
What is the clinical use?
Treatment of h)1Wri<'I1Sion and atrial

fil)Jillillion
What a te the adverse effects?
0Jthostatil' hypotl.'usio n and di'aincss
Carvedilol (Coreg)
13 blocktr thut al~o has a 1-hlockin).';

propertits
What is it?
Lis t the clinical uses.
Tn'alnwnl of li)lltrttnsion
Treatnwnt of chronw (.II F- Ait hough il
may seem paradoxical tom< 13
blocktrs in the trealnwnt of CHF,
since the, can also worst'n S\ mptoms.
tht') appc:ar to ht.ncflt tht palitnt b)
rcdut'ing sy1npatht>tic acth it). Tlw)
ma) also impro\C' cli<L,tolit dy,hulC'lion
by prolonging dia\tolic: fillin~ timP
What a r c t h e mechanh-ms
Reduction of spnpatlll'tic activit;
of action?
Imprownwnt of' cli.L\toliC' d)., funetion hy

prolonging dia\tolic fillin~ lime
What ate the contraindicatiuns to use?
13 blockers arc cuntraimlic:atld in the

treatment of acutt C ll F. Tht} are only
used wlwn the pal itnt is hC? iilOdymuniC'ally stahl <'
132 SELECTIVE BLOCKERS
Butoxamine
What is it?
t\ ~det'lh e (3 2-adrvmrgk anta~onist
Does lhh drug ha,e any

clinical use?
No. not currently
61
NEW 13-BLOCKING DRUGS
Atc the re many other

13 blockers?
Yes. New 13 hlockE>rs art produced yearly.
How d o these new dn.tgs

diffe r from the 13 blockers
discussed here?
Primarily in tht>1r pharmacokinetics
How can physicians

recognize the!te n ew drugs?
B) the -olol ending in their namt's
What are the indications

and adverse effects of the
n ew 13 blockers?
Generally tlwy wilJ be simila r to those of

othf> r 13 blockers.
INDIRECT ADRENERGIC ANTAGONISTS
Why are guanethidine and

reserpine considered
indirect adrenergic antagonists?
They do not directly block ex- or 13adrenergic receptors. They do, however,
block the release of norepinephrine from
nerve endings- in e ffect, they antagonize
the e ffects of the ~ympathctic system.
GUANETHIDINE (ISMELIN)
What is this drug's mechanism of action?
It enters the peripheral adrenergic ne rve

by a reuptake mechanism for norepinephrine and binds to storage vesicles, the
action of which subst>quently blocks the
release of stored norepinephrine.
Does guanethidine have a

clinical use?
Yes-treatment of hypertension
Orthostatic hypotPnsion and sexual

dysfunction
RESERPINE
What is it?
A Rauwolfia alkaloid
\\'hat is reserpine's mechanism of action?
Tt blocks nor'pinephrinc transport from

cytoplasm into intracellular storage
vesicles. Subsequently, the ne uron is not
able to release any catccholamines.
How is this drug used

clinically?
For treating hyp<.rtcnsion (very rare ly

used)
CNS depression and bradycardia
Section Ill
Central Nervous
System
10
Introduction to
Central Nervous
System Pharmacology
Naune the m ujor CNS

n c urobansmitters.
Atetyl<holiuP
Norcpilll'phrim
Dopan1inc
Scruton in
Gammn-a min nbut yric add (CABA) and
glycim-nrutal amino adds

ChJtanmtc/a~ partatc
addie a111i11o al'id!>
What ty p es of receptors a tc
most cornrnonlv fo und in
the CNS?
.
a rf'<Pplnr <llld .,uhscqtwntly
Wha t a rc the primary

fun ctions of a oewotransrnitlc r?
To hind
Wh at arc EPSPs?
E-.cilato.- pmh\ uaplic: potcntia].,_

inithLIPd "hen an l'\dtatOI) ncuro
cithl'r l''-C:ill' or 111hihit thl postsynaptic

ll(;'llf()ll
I ran~nliltlr at'ti\ all'' '\,a orCa
C h e fhe e xamples of
excita tor-y neurobansmitters.
chan1wls
1. :\orcpllll'phrilw
2. D opamine
3. Act-l\.kholinp
-i. Clut:tul.lte
5. Aspartalt>
What are lPSPs?
Inhibitory posts),~<~ pi il.: potl'ntialsiniliated wht>n an inhihilof\ ncurotransmiltrr opPns ddoridc~cl ~:ulnels und
the cell mvmhnuw lw<'onws h)1Wrpohuizcd. lPSPs utukt il111ore difReult
For the lll'llron to lwtouc atlivatcd
(l"igun> H)- I ).
C i\'e two examples of inhibit ory neurotransmitte rs.
1. Gly<.'int
2. CABA
65
66
Section Ill/ Central Nervous System
l l
Threst}.oj<! __ _
-------- ----------- ------
IPSP
Time~
Figure I 0-1. Interaction of excita[Qry and inhibitory synapses. On the left, 3 supra thresho ld stimulus is given to an excitatory pat hway (E). On the right, this same stimulus is given
shortly after stimulating an inhibitory pathway (I) , which preve nts the excitatory potential
from reaching thresho ld. (Redrawn from Katzung BG: Basic and Clinical Pharmacology, 7th
ed. Stamford, CT. Appleton & Lange, 1998, p 3-45.)
In general, how do d rugs

affecting the CNS work?
Most d rugs will allCd production,

releas<. or nwtaholism of a
ncurotra n~mi!tPr. Olhlr agents ma)
affe<t the pmh} naptit relPptor
\Vh a t are the maj or differe n ces b etween the a u tonomic

n crvou!t !tystem and the
centntl n ervous system?
T here are three major di fferences:

L. The number of nPurotransmitters is
greater in the C S.
2. The number of synapses L~ wcatcr in
the CNS.
3. Tlw Cr--S. unlike the autonomic
nervous system. has a large array of
inh ib itUJ) iiCLI I UllS l !J.tl ~<;;IVC ltJ
modulate act ion.
~torag<,
11
Anxiolytics,
Hypnotics, and
Sedatives
De 6nc anxiety.
An unplea.5ant emotional state consisting

of apprehension, tension, and feeling~ of
danger, without a real or logical cau~e
Wha t a re some of the

physical symptoms seen
with anxiety?
Tachycardia
Tachypnea
Sweating
T rembling
Weakness
Wh at a te t he major classes
of drugs used to treat
anxiety?
Benzodiazepines-the most frequently

used drugs for anxiety
A?,aspirones-for example, buspirone
Carbamates-for example, meprobamate
Barbiturates-rarely used today because
of severe side effects and a low
therapeutic index. These drugs have
generally been replacetl by the
benzodiazepines.
BENZODIAZEPINES
Give some examples of

b e n zodiazepincs and the ir
a pproxim ate duration of action.

Sho rt-Ac ting (2-8 hours):
Oxazepam (Serax)
Clonazepam(.Klonopin)
Midazolam (Versed)
Triazolam (Halcion)
Inte rmediate -Ac ting (10-20 ho u rs):
Temazepam (Restoril)
Lorazepam(Ativao)
Alprazolam (Xanax)
67
68
Section Ill/ Central Nervous Sys[em
Long-Acting(J-3 day'>):
Chlordiazcpoxitk(Libriunt)
Diazepam (Valium )
Flurazcpam ( Oalmane)
What is GABA?
GABA ('y-aminobut}ric acid) i~ the major

inhihitOI) neurot ran,mitter of the C'IS.
llow do benz.odiazepines
work?
When henzodiazcpincs h10d to srwcific

receptor~ that are ~<>parate from but
adjacent to the GA BA, receptor. they
potentiate the binding of CABA to its
own receptor. The bindin~ of CABA to its
ovm rt>ceptor results in increased chloride
ion comluctance, cell membrane
hyperpolarization, and decreased
initiation of action poteutials.
Remember that benzodiw-epines do not
bind to CABA receptors- they bind
adjacent to them (Figu re 11- 1).
What arc the therapeutic

indications for benzodiaze pioes?
These dru~s are used clinically as muscle

relaxants and in the treatment of the
following:
Anxiety disorders
Panic disorders-alprazolam is the drug
of choic:e
Stahts epilepticus-diazepam is the drug
of choice
Sleep disorders
Insomnia-All bcn1A>diazepines can be
sedating, hut lor.ll.ep;~m and
tcmazepam arc the most commonly
used.
Alcohol withdrawal--dia:r.ep.un most
commonly used
What is their route of

administration?
PO, lV, or IM
Where are benzodiaze pines
They <tre n tetabolizcd in the liver and

excreted in urine. Many of the
benzodiazepines have active metabolites.
metabolized?
Does dependence occur?
Yes. Prolonged usc tan result iu

dependence. Abntpt discontinuation can
result in withdrawal symptoms, including
coufusion, anxiety, and agitation.
Receptor Empty (No Agonists)

Chloride channel (closed)""-
c 1
"' ~ +
li'Wn'niMJH!~ c:r-----1 1lr1Mfrlrrnlf1'
+
~M~ U~~~~
Benzodiazepine receptor
Empty receptor is inactive, and

the coupled chloride channel
is closed.
Receptor Binding GABA
Binding of GABA causes the

chloride ion channel to open.
Receptor Binding GABA and Benzodiazepine
Entry of Cl- hyperpolarizes

cell making it more difficult
to depolarize and therefore
reduces neural excitability.
Binding of GABA to its

receptor is enhanced by
benzodiazepine, resulting
in a greater entry of
chloride ion.
Figure I 1- 1. Schematic diagram of benzodiazepine-GABA-chlorlde ion channel complex.

GABA -y-aminobucyric acid. (Redrawn from Mycek MJ. Gertner SB. Perper MM [Harvey
RA. Champe PC. eds}: uppmcott's Illustrated Reviews: Pharmacology, 2nd ed. Philadelphla,lippmcott-Raven Publishers, 1997, p 91.)
70
Section Ill/ Central Nervous System
What type of symptoms may

u patie nt taking benzodiazcpincs experien ce?
Drowsiness and con fusion-!he most

common sic.l< tff<cts
Ataxia
Dizziness
Respiratory depnssion and ciPath, if
taken with otlu..'r C>.S depressant!>

such as <thmwl
BENZODIAZEPINE ANTAGONIST: FLUMAZENIL
(ROMAZICON)
Flumazenil (Romazi<-on) is a competitive

of bcnz()(.liaz!.!pincs at tl1e
GABAA rcctptor
What is Humazenil's mechanism of action?
antagoni~t
.Desc.-ibe the clinical use of

this drug.
overdose
How long do the effects of

llumazenil last?
H(:'versal of benzodiazcpinc sC'datiou or
Only l hour- Repeal doses may h<'

necessary for a heavil)' st>dated patient to
remain alert.
AZASPIRONES: BUSPIRONE (BuSpar)
How does buspirone work?
It acts as a partial agonist at
~t>rotonin
(5-
HT1A) receptors.
Wbat are the indications

for this drug?
Buspironc is used for g<.ncr;t.lu.ld an.xiety;
howe,er. unlikt' lwnzodiazt>pines. its

effects mav takt 2 \H'<-k~ to l><.'Comc
apparent.
Wbat are the pharmacokioe lic properties of buspirone?
This dmg is metabolit.ed by tlw liver and

excreted in the urine>; 1ts half-life is 2 to
11 hours.
How do the actions of

buspirone diller from those
of the benzodiazepines?
Buspirone lac.:ks tht muscle> relaxw1t and

anticonvulsant propc:-rties of tlw benzo-
What advantages does

buspirone have over benzodinzepioes?
diazepincs.
Minimal sedation
Low ahuse poteutial
No overdose fatalitirs rl-porled
No withdrawal symptom~
What toxic e ffects are
associated with buspirone?
lleadache, nauSl'a,
dizzine~~
Chapter II I Anxiolytics. Hypnotics, and Sedatives
71
CARBAMATES: MEPROBAMATE
\Vhat is meprobamate's
mechanism of action?
It is not wPII known.
Wh at i~ the clinical use?
It is now virtuall~ ohsoiC'te. In the past it

wa~ u~ed primaril) in tlw trpatment of
all\iel\.
R<'spiratory tll"pr<ssion-major tm..ic
effPct
ll ypot('nsion
Shock
H l"art failure
BARBITURATES
G ive four examples of

barbitumtes.
I. l'lwuobarh ital (Lu nli11al) - longacting

2. Pcntuharuital ( rttnllutal)-shortacling
:3. Amobarbital (Amytnl) short-at:ting
4. TltiopPntal ( Ptulotlwl)-ultrashorla<:ting
How do these drugs work?
Like henzowaL<pine~. barbiturates

fadlitatc: GABA action on (hloricl<' Pntry
into tlw c.'t'll. which nsttlts in membrane
hypcrpolarimlitm and a dt<reasf' in
neuron excitability. Barbiturates do not.
howe,cr hind to henzodiaz<>pirw
rect>ptors.
\Vhat a.e the therape utic
indications for barbiturate
administration?
or
Induction
till('\( lt(~i;i-1 hiopt'ntal
Antic-orwttlsant..-'.)1;.. ph<'nol>arbital
Treatllll'llt of ;ulxicty
Induction of hypnosis
Why a re be nzodiazepines
favored over barbituratcs
liw the treatment of anxiety?
Henzodiazl'pilll's haw a nmch ltighl'r

tht>rapt> ttlic- indt'x titan do barbiturates
(Figwc 11-2).
By what routes can baabiturates be adminh1:ered ?
IV, PO, or IM
What are the phannacokinc tic ptoperties of barbiturates?
They arc ntctaholizld in the liver and

excreted in the 11rin<>.
72
Section Ill I Central Nervous System
Barbiturates, alcohol
,
,,
,,
Coma
Medullary depression,''
,
,,
Anesthesia
- - - - - Benzodiazepines
Sedation, anxiolysis
Increasing d o s e Figure I 1-2. Comparison of dose-response relationships of benzodiazepines and barbiturates.(Redrawn from Gallia G, Hann Cl, Hewson WH: The Pharmacology Companion.
Alert & Oriented Publishing Company. 1997, p 33, Fig 3. 1.)
What de termines the

dumtion of action of thiopental?
RPdis~ribution
Does btubiturale dependency occur?
Yf's-abn1pt cessation can lead to severe

witltdrawal symptoms (tremor, restlessness, nausea, seizures, and cardiac aJTcst).
For whom ae barbiturates

conbRindicatcd?
For patients who have acute intcnnitlrnt

porphyria, because they increase porphyrin synthesis
What ore the adverse e ffects

of these drugs?
to the other
Drowsiness and decreased motor control
Induction of the P-450 system

Addi<:tion
Respiratory depression and coma in high
doses
Allergic reactions, especially in patients
with ast hma
OTHER SEDATIVES
ZOLPIDEM (Ambien)
D escribe this drug's clinical

use.
ti.o;..~uPs
Treatment of insomnia
Chapter I I I Anxiolytics. Hypnotics. and Sedatives
What arc its adverse effects?
At<l.\.ia and conf11sion
CHLORAL HYDRATE
What are its clinical uses?
llypnosis
Sedatiml (in childn11)
Describe thi!> drug's adverse

effects.
Gastrointestinal clistrt'ss
Uupleasant taste
73
12
What are antipsychotic
drug~?
What b. their mechanism of

action?
Anti psychotics
Antipsythoti<s aho J..nown a' lll'llroleptics. an dru~' uscd primarih to tn'at

P')'dtolk ~l<llt'' \neh as sdti..:ophreni<t
delll~ion;tl cli,ordtr ami otlwr hallu<:inaton stat<s.
Atllipsychntil'' hlocJ.. 'ariom nc-tptors

including cholincrgic-, adremrgil. serotoninc>rgic, must:~rink, and hista111ine
rectptors. ll owC'wr, thcir <Hl lips)C'hot k
actiom arc tl~t~ughtlo I)(' dm to hlockiug

nr dopamine I'CC(' (>hH'S ill t)H' ('l'lllnt)
nc't'\'Oi ts ;yslent, parliC'nlarl) tht' I )~
rcceptw, in tlw tilt socmt kal and nwsolimhal systtms
or tlu brain.
Do antipsychotic agents
dilfe in potency?
YPs-u drug's pntC'nl: pamllc], its :~!Tinily

for D 2 rt'L't>ptor\ llaloptridol amlthiothi'.t'lll' <tre ltigh-potl'lll'\ dntgs lxl'au~e
the~ haw high aflinit\ li>1 tlw D2 rcc't'ptor-.. "lwna' dclorprom;I/IIW and thioridazim aw low-potctlt') dn..~s lwl'aust
th t>\ h;\\ t' low a !Tinily for ()~ l'l't'l'ptors
Do antip,ychotic' differ in
c fficac\?
'o! Tht traditional antp,)<'holk' an all

('<111\idtnd to lw t'<(lll\ altnt 111 dlieaty.
How are antipsychotics

us ually administered?
In 1110\1 t~l\l'' tlw"' drug' an gt\C'II orally:

thf') t'<lll I><' giqu tntralllltstulad, il' tlw
patiPnl is noneompliant.
Dcscdbc the abs01-ption

and me taboli.~ m of the l.-aclitional antip~ycboHcs.
Tltev an variahh ahsorlwd orally but thev
pas;i cclo tlw bn;incasily
:ttl(]
haw a largt:
volu nu.~ ol' dislrihtcliou. 'vll'taholism

OC(' II rS
l1y lhl' eytodtnlllll' p J5() systl'lll
in tlw liv('r.
What i.'> the onset of action?
14
Antipsychotics IIlli) not hcto tllc C'!Tet:liw

[()1' se' l'ml wceko.. ll mwwr, stdation and
other sidt' dlixts tau <X.'t'llr rapicUy.
Chapter 12/ Antipsychotics
75
Can these drugs cure illnesses such as schizophrenia?
Nol Antipsychotics only reduce the

symptoms of tlw illness; they cannot cure
the illness.
How are the antipsycbotics

cla!isified ?
Classification is based on structural

differences The major classes include
phenothiazines, hutyrophcnoncs, dibenzoxazepines, thioxanthines, and benzi-
soxazolcs.
TRADITIONAL ANTI PSYCHOTICS
PHENOTHIAZINES
What are some examples of

phe nothiazines?
Chlorpromazine (Thorazine )-prototype

f luphenazine (Prolixin)
TriOuoperazine (Stclazinc)
Thioridazine (Mellaril)
Perphenaziuc (Trilafon)
What distinctive side etiects

docs thioddazine cause?
Pigmentary retinopathy
May cause cardiac arrhythmias and conduction block
BUTYROPHENONES
Name two drugs in this cla!is.
Haloperidol (Haldol)
Droperidol (lnapsine)
Other than psychotic sta tes,

for what can haloperidol be
used?
Tourette s syndromE'
What type of side effect is

esp ecially ponounced with
halope-idol?
Extrapyramidal side efTeels(~ common

board question )
Huntington\ disease
Phencyclidine overdose-drug of choice
DIBENZOXAZEPINES
Name a drug that belongs
Loxapine (Loxitane)
to this class.
THIOXANTHENES
Name a drug that belongs

to this class.
Thiothixene (Navane)
76
Section Ill I Central N ervous System
CLINICAL USES AND SIDE EFFECTS

What arc the c linical applications of tr aditional a ntipsycho tic agents?
Traditional neuroleptics havp sPvPml

tlwra1wutk uses. but the most important
to l'l'llll'mher are:
TrPal nwnt of any agitated or p~ychotit
statl', Sll(h as hi polar d isease or
sdizopltrenia (These ageuts an
tspecially effective ii1r the positil'l'
symptoms of schizophrenia. !>ueh as
ddusious. thought disorder~. and
halldnations. )
t\ntilnwtiC' tlwrap) due to bl<x:kmlP of
dopamine in the chemoreceptor
tri~gtr wnP (Thioridaiuc. ho" <'"cr.
cannot he uscJ for this p1111)ose.)
Tnatnwnl of'Tourette's syndronwl talopvridol

T rt>a l ment of' iutraetahle hic:cnpscllorprom:~t.i 11c
Antipruritit therapy-prometl raziue
( lwcau~t of histamiue blockadP)
\Vha r , a n en'~ way to

rc mc mbc t the <;ide cffecb.
of the tra ditional antipsychotil-~?
With a fc\\ c\ecptions. all ofthc traditional anlipsychotk~ haw similar

lo\ldtits namelv, sedation. extrapyramidal ellecb: anticholincr1-,ril' cfltC'Is.
and et-adrener11;i<: effects ( hyputcn~ion).
or
Do nil tmditiona l antipsychotics p toduce the sam e

degree of each type of side
effect?
No. T it(' S('Vt>riry each adverse effect

varics ~1111011~ 1lit' classes of ttntipsydwtit
dn1~s. fo'or txamplc. high-potPncy drugs
sudt <L' haloperidol aud fluphenazine>
produce till' ~natest e\trap} rmnidal
Plllds. nmllow potency clru,g~ ""d' tl'
thioridatinP and chlorpromazint producc
tlw highl'\l anti<:holinergie eflt>c-ts (Tahlt
12- 1).
D cscdhc the toxicities of

lmditio nul a ntipsychotic
CNS I!Cdalion-Mc.n nuukedl) with the
agents.
:E ndocrine alte tatioo-14alaetorrlwa,

alltcnnrrhet\, aud infertilitY. likely dllt'
to blockade> of dopamine ~dea.st; from
tlw pituitan
Antich oline rgic e lfects-dr) mouth
tonstipation. urinan retentiou, ,111d
hlurn 1ision
phcllothia7ines
Table 12-1. Neuroleptic Drug Side-Effect Profiles
Potency
HfCH
LOW
*l = low, 4 = high
Side EfTects
Antichonlincrgic
Effects
Sedation
Extrapyramidal
Effects
Haloperidol
Fluphenazine
Thiothixene
Trifluoperazine
Loxapine
Chlorproma7Jne
Thioridazine
Drug
a -Aclrenergie
Efl'ects
.....
.....
78
Section Il l / Central Nervous System
Anliadrcne rgic effects-watch for

light-headcdness and orthostatic
hypotension ~econdary to aadrenergic blockade. Phenothiazine~
can cause failure to ejaculate.
E xlnlp)'lamidal side effects- akathisia
(motor rP.s tlessness), parkinsonian
S)1tdrome (hradykinic rigidity.
tremor), ac ute dystonic rcactious
(slow. prolonged muscle spasms of
tongue, neck. face), neuroleptic
malignant spulrome. and tardhc
d~skincsia (~ eommon board
question )
What is hudive dyskinesia?
Tardive dyskinesia is a symptom Lhat may

occur after prolonged therapy with
nenroleplics (6 months to 1 year). It is
characterized by rhythmical involuntary
movements of the tongue. lips, or jaw.
Patients may also demomtrate puckering
of the mouth, or even chewing
movements.
Is tardive dyskinesia
reversible?
There is no known treatment for

established cases of tardive dyskinesia.
The ~yndrome may remit partiaUy or
completely ir neuroleptic treatment is
withdrawn, although in many cases it is
irreversihle. Anticholinergic agents
actually increase the severity of tardive
dyskinesia.
What is ne uroleptic malig-
Patients who receive neuroleptics for

long-term treatment may ex-perience
rigidity. altered mental status, cardiac
arrh)'t.hmias, hypertension, and lifethreatening h)perpyrexia.
nant syndro m e?
What is the t.heapy for

ne urole ptic malignant
syndrome?
This disorder is treated with dantrolcnc, a

skeletal musc:le relaxant (~ commo n
board question).
ATYPICAL ANTIPSYCHOTIC DRUGS

Nume three examples of
atypical antipsychotic drugs.
1. Clo7.apine (Cio7.aril)
2. Risperidone (Risperdal)
3. Olanzapine (Z)'prexa)
Chapter 12 I Antipsychotics
79
Why a' tltese drugs

considered ~atypical"?
In addition to bloddng dopmnine

rC'ctptors. al)vical antipsychotic-s also
produce signifieant blockade on serotonin
(5 liT) reecptors. They also art' mrdy
assoeiatt.d with f'\trapyramichl side
(f'b:ts.
Describe the actions of

cl en:~ pi nc.
This a!-(Cilt is a clibenzodiazepine
What is it used for?
Clo:~,apine ha~ been effective in treating

cases of schizophrenia that are refm<:lol)
to other neuroleptic drugs. It is especially
cffcclive in trealing the negative
symptoms of' schizophrenia (blunted
emotion. withdrawal, rcducNl ahili!y to
l'onu relationships).
What ae the s ide effects?
Clo:wpine causes fewer extrapyramidal

sid( c>ITccts than tr.:t<litional neurol~>plics.
Clo:a~pine does cause seizures and a very
dangerous agranulocytosis in l 9t to 2% of
palic>nts (~ common board question).
Weekly bloocl tests are required for
patientl> receiving clozapine therapy.
Describe the actions of

rispet;done.
Risperidone (Risperdal) is a henzisoxazole

drug that, like clo:z..'lpine, has a vcty high
aHlnity for 5-HT2 receptors. It also has
anlidopaminergic (0 2) activity. However,
risperidone exhibits no anticholinergic
effects and diminished extrapyramidal
effects. Risperidone is a first-line agent
for the treatment of schizophrenia since it
is effective for both the positive and
negative symptoms of the disease. The
drug is also known to prolong QT
intervals and therefore should be used
with caution in patients who have
abnormal QT intervals.
Descdbe the actions of

olanzapinc.
Like risperidone and clozapine, olanzapine blocks both dopamine and serotonin
receptors. Effective in the treatment of
schizophrenia, it can produce anticholinergic effects as well as sedation and orthostatic hypotension.
ckrivativt. It eliff'er~ from traditional

antip~ychotics in its potent blockade of'
~crotonin (.'5- IIT2 ) receptors <\long with
the usual dopamine blockade.
13
Drugs Used to
Treat Depression
and Mania
ANTIDEPRESSANTS
What is dcpre!>sion?
An affectiv< ~ymptom dtaratteriz.<d h~
intense sadnlss. g<ncmllo~~ of inllnsl iu

tltt' l'Vl'l)'d:t) as ptlh of life. in~outnia,
changt'S i11 :tppf'lil<, and low sdi~P.~ I P<'m .
What does the biogenic

a mine lhe<ny of d epession
propose?
dcpr<"~sion b dm to a th: ndtnq of

uo r('pinepltrint, serotonin, ami dopUIIlillt'
in thf' synap~f'S of tlw C'JS.
That
List the maj01 categories of

a ntidepessanl'i.
Tricn:lics
Serotonnl-'>p<'dfit nuptak< inhibitors
(SSR ls )
\l onamint' m.t<la.~<' inhibitors ( l\IAOis )
Atypical ;mtidl'prts\allt'>
Which of these agents are

now <.-on~ideed fttst-line
hcatment for d epression ?
SSRis
Atypk-al antidtpr<'\\anl\
TRICYCLIC$
Civc some cx>tmplcs of
Tertiary Amine Tricydic...
tricyclic a ntide pressant<;.
A mil riptylirw- protol} p<

l m iprami lll'- protot\l'X
Doxepin
Clom ipnutt irw

Trimipramitl!'
Secondary Amine Tricydics

Amoxa p iI l l'
Maprotilin c:
Protriptyliw
Desipramitw
'\lnrtript}lint'
80
Chapter 13 I Drugs Used to Treat Depression and Mania

differences b etween tertiary
amine and secondary amine
tricyclic.<>?
81
The secondmy amine tricyclics in general

are less lihlv to cause sedation. hvputension. an(!' anticholine rgic effects.
However, they are more likely lo induce
psychosis.
What is the mechanio;m of
action of all the tricyclics?
These drngs are though t to incrP<.LSe lc,vds

of norepinephrine and serotonin in the
synaptic cleft hy blocking neuron;tl
re\lptakP. They abo Llock h istamine. cholilwrgic, and u -adrcnergie receptors.
which accounts for a large prop' lltion of
their side effects. Tricyclics are also
thought to causf;' a down- regulation of
monoamine recf;'ptors; this m;ty account
Cor some Iheir therapeutic henefit.
or
Do these drugs elevate

mood in normal individuals?
What are the clinical
indications for bicyclics?
No. These d rugs are nol CNS stimulants.
Mood dis<mlcrs (depression primarily)
P<U1ic disorder
Genemlized anxiely disorder
Posttraumatic strE~ss disorder
Obsessive-comp1 1lsive d isorder
(clomipramine)
Pain d isorders
En uresis in children (imipramine)
How are bicyclics administe re d?
They <ue well absorbed orally, <lnd

penetrate into the CNS easily.
How a1e these drugs

metabolized ?
They w1 dergo signific;mt firs t-pass

metabolism in the liver; t hey are conjugated witl1 glucmonic acid and excreted
through the lddneys.
Which of the bicyclic.o; a1e

mos t efficacious?
All arc C<.jually efficadous.
When should: a physician

e-"llect to see a change in
the patient's mood?
Altho ugh tlie uptako n Jcchaoism is

inhibited al most immediately, antidepressant dinical effects may require 2
to 8 weeks to Lccome apparent. This
snggests that thPir mec hanism of action is
not completely understood.
82
Section Ill I Central Nervous System
What arc the signs and

symptom.~ <>f tricyclic
toxicity?
Anticholinergic ~illt ciTet'ls-hlurred

vision, hot dry skin, t'(mstipation,
confu~ion, urinary reten tion
Autonomic eiTects-<>rthostatic
hn>otcnsion
ECG chan~es \vid(ning of tlw QRS
complc\, arrhythmia~
Weight gain
Sedation due to histamint blockade
Possible lowt'ring of sdzun thresholds
Ctm tdcyclics and .MAOis

be given together for added
No! There is a chane<' that this combination can lead to sevNe convulsions and
t'()ma.
benefit?
SEROTONIN-SPECIFIC REUPTAKE INHIBITORS (SSRIS)
Give some examples of SSRis.
What is their
mecbani~m
of
action?
Fluoxetine (Pro7..ac)-prototype
SertraJine (Zoloft)
Paroxetinc ( Paxi l)
Fluvoxaminc ( Luvox)
Inhibition of serotonin reuptake \vithout
significant eiTects on norcpinPphrine and
dopamine
When would these drugs be

indicated?
Depre~sion is the primal) reason for

prescribing these dntgs. FluoxetinP is also
used to treat obscssive-<.'()mpuJsivc
disorder.
How are SSRh administered?
Orally
How are they metabolized?
By the C}t()(hronw P-450 system.

Fluvoxamine is a pot<nt P-.JSO inhihitor.
Ocscdbc the side-effect

pro6le of SSRis.
In general SSR ls have f<wcr sidt- effects

(anticholinergic, antih istaminic, aadrenergic b lockade') than d() oth er
classes o f' antidepressants.
What adverse symptoms

may a patient taking SSRis
experience?
Nausea
Diarrhea
Netvousness
Insomnia
Dizziness
Jm potence
Decreased libido
Chapter 13/ Drugs Used to Treat Depression and Mania
"''he n a re SSRls contraindicated?
83
SS Rls arc contraindicated in combination

thcntpy with monoamine oxidase
inhibitors ( MAOIs) because this combination may result in the ..serotonin
syntlrome," characterized by hypcrthc nnia, 1nuscle rigidity, myoclonus, and
rapid changes in mental status.
MONOAMINE OXIDASE INHIBITORS (MAOis)
\Vhat
i.~
monoamine oxidase?
MAO b a mitochondrial enzyme that is

invoked in the metabolism of catecholamine m>urotransmjtters.
Where are the highest concentrations of this enzyme?
In the Liver, GI tract, and C:r\S
Descibe the mechanism of

action of the MAOIs.
Two types of MAO exist: MAO-A and

MAO-B.
Withln the neurons, MAO-A is
responsible for the inactivalion of any
serotonin or norepinephrine that may
leak out of presynaptic storage
vesicles. When MAO-A is blocked,
these neurotransmitters accumulate
and are released into the synapse.
MAO-l3 is responsible for the metabolism
of dopamine and works in a similar
1mumer. In general, the MAOis arc
nonspecific inhlbitors of MAO, except
for selegiline, which is a specific
inhibitor of MAO-B.
What are the M.AOls

indicate d for?
Treatment of atypical depression (with

phobm or psychotic features). Other
classes of antidepressants are more
frequently used today because they have
fewer toxic effects.
D escribe the pharmacologic

prope rties of MAOIs.
They arc well absorbed orally.

They are metabolized by acetylation in
the liver (half-life, 2- 3 hours).
They require 2 to 4 weeks of treatment to
reach a steady-state plasma level.
'Vhat ae the adverse effects

ofMAOb?
Hypertensi\'e crisis (headache, hypertension, arrh)'thmias, and possibly

stroke) if the patient does not avoid

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A ZUNG

PRINC IPLES OF PHARMACOLOGY

AUT ONOMIC NERVOUS SYSTEM

Introduction to Autonomic Nervous System Pharmacology

C EN T RAL NERVOUS SYSTEM

Introduction to Central Nervous System Pharmacology . . . . . . . . .

Drugs Used to Treat Asthma. Coughs. and Colds

Hypothalamic and Pituitary Hormones

Anti-inflammatory Drugs and Acetaminophen

Drugs Used to Treat Gastrointestinal Disorders

Introduction to Antimicrobial Drugs

PHARMACOLOGY POWER REVIEW

Pharmacology Power Review

Sample Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

The study of the interaction between

A drug is broadly defined as any chemical

Name and define the fom

For each of the following

phenothiazine-like anti psychotics (e.g.,

volatile general anesthetics (e.g.,

antianxiety drugs (e.g., dia7.epam)

Section I I Principles of Pharmacology

barbiturate sedative hypuotic drugs (e.g..

local ant>stht>ti<'s (e.g., ('IXainl'}

penicillins (e.g.. nafcillin)

tetra<.)dine-typ(' antibiotit's (<..g.

13-blockers (e.g.. propranolol)

ACE inhibitor1. (<-.g. captopril)

IIMG-CoA reductase inhibitors (e.g.,

postsynaptic a -receptor blockers (e.g.,

Should trade names be

~ In the past the Boards have not tested

Do I need to know every

1\o. However, it is absolutely critical that

Pharmacokint'lic~ deS<:ribcs actions of

Absorption i~ the rate at which and e~'tent

What does the rate and

Drug--<lrug inte ractions- When ~hen

In what way docs the pH of

Many drugs are t'itllcr wt'ak acids or weak

Section 1/ Principles of Pharmacology

How does charge affect a

Generally, a drug will pa!>~ through cell

The fraction of administered drug that

What is the bioavailability

100%-bccausc all of I he drug enters the

What is the bioavaiJabiUty

Less than I 00%-becuu~e some of the

What factor!> affect bioavailability?

When pH= pKa

When pH is less than pKa.

When pH is greater than pKa.

What factors affect bioavailability?

'W hat is ftst-pass

Riolransformation that occnrs he fore the

\Vhat arc the ro utes of drug

I. Orai-{'Ommoncst route. Adrmtlal!,es

2. Bucc;J (between ~urn and cheek~).

Name the fo ur pare nteral

I. I ntravenons--dircct inject ion into tht

Section I I Principles of Pharmacology

What category of drugs is

How are inhaled drugs

By machine aerosolization or vaporization