USMLE Road Map Pharmacology, 2nd Edition (LANGE USMLE Road Maps) PDF

A ZUNG
VOR
ECOND
ITID
Contents
PRINC IPLES OF PHARMACOLOGY
I Introduction to Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4 Drug Dosing and Prescription Writing . . . . . . . . . . . . . . . . . . . . . . . 17
II AUT ONOMIC NERVOUS SYSTEM
5 Introduction to Autonomic Nervous System Pharmacology 23

6 Cholinergic Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
7 Cholinergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
8 Adrenergic Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
9 Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Ill C EN T RAL NERVOUS SYSTEM
I0 Introduction to Central Nervous System Pharmacology . . . . . . . . . 65

II Anxiolytics, Hypnotics, and Sedatives . . . . . . . . . . . . . . . . . . . . . . . . 67
12 Ant.ipsychotlcs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
13 Drugs Used to Treat Depression and Mania . . . . . . . . . . . . . . . . . . . 80
14 Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
IS Drugs Used to Treat Parkinson s Disease and Other
Movement Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
16 Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I02
17 CNS Stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I IS
18 Alcohol and Other Drugs of Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . I 19
19 Opioid Analgesics and Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . 125
IV CARDIOVASCULAR SYSTEM
20 Antihypertensive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

21 Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
22 Drugs Used to Treat Congestive Heart Failure ....... ........ . 161
23 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
24 Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
25 Anticoagulant, Fibrinolytic, and Antiplatelet Drugs . . . . . . . . . . . . . . 179
26 Antihyperlipidemic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
27 Drugs Used to Treat Anemia .... ........ .............. .... . 195
xill
xiv Contents
V RESPIRATORY SYSTEM
28 Drugs Used to Treat Asthma. Coughs. and Colds 0 0 0 0 0 0 0 0 0 0 0 0 0 0 20 I
VI ENDOCRINE SYSTEM
29 Hypothalamic and Pituitary Hormones 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 21 I

30 Thyroid and Antithyroid Drugs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 215
31 Sex Steroids and Inhibitors 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 221
32 Corticosteroids and Inhibitors 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 229
33 lnsulins and Oral Hypoglycemic Drugs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 23S
34 Drugs That Affect Calcium Homeostasis 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 241
VII MUSCULOSKELETAL SYSTEM
35 Anti-inflammatory Drugs and Acetaminophen 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 247

36 Drugs Used to Treat Gout 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 255
37 Autocoids and Autocoid Antagonists 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 262
VIII GASTROINTESTINAL SYSTEM
38 Drugs Used to Treat Gastrointestinal Disorders 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 267
IX IMMUNE SYSTEM
39 Antineoplastic Drugs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 277
X ANTIMICROBIAL DRUGS
40 Introduction to Antimicrobial Drugs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 293

41 Penicillinso o o o o o o o o o 0 o o o o o o o o o o o o o o o o 0 0 0 0 0 0 0 0 0 0 0 o 0 0 0 0 0 0 0 0 297
42 Cephalosporins and Other Cell Wall Synthesis Inhibitors 0 0 0 0 0 0 0 0 303
43 Protein Synthesis Inhibitors 0 0 0 o 0 0 0 0 0 o o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 31 I
44 Quinolones and Drugs Used to Treat Urinary Tract Infections 0 0 0 0 320
45 Folate Antagonists o o o o o o o o o o o o o o 0 0 0 o o 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 323
46 Antifungal Drugs o o o o o o o o o o o o o o o o o o o o o o o o o o 0 0 0 o 0 0 o o 0 0 0 0 0 0 0 328
47 Antiprotozoal Drugs o o o 0 o o o o o o o o o o 0 o 0 0 o o 0 0 0 0 o 0 o o 0 0 0 0 0 0 0 0 335
48 Anthelmintic Drugs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 350
49 Antiviral Drugs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 357
50 Drugs Used to Treat Tuberculosis and leprosy 0 0 0 0 0 0 0 0. 0 0. 0 0 369
XI TOXICOLOGY
51 Toxicology o o o o o o o o o o o o o o o o 0 0 0 0 0 0 0 o 0 0 0 0 0 0 0 0 0 377
XII PHARMACOLOGY POWER REVIEW
52 Pharmacology Power Review o o o 0 0 o 0 0 0 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 397

Contents xv
APPENDICES
A Sample Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

B Recommended Antimicrobial Agents Against Selected Organisms . 454
C Comparison of Antimicrobial Spectra . . . . . . . . . . . . . . . . . . . . . . . . 461
Index 469
Section I Principles of
Pharmacology
1 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 1. Pharmacokinclics--<lescribes "what

major subdjvisions of the body does to tht> drug." This
pharmacology. 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 classifi-
calion 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
4 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 ~ In the past the Boards have not tested
memorized for the Boards? 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 1\o. However, it is absolutely critical that

characteristic of every drug? 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 Pharmacokinetics
Define 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 Route of administration Tlw

e fficncy of absorption intravenous route is 111ost eflcclive.
depe nd on? 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 Many drugs are t'itllcr wt'ak acids or weak
a drug affect its charge? 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
6 Section 1/ Principles of Pharmacology
How does charge affect a Generally, a drug will pa!>~ through cell
drug's ability to penneate a membranes more eusily if it is
ceU membrane? 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 100%-bccausc all of I he drug enters the

of an intravenously injected systemic circulation
drug?
What is the bioavaiJabiUty Less than I 00%-becuu~e some of the

of any drug that is not intra- drug ma) not be ahsorhed, or it may
vascuJaily injected? become inactintted
What factor!> affect bio- 1. First-pass mctaboli~m

availability? 2. All of tlw factors that affect absorption
When pH= pKa

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

the protonated forms the deprotonated forms
HA and BH+ predominate. A- and B predominate.
pHfK,
A
( pH< pKa
JLI J
I I I
pH 3 4 5 6I t 7 8 9 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 as-
signed 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, Uppin-
cott-Raven Publishers. 1997. p 6.)
Chapter 2 f Pharmacokinetics 7
What factors affect bio- I. First-pas~ metabolism

availability? 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 Riolransformation that occnrs he fore the
metabolism ? 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 first-
pass 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 Alinapntaa)'

adminbtnllion? Pnrenteral
lnhalatio11
Topic; a!
Tmnsdrnaaal
Subcutaawous
Name the fom typ es of I. Orai-{'Ommoncst route. Adrmtlal!,es
alime ntary routes of admin- includt' t-om enience/patient
is tra tio n and slate the <:ompliante and the utilil'..<ltion of tlw
a d vantage of each. \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 I. I ntravenons--dircct inject ion into tht

routes of a dministration and \'<LS<:ular sy,tem. Adcm;tage: l\lost
s ta te the advantage of e ach. rapid and potent mode of admini-
stration, 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 Pulmonary agents

commonJy administered by
inhalation?
How are inhaled drugs By machine aerosolization or vaporization

administered?
When is topical Usually for treatment of localized disease

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

ndmirustration used? 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 l. Pass ive diffus ion-governed by a

mechanisms are drugs concentration gradient acros~ a
absorbed into cells? 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 Blood Oow

depend upon? Capillary permeability- The structure
Chapter 2 I Pharmacokinetics 9
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 The lipophilic prop erties of drugs tl1at
biotransform d1ugs? 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 They are known as phase I and phase 11
sets of modifications that reactions.
occw in biotransfonnation?
What happens in a phase I Lipophilic molecules are converted into

1eaction? more-polar molecules by introduction of,
or unmasking of, a polar functional group.
What types of phase I Oxidation, reduction (dehydrogenation),

reactions occur? and hydrolysis
What happens in phase n Formation of a covalent linkage between

conjugation reactions? functional groups on the parent drug and
anotber substrate
Specifically, what substrates Glucuronate-Quantitatively, addition of

are added in phase II this substrate constitutes the most
conjugation reactions? important conjugation reaction.
Acetic acid
Glutathione
Sulfate
In what organ do phase I and Primarily in tl1e liver

phase n reactions occur?
I0 Section I I Principles of Pharmacology
Whcte do these r e action Pha.~P I reactions Ot'<ur in thf'

o ccrn on a ce llular level? Pncloplasmi(' rp!i('ulum.
Phu.~e II rtactions <X.'<.ur in tlw c~imol.
Wha t factots affect drug Genetic- dilfPrt'll('t>S- Eadt iudi\idual has

biotnamfonna tion? 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<.
sy~lt' ll l-may
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
Arc the .-ale!> for drug bio- In gttwral. dru).(s \\ill he. iuacth at(d
Yl'!>.
ttamfonnation pre dictable? or hiotr;llhlimnl'd att'onling to ou< of
two gt'nf'r.ll dwllll\11'\ prindple\: firsl-
ordl'r and z<roordPr kimties.
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
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 zero-
order kinetics.
EXCRETION
What is excretion ? The process by which a drug or

metabolite is removed from the body
What is the difference Excretion is the removal of a drug from

between excaetion and the body.
secaetion ? 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 Renal-urine is one of the most common
of excaelioo? routes of elimination
Fecal
Respiration-primarily for anesthetic
gases and vapors
Breast milk
Skin
3 Pharmacodynamics
Define pha rmacodynamics. 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 The phanna<.-<>J..;nPtic processes of

related to phannacokinetics? 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 1. Ligand binding

flmctions of receplors? 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
Pharmaco-
kinetics
ELIMINATION
J
Pharmacologic effect
~iJ\.
Pharmaco-
dynamics
Toxicity Efficacy
Figure 3-1. The relationship between dose and effect can be separated into pharmaco-
kinetic (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).
Nicotinic
Receptors as
acetylcholine R G Protein-Coupled Receptor systems
Enzymes
Glutamate R
GABAA R
Glycine R
5HT3 serotonin R
Cell
Trans-
membrane
receptors Catalytic Activities G Proteins Effectors
Tyrosine kinases
Growth factor receptors Regulated by a subunits:
Cytoplasm Neurotrophic factor receptors
Tyrosine phosphatases t Adenylyl cyclase,
Serine/threonine kinases t Ca2+ currents
TBF~-receptor + Adenylyl cyclase,
Guanylyl cyclase t K+ currents
ANF receptor +Ca2 currents
Guanylin receptor t Phospholipase cp
Nucleus Cytosolic
+ Na+tw exchange
t cGMP
Regulation of
transcription
Steroids
Aetinoids ~
~
1~ ~
0
Receptor -phosphodiesterase
(vision)
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 Phar-
macological Basis o(Therapeutlcs, 9th ed. New York, McGraw-Hill. 1996, p 32. Used with
permission of The McGraw-Hill Companies.)
What are second messenger Second messenger systems allow signals

systems? from cell surface receptors to be
conve1ted and amplified into a cellular
response.
What are the three best- 1. Cyclic adenosine monophosphate

known second messenger (cAMP)-produced by adenylate
systems, and which enzyme cyclase
produces each of them? 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? A drug that, when bound t o a receptor,

prod uces 100% of the maximum po~sible
biologic response
'W hat a1e partial agonists? 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 It binds reversibly to the same active site
antagonis t do? of an enzyme as an agonist.
How can a compe titive By increasing the concentration of the

antagonis t be overcome? tbug (agonist). The maximum efficacy of
the drug w ill not change in the presence
of a competitive antagonist.
What does a n oncompetitive It binds irreversibly to a di!Terent site on

antagonist do? Lhe enzyme than the antagonist.
Noncompetitive agonists cannot be
overcome hy increasing concentrations of
the drug.
H ow will the maximwn Maxim um efficacy will be reduced in the

efficacy of a dr ug b e presence of a noncompetitive antagonist
affected by such (Figure 3- 3).
noncompe titive antagonists?
DOSE- RESPONSE RELATIONSHIPS
What is the difference Efficacy is the ability to produce a

b etween e fficacy a nd biologic effect. Potency is re lated to the
potency? 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

Drug with non-competitive antagonist

'I
Drug concentration
1
EC 50 for drug alone or
1
EC50 for drug in presence
in presence of non- of partial agonist
competitive antagonist
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. Uppin-
cott-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).
4 Drug Dosing and
Prescription Writing
DRUG DOSING
What tlwee factors :ue l. T)pe of infection or disease

involved in dete rmining an 2. Patient variables (l'.g.. weight. li\'t>r or
a ppmpriute drug dose for a lddney disease )
patie nt? :3. Plasma concentration needPd to
achieve efFicacy
What is volume of di~bi The 1pparenl volume into wl lich a drug is

bution (Vd)? nbk to distribu te
H ow is Vd calculated ? V,1 = total drug in the body 7 plasma

conc:cntration of the dwg
What is the significance of a Based on the equation prest?ntf'd above. a

large Vtl? 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 \laintenance dose = clearance X d(o',irt>cl

calculating a maintenance phl,ma concentration
dose?
What is important to You must be absolutely certain that the

tcmc mbc r in pe rforming u nits arc correct.
Ulis calculation?
What is a loading dose? 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
\Vbat ~ the equation for Loading clo!>e - Vd X desired plasma

calculating a loading dose? COllCl'lltration
Define peal.. and trough Thest arc maximum and minimum

concenlnllions. plasma conccutrations, respectively,
which are observed during dosing
intervals.
What variable affects these They will fluctuate around the steady-
concentnltion.'i? slate plasma concentration (C,.,.).
What i~> the ~teady-state The point at which the rate of drug
pla.o;ma concent ration? availability is equal to the rate of dmg
elimination
How doc!> frectuency of It will not change.

dosing affect the steady-
state concentration?
What factors will dosing Using smaller doses more frequcutly will
frequency affect? help miuimiz<> swin11;s in drug
concentration (i.e . maximum and
minimum phl.~ma concentrations). See
Figure I L.
How many half-lives arc Approximate!) ..t~ half-lives. At 3.3X,

requicclto reach steady- the half-life of the drug will reach 90% of
state conccnhation? its ciTec:livr ha.lf-life.
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.
PRESCRIPTION WRITING
Define the following abbreviations:
q en'')' hour
qhl> CWI)' night

Chapter 4 I Drug Dosing and Prescription Writing 19
~ Injection of Injection of
'2 2 U of drug 1 U of drug
:I 3
~
~ ~y ~00}
:e
.!.
.g 2
.a
.5
en
2
'g
B
0
c c
:I
0
E '-continuous infusion of 2 U of drug/day
< o~L----------------------------
i
1
0 2 3
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 sin-
gle body compartment and a t 1n of 12 hours.( Redrawn from Mycek MJ, Gertner SB, Per-
per 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

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 See Figure 4-2.

prescript:ion written? 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 l. Central nerYous system

the human ner vous syste m. 2. PeriphPral nervous system
What are the two sub divisions 1. Somatic ncrvoul. system, which
of th e perip heral n e rvous innervates skeletal mtL~cle
syste m? 2. Autonomic nervous system (ANS)
What is the a utonomic A collection of nuclei, cell bodi<>s, ncrves.

system?
llC I'VOU S ganglia. <uH1 plell.uses that provides
<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 l . Sympathetic nervous system

su bdivisions of th e ANS? 2. Parasrmpathetic nervous <;ystem
\VItal are the anat o mic Tlw :.ympatbetic n e n ous system

diffe rence!> be tween these originates in the thoracolumbar
two syste ms? 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

a.
0
:::J
S}11lpat.hetic Parasvmpathetic =
)>
Effector Organs" c:
Heceplor Response Rccf'ptor Response 8:::J
0
Eye 3
;:;
Radial muscle (iris) Ql Contraction (wydriasis)
Circular muscle (iris)
z
Contractio n (miosis) CD
Ciliary muscle ~2 Relaxation Contraction (accommodation) ~

Heart
...c:
SA node J. IIR ~
~I iHR ;;
A\' node ~I i eonduction velocity and automaticity J. conduction velocity 3
Contractility ~I i force of contraction (atria & ventricles) J. contractility (atria)
Lung
Bronchial muscle ~2 Relaxation (bronchodilation) M3 Contraction (hronchocomtriction)
Blood vessels
Most (except skeletal muscle) a, Constriction
Skeletal muscle 132 Relaxation
GI (Stomach and Intestine)
Sphincter o:, Constriction (retention ) ~ 13 Relaxation (defecation)
~1otility and tone 0:, 132 J. M3 imotilit) and tone
GU
Urinary sphincter Ctl Constriction M3 Rehtxation
Bladder wall 132 Relaxation (retention) MJ Contraction
Uterus, pregnant et1; 13z Contraction; relaxation
Uterus, nonpregnant 132 He laxation 5"
Penis, seminal vesicles
Secretory glands
('(! Ejaculation M E rection a
Q.
c
n
Sweat <X I Localized secretion M Generalized secretion 5
::l
Intestinal a2 Inhibition M3 i secretion 8
Bronchial M i secretion >
c
Lacrimal a i secretion (moderate) M Profuse secretion 8::l
0
Metabolism 3
i'i'
Adrenal med ulla NN Secretion of catecholamines
z
Kidney 131 i renin release '"~
Skeletal muscle 132 Glycogenolysis, i contractility c
Pancreas (beta cells) ('(2 ! insulin release "'
~
Fat cells 133 Lipolysis ~
3
The parasympathetics system controls most organs except blood vessels, which are regulated by the sympathetic nervous syste m.
N,. = nicotinic; M = muscarinic receptors ..
"
-:T
(Adapted from Gallia G, Hann CL, Hewson WH: The Phannacology Companion. Ann Arbor, Ml, Alert & Oriented Publishing Company. 1997. ) ..
3
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 The sympathetic nervous system is

sympathetic nervous system? 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 Adrenergic receptors-alpha-l (a 1),

docs the sympathetic alpha-2 (cx 2). beta-1 (j3 1), beta-2 (132 ), and
nervou ~ system work? dopamine recxptors (Table 5-l)
What are the actions of the The parasp11pathetic nervous S)stem is

parao.ympathctic syste m? 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 fiJ:'i
system is also known as tlte rest ~x,
and digest system.
\Vhat eccptors does the Cholinf'rgic receptors-muscarinic and

parasympathetic syste m HJ<.'otinic
act upo n ?
How arc the parasympath e tic Thc\e two S)Stt'ms oppose each other's
and sympa thetic sy~>'tems aclions. Tiernember that both S")"Stems
elated? 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 T he calcium ion (Ca2 +) is required for
release of these neurotrans- the release of most neurotransmitters
mitters from their storage from their storage \'esicles.
vesicles?
How do autonomic drugs At S drugs achieve their effects by acting

function? as either agonists or antagonists at
cholinergic and adrenergic receptors. The
following four chapters discuss each of
these drug classes in greater detail.
6 Cholinergic Agonists
What are choline rgic Cholinergic agonists are drugs that mimic
agonists? or potentiate the actions of acetylcholine.
What are the two major 1. Muscarinic-This receptor family

families of cholinergic ean1cd its name because it was first
teceptors? 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 1. Neuronal nicotinic (K , ), located in

nicotinic receptors. autonomic ganglia
2. Muscular uicot.inic (N~.1 ), 1ocated in
tlae nC'uromuscular junction
Whe re in the body are Prcg;tnglionic fibers of the autonomic

choline rgic r eceptors found? 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 post-
gangliunic sympathetic nervous ~ystcm
Se<> Figure 6-1.
What types of choline rgic Cholinergic agonisls t:an be divided into

agonists a e available for two major groups:
clinical use? 1. Direct-acting agonists chemically
hind with and activate muscarinic and
nicotinic receplors in the body.
28
Chapter 6 I Cholinergic Agonists 29
Autonomic Nervous System Somatic

Nervous System
Sympathetic innervation Sympathetic Paresympathetlc
$L of adrenal medulla
ii!IIWII*'I,-~~ ~
18'/"W~ Acetylcholine Acelylcholin&
I
(no gangha)
.g
Acetylcholine
iu- i!. ~

~N'~cotinlc

~ J<icotinio
l
Niootinic
receptor receptor
~oooptor
Adren~medulla
~t-
Epinephrine NOleptnephnne AcetylchOline Acetylcholine
{released
into lhe blood)
~
.... ....
~
receptor
~
receptor
~
receptor
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 rurect- l. Acetylcholine~prototype

acting agonists. 2. Bethanechol
3. Carbachol
4. Pilocarpine
5. Methacholine
6. Nicotine (discussed in Chapter 17-
CNS Stinwlants)
ACETYLCHOLINE
What are the physiologic Acetylcholine affects almost every system

actions of acetylcholine? 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 Bod1 muscarinic and nicotinic

acetylcholine activate?
What are the clinical Acetylcholine is used to achieve miosis

indications? 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 The adverse effects result from excessive
reactions? generalized cholinergic stimulation. They
include:
D iarrhea and decreased blood pressme
Urination
Miosis
Bronchoconshiction
Excitation of skeletal muscle
Lacrimation
Salivation and sweating
DUMBELS l'fM
\;X,
NOTE: These adverse effects are
typical of all direct and indirect
cholinergic agonists, not just
acetylcholine.
BETHANECHOL (Urecholine)
What type of chemical A carbamic acid ester

compound i'i bethanechol?
What receptors does it Bethancchol works primarily on

work 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 The adverse effects are those that rel.ult
of bethanccbol administra- from generalized cholinergic stimulation
tion? (sec above).
CARBACHOL
What type of compound is A cnrb<Lmic acid ester similar to

carbachol? 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 Roth muscarinic and nicotinic receptors

catbachol work on?
What are iL<> adverse effects? Those that result from excessive
generalized cholinergic stimulation
PILOCARPINE (Pilocar)
Wha t type of compound is An alkaloid

piloca.-pine?
What are pilocarpine's Causes miosis and contraction of thE'

physiologic actions? 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

estera~e? enzyme.
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 Primarily muscarinic receptors

cllug work o n?
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 Diagnosis of asthma and bronchial

fm? hyp<'ITCaclivity
Wba t receptoas does it M uscarinic receptors

stimula te?
Wha t me the a d verse effects? Cener:1lized cholinergic stimulation
INDIRECT-ACTING AGONISTS
Give s ix examples of indirect- l. rso flu rophatc

acting cho linergic agonists. 2. Echoth iophatl:'
3. Parathion
4. 0:drophoniu11t
5. Physostigmine
6. 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 cholin- Only lhc organophosphates

e tgic agonis ts have the (isollumphatc, eehothiophale, and
ability to irreversibly inhibit parathion) inevcrsibly inhibit
acetylcho lineste rase? acetylcholinesterase.
Why mc p h ysostigmine, Because they do not bind covalently to

ne ostig m ine, c drophonium, acet) kholinesterase
a nd pyrido~ligmine
considered to be eversible?
Chapter 6 f Cholinergic Agonists 33
ORGANOPHOSPHATES (ISOFLUROPHATE. ECHOTHIOPHATE,

PARATHION)
Describe the mech anism Organophosphates bind covalently to

of action. 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'
acetylcholinesterase.
Is it at all possible to re verse In mos t cases, no. However, if

the effects of organophos- pralidox.ime (a cholinesterase reactivator)
phates? 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 Organophosphates were used in wars as

for in the pa!!1:? 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 Isoflurophate and echothiophate are used

for today? occasionally for glaucorna aml
accommodative esotropia.
\>Vhat drug is used to treat Atropine is nsed, along with gastric lavage
organophosphate poisoning? and chmcoal
'W hat a1e the toxicities of the l:i:xcessive cholinergic stimulation

01ganophosphates?
PHYSOSTIGMINE
w hen is physostigmine For glaucoma- second-choice drug after

administered ? pilocarpi ne
For overdoses of atropine,
phenotbiazines, and tricyclic
antidepressants
For intestinal ;mel bowel atony
For accommodative esotropia (rarely)
Phosphorylation of Enzyme
Enzyme inactivated
Pralidox1me (PAM) can
remove the inhibitor
0
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 Illus-
trated Revrews: Phormocology, Znd ed. Philadelphia, Upptncon-Raven Publishers. 1997, p 43.)
Can physo!.1igmine entet the Yes, because it is a tertiaryamine

CNS?
State the advetse effects. Convulsions

Muscle paralysis secondary to
overstimulation
Cataracts
Generalized excessive cholinergic
stimulation
NEOSTIGMINE (Prostigmin)
Does this drug enter the No, because it is a polar quaternary

CNS? carbamate
Describe the tbempeutic Treatment of myasthenia gravis

uses. Treatment of urinary retention and
paralytic ileus
Antidote for nondepolarinzing
neuromuscular blockade such as with
tubocurarine
What is the duration of Usually 2 to 4 hours

action?
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 Very long-usually 3 to 6 hours

duration of action?
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

7 Cholinergic
Antagonists
What rue cholinergic Dnags that bind to cholinergic receptors

antagonists? (muscarinic and/or nicotinic), but do not
trigger the usual intracellular response
Name three subclasses of 1. Muscarinic blockers

choline rgic antagonists. 2. Neuromuscular blocking agents-
inhihit 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 l. Atropine (prototype)

muscarinic blockers. 2. Scopolamine
3. l lomatropine
4. Cydopentolate
5. Tropicamide
6. Pirenzcpinc
Arc there other drugs that Yes-these include tbe anti-Parkinson's

exhibit antimuscarinic drugs (e.g.. benztroplne), the anti-
properties? depressants (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 Atropint <.'Omes f1om the plant Atropa

does atropine belong? bellodmmn and is known as a belladonna
alkaloid.
37
38 Section II / Autonomic Nervous System
What is the signi6cance of Belladonna in Latin means pretty lady.

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

ism of action? blockadu of muscarinic receptors.
What agent can be used to High concentrations of acetylcholine or

counte .-act the effects of an equivalent muscarinic agonist
atropine?
Does this drug cross the :>Jo. Atropine docs not readily cross the
blood-brain barrier? blood-hrain barrier.
What arc the phannacologic CNS-At toxic doses can cause restless-
actions of atropine? ness, 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 Bradycardia

atropine. 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 Do not dilatE> the eyes of a patient who
to effect mydriasis and has narrow-angle glmu.:oma, because this
cycloplegia contraindicated ? mar result in an acute crisis due to
closure of the canal of Schlemm.
How long is a tropmes Approximately 4 hours, except when it is

duation of action ? placed in tlw eye. where it usually lasts
ahout 14 days
How is a tropine absorbed It is well absorhed from the

a nd excrete d? gastrointestinal syst<>m and conjunctival
membrane. It is cxcrctcd through both
hepatic metnholism a11d rclltll AJtralion.
What mc the toxic effects 1'oxic Eff ect: Mnemonic:

of this cltug? Dry mouth " 0 1y as a bone"
Inhibition of ~-weating, " I lot as a hare"
especially in young
childnm
Tachycardia and "Hed as a beet"
cutaneous
vasodilation
Blurring of vision "Blind as a baf'
Hallucinations <tlld " Mad a~ a hatter
delirium
l'fM
\;X,
SCOPOLAMINE
What is the classification of LikP atropine, thi~ tln1g b a belladonna

scopolamine? alkaloid.
What is its mechanism of Nonsclcctivt' <.ompetitive blockade of

a c tion ? 1nuscarini<.: rct'l'ptor\
PrevPntion of motion
How is scopolamine used
thc n1pc utically? sickness "lotio11 for nwtion"
l'fM
\;X,
H ow docs this drug diiTer or
1t has a longer duratioll a<.:tion and
from alm pine? more potent CNS efT<"cts.
\Vhat is scopolamines oute It is often ~iVP11 transdtrmally.

or administalion?
Are there any adverse Yes-similar to tho~c of atropinr:

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

for? 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
What are the adverse effects? Similar to those for alrCipinc
NEUROMUSCULAR BLOCKING AGENTS
Name the two major sub- L r\ondcpolarizing blocking agents

divisions of neuromuscular 2. Depolarizing blocking agents
agents.
NONDEPOLARIZING BLOCKING AGENTS
Name four nondepolarizing l. Tubocumriru.'-prototypc

agents. 2. Pancuronium- longer duration of
action than tubo<-urarinc
3. Atracurium
4. Vecuronium
~'hat is their mechanism of These drugs competitively block

action? cholinergic tmnsmission at the nicotinic
receptors by preventing the binding of
acetylcholine to its receptor.
What is the therapeutic use They are used as adjuvant drugs for
of these agents? anesthesia-they promote muscle
relaxation.
Are all muscles equally No. The muscles of the eye and lace are
affected? affected first, whereas the respiratory
muscles are affected last.
Chapter 7 f Cholinergic Antagonists 41
What is th e mute of All neuromuscular junction blockrrs must

administration? 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 r- Because neuromuscular junction blockers

act tbe effects of thes e drugs? are competitive inhibitors. tludr ad ions
can be reversed with edrophonium or
neostigmine.
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS
Nam e the only depolarizing Succinylcholine

ne uromuscular blocking
agent used in the Unite d
States.
What is this drug's mechan-

ism of action? 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 3 to 6 min utes if given as u single dose

aclion?
What substance metabolizes Plasma cholinestcr;L~e

succinylcholine?
How is succinylcholine used As an adjuvant to general anesthesia

clinically? 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 bypet- Dantrolene is used. It blocks the release

thennia beate d ? of Ca2 + fro m tbe sarcop lasmic re ticulu m,
,,~, ich subsequently reduces skeletal
musde contraction.
Chapter 7 I Cholinergic Antagonists 43
Do neuromuscular blocking ln general, no. The skeletal muscle end

agents block autonomic plate and autonomic ganglia use different
ganglia as weU? subtypes of nicotinic receptors.
Tubocurarine can, however, produce a
small amount of ganglionic blockade.
GANGLIONIC BLOCKERS
Name four ganglionic 1. Nicotine

blockers. 2. Hexamethonium
3. Mecamylamine
4. Trimethaphan
What exactly do these Ganglionic inhibitors compete with

drugs do? acetylcholine to bind with nicotinic
receptors of both parasympathetic and
sympathetic ganglia.
"Vhat is the mechanism of Ganglionic blockers can be divided into

action? 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 The physiologic effects of ganglionic

effects. 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)
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.
8 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 According to mechanism of aclion (direct

be classified ? vs indirect) a~ well as receptor site
specificity (a 1, a 2 13 1. 132)
Num e the impm-tant a sel- Pbeuylcphrinc

ective d ire ct-acting agonists. Methoxamine
Clonidinc
Melhyldopa
Ide ntify the major {l select- DobutnmiJte

ive direct-acting agonh-ts. Isoproterenol
Albuterol
Mctaprotcrcnol
Terbutaliue
List the major a and 13 direct- Epinephrine

acting agoois ts. Norepinephrine
Dopamine
Which of the direct-acting Epinephrine, norepinephrine.

agonists are conside red isoprotere nol, dop<lmine, and dobutamine
catecbolamines?
Nam e two indirect-acting Tyramine and amphetamine

adrene rgic agonis ts.
Name two mixed (direct and Ephedrine and metaraminol

indirect) ago n ists.
DIRECT-ACTING a SELECTIVE RECEPTOR AGONISTS
Where are a 1 and ~ a 1 receptors are located on the effector

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

to the CNS and blood \CSsels.
What physiologic responses a 1 stimulation leads to the re lease of

occur whe n <X receptors are intracellular calcium from the endo-
stimulate d? plasmic 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 5-
lutroductlon 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 a 1 rec:eptors- phenylcphrine and

agonists that are selective methoxamine
for o: 1- and ~-adrenergic o.2 receptors-clonidinc:- and methyldopa
receptors. (discussed in Chapter 20-Antihyper-
tensive Dnl{!.S)
PHENYLEPHRINE (Nco-Synephrine)
What are phenylephrine's Primarily vasoconstriction. The

physiologic actions? subsequent rise in blood pressure also
leads to a reflex bradycardia.
Describe this drug's thera- As a nasal decongestant (primary use)

peutic uses. 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 ~ -v ca++
inosltldes 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 = diacylglyc-

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

associated with phenyl- h) pcrt<.usi\( headache
e phrine administration?
METHOXAMINE
Whnt eccplos docs As with phcnylepl11inc, methoxamine is

methoxamine w01k on? 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 The ad\'(rsP PITects are similar to tlu~l' of

adver~c cfTcc~? ph en) lcphrine.
CLONIDINE
Clonidillt' is also cliseussed in Chapter 20-Aillihyperlellsiue Drugs.
What eccptMs does cloni- Clouidin<' sti mulates cx2 receptors in tlw
dine work on? 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 Sedation

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

located? posts)~1aptic membrane. (3 2 receptors an'
found 0 11 both the pre-m1d posls}1utpt ic
membranes.
What arc the physiologic (3 1 stimulation activates adenylate

esponses once (3 receptors c:yda~e. which oppns calcium channels,
me stimulated ? 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.
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 a-
adn.'ner~c reteptors do) ~te also Table
5 1 in Clwptrr.5-bllmdrU"Iiou to Auto-
rumric Ncrrou.~ Sy\tcru 1'/wnnnrology.
DOBUTAMINE
Wlm t is it ? A dopamine a n a lo~ue
What ece ptors d oes Prim<trily f3 1, bnt it clews havt' somv action
dohuta mine act o n ? un 132 receptors a$ wd l
What ~we the physiologic l nc:n.:ascd heart ratl' and t'tHltnwh li ty (J3 1)
c flccts of do buta mine? Smooth nu tsde rdil\lltion (132)
W h a t is d o h u ta mine's the r a- T reatment o f' un~tab l t (; II F and shock

p e utic usc?
Wh at is the route of a clmin- IV

isl mtion?
W h a t are this drug's adverse Arrh) thmias

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

the e ffects of iso poterenol?
What a 1e its physiologic Increase~ cardiovascula r inot ropiC' anrl

actions? 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 (13 2 )
In wh al cliJ1ical sit ua tions is Stimulatiou oflt<'<llt rate in patients
it app.-op riate to use io;op ro- suffcriug fro tn he;~rt blo(k aud
teenol? bradycardia
l n the past, ustd for trcatu1e11t of asthma
What is the route of admin- 1\

is lralion?
Wlmt arc the toxicities of \rrll)tlnnhL~

isoprote renol? Palpitations
Tachycardia
lleadadH'
ALBUTEROL, METAPROTERENOL, AND TERBUTALINE
What :uc the phannacologic Stimulatiutl of smooth muscle dil<ltatum

action'> of these ~ 2 direct- Can stimulate ~ 1 T("<eptors at hi~lwr
acting agonist<;? dose>s
What i~> the route of admin- Albuterol ami metaproterenol an' usuall)
is tratio n? 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 Arrh) thmitt.s

adverse e ffects of the ~ 2 Tachycardia
selecti ve clmgs? lleadachc
Nausea and vomiting
DIRECT-ACTING o: AND~ AGONISTS
EPINEPHRINE
Which receptors does It stimulates o:1, o:2 , ~ 1 , and ~ 2 receptors.

epinephrine act upon? At low doses epinephrine stimulates ~
receptors and at high doses it stimulates o:
receptors.
What are the physiologic Canliovuscular- increased heart rate ;\nd

responses to epinephrine? 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 Given for bronchospasm secondary to

uses? 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 Cardiac arrhythmias

adverse effects? Hypertension
Palpitations
Dizziness, am.iety, headache
Tre mor
Myocardial infarction due to increased
cardiac work
Pulmonary edema
To what does the term When epinephrine is administe red alone,

"epinephrine reversal" it will cause an increase in systemic blood
refer? 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 nor- a 1, a 2 , and 131 receptors. :-Jorepinephrine

epinephrine stimulate? has a stronger affinity for a receptors than
for J3 receptors.
What are its physiologic Vasoconstriction

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

treatment of shock.
What are norepinephrine's Tissue hypoxia secondary to potent

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

ganglia, and adrcuul medulla.
What receplos does a 1 13 1, and 132 It also stiu1ttlates its own

dopamine act on? 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 thera- Treatment of shock-it rruses blood

peutic uses? 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 Decreased renal perfusion at rugher

adverse effects? 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 Tyramine is taken up by sympathetic

action of tyramine? neurons, which causes a release of
catechohunines.
Is there a therapeutic use No

for tyramine?
Chapter 8 I Adrenergic Ago nlsts 53
h at are tyramine's adverse

\ \1 It can cause a hype rte nsive em ergency
cflects? 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 It releases stores of norepinephrine and

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

adm inister amphetamine? 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
How does ephedrine work? It stimulates the release or

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

therapeutic uses? urinary incontiJlcnt:e. bronchospasm, and
hypotension.
What are the adverse effects? 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 Treatment of hypotension and

uses? temtination of PAT episodes
What are the adverse effects? Similar to tho~e of norepinephrine

9 Adrenergic
Antagonists
What arc adrenergic They are dm~s that hind to adrenergic

antagonists? receptors hut do not mitiate the usual
intracellular response.
Name the two major sub- 1. a hloektrs

divisions of this drug class. 2. f3 blocklrs
Is there anothe r class of Yes- the indirect aurCIWrgic antagonists
adrenetgic antagonists?
a BLOCKERS
Name ~ix a blockets. .l. Pn\'losin ( Minip nss)- a 1-mlr<'nergic

sdcctivc. revcrsihle
2. Doxazosin (Canlu ra) a 1-atlrcncrgic
sp]pdi\p . 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 They eompetiti vdy and stll'l'livdy block

action? a 1-adrenergi< r<><tplor~.
Describe tJ1e physiologic Blockade ol' a 1 -adn:ncr~ic rtc:eplors on
sequelae of Ot 1 blockade. 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
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 Orally
a dmi n istc 1cd?
What is Lhe duration of Because it binili covalently to the

action? 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. Phenoxy-
benzaminc 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- Orthostatie hypotension

ciated with the use of phe- Reflex tachycardia- If severe, it may
noxyb enzamine? 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 Reversibly blocks a 1 and a 2 receptors

action.
How is this drug used Because it has a half-life of only 4 hours,

clinically? phentolamine is used for the short-term
control of pheochromocytoma-inch Iced
hypertension.
\\!hat i'> the route of Nor 1M-poorly absorbed omlly

administration?
What are the adverse Orthostat1c hypotens1on

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

classified? antagonists; however, they can be
subgrouped according to tlrrct major
properties:
l. Selectivity of receptor blockade
2. Pmstssion of intrinsi<:
'' mpathmnimeti<: adhity
3 Capacit) to block a-adrenPr~it
r<<rptor~
13 1 SELECTIVE BLOCKERS
Name fom selective 13 1 I. At1nolol (Tenormin)
blockers. 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 \Jo. At high doses these dmgs \\ill hlod.

absolute? 132 I"('C'<ptor<..
What is the main advantage Thest dmgs arP sometimes called
of 13 1 selectivity? 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 Atenuloi-Jl~lwrtension. myoc<udial
wananl t he usc of cardio infarction
selective ~ blockers? 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 non- Propranolol

seleclh e ~ blocker?
Name the pharmacologic Dcc.rtascd carclia< output and blood
actions of nonselective 13 pr<S\UJ'l'
blockc as. Reduct inn of sinns rate and eon duct ion
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
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 propran- The liver
olol's me tabolism?
In what clinical situations Hn>ertension
are non.<;electiYe ~ blockers Angina. tachycardia
indicated? Arrh)1:hmia
Thyroid storm
Acute panic syndrome
M igraine headache~
Name two other nonselective Timolol and nadoloi- T hey have

~-adrenergicantagoni.'its. extremely long half-lives (20 hours).
What is the clinical use of T reatment of glaucoma They decrease
these two drugs? the production of aqueous humor by the
ciliary body.
What arc the adverse effects Bradycardia
of nonselective ~ blockers? 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
~ BLOCKERS W ITH INTRINSIC SYMPATHOMIMETIC ACTIVITY
Name two drugs that are Acebutolol and pindolol

classified as ~ blocke rs but
also have some ~-agonistic
properties.
Why ae these drugs They very mildly sti mulate hoth 1) 1- and
conside red to be partial 132-adrenergic receptors. However, t heir
agonists? intrinsic effect's are not as strong as that
of a fuJJ agonist, such as isoproterenol.
'W hat a1c these two drugs T reatoacut of hypenen~ion in patients

use d for? prone to bradycardia
Are the re any advantages to Acebutolol and pindolol produce

using these agents? bronchoconstriction only at extremely
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 mechan- !'\ons<>INtive 13-hlcKkadc alcmg with
i~m of action? 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)
What is it? A 13 blocktr thut al~o has a 1-hlockin).';
propertits
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 contraindica- 13 blockers arc cuntraimlic:atld in the

tiuns to use? treatment of acutt C ll F. Tht} are only
used wlwn the pal itnt is hC? iilOdymun-
iC'ally stahl <'
132 SELECTIVE BLOCKERS
Butoxamine
What is it? t\ ~det'lh e (3 2-adrvmrgk anta~onist
Does lhh drug ha,e any No. not currently

clinical use?
NEW 13-BLOCKING DRUGS
Atc the re many other Yes. New 13 hlockE>rs art produced yearly.
13 blockers?
How d o these new dn.tgs Primarily in tht>1r pharmacokinetics
diffe r from the 13 blockers
discussed here?
How can physicians B) the -olol ending in their namt's

recognize the!te n ew drugs?
What are the indications Generally tlwy wilJ be simila r to those of

and adverse effects of the othf> r 13 blockers.
n ew 13 blockers?
INDIRECT ADRENERGIC ANTAGONISTS
Why are guanethidine and They do not directly block ex- or 13-
reserpine considered adrenergic receptors. They do, however,
indirect adrenergic antag- block the release of norepinephrine from
onists? nerve endings- in e ffect, they antagonize
the e ffects of the ~ympathctic system.
GUANETHIDINE (ISMELIN)
What is this drug's mechan- It enters the peripheral adrenergic ne rve

ism of action? by a reuptake mechanism for norepin-
ephrine and binds to storage vesicles, the
action of which subst>quently blocks the
release of stored norepinephrine.
Does guanethidine have a Yes-treatment of hypertension

clinical use?
What are the adverse effects? Orthostatic hypotPnsion and sexual

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

ism of action? cytoplasm into intracellular storage
vesicles. Subsequently, the ne uron is not
able to release any catccholamines.
How is this drug used For treating hyp<.rtcnsion (very rare ly

clinically? used)
What are the adverse effects? CNS depression and bradycardia

Section Ill Central Nervous
System
10 Introduction to
Central Nervous
System Pharmacology
Naune the m ujor CNS Atetyl<holiuP

n c urobansmitters. 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? .
Wha t a rc the primary To hind a rf'<Pplnr <llld .,uhscqtwntly

fun ctions of a oewotrans- cithl'r l''-C:ill' or 111hihit thl postsynaptic
rnitlc r? ll(;'llf()ll
Wh at arc EPSPs? E-.cilato.- pmh\ uaplic: potcntia].,_

inithLIPd "hen an l'\dtatOI) ncuro
I ran~nliltlr at'ti\ all'' '\,a orCa chan1wls
C h e fhe e xamples of 1. :\orcpllll'phrilw

excita tor-y neurobansmitters. 2. D opamine
3. Act-l\.kholinp
-i. Clut:tul.lte
5. Aspartalt>
What are lPSPs? Inhibitory posts),~<~ pi il.: potl'ntials-

iniliated wht>n an inhihilof\ ncuro-
transmiltrr opPns ddoridc~cl ~:ulnels und
the cell mvmhnuw lw<'onws h)1Wr-
pohuizcd. lPSPs utukt il111ore difReult
For the lll'llron to lwtouc atlivatcd
(l"igun> H)- I ).
C i\'e two examples of inhib- 1. Gly<.'int

it ory neurotransmitte rs. 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 thresh-
o 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 Most d rugs will allCd production,

affecting the CNS work? ~torag<, 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 differ- T here are three major di fferences:
e n ces b etween the a u tonomic L. The number of nPurotransmitters is
n crvou!t !tystem and the greater in the C S.
centntl n ervous system? 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.
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 Tachycardia

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

of drugs used to treat used drugs for anxiety
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 When henzodiazcpincs h10d to srwcific

work? 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 These dru~s are used clinically as muscle
indications for benzodiaz- relaxants and in the treatment of the
e pioes? 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 PO, lV, or IM

administration?
Where are benzodiaze pines They <tre n tetabolizcd in the liver and
metabolized? excreted in urine. Many of the
benzodiazepines have active metabolites.
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)
c 1
Chloride channel (closed)""-
+ "' ~ +
li'Wn'niMJH!~ c:r-----1 1lr1Mfrlrrnlf1'
~M~ U~~~~
I
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 Binding of GABA to its

cell making it more difficult receptor is enhanced by
to depolarize and therefore benzodiazepine, resulting
reduces neural excitability. 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,lip-
pmcott-Raven Publishers, 1997, p 91.)
70 Section Ill/ Central Nervous System
What type of symptoms may Drowsiness and con fusion-!he most

u patie nt taking benzodiaz- common sic.l< tff<cts
cpincs experien ce? Ataxia
Dizziness
Respiratory depnssion and ciPath, if
taken with otlu..'r C>.S depressant!>
such as <thmwl
BENZODIAZEPINE ANTAGONIST: FLUMAZENIL

(ROMAZICON)
What is Humazenil's mecha- Flumazenil (Romazi<-on) is a competitive

nism of action? antagoni~t
of bcnz()(.liaz!.!pincs at tl1e
GABAA rcctptor
.Desc.-ibe the clinical use of H(:'versal of benzodiazcpinc sC'datiou or

this drug. overdose
How long do the effects of Only l hour- Repeal doses may h<'
llumazenil last? 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 Buspironc is used for g<.ncr;t.lu.ld an.xiety;

for this drug? howe,er. unlikt' lwnzodiazt>pines. its
effects mav takt 2 \H'<-k~ to l><.'Comc
apparent.
Wbat are the pharmacokio- This dmg is metabolit.ed by tlw liver and
e lic properties of buspirone? excreted in the urine>; 1ts half-life is 2 to
11 hours.
How do the actions of Buspirone lac.:ks tht muscle> relaxw1t and

buspirone diller from those anticonvulsant propc:-rties of tlw benzo-
of the benzodiazepines? diazepincs.
What advantages does Minimal sedation

buspirone have over benzo- Low ahuse poteutial
dinzepioes? No overdose fatalitirs rl-porled
No withdrawal symptom~
What toxic e ffects are lleadache, nauSl'a, dizzine~~

associated with buspirone?
Chapter II I Anxiolytics. Hypnotics, and Sedatives 71
CARBAMATES: MEPROBAMATE
\Vhat is meprobamate's It is not wPII known.

mechanism of action?
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\.
What are the adverse effects? R<'spiratory tll"pr<ssion-major tm..ic

effPct
ll ypot('nsion
Shock
H l"art failure
BARBITURATES
G ive four examples of I. l'lwuobarh ital (Lu nli11al) - long-

barbitumtes. acting
2. Pcntuharuital ( rttnllutal)-short-
acling
:3. Amobarbital (Amytnl) short-at:ting
4. TltiopPntal ( Ptulotlwl)-ultrashorl-
a<: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 Induction or

till('\( lt(~i;i-1 hiopt'ntal
indications for barbiturate Antic-orwttlsant..-'.)1;.. ph<'nol>arbital
administration? Treatllll'llt of ;ulxicty
Induction of hypnosis
Why a re be nzodiazepines Henzodiazl'pilll's haw a nmch ltighl'r

favored over barbituratcs tht>rapt> ttlic- indt'x titan do barbiturates
liw the treatment of anxiety? (Figwc 11-2).
By what routes can baabitu- IV, PO, or IM

rates be adminh1:ered ?
What are the phannaco- They arc ntctaholizld in the liver and
kinc tic ptoperties of barbi- excreted in the 11rin<>.
turates?
72 Section Ill I Central Nervous System
Barbiturates, alcohol
,
,,
Coma
,,,
Medullary depression,''
,
I
,, - - - - - Benzodiazepines
Anesthesia I
Sedation, anxiolysis
Increasing d o s e -
Figure I 1-2. Comparison of dose-response relationships of benzodiazepines and barbi-

turates.(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 RPdis~ribution to the other ti.o;..~uPs

dumtion of action of thio-
pental?
Does btubiturale depend- Yf's-abn1pt cessation can lead to severe

ency occur? witltdrawal symptoms (tremor, restless-
ness, nausea, seizures, and cardiac aJTcst).
For whom ae barbiturates For patients who have acute intcnnitlrnt

conbRindicatcd? porphyria, because they increase porphy-
rin synthesis
What ore the adverse e ffects Drowsiness and decreased motor control
of these drugs? 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 Treatment of insomnia

use.
Chapter I I I Anxiolytics. Hypnotics. and Sedatives 73
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 Gastrointestinal clistrt'ss

effects. Uupleasant taste
12 Anti psychotics
What are antipsychotic Antipsythoti<s aho J..nown a' lll'llro-

drug~? leptics. an dru~' uscd primarih to tn'at
P')'dtolk ~l<llt'' \neh as sdti..:ophreni<t
delll~ion;tl cli,ordtr ami otlwr hallu<:ina-
ton stat<s.
What b. their mechanism of Atllipsychntil'' hlocJ.. 'ariom nc-tptors

action? including cholincrgic-, adremrgil. sero-
toninc>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 nwso-
limhal systtms or tlu brain.
Do antipsychotic agents YPs-u drug's pntC'nl: pamllc], its :~!Tinily
dilfe in potency? for D 2 rt'L't>ptor\ llaloptridol amlthio-
thi'.t'lll' <tre ltigh-potl'lll'\ dntgs lxl'au~e
the~ haw high aflinit\ li>1 tlw D2 rcc't'p-
tor-.. "lwna' dclorprom;I/IIW and thio-
ridazim 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 'o! Tht traditional antp,)<'holk' an all

c fficac\? ('<111\idtnd to lw t'<(lll\ altnt 111 dlieaty.
How are antipsychotics In 1110\1 t~l\l'' tlw"' drug' an gt\C'II orally:

us ually administered? thf') t'<lll I><' giqu tntralllltstulad, il' tlw
patiPnl is noneompliant.
Dcscdbc the abs01-ption Tltev an variahh ahsorlwd orally but thev

and me taboli.~ m of the l.-a- pas;i cclo tlw bn;incasily :ttl(] haw a largt:
clitional antip~ycboHcs. 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? 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.
14
Chapter 12/ Antipsychotics 75
Can these drugs cure ill- Nol Antipsychotics only reduce the
nesses such as schizophrenia? symptoms of tlw illness; they cannot cure
the illness.
How are the antipsycbotics Classification is based on structural

cla!isified ? differences The major classes include
phenothiazines, hutyrophcnoncs, diben-
zoxazepines, thioxanthines, and benzi-
soxazolcs.
TRADITIONAL ANTI PSYCHOTICS
PHENOTHIAZINES
What are some examples of Chlorpromazine (Thorazine )-prototype

phe nothiazines? f luphenazine (Prolixin)
TriOuoperazine (Stclazinc)
Thioridazine (Mellaril)
Perphenaziuc (Trilafon)
What distinctive side etiects Pigmentary retinopathy

docs thioddazine cause? May cause cardiac arrhythmias and con-
duction block
BUTYROPHENONES
Name two drugs in this cla!is. Haloperidol (Haldol)

Droperidol (lnapsine)
Other than psychotic sta tes, Tourette s syndromE'

for what can haloperidol be Huntington\ disease
used? Phencyclidine overdose-drug of choice
What type of side effect is Extrapyramidal side efTeels(~ common

esp ecially ponounced with board question )
halope-idol?
DIBENZOXAZEPINES
Name a drug that belongs Loxapine (Loxitane)

to this class.
THIOXANTHENES
Name a drug that belongs Thiothixene (Navane)

to this class.
76 Section Ill I Central N ervous System
CLINICAL USES AND SIDE EFFECTS
What arc the c linical appli- Traditional neuroleptics havp sPvPml

cations of tr aditional a nti- tlwra1wutk uses. but the most important
psycho tic agents? 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 syndronw-
l talopvridol
T rt>a l ment of' iutraetahle hic:cnps-
cllorprom:~t.i 11c
Antipruritit therapy-prometl raziue
( lwcau~t of histamiue blockadP)
\Vha r , a n en'~ way to With a fc\\ c\ecptions. all ofthc tradi-

rc mc mbc t the <;ide cffecb. tional anlipsychotk~ haw similar
of the tra ditional antipsy- lo\ldtits namelv, sedation. extra-
chotil-~? pyramidal ellecb: anticholincr1-,ril' cfltC'Is.
and et-adrener11;i<: effects ( hyputcn~ion).
Do nil tmditiona l antipsy- or

No. T it(' S('Vt>riry each adverse effect
chotics p toduce the sam e varics ~1111011~ 1lit' classes of ttntipsydwtit
degree of each type of side dn1~s. fo'or txamplc. high-potPncy drugs
effect? 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 CNS I!Cdalion-Mc.n nuukedl) with the

lmditio nul a ntipsychotic phcllothia7ines
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
Table 12-1. Neuroleptic Drug Side-Effect Profiles
Side EfTects
Extrapyramidal Antichonlincrgic a -Aclrenergie
Potency Drug Sedation Effects Effects Efl'ects
HfCH Haloperidol 1 4 1 1
Fluphenazine 1 4 2 1
Thiothixene 2 3 2
Trifluoperazine 2 3 2 1
Loxapine 2 2 2 2
Chlorproma7Jne 4 2 3 4
LOW Thioridazine 4 1 4 4
*l = low, 4 = high
.....
.....
78 Section Il l / Central Nervous System
Anliadrcne rgic effects-watch for

light-headcdness and orthostatic
hypotension ~econdary to a-
adrenergic 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 There is no known treatment for

reversible? 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

nant syndro m e? long-term treatment may ex-perience
rigidity. altered mental status, cardiac
arrh)'t.hmias, hypertension, and life-
threatening h)perpyrexia.
What is the t.heapy for This disorder is treated with dantrolcnc, a

ne urole ptic malignant skeletal musc:le relaxant (~ commo n
syndrome? board question).
ATYPICAL ANTIPSYCHOTIC DRUGS
Nume three examples of 1. Clo7.apine (Cio7.aril)

atypical antipsychotic drugs. 2. Risperidone (Risperdal)
3. Olanzapine (Z)'prexa)
Chapter 12 I Antipsychotics 79
Why a' tltese drugs In addition to bloddng dopmnine

considered ~atypical"? 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 This a!-(Cilt is a clibenzodiazepine
cl en:~ pi nc. ckrivativt. It eliff'er~ from traditional
antip~ychotics in its potent blockade of'
~crotonin (.'5- IIT2 ) receptors <\long with
the usual dopamine blockade.
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 Risperidone (Risperdal) is a henzisoxazole
rispet;done. 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 Like risperidone and clozapine, olanza-
olanzapinc. pine blocks both dopamine and serotonin
receptors. Effective in the treatment of
schizophrenia, it can produce anticholin-
ergic effects as well as sedation and ortho-
static hypotension.
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 That dcpr<"~sion b dm to a th: ndtnq of

a mine lhe<ny of d epession uo r('pinepltrint, serotonin, ami dopUIIlillt'
propose? in thf' synap~f'S of tlw C'JS.
List the maj01 categories of Tricn:lics

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

now <.-on~ideed fttst-line Atypk-al antidtpr<'\\anl\
hcatment for d epression ?
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 81
What are the physiologic The secondmy amine tricyclics in general

differences b etween tertiary are less lihlv to cause sedation. hvpu-
amine and secondary amine tension. an(!' anticholine rgic effects.
tricyclic.<>? However, they are more likely lo induce
psychosis.
What is the mechanio;m of These drngs are though t to incrP<.LSe lc,vds

action of all the tricyclics? of norepinephrine and serotonin in the
synaptic cleft hy blocking neuron;tl
re\lptakP. They abo Llock h istamine. cho-
lilwrgic, 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
or
Cor some Iheir therapeutic henefit.
Do these drugs elevate No. These d rugs are nol CNS stimulants.
mood in normal individuals?
What are the clinical Mood dis<mlcrs (depression primarily)

indications for bicyclics? 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 admin- They <ue well absorbed orally, <lnd
iste re d? penetrate into the CNS easily.
How a1e these drugs They w1 dergo signific;mt firs t-pass

metabolized ? metabolism in the liver; t hey are con-
jugated witl1 glucmonic acid and excreted
through the lddneys.
Which of the bicyclic.o; a1e All arc C<.jually efficadous.

mos t efficacious?
When should: a physician Altho ugh tlie uptako n Jcchaoism is

e-"llect to see a change in inhibited al most immediately, anti-
the patient's mood? depressant 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 Anticholinergic ~illt ciTet'ls-hlurred

symptom.~ <>f tricyclic vision, hot dry skin, t'(mstipation,
toxicity? 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 No! There is a chane<' that this combi-
be given together for added nation can lead to sevNe convulsions and
benefit? t'()ma.
SEROTONIN-SPECIFIC REUPTAKE INHIBITORS (SSRIS)
Give some examples of SSRis. Fluoxetine (Pro7..ac)-prototype

SertraJine (Zoloft)
Paroxetinc ( Paxi l)
Fluvoxaminc ( Luvox)
What is their mecbani~m of Inhibition of serotonin reuptake \vithout

action? significant eiTects on norcpinPphrine and
dopamine
When would these drugs be Depre~sion is the primal) reason for

indicated? 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 In general SSR ls have f<wcr sidt- effects

pro6le of SSRis. (anticholinergic, antih istaminic, a-
adrenergic b lockade') than d() oth er
classes o f' antidepressants.
What adverse symptoms Nausea

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

indicated? thcntpy with monoamine oxidase
inhibitors ( MAOIs) because this combi-
nation may result in the ..serotonin
syntlrome," characterized by hypcr-
thc 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 catechol-
amine m>urotransmjtters.
Where are the highest con- In the Liver, GI tract, and C:r\S
centrations of this enzyme?
Descibe the mechanism of Two types of MAO exist: MAO-A and

action of the MAOIs. 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 Treatment of atypical depression (with

indicate d for? phobm or psychotic features). Other
classes of antidepressants are more
frequently used today because they have
fewer toxic effects.
D escribe the pharmacologic They arc well absorbed orally.

prope rties of MAOIs. 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 Hypertensi\'e crisis (headache, hyper-

ofMAOb? tension, arrh)'thmias, and possibly
stroke) if the patient does not avoid

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A ZUNG

PRINC IPLES OF PHARMACOLOGY

II AUT ONOMIC NERVOUS SYSTEM

5 Introduction to Autonomic Nervous System Pharmacology 23

Ill C EN T RAL NERVOUS SYSTEM

I0 Introduction to Central Nervous System Pharmacology . . . . . . . . . 65

20 Antihypertensive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

28 Drugs Used to Treat Asthma. Coughs. and Colds 0 0 0 0 0 0 0 0 0 0 0 0 0 0 20 I

29 Hypothalamic and Pituitary Hormones 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 21 I

VII MUSCULOSKELETAL SYSTEM

35 Anti-inflammatory Drugs and Acetaminophen 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 247

VIII GASTROINTESTINAL SYSTEM

38 Drugs Used to Treat Gastrointestinal Disorders 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 267

39 Antineoplastic Drugs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 277

40 Introduction to Antimicrobial Drugs 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 293

XII PHARMACOLOGY POWER REVIEW

52 Pharmacology Power Review o o o 0 0 o 0 0 0 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 397

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

What is pharmacology? The study of the interaction between

What is a drug? A drug is broadly defined as any chemical

Name and define the fom 1. Pharmacokinclics--<lescribes "what

For each of the following

-azine phenothiazine-like anti psychotics (e.g.,

-ane volatile general anesthetics (e.g.,

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

-hi tal barbiturate sedative hypuotic drugs (e.g..

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

-ciiJin penicillins (e.g.. nafcillin)

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

-olol 13-blockers (e.g.. propranolol)

-opril ACE inhibitor1. (<-.g. captopril)

-slatin IIMG-CoA reductase inhibitors (e.g.,

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

Do I need to know every 1\o. However, it is absolutely critical that

Define pharmacokinetics. Pharmacokint'lic~ deS<:ribcs actions of

De fine absorption. Absorption i~ the rate at which and e~'tent

What does the rate and Route of administration Tlw

Define bioavailability. 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 bio- 1. First-pass mctaboli~m

When pH= pKa

When pH is less than pKa. When pH is greater than pKa.

What factors affect bio- I. First-pas~ metabolism

\Vhat arc the ro utes of drug Alinapntaa)'

Name the fo ur pare nteral I. I ntravenons--dircct inject ion into tht

What category of drugs is Pulmonary agents

How are inhaled drugs By machine aerosolization or vaporization

When is topical Usually for treatment of localized disease

When is lransdermal For sustained release of a drug-for

Define distribution. The process by which a drug leaves the

By what three bioche mical l. Pass ive diffus ion-governed by a

What does distribution Blood Oow

of capillaries varies depending on the

What happens in a phase I Lipophilic molecules are converted into

What types of phase I Oxidation, reduction (dehydrogenation),

What happens in phase n Formation of a covalent linkage between

Specifically, what substrates Glucuronate-Quantitatively, addition of

In what organ do phase I and Primarily in tl1e liver

Whcte do these r e action Pha.~P I reactions Ot'<ur in thf'

Wha t factots affect drug Genetic- dilfPrt'll('t>S- Eadt iudi\idual has

De fine fint-orde r kine tics. Prcx.'t'ss h) \\ hid a t~mstant J'<'R't' nlag.>

D e!>cdbe ze to-orde r kinetics. PrO(e~s hy '' hith a tmtstnnl tlll10IIllt of