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4TH
GaIT C.
ProfesSor
Department
.md
COLOGY
1'11.0.
Integra tin> Biology nd Pharmacology
Graduate s . : h+o. of Biomedical Scie,c{'s
i\ssl stanl for Education Programs
Medical School at Houston
Dm'i d Loose, 1'11.0.
Associate ""'1"'"'
Department . Integrated [l iology and Pharmacology
ilnd
Graduat(' Seh,,101 of Biomedical SciellCl's
of Medical School . .It Iioustoll
I
With sp,celat contributions by
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Will iam
Royal Oak,
Todd \.
William
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.\J.D., 1'11.1).
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Third Edition,
Library of Cataloging-In-Puhlication Data
Rosenfeld, Ga ry C.
Pharmacology /
Kushell, Todd A.
p. ;
Includes index.
ISfiN-13:
Loose, David .
C. Rosenfeld, Dav d S. Loose; with special contributions by Medina
I. ted.
(alk. paper) I. Pharmacology-Examinations, questions, etc. l.
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This conci se
and others
for !
tiuns of
the mual
lati on of
e to the Fourth Edition
of medical pharmacology is designed for medi cal students, dental students.
health care professions. It is intended primarily to help students prepare
such as the Un ited States Medical Licensing Examination Step 1
examinations. This book presents condensed and succinct descrip-
and current BoorddJi ven i nformation pertaining to pharmacology without
-j details. 11 is not rneant to be a for the comprehensive presen
and difficult (oncepts found in standard pharmacology l{?xtS.
The fourth - ion begins with a chap: er devoted to the general principles of action, fol-
lowed concerned with dLlgs acting on the maj or body systems. Other chapters
discuss a " ergots, antiinflamnatory and Immunosuppressive agents, drugs used to
treat anemias disorders of hemos asis, infeCl ious diseases, ca nccr. and tOXicology.
Each indudes a presentali)n of specific drugs with a discussion of their general
propert ies, n ism of action, pharmacologic effects, thcrapeutic uses, and ad,'crsc effects.
A drug li sl, and figures surnmaTizc essential drug information included in all chapters,
Clinical ly USMLEstyle rfview questions and answers with cxplanations follow
each chapter help st udents assess their understa nding of the information, Similarl y, a com
prehen:.i,"e comisting of USMLE-stylc questi ons is included at the end of the
book. serve. as a self-a.\scssment tool to help determine their fund
of knowledge diagnose any weakr esses in pharmacology.
current drug infurmat ic'il
review tests feat ure updatr.-d questions
2colo! ""'"" summarize (sscntial lnformation for qukk recall
Drug !iSH
Addiltonal comprehellSi\-e examination questions and explanatIons
Gary C. Rosl'lI{,eld, PII.o.
Dm'ill S. i (K)\C, Pl!.lJ.
v
Acknowledgments
The aullmrs a ' knowledge and thank our for their .'IUppor! allll contributions to
thi s boo!.. and our medical students fo)r being OUf hars hest
vii
Contents
Preface v
Acknowledgn cnts vii
1 Gener I Principles of [)rug Action ......... . . .. . .. . . . . .. 1
I. D( se-Response Relation ;hips 1
II . 0 g Absorption 6
III . Dr g Dist ribution 9
IV. Dr g Elimi nation and Tt' rmi nat ion of Action 10
V. Bl )tramformal ion (Met,bolism) of Drugs 11
VI. E --ret lon of Drug.. \.;
VII . P rmacokinct in. 16
Re , iew cs t 19
2 Drugs cting on the Autonomic Nervous System .... 25
I. TI Peripheral Efferent Nervous System 2S
II . Pa asympat homimetit: Crug.. 10
III . :V1 scari ni c Receptor Antagonists .15
IV. G< nglionic-Blocking On. gs 3 7
V. Sk 'leta! Muscle Relaxanl'i 37
VI . Sy npathomimetic 42
VII . A energic Ikceptor Antlgonhls 47
Review r e:<ol 53
3 Drugs cling on the System ................ . . ... 60
I. Oi retics 60
II . N ndiuretic Inhi bi tors o Tubular Transpurt 66
Review cst 69
Drugs cting on the Cardiovascular System . . . . . .. . ... 73
I. ' nh Used to Treat Congestive Ileart J:ailure (CHF) 73
II . AI Dmgs 79
III. A ia ngi nal Agenh 81
IV. A ihypertcnsin' 86
v. Dr Igs that Lower Plasma Li pids 92
Review est 96
ix
X
5 Drugs
on the Central Nervous System .......... 101
I.
.. Drugs 101
II. .. (Neuroleptic) Drugs 106
III. Drugs ItO
IV. I1 S
V. Analgesics dnd Ant,lgonists L 16
VI . Drugs and Drugs Used to Treat Alzhdnll' r's Dise<lSl' 123
VII . 12.
VIII . 1JO
IX. ns
X. 117
Review 148
6 Ergots, Antiinflammatory Agents,
and Apnts IS3
I. and Anti histamines 153
II. and Seroto nin A ltagonists 157
Ill. 1 S9
IV.
V.
VI.
VII .
161
Antiinflammatory Drugs (:-.JSAIDs) 164
Used for Gout 171
VIII .
Imnilm''''' PI'''''''''' Agent -, 172
177
7 u,eo in Anemia and Disorders of Hemostasis .... 180
Used in the Treat me It of ISO
Act ing o n \-fyelo id (ells 184
III. USN in Hemostat ic )iso rders 184
Review 192
8 Drugs
on the Gast rointestinaJ Tract ........... 197
I. and Ant iemet ics 197
II . and Appet it" En hancers 199
III. f or Upper Gas :rointestinai !"ract 200
IV. Agents 205
V. Used to Disso lve Gallstones 20:5
VI.
VII .
Enzyme Hepl acements 20:5
A that Act on the LmH'r Gast rointestinal Tract 206
Review 210
9 Drugs
on the Pulmonary System ............... 214
I. 10 to Pulmonary l)isorders 2 14
II. Used to Treat Asthma and Other Bronchial I)isorders 21 S
III. Used to Treat Rhi nit S and Cough 220
Re view 223
10 Drugs
on the Endoc;rine System ................ 225
I. Recepto<s 22:
II. The 225
Ill. The.
IV. Th('
229
, Pituitary :!31
c ot\, F. :,\'TS xi
V.
!rugs Acting on the G'Jnadai and Reproductive Sys tem 232
VI . h e Adrenal Cortex 2-11
VII. he Thyroid 245
VIII. - he Pancreas and GlueJsc 2-1 7
IX. he Calcium Ho meost.lt ic System 252
x. I eti noie Aci d and Deri ' ati ves 256
Revie Test 260
11 Dru Used in Treatm.ent of Infectious Diseases ... . .... 262
I. l l fcc tioLLS Di sease Tht' lapy 262
II. ntibacterials 263
III . . ntimycobacterial Age1b 276
IV. f nti fungal Agent s
v. ntiparasit ic Drugs 282
VI. I nti viral Drugs 2R6
Rcvie Test 293
12 Cane r Chemotherapy ........................... . .... 298
I. r rinciples of Cancer Chemotherapy 29S
II . lkylat ing Agents 299
III . t nt imetabolites 30:;
IV. atural l'rodm1s 1[6
V. I iscellaneous Agents 308
VI . . ewid Hormones and 4..ntagonists and Rel at ed Drugs 3 t 1
VIT. d junct Agents 313
Revie ' Test 315
13 'foxi logy . . . . ................... . ..... . . . . . . .. ..... 320
I. I inci ples ami Tl'rminology 320
II , ir Pollutanb 322
III . S )Ivents 324
IV. J lsec ticides and lIerbi Cldes 324
V. F Jlll igants and Rodenticides .326
VI . r avy Metal POisoning and Ma nagrml' nt
VII. l rug Poison ing 330
Revic Test 333
Com rehensive Exami nation ............... , .. . . . .. . . 335
lode .. ... .... ..... .. . . .. . . . . 353
I
)
I
General Principles
of Drug Action
Relati onships
.\ (' fh 1\ are producl'd by alteJing t he normal funclions of and in t he body
via orl\' of fou general mechanisms:
I. /1111'1 <14 i OIl IIi'" rn, p/on, n,lturally occurring target th,lt mediate th'
cffe('l s )f endogenous physiolo!,iC suu)tanoc's such as neurotrallSmitters and
a. figu e 1-1 illustrat t:'s the four majm ela s)e) of drug-receptor intl' TKtions. using specific
cxar lples of endogenous li gands.
(1) .iga nd-acti\'atcd ion dlannels. Figure J-IA illustrat es aC{,I)' lcholi ne interacting
ilh a n icotinic receptor ttlat b a nonspecific Na' (K' tr<lmmembranc ion channt'!.
teract ion of a moltlllie :If acetylcholine wit h each subunit of Ihe channel produces
conformational change that permits the passage of Na' and K'. Ot her ch,mnels that
re targets for include SpKifK Cab and K chan neb.
(2) ;-pro l cin--<oupled rcctplOrs (Fig. l -I B- lJ). G-protcitl-(: oll pled reu!ptors com
ose the largest of receptors. The receptors al l have 7 tra nsmembrane scg-
lents, 3 intracellular 10Jps, and an intracellul,H tarboxy-terminal tail. The bio-
glc activit} of the r{'('ertors is rnaliated via interaction with a number o f G (GTP
I inding)-proteins .
1) Ga,-coupled receptors. Figure I-IB il lustrat es a B-adn.': IH.Kef)Wr, which when
<Ktivated h} ligand linding (e,g., epi nephrine) eXChanges GDP for GTI'. Thi s
the migrat on of Get., (Gu,"m"l"'o,,) and its int eraction with adenylyl
t}"dase rAC). Cru.,-bound AC the pnxh,il"lion of cAMl' from ATP; cAMP
activates protein kin;.se 1\ , whirh acts to phosphorylate and acti-
vate a number of effe ctor proteins. The [iy dimer may also :Ktivate some efte<:-
Hydrolysis of GTP bound to the Go. to GOP terminates the signal.
) GOI
I
(G1nhobowr,)-i.:ouplet.l rt'Ccptors (Fig. I- IC). Ligand binding (e.g., somat ostatin),
to Gu; (Ga,nIub,,,,,, )<Ol pl ed ft'(eptors, simi larly .\(hangt'!> G'I I' for li DI', but Go,
adenylyl ere asc, leading to reduced cAMl' prOOuftion.
{-l (and GIl)-coupletl ft'ceptors (Fig. 1-1.D). (and G,,) int eract with ligand
(e .g., serotonin )-,Kti " ated recept ors and increa se the 3cth ity of phospholi -
pa'ie C (PLC). PLe: cI 'aves the membrane phosphOlipid phosphatidylinmitol
(Pil l) to diacylglycerol (DAG) and inositoll,4,S-triphosphate
(II'; ). lJAG protein kinase C. which can subsequently phosphoryl ate
and acti\aie a n umb. 'f of cellula r prot eins; II'. cau'ies the release of Ca
2
from
the endoplasmic ret iculum int o the cyt oplasm, where it can activat e many
cellular processes.
B
o
c
Figure 1-1 Four m,liar
A. Acetylcholine i
[l'Captors. B. Epinephrine
(G",h,b<,C<"J-<..'oupil'd
ATP cAMP
ACh nicotinic receptor
-Ion channel
Na+ Acetylcholine
Epi lephrine
l5-adrenoreceptor coupled to Gas
Somatostatin
ATP
cAMP _ PKA
/\
Multiple cellular
effects
Somatostatin receptor
coupled to Gaj
Serotonin receptor
coupled to G
q
P1P2f'\
IP, +DAG
/ \
Ca
2
+ Activates
PKe
of drug-I('n:'ptor inter.Ktiam, with specific examples of l'mlog<.'num ligillids.
with a nilOtinic [('(cpIO! , I ligand-activated ion channel. IJ-O. (jprotdn ...... uupll'd
i Witll a GCI.,-coupled p-<1drenoceptur. C. jTlIl'[J(liOrl with J G()'
Serotonin interaction wLh a G" (and Gil l-coupled receptor. (Colltinucd)
\
,liuta.
,
""
""
G
\
:tlVates
PKe
E
I utin receptor
00
y y
F
HSP90 !
o A
I'RI",C!l' L1'5 OF DRU( , Acno:'\ 3
Ins Jlin receptor-activated tyrOSlr'le
kinase activity
Insulin
C>
po,
00 po,
y y
IRS f\
IRS - P0
4
\
PI3 K
\
AKT
I \
:Orlisol actIVatIOn of
9 ucocor1lcold receptor
0
Cortisol
:
\
"{
\
e
HSP90
Pol II
:
CoA
NA NA
Transcription
figure 1 1 t(, "imlt'n) E. In\ulin inlf'ral"ti. )11 with a trniUl' l in,IS('. F. COIIJ'101 interact ion
"ith an In\ .3r.'1 lar nudear R'O"pLor_
(3) ccptor-acthated t yrm inc l;:inaSel> (Fig. I- I E). Many growth-rt'l ated si gnal s
.g .. are mediated via m<;, mbr;mi..' rCCCplor\ that int ri nsi c tyrosine
nasI" acthLty iIIusl ral('d f{) r the renptor. Liga nd hi nding CillN'S confor-
t al ional changes in the n ccpt or; '>OfHe fl-'('eptor tyrosi m,' l,:inascs arc rnOllOmE'r:'> that
mcrilt> upon ligand hilK ing. The liga ndl-d recepto rs then aut ophosphorylatt> tyro-
4 URS
(4)
sine which recruits cytoplasmiC proteim to the plasma membrane where
aho tyrosine phosphor.dated and aClh'aled.
'n''''''t'",,, nudear receptor.; (Fig. l - lF). (e.g .. corliwl) for nuclear recep-
lipophilic and can diffuse rapidly IhrouRh the plasma membrane. In Ihe
of ligand. nuclear receptors are inaClh'e bccau\(' o f t heir inl eranion ,,-Uh
proteins such as heal -shock pro tei ns like IISP-90. Binding of ligand pro-
changes in the receptor t hai facili late of chaperones.
receptors in lo the nuclt-us, hetcfo- or homodilllt'li l Jtion of receptor" . md