GOODMAN and OILMAN' S
`GOODMAN and GILMAN's
`The
`The
`Pharmacological
`Pharmacological
`Basis of
`Basis of
`Therapeutics
`Therapeutics
`
`i
`
`S E V E N T H
`SEVENTH
`
`E D I T I O N
`T I ON
`EDI
`
`M A C M I L L A N P U B L I S H I N G C O M P A N Y
`MACMILLAN PUBLISHING COMPANY
`New York
`Near York
`C O L L I E R M A C M I L L A N C A N A D A , I N C .
`COLLIER MACMILLAN CANADA, INC.
`Toronto
`loronto
`C O L L I E R M A C M I L L A N P U B L I S H E R S
`COLLIER MACMILLAN PUBLISHERS
`London
`London
`
`MYLAN - EXHIBIT 1022
`
`

`

`nd G
`d
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`his work
`his wori(
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`xicology,
`updating
`. updating
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`the addit
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`same the
`and aul
`and aui
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`bjectives
`bjectives
`ghout.
`ghout. A:
`1) the CC
`1) the cc
`medical
`medical
`ions and
`tions and
`nportant ;
`nportant;
`of empl
`I of empl
`lamics to
`iamics to
`xt has bei
`xt has bei
`Ey of the
`ly of the
`be,
`have
`have be
`past five
`past five
`both ba
`i both ba
`that knoN
`that kno\
`or thorn
`• or thoro
`1 blockers
`1 blockers
`perlipop:
`.'perlipop
`ctive peps
`ctive pepl
`dins and
`dins and
`antihy
`is, antih>
`its, drugs
`its, drugs
`crobial
`crobial a)
`substitu
`is substitu
`ition sub
`ition sull
`gents, al
`gents, ai
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`ission of i
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`sign of di
`
`(Cod
`
`Ilan Publis
`illan Publis
`nc.
`Inc.
`
`COPYRIGHT © 1985, MACMILLAN PUBLISHING COMPANY,
`COPYRIGHT © 1985, MACMILLAN PUBLISHING COMPANY,
`A DIVISION OF MACMILLAN, INC.
`A DIVISION OF MACMILLAN. INC.
`
`PRINTED IN THE UNITED STATES OF AMERICA
`PRINTED IN THE UNITED STATES OF AMERICA
`
`All rights reserved. No part of this book may be reproduced or
`All rights reserved. No part of this book may be reproduced or
`transmitted in any form or by any means, electronic or mechanical,
`transmitted in any form or by any means, electronic or mechanical,
`including photocopying, recording, or any information storage and
`including photocopying, recording, or any information storage and
`retrieval system, without permission in writing from the Publisher.
`retrieval system, without permission in writing from the Publisher.
`
`Earlier editions entitled The Pharmacological Basis of Therapeutics
`Earlier editions entitled The Pharmacological Basis of Therapeutics
`copyright 1941 and 1955. © copyright 1965, copyright © 1970. and
`copyright 1941 and 1955, CO copyright 1965, copyright © 1970, and
`copyright © 1975 by Macmillan Publishing Company. Earlier edition
`copyright © 1975 by Macmillan Publishing Company. Earlier edition
`entitled Goodman and Oilman's The Pharmacological Basis of
`entitled Goodman and Gilman's The Pharmacological Basis of
`Therapeutics copyright © 1980 by Macmillan Publishing Company.
`Therapeutics copyright © 1980 by Macmillan Publishing Company.
`
`MACMILLAN PUBLISHING COMPANY
`MACMILLAN PUBLISHING COMPANY
`866 Third Avenue • New York. N.Y. 10022
`866 Third Avenue • New York, N.Y. 10022
`COLLIER MACMILLAN CANADA. INC.
`COLLIER MACMILLAN CANADA, INC.
`COLLIER MACMILLAN PUBLISHERS •• London
`COLLIER MACMILLAN PUBLISHERS • London
`
`Library of Congress catalog card number 85-15356
`Library of Congress catalog card number 85-15356
`
`Printing: 1 2 3 4 5 6 7 8
`Printing: 1 2 3 4 5 6 7 8
`
`Year: 5 6 7 8 9 0 1
`Year: 5 6 7 8 9 0 1
`
`In this textbook, reference to proprietary names of drugs is ordinar-
`In this textbook, reference to proprietary names of drugs is ordinar­
`ily made only in chapter sections dealing with preparations. Such
`ily made only in chapter sections dealing with preparations. Such
`names are given in SMALL-CAP TYPE, usually immediately following
`names are given in SMALL-CAP TYPE, usually immediately following
`the official or nonproprietary titles. Proprietary names of drugs also
`the official or nonproprietary titles. Proprietary names of drugs also
`appear in the Index.
`appear in the Index.
`
`PI
`P1
`
`TH
`T1-
`phi
`ph;
`app
`api
`me
`me
`san
`sar
`Og>
`ogy
`pos
`pos
`ten
`ten
`ano
`and
`clin
`clin
`her
`her
`all
`all
`sue
`suc
`StU(
`stu(
`Sta
`Sta
`T
`T
`org;
`orE
`Ne\
`doz
`doz
`5 y€
`5 ye
`that
`that
`a ci
`a C
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`mo 1
`imp
`imp
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`eve
`eve
`rom
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`cho
`cho
`prol
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`fpervcv(
`prec
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`fun(
`imp
`imp
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`topi
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`prac
`prat
`oftl
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`In
`1
`and
`and
`spec
`spec
`tion:
`tior
`
`

`

`Ph.D.. D.Sc.
`Ph.D., D.Sc.
`Pharmacology
`Pharmacology
`'harmacy. and
`'harmacy, and
`ology, Univer-
`ology, Univer-
`ine. Sail Lake
`ine, Salt Lake
`
`or and Head,
`or and Head,
`department of
`department of
`alifornia, San
`alifornia, San
`i Jolla. Califor-
`I Jolla, Califor-
`
`iroup Research
`iroup Research
`The Wellcome
`The Wellcome
`Kent. United
`L, Kent, United
`
`. Sc.D.(Hon.).
`Sc.D.(Hon.).
`Chairman. De-
`Chairman, De-
`nd Professor of
`nd Professor of
`srve University
`nwe University
`d. Ohio
`d, Ohio
`
`ssor of Pharma-
`ssor of Pharma-
`^ew York. Up-
`\lew York, Up-
`use. New York
`use, New York
`
`ssor and Chair-
`ssor and Chair-
`cology. Univer-
`cology,
`jdicine. Denver.
`Denver,
`
`Dunning Dripps
`Dunning Dripps
`partment of An-
`partment of An-
`Pharmacology,
`Pharmacology.
`School of Medi-
`School of Medi-
`ania
`
`CONTENTS
`CONTENTS
`
`PREFACE TO THE SEVENTH EDITION
`PREFACE TO THE SEVENTH EDITION
`
`PREFACE TO THE FIRST EDITION
`PREFACE TO THE FIRST EDITION
`
`CONTRIBUTORS
`CONTRIBUTORS
`
`SECTION
`SECTION
`
`I
`I
`General Principles
`General Principles
`INTRODUCTION
`INTRODUCTION
`Leslie Z. Benet and Lewis B. Sheiner
`Leslie Z. Benet and Lewis B. Sheiner
`PHARMACOKINETICS; THE DYNAMICS OF DRUG ABSORPTION. DISTRIBUTION,
`1. PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION,
`AND ELIMINATION
`AND ELIMINATION
`Leslie Z. Benet and Lewis B. Sheiner
`Leslie Z. Benet and Lewis B. Sheiner
`PHARMACODYNAMICS: MECHANISMS OF DRUG ACTION AND THE RELATION­
`2. PHARMACODYNAMICS: MECHANISMS OF DRUG ACTION AND THE RELATION-
`2a
`SHIP BETWEEN DRUG CONCENTRATION AND EFFECT
`SHIP BETWEEN DRUG CONCENTRATION AND EFFECT
`Elliott M. Ross and Alfred G. Gil man
`Elliott M. Ross and Alfred G. Gilman
`
`PRINCIPLES OF THERAPEUTICS
`3. PRINCIPLES OF THERAPEUTICS
`Terrence F. Blaschke. Alan S. Nies, and Richard I). Mamelok
`Terrence F. Blaschke, Alan S. Nies, and Richard D. Mamelok
`
`SECTION
`SECTION
`I I
`II
`Drugs Acting at Synaptic and Neuroeffector Junctional Sites
`Drugs Acting at Synaptic and Neuroeffector Junctional Sites
`NEUROHUMORAL TRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR
`4. NEUROHUMORAL TRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR
`NERVOUS SYSTEMS
`NERVOUS SYSTEMS
`Norman Weiner and Palmer Taylor
`Norman Weiner and Palmer Taylor
`CHOLINERGIC AGONISTS
`5.
`5. CHOLINERGIC AGONISTS
`Palmer Taylor
`Palmer Taylor
`ANTICHOLINESTERASE AGENTS
`6.
`6. ANTICHOLINESTERASE AGENTS
`Palmer Taylor
`Palmer Taylor
`ATROPINE. SCOPOLAMINE, AND RELATED ANTIMUSCARINIC DRUGS
`7. ATROPINE, SCOPOLAMINE, AND RELATED ANTIMUSCARINIC DRUGS
`Norman Weiner
`Norman Weiner
`8.
`NOREPINEPHRINE, EPINEPHRINE, AND THE SYMPATHOMIMETIC AMINES
`8. NOREPINEPHRINE, EPINEPHRINE, AND THE SYMPATHOMIMETIC AMINES
`Norman Weiner
`Norman Weiner
`DRUGS THAT INHIBIT ADRENERGIC NERVES AND
`9. DRUGS THAT INHIBIT ADRENERGIC NERVES AND BLOCK ADRENERGIC
`BLOCK ADRENERGIC
`RECEPTORS
`RECEPTORS
`Norman Weiner
`Norman Weiner
`GANGLIONIC STIMULATING AND BLOCKING AGENTS
`10.
`10. GANGLIONIC STIMULATING AND BLOCKING AGENTS
`Palmer Taylor
`Palmer Taylor
`NEUROMUSCULAR BLOCKING AGENTS
`11. NEUROMUSCULAR BLOCKING AGENTS
`11.
`Palmer Taylor
`Palmer Taylor
`
`V
`v
`
`vii
`VII
`
`vm
`Viii
`
`1
`1
`
`3
`3
`
`35
`35
`
`49
`49
`
`66
`66
`100
`100
`110
`110
`
`130
`130
`
`145
`145
`
`181
`181
`215
`215
`222
`222
`
`xi
`xi
`
`

`

`I
`
`Xli
`xii
`
`CONTENTS
`CONTENTS
`
`SECTION
`SECTION
`III
`III
`Drugs Acting on the Central Nervous System
`Drugs Acting on the Central Nervous System
`NEUROHUMORAL TRANSMISSION AND THE CENTRAL NERVOUS SYSTEM
`12.
`12. NEUROHUMORAL TRANSMISSION AND THE CENTRAL NERVOUS SYSTEM
`Floyd E. Bloom
`Floyd E. Bloom
`
`HISTORY AND PRINCIPLES OF ANESTHESIOLOGY
`13.
`13. HISTORY AND PRINCIPLES OF ANESTHESIOLOGY
`Theodore C. Smith and Harry Wollman
`Theodore C. Smith and Harry Wollman
`Bryan E. Marshall and Harry Wollman
`Bryan E. Marshall and Harry Wollman
`J. Murdoch Ritchie and Nicholas M. Greene
`J. Murdoch Ritchie and Nicholas M. Greene
`
`14.
`GENERAL ANESTHETICS
`14. GENERAL ANESTHETICS
`15.
`LOCAL ANESTHETICS
`15. LOCAL ANESTHETICS
`THE THERAPEUTIC GASES
`16.
`16. THE THERAPEUTIC GASES
`Theodore C. Smith, Jeffrey B. Gross, and Harry Wollman
`Theodore C. Smith, Jeffrey B. Gross, and Harry Wollman
`Oxygen, Carbon Dioxide. Helium, and Water Vapor
`Oxygen, Carbon Dioxide, Helium, and Water Vapor
`17.
`HYPNOTICS AND SEDATIVES
`Stewart C. Harvey
`17. HYPNOTICS AND SEDATIVES
`Stewart C. Harvey
`18.
`THE ALIPHATIC ALCOHOLS
`J. Murdoch Ritchie
`18. THE ALIPHATIC ALCOHOLS
`J. Murdoch Ritchie
`19.
`DRUGS AND THE TREATMENT OF PSYCHIATRIC DISORDERS
`19. DRUGS AND THE TREATMENT OF PSYCHIATRIC DISORDERS
`Ross J. Baldessarini
`Ross J. Baldessarini
`20.
`DRUGS EFFECTIVE IN THE THERAPY OF THE EPILEPSIES
`20. DRUGS EFFECTIVE IN THE THERAPY OF THE EPILEPSIES
`Theodore W. Rall and Leonard S. Schleifer
`Theodore W. Rail and Leonard S. Schleifer
`21.
`DRUGS FOR PARKINSON'S DISEASE, SPASTICITY,
`21. DRUGS FOR PARKINSON'S DISEASE, SPASTICITY, AND ACUTE MUSCLE
`AND ACUTE MUSCLE
`SPASMS
`Joseph R. Bianchine
`SPASMS
`Joseph R. Bianchine
`OPIOID ANALGESICS AND ANTAGONISTS
`22.
`22. OPIOID ANALGESICS AND ANTAGONISTS
`Jerome H. Jaffe and William R. Martin
`Jerome H. Jaffe and William R. Martin
`23.
`DRUG ADDICTION AND DRUG ABUSE
`Jerome H. Jaffe
`23. DRUG ADDICTION AND DRUG ABUSE
`Jerome H. Jaffe
`24.
`CENTRAL NERVOUS SYSTEM STIMULANTS
`Donald N. Franz
`24. CENTRAL NERVOUS SYSTEM STIMULANTS
`Donald N. Franz
`Strychnine. Picrotoxin, Pentylenetetrazol,
`Strychnine, Picrotoxin, Pentylenetetrazol, and Miscellaneous Agents
`and Miscellaneous Agents
`(Doxapram, Nikethamide, Methylphenidate)
`(Doxapram, Nikethamide, Methylphenidate)
`25.
`CENTRAL NERVOUS SYSTEM STIMULANTS (Continued)
`25. CENTRAL NERVOUS SYSTEM STIMULANTS (Continued)
`The Methylxanthines
`The Methylxanthines
`
`Theodore W. Rall
`Theodore W. Rail
`
`SECTION
`SECTION
`I V
`IV
`Autacoids
`Autacoids
`INTRODUCTION
`INTRODUCTION
`William W. Douglas
`William W. Douglas
`26.
`HISTAMINE AND 5-HYDROXYTRYPTAMINE
`26. HISTAMINE AND
`5-HYDROXYTRYPTAMINE
`(SEROTONIN) AND THEIR
`(SEROTONIN) AND THEIR
`ANTAGONISTS
`ANTAGONISTS
`William W. Douglas
`William W. Douglas
`27.
`POLYPEPTIDES—ANGIOTENSIN, PLASMA KININS. AND OTHERS
`27. POLYPEPTIDES—ANGIOTENSIN, PLASMA KININS, AND OTHERS
`William W. Douglas
`William W. Douglas
`28.
`PROSTAGLANDINS, PROSTACYCLIN. THROMBOXANE A2, AND LEUKOTRIENES
`28. PROSTAGLANDINS, PROSTACYCLIN, THROMBOXANE A2, AND LEUKOTRIENES
`Salvador Moncada. Roderick J. Flower, and John R. Vane
`Salvador Moncada, Roderick J. Flower, and John R. Vane
`
`236
`236
`
`260
`260
`276
`276
`302
`302
`
`322
`322
`
`339
`339
`372
`372
`
`387
`387
`
`446
`446
`
`473
`473
`
`491
`491
`532
`532
`582
`582
`
`589
`589
`
`604
`604
`
`605
`605
`
`639
`639
`
`660
`660
`
`'1
`1
`t
`h
`V
`u
`n
`n
`0
`o
`ti
`ti
`rr.
`IT
`in
`in
`
`ti(
`ti<
`pr
`PR
`m.
`m
`re]
`rei
`fr
`fix
`cif
`cii
`cai
`cai
`
`is
`is
`the
`the
`the
`the
`trei
`trei
`anc
`anc
`pra
`pra
`tior
`tier
`dru
`dru
`pan
`par
`tive
`tive
`end'
`end
`anti
`anti
`antii
`antic
`pres
`pm&
`agei
`ager
`mus
`mus
`agor
`agor
`placi
`place
`cludi
`cludi
`tical
`tical
`indiv
`indiv
`
`
`
`
`
`C7rvia i
`
`

`

`CONTENTS
`CONTENTS
`
`SECTION V
`SECTION V
`Drug Therapy of Inflammation
`Drug Therapy of Inflammation
`ANALGESIC-ANTIPYRETICS AND ANTI-INFLAMMATORY AGENTS; DRUGS
`29.
`29. ANALGESIC-ANTIPYRETICS AND ANTI-INFLAMMATORY AGENTS; DRUGS
`EMPLOYED IN THE TREATMENT OF GOUT
`EMPLOYED IN THE TREATMENT OF GOUT
`Roderick J. Flower, Salvador Moncada, and John R. Vane
`Roderick J. Flower, Salvador Moncada, and John R. Vane
`
`SECTION
`SECTION
`V I
`VI
`Cardiovascular Drugs
`Cardiovascular Drugs
`30. DIGITALIS AND ALLIED CARDIAC GLYCOSIDES
`DIGITALIS AND ALLIED CARDIAC GLYCOSIDES
`30.
`Brian F. Hoffman and J. Thomas Bigger, Jr.
`Brian F. Hoffman and J. Thomas Bigger, Jr.
`31. ANTIARRHYTHMIC DRUGS J. Thomas Bigger, Jr., and Brian F. Hoffman
`ANTIARRHYTHMIC DRUGS J. Thomas Bigger, Jr., and Brian F. Hoffman
`31.
`32. ANTIHYPERTENSIVE AGENTS AND THE DRUG THERAPY OF HYPERTENSION
`ANTIHYPERTENSIVE AGENTS AND THE DRUG THERAPY OF HYPERTENSION
`32.
`Peter Rudd and Terrence F. Blaschke
`Peter Rudd and Terrence F. Blaschke
`33. DRUGS USED FOR THE TREATMENT OF ANGINA; ORGANIC NITRATES,
`DRUGS USED FOR THE TREATMENT OF ANGINA; ORGANIC NITRATES,
`33.
`CALCIUM CHANNEL BLOCKERS, AND /3-ADRENERGIC ANTAGONISTS
`CALCIUM CHANNEL BLOCKERS, AND /3-ADRENERGIC ANTAGONISTS
`Philip Needleman, Peter B. Corr, and Eugene M. Johnson, Jr.
`Philip Needleman, Peter B. Corr, and Eugene M. Johnson, Jr.
`34. DRUGS USED IN THE TREATMENT OF HYPERLIPOPROTEINEMIAS
`34.
`DRUGS USED IN THE TREATMENT OF HYPERLIPOPROTEINEMIAS
`Michael S. Brown and Joseph L. Goldstein
`Michael S. Brown and Joseph L. Goldstein
`
`SECTION
`SECTION
`
`VII
`VII
`Water, Salts, and Ions
`Water, Salts, and Ions
`35. AGENTS AFFECTING VOLUME AND COMPOSITION OF BODY FLUIDS
`AGENTS AFFECTING VOLUME AND COMPOSITION OF BODY FLUIDS
`35.
`Gilbert H. Mudge
`Gilbert H. Mudge
`
`SECTION
`
`SECTION VIII
`VIII
`Drugs Affecting Renal Function and Electrolyte Metabolism
`Drugs Affecting Renal Function and Electrolyte Metabolism
`INTRODUCTION
`Gilbert H. Mudge and Irwin M. Weiner
`Gilbert H. Mudge and Irwin M. Weiner
`INTRODUCTION
`36. DIURETICS AND OTHER AGENTS EMPLOYED IN THE MOBILIZATION OF EDEMA
`DIURETICS AND OTHER AGENTS EMPLOYED IN THE MOBILIZATION OF EDEMA
`36.
`Irwin M. Weiner and Gilbert H. Mudge
`FLUID
`Irwin M. Weiner and Gilbert H. Mudge
`FLUID
`37. AGENTS AFFECTING THE RENAL CONSERVATION OF WATER
`AGENTS AFFECTING THE RENAL CONSERVATION OF WATER
`37.
`Richard M. Hays
`Richard M. Hays
`INHIBITORS OF TUBULAR TRANSPORT OF ORGANIC COMPOUNDS
`INHIBITORS OF TUBULAR TRANSPORT OF ORGANIC COMPOUNDS
`Irwin M. Weiner and Gilbert H. Mudge
`Irwin M. Weiner and Gilbert H. Mudge
`
`38.
`38.
`
`xiii
`Xiii
`
`674
`674
`
`716
`716
`
`748
`748
`
`784
`784
`
`806
`806
`
`827
`827
`
`846
`846
`
`879
`879
`
`887
`887
`
`908
`908
`
`920
`920
`
`oom
`oom
`
`236
`236
`
`man
`man
`man
`'man
`eene
`eene
`
`260
`260
`lib
`276
`302
`302
`
`'man
`'man
`
`322
`322
`
`irvey
`irvey
`tchie
`tchie
`
`339
`339
`372
`372
`
`•arini
`arini
`
`387
`387
`
`leifer
`leifer
`ISCLE
`JSCLE
`chine
`chine
`
`(art in
`Partin
`Jaffe
`Jaffe
`Franz
`Franz
`.gents
`gents
`
`446
`446
`
`473
`473
`
`491
`491
`532
`532
`582
`582
`
`'. Rail
`. Rall
`
`589
`589
`
`luglas
`uglas
`THEIR
`['HEIR
`)uglas
`Puglas
`
`juglas
`iuglas
`UENES
`IENES
`. Vane
`Vane
`
`604
`604
`
`605
`605
`
`639
`639
`
`660
`660
`
`

`

`xiv
`xiv
`
`CONTENTS
`CONTENTS
`
`SECTION
`SECTION
`I X
`IX
`Drugs Affecting Uterine Motility
`Uterine Motility
`Drugs Affecting
`OXYTOCIN, PROSTAGLANDINS, ERGOT ALKALOIDS, AND OTHER DRUGS;
`39.
`39. OXYTOCIN, PROSTAGLANDINS, ERGOT ALKALOIDS, AND OTHER DRUGS;
`Theodore W. Rail and Leonard S. Schleifer
`TOCOLYTIC AGENTS
`Theodore W. Rall and Leonard S. Schleifer
`TOCOLYTIC AGENTS
`
`SECTION
`
`SECTION X
`Locally Acting Drugs
`Locally Acting Drugs
`SURFACE-ACTING DRUGS
`40.
`Ewart A. Swinyard and Madhu A. Pathak
`40. SURFACE-ACTING DRUGS
`Ewart A. Swinyard and Madhu A. Pathak
`41.
`ANTISEPTICS AND DISINFECTANTS; FUNGICIDES; ECTOPARASITICIDES
`41. ANTISEPTICS AND DISINFECTANTS; FUNGICIDES; ECTOPARASITICIDES
`Stewart C. Harvey
`Stewart C. Harvey
`42.
`GASTRIC ANTACIDS, MISCELLANEOUS DRUGS FOR THE TREATMENT OF
`42. GASTRIC ANTACIDS, MISCELLANEOUS DRUGS FOR THE TREATMENT OF
`PEPTIC ULCERS, DIGESTANTS, AND BILE ACIDS
`Stewart C. Harvey
`PEPTIC ULCERS, DIGESTANTS, AND BILE ACIDS
`Stewart C. Harvey
`43.
`LAXATIVES
`Laurence L. Brunton
`43. LAXATIVES
`Laurence L. Brunton
`
`Chemotherapy
`
`of Parasitic
`
`Diseases
`
`SECTION
`SECTION
`
`XI
`
`
`X I
`Chemotherapy of Parasitic Diseases
`INTRODUCTION
`Leslie T. Webster, Jr.
`Leslie T. Webster, Jr.
`INTRODUCTION
`44.
`DRUGS USED IN THE CHEMOTHERAPY OF HELMINTHIASIS
`44. DRUGS USED IN THE CHEMOTHERAPY OF HELMINTHIASIS
`Leslie T. Webster, Jr.
`Leslie T. Webster, Jr.
`45.
`DRUGS USED IN THE CHEMOTHERAPY OF PROTOZOAL INFECTIONS
`45. DRUGS USED IN THE CHEMOTHERAPY OF PROTOZOAL INFECTIONS
`Leslie T. Webster, Jr.
`Malaria
`Malaria
`Leslie T. Webster, Jr.
`46.
`DRUGS USED IN THE CHEMOTHERAPY OF PROTOZOAL INFECTIONS (Continued)
`46. DRUGS USED IN THE CHEMOTHERAPY OF PROTOZOAL INFECTIONS (Continued)
`Leslie T. Webster, Jr.
`Amebiasis, Giardiasis, and Trichomoniasis
`Amebiasis, Giardiasis, and Trichomoniasis
`Leslie T. Webster, Jr.
`47.
`DRUGS USED IN THE CHEMOTHERAPY OF PROTOZOAL INFECTIONS {Continued)
`47. DRUGS USED IN THE CHEMOTHERAPY OF PROTOZOAL INFECTIONS (Continued)
`Leslie T. Webster, Jr.
`Leslie T. Webster, Jr.
`Leishmaniasis, Trypanosomiasis, and Other Protozoal Infections
`Leishmaniasis, Trypanosomiasis, and Other Protozoal Infections
`
`Chemotherapy
`
`of Microbial
`
`Diseases
`
`SECTION
`
`XII
`
`SECTION XII
`Chemotherapy of Microbial Diseases
`Merle A. Sande and Gerald L. Mandell
`48. ANTIMICROBIAL AGENTS
`Merle A. Sande and Gerald L. Mandell
`48. ANTIMICROBIAL AGENTS
`General Considerations
`General Considerations
`ANTIMICROBIAL AGENTS {Continued)
`49.
`49. ANTIMICROBIAL AGENTS (Continued)
`Gerald L. Mandell and Merle A. Sande
`Gerald L. Mandell and Merle A. Sande
`Sulfonamides, Trimethoprim-Sulfamethoxazole, and Agents for Urinary Tract
`Sulfonamides, Trimethoprim-Sulfamethoxazole, and Agents for Urinary Tract
`Infections
`Infections
`
`6 VVlll1./Yll,,
`t_opyr.i&nt %L., 170J, mat, iiiiii an
`^ouyngm ^ i y o j , maviuinou i uunaning,
`a Division of Macmillan, Inc.
`a Division of Macmillan, Inc.
`
`926
`926
`
`946
`946
`
`959
`959
`
`980
`980
`994
`994
`
`1004
`1004
`
`1009
`1009
`
`1029
`1029
`
`1049
`1049
`
`1058
`1058
`
`1066
`1066
`
`1095
`1095
`
`

`

`CONTENTS
`CONTENTS
`50. ANTIMICROBIAL AGENTS (Continued)
`50. ANTIMICROBIAL AGENTS (Continued)
`Gerald L. Mandell and Merle A. Sande
`Gerald L. Mandell and Merle A. Sande
`Penicillins, Cephalosporins, and Other Beta-Lactam Antibiotics
`Penicillins, Cephalosporins, and Other Beta-Lactam Antibiotics
`51. ANTIMICROBIAL AGENTS (Continued)
`51. ANTIMICROBIAL AGENTS (Continued)
`Merle A. Sande and Gerald L. Mandell
`Merle A. Sande and Gerald L. Mandell
`
`The Aminoglycosides
`The Aminoglycosides
`52. ANTIMICROBIAL AGENTS (Continued)
`52. ANTIMICROBIAL AGENTS (Continued)
`Merle A. Sande and Gerald L. Mandell
`Merle A. Sande and Gerald L. Mandell
`Tetracyclines, Chloramphenicol, Erythromycin, and Miscellaneous Antibac­
`Tetracyclines, Chloramphenicol, Erythromycin, and Miscellaneous Antibac-
`terial Agents
`terial Agents
`53. ANTIMICROBIAL AGENTS (Continued)
`53. ANTIMICROBIAL AGENTS (Continued)
`Gerald L. Mandell and Merle A. Sande
`Gerald L. Mandell and Merle A. Sande
`Drugs Used in the Chemotherapy of Tuberculosis and Leprosy
`Drugs Used in the Chemotherapy of Tuberculosis and Leprosy
`54. ANTIMICROBIAL AGENTS (Continued)
`54. ANTIMICROBIAL AGENTS (Continued)
`Merle A. Sande and Gerald L. Mandell
`Merle A. Sande and Gerald L. Mandell
`
`Antifungal and Antiviral Agents
`Antifungal and Antiviral Agents
`
`SECTION
`
`XIII
`
`SECTION XIII
`Chemotherapy of Neoplastic Diseases
`Chemotherapy of Neoplastic Diseases
`INTRODUCTION
`Paul Calabresi and Robert E. Parks, Jr.
`INTRODUCTION
`Paul Calabresi and Robert E. Parks, Jr.
`55. ANTIPROLIFERATIVE AGENTS AND DRUGS USED FOR IMMUNOSUPPRESSION
`55. ANTIPROLIFERATIVE AGENTS AND DRUGS USED FOR IMMUNOSUPPRESSION
`Paul Calabresi and Robert E. Parks, Jr.
`Paul Calabresi and Robert E. Parks, Jr.
`
`SECTION
`
`XIV
`
`SECTION XIV
`Drugs Acting on the Blood and the Blood-Forming Organs
`Drugs Acting on the Blood and the Blood-Forming Organs
`56. DRUGS EFFECTIVE
`IRON-DEFICIENCY AND OTHER HYPOCHROMIC
`IN
`56. DRUGS EFFECTIVE
`IN
`IRON-DEFICIENCY AND OTHER HYPOCHROMIC
`ANEMIAS
`Robert S. Hillman and Clement A. Finch
`ANEMIAS
`Robert S. Hillman and Clement A. Finch
`57. VITAMIN
`FOLIC ACID, AND THE TREATMENT OF MEGALOBLASTIC
`57. VITAMIN B1,, FOLIC ACID, AND THE TREATMENT OF MEGALOBLASTIC
`ANEMIAS
`Robert S. Hillman
`ANEMIAS
`Robert S. Hillman
`58. ANTICOAGULANT, ANTITHROMBOTIC, AND THROMBOLYTIC DRUGS
`58. ANTICOAGULANT, ANTITHROMBOTIC, AND THROMBOLYTIC DRUGS
`Robert A. O'Reilly
`Robert A. O'Reilly
`
`SECTION
`SECTION XV
`XV
`Hormones and Hormone Antagonists
`Hormones and Hormone Antagonists
`INTRODUCTION
`Ferid Murad and Robert C. Haynes, Jr.
`Ferid Murad and Robert C. Haynes, Jr.
`INTRODUCTION
`59. ADENOHYPOPHYSEAL HORMONES AND RELATED SUBSTANCES
`59. ADENOHYPOPHYSEAL HORMONES AND RELATED SUBSTANCES
`Ferid Murad and Robert C. Haynes, Jr.
`Ferid Murad and Robert C. Haynes, Jr.
`
`XV
`xv
`
`1115
`1115
`
`1150
`1150
`
`1170
`1170
`
`1199
`1199
`
`1219
`1219
`
`1240
`1240
`
`1247
`1247
`
`1308
`1308
`
`1323
`1323
`
`1338
`1338
`
`1360
`1360
`
`1362
`1362
`
`UJGS:
`LUGS;
`leifer
`!leifer
`
`926
`926
`
`athak
`athak
`
`946
`946
`
`arvey
`"arvey
`T OF
`T OF
`arvey
`rarvey
`unton
`unton
`
`959
`959
`
`980
`980
`994
`994
`
`?r, Jr.
`er, Jr.
`
`1004
`1004
`
`er, Jr.
`er, Jr.
`
`1009
`1009
`
`er. Jr.
`er, Jr.
`inued)
`inued)
`er. Jr.
`er, Jr.
`inued)
`inued)
`er. Jr.
`er, Jr.
`
`1029
`1029
`
`1049
`1049
`
`1058
`1058
`
`'andell
`"andell
`
`1066
`1066
`
`Sande
`Sande
`/ Tract
`Tract
`
`1095
`1095
`
`

`

`CONTENTS
`xvi
`CONTENTS
`XVi
`60. THYROID AND ANTITHYROID DRUGS
`60. THYROID AND ANTITHYROID DRUGS
`Robert C. Haynes, Jr., and Ferid Murad
`Robert C. Haynes, Jr., and Ferid Murad
`61.
`ESTROGENS AND PROGESTINS
`Ferid Murad and Robert C. Haynes, Jr.
`Ferid Murad and Robert C. Haynes, Jr.
`61. ESTROGENS AND PROGESTINS
`Ferid Murad and Robert C. Haynes, Jr.
`62. ANDROGENS
`Ferid Murad and Robert C. Haynes, Jr.
`62. ANDROGENS
`ADRENOCORTICOTROPIC HORMONE; ADRENOCORTICAL STEROIDS AND THEIR
`63.
`63. ADRENOCORTICOTROPIC HORMONE; ADRENOCORTICAL STEROIDS AND THEIR
`STEROID
`INHIBITORS OF ADRENOCORTICAL
`SYNTHETIC ANALOGS;
`INHIBITORS OF ADRENOCORTICAL
`STEROID
`SYNTHETIC ANALOGS;
`Robert C. Haynes, Jr., and Ferid Murad
`BIOSYNTHESIS
`Robert C. Haynes, Jr., and Ferid Murad
`BIOSYNTHESIS
`INSULIN AND ORAL HYPOGLYCEMIC DRUGS; GLUCAGON
`Joseph Larner
`64.
`Joseph Larner
`INSULIN AND ORAL HYPOGLYCEMIC DRUGS; GLUCAGON
`64.
`AGENTS AFFECTING CALCIFICATION: CALCIUM, PARATHYROID HORMONE,
`65.
`65. AGENTS AFFECTING CALCIFICATION: CALCIUM, PARATHYROID HORMONE,
`CALCITONIN, VITAMIN D, AND OTHER COMPOUNDS
`CALCITONIN, VITAMIN D, AND OTHER COMPOUNDS
`Robert C. Haynes, Jr., and Ferid Murad
`Robert C. Haynes, Jr., and Ferid Murad
`
`SECTION
`SECTION XVI
`XVI
`The Vitamins
`The Vitamins
`Robert Marcus and Ann M. Coulston
`INTRODUCTION
`Robert Marcus and Ann M. Coulston
`INTRODUCTION
`66.
`WATER-SOLUBLE VITAMINS
`Robert Marcus and Ann M. Coulston
`Robert Marcus and Ann M. Coulston
`66. WATER-SOLUBLE VITAMINS
`The Vitamin B Complex and Ascorbic Acid
`The Vitamin B Complex and Ascorbic Acid
`FAT-SOLUBLE VITAMINS
`H. George Mandel and Victor H. Cohn
`67.
`67. FAT-SOLUBLE VITAMINS
`H. George Mandel and Victor H. Cohn
`Vitamins A, K, and E
`Vitamins A, K, and E
`
`SECTION
`
`XVII
`
`SECTION XVII
`Toxicology
`Toxicology
`PRINCIPLES OF TOXICOLOGY
`Curtis D. Klaassen
`68.
`Curtis D. Klaassen
`68. PRINCIPLES OF TOXICOLOGY
`69. HEAVY METALS AND HEAVY-METAL ANTAGONISTS
`Curtis D. Klaassen
`Curtis D. Klaassen
`69. HEAVY METALS AND HEAVY-METAL ANTAGONISTS
`NONMETALLIC ENVIRONMENTAL TOXICANTS: AIR POLLUTANTS, SOLVENTS
`70.
`70. NONMETALLIC ENVIRONMENTAL TOXICANTS: AIR POLLUTANTS, SOLVENTS
`AND VAPORS, AND PESTICIDES
`Curtis D. Klaassen
`AND VAPORS, AND PESTICIDES
`Curtis D. Klaassen
`
`APPENDIX I. PRINCIPLES OF PRESCRIPTION ORDER WRITING AND PATIENT
`APPENDIX I. PRINCIPLES OF PRESCRIPTION ORDER WRITING AND PATIENT
`COMPLIANCE INSTRUCTION
`Ewart A. Swinyard
`Ewart A. Swinyard
`COMPLIANCE INSTRUCTION
`APPENDIX II. DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS; PHAR­
`APPENDIX II. DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS; PHAR-
`Leslie Z. Benet and Lewis B. Sheiner
`MACOKINETIC DATA
`Leslie Z. Benet and Lewis B. Sheiner
`MACOKINETIC DATA
`APPENDIX III. DRUG INTERACTIONS
`Ferid Murad and Alfred G. Gilman
`Ferid Murad and Alfred G. Gilman
`APPENDIX III. DRUG INTERACTIONS
`INDEX
`INDEX
`
`G
`T
`O
`O
`
`1389
`1389
`1412
`1412
`1440
`1440
`
`1459
`1459
`1490
`1490
`
`1517
`1517
`
`1544
`1544
`1551
`1551
`
`1573
`1573
`
`1592
`1592
`1605
`1605
`
`1628
`1628
`
`1651
`1651
`
`1663
`1663
`1734
`1734
`1751
`1751
`
`

`

`SECTION
`SECTION
`
`I
`I
`
`General Principles
`General Principles
`
`INTRODUCTION
`INTRODUCTION
`
`Leslie Z. Benet and Lewis B. Sheiner
`Leslie Z. Benet and Lewis B. Sheiner
`
`In its entirety, pharmacology embraces the knowledge of the history, source, physical
`In its entirety, pharmacology embraces the knowledge of the history, source, physical
`and chemical properties, compounding, biochemical and physiological effects, mechanisms
`and chemical properties, compounding, biochemical and physiological effects, mechanisms
`of action, absorption, distribution, biotransformation and excretion, and therapeutic and
`of action, absorption, distribution, biotransformation and excretion, and therapeutic and
`other uses of drugs. Since a drug is broadly defined as any chemical agent that affects living
`other uses of drugs. Since a drug is broadly defined as any chemical agent that affects living
`processes, the subject of pharmacology is obviously quite extensive.
`processes, the subject of pharmacology is obviously quite extensive.
`For the clinician and the student of health sciences, however, the scope of pharmacology
`For the clinician and the student of health sciences, however, the scope of pharmacology
`is less expansive than indicated by the above definitions. The clinician is interested primar­
`is less expansive than indicated by the above definitions. The clinician is interested primar-
`ily in drugs that are useful in the prevention, diagnosis, and treatment of human disease.
`ily in drugs that are useful in the prevention, diagnosis, and treatment of human disease.
`Study of the pharmacology of these drugs can be reasonably limited to those aspects that
`Study of the pharmacology of these drugs can be reasonably limited to those aspects that
`provide the basis for their rational clinical use. Secondarily, the clinician is also concerned
`provide the basis for their rational clinical use. Secondarily, the clinician is also concerned
`with chemical agents that are not used in therapy but are commonly responsible for house­
`with chemical agents that are not used in therapy but are commonly responsible for house-
`hold and industrial poisoning as well as environmental pollution. Study of these substances
`hold and industrial poisoning as well as environmental pollution. Study of these substances
`is justifiably restricted to the general principles of prevention, recognition, and treatment of
`is justifiably restricted to the general principles of prevention, recognition, and treatment of
`such toxicity or pollution. Finally, all health professionals share in the responsibility to help
`such toxicity or pollution. Finally, all health professionals share in the responsibility to help
`resolve the continuing sociological problem of the abuse of drugs.
`resolve the continuing sociological problem of the abuse of drugs.
`The basic pharmacological concepts summarized in this section apply to the characteriza­
`The basic pharmacological concepts summarized in this section apply to the characteriza-
`tion, evaluation, and comparison of all drugs. A clear understanding of these principles is
`tion, evaluation, and comparison of all drugs. A clear understanding of these principles is
`essential for the subsequent study of the individual drugs. The relationship between the
`essential for the subsequent study of the individual drugs. The relationship between the
`dose of a drug given to a patient and the utility of that drug in treating the patient's disease is
`dose of a drug given to a patient and the utility of that drug in treating the patient's disease is
`described by two basic areas of pharmacology: pharmacokinetics and pharmacodynamics.
`described by two basic areas of pharmacology: pharmacokinetics and pharmacodynamics.
`Operationally, these terms may be defined as what the body does to the drug (pharmacoki­
`Operationally, these terms may be defined as what the body does to the drug (pharmacoki-
`netics) and what the drug does to the body (pharmacodynamics).
`netics) and what the drug does to the body (pharmacodynamics).
`Pharmacokinetics (Chapter 1) deals with the absorption, distribution, biotransformation.
`Pharmacokinetics (Chapter 1) deals with the absorption, distribution, biotransformation,
`and excretion of drugs. These factors, coupled with dosage, determine the concentration of
`and excretion of drugs. These factors, coupled with dosage, determine the concentration of
`a drug at its sites of action and, hence, the intensity of its effects as a function of time. Many
`a drug at its sites of action and, hence, the intensity of its effects as a function of time. Many
`basic principles of biochemistry and enzymology and the physical and chemical principles
`basic principles of biochemistry and enzymology and the physical and chemical principles
`that govern the active and passive transfer and the distribution of substances across biologi­
`that govern the active and passive transfer and the distribution of substances across biologi-
`cal membranes are readily applied to the understanding of this important aspect of pharma­
`cal membranes are readily applied to the understanding of this important aspect of pharma-
`cology.
`cology.
`The study of the biochemical and physiological effects of drugs and their mechanisms of
`The study of the biochemical and physiological effects of drugs and their mechanisms of
`action is termed pharmacodynamics (Chapter 2). As a border science, pharmacodynamics
`action is termed pharmacodynamics (Chapter 2). As a border science, pharmacodynamics
`borrows freely from both the subject matter and the experimental technics of physiology,
`borrows freely from both the subject matter and the experimental technics of physiology.
`biochemistry, cellular and molecular biology, microbiology, immunology, genetics, and
`biochemistry, cellular and molecular biology, microbiology, immunology, genetics, and
`pathology. It is unique mainly in that attention is focused on the characteristics of drugs. As
`pathology. It is unique mainly in that attention is focused on the characteristics of drugs. As
`the name implies, the subject is a dynamic one. The student who attempts merely to memo­
`the name implies, the subject is a dynamic one. The student who attempts merely to memo-
`rize the pharmacodynamic properties of drugs is foregoing one of the best opportunities for
`rize the pharmacodynamic properties of drugs is foregoing one of the best opportunities for
`correlating the entire field of preclinical medicine. For example, the actions and effects of
`correlating the entire field of preclinical medicine. For example, the actions and effects of
`the saluretic agents can be fully understood only in terms of the basic principles of renal
`the saluretic agents can be fully understood only in terms of the basic principles of renal
`
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`2
`GENERAI PRINCIPLES
`GENERAI. PRINCIPLES
`2
`physiology and of the pathogenesis of edema. Conversely, great insight into normal and
`physiology and of the pathogenesis of edema. Conversely, great insight into normal and
`abnormal renal physiology can be gained by the study of the pharmacokinetics and pharma­
`abnormal renal physiology can be gained by the study of the pharmacokinetics and pharma-
`codynamics of the saluretic agents.
`codynamics of the saluretic agents.
`The clinician is understandably interested mainly in the effects of drugs in man. This
`The clinician is understandably interested mainly in the effects of drugs in man. This
`emphasis on clinical pharmacology is justified, since the effects of drugs are often charac­
`emphasis on clinical pharmacology is justified, since the effects of drugs are often charac-
`terized by significant interspecies variation, and since they may be further modified by
`terized by significant interspecies variation, and since they may be further modified by
`disease. In addition, some drug effects, such as those on mood and behavior, can be ade­
`disease. In addition, some drug effects, such as those on mood and behavior, can be ade-
`quately studied only in man. However, technical, legal, and ethica