GOODMAN & GILMAN’S The
`PHARMACOLOGICAL
`BASIS OF
`THERAPEUTICS
`
`Ninth Edition
`
`McGraw-Hill
`HENLTH PRUFERSIUXS DIVISION
`
`New York St. Louis San Francisco Auckland Bogotzi Caracas Lisbon London Madrid
`Mexico City Milan Montreal New Delhi San Juan Singapore Sydney Tokyo Toronto
`
`MYLAN INC. EXHIBIT NO. 1021 Page 1
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`MYLAN INC. EXHIBIT NO. 1021 Page 1
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`

`

`Mchw-Hill
`A Division of The McGraw-Ht'fl Companies
`
`:2\
`
`Goodman and Gilman’s THE PHARMACOLOGICAL BASlS OF THERAPEUTICS. 9/6
`
`Copyright © 1996, 1990, 1985. 1980, 1975, 1970, 1965, 1955, 1941 by The McGraw-Hill Companies,
`Inc. All rights reserved. Printed in the United States of America. Except as permitted under the United
`States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form
`or by any means, or stored in a data base or retrieval system. without the prior written permission of
`the publisher.
`
`1234567890 DOWDOW 98765
`
`ISBN 0-07-026266-7
`
`This book was set in Times Roman by York Graphic Services, Inc. The editors were Martin J.
`Wonsiewicz and Peter McCurdy; the production supervisors were Robert Laffler and Clare Stanley,
`and the cover designer was Marsha Cohen/Paralellogram. The index was prepared by Irving Condé
`Tullar.
`R.R. Donnelley and Sons Company was printer and binder.
`
`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in-Publication Data
`
`Goodman & Gilman’s The Pharmacological Basis of Therapeutics. —9th ed. I Joel G. Hardman,
`Alfred Goodman Gilman, Lee E. Limbird.
`p.
`cm.
`,
`includes bibliographical references and index.
`ISBN 0-07—026266-7 (hardcover)
`
`II. Gilman, Alfred.
`I. Goodman, Louis Sanford.
`2. Chemotherapy.
`l. Pharmacology.
`IV. Gilman, Alfred Goodman.
`V. Limbird, Lee E.
`III. Hardman, Joe] G.
`[DNLM: 1. Pharmacology.
`2. Drug Therapy.
`QV 4 G6532 1995]
`RM300.G644
`1995
`615’ .7—dc20
`
`DNLM/DLC
`for Library of Congress
`
`95-36658
`
`
`
`MYLAN INC. EXHIBIT NO. 1021 Page 2
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`

`

`Contributors
`
`Consultants to the Editors
`
`Preface
`
`Preface to the First Edition
`
`s E C T 1 o N
`
`1
`
`GENERAL PRINCIPLES
`
`Introduction
`Leslie Z. Benet
`
`l. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination
`Leslie Z. Benet. Deanna L. Kroetz. and Lewis B. Sheiner
`
`2. Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug
`Concentration and Effect
`Elliott M. Ross
`
`3. Principles of Therapeutics
`Alan S. Nies and Stephen P. Spielberg
`
`4. Principles of Toxicology and Treatment of Poisoning
`Curtis D. Klaassen
`
`5. Gene-Based Therapy
`Stephen L. Eek and James M. Wilson
`
`5 E C T I o N
`
`I
`
`1
`
`DRUGS ACTING A'l‘ SYNAI’TIC AND NEURUICFFECTOR
`.IUNCTIONAI, SITES
`
`6. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems
`
`Contents
`
`xiii
`
`xvii
`
`xix
`
`xxi
`
`1
`
`1
`
`3
`
`29
`
`43
`
`63
`
`77
`
`103
`
`IUS
`
`Brian B. Hofi‘inan, Robert J. Leflcowitz. and Palmer Taylor
`MYLAN INC. EXHIBIT NO. 1021 Page 3
`v
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`

`

`vi
`
`CONTENTS
`
`7. Muscarinic Receptor Agonists and Antagonists
`Joan Heller Brown and Palmer Taylor
`
`8. Anticholinesterase Agents
`Palmer Taylor
`
`.
`
`9. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia
`Palmer Taylor
`
`10. Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor
`Antagonists
`‘ .
`Brian B. Hafiman and Robert J. Lefkowitz
`
`11. 5-Hydroxytryptamine (Serotonin) Receptor Agonists and Antagonists
`Elaine Sanders-Bush and Steven E. Mayer
`
`SECTION III
`
`DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM
`
`12. Neurotransmission and the Central Nervous System
`
`Floyd E. Bloom
`
`13. History and Principles of Anesthesiology
`Sean K. Kennedy and David E. Longnecker
`
`14. General Anesthetics
`
`Bryan E. Marshall and David E. Longnecker
`
`15. Local Anesthetics
`
`William A. Catteralland Kenneth Mackie
`
`16. Therapeutic Gases
`Roderic G. Eckenhoff and David E. Longnecker
`
`17. Hypnotics and Sedatives; Ethanol
`William R. Hobbs, Theodore W. Rall, and Todd A. Verdoorn
`
`18. Drugs and the Treatment of Psychiatric Disorders: Psychosis and Anxiety
`Ross J. Baldessarim'
`
`19. Drugs and the Treatment of Psychiatric Disorders: Depression and Mania
`Ross J. Baldessarini
`
`20. Drugs Effective in the Therapy of the Epilepsies
`James 0. McNamara
`
`141
`
`161
`
`177
`
`199
`
`249
`
`265
`
`267
`
`295
`
`307
`
`'
`
`‘
`
`331
`
`349
`
`361
`
`399
`
`431
`
`461
`
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`

`

`.
`
`'
`
`'
`
`CONTENTS
`
`21. Drugs Effective in the Therany of Migraine
`Stephen J. Peroutka
`
`22. Treatment of Central Nervous System Degenerative Disorders
`David G. Standaert and Anne B. Young
`
`23. Opioid Analgesics and Antagonists
`Terry Reisine and Gavril Pasternak
`
`24. Drug Addiction and Drug Abuse
`Charles P. O'Brien
`
`'
`
`SECTION IV
`
`AUTACOIDS; DRUG THERAPY OF INFLAMMATION
`
`Introduction
`
`William E. Serafin and Kenneth S. Babe, Jr.
`
`25. Histamine, Bradykinin and Their Antagonists
`Kenneth S. Babe, Jr., and William E. Serafin
`
`26. Lipid-Derived Autacoids: Eicosanoids and Platelet-Activating Factor
`
`William B. Campbell and Perry V. Halushka
`
`27. Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in
`the Treatment of Gout
`Paul A. Insel
`
`28. Drugs Used in the Treatment of Asthma
`William E. Serafin
`
`SECTIONV
`
`DRUGS AFFECTING RENAL AND CARDIOVASCULAR
`
`FUNCTION
`
`29. Diuretics
`Edwin K. Jackson
`
`‘
`
`30. Vasopressin and Other Agents Affecting the Renal Conservation of Water
`Edwin K. Jackson
`
`31. Renin and Angiotensin
`Edwin K. Jackson and James C. Garrison
`
`vii
`
`487
`
`~.-
`
`503
`
`521
`
`557
`
`579
`
`579
`
`581
`
`601
`
`617
`
`659
`
`683
`
`685
`
`715
`
`733
`
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`

`

`viii
`
`CONTENTS
`
`32. Drugs Used for the Treatment of Myocardial Ischemia
`Rose Marie Robertson and David Robertson
`
`33. Antihypertensive Agents and the Drug Therapy of Hypertension
`John A. Oates
`
`34. Pharmacological Treatment of Heart Failure
`
`Ralph A. Kelly and Thomas W. Smith
`
`35. Antiarrhythmic Drugs
`Dan M. Roden
`
`36. Drugs Used in the Treatment of Hyperlipoproteinemias
`Joseph L. Witztum
`
`SECTION VI
`
`DRUGS AFFECTING GASTROINTESTINAL FUNCTION
`
`37. Agents for Control of Gastric Acidity' and Treatment of Peptic Ulcers
`Laurence L. Brunton
`
`38. Agents Affecting Gastrointestinal Water Flux and Motility; Emesis and
`
`Antiemetics; Bile Acids and Pancreatic Enzymes
`Laurence L. Brunton
`
`SECTION VII
`
`DRUGS AFFECTING UTERINE MOTILITY
`
`39. Agents That Cause Contraction or Relaxation
`of the Uterus
`Cornelia R. Graves
`
`SECTION VIII
`
`CHEMOTHERAPY OF PARASITIC INFECTIONS
`
`Introduction
`
`James W. Tracy and Leslie TI Webster; Jr.
`
`40. Drugs Used in the Chemotherapy of Protozoal Infections: Malaria
`
`James W. Tracy and Leslie T. Webster, Jr.
`
`759
`
`781
`
`809
`
`839
`
`875
`
`899
`
`901
`
`917
`
`937
`
`939
`
`955
`
`955
`
`965
`
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`

`

`CONTENTS
`
`41. Drugs Used in the Chemotherapy of Protozoal Infectionsi'l‘rypanosomiasis,
`Leishmaniasis, Amebiasis, Giardiasis, Trichomoniasis, and Other Protozoal Infections
`James W. Tracy and Leslie T. Webster; Jr.
`
`42. Drugs Used in the Chemotherapy of Helminthiasis
`James W. Tracy and Leslie T. Webster, Jr.
`
`SECTION IX
`CHEMOTHERAPY OF MICROBIAL DISEASES
`
`43. Antimicrobial Agents: General Considerations
`Henry F. Chambers and Merle A. Sande
`
`44. Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones,
`and Agents for Urinary Tract Infections
`Gerald L. Mandell and William A. Petri, Jr.
`
`45. Antimicrobial Agents: Penicillins, Cephaiosporins, and Other B-Lactam
`Antibiotics
`
`Gerald L. Mandell and William A. Petri, Jr.
`
`46. Antimicrobial Agents: The Aminoglycosides
`Henry F. Chambers and Merle A. Sande
`
`47. Antimicrobial Agents: Tetracyclines, Chloramphenicol, Erythromycin, and
`Miscellaneous Antibacterial Agents
`Joan E. Kapusnik-Uner, Merle A. Sande, and Henry F Chambers
`
`48. Antimicrobial Agents: Drugs Used in the Chemotherapy of Tuberculosis and Leprosy
`‘ Gerald L. Mandell and William A. Petri, Jr.
`
`49. Antimicrobial Agents: Antifungal Agents
`John E. Bennett
`
`50. Antimicrobial Agents: Antiviral Agents
`Frederick G. Hayden
`
`SECTIONX
`CHEMOTHERAPY OF NEOPLASTIC DISEASES
`
`Introduction
`
`Paul Calabresi and Bruce A. Chabner
`
`ix
`
`987
`
`1009
`
`1027
`
`1029
`
`1057
`
`1073
`
`1103
`
`1123
`
`1155
`
`1175
`
`1191
`
`1225
`
`1225
`
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`

`

`X
`
`CONTENTS
`
`51. Antineoplastic Agents
`Bruce A. Chabner, Carmen J. Allegra, Gregory A. Curt,
`and Paul Calabresi
`
`SECTION XI
`
`DRUGS USED FOR IMMUNOMODULATION
`
`52. Immunomodulators: Immunosuppressive Agents and Immunostimulants
`Robert B. Diasio and Albert F. LoBuglio
`
`SECTION XII
`
`DRUGS ACTING ON THE BLOOD AND THE BLOOD-FORMING
`ORGANS
`
`53. Hematopoietic Agents: Growth Factors, Minerals, and Vitamins
`Robert S. Hillman
`
`54. Anticoagulant, Thrombolytic, and Antiplatelet Drugs
`Philip W. Majerus, George J. Broze, Jr., Joseph P. Miletich, and Douglas M. Tollefsen
`
`SECTION XIII
`
`HORMONES AND HORMONE ANTAGONISTS
`
`55. Adenohypophyseal Hormones and Their Hypothalamic Releasing Factors
`Mario Ascoli and Deborah L Segalofi
`
`56. Thyroid and Antithyroid Drugs
`Alan P. Farwell and Lewis E. Braverman
`
`57. Estrogens and Progestins
`Cynthia L. Williams and George M. Stancel
`
`58. Androgens
`Jean D. Wilson
`
`59. Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic
`Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones
`Bernard P. Schimmer and Keith A Parker
`
`1233
`
`1289
`
`1291
`
`1309
`
`1311
`
`1341
`
`1361
`
`1363
`
`1383
`
`1411
`
`1441
`
`1459
`
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`

`

`CONTENTS
`
`60. Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Endocrine
`Pancreas
`
`Stephen N. Davis and Daryl K. Granner
`
`61. Agents Affecting Calcification and Bone rIllmover: Calcium, Phosphate,
`Parathyroid Hormone, Vitamin D, Calcitonin, and Other Compounds
`Robert Marcus
`
`SECTION XIV
`
`THE VITAMINS
`
`Introduction
`Robert Marcus and Ann M. Coulston
`
`62. Water-Soluble Vitamins: The Vitamin B Complex and Ascorbic Acid
`Robert Marcus and Ann M. Coulston
`
`63. Fat-Soluble Vitamins: Vitamins A, K, and E
`Robert Marcus and Ann M. Coulston
`
`SECTION XV
`
`DERMATOLOGY
`
`64. Dermatological Pharmacology
`Cynthia Guzzo, Gerald S. Lazarus, and Victoria P. Werth
`
`SECTION XVI
`
`OPHTHALMOLOGY
`
`65. Ocular Pharmacology
`Sayoko E. Moroi and Paul R. Lichter
`
`SECTION XVII
`
`TOXICOLOGY
`
`66. Heavy Metals and Heavy-Metal Antagonists
`Curtis D. Klaassen
`
`xi
`
`1487
`
`1519
`
`1547
`
`1547
`
`1555
`
`1573
`
`1591
`
`1593
`
`1617
`
`1619
`
`1647
`
`1649
`
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`

`

`xii
`
`CONTENTS
`
`67. Nonmetallic Environmental Toxicants: Air Pollutants, Solvents, Vapors,
`and Pesticides
`Curtis D. Klaassen
`
`APPENDICES
`
`1. Principles of Prescription Order Writing and Patient Compliance
`Instructions
`Leslie Z. Benet
`
`II. Design and Optimization of Dosage Regimens; Pharmacokinetic Data
`Leslie Z. Benet, Svein We, and Janice B. Schwartz
`
`Index
`
`1673
`
`1697
`
`1707
`
`1793
`
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`

`

`CHAPTERI
`
`PHARMACOKINETICS
`
`The Dynamics of Drug Absorption, Distribution,
`and Elimination
`
`Leslie Z. Benet, Deanna L. Kroetz, and Lewis B. Sheiner
`
`To produce its characteristic effects, a drug must be present
`in appropriate concentrations at its sites of action. Although
`obviously a function of the amount of drug administered,
`the concentrations attained also depend upon the extent and
`rate of its absorption. distribution, binding or localization
`in tissues, biotransformation, and excretion. These factors
`are depicted in Figure 1—1.
`
`PHYSICOCHEMICAL FACTORS
`IN TRANSFER OF DRUGS
`
`ACROSS MEMBRANES
`
`The absorption, distribution, biotransformation, and excre-
`tion of a drug all involve its passage across cell membranes.
`It is essential, therefore, to consider the mechanisms by
`which drugs cross membranes and the physicochemical
`properties of molecules and membranes that influence this
`transfer. Important characteristics of a drug are its molec-
`
`ular size and shape, solubility at the site of its absorption,
`degree of ionization, and relative lipid solubility of its ion-
`ized and nonionized forms.
`
`When a drug permeates a cell, it must obviously tra-
`verse the cellular plasma membrane. Other barriers to drug
`movement may be a single layer of cells (intestinal epi-
`thelium) or several
`layers of cells (skin). Despite these
`structural differences, the diffusion and transport of drugs
`across these various boundaries have many common char-
`acteristics, since drugs in general pass through cells rather
`than between them. The plasma membrane thus represents
`the common barrier.
`
`Cell Membranes. The plasma membrane consists of a bilayer of
`amphipathic lipids, with their hydrocarbon chains oriented inward to
`form a continuous hydrophobic phase and their hydrophilic heads
`oriented outward. Individual lipid molecules in the bilayer can move
`laterally, endowing the membrane with fluidity, flexibility. high elec—
`trical resistance, and relative impermeabiiity to highly polar mole—
`cules. Membrane proteins embedded in the bilayer serve as receptors
`to elicit electrical or chemical signaling pathways and provide se-
`lective targets for drug actions.
`
`
`
`
`EXCRETION
`
`Passive Processes. Drugs cross membranes either by passive
`processes or by mechanisms involving the active participation of
`components of the membrane. In the former, the drug molecule usu-
`ally penetrates by passive diffusion along a concentration gradient
`by virtue of its solubility in the lipid bilayer. Such transfer is directly
`proportional to the magnitude of the concentration gradient across
`the membrane and the lipid:water partition coefficient of the drug.
`The greater the partition coefficient, the higher is the concentration
`of drug in the membrane and the faster is its diffusion. After a steady
`state is attained, the concentration of the free drug is the same on
`both sides of the membrane, if the drug is a nonelectrolyte. For ionic
`compounds, the steady-state concentrations will be dependent on dif-
`ferences in pH across the membrane, which may influence the state
`of ionization of the molecule on each side of the membrane, and on
`the electrochemical gradient for the ion. Most biological membranes
`are relatively permeable to water, either by diffusion or by flow that
`results from hydrostatic or osmotic differences across the membrane.
`Such bulk flow of water can carry with it small, water-soluble sub-
`stances. Most cell membranes permit passage only of water, urea,
`and other small, water-soluble molecules by this mechanism. Such
`substances generally do not pass through cell membranes if their mol-
`ecular masses are greater than 100 to 200 Da.
`MYEAN INC. EXHIBIT NO. 1021 Page 11
`
`ABSORPTION
`
`BlOTFiANSFORMATION
`
`
`Figure 1—1. Schematic representation of the interrelationship
`of the absorption, distribution, binding, biotmnsformation, and
`excretion of a drug and its concentration at its locus of action.
`
`Possible distribution and binding of metabolites are not de-
`picted.
`
`MYLAN INC. EXHIBIT NO. 1021 Page 11
`
`

`

`.1
`
`SECTION I
`
`GENERAL l’RINt'll’H-IS
`
`While most inorganic ions would seem to be sufficiently small
`to penetrate the membrane, their hydrated ionic radius is relatively
`large. The concentration gradient of many inorganic ions is largely
`determined by active transport (e.g., NaJr and KT). The Lransmem-
`brane potential frequently determines the distribution of other ions
`(e.g., chloride) across the membrane. Channels with selectivity for
`individual ions are often controlled to allow regulation of specific
`ionic fluxes. Such mechanisms are of obvious importance in the gen-
`eration of action potentials in nerve and muscle (see Chapter 6) and
`in transmembrane signaling events (see Chapter 2).
`
`Weak Electrolytes and Influence of pH. Most drugs are
`weak acids or bases that are present in solution as both the
`nonionized and ionized species. The nonionized molecules
`are usually lipid soluble and can diffuse across the cell
`membrane. In contrast, the ionized molecules are usually
`unable to penetrate the lipid membrane because of their
`low lipid solubility.
`Therefore. the transmembrane distribution of a weak
`electrolyte usually is determined by its pKa and the pH gra-
`dient across the membrane. To illustrate the effect of pH
`
`on distribution of drugs, the partitioning of a weak acid
`(pK’a = 4.4) between plasma (pH = 7.4) and gastric juice
`(pH = 1.4) is depicted in Figure 1—2. It is assumed that
`the gastric mucosa] membrane behaves as a simple lipid
`barrier that is permeable only to the lipid-soluble, nonion-
`ized form of the acid. The ratio of nonionized to ionized
`drug at each pH is easily calculated from the Hender-
`son—Hasselbalch equation. Thus, in plasma, the ratio of
`nonionized to ionized drug is 1 : 1000; in gastric juice, the
`ratio is 1 :0.001. These values are given in brackets in Fig-
`ure l—2. The total concentration ratio between the plasma
`and the gastric juice would therefore be 1000: i if such a
`system came to a steady state. For a weak base with a pKa
`of 4.4 (BI-1+ .._——'* B + [-I+), the ratio would be reversed,
`as would the thick horizontal arrows in Figure 1—2, which
`
`ill
`
`mm
`[1000!
`I
`T l
`4-2—-
`-
`HA —A + H+ {HA]D+a[A‘]
`
`
`
`indicate the predominant species at each pH. These con-
`siderations have obvious implications for the absorption
`and excretion of drugs, as will be discussed more specifi-
`cally below. The establishment of concentration gradients
`of weak electrolytes across membranes with a pH gradi~
`cut is a purely physical process and does not require an ac-
`tive transport system. All that is necessary is a membrane
`preferentially permeable to one form of the weak electrolyte
`and a pH gradient across the membrane. The establishment
`of the pH gradient is, however, an active process.
`Bulk flow through intercellular pores is the major
`mechanism of passage of drugs across most capillary en-
`dothelial membranes, with the important exception of the
`central nervous system (CNS; see below). These inter-
`cellular gaps are sufficiently large that diffusion across
`most capillaries is limited by blood flow and not by the
`lipid solubility of drugs or pH gradients. This is an im-
`portant factor in filtration across glomerular membranes in
`the kidney (see below). Tight junctions are characteristic
`of capillaries of the CNS and a variety of epithelia. Inter-
`cellular diffusion is consequently limited. Pinocytosis, the
`formation and movement of vesicles across cell mem-
`
`branes, has been implicated in drug absorption. However,
`the quantitative significance of pinocytosis probably is
`negligible.
`
`Carrier-Mediated Membrane 'D'ansport. While passive diffusion
`through the bilayer is dominant in the absorption and distribution of
`most drugs. more active and selective mechanisms can play impor-
`tant roles. Active transport of some drugs occurs across neuronal
`membranes, the choroid plexus, renal tubular cells. and hepatocytes.
`The characteristics of active transport—selectivity, competitive inhi-
`bition by congeners, a requirement for energy, saturability, and move-
`ment against an electrochemical gradient—may be important in the
`mechanism of action of drugs that are subject to active transport or
`that interfere with the active transport of natural metabolites or neu-
`rotransmitters. The term facilitated difiitsion describes a carrier-
`mediated transport process to which there is no input of energy, and
`movement of the substance in question thus cannot occur against an
`electrochemical gradient. Such mechanisms. which also may be
`highly selective for specific conformational structures of drugs, are
`necessary for the transport of endogenous compounds whose rate of
`movement across biological membranes by simple diffusion other-
`wise would be too slow.
`
`DRUG ABSORPTION.
`
`Bl()AV’.—\1LABILITY. AND ROUTES
`OF ADMINISTRA'I‘ION
`
`Absorption describes the rate at which a drug leaves its
`site of administration and the extent to which this occurs.
`
`H]
`[o 00H
`1001
`HA = A'+ H+
`#—
`_..—p- A'+ H+
`ionized
`
`Weak Acid HA
`nonionlzed
`
`pKa = 4.4
`
`However, the clinician is concerned primarily with a pa—
`rameter designated as bioavaiiability, rather than absorp-
`Figure 1—2. Influence (:pr on the distribution of a weak acid
`tion. Bioavailability is a term used to indicate the extent
`between plasma and gastric juice, separated by a lipid barrier.
`MYLAN INC. EXHIBIT NO. 1021 Page 12
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`MYLAN INC. EXHIBIT NO. 1021 Page 12
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`

`

`CHAPTER 1 PHARMACOKINETICS
`
`5
`
`Enteral (Oral) vs. Parenteral Administration. Often
`there is a choice of the route by which a therapeutic agent
`may be given, and a knowledge of the advantages and dis-
`advantages of the different routes of administration is then
`of primary importance. Some characteristics of the major
`routes employed for systemic drug effect are compared in
`Table 1—1.
`
`Oral ingestion is the most common method of drug
`administration. It also is the safest, most convenient, and
`
`to which a drug reaches its site of action or a biological
`fluid from which the drug has access to its site of action.
`For example, a drug that is absorbed from the stomach and
`intestine must first pass through the liver before it reaches
`the systemic circulation. If the drug is metabolized in the
`liver or excreted in the bile, some of the active drug will
`be inactivated or diverted before it can reach the general
`circulation and be distributed to its sites of action. If the
`
`metabolic or excretory capacity of the liver for the agent
`in question is great, bioavailability will be substantially de-
`creased (the so-called first-pass effect). This decrease in
`availability is a function of the anatomical site from which
`absorption takes place; other anatomical, physiological,
`and pathological factors can influence bioavailability (see
`below), and the choice of the route of drug administration
`must be based on an understanding of these conditions.
`Moreover, factors that modify the absorption of a drug can
`change its bioavailability.
`
`most economical. Disadvantages to the oral route include
`the incapability to absorb some drugs because of their
`physical characteristics (e.g., polarity), emesis as a result
`of imitation to the gastrointestinal mucosa, destruction of
`some drugs by digestive enzymes or low gastric pH, ir-
`regularities in absorption or propulsion in the presence of
`food or other drugs, and necessity for cooperation on the
`part of the patient. In addition, drugs in the gastrointestinal
`tract may be metabolized by the enzymes of the mucosa,
`the intestinal flora, or the liver before they gain access to
`the general circulation.
`The parenteral injection of drugs has certain distinct
`advantages over oral administration. In some instances,
`parenteral administration is essential for the drug to be ab-
`sorbed in active form. Availability is usually more rapid
`and more predictable than when a drug is given by mouth.
`The effective dose can therefore be more accurately se-
`lected. In emergency therapy, parenteral administration is
`particularly serviceable. If a patient is unconscious, unco-
`operative, or unable to retain anything given by mouth, par-
`enteral therapy may be a necessity. The injection of drugs
`also has its disadvantages. Asepsis must be maintained, an
`intravascular injection may occur when it is not intended,
`pain may accompany the injection, and it is sometimes
`difficult for patients to perform the injections themselves
`if self-medication is necessary. Expense is another con-
`sideration.
`
`Factors That Modify Absorption. Many variables, in
`addition to the physicochemical factors that affect trans-
`port across membranes, influence the absorption of drugs.
`Absorption, regardless of the site, is dependent upon drug
`solubility. Drugs given in aqueous solution are more
`rapidly absorbed than those given in oily solution, sus-
`pension, or solid form, because they mix more readily with
`the aqueous phase at the absorptive site. For those given
`in solid form, the rate of dissolution may be the limiting
`factor in their absorption. Local conditions at the site of
`absorption alter solubility, particularly in the gastrointesti-
`nal tract. Aspirin, which is relatively insoluble in acidic
`gastric contents, is a common example of such a drug. The
`concentration of a drug influences its rate of absorption.
`Drugs introduced at an administration site in solutions of
`high concentration are absorbed more rapidly than are
`drugs in solutions of low concentration. The circulation to
`the site of absorption also affects drug absorption. In-
`creased blood flow, brought about by massage or local ap-
`Oral Ingestion. Absorption from the gastrointestinal
`plication of heat, enhances the rate of drug absorption; de-
`tract is governed by factors that are generally applicable,
`such as surface area for absorption, blood flow to the site
`creased blood flow, produced by vasoconstrictor agents,
`shock, or other disease factors, can slow absorption. The
`of absorption, the physical state of the drug, and its con—
`centration at the site of absorption. Since most drug ab-
`area of the absorbing surface to which a drug is exposed
`sorption from the gastrointestinal tract occurs via passive
`is one of the more important determinants of the rate of
`drug absorption. Drugs are absorbed very rapidly from
`processes, absorption is favored when the drug is in the
`nonionized and more lipophilic form. Thus, one might ex-
`large surface areas such as the pulmonary alveolar epithe-
`lium, the intestinal mucosa, or, in a few cases after exten-
`pect the absorption of weak acids to be optimal in the acidic
`environment of the stomach, whereas absorption of bases
`sive application, the skin. The absorbing surface is deter—
`might be favored in the relatively alkaline small intestine.
`mined largely by the route of administration. Each of these
`However, it is an oversimplification to extrapolate the pH—
`factors separately or in conjunction with one another may
`have profound effects on the clinical efficacy and toxicity
`partition concept presented'in Figure l~2 to a comparison
`MyYLANereEwmflgflanMfiihEagle 313
`of a drug.
`
`MYLAN INC. EXHIBIT NO. 1021 Page 13
`
`

`

`6
`
`Table 1—1
`
`SECTION I GENERAL PRINCIPLES
`
`Some Characteristics of Common Routes of Drug Administration*
`-—,—_____________________
`ABSORPTION
`LIMITATIONS AND
`ROUTE
`PATTERN
`SPECIAL UTILITY
`PRECAUTIONS
`
`
`Intravenous
`
`Absorption circumvented
`Potentially immediate effects
`
`Valuable for emergency use
`Permits titration of dosage
`Usually required for
`high molecular weight
`protein and peptide drugs
`Suitable for large volumes
`and for irritating substances,
`when diluted
`
`Increased risk of adverse
`effects
`Must inject solutions
`slowly, as a rule
`Not suitable for oily solutions
`or insoluble substances
`
`Subcutaneous
`
`Prompt, from aqueous
`solution
`Slow and sustained, from
`repository preparations
`
`Suitable for some insoluble
`suspensions and for
`implantation of solid pellets
`
`Not suitable for large volumes
`Possible pain or necrosis
`from irritating substances
`
`Intramuscular
`
`Prompt, from aqueous
`solution
`
`Slow and sustained, from
`repository preparations
`
`Suitable for moderate volumes,
`oily. vehicles, and some
`irritating substances
`
`Precluded during anticoagulant
`medication
`
`May interfere with interpretation
`of certain diagnostic tests
`(e.g., creatine kinase)
`
`Oral ingestion
`
`Variable; depends upon
`many factors (see text)
`
`Requires patient cooperation
`Availability potentially erratic
`and incomplete for drugs that
`are poorly. soluble, slowly
`absorbed, unstable, or exten-
`sively metabolized by the liver
`and/or gut
`
`Most convenient and
`
`economical; usually more
`safe
`
`*See text for more complete discussion and for other routes.
`
`ithelia of the stomach and the intestine. The stomach is
`
`at any particular site in the gastrointestinal tract. However,
`the rate of absorption of a drug from the intestine will be
`greater than that from the stomach even if the drug 'is» pre-
`dominantly ionized in the intestine and largely nonionized.
`in the stomach.
`
`lined by a thick, mucus-covered membrane with a small
`surface area and high electrical resistance. The primary
`function of the stomach is digestive. In contrast, the ep-
`ithelium of the intestine has an extremely large surface
`area; it is thin, it has low electrical resistance, and its pri—
`mary function is to facilitate the absorption of nutrients.
`Thus, any factor that accelerates gastric emptying will be
`likely to increase the rate of drug absorption, while any
`factor that delays gastric emptying will probably have the
`opposite effect, regardless of the'characteristics of the drug.
`The experimental data available from the classical work of
`Controlled-Release Preparations. The rate of absorption of a drug
`Brodie (1964) and more recent studies all are consistent
`administered as a tablet or other solid oral—dosage form is partly de-
`with the following conclusion: the nonionized form of a
`pendent upon its rate of dissolution in the gastrointestinal fluids. This
`factor is the basis for the so-called controlled-release, extended-
`drug will be absorbed more rapidly than the ionized form
`MYLAN INC. EXHIBIT NO. 1021 Page 14
`
`Drugs that are destroyed by gastric.juice or that cause
`gastric irritation sometimes are administered in dosage
`forms with a coating that prevents dissolution in the acidic
`gastric contents. However, some enteric-coated prepara-
`tions of a'"drug also may resist dissolution in the intestine,
`and very little of the drug may be absorbed.
`
`MYLAN INC. EXHIBIT NO. 1021 Page 14
`
`

`

`CHAPTER 1 PHARMACOKINETICS
`
`7
`
`release, sustained-release, or prolonged—action pharmaceutical prepa-
`rations that are designed to produce slow, uniform absorption of the
`drug for 8 hours or longer. Potential advantages of such preparations
`are reduction in the frequency of administration of the drug as com-
`pared with conventional dosage forms (possibly with improved com-
`pliance by the patient), maintenance of a therapeutic effect overnight,
`and decreased incidence and/or intensity of undesired effects by elim-
`ination of the peaks in drug concentration that often occur after ad-
`ministration of immediate-release dosage forms.
`Many controlled-release preparations fulfill these theoretical ex-
`pectations. However, the clinician must be aware of some drawbacks
`of these products. Generally, interpatient variability in terms of the
`systemic concentration of the drug that is achieved is greater for con-
`trolled-release than for immediate-release dosage forms. During re-
`peated drug administration, trough drug concentrations resulting from
`controlled—release dosage forms may not be different from those ob-
`served with immediate-release preparations, although the time inter-
`val between trough concentrations is greater for a well-designed con-
`trolled-release product. It is possible that the dosage form may fail,
`and “dose-dumping” with resultant toxicity can occur, since the to-
`tal dose of drug ingested at one time may be several times the amount
`contained in the conventional preparation. Controlled-release dosage
`forms are most appropriate for drugs with short half-lives (less than
`4 hours). So-called controlled-release dosage forms are sometimes
`developed for drugs with long half-lives (greater than 12 hours).
`These usually more expensive products should not be prescribed un-
`less specific advantages have been demonstrated.
`
`as proteins, slowly gain access to the circulation by
`way of lymphatic channels.
`Drugs administered into the systemic circulation by
`any route, excluding the intraarterial route, are subject to
`possible first-pass elimination in the lung prior to distrib—
`ution to the rest of the body. The lungs serve as a tempo-
`rary clearing site for a number of agents, especially drugs
`that are weak bases and are predominantly nonionized at
`the blood pH, apparently by their partition into lipid. The
`lungs also serve as a filter for particulate matter that may
`be given intravenously, and, of course, they provide a route
`of elimination for volatile substances.
`
`Intravenous. The factors concerned in absorption are cir-
`cumvented by intravenous injection of drugs in aqueous
`solution, and the desired concentration of a drug in blood
`is obtained with an accuracy and immediacy not possible
`by any other procedure. In some instances, as in the in-
`duction of surgical anesthesia by a barbiturate, the dose of
`a drug is not predetermined but is adjusted to the response
`of the patient. Also, certain irritating solutions can be given
`only in this manner, since the blood vessel walls are rela-
`
`tively insensitive, and the drug, if injected slowly, is greatly
`diluted by the blood.
`As there are assets to the use of this route of admin-
`istration, so are there liabilities. Unfavorable reactions are
`
`Sublingual Administration. Absorp