`PHARMACOLOGICAL
`BASIS OF
`THERAPEUTICS
`
`Ninth Edition
`
`.
`
`,.
`I
`I.
`i
`
`‘
`
`r
`
`\/
`1
`\.-/
`
`McGraw-Hill
`HEALTH PROFESSIONS DIVISION
`
`New York St. Louis San Francisco Auckland Bogota Caracas Lisbon London Madrid
`Mexico City Milan Montreal New Delhi San Juan Singapore Sydney Tokyo Toronto
`
`AMNEAL
`
`EXHIBIT NO. 1021 Page 1
`
` AMNEAL
`
`
`
`McGraw-Hill
`A Division ofTheMr:Gmuv-Hill Companies
`
`32
`
`Goodman and Gi1man’s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 9/e
`
`Copyright © 1996, I990, I985, 1980, 1975, 1970. 1965, 1955, 1941 by The McGmw-I-Iill Companies,
`Inc. All rights reserved. Printed in the United States ofAmerica. Except as permitted under the United
`States Copyright Act of I976, 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 Lafiler and Clare Stanley,
`and the cover designer was Marsha Cohen/Paralellogram. The index was prepared by Irving Condé
`'Ilul]ar.
`
`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 ofTherapeutics. —9th ed. Iloel G. Hardman,
`Alfred Goodman Gilmnn, Lee E. Limbird.
`p.
`cm.
`,
`Includes bibliographical references and index.
`ISBN 0-07-026266-7 (hardcover)
`ll. Gilman, Alfred.
`I. Goodman. Louis Sanford.
`I. Phannacology.
`2. Chemotherapy.
`III. Hardrnan, Joel G.
`IV. Gilman, Alfred Goodman.
`V. Limbird. Lee E.
`IDNLM: 1. Pharmacology.
`2. Drug Therapy.
`QV 4 G6532 1995]
`RM300.G644
`1995
`615’ .7—dc20
`
`DNLM/DDC
`for Library of Congress
`
`95-36658
`
`AMNEAL
`
`EXHIBIT NO. 1021 Page 2
`
` AMNEAL
`
`
`
`Contents
`
`s e c 'l'
`
`1 o N
`
`1
`
`GENERAL PRINCIPLES
`
`Introduction
`Leslie 2. Benet
`
`. Pharmacokinetics: The Dynami of Drug Absorption, Distribution. and Elimination
`Leslie Z. Benet. Deanna L. Kmetz. and Lewis B. Sheiner
`
`Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug
`Concentration and Effect
`Elliott M. Ross
`
`. Principles of Therapeutics
`Alan S. Nies and Stephen P. Spielberg
`
`. Principles of Toxicology and Treatment of Poisoning
`Curtis D. Klaassen
`
`. Gene-Based Therapy
`Stephen L. Eck and James M. Wilson
`
`SECTION II
`
`DRUGS ACTING AT SYNAPTIC AND NEUROEFFECTOR
`JUNCTIONAL SITES
`
`6. Neurotrlmsmission: The Autonomic and Somatic Motor Nervous Systems
`
`103
`
`105
`
`' Brian B. Hoflman. Robert J. Leflcowitz. and Palmer Tavlor
`AMNEAL
`V
`
`EXHIBIT NO. 1021 Page 3
`
` AMNEAL
`
`
`
`CONTENTS
`
`Muscarinlc Receptor Agonists and Antagonists
`Joan Heller Brown and Palmer Taylor
`
`. Anticholinterase Agents
`
`Palmer Taylor
`
`. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia
`Palmer Taylor
`
`. Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor
`
`Antagonists
`Brian B. Hofirnan 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. Nenrotransmission 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. Catteralfand Kenneth Mackie
`
`16. Therapeutic Gases
`Roderic G. Eckenhofl‘ and David E. Longnecker
`
`17. Hypnotlcs and Sedatives; Ethanol
`William R. Hobbs, Theodore W. Roll, and Todd A. Vendoorn
`
`13. Drugs and the Treatment of Psychiatric Disorders: Psychosis and Anxiety
`Ross J. Baldessafini
`
`19. Drugs and the 'fi'eatment of Psychiatric Disorders: Depression and Mania
`Ross J. Baldessarini
`
`20. Drugs Effective in the Therapy of the Epilepsies
`James 0. McNamara
`
`349
`
`361
`
`399
`
`431
`
`461
`
`AMNEAL
`
`EXHIBIT NO. 1021 Page 4
`
` AMNEAL
`
`
`
`CONTENTS
`
`21. Drugs Effective in the Theta]-Jy of Migraine
`Stephen .1. Pemutka
`
`22. "Ireatment 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 R O'Brien
`
`SECTION IV
`
`AUTACOIDS; DRUG THERAPY OF INFLAMMATION
`
`Introduction
`
`William E. Serafin and Kenneth S. Babe, Jr:
`
`25. Histamine, Bradyldnin and Their Antagonists
`
`Kenneth S. Babe, In. and William E. Serafin
`
`26. Lipid-Derived Autacoids: Eieosanoids and Platelet-Activating Factor
`
`William B. Campbell and Perry V Halushlca
`
`27. Analgesic-Antlpyretic 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
`
`685
`
`715
`
`31. Renin and Angiotensin
`EM" ‘Y’ ’“""’°" """ """" C‘ G“'"’°"
`
`AMNEAL
`
`733
`EXHIBIT N0. 1021 Page 5
`
` AMNEAL
`
`
`
`viii
`
`CONTENTS
`
`32. Drugs Used for the 'lreatment of Myocardial Ischemia
`Rose Marie Robertson and David Robertson
`
`33. Antihypertensive Agents and the Drug Therapy of Hypertension
`John A. Oates
`
`34. Pharmacological 'lreatment of Heart Failure
`Ralph A. Kelly and Thomas W Smith
`
`35. Antiarrhythmic Drugs
`Dan M. Roden
`
`36. Drugs Used in the '11-eatment of Hyperlipoproteinemias
`Joseph L. Witztum
`
`SECTION VI
`
`DRUGS AFFECTING GASTROINTESTINAL FUNCTION
`
`37. Agents for Control of Gastric Acidity’ and 'h'eatment 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 13 Webster: Jr:
`
`40. Drugs Used in the Chemotherapy of Protozoa] Infections: Malaria
`James W. Tracy and Leslie II Webster: Jr:
`
`965
`
`AMNEAL
`
`EXHIBIT NO. 1021 Page 6
`
` AMNEAL
`
`
`
`CONTENTS
`
`41. Drugs Used in the Chemotherapy of Protozoal Ini'ections:"Ii-ypanosomiasis,
`Leishmaniasis, Amebiasis, Giardiasis, lrichomoniasis, and Other Protozoa! Infections
`James W Tracy and Leslie 1". Webster; Jr:
`
`42. Drugs Used in the Chemotherapy of Helminthiasis
`James W. Tracy and Leslie 73 Webster: Jr:
`
`SECTION IX
`CHEMOTHERAPY OF MICROBIAL DISEASES
`
`43. Antimicrobial Agents: General Considerations
`Henry I7. Chambers and Merle A. Sande
`
`44. Antimicrobial Agents: Sulfonamides, 'l\'imethoprim-Sulfamethoxazole, Quinolones,
`and Agents for Urinary Tract Infections
`Gerald L. Mandell and William A. Perri, Jr:
`
`45. Antimicrobial Agents: Penicillins, Cephalosporins, and Other B-Lactam
`Antibiotics
`Gerald L Mandell and William A. Perri, Jr.
`
`46. Antimicrobial Agents: The Aminoglycosides
`Henry E Chambers and Merle A. Sande
`
`47. Antimicrobial Agents: Tetracyclines, Chloramphenicol, Erythnomycin, and
`Miscellaneous Antibacterial Agents
`Joan E Kapusnik-Uner; Merle A. Sande, and Henry E Chambers
`
`48. Antimicrobial Agents: Drugs Used in the Chemotherapy of Thberculosis and Leprosy
`" Gerald L. Mandel! and William A. Perri. Jr.
`
`49. Antimicrobial Agents: Antifungal Agents
`John E. Bennett
`
`50. Antimicrobial Agents: Antiviral Agents
`Frederick G. Hayden
`
`SECTION X
`
`CHEMOTHERAPY; OF NEOPLASTIC DISEASES
`
`1225
`
`1225
`
`~
`
`Introduction
`Paul Calabresi and Bruce A. Chabner
`
`AMNEAL
`
`EXHIBIT NO. 1021 Page 7
`
`‘
`
` AMNEAL
`
`
`
`CONTENTS
`
`51. Antineoplastic Agents
`Bruce A. Chabner, Carmen J. Allegra. Gregory A. Curt.
`and Paul Calabresi
`
`SECTION XI
`
`DRUGS USED FOR IMMUNOMODULATION
`
`52. Immnnomodulators: Immunosuppressive Agents and Immunostimulants
`
`Robert B. Diasio and Albert E 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 I-Iypothalamic Releasing Factors
`Mario Ascoli and Deborah L Segaloff
`
`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. Adrenooorticotropic Hormone; Adrenoeortical Steroids and Their Synthetic
`Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones
`Bernard P. Schimmer and Keith L. Parker
`
`1459
`
`AMNEAL
`
`EXHIBIT NO
`
`. 1021 Page8
`
` AMNEAL
`
`
`
`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 Ilirnover: 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 I’. Werth
`
`s E c 'r
`
`I o N
`
`x v 1
`
`OPHTHALMOLOGY
`
`65. Ocular Pharmacology
`
`Sayoko E. Momi and Paul R. Lichter
`
`SECTION XVII
`
`TOXICOLOGY
`
`66. Heavy Metals and Heavy-Metal Antagonists
`Curtis D. Klaassen
`
`AMNEAL
`
`EXHIBIT NO. 1021 Page 9
`
` AMNEAL
`
`
`
`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
`
`I]. Design and Optimization of Dosage Regimens; Pharmacokinetic Data
`Leslie Z. Benet, Svein ¢ie, and Janice B. Schwartz
`
`Index
`
`AMNEAL
`
`EXHIBIT NO. 1021 Page 10
`
` AMNEAL
`
`
`
`CHAPTER
`
`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, biotransfomration, 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-
`actcristics. 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, cndowing the membrane with fluidity. flexibility, high elec-
`trical resistance. and relative impermeability to highly polar mole-
`cules. Membrane proteins embedded in the bilayer serve as receptors
`to elicit electrical or chemical signaling pathways and provide sc-
`lective targets for drug actions.
`
`72 (V I >4-KIN‘-:+ "_}l'lt~‘:"« '
`
`\"..T:’~.
`
`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 coefiicient of the drug.
`The greater the partition coefiicient. the higher is the concentration
`of drug in the membrane and the faster is its difiusion. 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 difierences 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.
`AMNEAL EXHIBIT N0. 1021 Page 11
`
`Figure 1-1. Schematic representation ofthe inumlationship
`ofthe absorption, distribution, binding, biotransfonnation, and
`excretion ofa drug and its concentration at its locus of action.
`
`Possible distribution and binding of metabolites are not de-
`picted.
`
` AMNEAL
`
`
`
`SECTION I GENERAL PRINCIPLES
`
`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., Na* and K*). The transmem-
`brane potential frequently determines the distribution of other ions
`(e.g.. chloride) across the membrane. Channels with selectivity for
`individual ions are ofien 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 pK. 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. = 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 mucosal 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:l000; in gastric juice, the
`ratio is 1 :0.00l. These values are given in brackets in Fig-
`ure 1-2. The total concentration ratio between the plasma
`and the gastric juice would therefore be l000:1 if such a
`system came to a steady state. For a weak base with a pKa
`of 4.4 (BH* .—_e B + H*'). the ratio would be reversed,
`as would the thick horizontal arrows in Figure I-2, which
`
`[1]
`
`[1000]
`
`1001
`
`HA ——>A'+ H+ [H;]°:a[lA']
`
`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 elecuolytes across membranes with a pH gradi-
`cnt 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). ‘right 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 ‘Ii-ansport. While passive dilfusion
`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
`membr'anes, 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 difiiuion 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 difiusion other-
`wise would be too slow.
`
`1.001
`
`DRUG ABSORPTION.
`
`BIOAVAILABILITY, AND ROUTES
`OF ADMINISTRATION
`
`pK, = 4.4
`
`[o.oo1}
`HA "“'__. A'+ H‘*
`A
`Weak Acld HA ?,
`nonlonlzed
`
`A'+ I-1*
`ionized
`
`Absorption describes the rate at which a drug leaves its
`site of administration and the extent to which this occurs.
`However. the clinician is concerned primarily with a pa-
`rameter designated as bioavailability, rather than absorp-
`Figure 1-2. Influence ofpH on the distribution afa weak acid
`tion. Bioavailability is a term used to indicate the extent
`between plasma and gastric juice. separated by a lipid barrier.
`AMNEAL EXHIBIT NO. 1021 Page 12
`
` AMNEAL
`
`
`
`CHAPTER 1 PHARMACOKINETICS
`
`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 difierent 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 dmg 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 adminishation
`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 irritation 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 afiect 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,
`creased blood flow, produced by vasoconstrictor agents,
`such as surface area for absorption, blood flow to the site
`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 fonn. 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 adminisuation. Each of these
`However, it is an oversimplification to extrapolate the pH-
`factors separately or in conjunction with one another may
`nan-fifinn an
`t
`nmd ' F’
`1...2 [
`'
`have profound effects on the clinical eflicacy and toiricim
`AMNEAL "5:
`ii%zIti'i..p$-§..a.o21i.°§§'pg§"s£5
`of a dnig.
`
` AMNEAL
`
`
`
`SECTION I GENERAL PRINCIPLES
`
`Table 1-1
`
`Some Characteristics of Common Routes of Drug Administration*
`ABSORPTION
`I..IMl'l'A‘l'l0NS AND
`PATTERN
`PRECAUTIONS
`
`SP'BCIALU'l'ILl'l'Y
`
`ROUTE
`
`Intravenous
`
`Absorption circumvented
`Potentially immediate effects
`
`Subcutaneous
`
`Prompt, from aqueous
`solution
`
`Slow and sustained, from
`repository preparations
`
`Prompt, from aqueous
`solution
`
`Slow and sustained, from
`repository preparations
`
`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
`etfects
`
`Must inject solutions
`slowly, as a rule
`Not suitable for oily solutions
`or insoluble substances
`
`Suitable for some insoluble
`
`suspensions and for
`implantation of solid pellets
`
`Not suitable for large volumes
`Possible pain or necrosis
`from irritating substances
`
`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)
`
`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
`
`Oral ingestion
`
`Variable; depends upon
`many factors (see text)
`'
`
`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 thanthat 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 thecharacteristics 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
`drug -will be absorbed more rapidly than the ionized in-'-'0
`f-"""' ‘- '''- basis for the so-called controlled-release, extended-
`AMNEAL EXHIBIT NO. 1021 Page 14
`
`Drugs that are destroyed by gastric.juice or that cause
`gastric initation 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'dn1g also may resist dissolution in the intestine,
`and very little of the drug may be absorbed.
`
` AMNEAL
`
`
`
`CHAPTER 1 PHARMACOKINETICS
`
`release, sustained-release, or prolonged-action pharmaceutical prepa-
`rations that are designed to produce slow, unifonn 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 andlor intensity of undesired effects by elim-
`ination of the peaks in drug concentration that oflen occur after ad-
`ministration of immediate-release dosage forms.
`Many controlled-release preparations fulfill these theoretical ex-
`pectations. However, the
`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 difierent 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 conuolled-release dosage forms are sometimes
`developed for drugs with long half-lives (greater than I2 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. Absorption from the oral mucosa has
`special significance for certain drugs, despite the fact that the sur-
`face area available is small. For example, nitroglycerin is effective
`when retained sublingually because it is nonionic and has a very high
`lipid solubility. Thus, the drug is absorbed very rapidly. Nitrogly-
`cerin also is very potent; relatively few molecules need to be absorbed
`to produce the therapeutic effect. Since venous drainage from the
`mouth is to the superior vena cava. the drug also is protected from
`rapid first-pass metabolism by the liver. Hepatic first-pass metabo-
`lism is sufficient to prevent the appearance of any active nitroglyc-
`erin in the systemic circulation if the convenfional tablet is swal-
`lowed.
`
`Rectal Administration. The rectal route oflen is useful when ora.l
`ingestion is precluded by vomiting or when the patient is uncon-
`scious. Approximately 50% of the drug that is absorbed from the
`rectrmr will bypass the liver; the potential for hepatic first-pass
`metabolism is thus less than that for an