,
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`y
`
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`_—_
`
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`
`m
`
`BRUCE A. CHABNER©BJORN C. KNOLLMANN
`
`SL
`Baiai,S
`The Pharmacological
`Basis of
`
`is al ee
`
`LAURENCE L. BRUNTON
`
`1
`
`NEUROCRINE 1032
`
`

`

`Goodman & Gilman’s
`The Pharmacological Basis of
`THERAPEUTICS
`
`twelfth edition
`
`editor
`Laurence L. Brunton, PhD
`Professor of Pharmacology and Medicine
`School of Medicine, University of California, San Diego
`La Jolla, California
`
`associate editors
`Bruce A. Chabner, MD
`Professor of Medicine
`Harvard Medical School
`Director of Clinical Research
`Massachusetts General Hospital Cancer Center
`Boston, Massachusetts
`Bjorn C. Knollmann, MD, PhD
`Professor of Medicine and Pharmacology
`OatesInstitute for Experimental Therapeutics
`Division of Clinical Pharmacology
`Vanderbilt University School of Medicine
`Nashville, Tennessee
`
`raw Medical
`
`New York Chicago San Francisco Lisbon London Madrid Mexico City Milan
`New Delhi San Juan Seoul Singapore Sydney Toronto
`
`2
`
`

`

` The McGraw-Hill Companies
`
`Goodman and Gilman’s
`
`The Pharmacological Basis of Therapeutics, Twelfth Edition
`
`Copyright © 2011, 2006, 2001, 1996, 1990, 1985, 1980, 1975, 1970, 1965, 1955, 1941 by The McGraw-Hill Compa-
`nies, Inc. All rights reserved, Printed in China. Except as permitted under the United States Copyright Act of 1976,
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`retrieval system, without the prior written permission of the publisher.
`
`S67 8:9 0 CEP/ICTP
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`[7 16:15
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`ISBN 978-0-07-162442-8
`MHID 0-07-162442-2
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`Library of Congress Cataloging-in-Publication Data
`
`Goodman & Gilman’s pharmacological basis of therapeutics.—| 2th ed. / editor,
`Laurence L. Brunton ; associate editors, Bruce A, Chabner, Bjérn C. Knollmann.
`p..fcnk
`Other title: Goodman and Gilman’s pharmacological basis of therapeutics
`Othertitle: Pharmacological basis of therapeutics
`Rev, ed. of: Goodman & Gilman's the pharmacological basis of therapeutics.
`Laurence L. Brunton. c2006.
`
`| 1th ed. / editor,
`
`Includes bibliographical references and index.
`ISBN-13: 978-0-07-162442-8 (hardcover : alk. paper)
`ISBN- 10: 0-07-162442-2
`
`II. Brunton, Laurence L.
`I. Goodman, Louis Sanford, 1906-
`2. Therapeutics.
`|. Pharmacology.
`IV. Knollmann, Bjérn C. V. Goodman & Gilman’s the pharmacological
`III. Chabner, Bruce.
`basis of therapeutics. VI. Title: Goodman and Gilman’s pharmacological basis of therapeutics.
`VIL. Title: Pharmacological basis of therapeutics.
`[DNLM:
`1. Pharmacological Phenomena.
`2. Drug Therapy. QV 4 G6532 2011]
`RM300.G644 2011
`615’.7-de22
`
`2010000236
`
`McGraw-Hill booksare available at special quantity discounts to use as premiumsor sales promotions,or for use in
`corporate training programs. To contact a representative, please email us at bulksales@mcegraw-hill.com.
`
`3
`
`

`

`Contents
`
`Contributors xi
`
`Preface xvii
`
`Preface to the First Edition xix
`
`Acknowledgements xxi
`
`1
`
`SECTIONI
`General Principles
`l. Drug Invention and the Pharmaceutical
`TRUSEY xx or ss macexersvsuszwmmrerarcmnmcnnednaeemenensens Saeacncntions3
`Suzanne M. Rivera and Alfred Goodman Gilman
`. Pharmacokinetics: The Dynamics of Drug
`Absorption, Distribution, Metabolism,
`AN Elimination wo... ee ccesseseeseeeesseessseessssesenseers 17
`lain L. 0. Buxton and Leslie Z. Benet
`. Pharmacodynamics: Molecular Mechanisms
`OF Ee ACTION pccncccnscimmnemenrernnsrnnrertantemrneereal41
`Donald K. Blumenthal and James C. Garrison
`. Drug Toxicity and POiSOniNg......cceeeceeeeeeeeetseeeeees73
`Kevin C, Osterhoudt and Trevor M. Penning
`. Membrane Transporters and
`GEIRCSROSE 2.2.5 a5 se conea 89
`Kathleen M. Giacomini and Yuichi Sugiyama
`. Drug Metabolism.........c.c:cecsssesvesseessevsrecnssenseseeras 123
`Frank J. Gonzalez, Michael Coughtrie,
`and Robert H. Tukey
`, Pharnacopenctits:ccanninsniccinimmanen 145
`Mary V, Relling and Kathleen M, Giacomini
`
`SECTION II
`Neuropharmacology
`8. Neurotransmission: The Autonomic
`and Somatic Motor Nervous Systems .........600+ 171
`Thomas C. Westfall and David P. Westfall
`
`169
`
`2 —
`
`. Muscarinic Receptor Agonists
`And AntagOnistsscvsescissevivcasersnsvcecssssscetsvecsesscvressarss 219
`Joan Heller Brown and Nora Laiken
`. Anticholinesterase Agents.0.......cccceeseeeeeesersen 239
`Palmer Taylor
`. Agents Acting at the Neuromuscular
`Junction and Autonomic Ganglia...255
`Ryan E. Hibbs and Alexander C. Zambon
`. Adrenergic Agonists and Antagonists ...........608277
`Thomas C. Westfall and David P. Westfall
`. 5-Hydroxytryptamine (Serotonin)
`aiid Dapamime sescssasesicrinnsnsasivcuentsiemuaeies335
`Elaine Sanders-Bush and Lisa Hazelwood
`. Neurotransmission and the Central
`Nervous SYSt@M .....ccceesceccersseesenersterssrensnrerseeeetenes363
`Perry B. Molinoff
`. Drug Therapy of Depression
`and Anxiety Disorders............-.:cccsscereeseeeeeeeeeseesees 397
`James M. O'Donnell and Richard C. Shelton
`. Pharmacotherapy of Psychosis
`BUC Maia oicssciwcnmanenenancsreamuanornneiaicueceiervennes 417
`Jonathan M. Meyer
`. Hypnotics and Sedatives...........ccccccsseeseeseeeenseseees457
`S. John Mihic and R. Adron Harris
`. Opioids, Analgesia, and Pain
`ManaQeMient wicisiicscaissenisresvecarercavonseaessmacsversens48]
`Tony L. Yaksh and Mark S. Wallace
`. General Anesthetics and Therapeutic Gases .........$27
`Piyush M. Patel, Hemal H. Patel,
`and David M. Roth
`. Local Anesthetics .........ccccceccccesesecseesesseeserseeeeeeeeeee 565
`William A. Catterall and Kenneth Mackie
`. Pharmacotherapyof the Epilepsies..................++.583
`James 0. McNamara
`
`4
`
`

`

`viii
`
`22. Treatment of Central Nervous System
`Degenerative Disorders........::e:cceeseeeeeeterseeneeeeeeeee609
`David G. Standaert and Erik D. Roberson
`
`23. Ethanol and Methanol ..........cccsesseesseseersersserenses629
`Marc A. Schuckit
`DA, DriSAAGICHOivosce i secssewecccccrncenea cn esrsiceed649
`Charles P. O’Brien
`
`SLNILNOD
`
`SECTION II
`Modulation of Cardiovascular
`Function
`25. Regulation of Renal Function
`and: Vascular VONMIINIG .-.ccssicscidisdertsenaiaumanisnes 671
`Robert F, Reilly and Edwin K. Jackson
`26. Renin and Angiotensin ......... ccc cceeeeete cence721
`Randa Hilal-Dandan
`
`669
`
`27. Treatment of Myocardial Ischemia
`and Hypertension 0.0.0... ceeeesseseeseseeeeeeeesee745
`Thomas Michel and Brian B. Hoffman
`28. Pharmacotherapy of Congestive
`Heart Failure... ccc ccecsceesseseccseececsseenseeaeeseeenes789
`Bradley A. Maron and Thomas P. Rocco
`29, Anti-Arrhythmic Drugs... reeessseeeeeeeeeees 815
`Kevin J. Sampson and Robert S. Kass
`30. Blood Coagulation and Anticoagulant,
`Fibrinolytic, and Antiplatelet Drugs,........s-sse 849
`Jeffrey I, Weitz
`31. Drug Therapy for Hypercholesterolemia
`AUG Dy SPOS a vscssssccmcorsiseccseumreuesmaanyserrseass 877
`Thomas P. Bersot
`
`909
`
`SECTION IV
`Inflammation, Immunomodulation,
`and Hematopoiesis
`32. Histamine, Bradykinin, and Their
`AMLAGONISES 0c. .ceccececcececeeceneeesaeecseeseaeeneeeseeseneeee911
`Randal A. Skidgel, Allen P. Kaplan, and Ervin G. Erdos
`33. Lipid-Derived Autacoids: Eicosanoids
`and Platelet-Activating Factor...937
`Emer M. Smyth, Tilo Grosser, and Garret A. FitzGerald
`34. Anti-inflammatory, Antipyretic, and Analgesic
`Agents; Pharmacotherapy of Gout..........ccceeeeer959
`Tilo Grosser, Emer M. Smyth, and Garret A, FitzGerald
`35. Immunosuppressants, Tolerogens, and
`Immunostimulant ...........2.0....:ccecccccceceseeeeeeeeeeceees 1005
`
`Alan M. Krensky, William M. Bennett, and Flavio Vincenti
`36. Pulmonary Pharmacology......cccc:ccsssscssssesssseevenes 1031
`Peter J. Barnes
`37, Hematopoietic Agents: Growth Factors,
`Minerals, and Vitamins.............ccc:cccccceceeseeeeeereees 1067
`Kenneth Kaushansky and Thomas J. Kipps
`
`1101
`
`SECTION V
`Hormones and Hormone
`Antagonists
`38. Introduction To Endocrinology:
`The Hypothalamic-Pituitary Axis ...0..0..0...2.1103
`Keith L. Parker and Bernard P. Schimmer
`39. Thyroid and Anti-Thyroid Drugs 0... 1129
`Gregory A. Brent and Ronald J. Koenig
`40. Estrogens and Progestins......:ccccse serene l 163
`Ellis R. Levin and Stephen R. Hammes
`41. Androgens oe eeeeceeecseeeeeseeeeeeeneeteeeereneeeeeneenens 1195
`Peter J. Snyder
`42. ACTH, Adrenal Steroids, and Pharmacology
`of the Adrenal Cortex ...........:::ccceceesesseeseeseeeeeeeees 1209
`Bernard P. Schimmer and John W. Funder
`43. Endocrine Pancreas and Pharmacotherapy
`of Diabetes Mellitus and Hypoglycemia............. 1237
`Alvin C. Powers and David D'Alessio
`44, Agents Affecting Mineral Ion
`Homeostasis and Bone Turnover.................:0+ 1275
`Peter A. Friedman
`
`1307
`
`SECTION VI
`Drugs Affecting Gastrointestinal
`Function
`45, Pharmacotherapy of Gastric Acidity, Peptic
`Ulcers, and Gastroesophageal Reflux Disease....1309
`John L. Wallace and Keith A. Sharkey
`46. Treatment of Disorders of Bowel Motility and
`Water Flux; Anti-Emetics; Agents Used in
`Biliary and Pancreatic Disease ...............:0:eeeee 1323
`Keith A. Sharkey and John L. Wallace
`47, Pharmacotherapy of Inflammatory
`BOWE] DisS@aS.cccscinccucanscnamcncienemonnanie 1351
`John L. Wallace and Keith A. Sharkey
`
`1363
`
`SECTION VII
`Chemotherapy of Microbial
`Diseases
`48. General Principles of Antimicrobial
`SPRAY casccxonrinanasesin semeramncnevesnrcsnnirmcs sence. 1365
`Tawanda Gumbo
`49. Chemotherapy of Malaria ................................-.1383
`Joseph M, Vinetz, Jérome Clain, Viengngeun Bounkeua,
`Richard T. Eastman, and David Fidock
`50. Chemotherapy of Protozoal Infections:
`Amebiasis, Giardiasis, Trichomoniasis,
`Trypanosomiasis, Leishmaniasis, and Other
`Protozoal Infections jacisasscsiedsmnnaiiwaves 1419
`Margaret A. Phillips and Samuel L. Stanley, Jr.
`
`5
`
`

`

`. Chemotherapy of Helminth Infections................1443
`James McCarthy, Alex Loukas, and Peter J. Hotez
`. Sulfonamides, Trimethoprim-Sulfamethoxazole,
`Quinolones, and Agents for Urinary Tract
`LNTOQHOTIS ssacovascarsnscenaveassuersmenmenerniaanstancocnuaarenveses 1463
`William A. Petri, Jr.
`. Penicillins, Cephalosporins, and Other
`PLactati Antibighies viccsceseicisssciscnssesiaraamsarsisnnts 1477
`William A.Petri, Jr.
`AIMIMOBYOOSIOES iscccscevsnnccieorrnsvecnaiecsrvarens 1505
`Conan MacDougall and Henry F. Chambers
`Protein Synthesis Inhibitors and
`Miscellaneous Antibacterial Agents...................1521
`Conan MacDougall and Henry F. Chambers
`. Chemotherapy of Tuberculosis, Mycobacterium
`Avium Complex Disease, and Leprosy...............- 1549
`Tawanda Gumbo
`
`34,
`
`55,
`
`« PRDGAT ASONS asesssiice cccccarouincenaagmaaneponunausannsaes 1571
`John E, Bennett
`. Antiviral Agents (Nonretroviral)......0....00..00c000. 1593
`Edward P, Acosta and Charles Flexner
`. Antiretroviral Agents and
`Treatment of HIV Infectionniccc..ccccccccccccsccevessssees 1623
`Charles Flexner
`
`SECTIONVIII
`Chemotherapy of Neoplastic
`1665
`Diseases
`60. General Principles of Cancer Chemotherapy...... 1667
`Bruce A, Chabner
`Cytotoxic Agents cios.ccccccunipaieumcaiaionnes 1677
`Bruce A. Chabner, Joseph Bertino, James Cleary, Taylor Ortiz,
`Andrew Lane, Jeffrey G. Supko, and David Ryan
`
`61.
`
`SLNILNOD
`
`62.
`
`63.
`
`Targeted Therapies: Tyrosine Kinase Inhibitors,
`Monoclonal Antibodies, and Cytokines..............1731
`Bruce A. Chabner, Jeffrey Barnes, Joel Neal, Erin Olson,
`Hamza Mujagic, Lecia Sequist, Wynham Wilson, Dan L. Longo,
`Constantine Mitsiades, and Paul Richardson
`Natural Products in Cancer Chemotherapy:
`Hormones and Related Agents .............. eee 1755
`Beverly Moy, Richard J. Lee,
`and Matthew Smith
`
`SECTIONIX
`1771
`Special Systems Pharmacology
`64. Ocular Pharmacology ........seccsccsceseceeeseeeeeeeeseeeees 1773
`Jeffrey D. Henderer and Christopher J. Rapuano
`65. Dermatological Pharmacology... 1803
`Craig Burkhart, Dean Morrell,
`and Lowell Goldsmith
`Contraception and Pharmacotherapy of
`Obstetrical and Gynecological Disorders............ 1833
`Bernard P. Schimmer and Keith L. Parker
`Environmental Toxicology;
`Carcinogens and Heavy Metals...........::cccceseeees 1853
`Michael C. Byrns and Trevor M. Penning
`
`67.
`
`66.
`
`APPENDICES
`1.
`Principles of Prescription Order
`Writing and Patient Compliance.............ceee 1879
`lain L. 0. Buxton
`. Design and Optimization of Dosage
`Regimens: Pharmacokinetic Data ............::::0+- 189]
`Kenneth E. Thummel, Danny D. Shen, and Nina
`Isoherranen
`
`Index
`
`1991
`
`6
`
`

`

`Ch
`
`ler
`
`Pharmacokinetics: The Dynamics
`of Drug Absorption, Distribution,
`Metabolism, and Elimination
`
`Tain L. 0. Buxton and
`Leslie Z. Benet
`
`In order to understand and control the therapeutic action of
`drugs in the human body, one must know how much drug
`will reach the site(s) of drug action and when this will
`occur. The absorption,distribution, metabolism (biotrans-
`formation), and elimination of drugs are the processes of
`pharmacokinetics (Figure 2-1), Understanding and
`employing pharmacokinetic principles can increase the
`probability of therapeutic success and reduce the occur-
`rence of adverse drug effects in the body.
`
`PHYSICOCHEMICAL FACTORS IN
`
`TRANSFER OF DRUGS ACROSS
`MEMBRANES
`
`The absorption, distribution, metabolism, excretion, and
`action of a drug all involve its passage across cell mem-
`branes. Mechanisms by which drugs cross membranes
`and the physicochemical properties of molecules and
`membranesthat influence this transfer are critical to
`understanding the disposition of drugs in the human
`body. The characteristics of a drug that predict its move-
`ment and availability at sites of action are its molecular
`size and structural features, degree of ionization,relative
`lipid solubility ofits ionized and non-ionized forms, and
`its binding to serum andtissue proteins. In most cases,
`a drug must traverse the plasma membranes of many
`cells to reachits site of action. Although barriers to drug
`movement may be a single layer of cells (intestinal
`epithelium) or several
`layers of cells and associated
`extracellular protein (skin), the plasma membrane rep-
`resents the commonbarrierto drug distribution.
`Cell Membranes. The plasma membrane consists of a bilayer of
`amphipathic lipids with their hydrocarbon chains oriented inward to
`
`the center of the bilayer to form a continuous hydrophobic phase and
`their hydrophilic heads oriented outward, Individual lipid molecules
`in the bilayer vary according to the particular membrane and can
`movelaterally and organize themselves with cholesterol (e.g., sphin-
`golipids), endowing the membrane with fluidity, flexibility, organi-
`zation, high electrical resistance, and relative impermeability to
`highly polar molecules. Membrane proteins embedded in the bilayer
`serve as structural anchors, receptors, ion channels, or transporters
`to transduce electrical or chemical signaling pathways and provide
`selective targets for drug actions. In contrast to earlier proposals that
`cell membranes are fluid and thus proteins collide in an unordered
`fashion, we now understand that membranes are highly ordered and
`compartmented (Pinaud etal., 2009; Singer, 2004). These proteins
`may be associated with caveolin and sequestered within caveolae;
`they may be excluded from caveolae; or they may be organized in
`signaling domainsrich in cholesterol and sphingolipid not containing
`caveolin or other scaffolding proteins(1.c., lipid rafts).
`Cell membranes arerelatively permeable to watereither by
`diffusion or by flow resulting from hydrostatic or osmotic differ-
`ences across the membrane, and bulk flow of water can carry with
`it drug molecules. However, proteins with drug molecules bound to
`them are too large and polar for this type of membrane passage to
`occur. Transmembrane movement of drug generally is limited to
`unbound drug; thus drug-protein complexes constitute an inactive
`reservoir of drug that can influence both therapeutic as well as
`unwanted drug effects. Paracellular passage through intercellular
`gaps is sufficiently large that transfer across capillary endothelium
`is generally limited by blood flow and not by other factors. As
`described later, such membrane passage is an important factor in
`filtration across the glomerulus in the kidney.-Important exceptions
`exist in such capillary diffusion; “tight” intercellular junctions are
`present in specific tissues, and paracellular passage in them is lim-
`ited. Capillaries of the central nervous system (CNS) and a variety
`ofepithelial tissues have tight junctions. Bulk flow of water can
`carry with it small water-soluble substances, but bulk-flow transfer
`is limited when the molecular massofthe solute exceeds 100-200 Da.
`
`Accordingly, most large lipophilic drugs must pass through thecell
`membrane itself (Figure 2-2),
`
`7
`
`

`

` CENTRAL
` COMPARTMENT —
`
`
`
`
` CLEARANCE
`
`Figure 2-1 The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration
`at its sites of action. Possible distribution and binding of metabolites in relation to their potential actions at receptors are not depicted,
`
`18
`
` am=mz>f
`
`e7a—
`
`_=°—
`
`_7-r
`
`mw
`
`v
`
`nd
`
`in pH across the membrane, whichwill influencethestate of ionization
`of the moleculedisparately on either side of the membrane and can
`effectively trap drug on one side of the membrane.
`
`Passive Flux Across Membranes. Drugs cross membraneseither by
`passive processes or by mechanismsinvolving the active participation
`of componentsof the membrane. In passive transfer, the drug molecule
`usually penetrates by diffusion along a concentration gradient by virtue
`ofits solubility in the lipid bilayer. Such transfer1s directly proportional
`to the magnitude ofthe concentration gradient across the membrane, to
`the lipid-waterpartition coefficient of the drug, and to the membrane
`surface area exposed to the drug. The greaterthe partition coefficient,
`the higher is the concentration of drug in the membrane andthe faster
`is its diffusion. After a steady state is attained, the concentration ofthe
`unbound drugis the same on both sides of the membraneifthe drugis
`anon-electrolyte. For ionic compounds,the steady-state concentrations
`dependonthe electrochemical gradient for the ton and on differences
`
`Weak Electrolytes and the Influence of pH. Many drugs
`are weak acids or bases that are present in solution as
`both the non-ionized and ionized species. The non-ion-
`ized molecules usually are more lipid soluble and can
`diffuse readily across the cell membrane. In contrast, the
`ionized molecules usually are less able to penetrate the
`lipid membrane becauseof their low lipid solubility, and
`passage will depend on the leakiness of the membrane
`related to the membrane’s electrical resistance. Therefore,
`the transmembranedistribution of a weak electrolyte is
`influenced by its pK, and the pH gradient across the
`ACTIVE TRANSPORT
`PASSIVE TRANSPORT
`membrane. The pX,is the pH at whichhalf the drug
`Saeee
`(weak acid or base electrolyte) is in its ionized form.
`Paracellular Diffusion
`Facilitated
`Drug
`transport
`diffusion
`transporters
`To illustrate the effect of pH on distribution of
`drugs, the partitioning of a weak acid (pK, = 4.4)
`°
`= 6
`between plasma (pH = 7.4) and gastric juice (pH = 1.4)
`o
`is depicted in Figure 2-3. Assume that the gastric
`mucosal membrane behaves as a simple lipid barrier
`with a high electrical resistance that is permeable
`only to the lipid-soluble, non-ionized form of the
`acid. The ratio of non-ionized to ionized drug at each
`pH is
`readily calculated from the Henderson-
`Hasselbalch equation:
`
`
`
`ag
`a
`
`B
`
`a
`
`f
`
`+
`
`o°
`
`Figure 2—2. The variety of ways drugs move across cellular barriers
`in their passage throughout the body.
`
`log
`
`[protonated form] _=pK,-—pH
`[unprotonated form] pis
`PX
`
`;
`Fe
`(Equation 2-1)
`
`8
`
`

`

`histamine H, antagonists: second generation antihista-
`minesare ionized molecules (Jess lipophilic) that cross
`the blood-brain barrier poorly comparedto first gener-
`ation agents (uncharged at pH 7.4). The effects of net
`charge are observable elsewhere in the body, in the
`kidney tubules, for instance. Urine pH can vary over a
`ride range, from 4.5 to 8. As urine pH drops (as [H*]
`increases), weak acids (A~) and weak bases (B) will
`Lipid Mucosal Barrier
`exist to a greater extend in their protonated forms (HA
`Gastric juice||pH =1.4
`and BH*); the reverse is true as pH rises, where A~ and
`tt]
`[0.001]
`1.001 = [HA] + [A]
`B will be favored. In the kidney tubules where a lipid
`HA <—> A+ Ht
`soluble (uncharged) drug can be reabsorbed by passive
`diffusion, excretion of the drug can be promoted by
`altering the pH of the urine to favor the ionized state
`(Av or BH"). Thus, alkaline urine favors excretion of
`weakacids; acid urine favors excretion of weak bases.
`Elevation of urine pH (by giving sodium bicarbonate)
`will promote urinary excretion of weak acids such as
`aspirin (pK,~3.5) and urate (pK,~5.8). This principle of
`in trapping is an important process in drug distribution.
`
`B
`
`[1000]
`[1]
`
`HA ——} A+ Ht
`Plasma
`pH =7.4
`
`1001 = [HA] +[A7]
`
`Figure 2~3 Influence of pH on the distribution of a weak acid
`between plasma and gastric juice separated by a lipid barrier.
`A. The dissociation of a weak acid, pK, = 4.4.
`B. Dissociation of the weak acid in plasma (pH 7.4) and gastric
`acid (pH 1.4). The uncharged from, HA, equibrates across the
`membrane. Blue numbers in brackets show relative concentra-
`tions of HA and A.
`
`A
`
`‘
`
`pk,=44
`Weak Acid HA HH, A+ Ht
`honionized
`ionized
`
`
`This equation relates the pH of the medium around the
`drug and the drug’s acid dissociation constant (pK,) to
`the ratio of the protonated (HA or BH*) and unproto-
`nated (A~ or B) forms, where HA «@ Av + H* (K, =
`[A-]|H*|/[HA]) describes the dissociation of an acid,
`and BH‘ B + H* (K, = [B][H*]/[BH*]) describes the
`dissociation of the protonated form ofa base.
`In the example of Figure 2—3, the ratio of non-
`ionized to ionized drug in plasma is 1:1000; in gastric
`juice, the ratio is 1:0.001, as given in brackets in Figure
`2—3. The total concentration ratio between the plasma
`and the gastric juice therefore would be 1000:1 if such
`a system cameto a steady state. For a weak base with
`a pK,of 4.4 (e.g., chlordiazepoxide), the ratio would be
`reversed, as would the thick horizontal arrows in Figure
`2—3, which indicate the predominant species at each
`pH. Accordingly, at steady state, an acidic drug will
`accumulate on the more basic side of the membrane and
`a basic drug on the moreacidicside.
`Commonionizable groups on drug molecules are
`carboxylic acids (pK,~4.5) and primary amino groups
`(pK,~9.5), but myriad others are possible. Resonance
`structures and electron withdrawing groups can change
`the pK,, and many compoundshave multiple ionizable
`groups;
`thus, pK, values vary over a broad range.
`Furthermore, some drugs contain quaternary amines
`with a permanent positive change. One consequence of
`a drug being ionized at physiological pH is illustrated
`by the relative lack ofsedative effects of second generation
`
`These considerations have obvious implications for the
`absorption and excretion of many drugs, as will be discussed more
`specifically. The establishment of concentration gradients of weak
`electrolytes across membranes with a pH gradient is a physical
`process and does not require an active electrolyte transport system.
`All that is necessary is a membrane preferentially permeable to one
`form of the weak electrolyte and a pH gradient across the mem-
`brane. The establishment of the pH gradient, however, is an active
`process.
`
`Carrier-Mediated Membrane Transport. While passive diffusion
`through the bilayer is dominant in the disposition of most drugs, car-
`rier-mediated mechanismsalso play an important role. Activetrans-
`port is characterized by a direct requirement for energy, movement
`against an electrochemical gradient, saturability, selectivity, and
`competitive inhibition by co-transported compounds. Na*,K*-
`ATPase is an important example of an active transport mechanism
`that is a therapeutic target of digoxin in the treatmentof heart failure
`(Chapter 28). Secondary active transport uses the electrochemical
`energy stored in a gradient to move another molecule against a con-
`centration gradient; e.g., the Nat-Ca”* exchange protein uses the
`energy stored in the Na* gradient established by the Na*, K*-ATPase
`mechanism to export cytosolic Ca** and maintain it at a low basal
`level, ~100 nM in mostcells (Chapter 3); similarly, the Na*-dependent
`glucose transporters SGLT1 and SGLT2 move glucose across mem-
`branes of gastrointestinal (GI) epithelium and renal tubules by cou-
`pling glucose transport to downhill Na* flux,
`Facilitated diffusion describes a carrier-mediated transport
`process in which there is no input of energyeand therefore enhanced
`movement ofthe involved substance is down a chemical gradient as
`in the permeation ofglucose across a muscle cell membrane mediated
`by the insulin-sensitive glucose transporter GLUT4, Such mecha-
`nisms, which may be highly selective for a specific conformational
`structure of a drug, are involved in the transport of endogenous
`
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`20
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`SJIdIDNIddTVYINID
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`compounds whose rate of transport by passive diffusion otherwise
`would be too slow (Figure 54). In other cases, they function as
`exporters, creating a barrier to prevent the intracellular accumulation
`of potentially toxic substances. Pharmacologically important trans-
`porters may mediate either drug uptake or efflux and often facilitate
`vectorial transport across polarized cells. An important efflux trans-
`porter is the P-glycoprotein encoded by the multidrug resistance-|
`(MDR]) gene (Table 5-4). P-glycoprotein localized in the enterocyte
`limits the oral absorption oftransported drugs because it exports
`compounds back into the lumen of the GI tract subsequentto their
`absorption by passive diffusion. The P-glycoprotein also can confer
`resistance to some cancer chemotherapeutic agents (Chapters 60-63).
`Transporters and their roles in drug action are presented in detail in
`Chapter 5.
`
`DRUG ABSORPTION, BIOAVAILABILITY,
`
`AND ROUTES OF ADMINISTRATION
`
`Absorption is the movementof a drug from its site of
`administration into the central compartment (Figure 2-1)
`and the extent to which this occurs. For solid dosage
`forms, absorptionfirst requires dissolution ofthe tablet
`or capsule, thus liberating the drug. The clinician is
`concerned primarily with bioavailability rather than
`absorption, Bioavailabilityis a term used to indicate the
`fractional extent to which a dose of drug reachesits site
`of action or a biological fluid from which the drug has
`access to its site of action. For example, a drug given
`orally must be absorbedfirst from the GI tract, but net
`absorption may be limited by the characteristics of the
`dosage form, the drug’s physicochemical properties, by
`intestinal metabolism, and by transporter export back
`into the intestinal lumen, The absorbed drug then passes
`throughthe liver, where metabolism and biliary excre-
`tion may occurbefore the drug enters the systemic cir-
`culation. Accordingly, a fraction of the administered and
`absorbed dose of drug will be inactivated or diverted in
`the intestine and liver before it can reach the general
`circulation and be distributed to its sites of action. If the
`metabolic or excretory capacity of the liver and the intes-
`tine for the drug is large, bioavailability will be reduced
`substantially (first-pass effect). This decrease in availability
`is a function of the anatomical site from which absorp-
`tion takes place; other anatomical, physiological, and
`pathological
`factors can influence bioavailability
`(described later), and the choice of the route of drug
`administration must be based on an understanding of
`these conditions. Moreover, knowledge of drugs that
`undergosignificant metabolism or require active trans-
`port across the intestinal and hepatic membranes
`instructs our understanding of adverse events in thera-
`peutics, since some drugs are substrates for the same
`
`drug metabolizing enzymes or drug transporters and
`thus compete for metabolism and transport.
`
`Oral (Enteral) Versus Parenteral Administration, Often there is a
`choice of the route by which a therapeutic agent may be adminis-
`tered, and knowledge ofthe advantages and disadvantages ofthe dif-
`ferent routes of administrationis then of primary importance. Some
`characteristics of the major routes employed for systemic drug effect
`are compared in Table 2-1.
`Oral ingestion is the most common method of drug adminis-
`tration. It also is the safest, most convenient, and most economical.
`
`Disadvantages to the oral route include limited absorption of some drugs
`because of their physical characteristics (e.g., low water solubility or
`poor membrane permeability), emesis as a result ofirritation to the GI
`mucosa, destruction of some drugs by digestive enzymes or low
`gastric pH, irregularities in absorption or propulsion in the presence
`of food or other drugs, and the need for cooperation on the part of
`the patient. Such cooperation is frequently not forthcoming,sincetol-
`erating certain oral medications means accepting unwantedeffects,
`such as GI pain, which may require use of an alternate route of admin-
`istration (Cosman, 2009). In addition, drugs in the GI tract may be
`metabolized by the enzymesofthe intestinal flora, mucosa, orliver
`before they gain access to the general circulation.
`Parenteral injection of drugs has certain distinct advantages
`overoral administration. In some instances, parenteral administration
`is essential for the drug to be deliveredin its active form, as in the case
`of monoclonal antibodies such as infliximab, an antibody directed
`against tumor necrosis factor a (TNF @) used in the treatment of
`rheumatoid arthritis. Availability usually is more rapid, extensive, and
`predictable when a drug is given by injection. The effective dose can
`therefore be delivered more accurately. In emergency therapy and
`when a patient is unconscious, uncooperative, or unableto retain any-
`thing given by mouth, parenteral therapy may be a necessity. The
`injection of drugs, however, has its disadvantages: asepsis must be
`maintained, and this is of particular concern when drugsare given over
`time, such as in intravenous or intrathecal administration; pain may
`accompany the injection: and it is sometimes difficult for patients to
`perform the injections themselvesif self-medication is necessary,
`
`Oral Administration. Absorption from the GI tract is governed by
`factors such as surface area for absorption, blood flow tothe site of
`absorption, the physical state of the drug (solution, suspension, or
`solid dosage form), its water solubility, and the drug’s concentration
`at the site of absorption. For drugs givenin solid form, the rate ofdis-
`solution may limit their absorption, especially drugs of low aqueous
`solubility. Since most drug absorption from the GI tract occurs by
`passive diffusion, absorption is favored when the drug is in the non-
`ionized and more lipophilic form. Based on the pH-partition concept
`(Figure 2—3), one would predict that drugs that are weak acids would
`be better absorbed from the stomach (pH 1-2) than fromthe upper
`intestine (pH 3-6), and vice versa for weak bases. However, the
`epitheliumof the stomach is lined with a thick mucus layer, andits
`surface area is small; by contrast, the villi of the upper intestine pro-
`vide an extremely large surface area (~200 m?). Accordingly,the rate
`of absorption of a drug fromthe intestine will be greater than that
`from the stomach even if the drug is predominantly ionized in the
`intestine and largely non-ionized in the stomach. Thus, any factor
`that accelerates gastric emptying (recumbent position, right side)
`
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`Table 2-1
`
`SomeCharacteristics of Common Routes of Drug Administration®
`ROUTE
`ABSORPTION PATTERN
`SPECIAL UTILITY
`LIMITATIONS AND PRECAUTIONS
`
`Valuable for emergency use
`Permits titration of dosage
`Usually required for high-
`molecular-weight pro-
`tein and peptide drugs
`
`Increased risk of adverse effects
`Mustinject solutions slowly as a
`rule
`Notsuitable for oily solutions or
`poorly soluble substances
`
`Intravenous
`
`Subcutaneous
`
`Intramuscular
`
`Absorption circumvented
`Potentially immediate
`effects
`Suitable for large volumes
`andforirritating sub-
`stances, or complex
`mixtures, when diluted
`
`Prompt from aqueous
`solution
`Slow and sustained
`from repository
`preparations
`
`Prompt from aqueous
`solution
`Slow and sustained from
`
`repository preparations
`
`Suitabl