‘-
`
`.I"
`
`
`
`The Pharmacological
`Basis of
`
`BRUCE A. CHABNER
`
`BJéRN c. KNOLLMANN
`
`NEUROCRINE 1032
`
`TH ERAPEUTICS
`
`12"' EDITION
`
`LAURENCE L. BRUNTON
`
`1
`
`NEUROCRINE 1032
`
`

`

`Goodman & Gilman’s
`
`The Pharmacological Basis of
`
`TH ERAPEUTICS
`
`twelfth edition
`
`editor
`
`Laurence L. Brunton, PhD
`Professor of Pharmacology and Medicine
`School of Medicine, University ofCalifornia. 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
`
`Bjfirn C. Knollmann, MD, PhD
`Professor of Medicine and Pharmacology
`Oates Institute for Experimental Therapeutics
`Division of Clinical Pharmacology
`Vanderbilt University School of Medicine
`Nashville, Tennessee
`
`% Medical
`
`New York Chicago San Francisco Lisbon London Madrid Mexico City Milan
`New Delhi San Juan Seoul Singapore Sydney Toronto
`
`2
`
`

`

` The MCGI’IJW'HW Conioames
`
`Goodman and Gilman’s
`
`The Pharmacological Basis of Therapeutics, Twelfth Edition
`
`Copyright © 2011. 2006. 2001. 1996, 1990, 1935. 1980, 1975. 1970, [965, 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.
`no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or
`retrieval system. without the prior written permission of the publisher.
`
`5 6 7 8 9 0 CTPICTP
`
`171615
`
`ISBN 9?8-0-07-162442-8
`MHID 0-07-162442-2
`Book ISBN 978-0-07—175352-4 Book MHID0-07~175352A4
`DVD ISBN 978-0-07—l75306-7 DVD MHID 0-07-175306-0
`Set ISBN 978—0074624428
`Set MHID 0-07-162442-2
`
`This book was set in Times by Glyph International.
`The editors were James F. Shanahan and Christie Naglien'.
`The production manager was Sherri Soulfrance.
`Project management was provided by Rajni Pisharody, Glyph International.
`The illustration manager was Armen Ovsepyan.
`The designer was Janice Bielawa.
`The cover art director was Anthony Landi; the cover designer was Thomas De Pierre.
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`China Translation & Printing Services. Ltd.. was printer and hinder.
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`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in—Puhlication Data
`
`Goodman & Gilman’s pharmacological basis of therapeutics.— 12m ed. leditor,
`Laurence L. Brunton ; associate editors. Bruce A. Chahner. Bjorn C. Knollntann.
`p. ; cm.
`
`Other title: Goodman and Gilman’s pharmacological basis of therapeutics
`Other title: Pharmacological basis of therapeutics
`Rev. ed. of: Goodman & Gilman's the phannacologica] basis of therapeutics.
`Laurence L. Brunton. c2006.
`
`I 1th ed. i editor.
`
`Includes bibliographical references and index.
`ISBN-13: 978-0-07»162442-8 (hardcover : alk. paper)
`ISBN— 10: 0—07— 162442-12
`
`11. Brunton. Laurence L.
`I. Goodman. Louis Sanford. 1906»
`2. Therapeutics.
`l. Pharmacology.
`IV. Knollmann. Bjorn C. V. Goodman & Gilman's the pharmacological
`III. Chabnel‘. Bruce.
`basis of therapeutics. VI. Title: Goodman and Gilman’s phannacological basis of therapeutics.
`VII. Title: Pharmacological basis oftherapeutics.
`[DNLM1
`l. Pharmacological Phenomena.
`2. Drug Therapy. QV 4 (36532 201 l]
`RM300.6644 201 l
`6151741c22
`
`2010000236
`
`McGraw-l-Iill books are available at special quantity discounts to use as premiums or sales promotions. or for use in
`corporate training programs. To contact a representative, please email us at bulksales@mcgraw-hil|.com.
`
`3
`
`

`

`Contents
`
`Contributors xi
`
`Preface xvii
`
`Preface to the First Edition xix
`
`Acknowledgements xxi
`
`SECTION I
`
`General Principles
`1.
`Drug Invention and the Pharmaceutical
`Industry ..................................................................... 3
`Suzanne M. Rivera and Alfred Goodman Gilman
`
`1
`
`. Pharmacokinetics: The Dynamics of Drug
`Absorption. Distribution. Metabolism.
`and Elimination ....................................................... 17
`Iain L. O. Buxton and Leslie 2. Benet
`
`. Pharmacodynamics: Molecular Mechanisms
`of Drug Action ........................................................4|
`Donald K. Blumenthal and James C. Garrison
`
`. Drug Toxicity and Poisoning ...................................73
`Kevin C. Osterhoudt and Trevor M. Penning
`
`LA
`
`. Membrane Transporters and
`Drug Response ........................................................ 89
`Kathleen M. Giacomini and Yuichi Sugiyama
`
`. Drug Metabolism .................................................. 123
`Frank .1. Gonzalez, Michael Coughtn‘e.
`and Robert H. Tukey
`
`. Pharmacogenetics .................................................. 145
`Mary V. Relling and Kathleen M. Giacomini
`
`SECTION II
`
`Neuropharmacology
`8.
`Neurotransmission: The Autonomic
`
`169
`
`and Somatic Motor Nervous Systems ................... 171
`Thomas C. Westf'all and David P. Westfall
`
`9.
`
`IO.
`
`11.
`
`12.
`
`Muscarinic Receptor Agonists
`and Antagonists ..................................................... 2 [9
`Joan Heller Brown and Nora Laiken
`
`Anticholinesterase Agents ..................................... 239
`Palmer Taylor
`
`Agents Acting at the Neuromuscular
`Junction and Autonomic Ganglia .......................... 255
`Ryan E. Hibbs and Alexander C. Zambon
`
`Adrenergic Agonists and Antagonists ................... 277
`Thomas C. Westfall and David P. Westfali
`
`. 5-Hydroxytryptamine (Serotonin)
`
`14.
`
`15.
`
`16.
`
`IT.
`
`18.
`
`19.
`
`and Dopamine ....................................................... 335
`Elaine Sanders-Bush and lisa Hazelwood
`Neurotransmission and the Central
`
`Nervous System .................................................... 363
`Perry B. Moliooff
`
`Drug Therapy of Depression
`and Anxiety Disorders ........................................... 397
`James M. O’Donnell and Richard C. Shelton
`
`Pharmacotherapy of Psychosis
`and Mania .............................................................. 417
`
`Jonathan M. Meyer
`
`Hypnotics and Sedatives ....................................... 457
`5. John Mihic and R. Adron Harris
`
`Opioids. Analgesia. and Pain
`Management .......................................................... 481
`Tony L. Yal-rsh and Mark S. Wallace
`
`General Anesthetics and Therapeutic Gases ......... 527'
`Piyush M. Patel, Hemal H. Patel,
`and David M. Roth
`
`. Local Anesthetics .................................................. 565
`William A. Catterall and Kenneth Mackie
`
`21.
`
`Pharmacotherapy of the Epilepsies ....................... 583
`James D. McNamara
`
`4
`
`

`

`viii
`
`22. Treatment of Central Nervous System
`Degenerative Disorders .........................................609
`David G. Standaert and Erik B. Roberson
`
`SECTION V
`
`Hormones and Hormone
`
`SlNlLNOJ
`
`23. Ethanol and Methanol ...........................................629
`Marc A. Schuckit
`
`24. Drug-Addiction ......................................................649
`Charles P. O'Brien
`
`SECTION III
`
`Modulation of Cardiovascular
`
`Function
`
`669
`
`2.5. Regulation of Renal Function
`and Vascular Volume ............................................. 671
`
`Robert F. Reilly and Edwin K. Jackson
`
`26. Renin and Angiotensin ..........................................721
`Randa Hilal—Dandan
`
`27. Treatment of Myocardial lschemia
`and Hypertension ..................................................745
`Thomas Michel and Brian B. Hoffman
`
`28. Pharmacotherapy ofCongestive
`Heart Failure ..........................................................789
`Bradley A. Maron and Thomas P. Rocco
`
`29. Anti-Arrhythmic Drugs ......................................... 815
`Kevin J. Sampson and Robert 5. Kass
`
`30. Blood Coagulation and Anticoagulant.
`Fibrinolytic. and Antiplatelet Drugs ...................... 849
`Jeffrey I. Wait:
`
`31. Drug Therapy for Hypercholesterolemia
`and Dyslipidemia .................................................. 877
`Thomas P. Bersot
`
`SECTION IV
`
`Inflammation, Immunomodulation,
`
`and Hematopoiesis
`32. Histamine. Bradykinin. and Their
`Antagonists ............................................................ 91 |
`Randal A. Skidgel, Allen P. Kaplan, and Ervin G. Erdos
`
`909
`
`33. Lipid-Derived Autacoids: Eicosanoids
`and Platelet-Activating Factor ............................... 937
`Emer M. Smyth. Tilo Grosser. and Garret A. Fitzfierald
`
`34. Anti—inflammatory. Antipyretic, and Analgesic
`Agents: Pharmacotherapy of Gout ........................ 959
`Tito Grosser. Emer M. Smyth. and Garret A. FitzGerald
`
`35. Immunosuppressants. Tolerogens, and
`Immunostimulants ............................................... 1005
`
`Alan M. Krensky, Witliam M. Bennett. and Flavio Vincenti
`
`36. Pulmonary Pharmacology ................................... 1031
`Peter J. Barnes
`
`37. Hematopoietic Agents; Growth Factors.
`Minerals. and Vitamins........................................ 1067
`Kenneth Kaushansky and Thomas J. Kipps
`
`Antagonists
`38. Introduction To Endocrinology;
`The Hypothalamic-Pituitary Axis1103
`Keith L. Parker and Bernard F. Schimmer
`
`1 101
`
`39. Thyroid and Anti—Thyroid Drugs ....................... l 129
`Gregory A. Brent and Ronald J. Koenig
`
`40. Estrogens and Progestins.....................................I163
`Ellis R. Levin and Stephen R. Hammes
`
`41. Androgens ........................................................... l 195
`Peter J. Snyder
`
`42. ACTH, Adrenal Steroids. and Pharmacology
`of the Adrenal Cortex .......................................... 1209
`Bernard P. Schimmer and John W. Funder
`
`43. Endocrine Pancreas and Phannacotherapy
`of Diabetes Mellitus and Hypoglycemia ............. 1237
`Alvin C. Powers and David D'Alessio
`
`44. Agents Affecting Mineral [on
`Homeostasis and Bone Turnover......................... 1275
`Peter A. Friedman
`
`SECTION VI
`
`Drugs Affecting Gastrointestinal
`Function
`
`1307
`
`45. Pharmacothcrapy of Gastric Acidity. Peptic
`Ulcers, and Gastroesophageal Reflux Disease....l309
`John L. Wallace and Keith A. Sharkey
`
`46. Treatment of Disorders of Bowel Motility and
`Water Flux: Anti-Einetics: Agents Used in
`
`Biliary and Pancreatic Disease ............................ 1323
`Keith A. Sharkey and John L. Wallace
`
`47. Pharmacotherapy of Inflammatory
`Bowel Disease ..................................................... 1351
`John L. Wallace and Keith A. Sharkey
`
`SECTION WI
`
`Chemotherapy of Microbial
`Diseases
`
`1363
`
`48. General Principles ofAntimicrohiai
`Therapy ............................................................... 1365
`Tawanda Gumbo
`
`49. Chemotherapy of Malaria 1383
`Joseph M. Vinetz, Jerome Clain, Viengngeun Bounlceua,
`Richard T. Eastman, and David Fidock
`
`50. Chemotherapy of Protozoal Infections:
`Amebiasis. Giardiasis. Trichomoniasis.
`
`Trypanosomiasis, Leishmaniasis. and Other
`Protozoal Infections ............................................ 1419
`
`Margaret A. Phillips and Samuel L. Stanley. Jr.
`
`5
`
`

`

`62. Targeted Therapies: Tyrosine Kinase Inhibitors.
`
`ix
`
`Monoclonal Antibodies, and Cytokines
`Brute A. Chabner. Jeffrey Barnes. Joel Neal. Erin Olson.
`Hamza Mujagic, Lecia Sequist, Wynham Wilson, Dan L. Longo,
`Constantine Mitsiades, and Paul Richardson
`
`.1731
`
`()3. Natural Products in Cancer Chemotherapy:
`Hormones and Related Agents ............................ 1755
`Beverly Moy, Richard J. Lee,
`and Matthew Smith
`
`SlNEIlNO)
`
`5 I. Chemotherapy of Helminth Infections................1443
`James McCarthy, Alex Loukas, and Peter J. Hotez
`
`52. Sulfonamides. Trimethoprim-Sulfamethoxazole.
`Quinolones, and Agents for Urinary Tract
`Infections ............................................................. 1463
`William A. Petri. Jr.
`
`53. Penicillins. Cephalosporins. and Other
`BLLactam Antibiotics ........................................... 1477
`William A. Petri. Jr.
`
`54. Aminoglycosides ................................................. 1505
`Conan MacDougalland Henry F. Chambers
`
`SECTION {X
`
`55. Protein Synthesis Inhibitors and
`Miscellaneous Antibacterial Agents
`Conan MacDougall and Henry F. Chambers
`
`1521
`
`56. Chemotherapy of Tuberculosis. Mycobacrerr‘rmi
`Avr'rrm Complex Disease, and Leprosy ................ 1549
`Tawanda Gumbo
`
`57. Antii‘ungal Agents ............................................... 1571
`John E. Bennett
`
`58. Antiviral Agents (Nonretroviral) ......................... 1593
`Edward P. Acosta and Charles Flexner
`
`59. Antiretroviral Agents and
`Treatment of HIV Infection ................................. 1623
`Charles Flexner
`
`SECTION VII!
`
`Chemotherapy of Neoplastic
`Diseases
`
`1665
`
`60. General Principles of Cancer Chemotherapy ...... 1667r
`Bruce A. Chabner
`
`6 1. Cytotoxic Agents ................................................. 1677
`Bruce A. Chabner. Joseph Bertino. James Cleary. Taylor Ortiz,
`Andrew Lane, Jeffrey G. Supko, and David Ryan
`
`1771
`Special Systems Pharmacology
`64. Ocular Pharmacology .......................................... 1773
`Jeffrey D, Henderer and Christopher J. Rapuano
`
`65. Dermatological Pharmacology ............................ 1803
`Craig Burkhart, Dean Morreil.
`and Lowell Goldsmith
`
`66. Contraception and Pharmacotherapy of
`Obstetrical and Gynecological Disorders ............ [833
`Bernard P. Schimrner and Keith L. Parker
`
`67. Environmental Toxicology;
`Carcinogens and Heavy Metals ........................... 1853
`Michael C. Byrns and Trevor M. Penning
`
`APPENDICES
`
`1. Principles of Prescription Order
`Writing and Patient Compliance ......................... 1879
`lain L. O. Buxton
`
`11. Design and Optimization of Dosage
`Regimens: Pharmacokinetic Data ....................... 1891
`Kenneth E. Thummel. Danny B. Shen. and Nina
`Isoherranen
`
`Index
`
`1991
`
`6
`
`

`

`(I'll
`
`[(3 I”
`
`Pharmacokinetics: The Dynamics
`of Drug Absorption, Distn'bution,
`Metabolism, and Elimination
`
`Iain 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
`phamncukinetics (Figure 2—l ). Understanding and
`employing pharrnacokinetic 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
`membranes that 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 of its ionized and non~ionized forms, and
`its binding to serum and tissue proteins. In most cases.
`a drug must traverse the plasma membranes of many
`cells to reach its 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 common barrier to drug distribution.
`Cell Membranes. The plasma membrane consists of a bilaycr of
`amphipathic lipids with their hydrocarbon chains oriented inward to
`
`the center of the bi layer 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
`move laterally and organize themselves with cholesterol leg... sphin-
`golipids). endowing the membrane with fluidity. flexibility. organi—
`zation. high electrical resistance, and reiative impermeability to
`highly polar molecules. Membrane proteins embedded in the bilaycr
`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 et al., 2009'. Singer, 2004). These proteins
`may be associated with cavcolin and sequestered within caveolae:
`they may be excluded from caveolae: or they may be organized in
`signaling domains rich in cholesterol and sphingolipid not containing
`caveolin or other scaffolding proteins (i.e.. lipid rafts).
`Cell membranes are relatively permeable to water either 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 endotbelium
`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 kidneyslmportant exceptions
`exist in such capillary diffusion: “tight" intercellularjunctions are
`present in specific tissues. and paracellular passage in them is liin—
`ited. Capillaries of the central nervous system (CNS) and a variety
`of epithelial 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 mass of the solute exceeds [W200 Da.
`
`Accordingly. most large lipophilic drugs must pass through the cell
`membrane itself (Figure 2—2).
`
`7
`
`

`

`
`
`
`
`/
`
`
` CENTRAL
`COM PARTMENT ‘
`
`CLEARANCE
`
`
`
`proteinbound
`drug
`
`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.
`
`Passive Flux Across Membranes. Drugs cross membranes either by
`passive processes or by mechanisms involving the active participation
`of components of 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 transfer is directly proportional
`to the magnitude of the concentration gradient across the membrane. to
`the lipid-water partition 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 and the Faster
`is its diffusion. After a steady state is attained, the concentration of the
`unbound drug is the same on both sides of the membrane if the drug is
`a non-electrolyte. For ionic compounds. the steady-state concentrations
`depend on the electrochemical gradient for the ion and on differences
`
`PASSIVE TRANSPORT
`
`ACTIVE TRANSPORT
`
`F—%F__—%\
`Paracellular Diffusion
`Facilitated
`Drug
`diffusion
`transporters
`transport
`
`
`
`in pH across the membrane. which will influence the state of ionization
`of the molecule disparately on either side of the membrane and can
`effectively trap drug on one side of the membrane.
`
`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 because of their low lipid solubility, and
`
`passage will depend on the leakiness of the membrane
`related to the membrane’s electrical resistance. Therefore,
`
`the transmembrane distribution of a weak electrolyte is
`influenced by its pita and the pH gradient across the
`membrane. The pK:I is the pH at which half the drug
`(weak acid or base electrolyte) is in its ionized form.
`To illustrate the effect of pH on distribution of
`drugs. the partitioning of a weak acid (pKa : 4.4)
`between plasma (pH = 7.4) and gastric juice (pH = 1.4)
`is depicted in Figure 2—3. Assume that the gastric
`mucosa] 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:
`
`Figure 2-2. The variety of ways drugs move across cellular barriers
`in their passage throughout the body.
`
`[protonated form]
`log ——————‘.—
`[unprotonated form]
`
`: PKa ’PH (Equation 2—l)
`
`18
`
`
`
`Cl
`"I
`
`2"
`
`1abI
`
`"
`'U
`IH
`
`2nI
`
`—I
`—m
`U!
`
`‘l
`
`8
`
`

`

`A
`
`.
`
`Weak Acid HA _.. A‘ + H+
`pKfi: 4,4
`nonionizod
`Ionized
`
`
`B
`
`[ll
`
`[1000]
`
`HA —y A_+ H+
`Plasma
`pH : 1&4
`
`1001=[HA]+[A"]
`
`Lipid Mucosal Barrier
`
`Gastric juice
`
`pH =14 I
`
`[11
`
`{00th
`
`1.001 = [HA] + [A-]
`
`HA _,‘_— A‘+ H+
`
`Figure 2-3 Influence of pH on the distribution of a weak acid
`between plasma and gastric juice separated by a tipr’d barrier.
`A. The dissociation ofa weak acid, pKu = 4.4.
`B. Dissociation of the weak acid in plasma (pH 7.4) and gastric
`acid (pH L4). The uncharged from. HA, equihrates across the
`membrane. Blue numbers in brackets show relative concentra-
`tions of HA and A‘.
`
`This equation relates the pH of the medium around the
`
`drug and the drug’s acid dissociation constant (PKJ to
`the ratio of the protonated (HA or BHt} and unprote-
`
`nated (A' or B) forms, where HA 4—) A‘ + H+ (Ku :
`[A"][H*']J'[HA]) describes the dissociation of an acid,
`
`and BH+<—> B + l-I+ (Ku = [B][H+]/lBH*j) describes the
`dissociation of the protonated form of a 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 110.00], as given in brackets in Figure
`2—3. The total concentration ratio between the plasma
`and the gastric juice therefore would be 1000:l if such
`a system came to a steady state. For a weak base with
`a pKu of 4.4 (c.g.. chlordiachoxide), 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 more acidic side.
`Common ionizable groups on drug molecules are
`carboxylic acids (pig-«4.5) and primary amino groups
`(pK3~9.5), but myriad others are possible. Resonance
`structures and electron withdrawing groups can change
`the pKa, and many compounds have multiple ionizable
`groups;
`thus, pKa 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 of sedative effects of second generation
`
`histamine l-Il antagonists: second generation antihista-
`mines are ionized molecules (less Iipophilic) that cross
`the blood-brain barrier poorly compared to 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+l
`increases), weak acids (A') and weak bases (B) will
`
`exist to a greater extend in their protonated forms (HA
`and BH‘“): the reverse is true as pH rises, where A' and
`B will be favored. In the kidney tubules where a lipid
`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
`(A‘ or BH”). Thus. alkaline urine favors excretion of
`weak acids; 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 (pita-=35} and urate (pKa~5.8). This principle of
`in trapping is an important process in drug distribution.
`
`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 bilaycr is dominant in the disposition of most drugs, car—
`rier—mediated mechanisms also play an important role. rte-rive trans-
`pnrr is characterized by a direct requirement for energy. movement
`against an electrochemical gradient, saturability, selectivity, and
`competitive inhibition by co—transponed compounds, Na*.K+—
`ATPase is an important example of an active transport mechanism
`that is a therapeutic target of digoxin in the treatment of heart failure
`(Chapter 28). Secondary active transport uses the electrochemical
`energy stored in a gradient to move another molecule against a con,
`centt'ation gradient; e.g., the Nev—Ca“ exchange protein uses the
`energy stored in the Na" gradient established by the Na*. K+-ATPase
`mechanism to export cytosolic (3512* and maintain it at a low basal
`level. ~100 nM in most cells (Chapter 3); similarly, the Na*—dependent
`glucose transporters SGLT] and SGLTZ move glucose across mem-
`branes of gastrointestinal (GI) epithelium and renal tubules by cou-
`pling glucose transport to downhill Na" flux.
`Foeiiimted diffusion describes a carrier—mediated lransporl
`process in which there is no input of energy. and therefore enhanced
`movement ofthe involved substance is down a chemical gradient as
`in the permeation of glucose across a muscie cell membrane mediated
`by the insulin-sensitive glucose transporter GLUT4. Such mecha-
`nisms. which may be highly selective for a specific conformational
`slructure of a drug, are involved in the transport of endogenous
`
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`compounds whose rate of transport by passive diffusion otherwise
`would be too slow [Figure 5—4). In other cases. they function as
`exporters. creating a barrier to prevent the intracellular accumulation
`of potentially toxic substances. Pharmacologically important transi
`porters may mediate either drug uptake or efflux and often facilitate
`vectorial transport across polarized cells. An important efllux trans-
`porter is the P—glycoprotein encoded by the multidrug resistance—l
`(MUN.l ) gene (Table 5-4). P-glycoprotein localized in the enterocyte
`limits the oral absorption of transported drugs because it exports
`compounds back into the lumen of the GI tract subsequent to 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 movement of a drug from its site of
`administration into the central compartment (Figure 2, l)
`and the extent to which this occurs. For solid dosage
`forms. absorption first requires dissolution of the tablet
`or capsule, thus liberating the drug. The clinician is
`concerned primarily with hioavailabiliry rather than
`absorption. Bioavailabr'it'ty is a term used to indicate the
`fractional extent to which a dose of 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 given
`orally must be absorbed first from the GI tract. but net
`absorption may be limited by the characteristics of the
`
`dosage form. the drug‘s physicochcmical properties. by
`intestinal metabolism. and by transporter export back
`into the intestinal lumen. The absorbed drug then passes
`through the liver. where metabolism and biliary excre-
`tion may occur before 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 (find-pass cfiirct). 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
`undergo significant 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 adminisv
`tcrcd. and knowledge of the advantages and disadvantages of the dif-
`ferent routes of administration is 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 ofdrug 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 membrattc permeability). emesis as a result of irritation 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 pan of
`the patient. Such cooperation is frequently not forthcoming. since tol-
`crating certain oral medications means accepting unwanted effects.
`such as GI pain. which may require use of an alternate route ofadmins
`istration tCosman. 2009). In addition. drugs in the GI tract may be
`metabolized by the enzymes of the intestinal flora. mucosa. or liver
`before they gain access to the general circulation.
`Parenteral injection of drugs has certain distinct advantages
`over oral administration. In some instances, parenteral administration
`is essential for the drug to be delivered in its active form. as in the case
`of monoclonal antibodies such as infiixirnab. an antibody directed
`against tumor necrosis factor or tTNF on used in the treatment of
`rheumatoid arthritis. Availability tlsually 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 unable to retain any-
`thing given by mouth. parenteral therapy may be a necessity. The
`injection of drugs. however. has its disadvantages: ascpsis must be
`maintained. and this is of particular concern when drugs are given over
`time, such as in intravenous or intrathecal administration: pain may
`accompany the injection; and it is someti mes difiicull for patients to
`perform the injections themselves if self-medication is necessary.
`
`Oral Administration. Absorption from the (it tract is governed by
`factors such as surface area for absorption. blood tlow to the 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 given in solid form. the rate of dis—
`solution may limit their absorption. especially drugs of low aqueous
`solubility. Since most drug absorption from [he GI tract occurs by
`passive diffusion, absorption is favored when the drug is ill 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 {-2) than from the upper
`intestine {pH 3—6). and vice versa for weak bases. However. the
`epithelium of the stomach is lined with a thick mucus layer, and its
`surface area is small; by contrast. the villi of the upper intestine pro—
`vide an extremely large surface area [—400 m3). Accordingly. the rate
`of absorption of a drug front the intestine will be greater than that
`from the stomach even if the drug is predominantly ionized in the
`intestine and la