GOODMAL G LMAN'S Tie
`GOODMANGILMAS
`PHARMACOLOGICAL
`PHAKMACOLOGICAL
`BASIS OF
`BASIS OF
`THERAPEUTICS
`THERAPEUTICS
`
`Tenth Edition Tenth Edition
`
`McGraw-Hill
`McGraw-Hill
`MEDICAL PUBLISHING DIVISION
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`McGraw-Hill
`A Division of The McGrawilill Companies
`
`Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 10/e
`
`Copyright © 2001, 1996, 1990, 1985, 1980, 1975, 1970, 1965, 1955, 1941 by The McGraw-Hill
`Companies, Inc. All rights reserved. Printed in the United States of America. Except as
`permitted under the United States Copyright Act of 1976, no part of this publication may be
`reproduced or distributed in any form or by any means, or stored in a data base or retrieval
`system, without the prior written permission of the publisher.
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`1234567890 DOWDOW 0987654321
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`ISBN 0-07-135469-7
`
`This book was set in Times Roman by York Graphic Services, Inc. The editors were Martin J.
`Wonsiewicz and John M. Morriss; the production supervisor was Philip Galea; and the cover
`designer was Marsha Cohen/Parallelogram. The index was prepared by Irving Cond6 Tullar and
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`This book is printed on acid-free paper.
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`Library of Congress Cataloging-in-Publication Data
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`Goodman and Gilman's the pharmacological basis of therapeutics.-10th ed. / [edited by]
`Joel G. Hardman, Lee E. Limbird, Alfred Goodman Gilman.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN 0-07-135469-7
`1. Pharmacology. ' 2. Chemotherapy. I. Title: Pharmacological basis of therapeutics.
`II. Goodman, Louis Sanford HI. Gilman, Alfred IV. Hardman, Joel G.
`V. Limbird, Lee E. VI. Gilman, Alfred Goodman
`[DNLM: 1. Pharmacology. 2. Drug Therapy. QV 4 G6532 2002]
`RM300 G644 2001
`615'.7—dc21 (cid:9)
`
`2001030728
`
`INTERNATIONAL EDITION ISBN 0-07-112432-2
`Copyright © 2001. Exclusive rights by The McGraw-Hill Companies, Inc., for manufacture and export.
`This book cannot be re-exported from the country to which it is consigned by McGraw-Hill. The
`International Edition is not available in North America.
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`
`
`CHAPTER 1 CHAPTER 1
`
`PHARMACOKINETI Cs
`PHARMACOKINETI CS
`The Dynamics of Drug Absorption,
`The Dynamics of Drug Absorption,
`Distribution, and Elimination
`Distribution, and Elimination
`
`
`
`Grant R. Wilkinson Grant R. Wilkinson
`
`To produce its characteristic effects, a drug must be present in appropriate concentrations
`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, at its sites of action. Although obviously a 'Unction of the amount of drug adininistered,
`
`the concentrations of active, unbound (free) drug attained also depend upon the extent and the concentrations of active, unbound (free) drug attained also depend upon the extent and
`rate of its absorption, distribution (which mainly reflects relative binding to plasma and
`rate of its absorption, distribution (which mainly reflects relative binding to plasma and
`
`tissue proteins), metabolism (biotranslOmation), and excretion. These disposition factors tissue proteins), metabolism (biotransformation), and excretion. These disposition factors
`
`are depicted in Figure 1-1 and are described in this chapter are depicted in Figure I-1 and are described in this chapter.
`
`
`PHYSICOCHEMICAL FACTORS PHYSICOCHEMICAL FACTORS
`
`IN TRANSFER OF DRUGS IN TRANSFER OF DRUGS
`
`ACROSS MEMBRANES ACROSS MEMBRANES
`
`The absorption, distribution, metabolism, and excretion The absorption, distribution, metabolism, and excretion
`
`of a drug all involve its passage across cell membranes. of a drug all involve its passage across cell membranes.
`
`Mechanisms by which drugs cross membranes and the Mechanisms by which drugs cross membranes and the
`
`physicochemical properties of molecules and membranes physicochemical properties of molecules and membranes
`
`that influence this transfer are, therefore, important. The that influence this transfer are, therefore, important. The
`
`determining characteristics of a drug are its molecular size determining characteristics of a drug are its molecular size
`
`and shape, degree of ionization, relative lipid solubility of and shape, degree of ionization, relative lipid solubility of
`
`
`its ionized and nonionized forms, and its binding to tissue its ionized and nonionized forms, and its binding to tissue
`
`proteins. proteins.
`
`When a drug permeates a cell, it obviously must tra-When a drug permeates a cell, it obviously must tra-
`verse the cellular plasma membrane. Other barriers to drug
`verse the cellular plasma membrane. Other barriers to drug
`
`movement may be a single layer of cells (intestinal epi. movement may be a single layer of cells (intestinal epi-
`thelium) or several layers of cells (skin). Despite sucf
`thelium) or several layers of cells (skin). Despite such
`
`structural differences, the diffusion and transport of drug; structural differences, the diffusion and transport of drug:
`
`across these various boundaries have many common char across these various boundaries have many common char
`
`acteristics, since drugs in general pass through cells rathe acteristics, since drugs in general pass through cells rathe
`
`than between them. The plasma membrane thus represent than between them. The plasma membrane thus represent
`
`the common barrier. the common barrier.
`
`\ r (cid:9)
`,-, (cid:9)
`I
`TISSUE
`LOCUS OF ACTION (cid:9)
`TISSUE
`LOCUS OF ACTION (cid:9)
`RESERVOIRS
`"RECEPTORS" (cid:9)
`RESERVOIRS
`"RECEPTORS" (cid:9)
`bound —7 free (cid:9)
`bound
`free (cid:9)
`bound (cid:9)
` free (cid:9)
`free = bound
`..,
`
`-N
`
`\.. (cid:9)
`
`\ (cid:9)
`
`SYSTEMIC
`SYSTEMIC
`CIRCULATION
`CIRCULATION
`
`
`
`ABSORPTION
`ABSORPTION
`
`(cid:9)— free drug
`free drug
`
`EXCRETION
`EXCRETION
`
`/
`bound drug
`bound drug
`\-.. (cid:9)
`
`
`
`metabolites
`metabolites
`/
`
`BIOTRANSFORMATION
`BIOTRANSFORMATION
`
`
`Figure 1-1. Schematic representation of the interrelationship Figure 1-1. Schematic representation of the interrelationship
`
`of the absorption, distribution, binding, metabolism, and ex-of the absorption, distribution, binding, metabolism, and ex-
`cretion of a drug and its concentration at its locus of action.
`cretion of a drug and its concentration at its locus of action.
`
`
`Possible distribution and binding of metabolites are not Possible distribution and binding of metabolites are not
`depicted.
`depicted.
`
`3 3
`
`
`Cell Membranes. The plasma membrane consists of a bilaye Cell Membranes. The plasma membrane consists of a bilaye
`of amphipathic lipids, with their hydrocarbon chains oriente
`of amphipathic lipids, with their hydrocarbon chains oriente
`inward to form a continuous hydrophobic phase and their by
`inward to form a continuous hydrophobic phase and their 113.
`drophilic heads oriented outward. Individual lipid molecules i
`drophilic heads oriented outward. Individual lipid molecules i
`
`the bilayer vary according to the particular membrane and ca the bilayer vary according to the particular membrane and ca
`
`move laterally, endowing the membrane with fluidity, fiexibilit move laterally, endowing the membrane with fluidity, flexibilit:
`high electrical resistance, and relative impermeability to highl
`high electrical resistance, and relative impermeability to highl
`polar molecules. Membrane proteins embedded in the bilayi
`polar molecules. Membrane proteins embedded in the bilayt
`
`serve as receptors, ion channels, or transporters to elicit electr serve as receptors, ion channels, or transporters to elicit electr
`
`cal or chemical signaling pathways and provide selective targe cal or chemical signaling pathways and provide selective targe
`
`for drug actions. for drug actions.
`Most cell membranes are relatively permeable to wat,
`Most cell membranes are relatively permeable to wat,
`either by diffusion or by flow resulting from hydrostatic or o
`either by diffusion or by flow resulting from hydrostatic or o
`
`motic differences across the membrane, and bulk flow of wat motic differences across the membrane, and bulk flow of wat
`
`can carry with it drug molecules. Such transport is the map can carry with it drug molecules. Such transport is the maj,
`
`mechanism by which drugs pass across most capillary endoth mechanism by which drugs pass across most capillary endoth
`
`lial membranes. However, proteins and drug molecules boui lial membranes. However, proteins and drug molecules boui
`to them are too large and polar for this type of transport to o
`to them are too large and polar for this type of transport to o
`
`cur; thus, transcapillary movement is limited to unbound dru cur; thus, transcapillary movement is limited to unbound dru
`
`Paracellular transport through intercellular gaps is sufficient Paracellular transport through intercellular gaps is sufficient
`large that passage across most capillaries is limited by blo,
`large that passage across most capillaries is limited by blo,
`flow and not by other factors (see below). As described lat
`flow and not by other factors (see below). As described lat
`this type of transport is an important factor in filtration acrc
`this type of transport is an important factor in filtration acrc
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`4 (cid:9)4 (cid:9)
`
`
`
`SECTION I GENERAL PRINCIPLES SECTION I GENERAL PRINCIPLES
`
`
`glomerular membranes in the kidney. Important exceptions ex-glomerular membranes in the kidney. Important exceptions ex-
`
`ist in such capillary diffusion, however, since "tight" intercel-ist in such capillary diffusion, however, since "tight" intercel-
`lular junctions are present in specific tissues and paracellular
`lular junctions are present in specific tissues and paracellular
`
`transport in them is limited. Capillaries of the central nervous transport in them is limited. Capillaries of the central nervous
`
`system (CNS) and a variety of epithelial tissues have tight junc-system (CNS) and a variety of epithelial tissues have tight junc-
`tions (see below). Although bulk flow of water can carry with it
`tions (see below). Although bulk flow of water can carry with it
`
`small, water-soluble substances, if the molecular mass of these small, water-soluble substances, if the molecular mass of these
`
`compounds is greater than 100 to 200 daltons, such transport compounds is greater than 100 to 200 daltons, such transport
`
`is limited. Accordingly, most large lipophilic drugs must pass is limited. Accordingly, most large lipophilic drugs must pass
`
`through the cell membrane itself by one or more processes. through the cell membrane itself by one or more processes.
`
`Passive Membrane Transport. Drugs cross membranes either
`Passive Membrane Transport. Drugs cross membranes either
`
`by passive processes or by mechanisms involving the active par-by passive processes or by mechanisms involving the active par-
`
`ticipation of components of the membrane. In the former, the ticipation of components of the membrane. In the former, the
`
`drug molecule usually penetrates by passive diffusion along a drug molecule usually penetrates by passive diffusion along a
`
`concentration gradient by virtue of its solubility in the lipid bi-concentration gradient by virtue of its solubility in the lipid bi-
`
`layer. Such transfer is directly proportional to the magnitude of layer. Such transfer is directly proportional to the magnitude of
`
`the concentration gradient across the membrane, the lipid:water the concentration gradient across the membrane, the lipid:water
`partition coefficient of the drug, and the cell surface area. The
`partition coefficient of the drug, and the cell surface area. The
`
`greater the partition coefficient, the higher is the concentration greater the partition coefficient, the higher is the concentration
`
`of drug in the membrane and the faster is its diffusion. After a of drug in the membrane and the faster is its diffusion. After a
`
`steady state is attained, the concentration of the unbound drug 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-is the same on both sides of the membrane if the drug is a non-
`
`electrolyte. For ionic compounds, the steady-state concentrations electrolyte. For ionic compounds, the steady-state concentrations
`
`will be dependent on differences in pH across the membrane, will be dependent on differences in pH across the membrane,
`
`which may influence the state of ionization of the molecule on which may influence the state of ionization of the molecule on
`
`each side of the membrane and on the electrochemical gradient each side of the membrane and on the electrochemical gradient
`
`for the ion. for the ion.
`
`Weak Electrolytes and Influence of pH. Most drugs
`Weak Electrolytes and Influence of pH. Most drugs
`are weak acids or bases that are present in solution as
`are weak acids or bases that are present in solution as
`both the nonionized and ionized species. The nonionized
`both the nonionized and ionized species. The nonionized
`molecules are usually lipid-soluble and can diffuse across
`molecules are usually lipid-soluble and can diffuse across
`the cell membrane. In contrast, the ionized molecules are
`the cell membrane. In contrast, the ionized molecules are
`usually unable to penetrate the lipid membrane because
`usually unable to penetrate the lipid membrane because
`of their low lipid solubility.
`of their low lipid solubility.
`Therefore, the transmembrane distribution of a weak
`Therefore, the transmembrane distribution of a weak
`electrolyte usually is determined by its pK0 and the pH
`electrolyte usually is determined by its pK„ and the pH
`gradient across the membrane. The pKa is the pH at which
`gradient across the membrane. The pK„ is the pH at which
`half of the drug (weak electrolyte) is in its ionized form.
`half of the drug (weak electrolyte) is in its ionized form.
`To illustrate the effect of pH on distribution of drugs, the
`To illustrate the effect of pH on distribution of drugs, the
`partitioning of a weak acid (pK„ = 4.4) between plasma
`partitioning of a weak acid (pK„ = 4.4) between plasma
`(pH = 7.4) and gastric juice (pH = 1.4) is depicted in
`(pH = 7.4) and gastric juice (pH = 1.4) is depicted in
`Figure 1-2. It is assumed that the gastric mucosal mem-
`Figure 1 -2. It is assumed that the gastric mucosal mem-
`brane behaves as a simple lipid barrier that is permeable
`brane behaves as a simple lipid barrier that is permeable
`only to the lipid-soluble, nonionized form of the acid.
`only to the lipid-soluble, nonionized form of the acid.
`The ratio of nonionized to ionized drug at each pH is
`The ratio of nonionized to ionized drug at each pH is
`readily calculated from the Henderson—Hasselbalch equa-
`readily calculated from the Henderson—Hasselbalch equa-
`tion. Thus, in plasma, the ratio of nonionized to ionized
`tion. Thus, in plasma, the ratio of nonionized to ionized
`drug is 1:1000; in gastric juice, the ratio is 1:0.001. These
`drug is 1: 1 000; in gastric juice, the ratio is 1:0.001. These
`values are given in brackets in Figure 1-2. The total con-
`values are given in brackets in Figure 1-2. The total con-
`centration ratio between the plasma and the gastric juice
`centration ratio between the plasma and the gastric juice
`would therefore be 1000:1 if such a system came to a
`would therefore be 1000:1 if such a system came to a
`steady state. For a weak base with a pK0 of 4.4, the ratio
`steady state. For a weak base with a pK„ of 4.4, the ratio
`would be reversed, as would the thick horizontal arrows in
`would be reversed, as would the thick horizontal arrows in
`Figure 1-2, which indicate the predominant species at
`Figure 1-2, which indicate the predominant species at
`
`[1] (cid:9)
`11000] (cid:9)
`[1] (cid:9)
`iv+ H+
`
`HA (cid:9)HA ..„` (cid:9)
`PC-F- H+
`pH = 7.4
`Plasma
`pH = 7.4
`Plasma (cid:9)
`
`[10001 (cid:9)
`
`1001
`
`1001
`
`Total Total
`
`[HA] + [A-] [HA] + [A-]
`
`Lipid Mucosal Barrier
`Lipid Mucosal Barrier
`
`
`
`Gastric Juice (cid:9)Gastric Juice
`
`
`
`pH = 1.4 pH = 1.4
`
`
`1] (cid:9)11 (cid:9)
`
`HA (cid:9)HA (cid:9)
`
`
`
`[0.001] (cid:9)[0.001]
`
`
`
`H+ A"-F H+
`
`
`
`1 001 1.001
`
`Weak Acid HA (cid:9)
`Weak Acid HA (cid:9)
`
`nonionized (cid:9)nonionized (cid:9)
`
`H+
`H+
`
`ionized ionized
`
`
`
`= 4.4 pK,, = 4.4
`
`Figure 1-2. Influence of pH on the distribution of a weak
`Figure 1-2. Influence of pH on the distribution of a weak
`acid between plasma and gastric juice, separated by a lipid
`acid between plasma and gastric juice, separated by a lipid
`barrier.
`barrier.
`
`each pH. Accordingly, at steady state, an acidic drug will
`each pH. Accordingly, at steady state, an acidic drug will
`accumulate on the more basic side of the membrane and
`accumulate on the more basic side of the membrane and
`a basic drug on the more acidic side—a phenomenon
`a basic drug on the more acidic side—a phenomenon
`termed ion trapping. These considerations have obvious
`termed ion trapping. These considerations have obvious
`implications for the absorption and excretion of drugs, as
`implications for the absorption and excretion of drugs, as
`discussed more specifically below. The establishment of
`discussed more specifically below. The establishment of
`concentration gradients of weak electrolytes across mem-
`concentration gradients of weak electrolytes across mem-
`branes with a pH gradient is a purely physical process
`branes with a pH gradient is a purely physical process
`and does not require an active transport system. All that
`and does not require an active transport system. All that
`is necessary is a membrane preferentially permeable to
`is necessary is a membrane preferentially permeable to
`one form of the weak electrolyte and a pH gradient across
`one form of the weak electrolyte and a pH gradient across
`the membrane. The establishment of the pH gradient is,
`the membrane. The establishment of the pH gradient is,
`however, an active process.
`however, an active process.
`
`
`Carrier-Mediated Membrane Transport. While passive dif-Carrier-Mediated Membrane Transport. While passive dif-
`
`fusion through the bilayer is dominant in the disposition of fusion through the bilayer is dominant in the disposition of
`
`most drugs, carrier-mediated mechanisms also can play an im-most drugs, carrier-mediated mechanisms also can play an im-
`portant role. Active transport is characterized by a requirement
`portant role. Active transport is characterized by a requirement
`
`for energy, movement against an electrochemical gradient, sat-for energy, movement against an electrochemical gradient, sat-
`
`urability, selectivity, and competitive inhibition by cotransported urability, selectivity, and competitive inhibition by cotransported
`
`compounds. The term facilitated diffusion describes a carrier-compounds. The term facilitated diffusion describes a carrier-
`
`mediated transport process in which there is no input of energy mediated transport process in which there is no input of energy
`
`and therefore enhanced movement of the involved substance and therefore enhanced movement of the involved substance
`
`is clown an electrochemical gradient. Such mechanisms, which is clown an electrochemical gradient. Such mechanisms, which
`
`may be highly selective for a specific conformational structure may be highly selective for a specific conformational structure
`of a drug, are involved in the transport of endogenous com-
`of a drug, are involved in the transport of endogenous com-
`
`pounds whose rate of transport by passive diffusion otherwise pounds whose rate of transport by passive diffusion otherwise
`
`would be too slow. In other cases, they function as a barrier would be too slow. In other cases, they function as a barrier
`system to protect cells from potentially toxic substances.
`system to protect cells from potentially toxic substances.
`
`The responsible transporter proteins often are expressed The responsible transporter proteins often are expressed
`
`within cell membranes in a domain-specific fashion such that within cell membranes in a domain-specific fashion such that
`
`they mediate either drug uptake or efflux, and often such an they mediate either drug uptake or efflux, and often such an
`
`arrangement facilitates vectorial transport across cells. Thus, in arrangement facilitates vectorial transport across cells. Thus, in
`
`the liver, a number of basolaterally localized transporters with the liver, a number of basolaterally localized transporters with
`
`different substrate specificities are involved in the uptake of different substrate specificities are involved in the uptake of
`
`bile acids and amphipathic organic anions and cations into the bile acids and amphipathic organic anions and cations into the
`
`hepatocyte, and a similar variety of ATP-dependent transporters hepatocyte, and a similar variety of ATP-dependent transporters
`
`in the canalicular membrane export such compounds into the in the canalicular membrane export such compounds into the
`
`bile. Analogous situations also are present in intestinal and renal bile. Analogous situations also are present in intestinal and renal
`
`tubular membranes. An important efflux transporter present at tubular membranes. An important efflux transporter present at
`
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`CHAPTER I PHARMACOKINETICS (cid:9)
`CHAPTER 1 PHARMACOKINETICS (cid:9)
`
`5
`5
`
`these sites and also in the capillary endothelium of brain cap-
`these sites and also in the capillary endothelium of brain cap-
`illaries is P-glycoprotein, which is encoded by the multidrug
`illaries is P-glycoprotein, which is encoded by the multidrug
`resistance-I (MDRI) gene, important in resistance to cancer
`resistance-I (MDR/) gene, important in resistance to cancer
`chemotherapeutic agents (Chapter 52). P-glycoprotein localized
`chemotherapeutic agents (Chapter 52). P-glycoprotein localized
`in the enterocyte also limits the oral absorption of transported
`in the enterocyte also limits the oral absorption of transported
`drugs since it exports the compound back into the intestinal
`drugs since it exports the compound back into the intestinal
`tract subsequent to its absorption by passive diffusion.
`tract subsequent to its absorption by passive diffusion.
`
`DRUG ABSORPTION,
`DRUG ABSORPTION,
`BIOAVAILABILITY, AND ROUTES
`BIOAVAILABILITY, AND ROUTES
`OF ADMINISTRATION
`OF ADMINISTRATION
`
`Absorption describes the rate at which a drug leaves its
`Absorption describes the rate at which a drug leaves its
`site of administration and the extent to which this oc-
`site of administration and the extent to which this oc-
`curs. However, the clinician is concerned primarily with a
`curs. However, the clinician is concerned primarily with a
`parameter designated as bioavailability, rather than ab-
`parameter designated as biaavailability, rather than ab-
`sorption. Bioavailability is a term used to indicate the
`sorption. Bioavaiiability is a term used to indicate the
`fractional extent to which a dose of drug reaches its site
`fractional extent to which a dose of drug reaches its site
`of action or a biological fluid from which the drug has.
`of action or a biological fluid from which the drug has
`access to its site of action. For example, a drug given
`access to its site of action. For example, a drug given
`orally must be absorbed first from the stomach and intes-
`orally must be absorbed first from the stomach and intes-
`tine, but this may be limited by the characteristics of the
`tine, but this may be limited by the characteristics of the
`dosage form and/or the drug's physicochemical proper-
`dosage form and/or the drug's physicochemical proper-
`ties. In addition, drug then passes through the liver, where
`ties. In addition, drug then passes through the liver, where
`metabolism and/or biliary excretion may occur before it
`metabolism and/or biliary excretion may occur before it
`reaches the systemic circulation. Accordingly, a fraction of
`reaches the systemic circulation. Accordingly, a fraction of
`the administered and absorbed dose of drug will be inacti-
`the administered and absorbed dose of drug will be inacti-
`vated or diverted before it can reach the general circulation
`vated or diverted before it can reach the general circulation
`and be distributed to its sites of action. If the metabolic
`and be distributed to its sites of action. If the metabolic
`or excretory capacity of the liver for the agent in question
`or excretory capacity of the liver for the agent in question
`is large, bioavailability will be substantially reduced (the
`is large, bioavailability will be substantially reduced (the
`so-called first-pass effect). This decrease in availability is
`so-called first-pass effect). This decrease in availability is
`a function of the anatomical site from which absorption
`a function of the anatomical site from which absorption
`takes place; other anatomical, physiological, and patho-
`takes place; other anatomical, physiological, and patho-
`logical factors can influence bioavailability (see below),
`logical factors can influence bioavailability (see below),
`and the choice of the route of drug administration must
`and the choice of the route of drug administration must
`be based on an understanding of these conditions.
`be based on an understanding of these conditions.
`
`Oral (Enteral) versus Parenteral Administration. Of-
`Oral (Enteral) versus Parenteral Administration. Of-
`ten there is a choice of the route by which a therapeutic
`ten there is a choice of the route by which a therapeutic
`agent may be given, and a knowledge of the advantages
`agent may be given, and a knowledge of the advantages
`and disadvantages of the different routes of administra-
`and disadvantages of the different routes of administra-
`tion is then of primary importance. Some characteristics
`tion is then of primary importance. Some characteristics
`of the major routes employed for systemic drug effect are
`of the major routes employed for systemic drug effect are
`compared in Table 1-1.
`compared in Table I—I.
`Oral ingestion is the most common method of drug
`Oral ingestion is the most common method of drug
`administration. It also is the safest, most convenient, and
`administration. It also is the safest, most convenient, and
`most economical. Disadvantages to the oral route include
`most economical. Disadvantages to the oral route include
`limited absorption of some drugs because of their physi-
`limited absorption of some drugs because of their physi-
`cal characteristics (e.g., water solubility), emesis as a re-
`cal characteristics (e.g., water solubility), emesis as a re-
`sult of irritation to the gastrointestinal mucosa, destruction
`sult of irritation to the gastrointestinal mucosa, destruction
`of some drugs by digestive enzymes or low gastric pH,
`of some drugs by digestive enzymes or low gastric pH,
`
`irregularities in absorption or propulsion in the presence
`irregularities in absorption or propulsion in the presence
`of food or other drugs, and necessity for cooperation on
`of food or other drugs, and necessity for cooperation on
`the part of the patient. In addition, drugs in the gastroin-
`the part of the patient. In addition, drugs in the gastroin-
`testinal tract may be metabolized by the enzymes of the
`testinal tract may be metabolized by the enzymes of the
`intestinal flora, mucosa, or the liver before they gain ac-
`intestinal flora, mucosa, or the liver before they gain ac-
`cess to the general circulation.
`cess to the general circulation.
`The parenteral injection of drugs has certain distinct
`The parenteral injection of drugs has certain distinct
`advantages over oral administration. In some instances,
`advantages over oral administration. In some instances,
`parenteral administration is essential for the drug to be
`parenteral administration is essential for the drug to be
`delivered in its active form. Availability is usually more
`delivered in its active form. Availability is usually more
`rapid, extensive, and predictable than when a drug is given
`rapid, extensive, and predictable than when a drug is given
`by mouth. The effective dose therefore can be more accu-
`by mouth. The effective dose therefore can be more accu-
`rately delivered. In emergency therapy and when a patient
`rately delivered. In emergency therapy and when a patient
`is unconscious, uncooperative, or unable to retain anything
`is unconscious, uncooperative, or unable to retain anything
`given by mouth, parenteral therapy may be a necessity.
`given by mouth, parenteral therapy may be a necessity.
`The injection of drugs, however, has its disadvantages:
`The injection of drugs, however, has its disadvantages:
`asepsis must be maintained; pain may accompany the in-
`asepsis must be maintained; pain may accompany the in-
`jection; it is sometimes difficult for patients to perform the
`jection; it is sometimes difficult for patients to perform the
`injections themselves if self-medication is necessary; and
`injections themselves if self-medication is necessary; and
`there is the risk of inadvertent administration of a drug
`there is the risk of inadvertent administration of a drug
`when it is not intended. Expense is another consideration.
`when it is not intended. Expense is another consideration.
`
`Oral Ingestion. Absorption from the gastrointestinal
`Oral Ingestion. Absorption from the gastrointestinal
`tract is governed by factors such as surface area for ab-
`tract is governed by factors such as surface area for ab-
`sorption, blood flow to the site of absorption, the physical
`sorption, blood flow to the site of absorption, the physical
`state of the drug (solution, suspension, or solid dosage
`state of the drug (solution, suspension, or solid dosage
`form), its water solubility, and concentration at the site
`form), its water solubility, and concentration at the site
`of absorption. For drugs given in solid form, the rate of
`of absorption. For drugs given in solid form, the rate of
`dissolution may be the limiting factor in their absorption,
`dissolution may be the limiting factor in their absorption,
`especially if they have low water solubility. Since most
`especially if they have low water solubility. Since most
`drug absorption from the gastrointestinal tract occurs via
`drug absorption from the gastrointestinal tract occurs via
`passive processes, absorption is favored when the drug is
`passive processes, absorption is favored when the drug is
`in the nonionized and more lipophilic form. Based on the
`in the nonionized and more lipophilic form. Based on the
`pH-partition concept presented in Figure 1-2, it would be
`pH-partition concept presented in Figure 1-2, it would be
`predicted that drugs that are weak acids would be better
`predicted that drugs that are weak acids would be better
`absorbed from the stomach (pH 1 to 2) than from the upper
`absorbed from the stomach (pH 1 to 2) than from the upper
`intestine (pH 3 to 6), and vice versa for weak bases. How-
`intestine (pH 3 to 6), and vice versa for weak bases. How-
`ever, the epithelium of the stomach is lined with a thick
`ever, the epithelium of the stomach is lined with a thick
`mucous layer, and its surface area is small; by contrast, the
`mucous layer, and its surface area is small; by contrast, the
`villi of the upper intestine provide an extremely large sur-
`villi of the upper intestine provide an extremely large sur-
`face area (-200 m2). Accordingly, the rate of absorption
`face area (^-200 m2). Accordingly, the rate of absorption
`of a drug from the intestine will be greater than that from
`of a drug from the intestine will be greater than that from
`the stomach even if the drug is predominantly ionized in
`the stomach even if the drug is predominantly ionized in
`the intestine and largely nonionized in the stomach. Thus,
`the intestine and largely nonionized in the stomach. Thus,
`any factor that accelerates gastric emptying will be likely
`any factor that accelerates gastric emptying will be likely
`to increase