`
`JOEL G. H _.
`
`.
`
`EDET
`
`E. MMBE
`
`
`
`TEVA1 055
`
`1
`
`

`

`GooDMAN & GILMAN's The
`PHARMACOLOGICAL
`BASIS OF
`THERAPEUTICS
`Tenth Edition
`
`McGraw-Hill
`MEDICAL PUBLISHING DIVISION
`
`New York
`Milan
`
`Chicago
`New Delhi
`
`San Francisco
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`
`Lisbon
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`
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`
`2
`
`

`

`McGraw-Hill
`A Division of The McGraw Hill Companies
`
`Goodman and Gilman’s (cid:9)
`
`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.
`
`1234567890 DOWDOW 0987654321
`
`III
`
`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 CondØ Tullar and
`Coughlin Indexing Services, Inc.
`R.R. Donnelley and Sons Company was printer and binder.
`
`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in-Publication Data
`
`I [edited by]
`
`Goodman and Gilman’s the pharmacological basis of therapeutics.(cid:151)lOth ed.
`Joel G. Hardman, Lee E. Limbird, Alfred Goodman Gilman.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN 0-07-135469-7
`I. Title: Pharmacological basis of therapeutics.
`2. Chemotherapy. (cid:9)
`1. Pharmacology. (cid:9)
`II. Goodman, Louis Sanford III. 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(cid:151)dc2l
`
`2001030728
`
`INTERNATIONAL EDITION ISBN 0-07-112432-2
`2001. Exclusive rights by The McGraw-Hill Companies, Inc., for manufacture and export.
`Copyright '
`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.
`
`3
`
`(cid:9)
`

`

`CHAPTER
`
`1
`
`PHARMACOKINETICS
`The Dynamics of Drug Absorption,
`Distribution, and Elimination
`
`Grant R. Wilkinson
`
`To produce its characteristic effects, a drug must be present in appropriate concentrations
`at its sites of action. Although obviously a function of the amount of drug administered,
`the concentrations 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
`tissue proteins), metabolism (biotransformation), and excretion. These disposition factors
`are depicted in Figure 1-1 and are described in this chapter.
`
`PHYSICOCHEMICAL FACTORS
`IN TRANSFER OF DRUGS
`ACROSS MEMBRANES
`
`The absorption, distribution, metabolism, and excretion
`of a drug all involve its passage across cell membranes.
`Mechanisms by which drugs cross membranes and the
`physicochemical properties of molecules and membranes
`that influence this transfer are, therefore, important. The
`determining characteristics of a drug are its molecular size
`and shape, degree of ionization, relative lipid solubility of
`
`LOCUS OF ACTION
`"RECEPTORS"
`
`bound == free
`
`TISSUE
`RESERVOIRS
`free== bound
`
`Figure 1-1. Schematic representation of the interrelationship
`of the absorption, distribution, binding, metabolism, and ex(cid:173)
`cretion of a drug and its concentration at its locus of action.
`
`Possible distribution and binding of metabolites are not
`depicted.
`
`3
`
`its ionized and nonionized forms, and its binding to tissue
`proteins.
`When a drug permeates a cell, it obviously must tra(cid:173)
`verse the cellular plasma membrane. Other barriers to drug
`movement may be a single layer of cells (intestinal epi(cid:173)
`thelium) or several layers of cells (skin). Despite such
`structural differences, the diffusion and transport of drugs
`across these various boundaries have many common char(cid:173)
`acteristics, since drugs in general pass through cells rather
`than between them. The plasma membrane thus represents
`the common barrier.
`
`Cell Membranes. The plasma membrane consists of a bilayer
`of amphipathic lipids, with their hydrocarbon chains oriented
`inward to form a continuous hydrophobic phase and their hy(cid:173)
`drophilic heads oriented outward. Individual lipid molecules in
`the bilayer vary according to the particular membrane and can
`move laterally, endowing the membrane with fluidity, flexibility,
`high electrical resistance, and relative impermeability to highly
`polar molecules. Membrane proteins embedded in the bilayer
`serve as receptors, ion channels, or transporters to elicit electri(cid:173)
`cal or chemical signaling pathways and provide selective targets
`for drug actions.
`Most cell membranes are relatively permeable to water
`either by diffusion or by flow resulting from hydrostatic or os(cid:173)
`motic differences across the membrane, and bulk flow of water
`can carry with it drug molecules. Such transport is the major
`mechanism by which drugs pass across most capillary endothe(cid:173)
`lial membranes. However, proteins and chug molecules bound
`to them are too large and polar for this type of transport to oc(cid:173)
`cur; thus, transcapillary movement is limited to unbound drug.
`Paracellular transport through intercellular gaps is sufficiently
`large that passage across most capillaries is limited by blood
`flow and not by other factors (see below). As described later,
`this type of transport is an important factor in filtration across
`
`4
`
`

`

`4
`
`SECTION I GENERAL PRINCIPLES
`
`glomerular membranes in the kidney. Important exceptions ex(cid:173)
`ist in such capillary diffusion, however, since "tight" intercel(cid:173)
`lular junctions are present in specific tissues and paracellular
`transport in them is limited. Capillaries of the central nervous
`system (CNS) and a variety of epithelial tissues have tight junc(cid:173)
`tions (see below). Although bulk flow of water can carry with it
`small, water-soluble substances, if the molecular mass of these
`compounds is greater than 100 to 200 daltons, such transport
`is limited. Accordingly, most large lipophilic drugs must pass
`through the cell membrane itself by one or more processes.
`
`Passive Membrane Transport. Drugs cross membranes either
`by passive processes or by mechanisms involving the active par(cid:173)
`ticipation of components of the membrane. In the former, the
`drug molecule usually penetrates by passive diffusion along a
`concentration gradient by virtue of its solubility in the lipid bi(cid:173)
`layer. Such transfer is directly proportional to the magnitude of
`the concentration gradient across the membrane, the lipid:water
`partition coefficient of the drug, and the cell surface area. The
`greater the partition coefficient, the higher is the concentration
`of drug in the membrane and the faster is its diffusion. After a
`steady state is attained, the concentration of the unbound drug
`is the same on both sides of the membrane if the drug is a non(cid:173)
`electrolyte. For ionic compounds, the steady-state concentrations
`will be dependent on differences in pH across the membrane,
`which may influence the state of ionization of the molecule on
`each side of the membrane and on the electrochemical gradient
`for the ion.
`
`Weak Electrolytes and Influence of pH. Most drugs
`are weak acids or bases that are present in solution as
`both the nonionized and ionized species. The nonionized
`molecules are usually lipid-soluble and can diffuse across
`the cell membrane. In contrast, the ionized molecules are
`usually unable to penetrate the lipid membrane because
`of their low lipid solubility.
`Therefore, the transmembrane distribution of a weak
`electrolyte usually is determined by its pKa and the pH
`gradient across the membrane. The pKa is the pH at which
`half of the drug (weak 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 1-2. It is assumed that the gastric mucosal mem(cid:173)
`brane behaves as a simple lipid barrier that is permeable
`only to the lipid-soluble, nonionized form of the acid.
`The ratio of nonionized to ionized drug at each pH is
`readily calculated from the Henderson-Hasselbalch equa(cid:173)
`tion. Thus, in plasma, the ratio of nonionized to ionized
`drug is 1:1000; in gastric juice, the ratio is 1:0.001. These
`values are given in brackets in Figure 1-2. The total con(cid:173)
`centration ratio between the plasma and the gastric juice
`would therefore be 1000:1 if such a system came to a
`steady state. For a weak base with a pKa of 4.4, the ratio
`would be reversed, as would the thick horizontal arrows in
`Figure 1-2, which indicate the predominant species at
`
`[1]
`HA
`Plasma
`pH= 7.4
`
`--i~io--
`
`[1000]
`
`A-+ H+
`
`1001
`
`Total
`[HA] +[A-]
`
`Lipid Mucosal Barrier ~
`
`f
`
`Gastric Juice
`
`pH = 1.4
`
`[1]
`[0.001]
`HA ~:'A-+H+
`
`1.001
`
`WeakAcid HA
`noniomzed
`
`K+H+
`ionized
`
`pK8 = 4.4
`
`Figure 1-2. lnjluence of pH on the distribution of a weak
`acid between plasma and gastric juice, separated by a lipid
`barrier.
`
`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-a phenomenon
`termed ion trapping. These considerations have obvious
`implications for the absorption and excretion of drugs, as
`discussed more specifically below. The establishment of
`concentration gradients of weak electrolytes across mem(cid:173)
`branes with a pH gradient is a purely physical process
`and does not require an active transport system. All that
`is necessary is a membrane preferentially permeable to
`one form of the weak electrolyte and a pH gradient across
`the membrane. The establishment of the pH gradient is,
`however, an active process.
`
`Carrier-Mediated Membrane Transport. While passive dif(cid:173)
`fusion through the bilayer is dominant in•the disposition of
`most drugs, carrier-mediated mechanisms also can play an im(cid:173)
`portant role. Active transport is characterized by a requirement
`for energy, movement against an electrochemical gradient, sat(cid:173)
`urability, selectivity, and competitive inhibition by cotransported
`compounds. The term facilitated diffusion describes a carrier(cid:173)
`mediated transport process in which there is no input of energy
`and therefore enhanced movement of the involved substance
`is down an electrochemical gradient. Such mechanisms, which
`may be highly selective for a specific conformational structure
`of a drug, are involved in the transport of endogenous com(cid:173)
`pounds whose rate of transport by passive diffusion otherwise
`would be too slow. In other cases, they function as a barrier
`system to protect cells from potentially toxic substances.
`The responsible transporter proteins often are expressed
`within cell membranes in a domain-specific fashion such that
`they mediate either drug uptake or efflux, and often such an
`arrangement facilitates vectorial transport across cells. Thus, Ill
`the liver, a number of basolaterally localized transporters with
`different substrate specificities are involved in the uptake of
`bile acids and amphipathic organic anions and cations into the
`hepatocyte, and a similar variety of ATP-dependent transporters
`in the canalicular membrane export such compounds into the
`bile. Analogous situations also are present in intestinal and renal
`tubular membranes. An important efflux transporter present at
`
`5
`
`

`

`CHAPTER 1 PHARMACOKINETICS
`
`5
`
`'tes and also in the capillary endothelium of brain cap-
`h
`.
`h' h .
`d d b
`th
`l 'd
`t ese st
`.11
`· s P-glycoprotem, w tc
`IS enco e
`y
`e mu t1 rug
`·
`1 arieS 1
`.
`.
`.
`· t uce-1 (MDRI) gene, Important m resistance to cancer
`rehsts a therapeutic agents (Chapter 52). P-glycoprotein localized
`c emo
`.
`.
`h
`l b
`.
`f
`d
`·
`th enterocyte also hmtts t e ora a sorptiOn o transporte
`I
`·
`db k'
`h
`·
`m e
`s since it exports the compoun
`ac mto t e mtestma
`d
`·
`d'ff
`·
`·
`b
`rug
`b
`tract subsequent to its a sorptiOn y passtve 1 usron .
`
`DRUG ABSORPTION,
`BIOAVAILABILITY, AND ROUTES
`OF ADMINISTRATION
`
`Absorption describes the rate at which a drug leaves its
`site of administration and the extent to which this oc(cid:173)
`curs. However, the clinician is concerned primarily with a
`parameter designated as bioavailability, rather than ab(cid:173)
`sorption. Bioavailability 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 stomach and intes(cid:173)
`tine, but this may be limited by the characteristics of the
`dosage form and/or the drug's physicochemical proper(cid:173)
`ties. In addition, drug then passes through the liver, where
`metabolism and/or biliary excretion may occur before it
`reaches the systemic circulation. Accordingly, a fraction of
`the administered and absorbed dose of drug will be inacti(cid:173)
`vated or diverted before it can reach the general circulation
`and be distributed to its sites of action. If the metabolic
`or excretory capacity of the liver for the agent in question
`is large, bioavailability will be substantially reduced (the
`so-called first-pass effect). This decrease in availability is
`a function of the anatomical site from which absorption
`takes place; other anatomical, physiological, and patho(cid:173)
`logical factors can influence bioavailability (see below),
`and the choice of the route of drug administration must
`be based on an understanding of these conditions.
`
`Oral (Enteral) versus Parenteral Administration. Of(cid:173)
`ten there is a choice of the route by which a therapeutic
`agent may be given, and a knowledge of the advantages
`and disadvantages of the different routes of administra(cid:173)
`tion is then of primary importance. Some characteristics
`of the major routes employed for systemic drug effect are
`compared in Table 1-1.
`Oral ingestion is the most common method of drug
`administration. It also is the safest, most convenient, and
`ill.ost economical. Disadvantages to the oral route include
`limited absorption of some drugs because of their physi(cid:173)
`cal characteristics (e.g., water solubility), emesis as a re(cid:173)
`Sult of irritation to the gastrointestinal 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 necessity for cooperation on
`the part of the patient. In addition, drugs in the gast:roin(cid:173)
`testinal tract may be metabolized by the enzymes of the
`intestinal flora, mucosa, or the liver before they gain ac(cid:173)
`cess to the general circulation.
`The parenteral injection of drugs has certain distinct
`advantages over oral administration. In some instances,
`parenteral administration is essential for the drug to be
`delivered in its active form. Availability is usually more
`rapid, extensive, and predictable than when a drug is given
`by mouth. The effective dose therefore can be more accu(cid:173)
`rately delivered. In emergency therapy and when a patient
`is unconscious, uncooperative, or unable to retain anything
`given by mouth, parenteral therapy may be a necessity.
`The injection of drugs, however, has its disadvantages:
`asepsis must be maintained; pain may accompany the in(cid:173)
`jection; it is sometimes difficult for patients to perform the
`injections themselves if self-medication is necessary; and
`there is the risk of inadvertent administration of a drug
`when it is not intended. Expense is another consideration.
`
`Oral Ingestion. Absorption from the gastrointestinal
`tract is governed by factors such as surface area for ab(cid:173)
`sorption, blood flow to the site of absorption, the physical
`state of the drug (solution, suspension, or solid dosage
`form) , its water solubility, and concentration at the site
`of absorption. For drugs given in solid form, the rate of
`dissolution may be the limiting factor in their absorption,
`especially if they have low water solubility. Since most
`drug absorption from the gastrointestinal tract occurs via
`passive processes, absorption is favored when the drug is
`in the nonionized and more lipophilic form. Based on the
`pH-partition concept presented in Figure 1-2, it would be
`predicted that drugs that are weak acids would be better
`absorbed from the stomach (pH 1 to 2) than from the upper
`intestine (pH 3 to 6), and vice versa for weak bases. How(cid:173)
`ever, the epithelium of the stomach is lined with a thick
`mucous layer, and its smface area is small; by contrast, the
`villi of the upper intestine provide an extremely large sur(cid:173)
`face area ( ~200 m2). Accordingly, the rate of absorption
`of a drug from the intestine will be greater than that from
`the stomach even if the drug is predmninantly ionized in
`the intestine and largely nonionized in the stomach. Thus,
`any factor that accelerates gastric emptying will be likely
`to increase the rate of drug absorption, while any factor
`that delays gastric emptying will probably have the oppo(cid:173)
`site effect, regardless of the characteristics of the drug.
`Drugs that are destroyed by gastric juice or that cause
`gastric irritation sometimes are administered in dosage
`forms with a coating that prevents dissolution in the
`acidic gastric content&. However, some enteric-coated
`
`6
`
`

`

`6
`
`SECTION I GENERAL PRINCIPLES
`
`Table 1-1
`Some Characteristics of Common Routes of Drug Administration*
`
`ROUTE
`
`Intravenous
`
`ABSORPTION
`PATTERN
`
`Absorption circumvented
`Potentially immediate effects
`
`Subcutaneous
`
`Intramuscular
`
`Prompt, from aqueous
`solution
`Slow and sustained, from
`repository preparations
`
`Prompt, from aqueous
`solution
`Slow and sustained, from
`repository preparations
`
`SPECIAL UTILITY
`
`Valuable for emergency use
`Permits titration of dosage
`Usually required for
`high-molecular-weight
`protein and peptide drugs
`Suitable for large volumes
`and for irritating substances,
`when diluted
`
`LIMITATION AND
`PRECAUTIONS
`
`Increased risk of adverse
`effects
`Must inject solutions
`slowly, as a rule
`Not suitable for oily solutions
`or insoluble substances
`
`Suitable for some insoluble
`suspensions and for
`implantation of solid pellets
`
`Not suitable for large volumes
`Possible pain or necrosis
`from irritating substances
`
`Suitable for moderate volumes,
`oily vehicles, and some
`irritating substances
`
`Precluded during anticoagulant
`medication
`May interfere with interpretation
`of certain diagnostic tests
`(e.g., creatine kinase)
`
`Requires patient cooperation
`Availability potentially erratic
`and incomplete for drugs that
`are poorly soluble, slowly
`absorbed, unstable, or extensively
`metabolized by the liver and/or gut
`
`Oral ingestion Variable; depends upon
`many factors (see text)
`
`Most convenient and
`economical; usually more
`safe
`
`*See text for more complete discussion and for other routes.
`
`preparations of a drug also may resist dissolution in the
`intestine, and very little of the drug may be absorbed.
`
`Controlled-Release Preparations. The rate of absorption of a
`drug administered as a tablet or other solid oral-dosage form is
`partly dependent upon its rate of dissolution in the gastrointesti(cid:173)
`nal fluids. This factor is the basis for the so-called controlled(cid:173)
`release, extended-release, sustained-release, or prolonged-action
`pharmaceutical preparations that are designed to produce slow,
`uniform absorption of the drug for 8 hours or longer. Potential
`advantages of such preparations are reduction in the frequency
`of administration of the drug as compared with conventional
`dosage forms (possibly with improved compliance by the pa(cid:173)
`tient), maintenance of a therapeutic effect overnight, and de(cid:173)
`creased incidence and/or intensity of undesired effects by elim(cid:173)
`ination of the peaks in drug concentration that often occur after
`administration of immediate-release dosage forms.
`Many controlled-release preparations fulfill these expecta(cid:173)
`tions. However, such products have some drawbacks. Generally,
`interpatient variability, in terms of the systemic concentration
`of the drug that is achieved, is greater for controlled-release
`
`than for immediate-release dosage forms. During repeated drug
`administration, trough drug concentrations resulting from con(cid:173)
`trolled-release dosage forms may not be different from those ob(cid:173)
`served with immediate-release preparations, although the time
`interval between trough concentrations is greater for a well(cid:173)
`designed controlled-release product. It is possible that the dosage
`form may fail, and "dose-dumping" with resultant toxicity can
`occur, since the total dose of drug ingested at one time may be
`several times the amount contained in the conventional prepa(cid:173)
`ration. Controlled-release dosage forms are most appropriate
`for drugs with short half-lives (less than 4 hours). So-called
`controlled-release dosage forms are sometimes developed for
`drugs with long half-lives (greater than 12 hours). These usu(cid:173)
`ally more expensive products should not be prescribed unless
`specific advantages have been demonstrated.
`
`Sublingual Administration. Absorption from the oral mucosa
`has special significance for certain drugs, despite the fact that
`the surface area available is small. For example, nitroglycerin
`is effective when retained sublingually because it is nonionic
`and has a very high lipid solubility. Thus, the drug is absorbed
`
`7
`
`

`

`CHAPTER 1 PHARMACOKINETICS
`
`7
`
`Because of this, it is advisable to intravenously admin(cid:173)
`ister a drug slowly by infusion rather than by rapid in(cid:173)
`jection, and with close monitoring of the patient's re(cid:173)
`sponse. Furthermore, once the drug is injected there is
`no retreat. Repeated intravenous injections are dep~ndent
`upon the ability to maintain a patent vein. Drugs in an
`oily vehicle or those that precipitate blood constituents
`or hemolyze erythrocytes should not be given by this
`route.
`Injection of a drug into a subcutaneous
`Subcutaneolfs·
`site often is .used. It can be used only for drugs that are
`not irritating to tissue; otherwise, severe pain, necrosis,
`and tissue sloughing may occur. The rate of absorption
`following subcutaneous injection of a drug often is suf(cid:173)
`ficiently constant and slow to provide a sustained effect.
`Moreover, it may be varied intentionally. For example, the
`rate of absorption of a suspension of insoluble insulin is
`slow compared with that of a soluble preparation of the
`hormone. The incorporation of a vasoconstrictor agent in
`a solution of a drug to be injected subcutaneously also
`retards absorption. Absorption of drugs implanted under
`the skin in a solid pellet form occurs slowly over a pe(cid:173)
`riod of weeks or months; some hormones are effectively
`administered in this manner.
`Intramuscular. Drugs in aqueous solution are absorbed
`quite rapidly after intramuscular injection, depending upon
`the rate of blood flow to the injection site. This may be
`modulated to some extent by local heating, massage, or
`exercise. For example, jogging may cause a precipitous
`drop in blood sugar when insulin is injected into the thigh,
`rather than into the arm or abdominal wall, since run(cid:173)
`ning markedly increases blood flow to the leg. Generally,
`the rate of absorption following injection of an aqueous
`preparation into the deltoid or vastus lateralis is faster
`than when the injection is made into the gluteus max(cid:173)
`imus. The rate is particularly slower for females after in(cid:173)
`jection into the gluteus maximus. This has been attributed
`to the different distribution of subcutaneous fat in males
`and females, since fat is relatively poorly perfused. Very
`obese or emaciated patients may exhibit unusual patterns
`of absorption following intramuscular or subcutaneous in(cid:173)
`jection. Very slow, constant absorption from the intramus(cid:173)
`cular site results if the drug is injected in solution in oil or
`suspended in various other repository vehicles. Antibiotics
`often are administered in this manner. Substances too ir(cid:173)
`ritating to be injected subcutaneously sometimes may be
`given intramuscularly.
`
`Intraarterwl. Occasionally a drug is injected directly into an
`artery to localize its effect in a particular tissue or organ-for
`example, in the treatment of liver tumors and head/neck cancers.
`Diagnostic agents are sometimes administered by this route. In(cid:173)
`traarterial injection requires great care and should be reserved
`
`e
`rapidly. Nitroglycerin also is very potent; relatively few
`v j' cules need to be absorbed to produce the therapeutic effect.
`.0 ee venous drainage from the mouth is to the superior vena
`me
`·
`fi
`·d h
`·
`ed fr
`the drug also IS protect
`om rap1
`epatJc
`rst-pass
`f
`h
`.h.
`ffi "
`cP~
`tabolism, wh1c
`IS su Cient to prevent t e appearance o any
`:C~ve nitroglycerin in the systemic circulation if the sublingual
`tablet is swallowed.
`
`m5
`
`Rectal Administration. The rectal route o_ften is useful "':hen
`oral ingestion _is ~recluded beca~se ~he patJ~nt 1s unconsciOus
`when vomitmg 1s present-a s1tuauon particularly relevant to
`0~ung children. Approximately 50% of the drug that is absorbed
`~rom the rectum will bypass the liver; the potential for hepatic
`first -pass metabolism is thus less than that for an oral dose.
`However, rectal absorption often is irregular and incomplete,
`and many drugs cause irritation of the rectal mucosa.
`
`Parenteral Injection. The major routes of parenteral ad(cid:173)
`ministration are intravenous, subcutaneous, and intramus(cid:173)
`cular. Absorption from subcutaneous and intramuscular
`sites occurs by simple diffusion along the gradient from
`drug depot to plasma. The rate is limited by the area of
`the absorbing capillary membranes and by the solubility
`of the substance in the interstitial fluid. Relatively large
`aqueous channels in the endothelial membrane account
`for the indiscriminate diffusion of molecules regardless of
`their lipid solubility. Larger molecules, such as proteins,
`slowly gain access to the circulation by way of lymphatic
`channels.
`Drugs administered into the systemic circulation by
`any route, excluding the intraarterial route, are subject to
`possible first-pass elimination in the lung prior to distri(cid:173)
`bution to the rest of the body. The lungs serve as a tempo(cid:173)
`rary storage site for a number of agents, especially drugs
`that are weak bases and are predominantly nonionized at
`the blood pH, apparently by their partition into lipid. The
`lungs also serve as a filter for particulate matter that may
`be given intravenously, and, of course, they provide a route
`of elimination for volatile substances.
`Intravenous. Factors relevant to absorption are circum(cid:173)
`vented by intravenous injection of drugs in aqueous solu(cid:173)
`tion, because bioavailability is complete and rapid. Also,
`drug delivery is controlled and achieved with an accuracy
`and immediacy not possible by any other procedure. In
`some instances, as in the induction of surgical anesthesia,
`the dose of a drug is not predetermined but is adjusted
`to the response of the patient. Also, certain irritating so(cid:173)
`lutions can be given only in this manner, since the blood
`:essel walls are relatively insensitive, and the drug, if in(cid:173)
`Jected slowly, is greatly diluted by the blood.
`As there are advantages to the use of this route of
`administration, so are there liabilities. Unfavorable re(cid:173)
`actions are likely to occur, since high concentrations of
`drug rnay be attained rapidly in both plasma and tissues.
`
`8
`
`

`

`8
`
`SECTION I GENERAL PRINCIPLES
`
`for experts. The first-pass and cleansing effects of the lung are
`not available when drugs are given by this route.
`Intrathecal. The blood-brain barrier and the blood-cerebro(cid:173)
`spinal fluid barrier often preclude or slow the entrance of drugs
`into the CNS. Therefore, when local and rapid effects of drugs
`on the meninges or cerebrospinal axis are desired, as in spinal
`anesthesia or acute CNS infections, drugs are sometimes injec(cid:173)
`ted directly into the spinal subarachnoid space. Brain tumors also
`may be treated by direct intraventricular drug administration.
`
`Pulmonary Absorption. Provided that they do not cause irri(cid:173)
`tation, gaseous and volatile drugs may be inhaled and absorbed
`through the pulmonary epithelium and mucous membranes of
`the respiratory tract. Access to the circulation is rapid by this
`route, because the lung's surface area is large. The principles
`governing absorption and excretion of anesthetic and other ther(cid:173)
`apeutic gases are discussed in Chapters 13, 14, and 16.
`In addition, solutions of drugs can be atomized and the
`fine droplets in air (aerosol) inhaled. Advantages are the almost
`instantaneous absorption of a drug into the blood, avoidance of
`hepatic first-pass loss, and, in the case of pulmonary disease,
`local application of the drug at the desired site of action. For
`example, drugs can be given in this manner for the treatment
`of bronchial asthma (see Chapter 28). Past disadvantages, such
`as poor ability to regulate the dose and cumbersomeness of the
`methods of administration, have to a large extent been overcome
`by technological advances, including metered-dose inhalers and
`more reliable aerolizers.
`Pulmonary absorption is an important route of entry of
`certain d1ugs of abuse and of toxic environmental substances of
`varied composition and physical states. Both local and systemic
`reactions to allergens may occur subsequent to inhalation.
`
`Topical Application. Mucous Membranes. Drugs are ap(cid:173)
`plied to the mucous membranes of the conjunctiva, nasophar(cid:173)
`ynx, orophmynx, vagina, colon, urethra, and urinary bladder
`primarily for their local effects. Occasionally, as in the appli(cid:173)
`cation of synthetic antidiuretic hormone to the nasal mucosa,
`systemic absorption is the goal. Absorption through mucous
`membranes occurs readily. In fact, local anesthetics applied for
`local effect sometimes may be absorbed so rapidly that they
`produce systemic toxicity.
`Skin. Few drugs readily penetrate the intact skin. Absorption
`of those that do is dependent on the surface area over which
`they are applied and to their lipid solubility, since the epidermis
`behaves as a lipid barrier (see Chapter 65). The dermis, however,
`is freely permeable to many solutes; consequently, systemic ab(cid:173)
`sorption of drugs occurs much more readily through abraded,
`burned, or denuded skin. Inflammation and other conditions that
`increase cutaneous blood flow also enhance absorption. Toxic
`effects sometimes are produced by absorption through the skin
`of highly lipid-soluble substances (e.g., a lipid-soluble insecti(cid:173)
`cide in an organic solvent). Absorption through the skin can be
`enhanced by suspending the drug in an oily vehicle and rub(cid:173)
`bing the resulting preparation into the skin. Because hydrated
`skin is more permeable than dry skin, the dosage form may
`be modified or an occlusive dressing may be used to facilitate
`absorption. Controlled-release topical patches are becoming in(cid:173)
`creasingly available. A patch containing scopolamine, placed
`behind the ear where body temperature and blood flow enhance
`absorption, releases sufficient drug to the systemic circulation to
`
`protect the wearer from motion sickness. Transdermal estrogen
`replacement therapy yields low maintenance levels of estradiol
`while minimizing the high estrone metabolite levels observed
`following oral administration.
`Eye. Topically applied ophthalmic drugs are used primarily
`for their local effects (see Chapter 66). Systemic absorption
`that results from drainage through the nasolacrimal canal is
`usually undesirable. In addition, drug that is absorbed after
`such drainage is not subject to first-pass hepatic elimination.
`Unwanted systemic pharmacological effects may occur for this
`reason when J'l-adrenergic receptor antagonists are administered
`as ophthalmic drops. Local effects usually require absorption of
`the drug throug