GOODMAN & GILMAN'S The
`PHARMACOLOGICAL
`BASIS OF
`THERAPEUTICS
`
`Ninth Edition
`
`McGraw-Hill
`HEALTH PROFESSIONS DIVISION
`
`New York St. Louis San Francisco Auckland Bogota Caracas Lisbon London Madrid
`Mexico City Milan Montreal New Delhi San Juan Singapore Sydney Tokyo Toronto
`
`Ex.1094 - Page 1
`
`

`

`McGraw-Hill
`A Division of The McGraw Hill Companies
`
`Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 9/e
`
`Copyright © 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 98765
`
`ISBN 0-07-026266-7
`
`This book was set in Times Roman by York Graphic Services, Inc. The editors were Martin J.
`Wonsiewicz• and Peter McCurdy; the production supervisors were Robert Laffler and Clare Stanley,
`and the cover designer was Marsha Cohen/Paralellogram. The index was prepared by Irving Conde
`Tullar.
`R.R. Donnelley and Sons Company was printer and binder.
`
`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in-Publication Data
`
`Goodman & Gilman's The Pharmacological Basis of Therapeutics. —9th ed. / Joel G. Hardman,
`Alfred Goodman Gilman, Lee E. Limbird.
`cm.
`p. (cid:9)
`Includes bibliographical references and index.
`ISBN 0-07-026266-7 (hardcover)
`1. Pharmacology. 2. Chemotherapy. I. Goodman, Louis Sanford.
`II. Gilman, Alfred.
`III. Hardman, Joel G. IV. Gilman, Alfred Goodman. V. Limbird, Lee E.
`[DNLM: 1. Pharmacology. 2. Drug Therapy. QV 4 G6532 1995]
`RM300.G644 1995
`615' .7—dc20
`DNLM/DLC (cid:9)
`for Library of Congress
`
`95-36658
`
`Ex.1094 - Page 2
`
`

`

`SECTION (cid:9)
`
`I
`
`GENERAL PRINCIPLES
`
`INTRODUCTION
`Leslie Z. Benet
`
`In its entirety, pharmacology embraces the knowledge of the history, source, physical and
`chemical properties, compounding, biochemical and physiological effects, mechanisms of
`action, absorption, distribution, biotransformation and excretion, and therapeutic and other
`uses of drugs. Since a drug is broadly defined as any chemical agent that affects processes
`of living, the subject of pharmacology is obviously quite extensive.
`For the clinician and the student of health sciences, however, the scope of pharma-
`cology is less expansive than indicated by the above definitions. The clinician is interested
`primarily in drugs that are useful in the prevention, diagnosis, and treatment of human
`disease. Study of the pharmacology of these drugs can be reasonably limited to aspects
`that provide the basis for their rational clinical use. Secondarily, the clinician also is con-
`cerned with chemical agents that are not used in therapy but are commonly responsible
`for household and industrial poisoning as well as environmental pollution. Study of these
`substances is justifiably restricted to the general principles of prevention, recognition, and
`treatment of such toxicity or pollution. Finally, all health professionals share in the re-
`sponsibility to help resolve the continuing sociological problem of the abuse of drugs.
`The basic pharmacological concepts summarized in this section apply to the charac-
`terization, evaluation, and comparison of all drugs. A clear understanding and apprecia-
`tion of these principles is essential for the subsequent study of the individual drugs. The
`relationship between the dose of a drug given to a patient and the utility of that drug in
`treating the patient's disease is described by two basic areas of pharmacology: pharma-
`cokinetics and pharmacodynamics. Operationally, these terms may be defined as what the
`body does to the drug (pharmacokinetics) and what the drug does to the body (pharma-
`codynamics).
`Pharmacokinetics (Chapter 1) deals with the absorption, distribution, biotransfor-
`mation, and excretion of drugs. These factors, coupled with dosage, determine the con-
`centration of a drug at its sites of action and, hence, the intensity of its effects as a func-
`tion of time. Many basic principles of biochemistry and enzymology and the physical and
`chemical principles that govern the active and passive transfer and the distribution of sub-
`stances, both small molecules and protein drugs, across biological membranes are read-
`ily applied to the understanding of this important aspect of pharmacology.
`The study of the biochemical and physiological effects of drugs and their mechanisms
`of action is termed pharmacodynamics (Chapter 2). Pharmacodynamics borrows freely
`from both the subject matter and the experimental techniques of physiology, biochemistry,
`cellular and molecular biology, microbiology, immunology, genetics, and pathology. It is
`unique mainly in that attention is focused on the characteristics of drugs. As the name im-
`plies, the subject is a dynamic one. The student who attempts merely to memorize the
`pharmacodynamic properties of drugs is forgoing one of the best opportunities for corre-
`lating the entire field of preclinical medicine. For example, the actions and effects of the
`saluretic agents can be fully understood only in terms of the basic principles of renal phys-
`
`1
`
`Ex.1094 - Page 3
`
`

`

`2 (cid:9)
`
`SECTION I GENERAL PRINCIPLES
`
`iology and of the pathogenesis of edema. Conversely, great insight into normal and ab-
`normal renal physiology can be gained by the study of the pharmacokinetics and phar-
`macodynamics of the saluretic agents.
`The clinician is understandably interested mainly in the effects of drugs in human
`beings. This emphasis on clinical pharmacology is justified, since the effects of drugs of-
`ten are characterized by significant interspecies variation, and since they may be modi-
`fied further by disease. In addition, some drug effects, such as those on mood and be-
`havior, can be adequately studied only in human beings. However, technical, legal, and
`ethical considerations limit pharmacological evaluation in human subjects, and the choice
`of drugs must be based in part on their pharmacological evaluation in animals. Conse-
`quently, some knowledge of animal pharmacology and comparative pharmacology is help-
`ful in deciding the extent to which claims for a drug based upon studies in animals can
`be reasonably extrapolated to patients.
`Pharmacotherapeutics (Chapter 3) deals with the use of drugs in the prevention and
`treatment of disease. Many drugs stimulate or depress biochemical or physiological func-
`tion in human beings in a sufficiently reproducible manner to provide relief of symptoms
`or, ideally, to alter favorably the course of disease. Conversely, chemotherapeutic agents
`are useful in therapy because they have only minimal effects on human beings but can
`destroy or eliminate pathogenic cells or organisms.
`Whether a drug is useful for therapy is crucially dependent upon its ability to pro-
`duce its desired effects only with tolerable undesired effects. Thus, from the standpoint
`of the clinician interested in the therapeutic uses of a drug, the selectivity of its effects is
`one of its most important characteristics. Drug therapy is rationally based upon the cor-
`relation of the actions and effects of drugs with the physiological, biochemical, micro-
`biological, immunological, and behavioral aspects of disease. In addition, disease may
`modify the pharmacokinetic properties of a drug by alteration of its absorption into the
`systemic circulation and/or its disposition.
`Toxicology (Chapter 4) is the aspect of pharmacology that deals with the adverse ef-
`fects of drugs. It is concerned not only with drugs used in therapy but also with the many
`other chemicals that may be responsible for household, environmental, or industrial in-
`toxication. The adverse effects of the pharmacological agents employed in therapy are
`properly considered an integral part of their total pharmacology. The toxic effects of other
`chemicals is such an extensive subject that clinicians must usually confine their attention
`to the general principles applicable to the prevention, recognition, and treatment of drug
`poisonings of any cause.
`Traditionally, most drugs were small chemicals with molecular weights in the hun-
`dreds, as well as a few that were natural human or animal hormones. Within the past
`decade, through advances in molecular and cellular biology, a number of protein and pep-
`tide drugs have been approved for clinical use. These therapies are designed to interact
`with a particular receptor or enzyme to ameliorate disease. Today we now consider the
`possibility of the drug directly replacing a diseased receptor (or gene) or of administer-
`ing agents that allow patients to make their own therapeutic protein through gene-based
`therapy (Chapter 5). The emergence of gene therapy is based on the assumption that the
`best treatment for genetic diseases will be therapy that is directed to the mutant gene it-
`self. This requires a direct assault on mutant genes to replace or supplement defective ge-
`netic material with normal, functional genes. Pharmacokinetics of these new gene-based
`therapies, particularly delivery of the "drug" to its site of action or function, is a major
`hurdle for this new therapeutic modality. Gene therapy requires unique methods, many of
`which are gene-based themselves through enhanced uptake of DNA expression vectors,
`to deliver a gene to its target cell.
`
`Ex.1094 - Page 4
`
`

`

`CHAPTER 1
`
`PHARMACOKINETICS
`The Dynamics of Drug Absorption, Distribution,
`and Elimination
`
`Leslie Z Benet, Deanna L. Kroetz, and Lewis B. Sheiner
`
`To produce its characteristic effects, a drug must be present
`in appropriate concentrations at its sites of action. Although
`obviously a function of the amount of drug administered,
`the concentrations attained also depend upon the extent and
`rate of its absorption, distribution, binding or localization
`in tissues, biotransformation, and excretion. These factors
`are depicted in Figure 1-1.
`
`PHYSICOCHEMICAL FACTORS
`IN TRANSFER OF DRUGS
`ACROSS MEMBRANES
`The absorption, distribution, biotransformation, and excre-
`tion of a drug all involve its passage across cell membranes.
`It is essential, therefore, to consider the mechanisms by
`which drugs cross membranes and the physicochemical
`properties of molecules and membranes that influence this
`transfer. Important characteristics of a drug are its molec-
`
`Vq0FACTION7
`
`bound
`
`ABSORPTION
`
`EXCRETION_,
`
`BIOTRANSFORMATION.
`
`Figure 1-1. Schematic representation of the interrelationship
`of the absorption, distribution, binding, biotransformation, and
`excretion of a drug and its concentration at its locus of action.
`
`Possible distribution and binding of metabolites are not de-
`picted.
`
`3
`
`ular size and shape, solubility at the site of its absorption,
`degree of ionization, and relative lipid solubility of its ion-
`ized and nonionized forms.
`When a drug permeates a cell, it must obviously tra-
`verse the cellular plasma membrane. Other barriers to drug
`movement may be a single layer of cells (intestinal epi-
`thelium) or several layers of cells (skin). Despite these
`structural differences, the diffusion and transport of drugs
`across these various boundaries have many common char-
`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 hydrophilic heads
`oriented outward. Individual lipid molecules in the bilayer can move
`laterally, endowing the membrane with fluidity, flexibility, high elec-
`trical resistance, and relative impermeability to highly polar mole-
`cules. Membrane proteins embedded in the bilayer serve as receptors
`to elicit electrical or chemical signaling pathways and provide se-
`lective targets for drug actions.
`
`Passive Processes. Drugs cross membranes either by passive
`processes or by mechanisms involving the active participation of
`components of the membrane. In the former, the drug molecule usu-
`ally penetrates by passive diffusion along a concentration gradient
`by virtue of its solubility in the lipid bilayer. Such transfer is directly
`proportional to the magnitude of the concentration gradient across
`the membrane and the lipid: water partition coefficient of the drug.
`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 free drug is the same on
`both sides of the membrane, if the drug is a nonelectrolyte. For ionic
`compounds, the steady-state concentrations will be dependent on dif-
`ferences in pH across the membrane, which may influence the state
`of ionization of the molecule on each side of the membrane, and on
`the electrochemical gradient for the ion. Most biological membranes
`are relatively permeable to water, either by diffusion or by flow that
`results from hydrostatic or osmotic differences across the membrane.
`Such bulk flow of water can carry with it small, water-soluble sub-
`stances. Most cell membranes permit passage only of water, urea,
`and other small, water-soluble molecules by this mechanism. Such
`substances generally do not pass through cell membranes if their mol-
`ecular masses are greater than 100 to 200 Da.
`
`Ex.1094 - Page 5
`
`

`

`4 (cid:9)
`
`SECTION I GENERAL PRINCIPLES
`
`While most inorganic ions would seem to be sufficiently small
`to penetrate the membrane, their hydrated ionic radius is relatively
`large. The concentration gradient of many inorganic ions is largely
`determined by active transport (e.g., Na+ and K+). The transmem-
`brane potential frequently determines the distribution of other ions
`(e.g., chloride) across the membrane. Channels with selectivity for
`individual ions are often controlled to allow regulation of specific
`ionic fluxes. Such mechanisms are of obvious importance in the gen-
`eration of action potentials in nerve and muscle (see Chapter 6) and
`in transmembrane signaling events (see Chapter 2).
`
`Weak Electrolytes and Influence of pH. Most drugs are
`weak acids or bases that are present in solution as both the
`nonionized and ionized species. The nonionized molecules
`are usually lipid soluble and can diffuse across the cell
`membrane. In contrast, the ionized molecules are usually
`unable to penetrate the lipid membrane because of their
`low lipid solubility.
`Therefore, the transmembrane distribution of a weak
`electrolyte usually is determined by its pKa and the pH gra-
`dient across the membrane. 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 membrane behaves as a simple lipid
`barrier that is permeable only to the lipid-soluble, nonion-
`ized form of the acid. The ratio of nonionized to ionized
`drug at each pH is easily calculated from the Hender-
`son—Hasselbalch equation. Thus, in plasma, the ratio of
`nonionized to ionized drug is 1: 1000; in gastric juice, the
`ratio is 1:0.001. These values are given in brackets in Fig-
`ure 1-2. The total concentration ratio between the plasma
`and the gastric juice would therefore be 1000: 1 if such a
`system came to a steady state. For a weak base with a pKa
`of 4.4 (BH± (cid:9)
`B + 11±), the ratio would be reversed,
`as would the thick horizontal arrows in Figure 1-2, which
`
`[1] (cid:9)
`[1000] (cid:9)
`HAA-+ H-F
`
`•=1 ,11, (cid:9)
`
`1001
`Total
`[HA] + [A-]
`
`Plasma pH = 7.4
`
`Gastric Juice (cid:9)
`
`pH = 1.4
`
`[1] (cid:9)
`
`HA '4.=_" (cid:9)
`
`[0.001]
`
`H+
`
`1.001
`
`Weak Acid HA = A H
`ionized
`nonionized (cid:9)
`Figure 1-2. Influence of pH on the distribution of a weak acid
`between plasma and gastric juice, separated by a lipid barrier.
`
`pKa = 4.4
`
`indicate the predominant species at each pH. These con-
`siderations have obvious implications for the absorption
`and excretion of drugs, as will be discussed more specifi-
`cally below. The establishment of concentration gradients
`of weak electrolytes across membranes with a pH gradi-
`ent is a purely physical process and does not require an ac-
`tive transport system. All that is necessary is a membrane
`preferentially permeable to one form of the weak electrolyte
`and a pH gradient across the membrane. The establishment
`of the pH gradient is, however, an active process.
`Bulk flow through intercellular pores is the major
`mechanism of passage of drugs across most capillary en-
`dothelial membranes, with the important exception of the
`central nervous system (CNS; see below). These inter-
`cellular gaps are sufficiently large that diffusion across
`most capillaries is limited by blood flow and not by the
`lipid solubility of drugs or pH gradients. This is an im-
`portant factor in filtration across glomerular membranes in
`the kidney (see below). Tight junctions are characteristic
`of capillaries of the CNS and a variety of epithelia. Inter-
`cellular diffusion is consequently limited. Pinocytosis, the
`formation and movement of vesicles across cell mem-
`branes, has been implicated in drug absorption. However,
`the quantitative significance of pinocytosis probably is
`negligible.
`
`Carrier-Mediated Membrane Transport. While passive diffusion
`through the bilayer is dominant in the absorption and distribution of
`most drugs, more active and selective mechanisms can play impor-
`tant roles. Active transport of some drugs occurs across neuronal
`membranes, the choroid plexus, renal tubular cells, and hepatocytes.
`The characteristics of active transport—selectivity, competitive inhi-
`bition by congeners, a requirement for energy, saturability, and move-
`ment against an electrochemical gradient—may be important in the
`mechanism of action of drugs that are subject to active transport or
`that interfere with the active transport of natural metabolites or neu-
`rotransmitters. The term facilitated diffusion describes a carrier-
`mediated transport process to which there is no input of energy, and
`movement of the substance in question thus cannot occur against an
`electrochemical gradient. Such mechanisms, which also may be
`highly selective for specific conformational structures of drugs, are
`necessary for the transport of endogenous compounds whose rate of
`movement across biological membranes by simple diffusion other-
`wise would be too slow.
`
`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 occurs.
`However, the clinician is concerned primarily with a pa-
`rameter designated as bioavailability, rather than absorp-
`tion. Bioavailability is a term used to indicate the extent
`
`Ex.1094 - Page 6
`
`(cid:9)
`

`

`CHAPTER 1 PHARMACOKINETICS (cid:9)
`
`5
`
`to which a drug reaches its site of action or a biological
`fluid from which the drug has access to its site of action.
`For example, a drug that is absorbed from the stomach and
`intestine must first pass through the liver before it reaches
`the systemic circulation. If the drug is metabolized in the
`liver or excreted in the bile, some of the active drug will
`be inactivated or diverted before it can reach the general
`circulation and be distributed to its sites of action. If the
`metabolic or excretory capacity of the liver for the agent
`in question is great, bioavailability will be substantially de-
`creased (the so-called first-pass effect). This decrease in
`availability is a function of the anatomical site from whidh
`absorption takes place; other anatomical, physiological,
`and pathological factors can influence bioavailability (see
`below), and the choice of the route of drug administration
`must be based on an understanding of these conditions.
`Moreover, factors that modify the absorption of a drug can
`change its bioavailability.
`
`Factors That Modify Absorption. Many variables, in
`addition to the physicochemical factors that affect trans-
`port across membranes, influence the absorption of drugs.
`Absorption, regardless of the site, is dependent upon drug
`solubility. Drugs given in aqueous solution are more
`rapidly absorbed than those given in oily solution, sus-
`pension, or solid form, because they mix more readily with
`the aqueous phase at the absorptive site. For those given
`in solid form, the rate of dissolution may be the limiting
`factor in their absorption. Local conditions at the site of
`absorption alter solubility, particularly in the gastrointesti-
`nal tract. Aspirin, which is relatively insoluble in acidic
`gastric contents, is a common example of such a drug. The
`concentration of a drug influences its rate of absorption.
`Drugs introduced at an administration site in solutions of
`high concentration are absorbed more rapidly than are
`drugs in solutions of low concentration. The circulation to
`the site of absorption also affects drug absorption. In-
`creased blood flow, brought about by massage or local ap-
`plication of heat, enhances the rate of drug absorption; de-
`creased blood flow, produced by vasoconstrictor agents,
`shock, or other disease factors, can slow absorption. The
`area of the absorbing surface to which a drug is exposed
`is one of the more important determinants of the rate of
`drug absorption. Drugs are absorbed very rapidly from
`large surface areas such as the pulmonary alveolar epithe-
`lium, the intestinal mucosa, or, in a few cases after exten-
`sive application, the skin. The absorbing surface is deter-
`mined largely by the route of administration. Each of these
`factors separately or in conjunction with one another may
`have profound effects on the clinical efficacy and toxicity
`of a drug.
`
`Enteral (Oral) vs. Parenteral Administration. Often
`there is a choice of the route by which a therapeutic agent
`may be given, and a knowledge of the advantages and dis-
`advantages of the different routes of administration is then
`of primary importance. Some characteristics of the major
`routes employed for systemic drug effect are compared in
`Table 1-1.
`Oral ingestion is the most common method of drug
`administration. It also is the safest, most convenient, and
`most economical. Disadvantages to the oral route include
`the incapability to absorb some drugs because of their
`physical characteristics (e.g., polarity), emesis as a result
`of irritation to the gastrointestinal mucosa, destruction of
`some drugs by digestive enzymes or low gastric pH, ir-
`regularities in absorption or propulsion in the presence of
`food or other drugs, and necessity for cooperation on the
`part of the patient. In addition, drugs in the gastrointestinal
`tract may be metabolized by the enzymes of the mucosa,
`the intestinal flora, or the liver before they gain access to
`the general circulation.
`The parenteral injection of drugs has certain distinct
`advantages over oral administration. In some instances,
`parenteral administration is essential for the drug to be ab-
`sorbed in active form. Availability is usually more rapid
`and more predictable than when a drug is given by mouth.
`The effective dose can therefore be more accurately se-
`lected. In emergency therapy, parenteral administration is
`particularly serviceable. If a patient is unconscious, unco-
`operative, or unable to retain anything given by mouth, par-
`enteral therapy may be a necessity. The injection of drugs
`also has its disadvantages. Asepsis must be maintained, an
`intravascular injection may occur when it is not intended,
`pain may accompany the injection, and it is sometimes
`difficult for patients to perform the injections themselves
`if self-medication is necessary. Expense is another con-
`sideration.
`
`Oral Ingestion. Absorption from the gastrointestinal
`tract is governed by factors that are generally applicable,
`such as surface area for absorption, blood flow to the site
`of absorption, the physical state of the drug, and its con-
`centration at the site of absorption. Since most drug ab-
`sorption from the gastrointestinal tract occurs via passive
`processes, absorption is favored when the drug is in the
`nonionized and more lipophilic form. Thus, one might ex-
`pect the absorption of weak acids to be optimal in the acidic
`environment of the stomach, whereas absorption of bases
`might be favored in the relatively alkaline small intestine.
`However, it is an oversimplification to extrapolate the pH-
`partition concept presented in Figure 1-2 to a comparison
`of two different biological membranes, such as the ep-
`
`Ex.1094 - Page 7
`
`

`

`6 (cid:9)
`
`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 (cid:9)
`
`Intramuscular (cid:9)
`
`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
`
`LIMITATIONS 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 exten-
`sively metabolized by the liver
`and/or gut
`
`Oral ingestion (cid:9)
`
`Variable; depends upon
`many factors (see text)
`
`Most convenient and
`economical; usually more
`safe
`
`*See text for more complete discussion and for other routes.
`
`ithelia of the stomach and the intestine. The stomach is
`lined by a thick, mucus-covered membrane with a small
`surface area and high electrical resistance. The primary
`function of the stomach is digestive. In contrast, the ep-
`ithelium of the intestine has an extremely large surface
`area; it is thin, it has low electrical resistance, and its pri-
`mary function is to facilitate the absorption of nutrients.
`Thus, any factor that accelerates gastric emptying will be
`likely to increase the rate of drug absorption, while any
`factor that delays gastric emptying will probably have the
`opposite effect, regardless of the characteristics of the drug.
`The experimental data available from the classical work of
`Brodie (1964) and more recent studies all are consistent
`with the following conclusion: the nonionized form of a
`drug will be absorbed more rapidly than the ionized form
`
`at any particular site in the gastrointestinal tract. However,
`the rate of absorption of a drug from the intestine will be
`greater than that from the stomach even if the drug is pre-
`dominantly ionized in the intestine and largely nonionized
`in the stomach.
`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 contents. However, some enteric-coated prepara-
`tions 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 de-
`pendent upon its rate of dissolution in the gastrointestinal fluids. This
`factor is the basis for the so-called controlled-release, extended-
`
`Ex.1094 - Page 8
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`CHAPTER 1 PHARMACOKINETICS (cid:9)
`
`7
`
`release, sustained-release, or prolonged-action pharmaceutical prepa-
`rations 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 com-
`pared with conventional dosage forms (possibly with improved com-
`pliance by the patient), maintenance of a therapeutic effect overnight,
`and decreased incidence and/or intensity of undesired effects by elim-
`ination of the peaks in drug concentration that often occur after ad-
`ministration of immediate-release dosage forms.
`Many controlled-release preparations fulfill these theoretical ex-
`pectations. However, the clinician must be aware of some drawbacks
`of these products. Generally, interpatient variability in terms of the
`systemic concentration of the drug that is achieved is greater for con-
`trolled-release than for immediate-release dosage forms. During re-
`peated drug administration, trough drug concentrations resulting from
`controlled-release dosage forms may not be different from those ob-
`served with immediate-release preparations, although the time inter-
`val between trough concentrations is greater for a well-designed con-
`trolled-release product. It is possible that the dosage form may fail,
`and "dose-dumping" with resultant toxicity can occur, since the to-
`tal dose of drug ingested at one time may be several times the amount
`contained in the conventional preparation. Controlled-release dosage
`forms are most appropriate for drugs with short half-lives (less than
`4 hours). So-called controlled-release dosage forms are sometimes
`developed for drugs with long half-lives (greater than 12 hours).
`These usually more expensive products should not be prescribed un-
`less specific advantages have been demonstrated.
`
`Sublingual Administration. Absorption from the oral mucosa has
`special significance for certain drugs, despite the fact that the sur-
`face area available is small. For example, nitroglycerin is effective
`when retained sublingually because it is nonionic and has a very high
`lipid solubility. Thus, the drug is absorbed very rapidly. Nitrogly-
`cerin also is very potent; relatively few molecules need to be absorbed
`to produce the therapeutic effect. Since venous drainage from the
`mouth is to the superior vena cava, the drug also is protected from
`rapid first-pass metabolism by the liver. Hepatic first-pass metabo-
`lism is sufficient to prevent the appearance of any active nitroglyc-
`erin in the systemic circulation if the conventional tablet is swal-
`lowed.
`
`Rectal Administration. The rectal route often is useful when oral
`ingestion is precluded by vomiting or when the patient is uncon-
`scious. Approximately 50% of the drug that is absorbed from 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-
`ministration are intravenous, subcutaneous, and intramus-
`cular. Absorption from subcutaneous and intramuscu-
`lar 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 solu-
`bility of the substance in the interstitial fluid. Relatively
`large aqueous channels in the endothelial membrane ac-
`count for the indiscriminate diffusion of molecules re-
`gardless 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 distrib-
`ution to the rest of the body. The lungs serve as a tempo-
`rary clearing site for a number of agents, especially drugs
`that are weak bases and are predominantly nonionized at
`the blood pH, apparently by their partition into lipid. The
`lungs also serve as a filter for particulate matter that may
`be given intravenously, and, of course, they provide a route
`of elimination for volatile substances.
`Intravenous. The factors concerned in