THIEME FLEXIBOOK
`
`Color Atlas of
`
`Pharmacology
`
` DRL - EXHIBIT 1027
`
`

`

`Pocket Atlas of Pharmacology
`
`f
`
`'
`
`

`

`Pocket Atlas of
`Pharmacology
`
`Heinz Ltillrnann, Klaus Mohr,
`Albrecht Ziegler, and Detlef Bieger
`
`149 color plate s by J iirgen Wirth
`
`(
`
`1993
`Georg Thieme Verlag Stuttgart· New York
`Thieme Medical Publishers~ Inc. New York
`
`

`

`iv
`
`Heinz Uillmann, M.D.
`Professor, Dept. of Pharmacology
`University of Kiel
`Hospitalstrasse 4, 24105 Kiel, Germany
`
`Albrecht Ziegler, Ph. D.
`Professor, Dept. of P h armacology
`University of Kiel
`Hospitalstrasse 4, 24105 Kiel, Germany
`
`Klaus Mohr, M . D .
`Professor, Dept. of P h armacology
`and Toxicology, Institute of Pharmacy,
`University of Bonn
`Ander Immenburg 4 , 53121 Bonn , Germany
`
`Detlef Bieger, M.D.
`Professor, Division of Basic Medical Sciences
`Faculty of Medicine
`Memorial University of Newfoundland
`St. John's, Newfoundland Canada AlB 3V6
`
`Library of Congress Cataloging-in-Publication Data
`Pocket atlas of pharmaco logy I Heinz Ltillmann . . . [et aL]; 149 color plates by Jtirgen Wirth.
`Rev. and expanded translation o f : Tas<;:henatlas der Pharmakologie I
`Heinz Liillmann, Klaus Mohr, Albrecht Ziegler, 1990.
`Includes bibliographical references and indexes.
`1. Pharmacology-Atlases. 2 . Pharmacology-Handbooks, manuals.
`etc . I. Liillmann, Heinz. II. Title.
`[DNLM: 1. Pharmacology-atlases. 2 . Pharmacology-handbooks. QV
`17 Tl97p 1993]
`RM301.12.T3813 1993
`615' .1-dc20
`
`Important Note: Medicine is an ever-changing science underg oing continual development. Research
`and clinical e x perience are c ontinually expanding our knowledge, in particular our knowledge of pro per
`treatment and drug therapy. Insofa r as this book mentions any dos age or application, readers may rest
`assured that the authors, editors and publishers have made every eff ort to ensure that such references are
`in accordance with the s tate of knowledge at the time of production of the book.
`Nevertheless this does not involve, imply, or expres s any guarantee or responsibility on the part of the
`publishers in respect of any dosage instructions and forms of application stated in the book. Every user
`is requested to examine carefully the manufacture rs' leaflets accompanying each drug and to check, if
`necessary in consultation with a phys ician or specialist, whether the dosage schedules mentioned there(cid:173)
`in or the contraindications stated by the manufacturers differ from the statements made in the present
`book. Such exa mination is particularly important with drugs that are either rarely u sed or have been new(cid:173)
`ly released on the market. Every dosage schedule or every form of application used is entirely at the
`user's own risk and responsibility. The authors and publishers request every user to report to the pub(cid:173)
`lishers any dis crepanc ies or inaccuracies notic ed.
`
`This book is an autho rized, revised and e xpanded translation of the I st German editio n published
`and copyrighted 1990 by Geo rg Thieme Verlag, Stuttgart, Germany. Title of the G e rman
`edition: Taschenatlas der Pharmakologie
`
`1st German edition, 1990
`1st French edition, 1991
`
`I st Japanese edition, I 992
`I st Spanish edition, 1992
`
`Some ~?f the product names, patents and registered designs referred to in this book are in fact re gistered
`trademarks or proprietary names even though specific reference to this fact is not always made in the
`text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a
`representation by the publisher that it is in the public domain.
`This book, including all parts thereof, is legally protected by copyright. Any use, exploitation or com(cid:173)
`mercialization outside the narrow limits set by copyright legislation, without tl1e publisher's consent, is
`illegal and liable to prosecution. T h is applies in particular .to photostat reproduction, copying, mimeo(cid:173)
`graphing or duplication of any kind, translating, preparation of microfilms, and electronic data proces(cid:173)
`sing and storage.
`© 1993 Georg Thieme Verlag, Riidigerstrasse 14,70469 Stuttgart
`Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N.Y. 10016
`Printed in Germany by K. Grammlich, Pliezhausen
`
`ISBN 3-13-781701-3 (Georg Thieme Verlag, Stuttgart)
`ISBN 0-86577-455-2 (Thieme Medical Publishers, Inc. New York)
`
`1 2 3 4 5 6
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`

`

`I.
`' I
`I
`-1
`
`44
`
`Pharmacokinetics
`
`Drug Concentration in the Body
`as a Function of Time. First-Order
`(Exponential) Rate Processes
`
`Processes such as drug absorption and
`elimination display exponential char(cid:173)
`acteristics. As regards the former, this
`follows from the simple fact that the.
`amount of-drug being moved per unit
`of time depends on the concentration
`difference (gradient) between two
`bedy compartment's (Pick's Law). In
`drug absorption from the alimentary
`tract, the intestinal contents and the
`blood would represent the compart(cid:173)
`ments containing an initially high and
`low concentration, respectively. In
`drug elimination via the kidney, ex(cid:173)
`cretion often depends on glomerular
`filtration, i.e., the filtered amount of
`drug present in primary urine. As the
`blood concentration falls, the amount
`of drug filtered per unit of time dimin(cid:173)
`ishes., The resulting exponential de(cid:173)
`cline is illustrated in (A). The expo(cid:173)
`nential time course implies constancy
`of the interval during which the con(cid:173)
`centration decreases by one-half. This
`interval represents the half-life (tllz)
`and is related to the elimination rate
`constant k by the equation tth = ln2/k.
`The two parameters, together with the
`initial concentration C 0 , describe a
`first-order (exponential) rate process.
`The constancy of the process per(cid:173)
`mits calculation of the plasma volume
`that would be cleared of drug, if the
`remaining drug were not to assume a
`homogeneous distribution in the total
`volume (a condition not met in reali(cid:173)
`ty). The notional plasma volume
`freed of drug per ·unit of time is ter(cid:173)
`med the clearance. Depending on
`whether plasma concentration falls as
`a result of urinary excretion or of me(cid:173)
`tabolic alteration, ciearance is consid(cid:173)
`ered to be renal or hepatic. Rena] and
`hepatic clearances add up to total
`clearance (Cl101) in the case of drugs
`
`that are eliminated unchaQged via the
`kidney and biotransformed in the liv(cid:173)
`er. Cl101 represents the sum of all pro(cid:173)
`cesses contributing to elimination ; it
`is related to the half-life (tt/2 ) and the
`apparent volume of distribution Vapp
`(p. 28) by the equation:
`v
`app
`Cltot
`
`tl/2 = ln2 • -
`
`The smaller the volume of distri(cid:173)
`bution or the larger the total clearance ~
`the shorter is the half-life. -
`In the case of drugs renally elim(cid:173)
`inated in unchanged form, the half(cid:173)
`life of elimination can be calculated
`from
`the cumulative excretion in
`urine; the final total amount elimi(cid:173)
`nated corresponds to the aJVount ab(cid:173)
`sorbed.
`Hepatic elimination obeys expo(cid:173)
`nential kinetics because metabolizing
`enzymes operate in the quasilinear re(cid:173)
`gion of their concentration-'-activity
`curve, and hence the amount of drug
`metabolized per unit of time dimin(cid:173)
`ishes with decreasing blood concen(cid:173)
`tration.
`The best-known exception to ex(cid:173)
`ponential kinetics is the elimination of
`alcohol (ethanol), which obeys a lin(cid:173)
`ear time course (zero-order kinetics),
`at least at blood concentrations >
`0 .02%. It does so because the rate(cid:173)
`limiting enzyme, alcohol dehydro(cid:173)
`genase, achieves half saturation at
`very low substrate concentrations,
`i.e., at about 80 mg/L (0.008% ). Thus,
`reaction velocity reaches a plateau at
`blood ethanol concentrations of about
`0 .02%, and the amount of drug elimi(cid:173)
`nated per unit of time remains con(cid:173)
`stant at concentrations above this
`level.
`
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`

`

`46
`
`Pharmacokinetics
`
`Time Course of
`Drug Concentration in Plasma
`
`A. Drugs are taken up into and elimi(cid:173)
`nated from the body by various rou(cid:173)
`tes. T e body thus represents an open
`system wherein the actual drug con(cid:173)
`centration reflects the interplay of in(cid:173)
`take (ingestion) and egress (elimina(cid:173)
`tion).
`When orally administered drug is
`absorbed from the stomach and intes(cid:173)
`tine, speed of uptake depends on
`many factors, including the speed of
`drug dissolution (in the case of solid
`dosage forms) and of gastrointestinal
`transit; the membrane penetrability of
`the drug; its concentration gradient
`across the mucosa-blood barrier; and
`flow. Absorption
`mucosal blood
`from the intestine causes the drug
`concentration in blood to increase.
`Transport in blood conveys the drug
`to different organs (distribu tion),
`into which it is taken up to a degree
`compatible with its chemical proper(cid:173)
`ties and rate of blood flow through the
`organ. For instance, well-perfused or(cid:173)
`gans such as the brain receive a great(cid:173)
`er proportion than do less well-per(cid:173)
`fused ones. Uptake into tissue causes
`the blood concentration to fall. Ab(cid:173)
`sorption from the gut diminishes as
`the mucosa- blood gradient decreases.
`Plasma concentration reaches a peak
`when the amount of drug leav ing the
`blood per unit of time equals that
`being absorbed. Drug entry into he(cid:173)
`patic and renal
`tissue constitutes
`movement into the organs of elimi(cid:173)
`nation.
`The characteristic phasic time
`course of drug concentration in plas(cid:173)
`ma represents the sum of the constitu(cid:173)
`ent processes of absorption, distri(cid:173)
`bution, and elimination, which over(cid:173)
`lap in time. When distribution takes
`place significantly faster than elimi(cid:173)
`nation, there is an initial rapid and
`
`then a greatly retarded fall in the plas(cid:173)
`ma level, the former being designated
`the a-phase (distribution phase), the
`latter the 13-phase (elimination phase).
`When the drug is distributed more
`rapidly than it is absorbed, the time
`course of the plasma level can be de(cid:173)
`scribed in mathematically simplified
`form by the Bateman function (k 1 and
`k 2 represent the rate constants for ab(cid:173)
`sorption and elimination, respec(cid:173)
`tively).
`
`B. The velocity of absorption de(cid:173)
`pends on the route of administration.
`The more rapid the absorption, the
`shorter will be the time (t.nax) required
`to reach the peak plasma level (cmax),
`the higher will be the Cmax• and the ear(cid:173)
`lier the plasma level will begin to fall
`again.
`The area under the plasma level
`time curve (AUC) is independent of
`the route of administration, provided
`the doses and bioavailability are the
`same (Dost's law of corresponding
`areas). The AUC can thus be used to
`determine the extent of presystemic
`elimination or the bioavailability of a
`drug. The ratio of AUC values deter(cid:173)
`mined after oral or intravenous ad(cid:173)
`ministration of a given dose of a par(cid:173)
`ticular drug corresponds to the pro(cid:173)
`portion of drug entering the systemic
`circulation after oral administration.
`The determination of plasma levels
`affords a comparison of different pro(cid:173)
`prietary preparations containing the
`same drug in the same dosage. Identi(cid:173)
`cal plasma level time-curv es of differ(cid:173)
`ent manufacturers' products with ref(cid:173)
`erence to a standard preparation indi(cid:173)
`cate bioequivalence.
`
`

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`

`

`(C, graph at right linear scale). If the
`cumulative frequency (total number
`of animals responding at a given dose)
`is plotted against the logarithm of the
`dose (abscissa), a sigmoidal curve re(cid:173)
`sults (C, graph at left semi-logarithm(cid:173)
`ic scale). The inflection point of the
`curve lies at the dose at which one(cid:173)
`half of the group has responded. The
`dose
`range
`encompassing
`the
`dose-frequency relationship reflects
`the variation in individual sensitivity
`to the drug.
`Although similar in shape, a
`dose-frequency
`relationship
`has,
`thus, a different meaning than does a
`dose-effect relationship. The latter
`can be evaluated in one individual and
`results from an (intraindividual) de(cid:173)
`pendency of the effect on drug con(cid:173)
`centration.
`The evaluation of a dose-effect
`relationship within a group of individ(cid:173)
`uals is compounded by interindividu(cid:173)
`al differences in sensitivity. To ac(cid:173)
`count for the biological variation,
`measurements have to be carried out
`on a representative sample and there(cid:173)
`sults averaged. Thus, recommended
`therapeutic doses will be appropriate
`for the majority of patients, but not
`necessarily for each individual.
`The variation in sensitivity may
`be based on pharmacokinetic differ(cid:173)
`ences (same dose __, different plasma
`levels) or on differences in target or(cid:173)
`gan sensitivity (same plasma level---;.
`different effects).
`
`52
`
`Quantification of Drug Action
`
`Dose-Response Relationship
`
`The effect of a substance depends on
`the amount administered, i.e., the
`dose. If the dose chosen is below the
`critical threshold (subliminal dosing),
`an effect will be absent. Depending on
`the nature of the effect to be mea(cid:173)
`sured, ascending doses may cause the
`effect to increase in intensity. Thus,
`the effect of an antipyretic or hypoten(cid:173)
`sive drug can be quantified in a graded
`fashion, in that the extent of fall in
`body temperature or blood pressure is
`being measured. A dose-effect rela(cid:173)
`tionship is then encountered, as dis(cid:173)
`cussed on page 54.
`The dose-effect relationship may
`vary depending on the sensitivity of
`the individual person receiving the
`drug, i.e., for the same effect, different
`doses may be required in different in(cid:173)
`dividuals. The interindividual varia(cid:173)
`tion in sensitivity is especially obvi(cid:173)
`ous with effects of the "ali-or-none"
`kind.
`To illustrate this point, we con(cid:173)
`sider an experiment in which the sub(cid:173)
`jects individually respond in ali-or(cid:173)
`none fashion, as in the Straub tail phe(cid:173)
`nomenon (A). Mice react to morphine
`with excitation, evident in the form of
`an abnormal posture of the tail and
`limbs. The dose dependence of this
`phenomenon is observed in groups of
`animals (e.g ., 10 mice per group) in(cid:173)
`jected with increasing doses of mor(cid:173)
`phine. At the low dose, only the most
`sensitive, at increasing doses a grow(cid:173)
`ing proportion, at the highest dose all
`of the animals are affected (B) . There
`is a relationship between the frequen(cid:173)
`cy of responding animals and the dose
`given. At 2 mg/kg, 1 out of 10 animals
`reacts; at 10 mg/kg, 5 out of 10 re(cid:173)
`spond. The dose-frequency rela(cid:173)
`tionship results from the different
`sensitivity of individuals, which as a
`rule exhibits a log normal distribution
`
`

`

`

`

`54
`
`Quantification of Drug Action
`
`Concentration-Effect
`Relationship (A)
`
`The relationship between the concen(cid:173)
`tration of a drug and its effect is deter(cid:173)
`mined in order to define the range of
`active drug concentrations (potency)
`and the maximum possible effect (ef(cid:173)
`ficacy). On the basis of these parame(cid:173)
`ters, differences between drugs can be
`quantified. As a rule, the therapeutic
`effect or toxic action depends criti(cid:173)
`cally on the response of a single organ
`or a limited number of organs, e.g.,
`blood flow is affected by a change in
`vascular luminal width. By isolating
`critical organs or tissues from a larger
`functional system, these actions can
`be studied with more accuracy; for in(cid:173)
`stance, vasoconstr ictor agents can be
`examined
`in
`isolated preparations
`from different regions of the vascular
`tree, e.g., the portal or saphenous
`veins, or the mesenteric, coronary, or
`basilar artery. In many cases, isolated
`organs or organ parts can be kept via(cid:173)
`ble for hours in an appropriate nutri(cid:173)
`ent medium sufficiently supplied with
`oxygen and held at a suitable temper(cid:173)
`ature. Responses of the preparation to
`a physiological or pharmacological
`stimulus can be determined by a suit(cid:173)
`able recording apparatus. Thus, nar(cid:173)
`rowing of a blood vessel is recorded
`with the help o f two clamps by which
`the vessel is suspended under tension.
`Experimentation on isolated or(cid:173)
`gans offers several advantages:
`1. The drug concentration in the tis(cid:173)
`sue is usually known
`2 . Reduced complexity and ease of
`relating stimulus and effect
`3. It is possible to circumvent com(cid:173)
`pensatory responses that may par(cid:173)
`tially cancel the primary effect in
`the
`intact organism-e.g.,
`the
`heart rate-increasing action of nor(cid:173)
`epinephrine cannot be demon(cid:173)
`strated in the intact organism, be-
`
`cause a simultaneous rise in blood
`pressure elicits a counter-regulato(cid:173)
`ry reflex that slows cardiac rate;
`4. The ability to examine a drug ef(cid:173)
`fect over its full range of intensi(cid:173)
`ties-e.g., it would be impossible
`in the intact organism to follow
`negative chronotropic effect s to
`the point of cardiac arrest
`
`Disadvantages are:
`1. Unavoidable tissue injury during
`dissection
`2. Loss of physiological regulation of
`function in the isolated tissue
`3. The artificial milieu imposed on
`the tissue
`
`Concentration-Effect Curves (B)
`
`As the concentration is raised by a
`constant factor, the increment in effect
`diminishes steadily and tends asymp(cid:173)
`totically toward zero the closer one
`comes to the maximally effective con(cid:173)
`centration. The concentration
`at
`which a maximal effect occurs cannot
`be measured accurately; however,
`that eliciting a half-maximal effect
`(EC50) is readily determined. It typi(cid:173)
`cally corresponds to the inflection
`point of the concentration-response
`curve in a semilogarithmic plot (log
`concentration on abscissa). Full char(cid:173)
`acterization of a concentration-effect
`relationship requires determination of
`the EC50, the maximally possible ef(cid:173)
`fect (Emax), and the slope at the point
`of inflection.
`
`

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`

`56
`
`Quantification of Drug Action
`
`Concentration-Binding Curves
`
`In order to elicit their effect, drug mol(cid:173)
`ecules must be bound to the cells of
`the effector organ. Binding com(cid:173)
`monly occurs at specific cell struc(cid:173)
`tures, namely the receptors. The ana(cid:173)
`lysis of drug binding to receptors aims
`to determine the affinity of ligands,
`the kinetics of interaction, and the
`characteristics of the binding site it(cid:173)
`self.
`In studying the affinity and num(cid:173)
`ber of such binding sites, use is made
`of membrane suspensions of different
`tissues. This approach is based on the
`expectation that binding sites will re
`tain
`their characteristic properties
`during cell homogenization. Pro vided
`that binding sites are freely accessible
`in the medium in which membrane
`fragments are suspended, drug con(cid:173)
`centration at
`the "site of action"
`would equal that in the medium. The
`drug under study is radiolabeled (en(cid:173)
`abling low concentrations to be mea(cid:173)
`sured quantitatively), added to the
`membrane suspension, and allowed to
`bind to receptors. Membrane frag(cid:173)
`ments and medium are then separated,
`e.g., by filtration, and the amount of
`bound drug is measured. Binding in(cid:173)
`creases in proportion to concentration
`as long as there is a negligible reduc(cid:173)
`tion in the number of free binding si(cid:173)
`tes (C= 1 and B = 10% of maximum
`binding~ C=2 and B = 20%). As bind(cid:173)
`ing sites approach saturation,
`the
`number of free sites decreases and the
`increment in binding is no longer pro(cid:173)
`portional to the increase in concentra(cid:173)
`tion (in the example illustrated, an in(cid:173)
`crease in concentration by 1 is needed
`to increase binding from 10% to 20%;
`however, an increase by 20 is needed
`to raise it from 70% to 80%).
`The law of mass action de(cid:173)
`scribes the hyperbolic relationship be(cid:173)
`tween binding (B) and ligand concen-
`
`tration (c). This relationship is charac(cid:173)
`terized by the drug's affinity (l/K0 )
`and the maximum binding (Bmax), i.e.,
`the total number of binding sites per
`unit of weight of membrane homoge(cid:173)
`nate.
`
`B = Brnax ·
`
`c
`c+K0
`is the equilibrium dissocia(cid:173)
`K 0
`tion constant and corresponds to that
`ligand concentration at which 50% of
`binding sites are occupied. The values
`given in (A) and used for plotting the
`concentration-binding graph (B) re(cid:173)
`sult when K 0 = 10.
`The differing affinity of different
`ligands for a binding site can be dem(cid:173)
`onstrated elegantly by binding assays.
`Although simple to perform, these
`binding assays pose the difficulty o f
`correlating unequivocally the binding
`sites concerned with the pharmacolo(cid:173)
`gical effect; this is particularly diffi(cid:173)
`cult when more than one population
`of binding sites is present. Therefore,
`receptor binding must not be implied
`until it can be shown that
`1. binding is saturable ( saturability);
`2. the only substances bound are
`those possessing the same pharma(cid:173)
`cological mechanism of action
`(specificity);
`3. binding affinity of different sub(cid:173)
`stances is correlated with their
`pharmacological potency.
`
`Binding assays provide information
`about the affinity of ligands, but they
`do not give any clue as to whether ali(cid:173)
`gand
`is an agonist or antagonist
`(p. 60).
`to
`Radiolabeled drugs bound
`their receptors may be of help in puri(cid:173)
`fying and analyzing further the recep(cid:173)
`tor protein.
`
`

`

`