THIEME FLEXIBOOK
`
`Color Atlas of
`
`Pharmacology
`
`INTELGENX 1023
`
`

`
`Pocket Atlas of Pharmacology
`
`f
`
`'
`
`INTELGENX 1023
`
`

`
`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
`
`INTELGENX 1023
`
`

`
`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 continually expanding our knowledge, in particular our knowledge of pro per
`treatment and drug therapy. Insofa r as this book mentions any dosage or application, readers may rest
`assured that the authors, editors and publishers have made every effort 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 express 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 noticed.
`
`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
`
`INTELGENX 1023
`
`

`
`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.
`
`INTELGENX 1023
`
`

`
`Pharmacokinetics
`
`45
`
`Concentration (c) of drug in plasma (amount/val)
`
`Plasma half life t 112
`ct1/2 = j_c 2
`0
`ln2
`k
`
`ct: Drug concentration at time t
`co: ~~i1n~~~~~~~~~~~:gft~~se
`e : Base of natural logarithm
`
`k: Elimination constant
`
`Uni oftime
`
`~~==~~==~~==~~~~~==~~~
`= u ~t)
`
`=
`
`~Q~Q.
`
`= =
`= =1==
`= I =
`Amount excreted per unit of time (amountlt)
`
`~ c;;;:,
`
`=
`
`Total
`amount
`of drug
`excreted
`
`ount administere'd) = dose
`
`A. Exponential elimination of drug
`
`Time
`
`INTELGENX 1023
`
`

`
`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 leaving 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-curves of differ(cid:173)
`ent manufacturers' products with ref(cid:173)
`erence to a standard preparation indi(cid:173)
`cate bioequivalence.
`
`INTELGENX 1023
`
`

`
`Pharmacokinetics
`
`4 7
`
`Absorption
`Uptake from
`stomach and
`intestines into blood
`
`Distribution
`into body
`tissues:
`a-phase
`
`Elimination
`from body by
`biotransformation
`(chemical alteration),
`excretion via kidney:
`13-phase
`
`It
`
`Bateman function
`c = _o_ x
`k,
`Vapp
`k 2 - k,
`
`x (e - k.t- e - k,t)
`
`A. Time course of drug concentration
`
`- Time (t)
`
`B . Mode of application and time course of drug concentration
`
`Time
`
`INTELGENX 1023
`
`

`
`48
`
`Pharmacokinetics
`
`Time Course of Drug Plasma Lev(cid:173)
`els during Repeated Dosing (A)
`
`When a drug is administered at regu(cid:173)
`lar intervals over a prolonged period,
`the rise and fall of drug concentration
`in blood will be determined by there(cid:173)
`lationship between the half-life of
`elimination and the time interval be(cid:173)
`tween doses. If the drug amount ad(cid:173)
`ministered in each dose has been
`eliminated before the next dose is ap(cid:173)
`plied, repeated intake at constant in(cid:173)
`tervals will result in similar plasma
`levels. If intake occurs before the pre(cid:173)
`ceding dose has been eliminated com(cid:173)
`pletely, the next dose will add on to
`the residual amount still present in the
`body-i.e., the drug accumulates.
`The shorter the dosing interval rela(cid:173)
`tive to the elimination half-life, the
`larger will be the residual mount of
`drug to which the next dose is added
`and the more extensively the drug will
`accumulate in the body. However, at a
`given dosing frequency, the drug does
`not accumulate infinitely and a steady
`state (C 5 5 ) or accumulation equilib(cid:173)
`rium is eventually reached. This is so
`because the activity of elimination
`processes
`is
`concentration-depen(cid:173)
`dent; the higher the drug concentra(cid:173)
`tion rises, the greater is the amount
`eliminated per unit of time. After sev(cid:173)
`eral doses, the concentration will have
`climbed to a
`level at which the
`amounts eliminated and taken in per
`unit of time become equal, i.e., a
`steady state is reached. Within this
`concentration range, the plasma level
`wiJl continue to rise (peak) and fall
`(trough) as dosing is continued at a
`regular intervaL The height of the
`steady state (C 55 ) depends upon the
`amount (D) administered per dosing
`interval ('t) and the clearance (Cltot):
`
`D
`
`('t · Cltot)
`
`The speed at which the steady state is
`reached corresponds to the speed of
`elimination of the drug. The time
`needed to reach 90% of the concentra(cid:173)
`tion plateau is about three times the
`t lh of elimination.
`
`Time Course of Drug Plasma Lev(cid:173)
`els during Irregular Intake (B)
`
`it proves difficult to
`In practice,
`achieve a plasma level that undulates
`evenly around the desired effective
`concentration. For instance, if two
`successive doses are omitted,
`the
`plasma level will drop below the ther(cid:173)
`apeutic range and a longer period will
`be required to regain the desired plas(cid:173)
`ma leveL In everyday life, patients
`will be apt to neglect drug intake at the
`scheduled time. Patient compliance
`means strict adherence to the pre(cid:173)
`scribed regimen. Apart from poor
`compliance, the same problem may
`occur when the daily dose is divided
`into three individual doses and the
`first dose is taken at breakfast, the sec(cid:173)
`ond at lunch, and the third at supper.
`Under this condition, the nocturnal
`dosing interval will be twice the diur(cid:173)
`nal one. Consequently, plasma levels
`during the early morning hours may
`have fallen far below the desired or,
`possibly, urgently needed range.
`
`INTELGENX 1023
`
`

`
`Pharmacokinetics
`
`49
`
`Dosing interval
`
`..
`
`..
`
`t
`
`t
`
`t
`
`•
`
`Time
`
`Accumulation:
`administered drug is
`not completely eliminated
`during interval
`
`Steady state:
`drug intake equals
`elimination during
`dosing interval
`
`c
`0
`
`Q)
`
`~ c
`(.) c
`0
`(.)
`Ol
`::I
`
`0
`
`c
`0
`
`~ c Q)
`
`(.) c
`0
`(.)
`Ol
`2
`0
`
`' ------------
`
`t
`
`t
`t
`t
`t
`t
`t
`A. Time course of drug concentration in blood during regular intake
`
`...
`
`I
`
`Time
`
`c
`0
`~
`~ c
`
`0
`(.)
`Ol
`::I
`Ci
`
`t
`t
`t
`t
`t
`t
`t
`B. Time course of drug concentration with irregular intake
`
`t
`
`t
`
`?
`
`?
`
`?
`
`t
`
`Time
`
`INTELGENX 1023
`
`

`
`thumb, a plateau is reached after ap(cid:173)
`proximately three elimination half(cid:173)
`lives (t liz).
`For slowly eliminated drugs,
`which tend to accumulate extensively
`(phenprocoumon, digitoxin, metha(cid:173)
`done [p. 204 ]), the optimal plasma
`level is attained only after a long peri(cid:173)
`od. Here, increasing the initial doses
`(loading dose) will speed up the at(cid:173)
`tainment of equilibrium, which is sub(cid:173)
`sequently maintained with a lower
`dose (maintenan ce dose) .
`
`Change in Elimination Character(cid:173)
`istics during Drug Therapy (B)
`
`With any drug taken regularly and ac(cid:173)
`cumulating to the desired plasma lev(cid:173)
`el, it is important to consider that con(cid:173)
`ditions for biotransformation and ex(cid:173)
`cretion do not necessarily remain
`constant. Elimination may be has(cid:173)
`tened due to enzyme induction (p. 32)
`or to a change in urinary pH (p. 40).
`Consequently, the steady-state plasma
`level declines to a new value corre(cid:173)
`sponding to the new rate of elimina(cid:173)
`tion. The drug effect rnay diminish or
`disappear. Conversely, when elimina(cid:173)
`tion is impaired (e.g., in renal failure),
`the mean plasma level of renally elim(cid:173)
`inated drugs rises and may enter a tox(cid:173)
`ic concentration range.
`
`50
`
`Pharmacokinetics
`
`Accumulation: Dose, Dose Inter(cid:173)
`val, and Plasma Level }...,luctuation
`
`Successful drug therapy in many ill(cid:173)
`nesses is accomplished only if drug
`concentration
`is maintained at a
`steady high level. This requirement
`necessitates regular drug intake and a
`dosage schedule that ensures that the
`plasma concentration neither falls be(cid:173)
`low
`the
`therapeutically effective
`range nor exceeds the minitnal toxic
`concentration. A constant plasma lev(cid:173)
`el would, however, be undesirable if it
`accelerated a
`loss of effectiveness
`(development of tolerance), or if the
`drug were required to be present at
`specified times only.
`A steady plasma level can be
`achieved by giving the drug in a con(cid:173)
`stant intravenous infusion, the steady(cid:173)
`state plasma level being determined
`by the infusion rate: dose D per unit of
`timet:
`
`D
`
`t • Cltot
`
`This procedure is routinely used
`in hospital settings, but is generally
`impracticable. With oral administra(cid:173)
`tion, dividing the total daily dose into
`several individual ones, e.g., four,
`three, or two, offers a practical com(cid:173)
`promise. When the daily dose is given
`in several divided doses, the mean
`plasma level shows little fluctuation.
`In practice, it is found that a regimen
`of frequent regular drug ingestion is
`not well adhered to by patients. The
`degree of fluctuation in plasma level
`over a given dosing interval can be re(cid:173)
`duced by a use of dosage form per(cid:173)
`mitting
`slow
`(sustained)
`release
`(p. 1 0).
`reach
`to
`required
`time
`The
`during
`steady-state
`accumulation
`multiple constant dosing depends on
`the rate of elimination. As a rule of
`
`INTELGENX 1023
`
`

`
`Pharmacokinetics
`
`51
`
`4 x daily 50mg
`2 x daily 100 mg
`- - 1 x daily 200 mg
`50 mg
`-Single
`
`24
`t
`.,..
`•
`
`6
`t
`
`18
`t
`
`12
`.,..
`t
`
`6
`t
`
`12
`t
`1"'
`
`24
`t
`1"
`
`•
`
`"0
`0
`0
`.0
`c
`c
`0
`
`~ -c
`
`Q)
`(.)
`c
`0
`(.)
`Ol
`
`~ 0
`
`6
`t
`
`18
`t
`
`12
`t
`1"-
`
`24
`t
`..,..
`
`...
`
`t .,.. •
`
`6
`t
`
`12
`t
`..,..
`
`18
`t
`
`A . Accumulation: dose, dose interval, and fluctation of plasma level
`
`Inhibition of elimination
`
`Acceleration
`of elimination
`
`"0
`0
`0
`::0
`c
`c
`0
`
`~ c Q)
`
`(.)
`c
`0
`(.)
`Ol
`
`~ 0
`
`t
`
`6
`t
`
`12 18 24
`t
`t
`t
`
`.,.
`6
`
`12
`t
`
`18 24
`.,.
`t
`
`6
`t
`
`12 18
`t
`t
`
`24
`t
`
`6
`t
`
`12
`t
`
`18
`.._
`
`I
`
`B. Changes in elimination kinetics in the course of drug therapy
`
`INTELGENX 1023
`
`

`
`(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
`
`INTELGENX 1023
`
`

`
`Quantification of Drug Action
`
`53
`
`A. Abnormal posture in mouse given morphine
`
`Dose= 0
`
`= 2 mg/kg
`
`= 10 mg/kg
`~ ~~ - ~
`~ ~
`~ - ~
`
`= 20 mg/kg
`
`= 100 mg/kg
`
`= 140 mg/kg
`
`B. Incidence of effect as a function of dose
`
`%
`100
`
`80
`
`-
`60
`
`40
`
`-
`20
`
`C u mula t ive incidence
`I
`-
`-
`
`1
`
`-
`
`I
`
`-
`
`-_ .. IJI'
`
`~
`
`I
`
`-~ ) t- 1- H- - -
`
`~
`
`?'_ ,-
`t-
`
`I
`I
`,-~ l
`
`-Q
`1- -r-- -
`-
`r---
`
`I
`
`•
`
`,__
`
`t=-
`
`mg/kg
`
`2
`
`10
`
`20
`
`100 140
`
`210 20
`
`100
`
`140mg/kg
`
`C. Dose- frequency relationship
`
`INTELGENX 1023
`
`

`
`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 effects 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.
`
`INTELGENX 1023
`
`

`
`Quantification of Drug Action
`
`55
`
`Portal vein
`Mesenteric artery
`
`Coronary
`artery
`
`Basilar
`artery
`
`Saphenous
`vein
`
`0
`
`Vasoconstriction
`Activ~t9_!1§iO.!L.
`
`1 min
`
`(
`
`~ _~ J (
`-1
`-2 -5
`-10
`
`20
`Drug concentration
`
`30
`
`40
`
`50
`
`100
`
`A . Measurement of effect as a function of concentration
`
`Effect
`(% of maximum effect)
`e.g., t ens1on d eveloped
`
`%
`
`100
`
`80
`
`60
`
`40
`
`20
`
`100
`
`80
`
`60
`
`4 0
`
`20
`
`Effect
`(% of maximum effect)
`
`10
`Concentration
`B. Concentration-effect relationship
`
`20
`
`30
`
`40
`
`1
`Concentration
`
`10
`
`100
`
`INTELGENX 1023
`
`

`
`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.
`
`INTELGENX 1023
`
`

`
`Quanti fica t• :>n of Drug Action
`--------------------------------------------
`
`57
`
`(
`
`~9 I Organs
`r
`
`Homogenization
`
`Membrane
`suspension
`
`t
`
`Addition of
`radio labeled
`drug in
`different
`concentrations
`
`...
`
`Mixing and incubation
`
`c = 1
`B- 10%
`
`c = 2
`B- 20%
`
`c=5
`B- 30%
`
`c = 10
`B =50%
`
`c = 20
`B-70%
`
`c = 40
`B = 80%
`
`A . M easurement of binding (B) as a function of concentration (c)
`
`% Binding _{ill_
`
`100
`
`80
`
`60 -
`
`40 -
`
`:..;
`
`~
`20 - :..0
`
`7)
`
`·0
`
`·-
`
`-
`
`%
`100
`
`80
`
`60
`
`40 -
`
`20 -
`
`20
`10
`Concentration (c)
`!B. Concentration- binding relationship
`
`40
`
`50
`
`30
`
`Binding (8)
`
`:>
`
`~
`
`' J
`
`J
`
`---
`
`1
`Concentration (c)
`
`100
`
`INTELGENX 1023