Principles of Medical Pharmacology
`
`Edited by
`
`Derek Waller
`Senior Lecturer in Clinical Pharmacology
`Clinical Pharmacology, Faculty of Medicine
`University of Southampton, UK
`
`University of Southampton, UK
`
`and
`
`Andrew Renwick
`Reader in Clinical Pharmacology
`Clinical Pharmacology, Faculty of Medicine
`
`
`
`Mylan V. Janssen (IPR2020-00440) EX. 1022 p. 001
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`Mylan v. Janssen (IPR2020-00440) Ex. 1022 p. 001
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`

`

`
`
`Baz'llz'e‘rc Tz'ndall
`W. B. Saunders Company Ltd
`
`24—28 Oval Road
`London NW1 7DX
`
`The Curtis Center
`Independence Square West
`Philadelphia, PA 19106—3399, USA
`
`Harcourt Brace & Company
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`
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`Marrickville, NSW 2204, Australia
`
`Harcourt Brace & Company, Japan
`Ichibancho Central Building, 22—1 Ichibancho
`Chiyoda-ku, Tokyo 102, Japan
`
`(C) 1994 Bailliere Tindall
`
`This book is printed on acid—free paper
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by
`any means, electronic, mechanical, photocopying or otherwise, Without the prior permission of W. B. Saunders Company Ltd,
`24—28 Oval Road, London NW1 7DX, England
`
`
`
`
`
`A catalogue record for this book is available from the British Library
`ISBN 0—7020—1613—6
`
`'
`Typeset by Alden Multimedia, Northampton, England
`Printed in Great Britain by Butler and Tanner, Frome, Somerset
`
`‘
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`.
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`v
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`

`

`Contents
`
`Contributors
`Introduction
`
`General Principles
`1. Sites and mechanisms of drug action
`2. Pharmacokinetics
`3. Drug discovery, evaluation and safety
`4. The autonomic nervous system
`
`Cardiovascular System
`5.
`Introduction to the cardiovascular system
`Ischaemic heart disease
`6.
`7. Hypertension
`8. Positive inotropic agents and heart failure
`9. Cardiac arrhythmias
`10. Haemostasis
`
`Respiratory System
`11. Asthma
`12. Respiratory stimulants
`13. Cough
`
`Kidney and Urinary Tract
`14. Functions of the kidney
`15. Diuretics
`16. Bladder dysfunction
`
`The Nervous System
`17.
`Introduction to the nervous system
`18. General anaesthetics
`19. Local anaesthetics
`20. Narcotic or opiate analgesics
`21. Anxiolytics, sedatives and hypnotics
`22. Psychotic disorders
`23. Depression
`24. Epilepsy
`25. Extrapyramidal movement disorders and spasticity
`26. Migraine
`mismat,aria1wasrnpieo
`at th,a ti LM and may tMa
`iu b,j,e<:t US Cop, right Laws
`
`lX
`xi
`
`3
`11
`41
`47
`
`59
`63
`71
`79
`85
`93
`
`103
`109
`111
`
`115
`119
`125
`
`129
`135
`141
`145
`153
`157
`161
`167
`173
`179
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`(2) Firsr-pass merabolism -
`in the gut lumen,
`during passage across the gut wall, or by
`the liver.
`
`The bioavailability of a drug is determined by
`comparison of data obtained after oral adminis(cid:173)
`t~ation (when the fraction F enters the general
`~Irculation as
`the parent drug) with
`those
`following
`intravenous administration
`(when
`100% enters
`the general circulation as
`the
`parent drug). The amount in the circulation
`c_annot be compared at only one time point
`since intravenous and oral dosing will show
`different concentration-time profiles. This is
`avoided by using the total area under the curve
`(ADC) from r = O to r = infinity:
`
`F = ADCoral
`ADCiv
`
`if the oral and intravenous doses are equal,
`
`or
`
`F = ADC 0 ra1 X doseiv
`ADCiv
`doseara1
`
`for different doses.
`This calculation assumes that the metabolism
`is first order. The concept of ADC is discussed
`later under clearance.
`An alternative method is to measure the total
`urinary excretion of the parent drug
`(Aex)
`following oral and intravenous doses. Even
`though the urine may be a minor route of elimi(cid:173)
`nation the ratio of excretion unchanged after
`oral to excretion unchanged after intravenous
`dosing will give the bioavailability:
`
`F=
`
`Aexoral
`Aexiv
`
`for two equal doses,
`
`or
`
`F=
`
`'1/o Dose in urine as parent
`drug after oral dosing
`'1/o Dose in urine as parent
`drug after iv dosing
`
`THE MATHEMATICAL BASIS OF PHARMACOKINETICS
`
`29
`
`Rate of Distribution
`The rate of distribution usually can only be
`measured following an intravenous bolus dose.
`Some drugs reach equilibrium between blood/
`plasma and tissues very rapidly and a distinct
`distribution phase is not seen; only the terminal
`elimination phase is seen (Fig. 2.13a). Most
`drugs take some time to distribute into and equi(cid:173)
`librate with the tissues. This is shown as a rapid
`decrease, prior
`to
`the
`terminal elimination
`phase (which is given the symbol /J) (slope B-C
`in Fig. 2.13b). In Fig. 2.13b the processes of
`distribution are complete by point B. The distri(cid:173)
`bution rate constant cannot be derived from the
`slope A-B because elimination starts as soon as
`the drug enters the body. If distribution had
`been instantaneous then the initial concentra(cid:173)
`tion would be given by the point D and the
`distribution rate would be infinity. In practice
`the distribution rate (ex)
`is calculated for the
`difference between the line D-B for each time
`point and the actual concentration measured
`(given by the line A-B in Fig. 2.13b). Clearly
`situations a and b in Fig. 2.13 have to be
`described by different models. Figure 2.13a is
`described as a one-compartment model and all
`tissues are
`in equilibrium
`instantaneously.
`Figure 2.13b is described as a two-compart(cid:173)
`ment model in which the drug initially enters
`and reaches instantaneous equilibrium with one
`compartment (blood and possibly well-perfused
`tissues) prior to entering more slowly and equili(cid:173)
`brating with a second compartment (possibly
`poorly perfused tissues -
`refer back to Fig.
`2.5). This is shown schematically in Fig. 2.14.
`The rate of distribution is dependent on two
`main variables:
`
`(1) For water-soluble drugs, the rate of distribu(cid:173)
`tion depends on the rate of passage across
`membranes, that is the permeability charac(cid:173)
`teristics of the drug.
`(2) For lipid-soluble drugs, the rate of distribution
`depends on the rate of delivery to those
`tissues, such as adipose, which accumulate
`the drug.
`
`DISTRIBUTION
`
`This applies to the reversible movement of drug
`from the blood into the tissues such as occurs
`immediately following an
`intravenous bolus
`dose (single rapid injection) and its re-entry
`into blood as the parent drug during elimina(cid:173)
`tion.
`
`For some drugs the natural logarithm of the
`plasma concentration-time curve shows
`three
`distinct phases and such curves require three expo(cid:173)
`nential rates and represent a three-compartment
`model. Although
`two- or three-compartment
`models may be necessary to give a mathematical
`description of the data they are oflimited practical
`value since we rarely know which tissues belong to
`Th is materia I was rnpie<l
`atth,e NLM am:l mayb€
`~ubJect US Copyright La\'VS
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`34
`
`PHARMACOKINETICS
`
`CHAPTER 2
`
`Table 2.9 Pharmacokinetic parameters of selected drugs
`- -~ - - - - - - - - - - - - - - - - -~ - - - -
`Half-life
`Apparent volume of
`(h)
`distribution (litres/70 kg)
`
`Clearance
`(ml min- 1)
`
`Warfarin
`Digitoxin
`Diazepam
`Valproic acid
`Digoxin
`Ampicillin
`Lignocaine
`Propranolol
`lmipramine
`
`3
`4
`27
`76
`130
`270
`640
`840
`1050
`
`8
`38
`77
`27
`640
`20
`77
`270
`1600
`
`37
`161
`43
`5.6
`39
`1.3
`1.8
`3.9
`18
`
`Note:
`The drugs are arranged in order of increasing plasma clearance. A long half-life may
`result from a low clearance (e.g. digitoxin), a high apparent volume of distribution
`(e.g. imipramine) or both.
`
`which is not dependent on accurate determina(cid:173)
`tion of the intercept at t = O (point D on Fig.
`2.13b). The method uses the area under the
`plasma concentration-time curve (AUC) as
`follows:
`CL = Rate of elimination from the body
`Plasma concentration
`(see above).
`
`The rate of elimination from the body is
`equivalent to the rate of change of the amount
`in the body (Ab) with time, that is:
`
`CL = ~//c where C is plasma concentration
`
`rearranging
`
`CL x C = dAb
`dt
`CL x C dt = dAb
`and
`If the equation is integrated between t = 0 and
`t = infinity then the change in body load to infi(cid:173)
`nity (dAb) will equal the total dose given:
`
`CL x J: C dt = Dose.
`
`The integral between t = 0 and t = infinity of
`C dt is the area under the concentration-time
`curve to infinity:
`CL x AUC = Dose
`
`or
`
`CL
`
`Dose
`AUC
`
`This is an important and useful equation and
`allows an easy estimate of the ability of the body
`to remove the drug from the circulation. Factors
`to be considered in the use of this equation are:
`
`(1) The dose used has to be the dose in the
`circulation and available to the organs of
`elimination. For the intravenous route then
`the dose is that administered; however, for
`the oral route only a fraction (F; see earlier)
`may reach the general circulation and there(cid:173)
`fore the dose used in the calculation should
`be the administered dose x F. That is:
`Doseoral x F
`AUCoral
`
`CL= Doseiv
`AUCiv
`
`rearranging
`
`(see earlier).
`
`Doseiv
`AU Coral
`F = - - -x - - -
`AUCiv Doseoral
`(2) The AUC should be the area under the
`concentration-time curve not the ln concen(cid:173)
`tration-time curve, and should be extrapo(cid:173)
`lated to infinity.
`(3) The equation can be used to calculate the
`apparent volume of distribution and
`is
`more reliable than the extrapolation method
`given above (Fig. 2.13b):
`
`CL - Dose -
`- AUC -
`
`llV
`
`V
`
`Dose
`Dose
`AUC x /1
`AUC x h
`(for a two-compartment system).
`
`or
`
`This material w3sco,pied
`atth,e NLM and may t,-e
`'.?uhJe,rt US Copyright Law:S
`
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`THE MATHEMATICAL BASIS OF PHARMACOKINETICS
`
`37
`
`regimen which would eventually have resulted in
`the same steady-state concentration.
`The amount of drug equivalent to the steady(cid:173)
`state body load is the required or target steady(cid:173)
`state plasma concentration (C,,) multiplied by
`the apparent volume of distribution (V). That is:
`Loading dose = Cs, V
`In cases where C's, or V are not known, then
`the loading dose can be calculated based on the
`proposed maintenance regimen. This is done by
`
`replacing C 8, in the above equation by
`DxF
`Tx CL
`(where Dose and T refer to the maintenance
`regimen) and by replacing Vin the above equa-
`
`(see above)
`
`tion by CL (see earlier). Then:
`!?
`
`D xF CL
`Loading dose = - - - x ~
`T x CL
`h
`DxF
`TX!?
`D X F X 1.44 X t1;2
`T
`It is clear from this last equation that the
`magnitude of any loading dose compared with
`the maintenance dose is proportional to the
`half-life. Good examples of this are the cardiac
`glycosides digoxin and digitoxin, which are
`compared in Table 2.10.
`The values given in Table 2.10 are to illustrate
`the concept of a loading dose: the doses used
`clinically should take into account body weight,
`age and the presence of severe renal or liver
`impairment. The loading dose may need to be
`
`.
`.
`given in two or three fractions ov
`er a penod of
`about 24-36 h. The reason for
`.
`th·
`that
`.
`d"
`"b
`·
`IS
`IS
`d
`urmg 1stn ut1on of the loading d
`h
`h" h
`ose t ere arc
`1g er (non-steady-state) concentr t·
`.
`a ions m the
`.
`bl
`ood and rapidly equilibrating
`t·
`1
`issues and
`ower (non-steady-state) concentrat·
`.
`. .
`.
`.
`c tons m the
`1 1
`s ow y eqmltbratmg tissues (see Fi·
`'fl
`? _)
`1e
`g. -.') .
`·
`.
`excessive concentrations in rapid!
`.
`.1.b
`Y eqm 1 ratmg
`.
`.
`.
`tissues may give nse to toxicity
`'fl .
`·
`. .
`.
`. .
`11s can be
`mm1m1zed by g1vmg the loading d
`, .
`f
`.
`h" h
`ose m
`rac-
`.
`t·
`tlons w 1c would allow distribution 1.
`b t·
`.
`o one rac-
`tlon e ore the next was given
`'fl
`f
`.
`.
`·
`1e
`ract1onal
`loadmg doses should be given within the period
`of the normal dose interval.
`
`<
`
`FACTORS AFFECTING PHARMACOKINETICS
`
`The follow_ing account considers a number of
`factors which could influence drug h
`di"
`.
`.
`.
`an mg,
`based on the likely _effect 011 the physiological
`processes of absorpt1011, distribution and elimi(cid:173)
`nation. The impact of these effects on the h _
`fi
`.
`.
`k.
`p ar
`maco metlc pro 1le 1s then considered based
`largely on the possibl~ c~anges in bioavailability,
`apparent volume of d1stnbution and clearance.
`
`Drug interactions
`
`_
`Drugs can have a number of effects on phar
`.
`.
`ma
`I
`co ,metlc processes (see Fig. 2.19):
`
`( 1) Gastrointestinal transit - drugs such as meto(cid:173)
`clopramide, which increase gastrointestinal
`motility, can reduce the lag time prior to
`absorption following an oral dose. If the
`drug is poorly absorbed the total time avail(cid:173)
`able for absorption may decrease so that
`bioavailability could decrease. Drugs such as
`
`Table 2.10 Pharmacokinetics and dosage for digoxin and digitoxin
`
`Elimination half-life (days)
`Time to steady state (days; 4 x t1;2)
`"Therapeutic" plasma concentrations (ng m1- 1 or 11g 1- 1
`Volume of distribution (litres per 70 kg)
`Typical loading dose (Css x V)
`Bioavailability (F)
`
`)
`
`Normal oral maintenance dose
`
`(
`
`Dose x F
`T
`; mg day
`
`-1)
`
`Digoxin
`
`1.6
`6
`0.5-2.0
`600
`up to 1.2 mg
`0.75
`
`Digitoxin
`
`7
`28
`10-35
`40
`up to 1.4 mg
`>0.9
`
`0.125-0.5
`
`0.05-0 2
`
`Typical loading dose (maintenance dose x 1.44 x t1;2)
`
`0.3-1.2 mg
`
`0.5-2.0 mg
`
`This material was copied
`atth•e NLM and maybe
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`inducers and
`
`inhibitors of cyto(cid:173)
`
`Table 2.11 Common
`chrome P450
`
`Inducers
`
`Barbiturates
`(esp. phenobarbitone)
`Phenytoin
`Carbamazepine
`Griseofulvin
`Rifampicin
`Glutethimide
`
`Inhibitors
`
`Cimetidine
`Allopurinol
`lsoniazid
`Chloramphenicol
`Disulfiram
`Quinine
`Erythromycin
`
`THE MATHEMATICAL BASIS OF PHARMACOKINETICS
`
`39
`
`renal clearance of basic drugs
`by
`reducing
`the urine pH
`NH4Cl).
`
`is increased
`(e.g. with
`
`Age
`
`Age affects the body composition with respect to
`fat, muscle and water content and could alter the
`distribution characteristics of a drug. However
`of far greater importance is the fact that th~
`extremes of age -
`neonates and the elderly _
`show a reduced renal function and a decreased
`drug metabolizing ability due to lower enzyme
`activity (neonates) or reduced liver size and
`perfusion (elderly). Thus the extremes of age
`tend to show a decrease in plasma clearance
`whether the drug is handled primarily by th~
`liver or the kidneys. The decrease in clearance
`means that lower and less frequent doses may
`need to be given to these age groups.
`
`would result in an increase in terminal half(cid:173)
`life. However, the increase in free drug may
`facilitate an increase in extraction by the
`organs of elimination, that is, an increase
`in clearance would result in a decrease in
`terminal half-life. Overall the effect of such
`interactions on pharmacokinetics
`is of
`limited
`importance compared with
`the
`increase in free drug and increase in phar(cid:173)
`macological effect. The clinically impor(cid:173)
`tant interactions are those in which the
`initial drug is highly protein bound and
`shows a narrow therapeutic range, (e.g.
`tolbutamide and warfarin) while the displa(cid:173)
`cing drug is given in large doses (e.g. salicy(cid:173)
`late and sulphonamides) and can displace
`significant amounts of the initial drug. If
`the protein binding of a drug is decreased
`from 99 to 98'1/., this minor change results
`in a doubling of the free drug concentra(cid:173)
`tion from I to 2%. Since it is the free drug
`that interacts with receptors
`this could
`result in a greatly increased therapeutic
`and/or toxic effect (see Chapter 56).
`(7) Renal secretion -
`the renal tubular secretion
`of acidic drugs
`can be blocked by
`compounds such as probenecid and aspirin.
`This results in a decrease in renal clear(cid:173)
`ance. If this is the major route of elimina(cid:173)
`tion there will also be a decrease in plasma
`clearance and hence the half-life will be
`There are wide interindividual differences in
`increased.
`drug-metabolizing ability
`in normal healthy
`the renal clearance of weakly
`(8) Renal pH -
`subjects. These arise from genetically deter(cid:173)
`acidic and basic drugs is dependent on the
`mined differences in the basal level of expres(cid:173)
`pH of the urine. Urine pH affects the ioniza(cid:173)
`sion of the enzyme and can give rise to about
`tion of the drug in the renal tubule and
`two- to three-fold differences in bioavailability,
`hence its tendency to be reabsorbed. The
`systemic clearance and half-life.
`renal clearance of acidic drugs can be
`In most cases there is a normal (Gaussian)
`increased by increasing urine pH (e.g. with
`distribution of enzyme activity in the population.
`NaHC0 3) to increase ionization while the
`However, for some enzymes
`there
`is poly-
`This material wa:scopied
`at the NLM and may be
`'.?ubje,ct US Copyright La;.vs
`
`Disease
`
`Diseases can affect absorption, distribution and
`elimination. Conditions, such as achlorhydria
`and coeliac disease can influence both the rate
`and extent of absorption of an oral dose.
`Distribution can be affected by the changes in
`plasma proteins which can accompany disease
`states, for example there
`is an increase in
`plasma ix 1-acid glycoprotein in arthritis while
`cirrhosis is associated with a decrease in plasma
`albumin concentration. These changes could
`affect the apparent volume of distribution of
`drugs and hence their half-lives. Hepatic and
`renal diseases can decrease the ability of the
`organ of elimination to remove the drug from
`the blood, and hence there is a decrease in
`plasma clearance. This results in an increase in
`terminal half-life and an increase in steady-state
`plasma concentration.
`
`Pharmacogenetics
`
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`

`

`PHARMACOKINETICS
`40
`~ - - - - - - - - - - ------- - - - - - -
`
`CHAPTER 2
`
`Table 2.12 Pharmacogenetic differences in drug-metabolizing enzymes
`- - - - - - - - - - - - - - - - - - - - - - ---~------ - - -
`Incidence of deficiency·
`Enzyme
`or slow metabolizers
`
`Plasma pseudocholinesteraset
`Alcohol dehydrogenase
`Cytochrome P4502C18
`Cytochrome P450206
`
`1 in 3000
`5-10% (about 90% in Asians)
`5% (about 20% in Asians)
`5-10%
`
`Cytochrome P4502C?
`N-Acetyltransferase
`
`Methyltransferase
`
`Very rare
`Approx 60%
`(about 5% in Japanese)
`0.5%
`
`*For Caucasians.
`t A number of variants are known.
`
`Typical substrates
`
`Suxamethonium (succinylcholine)
`Ethanol
`S-Mephenytoin
`Debrisoquine, $parteine, metoprolol,
`dextromethorphan
`Phenytoin
`lsoniazid, hydralazine, procainamide
`
`6-Mercaptopurine
`
`morphic expression of the enzyme activity and it
`is possible to divide the population into two
`groups -
`"fast metabolizers" and "slow metabo(cid:173)
`lizers". This metabolizing status is genetically
`determined and therefore is an underlying char(cid:173)
`acteristic of the individual. Slow metabolizers
`have high plasma concentrations of the parent
`drug but lower concentrations of the metabo(cid:173)
`lite(s). In some cases the polymorphism arises
`from altered transcription of the normal enzyme
`protein, but frequently the "slow metabolizer"
`DNA codes for a modified enzyme protein with
`an altered binding site and which has a
`
`decreased substrate affinity. Drug-metabolizin~
`enzymes showing polymorphism or enzyme defi,
`ciencies are given in Table 2.12.
`Genetically determined expression of enzym~
`activity can be affected also by ethnic origins.
`Ethnic origins can affect the proportion of th~
`population showing a genetic deficiency or poly,
`morphism (see Table 2.12). In addition, th~
`extent of metabolism in the general populatio11.
`may be different, for example subjects from th~
`Indian subcontinent show a two- to three-fol(l
`slower elimination of cytochrome P4503i\
`substrates than Caucasians.
`
`This material wasco-pia<l
`at the NLM an<! may b,e
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