The ·.
`Pharmacological
`Basis of
`·
`Therapeutics
`
`.
`
`FIFTH EDITION
`
`ADAMIS EXHIBIT 1022
`
`Page A
`
`

`

`The Pharniacological
`
`EDITORS
`
`Louis S. Goodman
`
`M.A., M.D., D.Sc.(Hon.)
`Distinguished Professor of Pharmacology,
`University of Utah College of Medicine, Salt Lake City, Utah
`
`Alfred Gilman
`
`Ph.D.
`Lecturer in Pharmacology,
`Yale University School of Medicine, New Haven, Connecticut;
`Professor of Pharmacology,
`Albert Einstein College of Medicine of Yeshiva University, Bronx, New York
`
`ASSOCIATE EDITORS
`Alf red G. Gilman
`M.D., Ph.D.
`Associate Professor of Pharmacology,
`University of Virginia School of Medicine, Charlottesville, Virginia
`
`George B. Koelle
`Ph.D., M.D., D.Sc.(Hon.), D.Med.(Hon.)
`Elmer Holmes Bobs! Professor and Chairman, Department of Pharmacology,
`University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
`
`Page B
`
`ADAMIS EXHIBIT 1022
`
`

`

`Basis of Therapeutics
`
`FIFTH EDITION
`
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`MACMILLAN PUBLISHING CO., INC.
`New York
`
`COLLIER MACMILLAN CANADA, LTD.
`Toronto
`
`BAILLIERE TINDALL
`London
`
`Page C
`
`ADAMIS EXHIBIT 1022
`
`

`

`COPYRIGHT @ 1975, MACMILLAN PUBLISHING Co., INC.
`
`PRINTED I N THE UNITED STATES OP AMERICA
`
`All rights reserved. No part of this book may be reproduced or
`transmitted in any form or by any means, electronic or mechanical,
`including photocopying, recording, or any information storage and
`retrieval system, without permission in writing from the Publisher.
`
`Earlier editions copyright 1941 and 1955, © copyright 1965, and
`copyright © 1970 by Macmillan Publishing Co., Inc.
`
`MACMILLAN PUBLISHING Co., INC.
`866 Third Avenue· New York, N.Y. 10022
`COLLIER MACMILLAN CANADA, LTD.
`BAILLIERE TINDALL. London
`
`Library of Congress catalog card number 75-15903
`ISBN 0-02-344781-8
`Bailliere Tindall SBN 0 7020 0584 3
`
`Printing: l 2 3 4 5 6 7 8
`
`Year: 5 6 7 8 9 0 I
`
`The use of portions of the texts of the United States Pharmacopeia,
`Nineteenth Revision, official July l, 1975, and of its first supplement
`is by permission received from the Board of Trustees of the United
`States Pharmacopeial Convention, Inc. The said Convention is not
`responsible for any inaccuracy of quotation, or for any false or mis(cid:173)
`leading implication that may arise by reason of the separation of
`excerpts from the original context.
`
`The use of portions of the texts of the National Formulary, Fourteenth
`Edition, official July I, 1975, and of its first supplement is by permis(cid:173)
`sion received from the Board of Trustees of the United States Phar(cid:173)
`macopeial Convention, Inc. Neither the U.S.P. Convention, lnc., nor
`the American Pharmaceutical Association, original publisher of the
`N.F., is responsible for any inaccuracy of quotation, or for any false
`or misleading implication that may arise by reason of the separation
`of excerpts from the original context.
`
`In this textbook, reference to proprietary names of drugs is ordinarily
`made only in chapter sections dealing with preparations. Such names
`are given in SMALL-CAP TYPE, usually immediately fo llowing the offi(cid:173)
`cial or nonproprietary titles. Proprietary names of drugs also appear
`in the Index.
`
`Page D
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`ADAMIS EXHIBIT 1022
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`

`

`CHAPTER
`24 NOREPINEPHRINE, EPINEPHRINE, AND
`THE SYMPATHOMIMETIC AMINES
`
`Jan R. Innes and Mark Nickerson
`
`The sympathomimetic drugs make up one
`of the most extensively studied groups of
`pharmacological agents and, consequently,
`many are known and widely used. In general,
`their effects resemble the responses to stimu(cid:173)
`lation of adrenergic nerves, but there are
`often differences in the details and the inten(cid:173)
`sity of action of the drugs. Several have ad(cid:173)
`ditional properties, such as profound effects
`on the central nervous system (CNS), that
`are of value in specific clinical conditions.
`Sympathomimetic agents are used for a vari(cid:173)
`ety of purposes in therapeutics, and the phy(cid:173)
`sician must therefore understand the general
`pharmacology of the group and the differ(cid:173)
`ences between the effects of individual mem(cid:173)
`bers.
`Most of the actions of sympathomimetic
`agents can be classified into five broad types:
`(1) a peripheral excitatory action on certain
`types of smooth muscle, such as those in
`blood vessels supplying skin and mucous
`membranes, and also on salivary and certain
`sweat glands; (2) a peripheral inhibitory ac(cid:173)
`tion on certain other types of smooth muscle,
`such as those in the wall of the gut, in the
`bronchial tree, and in blood vessels supply(cid:173)
`ing skeletal muscle; (3) a cardiac excitatory
`action, responsible for an increase in heart
`rate and force of contraction; (4) metabolic
`actions, such as an increase in rate of glyco(cid:173)
`genolysis in liver and muscle, and liberation
`of free fatty acids from adipose tissue; and
`(5) CNS excitatory actions, such as respira(cid:173)
`tory stimulation and, with some of the drugs,
`an increase in wakefulness and a reduction
`in appetite. All sympathomimetic drugs do
`not show each of the above types of action
`to the same degree. Thus, doses of epineph(cid:173)
`rine and norepinephrine that cause an
`equal rise in arterial blood pressure have
`quite different effects on bronchial muscula(cid:173)
`ture, heart rate, and glycogen stores. How(cid:173)
`ever, many differences in the effects of the
`
`sympathomimetic amines are only quanti(cid:173)
`tative, and a description of the effects of each
`individual compound would be unnece.ssarily
`repetitive. Therefore, the pharmacological
`properties of these drugs as a class are de(cid:173)
`scribed in detai.I for the prototype agent,
`epinephrine. Indeed, most of the fundamental
`studies on the many properties of this class
`of drugs have been made with epinephrine
`as the model agent. Differences in the effects
`of the various congeners are particularly
`pronounced in the cardiovascular responses
`they evoke. These variations are largely due
`to differences in the intensity and the dura(cid:173)
`tion of their effects at the many possible sites
`where their sympathomimetic actions can
`OCCl,lT, and also to differences in the reflex
`responses of homeostatic mechanisms. Such
`factors are discussed below.
`
`History. The pressor effect of suprarenal extracts
`was first shown by Oliver and Schafer in 1895. The
`active principle was named epinephrine by Abel in
`1899 and synthesized independently by Stolz and
`Dakin. The history of its isolation and identification
`has been reviewed by Hartung ( 1931 ). The develop(cid:173)
`ment of our knowledge of epinephrine and nor(cid:173)
`epinephrine as neurohumoral transmitters is out(cid:173)
`lined in Chapter 21. Barger and Dale ( 1910) studied
`the pharmacological activity of a large series of
`synthetic amines related to epinephrine and termed
`their action sympathomimetic. This important study
`determined the basic structural requirements fOI
`activity and indicated that the sympathomimetic
`amines had qualitatively similar effects but that there
`were considerable quantitative differences. When it
`was found that cocaine or chronic denervation of
`effector organs reduced their responses to ephedrine
`and tyramine but enhanced the effects of epineph(cid:173)
`rine (Tainter and Chang, 1927; Bum and Tainter,
`1931), it became clear that the differences between
`sympathomimetic amines were not simply q uanti(cid:173)
`tative. It was then suggested that epinephrine acted
`directly on the effector cell while ephedrine and
`tyramine had an indirect effect by acting on the
`nerve endings. The discovery that reserpine depletes
`tissues of norepinephrine, first made by Bertler
`and coworkers ( 1956), was followed by evidence
`that tyramine does not act on reserpinized tissues
`477
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`Page 477
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`ADAMIS EXHIBIT 1022
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`

`EPINEPHRINE
`
`483
`
`Table 24-2. CHEMICAL STRUCTURES OF IMIDAZOLINE DERIVATIVES
`H
`I
`
`R-<:J
`
`R=
`
`Nophozoline
`
`Tetrohydrozoline
`
`Xylometozoline
`
`have rather more marked a than f3 activity, fitting
`them for use as nasal decongestants by virtue of their
`vasoconstrictor properties.
`Optical Isomerism. Substitution on either a or f3
`carbon yields optical isomers. Levorotatory substi(cid:173)
`tution on the /3 carbon confers the greater peripheral
`activity, so that the naturally occurring !-epinephrine
`and /-~orepinephrine. are ten or more times as potent
`as ~eir unnatural d isomers. Dextrorotatory substi(cid:173)
`tution on the a carbon generally provides a more
`potent compound than the l isomer in peripheral and
`central stimulant activity. d-Ampbetamine is more
`potent than /-amphetamine in central but not pe(cid:173)
`ripheral activity.
`
`I. Catecholamines
`
`EPINEPHRINE
`
`PHARMACOLOGICAL PROPERTIES
`In general, the responses to epinephrine
`resemble the effects of stimulation of adren(cid:173)
`ergic nerves. However, they are not identical
`due to differences between epinephrine and
`the adrenergic mediator, norepinephrine, in
`the proportion of their a-
`to ,B-receptor
`activity. Most of the responses listed in Table
`2 1- 1 (page 408) are seen after injection of
`epinephrine in man, but sweating, piloerec(cid:173)
`tion, and mydriasis occur only under special
`circumstances. Particularly prominent are
`the actions on the heart and the vascular and
`other smooth muscle. So enormous is the
`literature on almost every aspect of the many
`changes in bodily function caused by epi(cid:173)
`nephrine
`that
`this discussion
`is
`limited
`largely to the actions of the drug in man and
`refers to the more abundant results in ani(cid:173)
`mals when studies in man are limited.
`
`Blood Pressure. Epinephrine is one of the
`most potent vasopressor drugs known. Given
`rapidly intravenously it evokes a charac(cid:173)
`teristic effect on blood press ure, whjch rises
`rapidly to a peak that is proportional to the
`
`dose. The increase in systolic pressure is
`greater than in diastolic pressure, so that the
`pulse pressure increases. The pressure then
`falls below normal before returning to the con(cid:173)
`trol level. Repeated doses of epinephrine con(cid:173)
`tinue to have the same presser effect, in sharp
`contrast to amines that owe a major part
`of their effect to release of norepinephrine.
`The mechanism of the rise in blood pres(cid:173)
`sure due to epinephrine is threefold: a direct
`myocardial stimulation that increases the
`strength of ventricular contraction, an in(cid:173)
`creased heart rate, and, most important, vaso(cid:173)
`constriction in many vascular beds, espe(cid:173)
`cially in the precapillary resistance vessels of
`skin, mucosa, and kidney, along with marked
`constriction of the veins. The pulse rate, at
`first accelerated, may be slowed markedly at
`the height of the rise by compensatory vagal
`discharge. This bradycardia is absent if the
`effects of vagal discharge are blocked by
`atropine. Minute doses of epinephrine
`(0.1 µ.g/ kg) may cause the blood pressure to
`fall. The depressor effect of small doses and
`the diphasic response to larger doses are due
`to greater sensitivity to epinephrine of vaso(cid:173)
`dilator ,82 receptors than of constrictor a re(cid:173)
`ceptors.
`The effects are somewhat different when
`the drug is given by slow intravenous infusion
`or by subcutaneous injection. Absorption of
`epinephrine after subcutaneous injection is
`slow due to the drug's local vasoconstrictor
`action; the effects of doses as large as 0.5 to
`1.5 mg can be duplicated by intravenous in(cid:173)
`fusion at a rate of 10 to 30 µg per minute.
`There is a moderate increase in systolic pres(cid:173)
`sure, but the diastolic pressure usually falls
`(Figure 24- 1). Pulse pressure is increased,
`but the mean blood pressure is seldom
`greatly elevated. Peripheral resistance de(cid:173)
`creases, due to action on ,82 receptors of ves(cid:173)
`sels in skeletal muscle, where blood flow is
`
`Page 483
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`ADAMIS EXHIBIT 1022
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