_
`
`
`
`SHIRE EX. 2014
`KVK v. SHIRE
`
`IPR2018—00290
`
`page 1
`
`Page 1
`
`SHIRE EX. 2014
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`Entered according to Act of Congress, in the year 1885 by Joseph P Remingtoh,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894,.1905, 1907,1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 19.7.0, 1975, 1980, 1985, 1996, 1995, by The Philadelphia College of
`Pharmacy and Science
`
`All Rights Reserved .
`
`Library of Congress Catalog Card No. 60-53334
`
`ISBN 0-912734-04-3
`
`The use of structural formulas from USAN and the USP Dictionary of Drug Names is by
`pertnission ofThe USP Convention. The Convention is not responsible for any inaccuracy
`'contained herein
`
`Nonce—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`of or a substitute for the official-United States Pharmacopeia (USP) and / or the National
`Formular-y (NF). In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, quality, purity, packaging and labeling for drugs and
`representations of them herein, the context and effect of the official compendia shall prevail.
`
`Printed in the United States of Anierica by the Mack Printing CoMpany, Easton, Pennsylvania
`
`Page 2
`
`

`

`CH
`
`Donald Franz, PhD
`Professor of Pharmacology
`School of Medicine. University of Utah
`Soli Lake Ciry, UT 84132 -
`
`The next five chapters treat specifically of autonomic drugs,
`and several other chapters (eg, Chapters 5:3;55, 71, and 74)
`include .descriptions of i.r references to a number of auto-
`nomic drugs. ConSequently,-it will be-helpful to review briefly
`• the autonomic nervous system and the classification Of drugs
`that act on or simulate componentS of that system:
`
`Autonomic Nervous System and Autonomic Drugs
`
`The autonomic. (involnntai;y) nervous syst e In generally
`is. defined: as that system of motor (efferent) nerves which
`contains cell bodies and corresponding synapses (ie; ganglia)
`outside of the cerebrospinal axis. The definition includes the
`sensory (afferent) nerves that subserve functions mediated by
`the autonomic motor nerves, although a given sensory . nerve
`also May subserve somatic motor functions. This system
`modulates or controls the acti 3iLies of smooth (involuntary)
`- muscles Of the body, including those that control the caliber of
`blood .vessels, the Heart muscle and the digestive, salivary; •
`sweat and some endoerine glands. • Unconsciously (without
`conscious control), it tends to Maintain a constant state (ho-•
`meostasis) Oldie-vital functions of the body, constantly adjust-
`ing one or more factors to attempt to maintain equilibrium or
`• restore an equilibrium upset by external or internal influ-
`ences; cerebral blood flow, body temperature, visual accom-
`modation, .blood sugar and body fluid composition, for
`. example, are kept remarkably constant by means of setvoad-
`jUstrnents mediated through the 'autonomic nerves. How-
`ever, it should be noted that the somatic (voluntary) mire 'hums
`system also unconsciously subserveS vital functions such .as
`• respiration, posture, swallowing, motor reflexes,' body tem-
`perature and many less vital but important unconscious modu-
`lations of skeletal muscle tone; however ; the degree of con-
`scious modulation of thiS control is much greater tharrin the
`autonomic nervous system. These involuntary somatic mo-'
`for functions are coordinated with autonomic functions.
`There are two main motor divisions to the autonomic ner-
`vous systems—the sympathetic (thoracolumbar) and the
`parasympathetic (craniosacral) divisions .. Most organs or
`systems (effectors) receive innervation from both thesedivi-
`sions; generally ; but not invariably, the two divisiOns -qualita-
`tively are opposed in their actions on a given effector. An
`abridged list of responses is presented ih Table 1.
`The opposition of the two divisions of the autonomic ner-
`vous system reflects the fact that the chemical substances
`(mediator, transmitter or neurohurnor) liberated by the post-
`ganglioniC nerve terminals are not the Same for the two
`divisions. Parasympathetic .postganglionic nerves liberate
`acetylcholine and, hence, are called cholinergic nerves.
`Most sympathetic postganglionic. nerves liberate norepine-
`phine; however, sympathetic poStganglionic fibers to the sweat
`glands and a few fibers to the vascular beds of the-mouth, face
`and skeletal muscles liberate acetylcholine - (ie ; are
`cholinergic). The adrenal medulla, which is innervated by
``sympathetic preganglionic nerves, liberates mostly epineph:-
`rine, also known as adrenaline; since adrenaline originally was
`thought to be the sympathetic transmitter, norepinephrine-
`releasing nerves are termed adrenergic. • •
`•
`
`At the, ganglia, preganglionic nerves of either division liber-
`ate acetylcholine (ie, are cholinergic), but the character of the
`acetylcholine ganglionic receptors is different from those in`
`the neuroeffectors, so that the Iwo types of receptors are not
`blNked by the same drugs. Somatic motor nerves alsotiber-
`-ate acetylcholine•(ie, are cholinergic) and are.similar to auto --
`nomic preganglionicnerves in this regard.
`'
`- Autonomic drugs are classified according to their relation to
`the chemical mediator that. they either mitnic or-block. Thus,
`a drug is cholinergic if either mimics or •blocks stimulation
`by cholinergic nerves. The teriri-t (Ito/ iiimnimet lc and Mir--
`nomimelic have been advanced for,the appropriate mimetic
`agents.. There also .prevails an older terminology. Hence ;
`adrenomimetics are'usually called sympollonnimelics (this
`chapter) and cholinominietics are often called parasginpalbo-
`minielics (Chapter 58); the term parasyinpathomimetie ap-
`plies to thoSe drugs that act upon the cholinergi• neuroeffee-
`tots (ie, are muscarinic), not the ganglionic synapses.
`Agents that block the receptors are' called blocking agents,
`according to the nature of the chemical transmitter with which
`they compete.. Thus, there are an rcnergic blocking agauls
`(Chapter 59) and anti•thsc«.rinic agents (Chapter . 60), the
`latter term again restricted to those drilgs that. block acetylcho-.
`line at the neurtieffector receptors. Those agents that bloCk
`acetylcholine at the ganglionic synapses are simply called
`ganglionic block ing agents (Chapter 55); their somatic ino-
`tor counterparts.(generally loosely included among the auto-
`nomic drugs) are called neuromuscular blocking agentS
`(cur•ari.rniouetics) (Chapter (if): The suffix tylic sometimes
`is used in hen of the word blocking; thus, a sympatholytic
`agent, is. an adrenergic blocking agent. Also, agents, such as
`the anti cholinesterases, which enhance autonomic transmis-
`sion by preserving the transmitter from enzymatic destruc-
`tion, are endowed with no definitive designation; the anticho.-
`l•nesterases (Chapter -"58) are classified awkwardly as
`cholinomimetics or parasympathomimetics.
`An autonomic mediator not only is liberated at different
`sites and exerts different effects but also may act on different
`receptors. The actions 'of acetylcholine on the exocrine
`glands, smooth muscle' and heart differ from those on auto-
`nomic ganglia and the voluntary neuromuscular junction.
`The former (and not the latter) effects are hlocked,by atropine,
`whereas the latter (and not the former) are 'blocked- by
`tubocurarine. Since -mnscarine'exerts the former actions (and
`not the latter), the corresponding receptors are called musca-
`rinic; since nicotine exerts the latter reactions. (and not the.
`former), the corresponding receptors are called nicotinic.
`Three main types of muscarinic receptors are important:
`receptors predominate in the CNS.and on gastric parietal cells
`where stimulation increases gastric secretion; M2-receptors
`predominate in the' heart and M m-receptors are found in secre-
`tory glands and most smooth muscle.,
`In the adrehergic system there are also two main types
`of receptors a and' R. There are two types of .a- 'adreno-
`receptors: a m and, a2 . The. a radrenoreceptors subserve
`smooth muscular stimulant functions, adrenergic sweating
`and adrenergic salivation. The a 2-adrenoreceptors serve to
`inhibit the presynaptic release of norepinephrine and other
`mediators.and the postsynaptic activation of adenyl cyclase
`
`9$1
`
`Page 3
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`

`

`Peripheral. fellows 071(.-1 (ices
`
`.Not-alksystipathornimetics are capable of activating all ad-
`renetagic and doparninergic receptors; even among those which
`are, there is. marked variation in the relative intensities of
`activation of the several receptor types. Thus dopamine
`stimulates doParninergic receptors strongly, p radretiorecep-
`tors moderately, a-adrenoteceptors weakly and 13 2-adrenore-
`ceptors negligibly. The predominant sympWie tie neurotransmit-
`ter, norepinephrine, stimulates -a r and. p radrenoreceptors
`'strongly, a 2-a.drenoreceptors moderately, p radrenoreceptors
`weakly and dopaminergic receptors negligibly. Epinephrine
`stimulates all of the a t -, and P 2:adrenoreceptors
`strongly and dopaininergic receptors negligibly. Obviously,
`then, the .pharmacodynamic profiles of these three natural
`sympathomimetics differ considerably from one another.
`Several .sympathomimetics act sel ectively son a single type of
`-receptor.
`ot-Adrenoreeepto'r Agonists—a-Agonists cause arterio- .
`. lat and venoms constriction and, hence, have an action to
`increase blood pressure. This vasopressor action is :used to
`support' blood p]wasure in hypotensive states, such as in
`orthostatic hypotension, carotid sinus sYndrome, shock
`• and during spina/. anesthesia.. In the treatment of hypovate-
`mit; shock; the constriction of the capacitance vessels (ie,
`large veins) increases the venous return to the heart and,
`hence, the cardiac output, but once the blood volume is re-
`p leted, a-agonists. may-not be necessary. -In fact, the use of •
`a7agonists in airy kind of shack (except anaphylaxis) is usually
`counterproductive, because there is already ischemia of cer-
`Min critical organs like the kidney and bowel, and vasoconstric-
`tion exacerbates the ischernia in these two organs and contrib-
`utes to irreversible damage and life-tbreatening complications.
`The systemic vasoconstrictor effects also are employed in
`the management of a variety of serious allergic conditions,
`such as giant 'urtica.ria, serum sickness, drug .reactionsi
`angioneurolic edema and anaphylaxis. For these uses,
`epinephrine is the drug of choice. Also, the vasopressor
`effects of selective 'a-agonists (ie,, devoid of significant (3-actiV-
`ity) are sometimes used to elicit compensatory vagal reflexes,
`which slow the heart and depress atrioventricular conduction
`and, hen Ce, terminate paroxysmal supraventricular (atrial).
`or nodal, tachycardia.
`The a-agonists are applied topically to induce local vasocon-
`striction in the nasopharyngeal, scleroconjunctival and otic
`bloOd vessels in vasomotor rhinitis, acute rhinitis, acute
`coryza, nasopharyngitis, acute sinusitis, eustachiansal-
`conjuncavitis, scleritis, hay fever, otitis media, -
`baroliiS media, etc. This use to suppress hyperemia .arid
`the related edema is called decongeStion. Conjunctival and
`scieral decongestion may relieve irritative blepharospasm.
`a-Agonists that are capable of penetrating the cornea may be
`a-Agonists also are ap--
`used to relieve wveal congestion.
`plied topically -as styptics to arrest superficial hemorrhage.
`Lastly, they may be combined with local anesthetics,. vaso-
`constriction keeps the local anesthetic at the injection site for
`a longer time. •
`Topically administered a-agonists are used to stimulate the
`radial smooth muscle of the iris and, hence, cause myd•iasis
`for ophthalmologic examination or to break pOsterior syn-
`echiae nl uveitis.• Their effects on the ciliary-body are slight,
`and they do not cause significant .cycloplegia or increase
`intraocular pressure, even in susceptible persons. However,
`• their mydriatic effects are additive with those of antimusca-
`rinic drugs, with which they are sometimes combined, to
`produce maximum mydriasis for optimal examination of the
`eyegrounds. ...In open-angle glaucoma, intraocular vasocon-
`striction causes an increase in the outflow of aqueous humor
`and, hence, in the intraocular pressure; they are sometimes
`userlin combination with carbonic anhydrase inhibitors in this
`. use.
`p.,,,,AdyenerecepW Ago-mists.---The p ragonists increase
`
`-,
`
`
`
`902 (cid:9)
`
`CHAPTER 57
`
`-1---ficisporiiise of i-luihnsi, irscieq
`:Autonomic Nesve rripu[sei; (cid:9)
`
`•
`
`Effector (cid:9)
`system
`
`•SyrnpattMtic
`nerve.
`impulses
`
`Parasympathetic
`nerve
`impulses -
`
`Systemic blood vessels
`
`Pulmonary blood vessels
`Coronary blood vessels
`Bronchioles
`• Stomach motility and tone
`Gastric secretion
`Intestinal motility and Lone
`Urinary bladder sphincter
`.
`Heart . (cid:9)
`
`Pupil of eye
`Salivary glands
`
`Sweat glands .
`Lacrimal glands
`
`Constrict
`Dilate"
`Constrict,
`Dilate
`Dilater
`Decrease
`Little effect
`Decrease .
`
`Constrict
`Increase rate
`and strength
`Dilate
`Stimulate to
`viscid saliva
`Stimtdate
`Not innervated
`
`Innervate few systemic
`vessels, but dilate
`Dilate
`Dilate
`Constrict
`Increase.
`increase
`Increase
`Dilate •
`Decrease rate and
`strength, block.
`Constrict
`Stimulate to
`watery saliva
`Not innervated'
`Stimulate
`
`" Constriction is produced in most vascular beds by stimulation of
`• , a-receptors. Dilation is produced primarily in skeletal muscle and the
`liver by stimulation of S-receptors„
`Adrenergic nerves do not innervate directly bronchiolarsmooth muscle
`but instead act on Cholinergic nerve terminals to decrease the release of
`acetylcholine.
`Most sweat glands anatun*ally are •yrnpothetic but l'acncti.A.raal.ly
`' are ttamiarinic.
`
`(and hence inhibit postsynaptic responses).. The ri-adrenore-
`ceptors are subdivided into p,- and 13 2-adrenoreceptors, and
`perhaps more. They are characterized and defined by differ-
`ences in _responsiveness to sympathomimetics and blocking
`drugs.- [3 1 -Adrenoreceptors- effect cardiac stimulation and
`i32-adrenoreceptors sub•erve adrenergic smooth
`muscle relaxation (eg, vasodilatation, bronchodilatation and
`intestinal and uterine relaXation) and glycolysiS. Both a-ad-
`renoreceptors are blocked by phenoxybenzamine. a rAdre-
`noreceptors are blocked selectively by prazoSin and a*
`receptors by yohimbine and ranwolseine,. (1-Adrenoreceptors are
`blocked by propranolol. 13-Adrenoreceptors are blocked some-
`what selectively by rnetoprolol and 13 2:receptors somewhat selec.-
`tively by butoXamine. Dopamine excites dopamine recep-
`tors that are found in kidney and mesenteric blood vessels and
`are blocked by haloperidol; this receptor does not appear to
`be activated by other adrenergic
`
`The abbreviated list of functions greeted by sympathetic
`nerves, shown in Table 1, indicates the potential complexity of
`the pharmacology of the sympathomimetics. It is, in fact,
`considerably more complex than might be surmised from the
`table, not only because of the •several different receptors with
`.different functions and structure-activity requirements, but
`also because some sympathomimetics do not even act directly
`upon these receptors; these act indirectly by releasing norepi-
`neplirine from adrenergic nerve terminals. Furthermore,
`some sympathomimetics can pass through the blood-brain
`barrier-into the central nervous system, where they may elicit
`a variety of effects. Consequently, it is riot possible to de-
`scribe the actions, uses, adverse effects, etc of a prototype
`sympathomimetic that will apply to all sympathomimetics.
`The text below discusses prototypic actions rather than protos
`typic drugs, hi order to-explain the varied behavior among the
`sympathomimetics. The dependent uses, adverse effects :and
`• precauti Arts are discussed in relation to the actions, in order
`that the pliarniacodynamic bases of these may be compre-•
`hended better, •
`
`Page 4
`
`(cid:9)
`

`

`SYlViRi=)-(110lfill.V/IETiC fintJCTiG (cid:9)
`
`923
`
`Induce lipolysis and, urns, irtexease the cOlttie (cid:9)
`-
`They (cid:9)
`OD Of plasma free fatty acids. These effects are achieved, in
`post, through the activation of adenyiylcyclase and the synthe-
`sis of 3' ,5'-cyclic .adenosine monophosphate (CAMP), • In the
`heart, especially, (3 j agonists also increase calcium irfil u c. and •
`stora ge, M part the result of mediation by cAMP.
`Use is made of the cardiostitnulain6r effects of Pragonists,
`They may be administered by intracandia.c ffijeetion to restore
`the htso-Tt beat is cardiac al restand heart block with synco-
`pal seizures (as in Adams-Stokes syndrome) and by intrave-
`nous injection to sustain restored. rhythm or to .prevent a
`recurrence of arrests; however, p i -agonists are not the trcat-
`ment of .choice., and physical and electrical measures take
`precedence,More erten p l .;agonists are used for theipposi--
`isotropic actions in the treatment of acute heart failure
`and in cardisgenis or other types of shock, hi which contrac-
`tility often is diminisite6. However, they are less than ideal in
`the treatment. of shock, not only because they favor arrhyth-
`mias, which are ari e..,;p•eciiit threat in cardiogenic shock, but
`also because they pronicite a metabolic acidosis through the
`lipolytic action.
`p 2-agonists relax
`pr.A.,ditanosPer:ei-iitor (cid:9)
`smooth muscle and induce hepatic and muscle glycogenoly-
`sis, by activating the adenytyl c2,/clase system and increasing
`the intraceihilar levels of cAMF. Thus, they dilate the brim-
`chioles, arterioles in vascular beds which are invested with
`Ilipreceptors (such tis in skeletal muscle, splancimic and coro-
`nary but not renal-or cutaneous beds) and veins, and they relax
`the uterus and intestines. The glycogenolytic effects in liver
`and rraiSclA respectively, result in hyperglycemia and hype•-
`lactic acidemia. The hyperglycemic actions are sometimes
`used to treat insulin overdosage.. . At present, there are no
`"pure"- %-agonists without some degree of (3 r -agonist activ-
`ity.
`the treat-
`Most 13 2-agora:so are used as . bronchodil ators (cid:9)
`ment of bronchial asthma; ,emphysema, bronchitis and
`br(inchiectosis, often in combination with theOphylline.
`They also increase ciliary activity and liquefy tenacious mucus
`and so, haVe a milibexpectorant action. These effects are
`usually beneficial, but they fmay cause mucus plugs.
`Ta-ohyphylaxis to the bronchodilator effects sometimes (e-
`curs, especially if they are used continuously or in excess of
`recommended dosage or frequency.
`Selective P2-agonists, when administered by inhalation, may
`dilate bronchioles with aminirnum of hypotensive side effects.
`However, sonic degree of cardiostimulation can occur with
`current drugs: Muscle tremor, by an action on the skeletal
`muscle spindles, also commonly occurs.
`Certain 13-agonists may be used as vasodilators in the treat-
`ment of peripheral vascular diseases, 'There are two precon-
`ditions for efficacy: (1) the disease process•must predomi-
`nantly have a vasospastic and not obliterative component and
`(2) the vessels involved must have an effective population of
`(3,-receptors.
`•Fffica.cy, thus, is limited essentially to selected
`cases of intermittent claudication and thrombophlabilis.
`Some of the presumed selective 13 2-agonists for peripheral
`vascular disease relax vascular smooth muscle partly by a
`direct smooth muscle depressant mechanism. • . .
`112-Agbnists may be used to relax the uterus and delay
`delivery in premature labor. • Although-they do depress the
`premature contractions for a time, they seldom avoid subse-
`quent prentatitre
`nopasininerglic _Agonistn---Dopamine is the only marketed
`sympathomimetic with significant 'clopaminergic actions in
`the periphery. In the periphery, dopamine receptors are
`prominent in the splanchnic and renal vascular beds, where
`they mediate vasodilatation. Dilatation in these beds is im-
`portant in the treatment of's/lock and .acitte heart failure,
`since these beds often are constricted critically in these
`conditions. Dopamine is used in the Management of these
`disorders.
`Combined Agri:14.1A Activity---Most sympathdrnimetics -act
`upon- two or more receptor types, and the net effects are the
`algebraic sum of the a-, p i - and P2-activities. Iri deE.:Cribing
`
`the properties of a bympatho mimetic, ft is necessary to indi-
`cate the relative agonist activities in order to understand the•
`overall effects.
`
`Central Nervous 3ystaatActicms and Uses
`•
`9,Cii011r% of syMpatherriffneties hi the central nervous
`system are exceedingly complex. .- Noradrenergic and -dopa-
`mine/Sic nerves are disseminated widely throughout the cen-
`tral nervous system, and dopaminergic nerves are crucial to
`some "brain. functions. A limited number of epinephrine
`(adrenaline) nerves also are found in several areas. Not only ,
`are there a-, is-arirenergic and dopamine receptors at the
`synapses; but the actions subserved may be either excitatory
`or inhibitory at a specific structure, which structure may,:in
`turn, have facilitatbry or inhibitory influences on other
`structure:.. Furthermore,. some sympathomimetios appear
`to activate serotoninergic and pOssibly histarninergic recep-
`tors in the central nervous system: Also, some centrally
`acting sympathonsimetics appear to act as agonists at some
`toed and transmitter-releasing agents at other loci. One drug,
`thus, may display simultaneously a number of activities.. •
`The. most prominent central nervous system effects of cen-
`trally acting sympatimmimetics are various manifestations of -
`stimulation, which may give rise to nervousness, sleepless-
`ness, hyperactivity, irritability and increased respiration. In
`some - users they may induce anxiety and in others a kind of
`'euphoria that gives the user a feeling of accomplishment,
`expectation and affectations for which some sympathomimet-
`ics.may be abused widely. They allay the perception but not
`the reality of .fatigue, and users often drive themselves to
`physical and emotional exhaustion (the "crash"). Large
`doses can cause hallucinations, and long, continued use may
`result in paranoia and other dangerous behavior, as well as
`exhaustion.. Some tolerance to the euphoric and certain other
`central nervous system actions occurs.
`The effects to promote wakeWlness are used in the treat-
`ment of marcolepsy. They seldom are used any longer to
`treat central nervous system depression from overdoses of
`drugs, although the antagonism of respiratory depression is
`sometimes dramatic.
`The centrally acting symPathomircielics may be beriefiCial in
`certain disorders of movement. in parkinSonism they often
`diminish rigidity, relieve •culogyric crises and improve sleep.
`They also may provide relief in spasmodic torticollis. They
`also have a beneficial effect on mood in depressive states, but
`they have been superseded by other drugs. In the attention
`deficit hyperkinelic olitordop (ADHD) they have a paradoxiL
`cal calming • effect, but this use is controversial because of
`perceptions of overuse.
`A very widely used and greatly abused effect is that of the
`sari-fression of appetite (anorexiant, anorectic or anorexi-
`genic effect). The drugs.mayinduce temporary weight loss
`in etogoutnis obesity. However, the weight loss is usually
`the least in those who need it most and seldom exceeds 101b,
`the effectiveness usually lasts. but a few weeks (ie, tolerance
`develops).and there is danger of abuse; abuse potential varies
`among the sundry anorexiant drugs. At best, anorexiant
`drugs should he used only in a training program to condition
`the patient to new eating habits. Even -so, the patient usually
`resumes hyperphagic behavior eventually and may even show
`a rebound-like gain in weight.
`Centrally acting synniathomintetics- may exert autonomic
`actions by acting both in the periphery and upon the various .
`automarnic nervous centers hi the brain. Stimulants used for
`their pressor effects usually actin' the periphery, but central
`syrnpathoadrenal stimulation may augment such effects and
`may be an important factor in the cardiovascular effects of
`intoxication. Some centrally acting sympathornimetics are
`used to support blood pressure in the carotid sinus syn-
`drome or orthostatic hypotensidn; the oral efficacy and con- .
`venient duration of action offer advantages that partially offset
`disadv
`to sup
`
`Page 5
`
`

`

`984 (cid:9)
`
`CHAPTER 57
`
`•
`
`•
`rive from their central 'actions to increase the genitourinary
`autonomic nervous outflow. . 'They may . sornetirries relieve
`the pain of dysmenorrhea, probably by central nervous sys-
`tern and neuroen docrine mechanisms.
`Indirect Sy napathorninieties-----Marty sympathomimetics
`do hot conform to the structural requirements for adrenergic
`agonist activity. The aliphatic and cycloaliphatic amine syrit-
`pathornimeti cs, for example,. deviate greatly from the prereq-
`uisite structure. These compounds-derive their activity from
`an action to release norepinephrine from adrenergic nerve
`
`terminals, the final action, then, being mediated by • being
`norepinephrine. It might be expected that the oharmacody-
`. • namics of the indirect sympathomimetics Would be identical
`to'those of exogenously administered norepinephrine, but in
`some cases they are .not. Firstly, the release from nerve
`• endings may achieve high local concentrations of norepineph-
`rine at the cd_Tector. site that'could not be achieved' safely with
`. injected norepinephrine: Thus, therapeutic doses of ephed-
`. rine cause substantial bronchodilatation, while those of norepi-
`- nephrine do.not: Secondly, release is not equal
`For example, ephedrine releases norepinephrine More' enc-
`• tively in the bronchioles and heart than elsewhere; hence,
`considerable bronchodilatation and cardiostimulation often
`can be achieved with only mild to moderate vasoconstriction.
`AlSo,'hydroxyamphetamine fails to release norepinephrine
`the skin, although it does in the eye and the heart:
`Disposition--Part of the norepinephrine or dopamine that is released
`from -nerve Ler tni naIs is returned to thelriterior of the nerve by a meMbrane-
`transport system: This provides the principal means by which the action
`of adrehergic• neurotransmitters is terminated. Neuronal uptake also
`assists' in the termination of the action of small doses of exogenous
`norepinephrine. However, the predominant -route of elimination in the
`periphery is Om ethy ation at the ring :3-OH group by the ehzyme, catechol-
`.0-methyltransferase (cxmo. cow is found throughoutthe Peripheral
`tissues but Is quite aetive in the liver: Other ePtecholamines, and, to a
`„lesser extent, 3.:013 mojtophenolic amuses also are 9-methylated.. Ring
`• hydroxyl groups also are conjugated with sulfate and glycuropate in the
`liver. In the Oun, both nurepinephrine and dopamine are eliminated
`mostly by the mittoeqraid•iat enzyme, monoamine nxidase (MAO). in the
`periphery,. MAO is aIso important to the elimination of catecholamMes as
`well as to that of n•ncatecholic ar vlethylariiihes. The presence.of side-
`.. chain suliStloteets, at in ephedrine and amphetamine, renders the sympa-
`thomi melte t-nlim ls resist ant 4.0, oxidative deaminaition by MAO. Such
`MAO.
`drugs.do„ hovie .vo it, (cid:9)
`sympathombellic must run the gamut of . MAO,
`By the on -al (cid:9)
`COMT and c ot-tjt gases in the intestinal wailand liver. Sympathomimetics
`that are gond , ttiht_a ates for these enzymes are ineffective or erratic Orally.
`sys-•
`- Most normatecholantines also are oxidized-by the cytochrome P-4 (cid:9)
`tem in the lived
`
`
`
`Adt) „Se Effects, Precautions and Contraindieations.
`
`The multiple activities. of synapathomiinetics make for:nu-•
`merotis side effects. Sbme of these, stich . as reflex shomeo-
`, static adjustments, which act to counter :aneffect or the elicits-
`tion of sin; iiltaneous Physiologically-antagonistic effects; are'
`cOunterproduelive • but are -not necessarily adverse.- How-
`ever, some reflex effects may be adverse, such as the pro--
`longed reflex renal vasoconstriction that accrues to the use of
`isopmterenol infusion in shock. Some 'side effects, such as
`substerriat pain, occur only in patients with a 'particular dis-
`• ease and indicate an adverse 'effect only in such patients.. -
`The manufacturer's literature (packageinsert, Physicians'
`Desk. Ref iwnce. etc) tends to list for each syrnpathomimetic
`• drug all the collective side effects and contraindications of all
`syrup atho rn irrtetics, without regardto the individual properties.
`In the diseussion below, the adverse. effects are enumerated
`according to the type of activity. For drugs with multiple
`• activities; it will be necessary for the reader to synthesize the
`profile. f adverse effects and contraindications from the corn-
`. pOnent activities, However, certain precautions apply to all
`sympathomitnetics,, namely that elderly persons, infants and
`persons with thyrotoxicos.is tend to be more sensitive to syrre
`re-d:":e_.,imetics., and that adverse effects of one kind or another
`
`are much more -probable in persons with cardiovascular dis- -
`ease than in normal adults.
`ca-Agozaiste-----One . important (cid:9)
`
`i portant adverse effect of system- •
`cagy administered on-monists is an excessive increase in
`blood pressure.. In persons with weak or atfieromato us blood
`'vessels, a cerebrovaseular accident (eg, stroke), coronary ..
`occlusion,. aneurysm or other serious event may occur. . The
`heart works harder against the increased presSure, which pray
`induce an attack of angina pectoris or precipitate or aggravate
`heart failure,. Hypertensive or elderly persons may show
`an exaggerated pressor response, Vagal reflexes to the pres-
`sor response may cause bradycardia and various degrees of
`atrioventricular conduction block; the disturbed electrophysi-
`ology and myocardial stretch (the heart, enlarges to work
`against the increased. presSure) favor various serious cardiac .
`arrhythrnias in persons with certain types of heart damage.
`Therefore, except under the most careful medical supervi-
`sion, a-agonists•are cOntraindicate d in *persons with hype71 m,o-. -
`sion, coronary heart disease,• arteriosclerosis, atheroscle-
`rosis, diabetes (because of •VaScular. pathology), cardiac •
`arr•hyth iias or a history of myocardial infarction. They
`also are contraindicated in venous thrombosis; because veno-
`spasm not only may exacerbate the thrombosis but also May
`initiate thrornboernbolism.
`The possible adverse effects.of 6. 1 -agOrdsts in shock were
`mentioned under Peripheral Actions and Uses. Prolonged
`infusion of some sympatho•nimetics occasionally can cause
`shock. ExtraVasation of a-agonists during intravenous ad-
`ministration may result in a slough; sometimes phentolamine
`is; included in the solution to antagonize the .perivascula•
`vasoconstriction: Uterine and placental vasoconstriction in
`pregnancy may harm the fetus. a nAgonists interfere with .
`lactation. Signs and Symptoms of a strong vasoconstrictor .
`effect are bradycardia with a strong pulse, Occasional tingling
`in the extremities, headache• and sometimes anxiety, which
`results from the enteroceptive den- ction of the altered cardio- ,
`vasCular status and other autonomic disturbances.
`Other systeMic side effects of a-agortists include mydriasis
`and. .photophobia (if the drug can penetrate into the eye),
`sweating, piloerection and occasionally nausea and vomiting.
`Increased tens,ion in the trigone muscle and urethral contrac-
`tion may create. a • desire to urinate ; but urination may be
`difficult; oaagonists should be used cautiously in elderly men,
`.especially those with prostatic hypertrophy. • ,
`Adverse effects of a-agonista applied topically to the eye
`include photophobia (from m,ydriasis), browache, ocular pain,
`headache ; aftercongestion aeSpecially during chronic use, re- ,
`'bound miosis after the adrenergic effects wear off, floating .
`opacities and sclerocorMinctiyal .and especially corneal
`cherndsis:. Prolonged use, especially of .epinephrine, may
`cause pigmentation in the cornea, conjunctiva and lids. • In-
`tense irttraocular vasoconstriction can damage the retina;
`special *care' must be exercised when there is no • lens.
`Ophthalmologic syrnpathornimetics should be used cautiously
`when there is retinal detachment or-before cataract, surgery,
`because of poSsible rebound m