po
`
`CHAPTER 74
`
`Central Nervous System Stimulants
`
`P01rlda K Son:sollo, PhD
`.w:t...,.... _
`..... cI H.....oIogy
`l,In/Yot<$iI}' o(~ond ~b"yol Uew Iftay
`•
`I\abH Wood k>hnson MoodIcaI SdlOOI.
`1'IIcCfaW<>Y. IU OM~.
`
`I I,
`
`I
`
`Central nervQillI system (eNS) stimulants are substances '
`which increase excifability.withi.."l various regions of the brain
`or spinal coed. ' The prominent effects produced by mallY o(
`these drugs are arousal and-increased motor function. which
`result in subjec.tive feelings of increased mental alertness~
`decreased fatigue , impro\'ed cClnccntration, increased energy
`and motivation and an .elevation ill mood. Excessive excita(cid:173)
`tion can lead to conv.uls ions, and mJnit, ifnot ,Jll, of these drugs
`produce seizures in a dose-dependent mam\er.
`Excitability of the CNS Tt!fiects an intricate balance bel[ween
`excitatory and inhibitory activity' within the beain. ~tim­
`UIants of the eNS directly or iildirecUy enhanc-e excitatory .
`activity or block q\ll.ibitOlY components. The excitatory trans- .
`mitters, glutamate and aspartate, are impoltanl neurotrafl:Smit:
`ters at excitatory synapses where their actions are mediated
`· through N-methyl'D-Dspa~te (NMDA) or nQn-NMDA (kat(cid:173)
`In con~rast, gamn.13"
`nate.or AMPA/quisqualate) re<:eptors.
`aminobutyric acid (GABA) and gIycine are prominent inhibl·
`LOry neurotransmitters. The neuromodu.l3tor, adenosine, a1~
`'p1ays an importantrole In eNS el'citation in that it can exert a
`depressant action, mo$1, likely on the basis .of its ability to
`decrease impulse-generated ~smitter release and to limit
`excitation of postsynaptic elements by direct hyperpolari~.
`tion. Marll' eNS stimulants proquce excitation through their
`· antagonism at GADA, glycine or adenosule receptors whereas
`others, the indirect-actulg .l>-ympathQmimetics, prqduce pro(cid:173)
`'nounced eNS stimulation by enhancing the aj;:tions of endoge(cid:173)
`neous catecholamlnes dl.le to· their ability to increase release
`and/pr prevent the uptake of endoge'nous ~teehola!)1lnes
`(see Table 1).
`.
`The eNS stimulanl::s are much less imporant therapeutically
`than the eNS depressants; but they can produce dramatic
`pharmacological effects and some frequently. are abused.
`• Forexample, CNS stimu.\ants(eg, methylphenidate) are among
`Lh.e most commonly prescribed drugs for attention dejicu
`discmte"rs in children. The amphetamines or their analogs
`are used in narcolepsy, as adjunct therapy in aUenliondejicit
`· disorders and as appetite supp7-essams in- obesity. The '
`mild eNS stimulants, such as caffeine, are used in drug(cid:173)
`induced respiratory and! or ~rcularory depression and vas(cid:173)
`cular headaches; caffeine also is used in a number ofanalge(cid:173)
`'sic combinations. The strong CNS stimul('lnts, such as
`pentylenetetrazol" and picrotOXin, have no established .thera·
`· I?eutic use since the therapeutic dose is -.:ery close .to *,e
`cQnvulsant d.ose . ·
`. ' .
`A numt>er of eNS stimulants .t:aave therapeutically useful
`actions on other pam of the body, and a number-of drugs not
`included in this chapter stimulate the eNS when adJIlinistered
`in toxic doses. For example, caffeine, a' classical central
`nervous system stimulant, has clinically useful actions on the
`heart, blood vessels and kidneys.
`'On the other 'hand, atro(cid:173)
`pine and ephedrine, drugs with primary actions on the periph(cid:173)
`eral autonomic nerVous gyst.em, stimulate the eNS.
`Only those drugs which 'have cenlral sliin~lation as; a pre(cid:173)
`dominant action are fisted in this section. Those agents
`whose central stimulant properties are secondary (atropine,
`many sympathomimetic amines, nicotine, lobeline, carbon
`dioxide, 'cyanide, apomorphine and em~tine) .and those wh~se
`
`central stimulant properties are induced only with·toxic doses
`· (phenol, saucylates, locaianesthetics, ergot alkaloidS, etc) are
`listed In other chapters. For convenience, the drugs de(cid:173)
`scribed are divided into tJ:tree gro~ps: . xanthine derivatives,
`psychostimulants and miScellaneous eNS stimula!!ts.
`
`Xanthine Derivatives
`
`. Sturmlation of the eNS can be produced iJl man and animals
`by a large ' number of natural and synthetic. .substances.
`None, however, occupy as prominent a place in the environ(cid:173)
`m~nt of m'an as do the xanthine derivatives'. The most popu(cid:173)
`lar sources of theSe substances are the x9J)thine beverages,
`which incl~de coffee, tea, cocoa and coil~.flavored drinks.
`Coffee and tea contain caffeine, whereas cocoa contains .
`the·obromine. The caffeine 20nient of tea leaves (2 to 3%) is
`highe~ than that .of·coffee beanS (0.7 to 2.0%) b.ut the bever(cid:173)
`ages as fiimlly prepared contain abou,t equal amounts of this
`stimulant. Caffeine is present .in amounts of about 100 to
`150 mg/18p mL of ~rewed. coffee;' 60 to 80 mg/180 mL of
`instant coffee; .40 to 100 mg/lSO mL of tea and 17 to 55 ..
`mg/ISO mL of cola be~erage. There Is little doubt that the
`popularity of these beverages depends 9n their stimulant ac-
`· tioo, aitllough most people are.unaware of any stimulatl~:m . .
`Xanthine derivatives include caffeine, theo.bromine, theoph(cid:173)
`yUine and"a number of related synthetic derivatives, aU of '
`which have similar pharmacological propenies that differ
`markedly in th!,:! intensity oftl}elr ~ctions in various structures.
`For example, the stimulant effects of caffeine and theophyl(cid:173)
`line on the eNS and on skeletal muscle are much greater than
`those of theobromine. P.urthennore, theophylline surpasses
`caffeine in' its diuretic., cardiac and smooth m~cular. action5.
`Therefore, in the therapeutic application of these drugs for a
`speCific effect, side effects C3.1J be minimized and the: desired
`effect in~ensified by careful selection of tlie xanthine em-
`· ployed.
`. '
`The principal therapeutic application of caffeine is as a eNS
`stimulant. :Therefore, caffej.ne an~ i.ts congeners which pos(cid:173)
`sess this effec~ will be discussed in this:sectlot}. The princJ(cid:173)
`.pal therapeutic use of tlleophyllj.ne and related cqmpounds is
`as a bronchodi.lator in the management of asthma. For this
`reason theophylline derivatives are discussed in Chapter G6,
`.
`.
`~espir:aUJry Dnl{Js.
`Amioophylfine--:page'971:
`
`Caffeine
`-JH-P~rine:2,6.dione, 3_~:dil~Ydro:I,3,7'trimethyj_, Theine: Nil"
`ms'Z (Bristol-Myers); TlIend (NurclijJThayer); Vivarin (BeeCh"m);
`Dexitat: (Republic); Quick Pep (Thompson)
`
`1 ,3,7 -Trlmethylxanthlne i 58·08-21 CtH laN.O~ (194.19); mmwhydraUI
`' 57 43.12~J (212.21).
`I '
`.
`. •
`.
`· For the structural fonnula., see page 404 .
`.
`I're par.~on--CalTeine may be isolated from t.ea or coff~ by boiling
`,..jth water In the present:(! of lime or ma«ne5lum oxki<l!, whkh serves to
`precipitate·the tannins and some ofUle coloring matLer. After tiltntlon,
`the c:rude . t:all."e~~ I~at separates is rec!),stal1lud fl"9m hot wa~r·.affur
`
`..
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`. 1231
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`p. 1
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`SHIRE EX. 2011
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`IPR2018-00293
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`are not significant In nOIT.lal patients. Repeated use of thi.s substance
`mar result in the development oftQlerance to its diuretic, cardiov3c'lcular
`and cent"" nervoU$system effects .
`.
`This drug and other xanthine" may enhanc~ the cardiac inotropIc effects
`of beta-adrenergic stimulating ' agents and decrease the effect of
`benzodiazepines. ~cause c;o!feme ingestion restilts in reduced liver blood
`flo:»" the metabolism and elimination of drugs w.hJch are el~~ prmiar.
`lJ)' by hepatic metabolism may be slowed. TIle lng~~o,!\~t~#.~ine can
`ca~ a slight increase in wine levels of vanilly~d.~lic.\~id;·:Ctltf!ch(ll . .
`. ,amines M.d 5:~ydrQl<yindolea~tic add. Sine.e' hi~ ~ri~~l~!;;:?f ,:anil­
`Iylmandlilic aCId Of catechohmunes may result In a fal!ie-p!l.~\tJy,e:d1agnosls
`. of pheochromocytoma or neuroblastoma, c&lfeille intake shoUfd be avoided
`during thes;'i.eSts:
`.
`,
`'Acute toxicity involving calfeine has been reported only rarely.
`Overdosage lIslIally is associat~d with gastroi.ntestinal pain, mild deliriwn,
`, InSomnia, diuresis, dehydrntlon and fever. More seriowi sYmPto~ in·
`clude cardiac IUThythmlas and convuisiolU. 'The acuie lethal doie of
`caffeine in adults appear.; to be about 5 to 10 g eitner mtrav~no.u'slyor
`, orally. O<:'alh has DeClined in a child foUowing oral ingestlon of3 g.
`Prolonged, high intike mayproduee tolerance, habitllationand psycho-'
`logical dependence. Abrupt discontinuatklJl of rhe stimulant may result
`'in headache, irritation, nervousness, anilety 4nd dizziness.
`The ingestion of large amounts of combinations containing aspirin l\lld
`caffeine has been associated with analgesic nephropathy, ehariclerized by
`sterile pyUria, asymptomatic -bacteruria, pyelonepl)ritis, papillary necro·
`'sis, interstitial fibrosis rul'd nephritis. The role of caffeine in the etiology
`of this condition has not been established conclusively. For an indcpth
`~eview 'of "The Health Consequences of Calfe~ncO< the interested reader is
`referred to the interestirig article by Sawynok l\lld Yaksh (Pharma.col ~cv
`.45: 43, 1992).
`.
`.
`.
`Dose-lOO to 500 mg; IIsual, ZOO mgas necessary.
`. Dosage Forrlls-Extended-Release Capsules: 200 and 250 mg;
`Tablets: 100. 150 and 200 mg.
`
`Cilraled Caffeine
`
`Caffeine citrate (1:1) !69·22-il; a mbc;ture of caffeine and cltrie acid
`containing 50% C~ H,oN,O~ (anhydrous caffeine) and 50% C ~H~Or (anhy'(cid:173)
`drous citric acid).
`Pre paration- The.rormula of US,P IX was
`
`..... . . "., .. .
`Caffeine
`Citric Acid .. ..
`Oistilled Watc'r, 1I0t ... : ..
`
`· 50g 50,
`
`100mL
`
`Ois~olve the citric acid in the lint distilled water, add the caffeine, and
`evaporate' the resulting solution to dryness on a water bath, constantly
`~tirring towards tile end nf the operatIon. Reduce the product to A fine
`powder and transfer it to well·closed containers.
`It is, however, usually
`'prepared by mixing equal proportiol\ll of finely powdenid anhydrous caf(cid:173)
`feine and anhydrous citriC acid.
`Description- White, odorless powde'r; slightly bitter, acid taste: acid
`·reaction.
`SoJublUty-l g in about 4 mL warm water, rhe caffeine gradually
`precipitating on diluting·the solution with an equal volume of water but
`redisSolvillg on further dilution with sufficient water.
`lneompatiblUUes--Neulralization of the citric acid by alkalies or
`alkoline $01105 will cause precipitation of calf~ine 'If In s ufficient
`concentration.. The al kali salts of organic acids may release either caf(cid:173)
`feiile or the free organic' acid. 'Jifgencral i~ displays the incompatibilities
`of the dtric acid which It containS.
`.
`U!;es--See CfI!fe;r.R.
`008_100 to 500 mg; usual, 300 mg as necessary.
`Dosage' FOml$--Tablets: ~5 mg.
`
`Caffeine and Sodium Benzoate Injection
`
`A sterile solution of caffeine and mium benzoate In wa'ter for inJectioil;
`contnins an amount of anhydrous caffeine (C,H ,oN.Ol) equivalent to 45 to .
`52%, and an ~mountofsodium benzoate (CrHsNaO,J equivalent to 47.5 to
`55.5%, of the labeled amollnts of caffeine and sodium benzoate.
`Description-pH bctween6.{i and 8.5.
`. UlIe-----&!e Cqffeine, page 1231.
`Dose-Panmlend: 200 mg to 1 g; usU(d, 500 mg, repeated as neces(cid:173)
`sary.
`DoslIge Fo rm-Injection: 250 mg (Caffeine Anhydrous 125 mg lmd
`Sodium Benzoate 125 mg) per mL.
`Oyphylline--page 972.
`Oxtripl;1ylline-page 972.
`Theophylline--page 973.
`Theophylline Calcium Salicylate--see APS· 17, page B7~.
`
`CENTRAL I"ERVOUS ?YSTEM STIMULANTS
`
`1 ~3J
`
`TheophVUlI'I<t, ephed;lra~' Hydrodlloride end Phoocb3mltal-
`page 973.
`. .
`Theophylline Olamln~see APS· 18, page 868,
`. :rhetJphylllne Sodium Aceiate-:-see RPS-17, pagG 575.
`Theophylline Sodium Glycinale--see RPS-17, page 874.
`
`.Psychostim_ulants
`. Most pf the cqmpo~ds illcluded under this' heading' ar~
`indirect-acting sympathomimetic drugs and are more potent
`. central stimulants than the xanthine delivatlves. These com(cid:173)
`pounds (amphetamine and s.everai of its analog~, cocair,e,
`miziridol, .::nethylphenidate; see Table 1) do not stimulate
`'monoaminergic receptors directly, but rather increase the
`'adions of endogenous catecholamincs. This is due to their
`ability to inhibit the uptake of the catecholamine from the
`synaptjc cleft after rele!lSe or to cause catecholamine release. '
`Because of their propensity to produce euphoria, IT]any .of
`these drugs are widely abused and are controlled substances.'
`The approved use for most of these dIugs is as anoredic
`agents, although seVeral are llsed in' the treatment ofattentiori
`deficit disorders (methylphenidate, pemoline, amphetamine)
`or narcolepsy (amphetamme). Given the abuse liability and
`dependence potential of maity, ~fthese cornpoun<Is, the'thera(cid:173)
`peutic use of these drugs should be monitored closely.,
`A 'number of drugs that stimulate the central nerVous system
`are promoted for treatment of hyperactive behavior in children .
`'A degr.ee of hype.ractivity which is Bot acceptable, either at
`home or at school, often is accompanied by difficulty in learn(cid:173)
`ing and sometimes by other neurQlogicai sigrrs, such as
`~ ·dunlsiness." A1though ,the usefulness of psychostimutant
`.1 drugs in treatment of "hyperactivity'" has been controversial,
`there is n pat~ent group..,Vith severe, persistent hyperactivity
`and a short attention span that is likely to benetj.t from tr~at·
`menl with these agents. The psychosti.mulants most fre(cid:173)
`.queI;ltl1 used for th~ purpose in~lude melhylphenidaleiand
`"
`pemoline:
`Amphetamine and me~hamphetamine are two of the most
`pO,tent sympathomimetic.drugs with regard to eNS stimulation.
`They can improve psychomotor perfonn'ance and enhance
`wakefulness, althou~h 'it is questionable whether' conc~ntra­
`tion in complex learning situations or judgement is' i.oiproved.
`The effects of these amphetamines are thou~t to lie mediated
`through cortical stimulation and possibly througp stimulation
`of the reticular activating system. The (8), or (+}, isomer of
`amphetamine is three to four times more potent than·!.he (R),
`(only th~ (1
`or (--), isomer in elicitation of CNS J'€sponses
`isomer of methamphetamine is available clinically). The
`alerting effect of the amphetamines, their anorectic effect and
`some component of their locomotor-stimulating action,<lre
`likely mediated by nOJ'€pinep~ri.ne relt:ase. Some aspects of
`locomotor activity, as well as euphori.a, afe due to dopamine
`release within the basal gallgiia and tlle limbic system . .
`That the CNS stimulating effects of these compounds are
`mediated through the catecholamines is suggested by findings
`in animal studies that inhibition of catecholamine synthesis
`preve.nts the behavior<tlactivation produced by the drugs.
`In
`humans, acute toxicity produces' restlessness, dizziness,
`tremor', hyperactive reflexes, talkativeness, irritabilitY,'wealF
`ness, insomnia and fever. Larger doses can produce confu- .
`sion, increased libido, anxiety, panic 'states, hallucinatlons
`and psychotic behavior. Some of these effects may be due to
`the release of 5-hydroxytryptamine (5-Hn from serotonergic
`neurons.
`In addition, there-may be'pronounced cardiovascu(cid:173)
`lar and' gastrointestinal effects. Excessive toxicity results in
`convulsions , coma and ce r.eb~ hemo{rhages. , Sec Chapter
`57 for more discussion 011 the af!lphetamines.
`.
`Cocairie is also .il. potent sympathomimetic CNS stiinulant
`witl~ a,ctions very similar to those of the ~ phc~amines but
`with a much shorter duration of actjon . . CocaL'1e has local
`anesthetic actions; however, its use for this purp~ is limited,
`having been replaced by synthetic local anesthetics. which
`have little CNS stim
`aine)ics
`p. 3
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`
`. CENTRAL NEAVOU~ SYSTEM STIMUlANTS
`
`1235
`
`compounds is a safe and selectWe respiratory stin).want, al(cid:173)
`in the spinal coro, whereas bicuculline, ·plcrotoxin and pentyl(cid:173)
`enetetrazol are GABA antagonists which act within various
`though doxapram Is still available fpr use in certain
`circUmstances. Moreover. depressant drug intoxications can
`regions of. the .brain. Strychnine is used as a pesticide for
`be managed effectively with more conservative measures that
`destroying rodents and other predatory animals and thus is
`encountered-frequently as a ca.~e of poisoning iii man.
`stress intensive supportive care. Hence, the airway is kept
`clear by suction or by endotracheal tube, the patient is twned
`Doxapram Hydroc~lorlde-page 979.
`regularly an.d oxygen is administered as needed. ~hock is
`Nikethamide-see APSI8, page 1134.
`overcome by the use of blood or plasma expanders and
`vasopressors. Where available, dialysis is used to remove
`PentylenetetraZOl-see RPS-18, page .1134:
`the drug.
`. '
`Picrotoxin-see RPS-18, page 1135.
`AlUlough most of the formerly: classified analeptics are not
`Pipradrol Hydrochloride-see RPS-i5, page 1034:
`used therapeutically nor are available. clinically, several have
`-become important research tools for evaluating the efficacy
`R a ceph~ rine Hydrochloride-see RPS· l ?, p<:lge 893 .
`. and mechanism of acl.lon of various mugs, particularly'of
`Strychnine-see RPS-1 8, page 1136.
`_ anticonvu\sants, because the mechanism ~y which these con·
`Theobromine-see RPS· t8, page 941 .
`.
`. vulsants'exert their actions iswell characterized . . It is known
`that strychnine is !1 glycine antagonist with acti~ns primarily
`Theobromine Satts-see RPS-15, page 1070.
`
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`Entered accor,ding to Act or.congresS, In the year 1 .~5 by Joseph P RemingtOh,
`in the Office of the Librarlan of Congress, atYJashington DC
`I
`
`Copyright J 889, 1894, 1905, 1907,1917, bYJosep!i. P-Remlngton
`
`Copyright J 926, 1936, by the Joseph P Remington Estate
`
`CopYright 1948, 1951 , by The Philadelphia College otPharmacy and Science
`
`Copyright 1956, 1960, 1965, 19.10, 1975, 1980, 1985, 1990', 19,95, byTIie Philadelphia College of
`Pharmacy and Science
`' .
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`AU Rights Reserved.
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`ISBN ~9121~4-04:3.
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`oonlajP!6d hefej7'l.
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`NOf7CE-T1Ii.s lext 'is not intended to repi'esenl, nor shall it be ~n!eryreted to be, Ihe equivalent
`of or a substiMcfw- the qfJU;iaWniled. Stales Pharmacopeia (USP) and/or the Natianal
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