III----—
`‘CHAPTER 74
`
`
`
`Control Eiervo'os_ iysts-mi Stimulants
`
` _
`
`F
`
`Patricio K-Sonsolial, rho‘
`Alsslsl-onr Proiessor oi Neurology
`.Unlversiry of Medicine "and Dentistry of New Jersey
`Ruben Wood Johnson Medical School.
`_
`Plscorowoy. H) onus»:
`__
`
`'
`
`'
`
`'
`
`v
`
`_ central stimulant properties are induced onlywithtoxic-doses
`(phenol, salicylates, local anesthetics, ergot alkaloids", etc) are
`listed in other chapters. For convenience, the drugs de-
`' scribed are divided into three groups: , xanthinc derivatives,
`psychostimulants and miscellaneous CNS stimulants.
`
`Xanjthine Derivatives
`
`Central nervous system (CNS) stimulants are substances‘ '
`which ir{crcase_exciiIa_hility.withJ'n various-regioiis of the brain‘
`or spinal cord. The promi.ne'nt effects produced by many of
`these drugs are arousal andincreased motor function which
`result in subjective feelings of increased "mental aleitncss_,
`decreased fatigue, iri1pro\;ed concentration, increased energy -
`and motivation andan-elevation in mood." Excessive excita-
`tion can lead to corivlilsions, and most, if not all, of these drugs
`produce seizures in a dose-dependent manner.
`Ezrcitability of the CNS reflects an intricate balance between
`H" excitatory and inhibitory activitywithjn the brain.
`‘Stirri-
`ulants of the CNS directly or indirectly enhance excitatory "
`activity or block inhibitory components. The cxcitatory trans- .
`rnitters, glutamate and aspartate, are important neu3:0'transmit-‘
`'_ tcrs at excitatory synapses where their actions are mediated
`through N-methyl-D-asparlzate [NMDA) or non-NMDA {kai-
`nate or All/lPA!quisquaiate) receptors.
`in contrast, gamma:
`aminobutyric acid l:GABA) and glycine areprominent inhibiw '
`toiy-neurotransmitters. The neuromodulator, adcilosine, also
`‘plays an impoitantrole
`CNS excitation in that it can exert a
`depressant action, most lllcely on the‘ basis Of its ability to
`' decrease impulse-generated transmitter release and-to limit
`excitation of postsyriaptic elements by‘ direct hyperpolariz_a'- ;
`tion. Many CNS stimulants produce excitation through their
`, antagonism at GABA, glycine or adenosine receptors whereas
`-. others, the indirect-acthig sympathqmimctics, produce pro-
`. nounccd CNS stimulation by enhancing the actions of endoge-
`-neous catccholamines due to their ability to increase release -
`and/'_01‘ prevent the uptalte of endogenous catecholarnines
`(seeT'able1).
`_
`.-
`.
`-
`'
`.
`.'
`The CNS stimulants are much less imporant therapeutically
`than the CNS depressants; -but they can produce dramatic"
`‘pharmacological effects and some l'requently,are abused.
`For example, CNS stirnulants (eg, methyiphenidate) are among
`the most commonly prescribed drugs‘-for attention deficit
`disorders in children. The amphetamines or their analogs
`are used in narcolepsy, as adjunct therapy in ctttentton deficit
`.' disorders-and as appetite sap-presscmts in obesity, The:
`- mild CNS stimulants, such as caffeine, are used in drug-
`induced ?'“esp:".ratm“y andlo_1' circulatory depression and vas-
`cular headaches,‘ caffeine also is used in anumber ofanalge-
`‘sic combinations. The strong CNS stimulants, such as
`pentylenctetrazol' and picroto:-tin, have no established thera-
`. peutic use since the thc1‘apcutic.dose_is-very close to‘ the
`‘convulsant dose.
`'_
`_
`_
`_
`-
`-
`A number of_ CNS StiIrlul&'1nts.1-pave therapeutically useful
`actions on other parts of the body, and a number of drugs not
`included in this chapter stimulate the CNS when administered
`in toxic doses. For example, caffeine, a" classical central
`nervous system stimulant, hasclinically useful actions on the"
`heart, blood vessels and kidneys. "On the other-hand, atro-
`pine and ephedrine,-drugs with primary actionson thc'p'eriph-
`eral autonomic "nervous system, stimulate the CNS.
`' Only those drugs whichhavc central stimulation as, a pre-
`dominant action are listed -in this section. Those agents -
`whose central stimulant properties are secondary (atropine,
`many sympathomimetic amines, nicotine", lobeline, carbon.
`- dioxide, ‘cyanide, apornorphine and eme_tine),and those whose
`
`-
`
`,
`
`- Stimulation of the CNS can be produced in man and animals
`by a large ‘number of natural and synthetic substances.
`None, however, occupy as prominent aiplace in the environ-
`ment of-man as do the I-ranthine derivatives‘. The most popu-
`lar sources of these substances. are the xanthine beverages,
`which include coffee, tea, cocoa and cola-flavored drinks.
`' ‘Coffee and tea contain caffeine, whereas cocoa contains
`tl'1€lCllI)l‘C|1_;l'li.l'l€.
`The caffeine content of tea leaves (2 to 3%) is
`higher than that of coffee beans (0.7 to 2.0%) but the bever-
`ages as finally prepared contain-about equal amounts of this .
`stimulant.
`_Caffeine is present _in_ amounts of about 100 to
`"150" rngz’18_0 mL of brewed colfee';‘ 60 to'_80 r‘ngf_180 mL of
`-"instant coffee; _-40 to‘ 100 mg!l80 ml. of tea and 17 to 55 ,.
`mg{‘180 mL of cola beverage. There is little doubt that the
`popularity of these beverages depends on their stimulant ac-
`. tion, although most people areunaware of anystimulation. _
`Xanthine derivatives include caifeine, theqhromine, theopl1'-
`ylllne and anumber of related synthetic, derivatives, all of '
`which have similar pharmacological properties that differ
`markedly in the intensity of their actions in various structures.‘
`For example, the stimulant effects of caffeine and theophyl- _
`line on the CNS and on skeletal muscle are much greater than
`those ofthcobromine.
`Ffuzthennore, theophylline surpasses
`caffeine in‘ its diuretic, cardiac and smooth rnqscular. actions.
`Therefore, in the therapeutic application of these drugs for a_
`specific effect, side effects can be lninimized and the desired
`effect intensified by careful selection of the xanthinc cm-
`’ ployed.
`_
`,
`..
`'
`The principal therapeutic application of caffeine is as a CNS
`stimulant. _-'I‘he'1'efore, caffeine and its congeners which pos-
`sess this effect will be discussed in thisfsection. The princi-
`.'- _pa! therapeutic use of theophylline and related compounds is‘
`as a bronchodilator in‘ the mariagernent of
`For this
`reason theophylline derivatives arediscussed in Chapter 56,
`liespiijatory Drugs.
`'
`—
`-. Aniinophyiiine-—'p'age-9_?’1i
`
`_
`
`-
`
`I
`
`-
`
`_
`
`_ Caffeine-
`_
`'_1H-Purine-2',6-dione,3..'(3dihydI'o-l,3,74triIbcthy£l-,Theine: No
`"
`Do: (Bris:o1—Mp-era); 'I'i'1wend (Norch}‘j”Thaysr); VlV3.l_'lfI (Bceckam);
`Dexitac (Republic); Quick Pep (Thompson)
`-
`1,3,'7—'rnme£hy1xa:iihine153-as-2] cj,_.H..,N.og (194._19};m.mny¢mie_ .
`[5743-12'-4](212.22-).
`.
`' For the structural formula, see page 404,-
`'
`-
`_
`'
`Pr-eparati_on—Cafl'ei.ne may be isolated from tea or coffee by boiling
`with water in the presence of lime or magnesium oxide, which serves to
`precipitatcthe tanninsand some of the coloring matter. After filtration,
`the elrudecalfeine that separates is recrystallized from hot wate'r‘_after
`
`-
`
`
`
`"1231
`
`-i-Arneri§je'n'-'lE-X. 105-3,s p.
`1
`Amerigen Ex. 1053, p. 1
`
`

`
`
`CHAPTEH 74 I
`
`1232
`
`Table 1-'~Various Classes of cue" si:miuant.r,"ani;i
`'
`Representative Compounds/’
`
`
`
` Class 1 ' Compound Mechanism
`
`
`
`Xanthines
`
`'
`
`,
`.. Miscellaneous -
`stimulants
`'
`
`— Caffeine.
`Theophylline
`Psychostimulants Amphetamines
`Methylphenidate
`Cocaine
`lrfazindol
`Pemoline
`_ Diethylpropion
`‘Bicuculline
`"Picroto':rin
`-
`Pentyleneterrazol
`-
`'
`Strychnine
`
`Doxapram
`
`' Adenosine antagonist -
`Adenosine antagonist
`- Enhance actions of
`endogenous catecholarnines
`'
`'
`
`‘
`
`'
`
`-
`-
`_
`Competitive GABA antagonist-.
`Non—cornpetiti\'e GABA
`antagonist
`' Non~competiti\'e-GABA
`antagonist
`-
`-
`- Competitive antugoriiat at
`non-NMDA glycine receptor
`Unknown
`_
`'
`
`treatment with decolorizing charcoal. Asoiirce ofthe commercial supply
`is tea dust or sweepings.
`increasing quantities of. caffeine are now ob-
`Itis '
`tained as 2'} by—product in. the manufacture of "deca[l't-injzed coffee."
`also produced by mcthylation of rheobromine (partial synthesis) and by
`total synthesis from u_rea or diroethylurca by.ve.riations of 'l‘iaub_e‘s classic
`process (Her .'33:' 3052. 1900). The essential steps of :1 synthesis of
`theophflline and caffeine from urea are shown below‘.
`'
`
`' Ni-I3
`l
`[',',..—_-Q
`NH2 '
`
`Urea
`
`CH3NH.;i_
`-'-———'e-
`-
`
`._
`
`CHa_N|'-I
`'
`l
`.
`
`'
`
`CH:rNH
`
`_
`_
`Noon-,oooi-i
`-u—-er
`
`1,3-Dirnethylurea
`
`'
`
`,
`
`'
`
`0
`
`.
`no;
`
`'
`'
`mo,
`
`m,c,,°_
`_
`
`or-i—,—--N
`aJ~
`
`o
`
`.
`
`. NH
`
`ill
`_CHa
`
`cusp:
`l
`
`:0
`CH3NH
`
`co
`I
`
`_
`
`cu
`
`Alicmi
`
`0
`our-nrij‘
`44*
`
`0
`
`N
`"CH3,
`
`-
`MI-I
`
`0'
`
`'
`
`0
`
`‘
`
`I
`
`CH3 —-' M
`_ DAN
`.
`I
`CH3
`
`NH,
`an,
`
`'
`
`0
`
`:——--I-
`Home
`I.
`
`.
`CH3-— N
`DAN
`I
`CH3
`
`NH;
`NHCHO
`
`'
`
`:———p
`Alkali
`
`( ll“
`C|-I|a—_.N
`. A ¢GH
`o
`lfl
`N
`CH;
`Tlreophyiline
`
`"'—"—-Hr-ma!m'famn'
`
`Caffeine
`‘
`
`'
`
`'
`
`.
`
`awake and
`lllsea-—Used orally as a mild CNSstimuldrtt to aid in
`to restore mental alertness in- fatigued patients.
`In combination with
`- ergo;arnine'ta.rtrate'it is used to abort vascular lteoalocltes such as mi.
`gmine and cluster headac hes.
`it often is used in combination with analge.
`sics (acetaniinophen. aspirin. etc) for the treat.n1ent_of mild pain,
`since
`its analgesic activity is suspect. such use is controversial.
`It is Used in
`- combination with anthihistamines and other sedative agents to overcome
`the sedative properties of such drugs; however, effective dosage for this
`pu.rp'ose_has n-ot'bc'en established adequately.
`_h. is used parenterally in
`the form of ca'fi‘elne and sodium benzoate for the treatment of l'PSpfl‘flf_d'l'y
`depriessio rt-associated with overdosage of CNS depressant drugs [nan-_-uric _'
`analgesics. alcohol. etc]. Because ofthe questionable benefit of such use
`and its transient action. most authorities believe caffeine and other analep-
`tics should not be used in these conditions and recommend other suppm-i;._
`ive therapy.
`l~‘iually, calleine is used orally either alone or in combination
`with other drugs (analgesics, diuretics, etc] to relieve tension and fluid
`retention associated with menstruation.
`in view of its rn'inimal diuretic
`action. its usefulness in this condition is questionable. ‘
`_
`Caffeine and citrafed caffeine are absorbed well
`following oi-3|
`administration. Absorption by the oral route is more rapidthan that after
`intramuscular injection. Absorption from suppositories following rectal
`admiriiatration is slow and erratic. Following the oral ailnurdstration of
`100 mg bf caffeine (as in cofiee)-. peak plasma levels of about 1.5 to 1.3
`ug/_mL are reached after 50 to 1'5 min._ Following oral administration of
`250 mg to "caffeine--naive" subjects. peak plasma levels of‘ 4.2 to 26
`p.g.’rnL are reached in a mean time of fill min. Therapeutic plasma
`concentrations range -from 6 to 13 ug/mI..; concentrations >20 uglrnl.
`commonly produce adverse reactions. The lethal concentration is > 100
`i-1-E-"mL.
`Itis distributed rapidly throughout all body tissues, readily cross.
`ing the placenta and blood—brajn barrier. Approxj mately 17% of the drug
`Plasma half=lil'e is 3 to 4 hours in adults.-
`is bound to plasma proteins.
`Plasma half-life in neonates born ofwomen given caffeine prior to delivery
`has beertestirnated to be about 80 hr. The drug is metabolized rapidly by
`the liver to 1—rnethyluric acid. l-methylxanthine and 7—methylxanthine,
`About 1 0% is excreted unchanged by the kidneys.
`For many years it was thought that the stlmulaint actions of caffeine were
`due to its inhibition of the enzyme phosphodiesterase in the brain and the
`resulting accumulation and zicrions of cyclic 3',5'-adenosine mon'ophus-
`phate ‘(c-AMP). However, several compounds which are more potent
`than caffeine in inhibiting pbosphodiesterase activity lack CNS stin1u|a.nt-
`actions.
`iilloreover, the concentration of caffeine needed to‘ lhhlbit phos-
`phodie sterase activity is 100 times greater than blood levels achieved after
`caffeine . consumption. Rather. substantial evidence indicates that the
`stimulant actions of caffeine are due to its blockade of adenosine receptors.
`Adenosine exerts prominent. presynaptlc and postsynaptic inhibition of
`neuronal activity Blockade of this inhibitii_:_n by caffeine likely is respon-
`sible for its stimulant ellccts.
`'
`3
`_
`In one double-blind clinical stiidy, oral administration of 250 mg of the
`drug to nine healthyyoung non-coffee drinkers who ha.d'no coffee, tea or
`cola in the previous 3 wk '.-'nr:2'errsed plasma -rerun-activity 57%, plasma
`rro:'epinep}i;rin.e T596 and plasma epiriephr-fine by 20 7%; urinary 'n.o'_r'mela-_
`raeph:rr’ne and meinrtepltrinc were increased 52 and 100%, respectively;
`mean blood p're'ss1ire increased 14310 torr -within 1 l11';.lr.en.rt rate Iirst
`decreased and then increased; and -resp'imtory -rate irtcretised 20%.
`Caffeine stimulates all levels of the CNS.
`In oral doses-of 100 to 200
`mg, it stimulates the cerebral cortex producing a more rapid and clearflow
`. of thought, wal-:efulness or arousal infatigued patients and improved.
`its conical effects are -milder and of shorter '
`psychornotor coordination.
`duration than those of the amphetamines.‘
`In slightly larger doses, caf-
`feine stimulates niedullary vagal, vasomotor and respiratory centers, induc-
`ing bradycardia, vasoconstriction and an-increased respiratory rate.
`The drug exerts multiple elfecis on the heart. , it has apositlve lnotroplc
`effect on the niyocardiurn and a positive chronotropic-effect on the sinu-
`atrial node, causing a transient increase in heart rate, force of contraction, -
`cardiac output "and work of the heart.
`in doses in excess of 250 mg, the
`centrally mediated vagai effects of caffeine may be masked by increased
`sinus rates; tachycardia, extrasystoles or other ventricular arrhythmias
`may result.
`'
`'
`'
`.
`'
`_
`.
`Cafleine, in normally ingested amounts, produces vasoconstriction of
`blood vessels, presumably by blocking adenosinc receptors located in the
`smooth muscle of the vasculature.
`It is thought that the vasoconstriction
`of the cerebral bloodvessels by calfcine contributes to its ability to relieve
`headaches.‘ In the peripheral vac-sculature, caffeine ingestion results in
`increased vascular resistance and a slight increase in blood pressure,
`probably due to the action of cafieine on both the smooth muscle of the
`vessels and 0t1_€i1l._e(:holan1ine release.
`' "
`'
`it
`‘ Other pharmacological effects of caffeine include the following:
`stimulates voluntary skeletal ‘muscle’, increasing the force of muscle con-
`traction and decreasing muscular fatigure; it stimulates parietal cells,
`increasing gastric acid secretion; it induces in mild diuresis by iricreasing _
`renal blood flow and glorherular filtration rate and decreasing proximal
`tubular rcabsorption of sodium and water; and it I-ztimulates glycogenolysis
`and lipolysis, but the increases in blood glucoseand plasma lipidsusualiy
`Amerigen Ex. 1053, p. 2
`Amerigen EX. 1053, p. _2
`
`Description-—White powder or while, glistening needles, usually mat-
`ted; odorless and has. a. bitter taste; pH (1% solution) 6.9; the hydrate is
`cfllorescent in air and loses all its moisture at 80°; when rendered anhy-
`drous by drying, melts between 23 5° and 2:] 15°; pK,, 13.9.
`_
`Soluhility—1 g of anhydrous cafieine dissolves in about 50 ml. water, 6
`ml. water at 80“. 75 mL alcohol-, about 25 ml. alcohol at 60", about 6 ml.
`chloroform or 600 mL ether. Being a weak base, caffeine does not fonn
`stable salts, and even its salts of strong acids, such as the hydrochlorideor
`hyrlrobromide, are hydrolyzed readily by water. The solubility of caffeine
`in water is increased by the presence of organic acids or their alkali salts, .
`eg. benzoates, salicylates, cinnnmates or citrates and this is the reason for
`the use of several such r.='-'-paratiuns.
`'
`
`

`
`
`
`CENTRAL NERVOUS SYSTEM STIMULANTS
`
`.1233
`
`Theophyllina, Ephodrineliydi-oniiioride and Phenobarhit-3‘.‘—-
`page 973.
`.
`'
`'
`.
`.
`"
`
`Thoophylline 0iamlne—see RPS-18. page 868.
`_ Theophylline Sodium 'Ar:e1}ale~_—~see RPS-1?’, page 3T5.
`Theophylline Sodium Glycinatc-—see FIPS-17'. page 874.
`
`, are not significant in normal patients. Repeated use of this substance
`may result in the development of tolerance to its diuretic, cardiovascular
`and central nervoussystem efiects.
`-
`.
`'
`This drug and other xantltines may enhance the cardiac inotropic effects
`- of betmadrenergic stimulating 'agents and decrease the effect of
`benzodiazepines. Because caffeineingestion restiltsin reduced liver blood
`[lot-V’, the metabolism and elimination of drugs which are elirnin '
`'
`primar-
`ily by hepatic metaliolism -may be slowed. The lrlgestior] '
`'
`cause a slight increase in urine levels of variillybnandellc
`' amines and 5'-hydroxyindoleacetic acid.
`Since‘
`lyhnandelic acid o catecholamines may result in a falseep‘
`. of pheo_ch:o_i_no-cytoma or neuroblastoma, caffeine intake shouldbeavoided
`during these tests:
`'
`_
`-
`'_
`.-
`_
`-
`‘Acute toxicity involving caffeine has been reported only rarely.
`Overdosage usually is associated with gastrointestinal pain,
`delirium,
`‘insomnia’, diuresis, dehydration and fever. More serious sy'm'pto,tr,1s in-
`clude cardiac nrrhythrnias and convulsions.
`‘The acute_-letha_l.-'_dose._,oE
`cafl'ei.ne in adults appears to be about 5 to 10. g either intravenously ‘or
`Death has occurred in a child following oral ingestion of 3 g‘.
`_ orally.
`' Prolonged, high intake may produce tolerance, habituation and psycho-'
`logical dependence. Abrupt discontinuation of the stimulant may result
`in headache, irritation, nervousness, a.nx'iei;I,rand dizziness.
`_
`_
`The ingestionof large amounts of combinations conteini.rig_aspi.rin and
`calfeine has been associated with analgesic nephropathy, characterized by
`lsterile pyuria, asymptomatic bactel—fu:ria, pyeionephiitis, papillary necro-
`sis, interstitial fibrosis and nephritis." The role o£ caffeine in the etiology
`of this condition has not been established conclusively. For an iridcpth
`review of -' ‘The I-Iealth Consequences of Caffeine" the interested reader is
`referred to the iiiterestirig article by Sawynolt and Yaksh {Phormacol Rev
`.45: 43. 1992).
`.
`'
`Dose—1lJ0 to 500 mg; usual, 20'!) mg as necessary.
`-Dosage Fornis--Extended-Release Capsules:
`200 and 250 mg,
`Tablets:
`l0D._l5{l and 200 mg.
`
`
`
`Citraled Cafleine
`
`-50g _
`Caffeine. .......
`..............
`.........
`5Dg-
`-
`CitricAcid . .
`.
`.
`.
`.
`‘
`..
`. . . . . . . . ..
`
`l00rrIL
`_ Disti|ledWate'r,hot....'..............
`...............
`Dissolve the citric acid in the hot distilled water, add the calfeine, and
`evaporate the resulting solution to dryness on a water bath. constantly
`stirring towards the end of the operation. Reduce the product to 21 fine
`powder and transfer it to well-closed containers.
`It is, however, usually
`‘prepared by mixing equal proportions of finely powdered anhydrous caf-
`feine and anhydrous citric acid.
`.
`Description-—White, odorless powder; slightly bitter, acid taste: acid
`- reaction.
`'
`Solubility——'l g in about 4 mL warm water, the caffeine gradually
`precipitating on diluting-the solution‘ with an equal volume of water but
`redis-solving on further dilution with suflicienl. water.
`Incompatibilities-—l\leutralization of the citric acid by alkolics or
`alkaline salts will cause precipitation of caffeine ‘if
`in sufficient
`concentration, The alkali salts of organicacids may release either caf-
`feine or the free organicacid.
`’l’n‘gene'Ial it displays the incompatibilities
`ofthe citric acid which it contains.
`Us-:»e%See Cafieiné.
`Doee—100 to 500 mg; 'u.sum'., 300 mg as necessary.
`Dosage Forn1s—'1‘ableI.s:
`tit’) mg.
`-
`
`I
`
`I
`
`.
`
`tiafieine and Sodium E-lenzoale Injection .
`A sterile solution of caffeine and sodium benaoate in water for injection;
`contains an amount of anhydrous calfeine {CgH mN4O-2) equivalent to 45 to ‘
`52%, and an amount of sodium benzoate (C;H5Na0g_] equivalent to 4125 to
`55.5%, of the labeled amounts of caffeine and sodium benzoate.
`Description—pH between 6.5 and 8.5.
`'
`_
`'
`_ l'.lse—Scc Cojfeme, page 1231.
`- Dosc—Po.icnteml.' Elli} mg to 1 g; usual, 500 mg, repeated as neces-
`
`Sagosage Form—lnjection: 250 rug (Caffeine Anhydrous 125 mg and
`Sodium Benzoate 125 mg) per rnL.
`.
`
`DyphylIine~page 972.
`Oxtripl,1yllir_Ie~page 972. '
`.
`.
`Theophylline-—'-page 973.
`' Theophylline Calcium Salicylate-—see RIPS-17, page 375.
`
`_
`
`v
`
`_'
`
`' ._Psychostirr_I__ulants '
`Most of the compounds included under this‘ heading‘ are
`_ indirect-acting sympatlionurnetic drugs and are more potent
`central stimulants than the xanthinc derivatives. These com-
`pounds (amphetamine and several of its analogs, cocaine,
`rnasindol, tnethylphenidate; see Table 1)" do not stimulate '
`"r'nono'arniner'gic receptors directly, but rather increase the
`‘actions-of endogenous catecholamines. This is due to their
`ability to inhibit the uptake of the catecholarnine from the
`synaptic cleft after release or to cause catecholamine release.-
`Becausc of their. propensity to produce euphoria, many _.o£
`these drugs are widely abused and are controlled substarnces.
`‘The approved use for most of these drugs is as anorectic
`agents, although several are used in the treatment of "attention
`deficit disorders (rnethylphenidate, pemolinc, amphetamine)
`or _narcolepsy,(arnphetam_ine). Given the abuse liability and
`dependence potential of many of these compounds, the thera- =
`peutic use ofthcse drugs should be monitored closcbt.
`A number of drugs that stimulate the central nervous system
`are promoted for treatment of hyperactive behavior in children.
`A degree of hyperactivity which is not acceptable, either at
`home or at school, often is accompanied by difficulty in learn-
`ing and sometimes by other neurological signs, such as
`_ "clurnsiI1css.
`" Although-the usefulness of psychostimulant
`drugs in treatment of "hyperactivity" has been controversial,
`Caffeine citrate (1:1) [E9-22-'."|_; a mixture of caffeine and‘ citric acid -
`there is a patient group with severe, persistent hyperactivity
`containing 50% CaH.,,ll‘,0g (anhydrous cafieine) and 50% C5HflO7 (anhy-
`drous citric ncid)_
`.
`_
`.
`.
`'
`and a short attention span that is likely to benefit from treat-
`Prepa.ratlou—'I'he.l‘onnula ofUS_‘l-" {X was
`ment with these agents. The psychostimulants most _fre—
`,queI_1tly used. for this purpose include méthylpttenidatezand
`pe'nw££ne.'
`'
`'
`'
`,
`_
`Amphetamine and methamplietarnine are two of the most
`potent sympathomimctic,dr_ugs with regard to CNS stirnulatidn.
`They can improve psychomotor perl'orrn'ance and enhance
`wakefulness, although" it is questionable whether concentra-
`tion in complex leornillg situations or judgemerlt is‘ 'u:np1'oved'.
`The effects of these amphetamines are thoughtto be mediated
`through cortical stimulation and possibly through stimulation
`-of the reticular activating system. The (S), or [+)‘, isomer of
`arnphetamine is three to four times more potent than‘_thé (B),
`or (—), isomer in elicitation of CNS responses (only I:hc_aI
`isomer of lnctharnphetamine is available clinically]. The
`alerting effect of the amphetamines, their anorectic effect and '
`some component of their locomotor-stimulating actionare
`likely mediated by norepinephrine release. Some aspects of I-.
`locomotor activity, as well as euphoria, are due to dopamine
`. release within the basal ganglia and the 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 catccholainine synthesis
`' _prevcnt.s the beliavioralactivation produced by the drugs.
`In
`humans, acute" toxicity produces restlessness, dizziness,
`tremor", hyperactive reflexes, talkative-ness, irritability, weak-'
`ness, insomnia and fever.
`Larger doses can produce confu- .
`sion, increased libido, anxiety, panic "states, hallucinations
`and psychotic behavior. Some of these effects may be due to
`the release of 5-hY{lTOKyl.l“yp£all1'l.t'lB_{5-HT) from serotonergic
`neurons.
`In addition, there-may be pronounced cardiovascu-
`lar and gastrointestinal elfects. Excessive toxicity results in
`convulsions, coma and cerebral hemor_rhages.. See Chapter
`.57 for more discussion on the amphetamines.
`,
`Cocaine is also a potent sympathornimetic CNS stimulant
`with actions very similar to those of the amphetamines but
`with a much ‘shorter duration of action. _' Cocaine has local
`anesthetic actions; however, its use for this purpw is limited,
`having. been replaced by synthetic local anE:5tl'IetiC5.'wl1itfh
`have little CNS stimulation. The importance of cocainelics
`Amerigen Ex. 1053, p. 3
`Amerigen Ex. 1053, _p._ 3
`
`

`
`unstable patients, those with a history of drug dependency and those
`known to alter drug dosage on their own iriitiative.
`'
`'
`-
`Dose—.0ro._l, 10 to 60 mg eddy; -usual, .10 mg 2 or 3_I;i'rnes a day.
`Sustained—release tablets have an 8-lu‘ duration of action; these may he
`used when the dose of slow-release (SR) tablets correspond to the 3-111-
`_dose of the drug.
`.Sympto'rns of overdose may include ‘ironuting, agita-_
`tion, tremors, liyperretlexia, muscle twitching, convulsions [may be iol- _
`' Jowcd by coma), euphoria, -confiision, hallucinations,‘ delirium, swearing,
`hyperpy1rexia.'tachyca:dia, palpitations, cardlactirrhytliniias, hyper1.en-
`sjon, rrrydria.-sis and dryness ofthe mucous me:nbrar:o_s.
`_
`Dosage Forms—~Tablets:
`5, 10 and 20 "mg. Sustained—Release
`Tablets: 30 mg.
`'
`_
`.
`:
`'
`
`..
`
`Plemoline
`_ 4(5H)1ox'a:m-lone, 2-arnino—5-plienylq Cylert (Ashanti
`
`._
`
`,'
`
`_
`
`_
`'{21is2—34~3] CgHgNgO2 [1-?s.1".f),
`Prepuration_—Ethyl rnandeiate C5H5CH(OH)CDOC2I-I5, is reactedwith
`guanidine, HN=C[NHg)2. in boiling alcohol solution, US Pat 2,892,?53.
`- Description—Wl1lte, ‘crystalline powder; odorless and tasteless; melts"
`at about 256°vvith decomposition.
`.
`_ "Solubility-—PracticaIiy insoluble in Water, chl'o‘roform,'dilutel l{C| .or
`ether; slightly soluble in _alcoh_ol.or propylene glycol.
`_
`_
`-
`Uses-—A CNSstimub1otivlucl1 is structurally dissimilar to the amphet-
`-' amines and mctirylphenirlate. Although laboratory. studies indicate that
`pemoline may act tlupugli doparninergic mechanisms. the mechanism and
`Indicated as adjunctive therapy in
`'- ,_site of action in rn_an are not lrnorvn.
`I
`_
`" ‘cilildrcn wjlth ottantitmxlcficit disorder. _' It also has been used in the
`treatment of fatigue, mental depression, chronic schizophrenia and as :1
`roilcl stiinulant in geriatric patients; however. clirdca] benefits from such
`use are |I]'ll.fll.l."l13l.
`' It should not be used for the prevention or treatment of
`normal fatigue. Peak serum levels of the drug are reached}! to _4 hi’ aiter
`, ingestionof asingle oral dose: the serum half-Life is approximately 12 hr,
`and a steady state level is reached in 3‘to 3 days of multiple dosage.
`About 5.0% of the drug is bound to serum proteins. Approfimatcly 75%."
`I of an oral dose is excreted in the urine vi-ithin 24 hr, about 43% unchanged
`a.nd'22% us pernoline conjugates.
`.
`_
`Insomnia, usually. t'ra.r'.sient, is the principal adverseeffect. Anorexia
`_with weight loss may occur during-_carly weeks of therapy; weight gain
`usually resumes within 3 to 8 mo. Storhachache, skin rashes, increased
`ii'ritability,inild depression, nausea, dizziness-, headache, drowsiness and I
`hailricinations have been reported._ Other adverse effects reported in--'
`clude seizures; dyslrinetic rnovemc nts of the tongue, lips, face and extremi-
`ties; abnorrnai aculogyric function (nystagmus and ocuiogrric crises) and
`- syniptoms o_f_Toim:tte’s -.Sy'l'ld'.l"O??'l'-1?.
`_
`I
`.
`_
`_
`'
`It is contraindicateci in patients with liypersensitivity or idiosyncfasy to r
`the drug.
`It is not recornmended fO1'_Cl1iidl‘€l‘r
`less than 6 yr of ago since
`safety and efficacy in this age group have not been established. Sufficient
`data on safety and cfiicacy oflong-tr: rm pse in children are notyet available.
`Safety for use during pregnancy and lactatiori has not been established
`Dose———O'rct’., im'l.io.l.. 3-7.5 rug giver: as a single dose each mowing; may
`" be increased by 13.75 -mg a day at wccirly intervals until the desired
`clinical response is obtained, The élliective dose i‘-'Jr'rnost ‘patients is
`_- 56.25 to [T5 rngla day; the nuzxinmm recommended dose is 112.5 mg a '
`day. Significant bcncli]. from the drug may not be evident until the 3rd or
`4th wk-of treatment. -
`'
`"
`.
`__
`'
`'
`,
`'
`18.".-‘.5, 37.5 and '?51ng. CliewableTablets:
`' Dosag-eForrns—_'I'ablets:
`37.5 mgg
`'
`'
`-
`'
`'
`Phendimelrazine Tarirate---page. 995.
`'- Phenrnelrazine‘llydrochloridefipage-986. I
`Phen_tennin_e——-page 996.
`'
`._
`
`E234
`
`_Cl:lAF"l'ER r4_
`
`'1
`
`'
`
`'
`
`currently one of the most widely
`in its abuse. pol'.e11ti4'1l;' it
`_ abused drugs in the US. See also Chapters 47 and 53.
`Amphetamine Sulfate——page_98B.
`' Benzpheiamine Hy‘drochloride—page 98?.
`.
`--Coc'ain%page1i51._ ,
`'
`'
`-
`T Deanol Melaminobenzoatwsee Fl_F'S—1B. page 1136. -
`. Dexlroampheiamine Phosphaier-see-RPS-16_, paigetlzfl.
`Dextroarnphelamine Sulfate-—-page 987.
`. _l_Jlelhylpropion—__-page 93?.
`llllazindoI—page 992._
`
`l.llsthar_nphelamine—page 994.
`
`'
`
`' Meihylphenidate Hydrochloride
`
`2—Pipei'idineacetic acid, {R *, R *)-(i)-'cr—pheny'l—, methyl ester,
`"
`l1y_d1'ochlor_ide, Ritalin (Cibo)
`
`'
`
`flue”:
`f”
`HM
`\_
`
`_
`
`.
`
`-_ HCl
`-.
`
`,
`
`_
`
`_
`
`_
`
`_
`
`r,
`'-
`
`.
`
`_
`
`._
`
`.
`
`'
`
`"[293-59-9]c;.,H,,.1ro2,Iro:.(2s9.r7).
`Prep'arotion—2-Chloropyridlne is condensed with phenylacetonitrile _
`and the’resuliing o-pl1enyl=2-pyridincacctonitrile.is hydrated to its corre-
`' sponding,amide. The pyridine ring then is Iwdrogenated cutalytically and
`the amide converted to its corresponding carboniylrc acid. Estenficatlon _
`with methanol. withthe aid of Hill, yields the final product.
`' Descri'ption—-—Wl1.ite, odorless, fine, crystalline powder; melts about-
`75‘‘; solutions are acid to li_t;rnus,'pK, 3.9.
`.
`Solubi1It;y——Freely soluble in water or methanol; soluble i.n.alcoho'_l;
`' slightly soluble in 'cliloroforn1'or acetone.
`Uses—A mild CNS stimulant with a potency intermediate to celfeinc
`,and amphetamine. ' Its pharmacological properties are essentially the
`some as‘those of t]1e'ampheI:amines.
`it also shares the abuse potential of
`the amphetamines.
`It is ra‘i”ec£iiae_as adjunctivetherapyto other remedial
`measures (psychological, educational and social) in the management -of
`attention deficit _cliso'r_ders. Double’ blind studies with placebo control
`demonstrate that methylphenid_a1e'can improve behavior, concentration
`‘and lcarn.ing_ ability in 70 to 30% of children with this disorder. Dhlg
`treatment is not lndi cated for all children with thisdisorder; stimulant-3 are
`n'otin_tended in the child who exhibits symptoms-secondary to environmen-
`tal factors or primary psychiatric disorders. Consequently, these should
`. be ruled out and ava.ilable.psychological, educational and socia_l_1'esources
`should be used before drug tlierapy is instituted.
`It also is effociirie in _
`' -1_ru_:t1_'cotepsy_and possibly effective in mild clepressimi, as well as opo-
`' -thotic or itrithdroum senile behavior.
`_
`.
`_
`'_It appears to be absorbed well from-the gastrointestinal tract. Peak-
`bloocl levels are reached in l to 3 hrancl the plasma half~li[e ranges from 1
`to 3‘hr.
`_Tl1e pharmacological eliects persist Iroin 4 to 6' hr. Ap-
`proximately 80'lt~ of an oral dose is metabolized to ritaiinic acid and
`"excreted inthe urine. The mechanism of action has not been de'r.en:1'Ined._ _
`.11; is thought to act on the cerebral cortex and" subcortical strucLru'-3:3",
`inciuiling the thalainus; stimulation by this drug causes an hicrease in _
`motor activity, mental alertness, diminished sense of t‘atiguc..briglitoi"
`spirits and mild euphoria.
`It also produces an ano_re:o'gcr1ic effect.
`_
`The drug is contraindicated in patients with anxiety, tensronand agron-
`tion or those known to be sensitive to the drug. The safe use lIi.1.‘.i\1l|.'il.'-HI‘!
`- under 6 yr of age has not been established.
`it also is coritraindicated in
`patients with a prior history of epilepsy or those with EEG £1lJ11C‘i'l'I1é_llll1lt3lI'l
`absence of sejaures and in patients with glaucoma, motor tics or 'Jl'ii’.l1 a I
`family history or diagnosis of Tourette ‘s syndmme:
`.lt inuydecrease the
`'hypotensive.effect of guanethidlne.
`It should be used with cautionln
`patients on pressor agents or MAO inhibitors. _l-Iuman phannacologicul
`' studies inizlicate the drug rnay‘inh.iblt metabolism of coumarin an1.icoagu- '
`'la.nl3, antlconvulsants and tricyclic antidepressants. Dosage of these
`agents may require downward acliustrnent when given concomitantly with
`this drug.
`'
`_
`'
`Adverse reactions include nervousness, insomnia, hypersensitivity reac-
`tions (incliiding various skin manifestations), anorexia, nausea, dizziness?
`.p_alpi_tations, headache, dyskinesis, blood pressure and pulse clianges,
`tachycardia, angina. cardiac arrhythmias, abdominal pain and weight loss.
`Toxic psychoses, leokopcnia, ‘anemia and a few cases olf scalp hair loss
`have been reported.
`‘Tolerance, psychic dependence and abnormal behav-
`ior hnve been reported in patients who have abused this drug.
`Consequently. itslhould be adininistercd cautiously, ifa