CB
`XP008031884
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`HUMAN PSYCHOPHARMACOLOGY, VOL. 12, 527-546 (1997)
`
`REVIEW
`
`Pharmacology of Methylphenidate, Amphetamine
`Enantiomers and Pemoline in Attention-Deficit
`Hyperactiv~ty Disorder
`KENNERLY S. PATRICK 1 and JOHNS, MARKOWITZ*2
`1 Depal'tment of Pharmaceutical Sclimces, Medical Un/1•ersity of South Ca1'0/i11a, 17 J Ashley Avenue, Cltar/e.~tmt,
`SC 29425, USA
`.
`'
`2 Dt?partmfmt of Phal'macy PracticC!, Institute ·of Psychiatry, Medical Ulzivel'slly of Sau/11 Carolina, !71 Ashley A1•emte,
`·
`Char/esto/1, SC 29425, USA
`
`Rucemic methylphenidate l'emnins the drug of choice for attention-deficit hyperactivity disorder (ADH:b).
`Melhylphenidate appears to produce psychostimulntion by inhibiting the presynaptic uptake of impulse-released
`dopamine. The abso]ute bioavailability of methylphenidate in humans is quite low and variable: mean 23 per cent for
`the.thernpeutic (+):-isomer llnd 5 pel' cent for the (-)-isomer. The primary site ofpresystemic metabolism may be the
`gut and/or intestina] wall. Brain concentrations of methylphenidate avemge eight times thnt of blood. A T mnJI of
`1·5-2·5 h, a CnmK of 6-15 ng/ml and a T1p. of 2-3·5 h are typical. The area under the plasma concentratiou-tune
`curves for immediate-release versus sustained-release formulations at-e nearly identical, but the relative effic11cy is·
`\Jntesolved. Dextroamphetamine has generally been found to compare favourably with methylphenidate in ADHD;
`it acts tbl'Ough release of newly synthesized dopamine. Levoamphetamine is present ns a minor component Jn u
`combination product {AdderaWlO), but the rationale for inclusion of the levo isomer remains unclear. Pemoline
`uppears to both release and block the uptake of dopamine. Though rarely exhibiting sympathomimetic slde·effects,
`potential hepatotoxicity relegates pemoline to a second-line status. © 1997 John Wiley & Sons, Ltd,
`
`Hum. Psychopharmncol. Clin. Exp. 12:· 527.,..546, 1997.
`No. of Figures: 2. No. of Tables: 4. No, of References: 174.
`
`KEY woRos- methylphenidate; dextroamphetamine; levoamphelamine; pe1noline; attention-deficit hyperactivity
`disorder; dopamine; pharmacokinetics; phnrmocodynamics; enantiomers; AdderalJ®
`.
`.
`
`INTRODUCTION
`The present review focuses on the psychostimulants
`used to treat attention-deficit hyperactivity disordeJ.'
`(ADHD);
`their pharmacodynamics,· pharmaco~
`kinetics, and clinical utilization. ADHD as defined
`by the Diagnostic and Statistical Manual of Menial
`Disorders (DSM-IV, American Psychiatric Associ~
`ation, 1994), or hyperkinetic disorder as defined
`by the International Statfsticaf Classification of
`Diseases and Related Health Problems (ICD-10,
`World Health Organization, 1992), is a complex.
`heterogeneous and pet·vasive psychiatric illness.
`
`'Correspondence to: J, S. Markowitz, Depnrtmellt of Pharmacy
`Practice, Institute of Psychiatry, Medlen! University of South
`Cnro11na, 171 Ashley Avenue, Chnl'l"ston, SC 29425, USA,
`
`CCC 0885-6222/97/060527-20$17·50
`© 1997 John Wiley & Sons,, Ltd.
`
`Symptoms frequently 1nclude varying degrees of
`inattention, hyperactivity, and impulsivity. The
`ultimate manifestations of ADHD can range from
`mild to severe decrements in academic, social, and
`occupational performance. This disorder occurs in
`approximately 3-5 per cent of .school~aged chil"
`dren (Szatmari et a/., 1989), is diagnosed 4-9· times
`more frequently in boys than in girls~ and presents
`as the most common mental disorder in childhood
`(Sandberg, 1996). Indeed, ADHD has been re"
`ported to account for up to 50 per cent of the child
`psychiatric population seen in .the clinic (Cantwell,
`1996). .
`.
`.
`The biological· basis of ADHD remains elusive.
`A genetic predisposition is frequently in evidence
`(Castellanos and Rapoport, 1992) and in some
`Received 3 Mar<:h /997
`Accepted 1.2 May 1997
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`A1'TENTION·DEFICIT HYI1ERACTfV11'Y DISORDER
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`of numerous media reports regarding met11yl(cid:173)
`phenidate recreational abuse.
`
`Chemistl'y
`The drug is formulated as Lhe freely soluble
`hydrochloride salt. The basicity of methyl(cid:173)
`phenidate, pKa 8·5 (Maxwell et al., 1970) or 8·8
`(Siegal et al., 1959), is more than one pK unit lowe!"
`than amphetamine. Thus, at physiologic pH
`approximately: 3 per cent is calculated to be found
`as the lipid· diffusible free base versus > 1 per cent
`for amphetamine. This may have implications for
`the rate and extent of tissue accumulation (Patrick
`et a/., 1984). Though the presence of the methyl
`ester
`is essential
`for
`the pharmacodynamic
`actions (Patl'ick eta/., 1987a), this functional group
`renders the drug subject to hydrolytic degrada(cid:173)
`tion in biological samples, with implications for
`pharmacokinetic sample collection/storage proto(cid:173)
`cols. At pH 7·4 and 37°C methylphenidate hydro(cid:173)
`lyses with a T 112 of approxiniately 9 h; in plasma at
`room temperature the T112 is 43 b (Wargin eta/.,
`1983). The non-enzymatic mechanism of hydrolysis
`primarily involves base cutalysis as is consistent
`with an acid pH of 2·86 offering the drug the
`greatest aqueous stability (Siegal et al., 1959).
`All current methylphenidate products contain
`the drug in the racemic form, a 50: 50 mixture of the
`ihreo-R,R( + )- and threo-S,S(- )-isomers. The pre(cid:173)
`sence of two chiral centl·es in the structure of
`methylphenidate allows for four possible stereo(cid:173)
`isomers, and in fact,· an early methylphenidate
`product contained all four which are invariably
`generated during industrial synthesis. However;
`Ciba Pharmaceutical patented a process to isomer(cid:173)
`ize the therapeutically inactive but sympathomi(cid:173)
`metic (Szporny and Gorog, 1961) erythro-SR- and
`erythro-RS-isomers into the desired threo config(cid:173)
`uration (Rometsch, 1958), thereby improving the
`therapeutic index of the product by reducing .the
`cardiovascular toxicity associated with these ery(cid:173)
`thro isomers. Whether a further improvement in the
`margin of safety would result from the resolution of
`the remaining two threo-( + )- and thteo-(- )-iso(cid:173)
`mers, in order to allow administration of only one
`of the two l'emains equivocal.
`The threo~RR( +).:stereoisomer appears to be
`almost exclusively responsible for the catecho(cid:173)
`(Patrick et al.,
`laminergic
`1987a)fbeneficial
`(Srinivas et al., 1992) effects of racemic methyl(cid:173)
`phenidate. Accordingly, the threo~SS(-)-isomer
`might be viewed as merely 'isomeric ballast', very
`
`ex.pensive to remove by conventional technology
`but benign; or possibly the (-)-isomer poses
`some therapeutic liability. In any case, the pressor
`(Patrick et al., I987a) and an01'eC~ic (Eckerman
`· et a!., 1991)
`side-effects of methylphenidate
`appear to be .limited, unfortunately, to the them~
`peutic (+)-isomer.
`
`Pharmacodynamic~·
`The molecular . structure of methylphenidate
`contains a phenethylmnine ·moiety which super(cid:173)
`imposes on its putative neural substrates dopamine
`and norepinephrine (Figure 1), providing for the
`essential receptor interactions.
`The behavioural manifestations of ADHD
`to involve an interactive
`have been
`theorized
`imbalance between dopaminergic~ noradreuergic
`and serotonergic neurotransmitter systems (Pliszka
`et al., 1996). However, a fundamental dopamin~
`ergic dysfunction appears to have special signifi·
`cance. This is evidenced by a tomography study of
`ADHD patients where hypoperfusion of the
`dopamine terminal-rich striatum has been imaged
`(Lou et al., 1989). A high regional uptake. of
`11 C-labelled methylphenidate occurs
`in
`this
`structl.U;e (Ding et a/., 1994), whereupon the drug
`increases striatal blood perfusion .(Lml eJ al., 1989).
`The mechanism by which methylphenidate
`produces psychostimulant eJrects appears
`to
`the
`depend prominently upon
`facilitation of
`catecholaminergic neurotransmission, Recognizing
`that methylphenidate binds with high affinity to
`the dopamine
`tl·ansporter or uptake channel
`(Schweri et a/., 1985; Gatley et a! .• 1996), ·it has
`been advanced that this bindi1,1g blocks the synaptic
`·clearance of impulse-released dopamine, leading
`to prolonged postsynaptic neurochemical media(cid:173)
`tion. In a baboon study, methylphenidate has
`been shown to accumulate in the striatum and bind
`to the dopamine transporter (Ding et at.~ 1994).
`Further, this binding occurs enantioselectively,
`favouring the therapeutic (+)-isomer (Aoyama
`et al., I994b). Microdialysis of striatal extracellular
`fluid in rats has demonstrated a methylphenidate(cid:173)
`induced elevation of dopamine, which again occurs
`enantioselectively (Aoyama et al., 1996). Synapto(cid:173)
`somal studies
`indicate
`that methylphenidate
`inhibits dopamine uptake more potently
`than
`norepinephrine uptake, and much more so than
`serotonin uptake (Gatley et al., 1996).
`Cocaine may be viewed as a prototypic dopa(cid:173)
`.mine uptake inhibitor (Sonders et al., 1997). It
`
`© 1997 John Wiley & Sons, Ltd.
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`K. S. PATRICK AND J. S. MARKOWITZ
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`competes with methylphenidate for accumulation
`in the striatum (Volkow et a/., 1995) and both
`drugs elevate extt·acellular dopamine concen(cid:173)
`trations (Gatley er al., 1996). X-ray crystallo(cid:173)
`graphic structures of methylphenidate and cocaine
`(Froimowitz et a/., l995) support the existence of a
`. phannacophore common to the structures of both
`drugs, i.e., spatially analogous methyl ester, amine
`and phenyl groups; features all considered essential
`for dopamine transporter inhibition by methyl(cid:173)
`phenidate (Patrick eta/., 1987a) Ol' cocaine (Carroll
`et a/., 1992).
`A dopaminergic mechanism of action
`for
`methylphenidate based on dopamine synaptic
`uptake inhibition, rather than dopamine release
`from presynaptic ~tores, is supported by experi(cid:173)
`ments using differential depletion of stored
`(vesicular) dopamine versus the newly synthesized
`cytoplasmic pool (Braestl'up, 1977): reserpine is
`believed to reduce vesicular dopamine levels by ·
`disrupting vesicular membranes. Further, reserpine
`pretreatment attenuates. the response to a methyl";
`to
`phenidate challenge, but not significantly
`dextroamphetamine (a putative releasing agent).
`In that the vesicular dopamine pool is released in
`to a nerve impulse, it follows
`response
`that
`reduction of vesicular dopamine should diminish
`an agonist response dependent upon tho availa(cid:173)
`bility of ·impulse· released extraneuronal dopamine
`i.e, methylphenidate.
`for uptake
`inhibition,
`Conversely, depletion of the newly synthesized
`cytoplasmic pool of dopamine by tyrosine hydro~
`xylase (the rate-limiting anabolic enzyme) inhib(cid:173)
`ition using a-methyltyrosine primarily reduces the
`response to a dopamine~releasing type agent such
`as dextroamphetamine, but not by methylpheni(cid:173)
`date. (Releasing agents are believed to act on the
`cytoplasmic dopamine pool rathe1· than on the
`'protected' vesicular stores.)
`·
`Results using synaptosomal preparations and
`[3HJ-dopamine are also consistent with this dis(cid:173)
`tinction between the two indirect mechanisms of
`action for methylphenidate versus dextroampheta(cid:173)
`mine (Ross, 1977;· Ross·, 1979; Patrick et al., 1987a).
`Additional
`lines of experimental evidence
`support the fundamental importance of dopa(cid:173)
`minergic agonism in eliciting the response to
`methylphenidate. These include correlation of
`cerebrospinal fluid levels of the dopamine catabo(cid:173)
`lite homovanillic acid with therapeutic response to
`methylphenidate (Castel1anos et a!., 1996), select(cid:173)
`ive chemical lesioning studies (Breese et a/.,
`1976). antagonism of methylphenidate induced
`
`behaviours by antipsychotics (Koek and Colpaert,
`1993; Levy and Hobbes, 1996), and differential
`effects of selective monoamine uptake inhibitol's
`(Scheel-Kruger, 1972).
`
`P ltarmacok lne 1 ics .
`After an oral dose of methylphenidate, very little
`acid-catalysed hydrolysis of the methyl ester
`is likely to occur in the stomach in view of the
`relative acid stability of the drug (Sjegal et a/.,
`19 59). In test ina! absorption of [ 14C]-methylpheni(cid:173)
`date (carbonyl labelled) is nearly complete as
`indicated by neat· total recovery of radioactivity in
`the urine (Fu.ntj et al., 1974). However, the
`absolute bioavailability (F} in humans is quite
`low and variable. In five children, F was found to
`range from 11-53 per cent, with a mean of 28 per
`cent in the fasted state, and 31 per cent when
`(Chan et a/., 1983).
`dosing with breakfast
`Gualtieri et al. (1982) also found little influence
`of food on the relative bioavailability in children.
`This extensive presystemic metabolism of methyl(cid:173)
`phenidate occurs enantioselectively, providing a
`mean F of 23 per cent for (+)·methylphenidate
`and only 5 per cent for the (-)-isomer (Srinivas
`et a/., 1993). Surprisingly, in dog (- )-methylphe(cid:173)
`nidate exhibits greater bioavailability than its
`antipode (Srinivas et a/., 1991 ), pointing to the
`limitation of using ~nimal models for clinical
`extrapolation. A low F for methylphenidate has
`in rat (19 per cent) and
`also been reported
`monkey (22 per cent) (Wargin et at., 1983}.
`Bioavailability studies in rats dosed with methyl(cid:173)
`phenidate orally or via the portal vein indicate
`that the primary" site of presystemic metabolism is
`the gut and/or intestinal wall, not the. liver or
`lungs (Aoyama et at., I 990c).
`.
`At moderate doses, methylphenidate has gener(cid:173)
`ally been reported to provide linear pharmaco~
`kinetics (Patrick et al., l987b). But at robust doses
`in humans (Aoyama et al., 1993) or rat (Aoyama
`et al., 1990b} presystemic metabolism may become
`saturated, allowing for increased bloavnilability.
`Plasma protein binding is approximately 15 per
`cent (Hungund et a/., 1979). Upon reaching the
`general circulation (of the rat), methy1phenidate
`rapidly accumulates in highly perfused tissues,
`·kidney > lung > bmin > heal'~ >
`favouring
`the
`liver. Brain concentrations of methylphenidate
`average eight times that of serum over time and
`attain this relationship within 1 min after lntru(cid:173)
`venous administration (Patrick ee al., 1984).
`
`© 1997 John Wiley & Sons, Ltd.
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`ATTiiNTION·DEFICIT l1YPERACTIVITY DISORDER
`
`531
`
`XP008031884
`
`'Dose, route
`
`Population
`
`Hungund et al. (1979)
`Chnn et a/. ( 1980)
`Shaywitz c/ a/. (1982)
`Chan et a!. (1983)
`· Wnrgin er a/. ( 1983)
`
`Bh·maher et af. ( 1989)
`Patrick et a/. ( 1989)
`
`Jarvi ef ul. (1990)
`
`Table I. Summary of non-enantiospecific parameters (mean) of methylphenidate*
`Number of
`References
`subjects
`4
`10-20 mg
`Child
`6
`10-20 mg. i.v.
`Child
`0·34-0·65 mg/kg
`12-14
`Child
`1·9-2·5
`5
`0·25·-0·65 mgjkg
`1·0
`Child
`Child
`0·3 mg/kg
`5
`1·5
`0·3 mg/ks
`Adult
`10
`2·1
`0·15 mgfkg
`Adult
`5
`2·2
`20 mg, SR
`3·36
`Child
`9
`Adult
`5·33
`10 mg, IR, b.i.d.
`1B
`Adult
`20 mg, SR; Ritalin®
`18
`3·34
`20 mg, SR; generic
`3·25
`1B
`Adult
`20 mg, IR; Ritalin®
`24 X 2
`Adult
`2·1
`Adult·
`20 mg, IR; generic
`24 X 2
`1·6
`·Abbrevinti~lls: T mu~· time of peak concentration; CIIWI' peak concentration: Tl/2' hulf-life; IR, immediat.e-rolease; SR, sustained·
`release.
`.
`·
`·
`.
`
`T112
`(h)
`2·56
`2·02
`2·53
`2·14
`2·43
`2·14
`2·05
`4·12
`
`TIULIX (h)
`
`c~ox
`(ng rnl)
`
`11·2-20·2
`34·7
`10·8
`7·8
`3·5
`8·54
`6·4
`4·8
`.4·6
`
`Prior to the development of enantiospecific
`analytical methodology for plasma methylpheni(cid:173)
`date determinations, concenti·ations necessarily
`were reported as pooled values (Patrick et a!.,
`W85), i.e., the smn of both isomers. Pharmaco(cid:173)
`kinetic parameters from non·ennntiospecific deter(cid:173)
`minations are summarized· in Table 1, Cbiral
`del'ivatization of methylphenidate samples using
`N-acylated S-proline (Lim · et al., 1986; Patrick
`et a/., 1986) generates gas chromatographically
`res.olvable diastereomers which permits separate
`quantitation of the active and inactive methyl(cid:173)
`phenidate isomers. Results from ·application of
`enantiospecific methodology, or where or.ily one
`enantiomer has been administered as an experi(cid:173)
`mental 'new chemical entity', are summarized in
`Table 2. Generalizing fl'om the parameters listed in
`these two
`tables, typioa1 therapeutic doses of
`meth¥lphenidate provide a T mix o_f 1·5-2·5 h,
`reachmg a Cmnx of 6-15 ngfm , w1th a T1t2 of
`2-3·5 h. The mean Cmox and T, nx values from the
`Jarvi et al. study .(1990) fell weli within this range
`(unpublished resuJts,.see Patrick and Jarvi (1990)
`for a representative concentration-time profile),
`The Jarvi results are significant in that the study
`· represents the largest methylphenidate pharmnco(cid:173)
`kinetic investigation of its kind. In that study, tile
`bioavailability of the branded immediate-release
`(IR) formulation was co:n1pared to that of the
`generic product. Though a shorter Tn1o was found
`for the generic formulation ('rable 1), tbe products
`
`met the FDA•s criteria for bioequivalence. How(cid:173)
`ever, anecdotal reports of methylphenidate bio·
`equivalence problems do exist (Weinberg, 1995).
`It is noted that the Srinivas findings (Table 2)
`consistently indicate a longer T 112 for methylphe(cid:173)
`nidate than most others have reported.
`The considerably greater bioavailability of
`(+)-methylphenidate than (-)~methylphenidate is
`reflected in the several-fold higher concentration of
`·the (+)-isomer in the circulation over time. The
`(+)-methylphenidate isomer appears to influence
`the pharmacokinetics of the (-)-isomers. but not
`conversely. No metabolic interconversion between
`(+)-methylphenidate and
`(-)-methylphenidate
`was observed ·when the sepamte isomers were
`administered to ADHD children (Srinivas et aJ.,
`1992). However, unlike the well-documented meta(cid:173)
`bolic isomerization of ibuprofen (Tracy et a/,,
`1993), a drug containing a single chiral centre,
`interconversion of ( + )· and (- )-threo-methyl(cid:173)
`phenidate would require the unprecedented inver(cid:173)
`sion of both stereocentres. The remote possibility
`.of me.thylphenidate metabolic epimed:z;ation,
`i.e., inversion of only one stereocentre. to yield
`erythro configurationst still exists. -
`·
`Most of a dose of methylphenidate can be
`accounted for in urine a{the deesterlfied product
`ritalinic acid (Redalieu et al., 1982; Aoyama et al.,
`1990a), This polar metabolite attains ·blood con(cid:173)
`centrations 30-60 times that of methylphenidate
`(Wargin et al., 1983; Aoyama et at., 1990a), but
`
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`has been associated with less insomnia than with
`dextroamphetamine or pemoline (Pelham et a/.,
`1990).)
`time-response analysis (Swanson
`Based on
`et al., 1978), the first 2-.3 h after JR methylpheni(cid:173)
`date administration corresponds to the greatest
`improvement
`in cognitive performance: This
`period also corresponds to the absorption phase
`for IR methyJphenidate, leading to the hypothesis
`that the therapeutic· response to methylphenidate is
`associated more with the rate of rise jn the blood
`drug concentration than with the extent of drug
`absorption, or with the ultimate concentl'ation
`attained. This absorption phase-response relation(cid:173)
`ship for methylphenidate lias been termed the
`'ramp' (Greenhill, 1992) or 'gradient' effect. Taking
`this supposition further, the steepet· absorption
`curve associated with IR methylphenidate. relative
`the SR form may constitute a basis for
`to
`differential efficacies.
`
`Adver.se effects
`The most frequently reported side-effects with
`methylphenidate at·e those shared wj th other
`psychostimulants: anorexia, insomnia, weight loss,
`abdominal pain, dizziness, tachycardia and head(cid:173)
`ache (Barkley, 1977; Barkley et al., 1990; Go}inko,
`1984; Murray, 1987; Ahmann et a!., 1993). SR
`methylphenidate may have a greater effect on lunch
`appetite than b.i.d. methylphenidate (Pelham et al.,
`1990; Ahmann et al., 1993); especially since at
`lunchtime with b.i.d. dosing blood levels will have
`declined relative to SR (Figure 2).
`High methylphenidate doses and high drug
`serum concentrations have both correlated with
`adverse effects (Gualtieri et a!., 1984). Howevel',
`side~efl'ects frequently resolve after several weeks of
`treatment (or with dose adjustment) (Murray,
`1987).
`Though stimulant-induced psychoses are rarely
`seen in patients receiving therapeutic doses of
`methylphenidate (Wilens and Biederman, 1992),
`the drug may exacerbate· preexisting psychotic
`symptoms (Janowsky et a/.,_1973). Further, in view
`of reported psychotic reacti<ms in methylphenidate
`abusers (Spensley nnd Roc~well, 1972), the drug
`should be used with caution in patients with a
`his-tory of psychotic behaviour.
`Suppression of growth has been a concern
`following long-term methylphenidate use (Safer
`et al., 1972, 1975; Safer and Allen, 1973; Loney
`e1 a!., 1981; Mattes an(~ Gittleman, 1983; Klein .
`
`et al., 1988). Specifically, a deceleration in growth
`velocity has been reported, though a lack of signifi(cid:173)
`cant effect on ultimate height appears to result
`(Klein and Mannuzza, 1988). Any potential effect
`oit growth may only become discernible aftet' years
`of treatment, and at doses greater than 20 rngfday
`(Mattes and Gittleman, 1983). Weight loss is
`possibly more slgnificaut in patients with higher
`baseline weights (Schertz et al., 1996). lt has been
`suggested that· growth deficits (Spencer et al.,
`1996a), as with some other side-effects (Fine and
`Johnson, 1993), could be reJated, at least in part, to
`the ADHD · condition itself rather than solely
`·attributable to methylphenidate. (Spencer et a/.,
`1996a).
`·
`.Methylphenidate may precipitate or worsen
`motor and vocal tic disorders such as Tolll'ette's
`syndrome (Gndow, 1992), though the benefits of
`ADHD treatment may outweigh such liabilities.
`Note that a high comorbidity (21-54 per cent) of
`ADHD and Tourette's syndrome exists in boys
`(Wilens and Biederman, 1992). In some patients an
`amelioration of motor tics may actually occur with
`methylphenidate treatment (Gadow and Sverd,
`1990). Nevettheless, . patients . with a known tic
`disorder, or a family history. thereof, should be
`monitored carefully if the decision is made to
`initiate methylphetddate therapy (Gadow ei ell.,
`1995).
`
`Toxicology
`(2-year), high-dose carcinogencity
`Long-term
`studies of methylphenidate have recently been
`concluded by the United States National Toxico(cid:173)
`logical Programme. A slight increase in hepato(cid:173)
`ce1lular
`adenomas
`(benign
`and
`t~Jmours)
`hepntoblastomas (rare malignant tumours) was
`reported
`in
`the mice
`receiving
`the highest
`.(67 mgfkg/day) suprapharmacologic methylpheni(cid:173)
`date dose (Dunnick and Hailey, 1995). A lowet·
`than expected incidence of cancer was found in
`similarly treated rats (Dunnick et al., 1996). The
`Food and DI'Ug Administration (FDA) considered
`these findings
`to represent a weak indicatio11
`of carcinogenic potential, pl'ompting a labe1ling
`change in 1996 stating· such. The long-term
`cancer rate in patients who had received methyl~
`phenidate therapy wns found to be lower than
`would be statistically predicted (Dunnick tmd
`Hailey, 1995).
`The general toxicology of methylphenidate has
`previously been reviewed (Diener, 1991).
`
`© 1997 Jolm Wiley & Sons, Ltd.
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`K. S. PATRJCK AND J. S. MARKOWJTZ
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`XP008031884
`
`relative to cognitive flexibility versus enhanced
`response inhibitioll (Tannock et al., 1995). While
`the manufacturer suggests dosing prior to meal~,
`administration with ot· after meals may minimize
`the potential for stomach-ache and anorexia. ·
`Food does not appear to significantly affect the
`bioavailabiHty (see Pharmacokinetics). The drug is
`typically given b.Ld., at breakfast and lunch, with
`gradual titration. A common initiation and titra(cid:173)
`tion schedule may be as follows: 5 mg at 8 am and
`noon for several days to several months, then 10 mg
`at 8 am and 5 mg at noon, the:-1 10 mg b.i.d., with
`possible further dosing adjustments (Greenhill,
`1992). Some clinicians recommend an initial dose
`of 0·25 mg/kg daily. If adverse effects are not
`observed, the daily dose may then be doubled until
`an optimal dose is reached, generally not to exceed
`a total of 60 mgfday. For some patients, three(cid:173)
`times-daily· dosing is optimal (see IR versus SR
`methylphenidate). Weekend aridjo1· summer drug
`holidays have been suggested to offer some benefits
`(Committee on Children with Disabilities, 1996).
`
`DEXTROAMPHETAMINE
`Dextroamphetamine sulfate (Dexedrine®, S( + )(cid:173)
`amphetamine, tX~methylphenethyJamine, Figure 1),
`is usually considered a second-line psychostimulant
`for the treatment of ADHD, but has generally been
`found to compare favourably with methylpheni(cid:173)
`date (Pelham e.t al., 1990; Elia et a/., 1993).
`Racemic amphetamine (dextroamphetamine and
`levoamphetamine, 50: 50) was the first psychosti(cid:173)
`mulant used to treat children with behavioural
`disorders (Bradley, 1937). Although each enantio·
`mer of atnphetamine has been found to be more
`effective than the other in different subpopulations
`of ADHD patients (Arnold et al., 1972, 1976),
`dextroamphetamine is more frequently the most
`efficacious (Gross, 1976a). · Accordingly,
`levo(cid:173)
`amphetaniine is not a marketed drug product
`in· its ·own right. However, with
`the recent
`remarketing or a · mixed
`isomer amphetamine
`product (AdderaiJ®, see below), a consideration
`of enan tioselective pharmacological eff~cts of
`amphetamine follows.
`
`Pharmacodynamics (also see .Met!Jylplumldaie -
`'Pharmacodynamics')
`Amphetamine appears to release newly synthesized
`into
`the synapse
`to
`extravesicular dopamine
`mediate neurotransmission (Ross, 1977). Thus,
`
`unlikemethylphenidate, the amphetamine-induced
`elevation of synaptic dopamine does not appear
`to be highly dependent upon impulse-released
`dopamine. Dextroamphetamine exhibits greater
`than levoamphet~unine in pl·omoting
`potency
`dopamine release, while studies ·comparing the .
`effects of the two enantiomers on norepinephrine
`release show little difference (see van Kammen
`et a/., 1984). As a minor component of acti()n,
`amphetamine may also
`inhibit catecholamine
`uptake. Dextroamphetamine has been reported to
`be 3-5 times mol'e potent than levoamphetamine
`in blocking the uptake of dopamine while "these
`the same
`cnantiomers e.xhibit approxin11ttely
`potency in blocking the upwke of norepinepl.rine
`(Thornburg and Moore, I 973~. Coyle and Snyder,
`1969). Amphetamine is also a weak inhibitor of
`MAO (Seiden et ttl., 1993). In
`this
`regard,
`dextroamphetamine exhibits approximately three
`times the activity of levoamphetmnine (Grana and
`Lilla, 1959). Similarly, dextroamphetamine pro~
`duces more pronounced psychopharmacological
`effects than ·the (-)-isomer (Taylor and Snyc!.er,
`1970; Segal, 1975), including grea.ter euphoria
`(Smith and Davis, 1977). However. dextro~
`amphetamine may produce more pronounced
`peripheral sympathomimetic side~effects than the
`·levoamphetamine (Jatiowsky and Davis, 1976), ·
`and possibly greater neurotoxic ·effects after
`long-term suprapharmacologic dosing (Steraka,
`1981).
`
`Phcll'macokinetics
`Both isomers of amphetamine are well abso1·bed
`orally. There appears to be little effect of food on
`the extent of absorption of dextroamphetamine in
`either IR (Angrist eta/., 1987) or SR fol'mulations
`(Brown et a!., 1980). Plasma. protein binding,
`16 per cent, and volume of distribution are similar
`for both the isomers (Wan et al., 1978). The T 11x
`of dextt·oamph~tamine generally occurs wit~m
`2-3 h, though substantial intersubject variability
`has been reported, For the SR formulation, the
`Tmnx is 3-:-6 h (Brown et al., 1980). The mean Cmnx
`values after 0·25 or 0·5 mgfkg doses of dcxtt·oam~
`phetamine al'e approx..hnately 40 and 70 ng/ml,
`respectively (Angrist et a/., 1987). A Tlh of 7 h is
`typical (Brown et a/., 1979). However, urinary
`acidifying agents such as ascorbic acid or ammo(cid:173)
`nium chloride dramatically increase amphetamine
`urinary excretion and reduce Tv.. Conversely,
`urinary alkalinizing agents such as acetazolamide
`
`© 1997 John Wiley & Sons, Ltd.
`
` (1997)
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`ATIENTlON-DEFICIT HYPERACTJVJTY DISORDER
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`XP008031884
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`537
`
`facilitate renal tubular reabsorption and extend 1''1:
`(Beckett et al., 1965). The Tv. of dextro:
`amphetamine appears to be somewhat shorter
`it has been
`levoamphetamine and
`than for
`postulated that stereoselective differences in meta(cid:173)
`this disparity
`bolic deamination account for
`. (Wan et· al.t 1978). Although both enantiomers
`in
`the
`.brain, dextroamphetamine
`accumulate
`may attain higher concentrations (Goldstein and
`Anugnoste, 1965).
`Amphetamine is primarily eliminated as benzoic
`a~id B:nd
`i.ts correspo_ndin~ glycine conjugate,
`h1ppur1c ac1d. Metabollc oxidation may proceed
`t)lrough the intermediate phenylpropanone, part of
`which i~ eliminated as a sulfate conjugate (Smith
`and D~mg, 1970). At an unadjusted urinary pH,
`approximately one~third of n dose is excreted
`unchanged. Some 5 per cent of a dose may be
`converted into pharmacologically active metabo(cid:173)
`lites (e.g. p-hydroxyamphetamine and phenylpro~
`panolamine {Caldwell et a/.t 1972). Although
`p-hydroxylation is not a major metabolic pathway
`in mant there is evidence thal dextroamphetaminet
`but not levoamphetltmine, may be metabolized to
`p-hydroxynorepinephrine, a prod·uct implicated in
`the depletion of brain norepinephrine and post(cid:173)
`amphetamine depression (see van Kammen et al.,
`1984).
`
`Adverse effects
`side-effects of dextro(cid:173)
`The most
`frequent
`amphetamine are generally the same as those
`reported for methylphenidate: insomnia, anorexia,
`loss,
`irritability1 abdominal paint and
`weight
`headache (Barkley, 1977). Additiona1ly, other
`sympathomimetic effects may include tachycardia
`and elevated blood pressure. Exacerbation of
`motor and phonic tics of Tourette's. syndrome
`may occur. While drugNinduced psychotic episodes
`at therapeutic doses of dextroamphetamine are
`rare, they have been reported. The significance
`of any effect by dextroamphetamine on growth
`l'emains unresolved. Some studies r~port a diminu~
`tion in height and weight of children chronically
`treated with dextroamphetamine but compensa(cid:173)
`tory growth genemlly follows (Safer et al., 1972;
`Gross, I976b; Oadow, 1992).
`·
`Qextroamphetamine has been widely utilized
`for appetite suppression, hut this practice has
`largely been discontinued due to the rapid develop(cid:173)
`ment of anorectic tolerance ·and to the considerable
`risk of amphetamine abuse and dependence.
`
`Drug interactions
`Caution should be exercised when co-administer(cid:173)
`ing .dextroamphetamine with other sympathomi-
`. met!c drugs .. Similarly, MAO inhibitors should be
`avotded (Knsko eta!., 1969). Dex~roamphetamine
`may reverse the hypotensive effect on the anti(cid:173)
`hypertensive agent guanethidine (Gulati et al.
`1966). A psychotic reaction has been reported
`in a patient who received fiuoxetine ·and dextro~
`amphetamine (Barrett ei ll/., 1996).
`
`Prescribing guidelines (see Tables 3 and 4)
`Administration ofiR dextroamphetamine has been
`!'ecommended to be initiated at 2·5-5 mg once or
`twice daily (with a 4-6 h interval), increasing
`weekly by 2·5-5 mg until an optimal response Is
`achieved. SR dextroamphetamine offers once-a(cid:173)
`day dosing convenience. Doses greater than the
`usual limit of 40 mg/day may be necessary in some
`patients.
`
`DEXTROAMPHETAMINE AND
`LEVOAMPHETAMINE MIXED
`·SALTS (ADDERALL®)
`racemic dt·ug may
`Both enantiomers of a
`possibly be therapeutic) and each isomer could
`act through a unique pharmacological mechan(cid:173)
`ism. However, in this event the optimal 'combina(cid:173)
`tion' of enantiomers may not be the 50: 50
`mixture present in all racemic drugs (Hutt and
`Tan, 1996).
`.
`AdderalJ®, previously marketed in the US as
`the anorectic product Obetrol® (Berman and
`Anderson, 1966), may broadly be considered a
`tha