Methylphenidate: Its Pharmacology and Uses
2000; Elsevier BV; Volume: 75; Issue: 7 Linguagem: Inglês
10.1016/s0025-6196(11)64618-1
ISSN1942-5546
AutoresThomas D. Challman, James J. Lipsky,
Tópico(s)Epilepsy research and treatment
ResumoMethylphenidate is a commonly used medication in the United States. This central nervous system stimulant has a mechanism of action distinct from that of amphetamine. The Food and Drug Administration has approved methylphenidate for the treatment of attentlon-deficit/hyperactivity disorder and narcolepsy. Treatment with methylphenidate has been advocated in patients with traumatic brain injury and stroke, cancer patients, and those with human immunodeficiency virus infection. Placebo-controlled trials have documented its efficacy as an adjunctive agent in the treatment of depression and pain. This article reviews the current understanding of the mechanism of action and efficacy of methylphenidate in various clinical conditions. Methylphenidate is a commonly used medication in the United States. This central nervous system stimulant has a mechanism of action distinct from that of amphetamine. The Food and Drug Administration has approved methylphenidate for the treatment of attentlon-deficit/hyperactivity disorder and narcolepsy. Treatment with methylphenidate has been advocated in patients with traumatic brain injury and stroke, cancer patients, and those with human immunodeficiency virus infection. Placebo-controlled trials have documented its efficacy as an adjunctive agent in the treatment of depression and pain. This article reviews the current understanding of the mechanism of action and efficacy of methylphenidate in various clinical conditions. Methylphenidate (Ritalin) is a commonly used medication in the United States. First synthesized in 1944, methylphenidate was initially used as an analeptic for reversal of barbiturate-induced coma.1Wax PM Analeptic use in clinical toxicology: a historical appraisal.J Toxicol Clin Toxicoi. 1997; 35: 203-209Crossref PubMed Google Scholar It is now primarily used as treatment of attention-deficit/hyperactivity disorder (ADHD). 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The earliest marketed preparations of methylphenidate contained all 4 enantiomers. Subsequent study revealed, however, that the erythro isomers were devoid of any major central nervous system stimulant effect11Szporny L Görög P Investigations into the correlations hetween monoamine oxidase inhibition and other effects due to methylphcnydate and its slercoisomcrs.Biochem Pharmacol. 1961; 8: 263-268Crossref Google Scholar a result, currently available preparations of methylphenidate contain a racemic mixture of only d,l-threo-methylphenidate. As discussed later, the pharmacological activity is attributable to just the d-threo isomer.12Ding YS Fowler JS Volkow ND et al.Chiral drugs: comparison of the pharmacokinctics of Cd-threo and L-three-methyl-phenidate in the human and baboon brain.Psyckopharmacotogy (Berit. 1997; 131: 71-78Crossref PubMed Scopus (103) Google Scholar The complete mechanism by which methylphenidate exerts its behavioral effect remains unknown. 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Increasing brain serotonin levels in these mice also had a similar effect.44Gaincldinov RR Wetsel WC Jones SR Levin KD Jaber M Caron MG Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.Science. 1999; 283: 397-401Crossref PubMed Scopus (500) Google Scholar Therefore, investigators have postulated that methylphenidate may work via serotonergic neurons to. reduce hyperactivity by restoring a lost balance between certain dopaminergic and serotonergic neuronal circuits.44Gaincldinov RR Wetsel WC Jones SR Levin KD Jaber M Caron MG Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.Science. 1999; 283: 397-401Crossref PubMed Scopus (500) Google Scholar In an earlier study, however, methylphenidate had no effect on extracellular serotonin levels,35Kuczenski R Segal DS Effects of methylphenidate on extracellular dopamine, serotonin, and norcpinephrine: comparison with amphetamine [published correction appears in J Neumchem. 1997;69:1332).J Neurochcm. 1997; 68: 2032-2037Crossref PubMed Google Scholar and since the dose of methylphenidate used in the aforementioned dopamine transporter knockout mouse study was 50 to 100 times the usual therapeutic ADHD dose, the direct applicability of these results to humans remains uncertain. After oral administration, methylphenidate is almost completely absorbed and is primarily metabolized via de-esterification to ritalinic acid.45Faraj BA Israili ZH Pcrel JM et al.Metabolism and disposition of methylphenidate-IJC: studies in man and animals.J Pharmacol Exp Ther. 1974; 191: 535-547PubMed Google Scholar Peak plasma concentrations (Cmax) occur 1 to 3 hours (Tmax) after an oral dose of stan- dard methylphenidate, with a plasma half-life (T1/2) of 1.5 to 2.5 hours.45Faraj BA Israili ZH Pcrel JM et al.Metabolism and disposition of methylphenidate-IJC: studies in man and animals.J Pharmacol Exp Ther. 1974; 191: 535-547PubMed Google Scholar, 46Redalieu E Bartlctt MF Waldes LM Darrow WR Egger II Wagner WE A study of methylphenidate in man with respect to its major metabolite.Drug Metab Dispos. 1982; 10: 708-709PubMed Google Scholar, 47Shaywilz SE Hunt RD Jatlow P et al.Psychophamiacology of attention deficit disorder: pharmacokinctic. ncuroendocrinc, and behavioral measures following acute and chronic treatment with methylphenidate.Pediatrics. 1982; 69: 688-694PubMed Google Scholar, 48Wargin W Patrick K Kilts C et al.Pharmacokinetics of methylphenidate in man, rat and monkey.J Pharmacol Exp Ther. 1983; 226: 382-386PubMed Google Scholar Absorption seems to be enhanced when methylphenidate is taken with food.49Chan YP Swanson JM Soldin SS Thiessen JJ Macleod SM Logan W Methylphenidate hydrochloride given with or before breakfast, II: effects on plasma concentration of methylphenidate and ritalinic acid.Pediatrics. 1983; 72: 56-59PubMed Google Scholar Protein binding of methylphenidate is low50Winsberg BG Hungund BL Perel JM Pharmacological factors of methylphenidate metabolism in behaviorally disordered children.Psychopharmacol Bull. 1980; 16: 69-71PubMed Google Scholar, 51Hungund BL Percl JM Hurwic MJ Sverd J Winsberg BG Pharmacokinetics of methylphenidate in hyperkinetic children.Br J Clin Pharmacol. 1979; 8: 571-576Crossref PubMed Google Scholar which may. contribute to its relatively brief T1/2. The metabolism of the enantiomers of methylphenidate is stereoselective. As previously mentioned, the currently available preparations of methylphenidate contain a racemic mixture of d,l-threo-methyl phenidate. After oral administration of methylphenidate, blood levels of the d-isomer are significantly higher.52Wong YN King SP Laughton WB McCormick GC Grebow PE Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers.J Clin Pharmacol. 1998; 38: 276-282Crossref PubMed Google Scholar, 53Aoyama T Kotaki H Sasaki T Sawada Y Honda Y Iga T Nonlinear kinetics of /Areo-mcthylphcnidate cnantiomers in a patient with narcolepsy and in healthy volunteers.Fur J Clin Pharmacol. 1993; 44: 79-84Crossref Scopus (24) Google Scholar, 54Aoyama T Kotaki H Honda Y Nakagawa K Kinetic analysis of cnantiomers of co-methylphenidate and ils metabolite in two healthy subjects after oral administration as determined by a gas chromatographic-mass spectrometric method.J Pharm Set. 1990; 79: 465-469Crossref PubMed Scopus (30) Google Scholar No difference is seen in the plasma levels or renal clearance of the isomers in the first 1.5 hours after intravenous administration, indicating that there is enhanced presystemic metabolism of the 1-somer after oral administration55Snnivas NR Hubburd JW Korchinski ED Midha KK Enantioselective pharmacokinetics of rt-al-threo-methylplienidatc in humans.Pharm Res. 1993; 10: 14-21Crossref PubMed Scopus (61) Google Scholar Methylphenidate is available in 5-, 10-, and 20-mg tablets, as well as a 20-mg sustained-release tablet in which the drug is embedded in a wax matrix.56Sustained-release methylphenidate.Med cit Drugs Ther. 1984; 26: 97-98Google Scholar, 57Methylphenidate revisited Med Lett Drugs Ther. 1988; 30: 51-52PubMed Google Scholar This formulation has been used for once-daily morning dosing in children with ADHD who would rather not take a noon dose of methylphenidate at school. 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Differences in the plasma concentrations of these isomers in “responders” vs “nonresponders” to methylphenidate66Jonkman LM Verbaten MN de Boer D et al.Differences in plasma concentrations of the D- and L-threo methylphenidate enantiomers in responding and non-responding children with attention-deficit hyperactivity disorder.Psychiatry Res. 1998; 78: 115-118Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar indicate that the determination of variation in drug metabolism among individuals may eventually help identify those patients most likely to benefit from treatment with racemic methylphenidate. Clinical trials of a chirally pure preparation of d-threo-methylphenidate are in progress.67Celgene Corporation announces launch of Canadian clinical trial program for chirally pure version of Ritalin(R) [press release]. Celgene Corporation, Warren, NJFebruary 6, 1999Google Scholar The Food and Drug Administration (FDA) has approved methylphenidate for the treatment of ADHD and narcolepsy. 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Psychostimulants were first used to treat disruptive behavior in children in 1937.71Bradley C Behavior of children receiving benzedrine.Am J Psychiatry. 1937; 94: 577-585Google Scholar Since that era, further research and diagnostic refinement have led to the recognition of ADHD as a distinct clinical entity, with an estimated prevalence in children between 3% and 5%.72American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 4th cd. American Psychiatric Association, Washington, DC1994: 78-85Google Scholar Methylphenidate is the most widely used medication for the treatment of ADHD. While dilemmas remain in the accurate diagnosis of ADHD,73 a myriad of studies support the efficacy of methylphenidate and other psychostimulants in the treatment of the symptoms of ADHD in children.74Wilens TR Biedcrman J The stimulants.Psychiatr Clin North Am. 1992; 15: 191-222PubMed Google Scholar, 75Grccnhill LL Pharmacologie treatment of attention deficit hypcr-aclivity disorder.Psychiatr Clin North Am. 1992; 15: 1-27Google Scholar, 76Swanson JM McBumett K Wigal T et al.Effect of stimulant medication on children with attention deficit disorder: a “review of reviews.”.Except Child. 1993; 60: 154-162Crossref Google Scholar, 77Shaywiiz BA Reicher JM Shaywitz SE Attcntion-deficit/hy-pcractivity disorder.Adv Pediatr. 1997; 44: 331-367PubMed Google Scholar Methylphenidate may also have a role in the treatment of neurobehavioral symptoms in patients with other developmental disabilities. 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