Pharmacokinetics and clinical effectiveness of methylphenidate

Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD ha s been widely studied, the use of methylphenidate in ADHD still poses a num ber of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatm ent on the patient's psychopathology later in life. The objective of this r eview is to provide an analysis of the pharmacokinetic-pharmacodynamic prop erties and therapeutic effectiveness of methylphenidate that may help to an swer some of these questions. Methylphenidate has 2 chiral centres, but the drug used in therapy comprise s only the three pair of enantiomers. d-threo-Methylphenidate is more poten t than the l-enantiomer. Methylphenidate is administered as a racemic mixtu re that undergoes stereoselective clearance. Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug co ncentration after oral administration occurs at about 2 hours. Methylphenid ate is absorbed well from the gastrointestinal tract and easily passes to t he brain. Methylphenidate is efficacious for short term treatment for child ren with ADHD. Its mechanism of action is not understood, but may be associ ated with its influence on multiple neurotransmitters, especially the relea se and reuptake of dopamine in the striatum. There is marked individual variability in the dose-response relationship fo r methylphenidate. and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variab ility is predominantly pharmacokinetic or pharmacodynamic. If variable ster eoselective metabolism occurs clinically, therapeutic drug monitoring of me thylphenidate will require the application of chiral assay methods fur the analysis of the active component, d-threo-methylphenidate. It is difficult to predict which children will have a favourable response t o methylphenidate, Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methyl phenidate. Thr use of individual single-blind medication trials may be prac tical solution to this problem. Additionally, the targeted condition warran ts careful consideration, since different conditions (e.g.f misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic proper ties of methylphenidate are required to allow the development of optimal do sage regimens.