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Pharmacological therapy
Methylphenidate
Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, an aromatic hydrocarbon with a molecular weight of 269.77 Daltons.1 This molecule contains two chiral carbon centres and therefore normally exists as a racemic mixture of four isomers (Figure).2
Although the precise mechanism of action of methylphenidate in patients with ADHD is poorly understood,1 a number of studies has provided some insight into how this molecule imparts its therapeutic effects. Methylphenidate is a central nervous system stimulant1 and is a structural homologue to norepinephrine and dopamine (Figure).3
Comparison of the chemical structures for methylphenidate, norepinephrine and dopamine. Structural regions common to all three compounds are shown in blue.
By structurally mimicking these molecules, methylphenidate binds to dopamine and norepinephrine transporters.4 The secretion of these neurotransmitters and the action of methylphenidate on their release and reuptake are illustrated below. The numbers in the Figure are explained in the subsequent text.
- As an electrical impulse passes down the neuronal axon, the neurotransmitters dopamine and norepinephrine are released from their presynaptic vesicles into the synapse.
- The neurotransmitters reversibly attach to their appropriate receptors on the postsynaptic terminal. Inactivation of the neurotransmitters occurs via diffusion and reuptake by the relevant transporters.
- Methylphenidate binds to and blocks the dopamine and norepinephrine transporters resulting in elevated levels of both neurotransmitters in the synapse and increased postsynaptic neurotransmission.4,5
References:
1. Ritalin®LA™ PI. 2004.
2. McGough JJ, Pataki CS, Suddath R. Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder. Expert Rev Neurother 2005; 5: 437–41.
3. Markowitz JS, Straughn AB, Patrick KS. Advances in the pharmacotherapy of attention-deficit-hyperactivity disorder: Focus on methylphenidate formulations. Pharmacotherapy 2003; 23: 1281–99.
4. Kuczenski R, Segal DS. Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine. J Neurochem 1997; 68: 2032–37.
5. Volkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L, et al. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 2001; 21: RC121.