Selegiline (deprenyl) is a selective inhibitor of cerebral monoamine oxidase type B at the dosage (10 mg/day) used in patients with Parkinson’s disease. Through this activity, the drug increases nigrostriatal dopamine levels, and may protect neurons against damage by free radicals and possibly exogenous neurotoxins. Selegiline also inhibits dopamine reuptake from the synaptic cleft. Because of its selectivity, selegiline 10mg daily does not prevent the breakdown and exacerbate the indirect pressor effects of dietary amines such as tyramine; it is devoid of the ‘cheese’ effect.

Following oral administration, selegiline is rapidly metabolised to L-methamphetamine and L-amphetamine, which may account for the euphoria and insomnia seen in many patients, although potentiation of dopaminergic activity with concurrent levodopa appears more likely. The drug is a useful adjunct to levodopa in Parkinsonism, improving ‘end-of dose’ fluctuations, producing modest improvements in motor function, and allowing a reduction in levodopa dosage. Indeed, if levodopa dosages are not decreased when selegiline is added to the therapeutic regimen, peak concentration dyskinesias due to levodopa are often exacerbated. However, symptomatic benefits are rarely maintained for more than a year and selegiline is relatively ineffective in allaying the abrupt swings in response to levodopa (‘on/off’ effects). When used alone in patients with mild disease, selegiline appears to slow the rate of symptom progression and may extend survival, through either neuroprotection or symptom relief Whichever mechanism(s) is responsible, there is strong evidence to suggest that selegiline should be considered both in patients newly diagnosed with Parkinson’s disease in an attempt to delay symptom progression, and in those experiencing dose-dependent fluctuations in response to levodopa.

At the dosage recommended for use in patients with Parkinson’s disease (10 mg/day), selegiline is an irreversible selective inhibitor of monoamine oxidase type B (MAO-B), an enzyme responsible for dopamine metabolism in the brain. Post mortem studies in recipients of selegiline and levodopa indicate about 90% inhibition of nigrostriatal MAO-B activity resulting in a 70% increase in dopamine levels compared with untreated patients with Parkinson’s disease.

Deamination of dopamine by MAO-B produces oxygen free radicals, which may be implicated in the progressive nigrostriatal degeneration in idiopathic Parkinson’s disease. Selegiline should therefore limit this oxidative stress by blocking MAO-B, and indeed this hypothesis has been supported by animal studies. MAO-B also catalyses the formation of the neurotoxic 1-methyl-4-phenylpyridinium ion (MPP⁺) from l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a compound which causes symptoms and pathology very similar to those of idiopathic Parkinsonism. Pretreatment with selegiline prevented the signs and symptoms of MPTP-induced neuronal damage in animals.

Dopaminergic function is also enhanced by the ability of selegiline to block synaptic dopamine reuptake.

Because selegiline is extensively and rapidly metabolised, mainly to L-methamphetamine, L-amphetamine and demethyl-selegiline, pharmacokinetic analysis to date is limited. The parent drug is undetectable following oral administration, but peak serum concentrations of the metabolites occurred within 0.5 to 2 hours with an absorption half-life of 24 minutes. Mean serum concentrations of L-methamphetamine …