Selegiline

Summary

Synopsis

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.

Pharmacological and Pharmacokinetic Properties

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, L-amphetamine and demethyl-selegiline were 9, 1.3 and 5.8 µg/L, respectively, after selegiline 10 mg/day orally for 22 to 24 months in 4 patients with Parkinson’s disease. Selegiline is extensively distributed, despite being 94% bound to plasma proteins, and binds to striatum, cortex and brain stem. Renal elimination is the predominant route of selegiline excretion, with 86% of an oral dose recovered in the urine, principally as L-methamphetamine (59%) and L-amphetamine (26%).

Therapeutic Use

Selegiline 10mg daily has been investigated as a supplement to standard levodopa plus decarboxylase inhibitor regimens in an attempt to smooth out response fluctuations, and as monotherapy in patients with early mild disease to try to slow symptom progression of Parkinson’s disease.

The many noncomparative and placebo-controlled studies demonstrated that the addition of selegiline to levodopa improved the disability rating scores by 18 to 32%, compared with 8 to 27% in placebo recipients. Tremor was more frequently relieved than rigidity. The dosage of levodopa was reduced by approximately 10 to 30% without adversely affecting the degree of symptom control. ‘End-of-dose’ fluctuations in response to levodopa significantly improved in 50 to 63% of selegiline recipients, and early morning akinesias in 56%, but the drug had no significant effect in improving ‘on/off’ oscillations. Moreover, the benefits of adding selegiline declined with time, with a reduction in both the proportion of adequately controlled patients and the extent of improvement; the mean duration of benefit was 7 to 8 months in 1 long term study. A retrospective study suggested that addition of selegiline to a levodopa regimen extended life expectancy by 15 months.

Encouraging results have been obtained with selegiline monotherapy in patients with early and mildly symptomatic Parkinson’s disease. Prospective trials revealed that selegiline monotherapy delayed, but did not prevent, the progression of symptoms and prolonged mobility without additional levodopa by 6 to 11 months. After 12 months, 26 to 44% of selegiline recipients compared with 47 to 56% of placebo-treated patients had symptoms sufficiently severe to justify starting levodopa therapy. It is unclear if these results are a consequence of protection against further neuronal destruction or are symptomatic effects. The latter seems less likely since selegiline alone provides little symptom relief.

Tolerability

Selegiline does not significantly inhibit MAO type A at therapeutic doses used to treat Parkinson’s disease. It is therefore not associated with the ‘cheese’ effect, which occurs when the indirect pressor effects of dietary amines (e.g. tyramine) are exacerbated because of accumulation resulting from nonselective MAO inhibition. Headache has, however, been reported by 4 to 26% of patients and a single hypertensive episode has been documented. Orthostatic hypotension, occasionally causing syncope, has occurred in several patients.

Because it potentiates striatal dopaminergic activity, selegiline exacerbates peak concentration dyskinesias due to levodopa in approximately 28% of patients. Symptoms usually resolve when the levodopa dosage is reduced.

Mood elevation (in 6 of 11 patients), insomnia (in 10 to 32%; similar to levodopa alone), hallucinations (in 2 to 9%) and confusion (in 5 to 10%) have occurred during coadministration of selegiline and levodopa, indicating caution when introducing selegiline in some elderly demented patients. The most likely cause of these effects appears to be increased dopaminergic activity, but there is possibly some contribution from the selegiline metabolites L-methamphetamine and L-amphetamine since insomnia and euphoria have been noted during selegiline monotherapy. Gastrointestinal symptoms, primarily nausea, occur in 12% of selegiline recipients, and pre-existing peptic ulcer may be exacerbated.

Drug Interactions

The concurrent use of selegiline with pethidine (meperidine) is contraindicated, and fluoxetine should be avoided. Coadministration of medications containing sympathomimetic amines (e.g. cold remedies) appears to be safe if the daily dosage of selegiline does not exceed 10mg.

Dosage and Administration

In the treatment of patients with Parkinson’s disease, selegiline 5mg orally twice daily, with breakfast and at midday, is recommended. Higher dosages are no more effective than 10 mg/day, and restriction of both tyramine-containing food and indirect sympathomimetic medications may be necessary above this dosage.