Selegiline is a lipophilic, relatively selective MAO-B inhibitor, which is readily absorbed from the gastrointestinal tract. Maximal concentrations occur 30 to 120 minutes after ingestion (58), and over 90% is bound to plasma proteins (59). Platelet MAO-B activity is inhibited by more than 85% within four hours after selegiline 5 mg, and by almost 98% within 24 hours after selegiline 10 mg (60). Selegiline passes through the blood-brain barrier and accumulates in MAO-B rich brain areas, including the striatum, thalamus, cortex, and brain stem (61). Selegiline is considered a "suicide inhibitor," as it forms an irreversible covalent bond with MAO-B. Enzyme activity returns only when new MAO-B is produced. Selegiline is primarily metabolized by the liver P-450 system with some extrahepatic metabolism (62). Three metabolites are identified in serum and urine: l-(-)-methamphetamine, l-(-)-amphetamine, and (-)-desmethylselegiline (63). Desmethylselegiline has neuroprotective activity (34) and also irreversibly inhibits MAO-B (although less so than selegiline) (64-66).
Symptomatic benefit from selegiline in PD is mediated through MAO-B inhibition, thereby inhibiting catabolism of dopamine, both endogenous and exogenous (from levodopa). Selegiline may also inhibit dopamine reuptake (66) and block presynaptic dopamine receptors (67). Amphetamine metabolites of selegiline may also promote dopamine release.
Oral selegiline is generally well tolerated. The usual dose is 5 mg with breakfast and lunch. Potential adverse effects include nausea, dizziness, confusion, anxiety, dry mouth, and hallucinations. Selegiline is not recommended after early afternoon because of the risk of insomnia from its amphetamine metabolites. With concomitant levodopa use, orthostatic hypotension may be significant. Selegiline added to levodopa may worsen dyskinesia. Dopaminergic side effects including dyskinesia can usually be managed by lowering the dose of levodopa. Serotonin syndrome may be seen when selegiline is combined with selective serotonin reuptake inhibitors (SSRIs); however, this interaction is rare (68). Selegiline may produce altered mental state, rigidity, and fever in some patients receiving meperidine (69). Concomitant use of selegiline with meperidine is contraindicated, and this contraindication is often extended to other opioids.
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