In short, attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet and concomitant drug use although, as noted above, a few cases of hypertensive reactions have been reported at the recommended dose. (See Warnings and Precautions.)

It is important to be aware that selegiline may have pharmacological effects unrelated to MAO B inhibition. As noted above, there is some evidence that it may increase dopaminergic activity by other mechanisms, including interfering with dopamine re-uptake at the synapse. Effects resulting from selegiline administration may also be mediated through its metabolites. Two of its three principal metabolites, amphetamine and methamphetamine, have pharmacological actions of their own; they interfere with neuronal uptake and enhance release of several neurotransmitters (e.g., norepinephrine, dopamine, serotonin). However, the extent to which these metabolites contribute to the effects of selegiline are unknown.

Rationale for the Use of a Selective Monoamine Oxidase Type B Inhibitor in Parkinson's Disease

Many of the prominent symptoms of Parkinson's disease are due to a deficiency of striatal dopamine that is the consequence of a progressive degeneration and loss of a population of dopaminergic neurons which originate in the substantia nigra of the midbrain and project to the basal ganglia or striatum. Early in the course of Parkinson's Disease, the deficit in the capacity of these neurons to synthesize dopamine can be overcome by administration of exogenous levodopa, usually given in combination with a peripheral decarboxylase inhibitor (carbidopa).

With the passage of time, due to the progression of the disease and/or the effect of sustained treatment, the efficacy and quality of the therapeutic response to levodopa diminishes. Thus, after several years of levodopa treatment, the response, for a given dose of levodopa, is shorter, has less predictable onset and offset (i.e., there is 'wearing off'), and is often accompanied by side effects (e.g., dyskinesia, akinesias, on-off phenomena, freezing, etc.).

This deteriorating response is currently interpreted as a manifestation of the inability of the ever decreasing population of intact nigrostriatal neurons to synthesize and release adequate amounts of dopamine.

MAO B inhibition may be useful in this setting because, by blocking the catabolism of dopamine, it would increase the net amount of dopamine available (i.e., it would increase the pool of dopamine). Whether or not this mechanism or an alternative one actually accounts for the observed beneficial effects of adjunctive selegiline is unknown.

Selegiline's benefit in Parkinson's disease has only been documented as an adjunct to levodopa/carbidopa. Whether or not it might be effective as a sole treatment is unknown, but past attempts to treat Parkinson's disease with non-selective MAOI monotherapy are reported to have been unsuccessful. It is important to note that attempts to treat Parkinsonian patients with combinations of levodopa and currently marketed non-selective MAO inhibitors were abandoned because of multiple side effects including hypertension, increase in involuntary movement, and toxic delirium.

Pharmacokinetic Information (Absorption, Distribution, Metabolism and Elimination-ADME)

The absolute bioavaliability of selegiline following oral dosing is not known; however, selegiline undergoes extensive metabolism (presumably attributable to presystemic clearance in gut and liver). The major plasma metabolites are N-desmethylselegiline, L-amphetamine and L-methamphetamine. Only N-desmethylselegiline has MAO-B inhibiting activity. The peak plasma levels of these metabolites following a single oral dose of 10 mg are from 4 to almost 20 times greater than that of the maximum plasma concentration of selegiline [1 ng/mL]. The maximum concentrations of amphetamine and methamphetamine, however, are far below those ordinarily expected to produce clinically important effects.

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