CLINICAL PHARMACOLOGY

The mechanisms accounting for selegiline's beneficial adjunctive action in the treatment of Parkinson's disease are not fully understood. Inhibition of monoamine oxidase, type B, activity is generally considered to be of primary importance; in addition, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.

Selegiline is best known as an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline inhibits MAO by acting as a 'suicide' substrate for the enzyme; that is, it is converted by MAO to an active moiety which combines irreversibly with the active site and/or the enzyme's essential FAD cofactor. Because selegiline has greater affinity for type B rather than for type A active sites, it can serve as a selective inhibitor of MAO type B if it is administered at the recommended dose.

MAOs are widely distributed throughout the body; their concentration is especially high in liver, kidney, stomach, intestinal wall, and brain. MAOs are currently subclassified into two types, A and B, which differ in their substrate specificity and tissue distribution. In humans, intestinal MAO is predominantly type A, while most of that in brain is type B.

In CNS neurons, MAO plays an important role in the catabolism of catecholamines (dopamine, norepinephrine and epinephrine) and serotonin. MAOs are also important in the catabolism of various exogenous amines found in a variety of foods and drugs. MAO in the GI tract and liver (primarily type A), for example, is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a 'hypertensive crisis,' the so-called 'cheese reaction.' (If large amounts of certain exogenous amines gain access to the systemic circulation - e.g., from fermented cheese, red wine, herring, over-the-counter cough/cold medications, etc. - they are taken up by adrenergic neurons and displace norepinephrine from storage sites within membrane bound vesicles. Subsequent release of the displaced norepinephrine causes the rise in systemic blood pressure, etc.)

In theory, since MAO A of the gut is not inhibited, patients treated with selegiline at a dose of 10 mg a day should be able to take medications containing pharmacologically active amines and consume tyramine-containing foods without risk of uncontrolled hypertension. Although rare, a few reports of hypertensive reactions have occurred in patients receiving Eldepryl at the recommended dose, with tyramine-containing foods. In addition, one case of hypertensive crisis has been reported in a patient taking the recommended dose of selegiline and a sympathomimetic medication, ephedrine. The pathophysiology of the 'cheese reaction' is complicated and, in addition to its ability to inhibit MAO B selectively, selegiline's relative freedom from this reaction has been attributed to an ability to prevent tyramine and other indirect acting sympathomimetics from displacing norepinephrine from adrenergic neurons. However, until the pathophysiology of the cheese reaction is more completely understood, it seems prudent to assume that selegiline can ordinarily only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO B (e.g., 10 mg/day).

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