MONOAMINE OXIDASE INHIBITORS
Two types of monoamine oxidase have been distinguished in the nervous system. Monoamine oxidase A metabolizes norepineph-rine, serotonin, and dopamine; monoamine oxidase B metabolizes dopamine selectively. Selegiline (deprenyl) (Figure 28–3), a selec-tive irreversible inhibitor of monoamine oxidase B at normal doses (at higher doses it inhibits monoamine oxidase A as well), retards the breakdown of dopamine (Figure 28–5); in consequence, it enhances and prolongs the antiparkinsonism effect of levodopa (thereby allowing the dose of levodopa to be reduced) and may reduce mild on-off or wearing-off phenomena. It is therefore used as adjunctive therapy for patients with a declining or fluctuating response to levodopa. The standard dose of selegiline is 5 mg with breakfast and 5 mg with lunch. Selegiline may cause insomnia when taken later during the day.
Selegiline has only a minor therapeutic effect on parkin-sonism when given alone. Studies in animals suggest that it may reduce disease progression, but trials to test the effect of selegi-line on the progression of parkinsonism in humans have yielded ambiguous results. The findings in a large multicenter study were taken to suggest a beneficial effect in slowing disease pro-gression but may simply have reflected a symptomatic response.
Rasagiline, another monoamine oxidase B inhibitor, is morepotent than selegiline in preventing MPTP-induced parkinsonism and is being used for early symptomatic treatment. The standard dosage is 1 mg/d. Rasagiline is also used as adjunctive therapy at a dosage of 0.5 or 1 mg/d to prolong the effects of levodopa-carbidopa in patients with advanced disease. A large double-blind, placebo-controlled, delayed-start study (the ADAGIO trial) to evaluate whether it had neuroprotective benefit (ie, slowed the disease course) yielded unclear results: a daily dose of 1 mg met all the end points of the study and did seem to slow disease progres-sion, but a 2-mg dose failed to do so. These findings are difficult to explain and the decision to use rasagiline for neuroprotective purposes therefore remains an individual one.
Neither selegiline nor rasagiline should be taken by patients receiving meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, or St. John’s wort. The antitussive dextromethor-phan should also be avoided by patients taking one of the mono-amine oxidase B inhibitors; indeed, it is wise to advise patients to avoid all over-the-counter cold preparations. Rasagiline or selegi-line should be used with care in patients receiving tricyclic antide-pressants or serotonin reuptake inhibitors because of the theoretical risk of acute toxic interactions of the serotonin syn-drome type , but this is rarely encountered in practice. The adverse effects of levodopa may be increased by these drugs.
The combined administration of levodopa and an inhibitor of both forms of monoamine oxidase (ie, a nonselective inhibitor) must be avoided, because it may lead to hypertensive crises, prob-ably because of the peripheral accumulation of norepinephrine.