Rasagiline, another monoamine oxidase B inhibitor, is more potent than selegiline in preventing MPTP-induced parkinsonism and is being used for early treatment in patients with mild symptoms. 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 carbidopa-levodopa in patients with advanced disease and response fluctuations. 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 progression, 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.
A third monoamine oxidase B inhibitor, safinamide, was approved by the FDA while this book was in production. It is used to reduce response fluctuations in patients taking carbidopalevodopa, diminishing off-periods in patients with wearing-off effect or on-off phenomena. It is not effective as monotherapy for Parkinson’s disease. The starting dose is 50 mg orally once daily, increased after 2 weeks to 100 mg once daily.
Monoamine oxidase B inhibitors should not be taken by patients receiving meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, or St. John’s wort. The antitussive dextromethorphan should also be avoided by patients taking one of the monoamine oxidase B inhibitors; indeed, it is wise to advise patients to avoid all over-the-counter cold preparations. Rasagiline, selegiline, or safinamide should not be taken with other monoamine oxidase inhibitors and should be used with care in patients receiving tricyclic antidepressants or serotonin reuptake inhibitors because of the theoretical risk of acute toxic interactions of the serotonin syndrome type (see Chapter 16), but this is rarely encountered in practice. The adverse effects of levodopa, especially dyskinesias, mental changes, nausea, and sleep disorders, may be increased by these drugs. Hypertension may be precipitated or aggravated.
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, probably due to the peripheral accumulation of norepinephrine.
Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, especially catechol-O-methyltransferase (COMT), and this increases plasma levels of 3-O-methyldopa (3-OMD). Elevated levels of 3-OMD have been associated with a poor therapeutic response to levodopa, perhaps in part because 3-OMD competes with levodopa for an active carrier mechanism that governs its transport across the intestinal mucosa and the blood-brain barrier. Selective COMT inhibitors such as tolcapone and entacapone also prolong the action of levodopa by diminishing its peripheral metabolism (Figure 28–5). Levodopa clearance is decreased, and relative bioavailability of levodopa is thus increased. Neither the time to reach peak concentration nor the maximal concentration of levodopa is increased. These agents may be helpful in patients receiving levodopa who have developed response fluctuations—leading to a smoother response, more prolonged on-time, and the option of reducing total daily levodopa dose. Tolcapone and entacapone are both widely available, but entacapone is generally preferred because it has not been associated with hepatotoxicity.