The pharmacologic effects of tolcapone and entacapone are similar, and both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. The half-life of both drugs is approximately 2 hours, but tolcapone is slightly more potent and has a longer duration of action. Tolcapone is taken in a standard dosage of 100 mg three times daily; some patients require a daily dose of twice that amount. By contrast, entacapone (200 mg) needs to be taken with each dose of levodopa, up to six times daily.
Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been associated rarely with death from acute hepatic failure; accordingly, it should not be used in patients with abnormal liver function test results. Its use in the USA requires signed patient consent (as provided in the product labeling) plus monitoring of liver function tests every 2–4 weeks during the first 6 months and periodically but less frequently thereafter. The medication should be withdrawn and not reintroduced if hepatic damage becomes evident. No such toxicity has been reported with entacapone.
The commercial preparation named Stalevo consists of a combination of levodopa with both carbidopa and entacapone. It is available in three strengths: Stalevo 50 (50 mg levodopa plus 12.5 mg carbidopa and 200 mg entacapone), Stalevo 100 (100 mg, 25 mg, and 200 mg, respectively), and Stalevo 150 (150 mg, 37.5 mg, and 200 mg, respectively). Use of this preparation simplifies the drug regimen and requires the consumption of fewer tablets than otherwise. Stalevo is priced at or below the price of its individual components. The combination agent may provide greater symptomatic benefit than carbidopa-levodopa alone. However, despite the convenience of a single combination preparation, use of Stalevo rather than carbidopa-levodopa has been associated with earlier occurrence and increased frequency of dyskinesia. An investigation as to whether the use of Stalevo is associated with an increased risk for cardiovascular events (myocardial infarction, stroke, cardiovascular death) is ongoing.
Subcutaneous injection of apomorphine hydrochloride (Apokyn), a potent nonergoline dopamine agonist that interacts with post-synaptic D2 receptors in the caudate nucleus and putamen, is effective for the temporary relief (“rescue”) of off-periods of akinesia in patients on optimized dopaminergic therapy. It is rapidly taken up in the blood and then the brain, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours. The optimal dose is identified by administering increasing test doses until adequate benefit is achieved or a maximum of 0.6 mL (6 mg) is reached, with the supine and standing blood pressures monitored before injection and then every 20 minutes for an hour after it. Most patients require a dose of 0.3–0.6 mL (3–6 mg), and this should be given usually no more than about three times daily, but occasionally up to five times daily.