Tolcapone adverse effects

Because entacapone has a shorter half-life, 200 mg is given with each dose of carbidopa/L-dopa up to eight times a day. Dopaminergic adverse effects may occur and are managed easily by reducing the carbidopa/L-dopa dose. Brownish-orange urine discoloration may occur (as with tolcapone), but there is no evidence of hepatotoxicity from entacapone. 

The two COMT inhibitors in clinical use are tol-capone (Tasmar) and entacapone fComtan). They are used in combination with levodopa-carbidopa. In patients with motor fluctuations, they increase the on time. Adverse effects are similar to those observed with levodopa-carbidopa alone. Tolcapone therapy can cause fatal hepatotoxicity and so should be used only in patients who do not respond to other therapies. Patients taking tolcapone require close monitoring of liver enzymes for signs of hepatic changes. 

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... 

Adverse effects Diarrhea is the most common side effect of tolcapone. As expected, /evocfopa-related adverse effects increase when tolcapone is added. These include postural hypotension, nausea, sleep disorders, anorexia, dyskinesias, and hallucinations. Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Baseline and frequent, regular determinations of hepatic serum enzymes are suggested by the manufacturer. Any elevations above normal are cause for discontinuation. Because of the hepatotoxicity, tolcapone should only be used as an adjunct in patients on levodopa/carbidopa who are experiencing symptom fluctuations. 

In 40 patients (mean age 64 years, 22 men) who took tolcapone for 3-7 months and were given entacapone in dosages titrated to 800-2000 mg/day after a transition period of 3-6 months with co-beneldopa, the improvements in on and off times were less impressive than they had been with tolcapone and there were more adverse effects (3). One patient had diarrhea and orthostatic hypertension with both drugs, but another six patients had increased dyskinesias and hallucinations and one developed myoclonus. There was no evidence of liver toxicity with either drug. The authors pointed out that entacapone, unlike tolcapone, not only increases the half-life of levodopa but also its peak concentration, causing significantly enhanced levodopa-related adverse effects. There is therefore a paradox entacapone appears to be safer but overall causes more adverse effects. 

In early studies the most frequent adverse effects of tolcapone were dyskinesias, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, and hallucinations (1). However, very soon tolcapone was withdrawn in most countries, because of reports of severe hepatotoxicity. The background to these events has been briefly reviewed (2). 

Two COMT inhibitors are available for this use, tolcapone (tasmar) and entacapone (comtan). Tolcapone has a relatively long duration of action, allowing for administration two to three times a day, and appears to act by both central and peripheral inhibition of COMT. The duration of action of entacapone is short, around 2 hours, so it usually is administered simultaneously with each dose of levodopa/carbidopa. The action of entacapone is attributable principally to peripheral inhibition of COMT. The common adverse effects of these agents are similar to those observed in patients treated with levodopa/carbidopa alone and include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An adverse effect associated with tolcapone is hepatotoxicity tolcapone should be used only in patients who have not responded to other therapies and with appropriate monitoring of hepatic transaminases. Entacapone has not been associated with hepatotoxicity and requires no special monitoring. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (stalevo). 

Toxicity Adverse effects related to increased levels of levodopa include dyskinesias, gastrointestinal distress, and posmral hj otension. Tolcapone has caused acute hepatic failure, necessitating routine monitoring of liver function tests. 

In a single dose study, there was no adverse effect on heart rate or blood pressure when entacapone was given with moclobemide (a RIMA), but caution is recommended until further clinical experience is gained. The COMT inhibitors may be used with the MAO-B inhibitors (such as selegiline). However, the manufacturers of entacapone and tolcapone contraindicate concurrent use of non-selective MAOIs or a combination of both a RIMA and a MAO-B inhibitor. 

Tolcapone and entacapone inhibit the enzyme oateohol-O-methyl transferase (COMT), whioh is oonoemed with the metabolism of drugs such as adrenaline (epinephrine) and isoprenaline (isoproterenol). There is therefore a possibility of inoreased serum levels and related adverse effects of these drugs. 

Entacapone and tolcapone have been shown to increase the AUC and prolong the elimination half-life of levodopa (as levodopa/benser-azide or levodopa/carbidopa) without altering the maximum levodopa level. COMT inhibitors can therefore improve the clinical condition of patients with Parkinson s disease, which is mainly seen as a decrease in off time. However, as levodopa levels are raised, there may be an accompanying increase in the adverse effects oflevodopa (e.g. dyskinesias, nausea, vomiting, orthostatic hypotension, hallucinations). " ... 

In patients having Parkinson s disease, both entacapone and tolcapone potentiate the therapeutic effect of L-dopa and prolong the daily ON time by 1-2 h. In the clinic, COMT inhibitors have been well tolerated, and the number of premature terminations has been low. In general, the incidence of adverse events has been higher in tolcapone-treated patients than in entacapone-treated patients. The main events have comprised of dopaminergic and gastrointestinal problems [2,3]. 

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