Drugs 2000 Jun;59(6):1233-50
Clinical pharmacology, therapeutic use and potential of COMT inhibitors in
Parkinson's disease.
Kaakkola S
Department of Neurology, University of Helsinki, Finland.
When peripheral decarboxylation is blocked by carbidopa or
benserazide, the main metabolic pathway of levodopa is O-methylation by
catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new
potent, selective and reversible nitrocatechol-type COMT inhibitors.
Animal studies have demonstrated that entacapone mainly has a
peripheral effect whereas tolcapone also inhibits O-methylation in the
brain. In human volunteers, both entacapone and tolcapone dose-dependently
inhibit the COMT activity in erythrocytes, improve the bioavailability and
decrease the elimination of levodopa, and inhibit the formation of
3-O-methyldopa (3-OMD).
Entacapone is administered with every scheduled dose of levodopa
whereas tolcapone is administered 3 times daily. The different
administration regimens for these agents are based on their different
pharmacokinetic and pharmacodynamic profiles.
Both entacapone and tolcapone enhance and extend the therapeutic
effect of levodopa in patients with advanced and fluctuating Parkinson's
disease. They prolong the duration of levodopa effect.
Clinical studies show that they increase the daily ON time by an
average 1 to 3 hours, improve the activities of daily living and allow daily
levodopa dosage to be decreased. Correspondingly, they significantly reduce
the daily OFF time. No comparative studies between entacapone and tolcapone
have been
performed. Tolcapone also appears to have a beneficial effect in patients
with nonfluctuating Parkinson's disease.
The main adverse effects of the COMT inhibitors are related to their
dopaminergic and gastrointestinal effects. Enhancement of dopaminergic
activity may cause an initial worsening of levodopa-induced adverse effects,
such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep
disorders and hallucinations. Levodopa dose adjustment is recommended to
avoid these events.
Tolcapone is associated with diarrhoea in about 16 to 18% of
patients and entacapone in less than 10% of patients. Diarrhoea has led to
discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of
those treated with entacapone. Urine discoloration to dark yellow or orange
is related to the colour of COMT inhibitors and their metabolites.
Elevated liver transaminase levels are reported in 1 to 3% of
patients treated with tolcapone but very rarely, if at all, in patients
treated with entacapone. The descriptions of acute, fatal fulminant
hepatitis and
potentially fatal neurological reactions, such as neuroleptic malignant
syndrome and rhabdomyolysis, in association with tolcapone led to the
suspension of its marketing authorisation in the European Community and
Canada. In many other countries, the use of tolcapone is restricted to
patients who are not responding
satisfactorily to other therapies. Regular monitoring of liver enzymes is
required if tolcapone is used. No such adverse reactions have so far been
described for entacapone and no laboratory monitoring has been proposed.
COMT inhibitors added to levodopa therapy are beneficial,
particularly in patients with fluctuating disease. They may be combined with
other antiparkinsonian drugs, such as dopamine agonists, selegiline and
anticholinergics without adverse interactions. They provide a new treatment
possibility in patients with
Parkinson's disease who have problems with their present levodopa therapy.
