COMT inhibitors are used as adjuncts to levodopa-carbidopa ther-apy in managing patients with Parkinson’s disease who experi-ence the wearing-off effect at the end of a dosing interval.
Currently two COMT inhibitors are available:
Tolcapone and entacapone are rapidly absorbed in the GI tract and have an absolute bioavailability of 65% and 35%, respectively. Both drugs are highly bound to albumin and therefore have limit-ed distribution to the tissues. They’re almost completely metabo-lized in the liver to inactive metabolites and are excreted in urine.
Tolcapone and entacapone are selective and reversible inhibitors of COMT, the major metabolizing enzyme for levodopa, in the presence of a decarboxylase inhibitor such as carbidopa. Inhibi-tion of COMT alters the pharmacokinetics of levodopa, leading to sustained plasma levels of this drug. This results in more sus-tained dopaminergic stimulation in the brain and improvement in signs and symptoms of Parkinson’s disease.
Either tolcapone or entacapone may be added to the carbidopa-levodopa regimen of a patient who experiences wearing-off symp-toms at the end of a dosing interval or random “on-off” fluctua-tions in response to carbidopa-levodopa. COMT inhibitors have no antiparkinsonian effect when used alone and should always be combined with carbidopa-levodopa. The addition of a COMT in-hibitor often requires a decrease in the carbidopa-levodopa dosage, particularly for patients receiving a levodopa dose of more than 800 mg.
Rapid withdrawal of a COMT inhibitor may lead to parkinsonian crisis and may cause a syndrome of muscle rigidity, high fever, tachycardia, elevated serum creatine kinase, and confusion simi-lar to neuroleptic malignant syndrome. Although tapering sched-ules haven’t been evaluated, a slow tapering of the dosage is sug-gested
· COMT inhibitors shouldn’t be used concurrently with Type A MAOIs but may be used with selegiline.
· Because of MAO inhibition, COMT inhibitors shouldn’t be used with linezolid.
· Significant cardiac effects or arrhythmias may result when COMT inhibitors are combined with catecholamine drugs (dopamine, dobutamine, epinephrine, methyldopa, or norepineph-rine).
· Use of COMT inhibitors with CNS depressants (benzodi-azepines, tricyclic antidepressants, antipsychotics, ethanol, opioid analgesics, and other sedative hypnotics) may cause additive CNS effects.
· Concurrent use of entacapone and bromocriptine may cause fi-brotic complications.
· Drugs that interfere with glucuronidation (erythromycin, ri-fampin, cholestyramine, and probenecid) may decrease enta-capone elimination.
· Use of COMT inhibitors may increase the risk of orthostatic hy-potension in patients receiving dopaminergic therapy.
· Tolcapone shouldn’t be initiated in patients with evidence of liv-er disease or alanine aminotransferase or aspartate aminotrans-ferase values greater than the upper limit of normal. In addition, the patient must be advised of the risks of liver injury and must give written informed consent before receiving tolcapone. (See Adverse reactions to COMT inhibitors.)