COMT inhibitors
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
·
entacapone.
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.)
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