Catechol-O-methyltransferase Inhibitors

views updated

Catechol-O-methyltransferase inhibitors


Catechol-O-methyltransferase (COMT) inhibitors are a class of medication used in combination with levodopa and carbidopa in the treatment of symptoms of Parkinson's disease (PD). COMT inhibitors such as tolcapone and entacapone optimize the active transport of levodopa to the central nervous system (CNS) and allow the administration of lower doses of both levodopa and carbidopa, which decreases or even prevents the side effects related to these two drugs.


Levodopa is a drug that helps to supplement dopamine, a neurotransmitter, to the brain of persons with PD. A neurotransmitter is a chemical that is released during a nerve impulse that transmits information from one nerve cell to another. In PD, levels of the neurotransmitter dopamine progressively decrease as the disease evolves. Drug therapy with levodopa also leads to dopamine formation in tissues outside the brain and in the gastrointestinal tract, causing undesirable side effects and reduced availability of levodopa to the nerve cells. The addition of carbidopa to the treatment regimen inhibits this action and thus, increases levodopa uptake into the brain. However, the inhibition of dopamine results in activation of certain enzymes (including catechol-O-methyltransferase) that compete with levodopa for transport to the brain. By giving drugs that reduce these enzymes, competition is reduced, and more levodopa is utilized by the brain. The administration of a COMT inhibitor drug prolongs the duration of each levodopa dose, and allows the reduction of doses of both levodopa and carbidopa by approximately 30%.


Tolcapone was the first COMT inhibitor approved by the United States Food and Drug Administration to be taken orally in association with the levodopa/carbidopa regimen. Tolcapone is readily absorbed through the gastrointestinal tract and has a fairly rapid action. The drug is metabolized in the liver and eliminated from the body through the feces and urine. However, its COMT inhibitory activity lasts much longer, due to the high affinity of tolcapone with the enzyme.

Entacapone, another COMT inhibitor, was first approved in the European Union and its effects are similar to those obtained with tolcapone when added to levodopa/carbidopa regimen.

Recommended dosage

The physician will adjust the dose of either tolcapone or entacapone to each patient in accordance with other individual clinical characteristics.


The use of tolcapone requires a reduction of levodopa/carbidopa to prevent the occurrence of levodoparelated side effects, such as low blood pressure and dizziness when rising, loss of appetite, nausea, drowsiness, and hallucinations. Patients with liver disorders or reduced liver function should not receive tolcapone due to its high toxicity to the liver cells. All patients using tolcapone should be regularly monitored by their physician and laboratory blood tests to determine the concentrations of liver enzymes should be periodically performed. As the chronic use of tolcapone may cause irreversible liver injury, any signs of dark urine, pale stools, unusual fatigue , fever, jaundice, persistent nausea or vomiting, and tenderness in the upper right side of the abdomen should be reported to the physician. Tolcapone is contraindicated in pregnant women and during breast-feeding, or to patients already suffering from low blood pressure. Kidney deficiency reduces the elimination rate of tolcapone metabolites and increases the severity of adverse effects.

Entacapone is metabolized in the liver and a pre-existing reduced liver function or chronic deficiency should be reported to the physician to allow for adjustments in dosage. Dosage adjustments or special precautions may be also necessary when entacapone is administered to patients under treatment with one or more of the following medications: isoproterenol, epinephrine, apomorphine, isoetherine, or bitolterol. Except for selegiline, all monoamine oxidase (MAO) inhibitors are contraindicated when using entacapone.

Side effects

The more common tolcapone-related side effects are abdominal pain , nausea, vomiting, diarrhea, drowsiness, sleep disorders, headache , and dizziness, especially in the first few days of treatment. Elderly patients may have hallucinatory episodes (sensations of seeing, hearing or feeling something that does not exist). Some patients report irritability, aching joints and neck, muscle cramps, agitation, ataxia , difficulty in concentrating, and increased urination. Severe episodes of diarrhea may occur after the second month of treatment.

Common side effects with entacapone are abdominal discomfort (constipation, nausea, diarrhea, abdominal pain) and fatigue, which tend to disappear as the body adapts to the medication. Some patients may experience gastritis, heartburns, belching, sleep disorders, increased perspiration, drowsiness, agitation, irritation and mood changes, and fatigue.


Patients should inform the physician of any other medication in use when tolcapone prescription is being considered. The concomitant use of entacapone and methyldopa may cause heart rhythm disturbances and abrupt changes in blood pressure.



Champe, Pamela C., and Richard A. Harvey, eds. Pharmacology, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2000.

Weiner, William J., M.D., Parkinson's Disease: A Complete Guide for Patients and Families. Baltimore: Johns Hopkins University Press, 2001.


Hubble, Jean Pintar, M.D., Richard C. Berchou, Pharm. D. "CATECHOL-O-METHYL TRANSFERASE (COMT) INHIBITORS." The National Parkinson Foundation, Inc. (April 25, 2004). <>.

"Entacapone and Tolcapone." We Move. July 25, 1999. (April 24, 2004). <>.


National Parkinson Foundation. 1501 N.W. 9th Avenue, Bob Hope Research Center, Miami, FL 33136-1494. (305) 243-6666 or (800) 327-4545; Fax: (305) 243-5595. [email protected] <>.

Sandra Galeotti