Pharmacology · COMT inhibitors
Tolcapone !
A COMT inhibitor that extends levodopa, reserved for selected patients because it can cause fatal liver failure.
Updated 2026-11-01
The figure shows tolcapone bound to rat COMT with its methyl donor SAM; the human enzyme has the same catechol site.
Mechanism of action
Tolcapone inhibits catechol-O-methyltransferase in the periphery and, to a small extent, in the brain. With carbidopa blocking decarboxylation, this keeps levodopa levels up for longer and increases its effect, including its adverse effects.
- Tolcapone blocks COMT in blood and, partly, in brain
- Levodopa is not methylated to 3-O-methyldopa
- Levodopa levels last longer; off time shortens
Pharmacokinetics
- Distribution
- Enters the brain only to a small extent
- Metabolism
- Extensively metabolized in the liver
Indications
- Adjunct to levodopa + carbidopa in Parkinson disease with motor fluctuations, when other add-on treatments have failed or are unsuitable Parkinson disease →
Adverse effects
Common
- Dyskinesia and nausea
- Diarrhoea
- Sleep disorders and somnolence
- Urine discoloration
Contraindications
- Liver disease, or raised liver enzymes before starting
- Previous tolcapone-induced liver injury
- History of non-traumatic rhabdomyolysis or hyperpyrexia and confusion related to medication
- Hypersensitivity to tolcapone
Key interactions
- Nonselective MAO inhibitors
- Would block most catecholamine metabolism; avoided
- Other liver-toxic drugs
- Added risk of liver injury
- Drugs metabolized by COMT (isoproterenol, epinephrine, dobutamine)
- Stronger cardiovascular effects
What is monitored
- Liver tests (ALT, AST) before starting and regularly during treatment
- Symptoms of liver injury: nausea, fatigue, anorexia, jaundice, dark urine, itching, right upper abdominal pain
- Clinical benefit early on: it is stopped if no clear benefit appears within about three weeks
Administration and safety
- Used only with levodopa + carbidopa and after informed discussion of the liver risk
- Not stopped abruptly; levodopa may need adjusting
Nursing care
- Check that liver tests are done on schedule
- Teach the warning signs of liver injury and to report them at once
- Watch for dyskinesia and hallucinations
Pregnancy and breastfeeding
Human data are lacking; it is used only if clearly needed.
Test yourself
Think of the answer, then tap the question to see it.
What is the main safety concern with tolcapone?
Fulminant, potentially fatal liver failure.
When is tolcapone stopped for lack of effect?
If no substantial clinical benefit appears within about three weeks.
How does tolcapone differ from entacapone in distribution?
Tolcapone also inhibits COMT in the brain to some extent; entacapone acts almost only peripherally.
Related drugs
Related conditions
← Back to the class: COMT inhibitors
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: DailyMed - TOLCAPONE tablet, film coated (DailyMed (U.S. National Library of Medicine), 2021); Tolcapone: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 21 (McGraw Hill, 2023).
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Representative model, for educational purposes only.