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Pharmacology · COMT inhibitors

Entacapone !

A COMT inhibitor given with every levodopa + carbidopa dose to make it last longer. Colours urine brownish-orange.

Updated 2026-11-01

  • Class: COMT inhibitors
  • Enzyme: Catechol-O-methyltransferase (COMT)
  • ATC code: N04BX02

The figure shows tolcapone in rat COMT; entacapone is a related nitrocatechol that occupies the same catechol site.

Target in 3D: Catechol-O-methyltransferase (COMT). PDB structure 3S68 (RCSB PDB, public domain). View the structure at RCSB PDB

Mechanism of action

Entacapone reversibly inhibits catechol-O-methyltransferase, mostly outside the brain. With DOPA decarboxylase blocked by carbidopa, COMT becomes the main route that destroys levodopa; blocking it raises levodopa exposure and prolongs its half-life, so each dose lasts longer.

  1. Carbidopa blocks decarboxylation of levodopa
  2. Entacapone blocks COMT, the next breakdown route
  3. Levodopa stays longer in the blood
  4. On time lasts longer; wearing-off is reduced

Pharmacokinetics

Metabolism
Almost completely metabolized before excretion; very little unchanged in urine
Elimination
Mainly through the bile
Onset and duration
From the first dose; it raises levodopa exposure and prolongs levodopa's half-life

Indications

Adverse effects

Common

  • Dyskinesia (levodopa effect increased)
  • Nausea and abdominal pain
  • Diarrhoea
  • Brownish-orange urine (harmless)

Contraindications

  • Hypersensitivity to entacapone
  • Nonselective MAO inhibitors (combination avoided)

Key interactions

Nonselective MAO inhibitors (phenelzine, tranylcypromine)
Would block most catecholamine metabolism; avoided
Drugs metabolized by COMT (isoproterenol, epinephrine, dobutamine)
Greater rise in heart rate and possible arrhythmias

What is monitored

  • Dyskinesia (levodopa dose may need lowering)
  • Bowel habit and weight (diarrhoea)
  • Blood pressure and hallucinations

Administration and safety

  • Always given together with each levodopa + carbidopa dose
  • Also exists in a fixed tablet with levodopa and carbidopa
  • Not stopped abruptly: withdrawal can worsen parkinsonism

Nursing care

  • Explain the urine colour change in advance
  • Record dyskinesias and off periods after starting
  • Ask about diarrhoea, which can appear weeks or months later
  • Teach to rise slowly

Pregnancy and breastfeeding

Human data are lacking; animal studies at high doses showed fetal variations.

Test yourself

Think of the answer, then tap the question to see it.

Why does entacapone only work when levodopa is given with carbidopa?

With decarboxylase blocked, COMT is the main route destroying levodopa; entacapone has no effect of its own.

Which harmless change should patients be warned about?

Brownish-orange discolouration of the urine.

Why can dyskinesia increase after adding entacapone?

It raises and prolongs levodopa levels, so the levodopa dose may need to be lowered.

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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 - ENTACAPONE tablet (DailyMed (U.S. National Library of Medicine), 2026); Entacapone: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2024); 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.