Entacapone

⚠️ Key Point: Always reduce the total Levodopa (Madopar/Sinemet) dose by 10–30% before starting Entacapone to prevent excessive dopaminergic side effects such as dyskinesia or hallucinations. 🔗 Check the BNF entry here for latest dosing and cautions.

🧠 About

• Entacapone is a selective, reversible catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to Levodopa in the management of Parkinson’s disease.
• By inhibiting peripheral metabolism of Levodopa, it increases the plasma half-life and CNS availability of Levodopa.
• It is used when patients experience "wearing-off" fluctuations between Levodopa doses despite optimal dopaminergic therapy.
• Always used in combination with Levodopa/Carbidopa or Levodopa/Benserazide; never as monotherapy.

⚙️ Mode of Action

• Levodopa is metabolised by two main enzymes: dopa decarboxylase and COMT.
• COMT converts Levodopa into 3-O-methyldopa (3-OMD), which competes with Levodopa for CNS transport across the blood–brain barrier.
• Entacapone inhibits COMT in the periphery, leading to:
  • ↑ plasma Levodopa concentration and duration of action,
  • ↓ formation of 3-OMD,
  • Improved “on-time” and reduced motor fluctuations.
• It does not cross the blood–brain barrier (unlike tolcapone).

💊 Indications & Dose

• Parkinson’s disease with motor fluctuations (“wearing-off” phenomenon):
  • Entacapone 200 mg orally with each dose of Levodopa/Carbidopa or Levodopa/Benserazide.
  • Maximum total daily dose: 2 g (10 doses per day).
  • Entacapone is also available as a combination tablet with Levodopa/Carbidopa (e.g. Stalevo®).
• Reduce Levodopa by 10–30% before starting to avoid dopaminergic overstimulation.

🧪 Pharmacology

• Class: Catechol-O-methyltransferase inhibitor (COMT inhibitor).
• Half-life: ~1.5–2 hours.
• Metabolism: Hepatic (glucuronidation); inactive metabolites.
• Excretion: Mostly faecal, minimal renal elimination.
• Colour change: May cause harmless brown-orange urine discolouration due to metabolites.

🤝 Interactions

• Iron tablets: may reduce absorption — separate by at least 2–3 hours.
• Levodopa: potentiates effects; adjust dose carefully.
• MAO inhibitors (non-selective): contraindicated — risk of hypertensive crisis.
• Warfarin: may increase INR; monitor more frequently.

⚠️ Cautions

• Always reduce existing Levodopa dose before initiation to reduce risk of dyskinesia and confusion.
• Ischaemic heart disease or arrhythmias: monitor carefully for dopaminergic side effects (palpitations, orthostatic hypotension).
• Psychiatric disease: may exacerbate hallucinations or impulse-control disorders.
• Hepatic impairment: avoid in moderate–severe dysfunction.

⛔ Contraindications

• History of neuroleptic malignant syndrome (NMS).
• Rhabdomyolysis (previous or current).
• Phaeochromocytoma (risk of hypertensive crisis).

💢 Side Effects

• Common: dyskinesias, nausea, vomiting, diarrhoea, abdominal pain, constipation, dry mouth.
• Neuropsychiatric: confusion, hallucinations, vivid dreams, insomnia.
• Autonomic: hypotension, sweating, fatigue.
• Cardiovascular: may exacerbate ischaemic heart disease.
• Urine: harmless brown-orange discolouration.

🧠 Clinical Pearls

• Entacapone is particularly useful when “end-of-dose” deterioration appears despite optimised Levodopa dosing.
• Unlike Tolcapone, Entacapone is not hepatotoxic and does not require liver function monitoring.
• If dyskinesia worsens after initiation, reduce Levodopa dose slightly rather than discontinuing Entacapone.
• Explain urine discolouration to patients to prevent anxiety.
• In advanced disease, consider triple therapy (Levodopa + DDC inhibitor + COMT inhibitor) before moving to apomorphine or deep brain stimulation.

📚 References

• BNF: Entacapone
• NICE NG71: Parkinson’s disease in adults (2023 update).
• UpToDate: “COMT inhibitors in Parkinson’s disease.”
• British Geriatrics Society: “Dopaminergic therapy and delirium risk in older adults.”