Amantadine and NMDA Related Therapy

Amantadine is a weak NMDA receptor antagonist with additional dopaminergic and anticholinergic effects. It reduces levodopa-induced dyskinesia and gives mild benefit in early Parkinson disease. Memantine is the related NMDA antagonist for dementia.

Pharmacokinetics. Eliminated unchanged by the kidney with a half life of about 12 to 18 hours, rising sharply in kidney impairment. Elimination uses renal tubular cation transport.

• Amantadine 100 mg once daily, increased to 100 mg twice daily; maximum 400 mg daily. Extended-release 137 to 274 mg once daily where available.
• Memantine 5 mg daily, increased to 20 mg daily; used in dementia.

Differences. Amantadine acts within days; benefit may fade over months. Memantine is not used for Parkinson disease motor symptoms.

• Levodopa-induced dyskinesia: amantadine 100 mg twice daily reduces dyskinesia by about 40 percent.
• Early mild Parkinson disease: short-term option.
• Drug-induced parkinsonism: alternative to an anticholinergic drug.
• Fatigue in multiple sclerosis: 100 mg twice daily.

Selection. Avoid in older adults with cognitive impairment.

Contraindications. Severe kidney failure (creatinine clearance under 15 mL/min) unless dose adjusted, uncontrolled epilepsy, QT prolongation, untreated narrow-angle glaucoma.

Adverse effects. Livedo reticularis, ankle oedema, confusion, hallucinations, insomnia, vivid dreams, dry mouth, nausea, orthostatic hypotension, seizures, delirium. Abrupt withdrawal can cause rebound and a neuroleptic malignant-like state.

Interactions. Anticholinergic drugs add confusion. Memantine, ketamine and dextromethorphan add NMDA effects. Trimethoprim with sulfamethoxazole, thiazides and triamterene raise amantadine levels. QT-prolonging drugs add risk.

Special groups.

• Kidney impairment: creatinine clearance 30 to 50 mL/min, 200 mg on the first day then 100 mg daily; 15 to 29 mL/min, 200 mg on the first day then 100 mg on alternate days; under 15 mL/min or on haemodialysis, 200 mg every 7 days.
• Pregnancy: avoid.
• Breastfeeding: avoid.
• Older adults: use the lowest dose and monitor confusion.
• Liver impairment: no adjustment.

Monitoring. Kidney function, mental state, oedema, skin, and ECG when QT risk exists.

Referral and escalation. New psychosis, seizures or rising creatinine; severe dyskinesia needs consideration of advanced therapy.