NMDA Receptor Antagonists for Dementia

NMDA receptor antagonists for dementia block excess glutamatergic stimulation of NMDA receptors that contributes to neuronal injury. Memantine is the only licensed drug and is used for moderate to severe Alzheimer disease.

Pharmacokinetics. Mostly eliminated unchanged by the kidney with a half life of 60 to 100 hours. Excretion falls when urine pH rises above 8.

• Memantine 5 mg once daily in week 1, 10 mg in week 2 (5 mg twice daily), 15 mg in week 3, then 20 mg once daily from week 4; maximum 20 mg daily.

Differences. Memantine adds to a cholinesterase inhibitor in moderate to severe disease; benefit is small.

• Moderate to severe Alzheimer disease, alone or with a cholinesterase inhibitor.
• Intolerance of or contraindication to cholinesterase inhibitors.
• Not proven in mild disease, vascular dementia or Parkinson disease dementia.

Selection. Reassess every 6 months and stop when there is no benefit or in end-stage disease.

Contraindications. Hypersensitivity. Caution in epilepsy, recent myocardial infarction, uncontrolled hypertension, and severe liver impairment.

Adverse effects. Dizziness, headache, constipation, somnolence, hypertension, confusion, hallucinations, seizures.

Interactions. Amantadine, ketamine and dextromethorphan add NMDA antagonism; avoid. Drugs that alkalinise urine (acetazolamide, topiramate, sodium bicarbonate) reduce memantine clearance.

Special groups.

• Kidney impairment: creatinine clearance 30 to 49 mL/min, 10 mg daily initially, increased to 20 mg daily if tolerated; under 30 mL/min, 10 mg daily.
• Pregnancy and breastfeeding: not indicated.
• Older adults: monitor sedation and blood pressure.
• Liver impairment: no data in severe impairment.

Monitoring. Blood pressure, confusion, sleep, kidney function, and cognition and function scores.

Referral and escalation. New seizures, worsening agitation, or persistent hypertension.