AMPA Receptor Antagonists

AMPA receptor antagonists block postsynaptic glutamate AMPA receptors and reduce excitatory transmission. Perampanel is the only licensed drug in this class and is used as an add-on for focal seizures and generalised tonic-clonic seizures.

Pharmacokinetics. Fully absorbed; half life about 105 hours, shortening to about 25 hours with enzyme inducers. Cleared by CYP3A4 and glucuronidation.

• Perampanel 2 mg once daily at bedtime, increased by 2 mg every 1 to 2 weeks to 4 to 8 mg daily; maximum 12 mg daily.

Differences. Once daily dosing is convenient but the long half life delays steady state and withdrawal effects.

• Add-on therapy for focal seizures with or without secondary generalisation from age 4, and for primary generalised tonic-clonic seizures from age 7 where licensed.
• Use after at least 2 other drugs have failed.
• Start at 2 mg, even in patients on enzyme inducers, and increase slowly.

Selection. Not first-line. Avoid in people with a history of aggression or psychiatric disease.

Contraindications. Hypersensitivity. Serious psychiatric or behavioural reactions are a boxed warning.

Adverse effects. Dizziness, somnolence, ataxia, falls, irritability, aggression, hostility, weight gain, and rarely suicidal ideation.

Interactions. Carbamazepine, oxcarbazepine and phenytoin reduce perampanel levels by about two thirds. At 12 mg daily perampanel reduces levonorgestrel contraceptive efficacy.

Special groups.

• Pregnancy: limited data; avoid unless needed.
• Breastfeeding: avoid.
• Children: licensed doses start at 2 mg from age 4.
• Older adults: increase slowly; falls.
• Liver impairment: mild to moderate, maximum 8 mg daily; avoid in severe.
• Kidney impairment: moderate, use caution; avoid in severe.

Monitoring. Mood, behaviour, falls and weight at each dose step.

Referral and escalation. Stop for new aggression, psychosis or suicidal thoughts and seek psychiatric review.