Calcium Channel Modulating Antiseizure Medicines

Calcium channel modulating antiseizure medicines act on voltage-gated calcium channels. Ethosuximide blocks T-type channels in the thalamus. Gabapentin and pregabalin bind the alpha2delta subunit of N-type and P/Q-type channels and reduce neurotransmitter release.

Pharmacokinetics. Gabapentin absorption is saturable, so bioavailability falls as dose rises. Pregabalin absorption is linear. Both are cleared unchanged by the kidney. Ethosuximide has a long half life of 30 to 60 hours.

• Ethosuximide 250 mg twice daily, increased every week to 500 to 1,000 mg daily, maximum 1,500 mg daily; level 40 to 100 mg/L. Children 10 to 20 mg/kg daily.
• Gabapentin 300 mg on day 1, 300 mg twice daily on day 2, 300 mg three times daily on day 3, then 900 to 3,600 mg daily in three doses.
• Pregabalin 75 mg twice daily, increased to 150 to 300 mg twice daily; maximum 600 mg daily.

Differences. Ethosuximide acts only on absences. Gabapentin and pregabalin are adjuncts for focal seizures and are used more for neuropathic pain and anxiety.

• Childhood absence epilepsy: ethosuximide first-line; valproate if tonic-clonic seizures coexist.
• Focal seizures: gabapentin or pregabalin as add-on.
• Neuropathic pain: gabapentin and pregabalin are also used, with doses set by indication.

Selection. Gabapentin and pregabalin can aggravate myoclonic and absence seizures; do not use in generalised epilepsies.

Contraindications. Hypersensitivity. Ethosuximide: acute porphyria, with caution in liver disease.

Adverse effects. Gabapentin and pregabalin: dizziness, drowsiness, ataxia, weight gain, peripheral oedema, myoclonus, blurred vision, angioedema, misuse and dependence, respiratory depression with opioids. Ethosuximide: nausea, anorexia, hiccups, drowsiness, behavioural change, rarely psychosis or blood dyscrasias.

Interactions. Opioids, benzodiazepines and alcohol add central depression with pregabalin and gabapentin. Valproate raises ethosuximide levels. Aluminium antacids lower gabapentin absorption; take gabapentin 2 hours after antacids.

Special groups.

• Kidney impairment (gabapentin): creatinine clearance 30 to 59 mL/min, 400 to 1,400 mg daily in two doses; 15 to 29 mL/min, 200 to 700 mg daily; under 15 mL/min, 100 to 300 mg daily.
• Kidney impairment (pregabalin): 30 to 60 mL/min, 75 to 300 mg daily; 15 to 30 mL/min, 25 to 150 mg daily; under 15 mL/min, 25 to 75 mg daily.
• Pregnancy: limited data; avoid unless needed.
• Breastfeeding: gabapentin passes into milk in low amounts; monitor infant.
• Children: ethosuximide 10 to 20 mg/kg daily; gabapentin and pregabalin by weight.
• Older adults: lower doses; falls and confusion.
• Liver impairment: no adjustment for gabapentin and pregabalin.

Monitoring. Sedation, falls, weight, oedema, mood; ethosuximide levels and full blood count if symptoms.

Referral and escalation. Abrupt withdrawal of gabapentin or pregabalin can cause seizures; taper over at least 1 week. Suspected misuse needs review.