Overview
This lecture reviews newer anticonvulsant drugs, their mechanisms, indications, adverse effects, and key drug interactions, with emphasis on clinical highlights and dosing considerations.
Lamotrigine
- Used as adjunct for refractory epilepsy and as a mood stabilizer in bipolar disorder.
- Also indicated for Lennox-Gastaut syndrome (combined seizure types).
- Lacks IV formulation; ODT form may help patients with swallowing issues.
- Mechanism: blocks sodium channels, may affect calcium channels and neurotransmitter release.
- Start low and titrate dose slowly to minimize risk of skin rash, especially Stevens-Johnson syndrome.
- Major interaction: valproic acid inhibits metabolism, increasing lamotrigine levels and rash risk.
- Metabolized via UGT1A1, 1A4, 2B7.
Gabapentin & Pregabalin
- Both are structural GABA analogs but do not act as GABA agonists.
- Mechanism: bind to calcium channel subunit, reducing neurotransmitter release.
- Indications: partial seizures, neuropathic pain (post-herpetic neuralgia, diabetic neuropathy), restless leg, fibromyalgia.
- Dose adjustment required for renal impairment; sedation is the primary side effect.
- Pregabalin is about 3x more potent than gabapentin.
- Minimal clinically relevant drug interactions, except additive sedation.
Other Anticonvulsants: Mechanism & Side Effects
- Felbamate: NMDA receptor antagonist, used for Lennox-Gastaut; risk of aplastic anemia.
- Tiagabine: Inhibits GABA reuptake, increases GABA availability; substrate of CYP3A4; causes drowsiness, weakness.
- Topiramate: Blocks sodium channels, enhances GABA, antagonizes glutamate receptors, inhibits carbonic anhydrase; used for migraine prophylaxis; risk of acute angle-closure glaucoma, metabolic acidosis, nephrolithiasis.
- Lacosamide: Adjunct in adults, oral/IV; selectively blocks slow sodium inactivation, binds CRMP-2; risk of DRESS and first-degree heart block.
- Levetiracetam: Broad seizure use, TBI prophylaxis; mechanism may involve synaptic vesicle protein 2A; adjust dose for renal function; main issue is behavioral problems in predisposed patients.
- Vigabatrin: Irreversible inhibitor of GABA transaminase; for infantile spasms; risk of irreversible visual field loss—requires regular vision checks.
- Zonisamide: Blocks sodium and calcium channels; risk of kidney stones, hyperthermia in children, avoid in sulfa allergy due to Stevens-Johnson risk.
- Perampanel: AMPA receptor antagonist for partial/generalized seizures; black box for severe psychiatric events.
- Rufinamide: Used for Lennox-Gastaut; prolongs inactive state of sodium channels; risk of QT interval shortening.
Core Clinical Concepts
- Choose anticonvulsants based on specific indications and patient characteristics.
- Individualize therapy and educate patients/families about monitoring for side effects.
- Monotherapy effective in most, but many adjunct options exist.
- Monitor drug levels for older agents; be aware of drug interactions, especially with enzyme inducers.
- Note unusual renal dosing cutoffs for some drugs (e.g., levetiracetam).
Key Terms & Definitions
- Lennox-Gastaut syndrome — Epilepsy with mixed seizure types, often refractory to treatment.
- ODT (Oral Disintegrating Tablet) — Tablet form that dissolves in the mouth.
- Stevens-Johnson syndrome — Severe, potentially life-threatening skin reaction.
- DRESS — Drug reaction with eosinophilia and systemic symptoms (rash, organ involvement).
- AMPA/NMDA receptors — Glutamate receptors involved in excitatory neurotransmission.
- Synaptic vesicle protein 2A — Target for levetiracetam, affects neurotransmitter release.
Action Items / Next Steps
- Review part one of the anticonvulsant lecture if not already done.
- Memorize key drug indications, mechanisms, and major side effects for high-yield agents.
- Study specific drug interactions and renal dosing adjustments.
- Complete any assigned readings or practice questions on anticonvulsant pharmacology.