Overview
This lecture reviews the major anticonvulsant (antiepileptic) drug classes, focusing on their mechanisms, clinical use, side effects, and important exam-related pearls, especially for seizure management and epilepsy.
Seizure Pathophysiology & Drug Mechanisms
- Seizures result from abnormal, excessive neuronal firing, often due to imbalances in excitation (glutamate) and inhibition (GABA).
- Action potentials are propagated by sodium (Na+) influx; some drugs block this to prevent firing.
- Refractory periods after depolarization are targeted to prevent rapid, repetitive firing.
- Chloride (Cl-) influx (via GABA activation) hyperpolarizes neurons, making them less excitable.
- Calcium (Ca2+) influx is essential for neurotransmitter release; some drugs block Ca2+ channels.
Sodium Channel Blockers: Key Agents
- Phenytoin: Used for generalized tonic-clonic seizures; worsens absence seizures; blocks Na+ channels, prolongs inactivation, and stabilizes membranes.
- Narrow therapeutic window; nonlinear (zero-order) kinetics at higher doses.
- Requires drug-level monitoring; highly protein-bound—measure free levels if albumin is low.
- Side effects: CNS depression, gingival hyperplasia, hirsutism, fetal hydantoin syndrome, drug interactions (CYP450 inducer), DRESS syndrome.
- IV formulation only (not IM); use IV slowly to avoid arrhythmias/hypotension.
- Fosphenytoin: Prodrug of phenytoin, can be given IM or IV faster.
- Carbamazepine: Used for partial/tonic-clonic seizures, trigeminal neuralgia, and bipolar disorder.
- Also blocks Na+ channels; worsens absence/myoclonic seizures.
- Induces its own metabolism and CYP450s, leading to autoinduction.
- Black box: HLA-B*1502 increases risk of Stevens-Johnson Syndrome, especially in Asian patients.
- Other side effects: agranulocytosis, hyponatremia (SIADH), CNS depression.
- Oxcarbazepine/Eslicarbazepine: Related to carbamazepine, used for partial seizures, less enzyme induction, but may still cause similar side effects.*
Other Mechanism Agents & Indications
- Valproic Acid: Broad spectrum—used in absence, complex partial, tonic-clonic seizures, bipolar disorder, migraine prophylaxis.
- Inhibits Na+ channels and increases GABA by blocking GABA transaminase.
- Side effects: GI upset, weight gain, liver toxicity, teratogenicity (neural tube defects), thrombocytopenia, hyperammonemia (treat with L-carnitine if ammonia >100).
- Drug interactions: inhibits UGT (notably increases lamotrigine levels).
- Ethosuximide: Drug of choice for absence seizures; blocks T-type Ca2+ channels.
- Side effects: GI upset, rash, leukopenia.
- Phenobarbital/Primidone: Enhances GABA-mediated inhibition, direct GABA channel action, and may decrease glutamate.
- Used for generalized seizures; high sedation risk; monitor levels; induces CYP450; risk of respiratory depression at high levels.
Key Terms & Definitions
- Action Potential — Electrical signal carried along neurons.
- GABA — Major inhibitory neurotransmitter in the CNS.
- Glutamate — Major excitatory neurotransmitter in the CNS.
- Zero-Order Kinetics — Drug elimination rate becomes constant regardless of concentration.
- Autoinduction — A drug increases its own metabolism over time.
- DRESS Syndrome — Drug Reaction with Eosinophilia and Systemic Symptoms.
- SIADH — Syndrome of Inappropriate Antidiuretic Hormone secretion.
Action Items / Next Steps
- Memorize drug indications, mechanisms, and key side effects.
- Know which drugs worsen absence seizures.
- Remember major genetic risks (e.g., HLA-B*1502 for carbamazepine).
- Review dosing principles, especially therapeutic ranges and loading doses.
- Read about newer anticonvulsants and their unique features for part two.*