Neuropharmacology
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Pharmacology of Epilepsy
Antiseizure drug mechanisms grouped by sodium channel blockade, GABAergic enhancement, and synaptic vesicle protein binding.
Seizure Pathophysiology
Seizures result from excessive, synchronous neuronal firing. An imbalance between excitation (glutamate) and inhibition (GABA) is fundamental. Focal seizures arise from a discrete cortical focus; generalized seizures involve both hemispheres from onset. The choice of antiseizure medication (ASM) depends on seizure type.
Mechanism-Based Classification
Sodium Channel Blockers
These drugs stabilize the inactivated state of voltage-gated sodium channels, reducing repetitive neuronal firing without affecting normal single action potentials (use-dependent blockade).
- Carbamazepine, oxcarbazepine -- first-line for focal seizures; carbamazepine induces CYP3A4 (drug interactions)
- Phenytoin -- effective but narrow therapeutic index, saturation kinetics, and cosmetic side effects (gingival hyperplasia, hirsutism)
- Lamotrigine -- broad-spectrum (focal and generalized); also reduces glutamate release; requires slow titration to avoid Stevens-Johnson syndrome
- Lacosamide -- enhances slow inactivation of sodium channels (distinct mechanism)
GABAergic Enhancement
- Valproate -- multiple mechanisms (sodium channels, T-type calcium channels, GABA-T inhibition); broad-spectrum; teratogenic (neural tube defects)
- Phenobarbital -- enhances GABA-A (prolongs channel opening); oldest ASM, still used in resource-limited settings
- Benzodiazepines -- first-line for status epilepticus (IV diazepam, lorazepam, midazolam)
- Vigabatrin -- irreversible GABA-T inhibitor; risk of visual field defects
Synaptic Vesicle Protein 2A (SV2A) Binding
- Levetiracetam -- binds SV2A to modulate neurotransmitter release; broad-spectrum, few drug interactions, renal clearance; may cause irritability
- Brivaracetam -- higher SV2A affinity than levetiracetam
Calcium Channel Modulation
- Ethosuximide -- blocks T-type calcium channels in thalamocortical neurons; first-line for absence seizures only
- Gabapentin, pregabalin -- bind alpha-2-delta subunits; adjunctive for focal seizures and neuropathic pain
Glutamate Antagonism
- Perampanel -- non-competitive AMPA receptor antagonist; adjunctive for focal and primary generalized tonic-clonic seizures
Key Takeaways
- Sodium channel blockers are the backbone of focal epilepsy treatment
- Broad-spectrum agents (valproate, lamotrigine, levetiracetam) treat both focal and generalized seizures
- Ethosuximide is uniquely effective for absence seizures via T-type calcium channel blockade
- Status epilepticus requires urgent IV benzodiazepines as first-line therapy