Pharmacology of Epilepsy

## 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