## Valproic Acid: Dual Mechanism of Action **Key Point:** Valproic acid is a broad-spectrum antiepileptic with two well-established mechanisms: (1) blockade of voltage-gated sodium channels and (2) enhancement of GABAergic inhibition. ### Mechanism 1: Sodium Channel Blockade Valproic acid stabilizes the inactive state of voltage-gated sodium channels, similar to phenytoin, reducing repetitive neuronal firing and membrane excitability. ### Mechanism 2: GABA Enhancement Valproic acid increases GABAergic neurotransmission through multiple pathways: - Inhibition of GABA transaminase (GABA-T), the enzyme responsible for GABA catabolism → ↑ GABA levels - Increased GABA synthesis via activation of glutamate decarboxylase (GAD) - Enhanced GABA release from presynaptic terminals **Clinical Pearl:** The dual mechanism explains valproic acid's broad efficacy across multiple seizure types (generalized tonic-clonic, absence, myoclonic, focal seizures) — a property that makes it a first-line agent in many countries despite its side-effect burden. ### Clinical Profile | Feature | Detail | |---------|--------| | **Seizure types** | Generalized, focal, absence, myoclonic | | **Major side effects** | Hepatotoxicity, teratogenicity (neural tube defects), weight gain, tremor, hair loss | | **Monitoring** | LFTs, ammonia levels (hyperammonemia), CBC | | **Pregnancy** | Contraindicated; high teratogenic risk | **High-Yield:** The GABA enhancement mechanism is frequently tested as a distinguishing feature of valproic acid from other antiepileptics.
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