Mechanism of Action of Valproate
Valproate primarily works by inhibiting γ-aminobutyric acid (GABA) transaminase, which increases GABA levels in the brain, leading to enhanced inhibitory neurotransmission, while also acting as a voltage-gated sodium channel modulator to inhibit excitatory neurotransmission. 1
Primary Mechanisms
GABA-ergic Effects
- Increases brain concentrations of GABA through multiple pathways:
- These effects enhance inhibitory neurotransmission in the brain, which is crucial for seizure control
Voltage-Gated Sodium Channel Modulation
- Acts as a voltage-gated sodium channel (VGSC) modulator 1
- Inhibits sodium channels, reducing neuronal excitability 4
- This mechanism contributes significantly to its antiseizure effects
Secondary Mechanisms
Effects on Excitatory Neurotransmission
- Reduces release and/or effects of excitatory amino acids 4
- Inhibits glutamate/NMDA receptor-mediated neuronal excitation 5
- This dual action (enhancing inhibition while reducing excitation) contributes to its broad spectrum of efficacy
Neurotransmitter Modulation
- Modulates dopaminergic and serotoninergic transmission 1, 4
- May reduce gamma-hydroxybutyrate (GHB) release, which could explain its efficacy in absence seizures 5
Metabolic Effects
- May inhibit the tricarboxylic acid (TCA) cycle at the alpha-ketoglutarate dehydrogenase step 2
- Affects cerebral metabolism, which may contribute to its therapeutic effects
Clinical Relevance of Mechanisms
The multiple mechanisms of action explain valproate's broad spectrum of efficacy across different seizure types:
- Effective against generalized seizures (tonic-clonic, myoclonic, absence) and partial seizures 4
- Particularly effective in photosensitive epilepsy and myoclonus 6
- Highly effective in refractory status epilepticus with success rates of approximately 88% 1
Important Considerations
- The FDA notes that "the mechanisms by which valproate exerts its antiepileptic effects have not been established" but suggests it is related to increased brain GABA concentrations 7
- No single mechanism fully accounts for valproate's diverse clinical effects 5
- The combination of several mechanisms in one molecule likely explains its broad efficacy across different seizure types and neuropsychiatric conditions 5
The complex and multifaceted mechanism of action of valproate makes it one of the most versatile antiepileptic drugs, explaining its widespread use for various seizure types and other neuropsychiatric conditions including bipolar disorder, neuropathic pain, and migraine prophylaxis.