What is the mechanism of action of valproic acid (Valproate)?

Mechanism of Action of Valproic Acid

Valproic acid 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 (VGSC) modulator to inhibit excitatory neurotransmission. 1

Primary Mechanisms

Valproic acid has multiple mechanisms of action that contribute to its effectiveness as an antiseizure medication:

1. GABA-ergic Effects:

   • Inhibits GABA transaminase, increasing GABA levels in the brain 1, 2
   • Enhances inhibitory neurotransmission by potentiating GABAergic functions in specific brain regions involved in seizure control 3
   • Increases GABA synthesis and release 4

2. Voltage-Gated Sodium Channel Modulation:

   • Acts as a voltage-gated sodium channel (VGSC) modulator 1
   • Inhibits sodium channels, reducing neuronal excitability 3
   • Produces direct effects on excitable membranes 4

3. Effects on Excitatory Neurotransmission:

   • Reduces release and/or effects of excitatory amino acids 3
   • Attenuates neuronal excitation induced by NMDA-type glutamate receptors 4
   • Reduces the release of the epileptogenic amino acid gamma-hydroxybutyric acid 4

Secondary Mechanisms

Beyond its primary antiepileptic mechanisms, valproic acid also affects:

• Monoaminergic Transmission:

  • Modulates dopaminergic and serotoninergic transmission 1, 4
  • Alters dopaminergic and serotonergic functions as demonstrated in microdialysis studies 4

• Intracellular Signaling:

  • Affects intracellular signaling proteins 5
  • Regulates gene expression through epigenetic mechanisms 6

• Epigenetic Effects:

  • Directly inhibits histone deacetylases (HDACs) activity 6
  • Induces chromatin remodeling 6

Clinical Relevance of Mechanism

The multiple mechanisms of action explain valproic acid's broad spectrum of activity:

• Effective against all seizure types, including partial seizures and generalized tonic-clonic seizures 3
• First-choice agent for most forms of idiopathic and symptomatic generalized epilepsies 3
• Particularly valuable in epilepsy syndromes with multiple seizure types (tonic-clonic, myoclonic, absence) 3
• Effective in refractory status epilepticus with a high success rate (88%) 7

Pharmacodynamic Considerations

• The relationship between plasma concentration and clinical response is not well documented 2
• Therapeutic range in epilepsy is commonly considered to be 50-100 mcg/mL of total valproate 2
• Protein binding is concentration-dependent, with the free fraction increasing from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL 2

Important Clinical Implications

• Valproate has a more favorable side effect profile compared to barbiturates and propofol for status epilepticus, with less respiratory depression and hypotension 7
• For refractory status epilepticus, valproic acid can be administered at 30 mg/kg IV infused at 6 mg/kg per hour, followed by maintenance at 1-2 mg/kg per hour 7
• Common adverse effects include gastrointestinal disturbances, tremor, and weight gain 3
• Rare but serious adverse effects include hepatotoxicity, pancreatitis, and teratogenicity 3

The complex and multifaceted mechanism of action of valproic acid explains its broad spectrum of efficacy in treating various seizure types and its utility in other neuropsychiatric conditions beyond epilepsy.