Valproic acid exerts its therapeutic effects through multiple mechanisms, which contribute to its efficacy in treating epilepsy, bipolar disorder, and migraines. Its key mechanisms include:

1. Enhancement of GABAergic Activity:
   • Valproic acid increases the levels of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, by inhibiting GABA transaminase and enhancing GABA synthesis.
   • This results in increased neuronal inhibition, reducing seizure activity and stabilizing mood.
2. Sodium Channel Blockade:
   • Valproic acid inhibits voltage-gated sodium channels, stabilizing neuronal membranes and preventing the spread of abnormal electrical activity in the brain.
3. Calcium Channel Modulation:
   • It blocks T-type calcium channels, which play a role in thalamocortical circuitry involved in absence seizures.
4. Histone Deacetylase (HDAC) Inhibition:
   • Valproic acid inhibits HDAC, which may contribute to its mood-stabilizing effects by modulating gene expression.
5. Reduction of Excitatory Neurotransmission:
   • It decreases the release of excitatory neurotransmitters like glutamate, further contributing to its anticonvulsant and neuroprotective effects.

Valproic acid is approved for a variety of clinical conditions, including:

1. Epilepsy:
   • Treatment of generalized seizures (e.g., tonic-clonic, absence, and myoclonic seizures).
   • Focal (partial) seizures with or without secondary generalization.
   • Lennox-Gastaut syndrome.
2. Bipolar Disorder:
   • Management of acute manic or mixed episodes.
   • Prophylaxis of bipolar disorder to prevent recurrence of manic or depressive episodes.
3. Migraine Prophylaxis:
   • Prevention of migraine headaches in adults and adolescents.
4. Off-Label Uses:
   • Schizophrenia (adjunctive therapy).
   • Neuropathic pain.

Agitation and aggression in dementia

The dosage of valproic acid varies depending on the indication, patient age, and clinical response. The following dosing guidelines are based on the British National Formulary (BNF) and clinical pharmacology references:

1. Epilepsy:
   • Adults: Start with 300–500 mg daily in divided doses, gradually increasing to a maintenance dose of 1–2 g daily.
   • Children: 20–30 mg/kg/day in divided doses, adjusted based on response and tolerability.
2. Bipolar Disorder:
   • Adults: Start with 750 mg daily in divided doses, increasing gradually to 1–2 g daily.
3. Migraine Prophylaxis:
   • Adults: Start with 250 mg twice daily, increasing gradually to 1 g daily if needed.

Important Considerations:

• Valproic acid is available in immediate-release, extended-release, and enteric-coated formulations.
• Therapeutic drug monitoring is recommended to maintain plasma levels within the therapeutic range (50–100 mg/L).
• Dose adjustments may be necessary for elderly patients or those with hepatic or renal impairment.

Valproic acid is associated with a range of side effects, some of which can be serious. Common side effects include:

1. Gastrointestinal: Nausea, vomiting, diarrhea, and abdominal pain.
2. Central Nervous System: Drowsiness, tremor, dizziness, and headache.
3. Weight Gain: A common side effect that may lead to metabolic syndrome.
4. Hepatotoxicity: Elevated liver enzymes and, rarely, severe liver damage.
5. Hematological: Thrombocytopenia and leukopenia.

Serious Side Effects:

• Pancreatitis: A rare but life-threatening complication.
• Hyperammonemia: Elevated ammonia levels, which can lead to encephalopathy.
• Teratogenicity: Valproic acid is associated with a high risk of congenital malformations (e.g., neural tube defects) and developmental delays when used during pregnancy.
• Hair Loss: Reversible alopecia may occur in some patients.

Valproic acid requires careful monitoring and adherence to specific precautions to ensure patient safety:

1. Pregnancy and Lactation:
   • Valproic acid is contraindicated in pregnancy unless there is no safer alternative. It is associated with a high risk of teratogenicity and neurodevelopmental disorders.
   • It is excreted in breast milk, so breastfeeding is generally not recommended.
2. Hepatic Monitoring:
   • Regular monitoring of liver function tests is essential, especially during the first six months of treatment.
3. Metabolic Monitoring:
   • Monitor for weight gain, insulin resistance, and lipid abnormalities.
4. Elderly Patients:
   • Lower doses may be required due to increased sensitivity to side effects.
5. Suicidal Risk:
   • Like other anticonvulsants, valproic acid may increase the risk of suicidal thoughts or behavior.

Valproic acid has a significant potential for drug interactions due to its effects on hepatic metabolism and protein binding. Key interactions include:

1. Other Anticonvulsants:
   • Phenytoin and carbamazepine: Reduced valproic acid levels due to enzyme induction.
   • Lamotrigine: Increased risk of severe skin reactions.
2. Antidepressants:
   • SSRIs and tricyclic antidepressants: Increased risk of serotonin syndrome.
3. Anticoagulants:
   • Warfarin: Altered anticoagulant effect due to protein binding displacement.
4. Other Interactions:
   • Aspirin: Increased valproic acid levels due to protein binding displacement.

Benzodiazepines: Enhanced CNS depression

Valproic acid is the generic name for this medication. It is marketed under various brand names, depending on the country and manufacturer. Some examples include:

• Depakote (a well-known brand in the United States and other regions).
• Epilim.
• Convulex.
• Valpro.
• Divalproex Sodium (a stabilized formulation of valproic acid).