Valproate

1. Drug Name

• Generic Name: Valproate (Valproic Acid)

• Brand Names: Depakote, Depakene, Epival

2. Drug Classification

• Class: Anticonvulsant

• Subclass: Fatty acid derivative

3. Mechanism of Action

• Valproate increases gamma-aminobutyric acid (GABA) levels in the brain by enhancing GABA synthesis and inhibiting GABA degradation, leading to reduced excitability of neurons.

• It also inhibits voltage-gated sodium channels and T-type calcium channels, which contributes to its anticonvulsant and mood-stabilizing effects by stabilizing neuronal membranes and preventing rapid firing of neurons.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Nearly 100% with oral administration; varies with formulation.

  • Tmax: Peaks at around 1–4 hours (delayed with enteric-coated or extended-release formulations).

• Distribution:

  • Volume of Distribution (Vd): Approximately 0.1–0.4 L/kg.

  • Protein Binding: Highly protein-bound (~90%); binding decreases with higher doses.

• Metabolism:

  • Primary Site: Extensively metabolized in the liver via glucuronidation and beta-oxidation.

  • Minor metabolism via CYP2C9, CYP2C19, and CYP2A6 enzymes.

• Excretion:

  • Half-life (t½): Ranges from 9–16 hours, longer in elderly or with impaired hepatic function.

  • Routes: Primarily excreted in the urine as metabolites.

• Special Considerations:

  • Renal/Hepatic Impairment: Reduced clearance in hepatic impairment; dose adjustment required.

  • Age/Gender: Half-life may vary by age, with shorter half-lives in children.

5. Indications

• Primary Indications:

  • Epilepsy: Effective for generalized seizures (e.g., absence, myoclonic, tonic-clonic).

  • Bipolar Disorder: Commonly used for acute manic episodes and maintenance.

• Off-label Uses:

  • Migraine Prophylaxis: Reduces frequency of migraines in chronic migraine sufferers.

• Special Populations:

  • Often preferred in adolescents with epilepsy but avoided in pregnant women due to teratogenic risks.

6. Dosage and Administration

• Adult Dosing:

  • Epilepsy: Initial dose of 10–15 mg/kg/day, increasing by 5–10 mg/kg/week to a typical maintenance dose of 30–60 mg/kg/day.

  • Bipolar Disorder: Starting dose of 750 mg/day in divided doses, adjusted to clinical response.

• Pediatric Dosing:

  • Epilepsy: Start with 10–15 mg/kg/day, increase gradually to a maximum of 60 mg/kg/day.

• Dose Adjustments:

  • Liver Disease: Lower doses due to reduced clearance.

  • Elderly Patients: Generally require lower doses; monitor plasma levels carefully.

7. Contraindications

• Absolute Contraindications:

  • Severe hepatic impairment and known mitochondrial disorders (e.g., Alpers-Huttenlocher syndrome).

  • Hypersensitivity to valproate or its components.

  • Pregnancy: Strong contraindication due to teratogenicity and developmental risks.

• Relative Contraindications:

  • Thrombocytopenia: Caution due to risk of further lowering platelet count.

  • Pancreatic Disease: History of pancreatitis is a relative contraindication.

8. Warnings and Precautions

• Black Box Warnings:

  • Hepatotoxicity: Increased risk of severe liver failure, especially in children under two or in patients with mitochondrial disorders; regular liver function monitoring required.

  • Pancreatitis: Risk of life-threatening pancreatitis; patients should be advised to report abdominal pain, nausea, and vomiting.

  • Teratogenicity: High risk of neural tube defects and other congenital malformations when used in pregnancy.

• Other Warnings:

  • Hyperammonemia: May cause hyperammonemia, particularly when combined with other antiepileptics.

  • Thrombocytopenia: Risk of low platelet count; monitor platelet levels regularly.

  • CNS Effects: Sedation and cognitive impairment are common, especially at higher doses.

9. Adverse Effects

• Common Adverse Effects:

  • GI Symptoms: Nausea, vomiting, and indigestion.

  • Weight Gain and increased appetite.

  • CNS Effects: Drowsiness, dizziness, and tremors.

• Less Common but Clinically Significant:

  • Alopecia: Hair loss, which may be dose-dependent.

  • Menstrual Irregularities: Amenorrhea or dysmenorrhea.

• Rare/Serious:

  • Liver Failure: Potentially fatal, especially in young children.

  • Pancreatitis: Rare but severe risk; requires immediate discontinuation if suspected.

  • Bone Marrow Suppression: Risk of anemia, leukopenia, and thrombocytopenia.

10. Drug Interactions

• CYP Inhibitor: Valproate inhibits CYP2C9 and may raise levels of drugs like warfarin and phenytoin.

• Other Anticonvulsants: Interacts with carbamazepine, phenytoin, and lamotrigine, affecting plasma concentrations and efficacy.

• Alcohol and CNS Depressants: Increase sedation and CNS depression risk.

• Carbapenem Antibiotics: Rapidly decrease valproate levels, leading to loss of seizure control.

11. Clinical Pharmacology

• Pharmacodynamics: Increases GABA availability and stabilizes neuronal activity through inhibition of sodium and calcium channels.

• Therapeutic Range: Plasma levels for seizure control are typically between 50–100 µg/mL.

12. Special Populations

• Pregnancy: Category D; associated with neural tube defects and cognitive impairment; alternative treatments are recommended.

• Lactation: Excreted in breast milk; generally considered safe, but monitor infant for sedation or feeding issues.

• Geriatrics: Increased sensitivity to adverse effects; lower initial doses and frequent monitoring are advised.

• Pediatrics: Higher risk of hepatotoxicity, especially in children under two years.

13. Therapeutic Uses

• First-Line: Widely used for generalized seizures and as an alternative for partial seizures.

• Second-Line: For bipolar disorder as an alternative or adjunct to lithium or atypical antipsychotics.

• Migraine Prophylaxis: Especially in cases unresponsive to other treatments.

14. Monitoring and Follow-Up

• Liver Function Tests: Baseline and regular monitoring, especially in the first six months.

• Blood Ammonia Levels: Monitor if there are signs of hyperammonemia.

• Platelet Count and Coagulation Tests: Baseline and periodic checks due to thrombocytopenia risk.

• Therapeutic Drug Monitoring: Periodic plasma level assessments to ensure therapeutic range.

15. Overdose Management

• Symptoms of Overdose: CNS depression, respiratory depression, hypotension, metabolic acidosis, and hyperammonemia.

• Treatment:

  • Supportive Care with airway management, IV fluids, and symptomatic treatment.

  • Activated Charcoal if overdose occurred within 1–2 hours.

  • Hemodialysis in severe cases or in patients with renal impairment to enhance clearance.

16. Patient Counseling Information

• Key Points:

  • Take valproate with food to reduce GI upset.

  • Adherence: Emphasize the importance of consistent daily intake and not skipping doses.

  • Report symptoms like severe abdominal pain (pancreatitis), jaundice, or unusual bleeding immediately.

• Signs to Watch For:

  • Unusual fatigue or jaundice as indicators of liver problems.

  • Severe abdominal pain that could indicate pancreatitis.

• Lifestyle: Avoid alcohol and sedatives as they may enhance drowsiness and CNS depression.