Valproic acid
Valproic acid (also known as valproate, sodium valproate, or divalproex sodium)
Generic Name
Valproic acid (also known as valproate, sodium valproate, or divalproex sodium)
Mechanism
- Augments GABAergic transmission
* Inhibits GABA‑transaminase, reducing GABA degradation.*
* Enhances GABA transporter activity, increasing synaptic GABA levels.*
• Voltage‑gated Na⁺‑channel blockade
* Shortens the action potential by slowing depolarization.*
• Inhibition of T-type Ca²⁺ channels (particularly in thalamocortical neurons) – important for absence seizures.
• Histone deacetylase inhibition – contributes to neuroprotective and mood‑stabilizing effects.
These complementary mechanisms account for its efficacy across multiple seizure types and psychiatric indications.
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Pharmacokinetics
- Absorption – Rapid oral absorption; peak plasma levels 1–2 h after dosing.
- Distribution – Highly protein‑bound (~90 %); crosses the blood‑brain barrier readily.
- Metabolism – Primarily hepatic via glucuronidation (UGT) and sulfation; minor CYP oxidation.
- Elimination – Renal excretion of metabolites; terminal half‑life ≈8–12 h (IV: ~3–9 h).
- Drug interactions – Metabolized by CYP2C9, CYP2C19, and CYP3A4; inhibitors/inducers alter levels (e.g., carbamazepine, phenytoin, phenobarbital).
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Indications
- Epilepsy – Myoclonic, generalized tonic‑clonic, absence, and Lennox‑Gastaut syndrome.
- Bipolar Disorder – Acute mania prophylaxis and maintenance therapy.
- Migraine Prophylaxis – When first‑line agents (e.g., propranolol) are inadequate.
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Contraindications
| Category | Key Points |
| Absolute Contraindication | Known hypersensitivity, severe hepatic disease, pregnancy (trisomy 18 & neural‑tube defects). |
| Relative Contraindication | Elderly patients, metabolic syndrome, acute pancreatitis, hyperammonemia. |
| Warnings |
• Hepatotoxicity – especially in first‑year treatment or when combined with other hepatotoxic drugs. • Pancreatitis – monitor abdominal pain and serum lipase. • Thrombocytopenia / aplastic anemia – watch platelet count. • Pregnancy – teratogenic (neural tube defects, facial dysmorphisms). • Psychiatric – may induce agitation, aggression, or depression. |
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Dosing
| Population | Loading Dose | Maintenance Dose | Formulations | Notes |
| Adults | 20–30 mg/kg/day in divided doses, max 2000 mg/day | 500–2000 mg/day (2–5 mg/kg) | Immediate‑release (IR) 250 mg tablets, extended‑release (ER) 250–500 mg tablets, sodium valproate 160 mg tablets | Start IR for rapid seizure control; switch to ER for steady state. |
| Children | 20–30 mg/kg/day (max 4000 mg/day) | 10–20 mg/kg/day | Same | Weight‑adjusted; monitor growth & developmental milestones. |
| Elderly | 2–3 mg/kg/day | 10–20 mg/kg/day | Same | Reduced metabolism; lower loading dose. |
• Administration – Oral; if vomiting, consider rectal or IV formulation.
• Titration – Increase gradually by 200–400 mg weekly, aiming for serum trough 50–100 µg/mL.
• Abrupt discontinuation – Avoid; risk of seizure recurrence and toxicity.
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Adverse Effects
Common (≥10 %)
• Gastro‑intestinal upset (nausea, vomiting, reflux)
• Tremor, ataxia, dysarthria
• Weight gain, sedation, insomnia
• Hair loss (alopecia)
• Mild elevation of transaminases
• Vitamin B6 deficiency → peripheral neuropathy
Serious (≤1 %)
• Hepatotoxicity – Acute liver failure; monitor LFTs.
• Pancreatitis – Epigastric pain, nausea, vomiting; check lipase.
• Hyperammonemia – Confusion, lethargy.
• Thrombocytopenia, aplastic anemia – Monitor CBC.
• Birth defects – Neural tube defects, facial dysmorphism.
• Psychiatric – Depression, suicidality, agitation.
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Monitoring
- Serum trough level (5–50 µg/mL for epilepsy; 50–100 µg/mL for bipolar).
- Baseline & periodic liver function tests (ALT, AST, bilirubin; every 3–6 weeks in first year).
- Lipase/amylase if abdominal pain.
- CBC, particularly platelet count; every 3–6 weeks or if clinical suspicion.
- Serum ammonia on presentation with altered mental status.
- Pregnancy test for women of childbearing potential; repeat quarterly.
- ECG if dose >1200 mg/day or with concomitant QT‑prolonging drugs.
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Clinical Pearls
- Use in the first trimester? No – the teratogenic risk far outweighs benefits. Consider lithium or other safer antimanic agents.
- Why do some patients develop pancreatitis? Often occurs early in therapy; symptoms can precede serum lipase elevation, so clinical vigilance is key.
- Extended‑release (ER) vs. immediate‑release (IR): ER offers smoother serum levels, reducing breakthrough seizures but may delay onset of action when urgently needed.
- Vitamin B6 supplementation (pyridoxine 25–100 mg/day) is reasonable for long‑term therapy to prevent neuropathy.
- Contra‑drug interactions: Concomitant carbamazepine or phenytoin *lowers* valproate levels; conversely, valproate *inhibits* phenobarbital metabolism, increasing its effects.
- Neurocognitive testing: Routine screening for learning disorders in children, as valproate may mildly affect cognitive performance when used long‑term.
- Migraine prophylaxis: Valproate’s efficacy is dose‑dependent; 250–500 mg/day is usually adequate for most patients.
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• Key Takeaway:
*Valproic acid* is a cornerstone antiepileptic and mood stabilizer, but its broad hepatic metabolism and teratogenic risk necessitate cautious dosing, vigilant monitoring, and patient education.