Valproate sodium
Valproate sodium
Generic Name
Valproate sodium
Mechanism
Valproate sodium is a broad‑spectrum antiepileptic and mood stabilizer that exerts its therapeutic effects through multiple, partially overlapping mechanisms:
• Neurotransmitter modulation – increases gamma‑aminobutyric acid (GABA) availability by inhibiting GABA transaminase and succinate‑CoA ligase, thereby enhancing inhibitory synaptic transmission.
• Sodium‑channel blockade – covalently attaches to the inactivated state of voltage‑gated sodium channels, prolonging depolarization and reducing burst firing.
• T-type calcium‑channel inhibition – suppresses low‑threshold calcium currents, limiting rebound excitatory activity.
• Metabolism‑related actions – increases free radical scavenging and reduces lipid peroxidation, contributing to neuroprotection.
These actions account for its efficacy in generalized seizures, absence seizures, myoclonic epilepsy, and bipolar disorder.
Pharmacokinetics
| Parameter | Typical Value | Notes | |
| Absorption | Rapid oral absorption (T_max ≈ 2 h) | Complete bioavailability ≈ 90 % under therapeutic dosing; fasting slightly ↓ | |
| Distribution | Volume of distribution ≈ 0.3–0.8 L/kg (protein‑binding ≈ 90 %) | Serum albumin ↓ → ↑ free drug; dose adjustment in hepatic disease | |
| Metabolism | Primarily hepatic conjugation; ~30 % glucuronidation, ~70 % mitochondrial β‑oxidation; minor CYP450 involvement | Saturable metabolism at high doses | |
| Elimination | Renal excretion accounts for ~25 % of dose; enterohepatic circulation common | Half‑life 9–16 h (oral), 2–3 h (IV) | |
| Toxicity threshold | Plasma valproate > 50 µg/mL (≈ 200 mg/L) ↑ adverse effect risk |
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Indications
Valproate sodium is indicated for:
• Epilepsy – generalized tonic–clonic, absence, myoclonic, Lennox‑Gastaut, and juvenile myoclonic epilepsy.
• Bipolar disorder – acute mania and maintenance therapy.
• Migraine prophylaxis – moderate‑to‑severe episodic migraine.
• Antiepileptogenic – prophylaxis post‑traumatic brain injury (off‑label, evidence evolving).
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Contraindications
- Absolute contraindications
- Hepatic disease with altered liver function tests (AST/ALT > 3× ULN)
- Known hypersensitivity to valproate or its excipients
- Relative contraindications
- Pregnancy (teratogenic risk → must use effective contraception)
- Women of childbearing potential unless on reliable contraception
- Severe renal insufficiency (eGFR < 30 mL/min/1.73 m²)
- Warnings
- Hepatotoxicity – periodic LFTs, especially first 12 weeks.
- Pancreatitis – acute abdominal pain & elevated lipase.
- Weight gain & metabolic syndrome – monitor BMI and fasting lipids.
- Teratogenicity – neural tube defects, oral clefts, developmental delay.
- Drug interactions – CYP inhibitors/inducers, other anticonvulsants (e.g., carbamazepine).
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Dosing
| Population | Loading Dose | Maintenance Dose | Titration |
| Adults (egfr > 30 mL/min) | 15–20 mg/kg IV over 10 min (max 1,500 mg) | 1,000–2,000 mg/day in 2–4 divided doses | Increase 200 mg/day every 1–2 weeks, aim for serum 50–100 µg/mL |
| Children 2–11 yrs | 40–60 mg/kg/day (1–2 divided doses) | 20–60 mg/kg/day | Adjust per serum levels |
| Pregnancy (pregnancy‑3) | 1,200–2,400 mg/day | 1,000–1,800 mg/day | Maintain therapeutic trough 50–100 µg/mL; avoid early pregnancy |
| Renal impairment | 10–15 mg/kg/day | 15–25 mg/kg/day | Titrate slower; monitor serum levels |
• Route – oral tablets or liquid suspension; IV infusion for status epilepticus.
• Food – absorption unaffected; can be taken with or without meals.
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Adverse Effects
Common (≥5 %)
• Nausea, vomiting, dizziness, somnolence, ataxia
• Weight gain, tremor, blurred vision
• Alopecia, mild hypertrichosis
Serious (≤1 %)
• Hepatotoxicity – liver enzyme elevation, jaundice, hepatic failure
• Pancreatitis – epigastric pain, nausea, vomiting, abdominal tenderness
• Teratogenicity – neural tube defects, developmental delay, craniofacial anomalies
• Serotonin syndrome – when combined with SSRIs, SNRIs, tramadol, or MAOIs
• Wernicke encephalopathy – thiamine depletion in long‑term therapy
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Monitoring
| Parameter | Frequency | Rationale |
| Serum valproate | 1–2 weeks after initiation, then monthly for first 3 months, quarterly thereafter | Ensure therapeutic range, avoid toxicity |
| Liver function tests (AST, ALT, bilirubin) | Pretreatment, 2 weeks, 4 weeks, 6 weeks, 3 months | Detect hepatotoxicity early |
| Lipase / amylase | Before dose > 1,000 mg/day or if abdominal pain | Pancreatitis screening |
| CBC (especially platelets) | Quarterly | Thrombocytopenia or anemia risk |
| Renal panel | Every 3 months | Adjust dosing in renal compromise |
| Pregnancy test | Before therapy & periodically in women of childbearing age | Teratogenic monitoring |
| Weight & BMI | Every visit | Monitor metabolic side effect |
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Clinical Pearls
- “Therapeutic window” – Keep trough levels 50–100 µg/mL; above 100 µg/mL increases hepatotoxicity without added benefit.
- “Add‑on” caution – Avoid co‑administration with phenytoin, carbamazepine, or allopurinol; these induce valproate metabolism and lower serum levels.
- “Embryo risk” – Counsel all women of childbearing potential on strict contraception; consider alternative monotherapy for acute mania during pregnancy.
- “IV loading dose” – Even at 1,500 mg IV, do *not* exceed the recommended daily maintenance limit; this prevents paradoxical seizure aggravation.
- “Weight loss strategy” – Combine valproate with lifestyle counseling and consider switching to levetiracetam or lamotrigine if weight gain exceeds 10 % body weight.
- “Tapering” – When discontinuing, taper at 50–75 mg/day every 4–6 weeks to prevent breakthrough seizures.
- “Toxicity signs” – Promptly evaluate any onset of abdominal pain, jaundice, or elevated LFTs; early intervention improves outcomes.
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