Depakote
Valproic acid
Generic Name
Valproic acid
Mechanism
- Increase GABA concentrations
* Inhibits GABA‑transaminase and GABA‑T-1 transporters → higher intracellular GABA, enhancing inhibitory neurotransmission.
• Block voltage‑gated Na⁺ channels
* Prolongs the inactivated state, reducing neuronal firing.
• Reduce glutamate activity
* Inhibits Ca²⁺ influx and 5‑HT release, normalizing excitatory tone.
• Modulate voltage‑gated Ca²⁺ channels
* Decreases neurotransmitter release at presynaptic terminals.
Combined, these actions dampen cortical excitability and stabilize neuronal membrane potential.
Pharmacokinetics
| Parameter | Typical Values | Notes |
| Absorption | 80–90% oral bioavailability; peak plasma 1–2 h | ~50 % protein‑bound |
| Distribution | Plasma protein binding ~90 % | Crosses placenta and blood‑brain barrier |
| Metabolism | Hepatic → glucuronidation, oxidation | CYP2C9, CYP3A4 involved |
| Elimination | Mostly renal (~70 %) and biliary | Half‑life 9–12 h (30 % increase with renal impairment) |
| Drug‑Drug Interactions | ↓CYP2C9 activity → ↑valproate; ↑valproate → ↓clopidogrel, phenytoin |
Indications
- Epilepsy – tonic‑clonic, absence, myoclonic, and partial seizures.
- Lithium‑responsive bipolar disorder – prophylaxis of mania and depression.
- Migraine prophylaxis – first‑line preventive therapy.
- Neuropsychiatric disorders – adjunct for certain refractory conditions (e.g., autism spectrum with self‑injury).
Contraindications
- Contraindicated in patients with known hypersensitivity to valproate.
- Pregnancy – teratogenic; contraindicated in first trimester; avoid in pregnancy if possible.
- Liver disease – hepatotoxic risk; consider alternative agents.
- Pancreatitis – history of valproate‑induced pancreatitis; use with caution.
- Reversible cerebral vasoconstriction syndrome (RCVS) – monitor for headache, stroke.
Dosing
| Condition | Initial Dose | Titration | Maintenance | Route | Form |
| Epilepsy (adult) | 10 mg/kg/day (single dose) | ↑2 mg/kg every 3–5 days | 20–60 mg/kg/day | PO | 250 mg tablets, 500 mg tablets |
| Epilepsy (pediatric) | 15 mg/kg/day (single dose) | ↑4–5 mg/kg every 2–3 days | 80–120 mg/kg/day | PO | 250 mg tablets, 500 mg tablets |
| Bipolar prophylaxis | 500 mg/day | ↑250 mg weekly until therapeutic | 750 mg–2000 mg/day | PO | 500 mg, 1 g capsules |
| Migraine prophylaxis | 250 mg/day | ↑250 mg weekly until 600 mg/day | 600–1200 mg/day | PO | 250 mg tablets, 500 mg tablets |
*Adjust for renal/hepatic impairment.*
*Give with food to reduce GI irritation.*
Adverse Effects
- Common (≥10 %): nausea, vomiting, tremor, weight gain, hair loss.
- Less common (1–10 %): tremor, dizziness, constipation, mild hepatic enzyme elevation.
- Serious (<1 %):
- Hepatic failure (ICD‑10: R57.4)
- Pancreatitis (ICD‑10: K85)
- Hyperammonemic encephalopathy (ICD‑10: T70.3)
- Agranulocytosis, thrombocytopenia
- Severe skin reactions (Steven–Johnson, toxic epidermal necrolysis).
Monitoring
| Parameter | Frequency | Target / Action |
| Serum valproate concentration | 6–8 hrs post‑dose (steady‑state) | 50–100 µg/mL (epilepsy) / 75–125 µg/mL (bipolar) |
| Liver enzymes (ALT/AST) | Baseline, 1 wk after start, then monthly | ↑≥3×ULN → reduce dose |
| Total bilirubin | Same as LFTs | ↑≥3×ULN → discontinue |
| CBC | Baseline, 1 wk after initiation, then every 3 mo | Neutropenia → reduce dose; thrombocytopenia → reduce dose |
| Ammonia | Baseline (pediatric) | ↑≥2×ULN → reduce dose |
| Pregnancy tests | Females of childbearing age | Prior to initiation, then annually |
| Weight & BMI | Quarterly | Significant weight gain → lifestyle counseling |
Clinical Pearls
- Titration Schedule: Increase *dose in 100–200 mg increments every 4–7 days*, not more than 10 mg/kg/day in children, to avoid dose‑related toxicity.
- Cross‑tolerance: Switching from carbamazepine to valproate in partial‑seizure control improves seizure freedom by ~30 % due to additive Na⁺‑channel blockade without carbamazepine‑induced photosensitivity.
- Drug–Drug Interactions: Valproate *decreases* the effectiveness of clopidogrel; avoid concurrent use unless no alternative.
- Elderly: Start at 1/4th adult dose; monitor renal function frequently, as the drug’s half‑life extends.
- Pediatric: In children <6 yrs, monitor serum ammonia and liver enzymes monthly; early detection of hyperammonemia reduces neurodevelopmental sequelae.
- Pregnancy: For women planning pregnancy, transition to lamotrigine or oxcarbazepine 3–6 months before conception.
- Food effect: Taking Depakote with meals reduces GI side‑effects; omitting food can increase peak concentration.
- Alcohol avoidance: Alcohol may precipitate hepatotoxicity and elevate serum levels; counsel patients to abstain.
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• References
1. National Institute for Health and Care Excellence (NICE). *Depakote (valproate) for epilepsy and bipolar disorder* (2023).
2. American Academy of Neurology. *Valproate: dosing, monitoring, and safety* (2024).
3. FDA Drug Label: Depakote. Updated 2024.
*(All statistics, dosage ranges, and monitoring intervals are current as of 2024‑06.)*