Valproate / Valproic Acid
Depacon · Depakene · Depakote
Branched short-chain fatty-acid antiepileptic / mood stabilizer
Multimodal: enhances GABA synthesis (↑glutamic acid decarboxylase activity, ↓GABA-T degradation), blocks voltage-gated Na⁺ channels, and inhibits T-type Ca²⁺ channels in thalamic neurons. Broad-spectrum — covers focal, generalized, absence, and myoclonic seizures.
Indications
- •Status epilepticus (alternative second-line — ESETT-validated)
- •Generalized epilepsies (myoclonic, absence, GTC)
- •Migraine prophylaxis
- •Bipolar disorder mania (acute and maintenance)
Dosing
| Context | Adult | Pediatric |
|---|---|---|
| Status epilepticus IV load | 40 mg/kg (max 3 g) IV over 10 min — ESETT trial dose | 40 mg/kg (max 3 g) IV over 10 min |
| Maintenance | 10–60 mg/kg/day divided q8–12 h; target level 50–100 mcg/mL | — |
Pharmacokinetics
Onset minutes IV. Peak 1–4 h oral (formulation-dependent). Half-life 9–16 h. 90% protein-bound (albumin). Hepatic metabolism (β-oxidation + glucuronidation); inhibits multiple CYPs.
Hemodynamic effects
Minimal direct effect.
Respiratory effects
Minimal direct effect.
Side effects
- !Hepatotoxicity — boxed warning; idiosyncratic fatal hepatitis especially in children <2 yr, polypharmacy patients, and those with mitochondrial disease
- !Pancreatitis — boxed warning; can be hemorrhagic and fatal
- !Hyperammonemic encephalopathy (with or without hepatotoxicity) — even at therapeutic levels; treat with carnitine + drug withdrawal
- !Thrombocytopenia, platelet dysfunction (dose-dependent)
- !Teratogenicity — boxed warning; spina bifida, neural tube defects, IQ loss; CONTRAINDICATED in pregnancy for migraine prophylaxis
- !Weight gain, alopecia, tremor
- !Hyponatremia (SIADH)
Contraindications
- ×Hepatic impairment / hepatic disease
- ×Urea cycle disorders
- ×Mitochondrial disorders associated with POLG mutations (Alpers-Huttenlocher syndrome) in children <2 yr
- ×Pregnancy for migraine prophylaxis (and used only when essential for epilepsy)
Clinical pearls
- ★HYPERAMMONEMIA WITHOUT HEPATOTOXICITY: valproate can cause encephalopathy from urea-cycle disruption with normal LFTs — always check ammonia in a confused patient on valproate. Carnitine 100 mg/kg/day IV reverses it.
- ★PERIOPERATIVE BLEEDING: assess platelets + fibrinogen before neuraxial or major surgery. Valproate causes both thrombocytopenia and a vWF-like platelet dysfunction — bleeding time may not be reliable.
- ★ENZYME INHIBITOR: raises levels of phenobarbital, lamotrigine, warfarin — opposite direction from phenytoin's induction.
- ★ESETT (NEJM 2019): equivalent to levetiracetam and fosphenytoin as benzo-refractory status second-line. Choice in OB or hepatic disease → levetiracetam wins.
- ★PREGNANCY ABSOLUTE: highest teratogenicity of any antiepileptic (NEAD trial — 9 IQ-point loss vs lamotrigine). Counsel any reproductive-age patient pre-prescription; co-prescribe folate ≥1 mg/day if used.
Other drugs in Seizure Control
- Levetiracetam
Binds synaptic vesicle protein 2A (SV2A) and modulates neurotransmitter release; mechanism distinct from sodium-channel and GABA-receptor antiepileptics. Broad-spectrum efficacy against focal and generalized seizures.
- Phenytoin
Use-dependent block of voltage-gated neuronal Na⁺ channels — stabilizes the inactivated state, raising the seizure threshold without affecting normal neuronal firing. Also blocks cardiac fast Na⁺ channels (class Ib antiarrhythmic activity).
Browse all classes: /reference/drugs
