Valproate: Indications, Mechanism of Action, Dosages, and Side Effects
Valproate (valproic acid) is a broad-spectrum anticonvulsant with established efficacy for multiple seizure types, migraine prevention, and bipolar disorder, with dosing typically starting at 10-15 mg/kg/day and titrating up to a maximum of 60 mg/kg/day while monitoring blood levels.
Indications
Seizure Disorders
- Effective as monotherapy and adjunctive therapy for complex partial seizures in adults and children 10 years and older 1
- Indicated for simple and complex absence seizures 1
- Particularly effective in refractory status epilepticus, with studies showing 79% seizure control when used as a second-line agent versus 25% with phenytoin 2
- May be especially useful in patients with prolonged or atypical migraine aura 2
Migraine Prevention
- Established efficacy for migraine prophylaxis with good evidence from multiple clinical trials 2
- Small trials support efficacy in chronic daily headache 2
- Not recommended for migraine prevention in women of childbearing potential due to teratogenic risk 2
Bipolar Disorder
- Used in the management of bipolar disorder, particularly for manic episodes 2
- Requires baseline and follow-up monitoring of symptoms, side effects, and laboratory values 2
Mechanism of Action
Valproate works through multiple mechanisms:
- Increases gamma-aminobutyric acid (GABA)-ergic transmission, enhancing inhibitory neurotransmission 3
- Reduces release and/or effects of excitatory amino acids 3
- Blocks voltage-gated sodium channels 3
- Modulates dopaminergic and serotoninergic transmission 3
- In migraine, may suppress neurogenic inflammation and attenuate nociceptive neurotransmission 4
- May suppress migraine-related events in the cortex, perivascular parasympathetics, or trigeminal nucleus caudalis 4
Dosages
Seizure Disorders
- Initial therapy: 10-15 mg/kg/day 1
- Titration: Increase by 5-10 mg/kg/week to achieve optimal clinical response 1
- Maximum recommended dose: 60 mg/kg/day 1
- Therapeutic plasma concentration range: 50-100 μg/mL 1
- Risk of thrombocytopenia increases significantly at trough concentrations above 110 μg/mL in females and 135 μg/mL in males 1
- For status epilepticus: 30 mg/kg IV at 6 mg/kg/hour, followed by infusion at 1-2 mg/kg/hour 2
Migraine Prevention
- Typical dosing similar to seizure management 2
- Therapeutic blood levels typically maintained between 50-100 μg/mL 1
Side Effects
Common Side Effects
- Gastrointestinal disturbances (nausea, vomiting) 1, 3
- Tremor 1, 3
- Weight gain 2, 1, 3
- Hair loss (alopecia) 2, 3
- Drowsiness or sleepiness 1
- Dizziness 1
- Weakness 1
Serious Adverse Effects
- Hepatotoxicity - rare but potentially fatal, with overall incidence of 1 in 20,000, but higher risk (1 in 600-800) in high-risk groups such as infants below 2 years receiving polytherapy 3
- Teratogenicity - 1-3% risk of neural tube defects, absolutely contraindicated in women of childbearing potential 2, 3
- Pancreatitis 3
- Thrombocytopenia and other platelet disorders 1, 3
- Encephalopathy, sometimes associated with hyperammonemia 1, 3
- Reproductive system disorders in women, including polycystic ovary syndrome 3
Monitoring Requirements
- Before starting therapy: Complete blood count, liver function tests, and pregnancy test in females 2
- Once stable dose is achieved: Monitor drug levels, renal and thyroid function every 3-6 months 2
- Regular monitoring of hepatic and hematological indices 2
- Body mass index monitoring due to potential weight gain 2
Important Considerations
- Valproate has extensive drug interactions - it can inhibit metabolism of other drugs including phenobarbital and lamotrigine 3
- Unlike phenytoin, valproate rarely causes hypotension during IV administration, making it advantageous in certain emergency settings 2
- Valproate is approximately 90% protein-bound, with binding decreasing as concentration increases 3
- Elimination half-life is typically 9-18 hours but can be shortened (5-12 hours) when co-administered with enzyme-inducing drugs like phenytoin, carbamazepine, and barbiturates 3