Valproate

Actions

• May enhance GABA transmission in specific circuits.
• Modulates T-type Ca++ channels.
• Blocks voltage-dependent Na+ channels.

Metabolism

Hepatic

Enzymes involved

• CYP2C9
• UGT

Elimination

Renal 30–50%

Enzyme inhibition

• UGT
• CYP2C19

Therapeutic serum concentration range

50 - 100 μg/ml

Half-life

6-18 hours

Plasma protein binding

75-95%

Important side-effects

Hepatotoxicity and hepatic failure.

Pancreatitis.

Fetal exposure can cause major congenital malformations, particularly neural tube defects.

Decreased IQ Following in utero exposure.

Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders.

Hyperammonemia.

Weight gain.

Hematopoietic disorders.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Indications

Generalized tonic-clonic seizures.

Absence seizures.

Focal seizures with or without generalization.

Myoclonic and atonic seizures.

Dosing recommendation

Start with 500 mg/day.

Increase if indicated after 1 week.

Target dose: 500–2500 mg/day divided in 2 doses.

Renal impairment

Caution is advised in patients with impaired renal function. The free (not protein-bound) serum fraction of valproate should be monitored and dose titrated accordingly.

Hepatic impairment

Valproate is not recommended in patients with impaired hepatic function.

Serum concentration changes during pregnancy

Total level decreases by ~30%.