Carboxylic acid derivatives
Valproic acid, the most widely used carboxylic acid derivative, is unrelated structurally to the other anticonvulsants. Valproic acid is also available as:
Valproate is converted rapidly to valproic acid in the stomach. Di-valproex is a precursor of valproic acid and separates into val-proic acid in the GI tract. Valproic acid is a hepatic enzyme in-hibitor; it’s absorbed well, is strongly protein-bound, and is metabolized in the liver. Metabolites and unchanged drug are excreted in urine.
Valproic acid readily crosses the placental barrier and also ap-pears in breast milk.
The mechanism of action for valproic acid remains unknown. The drug is thought to increase levels of GABA, an inhibitory neuro-transmitter, and to have a direct membrane-stabilizing effect.
Valproic acid is prescribed for long-term treatment of:
· absence seizures
· myoclonic seizures
· tonic-clonic seizures
· partial seizures.
Valproic acid may also be useful for neonatal seizures.
Valproic acid must be used cautiously in children under 2 years old, particularly those receiving multiple anticonvulsants and those with congenital metabolic disorders, severe seizures with mental retardation, or organic brain disease. In these patients, val-proic acid carries a risk of potentially fatal liver toxicity (primarily in the first 6 months of treatment).
This risk limits its use as a drug of choice for seizure disorders. However, while it’s a risk for all patients, the risk decreases with age. Caution should also be taken with patients with hepatic dis-ease.
These are the most significant drug interactions associated with valproic acid:
· Cimetidine, aspirin, erythromycin, and felbamate may increase levels of valproic acid.
· Carbamazepine, lamotrigine, phenobarbital, primidone, pheny-toin, and rifampin may decrease levels of valproic acid.
· Valproic acid may decrease the effects of felbamate, phenobar-bital, primidone, benzodiazepines, CNS depressants, warfarin, and zidovudine. (See Adverse reactions to valproic acid)