Valproate or the dimeric form, divalproex, offers a useful alternative to phenytoinphenobarbital, and carbamazepine, especially with the intravenous formulation that became available in the mid-1990s. It is effective against tonic-clonic seizures (including secondarily generalized seizures), as well as absence, myoclonic, and simple and complex partial seizures. Carbamazepine may have slight advantages for patients whose partial seizures do not secondarily generalize.

Because of valproate's short half-life (12–16 hours without concomitant administration of P-450–inducing drugs, 5–10 hours with such administration), a steady state is reached rapidly at the maintenance dose of 15–30 mg/kg. Higher loading doses may also be used, although gastrointestinal upset can occur. A liquid form is also available, at 250 mg/5 mL.

The enteric-coated divalproex preparation, although less likely to produce gastrointestinal upset, has delayed absorption, resulting in peak levels 4–6 hours after administration.

The intravenous formulation offers an option when gastrointestinal administration is unavailable, such as postoperatively or with impaired swallowing and no nasogastric access. It also has been used successfully off label in treating status epilepticus, often at administration rates much faster than the recommended 20 mg/kg per hour.

One advantage of valproate is its lack of cross-reactivity with phenytoin, phenobarbital, and carbamazepine. Rashes and other overt allergic reactions are uncommon. Although idiosyncratic hepatic dysfunction and pancreatitis are the most feared adverse reactions, these are extremely rare after infancy in the absence of pre-existing organ dysfunction.

A potentially more important risk in an ill, elderly patient is the possibility of thrombocytopenia or thrombocytopathy. Although idiosyncratic, this is more common at high doses and levels. Bleeding time is not always abnormal, and aspirin can potentiate this effect. There have been no studies of whether this antiplatelet effect can be beneficial in patients with vascular disease.

Aspirin also potentiates the therapeutic effects of valproate by displacing it from binding sites, thereby elevating free levels. The total level may be unchanged or even decline slightly because of increased free drug as a substrate for metabolism.

Among other potential adverse effects, tremor is most common at high doses and levels. Weight gain with chronic use occurs in about 30% of patients.

With respect to cognitive effects, no major differences have been found among valproate, phenytoin, and carbamazepine.104,105 (Phenobarbital is likely to have more detrimental effects, on average.) Further studies are needed to establish whether newer AEDs have less effect on cognition than valproate and the other older AEDs.

Reviewed By: 
Steven C. Schachter, MD
Thursday, April 1, 2004