Free Anticonvulsants in Pregnancy

The pharmacokinetics of many anticonvulsants undergo important changes in pregnancy because of modification in body weight, altered plasma composition, hemodynamic alteration, hormonal influence, and contribution of the fetoplacental unit to drug distribution and disposition. Pregnancy thus affects absorption of drugs, binding to plasma protein, distribution, metabolism, and elimination (87). At constant dosages, plasma levels of anticonvulsants such as phenytoin, valproic acid, carba-mazepine, phenobarbital, and primidone tend to decrease during pregnancy and then return to normal within the first or second month after delivery. Marked decrease in total phenytoin concentrations (about 40% of pre-pregnancy level) have been reported while free phenytoin level decreased to a much lesser extent (88). Reports on the decline in total and free carbamazepine during pregnancy are conflicting. One study reports a 42% decline in total carbamazepine concentration and 22% decrease in free carbamazepine concentration from pregnancy to delivery in 22 patients (89), whereas another study reported only a slight decrease in total carbamazepine concentration and an insignificant decrease in free carbamazepine concentration from pregnancy to delivery. For valproic acid, no significant change in free concentration was observed despite reduction in total valproic acid concentration. Tomson (90) commented that for highly protein-bound drugs such as phenytoin and valproic acid, total plasma concentrations may be misleading during pregnancy, underestimating the pharmacological effects of the drug.

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