Elevated Free Anticonvulsant Levels in Hepatic Disease

Patients with hepatic disease usually have hypoalbuminemia. Because albumin is the major binding protein for phenytoin, valproic acid, and carbamazepine, elevated free anticonvulsant concentration is expected in patients with liver disease. Elevated free phenytoin concentration occurs in patients with hepatic disease because of hypoal-buminemia (78). In hepatic failure, the hepatic clearance of unbound phenytoin may also be reduced because of hepatic tissue destruction and a reduction in hepatic enzyme activities responsible for metabolism of phenytoin. When this occurs, a reduction of phenytoin dose is necessary to maintain unbound phenytoin concentration below toxic level. Prabhakar and Bhatia (79) reported that free phenytoin levels are elevated in patients with hepatic encephalopathy. Fosphenytoin is a phosphate ester prodrug of phenytoin developed as an alternative to phenytoin for acute treatment of seizures. Fosphenytoin is rapidly converted to phenytoin in vivo with a half-life of 7-15 min. The unbound plasma phenytoin concentrations achieved with standard fosphenytoin intravenous loading doses are similar to that achieved by equivalent phenytoin administration. However, earlier and higher unbound phenytoin concentrations and thus an increase in systemic adverse effect may occur following intravenous fosphenytoin-loading doses in patients with impairment in fosphenytoin (93-98% bound to protein) and phenytoin protein binding (hepatic or renal disease, hypoalbu-minemia, and elderly) (80).

Hepatic disease can alter pharmacokinetic parameters of valproic acid. Klotz et al. reported that alcoholic cirrhosis and viral hepatitis decreased valproic acid protein binding from 88.7 to 70.3 and 78.1%, respectively, with a significant increase in volume of distribution. Elimination half-life was also prolonged (81). An increase in unbound concentration of carbamazepine has been reported in patients with hepatic disease (82).

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