Pharmacokinetic pitfalls of present antiepileptic medications

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41 Scopus citations


Some patients fail to respond to antiepileptic drugs (AEDs) or their response varies over time. Unexpected fluctuations in AED concentrations can cause loss of seizure control or side effects. Recent advances in AED clinical pharmacology have characterized a number of factors that alter AED concentrations. Storage of carbamazepine (CBZ) and phenytoin (PHT) formulations in hot, humid conditions alters the dosage form and reduces bioavailability up to 50%. Diurnal changes in gastrointestinal physiology affect disintegration of valproate (VPA) enteric-coated tablets, reducing nighttime drug concentrations 30 to 40% compared with daytime values. Drug-drug interactions or pathophysiologic conditions (e.g., hypoalbuminemia) may displace AEDs from protein-binding sites reducing total but not unbound drug concentrations decrease. VPA not only displaces PHT from protein-binding sites but inhibits its metabolism, causing a decrease in total concentration and an increase in the unbound concentration, occasionally necessitating a reduction in PHT dosage. Alterations in drug metabolism can cause fluctuations in the concentrations of AEDs and active metabolites. Enzyme inhibitors such as cimetidine or VPA can increase concentrations of both CBZ and CBZ epoxide (CBZE). Enzyme inducers such as ethanol, PHT, CBZ, and phenobarbital accelerate the metabolism of other AEDs. Some forms of physiologic stress increase binding to α1-acid glycoprotein (AAG), which is stimulated within hours of a myocardial infarction or major surgery. Total CBZ and CBZE, both of which bind to AAG, increase over the same period. Stress may also activate hepatic drug metabolism. Unbound PHT clearance increases 7 to 21 days following head trauma, necessitating larger maintenance doses. Age > 65 years is associated with decreases in protein binding and drug clearance and longer elimination half-lives. In elderly patients, AED dosage may need to be reduced and the dosing interval extended. Knowledge of these factors permits prospective assessment of risk and the design of treatment plans that minimize fluctuations in response.

Original languageEnglish (US)
Pages (from-to)S53-S65
Issue numberSUPPL. 5
StatePublished - Jan 1 1991


  • Anticonvulsants
  • Carbamazepine
  • Drug interactions
  • Drug metabolism
  • Epilepsy
  • Pharmacokinetics
  • Phenytoin
  • Protein binding
  • Stress-aging
  • Valproate


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