Optimizing therapy of seizures in patients with renal or hepatic dysfunction

Abstract

Patients with epilepsy may suffer from renal or hepatic diseases that interfere with their antiepileptic drug (AED) treatment. Furthermore, such diseases may themselves cause seizures. Reduced renal function and hypoalbuminemia lead to accumulation of renally excreted AEDs, such as gabapentin, vigabatrin, topiramate, levetiracetam, and phenytoin. Valproate, lamotrigine, and benzodiazepines are less affected. Low protein-bound AEDs are extensively removed by hemodialysis and supplemental doses are required for dialysis patients. Uremia and related conditions, including intracranial hemorrhage, glucose and electrolyte imbalances, and concomitant drug use, can cause seizures, as can dialysis encephalopathy, primary cerebral lymphoma, fungal infections, and immunosuppressant toxicity in renal transplant recipients. Hepatic dysfunction reduces enzymatic metabolism of AEDs and causes hypoalbuminemia. Gabapentin, topiramate, and levetiracetam are preferred in these conditions, whereas conversely valproate and felbamate are potentially hepatotoxic and should be avoided. Seizures related to hepatic encephalopathy are controlled by oral lactulose or neomycin. Porphyria sufferers may benefit from gabapentin, oxcarbazepine, or levetiracetam. Seizures in Wilson's disease may derive from d-penicillamine-induced pyridoxine deficiency. Effective treatment of seizures in renal and hepatic diseases requires attention to changes in AED pharmacokinetics and adequate care of the underlying illnesses. Monitoring of free drug concentrations is a valuable aid to therapy.

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…For some AEDs, there has been little investigation of the effect of dialysis on AED plasma concentration. In general, AEDs with low degrees of plasma protein binding are cleared more effectively by dialysis than those AEDs with high degrees of protein binding [19]. In the discussion of the specific AEDs in this review, studies of the effect of dialysis on AED are mentioned if available in the published literature.…”

“…Approximately 40% of the drug is ultimately excreted by the kidney with the remainder cleared by metabolism. Although the effect of hemodialysis on lacosamide pharmacokinetics has not been reported, the low plasma protein binding of lacosamide suggests that this drug should be effectively cleared by dialysis [19]. CYP2C19 (an enzyme that can show pharmacogenetic variation) catalyzes the metabolism of lacosamide to an inactive metabolite.…”

“…Approximately 100% of the absorbed drug is excreted by the kidneys [110], with approximately two-thirds as the parent drug and the remainder as the metabolite LO57, formed by hydrolysis in the blood [111]. Although the effect of hemodialysis on levetiracetam pharmacokinetics has not been reported, the low plasma protein binding of levetiracetam suggests that this drug should be effectively cleared by dialysis [19]. In performing TDM, it is important to separate serum or plasma from whole blood rapidly, as artefactual hydrolysis of levetiracetam can occur in the blood tube [111].…”

“…A major challenge to the dosing of stiripentol is that the drug shows non-linear pharmacokinetics, with a marked decrease in clearance with increased dosage [148]. Stiripentol is also highly (>99%) protein bound which likely limits clearance of this drug by hemodialysis procedures [19]. The reference range for stiripentol is not well-defined but serum concentrations of 4–22 mg/L correlate with control of absence seizures in children [49].…”

“…Children generally eliminate topiramate faster than adults [14,165]. Although the effect of hemodialysis on topiramate pharmacokinetics has not been reported, the low plasma protein binding of topiramate suggests that this drug should be effectively cleared by dialysis [19]. A reference range of 5–20 mg/L has been proposed for topiramate for epilepsy therapy [51].…”