Antiepileptic Drugs and Liver Disease

Abstract

Acute, symptomatic seizures or epilepsy may complicate the course of hepatic disease. Choosing the most appropriate antiepileptic drug in this setting represents a difficult challenge, as most medications are metabolized by the liver. This article focuses on the acute and chronic treatment of seizures in patients with advanced liver disease and reviews the hepatotoxic potential of specific antiepileptic drugs. Newer antiepileptic drugs without, or with minimal, hepatic metabolism, such as levetiracetam, lacosamide, topiramate, gabapentin, and pregabalin should be used as first-line therapy. Medications undergoing extensive hepatic metabolism, such as valproic acid, phenytoin, and felbamate should be used as drugs of last resort. In special circumstances, as in patients affected by acute intermittent porphyria, exposure to most antiepileptic drugs could precipitate attacks. In this clinical scenario, bromides, levetiracetam, gabapentin, and vigabatrin constitute safe choices. For the treatment of status epilepticus, levetiracetam and lacosamide, available in intravenous preparations, are good second-line therapies after benzodiazepines fail to control seizures. Hepatotoxicity is also a rare and unexpected side effect of some antiepileptic drugs. Drugs such as valproic acid, phenytoin, and felbamate, have a well-recognized association with liver toxicity. Other antiepileptic drugs, including phenobarbital, benzodiazepines, ethosuximide, and the newer generations of antiepileptic drugs, have only rarely been linked to hepatotoxicity. Thus physicians should be mindful of the pharmacokinetic profile and the hepatotoxic potential of the different antiepileptic drugs available to treat patients affected by liver disease.

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

“…VPA-induced liver toxicity is related to (a) the formation of reactive metabolites; (b) the induction of oxidative stress caused by mitochondrial oxidative phosphorylation; (c) VPA capability to release protons and consequently disrupt electron transport chain and ATP generation; and (d) the impairment of ROS detoxification system. 10 Drug-induced liver injury (DILI) can cause morbidity and mortality following the assumption of drugs in therapeutic doses. 10 Drug-induced liver injury (DILI) can cause morbidity and mortality following the assumption of drugs in therapeutic doses.…”

Potential biomarker of fibroblast growth factor 21 in valproic acid‐treated livers

“…The valproic metabolism occurs in the liver, mainly being decomposed by the cytochrome P450 enzymes and mitochondrial beta‐oxidation. Mounting evidence shows that the long‐term VPA monotherapy is involved in significantly increased risks of liver injury, as revealed in human and animal studies . Theoretically, the potential risk of VPA‐induced hepatotoxicity should be monitored for detectable signs of liver injury, especially in early therapy.…”

“…Mounting evidence shows that the long-term VPA monotherapy is involved in significantly increased risks of liver injury, as revealed in human and animal studies. 20,21 Theoretically, the potential risk of VPA-induced hepatotoxicity should be monitored for detectable signs of liver injury, especially in early therapy. As it was limited in the published data, the study of VPA-related EULI remains uninvestigated.…”

Identification of significant protein markers by mass spectrometry after co‐treatment of cells with different drugs: An in vitro survey platform

“…Hence, for many drugs used in disease treatment we should be concerned about how to decrease the undesired effects for patients from drug–drug interaction and oxidative stress. For example, ethosuximide, used for the treatment of absence seizures, is associated with hepatotoxicity when used in combination with other drugs, because the enzyme systems in its metabolism can be both induced and inhibited by other drugs, resulting in drug–drug interaction . As such, developing useful strategies to predict and reduce drug–drug interactions is necessary to avoid drug‐induced side effects.…”