Anticonvulsants (128) • Drugs used to prevent SEIZURES or reduce their severity
Liver safety of Anticonvulsants
Anticonvulsant medications include many agents that have been incriminated in causing idiosyncratic drug induced liver disease. Indeed, several commonly used anticonvulsants (phenytoin, valproate, carbamazepine) are consistently ranked in the top causes of clinically apparent drug induced liver injury and are frequently listed in causes of drug induced acute liver failure. Because of the importance of pharmacotherapy of epilepsy, the potential hepatotoxicity of these agents has been considered acceptable. Nevertheless, attempts at developing safer agents of equivalent or superior efficacy continue.
Common anticonvulsants =
Major anticonvulsants include hydantoin derivatives, barbiturates, benzodiazepines, succinimides, valproic acid, gamma amino butyric acid (GABA) precursors and analogues, inhibitors of DMDA receptors and a multitude of miscellaneous recently introduced agents. At least two dozen agents are licensed and approved for use as anticonvulsants in the United States. The anticonvulsants that are available in the United States, the likelihood score for hepatotoxicity, their year of introduction or approval and their major approved indications are shown in the Table which includes links to the individual agents with the full description and discussion of their potential for hepatiotoxicity.
Phenobarbital is the oldest antiepileptic medication still in use, having been introduced into clinical medicine in 1916. Phenobarbital is an aromatic anticonvulsant and, like phenytoin and carbamazepine, can cause the aromatic anticonvulsant hypersensitivity syndrome, a form of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Questions remain regarding the anticonvulsant efficacy of phenobarbital and it is now rarely used for this indication.
Phenytoin, formerly known as diphenylhydantoin, was introduced into use as an anticonvulsant in 1938 and remains one of the most commonly used medications for epilepsy. Fosphenytoin is an intravenous formulation of phenytoin that has been available since 1995 and is used for status epilepticus and as a substitute for oral phenytoin during surgery. Phenytoin is a well known cause of acute liver injury, which is usually part of the anticonvulsant hypersensitivity syndrome and can be severe and lead to acute liver failure and death.
Carbamazepine was introduced into use in 1963 for treatment of generalized seizures and with other carbamazepines (oxcarbazepine, eliscarbazepine) is still widely used. Carbamazepine can also cause the anticonvulsant hypersensitivity syndrome and is a well known cause of acute drug induced liver injury as well as serious cutaneous reactions such as Stevens Johnson syndrome and toxic epidermal necrolysis.
Lamotrigine is a more recently developed anticonvulsant that has broad antiseizure activity. Lamotrigine can also cause the anticonvulsant hypersensivity sydrome and has become one of the most common causes of clinically apparent drug-induced liver injury.
The benzodiazepines are both anxiolytic and antiepileptic and several including diazepam, clonazepam and clorazepate are used in the therapy of epilepsy. Benzodiazepines are also discussed under the antianxiolytic medications. They appear to act by enhancing gamma aminobutyric acid (GABA) receptor activity. While many benzodiazepines have antiseizure activity, only clonazepam and cloazepate are commonly used in long term treatment of epilepsy. Diazepam and other parentally administered benzodiazepams are also used for therapy of status epilepticus. Benzodiazepines have only rarely been implicated in causing drug induced liver injury and have not been implicated in the anticonvulsant hypersensitivity syndrome.
The succinimides are active against clonic motor seizures and absence seizures (petit mal) in humans. This class includes ethosuximide (1960) and methsuximide (1957).
Valproic acid or valproate is a branched chain carboxylic acid that was found to have antiseizure activity somewhat by accident. Valproate was introduced in 1978 and rapidly became a commonly used agent for partial seizures and for poorly controlled generalized seizures. Valproic acid is also used in the treatment of mood and bipolar disorders. Valproate can cause several distinctive forms of liver injury, ranging from asymptomatic serum aminotransferase elevations or an acute hepatitis which can be severe and even fatal, to a Reye syndrome like syndrome of hepatic dysfunction and microvesicular fatty liver. High doses of valproic acid can also cause stupor and coma from hyperammonemia without accompaning severe liver injury.
Topiramate is a sulfamate-substituted monosaccharide and unique and broadly active anticonvulsant introduced in 1996 that is still widely used. Topiramate is also used for prevention of migraine headaches, as a weight loss agent and (off label) for mood disorders and bipolar illness.
Levetiracetam is a pyrrolidine derivative and unique anticonvulsant introduced in 1999 that has been increasing used because of its safety and excellent tolerability. Levetiracetam binds to the synaptic vesicle glycoprotein SV2A and appears to act by inhibiting calcium channels which participate in neurotransmitter release. Levetiracetam has been linked to rare instances of drug induced liver disease, but not with the anticonvulsant hypersensivity syndrome. Brivaracetam is an anticonvulsant of similar structure and activity was approved in 2016.
Other agents active against seizures have been developed in recent years, many of which act by uncertain mechanisms and which belong to different classes of agents. These agents, their likelihood score, year of approval and major indications are given below.