Anticonvulsants

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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

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

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

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

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.

Benzodiazepines

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.

Succinimides

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

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

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

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.

Anticonvulsants

Generic Name / Brand Name Liver Toxicity Score Approval Year Major Indications
Brivaracetam / Briviact E 2016 Partial seizures
Carbamazepine / Tegretol A 1968 Partial, mixed and generalized seizures, trigeminal neuralgia
Clobazam / Onfi E 2011 Seizures assocated with Lennox-Gastaut syndrome
Clonazepam / Klonopin D 1975 Absence and myoclonic seizures, anxiety and panic disorders
Clorazepate / Tranxene E 1972 Partial seizures, anxiety disorders, and alcohol withdrawal
Diazepam / Valium E 1963 Convulsions, anxiety disorders, muscle spasms
Eslicarbazepine / Aptiom D 2013 Partial seizures
Ethosuximide / Zarontin E 1960 Absence seizures
Ezogabine / Potiga E 2011 Partial seizures
Felbamate / Febatol B 1993 Refractory or severe epilepsy
Fosphenytoin / Cerebyx A 1996 Tonic-clonic seizures, status epilepticus
Gabapentin / Neurontin C 1993 Partial seizures, post-herpetic neuralgia
Lacosamide / Vimpat D 2008 Partial seizures
Lamotrigine / Lamictal B 1994 Partial and generalized tonic-clonic seizures, bipolar disorder
Levetiracetam / Keppra C 1999 Partial, generalized tonic-clonic, and myoclonic seizures
Methsuximide / Celontin E 1957 Absence seizures
Oxcarbazepine / Trileptal D 2000 Partial seziures
Perampanel / Fycompa E 2012 Partial and generalized tonic-clonic seizures
Phenobarbital / Luminal A 1916 Partial and generalized seizures, anxiety, and irritable bowel syndrome
Phenytoin / Dilantin A 1938 Generalized tonic-clonic and partial onset seizures, status epilepticus
Pregabalin / Lyrica C 2004 Partial seizures, fibromyalgia, and neuropathic pain
Primidone / Mysoline E 1954 Partial and generalized tonic-clonic seizures
Rufinamide / Banzel E 2008 Seizures associated with Lennox-Gastaut syndrome
Tiagabine / Gabitril E 1997 Partial seizures
Topiramate / Topamax C 1996 Partial and generalized tonic-clonic seizures, migraine headaches
Valproate / Depakene A 1978 Absence and complex partial seizures
Vigabatrin / Sabril D 2009 Refractory, complex partial seizures, and infantile spasms
Zonisamide / Zonegran D 2000 Partial seizures

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