What is anticonvulsant

Anticonvulsant also called antiepileptic is a medication used to control seizures and epilepsy. In general, seizures result from excessive neuronal firing related to an imbalance of inhibitory and excitatory activity in the brain. While there is a multitude of different antiepileptic agents used in practice today, they all primarily act via interference with one or more of several cellular mechanisms believed to cause seizures.

Anticonvulsants act primarily through one, or a combination of five, mechanisms. These mechanisms and common medications that act on these mechanisms include ¹:

1. Inhibition of sodium channels: carbamazepine, lacosamide, lamotrigine, oxcarbazepine, phenytoin, valproic acid, topiramate, zonisamide
2. Inhibition of calcium conductance: ethosuximide, zonisamide, valproic acid, pregabalin, gabapentin
3. Inhibition of excitatory neurotransmitters N-methyl-D-aspartate (NMDA): perampanel, felbamate, lamotrigine, topiramate
4. Stimulation of Inhibitory neurotransmitter gamma-aminobutyric acid (GABA): benzodiazepines, phenobarbital, tiagabine, vigabatrin
5. Interaction with synaptic vesicle protein 2A (SV2A) proteins: levetiracetam

Anticonvulsant medications mechanisms of action include inhibition of sodium channels, inhibition of calcium channels, inhibition of the excitatory interaction between glutamate and N-methyl-D-aspartate (NMDA), enhancement of gamma-aminobutyric acid (GABA) activity, and inhibition of neuronal exocytosis via interaction with synaptic vesicle protein 2A (SV2A) ².

Major anticonvulsants include hydantoin derivatives, barbiturates, benzodiazepines, succinimides, valproic acid, gamma amino butyric acid (GABA) precursors and analogues, inhibitors of N-methyl-D-aspartate (NMDA) 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, their year of introduction or approval and their major approved indications are shown in the Table 1 below.

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.

DRESS syndrome, or Drug Reaction with Systemic Symptoms, is a drug-induced reaction. The DRESS syndrome usually involves skin rash eosinophilia and other organ system involvement, most commonly liver or kidney ². Carbamazepine, lamotrigine, and valproic acid and other aromatic anticonvulsants are well known to cause DRESS syndrome. Delayed treatment of DRESS syndrome can lead to end-stage organ disease and toxic epidermal necrosis. Obtaining skin biopsies should be a diagnostic exam in the setting of suspected DRESS. Patients with DRESS syndrome should be admitted to the hospital and started on systemic corticosteroids (1kg/mg/day). IV Immunoglobulin is also a treatment option that has been successful ³.

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.

Anticonvulsant drugs list

Anticonvulsant drugs

Brivaracetam

Brivaracetam is a relatively unique anticonvulsant that is typically used in combination with other antiepileptic medications for partial onset seizures. Brivaracetam was approved for use in epilepsy in 2016 and current indications are as adjunctive therapy for partial onset seizures in adults and in children 16 years or older.

Brivaracetam is a pyrrolidine derivative related in structure to levetiracetam. Brivaracetam mechanism of action is not known, but it, like levetiracetam, binds to the synaptic vesicle protein 2A (SV2A) in the brain and appears to act by preventing secondary spread of focal seizure activity and decreasing simultaneous neuronal firing.

Brivaracetam is available as tablets of 10, 25, 50, 75 and 100 mg under the brand name Briviact. Liquid oral and injectable forms are also available. The recommended initial dose in adults is 50 mg twice daily, with dose adjustment based upon tolerance and effect downward or upward to a maximum of 100 mg twice daily.

Brivaracetam common side effects include dizziness, somnolence, fatigue, and nausea and vomiting.

Carbamazepine

Carbamazepine is an aromatic anticonvulsant that is widely used in therapy of epilepsy and trigeminal neuralgia and is a well established cause of clinically apparent liver injury which can be severe and even fatal. Current indications include prevention and management of partial, complex, mixed and generalized seizures. It is used alone or in combination with other anticonvulsants. Carbamazepine is also effective in trigeminal neuralgia and peripheral neuropathies, but the mechanisms of its analgesic actions are not known. Carbamazepine is used off label for behavioral disorders and depression.

Carbamazepine was approved for use in epilepsy in the United States in 1968 and it is still in common use with more than 2 million prescriptions being written yearly.

Carbamazepine is an iminostilbene that is chemically related to tricyclic antidepressants and unrelated in structure to other anticonvulsants. Carbamazepine suppresses spread of seizure activity by reduction in the post-tetanic potentiation of synaptic transmission.

Carbamazepine is available in tablets of 100 mg and 200 mg and extended release capsules of 100, 200 and 400 mg, as are liquid formations and chewable forms for use in pediatrics. Carbamazepine is available in multiple generic forms and under the commercial names as Tegretol, Carbatrol, Equetro and Epitol.

Carbamazepine recommended starting dose in adults for seizures is 200 mg twice daily or 100 mg four times daily, with increase in dose by 100 to 200 mg at weekly intervals based upon clinical response, but generally not exceeding 1200 mg daily. Doses in children are based upon body weight. Typically, lower doses are used for trigeminal neuralgia and other less established indications (restless leg syndrome, bipolar disorders, chorea).

Carbamazepine frequent side effects include drowsiness, sedation, ataxia, blurred vision, nausea, vomiting, and skin rash.

Clobazam

Clobazam is a benzodiazepine that is used as an anticonvulsant in the therapy of severe childhood epilepsy. Clobazam was approved for use in the United States in 2011 as an anticonvulsant to be used either alone or in combination with other agents as therapy of the severe form of childhood epilepsy known as Lennox-Gastaut syndrome.

Clobazam is a unique 1,5 benzodiazepine which is used in the United States as an anticonvulsant, but is available in other countries for therapy of anxiety as well as epilepsy. The anticonvulsant activity of clobazam appears to be mediated by its ability to enhance gamma-aminobutyric acid (GABA) medicated inhibition of synaptic transmission via binding to the GABA-A receptor.

Clobazam is available in tablets of 5, 10 and 20 mg under the brand name Onfi in the United States and Frisium and Urbanol elsewhere. The recommended initial dose is 5 mg once or twice daily, with subsequent increases to a usual maintenance dose of 20 mg twice daily. The dose should be increased and tapered gradually.

Clobazam most common side effects are dose related and include dizziness, somnolence, impaired concentration, nervousness, aggression, antegrade amnesia, headache, fatigue, nausea and weakness. Clobazam can also lead to physical dependence and sudden discontinuation can cause withdrawal symptoms and rebound seizure activity.

Clonazepam

Clonazepam is a benzodiazepine used predominantly as an anticonvulsant as adjunctive therapy in management of epilepsy. Clonazepam is currently indicated for management of absence seizures and myoclonic seizures in children as well as generalized seizure disorders in both adults and children. Clonazepam is effective in status epilepticus, but diazepam and lorazepam are preferable because of their longer half lives. Clonazepam is also used for restless leg syndrome, dysarthria, tic disorders, panic disorder and acute mania.

Clonazepam was approved in the United States for treatment of epilepsy in 1997 and currently more than 20 million prescriptions are filled yearly.

Clonazepam is a benzodiazepine with particularly potent activity against spread of seizure activity in several animal models. The antiseizure activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutyric acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA A receptor.

Clonazepam is available in generic forms and under the brand name Klonopin in tablets of 0.5, 1.0 and 2 mg as well as in orally disintegrating tablets for pediatric use. The recommended initial dose for adults is 1.5 mg daily in three divided doses, increasing as needed to a maximum dose of 20 mg daily.

Clonazepam most common side effects of clonazepam are dose related and include drowsiness, lethargy, ataxia, dysarthria and dizziness. Tolerance develops to these side effects, but tolerance may also develop to the antiseizure effects.

Clorazepate

Clorazepate is a benzodiazepine used as an anticonvulsant as adjunctive therapy in management of epilepsy and as an anxiolytic for therapy of anxiety and alcohol withdrawal. Current indications are as adjunctive therapy in management of partial seizures and for treatment of anxiety disorders and acute alcohol withdrawal.

Clorazepate was approved in the United States in 1972 and currently more than 3 million prescriptions are filled yearly.

Clorazepate is a benzodiazepine with particular activity against spread of seizure activity in several animal models. The antiseizure activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutryic acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA A receptor. Clorazepate is used both as an anticonvulsant and anxiolytic agent.

Clorazepate is available in generic forms and under the brand name Tranxene in tablets and capsules in concentrations of 3.75, 7.5, 11.25, 15 and 22.5 mg. Delayed release formulations are also available. The recommended initial dose for adults with seizures is 7.5 mg three times daily, with gradual dose increases generally to an average dose of 30 to 60 mg daily and not in excess of 90 mg daily.

Clorazepate common side effects of clorazepate include drowsiness, lethargy, ataxia, dysarthria and dizziness. Tolerance develops to these side effects, but tolerance can also develop to the therapeutic effects.

Diazepam

Diazepam is a benzodiazepine that is available for both oral and intravenous administration; oral diazepam is used predominantly as an anxiolytic agent, while the intravenous form is used as an anticonvulsant. The use of diazepam as an anticonvulsant is limited largely to intravenous therapy of status epilepticus. Oral diazepam is not as effective or well tolerated as a therapy for epilepsy as are other benzodiazepines such as clobazam, clonazepam and clorazepate. Diazepam indications also include premedication before surgical operations and as conscious sedation for minor invasive procedures.

Diazepam was approved in the United States in 1963 and it is currently widely used to treat acute seizures and status epilepticus.

Diazepam is a benzodiazepine with particularly potent activity against spread of seizure activity in several animal models. The antiseizure activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutryic acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA A receptor.

Several generic forms of parenteral diazepam are available in ampules of 5 mg/mL. The typical recommended dose for status epilepticus is 5 to 10 mg given intravenously, which can be repeated at 10 to 15 minute intervals until control of seizure activity or to a maximum of 30 mg. Intramuscular administration can be used for premedication before general anesthesia.

Diazepam common effects of the use of parenteral diazepam include somnolence, confusion, dysarthria, diplopia and coma. Acute overdose of diazepam can cause respiratory arrest and death.

Eslicarbazepine

Eslicarbazepine is an aromatic anticonvulsant similar to oxcarbazepine that is used in combination with other antiepileptic agents as therapy of partial onset seizures. Eslicarbazepine was approved for use in the United States in 2013 as an anticonvulsant to be used alone or in combination with other agents in the therapy of partial onset seizures.

Eslicarbazepine is an aromatic anticonvulsant related in structure and activity to oxcarbazepine. Its mechanism of action is unknown but, like other carboxamides, eslicarbazepine is believed to inhibit voltage-gated sodium channels and thereby slow neurotransmission and interrupt the rapid, repetitive firing that is characteristic of epilepsy.

Eslicarbazepine is available in tablets of 200, 400, 600 and 800 mg under the brand name Aptiom. The recommended initial dose in adults is 400 mg once daily, which can be increased to 800 to 1600 mg once daily based upon tolerance and effect. The recommended initial doses in children are 200 to 400 mg once daily based upon body weight with maintenance dosages ranging from 400 to 1200 mg.

Eslicarbazepine side effects may include headache, dizziness, ataxia, blurred vision, nausea, fatigue and tremor. Rare, but potentially serious adverse events include hyponatremia, suicidal ideation or behavior and hypersensitivity reactions including DRESS and Stevens Johnson syndrome.

Ethosuximide

Ethosuximide is an succinimide based anticonvulsant commonly used for absence (petit mal) seizures in both adults and children. Ethosuximide was approved for use in epilepsy in 1960 for use alone or in combination with other agents to treat absence seizures.

Ethosuximide is a succinimide derivative and potent anticonvulsant that has been used to treat absence (petit mal) seizures for more than 50 years. Ethosuximde reduces theshold calcium currents in thalamic neurons and suppresses the paroxysmal spike and wave activity that is associated with lapses of consciousness that occur with absence seizures.

Ethosuximide is available as tablets of 250 mg and as syrup for pediatric use in several generic forms and under the brand name of Zarontin. The recommended initial dose in adults and children above the age of 6 years is 250 mg twice daily with dose escalation weekly based upon tolerance and effect.

Ethosuximide common side effects include dizziness, somnolence, ataxia, fatigue, irritability, anorexia and epigastric discomfort. Rare, but potentially severe adverse events include hypersensitivity reactions and drug induced lupus erythematosus and scleroderma.

Ezogabine

Ezogabine, which is known as retigabine in Europe, is a unique anticonvulsant used largely as an adjunctive agent in the treatment of partial seizures. Ezogabine was approved for use in the United States in 2011 and current indications are as adjunctive therapy for partial seizures.

Ezogabine is an anticonvulsant with a unique mechanism of action, decreasing excitability and seizure activity by opening voltage-gated potassium channels in the brain. Ezogabine has been shown to be effective both as monotherapy and in combination with other anticonvulsants for partial seizures.

Ezogabine is available in tablets of 50, 200, 300 and 400 mg under the brand name Potiga in the United States and Trobalt in Europe and elsewhere. The recommended initial dose in adults is 100 mg three times daily, which can be increased to 200 to 400 mg three times daily. The dose should be increased and tapered gradually.

Ezogabine most common side effects are dose related and include dizziness, somnolence, impaired concentration, nervousness, headache, fatigue nausea, weakness and tremor. Long term therapy has been associated with urinary retention and blue discoloration of the skin, lips, sclera and retina. Rare, but potentially severe adverse events include psychiatric symptoms such as confusion and hallucination and decrease in visual acuity as a result of retinal pigmentation.

Felbamate

Felbamate is a dicarbamate derivative anticonvulsant that is typically used in combination with other antiepileptic medications for refractory partial onset or generalized seizures. Felbamate is recommended only for refractory and severe epilepsy unresponsive to other agents. Felbamate has been associated with multiple cases of aplastic anemia and acute liver failure and its use is now restricted.

Felbamate was approved for use the United States in 1993, the first new anticonvulsant medication in more than a decade. Within a year of release, however, reports of aplastic anemia and severe hepatotoxicity were received and severe warnings were placed on its use. Although still available, felbamate is rarely used because of the availability of other anticonvulsants with better safety record.

Felbamate is a dicarbamate that has unique anticonvulsant activity. Its exact mechanism of action has not been established.

Felbamate is available as tablets of 400 and 600 mg and as an oral solution fo pediatric use generically and under the brand name Febatol, but only on a limited named-patient basis. The recommended initial dose in adults is 400 to 600 mg twice daily, with dose escalation based upon tolerance.

Felbamate common side effects include dizziness, nausea, somnolence and fatigue. Rare but potentially severe adverse events include suicidal thoughts and behaviors, aplastic anemia and acute hepatic failure.

Fosphenytoin

Fosphenytoin is a prodrug of phenytoin available in parenteral forms only. Fosphenytoin was approved for use in the United States in 1996. Current indications are for the short term treatment of tonic-clonic seizures and status epilepticus.

Fosphenytoin is a hydantoin derivative that is a prodrug of phenytoin and converted rapidly to phenytoin and is likely to have the same mechanisms of activity, efficacy and side effects as phenytoin. Phenytoin acts by stablization of neuronal membranes through increasing the efflux and decreasing the influx of sodium ions across GABA regulated Na+ channels in neuron cell membranes.

Fosphenytoin is available in parenteral formulations in 2 and 10 mL vials in concentrations of 50 mg/mL generically and under the brand name Cerebyx. The recommended dose in adults is 10 to 20 phenytoin sodium equivalents intramuscularly or intravenously initially, and then 4 to 6 equivalents each day for maintenance dosing. Once oral therapy can be introduced, phenytoin is usually substituted.

Gabapentin

Gabapentin is a unique anticonvulsant that is used as adjunctive therapy in management of epilepsy and for neuropathic pain syndromes. Current indications include add-on therapy for partial seizures which do not have adequate control with other anticonvulsants, and to reduce neuropathic pain from diabetic and postherpetic neuropathy.

Gabapentin was approved for use in the United States in 1993 and is a widely used medication with more than 18 million prescriptions filled yearly.

Gabapentin is a structural analogue of gamma-aminobutryic acid (GABA), but demonstrates little or no interaction with GABA receptors and does not appear to alter GABA uptake, synthesis or metabolism. While initially believed to act on the GABA-ergic neurotransmitter system, the actual mechanism of action of gabapentin as an anticonvulsant and agent for neuropathy is unknown.

Gabapentin is available as capsules or tablets of 100, 300, 400, 600 and 800 mg and in oral solution for pediatric use generically and under the brand names Neurontin and Gabarone. The recommended initial dose for adults is 300 mg three times daily increasing as needed to a maximum dose of 1800 mg daily.

Gabapentin most common side effects of gabapentin are dose related and include dizziness, somnolence, tremor, ataxia, blurred vision, anxiety, and gastrointestinal upset or nausea. Rare, but potentially severe adverse events include hypersensitivity reactions such as angioneurotic edema, drug rash with eosinophilia with systemic manifestations (DRESS syndrome) and Stevens Johnson syndrome.

Lacosamide

Lacosamide is an amino acid derivative with a unique anticonvulsant activity that is used in combination with other agents as therapy of partial onset seizures. Lacosamide was approved for use in the United States in 2011 as an anticonvulsant to be used in combination with other agents in the (adjunctive) therapy of partial onset seizures in patients 17 years of age or above.

Lacosamide is a functionalized amino acid derivative that appears to act by slow inactivation of voltage gated sodium channels in the central nervous system, which decreases the rate of neurotransmission and diminishes rapid, repetitive neuronal firing.

Lacosamide is available in tablets of 50, 100, 150 and 200 mg under the brand name Vimpat. It is also available in solution as for oral (10 mg/mL) use and in an intravenous (200 mg/20 mL vials) form for short term use when oral administration is not possible. The typical dose is 50 mg twice daily initially, with subsequent dose increases to an average of 200 to 400 mg daily.

Lacosamide side effects may include headache, dizziness, ataxia, blurred vision, nausea, fatigue and tremor.

Lamotrigine

Lamotrigine is indicated for prevention and management of partial and generalized seizures either alone or in combination with other anticonvulsant agents. Lamotrigine is also approved for use as a mood stabilizer in bipolar disorders. It is used off-label for several other conditions, including peripheral neuropathy, neuropathic pain, migraine headaches and trigeminal neuralgia.

Lamotrigine was approved for use in the United States for epilepsy in 1994 and it is still in common use.

Lamotrigine is a phenyltriazine and belongs to an anticonvulsant class of its own. Lamotrigine is believed to inhibit the release of excitatory neurotransmitters, particularly glutamate and aspartate but may also act directly on sodium channels on neuronal cells.

Lamotrigine is available tablets of 25, 100, 150 and 200 mg in generic formulations and under the brand name Lamictal. Pediatric formulations as chewable tablets are available in doses of 2, 5 and 25 mg. The recommended starting dose is 25 mg taken orally once daily, escalating to a maximum dose of 400 mg in two divided doses daily.

Lamotrigine common side effects include somnolence, fatigue, nervousness, dizziness, and rash.

Levetiracetam

Levetiracetam is a relatively unique anticonvulsant that is typically used in combination with other antiepileptic medications for partial onset seizures. Levetiracetam was approved for use in epilepsy in 1999 and current indications are as adjunctive therapy for partial onset seizures, generalized tonic-clonic seizures and myoclonic seizures in both children and adults.

Levetiracetam is a pyrrolidine derivative unrelated in structure to other anticonvulsant medications. Its mechanism of action is not known, but it is believed to act by preventing secondary spread of focal seizure activity and to decrease simultaneous neuronal firing.

Levetiracetam is available as tablets of 250, 500, 750 and 1000 mg generically and under the brand name Keppra. Liquid oral and injectable forms are also available. The recommended initial dose in adults is 500 mg twice daily with dose escalation based upon tolerance and effect to a maximum of 1500 mg twice daily. Dosing in children is based upon body weight.

Levetiracetam common side effects include dizziness, somnolence and fatigue.

Methsuximide

Methsuximide also called mesuximide, is a succinimide-based anticonvulsant similar to ethosuximide that is used for absence (petit mal) seizures in both adults and children. Methsuximide was first approved in 1957 for use alone or in combination with other agents to treat absence seizures. Methsuximide is no longer in common use, having been replaced by ethosuximide, the most active of the succinimide anticonvulsants and first line therapy for petit mal epilepsy.

Methsuximide is a succinimide derivative and anticonvulsant that is used to treat absence (petit mal) seizures. The succinimide anticonvulsants reduce low threshold calcium currents in thalamic neurons, and suppress the paroxysmal spike and wave activity that is associated with lapses of consciousness that occur with absence seizures.

Methsuximide is still available, generically and under the brand name Celontin as capsules of 150 and 300 mg. The recommended initial dose in adults and children above the age of 6 years is 300 mg once daily, with gradual dose escalation weekly based upon tolerance and effect to a maximum of 1200 mg daily.

Methsuximide common side effects include dizziness, somnolence, ataxia, fatigue, irritability, anorexia and epigastric discomfort.

Oxcarbazepine

Oxcarbazepine is a keto analogue of carbamazepine and, like the parent drug, is a potent anticonvulsant used alone or in combination with other agents in the therapy of poartial seizures. Oxcarbazepine is indicated for prevention and management of partial, complex, mixed and generalized seizures and is commonly used alone or in combination with other anticonvulsants. It is used off-label to treat bipolar disorder.

Oxcarbazepine was approved for use in epilepsy in the United States in 2000 and remains in common use.

Oxcarbazepine is a keto analog of carbamazepine and functions as a prodrug being rapidly converted to 10-hydroxycarbazepine. Oxcarbazepine and carbamazepine are iminostilbenes related chemically to the tricyclic antidepresants and unrelated in structure to most other anticonvulsants. They appear to act by suppression of spread of seizure activity by reduction in the posttetanic potentiation of synaptic transmission.

Oxcarbazepine is available as tablets of 150, 300 and 600 mg generically and under the commercial name of Trileptal and as an extended release form under the name Oxtellar XR. Oral formulations for use in children are also available. The recommended starting dose in adults is 300 mg twice daily followed by increases at weekly intervals based upon clinical response, the usual final dose being 600 mg twice daily.

Oxcarbazepine frequent side effects include drowsiness, sedation, ataxia, blurred vision, nausea, vomiting, and skin rash.

Perampanel

Perampanel is glutamate receptor antagonist that is used as an anticonvulsant in the therapy of partial onset seizures. Perampanel was approved for use in the United States in 2012 as an anticonvulsant to be used in combination with other agents as adjunctive therapy of partial onset seizures. In several large, prelicensure randomized controlled trials, addition of perampanel to conventional anticonvulsant medications led to improved control of epilepsy attributed to partial onset seizures.

Perampanel is a glutamate receptor antagonist that is used to treat severe or refractory partial onset seizures. Perampanel binds to the alpha-amino-3-hydroxyl-5-methyl-4-isooxazole-propionate receptor (AMPAR) for glutamate, a major central nervous system excitatory neurotransmitter. The inhibition of the AMPAR leads to reduction in seizure activity in animal models as well as in patients with difficult to control seizures.

Perampanel is available in tablets of 4, 6, 8, 10 and 12 mg under the brand name Fycompa. The recommended initial dose is 2 mg once daily, which can be increased subsequently based upon tolerance and efficacy to a dose of 4 to 12 mg once daily. The dose should be increased and tapered gradually.

Perampanel most common side effects include dizziness, somnolence, impaired concentration, vertigo, ataxia, nervousness, irritability, anger, aggression, blurred vision, headache, weight gain, fatigue, nausea and weakness. Rare, but potentially severe side effects include serious psychiatric and behavioral reactions including homicidal ideation and threats. Perampanel can cause euphoria for which reason it is classified as a scheduled III controlled substance, meaning that it has accepted medical uses, but also has a moderate or low potential for physical or psychological dependence.

Phenobarbital

Phenobarbital is a barbiturate that is widely used as a sedative and an antiseizure medication. Phenobarbital was introduced into clinical medicine in 1911 but was never subjected to critical controlled studies to demonstrate safety and efficacy. For these reasons, phenobarbital is now considered of unproven benefit in controlling seizures. Neverthess, it is commonly used for prevention and management of partial and generalized seizures, usually as an adjunctive agent in combination with other anticonvulsants. Phenobarbital is also used for sedation and insomnia although its use for these conditions is now uncommon. Phenobarbital is also used in fixed combinations with other antispasmotics or anticholinergic agents and used for gastrointestinal complaints, including irritable bowel syndrome.

Phenobarbital is a barbiturate and is believed to act as a nonselective depressant. Phenobarbital also has anticonvulsant activity and is believed to act by suppressing spread of seizure activity by enhancing the effect of gamma aminobutyric acid (GABA), raising the seizure threshold.

Phenobarbital typical starting dose in treating seizures in adults is 60 to 100 mg in three divided doses daily. Oral formulations of tablets or capsules of 15, 16, 30, 60, 90 and 100 mg are available in multiple generic forms. Parenteral formations and oral elixirs for pediatric use are also available.

Phenobarbital frequent side effects include drowsiness, sedation, hypotension, and skin rash.

Phenytoin

Phenytoin, formerly known as diphenylhydantoin, is perhaps the most commonly used major anticonvulsant agent. Phenytoin was first approved for use in the United States in 1946, and currently more than 3 million prescriptions are filled yearly. Current indications for phenytoin are treatment and prevention of generalized tonic-clonic (grand mal) seizures and complex partial seizures and management of status epilepticus. It is now rarely used to suppress ventricular arrhythmias in patients unresponsive to lidocaine.

Phenytoin is a hydantoin derivative that has potent anti-seizure activity that is believed to be based upon stablization of neuronal membranes caused by an increase in the efflux and decrease in the influx of sodium ions across GABA regulated sodium channels. A similar action in cardiac muscle may account for its activity against ventricular arrhythmias.

Phenytoin is available generically in oral and parenteral formulations. Oral forms include tablets and capsules of 100 to 300 mg, including extended release formations for once daily dosing. Commercial names include Dilantin. Chewable tablets and oral suspensions are available for pediatric use. The recommended dose of phenytoin for chronic use is 100 mg three times daily.

Phenytoin common side effects include dizziness, ataxia, nausea, gum hyperplasia and rash (which can occur in 10% of patients). Phenytoin has major effects on metabolism of other medications, and patients should be provided specific advice about other medications that can be used during long term phenytoin therapy.

Pregabalin

Pregabalin is an inhibitor of neuronal activity used for therapy of neuropathy and as an anticonvulsant. Pregabalin has been shown to be effective in reducing neuropathic pain from diabetic and postherpetic neuropathy and is an effective anticonvulsant. Current indications include diabetic and post-herpetic neuropathy and as adjunctive therapy of partial onset seizures. Pregabalin is also used for fibromyalgia and off-label for generalized anxiety disorders and migraine.

Pregabalin was approved for use in the United States in 2004.

Pregabalin is a structural analogue of gamma-aminobutyric acid (GABA) but is novel in its activity, having no effects on GABA-A or GABA-B receptors. Instead, the neuronal acitivity of pregabalin appears to be mediated by its binding to the alpha-2-delta subunit of the presynaptic voltage-gated calcium channel whcih leads to a decrease in release of neuroexcitatory neurotransmitters by hyperexcited neurons.

Pregabalin is available in capsules in varying concentrations from 25 to 300 mg under the brand name of Lyrica. The recommended initial dose for neuropathic pain is 50 to 75 mg two to three times daily, the maximum dose being 300 mg daily. Higher doses are used in treating seizures. The dose should be increased and tapered gradually.

Pregabalin most common side effects of pregabalin are dose related and include peripheral edema, weight gain, dizziness, somnolence, confusion, headache, blurred vision, tremor and ataxia.

Primidone

Primidone is an aromatic anticonvulsant used to treat complex, partial and generalized seizures. Primidone was approved for use in epilepsy in the United States in 1954. For many years, primidone was considered a first line anticonvulsant agent, but it has been largely replaced by more recently developed anticonvulsants that are better tolerated, less sedative and have fewer long term adverse side effects. Primidone has also been used to treat essential tremor.

Primidone is a pyrimidinedione anticonvulsant and is partially metabolized to phenobarbital. Primidone is effective in suppressing seizure activity, but its mechanism of action is not well defined. It is believed to work centrally via interactions with voltage-gated sodium channels inhibiting repetitive firing of action potentials.

Primidone is available as tablets of 50 and 250 mg in several generic formulations and under the brand names Mysoline, Myidone, Sertan and Apo-Primidone. The recommended initial dose for adults is 100 to 125 mg daily, increasing slowly to a maintenance dose of 250 mg three times daily. The most common side effects are dose related and include drowsiness, ataxia, diplopia, and headache. The initial dose may be associated with an acute toxic reaction with nausea, malaise, sedation, ataxia and confusion.

Primidone long term therapy may be associated with megaloblastic anemias and birth defects.

Rufinamide

Rufinamide is a unique anticonvulsant that is used in combination with other agents as therapy of severe forms of seizure disorders. Rufinamide was approved for use in the United States in 2008 as an anticonvulsant to be used in combination with other agents (adjunctive therapy) for Lennox-Gastaut syndrome in adults and children 1 year of age and older.

Rufinamide is a unique triazole derivative that appears to act by prolonging the inactivation of voltage gated sodium channels in the central nervous system, thus slowing the rate of neurotransmission and decreasing rapid, repetitive neuronal firing.

Rufinamide is available in tablets of 200 and 400 mg and as an oral suspension of 40 mg/mL under the brand name Banzel. The typical dose in children is 10 mg/kg in two divided doses daily, which can be increased to a maximum of 45 mg/kg daily. In adults the dose is 400 to 800 mg daily in two divided doses, which can be increased to a maximum of 3200 mg daily.

Rufinamide side effects may include headache, dizziness, somnolence, ataxia, tremor, fatigue, nausea and rash. Rare, but potentially severe adverse events include depression, suicidal thoughts and behavior, mood changes and hypersensitivity reactions including Stevens Johnson syndrome.

Tiagabine

Tiagabine is a unique anticonvulsant used largely as an adjunctive agent in therapy of partial seizures in adults or children. Tiagabine has been shown to be effective both as monotherapy and in combination with other anticonvulsants for partial seizures. Tiagabine was approved for use in epilepsy in the United States in 1997 and is currently used predominantly as adjunctive therapy with other major anticonvulsants for partial seizures. Tiagabine is occasionally used off-label to treat anxiety disorders and neuropathic pain.

Tiagabine is a selective gamma aminobutyric acid (GABA) reuptake inhibitor that increases synactive concentrations of this major neuroinhibitory transmitter, thus decreasing spread of abnormal neuronal impulses that contribute to seizures.

Tiagabine is available in tablets of 2, 4, 12 and 16 mg in generic formulations and under the brand name of Gabitril. The recommended initial dose in adults is 4 mg once daily, increasing by 4 to 8 mg at weekly intervals based upon clinical response, but not exceeding 56 mg daily. The dose should be increased and tapered gradually.

Tiagabine most common side effects of tiagabine are dose related and include dizziness, somnolence, impaired concentration, nervousness, nausea, weakness and tremor.

Topiramate

Topiramate is a unique antiseizure medication that is used in treatment of partial and generalized seizures. Topiramate current indications are for prevention and management of partial and generalized seizures used either as monotherapy or in combination with other anticonvulsants. Topiramate is also used for migraine and for bipolar disorder.

Topiramate was approved for use in epilepsy in the United States in 1996 and it is still widely used.

Topiramate is a sulfamate-substituted monosaccharide and belongs to an anticonvulsant class of its own. Topiramate is believed to act by reducing sodium channel currents and enhancing gamma aminobutyric acid (GABAA) receptor activity.

The recommended starting dose in adults is 25 mg twice daily, escalating at weekly intervals to a maximum of 200 mg twice daily. Topiramate is available in 25, 100 and 200 mg tablets in multiple generic forms and under the brand name Topromax. Pediatric formulations as sprinkle capsules are available in doses of 15 and 25 mg.

Topiramate common side effects include dizziness, somnolence, paresthesias, change in taste, anorexia, weight loss, itching, difficulty concentrating and nervousness.

Valproate

Valproate or valproic acid is a branched chain organic acid that is used as therapy of epilepsy, bipolar disorders and migraine headaches. Valproate was approved for therapy of epilepsy in adults and children in 1978 and is currently one of the major anticonvulsant medications used. Current approved uses include both monotherapy and in combination with other anticonvulsants for complex absence seizures, complex partial seizures and mixed seizure types. Valproate is also used for prevention of migraine headaches and for bipolar disorders. The recommended dose of valproate varies by indication.

Valproate is a carboxylic acid derivative that appears to act by increasing brain levels of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human brain. Valproate has been shown to be effective in several forms of seizures.

The initial recommended dose for therapy of seizures is 10 to 15 mg/kg/day, with increases of 5 to 10 mg/kg/day weekly to achieve an optimal clinical response. Monitoring of drug levels is often recommended. Valproate is available in multiple generic and brand formulations as capsules, tablets and syrups and in delayed release forms of 125, 250 and 500 mg. Oral forms also include divalproex, which dissociates into valproate in the gastrointestinal tract and is available in capsules of 125 mg under the brand name Depakote. Valproate sodium is also available in parenteral formulations.

Valproate has multiple side effects and clinically significant drug interactions; common side effects include headache, insomnia, nervousness, somnolence, tremor, blurred vision, nausea, weight gain and rash.

Vigabatrin

Vigabatrin is a GABA derivative that is used in combination with other agents as therapy of refractory complex partial seizures and as monotherapy for infantile spasms. Vigabatrin has been shown to be effective in reducing seizure activity as add on therapy in patients with refractory partial onset seizures. It has been available in other countries for more than a decade, but was first approved for use in the United States in 2009. Current indications include as adjuvant therapy in patients with refractory complex partial seizures and as monotherapy for infantile spasms in children ages 1 month to 2 years.

Vigabatrin is a vinyl derivative of gamma-aminobutyric acid (GABA) that acts as a competitive inhibitor of GABA transaminase. Vigabatrin prevents the breakdown of GABA and thus may increase GABAergic, neuroinhibitory activity.

Vigabatrin is available in tablets of 500 mg and as a powder for oral solution under the brand name Sabril. The typical initial dose is 500 mg twice daily, with subsequent increases to a recommended average dose of 3000 mg daily in adults and 2000 mg in children 10 to 16 years of age.

Vigabatrin side effects may include fatigue, somnolence, nystagmus, tremor, blurred vision, memory impairment, mood changes, confusion and weight gain. Rare, but severe adverse events include visual loss, visual field constriction and retinal dysfunction, for which reason vigabatrin is available only through a restricted program that requires prospective ophthalmologic monitoring.

Zonisamide

Zonisamide is a new generation anticonvulsant that is typically used in combination with other antiepileptic medications for partial onset seizures. Zonisamide was approved for use in epilepsy in Japan in 1989 and in the United States in 2000. Current indications include adjunctive therapy for partial seizures in adults. Zonisamide is used off-label for therapy of migraine headaches, mood disturbances and recently for weight loss.

Zonisamide is synthetic sulfonamide derivative related somewhat in structure to acetazolamide, but not to other anticonvulsant medications. Zonisamide appears to block the spread of seizure discharges by affecting repetitive firing of voltage-sensitive sodium and calcium channels and stabilizing neuronal membranes.

Zonisamide is available as capsules of 25, 50 and 100 mg generically and under the brand name of Zonegran. The recommended initial dose in adults with epilepsy is 100 mg in one or two doses daily, with dose escalation based upon tolerance and effect to a maximum of 200 mg twice daily.

Zonisamide common side effects include drowsiness, dizziness, headache, nausea, poor appetite and weight loss. Rare, but serious side effects include Stevens Johnson syndrome, toxic epidermal necrolysis, aplastic anemia and agranulocytosis.

1. Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology. 2002 Apr 23;58(8 Suppl 5):S2-8[↩]
2. Springer C, Nappe TM. Anticonvulsants Toxicity. [Updated 2019 Jan 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537206[↩][↩]
3. Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, Roujeau JC. The DRESS syndrome: a literature review. Am. J. Med. 2011 Jul;124(7):588-97[↩]