Medication Summary
Anticonvulsant medication is the mainstay of treatment for seizures, although the choice of anticonvulsant drug varies with different seizure types and epileptic syndromes. The number of anticonvulsants has increased, offering many more medication choices for physicians and their patients. For more information, see Antiepleptic Drugs.
Anticonvulsants, Other
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical seizure activity. Anticonvulsants are normally reserved for patients who are at increased risk for recurrent seizures.
Carbamazepine (Tegretol, Tegretol XR, Carbatrol, Epitol, Equetro)
Carbamazepine is indicated for the management of partial seizures and generalized tonic-clonic seizures. It has an active metabolite, 10-11 epoxide, which has anticonvulsant activity and can be measured in the serum. This agent works by binding to voltage-dependent sodium channels and inhibiting the generation of action potentials. Serum carbamazepine levels should be measured frequently when initially starting this medication, with a goal of being seizure free. Like phenytoin, carbamazepine has been associated with osteopenia.
Felbamate (Felbatol)
Felbamate is approved by the FDA for medically refractory partial seizures and Lennox-Gastaut syndrome. This agent has multiple mechanisms of action, including (1) inhibition of N-methyl-D-aspartate (NMDA)–associated sodium channels, (2) potentiation of GABAergic activity, and (3) inhibition of voltage-sensitive sodium channels. Felbamate is used only as a drug of last resort in medically refractory cases because of the risk of aplastic anemia and hepatic toxicity, which necessitates regular blood tests.
Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)
Lamotrigine, a triazine derivative, is an antiepileptic drug with a very broad spectrum of activity, like valproate. It is approved by the FDA for primary generalized and partial-onset epilepsy. Other indications include adjunctive therapy in the treatment of generalized seizures of Lennox-Gastaut syndrome, treatment of juvenile myoclonic epilepsy (JME) and maintenance treatment of bipolar I disorder. The mechanism of action is based on inhibiting the release of glutamate and voltage-sensitive sodium channels, leading to stabilization of the neuronal membrane.
Lamotrigine is quickly absorbed when given orally, and 55% is bound to plasma proteins. The therapeutic serum levels have not been definitively established.
Side effects of lamotrigine include rash and nausea. The dose has to be increased very slowly over several weeks to minimize the chance of rash, especially if the patient is on valproic acid. The risk of developing Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema is 1 in 1000 adults and higher in children, but this risk is decreased with slower titration.
Levetiracetam (Keppra, Keppra XR)
Levetiracetam is indicated for adjunctive therapy in the treatment of primary generalized tonic-clonic seizures, JME, and partial-onset seizures in adults and children. The mechanism of action is thought to be through modulation of synaptic vesicle proteins. The metabolism of this drug is independent of the CYP450 system, which limits the potential for interaction with other antiepileptic drugs.
Levetiracetam has a rapid onset of action and is well tolerated. Common side effects include fatigue, somnolence, dizziness, and irritability. This medication is available in oral (including extended-release) and intravenous formulations.
Rufinamide (Banzel)
Rufinamide modulates sodium channel activity, particularly prolongation of the channel's inactive state. It significantly slows sodium channel recovery and limits sustained, repetitive firing of sodium-dependent action potentials. Rufinamide is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. It is well tolerated, with the most common side effects being somnolence and vomiting.
Topiramate (Topamax)
Topiramate is an AED with a broad spectrum of antiepileptic activity. This agent is approved for generalized, primary generalized, tonic-clonic, and partial-onset seizures. Topiramate has multiple mechanisms of action, including state-dependent sodium channel ̶ blocking action, enhancement of the inhibitory activity of the neurotransmitter GABA, and antagonism of the NMDA-glutamate receptor. It may block glutamate activity and is a weak carbonic anhydrase inhibitor. Weight loss, impaired cognition, and mood problems are common side effects of topiramate. The drug is also approved for migraine prevention.
Valproic acid (Depacon, Depakene, Stavzor)
Valproate, a broad-spectrum AED, is effective against most seizure types, including myoclonic seizures. It can also be used alone or in combination for the treatment of generalized or partial seizures. Valproate has multiple mechanisms of anticonvulsant action, including increasing GABA levels in the brain, as well as T-type calcium channel activity.
Divalproex sodium (Depakote, Depakote ER, Depakote Sprinkles)
Indicated for complex partial seizures and also for simple and complex absence seizures. May be used as monotherapy or adjunctive therapy. Valproate has multiple mechanisms of anticonvulsant action, including increasing GABA levels in the brain, as well as T-type calcium channel activity. The extended-release (ER) formulation allows for once-a-day administration.
Zonisamide (Zonegran)
Zonisamide is indicated for partial seizures. It blocks T-type calcium channels, prolongs sodium channel inactivation, and is a carbonic anhydrase inhibitor.
Dose adjustments may be required when zonisamide is given with other anticonvulsants, such as carbamazepine, phenytoin, and phenobarbital. The most common side effects of this drug include ataxia, anorexia, and fatigue.
Perampanel (Fycompa)
Perampanel is a noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor. It is indicated as adjunct treatment for partial-onset seizures (with or without secondary generalized seizures) and for primary generalized tonic-clonic seizures in adults and children aged 12 years or older.
Lacosamide (Vimpat)
Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. It is indicated as monotherapy or adjunctive therapy for partial-onset seizures.
Cannabidiol (Epidiolex)
Purified formulation of cannabidiol indicated for treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients aged 1 year or older. Cannabidiol is a structurally novel anticonvulsant and the exact mechanism by which it produces anticonvulsant effects is unknown. It does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.
Stiripentol (Diacomit)
Allylic alcohol that is unrelated to other anticonvulsants. The precise anticonvulsant effect in humans is unknown. Possible mechanisms of action include direct effects mediated through the GABA-A receptor and indirect effects involving inhibition of cytochrome P450 activity with resulting increase in blood levels of clobazam and its active metabolite. It is indicated for treatment of seizures associated with Dravet syndrome in patients aged 6 months and older who are taking clobazam. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome.
Cenobamate (Xcopri)
The precise mechanism is unknown, but it has shown to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of GABA-A ion channel. It is indicated for adults with partial-onset seizures as either monotherapy or adjunctive therapy.
Vigabatrin (Sabril, Vigadrone)
Irreversible inhibitor of gamma aminobutyric acid (GABA) transaminase, resulting in increased GABA (inhibitory neurotransmitter) in the brain. It is indicated as adjunctive therapy for adults and pediatric patients aged 2 years or older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss. It is only available through a restricted access program.
Fenfluramine (Fintepla)
Fenfluramine and its metabolite, norfenfluramine, increase extracellular levels of serotonin through interaction with serotonin transporter proteins, and exhibit agonist activity at serotonin 5HT-2 receptors. The precise mechanism of action for the treatment of seizures associated with Dravet syndrome is unknown. It is indicated for treatment of seizures associated with Dravet syndrome in patients aged 2 years and older.
Anticonvulsants, Barbiturates
Class Summary
Like benzodiazepines, barbiturates bind to the gamma-aminobutyric acid (GABA) receptor, enhancing the actions of GABA by extending GABA-mediated chloride channel openings and allowing neuronal hyperpolarization. The principal barbiturate used for status epilepticus is phenobarbital; for refractory cases, pentobarbital is used.
Phenobarbital (Luminal)
Phenobarbital works at GABA receptors in the central nervous system (CNS) to potentiate CNS inhibition. This agent is the best-studied barbiturate for the treatment of status epilepticus.
In status epilepticus, achieving therapeutic levels as quickly as possible is important. Intravenous dosing may require approximately 15 minutes to attain peak levels in the brain. To terminate generalized convulsive status epilepticus, administer up to 15-20 mg/kg. If the patient has received a benzodiazepine, the potential for respiratory suppression significantly increases. Ventilation and intubation may be necessary. Hypotension may require treatment.
In status epilepticus, phenobarbital is generally used after phenytoin or fosphenytoin fails. However, it can be used in lieu of phenytoin in certain circumstances. A trend is to recommend agents other than phenobarbital (propofol, midazolam, other barbiturates) for refractory status epilepticus; however, for super-refractory status epilepticus, phenobarbital should be used.
Primidone (Mysoline)
Primidone is indicated for the management of grand mal, psychomotor, and focal seizures. In addition, it is commonly used for benign familial tremors. When metabolized, primidone breaks down to phenobarbital, another active antiepileptic drug. Primidone decreases neuron excitability and increases the seizure threshold. Common side effects of this drug include sedation, drowsiness, fatigue, and depression.
Anticonvulsants, Benzodiazepine
Class Summary
These agents bind to the gamma-aminobutyric acid (GABA) receptor, thereby enhancing the actions of GABA.
Clobazam (ONFI)
Clobazam is a 1,5-benzodiazepine that possesses potent anticonvulsant properties. Its mechanism of action is binding to the gamma-aminobutyric acid–A (GABA-A) receptor. This agent is thought to potentiate GABAergic neurotransmission. The active metabolite, N-demethylclobazam, is largely responsible for its long duration of action. Clobazam is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients older than 2 years.
Midazolam intranasal (Nayzilam)
Short-acting, water-soluble imidazobenzodiazepine. Thought to potentiate GABAergic neurotransmission which results from binding at the benzodiazepine site of the GABA-A receptor. It is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in adults and children aged 12 years or older with epilepsy.
Diazepam intranasal (Valtoco)
The exact mechanism of action for diazepam is not fully understood, but it is thought to involve potentiation of gamma aminobutyric acid (GABA) neurotransmission resulting from binding at the benzodiazepine site of the GABA-A receptor. Diazepam intranasal is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy aged 6 y or older.
Anticonvulsants, Succinimide
Class Summary
These agents reduce current in T-type calcium channels.
Ethosuximide (Zarontin)
Ethosuximide is a succinimide antiepileptic drug (AED) that is effective only against absence seizures. It has no effect on generalized tonic-clonic, myoclonic, atonic, or partial seizures.
The mechanism of action is based on reducing current in T-type calcium channels on thalamic neurons. The spike-and-wave pattern during petit mal seizures is thought to be initiated in thalamocortical relays by activation of these channels. Ethosuximide is available in large 250-mg capsules, which may be difficult for some children to swallow, and as a syrup (250 mg/5 mL).
Blood levels should be measured 1-3 weeks after starting ethosuximide. The therapeutic concentration of ethosuximide is 40-100 mcg/mL. The major side effects of the drug include nausea, vomiting, drowsiness, hyperactivity and sleep disturbance.
Anticonvulsants, Neuronal Potassium Channel Opener
Class Summary
Stabilizes neuronal KCNQ (Kv7) channels in the open position, increasing the stabilizing membrane current and preventing bursts of action potentials during the sustained depolarizations associated with seizures.
Ezogabine (Potiga)
Ezogabine is a neuronal potassium channel opener that stabilizes neuronal KCNQ (Kv7) channels in the open position, increasing the stabilizing membrane current and preventing bursts of action potentials during the sustained depolarizations associated with seizures. It is indicated as adjunctive therapy in partial-onset seizures uncontrolled by current medications.
Owing to the presence of potassium channels in the bladder, there is a small risk of urinary retention. Ezogabine can cause skin discoloration and abnormalities of the eye characterized as changes in the pigment in the retina. Whether these changes are permanent and whether pigment changes in the retina have the potential to cause loss of vision are unknown.
The FDA recommends that all patients taking ezogabine undergo baseline and periodic eye examinations and discontinue the medication if changes are observed, unless there is no other treatment option. Skin discoloration most often appeared as blue around the lips and nail beds but was also reported to be widespread on the face and legs. In patients with skin discoloration, alternative treatments should be considered, but the FDA warns of serious and life-threatening reactions to the sudden discontinuance of the medication.
Anticonvulsants, Hydantoins
Class Summary
These agents stabilize sodium channels and prevent return of the channels to the active state.
Phenytoin (Dilantin, Phenytek)
Phenytoin is used to treat patients with partial, generalized, or mixed seizures, such as the tonic-clonic (grand mal) type. This agent works by blocking voltage-dependent neuronal sodium channels. The therapeutic concentration range of phenytoin in serum is 10-20 mcg/mL for patients who have normal renal function and serum albumin levels.
The risk of osteopenia and cerebellar ataxia, both of which are long-term adverse effects associated with phenytoin, now temper the drug's use by neurologists. This agent is one of the most difficult AEDs to use because of its zero-order kinetics and narrow therapeutic index. In addition, it can have significant bidirectional drug interactions.
GABA Receptor Positive Modulators
Class Summary
Precise mechanism is unknown, but anticonvulsant effects are thought to result from positive allosteric modulation of the gamma-aminobutyric acid type A (GABAA) receptor in the CNS.
Ganaxolone (Ztalmy)
Indicated for seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2 years and older.
