Anticonvulsants (also commonly known as antiepileptic drugs or as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the rapid and excessive firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain. Some investigators have observed that anticonvulsants themselves may cause reduced IQ in children.[1] However these adverse effects must be balanced against the significant risk epileptic seizures pose to children and the distinct possibility of death and devastating neurological sequelae secondary to seizures. Anticonvulsants are more accurately called antiepileptic drugs (abbreviated "AEDs"), and are often referred to as antiseizure drugs because they provide symptomatic treatment only and have not been demonstrated to alter the course of epilepsy.
Conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid (GABA) function. Several antiepileptic drugs have multiple or uncertain mechanisms of action.[2] Next to the voltage-gated sodium channels and components of the GABA system, their targets include GABAA receptors, the GAT-1 GABA transporter, and GABA transaminase.[3] Additional targets include voltage-gated calcium channels, SV2A, and α2δ.[4][5] By blocking sodium or calcium channels, antiepileptic drugs reduce the release of excitatory glutamate, whose release is considered to be elevated in epilepsy, but also that of GABA.[6] This is probably a side effect or even the actual mechanism of action for some antiepileptic drugs, since GABA can itself, directly or indirectly, act proconvulsively.[6] Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha.[7][8][9][10][11][12][13] The drug class was the 5th-best-selling in the US in 2007.[14]
Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.[15] That is, they either prevent the development of epilepsy or can halt or reverse the progression of epilepsy. However, no drug has been shown in human trials to prevent epileptogenesis (the development of epilepsy in an individual at risk, such as after a head injury).[16].
Approval[edit]
The usual method of achieving approval for a drug is to show it is effective when compared against placebo, or that it is more effective than an existing drug. In monotherapy (where only one drug is taken) it is considered unethical by most to conduct a trial with placebo on a new drug of uncertain efficacy. This is because untreated epilepsy leaves the patient at significant risk of death. Therefore, almost all new epilepsy drugs are initially approved only as adjunctive (add-on) therapies. Patients whose epilepsy is currently uncontrolled by their medication (i.e., it is refractory to treatment) are selected to see if supplementing the medication with the new drug leads to an improvement in seizure control. Any reduction in the frequency of seizures is compared against a placebo.[16] The lack of superiority over existing treatment, combined with lacking placebo-controlled trials, means that few modern drugs have earned FDA approval as initial monotherapy. In contrast, Europe only requires equivalence to existing treatments, and has approved many more. Despite their lack of FDA approval, the American Academy of Neurology and the American Epilepsy Society still recommend a number of these new drugs as initial monotherapy.[16]
Drugs[edit]
This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2010)
In the following list, the dates in parentheses are the earliest approved use of the drug.
Aldehydes[edit]
Main article: Aldehyde
Paraldehyde (1882). One of the earliest anticonvulsants. It is still used to treat status epilepticus, particularly where there are no resuscitation facilities.
Aromatic allylic alcohols[edit]
Stiripentol (2001 - limited availability). Indicated for the treatment of severe myoclonic epilepsy in infancy (SMEI).[17][18]
Barbiturates[edit]
Main article: Barbiturate
Barbiturates are drugs that act as central nervous system (CNS) depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. The following are classified as anticonvulsants:
Phenobarbital (1912). See also the related drug primidone.
Methylphenobarbital (1935). Known as mephobarbital in the US. No longer marketed in the UK
Barbexaclone (1982). Only available in some European countries.
Phenobarbital was the main anticonvulsant from 1912 until the development of phenytoin in 1938. Today, phenobarbital is rarely used to treat epilepsy in new patients since there are other effective drugs that are less sedating. Phenobarbital sodium injection can be used to stop acute convulsions or status epilepticus, but a benzodiazepine such as lorazepam, diazepam or midazolam is usually tried first. Other barbiturates only have an anticonvulsant effect at anaesthetic doses.
Benzodiazepines[edit]
Main article: Benzodiazepine
The benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsive, amnestic and muscle relaxant properties. Benzodiazepines act as a central nervous system depressant. The relative strength of each of these properties in any given benzodiazepine varies greatly and influences the indications for which it is prescribed. Long-term use can be problematic due to the development of tolerance to the anticonvulsant effects and dependency.[19][20][21][22] Of the many drugs in this class, only a few are used to treat epilepsy:
Clobazam (1979). Notably used on a short-term basis around menstruation in women with catamenial epilepsy.
Clonazepam (1974).
Clorazepate (1972).
The following benzodiazepines are used to treat status epilepticus:
Diazepam (1963). Can be given rectally by trained care-givers.
Midazolam (N/A). Increasingly being used as an alternative to diazepam. This water-soluble drug is squirted into the side of the mouth but not swallowed. It is rapidly absorbed by the buccal mucosa.
Lorazepam (1972). Given by injection in hospital.
Nitrazepam, temazepam, and especially nimetazepam are powerful anticonvulsant agents, however their use is rare due to an increased incidence of side effects and strong sedative and motor-impairing properties.
Bromides[edit]
Main article: Bromide
Potassium bromide (1857). The earliest effective treatment for epilepsy. There would not be a better drug until phenobarbital in 1912. It is still used as an anticonvulsant for dogs and cats.
Carbamates[edit]
Main article: Carbamate
Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.[23][24][25]
Carboxamides[edit]
Carbamazepine
Main article: Carboxamide
The following are carboxamides:
Carbamazepine (1963). A popular anticonvulsant that is available in generic formulations.
Oxcarbazepine (1990). A derivative of carbamazepine that has similar efficacy but is better tolerated and is also available generically.
Eslicarbazepine acetate (2009)
Fatty acids[edit]
Main article: Fatty acid
The following are fatty-acids:
The valproates — valproic acid, sodium valproate, and divalproex sodium (1967).
Vigabatrin (1989).
Progabide
Tiagabine (1996).
Vigabatrin and progabide are also analogs of GABA.
Fructose derivatives[edit]
Main article: Fructose
Topiramate (1995).
GABA analogs[edit]
Gabapentin (1993).
Pregabalin (2004).
Hydantoins[edit]
Main article: Hydantoin
The following are hydantoins:
Ethotoin (1957).
Phenytoin (1938).
Mephenytoin
Fosphenytoin (1996).
Oxazolidinediones[edit]
Main article: Oxazolidinedione
The following are oxazolidinediones:
Paramethadione
Trimethadione (1946).
Ethadione
Propionates[edit]
Main article: Propionate
Beclamide
Pyrimidinediones[edit]
Main article: Pyrimidinedione
Primidone (1952).
Pyrrolidines[edit]
Main article: Pyrrolidine
Brivaracetam
Levetiracetam (1999).
Seletracetam
Succinimides[edit]
Main article: Succinimide
The following are succinimides:
Ethosuximide (1955).
Phensuximide
Mesuximide
Sulfonamides[edit]
Main article: Sulfonamide (medicine)
Acetazolamide (1953).
Sultiame
Methazolamide
Zonisamide (2000).
Triazines[edit]
Main article: Triazine
Lamotrigine (1990).
Ureas[edit]
Main article: Urea
Pheneturide
Phenacemide
Valproylamides (amide derivatives of valproate)[edit]
Main article: Amide
Valpromide
Valnoctamide
Other[edit]
Perampanel
Non-medical anticonvulsants[edit]
This article is about anticonvulsant drugs. For non-medical "anticonvulsants", see Epilepsy#Other treatment.
Sometimes, ketogenic diet or vagus nerve stimulation are described as "anticonvulsant" therapies as well.
Treatment guidelines[edit]
According to guidelines by the AAN and AES,[26] mainly based on a major article review in 2004,[27] patients with newly diagnosed epilepsy who require treatment can be initiated on standard anticonvulsants such as carbamazepine, phenytoin, valproic acid/valproate semisodium, phenobarbital, or on the newer anticonvulsants gabapentin, lamotrigine, oxcarbazepine or topiramate. The choice of anticonvulsants depends on individual patient characteristics.[26] Both newer and older drugs are generally equally effective in new onset epilepsy.[26] The newer drugs tend to have fewer side effects.[26] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.[26] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.[26]
Conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid (GABA) function. Several antiepileptic drugs have multiple or uncertain mechanisms of action.[2] Next to the voltage-gated sodium channels and components of the GABA system, their targets include GABAA receptors, the GAT-1 GABA transporter, and GABA transaminase.[3] Additional targets include voltage-gated calcium channels, SV2A, and α2δ.[4][5] By blocking sodium or calcium channels, antiepileptic drugs reduce the release of excitatory glutamate, whose release is considered to be elevated in epilepsy, but also that of GABA.[6] This is probably a side effect or even the actual mechanism of action for some antiepileptic drugs, since GABA can itself, directly or indirectly, act proconvulsively.[6] Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha.[7][8][9][10][11][12][13] The drug class was the 5th-best-selling in the US in 2007.[14]
Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.[15] That is, they either prevent the development of epilepsy or can halt or reverse the progression of epilepsy. However, no drug has been shown in human trials to prevent epileptogenesis (the development of epilepsy in an individual at risk, such as after a head injury).[16].
Approval[edit]
The usual method of achieving approval for a drug is to show it is effective when compared against placebo, or that it is more effective than an existing drug. In monotherapy (where only one drug is taken) it is considered unethical by most to conduct a trial with placebo on a new drug of uncertain efficacy. This is because untreated epilepsy leaves the patient at significant risk of death. Therefore, almost all new epilepsy drugs are initially approved only as adjunctive (add-on) therapies. Patients whose epilepsy is currently uncontrolled by their medication (i.e., it is refractory to treatment) are selected to see if supplementing the medication with the new drug leads to an improvement in seizure control. Any reduction in the frequency of seizures is compared against a placebo.[16] The lack of superiority over existing treatment, combined with lacking placebo-controlled trials, means that few modern drugs have earned FDA approval as initial monotherapy. In contrast, Europe only requires equivalence to existing treatments, and has approved many more. Despite their lack of FDA approval, the American Academy of Neurology and the American Epilepsy Society still recommend a number of these new drugs as initial monotherapy.[16]
Drugs[edit]
This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2010)
In the following list, the dates in parentheses are the earliest approved use of the drug.
Aldehydes[edit]
Main article: Aldehyde
Paraldehyde (1882). One of the earliest anticonvulsants. It is still used to treat status epilepticus, particularly where there are no resuscitation facilities.
Aromatic allylic alcohols[edit]
Stiripentol (2001 - limited availability). Indicated for the treatment of severe myoclonic epilepsy in infancy (SMEI).[17][18]
Barbiturates[edit]
Main article: Barbiturate
Barbiturates are drugs that act as central nervous system (CNS) depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. The following are classified as anticonvulsants:
Phenobarbital (1912). See also the related drug primidone.
Methylphenobarbital (1935). Known as mephobarbital in the US. No longer marketed in the UK
Barbexaclone (1982). Only available in some European countries.
Phenobarbital was the main anticonvulsant from 1912 until the development of phenytoin in 1938. Today, phenobarbital is rarely used to treat epilepsy in new patients since there are other effective drugs that are less sedating. Phenobarbital sodium injection can be used to stop acute convulsions or status epilepticus, but a benzodiazepine such as lorazepam, diazepam or midazolam is usually tried first. Other barbiturates only have an anticonvulsant effect at anaesthetic doses.
Benzodiazepines[edit]
Main article: Benzodiazepine
The benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsive, amnestic and muscle relaxant properties. Benzodiazepines act as a central nervous system depressant. The relative strength of each of these properties in any given benzodiazepine varies greatly and influences the indications for which it is prescribed. Long-term use can be problematic due to the development of tolerance to the anticonvulsant effects and dependency.[19][20][21][22] Of the many drugs in this class, only a few are used to treat epilepsy:
Clobazam (1979). Notably used on a short-term basis around menstruation in women with catamenial epilepsy.
Clonazepam (1974).
Clorazepate (1972).
The following benzodiazepines are used to treat status epilepticus:
Diazepam (1963). Can be given rectally by trained care-givers.
Midazolam (N/A). Increasingly being used as an alternative to diazepam. This water-soluble drug is squirted into the side of the mouth but not swallowed. It is rapidly absorbed by the buccal mucosa.
Lorazepam (1972). Given by injection in hospital.
Nitrazepam, temazepam, and especially nimetazepam are powerful anticonvulsant agents, however their use is rare due to an increased incidence of side effects and strong sedative and motor-impairing properties.
Bromides[edit]
Main article: Bromide
Potassium bromide (1857). The earliest effective treatment for epilepsy. There would not be a better drug until phenobarbital in 1912. It is still used as an anticonvulsant for dogs and cats.
Carbamates[edit]
Main article: Carbamate
Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.[23][24][25]
Carboxamides[edit]
Carbamazepine
Main article: Carboxamide
The following are carboxamides:
Carbamazepine (1963). A popular anticonvulsant that is available in generic formulations.
Oxcarbazepine (1990). A derivative of carbamazepine that has similar efficacy but is better tolerated and is also available generically.
Eslicarbazepine acetate (2009)
Fatty acids[edit]
Main article: Fatty acid
The following are fatty-acids:
The valproates — valproic acid, sodium valproate, and divalproex sodium (1967).
Vigabatrin (1989).
Progabide
Tiagabine (1996).
Vigabatrin and progabide are also analogs of GABA.
Fructose derivatives[edit]
Main article: Fructose
Topiramate (1995).
GABA analogs[edit]
Gabapentin (1993).
Pregabalin (2004).
Hydantoins[edit]
Main article: Hydantoin
The following are hydantoins:
Ethotoin (1957).
Phenytoin (1938).
Mephenytoin
Fosphenytoin (1996).
Oxazolidinediones[edit]
Main article: Oxazolidinedione
The following are oxazolidinediones:
Paramethadione
Trimethadione (1946).
Ethadione
Propionates[edit]
Main article: Propionate
Beclamide
Pyrimidinediones[edit]
Main article: Pyrimidinedione
Primidone (1952).
Pyrrolidines[edit]
Main article: Pyrrolidine
Brivaracetam
Levetiracetam (1999).
Seletracetam
Succinimides[edit]
Main article: Succinimide
The following are succinimides:
Ethosuximide (1955).
Phensuximide
Mesuximide
Sulfonamides[edit]
Main article: Sulfonamide (medicine)
Acetazolamide (1953).
Sultiame
Methazolamide
Zonisamide (2000).
Triazines[edit]
Main article: Triazine
Lamotrigine (1990).
Ureas[edit]
Main article: Urea
Pheneturide
Phenacemide
Valproylamides (amide derivatives of valproate)[edit]
Main article: Amide
Valpromide
Valnoctamide
Other[edit]
Perampanel
Non-medical anticonvulsants[edit]
This article is about anticonvulsant drugs. For non-medical "anticonvulsants", see Epilepsy#Other treatment.
Sometimes, ketogenic diet or vagus nerve stimulation are described as "anticonvulsant" therapies as well.
Treatment guidelines[edit]
According to guidelines by the AAN and AES,[26] mainly based on a major article review in 2004,[27] patients with newly diagnosed epilepsy who require treatment can be initiated on standard anticonvulsants such as carbamazepine, phenytoin, valproic acid/valproate semisodium, phenobarbital, or on the newer anticonvulsants gabapentin, lamotrigine, oxcarbazepine or topiramate. The choice of anticonvulsants depends on individual patient characteristics.[26] Both newer and older drugs are generally equally effective in new onset epilepsy.[26] The newer drugs tend to have fewer side effects.[26] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.[26] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.[26]
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