The anticonvulsants (also commonly known as antiepileptic drugs) are a diverse group of pharmaceuticals 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. The goal of an anticonvulsant is to suppress the rapid and excessive firing of neurons that start a seizure. Failing this, an effective anticonvulsant would prevent the spread of the seizure within the brain and offer protection against possible excitotoxic effects, that may result in brain damage. Some studies have cited that anticonvulsants themselves are linked to lowered IQ in children. However these adverse effects must be balanced against the significant risk epileptiform seizures pose to children and the distinct possibility of death and devastating neurological sequela secondary to seizures. Anticonvulsants are more accurately called antiepileptic drugs (abbreviated "AEDs"), and are sometimes referred to as antiseizure drugs. While the term 'anticonvulsant' is a fair description of AEDs, the use of this term tends to lead to confusion between epilepsy and non-epileptic convulsions. Convulsive non-epileptic seizures are quite common, and these types of seizures do not respond to antiepileptic drugs. In epilepsy, an area of the cortex is typically hyper-irritable. This condition can often be confirmed by completing a diagnostic EEG. Antiepileptic drugs function to help reduce this area of irritability and thus prevent epileptiform seizures.
Conventional antiepileptic drugs block sodium channels or enhance g-aminobutyric acid function. Several antiepileptic drugs have multiple or uncertain mechanisms of action. 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. Additional targets include voltage-gated calcium channels, SV2A, and α2δ. The drug class was the US's 5th-best-selling in 2007.
Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy. That is, they either prevent the expected development of epilepsy or can halt or reverse the progression of epilepsy. However, no drug has been shown to prevent epileptogenesis (the development of epilepsy after an injury such as a head injury) in human trials.
- 1 Approval
- 2 Drugs
- 2.1 Aldehydes
- 2.2 Aromatic allylic alcohols
- 2.3 Barbiturates
- 2.4 Benzodiazepines
- 2.5 Bromides
- 2.6 Carbamates
- 2.7 Carboxamides
- 2.8 Fatty acids
- 2.9 Fructose derivatives
- 2.10 GABA analogs
- 2.11 Hydantoins
- 2.12 Oxazolidinediones
- 2.13 Propionates
- 2.14 Pyrimidinediones
- 2.15 Pyrrolidines
- 2.16 Succinimides
- 2.17 Sulfonamides
- 2.18 Triazines
- 2.19 Ureas
- 2.20 Valproylamides (amide derivatives of valproate)
- 3 Non-medical anticonvulsants
- 4 Treatment guidelines
- 5 History
- 6 Use in pregnancy
- 7 See also
- 8 References
- 9 External links
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. 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.
In the following list, the dates in parentheses are the earliest approved use of the drug.
- Paraldehyde (1882). One of the earliest anticonvulsants. Still used to treat status epilepticus, particularly where there are no resuscitation facilities.
Aromatic allylic alcohols
- Stiripentol (2001 - limited availability). Indicated for the treatment of severe myoclonic epilepsy in infancy (SMEI).
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 till 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.
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. 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.
- 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.
- Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.
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)
The following are fatty-acids:
- The valproates — valproic acid, sodium valproate, and divalproex sodium (1967).
- Vigabatrin (1989).
- Tiagabine (1996).
Vigabatrin and progabide are also analogs of GABA.
- Topiramate (1995).
The following are hydantoins:
The following are oxazolidinediones:
- Primidone (1952).
The following are succinimides:
- Lamotrigine (1990).
Valproylamides (amide derivatives of valproate)
According to guidelines by the AAN and AES, mainly based on a major article review in 2004, 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. Both newer and older drugs are generally equally effective in new onset epilepsy. The newer drugs tend to have fewer side effects. For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy. Lamotrigine can be included in the options for children with newly diagnosed absence seizures.
The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Bromides are effective against epilepsy, and also cause impotence, which is not related to its anti-epileptic effects. Bromide also suffered from the way it affected behaviour, introducing the idea of the 'epileptic personality' which was actually a result of medication. Phenobarbital was first used in 1912 for both its sedative and antiepileptic properties. By the 1930s, the development of animal models in epilepsy research led to the development of phenytoin by Tracy Putnam and H. Houston Merritt, which had the distinct advantage of treating epileptic seizures with less sedation. By the 1970s, an National Institutes of Health initiative, the Anticonvulsant Screening Program, headed by J. Kiffin Penry, served as a mechanism for drawing the interest and abilities of pharmaceutical companies in the development of new anticonvulsant medications.
Marketing approval history
The following table lists anticonvulsant drugs together with the date their marketing was approved in the US, UK and France. Data for the UK and France are incomplete. In recent years, the European Medicines Agency has approved drugs throughout the European Union. Some of the drugs are no longer marketed.
|acetazolamide||Diamox||27 July 1953||1988|
|carbamazepine||Tegretol||15 July 1974||1965||1963|
|clonazepam||Klonopin/Rivotril||4 June 1975||1974|
|diazepam||Valium||15 November 1963|
|divalproex sodium||Depakote||10 March 1983|
|ethosuximide||Zarontin||2 November 1960||1955||1962|
|ethotoin||Peganone||22 April 1957|
|felbamate||Felbatol||29 July 1993|
|fosphenytoin||Cerebyx||5 August 1996|
|gabapentin||Neurontin||30 December 1993||May 1993||October 1994|
|lamotrigine||Lamictal||27 December 1994||October 1991||May 1995|
|lacosamide||Vimpat||28 October 2008|
|levetiracetam||Keppra||30 November 1999||29 September 2000||29 September 2000|
|mephenytoin||Mesantoin||23 October 1946|
|methsuximide||Celontin||8 February 1957|
|methazolamide||Neptazane||26 January 1959|
|oxcarbazepine||Trileptal||14 January 2000||2000|
|pregabalin||Lyrica||30 December 2004||6 July 2004||6 July 2004|
|primidone||Mysoline||8 March 1954||1952||1953|
|sodium valproate||Epilim||December 1977||June 1967|
|stiripentol||Diacomit||5 December 2001||5 December 2001|
|tiagabine||Gabitril||30 September 1997||1998||November 1997|
|topiramate||Topamax||24 December 1996||1995|
|trimethadione||Tridione||25 January 1946|
|valproic acid||Depakene/Convulex||28 February 1978||1993|
|vigabatrin||Sabril||21 August 2009||1989|
|zonisamide||Zonegran||27 March 2000||10 March 2005||10 March 2005|
Use in pregnancy
During pregnancy, the metabolism of several anticonvulsants is affected. There may be an increase in the clearance and resultant decrease in the blood concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. Therefore, these drugs should be monitored during use in pregnancy. Taking valproic acid or divalproex sodium during pregnancy should be cautioned against, as this class of medications has been linked to birth defects (teratogenic).
Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam. On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.
- Drug Reference for FDA Approved Epilepsy Drugs
- Epilepsy Action: UK Anti-Epileptic Drugs List
- eMedicine: Antiepileptic Drugs: an overview
- NINDS: Anticonvulsant Screening Program
- Use of Anticonvulsants in Pharmacotherapy of Bronchial Asthma
- MDNG: Anticonvulsants and Bone Health
- Miami Children's Brain Institute - Anticonvulsants