The anticonvulsants 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 in 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.[1] 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"), sometimes referred to as antiseizure drugs. While an anticonvulsant is a fair description of AEDs, it neglects to differentiate the difference between convulsions and epilepsy. Convulsive non-epileptic seizures are quite common and these types of seizures will not have any response to an antiepileptic drug. In epilepsy an area of the cortex is typically hyperirritable that can often be confirmed by completing an EEG. Antiepileptic drugs function to help reduce this area of irritability and thus prevent epileptiform seizures.
The major molecular targets of marketed anticonvulsant drugs are voltage-gated sodium channels and components of the GABA system, including GABAA receptors, the GAT-1 GABA transporter, and GABA transaminase.[2] Additional targets include voltage-gated calcium channels, SV2A, and α2δ.[3][4] The drug class was the US's 5th-best-selling in 2007.[5]
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.[6]
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.[6]
Once there is confidence that a drug is likely to be effective in monotherapy, trials are conducted where the drug is compared to an existing standard. For partial-onset seizures, this is typically carbamazepine. Despite the launch of over ten drugs since 1990, no new drug has been shown to be more effective than the older set, which includes carbamazepine, valproate and phenytoin. 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.[6]
In the following list, the dates in parentheses are the earliest approved use of the drug.
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 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.[7][8][9][10] Of the many drugs in this class, only a few are used to treat epilepsy:
The following benzodiazepines are used to treat status epilepticus:
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.
The following are carboxamides:
The following are fatty-acids:
Vigabatrin and progabide are also analogs of GABA.
The following are hydantoins:
The following are oxazolidinediones:
The following are succinimides:
Sometimes, ketogenic diet or vagus nerve stimulation are described as "anticonvulsant" therapies as well.
According to guidelines by the AAN and AES,[11] mainly based on a major article review in 2004,[12] 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.[11] Both newer and older drugs are generally equally effective in new onset epilepsy.[11] The newer drugs tend to have fewer side effects.[11] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy.[11] Lamotrigine can be included in the options for children with newly diagnosed absence seizures.[11]
The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Potassium bromide was also noted to cause impotence in men. Authorities concluded that potassium bromide would dampen sexual excitement thought to cause the seizures. In fact, bromides were effective against epilepsy, and also caused impotence; it is now known that impotence is a side effect of bromide treatment, which is not related to its anti-epileptic effects. It also suffered from the way it affected behaviour, introducing the idea of the 'epileptic personality' which was actually a result of the 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.[13] 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.
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.
| Drug | Brand | US | UK | France |
|---|---|---|---|---|
| acetazolamide | Diamox | 27 July 1953[14] | 1988[15] | |
| carbamazepine | Tegretol | 15 July 1974[16][17] | 1965[15] | 1963[18] |
| clobazam | Frisium | 1979[15] | ||
| clonazepam | Klonopin/Rivotril | 4 June 1975[19] | 1974[15] | |
| diazepam | Valium | 15 November 1963[20] | ||
| divalproex sodium | Depakote | 10 March 1983[21] | ||
| ethosuximide | Zarontin | 2 November 1960[22] | 1955[15] | 1962[18] |
| ethotoin | Peganone | 22 April 1957[23] | ||
| felbamate | Felbatol | 29 July 1993[24] | ||
| fosphenytoin | Cerebyx | 5 August 1996[25] | ||
| gabapentin | Neurontin | 30 December 1993[26] | May 1993[15][18] | October 1994[18] |
| lamotrigine | Lamictal | 27 December 1994[27] | October 1991[15][18] | May 1995[18] |
| lacosamide | Vimpat | |||
| levetiracetam | Keppra | 30 November 1999[28] | 29 September 2000[15][29] | 29 September 2000[29] |
| mephenytoin | Mesantoin | 23 October 1946[30] | ||
| metharbital | Gemonil | 1952[31][32] | ||
| methsuximide | Celontin | 8 February 1957[33] | ||
| methazolamide | Neptazane | 26 January 1959[34] | ||
| oxcarbazepine | Trileptal | 14 January 2000[35] | 2000[15] | |
| phenobarbital | 1912[15] | 1920[18] | ||
| phenytoin | Dilantin/Epanutin | 1938[18][36] | 1938[15] | 1941[18] |
| phensuximide | Milontin | 1953[37][38] | ||
| pregabalin | Lyrica | 30 December 2004[39] | 6 July 2004[15][40] | 6 July 2004[40] |
| primidone | Mysoline | 8 March 1954[41] | 1952[15] | 1953[18] |
| sodium valproate | Epilim | December 1977[18] | June 1967[18] | |
| stiripentol | Diacomit | 5 December 2001[42] | 5 December 2001[42] | |
| tiagabine | Gabitril | 30 September 1997[43] | 1998[15] | November 1997[18] |
| topiramate | Topamax | 24 December 1996[44] | 1995[15] | |
| trimethadione | Tridione | 25 January 1946[45] | ||
| valproic acid | Depakene/Convulex | 28 February 1978[46] | 1993[15] | |
| vigabatrin | Sabril | 21 August 2009[47] | 1989[15] | |
| zonisamide | Zonegran | 27 March 2000[48] | 10 March 2005[15][49] | 10 March 2005[49] |
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.[50] Therefore, these drugs should be monitored during use in pregnancy.[50] Taking valproic acid or divalproex sodium during pregnancy should be cautioned against, as this class of medications has been linked to birth defects (teratogenic).
There is inadequate evidence to determine if newborns of women with epilepsy taking anticonvulsants have a substantially increased risk of hemorrhagic disease of the newborn.[50]
Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam.[50] On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.[50]
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