Anticonvulsant


Anticonvulsants 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 and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain.
Conventional antiepileptic drugs may block sodium channels or enhance γ-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. 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. 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. Another potential target of antiepileptic drugs is the peroxisome proliferator-activated receptor alpha. The drug class was the fifth-best-selling in the United States in 2007.
Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy. 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.

Terminology

Anticonvulsants are more accurately called antiepileptic drugs, 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.

Approval

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 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 therapies. Patients whose epilepsy is currently uncontrolled by their medication 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.

Drugs

In the following list, the dates in parentheses are the earliest approved use of the drug.

Aldehydes

s are drugs that act as central nervous system 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 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

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:
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.

Bromides

The following are carboxamides:
The following are fatty-acids:
Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives

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. However, they do not work as well as the anticonvulsant drugs.

Treatment guidelines

According to guidelines by the American Academy of Neurology and American Epilepsy Society, 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.

History

The first anticonvulsant was bromide, suggested in 1857 by the British gynecologist Charles Locock who used it to treat women with "hysterical 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, a 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.
DrugBrandUSUKFrance
acetazolamideDiamox1953-07-2727 July 19531988
brivaracetamBriviact2016-02-1818 February 2016
carbamazepineTegretol1974-07-1515 July 197419651963
cenobamateXcopri2019-11-2121 November 2019
clobazamOnfi/Frisium2011-10-2121 October 20111979
clonazepamKlonopin/Rivotril1975-06-044 June 19751974
diazepamValium1963-11-1515 November 1963
divalproex sodiumDepakote1983-03-1010 March 1983
eslicarbazepineAptiom2013-08-1111 August 2013
ethosuximideZarontin1960-11-022 November 196019551962
ethotoinPeganone1957-04-2222 April 1957
everolimusAfinitor/Votubia2009-03-3030 January 2009
felbamateFelbatol1993-07-2929 July 1993
fosphenytoinCerebyx1996-08-055 August 1996
gabapentinNeurontin1993-12-3030 December 19931993-05May 19931994-10October 1994
lacosamideVimpat2008-10-2828 October 2008
lamotrigineLamictal1994-12-2727 December 19941991-10October 19911995-05May 1995
levetiracetamKeppra1999-11-3030 November 19992000-09-2929 September 20002000-09-2929 September 2000
mephenytoinMesantoin1946-10-2323 October 1946
metharbitalGemonil1952
methsuximideCelontin1957-02-088 February 1957
methazolamideNeptazane1959-01-2626 January 1959
oxcarbazepineTrileptal2000-01-1414 January 20002000
phenobarbital19121920
phenytoinDilantin/Epanutin193819381941
piracetamNootropilData needed
phensuximideMilontin1953
pregabalinLyrica2004-12-3030 December 20042004-07-066 July 20042004-07-066 July 2004
primidoneMysoline1954-03-088 March 195419521953
rufinamideBanzel/Inovelon2008-11-1414 November 2008
sodium valproateEpilim1977-12December 19771967-06June 1967
stiripentolDiacomit2018-08-2020 August 20182001-12-055 December 20012001-12-055 December 2001
tiagabineGabitril1997-09-3030 September 199719981997-11November 1997
topiramateTopamax1996-12-2424 December 19961995
trimethadioneTridione1946-01-2525 January 1946
valproic acidDepakene/Convulex1978-02-2828 February 19781993
vigabatrinSabril2009-08-2121 August 20091989
zonisamideZonegran2000-03-2727 March 20002005-03-1010 March 20052005-03-1010 March 2005

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.
Many of the common used medications, such as valproate, phenytoin, carbamazepine, phenobarbitol, gabapentin have been reported to cause increased risk of birth defects. Among anticonvulsants, levetiracetam and lamotrigine seem to carry the lowest risk of causing birth defects. The risk of untreated epilepsy is believed to be greater than the risk of adverse effects caused by these medications, necessitating continuation of antiepileptic treatment.
Valproic acid, and its derivatives such as sodium valproate and divalproex sodium, causes cognitive deficit in the child, with an increased dose causing decreased intelligence quotient. On the other hand, evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure. Similarly, children exposed lamotrigine or phenytoin in the womb do not seem to differ in their skills compared to those who were exposed to carbamazepine.
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.
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.
Data from studies conducted on women taking antiepileptic drugs for non-epileptic reasons, including depression and bipolar disorder, show that if high doses of the drugs are taken during the first trimester of pregnancy then there is the potential of an increased risk of congenital malformations.
Pregnancy planning is being explored as a method that could decrease the risk of possible birth defects. Since the first trimester is the most susceptible period for fetal development, planning a routine antiepileptic drug dose that is safer for the first trimester could be beneficial to prevent pregnancy complications.
In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.