Anticonvulsant

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.[1]
Anticonvulsants are also increasingly being used in the treatment of bipolar disorder[2][3] and
borderline personality disorder,[4] since many seem to act as mood stabilizers, and for the treatment
of neuropathic pain.[5] Anticonvulsants suppress the excessive rapid firing of neurons during
seizures.[6] Anticonvulsants also prevent the spread of the seizure within the brain.[7]

Anticonvulsant

Drug class

Class identifiers

Synonyms Antiepileptic drugs, antiseizure drugs

Use Epilepsy

ATC code N03

Biological target Brain

In Wikidata

Conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid
(GABA) function. Several antiepileptic drugs have multiple or uncertain mechanisms of action.[8]
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.[9] Additional targets
include voltage-gated calcium channels, SV2A, and α2δ.[10][11] 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.[12] 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.[12] Another potential target of antiepileptic drugs is the peroxisome
proliferator-activated receptor alpha.[13][14][15][16][17][18][19] The drug class was the fifth-best-selling in
the United States in 2007.[20]

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy.[21] 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).[22]

Terminology

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.

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 (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.[22] 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.[22]

Drugs

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

Aldehydes
…
Paraldehyde (1882). One of the earliest anticonvulsants. It is still used to treat status epilepticus,
particularly where there are no resuscitation facilities.[23][24]

Aromatic allylic alcohols

…
 Stiripentol (2001 – limited availability). Indicated for the treatment of Dravet syndrome.[25][26]

Barbiturates
…
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
…
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.[27][28][29][30] 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
…
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
…
Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare
but life-threatening side effects.[31][32][33]

Carboxamides
…

Carbamazepine

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
…
The following are fatty-acids:

The valproates — valproic acid, sodium valproate, and divalproex sodium (1967).

Vigabatrin (1989).

Progabide (1987)
 Tiagabine (1996).

Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives
…
Topiramate (1995).

Hydantoins
…
The following are hydantoins:

Ethotoin (1957).

Phenytoin (1938).

Mephenytoin

Fosphenytoin (1996).

Oxazolidinediones
…
The following are oxazolidinediones:

Paramethadione

Trimethadione (1946).

Ethadione

Propionates
…
Beclamide

Pyrimidinediones
…
Primidone (1952).

Pyrrolidines
…
Brivaracetam (2016).

Etiracetam

Levetiracetam (1999).

Seletracetam

Succinimides
…
The following are succinimides:
 Ethosuximide (1955).

Phensuximide

Mesuximide

Sulfonamides
…
Acetazolamide (1953).

Sultiame

Methazolamide

Zonisamide (2000).

Triazines
…
Lamotrigine (1990).

Ureas
…
Pheneturide

Phenacemide

Valproylamides
…
Valpromide

Valnoctamide

Other
…
Perampanel

Stiripentol[34]

Pyridoxine (1939)

Non-pharmaceutical anticonvulsants

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,[35]
mainly based on a major article review in 2004,[36] 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.[35] Both newer and older drugs are generally equally effective in new onset
epilepsy.[35] The newer drugs tend to have fewer side effects.[35] For newly diagnosed partial or
mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as
monotherapy.[35] Lamotrigine can be included in the options for children with newly diagnosed
absence seizures.[35]

History

The first anticonvulsant was bromide, suggested in 1857 by the British gynecologist 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.[37] 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.
 Drug Brand US UK France

acetazolamide Diamox 27 July 1953[38] 1988[39]

18 February
brivaracetam Briviact
2016[40][41]

carbamazepine Tegretol 15 July 1974[42][43] 1965[39] 1963[44]

cenobamate Xcopri 21 November 2019

21 October
clobazam Onfi/Frisium [45][46]
1979[39]
2011

clonazepam Klonopin/Rivotril 4 June 1975[47] 1974[39]

15 November
diazepam Valium
1963[48]

divalproex
Depakote 10 March 1983[49]
sodium

11 August
eslicarbazepine Aptiom
2013[50][51]

2 November
ethosuximide Zarontin 1955[39] 1962[44]
1960[52]

ethotoin Peganone 22 April 1957[53]

everolimus Afinitor/Votubia 30 January 2009[54]

felbamate Felbatol 29 July 1993[55]

fosphenytoin Cerebyx 5 August 1996[56]

30 December
gabapentin Neurontin May 1993[39][44] October 1994[44]
1993[57]

lacosamide Vimpat 28 October 2008[58]

27 December
lamotrigine Lamictal October 1991[39][44] May 1995[44]
1994[59]

30 November 29 September 29 September

levetiracetam Keppra
1999[60] 2000[39][61] 2000[61]

mephenytoin Mesantoin 23 October 1946[62]

metharbital Gemonil 1952[63][64]

methsuximide Celontin 8 February 1957[65]