View source for Anticonvulsant

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The '''anticonvulsants''', sometimes also called '''antiepileptics''', belong to a diverse group of [[pharmacology|pharmaceuticals]] used in prevention of the occurrence of [[epilepsy|epileptic]] [[seizure]]s. More and more, anticonvulsants are also finding ways into the treatment of [[bipolar disorder]], since many seem to act as [[mood stabilizers]]. The goal of an anticonvulsant is to suppress the rapid and excessive firing of [[neuron]]s that start a seizure. Failing this, a good anticonvulsant would prevent the spread of the seizure within the brain and offer protection against possible [[excitotoxicity|excitotoxic]] effects that may result in [[brain damage]]. However, anticonvulsants themselves have been linked to lowered IQ<ref>{{cite journal
 | last = Loring
 | first = David W
 | date = [2005-09-01]]
 | title = Cognitive Side Effects of Antiepileptic Drugs in Children
 | journal = Psychiatric Times
 | volume = XXII
 | issue = 10
 | url = http://www.psychiatrictimes.com/showArticle.jhtml?articleID=171201519
}}</ref> and cell apoptosis.<ref>{{cite journal
 | author = Bittigau P, Sifringer M, Genz K, ''et al''
 | date = [[2002-11-12]]
 | title = Antiepileptic drugs and apoptotic neurodegeneration in the developing brain
 | journal = PNAS
 | volume = 99
 | issue = 23
 | pages = 15089-15094
 | url = http://www.pnas.org/cgi/content/full/99/23/15089
 | language = 
 | format = 
}}</ref>

Many anticonvulsants block [[Sodium ion channel|Sodium (Na<sup>+</sup>) channels]], [[Voltage-dependent calcium channel|Calcium (Ca<sup>2+</sup>) channels]], [[AMPA receptor]]s or [[NMDA receptor]]s. Some anticonvulsants inhibit the metabolism of [[Gamma-aminobutyric acid|GABA]] or increase its release.

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 shown this effect in human trials.<ref name="pmid17998971">{{cite journal |author=Abou-Khalil BW |title=Comparative monotherapy trials and the clinical treatment of epilepsy |journal=Epilepsy currents / American Epilepsy Society |volume=7 |issue=5 |pages=127–9 |year=2007 |pmid=17998971 |doi=10.1111/j.1535-7511.2007.00198.x}}</ref>

==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 not ethical 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 who's 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.<ref name="pmid17998971"/>

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 the lack of 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.<ref name="pmid17998971"/>

==Drugs==

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

===Aldehydes===
''Main article: [[Aldehyde]]s''
* [[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 seizure|myoclonic]] epilepsy in infancy (SMEI).

===Barbiturates===
''Main article: [[Barbiturate]]s''

[[Barbiturate]]s are [[medication|drugs]] that act as central nervous system (CNS) [[depressant]]s, and by virtue of this they produce a wide spectrum of effects, from mild [[sedation]] to [[anesthesia]].  The following are [[ATC code N03|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
* [[Metharbital]] (1952). No longer marketed in the UK or US.
* [[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.
<!-- Source: British National Formulary 50, www.drugs.com and www.rxlist.com. -->

===Benzodiazepines===
''Main article: [[Benzodiazepine]]s''

The benzodiazepines are a class of [[medication|drugs]] with [[hypnotic]], [[anxiolytic]], anticonvulsive, [[amnesia|amnestic]] and [[muscle relaxant]] properties. 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 [[drug tolerance|tolerance]] and [[addiction|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 do to an increased incidence of side effects and strong sedative and motor-impairing properties.

===Bromides===
''Main article: [[Bromide]]s''
* [[Potassium bromide]] (1857). The earliest effective treatment for epilepsy. There would not be a better drug for epilepsy until phenobarbital in 1912. It is still used as an anticonvulsant for dogs and cats.

===Carbamates===
''Main article: [[Carbamate]]s''

* [[Felbamate]] (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.

===Carboxamides===
''Main article: [[Carboxamide]]s''

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.

===Fatty acids===
''Main article: [[Fatty acid]]s''

The following are fatty-acids:
* The [[valproic acid|valproates]] &mdash; [[valproic acid]], [[sodium valproate]], and [[divalproex sodium]] (1967).
* [[Vigabatrin]] (1989).
* [[Progabide]]
* [[Tiagabine]] (1996).

''Vigabatrin and progabide are also analogs of GABA.''

===Fructose derivatives===
''Main article: [[Fructose]]''

*[[Topiramate]] (1995).

===Gaba analogs===

* [[Gabapentin]] (1993).
* [[Pregabalin]] (2004).

===Hydantoins===
''Main article: [[Hydantoin]]s''

The following are hydantoins:

*[[Ethotoin]] (1957).
*[[Phenytoin]] (1938).
*[[Mephenytoin]]
*[[Fosphenytoin]] (1996).

===Oxazolidinediones===
''Main article: [[Oxazolidinedione]]s''

The following are oxazolidinediones:

* [[Paramethadione]]
* [[Trimethadione]] (1946).
* [[Ethadione]]

===Propionates===
''Main article: [[Propionate]]s''

* [[Beclamide]]

===Pyrimidinediones===
''Main article: [[Pyrimidinedione]]s''

* [[Primidone]] (1952).

===Pyrrolidines===
''Main article: [[Pyrrolidine]]s''

* [[Brivaracetam]]
* [[Levetiracetam]] (1999).
* [[Seletracetam]]

===Succinimides===
''Main article: [[Succinimide]]s''

The following are succinimides:

* [[Ethosuximide]] (1955).
* [[Phensuximide]]
* [[Mesuximide]]

=== Sulfonamides ===
''Main article: [[Sulfonamide (medicine)|Sulfonamide]]s''
* [[Acetazolamide]] (1953).
* [[Sulthiame]]
* [[Methazolamide]]
* [[Zonisamide]] (2000).

===Triazines===
''Main article: [[Triazine]]s''

* [[Lamotrigine]] (1990).

===Ureas===
''Main article: [[Urea]]s''

*[[Pheneturide]]
*[[Phenacemide]]

===Valproylamides (amide derivatives of valproate)===
''Main article: [[Amide]]s''

* [[Valpromide]]
* [[Valnoctamide]]

==Diet==

The [[Ketogenic diet|Ketongenic Diet Program]] is a strict medically supervised diet that has an anticonvulsant effect. It is typically used in children with refractory epilepsy.

==Devices==

The [[Vagus nerve stimulation|vagus nerve stimulator]] (VNS) is a device that sends electric impulses to the left [[vagus nerve]] in the neck via a lead implanted under the skin. It was FDA approved in 1997 as an adjunctive therapy for partial-onset epilepsy.

==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 is incomplete. In recent years, the [[European Medicines Agency]] has approved drugs throughout the European Union. Some of the drugs are no longer marketed.

{| class="wikitable sortable" 
|-
!Drug!!Brand!!US!!UK!!France
|-
|[[acetazolamide]]
|Diamox
|<span style="display:none">1953-07-27</span>1953-07-27<ref name="NDA 008943">[[New drug application|NDA]] 008943</ref>
|1988<ref name="EpilepsyAction">[http://www.epilepsy.org.uk/info/drugslist.html Epilepsy Action: Druglist.] Retrieved on 2007-11-01.</ref>
|
|-
|[[carbamazepine]]
|Tegretol
|<span style="display:none">1974-07-15</span>1974-07-15<ref name="NDA 016608">NDA 016608 (Initial approval on 1968-03-11 was for trigeminal neuralgia.)</ref><ref name="Tegretol1978WJM">{{cite journal | last = Schain | first = Richard J. | month = March | year = 1978 | title = Pediatrics—Epitomes of Progress: Carbamazepine (Tegretol®) in the Treatment of Epilepsy | journal = Western Journal of Medicine | volume = 128 | issue = 3 | pages = 231&ndash;232 | id = {{PMID|}} | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1238063 | accessdate = 2007-03-14}}</ref>
|1965<ref name="EpilepsyAction"/>
|1963<ref name="Loiseau_et_al_1999">{{cite journal | last = Loiseau | first = Pierre Jean-Marie | month = June | year = 1999 | title = Clinical Experience with New Antiepileptic Drugs: Antiepileptic Drugs in Europe | journal = [[Epilepsia]] | volume = 40 | issue = Suppl 6 | pages = S3&ndash;8 | doi = 10.1111/j.1528-1157.1999.tb00925.x | id = {{PMID|10530675}} | url = http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1528-1157.1999.tb00925.x | format = [[PDF]] | accessdate = 2007-03-26}}</ref>
|-
|[[clobazam]]
|Frisium
|
|1979<ref name="EpilepsyAction"/>
|
|-
|[[clonazepam]]
|Klonopin/Rivotril
|<span style="display:none">1975-06-04</span>1975-06-04<ref name="NDA 017533">NDA 017533</ref>
|1974<ref name="EpilepsyAction"/>
|
|-
|[[diazepam]]
|Valium
|<span style="display:none">1963-11-15</span>1963-11-15<ref name="NDA 013263">NDA 013263</ref>
|
|
|-
|[[divalproex sodium]]
|Depakote
|<span style="display:none">1983-03-10</span>1983-03-10<ref name="NDA 018723">NDA 018723</ref>
|
|
|-
|[[ethosuximide]]
|Zarontin
|<span style="display:none">1960-11-02</span>1960-11-02<ref name="NDA 012380">NDA 012380</ref>
|1955<ref name="EpilepsyAction"/>
|1962<ref name="Loiseau_et_al_1999"/>
|-
|[[ethotoin]]
|Peganone
|<span style="display:none">1957-04-22</span>1957-04-22<ref name="NDA 010841">NDA 010841</ref>
|
|
|-
|[[felbamate]]
|Felbatol
|<span style="display:none">1993-07-29</span>1993-07-29<ref name="NDA 020189">NDA 020189</ref>
|
|
|-
|[[fosphenytoin]]
|Cerebyx
|<span style="display:none">1996-08-05</span>1996-08-05<ref name="NDA 020450">NDA 020450</ref>
|
|
|-
|[[gabapentin]]
|Neurontin
|<span style="display:none">1993-12-30</span>1993-12-30<ref name="NDA 020235">NDA 020235</ref>
|<span style="display:none">1993-05</span>May 1993<ref name="EpilepsyAction"/><ref name="Loiseau_et_al_1999"/>
|<span style="display:none">1994-10</span>October 1994<ref name="Loiseau_et_al_1999"/>
|-
|[[lamotrigine]]
|Lamictal
|<span style="display:none">1994-12-27</span>1994-12-27<ref name="NDA 020241">NDA 020241</ref>
|<span style="display:none">1991-10</span>October 1991<ref name="EpilepsyAction"/><ref name="Loiseau_et_al_1999"/>
|<span style="display:none">1995-05</span>May 1995<ref name="Loiseau_et_al_1999"/>
|-
|[[levetiracetam]]
|Keppra
|<span style="display:none">1999-11-30</span>1999-11-30<ref name="NDA 021035">NDA 021035</ref>
|<span style="display:none">2000-09-29</span>2000-09-29<ref name="EpilepsyAction"/><ref name="keppra">[http://www.emea.europa.eu/humandocs/Humans/EPAR/keppra/keppra.htm EPAR: Keppra.] Retrieved on 2007-11-01.</ref>
|<span style="display:none">2000-09-29</span>2000-09-29<ref name="keppra"/>
|-
|[[mephenytoin]]
|Mesantoin
|<span style="display:none">1946-10-23</span>1946-10-23<ref name="NDA 006008">NDA 006008</ref>
|
|
|-
|[[metharbital]]
|Gemonil
|1952<ref name="NDA 008322">NDA 008322</ref><ref name="0632060468>{{cite book |author=Dodson, W. Edwin; Giuliano Avanzini; Shorvon, Simon D.; Fish, David R.; Emilio Perucca |title=The treatment of epilepsy |publisher=Blackwell Science |location=Oxford |year=2004 |pages=xxviii |isbn=0-632-06046-8}}</ref>
|
|
|-
|[[methsuximide]]
|Celontin
|<span style="display:none">1957-02-08</span>1957-02-08<ref name="NDA 010596">NDA 010596</ref>
|
|
|-
|[[methazolamide]]
|Neptazane
|<span style="display:none">1959-01-26</span>1959-01-26<ref name="NDA 011721">NDA 011721</ref>
|
|
|-
|[[oxcarbazepine]]
|Trileptal
|<span style="display:none">2000-01-14</span>2000-01-14<ref name="NDA 021014">NDA 021014</ref>
|2000<ref name="EpilepsyAction"/>
|
|-
|[[phenobarbital]]
|
|
|1912<ref name="EpilepsyAction"/>
|1920<ref name="Loiseau_et_al_1999"/>
|-
|[[phenytoin]]
|Dilantin/Epanutin
|1938<ref name="NDA 008762">NDA 008762 (Marketed in 1938, approved 1953)</ref><ref name="Loiseau_et_al_1999"/>
|1938<ref name="EpilepsyAction"/>
|1941<ref name="Loiseau_et_al_1999"/>
|-
|[[phensuximide]]
|Milontin
|1953<ref name="NDA 008855">NDA 008855</ref><ref name="isbn0824785495">{{cite book |author=Kutt, Henn; Resor, Stanley R. |title=The Medical treatment of epilepsy |publisher=Dekker |location=New York |year=1992 |pages=385 |isbn=0-8247-8549-5}} (first usage)</ref>
|
|
|-
|[[pregabalin]]
|Lyrica
|<span style="display:none">2004-12-30</span>2004-12-30<ref name="NDA 021446">NDA 021446</ref>
|<span style="display:none">2004-07-06</span>2004-07-06<ref name="EpilepsyAction"/><ref name="lyrica">[http://www.emea.europa.eu/humandocs/Humans/EPAR/lyrica/lyrica.htm EPAR: Lyrica] Retrieved on 2007-11-01.</ref>
|<span style="display:none">2004-07-06</span>2004-07-06<ref name="lyrica"/>
|-
|[[primidone]]
|Mysoline
|<span style="display:none">1954-03-08</span>1954-03-08<ref name="NDA 009170">NDA 009170</ref>
|1952<ref name="EpilepsyAction"/>
|1953<ref name="Loiseau_et_al_1999"/>
|-
|[[sodium valproate]]
|Epilim
|
|<span style="display:none">1977-12</span>December 1977<ref name="Loiseau_et_al_1999"/>
|<span style="display:none">1967-06</span>June 1967<ref name="Loiseau_et_al_1999"/>
|-
|[[stiripentol]]
|Diacomit
|
|<span style="display:none">2001-12-05</span>2001-12-05<ref name="diacomit">[http://www.emea.europa.eu/humandocs/Humans/EPAR/diacomit/diacomit.htm EPAR: Diacomit.]] Orphan designation: 2001-12-05, full authorisation: 2007-01-04 Retrieved on [[2007-11-01]].</ref>
|<span style="display:none">2001-12-05</span>2001-12-05<ref name="diacomit"/>
|-
|[[tiagabine]]
|Gabitril
|<span style="display:none">1997-09-30</span>1997-09-30<ref name="NDA 020646">NDA 020646</ref>
|1998<ref name="EpilepsyAction"/>
|<span style="display:none">1997-11</span>November 1997<ref name="Loiseau_et_al_1999"/>
|-
|[[topiramate]]
|Topamax
|<span style="display:none">1996-12-24</span>1996-12-24<ref name="NDA 020505">NDA 020505</ref>
|1995<ref name="EpilepsyAction"/>
|
|-
|[[trimethadione]]
|Tridione
|<span style="display:none">1946-01-25</span>1946-01-25<ref name="NDA 005856">NDA 005856</ref>
|
|
|-
|[[valproic acid]]
|Depakene/Convulex
|<span style="display:none">1978-02-28</span>1978-02-28<ref name="NDA 018081">NDA 018081</ref>
|1993<ref name="EpilepsyAction"/>
|
|-
|[[vigabatrin]]
|Sabril
|
|1989<ref name="EpilepsyAction"/>
|
|-
|[[zonisamide]]
|Zonegran
|<span style="display:none">2000-03-27</span>2000-03-27<ref name="NDA 020789">NDA 020789</ref>
|<span style="display:none">2005-03-10</span>2005-03-10<ref name="EpilepsyAction"/><ref name="zonegran">[http://www.emea.europa.eu/humandocs/Humans/EPAR/zonegran/zonegran.htm EPAR: Zonegran.] Retrieved on [[2007-11-01]]</ref>
|<span style="display:none">2005-03-10</span>2005-03-10<ref name="zonegran"/>
|}

==See also==
* [[ATC code N03]]

==References==

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* [http://www.neurotransmitter.net/epilepsy_drug_reference.html Drug Reference for FDA Approved Epilepsy Drugs]
* [http://www.epilepsy.org.uk/info/drugslist.html Epilepsy Action: UK Anti-Epileptic Drugs List]

==External links==

* [http://www.emedicine.com/neuro/topic692.htm eMedicine: Antiepileptic Drugs: an overview]

* [http://www.ninds.nih.gov/funding/research/asp/ NINDS: Anticonvulsant Screening Program]

* [http://www.asthma.ge/ Use of Anticonvulsants in Pharmacotherapy of Bronchial Asthma]

* [http://www.mdng.com/departments/2005-August/neuro_feature.htm MDNG: Anticonvulsants and Bone Health]

{{Anticonvulsants}}
{{Major Drug Groups}}


[[Category:Anticonvulsants|*]]
[[Category:Epilepsy]]
[[Category:Hematology]]

[[ca:Anticonvulsiu]]
[[de:Antikonvulsivum]]
[[es:Anticonvulsivo]]
[[fr:Antiépileptique]]
[[hr:Antikonvulzivi]]
[[it:Anticonvulsante]]
[[hu:Antiepileptikumok]]
[[ja:抗てんかん薬]]
[[no:Antiepileptikum]]
[[pl:Leki przeciwpadaczkowe]]
[[pt:Anticonvulsivo]]
[[sr:Антиепилептик]]
[[sv:Antiepileptika]]
[[th:แอนตี้อิพิเลปติก]]

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