Anticonvulsant

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Anticonvulsant
Drug class
Class identifiers
Synonyms Antiepileptic drugs, antiseizure drugs
UseEpilepsy
ATC code N03
Biological target Brain
Legal status
In Wikidata

Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) 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]

Contents

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 GABA transporter type 1, 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]

Some anticonvulsants have shown antiepileptogenic effects in animal models of epilepsy. [20] 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). [21]

Many anticonvulsants can cause birth defects in the unborn child if taken while pregnant. [22]

Terminology

Anticonvulsants are more accurately called antiepileptic drugs (AEDs) because not every epileptic seizure involves convulsion, and vice versa, not every convulsion is caused by an epileptic seizure. [23] They are also often referred to as antiseizure drugs because they provide symptomatic treatment only and have not been demonstrated to alter the course of epilepsy. [24]

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 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. [21] 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. [21]

Drugs

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

Aldehydes

Aromatic allylic alcohols

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: [31]

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. [32] [33] [34] [35] Of 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

Carbamates

Carboxamides

Carbamazepine Carbamazepine 3D.png
Carbamazepine

The following are carboxamides:

Fatty acids

The following are fatty-acids:

Vigabatrin and progabide are also analogs of GABA.

Fructose derivatives

Gabapentinoids

Phenibut and analogues.png
GABA analogues
Voltage gated calcium channel.jpg
Voltage-gated calcium channel

Gabapentinoids are used in epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety disorder (GAD). Gabapentinoids block voltage-gated calcium channels, mainly the N-Type, and P/Q-type calcium channels. The following are gabapentinoids:

Gabapentinoids are analogs of GABA, but they do not act on GABA receptors. They have analgesic, anticonvulsant, and anxiolytic effects.

Hydantoins

The following are hydantoins:

Oxazolidinediones

The following are oxazolidinediones:

Propionates

Pyrimidinediones

Pyrrolidines

Succinimides

The following are succinimides:

Sulfonamides

Triazines

Ureas

Valproylamides

Other

A Non-pharmaceutical anticonvulsants

The ketogenic diet and vagus nerve stimulation are alternative treatments for epilepsy without the involvement of pharmaceuticals. The ketogenic diet consists of a high-fat, low-carbohydrate diet, and has shown good results in patients whose epilepsy has not responded to medications and who cannot receive surgery. The vagus nerve stimulator is a device that can be implanted into patients with epilepsy, especially that which originates from a specific part of the brain. However, both of these treatment options can cause severe adverse effects. Additionally, while seizure frequency typically decreases, they often do not stop entirely. [40] [41]

Treatment guidelines

According to guidelines by the American Academy of Neurology and American Epilepsy Society, [42] mainly based on a major article review in 2004, [43] 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. [42] Both newer and older drugs are generally equally effective in new onset epilepsy. [42] The newer drugs tend to have fewer side effects. [42] For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy. [42] Lamotrigine can be included in the options for children with newly diagnosed absence seizures. [42]

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. [44] 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. The European Medicines Agency approves drugs throughout the European Union. Some of the drugs are no longer marketed.

DrugBrandUSUKFrance
acetazolamide Diamox27 July 1953 [45] 1988 [46]
brivaracetam Briviact18 February 2016 [47] [48]
carbamazepine Tegretol15 July 1974 [49] [50] 1965 [46] 1963 [51]
cenobamate Xcopri21 November 2019
clobazam Onfi/Frisium21 October 2011 [52] [53] 1979 [46]
clonazepam Klonopin/Rivotril4 June 1975 [54] 1974 [46]
diazepam Valium15 November 1963 [55]
divalproex sodium Depakote10 March 1983 [56]
eslicarbazepine Aptiom11 August 2013 [57] [58]
ethosuximide Zarontin2 November 1960 [59] 1955 [46] 1962 [51]
ethotoin Peganone22 April 1957 [60]
everolimus Afinitor/Votubia30 January 2009 [61]
felbamate Felbatol29 July 1993 [62]
fosphenytoin Cerebyx5 August 1996 [63]
gabapentin Neurontin30 December 1993 [64] May 1993 [46] [51] October 1994 [51]
lacosamide Vimpat28 October 2008 [65]
lamotrigine Lamictal27 December 1994 [66] October 1991 [46] [51] May 1995 [51]
levetiracetam Keppra30 November 1999 [67] 29 September 2000 [46] [68] 29 September 2000 [68]
mephenytoin Mesantoin23 October 1946 [69]
metharbital Gemonil1952 [70] [71]
methsuximide Celontin8 February 1957 [72]
methazolamide Neptazane26 January 1959 [73]
oxcarbazepine Trileptal14 January 2000 [74] 2000 [46]
phenobarbital LuminalUnknown1912 [46] 1920 [51]
phenytoin Dilantin/Epanutin1938 [51] [75] 1938 [46] 1941 [51]
piracetam Nootropilnever approved
phensuximide Milontin1953 [76] [77]
pregabalin Lyrica30 December 2004 [78] 6 July 2004 [46] [79] 6 July 2004 [79]
primidone Mysoline8 March 1954 [80] 1952 [46] 1953 [51]
rufinamide Banzel/Inovelon14 November 2008 [81] [82]
sodium valproate EpilimUnknownDecember 1977 [51] June 1967 [51]
stiripentol Diacomit20 August 2018 [83] [84] January 2007 [29] January 2007 [29]
tiagabine Gabitril30 September 1997 [85] [86] 1998 [46] November 1997 [51]
topiramate Topamax24 December 1996 [87] 1995 [46]
trimethadione Tridione25 January 1946 [88]
valproic acid Depakene/Convulex28 February 1978 [89] 1993 [46]
vigabatrin Sabril21 August 2009 [90] 1989 [46]
zonisamide Zonegran27 March 2000 [91] 10 March 2005 [46] [92] 10 March 2005 [92]

Pregnancy

Many of the commonly used anticonvulsant/anti-seizure medications (ASMs), such as valproate, phenytoin, carbamazepine, phenobarbitol, gabapentin have been reported to cause an increased risk of birth defects including major congenital malformations such as neural tube defects. [93] The risk of birth defects associated with taking these medications while pregnant may be dependent on the dose and on the timing of gestation (how well developed the baby is). [93] While trying to conceive a child and during pregnancy, medical advice should be followed to optimize the management of the person's epilepsy in order to keep the person and the unborn baby safe from epileptic seizures and also ensure that the risk of birth defects due to in utero exposure of anticonvulsants is as low as possible. Use of anticonvulsant medications should be carefully monitored during use in pregnancy. [94] For example, 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. [95]

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 and use is associated with adverse neurodevelopmental outcomes (cognitive and behavioral)  in children. [96] [97] On the other hand, evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure. [96] 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. [96]

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. [94]

There is little evidence to suggest that anticonvulsant/ASM exposure through breastmilk has clinical effects on newborns. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study showed that most blood concentrations in breastfed infants of mothers taking carbamazepine, oxcarbazepine, valproate, levetiracetam, and topiramate were quite low, especially in relationship to the mother's level and what the fetal level would have been during pregnancy. (Note: valproic acid is NOT a recommended ASM for people with epilepsy who are considering having children.) [98]

Infant exposure to newer ASMs (cenobamate, perampanel, brivaracetam, eslicarbazepine, rufinamide, levetiracetam, topiramate, gabapentin, oxcarbazepine, lamotrigine, and vigabatrin) via breastmilk was not associated with negative neurodevelopment (such as lower IQ and autism spectrum disorder) at 36 months. [99]

Several studies that followed children exposed to ASMs during pregnancy showed that a number of widely used ones (including lamotrigine and levetiracetam) carried a low risk of adverse neurodevelopmental outcomes (cognitive and behavioral) in children when compared to children born to mothers without epilepsy and children born to mothers taking other anti-seizure medications. Data from several pregnancy registries showed that children exposed to levetiracetam or lamotrigine during pregnancy had the lowest risk of developing major congenital malformations compared to those exposed to other ASMs. The risk of major congenital malformations for children exposed to these ASMs were within the range for children who were not exposed to any ASMs during pregnancy. [100]

People with epilepsy can have healthy pregnancies and healthy babies. However, proper planning and care is essential to minimize the risk of congenital malformations or adverse neurocognitive outcomes for the fetus while maintaining seizure control for the pregnant person with epilepsy. If possible, when planning pregnancy, people with epilepsy should switch to ASMs with the lowest teratogenic risk for major congenital malformations as well as the least risk of adverse neurodevelopmental outcomes (e.g., lower IQ or autism spectrum disorder). They should also work with their healthcare providers to identify the lowest effective ASM dosage that will maintain their seizure control while regularly checking medication levels throughout pregnancy. [101]

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. [102]

Research

The mechanism of how anticonvulsants cause birth defects is not entirely clear. During pregnancy, the metabolism of many 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. [94] In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain. [103] [104] [105] [106] [107]

Related Research Articles

<span class="mw-page-title-main">Carbamazepine</span> Anticonvulsant medication

Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as a second-line agent in bipolar disorder. Carbamazepine appears to work as well as phenytoin and valproate for focal and generalized seizures. It is not effective for absence or myoclonic seizures.

<span class="mw-page-title-main">Phenytoin</span> Anti-seizure medication

Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures and focal seizures, but not absence seizures. The intravenous form, fosphenytoin, is used for status epilepticus that does not improve with benzodiazepines. It may also be used for certain heart arrhythmias or neuropathic pain. It can be taken intravenously or by mouth. The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours. Blood levels can be measured to determine the proper dose.

<span class="mw-page-title-main">Valproate</span> Medication used for epilepsy, bipolar disorder and migraine

Valproate are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.

<span class="mw-page-title-main">Topiramate</span> Medication used to treat epilepsy and migraine

Topiramate, sold under the brand name Topamax among others, is a medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence and essential tremor. For epilepsy this includes treatment for generalized or focal seizures. It is taken orally.

<span class="mw-page-title-main">Lamotrigine</span> Medication used for bipolar disorder, epilepsy, & many seizure disorders

Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome. In bipolar disorder, lamotrigine has not been shown to reliably treat acute depression in any groups except for the severely depressed; but for patients with bipolar disorder who are not currently symptomatic, it appears to reduce the risk of future episodes of depression.

<span class="mw-page-title-main">Oxcarbazepine</span> Anticonvulsant medication

Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with bipolar disorder who have had no success with other treatments. It is taken by mouth.

<span class="mw-page-title-main">Levetiracetam</span> Medication

Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.

<span class="mw-page-title-main">Clonazepam</span> Benzodiazepine medication

Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and akathisia. It is a long-acting tranquilizer of the benzodiazepine class. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally but is also used intravenously. Effects begin within one hour and last between eight and twelve hours in adults.

<span class="mw-page-title-main">Primidone</span> Barbiturate medication used to treat seizures and tremors

Primidone, sold under various brand names, is a barbiturate medication that is used to treat partial and generalized seizures and essential tremors. It is taken by mouth.

<span class="mw-page-title-main">Clobazam</span> Benzodiazepine class medication

Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

<span class="mw-page-title-main">Stiripentol</span> Anticonvulsant medication

Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of Dravet syndrome - a serious genetic brain disorder.

<span class="mw-page-title-main">Felbamate</span> Chemical compound

Felbamate is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures in adults and partial and generalized seizures associated with Lennox–Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure limit the drug's usage to severe refractory epilepsy.

<span class="mw-page-title-main">Rufinamide</span> Chemical compound

Rufinamide is an anticonvulsant medication. It is used in combination with other medication and therapy to treat Lennox–Gastaut syndrome and various other seizure disorders. Rufinamide, a triazole derivative, was developed in 2004 by Novartis Pharma, AG, and is manufactured by Eisai.

<span class="mw-page-title-main">Carisbamate</span> Experimental anticonvulsant drug

Carisbamate is an experimental anticonvulsant drug that was under development by Johnson & Johnson Pharmaceutical Research and Development but never marketed.

<span class="mw-page-title-main">Seletracetam</span> Chemical compound

Seletracetam is a pyrrolidone-derived drug of the racetam family that is structurally related to levetiracetam. It was under development by UCB Pharmaceuticals as a more potent and effective anticonvulsant drug to replace levetiracetam but its development has been halted.

<span class="mw-page-title-main">Brivaracetam</span> Medication used to treat seizures

Brivaracetam, sold under the brand name Briviact among others, is a chemical analog of levetiracetam, a racetam derivative with anticonvulsant (antiepileptic) properties. It has been approved since 2016. It is marketed by the pharmaceutical company UCB. It is used to treat partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs.

<span class="mw-page-title-main">Lacosamide</span> Anticonvulsant and analgesic medication

Lacosamide, sold under the brand name Vimpat among others, is a medication used for the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. It is used by mouth or intravenously.

<span class="mw-page-title-main">Retigabine</span> Anticonvulsant, which works as a potassium-channel opener

Retigabine (INN) or ezogabine (USAN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011. Production was discontinued in June 2017.

<span class="mw-page-title-main">Eslicarbazepine acetate</span> Anticonvulsant medication

Eslicarbazepine acetate (ESL), sold under the brand names Aptiom and Zebinix among others, is an anticonvulsant medication approved for use in Europe and the United States as monotherapy or as additional therapy for partial-onset seizures epilepsy.

Antimanic drugs are psychotropic drugs that are used to treat symptoms of mania. Though there are different causes of mania, the majority is caused by bipolar disorder, therefore antimanic drugs are mostly similar to drugs treating bipolar disorder. Since 1970s, antimanic drugs have been used specifically to control the abnormal elevation of mood or mood swings during manic episodes. One purpose of antimanic drugs is to alleviate or shorten the duration of an acute mania. Another objective is to prevent further cycles of mania and maintain the improvement achieved during the acute episode. The mechanism of antimanic drugs has not yet been fully known, it is proposed that they mostly affect chemical neurotransmitters in the brain. However, the usage of antimanic drugs should be consulted with a doctor or pharmacist due to their side effects and interactions with other drugs and food.

References

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