Anticonvulsant

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. Anticonvulsants are also 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.

Conventional antiepileptic drugs have diverse mechanisms of action but many block sodium channels or enhance γ-aminobutyric acid (GABA) function. Several antiepileptic drugs have multiple or uncertain mechanisms of action. Next to voltage-gated sodium channels and components of the GABA system, their targets include GABAA receptors, the GABA transporter type 1, 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 the excitatory neurotransmitter 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 pro-convulsively.

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 (the development of epilepsy in an individual at risk, such as after a head injury).

Many anticonvulsants are known teratogens and increase the risk of birth defects in the unborn child if taken while pregnant.

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. 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.

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.

Aromatic allylic alcohols

Stiripentol (2007). Indicated for the treatment of Dravet syndrome.

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.

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 many drugs in this class, only a few are used to treat epilepsy:

Clobazam (1970).
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 but is no longer used in humans.

Carbamates

Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.
Cenobamate (2019).

Carboxamides

thumb|right|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 and is better tolerated and is also available generically.
Eslicarbazepine acetate (2009).
Photoswitchable analogues of carbamazepine (2024) are research compounds developed to control its pharmacological activity locally and on demand using light, with the purpose to reduce adverse systemic effects. One of these compounds (carbadiazocine, based on a bridged azobenzene) has been shown to produce analgesia with noninvasive illumination in a rat model of neuropathic pain.

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).

Gabapentinoids

</div>

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:

Pregabalin (2004)
Mirogabalin (2019) (Japan only)
Gabapentin (1993)
Gabapentin enacarbil (Horizant) (2011)
Gabapentin extended release (Gralise) (1996)

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:

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.
Pyridoxine (1939).

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.

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. 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.

{| class="wikitable sortable"

!Drug!!Brand!!US!!UK!!France

|acetazolamide

|Diamox

|1953-07-2727 July 1953

|1988

|brivaracetam

|Briviact

|2016-02-1818 February 2016

|carbamazepine

|Tegretol

|1974-07-1515 July 1974

|1965

|cenobamate

|Xcopri

||2019-11-2121 November 2019

|clobazam

|Onfi/Frisium

|2011-10-2121 October 2011

|1979

|1974

|divalproex sodium

|Depakote

|1983-03-1010 March 1983

|eslicarbazepine

|Aptiom

|2013-08-1111 August 2013

|ethosuximide

|Zarontin

|1960-11-022 November 1960

|1955

|everolimus

|Afinitor/Votubia

|2009-03-3030 January 2009

|felbamate

|Felbatol

|1993-07-2929 July 1993

|fosphenytoin

|Cerebyx

|1996-08-055 August 1996

|gabapentin

|Neurontin

|1993-12-3030 December 1993

|1993-05May 1993

|lamotrigine

|Lamictal

|1994-12-2727 December 1994

|1991-10October 1991

|2000-09-2929 September 2000

|metharbital

|Gemonil

|1952

|methsuximide

|Celontin

|1957-02-088 February 1957

|methazolamide

|Neptazane

|1959-01-2626 January 1959

|oxcarbazepine

|Trileptal

|2000-01-1414 January 2000

|2000

|1938

|pregabalin

|Lyrica

|2004-12-3030 December 2004

|2004-07-066 July 2004

|1952

|sodium valproate

|Epilim

|Unknown

|1977-12December 1977

|2007-01January 2007

|1998

|1995

|valproic acid

|Depakene/Convulex

|1978-02-2828 February 1978

|1993

|1989

|2005-03-1010 March 2005

|2005-03-1010 March 2005 The risk of birth defects associated with taking these medications while pregnant may be dependent on the dose of the drug and on the timing of gestation (how well developed the baby is). 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.

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. On the other hand, evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure.

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.

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.

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.

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.

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.

References

External links

Drug Reference for FDA Approved Epilepsy Drugs