Conventional antiepileptic drugs may block sodium channels or enhance γ-aminobutyric acid (GABA) 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.
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).
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.
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. 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.
In the following list, the dates in parentheses are the earliest approved use of the drug.
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.
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:
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.
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.
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.
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. 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.
Many of the commonly used medications, 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. 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). 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. 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.
There is little evidence to suggest that anticonvulsant (anti-seizure medication or ASM) exposure from 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.) 
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.
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. However, 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 anti-seizure medications. 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.
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. In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.
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