Category:Anticonvulsants

The anticonvulsants — also called antiepileptic or antiseizure medicines — are the class of medicines used to prevent and control epileptic seizures. Their history is, more than most, a history of accident: several of the most important were found to work against seizures by chance, and the systematic search for them was one of the earliest examples of modern drug screening.

For most of recorded history epilepsy had no effective medical treatment. That changed in 1857, when the English physician Charles Locock reported to a London medical society that potassium bromide appeared to reduce seizures in a group of his patients. Locock's reasoning was mistaken — he believed epilepsy was linked to excessive sexual excitement, and used bromide because it was thought to dampen sexual drive — but the observation itself held up, and potassium bromide became the first genuinely useful antiseizure medicine.^[1] Bromide had serious drawbacks — sedation, skin eruptions, and effects on mood and behaviour — but for half a century it was essentially all there was.

The next advance, in 1912, was also accidental. The German physician Alfred Hauptmann was using phenobarbital — then a new barbiturate — as a sedative to quiet his epileptic patients at night, partly so that he himself could sleep; he noticed that the patients given it had markedly fewer seizures.^[1] Phenobarbital proved far more effective than bromide and much better tolerated, and it became the leading antiseizure medicine for decades. It remains in use worldwide today, particularly where cost matters, a century after that chance observation.

The modern era of antiseizure medicine began in the 1930s with a change in method. Rather than waiting for a chance observation, the American neurologists Houston Merritt and Tracy Putnam developed an animal model — an electrically induced seizure in cats — against which candidate compounds could be systematically tested. Screening a series of compounds chemically related to phenobarbital, they identified one that suppressed seizures with far less sedation, and in 1938 introduced it as phenytoin.^[2] The achievement was twofold: phenytoin itself, which would treat epilepsy for decades, and the demonstration that antiseizure medicines could be found by deliberate screening rather than luck — the model on which later drug discovery was built.

A first generation of antiseizure medicines followed over the next decades, among them primidone, ethosuximide, carbamazepine, and valproic acid — the last, like several before it, found to have antiseizure activity by chance.^[1] The benzodiazepines, developed as sedatives and anti-anxiety medicines, were also soon recognized to have antiseizure activity, and some came into use for epilepsy.

From the late twentieth century a second generation of antiseizure medicines was developed, including lamotrigine, levetiracetam, gabapentin, topiramate, oxcarbazepine, and others. These newer medicines are not, in general, more effective at controlling seizures than the older ones, but many are better tolerated and have fewer interactions with other medicines.^[3] The choice of medicine depends heavily on the type of seizure and on the individual patient; for a substantial minority of people with epilepsy, seizures remain difficult to control despite treatment.

The anticonvulsants do not share a single mechanism — the class is defined by what its members do (suppress seizures) rather than by how. A seizure is, in broad terms, a burst of excessive and synchronized electrical activity in the brain, and antiseizure medicines are understood to act by damping that activity through several different routes. Some, such as phenytoin and carbamazepine, are understood to act mainly by blocking voltage-gated sodium channels, reducing the rapid repetitive firing of neurons. Others enhance the inhibitory neurotransmitter GABA — the route by which phenobarbital and the benzodiazepines are understood to act. Still others act on calcium channels or on the release of neurotransmitters. For several agents more than one mechanism is involved, and for some the full picture is not established. That these medicines have these actions is reasonably well established; the fuller relationship between a given action and the control of seizures in a particular person remains a subject of research.

The first-generation anticonvulsants include phenobarbital, phenytoin, primidone, ethosuximide, carbamazepine, and valproic acid. The second-generation agents include lamotrigine, levetiracetam, gabapentin, pregabalin, topiramate, oxcarbazepine, lacosamide, zonisamide, and vigabatrin, among others. Several benzodiazepines are also used for their antiseizure activity. The list is not exhaustive.

Most anticonvulsants cause dose-related effects on the central nervous system — drowsiness, dizziness, unsteadiness — particularly when treatment begins or the dose is raised. Beyond these, individual medicines carry their own characteristic risks: some are associated with serious skin reactions, some with effects on the liver or blood, and abrupt withdrawal of an antiseizure medicine can itself provoke seizures, so treatment is not stopped suddenly.

A particularly important consideration is use in pregnancy. Several anticonvulsants, taken during pregnancy, are associated with an increased risk of birth defects and of effects on a child's later development. This risk is not uniform across the class: it is greatest for valproic acid, for which the risk is substantial and dose-dependent, and considerably lower for some other agents such as lamotrigine and levetiracetam. Because of this, the use of valproic acid in people who may become pregnant has become increasingly restricted. As with all medicines, figures for these risks are population estimates that vary between studies, decisions involve balancing the risks of medication against the serious risks of uncontrolled seizures, and individual response varies considerably between people.