Anticonvulsive drugs

The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs"), belong to a diverse group of pharmaceuticals used in prevention of the occurrence of epileptic seizures. 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 neurons that start a seizure. Failing this, a good anticonvulsant would prevent the spread of the seizure within the brain and offer protection against possible excitotoxic effects that may result in brain damage. However, anticonvulsants themselves have been linked to lowered IQ and cell apoptosis.

Many anticonvulsants block Sodium (Na+) channels, Calcium (Ca2+) channels, AMPA receptors or NMDA receptors. Some anticonvulsants inhibit the metabolism of 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.

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 whose 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.

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.

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

Aldehydes
Main article: Aldehydes
 * 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 epilepsy in infancy (SMEI).

Barbiturates
Main article: 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
 * 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.

Benzodiazepines
Main article: 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 and 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 due to an increased incidence of side effects and strong sedative and motor-impairing properties.

Bromides
Main article: Bromides
 * 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: Carbamates


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

Carboxamides
Main article: Carboxamides

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 acids

The following are fatty-acids:
 * The 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: Hydantoins

The following are hydantoins:


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

Oxazolidinediones
Main article: Oxazolidinediones

The following are oxazolidinediones:


 * Paramethadione
 * Trimethadione (1946).
 * Ethadione

Propionates
Main article: Propionates


 * Beclamide

Pyrimidinediones
Main article: Pyrimidinediones


 * Primidone (1952).

Pyrrolidines
Main article: Pyrrolidines


 * Brivaracetam
 * Levetiracetam (1999).
 * Seletracetam

Succinimides
Main article: Succinimides

The following are succinimides:


 * Ethosuximide (1955).
 * Phensuximide
 * Mesuximide

Sulfonamides
Main article: Sulfonamides
 * Acetazolamide (1953).
 * Sulthiame
 * Methazolamide
 * Zonisamide (2000).

Triazines
Main article: Triazines


 * Lamotrigine (1990).

Ureas
Main article: Ureas


 * Pheneturide
 * Phenacemide

Valproylamides (amide derivatives of valproate)
Main article: Amides


 * Valpromide
 * Valnoctamide

Diet
The ketogenic diet is a strict medically supervised diet that has an anticonvulsant effect. It is typically used in children with refractory epilepsy.

Devices
The 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.