Anticonvulsant

The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an anticonvulsant is to suppress the rapid and excessive firing of neurons that start a seizure. Failing this, an effective anticonvulsant would prevent the spread of the seizure within the brain and offer protection against possible excitotoxic effects that may result in brain damage. Some studies have cited that anticonvulsants themselves are linked to lowered IQ in children. However these studies may be moot given the significant risk epileptiform seizures pose to children and the distinct possibility of death and devastating neurological sequela secondary to seizures. Anticonvulsants are more accurately called antiepileptic drugs (abbreviated "AEDs"), sometimes referred to as antiseizure drugs. While an anticonvulsant is a fair description of AEDs, it neglects to differentiate the difference between convulsions and epilepsy. Convulsive non-epileptic seizures are quite common and these types of seizures will not have any response to an antiepileptic drug. In epilepsy an area of the cortex is typically hyperirritable that can often be confirmed by completing an EEG. Antiepileptic drugs function to help reduce this area of irritability and thus prevent epileptiform seizures.

The major molecular targets of marketed anticonvulsant drugs are voltage-gated sodium channels and components of the GABA system, including GABA A receptors, the GAT-1 GABA transporter, and GABA transaminase. Additional targets include voltage-gated calcium channels, SV2A, and α2δ. The drug class was the US's 5th-best-selling in 2007.

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 been shown to prevent epileptogenesis (the development of epilepsy after an injury such as a head injury) 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 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 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 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.

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

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
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
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 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

 * 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.

Carbamates

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

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 and is also available generically.
 * Eslicarbazepine acetate (2009)

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

 * Topiramate (1995).

GABA analogs

 * Gabapentin (1993).
 * Pregabalin (2004).

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
 * 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 (amide derivatives of valproate)

 * Valpromide
 * Valnoctamide

Non-medical anticonvulsants
Sometimes, ketogenic diet or vagus nerve stimulation are described as "anticonvulsant" therapies as well.

Treatment guidelines
According to guidelines by the AAN and AES, 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. Both newer and older drugs are generally equally effective in new onset epilepsy. The newer drugs tend to have fewer side effects. For newly diagnosed partial or mixed seizures, there is evidence for using gabapentin, lamotrigine, oxcarbazepine or topiramate as monotherapy. Lamotrigine can be included in the options for children with newly diagnosed absence seizures.

History
The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Potassium bromide was also noted to cause impotence in men. Authorities concluded that potassium bromide would dampen sexual excitement thought to cause the seizures. In fact, bromides were effective against epilepsy, and also caused impotence; it is now known that impotence is a side effect of bromide treatment, which is not related to its anti-epileptic effects. It also suffered from the way it affected behaviour, introducing the idea of the 'epileptic personality' which was actually a result of the 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, an 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. In recent years, the European Medicines Agency has approved drugs throughout the European Union. Some of the drugs are no longer marketed.

Use in pregnancy
During pregnancy, the metabolism of several anticonvulsants is affected. There may be an increase in the clearance an 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. Therefore, these drugs should be monitored during use in pregnancy. Taking valproic acid or divalproex sodium during pregnancy should be cautioned against, as this class of medications has been linked to birth defects (teratogenic).

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.

Regarding breastfeeding, some anticonvulsants probably pass into breast milk in clinically significant amounts, including primidone and levetiracetam. On the other hand, valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts.