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Anticonvulsive drugs (also called anticonvulsants and antiepileptic drugs,abbreviated "AEDs"), belong to a diverse group of pharmaceuticals used in prevention of the occurrence of convulsions, spasms and 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.
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.
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.
In the following list, the dates in parentheses are the earliest approved use of the drug.
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 alcoholsEdit
- Stiripentol (2001 - limited availability). Indicated for the treatment of severe myoclonic epilepsy in infancy (SMEI).
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.
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.
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.
Main article: Carbamates
- Felbamate (1993). This effective anticonvulsant has had its usage severely restricted due to rare but life-threatening side effects.
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.
Main article: Fatty acids
The following are fatty-acids:
- The valproates — valproic acid, sodium valproate, and divalproex sodium (1967).
- Vigabatrin (1989).
- Tiagabine (1996).
Vigabatrin and progabide are also analogs of GABA.
Main article: Fructose
- Topiramate (1995).
Main article: Hydantoins
The following are hydantoins:
Main article: Oxazolidinediones
The following are oxazolidinediones:
Main article: Propionates
Main article: Pyrimidinediones
- Primidone (1952).
Main article: Pyrrolidines
Main article: Succinimides
The following are succinimides:
Main article: Sulfonamides
Main article: Triazines
- Lamotrigine (1990).
Main article: Ureas
Valproylamides (amide derivatives of valproate)Edit
Main article: Amides
The ketogenic diet is a strict medically supervised diet that has an anticonvulsant effect. It is typically used in children with refractory epilepsy.
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 historyEdit
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.
- Anesthetic drugs
- Antispasmodic drugs
- ATC code N03 US classification of antiepileptic drugs
- CNS depressant drugs
- Chloral hydrate
- Hypnotic drugs
- Mood stabilizers
- Muscle relaxing drugs
- Narcotic drugs
- Tranquilizing drugs
- ↑ Loring, David W ([2005-09-01]]). Cognitive Side Effects of Antiepileptic Drugs in Children. Psychiatric Times XXII (10).
- ↑ Bittigau P, Sifringer M, Genz K, et al (2002-11-12). Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. PNAS 99 (23): 15089-15094.
- ↑ 3.0 3.1 3.2 Abou-Khalil BW (2007). Comparative monotherapy trials and the clinical treatment of epilepsy. Epilepsy currents / American Epilepsy Society 7 (5): 127–9.
- ↑ NDA 008943
- ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 Epilepsy Action: Druglist. Retrieved on 2007-11-01.
- ↑ NDA 016608 (Initial approval on 1968-03-11 was for trigeminal neuralgia.)
- ↑ Schain, Richard J. (March 1978). Pediatrics—Epitomes of Progress: Carbamazepine (Tegretol®) in the Treatment of Epilepsy. Western Journal of Medicine 128 (3): 231–232. PMID .
- ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 Loiseau, Pierre Jean-Marie (June 1999). Clinical Experience with New Antiepileptic Drugs: Antiepileptic Drugs in Europe. Epilepsia 40 (Suppl 6): S3–8. PMID 10530675.
- ↑ NDA 017533
- ↑ NDA 013263
- ↑ NDA 018723
- ↑ NDA 012380
- ↑ NDA 010841
- ↑ NDA 020189
- ↑ NDA 020450
- ↑ NDA 020235
- ↑ NDA 020241
- ↑ NDA 021035
- ↑ 19.0 19.1 EPAR: Keppra. Retrieved on 2007-11-01.
- ↑ NDA 006008
- ↑ NDA 008322
- ↑ Dodson, W. Edwin; Giuliano Avanzini; Shorvon, Simon D.; Fish, David R.; Emilio Perucca (2004). The treatment of epilepsy, xxviii, Oxford: Blackwell Science.
- ↑ NDA 010596
- ↑ NDA 011721
- ↑ NDA 021014
- ↑ NDA 008762 (Marketed in 1938, approved 1953)
- ↑ NDA 008855
- ↑ Kutt, Henn; Resor, Stanley R. (1992). The Medical treatment of epilepsy, 385, New York: Dekker. (first usage)
- ↑ NDA 021446
- ↑ 30.0 30.1 EPAR: Lyrica Retrieved on 2007-11-01.
- ↑ NDA 009170
- ↑ 32.0 32.1 EPAR: Diacomit.] Orphan designation: 2001-12-05, full authorisation: 2007-01-04 Retrieved on 2007-11-01.
- ↑ NDA 020646
- ↑ NDA 020505
- ↑ NDA 005856
- ↑ NDA 018081
- ↑ NDA 020789
- ↑ 38.0 38.1 EPAR: Zonegran. Retrieved on 2007-11-01