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Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of
pharmacological Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemic ...
agents used in the treatment of epileptic
seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
s. Anticonvulsants are also increasingly being used in the treatment of
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of
neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli ( allodynia). It may have continuo ...
. Anticonvulsants suppress the excessive rapid firing of
neuron A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...
s during seizures. Anticonvulsants also prevent the spread of the seizure within the brain. 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 Synaptic vesicle glycoprotein 2A is a ubiquitous synaptic vesicle protein that in humans is encoded by the ''SV2A'' gene. The protein is targeted by the anti-epileptic drugs (anticonvulsants) levetiracetam and brivaracetam Brivaracetam, sold u ...
, and α2δ. By blocking sodium or calcium channels, antiepileptic drugs reduce the release of excitatory
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, 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 Epileptogenesis is the gradual process by which a typical brain develops epilepsy. Epilepsy is a chronic condition in which seizures occur. These changes to the brain occasionally cause neurons to fire in an abnormal, hypersynchronous manner, know ...
(the development of epilepsy in an individual at risk, such as after a
head injury A head injury is any injury that results in trauma to the skull or brain. The terms ''traumatic brain injury'' and ''head injury'' are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of in ...
).


Terminology

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.


Approval

The usual method of achieving approval for a drug is to show it is effective when compared against
placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
, 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. 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 Paraldehyde is the cyclic trimer of acetaldehyde molecules. Formally, it is a derivative of 1,3,5-trioxane, with a methyl group substituted for a hydrogen atom at each carbon. The corresponding tetramer is metaldehyde. A colourless liquid, it ...
(1882). One of the earliest anticonvulsants. It is still used to treat
status epilepticus Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...
, particularly where there are no
resuscitation Resuscitation is the process of correcting physiological disorders (such as lack of breathing or heartbeat) in an acutely ill patient. It is an important part of intensive care medicine, anesthesiology, trauma surgery and emergency medicine. ...
facilities.


Aromatic allylic alcohols

*
Stiripentol Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of Dravet syndrome - a serious genetic brain disorder. The most common side effects include loss of appetite, weight loss, insomnia (diffic ...
(2007). Indicated for the treatment of Dravet syndrome.


Barbiturates

Barbiturate Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as ...
s are
drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
that act as
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS)
depressant A depressant, or central depressant, is a drug that lowers neurotransmission levels, which is to depress or reduce arousal or stimulation, in various areas of the brain. Depressants are also colloquially referred to as downers as they lower the ...
s, and by virtue of this they produce a wide spectrum of effects, from mild
sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ethe ...
to
anesthesia Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), a ...
. The following are
classified Classified may refer to: General *Classified information, material that a government body deems to be sensitive *Classified advertising or "classifieds" Music *Classified (rapper) (born 1977), Canadian rapper *The Classified, a 1980s American roc ...
as anticonvulsants: *
Phenobarbital Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
(1912). See also the related drug primidone. * Methylphenobarbital (1935). Known as mephobarbital in the US. No longer marketed in the UK. * 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 Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...
, but a benzodiazepine such as
lorazepam Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, insomnia, trouble sleeping, Psychomotor agitation, severe agitation, active Epileptic seizure, seizures including ...
, diazepam or
midazolam Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of ...
is usually tried first. Other barbiturates only have an anticonvulsant effect at
anaesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into ...
doses.


Benzodiazepines

The benzodiazepines are a class of
drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
with
hypnotic Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...
, 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 Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...
to the anticonvulsant effects and dependency. Of 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 Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...
: * Diazepam (1963). Can be given rectally by trained care-givers. *
Midazolam Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of ...
(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 Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, insomnia, trouble sleeping, Psychomotor agitation, severe agitation, active Epileptic seizure, seizures including ...
(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 Potassium bromide ( K Br) is a salt, widely used as an anticonvulsant and a sedative in the late 19th and early 20th centuries, with over-the-counter use extending to 1975 in the US. Its action is due to the bromide ion ( sodium bromide is equ ...
(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.


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 Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...
(1963). A popular anticonvulsant that is available in generic formulations. * Oxcarbazepine (1990). A derivative of carbamazepine that has similar efficacy and is better tolerated and is also available generically. * Eslicarbazepine acetate (2009).


Fatty acids

The following are fatty-acids: * The valproatesvalproic acid, sodium valproate, and divalproex sodium (1967). * Vigabatrin (1989). *
Progabide Progabide ( INN; trade name Gabrene, Sanofi-Aventis) is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ r ...
(1987). * Tiagabine (1996). ''Vigabatrin and progabide are also analogs of GABA.''


Fructose derivatives

* Topiramate (1995).


Gabapentinoids

Gabapentinoids are used in,
epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
,
neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli ( allodynia). It may have continuo ...
,
fibromyalgia Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hype ...
, restless leg syndrome, opioid withdrawal and
generalized anxiety disorder Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functio ...
(GAD). Gabapentinoids block Voltage gated Calcium channels, mainly the N-Type, and P/Q type calcium channels. The following are Gabapentinoids: * Pregabalin (2004) *
Mirogabalin Mirogabalin (brand name Tarlige; developmental code name DS-5565) is a medication developed by Daiichi Sankyo, a gabapentinoid. Gabapentin and pregabalin are also members of this class. As a gabapentinoid, mirogabalin binds to the α2δ subu ...
(2019) (Japan only) *
Gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diab ...
(1993) * Gabapentin Encarbil (2011). * Gabapentin Extended Release (Gralise) (1996). ''Gabapentinoids are analogs of GABA, but they do not act on GABA. They have analgesic anticonvulsant and anxiolytic effects.''


Hydantoins

The following are hydantoins: * Ethotoin (1957). * Phenytoin (1938). * Mephenytoin. * Fosphenytoin (1996).


Oxazolidinediones

The following are oxazolidinediones: *
Paramethadione Paramethadione (brand name Paradione) is an anticonvulsant in the oxazolidinedione class developed by the Illinois-based pharmaceutical company Abbott Laboratories (known as AbbVie since January 1, 2013 ), and approved by the Food and Drug Admin ...
. * Trimethadione (1946). * Ethadione.


Propionates

*
Beclamide Beclamide (marketed as Chloracon, Hibicon, Posedrine, Nydrane, Seclar, and other names) is a drug that possesses anticonvulsant activity. It is no longer used. Uses It has been used as a sedative and as an anticonvulsant. It was studied in ...
.


Pyrimidinediones

* Primidone (1952).


Pyrrolidines

* Brivaracetam (2016). * Etiracetam. * Levetiracetam (1999). * Seletracetam.


Succinimides

The following are succinimides: * Ethosuximide (1955). * Phensuximide. * Mesuximide.


Sulfonamides

*
Acetazolamide Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, altitude sickness, periodic paralysis, idiopathic intracranial hypertension (raised brain pressure of unclear cause), urine alka ...
(1953). * Sultiame. *
Methazolamide Methazolamide (trade name Neptazane) is a potent carbonic anhydrase inhibitor. It is indicated in the treatment of increased intraocular pressure (IOP) in chronic open-angle glaucoma and secondary glaucoma. Also it is used preoperatively in ...
. * Zonisamide (2000).


Triazines

* Lamotrigine (1990).


Ureas

* Pheneturide. * Phenacemide.


Valproylamides

* Valpromide. * Valnoctamide.


Other

* Perampanel. *
Stiripentol Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of Dravet syndrome - a serious genetic brain disorder. The most common side effects include loss of appetite, weight loss, insomnia (diffic ...
. * Pyridoxine (1939).


Non-pharmaceutical anticonvulsants

The ketogenic diet and vagus nerve stimulation are alternative treatments for epilepsy without the involvement of pharmaceuticals. However, both of them can cause severe adverse effects. The adverse effects of vagus nerve stimulation are more severe, and its efficacy is questionable in comparison to medications or the ketogenic diet.


Treatment guidelines

According to guidelines by the American Academy of Neurology and American Epilepsy Society,AAN Guideline Summary for Clinicians – Efficacy and Tolerability of the New Antiepileptic Drugs, I: Treatment of New Onset Epilepsy
Retrieved on 29 June 2010
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 Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...
, phenytoin, valproic acid/ valproate semisodium,
phenobarbital Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
, or on the newer anticonvulsants
gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diab ...
, 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 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 Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
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 The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government The federal government of the United States (U.S. federal government or U ...
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 The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been ...
. Some of the drugs are no longer marketed.


Pregnancy

During
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
, the metabolism of several 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. Therefore, these drugs should be monitored during use in pregnancy. Many of the common used medications, such as valproate, phenytoin, carbamazepine, phenobarbitol, gabapentin have been reported to cause increased risk of
birth defect A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities c ...
s. Among anticonvulsants, levetiracetam and lamotrigine seem to carry the lowest risk of causing birth defects. The risk of untreated epilepsy is believed to be greater than the risk of adverse effects caused by these medications, necessitating continuation of antiepileptic treatment. Valproic acid, and its derivatives such as sodium valproate and divalproex sodium, causes cognitive deficit in the child, with an increased dose causing decreased
intelligence quotient An intelligence quotient (IQ) is a total score derived from a set of standardized tests or subtests designed to assess human intelligence. The abbreviation "IQ" was coined by the psychologist William Stern for the German term ''Intelligen ...
. On the other hand, evidence is conflicting for
carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...
regarding any increased risk of congenital physical anomalies or
neurodevelopmental disorder Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental ...
s by intrauterine exposure. Similarly, children exposed lamotrigine or phenytoin in the womb do not seem to differ in their skills compared to those who were exposed to carbamazepine. 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 Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...
, some anticonvulsants probably pass into
breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates (lac ...
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. 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. Pregnancy planning is being explored as a method that could decrease the risk of possible birth defects. 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. In animal models, several anticonvulsant drugs have been demonstrated to induce neuronal apoptosis in the developing brain.


References


Further reading

* Anti epileptic activity of novel substituted fluorothiazole derivatives by Devid Chutia, RGUHS


External links


eMedicine: Antiepileptic Drugs: an overview

NINDS: Anticonvulsant Screening Program

Use of Anticonvulsants in Pharmacotherapy of Bronchial Asthma



Miami Children's Brain Institute – Anticonvulsants




{{Authority control Epilepsy