Topiramate
Encyclopedia
Topiramate is an anticonvulsant
(antiepilepsy) drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson
Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff
and Joseph F. Gardocki during their research work at McNeil Pharmaceutical. Generic versions are available in Canada and these were approved by the Food and Drug Administration
(FDA) in September 2006. Mylan Pharmaceuticals was recently granted final approval for generic topiramate 25, 100, and 200 mg tablets and sprinkle capsules by the FDA for sale in the United States
. 50 mg tablets were granted tentative approval. The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009. On May 21, 2010, Ortho-McNeil pled guilty and was fined $6.14 million by the FDA for promoting Topamax to treat psychiatric disorders, without applying for any Federal government approval. Also, there was no data from any well-controlled clinical trial to demonstrate that Topamax was safe and/or effective to treat any psychiatric conditions at all.
in children and adults, and it was originally used as an anticonvulsant
. In children, it is indicated for the treatment of Lennox-Gastaut syndrome
, a disorder that causes seizures and developmental delay. It is also Food and Drug Administration
(FDA) approved for, and most frequently prescribed for, the prevention of migraine
s. Psychiatrist
s have used topiramate to treat bipolar disorder
, and they sometimes use topiramate to augment psychotropics, or to counteract the weight gain associated with numerous antidepressants. In 2006, a Cochrane review concluded that there is insufficient evidence on which to base any recommendations regarding the use of topiramate in any phase of bipolar illness. However, a more recent Cochrane review, published in 2010, concluded that there was evidence for the efficacy of topiramate in the treatment of symptoms of borderline personality disorder
, including mood instability.
This drug has been investigated for use in treating alcoholism and obesity, especially to reduce binge eating
.
The drug is also used in clinical trials to treat posttraumatic stress disorder. A pilot study suggested that topiramate is effective against infantile spasms. Another study recommends topiramate as an effective treatment in the prevention of periventricular leukomalacia
in preterm infants after an hypoxic
-ischemic injury.
Other off-label and investigational uses of topiramate include the treatment of essential tremor
, bulimia nervosa
, obsessive-compulsive disorder
, alcoholism
, smoking cessation
, idiopathic intracranial hypertension
, neuropathic pain
, cluster headache, migraine
headache, cocaine
dependence, and Borderline Personality Disorder.
Topiramate is also being studied with a mixture of phentermine
to form a drug called Qnexa for the treatment of obesity
.
-sponsored Phase IV study suggested that cognitive side effects may be more common with topiramate than with lamotrigine
. In studies of healthy volunteers, therapeutic doses of topiramate for bipolar disorder produced greater cognitive deficits than lamotrigine, including short term memory loss and word-finding difficulty.
The side-effects reported by > 10% of subjects in at least one clinical study
Listed by prevalence:
The side-effects most frequently leading to discontinuation of therapy with topiramate were:
That same study also reported that in adult patients with Bipolar 1 disorder who were already receiving either lithium
or valproate, the addition of topiramate did not produce a statistically-significant improvement versus placebo, while adding the above adverse reactions.
Rarely, the inhibition of carbonic anhydrase
may be strong enough to cause metabolic acidosis
of clinical importance.
The U.S. Food and Drug Administration
(FDA) has notified prescribers that topiramate can cause acute myopia
and secondary angle closure glaucoma
in a small subset of people who take topiramate regularly. The symptoms, which typically begin in the first month of use, include blurred vision and eye pain. Discontinuation of topiramate may halt the progression of the ocular damage, and may reverse the visual impairment.
Preliminary data suggests that, as with several other anti-epileptic drugs, topiramate carries an increased risk of congenital malformations. This might be particularly important for women who take topiramate to prevent migraine attacks.
Topiramate has been associated with a statistically significant
increase in suicidality
.
In March 2011 the FDA notified healthcare professionals and patients of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during pregnancy.
Symptoms of overdose may include but are not limited to:
A specific antidote is not available. Treatment is entirely supportive.
-substituted monosaccharide
, related to fructose
, a rather unusual chemical structure for an anticonvulsant.
Topiramate is quickly absorbed after oral use. Most of the drug (70%) is excreted in the urine unchanged. The remainder is extensively metabolized by hydroxylation
, hydrolysis
, and glucuronidation
. Six metabolite
s have been identified in humans, none of which constitutes more than 5% of an administered dose.
The exact mechanism of action is unknown, but four properties that may contribute to topiramate's antiepileptic and antimigraine efficacy include a blockage of voltage-dependent sodium channels, an augmentation of gamma-aminobutyrate acid activity at some subtypes of the GABA- A receptors, antagonism of AMPA/kainate subtype of the glutamate receptor, and inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV .
Its possible effect as a mood stabilizer
seems to occur before anticonvulsant qualities at lower dosages. Topiramate inhibits maximal electroshock and pentylenetetrazol
-induced seizures as well as partial and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of activities clinically. Its action on mitochondrial permeability transition pores has been proposed as a mechanism.
While many anticonvulsants have been associated with apoptosis in young animals, animal experiments have found that topiramate is the only anticonvulsant that does not induce apoptosis
in young animals at doses needed to produce an anticonvulsant effect.
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...
(antiepilepsy) drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson
Johnson & Johnson
Johnson & Johnson is an American multinational pharmaceutical, medical devices and consumer packaged goods manufacturer founded in 1886. Its common stock is a component of the Dow Jones Industrial Average and the company is listed among the Fortune 500....
Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff
Bruce E. Maryanoff
Bruce Eliot Maryanoff is an American medicinal and organic chemist.-Background and contributions:...
and Joseph F. Gardocki during their research work at McNeil Pharmaceutical. Generic versions are available in Canada and these were approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in September 2006. Mylan Pharmaceuticals was recently granted final approval for generic topiramate 25, 100, and 200 mg tablets and sprinkle capsules by the FDA for sale in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. 50 mg tablets were granted tentative approval. The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009. On May 21, 2010, Ortho-McNeil pled guilty and was fined $6.14 million by the FDA for promoting Topamax to treat psychiatric disorders, without applying for any Federal government approval. Also, there was no data from any well-controlled clinical trial to demonstrate that Topamax was safe and/or effective to treat any psychiatric conditions at all.
Medical uses
Topiramate is used to treat epilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
in children and adults, and it was originally used as an anticonvulsant
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...
. In children, it is indicated for the treatment of Lennox-Gastaut syndrome
Lennox-Gastaut syndrome
Lennox–Gastaut syndrome , also known as Lennox syndrome, is a difficult-to-treat form of childhood-onset epilepsy that most often appears between the second and sixth year of life, and is characterized by frequent seizures and different seizure types; it is often accompanied by developmental delay...
, a disorder that causes seizures and developmental delay. It is also Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approved for, and most frequently prescribed for, the prevention of migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
s. Psychiatrist
Psychiatrist
A psychiatrist is a physician who specializes in the diagnosis and treatment of mental disorders. All psychiatrists are trained in diagnostic evaluation and in psychotherapy...
s have used topiramate to treat bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, and they sometimes use topiramate to augment psychotropics, or to counteract the weight gain associated with numerous antidepressants. In 2006, a Cochrane review concluded that there is insufficient evidence on which to base any recommendations regarding the use of topiramate in any phase of bipolar illness. However, a more recent Cochrane review, published in 2010, concluded that there was evidence for the efficacy of topiramate in the treatment of symptoms of borderline personality disorder
Borderline personality disorder
Borderline personality disorder is a personality disorder described as a prolonged disturbance of personality function in a person , characterized by depth and variability of moods.The disorder typically involves unusual levels of instability in mood; black and white thinking, or splitting; the...
, including mood instability.
This drug has been investigated for use in treating alcoholism and obesity, especially to reduce binge eating
Binge eating
Binge eating is a pattern of disordered eating which consists of episodes of uncontrollable eating. It is sometimes as a symptom of binge eating disorder. During such binges, a person rapidly consumes an excessive amount of food...
.
The drug is also used in clinical trials to treat posttraumatic stress disorder. A pilot study suggested that topiramate is effective against infantile spasms. Another study recommends topiramate as an effective treatment in the prevention of periventricular leukomalacia
Periventricular leukomalacia
Periventricular leukomalacia is a form of white-matter brain injury, characterized by the necrosis of white matter near the lateral ventricles. It can affect newborns and fetuses; premature infants are at the greatest risk of the disorder...
in preterm infants after an hypoxic
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
-ischemic injury.
Other
Recent clinical reports indicate that it may have mood stabilizing properties.Other off-label and investigational uses of topiramate include the treatment of essential tremor
Essential tremor
Essential tremor is a slowly progressive neurological disorder whose most recognizable feature is a tremor of the arms that is apparent during voluntary movements such as eating and writing...
, bulimia nervosa
Bulimia nervosa
Bulimia nervosa is an eating disorder characterized by binge eating and purging or consuming a large amount of food in a short amount of time, followed by an attempt to rid oneself of the food consumed, usually by purging and/or by laxative, diuretics or excessive exercise. Bulimia nervosa is...
, obsessive-compulsive disorder
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
, alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
, smoking cessation
Smoking cessation
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...
, idiopathic intracranial hypertension
Idiopathic intracranial hypertension
Idiopathic intracranial hypertension , sometimes called by the older names benign intracranial hypertension or pseudotumor cerebri , is a neurological disorder that is characterized by increased intracranial pressure in the absence of a tumor or other diseases...
, neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
, cluster headache, migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
headache, cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
dependence, and Borderline Personality Disorder.
Topiramate is also being studied with a mixture of phentermine
Phentermine
Phentermine, a contraction of "phenyl-tertiary-butylamine", is a psychostimulant drug of the phenethylamine class, chemically related to amphetamine. It is used medically as an appetite suppressant....
to form a drug called Qnexa for the treatment of obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
Adverse effects
A GlaxoSmithKlineGlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
-sponsored Phase IV study suggested that cognitive side effects may be more common with topiramate than with lamotrigine
Lamotrigine
Lamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
. In studies of healthy volunteers, therapeutic doses of topiramate for bipolar disorder produced greater cognitive deficits than lamotrigine, including short term memory loss and word-finding difficulty.
The side-effects reported by > 10% of subjects in at least one clinical study
Listed by prevalence:
- paresthesiaParesthesiaParesthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
(numbness & tingling) (23.7%) - upper respiratory tract infectionUpper respiratory tract infectionUpper respiratory tract infections are the illnesses caused by an acute infection which involves the upper respiratory tract: nose, sinuses, pharynx or larynx...
(17.5%) - diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
(16.8%) - nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
(15.4%) - anorexiaAnorexia (symptom)Anorexia is the decreased sensation of appetite...
(loss of appetite) (13.3%) - memory problems (11.2%)
The side-effects most frequently leading to discontinuation of therapy with topiramate were:
- psychomotor slowingPsychomotor retardationPsychomotor retardation involves a slowing-down of thought and a reduction of physical movements in an individual. Psychomotor retardation can cause a visible slowing of physical and emotional reactions, including speech and affect...
(4.1%) - memory problems (3.3%)
- fatigue (3.3%)
- confusionConFusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
(3.2%) - somnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(3.2%)
That same study also reported that in adult patients with Bipolar 1 disorder who were already receiving either lithium
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
or valproate, the addition of topiramate did not produce a statistically-significant improvement versus placebo, while adding the above adverse reactions.
Rarely, the inhibition of carbonic anhydrase
Carbonic anhydrase
The carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...
may be strong enough to cause metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
of clinical importance.
The U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) has notified prescribers that topiramate can cause acute myopia
Myopia
Myopia , "shortsightedness" ) is a refractive defect of the eye in which collimated light produces image focus in front of the retina under conditions of accommodation. In simpler terms, myopia is a condition of the eye where the light that comes in does not directly focus on the retina but in...
and secondary angle closure glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
in a small subset of people who take topiramate regularly. The symptoms, which typically begin in the first month of use, include blurred vision and eye pain. Discontinuation of topiramate may halt the progression of the ocular damage, and may reverse the visual impairment.
Preliminary data suggests that, as with several other anti-epileptic drugs, topiramate carries an increased risk of congenital malformations. This might be particularly important for women who take topiramate to prevent migraine attacks.
Topiramate has been associated with a statistically significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
increase in suicidality
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
.
In March 2011 the FDA notified healthcare professionals and patients of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with Topamax (topiramate) during pregnancy.
Interactions
Topiramate has many drug-drug interactions. Some of the most common are listed below:- As topiramate inhibits carbonic anhydraseCarbonic anhydraseThe carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...
, use with other inhibitors of carbonic anhydrase (e.g. acetazolamideAcetazolamideAcetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension , altitude sickness, cystinuria, and dural ectasia...
) increases the risk of kidney stones. - Enzyme inducerEnzyme inducerAn enzyme inducer is a type of drug which binds to an enzyme and increases its metabolic activity.Classic examples: barbiturates , antiepileptics and rifampin....
s (e.g. carbamazepineCarbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
) can increase the elimination of topiramate, possibly necessitating dose escalations of topiramate. - Topiramate may increase the plasma-levels of phenytoin.
- Topiramate itself is a weak inhibitor of CYP2C19CYP2C19Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
and induces CYP3A4CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
; a decrease in plasma levels of estrogens and digoxinDigoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
has been noted during topiramate therapy. This can reduce the effectiveness of oral contraceptives (the pill); use of alternative birth control methods is recommended. Neither intrauterine deviceIntrauterine deviceA copper IUD is a type of intrauterine device. Most IUDs have a plastic T- or U-shaped frame which is wrapped in copper wire, with the exception of Gynefix, which is a plastic string with several copper beads, affixed to the fundus of the uterus...
s (IUDs) nor Depo-Provera are affected by topiramate. - Alcohol may cause increased sedation or drowsiness, and increase the risk of having a seizure.
- As listed in the 06/29/2005 label posted at the Drugs@FDA website page 14,'conditions or therapies that predispose to acidosis may be additive to the bicarbonate lowering effects of Topiramate'.
- OligohidrosisAnhidrosisAnhidrosis means lack of sweating. It is also known by a number of other names including Adiaphoresis, Ischidrosis, Hypohidrosis, Oligidria, Oligohidrosis and Sweating deficiency.-Causes:...
and hyperthermia were reported in post-marketing reports about topiramate; antimuscarinic drugs (like trospium) can aggravate these disorders.
Overdose
Overdose is rare. In most cases, acute exposure produced only minimal to moderate effects. Fatalities have occurred, but were the result of polydrug exposure.Symptoms of overdose may include but are not limited to:
- Agitation
- Depression
- Speech problems
- Blurred vision, double vision
- Troubled thinking
- Loss of coordination
- Inability to respond to things around you
- Loss of consciousness
- Confusion and coma
- Fainting
- Upset stomach and stomach pain
- Loss of appetite and vomiting
- Shortness of breath; fast, shallow breathing
- Pounding or irregular heartbeat
- Muscle weakness
- Bone pain
A specific antidote is not available. Treatment is entirely supportive.
Detection in body fluids
Blood, serum or plasma topiramate concentrations may be measured using immunoassay or chromatographic methods to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 10 mg/L during therapeutic administration, but can range from 10–150 mg/L in overdose victims.Warnings
People taking topiramate should be aware of the following risks:- Avoid activities requiring mental alertness and coordination until drug effects are realized
- Topiramate may impair heat regulation, especially in children. Use caution with activities leading to an increased core temperature, such as strenuous exercise, exposure to extreme heat, or dehydration
- Topiramate may decrease effectiveness of estrogen-containing oral contraceptives
- Topiramate should not be suddenly discontinued, as this may cause increased seizure activity.
- Avoid evening primroseEvening PrimroseEvening Primrose is a musical with a book by James Goldman and lyrics and music by Stephen Sondheim. It is based on a John Collier short story published in the 1951 collection Fancies and Goodnights....
(seizure threshold decreased)
Pharmacology
Chemically, topiramate is a sulfamateSulfamic acid
Sulfamic acid, also known as amidosulfonic acid, amidosulfuric acid, aminosulfonic acid, and sulfamidic acid, is a molecular compound with the formula H3NSO3...
-substituted monosaccharide
Monosaccharide
Monosaccharides are the most basic units of biologically important carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble, crystalline solids. Some monosaccharides have a sweet taste. Examples of monosaccharides include glucose , fructose , galactose, xylose...
, related to fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
, a rather unusual chemical structure for an anticonvulsant.
Topiramate is quickly absorbed after oral use. Most of the drug (70%) is excreted in the urine unchanged. The remainder is extensively metabolized by hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
, hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
, and glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
. Six metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s have been identified in humans, none of which constitutes more than 5% of an administered dose.
The exact mechanism of action is unknown, but four properties that may contribute to topiramate's antiepileptic and antimigraine efficacy include a blockage of voltage-dependent sodium channels, an augmentation of gamma-aminobutyrate acid activity at some subtypes of the GABA- A receptors, antagonism of AMPA/kainate subtype of the glutamate receptor, and inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV .
Its possible effect as a mood stabilizer
Mood stabilizer
A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder.-Uses:...
seems to occur before anticonvulsant qualities at lower dosages. Topiramate inhibits maximal electroshock and pentylenetetrazol
Pentylenetetrazol
Pentylenetetrazol , also known as metrazol, pentetrazol, pentamethylenetetrazol, Cardiazol or PTZ, is a drug used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by the Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934...
-induced seizures as well as partial and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of activities clinically. Its action on mitochondrial permeability transition pores has been proposed as a mechanism.
While many anticonvulsants have been associated with apoptosis in young animals, animal experiments have found that topiramate is the only anticonvulsant that does not induce apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in young animals at doses needed to produce an anticonvulsant effect.
External links
- Topamax (topiramate): Treatment for Migraine Prevention
- Topamax: Treatment for Epilepsy
- Currently listed clinical trials related to topiramate
- FDA topiramate safety
- MSN article
- Effects of topiramate
- MedlinePlus: Topiramate
- FAQ: Topiramate (Topamax), Mood Disorders and PTSD
- RxList.com: Topiramate
- Focus on Topiramate - a new anti-epileptic, Ben Green, Priory Lodge Education Ltd., 1997-99. Version 1.1