Ethosuximide
Encyclopedia
Ethosuximide is a succinimide
anticonvulsant
, used mainly in absence seizure
s.
.
in 1980 by Drs Andrulonis, Donnelly, Glueck, Stroebel, and Szabek.
in 2007. Syrup preparations of both brands are still available.
In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+
current
s in T-type Ca2+ channel
s in freshly removed thalamic
neuron
s. In June of that same year, they also found the mechanism of this reduction to be voltage
-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid
, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not. The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root
ganglia
at concentration
s ranging from 7 µmol/L
to 1 mmol/L.
That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. The year after, a study conducted on human neocortical
cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.
In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+
current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.
In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia
in Charlottesville
pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. Using cloned α1G, α1H, and α1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide
) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.
s can either decrease or increase the levels of ethosuximide; However, combinations of valproate
s and ethosuximide had a greater Protective Index
than either drug alone.
It may elevate serum phenytoin
levels.
. Then hydrogen cyanide is added. After acidic hydrolysis and decarboxylation of the synthesized dinitrile, 2-methyl-2-ethylsuccinic acid is formed. Reacting this product with ammonia gives the diammonium salt, and heterocyclization into ethosuximide takes place during subsequent heating.
Ethosuximide is a succinimide
anticonvulsant
, used mainly in absence seizure
s.
.
in 1980 by Drs Andrulonis, Donnelly, Glueck, Stroebel, and Szabek.
in 2007. Syrup preparations of both brands are still available.
In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+
current
s in T-type Ca2+ channel
s in freshly removed thalamic
neuron
s. In June of that same year, they also found the mechanism of this reduction to be voltage
-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid
, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not. The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root
ganglia
at concentration
s ranging from 7 µmol/L
to 1 mmol/L.
That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. The year after, a study conducted on human neocortical
cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.
In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+
current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.
In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia
in Charlottesville
pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. Using cloned α1G, α1H, and α1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide
) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.
s can either decrease or increase the levels of ethosuximide; However, combinations of valproate
s and ethosuximide had a greater Protective Index
than either drug alone.
It may elevate serum phenytoin
levels.
. Then hydrogen cyanide is added. After acidic hydrolysis and decarboxylation of the synthesized dinitrile, 2-methyl-2-ethylsuccinic acid is formed. Reacting this product with ammonia gives the diammonium salt, and heterocyclization into ethosuximide takes place during subsequent heating.
Ethosuximide is a succinimide
anticonvulsant
, used mainly in absence seizure
s.
.
in 1980 by Drs Andrulonis, Donnelly, Glueck, Stroebel, and Szabek.
in 2007. Syrup preparations of both brands are still available.
In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+
current
s in T-type Ca2+ channel
s in freshly removed thalamic
neuron
s. In June of that same year, they also found the mechanism of this reduction to be voltage
-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid
, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not. The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root
ganglia
at concentration
s ranging from 7 µmol/L
to 1 mmol/L.
That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. The year after, a study conducted on human neocortical
cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.
In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+
current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.
In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia
in Charlottesville
pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. Using cloned α1G, α1H, and α1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide
) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.
s can either decrease or increase the levels of ethosuximide; However, combinations of valproate
s and ethosuximide had a greater Protective Index
than either drug alone.
It may elevate serum phenytoin
levels.
. Then hydrogen cyanide is added. After acidic hydrolysis and decarboxylation of the synthesized dinitrile, 2-methyl-2-ethylsuccinic acid is formed. Reacting this product with ammonia gives the diammonium salt, and heterocyclization into ethosuximide takes place during subsequent heating.
Succinimide
Succinimide is a cyclic imide with the formula C4H5NO2. It is used in a variety of organic syntheses, as well as in some industrial silver plating processes.-Succinimides:...
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...
, used mainly in absence seizure
Absence seizure
Absence seizures are one of several kinds of seizures. These seizures are sometimes referred to as petit mal seizures ....
s.
Approved
It is approved for absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug, valproic acidValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
.
Unapproved
It was reported to have been used for intermittent explosive disorderIntermittent explosive disorder
Intermittent explosive disorder is a behavioral disorder characterized by extreme expressions of anger, often to the point of violence, that are disproportionate to the situation at hand. It is currently categorized in the Diagnostic and Statistical Manual of Mental Disorders as an impulse...
in 1980 by Drs Andrulonis, Donnelly, Glueck, Stroebel, and Szabek.
Dosage
Therapeutic drug concentrations are individualized according to response and tolerance. Common Serum Therapeutic Range: 40-100 µg/mL. Potentially Toxic Serum Concentration: >100 µg/mL.Availability
Ethosuximide is marketed under the trade names Emeside and Zarontin. However, both capsule preparations were discontinued from production, leaving only generic preparations available. Emeside capsules were discontinued by their manufacturer, Laboratories for Applied Biology, in 2005. Similarly, Zarontin capsules were discontinued by PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in 2007. Syrup preparations of both brands are still available.
Mechanism of action
There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the view that ethosuximide is a T-type calcium channel blocker gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
current
Electric current
Electric current is a flow of electric charge through a medium.This charge is typically carried by moving electrons in a conductor such as wire...
s in T-type Ca2+ channel
T-type calcium channel
The T-type calcium channel is a type of voltage-gated calcium channel. "T" stands for transient referring to the length of activation. As with other sub-types of voltage-gated calcium channel, the α1 subunit is the one that determines most of the channel's properties...
s in freshly removed thalamic
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. In June of that same year, they also found the mechanism of this reduction to be voltage
Voltage
Voltage, otherwise known as electrical potential difference or electric tension is the difference in electric potential between two points — or the difference in electric potential energy per unit charge between two points...
-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not. The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root
Dorsal root
In anatomy and neurology, the dorsal root is the afferentsensory root of a spinal nerve.At the distal end of the dorsal root is the dorsal root ganglion, which contains the neuron cell bodies of the nerve fibres conveyed by the root.If the dorsal root of a spinal nerve were severed it would lead...
ganglia
Ganglion
In anatomy, a ganglion is a biological tissue mass, most commonly a mass of nerve cell bodies. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
at concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
s ranging from 7 µmol/L
Litre
pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...
to 1 mmol/L.
That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. The year after, a study conducted on human neocortical
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.
In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.
In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia
University of Virginia
The University of Virginia is a public research university located in Charlottesville, Virginia, United States, founded by Thomas Jefferson...
in Charlottesville
Charlottesville, Virginia
Charlottesville is an independent city geographically surrounded by but separate from Albemarle County in the Commonwealth of Virginia, United States, and named after Charlotte of Mecklenburg-Strelitz, the queen consort of King George III of the United Kingdom.The official population estimate for...
pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. Using cloned α1G, α1H, and α1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide
Mesuximide
Mesuximide is an succinimide anticonvulsant medication. It is sold as a racemate by Pfizer under the tradenames Petinutin and Celontin...
) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.
Common
- suicidal tendencies
- drowsiness
- mental confusion
- insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
- nervousness
- headacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
- euphoriaEuphoria (emotion)Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy...
- ataxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
- hiccups
- impaired concentration
- irritability
- hyperactivity
- loss of taste
- night terrorNight terrorA night terror, also known as a sleep terror, incubus attack, or pavor nocturnus, is a parasomnia disorder that predominantly affects children, causing feelings of terror or dread, typically occur in the first few hours of sleep during stage 3 or 4 NREM sleep...
s
Rare
- paranoidParanoiaParanoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
psychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"... - increased libido
- exacerbation of depressionClinical depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
Gastrointestinal
- dyspepsiaDyspepsiaDyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
- vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
- 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...
- cramps
- constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
- 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...
- stomach pain
- loss of appetite
- weight loss
- gingival hyperplasiaHyperplasiaHyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
- swelling of tongue
Hematopoietic
The following can occur with or without bone marrow loss:- pancytopeniaPancytopeniaPancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
- agranulocytosisAgranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
- leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
- eosinophiliaEosinophiliaEosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.45×109/L . A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being...
Integumentary
- urticariaUrticariaUrticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
- systemic lupus erythematosusSystemic lupus erythematosusSystemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
- Stevens–Johnson syndrome
- hirsutismHirsutismHirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
- pruriticItchItch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
erythematous rashLupus erythematosusLupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
es
Drug interactions
ValproateValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
s can either decrease or increase the levels of ethosuximide; However, combinations of valproate
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
s and ethosuximide had a greater Protective Index
Protective index
The protective index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. Quantitatively, it is the ratio given by the toxic dose divided by the therapeutic dose. A protective index is the toxic dose of a drug for 50% of the...
than either drug alone.
It may elevate serum phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
levels.
Chemistry
Ethosuximide, 3-ethyl-3-methypyrrolidine-2,5-dione is synthesized from methylethylketone and cyanoacetic ester, which undergo a Knoevenagel condensationKnoevenagel condensation
The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the Aldol condensation.A Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule...
. Then hydrogen cyanide is added. After acidic hydrolysis and decarboxylation of the synthesized dinitrile, 2-methyl-2-ethylsuccinic acid is formed. Reacting this product with ammonia gives the diammonium salt, and heterocyclization into ethosuximide takes place during subsequent heating.
- L.M. Long, Ch.A. Miller, (1961).
- S.S.G. Sircar, J. Chem. Soc., 1252 (1927).
External links
- Ethosuximide Internet Mental Health.
- MedlinePlus Drug Information: Ethosuximide Oral
- Zarontin Pfizer.
- Zarontin Drug information, published studies and current trials
Ethosuximide is a succinimide
Succinimide
Succinimide is a cyclic imide with the formula C4H5NO2. It is used in a variety of organic syntheses, as well as in some industrial silver plating processes.-Succinimides:...
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...
, used mainly in absence seizure
Absence seizure
Absence seizures are one of several kinds of seizures. These seizures are sometimes referred to as petit mal seizures ....
s.
Approved
It is approved for absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug, valproic acidValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
.
Unapproved
It was reported to have been used for intermittent explosive disorderIntermittent explosive disorder
Intermittent explosive disorder is a behavioral disorder characterized by extreme expressions of anger, often to the point of violence, that are disproportionate to the situation at hand. It is currently categorized in the Diagnostic and Statistical Manual of Mental Disorders as an impulse...
in 1980 by Drs Andrulonis, Donnelly, Glueck, Stroebel, and Szabek.
Dosage
Therapeutic drug concentrations are individualized according to response and tolerance. Common Serum Therapeutic Range: 40-100 µg/mL. Potentially Toxic Serum Concentration: >100 µg/mL.Availability
Ethosuximide is marketed under the trade names Emeside and Zarontin. However, both capsule preparations were discontinued from production, leaving only generic preparations available. Emeside capsules were discontinued by their manufacturer, Laboratories for Applied Biology, in 2005. Similarly, Zarontin capsules were discontinued by PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in 2007. Syrup preparations of both brands are still available.
Mechanism of action
There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the view that ethosuximide is a T-type calcium channel blocker gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
current
Electric current
Electric current is a flow of electric charge through a medium.This charge is typically carried by moving electrons in a conductor such as wire...
s in T-type Ca2+ channel
T-type calcium channel
The T-type calcium channel is a type of voltage-gated calcium channel. "T" stands for transient referring to the length of activation. As with other sub-types of voltage-gated calcium channel, the α1 subunit is the one that determines most of the channel's properties...
s in freshly removed thalamic
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. In June of that same year, they also found the mechanism of this reduction to be voltage
Voltage
Voltage, otherwise known as electrical potential difference or electric tension is the difference in electric potential between two points — or the difference in electric potential energy per unit charge between two points...
-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not. The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root
Dorsal root
In anatomy and neurology, the dorsal root is the afferentsensory root of a spinal nerve.At the distal end of the dorsal root is the dorsal root ganglion, which contains the neuron cell bodies of the nerve fibres conveyed by the root.If the dorsal root of a spinal nerve were severed it would lead...
ganglia
Ganglion
In anatomy, a ganglion is a biological tissue mass, most commonly a mass of nerve cell bodies. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
at concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
s ranging from 7 µmol/L
Litre
pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...
to 1 mmol/L.
That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. The year after, a study conducted on human neocortical
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.
In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.
In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia
University of Virginia
The University of Virginia is a public research university located in Charlottesville, Virginia, United States, founded by Thomas Jefferson...
in Charlottesville
Charlottesville, Virginia
Charlottesville is an independent city geographically surrounded by but separate from Albemarle County in the Commonwealth of Virginia, United States, and named after Charlotte of Mecklenburg-Strelitz, the queen consort of King George III of the United Kingdom.The official population estimate for...
pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. Using cloned α1G, α1H, and α1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide
Mesuximide
Mesuximide is an succinimide anticonvulsant medication. It is sold as a racemate by Pfizer under the tradenames Petinutin and Celontin...
) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.
Common
- suicidal tendencies
- drowsiness
- mental confusion
- insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
- nervousness
- headacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
- euphoriaEuphoria (emotion)Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy...
- ataxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
- hiccups
- impaired concentration
- irritability
- hyperactivity
- loss of taste
- night terrorNight terrorA night terror, also known as a sleep terror, incubus attack, or pavor nocturnus, is a parasomnia disorder that predominantly affects children, causing feelings of terror or dread, typically occur in the first few hours of sleep during stage 3 or 4 NREM sleep...
s
Rare
- paranoidParanoiaParanoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
psychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"... - increased libido
- exacerbation of depressionClinical depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
Gastrointestinal
- dyspepsiaDyspepsiaDyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
- vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
- 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...
- cramps
- constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
- 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...
- stomach pain
- loss of appetite
- weight loss
- gingival hyperplasiaHyperplasiaHyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
- swelling of tongue
Hematopoietic
The following can occur with or without bone marrow loss:- pancytopeniaPancytopeniaPancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
- agranulocytosisAgranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
- leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
- eosinophiliaEosinophiliaEosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.45×109/L . A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being...
Integumentary
- urticariaUrticariaUrticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
- systemic lupus erythematosusSystemic lupus erythematosusSystemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
- Stevens–Johnson syndrome
- hirsutismHirsutismHirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
- pruriticItchItch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
erythematous rashLupus erythematosusLupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
es
Drug interactions
ValproateValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
s can either decrease or increase the levels of ethosuximide; However, combinations of valproate
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
s and ethosuximide had a greater Protective Index
Protective index
The protective index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. Quantitatively, it is the ratio given by the toxic dose divided by the therapeutic dose. A protective index is the toxic dose of a drug for 50% of the...
than either drug alone.
It may elevate serum phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
levels.
Chemistry
Ethosuximide, 3-ethyl-3-methypyrrolidine-2,5-dione is synthesized from methylethylketone and cyanoacetic ester, which undergo a Knoevenagel condensationKnoevenagel condensation
The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the Aldol condensation.A Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule...
. Then hydrogen cyanide is added. After acidic hydrolysis and decarboxylation of the synthesized dinitrile, 2-methyl-2-ethylsuccinic acid is formed. Reacting this product with ammonia gives the diammonium salt, and heterocyclization into ethosuximide takes place during subsequent heating.
- L.M. Long, Ch.A. Miller, (1961).
- S.S.G. Sircar, J. Chem. Soc., 1252 (1927).
External links
- Ethosuximide Internet Mental Health.
- MedlinePlus Drug Information: Ethosuximide Oral
- Zarontin Pfizer.
- Zarontin Drug information, published studies and current trials
Ethosuximide is a succinimide
Succinimide
Succinimide is a cyclic imide with the formula C4H5NO2. It is used in a variety of organic syntheses, as well as in some industrial silver plating processes.-Succinimides:...
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...
, used mainly in absence seizure
Absence seizure
Absence seizures are one of several kinds of seizures. These seizures are sometimes referred to as petit mal seizures ....
s.
Approved
It is approved for absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug, valproic acidValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
.
Unapproved
It was reported to have been used for intermittent explosive disorderIntermittent explosive disorder
Intermittent explosive disorder is a behavioral disorder characterized by extreme expressions of anger, often to the point of violence, that are disproportionate to the situation at hand. It is currently categorized in the Diagnostic and Statistical Manual of Mental Disorders as an impulse...
in 1980 by Drs Andrulonis, Donnelly, Glueck, Stroebel, and Szabek.
Dosage
Therapeutic drug concentrations are individualized according to response and tolerance. Common Serum Therapeutic Range: 40-100 µg/mL. Potentially Toxic Serum Concentration: >100 µg/mL.Availability
Ethosuximide is marketed under the trade names Emeside and Zarontin. However, both capsule preparations were discontinued from production, leaving only generic preparations available. Emeside capsules were discontinued by their manufacturer, Laboratories for Applied Biology, in 2005. Similarly, Zarontin capsules were discontinued by PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in 2007. Syrup preparations of both brands are still available.
Mechanism of action
There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the view that ethosuximide is a T-type calcium channel blocker gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
current
Electric current
Electric current is a flow of electric charge through a medium.This charge is typically carried by moving electrons in a conductor such as wire...
s in T-type Ca2+ channel
T-type calcium channel
The T-type calcium channel is a type of voltage-gated calcium channel. "T" stands for transient referring to the length of activation. As with other sub-types of voltage-gated calcium channel, the α1 subunit is the one that determines most of the channel's properties...
s in freshly removed thalamic
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. In June of that same year, they also found the mechanism of this reduction to be voltage
Voltage
Voltage, otherwise known as electrical potential difference or electric tension is the difference in electric potential between two points — or the difference in electric potential energy per unit charge between two points...
-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not. The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root
Dorsal root
In anatomy and neurology, the dorsal root is the afferentsensory root of a spinal nerve.At the distal end of the dorsal root is the dorsal root ganglion, which contains the neuron cell bodies of the nerve fibres conveyed by the root.If the dorsal root of a spinal nerve were severed it would lead...
ganglia
Ganglion
In anatomy, a ganglion is a biological tissue mass, most commonly a mass of nerve cell bodies. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
at concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
s ranging from 7 µmol/L
Litre
pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...
to 1 mmol/L.
That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. The year after, a study conducted on human neocortical
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.
In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.
In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia
University of Virginia
The University of Virginia is a public research university located in Charlottesville, Virginia, United States, founded by Thomas Jefferson...
in Charlottesville
Charlottesville, Virginia
Charlottesville is an independent city geographically surrounded by but separate from Albemarle County in the Commonwealth of Virginia, United States, and named after Charlotte of Mecklenburg-Strelitz, the queen consort of King George III of the United Kingdom.The official population estimate for...
pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. Using cloned α1G, α1H, and α1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide
Mesuximide
Mesuximide is an succinimide anticonvulsant medication. It is sold as a racemate by Pfizer under the tradenames Petinutin and Celontin...
) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.
Common
- suicidal tendencies
- drowsiness
- mental confusion
- insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
- nervousness
- headacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
- euphoriaEuphoria (emotion)Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy...
- ataxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
- hiccups
- impaired concentration
- irritability
- hyperactivity
- loss of taste
- night terrorNight terrorA night terror, also known as a sleep terror, incubus attack, or pavor nocturnus, is a parasomnia disorder that predominantly affects children, causing feelings of terror or dread, typically occur in the first few hours of sleep during stage 3 or 4 NREM sleep...
s
Rare
- paranoidParanoiaParanoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
psychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"... - increased libido
- exacerbation of depressionClinical depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
Gastrointestinal
- dyspepsiaDyspepsiaDyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
- vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
- 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...
- cramps
- constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
- 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...
- stomach pain
- loss of appetite
- weight loss
- gingival hyperplasiaHyperplasiaHyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
- swelling of tongue
Hematopoietic
The following can occur with or without bone marrow loss:- pancytopeniaPancytopeniaPancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
- agranulocytosisAgranulocytosisGranulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
- leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
- eosinophiliaEosinophiliaEosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.45×109/L . A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being...
Integumentary
- urticariaUrticariaUrticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
- systemic lupus erythematosusSystemic lupus erythematosusSystemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
- Stevens–Johnson syndrome
- hirsutismHirsutismHirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
- pruriticItchItch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
erythematous rashLupus erythematosusLupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
es
Drug interactions
ValproateValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
s can either decrease or increase the levels of ethosuximide; However, combinations of valproate
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
s and ethosuximide had a greater Protective Index
Protective index
The protective index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. Quantitatively, it is the ratio given by the toxic dose divided by the therapeutic dose. A protective index is the toxic dose of a drug for 50% of the...
than either drug alone.
It may elevate serum phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
levels.
Chemistry
Ethosuximide, 3-ethyl-3-methypyrrolidine-2,5-dione is synthesized from methylethylketone and cyanoacetic ester, which undergo a Knoevenagel condensationKnoevenagel condensation
The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the Aldol condensation.A Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule...
. Then hydrogen cyanide is added. After acidic hydrolysis and decarboxylation of the synthesized dinitrile, 2-methyl-2-ethylsuccinic acid is formed. Reacting this product with ammonia gives the diammonium salt, and heterocyclization into ethosuximide takes place during subsequent heating.
- L.M. Long, Ch.A. Miller, (1961).
- S.S.G. Sircar, J. Chem. Soc., 1252 (1927).
External links
- Ethosuximide Internet Mental Health.
- MedlinePlus Drug Information: Ethosuximide Oral
- Zarontin Pfizer.
- Zarontin Drug information, published studies and current trials