エトスクシミド

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Antiepileptics

Pharmaceuticals

log Kow = 0.38

0.1

0.23

Crystals from acetone and ether

WHITE TO OFF-WHITE CRYSTALLINE POWDER OR WAXY SOLID

Freely soluble in water

VERY SLIGHTLY SOL IN SOLVENT HEXANE

1.01e+02 g/L

Breast Feeding; Lactation; Milk, Human; Anticonvulsants

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Antiseizure medicines

64 - 65 °C

64.5 °C

Commercially available capsules have an expiration date of 5 years and the oral solution has an expiration date of 4 years following the date of manufacture.

Stable in light, air, and heat at 37 °C

Warning

H302 (95.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 46 reports by companies from 4 notifications to the ECHA C&L Inventory.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ethosuximide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Ethosuximide capsules should be stored in tight containers at a temperature less than 30 °C, preferably between 15-30 °C. Ethosuximide oral solution should be stored in tight, light-resistant containers at a temperature less than 30 °C, preferably between 15-30 °C; freezing should be avoided.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Treatment should include emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing) or gastric lavage, activated charcoal, cathartics, and general supportive measures. Hemodialysis may be useful to treat ethosuximide overdose. Forced diuresis and exchange transfusions are ineffective. (L1712)

... It is thus assumed that the probable mechanism of action of ethosuximide consists in lowering calcium transport since the inhibitors of calcium transport sodium nitroprusside and verapamil intensify the blocking effect of ethosuximide on smooth muscle contractile activity.

Concurrent use /with alcohol; central nervous system depression-producing medications; tricyclic antidepressants; loxapine; maprotiline; molindone; monoamine oxidase inhibitors; phenothiazines; pimozide; thioxanthenes/ may lower the convulsive threshold, enhance CNS depression, and decrease the effects of the anticonvulsant medication. /Succinimide anticonvulsants/

Requirements for folic acid may be increased in patients receiving anticonvulsant therapy. /Succinimide anticonvulsants/

Induction of hepatic microsomal enzyme activity resulting in increased metabolism and decreased serum concentrations and elimination half-lives of succinimide anticonvulsants and/or these medications /carbamazepine, phenobarbital, phenytoin, primidone/ may occur during concurrent therapy; monitoring of serum concentrations as a guide to dosage is recommended, especially when any anticonvulsant is added to or withdrawn from an existing regimen. /Succinimide anticonvulsants/

For more Interactions (Complete) data for ETHOSUXIMIDE (8 total), please visit the HSDB record page.

Prospective studies suggest that chronic ethosuximide therapy is not accompanied by significant elevations in serum aminotransferase levels, but can increase gamma glutamyltranspeptidase levels. Clinically apparent hepatotoxicity from ethosuximide is very rare with few case reports published despite use of this agent for half a century. Futhermore, the liver injury in reported cases was usually mild and asymptomatic and a part of a generalized hypersensitivity syndrome with fever, rash, facial edema, lymphadenopathy, and eosinophilia or atypical lymphocytosis. The usual latency to onset of the hypersensitivity syndrome is 2 to 8 weeks. The typical serum enzyme elevations are a mixed-cholestatic-hepatocellular pattern and reported cases have not been jaundiced. While the product labeling for ethosuximide warns of hepatic dysfunction and recommends periodic monitoring of liver tests, clinically apparent liver injury with jaundice from ethosuximide is rare.

The overall incidence of adverse effects associated with ethosuximide therapy is lower compared to most other anti-seizure medications (ASMs). Gastrointestinal adverse effects (eg, nausea, vomiting, diarrhea, anorexia) are common initially and often diminish within 2 weeks. Other common adverse effects include drowsiness, lethargy, insomnia, and hiccups. Headache may occur in 14% of children taking ethosuximide.

...The breast milk concentrations of ES were similar to those in maternal serum (milk/serum: 0.86 +/- 0.08, n = 12) and the nursed infants maintained serum levels between 15 and 40 micrograms/mL. ...

... Concentrations of ethosuximide in breast milk may approach 94% of plasma concentrations.

A total of 10 epileptic mothers treated with ethosuximide (ES) as well as their 13 newborns were included in this study. ... The breast milk concentrations of ES were similar to those in maternal serum (milk/serum: 0.86 +/- 0.08, n = 12) and the nursed infants maintained serum levels between 15 and 40 ug/mL. ...

Signs and Symptoms of Overdose

Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes.

/HUMAN EXPOSURE STUDIES/ A total of 10 epileptic mothers treated with ethosuximide (ES) as well as their 13 newborns were included in this study. At birth fetal/maternal serum concentration ratios were 0.97 +/- 0.02 (n = 7) and ES half-lives in three neonates were 32, 37 and 38 hr. The breast milk concentrations of ES were similar to those in maternal serum (milk/serum: 0.86 +/- 0.08, n = 12) and the nursed infants maintained serum levels between 15 and 40 ug/mL. Two major malformations (bilateral clefting, hare-lip) were observed in two neonates whose mothers received either ES/PB or ES/PMD comedication. The number of minor anomalies was higher in the ES group (6.2, n = 12) than in the pair-matched control group of infants born to non-epileptic mothers (2.1, n = 10). Neonatal behaviour complications occurred in seven infants, two of them were severely affected.

/HUMAN EXPOSURE STUDIES/ The use of ethosuximide has been reported in 163 pregnancies. Due to the lack of specific information on the observed malformations, mutiple drug therapies, and differences in study methodology, conclusions linking the use of ethosuximide with congenital defects are difficult. Spontaneous hemorrhage in the neonate following in utero exposure to ethosuximide has been reported. Abnormalities identified with ethosuximide use in 10 pregnancies include: patent ductus arteriosus (eight cases); cleft lip and/or palate (seven cases); mongoloid faces, short neck, altered palmar crease and accessory nipple (one case); hydrocephalus (one case).

/SIGNS AND SYMPTOMS/ Acute overdoses may produce nausea, vomiting, and CNS deppression including coma with respiratory depression. A relationship between ethosuximide toxicity and plasma levels has not been established.

/SIGNS AND SYMPTOMS/ The use of ethosuximide has also been associated with blood dyscrasias including leukopenia, eosinophilia, agranulocytosis, pancytopenia, (with or without bone marrow depression) and aplastic anemia which have sometimes resulted in fatalities.

For more Human Toxicity Excerpts (Complete) data for ETHOSUXIMIDE (13 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ethosuximide

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ethosuximide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N03AD01

N - Nervous system

QN - Nervous system

N03AD01

Used in the treatment of epilepsy. Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.

Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes.

Succinimide anticonvulsants are thought to increase the seizure threshold and suppress the paroxysmal three-cycle-per-second spike-and-wave pattern seen with absence (petit mal) seizures. The frequency of attacks is reduced by depression of nerve transmission in the motor cortex. These effects may be due to direct modification of membrane function in excitable cells and/or alteration of chemically mediated neurotransmission. The specific effect of ethosuximide against absence seizures appears to be due to its ability to block T-type calcium channels at concentrations that do not affect other ion channels. /Succinimide Anticonvulsants/

Ethosuximide reduces low threshold Ca(2+) currents (T currents) in thalamic neurons. The thalamus plays an important role in generation of 3 Hz spike-wave rhythms typical of absence seizures. Neurons in the thalamus exhibit a large amplitude T current spike that underlies bursts of action potentials and likely plays an important role in thalamic oscillatory activity such as 3 Hz spike-wave activity. At clinically relevant concentrations, ethosuximide inhibits the T current, as evident in voltage-clamp recordings in acutely isolated, ventrobasal thalamic neurons from rats and guinea pigs. Ethosuximide reduces this current without modifying the voltage dependence of steady-state inactivation or the time course of recovery from inactivation. By contrast, succinimide derivatives with convulsant properties do not inhibit this current. Ethosuximide does not inhibit sustained repetitive firing or enhance GABA responses at clinically relevant concentrations. Current data are consistent with the idea that inhibition of T currents is the mechanism by which ethosuximide inhibits absence seizures.

Ethosuximide is an alternative medicament that is used for coupling of petit mal, especially in childhood. Some clinical observations show that it has secondary effects on the gastro intestinal tract (GIT). The present research tries to define the characteristics of Ethosuximide--the inducted secondary effects on the GIT, and to explain some of the possible mechanisms that cause them. The changes that occur in the GIT of patients cured with Ethosuximide are registered roentgenologically. The main change is the atony of the stomach and intestines and the reduced peristaltic activity. The influence of Ethosuximide is examined on smooth muscular samples of human stomach, taken in vitro using stomach resection. The medicament authoritatively reduce the spontaneous bioelectrical activity of the smooth muscular tissue, influences mainly it's components that have Ca+ nature. Together with that is indicated relaxation of the smooth muscular samples. In that research is expressed the thesis that this Ethosuximide reduction of the Ca(+)-influx in the smooth muscular cells and the related relaxation probably are one of the main reasons of the secondary effects on the GIT.

Ethosuximide is one of the means of treatment of minor epilepsy but hardly any data on its mechanism of action are available in the literature. Anticonvulsant agents are known to bring about changes in the functions and in the interaction between some of the mediator systems within the central nervous system. An assessment of the status of neuromediator systems can be made on the basis of the response of isolated smooth muscle strips to the action of agonists and antagonists of various receptors. It was found by the pharmacological analysis of isolated strips from the rat stomach (antrum and corpus strips), the seminal duct and the cervical vein that ethosuximide induces a reduction in the physical contractile activity and the tone of smooth muscle preparations. Smooth muscle relaxation caused by ethosuximide is not blocked by different receptor inhibitors such as dihydroergotamine, propranolol, atropine, chlorpromazine, haloperidol and indomethacin. Ethosuximide causes a significant reduction in the physical contraction of smooth muscles produced by potassium chloride depolarization, with a stronger impact on the subsequent tonic contraction caused by calcium ions. A reduction in the potassium content of the solution has no effect on the nature of the action of ethosutimide. It is thus assumed that the probable mechanism of action of ethosuximide consists in lowering calcium transport since the inhibitors of calcium transport sodium nitroprusside and verapamil intensify the blocking effect of ethosuximide on smooth muscle contractile activity.

53 hours

A total of 10 epileptic mothers treated with ethosuximide (ES) as well as their 13 newborns were included in this study. At birth fetal/maternal serum concentration ratios were 0.97 +/- 0.02 (n = 7) and ES half-lives in three neonates were 32, 37 and 38 hr. ...

The plasma half-life of ethosuximide is about 60 hours in adults and about 30 hours in children.

A total of 10 epileptic mothers treated with ethosuximide (ES) as well as their 13 newborns were included in this study. At birth fetal/maternal serum concentration ratios were 0.97 +/- 0.02 (n = 7) and ES half-lives in three neonates were 32, 37 and 38 hr.

Hepatic, via CYP3A4 and CYP2E1.

... Metabolized by hepatic microsomal enzymes.

In rats, ethosuximide ... is metabolized into monohydroxyethosuximides, 2-ethyl-3-hydroxy-2-methyl-succinimide ... stereoisomeric 2-(1-hydroxyethyl)-2-methylsuccinimides & ... 2-(2-hydrox yethyl)-2-methylsuccinimide ... which are excreted, in urine, in free form and as ether glucuronides.

Different plasma profiles were obtained following admin of ethosuximide...to rat & man... Unchanged drug & only trace amt of metabolites were detected in rat plasma. In human plasma, diastereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide...were major components.

Ethosuximide is a chiral drug substance primarily indicated for the treatment of absence seizures. This drug is used clinically as the racemate. The human urinary metabolites of ethosuximide (I) have been studied using chiral gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). The metabolites identified were the previously reported unchanged ethosuximide (I) enantiomers, all four stereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide (II), and the four stereoisomers of 2-ethyl-3-hydroxy-2-methylsuccinimide (III). Through chemical derivatization methodology and GC/MS two enantiomers of a previously unreported metabolite of ethosuximide, 2-ethyl-2-hydroxymethylsuccinimide (VI), have been identified.

Hepatic, via CYP3A4 and CYP2E1. Half Life: 53 hours

5SEH9X1D1D

ETHOSUXIMIDE

Established Pharmacologic Class [EPC] - Anti-epileptic Agent

Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity

Ethosuximide is an Anti-epileptic Agent. The physiologic effect of ethosuximide is by means of Decreased Central Nervous System Disorganized Electrical Activity.

ETHOSUXIMIDE

Bioavailability following oral administration is 93%.

Ethosuximide is absorbed from the GI tract. Following oral administration of a single dose, peak blood concentrations are reached within 4 hours; however, about 4-7 days of therapy at usual dosage are required to achieve steady-state plasma concentrations. The plasma concentration required for therapeutic effect is generally considered to range from 40-100 ug/mL; plasma concentrations less than 40 ug/mL are rarely effective. The relationship between plasma ethosuximide concentrations and toxic effects of the drug has not been clearly established; however, plasma concentrations as high as 150 ug/mL have not been associated with signs of toxicity.

Absorption of ethosuximide appears to be complete, and peak concentrations occur in plasma within about 3 hr after a single oral dose. Ethosuximide is not significantly bound to plasma proteins; during long-term therapy, the concentration in the CSF is similar to that in plasma. The apparent volume of distribution averages 0.7 L/kg.

In vitro data suggest that there is no substantial degree of protein binding for ethosuximide. In one study in children, peak CSF concentrations of 25-50 ug/mL were achieved within 1-2 hours following a single 250-mg dose of ethosuximide. These concentrations were maintained for 12-24 hours, and the drug was still detectable in the CSF 65 hours after the drug was given.

Ethosuximide is excreted slowly in urine. Approximately 20% of a dose is excreted unchanged and up to 50% may be excreted in urine as the hydroxylated metabolite and/or its glucuronide. Small amounts of unchanged drug are also excreted in bile and feces.

For more Absorption, Distribution and Excretion (Complete) data for ETHOSUXIMIDE (9 total), please visit the HSDB record page.

Antiepileptic

THERAP CAT: Anticonvulsant

MEDICATION

For the treatment of petit mal epilepsy.

(1972) No Data

(1975) No Data

(1972) No Data

(1975) No Data

The condensation of butanone with cyano ethyl acetate and subsequent reaction with NaCN and H2SO4 gives 2-ethyl-2-methyl-succinic acid, which is ring-closed via the diammonium salt to yield ethosuximide.

Methyl ethyl ketone + ethyl cyanoacetate + hydrogen cyanide + ammonia (Cope reaction/addition/nitrile hydrolysis/decarboxylation/ester hydrolysis/amide formation)

ASAMID

ATYSMAL

CAPITUS

EMESIDE

For more Formulations/Preparations (Complete) data for ETHOSUXIMIDE (31 total), please visit the HSDB record page.