Ethosuximide

Ethosuximide

Clinical data
Trade names	Zarontin
AHFS/Drugs.com	Monograph
MedlinePlus	a682327
Pregnancy category	AU: D
Routes of administration	by mouth (capsules, solution)
ATC code	N03AD01 (WHO)
Legal status
Legal status	US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	93%
Metabolism	liver (CYP3A4, CYP2E1)
Elimination half-life	53 hours
Excretion	kidney (20%)
Identifiers
IUPAC name (RS)-3-Ethyl-3-methyl-pyrrolidine-2,5-dione
CAS Number	77-67-8 Y
PubChem CID	3291
IUPHAR/BPS	7182
DrugBank	DB00593 Y
ChemSpider	3175 Y
UNII	5SEH9X1D1D
KEGG	D00539 Y
ChEBI	CHEBI:4887 Y
ChEMBL	ChEMBL696 Y
CompTox Dashboard (EPA)	DTXSID7023019
ECHA InfoCard	100.000.954
Chemical and physical data
Formula	C7H11NO2
Molar mass	141.168 g/mol g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
Melting point	64 to 65 °C (147 to 149 °F)
SMILES O=C1NC(=O)CC1(C)CC
InChI InChI=1S/C7H11NO2/c1-3-7(2)4-5(9)8-6(7)10/h3-4H2,1-2H3,(H,8,9,10) Y Key:HAPOVYFOVVWLRS-UHFFFAOYSA-N Y
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Ethosuximide, sold under the brand name Zarontin among others, is a medication used to treat absence seizures. It may be used by itself or with other antiseizure medications such as valproic acid. Ethosuximide is taken by mouth.

Side effects are generally minimal. Common side effects include loss of appetite, abdominal pain, diarrhea, and feeling tired. Serious side effects include suicidal thoughts, low blood cell levels, and lupus erythematosus. It is unclear if use during pregnancy or under the age of three is safe for the baby. Ethosuximide is in the succinimide family of medications. How exactly it works is unclear.

Ethosuximide was approved for medical use in the United States in 1960. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system. Ethosuximide is available as a generic medication.

Medical uses

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 acid.

Adverse effects

Central nervous system

Common

• drowsiness
• mental confusion
• insomnia
• headache
• ataxia

Rare

• paranoid psychosis
• increased libido
• exacerbation of depression

Gastrointestinal

• dyspepsia
• vomiting
• nausea
• cramps
• constipation
• diarrhea
• stomach pain
• loss of appetite
• weight loss
• gum enlargement
• swelling of tongue
• abnormal liver function

Genitourinary

• microscopic hematuria
• vaginal bleeding

Blood

The following can occur with or without bone marrow loss:

• pancytopenia
• agranulocytosis
• leukopenia
• eosinophilia

Skin

• urticaria
• systemic lupus erythematosus
• Stevens–Johnson syndrome
• hirsutism
• pruritic erythematous rashes

Eyes

• myopia

Drug interactions

Valproates can either decrease or increase the levels of ethosuximide; however, combinations of valproates and ethosuximide had a greater protective index than either drug alone.

It may elevate serum phenytoin levels.

Mechanism of action

The mechanism by which ethosuximide affects neuronal excitability includes block of T-type calcium channels, and may include effects of the drug on other classes of ion channel. The primary finding that ethosuximide is a T-type calcium channel blocker gained widespread support, but initial attempts to replicate the finding were inconsistent. Subsequent experiments on recombinant T-type channels in cell lines demonstrated conclusively that ethosuximide blocks all T-type calcium channel isoforms. Significant T-type calcium channel density occurs in dendrites of neurons, and recordings from reduced preparations that strip away this dendritic source of T-type calcium channels may have contributed to reports of ethosuximide ineffectiveness.

In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca²⁺ currents in T-type calcium channels in freshly removed thalamic neurons. In June of that same year, they also found the mechanism of this reduction to be voltage-dependent, using acutely dissociated 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 pro-convulsant 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 concentrations 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.

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 Pfizer in 2007. Syrup preparations of both brands remained available.

Stereochemistry

Ethosuximide is a chiral drug with a stereocenter. Therapeutically, the racemate, the 1: 1 mixture of ( S ) and ( R ) - isomers used.

Enantiomers of ethosuximide
CAS-Nummer: 39122-20-8	CAS-Nummer: 39122-19-5

See also

• Phensuximide
• Methsuximide

External links

• Ethosuximide Internet Mental Health.
• MedlinePlus Drug Information: Ethosuximide Oral
• Zarontin Pfizer.
• Zarontin Drug information, published studies and current trials