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| Trade names | Zarontin, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682327 |
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| Routes of administration | By mouth (capsules,solution) |
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| Pharmacokinetic data | |
| Bioavailability | 93%[3] |
| Metabolism | liver (CYP3A4,CYP2E1) |
| Eliminationhalf-life | 53 hours |
| Excretion | kidney (20%) |
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| ECHA InfoCard | 100.000.954 |
| Chemical and physical data | |
| Formula | C7H11NO2 |
| Molar mass | 141.170 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
| Melting point | 64 to 65 °C (147 to 149 °F) |
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Ethosuximide, sold under the brand nameZarontin among others, is a medication used to treatabsence seizures.[4] It may be used by itself or with otherantiseizure medications such asvalproic acid.[4] Ethosuximide is taken by mouth.[4]
Ethosuximide is usually well tolerated.[5] Common side effects include loss of appetite, abdominal pain, diarrhea, and feeling tired.[4] Serious side effects includesuicidal thoughts,low blood cell levels, andlupus erythematosus.[4][5] It is unclear if it has adverse effects on the fetus duringpregnancy.[4] Ethosuximide is in thesuccinimide family of medications. Its mechanism of action is thought to be due to antagonism of the postsynaptic T-type voltage-gated calcium channel.[6]
Ethosuximide was approved for medical use in the United States in 1960.[7] It is on theWorld Health Organization's List of Essential Medicines.[8] Ethosuximide is available as ageneric medication.[4] As of 2019[update], its availability was limited in many countries, with concerns aboutprice fixing in the United States.[9][10][11]
Ethosuximide is approved forabsence seizures,[12] and is considered the first choice medication for treating them, in part because it lacks the idiosyncratichepatotoxicity of the alternative anti-absence drug,valproic acid.[13]
As with other anticonvulsants, ethosuximide carries a warning about use during pregnancy. Although a causal relationship with birth defects has not be established, the potential for harm to the baby is weighed against the known harm caused by a mother having even minor seizures.[4]
The following can occur with or without bone marrow loss:
Valproates can either decrease or increase the levels of ethosuximide; however, combinations ofvalproates and ethosuximide had a greaterprotective index than either drug alone.[14]
It may elevate serumphenytoin levels.
The mechanism by which ethosuximide affects neuronal excitability includes block ofT-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.[citation needed] 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 anddimethadione, both effective anti-absence agents, reduced low-thresholdCa2+currents inT-type calcium channels in freshly removedthalamicneurons.[15] In June of that same year, they also found the mechanism of this reduction to bevoltage-dependent, using acutely dissociated neurons of rats and guinea pigs; it was also noted thatvalproic acid, which is also used in absence seizures, did not do that.[16] The next year, they showed that anticonvulsant succinimides did this and that thepro-convulsant ones did not.[17] The first part was supported byKostyuk et al. in 1992, who reported a substantial reduction in current indorsal rootganglia at concentrations ranging from 7 μmol/L to 1 mmol/L.[18]
That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L.[19] The year after, a study conducted on humanneocortical 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.[20]
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.[21] That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivatingNa+ 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.[22]
In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at theUniversity of Virginia inCharlottesville pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels.[23] Using clonedα1G,α1H, andα1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with anIC50 of 12 ± 2 mmol/L and that ofN-desmethylmethsuximide (the active metabolite ofmesuximide) 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.
Ethosuximide is a chiral drug with astereocenter. Therapeutically, theracemate, the 1: 1 mixture of ( S) and ( R) - isomers used.[24]
| Enantiomers of ethosuximide | |
|---|---|
-Ethosuximid_Structural_Formula_V1.svg) CAS-Number: 39122-20-8 | -Ethosuximid_Structural_Formula_V1.svg) CAS-Number: 39122-19-5 |
As of 2019 there were concerns in the United States that the price of ethosuximide was inflated by manufacturers.[11][25]
Availability of ethosuximide is limited in many countries.[9] It was 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.[26] Similarly, Zarontin capsules were discontinued byPfizer in 2007.[27] Syrup preparations of both brands remained available.
