Ethosuximide

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Ethosuximide
Clinical data
Trade namesZarontin, others
AHFS/Drugs.comMonograph
MedlinePlusa682327
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth (capsules, solution)
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances)[1]
  • US: ℞-only
  • EU: Rx-only[2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability93%[3]
Metabolismliver (CYP3A4, CYP2E1)
Elimination half-life53 hours
Excretionkidney (20%)
Identifiers
  • (RS)-3-Ethyl-3-methyl-pyrrolidine-2,5-dione
JSmol)
ChiralityRacemic mixture
Melting point64 to 65 °C (147 to 149 °F)
  • O=C1NC(=O)CC1(C)CC
  • InChI=1S/C7H11NO2/c1-3-7(2)4-5(9)8-6(7)10/h3-4H2,1-2H3,(H,8,9,10) checkY
  • Key:HAPOVYFOVVWLRS-UHFFFAOYSA-N checkY
  (verify)

Ethosuximide, sold under the brand name Zarontin among others, is a medication used to treat

valproic acid.[4] Ethosuximide is taken by mouth.[4]

Ethosuximide is usually well tolerated.

suicidal thoughts, low blood cell levels, and lupus erythematosus.[4][5] It is unclear if it has adverse effects on the fetus during pregnancy.[4] Ethosuximide is in the succinimide 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.

generic medication.[4] As of 2019 its availability was limited in many countries with concerns of price fixing in the United States.[9][10][11]

Medical uses

It is approved for

valproic acid.[13]

Adverse effects

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]

Central nervous system

Common

Rare

Gastrointestinal

Genitourinary

Blood

The following can occur with or without bone marrow loss:

Skin

Eyes

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.[14]

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.[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 and

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.[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 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.[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 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.[22]

In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the

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.

Stereochemistry

Ethosuximide is a chiral drug with a

racemate, the 1: 1 mixture of ( S ) and ( R ) - isomers used.[24]

Enantiomers of ethosuximide

CAS-Nummer: 39122-20-8
CAS-Nummer: 39122-19-5

Society and culture

Cost

As of 2019 there were concerns in the United States that the price of ethosuximide was inflated by manufacturers.[11][25]

Availability

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 by Pfizer in 2007.[27] Syrup preparations of both brands remained available.

See also

References

  1. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ^ "List of nationally authorised medicinal products" (PDF). European Medicines Agency.
  3. S2CID 19462889
    .
  4. ^ a b c d e f g h "Ethosuximide". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  5. ^
    ISBN 9789241547659
    .
  6. PMID 15309165
    .
  7. ^ "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration. Retrieved 29 December 2020.
  8. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. ^
    ISBN 978-0-444-64067-3
    .
  10. ^ "Attorney General Tong leads 44-state coalition in antitrust lawsuit against Teva Pharmaceuticals, 19 other generic drug manufacturers, 15 individuals in conspiracy to fix prices and allocate markets for more than 100 different generic drugs" (Press release). Office of the Attorney General of the State of Connecticut. 12 May 2019. Retrieved 5 April 2020.
  11. ^ a b "States sue generic drug makers, claiming a conspiracy to fix prices". consumeraffairs.com. 14 May 2019. Retrieved 5 April 2020.
  12. ^ Pharmaceutical Associates, Incorporated (2000). "Ethosuximide Approval Label" (PDF). Label and Approval History. Food and Drug Administration Center for Drug Evaluation and Research. Retrieved 2006-02-05.
  13. ISBN 0071410929
    .
  14. PMID 3144596
    .
  15. S2CID 13413993
    .
  16. S2CID 20670160
    .
  17. PMID 2169941
    .
  18. S2CID 41451332
    .
  19. PMID 1325546
    .
  20. PMID 8389832
    .
  21. PMID 9425195
    .
  22. PMID 9634550
    .
  23. S2CID 7098669
    .
  24. ISBN 978-3-946057-10-9
    , S. 182.
  25. ^ Staff, WMBF News. "South Carolina joins lawsuit against manufacturers in alleged conspiracy to fix prescription drug prices". wmbfnews.com. Retrieved 5 April 2020.
  26. ^ "Concern over ethosuximide capsule discontinuation". Pharm J. 275: 539. Oct 29, 2005. Archived from the original on 2008-10-13. Retrieved 2008-08-31. (paywalled archive)
  27. ^ "Zarontin capsules discontinued". Archived from the original on 2012-06-26. Retrieved 2012-10-24.
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