Ethosuximide is usually well tolerated.[5] Common side effects include loss of appetite, abdominal pain, diarrhea, and feeling tired.[4] Serious side effects include 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 is approved for absence seizures,[12] and is considered the first choice medication for treating them, in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug, 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]
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]
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 dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+currents in T-type calcium channels in freshly removed thalamicneurons.[15] 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.[16] The next year, they showed that anticonvulsant succinimides did this and that the pro-convulsant ones did not.[17] The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal 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 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 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.[23] 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.
Stereochemistry
Ethosuximide is a chiral drug with a stereocenter. Therapeutically, the 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.
^ abcdefgh"Ethosuximide". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Katzung, B., ed. (2003). "Drugs used in generalized seizures". Basic and Clinical Pharmacology (9th ed.). Lange Medical Books/McGraw-Hill. ISBN0071410929.
^Bourgeois BF (December 1988). "Combination of valproate and ethosuximide: antiepileptic and neurotoxic interaction". The Journal of Pharmacology and Experimental Therapeutics. 247 (3): 1128–32. PMID3144596.
^Coulter DA, Huguenard JR, Prince DA (March 1989). "Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons". Neuroscience Letters. 98 (1): 74–8. doi:10.1016/0304-3940(89)90376-5. PMID2710401. S2CID13413993.
^Coulter DA, Huguenard JR, Prince DA (June 1989). "Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons". Annals of Neurology. 25 (6): 582–93. doi:10.1002/ana.410250610. PMID2545161. S2CID20670160.
^Kostyuk PG, Molokanova EA, Pronchuk NF, Savchenko AN, Verkhratsky AN (December 1992). "Different action of ethosuximide on low- and high-threshold calcium currents in rat sensory neurons". Neuroscience. 51 (4): 755–8. doi:10.1016/0306-4522(92)90515-4. PMID1336826. S2CID41451332.
^Herrington J, Lingle CJ (July 1992). "Kinetic and pharmacological properties of low voltage-activated Ca2+ current in rat clonal (GH3) pituitary cells". Journal of Neurophysiology. 68 (1): 213–32. doi:10.1152/jn.1992.68.1.213. PMID1325546.
^Sayer RJ, Brown AM, Schwindt PC, Crill WE (May 1993). "Calcium currents in acutely isolated human neocortical neurons". Journal of Neurophysiology. 69 (5): 1596–606. doi:10.1152/jn.1993.69.5.1596. PMID8389832.
^Todorovic SM, Lingle CJ (January 1998). "Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents". Journal of Neurophysiology. 79 (1): 240–52. doi:10.1152/jn.1998.79.1.240. PMID9425195.
^Gomora JC, Daud AN, Weiergräber M, Perez-Reyes E (November 2001). "Block of cloned human T-type calcium channels by succinimide antiepileptic drugs". Molecular Pharmacology. 60 (5): 1121–32. doi:10.1124/mol.60.5.1121. PMID11641441. S2CID7098669.
^Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN978-3-946057-10-9, S. 182.
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