|Oral (capsules, oral solution)|
|ATC code||N03AD01 (WHO)|
|Metabolism||Hepatic (CYP3A4, CYP2E1)|
|Biological half-life||53 hours|
|Chemical and physical data|
|Molar mass||141.168 g/mol|
|3D model (Jmol)||Interactive image|
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.
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.
Central nervous system
- stomach pain
- loss of appetite
- weight loss
- gum enlargement
- swelling of tongue
- microscopic hematuria
- vaginal bleeding
The following can occur with or without bone marrow loss:
- systemic lupus erythematosus
- Stevens–Johnson syndrome
- pruritic erythematous rashes
- abnormal liver function
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.
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.
- "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- "Concern over ethosuximide capsule discontinuation". Pharm J. Oct 29, 2005. p. 539. Retrieved 2008-08-31. (paywalled archive)
- "Zarontin capsules discontinued". Retrieved 2012-10-24.
- ^ Patsalos, P. N. (November 2005). "Properties of Antiepileptic Drugs in the Treatment of Idiopathic Generalized Epilepsies". Epilepsia. 46 (s9): 140–144. doi:10.1111/j.1528-1167.2005.00326.x. PMID 16302888.
- ^ 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.
- ^ Katzung, B., ed. (2003). "Drugs used in generalized seizures". Basic and Clinical Pharmacology (9th ed.). Lange Medical Books/McGraw-Hill. ISBN 0071410929.
- ^ Andrulonis, P. A.; J. Donnelly; B. C. Glueck; C. F. Stroebel; B. L. Szabek (November 1980). "Preliminary data on ethosuximide and the Episodic dyscontrol syndrome". American Journal of Psychiatry. 137 (11): 1455–6. PMID 7435689.
- ^ Coulter DA, Huguenard JR, Prince DA (Mar 13, 1989). "Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons". Neurosci Lett. 98 (1): 74–8. doi:10.1016/0304-3940(89)90376-5. PMID 2710401.
- ^ 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. PMID 2545161.
- ^ Coulter DA, Huguenard JR, Prince DA (August 1990). "Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction". British Journal of Pharmacology. 100 (4): 800–6. doi:10.1111/j.1476-5381.1990.tb14095.x. PMC . PMID 2169941.
- ^ 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. PMID 1336826.
- ^ 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. PMID 1325546.
- ^ Sayer RJ, Brown AM, Schwindt PC, Crill WE. "Calcium currents in acutely isolated human neocortical neurons." Journal of Neurophysiology. 1993 May;69(5):1596-606. PMID 8389832 Fulltext
- ^ Todorovic SM, Lingle CJ (January 1, 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. PMID 9425195.
- ^ Leresche N, Parri HR, Erdemli G, Guyon A, Turner JP, Williams SR, Asprodini E, Crunelli V (July 1, 1998). "On the action of the anti-absence drug ethosuximide in the rat and cat thalamus". Journal of Neuroscience. 18 (13): 4842–53. PMID 9634550.
- ^ Gomora JC, Daud AN, Weiergraber M, Perez-Reyes E (2001). "Block of cloned human T-type calcium channels by succinimide antiepileptic drugs". Molecular Pharmacology. 60 (5): 1121–32. PMID 11641441.
- ^ Bourgeois, BF (December 1988). "Combination of valproate and ethosuximide: antiepileptic and neurotoxic interaction". The Journal of Pharmacology and Experimental Therapeutics. 247 (3): 1128–32. PMID 3144596.