|Trade names||Zarontin, others|
|By mouth (capsules, solution)|
|Defined daily dose||1.25 grams|
|Metabolism||liver (CYP3A4, CYP2E1)|
|Elimination half-life||53 hours|
|Chemical and physical data|
|Molar mass||141.170 g·mol−1|
|3D model (JSmol)|
|Melting point||64 to 65 °C (147 to 149 °F)|
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. Ethosuximide is available as a generic medication. As of 2004 it was generally affordable in most areas of the world. As of 2019 its availability was limited in many countries with concerns of price fixing in the United States.
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
- abnormal liver function
- microscopic hematuria
- vaginal bleeding
The following can occur with or without bone marrow loss:
- systemic lupus erythematosus
- Stevens–Johnson syndrome
- pruritic erythematous rashes
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.
|Enantiomers of ethosuximide|
Society and culture
This section's factual accuracy is disputed. (March 2020) (Learn how and when to remove this template message)
Ethosuximide, along with phenobarbital and phenytoin, is one of the few antiepileptic medications that people can generally afford in most areas of the world as of 2004.[disputed ] The wholesale cost from an NGO in the Democratic Republic of Congo is about US$28 per month for the defined daily dose of 1,250 mg as of 2014.[disputed ]
In the United States the wholesale cost of this amount is about US$96 per month as of 2019.[disputed ] With discounts this amount may be purchased for around US$57 in the United States. As of 2019 there were concerns in the United States that the price of ethosuximide was inflated by manufacturers.
In Italy the retail price of 750 mg per day for a year was about 133 Euro in 2011.[disputed ] In the United Kingdom the syrup formulation in 2011 was less expensive than the tables on a per mg basis (£0.68 per 250 mg tablet versus £0.11 per 250 mg of liquid).[disputed ]
Availability of ethosuximide is limited in many countries. 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. Similarly, Zarontin capsules were discontinued by Pfizer in 2007. Syrup preparations of both brands remained available.
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- 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.19188.8.131.52. PMID 1325546.
- 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.19184.108.40.2066. PMID 8389832.
- 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.19220.127.116.11. PMID 9425195.
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Capsules, ethosuximide 250 mg, net price 56-cap pack = £38.23. Zarontin, ethosuximide oral solution, 250 mg/5 ml, net price 200 ml pack = £4.22. (Costs taken from the Electronic drugs tariff, November 2011).CS1 maint: discouraged parameter (link)
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- "Zarontin capsules discontinued". Archived from the original on 2012-06-26. Retrieved 2012-10-24.