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Ethosuximide

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Ethosuximide chemical structure
Ethosuximide

3-ethyl-3-methyl-pyrrolidine-2,5-dione
IUPAC name
CAS number
77-67-8
ATC code

N03AD01

PubChem
3291
DrugBank
APRD00318
Chemical formula {{{chemical_formula}}}
Molecular weight 141.168 g/mol
Bioavailability 93%[1]
Metabolism Hepatic (CYP3A4, CYP2E1)
Elimination half-life 53 hours
Excretion Renal (20%)
Pregnancy category D (Au, U.S.)
Legal status ℞-only (U.S.)
Routes of administration Oral

Ethosuximide is a succinimide anticonvulsant, used mainly in absence seizures.

UsesEdit

ApprovedEdit

It is approved for absence seizures.[2] 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.[3]

UnapprovedEdit

It was reported to have been used for intermittent explosive disorder in 1980 by Drs Andrulonis, Donnelly, Glueck, Stroebel, and Szabek.[4]

DosageEdit

Therapeutic drug concentrations are individualized according to response and tolerance. Common Serum Therapeutic Range: 40-100 µg/mL. Potentially Toxic Serum Concentration: >100 µg/mL.

AvailabilityEdit

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.[1] Similarly, Zarontin capsules were discontinued by Pfizer in 2007. [2] Syrup preparations of both brands are still available.

Mechanism of actionEdit

There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the view that ethosuximide is a T-type calcium channel blocker gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.

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 Ca2+ channels in freshly removed thalamic neurons.[5] In June of that same year, they also found the mechanism of this reduction to be voltage-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid, which is also used in absence seizures, did not do that.[6] The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not.[7] 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.[8]

That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L.[9] 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.[10]

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.[11] 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.[12]

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.[13] 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.

Adverse effectsEdit

Central nervous systemEdit

CommonEdit

RareEdit

GastrointestinalEdit

GenitourinaryEdit

HematopoieticEdit

The following can occur with or without bone marrow loss:

IntegumentaryEdit

OcularEdit

ComplicationsEdit

Drug interactionsEdit

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.

ReferencesEdit

NotesEdit

  1. ^  Patsalos, P. N. (November 2005). Properties of Antiepileptic Drugs in the Treatment of Idiopathic Generalized Epilepsies. Epilepsia 46 (s9): 140–144.
  2. ^  Pharmaceutical Associates, Incorporated (2000). Ethosuximide Approval Label. (PDF) Label and Approval History. Food and Drug Administration Center for Drug Evaluation and Research. URL accessed on 2006-02-05.
  3. ^  "Drugs used in generalized seizures." Katzung, B. Basic and Clinical Pharmacology. 9th Ed. 2003. Lange Medical Books/McGraw-Hill.0071410929.
  4. ^  Andrulonis, P. A., J. Donnelly, B. C. Glueck, C. F. Stroebel, and B. L. Szabek (November 1980). Preliminary data on ethosuximide and the Episodic dyscontrol syndrome. American Journal of Psychiatry 137 (11): 1455–6.
  5. ^  Coulter DA, Huguenard JR, Prince DA. "Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons." Neurosci Lett. 1989 Mar 13;98(1):74-8. PMID 2710401
  6. ^  "Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons." Annals of Neurology. 1989 Jun;25(6):582-93. PMID 2545161
  7. ^  Coulter DA, Huguenard JR, Prince DA. "Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction." British Journal of Pharmacology. 1990 Aug;100(4):800-6. PMID 2169941
  8. ^  Kostyuk PG, Molokanova EA, Pronchuk NF, Savchenko AN, Verkhratsky AN. "Different action of ethosuximide on low- and high-threshold calcium currents in rat sensory neurons." Neuroscience. 1992 Dec;51(4):755-8. PMID 1336826
  9. ^  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.
  10. ^  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
  11. ^  Todorovic SM, Lingle CJ (Jan 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.
  12. ^  Leresche N, Parri HR, Erdemli G, Guyon A, Turner JP, Williams SR, Asprodini E, Crunelli V (Jul 1998). On the action of the anti-absence drug ethosuximide in the rat and cat thalamus. Journal of Neuroscience 18 (13): 4842–53.
  13. ^  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.
  14. ^  Bourgeois, BF (December 1988). Combination of valproate and ethosuximide: antiepileptic and neurotoxic interaction. The Journal of Pharmacology and Experimental Therapeutics 247 (3): 1128–32.

External linksEdit


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