Article: Ethosuximide

Ethosuximide
Systematic (IUPAC) name
3-ethyl-3-methyl-pyrrolidine-2,5-dione
Identifiers
CAS number	77-67-8
ATC code	N03AD01
PubChem	3291
DrugBank	APRD00318
Chemical data
Formula	C7H11NO2
Mol. weight	141.168 g/mol
Pharmacokinetic data
Bioavailability	93%[1]
Metabolism	Hepatic (CYP3A4, CYP2E1)
Half life	53 hours
Excretion	Renal (20%)
Therapeutic considerations
Pregnancy cat.	D (Au, U.S.)
Legal status	℞-only (U.S.)
Routes	Oral

Ethosuximide is a succinimide anticonvulsant, used mainly in absence seizures. It is sold by Pfizer under the name Zarontin® and was once also sold under the name Emeside®, both of which were discontinued from the United Kingdom market in capsule form in November of 2005.^[2]

Uses

Approved

It is approved for absence seizures.^[3]

Unapproved

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

Mechanism of Action

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

In March of 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 μM to 1 mM.^[8]

That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mM.^[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 mM, 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 mM and that of N-desmethylmethsuximide (the active metabolite of mesuximide) is 1.95 ± 0.19 mM for α1G, 1.82 ± 0.16 mM for α1I, and 3.0 ± 0.3 mM 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 Effects

Central Nervous System

Common

• drowsiness
• mental confusion
• insomnia
• nervousness
• headache
• euphoria
• ataxia
• hiccups
• impaired concentration
• irritability
• hyperactivity
• loss of taste
• night terrors

Rare

• paranoid psychosis
• increased libido
• exacerbation of depression

Gastrointestinal

• dyspepsia
• vomiting
• nausea
• cramps
• constipation
• diarrhea
• stomach pain
• loss of appetite
• weight loss
• gingival hyperplasia
• swelling of tongue

Genitourinary

• microscopic hematuria
• vaginal bleeding

Hematopoietic

The following can occur with or without bone marrow loss:

• pancytopenia
• agranulocytosis
• leukopenia
• eosinophilia

Integumentary

• urticaria
• systemic lupus erythematosus
• Stevens-Johnson syndrome
• hirsutism
• pruritic erythematous rashes

Ocular

• myopia

Complications

• abnormal liver function

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.