Ethosuximide

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 .

Approved

It is approved for absence seizures.

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. 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. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant 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 M to 1 mM.

That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2. mM. 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 % block of T-type current in dorsal root ganglia at .7 ± . mM, 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 % and the Ca2+-activated K+ currents by 9.1 ± 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 1, 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 &#;1G, &#;1H, and &#;1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC of 12 ± 2 mM and that of N-desmethylmethsuximide (the active metabolite of mesuximide) is 1. ± .19 mM for &#;1G, 1.82 ± .16 mM for &#;1I, and . ± . mM for &#;1H. 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
diarrhoea
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:

pancytopaenia
agranulocytosis
leukopaenia
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.

It may elevate serum phenytoin levels.

© Medic8 ® All Rights Reserved.