The similarity of ethosuximide, 2-ethyl-2-methylsuccinimide (Fig. 1), to other traditional antiepileptic drugs (AEDs) with a five- or six-membered heterocyclic ring structure is apparent, with a nitrogen atom located between two carbonyl groups. Unlike most, however, it is highly water-soluble. It has one asymmetric carbon and is used in its racemic form.²² It is a crystalline powder or a waxy solid, sold as a liquid-filled capsule (250 mg) or as syrup (250 mg/5 mL). High-performance liquid chromatography can be used to measure plasma levels.²⁸

Ethosuximide’s efficacy against absence seizures is consistent with its potency in several chemical convulsant models, particularly pentylenetetrazol, as opposed to the maximal electroshock model.¹⁴ It is also successful in other models believed to mimic absence seizures, including systemic penicillin, intravenous γ-hydroxybutyrate, intraventricular leucine-enkephalin, and spontaneous seizures in selected genetically epilepsy-prone rodents (Strasbourg), and as well experimental seizures induced by fluorothyl, enflurane, barbiturate withdrawal, and cortical estrogen or cobalt.^14,19,21,25 On the other hand, ethosuximide is relatively ineffective against seizures induced by bicuculline, strychnine, aminophylline, kainic acid, and N-methyl-D-aspartate, as well as cortical aluminum or amygdaloid kindling.^14,21,25

Low-threshold, “transient” (T-type) calcium (Ca) channels on thalamic neurons seem to play a critical role in the thalamocortical interactions that underlie the 3-Hz spike-and-wave pattern characteristic of absence seizures.^14,19 Ethosuximide blocks the low-threshold Ca current mediated by these channels in a voltage-dependent manner, such that the degree of current blockade increases at more hyperpolarized conditions.^8,14,25 That this mechanism is adequate to decrease abnormal thalamocortical excitability without affecting normal, tonic thalamic cell activity has been demonstrated in a computer simulation.¹⁷ Dimethadione, another specific antiabsence drug, also blocks these currents at therapeutically relevant concentrations, whereas carbamazepine and phenytoin do not,^8,19 and valproate does so to a much lesser degree.¹⁹ Ethosuximide also has other potentially important ionic effects, such as partial blockade of noninactivating sodium (Na) currents and Ca-dependent potassium (K) channels.^14,16

Although the main effect of Ca-current blockade appears to be a decrease in thalamocortical excitation, ethosuximide may also interfere with rhythmic inhibitory activity,^11,14 which appears to be important in generating absence seizures.² Effects on neurotransmitter synthesis, metabolism, or action do not seem to underlie these effects, but the effects on T-type Ca channels discussed earlier could be responsible.^8,14

Absorption after oral administration is essentially complete, and peaks 3 to 5 hours after ingestion of the capsule;²² absorption occurs slightly more quickly in acute than in long-term administration, and with the syrup as opposed to the capsule formulation. No significant first-pass metabolism occurs.

Because of ethosuximide’s high water solubility, its volume of distribution is high, estimated at 0.7 L/kg.²² Concentrations in adipose tissue are about one-third of those in plasma.²² Ethosuximide rapidly crosses the blood–brain barrier, and equilibration between plasma and cerebrospinal fluid occurs in 20 to 30 minutes; this is three to four times as rapid as for valproate, phenobarbital, phenytoin, or carbamazepine.²² Concentration is uniform within the brain. Because ethosuximide is not significantly protein-bound, cerebrospinal, salivary, and lacrimal concentrations are similar to those of plasma. Breast milk has only slightly lower concentrations, with a milk-to-plasma ratio of 0.8 to 0.9.^15,22

During long-term administration, approximately 20% of the dose is excreted renally unchanged, with the remainder
hepatically metabolized to inactive compounds via the cytochrome P450/mixed-function oxidase system, principally CYP3A.^1,22 These reactions include mainly hydroxylation of the ethyl side chain in either the 1- or 2- position (see Fig. 1), with metabolites conjugated predominantly with glucuronic acid and then excreted in the urine. Elimination of ethosuximide follows first-order kinetics.²² In adults, serum half-life is approximately 40 to 60 hours, with substantial variation between individuals; in children and newborns, half-life is slightly shorter, 30 to 40 hours.^15,22 Levels during pregnancy may fall, but not as much as those of some other drugs.^15,22 Although autoinduction of metabolism has been demonstrated in rats, this process probably does not occur in humans.²²

There is little data on ethosuximide concentrations in hepatic or renal disease, but increases would be expected. Ethosuximide is dialyzable, with an estimate of a 50% decrease in levels over a 6-hour dialysis session.²²

Given ethosuximide’s relatively long half-life, it takes 7 to 12 days of administration to reach steady-state plasma levels, and little variation is noted between peaks and troughs, even with once-daily administration,²² although it is usually administered twice a day. Average daily doses are 15 to 40 mg/kg to achieve the usual therapeutic range of 40 to 100 μg/mL. Although the dose-level relationship is generally linear within the usual dose range, there is evidence of saturation kinetics in some patients.²² Among 33 patients with complete control of absence seizures, 91% had levels of at least 40 μg/mL.²⁹