Ethosuximide is a first-line drug for the treatment of generalized absence seizures. It can be used as monotherapy unless generalized tonic-clonic seizures are also present, in which case valproate is preferred or ethosuximide can be combined with another drug effective against generalized tonic-clonic seizures.
Ethosuximide was introduced in 1958 as the third of three marketed succinimides; the other two, phensuximide and methsuximide, are rarely used. Ethosuximide and methsuximide have asymmetric carbons (asterisks in below figure) and are used as racemates.
Mechanism of Action
Ethosuximide is thought to act by inhibition of low-voltageactivated T-type calcium channels in thalamocortical neurons that underlie the 3-Hz spike-wave discharges of generalized absence seizures. Other ion channels affected include voltage-gated sodium channels, calcium-activated potassium channels, and inward rectifier potassium channels; these actions may contribute to the efficacy of ethosuximide in absence epilepsy.
Studies in the mid-1970s provided evidence that monotherapy with ethosuximide is effective in the treatment of childhood generalized absence seizures. There is also evidence that it is effective in the treatment of atypical absence and epileptic negative myoclonus, a rare seizure type characterized by interruption of ongoing electromyographic activity contralateral to a lateralized spike-and-wave discharge. If ethosuximide in monotherapy does not lead to seizure control, the drug can be used in combination with valproate or other agents such as benzodiazepines.
Absorption is complete following administration of the oral dosage forms. Peak levels are observed 3–7 hours after oral administration of the capsules. Ethosuximide is not protein bound. During longterm administration, approximately 20% of the dose is excreted unchanged by the kidney. The remaining drug is metabolized in the liver, principally by CYP3A hydroxylation, to inactive metabolites. Ethosuximide has a very low total body clearance (0.25 L/kg/d). This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported.
In children, a common starting dose is 10–15 mg/kg/d, with titration according to clinical response to a maintenance dose of 15–40 mg/kg/d. In older children and adults, the initial dose is 250 or 500 mg/d, increasing in 250-mg increments to clinical response to a maximum of 1500 mg/d. While dosing is based on titration to maximal seizure control with acceptable tolerability, the accepted therapeutic serum concentration range is 40–100 mcg/mL (although plasma levels up to 150 mcg/mL may be necessary and tolerated in some patients). There is a linear relationship between ethosuximide dose and steady-state plasma levels. While the long half-life could allow once-daily dosing, ethosuximide is generally administered in two or even three divided doses to minimize adverse gastrointestinal effects.
Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations owing to inhibition of ethosuximide metabolism. No other important drug interactions have been reported. The most common dose-related adverse effect of ethosuximide is gastric distress, including pain, nausea, and vomiting. When an adverse effect does occur, temporary dosage reductions may allow adaptation. Other dose-related adverse effects are transient lethargy or fatigue and, much less commonly, headache, dizziness, hiccup, and euphoria. Behavioral changes are usually in the direction of improvement. Non-dose-related or idiosyncratic adverse effects of ethosuximide are extremely uncommon.