Ethosuximide, 2-ethyl-2-methylsuccinimide, has been used extensively for "petit mal"
seizures and it is a valuable agent in studies of
absence epilepsy. In the treatment of
epilepsy,
ethosuximide has a narrow therapeutic profile. It is the
drug of choice in the monotherapy or combination
therapy of children with generalized absence (
petit mal) epilepsy. Commonly observed side effects of
ethosuximide are dose dependent and involve the gastrointestinal tract and central nervous system.
Ethosuximide has been associated with a wide variety of idiosyncratic reactions and with hematopoietic adverse effects. Typical absence
seizures are generated as a result of complex interactions between the thalamus and the cerebral cortex. This thalamocortical circuitry is under the control of several specific inhibitory and excitatory systems arising from the forebrain and brainstem. Corticothalamic rhythms are believed to be involved in the generation of spike-and-wave discharges that are the characteristic electroencephalographic signs of absence
seizures. The spontaneous pacemaker oscillatory activity of thalamocortical circuitry involves low threshold T-type Ca2+ currents in the thalamus, and
ethosuximide is presumed to reduce these low threshold T-type Ca2+ currents in thalamic neurons.
Ethosuximide also decreases the persistent Na+ and Ca2+ -activated K+ currents in thalamic and layer V cortical pyramidal neurons. In addition, there is evidence that in a genetic
absence epilepsy rat model
ethosuximide reduces cortical
gamma-aminobutyric acid (
GABA) levels. Also, elevated
glutamate levels in the primary motor cortex of rats with
absence epilepsy (but not in normal animals) are reduced by
ethosuximide.