Drug of Choice for Absence Seizures: Mechanism of Action
The correct answer is d) Inhibition of the T-type calcium channels—this is the mechanism of action of ethosuximide, the drug of choice for childhood absence seizures.
Ethosuximide as First-Line Treatment
Ethosuximide is the drug of choice for monotherapy of childhood absence epilepsy (petit mal seizures), controlling approximately 70% of absence seizures. 1, 2
- The drug specifically targets the pathophysiology of absence seizures by suppressing the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness 1
- It reduces the frequency of epileptiform attacks by depressing the motor cortex and elevating the threshold of the central nervous system to convulsive stimuli 1
Mechanism of Action: T-Type Calcium Channel Blockade
Ethosuximide primarily works by reducing low threshold T-type Ca²⁺ currents in thalamic neurons, which are critical for generating the abnormal thalamocortical rhythms seen in absence seizures. 3, 4
- The drug specifically targets T-type calcium channels in thalamocortical circuitry, which are involved in generating spike-and-wave discharges characteristic of absence seizures 3
- Research demonstrates that T-type calcium channel blockers potently suppress absence seizures by 85-90% through attenuation of burst firing in thalamic reticular nucleus neurons 5
- Ethosuximide also decreases persistent Na⁺ and Ca²⁺-activated K⁺ currents in thalamic and cortical pyramidal neurons 3
Additional Mechanisms
Beyond T-type calcium channel inhibition, ethosuximide has secondary effects:
- It increases GABA release in cortical networks, elevating the ratio of network inhibition to excitation 6
- The drug reduces cortical GABA levels in genetic absence epilepsy models and decreases elevated glutamate levels in the primary motor cortex 3
Why Other Options Are Incorrect
Option a) Sodium and calcium channel blockade describes drugs like valproate or lamotrigine, which are broader-spectrum agents 2
Option b) GABA uptake inhibition describes the mechanism of tiagabine, not ethosuximide 7
Option c) GABA potentiation describes benzodiazepines or barbiturates, which are not first-line for absence seizures 7
Clinical Considerations
- Ethosuximide has a narrow therapeutic profile and is specifically indicated for absence seizures 3
- It is unsuitable as monotherapy if other generalized seizures (tonic-clonic or myoclonic) coexist, as it only controls absence seizures 2
- Valproic acid may be preferred when multiple seizure types are present, as it controls absences (75%), generalized tonic-clonic seizures (70%), and myoclonic jerks (75%) 2
- Common side effects are dose-dependent and involve the gastrointestinal tract and central nervous system 3