Electrocardiographic analysis of cardiac effects of anticonvulsant doses of digoxin and its combinations with sodium valproate and carbamazepine in rats

Abstract

Treatment of drug-resistant epilepsy is a complex problem, one of the ways to solve which may be the use of adjuvants that enhance the effects of antiepileptic drugs (AEDs). Such adjuvants include digoxin in subcardiotonic doses. Clinically, positive experience of its use is accumulating, a number of mechanisms have been investigated in the experiment and the most effective combinations with classical AEDs have been identified. The question arises about the effect of anticonvulsant doses of digoxin on the heart. The aim of the study – to determine the effect of digoxin in an anticonvulsant dose per se and in combination with sodium valproate and carbamazepine on the ECG in rats. The experiments were conducted using albino male rats, in which ECG was recorded under thiopental
induced anesthesia. Animals of group 1 at the beginning of the experiment served as vehicle control (baseline ECG was recorded), after which digoxin 0.57 mg/kg was administered intraperitoneally (i.p.) and after 25–30 min its effect on electrophysiological parameters of cardiac function was determined. For this purpose, animals of group 2 were administered sodium valproate 215 mg/kg i.p., anesthesia was given 20–25 min later, ECG was recorded 5 min after its onset (intrinsic effect of valproate), digoxin was administered and after another 25–30 min ECG was recorded again (effect of the combination). In rats of group 3, the electrocardiographic effects of carbamazepine 28.6 mg/kg intragastrically and its combination with digoxin were determined according to a similar protocol. The indicated doses were calculated from effective anticonvulsant doses for mice (digoxin 0.8 mg/kg, sodium valproate 300 mg/kg, carbamazepine 40 mg/kg) using the species stability coefficient. ECG was recorded in the II standard lead on the ЕСІТ03М2 device with needle electrodes. Standard ECG parameters were measured, and the systolic index (SI) was determined as the ratio of the QT interval to the RR cardiac cycle duration (QT/RR, %). It was established that digoxin in an anticonvulsant dose does not cause dangerous ECG abnormalities in rats anesthetized with thiopental sodium: its effect is limited to moderate bradycardia within the species norm of heart rate (HR) – a decrease on 12% (p < 0.05) and a tendency to increase in the PQ interval by 4 ms (8%), the QT interval by 4 ms (5%). Sodium valproate does not cause changes in ECG parameters, and when used against the background of digoxin, the decrease in heart rate is 14% (p < 0.05), the PQ interval increases by an average of 8 ms (16%, p < 0.05), the QT interval – by 6 ms (8%, p < 0.05). Carbamazepine also does not affect ECG parameters, and when combined with digoxin, the heart rate is reduced insignificantly by 9%, the PQ intervals tend to increase by 5 ms (10%) and QT by 5 ms (7%). SI with the combined use of digoxin and carbamazepine significantly decreases by 3.7% (p < 0.05), which indicates an increase in cardiac contractile function. Thus, no dangerous effects of digoxin in an anticonvulsant dose of 0.57 mg/kg on the ECG of rats were detected, only moderate bradycardia occurs. When combining digoxin with sodium valproate, more pronounced bradycardia is observed than under the influence of digoxin per se, a significant slowdown of atrioventricular conduction and prolongation of the QT interval, which requires electrocardiographic monitoring. When combining digoxin with carbamazepine, significant bradycardia and prolongation of the PQ and QT intervals are not observed.