Antiarrhythmic and Proarrhythmic Potential of Pharmacological Agents
Authors: Naveed Muhammad 
Published: July 2023

Antiarrhythmic therapy in general has a problem ‘especially in the treatment
of ventricular arrhythmias’ that the compounds have proarrhythmic potential
which is due to the same cellular mechanism that is responsible for their
antiarrhythmic properties. Drug-induced arrhythmia can be attributed to either
excessive conduction slowing (e.g. with class Ia or Ic Na+ channel blockers) or
excessive prolongation of ventricular action potential duration (APD) (e.g. with
class III antiarrhythmic agents), or both. The aim of the presents study was to
investigate the antiarrhythmic and proarrhythmic potential of some
pharmacological agents. We therefore thoroughly investigated and compared the
kinetics of these Na+ channel blockers to provide further experimental data and
to differentiate between their antiarrhythmic and proarrhythmic properties. In
the present study, conventional microelectrode and patch clamp techniques were
used to measure the action potential (AP) parameters and the transmembrane ionic
currents underlying the AP, respectively. The results show that GS967 inhibits
INaP similarly to the class Ib antiarrhythmic drug mexiletine, but with higher
potency and three fold faster offset kinetics. Both GS967 and mexiletine
significantly depressed V+max at high stimulation rates. Flecainide lengthened
APD only at faster stimulation frequencies having cycle length (CL) shorter than
500 ms and increased the APDs of early extrasystoles noticeably. Moreover,
flecainide reduced V+max in the entire frequency range exhibiting much slower
offset kinetics than mexiletine. Similarly, quinidine depressed V+max
use-dependently showing slower offset kinetics than mexiletine. Although,
quinidine slowed the restitution kinetics of APD, however, it exhibited a
reverse rate-dependent prolongation on APD90. In addition, acute
desethylamiodarone (DEA) administration exerted a mild but not reverse
rate-dependent APD90 prolongation and significant V+max inhibition at short CLs.
Furthermore, cannabidiol lengthened APD90 significantly at the concentration of
5 µM without changing any other AP parameter significantly. These findings
suggest that the frequency dependence, restitution kinetics and onset kinetics
are important electrophysiological determinants which can discriminate Na+
channel blockers with proarrhythmic and antiarrhythmic potential. Moreover, the
current data suggest that compounds which do not block impulse conduction at
normal heart rate and have a fast recovery such as mexiletine and GS967, can be
promising for future drug development. Also the interesting big APD lengthening
effect on the early extrasystole observed with flecainide would be probably
useful but the effect on sodium current at normal heart rate can be potentially
proarrhythmic. Furthermore, the absence of an increase in dispersion of
ventricular repolarization with DEA correlates with its clinically observed
lower incidence of proarrhythmia. In addition, the physicians should be aware in
recognizing of the deleterious effects of compounds that affect the
repolarization reserve in co-morbid or polypharmacy patient.