Predicting drug‐induced slowing of conduction and pro‐arrhythmia: identifying the ‘bad’ sodium current blockers

Abstract

Background and purpose:The regulatory guidelines (ICHS7B) for the identification of only drug-induced long QT and pro-arrhythmias have certain limitations. Experimental approach: Conduction time (CT) was measured in isolated Purkinje fibres, left ventricular perfused wedges and perfused hearts from rabbits, and sodium current was measured in Chinese hamster ovary cells, transfected with Nav1.5 channels. Key results: A total of 355 compounds were screened for their effects on CT: 32% of these compounds slowed conduction, 65% had no effect and 3% accelerated conduction. Lidocaine and flecainide, which slow conduction, were tested in more detail as reference compounds. In isolated Purkinje fibres, flecainide largely slowed conduction and markedly increased triangulation, while lidocaine slightly slowed conduction and did not produce significant triangulation. Also in isolated left ventricular wedge preparations, flecainide largely slowed conduction in a rate-dependent manner, and elicited ventricular tachycardia (VT). Lidocaine slightly slowed conduction, reduced Tp-Te and did not induce VT. Similarly in isolated hearts, flecainide markedly slowed conduction, increased Tp-Te and elicited VT or ventricular fibrillation (VF). The slowing of conduction and induction of VT/VF with flecainide was much more evident in a condition of ischaemia/reperfusion. Lidocaine abolished ischaemia/reperfusion-induced VT/VF. Flecainide blocked sodium current (INa) preferentially in the activated state (i.e. open channel) with slow binding and dissociation rates in a use-dependent manner, and lidocaine weakly blocked INa. Conclusion and implications: Slowing conduction by blocking INa could be potentially pro-arrhythmic. It is possible to differentiate between compounds with 'good' (lidocaine-like) and 'bad' (flecainide-like) INa blocking activities in these models.

A Computational Model to Predict the Effects of Class I Anti-Arrhythmic Drugs on Ventricular Rhythms

“…Cells were stimulated at 80 BPM with concentrations of flecainide (left panel, 0.5 and 2 μM) (16) and lidocaine (right panel, 5 and 20 μM) corresponding to low and high clinical doses (16). High-dose lidocaine (20 μM) maintained upstroke velocity above 315 V/s, consistent with experiments (27), suggesting that therapeutic lidocaine minimally affects cardiac excitation. Therapeutic flecainide had disparate effects on excitability; 0.5 μM resembled lidocaine, whereas 2 μM substantially reduced upstroke velocity (<285 V/s).…”

Engineered heart slices for electrophysiological and contractile studies

“…We found a 19% and 14% decrease in CV at 2 Hz by 90 µM lidocaine in the longitudinal and transverse directions, respectively (Fig. 8C), which is similar to the reported ~19% increase in conduction time at 1 Hz by 100 µM lidocaine in Langendorff-perfused rabbit hearts [42], although direct comparison of these values is complicated by the different models and pacing rates. Additionally, we found more fractional slowing in the longitudinal direction (Fig.…”

Pharmacology and Toxicology of Nav1.5-Class 1 Antiarrhythmic Drugs

“…One report suggested that drugs for which the maximum expected plasma concentration was at least thirtyfold lower than the concentration required to block 50% of sodium current was an acceptable safety margin. 54 However, the blocking potency of drug as a function of voltage or rate was not explicitly considered. Further, animal studies have indicated that the relationship between sodium current recorded in a cardiomyocyte and fast conduction may be dissociated with specific mutations in the channel itself 55 or altered function of proteins such as dystrophin and SAP97 that guide its delivery to specific subdomains in the cell.…”