A critical reconsideration of the clinical effects and treatment recommendations for sodium channel blocking drug cardiotoxicity

Abstract

The cardiac sodium channel is comprised of proteins that span the cardiac cell membrane and form the channel pore. Depolarisation causes the proteins to move and open the sodium channel. Once the channel is open (active conformation), sodium ions move into the cell. The channel then changes from the active conformation to an inactive conformation - the channel remains open, but influx of sodium ions ceases. Recovery occurs as the channel moves from the inactive conformation back to the closed conformation and is then ready to open following the next depolarisation. Sodium channel blocking drugs (NCBDs) occupy receptors in the channel during the active and inactive conformations. The drug dissociates from most of the channel receptors during recovery, but the time it takes the drug to dissociate slows recovery. The slowed recovery prolongs conduction time, the main toxicity of NCBD overdose. Conduction time is further prolonged if heart rate increases as there are more available active and inactive conformations/unit time, which increases channel receptor binding sites for the NCBD. In addition to prolonging conduction time, NCBDs also decrease inotropy. Treatment of NCBD cardiotoxicity has been based on in vitro and animal experiments, and case reports. Assumptions based on this evidence must now be reassessed. For example, canines consistently develop ventricular tachycardia (VT) when tricyclic antidepressants (TCAs) are administered. Much of the literature discussing NCBD cardiotoxicity assumes that TCA poisoning induces VT in humans with the same regularity that occurs in canines. Seemingly, in support of this assumption was the finding that patients with remote myocardial infarction developed VT when therapeutically ingesting a NCBD. However, conduction is prolonged in myocardium that is or has been ischaemic. NCBD prolong conduction more in previously ischaemic myocardium than in normal myocardium, which causes nonuniform conduction and allows the development of re-entrant arrhythmias such as VT. Although some nonuniform conduction may occur in the healthy heart following a NCBD overdose, there is no evidence that nonuniform conduction occurs to the extent that it will cause re-entrant arrhythmias in this setting. Using various animal models and a variety of NCBDs, sodium ions, bicarbonate ions and alkalosis have been compared for the treatment of ventricular arrhythmias, hypotension and mortality. The results of these experiments have been extrapolated to NCBD overdose in humans. Animal models and single treatment approaches may have narrowed our scope. More recent evidence indicates that properties of each individual NCBD may require unique treatment. There is limited evidence that glucagon, which increases initial sodium ion influx into the cardiac cell, should be considered early in the treatment of cardiotoxicity. Another consideration may be treatment of NCBD with faster kinetics. Conduction time is decreased if a NCBD occupying the receptor is replaced by a NCBD that moves off and on the receptor more quickly. There is less evidence for this treatment, as risk may be greater. With greater understanding of the sodium channel and NCBDs, we must reassess our approach to the treatment of patients with healthy hearts who overdose on NCBD.