Chapter 34: Antiarrhythmic Drugs

INTRODUCTION

Cardiac cells undergo depolarization and repolarization about 60 times per minute to form and propagate cardiac action potentials. The shape and duration of each action potential are determined by the activity of ion channel protein complexes in the membranes of individual cells, and the genes encoding most of these proteins and their regulators have now been identified. Action potentials in turn provide the primary signals to release Ca²⁺ from intracellular stores (sarcoplasmic reticulum) and to thereby initiate contraction. Thus, each normal heartbeat results from the highly integrated electrophysiological behavior of multiple proteins on the surface and within multiple cardiac cells. Disordered cardiac rhythm can arise from influences such as inherited variation in ion channels or other genes, ischemia, sympathetic stimulation, or myocardial scarring. Available antiarrhythmic drugs suppress arrhythmias by modulating flow through specific ion channels or by altering autonomic function. An increasingly sophisticated understanding of the molecular basis of normal and abnormal cardiac rhythm may lead to identification of new targets for antiarrhythmic drugs and perhaps improved therapies (Al-Khatib et al., 2018).

Arrhythmias can range from incidental, asymptomatic clinical findings to life-threatening abnormalities. Mechanisms underlying cardiac arrhythmias have been identified in cellular and animal experiments. For some human arrhythmias, precise mechanisms are known, and treatment can be targeted specifically to those mechanisms. In other cases, mechanisms can only be inferred, and the choice of drugs is based largely on results of prior experience. Antiarrhythmic drug therapy has two goals: termination of an ongoing arrhythmia or prevention of an arrhythmia. Unfortunately, antiarrhythmic drugs not only may help control arrhythmias but also can cause them, even during long-term therapy. Thus, prescribing antiarrhythmic drugs requires that precipitating factors be excluded or minimized, that a precise diagnosis of the type of arrhythmia (and its possible mechanisms) be made, that the prescriber has reason to believe that drug therapy will be beneficial, and that the risks of drug therapy can be minimized.

ABBREVIATIONS

PRINCIPLES OF CARDIAC ELECTROPHYSIOLOGY

The flow of ions across cell membranes generates the currents that make up cardiac action potentials. Factors that determine the magnitude of individual currents and their modulation by drugs include transmembrane potential, time since depolarization, and the presence of specific ligands (Priori et al., 1999). Further, because the function of many channels is time and voltage dependent, even a drug that targets a single ion channel may, by altering the trajectory of ...