The Molecular and Ionic Specificity of Antiarrhythmic Drug Actions

Virtually all clinical antiarrhythmic agents act by reducing ion channel conductance, with sodium (Na+), potassium (K+), and calcium (Ca++) channels the primary targets. Na+ channel blockers increase the risk of ischemic ventricular fibrillation and are relatively contraindicated in the presence of active coronary heart disease. Ca++ channel blockers suppress AV nodal conduction and are used to terminate reentrant supraventricular arrhythmias and control the ventricular response to atrial fibrillation. K+ channels constitute the most diverse group of cardiac ion channels. They are the primary targets of Class III antiarrhythmic drugs, the category of such agents presently undergoing the most active development. The rapid delayed rectifier, IKr, plays a key role in repolarization of all cardiac tissues and is the most common (and often only) target of action potential-prolonging drugs. Unfortunately, because of the ubiquity of IKr and the reverse use-dependent action potential prolongation that results from blocking it, IKr blockers are likely to cause torsades de pointes ventricular proarrhythmia. K+ channel blockers, such as amiodarone and azimilide, that affect the slow delayed rectifier IKs as well as IKr, appear to produce a more desirable rate-dependent profile of Class III action. Recently, much has been learned about the molecular basis of K+ channels based on their role in the congenital long QT syndrome. The availability of molecular clones that encode many of the channels in the human heart allows for the rapid screening of many potential new drugs, making possible the development of "designer" antiarrhythmic drugs with specific profiles of channel-blocking selectivity.