Translation in Antiarrhythmic Drug Treatment

Jonathan C Makielski, MD, Lee Eckhardt MD
Department of Medicine, University of Wisconsin, Madison, WI

Cardiac arrhythmias have complex and heterogeneous mechanisms including triggered automaticity (both early and late afterdepolarizations) and micro and macro re-entry.  Rational drug design based on choosing ion channel targets for antiarrhythmic drug therapy based upon these mechanisms has been disappointing, and has often resulted in pro-arrhythmia.  Classic examples of this “on target” failure are the long QT pro-arrhythmia of potassium channel blockers as Class III antiarrhythmic drugs (eg, L-sotalol), and the excess mortality from pro-arrhythmia found in the CAST trial for Na channel blocking drugs of Class I (eg encainide).   For malignant ventricular arrhythmias the non-pharmacological approach of implanted defibrillators is standard care, but drugs are useful and needed for reducing symptomatic ventricular arrhythmias and for atrial arrhythmias, especially atrial fibrillation.  Amiodarone, arguably the best antiarrhythmic drug in clinical use for atrial and ventricular arrhythmias, has multiple targets.  The success of amiodarone was thought to result from a proper balance of multiple actions, belying the usual paradigm that target specificity was best for drug development.  Amiodarone was developed as an anti-anginal drug and antiarrhythmic action was a serendipitous discovery.  Serendipity may repeat itself, as the drug ranolazine developed and approved as an antianginal may be antiarrhythmic.  The late Na current may be a common target of amiodarone and ranolazine in the treatment of the very common arrhythmia atrial fibrillation and may represent a target breakthrough.  Other strategies for atrial fibrillation exploit differences between ventricular and atrial electrophysiology (eg  vernaklant).  Future drug development may use these and other newer target strategies.

Click to read Jonathan Makielski's biography