Amiodarone and Homogeneity of Ventricular Repolarization and Refractoriness

Aniiodarone was synthesized in 1962 by a brilliant team of pharmacologists and organic chemists who were looking for a potent coronary vasodilator as a derivative of the khellin molecule (1). They focused on the benzfunn part of the molecule with the addition of a benzene ring and terminal nitrogen in the side chain. They came up with a series of benzfunn derivatives, but these early compounds were found to be unsuitable for clinical development. The insertion of two atoms of iodine in the outer part of the aromatic ring, however, gave stability as well as augmented potency to the resulting compound that met their original objective. The agent synthesized in this manner was indeed a potent coronary vasodilator. The compound was called amiodarone. The team that developed amiodarone in 1962 recognized early the broad pharmacologic profile of the drug (2). Little did they suspect that decades later the drug they developed would become the leading antiarrhythmic and antifibrillatory agent, in a class all its own. Perhaps of no less historical interest is the fact that in 1970 Singh and Vaughan Williams (3) described, in the gross, the drug's unique electrophysiologic properties in the atria and the ventricle (the drug's propensity to increase the time course of repolarization as a function of time at a constant dose). The prolongation of repolarization, as in the case of sotalol, was suggested as the cornerstone of the concept of the class 111 antiarrhythmic action (4). In 1996, amiodarone is clearly a drug that has an established role in the control of recurrences of cardiac arrests in sudden deal11 survivors (5); it is competitive with implantable cardioverter defibrillators (ICDs), and it figures prominently in numerous trials involving ICDs and antiarrhythmic agents (6,7). It is an important agent for the suppression and prevention of destabilizing ventricular tachycardia and fibrillation (VTNF) (8,9) and for the prophylactic suppression of VT in patients with structural heart disease (10). A compelling number of trials, albeit uncontrolled, attest to the drug's powerful suppressant effect on paroxysmal atrial fibrillation and flutter and to the drug's ability to maintain sinus rhythm following chemical or electrical conversion (1 1,12). These data have attracted serious attention for the mounting of blinded and unblinded controlled clinical trials to examine the drug's precise efficacy (alongside that of others) in maintaining sinus rhythm and possibly on morbidity and mortality associated with atrial fibrillation. There are also emerging favorable findings on the effects of the drugs for prolonging survival in certain subsets of patients with severe heart failure (10,13) and those surviving myocardial infarction (14). Clearly, as an antiarrhythmic drug, amiodarone will continue to be developed despite its exceedingly long refractory period (in the popular sense rather than in its electrophysiologic connotations) in the synthetic laboratory for use in controlling supraventricular and ventricular tachyarrhythmias. But how does it work? Any scientific or mechanistic explanations of its efficacy must encompass the drug's variegated array of electropharmacologic and pharmacodynamic actions including: