Amiodarone as paradigm for developing new drugs for atrial fibrillation

Abstract

Introduced as an anti-anginal compound in 1962, amiodarone emerged in the 1970s as a uniquely effective antiarrhythmic and antifibrillatory drug with a multiplicity of properties, the most striking being the lengthening of the repolarization in the atria and ventricles associated with bradycardia but without a significant propensity for inducing torsade de pointes. Amiodarone is now the most frequently used agent for maintaining sinus rhythm in patients with AF. Its effectiveness for maintaining sinus rhythm remains unrivalled. Although the drug has few absolute contraindications to its use as an antiarrhythmic agent, limiting side effects such as thyroid dysfunction, pulmonary fibrosis, dermatological changes, and myriad lesser adverse effects often limit the use of the drug long-term in a proportion of patients. Thus, the idea has arisen that amiodarone might serve as a model for the synthesis and development of newer and novel antiarrhythmic agents devoid of organ toxicity. Amiodarone is an iodinated compound, and the possibility that its molecule may be modified with or without elimination of the iodine is being tested. The deletion of the iodine radical, substituting ethyl with butyl in the side chain of the aromatic ring, and adding a methylsulphonyl radical to the benzofuran component of the molecule leads to the loss of thyroid and pulmonary effects. The resulting compound, dronedarone, is in advanced clinical development. It is likely the first amiodarone congener that will be used in the control of atrial fibrillation. Others are in earlier phases of development.