Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

Abstract

Cardiac arrhythmias are a major cause of morbidity and mortality in the industrialized world. Among their treatment regimens one can find the calcium channel antagonists (CCAs), the class IV agents. In the cardiovascular system Land T-type calcium channels are found on vascular smooth muscle cells and cardiac myocytes with well defined physiological roles. Inhibition of calcium channels by CCAs has widely been used in clinical practice for several decades. Cardiovascular disorders are one of the many fields of medicine in which CCAs are used for various reasons and conditions. The three main indications of them are hypertension, angina and various cardiac arrhythmias. The most important classes of CCAs are dihydropyridines, phenylalkylamines and benzothiazepines but some newer compounds do not fall into any of these major classes. Dihydropyridines are not used in the antiarrhythmic therapy but are good vasodilators and antianginal agents. In contrast, phenylalkylamines and benzothiazepines exert cardiac actions in vivo and therefore these are one choice of antiarrhythmic drugs. This review focuses on phenylalkylamines, benzothiazepines and on new drugs with potential antiarrhythmic action in the heart as well as the mechanisms how calcium channels antagonism can lead to an antiarrhythmic action.

Linked biaromatic compounds as cardioprotective agents

“…Inactivation of T‐type Ca 2+ channels results in bradycardia and delayed AV conduction, highlighting the importance of the channel in cardiac rhythm. [ 181–183 ]…”

“…Beneficial actions of SR 33805 include the reduction of calcium overload induced with vitamin D3 and its deleterious consequences (lesions appearing in the tissue adjacent to the arteries) of rat hearts, the restoration of MI altered cell shortening without affecting the calcium transient amplitude in cardiomyocytes isolated from rat with end‐stage HF and the improvement of end‐systolic strain and fractional shortening of hearts with MI in vivo. [ 181 ]…”

“…[ 211 ] A large number of in vivo experiments indicate excellent antiarrhythmic properties of levosemotiadil in ventricular arrhythmias. [ 181 ]…”

“…[ 222 ] In a number of animal studies, mibefradil demonstrated antiarrhythmic and antianginal action during ischemia and during reperfusion. [ 181 ]…”

“…[207] Beneficial actions of SR 33805 include the reduction of calcium overload induced with vitamin D3 and its deleterious consequences (lesions appearing in the tissue adjacent to the arteries) of rat hearts, the restoration of MI altered cell shortening without affecting the calcium transient amplitude in cardiomyocytes isolated from rat with end-stage HF and the improvement of end-systolic strain and fractional shortening of hearts with MI in vivo. [181] In clinical trials, fantofarone was effective and safe in the treatment of patients with chronic, stable angina pectoris as the drug prolonged exercise time without any effect on systolic BP both at rest and during exercise. [208] Despite its successful development, the drug has not been used in clinical practice.…”