Trecetilide Fumarate

Ibutilide is a 'pure' class III antiarrhythmic drug, used intravenously against atrial flutter and fibrillation. At a cellular level it exerts two main actions: induction of a persistent Na+ current sensitive to dihydropyridine Ca2+ channel blockers and potent inhibition of the cardiac rapid delayed rectifier K+ current, by binding within the channel pore cavity upon channel gating. Ibutilide has been shown to terminate atrial flutter and fibrillation in animal studies, with some risk of ventricular pro-arrhythmia. Experimental models of hypertrophy/heart failure show altered sensitivity to ibutilide, with increased dispersion of repolarisation and incidence of pro-arrhythmia. Patient trials show that ibutilide is effective at terminating atrial arrhythmias when given alone, and that it can increase effectiveness and reduce energy requirements of electrical cardioversion. The risk to patients of polymorphic ventricular tachycardia necessitates careful patient selection and monitoring during and after treatment. An ibutilide analogue, trecetilide, requires further investigation but may offer a less readily metabolised and pro-arrhythmic alternative to ibutilide.

There have been extensive efforts to develop I(Kr) channel blockers as a new antiarrhythmic agent for atrial or ventricular fibrillation, since it was demonstrated that selective blockade of the rapidly activating delayed rectifier K+ channel (I(Kr)) in the heart is not deleterious for the total mortality in fatal ventricular arrhythmia patients. Among them, dofetilide and KCB-328 blocks the I(Kr) specifically. Therefore, it increases the action potential duration (APD) selectively. Ibutilide, trecetilide, nifekalant, dronedarone, BRL-32872, H345/52 and ersentilide block the I(Kr). However, they modify also other cardiac channels or receptors. The frequency dependence of the compounds in prolonging the APD varies from the strong reversed tendency of dofetilide to the relatively neutral profile of KCB-328 and BRL-32872. Every compound reported so far has a proarrhythmic potential of torsade de pointes induction under certain conditions, although depending on the structure, the intensity may be somewhat different. In the coming decade, efforts to improve the reverse frequency dependence profile of the I(Kr) blockers by optimizing the onset and recovery time constant of the HERG block (e.g. KCB-328, vesnarinone) or the balance between the block of I(Kr) and Ca++ channels in the heart (e.g. BRL-32872, H 345/52) to eliminate the proarrhythmic potential of the currently known I(Kr) blockers are warranted. Further trials are also needed to discover more favorable compounds with multiple receptors including I(Kr) (e.g. nifekalant, dronedarone) for treating ventricular arrhythmias.