Dofetilide, a New Class III Antiarrhythmic Agent

Abstract

Dofetilide is a new antiarrhythmic agent recently approved for conversion and maintenance of sinus rhythm in patients with atrial fibrillation (AF) and atrial flutter (AFl). It is a class III antiarrhythmic that works by selectively blocking the rapid component of the delayed rectifier outward potassium current. Dofetilide prolongs the effective refractory period in accessory pathways, both anterograde and retrograde. This can be seen on the electrocardiogram through a dose-dependent prolongation of the QT and QTc intervals, with parallel increases in ventricular refractoriness. Approximately 80% of drug is excreted in urine, so dosing must be based on creatinine clearance. The elimination half-life is approximately 10 hours. In clinical trials dofetilide was superior to flecainide in converting patients with AFl to normal sinus rhythm (NSR; 70% vs 9%, p<0.01). It also was more effective than sotalol in converting patients with both AF and AFl to NSR (29% vs 6%, p<0.05) and maintaining them in NSR for up to 1 year. Most patients converted within 24-36 hours. Dofetilide has a favorable risk:benefit profile. Torsades de pointes is the most serious side effect; it occurs in 0.3-10.5% of patients and is dose related. To minimize the risk of induced arrhythmia, patients who start or restart the drug should be hospitalized a minimum of 3 days for creatinine clearance measurements, continuous electrocardiographic monitoring, and cardiac resuscitation, if necessary.

Structural Defects Lead to Dynamic Entrapment in Cardiac Electrophysiology

“…One is to alter the system (either its structure or the values of its parameters) in such a way as to eliminate aberrant basins of attraction. As an example, anti-arrhythmic drugs may prolong WL [40,41], which in our model could have the effect of pushing the system into Region 1 where it has no choice but to behave normally. Another example is the creation of strategically placed non-conducting scar tissue (via catheter ablation) to change the physical structure of the system.…”

Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review

“…In order to overcome the resistance and to reduce the adverse effects, continuous efforts are made to synthesize novel multi-targeted bioactive sulfonamide analogues. In this regard, combinations of certain sulfonamides and other drug molecules are being used to develop novel formulations with greater effectiveness as well as less toxicity [55].…”

Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels

“…It selectively blocks the rapid delayed rectifier potassium channel (I Kr ), but does not slow the delayed rectifier potassium channel (I Ks ) I K1 , sodium channels or calcium channels [11,12] . To discover more effective class III antiarrhythmic agents, we www.chinaphar.com Li P et al Acta Pharmacologica Sinica npg have designed and synthesised a series of new methylsulfonamido phenylethylamine analogues based on the structure and pharmacophore of dofetilide [13,14] .…”