Dofetilide, a New Class III Antiarrhythmic Agent
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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.Keywords:
Dofetilide
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Objective. To determine how well dofetilide and Betapace AF (sotalol, approved solely for atrial fibrillation and atrial flutter), with their detailed dosing and monitoring guidelines for safety, were accepted into clinical practice during the 2 calendar years after their introduction. Methods and Results. We reviewed the number of new, refill, and total prescriptions of all antiarrhythmic agents in the United States from April 2000‐December 2001 to assess use of dofetilide and Betapace AF in the drug market. Both were prescribed very infrequently throughout the study period. In addition, the infrequent reported use of these drugs for patients with atrial fibrillation and flutter indicated poor acceptance of these agents by prescribing physicians. We speculated that the restricted distribution and required educational program for dofetilide, as well as the availability of generic sotalol products, may have discouraged physicians from prescribing both dofetilide and Betapace AF. Conclusion. A common goal for both the dofetilide risk‐management program and the creation of a sotalol product indicated solely for atrial fibrillation and atrial flutter was to provide safer treatment for patients with these arrhythmias. Unfortunately, limited penetration of dofetilide and Betapace AF into the U.S. market suggests that drugs without a risk‐management program or detailed dosing guidelines were more likely than dofetilide or Betapace AF to be selected for treatment of atrial fibrillation and atrial flutter.
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A noteworthy shift from class I to class III antiarrhythmic agents for suppression of atrial fibrillation has occurred. Sotalol, amiodarone, and dofetilide have been evaluated for their ability to maintain sinus rhythm in patients with chronic atrial fibrillation. All of these agents are moderately effective; however, amiodarone appears to be most efficacious. Aside from their common class III actions, these agents have profoundly different pharmacologic, pharmacokinetic, safety, and drug interaction profiles that help guide drug selection. Amiodarone and dofetilide are safe in patients who have had a myocardial infarction and those with heart failure. The safety of commercially available d,l‐sotalol in these patients is poorly understood. Torsades de pointes is the most serious adverse effect of sotalol and dofetilide, and risk increases with renal dysfunction. Amiodarone has minimal proarrhythmic risk but has numerous noncardiac toxicities that require frequent monitoring. Overall, an ideal antiarrhythmic agent does not exist, and drug selection should be highly individualized.
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Objectives: This study was designed to evaluate how the atrial electrophysiological and antiarrhythmic effects of azimilide compare with those of the specific rapid delayed rectifier (IKr) blocker dofetilide. Background: Azimilide, a new class III drug, was initially believed to be a highly selective blocker of the slow delayed rectifier (IKs), but recent studies suggest that azimilide potently blocks IKr. Thus, it has been suggested that azimilide's in vivo effects may simply be due to IKr blockade. Methods: Dose regimens producing stable effects over time were developed, and two dose levels of azimilide (10 and then 20 mg/kg) or dofetilide (0.08 and then 0.16 mg/kg) were administered to morphine/chloralose-anesthetized dogs during sustained vagal atrial fibrillation (AF). Epicardial mapping was used to measure conduction velocity and AF cycle length. Results: Azimilide terminated AF in 13/14 dogs (93%), while dofetilide terminated AF in 6/12 (50%, P<0.05). While dofetilide had strong reverse use-dependent effects on atrial ERP (e.g. at lower doses, dofetilide increased ERP by 51±3% at a basic cycle length, BCL, of 400 ms and by 17±3% at a BCL of 200 ms), azimilide's effects on ERP were rate-independent (ERP increased at lower dose by 38±6%, BCL 400 ms; 35±10%, BCL 200 ms). Neither drug affected conduction. Conclusions: Azimilide is effective against experimental AF, and increases ERP with a frequency dependence different from the IKr blocker dofetilide, suggesting that azimilide's actions on atrial tissue cannot be attributed exclusively to IKr block, and that effects on other currents (such as IKs) are likely to be important.
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We studied the effect of two new class II antiarrhythmics, ambasilide and dofetilide, on the action potential duration (APD) of guinea pig right ventricular papillary muscle at different extracellular potassium concentrations ([K+e]) and pacing frequencies. Under normal [K+e], both drugs significantly prolonged APD90 (APD at 90% repolarization) at 0.5 Hz. The effect of ambasilide was well preserved at rapid pacing rates, independent of [K+e]. The effect of dofetilide was markedly reduced with increasing pacing rate, especially in high [K+e]. Therefore, ambasilide may be useful in treating tachyarrhythmias in normal, as well as in altered [K+e] conditions.
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The I(Kr) blocker EGIS-7229 (S-21407), displays class Ib and class IV effects that may alter its pharmacologic profile compared with those of pure I(Kr) blockers. Therefore, the concentration- and frequency-dependent effects of EGIS-7229, and of the I(Kr) blockers d,l-sotalol and dofetilide, on the effective refractory period (ERP) were measured in isolated right ventricular papillary muscle of the rabbit in vitro. The effects of these drugs on right ventricular fibrillation threshold (RVFT) at increasing intravenous doses were also determined in anesthetized cats. Dofetilide and d,l-sotalol increased ERP in a concentration-dependent manner (dofetilide: 3-100 nM; d,l-sotalol: 3-100 microM) with strong reverse frequency dependence at high concentrations. EGIS-7229 concentration dependently lengthened ERP at 1-30 microM. Its effect on ERP was clearly reverse frequency dependent at 3 microM, but this feature of the drug diminished at 10 microM and was not apparent at 30 microM. The effect of EGIS-7229 (30 microM) on ERP was devoid of reverse frequency dependence as it was more effective (31%) than dofetilide (16 %) at high-pacing rate (3 Hz), whereas it was less effective (50%) than dofetilide (70%) at slow-pacing rate (1 Hz). Reverse frequency-dependent ERP effect of dofetilide (100 nM) was similarly abolished by the addition of lidocaine (30 microM). EGIS-7229 (1-8 mg/kg iv), d,l-sotalol (1-8 mg/kg iv), and dofetilide (10-80 microg/kg iv) caused a dose-dependent increase in RVFT. The minimum effective dose of d,l-sotalol and EGIS-7229 was 1 and 2 mg/kg, respectively, whereas that of dofetilide was 10 microg/kg. EGIS-7229 induced a smaller peak effect in RVFT than sotalol or dofetilide. In conclusion, EGIS-7229 markedly increased refractoriness to electrical stimulation in vitro and in vivo. Compared with pure I(Kr) blockers, the benefits of EGIS-7229 seem to be a greater lengthening of effective refractory period at rapid stimulation rates, suggesting a strong antiarrhythmic action, and a smaller effect at slow stimulation rates, suggesting low potential to induce early afterdepolarizations.
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Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects, amiodarone primarily has adverse non-cardiac effects. Pharmacological inhibition of small conductance Ca2+-activated K+ (SK) channels has recently been reported to be antiarrhythmic in a number of animal AF models. In a Langendorff model of acutely induced AF on guinea pig hearts, it was investigated whether a combination of the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) together with either dofetilide or amiodarone provided a synergistic effect. The duration of AF was reduced with otherwise subefficacious concentrations of either dofetilide or amiodarone when combined with ICA, also at a subefficacious concentration. At a concentration level effective as monotherapy, dofetilide produced a marked increase in the QT interval. This QT prolonging effect was absent when combined with ICA at non-efficacious monotherapy concentrations. The results thereby reveal that combination of subefficacious concentrations of an SK channel blocker and either dofetilide or amiodarone can maintain anti-AF properties, while the risk of ventricular arrhythmias is reduced.
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The novel compound AVE1231 was investigated in order to elucidate its potential against atrial fibrillation. In CHO cells, the current generated by hKv1.5 or hKv4.3 + KChIP2.2b channels was blocked with IC50 values of 3.6 μM and 5.9 μM, respectively. In pig left atrial myocytes, a voltage-dependent outward current was blocked with an IC50 of 1.1 μM, mainly by accelerating the time constant of decay. Carbachol-activated IKACh was blocked by AVE1231 with an IC50 of 8.4 μM. Other ionic currents, like the IKr, IKs, IKATP, ICa, and INa were only mildly affected by 10 μM AVE1231. In guinea pig papillary muscle the APD90 and the upstroke velocity were not significantly altered by 30 μM AVE1231. In anesthetized pigs, oral doses of 0.3, 1, and 3 mg/kg AVE1231 caused a dose-dependent increase in left atrial refractoriness (LAERP), associated by inhibition of left atrial vulnerability to arrhythmia. There were no effects on the ECG intervals, ventricular monophasic action potentials, or ventricular refractory periods at 3 mg/kg AVE1231 applied intravenously. In conscious goats, both AVE1231 (3 mg/kg/h iv) and dofetilide (10 μg/kg/h iv) significantly prolonged LAERP. After 72 hours of tachypacing, when LAERP was shortened significantly (electrical remodelling), the prolongation of LAERP induced by AVE1231 was even more pronounced than in sinus rhythm. In contrast, the effect of dofetilide was strongly decreased. The present data demonstrate that AVE1231 blocks early atrial K+ channels and prolongs atrial refractoriness with no effects on ECG intervals and ventricular repolarisation, suggesting that it is suited for the prevention of atrial fibrillation in patients.
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Class III antiarrhythmic agents act by selective prolongation of cardiac action potential duration (APD). Methanesulfonanilide class III agents (e.g., E-4031 and dofetilide) are extremely potent and lengthen action potentials in a reverse rate-dependent manner; i.e., effects are greater at low compared with high rates of stimulation. By using the whole-cell current-clamp technique in isolated guinea pig ventricular myocytes, APD was shortened by rapid pacing (244 +/- 16 msec at 30 pulses per minute, 166 +/- 8 msec at 240 pulses per minute; n = 8). Dofetilide (1 microM) prolonged APD more when cells were stimulated at the rate of 30 pulses per minute (44 +/- 10-msec increase) than at 240 pulses per minute (21 +/- 5-msec increase). We investigated the mechanism of APD prolongation using voltage-clamp techniques. Dofetilide selectively inhibited IKr (IC50, 31.5 nM), defined as the rapidly activating inward rectifying component of net delayed rectifier K+ current (IK), without effects on the larger but more...
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