Dofetilide has class 3 action potential prolonging action. This action is effected by a dose-dependent blockade of the rapid component of the delayed rectifier potassium current (IKr) and the blockade of IKr increases in hypokalemia. Dofetilide produces no relevant blockade of the other potassium channels or the sodium channel. Because of the slow rate of recovery from blockade, the extent of blockade shows little dependence on stimulation frequency. However, dofetilide does show less action potential prolongation at rapid rates because of the increased importance of other potassium channels such as IKs at higher frequencies.
Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated unchanged by the kidneys; the remainder is eliminated in the urine as inactive metabolites. Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dosage must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the rate-corrected QT interval (QTc) and serum electrolytes. A baseline QTc of greater than 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of less than 50 bpm, and hypokalemia are relative contraindications to its use.
Dofetilide is approved for the maintenance of normal sinus rhythm in patients with atrial fibrillation. It is also effective in restoring normal sinus rhythm in patients with atrial fibrillation.
Ibutilide, like dofetilide, slows cardiac repolarization by blockade of the rapid component (IKr) of the delayed rectifier potassium current. Activation of slow inward sodium current has also been suggested as an additional mechanism of action potential prolongation. After intravenous administration, ibutilide is rapidly cleared by hepatic metabolism and the elimination half-life averages 6 hours. The metabolites are excreted by the kidney.
Intravenous ibutilide is used for the acute conversion of atrial flutter and atrial fibrillation to normal sinus rhythm. The drug is more effective in atrial flutter than atrial fibrillation, with a mean time to termination of 20 minutes. The most important adverse effect is excessive QT-interval prolongation and torsades de pointes. Patients require continuous ECG monitoring for 4 hours after ibutilide infusion or until QTc returns to baseline.
These drugs, of which verapamil is the prototype, were first introduced as antianginal agents and are discussed in greater detail in Chapter 12. Verapamil and diltiazem also have antiarrhythmic effects. The dihydropyridines (eg, nifedipine) do not share antiarrhythmic efficacy and may precipitate arrhythmias.
Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the SA and AV nodes. AV nodal conduction time and effective refractory period are consistently prolonged by therapeutic concentrations. Verapamil usually slows the SA node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of SA rate.
Verapamil can suppress both early and delayed afterdepolarizations and may abolish slow responses arising in severely depolarized tissue.
Verapamil causes peripheral vasodilation, which may be beneficial in hypertension and peripheral vasospastic disorders. Its effects on smooth muscle produce a number of extracardiac effects (see Chapter 12).