Chapter: Modern Pharmacology with Clinical Applications: Pharmacological Management of Chronic Heart Failure

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Dofetilide

Dofetilide (Tikosyn) is a “pure” class III drug. It pro-longs the cardiac action potential and the refractory pe-riod by selectively inhibiting the rapid component of the delayed rectifier potassium current (IKr).

Dofetilide

Dofetilide (Tikosyn) is a “pure” class III drug. It pro-longs the cardiac action potential and the refractory pe-riod by selectively inhibiting the rapid component of the delayed rectifier potassium current (IKr).

Electrophysiological Actions

Dofetilide’s mechanism of action involves blockade of the cardiac ion channel that carries the rapid compo-nent of the delayed rectifier potassium current, IKr. Dofetilide inhibits IKr with no significant effects on other repolarizing potassium currents (e.g., IKs, IK1) over a wide range of concentrations. At plasma concen-trations within the therapeutic range, dofetilide has no effect on sodium channels or on either α1- or β-adreno-ceptors.

Dofetilide blocks IKr in all myocardial tissues. It blocks open channels, and its binding and release from the channels is voltage dependent. The effects of dofetilide are exaggerated when the extracellular potas-sium concentration is reduced, which is important, as many patients may be receiving diuretics concurrently. Conversely, hyperkalemia decreases the effects of dofetilide, which may limit its efficacy when local hy-perkalemia occurs, such as during myocardial ischemia. Dofetilide demonstrates reverse use dependence, that is, less influence on the action potential at faster heart rates. This is likely due to a greater influence of other repolarizing currents such as the slowly activating com-ponent of the delayed rectifier current (IKs).

Sinoatrial Node

Dofetilide induces a minor slowing of the sponta-neous discharge rate of the sinoatrial node via a reduc-tion in the slope of the pacemaker potential and hyper-polarization of the maximum diastolic potential.

Atrium

Dofetilide prolongs the plateau phase of the action potential, thereby lengthening the refractory period of the myocardium. The effects on atrial tissue appear to be more profound than those observed in the ventricle. The reason for this is unclear. There is no effect on the voltage-gated sodium channel and as such no effect on the conduction velocity.

A-V Node

There is no effect on conduction through the A-V node.

His-Purkinje System and Ventricular Muscle

Dofetilide increases the ERP of ventricular myo-cytes and Purkinje fibers. The ERP-prolonging effect on the ventricular tissue is somewhat less than that in atrial tissue.

Electrocardiographic Changes

There are no changes in the PR or QRS intervals, which reflects a lack of effect on the conduction velocity. The QT interval is prolonged as a result of an increase in both the effective and functional refractory periods in the His-Purkinje system and the ventricles. The increase in the QT interval is directly related to the dofetilide dose and plasma concentration.

Hemodynamic Effects

Dofetilide does not significantly alter the mean arterial blood pressure, cardiac output, cardiac index, stroke volume index, or systemic vascular resistance. There is a slight increase in the delta pressure/delta time (dP/dt) of ventricular myocytes.

Pharmacokinetics

The pharmacokinetic characteristics of dofetilide are summarized below. Although the absorption of dofetilide is delayed by ingestion of food, the total bioavailability is not affected. Dosing requires adjust-ment in patients with renal insufficiency.

Oral bioavailability : >90%

Onset of action : 0.5 hour

Peak response : 23 hours

Duration of action : 8–10 hours

Plasma half-life : 7–10 hours

Primary route of metabolism : Hepatic (CYP3A4)

Primary route of excretion : Renal (80% unchanged; 20% metabolites)

Therapeutic serum concentration: Not established

Clinical Uses

Dofetilide is approved for the treatment of atrial fibrilla-tion and atrial flutter. Because of the lack of significant hemodynamic effects, dofetilide may be useful in pa-tients with CHF who are in need of therapy for supraventricular tachyarrhythmias. Dofetilide is not in-dicated for use in the setting of ventricular arrhythmias.

Adverse Effects

The incidence of noncardiac adverse events is not dif-ferent from that of placebo in controlled clinical trials. The principal cardiac adverse effect is the risk of tor-sades de pointes due to QT prolongation. The risk is ap-proximately 3%, and most cases are observed in the first 3 days of therapy. As such, initiation of therapy should be performed with the patient in hospital.

Contraindications

Contraindications include baseline prolongation of the QT interval, use of other QT-prolonging drugs; history of torsades de pointes; a creatinine clearance of less than 20 mL/minute; simultaneous use of verapamil, cimetidine, or ketoconazole; uncorrected hypokalemia or hypomagnesemia; and pregnancy or breast-feeding.

Drug Interactions

Verapamil increases serum dofetilide levels, as do drugs that inhibit cationic renal secretion, such as ketocona-zole and cimetidine, raise serum levels.

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