How does Tikosyn (dofetilide) work in patients with atrial fibrillation or atrial flutter?

How Tikosyn (Dofetilide) Works

Tikosyn works by selectively blocking the rapid component of the delayed rectifier potassium current (IKr) in cardiac myocytes, which prolongs the action potential duration and effective refractory period, thereby terminating reentrant atrial arrhythmias and preventing their recurrence. 1

Mechanism of Action

Dofetilide is a pure Class III antiarrhythmic agent that acts exclusively on cardiac potassium channels. 1 The drug demonstrates remarkable selectivity:

• Blocks only IKr potassium channels with no relevant effect on other repolarizing potassium currents (IKs, IK1) 1
• Has no effect on sodium channels (no Class I activity), alpha-adrenergic receptors, or beta-adrenergic receptors at clinically relevant concentrations 1
• Does not affect cardiac conduction velocity or sinus node function, which explains why it doesn't alter PR interval or QRS width 1

Electrophysiologic Effects

The potassium channel blockade produces specific measurable changes in cardiac electrophysiology:

• Prolongs the monophasic action potential duration in a concentration-dependent manner, primarily by delaying repolarization 1
• Increases effective refractory periods in both atria and ventricles, as well as in the His-Purkinje system 1
• Prolongs QT interval on surface ECG as a direct result of prolonged ventricular refractoriness 1, 2
• Terminates reentrant tachyarrhythmias (atrial fibrillation, atrial flutter, ventricular tachycardia) and prevents their reinduction 1

Clinical Translation

The mechanism translates to clinical efficacy through a straightforward pathway:

• The prolonged refractory period increases the likelihood that a reentrant wavefront will encounter refractory tissue and terminate 3
• Most conversions to sinus rhythm occur within 24-36 hours of initiating therapy, with 87% converting within 30 hours 4, 2
• In the SAFIRE-D trial, dofetilide 500 mcg twice daily achieved 32% conversion rate versus 1% with placebo after 3 days 3

Hemodynamic Neutrality

A critical advantage of dofetilide's mechanism is its lack of hemodynamic effects:

• No effect on cardiac output, cardiac index, stroke volume, or systemic vascular resistance 1
• No negative inotropic effect, making it safe in heart failure patients 1
• No effect on blood pressure, though heart rate decreases by 4-6 bpm 1
• This hemodynamic neutrality distinguishes dofetilide from amiodarone and beta-blockers, which have significant rate and blood pressure effects 5

Safety Profile Related to Mechanism

The same mechanism that provides efficacy creates the primary safety concern:

• QT prolongation is dose-dependent and directly correlates with plasma concentrations 1
• Risk of torsades de pointes is 0.8-3.3%, with 76% of episodes occurring in the first 3 days 4, 5
• The drug is 80% renally excreted, requiring dose adjustment based on creatinine clearance to prevent excessive QT prolongation 1, 2
• Dofetilide and amiodarone are the only antiarrhythmics proven safe in heart failure patients with ejection fraction ≤35%, as demonstrated in the DIAMOND trials 5, 4

Pharmacokinetic Considerations

Understanding the pharmacokinetics explains the dosing and monitoring requirements:

• >90% oral bioavailability with peak concentrations at 2-3 hours 1
• Terminal half-life of approximately 10 hours, reaching steady state in 2-3 days 1, 2
• 80% excreted unchanged in urine via glomerular filtration and active tubular secretion through the cation transport system 1
• Drugs that inhibit cation transport (cimetidine, trimethoprim, ketoconazole, verapamil) are contraindicated as they increase dofetilide levels and torsades risk 1, 6

Clinical Context

Dofetilide is specifically indicated for conversion and maintenance of sinus rhythm in atrial fibrillation/flutter lasting >1 week 1. The ACC/AHA guidelines position it as:

• First-line agent (with amiodarone) in heart failure patients due to proven safety in this population 4, 5
• Second-line agent in coronary artery disease after beta-blockers and sotalol, based on DIAMOND-MI data 4
• Requires mandatory 3-day inpatient initiation with continuous ECG monitoring and QTc measurement 2-3 hours after each of the first 5 doses 5

The drug must be permanently discontinued if QTc exceeds 500 ms after the second dose, or if QTc increases >15% from baseline. 5