What is the mechanism of action and clinical use of dofetilide (Tikosyn)?

From the Guidelines

Dofetilide is a potent antiarrhythmic medication that should be used with caution due to its potential to cause dangerous heart rhythm problems, particularly torsades de pointes, and its use is typically reserved for patients who haven't responded to other antiarrhythmic medications or cannot tolerate them. It belongs to class III antiarrhythmic drugs and works by blocking potassium channels in the heart, which prolongs the cardiac action potential and effective refractory period. The typical dosage ranges from 125 to 500 mcg twice daily, with the specific dose determined by kidney function and QT interval measurements, as recommended by the guidelines 1.

Mechanism of Action and Clinical Use

• Dofetilide is used to treat serious heart rhythm disorders, specifically atrial fibrillation and atrial flutter.
• It works by blocking potassium channels in the heart, which prolongs the cardiac action potential and effective refractory period.
• The medication requires mandatory hospitalization for at least 3 days when initiating therapy due to its potential to cause dangerous heart rhythm problems, particularly torsades de pointes, as stated in the guidelines 1.
• Regular ECG monitoring and blood tests to check kidney function and electrolyte levels are essential during treatment, as dofetilide can interact with many common medications and electrolyte imbalances increase the risk of serious side effects.

Dosage and Administration

• The typical dosage ranges from 125 to 500 mcg twice daily, with the specific dose determined by kidney function and QT interval measurements.
• Dofetilide should be initiated in the hospital at a dose titrated to renal function and the QT interval, as recommended by the guidelines 1.
• Patients should maintain normal potassium and magnesium levels while taking this medication, as electrolyte imbalances increase the risk of serious side effects.

Safety and Efficacy

• Dofetilide has been shown to be effective in preventing AF or atrial flutter, with a response rate of 6%, 10%, and 30% of patients responding within 72 h to 125,250, and 500 μg twice a day, respectively, as reported in the SAFIRE-D and EMERALD studies 1.
• However, the medication carries a risk of torsades de pointes, with an incidence of 0.8% reported in the studies 1.
• Due to its narrow therapeutic window and significant risks, dofetilide is typically reserved for patients who haven't responded to other antiarrhythmic medications or cannot tolerate them, as recommended by the guidelines 1.

From the FDA Drug Label

TIKOSYN (dofetilide) shows Vaughan Williams Class III antiarrhythmic activity. The mechanism of action is blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr At concentrations covering several orders of magnitude, dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). In patients, dofetilide terminates induced re-entrant tachyarrhythmias (e.g., atrial fibrillation/flutter and ventricular tachycardia) and prevents their re-induction.

The mechanism of action of dofetilide (Tikosyn) is the blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr.

• Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents.
• The clinical use of dofetilide is to terminate induced re-entrant tachyarrhythmias, such as atrial fibrillation/flutter and ventricular tachycardia, and prevent their re-induction 2.
• Dofetilide is used in patients with supraventricular arrhythmias and has been shown to be effective in reducing the incidence of torsade de pointes when dosed according to renal function 2.
• The drug has a low negative inotropic effect and does not affect blood pressure or cardiac output in patients with ventricular tachycardia, mild to moderate congestive heart failure, or angina 2.
• Key contraindications include the use of drugs that interfere with the metabolism or renal elimination of dofetilide, such as cimetidine, trimethoprim, and ketoconazole, as well as the use of other drugs that prolong the QT interval 2.

From the Research

Mechanism of Action

• Dofetilide is a class III anti-arrhythmic drug that works by selectively blocking the rapid component of the delayed rectifier outward potassium current (I(kr)) 3.
• This action prolongs the effective refractory period, which is accompanied by a dose-dependent prolongation of the QT and QTc intervals, with parallel increases in ventricular refractoriness 3.
• Dofetilide has no beta-blocking or calcium channel-blocking properties, making it unique among established class III agents 4.

Clinical Use

• Dofetilide is approved for the conversion of atrial fibrillation and atrial flutter and maintenance of sinus rhythm in symptomatic patients with persistent arrhythmia 5, 6.
• It is effective in converting atrial and ventricular arrhythmias, and in maintaining sinus rhythm after cardioversion 4.
• Dofetilide has been shown to be superior to other anti-arrhythmic agents, such as flecainide and sotalol, in converting patients to normal sinus rhythm 3.
• The drug is typically initiated in-hospital under continuous electrocardiographic monitoring, with careful adjustment of dosage based on the length of QTc interval, calculated creatinine clearance, and the presence of heart failure or recent infarction 5, 7, 3, 4.

Safety and Side Effects

• The most serious side effect of dofetilide is torsade de pointes ventricular tachycardia, which can occur in 0.3-10.5% of patients and is dose-related 3.
• Other common side effects include headache, chest pain, and dizziness 3.
• To minimize the risk of induced arrhythmia, patients initiated or reinitiated on dofetilide should be hospitalized for a minimum of 3 days with continuous electrocardiographic monitoring and evaluation of renal function and serum electrolytes 3.
• Dofetilide can be co-administered with digoxin and beta-blockers, but other anti-arrhythmic drugs and drugs that interfere with renal elimination or metabolism of dofetilide should be avoided 5.