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Tikosyn

Dofetilide is a class III antiarrhythmic agent that is approved by the FDA for the maintenance of sinus rhythm in individuals prone to the formation of atrial fibrillation and flutter, and for the chemical cardioversion to sinus rhythm from atrial fibrillation and flutter. more...

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The chemical name for dofetilide is N-- methanesulphonamide. It is marketed under the trade name Tikosyn® by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide. Due to the pro-arrhythmic potential of dofetilide, it is only available by prescription by physicians who have undergone specific training in the risks of treatment with dofetilide. In addition, it is only available by mail order or through specially trained local pharmacies to individuals who are prescribed dofetilide by a physician who is registered as being able to prescribe the pharmaceutical.

The elimination half-life of dofetilide is roughly 10 hours, however this is variable based on many physiologic factors (most significantly creatinine clearance), and ranges from 4.8 to 13.5 hours.

Mechanism of action

Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current (IKr).

This causes prolongation of the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway). It is this selective action on accessory pathways that makes dofetilide effective in the treatment of atrial fibrillation and flutter.

Dofetilide does not effect Vmax (The slope of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.

There is a dose-dependant increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.

Metabolism

A steady-state plasma level of dofetilide is achieved in 2-3 days.

80% of dofetilide is excreted by the kidneys, so the dose of dofetilide should be adjusted in individuals with renal insufficiency, based on creatinine clearance.

In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as verapamil, cimetidine, hydrochlorothiazine, itraconazole, ketoconazole, prochlorperazine, and trimethoprim should not be administered to individuals taking dofetilide.

About 20 percent of dofetilide is metabolized in the liver via the CYP3A4 isoenzyme of the Cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4 isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the CYP3A4 isoenzyme system.

Read more at Wikipedia.org


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