Dofetilide

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Dofetilide
File:Dofetilide.png
Systematic (IUPAC) name
N-[4-(2-{[2-(4-methanesulfonamidophenoxy)ethyl](methyl)amino}ethyl)phenyl]methanesulfonamide
Pharmacokinetic data
Bioavailability 96% (oral)
Protein binding 60% -70%
Biological half-life 10 hours
Identifiers
CAS Number 115256-11-6
ATC code C01BD04 (WHO)
PubChem CID 71329
DrugBank APRD00367
ChemSpider 64435
Chemical data
Formula C19H27N3O5S2
Molar mass 441.567 g/mol[[Script error: No such module "String".]]
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Dofetilide is a class III antiarrhythmic agent.[1]

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.

Uses

It is used 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.[2][3]

Pharmacokinetics

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).[4]

This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial 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-dependent 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, hydrochlorothiazide, 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.

Side effects

Torsades de pointes is the most serious side effect of dofetilide therapy. The incidence of torsades de pointes is dose-related, and is 0.3-10.5%. The risk appears to be dose-dependent, with an increased incidence of torsades de pointes associated with higher doses of dofetilide administered.

The risk of inducing torsades de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial creatinine measurement, continuous telemetry monitoring and availability of cardiac resuscitation.

Clinical use

Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide (DIAMOND) study, dofetilide does not affect mortality in the treatment of patients post-myocardial infarction with left ventricular dysfunction.[5] Because of the results of the DIAMOND study, many physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction.

See also

References

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