Dofetilide

Dofetilide
Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a601235
ATC code C01BD04 (WHO)
Pharmacokinetic data
Bioavailability 96% (oral)
Protein binding 60% -70%
Biological half-life 10 hours
Identifiers
CAS Number 115256-11-6 YesY
PubChem (CID) 71329
IUPHAR/BPS 2604
DrugBank DB00204 YesY
ChemSpider 64435 YesY
UNII R4Z9X1N2ND YesY
KEGG D00647 YesY
ChEBI CHEBI:4681 YesY
ChEMBL CHEMBL473 YesY
ECHA InfoCard 100.166.441
Chemical and physical data
Formula C19H27N3O5S2
Molar mass 441.567 g/mol
3D model (Jmol) Interactive image
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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. It is not available in Europe[2] or Australia.[3]

Due to the pro-arrhythmic potential of dofetilide, it is only available by prescription from 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.[4]

Uses

Dofetilide is used for the maintenance of sinus rhythm in individuals prone to the occurrence of atrial fibrillation and flutter arrhythmias, and for chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.[5][6]

Pharmacokinetics

Dofetilide is well absorbed in its oral form, with a bioavailability of >90%.

The elimination half-life of dofetilide is roughly 10 hours; however, this varies based on many physiologic factors (most significantly creatinine clearance), and ranges from 4.8 to 13.5 hours. Due to the significant level of renal elimination (80% unchanged, 20% metabolites), the dose of dofetilide must be adjusted to prevent toxicity due to impaired renal function.[7]

Mechanism of action

Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current (IKr).[8]

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 affect 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 0.3-10.5% and is dose-related, with increased incidence associated with higher doses.

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,[9] dofetilide does not affect mortality in the treatment of patients post-myocardial infarction with left ventricular dysfunction, however it was shown to decrease all-cause readmissions as well as CHF-related readmissions.[10] Because of the results of the DIAMOND study, some physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction, however use appears limited: After initially receiving marketing approval in Europe in 1999, Pfizer voluntarily withdrew this approval in 2004 for commercial reasons[11] and it is not registered in other first world countries. It has clinical advantages over other class III antiarrythmics in chemical cardioversion of atrial fibrillation, and maintenance of sinus rhythm, and does not have the pulmonary or hepatotoxicity of amiodarone, however atrial fibrillation is not generally considered life-threatening, and dofetilide causes an increased rate of potentially life-threatening arryrthmias in comparison to other therapies.[12]

See also

References

  1. ↑ Lenz TL; Hilleman DE (July 2000). "Dofetilide, a new class III antiarrhythmic agent". Pharmacotherapy. 20 (7): 776–86. doi:10.1592/phco.20.9.776.35208. PMID 10907968.
  2. ↑ http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/12/WC500018370.pdf[]
  3. ↑ Australian Medicines Handbook 2014
  4. ↑ TIKOSYN® (dofetilide). Pfizer. <http://www.tikosyn.com/>.
  5. ↑ Banchs JE; Wolbrette DL; Samii SM; et al. (November 2008). "Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter". J Interv Card Electrophysiol. 23 (2): 111–5. doi:10.1007/s10840-008-9290-6. PMID 18688699.
  6. ↑ Lenz TL; Hilleman DE (November 2000). "Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter". Drugs Today. 36 (11): 759–71. doi:10.1358/dot.2000.36.11.601530. PMID 12845335.
  7. ↑ "Dofetilide." Lexicomp. Wulters Kluwer Health, n.d. Web. <online.lexi.com>.
  8. ↑ Roukoz H; Saliba W (January 2007). "Dofetilide: a new class III antiarrhythmic agent". Expert Rev Cardiovasc Ther. 5 (1): 9–19. doi:10.1586/14779072.5.1.9. PMID 17187453.
  9. ↑ Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. (September 1999). "Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group". The New England Journal of Medicine. 341 (12): 857–65. doi:10.1056/NEJM199909163411201. PMID 10486417.
  10. ↑ Torp-Pedersen C; ller M; Mø Bloch-Thomsen PE; et al. (September 1999). "Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group". N. Engl. J. Med. 341 (12): 857–65. doi:10.1056/NEJM199909163411201. PMID 10486417.
  11. ↑ http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/12/WC500018370.pdf[]
  12. ↑ Micromedex Drugdex drug evaluations micromedex.com


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