Dofetilide: Information from Answers.com


Dofetilide
Systematic (IUPAC) name
N-[4-(2-{[2-(4-methanesulfonamidophenoxy)ethyl](methyl)amino}ethyl)phenyl]methanesulfonamide
Identifiers
CAS number	115256-11-6
ATC code	C01BD04
PubChem	71329
DrugBank	APRD00367
ChemSpider	64435
Chemical data
Formula	C₁₉H₂₇N₃O₅S₂
Mol. mass	441.567 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	96% (oral)
Protein binding	60% -70%
Metabolism	?
Half life	10 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	?
Y(what is this?) (verify)

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.

1 Uses
2 Pharmacokinetics
3 Mechanism of action
4 Metabolism
5 Side effects
6 Clinical use
7 See also
8 References

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 (I_Kr).^[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 V_max (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.

References

^ 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.
^ 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.
^ 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. http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=601530.
^ 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. http://www.future-drugs.com/doi/abs/10.1586/14779072.5.1.9?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov.
^ 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. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10486417&promo=ONFLNS19.

v • d • e Channel blocker: potassium channel blockers

Antiarrhythmic III/delayed rectifier	benzofuran (Amiodarone) • quaternary ammonium (Bretylium) • naphthalene (Bunaftine) • phenethylamine (Dofetilide) • sulfonamide (Ibutilide) • pyrimidinone (Nifekalant) • ethanolamine (Sotalol) • cyclopropane (Tedisamil) • E-4031

Other/ungrouped/unknown	aminopyridine (3,4-Diaminopyridine, 4-Aminopyridine) • indole (Linopirdine, Paxilline) • quaternary ammonium (Tetraethylammonium) • peptide (Maurotoxin, Charybdotoxin)

Antiarrhythmic agents (C01B)

Channel blockers

class I
(Na⁺ channel blockers)

class Ia (Phase 0→ and Phase 3→)	Procainamide # • Quinidine # • Ajmaline • Disopyramide • Prajmaline • Sparteine

class Ib (Phase 3←)	IV (Lidocaine #) • enteral (Mexiletine, Tocainide, Aprindine)

class Ic (Phase 0→)	Encainide • Flecainide • Lorcainide • Moricizine • Propafenone

class III
(Phase 3→, K⁺ channel blockers)

Amiodarone • Bretylium • Bunaftine • Dofetilide • Ibutilide • Nifekalant • Sotalol • Tedisamil • E-4031

class IV
(Phase 4→, Ca²⁺ channel blockers)

Verapamil # • Diltiazem

Receptor agonists
and antagonists

class II (Phase 4→, β blockers)	Propranolol • Nadolol • Pindolol • cardioselective (Atenolol, Metoprolol, Acebutolol, Esmolol)

A1 agonist	Adenosine

M2	muscarinic antagonist: Atropine • Quinidine • Disopyramide muscarinic agonist: Digoxin

α receptors	Quinidine • Verapamil • Amiodarone • Bretylium

Ion transporters

Na⁺ / K⁺-ATPase

Digoxin

# = WHO-EM

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