View source for Dofetilide

{{drugbox | verifiedrevid = 322182711
| IUPAC_name = ''N''-[4-(2-{[2-(4-methanesulfonamidophenoxy)ethyl](methyl)amino}ethyl)phenyl]methanesulfonamide | image = Dofetilide.png | ChemSpiderID = 64435
| InChI = 1/C19H27N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h4-11,20-21H,12-15H2,1-3H3
| smiles = O=S(=O)(Nc1ccc(cc1)CCN(CCOc2ccc(cc2)NS(=O)(=O)C)C)C
| InChIKey = IXTMWRCNAAVVAI-UHFFFAOYAP
| CASNo_Ref = {{cascite}}
| CAS_number = 115256-11-6 | ATC_prefix = C01 | ATC_suffix = BD04 | ATC_supplemental = | PubChem = 71329 | DrugBank = APRD00367 | C=19 | H=27 | N=3 | O=5 | S=2 | molecular_weight = 441.567 g/mol | bioavailability = 96% (oral) | protein_bound = 60% -70% | metabolism = | elimination_half-life = 10 hours | pregnancy_category = | legal_status = | routes_of_administration = }}
'''Dofetilide''' is a class III [[antiarrhythmic agents|antiarrhythmic agent]].<ref name="pmid10907968">{{cite journal |title=Dofetilide, a new class III antiarrhythmic agent |journal=Pharmacotherapy |volume=20 |issue=7 |pages=776–86 |year=2000 |month=July |pmid=10907968 |doi= 10.1592/phco.20.9.776.35208|url= |author1=Lenz TL |author2=Hilleman DE |author-separator=,}}</ref>

It is marketed under the trade name '''Tikosyn''' by [[Pfizer]], and is available in the [[United States]] in capsules containing 125, 250, and 500 [[microgram|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 [[atrial flutter|flutter]], and for the chemical [[cardioversion]] to sinus rhythm from [[atrial fibrillation]] and [[atrial flutter|flutter]].<ref name="pmid18688699">{{cite journal |title=Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter |journal=J Interv Card Electrophysiol |volume=23 |issue=2 |pages=111–5 |year=2008 |month=November |pmid=18688699 |doi=10.1007/s10840-008-9290-6 |display-authors=3 |author1=Banchs JE |author2=Wolbrette DL |author3=Samii SM |author-separator=, |last4=Penny-peterson |first4=ED |last5=Patel |first5=PP |last6=Young |first6=SK |last7=Gonzalez |first7=MD |last8=Naccarelli |first8=GV}}</ref><ref name="pmid12845335">{{cite journal |title=Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter |journal=Drugs Today |volume=36 |issue=11 |pages=759–71 |year=2000 |month=November |pmid=12845335 |doi= 10.1358/dot.2000.36.11.601530|url=http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=601530 |author1=Lenz TL |author2=Hilleman DE |author-separator=,}}</ref>

==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<sub>Kr</sub>).<ref name="pmid17187453">{{cite journal |title=Dofetilide: a new class III antiarrhythmic agent |journal=Expert Rev Cardiovasc Ther |volume=5 |issue=1 |pages=9–19 |year=2007 |month=January |pmid=17187453 |doi=10.1586/14779072.5.1.9 |url=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 |author1=Roukoz H |author2=Saliba W |author-separator=,}}</ref>

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<sub>max</sub> (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 [[kidney]]s, 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 ventricle|left ventricular]] dysfunction.<ref name="pmid10486417">{{cite journal |title=Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group |journal=N. Engl. J. Med. |volume=341 |issue=12 |pages=857–65 |year=1999 |month=September |pmid=10486417 |doi= 10.1056/NEJM199909163411201|url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10486417&promo=ONFLNS19 |display-authors=3 |author1=Torp-Pedersen C |author2=ller M |author3=Mø Bloch-Thomsen PE |author-separator=, |last4=Køber |first4=L |last5=Sandøe |first5=E |last6=Egstrup |first6=K |last7=Agner |first7=E |last8=Carlsen |first8=J |last9=Videbaek |first9=J}}</ref> 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==
*[[Antiarrhythmic agents]]
*[[Cardiac action potential]]
*[[Electrocardiogram]]

==References==
{{reflist|2}}

{{Potassium channel blockers}}
{{Antiarrhythmic agents}}

[[Category:Sulfonamides]]
[[Category:Pfizer]]
[[Category:Potassium channel blockers]]
[[Category:Phenol ethers]]

[[it:Dofetilide]]
[[Category:2Fix]]