Dofetilide Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
Dofetilide was launched in the US as a novel class III antiarrhythmic for treatment of
cardiac patients with highly symptomatic atrial fibrillation This bisarylsulfonamide can be
obtained by a three step synthesis starting from 4-nitro-N-methylphenethylamine and
involving simultaneous nitro reduction and mesylation on both aromatic amine functions. In
contrast to other class III antiarrhythmic agents such as amiodarone, dofetilide potently
and selectively inhibits a single potassium channel, Ikr, the rapidly acting component of the
delayed rectifier potassium current, Accordingly, by blocking the open state of Ikr,
dofetilide is able to prolong the effective refractory period (ERP) in both atrial and
ventricular myocardium and the monophasic action potential duration. Moreover, as it targets only one cardiac ion channel, it does not produce any effects on the sinus node,
cardiac conduction system and other extracardiac organs, making it unique among
established class III agents. Several pharmacological studies with models using different
animal species indicated that dofetilide was a potent and highly selective class III
antiarrhythmic agent devoid of cardiodepressive effects. During clinical trials in patients
with paroxysmal atrial or supraventricular fibrillation, dofetilide was found to increase atrial
and ventricular refractory periods without affecting conduction or sinus node function. If
increases in the QT/QTc interval after oral or intravenous dofetilide are expected, as for
other class III antiarrhythmic agents, other electrocardiographic intervals are unaffected.
Chemische Eigenschaften
White Crystalline Solid
Verwenden
Dofetilide (90%) , is a potassium channel blocker. Antidysrhythmic drug.
Definition
ChEBI: A tertiary amino compound that is N-ethyl-N-methylethanamine substituted by a 4-[(methylsulfonyl)amino]phenoxy and a 4-[(methylsulfonyl)amino]phenyl group at the terminal carbon atoms respectively. It is used as an an
i-arrhythmia drug.
Allgemeine Beschreibung
Dofetilide, N-[4-(3-{[2-(4-methanesulfonylaminophenyl)ethyl]methylamino}propoxy)phenyl]methane-sulfonamide (Tikosyn), acts by blocking thecardiac ion channel carrying the rapid component of thedelayed rectifier potassium currents (Ikr) and is used toterminate supraventricular arrhythmias, prevent the recurrenceof atrial fibrillation, and treat life-threatening ventriculararrhythmias. Unlike sotalol and ibutilide, whichare also methanesulfonanilides, it has no effect on adrenergicreceptors or sodium channels, respectively. Dofetilidehas high specificity for the delayed rectifier potassiumcurrents.
Biologische Aktivität
Selective potassium channel blocker. Blocks hERG K + channels; inhibits the rapid delayed-rectifier K + current (I Kr ). Displays class III antiarrhythmic properties.
Clinical Use
Dofetilide (Tikosyn) is a “pure” class III drug. It prolongs
the cardiac action potential and the refractory period
by selectively inhibiting the rapid component of
the delayed rectifier potassium current (IKr).
Dofetilide is approved for the treatment of atrial fibrillation
and atrial flutter. Because of the lack of significant
hemodynamic effects, dofetilide may be useful in patients
with CHF who are in need of therapy for
supraventricular tachyarrhythmias. Dofetilide is not indicated
for use in the setting of ventricular arrhythmias.
Nebenwirkungen
The incidence of noncardiac adverse events is not different
from that of placebo in controlled clinical trials.
The principal cardiac adverse effect is the risk of torsades
de pointes due to QT prolongation.The risk is approximately
3%, and most cases are observed in the first
3 days of therapy.As such, initiation of therapy should
be performed with the patient in hospital.
Arzneimittelwechselwirkung
Verapamil increases serum dofetilide levels, as do drugs
that inhibit cationic renal secretion, such as ketoconazole
and cimetidine, raise serum levels.
Stoffwechsel
Dofetlide is used orally to suppress atrial
fibrillation and flutter. It is more potent and selective than other Class III methanesulfonanilides,
including sotalol. Dofetilide is well absorbed from the gastrointestinal tract, with a bioavailability of
96 to 100%. The bioavailability of oral dofetilide is not affected by food or antacids. Protein binding
is 60 to 70%. Dofetilide is metabolized by the hepatic CYP3A4 enzyme system via N-dealkylation and
N-oxidation to inactive or minimally active metabolites. Of the approximately 80% of a dose excreted
in urine, approximately 80% is excreted unchanged, with the other 20% as metabolites.
Vorsichtsmaßnahmen
Contraindications include baseline prolongation of
the QT interval, use of other QT-prolonging drugs;
history of torsades de pointes; a creatinine clearance of
less than 20 mL/minute; simultaneous use of verapamil,
cimetidine, or ketoconazole; uncorrected hypokalemia or
hypomagnesemia; and pregnancy or breast-feeding.
Dofetilide Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
