Dofetilide
Dofetilide (Tikosyn) is a “pure” class III drug. It
pro-longs the cardiac action potential and the refractory pe-riod by
selectively inhibiting the rapid component of the delayed rectifier potassium
current (IKr).
Dofetilide’s mechanism of
action involves blockade of the cardiac ion channel that carries the rapid
compo-nent of the delayed rectifier potassium current, IKr. Dofetilide inhibits
IKr with no significant effects on other repolarizing potassium currents (e.g.,
IKs, IK1) over a wide range of concentrations. At plasma concen-trations within
the therapeutic range, dofetilide has no effect on sodium channels or on either
α1- or β-adreno-ceptors.
Dofetilide blocks IKr in all
myocardial tissues. It blocks open channels, and its binding and release from
the channels is voltage dependent. The effects of dofetilide are exaggerated
when the extracellular potas-sium concentration is reduced, which is important,
as many patients may be receiving diuretics concurrently. Conversely,
hyperkalemia decreases the effects of dofetilide, which may limit its efficacy
when local hy-perkalemia occurs, such as during myocardial ischemia. Dofetilide
demonstrates reverse use dependence, that is, less influence on the action
potential at faster heart rates. This is likely due to a greater influence of
other repolarizing currents such as the slowly activating com-ponent of the
delayed rectifier current (IKs).
Dofetilide induces a minor
slowing of the sponta-neous discharge rate of the sinoatrial node via a
reduc-tion in the slope of the pacemaker potential and hyper-polarization of
the maximum diastolic potential.
Dofetilide prolongs the
plateau phase of the action potential, thereby lengthening the refractory
period of the myocardium. The effects on atrial tissue appear to be more
profound than those observed in the ventricle. The reason for this is unclear.
There is no effect on the voltage-gated sodium channel and as such no effect on
the conduction velocity.
There is no effect on
conduction through the A-V node.
Dofetilide increases the ERP
of ventricular myo-cytes and Purkinje fibers. The ERP-prolonging effect on the
ventricular tissue is somewhat less than that in atrial tissue.
There are no changes in the
PR or QRS intervals, which reflects a lack of effect on the conduction
velocity. The QT interval is prolonged as a result of an increase in both the
effective and functional refractory periods in the His-Purkinje system and the
ventricles. The increase in the QT interval is directly related to the
dofetilide dose and plasma concentration.
Dofetilide does not
significantly alter the mean arterial blood pressure, cardiac output, cardiac
index, stroke volume index, or systemic vascular resistance. There is a slight
increase in the delta pressure/delta time (dP/dt) of ventricular myocytes.
The pharmacokinetic
characteristics of dofetilide are summarized below. Although the absorption of
dofetilide is delayed by ingestion of food, the total bioavailability is not
affected. Dosing requires adjust-ment in patients with renal insufficiency.
Oral bioavailability : >90%
Onset of action : 0.5 hour
Peak response : 23 hours
Duration of action : 8–10
hours
Plasma half-life : 7–10 hours
Primary route of metabolism :
Hepatic (CYP3A4)
Primary route of excretion : Renal
(80% unchanged; 20% metabolites)
Therapeutic serum concentration:
Not established
Dofetilide is approved for the treatment of atrial fibrilla-tion
and atrial flutter. Because of the lack of significant hemodynamic effects, dofetilide may be useful in pa-tients with
CHF who are in need of therapy for supraventricular tachyarrhythmias.
Dofetilide is not in-dicated for use in the setting of ventricular arrhythmias.
The incidence of noncardiac
adverse events is not dif-ferent from that of placebo in controlled clinical
trials. The principal cardiac adverse effect is the risk of tor-sades de
pointes due to QT prolongation. The risk is ap-proximately 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.
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.
Verapamil increases serum
dofetilide levels, as do drugs that inhibit cationic renal secretion, such as
ketocona-zole and cimetidine, raise serum levels.
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