Warfarin (Coumadin, Jantoven) is an oral
anticoagulant most commonly used for the prevention and treatment of
thromboembolic events (blood clots) in patients with atrial fibrillation,
prosthetic heart valves, venous thrombosis and/or pulmonary embolism.1 As
a complication of their diagnosis, some patients taking warfarin will also
develop supraventricular or ventricular arrhythmias which may require treatment
with an antiarrhythmic medication. Amiodarone (Cordarone, Pacerone) is
considered one of the first-line antiarrhythmics for these conditions.2,3
Therefore, many patients will have an indication for concomitant warfarin and
amiodarone therapy.
The
reason for considering a dosage reduction of warfarin when initiating
amiodarone is the effect of amiodarone on warfarin metabolism. Warfarin
is a racemic (equal) mixture of two enantiomers, S-warfarin and
R-warfarin. While both enantiomers are pharmacologically active,
S-warfarin is known to be responsible for the majority of the clinical effect
and toxicity of warfarin as it is five times more potent than R-warfarin.
Both S-warfarin and R-warfarin are metabolized by cytochrome P450 (CYP) enzymes
(a group of gastrointestinal and liver enzymes responsible for drug
metabolism). Amiodarone is a potent inhibitor of a number of cytochrome
P450 enzymes. This includes CYP2C9 and CYP(1A2 and 3A4) which are largely
responsible for S-warfarin and R-warfarin metabolism, respectively.4,5
Inhibition of these enzymes by amiodarone will result in increased plasma
concentrations and decreased clearance of both enantiomers, thereby increasing
the patient's prothrombin time and international normalized ratio (INR).5
This places the patient at significant risk for bleeding complications.
Therefore, initiation of amiodarone in a patient receiving stable doses of
warfarin will potentiate the action of warfarin and result in an increased risk
of hemorrhagic complications.
The
effects of this interaction are typically seen in the first two weeks, usually
within the first few days.6,7 However, in some patients the full
manifestation of this effect may not be evident for several weeks.7
Because of the severity and consistency of this interaction, it is recommended
that the dose of warfarin be reduced by one-third to one-half when initiating
amiodarone therapy.6-8 Furthermore, given the long-half life of
amiodarone, several dosage adjustments maybe needed before the patient's new
warfarin dosage is finally determined and the INR has completely
stabilized. This would be especially true in patients whose amiodarone
dose has been changed as well.
