The
use of the cardiac glycoside, digoxin (Digitek; Lanoxin) is common in the
treatment of symptomatic heart failure (HF) as well as in patients with atrial
arrhythmias in need ventricular rate control.1,2 While digoxin therapy
does offer a number of therapeutic benefits, unfortunately, it has not been
proven to reduce mortality in patients with HF. In addition, it is a
narrow therapeutic index medication and thus requires monitoring of serum
concentrations to avoid toxicity. In regard to digoxin use for
arrhythmias, some patients will require antiarrhythmic treatment for
ventricular arrhythmias in addition to the rate control offered by digoxin; the
well known antiarrhythmic medication, amiodarone (Cordarone), is frequently
used in these scenarios.2,3 This is an example of a handful of patient
populations with multiple cardiovascular problems that are candidates for and
often receive treatment with both digoxin and amiodarone. Unfortunately,
there is a clinically relevant drug interaction between the two, wherein
amiodarone increases the concentration of digoxin. If ignored, the
patient is at increased risk for digoxin toxicity.4-8
What
is the mechanism by which amiodarone increases digoxin concentrations?
First, it is important to recognize the profiles of each of these medications
as it relates to their metabolism and elimination. Digoxin does not
undergo any metabolism via the cytochrome P450 (CYP450) enzyme system but
rather is a major substrate for the efflux pump known as multidrug
resistance-associated protein (MDR) or more commonly called, P-glycoprotein
(P-gp).9,10 P-glycoprotein is normally found on the epithelial and
endothelial surfaces in the gastrointestinal tract, blood brain barrier, liver
and kidney and is involved in moving drug from the inside of the cell to the
outside of the cell (i.e., efflux).11 Amiodarone, on the other hand, is
metabolized to an active metabolite, desethylamiodarone (DEA), mainly by CP450
2C8 and 3A4. In addition, amiodarone is also a known inhibitor of both
CYP3A4 and P-gp.12 Therefore, since digoxin is a major substrate for P-gp
and amiodarone is a known inhibitor of P-gp, the primary mechanism by which
amiodarone increases digoxin concentrations is through its ability to inhibit
the efflux of digoxin (gastrointestinal elimination and renal tubular
secretion) from the body.13 It does appear
that DEA (rather than the parent drug, amiodarone) is the primary contributor
of inhibition to the P-gp mediated elimination of digoxin.13
A second mechanism that may also be contributing to the changes in serum
concentrations is a redistribution of digoxin from tissue to serum.8,14,15
This appears to be based on the concentrations of amiodarone present; as
amiodarone concentrations increase so do serum digoxin concentrations.8
This change in tissue distribution can affect the interpretation of serum
digoxin levels.
As
a result of amiodarone's inhibition of P-gp, the gastrointestinal (which
includes biliary) and renal clearance of digoxin is decreased.
Amiodarone's inhibition of P-gp on the apical side of the enterocyte and
on the bile canalicular membrane results in an overall increase in
bioavailability of digoxin.3 However, it has been suggested that the
formulation of digoxin used may also influence the scale of this drug
interaction. For example, digoxin in the form of a solution may be less
of a concern due to the P-gp liability in the gastrointestinal tract.10 Lastly,
serum concentrations of digoxin appear to fluctuate based on the concentrations
of amiodarone, thus adding another factor that needs to be taken into
consideration when interpreting the concentrations of digoxin.
