Mechanism of Action
All of digoxin's actions are
mediated through its effects on Na-K ATPase. This enzyme, the “sodium pump,” is
responsible for maintaining the intracellular milieu throughout the body by
moving sodium ions out of and potassium ions into cells. By inhibiting Na-K
- causes increased availability of intracellular calcium in
the myocardium and conduction system, with consequent increased inotropy,
increased automaticity, and reduced conduction velocity
- indirectly causes parasympathetic stimulation of the
autonomic nervous system, with consequent effects on the sino-atrial (SA) and
atrioventricular (AV) nodes
- reduces catecholamine reuptake at nerve terminals, rendering
blood vessels more sensitive to endogenous or exogenous catecholamines
- increases baroreceptor sensitization, with consequent
increased carotid sinus nerve activity and enhanced sympathetic withdrawal for
any given increment in mean arterial pressure
- increases (at higher concentrations) sympathetic outflow
from the central nervous system (CNS) to both cardiac and peripheral
- allows (at higher concentrations) progressive efflux of
intracellular potassium, with consequent increase in serum potassium levels.
The cardiologic consequences of these direct and indirect
effects are an increase in the force and velocity of myocardial systolic
contraction (positive inotropic action), a slowing of the heart rate (negative
chronotropic effect), decreased conduction velocity through the AV node, and a
decrease in the degree of activation of the sympathetic nervous system and
renin-angiotensin system (neurohormonal deactivating effect).
The times to onset of pharmacologic effect and to peak
effect of preparations of LANOXIN are shown in Table 7.
Table 7: Times to Onset of Pharmacologic Effect and to
Peak Effect of Preparations of LANOXIN
||Time to Onset of Effecta
||Time to Peak Effecta
||0.5 -2 hours
||2 -6 hours
||5 -30 minutes b
||1 -4 hours
|aDocumented for ventricular response rate in atrial
fibrillation, inotropic effects and electrocardiographic changes.
bDepending upon rate of infusion.
Short-and long-term therapy with
the drug increase cardiac output and lowers pulmonary artery pressure,
pulmonary capillary wedge pressure, and systemic vascular resistance in
patients with heart failure. These hemodynamic effects are accompanied by an
increase in the left ventricular ejection fraction and a decrease in end-systolic
and end-diastolic dimensions.
The use of therapeutic doses of
LANOXIN may cause prolongation of the PR interval and depression of the ST
segment on the electrocardiogram. LANOXIN may produce false positive ST-T
changes on the electrocardiogram during exercise testing. These electrophysiologic
effects are not indicative of toxicity. LANOXIN does not significantly reduce
heart rate during exercise.
Following oral administration, peak serum concentrations of
digoxin occur at 1 to 3 hours. Absorption of digoxin from LANOXIN Tablets has
been demonstrated to be 60% to 80% complete compared to an identical
intravenous dose of digoxin (absolute bioavailability). When LANOXIN Tablets
are taken after meals, the rate of absorption is slowed, but the total amount
of digoxin absorbed is usually unchanged. When taken with meals high in bran
fiber, however, the amount absorbed from an oral dose may be reduced.
Comparisons of the systemic availability and equivalent doses for oral
preparations of LANOXIN are shown in Dosage and Administration (2.6).
Digoxin is a substrate for P-glycoprotein. As an efflux
protein on the apical membrane of enterocytes, P-glycoprotein may limit the
absorption of digoxin.
In some patients, orally administered digoxin is converted
to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in
the gut. Data suggest that 1 in 10 patients treated with digoxin tablets,
colonic bacteria will degrade 40% or more of the ingested dose. As a result,
certain antibiotics may increase the absorption of digoxin in such patients.
Although inactivation of these bacteria by antibiotics is rapid, the serum
digoxin concentration will rise at a rate consistent with the elimination
half-life of digoxin. Serum digoxin concentration relates to the extent of
bacterial inactivation, and may be as much as doubled in some cases [see DRUG
Patients with malabsorption syndromes (e.g., short bowel
syndrome, celiac sprue, jejunoileal bypass) may have a reduced ability to
absorb orally administered digoxin.
Following drug administration, a 6-to 8-hour tissue
distribution phase is observed. This is followed by a much more gradual decline
in the serum concentration of the drug, which is dependent on the elimination
of digoxin from the body. The peak height and slope of the early portion
(absorption/distribution phases) of the serum concentration-time curve are
dependent upon the route of administration and the absorption characteristics
of the formulation. Clinical evidence indicates that the early high serum
concentrations do not reflect the concentration of digoxin at its site of
action, but that with chronic use, the steady-state post-distribution serum
concentrations are in equilibrium with tissue concentrations and correlate with
pharmacologic effects. In individual patients, these post-distribution serum
concentrations may be useful in evaluating therapeutic and toxic effects [see DOSAGE
Digoxin is concentrated in tissues and therefore has a large
apparent volume of distribution (approximately 475 to 500L). Digoxin crosses
both the blood-brain barrier and the placenta. At delivery, the serum digoxin
concentration in the newborn is similar to the serum concentration in the
mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum
digoxin concentrations are not significantly altered by large changes in fat
tissue weight, so that its distribution space correlates best with lean (i.e.,
ideal) body weight, not total body weight.
Only a small percentage (13%) of a dose of digoxin is
metabolized in healthy volunteers. The urinary metabolites, which include
dihydrodigoxin, digoxigenin bisdigitoxoside, and their glucuronide and sulfate
conjugates, are polar in nature and are postulated to be formed via hydrolysis,
oxidation, and conjugation. The metabolism of digoxin is not dependent upon the
cytochrome P-450 system, and digoxin is not known to induce or inhibit the
cytochrome P-450 system.
Elimination of digoxin follows first-order kinetics (that
is, the quantity of digoxin eliminated at any time is proportional to the total
body content). Following intravenous administration to healthy volunteers, 50%
to 70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of
digoxin is proportional to creatinine clearance and is largely independent of
urine flow. In healthy volunteers with normal renal function, digoxin has a
half-life of 1.5 to 2 days. The half-life in anuric patients is prolonged to
3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis,
exchange transfusion, or during cardiopulmonary bypass because most of the drug
is bound to extravascular tissues.
Geriatrics: Because of age-related declines in renal
function, elderly patients would be expected to eliminate digoxin more slowly
than younger subjects. Elderly patients may also exhibit a lower volume of
distribution of digoxin due to age-related loss of lean muscle mass. Thus, the
dosage of digoxin should be carefully selected and monitored in elderly
patients [see Use In Specific Populations].
Gender: In a study of 184 patients, the clearance of
digoxin was 12% lower in females than in male patients. This difference is not
likely to be clinically important.
Hepatic Impairment: Because only a small percentage
(approximately 13%) of a dose of digoxin undergoes metabolism, hepatic
impairment would not be expected to significantly alter the pharmacokinetics of
digoxin. In a small study, plasma digoxin concentration profiles in patients
with acute hepatitis generally fell within the range of profiles in a group of
healthy subjects. No dosage adjustments are recommended for patients with
hepatic impairment; however, serum digoxin concentrations should be used as
appropriate to help guide dosing in these patients.
Renal Impairment: Since the clearance of digoxin
correlates with creatinine clearance, patients with renal impairment generally
demonstrate prolonged digoxin elimination half-lives and greater exposures to
digoxin. Therefore, digoxin must be carefully titrated in these patients based
on clinical response, and based on monitoring of serum digoxin concentrations,
Race: The impact of race differences on digoxin
pharmacokinetics has not been formally studied. Because digoxin is primarily
eliminated as unchanged drug via the kidney and because there are no important
differences in creatinine clearance among races, pharmacokinetic differences
due to race are not expected.
Based on literature reports no significant changes in
digoxin exposure were reported when digoxin was co-administered with the
alfuzosin, aliskiren, amlodipine, aprepitant, argatroban,
aspirin, atorvastatin, benazepril, bisoprolol, black cohosh, bosentan, candesartan,
citalopram, clopidogrel, colesevelam, dipyridamole, disopyramide, donepezil,
doxazosin, dutasteride, echinacea, enalapril, eprosartan, ertapenem,
escitalopram, esmolol, ezetimibe, famciclovir, felodipine, finasteride,
flecainide, fluvastatin, fondaparinux, galantamine, gemifloxacin, grapefruit
juice, irbesartan, isradipine, ketorlac, levetiracetam, levofloxacin,
lisinopril, losartan, lovastatin, meloxicam, mexilitine, midazolam, milk
thistle, moexipril, montelukast, moxifloxacin, mycophenolate, nateglinide,
nesiritide, nicardipine, nisoldipine, olmesartan, orlistat, pantoprazole,
paroxetine,perindopril, pioglitazone, pravastatin, prazosin, procainamide,
quinapril, raloxifene, ramipril, repaglinide, rivastigmine, rofecoxib,
ropinirole, rosiglitazone, rosuvastatin, sertraline, sevelamer, simvastatin,
sirolimus, solifenacin, tamsulosin, tegaserod, terbinafine, tiagabine,
ticlopidine, tigecycline, topiramate, torsemide, tramadol, trandolapril,
triamterene, trospium, trovafloxacin, valacyclovir, valsartan, varenicline,
voriconazole, zaleplon, zolpidem
Chronic Heart Failure
Two 12-week, double-blind, placebo-controlled studies
enrolled 178 (RADIANCE trial) and 88 (PROVED trial) patients with NYHA class II
or III heart failure previously treated with digoxin, a diuretic, and an ACE
inhibitor (RADIANCE only) and randomized them to placebo or treatment with
LANOXIN. Both trials demonstrated better preservation of exercise capacity in
patients randomized to LANOXIN. Continued treatment with LANOXIN reduced the
risk of developing worsening heart failure, as evidenced by heart
failure-related hospitalizations and emergency care and the need for
concomitant heart failure therapy.
Dig Trial of LANOXIN in Patients with Heart Failure
The Digitalis Investigation Group (DIG) main trial was a
37-week, multicenter, randomized, double-blind mortality study comparing
digoxin to placebo in 6800 adult patients with heart failure and left
ventricular ejection fraction ≤ 0.45. At randomization, 67% were NYHA
class I or II, 71% had heart failure of ischemic etiology, 44% had been
receiving digoxin, and most were receiving a concomitant ACE inhibitor (94%)
and diuretics (82%). As in the smaller trials described above, patients who had
been receiving open-label digoxin were withdrawn from this treatment before randomization.
Randomization to digoxin was again associated with a significant reduction in
the incidence of hospitalization, whether scored as number of hospitalizations
for heart failure (relative risk 75%), risk of having at least one such
hospitalization during the trial (RR 72%), or number of hospitalizations for
any cause (RR 94%). On the other hand, randomization to digoxin had no apparent
effect on mortality (RR 99%, with confidence limits of 91 to 107%).
Chronic Atrial Fibrillation
Digoxin has also been studied as a means of controlling the
ventricular response to chronic atrial fibrillation in adults. Digoxin reduced
the resting heart rate, but not the heart rate during exercise.
In 3 different randomized, double-blind trials that included
a total of 315 adult patients, digoxin was compared to placebo for the
conversion of recent-onset atrial fibrillation to sinus rhythm. Conversion was
equally likely, and equally rapid, in the digoxin and placebo groups. In a randomized
120-patient trial comparing digoxin, sotalol, and amiodarone, patients
randomized to digoxin had the lowest incidence of conversion to sinus rhythm,
and the least satisfactory rate control when conversion did not occur.
In at least one study, digoxin was studied as a means of
delaying reversion to atrial fibrillation in adult patients with frequent
recurrence of this arrhythmia. This was a randomized, double-blind, 43-patient
crossover study. Digoxin increased the mean time between symptomatic recurrent
episodes by 54%, but had no effect on the frequency of fibrillatory episodes
seen during continuous electrocardiographic monitoring.