Short- and long-term treatment with digoxin slows heart rate, increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions.
Following oral administration, peak serum concentrations of digoxin occur at 30 to 90 minutes. In pediatric patients and in adult volunteers, absolute bioavailability of digoxin from the solution formulation is 70 to 85%, similar to that seen (in adults) with standard tablets (60 to 80%). When the solution is taken after meals, the peak serum concentrations increase by 20% and the total amount of digoxin absorbed increases by 43%, but the rate of digoxin absorption is unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Digoxin absorption may also be affected by various concomitant therapy modulating gastric pH and P-glycoprotein . [see ] Drug Interactions (7)
Comparisons of the systemic availability and equivalent doses for preparations of digoxin are shown in . Table 5
In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggested that one in ten patients treated with digoxin will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. The magnitude of rise in serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as two-fold in some cases.
Distribution
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. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its sites 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 and Administration (2.2)
Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. 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 with lean (i.e., ideal) body weight, not total body weight.
Metabolism
Sixteen percent of digoxin is metabolized. The end metabolites include 3-β-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates. The metabolism of digoxin is not dependent on the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system.
Excretion
Elimination of digoxin is predominantly renal, although in adult volunteers about a quarter of serum digoxin is eliminated through the intestine, excreted in bile or secreted directly into the lumen by P-glycoprotein. Elimination of digoxin follows first order kinetics.
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 glomerular filtration rate.
The serum half-life of digoxin in pediatric patients is reported to be 18 to 36 hours, and in adults it is typically 36 to 48 hours. 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 cardiopulmonary bypass because most of the drug is bound to tissue.
Drug-drug Interactions
Based on literature reports no significant changes in digoxin exposure were reported when digoxin was co-administered with the following drugs: 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, ketorolac, 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, and zolpidem.