Digoxin

(BAN, rINN)
Digoxin Chemical formula
Synonyms: Digoksiini; Digoksin; Digoksinas; Digoksyna; Digoxina; Digoxine; Digoxinum; Digoxosidum. 3 pyranosyl-(1→4)O-2,6-dideoxy2,6-dideoxy5
Cyrillic synonym: Дигоксин.

💊 Chemical information

Chemical formula: C41H64O14 = 780.9.
CAS — 20830-75-5.
ATC — C01AA05.
ATC Vet — QC01AA05.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 6.2

(Digoxin). A white or almost white powder or colourless crystals. Practically insoluble in water; slightly soluble in alcohol; freely soluble in a mixture of equal volumes of dichloromethane and methyl alcohol. Protect from light.

USP 31

(Digoxin). A cardiotonic glycoside obtained from the leaves of Digitalis lanata (Scrophulariaceae). Clear to white, odourless, crystals, or a white, odourless, crystalline powder. Practically insoluble in water and in ether; slightly soluble in diluted alcohol and in chloroform; freely soluble in pyridine. Store in airtight containers.

💊 Adverse Effects

Digoxin and the other cardiac glycosides commonly produce adverse effects because the margin between the therapeutic and toxic doses is small; plasma concentrations of digoxin in excess of 2 nanograms/mL are considered to be an indication that the patient is at special risk although there is considerable interindividual variation. There have been many fatalities, particularly due to cardiac toxicity. Nausea, vomiting, and anorexia may be among the earliest symptoms of digoxin toxicity or overdosage; diarrhoea and abdominal pain may occur. Certain neurological effects are also common symptoms of digoxin overdosage and include headache, facial pain, fatigue, weakness, dizziness, drowsiness, disorientation, mental confusion, bad dreams and more rarely delirium, acute psychoses, and hallucinations. Convulsions have been reported. Visual disturbances including blurred vision may occur; colour vision may be affected with objects appearing yellow or, less frequently, green, red, brown, blue, or white. Hypersensitivity reactions are rare; thrombocytopenia has been reported. The cardiac glycosides may have some oestrogenic activity and occasionally cause gynaecomastia at therapeutic doses. Rapid intravenous injection of digoxin may cause vasoconstriction and transient hypertension. Intramuscular or subcutaneous injection can cause local irritation. The most serious adverse effects are those on the heart. Toxic doses may cause or aggravate heart failure. Supraventricular or ventricular arrhythmias and defects of conduction are common and may be an early indication of excessive dosage, particularly in children. In general the incidence and severity of arrhythmias is related to the severity of the underlying heart disease. Almost any arrhythmia may ensue, but particular note should be made of supraventricular tachycardia, especially AV junctional tachycardia and atrial tachycardia with block. Ventricular arrhythmias including extrasystoles, sinoatrial block, sinus bradycardia, and AV block may also occur. Hypokalaemia predisposes to digoxin toxicity; adverse reactions to digoxin may be precipitated if hypokalaemia occurs, for example after prolonged use of diuretics. Hyperkalaemia occurs in acute digoxin overdosage. Digoxin is mainly excreted unchanged in the urine but rifampicin increased digoxin dose requirements substantially in 2 patients dependent on dialysis.12When rifampicin was stopped digoxin requirements fell by about 50%.
1. Doherty JE. A digoxin-antibiotic drug interaction. N Engl J Med 1981; 305: 827–8
2. Lindenbaum J, et al. Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. N Engl J Med 1981; 305: 789–94
3. Maxwell DL, et al. Digoxin toxicity due to interaction of digoxin with erythromycin. BMJ 1989; 298: 572
4. Morton MR, Cooper JW. Erythromycin-induced digoxin toxicity. DICP Ann Pharmacother 1989; 23: 668–70
5. Ten Eick AP, et al. Possible drug interaction between digoxin and azithromycin in a young child. Clin Drug Invest 2000; 20: 61–64
6. Midoneck SR, Etingin OR. Clarithromycin-related toxic effects of digoxin. N Engl J Med 1995; 333: 1505
7. Nawarskas JJ, et al. Digoxin toxicity secondary to clarithromycin therapy. Ann Pharmacother 1997; 31: 864–6
8. Laberge P, Martineau P. Clarithromycin-induced digoxin intoxication. Ann Pharmacother 1997; 31: 999–1002
9. Corallo CE, Rogers IR. Roxithromycin-induced digoxin toxicity. Med J Aust 1996; 165: 433–4
10. Wakasugi H, et al. Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther 1998; 64: 123–8
11. Greiner B, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 1999; 104: 147–53
12. Gault H, et al. Digoxin-rifampin interaction. Clin Pharmacol Ther 1984; 35: 750–4.

Antidepressants.

In a study1 in healthy subjects, use of digoxin together with an extract of St John’s wort for 10 days resulted in a significant decrease in the plasma-digoxin concentration. It was suggested that the interaction might be due to induction of the P-glycoprotein transporter. In a study2 in healthy male subjects, nefazodone increased steady-state plasma-digoxin concentrations by about 30% but no adverse or clinical effects were associated with the increase. However, due to the narrow therapeutic range of digoxin, it was suggested that plasma-digoxin concentrations should be monitored in patients also given nefazodone. Similar recommendations have been made for trazodone. Digoxin toxicity developed in a patient shortly after starting paroxetine and was associated with increased serum-digoxin concentrations.3 However, the role of paroxetine in the reaction has been queried.4,5
1. Johne A, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999; 66: 338–45
2. Dockens RC, et al. Assessment of pharmacokinetic and pharmacodynamic drug interactions between nefazodone and digoxin in healthy male volunteers. J Clin Pharmacol 1996; 36: 160–7
3. Yasui-Furukori N, Kaneko S. Digitalis intoxication induced by paroxetine co-administration. Lancet 2006; 367: 788
4. Bateman DN, et al. Digitalis intoxication induced by paroxetine co-administration. Lancet 2006; 368: 1962–3
5. Hallberg P, Melhus H. Digitalis intoxication induced by paroxetine co-administration. Lancet 2006; 368: 1963.

Antidiabetics.

Subtherapeutic plasma-digoxin concentrations were noted in a diabetic woman receiving acarbose and digoxin.1 The plasma concentration of digoxin increased to a therapeutic level when acarbose was stopped. A study2 in healthy subjects suggested that the interaction was due to inhibition of the absorption of digoxin by acarbose.
1. Serrano JS, et al. A possible interaction of potential clinical interest between digoxin and acarbose. Clin Pharmacol Ther 1996; 60: 589–92
2. Miura T, et al. Impairment of absorption of digoxin by acarbose. J Clin Pharmacol 1998; 38: 654–7.

Antiepileptics.

Phenytoin caused a marked decrease in steadystate serum-digoxin concentrations when given with digoxin and acetyldigoxin to 6 healthy subjects for 7 days.1 Total digoxin clearance was increased by an average of 27% and elimination half-life was reduced by an average of 30%. This interaction may be more likely with digitoxin, since digitoxin is more dependent on the liver for elimination. A brief report of an open study2 in 12 subjects indicated a slight but significant decrease in digoxin bioavailability when topiramate was also given, although half-life and renal clearance of digoxin did not appear to be affected.
1. Rameis H. On the interaction between phenytoin and digoxin. Eur J Clin Pharmacol 1985; 29: 49–53
2. Liao S, Palmer M. Digoxin and topiramate drug interaction study in male volunteers. Pharm Res 1993; 10 (suppl): S405.

Antifungals.

Two men given itraconazole while receiving digoxin developed signs and symptoms of digoxin toxicity and elevated serum-digoxin concentrations.1,2 A further case report3suggested that the interaction was due to a reduction in the renal clearance of digoxin when itraconazole was given. Additive adverse effects due to hypokalaemia may occur when digoxin is given with amphotericin B.
1. Rex J. Itraconazole–digoxin interaction. Ann Intern Med 1992; 116: 525
2. Alderman CP, Jersmann HPA. Digoxin–itraconazole interaction. Med J Aust 1993; 159: 838–9
3. Alderman CP, Allcroft PD. Digoxin-itraconazole interaction: possible mechanisms. Ann Pharmacother 1997; 31: 438–40.

Antimalarials.

In 6 subjects given quinine sulfate, total body clearance of digoxin after an intravenous dose was decreased by 26%, primarily through a reduction in nonrenal clearance.1 Increased urinary excretion of digoxin was consistent with alterations in the nonrenal clearance of digoxin and might be due to changes in the metabolism or biliary secretion of digoxin. Quinine increased the mean elimination half-life of digoxin from 34.2 to 51.8 hours but did not consistently change the volume of distribution. An increase in the plasma-digoxin concentration, but without symptoms of toxicity, was noted in 2 women given hydroxychloroquine (for rheumatoid arthritis) in addition to long-term digoxin therapy.2
1. Wandell M, et al. Effect of quinine on digoxin kinetics. Clin Pharmacol Ther 1980; 28: 425–30
2. Leden I. Digoxin–hydroxychloroquine interaction? Acta Med Scand 1982; 211: 411–12.

Antineoplastics.

A study1 in patients undergoing antineoplastic therapy found that the absorption of digoxin from tablets was reduced by an average of 46.5%, whereas that of digoxin from liquid-filled capsules was not significantly changed. Another study2 in similar patients found that the steady-state concentration of digoxin after giving acetyldigoxin was reduced, but that digitoxin concentrations were maintained. It was suggested that the interaction was due to reduced absorption of digitalis glycosides through the damaged gastrointestinal mucosa and that liquid-filled capsules or digitoxin might be preferred in these patients. Licensed product information for lenalidomide states that it may increase plasma exposure of digoxin and recommends that digoxin concentrations should be monitored.
1. Bjornsson TD, et al. Effects of high-dose cancer chemotherapy on the absorption of digoxin in two different formulations. Clin Pharmacol Ther 1986; 39: 25–8
2. Kuhlmann J. Inhibition of digoxin absorption but not of digitoxin during cytostatic drug therapy. Arzneimittelforschung 1982; 32: 698–704.

Antithyroid drugs.

Reduced peak serum-digoxin concentrations were noted in 9 of 10 healthy subjects after a single oral dose of carbimazole although conversely in the tenth subject digoxin concentrations rose.1 Caution is also needed since changes in thyroid function may independently affect sensitivity to digoxin (see Precautions, above).
1. Rao BR, et al. Influence of carbimazole on serum levels and haemodynamic effects of digoxin. Clin Drug Invest 1997; 13: 350–4.

Antivirals.

A woman stabilised on digoxin and tolerating lamivudine, indinavir and stavudine for HIV infection, developed symptoms of digoxin toxicity 3 days after ritonavir was added to her treatment.1 It was suggested that the interaction might be due to inhibition of the P-glycoprotein transporter system by ritonavir. A pharmacokinetic study2 showing significant inhibition of renal digoxin clearance by ritonavir seemed to support this hypothesis.
1. Phillips EJ, et al. Digoxin toxicity and ritonavir: a drug interaction mediated through p-glycoprotein? AIDS 2003; 17: 1577–8
2. Ding R, et al. Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin Pharmacol Ther 2004; 76: 73–84.

Benzodiazepines.

Raised serum-digoxin concentrations have been reported in patients also taking diazepam1 or alprazolam.2,3The clearance of digoxin was reduced by these benzodiazepines.
1. Castillo-Ferrando JR, et al. Digoxin levels and diazepam. Lancet 1980; ii: 368
2. Tollefson G, et al. Alprazolam-related digoxin toxicity. Am J Psychiatry 1984; 141: 1612–14
3. Guven H, et al. Age-related digoxin-alprazolam interaction. Clin Pharmacol Ther 1993; 54: 42–4.

Beta2 agonists.

A single intravenous1,2 or oral3 dose of salbutamol has been reported to decrease steady-state serum-digoxin concentrations by up to 16% and 22% respectively in healthy subjects. Although salbutamol had no significant effect on the concentration of digoxin in skeletal muscle, it was considered that increased binding to skeletal muscle could explain the interaction.

Beta

2 agonists such as salbutamol can also cause hypokalaemia which may increase susceptibility to digoxin-induced arrhythmias.
1. Edner M, Jogestrand T. Effect of salbutamol on digoxin concentration in serum and skeletal muscle. Eur J Clin Pharmacol 1989; 36: 235–8
2. Edner M, et al. Effect of salbutamol on digoxin pharmacokinetics. Eur J Clin Pharmacol 1992; 42: 197–201
3. Edner M, Jogestrand T. Oral salbutamol decreases serum digoxin concentration. Eur J Clin Pharmacol 1990; 38: 195–7.

Beta

blockers.

Beta

blockers may increase the risk of heart block and bradycardia with digoxin. In addition, carvedilol has been reported1-3 to increase plasma concentrations of digoxin, although the effect is generally small and probably not clinically significant. However, a study4 in 8 children (aged 2 weeks to 7.8 years) found that the clearance of digoxin was about halved by carvedilol and 2 of the children developed digoxin toxicity. An increase in digoxin bioavailability has also been reported with talinolol.5
1. Grunden JW, et al. Augmented digoxin concentrations with carvedilol dosing in mild-moderate heart failure. Am J Ther 1994; 1: 157–161
2. Wermeling DP, et al. Effects of long-term oral carvedilol on the steady-state pharmacokinetics of oral digoxin in patients with mild to moderate hypertension. Pharmacotherapy 1994; 14: 600–6
3. De Mey C, et al. Carvedilol increases the systemic bioavailability of oral digoxin. Br J Clin Pharmacol 1990; 29: 486–90
4. Ratnapalan S, et al. Digoxin-carvedilol interactions in children. J Pediatr 2003; 142: 572–4
5. Westphal K, et al. Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein. Clin Pharmacol Ther 2000; 68: 6–12.

Calcium-channel blockers.

Studies on interactions between digoxin and calcium-channel blockers appear to show that verapamil increases plasma-digoxin concentrations1-3 by up to 70%. The effect of nifedipine is not as clear. Although it has been reported1 to produce a 45% increase in plasma-digoxin concentrations, other studies4,5 have reported little or no increase and the interaction is unlikely to be of clinical significance for most patients. Studies on the interaction between digoxin and diltiazem have also produced conflicting results. Increases in plasma-digoxin concentrations of 20% and up to 59% have been reported6,7and an increase in metildigoxin concentrations7 of up to 51%. However, other studies8,9 have shown no diltiazem-induced change in digoxin pharmacokinetics or plasma concentration. Bepridil,10 gallopamil,1 mibefradil,11 nisoldipine,12 and nitrendipine13 have all been reported to increase plasma-digoxin concentrations. Bepridil increased the concentration by 34% and it was recommended that patients given this combination be monitored carefully. Felodipine14,15 and isradipine3 have both been reported to increase peak serum-digoxin concentrations, but steady-state digoxin concentrations were not affected and the interactions were unlikely to be of clinical relevance. The mechanism of interaction between calcium-channel blockers and digoxin is not completely understood but appears to be related to decreased renal and nonrenal clearance of digoxin. The pharmacodynamic effects of digoxin and calcium-channel blockers may also be additive.
1. Belz GG, et al. Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther 1983; 33: 410–17
2. Pedersen KE, et al. Influence of verapamil on the inotropism and pharmacokinetics of digoxin. Eur J Clin Pharmacol 1983; 25: 199–206
3. Rodin SM, et al. Comparative effects of verapamil and isradipine on steady-state digoxin kinetics. Clin Pharmacol Ther 1988; 43: 668–72
4. Schwartz JB, Migliore PJ. Effect of nifedipine on serum digoxin concentration and renal digoxin clearance. Clin Pharmacol Ther 1984; 36: 19–24
5. Kleinbloesem CH, et al. Interactions between digoxin and nifedipine at steady state in patients with atrial fibrillation. Ther Drug Monit 1985; 7: 372–6
6. Rameis H, et al. The diltiazem-digoxin interaction. Clin Pharmacol Ther 1984; 36: 183–9
7. Oyama Y, et al. Digoxin-diltiazem interaction. Am J Cardiol 1984; 53: 1480–1
8. Beltrami TR, et al. Lack of effects of diltiazem on digoxin pharmacokinetics. J Clin Pharmacol 1985; 25: 390–2
9. Elkayam U, et al. Effect of diltiazem on renal clearance and serum concentration of digoxin in patients with cardiac disease. Am J Cardiol 1985; 55: 1393–5
10. Belz GG, et al. Digoxin and bepridil: pharmacokinetic and pharmacodynamic interactions. Clin Pharmacol Ther 1986; 39: 65–71
11. Siepmann M, et al. The interaction of the calcium antagonist RO 40-5967 with digoxin. Br J Clin Pharmacol 1995; 39: 491–6
12. Kirch W, et al. Influence of nisoldipine on haemodynamic effects and plasma levels of digoxin. Br J Clin Pharmacol 1986; 22: 155–9
13. Kirch W, et al. Nitrendipine increases digoxin plasma levels dose dependently. J Clin Pharmacol 1986; 26: 553
14. Rehnqvist N, et al. Pharmacokinetics of felodipine and effect on digoxin plasma levels in patients with heart failure. Drugs 1987; 34 (suppl 3): 33–42
15. Dunselman PHJM, et al. Digoxin-felodipine interaction in patients with congestive heart failure. Eur J Clin Pharmacol 1988; 35: 461–5.

Diuretics.

Amiloride increased renal clearance of digoxin and reduced the extrarenal digoxin clearance in 6 healthy subjects after a single intravenous dose of digoxin.1 Amiloride also inhibited the digoxin-induced positive inotropic effect, but the clinical implications in cardiac patients are unknown. A further study2failed to confirm this effect. Spironolactone and its metabolites have been reported to interfere with serum-digoxin determinations by radio-immunoassay or fluorescence-polarisation immunoassay resulting in falsely elevated measurements.3,4 The interference with digoxin assays is neither consistent nor predictable and falsely low readings have also been reported.5 Serum-digoxin concentrations should be interpreted with caution when digoxin is given together with spironolactone or canrenoate, especially since spironolactone has also been reported to decrease digoxin clearance by a median of 26% resulting in a true increase in the serum-digoxin concentration.6 Diuretic therapy with triamterene in association with a thiazide or loop diuretic increased the mean serum-digoxin concentration; this interaction was considered unlikely to be of clinical importance, except perhaps in patients with renal impairment.7
1. Waldorff S, et al. Amiloride-induced changes in digoxin dynamics and kinetics: abolition of digoxin-induced inotropism with amiloride. Clin Pharmacol Ther 1981; 30: 172–6
2. Richter JP, et al. The acute effects of amiloride and potassium canrenoate on digoxin-induced positive inotropism in healthy volunteers. Eur J Clin Pharmacol 1993; 45: 195–6
3. Paladino JA, et al. Influence of spironolactone on serum digoxin concentration. JAMA 1984; 251: 470–1
4. Foukaridis GN. Influence of spironolactone and its metabolite canrenone on serum digoxin assays. Ther Drug Monit 1990; 12: 82–4
5. Steimer W, et al. Intoxication due to negative canrenone interference in digoxin drug monitoring. Lancet 1999; 354: 1176–7
6. Waldorff S, et al. Spironolactone-induced changes in digoxin kinetics. Clin Pharmacol Ther 1978; 24: 162–7
7. Impivaara O, Iisalo E. Serum digoxin concentrations in a representative digoxin-consuming adult population. Eur J Clin Pharmacol 1985; 27: 627–32.

Gastrointestinal drugs.

Some gastrointestinal drugs can affect the absorption of digoxin by binding to it or by changing gastrointestinal motility. The problem has often been related to the bioavailability of the digoxin formulation and appears to be less important with currently used preparations. Some antacids,1,2 particularly liquid formulations, and adsorbents1 such as kaolin-pectin, can reduce the absorption of digoxin from the gastrointestinal tract and doses should probably be separated by at least 2 hours. Activated charcoal, and ion-exchange resins such as colestyramine and colestipol, also reduce digoxin absorption. Sucralfate3 may also reduce the absorption of digoxin. Omeprazole and possibly other gastric acid inhibitors may reduce the gastrointestinal metabolism and enhance the absorption of unchanged digoxin,4 although the clinical relevance of this is uncertain.5 Drugs that increase gastrointestinal motility can reduce the absorption of digoxin, especially if digoxin is given as a slowly dissolving formulation. Reduced absorption of digoxin has occurred when digoxin and metoclopramide have been given together,6 and a similar effect has been reported with cisapride7and tegaserod.8 Conversely, anticholinergics reduce motility, and propantheline has increased digoxin absorption. Sulfasalazine has been found to impair the absorption of digoxin and to reduce the serum-digoxin concentration,9 but the mechanism is unclear.
1. Rodin SM, Johnson BF. Pharmacokinetic interactions with digoxin. Clin Pharmacokinet 1988; 15: 227–44
2. Gugler R, Allgayer H. Effects of antacids on the clinical pharmacokinetics of drugs: an update. Clin Pharmacokinet 1990; 18: 210–19
3. Rey AM, Gums JG. Altered absorption of digoxin, sustained-release quinidine, and warfarin with sucralfate administration. DICP Ann Pharmacother 1991; 25: 745–6
4. Cohen AF, et al. Influence of gastric acidity on the bioavailability of digoxin. Ann Intern Med 1991; 115: 540–5
5. Oosterhuis B, et al. Minor effect of multiple dose omeprazole on the pharmacokinetics of digoxin after a single oral dose. Br J Clin Pharmacol 1991; 32: 569–72
6. Johnson BF, et al. Effect of metoclopramide on digoxin absorption from tablets and capsules. Clin Pharmacol Ther 1984; 36: 724–30
7. Kubler PA, et al. Possible interaction between cisapride and digoxin. Ann Pharmacother 2001; 35: 127–8
8. Zhou H, et al. The effects of tegaserod (HTF 919) on the pharmacokinetics and pharmacodynamics of digoxin in healthy subjects. J Clin Pharmacol 2001; 41: 1131–9
9. Juhl RP, et al. Effect of sulfasalazine on digoxin bioavailability. Clin Pharmacol Ther 1976; 20: 387–94.

Ginseng.

Varieties of ginseng may interfere with plasma-digoxin assays (see under Precautions, above).

Immunosuppressants.

Increased serum-digoxin concentrations with symptoms of toxicity have been reported in patients when ciclosporin was added to their digoxin therapy.1,2
1. Dorian P, et al. Digoxin-cyclosporine interaction: severe digitalis toxicity after cyclosporine treatment. Clin Invest Med 1988; ii: 108–12
2. Robieux I, et al. The effects of cardiac transplantation and cyclosporine therapy on digoxin pharmacokinetics. J Clin Pharmacol 1992; 32: 338–43.

Lipid regulating drugs.

Small increases in plasma-digoxin concentrations have been reported with some statins, although the clinical significance is not clear. Atorvastatin at doses of 80 mg, but not of 10 mg, has been shown1 to increase plasma digoxin concentrations by about 20%. This may be due to the inhibition of P-glycoprotein-mediated secretion of digoxin in the intestine by atorvastatin.
1. Boyd RA, et al. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoproteinmediated secretion. J Clin Pharmacol 2000; 40: 91–98.

Neuromuscular blockers.

Pancuronium or suxamethonium may interact with digitalis glycosides resulting in an increased incidence of arrhythmias; the interaction is more likely with pancuronium.1
1. Bartolone RS, Rao TLK. Dysrhythmias following muscle relaxant administration in patients receiving digitalis. Anesthesiology 1983; 58: 567–9.

NSAIDs.

An increase in serum-digoxin concentration has been reported with aspirin, ibuprofen, indometacin, fenbufen, and diclofenac.1 Potentially toxic serum-digoxin concentrations occurred in preterm infants2 with patent ductus arteriosus receiving digoxin when given indometacin orally in a mean total dose of 320 micrograms/kg; it was recommended that the dose of digoxin should be halved initially if indometacin is also given. Lack of increase in serum-digoxin concentrations has also been reported with aspirin or indometacin, as well as with ketoprofen, and tiaprofenic acid,1and also with rofecoxib,3 but some of these studies were in healthy subjects and it is advised that digoxin therapy be monitored carefully whenever any NSAID is started or stopped in digitalised patients.
1. Verbeeck RK. Pharmacokinetic drug interactions with nonsteroidal anti-inflammatory drugs. Clin Pharmacokinet 1990; 19: 44–66
2. Koren G, et al. Effects of indomethacin on digoxin pharmacokinetics in preterm infants. Pediatr Pharmacol 1984; 4: 25–30
3. Schwartz JI, et al. Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol 2001; 41: 107–112.

💊 Pharmacokinetics

The absorption of digoxin from the gastrointestinal tract is variable depending upon the formulation used. About 70% of a dose is absorbed from tablets which comply with BP or USP specifications, 80% is absorbed from an elixir, and over 90% is absorbed from liquid-filled soft gelatin capsules. The generally accepted therapeutic plasma concentration range is 0.5 to 2.0 nanograms/mL but there is considerable interindividual variation. Digoxin has a large volume of distribution and is widely distributed in tissues, including the heart, brain, erythrocytes, and skeletal muscle. The concentration of digoxin in the myocardium is considerably higher than in plasma. From 20 to 30% is bound to plasma proteins. Digoxin has been detected in CSF and breast milk; it also crosses the placenta. It has an elimination half-life of 1.5 to 2 days. Digoxin is mainly excreted unchanged in the urine by glomerular filtration and tubular secretion; reabsorption also occurs. Extensive metabolism has been reported in a minority of patients (see under Metabolism and Excretion, below). Excretion of digoxin is proportional to the glomerular filtration rate. After intravenous injection 50 to 70% of the dose is excreted unchanged. Digoxin is not removed from the body by dialysis, and only small amounts are removed by exchange transfusion and during cardiopulmonary bypass.
1. Iisalo E. Clinical pharmacokinetics of digoxin. Clin Pharmacokinet 1977; 2: 1–16
2. Aronson JK. Clinical pharmacokinetics of digoxin 1980. Clin Pharmacokinet 1980; 5: 137–49
3. Mooradian AD. Digitalis: an update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Clin Pharmacokinet 1988; 15: 165–79.

Absorption.

Studies in 6 healthy subjects found that food decreased the rate but not the extent of absorption of digoxin.1
1. Johnson BF, et al. Effect of a standard breakfast on digoxin absorption in normal subjects. Clin Pharmacol Ther 1978; 23: 315–19.

Bioavailability.

Large variations in the content, disintegration, and dissolution of solid dosage forms of digoxin preparations have led to large variations in plasma concentrations from different proprietary preparations. Other factors involved in varying bioavailability include the pharmaceutical formulation and presentation (capsules, solution, or tablets), particle size, and biological factors. Serious problems occurred in the UK1 in 1972 and in Israel2 in 1975 after changes in the manufacturing procedure for Lanoxin led to a twofold increase in bioavailability.
1. Anonymous. Therapeutic non-equivalence. BMJ 1972; 3: 599–600
2. Danon A, et al. An outbreak of digoxin intoxication. Clin Pharmacol Ther 1977; 21: 643–6.

Distribution and protein binding.

Digoxin has been reported to be 5 to 60% bound to plasma proteins,1 depending partly on the method of measurement, but the figure is usually around 20%. Protein binding is reduced in patients undergoing haemodialysis; mean reductions of about 8 and 10% have been reported.1,2 Injection of heparin has produced a similar reduction.2 Digoxin is widely distributed to tissues and serum-digoxin concentrations have been reported to be increased during immobilisation3 and decreased during exercise4,5 due to changes in binding to tissues such as skeletal muscle.
1. Storstein L. Studies on digitalis V: the influence of impaired renal function, hemodialysis, and drug interaction on serum protein binding of digitoxin and digoxin. Clin Pharmacol Ther 1976; 20: 6–14
2. Storstein L, Janssen H. Studies on digitalis VI: the effect of heparin on serum protein binding of digitoxin and digoxin. Clin Pharmacol Ther 1976; 20: 15–23
3. Pedersen KE, et al. Effects of physical activity and immobilization on plasma digoxin concentration and renal digoxin clearance. Clin Pharmacol Ther 1983; 34: 303–8
4. Joreteg T, Jogestrand T. Physical exercise and digoxin binding to skeletal muscle: relation to exercise intensity. Eur J Clin Pharmacol 1983; 25: 585–8
5. Joreteg T, Jogestrand T. Physical exercise and binding of digoxin to skeletal muscle—effect of muscle activation frequency. Eur J Clin Pharmacol 1984; 27: 567–70.

The elderly.

For references to alterations in the pharmacokinetics of digoxin in the elderly, see under Uses and Administration, below.

Infants and neonates.

Digoxin has been widely used in the treatment of cardiac disorders in neonates and infants and its pharmacokinetics in this age group have been reviewed.1,2 In full-term neonates or infants, 80 to 90% of a dose of digoxin given orally in liquid form is absorbed, with peak plasma concentrations occurring within 30 to 120 minutes. The rate of absorption may be slower in preterm and low birth-weight infants, with peak concentrations achieved at 90 to 180 minutes, and may be significantly reduced in severe heart failure and in malabsorption syndromes. After digoxin is given intravenously there is a rapid distribution phase with an apparent half-life of 20 to 40 minutes followed by a slower exponential decay of plasma concentrations. In full-term neonates, digoxin has an apparent volume of distribution of 6 to 10 litres/kg. Low birth-weight infants have a volume of distribution of 4.3 to 5.7 litres/kg while in older infants the volume may range from 10 to 22 litres/kg which is 1.5 to 2 times reported adult values. This large volume of distribution in full-term neonates and infants is thought to be due to increased tissue binding, a larger extracellular fluid volume, and slightly lower plasma protein binding. The apparent plasma half-life in healthy and sick neonates is generally very long and may range from 20 to 70 hours in full-term neonates or from 40 to 180 hours in preterm neonates. Digoxin is eliminated at a considerably faster rate in infants than in neonates and, in parallel with maturation of kidney function, a marked increase in clearance rate is usually observed between the second and third month of life. The large apparent volume of distribution, higher clearance values, and greater concentrations of digoxin in the myocardial tissue and red cells of infants might justify the traditional assumption that infants tolerate digoxin better than adults and that higher doses are consequently needed in infants. However, studies have shown that in infants, as in adults, toxic signs become evident at plasma-digoxin concentrations above 3 nanograms/mL and that the therapeutic range may be 1.5 to 2 nanograms/mL.
1. Morselli PL, et al. Clinical pharmacokinetics in newborns and infants: age-related differences and therapeutic implications. Clin Pharmacokinet 1980; 5: 485–527
2. Besunder JB, et al. Principles of drug biodisposition in the neonate: a critical evaluation of the pharmacokinetic-pharmacodynamic interface. Clin Pharmacokinet 1988; 14: 189–216 (part I) and 261–86 (part II).

Metabolism and excretion.

Although digoxin is reported to be excreted mainly unchanged in the urine there is evidence to suggest that metabolism may sometimes be extensive. Metabolites that have been detected in the urine include digoxigenin, dihydrodigoxigenin, the mono- and bisdigitoxosides of digoxigenin, and dihydrodigoxin. Digoxigenin mono- and bisdigitoxosides are known to be cardioactive whereas dihydrodigoxin is probably much less active than digoxin.1 In about 10% of patients there is considerable reduction to cardio-inactive metabolites, chiefly dihydrodigoxin, and 40% or more of a dose may be excreted in the urine as dihydrodigoxin.2-4Bacterial flora in the gastrointestinal tract appear to be responsible for this metabolism and antibacterials can reduce the process. Oral digoxin formulations with a high bioavailability are mostly absorbed in the stomach and upper small intestine and little digoxin is available in the lower intestine for bacterial degradation to dihydrodigoxin.4 The excretion of digoxin is thought to be mediated by the efflux pump, P-glycoprotein,5 which transports its substrates out of the cell. This may be the basis for some interactions hitherto poorly understood,6 although the hypothesis has been questioned.7
1. Iisalo E. Clinical pharmacokinetics of digoxin. Clin Pharmacokinet 1977; 2: 1–16
2. Doherty JE. A digoxin-antibiotic drug interaction. N Engl J Med 1981; 305: 827–8
3. Rund DG, et al. Decreased digoxin cardioinactive-reduced metabolites after administration of an encapsulated liquid concentrate. Clin Pharmacol Ther 1983; 34: 738–43
4. Lofts F, et al. Digoxin metabolism to reduced products: clinical significance. Br J Clin Pharmacol 1986; 21: 600P
5. Tanigawara Y. Role of P-glycoprotein in drug disposition. Ther Drug Monit 2000; 22: 137–40
6. Fromm MF. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 2000; 38: 69–74
7. Chiou WL, et al. A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans. Int J Clin Pharmacol Ther 2001; 39: 93–101.

Renal impairment.

For references to alterations in the pharmacokinetics of digoxin in patients with renal impairment, see under Uses and Administration, below.

💊 Uses and Administration

Digoxin is a cardiac glycoside used in the management of supraventricular arrhythmias, particularly atrial fibrillation, and in heart failure. The principal actions of digoxin are an increase in the force of myocardial contraction (positive inotropic activity) and a reduction in the conductivity of the heart, particularly in conduction through the atrioventricular (AV) node. Digoxin also has a direct action on vascular smooth muscle and indirect effects mediated primarily by the autonomic nervous system, and particularly by an increase in vagal activity. There are also reflex alterations in autonomic activity due to the effects on the circulation. Overall, these actions result in positive inotropic effects, negative chronotropic effects, and decreased AV nodal activity. Cardiac arrhythmias. In atrial arrhythmias digoxin’s actions cause a decrease in the conduction velocity through the AV node and an increase in the effective refractory period, thus reducing ventricular rate. In addition there is a decrease in the refractory period of the cardiac muscle and depression of the sinus node partly in response to the increase in vagal activity. Digoxin is thus given to slow the increased ventricular rate that occurs in response to atrial fibrillation, although other drugs may be preferred; treatment is usually long term. In patients with the Wolff-ParkinsonWhite syndrome and atrial fibrillation, digoxin can cause rapid ventricular rates, and possibly ventricular fibrillation, and should be avoided. In atrial flutter, the ventricular rate is normally more difficult to control with digoxin. Drug therapy is not the preferred method of treatment, but treatment with digoxin may restore sinus rhythm, or it may convert the flutter to fibrillation and sinus rhythm may then be induced by subsequent withdrawal of digoxin. Digoxin may be given to relieve an attack of paroxysmal supraventricular tachycardia and has also been given to prevent further attacks. Heart failure. Digoxin and other cardiac glycosides directly inhibit the activity of the enzyme sodium-potassium adenosine triphosphatase (Na/K-ATPase), which is required for the active transport of sodium from myocardial cells. The result is a gradual increase in the intracellular sodium concentration and a decrease in the intracellular potassium concentration. The increased concentration of sodium inside the cells leads, by stimulation of sodium-calcium exchange, to an increase in the intracellular calcium concentration with enhancement of mechanical contractile activity and an increased inotropic effect. When used in heart failure the increased force of myocardial contraction results in increased cardiac output, decreased end-systolic volume, decreased heart size, and decreased end-diastolic pressure and volume. Increased blood flow through the kidneys results in diuresis with a reduction in oedema and blood volume. The decrease in pulmonary venous pressure relieves dyspnoea and orthopnoea. Digoxin may thus provide symptomatic improvement in patients with heart failure and is mainly used for adjunctive therapy. Dosage. When given orally, digoxin may take effect within about 2 hours and the maximum effect may be reached in about 6 hours. Initially a loading dose may be given to digitalise the patient, although this may not be necessary in, for example, mild heart failure. Dosage should be carefully adjusted to the needs of the individual patient. Factors which may be considered include the patient’s age, lean body-mass, renal status, thyroid status, electrolyte balance, degree of tissue oxygenation, and the nature of the underlying cardiac or pulmonary disease. Bearing in mind the above factors, steady-state plasma-digoxin concentrations (in a sample taken at least 6 hours after a dose) of 0.5 to 2 nanograms/mL are generally considered acceptable, although in patients with heart failure concentrations at the lower end of the range may be more appropriate. For reference to therapeutic drug monitoring, see below. If rapid digitalisation is required then a loading dose is given to allow for the large volume of distribution. A total loading dose of 750 to 1500 micrograms of digoxin may be given by mouth during the initial 24-hour period, either as a single dose, or where there is less urgency or greater risk of toxicity, in divided doses at 6-hourly intervals. In some patients, for example those with mild heart failure, a loading dose may not be necessary, and digitalisation may be achieved more slowly with doses of 250 micrograms once or twice daily; steady-state plasma concentrations are achieved in about 7 days in patients with normal renal function. The usual maintenance dose of digoxin is 125 to 250 micrograms by mouth daily, but may range from 62.5 to 500 micrograms daily. In elderly patients therapy should generally start gradually and with smaller doses (but see under Administration in the Elderly, below). In urgent cases, provided that the patient has not received cardiac glycosides during the previous 2 weeks, digoxin may be given intravenously initially. The intravenous dose ranges from 500 to 1000 micrograms and generally produces a definite effect on the heart rate in about 10 minutes, reaching a maximum within about 2 hours. It is given by intravenous infusion, either as a single dose given over 2 or more hours, or in divided doses each over 10 to 20 minutes. Maintenance treatment is then usually given by mouth. Digoxin has also been given intramuscularly but this route is not generally recommended since such injections may be painful and tissue damage has been reported. Digoxin should not be given subcutaneously as intense local irritation may occur. Children’s doses are complex. They are based on bodyweight and the developmental stage of the child as well as on response. Premature infants are especially sensitive to digoxin but, along with all other neonates, infants, and children up to about 10 years of age, still require doses that are higher per kg body-weight than those used for adults. Preterm infants receive lower doses than full-term infants, while children aged 2 to 10 years require lower doses than children up to 2 years of age. As an indication of the doses used, oral loading doses recommended by licensed product information in the UK range from 25 to 45 micrograms/kg over 24 hours and in the USA the range is 20 to 60 micrograms/kg; the range for intravenous loading doses given over 24 hours is 20 to 35 micrograms/kg in the UK and 15 to 50 micrograms/kg in the USA. Doses should be reduced in patients with renal impairment (see below).
1. Opie LH. Digitalis and sympathomimetic stimulants. Lancet 1980; i: 912–18
2. Taggart AJ, McDevitt DG. Digitalis: its place in modern therapy. Drugs 1980; 20: 398–404
3. Chamberlain DA. Digitalis: where are we now? Br Heart J 1985; 54: 227–33
4. Doherty JE. Clinical use of digitalis glycosides: an update. Cardiology 1985; 72: 225–54
5. Smith TW. Digitalis: mechanisms of action and clinical use. N Engl J Med 1988; 318: 358–65
6. Hampton JR. Digoxin. Br J Hosp Med 1997; 58: 321–3
7. Riaz K, Forker AD. Digoxin use in congestive heart failure: current status. Drugs 1998; 55: 747–58
8. Campbell TJ, MacDonald PS. Digoxin in heart failure and cardiac arrhythmias. Med J Aust 2003; 179: 98–102.

Administration in the elderly.

The volume of distribution of digoxin and the elimination half-life increase with age.1 Therefore there are problems in giving digoxin to elderly patients since steady-state plasma concentrations may not be reached for up to 2 weeks. Fears of toxicity have led some practitioners to use a fixed ‘geriatric’ dose of 62.5 micrograms daily. However, such a dose can produce subtherapeutic concentrations.2 The routine use of very low doses of digoxin in the elderly is inappropriate and dosage should be individualised.
1. McMurray J, McDevitt DG. Treatment of heart failure in the elderly. Br Med Bull 1990; 46: 202–29
2. Nolan L, et al. The need for reassessment of digoxin prescribing for the elderly. Br J Clin Pharmacol 1989; 27: 367–70.

Administration in renal impairment.

The pharmacokinetics of cardiac glycosides in patients with renal impairment have been reviewed.1 The rate but not the extent of digoxin absorption is reduced in renal impairment but this is unlikely to be clinically important. Plasma-protein binding may also be reduced but since digoxin is poorly bound to these proteins and has a large apparent volume of distribution this also is unlikely to be important. The apparent volume of distribution is reduced by one-third to onehalf and the loading dose of digoxin should therefore be reduced; an oral loading dose of 10 micrograms/kg is suggested (but see also under Therapeutic Drug Monitoring, below). Non-renal clearance of digoxin is unaffected or only slightly reduced but renal clearance is reduced, the extent being closely related to creatinine clearance. The elimination half-life of digoxin is prolonged and it therefore takes longer to reach steady state and longer for toxicity to resolve. Because of the reduction in renal clearance of digoxin, maintenance doses must be reduced in line with renal function. Serum-digoxin concentration should be monitored although the presence of digoxin-like immunoreactive substances may make interpretation difficult. In addition, the presence of hyperkalaemia in patients with renal impairment may reduce sensitivity to the effects of digoxin.2 Since digoxin has such a large distribution volume, procedures such as peritoneal dialysis and haemodialysis remove only very small amounts of drug from the body and no dosage supplement is needed.
1. Aronson JK. Clinical pharmacokinetics of cardiac glycosides in patients with renal dysfunction. Clin Pharmacokinet 1983; 8: 155–78
2. Matzke GR, Frye RF. Drug administration in patients with renal insufficiency: minimising renal and extrarenal toxicity. Drug Safety 1997; 16: 205–31.

Therapeutic drug monitoring.

Digoxin has a narrow therapeutic index. It is generally considered that plasma-digoxin concentrations required for a therapeutic effect are usually between 0.5 and 2.0 nanograms/mL,1-3 although some studies4-6 have suggested that concentrations of 0.5 to 0.9 nanograms/mL are adequate for heart failure; concentrations at the upper end of the range may be associated with worse outcomes.5,6 The factor for converting nanograms/mL to nanomoles/litre is 1.28. Digoxin dosage can be calculated in uncomplicated cases by considering the patient’s weight, renal function, and clinical status. Therapeutic drug monitoring is not considered to be necessary in patients with a satisfactory clinical response to conventional doses in the absence of signs or symptoms of toxicity.1,2Measurement of plasma-digoxin concentrations is useful if poor compliance is suspected, if response is poor or there is a deterioration in response without apparent reason, if renal function is fluctuating, when it is unknown if a cardiac glycoside has been previously taken, during drug interactions, and to confirm clinical toxicity.1,3,7 A plasma concentration should never be considered in isolation and should be used with other patient data as an important component in clinical decision making. This is particularly important in the diagnosis of digoxin toxicity since signs and symptoms of toxicity may be difficult to distinguish from the underlying disease and can occur within the usual therapeutic range. A number of factors may influence the response to digoxin and thus the interpretation of digoxin assays. These include renal impairment, extremes of age, thyroid disease, patient compliance, drug interactions, and electrolyte disturbances.1-3,7 Variations in the bioavailability of different digoxin preparations have also caused problems. Renal impairment and hypokalaemia are two of the most important factors affecting dosage of digoxin and whenever plasma-digoxin concentrations are assayed renal function and plasma potassium should also be measured. A dosing nomogram has been proposed8 relating dose in patients with heart failure to renal function and either height or ideal body weight: for most patients with moderate or severe renal impairment (creatinine clearance below 60 mL/minute) an oral dose of 125 micrograms every other day was considered sufficient. The interpretation of digoxin assays is further confounded by the presence of digoxin-like immunoreactive substances in patients with renal or hepatic impairment, in pregnant women, and in neonates. Blood samples for digoxin assay should be taken at least 6 hours after a dose to allow for distribution.1,3,7 The usefulness of plasma-digoxin concentrations in the diagnosis of toxicity in children is unclear. For children older than 12 months the adult guidelines can probably be followed, and for younger children the trend for increased risk of toxicity at increased plasma-digoxin concentrations appears to hold but the threshold for toxicity may be higher, especially in children less than 3 months old.1
1. Aronson JK. Indications for the measurement of plasma digoxin concentrations. Drugs 1983; 26: 230–42
2. Lee TH, Smith TW. Serum digoxin concentration and diagnosis of digitalis toxicity: current concepts. Clin Pharmacokinet 1983; 8: 279–85
3. Aronson JK, Hardman M. Digoxin. BMJ 1992; 305: 1149–52
4. Adams KF, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002; 39: 946–53
5. Rathore SS, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289: 871–8
6. Adams KF, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the Digitalis Investigation Group trial: a retrospective analysis. J Am Coll Cardiol 2005; 46: 497–504
7. Brodie MJ, Feely J. Practical clinical pharmacology: therapeutic drug monitoring and clinical trials. BMJ 1988; 296: 1110–14
8. Bauman JL, et al. A method of determining the dose of digoxin for heart failure in the modern era. Arch Intern Med 2006; 166: 2539–45.

💊 Preparations

BP 2008: Digoxin Injection; Digoxin Tablets; Paediatric Digoxin Injection; Paediatric Digoxin Oral Solution; USP 31: Digoxin Elixir; Digoxin Injection; Digoxin Tablets.

Proprietary Preparations

Arg.: Cardiogoxin; Digocard-G; Lanicor; Lanoxin; Austral.: Lanoxin; Sigmaxin; Austria: Lanicor; Belg.: Lanoxin; Braz.: Cardcor; Cardionil; Cimecard; Digitax; Digixina†; Digobal; Digox†; Digoxan†; Digoxen; Digoxil; Lanoxin†; Valoxin; Canad.: Lanoxin; Fr.: Hemigoxine Nativelle; Ger.: Digacin; Digoregen†; Dilanacin†; Lanicor; Lenoxin; Hong Kong: Lanoxin; India: Cardioxin†; Lanoxin; Indon.: Fargoxin; Lanoxin; Irl.: Lanoxin; Israel: Lanoxin; Ital.: Eudigox; Lanoxin; Jpn: Digosin; Malaysia: Lanoxin; Mex.: Lanoxin; Mapluxin; Neth.: Lanoxin; Norw.: Lanoxin; NZ: Lanoxin; Philipp.: Lanoxin; Port.: Lanoxin; S.Afr.: Lanoxin; Purgoxin; Singapore: Lanoxin; Spain: Lanacordin; Swed.: Lanacrist; Lanoxin; Thai.: Grexin; Lanoxin; To l o x i n ; UK: Lanoxin; USA: Digitek; Lanoxicaps†; Lanoxin; Venez.: Lanicor.
Published January 28, 2019.