Abstract
Digoxin remains one of the most commonly prescribed of all cardiac medications. The main indications for digoxin usage include atrial fibrillation and heart failure; both these conditions are more prevalent in older patients. Given the aging population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even increase in older patients. Older patients are also more likely to develop toxicity and diagnosis of digoxin toxicity can be difficult in this group. Numerous components contribute to the development of toxicity in older patients, ranging from aging-related changes in renal function or body mass to polypharmacy and possible interactions with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. Application of basic pharmacological principles may be helpful in anticipating these problems. This review describes the pharmacokinetics of digoxin, the changes in pharmacokinetics with increasing age and how concomitant disease states or drug interactions may affect the pharmacokinetics of digoxin. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin toxicity, especially in the elderly population.
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References
Passmore AP, Crawford VL, Beringer TR, et al. Determinants of drug utilisation in an elderly population in North and West Belfast. Pharmacoepidemiol Drug Saf 1995; 4: 147–60
Smith TW. Pharmacokinetics, bioavailability and serum levels of cardiac glycosides. J Am Coll Cardiol 1985; 5: 43–50
Caldwell JH, Martin JF, Dutta S, et al. Intestinal absorption of digoxin-3H in the rat. Am J Physiol 1969; 217: 1747–51
Cusack B, Kelly J, O’Malley K, et al. Digoxin in the elderly: pharmacokinetic consequences of old age. Clin Pharmacol Ther 1979; 25: 772–6
Passmore AP, Johnston GD. Digoxin toxicity in the aged: characterising and avoiding the problem. Drugs Aging 1991; 1: 364–79
Sumner DJ, Russell AJ. Digoxin pharmacokinetics: multi-compartmental analysis and its clinical implications. Br J Clin Pharmacol 1976; 3: 221–9
Su SF, Huang JD. Inhibition of the intestinal digoxin absorption and exsorption by quinidine. Drug Metab Dispos 1996; 24: 142–7
de Lannoy IA, Silverman M. The MDR1 gene product, P-glycoprotein, mediates the transport of the cardiac glycoside, digoxin. Biochem Biophys Res Commun 1992; 189: 551–7
Hammerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly: clinical implications. Clin Pharmacokinet 1998; 35: 49–64
Castleden CM, Volans CN, Raymond K. The effect of ageing on drug absorption from the gut. Age Ageing 1977; 6: 138–43
Rowe JW, Andres R, Tobin JD, et al. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol 1976; 31: 155–63
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41
Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993; 22: 955–62
Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors: RADIANCE Study. N Engl J Med 1993; 329: 1–7
Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33
Falk RH, Knowlton AA, Bernard SA, et al. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm: a randomized, double-blinded trial. Ann Intern Med 1987; 106: 503–6
Galun E, Flugelman MY, Glickson M, et al. Failure of long-term digitalization to prevent rapid ventricular response in patients with paroxysmal atrial fibrillation. Chest 1991; 99: 1038–40
Shammas FV, Dickstein K. Clinical pharmacokinetics in heart failure: an updated review. Clin Pharmacokinet 1988; 15: 94–113
Borst SE, Lowenthal DT. Cardiovascular drugs in the elderly. Cardiovasc Clin 1992; 22: 161–73
Brown DD, Dormois JC, Abraham GN, et al. Effect of furosemide on the renal excretion of digoxin. Clin Pharmacol Ther 1976; 20: 395–400
Hall RJ, Gelbart A, Billingham M, et al. Effect of chronic potassium depletion on digitalis-induced inotropy and arrhythmias. Cardiovasc Res 1981; 15: 98–107
Steiness E. Digoxin toxicity compared with myocardial digoxin and potassium concentration. Br J Pharmacol 1978; 63: 233–7
Waldorff S, Hansen PB, Egeblad H, et al. Interactions between digoxin and potassium-sparing diuretics. Clin Pharmacol Ther 1983; 33: 418–23
Hedman A, Angelin B, Arvidsson A, et al. Digoxin-interactions in man: spironolactone reduces renal but not biliary digoxin clearance. Eur J Clin Pharmacol 1992; 42: 481–5
Cleland JG, Dargie HJ, Pettigrew A, et al. The effects of captopril on serum digoxin and urinary urea and digoxin clearances in patients with congestive heart failure. Am Heart J 1986; 112: 130–5
Miyakawa T, Shionoiri H, Takasaki I, et al. The effect of captopril on pharmacokinetics of digoxin in patients with mild congestive heart failure. J Cardiovasc Pharmacol 1991; 17: 576–80
Doering W, Maass L, Irmisch R, et al. Pharmacokinetic interaction study with ramipril and digoxin in healthy volunteers. Am J Cardiol 1987; 59: 60–4
Vandenburg MJ, Stephens JD, Resplandy G, et al. Digoxin pharmacokinetics and perindopril in heart failure patients. J Clin Pharmacol 1993; 33: 146–9
De Smet M, Schoors DF, De Meyer G, et al. Effect of multiple doses of losartan on the pharmacokinetics of single doses of digoxin in healthy volunteers. Br J Clin Pharmacol 1995; 40: 571–5
Martin DE, Tompson D, Boike SC, et al. Lack of effect of eprosartan on the single dose pharmacokinetics of orally administered digoxin in healthy male volunteers. Br J Clin Pharmacol 1997; 43: 661–4
Lefebvre RA, Bogaert MG, Duprez D. et al. Investigation of possible pharmacokinetic and pharmacodynamic interactions between epanolol and digoxin. Eur J Clin Pharmacol 1990; 38: 505–7
Ryan JR. Clinical pharmacology of acebutolol. Am Heart J 1985; 109: 1131–6
Lowenthal DT, Porter RS, Achari R, et al. Esmolol-digoxin drug interaction. J Clin Pharmacol 1987; 27: 561–6
Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334: 1349–55
De Mey C, Brendel E, Enterling D. Carvedilol increases the systemic bioavailability of oral digoxin. Br J Clin Pharmacol 1990; 29: 486–90
Ejvinsson G. Effect of quinidine on plasma concentrations of digoxin. BMJ 1978; I: 279–80
Schenck-Gustafsson K, Dahlqvist R. Pharmacokinetics of digoxin in patients subjected to the quinidine-digoxin interaction. Br J Clin Pharmacol 1981; 11: 181–6
Doering W. Quinidine-digoxin interaction: pharmacokinetics, underlying mechanism and clinical implications. N Engl J Med 1979; 301: 400–4
Fromm MF, Kim RB, Stein CM, et al. Inhibition of P-glyco-protein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 1999; 99: 552–7
Doering W, Fichtl B, Herrmann M, et al. Quinidine-digoxin interaction: evidence for involvement of an extrarenal mechanism. Eur J Clin Pharmacol 1982; 21: 281–5
Fenster PE, Hager WD, Perrier D, et al. Digoxin-quinidine interaction in patients with chronic renal failure. Circulation 1982; 66: 1277–80
Angelin B, Arvidsson A, Dahlqvist R, et al. Quinidine reduces biliary clearance of digoxin in man. Eur J Clin Invest 1987; 17: 262–5
Leahey EBJ, Bigger JTJ, Butler VPJ, et al. Quinidine-digoxin interaction: time course and pharmacokinetics. Am J Cardiol 1981; 48: 1141–6
Leahey EBJ, Reiffel JA, Drusin RE, et al. Interaction between quinidine and digoxin. JAMA 1978; 240: 533–4
Leahey EBJ, Reiffel JA, Heissenbuttel RH, et al. Enhanced cardiac effect of digoxin during quinidine treatment. Arch Intern Med 1979; 139: 519–21
Reiffel JA, Leahey EBJ, Drusin RE, et al. A previously unrecognized drug interaction between quinidine and digoxin. Clin Cardiol 1979; 2: 40–2
Gessman L, Danilo PJ, Rosen MR. An electrophysiologic study of the digoxin-quinidine interaction. J Clin Pharmacol 1982; 23: 16–23
Walker AM, Cody RJJ, Greenblatt DJ, et al. Drug toxicity in patients receiving digoxin and quinidine. Am Heart J 1983; 105: 1025–8
Moysey JO, Jaggarao NS, Grundy EN, et al. Amiodarone increases plasma digoxin concentrations. BMJ 1994; 1981: 272
Fenster PE, White NWJ, Hanson CD. Pharmacokinetic evaluation of the digoxin-amiodarone interaction. J Am Coll Cardiol 1985; 5: 108–12
Nademanee K, Kannan R, Hendrickson J, et al. Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications. J Am Coll Cardiol 1984; 4: 111–6
Bajaj BP, Baig MW, Perrins EJ. Amiodarone-induced torsades de pointes: the possible facilitatory role of digoxin. Int J Cardiol 1991; 33: 335–7
Leahey EBJ, Reiffel JA, Giardina EG, et al. The effect of quinidine and other oral antiarrhythmic drugs on serum digoxin: a prospective study. Ann Intern Med 1980; 92: 605–8
Lewis GP, Holtzman JL. Interaction of flecainide with digoxin and propranolol. Am J Cardiol 1984; 53: 52–7
Wellens HJ, Gorgels AP, Braat SJ, et al. Effect of oral disopyramide on serum digoxin levels: a prospective study. Am Heart J 1980; 100: 934–5
Schwartz JB, Migliore PJ. Effect of nifedipine on serum digoxin concentration and renal digoxin clearance. Clin Pharmacol Ther 1984; 36: 19–24
Klein HO, Lang R, Di Segni E, et al. Verapamil-digoxin interaction [letter]. N Engl J Med 1980; 303: 160–160
Pedersen KE, Dorph-Pedersen A, Hvidt S, et al. Digoxin-verapamil interaction. Clin Pharmacol Ther 1981; 30: 311–6
Rodin SM, Johnson BF, Wilson J, et al. Comparative effects of verapamil and isradipine on steady-state digoxin kinetics. Clin Pharmacol Ther 1988; 43: 668–72
Beltrami TR, May JJ, Bertino JSJ. Lack of effects of diltiazem on digoxin pharmacokinetics. J Clin Pharmacol 1985; 25: 390–2
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9
Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–9
Garnett WR, Venitz J, Wilkens RC, et al. Pharmacokinetic effects of fluvastatin in patients chronically receiving digoxin. Am J Med 1994; 96: 84–6
Triscari J, Swanson BN, Willard DA, et al. Steady state serum concentrations of pravastatin and digoxin when given in combination. Br J Clin Pharmacol 1993; 36: 263–5
Weber P, Lettieri JT, Kaiser L, et al. Lack of mutual pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin in healthy normocholesterolemic volunteers. Clin Ther 1999; 21: 1563–75
Boyd RA, Stern RH, Stewart BH, et al. Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol 1999; 40: 91–8
Brown DD, Juhl RP, Warner SL. Effects of hypocholesterolemic interventions on digoxin bioavailability. Drug Metab Rev 1979; 9: 107–17
Bizjak ED, Mauro VF. Digoxin-macrolide drug interaction. Ann Pharmacother 1997; 31: 1077–9
Nawarskas JJ, McCarthy DM, Spinler SA. Digoxin toxicity secondary to clarithromycin therapy. Ann Pharmacother 1997; 31: 864–6
de Lannoy IA, Koren G, Klein J, et al. Cyclosporin and quinidine inhibition of renal digoxin excretion: evidence for luminal secretion of digoxin. Am J Physiol 1992; 263: 613–22
Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 1999; 104: 147–53
Fenster PE, Comess KA, Hanson CD, et al. Kinetics of the digoxin-aspirin combination. Clin Pharmacol Ther 1982; 32: 428–30
Finch MB, Johnston GD, Kelly JG, et al. Pharmacokinetics of digoxin alone and in the presence of indomethacin therapy. Br J Clin Pharmacol 1984; 17: 353–5
Jorgensen, HS, Christensen HR, Kampmann JP. Interaction between digoxin and indomethacin or ibuprofen. Br J Clin Pharmacol 1991; 31: 108–10
Davies NM, Anderson KE. Clinical pharmacokinetics of diclofenac: therapeutic insights and pitfalls. Clin Pharmacokinet 1997; 33: 184–213
Zoller B, Engel HJ, Faust-Tinnefeldt G, et al. An interaction study between benoxaprofen and digoxin. Eur J Rheumatol Inflamm 1982; 5: 82–6
Doering W, Isbary J. Effect of tiaprofenic acid on serum digoxin concentration. Arzneimittel Forschung 1983; 33: 167–8
Rodin SM, Johnson BF. Pharmacokinetic interactions with digoxin. Clin Pharmacokinet 1988; 15: 227–44
Crome P, Curl B, Holt D, et al. Digoxin and cimetidine: investigation of the potential for a drug interaction. Hum Toxicol 1985; 4: 391–9
Fraley DS, Britton HL, Schwinghammer TL, et al. Effect of cimetidine on steady-state serum digoxin concentrations. Clin Pharm 1983; 2: 163–5
Ochs HR, Gugler R, Guthoff T, et al. Effect of cimetidine on digoxin kinetics and creatinine clearance. Am Heart J 1984; 107: 170–2
Oosterhuis B, Jonkman JH, Andersson T, 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
Miura T, Ueno K, Tanaka K, et al. Impairment of absorption of digoxin by acarbose. J Clin Pharmacol 1998; 38: 654–7
Ochs HR, Greenblatt DJ, Verburg-Ochs B, et al. Effect of alprazolam on digoxin kinetics and creatinine clearance. Clin Pharmacol Ther 1985; 38: 595–8
Guven H, Tuncok Y, Guneri S, et al. Age-related digoxin-alprazolam interaction. Clin Pharmacol Ther 1993; 54: 42–4
Tiseo PJ, Perdomo CA, Friedhoff LT. Concurrent administration of donepezil HCl and digoxin: assessment of pharmacokinetic changes. Br J Clin Pharmacol 1998; 46: 40–4
Cooper SJ, Kelly JG, Johnston GD, et al. Pharmacodynamics and pharmacokinetics of digoxin in the presence of lithium. Br J Clin Pharmacol 1984; 18: 21–5
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Hanratty, C.G., McGlinchey, P., Johnston, G.D. et al. Differential Pharmacokinetics of Digoxin in Elderly Patients. Drugs & Aging 17, 353–362 (2000). https://doi.org/10.2165/00002512-200017050-00003
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DOI: https://doi.org/10.2165/00002512-200017050-00003