Because of the common use of digoxin and because of its narrow therapeutic index, digoxin toxicity has been prevalent historically and, therefore, most clinicians are well aware of the classical dose/concentration-related signs and symptoms of toxicity. Yet, in the modern era the incidence of digoxin toxicity has been declining for a variety of reasons, including a new (lower) therapeutic range, the development of more effective drug therapies for heart failure, and more accurate dosing methods. In addition, digoxin toxicity, once commonly fatal, can now be quickly and effectively treated by the emergency administration of antidigoxin Fab fragments. Indeed, it may be possible to expand the use of Fab fragments to select patients with non-life-threatening digoxin toxicity, in order to save costs and improve patient comfort. Most cases of digoxin toxicity are caused by inappropriately high dosages, which are usually prescribed in the setting of renal dysfunction, while other cases can be attributed to system errors such as multiple prescriptions, poor patient counseling, or errors in transcribing. With modern computerized prescribing systems, such as direct physician order entry and prompts that alert the clinician to the potential for error, it is possible to decrease the incidence of digoxin toxicity even further. A realistic goal is to nearly eradicate once commonplace digoxin toxicity or at least make its occurrence a rare event.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
The use of trade names is for product identification purposes only and does not imply endorsement.
Smith TW, Haber E. Digoxin intoxication: the relationship of clinical presentation to serum digoxin concentration. J Clin Invest 1970; 49: 2377–86.
Beller GA, Smith TW, Abelmann WH, et al. Digitalis intoxication: a prospective clinical study with serum level correlations. N Engl J Med 1971; 284: 989–97.
Duhme DW, Greenblatt DJ, Koch-Weser J. Reduction of digoxin toxicity associated with measurement of serum levels: a report from the Boston Collaborative Drug Surveillance Program. Ann Intern Med 1974; 80: 516–9.
Jelliffe R. A mathematical analysis of digitalis kinetics in patients with normal and reduced renal function. Math Biosci 1967; 1: 305–25.
Jelliffe RW. An improved method of digoxin therapy. Ann Intern Med 1968; 69: 703–17.
The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33.
Adams Jr KF, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002; 39: 946–53.
Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289: 871–8.
Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: mechanisms and manifestations of toxicity. Part I. Prog Cardiovasc Dis 1984; 26: 413–58.
Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: mechanisms and manifestations of toxicity. Part II. Prog Cardiovasc Dis 1984; 26: 495–540.
Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: mechanisms and manifestations of toxicity. Part III. Prog Cardiovasc Dis 1984; 27: 21–56.
Irons Jr GV, Orgain ES. Digitalis-induced arrhythmias and their management. Prog Cardiovasc Dis 1966; 8: 539–69.
Geering K. Na+-K+-ATPase. Curr Opin Nephrol Hypertens 1997 Sep; 6(5): 434–9.
Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis 2002; 44(4): 251–66.
Hauptman PJ, Kelly RA. Digitalis. Circulation 1999; 99: 1265–70.
Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol 1992; 69: 108–8G.
Xie JT, Cunningham PM, January CT. Digoxin-induced delayed afterdepolarizations: biphasic effects of digoxin on action potential duration and the Q-T interval in cardiac Purkinje fibers. Methods Find Exp Clin Pharmacol 1995; 17: 113–20.
Rocchetti M, Besana A, Mostacciuolo G, et al. Diverse toxicity associated with cardiac Na+/K+ pump inhibition: evaluation of electrophysiological mechanisms. J Pharmacol Exp Ther 2003; 305: 765–71.
Krum H, Bigger Jr JT, Goldsmith RL, et al. Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol 1995; 25: 289–94.
Newton GE, Tong JH, Schofield AM, et al. Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol 1996; 28: 155–61.
Gheorghiade M, Ferguson D. Digoxin: a neurohormonal modulator in heart failure? Circulation 1991; 84: 2181–6.
Gheorghiade M, Hall VB, Jacobsen G, et al. Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors. Circulation 1995; 92: 1801–7.
Ieiri I, Takane H, Otsubo K. The MDR1 (ABCB1) gene polymorphism and its clinical implications. Clin Pharmacokinet 2004; 43(9): 553–76.
Iisalo E. Clinical pharmacokinetics of digoxin. Clin Pharmacokinet 1977; 2(1): 1–16.
Fromm MF, Kim RB, Stein CM, et al. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 1999; 99: 552–7.
Yamreudeewong W, DeBisschop M, Martin LG, et al. Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Saf 2003; 26: 421–38.
Kernan WN, Castellsague J, Perlman GD, et al. Incidence of hospitalization for digitalis toxicity among elderly Americans. Am J Med 1994; 96: 426–31.
Williamson KM, Thrasher KA, Fulton KB, et al. Digoxin toxicity: an evaluation in current clinical practice. Arch Intern Med 1998; 158: 2444–9.
Mahdyoon H, Battilana G, Rosman H, et al. The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. Am Heart J 1990; 120: 1189–94.
Rahimtoola SH. Digitalis therapy for patients in clinical heart failure. Circulation 2004; 109: 2942–6.
Gandhi AJ, Vlasses PH, Morton DJ, et al. Economic impact of digoxin toxicity. Pharmacoeconomics 1997; 12: 175–81.
Hickey AR, Wenger TL, Carpenter VP, et al. Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study. J Am Coll Cardiol 1991; 17: 590–8.
Abad-Santos F, Carcas AJ, Ibanez C, et al. Digoxin level and clinical manifestations as determinants in the diagnosis of digoxin toxicity. Ther Drug Monit 2000; 22: 163–8.
Ma G, Brady WJ, Pollack M, et al. Electrocardiographic manifestations: digitalis toxicity. J Emerg Med 2001; 20: 145–52.
Antman EM, Wenger TL, Butler Jr VP, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a multicenter study. Circulation 1990; 81: 1744–52.
Sharff JA, Bayer MJ. Acute and chronic digitalis toxicity: presentation and treatment. Ann Emerg Med 1982; 11: 327–31.
Ekins BR, Watanabe AS. Acute digoxin poisonings: review of therapy. Am J Hosp Pharm 1978; 35: 268–77.
Park GD, Goldberg MJ, Spector R, et al. The effects of activated charcoal on digoxin and digitoxin clearance. Drug Intell Clin Pharm 1985; 19: 937–41.
Lalonde RL, Deshpande R, Hamilton PP, et al. Acceleration of digoxin clearance by activated charcoal. Clin Pharmacol Ther 1985; 37: 367–71.
Rawashdeh NM, al-Hadidi HF, Irshaid YM, et al. Gastrointestinal dialysis of digoxin using cholestyramine. Pharmacol Toxicol 1993; 72: 245–8.
Neuvonen PJ, Kivisto K, Hirvisalo EL. Effects of resins and activated charcoal on the absorption of digoxin, carbamazepine and frusemide. Br J Clin Pharmacol 1988; 25: 229–33.
Smith TW, Haber E, Yeatman L, et al. Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976; 294: 797–800.
Flanagan RJ, Jones AL. Fab antibody fragments: some applications in clinical toxicology. Drug Saf 2004; 27: 1115–33.
DiDomenico RJ, Walton SM, Sanoski CA, et al. Analysis of the use of digoxin immune Fab for the treatment of non-life-threatening digoxin toxicity. J Cardiovasc Pharmacol Ther 2000; 5: 77–85.
Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicol Rev 2004; 23: 135–43.
Kaushal R, Bates DW, Landrigan C, et al. Medication errors and adverse drug events in pediatric inpatients. JAMA 2001; 285: 2114–20.
Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse drug events and potential adverse drug events: implications for prevention: ADE Prevention Study Group. JAMA 1995; 274: 29–34.
Leape LL, Lawthers AG, Brennan TA, et al. Preventing medical injury. QRB Qual Rev Bull 1993; 19: 144–9.
Bates DW, Leape LL, Petrycki S. Incidence and preventability of adverse drug events in hospitalized adults. J Gen Intern Med 1993; 8: 289–94.
Bates DW, Boyle DL, Vander Vliet MB, et al. Relationship between medication errors and adverse drug events. J Gen Intern Med 1995; 10: 199–205.
Bates DW, Leape LL, Cullen DJ, et al. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA 1998; 280: 1311–6.
Potts AL, Barr FE, Gregory DF, et al. Computerized physician order entry and medication errors in a pediatric critical care unit. Pediatrics 2004; 113: 59–63.
King WJ, Paice N, Rangrej J, et al. The effect of computerized physician order entry on medication errors and adverse drug events in pediatric inpatients. Pediatrics 2003; 112: 506–9.
Kaushal R, Shojania KG, Bates DW. Effects of computerized physician order entry and clinical decision support systems on medication safety: a systematic review. Arch Intern Med 2003; 163: 1409–16.
Evans RS, Pestotnik SL, Classen DC, et al. A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med 1998; 338: 232–8.
Falconnier AD, Haefeli WE, Schoenenberger RA, et al. Drug dosage in patients with renal failure optimized by immediate concurrent feedback. J Gen Intern Med 2001; 16: 369–75.
Chertow GM, Lee J, Kuperman GJ, et al. Guided medication dosing for inpatients with renal insufficiency. JAMA 2001; 286: 2839–44.
Galanter WL, DiDomenico RJ, Polikaitis A. Preventing exacerbation of an ADE with automated decision support. J Healthc Inf Manag 2002; 16: 44–9.
Galanter WL, Polikaitis A, DiDomenico RJ. A trial of automated safety alerts for inpatient digoxin use with computerized physician order entry. J Am Med Inform Assoc 2004; 11: 270–7.
Galanter WL, Didomenico RJ, Polikaitis A. A trial of automated decision support alerts for contraindicated medications using computerized physician order entry. J Am Med Inform Assoc 2005; 12: 269–74.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.
No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review.
About this article
Cite this article
Bauman, J.L., DiDomenico, R.J. & Galanter, W.L. Mechanisms, Manifestations, and Management of Digoxin Toxicity in the Modern Era. Am J Cardiovasc Drugs 6, 77–86 (2006). https://doi.org/10.2165/00129784-200606020-00002
- Clinical Decision Support System
- Digoxin Concentration
- Computerize Physician Order Entry
- Serum Digoxin Concentration