US Pharm. 2006;2:HS-28-HS-36.      

Digoxin is a compound in the drug family known as cardiac glycosides or cardenolides. The cardenolides contain a five- or a six-membered lactone ring that is attached to a steroid nucleus at position 17. Of the more than 300 known digitalis compounds, two natural products have been used most often in clinical settings: ouabain and digoxin. Ouabain is derived from the plant Strophanthus gratus, and digoxin originates from the leaves of the purple foxglove (Digitalis purpurea).1,2 Although the clinical efficacy of foxglove plant extracts is a discovery attributed to English physician William Withering in 1785, these compounds have been used medicinally for more than 2,000 years. 3,4 Both a botanist and a physician, Withering knew of an herbal remedy used for dropsy, a condition involving excess fluid retention. Dr. Withering believed that digitalis produced a diuretic effect in those with an irregular, weak pulse and concomitant edema.2,5

Current Indications and Uses
Therapeutic indications and uses for digoxin are based on its mechanisms of action, which include effects on cardiac rate and rhythm, as well as effects on the force of cardiac contraction. The slowing of rate and rhythm are attributed to digoxin's impact on the central nervous system, leading to increased vagal activity that results in slowed conduction in the atrioventricular (AV) node. The increase in force of contraction is attributed to digoxin's binding to the Na+/K+-ATPase pump. By binding to the K+ -binding site of the pump, digoxin leads to inhibition of the pump. The consequent rise in Na+ concentration causes slowing of Ca++ efflux via the Na+/Ca++ exchanger and a relative increase in intracellular Ca++. The extra Ca++ causes the action potential of cardiac cells to be greater with more activation of the contractile machinery.6

Control of ventricular rate in the setting of atrial fibrillation has long been accomplished with digoxin. In fact, for more than 200 years, digoxin was the main agent used for this indication.7 Clinical trials have shown that 54% to 70% of patients with atrial fibrillation are treated with digoxin.8,9 However, digoxin is not effective in controlling ventricular rate in atrial fibrillation during exercise.10 For this reason, some guidelines recommend digoxin as second-line therapy for rate control in atrial fibrillation.11 Still, digoxin is commonly used in this setting. Recent data have raised the question of digoxin's potential to increase the risk of stroke in patients with atrial fibrillation due to a possible role in thrombogenesis mediated through increased intracellular calcium levels.12 This possibility could have substantial clinical implications because of the large numbers of such patients receiving digoxin therapy. More trials are needed to further test this theory.

Digoxin is an appealing therapeutic option in elderly patients with atrial fibrillation. Unlike other rate-control strategies (e.g., calcium channel blockers and beta-blockers), digoxin does not cause hypotension or have negative inotropic effects. However, caution is advised regarding potential drug interactions with digoxin use in the elderly. In a clinical trial evaluating elderly patients admitted to the hospital with specific drug toxicities, those on digoxin who experienced toxicity were about 12 times as likely to have been treated with clarithromycin in the previous week.13 Otherwise, provided that the dosage is adjusted for renal function in elderly patients, digoxin can be an inexpensive, well-tolerated therapy.14

Treatment of heart failure is another historical use. Digoxin has been proven beneficial for symptomatic control in sinus rhythm in patients with mild to moderate heart failure. In the PROVED trial, symptoms that improved secondary to digoxin therapy included ejection fraction, heart rate, and exercise capacity.15 In the RADIANCE study, digoxin withdrawal resulted in clinical deterioration, such as reductions in systolic function and worsening of exercise tolerance.16 However, no studies to date have shown any improvement in the incidence of mortality with the use of digoxin in patients with heart failure.4 The most recent practice guidelines for the treatment of heart failure recommend considering the addition of digoxin in patients with persistent symptoms during therapy with diuretics, an angiotensin-converting enzyme (ACE) inhibitor (or angiotensin receptor blocker), and a beta-blocker. Furthermore, digoxin may be added to the initial regimen in patients with severe symptoms who have not yet responded symptomatically during treatment with diuretics, an ACE inhibitor, or a beta-blocker.17

Based on the results of the Digitalis Investigation Group (DIG), digoxin is most often currently used for its ability to reduce hospitalizations for declining heart failure.18 Evaluation of the DIG trial resulted in a revision of the current perspective regarding therapeutic digoxin plasma concentrations.19,20 While initially it appeared that digoxin may exhibit differing effects in men and women, further analysis demonstrated the variations were more likely related to differences in serum concentrations of digoxin.20,21 Digoxin serum concentrations greater than 1.2 ng/mL lead to an increased risk of mortality in patients with heart failure. Thus, the therapeutic range of digoxin concentration currently recommended for the treatment of heart failure is 0.5 to 0.9 ng/mL.19,20

Although digoxin was historically used in the treatment of heart failure for its positive inotropic effects, it has now become apparent that the neurohormonal effects of digoxin may be equally or more important.22-25 Digoxin's effects on the autonomic nervous system improve autonomic dysfunction in heart failure, as indicated by decreases in plasma norepinephrine levels of up to 42%.26 Furthermore, digoxin has been shown to benefit outcomes in patients with heart failure, even when patients remain in sinus rhythm, suggesting that the beneficial effects are unrelated to the treatment of arrhythmia.27

Digoxin Pharmacokinetics
Digoxin bioavailability varies based on the dosage. In tablet form, the bioavailability ranges from 0.5 (50%) to more than 0.9 (90%); a value of 0.7 (70%) is often used as a standard for digoxin tablets.28 While soft-gelatin digoxin capsules seem to be completely absorbed (bioavailability =1.0), digoxin elixir exhibits a bioavailability of approximately 80% (0.8). 28 Administered intravenously, digoxin is assumed to have a bioavailability of 100% (1.0). Such products as clarithromycin, erythromycin, and itraconazole may increase digoxin's bioavailability, whereas charcoal, cholestyramine, and St. John's wort may decrease it.

On average, the volume of digoxin distribution is about 7.3 L/kg, based on ideal body weight.28 Thus, digoxin is distributed widely throughout the body. Although digoxin is virtually insoluble in water, Na+/K+-ATPase pumps are found in all tissues, and digoxin binds to these pumps, accounting for its wide distribution throughout the body's tissues.29 This characteristic is important in the treatment of digoxin toxicity with digoxin-specific antibody fragments, as drug distributed in the tissue compartments will reequilibrate following initial antibody fragment treatment.

Equations are also available for more patient-specific calculations of digoxin's volume of distribution that consider patient weight and creatinine clearance.28 In addition, other factors may alter its volume of distribution: quinidine and hypothyroidism decrease volume, and hyperthyroidism increases volume.28 Digoxin distributes relatively slowly, following a two-compartment model. Complete distribution generally takes at least three to four hours. Since the heart responds as part of the second compartment, therapeutic effects are delayed until distribution is complete.

The clearance of digoxin involves both metabolic and renal clearance from the body. In about 10% to 30% of the population, metabolic elimination partially occurs as a result of digoxin conversion by Eubacterium lentum in the gut to digoxin-reduction products.30 Another component of digoxin metabolism is postulated to occur because of hepatic conversion to 3-keto-digoxigenin and 3-epidigoxigenin metabolites, followed by conjugation.31 Additionally, digoxin is metabolized in the stomach by gastric acid, which removes digitoxose sugars to form deglycosylated congeners. These sugars are hydrolyzed, and the resulting products are oxidized and undergo epimerization through hepatic uridine diphosphoglucose-glucuronosyltransferase, followed by conjugation.32,33 Overall, the metabolic clearance of digoxin averages approximately 0.8 mL/kg/minute.

Renal clearance of digoxin is generally equivalent to creatinine clearance. In patients with heart failure, both the metabolic and renal components of digoxin clearance decrease, but the metabolic component decreases more dramatically. Clearance of digoxin is also decreased in patients with hypothyroidism and in drug interactions with amiodarone, quinidine, and verapamil. Alternatively, clinical hyperthyroidism may increase digoxin clearance.28

In patients with normal renal function, the half-life of digoxin ranges from 36 to 48 hours. In those with renal insufficiency, the half-life can increase to six days.28,31 This has obvious implications for the timing of serum sampling for measurement of serum digoxin levels, as discussed further in the following section.

Measurement of Digoxin Serum Concentrations
Considering there is some overlap between therapeutic and toxic serum digoxin levels, symptoms of toxicity may be reported in patients whose levels are within the therapeutic range, while others may have no symptoms when their serum digoxin levels are above the therapeutic threshold.31 As previously mentioned, the therapeutic range for digoxin may be lower for patients with heart failure than what is traditionally accepted (0.5 to 2 ng/mL). 19,20,28,31 However, digoxin's effects on rate control in atrial fibrillation may require levels on the higher end of that range.31 Therefore, measurement of serum digoxin concentrations is necessary when monitoring this medication to ensure its safe and effective use.

As is true in therapy with any drug whose dosage is based on serum drug concentrations, routine measurement of digoxin levels should occur once the steady state has been reached. Since steady state is assumed following three to five half-lives of a consistent dosing regimen, using five half-lives should ensure steady state for a drug such as digoxin, which can demonstrate variations in pharmacokinetic values, based on distribution and clearance. Specifically, in a patient with normal renal function who receives digoxin therapy, steady state should be achieved after at least seven to 10 days of treatment. In patients experiencing end-stage renal disease, the lengthened half-life of digoxin will translate into achievement of steady state, requiring 15 to 20 days.

Digoxin levels should be measured once steady state has occurred, but the distribution of a given dose must also be taken into consideration. Due to the relatively long distribution phase of digoxin, drawing levels within this phase can be avoided best by drawing trough levels. However, if one must draw a level sooner for practical timing concerns, waiting at least four hours after an intravenous dose or six hours after an oral dose is generally sufficient.28

Circumstances that necessitate the measurement of digoxin serum concentrations are the subject of some debate. Some recommended indications for the cost-effective use of serum digoxin monitoring include measurement: (1) following initial digoxin doses; (2) to ascertain patient adherence with therapy; (3) in patients with dynamic or impaired renal function; (4) in patients receiving potentially interacting concomitant medications; (5) in patients not experiencing adequate clinical response; and (6) to prevent and diagnose toxicity.34 If measurement is limited to these situations and performed following the guidelines related to achieving steady state and digoxin distribution, clinically useful levels can be reliably attained.

Some individuals, including neonates, pregnant women, patients with renal failure, and those with hepatic failure, who are not taking digoxin possess digoxin-like immunoreactive substances that can interfere with the measurement of digoxin levels via immunoassay.35,36 Awareness of this occurrence can ensure that clinicians heed such factors when interpreting serum digoxin concentrations. A patient's clinical condition should always be considered in conjunction with measured serum concentrations when adjusting digoxin-dosing regimens so that serum concentrations are not the sole indicator used in the decision-making process.

Digoxin Drug Interactions
Digoxin is known to interact with a wide variety of medications (table 1). One mechanism of drug interaction with digoxin is change in absorption due to increased contact time in the small intestine. This can occur with concomitant use of anticholinergic agents, e.g., atropine, diphenhydramine, phenothiazines, scopolamine, and benztropine, which slow gastrointestinal motility.37 Two other mechanisms believed to account for many drug interactions with digoxin are the inhibition of P-glycoprotein, located in the brush borders of the proximal tubule, and inhibition of digoxin metabolism, secondary to a lack of Eubacterium lentum in the gastrointestinal tract.30 The antibiotics clarithromycin, erythromycin, and tetracycline alter the flora of the gut, leading to decreased digoxin metabolism and consequent increases in digoxin levels.30,37 The antiarrhythmics quinidine, amiodarone, and verapamil inhibit P-glycoprotein in the kidney, resulting in decreased renal clearance of digoxin.37




Digoxin can lead to life-threatening hyperkalemia. This potential adverse effect of digoxin could cause interactions with medications that also affect potassium homeostasis, such as ACE inhibitors, angiotensin receptor–blocking drugs, spironolactone, eplerenone, and potassium supplements.37 Both pharmacokinetic and pharmacodynamic mechanisms should be noted regarding digoxin drug interactions.

Risk Factors
Patients at highest risk for digoxin toxicity include those with renal insufficiency, heart failure, and dehydration.37 Hypoxia secondary to chronic pulmonary disease, hypokalemia, hypomagnesemia, and hypercalcemia are also indicated to increase the risk of developing arrhythmias induced by digoxin. 2,38 The mechanism for the increase in digoxin toxicity risk secondary to hypokalemia derives from the fact that when K+ is low, more K +-binding sites are open for digoxin binding, increasing the effective concentration of digoxin within the heart.6

Signs and Symptoms
Although digoxin toxicity may lead to the development of any type of arrhythmia, bradycardia and AV block are predicted conditions due to digoxin's mechanism of action. The inhibition of the Na+/K+ pump by digoxin leads to an increase in intracellular Ca++. This increase in Ca++ then leads to an increase in the strength of contraction or inotropy. However, these same pharmacological effects that cause inotropy may also cause the development of arrhythmias.39 In the event of severe intoxication, such as that seen in suicide attempts, both severe hyperkalemia and extreme bradycardia occur.2 The hyperkalemia is a result of digoxin inhibition of the Na+/K+-ATPase activity in skeletal muscle.2,40

When digoxin levels in the body are elevated, adverse effects due to accumulation in the central nervous system may occur. Some of these effects include blurred vision, xanthopsia (disturbances in color vision), and retrobulbar optic neuritis.2,38 Additional effects that may be seen because of mediation of the central nervous system by digoxin include nausea, vomiting, increased respiration rate, excitation, headache, malaise, drowsiness, dizziness, and apathy. 4,38 Notably, cardiac symptoms of toxicity may appear before noncardiac symptoms.38

Treatment of Digoxin Toxicity
Activated charcoal can be used in the treatment of digoxin toxicity. The use of activated charcoal can lead to a 30% to 40% drop in digoxin levels within 12 to 18 hours. Unlike the use of digoxin antibodies, the drop in digoxin levels produced by activated charcoal avoids complete reversal of the therapeutic effects of digoxin in patients using the medication for treatment of cardiac disease.41 This may be a beneficial strategy in patients whose digoxin concentrations do not greatly exceed those in the therapeutic range and who could benefit from conservative medical care. Additionally, supportive care involving potassium administration, discontinuation of digoxin therapy, and assessment of magnesium and calcium levels should be employed as indicated by the patient's clinical condition.41

Digoxin-specific antibody fragments, or digoxin immune Fab, was introduced in the 1970s and is indicated for the treatment of life-threatening or potentially life-threatening digoxin toxicity or overdose.40,42 The two products currently available in the U.S. market are Digibind and DigiFab. Both of these products are ovine in origin, collected and purified from sheep immunized with human albumin conjugated with digoxin. Digoxin molecules bind preferentially to the antibody fragments, making them unavailable for binding to their receptors. The digoxin-antibody complexes are then renally eliminated.

The clinical conditions indicating the need for these products as defined in their package inserts include the following: acute ingestion of greater than 10 mg of digoxin in adults or 4 mg of digoxin in children, acute ingestion of digoxin leading to a serum level of more than 10 ng/mL, chronic ingestion of digoxin leading to a serum level higher than 6 ng/mL in adults or 4 ng/mL in children, or manifestations of life-threatening digoxin toxicity, such as severe ventricular arrhythmias, progressive bradycardia, second- or third-degree heart block not responsive to atropine, or serum potassium levels exceeding 5 mEq/L in adults or 6 mEq/L in children with rapidly progressive signs and symptoms of digoxin toxicity.42 Digibind has also been suggested and used in the treatment of poisoning with oleander, bufadienolide-containing aphrodisiacs, digitoxin, and foxglove extract.4

For both brands of digoxin immune Fab, one vial of the product will bind approximately 0.5 mg of digoxin. Therefore, the dose of digoxin immune Fab is based on the amount of excess digoxin believed to be present in the patient experiencing toxicity. In some cases, this amount is known, such as in situations of suicide attempt with deliberate overdose or unintentional ingestion by a child. However, in cases of chronic ingestion, this may be more difficult to ascertain, especially as the toxicity may have developed over time with changes in renal function. To calculate digoxin immune Fab dose for patients experiencing an acute ingestion of digoxin, one must first determine the total body load of digoxin. This can be accomplished by multiplying the amount of digoxin ingested (in milligrams) by the bioavailability for the product ingested (0.7 for tablets). To determine the total body load of digoxin (in milligrams) for patients experiencing toxicity as a result of chronic ingestion of digoxin, one should multiply the serum digoxin level (in ng/mL) by the volume of distribution of digoxin (7.3 L/kg) by the patient's ideal body weight (in kg) and divide by 1,000. Once the body load of digoxin is determined, the amount should be divided by 0.5, to account for the approximate amount of digoxin neutralized by one vial of digoxin immune Fab, to determine the number of vials of digoxin immune Fab that should be administered.

An understanding of both digoxin and digoxin-immune Fab pharmacokinetics is crucial to developing a therapeutic dosing regimen.40 The volume of distribution for digoxin immune Fab is approximately 0.35 L/kg, indicating penetration into the extracellular space.42 However, this volume is much smaller than that of digoxin, signifying that shifts from deeper tissue stores of digoxin may occur as the antibody complexes with digoxin in the central circulation as well as more accessible tissue stores.40 The half-life of digoxin immune Fab is reported to be between 15 and 30 hours.40,42 This pharmacokinetic parameter is important from the standpoint that if the entire dose of digoxin immune Fab is given at one time, it may be eliminated from the body before digoxin reequilibration from deeper tissue stores and an optimal degree of digoxin-antibody complexing can occur. For this reason, it has been recommended that half of the calculated necessary digoxin immune Fab dose be given initially, in both acute and chronic poisoning situations, followed by additional doses administered in one to two hours if no clinical response is seen or in six to 12 hours if toxicity recurs.40

The costs associated with digoxin toxicity should be considered. It has been shown that the mean overall cost associated with digoxin toxicity is approximately $4,000 per episode. 43 This cost may be somewhat variable with the use of digoxin immune Fab, especially in the treatment of patients with renal dysfunction and a serum digoxin concentration of 2.3 ng/mL or higher.  In such cases, the use of digoxin immune Fab can result in a reduction in length of stay and overall lower treatment costs.44

Because papain is used in the process of producing digoxin immune Fab, patients with hypersensitivity to papain, chymopapain, other papaya extracts, or the pineapple enzyme bromelain may be at risk for such a reaction. Additionally, patients with allergies to latex or dust mites may have cross-sensitivity to papain and experience hypersensitivity to digoxin immune Fab. Finally, those with allergies to sheep or ovine products or who have previously received ovine products may be at increased risk for hypersensitivity to digoxin immune Fab. The benefit of using this product in such patients should be weighed against the risks, and as a safety measure, treatment for anaphylaxis should be readily available. 42

Summary
Digoxin toxicity can occur as a result of many situations, including drug interactions, electrolyte abnormalities, changes in renal function, acute ingestion of large amounts of the substance, or chronic ingestion of doses larger than necessary for therapeutic effects. Clinicians should monitor patients for the signs and symptoms of digoxin toxicity while utilizing preventive measures. Such preventive measures should include appropriate digoxin serum concentration measurement, evaluation of pharmacotherapy regimens for potential drug interactions, assessment of electrolytes, and digoxin regimen determination based on pharmacokinetic parameters. If digoxin toxicity occurs, treatment should be implemented based on the patient's clinical condition. With appropriate care, digoxin can be an efficacious, safe, and cost-effective treatment.

REFERENCES
1. Smith TW, Haber E. Digitalis (first of four parts). N Engl J Med. 1973;289:945-952.
2. Rocco TP, Fang JC, Roden DM. Cardiac glycosides. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill; 2006:886-889, 921-923.
3. Withering W. An Account of the Foxglove and Some of its Medical Uses: With Practical Remarks on Dropsy and Other Diseases. London: J and J Robinson; 1785.
4. Jortani SA, Valdes R Jr. Digoxin and its related endogenous factors. Crit Rev Clin Lab Sci . 1997;34:225-274.
5. Eichhorn EJ, Gheorghiade M. Digoxin--new perspective on an old drug. N Engl J Med . 2002;347:1394-1395.
6. Rang HP, Dale MM, Ritter JM, Gardner P. Pharmacology. New York: Churchill Livingstone; 1995:283-284.
7. Khan IA, Nair CK, Singh N, et al. Acute ventricular rate control in atrial fibrillation and atrial flutter. Int J Cardiol. 2004;97:7-13.
8. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med . 2002;347:1834-1840.
9. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-1833.
10. Beasley R, Smith DA, McHaffie DJ. Exercise heart rates at different serum digoxin concentrations in patients with atrial fibrillation. Br Med J. 1985;290:9-11.
11. Holten KB. How should we manage newly diagnosed atrial fibrillation? J Fam Prac. 2004;53:641-643.
12. Chirinos JA, Castrellon A, Zambrano JP, et al. Digoxin use is associated with increased platelet and endothelial cell activation in patients with nonvalvular atrial fibrillation. Heart Rhythm. 2005;2:525-529.
13. Juurlink DN, Mamdani M, Kopp A, et al. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003;289:1652-1658.
14. Rosenfeld LE. Atrial fibrillation: how to approach rate control. Curr Cardiol Rep. 2005;7:391-397.
15. 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;22:955-962.
16. 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.
17. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005;46:1-82.
18. Garg R, Gorlin R, Smith T, Yusuf S, on behalf of the Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-533.
19. Adams KF Jr, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the Digitalis Investigation Group Trial. J Am Coll Cardiol. 2005;46:497-504.
20. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289:871-878.
21. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347:1403-1411.
22. Terra SG, Washam JB, Dunham GD, Gattis WA. Therapeutic range of digoxin's efficacy in heart failure: what is the evidence? Pharmacotherapy. 1999;19:1123-1126.
23. Slatton ML, Irani WN, Hall SA, et al. Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhythm? J Am Coll Cardiol. 1997;29:1206-1213.
24. Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20:248-254.
25. Newton GE, Tong JH, Schofield AM, et al. Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol. 1996;28:155-161.
26. Krum H, Bigger T, Goldsmith RL, et al. Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol. 1995;25:289-294.
27. The Task Force of the Working Group on Heart Failure of the European Society of Cardiology. The treatment of heart failure. Eur Heart J. 1997;18:736-753.
28. Winter ME. Digoxin. In: Winter ME. Basic Clinical Pharmacokinetics. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2004:183-221.
29. Clausen T. The Na+, K+ pump in skeletal muscle: quantification, regulation and functional significance. Acta Physiol Scand. 1996;156:227-235.
30. Hirata S, Izumi S, Furukubo T, et al. Interactions between clarithromycin and digoxin in patients with end-stage renal disease. Int J Clin Pharmacol Ther. 2005;43:30-36.
31. Mutnick AH. Digoxin. In: Schumacher GE, ed. Therapeutic Drug Monitoring. Norwalk: Appleton & Lange; 1995:469-491.
32. Gault MH, Charles JD, Sugden DI, et al. Hydrolysis of digoxin by acid. J Pharm Pharmacol. 1980;29:27-32.
33. Gault MH, Karla J, Ahmed M, et al. Influence of gastric pH on digoxin biotransformation. I. Intragastric hydrolysis. Clin Pharmacol Ther. 1980;27:16-21.
34. Lewis RP. Clinical use of serum digoxin concentrations. Am J Cardiol. 1992;69:97G-107G.
35. Pudek MR, Seccombe DW, Jacobson BE, Humphries K. Effect of assay conditions on cross reactivity of digoxin-like immunoreactive substance(s) with radioimmunoassay kits. Clin Chem. 1985;31:1806-1810.
36. Way BA, Wilhite TR, Miller R, et al. Vitros digoxin immunoassay evaluated for interference by digoxin-like immunoreactive factors. Clin Chem. 1998;44:1339-1340.
37. Prybys KM. Deadly drug interactions in emergency medicine. Emerg Med Clin North Am. 2004;22:845-863.
38. Parker RB, Patterson JH, Johnson JA. Heart failure. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:219-260.
39. 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;305:765-771.
40. Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicol Rev. 2004;23:135-143.
41. Fee WH Jr. Activated charcoal safe and effective for digoxin toxicity [letter]. Am J Med. 2004;116:430.
42. Facts & Comparisons 4.0. Digoxin immune Fab. Available at: online.factsandcomparisons.com. Accessed December 12, 2005.
43. Gandhi AJ, Vlasses PH, Morton DJ, Bauman JL. Economic impact of digoxin toxicity. Pharmacoeconomics. 1997;12:175-181.
44. DiDomenico RJ, Walton SM, Sanoski CA, Bauman JL. 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.

To comment on this article, contact editor@uspharmacist.com.