Vol. 10 Issue 6
Cost-Effective Laboratory Monitoring of Digoxin
Mrs. F is a 65-year-old Caucasian woman with a history of congestive heart failure, hypertension and type 2 diabetes. She presents to the clinic for her routine six-month follow-up visit. She has no complaints and is requesting refills for her digoxin 0.125 mg daily, lisinopril 20 mg daily, metoprolol 50 mg twice daily and glyburide 10 mg daily. Her last digoxin level, drawn at her last visit, was 0.7 ng/mL.
What is her goal digoxin level? How often should a digoxin level be checked? What other laboratory parameters should be assessed?
Introduction to Digoxin
Digoxin is one of several cardiac glycosides isolated from the foxglove flower. Extracts of foxglove were first used in medicine more than 200 years ago. Digoxin is the only cardiac glycoside commercially available in the United States, and it ranks in the top 50 of all prescription medications dispensed.1 Digoxin is primarily used in the treatment of systolic heart failure and to control ventricular rate in cases of supraventricular tachycardia.2
Digoxin usually is initiated at 0.125 mg daily. Elderly patients and patients with impaired renal function exhibit decreased digoxin clearance and usually require smaller doses. Of note, digoxin has a narrow therapeutic index, meaning there is only a small difference between therapeutic and toxic drug concentrations. Additionally, digoxin is involved in several drug interactions that can cause either an increase or a decrease in digoxin levels. For these reasons, digoxin levels are frequently assessed to monitor efficacy and toxicity. The manufacturer reports the therapeutic range as 0.8 to 2.0 ng/mL.2
In supraventricular tachycardia, digoxin exerts a negative chronotropic effect (decreased rate of contraction) by directly suppressing the atrioventricular node. It is used strictly to control ventricular rate and cannot restore normal sinus rhythm. In this case, digoxin is usually dosed to achieve a target heart rate less than 100 beats per minute and concentrations less than 2.0 ng/mL. Higher concentrations are associated with increased adverse effects.3
Digoxin is used in heart failure for its positive inotropic effects (increased strength of contractions). It affects cardiac cells' ability to import potassium and export sodium, resulting in increased contractility. Therapeutic drug concentrations are less clearly defined in patients with heart failure. Several studies have shown an increase in morbidity in heart failure patients with digoxin levels in the higher end of the therapeutic range. For this reason, a new therapeutic range of 0.5 to 1.0 ng/mL has been suggested for these patients.4
Cost Effective Monitoring
A baseline digoxin level should be assessed at the start of therapy. As with most other drugs, serum levels should not be checked until drug concentrations have reached steady state, the point at which drug absorption equals drug clearance. Digoxin has an average half-life of 38 hours, so levels should be drawn five to seven days after initiation or changes in digoxin dose. In patients with renal failure, half-life may be prolonged, consequently delaying the time to reach steady state.
The most valuable digoxin serum concentrations are trough levels, or levels drawn just before (within one hour) the next dose. Levels drawn before this time are unreliable and should not be the basis for therapeutic decisions.5 Patients may be charged between $50 and $100 for a digoxin level. Accordingly, obtaining appropriate levels is a cost-saving measure, as well.
Digoxin levels should be assessed in conjunction with blood chemistries, including serum creatinine, sodium and potassium. Because digoxin is primarily eliminated renally, it is important to assess kidney function when monitoring digoxin levels. Acute changes in renal function can have drastic effects on digoxin levels. Additionally, since digoxin inhibits the action of potassium, low potassium levels may potentiate the effects of digoxin without increasing digoxin levels. Conversely, high potassium levels can decrease the effectiveness of digoxin despite normal therapeutic levels.
Frequent follow-up digoxin levels increase the cost of care and are not necessary in stable patients. In this population, digoxin levels are needed only when patients exhibit signs or symptoms of digoxin toxicity, exhibit decreased digoxin effectiveness or develop changes in renal function. Traditionally, digoxin levels are evaluated at yearly intervals in the stable patient. In the unstable hospitalized patient, repeat levels can be obtained at least five to seven days after a dose change so as to allow serum concentrations to reach steady state.
A narrow therapeutic window contributes to the high incidence of toxicity associated with digoxin. Because signs and symptoms of digoxin toxicity are a reason to order serum digoxin levels, clinicians should be familiar with them.
Most side effects are associated with levels exceeding 2.0 ng/mL. Nausea and vomiting are the most frequent side effects reported with digoxin. Additional gastrointestinal effects include excessive salivation, abdominal pain and changes in bowel habits.
Ocular effects are the most unique signs of digoxin toxicity. Digoxin can impart a yellow-green tinge to patients' vision. Patients may also develop visual changes described as halos around objects. Central nervous system effects may include headache, fatigue and muscle weakness. Patients with acute digoxin toxicity can present with hyperkalemia. Conversely, patients with chronic digoxin toxicity may be normokalemic or hypokalemic. The most dangerous effects of digoxin toxicity manifest in the cardiovascularly. Digoxin can cause bradycardia as well as severe ventricular arrhythmias.3
Severe, potentially life-threatening digoxin toxicity is managed with digoxin immune Fab (Digibind, DigiFab), an antigen-binding agent that is considered an antidote. Digoxin immune Fab is indicated when digoxin toxicity presents with arrhythmias refractory to other treatment, with hyperkalemia refractory to other measures, with ingestion of greater than 10 mg in an adult (greater than 4 mg in children) or with levels exceeding 10 ng/mL at least six hours after the dose. In cases of documented digoxin toxicity, levels should be drawn before the administration of digoxin immune Fab. Repeat digoxin levels should not be drawn for at least 72 hours (seven days in patients with renal failure) following the administration of digoxin immune Fab. Levels drawn too early after digoxin immune Fab will be falsely elevated by as much as 20-fold.6
Digoxin is an old drug that still finds utility for the treatment of systolic heart failure and supraventricular arrhythmias. It has a narrow therapeutic window and the potential to cause serious, life-threatening side effects. The therapeutic range for heart failure is less than that for arrhythmias. Baseline monitoring of digoxin levels is indicated in patients beginning therapy; however, frequent follow-up monitoring of digoxin levels in stable patients is not indicated and can usually be done yearly.
Keith A. Hecht is a pharmacy practice resident at the University of Kentucky Chandler Medical Center in Lexington, Ky. Frank Romanelli is an assistant professor of pharmacy in the college of pharmacy and college of allied health at the University of Kentucky in Lexington, Ky.
1. The top 200 prescriptions for 2001 by number of US prescriptions dispensed. RxList Web page. Available at: http://www.rxlist.com/top200.htm. Accessed March 26, 2002.
2. Lanoxin tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2000.
3. Digoxin. In: McEvoy GK, ed. AFHS Drug Information 2002. Bethesda, Md: American Society of Health-System Pharmacists; 2002:1558-1560.
4. 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.
5. Matzuk MM, Shlomchik M, Shaw LM. Making digoxin therapeutic drug monitoring more effective. Ther Drug Monit. 1991;13:215-219.
6. DigiFab [package insert]. Nashville, Tenn: Protherics Inc; 2001.