Digoxin is one of the most commonly used drugs in medicine. Despite this widespread use and a history of over 200 years of clinical use and research, much controversy continues concerning its efficacy and safety.

Two of the most prominent features of the clinical use of digoxin are its narrow therapeutic index and an endpoint of therapy which is difficult to define and measure. Digitalis toxicity is one of the most frequently encountered drug-related causes of hospitalization. Conversely, the effect of serum digoxin concentrations below 0.8 ng/ml is clinically unimportant in most patients.

The great variability in serum digoxin concentrations in patients given the same dose has led to the development of nomograms and equations designed to estimate the optimal digoxin dosage. These methods include factors such as age, weight, sex, renal function, disease state, and concurrent drug therapy to calculate the dose and corresponding serum concentration. An accurate method could decrease the potential for drug toxicity, which can be life-threatening, and decrease the time period required to optimize therapy, which is otherwise done by trial and error.

Lalonde and Pao compared the accuracy of eighteen different digoxin dosing methods. The method of Dobbs and Koup as modified by Koda-Kimble, appeared to produce the best balance of minimum bias and greatest precision. Using a target concentration of 1.2 ng/ml, the Koda-Kimble method achieves a concentration between 0.9 and 1.5 ng/ml in 80% of cases. However, some patients will have measured serum digoxin concentrations well outside this range.

An adequate loading dose is necessary for rapid attainment of therapeutic serum levels. Choosing to initiate therapy with out a loading dose means that, because of digoxin's long half-life, therapeutic serum levels may not be achieved for weeks.

- The following patient parameters should be monitored during digoxin therapy:
- Digoxin serum level

Obtain level within 24 hours of digitalization, weekly until stable, and at steady state. - BUN and serum creatinine

Measure every two days, or every day in unstable renal function. - Weigh patient daily.
- Measure and monitor urine output daily
- Monitor apical pulse daily.

- Digoxin serum level
- Therapeutic serum concentrations

The usual digoxin therapeutic range is 0.8 to 2 ng/ml.

- Proper timing of serum sampling is critical.

Serum samples should be drawn just prior to the daily dose and no sooner than six hours after administration of the drug. - Factors affecting digoxin pharmacokinetics

- Factors which predispose to digoxin toxicity:

Hypokalemia, hypomagnesemia, coronary artery disease, cor pulmonale, uncorrected hypothyroidism, renal dysfunction, and interacting drugs which decrease digoxin clearance (quinidine, spironolactone, and verapamil). - Factors which predispose to suboptimal clinical response:

Hyperkalemia, uncorrected hyperthyroidism, interacting drugs which delay or prevent oral absorption (antacids, cholestyramine, metoclopramide).

- Factors which predispose to digoxin toxicity:

Before calculating an initial dose or adjusting the maintenance dose the program must know the target digoxin serum level, whether the patient is in acute congestive failure and whether any interacting drugs are being concurrently administered.

- Initial dosing
The program first calculates an ideal loading dose, enter a practical dose and the desired dosage form of the loading dose. Enter 0 if no loading dose is desired. The program calculates an ideal maintenance dose, the user enters a practical maintenance dose and interval. The program then displays an estimated steady-state serum level.

- Dosage adjustment based on serum levels

First enter the measured serum digoxin concentration, the dosage form, digoxin dose and interval. The program then requires the date and time the current dosage regimen was initiated, this is used to determine whether the patients digoxin level is at a steady-state. The program then calculates an incremental loading dose or temporary interruption, depending upon whether the serum level is below or above the target level. The user enters a practical loading dose or temporary interruption. The program calculates an ideal maintenance dose and the user enters a practical maintenance dose and interval. The program then displays an estimated steady-state serum level.

The digoxin model is not hard-coded into the program. The parameters are found in the drug model database and are fully user-editable. You can tailor each drug model to fit your patient population, or you can create your own models.

- Initial dosing

- Estimate Volume of Distribution (Jusko Equation)

Vd = 226 + [(298 x CrCl) / (29.1 + CrCl)] x (BSA / 1.73)

where CrCl = normalized creatinine clearance (ml/min)

BSA = Body surface area (square meters) - Calculate Loading Dose

LD = Vd x Cp/F

where Vd = Volume of distribution (liters)

Cp = target serum level (mcg/l)

F = bioavailability factor

- IV push = 1
- capsules= 0.95
- elixir = 0.8
- tablets = 0.75

- Estimate Clearance (Koda-Kimble)

Cl = [(A x CrCl) + B] x C

where A = 0.88, for patient with Acute CHF, otherwise=1

B = 23, for patient with Acute CHF, otherwise=40

C = correction factor for interacting drugs

- Quinidine = 0.65

- Spironolactone = 0.75

- Verapamil = 0.7

- Quinidine = 0.65
- Calculate Maintenance Dose

MD = (Cl x Cp x tau) / F

where Cl = Clearance (liters/hour)

Cp = target serum level (mcg/l)

tau = dosing interval (hours)

F = bioavailability factor - Estimate steady-state trough level

Cpss = (MD x F) / (Cl x tau)

where MD = Maintenance dose (mcg)

F = bioavailability factor

Cl = Clearance (liters/hour)

tau = dosing interval (hours)

- Estimate Volume of Distribution (Jusko Equation)
- Adjust maintenance dose
- Estimate Volume of Distribution (Jusko Equation - see above)

- Calculate digoxin clearance

Cl = [(MD x F) / Cp] / tau

where MD = Maintenance dose (mcg)

F = Bioavailability factor

Cp = Steady-state serum digoxin concentration (mcg/l)

tau = Dosing interval (hours)

- Calculate Maintenance Dose

MD = (Cl x Cp x tau) / F

where Cl = Digoxin clearance (l/hr)

Cp = target serum level (mcg/l)

tau = dosing interval (hours)

F = bioavailability factor

- Estimate steady-state trough level

Cpss = (MD x F) / (Kel x Vd x tau)

where MD = Maintenance dose (mcg)

F = bioavailability factor

Kel = Elimination rate (1/hours)

Vd = Volume of distribution (liters)

tau = dosing interval (hours)

- Estimate Volume of Distribution (Jusko Equation - see above)

- Jusko WJ, et al. Pharmacokinetic design of digoxin dosage regimens in relation to renal function. J Clin Pharmacol 1974;14:525-35.
- Koup JR, et al. Digoxin pharmacokinetics: role of renal failure in dosage regimen design. Clin Pharmacol Ther 1975;18:9-21.
- Walsh FM, Sode J. Significance of non-steady-state serum digoxin concentrations. Am J Clin Pathol 1975;63:446-50.
- Dobbs SM, Mawer GE. Prediction of digoxin dose requirements. Clin Pharmacok 1977;2:281-91.
- Koda-Kimble MA: Congestive heart failure, in Applied Therapeutics for Clinical Pharmacists, 2nd ed, edited by MA Koda-Kimble et al, Applied Therapeutics, Inc, San Francisco 1978; pp 161-86.
- Thomas RW, Maddox RR. The interaction of spironolactone and digoxin: a review and evaluation. Ther Drug Monit 1981;3:117-20.
- Klein HO, et al. The influence of verapamil on serum digoxin concentration. Circul 1982;65:998-1003.
- Hyneck ML, et al. Comparison of methods for estimating digoxin dosing regimens. AJHP 1981;38:69-73.
- Bigger JT. The quinidine-digoxin interaction. Mod Con Card Dis 1982;51:73-78.
- Lalonde RL, Pao D. Correlation coefficient versus prediction error in assessing the accuracy of digoxin dosing methods. Clin Pharm 1984;3:178-83.
- Reuning RH, Garaets DR. "Digoxin", in Evans W, Schentag J, Jusko J (eds): Applied Pharmacokinetics. Applied Therapeutics, Inc, San Francisco 1986; pp 908-43.