Digoxin dosing

I. Introduction

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.
II. Monitoring parameters
1. The following patient parameters should be monitored during digoxin therapy:
o Digoxin serum level
Obtain level within 24 hours of digitalization, weekly until stable, and at steady state.
o BUN and serum creatinine
Measure every two days, or every day in unstable renal function.
o Weigh patient daily.
o Measure and monitor urine output daily
o Monitor apical pulse daily.
2. Therapeutic serum concentrations
The usual digoxin therapeutic range is 0.8 to 2 ng/ml.

III. Precautions

1. 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.
2. Factors affecting digoxin pharmacokinetics
a. 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).
b. Factors which predispose to suboptimal clinical response:
Hyperkalemia, uncorrected hyperthyroidism, interacting drugs which delay or prevent oral absorption
(antacids, cholestyramine, metoclopramide).

IV. Program procedure

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.
1. 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.
2. 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 patient’s 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.
V. Digoxin dosing flow chart

VI. Pharmacokinetic formulas

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

1. 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)
2. 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

3. 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

4. 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

5. 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)

B. Adjust maintenance dose

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

2. 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)

3. 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

4. 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)
VII. Bibliography

1. Jusko WJ, et al. Pharmacokinetic design of digoxin dosage regimens in relation to renal function. J Clin
Pharmacol 1974;14:525-35.
2. Koup JR, et al. Digoxin pharmacokinetics: role of renal failure in dosage regimen design. Clin Pharmacol Ther
1975;18:9-21.

3. Walsh FM, Sode J. Significance of non-steady-state serum digoxin concentrations. Am J Clin Pathol 1975;63:446-
50.

4. Dobbs SM, Mawer GE. Prediction of digoxin dose requirements. Clin Pharmacok 1977;2:281-91.

5. 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.

6. Thomas RW, Maddox RR. The interaction of spironolactone and digoxin: a review and evaluation. Ther Drug
Monit 1981;3:117-20.

7. Klein HO, et al. The influence of verapamil on serum digoxin concentration. Circul 1982;65:998-1003.

8. Hyneck ML, et al. Comparison of methods for estimating digoxin dosing regimens. AJHP 1981;38:69-73.

9. Bigger JT. The quinidine-digoxin interaction. Mod Con Card Dis 1982;51:73-78.

10. Lalonde RL, Pao D. Correlation coefficient versus prediction error in assessing the accuracy of digoxin dosing
methods. Clin Pharm 1984;3:178-83.

11. Reuning RH, Garaets DR. "Digoxin", in Evans W, Schentag J, Jusko J (eds): Applied Pharmacokinetics. Applied
Therapeutics, Inc, San Francisco 1986; pp 908-43.