
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 drugrelated
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 lifethreatening, 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 KodaKimble, appeared to produce the best balance
of minimum bias and greatest precision. Using a target concentration
of 1.2 ng/ml, the KodaKimble 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 halflife,
therapeutic serum levels may not be achieved for weeks. II. Monitoring parameters
 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.
 Therapeutic serum concentrations
The usual digoxin therapeutic range is 0.8 to 2 ng/ml.
III. Precautions
 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).
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.
 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
steadystate 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
steadystate. 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 steadystate serum level.
V. Digoxin dosing flow chart
VI. Pharmacokinetic formulas
The digoxin model is not hardcoded into the program. The parameters are
found in the drug model database and are fully usereditable. 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 (KodaKimble)
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
 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 steadystate 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)
 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 = Steadystate 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 steadystate 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
 Jusko WJ, et al. Pharmacokinetic design of digoxin
dosage regimens in relation to renal function. J Clin Pharmacol
1974;14:52535.
 Koup JR, et al. Digoxin pharmacokinetics: role
of renal failure in dosage regimen design. Clin Pharmacol Ther
1975;18:921.
 Walsh FM, Sode J. Significance of nonsteadystate
serum digoxin concentrations. Am J Clin Pathol 1975;63:44650.
 Dobbs SM, Mawer GE. Prediction of digoxin dose
requirements. Clin Pharmacok 1977;2:28191.
 KodaKimble MA: Congestive heart failure, in Applied Therapeutics
for Clinical Pharmacists, 2nd ed, edited by MA KodaKimble et al,
Applied Therapeutics, Inc, San Francisco 1978; pp 16186.
 Thomas RW, Maddox RR. The interaction of spironolactone
and digoxin: a review and evaluation. Ther Drug Monit 1981;3:11720.
 Klein HO, et al. The influence of verapamil on serum digoxin
concentration. Circul 1982;65:9981003.
 Hyneck ML, et al. Comparison of methods for estimating
digoxin dosing regimens. AJHP 1981;38:6973.
 Bigger JT. The quinidinedigoxin interaction. Mod Con Card Dis
1982;51:7378.
 Lalonde RL, Pao D. Correlation coefficient versus prediction
error in assessing the accuracy of digoxin dosing methods. Clin
Pharm 1984;3:17883.
 Reuning RH, Garaets DR. "Digoxin", in Evans W,
Schentag J, Jusko J (eds): Applied Pharmacokinetics. Applied
Therapeutics, Inc, San Francisco 1986; pp 90843.
