**McAuley, GlobalRPh Inc.**

There are many problems encountered in writing a program to effectively dose a drug such as digoxin. It is inherently difficult because of such components as narrow therapeutic index, difficult to define therapeutic endpoints, inter and intra-patient variability, and varying effects of pathological states and drugs on digoxin’s disposition. In sum, there exists significant variability as far as a given dose and concentration produced in a given patient. It is important to be able to determine various patient attributes that may help predict drug concentrations for any given patient. There are several known attributes that have a direct correlation with the eventual therapeutic dose. Variables such as ideal body weight, serum creatinine, age, concomitant drug therapy all have great influence on the eventual therapeutic dosing regimen. The mathematical “backbone” of this program is based on the references below. You will notice two sets of responses when using this program. The first result is based on the “Jelliffe” method which attempts to predict the percentage of digoxin eliminated in a 24 hour period and the dose of digoxin required to maintain the concentration in the therapeutic range. The other result is based primarily on the “Jusko equations (below) and “Koda-Kimble” which attempts to calculate the effective digoxin clearance. After estimating the digoxin clearance, it is possible to make predictions regarding the steady state concentration:

Css = (Maint dose x F) /( dig cl x T)

F= bioavailability factor

T= dosing interval

dig cl= digoxin clearance obtained as noted above.

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The “Jusko” Dosing section is based on the following equations.

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

Other= 0.71

**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)

**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)

These equations were provided by Rick Tharp of RXkinetics (https://www.rxkinetics.com). His site contains additional information on digoxin dosing as well as several other clinical areas.

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__General info:__

**Loading dose:** ** CHF**: 8-12 mcg/kg in divided doses (q4-8h) over 12 to 24 hours. [Normally, give 50% of the total digitalizing dose in the initial dose, then give 25% of the total dose in each of the two subsequent doses at 8 to 12 hr intervals-Obtain EKG 6 hours after each dose to assess potential toxicity (AV block, sinus bradycardia, atrial or nodal ectopic beats, ventricular arrhythmias); Other: vision changes, confusion.] If pt has

__give 6 to 10 mcg/kg IBW.__

**renal insufficiency**__10 to 15 mcg/kg IBW given as above. (If given IVPush-admin over at least 5 min).__

**A-fib:****Digoxin clearance= [CRCL + 40] x 1.44 (add 20 instead of 40 if pt has CHF). Predicted Css= (Dose) (0.65 to 0.8)/ Digoxin clearance. Alternatively, maint dose= Loading dose x [0.14 + crcl/500 ] Avoid IM injections-can lead to severe pain (If it must be given by this route, give deep IM followed by massage).**

__Maintenance dose:__**: Obtain blood samples at least 4 hrs after IV dose and 6-8hrs after oral dose.**

__Monitoring__**Serum levels**: 0.5 to 2.0 ng/ml. Obtain first level within 24 hours of digitalization. Monitor BUN and serum creatinine q2days (qd if unstable). Monitor apical pulse daily..

__Onset/peak:____: 5-30min/ 1-4hrs__

**IV**__: 1-2hrs/ 2-8 hrs. Time to steady state: 5-7 days (average) ESRD: 15-20 days. Half-life: 38-48 hrs. (anephric: 4-6 days).__

**Oral**__: Decrease IV dose by 20 to 25%. When the maintenance dose is given IV, the onset and peak will occur earlier, however the duration of action is the same. Patients’ on the “floors” may receive once daily IV maintenance doses, however, IV loading regimens (multiple doses) are restricted to pts on a monitor- ICU’s. [Oral bioavailability (tablets): 70 to 80%].__

**Conversion from oral to IV****Factors that increase likelihood of digoxin toxicity: **Hypokalemia, hypomagnesaemia, hypothyroidism, renal dysfunction, interacting drugs (eg quinidine, verapamil).

**Distribution:** only a small fraction of digoxin in present in blood (little is removed by hemodialysis). Digoxin distributes very little into body fat–doses must be based on lean body weight. Distribution is not altered by obesity. There appears to be a gradual contraction in the volume of distribution as renal function deteriorates. Therefore, extreme caution is necessary when dosing patients with renal failure.

**Maximal response** from any maintenance dose of digoxin will be obtained when serum concentrations are at steady state and maximal body stores for that dose have been obtained. It should be noted that any adjustment of dose or change in the elimination of digoxin requires a waiting period of 4-5 times the half-life (1 week with normal renal function) before the new steady state concentration is achieved.

References: |

Aronson JK: Clinical pharmacokinetics of cardiac glycosides in patients with renal dysfunction. Clin Pharmacokinet 1983; 8:155-178.
Behr ER, Veysey MJ, Berry D, Volans GN. Optimum dose of digoxin. Lancet. 1997 Jun 21;349(9068):1845 Bennett WM, Aronoff GR, Golper TA et al: Drug Prescribing in Renal Failure. American College of Physicians, Philadelphia, PA, 1987. Cauffield JS, Gums JG, Grauer K. The serum digoxin concentration: ten questions to ask. Am Fam Physician. 1997 Aug;56(2):495-503, 509-10 Cheng JW, Charland SL, Shaw LM, Kobrin S, Goldfarb S, Stanek EJ, Spinler SA. Is the volume of distribution of digoxin reduced in patients with renal dysfunction? Determining digoxin pharmacokinetics by fluorescence polarization immunoassay. Pharmacotherapy. 1997 May-Jun;17(3):584-90. Fenster PE, Hager WD & Goodman MM: Digoxin-quinidine-spironolactone interaction. Clin Pharmacol Ther 1984; 36:70-73. Gilman AG, Rall TW, Nies AS et al (Eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 8th ed. Macmillan Publishing Co, New York, NY, 1990. Hammerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly. Clinical implications. Hui J, Wang YM, Chandrasekaran A, Geraets DR, Caldwell JH, Robertson LW, Reuning RH. Disposition of tablet and capsule formulations of digoxin in the elderly. Pharmacotherapy. 1994 Sep-Oct;14(5):607-12. Jelliffe, 1968; Product information Lanoxin (R), Glaxo Wellcome Inc. (Jelliffe RW: An improved method digoxin therapy. Ann Intern Med 1968; 69:703.) Jusko WJ, Szefler SJ & Goldfarb AL: Pharmacokinetic design of digoxin dosage regimens in relation to renal function. J Clin Pharmacol, 1974; 14:525-535. Koda-Kimble MA: Congestive heart failure, in Applied Therapeutics for Clinical Pharmacists, 2nd ed, edited by Koda-Kimble et al, Applied Therapeutics, Inc., San Francisco 1978; pp 161-86. Kramer WG, Lewis RP, Cobb TC et al: Pharmacokinetics of digoxin: comparison of a two and a three compartment model in man. J Pharmacokinet Biopharm 1974; 2:299. Lee CH, Park YJ, Sands CD, Jones DW, Trang JM. Bioavailability of digoxin tablets in healthy volunteers. Arch Pharm Res. 1994 Apr;17(2):80-6. Mooradian AD: Digitalis: An update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Clin Pharmacokinet 1988; 15:165-179. |