Therapeutic Guidelines
Administration of Digoxin

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Introduction

Many factors affect a patient's response to digitalis therapy. Ischemia, electrolyte imbalance, sympathetic support to the myocardium, the ability of the myocardium to respond to digitalis, and the total amount or concentration of digitalis present in the patients body are some of many important factors which may affect a patient's response to digoxin therapy.

The therapeutic approach described here employs methods which help to clarify one of these important parameters, that of the total amount or concentration of glycoside in the patient's body.1, 2, 3, 4 This approach is presently intended for adult euthyroid patients in normal electrolyte balance who have no obvious abnormality of gastrointestinal absorption. The influence of altered electrolyte balance upon this therapeutic approach is currently under study.

Digoxin losses from the body are proportional to the total amount present in the body. Because of this, a certain percent of the total amount of digoxin in a patient's body is lost each day.

The initial dose given a patient sets total body digoxin stores at the level of that dose, adjusted for gastrointestinal absorption as shown later. By the time the next dose is given, a certain percent has been lost from the body by various routes, and a certain percent still remains. The next dose given raises total body digoxin stores to a new level, and once again approximately the same percent of the new total is lost per day, if renal function remains stable.

It has been shown that the percent of total body digoxin lost per day is highly correlated with a patient's endogenous creatinine clearance.3, 4 Thus if one knows the daily doses given and the percent of the total amount lost between each dose, he can serially calculate his patient's cumulated total body digoxin stores. It is this total cumulated amount in the patient's body that essentially determines pharmacologic effect and toxicity, as the myocardium appears to take up its usual share from the total amount present in the body. As shown in Figure 1, for example, myocardial digoxin concentrations, chemically measured at autopsy, are highly correlated with calculated total body digoxin stores at death, when they are expressed as milligram per kilogram.5

Digitalis toxicity is also highly correlated with total body concentrations of digoxin, as shown in Figure 2, obtained from data on 59 patients, 19 of whom had developed evidence of digitalis toxicity on other treatment programs (see Discussion).

The ability to calculate total body digoxin stores (milligrams) and concentrations (milligrams per kilograms) in patients thus gives the physician a new and useful guide to digoxin therapy. He can know with reasonable confidence whether or not total body digoxin stores are rising or falling on his present dosage program, and he can, using his traditional clinical judgment, now adjust digoxin dosage to the patient's weight and renal function to keep body stores reasonably close to any selected level he desires for his patient.

If you can get a creatinine clearance on your patient, do so. If not, make a reasonable initial estimate of what you think his creatinine clearance is, and use this estimate until you can obtain a true measurement of endogenous creatinine clearance. If you have a stable serum creatinine level which is greater than 1 mg/100 ml, a very rough but simple estimate of creatinine clearance in patients who are not cachectic or on a dialysis program can be obtained by saying that creatinine clearance = 100 × (1/serum creatinine). If possible, however, use a 24 hour urine specimen and a fasting serum creatinine, since the subsequent data of daily percent digoxin losses were obtained using that method to determine endogenous creatinine clearance.4

Section snippets

The Loading Dose

Let us begin by asking what amounts of digoxin are present in patients with normal renal function (creatinine clearance = 105 ml/min) who are in the steady state on the common fixed oral daily doses of 0.25, 0.375, and 0.5 mg of digoxin respectively.

Parenteral digoxin is fully absorbed. However, only about 80 to 90 percent of oral digoxin passes the portal and hepatic circulation and gains access to the rest of the body.6, 7 It thus appears reasonable to assume that 85 percent of oral digoxin,

The Maintenance Dose

After the total loading dose has been given, look at Figure 4 or use equation (3) to find the proper daily maintenance dose to sustain body digoxin concentrations at your desired level. Start this dose one day after the loading dose has been given.

Figure 4 shows the relationship between the percent of total body digoxin lost each day from patients and their endogenous creatinine clearance. The maintenance dose, shown on the vertical axis, is designed to replace such daily losses.4 A patient

Patients with Changing Renal Function

If a patient with known creatinine clearance was doing well on a certain daily dose of digoxin and then suffered a sudden reduction in renal function, you may then:

  • 1.

    Calculate his previous total body digoxin stores.

  • 2.

    Try to preserve these stores through his period of altered renal function.

  • 3.

    Get frequent (preferably daily) measurements of endogenous creatinine clearance.

  • 4.

    Adjust tomorrows digoxin dose to his most recent creatinine clearance, to keep total body digoxin stores constant at the level

Preparations of Digoxin

Current preparations leave much to be desired when one wishes to give a dose of 0.216 mg of digoxin by mouth, for example. Tablets are at present available only in 0.125, 0.25, and 0.5 mg sizes. After the physician has calculated the oral dose he ideally would desire for his patient, he then is faced with having to have pills cut into halves and quarters to reach reasonable approximations of the selected dose. One can only hope that pharmaceutical companies will provide a greater range of

Discussion

This method of therapy requires arithmetic. Arithmetic produces arithmetical errors. A pocketsize slide rule is most helpful. Even this, however, can be laborious if one must do serial calculations of cumulated total body digoxin stores and concentrations over a long period of past historical or hospital data to find out what a patient's present calculated body digoxin concentration is. To alleviate this problem and to extend this basic approach to therapy with other glycosides as well,

Summary

Administration of digoxin to the type of patient described here requires clinical judgment plus careful adjustment of dosage to the patient's renal function and body weight. Calculated body digoxin concentrations of 0.0085, 0.013, and 0.0175 mg/kg appear to give reasonable therapeutic response for many patients. These concentrations include approximately 5, 9 and 29 percent respectively of patients with digitalis toxicity. Start with the lower concentrations if possible. Greater concentrations

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