The Relationship Between Cardiotoxicity and Plasma Digoxin Concentration in Conscious Dogs

Abstract

I The tendency of a given oral dose of digoxin to induce cardiac dysrhythmia was determined indirectly at various times after its administration to eight conscious dogs by measurement of the intravenous dose of acetylstrophanthidin necessary to induce toxic changes in the ECG. Acetylstrophanthidin was used because its rapid elimination from the body permitted estimates to be made 45, 180 and 360 min after digoxin administration. 2 Each dog underwent four studies in which doses of 0.05, 0.1, 0.2 and 0.4 mg/kg digoxin were used in a randomized sequence allowing at least ten days between each dose. 3 Digoxin reduced the amount of acetylstrophanthidin required to cause toxic changes in the ECG; this increase in cardiac sensitivity was dose-dependent. 4 There was no correlation between plasma levels of digoxin and the tendency to dysrhythmia, since peak plasma concentrations of digoxin were reached at about 60 min after dosing whereas maximal sensitivity to acetylstrophanthidin was found 3 to 6 h after administration of digoxin. 5These results suggest that there is little or no increased risk of cardiotoxicity during periods of transient increase in plasma levels ofdigoxin.

Arrhythmogenic dose of acetylstrophanthidin unchanged by beta-sympathomimetics in conscious dogs

“…Indeed, the mean arrhythmogenic doses in our study were almost the same as those found in previous investigations (8,28). Differences from the results of other investigators (3,10,14) are obviously due to anesthesia, different infusion rates and finally to different definitions of the arrhythmogenic dose.…”

Transient Changes in Plasma Digoxin Concentration and the Development of Cardiotoxicity

“…This difference was not associated with any alteration in delayed cardiotoxicity, whether assessed by cardiac sensitivity to acetylstrophanthidin or by the time for subsequent recovery to sinus rhythm. As in previous studies (Chapple et al, 1976), it was noted that recovery time was the less sensitive index of cardiotoxicity. It appears that the tendency to cardiotoxicity is determined solely by the quantity of digoxin entering into the circulation and is unrelated to rate of entry.…”

“…The effects of a single dose of digoxin on the heart have been shown to be delayed and to be maximal at a time when plasma levels are diminishing. This relationship has been demonstrated for both chronotropic and inotropic effects in man (Ganz, Fujimari, Penna, Greiner & Gold, 1957;Shapiro, Narahara & Taubert, 1970) and for cardiotoxic effects in dogs (Chapple, Hughes & Johnson, 1976). However it seems possible that the extent of digoxin cardiotoxicity could be quantitatively related to the preceding peak plasma level, if drug binding to cardiac receptor sites were related in intensity or extent to the peak plasma level of digoxin.…”

“…Our previous work suggested that there was no temporal relationship between transiently high concentrations and increased tendency to cardiac toxicity (Chapple et al, 1976). However, it was still necessary to assess any effect of such plasma concentration changes upon the delayed cardiac effects.…”

“…The cardiac tolerance to acetylstrophanthidin was assessed in each animal by the recognition of well-defined changes in the electrocardiogram (ECG) during infusion of a 100 gg/ml solution in 0.9% w/v NaCl solution (saline) and 7% ethanol at a rate of 0.095 mg/min, as described previously (Chapple et al, 1976 0,5,10,15,20,30,60,90,120,150 and 360 min, and for serum potassium, calcium, bicarbonate and urea at 0 and 6 h after the administration of digoxin. Plasma levels of digoxin were determined by radioimmunoassay using methods already described (Chapple et al, 1976). The significance of the results was tested by analysis of variance and t test where appropriate, recovery times being transformed into logarithms prior to analysis.…”