NONLINEAR KINETICS OF ATROPINE ACTION ON THE PACEMAKER OF THE ISOLATED GUINEA-PIG ATRIUM

¹ Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New hampshire

The question was examined, whether the kinetics of atropine action fit the hypothesis that diffusion of the drug to the site of action was the rate-limiting process. The theory of diffusion kinetics in an isolated bit of tissue maintained in a tissue bath was worked out on the basis of a multicompartment model, and it was shown that if the tissue. equilibrated with some applied drug concentration, is abruptly exposed to a new, constant drug concentration, then as the concentration x_i in the ith compartment changes from its initial value x_{i 0} to its final steady-state value x_i, the function (x_i — x_{i 0})/(x_{i 0} — x_i) decreases from 1 to 0, following a time course which is independent of the initial and final applied drug concentrations. Similar behavior may in certain cases be predicted for observed drug effects; and in the case of atropine and the atrial pacemaker, it can be shown theoretically that, for the dose ratio , the function ( — )/(_o — ) should fall from 1 to 0 following always the same time course. Curves of this function, plotted against time for the onset of action of different atropine concentrations, were not superimposable, however. Therefore, it was concluded that either atropine kinetics are not limited by simple diffusion, or there is a quantitatively non-negligible amount of drug taken up by the receptors, the uptake introducing non-linearity into the system.