Sensitivity of Action Potential Triggering is Normally Distributed as a Function of Mean Fractional Receptor Activation

Abstract

In 1968, Waud presented his general pharmacodynamic model consisting of two sub-functions that divide the pharmacodynamic cascade from drug concentration to cell effect/response into two successive steps: Step one (the internal function) characterizes the binding of agonist drug molecules to the post-synaptic receptors and the subsequent receptor activation, and step two (the external/effect function) characterizes the cell response induced by a critical receptor pool activation. According to Waud, the problem of determining the relation between drug concentration and cell response/effect reduces to the second step in the pharmacodynamic cascade. In this paper, we suggest a new external/effect-function, the cumulative Normal population-effect-function. It describes how muscle fibre excitability (all-or-none phenomenon) is distributed as a function of mean fractional receptor activation in a muscle fibre population. This function fits to empirical data and explains logically why the sigmoid muscle effect, from minimal to maximal, is seen in such a narrow range of antagonist concentrations and receptor occupancies.