Demystifying the Concept of “Spare Receptors” in Pharmacology Education Through Novel Didactic Approaches

Abstract

<b>Abstract ID 23348</b> <b>Poster Board 189</b> A major goal of pharmacology education is to provide learners with a solid understanding of the factors that drive the relationship between administered dose and both therapeutic and undesirable effects. Among the most challenging pharmacodynamic concepts to convey is the idea of “receptor reserve” or “spare receptors”. This concept is difficult to define and explain, even for seasoned pharmacologists. It is often introduced using an example: If the number of receptors in a system Is reduced, and an agonist can still generate a maximal response, this means that there were “spare receptors” or that there was “receptor reserve”. This operational definition, however, describes only an extreme condition that puts receptor number as the only relevant parameter and obscures the key underlying agonist, and system properties that give rise to this important behavior. As part of my involvement in pharmacology instruction at undergraduate, graduate, and professional levels, I have found that concept of receptor reserve can be introduced effectively as part of a comprehensive pharmacodynamic framework complemented with illustrative analogies and simulations. This didactic framework is based on a generalization of the classical Furchgott model of agonism, and leverages a <i><b>Ve</b></i>rsatile <i><b>S</b></i>imulation tool for effective didactic illustration of <i><b>Pha</b></i>rmacodynamic concepts (<b><i>VesPha</i></b>) that I have created. In this framework, the system mounts a response based on its sensitivity to the stimulus generated by occupied receptors. The stimulus, in turn, is proportional to the number of occupied receptors and their intrinsic efficacy, that is, the amount of stimulus each occupied receptor generates. The number of occupied receptors, in turn is driven by the concentration and affinity of the agonist and the total number of receptors. At its core, receptor reserve can be viewed as conditions where a significant response can be generated by agonist occupancy of a relatively low fraction of available receptors, that is, when the IC₅₀ is significantly lower than the Kd. In the context of the above framework, it is clear that receptor reserve is not simply a consequence of receptor number but depends critically on the intrinsic efficacy (a property of the drug-receptor complex) and the sensitivity of the system to the stimulus generated by the receptors, (a property of the system). The influence of each of these parameters on receptor reserve can be easily illustrated by dynamic simulations in <i><b>VesPha</b></i>. Using this tool, it is easy to demonstrate how the response to a ligand with higher intrinsic efficacy can display higher receptor reserve than one with a lower intrinsic efficacy in the same system despite a constant receptor number. Similarly, it is possible to illustrate how response to a particular agonist can display higher receptor reserve in a system that has higher sensitivity than another, even if the number of receptors is the same in both. It is also easy to illustrate how signal amplification contributes to receptor reserve, i.e., how, for the same agonist and system, receptor reserve increases as responses further down the amplification cascade are measured. In conclusion, providing a self-consistent framework for pharmacodynamics and appropriate tools to illustrate it, is an effective way for learners to master fundamental concepts and demystify terms that are otherwise challenging to grasp.