Quantitative Pharmacodynamics: Receptor Occupancy, Hill-Langmuir & Antagonism Models (Clinical Treatise 2020)
The magnitude of a pharmacological response reflects a dynamic equilibrium between ligand concentration, receptor occupancy, and intracellular intrinsic efficacy.
Pharmacological Mechanism & Kinetic Schema
The Classical Occupancy Theory vs Modern Operational Models
AJ Clark's classical occupancy model postulated that response is directly proportional to the fraction of occupied receptors. Stephenson and Furchgott revised this to introduce intrinsic efficacy (e) and receptor reserve (spare receptors): in systems with high receptor density, a full agonist can elicit a maximal tissue response (Emax) while occupying less than 5% of available receptors.
Competitive Antagonism and the Gaddum-Schild Equation
A reversible competitive antagonist binds mutually exclusively to the orthosteric binding pocket. The concentration-response curve shifts parallel to the right without reducing Emax. The magnitude of this shift is governed by the Schild equation: log(CR - 1) = log[B] - log(Kb), where CR is the concentration ratio and Kb is the antagonist dissociation equilibrium constant.
Non-Competitive, Allosteric, and Irreversible Inactivation
Allosteric modulators and irreversible covalent antagonists (such as phenoxybenzamine at alpha-adrenoceptors) decrease the pool of functional receptors. Once the receptor reserve is completely exhausted, progressive insurmountable depression of maximal efficacy (Emax) occurs.
Clinical Pharmacologist & Biochemist · Specialist in Pharmacokinetics & Hospital Pharmacotherapy · Published on December 23, 2020 at 02:28
