3.4 Receptor Theory
Receptor theory provides the mathematical framework for understanding drug-receptor interactions and predicting drug effects.
Occupancy Theory (Clark)
\( \frac{E}{E_{max}} = \frac{[D]}{K_d + [D]} \)
Effect proportional to receptor occupancy
Simple model assumes: (1) Effect ∝ occupancy, (2) Bmax receptors, (3) Equilibrium binding. Does not account for partial agonists or spare receptors.
Two-State Model
Receptors exist in equilibrium between active (R*) and inactive (R) conformations.
Agonist
Preferentially binds R*, shifts equilibrium to active state.
Inverse Agonist
Preferentially binds R, reduces constitutive activity.
Neutral Antagonist
Binds R and R* equally, blocks both agonist and inverse agonist.
Constitutive Activity
Baseline receptor activity without ligand. Important in disease states.
Spare Receptors
Maximum response achieved before all receptors occupied. EC50 < Kd.
Clinical implication: System has receptor reserve. Irreversible antagonism may not reduce Emax until significant receptor loss.