--- module: 097-01 language: en chapter: 97 title: "Receptor Theory, Experimental Pharmacology, Drug Discovery, and Pharmacogenomics" module_title: "Quantitative receptor theory and dose-response reasoning" source_sha256: 09948eb4a680931feaeeb13e80cd863ce2e4ea691c7dd897669c6a8f233f25a4 --- # Quantitative receptor theory and dose-response ## From binding to clinical response ### Receptors, enzymes, channels, transporters, others ### Binding alone is not a clinical effect ### Chain from free concentration to whole person #### Each link amplifies, buffers, delays, or opposes #### Concentration, occupancy, effect need not be parallel ## Binding by mass action ### Association and dissociation rates set equilibrium ### KD: free concentration for half occupancy #### Lower KD means higher affinity ### Occupancy = C / (C + KD) #### Hyperbola approaches full occupancy asymptotically ### Residence time is about 1 / dissociation rate #### Slow dissociation sustains engagement as levels fall #### Fast association matters for brief transmitter ### In vivo: membranes, rebinding, compartments ## Efficacy and ligand classes ### Affinity is binding, efficacy is response ### Full agonist reaches the system maximum ### Partial agonist cannot, even at high occupancy #### System-dependent: receptor density, signalling #### Lowers response beside a full agonist ### Inverse agonist stabilises inactive conformations #### Reduces constitutive activity ### Neutral antagonist leaves basal activity unchanged ### Biased agonism: pathways in different proportions #### Needs explicit reference ligand and assay ## Potency and receptor reserve ### Log concentration-response curve is sigmoid ### Emax is the maximum observed effect ### EC50 measures potency, not necessarily affinity #### Affinity, efficacy, abundance, coupling, access ### More potent is not more efficacious or safer ### Spare receptors: maximum before full occupancy #### Amplification lets few receptors give full effect #### EC50 may fall below KD ### Irreversible inactivation consumes reserve first #### Rightward shift, then falling maximum ### Reserve varies among tissues ## Antagonism ### Competitive: reversible at the agonist site #### Surmountable parallel rightward shift #### Concentration ratio and Schild analysis #### Nonparallel: equilibration, depletion, populations ### Noncompetitive: not overcome by more agonist #### Irreversible, allosteric, transducer, channel block #### Maximum falls, reserve may conceal it ### Allosteric modulators alter affinity or efficacy #### Ceiling as their own site saturates ### Physiological antagonism: opposing functions ### Chemical antagonism: interaction or sequestration ### Supra-additive effect without target synergy ## Population responses and time course ### Did each individual reach a defined outcome ### ED50, TD50, LD50 are population distributions ### Therapeutic index TD50 / ED50 is crude #### Ignores tails, severity, monitoring, heterogeneity ### Therapeutic window boundaries are soft ### Hysteresis: effect lags or outlasts concentration #### Effect compartment, slow kinetics, metabolites #### Single blood sample can mislead ## Adaptation and receptor regulation ### Desensitisation over seconds to hours ### Downregulation lowers receptor abundance ### Tolerance: pharmacodynamic, pharmacokinetic, learned ### Tachyphylaxis is particularly rapid loss ### Withdrawal and rebound from persisting adaptation ### Supersensitivity after chronic antagonism, denervation ### Disease reshapes targets and signalling #### Curve belongs to a drug-system pair at a time ## Experimental design and model fitting ### Free, not nominal, concentration ### Vehicle controls, randomisation, blinding ### Independent preparations versus repeated wells ### Conditions reshape curves, models cannot rescue ### Hill coefficient is not the number of sites #### Steep slope: cooperativity, amplification, thresholds ### Missing plateau weakly identifies Emax and EC50 ### Self-normalisation hides efficacy differences ## Translation and reasoning grammar ### Target plausibility is not therapeutic value #### Inaccessible cells, redundancy, harm elsewhere ### Selectivity is concentration-dependent ### Achievable exposure, benefit, acceptable harm ### State system, endpoint, timescale, uncertainty