<?xml version="1.0" encoding="UTF-8"?>
<opml version="2.0">
  <head>
    <title>097-01 Quantitative receptor theory and dose-response reasoning</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Quantitative receptor theory and dose-response">
      <outline text="From binding to clinical response">
        <outline text="Receptors, enzymes, channels, transporters, others"/>
        <outline text="Binding alone is not a clinical effect"/>
        <outline text="Chain from free concentration to whole person">
          <outline text="Each link amplifies, buffers, delays, or opposes"/>
          <outline text="Concentration, occupancy, effect need not be parallel"/>
        </outline>
      </outline>
      <outline text="Binding by mass action">
        <outline text="Association and dissociation rates set equilibrium"/>
        <outline text="KD: free concentration for half occupancy">
          <outline text="Lower KD means higher affinity"/>
        </outline>
        <outline text="Occupancy = C / (C + KD)">
          <outline text="Hyperbola approaches full occupancy asymptotically"/>
        </outline>
        <outline text="Residence time is about 1 / dissociation rate">
          <outline text="Slow dissociation sustains engagement as levels fall"/>
          <outline text="Fast association matters for brief transmitter"/>
        </outline>
        <outline text="In vivo: membranes, rebinding, compartments"/>
      </outline>
      <outline text="Efficacy and ligand classes">
        <outline text="Affinity is binding, efficacy is response"/>
        <outline text="Full agonist reaches the system maximum"/>
        <outline text="Partial agonist cannot, even at high occupancy">
          <outline text="System-dependent: receptor density, signalling"/>
          <outline text="Lowers response beside a full agonist"/>
        </outline>
        <outline text="Inverse agonist stabilises inactive conformations">
          <outline text="Reduces constitutive activity"/>
        </outline>
        <outline text="Neutral antagonist leaves basal activity unchanged"/>
        <outline text="Biased agonism: pathways in different proportions">
          <outline text="Needs explicit reference ligand and assay"/>
        </outline>
      </outline>
      <outline text="Potency and receptor reserve">
        <outline text="Log concentration-response curve is sigmoid"/>
        <outline text="Emax is the maximum observed effect"/>
        <outline text="EC50 measures potency, not necessarily affinity">
          <outline text="Affinity, efficacy, abundance, coupling, access"/>
        </outline>
        <outline text="More potent is not more efficacious or safer"/>
        <outline text="Spare receptors: maximum before full occupancy">
          <outline text="Amplification lets few receptors give full effect"/>
          <outline text="EC50 may fall below KD"/>
        </outline>
        <outline text="Irreversible inactivation consumes reserve first">
          <outline text="Rightward shift, then falling maximum"/>
        </outline>
        <outline text="Reserve varies among tissues"/>
      </outline>
      <outline text="Antagonism">
        <outline text="Competitive: reversible at the agonist site">
          <outline text="Surmountable parallel rightward shift"/>
          <outline text="Concentration ratio and Schild analysis"/>
          <outline text="Nonparallel: equilibration, depletion, populations"/>
        </outline>
        <outline text="Noncompetitive: not overcome by more agonist">
          <outline text="Irreversible, allosteric, transducer, channel block"/>
          <outline text="Maximum falls, reserve may conceal it"/>
        </outline>
        <outline text="Allosteric modulators alter affinity or efficacy">
          <outline text="Ceiling as their own site saturates"/>
        </outline>
        <outline text="Physiological antagonism: opposing functions"/>
        <outline text="Chemical antagonism: interaction or sequestration"/>
        <outline text="Supra-additive effect without target synergy"/>
      </outline>
      <outline text="Population responses and time course">
        <outline text="Did each individual reach a defined outcome"/>
        <outline text="ED50, TD50, LD50 are population distributions"/>
        <outline text="Therapeutic index TD50 / ED50 is crude">
          <outline text="Ignores tails, severity, monitoring, heterogeneity"/>
        </outline>
        <outline text="Therapeutic window boundaries are soft"/>
        <outline text="Hysteresis: effect lags or outlasts concentration">
          <outline text="Effect compartment, slow kinetics, metabolites"/>
          <outline text="Single blood sample can mislead"/>
        </outline>
      </outline>
      <outline text="Adaptation and receptor regulation">
        <outline text="Desensitisation over seconds to hours"/>
        <outline text="Downregulation lowers receptor abundance"/>
        <outline text="Tolerance: pharmacodynamic, pharmacokinetic, learned"/>
        <outline text="Tachyphylaxis is particularly rapid loss"/>
        <outline text="Withdrawal and rebound from persisting adaptation"/>
        <outline text="Supersensitivity after chronic antagonism, denervation"/>
        <outline text="Disease reshapes targets and signalling">
          <outline text="Curve belongs to a drug-system pair at a time"/>
        </outline>
      </outline>
      <outline text="Experimental design and model fitting">
        <outline text="Free, not nominal, concentration"/>
        <outline text="Vehicle controls, randomisation, blinding"/>
        <outline text="Independent preparations versus repeated wells"/>
        <outline text="Conditions reshape curves, models cannot rescue"/>
        <outline text="Hill coefficient is not the number of sites">
          <outline text="Steep slope: cooperativity, amplification, thresholds"/>
        </outline>
        <outline text="Missing plateau weakly identifies Emax and EC50"/>
        <outline text="Self-normalisation hides efficacy differences"/>
      </outline>
      <outline text="Translation and reasoning grammar">
        <outline text="Target plausibility is not therapeutic value">
          <outline text="Inaccessible cells, redundancy, harm elsewhere"/>
        </outline>
        <outline text="Selectivity is concentration-dependent"/>
        <outline text="Achievable exposure, benefit, acceptable harm"/>
        <outline text="State system, endpoint, timescale, uncertainty"/>
      </outline>
    </outline>
  </body>
</opml>
