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  <head>
    <title>005-02 Exposure, variability, and prescribing as a control process</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Exposure, variability, and prescribing as control">
      <outline text="Concentration over time">
        <outline text="Dose is input, exposure is the concentration pattern"/>
        <outline text="Area under the curve: total systemic exposure"/>
        <outline text="Peak, time above target, or total exposure">
          <outline text="Each predicts different effects or toxicity"/>
        </outline>
        <outline text="Same daily dose, not always equivalent regimens">
          <outline text="Divided dosing lowers peaks, raises troughs"/>
          <outline text="Rapid bolus: high early concentration"/>
        </outline>
        <outline text="Distribution phase fall, then slower elimination">
          <outline text="Early sampling overstates clearance"/>
        </outline>
        <outline text="Lipid-soluble redistribution prolongs sedation"/>
        <outline text="Half-life rises as clearance falls or volume rises">
          <outline text="Critical illness changes both at once"/>
        </outline>
      </outline>
      <outline text="Capacity, extraction, and organ disease">
        <outline text="High extraction: clearance follows liver blood flow"/>
        <outline text="Low extraction: enzyme activity and unbound fraction"/>
        <outline text="Liver disease does not reduce pathways uniformly">
          <outline text="Liver tests do not quantify drug clearance"/>
        </outline>
        <outline text="Active secretion removes protein-bound drug"/>
        <outline text="Competing drugs inhibit renal transporters"/>
        <outline text="Urine pH alters weak acid and base reabsorption"/>
        <outline text="Creatinine estimate lags behind changing filtration"/>
        <outline text="Replacement therapy removes small, unbound, low-volume drugs">
          <outline text="Levels help only with meaningful assay and timing"/>
        </outline>
        <outline text="Saturable metabolism creates non-linearity">
          <outline text="Near saturation, small dose rise, large level rise"/>
        </outline>
        <outline text="Autoinduction and active metabolites add delay"/>
      </outline>
      <outline text="Free concentration and binding shifts">
        <outline text="Total level includes bound and unbound drug"/>
        <outline text="Low albumin raises the unbound fraction">
          <outline text="Total falls while active exposure is adequate"/>
          <outline text="Total-only reading can prompt unsafe increase"/>
        </outline>
        <outline text="Displacement is usually transient">
          <outline text="Matters with limited clearance, narrow margin"/>
        </outline>
        <outline text="Bilirubin and uraemic toxins alter binding"/>
        <outline text="Tissue binding prolongs action">
          <outline text="Lysosomes, bone, melanin, intracellular targets"/>
          <outline text="Normal level does not exclude drug toxicity"/>
        </outline>
      </outline>
      <outline text="Receptor pharmacology into dose choice">
        <outline text="Individual dose-response curve rarely known"/>
        <outline text="Therapeutic and adverse curves differ">
          <outline text="Benefit plateaus while harm keeps rising"/>
          <outline text="Useful dose is not the maximum tolerated"/>
        </outline>
        <outline text="Competitive blockade fails when agonist is limited"/>
        <outline text="Irreversible antagonist: wait for new receptors"/>
        <outline text="Physiological antagonist opposes via another process"/>
        <outline text="Tolerance should trigger mechanistic review">
          <outline text="Faster metabolism, desensitisation, progression"/>
          <outline text="Poor adherence or interaction mimics tolerance"/>
        </outline>
        <outline text="Placebo and nocebo are genuine effects">
          <outline text="Balanced explanation reduces nocebo burden"/>
        </outline>
      </outline>
      <outline text="Interactions as mechanisms">
        <outline text="Move beyond counting alerts"/>
        <outline text="Absorption: chelation, acidity, gut binding, motility"/>
        <outline text="Metabolism: specific enzyme inhibition or induction"/>
        <outline text="Transporters: uptake, hepatic entry, biliary, renal"/>
        <outline text="Perpetrator affects only pathway-dependent drugs"/>
        <outline text="Pharmacodynamic: additive, synergistic, antagonistic">
          <outline text="Sedatives converge on ventilation and airway"/>
          <outline text="Small effects sum beyond physiological reserve"/>
        </outline>
        <outline text="Inhibition starts fast, induction builds and fades">
          <outline text="Effect persists beyond the final dose"/>
        </outline>
        <outline text="Avoid, adjust, monitor levels, or substitute"/>
      </outline>
      <outline text="Prescribing as feedback control">
        <outline text="Target, intervene, measure, adjust or stop"/>
        <outline text="No review time or success criterion is open loop">
          <outline text="Unsafe when physiology is changing"/>
        </outline>
        <outline text="Keep the indication attached to each medicine"/>
        <outline text="Make duration explicit"/>
        <outline text="Deprescribing is not simply deleting">
          <outline text="Anticipate withdrawal, change one variable"/>
          <outline text="Taper when cessation exposes adaptation"/>
        </outline>
      </outline>
      <outline text="Execution and reassessment">
        <outline text="Patient ability shapes real exposure">
          <outline text="Vision, dexterity, cognition, cost, support"/>
        </outline>
        <outline text="Simplify, demonstrate, pharmacist review"/>
        <outline text="Deterioration: build a medication timeline">
          <outline text="Caused, unmasked, failed, or obscured"/>
        </outline>
        <outline text="Confirm what was actually taken and when"/>
        <outline text="Match levels to sampling and last dose times"/>
        <outline text="Loop closes when patient and clinician share goal"/>
      </outline>
    </outline>
  </body>
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