--- module: 005-02 language: en chapter: 5 title: "Pharmacokinetics, Pharmacodynamics, and Safe Prescribing" module_title: "Exposure, variability, and prescribing as a control process" source_sha256: eeb6d62a703768da9ac3dc39b8b4c87adccc7052404edd5117bfb069e1839a5c --- # Exposure, variability, and prescribing as control ## Concentration over time ### Dose is input, exposure is the concentration pattern ### Area under the curve: total systemic exposure ### Peak, time above target, or total exposure #### Each predicts different effects or toxicity ### Same daily dose, not always equivalent regimens #### Divided dosing lowers peaks, raises troughs #### Rapid bolus: high early concentration ### Distribution phase fall, then slower elimination #### Early sampling overstates clearance ### Lipid-soluble redistribution prolongs sedation ### Half-life rises as clearance falls or volume rises #### Critical illness changes both at once ## Capacity, extraction, and organ disease ### High extraction: clearance follows liver blood flow ### Low extraction: enzyme activity and unbound fraction ### Liver disease does not reduce pathways uniformly #### Liver tests do not quantify drug clearance ### Active secretion removes protein-bound drug ### Competing drugs inhibit renal transporters ### Urine pH alters weak acid and base reabsorption ### Creatinine estimate lags behind changing filtration ### Replacement therapy removes small, unbound, low-volume drugs #### Levels help only with meaningful assay and timing ### Saturable metabolism creates non-linearity #### Near saturation, small dose rise, large level rise ### Autoinduction and active metabolites add delay ## Free concentration and binding shifts ### Total level includes bound and unbound drug ### Low albumin raises the unbound fraction #### Total falls while active exposure is adequate #### Total-only reading can prompt unsafe increase ### Displacement is usually transient #### Matters with limited clearance, narrow margin ### Bilirubin and uraemic toxins alter binding ### Tissue binding prolongs action #### Lysosomes, bone, melanin, intracellular targets #### Normal level does not exclude drug toxicity ## Receptor pharmacology into dose choice ### Individual dose-response curve rarely known ### Therapeutic and adverse curves differ #### Benefit plateaus while harm keeps rising #### Useful dose is not the maximum tolerated ### Competitive blockade fails when agonist is limited ### Irreversible antagonist: wait for new receptors ### Physiological antagonist opposes via another process ### Tolerance should trigger mechanistic review #### Faster metabolism, desensitisation, progression #### Poor adherence or interaction mimics tolerance ### Placebo and nocebo are genuine effects #### Balanced explanation reduces nocebo burden ## Interactions as mechanisms ### Move beyond counting alerts ### Absorption: chelation, acidity, gut binding, motility ### Metabolism: specific enzyme inhibition or induction ### Transporters: uptake, hepatic entry, biliary, renal ### Perpetrator affects only pathway-dependent drugs ### Pharmacodynamic: additive, synergistic, antagonistic #### Sedatives converge on ventilation and airway #### Small effects sum beyond physiological reserve ### Inhibition starts fast, induction builds and fades #### Effect persists beyond the final dose ### Avoid, adjust, monitor levels, or substitute ## Prescribing as feedback control ### Target, intervene, measure, adjust or stop ### No review time or success criterion is open loop #### Unsafe when physiology is changing ### Keep the indication attached to each medicine ### Make duration explicit ### Deprescribing is not simply deleting #### Anticipate withdrawal, change one variable #### Taper when cessation exposes adaptation ## Execution and reassessment ### Patient ability shapes real exposure #### Vision, dexterity, cognition, cost, support ### Simplify, demonstrate, pharmacist review ### Deterioration: build a medication timeline #### Caused, unmasked, failed, or obscured ### Confirm what was actually taken and when ### Match levels to sampling and last dose times ### Loop closes when patient and clinician share goal