--- module: 005-01 language: en chapter: 5 title: "Pharmacokinetics, Pharmacodynamics, and Safe Prescribing" module_title: "Foundations" source_sha256: 69f1352d8348382abbc2e453862e348956bf3e1854537ba6dc3cbcf413b1e364 --- # Pharmacokinetics, pharmacodynamics, and safe prescribing ## Orientation ### Dose to target concentration to response ### Pharmacokinetics: what the body does to the drug #### Absorption, distribution, metabolism, excretion ### Pharmacodynamics: what the drug does to the body #### Receptors, enzymes, channels, transporters ### Safe prescribing adds indication, monitoring, stop plan ## Routes and absorption ### Intravenous: complete bioavailability ### Oral: convenient but many barriers #### Dissolution, stability, membrane passage #### Intestinal and hepatic first-pass metabolism ### Bioavailability: fraction reaching circulation unchanged ### Absorption depends on formulation, flow, food, pH ### Lipid-soluble uncharged molecules cross readily #### Many drugs still rely on transporters ### Ionisation follows pH and dissociation constant #### pH alone cannot predict clinical behaviour ### Inhaled rapid, transdermal slow and sustained ### Intramuscular and subcutaneous unreliable in shock ## Distribution ### Perfusion, permeability, tissue and plasma binding ### Albumin binds acids, alpha one acid glycoprotein bases ### Only unbound drug crosses, acts, is filtered #### Bound drug dissociates as a reservoir ### Volume of distribution relates amount to concentration #### Small: mainly plasma; large: tissue binding #### Proportional concept, not an anatomical space ### Older adults: less water and lean mass, more fat ### Oedema, pregnancy, burns, obesity alter distribution ### Blood-brain barrier restricts polar compounds #### Tight junctions and active efflux ## Clearance, metabolism, and half-life ### Clearance: plasma volume cleared per unit time #### Elimination rate equals clearance times concentration ### Half-life depends on volume divided by clearance ### Hepatic: blood flow, enzymes, biliary transport, binding ### Phase one oxidation, reduction, hydrolysis ### Phase two conjugation with polar groups ### Metabolism inactivates, activates prodrugs, or intoxicates ### Inhibition acts quickly, induction takes days #### New enzyme protein must be produced ### Grapefruit effect is drug-specific ### Renal filtration, secretion, reabsorption #### Only unbound drug is filtered ### Estimated filtration imperfect at extremes ### Dialysis removal: size, binding, volume, membrane ## Dosing over time ### Loading dose follows volume of distribution ### Maintenance dose follows clearance ### Steady state after four to five half-lives, any dose ### Short intervals reduce peak-to-trough fluctuation ### Modified release must not always be crushed ### Zero-order elimination saturates capacity #### Small dose rise, disproportionate concentration rise ### Therapeutic drug monitoring for narrow ranges #### Level needs timing, dose history, clinical context ### Worked model: concentration times volume gives amount #### Concentration times clearance gives amount per time #### Halved clearance halves maintenance, not loading #### Half bioavailability doubles the oral input ## Receptors and response ### Full agonist reaches the system maximum ### Partial agonist can oppose a full agonist ### Competitive antagonism overcome by more agonist #### Irreversible effects lower achievable response ### Potency is dose needed, efficacy is maximum effect #### More potent is not more effective or safer ### Spare receptors and amplification break linearity ### Tolerance from desensitisation, metabolism, compensation ### Physical dependence differs from substance-use disorder ## Variability and interactions ### Genetics, age, organ function, adherence vary response ### Children not scaled simply from adult weight ### Frail older adults: falls, delirium, bleeding ### Pharmacokinetic interactions change concentration ### Pharmacodynamic interactions change combined effect #### Sedatives, QT prolongers, bleeding, potassium ### Medication reconciliation: what is actually taken ## Adverse reactions and safety ### Predictable dose-related versus unpredictable reactions ### Side effect is not automatically allergy #### Mislabelled allergy denies useful treatment ### Before prescribing: goal, contraindications, interactions ### Explain benefit, risks, timing, warning symptoms ### Plan monitoring, duration, deprescribing ### Errors from names, decimals, units, transitions #### Leading zeros, no trailing zeros ### Deterioration: review new drugs and dose changes