--- module: 097-03 language: en chapter: 97 title: "Receptor Theory, Experimental Pharmacology, Drug Discovery, and Pharmacogenomics" module_title: "Pharmacogenomics, adverse effects, interactions, and regulation" source_sha256: 242ddf8b806467fd074ba75c5c762e152183461d70edcbb27c82c0d0a3aa7e42 --- # Pharmacogenomics, adverse effects, regulation ## Variation and useful pharmacogenomics ### Exposure, target, disease, behaviour, chance ### Inherited and acquired genomic variation ### A useful result changes a decision #### Prescribe, choose, starting dose, adjust, monitor ### Association alone is insufficient #### Accurate measurement, reproducible phenotype #### Interpret in ancestry and clinical context ## Pharmacokinetic genes ### Absorption, transport, metabolism, elimination ### Alleles: absent to increased or altered function ### Metaboliser categories simplify a continuum ### Active parent drug: reduced metabolism, toxicity ### Prodrug: reduced activation, less efficacy #### Direction requires knowing the pathway ### Phenoconversion by enzyme inhibition ### Induction raises capacity over days ### Disease, age, diet, smoking alter expression ### Limited panels miss rare and copy-number variants ## Pharmacodynamic and somatic variation ### Receptor and signalling variants alter sensitivity ### Antigen-presenting variant presents drug antigen #### Strong risk of specific hypersensitivity ### Tumour changes predict dependence or resistance #### One biopsy may miss clones ### Germline: person and relatives; somatic: tissue ## Testing strategy and decision support ### Pre-emptive: before prescription, reusable #### Needs records, updates, misuse protection ### Reactive: at decision, may be too late ### Support states gene, phenotype, action, limits ## Adverse reactions and causality ### Intended pharmacology, off-target, immune, errors ### Predictable dose-related reactions are common ### Unpredictable reactions may still be genetic ### Classification is an aid, not a law ### An event after a drug is not automatically caused ### Timing, mechanism, dechallenge, rechallenge #### Rechallenge unethical after severe reaction #### Dechallenge misleads if disease resolves ### Scales improve consistency, not judgment ## Immune reactions and organ toxicity ### Antibody, cytotoxic, immune-complex, T-cell ### Prior uneventful exposure does not exclude it ### Severe reactions can progress after stopping #### Immune activation becomes self-sustaining ### Document culprit, phenotype, severity, certainty ### Liver: high first-pass concentrations ### Kidney: concentrated filtrate exposes tubules ### Heart: conduction, repolarisation, contractility ### Monitor by latency and mechanism ## Drug interactions ### Pharmacokinetic: one changes another's exposure ### Absorption: binding, pH, motility, transport ### Inhibition starts as inhibitor rises ### Induction develops and resolves slowly #### Protein abundance must change ### Protein displacement alone often transient ### Pharmacodynamic: additive, synergistic, antagonistic #### Sedatives jointly depress ventilation #### Different mechanisms increase bleeding #### Repolarisation delay conditioned by electrolytes ### Databases flag, management estimates magnitude ## Age, pregnancy, and organ function ### Neonates: immature clearance pathways ### Children: maturation is nonlinear ### Older adults: reserve, frailty, sensitivity #### Low muscle mass hides low filtration ### Polypharmacy: review indication and net benefit ### Pregnancy alters volume, binding, filtration #### Fetal risk depends on developmental timing #### Untreated illness is not zero risk ### Lactation: milk transfer, infant clearance ### Loading by volume, maintenance by clearance ## Medication safety and regulation ### Errors: names, units, decimals, reconciliation ### Systems make the intended action easy ### Blame without workflow review preserves errors ### Approval: favourable benefit-risk in conditions #### Not complete knowledge or superiority ### Tools: labels, controlled distribution, studies ### Regulators can reasonably differ ### New risks weighed by absolute frequency #### Relative risk can sound dramatic ## Responsible pharmacology ### Genomics refines probability, rarely replaces ### Signals need investigation, not reflex certainty ### Choose exposure, anticipate, detect, revise