Anaes · Applied cardiovascular & respiratory physiology

Pharmacogenetics and variability in drug response

Also known as Pharmacogenetics · Pharmacogenomics · Drug response variability · CYP2D6 polymorphism · Pseudocholinesterase deficiency · Malignant hyperthermia genetics

Patients vary enormously in their response to the same dose of a drug, and a major, inherited component of that variability is pharmacogenetics — the influence of genetic differences on drug absorption, distribution, metabolism, excretion and effect. The framework rests on six exam-critical ideas. First, variability is multifactorial: genetic (the largest single factor for many drugs), age (the neonate and the elderly at the extremes), sex and body habitus, organ function (hepatic and renal), and drug interactions all contribute, but genetics explains a large fraction of the inter-individual difference in drug handling. Second, the cytochrome P450 enzymes are highly polymorphic and are classified into metaboliser phenotypes — poor, intermediate, extensive (normal) and ultra-rapid — by the activity of the enzyme variant a person inherits; about 5 to 10 percent of Caucasians are CYP2D6 poor metabolisers, while CYP2D6 ultra-rapid metabolisers are common in North African and Middle Eastern populations. Third, the clinical consequences are dramatic for prodrugs and drugs with a narrow therapeutic index: a CYP2D6 poor metaboliser given codeine converts almost none of it to morphine and gets no analgesia, while an ultra-rapid metaboliser can generate lethal morphine concentrations from a normal codeine dose — which is why codeine is now contraindicated in children and breastfeeding mothers. Fourth, several anaesthesia-critical enzymes are genetically determined: butyrylcholinesterase (pseudocholinesterase) deficiency causes prolonged paralysis after suxamethonium or mivacurium; thiopurine methyltransferase (TPMT) and NUDT15 deficiency predict catastrophic myelosuppression from azathioprine and 6-mercaptopurine; and the ryanodine receptor (RYR1) variants underlie susceptibility to malignant hyperthermia. Fifth, pharmacogenetics also guides dosing of common drugs: warfarin dose depends on CYP2C9 (metabolism) and VKORC1 (sensitivity) genotype, and clopidogrel efficacy depends on CYP2C19 status (poor metabolisers cannot activate the prodrug and have a higher risk of stent thrombosis). Sixth, pharmacogenetic variation interacts with the other sources of variability — the neonate is both genetically and developmentally a slow metaboliser — so safe prescribing integrates all of them. Built on the Ontario CYP metaboliser-distribution cohort (Thamilselvan 2026, n-8280 psychotropic cohort, PM plus UM extremes about 8 percent each for CYP2C19 and CYP2D6, Caribbean 24 percent vs Latin 7 percent, 5.1 percent normal across all enzymes), the pre-emptive-testing discontinuation cohort (Baye 2026, n-5808 patients and 8571 orders, 51 percent discontinued pre-testing, CYP2C19 increased HR 1.17 for citalopram/escitalopram/sertraline, venlafaxine HR 1.23), the elderly mivacurium secondary analysis (Kempff-Andersen 2026, age 80-plus, title-anchored and abstract-less), the Arab genotype-guided warfarin model (Fahmi 2026, n-405, VKORC1 plus CYP2C9 model R2 51.6 percent, MAE 9.3 vs 12.4 mg/week p 0.03 vs Gage), the paediatric NUDT15 myelosuppression brief report (Fry 2026, 4-year-old ALL with NUDT15 star-1/star-6, standard mercaptopurine not tolerated down to 27 percent, CPIC reclassification to intermediate), the paediatric G6PD anaesthetic case (Khaliq 2026, 23-month-old 8 kg coin esophagoscopy, oxidant avoidance with 24-hour surveillance), the familial RYR1 residual-risk comment (Gulen 2026, title-anchored and abstract-less), and the CRISPR CYP2C19 point-of-care assay (Schubert 2026, star-2/star-3/star-17, n-110, 97.3/100/99.1 percent vs Sanger). Phenotype frequencies, dibucaine numbers, inheritance patterns, and contraindication ages below are viva teaching carried with honesty notes, not numbers from these abstracts.