Chapter 1 · Module 5 of 6 · General Principles

Sources of Variability in Drug Response

Why the same drug and dose produces different outcomes in different patients — pharmacogenomics, age, disease state, and the framework for individualized prescribing

Metabolizer phenotype is determined by inherited variants in drug-metabolizing enzymes: poor metabolizers accumulate active drugs (toxicity) and fail to activate prodrugs (no effect); ultrarapid metabolizers show the opposite pattern — both extremes demand dose individualization
High-yield gene-drug pairs with mandatory or guideline-recommended testing include CYP2D6/codeine, CYP2C19/clopidogrel, CYP2C9/warfarin, TPMT/thiopurines, and HLA-B*5701/abacavir — each with documented life-threatening consequences of ignoring genotype
Pediatric pharmacology is governed by immature enzyme and renal systems; geriatric pharmacology by progressive decline in renal and hepatic clearance, altered body composition, and increased CNS sensitivity — dosing cannot be extrapolated between age groups
Renal impairment prolongs the half-life of renally cleared drugs causing accumulation; hepatic impairment reduces metabolism, lowers albumin increasing free drug fractions, and increases oral bioavailability through reduced first-pass extraction
Individualized prescribing integrates all variability sources simultaneously: identify the elimination pathway, check renal and hepatic function, assess age-related factors, review available pharmacogenomic data, and screen for interactions — narrow therapeutic index drugs require explicit evaluation of every factor

Section 1 — Pharmacogenomics

Section 1

Metabolizer Phenotypes and High-Yield Gene-Drug Pairs

Poor Metabolizer (PM)

No enzyme activity

Active drug: accumulates → toxicity at standard dose. Prodrug: no activation → no therapeutic effect.

Intermediate (IM)

Reduced activity

Partial effect. Dose adjustment may be needed for narrow therapeutic index drugs.

Extensive (EM)

Normal activity

Standard dosing appropriate. Represents the majority of the population.

Ultrarapid (UM)

Increased activity

Active drug: clears rapidly → subtherapeutic. Prodrug: excess activation → toxicity.

High-Yield Gene-Drug Pairs

Gene / Enzyme	Drug	Drug Type	Clinical Consequence of Variant
CYP2D6	Codeine	Prodrug	PM: no analgesia. UM: fatal respiratory depression from morphine accumulation. Black box warning — contraindicated in children post-tonsillectomy.
CYP2C19	Clopidogrel	Prodrug	PM: inadequate platelet inhibition → stent thrombosis risk. Black box warning. High PM prevalence in East Asian populations.
CYP2C9	Warfarin	Active drug	PM: reduced clearance → lower maintenance dose required to avoid bleeding. Incorporated into pharmacogenomic dosing algorithms.
TPMT	Azathioprine / 6-MP	Prodrug	PM (1 in 300 people): standard dose → life-threatening bone marrow suppression. Pre-treatment TPMT testing is standard of care.
HLA-B*5701	Abacavir	Active drug	Allele present: severe hypersensitivity syndrome — potentially fatal. Mandatory pre-treatment genetic screening eliminates risk entirely.

Section 2 — Age-Related Variability

Section 2

Pediatric and Geriatric Pharmacology

Pediatric

Immature Systems

CYP enzymes immature at birth — slow metabolism in neonates
Renal function matures over the first two years of life
Dosing must be weight-based (mg/kg) — adult doses are never appropriate
Classic example: neonatal gray baby syndrome from chloramphenicol — insufficient glucuronidation leads to toxic accumulation
Young children may metabolize some drugs faster than adults on a weight-adjusted basis once enzymes mature

Geriatric

Declining Systems

eGFR falls approximately 1% per year after age 40
Reduced hepatic blood flow and liver mass slow clearance
Higher fat-to-lean ratio increases volume of distribution for lipophilic drugs
Increased CNS sensitivity to sedatives and opioids
Polypharmacy compounds all pharmacokinetic and pharmacodynamic risks
Beers Criteria identify drugs potentially inappropriate in older adults

Sections 3 & 4 — Disease-Induced Variability and Individualized Prescribing

Sections 3 & 4

Organ Impairment Effects and the Pre-Prescribing Checklist

Organ	Pharmacokinetic Effect	Clinical Consequence	High-Risk Drugs
Kidney	Reduced eGFR → slower elimination of renally cleared drugs	Drug accumulation → toxicity at standard doses. Half-life prolonged proportionally to degree of impairment.	Digoxin, aminoglycosides, lithium, metformin, direct oral anticoagulants
Liver	Reduced Phase I and II metabolism; reduced albumin; portosystemic shunting increases oral bioavailability	Drug accumulation; increased free fraction of protein-bound drugs; higher plasma levels from oral doses via reduced first-pass extraction	Most hepatically metabolized drugs; warfarin, benzodiazepines, opioids, statins

The pre-prescribing checklist for variable drug response: Identify the primary elimination pathway. Check renal function (eGFR). Assess hepatic function (Child-Pugh score if indicated). Review age-related adjustments. Check for available pharmacogenomic tests for this drug. Review concurrent medications for interactions. Narrow therapeutic index drugs demand explicit evaluation of every factor before each prescribing decision.

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th edition	McGraw-Hill, 2021
Brunton LL, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th edition	McGraw-Hill, 2023
Relling MV, Evans WE	Pharmacogenomics in the clinic	Nature, 2015; 526(7573):343–350
Scott SA	Personalizing medicine with clinical pharmacogenomics	Genetics in Medicine, 2011; 13(12):987–995
Katzung BG, Trevor AJ, eds.	Basic and Clinical Pharmacology, 15th edition	McGraw-Hill, 2021
American Geriatrics Society Beers Criteria Update Expert Panel	American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults	Journal of the American Geriatrics Society, 2023; 71(7):2052–2081
Brunton LL, Hilal-Dandan R, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th edition	McGraw-Hill, 2018
Waller DG, Sampson AP	Medical Pharmacology and Therapeutics, 5th edition	Elsevier, 2018