Chapter 1  ·  Module 5

Sources of Variability in Drug Response

Section 1 — Pharmacogenomics

Metabolizer Phenotypes

Poor Metabolizer

No enzyme activity

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

Intermediate

Reduced activity

Partial effect. May need dose adjustment for drugs with narrow therapeutic index.

Extensive

Normal activity

Standard dosing appropriate. Majority of the population.

Ultrarapid

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 Poor metabolizer: no analgesia. Ultrarapid: fatal respiratory depression from morphine accumulation. Black box warning.
CYP2C19 Clopidogrel Prodrug Poor metabolizer: inadequate platelet inhibition → stent thrombosis risk. Black box warning. Common in East Asians.
CYP2C9 Warfarin Active drug Poor metabolizer: reduced clearance → lower dose required to avoid bleeding. Guides dosing algorithms.
TPMT Azathioprine / 6-mercaptopurine Prodrug Poor metabolizer (1 in 300): standard dose → life-threatening bone marrow suppression. Pre-treatment testing is standard of care.
HLA-B*5701 Abacavir Active drug Allele present: severe hypersensitivity syndrome (potentially fatal). Mandatory pre-treatment genetic testing eliminates risk.

Section 2

Age-Related Variability

Pediatric

Immature Systems

  • Cytochrome P450 enzymes immature at birth — slow metabolism in neonates
  • Renal function matures over first two years of life
  • Dosing must be weight-based (mg/kg), never adult doses
  • Classic example: neonatal gray baby syndrome from chloramphenicol (insufficient glucuronidation)
  • Young children may metabolize some drugs faster than adults on weight-adjusted basis

Geriatric

Declining Systems

  • Glomerular filtration rate falls ~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 central nervous system sensitivity to sedatives and opioids
  • Polypharmacy compounds all pharmacokinetic risks
  • Beers criteria identify drugs potentially inappropriate in older adults

Sections 3 & 4

Disease-Induced Variability and Individualized Dosing

Organ Pharmacokinetic Effect Clinical Consequence High-Risk Drugs
Kidney Reduced glomerular filtration rate → slower elimination of renally cleared drugs Drug accumulation → toxicity at standard doses. Half-life prolonged. 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 Most hepatically metabolized drugs; warfarin, benzodiazepines, opioids, statins

The pre-prescribing checklist: Identify the primary elimination pathway. Check renal function (estimated glomerular filtration rate). Assess liver function (Child-Pugh score if indicated). Review age-related adjustments. Check for pharmacogenomic tests available for this drug. Review concurrent medications for interactions. Narrow therapeutic index drugs demand explicit evaluation of all factors.