• The study of how an individuals genetic inheritance affects the body's response to drugs
• inter-individual differences seen in genes that encode drug targets, drug transporters, or enzymes that catalyze drug metabolism
• Genetic make-up cold be used to enhance pharmacotherapy, maximize drug efficacy , and/or reduce incidence of side effects

• Age
• Gender
• Body size
• Disease state/ body system function
• drug or dietary interactions
• hypoalbuminemia
• fever, stress, exercise
• pregnancy
• Genetic Factors

1. variations in enzymes of drug metabolism (affect pharmacokinetics) e.g. CYP450
2. Variations in drug targets (affect pharmacodynamics) e.g. receptors
3. Idiosyncratic drug reactions (everything else)

• CYP3A4 involved in 40-45% of drug metabolism, but polymorphisms are rare
• CYP2D6 gene is extremely polymorphic with > 70 allelic variants described. CYP2D6 is involved in 20-30% of drug metabolism
• CYP2C19, and CYP2C9 are also know to have polymorphisms 

• Ultra-rapid metabolizer: no drug response at ordinary dosage (non-responders)
• Extensive metabolizer: Expected response to standard dose
• Intermediate metabolizer: may experience a lesser degree of consequences of poor metabolizers
• Poor metabolizer: Too slow or no drug metabolism
  • too high drug levels at usual doses
  • high risk for adverse drug rxns (toxicity)

the opposite phenomenon as that with active drug occurs.

Ultra-rapid metabolizers may suffer adverse events and poor metabolizers may not respond

Clopidogrel (CYP3A)

Warfarin (CYP2C9)

many others such as NSAIDS, some beta blockers, codeine, ethanol, some PPIs, some antidepressants...

• Drugs exert their effects by interacting with specific target proteins
• Genetic variations in target proteins can influence the outcome of pharmacotherapy
• examples:
  • ACEI (e.g lisinopril)
  • Epidermal growth factor receptors (e.g. gefitinib)
  • Vitamin K epoxide reductase complex 1 (e.g. warfarin)
  • Apolipoprotein E (e.g. pravastatin)

• ACEI (e.g lisinopril)
• Epidermal growth factor receptors (e.g. gefitinib)
• Vitamin K epoxide reductase complex 1 (e.g. warfarin)
• Apolipoprotein E (e.g. pravastatin)
  
  

• affects response to lisinopril
• enhanced renoprotective effects

• affects response to Albuterol
• increased forced expiratory volume in one second (FEV₁)

• affects response to Gefitinib
• more favorable response
• majority of human epithelial cancers are marked by functional activation of growth factors and receptors of the epidermal growth factor receptor (EGFR) family
• EGFR was the first growth factor receptor to be proposed as a target for cancer therapy
• in pts with non-small cell lung cancer (NSCLC) response to EGFR inhibitor gefitinib was strongly influenced by somatic mutations that affect receptor binding

• Difficult or impossible to predict. Pharmacogenetics may help screen for unanticipated drug reactions
• least predictable effect of inter-individual genetic variation
• e.g. G6PD deficiency
• result from interaction between medication and pts unique physiology

• maximize drug efficacy
• minimize toxicity by refining drug dosing
• reduce time to efficacious dose
• development of drugs that maximize therapeutic effects but decrease damage to nearby healthy cells
• manufacture more powerful medications
• predicts most suitable drug