Pharmacogenetics is the study of how genetic variations influence an individual’s response to drugs. These genetic differences affect pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics (drug–receptor interactions). Understanding pharmacogenetics helps clinicians optimize therapy, minimize adverse effects, and tailor treatment to individual patient needs.
With advances in genomic testing, pharmacogenetics has become a key component of personalized medicine and precision pharmacotherapy.
Definition of Pharmacogenetics
Pharmacogenetics is defined as the study of inherited genetic differences that lead to variable drug responses among individuals. These variations often occur in genes responsible for:
- Drug-metabolizing enzymes
- Drug transporters
- Drug receptors
- Immune system components
As a result, two patients receiving the same drug and dose may exhibit different therapeutic effects or toxicity profiles.
Importance of Pharmacogenetics
Pharmacogenetic differences can lead to:
- Adverse drug reactions
- Therapeutic failure
- Need for dose adjustment
- Drug interactions due to metabolic pathway variations
Identifying these genetic variations allows clinicians to predict response and select the safest and most effective dose for each patient.
Genetic Variability in Drug Metabolism
Most pharmacogenetic variations occur in the cytochrome P450 (CYP450) family of enzymes, which are responsible for the metabolism of majority of drugs.
1. CYP2D6 Polymorphism
This enzyme metabolizes antidepressants, antipsychotics, beta-blockers, opioids, and tamoxifen.
Individuals may be:
- Poor metabolizers (PM) – risk of toxicity
- Intermediate metabolizers (IM)
- Extensive metabolizers (EM) – normal
- Ultrarapid metabolizers (UM) – therapeutic failure at standard doses
2. CYP2C9 Polymorphism
Important for drugs such as warfarin and phenytoin.
Variants (*2, *3) reduce enzyme activity, causing increased drug exposure and bleeding risk.
3. CYP2C19 Polymorphism
Involved in metabolism of clopidogrel, proton pump inhibitors, and antidepressants.
Poor metabolizers have reduced activation of clopidogrel, increasing cardiovascular risk.
4. CYP3A4 and CYP3A5 Variants
Impact tacrolimus, midazolam, and many anticancer drugs.
CYP3A5 expressers (common in some ethnic groups) require higher tacrolimus doses to maintain therapeutic levels.
Genetic Variability in Drug Transport
Drug transporters influence absorption, tissue distribution, and elimination.
1. P-glycoprotein (ABCB1)
Affects drugs such as digoxin, cyclosporine, and many antineoplastic drugs.
Genetic variants change drug absorption and efflux at the intestine, liver, kidney, and blood-brain barrier.
Genetic Variability in Drug Targets (Receptors)
Mutations in receptors or signaling proteins can alter drug response.
- β-adrenergic receptor polymorphisms affect response to beta-blockers and bronchodilators.
- VKORC1 gene influences warfarin dose by modifying target enzyme sensitivity.
Immunogenetics and Adverse Drug Reactions
Genetic variations in immune-related genes can predispose individuals to severe drug reactions.
HLA-B*1502
Associated with Stevens–Johnson syndrome and toxic epidermal necrolysis from carbamazepine in Asian populations.
HLA-B*5701
Linked with hypersensitivity reactions to abacavir.
Pharmacokinetics vs. Pharmacodynamics in Pharmacogenetics
Pharmacokinetic Effects
- Altered absorption
- Changes in drug distribution
- Reduced or increased metabolism
- Impaired drug elimination
Pharmacodynamic Effects
- Changes in receptor structure
- Altered drug sensitivity
- Modified signal transduction
Both mechanisms contribute to variability in drug response.
Applications of Pharmacogenetics in Clinical Practice
1. Personalizing Drug Therapy
Drug doses can be tailored based on genetic profile, improving safety and efficacy.
2. Reducing Adverse Drug Reactions
Screening for HLA variants prevents life-threatening hypersensitivity reactions.
3. Optimizing Drugs with Narrow Therapeutic Index
- Warfarin
- Phenytoin
- Tacrolimus
- Theophylline
4. Improving Outcomes in Oncology
Pharmacogenetic testing is widely used for drugs like 6-mercaptopurine (TPMT deficiency) and irinotecan (UGT1A1*28 variant).
5. Guiding Therapeutic Drug Monitoring (TDM)
Genetic data helps interpret TDM results and adjust doses more precisely.
Pharmacogenetic Testing
Pharmacogenetic tests detect variations in genes affecting drug response. These tests may be:
- Pre-emptive (before prescribing)
- Reactive (after ADR or therapeutic failure)
Examples of commonly tested genes include:
- CYP2D6 – antidepressants, opioids
- CYP2C9 & VKORC1 – warfarin
- TPMT – thiopurines
- UGT1A1 – irinotecan
- CYP3A5 – tacrolimus
Limitations of Pharmacogenetics
- Genetic tests may not cover all variants
- Environmental and lifestyle factors also influence drug response
- Cost and availability of testing
- Incomplete understanding of all gene–drug relationships
Detailed Notes:
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