BS3054 - Pharmacogenomics 2024

Introduction to Pharmacogenomics

  • Focuses on how genes affect a person's response to drugs.

  • Encompasses both pharmacogenetics (single gene mutations) and pharmacogenomics (multiple gene variants).

  • Aims for personalized medicine strategies.

Learning Objectives

  • Provide an overview of pharmacogenomics and its significance in healthcare.

  • Define key terms: SNP, ADR, polymorphism, mutation, pharmacogenetics, pharmacogenomics, pharmacokinetics, pharmacodynamics.

  • Discuss genetic variation impacts on drug responses and specific medication examples for pretreatment genotyping.

Current Medical Treatment Strategies

  • Reliance on trial and error in treatment selection.

  • Issues arise from incorrect treatments leading to adverse drug reactions (ADRs).

  • The volume and consequences of ADRs can be considerable for patients.

Categories of Drug Responses

  • Diverse responses to the same drug across patients:

    • Drug beneficial but harmful.

    • Drug not beneficial and harmful.

  • Same disease can result in different treatment responses.

Adverse Drug Reactions (ADRs)

  • Definition: A response to medicinal products that is noxious and unintended.

  • Common major ADRs: heart issues, liver failure, skin conditions, kidney failures, and bleeding.

  • Linked to certain drug classes: NSAIDs, antibiotics, and others.

  • Demographics like age, sex, and polytherapy increase ADR risk.

Consequences of ADRs

  • Significant healthcare costs due to prolonged hospital stays and additional treatments.

  • Estimations show substantial bed-days and fatalities due to ADRs annually.

  • Erosion of patient trust in the healthcare system.

Towards Precision Medicine

  • Personalized medicine's ideal scenario:

    • Optimization of drug dosages based on individual needs to maximize efficacy and minimize toxicity.

Factors Affecting Drug Response

  • Key influencers include:

    • Age, gender, body mass, co-medications, lifestyle factors, health conditions, and genetic factors.

  • FDA recognizes over 500 gene-drug associations to understand individual drug responses better.

Genetic Variations in Drug Response

  • Human genome has approximately 3 billion DNA bases, with minor variances having considerable effects.

  • Polymorphism: Variations in DNA present in more than 1% of the population.

  • Mutation: Variations in DNA present in less than 1% of the population.

  • Major contributor to variations: Single Nucleotide Polymorphisms (SNPs) that change amino acids.

  • Human Genome Project has largely completed sequencing relevant genomic regions.

Haplotype and Genetic Diversity

  • Haplotype: sets of linked SNP alleles inherited together, with genetic diversity impacting health and drug response.

  • The International HapMap Project facilitated insights into genetic associations impacting medication responses.

Pharmacogenomics Definitions

  • Pharmacogenetics: Individual gene variants and drug effects.

  • Pharmacogenomics: Multifactorial relationship between gene variants and drug effects across many genes.

Pharmacokinetics vs Pharmacodynamics

  • Pharmacokinetics: Examines how the body interacts with substances (absorption, distribution, metabolism, elimination).

  • Pharmacodynamics: Assesses biochemical and physiological effects of drugs on the body.

Drug Absorption and Genetic Influence

  • Variations can affect how drugs enter cells (e.g., via diffusion mechanisms).

  • OATP1B: Example of an organic anion transporting polypeptide influencing drug uptake and metabolism.

Drug Metabolism and Excretion

  • Metabolism alters drug solubility for excretion.

  • Genomic variations can affect enzyme functions leading to altered drug metabolism and effects.

Alcohol Metabolism and Genetic Variants

  • ALDH2 Gene Variants: Significant in East Asians, impacting alcohol metabolism and associated health risks.

  • Variations contribute to conditions like esophageal cancer based on alcohol consumption responses.

Cytochrome P450 Family in Pharmacogenomics

  • Cytochrome P450 enzymes crucial for drug metabolism; variations can affect efficacy and toxicity.

  • Variants in specific P450 genes impact the metabolism of common drugs.

Examples of Drug Variations Due to Genetics

  • Clopidogrel and Codeine: Genetic factors affecting metabolism leading to differing therapeutic responses.

  • Genetic polymorphisms can result in either inadequate treatment or severe drug reactions.

Polygenic Drug Responses

  • Drug effects influenced by multiple genes affecting pharmacodynamics and pharmacokinetics.

  • Changes in genotype can lead to diverse medication responses among patients.

Pharmacogenomics in Clinical Practice

  • Potential benefits include:

    • Efficient personalized medicine.

    • Reduced adverse drug reactions.

    • Modification of therapeutic interventions based on genetic profiling.

  • Challenges such as costs and ethical considerations remain prominent.

Conclusion

  • There is a growing awareness and potential in utilizing pharmacogenomics to enhance patient care and treatment efficacy.

  • Education and further integration of genomic data into healthcare practice are essential.