Pharmacogenetics & Pharmacogenomics Quiz

Adverse Drug Reactions (ADRs)

• ADRs account for 6.5% of UK hospital admissions and 15% of hospital inpatients, resulting in around 8,000 overnight stays in hospital beds per year, costing the taxpayer £1 billion.
• Up to 70% of ADRs are avoidable, making improvement a significant interest to medics and scientists.

Pharmacogenetics and Pharmacogenomics

• Pharmacogenetics and pharmacogenomics are crucial in understanding the variation in response to medication, leading to poorer individual and societal outcomes.
• The field focuses on the influence of genetic variations on drug response, metabolism, and efficacy.

Pharmacokinetics (ADME)

• Absorption: the process of how a drug enters the body.
• Distribution: describes where the drug travels after absorption and how much of the drug reaches the target site.
• Metabolism: how the drug gets broken down in the body, which can happen immediately by enzyme action in the stomach.
• Excretion: describes how drugs leave the body, whether by urine, bile, or, in some cases, exhalation.

Pharmacodynamics

• Describes the effect (molecular action) of a drug on its target in the body, such as heart tissue or neurons.
• Encompasses "off-target" effects of drugs, which are a major factor in side effects.
• The body's ability to break down a particular drug or efficacy in drug response is markedly influenced by DNA variation.

Cytochrome P450 Enzymes (CYPs)

• CYPs commonly impact drug metabolism and are coded by genes that vary in the population.
• Differential metabolism by such enzymes can lead to diverse metabolizer phenotypes, ranging from ultrarapid to poor metabolizers.
• Proportion of drugs metabolized by CYP450 isoenzymes.

Genotype-Phenotype Relationships

• Genotype-phenotype relationships between variants and drug metabolism, such as alleles with gene deletions or duplications, can lead to increased enzyme activity.
• Extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultrarapid metabolizers (UMs) are classified based on genotype and phenotype.

CYP2D6

• CYP2D6 is a drug-metabolizing enzyme in the liver that breaks down and terminates the action of certain antidepressant, antiarrhythmic, and antipsychotic drugs.
• 70 variant alleles have been described by molecular cloning studies.
• Alleles with gene deletions or duplications can lead to increased enzyme activity.
• CYP2D6 overlaps with four distinct therapeutic areas.

Warfarin Metabolism

• Warfarin is a common anticoagulant that prevents blood clots from forming.
• The correct dosage of warfarin is crucial, as incorrect dosage can lead to life-threatening side effects.
• Two types of genetic changes are involved in warfarin metabolism: those affecting the breakdown of warfarin by CYPs in the liver and those involved in how the drug slows down blood clotting.

Immune-Mediated Adverse Drug Reactions (ADRs)

• Severe drug-induced hypersensitivity and drug-induced liver injury are a heterogeneous group of type B or off-target adverse reactions.

• These reactions are rare, but can be potentially lethal and have considerable economic implications.

• The genetic association with immune ADRs can be drug-specific, phenotype-specific, or ethnicity-specific.

• HLA alleles are strongly associated with immune ADRs.### Pharmacogenomics and Personalized Medicine

• Pharmacogenomics is the study of how a person's genome affects their response to particular drugs.

• It can help identify the right medication and dosage for an individual, reducing the risk of adverse drug reactions (ADRs).

Adverse Drug Reactions (ADRs)

• ADRs account for 6.5% of UK hospital admissions and 15% of hospital inpatients.
• Up to 70% of ADRs are avoidable, resulting in around 8,000 overnight stays in hospital beds per year, costing the taxpayer £1 billion.
• The goal of integrating pharmacogenomics into routine NHS practice is to provide patients with safer and more appropriate therapies, avoiding ineffective or harmful treatments.

Pharmacogenomic Testing

• At least 18 pharmacogenomic tests are available for variants in the ABCB1 gene, which affects the response to certain medications.
• Pharmacogenomic testing can help reduce treatment costs in patients with mental health illness by identifying the right medication and dosage.

Pharmacokinetics and Pharmacodynamics

• Pharmacokinetics describes how a drug is absorbed, distributed, metabolized, and eliminated by the body.
• Pharmacodynamics studies the effects of drugs on the body, including the intended therapeutic effects and potential ADRs.

Genomic Variants and Drug Response

• Genetic variants can affect drug response, leading to ADRs or reduced efficacy.
• Different ancestries are associated with different genomic variants, requiring different approaches to monitor which medications are most likely to be linked to ADRs.

HLA Genes and Immune-Mediated ADRs

• HLA genes are associated with immune-mediated ADRs, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Genetic testing for HLA alleles can help identify individuals at risk of ADRs and inform treatment decisions.

Specific Medications and Genomic Variants

• Abacavir, an antiviral medication, is associated with hypersensitivity reactions in individuals with the HLA-B*5701 variant.
• Carbamazepine, an anticonvulsant medication, is associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in individuals with the HLA-B*1502 variant.
• Gentamycin, an antibiotic, can cause hearing loss in individuals with the MT-RNR1 genetic variant.
• Thiopurines, such as azathioprine, are associated with toxicity in individuals with TPMT genetic variants.

Point-of-Care Testing and Pharmacogenomics

• The NHS is establishing point-of-care testing (POCT) in community pharmacies, including equipment and devices for diagnosis, monitoring, and screening.
• POCT can help facilitate the integration of pharmacogenomics into routine NHS practice, providing patients with safer and more appropriate therapies.

Future of Pharmacogenomics

• The goal of pharmacogenomics is to move from a reactive approach, where patients are screened when they become ill, to a pre-emptive approach, where genomic data is increasingly integrated into healthcare.
• Pharmacogenomics has enormous potential to enable more accurate prescribing, reduce waste, and improve patient outcomes.