Pharmacogenomics and Drug Response

Vocabulary-style flashcards covering the definitions and key concepts of Pharmacogenomics, enzyme phenotypes, and specific drug interactions like Warfarin and Carbamazepine.

Pharmacogenetics

The study of the relationship between individual gene variants and drug effects.

Pharmacogenomics

The study of the relationship between variants in a large collection of genes (up to the whole genome) and drug effects.

PGX

The molecular study of genetic factors that determine efficacy and toxicity.

Physiological Factors

Factors including age, sex, weight, disease status, and ethnicity that influence an individual's response to a drug.

Environmental Factors

Factors including polypharmacy, diet, smoking, alcohol, and substance use that influence an individual's response to a drug.

Genetic Factors

Variations in PK (pharmacokinetics) and PD (pharmacodynamics) pharmacogenes that influence drug response.

Adverse Drug Reactions (ADR)

A consequence of gene variations associated with pharmacokinetics, ranging from major issues like liver failure to minor problems like GI discomfort.

Cytochrome P450S

A group of 57 genes in the human genome, with less than 12 responsible for the phase 1 oxidative metabolism of most xenobiotics.

Metaboliser Phenotypes

The four common classifications of enzyme activity: poor, intermediate, extensive/normal, and ultra.

CYP2C9

An enzyme subtype where alleles are associated with the altered response of the drug warfarin.

CYP2C19

An enzyme subtype where alleles are associated with altered responses to PPI (Proton Pump Inhibitors) and Clopidogrel.

CYP2D6

An enzyme responsible for metabolising $25\%$ of drugs, including codeine, tamoxifen, antipsychotics, and antidepressants.

Poor Metaboliser (PM) status

A phenotype that may suffer ADRs from narrow therapeutic range drugs (e.g., Risperidone, Metoprolol) and does not respond to prodrugs like codeine.

Phenocopy

A PM phenotype resulting from drug interactions, such as SSRI inhibitors inhibiting the activity of CYP2D6.

Ultra Metaboliser (UM) status

A phenotype that may suffer toxicity from prodrugs requiring activation or fail to reach therapeutic doses for other drugs.

Codeine and UM CYP2D6 Status

Contraindicated in breastfeeding women as UM status may result in higher levels of active metabolites in breast milk, causing potentially fatal opioid toxicity in infants.

Warfarin

A coumarin anticoagulant used for thromboprophylaxis that has a narrow therapeutic index.

INR (International Normalized Ratio)

A measurement of clotting rate; normal range is $0.8-1.2$, while the target for patients on warfarin is $2-3$.

INR >5

A state of too little coagulation that puts a patient at risk of haemorrhage.

INR <2

A state of too much coagulation that increases the risk of thrombosis.

S-Warfarin

An isomer that is $3-5 \times$ more potent than R-Warfarin and is metabolised principally by the polymorphic CYP2C9 isoform.

VKORCI

Vitamin K epoxide reductase, the enzyme inhibited by warfarin to achieve its anticoagulant effect.

VKORCI*2 'A' allele

A SNP (Single Nucleotide Polymorphism) in the promoter region associated with reduced expression of the enzyme and a reduced dose phenotype.

Steven-Johnson Syndrome (SJS)

A drug-induced hypersensitivity causing skin blistering that affects $10\%$ of the skin.

Overlap Syndrome

A drug-induced hypersensitivity causing skin blistering that affects $10-30\%$ of the skin.

Toxic Epidermal Necrolysis (TEN)

A drug-induced hypersensitivity causing skin blistering that affects $>30\%$ of the skin and 2 mucous membranes.

Carbamazepine

An anticonvulsant used for epilepsy and bipolar disorder that can cause rashes or lead to SJS/TEN in certain patients.

HLA-B*1502

An allele associated with Carbamazepine-induced SJS, with high incidence in Chinese ($10-15\%$) and Thai ($2-4\%$) populations.