Lecture 1

Question 1

What is pharmacogenetics?

Answer 1

The study of inherited differences in drug metabolism and response

Pharmacogenetics focuses on how genetic variations affect individual responses to drugs.

Question 2

What are the four main processes involved in drug disposition?

Answer 2

• Absorption
• Distribution
• Metabolism
• Excretion

These processes are collectively referred to as ADME.

Question 3

Define genetic polymorphism.

Answer 3

The presence of two or more clearly different traits in the same population

Genetic polymorphisms can include nucleobase variants (SNPs), indels, and gene deletions.

Question 4

What is the effect of inherited variation in cytochrome P450 (CYP) enzymes?

Answer 4

It can lead to differences in drug metabolism and response

CYP enzymes are crucial for the metabolism of many drugs.

Question 5

What does the term ‘poor metaboliser’ refer to?

Answer 5

An inherited loss of function in a drug metabolising enzyme leading to null enzyme activity

Poor metabolizers may experience elevated drug levels and increased risk of adverse effects.

Question 6

What is the prevalence of the poor metaboliser phenotype in European populations?

Answer 6

~3%

This low prevalence is important for understanding the risk of adverse drug reactions in these populations.

Question 7

Fill in the blank: The major drug metabolising CYP families are CYP1, CYP2, and _______.

Answer 7

CYP3

Each family contains multiple subfamilies and individual isoforms.

Question 8

What is the significance of the CYP gene name format?

Answer 8

The gene name is italicized while the protein name is in normal case

This distinction helps in identifying genetic variants and their functions.

Question 9

True or False: A variant allele may result from a single nucleotide change (SNP).

Answer 9

True

Variants can also arise from combinations of SNPs, gene duplications, or deletions.

Question 10

What are the possible outcomes of inherited variation in drug metabolism?

Answer 10

• Increased drug efficacy
• Increased risk of toxicity
• Altered therapeutic response

These outcomes can significantly affect patient treatment plans.

Question 11

What is the effect of being a poor metaboliser of omeprazole?

Answer 11

Elevated plasma concentrations due to decreased hepatic clearance

Poor metabolizers may require careful monitoring to avoid toxicity.

Question 12

Define the term ‘extensive metaboliser’.

Answer 12

An individual homozygous for the wild type allele with normal enzyme function

Extensive metabolizers typically have drug levels within the expected therapeutic range.

Question 13

What does the abbreviation AUC stand for in pharmacokinetics?

Answer 13

Area Under the Curve

AUC measures drug exposure over time and is critical for understanding drug clearance.

Question 14

Which CYP enzyme is primarily responsible for the metabolism of omeprazole?

Answer 14

CYP2C19

Variants in CYP2C19 can significantly affect omeprazole plasma concentrations.

Question 15

Fill in the blank: The phenotype of an individual with two null function alleles for CYP2C19 is _______.

Answer 15

Poor metaboliser (PM)

PM individuals may have significantly higher drug levels due to inefficient metabolism.

Question 16

What is the inheritance pattern of the poor metaboliser phenotype?

Answer 16

Autosomal co-dominant Mendelian manner

This means both alleles contribute to the phenotype.

Question 17

What is the role of ABCC11 in ear wax production?

Answer 17

It is a transporter (efflux pump) responsible for cerumen secretion

Variants in this gene can lead to different ear wax types (wet or dry).

Question 18

What is the clinical importance of genetic polymorphisms in CYP enzymes?

Answer 18

They can influence drug metabolism and risk of adverse drug reactions

Understanding these polymorphisms is essential for personalized medicine.

Question 19

What are the potential consequences of inherited variation on drug safety?

Answer 19

• Increased risk of adverse drug reactions
• Variability in therapeutic efficacy
• Need for dose adjustments

These factors highlight the importance of pharmacogenetic testing.

Question 20

What is the definition of a Poor Metaboliser (PM) in pharmacogenomics?

Answer 20

A Poor Metaboliser (PM) has a significantly reduced ability to metabolize certain drugs due to genetic variations.

Question 21

What does CYP2C19 genotype correlate with in relation to omeprazole?

Answer 21

CYP2C19 genotype correlates with omeprazole plasma concentrations.

Question 22

What is the significance of the *17 allele in CYP2C19?

Answer 22

CYP2C19 *17 carriers have higher clearance rates, which may lead to sub-therapeutic plasma concentrations.

Question 23

What is a prodrug?

Answer 23

A prodrug is an inactive medication that requires metabolic conversion to become an active drug.

Question 24

What can result from an inherited lack of enzyme activation for a prodrug?

Answer 24

Absent or very low plasma concentrations of the active drug, leading to ineffective therapy.

Question 25

What is the primary use of clopidogrel?

Answer 25

Clopidogrel is used as antiplatelet therapy after percutaneous coronary intervention to minimize the risk of ischemia.

Question 26

How is clopidogrel activated?

Answer 26

Clopidogrel is bioactivated by the CYP2C19 enzyme.

Question 27

What is the relationship between CYP2C19 *2 carriers and clopidogrel activation?

Answer 27

CYP2C19 *2 carriers experience poor activation of clopidogrel.

Question 28

What are some examples of drugs metabolized by CYP2C19?

Answer 28

* Anti-infectives: proguanil, nelfinavir, voriconazole * Chemotherapy: cyclophosphamide, bortezomib, teniposide, thalidomide * Proton pump inhibitors: omeprazole, lansoprazole, pantoprazole, rabeprazole * Other: clopidogrel, progesterone

Question 29

What does the nomenclature * in CYP gene variants indicate?

Answer 29

The * indicates polymorphic forms of each CYP gene, with the wild-type form typically denoted as *1.

Question 30

What is the frequency of the CYP2D6 *1 allele in European populations?

Answer 30

CYP2D6 *1 allele frequency is approximately 54%.

Question 31

What are the phenotypes associated with CYP2D6?

Answer 31

* Ultra-rapid Metabolisers (UM) * Extensive Metabolisers (EM) * Intermediate Metabolisers (IM) * Poor Metabolisers (PM)

Question 32

What is the expected outcome for a CYP2D6 poor metaboliser given a standard dose of metoprolol?

Answer 32

Elevated plasma concentrations of metoprolol, increasing the risk of bradycardia.

Question 33

What is the risk associated with CYP2D6 ultra-rapid metabolizers taking codeine?

Answer 33

Increased formation of morphine, leading to a higher risk for opioid intoxication or dependence.

Question 34

Fill in the blank: Codeine requires conversion to _______ for its analgesic properties.

Answer 34

morphine

Question 35

What are the two main factors affecting CYP2D6 activity?

Answer 35

* Genetic polymorphisms * Copy number variations (CNV)

Question 36

True or False: Most drugs can only be metabolized by one CYP enzyme.

Answer 36

False

Question 37

What is the role of CYP2D6 in the metabolism of metoprolol?

Answer 37

CYP2D6 is responsible for metabolizing over 70% of the metoprolol dose.

Question 38

What is the consequence of having a gene duplication in CYP2D6?

Answer 38

It may lead to ultra-rapid metabolism of drugs.

Question 39

Identify the main substrates of CYP2D6.

Answer 39

* Antidepressants * Neuroleptics * Beta blockers * Anti-arrhythmics

Question 40

What does the term 'null metaboliser' refer to in the context of CYP2D6?

Answer 40

A person with genetic variants that result in complete lack of CYP2D6 enzyme activity.

Question 41

What ethnic group shows the highest prevalence of ultra-rapid metabolizers?

Answer 41

Maori & Pacific peoples.

Question 42

What is the concern regarding individuals who rapidly bioactivate codeine to morphine?

Answer 42

Higher risk for opioid intoxication or developing codeine dependence ## Footnote Individuals with CYP2D6 duplication may metabolize codeine to morphine more efficiently, increasing these risks.

Question 43

What are the effects of 'poor metabolism' of drugs?

Answer 43

Increased drug levels, risk of toxicity, particularly if the drug has a narrow therapeutic index (TI) ## Footnote A narrow TI indicates a small margin between effective and toxic doses.

Question 44

What are the effects of 'ultra-rapid metabolism' of drugs?

Answer 44

Decreased drug levels, risk of treatment failure, may have no substantial therapeutic consequence ## Footnote Treatment failure occurs when the drug does not achieve its intended effect.

Question 45

What does a narrow therapeutic index (TI) imply?

Answer 45

A small margin between effective and toxic doses of a drug ## Footnote Drugs with a narrow TI require careful monitoring to avoid toxicity.

Question 46

What are two bad therapeutic outcomes for patients?

Answer 46

Lack of effect and lack of safety ## Footnote Both outcomes indicate that the treatment is either ineffective or harmful.

Question 47

Name three pharmacogenes mentioned in the text.

Answer 47

* TMPT * DPYD * UGT1A1 ## Footnote These genes are involved in drug metabolism and response.

Question 48

What is pharmacogenomics?

Answer 48

Study of complex interactions of genes which determine drug behavior ## Footnote This field aims to personalize medicine based on genetic profiles.

Question 49

What can predictive genetic markers indicate in pharmacogenomics?

Answer 49

A patient's ability to metabolize drugs, identifying them as Poor Metabolizers or Ultra-rapid Metabolizers ## Footnote This information can guide drug dosing and therapy choices.

Question 50

Fill in the blank: Pharmacogenetics is the study of _______.

Answer 50

[single genes that determine drug behavior]

Question 51

What factors can influence drug disposition besides genetics?

Answer 51

* Age * Co-morbidities * Polypharmacy * Drug interactions ## Footnote These factors can significantly affect how a drug is metabolized and its overall effectiveness.

Question 52

What was accelerated by the publication of the human genome project?

Answer 52

Interest in pharmacogenomics and its potential to personalize medicine ## Footnote This project provided insights into genetic variations that affect drug response.

Question 53

What does the phrase 'the right drug for the right patient at the right dose' refer to?

Answer 53

The goal of pharmacogenetics in tailoring medication based on individual genetic profiles ## Footnote This approach aims to optimize therapeutic outcomes and minimize adverse effects.

Question 54

What is the role of environmental factors in drug metabolism phenotype?

Answer 54

They influence the expression of genes and thus affect drug metabolism ## Footnote Environmental factors can include diet, lifestyle, and exposure to other substances.

Question 55

Is the statement true or false? 'Both lack of effect and lack of safety are bad therapeutic outcomes for the patient.'

Answer 55

True ## Footnote Both scenarios indicate that treatment is failing to provide benefits or is causing harm.