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Medsci 338 > Lecture 1 > Flashcards

Lecture 1 Flashcards

1
Q

What is pharmacogenetics?

A

The study of inherited differences in drug metabolism and response

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

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2
Q

What are the four main processes involved in drug disposition?

A
  • Absorption
  • Distribution
  • Metabolism
  • Excretion

These processes are collectively referred to as ADME.

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3
Q

Define genetic polymorphism.

A

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

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

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4
Q

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

A

It can lead to differences in drug metabolism and response

CYP enzymes are crucial for the metabolism of many drugs.

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5
Q

What does the term ‘poor metaboliser’ refer to?

A

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.

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6
Q

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

A

~3%

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

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7
Q

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

A

CYP3

Each family contains multiple subfamilies and individual isoforms.

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8
Q

What is the significance of the CYP gene name format?

A

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

This distinction helps in identifying genetic variants and their functions.

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9
Q

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

A

True

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

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10
Q

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

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

These outcomes can significantly affect patient treatment plans.

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11
Q

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

A

Elevated plasma concentrations due to decreased hepatic clearance

Poor metabolizers may require careful monitoring to avoid toxicity.

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12
Q

Define the term ‘extensive metaboliser’.

A

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

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

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13
Q

What does the abbreviation AUC stand for in pharmacokinetics?

A

Area Under the Curve

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

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14
Q

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

A

CYP2C19

Variants in CYP2C19 can significantly affect omeprazole plasma concentrations.

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15
Q

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

A

Poor metaboliser (PM)

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

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16
Q

What is the inheritance pattern of the poor metaboliser phenotype?

A

Autosomal co-dominant Mendelian manner

This means both alleles contribute to the phenotype.

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17
Q

What is the role of ABCC11 in ear wax production?

A

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

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

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18
Q

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

A

They can influence drug metabolism and risk of adverse drug reactions

Understanding these polymorphisms is essential for personalized medicine.

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19
Q

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

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

These factors highlight the importance of pharmacogenetic testing.

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20
Q

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

A

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

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21
Q

What does CYP2C19 genotype correlate with in relation to omeprazole?

A

CYP2C19 genotype correlates with omeprazole plasma concentrations.

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22
Q

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

A

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

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23
Q

What is a prodrug?

A

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

24
Q

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

A

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

25
Q

What is the primary use of clopidogrel?

A

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

26
Q

How is clopidogrel activated?

A

Clopidogrel is bioactivated by the CYP2C19 enzyme.

27
Q

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

A

CYP2C19 *2 carriers experience poor activation of clopidogrel.

28
Q

What are some examples of drugs metabolized by CYP2C19?

A
  • Anti-infectives: proguanil, nelfinavir, voriconazole
  • Chemotherapy: cyclophosphamide, bortezomib, teniposide, thalidomide
  • Proton pump inhibitors: omeprazole, lansoprazole, pantoprazole, rabeprazole
  • Other: clopidogrel, progesterone
29
Q

What does the nomenclature * in CYP gene variants indicate?

A

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

30
Q

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

A

CYP2D6 *1 allele frequency is approximately 54%.

31
Q

What are the phenotypes associated with CYP2D6?

A
  • Ultra-rapid Metabolisers (UM)
  • Extensive Metabolisers (EM)
  • Intermediate Metabolisers (IM)
  • Poor Metabolisers (PM)
32
Q

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

A

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

33
Q

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

A

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

34
Q

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

A

morphine

35
Q

What are the two main factors affecting CYP2D6 activity?

A
  • Genetic polymorphisms
  • Copy number variations (CNV)
36
Q

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

A

False

37
Q

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

A

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

38
Q

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

A

It may lead to ultra-rapid metabolism of drugs.

39
Q

Identify the main substrates of CYP2D6.

A
  • Antidepressants
  • Neuroleptics
  • Beta blockers
  • Anti-arrhythmics
40
Q

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

A

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

41
Q

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

A

Maori & Pacific peoples.

42
Q

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

A

Higher risk for opioid intoxication or developing codeine dependence

Individuals with CYP2D6 duplication may metabolize codeine to morphine more efficiently, increasing these risks.

43
Q

What are the effects of ‘poor metabolism’ of drugs?

A

Increased drug levels, risk of toxicity, particularly if the drug has a narrow therapeutic index (TI)

A narrow TI indicates a small margin between effective and toxic doses.

44
Q

What are the effects of ‘ultra-rapid metabolism’ of drugs?

A

Decreased drug levels, risk of treatment failure, may have no substantial therapeutic consequence

Treatment failure occurs when the drug does not achieve its intended effect.

45
Q

What does a narrow therapeutic index (TI) imply?

A

A small margin between effective and toxic doses of a drug

Drugs with a narrow TI require careful monitoring to avoid toxicity.

46
Q

What are two bad therapeutic outcomes for patients?

A

Lack of effect and lack of safety

Both outcomes indicate that the treatment is either ineffective or harmful.

47
Q

Name three pharmacogenes mentioned in the text.

A
  • TMPT
  • DPYD
  • UGT1A1

These genes are involved in drug metabolism and response.

48
Q

What is pharmacogenomics?

A

Study of complex interactions of genes which determine drug behavior

This field aims to personalize medicine based on genetic profiles.

49
Q

What can predictive genetic markers indicate in pharmacogenomics?

A

A patient’s ability to metabolize drugs, identifying them as Poor Metabolizers or Ultra-rapid Metabolizers

This information can guide drug dosing and therapy choices.

50
Q

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

A

[single genes that determine drug behavior]

51
Q

What factors can influence drug disposition besides genetics?

A
  • Age
  • Co-morbidities
  • Polypharmacy
  • Drug interactions

These factors can significantly affect how a drug is metabolized and its overall effectiveness.

52
Q

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

A

Interest in pharmacogenomics and its potential to personalize medicine

This project provided insights into genetic variations that affect drug response.

53
Q

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

A

The goal of pharmacogenetics in tailoring medication based on individual genetic profiles

This approach aims to optimize therapeutic outcomes and minimize adverse effects.

54
Q

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

A

They influence the expression of genes and thus affect drug metabolism

Environmental factors can include diet, lifestyle, and exposure to other substances.

55
Q

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

A

True

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

Medsci 338 (1 decks)

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