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DEN 7203 Pharmacological Concepts > Pharmacogenetics > Flashcards

Pharmacogenetics Flashcards

Lecture 5

1
Q

Every year, more than 100,000 people in die in the US because they carry ____ genes that make medications either ineffective or deadly

A

Misspelled

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2
Q

In addition to drug-drug interactions, there are also ____ interactions

A

gene-drug

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3
Q

Genetic differences in plasma proteins results in:

A

Differences in affinity and extent of drug binding

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4
Q

Genetic differences in metabolic enzymes results in:

A

Differences in concentration of drug, active metabolites, toxic derivatives

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5
Q

Genetic differences in membrane proteins results in:

A

Differences in absorption, distribution, excretion

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6
Q

Genetic differences in receptors results in:

A

Differences in abundance or sensitivity –> therapeutic vs adverse effects

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7
Q

____ is the study of differences in drug response due to allelic variation in genes affecting drug efficacy, metabolism, toxicity (variable response due to individual genes)

A

Pharmacogenetics

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8
Q

Every person carries ____ copies of every gene

A

Two (homozygous or heterozygous)

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9
Q

What is pharmacogenomics?

A

Genomic approach to pharmacogenetics concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy

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10
Q

____ is involved with a variable response due to multiple loci across the genome (different alleles across many different genes affecting the response of a drug)

A

Pharmacogenomics

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11
Q

Large single-variant effect caused by:

A

Pharmacogenetics

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12
Q

Smaller effect with multiple variants caused by:

A

Pharmacogenomics

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13
Q

What two types of genetic mutation events create all forms of variations?

A
  • Single nucleotide polymorphisms (substitute one nucleotide for another)
  • Insertion or deletion polymorphisms
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14
Q

What is a polymorphism?

A

A genetic variation observed at a frequency of more than 1% in a population

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15
Q

What is a mutation?

A

Genetic variation in less than 1% in a population

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16
Q

True or false: SNPs are rare in the human population

A

False - very common

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17
Q

Between any two people, there is an average of one SNP every ____ bases

A

1000

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18
Q

Do most SNPs have a phenotypic effect?

A

No

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19
Q

Estimate that ____ SNPs in the genome (how many bases total in the genome?)

A

3.2 million; 3 billion total

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20
Q

Only ____ of all human SNPs impact protein function (most in non-coding regions)

A

< 1%

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21
Q

What is a missense mutation?

A

Mutated codon codes for a different amino acid (could be significant)

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22
Q

What is a nonsense mutation?

A

Mutated codon is a premature stop codon (usually serious)

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23
Q

Insertion/deletion (INDEL) polymorphisms are ____ and ____ distributed throughout the human genome

A

Quite common; widely

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24
Q

INDEL that add or subtract amino acids may:

A

Have no effect, alter the activity or abolish all activity of the affected protein

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25
Q

LARGE deletions result in:

A

Complete loss of protein expression

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26
Q

Gene duplication results in:

A

Stably transmitted inherited genes that cause increased protein expression and activity

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27
Q

Every person has two copies of every gene that are inherited ____

A

Independently

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28
Q

CYP450 genotypes result in:

A

Various combinations of wild-type or decreased activity, inactive, or duplicated alleles

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29
Q

List the different CYP450 Phenotypes

A
  • Poor metabolizer
  • Intermediate metabolizer
  • Extensive metabolizer
  • Ultrarapid metabolizer
30
Q

Poor metabolizer - genotype

A

2 inactive alleles of CYP450

31
Q

Intermediate metabolizer - genotypes?

A
  • 2 decreased activity alleles
  • One active allele and one inactive
  • One decreased activity allele and one inactive

(CYP450)

32
Q

Extensive metabolizer - genotype

A

2 functional alleles (wild type)

33
Q

Ultrarapid metabolizer - genotype

A

Gene duplication in the absence of inactive or decreased alleles

34
Q

Describe the pharmacokinetic effects of a poor metabolizer (CYP450)

A

Drug enters toxic range and tapers off but remains in toxic range

35
Q

Describe the pharmacokinetic effects of an intermediate metabolizer (CYP450)

A

Drug enters toxic range but tapers off into therapeutic range and doesn’t go below that

36
Q

Describe the pharmacokinetic effects of an extensive metabolizer (CYP450)

A

Drug concentration peaks at therapeutic range and tapers off below this range as it is being broken down

37
Q

Describe the pharmacokinetic effects of an ultrarapid metabolizer (CYP450)

A

Drug enters therapeutic range but quickly decreases below therapeutic range

38
Q

If a patient is an ultrarapid metabolizer, how do you modify their treatment?

A

May have to prescribe a higher dose due to much more CYP450 being available

39
Q

List examples of gene-drug interactions

A
  • CYP2D6 and Codeine
  • ALDH2 and Ethanol
  • CYP2D6 and Tamoxifen
40
Q

What is codeine?

A

Analgesic (painkiller)

41
Q

____ is a prodrug

A

Codeine (inactive compound that when metabolized becomes an active drug)

42
Q

____ is critical for codeine’s analgesic effect

A

CYP2D6-mediated bioactivation

43
Q

What is codeine metabolized into?

A

Morphine

44
Q

What is the difference in structure between codeine and morphine?

A

Methyl group removed to create morphine

45
Q

Codeine is more ____
Morphine is more ____

A

Lipophilic; hydrophilic

46
Q

A poor metabolizer (CYP2D6) of codeine would result in:

A

No analgesic effect of morphine (no metabolism = no activation of codeine)

47
Q

An intermediate metabolizer (CYP2D6) of codeine would result in:

A

Slight analgesic effect of morphine

48
Q

An extensive metabolizer (CYP2D6) of codeine would result in:

A

Effective pain relief from morphine

49
Q

An ultra metabolizer (CYP2D6) of codeine would result in:

A

“overdose” effect

50
Q

Low dose of ethanol causes:

A
  • Muscle relaxant
  • Euphoria
  • Impaired judgment
51
Q

High dose of ethanol causes:

A
  • CNS depressant
  • Impaired sensory/motor function
52
Q

When does ethanol become toxic?

A

When BAC > 400mg/dL (0.4%)

53
Q

How does ethanol metabolism occur?

A

Two steps:
- Alcohol dehydrogenase (ADH) converts ethanol to acetaldehyde
- Aldehyde dehydrogenase (ALDH2) converts acetaldehyde to acetic acid (detoxification step)

54
Q

____ is a toxic metabolite during ethanol metabolism

A

Acetaldehyde

55
Q

ALDH2 has an alternative allele in which:

A

Lysine residue replaces a glutamate in the active site at position 487 of ADH2

56
Q

ALDH2 alternative allele can result in what genotypes?

A
  • ALDH2 1/1 wild type homozygous
  • ALDH2 1/2 Heterozygous
  • ALDH2 2/2 Variant homozygous
57
Q

Homozygous individuals (ALDH2 2/2) with the variant allele have:

A

Almost no ALDH2 activity (8% of normal)

58
Q

Heterozygous individuals (ALDH2 1/2) have:

A

Reduced activity

59
Q

ALDH2 is a ____ (structure)

A

Tetramer

60
Q

ALDH2 influence on acetaldehyde blood levels following ethanol ingestion: WT

A

No flushing, no hangover effects

61
Q

ALDH2 influence on acetaldehyde blood levels following ethanol ingestion: Heterozygous

A

Some flushing, some hangover effects

62
Q

ALDH2 influence on acetaldehyde blood levels following ethanol ingestion: Homozygous variant

A

Flushing, hangover effects (not converting acetaldehyde toxic metabolite into acetic acid)

63
Q

What is disulfiram?

A
  • Drug used to treat chronic alcoholism
  • Inhibits aldehyde dehydrogenase resulting in acetaldehyde accumulation
64
Q

Estrogen receptor-positive breast cancer is under the control of ____ and can be effectively treated with ____

A

Estrogen; anti-estrogens

65
Q

Anti-estrogens work by:

A

Binding to estrogen receptors, blocking estrogen from binding, stopping cell proliferation

66
Q

____ is an anti-estrogen

A

Tamoxifen

67
Q

CYP2D6 biotransforms tamoxifen into:

A

Endoxifen (potent antiestrogen)

68
Q

CYP2D6 genotypes have been associated with ____ of endoxifen

A

Variability in plasma concentrations

69
Q

PM phenotype results in ____ endoxifen plasma concentrations in tamoxifen-treated breast cancer patients

A

Reduced

70
Q

EM phenotype results in ____ serum concentrations of endoxifen

A

Significantly higher

71
Q

PM phenotype serves as:

A

A predictor of breast cancer outcome in postmenopausal women taking tamoxifen for breast cancer (shorter time to cancer recurrence, worse relapse-free survival)

72
Q

True or false: Dentists will be accountable for prescribing drugs appropriately to genetic subgroups

A

True

DEN 7203 Pharmacological Concepts (7 decks)

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