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Pharmacology II > Pharmacogenetics > Flashcards

Pharmacogenetics Flashcards

1
Q

4 different drug responses?

A

toxic + beneficial
toxic + not beneficial
non-toxic + beneficial
non-toxic + non-beneficial

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2
Q

3 goals for personalized medecine?

A
  • Identify genetic differences between people that affect drug response
  • Develop genetic tests that predict an individual’s response to a drug
  • Tailor medical treatments to the individual
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3
Q

Difference between pharmacogenetics and pharmacogenomics?

A

genetics : evaluate how an individual’s genetic makeup corresponds to their response to a particular medication
genomics : large group of patient to evaluate how drugs interact with many different genes and their proteins

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4
Q

5 drugs that are ineffective in a certain percentage of people?

A
  1. ACE inhibitors - Hypertension (10-30%)
  2. Beta blockers - Heart Failure (15-25%)
  3. Anti-depressants (20-50%)
  4. Statins - Cholesterol (30-70%)
  5. B2 agonists - asthma (40-70%)
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5
Q

How can a change in a gene lead to toxicity/low efficacy in PK? (3)

A

Gene that affects ADME
Drug metabolizing enzymes
T.I.

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6
Q

How can a change in a gene lead to toxicity/low efficacy in PD? (1)

A

Slightly different target or loss of target

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7
Q

The two major types of drug metabolizing enzymes? What do they act on? (2)

A

Ultra drug metabolizer
Poor drug metabolizer

They act on drugs and pro-drugs

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8
Q

Effect of ultra drug and poor drug metabolizers on drugs?

A

UM : rapid inactivation so ineffective

PM : toxic doses

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9
Q

Effect of ultra drug and poor drug metabolizers on prodrugs?

A

UM : metabolized to active form rapidly, toxic doses

PM : Little conversion of prodrug to active form, ineffective

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10
Q

Three reasons why there can be NO consequences of genetic polymorphisms?

A
  1. Outside of coding and regulatory regions
  2. Synonymous substitution
  3. No signi. effect on function
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11
Q

4 consequences of genetic polymorphisms?

A

None
Decrease/loss function of protein
Increase function of protein
Change is compared to population majority

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12
Q

What are 4 reasons why there can be decreased function in a protein due to genetic polymorphisms?

A
  1. Less enzyme produced
  2. Enzyme not complete (stop codon)
  3. Enzyme not stable
  4. Less affinity for substrate
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13
Q

What are 3 reasons why there can an increased function in a protein due to genetic polymorphisms?

A
  1. More production
  2. More stable
  3. More affinity for substrate
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14
Q

3 enzymes with genetic polymorphisms that cause disease?

A

NAT2
TPMT
ALDH2

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15
Q

NAT2 involved in what disease?

A

Tuberculosis

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16
Q

Tuberculosis is an infection of which bacteria

A

mycobacterium tuberculosis

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17
Q

Tuberculosis attacks mainly what?

A

lungs

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18
Q

Which drug targets TB? It is metabolized by the _____ via which modification?
When the drug reaches toxic levels it causes what?

A

Isoniazid
Liver
Acetylation
Peripheral neuropathy

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19
Q

Which enzyme acetylates isoniazid?

A

NAT2 : N-acetyl-transferase

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20
Q

Two types of NAT2 acetylators? Which is WT and which has many AA substitutions?

A

Rapid: WT

Slow : many alleles

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21
Q

11 haplotypes of NAT2? Rapid or slow?

A 
4 : rapid
5A : slow
5B : slow
6A : slow
7B : slow
7Bnew : unknown
10 : unknown
11 : unknown
12A : rapid
13 : rapid
14B : slow
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22
Q

Thiopurines treat which diseases? (4)

A
  1. Leukemia
  2. Inflammatory bowel disease
  3. Prevent organ rejection
  4. Other autoimmune diseases
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23
Q

Enzyme that acts on thiopurines? What modification does it do

A

Thiopurine methyltransferase

Methylation

24
Q

Thiopurines are converted into __________
This gets inserted in _______ and can have toxic effects at high levels.
Reduced TPMT activity leads to ___________

A

Thioguanine nucleotides (TGNs)
DNA bases
Fatal toxicity

25
Q

5 Haplotypes of TPMT?

A 
1
2
3A
3B
3C
26
Q

If a patient have two nonfunctional variant alleles of TPMT (homozygous), what changes with dosage?
What about heterozygous?

A

Homo : 6-10% of regular dose

Hetero : normal dose but monitor closely

27
Q

Role of ALDH2?

A

Produces Acetate from Acetaldehyde

28
Q

Mutation in ALDH2? What does this cause?

A

ALDH2*2

Accumulation of acetaldehyde, less clearance from liver

29
Q

Acetaldehyde is a known _________

A

carcinogen

30
Q

Drug that acts on ALDH2? What does it do?

A

Disulfiram

Blocks ALDH2 and is used for alcohol dependence

31
Q

Main drug metabolizing enzyme?

A

CYP450

32
Q

4 consequences to having no CYP2D6 enzymes? (PMs)

A
  1. Slow drug metabolism
  2. High drug levels
  3. High risk for adverse drug effects
  4. No response to certain prodrugs
33
Q

2 consequences to having CYP2D6 duplicates?

A
  1. Too rapid metabolism

2. No drug response at ordinary dose

34
Q

Example of drug that is metabolized by CYP2D6?What is i?

A

Nortriptyline

Antidepressant

35
Q

Does nortriptyline have a low or high therapeutic index?

A

Narrow

36
Q

If nortriptyline is metabolized by a CYP2D6 POOR drug metabolizer : what is the effect?
What about an ultra drug metabolizer?

A

Poor : toxic doses of the drug

Ultra : inactivation of drug rapidly, becomes ineffective

37
Q

If a patient carries ultra drug metabolizer alleles of CYP2D6, should the dosage of a drug increase or decrease?

A

Increase

38
Q

which drug is used for breast cancer?

A

Tamoxifen

39
Q

Tamoxifen is metabolized by _______ to which metabolites?

A

CYP2D6

4-hydroxytamoxifen and endoxifen

40
Q

Which drug is used to treat blood clots?

A

Plavix

41
Q

Which enzyme metabolizes plavix into it’s active form?

A

CYP2C19

42
Q

How does Plavix become inactive?

A

CYP2C19 alleles resulting in poor metabolizers

43
Q

Inactive plavix results to clots leading to __________

A

MI

44
Q

Drug used for anti-coagulation?

Narrow or large TI?

A

Warfarin

Narrow

45
Q

What metabolizes warfarin? what are it’s alleles?

A

CYP2C9

CYP2C91
CYP2C92
CYP2C9*3

46
Q

What is the target of warfarin? How many polymorphisms does it have and how does this affect dosage of warfarin?

A

VKORC1
2 major polymorphisms
Lower expression so less warfarin dosing required

47
Q

Pharmacogenetics gives us the knowledge of what?
direct link between _____ and ______
requires small or large sample sizes?

A

Target genes ahead of time
SNP and phenotype
Small

48
Q

Pharmacogenomics has what target?
Does identified SNP have a direct link to phenotype?
Requires small or large sample sizes?

A

No target known
Maybe
Large

49
Q

3 types of point mutations?

A

Silent
Nonsense
Missense

50
Q

Steps to detecting SNPs? (5)

A
  1. Isolate DNA
  2. Digest DNA
  3. Label DNA with fluorescence probe
  4. Hybridize onto matrix containing an array of oligonucleotides (known SNPs)
  5. Detect signal for each SNP spot on the array
51
Q

Graph that detects SNPs associated with disease?

A

GWAS Manhattan plot

52
Q

Which drugs treats hepatitis C?

A

Interferon

53
Q

Hepatitis C is the leading cause of what?

A

liver cirrhosis

54
Q

The GWAS plot revealed what region to correlate with response to interferon?

A

Region on chromosome 19

55
Q

Which genotype is more likely to clear hepatitis C infection?
Which ancestry is more likely to have C/C? Lowest?

A

C/C
Highest : East Asian
Lowest : African

Pharmacology II (21 decks)

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