Pharmacogenetics

Question 1

The most well-documented examples of differences in drug effects are due to what? What branch is now starting to be heavily researched?

Answer 1

1. Metabolism- liver enzymes

2. pharmocodynamic- mechanism of action

Question 2

Phase I enzymes are associated with what? Phase II?

Answer 2

1. CYP-oxidation, hydrolysis, reduction

2. Conjugating enzymes

Question 3

What variant number is the most clinically important UGT variant?

Answer 3

28

Question 4

Ultra rapid metabolizers with usually gene multiplication are usually associated with what enzyme?

Answer 4

CYP2D6

Question 5

The extensive metabolizer is characterized as what?

Answer 5

Normal activity, two copies of normal gene

Question 6

The intermediate metabolizer is characterized as what?

Answer 6

– Roughly half-normal enzyme activity

– Usually one copy of low activity active gene

Question 7

The poor metabolizer is characterized as what/

Answer 7

– Little or no enzyme activity

– Two copies of low activity gene

Question 8

Wat are the 4 most important CYP enzymes?which one does over half of prescription drugs? 25%?

Answer 8

1. 2C9, 2C19, 2D6, 3A4
2. 3A4
3. 2D6

Question 9

What enzyme converts tomoxifen to active metabolite?

Answer 9

CYP2D6

Question 10

What converts codeine to morphine

Answer 10

CYP2D6

Question 11

What are 3 major drug class metabolized by CYP 2 D6

Answer 11

• Anti-depressants (SSRIs, tricyclics)
• Anti-psychotics (aripiprazole, olanzapine)
• -Adrenergic antagonists (carvedilol, metoprolol)

Question 12

What converts azathioprine and 6 mercaptopurine?

Answer 12

Thiopurine methyltransferase TPMT

Question 13

What metabolizes irinotecan?

Answer 13

UGT1A1- Gilbert’s syndrome

Question 14

What metabolizes warfarin and phenytoin?

Answer 14

CYP2C9

Question 15

What metabolizes isoniazid, hydalazine, procainamide?

Answer 15

N-acetyltransferase

Question 16

What enzyme converts clopidogrel, carisoprodol, and diazepam?

Answer 16

CYP2C19

Question 17

Variant 3 for CYP2D6 is what mutation and population percentage? 4? 5?

Answer 17

1. frame shift- 2%
2. Splicing- 22 %
3. gene deletion- 5%

Question 18

If metabolism of a drug is slower than average, what do we often see?

Answer 18

wanted effects not elicited from certain prodrugs, but toxicity on standard dose

Question 19

If metabolism of a drug is faster than average, what do we often see?

Answer 19

-no drug response at ordinary dosage

Question 20

If you are a rapid metabolizer with CYP2D6 multiplication, what happens?

Answer 20

Convert codeine very rapidly to morphine,
sometimes resulting in toxicity

[Tragic cases reported in infants who breast-fed from mothers who were ultra-rapid
metabolizers and had taken codeine Infants died of respiratory arrest from
excess levels of morphine that transferred to
the breast milk]

Question 21

What protein kinase is important in regards to being mutated for melanoma? What drug is used to inhibit its constitutive activity?

Answer 21

1. B-RAF

2. Vemurafenib

Question 22

What is the importance of vemuradenib?

Answer 22

It was part of the first wave of companion diagnostics specifically targeted at a subset of cancers with a particular molecular alterations

Question 23

A mutation in VKORC1 causes what?

Answer 23

warfarin resistance in humans and rats

Question 24

What CYP enzyme metabolizes warfarin? what are the most common variants?

Answer 24

1. CYP2C9

2. 2 and 3

Question 25

if evidence is available to support
the safety and effectiveness of the
drug only in selected subgroups of
the large population with a disease,, what then needs to happen?

Answer 25

identify specific tests
needed for selection or monitoring of
patients who need the drug

Question 26

How much does genetic variation account for of clinical variation in warfarin effects?

Answer 26

only 1/3

medications, diet, age, weight, and sex
[all included only account for about 50% of effect]

Question 27

What are the 5 general issues in implementing pharmacogenetics in clinical practice?

Answer 27

1. Nomenclature
2. Understanding genetic variation in context
3. Insurance coverage
4. Inertia of status quo
5. Establish new standard of care