Pharmcogenetics.

Question 1

pharmacogenetics vs pharmacogenomics

Answer 1

pharmacogenetics: study of genes and their alleles in relationship to drug response in a given patient pharmacogenomics: study of genes related to drug metabolism, and the use of this knowledge to develop new, targeted drugs (creation of personalized medicine)

Question 2

Adverse drug reactions

Answer 2

4 or 5th leading cause of death - some related to genetic differences in individuals

Question 3

clopidogrel

Answer 3

antiplatelet agent used to inhibit blood clotting - about 30% of patients fail to respond - activated by several P450 enzymes - active metabolite irreversibly binds P2Y12 receptor on surface of platelets inhibiting platelet aggregation

Question 4

How are drugs developed?

Answer 4

one primary drug for each disease (easier and more profitable), easier for physicians to have fewer drug options

Question 5

efficacy

Answer 5

how well a drug works

Question 6

toxicity

Answer 6

possible negative side effects of a drug

Question 7

What do we need to know for pharmacogenomics?

Answer 7

1. metabolic pathway for each drug 2. all of the genes involved in the pathway and how mutations affect the outcome 3. a patient’s genetic profile 4. an understanding of how the drug works (pro drug or active - what level necessary for effective and toxic)

Question 8

CYP2D6

Answer 8

chrom 22 - involved in metabolism of ~100 drugs (antidepressants, neuroleptics, beta blockers, analgesics) - have 4 types of metabolizers (extensive/normal, ultra, intermediate, poor)

Question 9

Prodrug in an ultra metabolizer: how is dose changed and why

Answer 9

possible overdose (converted very rapidly into active form) - need to reduce dose

Question 10

Prodrug in a poor metabolizer: how is dose changed and why

Answer 10

little or no conversion: use a different drug because zero effect

Question 11

Prodrug in an intermediate metabolizer: how is dose changed and why

Answer 11

slow or limited activation: increase dose

Question 12

Active compound in a poor metabolizer: how is dose changed and why

Answer 12

accumulate toxic leves - decrease dose or use different drug

Question 13

Active compound in an intermediate metabolizer: how is dose changed and why

Answer 13

moderate to toxic levels - reduce dose

Question 14

Active compound in an ultra metabolizer: how is dose changed and why

Answer 14

rapid degradation/elimination of drug so need to increase dose - careful of reaching toxic level

Question 15

Codeine

Answer 15

a prodrug converted to active form morphine by CYP2D6 - poor metabolizers cannot convert while ultra metabolizers may become intoxicated at low doses

Question 16

Which gene explains ~half of the variability in clopidogrel response?

Answer 16

CYP2C19, alleles 2,3,17

Question 17

Which alleles are the loss of function alleles in CYP2C19?

Answer 17

2 and 3

Question 18

Which alleles are the gain of function alleles in CYP2C19?

Answer 18

17

Question 19

Which ethnicity is likely to see a loss of function allele in CYP2C19? gain of function?

Answer 19

loss: asian; gain: african and caucasian

Question 20

6-mercaptopurine

Answer 20

leukemia therapy prodrug - metabolized to active form (TdGTP) incorporates into DNA - too much TdGTP can be toxic - TPMT converts TGMP to methyl-TGMP which is eliminated

Question 21

A defect in which enzyme requires a much lower does in 6-mercaptopurine?

Answer 21

TPMT

Question 22

G6PD deficiency leaves patients susceptible to what?

Answer 22

drug induced hemolysis by oxidant drugs such as primaquine

Question 23

G6PD

Answer 23

deficiency in med and african americans - enzyme deficiency is related to increased fitness where malaria is a problem - but can only take oxidant drugs for a short time because long exposure leads to jaundice and hemolysis

Question 24

malignant hyperthermia

Answer 24

negative response to inhalation anesthetics due to elevation of ionized calcium in the muscle - AD

Question 25

Abacavir

Answer 25

HIV anti retroviral drug - can get hypersensitivity reaction due to HLA-B*57:01 causing T cells to secrete TNF-a

Question 26

How does warfarin work?

Answer 26

inhibits enzyme vitamin K epoxide reductase resulting in inhibition of vit K metabolism

Question 27

What things have an effect on warfarin?

Answer 27

foods with high concentration bit K, alcohol, drugs such as aspirin, ibuprofen, acetaminophen, antibiotics, 2 known gene alleles

Question 28

How is dosing of warfarin done?

Answer 28

trial and error fashion

Question 29

What are the genes that affect warfarin metabolism?

Answer 29

VKORC1 (30%) and CYP2C9 p450 (10%) - complex interactions between genes, environment, other drugs, etc.