Pharmacogenomics

Question 1

1. What is pharmacogenetics❓

2. What is pharmagenomics❓

Answer 1

1. Study of individual gene-drug interactions
2. Study of genomic influence on drug response

Question 2

The human genome project was a research program for mapping and understanding of all the genes in human beings.

When did it begin❓

When was it completed❓

How many genes were discovered❓

Answer 2

1984
2003

20,500 genes

Question 3

If humans are 99.9% identical at the DNA level, what influences the differences in appearance/behavior/response to medications❓

Answer 3

The 0.1% difference is responsible about 3,000,000 specific DNA differences btwn pple

Question 4

What are mutations❓

What is the normal codon for:

1. Methionine
2. Valine
3. Leucine
4. Serine
5. Proline
6. Tyrosine

Answer 4

Changes in DNA

1. ATG
2. GTG
3. CTG
4. TCT
5. CCT
6. ACT

Question 5

What would you observe with administration of suxamethonium to a patient deficient in serum pseudocholinesterase❓

What is the rate of prevalence of this deficiency❓

Answer 5

Prolonged respiratory paralysis

1 in 2000 caucasians

Question 6

What would you observe with administration of an anti-malaria to a patient deficient in G6PD❓

What is the rate of prevalence of this deficiency❓

Answer 6

Hemolysis of RBC (anemia)

1 in 100 African American

Question 7

What enzyme is probably deficient in a pt that presents with bone marrow toxicity from administration of thiopurine/mercaptopurine❓

Answer 7

Thiopurine methyl transferase (TPMT)

• 70% -High expression
• 20% -Medium
• 2% -Low

Question 8

1. A deficiency in N-acetylase (NAT2) transferase will lead to a slow inactivation of which drugs❓
2. What is the rate of prevalence of this deficiency….
   a) Caucasians
   b) Africans

Answer 8

1. Isoniazid
   Dapsone

2.

a. 45-65%
b. 10-15%

Question 9

ADRs rank as the fourth leading cause of death (40,000-100,000 per year)

True or false

Answer 9

True

Question 10

Drugs have a patent life of about 20 years

True or false❓

Answer 10

True

Question 11

Cytochrome P450 is a family of isozymes that bio transform several drugs.

How many genes code for it❓

Divided among how families❓

Which are responsible for metabolizing most clinically important drugs❓

Answer 11

57 genes

18 families

CYP 2A6
CYP 2B6

CYP 2C9
CYP 2C19

CYP 2D6

CYP 2E1

CYP 3A4

Question 12

What is the function of CYP1❓

How many subfamilies does it have❓

How many genes does it have❓

Answer 12

Drugs metab
Steroid (esp. estrogen) metab

2 subfamilies

3 genes

Question 13

What is the function of CYP2❓

How many subfamilies does it have❓

How many genes does it have❓

Answer 13

Drug and steroid metab

13 subfamilies

16 genes

Question 14

What is the function of CYP3❓

How many subfamilies does it have❓

How many genes does it have❓

Answer 14

Drug and steroid (+testosterone) metab

1 subfamily

4 genes

Question 15

The CYP enzyme, 1A1, is responsible for the metabolism of which drugs❓

Answer 15

Caffeine
Testosterone
R-Warfarin

Question 16

The CYP enzyme, 1A2, is responsible for the metabolism of which drugs❓

Answer 16

Acetaminophen
Caffeine
R-Warfarin

Phenacetin

Question 17

The CYP enzyme, 2A6, is responsible for the metabolism of which drugs❓

Answer 17

Testosterone

17beta-Estradiol

Question 18

The CYP enzyme, 2B6, is responsible for the metabolism of which drugs❓

Answer 18

Cyclophosphamide

Erythromycin
Testosterone

Question 19

The CYP enzyme, 2C-family, is responsible for the metabolism of which drugs❓

Answer 19

Acetaminophen
Testosterone
R-Warfarin

Phenytoin 
Zidovudine 
S-Warfarin 
Hexobarbital
Tolbutamide

Question 20

The CYP enzyme, 2E1, is responsible for the metabolism of which drugs❓

Answer 20

Acetaminophen

Caffeine

Question 21

The CYP enzyme, 2D6, is responsible for the metabolism of which drugs❓

Answer 21

Acetaminophen

Codeine

Question 22

The CYP enzyme, 3A4, is responsible for the metabolism of which drugs❓

Answer 22

Acetaminophen 
Caffeine 
Cyclophosphamide 
Testosterone 
S and R-Warfarin 

Erythromycin 
Phenytoin 
Carbamazepine 
Cortisol 
Zidovudine

Question 23

1. What substance can induce the action of CYP 3A4,5,7 on Felodipine❓
2. a. What substance can inhibit it❓
   b. Will its concentration ⬆️/⬇️❓

Answer 23

1. Glucocorticoid

2a. Grapefruit juice
b. It will increase if 3A4,5,7 is inhibited

Question 24

1. What substance can induce the action of CYP 1A2 on Clozapine/Haloperidol❓
2. a. What substance can inhibit it❓
   b. Will its concentration ⬆️/⬇️❓

Answer 24

1. Tobacco smoke

2a. Cimetidine
b. It will increase if 1A2 is inhibited

Question 25

What is the risk associated with CYP enzyme inhibition❓

Answer 25

``` Inhibition of enzyme ⬇️ Decreased degradation of drug ⬇️ Increased drug plasma conc. ⬇️ Risk of adverse effect ```

Question 26

What is the risk associated with CYP enzyme induction❓

Answer 26

``` Increased degradation ⬇️ Decreased drug plasma conc. ⬇️ 🚫pharmacological effect ⬇️ Risk of therapeutic failure ```

Question 27

What do tricyclic antidepressants do❓

Answer 27

⬇️serotonin reuptake ⬆️serotonin levels in cleft

Question 28

Response rates of antidepressants are low (1/3 +) 1. True or false 2. Why❓ 3. Give examples of TCA 4. Give examples of SSRI

Answer 28

1. True 2. Biomarkers that can predict clinical efficacy or safety responses are not utilized 3. Nortriptyline Imipramine 4. Fluoxetine Paroxetine

Question 29

Which CYP enzyme is the most investigated with regard to antidepressant pharmacogenomics❓

Answer 29

CYP 2D6

Question 30

Hanson’s

Answer 30

Havana

Question 31

1. Which drug group does codeine belong❓ 2. Is codeine a pro-drug❓ 3. What is it’s metabolizing enzyme❓ 4. What is the rate of deficiency of this enzyme❓

Answer 31

1. Opioid 2. Yes, it must be metabolized into morphine for activity 3. CYT P450 Allele CYP 2D6 7% of Caucasians are deficient

Question 32

1. Which drug group does tamoxifen belong❓ 2. What is it’s metabolizing enzyme❓ 3. What is it metabolized to for its activity❓ 4. What is the rate of deficiency of this enzyme❓

Answer 32

1. Antineoplastic (breast ca) 2. CYP 2DE 3. Endoxifen 6-10% European population

Question 33

What are the benefits of pharmacogenomics❓ What are it’s limitations❓

Answer 33

``` 1. Max. drug efficacy Min. drug toxicity Predict pt that respond to interventions Aid in new drug development ``` 2. Costs and access to technology Confidentiality of information