Pharmacogenetics

Question 1

Pharmacogenetics

Answer 1

The study of differences in drug response due to allelic variation in genes. Affects drug metabolism; efficacy;; and toxicity. Typically involves study of just a few genes selected by their known role in drug metabolism

Question 2

Pharmacogenomics

Answer 2

Concerned with assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy. Large numbers of polymorphic loci being identified in Pts who have responded adversely vs. those who had no adverse response

Question 3

Pharmacokinetics

Answer 3

Describes absorption; distribution; metabolism and excretion of drugs (ADME). IE whether or how much drug reaches targets. Drug removal. EX Cytochrom P450; thiopurine methyltransferase; etc.

Question 4

Pharmacodynamics

Answer 4

Describes the relationship between the concentration of a drug at its site of action and the observed biological effects. IE what happens when the drug successfully reaches its target. Drug effect. EX G-6-P dehydrogenase; vit. K epozide complex

Question 5

How can you further breakdown pharmacokinetics?

Answer 5

2 basic ways that drugs are metabolized: Phase I and Phase II

Question 6

Phase I

Answer 6

Attach a polar group onto the compound to make it more soluble; usually a hydroxylation step

Question 7

Phase II

Answer 7

Attach a sugar/acetyl group to detoxify the drug and make it easier to excrete

Question 8

What does the cytochrome P450 gene encode for? What do they do? Where are they active?

Answer 8

CYP450 genes encode enzymes that metabolize (through Phase I) a large number of drugs (90% of all common meds). Very active in the liver and a bit in epithelium of the small intestine.

Question 9

What is the most active gene in the CYP family?

Answer 9

CYP3A4 - take part in metabolism of >40% of all drugs

Question 10

What does CYP2D6 activity do in regard to codeine?

Answer 10

Activates codeine by converting it to morphine. (Note:this is different than most CYP genes that inactivate drugs)

Question 11

What are the 3 different phenotypes when it comes to drug metabolism?

Answer 11

Normal; poor; Ultrarapid/ultrafast

Question 12

What is an important CYP3A substrate?

Answer 12

Cyclosporine (an immunosuppressant)

Question 13

Name 2 CYP3A inhibitors

Answer 13

Ketoconazole (antifungal agent); Grapefruit juice

Question 14

Name 2 CYP2D6 substrates

Answer 14

Tricyclic antidepressants; Opioids (codeine-activates)

Question 15

Name 3 CYP2D6 inhibitors

Answer 15

Quinidine (antiarrhythmic); Fluoxetine (Prozac); Paroxetine (Paxil - SSRI)

Question 16

Name 1 substrate of CYP2C9

Answer 16

warfarin

Question 17

What is a substrate of the NAT gene?

Answer 17

Isoniazid for tuberculosis

Question 18

What 2 substrates are there for the TMPT gene?

Answer 18

6-mercaptopurine; 6-thioguanine

Question 19

What do 6-mercaptopurine; 6-thioguanine treat? What must you remember about these drugs?

Answer 19

Immunosuppresant. Used to treat ALL et al. Must remember that if you give children with ALL standard doses you will KILL the child due to immunosuppression

Question 20

Name 2 substrates of G6PD gene

Answer 20

Sulfonamide antibiotics; dapsone (antibiotic)

Question 21

What is important to remember about the mechanism of G6PD enzymes?

Answer 21

X-linked enzyme

Question 22

If a Pt is G6PD deficient; what are they susceptible to after drug exposure?

Answer 22

hemolytic anemia

Question 23

What is a substrate of VKORC1 gene?

Answer 23

warfarin (blood thinner)

Question 24

Most major drugs are effective in what percentage of Pts?

Answer 24

25% - 60%

Question 25

What are the expected mutations on poor drug metabolizers?

Answer 25

Frameshift; splicing; nonsense; missense (some)

Question 26

What happens if poor metabolizers are given normal doses?

Answer 26

Since most CYP genes are inactivators; Pts will usually be overdosed

Question 27

What are the expected mutations on ultrafast drug metabolizers?

Answer 27

Increased copy number; missense (some)

Question 28

What happens if ultrafast metabolizers are given normal doses?

Answer 28

Since most CYP genes are inactivators; Pts will usually be underdosed