Pharmacogenetics

Question 1

What is the difference between pharmacogenetics and pharmacogenomics?

Answer 1

Pharmacogenetics is the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity.

The key conceptual elements here are that pharmacogenetics typically involves the study of just a few genes and these genes are selected based on a prior knowledge of their role(s) in drug metabolism.

On the other hand, pharmacogenomics, the genomic approach to pharmacogenetics, is concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy.

Instead of analyzing individual genes and their variants according to what is known about how they influence pharmacokinetic and pharmacodynamic pathways, sets of alleles at a large number of polymorphic loci are being identified that distinguish patients who have responded adversely to what was considered a beneficial drug from those who had no adverse response.

Question 2

Pharmacokinetics has two basic ways to metabolize drugs:

Phase I and Phase II

Answer 2

Phase I: attaches a polar group onto the compound to make it more soluble in the body, ususally a HYDROXYLATION STEP.

Phase II: attaches a sugar/acetyl group to detoxify the drug and make it easier to excrete.

Question 3

The cytochrome P450 (CYP450) genes encode important enzymes that are very active in the liver and to a lesser extent in the epithelium of the small intestine. CYP450 enzymes metabolize a wide number of drugs.

What CYP itself takes part in the metabolism of over 40% of all drugs used in clinical medicine?

Answer 3

CYP34A

Question 4

Which CYP converts codeine to morphine?

Answer 4

CYP2D6

Question 5

Using the CYP2D6 example again (important since CYP2D6 is the principle Phase I metabolizer of ~70 drugs). Lots of mutations, several of which affect function are possible and the alleles are generally classified here as:

• Frameshift - alter reading frame  NO ACTIVITY
• Splicing - skip exons and/or alter reading frame  NO ACTIVITY
• Missense -> alter protein function –> usually REDUCED ACTIVITY
• Copy number alleles–> increased gene copy

alleles –> ___________

Answer 5

INCREASED (ULTRAFAST)

Question 6

Gene:

CYP3A

Substrates: Felodipine and cyclosporine

Inhibitors: *Ketoconazole and *grape juice

Inducers (increase its activity): _________

Answer 6

Rifampin

Question 7

Gene:

CYP2D6

Substrates: Tricyclic antidepressants, codeine

Inhibitors: ___________

Answer 7

Quinidine, Fluoxetine, Paroxetine

Question 8

CYP2C9 and VKORC1

Answer 8

Substrates: Warfarin

Question 10

Gene: NAT

Substrate:_________

Answer 10

Isoniazid for tuberculosis

Question 11

Gene: TMPT

Substrates: 6-mercaptopurine and 6-thioguanine

Answer 11

Need to be careful with kids with ALL, since giving then standard doses will KILL them due to immunosupresion.

*Classic example of pharmacogentic fatal outcome

Question 12

Gene: G6PD

Substrates: sulfonamide and dapsone

What are G6PD deficient individual susceptible to if exposed to drugs that are substrates for G6PD?________

Answer 12

Hemolytic anemia