L7 Pharmacogenomics

Question 1

What are the main factors that affect the genetic variability of the drug response?

Answer 1

1. Pharmacokinetics: drug metabolizing enzymes and drug transporters
2. Pharmacodynamics: drug therapeutic targets and drug toxic targets

Question 2

What is the most common factor responsible for inter-individual differences in drug responses?

Answer 2

Differences in drug metabolic enzymes

Question 3

Many of the enzymes involved in drug metabolism are ___.

Answer 3

Polymorphic

Question 4

The CYP450 family of drug metabolizing enzymes are highly polymorphic, especially these three - ?

Answer 4

CYP2C9, CYP2C19, CYP2D6

Question 5

Describe how a variant CYP450 enzyme affects serum drug concentrations.

Answer 5

Decreased enzymatic activity leads to less efficient drug metabolism, increased drug concentration, increased efficacy, and increased toxicity risk

Question 6

What happens when a patient has multiple copies of an allele for a CYP450 gene?

Answer 6

Increased gene expression and increased metabolic activity

Question 7

How do polymorphisms in CYP2C9 affect warfarin?

Answer 7

Warfarin has a narrow therapeutic window. Normally, CYP2C9 inactivates warfarin. Polymorphisms lead to decreased inactivation, increased active warfarin, and potential for bleeding events.

Question 8

Genetic variation in Phase II enzymes can dramatically ___ drug elimination and ___ the risk of drug toxicities.

Answer 8

Decrease; increase

Question 9

What are the effects of decreased activity in influx pumps?

Answer 9

Reduced cellular uptake, decreased efficacy, increased potential for off-target toxicity

Question 10

What are the effects of decreased activity in efflux pumps?

Answer 10

Reduced cellular excretion, potential increased efficacy and toxicity, potential decrease in drug excretion, potential compromise of BBB

Question 11

Genetic variation in pharmacokinetic genes influence the concentration of the drug at the site of its target. Genetic variation in the direct drug target or other downstream pharmacodynamic genes can significantly influence the drug ___.

Answer 11

Response

Question 12

What is the direct target of warfarin?

Answer 12

VKORC1

Question 13

A common polymorphism in the VKORC1 promoter region (G to A) is associated with ___ expression and the need for a ___ warfarin dose.

Answer 13

Lower; lower

Question 14

Adverse drug reactions related to pharmacogenetics are typically ___.

Answer 14

Dose-dependent