Genetic and Genomic Considerations in Pharmacotherapeutics

Question 1

Genetic variants alter drug metabolism by

Answer 1

either reducing benefits or increasing toxicity

Question 2

Drugs with high therapeutic index, altered rates of metabolism may have ____ effect on the clinical outcome

Answer 2

little

Question 3

Dugs with low or narrow therapeutic index, small increases in drug levels can lead to ______ and small decrease can lead to _____

Answer 3

toxicity/therapeutic failure

Question 4

P450-2D6 (CYP2D6) variants

Answer 4

drug metabolism can reduce the benefits of therapy
women with inadequate CYP2D6 activity cannot convert tamoxifen to its active form therefore the drug cannot adequately protect from breast cancer

Question 5

CYP2C19 variants

Answer 5

drug metabolism can reduce the benefits of therapy
reduces benefits of clopidogrel (Plavix), a drug that prevents platelet aggregation. Patients are at increased risk of stroke, MI
People with this genetic variation should use a different antiplatelet drug

Question 6

N-acetyltransferase-2

Answer 6

drug metabolism can reduce the benefits of therapy
the enzyme that metabolizes isoniazid, Americans of European heritage metabolize isoniazid rapidly and produce 2 forms of N-acetyltransferase-2.
Dosage must be adjusted

Question 7

CYP2D6 variants

Answer 7

drug metabolism can reduce the benefits of therapy

European heritage are unable to convert codeine to morphine. Pain is not relieved.

Question 8

CYP2C9 variants

Answer 8

drug metabolism can increase drug toxicity

increased risk for toxicity from warfarin (coumadin), an anticoagulant with a narrow therapeutic index.

Question 9

TMPT variants

Answer 9

drug metabolism can increase drug toxicity
standard doses of thiopurine or mercaptopurine can accumulate at high levels posing a risk for fatal bone marrow damage
FDA recommends testing before use

Question 10

dihydropyrimidine dehydrogenase

Answer 10

drug metabolism can increase drug toxicity

poor job of metabolizing fluorouracil, a drug used to treat cancer

Question 11

Genetic variants that alter the structure of drug receptors and other target molecules and can influence drug responses

Answer 11

Beta adrenergic receptor (ADRB1)

Vitamin K epoxide reductase complex 1 (VKORC1)

Question 12

Beta adrenergic receptor (ADRB1)

Answer 12

beta receptors produced by ADRB1 variant genes respond more intensely to beta agonists, causing enhanced effects of blockade by beta antagonist. hypertension activation of these receptors may produce an exaggerated increase in blood pressure. Hypertension blockade of these receptors may produce an exaggerated decrease in blood pressure.
explains why beta blockers work better against hypertension in people with light skin

Question 13

Vitamin K epoxide reductase complex 1 (VKORC1)

Answer 13

readily inhibited by warfarin, allowing anticoagulation with a reduced warfarin dosage. FDA recommends testing before warfarin is used

Question 14

Genetic variants that affect drug targets on cancer cells and viruses

Answer 14

HER2 overexpression
EGFR expression
CCR5 tropism

Question 15

HER2 overexpression

Answer 15

Increased therapeutic effect
trastuzumab only acts against breast cancers that overexpress HER2
FDA requires positive test for HER2 overexpression before trastuzumab is used

Question 16

EGFR expression

Answer 16

Increased therapeutic effect
Cetuximab only works against colorectal cancers that express EGFR
FDA requires evidence of EGFR expression

Question 17

CCR5 tropism

Answer 17

Increased therapeutic effect
Maraviroc only acts against HIV strains that express CCR5
FDA requires evidence of CCR5 tropic strain

Question 18

Genetic variants that affect the immune system

Answer 18

HLA-B 1502

HLA-B 5

Question 19

HLA-B 1502

Answer 19

increases risk for life-threatening skin reaction in patients taking carbamazepine
Asian ancestry

Question 20

HLA-B 5

Answer 20

increases risk for fatal hypersensitivity reactions in patients taking abacavir

Question 21

Barriers to pharmacogenomics

Answer 21

lack of education

financial cost for testing

Question 22

What is needs to be done before testing?

Answer 22

obtain informed consent
educate patient on reason for testing, potential results, and options for treatment based on results
also inform that results may more received for weeks or more