Pharmacogenetics

Question 1

Pharmacogenetics is

Answer 1

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

Question 2

Pharmacogenomics, the genomic approach to _______, is concerned with _______

Answer 2

genomic approach to pharmacogenetics;

the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy.

Question 3

Pharmacokinetics:

Answer 3

the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites.

Question 4

Pharmacodynamics:

Answer 4

the response of the drug binding to its targets and downstream targets, such as receptors, enzymes, or metabolic pathways

Question 5

pharmacokinetics is concerned with _______ and pharmacodynamics is concerned with _______

Answer 5

• whether or how much drug reaches the target(s)

- what happens when the drug successfully reaches its target

Question 6

both phenomenon occur simultaneously in the race between drug effect (_______) and removal (_______).

Answer 6

dynamics

kinetics

Question 7

two basic ways that drugs are metabolized through biotransformations:

Answer 7

• Phase I (simplified): attach a polar group onto the compound to make it more soluble; usually a hydroxylation step
• Phase II (simplified): attach a sugar/acetyl group to detoxify the drug and make it easier to excrete

Question 8

The cytochrome P450 (CYP450) genes encode important enzymes that are

Answer 8

very active in the liver and to a lesser extent in the epithelium of the small intestine

Question 9

CYP450 genes

Answer 9

• The CYP families
• CYP3A4
• There is wide genetic polymorphic variation with phenotypic consequences in the CYP families of genes, which is why they are so important to prescribing physicians.

Question 10

CYP families

Answer 10

The CYP families (CYP1, CYP2, CYP3) are particularly active including six genes (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) that are involved in the Phase I metabolism of ~90% of all commonly used medications, and CYP3A4 itself takes part in the metabolism of over 40% of all drugs used in clinical medicine.

Question 11

While most CYP genes are important in the rate of inactivation of a drug, in some cases the CYP gene(s) is required to activate a drug. The classic example of this is _______ activity being necessary to convert codeine (inactive, almost no analgesic effect) to morphine (active with a potent analgesic effect).

Answer 11

CYP2D6

Question 12

Frameshift

Answer 12

alter reading frame –> NO ACTIVITY

Question 13

Splicing

Answer 13

skip exons and/or alter reading frame –> NO ACTIVITY

Question 14

Missense

Answer 14

alter protein function –> usually REDUCED ACTIVITY

Question 15

Copy number alleles

Answer 15

increased gene copy alleles –> INCREASED (‘ULTRAFAST)

Question 16

Based on the combinations (since individuals have 2 alleles in their genotypes) have 3 major phenotypes: _______, _______, and _______

Answer 16

normal, poor (includes null alleles), and ultrarapid/ultrafast

Question 17

drinking grapefruit juice while taking felodipine for hypertension can lead to significant hypotension due to

Answer 17

• significant hypotension
• potentiation of the felodipine effect since CYP3A activity is reduced and metabolism/elimination of felodipine is similarly slowed

Question 18

Dosage of the immunosuppressive drug _______ (used in kidney transplants for instance) must be reduced by 75% to avoid toxicity when the antifungal _______ is added to treat a fungal infection

Answer 18

cyclosporine

ketoconazole

Question 19

ketoconazole temporarily inhibits _______ which leads to raised levels of _______ which can be _______.

Answer 19

CYP3A metabolism
cyclosporine
neprotoxic

Question 20

Renal transplant patient who is exposed to tuberculosis and requires rifampin prophylaxis: In this case, the dose of cyclosporine must be _______ since rifampin is a _______ and leads to more _______

Answer 20

• increased
• CYP3 inducer
• more rapid metabolism and elimination of cyclosporine

Question 21

CYP3A

Answer 21

Cyclosporine (substrate),
ketoconazole (inhibitor), rifampin (inducer), grapefruit juice (inhibitor) [here more relevance of environmental factors than specific genotypes]

Question 22

CYP2D6

Answer 22

tricyclic antidepressants, quinidine, fluozetine, paroxetine and codeine-remember CPY2D6 is needed to activate codeine into morphine

Question 23

CYP2C9 + VKORC1

Answer 23

warfarin (blood thinner)

Question 24

NAT

Answer 24

Isoniazid for TB

Question 25

TPMT

Answer 25

6-mercaptopurine/6-thiguanine and childhood ALL (leukemia) | ***often presented as the classic example of a pharmocogenetic mechanism that can be fatal if ignored

Question 26

G6PD

Answer 26

X linked enzyme | Chemolytic anemia after sulfa drugs or maybe dapsone