Pharmacogenetiocs

Question 1

What are the three types of interindividual genetic variation that can influence pharmacotherapy?

Answer 1

• variation in drug metabolism or transport (pharmacokinetic)
• variation in drug targets (pharmacodynamics)
• variation associated with idiosyncratic adverse drug effects

Question 2

NAT-2 catalyzes ____________ which activates/deactivates __________

Answer 2

Acetylation of isoniazid an antimycobacterial agent;

Deactivates isoniazid

Question 3

Slow/fast acetylators will have high levels of blood drug levels
Mode of inheritance?

Answer 3

Slow; slow acetylators are homozygous recessive

Question 4

Examples of drugs that slow acetylators are at risk for toxicity:

Answer 4

Isoniazid
Hydralazine and procainamide
Sulfonamides

Question 5

Adverse effects of isoniazid toxicity

Answer 5

Neuropathy and hepatotoxicity

Question 6

Adverse effects of hydralazine and procainamide toxicity

Answer 6

SLE

Question 7

Adverse effects of sulfonamide toxicity

Answer 7

HS reactions, hemolytic anemia and SLE

Question 8

Patients with genetic variations in butyrlcholinesterase have decreased rate of _______________

Answer 8

Metabolism of succinylcholine resulting in prolonged paralysis

Question 9

Hereditary mode of transmission of BCHE gene

Answer 9

Autosomal recessive

Question 10

What kind of drugs and specific ones are metabolized by CYP2D6

Answer 10

Antidepressants: fluoxetine, imipramine, desipramine
antiarrhythmics: metoprolol (β adrenergic blocker)
analgesics: codeine and dextromethorphan
Antipsychotics: haloperidol

Question 11

What are the 3 different types of metabolizers of CYP2D6 and the hereditary form of each

Answer 11

Poor metabolizers: homozygous recessive
Extensive metabolizers: homozygous wild or heterozygous
Ultra rapid metabolizers: have multiple copies of the gene

Question 12

Poor metabolizers of CYP2D6 are at risk for adverse effects when taking _________

Answer 12

Metroprolol (β adrenergic blocker) because it stays in the system for longer so need to give a smaller dose

Question 13

Ultra rapid metabolizers of CYP2D6 are at more risk for adverse effects when taking ________

Answer 13

Codeine because when it is metabolized it is converted to morphine → at risk for respiratory arrest

Question 14

Function of thiopurine S- Methyltransferase

Answer 14

Catalyzes the S- methylation and thus inactivation of anticancer thiopurines:
6- mercaptopurine
Azathiprine

Question 15

What are patients with low TPMT activity at risk for when taking thiopurines

Answer 15

Myelosuppression; these patients are homozygous recessive

Question 16

_________ is often overexpressed in NSLC (non small cell lung cancer)

Answer 16

EGFR (a tyrosine kinase receptor) aka epidermal growth factor receptor

Question 17

_______ inhibits the ______________ kinase of EGFR

Answer 17

Gefitinib; tyrosine

Used to treat NSLC

Question 18

Patients with what mutation respond better to gefitinib

Answer 18

Those with a mutation in the ATP binding site of the tyrosine kinase domain of the EGFR

Question 19

What is the molecular target of warfarin and use?

Answer 19

Targets vitamin K epoxide reductase which supplies reduced vitamin K for the enzyme gamma glutamyl carboxylase which produces clotting factor
Warfarin is an anti-coagulant

Question 20

Pharmacokinetic variation in warfarin

Answer 20

There are 2 enantiomers of warfarin: S-warfarin is more potent and is mainly metabolized by CYP2C9 while R-warfarin is metabolized by others like CYP3A4 and other isoforms

Question 21

Explain the importance of genetic variation in the CYP2C9 gene

Answer 21

CYP2C9 is what metabolizes S-enantiomer of warfarin;

Those with variant Allen require ↓ doses of warfarin

Question 22

Explain the pharmacodynamic component of warfarin

Answer 22

The gene that encodes for the target enzyme Vit K epoxide reductase is called VKORC1 and has a number of polymorphisms that affect therapeutic warfarin dose

Question 23

What metabolizes the S enantiomer of warfarin?

Answer 23

CYP2C9

Question 24

Drugs that cause oxidative stress:

Answer 24

Sulfonamides, antimalarials (primaquine and chloroquine) and chloramphenicol