Pharmacogenomics

Question 1

three types of interindividual genetic variation that can influence pharmacotherapy

Answer 1

• proteins involved in drug metabolism or transport (pharmacokinetic)
• drug targets or pathway (pharmacodynamics)
• idiosyncratic adverse drug effects

Question 2

enzymes involved in drug metabolism that display polymorphism

Answer 2

• butyrylcholinesterase (pseudocholinesterase)
• N acetyltransferase 2
• CYP2D6
• Thiopurine S-methyltransferase

Question 3

what is the function of butyrylcholinesterase

Answer 3

it metabolizes succinylcholine

Question 4

what occurs if there is a polymorphism in butyrylcholinesterase

Answer 4

-there would be a decreased rate of metabolism of succinylcholine leading to prolonged flaccid paralysis

Question 5

type of inheritance of butyrylcholinesterase

Answer 5

hereditary autosomal recessive trait

Question 6

how do you treat those with polymorphism in butyrylcholinesterase

Answer 6

you treat with continued mechanical ventilation until muscle function returns to normal

Question 7

function of N acetyltransferase 2 and the types

Answer 7

• catalyzed the acetylation of isoniazid and other drugs
• slow acetylators: metabolize isoniazid slowly and have high drug blood levels
• fast acetylators: metabolizes isoniazid fast and have low drug blood levels

Question 8

inheritance of slow acetylators

Answer 8

autosomal recessive

Question 9

adverse effects of slow acetylators

Answer 9

since it keeps drug in plasma high and longer, it causes toxicity

Question 10

examples of slow acetylators effects on drugs

Answer 10

• keeps isoniazid high in blood so lead to neuropathy and hepatotoxicity
• keeps hydralazine and procainamide high in blood leading to SLE
• keeps sulfonamides high leading to hypersensitivity, hemolytic anemia, and SLE

Question 11

function of CYP2D6

Answer 11

it is part of the CYP450 family and hence metabolizes a lot of drugs

Question 12

discuss different types of metabolizers of CYP2D6

Answer 12

• poor metabolizers: homozygous for recessive the allele leading hence low activity
• extensive metabolizers: heterozygous or homozygous for wild type allele
• ultrarapid metabolizers: multiple copies of CYP2D6 genes –> up to 13 copies

Question 13

name drugs that are metabolized by CYP2D6

Answer 13

• beta blocker metoprolol
• neuroleptic haloperidol
• opioids codeine and dextromethorphan
• antidepressants: fluoxetine, imipramine, desipramine

Question 14

what happens with poor metabolizers of CYP2D6 and give some examples

Answer 14

they suffer side effects when treated with standard doses as seen with metoprolol

or with codeine, it is ineffective since it needs to be converted by the enzyme to morphine

Question 15

what happens when you give standard doses of codeine to ultrarapid metabolizers

Answer 15

overdose on codeine –> respiratory depression or respiratory arrest

Question 16

what does thiopurine S-methyltransferase (TPMT) do

Answer 16

it methylates anti cancer drugs thiopurines 6 mercaptopurine and azathioprine which is good because they have a small therapeutic window

Question 17

what happens then if one is homozygous for the polymorphism in TPMT (thiopurine S-methyltransferase)

Answer 17

they have to be given 1/10 of the standard dose so as not to have a toxic effects of the cancer drugs

Question 18

when is EGFR (epidermal growth factor receptor) expressed

Answer 18

in non-small cell lung cancer (NCLC)

Question 19

what drugs is approved for non-small cell lung cancer and how does it work

Answer 19

Gefitinib and it is an inhibitor of tyrosine kinase on EGFR

Question 20

drug that is affected by both pharmocokinetics and pharmacodynamics

Answer 20

warfarin

Question 21

lower doses of warfarin should be considered in what types of patients

Answer 21

those with polymorphism in CYP2C9 and VKORC1

Question 22

how does racemic mixture of warfarin affects its metabolism

Answer 22

• S-warfarin is 3-5 times more potent than R-warfarin
• S-warfarin is metabolized by CYP2C9 which has a highly polymorphic gene while R-warfarin is metabolized by CYP3A4 and other CYP isoforms

Question 23

what is idiosyncratic effect a result of

Answer 23

interaction between the drug and unique aspect of the physiology of the individual patient

Question 24

condition that causes an idiosyncratic adverse effect

Answer 24

G6PD deficiency –> formation of heinz bodies (oxidized hemoglobin)

Question 25

drugs that cause oxidative stress in G6PD deficiency

Answer 25

sulfonamides antimalarials (primiquine and chloroquine) chloramphenicol

Question 26

what happens to individuals with G6PD deficiency who are exposed to drugs that cause oxidative stress

Answer 26

can cause acute hemolytic anemia