Lecture 4 - Drug Individualization Flashcards

Question

types of genetic variations and enzymatic activity ( phenotypes)

Answer 1

extensive metabolizers, poor metabolizer, intermediate metabolizer, ultra rapid metabolizer

Answer 2

(EM or WT) - individuals who are homozygous for the two alleles coding for "normal" enzyme function ("normal" is middle of everyone)

Answer 3

PM - individuals who are homozygous with two variant alleles resting in inactive or absent enzymes (cant metabolize- reduced or none) *has certain enzymes

Answer 4

IM those who are heterozygous manifest phenotype with reduced function of the heterozygous EM (low but not too low)

Answer 5

unstable enzyme formation and decreased metabolism of the parents drug normal metabolism of the parent drug altered metabolism and this formation of other metabolites

Answer 6

UM - resulted from gene duplication or multiplication

Answer 7

*1 is normal- functioning enzyme, person able to metabolize well *2, 3+ is not normal and requires to be looked into if a person has a gene deletion, they have no mRNA to make a specific enzyme and therefore will not have the enzyme to break down specific drug so... you wont give the person that drug because if with the gene for it they don't have the enzyme to metabolize it ( if a person has *2N you need to determine if its n=toxic or not- they have two copies of the same gene meaning ultra metabolism so you may want to decrease the dose or not use a drug

Answer 8

creates no mRNA so no specific enzyme is produced leading to inability to metabolize

Answer 9

could have mRNA that doesn't code for a protein- leading to no metabolism could have a unstable enzyme made by mRNA- leading to decreased metabolism of parent drug could have- normal enzyme made leading to normal metabolism of parent drug could have altered substrate specificity leading to other metabolites

Answer 10

ATP binding cascade

Answer 11

(more common- and you want to know this before prescribing a drug) ABC-----> ABCB------> MDR1------> reduced expression-------->higher drug plasma level (eg digoxin) -------> C1236T, C3435T, G2677T/A ( so with digoxin, the levels in the plasma rise to more than what you think you are prescribing)

Answer 12

Multidrug Resistance 1 it is drug sensitivity as a result of a genetic variant that can cause severe or life threatening complications after taking particular medication and specific doses

Answer 13

(example in breast tissue) - it is metabolized before it can act - enzyme TAM can act then CYP2D6 enzyme acts (hydrolyzes) and turn it into its active form of endoxifen ( or CY first then different enzyme works to demethylate) - drug must be demethylated (by other enzymes working behind CYP2D6), and hydrolyzed (CYP2D6) before it is in its active form -CYP2D6- common to be mutated in people (CYP2C9 is the mutation)

Answer 14

overall recurrence rate - EM: 14.9% -IM 20.9% ***- PM 29% All cause mortality rates -EM:14.9% -IM: 18% ***- PM: 22.8%

Answer 15

aromatase inhibitors - blocks aromatase enzyme (converts androgen into estrogen) - anastrazole - letrozole

Answer 16

initial dose: - initial dose (2-10mg) based on medical need and factors that will alter the PK or PD of warfarin like OTC products, green leafy, cranberry juice, etc (must check with patient) maintenance dose: adjust the maintenance dose by X% up or down based on INR (internationalized normalized ratio- how fast it takes blood to clot based on blood test): caution about factors that will alter the PK and PD of warfarin, OTC products, green leafy, cranberry juice, etc

Answer 17

S-warfarin is more potent than R- warfarin (more active in stopping coagulation) VKOR enzyme is a vitamin K opoxide reductase that reduced vitamin K is needed to start the pathway (factors that work together for blood clotting) and then will stay in the bod as the active form activation = coagulation -->warfarin blocks the VKOR enzyme from activating these factors that cause coagulation

Answer 18

more sensitive- should recieve lower dose

Answer 19

least active, least sensitive, needs more dose

Answer 20

poor metabolizer

Answer 21

( so these are the pathways that activate warfarin then block the pathway enzyme that causes coagulation) GG allele- needs 5-7mg if *1/*1 or *1/*2 but if patient is *2/*3 they can only handle 3-4 mg or *3/*3 ( worst) then they can only handle .5-2 mg so if they are given the "normal" dose they will have excessive bleeding which is not what we want

Answer 22

(example of PGX application) Medication = Irinotecan Genetic variant/marker = UGT1A1*28 Effect = Neutropenia

Answer 23

(example of PGX application) Medication= Codeine (prodrug) Genetic Variant/Marker = CYP2D6 Effect = PM- no analgesic effect UM- respiratory depression the genetic marker demethylates and removes hydroxylate making it into morphine essentially

Answer 24

codeine is prodrug of morhpine- codeine ha a hydroxyl group on aromatic ring morphine has a hydroxyl by itself

Answer 25

Medication= clopidogrel (prodrug) Genetic variant/ marker = CYP2C19 (low C19 means no activation so no drug activity) Effect= PM- no drug activity

Answer 26

Process by which information from DNA strand, is coupled into a new mRNA molecule

Answer 27

Process by which a cell makes proteins, using the genetic information carried in mRNA