Genetic Variations in Indivdiuals/Populations

Question 1

pharmacogenetics

Answer 1

study of inherited differences in drug metabolism/response

Question 2

Pharmacokinetics

Answer 2

Clearance/excretion, metabolism, etc.

How long thing is in body
(longer in body-stronger the effect)

Affected by genetic variability

Happens away from site of action

Action of drug in body of period of time

Question 3

Pharmacodynamics

Answer 3

Drug activity/interaction with downstream targets

Site of action

Question 4

Pharmacogenomics

Answer 4

using GWAS to assess the impact of an ensemble of SNPs and how they impact drug therapy

Question 5

Warfrin

Answer 5

Blood thinner/rat poison

Question 6

INR

Answer 6

Internaltionalized normalized ratio

-how quick blood clots

Question 7

Therapeutic window

Answer 7

Range of doses that help patient and do not hurt them by being excessive

Question 8

Sensitive vs Tolerant/what does it tell you?

Answer 8

Sensitive-need lower dosage to have same effect as normal

Tolerant-need higher

If know this earlier, can provide better care

Question 9

CYP

Answer 9

Cytochrome P450’s

Hemecontaining=expressed primarily in liver

56 enzymes

Detoxify/export endogenous/xenobiotic compounds

Activate drugs

Question 10

CYP role in drug metabolism

Answer 10

Accept e- from donors to catalyze a number of different rxns

Most important-addition of O to C, N, or S

Question 11

Drug metabolism phases

Answer 11

1-addition of OH group

2-Functionaliztion of OH group by sugar or acetyl group, increase solubility, allowing to be excreted

Question 12

CYP Structure

Answer 12

Heme group in middle

Beta hairpin open and allows drugs to go in, drug can then affect heme

Flap then closes to keep drug in

Also anything hydrophobic goes into the flap when open
-adaptablility if run into new toxin

Question 13

Tylenol toxicity

Answer 13

Slowly convert acetaminophen to something deadly

Too much tylenol-pushes reaction towards the toxin

Question 14

CYP functions

Answer 14

Do many chemical reactions that are not easy to do

Extremely sophisticated

Question 15

Warfarin

Answer 15

Coumadin

Used in prevention of thrombosis, embolism

Cases include heart valve prosthesis, recurrent, stroke, DVT, pulmonary emobolism

Prevents synthesis of vit K dependent clotting factors

• inhibhts vit K reductase
  - key enzyme in vitamin K recycling

Question 16

Warfarin Structure

Answer 16

Polar on right side

R form is more reactive

S bind to CYP2C9

Some oxygens above and below

LOOKS VERY SIMILAR TO VIT K (competitive inhib?)

Question 17

CYP and Warfarin

Answer 17

Modifies warfrin to increase solubility-allowing to be excreted earlier
-MORE TOLERANT

There is also mutation that makes warfarin excrete slower
-MORE SENSITIVE

Question 18

P450 variability between individiauls

Answer 18

drastically different

If one enzyme is responsible for breaking up a particular drug-makes humans very fragile

Question 19

CYP2C9 mutation

Answer 19

Mutation that makes warfarin excrete slower
-MORE SENSITIVE

Pharmacodynamic (site of action-tighter binding)
-OR IS IT KINECTIC=ACTION OF DRUG IN BODY OVER PERIOD OF TIME???

Subtle mutations can decrease dose reduction (activity of enzyme)

Mutation on both chromosomes result in even poorer metabolizer

Question 20

CYP variants classifcations and graphs of what they look lie

Answer 20

Poor-Slow, Normal=middle w/ variations, Ultrafast….

Normal (extensive)-injection, quadratic down
-only not in window when levels of drug is very low

Poor-injection, step function up after each injection
-easily out of safe therapeutic window

UF-same as normal but quadratic down is much fast
-not in therapeutic window when levels of drug very low which happens quickly

Question 21

Extensive metabolizer vs Intermeddaite, vs poor

Answer 21

all copies, 1 copy mutated, 2 copies mutated

Question 22

VKORC1

Answer 22

Vitamin K epoxide reductase
-target of warfarin

Prevents regeneration of reduced vitamin K
-necessary for carboxylation of coagulation factors

Essentially less active (oxidized) vitamin K in cell

Pharmacodynamic ??

Question 23

SNPs in VKORC1/increases in…

Answer 23

Found by GWAS

Create warfarin tolerance/sensitivty

Sensitivity increase-less drug to displace vitamin k-allele is increasing affinity of receptor for drug

Tolerance increase-reduced binding, need more drug to have binding

Question 24

Additive effect of SNP on VKORC1

Answer 24

Tolerate more drug but also more sensitive to drug

Question 25

Linkage Disequilibrum

Answer 25

Combinations of allies or genetic markers which occur more or less frequently than expected randomly

Question 26

100% SNPS=senstivity change?

Answer 26

No-environemtn plays role-maybe not enough it k or lifestyle problems

Question 27

Codeine Intoxication assocated with ultra rapid CYP2D6 metabolism

Answer 27

Found 3+ copies on CYP2D6 allele

CYP3A4-takes codeine and processes so can be cleared from body-antibiotics stopped this from occuring

Ultrarapid conversion of codeine to morphne
-acute renal failure

TREAT PAITENT AS A SYSTEM