Genetic Variations in Indivdiuals/Populations Flashcards
pharmacogenetics
study of inherited differences in drug metabolism/response
Pharmacokinetics
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
Pharmacodynamics
Drug activity/interaction with downstream targets
Site of action
Pharmacogenomics
using GWAS to assess the impact of an ensemble of SNPs and how they impact drug therapy
Warfrin
Blood thinner/rat poison
INR
Internaltionalized normalized ratio
-how quick blood clots
Therapeutic window
Range of doses that help patient and do not hurt them by being excessive
Sensitive vs Tolerant/what does it tell you?
Sensitive-need lower dosage to have same effect as normal
Tolerant-need higher
If know this earlier, can provide better care
CYP
Cytochrome P450’s
Hemecontaining=expressed primarily in liver
56 enzymes
Detoxify/export endogenous/xenobiotic compounds
Activate drugs
CYP role in drug metabolism
Accept e- from donors to catalyze a number of different rxns
Most important-addition of O to C, N, or S
Drug metabolism phases
1-addition of OH group
2-Functionaliztion of OH group by sugar or acetyl group, increase solubility, allowing to be excreted
CYP Structure
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
Tylenol toxicity
Slowly convert acetaminophen to something deadly
Too much tylenol-pushes reaction towards the toxin
CYP functions
Do many chemical reactions that are not easy to do
Extremely sophisticated
Warfarin
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
Warfarin Structure
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?)
CYP and Warfarin
Modifies warfrin to increase solubility-allowing to be excreted earlier
-MORE TOLERANT
There is also mutation that makes warfarin excrete slower
-MORE SENSITIVE
P450 variability between individiauls
drastically different
If one enzyme is responsible for breaking up a particular drug-makes humans very fragile
CYP2C9 mutation
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
CYP variants classifcations and graphs of what they look lie
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
Extensive metabolizer vs Intermeddaite, vs poor
all copies, 1 copy mutated, 2 copies mutated
VKORC1
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 ??
SNPs in VKORC1/increases in…
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
Additive effect of SNP on VKORC1
Tolerate more drug but also more sensitive to drug
Linkage Disequilibrum
Combinations of allies or genetic markers which occur more or less frequently than expected randomly
100% SNPS=senstivity change?
No-environemtn plays role-maybe not enough it k or lifestyle problems
Codeine Intoxication assocated with ultra rapid CYP2D6 metabolism
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
