PG Flashcards
Her2+ gene treatment?
Trastuzumab or herceptin
treatment of oncogene V600E BRaf melanoma?
vemurafenib
treatment of myelogenous leukaemia
gleevec or imatinab
is haemophilia a simple disease and what does it affect?
simple genetic disease only affecting on gene - Factor 8 decrease in co-ag cascade
whats the gene that causes late onset alzhiemers called?
apolipoprotein E
how many variants of apolipoprotein?
E2,E3,E4
How much of a risk do you have to develop alzhiemers if you have one parent with E4 variant
4x
how much of a risk do you have of developing late onset alzheimers if you have both parents with the E4 variant
10x
difference between the variant (alleles) E4 and E2 apolipoprotein genes
E2 decreases risk of Azmrs
E4 increases risk of Azmrs
How are the variants caused?
SINGLE NUCLEOTIDE POLYMORPHISM
which genes that code for cytochrome p450 enzymes help treatment with warfarin? (anticoagulant)
CYP2C9
VKORC1 (vitamin k reductase)
which cytochrome p40 enzyme gene codes for anti-platelet drugs? and what are antiplatelet drugs called?
CYP2C19
and clopidogrels
what is the main component of coagulation?
fibrin
fluid converted into gel/like fibrin mixture
fibrous network/wall is responsible for what?
- trapping and stopping microorganisms from entering the body
- stopping bleeding by forming platelet plug
- forming a bases for initiation of repair
What are co-agulation factors
plasma proteins that are inactive in the liver but become active once they are faced with vessel injury which causes them to undergo proteolytic cleavage - become active
phospholipids
found on the membrane of the platelets which are ACTIVATED
calcium ions
help coagulation factors to be activated
what does thrombin (factor 2 produce)
fibrinogen is activated (soluble) which is converted to fibrin (insoluble)
describe extrinsic pathway of coagulation
Factor 3 is converted into factor 3a
then factor 7 is converted into 7a which activates factor 10a from factor 10
then thrombin is activated (2a)
thrombin causes fibrinogen to be converted into fibrin
factor 13 causes the formation of fibrin polymer
describe the intrinsic pathway of coagulation
factor 12 into 12 a then 11 into 11a then causes 9 into 9 a which causes 8 into 8a
8a and 9a activate 10a from 10
causes thrombin to be activated (factor 2 to 2a)
causes thrombin to cause fibrinogen to convert into fibrin
factor 13 a causes fibrin polymer to be formed
intrinsic pathway caused by:
exposure to endothelial collegen
extrinsic pathway caused by
exposure to tissue factor (released during injury)
extrinsic occurs first
what is deep vein thrombosis?
venous thrombosis
thrombus formed in deep veins such as legs due to sluggish flow - this causes clots to form
this causes the venous thromboembolism to bud off into pulmonary ciruculation and block pulonary artery
treatment for deep vein thrombosis
anticoagulants such as warfarin
what is arterial thrombosis?
diseases associated?
platelets start to aggregate and form clots in the arteries which may cause myocardial infarction and ischaemic stroke
treatment of arterial thrombosis
anticoagulants long term/prophylaxis
fribrinolytics - clot busters (short term)
which four diseases does warfarin treat
DVT pulmonary embolisms arterial fibrillation heart valve receivers and can be used as aprophylactic drug (days before opperation)
whats a narrow therapeutic range
small changes in the dose can cause major changes so have to administer dose carefully
side effects of warfarin
haemorrhage and bleeding
what does vitamin K? reductase do?
VKR is cofactor for GGCX (gamma glutamyl carboxylase)
which activates factor 2,7,9 and 10 by binding calcium
what does warfarin do to vitamin k reductase
acts as an antagonist - inhibits it
inhibiting doesnt allow it to co-factor for GGCX which prevents activation of factor 2,7,9 and 10 by calcium binding not happening
DECREASES COAGULATION
dosing depends on what?
genetics, weight, other medications and diseases and diet
which enzymes cause variability in pharmacokinetics of warfarin?
CYP2C9(liver enzyme) and VKORC1 (site of warfarin action - antagonist)
what are the two stereoisomers of warfarin?
R and S at chiral centre 9
S is 5x more effective at breaking down cytocrhome p450 in the liver to produce metabolites
what metabolites of CYP2C9 are formed?
6 and 7 hydroxy metabolites
which variant of CYP2C9 is more effective?
variant 3
what causes the variant CYP2C9 2
arginine replaced with cystine at 144 position
what causes variant cyp2c9 3
isoleucine replaced with leucine at 359 position
warfarin dose in lower in patients with what phenotype? a. TT b.CC c.CT why?
a.TT because people with this genotype have a rare recessive bleeding disorder (deficiency of vitamin K reductase)
affected in INTRON 1
Highest sensitivity to dosage?
variant 3 (more effective breakdown)
highest resistance to warfarin?
VKORC1 - coding region cause warfarin resistance
which ethnicity has more CYP2C9 3 and 2?
caucasians more than asians and africans
which ethnicty has more noncoding (C) VKORC1?
asians
which ethnicity has more coding TVKROC1?
cacasians more than africans
whats the function first approach or genomic first approach?
genes should be analysed first before drug administration to find the best match of drug to suit the variations in each individual
why percision medicine now?
we have the human genome project
we have better technologies (biomed analysis) now
we have better datasets to record information in
ethical and legal issues with percision medicine
confidentiality of genetic info
fairness (insurance, employers)
- psychological impact
- reproductive use (having kids)
- clinical issues (doctors need to know how to handle patient - quality control)
- uncertanities with complex diseases (just cause you have succeptibility doesnt mean you have disease)
-expensive
