CHEST-2012 Oral Anticoagulants Flashcards
MOA of anticoagulant effect of Vitamin K Antagonists
Interfere with the cyclic interconversion of Vitamin K via enzyme Vit K epoxide reductase (VKOR) –> decreases formation of coagulation factors II, VII, IX, X
VKAs produce their anticoagulant effect by interfering
with the cyclic interconversion of vitamin K
and its 2,3 epoxide (vitamin K epoxide), thereby
modulating the g -carboxylation of glutamate residues
(Gla) on the N-terminal regions of vitamin K-dependent
proteins ( Fig 1 ). 1-8 The vitamin K-dependent coagulation
factors II, VII, IX, and X require g -carboxylation
for their procoagulant activity, and treatment with
VKAs results in the hepatic production of partially
carboxylated and decarboxylated proteins with reduced
coagulant activity. 9,10 Carboxylation is required for a
calcium-dependent conformational change in coagulation
proteins 11-13 that promotes binding to cofactors
on phospholipid surfaces.
MOA of procoagulant effect of VKA
VKAs inhibit carboxylation of the regulatory anticoagulant proteins C, S
Transient procoagulant effect caused when baseline anticoag protein C and protein S levels are reduced before the other procoag factors are decreased
Peak warfarin drug level after oral administration
90 minutes after administration
Half-life of racemic warfarin
36-42hr half-life
Which warfarin enantiomer is more potent?
S-enantiomer (about 3-4 times more potent than R)
Genetic mutations of which CYP enzyme has most interactions with warfarin metabolism
CYP2C9 (most mutations result is reduced S-warfarin clearance –> prolongs half-life of S enantiomer)
Genetic mutations of — can lead to increased warfarin resistance
VKORC1. Mutations on this gene lead to decreased warfarin effects on the Vitamin K cycle, so higher doses will be required to achieve goal INR
Why is the PT test used to monitor VKA therapy?
PT responds to changes in 3 of the 4 factors reduced by warfarin (II, VII, and X)
PT measured in the first few days of therapy represents a reduction of which clotting factor?
Factor VII (half-life is only 6 hours)
Half-life of factor II is 60 hours
Half-life of factor X is 48-72 hours
Formula for INR calculation
INR = (patient’s PT/mean normal PT)^ISI of thromboplastin
Effect of gender on warfarin dosing
Generally women need less warfarin to maintain INR than men at equivalent age
Effect of physical activity on warfarin dosing
Increased physical activity can decrease warfarin’s anticoag effect –> require more warfarin to maintain INR
How does POC INR testing work
POC monitor measures thromboplastin-mediated clotting time, and microprocess converts the time into a PT/INR result
Uses capillary blood or venous blood
Time of effect of Vitamin K
Begins at 2 hours after administration, INR correction within 24 hours
Dose equivalent of IV vs oral Vitamin K at 24 hours
Effect on INR of 5mg oral = 1mg IV vitamin K at 24 hours
