Anticoag Medchem Flashcards
(42 cards)
how is a fibrin clot formed?
a protease converting an inactive precursor protein (zymogen) into another catalytically-active protease
describe the process of turning the inactive Factor X into an insoluble fibrin clot
Factor X (inactive) is activated by the tissue factor pathway and the contact activation pathway which are vitamin K dependent to become Factor Xa (active). Factor Xa then activates Prothrombin (Factor II, inactive) to Thrombin (Factor IIa, active) which is also vitamin K dependent. Factor IIa then activates Fibrinogen to Fibrin. Fibrin Stabilizing Factor (Factor XIIIa) then activates Fibrin to a fibrin clot
what is the mechanism of vitamin K-dependent clotting factor activation? where does warfarin interfere?
Vitamin K epoxide is reduced by Vitamin K oxido-reductase (VKOR) into reduced vitamin K. This reduced vitamin K is used by vitamin k-dependent carboxylate to activate prothrombin to thrombin.
warfarin blocks VKOR which will ultimately block the process of forming a fibrin clot
warfarin is converted to 7-hydroxywarfarin via which enzyme?
CYP2C19
why does warfarin have slow onset?
functional coagulation cofactors are not affected by warfarin, so normal protein catabolism slowly breaks them down
for warfarin: normal genotype is cyp2C91/1. how do the following mutations affect warfarin dosing?
CYP2C92/1
CYP2C93/1
CYP2C93/3
CYP2C92/1: 19% lower dose
CYP2C93/1: 34% lower dose
CYP2C93/3: 78% lower dose
Tecarfarin is a prodrug that functions similarly to warfarin. It is converted to it’s active metabolite via?
esterase
dabigatran etexilate (pradaxa) is a prodrug converted to dabigatran via?
what is it mainly used for?
esterase
preventing VTE after knee or hip surgery
which factor IIa inhibitor was taken off the market due to concerns over potential liver toxicity?
ximelagatran (Exanta)
what routes of metabolism does Rivaroxaban (Xarelto) have?
what is it used for?
which drugs are strong inducers of cyp3A4 that we need to use caution for?
Cyp3A4 and oxidation
prevention of VTE after knee or hip surgery
rifampicin and phenytoin
what is apixaban (eliquis) used for?
prevention of VTE after knee or hip surgery, and reducing the risk of stroke and systemic embolism in pts with afib
what is edoxaban (savaysa) used for?
afib, DVT, and pulmonary embolism
what is betrixaban (bevyxxa) used for?
reversal agent for inhibiting Xa drugs causing bleeding or when emergency surgery is required
what is the structuring of heparin?
a large polysaccharide chain of alternating D-glucuronic acid and N-Ac-D-glucosamine units. It is heavily O- and N-sulfated
Heparin is considered a key pentasaccharide that’s recognized by?
antithrombin III
why is heparin no longer isolated from bovine lung?
what is it isolated from instead?
how can it be administered?
due to bovine spongiform encepalopathy aka mad cow disease
porcine
IV or SC
what is heparins mechanism of action?
heparin binds to antithrombin III and induces a conformational change to ATIII that promotes binding to thrombin. Thrombin then binds to the heparin ATIII complex which inactivates the thrombin. the thrombin ATIII complex is released from heparin and it can bind again
what is low molecular weight heparins mechanism of action?
ATIII binds to LMWH and induces a conformational change. Factor Xa then binds to ATIII and becomes inactivated. the Xa ATIII complex is released and LMWH can bind again
how is fondaparinux sodium different from heparins and LMWH?
it is more selective for inhibiting factor Xa. it is more effective in preventing VTE after surgery
Idrabiotaparinux is a derivative of fondaparinux, what is its main advantage?
it is easily suppressed with IV administration of avidin
what are the SEs of heparin?
heparin induced thrombocytopenia (HIT) which is divided into 2 types:
HIT type I is a non-immunologic response to heparin which causes transient thrombocytopenia but little increase in thrombosis risk
HIT type II results in formation of antibodies that activate platelets. its a main complex of heparin with platelet factor 4 causing thrombocytopenia and excessive thrombin generation with increased risk of thrombosis. this requires immediate stopping of heparin use and administration of a direct thrombin inhibitor
if a patient hemorrhages from using heparin, what do we use to inactivate it?
protamine sulfate
what is lepirudin?
a recombinant hirudin that works as a direct thrombin inhibitor that does not require antithrombin III
what is argatroban?
what metabolizes it?
how is it administered?
a reversible direct thrombin inhibitor for prophylaxis and treatment of thrombosis in pts with HIT
Cyp3A4
IV or SC
