Anticoag Medchem Flashcards
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
describe the process of platelet activation/aggregation
Arachidonic acid is converted to Thromboxane A2 via COX1 which causes phospholipase C activation. Then platelet calcium levels increase causing a conformational change in glycoproteins IIb/IIIa which increases its affinity for fibrinogen leading to increased platelet aggregation
what drugs can we use to inhibit COX1 to prevent platelet aggregation? what step in specific do they block?
aspirin and sulfinpyrazone
thromboxane A2 synthesis
how does adenylate cyclase decrease platelet calcium to prevent platelet aggregation?
it converts ATP to cAMP which blocks calcium from binding to platelets
how does PDE3 increase platelet calcium to promote platelet aggregation?
converts cAMP to AMP to prevent cAMP from blocking calcium
how do the antiplatelet drugs clopidogrel and prasugrel inhibit platelet aggregation?
they bind and block the P2Y12 receptor (aka ADP receptor antagonist), an inhibitor of adenylate cyclase, to increase cAMP and inhibit platelet aggregation
how do the antiplatelet drugs dipyridamole and cilostazol inhibit platelet aggregation? when do we use these drugs?
they inhibit PDE3 to increase cAMP and inhibit platelet aggregation
to prevent thrombus formation on prosthetic heart valves
what was the first generation drug that was an ADP receptor antagonist and what was the issue with it?
ticlopidine: had GI effects and risk of neutropenia
clopidogrel is a prodrug that is metabolized to its active metabolite by?
CYP2C19 and 3A4
in regards to clopidogrel, in CYP2C19 loss-of-function carriers, what enzyme’s activity seems to be correlated with responsiveness to clopidogrel activity?
paraoxonase-1, a lactonase
what metabolizes prasugrel?
what polymorphism causes increased thrombosis?
what is it used for?
is it faster or slower than clopidogrel? more or less bleeding risk?
esterase and cyp2B6
2B6*2
preventing atherothrombotic complications in pts undergoing percutaneous coronary intervention
faster, more bleeding risk
what is ticagrelors mechanism of action?
what does it treat?\
metabolism?
a reversible inhibitor of P2Y12 receptor
acute coronary syndrome
O-deethylation
what drug class is Abciximab?
what is it used for?
GP IIb/IIIa receptor antagonist
percutaneous coronary intervention
what drug class is tirofiban?
what does it treat?
how is it administered?
what is an adverse effect?
GP IIb/IIIa receptor antagonist
unstable angina
as an injection
can cause bleeding
what drug class is eptifibatide?`
what does it treat?
how is it administered?
what is an adverse effect?
GP IIb/IIIa receptor antagonist
unstable angina and during percutaneous transluminal angioplasty
can cause bleeding
what is our bodies natural way to break up clots?
Tissue plasminogen activator activates plasminogen to plasmin which can turn an insoluble fibrin clot into soluble fibrin fragments
what drug class is streptokinase?
what is it used for?
what are the issues with it?
indirect plasminogen activator
acute pulmonary embolism, DVT, acute MI
activates antibodies, so it can’t be used for several months. it also can cause bleeding
what is Anistreplase?
what does it treat?
anisoylated plasminogen streptokinase activator complex
pulmonary embolism and DVT
what is urokinase used to treat?
pulmonary embolism and DVT
