Anticoagulants Flashcards
What are the positive feedback of Thrombin?
Thrombin activates V->Va and VIII->VIIIa, which both contribute to activating Xa or Thrombin itself.
What is an endogenous way of clot breatkdown?
Thrombomodulin activating protein C, combines with protein S to degrade factor Va and VIIIa.
Why can Heparin not be given orally?
Heparin is a long sulfated polysaccharide that is highly negative.
What is the mechanism of Heparin?
Binds to Antithrombin in one of the exosites, causing increased activity of the active site of anti-thrombin degrading activated clotting factors Xa, IXa, and Thrombin itself. The long polysaccharide helps arrange Thrombin in the active site for cleavage.
What is the different between low molecular weight heparin and regular heparin?
The low molecular weight heparin does not have the long polysaccharide tail to hep Thrombin into the binding site, so it only deactivates clotting factors. Neither lyse clots or affect synthesis of the clots.
When is heparin used?
PE/DVT, Prevention of clots prior to surgery, MI, and heart surgery. Also anti-coagulant for pregnancy.
What is a major adverse effect of heparin?
Increased chances of bleeding, and Thrombocytopenia (causing aggregation)
What are the two named Low Molecular Weight Heparins?
Enoxaparin and Dalteparin
What is the key difference between LMWH and Heparin?
LMWH does not inactivate thrombin. Typically given SubQ
When is LMWH used over Heparin?
Primarily to prevent blood clots after surgery and bridging before oral anticoagulants become effective. Has longer half life than regular heparin.
What is an inhibitor of heparin incase of overdose?
Protamine Sulfate. Positively charged, binds heparin inactivating it.
What is used as an alternative to heparin?
Lepirudin and Bivalirudin.
How do the alternatives Lepirudin and Bivalirudin work?
They are direct inhibitors of Thrombin binding in the catalytic site preventing thrombin activity. IV Only.
What is an indirect inhibitor of Thrombin?
Fondaparinux. Used to prevent clots after joint surgeries and treatment of PE/DVT.
When is Fondaparinux beneficial over Heparin?
Is used as an alternative to Heparin when the patient has had thrombocytopenia before in the past, since there is a lower risk using Fondaparinux.
How does Fondaparinux work?
Indirect inhibitor of Thrombin by inhibiting Xa, which prevents any further production of Thrombin.
What enzyme does Warfarin inhibit?
Vitamin K Reductase - VKORC1, prevents reduction of vitamin K.
Why is reduced Vitamin K important?
Vitamin K is a co-factor required to activate II, VII, IX, and X via gamma-glutamyl carboxylase, if it is not in the reduced form, then the clotting factors are not activated.
What is the active form of Warfarin and how is it broken down?
S-Warfarin is primarily active and is metabolized by CYP2C9
Why does Warfarin take several days to take full effect and how is it monitored?
Due to the activated clotting factors taking time to degrade since they are unaffected by warfarin. Also takes the body time to use up all the reduced Vit K that was already produced. INR/PTT is used to monitor.
What can change levels of Warfarin in the body?
Polymorphisms of CYP2C9 and VKORC1. Dietary changes in Vitamin K.
What are adverse side effects of Warfarin?
Increased risk of bleeding, Purple toe syndrome, and gangrene/necrosis due to clots in microvasculature.
How do you reverse warfarin if there is an overdose?
Vitamin K infusion to out compete with the warfarin or FFP
What is Warfarin used therapeutically?
Thrombus prevention due to Afib, artificial heart valve, cardiomyopathy. Long term treatment of DVT.
How does Dabigatron work?
Binds in the active site of Thrombin both in free thrombin and fibrin-bound thrombin. Does not change PT/INR, no monitoring needed.
What can influence levels of Dabigatron?
Changes in Pgp, which pump Dabigatron into the lumen of the intestines. Verapamil can inhibit Pgp causing increased Dabigatron concentrations.
How is warfarin different from Dabigatron?
Concentration peak is 2 hours with a short half-life, causing effects the same day. Shown to have lower risk of bleeding events, except in the GI, and lower mortality comparably.
What are common uses of Dabigatron?
Thrombus prevention in Afib and prophylaxis with joint surgeries. (Not good with abnormal valves)
What drug is used for Xa inhibition?
Rivaroxaban. Inhibits Xa both free and bound in the clot complex, preventing Thrombin from being produced.
How is Rivaroxaban metabolized?
Primarily efflux by Pgp. Rivaroxaban has rapid onset and long half-life, excreted in both liver and kidney.
How does Rivaroxaban compare to Warfarin?
Causes less ICH and critical bleedings and just as good at preventing thrombus. Doesn’t need to be monitored.
Compare advantages of new drugs to Warfarin?
Fast onset without bridging needed, less interactions with food/drugs, no need to monitor levels due to being predictable, and lower risk of bleeding complications.
Disadvantages of the new anti-coagulants compared to Warfarin?
Limited by kidney disease, More expensive, missed doses are more detrimental, No antidote, and unable to monitor levels.
