Anticoagulants Flashcards
What are the four broad classes of anticoagulants?
Heparin/LMWH/Fondaparinux, Warfarin, Direct Factor X Inhibitors, Thrombin Inhibitors
Mechanism of unfractionated Heparin
Binds and activates antithrombin III, which degrades factor II, IX, X. Unfractionated heparin also has a binding site for thrombin (factor II), bringing it in close proximity with antithrombin III to allow for effective degradation.
Molecular structure of unfractionated Heparin
A glycosaminoglycan (GAG) consisting of 30-50 monosaccharide units. Has a 5-saccharide binding site for antithrombin III as well as a separate binding site for thrombin.
Administration and monitoring of Heparin
IV or subcutaneous administration. Monitored using aPTT since the factors inhibited by Heparin are part of the intrinsic pathway.
Clinical uses of Heparin
Prevention of clotting during CV intervention/surgery and in patients with heart valves, treatment of very severe/acute thrombosis, dialysis, extracorporeal membrane oxygenation (ECMO, aka life support).
CAD/IHD: Inpatient (acute, stop clot formation)
Mechanism of LMWH
Binds and activates antithrombin III, but cannot bind thrombin as well. Antithrombin III thus can only inhibit factor X, resulting in lower anti-clotting activity than unfractionated Heparin
Molecular structure of LMWH
A glycosaminoglycan (GAG) consisting of <20 monosaccharide units. Has a 5-saccharide binding site for antithrombin III
Administration and monitoring of LMWH
Subcutaneous administration. 0.1-0.3 units for prophylaxis and 1.0-2.0 units for treatment. Drug monitoring is not needed since LMWH has lower activity than Heparin (thus a higher therapeutic index).
Clinical uses of LMWH
Treatment of thrombolytic diseases, prophylaxis post-surgery to prevent clotting, prophylaxis and treatment of acute venous thromboembolism (AVT, includes DVT and PE)
CAD/IHD: Inpatient (acute, stop clot formation)
What are the pros/cons of using Heparin vs LMWH and Fondaparinux?
Heparin has higher actvity than LMWH and fondaparinux. Heparin also has a shorter half life, meaning that its effects will quickly be stopped upon cessation. As a result, heparin is more useful in acute settings, and is usually used during surgical operations and in in-patient settings. The longer half-life of LMWH and fondaparinux is more useful in out-patient settings, where it can be used to treat chronic illnesses and for prophylaxis.
Mechanism and Molecular Structure of Fondaparinux
Fondaparinux is the isolated 5-saccharide binding site of unfractionated Heparin. Thus, it can only bind antithrombin III and only has anti-factor X activity. However, the small size of the molecule allows it to have an extremely long half-life.
Administration and monitoring of Fondaparinux
Subcutaneous administration. Drug monitoring is not needed since Fondaparinux has lower activity than Heparin (thus a higher therapeutic index).
Clinical uses of Fondaparinux
Treatment of thrombolytic diseases, prophylaxis post-surgery to prevent clotting, prophylaxis and treatment of acute venous thromboembolism (AVT, includes DVT and PE)
CAD/IHD: Inpatient
Mechanism of Warfarin (Coumadin)
Inhibits Vit K reductase, which normally reduces Vit K epoxide to reduced Vit K. Reduced Vit K is converted to Vit K epoxide during gamma-carboxylation of factor II, IX, X, VII. Thus, inhibition of Vit K reductase prevents the proper function of these clotting factors.
Clinical uses of Warfarin (Coumadin)
Prevent thromboembolism in patients with Afib or prosthetic valves, treat recurring venous thromboembolism (VT), long term anti-coagulation treatment
CAD/IHD: Outpatient
Administration and monitoring of Warfarin (Coumadin)
Oral or intravenous administration. Requires drug monitoring via prothrombin time (PT, goal of INR 2-3) due to its low therapeutic index. PT is used since Warfarin inhibits extrinsic pathway factors, including factor VII.
Pharmacokinetics of Warfarin (Coumadin)
Good GI absorption, long half life. Takes 3-5 days before effect is seen. Low therapeutic index. Metabolized by CYP2C9. Inhibits a protein made from VKORC1 gene.
Mechanism of direct Factor Xa inhibitors
Directly bind and inhibit activated Factor X
Naming of direct Factor Xa inhibitors
-xaban suffix (apixaban, rivaroxaban, edoxaban, betrixaban)
Clinical uses of direct Factor Xa inhibitors
Prevention of thromboembolism in patients with Afib (EXCEPT betrixaban), prophylaxis for patients that have undergone surgical procedures, treatment of venous thromboembolism
CAD/IHD: Inpatient
Administration and monitoring of direct Factor Xa inhibitors
Oral administration. No monitoring required.
Pros/cons of Warfarin vs. direct Factor Xa inhibitors
Factor Xa inhibitors do not require monitoring, have a much faster onset/offset, have no effect on diet, have fewer drug-drug interactions, and have fewer instances of intracranial bleeding. However, Warfarin is much cheaper.
Mechanism of Thrombin Inhibitors
All three drugs bind and inhibit the catalytic site of thrombin. Bivalirudin also blocks the fibrinogen binding site on thrombin.
Naming of Thrombin Inhibitors
Dabigatran, Bivalirudin, Argatroban
Administration and monitoring of Thrombin inhibitors
Oral administration for Dabigatran. IV administration for Bivalirudin and Argatroban. Argatroban requires monitoring via aPTT. Bivalirudin has a super short half-life (25 min).
Clinical uses of Thrombin inhibitors
Dabigatran: prevent thromboembolism in patients with Afib, prophylaxis after surgery, treatment of venous thromboembolism; CAD/IHD: Outpatient
Bivalirudin: prevent clotting during angioplasty
Argatroban: used as backup in patients with Heparin Induced Thrombocytopenia (HIT)
What is an adverse effect that is common to all anticoagulant medications?
Bleeding.
Which anticoagulants are safe in pregnant women? Which are contraindicated?
Safe: LMWH (w/monitoring)
Contraindicated: Fondaparinux, Warfarin, factor Xa inhibitors
Which anticoagulants are safe in patients with kidney disease/failure? Which are contraindicated? What should you do with the dosing if administering in a patient with kidney disease/failure?
Always lower the dose in patients with kidney disease/failure.
Safe: LMWH, factor Xa inhibitors, argatroban
Contraindicated: Fondaparinux (half-life is too long), Warfarin (shown to exacerbate kidney disease)
What is the mechanism of Heparin-induced thrombocytopenia (HIT)? How does the risk of HIT differ amongst the three Heparin-related drugs?
The (-) charged drug binds to the (+) charged platelet-factor 4. Antibodies recognize and bind this complex, agglutinating the cells and drastically reducing platelet count.
The risk of HIT gets lower the smaller the drug is, since there is less room to bind. The risk is 5-10x lower in LMWH than in Heparin, and HIT basically never develops with Fondaparinux.
Adverse effects of Warfarin?
Subcutaneous fat necrosis in patients with congenital Vit K deficiency. Liver disease/diarrhea can also decrease the amount of Vit K available, making bleeding more likely.
What is 4-factor prothrombin complex concentrate (4-factor PCC)? What is it used for?
A solution containing high concentrations of factor II, IX, X, VII. It is used to reverse the effects of Warfarin and Factor Xa inhibitors.
What should you do if a patient develops HIT from Heparin administration?
Stop Heparin administration and use argatroban instead.
What is used to reverse the effects of Heparin in the event of an overdose?
Protamine sulfate
How do you reverse the effects of Warfarin during an adverse event? How long does it take to reverse?
Either administrate Vit K + plasma, or use 4-factor PCC. Takes 1-2 days for reversal of effects to take place.
Adverse effects of factor Xa inhibitors?
Bleeding, especially when taken alongside p-gp or CYP3A4 inhibitors (ritonavir, clarithromycin, azoles, etc.)
How do you reverse the effects of factor Xa inhibitors during an adverse event?
Administrate andexanet, which is a Factor Xa mimic that will bind the drug and prevent its action. Can also use 4-factor PCC.
Mechanism of Plasminogen Activators
Converts plasminogen into plasmin, which lyses the fibrin meshwork to break up a blood clot.
Naming of Plasminogen Activators
Streptokinase
-teplase suffix (alteplase, tenecteplase, reteplase)
Clinical Uses of Plasminogen Activators
CAD/IHD: inpatient (acute, break up blood clot)
