BL.2.3: Anticoagulation therapy Flashcards
Describe the mechanism of action of heparin and low molecular weight heparins.
Heparins bind to antithrombin III, a natural protease inhibitor present at high concentrations in plasma that inactivates coagulation factors. Binding of heparin to antithrombin III greatly increases the rate of thrombin inactivation by 1000X. Heparin also accelerates the rate of decay of IXa, Xa, and XIIa by antithrombin III. Once thrombin is bound to the antithrombin /heparin complex, heparin is released and can be reused. It can also bind to thrombin itsself.LMWH only bind to AT-III, which inactivates Xa and prevents the coagulation cascade anyways.
Please tell me about the pharmacokinetics and management of patients on heparin and LMWH’s.
Unfractionated heparinis not absorbed from the GI tract so it cannot be given orally.It is given I.V. for an immediate effect or sub-cutaneously for a delayed effect, has poor pharmacokinetics, poor bioavailability and relatively short half-life (1-5 hr) resulting in an unpredictable dose response, requires hospital admission and careful monitoring, does not cross the placenta therefore it is the drug of choice during pregnancy.LMWHs (and fondaparinux): a. are given subcutaneously and effects are more prolonged due to a longer half-life. b. have better bioavailability and more predictable dose response than unfractionated heparin and require less monitoring (outpatient treatment).
Describe the complications associated with heparin therapy, including excessive bleeding and heparin-induced thrombocytopenia with associated thrombosis.
Bleeding - The anticoagulant effect of heparin disappears within hours of discontinuation of the drug. If life-threatening hemorrhage occurs, the effect of heparin (and LMWH) can be reversed with protamine sulfate, a positively charged compound that neutralizes heparin.Platelet count decreases (>50%) in 3-5% of patients 5-10 days after heparin. Caused by development of antibodies to platelet factor 4/heparin complexes. The antibodies bind to and activate platelets resulting in a prothrombotic state (venous thromboembolism, arterial thrombosis, myocardial infarction, stroke).Thrombocytopenia is less common with LMWH.
Describe the alternative anticoagulant therapies used for patients with heparin-induced thrombocytopenia.
Patients treated with direct thrombin inhibitors: Argatroban (Novastan) - A small molecule inhibitor and Lepirudin (Refludan) - Recombinant form of hirudin, the anticoagulant from leeches.
What is the mechanism of action of Warfarin?
Warfarin inhibits enzymes that use vitamin K as a cofactor. Several coagulation proteins (II, VII, IX and X) undergo vitamin K-dependent gamma carboxylation of N-terminal glutamates. Vitamin K undergoes oxidation/reduction during the reaction. The recycling of vitamin K to the reduced form by reductases is inhibited by warfarin resulting in depletion of vitamin K. Coagulation proteins lacking gamma carboxylation cannot bind calcium and are non-functional.
Describe the pharmacokinetics and uses of oral anticoagulant warfarin.
It is rapidly absorbed (90 min), has good bioavailability and a long half-life (36-48 hr). The full antithrombotic effect of warfarin is not achieved until the existing coagulation factors in the circulation are removed (requires 2-3 days).Warfarin is used to prevent: Venous thromboembolism (in combination with heparin, which acts more rapidly), Systemic embolism in patients with prosthetic heart valves or atrial fibrillation, Stroke, recurrent infarction, or death in patients with acute myocardial infarction.
Describe the adverse effects and potential complications associated with use of warfarin.
Hemorrhage. The drug is stopped and vitamin K is administered (takes 24-48 hr for reversal since coagulation factors have to be resynthesized). Plasma can be transfused to replace coagulation factors.Warfarin cannot be used during pregnancy since it crosses the placenta and is teratogenicIt also has many D-D interactions and D-Food interactions
Describe the relationship between mechanisms of action and speed of onset of action of heparin and oral anticoagulants.
Heparin actively inactivates clotting factors; warfarin inactivates the synthesis of new clotting factors.Makes sense, then, that heparin is fast-acting and warfarin takes a while to ramp up– the old clotting factors are still rattling around in the blood for a few days.
Describe the mechanisms of action and uses of fibrinolytic agents.
Fibrinolytic agents: Fibrinolytic drugs promote lysis of clots by increasing formation of plasmin, a serine protease that degrades fibrin.Uses of fibrinolytic agents include: Acute myocardial infarction (AMI) - Used in combination with aspirin.Ischemic stroke. Effective if administered within 3 hr after stroke.Deep vein thrombosis. Used in conjunction with heparin/warfarin treatment.Pulmonary embolism.
Describe the mechanisms of action and uses of antiplatelet agents.
Anti-platelet drugs inhibit formation of platelet products or block platelet adhesion thus preventing platelet aggregation and clot formation.Three classes of anti-platelet drugs inhibit formation of platelet products (aspirin), prevent activation/aggregation (ADP receptor antagonists), and block adhesion proteins (glycoprotein IIb/IIIa inhibitors).Antiplatelet drugs are used to treat acute coronary syndrome (angina, myocardial infarction) characterized by atherosclerotic plaque rupture and platelet-mediated thrombosis.
