Pharmacology of Anticoagulation Therapy Flashcards
MOA of unfractioned heparin
serine protease inhibitor that binds to AT III to increase the inactivation of coagulation factors (IXa, Xa, XIIa) -> prevents conversion of fibrinogen to fibrin
PK of heparin
not absorbed from GI
- IV or SQ
- short T1/2
MOA of LMWH
selectively binds to and inactivates factor Xa by antithrombin. cannot inhibit thrombin by antithrombin
PK of LMWH
- SQ
- better bioavailability, more predictable dose response, longer T1/2
- outpt
management of heparin and LMWH
Venous thrombosis, pulmonary embolism (rapid onset). Used with oral anticoagulants (warfarin) and fibrinolytics. Fondaparinux approved for this use. Management of unstable angina or acute MI. During/after coronary angioplasty or stent placement. During surgery requiring cardiopulm bypass. Kidney dialysis.
complications associated with heparin therapy
a. Bleeding
i. Usually the anticoagulant effect of heparin wears off within hours of discontinuing the drug. If life-threatening hemorrhage occurs, the effects of heparin and LMWH, can be reversed with PROTAMINE SULFATE, a positively charged compound that neutralizes heparin (binds up all the (-) charge).
b. Heparin-induced thrombocytopenia syndrome (HIT)
i. In 3-5% of patients, 5-10 days after heparin use, their platelet count decreases by ˃50%. Caused by antibodies to platelet factor 4/heparin complexes. Antibodies bind to and activate platelets resulting in prothrombotic state and clots develop: venous thromboembolism, arterial thrombosis, MI and stroke. Thrombocytopenia is less common with LMWH.
c. Allergic event
i. Activation of the contact system (production of bradykinin and complement activation)
Describe the alternative anticoagulant therapies used for patients with heparin-induced thrombocytopenia
a. Direct thrombin inhibitors:
i. Argatroban (Novastan), a small molecule inhibitor
ii. Lepirudin (Refludan), recombinant form of hirubdin—anticoagulant from leeches.
MOA of warfarin
inhibits enzymes that use vitamin K as a cofactor. Warfarin inhibits that recycling of vitamin K to the reduced form (by reductases) -> cannot bind Ca++ and are non-functional
PK of warfarin
Rapidly absorbed (90 minutes), good bioavailability, long half-life (36-48 hours). Disadvantage: Full antithrombotic effect of warfarin isn’t achieved until existing coagulation factors in circulation are removed (requires 2-3 days) because only NEWLY synthesized coagulation factors will be effected (SLOW ONSET).
uses of warfarin
prevent venous thromboembolism (in combo with heparin—which acts rapidly), systemic embolism in patients with prosthetic heart valves or atrial fibrillation, stroke, recurrent infarction or death in patients with acute MI
adverse effects and potential complications associated with use of warfarin
- hemorrhage (administer vit K/plasma)
- crosses placenta - tetragenic
- drug interactions
- delayed onset of action
- requires monitoring (INR checks)
relationship between mechanisms of action and speed of onset of action of heparin
rapid onset of action because it works by binding antithrombin III, an inactivator of thrombin. Thrombin is an essential component of the coagulation cascade. Therefore, once it is inactivated by heparin bound antithrombin III, no coagulation can occur. Heparin is rapid because it causes the inactivation of a direct component of the coagulation cascade
relationship between mechanisms of action and speed of onset of action of oral anticoagulants
slower onset of action because it acts on an enzyme that is part of the external machinery of the coagulation cascade (the enzyme that causes vitamin K reduction). Warfarin prevents Vitamin K from being reduced thereby preventing new coagulation factors, which require vitamin K mediated gamma carboxylation, from being manufactured. However, because it does not act on a direct component of the coagulation cascade, warfarin has a slower onset of action than other drugs. This is because it takes a bit of time for the coagulation cofactors that were present in circulation before warfarin administration to be degraded
mechanisms of action and uses of fibrinolytic agents
- converting plasminogen to plasmin, a protease that degrades fibrin and fibrin clots
- treat acute myocardial infarction (AMI) in combination with aspirin (Must be given within 6 hrs ideally and a max of 12 hrs after eent). They also are used to treat ischemic stroke (given within 3 hrs. of event), deep vein thrombosis (combo w/ warfarin/heparin), and pulmonary embolism
mechanisms of action and uses of antiplatelet agents: ASA
inhibits formation of platelet products
i. Works by irreversibly inactivating cyclooxygenase preventing thromboxane A2 formation by platelets. Thromboxane A2 normally stimulates platelet activation and aggregation. Aspirin’s effect is permanent and lasts the life of a platelet or around 7-10 days.
ii. Aspirin is used in combo with thrombolytic therapy after AMI and thrombotic stroke. It has been shown to prevent secondary events
mechanisms of action and uses of antiplatelet agents: ADP receptor antagonists
bind ADP receptor on platelets and block platelet activation by ADP, thereby inhibiting the secretion of alpha granules and blocking the expression of adhesion proteins like GPIIb/IIIa
i. slow onset of action due to being prodrugs that must be metabolized in the liver to active intermediate
ii. Used in combination with aspirin to prevent cardiac events in patients with atherosclerosis and unstable angina
iii. Used in patients with aspirin intolerance
mechanisms of action and uses of antiplatelet agents: glycoprotein IIb/IIIa inhibitors
Glycoprotein IIb/IIIa are integrin (adhesion protein ) on the surface of platelets that acts as a receptor for fibrinogen. Inhibitors of the integrin prevent platelet aggregation by preventing fibrinogen from binding.
i. use is declining
ii. used for treatment during angioplasty and for unstable angina. Also used in combo with aspirin and heparin to prevent recurrent MI or in combination with throbolitic drugs for “AMI.”
iii. Adverse effects like bleeding and thrombocytopenia can be reversed by platelet infusions
