Drugs Affecting Coagulation PDF

Anticoagulants Clotting cascade Clotting factors circulate as inactive zymogens Must be activated quickly when needed Each is a protease which activates the next Ends with production of fibrin from fibrinogen Thrombin from prothrombin...

Anticoagulants Clotting cascade Clotting factors circulate as inactive zymogens Must be activated quickly when needed Each is a protease which activates the next Ends with production of fibrin from fibrinogen Thrombin from prothrombin Factor Xa is responsible for this conversion Drugs will target some aspect of this cascade Antiplatelet drugs , some target clotting factors, etc Fibrinolysis Important Clots no longer needed must be dissolved Plasminogen activated to plasmin by tissue plasminogen activator (TPA)  Simplified view Clotting cascade fibrinogen Platelet activation Tissue damage  Basic mechanisms Platelet plug must be reinforced by fibrin. It is a temporary fix Platelet activation releases platelet derived ADP- stimulates further platelet aggregation and synthesis and release of thromboxane A2 from arachidonic acid in platelet membrane TXA2: vasoconstriction and thrombogenesis Serotonin: from platelets reinforces vasoconstriction and platelet aggregation Platelets are central to proper clotting Differences between arterial and venous blood Platelets implicated in thromboembolic disorders Will aggregate to areas of damaged endothelium in high pressure arteries Termed white thrombus As arterial flow is reduced, fibrin will be activated forming a red thrombus In arteries tendency is to form occlusion causing ischemia In veins ( lower pressure) Fibrin is activated immediately following platelet aggregation Will form a long clot that can detach easily ( DVT) Can embolize In veins tendency is for emboli to form  Drugs that modify coagulation are used to treat life threatening conditions Stroke, MI , PE, Disseminated intravascular clotting (DIC), DVT Mechanisms are varied and include Fibronolysis ( Clot busters) Inhibit clots that have already formed Usefulness is inversely proportional to the time elapsed since the event ( stroke, MI) Inhibit clotting mechanisms (anticoagulants) Prevent clots in the venous system or heart Antiplatelet drugs Prevent clots primarily in arterial blood All will have bleeding as an adverse effect The above statements are generalizations  Heparin and indirect thrombin inhibitors Heparin greatly increases the activity of antithrombin III ( ATIII) Unfractionated heparin, low molecular weight heparins , and others Heparin Heterogenous mixture of sulfated mucopolysaccharides Activates ATIII, which inhibits IIa( thrombin), Xa and IXa, by binding Heparin speeds this inhibition 1000X Binds ATIII with high affinity cause a conformational change that accelerates its activity Exposes the active site of ATIII Heparin is not consumed Heparin is a mixture with some molecules lacking the pentasaccharide sequence needed for efficient ATIII binding Mixture is variable within and between batches ( MW range from 5000-30000) Only the high molecular weight molecules bind with high affinity and inhibit all three clotting factors Shorter chain will inhibit Xa, but less activity against thrombin Response variable and not very predictable between different batches Dose adjusted to double aPTT , IV or subcu LMWHs more predictable Equal efficacy increased bioavailabilty and less frequent dosing with subcu, administration Enoxaparin ( lovenox) Deltaparin ( fragmin), tinzaparin (Innohep ( low mw fragments) Fondaparinux( Arixtra) : is synthetic works as a Xa inhbitor Indications DVT and DVT prophylaxis in high risk groups, PE Lovenox is indicated for unstable angina  Adverse effects Bleeding Elderly females more at risk, renal failure also Monitoring of aPTT required for unfractionated heparin LMW more predictable Less monitoring required in presence of normal renal function Allergy From animal sources Osteoporosis with long term use , mineralocorticoid deficiency Thrombocytopenia Often transient Severe in 5% HIT, heparin induced ab complex that binds platelets Aggregation of platelets and thromboembolism , causes platelet destruction also Platelet counts should be monitored Requires discontinuation and treatment with HIT drugs Contraindications: Allergy, active bleeding, hemophilia, thrombocytopenia, intracranial hemorrhage, Ulcers, Severe renal or liver disease  Protamine sulfate is an antidote for heparin Binds heparin and inactivates Also neutralizes LMWH but incomplete Works on enoxaparin but not fondaparinux Direct Thrombin inhibitors (HIT drugs primarily) Bind directly to thrombin Used to treat HIT Rudins and, dabigatran ( Pradaxa), argatroban Useful for patients with HIT Lepirudin( refludan) and bivalirudin (Angiomax) effective in patients with HIT Short half life , argatroban metabolized by the liver and also useful in patients with HIT Dose reduced in liver failure Argatroban interferes with INR test , gives false readings Dabigatran is a newer oral drug : Idarucizumab antidote for dabigatran Reverses the anticoagulant effects for emergency surgery or in life-threatening or uncontrolled bleeding Direct Xa inhibitors rivaroxaban(Xarelto), Apixaban(Eliquis),and edoxaban(Savaysa) (oral and bind directly to Xa) Direct Xa inhibitors Newer oral agents Relatively fast onset of action, may be useful for clot prevention in A-fib (Warfarin has been DOC) Reversal agent Andexxa : Decoy factor Xa that ties up drugs Rivaroxaban (Xarelto) Does not affect thrombin or platelets DVTs or PE Apixaban ( Eliquis) Xa inhibitor Approved for prevention of stroke and emboli in non-valvular A fib Not recommended for patients with prosthetic heart valves Adverse effect Bleeding Endoxaban(Savaysa) Approved for prevention of stroke and emboli in non-valvular A fib DVT and PE Coumarins Warfarin Highly plasma protein bound Eliminated by Cyt P450 system Many drugs induce or inhibit Long half life ( 36 hours) Narrow TI Racemic mixture of D and L forms. L form more potent Mechanism Inhibit Activation of vitamin K Required for clotting factors II, VII, IX , and X 12 hour delay in effects Available clotting factors can be used for a short time Contraindicated in pregnancy ( crosses placenta) Bleeding Dosed to achieve PT/INR of 2.5-3.5 Indications Prophylaxis for thromboembolic events from A fib or valve replacement DVT /PE prevention Post MI also  Interactions Numerous Antidote: Vitamin K Stop drug and administer Takes time Also Fresh frozen plasma and Factor VII a More rapid  Antiplatelet drugs In general platelet activation is important to clots causing occlusion in arterial blood. These drugs major use is TIA, post MI , prevention of clots in coronary arteries with indwelling devices or procedures. They are not generally used for conditions of venous blood ( DVTs, PEs) ASA Inhibits cyclooxygenase irreversibly Inhibits synthesis of TXA2 Clopidogrel (Plavix) and Ticlopidine (Ticlid) Irreversibly Inhibit ADP receptor in platelets Reduce aggregation Use: TIA prophylaxis , unstable Angina, placement of coronary stents Adverse effects Ticlopidine Leukopenia Requires monitoring Hemorrhage Nausea, diarrhea ( 20 %) Clopidogrel (Plavix) Thrombotic thrombocytopenia purpura Serious- disseminated clots in small vessels  Platelet GpIIB/IIIA receptors Cilostazol (Pletal) Inhibits platelet aggregation Eptifibatide (Integrilin), Tirofiban (aggrastat) Block IIB receptor occupancy Abciximab ( Reopro) Monoclonal antibody against IIB/IIIA Used most during angioplasty procedures Cilostazol is oral and is used for intermittent claudication, others IV and used primarily during angioplasty Fibrinolytic agents All activate plasmin in some way Dissolve existing life threatening clots Must be administered within 6 h of thrombotic event Act quickly but brief half lives Tissue plasminogen activators : Alteplase reteplase, tenecteplase urokinase, streptokinase cause conversion of plasminogen to plasmin Indicated for Recent acute MI PE Severe DVT Thromboembolic stroke (TPAS only) Contraindications and caution Cause bleeding Hemorrhagic conditions or risk for hemorrhagic stroke Recent surgery (10 days) GI bleed within 3 months Pregnancy HTN with elevated diastolic pressure Aortic dissection