Antiplatelet, Anticoagulants, and Fibrinolytic Agents*.pdf

Antiplatelet, Anticoagulants, and Fibrinolytic Agents Advanced Pharmacology Dru Riddle Student Performance Objectives • List and describe the mechanism of action, route of administration, time course of action, indications, adverse effects, and contraindications for the following therapeutic agent...

Antiplatelet, Anticoagulants, and Fibrinolytic Agents Advanced Pharmacology Dru Riddle Student Performance Objectives • List and describe the mechanism of action, route of administration, time course of action, indications, adverse effects, and contraindications for the following therapeutic agents: a. heparin b. low molecular weight heparins c. warfarin • Discuss the reasons why anticoagulant therapy with heparin and warfarin are often overlapped. • List factors that can influence the effects of warfarin, especially patient compliance and drug-drug interactions. • Describe the mechanisms underlying the antiplatelet effect of low-dose aspirin and the use of aspirin in the prophylaxis and prevention of stroke and myocardial infarction. • Describe the therapeutic uses of the antiplatelet drugs, clopidogrel, prasugrel, ticagrelor, abciximab, eptifibatide, tirofiban, cilostazol, and dipyridamole,. • Discuss the use of new direct thrombin inhibitors such as dabigatran. • Describe the clinical indications and mechanism of action new factor Xa inhibitors such as rivaroxaban, apixaban and edoxaban. Student Performance Objectives • Discuss the problem of heparin-induced thrombocytopenia and the use of direct thrombin inhibitors such as, lepirudin, bivalirudin, and argatroban, for its treatment. • Describe the clinical indications and mechanism of action of fibrinolytic agents such as (tPA) alteplase- reteplase- tenecteplase, streptokinase and urokinase. • Describe the clinical indications and mechanism of action of anticoagulant reversing agents such as Vitamin K, KCENTRA® (prothrombin complex concentrate-human), protamine sulfate and idarucizumab (PraxBind) and Andexxa®. Drugs • Anti-platelet • • • • Aspirin Prasugrel, Clopidogrel, Ticagrelor Abciximab, Eptifibatide, Tirofiban-IV Cilostazol and Dipyridamole • Anticoagulants Heparin (UFH)-IV/SQ Low MW Heparin (LMWH)-Enoxaparin, Dalteparin and Tinzaparin-SQ Rivaroxaban, Apixaban, Edoxaban-PO Direct Xa Inhibitor Hirudin, Lepirudin, Bivalirudin, Agratroban-Parenteral DTI // Dabigatran (Pradaxa)-PO DTI • Warfarin • • • • Drugs • Reversing Agents • • • • • Vitamin K KCENTRA® (prothrombin complex concentrate-human) Protamine sulfate PraxBind (idarucizumab). Andexxa (coag factor Xa-inactivated-zhzo) • Thrombolytic Drugs • Recombinant tissue plasminogen activator (t-PA) = Alteplase, Reteplase, or Tenecteplase • Streptokinase • Urokinase Katzung, 15th ed, pg. 633 Katzung, 15th ed, Figure 34-3 Antiplatelet Drugs • Platelets form initial hemostatic plug • Platelets are associated with atherosclerotic plague deposits and pathological thrombi • A key activator of platelet aggregation is Thromboxane A2 (TXA2) • TXA2 is a product of the arachidonic acid pathway that involves formation of prostaglandins by the enzyme cyclooxygenase Aspirin: Antiplatelet Effects • Aspirin, at very low doses, irreversibly inhibits cyclooxygenase • Since platelets cannot synthesize new enzyme, aspirin inhibits TXA2 formation and platelet aggregation for the life of the platelet (7-10 days). Aspirin: Antiplatelet Effects • Only low doses are required to inhibit cyclooxygenase. • Higher doses inhibit the enzyme in endothelial cells and prevent the formation of prostacyclin (PGI2), a compound that inhibits platelet secretion and stimulates vasodilation. Aspirin: Therapeutic Uses • Should be administered routinely to virtually all patients with myocardial infarction • Secondary prevention of MI and stroke • Primary prevention of cardiovascular disease (benefits less clear) • Reduction of thromboembolic complications in patient with artificial heart valves, hemodialysis, coronary bypass grafts Other Antiplatelet Drugs Cilostrazol (Pletal) • Inhibits PDE III (écyclic AMP) • Inhibits platelet aggregation • Stimulates vasodilation • Indicated for reduction of symptoms of intermittent claudication • Contraindicated in patients with CHF Dipyridamole (Persantine) • inhibits platelet aggregation & weak vasodilator • may be useful in secondary prevention of MI and stroke, but disappointing clinical trial Abciximab • Abciximab (ReoPro) = monoclonal antibody • Prevents fibrinogen binding to glycoprotein GP IIb-IIIa, thus inhibiting platelet aggregation • Greater antithrombotic activity than aspirin or heparin • Approved as antithrombotic during angioplasty • Others = eptifibatide & tirofiban approved for acute coronary syndromes Clopidogrel, Prasugrel & Ticagrelor • Clopidogrel (Plavix), Prasugrel (Effient) and Ticagrelor (Brillinta) is approved for the prophylaxis of stroke, MI, peripheral arterial disease, and acute coronary syndrome. • Clopidogrel and Prasugrel irreversibly inhibits the platelet adenosine diphosphate (ADP-P2Y12) receptor and thus blocks the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. This inhibits fibrinogen binding and platelet aggregation. • Whereas Ticagrelor reversibly inhibits the ADP-P2Y12 receptor. • Since clopidogrel and prasugrel irreversibly inhibits the ADP-P2Y12 receptor, platelets exposed to clopidogrel are affected for the remainder of their lifespan • Ticlopidine (Ticlid) • inhibits fibrinogen binding to platelets and blocks platelet aggregation and clot retraction. • approved for prevention of thrombotic stroke in patients who have experienced TIAs • adverse side effects limit its use Pentoxifylline (Trental) • Hemorrheologic Agent = improves blood flow • mechanism is unclear, but appears to enhance RBC flexibility, decreases blood viscosity • may decrease TXA 2 levels and increase PGI2 levels • Indications • intermittent claudication, chronic occlusive arterial disease of the limbs Therapeutic Objectives • Prevent formation of pathological thrombus • Traditional approach is to use anticoagulant drugs: heparin and warfarin • Current approaches include prevention of arterial damage, i.e., atherosclerosis, and inhibition of platelet aggregation, e.g., with aspirin, clopidogrel, ticlopidine or abciximab Therapeutic Objectives • Destroy formed pathological thrombus • Dissolving preformed clots is difficult to achieve without causing bleeding, but fibrinolytic drugs like rtPA, reteplase, streptokinase, and urokinase can be used in special situations. Heparin • Heparin is the drug of choice for parenteral anticoagulant therapy • Mechanism: • heparin binds to antithrombin III • heparin-antithrombin complex binds to and inactivates coagulation factors of common and intrinsic pathways: thrombin, Xa, IXa, XIa, XIIa • heparin prolongs both the aPTT and the thrombin time; at higher doses can also prolong the PT time Routes of Administration • Continuous IV (often preceded by IV bolus) • Intermittent IV (not recommended) • Subcutaneous Minidose • for post-surgery prophylaxis • NOT GIVEN IM • NOT GIVEN ORAL Heparin Pharmacokinetics • Onset * I.V. - immediate anticoagulant * S.C. - begins in 20 - 30 minutes * Continuous IV infusion: 2 -3 hour delay unless an initial bolus injection is administered • Duration (of a single dose) * IV - 1 - 3 hours * SQ - 12-24 hours * Plasma t1/2 is dose-dependent, 1 -2.5 hours • Termination: metabolized in liver or excreted unchanged Indications for Heparin Therapy • Prophylaxis of postoperative thrombosis - SQ • Myocardial infarction and unstable angina • Deep venous thrombosis and pulmonary embolism • Extra-corpeal circulation (hemodialysis or heart-lung machine • Disseminated Intravascular Coagulation (DIC) • TIA - probably effective, but very risky - not used if stokein-progress Heparin: Therapeutic Use • Heparin is used when rapid onset of anticoagulation is required • Small doses to prevent thromboembolism • Medium doses to prevent propagation of thrombus • Large doses to inhibit established pulmonary embolus • If prolonged anticoagulation is necessary, the initial heparin therapy is overlapped with and then replaced with oral anticoagulant, i.e., warfarin Heparin Toxicity • Hemorrhage: from inadvertent overdose or from undiagnosed disease site • Hematoma at site of injection • Less common side effects: platelet aggregation, thrombocytopenia (heparin-induced thrombocytopenia or HIT), acute hypersensitivity, alopecia, osteoporosis, priapism Heparin-Induced Thrombocytopenia (HIT) • HIT-Type II • delayed onset (5-14 days) • severe thrombocytopenia (platelet counts< 100,000). • This is an immune-mediated reaction, a heparinantibody complex caused significant platelet aggregation. • Recovery can be delayed and consequences of peripheral thrombosis can be severe, including stroke, acute MI, skin necrosis. Amputation is necessary in up to 25% of patients and mortality approaches 25%. • Incidence of Type II HIT is about 3% of all treated Heparin-Induced Thrombocytopenia (HIT) • HIT-Type I • transient, reversible clumping of platelets • platelet count >100,000 • Usually occurs within first few days of therapy • Usually asymptomatic and recover OK even if heparin continued. Heparin Contraindications • Any site of active or potential bleeding • Severe hypertension or known vascular aneurysm • Recent head, eye, or spinal cord surgery • Head trauma • Lumbar puncture or regional anesthetic block • Tuberculosis, visceral carcinoma, GI ulcers Monitoring Heparin Therapy • aPTT tested prior to starting therapy • aPTT of 1.5 -2.0 times control is the typical therapeutic goal Treatment of Heparin Overdose • Stop administration • Protamine sulfate • binds to and inactivates heparin • must be given slowly IV • Infusion of fresh-frozen plasma Low Molecular Weight Heparin Enoxaparin, Dalteparin, Ardeparin, Danaparoid Smaller, active pieces of regular heparin Greater anti-Xa activity, less anti-platelet activity Used (SQ injection) for prophylaxis of DVT associated with hip, knee, and abdominal surgery • Longer duration, simpler kinetics, clotting tests not usually required • • • • Comparison of UFH and LMWH Property UFH LMWH Anti-Xa : anti-IIa activity 1:1 2:1 – 3:1 aPTT monitoring required Yes No Inactivation of platelet factor 4 Yes No Inactivates platelet-bound factor Xa No Yes Inhibits platelet function ++++ ++ Increases vascular permeability Yes No Protein binding ++++ + Endothelial cell binding +++ - Dose-dependent clearance Yes No Primary route of elimination 1. Saturable binding 2. Renal Renal Elimination half-life 30-150 min 2-5 times longer Oral Anticoagulants: Warfarin • Warfarin = Coumadin® • Mechanism: • inhibits vitamin K epoxide reductase • inhibits vitamin K-dependent posttranslation modification of clotting factors: thrombin, VII, IX, X, Protein C and S • without addition of the g carboxyglutamic acid residue the clotting factors cannot bind Ca++ and are inactive Warfarin: Pharmacokinetics • Onset: considerably delayed (36 - 72 hours) • delay in onset is due to long t1/2 of warfarin and the fact that pre-existing clotting factors are slowly cleared from the blood (t1/2 for VII = 6 hours) • Duration: prolonged • proportional to the elimination t1/2 (25-60 hours) Warfarin: Pharmacokinetics • Distribution: • rapid and complete absorption • highly fat-soluble • 99% bound to plasma albumin • Termination: delayed (2 -5 days) • liver and kidney metabolism • long elimination t1/2 • new, active clotting factor must be synthesized Warfarin:Toxicities and Contraindications • Hemorrhage • Anorexia, nausea, vomiting, diarrhea • Skin necrosis • Contraindications • pregnant patients: congenital abnormalities • unreliable patient • any recent bleeding • recent eye, brain, or spinal cord surgery; head injury • severe hypertension or known vascular aneurysm Warfarin: Indications • Overlap with heparin therapy to avoid long delay in onset of action • Deep venous thrombosis • Pulmonary embolism • Atrial fibrillation • Rheumatic heart disease • Mechanical and prosthetic heart valves Warfarin: Therapeutic Guidelines • Warfarin is only given orally • Initial doses followed by maintenance doses • adjust according to PT time (INR) • Determine PT time (INR) prior to starting therapy, daily until response stabilized, weekly until maintenance dose established • Warfarin is often administered concurrently with heparin until target INR is achieved and then patient is maintained on warfarin. Warfarin: Patient Variability • Individual patient variation is very high • Due to differences in absorption, elimination, liver function, and drug-drug interactions. • Noncompliant and unreliable patients are not good candidates for warfarin therapy • Potential drug-drug interactions are numerous Warfarin: Drug-drug Interactions • Warfarin is a classic example for many types of drug-drug interaction • Inhibition or acceleration of warfarin metabolism • Displacement from plasma protein binding sites • Interference with mechanism of action • Interference with absorption Warfarin: TX Overdosage • Vitamin K—to overcome antagonism and maintain Vitamin K clotting factor formation. • KCentra®Prothrombin Complex Concentrate (Human)—contains Factor II, VII, IX-potency, Protein C and S. • [Data demonstrated with INR >3 prior to infusion decreased to INR of 1.2 by 30 minute time point. (CSL Behring Prescribing Information, 2015)] Rivaroxaban, Apixaban & Edoxaban. • Rivaroxaban (Xarelto), Apixaban (Eliqus) and Edoxaban (Savaysa) are approved for the treatment of venous thrombosis, pulmonary embolism, prevention of stroke with atrial fibrillation and acute coronary syndrome. • Binds to the active site of factor Xa and inhibits its enzymatic action. • Rivaroxaban is eliminated 66% via metabolism in the liver and 33% unchanged drug in the urine. Apixaban is metabolized by the CYP450 system in the liver and excreted by renal and GI system. • Since these factor Xa inhibitors prevent thrombin generation, via the intrinsic and extrinsic coagulation pathways they will prolong both aPTT and PT times. • Therefore no routine monitoring of these laboratory parameters. Direct Xa Inhibitor:TX Overdosage • Coagulation Factor Xa-recombinant and inactivate(Andexxa) Direct Thrombin Inhibitors • These agents all bind directly to thrombin, are highly selectively for thrombin, do not required other proteins such as antithrombin III for activity, and are expensive. • These agents are approved for use in patients with thrombosis related to heparin-induced thrombocytopenia (HIT) and during coronary angioplasty. • Hirudin & lepirudin • an irreversible thrombin inhibitor produced by medicinal leeches now available as the recombinant protein, lepirudin • Bivalirudin • short-acting, synthetic thrombin inhibitor • Argatroban • short-acting, synthetic thrombin inhibitor • Dabigatran (Pradaxa) Dabigatran: TX Overdosage • Idarucizumab (PraxBind) is an antibody fragment that binds free and thrombin-bound dabigatran and neutralizes the dabigatran activity. Katzung, 15th ed, Figure 34-3 Thrombolytic Agents • Thrombolytic = fibrinolytic • Normal fibrinolysis: • Clots are dissolved by the action of the protease plasmin • Plasmin is formed from inactive plasminogen by tissue plasminogen activator (tPA) • fibrinolysis is controlled by fast clearance of tPA, by a circulating inhibitor of tPA, and by the fact that tPA has much higher activity against fibrinogen bound to clots than free fibrinogen in circulation Thrombolytic Therapy • Objective: dissolve pathological blood clots by injecting a fibrinolytic enzyme or an activator of endogenous fibrinolysis without causing uncontrolled bleeding. Thrombolytic Therapy • Indications • • • • Acute myocardial infarction Pulmonary embolism Deep venous thrombosis Ischemic stroke (special circumstances only) • CAT scan, MRI first tPA, Alteplase, Activase • Recombinant Tissue Plasminogen Activator (rtPA, Alteplase, Reteplase and Tenecteplase) • tPA produced by genetic engineering • t1/2 = 3 min • IV bolus followed by IV infusion • adverse effects: serious hemorrhage • expensive • advantages over less expensive streptokinase difficult to demonstrate Reteplase • A shorter, genetically engineered form of r-TPA • Diffuses more freely into clot than alteplase • Shorter half-life than alteplase Streptokinase • a nonenzymatic activator of plasminogen extracted from hemolytic streptococci • a loading dose of streptokinase used to saturate preexisting antibodies • serious hemorrhage is a potential side effect