W1 Blood Clotting and Drugs for Hemostasis 2 (Mayers-Aymes).pdf

Blood Clotting and Drugs for Hemostasis Dr. Mayers-Aymes, PharmD [email protected] Turning point: pharmmcqs 1 Reading List Access Medicine supplemental reading: Chapter 34, Drugs Used in Disorders of Coagulation. In: Basic & Clinical Pharmacology, 14th Edition, by Bertram Katzung Access Medici...

Blood Clotting and Drugs for Hemostasis Dr. Mayers-Aymes, PharmD [email protected] Turning point: pharmmcqs 1 Reading List Access Medicine supplemental reading: Chapter 34, Drugs Used in Disorders of Coagulation. In: Basic & Clinical Pharmacology, 14th Edition, by Bertram Katzung Access Medicine https://accessmedicine-mhmedicalcom.rossuniversity.idm.oclc.org/content.aspx?bookid=2249&sectionid=1752 20898 USMLE Rx Bricks created for the purpose of this lecture and available in the Additional Information Section Practice questions in Canvas 2 Learning Objectives (Pharmacology) Describe the mechanism of action of antiplatelet drugs. Describe the mechanism of action of anticoagulants. Identify which tests are used to determine therapeutic success of the drugs used for management of hemostasis. Describe the mechanism of action of anti fibrin drugs Describe the mechanism of action warfarin. For each drug class (antiplatelets, anticoagulants and fibrinolytics), ✓ State the therapeutic uses & pharmacological effects ✓ Describe the adverse effects, contraindications & precautions ✓ Describe key pharmacokinetic properties 3 Introduction Hemostasis refers to the finely regulated process of maintaining fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs. Either extreme: excessive bleeding or thrombosis—represents a breakdown of the hemostatic mechanism. Thrombosis describes a pathologic state in which normal hemostatic processes are activated inappropriately. Recall the distinction between a thrombus and embolus 4 Blood Clotting Lecture 5 Process of Hemostasis Localized vasoconstriction occurs as a response to the secretion of endothelium-derived vasoconstrictors such as endothelin. Primary hemostasis: platelet activation (change in shape and release of secretory granule contents which recruit other platelets, causing more platelets to adhere to the subendothelial matrix and to aggregate with one another at the site of vascular injury) - primary hemostatic plug. Secondary hemostasis (coagulation cascade) - the activated endothelium and other nearby cells express tissue factor, which complexes with coagulation factor VII to initiate the coagulation cascade Activation of thrombin is the end result of the cascade 6 (Katzung, 12/2017)Katzung, B., Trevor, A. (2017). Pharmacology: Basic and Clinical Pharmacology, 14th Edition. [[VitalSource Bookshelf version]]. Retrieved from vbk://1260135993 7 8 Regulation of Hemostasis Antithrombin: inactivates thrombin (IIa) and other coagulation factors (IXa, Xa, XIa, and XIIa) by forming stable complexes with them Proteins C and S: proteolysis of Va and VIIIa Prostacyclin (PGI2): a metabolite of arachidonic acid that is synthesized and secreted by the endothelium. Increases cAMP levels within platelets and thereby inhibits platelet aggregation and platelet granule release. Tissue factor pathway inhibitor (TFPI): limits the action of tissue factor (TF). 9 ANTI-PLATELET DRUGS 10 Main targets for antiplatelet drugs Inhibition of ADP-induced platelet aggregation – e.g. clopidogrel Inhibition of prostaglandin synthesis (thromboxane A2) – e.g. aspirin Blockade of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets – e.g. abciximab 11 Platelet activation by ADP 1. Binding of ADP to the P2Y (ADP) receptor also called P2Y12 2. Activation of a Gi protein which inhibits adenylyl cyclase 3. Decrease synthesis of cAMP which leads to decreased protein kinase A activation 4. Platelet aggregation Modified from: Golan, D. E. (2016). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. [VitalSource Bookshelf]. Retrieved 12 from https://bookshelf.vitalsource.com/#/books/9781496327062/ Antiplatelets (e.g. clopidogrel) Mechanism of action: Irreversibly blocks ADP P2Y12 receptors on platelets thereby inhibiting activation of glycoprotein IIb/IIIa receptors. This reduces platelet aggregation and binding to fibrinogen. Therapeutic Uses (1)secondary prevention of atherosclerotic events in patients with recent MI, stroke and PVD (2) treatment of acute coronary syndromes (3) prevention of stent thrombosis (in combination with aspirin). 13 Antiplatelets (e.g. clopidogrel) Pharmacokinetics Undergoes oxidation by hepatic P450 CYP2C19 to the active drug Administration: oral Excretion: equally in urine and feces Adverse effects Diarrhea, abdominal pain (3%), Bleeding (2%) (intracranial, gastrointestinal), Thrombotic thrombocytopenic purpura ( very rare) 1. What type of drug is clopidogrel (based on the fact that it is oxidized to an active drug)? 2. What will be the result of co-prescribing a CYP2C19 inhibitor (or inducer) with clopidogrel? 14 Pharmacogenomics and Clopidogrel Variability in response to clopidogrel administration may be due to genetic differences in CYP2C19. Poor metabolizers of clopidogrel may experience an inadequate drug effect leading to increased cardiovascular events. FDA recommendation: use of other anti-platelet drugs Also drug interactions possible: e.g. clopidogrel and omeprazole (inhibits CYP 2C19 function) 15 Antiplatelets (e.g. abciximab) Mechanism of action: A glycoprotein IIb/IIIa antagonist. Abciximab is humanized monoclonal antibody, which binds non-competitively to the platelet glycoprotein IIb/IIIa receptor complex to prevent the binding of any aggregating substance to prevents platelet aggregation. Eptifibatide and Tirofiban are competitive antagonists of the glycoprotein IIb/IIIa receptor complex which appear to be less effective than abciximab.. Therapeutic Uses used in patients undergoing percutaneous coronary intervention (PCI) to prevent acute cardiac ischemic complications, manage patients with unstable angina not responding to conventional therapy in patients scheduled for PCI. 16 Prostanoid biosynthesis Katzung, B. G. (2017). Basic and Clinical Pharmacology 14th Edition. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781259641169/ 17 Antiplatelets (e.g., aspirin) Mechanism of action: Aspirin inhibits the action of the enzyme cyclooxygenase (COX) COX blockade reduces both the platelet-mediated production of TA2 (via COX-1) which promotes aggregation, and the endothelial cells-mediated production of prostacyclin (PGI2) (via COX-2), which inhibits aggregation. Low doses of aspirin provide an antiplatelet effect via the inhibition of synthesis of thromboxane A2 by irreversible acetylation of the enzyme COX- I 18 Antiplatelets (e.g., aspirin) Therapeutic uses (1) prophylaxis against transient ischemic attack, MI and thromboembolic disorders (2) treatment of Acute Coronary Syndromes (ACS) (3) prevention of re-occlusion in coronary artery revascularization procedures and stent placement. 19 Contraindications and precautions of anti-platelet drugs Bleeding (gastrointestinal, intracranial, retinal) Surgery Coagulopathy (hemophilia, etc.) Any disease that increases the risk of hemorrhage (i.e., aplastic anemia, leukemia, thrombocytopenia, infective endocarditis, inflammatory bowel disease, gastrointestinal neoplasms, etc.) Venous thromboembolism (antiplatelet effect can increase the risk of thromboembolism. Reasons are unknown) 20 ANTI-COAGULANT DRUGS 21 Recall Antithrombin inactivates coagulation factors by forming stable complexes with them. Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 22 Heparins Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 23 Heparin Mechanism of action: binds tightly to antithrombin and causes a conformational change which exposes the active site for more rapid interaction with the activated clotting factors. Functions as a cofactor for the antithrombin-protease reaction without being consumed High molecular weight fractions inhibit blood coagulation by inhibiting IIa, IXa, Xa Lower molecular weight heparin have less effect on IIa and a greater effect on Xa. 24 Heparins Pharmacological Effect limit the expansion of thrombi by preventing fibrin formation Therapeutic Use: both prophylaxis and treatment of thromboembolic diseases for prophylaxis of postoperative venous thrombosis in patients undergoing surgery and those with acute myocardial infarction 25 Heparins Pharmacokinetics Administration: IV, SC Onset of action: IV (within minutes), SC (1-2 hours) UFH has unpredictable PK so monitor (aPTT), LMWH have more predictable PK so monitoring not necessary for most patients Elimination: LMWH (primarily urine – why is this important to note?), UFH: small amounts in urine (primarily non-renal elimination) Adverse Effects Bleeding, chills, fever, urticaria, osteoporosis, heparin induced thrombocytopenia (HIT) LMWH has a lower risk of adverse effects particularly HIT and osteoporosis 26 Heparins The preferred treatment of thromboembolism in pregnancy is anticoagulation with low molecular weight heparin (LMWH) LMWHs in comparison to UFH have: equal efficacy increased bioavailability from the SC site of injection A more predictable response less frequent dosing requirements Less Adverse Drug Reactions (ADRs) 27 Heparins Precautions Linked closely to adverse effects (e.g. osteoporosis) Contraindications hypersensitivity to heparin, bleeding disorders, alcoholism, or who have had recent surgery of the brain, eye, or spinal cord. Excessive bleeding may managed with protamine sulphate - it combines with heparin to form a stable 1:1 inactive complex 28 Warfarin (Mechanism of action): 1. Factors II, VII, IX and X (as well as proteins C and S require vitamin K as a cofactor for their synthesis in the liver. 2. During this reaction, vitamin K is oxidized to the inactive form. 3. An enzyme, vitamin K epoxide reductase (also called VKORC1), is then required to convert the inactive 2,3-epoxide into the active, reduced form of vitamin K. 4. Warfarin inhibits epoxide reductase. 29 Warfarin Pharmacological effect Decreases blood coagulation Therapeutic Use: prevention and treatment of DVT and PE, stroke prevention, atrial fibrillation Pharmacokinetics: Administration: Oral (100% bioavailability) Highly bound to albumin (99%) Peak effects: 72 – 96 hours after initiation (what is the implication of this?) Excretion: Primarily urine as metabolites Monitoring: PT/INR test 30 Warfarin Adverse Effects Bleeding, skin and tissue necrosis Minor bleeding may be treated by withdrawal of the drug or administration of oral vitamin K, but severe bleeding may require greater doses of vitamin K given intravenously, whole blood or fresh frozen plasma. Precautions Elderly more sensitive to anticoagulation effects Dietary insufficiency (vitamin K) – what happens if a patient consumes large quantities of green leafy vegetables while on warfarin? Contraindications Teratogenic (Pregnancy Category X) , active bleeding or an increase risk for hemorrhage 31 Direct Thrombin Inhibitors (Bivalirudin, argatroban, dabigatran) Mechanism of action DTIs bind to the active site of both free and fibrin-bound thrombin, thus preventing its coagulant activity. Pharmacokinetics Bivalirudin and argatroban are parenteral DTIs whereas dabigatran is an oral DTI. Therapeutic Uses: Bivalirudin: as an alternative to heparin in patients with or at risk of heparin-induced thrombocytopenia. Also, for use in patients undergoing PCI. Dabigatran: prophylaxis and treatment of DVT and PE, to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. When used to treat, VTE, dabigatran follows 5–7 days of initial heparin or LMWH therapy. 32 Direct Thrombin Inhibitors (Bivalirudin, argatroban, dabigatran) Adverse Effects Bleeding With dabigatran, gastrointestinal adverse effects are common (up to 20%) and include epigastric discomfort, abdominal pain, gastroesophageal reflux, peptic ulcer, esophagitis,). – The antidote for dabigatran is a monoclonal antibody, idarucizumab that can effectively neutralize the dabigatran molecule in the blood. 33 Rivaroxaban Mechanism of action binds to the active site of factor Xa, preventing its coagulant activity (direct factor Xa inhibitor). Pharmacokinetics: It is administered orally. Has an oral bioavailability ≈90%. When compared to warfarin, rivaroxaban has a faster onset of action and a shorter half-life. Adverse effects: Include bleeding. Andexanet alfa is the antidote for reversing the effects of rivaroxaban. The precautions and contraindications are similar to those of other anticoagulants. 34 FIBRINOLYTICS 35 Alteplase Fibrinolytic/thrombolytic agents are used to lyse already-formed clots Thrombolytic agents act by converting the inactive zymogen plasminogen to the active protease plasmin. Tissue plasminogen activator (t-PA) achieves this: t-PA is a serine protease produced by human endothelial cells; it is a potent activator of plasminogen. Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ Alteplase is recombinant t-PA 36 Alteplase Mechanism of action: Converts plasminogen into active plasmin. The massive activation of plasminogen causes a ‘systemic lytic state’ in which hemostasis is impaired. Pharmacological effect Breakdown fibrin (lyse clots) Therapeutic use Myocardial infarction, stroke, thromboembolism 37 Alteplase Pharmacokinetics Administration: IV Elimination: primarily hepatic Adverse Effects: bleeding Contraindications and precautions Any active internal bleeding or hemorrhagic disorder, Recent severe trauma or major surgery, pregnancy, Severe hypertension (>180/110 mm Hg). 38 Drugs used for bleeding disorders Vitamin K (discussed previously) vegetables. found primarily in leafy green Factor VIII deficiency (classic hemophilia, or hemophilia A) and factor IX deficiency (Christmas disease, or hemophilia B) account for most of the heritable coagulation defects. Recombinant factor VIII and IX, are used to treat hemophilia. Desmopressin increases factor VIII activity and is used to treat hemophilia and von Willebrand disease. 39 A 34-year-old man presents to the ED with complaints of severe shortness of breath and chest pain. After appropriate investigations, the patient was diagnosed with a pulmonary embolism and was started on a medication which binds to antithrombin. Which drug did the patient receive to manage the pulmonary embolism? A. B. C. D. E. Clopidogrel Alteplase Warfarin Heparin Desmopressin Turning point: pharmmcqs 40 b) Which laboratory test should the physician use to monitor heparin therapy? 41 (c) The patient started to experience adverse effects to heparin therapy. Which drug should be used to reverse the action of heparin? 42 A transition from heparin to warfarin anticoagulant therapy is initiated while the patient is in the hospital. After discharge of the patient from the hospital, warfarin anticoagulant therapy is continued. Following discharge, the patient decides to institute lifestyle changes, including diet and exercise. His dietary plan is to dramatically decrease his intake of meat to try to become a vegetarian. How would an increased consumption of green leafy vegetables be expected to alter the patient’s International Normalized Ratio (INR)? A. B. C. D. It would be increased. It would be decreased. It would be unchanged. It would be doubled. 43 A patient undergoes a percutaneous coronary angiography procedure and placement of a stent in a coronary blood vessel, he will need to be on dual antiplatelet therapy, for example, aspirin and clopidogrel, for at least a year. Which of the following most accurately describes the mechanism of action of clopidogrel? A. B. C. D. Clopidogrel irreversibly inhibits cyclooxygenase Clopidogrel facilitates the action of antithrombin III The active metabolite of clopidogrel binds to and inhibits the platelet ADP receptors The active metabolite of clopidogrel binds to and inhibits the platelet glycoprotein IIb/IIIa receptors 44 A 46-year-old man presents to the emergency department with severe chest pain. After doing appropriate tests(ECG and cardiac enzymes) the physician confirmed that he had a myocardial infarction and therapy was initiated with a fibrinolytic drug. Which one of the following drugs was used to manage the man? A. B. C. D. E. Clopidogrel Warfarin Alteplase Desmopressin Heparin 45