Antithrombotics and Anticoagulants PDF

Antithromboti cs and Anticoagulant s Jody Jonathan Haigh, Ph.D. [email protected] (adapted from Dr. Curtis Oleschuk) Objectives for lecture 1 2 3 Briefly describe: Describe the Understand the How a p...

Antithromboti cs and Anticoagulant s Jody Jonathan Haigh, Ph.D. [email protected] (adapted from Dr. Curtis Oleschuk) Objectives for lecture 1 2 3 Briefly describe: Describe the Understand the How a platelet mechanism of more common side plug is formed action of effect(s) associated The coagulation Antiplatelet agents with clinical cascade (clot Anticoagulants application for stabilization) and commonly used Anticoagulant agents (i.e. the The fibrinolytic antidotes drugs you need to pathway (clot Fibrinolytic agents know for this resolution) section)  Agents for Treatment Anticoagulants: drugs which interfere with coagulation cascade Antiplatelet agents: drugs which interfere with platelet function Fibrinolytic drugs: clot “busters” Treating arterial thromboembolic disease: antiplatelet agents Treating venous thromboembolism: anticoagulants  Drugs to know for this section Antiplatelet 1. AspirinCOX I and II inhibitor 2. Clopidogrel ADP receptor antagonist 3. Ticagrelor ADP receptor antagonist 4. Prasugrel ADP receptor antagonist Anticoagulant 5. Heparinantithrombin III activator 6. LMW heparin antithrombin III activator 7. Warfarin vitamin K antagonist 8. Dabigatran direct thrombin inhibitor 9. Idarucizumab direct thrombin inbibitor 10.Rivaroxaban direct Factor Xa inhibitor Clot resolving 11.Tissue plasminogen activator (TPA) activates plasminogen 12.Steptokinase activates plasminogen  Thromboembolic Disease Thromboembolism: Formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vesse Gross and Weitz, Clinical Pharmacology and Therapeutics, 2009  Concept: Appropriate Targets for Treatment Arterial and venous thrombi are composed of platelet aggregates, fibrin and red blood cells Arterial thrombi form under high sheer stress conditions: platelets abundant and fibrin sparse Venous thrombi form under low sheer stress conditions: rich in fibrin and trapped red blood cells and contain fewer platelets  Hemostasis: cessation of blood loss from a damaged vessel Coagulation: formation of a blood clot Definitio Blood clot: also called hemostatic plug, is formed by ns aggregation of platelets and stabilized by fibrin Thrombosis: a pathologic process in which a platelet aggregate and/or fibrin blot occludes a blood vessel Hemostasis o Normal physiological process of terminating blood loss from a vascular wall o Involves: o platelet activation o coagulation cascade thrombin formation o clot resolution  Pathology of thrombosis Rupture of fibrous cap Exposure of lipid core (Tissue Factor: procoagulant) Platelet adherence and activation Thromboxane A2 release Membrane glycoprotein IIb/IIIa receptor activation to bind fibrinogen Complex platelet linkage o Process above continues with further fibrin incorporation and inclusion of red blood cells within clot o End result is partial or total occlusion of vessel (coronary artery) Thrombosis Antiplatelet drugs  Platelet binding and activation https://www.youtube.com/watch?v=R8JMfbYW2p4 Clinical pharmacology & Therapeutics | VOLUME 86 NUMBER 2 | AUGUST 2009 vWF = von Willebrand Factor o In healthy vasculature, platelets are maintained in an inactive state by nitric oxide and prostacyclin (PGI2) released by endothelial cells and ADPase which degrades Platelet Binding and Activation Signaling pathways involved in the regulation of platelet activation. -receptor binding -granule release -amplification -mediated/mediates other components of the blot clot process Sites of actions of antiplatelets Clinical pharmacology & Therapeutics | VOLUME 86 NUMBER 2 | AUGUST 2009  Drugs that inhibit platelet aggregation, Aspirin Aspirin inhibits TXA2 synthesis by irreversibly acetylating cyclooxygenase 1 COX is the enzyme necessary for the formation of prostaglandins among other lipid-mediators of inflammatory response In platelets, COX produces thromboxane A2, which promotes aggregation In vascular endothelium, COX produces prostacyclin (PGI2) which increases platelet stability (less likely to aggregate)  Other NSAIDS (reversible inhibitors of COX- 1) have not been shown to have anti-thrombotic efficancy and may even interfere with low-dose aspirin regimes  Why does aspirin not promote aggregation given its effect on vascular endothelium production of prostacyclin? o Aspirin irreversibly blocks COX o Platelets lack a nucleus – can’t make new COX o Vascular endothelial cells have a nucleus o Vascular endothelial cells have ability to continually remake COX and hence maintain prostacyclin production Drugs that reduce platelet aggregation, Aspirin Aspirin uses: Reduce the risk of fatal and non-fatal myocardial infarction by at least 50% in patients with unstable angina Cornerstone treatment in acute coronary syndrome with benefits being seen for at least 2 years regardless of dose use Aspirin use associated with increased bleeding hemorrhagic stroke (stroke due to bleeding into brain) gastrointestinal bleeding easy bruising Dose must be balance with benefit to risk (50 – 325 mg/day); complete inactivation of COX-1 achieved with daily 75 mg dose. Aspirin resistance (incomplete suppression of TXA2 synthesis correlated with increased risk of cardiovascular events  Drugs that reduce platelet aggregation, Clopidogrel Platelets contain two GCPCR P2Y1 and P2Y12 both are site for platelet activation by ADP Both must be stimulated for platelet activation Irreversible inhibitor of platelet P2Y12 receptors -increased risk of bleeding if patients require surgery unless drug not taken 5 days prior to surgery Prodrug with slow onset of action Examples of use: Used alone in secondary prevention of stroke Used in combination with aspirin to prevent recurrent ischemia in patients with unstable angina Wide inter-individual variability in capacity of clopidogrel to inhibit ADP-induced platelet aggregation: genetic polymorphisms in drug metabolism Bleeding prolonged and hard to stop Drugs that prevent platelet aggregation, Ticagrelor Used alone or along with aspirin Orally active reversible antagonist of the P2Y12 receptor More rapid onset and predictable inhibition than clopidogrel In patients with ACS, greater reduction in cardiovascular death, MI and stroke at 1 year in comparison to clopidogrel No difference in rates of major bleeding in comparison to clopidogrel but more common incidence of minor bleeding metabolized in the liver predominantly via CYP 3A4 and it should be used with caution in patients taking CYP 3A4 inhibitors Drugs that prevent platelet aggregation, Prasugrel Used in combination with aspirin member of the thienopyridine class of ADP receptor inhibitors prodrug that requires enzymatic transformation in the liver to its active metabolite, R-138727. R-138727 Onset of action more rapid that clopidegrel and produces greater and more predictable inhibition irreversibly binds to P2Y12 type ADP receptors on platelets thus preventing activation of the GPIIb/IIIa receptor complex Reduced incidence of cardiovascular death (MI) and stent thrombosis compared with clopidogrel Increased risk of fatal and life-threatening bleed Drugs that prevent platelet aggregation, Abciximab Fab fragments directed against αIIbβ3 receptor Also binds to vitronectin receptor (involved in cell-cell adhesion) of platelets, vascular endothelial and smooth muscle cells Unbound abciximab clears quickly, t1/2 of 30 minutes Bound abciximab clearance 18 – 25 hours Major side-effect is hemorrhage (frequency of major hemorrhage: 1 – 10 %) and thrombocytopenia (2%) Platelet transfusion can reverse rapidly the aggregation defect (free antibody clear quickly) Additionally, can block binding to vWF IV administered Prevent cardiac ischemia with PCI Prevention of ischemic cardiac complication with unstable angina or NSTEMI  Summary of Antiplatelet Drugs Plaque Disruption Collagen vWF Platelet adhesion and secretion Aspirin COX-1 Clopidogrel TXA2-mediated ADP-mediatedPrasugrel Ticagrelor Platelet recruitment and activation GPIIb/IIIa activation Abciximab Platelet aggregation  Topic break Clotting Factor Nomenclature  https://www.youtube.com/watch?v=cy3a__OOa2M https://www.khanacademy.org/science/health-and-medicine/advanc ed-hematologic-system/hematologic-system-introduction/v/coagula tion-cascade  Fibrin Fibrinogen converted to fibrin by thrombin Activation involves protease cleavage of fibrinogen to release fibrinopeptides that fit into pre-formed holes in other fibrin monomers to form a fibrin gel Fibrin monomers are initially bound non-covalently Activation of factor XIII by thrombin results in activation of this enzyme that catalyzes interchain covalent cross links Coagulation Cascade Drugs that prevent coagulation, Heparin and LMWH Heparin is a glycosaminoglycan (10-15 chains) with MW of 15,000 Da Can be found in secreted granules of mast cells Commonly extracted from porcine intestinal mucosa regulatory requirements for production: activity assessed by residual factor Xa activity LMWH (low-molecular weight heparin) also derived from animal tissues with MW 5000 Da Heparin and LMWH have no intrinsic activity: bind to antithrombin to accelerate inhibition Antithrombin is a suicide-substrate for proteases of intrinsic pathway Heparin-induced thrombocytopenia (HIT) is a severe complication! Drugs that prevent coagulation, Warfarin Also known as coumarin, discovered from the observation of hemorrhagic disorder in cattle that consumed spoiled sweet clover silage  Drugs that prevent coagulation, Warfarin o Oral administration making it convenient for use o Requires INR monitoring to titrate dose o Dosing also related to vitamin K dietary sufficiency o R versus S forms o Avoid during pregnancy o Excessive bleeding or overdose treament with vitamin K  PT Test APTT Test https://www.medicine.mcgill.ca/physio/vlab/bloodlab/PT_PTT.htm Warfarin Drugs that prevent coagulation, Dabigatran and Rivaroxaban Prevents clot stabilization Oral administration More predictable dose-response in comparison with warfarin Used with patients with atrial fibrillation, treat and prevent DVT and PE Overdose management now available IV idarucizumab for dabigatran: antibody therapy (350 times binding affinity) which traps drug from active stores Andeaxenat alpha: modified factor Xa that binds directly to Factor Xa inhibitors Fibrinolytic Drugs  Fibrinolysis Plasminogen activators (tPA) tPA activity increases 300-fold in presence of fib plasminogen fibrin plasmin Clot breakdown fibrinolysis Plasminogen activators: tissue plasminogen activator (tPA) synthesized in endothelial urokinase plasminogen activator (uPA) cells, released in conditions of blood stasis o tPA plays predominant role in intravascular fibrinolysis o tPA is released from endothelial cells in response to stimuli such as stasis o tPA activity increases 300-fold in presence of fibrin o tPA is rapidly cleared or inhibited by plasminogen activator inhibitor (PAI-1 and/or PAI-2) o Plasmin is inhibited by alpha-2-antiplasmin (occurs when plasmin not bound to fibrin)  t-PA exerts little effect on plasminogen in absence of fibrin  Briefly describe: How a platelet plug is formed The coagulation cascade (clot stabilization) and The fibrinolytic pathway (clot resolution) Describe the mechanism of action of Antiplatelet agents Anticoagulants Anticoagulant antidotes Fibrinolytic agents Understand the more common side effect(s) associated with clinical application for commonly Objectives used agents (i.e. the drugs you need to know for this section) for lecture