Med Phys Pharm L28 Antiplatelet Pharmacology (student) PDF

Activation Lecture #28: Antiplatelet Pharmacology Brian Skinner, PharmD, BCPS Associate Professor of Internal Medicine Marian University – College of Osteopathic Medicine BMS 551 Med Phys Pharm...

Activation Lecture #28: Antiplatelet Pharmacology Brian Skinner, PharmD, BCPS Associate Professor of Internal Medicine Marian University – College of Osteopathic Medicine BMS 551 Med Phys Pharm Schedule Office Hours Fall 2024 Citation: Chapter 13 Overview of Hemostasis, Aster JC, Bunn H. Pathophysiology of Blood Disorders, 2e; 2016. Available at: https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=249048269&gbosContainerID=0&gbosid=0&groupID=0&sectionId=1373952 49&multimediaId=undefined Accessed: November 21, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved  Objectives 1. Describe the steps of platelet plug formation 1. Specifically, identify the role of the following as it relates to platelet plug formation: cAMP, Ca2+, vWF, PLA2, arachidonic acid, TxA2, ADP, PKC, PKA, PDE 2. Specifically, identify the role of the following platelet glycoproteins: Ib, IIb/IIIa, VI 2. Identify the mechanism of action, dosage form, adverse events, indications, and contraindications of the highlighted antiplatelets discussed in this lecture 3. Describe the clinically significant metabolic pathway for clopidogrel 4. Identify the structure of the active metabolite for clopidogrel 5. Diagram the arachidonic acid pathway as it relates to PGE2, TxA2, and leukotriene synthesis 6. Given a simplified patient case, recommend the most appropriate pharmacotherapeutic strategy Unless otherwise noted, figures in today’s lecture are from: Principles of Pharmacology 4e Golan (Ch. 22), Lippincott Illustrated Reviews: Pharmacology 6e Whelan (Ch. 22)  Drug Overview Classification of antiplatelet drugs based on mechanism of action. PAR-1, protease-activated receptor-1 Citation: Chapter 3 Antiplatelet Therapy, Crawford MH. Current Diagnosis & Treatment: Cardiology, 6e; 2023. Available at: https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=275244953&gbosContainerID=0&gbosid=0&groupID=0&sectionId=275244945&multimediaId=undefined Accessed: November 21, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved  AKA Factor III Drug Overview Site of action of antiplatelet drugs. Aspirin inhibits the synthesis of thromboxane A2 (TXA2) by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TXA2 release attenuates platelet activation and recruitment to the site of vascular injury. Ticlopidine, clopidogrel, and prasugrel irreversibly block P2Y12, a key adenosine diphosphate (ADP) receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12. Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor (vWF) binding to activated glycoprotein (GP) IIb/IIIa. Vorapaxar inhibits thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on human platelets. (Reproduced with permission from Kasper D, et al., eds. Harrison’s Principles of Internal Medicine, 19th ed. New York: McGraw-Hill; 2015.) Citation: Chapter 3 Antiplatelet Therapy, Crawford MH. Current Diagnosis & Treatment: Cardiology, 6e; 2023. Available at: https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=275244950&gbosContainerID=0&gbosid=0&groupID=0&sectionId=275244945&multimediaId=undefined Accessed: November 21, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved Drug Overview Hemostasis and Thrombosis Hemostasis – the stopping of blood flow Thrombosis – the most common abnormality of hemostasis Platelet-rich clots (White thrombus) Myocardial Infarction (MI) Focus of L28 Transient Ischemic Attacks (TIAs) Peripheral Arterial Clots Fibrin-rich clots (Red thrombus) Cardioembolic strokes from atrial fibrillation Focus of L27 Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE) Hemostasis and Thrombosis Hemostasis – the stopping of blood flow Thrombosis – the most common abnormality of hemostasis Platelet-rich clots (White thrombus) Myocardial Infarction (MI) Focus of L28 Transient Ischemic Attacks (TIAs) Peripheral Arterial Clots Fibrin-rich clots (Red thrombus) Cardioembolic strokes from atrial fibrillation Focus of L76 Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE)  Formation of a Hemostatic Plug 3 Main Steps: 1. Adhesion 2. Granule Release 3. Aggregation & Consolidation GP VI & vWF Formation of a Hemostatic Plug 3 Main Steps: 1. Adhesion  Platelet Adhesion Platelet adhesion requires two molecular interactions von Willebrand Factor (vWF) Secreted by activated platelets and exposed collagen Binds to Glycoprotein Ib on the surface of the activated platelet GPIb:vWF:collagen interaction Platelet Glycoprotein VI (GPVI) Expressed on surface of platelet & interacts with exposed collagen GPVI:collagen interaction GP VI & vWF  Formation of a Hemostatic Plug 3 Main Steps: 1. Adhesion 2. Granule Release 3. Aggregation & Consolidation GP VI & vWF  Granule Release Numerous chemical mediators are released in response to platelet activation 1. ADP, epinephrine, and collagen activates phospholipase A2 (PLA2) which is responsible for liberating arachidonic acid and activating glycoprotein IIb/IIIa (GPIIb/IIIa) 2. Arachidonic acid is converted into thromboxane A2 by cyclooxygenase-1 (COX-1) 3. ADP, Ca2+, ATP, serotonin, vWF, and platelet factor 4 are released during degranulation GP VI & vWF Aggregation & Consolidation Aggregation & Consolidation  Formation of a Hemostatic Plug 3 Main Steps: 1. Adhesion 2. Granule Release 3. Aggregation & Consolidation GP VI & vWF  Platelet Aggregation Inhibitors COX-1 P2Y12 GPIIb/IIIa PDE Inhibitors Inhibition Inhibitors Inhibitors Aspirin Clopidogrel Abciximab Cilostazol Prasugrel Eptifibatide Dipyrimadole Ticlopidine Tirofiban Ticagrelor Cangrelor The Arachidonic Acid Pathway  COX-1 Inhibitors: Aspirin Mechanism: Decreased TxA2 production via acetylation of a serine residue on COX-1 enzyme Irreversible Indications: Secondary prophylaxis following MI or stroke Prevention of thrombotic events after/during percutaneous coronary intervention Adverse effects: GI bleeding & ulcer formation due to decreased production of PgE2 Increased risk of asthma exacerbations due to increased leukotriene production Dosage Forms: oral tablet, enteric coated tablet  P2Y12 ADP Receptor Inhibitors: Clopidogrel Mechanism of Action: Prodrug that upon activation by CYP2C19 irreversibly binds to, and inactivates, the ADP receptor at a cysteine residue by creating a disulfide bond Indications: Secondary prophylaxis following MI or stroke Prevention of thrombotic events after/during percutaneous coronary intervention (PCI) Adverse effects: Bleeding Increased risk of treatment failure in CYP2C19 poor metabolizers and in patients on CYP2C19 inhibitors Dosage forms: oral tablet CYP2c19 CYP2c19 Clopidogrel (inactive) Thiolactone metabolite (inactive) Active metabolite  P2Y12 ADP Receptor Inhibitors: Ticagrelor Mechanism of Action: Active drug that reversibly binds to ADP receptor by mimicking adenosine Indications: Secondary prophylaxis following MI or stroke Prevention of thrombotic events after/during percutaneous coronary intervention (PCI) Adverse effects: Bleeding Dosage forms: oral tablet Ticagrelor Adenosine  GPIIb/IIIa Inhibitors: Abciximab Mechanism of Action: Monoclonal antibody that reversibly binds to, and inactivates, GPIIb/IIIa preventing its interaction with fibrinogen and platelet aggregation Indications: Prevention of thrombotic events DURING percutaneous coronary intervention (PCI) as an alternative to P2Y12 inhibitor Adverse effects: Bleeding Dosage forms: Intravenous bolus followed by intravenous infusion  GPIIb/IIIa Inhibitors: Eptifibatide Mechanism of Action: Cyclic peptide that reversibly binds to, and inactivates, GPIIb/IIIa preventing its interaction with fibrinogen and platelet aggregation Indications: Prevention of thrombotic events DURING percutaneous coronary intervention (PCI) as an alternative to P2Y12 inhibitor Adverse effects: Bleeding Dosage forms: Intravenous bolus followed by intravenous infusion Phosphodiesterase Inhibitors: Cilostazol Mechanism of Action: inhibition of phosphodiesterase- 3 (PDE3) resulting in increased catabolism of cAMP Stabilization of inactive GP IIb/IIIa Stabilization of secretory granules X Decreased arachidonic acid release therefore decreased TxA2 Smooth muscle relaxation Indications: Intermittent claudication (used in combination with aspirin or clopidogrel) Adverse effects: Bleeding Headache (vasodilation of cerebral arteries) Contraindication: heart failure Dosage forms: Oral tablet  Activation Lecture #28: Antiplatelet Pharmacology Brian Skinner, PharmD, BCPS Associate Professor of Internal Medicine Marian University – College of Osteopathic Medicine BMS 551 Med Phys Pharm Schedule Office Hours Fall 2024 Citation: Chapter 13 Overview of Hemostasis, Aster JC, Bunn H. Pathophysiology of Blood Disorders, 2e; 2016. Available at: https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=249048269&gbosContainerID=0&gbosid=0&groupID=0&sectionId=1373952 49&multimediaId=undefined Accessed: November 21, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved