Anticoagulants Thrombolytic Agents and Antiplatelet Drugs Management and

Anticoagulants, Thrombolytic Agents and Antiplatelet Drugs Management and Prevention of Vascular Thrombosis Benedict R. Lucchesi, M. D. , Ph. D. Department of Pharmacology University of Michigan Medical School Revised 10/03

Anticoagulant Therapy • Areas of Concentration and Drugs to Know Required Reading Goodman and Gilman 10 ed pages 1519 -1536. • Mechanisms for hemostasis – Thrombus Formation – Role of platelets – Venous thrombosis – Arterial thrombosis • • Biochemistry of coagulation Role of vitamin K Platelet Biology Thrombolysis

Drugs to Know • Anticoagulants and Adjuncts – Heparin – Protamine Sulfate – Low-molecular weight heparins » Enoxaparin (Lovenox™) » Dalteparin (Fragmin™) – Danaparoid (Orgaran™) – Lepirudin [r. DNA] (Refludan™) – Bivalirudin (Hirulog, Angiomax™) – Argatroban – Danaparoid (Orgaran™)

• Coumarin Derivatives – Warfarin – Dicumarol • Antiplatelet Drugs – Aspirin – Dipyridamole – Ticlopidine (Ticlid™) – Clopidogrel (Plavix™) – Abciximab (Reo. Pro™; Antibody to platelet GPIIb/IIIa receptor) – Tirofiban (Aggrastat™) Reversible, nonpeptide GPIIb/IIIa receptor antagonist – Eptifibatide (Integrilin™) cyclic peptide GPIIb/IIIa receptor blocker – Anagrelide (Agrylin™)

• Thrombolytic Agents –Streptokinase –Tissue plasminogen activator (rt-PA) » Alteplase (Activase™) » Reteplase (Retavase™) » Tenecteplase, TNK-t. PA (TNKase™) –Urokinase –Anisoylated plasminogen streptokinase activator complex (APSAC)

Development of Atherosclerotic Plaques

Thrombin

INTRINSIC PATHWAY EXTRINSIC PATHWAY IXa VIIa / Tissue Factor TFPI VIIIa a. PC Platelet Aggregation FACTOR Xa Prothrombin a. PC Protein S Va Thrombin PC / Thrombomodulin a. PC Inactivation Va & VIIIa Fibrinogen XIIIa Fibrin

Direct & Indirect Thrombin Inhibitors Thrombin Direct Inhibitors Hirudin Hirulog Argatroban Lepirudin [r. DNA] Other Agents Danaparoid Dermatan Sulfate Indirect Inhibitors ATIII Heparin LMWHs -dalteparin -enoxaparin

Anticoagulant Therapy • Reduce the formation of fibrin clots • Consist of two major types –Heparin and other Factor Xa, IIa inhibitors » LMWHs » Danaparoid » Lepirudin (Refludin™) » Bivalirudin (Angiomax™) » Argatroban –Warfarin