Anticoagulants and Thrombolytic

1. Anticoagulants and Thrombolytic

2. Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Tissue Factor XIIa XII Thromboplastin XIa XI IXa IX VIIa VII Xa X X Prothrombin Thrombin Factors affected By Heparin Fribrin monomer Fibrinogen Vit. K dependent Factors Affected by Oral Anticoagulants Fibrin polymer XIII

3. Classes of Drugs • Prevent coagulation • Dissolve clots • Prevent bleeding and hemorrhage - Hemostatic • Overcome clotting deficiencies (replacement therapies)

4. Classification A. Reduce the formation of fibrin clots. 1. INDIRECT THROMBIN INHIBITORS • UFH: Heparin • LMWH: Enoxaparin, dalteparin, tinzaparin • SYNTHETIC: Fondaparinux 2. DIRECT THROMBIN INHIBITORS • Parenteral: Hirudin, lepirudin • Oral: Ximelagatran, dabigatran 3. ORAL ANTICOAGULANT DRUGS • Coumarin anticoagulants • warfarin – dicumarol

5. ANTICOAGULANT DRUGS (contd.) B. Lyse thrombi already formed • Streptokinase, Urokinase, Anistreplase • Tissue Plasminogen Activator: Alteplase, Reteplase, Tenecteplase C. Antiplatelet drugs • Aspirin, clopidogrel, ticlopidine • Platelet glycoprotein IIa/IIIb Receptor blockers • Others: dipyridamole, cilostazol

6. Monitoring anticoagulant therapy • INR • Ratio of PT of patient • PT of normal person plasma INR = (patient PT/mean normal PT)ISI ISI= International sensitivity Index Relate measured prothrombin time to WHO reference standard thromboplastin ISI = 1

7. Fibrinolytic drugs • Life saving drugs • Enhance degradation of clots • Activation of endogenous protease • Plasminogen (inactive form) is converted to Plasmin (active form) • Plasmin breaks down fibrin clots • Recently formed thrombus is easily lysed by these drugs. • Aged thrombi (72 hrs) are usually resistant.

8. Fibrinolysis • Exogenously administered drugs • Streptokinase - synthesized by streptococci convert plasminogen to plasmin • Urokinase- human enzyme synthesized by kidney convert plasminogen to plasmin no immune response Plasmin is formed inside a thrombus , is protected from plasma antiplasmins , which allow it lyse the thrombus from within

9. Alteplase: Tissue plasminogen activator (tPA) - genetically cloned • no immune reaction • EXPENSIVE • Activate plasminogen bound to fibrin Tenectreplase mutant form of t PA has longer half life Anistreplase (APSAC) Purified human plasminogen and bacterial streptokinase

10. MECHANISMOF ACTION

11. Clinical uses of fibrinolytic drugs • Pulmonary embolism with hemodynamic instability • Severe deep venous thrombosis • Ascending thromboplebitis • Acute myocardial infarction (streptokinase loading dose 250,000 units) • Acute ischemic stroke (Recombinant t PA)

12. Adverse effects • Bleeding: • Fibrinolytic drugs may lyse both normal and pathologic thrombi. • Less effect is seen with t-PA (selectively activates plasminogen that is bound to fibrin) than streptokinase. • Bleeding can be controlled by Aminocaproic acid (inhibits plasminogen activation) • Hypersensitivity reaction: streptokinase • Arrhythmias: • Bradycardia, tachycardia • Free radicals generated after fibrinolysis.

13. Contraindications Absolute • Prior intracranial hemorrhage • Known structural cerebral vascular lesion • Known malignant intracranial neoplasm • Ischemic stroke within 3 months • Suspected aortic dissection • Active bleeding or bleeding diathesis

14. Relative • Uncontrolled hypertension • Major surgery within 3 weeks • Recent internal bleeding • For streptokinase prior allergic reaction • Pregnancy • Active peptic ulcer • Current use of warfarin

15. Antifibrinolytics • Drugs which inhibit plasminogen activation and dissolution of clot • 1- Epsilon amino-caproic acid (EACA) • 2- Tranexaemic acid Indications • Overdose of streptokinase • To prevent recurrence of subarachnoid and G.I hemorhage • Abruptio placentae, PPH and menorhagia

16. ANTIPLATELET DRUGS • THROMBOXANE A2 INHIBITORS • Aspirin • ADP RECEPTOR INHIBITORS • Ticlopidine • Clopidogrel • Prasugrel • GLYCOPROTEIN IIB/IIA INHIBITORS • Abciximab • Eptifibatide • PHOSPHODIESTERASE INHIBITORS • Cilostazol

17. Platelet aggregation & sites of drug action Vascular Endothelium         Collagen vWF Granules GP Ib GP Ia Aspirin . . . ... Platelet .. .. TXA2 ADP 5-HT … … .. .. . … … GP IIb/IIIa … … … Abciximab Clopidogrel Ticlopidine Fibrinogen GP IIb/IIIa  GP GP

18. ASPIRIN Mechanism & Pharmacological effects • Aspirin and most other NSAIDs inhibit the synthesis of prostaglandins: • Decrease endothelial synthesis of PGI2 (prostacyclin) • Decrease thromoboxane A2 production in platelets by inhibiting cyclooxygenase type I and type 2 • Irreversible inhibition of cyclooxygenase and platelet aggregation for the life of the platelet • It may cause bleeding, especially in the GI, and hypoprothrombinemic effect (high doses)

19. THERAPEUTIC USES OF ASPIRIN • Dose of aspirin 75-325 mg • Prophylactic for transient cerebral ischemia • Reduce the incidence of recurrent MI • Decrease mortality in postmyocardial infarction patients

20. TICLOPIDINE/CLOPIDOGREL Mechanisms and Pharmacological effects: • Inhibits adenosine diphosphate (ADP)-induced expression of platelet glycoprotein receptors & reduces fibrinogen binding and platelet aggregation. • Can be used in patients who are unresponsive to aspirin to prevent thrombotic stroke.

21. Clinical use • Prevent thrombosis in patients undergoing placement of a coronary stent • Ticlopidine Prevention of stroke in patients with a history of transient ischemic attack (TIA) or thrombotic stroke Adverse effects: Nausea, dyspepsia and diarrhea, thrombotic thrombocytopenic purpura

22. Clopidogrel • Unstable angina or non-ST elevation acute myocardial infarction in combination with aspirin • Neutropenia- Less with clopidogrel • Clopidogrel is preferred over ticlopidine

23. GLYCOPROTEIN IIB/IIA INHIBITORSABCIXIMAB • Chimeric (human-murine) monoclonal antibody • binds to platelet glycoprotein IIb/IIIa receptors and prevents binding by fibrinogen • used solely for the prevention of thrombosis in patients undergoing coronary angioplasty • Parenteral administration

24. DIPYRIDAMOLE (vasodilator) • Inhibits platelets adhesion to damaged blood vessels •  dosage  increase in platelets cAMP formation and  platelet Ca++ which inhibits platelets aggregation • Used in combination with aspirin to prevent cerebrovascular ischemia

25. Drugs used in bleeding disorders • Vitamin K (oral and parenteral forms) K1 and K2 newborns, vit k deficiency in patients with poor diet, parenteral nutrition, recent surgery • Plasma factors: factor VII, VIII, IX • Desmopressin acetate (increase the factor VIII activity) • Autoplex (factor VIII) • Cryoprecipitate (plasma protein fraction) Used in DIC

26. Fibrinolytic Inhibitors • Aminocaproic acid • Tranexamic acid

27. Uses of antifibrinolytic drugs • Adjunctive therapy in hemophilia • Control bleeding from fibrinolytic therapy • Prophylaxis for bleeding from intracranial aneurysms • Post-surgical GI bleeding • Bladder hemorrhage secondary to radiation & drug-induced cystitis • Gynecological bleeding – fibroids, PPH

28. Anticoagulants used in vitro • Calcium complexing agents sodium oxalate sodium edetate