Drugs used in coagulation disorders

1. Drugs used in coagulation disorders By S.Bohlooli, Ph.D.

2. Mechanism of blood coagulation • Thrombogenesis • Blood coagulation • Regulation of coagulation and fibrinolysis • Fibrin inhibition: 1-antiprotease, 2-macroglobulin, 2-antiplasmin, antithrombin • Fibrinolysis: plasmin

3. Thrombogenesis

4. Blood coagulation

5. A model of blood coagulation

6. Fibrinolysis

7. Basic pharmacology of the anticoagulant drugs • Indirect thrombin inhibitors • Direct thrombin inhibitors • Warfarin and the Coumarin anticoagulants

8. Indirect thrombin inhibitors • Unfractioned heparin • Low molecular-weight heparin: • Enoxoparin, daltaparin, tinzaprin • foundaparinux

9. Differences between fondaparinux, LMWH and HMWH heparin

10. The antithrombin-binding structure of heparin

11. Toxicity • Bleeding • Thrombocytopenia • Caution in patient with allergy • Contraindicated in: • Hypersensitive • Actively bleeding • Hemophilia • Thrombocytopenia • Sever Hypertension • Intracranial hemorrhage • Advanced renal or hepatic disease

12. Direct thrombin inhibitors • Hirudin, lepirudin • Bivalirudin • Agatroban • Melagatran • Ximelagatran: oral prodrug

13. Warfarin and the Coumarin anticoagulants

14. Warfarin :Mechanism of action • Block the -carboxylation of several glutamate residue in prothrombine and factors VII, IX, and X • As well as the endogenous antigoagulant proteins C and S • There is 8- to 12-hour delay in the action of warfarin

15. Warfarin :Mechanism of action

16. Warfarin: Toxicity • bleeding • Readily crosses the placenta • Hemorrhagic disorders • Abnormal bone formation • Cutaneous necrosis • Frank infarction of breast, fatty tissues intestine, and extremities • Venous thrombosis

17. Basic pharmacology of the Fibrinolytic drugs

18. Contraindications to Thrombolytic Therapy • Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious trauma, cardiopulmonary resuscitation • Serious gastrointestinal bleeding within 3 months • History of hypertension (diastolic pressure >110 mm Hg) • Active bleeding or hemorrhagic disorder • Previous cerebrovascular accident or active intracranial process • Aortic dissection • Acute pericarditis

19. Basic pharmacology of Antiplatelet agents • Clyclooxygenase inhibitors:Aspirin • ADP receptor antagonists: Clopidogrel, ticlopidine • Blockers of GP IIB/IIIA receptors: abciximab, eptifibatide, tirofiban • Phosphodiesterase inhibitors: dipyridamole, cilostazol

20. Structure of ticlopidine and clopidogrel

21. Toxicity:Ticlopidine • nausea, vomiting, and diarrhea • severe neutropenia: 2.4% patients • Fatal agranulocytosis with thrombopenia

22. Clinical pharmacology of drugs used to prevent clotting • Venous thrombosis • Risk factors: • Inherited disorders • Acquired diseases • Anithrombotic management • Prevention • Treatment of established disease • Arterial thrombosis • Antiplatelet drugs

23. Drugs used in bleeding disorders • Vitamin K • Plasma fractions • Fibrinolytic inhibitors: aminocaproic acid • Serine protease inhibitors: aprotinin

24. Vitamin K

25. Vitamin K • to promote the biosynthesis of the -carboxy-glutamate (Gla) forms of: • factors II (prothrombin), VII, IX, and X • anticoagulant proteins C and S, protein Z (a cofactor to the inhibitor of Xa) • the bone Gla protein osteocalcin, matrix Gla protein, growth arrest-specific protein 6 (Gas6) • four transmembrane monospans of unknown function

26. Vitamin K Deficiency • increased tendency to bleed • Ecchymoses, epistaxis, hematuria, gastrointestinal bleeding, and postoperative hemorrhage • fetal warfarin syndrome: vitamin K-dependent protein in bone • deficits in bone mineral density and fractures

27. Toxicity • Phylloquinone and the menaquinones are nontoxic • menadione and its derivatives: • hemolytic anemia and kernicterus in neonates, especially in premature infants