Drug used in disorders of coagulation

1. Drug used in disorders of coagulation Vladimír Moravec, M.D.

2. Mechanisms of blood coagulation • Trombogenesis: • the platelet - white trombus - red trombus • Hemostasis: • 1.adhesion and activation of platelets • 2.fibrin formation • 3.vascular contraction

4. Blood coagulation • Two pathways: • 1.Intrinsic system • 2.Extrinsic system • Viz.Figure

6. Monitoring of coagulation • 1. Extrinsic koagulo-pathways - components presents in plasma – aPTT • 2. Intrinsic koagulo-pathways – with participation of tishue components – • Prothrombin time (Quick test), • INR (International normalized ratio)

7. Bleeding therapy • Haemostatics - local vasoconstriction • Antifibrinolytics- inhibit fibrinolysis • Antiaggregants – against platelets agregation • Fibrinolytics– rapidly lyse thrombus • Anticoagulants -blood coagulation

8. 1. Haemostatic drugs • Somatostatin • Antithrombin III • Protamine sulfate, vitamin K - antidotum • Ethamsylate - facility of platelets agregation • Desmopressin, Terlipressin • Vasopresin, alfamimetics – vasoconstriction • Global efficacy : plasma, coagul. factors • Local efficacy: gelatin, collagen • Deficience of factors F. VIII., F. IX.

9. Somatostatin • naturally occurring tetradecapeptide that produces numerous physiologic effects. • rapidly inactivated by peptidase enzymes; its plasma half-life is 1 to 3 minutes.

10. Clinicalapplications • efficacy in a variety of clinical conditions, including carcinoid syndrome, enterocutaneous and pancreatic fistulas, the dumping syndrome, VIPomas, glucagonomas, diabetes mellitus, insulin excess in neonates, psoriasis, and short-bowel syndrome • its efficacy in upper gastrointestinal bleeding is controversial

11. ANTITHROMBIN III • purified preparations of antithrombin III derived from human plasma. • Antithrombin III concentrate is primarily used for the prophylaxis and treatment of patients with congenital antithrombin III deficiency and disseminative intravascular coagulopathy.

12. PROTAMINE SULFAT • strongly basic protein that is capable of neutralizing the effects of HEPARIN. • dose is 1 mg IV for every 100 units of HEPARIN remaining in the patient; doses of 50 mg should not be exceeded within a 10-minute period to decrease the risk of adverse effects; the dose is usually administered by intravenous bolus over 1 to 3 minutes, but a constant infusion over 30 minutes may also be given.

13. 2. Pharmacology of the anticoagulantdrugs • 1.- Heparin X Protamin sulfat, Antitrombin III., LMWH, Fraxiparin • 2. - Warfarin X Vit K, Pelentan • Dicumarol, Phenprocoumon (6days)

14. ANTICOAGULANTS 1. direct - Heparin (antidotum-Protamin sulfat), Antithrombin III., Low-molecula-weight-heparin(LMWH) , Heparinoids – (local)

15. ANTICOAGULANTS • 2. indirect - Warfarin (antidotum Vit K), Pelentan

16. Heparin • aktivation Antithrombin III. • Inhibition of thrombocyt agregation • Aktivation of lipoprotein lipase (hypolipidemic effect) • bolus 5-10 tis. m.j., 1 tis. J/hod, aPTT • Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT) • In contrast, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin.

19. LMWH Generic name: antiXa/IIa t 1/2 (hod) Dalteparin 2 : 1 119-139 sodium Nadroparin 3,2 : 1 132-162 calcium Enoxaparin 2,7 : 1 129-180 sodium Tinzaparin 1,9 : 1 111 sodium

20. Hirudin In nature - Hirudo medicinalis Specific thrombin inhibitor from the leech. Now is prepared by recombinant DNA technology – lepirudin • selective inhibitor of thrombinu, • action is independent of ATIII. • Hirudin has litle effect on platelets or the bleeding time. APTT monitoring antidotum is not available

21. Cumarine anticoagulants • Oral anticoagulants. • Block the carboxylation of several glutamate residues in prothrombin and factors VII, IX, X., and protein C.(endogenous anticoagulans) • antagonists of Vitamin K - f. VII, IX, X, • dicumarol - Etylbiskumacetate (Pelentan) • monocumarin - Warfarin , 1xd

22. 3. Fibrinolytic drugs • Rapidly lyse thrombi by catalyzing plasmin protease from its precursor plasminogen. • Fibrin degradation • Administered by intravenous infusion (250 000 units, followed by 100 000 units/h • Indication: multiple pulmonary emboli, central deep venous thrombosis, acute myocardial infarction • Viz figure

24. Fibrinolytics drugs • trombolytics 1. generation : streptokinase, urokinase – notselective, systemic fybrinolysis • trombolytics 2. generation: tissue plasminogen activators (tPA) with recombinant types: rt-PA Alteplase -is unmodified human t-PA. Antistreplase(ASPAC)- anisolated plasminogen streptokinase activator complex.

25. Fibrinolytics drugs • Streptokinase is a protein synthetised by streptococci that combines with the plasminogen. This complex catalyzes the conversion of inactive plasminogen to active plasmin. • Urokinase is a human enzyme synth. By the kidney that directly converts to plasmin. • Antistreplase consists of a complex plasminogen and streptokinase that has been acylated to protect.

26. FIBRINOLYTICS FIBRINOLYTICS Plasminogen Inhibition Activation Various stimuli + Blood proactivator Blood activator - + Antiactivators urokinase - + Streptokinase Activator + Proactivator Plasmin t-PA Anistreplase + + Thrombin Fibrin split products Degradation products Fibrinogen Fibrin

28. Antifibrinolytics • Antidotum: Aprothinin, PAMBA, Etha aminokapronic acid.

30. 4. Antitrombotic drugs: Drug that antagonize pathway interfere with platelet agregation in vitro and prolong the bleeding time in vivo.

31. Platelet function is regulated • Platelet function is regulated by three categories of substances: • Contains agents generated within the platelet that interact with membrane receptors: • Catecholamines, collagen, thrombin, prostacyclin • ADP, prostaglandinD2, E2, serotonin • Paltelets within platelet: cAMP a cGMP, TxA2

32. Antitrombotic - antiplatelet drugs • Representants: • Aspirin – inhibition of prostaglandine meetabolisme • Ticlopidin, Clopidogrel – inhibition of ADP-induced platelet aggregation • Dipyridamol • Abciximab – parenteral – blockade of GP 2b/3a

35. Aspirin, ASA • Aspirin inhibits the synthesis of TxA by irreversible acetylation of the enzyme cyclooxygenase 2. The platelet canot manufacture new enzyme during its 10-day lifetime. • Prolong the bleeding time. • Studies were conducted to ëwaluate the use of aspirin for 4-5 years in the primary profylaxis of cardiovascular mortality. • Dosses?? 100-325 mg/day

36. Ticlopidine • Reduce platelet aggregation by inhibiting the ADP pathways of platelets. • Adverse effects include nausea, dyspepsia, hemorage, leukopenia. • Dosage is 250 mg/twice day • Its useful in patients who cannot tolerate aspirin.

37. Ticlopidin a Clopidogrel

38. Ticlopidin - negatives?? • Adverse ractions: Granulocytopenie ( 2,4% cases). • Ticlopidin is more Expensive against aspirin.

39. Abciximab • New class of platelet-inhibiting drug that blocks platelet receptors. • Is a mouse/human chimeric monoclonal antibody that blocks IIb/ IIIa receptors.

40. 5. Drugs used in bleeding disorders • Vitamin K • Fibrinogen • Deficience of f. VIII., f. IX. • Fibrinolytic inhibitors: Aminocapronic acid, PAMBA, Aprothinin

41. Thank you...