Fibrinolytics and antifibrinolytics

Fibrinolytics and antifibrinolytics

1. Moderator: Dr Ravichandra Presenter: Dr Manjuprasad Fibrinolytics and Ant ifibrinolytics 1

2. overview Coagulation cascade Fibrinolytic system Fibrinolytic agents Antifibrinolytic agents 2

3. The agents commonly used for controlling blood fluidity: Parenteral and oral anticoagulants Antiplatelets Antifibrinolytics 3

4. Coagulation cascade 4

5. Initiation of coagulation Tissue factor exposed Form complex with VIIa This complex activates factor X and IX 5

6. intrinsic pathway activated when Factor XII, prekallikrein and higher molecular weight kininogen interact with kaolin glass or other surface to generate small amounts of factor XIIa 6

7. Activation of Prothrombin By cleaving two peptide bonds on prothrombin , factor Xa converts it to thrombin. presence of factor Va , a negatively charged phospholipid surface, and Ca 2+ , factor Xa activates prothrombin with 10 9 -fold greater efficiency. 7

8. Conversion of fibrinogen to fibrin - Fibrinogen is a dimer - Each half has 3 pairs of polypeptide chain (A α , B β , γ ) - Disulphide bonds links the two chains 8

9. Thrombin converts fibrinogen to fibrin monomers by releasing fibrinopeptide A and fibrinopeptide B from amino terminus of A α and B β respectively. New amino terminus formed Fits into preformed holes on other fibrin monomers to form fibrin gel 9

10. Fibrin is a potent platelet agonist Amplifies platelet activation and aggregation 10

11. THROMBUS 1 . Arterial – Mainly by platelet 2 . Venous - Mainly by fibrin 11

12. fibrinolysis Plasminogen activator activates plasminogen to plasmin Two types- t-PA u-PA Plasminogen and plasmin binds to lysine residues on fibrin - kringle domains 12

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14. Physiological inhibitors of fibrinolysis Plasminogen activator inhibitor 1 Plasminogen activator inhibitor 2 ἀ2 – antiplasmin inhibits plasmin generated by binding to first kringle domain Plasma carboxypeptidase removes the lysine residue on fibrin at carboxyterminal 14

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16. To prevent premature clot lysis factor XIIIa mediates covalent cross linking of small amounts of α 2-antiplasmin onto fibrin surface. 16

17. FIBRINOLYTIC DRUGS PLASMINOGEN ACTIVATORS : 1ST generation : Streptokinase Urokinase 2nd generation : Anistreplase Alteplase Reteplase Tenecteplase 17

18. NEWER PLASMINOGEN ACTIVATOR Saruplase Monteplase Lanoteplase NEWER FIBRINOLYTICS Desmoteplase Alfimerase BB 10153 18

19. Endopeptidases : Ancrod Fibrinolysin Factor XIIIa inhibitors TRIDEGIN DESTABILASE 19

20. STREPTOKINASE Protein obtained from Group-C ß hemolytic streptococci. No intrinsic enzyme activity. Forms a stable non covalent 1:1 complex with plasminogen. Causes the conformational change in the plasminogen. Exposes the active site and converts to plasmin. 20

21. Sk -plasminogen complex Free and fibrin bound plasminogen Plasmin Systemic lytic state Half life 60-80 min 21

22. uses In acute MI In Pulmonary Thromboembolism A/E : Hemorrhage ,Allergic reaction like rash, chills ,rigor ,fever . rarely anaphylaxis 22

23. To be avoided in patient -with recent major streptococcal infection -previous treatment by streptokinase because antibodies diminishes efficacy 23

24. ANISTREPLASE Anisolyated plasminogen streptokinase activator complex (APSAC) Complex consist of purified human plasminogen & streptokinase in which active site is masked with anisoylation On administration acyl group hydrolyses spontaneously releasing activated SK-plasminogen complex 24

25. Has a longer half life of 100min A/E : Hemorrhage Allergic reaction Hypotension 25

26. UROKINASE Two chain serine protease enzyme derived from cultured fetal kidney cells Direct plasminogen activator which degrades both fibrinogen and fibrin More fibrin specific than streptokinase Produces systemic lytic state t1/2 – 20 min 26

27. ALTEPLASE Recombinant form of single chain t-PA Rapidly activates plasminogen bound to fibrin Fibrin specific ,but not selective Not antigenic but anaphylactoid reaction in atopic patient . t ½ 5-10 min DUTEPLASE - Double chain recombinant t-PA 27

28. TENECTEPLASE Genetically engineered mutant form of alteplase Longer half life Resistance to inhibition by PAI 1 .t1/2- 2hrs Dosage: single bolus dose of 50mg over 5sec 28

29. SARUPLASE Recombinant nonglycosylated form of single chain urokinase type plasminogen activator Derived from genetically transformed E.coli Dose :20 mg infusion immediately followed by 60 mg over 1hr or Double bolus 40 mg 30 min apart 29

30. MONTEPLASE Mutant type of t-PA Independent of PAI Uses: Myocardial infarction Pulmonary thromboembolism thrombolysis Endovascular thrombolysis for DVT Dose- 160x104 IU 30

31. LANOTEPLASE Recombinant t-PA long half life Single bolus dose 120 KU /kg Plasma activity lasts for 6 hrs compared to alteplase 4hrs Disadvantage - Intracranial hemorrhage rate higher 31

32. Therapeutic indications STEMI : Should be initiated within 30 minutes Benefit most if Rx within 1-3 hrs In massive pulmonary thromboembolism reverses the condition by 1. dissolving the thrombus obstructing pulmonary artery 2. prevent the continued release of serotonin and other neurohormonal factor which aggrevate pulmonary HTN 3.lysis of much of source of thrombus in pelvic or deep vein reduces recurrent PE 32

33. Acute deep vein thrombosis Peripheral arterial thromboembolism Thrombosis on prosthetic material Acute ischemic stroke Clear the occluded cannula 33

34. CONTRAINDICATIONS Absolute : Prior intracranial hemorrhage Known structural cerebral vascular lesion Known malignant intracranial neoplasm Ischemic stroke within 3 months 34

35. Suspected aortic dissection Active bleeding or bleeding diathesis Significant closed head trauma or facial trauma within 3 months. 35

36. Relative : - Uncontrolled hypertension (SBP>180,DBP>110mm of Hg) - Traumatic or prolonged CPR or major Surgery within 3 weeks -Pregnancy -Active peptic ulcer -Current use of warfarin and INR>1.7 . 36

37. ALFIMERASE Recombinant form of fibrolase (zinc metalloprotease from venom of southern copper head snake) Degrades directly alpha chain of fibrin and fibrinogen Action independent of plasminogen concentration and not inhibited by PAI 1 Inhibited by ἀ2 macroglobulin limits systemic effects 37

38. Uses: 1.Catheter directed lysis of peripheral arterial occlusion 2. Local delivery to restore flow in indwelling catheter blocked by thrombus 38

39. DESMOTEPLASE Recombinant analogue of full length plasminogen activator from saliva of vampire bat Binding via finger like domain and catalytic activity enhanced in the presence of fibrin Use : Acute ischemic stroke but lacks efficacy 39

40. BB10153 Variant form of plasminogen t1/2 4.4hrs Use: Acute ischemic stroke ,Peripheral arterial occlusion 40

41. TRIDEGIN – Isolated from giant amazon leech DESTABILASE-From leech Not tested in humans 41

42. FIBRINOLYSIN Enzyme derived from plasma of bovine origin or extracted from the culture of certain bacteria Used along with desoxyribonuclease which destroys DNA Acts locally by inactivating fibrin molecule Uses: Superficial wound , minor burn, ulcer CI: Hypersensitivity A/E: Increased pain, Burning sensation 42

43. ANCROD Proteolytic enzyme derived from the venom of Malayan pit viper Action through fibrinogen degraded product ,acts as a cofactor for t-PA induced plasminogen activation Reduction in blood viscosity Use : Atherosclerotic disease 43

44. t ½ 3-5 hrs Eliminated renally Administered parenterally A/E: Hypersenstivity , thrombophlebitis of injected vessel 44

45. ANTI FIBRINOLYTIC DRUGS LYSINE ANALOGUES: EPSILON AMINO CAPROIC ACID TRANEXAMIC ACID SERINE PROTEASE INHIBITOR APROTININ 45

46. EPSILON AMINO CAPROIC ACID Competes for lysine binding site on plasminogen and plasmin , blocks the interaction of plasmin with fibrin Rapidly absorbed orally Removed by kidney Dose : 5 g orally 4 times a day IV – 5 g loading dose infusion over 30 min 1-1.25 g/ hr – till bleeding stopped 46

47. Therapeutic uses : - Over dose of thrombolytic agent t-PA , Streptokinase - Post surgical bleeding – GIT , cardiac , orthopedic, prostatic - Adjuvant treatment in hemophilia - Prophylaxis for rebleeding from intracranial hemorrhage - Bladder hemorrhage secondary to radiation - Hereditary angioneurotic edema 47

48. A/E: Nausea Hypotension Myopathy Muscle necrosis Abdominal discomfort Nasal stuffiness Intravascular thrombosis. 48

49. TRANEXAMIC ACID Analogue of aminocaproic acid More potent than EACA t1/2 : 2hrs Less protein bound Excreted in urine Dose : oral 1 to 1.5 g , 2 to 3 times /day I.V inj 10 mg/kg tid 49

50. Therapeutic uses: Treatment and prophylaxis of hemorrhage with excessive fibrinolysis Prevention of bleeding after surgery or trauma -Tooth extraction in patient with hemophilia -Cervical conisation -Prostatic surgery -Cardiac surgery 50

51. Primary or IUD induced hemorrhage Heavy bleeding associated with fibroid Prevent rebleeding in ruptured intracranial hemorrhage Dentistry 5% mouth rinse Hereditary angioneurotic edema Treatment of recurrent epistaxis 51

52. 52 A/E: GIT distress Hypersensitivity skin reaction Musculoskeletal pain DVT Ocular and visual disturbance Post operative convulsion

53. APROTININ 53 Monomeric globular polypeptide derived from bovine lung tissue Inhibits several serine protease – trypsin, chymotrypsin, plasmin, kallikrein t ½ 5 – 10 hrs 2KIU bolus then 2 to 5 KIU IV every 4hr slow infusion

54. 54 USES: Reduce bleeding from open heart surgery Liver transplantation Blood loss in obstetric patient Prostate surgery Ruptured intracranial aneurysm Prevention of post operative DVT Acute pancreatitis Topical use in neurosurgery

55. 55 A/E: Acute renal failure Heart attack Stroke Encephalopathy Anaphylaxis Thrombosis DIC

56. REFERENCES 56 Goodmann and Gilman’s The pharmacological basis of therapeutics 12 th edition Principles of pharmacology HL Sharma KK Sharma 2 nd edition Textbook of medical pharmacology – Padmaja udaykumar Basic clinical pharmacology Katzung 11 th edition

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