Antiplatelet new and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations

Dr Rahul Kunkulol's Power Point Presentations

1. Anticoagulants Dr Rahul Kunkulol Department of Pharmacology, RMC,LONI

2. ANTIPLATELETS Dr Rahul Kunkulol Department of Pharmacology, RMC,LONI

3. HAEMOSTASIS- Cessation of blood loss from damaged blood

4. Vascular Phase Tissue Factor

5. Platelet Phase

6. WHAT ARE PLATELETS ?

7. Normal Function of Platelets

8. Adhesion , shape change, spreading and secretion

9. Platelet Aggregation Fibrinogen binding to Glycoprotein IIb-IIIa on activated platelets

10. Collagen VWF INJURY Platelet Adhesion & Secretion Platelet aggregation Tissue Factor Coagulation Cascade Thrombin Fibrin Haemostatic plug Vaso - constriction Blood Vessel Endothelium Subendothelium

11. Thrombogenesis Arterial thrombi Platelet aggregates bound together by fibrin strands (white clots) Venous thrombi Consist mainly of fibrin and RBCs (red clots) Arterial thrombus

12. Platelets and Thromboemolism Arterial thrombus (white) O ccludes artery / disintegrates into emboli occluding distal vessels resulting in ischemic necrosis of tissue supplied by the artery.(AMI) Venous thrombus (red) Veins low pressure : Reduced blood flow (stasis) Especially in valve pockets Causes tissue drained by the vein to be edematous and inflamed (DVT)

13. Virchow’s Triad Thrombosis Stasis Hypercoag- ulability Vascular Injury Venous Arterial Rudolph Virchow

14. Vascular Injury Trauma Surgical manipulation Prior thrombosis Atherosclerosis Vascular Injury

15. PLATELET AGGREGATORS

16. Damaged blood vessel Release of collagen Activation of platelets Arachidonic acid Release of thrombin Release of ADP Cyclic endperoxidase COX Release of TXA2 Activation of glycoprotein IIB/IIIA receptors Fibrinogen fibrin Activates P2Y1 Gq Gi Changes in platelet shape Increases phospoinositol inhibits adenylcyclase , decrease CAMP ?

17. Targets for anti-platelet therapy Aspirin NSAIDs ADP receptor COX-1 TXA2 GP IIb - III a Signalling pathways ADP receptor antagonists Clopidogrel THROMBIN receptor Thrombin inhibitors II Fibrinogen Phosphodiesterase inhibitors dipyridamole Fibrinogen Receptor Antagonists AA

18. PGI 2- (Prostacyclins)

19. CLASSIFICATION OF ANTIPLATELET AGENT-

20. Damaged blood vessel Release of collagen Activation of platelets Arachidonic acid Release of thrombin Release of ADP Cyclic endperoxidase COX Release of TXA2 Activation of glycoprotein IIB/IIIA receptors Fibrinogen fibrin Activates P2Y1 Gq Gi Changes in platelet shape Increases phospoinositol inhibits adenylcyclase , decrease CAMP ?

21. Pentoxifyllines

22. Questions Discuss in detail antiplatelet drugs. Add note on use of low dose Aspirin as an antiplatelet agent. Short note: Low dose Aspirin Ticlopidine Glycoprotein IIb / IIIa antagonists

23. Anticoagulants Dr Rahul Kunkulol Department of Pharmacology, RMC,LONI

24. Coagulation Phase

25. Clotting factors 35

26. Intrinsic Pathway All clotting factors are within the blood vessels Clotting slower Activated partial thromboplastin test ( aPTT ) Blood sample + calcium Mix with negatively charged phospholipid Kaoline (aluminum silicate) Determine clotting time Generally clotting occurs in 26 to 33 seconds Used to detect defects in the intrinsic pathway Extrinsic Pathway Initiating factor outside the blood vessels - tissue factor Clotting - faster - in Seconds Prothrombin test (PT) Tissue Thromboplastin factor III Mix with phospholipid extract Add calcium and blood sample Determine clotting time Generally 12 - 14 seconds Used to detect defects in extrinsic pathway

27. Diagnosis of coagulation defects

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

29. Activation Inactive XI Active XIa XIIa +

30. ANTICOAGULANTS These are the drugs used to reduce coagulability of blood. Classification In vitro anticoagulants In vivo anticoagulants Heparin A) -Heparin Sodium citrate -Low molecular weight Heparin Sodium oxalate - Danaparoid Sodium edetate - Lepirudin - Heparan sulfate B) Oral anticoagulants

31. B) Oral anticoagulants Warfarin sodium Bishydroxycoumarin ( dicumarol ) Acenocoumarol Phenindione

32. Heparin

33. MOA Heparin binds to antithrombin III -----complex Increases thrombin –AT reaction 1000folds. Heparin induces conformational change in ATIII to expose its interactive sites . Long heparin molecule provides scaffolding for clotting factors ( Xa & IIa ) aswellas ATIII. At low conc. interferes with intrinsic pathway while at high common pathway. ATIII inhibits activated clotting factors of intrinsic and common pathway including thrombin, Xa , IXa and thus acts as S uccide substrate

34. ATIII-SUCCIDE SUBSTRATE

35. Thrombin inhibition catalysed by heparin AT R H AT H IIa AT H IIa IIa AT H IIa R P P P P R R

36. FXa inhibition catalysed by heparin AT R H AT H Xa AT H Xa Xa AT H Xa R P P P P R R

37. Anticoagulant Properties of Heparin Inhibits the thrombin-mediated conversion of fibrinogen to fibrin Inhibits the aggregation of platelets by thrombin Inhibits activation of fibrin stabilizing enzyme Inhibits activated factors XII, XI, IX, X and II

38. Pharmacokinetics Not effective orally Sc / iv administration Onset immediate, peak in 5-10mins Metabolized in liver Excretion through kidney.

39. Unfractionated Heparin High Dose Treatment of venous/arterial thrombi Requires monitoring IV- 5,000 Units bolus, then 30,000-35,000 units/24 hrs 80 Units/kg bolus, then 18 Units/kg/ hr to maintain aPTT in therapeutic range therapeutic goal – 2-2.5 times normal control value (-30 sec)

40. Low Dose Unfractionated Heparin Surgical Prophylaxis 5,000 Units SC 2 hr preop 5,000 Units SC every 12 hours Medical Prophylaxis 5,000 Units SC every 12 hours No monitoring required

41. ADVANTAGES OF LMWH Less anti IIa activity than anti Xa activity Good pk profile More predictable dose response Can be given by subcutaneous route No monitoring required, can be given OPD basis Less anti-platelet effects Longer t 1/2 ’s Decreased hospital stay More favorable benefit –risk ratio

42. LMWH Enoxa parin 1mg/ kg S.C BD for DVT 30mg/ Kg S.C. for DVT prophylaxis of Knee and hip surgery Dalteparin 1mg/ kg S.C BD for DVT 30mg/ Kg S.C. for DVT prophylaxis of Knee and hip surgery Newer Ardeparin Nadroparin Tinzaprin Reviparin

43. Adverse effects Allergic and anaphylactic manifestations Bleeding (1-33%)-antidote- Protamine sulphate Heparin induced thromocytopenia . (more than 25%) Alopecia Osteoporosis Hyperkalemia

44. Mechanisms of HIT Type 1 (Non immune): F all in platelet count occurs within the first two days after heparin initiation, and r eturns to normal with continued heparin administration, and is of no clinical consequence. D irect effect of heparin on platelet activation.    Type 2 (Immune): Approx 0.3 to 3 percent of patients receiving heparin M ediated by antibodies to a heparin-platelet factor 4 complex. Seen with unfractionated heparin but in not with LMWH

45. Anticoagulants II Dr Rahul Kunkulol Department of Pharmacology, RMC,LONI

46. Warfarin

47. Oral anticoagulants : warfarin , dicumarol Coumarins - warfarin , dicumarol Isolated from clover leaves Structurally related to vitamin K Inhibits production of active clotting factors Absorption rapid –high plasma protein binding binds to albumin Clearance is slow - 36 hrs Delayed onset 8 - 12 hrs Overdose - reversed by vitamin K infusion Can cross placenta - do not use during late pregnancies

48. Mechanism of action Descarboxy Prothrombin Prothrombin Reduced Vitamin K Oxidized Vitamin K NADH NAD Warfarin

49. Warfarin Monitoring

50. INR : International Normalized Ratio. Different thromboplastins vary in sensitivity T o give PT values a consistent basis of comparison from lab to lab, WHO instituted the INR: A uniform value in which the PT is expressed as a ratio. Many manufacturers aim for an ISI of 1.0 . INR is affected by diet (because of the vitamin K dependent mechanism of action), other medications, M onitored routinely, every 2 to 4 weeks

51. Drug interaction- Prototype Warfarin Category Mechanisms Examples of drugs Drugs that Increase Warfarin Activity Decrease binding to Albumin Aspirin, Sulfonamides Inhibit Degradation Cimetidine, Decrease synthesis of Clotting Factors Antibiotics (oral) Drugs that promote bleeding Inhibition of platelets Aspirin Inhibition of clotting Factors Heparin Antimetabolites Drugs decrease Warfarin activity Induction of metabolizing Enzymes Barbiturates Increases synthesis of Clotting Factors Vitamin K

52. Contraindications to Antithrombotic Therapy Specific to warfarin (ambulatory patients) -Early and late pregnancy -Poor patient cooperation, understanding, reliability -Unsatisfactory laboratory or patient follow-up -Occupational risk to trauma

53. New Anticoagulants

54. New Anticoagulants

55. FXa Inhibitors Parenteral synthetic pentasaccharide analogs

56. FXa Inhibitors Parenteral synthetic pentasaccharide analogs

57. Anticoagulant Drugs

58. Direct Thrombin Inhibitors

59. Direct Thrombin Inhibitors

60. Direct Thrombin Inhibitors

61. Direct Thrombin Inhibitors

62. Indications for and Contraindications to Parenteral Anticoagulant Agents Anticoagulant Agent Class Approved & Appropriate Indications Unfractionated heparin Enoxaparin ( Lovenox ) Dalteparin ( Fragmin ) Tinzaparin ( Innohep ) Antithrombin III inhibitor Low-molecular-weight heparin Low-molecular-weight heparin Low-molecular-weight heparin Treatment of venous thromboembolism or unstable angina; used when rapid reversal is important Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism

63. Indications for and Contraindications to Parenteral Anticoagulant Agents (cont’d) Ardeparin Lepirudin Argatroban Danaparoid Bivalirudin Fondaparinux ( Arixtra ) Low-molecular-weight heparin Hirudin derivative (medicinal Leech) Direct thrombin inhibitor Heparinoid Hirudin derivative Synthetic factor Xa inhibitor Approved; not being marketed Heparin-induced thrombocytopenia with thrombosis Heparin-induced thrombocytopenia with thrombosis Prophylaxis against thrombosis in heparin-induced thrombocytopenia Unstable angina or angioplasty Prophylaxis in high-risk patients?

64. The Extent of Thrombotic Disease Annually in the U.S.

65. Venous Thromboembolism

66. Economy Class Syndrome

67. Deep Vein Thrombosis Blood clot of lower leg or thigh Approximately 1 per 1,000 people affected by DVT Hospitalization for 5 to 7 days 50% of patients with DVT are asymptomatic

68. Pulmonary Embolism CT Scan of Pulmonary Embolism

69. D eep V ein T hrombosis Embolus P ulmonary E mbolism

70. AMI AND UNSTABLE ANGINA

71. RHD, AF

72. Blood Hypercoagulability

73. FIBRINOLYTICS Dr Rahul Kunkulol Department of Pharmacology, RMC,LONI

74. FIBRINOLYTICS

75. Fibrinolysis

76. Streptokinase Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the pro-activator plasminogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin

77. Urokinase Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins , which allows it to lyse the thrombus from within

78. Tissue plasminogen activators ( t-PAs). Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs). Activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. Human t-PA is manufactured as ALTEPLASE by means of recombinant DNA technology.

79. Tissue plasminogen activators (t-PAs). RETEPLASE is less expensive than Alteplase . I t lacks the major fibrin-binding domain thus is less fibrin-specific than Alteplase TENECTEPLASE is a mutant form of t-PA that has a longer half-life, and it can be given as an intravenous bolus. Tenecteplase is slightly more fibrin-specific than Alteplase

80. Current status

81. DOSES

82. Contraindications to Antithrombotic Therapy

83. Contraindications to Antithrombotic Therapy

84. Drug preparations : to lyse clots

85. Drug preparations : to stop bleeding

86. Fibrinolytic Inhibitors: Aminocaproic Acid Similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis Competitively inhibits plasminogen activation Oral dosage of EACA is 6 g four times a day Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15 mg/kg loading dose followed by 30 mg/kg every 6 hours

87. USES Adjunctive therapy in hemophilia Bleeding from fibrinolytic therapy Prophylaxis for re-bleeding from intracranial aneurysms. Postsurgical gastrointestinal bleeding ,post prostatectomy bleeding ,bladder hemorrhage secondary to radiation and drug-induced cystitis. Adverse effects Intravascular thrombosis from inhibition of plasminogen activator Hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness

88. Drug preparations: clotting deficiencies