Anticoagulants, throbolytics and antithrombolytics.pptx

detailed lecture covering anticoagulants, thrombolytics and antithromobolytics

1. Anticoagulants, thrombolytics and antithrombolytics

2. 7 Acute Myocardial Infarction Left Ventricular Thrombus Atrial Fibrillation Left Ventricular Aneurysm Prosthetic Heart Valve Venous Thromboembolism- Treatment and Prophylaxis Venous Thromboembolism- Patients of cancer Heparin Induced Thrombocytopenia Pregnancy COVID-19 NEED FOR ANTICOAGULATION

3. ANTICOAGULANTS These are drugs used to reduce the coagulability of blood.

4. ORAL ANTICOAGULANTS

5. Warfarin Wisconsin Alumni Research Foundation (WARF)

6. Warfarin Absorption: Bioavailability : Nearly 100% orally or intravenously Food Can decrease the absorption. Detectable in plasma within 1 hour of its oral administration, and concentrations peak in 2-8 hours.

7. Warfarin Distribution Almost completely (99%) bound to plasma proteins, principally albumin Rapidly Distribution into a volume equivalent to the albumin space (0.14 L/kg). Concentrations in fetal plasma approach the maternal values, but active warfarin is not found in milk

8. Biotransformation and Elimination Racemic mixture of S- and R-warfarin S-warfarin is 3-5 fold more potent than R-warfarin metabolized principally by CYP2C9. Inactive metabolites of warfarin are excreted in urine and stool. The average rate of clearance from plasma is 0.045 mL/min / kg . The t 1/2 varies (25-60 hours), with a mean of  40 hours; the duration of action of warfarin is 2-5 days. Warfarin CYP2C9 and VKORC1 ( vitamin K epoxide reductase complex, subunit 1) CYP2C9 - pharmacokinetics VKORC1 - pharmacodynamics Common variations in the CYP2C9  gene (designated CYP2C9*2 and *3 ), encode an enzyme with decreased activity, and thus are associated with higher drug concentrations and reduced warfarin dose requirements.

9. Prophylaxis and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) Prophylaxis and treatment of Atrial fibrillation Valvular stenosis Heart valve replacement Myocardial infarction Indications

10. Narrow therapeutic range Can increase risk of bleeding Why to monitor Warfarin therapy? Answer Is

11. Prothrombin time INR (International Normalized Ratio) Monitoring of warfarin therapy

12. Prothrombin time Performed by adding a mixture of calcium and thromboplastin to citrated plasma As a control, a normal blood sample is tested continuously PT ratio (PTR) = Patient’s PT Control PT

13. International Normalised Ratio (INR) INR = [ PT pt ] ISI [ PT Ref ] PT pt – prothrombin time of patient PT Ref – prothrombin time of normal pooled sample ISI – International Sensitivity Index

14. The usual adult dosage of warfarin is 2-5 mg/day for 2-4 days, followed by 1-10 mg/day as indicated by measurements of the international normalized ratio (INR), a value derived from the patient's PT A lower initial dose should be given to patients with an increased risk of bleeding, including the elderly Usually is administered orally can be given intravenously without modification of the dose Intramuscular injection is not recommended -risk of hematoma formation Dosage

15. Optimizing Warfarin Therapy Dosage to be individualized according to patient’s INR response. Use of large loading dose may lead to hemorrhage and other complications. Initial dose: 2-5 mg once daily Maintenance dose: 2-10 mg once daily Immediate anticoagulation required: Start heparin along with loading dose of warfarin 10 mg. Heparin is usually discontinued after 4-5 days. Before discontinuing, ensure INR is in therapeutic range for 2 consecutive days Monitor daily until INR is in therapeutic range, then 3 times weekly for 1-2 weeks, then less often (every 4 to 6 weeks)

16. Optimal Therapeutic Range Indication INR Prophylaxis of venous thromboembolism 2.0-3.0 Treatment of venous thromboembolism 2.0-3.0 Atrial fibrillation 2.0-3.0 Mitral valve stenosis 2.0-3.0 Heart valve replacement Bioprosthetic valve Mechanical valve 2.0-3.0 2.5-3.5 Myocardial infarction 2.0-3.0 2.5-3.5 (high risk patients) ACCP 2012 guidelines

17. Duration Of Therapy Venous thromboembolism: Minimum 3 months, usually 6 months AMI: During initial 10-14 days of hospitalization or until patient is ambulatory Mitral valve disease/Mechanical heart valves: Lifelong Atrial fibrillation: Lifelong Prevention of cerebral embolism: 3-6 months

18. Contraindication's And Precautions Hypersensitivity to warfarin Condition with risk of hemorrhage Hemorrhagic tendency Protein C & S deficiency Vitamin K deficiency Intramuscular injections Hepatic and renal function

19. Drugs that increase the effect Drugs that decrease the effect Contraindication's And Precautions

20. Adverse Effects

21. Bleeding Most common adverse effect Intensity and duration of therapy A median annual rate of 0.9 to 2.7% Hemoptysis , excessive bruising, bleeding from nose or gums, or blood in urine or stool, intracranial, intraperitoneal bleeding The most accurate clinical prediction rule for estimating the risk of bleeding is the HAS-BLED score.

22. Treatment of bleeding Vitamin K1 ( phytonadione ) orally at a dose of 1-2.5 mg (for 5 INR 9) or 3-5 mg (for INR >9) Immediate hemostatic competence (INR >20), fresh frozen plasma (10-20 mL/kg), supplemented with 10 mg of vitamin K1, given by slow intravenous infusion.

23. Abortion A syndrome characterized by nasal hypoplasia and stippled epiphyseal calcifications that resemble chondrodysplasia punctata may result from maternal ingestion of warfarin during the first trimester. Central nervous system abnormalities have been reported following exposure during the second and third trimesters. Fetal or neonatal hemorrhage and intrauterine death may occur, even when maternal PT values are in the therapeutic range.

24. Rare but serious Massive thrombosis with skin necrosis and gangrene of limbs. Due to shorter half life of Protein C Occurs mainly in patients with Protein C Deficiency Warfarin Skin necrosis

25. Purple toe syndrome Other infrequent reactions include alopecia, urticaria , dermatitis, fever, nausea, diarrhea, abdominal cramps, and anorexia.

26. Concomitant treatment with any other anticoagulant agent— eg , unfractionated heparin, low molecular weight heparin (such as enoxaparin or dalteparin ), heparin derivatives (such as fondaparinux), or oral anticoagulants (such as warfarin). Exceptions are switching of therapy to or from the medicine, or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter Additional advice and information for healthcare professionals: Special care should be taken when deciding to prescribe these anticoagulant medicines to patients with other conditions, procedures, and concomitant treatments ( eg , non-steroidal anti-inflammatory drugs, antiplatelets), which may increase the risk of major bleeding  Attention should be paid to renal function. Impaired renal function may constitute a contraindication or recommendation not to use the anticoagulant medicine, or may require a dose reduction; recommendations differ for the three medicines The contraindications, posology, and warnings and precautions for use specific to each medicine, together with the individual’s risk factors for bleeding ( eg , renal function), should be considered before prescribing these medicines

27. The following contraindications now apply to all three new oral anticoagulants, for all doses and indications: A lesion or condition, if considered a significant risk factor for major bleeding. This may include: current or recent gastrointestinal ulceration presence of malignant neoplasm at high risk of bleeding recent brain or spinal injury recent brain, spinal, or ophthalmic surgery recent intracranial haemorrhage known or suspected oesophageal varices arteriovenous malformation vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities

28. ORAL DIRECT THROMBIN INHIBITOR

29. Prodrug, which reversibly blocks the active site of thrombin. The drug has oral bioavailability of 6%, a peak onset of action in 2 hours, and a plasma t 1/2 of 12-14 hours. Predictable anticoagulant response : routine coagulation monitoring is unnecessary. Dabigatran etexilate was non-inferior to warfarin for treatment of patients with venous thromboembolism (Schulman et al., 2009) and superior to warfarin for stroke prevention in patients with atrial fibrillation (Connolly et al., 2009). Approved for prevention of venous thromboembolism after elective hip or knee replacement surgery. For prevention of stroke, systemic embolism and reduction of vascular mortality in adult patients with atrial fibrillation.

30. Dabigatran Etexilate Prodrug, which reversibly blocks the active site of thrombin. The drug has oral bioavailability of 6%, a peak onset of action in 2 hours, and a plasma t 1/2 of 12-14 hours. Predictable anticoagulant response : routine coagulation monitoring is unnecessary. Dabigatran etexilate was non-inferior to warfarin for treatment of patients with venous thromboembolism (Schulman et al., 2009) and superior to warfarin for stroke prevention in patients with atrial fibrillation (Connolly et al., 2009). Approved for prevention of venous thromboembolism after elective hip or knee replacement surgery. For prevention of stroke, systemic embolism and reduction of vascular mortality in adult patients with atrial fibrillation.

31. ORAL DIRECT FACTOR Xa INHIBITOR

32. Rivaroxaban Oral factor Xa inhibitor 80% oral bioavailability, a peak onset of action in 3 hours, and a plasma t 1/2 of 7-11 hours. About one-third of the drug is excreted unchanged in the urine, the remainder is metabolized by the liver, and inactive metabolites are excreted in the urine or feces. Given in fixed doses(10mg) and does not require coagulation monitoring. Approved in India for the prevention of venous thromboembolism in patients (VTE) in adult patients undergoing hip or knee replacement surgery. Ongoing trials are comparing Rivaroxaban with Warfarin for treatment of venous thromboembolism and stroke prevention in patients with atrial fibrillation.

33. Apixaban Approved in India for the Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

34. The risk of non-hemorrhagic stroke and systemic embolic events (SEE) was similar with the NOAC and warfarin (RR = 0.93; 95% CI = 0.83-1.04), while the risk of intracranial bleeding (ICB) with the NOAC was lower than with warfarin (RR = 0.46; 95% CI = 0.33-0.65). Gómez et al. Dabigatran , Rivaroxaban , or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups. Thrombosis. 2013;2013:640723.

35. Advantages of NOAC over Warfarin Rapid onset and offset of therapeutic effect Short half life No laboratory monitoring required Fixed dosage guidelines depending on the indication Antithrombotic efficacy equal to/better than warfarin. Lower risk of bleeding compared to warfarin Fewer drug interactions

36. PARENTERAL ANTICOAGULANTS

37. Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin XII, Prekallikrein , High Mol. Wt. Kininogen XIIa XI XIa IX IXa + VIIIa Prevented by Antithrombin III Protein C Protein S Tissue Factor Pathway Inhibitor 44 Synthesis Vitamin K HEPARIN

38. HEPARIN Bussey H, Francis JL; Heparin Consensus Group. Heparin overview and issues. Pharmacotherapy. 2004 Aug;24(8 Pt 2):103S-107S. doi : 10.1592/phco.24.12.103s.36109. PMID: 15334855. 45 Discovered in 1916 Approved in 1942 Drawbacks- Limited ability to prevent clot propagation and extension Difficult to dose due to unpredictable PK, shorter t1/2 Dosing depends on continuous monitoring by aPTT Immune-mediated Heparin induced Thrombocytopenia results from antibodies formed against the heparin–platelet factor 4 complex. Higher risk of bleeding, osteoporosis

39. Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin XII, Prekallikrein , High Mol. Wt. Kininogen XIIa XI XIa IX IXa + VIIIa Prevented by Antithrombin III Protein C Protein S Tissue Factor Pathway Inhibitor 46 Synthesis Vitamin K HEPARIN LOW MOLECULAR WEIGHT HEPARINS

40. HEPARIN Heparin is a large, highly ionized molecule; there fore not absorbed orally. Injected i.v. it acts instantaneously, but after s.c. injection anticoagulant effect develops over ~60 min. Bioavailability of s.c. heparin is inconsistent. Heparin does not cross blood-brain barrier or placenta (it is the anticoagulant of choice during pregnancy). It is metabolized in liver by heparinase and fragments are excreted in urine. Heparin released from mast cells is degraded by tissue macrophages, and it is not a physiologically circulating anticoagulant. After i.v. injection of doses < 100 U/kg, the t½ averages 1 hr. Beyond this, dose-dependent inactivation is seen and pharmacokinetics is inconsistent; t½ is prolonged to 1–4 hrs. The t½ is longer in cirrhotics and kidney failure patients, and shorter in patients with pulmonary embolism. However, UFH is safer than LMW heparins or fondaparinux in kidney failure patients.

41. Heparin Heparin is conventionally given i.v. in a bolus dose of 5,000–10,000 U (children 50–100 U/kg), followed by continuous infusion of 750–1000 U/hr. Intermittent i.v. bolus doses of UFH are no longer recommended. The rate of infusion is controlled by aPTT measurement which is kept at 50–80 sec. or 1.5–2.5 times the patient’s pretreatment value. Adverse effects 1. Bleeding due to overdose is the most serious complication of heparin therapy. Since heparin (and other anticoagulants) interfere with secondary haemostasis , bleeding from deeper organs is more common. Haematuria is generally the first sign; other sites are g.i. tract, brain, joints, muscles, etc. With proper monitoring, serious bleeding occurs only in 1–3% patients.

42. Heparin Induced Thrombocytopenia Occurs in about 0.5% patients 5 to 10 days after initiation of therapy with heparin or LMWH. Heparin or LMWH should be discontinued immediately. An alternative anticoagulant such as bivalirudin, argatroban , or rivaroxaban can be used. Fondaparinux is another alternative, although fondaparinux-induced thrombocytopenia has been reported.

43. Heparin 3. Transient and reversible alopecia is infrequent. Serum transaminase levels may rise. 4. Osteoporosis may develop on long-term use of relatively high doses. 5. Hypersensitivity reactions are rare; manifestations are urticaria, rigor, fever and anaphylaxis. Patients with allergic diathesis are more liable.

44. 51 LOW MOLECULAR WEIGHT HEPARINS LMWH Enoxaparin Dalteparin Tinzaparin Approved in 1993 1994 2000 Advantages Longer t1/2 Weight based predictable dosing No need for routine laboratory monitoring Less incidence of bleeding, osteoporosis and heparin induced thrombocytopenia Drawbacks Cannot be used in renal impairment Unpredictable response to protamine sulphate Parenteral administration- poor compliance Lu X, Lin J. Low molecular weight heparin versus other anti-thrombotic agents for prevention of venous thromboembolic events after total hip or total knee replacement surgery: a systematic review and meta-analysis. BMC Musculoskelet Disord . 2018 Sep 8;19(1):322. doi : 10.1186/s12891-018-2215-3. PMID: 30193575; PMCID: PMC6129001. Fondaparinux- 2001

45. LOW MOLECULAR WEIGHT HEPARINS (LMWH) Fractionated form of heparin (MW 3000–7000). Selectively inhibits Factor Xa , minimal effect on Factor IIa (thrombin) . Acts by inducing conformational change in Antithrombin III (AT III) —does not provide scaffolding for thrombin interaction. Less effect on aPTT and whole blood clotting time compared to Unfractionated Heparin (UFH). Reduced antiplatelet action → less interference with hemostasis. Lower incidence of thrombocytopenia and possibly major bleeding . E.G Enoxaparin, Dalteparin , Reviparin

46. Parameter Heparin (Unfractionated) LMWH (e.g., Enoxaparin) Source Porcine/bovine mucosa Derived from heparin via depolymerization Molecular Weight 5,000–30,000 Da ~4,000–6,000 Da Mechanism of Action Inhibits thrombin & factor Xa equally Preferentially inhibits factor Xa Administration IV or SC SC only Monitoring aPTT required Routine monitoring not needed Half-life Short (1–2 hours) Longer (4–6 hours) Dosing Weight-adjusted; continuous infusion possible Fixed or weight-based dosing Antidote Protamine sulfate (complete reversal) Protamine (partial reversal) Use in Pregnancy Safe Safe Cost Less expensive More expensive Heparin vs. Low Molecular Weight Heparin (LMWH)

47. Clinical Indications: Prophylaxis of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in high-risk surgical or immobilized patients. Treatment of established DVT. Unstable Angina (UA) and Myocardial Infarction (MI) —preferred over continuous UFH infusion. Maintaining patency of cannulae and shunts in dialysis patients. LOW MOLECULAR WEIGHT HEPARINS (LMWH)

48. LOW MOLECULAR WEIGHT HEPARINS (LMWH) Better subcutaneous bioavailability (70–90%) than UFH (20–30%). Longer, consistent half-life (4–6 hours) → once-daily s.c. dosing. No need for lab monitoring (e.g., aPTT ); dose based on body weight . Lower risk of osteoporosis with long-term use compared to UFH. Renal excretion — avoid in renal failure .

49. Limitations: Less effective than UFH during cardiopulmonary bypass surgery (UFH preferred). Less effective in preventing catheter thrombosis . Incomplete reversal by protamine sulfate . LOW MOLECULAR WEIGHT HEPARINS (LMWH)

50. fondaparinux Mechanism of Action: Synthetic pentasaccharide that binds to Antithrombin III (AT-III) with high affinity. Induces irreversible conformational change in AT-III. Selectively inhibits Factor Xa — does not bind or inhibit thrombin (Factor IIa ) . 🔹 Pharmacokinetics: 100% subcutaneous bioavailability . Peak effect in ~2 hours. Long half-life : ~17 hours → allows once-daily dosing . Minimal metabolism ; excreted unchanged via kidneys → contraindicated in renal failure .

51. fondaparinux Advantages: Lower risk of thrombocytopenia than even LMW heparins. Reduced bleeding risk compared to UFH/LMWH. Minimal risk of osteoporosis with long-term use. No need for aPTT monitoring . Preferred long-acting alternative to LMW heparins. 🔹 Clinical Indications: Prophylaxis of DVT and Pulmonary Embolism (PE) . Treatment of established DVT and PE. Acute Coronary Syndromes (ACS) — especially when immediate intervention is not planned .

52. Reversal agents Life-threatening bleeding can occur with the direct oral anticoagulants Specific reversal agents streamlines the management of such patients IDARUCIZUMAB ANDEXANTE ALFA CIRAPARANTAG

53. Humanized mouse monoclonal antibody fragment directed against dabigatran. Antibody binds dabigatran with an affinity 350-fold higher than that of dabigatran for thrombin. Idarucizumab is infused as two intravenous boluses, each of 2.5 g. Serious bleeding with Dabigatran in acute renal failure patients, even haemodialysis is useful. IDARUCIZUMAB

54. Recombinant coagulation factor Xa , inactivated- zhzo , also called Andexanet alfa Active against Rivaroxaban and Apixaban with serious bleeding Also reverses the anticoagulant effect of heparin and LMWH Expensive hence reserved for serious bleeds(intracranial hemorrhage) If unavailable, four-factor prothrombin complex concentrate improves hemostasis. ANDEXANTE ALFA

55. Not in use Currently in phase 4 clinical trial CIRAPARANTAG

56. ANDEXANTE ALFA Four-Factor prothrombin complex Expensive or unavailable If ineffective Recombinant factor VIIa DIALYSIS As Epixaban , Rivaroxaban are bound to plasma proteins dialysis is not useful

57. THROMBOLYTICS These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels (mainly coronary artery). They are therapeutic rather than prophylactic and work by activating the natural fibrinolytic system Venous thrombi are lysed more easily by fibrinolytics than arterial thrombi, and recent thrombi respond better. Fibrinolytics have little effect on thrombi > 3 days old. 65

58. fibrinolytic drugs Streptokinase Urokinase Alteplase (rt-PA) Reteplase Tenecteplase 66

59. The plasminogen-plasmin system 67

60. Streptokinase Obtained from B haemolytic Streptococci group C It is the first fibrinolytic drug to be used clinically, but is not employed now because it is non-fibrin specific, i.e. activates both circulating as well as fibrin bound plasminogen. Therefore, it depletes circulating fibrinogen and predisposes to bleeding. 68

61. Compared to newer more fibrin-specific tissue plasminogen activators (alteplase, etc.) it is less effective in opening occluded coronary arteries, and causes less reduction in MI related mortality. 69

62. It is antigenic and pyrogenic. Antistreptococcal Ab are formed within 4-5 days after streptokinase, which destroy the drug. So, should not be used again. If needed, can be used after a gap of 1 year. Advantage- Cheapest 70

63. Adverse effects Bleeding Allergic reactions like fever Chills Skin rash Hypotension anaphylactoid reaction 71

64. Dose- Loading dose 2.5lac units over 10min followed by 1 lac units/hr for 1-3 days 72

65. UROKINASE It is an enzyme isolated from human urine But commercially prepared from cultured human kidney cells. Directly converts plasminogen to plasmin Due to availability of better fibrinolytics, it has gone out of use. Dose- loading dose 3 lac units over 10min followed by 3 lac units/ hr for 12 hour 73

66. ALTEPLASE Recombinant tissue plasminogen activator (rt-PA) Produced by recombinant DNA technology from human tissue culture, it catalyses the cleavage of endogenous plasminogen to generate plasmin, and is moderately specific for fibrin-bound plasminogen, so that circulating fibrinogen is lowered only by 50%. 74

67. It is rapidly cleared by liver and inactivated by plasminogen activator inhibitor-1 (PAI-1). The plasma t1/2 is 4- 8 min. Because of the short t½, it needs to be given by slow i.v. infusion and often requires heparin coadministration. Aspirin is also routinely given after establishing reperfusion. 75

68. Risk of bleeding (0.5 - 5%) is the most important concern. A/E- nausea, mild hypotension and fever may occur. It is expensive. ACTILYSE 50 mg vial with 50 ml solvent water. 76

69. For MI: 15 mg iv. Bolus injection followed by 50 mg over 30 minute, then 35 mg over the next 1 hr (total 100mg in 90min) For Pulmonary embolism: 100mg i.v infused over 2 hr For ischemic stroke- 0.9 mg/kg by i.v infusion over 60min, with 10% of the dose injection in the first minute 77

70. reteplase It is a nonglycosylated deletion mutant of rt.PA produced by recombinant technology in which some amino acids of native t-PA are missing. This change makes it longer acting, but somewhat less selective for fibrin bound plasminogen. It is cleared by both liver and kidney with an effective of13-16 min. 78

71. The longer action permits a double bolus i.v. administration of 18 mg (10U) over 2 min each 30 min apart in cases of STEMI and in PE. Dose adjustment is needed in liver and kidney damage. RETELEX 18 mg (10U)/vial injection kit. 79

72. TENECTEPLASE This genetically engineered substitution mutant of native t-PA has higher fibrin selectivity, slower plasma clearance (longer duration of action) and resistance to inhibition by PAI-1. It is the only fibrinolytic agent that can be injected i.v. as a single bolus dose over 10 sec, while alteplase requires 90 min infusion and reteplase needs 2 injections at 30 min interval. 80

73. This feature makes it possible to institute fibrinolytic therapy immediately on diagnosis of STEMI, even during transport of the patient to the hospital. Several randomized multicentric trials have assessed its efficacy in STEMI and found it to be at least equally efficacious to alteplase. 81

74. Risk of noncerebral bleeding was found to be lower with tenecteplase in the ASSENT-2 trial, but cranial bleeding incidence was similar: Dose: 0.5 mg/kg single i.v. bolus injection. ELAXIM 30 mg, 50 mg per vial inj. 82

75. Uses of fibrinolytics 1. Acute Myocardial infarction- The chief indication for fibrinolytic therapy is STEMI. They are not indicated or may even be harmful in UA and in low risk NSTEMI. In STEMI fibrinolytics are an alternative first line approach to emergency percutaneous coronary intervention (PCI) with stent placement. Recanalization of thrombosed coronary artery has been achieved in50-90% cases. Time lag in starting the infusion is critical for reducing area of necrosis, preserving ventricular function and reducing mortality. 83

76. Aspirin with or without heparin is generally started concurrently or soon after thrombolysis to prevent reocclusion . Recanalization efficacy is similar with alteplase, reteplase and tenecteplase , but tenecteplase has the simplest regimen. Risk of hypotension and allergic reactions is also comparable among 84

77. 2. Deep vein thrombosis (DVT)- In leg, pelvis, shoulder etc.; up to 60% patients of DVT can be successfully treated by fibrinolytics. They can decrease subsequent pain and swelling, but the main advantage is preservation of venous valves and may be a reduced risk of PE, though at the risk of haemorrhage . Comparable results have been obtained with Stk , urokinase and alteplase. 85

78. 3. Pulmonary embolism- Fibrinolytic therapy is indicated in large, life-threatening PE. Lung function may be better preserved, but reduction in mortality is not established. 86

79. 4. Peripheral arterial occlusion- Fibrinolytics recanalise ~40% limb artery occlusions, especially those treated within 72 hr. However, it is indicated only when surgical thrombectomy is not possible. Regional intraarterial fibrinolytics have been used for limb arteries with greater success. 87

80. Peripheral arterial thrombolysis is followed by short-term heparin and long-term aspirin therapy. Fibrinolytics have no role in chronic peripheral vascular diseases. 88

81. 5. Stroke- Thrombolytic therapy of ischaemic stroke is dependent on time-lapse since symptom onset; earlier, the better. Possibility of improved neurological outcome is to be balanced with risk of intracranial haemorrhage . Alteplase is approved for use in ischaemic stroke, and current opinion strongly recommends use of i.v. 89

82. alteplase in carefully selected patients who can be treated within 3 4.5 hours of onset, and in whom intracranial haemorrhage is ruled out along with all risk factors for bleeding. After 4.5 hours of symptom onset, the risk of intracranial haemorrhage outweighs the likelihood of benefit. 90

83. CONTRAINDICATION 1. H/o intracranial haemorrhage 2. H/o ischaemic stroke in past 3 months 3. H/o head injury in past 3 months 4. Intracranial tumour/vascular abnormality/ aneurysms 5. Active bleeding/bleeding disorders 91

84. 6. Patients receiving anticoagulants 7. Peptic ulcer, esophageal varices 8. Any wound or recent fracture or tooth extraction 9. H/o major surgery within 3 weeks 10. Uncontrolled hypertension 11. Pregnancy 92

85. Heparin Heparin is a powerful and instantaneously acting anticoagulant, effective both in vivo and in vitro. It acts indirectly by activating plasma antithrombin III The heparin-AT III complex then binds to clotting factors of the intrinsic and common pathways (Xa, IIa , IXa , XIa , XIIa and XIIIa ) and inactivates them but not factor VIIa operative in the extrinsic pathway. At low concentrations of heparin, factor Xa mediated conversion of prothrombin to thrombin is selectively affected. The anticoagulant action is exerted mainly by inhibition of factor Xa as well as thrombin ( IIa ) mediated conversion of fibrinogen to fibrin.

86. 94 Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin Antithrombin III Plasminogen activators Plasminogen Plasmin

87. Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin XII, Prekallikrein , High Mol. Wt. Kininogen XIIa XI XIa IX IXa + VIIIa Prevented by Antithrombin III Protein C Protein S Tissue Factor Pathway Inhibitor 95 Synthesis Vitamin K EXTRINSIC PATHWAY INTRINSIC PATHWAY COMMON PATHWAY

88. Yang R, Zubair M, Moosavi L. Prothrombin Time. [Updated 2024 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544269 / 96 COMMON PATHWAY INTRINSIC PATHWAY EXTRINSIC PATHWAY MEASURES OF COAGULATION PT aPTT Normal Normal Prolonged Prolonged Prolonged Prolonged PROTHROMBIN TIME (PT) ACTIVATED PARTIAL THROMBOPLASTIN TIME (aPTT) Time taken for plasma to clot after adding thromboplastin to patients plasma sample Normal value- 12-14 sec Time taken for fibrin clot to form after an activator, phospholipid and calcium chloride is added. Normal value- 26-32 sec INTERNATIONAL NORMALISED RATIO (INR) Ratio of the patient’s prothrombin time divided by a control value using international reference thromboplastin agent by WHO (Normal </= 1.1)

89. 97 Acute Myocardial Infarction Left Ventricular Thrombus Atrial Fibrillation Left Ventricular Aneurysm Prosthetic Heart Valve Venous Thromboembolism- Treatment and Prophylaxis Venous Thromboembolism- Patients of cancer Heparin Induced Thrombocytopenia Pregnancy COVID-19 NEED FOR ANTICOAGULATION

90. Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin XII, Prekallikrein , High Mol. Wt. Kininogen XIIa XI XIa IX IXa + VIIIa Prevented by Antithrombin III Protein C Protein S Tissue Factor Pathway Inhibitor 98 Synthesis Vitamin K HEPARIN

91. HEPARIN Bussey H, Francis JL; Heparin Consensus Group. Heparin overview and issues. Pharmacotherapy. 2004 Aug;24(8 Pt 2):103S-107S. doi : 10.1592/phco.24.12.103s.36109. PMID: 15334855. 99 Discovered in 1916 Approved in 1942 Drawbacks- Limited ability to prevent clot propagation and extension Difficult to dose due to unpredictable PK, shorter t1/2 Dosing depends on continuous monitoring by aPTT Immune-mediated Heparin induced Thrombocytopenia results from antibodies formed against the heparin–platelet factor 4 complex. Higher risk of bleeding, osteoporosis

92. Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin XII, Prekallikrein , High Mol. Wt. Kininogen XIIa XI XIa IX IXa + VIIIa Prevented by Antithrombin III Protein C Protein S Tissue Factor Pathway Inhibitor 100 Synthesis Vitamin K HEPARIN LOW MOLECULAR WEIGHT HEPARINS

93. 101 LOW MOLECULAR WEIGHT HEPARINS LMWH Enoxaparin Dalteparin Tinzaparin Approved in 1993 1994 2000 Advantages Longer t1/2 Weight based predictable dosing No need for routine laboratory monitoring Less incidence of bleeding, osteoporosis and heparin induced thrombocytopenia Drawbacks Cannot be used in renal impairment Unpredictable response to protamine sulphate Parenteral administration- poor compliance Lu X, Lin J. Low molecular weight heparin versus other anti-thrombotic agents for prevention of venous thromboembolic events after total hip or total knee replacement surgery: a systematic review and meta-analysis. BMC Musculoskelet Disord . 2018 Sep 8;19(1):322. doi : 10.1186/s12891-018-2215-3. PMID: 30193575; PMCID: PMC6129001. Fondaparinux- 2001

94. Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin XII, Prekallikrein , High Mol. Wt. Kininogen XIIa XI XIa IX IXa + VIIIa Prevented by Antithrombin III Protein C Protein S Tissue Factor Pathway Inhibitor 102 Synthesis Vitamin K LOW MOLECULAR WEIGHT HEPARINS VITAMIN K ANTAGONISTS

95. Zirlik A, Bode C. Vitamin K antagonists: relative strengths and weaknesses vs. direct oral anticoagulants for stroke prevention in patients with atrial fibrillation. J Thromb Thrombolysis. 2017 Apr;43(3):365-379. doi : 10.1007/s11239-016-1446-0. PMID: 27896543; PMCID: PMC5337242. 103 VITAMIN K ANTAGONISTS Warfarin Acenocoumarol Phenprocoumon Approval 1954 2006 (Not by FDA) Not FDA approved Advantages Not eliminated by kidneys hence used in renal impairment Less risk of a thrombotic event on missing a dose (non-adherent patients benefit from the slow decline of action) Lower cost as compared to NOACs Drawbacks Longer time for onset and cessation of action Multiple interactions with other drugs and food Narrow therapeutic window Studies show suboptimal INR control Initial prothrombotic action

96. Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin XII, Prekallikrein , High Mol. Wt. Kininogen XIIa XI XIa IX IXa + VIIIa Prevented by Antithrombin III Protein C Protein S Tissue Factor Pathway Inhibitor 104 Synthesis Vitamin K VITAMIN K ANTAGONISTS DIRECT THROMBIN INHIBITORS

97. Lee CJ, Ansell JE. Direct thrombin inhibitors. Br J Clin Pharmacol . 2011 Oct;72(4):581-92. doi : 10.1111/j.1365-2125.2011.03916.x. Erratum in: Br J Clin Pharmacol . 2011 Oct;72(4):718. Dosage error in article text. PMID: 21241354; PMCID: PMC3195735. 105 DIRECT THROMBIN INHIBITORS Agratroban Bivalirudin Desirudin Dabigatran Approval 2000 2001 2003 2010 Advantages Predictable PK and PD Rapid onset and offset of action Fewer drug and food interactions No need for bridging therapy Reduced risk of intracranial haemorrhage as compared to warfarin Availability of reversal agents Targeted approach with reduced off-target effects Drawbacks Bleeding risk Renal clearance Higher cost

98. Tissue factor + VIIa X Xa Prothrombin Thrombin Fibrinogen Fibrin XII, Prekallikrein , High Mol. Wt. Kininogen XIIa XI XIa IX IXa + VIIIa Prevented by Antithrombin III Protein C Protein S Tissue Factor Pathway Inhibitor 106 Synthesis Vitamin K DIRECT THROMBIN INHIBITORS DIRECT FACTOR Xa INHIBITORS

99. Muscente F, De Caterina R. The new in anticoagulation: factor XI inhibitors. Eur Heart J Suppl. 2023 Apr 21;25( Suppl B):B65-B68. doi : 10.1093/ eurheartjsupp /suad070. PMID: 37091652; PMCID: PMC10120978 . 107 Rivaroxaban Apixaban Edoxaban Betrixaban Approval 2011 2012 2015 2017 Advantages Oral dosing Single targets in the coagulation cascade More predictable PK Do not require regular monitoring Lesser incidence of bleeding Rapid onset of action Can be given in fixed dose Drawbacks High cost Renal clearance Inferior to Vit K antagonists in case of mechanical prosthetic heart valves or patients with antiphospholipid antibody syndrome DIRECT FACTOR Xa INHIBITORS

100. 108 CURRENTLY AVAILABLE ANTICOAGULANTS Heparin Low Molecular Weight Heparins Vitamin K antagonists Direct Thrombin Inhibitors Direct Factor Xa Inhibitors Oral Parenteral Warfarin Rivaroxaban Apixaban Edoxaban Betrixaban Dabigatran Enoxaparin Dalteparin Fondaparinux Direct Thrombin Inhibitors Bivalirudin, Agratroban

101. 109 SHORTCOMINGS TO CURRENT ANTICOAGULANTS Koolian M, Wiseman D, Mantzanis H, Kampouris N, Kerzner RS, Kahn SR. Anticoagulation stewardship: Descriptive analysis of a novel approach to appropriate anticoagulant prescription. Res Pract Thromb Haemost . 2022 Sep 25;6(6):e12758. doi : 10.1002/rth2.12758. PMID: 36186105; PMCID: PMC9510439. Leading cause of emergency department visits due to adverse drug reaction (15%) Drugs like warfarin are prone to drug interaction Most drugs not used in chronic kidney disease due to their renal clearance DOACs prove inefficient in preventing thrombosis associated with foreign material, primarily driven by the contact/intrinsic pathway E.g. mechanical valve prosthesis Need for alternative anticoagulant options for specific patient populations, such as those with antiphospholipid syndrome.

102. X Prothrombin Thrombin Fibrinogen Fibrin Direct Xa Inhibitors Direct Thrombin Inhibitors

103. Direct Xa Inhibitors ORAL Apixaban Edoxaban Rivoroxaban Betrixaban Dabigatran Lepirudin Desirudin Bivalirudin Argatroban NOVEL/NEWER ANTICOAGULANTS

104. Direct Xa Inhibitors ORAL Apixaban Edoxaban Rivoroxaban Betrixaban Dabigatran NOVEL/NEWER ANTICOAGULANTS Stopped manufacture In 2020 Idarucizumab Andexanet alfa Reversal agents

105. DABIGATRAN ETEXILATE It is a Prodrug Rapidly hydrolysed to Dabigatran Competitively and reversibly blocks active site of free and clot bound thrombin Inhibits thrombin mediated fibrinogen to fibrin conversion, feedback activation of anticoagulation and platelet activation Direct Thrombin Inhibitors MECHANISM OF ACTION

106. DABIGATRAN ETEXILATE ADME Low oral bioavailability(6%) and plasma t1/2 is 12-14 h Hence given in capsule dosage and in BD dosing Excreted unchanged by kidneys therefore dosage adjustments required in severe renal impairment Effect is predictable, monitoring usually not required Yet for monitoring, INR is unreliable and Thrombin time is too sensitive hence Diluted Thrombin Assay is developed. ADME

107. DABIGATRAN ETEXILATE Therapeutic uses Adverse Effects Interactions Approved in Venous Thromboembolism f ollowing hip/knee joint replacement surgery After 5 days of parenteral anticoagulation with Heparin/LMWH. Bleeding is the major side effect Avoided with drugs causing renal impairment Dyspepsia is frequent and heapatobiliary disorder is rare S/E. Substrate for Pgp pump Secondary prevention of venous thromboembolism in non-valvular atrial fibrillation. Risk of intracranial bleeding is ↓and GI bleed is ↑ as compared to warfarin Verapamil, quinidine and ketoconazole can ↑ concentrations, Contraindicated in mechanical heart valves. Used cautiously with concurrent use of antiplatelet drugs and NSAIDs Rifampicin may ↓ concentration.

108. EDOXABAN Inhibit free and clot-associated factor Xa Reduced thrombin generation Platelet aggregation and fibrin formation are suppressed APIXABAN MECHANISM OF ACTION

109. ADME Therapeutic uses Adverse Effects Drug interactions Oral BA: 80%, plasma t1/2: 7-11 h Highly protein bound Prophylaxis of venous thromboembolism following total knee/hip replacement (HR/KR) Started 10 mg OD 6-10 hrs post surgery Given till 12–14 days after KR replacement 35 days after HR Bleeding, nausea, hypotensiontachycardia and edema. Potent inhibitors or inducers of P-glycoprotein will ↑ or ↓ drug concentrations Maximum absorption in stomach, food enhances absorption Started 10 mg OD 6-10 hrs post surgery Given till 12–14 days after KR replacement 35 days after HR Given in tablet form, crushed and given via nasogastric tube For DVT and PE: 15 mg BD for 3 weeks followed by 20 mg/day Risk of intracranial bleeding is ↓and GI bleed is ↑ as compared to warfarin Excreted equally via renal and hepatic pathway Coadministration with aspirin and clopidogrel for prophylaxis of ACS: 2.5 mg/day

110. ADME Therapeutic uses Adverse Effects Drug interactions Oral BA: 50%, plasma t1/2: 12 h Effect in 1-3 h Highly protein bound Prophylaxis of venous thromboembolism following Treatment of DVT and PE Prophylaxis of total knee/hip replacement Prophylaxis of stroke in AF Bleeding is a adverse effect Risk of intracranial bleeding is ↓and GI bleed is ↑ as compared to warfarin Drug interactions with inducers and inhibitors of CYP3A4 are possible Metabolized by hepatic Cyp3A4 rest unchanged by kidney For DVT: 10 mg BD 6-10 hrs post surgery for 7 days 5 mg BD thereafter >6-12 months required dose reduced to 2.5 mg Used cautiously with concurrent use of antiplatelet drugs and NSAIDs Given in tablet form, crushed and given via nasogastric tube Prophylaxis of THR: 2.5 mg BD Prophylaxis of stroke: 5 mg BD Avoided patients with hepatic or renal impairment

111. ADME Therapeutic uses Adverse Effects Oral BA: 62%, Effect in 1-2 h Highly protein bound Drug exposure is ↑ in renal impairment low body weight intake of potent P-glycoprotein inhibitors Therefore dose reduced from 60  30 mg OD creatinine clearance Ccl between 15- 50 mL/min, body weight of 60 kg or less quinidine, dronedarone, rifampin, erythromycin, ketoconazole, or cyclosporine. Bleeding is a major adverse effect Risk of intracranial bleeding is ↓and GI bleed is ↑ as compared to warfarin Food does not affect metabolism Minimal hepatic metabolism hence preferred in liver disease dose from 60  30 mg OD in creatinine clearance Ccl between 15- 50 mL/min, body weight of 60 kg or less quinidine, dronedarone, rifampin, erythromycin, ketoconazole, or cyclosporine. Used cautiously with concurrent use of antiplatelet drugs and NSAIDs Given in tablet form, crushed and given via nasogastric tube Used in acute DVT and PE Prophylaxis for stroke prevention in patients with AF Avoided patients with hepatic or renal impairment (C/I with <1.5 ml/min Ccl )

112. Antiplatelet Agents

113. ANTIPLATELET DRUGS (Antithrombotic drugs) These are drugs which interfere with platelet function and are useful in the prophylaxis of thromboembolic disorders. Platelets express several glycoprotein (GP) integrin receptors on their surface. Reactive proteins like collagen and von Willebrand factor ( vWF ) are exposed when there is damage to vascular endothelium, and they react respectively with platelet GPIa and GPIb receptors.

114. Blood Clotting Vascular Phase Platelet Phase Coagulation Phase Fibrinolytic Phase

115. 1. Vascular Phase Vasoconstriction Exposure to tissues activate tissue factor and initiate coagulation Tissue Factor

116. 2. Platelet phase . After vessel injury: Platelets adhere & aggregate Release permeability increasing factors (e.g. vascular permeability factor, VPF) Loose their membrane & form a viscous plug

117. 3. Coagulation Phase 2 major pathways Intrinsic pathway Extrinsic pathway Both converge at a common point :Activation of Xa Clotting factors: There are 13 soluble Biosynthesis is dependent on Vitamin K1& K2 Most are proteases Normally inactive & sequentially activated

118. 4 . Fibrinolysis Enhance degradation of clots Activation of endogenous protease Plasminogen (inactive form) is converted to Plasmin (active form) Plasmin breaks down fibrin clots

119. Role of platelet in thrombus formation One of the early events following vascular injury is the adhesion of circulating platelets to exposed sub endothelium . Major steps in arterial thrombosis include platelet activation and aggregation , both following contact with sub endothelial structures and via thrombin generation. Antiplatelet agents (APA) are therefore key tools in the treatment of atherothrombosis .

120. In addition to their well-established role in thrombus formation, there is growing evidence that platelets are also involved in the progression of atherosclerotic lesions. When activated, platelets release granules containing cytokines and growth factors that, together with thrombin, contribute to the migration and proliferation of smooth-muscle cells and monocytes . Thus, in addition to their preventive role in acute thrombosis, Anti-platelet agents can also inhibit the platelet contribution to lesion progression.

121. Mechanism of Platelet Aggregation and inhibition In undamaged endothelium, PGI  synthesized and released in plasma, activates PGI2 receptors on platelets- Increases cAMP levels which inhibit platelet aggregation. Damaged endothelium can not synthesize PGI 2 so decrease in cAMP levels. cAMP is metabolized to 5’AMP by phosphodiesterase enzyme. Any drug which inhibit Phosphodiesterase enzyme would increase cAMP levels and would inhibit platelet aggregation.

122. Exposure of underlying collegen activates dorment receptors on platelets which triggers the release of ADP and 5-HT along with Ca2+ and fibrin stabilizing factors. This is known as “ platelet release reaction ”. 5-HT, being vasoconstrictor, decrease blood flow to injured vessels. ADP activates ADP receptors of other platelets to induce shape change and aggregation and to increase their adhesiveness. Hence any drug which inhibit ADP binding to its receptor would inhibit platelet aggregation.

123. Stimulation of platelet by collegen/ADP also activates platelet membrane phospholipaseA2 to synthesize arachidonic acid from membrane phospholipids. It is then converted ultimately to thromboxane A 2 (TXA 2 )by COX-1 which is released into plasma to activate TXA 2 receptors present on platelets and activate platelets. Hence any drug which irreversibly inhibits platelet COX-1 would also prevent platelet aggregation.

124. Platelet contains numerous glycoprotein receptors which remains in inactive conformation which does not support fibrinogen binding. On activation of platelet (by ADP/TXA 2 /thrombin), the GPIIb-IIIa receptors assume an active conformation which is capable of binding fibrinogen. This leads to formation of platelet clumps. Any drug which blocks GPIIb-IIIa receptors , would inhibit thrombus formation.

125. Regulation of platelet aggregation Anti- aggregatory Inactivated Platelets Proaggregatory Intact endothelium Prostacycline Nitric oxide - Activation Thrombin A-II, NE Platelet Damage + ADP Serotonin TXA2 Calcium Receptors Expressed on surface Aggregation Von WF Collagen Fibrinogen INTACT ENDOTHELIUM PROTECTS

126. Thrombi According to composition. Arterial Occur in areas of rapid flow (arteries) In response to an injured or abnormal vessel wall White Composed: primarily of platelets, also fibrin & occasional leukocytes Associated with MI Stroke Ischemia Venous Occur primarily in the venous circulation In response to venous stasis or vascular injury Red Composed: almost entirely of fibrin & erythrocytes Associated with Congestive Heart Failure, Surgery.

127. Antithrombotic drugs

128. Antithrombotic drugs

129. Antithrombotic drugs

130. Antithrombotic drugs Fibrinolytics

131. Targets for Antiplatelet Drugs Activation and aggregation of platelets is a major component of thrombosis especially in arteries Targets for platelet inhibitory drugs: (a) Inhibition of prostaglandin metabolism through inhibition of cyclooxygenase (aspirin) (b) Inhibition of ADP-induced platelet aggregation ( ticlopidine ) (c) Inhibition of GPIIb-IIIa Receptors. (d) Inhibition of Adenosine Reuptake. (e) Inhibition of Phosphodiesterase enzyme.

132. Cyclo-oxygenase Inhibitors Aspirin Also known as acetyl salicylic acid One of the most widely used medication with an estimated 40,000  tonnes  of it being consumed each year

133. History of Aspirin Use…. 1826- Henri Lerouxhad isolated a tiny amount of bitter tasting yellow, needle-like crystals, (later salicin ) 1828- Johann Buchner , at the University of Munich, purified the compound which he called salicin . 1838- Raffaele Piria [an Italian chemist] working in Paris, split salicin into a sugar and an aromatic component ( salicylaldehyde ) and converted the latter, by hydrolysis and oxidation , to an acid of crystallised colourless needles, “ salicylic acid ."

134. 1853-Gerhardt neutralized salicylic acid by buffering it with sodium (sodium salicylate ) and acetyl chloride, creating acetylsalicylic acid Gerhardt has shown no interest in marketing drug ,so it has remained in curtains.

135. In 1899, a German chemist named Felix Hoffmann, who worked for a German company called Bayer , rediscovered Gerhardt's formula along with Arthur Eichengrün , a colleague of Hoffmann. Felix Hoffmann made the formula and gave it to his father who was suffering from the pain of arthritis with good results Felix Hoffmann Rediscoverer of Acetylsalicylic Acid

136. Bayer came up with the name Aspirin , it comes from the “A” in - acetyl chloride , “ spir ” in- spiraea ulmaria (the plant they derived the salicylic acid from) “in” - was a then familiar name ending for medicines Aspirin was patented on February 27, 1900. In 1915, the first Aspirin tablets were made.

137. Aspirin as Antiplatelet … Low dose aspirin could prevent MI and stroke was first reported by Dr.Lawrence Craven , a suburban general practitioner in California. Unfortunately, Craven’s work went largely unnoticed, and decades passed before his observations were verified by clinical trial. Dr. Lawrence Craven

138. Aspirin Mechanism: Inhibits cyclooxygenase (COX1) irreversibly COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins). Aspirin irreversibly acetylates a serine residue at position 529 in platelet cyclooxygenase-1 (COX-1). This prevents metabolism of arachidonic acid into the cyclic endoperoxides PGG2 and PGH2 for the lifetime of the platelet thereby impairing thromboxane A2 production. Inhibits platelet aggregation  

139. Long acting because new proteins must be synthesized As platelet lacks nucleus, activity is not restored until new platelets are formed. Weak antithrombotic agent Other NSAIDS: shorter duration because of reversible competitive inhibitory action potency varies, e.g. Naproxen, meclofenamic acid, Ibuprofen, Indomethacin , phenylbutazare

140. It eventually act as a indirect antithrombotic agent On the other hand, it inactivates cyclooxygenase in vascular endothelium which may diminish the formation of antiaggregatory prostacycline . But cyclooxygenase can be synthesized within hours in vascular endothelium. So, antithrombotic activity predominates

141. Aspirin is a weak acid ( pKa 3.4). Acidic drugs in an acidic environment (like gastric lumen) are most likely to be in their neutral form ( non-ionized ) Non-ionized drugs are more lipid soluble. Hence, they can be readily absorbed Since aspirin is a weak acid and gastric pH is an acidic environment,  it can be readily absorbed. Bloodstream has a pH of around 7.4, therefore aspirin tends to be ionized. This prevents the drug from diffusing back to the stomach. This is ion trapping

142. Dose: Low dose daily (75-100 mg/day): Prevents ischemic attack ( ministroke ) and MI 320 mg/day: Should be given urgently at the onset of the symptoms of acute myocardial infarction. Use : Prevention of recurrent infarcts in patients with myocardial infarction In stable angina, 75 mg per day reduce sudden death by 34% Secondary prevention after TIA (22% risk reduction as compared to placebo) .

143. low-dose aspirin, compared with placebo, reduces by 36% the risk of Venous thromboembolism after orthopaedic surgery Meta-analysis of trials in surgical and medical patients: significant reduction in DVT and PE with antiplatelet prophylaxis

144. Contraindications Patients with glucose 6-PO4 dehydrogenase deficiency Hemophilia Patients with gastro-intestinal bleed Intolerance to aspirin Peptic ulcer

145. Drug interactions: Concurrent warfarin and aspirin therapy increases the risk of bleeding. ACE inhibitors and aspirin have potentially opposite effect on renal hemodynamics . Phenobarbitone , Rifampicin , Phenytoin decreases the efficacy of aspirin through induction of hepatic enzymes.

146. Side effects Gastrointestinal bleeding Reye’s syndrome  a rare but severe illness characterized by acute  encephalopathy  and  fatty liver , can occur when children are given aspirin for a fever or other illnesses or infections most commonly with a  respiratory infection,  chickenpox, or  diarrhea

147. Salicylism Precipitation of asthma Angioedema

148. Aspirin Resistence Occurring in 5-20 % of patients Defined as a failure of supression of thromboxane generation with high urinary concentration of metabolite of thromboxane A 2. Mechanism- Platelet glycoprotein polymorphism Activation of platelet by mechanism other than cyclooxygenase pathway Enhanced inflammatory activity with increased expression of COX-2

149. Thienopyridine Derivatives Decrease platelet aggregation by inhibiting ADP pathway of platelets no effect on Prostaglindin metabolism ADP attracts other platelets by binding to two types of receptors: Low affinity type 2 purinergic receptors (P2Y12), High affinity purinergic receptors (P2Y1) Thienopyridins ( ticlopidine , clopidogrel ) block the binding of ADP to P2Y12 and prevent the activation of the GPIIb-IIIa receptor complex and subsequent activation of platelet.

150. Ticlopidine Prevent platelet aggregation MOA : It irreversibly inhibits binding of ADP to purine receptors. It is a prodrug ; require conversion to active thiol metabolite by hepatic cytochrome P450 enzyme. Dose: 250 mg BD.

151. Use: To prevent repeat stroke or TIA in those intolerant of or resistant to aspirin Coronary artery stenting with aspirin for upto 30 days after stenting Generally reserved for those who are intolerant to aspirin

152. Side effects: Neutropenia (2.4%) Thrombotic thrombocytopenic purpura which may be life threatning (0.01%) Minor bleeding (10%) Skin rash (15%) Liver toxicity (4%) Should be monitored with complete blood count

153. Clopidogrel Action: It prevent platelet activation Mechanism of Action: It irreversibly inhibits the binding of ADP to the purine receptors on platelets thus inhibiting ADP mediated platelet activation. Given orally : First loading dose followed by once daily administration. Dose: Loading dose-300-600 mg orally followed by 75 mg O.D. Metabolized to active compound

154. As it is a irreversible inhibitor, effects lasts several days Metabolism Hepatic 90-94% protein bound Uses: Reduction of atherosclerotic events( MI, stroke) in patients with atherosclerosis as documented by recent stroke, recent MI. For acute coronary syndrome.   Along with aspirin, for the prevention of  thrombosis  after placement of intracoronary  sten t

155. According to AHA/ACC 2007 guidelines for unstable angina/ non-ST segment elevated myocardial infarction: Clopidogrel should be administered and continued for at least 1 month preferably for 1 year.

156. Adverse effects: Bleeding Gastrointestinal discomfort Rashes Rarely Neutropenia . Effect increased by other antithrombotic drugs Interactions: Inhibits metabolism of NSAIDs, phenytoin . Proton Pump Inhibitors may increase adverse effects of Clopidogrel

157. Clopidogrel Resistence Approximately 29% of people are resistant to clopidogrel . Several possible mechanisms have been proposed. Variable bioavailability Due to drug-drug interactions or Failure to convert clopidogrel into its active metabolite. Genetic Polymorphisms in the P2Y12 receptor. Certain alleles of this receptor do not bind ADP-receptor antagonists effectively. Polymorphisms in the cytochrome P450 system

158. The “resistance ” rate for combination aspirin plus clopidogrel is approximately 9%.

159. GPIIb-IIIa Inhibitors The glycoprotein IIb / IIIa receptor located on the platelet surface plays a pivotal role in platelet thrombus formation by binding to fibrinogen thereby facilitating cross linkage of platelets. GPIIb-IIIa receptor antagonist are most potent antiplatelet agents commonly used.

160. GPIIb/IIIa-receptor antagonists – mechanism of action

161. GPIIb/IIIa-receptor antagonists – mechanism of action

162. GPIIb / IIIa -receptor antagonists – mechanism of action

163. GPIIb/IIIa-receptor antagonists – mechanism of action