Anticoagulants

coagulation cascade
coagulants and anticoagulants
fibrinolytics
antiplatelets

1. COAGULANTS AND Presenter: Dr.Roohana Hasan Moderator: Dr.D.A.Rizvi

2. Overview Introduction Coagulation Cascade Fibrinolysis Natural Anticoagulants Coagulants Anticoagulants Newer Anticoagulants Fibrinolytics Antiplatelets

3. Hemostasis is the cessation of blood loss from a damaged vessel. Vascular Spasm Platelet Plug Formation Blood Coagulation Wound causes vasoconstriction which prevents blood loss Starts with Platelet Adhesion (to the exposed collagen of the damaged endothelium) Followed by Platelet Aggregation (by loosing their individual membrane and forming a gelatinous mass- Platelet Plug loose initially but tightens when reinforced by fibrin) Introduction

4. Thrombosis is a pathological condition resulting from inappropriate activation of haemostatic mechanisms: - venous thrombosis is usually associated with stasis of blood; a venous thrombus has a small platelet component and a large component of fibrin - arterial thrombosis is usually associated with atherosclerosis, and the thrombus has a large platelet component. A portion of a thrombus may break away, travel as an embolus and lodge downstream, causing ischaemia and/or infarction .

5. COAGULATION CASCADE

6. VIIa Prothrombinase

7. This system provides check and balances so that clotting process does not go out of hands. It dissolves clots at the site of damage once the damage is repaired. The process of dissolution of the clot is called Fibrinolysis . Fibrinolytic System

8. FIBRINOGEN Fibrin degraded products Thrombin

9. Natural Anticoagulant Mechanisms Prostacyclin (PGI2)- a metabolite of arachidonic acid, produced by endothelial cells. Opposes the action of TXA2 Inhibits the platelet aggregation and release Antithrombin III (AT3)- a plasma protein. Blocks the action of factor XII, XI, IX, X and II

10. Protein C- plasma protein Inactivates Factor VIII and V – not blocked by AT3 Enhances the activity of t-PA. It is a Vitamin K endogenous anticoagulant which is activated by thrombin through binding to its receptor Thrombomodulin . Heparan Sulfate- a proteoglycan related to heparin, synthesized by endothelial cells. Serves as a Cofactor Enhances the activity of Antithrombin III

11. Coagulants

12. These are substances which promote coagulation, and are indicated in haemorrhagic states. Fresh whole blood or plasma provide all the factors needed for coagulation and are the best therapy for deficiency of any clotting factor; also they act immediately.

13. Classification Vitamin K K1 (from plants, fat-soluble) : Phytonadione ( Phylloquinone ) K2 : Menaquinone K3 (Synthetic) : Fat Soluble- Menadione , Acetomenaphthone Water-soluble- Menadione sod. bisulfite , Menadione sod. diphosphate Miscellaneous Plasma Fractions- VIII, IX and mixed factors Antifibrinolytics - Aminocaproic Acid, Trenexamic acid Aprotinin Fibrinogen (human) Antihaemophilic factor Desmopressin Adrenochrome monosemicarbazone Rutin , Ethamsylate

14. It is a fat-soluble dietary principle required for the synthesis of clotting factors II ( prothrombin ), VII, IX, and X. Vitamin K is a fat soluble vitamin found in green leafy vegetables, such as cabbage, spinach; and liver, cheese, etc. Vitamin K

15. - Vitamin K and its Analogues Natural Vitamin K or Phytonadione Obtained from leafy vegetables. Can be given orally or by IV injection. Rapid onset and prolonged effect. Requires bile salts for absorption. Deficiency can occur in obstructive jaundice and any disease involving mal absorption of fats.

16. Vitamin K 2 or Menaquinone - synthesized by intestinal flora. Hence, prolonged inhibition of growth of iintestinal bacteria from antibiotic therapy can lead to deficiency of Vitamin K. Vitamin K3 or Menadione - synthetic water soluble analogue. Bile salts are not needed for absorption, can be given orally in case of obstructive jaundice.

17. Mechanism of Action

18. Dietary deficiency : of vit K is very rare in adults. However, when it occurs 5–10 mg/day oral or parenteral vit K rapidly corrects the defects. Prolonged antimicrobial therapy : treat in the same way as dietary deficiency of vit K. Obstructive jaundice or malabsorption syndromes ( sprue , regional ileitis, steatorrhoea , etc.): vit K 10 mg i.m ./day, or orally along with bile salts. Indications

19. Liver disease (cirrhosis, viral hepatitis): Newborns: All newborns have low levels of prothrombin and other clotting factors. The cause is both lower capacity to synthesize clotting factors as well as deficiency of vit K. The defect is exaggerated in the premature infant. Vit K 1 mg i.m . soon after birth has been recommended routinely. Some prefer administering 5–10 mg i.m . to the mother 4–12 hours before delivery. Haemorrhagic disease of the newborn can be effectively prevented/treated.

20. Overdose of oral anticoagulants : Phytonadione (K1) is the preparation of choice, because it acts most rapidly; dose depends on the severity of hypoprothrombinaemia (measured INR) and bleeding. Severe: 10 mg i.m . followed by 5 mg 4 hourly; bleeding generally stops in 6–12 hours, but normal levels of coagulation factors are restored only after 24 hr. This dose of vit K will block anticoagulant action for 7–10 days. Moderate : 10 mg i.m . followed by 5 mg once or twice according to response. Mild: Just omit a few doses of the anticoagulant. Prolonged high dose salicylate therapy causes hypoprothrombinemia ; vit K should be given prophylactically . If bleeding occurs—treat as for oral anticoagulants.

21. Adverse Effects Phytonadione injected i.m . or given orally hardly produces any adverse effect; allergic reactions are rare. Anaphylactic Reaction Hemolysis - in G6PD deficient patient. In the newborn menadione or its salts can precipitate kernicterus : by inducing haemolysis and increasing bilirubin load. by competitively inhibiting glucuronidation of bilirubin . Glucuronide conjugation is, as such, inadequate in neonates.

22. Desmopressin - It releases factor VIII and von Willebrand’s factor from vascular endothelium and checks bleeding in haemophilia and von Willebrand’s disease. Fibrinogen- The fibrinogen fraction of human plasma is employed to control bleeding in haemophilia , antihaemophilic globulin (AHG) deficiency and acute afibrinogenemic states;

23. Antihaemophilic factor- It is concentrated human AHG prepared from pooled human plasma. It is indicated (along with human fibrinogen) in haemophilia and AHG deficiency. It is highly effective in controlling bleeding episodes, but action is short-lasting (1 to 2 days). Adrenochrome monosemicarbazone - It is believed to reduce capillary fragility, control oozing from raw surfaces and prevent microvessel bleeding, e.g. epistaxis , haematuria , secondary haemorrhage from wounds, etc.

24. Ethamsylate - It reduces capillary bleeding when platelets are adequate; probably exerts antihyaluronidase action or corrects abnormalities of platelet adhesion, but does not stabilize fibrin (not an antifibrinolytic ). Ethamsylate has been used in the prevention and treatment of capillary bleeding in menorrhagia , after abortion, PPH, epistaxis , malena , hematuria and after tooth extraction. Side effects are nausea, rash, headache, and fall in BP (only after i.v . injection).

25. Aprotinin - inhibits plasmin , kallikrein and platelet activation . Used for hyperplasminemia caused by fibrinolytic drug overuse and to prevent blood loss from cardiac bypass surgery. Rutin -It is a plant glycoside claimed to reduce capillary bleeding.

26. Anticoagulants

27. Drugs affecting Coagulation Classes Drugs Parenteral Indirect thrombin inhibitors Direct thrombin inhibitors Heparin, LMWH and fondaparinux Lepirudin , Bivalirudin and Argotroban Indandione Phenindione Anticoagulant s

28. Heparin & its derivatives Heparin, a glycosaminoglycan found in the secretory granules of mast cells is synthesized from UDP-sugar precursors as a polymer of alternating D- glucuronic acid and N -acetyl-D-glucosamine residues Heparin is artificially extracted from porcine intestinal mucosa which is rich in mast cells. Heparin derivatives are fragments of heparin ranging in molecular weight from 1-10 kDa . LMWH preparations differ from heparin and, to a lesser extent, from each other in their pharmacokinetic properties.

29. Mechanism of Action: Heparin binding to antithrombin 3 induces a conformational change in antithrombin that renders its reactive site more accessible to the target protease Antithrombin inhibits activated coagulation factors ( Xa , IIa , IXa , XIa , XIIa and XIIIa )in the intrinsic and common pathways This induces a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa and IIa . To potentiate thrombin inhibition 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. Inhibition of Thrombin

30. Other Pharmacological Properties: High doses of heparin can interfere with platelet aggregation and thereby prolong the bleeding time . Lipoprotein lipase hydrolyzes triglycerides to glycerol and free fatty acids. Heparin "clears" lipemic plasma in vivo by causing the release of lipoprotein lipase into the circulation

31. LMWH Predominat effect on factor Xa LMWHs have greater anti-factor Xa activity than anti- IIa activity, and the ratio ranges from 3:1 to 2:1 depending on the preparation. Given by subcutaneous route and have a greater half life

32. Fondoxiparinux It is a synthetic derivative of heparin It causes selective inhibition of factor Xa without binding thrombin Does not show any effect on thrombin itself due to its shorter polymer length It has lesser antiplatelet effect hence chances of bleeding in minimal.

33. LMWH preparations Enoxaparin D alteparin T inzaparin A rdeparin N adroparin R eviparin Not absorbed through the GI mucosa and therefore must be given parenterally . LMWH and fondaparinux are absorbed more uniformly after subcutaneous injection. Heparin appears to be cleared and degraded primarily by the reticuloendothelial system; a small amount of undegraded heparin also appears in the urine.

34. Toxicity and Adverse Events Bleeding Major bleeding occurs in 1-5% of patients treated with intravenous heparin for venous thromboembolism Incidence of bleeding is proportionate to the degree of prolongation of the aPTT If life-threatening hemorrhage occurs, the effect of heparin can be reversed quickly by the intravenous infusion of protamine sulfate, a mixture of basic polypeptides isolated from salmon sperm. Protamine binds tightly to heparin and thereby neutralizes its anticoagulant effect . Heparin-Induced Thrombocytopenia: Heparin-induced thrombocytopenia (platelet count <150,000/mL or a 50% decrease from the pretreatment value) occurs in 0.5% of medical patients 5-10 days after initiation of therapy with heparin Abnormalities of hepatic function test Risk of osteoporosis is lower with LMWHs or fondaparinux than it is with heparin

35. Contraindications Bleeding disorders, history of heparin induced thrombocytopenia. Severe hypertension (risk of cerebral haemorrhage ), threatened abortion, piles, g.i . ulcers (risk of aggravated bleeding). Subacute bacterial endocarditis (risk of embolism), large malignancies (risk of bleeding in the central necrosed area of the tumour ), tuberculosis (risk of hemoptysis ). Ocular and neurosurgery, lumbar puncture. Chronic alcoholics, cirrhosis, renal failure. Aspirin and other antiplatelet drugs should be used very cautiously during heparin therapy.

36. Protamine Sulfate The effect of heparin can be reversed quickly by the intravenous infusion of protamine sulfate, a mixture of basic polypeptides isolated from salmon sperm. Protamine binds tightly to heparin and thereby neutralizes its anticoagulant effect Dose : 1 mg of Protamine Sulfate for 100 U of Heparin Protamine only binds long heparin molecules. Therefore , protamine only partially reverses the anticoagulant activity of LMWHs and has no effect on that of fondaparinux . Heparin Antagonist

37. Parenteral Anticoagulants Hirudin is a specific irreversible inhibitor of thrombin obtained from salivary gland of Leech. Lepirudin is the recombinant form of Hirudin . Used as an anticoagulant in hepain induced thrombocytopenia and associated thromboembolic disease. It has an off- labelled use in prevention of ischemic complications associated with unstable angina. Side effects- heamorrhage , heamaturia and increased transaminase .

38. Other Parenteral Anticoagulants Drug Mechanism Uses Drotrecogin Alfa- human recombinant protein C inhibitor of Va and VIIIa Used as an anticoagulant and decrease mortality risk from severe sepsis. Desirudin A direct thrombin inhibitor Desirudin is indicated for the prophylaxis of DVT in patients undergoing elective hip replacement surgery Bivalirudin A direct thrombin inhibitor Used as an alternative to heparin in patients undergoing percutaneous coronary angioplasty or cardiopulmonary bypass surgery. Argatroban A direct thrombin inhibitor used in heparin induced thrombocytopenia. Higher risk of bleeding, monitoring of aPTT and PT Danaparoid Inhibits activation of factor Xa Used for the treatment of heparin induced thrombocytopenia and postoperative DVT

39. DIRECT FACTOR Xa INHIBITORS Rivaroxaban and Apixaban It is an orally active direct inhibitor of activated factor Xa which has become available for prophylaxis and treatment of DVT. Its anticoagulant action develops rapidly within 3–4 hours of ingestion and lasts for ~24 hours. It requires no laboratory monitoring of PT or aPTT , and is recommended in a fixed dose of 10 mg once daily starting 6–10 hours after surgery for prophylaxis of venous thromboembolism following total knee/hip replacement. In comparative trials, its efficacy has been found similar to a regimen of LMW heparin followed by warfarin . Rivaroxaban has also been found equally effective as warfarin for preventing stroke in patients with atrial fibrillation. Side effects reported are bleeding, nausea, hypotension, tachycardia and edema.

40. ORAL DIRECT THROMBIN INHIBITOR Dabigatran etexilate It is a prodrug which after oral administration is rapidly hydrolysed to dabigatran,a direct thrombin inhibitor which reversibly blocks the catalytic site of thrombin and produces a rapid (within 2 hours) anticoagulant action. In the UK, Canada and Europe it is approved for prevention of venous thromboembolism following hip/knee joint replacement surgery. Administered in a dose of 110 mg (75 mg for elderly > 75 years) once daily, it has been found comparable to warfarin . In another large trial dabigatran etexilate 150 mg twice daily has yielded superior results to warfarin for prevention of embolism and stroke in patients of atrial fibrillation. In the USA it is approved for this indication. Adverse effects are bleeding and less commonly hepatobiliary disorders.

41. Oral Anticoagulants Warfarin and related compounds: Chemically various derivatives of 4-hydroxycoumarin are available and have activity as vitamin K antagonists

42. Mechanism of Action They inhibit the enzyme vit K epoxide reductase (VKOR) and interfere with regeneration of the active hydroquinone form of vit K which acts as a cofactor for the enzyme γ- glutamyl carboxylase that carries out the final step of γ carboxylating glutamate residues of prothrombin and factors VII, IX and X

43. Pharmacological Properties 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 ) Because of the long t1/2 of some of the coagulation factors, in particular factor II, the full anti-thrombotic effect of warfarin is not achieved for several days. Warfarin also can be given intravenously without modification of the dose. Intramuscular injection is not recommended because of the risk of hematoma formation.

44. Drug Polymorphism: Polymorphisms in two genes, CYP2C9 and VKORC1 (vitamin K epoxide reductase complex, subunit 1) account for most of the genetic contribution to the variability in warfarin response CYP2C9 Pharmacokinetics Common variations in the CYP2C9  gene are associated with higher drug concentrations and reduced warfarin dose requirements VKORC1 Pharmacodynamics Polymorphism in VKORC1 explains 30% of the variability in warfarin dose requirements.

45. Uses 1.Treatment & Prevention of Deep Venous Thrombosis in- • Bedridden (Immobilized patients) • Old people • Post-operative • Post-stroke patients • Leg fractures • Elective Surgery Ischemic Heart Disease Unstable angina -After MI After angioplasty CABG, stent replacement; Prevent recurrence Rheumatic Heart Disease/ Atrial Fibrillation Warfarin , heparin, low dose aspirin, Decrease stroke due to emboli

46. Cerebrovascular Diseases- Cerebral Emboli (Prevention of recurrence) Vascular Surgery, Prosthetic heart valves, Retinal vessel thrombosis, Extracorporeal circulation, Hemodialysis To prevent Thromboembolism Defibrination syndrome or DIC- Abruptio placenta, malignancies, infections; increased consumption of clotting factors

47. Adverse Effect and Toxicities: Haemorrhage: INR should be maintained between 2-3 and risk of bleeding is potentiated beyond INR 3. Risk of Intracranial haemorrhage, GI bleeding, intraperitoneal, retroperitoneal increases Vitamin K supplementation( iV /oral) is required when INR >5 with temporary discontinuation of drug Birth defects: Administration of warfarin during pregnancy causes birth defects and 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 Skin necrosis: Rare Purple Toe Syndrome: painful , blue-tinged discoloration of the plantar surfaces and sides of the toes that blanches with pressure and fades with elevation of the legs.

48. Contraindications Hypersensitivity Bleeding Disorders like Hemophilia Thrombocytopenia Intracranial Hemorrhage GIT Ulcerations Threatened abortion Advanced renal or hepatic disease

49. Other Vitamin K Antagonists Phenprocoumon It has a longer plasma t1/2 (5 days) than warfarin, as well as a somewhat slower onset of action and a longer duration of action (7-14 days). Acenocoumarol It has a shorter t1/2 (10-24 hours), a more rapid effect on the PT, and a shorter duration of action (2 days). The maintenance dose is 1-8 mg daily. Indandione It is similar to warfarin in its kinetics of action, has higher chances of Hypersensitivity

50. Indandione Derivatives Anisindione (MIRADON) is available for clinical use in some countries. It is similar to warfarin in its kinetics of action but offers no clear advantages and may have a higher frequency of untoward effects. Phenindione (DINDEVAN) still is available in some countries. Serious hypersensitivity reactions, occasionally fatal, can occur within a few weeks of starting therapy with this drug, and its use can no longer be recommended

51. FIBRINOLYTICS ( 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 .

52. Streptokinase Streptokinase was the first thrombolytic agent approved for clinical use, and it has been used extensively .  Streptokinase is a purified bacterial protein isolated from Lancefield group C strains of b-hemolytic streptococci . This produces a conformational change that exposes the active site on plasminogen that cleaves Arg 560 on free plasminogen to form plasmin . Due to its bacterial origin, streptokinase stimulates an immune response and the production of antibodies in humans. Because circulating (neutralizing) antibodies can inactivate the drug, streptokinase cannot be re-administered for at least 6 months

53. Tissue Plasminogen Activator and R- tpa It is a poor plasminogen activator in the absence of fibrin t-PA activates fibrin-bound plasminogen several hundredfold more rapidly than it activates plasminogen in the circulation Alteplase (ACTIVASE) is produced by recombinant DNA technology . The currently recommended regimen for coronary thrombolysis 15-mg intravenous bolus, followed by 0.75 mg/kg of body weight over 30 minutes 0.5 mg/kg (up to 35 mg accumulated dose) over the following hour Reteplase : is a recombinant form of TPA having a longer half life.

54. 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. This feature makes it possible to institute fibrinolytic therapy immediately on diagnosis of ST segment elevation myocardial infarction (STEMI),

55. Urokinase : It is a protease enzyme obtained from human urine and is now produced by cultured human kidney cells. It is a direct plasminogen activator and degrades both fibrinogen and fibrin. Half life is 20 min It has more fibrin specificity than Streptokinase.

56. Hemorrhagic Toxicity of Thrombolytic Therapy The major toxicity of all thrombolytic agents is hemorrhage, which results from two factors: T he lysis of fibrin in hemostatic plugs at sites of vascular injury, and T he systemic lytic state that results from systemic plasmin generation, which produces fibrinogenolysis and degradation of other coagulation factors (especially factors V and VIII ). Intracranial hemorrhage is by far the most serious problem. Hemorrhagic stroke occurs with all regimens and is more common when heparin is used

57. Uses of fibrinolytics Acute myocardial infarction Deep vein thrombosis Pulmonary embolism Peripheral arterial occlusion Stroke

58. Contraindicatons

59. Inhibitors of Fibrinolysis Aminocaproic Acid Aminocaproic acid is a lysine analog that competes for lysine binding sites on plasminogen and plasmin, blocking the interaction of plasmin with fibrin. Aminocaproic acid is thereby a potent inhibitor of fibrinolysis and can reverse states that are associated with excessive fibrinolysis . For intravenous use, a loading dose of 4-5 g is given over 1 hour, followed by an infusion of 1-1.25 g/hour until bleeding is controlled. No more than 30 g should be given in a 24-hour period. Rarely , the drug causes myopathy and muscle necrosis.

60. Tranexamic Acid Tranexamic acid is a lysine analog that, like aminocaproic acid, competes for lysine binding sites on plasminogen and plasmin, thus blocking their interaction with fibrin. The FDA approved oral tranexamic acid tablets for treatment of heavy menstrual bleeding in 2009 . When used for this indication, tranexamic acid usually is given at a dose of 1 g four times a day for 4 days.

61. Newer Anticoagulants

62. AVE5026 Ultralow-molecular-weight heparin with a mean molecular weight of 2400 Primarily targets fXa Given subcutaneously, the half-life is 16 to 20 hours, enabling once-daily administration. Excreted renally Anticoagulant effects are not neutralized by protamine sulfate

63. Idrabiotaparinux Hypermethylated derivative of fondaparinux Binds antithrombin with high affinity Has a half-life of 130 hours; idrabiotaparinux is given subcutaneously on a once-weekly basis. Excreted unchanged by the kidneys. Differs from idraparinux in that it contains a biotin moiety that enables reversal with intravenous avidin

64. Ximelagatran First target-specific oral anticoagulant in trials Ximelagatran is the oral prodrug of Melagatran Hepatotoxicity Did not receive FDA approval in 2004 On the market in Europe but pulled in 2006 ‘proof of principle’ “efficacious” as warfarin Wider therapeutic index Little dosage adjustment/ no monitoring

65. Otamixaban A parenteral direct fXa inhibitor Has a rapid onset of action produces a predictable anticoagulant effect Has a short half-life 25% of the drug is cleared by the kidneys. These features render otamixaban an attractive candidate to replace heparin in patients with ACS

66. RB006 An RNA aptamer that targets factor IXa with high affinity and specificity, When given intravenously, produces a rapid and dose-proportional anticoagulant effect Immediately reversed by intravenous administration of RB007, the complementary oligonucleotide antidote. RB006 is not cleared renally does not appear to be immunogenic has the potential to inhibit the activation of coagulation induced by exposure of blood to artificial surfaces, such as stents or cardiac bypass circuits potential to replace heparin and protamine sulfate in patients undergoing cardiopulmonary bypass surgery. May also be useful for patients at high risk of bleeding and for those with renal impairment Phase II REVERSAL-PCI study, the efficacy and safety of RB006/RB007 are being compared with those of heparin in 26 patients undergoing elective PCI

67. Edoxaban Oral thrombin Inhibitor rapidly absorbed half-life of 9 to 11 hours ENGAGE-AF-TIMI 48 trial is comparing 2 doses of edoxaban (30 or 60 mg once daily) with warfarin in 16 500 patients with AF.

68. Other oral fXa inhibitors under development include B etrixaban (15-hour half-life and extrarenal clearance) YM150 TAK442

69. Anti Platelets

70. PRIMARY HEMOSTATIC PLUG Platelet activation and aggregation: Change in shape of the platelets Release of Ca and ADP from the platelet granules. Receptor activation Platelets have 2 receptors: GpIb : binds to vWF leading to adhesion GpIIb-IIIa complex: leading to aggregation by collagen

71. Role of Cyclooxygenase PAR1 and PAR4 are protease-activated receptors that respond to thrombin ( IIa ) to promote platelet aggregation and secretion. P2Y 1 and P2Y 12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb / IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion

72. Classification TXA2 inhibitors- Aspirin ADP antagonists- Ticlopidine , Clopidogrel , Ticaglelor , Canglelor Phospodiesterase inhibitor- Dipyramidole , Cilostazol Glycoprotein IIB/IIIA receptors antagonists - Abciximab , Eptifibatide , Tirofiban

73. Aspirin In platelets major COX product is TXA2 , a labile inducer of platelet aggregation and potent vasoconstrictor. Aspirin blocks production of TXA2 by covalently acetylating serine residue near the active site of COX, this enzyme produces cyclic endperoxidase precursor of TXA2. Since platelets do not synthesize new proteins hence the action of aspirin on platelets is permanent (7-10 days)

74. Uses Prevention of AMI in pts. Of unstable angina Prevention of reinfarction in pts. Of AMI and IHD Prevention of stroke in pts. Of cerbrovascular accidents and h/o TIA For improving prognosis in patients with atherosclerotic peripheral vascular diseases Percutaneous angioplasty for coronary thrombosis , Primary prophylaxis of thromboembolism in pts with prosthetic heart valves

75. ADP antagonists- Ticlopidine Ticlopidine blocks Gi coupled ADP receptors It is a prodrug requires conversion to active form by Cyp450. Rapid absorp . ,high bioavailability Maximal inhibition of platelet inhibition it takes 8-11 days after starting therapy. AE- Nausea ,Vomiting, Diarrhea, Neutropenia , Thrombotic Thrombocytopenia Uses- Prevention cerebrovascular events, in secondary prevention of stroke Unstable angina Combination –Aspirin + ticlopidine ---angioplasty, coronary artery stenti

76. Clopidogrel This newer and more potent congener of ticlopidine has similar mechanism of action, ability to irreversibly inhibit platelet function and range of therapeutic efficacy, but is safer and better tolerated

77. Dipyramidole It inhibits phosphodiesterase as well as blocks uptake of adenosine to increase platelet cAMP which in turn potentiates PGI2 and interferes with aggregation. Levels of TXA2 or PGI2, are not altered, but platelet survival time reduced by disease is normalized.

78. Glycoprotein (GP) IIb / IIIa receptor antagonists GP IIb / IIIa antagonists are a newer class of potent platelet aggregation inhibitors which act by blocking the key receptor involved in platelet aggregation. The GPIIb / IIIa is an adhesive receptor ( integrin ) on platelet surface for fibrinogen and vWF through which agonists like collagen, thrombin, TXA2, ADP, etc. finally induce platelet aggregation. Thus, GP IIb / IIIa antagonists block aggregation induced by all platelet agonists.

79. Uses Coronary artery disease Acute coronary syndromes (ACSs) Cerebrovascular disease Prosthetic heart valves and arteriovenous shunts Venous thromboembolism Peripheral vascular disease

80. Drug Interactions Amiodarone Cimetidine Clopidogrel Azole antifungals Cotrimoxazole Fluoxetine