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Antixcoagulants
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- 2. Anticoagulants Thrombus - Anabnormal clot that develops in a blood vessel Coagulation/clot Embolus -Once a clot has developed, continued flow of blood past the clot is likely to break it away from its attachment and cause the clot to flow with the blood; such freely flowing clots are known as emboli
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- 7. COAGULANTS • Substances whichpromote coagulation • Indicated in haemorrhagic states
- 8. Classification • Vitamin K •K1 – (from plants, : Phytonadione – fat-soluble) (Phylloquinone) • K3 (synthetic) —Fat-soluble : Menadione, Acetomenaphthone —Water-soluble : Menadione sod. bisulfite: Menadione ,sod. diphosphate
- 9. Others • Fibrinogen (human) •Antihaemophilic factor • Desmopressin • Adrenochrome monosemicarbazone • Rutin, Ethamsylate
- 10. VITAMIN K • Fat-solubledietary principle required for the synthesis of clotting factors. • acts as a cofactor at a late stage in the synthesis by liver of coagulation proteins— • Prothrombin • Factors VII • IX • X.
- 11. Deficiency • Liver disease •Obstructive jaundice • Malabsorption • Long-term antimicrobial therapy • Most important manifestation is bleeding tendency
- 12. USES • Dietary deficiency •Prolonged antimicrobial therapy • Obstructive jaundice or malabsorption syndromes • Liver disease (cirrhosis, viral hepatitis) • Newborns
- 13. Contd. • Overdose oforal anticoagulants – Phytonadione (K1) is the preparation of choice, because it acts most rapidly • Prolonged high dose salicylate therapy causes hypoprothrombinemia
- 14. Adverse effects • Rarelyallergic reaction • Severe anaphylactoid reactions on i.v. injection of emulsified formulation
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- 17. Heparin • Mucopolysaccharides withMW 10,000 to 20,000 • Commercially it is produced from ox lung and pig intestinal mucosa.
- 18. Heparin History • McLean, amedical student ,discovered in 1916 that liver contains a powerful anticoagulant. • Howell and Holt in 1918 named it ‘HEPARIN’ because it was obtained from liver.
- 19. ACTIONS Anticoagulant • Acts indirectlyby activating plasma antithrombin III • heparin-AT III complex then binds to clotting factors of the intrinsic and common pathways (Xa, IIa, IXa, XIa, XIIa and XIIIa) &inactivates them • Low concentrations of heparin, factor Xa mediated conversion of prothrombin to thrombin is selectively affected.
- 20. Contd. Antiplatelet • Heparin inhigher doses inhibits platelet aggregation and prolongs bleeding time Lipaemia clearing • Injection of heparin clears turbid post-prandial lipaemic plasma by releasing a lipoprotein lipase hydrolyses triglycerides of chylomicra and very low density lipoproteins to free fatty acids
- 21. Heparin Unitage 1 Unit= amount of heparin that will prevent 1 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2ml of 1% CaCl2 1mg = 120-140 units Can’t cross placenta Safe in pregnancy Use as IV bolus/infusion SC Monitoring heparin therapy aPTT – activated partial thromboplastin time N= 26-32 sec
- 22. ADVERSE EFFECTS 1. Bleedingdue to overdose is the most serious complication of heparin therapy. Haematuria is generally the first sign. 2. Thrombocytopenia 3. Alopecia 4. Osteoporosis 5. Hypersensitivity reactions are rare.
- 23. Contraindications • Bleeding disorders,history of heparin induced thrombocytopenia • Severe hypertension, threatened abortion, piles, g.i. ulcers • Subacute bacterial endocarditis • Large malignancies, tuberculosis • Ocular and neurosurgery, lumbar puncture.
- 24. Contd. • Chronic alcoholics,cirrhosis, renal failure • Aspirin and other antiplatelet drugs should be used very cautiously during heparin therapy
- 25. Heparin antagonist Protamine sulfate:- •It is a strongly basic, low molecular weight protein obtained from the sperm of salmon fish. • Given i.v. it neutralises heparin weight for weight,i.e. 1 mg is needed for every 100 U of heparin. • In the absence of heparin, protamine itself acts as a weak anticoagulant by interacting with platelets and fibrinogen.
- 26. LMW heparin • MW:3000-7000 •selectively inhibit factor Xa with little effect on Iia • Act only by inducing conformational change in AT III
- 27. Advantages • Better subcutaneousbioavailability (70–90%) compared to UFH (20–30%): Variability in response is minimized • Longer and more consistent t½: (4–6 hours) • Since aPTT/clotting times are not prolonged, laboratory monitoring is not needed • Risk of osteoporosis: less • No thrmbocytopenia
- 28. USES • Prophylaxis ofdeep vein thrombosis and pulmonary embolism • Treatment of established deep vein thrombosis • Unstable angina and MI • To maintain patency of cannulae and shunts in dialysis patients
- 29. Synthetic heparin Fondaparinux • Use:Prophylaxis of patients undergoing hip or knee surgery and therapy of pulmonary embolism • Route: Subcuteneous • Bioavailability: 100%
- 30. Oral anticoagulant –Warfarin Vitamin K antagonist Acts indirectly Competitive antagonist Inhibits synthesis of active forms of vitamin K dependent factors Prevents ɣ carboxylation of glutamate residues Anticoagulant effect of Warfarin – onset is slow – 1 to 3 days ??? Vitamin K dependent factors t1/2 VII - 6 hrs IX - 24 hrs X – 40 hrs II – 60 hrs Effect develops gradually as the levels of clotting factors already present in plasma decline progressively
- 32. Pharmacokinetics • Warfarin israpidly and completely absorbed from intestines • 99% plasma protein bound • It crosses placenta and is secreted in milk • Partially conjugated with glucuronic acid and undergo some enterohepatic circulation • Excreted in urine.
- 33. Adverse effects Bleeding • Ecchymosis •Epistaxis, • hematuria, • Bleeding in the g.i.t. • Intracranial or other internal haemorrhages
- 34. Birth Defects • Nasalhypoplasia • chondrodysplasia punctata • Central nervous system abnormalities
- 35. Skin Necrosis • Inpatients with protein C or protein S deficiency Other Toxicities • Nausea and vomiting • Fever or flu-like symptoms • Joint and muscle aches • Diarrhea • Purple toe syndrome
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- 37. Drug interaction- withWarfarin Drugs that Increase Warfarin Activity Decrease binding to Albumin Inhibit Degradation Decrease synthesis of Clotting Factors Aspirin, Sulfonamides Cimetidine, Disulfiram Antibiotics (oral) Category Mechanism Representative Drugs
- 38. Drug interaction withWarfarin Drugs that promote bleeding Inhibition of platelets Aspirin Inhibition of clotting heparin Factors antimetabolites Drugs that decrease Warfarin activity Induction of metabolizing Barbiturates Enzymes Phenytoin Promote clotting factor Vitamin K Synthesis Reduced absorption cholestyramine colestipol
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- 40. •Anticoagulant part II DrSoham Solanki
- 41. DIRECT FACTOR XaINHIBITORS • Rivaroxaban • orally active direct inhibitor of activated factor Xa • Available for prophylaxis and treatment of DVT • Anticoagulant action develops rapidly within 3 4 hours of ingestion and lasts for ~24 hours • It requires no laboratory monitoring of PT or aPTT • Routinely used for prophylaxis of thrmoboembolism following knee replacement • Effective as warfarin for prevention of stroke
- 42. Contd. ADR • Bleeding • Nausea •Hypotension • Tachycardia • Edema
- 43. Advantages of neweroral anticoagulants over warlarin • 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 • warfarin. • Lower risk of bleeding compared to warfarin • Fewer drug interactions.
- 45. Fibrinolytics = Thrombolytics PlasminogenPlasmin Fibrin (insoluble) Fibrin fragments Activators Extrinsic Streptokinase Urokinase rt-PA Intrinsic t-PA Kallikrein Drugs used to lyse thrombi to recanalize occluded blood vessels
- 46. Fibrinolytics = Thrombolytics Streptokinase Urokinase rt-PA= Alteplase Reteplase Tenecteplase USES •Acute MI – main use – ideally given within 1-2 hrs •DVT/pulmonary embolism •Peripheral arterial occlusion •Stroke - only rt-PA is used
- 47. tenecteplase • Genetically engineeredmutant form of alteplase • Longer half life-2 hour • Increased fibrin specificity and • increased resistance to plasminogen activated inhibitor-1 • Given as a single bolus injection over 5 sec • Side effect Same as streptokinase except least or no allergic reaction • Very expensive
- 48. Fibrinolytics = Thrombolytics ADR Hemorrhage -the lysis of fibrin in haemostatic plugs at sites of vascular injury -the systemic lytic state that results from systemic plasmin generation Streptokinase – allergic reactions
- 49. Contd. • Contraindications • Priorintracranial hemorrhage • structural cerebral vascular lesion • malignant intracranial neoplasm • Ischemic stroke within 3 months • Patient receiving anticoagulants • Peptic ulcer,esophageal varices • Active bleeding/bleeding disorders • Uncontrolled hypertension • Pregnancy • Major surgery within 3 weeks
- 50. Plasminogen Plasmin Fibrin (insoluble) Fibrin fragments Activators Extrinsic Streptokinase Urokinase rt-PA Intrinsic t-PA Kallikrein InhibitorsExtrinsic Aminocaproic acid Tranexaemic acid Intrinsic α2 antiplasmin
- 51. Antifibrinolytic • Tranexamic acid •Epslison amino caproic acid
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- 55. Aspirin • Acetylates andinhibits the enzyme COX1 and TX-synthase—inactivating them irreversibly • Low doses:TXA2 synthesis inhibited • Prolongation of bleeding time lasts for 5–7 days • Dose:75–150 mg /day • Higher doses (> 900 mg/day) may decrease both TXA2 and PGI2 production
- 56. Dipyridamole • Vasodilator thatwas introduced for angina pectoris • Phoshodiesterase inhibitor-increase c-AMP- by decreasing its degradation • Potentiates PGI2 & interfere with aggregation • Used to increase antiplatelet action of aspirin
- 57. Clopidogrel • Prodrug • Mechanism:Gicoupled P2Y12 type of purinergic receptors are blocked Activation of platelets is interfered • Synergistic combination with aspirin • Exibit genetic polymorphism • Omeprazole, an inhibitor of CYP2C19, reduces metabolic activation of clopidogrel and its antiplatelet action • ADR:bleeding, diarrhoea, epigastric pain and rashes
- 58. Prasugrel Advantages: • Rapid action •No genetic polymorphism • interference by omeprazole treatment has not been prominent
- 59. Uses • Coronary arterydisease • Acute coronary syndromes (ACSs) • Cerebrovascular disease • Prosthetic heart valves and arteriovenous shunts • Venous thromboembolism • Peripheral vascular disease
- 60. • In lowdose aspirin acts on • (a) Cyclooxygenase • (b) Thromboxane A2 synthase • (c) PGI2 synthase • (d) Lipoxygenase
- 61. • Glycoprotein IIb/IIIareceptor antagonist is: • (a) Clopidogrel • (b) Abciximab • (c) Tranexamic acid • (d) Ticlopidine
- 62. • All areantiplatelet drugs Except • (a) Aspirin • (b) Clopidogrel • (c) Dipyridamole • (d) Warfarin
- 63. • Clopidogrel isan antiplatelet agent that acts by: (a)Reducing myocardial oxygen requirements during exertion and stress (b) Reducing myocardial oxygen requirements and by inducing coronary artery vasodilatation (c) Inhibiting ADP-induced platelet aggregation (d) None of the above
- 64. • Recent oraldirect thrombin inhibitor which can be used for prevention of stroke is: • (a) Dabigatrin • (b) Ximelagatron • (c) Lepirudin • (d) Saxagliptin
- 65. • Vitamin Kdependent clotting factors are: • (A)Factor ix and x • (b) Factor iv • (c) Factor xii • (d) Factor i
- 66. • Drug usedin heparin overdose is • (a) Protamine sulfate • (b) Phylloquinone • (c) Ticlopidine • (d) Clopidogrel
- 67. • Vitamin Kis involved in the post-translational modification of • (a) Glutamate • (b) Aspartate • (c) Glycine • (d) GABA
- 68. • True statementsabout heparin are all EXCEPT: • (a) It prolongs aPTT • (b) Hypersensitivity is not seen • (c) It can result in alopecia • (d) It can cause thrombocytopenia
- 69. • Which ofthe following is NOT an advantage of low molecular weight heparin over unfractionated heparin? • (a) Higher efficacy in arterial thrombosis • (b) Less frequent dosing • (c) Higher and more consistent subcutaneous bioavailability • (d) Laboratory monitoring of response not required
- 70. • In whichof the following clinical conditions, use of anticoagulants provide maximum benefit? • (a) Prevention of recurrences of myocardial infarction • (b) Prevention of venous thrombosis and pulmonary embolism • (c) Cerebrovascular accident • (d) Retinal artery thrombosis
- 71. • All ofthe following are anticoagulants, except: • (a) Phytonadione • (b) Warfarin • (c) LMW heparin • (d) Lepirudin
- 72. • Heparin doesnot cause • (a) Osteoporosis • (b) Factor V inhibition • (c) Thrombocytopenia • (d) Prolongation of aPTT
- 73. • The anticoagulantof choice in pregnancy is: • (a) Heparin • (b) Warfarin • (c) Dicumarol • (d) Phenindione
- 74. • A usefulthrombolytic agent that leads to plasmin activation is • (a) Vitamin K • (b) Heparin • (c) Streptokinase • (d) Aspirin
- 75. • Epsilon aminocaproicacid (EACA) can be used in the treatment of adverse effects caused by: • (a) Streptokinase • (b) Heparin • (c) Warfarin • (d) Any of the above
- 76. • Low molecularweight heparin acts on factor– • (a) Xla • (b) Xa • (c) IXa • (d) IIa
Editor's Notes
- #22 An aPTT two to three times the normal mean aPTT value generally is assumed to be therapeutic aPTT – citrated plasma is mixed with phospholipid,kaolin(intrinsic pathway activator) and Calcium. The time is measured until a clot forms. IMP points about == HEPARIN Heparin Unitage 1 Unit = amount of heparin that will prevent 1 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2ml of 1% CaCl2 1mg = 120-140 units Can’t cross placenta ------------- SAFE in PREGNANCY Monitoring heparin therapy BY --- aPTT aPTT – activated partial thromboplastin time N= 26-32 sec Heparin Antagonist - PROTAMINE sulfate
- #31 Effect develops gradually as the levels of clotting factors already present in plasma decline progressively
- #61 B
- #62 B
- #63 D
- #64 C
- #65 A
- #66 A
- #67 A
- #68 A
- #69 B
- #70 A
- #71 B
- #72 B
- #73 B
- #74 A
- #75 C
- #76 A
- #77 B