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ANTI-COAGULANTS

ANTI-COAGULANTS. DR.UZMA RIAZ. Thrombosis. Venous thrombosis is associated with stasis of blood Has small platelet component and large component of fibrin Arterial thrombosis is associated with atherosclerosis -initiated due to endothelial injury leads to atheromatous plaque formation

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ANTI-COAGULANTS

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  1. ANTI-COAGULANTS DR.UZMA RIAZ

  2. Thrombosis • Venous thrombosis is associated with stasis of blood • Has small platelet component and large component of fibrin • Arterial thrombosis is associated with atherosclerosis -initiated due to endothelial injury leads to atheromatous plaque formation • Plaque rupture, platelet adhesion, activation, aggregation initiates thrombus growth • Thrombus has large platelet component • Arterial thrombus may break away, emboli form leads to ischemia and infarction

  3. Hemostasis • Spontaneous Arrest of Bleeding from a Damaged Blood Vessel; This occurs by the following steps 1. Vasospasm 2. Platelet Adhesion 3. Platelet Aggregation 4. Platelet Plug 5. Fibrin Reinforcement of platelet plug

  4. Coagulation This is the conversion of blood in the liquid form to a solid gel or clot. Normally there is a balance between Procoagulants (thromboxane, thrombin, activated platelets etc.) and Anti-coagulants (heparan sulfate, Antithrombin III, Nitric oxide and Prostacyclin) Whenever this balance is disturbed coagulation occurs: • Procoagulants > Anticoagulants • Injury to blood vessel • Blood stasis

  5. Clotting Factors • I - Fibrinogen • II - Prothrombin • III - Tissue Thromboplastin • IV - Calcium • V - Proaccelerin • VII - Proconvertin • VIII- Antihemophilic globulin • IX - Christmas Factor • X - Stuart Power Factor • XI - Plasma Thromboplastin anticedent (PTA) • XII - Hageman Factor • XIII -Fibrin-stabilizing factor

  6. INITIATION OF BLOOD COAGULATION Extrinsic Pathway Intrinsic Pathway Blood trauma/ contact with collagen Tissue trauma Leakage of Tissue Factor Activation of factor XII, IX, VIII Ca+2, factor VII X Xa X Xa Ca+2 Ca+2 Prothrombin activator Prothrombin activator Ca+2 Prothrombin Thrombin (factor II) Prothrombin Thrombin (factor II) Activation of certain factors (VII, II, X and protein C and S) is essential for coagulation. This activation requires vit K (reduced form)

  7. Classification A. Parenteral Anti-Coagulants 1. Indirect Thrombin Inhibitors a) Heparins i) High Molecular Weight Heparin Unfractionated Heparin (UFH) ii) Low Molecular Weight Heparins Enoxaparin Dalteparin Tinzaparin Reviparin Danaparoid

  8. 2. Direct Thrombin Inhibitors Hirudin Lepirudin Bivalirudin Argatroban B. Oral Anti-Coagulants 1. Coumarins Warfarin Dicumarol 2. Indanediones Phenindione

  9. Heparin,History • McLean, a 2nd year medical student attempting to extract coagulant substances from various tissues during a vacation project. But found instead a powerful anticoagulant. He discovered in 1916 that liver contains a powerful anticoagulant. • Howell and Holt in 1918 named it heparin because it was obtained from liver • Occurs in mast cells (richest source of mast cells are lungs, liver and intestinal mucosa) • Commercial heparin is extracted from porcine intestinal mucosa and bobine lung • It is a mixture of straight chain anionic (negative charge) glycosaminoglycan with a wide range of molecular weights • It is strongly acidic because of presence of sulfate and carboxylic acid groups

  10. Heparin-Kinetics • Heparin is highly charged, thus crosses cell membranes very poorly, hence given Parenterally • Low dose: Subcutaneous • High Dose: Subcutaneous or IV Injection • Metabolized by liver, half life depends on dose

  11. Heparin-Mechanism of Action • Once the coagulation pathways are activated, factors IXa, Xa, XIa, XIIa and IIa (especially IIa,IXa,Xa), need to be neutralized by Anti-thrombin III (AT III). • Heparin accelerates the interaction of the active clotting factors with AT III. • The negatively charged heparin molecule binds to the positively charged lysine sites on AT III • This causes a conformational change in AT III and exposing its active arginine site • The serine active sites of the active clotting factors bind to the reactive arginine site of AT III • The resulting complex is removed by the reticuloendothelial system • This process is accelerated 1000-3000 times by heparin • The active heparin molecules bind tightly to antihormbin and cause a conformational change in this inhibitor. The conformational change of antithrombin exposes its active site for more rapid interaction with the proteases (the activated clotting factors) Heparin functions as a cofactor for the antithrombin protease reactio without being consumed. Once the antithrombin protease complex is formed, heparin is released intact for renewed binding to more antithrombin.

  12. Heparin catalyzes the reaction without being consumed • Once antithrombin-clotting factor complex is formed, heparin is released for renewed binding to more antithrombin • High molecular weight Heparins accelerates the inactivation of clotting factors IIa and Xa. • Low molecular weight heparins accelerate the inactivation of only Factor Xa

  13. Mechanism Heparin Active clotting factors Fast Antithrombin III + Heparin Inactive clotting factors No heparin Active clotting factors Slow Antithrombin III Inactive clotting factors

  14. Advantages of LMWH over UFH • Better subcutaneous bioavailability(70-90%) compared to UFH(20-30%) • Longer and more consistent half life: once daily subcutaneous administration • Since aPTT/clotting times are not prolonged, lab. monitoring is not needed • Lower incidence of haemorrhagic complications • Appear to have lesser antiplatelet action so less interference with haemostasiss

  15. Uses of Heparin (Anti-coagulants in General) 1.Treatment & Prevention of Deep Venous Thrombosis in • Bedridden (Immobilized patients) • Old people • Post-operative • Post-stroke patients • Leg fractures • Elective Surgery

  16. 2. Ischemic Heart Disease Unstable angina After MI After angioplasty CABG, stent replacement; Prevent recurrence 3. Rheumatic Heart Disease/ Atrial Fibrillation Warfarin, heparin, low dose aspirin, Decrease stroke due to emboli

  17. 4. Cerebrovascular Diseases Cerebral Emboli (Prevention of recurrence) 5. Vascular Surgery, Prosthetic heart valves, Hemodialysis To prevent thromboembolism 6. DIC Abruptio placenta, malignancies, infections; increased consumption of clotting factors

  18. Adverse Effects 1.Bleeding(most common) 2. Allergy and Anaphylaxis 3. Increased hair loss, alopecia 4. Long term-Osteoporosis, spontaneous fractures 5. Thrombocytopenia

  19. Heparin-induced Thrombocytopenia HIT) • 2nd most common side effect after bleeding • Occurs in 3-5% of patients 5 to 10 days after initiation of therapy of standard heparin • Lower incidence in low molecular wt heparin. • In 1/3 of pts is preceded by thrombosis • Can be life-threatening. • Due to production of IgG against complexes of heparin with platelet (platelet factor 4) • The complexes activate more platelets with the release of more platelet factor 4 or other cytokines. • This stimulates the formation of more IgG. • This snow-ball effect uses up platelets and also leads to thrombosis. Systemic bleeding and localized infarction (due to thrombosis) occur.

  20. 3 • Once thrombocytopenia is determined, heparin must be stopped. Direct thrombin inhibitor should be given • Platelets must NOT be given because they will react with antibody already being produced against them, causing greater chance of thrombosis.

  21. Heparin and Pregnancy • Heparin does not cross the placenta, therefore it must be used instead of warfarin in cases of requiring anticoagulant therapy in pregnancy. • Warfarin crosses the placenta and induces changed in the fetus to produce the fetal warfarin syndrome – not good.

  22. Contraindications 1.Hypersensitivity 2. Bleeding Disorders like Hemophilia 3. Thrombocytopenia 4-. Intracranial Hemorrhage 5. GIT Ulcerations 6. Threatened abortion 7. Advanced renal or hepatic disease

  23. Antidote –Protamine Sulfate • Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity • Hemorrhage – can be reversed by protamine sulfate titrated so that 1 mg of protamine sulfate is administered for every 100 U of heparin remaining in the patient. • Protamine sulfate is also an anticoagulant because it interacts with platelets, fibrinogen, and other clotting factors – so it can make hemorrhage worse if more is given than necessary.

  24. Direct Thrombin Inhibitors (DTIs) • The DTIs bind thrombin without additional binding proteins, such as anti-thrombin, and they do not bind to other plasma proteins such as platelet factor 4. • Hirudin and Bivalirudin bind at both the catalytic or active site of thrombin as well as at a substrate recognition site • Argatroban bind only at the thrombin active site

  25. Lepirudin • Monitored by aPTT • Action independent of antithrombin • Use in thrombosis related to heparin induced thrombocytopenia • No antidote • Adverse effect: Antibody formation against thrombin-lepirudin complex

  26. Bivalirudin: Inhibits platelet activation also Use in percutaneous coronary angiography Argatroban: Used in heparin induced thrombocytopenia with or without thrombosis Monitored by aPTT Dose reduction in liver disease

  27. Oral Anti-Coagulants,History • Following the report of a hemorrhagic disorder in cattle that resulted from the ingestion of spoiled sweet clover silage, Campbell and Link, in 1939, identified the hemorrhagic agent as bishydroxycoumarin (dicoumarol). • In 1948, a more potent synthetic congener was introduced as an extremely effective rodenticide; the compound was named warfarin as an acronym derived from the name of the patent holder, Wisconsin Alumni Research Foundation. • Warfarin's potential as a therapeutic anticoagulant was recognized but not widely accepted, partly due to fear of unacceptable toxicity. • However, in 1951, an Army inductee uneventfully survived an attempted suicide with massive doses of a preparation of warfarin intended for rodent control. • Since then, these anticoagulants have become a mainstay for prevention of thromboembolic disease

  28. Wisconsin Alumni Research Foundation Coumarin--Warfarin Warfarin-Pharmacokinetics 1. Rapidly and completely absorbed after oral administration 2. 100% Bioavailability 3. Highly plasma protein bound (99%) 4. Crosses the placenta (teratogenic) 5. Appears in milk; infants given Vitamin K 6. Variable but slow clearance;depends on hepatic P450s 7. Biotransformation by the liver: Oxidation, Glucuronidation 8. Takes 12-16 hours before effect is observed

  29. Vitamin K-Dependent Clotting Factors Vitamin K VII IX X II Synthesis of Functional Coagulation Factors

  30. Warfarin Mechanism of Action Vitamin K VII Antagonism of Vitamin K IX X II No Synthesis of Functional Coagulation Factors Warfarin

  31. Mechanism of Action • Coumarins block the Gamma Carboxylation of glutamic acid residues of Clotting factors II,VII, IX, X as well as the endogenous anti-coagulants C & S. • This is coupled with oxidative deactivation of Vitamin K • Coumarins and Indanediones inhibit the enzyme Vitamin Kepoxidereductase that converts Vitamin K epoxide back into the active hydroquinone (reduced form) • Thus they prevent the activation of Vitamin K and hence along with it carboxylations of clotting factor residues

  32. Why Carboxylation is necessary? • Carboxylation is necessary for ability of clotting factors to bind Ca and to get bound to phospholipid surfaces which is necessary for coagulation • Factor VII affected first, then IX, X, and finally Factor II (dependsupon half lives of circulating factors)

  33. Uses • Same as Heparin and other Anticoagulants • Monitoring necessary because of its low therapeutic index • PT (Prothrombin time is noted; time taken for blood to clot) • Patients on Heparin are shifted to oral warfarin after 3-5 days

  34. Adverse Effects 1. Bleeding Most common and most serious adverse effect; Epistaxis, hematuria, GIT Bleeding, internal hemorrhages 2. Cutaneous Necrosis This is due to decreased activity of Protein C Protein C and Protein S found in bone & other tissues also require Gamma carboxylations 3. Infarction of breast, fatty tissues, intestine and extremities due to venous thrombosis caused by again decreased activity of Protein C

  35. Antidote of Warfarin • Stop Warfarin • Give Vitamin K (Antidote) • Also Fresh frozen plasma, Prothrombin complex concentrates and Recombinant factor VIIa can be administered

  36. Contraindications 1. Pregnancy Fetal protein in bone and blood affected -Causes birth defects including abnormal bone formation, bone hyperplasia -CNS Defects, fetal hemorrhage, fetal hypoprothrombinemia and fetal death may occur 2. Other contraindications same as heparin

  37. Drug Interactions of Warfarin A.Pharmacokinetic Interactions 1. Agents that inhibit metabolism of warfarin • Cimetidine • Imipramine • Cotrimoxazole • Chloramphenicol • Ciprofloxacin • Metronidazole • Amiodarone

  38. 2. Drugs that increase metabolism of Warfarin • Barbiturates • Rifampin 3. Drugs that displace warfarin from binding sites on plasma albumin • Chloral hydrate • NSAIDs 4. Drugs that decrease GIT absorption of warfarin • Cholestyramine

  39. B. Pharmacodynamic Interactions 1. Synergistic effect • Heparin • Aspirin • Antibiotics: Decrease bacterial flora—decrease Vitamin K synthesis—increased warfarin effect

  40. Physiological/Pathological Factors affecting Warfarin Action 1. Increased warfarin action • Malnutrition, debility (Decreased Vit. K) • Liver disease, chronic alcoholism (Decreased clotting factors) • Hyperthyroidism (Increased degradation of Clotting factors) • Newborns (Decreased vitamin K)

  41. 2. Decreased Warfarin Action • Pregnancy (Increased clotting factors) • Nephrotic syndrome • Warfarin resistance (Genetic)

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