Class anticoagulants 2

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  • The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway).
    Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by Ixa (in the presence of Factor VIII).
    The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor Ixa then activates Factor X.
    Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin.
    Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide.
    Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 4–5 days when starting therapy.
  • Class anticoagulants 2

    1. 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC.
    2. 2. Parenteral Anticoagulants  Heparin  Low Molecular Weight Heparins- Enoxaparin Dalteparin, Tinzaparin, Ardeparin, Nadroparin, Reviparin  Synthetic Heparin Derivatives- Fondaparinux  Thrombin Inhibitors-lepirudin, Bivalirudin, Desirudin, Argatroban, Danaparoid, Drotecogin Alfa (All Parentral), Rivaroxiban, Dabigatran (Oral)
    3. 3.  Coumarin derivatives: warfarin, acenocumarol, ethyl biscoumacetate and dicumarol  Indanedione group: phenindione and Anisindione
    4. 4. Factor Name I Fibrinogen II Prothrombin III Tissue Factor or thromboplastin IV Ca++ V Proaccelerin VII Proconvertin VIII Antihemophilic A factor IX Christmas factor or X Stuart factor XI Plasma thomboplastin antecedent XII Hageman factor XIII Fibrin stabilizing factor
    5. 5. INTRINSIC PATHWAY All clotting factors are within the blood vessels  Clotting slower  Activated partial thromboplastin test (aPTT) EXTRINSIC PATHWAY Initiating factor is outside the blood vessels - tissue factor  Clotting - faster - in Seconds  Prothrombin test (PT)
    6. 6.  Heparin is a non-uniform mixture of straight chain mucopolysaccharide molecules  The mean molecular weight of heparin is 15,000 D  Strongest organic acid present in body  Source- mast cells lung, liver, Int.mucosa  Actions –acts both in-vivo and invitro  Antithrombin III (ATIII) binding is necessary for its anticoagulant activity
    7. 7.  Antithrombin III (ATIII) is a slow endogenous progressive inhibitor of thrombin and other clotting enzymes.  Higher doses inhibits platelet aggregation and Prolongs bleeding time.  Lipaemia clearing
    8. 8.  Large, highly ionised molecule,  Bioavailability- sc -variable, IV  Does not cross –BBB or placenta  Excreted in urine  T1/2-1-4 hrs  1000, 5000 u/ml 5ml vials  Should not be mixed with penicillin, tetracyclines.
    9. 9.  Bleeding: they both lead to bleeding but the bleeding is less in LMWH  To treat bleeding: inject antidote protamine sulphate (1mg IV for each 100 units of UFH) (reversal effect)  Thrombosis: heparin ↓ ATIII ↑risk of thrombosis
    10. 10.  Thrombocytopenia: Heparin-induced thrombocytopenia (HIT) is a life threatening immune reaction  HIT ↑ platelet activation platelet aggregation thrombosis.  HIT endothelial damage  HIT may occur in the early stages of treatment (within 5 days) but it’s non-immune reaction (not life threatening)  LMWHs, though of lower risk, are contraindicated with HIT.  Osteoporosis, hyperkalemia, hypersensitivity
    11. 11.  Bleeding or hemophilia  Severe hypertension  Thrombocytopenia or purpura-HIT  Intracranial hemorrhage  Recent surgery-ocular, neuro, lumbar  Hypersensitivity to heparin  TB  GIT ulcer  Hepatic or renal disease, chronic alcoholics  Use of digoxin
    12. 12.  M.Wt 2000-8000 Da ( avg 4500 Da )- prepared from SH by fractionation & enzymatic degradation .  Commercial preprn : Enoxaparin, Dalteparin, Ardeparin, Tinzaparin, Reviparin, Nadroparin  Routes : SC (OD)  High anti-Xa and low anti-IIa activity↔ greater antithrombotic and lower anticoag activity  Low anti-IIa activity, hence, aPTT, TT are not ideal for monitoring. Anti-Xa assay ideal  Less complicated, dose independent clearance and more predictable anticoagulant response than UFH.
    13. 13. 1. Heparin –IV -5000-10000 units 2. Low dose regimen-sc-DVT LMWH- 1. Prophylaxis and trmt of DVT, pulm. Embolism- enoxaparin -30mg sc 2. Unstable angina and MI- 3. To maintain patency of canula and shunts 4. RHD 5. Cerebrovascular diseases 6. DIC 7. Anticoagulation in pregnancy 8. Treatment of peripheral embolism
    14. 14.  Dabigatran etexilate is a new oral direct thrombin inhibitor and the prodrug of Dabigatran  Rivaroxaban is an orally available, small-molecule, active site-directed factor Xa inhibitor  Knee replacement surgeries  Equivalent to LMWH
    15. 15.  first selective factor Xa inhibitor,  55% better than enoxaparin (LMWH) at reducing risk of VTE  synthetic pentasaccharide: “represents the oligosaccharide consensus sequence of heparin”  Indirect inhibition: binds to antithrombin and increases antithrombin’s affinity for factor Xa by 300-fold
    16. 16.  Fondaparinux is given –sc- once daily  Long elimination t 1/2 (20 hrs). Renal clearance Uses 1. Initial treatment of deep vein thrombosis (DVT) 2. pulmonary embolism (PE) and for 3. Venous thromboembolism prevention in patients undergoing surgery for hip fracture or hip/knee replacement
    17. 17.  Lepirudin (DTI) derived from hirudin from leech salivary glands.  -ischemic conditions associated with unstable angina  Better in hepatic insufficiency patients  Bivalirudin (DTI) approved for use during heparin- induced thrombocytopenia (HIT) & percutaneous coronary interventions  Argatroban (DTI) can be used in patients with risk of (HIT)  Desirudin -DVT
    18. 18.  Danaparoid-84% heparan sulphate+12% dermatan sulphate+ 4% chondroitin sulphate  Drotrecogin Alfa  Human recombinant activated protein C  used in patients with sepsis; recombinant form of activated protein C that inhibits f Va and f VIIIa
    19. 19. Vitamin K Antagonists (The Coumarins) Vitamin K is co-factor for the hepatic synthesis of clotting factors II, VII, IX & X Warfarin inhibits Vit. K reductase  no active form of Vit. K  no synthesis of clotting factors Clinical anticoagulant activity needs several days to develop (due to the already circulating clotting factors) So the action of warfarin will appear after the elimination of prior clotting factors.
    20. 20.  Onset: starts after 12-16 hours  lasts for 4-5 days  Elimination time (factor II needs: 60 hours factor X: 40 hours)  Overlap heparin & warfarin therapy taken together until the effect of warfarin appears (after 5 days) then stop taking heparin.
    21. 21.  Warfarin has 100% oral bioavailability,  plasma protein binding-99% &  long plasma t1/2 of 36 hours  A high loading dose followed by an adjusted maintenance dose Contraindicated with pregnancy -is teratogenic in the first trimester & and induce intracranial hemorrhage in the baby during delivery  Warfarin is metabolized by hepatic Cytochrome P450 enzymes with half-life of 40 hrs
    22. 22.  Dicumerol-bishydroxycoumarin-slowly, unpredictably  t1/2-prolonged GI-intolerance Acenocumarol-t1/2 -8hrs active metabolite-24hrs rapid action 1, 2, 4mg Ethyl biscoumoacetate-rapid and brief action Indandione derivative-Phenindione-S/E-leucopenia, agranulocytosis, haemorrhage Anisindione- S/E-vasculitis, haemorrhage, hematuria
    23. 23.  Prophylaxis and/or treatment of:  Venous thrombosis and its extension-2-2.5  Pulmonary embolism  Thromboembolic complications associated with AF and cardiac valve replacement-  Post MI, to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization-3-3.5  Prevention and treatment of cardiac embolism.
    24. 24.  INR= patients PT in seconds  mean normal PT in seconds ISI INR = International Normalized Ratio ISI = International Sensitivity Index
    25. 25.  Food and drug interactions  Genetic variation in metabolism  narrow therapeutic window  slow onset of action overlap with parenteral drugs dosage adjustments & freq. monitor with INR
    26. 26. 1. Induce microsomal enzymes (barbiturates, meprobamate and other sedative-hypnotic drugs; griseofulvin). 2. Inhibition of metabolism (e.g., allopurinol disulfiram. 3. Displaced from binding sites by phenylbutazone, phenytoin, sulfinpyrazone, clofibrate, Salicylates, Indomethacin, Oral Contraceptives 4. Acetaminophen inhibits warfarin degradation 5. Effect of anticoagulants on other drugs -Coumarin agents prolong and intensify action of chlorpropamide, tolbutamide, phenytoin and phenobarbital.

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