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to know about heparin and hirudin receptor

to know about heparin and hirudin receptor

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  • 1. KISHAN SINGH M.PHARM (Pharmacology) GLAIPR MATHURA11 March 2013 Kishan singh 1
  • 2. Coagulation is the process whereby blood forms clots to repair vascular injury and prevent blood loss. Excessive coagulation can lead to vascular obstruction. Poor coagulation can lead to increased bleeding. Anticoagulation drugs inhibit the action of coagulation factors- heparin or interfere with the synthesis of coagulation factors(like vitamin K antagonist, such as warfarin)11 March 2013 Kishan singh 2
  • 3. ANTICOAGULANT  anticoagulant is a substance that prevents coagulation; it stops blood from clotting. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders.11 March 2013 Kishan singh 3
  • 4. 1. Direct Thrombin Inhibitors 2a. Indirect Thrombin Inhibitors 2b. Coumarins 3. Fibrinolytic Drugs 4. Anti-Platelet Agents11 March 2013 Kishan singh 4
  • 5. HIRUDIN11 March 2013 Kishan singh 5
  • 6. Class I: Direct Thrombin InhibitorsHirudinis a naturally occurring peptide inthe salivary glands of medicinalleeches that has a bloodanticoagulant property. This is fundamental for the leeches’alimentary habit ofhematophagy, since it keeps theblood flowing after the initialphlebotomy performed by the wormon the host’s skin.11 March 2013 Kishan singh 6
  • 7. HirudinPresent in leech saliva. Hirudin irreversibly binds to thrombin.Purpose of leeches are used: 1. Improve circulation. 2. leeches are used to remove bad blood from vein. 3. Hirudin stays in circulation after leeches have been removedreducing the chance of clot formation, and allowing the woundto continue to bleed.3. Bactericidal Effect 11 March 2013 Kishan singh 7
  • 8.  leech secreted a powerful anticoagulant, called Hirudin.  Hirudin is made up of 65 amino acids.  These amino acids are organized into a compact N- terminal domain containing three disulfide bonds and a C-terminal domain which is completely disordered.[  Natural Hirudin contains a mixture of various forms of the protein.11 March 2013 Kishan singh 8
  • 9.  blood coagulation is the conversion of fibrinogen into fibrin by the serine protease enzyme thrombin  Thrombin is produced from prothrombin, by the action of an enzyme prothrombinase, in the final stage of coagulation.  Fibrin is then cross linked by factor XIII to form a blood clot11 March 2013 Kishan singh 9
  • 10.  The principal inhibitor of thrombin in normal blood circulation is antithrombin III. Similar to antithrombin III, the anticoagulation activity of Hirudin is based on its ability to inhibit the pro-coagulant activity of thrombin.  Hirudin is the most potent natural inhibitor of thrombin.  antithrombin III Hirudin binds and inhibits only the activity of thrombin forms with a specific activity on fibrinogen.11 March 2013 Kishan singh 10
  • 11.  Hirudin prevents or dissolves the formation of clots and thrombi (i.e. it has a thrombolytic activity) Hirudin has advantages over commonly used anticoagulants and thrombolytic like heparin, it not interfere with the biological activity of other serum proteins and can also act on complexed thrombin.11 March 2013 Kishan singh 11
  • 12.  It is difficult to extract large amounts of Hirudin from natural sources, so a method for producing and purifying this protein using recombinant biotechnology has been developed.  Marketed preparation of Hirudin :- Lepirudin (Refludan®) Desirudin (Revasc/Iprivask®). Several other direct thrombin inhibitors are derived chemically from Hirudin.11 March 2013 Kishan singh 12
  • 13. HeparinHeparin discovered by Maclean in 1916 by a secondyear medical student at johns Hopkins hospitalThis was name heparin ,because it was first extractedfrom liverHeparin is not a single substance it is a mixture ofsulfated mucopolysacharidesIts molecular weight is 10000-40000Itpresent together with histamine in the granules ofmast cellsCommercial preparations are obtained from beef lungand pig intestinal mucosa .Heparin antagonist is protamine sulfate 11 March 2013 Kishan singh 13
  • 14.  Heparin is a naturally-occurring anticoagulant produced by basophiles and mast cells to prevent formation and extension of blood clots Heparin does not disintegrate clots that have already formed. It permits the bodys natural clot lysis mechanisms, i.e. Fibrinolytic As the thrombokinase is released, it neutralizes the action of heparin to allow clotting to occur14 11 March 2013 Kishan singh
  • 15. Adverse Effects: Increases bleeding because it inhibits blood clotformation. Risk of bleeding can be mitigated by closemonitoring. heparin is contraindicated in patients with: activebleeding; haemophilia; ulcerative lesions ofgastrointestinal tract; recent surgery in the brain. Heparin overdose is managed by discontinuing thedrug, and if bleeding occurs: administer protaminesulphate which combines with heparin to form a stableion pair complex (inactivated).11 March 2013 Kishan singh 15
  • 16.  Heparin is given by injection or drip into a vein intravenously or by subcutaneously Heparin works by inhibiting the three major clotting factors (thrombin, thromboplastin, and prothrombin) It slows the process of thromboplastin synthesis, decelerates the conversion of prothrombin to thrombin, and inhibits the effects of thrombin on fibrinogen, blocking its conversion to fibrin.16 11 March 2013 Kishan singh
  • 17.  Low-molecular weight heparin is gradually replacing heparin for treatment of most patients with venous thromboembolism and acute coronary syndromes because it has more convenient and cost-effective  It has similar results to heparin  Administered by subcutaneous injection  Examples of LMWH:- lovenox® tinzaparin, certoparin, parnaparin, revipari11 March 2013 n and Kishan singh 17
  • 18.  LMWH is obtained by alkaline degradation of heparin benzyl ester  LMWH molecules are enriched with short chains with higher anti-Xa: IIa ratio  Low molecular weight heparins (LMWHs) are fragments of standard unfractionated heparin (UH) formed by depolymerisation by different methods of manufacture. The heparinoid, danaparoid, is a mixture of heparin11 March 2013 Kishan singh 18
  • 19.  Less inhibition of platelet function  potentially less bleeding risk, but not shown in clinical use  Lower incidence of thrombocytopenia and thrombosis  less interaction with platelet factor 4  fewer heparin-dependent IgG antibodies11 March 2013 Kishan singh 19
  • 20.  No need for laboratory monitoring  Higher bioavailability - 90% vs 30%  Longer plasma half-life Decreased “heparin resistance” pharmacokinetics of UH are influenced by its bindings to plasma protein, endothelial cell surfaces, macrophages, and other acute phase reactants 11 March 2013 Kishan singh 20
  • 21. COMPLICATIONS OF THERAPY  bleeding more with uf than lmw heparin  osteoporosis  thrombocytopenia  rapid clearance of lipoproteins  hypersensitivity reactions11 March 2013 Kishan singh 21
  • 22. UF HEPARIN LMW HEPARIN SHORTER HALF LIFE LONGER HALF LIFE LOWER & LESS RELIABLE HIGHER &MORE BIOAVAILABILITY RELIABLE BIOAVAILABILITY ANTI-Xa : ANTI- ANTI-Xa : ANTI- THROMBIN THROMBIN ACTIVITY ACTIVITY S/C INJECTION S/C INJECTION 8- HOURS ONCE / 24 HOURS11 March 2013 Kishan singh 22
  • 23.  Coagulation is the process whereby blood forms clots to repair vascular injury and prevent blood loss.1. Direct Thrombin InhibitorsExample: Hirudin Binds directly to the active site/substance recognition site of thrombin, preventing the enzyme from converting fibrinogen to fibrin.Indication: Heparin Induced Thrombocytopenia; Acute Coronary Syndrome.2a. Indirect Thrombin InhibitorsExample: Heparin Anticoagulant that works by indirectly inhibiting thrombin and other clotting factors by increasing the activity of antithrombin. 11 March 2013 Kishan singh 23
  • 24. ANY QUERY11 March 2013 Kishan singh 24
  • 25. 11 March 2013 Kishan singh 25