Anticoagulant-medicinal chemistry

It contains normal coagulation pathway in our body,natural anti coagulants,anti coagulant drug's classification,mechanism of actions and their uses.

1. ANTI COAGULANTS Presented By, ASWIN K B.Pharmacy, Final Year, KMCH College of Pharmacy. 1 MEDICINAL CHEMISTRY II

2. COAGULATION Coagulation is the process of conversion of Blood from a liquid form into a gel form and formation of a blood clot. Homeostasis is the process of Cessation of blood loss from a damaged vessel and followed by Repair. 2 MEDICINAL CHEMISTRY II

3. MECHANISM CELLULAR (PLATELETS) PROTEIN (COAGULATION FACTOR) Activation A dhesion Aggregation of   platelets Deposition and maturation of fibrin By Activating, Factor I - fibrinogen Factor II - prothrombin Factor III - tissue thromboplastin (tissue factor) Factor IV - ionized calcium ( Ca++ ) Factor V - labile factor or proaccelerin Factor VI - unassigned Factor VII - stable factor or proconvertin Factor VIII - antihemophilic factor Factor IX - plasma thromboplastin component, Christmas factor Factor X - Stuart- Prower factor Factor XI - plasma thromboplastin antecedent Factor XII - Hageman factor Factor XIII - fibrin-stabilizing factor 3 MEDICINAL CHEMISTRY II

4. DISORDERS  B leeding (hemorrhage or bruising) Obstructive clotting (thrombosis ). 4 MEDICINAL CHEMISTRY II

5. Normal coagulation proess Coagulation begins after injury to the Blood vessel has damaged the Endothelium lining of blood vessels. Blood vessel Damage Explosure of Blood to subendothelial space Explosure of subendothelial Tissue Factor to Plasma factor VII &Change in Platelets. 5 MEDICINAL CHEMISTRY II

6. TYPES PRIMARY HEMOSTASIS : Platelets forms a plug at the site of injury is called primary hemostasis . SECONDARY HEMOSTASIS: Additional coagulation factor/clotting factors beyond Factor VII forms a Fibrin strands to strengthen the platelet plug is called secondary hemostasis . 6 MEDICINAL CHEMISTRY II

7. PLATELET ACTIVATION Endothelium damage Circulating platelets +underlying collagen (via gp VI receptor) Signal cascade &Activation of platelet Integrins Tight binding of platelet to the extracellular matrix Process of adhere platelet to the site of injury 7 MEDICINAL CHEMISTRY II

8. Activated platelets release ADP , Serotonin, PAF, Platelet factor 4, Thromboxane A2. Activated platelets also activate o ther platelets. Activated platelets changes its shape from Spherical to Satellite. Fibrinogen Cross-links between glycoprotein & aggregation of adjacent platelets. 8 MEDICINAL CHEMISTRY II

9. Activated platelet Release granular substances Activate Gq -linked receptor Increases the coc.of Calcium in the platelet’s cytosol Activate protein kinase C act Phospholipase A2 Modify Integrin membrane glycoprotein & Increases affinity to bind Fibrinogen 9 MEDICINAL CHEMISTRY II

10. PROTEIN (COAGULATION FACTOR) PATHWAY 10 MEDICINAL CHEMISTRY II

11. CO-FACTORS 1.Calcium & phospholipids : Require for tenase & prothrombinase complexes to function. 2.Vitamin K: Gamma- glutamyl carboxylase add -COOH group to glutamic acid residues (F,II,VII,IX,X Protein S,C,Z) 11 MEDICINAL CHEMISTRY II

12. Vitamin K Vitamin K epoxide reductase Active form Maturation of Clotting Factors Vitamin k (co factor) 12 MEDICINAL CHEMISTRY II

13. NATURAL ANTI COAGULANTS Protein C: Thrombin Act on Protein C Activated Protein C APC Protein + S Phospholipid (Co factor) Degrade Fva &FVIIIa 13 MEDICINAL CHEMISTRY II

14. ANTI THROMBIN Serine protease inhibitor (serpin) degrade FIXa,Fxa,FXIIa,FXIIa 14 MEDICINAL CHEMISTRY II

15. TISSUE FACTOR PATHWAY INHIBITOR(TFPI) Limit the action of TF Inhibit excessive TF-mediated activation of FVII &FV 15 MEDICINAL CHEMISTRY II

16. PLASMIN Plasminogen (plasma protein) Tissue plasminogen activate(t-PA) Plasmin Fibrin Fibrin degrade product 16 MEDICINAL CHEMISTRY II

17. PROSTACYCLIN Endothelium release PG I2 Activate Gs protein – linked receptor Adenyl cyclase cAMP Cytosolic Calcium level decreases 17 MEDICINAL CHEMISTRY II

18. FIBRINOLYSIS It is the process of Desorption & Reorganisation of Blood clot. 18 MEDICINAL CHEMISTRY II

19. anticoagulants Anticoagulants also called as blood thinners . These are chemical substances that prevent or reduce coagulation of blood & prolonging the clotting time. 19 MEDICINAL CHEMISTRY II

20. CLASSIFICATION 20 MEDICINAL CHEMISTRY II

21. HEPARIN Heparin also known as unfractionated heparin (UFH). HISTORY: : 1. Heparin was discovered by  Jay McLean  and William Henry Howell in 1916. 2.  In 1918, Howell coined the term 'heparin' for this type of fat-soluble anticoagulant.  3. In the early 1920s, Howell isolated a water-soluble  polysaccharide  anticoagulant, which he also termed 'heparin', CHEMISTRY: Native heparin is a polymer with a  molecular weight  ranging from 3 to 30  kDa and commercial heparin preparations is in the range of 12 to 15 kDa. [ Heparin is a member of the  glycosaminoglycan  family of  carbohydrates   and consists of a variably sulfated repeating  disaccharide  unit MOA: Binds with antithrombin III Inactivate thrombin,factor Xa and protease ANTODOTE: 1.Protamine sulfate   (1 mg per 100 units of heparin that had been given over the past four hours). 21 MEDICINAL CHEMISTRY II

22. Low molecular weight heparins Heparin (M.Wt- 5000 -40,000Da) is a naturally occurring polysaccharide that inhibits coagulation. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da ANTIDOTE : 1.Protamine 22 MEDICINAL CHEMISTRY II

23. LMWH’s mechanism AntiThrombin (Serine protease inhibitor) Degrade Activate FIXa,Fxa,FXIIa,FXIIa LMWHs DRUGS: 1. Bemiparin 2. Nadroparin 3. Reviparin 4. Enoxaparin 5. Parnaparin 6. Certoparin 23 MEDICINAL CHEMISTRY II

24. VITAMIN K ANTAGONISTS MECHANISM Vitamin Vitamin K epoxide reductase Active form Block Maturation of Clotting Factors Vitamin K antagonists 24 MEDICINAL CHEMISTRY II

25. VITAMIN K ANTAGONISTS Dicumarol Phenindione Coumarin Warfarin Ethyl Bicoumacetate 25 MEDICINAL CHEMISTRY II

26. DIRECT THROMBIN INHIBITORS MECHANISM Fibrinogen Thrombin Fibrin (clot) Inhibit DTI 26 MEDICINAL CHEMISTRY II

27. DIRECT THROMBIN INHIBITORS Bivalent: Bivalirudin : Hirudin Bivalirudin Lepirudin Desirudin Univalent: Argatroban Inogatran Melagatran (and its prodrug  ximelagatran) Dabigatran Argatroban  ximelagatran 27 MEDICINAL CHEMISTRY II

28. Direct xa inhibitors These are a class of anticoagulant drugs which act directly upon Factor X in the coagulation cascade, without using antithrombin as a mediator. These compounds as substitutes for the currently administered vitamin K antagonists or low molecular weight heparin. ADVANTAGES:  1.Rapid onset and offset of action. 28 MEDICINAL CHEMISTRY II

29. DIRECT FXA INHIBITORS (ORAL) Rivaroxaban Apixaban   Edoxaban DRUGS: 1.Rivaroxaban 2.Apixaban 3.Edoxaban 4.Darexaban 5.Eribaxaban 29 MEDICINAL CHEMISTRY II

30. SYNTHETIC PENTASACCHARIDE FXA INHIBITORS (PARENTERAL) Fondaparinux Idraparinux sodium DRUGS : 1.Fondaparinux 2.Idraparinux sodium 3.Idrabiotaparinum 30 MEDICINAL CHEMISTRY II

31. ANTIPLATELET DRUGS(ANTIAGGREGANT) These are agents which decrease platelet aggregation and inhibit thrombus formation They are effective in the arterial circulation, where anticoagulants have little effect. 31 MEDICINAL CHEMISTRY II

32. classification Irreversible cyclooxygenase inhibitors Aspirin Triflusal Adenosine diphosphate (ADP) receptor inhibitors Cangrelor Clopidogrel Prasugrel Ticlopidine Phosphodiesterase inhibitors Cilostazol Protease-activated receptor-1 (PAR-1) antagonists Vorapaxar Glycoprotein IIB/IIIA inhibitors (intravenous use only ) Abciximab Eptifibatide Tirofiban Adenosine reuptake inhibitors Dipyridamole Thromboxane inhibitors Thromboxane synthase inhibitors Thromboxane receptor antagonists 32 MEDICINAL CHEMISTRY II

33. Anti platelet drugs Aspirin Trifusal Ticlopidine Clopidogrel Tirofiban 33 MEDICINAL CHEMISTRY II

34. Anti fibrinolytics Antifibrinolytics  are a class of medication that are inhibitors of fibrinolysis. These drugs block the binding sites of the enzymes or plasminogen respectively and thus stop plasmin formation. MECHANISM OF ACTION: Plasminogen (plasma protein) Tissue plasminogen activate(t-PA) Plasmin Block Fibrin Fibrin degrade product Anti Fibrinolytics MEDICINAL CHEMISTRY II 34

35. Anti fibrinolytics 6-aminocaproic acid Tranexamic acid DRUGS: 1.Aminocaproic acid 2.Tranexamic acid (Cyclokapron) 3.Ethamsylate 4.Aprotinin MEDICINAL CHEMISTRY II 35

36. uses Strokes  – where a blood clot restricts the flow of blood to your brain , causing brain cells to die and possibly resulting in permanent brain damage or death. Transient ischemic attacks (TIAs)  – also called " mini-strokes ", these have similar symptoms to a stroke, but the effects usually last less than 24 hours. Heart attacks – where a blood clot blocks a blood vessel supplying your heart , starving it of oxygen and causing chest pain and sometimes death. Deep vein thrombosis (DVT)  – where a blood clot forms in one of the deep veins in your body, usually your legs, causing pain and swelling. Pulmonary embolism  – where a blood clot blocks one of the blood vessels around the lungs , stopping the supply of blood to the lungs. 36 MEDICINAL CHEMISTR Y II

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