Anticoagulants

Introduction to Anticoagulants
Coagulants, Local agents, Systemic agents, Anticoagulants, Heparin, Low molecular weight heparins, Heparinoids, Oral anticoagulants (Warfarin), Therapeutic uses
Presented by
N. Ramya
Department of Pharmacology

1. 1 A Seminar as a part of curricular requirement for I year M. Pharm I semester Presented by N. Ramya (Reg. No. 20L81S0110) Department of Pharmacology Under the guidance/Mentorship of Mr. A. Sudheer Kumar., M.Pharm . Associate Professor Dept. of Pharmacology Anticoagulants

2. 2 Contents Coagulants Local agents Systemic agents Anticoagulants Heparin Low molecular weight heparins Heparinoids Oral anticoagulants ( Warfarin ) Therapeutic uses References

3. 3 Coagulants Coagulants promote coagulation of blood Classification Local agents Systemic agents Astringents Antihaemophilic factor Adrenaline Adrenochrome monosemicarbazone Calcium alginate Desmopressin Fibrin Ethamsylate Gelatin Fibrin ogen Oxidized cellulose Vitamin k

4. 4 Local agents Astringents Precipitate proteins locally in bleeding site and control capillary oozing. example : fecl3 solution, tannic acid Adrenaline It c ause vasoconstriction and arrest bleeding cotton pad soaked in 0.1% adrenaline solution. Applied on bleeding site causes control oozing. Thrombin Freeze dried powder from bovine or human plasma. It causes control bleeding Fibrin It contains fibrinogen, xIII , thrombin, calcium and clotting factors It is use as spray form durning surgary

5. 5 Systematic agents Vitamin K It is a fat soluble vitamin which is used in synthesis of clotting factors. K1[ phytonodione ] from plants and animals k2 [ menoquinone ] from intestinal bacteria k3 [ menadione fat solube ] synthetic form Dieatary source : spinach, cabbage, butter milk, cauliflower and tomatoes Actions : cofactor for γ carboxylation of glutamic acid resiues of clotting factors [ 2,7,9and10] Uses T reat bleeding associated with obstructive jaundice , vitamin K deficiency Treat salicylate poisoning

6. 6 Fibrinogen Control bleeding associated with hypofibrinogenamia Antihaemophillic factor It c ontains coagulation factor vIII + von lliebranda factor Fever headache sking rashes Adremochrome monosemicarbazone Oral and parentral admin control capillary oozing Desmarpressin Synthetic analogue of vasopressin Control mild to moderate bleeding haemophilia

7. 7 Anticoagulants are drugs that prevent or reduce coagulability of blood. The major classes of anticoagulant drugs have distinctly different mechanisms of action, routes of administration and adverse effects. Anticoagulants

8. 8 Classification In vivo Parenteral anticoagulants Indirect thrombin inhibitors: Heparin, Low molecular weight heparin, Fondaparinux , Danaparoid Direct thrombin inhibitors: Lepirudin , Bivalirudin Oral anticoagulants: Coumarin Derivative: Bishydroxycoumarin ( dicumarol ), Warfarin sodium, Acenocoumarol Inandione derivatives: Phenindione Direct factor Xa inhibitors: Rivaroxaban In vitro Heparin , Sodium citrate, Sodium oxalate and Sodium edetate

9. 9 Heparin Mechanism of action Heparin binds and accelerates the activity of plasma antithrombin-lll . Antithrombin-lll then inhibits activated clotting factors Xa , lla , lXa , Xla , Xlla and Xllla by forming stable complex with them. At low concentration, heparin selectively inhibits the conversion of prothrombin to thrombin. Heparin thus prevents further thrombus formation, but it does not have thrombolytic action Adverse effects Bleeding Heparin-induced thrombocytopenia Hypersensitivity reactions Osteoporosis Reversible alopecia

10. 10 Pharmacokinetics Heparin is not absorbed after oral administration because of its high negative charge and large molecular size. Therefore, it must be given parenterally . On i.v . administration, the anticoagulant effect starts immediately, whereas on s.c . route, it takes 1-2 hours. Heparin is highly protein bound. It does not cross the BBB or placental barrier and is safe during pregnancy.

11. 11 Low molecular weight heparins (LMWH) Enoxaparin Dalteparin Tinzaparin Ardeparin LMWHs produce anticoagulant effect mainly by antifactor Xa activity. LMWH therapy usually does not require a PPT (Partial thromboplastin time ). LMWHs are given subcutaneously . Advantages of LMWHs They have longer duration of action. They do no routinely require a PPT monitoring. There is a lower incidence of thrombocytopenia. Better patient compliance as there is no need for blood tests.

12. 12 Heparinoids LEPIRUDIN : It is a recombinant hirudin . It directly inhibits thrombin and is used as an anticoagulant in patients with heparin-induced thrombocytopaenia (HIT). It is administered i.v , it requires a PPT monitoring. No antidote is available . BILVALIRUDIN: It is a synthetic heparinoid and has a mechanism similar to that of lepirudin . It can be used in coronary angioaplasty as an alternative to heparin.

13. 13 DANAPAROID: It is isolated from pig intestinal mucosa, and it has mainly antifactor Xa activity. It is administered subcutaneously for prophylaxis and intravenously for treatment of deep vein thrombosis especially in patients with HIT.

14. 14 oral anticoagulants Among oral anticoagulants, coumarin derivatives are commonly used. Oral anti coagulants like warfarin act only in vivo. They are vitamin K antagonists . Warfarin Mechanism of action Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors.

15. 15 Pharmacokinetics Completely absorbed after oral administration. It can also be given i.v or rectal. Food interferes with the absorption of warfarin . Highly bound to plasma proteins, freely crosses the placental barrier. Metabolized in liver, inactive metabolities are excreted in urine and stool . Half life – 40hours. Duration of action is 2-5 days . Adverse effects Bleeding Teratogenic effect Skin necrosis Other rare side effects: diarrhoea , alopecia, dermatitis, abdominal cramps, anorexia.

16. 16 Drug interactions Warfarin X cholestyramine : Cholestyramine is a bile acid-binding resin. It reduces the absorption of warfarin from gut, thus decreases bioavailability of warfarin . Oral anticoagulants X barbiturates/ rifampicin : They are enzyme inducers, increase metabolic clearance of oral anticoagulants and hence decrease the anticoagulant effect . Wafarin X salicylates / sulphonamide : Warfarin is highly protein bond. These drugs displace warfarin from plasma-protein binding site and increase the free plasma concentration of warfarin and thus lead to bleeding. Warfarin X alcohol,chloramphenicol,isoniazid : They are enzyme inhibitors, decrease metabolic clearance of warfarin and hence increase the anticoagulant effect .

17. 17 Therapeutic uses of anti coagulants To prevent the formation of intravascular thrombus or to prevent the future extension of the already formed clot. Treatment is initiated with LMWH or UFH and continued for at least 4-5 days . 1.Deep-vein thrombosis and pulmonary embolism : Venous thrombi are mainly formed of fibrin network with a long tail that can easily detach and result in a mobilization of pulmonary arteries. 2. Myocardial infarction: Help to prevent recurrent attacks of MI and stroke especially when given in combination with a low dose of aspirin. It is also used during and after stent placement, coronary angioplasty.

18. 18 3. Unstableangina : The use of LMWH reduces the occurrence of MI in these patients. 4. Atrialfibrillation : These patients require prolonged anticoagulant therapy as they are at high risk for stroke. 5. Thromboembolism : Anticoagulants are used along with low-dose aspirin to prevent thrombo - embolism in patients undergoing haemodialysis and those with prosthetic heart valves.

19. 19 References Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, et al.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.2011;365:883–891. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al‐ Khalidi HR, Ansell J, Atar D, Avezum A, et al.  Apixaban versus warfarin in patients with atrial fibrillation.2011 ; 365:981–992 . van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism : a systematic review and meta‐analysis.2014;12:320–328 .

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