Coagulant and anti coagulant

pharmacology# coagulats and its mechanism,anticoagulants and its uses and adverse effects

1. SUBMITTED TO Mr.G.Sivakumar Dept of Pharmacology KMCH College of Pharmacy SUBMITTED BY Pavithra.V M.Pharm-1 st SEM June(2018-2019) Dept of Pharmacology KMCH College of Pharmacy SUBMITTED ON 10.10.2018 COAGULATION AND ANTI-COAGULATION

2. INTRODUCTION What is Haemostasis ? Stoppage of bleeding from vessels at the site of injury 3 steps 1.Initially vasospasm of small capillarie 2.Formation of platelet plug 3.Blood clot 09/10/2018 2 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

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4. COAGULATION Complex process of enzymatic reactions in which Clotting factors activates other clotting factors in a fixed sequence until a clot is formed Disorders of coagulation can lead to an increased risk of bleeding or clotting (thrombosis). 3 stages of coagulation: 1-Intrinsic/extrinsic 2.Thrombin formation 3.Fibrin formation 09/10/2018 4 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

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8. COAGULANTS coagulants substances which promote coagulation Indicated in Hemorrhagic states- Haemophilia,Von willibrands disease Fresh whole blood or plasma -best therapy for deficiency of any clotting factor but carries the risk of HIV, hepatitis transmission, They act immediately 1.Hemophilia- antihemophilic factor ( 8 th , 9 th factor) 2.Fibrinogen- heamophilia,acute afibrinogenemia -I.V. infusion 3.Desmopressin –Analogue of vasopressin used in von willibrand disease stimulate release of vwf from endothelial cells(3 to 5 fold increase) –I.V., S.C,Intra nasal No risk of HIV and hepatitis 09/10/2018 8 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

9. VITAMIN K Vitamin k It is a fat soluble vitamin required for the synthesis of clotting factors(2,7,9,10) Dietary sources - cabbage,spinach,liver , cheese etc. Forms : phytonadione k1 leafy veg natural, menaquinone –k2, menadione k3 water soluble synthetic 09/10/2018 9 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

10. Deficiency : Liver disease like Obstructive jaundice Malabsorption Long-term antimicrobial therapy which alter the intestinal flora Deficient diet is not most common Lowering of the levels of prothrombin and other clotting factors Therapeutic uses : 5 -10 mg /day orally/ parentrally Newborn vitamin k( phytona )I.M routine 1mg Deficiency due to chronic use of antibiotics Antidote to oral anticoagulants Osteoporosis adjuvant 09/10/2018 10 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

11. OTHER COAGULANTS: Adrenochrome semicarbazone Decrease capillary fragility,control microvessel bleeding Antifibrinolytics Decrease fibrinolytic activity Fibrinolysis – dissolution of blood clot Eg of antifibrinolytics :Amino caproic acid(EACA) Tranexemic acid is better tolerated ,7-10 times more potent than EACA , high dose – DVT Aprotinin Rutin -plant glycoside used along with vit c Ethamsylate - Anti hyaluronidase activity 09/10/2018 11 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

12. Therapeutic uses: 1.Over dose of fibrinolytics 2.Traumatic and surgical bleeding -prostatectomy, tonsillectomy, tooth extraction 3.Abruptio placentae , PPH, menorrhagia ( meftal spas+tranexamic acid combo),recurrent epistaxis . 4.Adjuvant therapy in haemophilia Adverse reactions : Vomiting diarrhea , abdominal discomfort, Dyspepsia Hypotension conjunctival erythema Nasal stuffiness 09/10/2018 12 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

13. LOCAL HEMOSTATICS -STYPTICS: control bleeding from a local and approachable site Local application-Tooth extraction,abrasions,nasal bleeds E.g. : Thrombin Fibrin sealant-fibrinogen and aprotinin –biodegradable-powder, patch Gelatin foam Oxidized cellulose strips 0.1% epinephrine soaked in sterile cotton gauze 1% tannic acid -astringent Ice(natural ) 09/10/2018 13 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

14. SCLEROSING AGENTS Sclerosing agents Irritants which cause inflammation,coagulation and fibrosis Used in varicose veins, heamorrhoids Local injection only E.g. phenol 5% Hypertonic saline Ethanolamine oleate ,Sodium tetradecyl sulphate 09/10/2018 14 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

15. Anti coagulants 09/10/2018 15 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

16. Anticoagulants: Anticoagulants Drugs which helps prevent the clotting of blood. prevent formation of new clots or an existing clot from enlarging. They don't dissolve already formed blood clot. Natural : Prostacyclin PG I2 –platelet aggregation Antithrombin –Inactivates factor 2 Heparan sulfate(leech)-not heparin –increase activity of antithrombin Protein C- Inactivates 5,7 09/10/2018 16 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

17. Drugs used in vivo :- Parentral anticoagulants : Indirectly thrombin inhibitor: Heparin , low molecular weight heparin,fondaparinux,danaparoid,Heparinoids-Heparan sulfate,Dermatan sulphate , Direct thrombin inhibitor: hirudin,Lepirudin,Ancrod Oral anticoagulants : Coumarin derivatives : Bishydroxy coumarin ( dicumarol ), Warfarin sodium Indandione derivative :-Phenindione 09/10/2018 17 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

18. Used in vitro : Heparin(150 U to prevent clotting of 100 ml blood.) Calcium complexing agents:- Sodium citrate & Sodium oxalate Heparin-both in vivo and i n vitro 09/10/2018 18 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

19. HEPARIN: Heparin McLean, a medical student ,discovered that liver contains a powerful anticoagulant.Howell and Holt named it ‘HEPARIN’ -obtained from liver. Mixture of mucopolysaccharides with MW 10,000 to 20,000. It contains D-glucosamine-L- iduronic acid and D-glucosamine-D-glucuronic acid It carries strong electronegative charge and is the strongest organic acid present in the body . Found in the secretory granules of mast cells. Richest sources are lung , liver and intestinal mucosa. Commercially produced from ox lung and pig intestinal mucosa. Heparin produces its anticoagulant effect by activating plasma antithrombin iii and inhibiting factors 2A and XA 09/10/2018 19 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

20. Other actions of heparin ANTIPLATELET :- Higher doses inhibits platelet aggregation prolongs bleeding time Thrombocytopenia LIPAEMIA CLEARING Injection of heparin clears turbid post- prandial lipaemia by releasing a lipoprotein lipase from the vessel wall ANAGONIST : Protamine sulfate: It is a strongly basic, low molecular weight protein obtained from the sperm of certain fish. Weight basis :I.V . 1 mg is needed for every 100 U of heparin . In the absence of heparin, protamine itself acts as a weak anticoagulan 09/10/2018 20 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

21. PHARMACOKINETICS large , highly ionized molecule; therefore not absorbed orally. I.V. -instantaneously, s.c . injection -after 60 min. Does not cross blood-brain barrier or placenta. safe in pregnancy It is metabolized in liver by heparinase fragments are excreted in urine. 09/10/2018 21 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

22. LOW MOLECULAR WEIGHT HEPARIN Commercially prepared by fractionation(molecular weight 4000 - 6500) Advantages over conventional heparin: Uniform absorption Longer duration of action. Less antigenic, less interaction with platelets- Less risk of thrombocytopenia Examples : ENOXAPARIN,DALTEPARIN,TINZAPARIN,PARNAPARIN,REVIPARIN . 09/10/2018 22 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

23. DALTEPARIN Prophylaxis 2500 U S.C 1hr before surgery, then 2500 U every day for 5-7 days Therapeutics 100 U / kg BD for 5 days. Thrombin inhibitors : Inactivates free as well as fibrin – bound thrombin, does not require antithrombin III like heparin No antidote. Parenteral thrombin inhibitors : Hirudin (leech), lepirudin (Recombinant DNA ) Orally used : dabigatran,epixaban,rivoroxiban 09/10/2018 23 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

24. ORAL ANTICOAGULANTS Oral anticoagulants Given by oral route Teratogenic More drug interactions Eg : Warfarin sodium, Bishydroxycoumarin ( Dicumarol ) Acenocoumarol / Nicomalone , Phenindione 09/10/2018 24 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

25. WARFARIN: Warfarin synthetic derivative of coumarin Mechanism of action : Inhibits vitamin K-dependent synthesis of active forms of the clotting factors II, VII, IX and X . Monitoring of PT (time to take the clot to form)is required, Highly protein bound DDI: Increased effect 1.Enzyme inhibitors – disulfiram,allopurinol,cemitidine 2.Displace from protein binding sites – phenytoin, probenecid 3.liquid paraffin – increased excretion of vitamin K 4.long term antibiotics-decreased vitamin K synthesis and with Aspirin 5.Decreased effect:Enzyme inducers,hereditary resistance,cholestyramine,sucralfate -decrease absorption 09/10/2018 25 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

26. ADVERSE EFFECTS OF ANTICOAGULANTS: Bleeding Alopecia Hypersenstivity - Dermatitis,Urticaria Thrombocytopenia Teratogenecity (warfarin)-Fetal warfarin syndrome- hypoplasia of nasal bridge, heart defects , Growth retardation,laryngomalacia Warfarin poisoning : increased bleeding,no 2,7,9,10 synthesis TREATMENT : Give fresh blood transfusion(acts immediately)- clotting factors & lost blood . Give vit K-specific antidote-But it doesn’t act immediately It takes 6-24 hours for clotting factors to be re- synthesised & released in blood 09/10/2018 26 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

27. THERAPEUTIC USES OF ANTI COAGULANTS : Heparin and warfarin both are started initially later heparin is discontinued after 5 days and warfarin continued .warfarin action starts only after 3-4 days USES :- 1.Prophylaxis of Deep vein thrombosis and pulmonary embolism. In bed ridden patients and those undergoing knee, hip replacement surgeries 2.Myocardial infarction 3.Unstable angina 4.Rheumatic heart disease; Atrial fibrillation 5.During bypass surgery ,Vascular surgery 6.prostatic heart valves, retinal vessel thrombosis, hemodialysis . 7.D.I.C 09/10/2018 27 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

28. References: Text book of Essentials of medical pharmacology(seventh edition), K.D.Tripathi (613-631) Reference book of pharmacology,Rang and Dale`s(seventh edition)(294-297) 09/10/2018 28 KMCH COLLEGE OF PHARMACY,DEPT OF PHARMACOLOGY

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