Anticoagulants

Useful study material for MBBS

1. COAGULANTS AND ANTICOAGULANTS Dr.SUMITHA A MBBS.,MD Assistant professor Pharmacology

2. COAGULANTS 1. Vitamin K K1 (from plants, : Phytonadione fat-soluble) ( Phylloquinone ) K3 (synthetic) —Fat-soluble : Menadione , —Water-soluble : Menadione sod. bisulfite 2. Miscellaneous Fibrinogen (human) Antihaemophilic factor Desmopressin Adrenochrome monosemicarbazone Rutin , Ethamsylate

3. Vitamin k

4. USES OF VITAMIN K Prolonged antimicrobial therapy Obstructive jaundice ,Malabsorption syndrome:vitamin k 10 mg i.m ./day Dietary deficiency of vitamin k Liver disease:cirrhosis,viral hepatitis Newborn :have low levels of clotting factors and prothrombin –lower capacity to synthesise . 1 mg im vitamin k1 soon after birth. Menadione vitamin K3 not used.

5. Overdose of oral anticoagulants: 10 mg i.m.followed by 5 mg 4 th hourly.bleeding stops in 6-10 hrs.Normal levels of coagulation after 24 hrs. Adverse effects: Menadione -not used in newborns. Hemolysis,increased bilirubin load. Competitively Inhibits glucoronidation of bilirubin .

6. OTHER COAGULANTS Adrenochrome monosemicarbazone-styptochrome inj 3mg/2 ml inj Rutin : cadisper –c 60 mg tab Ethamsylate:250-500 mg tds oral / inj Desmopressin,Antihaemophilic factor Used in hematuria,bleeding after tooth extraction epistaxis

7. I. Used in vivo A. Parenteral anticoagulants ( i ) Indirect thrombin inhibitors : Heparin, Low molecular weight heparins, Fondaparinux , Danaparoid (ii) Direct thrombin inhibitors: Lepirudin , Bivalirudin , Argatroban B . Oral anticoagulants ( i ) Coumarin derivatives : Bishydroxycoumarin Warfarin sod, Acenocoumarol Ethylbiscoumacetate ANTICOAGULANTS

8. ii) Indandione derivative: Phenindione . (iii ) Direct factor Xa inhibitors : Rivaroxaban (iv) Oral direct thrombin inhibitor : Dabigatran etexilate II. Used in vitro A. Heparin: 150 U to prevent clotting of 100 ml blood. B. Calcium complexing agents: Sodium citrate

9. ORAL ANTICAGULANTS -WARFARIN

10. ORAL ANTICAGULANTS

11. Warfarin Dose Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE) Initial dose: 2-5 mg PO qDay for 2 days. Initiate warfarin on day 1 or 2 of LMWH or unfractionated heparin therapy and overlap until desired INR,then discontinue heparin. Check INR after 2 days and adjust dose according to results Maintenance dose - 2 and 10 mg/day

12. Adverse effects Bleeding- ecchymosis,hematuria,bleeding in git . Occurs if INR –Exceeds 4 INR-International normalised ratio. INR-ratio of prothrombin time during treatment with ora;l anticoagulant with normal value of prothrombin In healthy people an INR of 1.1 or belowis normal. 2.Teratogenic effects: Foetal warfarin syndrome- hypoplasia of nose.eye socket,hand bones ,growth retardation. 3.Alopecia,dermatitis,diarrhoea

13. DRUG INTERACTIONS OF WARFARIN

14. Newer oral anticoagulants Direct factor Xa inhibitors : Rivaroxaban,apixaban,Edoxaban Apixaban -10 mg BD for 7 days followed by 5 mg BD.For TREATMENT OF DVT and PE. Oral direct thrombin inhibitor : Dabigatran Etexilate . Rapid onset and offset of therapeutic effect. Short half life No laboratory monitoring required Lower risk of bleeding Fewer drug interactions Antithrombotic efficacy equal to warfarin .

15. Parenteral anticoagulants- Heparin HEPARIN Activates plasma AT III Heparin-AT III complex Binds to clotting factors of intrinsic and common pathways (Xa, IIa, IXa, XIa, XIIa and XIIIa) and inactivates them

16. A T I I I T h r o m b i n 5 13 or more saccharide units Heparin Lysine Sites A T I I I F a c t o r X a 5 Low Molecular Weight Heparin Lysine Sites <13

17. PHARMACOKINETICS  Heparin is not absorbed orally.  If Injected i.v. - acts instantaneously.  After s.c. injection anticoagulant effect develops after ~60 min.  Bioavailability of s.c. heparin is inconsistent.  Heparin does not cross blood-brain barrier or placenta  It is metabolized in liver by heparinase.  Fragments are excreted in urine.

18. Heparin - Clinical Uses venous thrombosis and pulmonary embolism mural thrombosis after acute MI managing unstable angina prevention of coronary artery rethrombosis treat selected cases of disseminated intravas-cular coagulation (DIC) Effective for the prevention and treatment of:

19. For thromboembolic disorder : Continuous IV infusion : -Initial dose: 5000 units by IV injection -Maintenance dose: 20,000 to 40,000 units per 24 hours by continuous IV infusion

20. Heparin - Recommendations for Clinical Use Pregnancy - heparin is the anticoagulant of choice does not cross the placenta no untoward effects in the fetus or newborn given in therapeutic doses - 15,000 U sc 12 hrs to women with prosthetic heart valves or venous thromboembolism

21. Adverse effects of Heparin 1.Bleeding(most common) 2. Allergy and Anaphylaxis 3. Increased hair loss, alopecia 4. Long term-Osteoporosis, spontaneous fractures 5. Heparin induced thrombocytopenia (HIT)

22. HIT 2-occurs 5-10 days after heparin therapy. Platelet count drops more than 50%.Antibody mediated Treatment:Direct thrombin inhibitor

23. Heparin - Contraindications Patients who are hypersensitive Presence of active bleeding or hemophilia Thrombocytopenia Severe hypertension Intracranial hemorrhage Bacterial endocarditis –risk 0f embolism Active tuberculosis (risk of hemoptysis ) Ulcerative lesions of GI tract

24. Heparin - Contraindications Large malignancies(risk of bleeding in central necrosed area of tumour ) During or after surgery on the brain, spinal cord or ocular surgery. History of heparin-induced thrombocytopenia.

25. Heparin antagonist: Protamine sulphate –Basic in nature,i.v . 1 mg neutralises 100 U of heparin Hypersensitivity reactions can occur. Fondaparinux : Selectively inhibits factor Xa . Pentasaccharide,s.c . Bioavailability 100 % Risk of bleeding osteoporosis minimal 5mg/0.4 ml syringe

26. Low Molecular-Weight Heparins Enoxaparin 20 (0.2 ml ) prefilled syringe Dalteparin Reviparin Ardeparin , Nadroparin Molecular weight -3000-4000 Selectively inhibit factor X a they increase the action of ATIII on factor Xa , but not its action on thrombin.

27. Low Molecular Weight Heparins Better s.c.bioavailability (70-90% ) Do not require routine monitoring of aPTT . Risk of osteoporosis is less. Uses: Prophylaxis and treatment of DVT. Unstable angina and MI. To maintain patency of cannulae and stents.

28. Direct thrombin inhibitors Lepirudin Bivalirudin Desirudin Argatroban Bivalirudin : Synthetic congener of anticoagulant hirudin , obtained from salivary gland of leech . Binds to catalytic and substrate binding site of thrombin without binding to antithrombin

29. Direct thrombin inhibitors

30. Given i.v. -anticoagulant in patients undergoing PCI for STEMI. value in patients at risk of HIT. Argatroban : Reversibly binds to catalytic site of thrombin.

31. THANK YOU