Anti coagulants

Lecture class for MBBS Sem II

1. Anti-Coagulants Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Lecturer, Lumbini Medical College 12 June, 2018 (29 Jestha , 2075), Tuesday

2. By the end of the class, MBBS Sem II students will be able to: Classify drugs used to achieve anti-coagulation Describe the pharmacology of anticoagulants (heparin, warfarin) List directly acting anti-coagulants List the antidotes of heparin and warfarin

3. A case scenario A 40 years male patient Planned for Open cholecystectomy for gall stones Surgeon worried for the patient might develop deep vein thrombosis and requests your consultation Which anti-coagulant would you choose?

4. Anti –coagulants: Classification Used in vivo Parenteral anticoagulants Indirect thrombin inhibitors: Heparin, Low molecular weight heparin, Fondaparinux, Danaparoid Direct thrombin inhibitors: Lepirudin , Bivalirudin, Argatroban Continued…

5. Anti –coagulants: Classification Used in vivo Oral anticoagulants Coumarin derivatives: Bishydroxycoumarin ( Dicumarol ), Warfarin , acenocoumarol ( Nicoumalone ), Ethylbiscoumacetate Indandione derivative: Phenindione Continued…

6. Anti –coagulants: Classification Used in vivo Oral anticoagulants D irect factor Xa inhibitor: R ivaroxaban O ral direct thrombin inhibitor: D abigatran etexilate Continued…

7. Anti –coagulants: Classification Used in vitro H eparin C alcium complexing agents: Sodium citrate Sodium oxalate Sodium edetate

8. Heparin Non-uniform mixture of straight chain mucopolysaccharides Present in tissues rich in mast cells Lung, liver, intestinal mucosa Commercially prepared from ox lung and pig mucosa

9. Heparin: Anticoagulant Action Effective both in vivo and in vitro Heparin binds with and activates Anti-thrombin III (AT III) Increases interaction between AT III and clotting factors ( IIa , Xa , IXa , XIa , XIIa and XIIIa ) Intrinsic and common pathway affected ( aPTT prolonged)

10. Heparin: Anticoagulant action Provides scaffolding Activates AT III Simultaneously bound to thrombin

11. Heparin: Other actions Antiplatelet action Higher dose  inhibits platelet aggregation Prolonged bleeding time

12. Heparin: Other actions Lipaemia clearing Lower concentration of heparin Lipoprotein lipase released from vessel wall and tissues Hydrolyses triglycerides of chylomicron and very low density lipoprotein to free fatty acids Passes into tissue  turbid post-prandial lipaemic plasma becomes clear

13. Absorption: Oral: not absorbed (large, highly ionised) Intravenous: instant action (bolus, continuous infusion) Subcutaneous: inconsistent (every 8-12 hrs) Distribution: Does not cross blood brain barrier, placenta Metabolised in liver (heparinise) Excreted in urine Heparin: Pharmacokinetics

14. Heparin: Adverse effects Bleeding due to overdose Proper monitoring required ( aPTT ) Thrombocytopenia Discontinue heparin Osteoporosis on long term use Hypersensitivity reactions (rare)

15. Heparin: Contraindications Bleeding disorders History of heparin induced thrombocytopenia Severe hypertension, threatened abortion, piles, g.i. ulcers Subacute bacterial endocarditis, large malignancies, tuberculosis

16. Heparin: Contraindications Ocular and neurosurgery, lumbar puncture Chronic alcoholics, cirrhosis Renal failure Caution: Co-administered antiplatelet drugs Aspirin, Clopidrogrel

17. Low molecular weight Heparin (LMWH) Fractionated heparin Enoxa parin , Revi parin , Nadro parin , Dalte parin , Parna parin , Arde parin Selectively inhibits factor Xa Little effect on factor IIa Lesser effect on aPTT , clotting time as compared to unfractionated heparin (UFH)

18. LMWH: Anticoagulant action Activation Cannot bind to IIa Shorter

19. LMWH: Advantages over UFH Better subcutaneous bioavailability Minimal variation in response Once daily dosing Dose calculated on body weight basis aPTT and CT not required Lower risk of osteoporosis on long term use Lesser antiplatelet action

20. LMWH: Indications Prophylaxis of deep vein thrombosis and pulmonary embolism Treatment of established deep vein thrombosis Unstable angina and myocardial infarction Maintain patency of cannula and shunts in dialysis patients

21. Fondaparinux Synthetic pentasaccharide molecule Binds to AT III Selectively inactivates factor Xa Less likely to cause: Thrombocytopenia Osteoporosis (on long term use) Does not require aPTT monitoring

22. Fondaparinux: Mechanism of Action Fonda- parinux Activation No Scaffolding

23. Fondaparinux: Pharmacokinetics Subcutaneous bioavailability 100% Longer acting (t ½ 17 hours) Minimally metabolised Excreted unchanged in urine Not to be used in renal failure patients

24. Danaparoid Heparan sulfate Less potent anti-coagulant than heparin Less abundant 3-O-sulphated glucosamine residue on pentasaccharide sequence Obtained from pig gut mucosa Used in cases with heparin induced thrombocytopenia

25. Anti –coagulants Used in vivo Parenteral anticoagulants Indirect thrombin inhibitors: Heparin, Low molecular weight heparin, Fondaparinux, Danaparoid Direct thrombin inhibitors: Lepirudin , Bivalirudin, Argatroban

26. Direct Thrombin Inhibitors Lepi rudin , Desi rudin Recombinant preparation of hirudin Binds to thrombin and inhibits it directly Catalytic site as well as substrate recognition site

27. Direct Thrombin Inhibitors Lepi rudin , Desi rudin Administered intra-venously Indicated in patients at risk of heparin induced thrombocytopenia Antibodies against lepurin -thrombin complex may develop on prolonged use Prolonged anti-coagulant effect Anaphylaxis

28. Direct Thrombin Inhibitors Bivali rudin Synthetic peptide Similar to lepirudin Action slowly reversible

29. Direct Thrombin Inhibitors Argatroban Synthetic nonpeptide Binds to catalytic site reversibly Rapid and short lasting action Indicated in patients with heparin induced thrombocytopenia

30. Direct Thrombin Inhibitors: Interaction with thrombin

31. Oral Anti –coagulants

32. Coumarin derivatives Warfarin, Nicomalone Active in vivo only Acts indirectly by: Interfering with synthesis of vitamin K dependent clotting factors Lowers plasma level of clotting factors in dose dependent manner

33. Coumarin derivatives: Mechanism of action Clotting factors precursors (Vitamin K dependent) Inactive Clotting factors Vitamin K hydroquinone Vitamin K epoxide Vitamin K epoxide reductase NADH NAD γ - glutamyl carboxylase Warfarin

34. Fall in levels of clotting factors due to administration of coumarin derivatives Warfarin given Factor VII (t 1/2 6) Factor IX (t 1/2 24) Factor X (t 1/2 40) Factor II (t 1/2 60) Time (hrs)

35. Warfarin: Pharmacokinetics Parameters Character Remarks Absorption Rapidly and completely absorbed from intestine Given orally Distribution 99% plasma protein bound Drug interaction Crosses placenta Contraindicated in pregnancy Secreted in breast milk Insignificant Metabolism R-form: CYP 1A, CYP3A4 Degraded slowly S-form: CYP2C9 More potent Both undergo glucuronidation and enterohepatic circulation Excretion Urine

36. Coumarin Derivatives Adverse effects Bleeding Ecchymosis Epistaxis Hematuria Intracranial bleeding

37. Coumarin derivatives Contraindications Pregnancy Early: Foetal warfarin syndrome , skeletal abnormalities Late: CNS defects, foetal haemorrhage, foetal death, neonatal hypoprothrombinaemia (accentuated) Bleeding disorders, patient at risk of bleeding, patient undergoing ocular surgery, neurosurgery

38. Foetal Warfarin Syndrome

39. Warfarin: Interactions Increased effect Prolonged antibiotic therapy, malnutrition, malabsorption Liver disease, chronic alcoholism Hyperthyroidism Decreased effect Pregnancy Nephrotic Syndrome Genetic warfarin resistance

40. Warfarin: Interactions Factors increasing effect Reduced vitamin K to liver: Prolonged antibiotic therapy, malnutrition, malabsorption Deficient synthesis of clotting factors: Liver disease, chronic alcoholism Hyperthyroidism Faster degradation of clotting factors

41. Warfarin: Interactions Factors decreasing effect Pregnancy Increased levels of plasma clotting factors Nephrotic Syndrome Loss of protein bound drug Genetic warfarin resistance Lower affinity of VKOR enzyme to warfarin

42. Warfarin: Drug Interaction Enhanced activity Absorption: Liquid paraffin Distribution: Indomethacin, phenytoin, probenecid, aspirin (high dose) Metabolism: Enzyme inhibitors, Tolbutamide Pharmacodynamic: Broad-spectrum antibiotics Ceftriaxone, cefoperazone ; Aspirin (antiplatelet)

43. Warfarin: Drug Interaction Decreased activity Pharmacokinetic: Enzyme inducers Higher dose of anticoagulant required Pharmacodynamic: Oral contraceptives

44. Direct Xa inhibitor: Rivaroxaban Action develops within 3-4 hrs, lasts for 24 hrs Laboratory monitoring of PT and aPTT not required Prophylaxis and treatment of deep vein thrombosis After 6-10 hrs of surgery, 10 mg, oral, daily Side effects: bleeding, nausea, hypotension, tachycardia, edema

45. Oral Direct IIa inhibitor: Dabigatran etexilate Prodrug  gets converted to dabigatran Blocks catalytic site of thrombin Duration of action ~24 hrs Laboratory monitoring not required Prevention of deep vein thrombosis Adverse effects : bleeding, hepatobiliary disorders

46. Anticoagulants: Indications Deep vein thrombosis, pulmonary embolism Myocardial infarction Prevent mural thrombi at the site of infarction and venous thrombi in leg veins Unstable angina Along with aspirin Rheumatic heart disease, atrial fibrillation Prevent thromboembolism Prior attempting rhythm conversion

47. Anticoagulants: Indications Embolic stroke (cerebrovascular disease) Vascular surgery, prosthetic heart valves, retinal vessel thrombosis, extracorporeal circulation, haemodialysis Prevent thromboembolism Defribrination syndrome Heparin (paradoxical effect)

48. Anticoagulant Overdose…. What to do? Anticoagulant used Treatment Unfractionated Heparin (UFH) Whole blood transfusion (BT) UFH (Rapid termination of action required) Protamine sulfate Low Molecular Weight Heparin (LMWH) Protamine sulfate (partially reversed) Fondaparinux -- Lepirudin -- Warfarin BT, Vitamin K

49. Conclusion Heparin effects intrinsic and common pathway of clot formation Inactivates both Xa and IIa LMWH is more selective for Xa ; Fondaparinux is selective for Xa Problems of UFH are minimal with LMWH and Fondaparinux