Drugs modifying blood coagulation

BDS 2nd year theory class

1. Drugs modifying blood coagulation Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Assistant Professor, Maharajgunj MedicalCampus 6 February, 2020 (23 Magh , 2076), Thursday

2. A case scenario A 35 years male patient with impacted tooth Started tooth extraction Bleeding seen ….. What would you do? By your experience, the bleeding was more than expected What could be the reason?

3. Another case scenario

4. By the end of the class, BDS II Year students will be able to: List drugs used to achieve coagulation and anti-coagulation Describe the pharmacology of heparin and warfarin Explain the pharmacological basis of protamine and vitamin K

5. By the end of the class, BDS II Year students will be able to: Describe the pharmacology of anti-platelet drugs (aspirin, dipyridamole) Describe the pharmacology of thrombolytic agents (streptokinase, urokinase)

6. Anti-coagulants: Classification Used in-vivo Used in-vitro Parenteral Oral Heparin Low Molecular Weight Heparin Lepirudin , Bivalirudin Warfarin Rivaroxaban Heparin Calcium complexing salts

7. 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…

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

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

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

11. Heparin Non-uniform mixture of straight chain mucopolysaccharides 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)

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

13. Heparin: Other actions Antiplatelet action Seen at higher dose Prolonged bleeding time Lipaemia clearing Seen at lower concentration Releases Lipoprotein lipase from vessel wall Hydrolyses triglycerides of chylomicron and very low density lipoprotein to free fatty acids Passes into tissue  turbid post-prandial lipaemic plasma becomes clear

14. 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

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

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

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

18. 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

19. 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

20. 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

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

22. 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

23. Foetal Warfarin Syndrome

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

25. 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

26. 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

27. 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)

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

29. 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

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

31. Protamine Strongly basic, low molecular weight protein Administered intravenously 1 mg for 100 U of heparin More commonly used when heparin action needs to be terminated rapidly, e.g. after cardiac or vascular surgery Has weak anticoagulant in the absence of heparin Adverse effects: Hypersensitivity reaction, flushing and breathing difficulties on rapid i.v. injection

32. Coagulants: Classification Coagulants Fresh whole blood/ plasma Vitamin K: K 1 , K 3 Miscellaneous: Fibrinogen, Antihaemophilic factor Local Haemostatics Styptics: fibrin, thrombin, vasoconstrictors, astringents Sclerosing agents Anti-fibrinolytics Epsilon amino- caproic acid (EACA), Tranexamic acid

33. Vitamin K K 1 : Phyton adione, Phylloquinone Plant source, Fat soluble K 3 : Synthetic Fat soluble: Menadione, acetomenaphthone Water soluble: Menadione sod. bisulphite, menadione sod. diphosphate

34. Vitamin K Co-factor for synthesis of coagulation proteins by liver Coagulation protein precursors (factor II, VII, IX, X) Coagulation protein (factor II, VII, IX, X) γ glutamyl carboxylase Vitamin K Can bind to Ca 2+ and phospholipid surface

35. Vitamin K Absorption Fat soluble: lymphatics of intestine, bile salts required Water soluble: portal blood Distribution: Temporarily stored in liver Metabolism: Liver (side chain cleavage and glucuronidation) Excretion: bile and urine

36. Vitamin K: Uses Newborn baby Prevent/treat haemorrhagic disease of the newborn Overdose of oral anticoagulants Phytonandione Prolonged high dose salicylate therapy

37. Vitamin K: Uses Dietary deficiency Prolonged antimicrobial therapy Obstructive jaundice Malabsorption syndromes Sprue, Regional ileitis, Steatorrhoea Liver disease

38. Vitamin K: Adverse effects Oral, intra-muscular injection: Safe Intra-venous injection: severe anaphylactoid reaction by emulsified preparation Menadione, Water soluble K3: Haemolysis in dose-dependent manner Kernicterus in newborn

39. Fibrinolytics (Thrombolytics) These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels (mainly coronary artery) Work by activating the natural fibrinolytic system Includes: Streptokinase, Urokinase Alteplase, Tenecteplase , Reteplase

40. Thrombolytics: Mechanism of action Plasmin tissue Plasminogen Activator Fibrin (insoluble) Fibrin (soluble) Plasminogen Plasminogen Plasminogen Plasmin Plasmin Antiplasmin PAI-1, PAI-2

41. Streptokinase Obtained from β haemolytic Streptococci group C Combines with circulating plasminogen molecules Gets activated Breaks plasminogen to plasmin (in a limited manner) Non-fibrin specific

42. Streptokinase Drawbacks: Less effective than newer agents Increased risk of bleeding Inactivated by antibodies to past streptococcal infection Is antigenic Cannot be used second time Fever, hypotension, arrhythmia

43. Urokinase Commercially prepared from cultured human kidney cells. Activates plasminogen directly and has a plasma t½ of 10–15 min It is nonantigenic Side effects: Fever Indicated in patients in whom streptokinase has been given for an earlier episode

44. Thrombolytics: Uses Acute myocardial infarction Deep vein thrombosis Pulmonary embolism Stroke Peripheral arterial occlusion

45. Thrombolytics: Contraindications H/o Intracranial haemorrhage H/o Ischaemic stroke in past 3 months H/o Head injury in past 3 months Intracranial tumour /vascular abnormality/ aneurysms Active bleeding/bleeding disorders Peptic ulcer, esophageal varices Any wound or recent fracture or tooth extraction H/o major surgery within 3 weeks Uncontrolled hypertension Pregnancy

46. Anti-platelet drugs (anti-thrombotic drugs) These are drugs which interfere with platelet function and are useful in the prophylaxis of thromboembolic disorders. More useful in arterial thrombosis Includes: Aspirin, Dipyridamole Ticlopidine, Clopidogrel, Prasugrel Abicximab , Eptifibatide, Tirofiban