2. At the end of session students should be able to:  Know the normal hemostatic pathway  Know Parenteral anticoagulant drugs  Know pharmacokinetics, dynamics of heparin  Know the oral anticoagulants  Know pharmacokinetics and pharmacodynamics of warfarin

3.  Maintaining fluidity of blood  Repairing vascular injury  Limiting blood loss  Break down of hemostasis lead to  Excessive bleeding and thrombosis

4.  Vascular Phase  Platelet Phase  Coagulation Phase  Fibrinolytic Phase

5.  Vasoconstriction  Exposure to tissues activate Tissue factor and initiate coagulation Tissue Factor

6.  Blood vessel wall (endothelial cells) prevent platelet adhesion and aggregation  In vascular injury, sub endothelial matrix proteins, collagen and von Willebrand factor  Platelets contain receptors for fibrinogen and von Willebrand factor  After vessel injury Platelets adhere and aggregate  Thromboxane A2 is synthesized from Arachidonic acid  ADP released from platelet granules cause platelet aggregation and formation of platelet plug  Activation of platelets result in conformational change in the IIb/IIIa receptor, enabling it to bind fibrinogen, which cross link adjacent platelets

7.  Two major pathways Intrinsic pathway Extrinsic pathway  Both converge at a common point  Biosynthesis of these factors are dependent on Vitamin K1 and K2  Hereditary lack of clotting factors lead to hemophilia -A

8. Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic PathwayExtrinsic Pathway Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants

9.  Prevent coagulation  Dissolve clots  Prevent bleeding and hemorrhage - Hemostatic  Overcome clotting deficiencies (replacement therapies)

10. A. Reduce the formation of fibrin clots. 1. INDIRECT THROMBIN INHIBITORS  UFH: Heparin  LMWH: Enoxaparin, dalteparin, tinzaparin  SYNTHETIC: Fondaparinux 2. DIRECT THROMBIN INHIBITORS  Parenteral: Hirudin, lepirudin  Oral: Ximelagatran, dabigatran 3. ORAL ANTICOAGULANT DRUGS  Coumarin anticoagulants ▪ warfarin – dicumarol

11. B. Lyse thrombi already formed  Streptokinase, Urokinase, Anistreplase  Tissue Plasminogen Activator: Alteplase, Reteplase, Tenecteplase C. Antiplatelet drugs  Aspirin, clopidogrel, ticlopidine  Platelet glycoprotein IIa/IIIb Receptor blockers  Others: dipyridamole, cilostazol

12.  It is heterogeneous mixture of sulfated mucopolysaccharides  It is glycosaminoglycan found in secretory granules of mast cells, polymer of alternating D-glucronic acid and N- acetyl-D-glucosamine residues  These are D-glucosamine-L-iduronic acid and D- glucosamine-D-glucuronic acid

14.  Source: commonly extracted from porcine intestinal mucosa or bovine lung and preparations contain small amount of other glycosaminoglycans.

15.  Not absorbed through GI mucosa  Heparin is given as continuous intravenous infusion  Immediate onset of action when given intravenously  Half life depend on the dose administered  Destroyed in liver by heparinase  Drug can accumulate in patients with renal impairment  I/M can lead to hematoma

16. Unit of Heparin The USP unit of Heparin is defined as the quantity of Heparin that prevents 1.0 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1% Calcium chloride (CaCl 2 ) solution

17. Standard Heparin or Unfractioned Heparin (UFH) MW 5000-30000 Low MW Forms of Heparin preparations (2000- 6000 MW) Enoxaparin Tinzaparin Dalteparin Danaparoid Fondaparinux

18. Heparin Antithrombin III Thrombin

19.  Heparin binds to endothelial blood surface  It activates ant thrombin III  It inhibits thrombin IIa, IXa and Xa  In the absence of heparin these reactions are slow  LMW heparin and fondaparinux have same mechanism of action

20.  PTT or a PTT  Level of UFH determined by protamine titration or anti Xa units  Weight based dosing of LMW heparin is important in renal insufficiency, obesity and pregnancy

21.  Initiate treatment of venous thrombosis and pulmonary embolism Inherited and acquired (atrial fibrillation, prolonged bed rest, high risk surgical procedures and cancer)  Prevention as well as treatment  Oral anticoagulant is started concurrently  Heparin is continued for at least 5 days to allow warfarin to achieve full therapeutic effect

22.  Initial management of unstable angina  Acute myocardial infarction  Venous thrombosis and pulmonary embolism

23.  Bleeding Major bleeding occur in 1-5% of patients Less bleeding with LMWH Mild bleeding can be controlled without antagonist Protamine sulfate is the antidote (highly basic positively charged peptide, combine with negatively charged heparin 1 mg of protamine neutralize 100 units of heparin

24.  Thrombocytopenia platelet count <150,000/ml This also occur with LMWH and fondaparinux

25.  Mild elevation of hepatic transaminases  Osteoporosis  Inhibit the synthesis of aldosterone

26.  Hypersensitivity to drug  Active bleeding  Hemophilia  Significant thrombocytopenia  Purpura  Severe hypertension  Intracranial hemorrhage  Infective endocarditis  Active tuberculosis  Ulcerative lesion of GIT 

27.  Threatened abortion  Visceral carcinoma  Advanced hepatic or renal disease  Recent surgery of brain, spinal cord or eye  Careful use in pregnancy

28. FeaturesHeparinLMWH Fondaparinux Source Molecular weight Target Bioavailability % Half life Antidote effect Biological 15,000 X a and II a 30 1 Complete Biological 5000 X a and II a 90 4 Partial Synthetic 1500 X a 100 17 None

29. FeaturesHeparinLMWH Fondaparinux Administration Monitoring Adverse effect Effect on platelet Dose I/V infusion a PTT Thrombocytopenia Osteoporosis High dose of heparin interfere with platelets aggregation In units Subcutaneous administration Do not require monitoring Less incidence of thrombocytopenia and osteoporosis Little effect on platelets In mg Subcutaneous Do not require monitoring Less incidence Little effect on platelets In mg

30.  Exert their anticoagulant effect by directly binding to active site of thrombin  Hirudin and bivalirudin  Agatroban and melagatran

31.  Lepirudin (leech saliva)  It inactivate fibrin-bound thrombin in thrombi  Monitored by aPTT  Clinical use: thrombosis related to heparin induced thrombocytopenia  Excreted by kidney  Anaphylactic reaction

32.  Predictable pharmacokinetics and bioavailability  Debigatran etexilate mesylate  Debigatran is the active form  Clinical use: prevention of stroke and systemic embolism in non valvular atrial fibrillation  Prolong PTT and thrombin time

33.  Bleeding  More in patients >75 years  No antidote

34.  Coumarins - warfarin, dicumarol used as rodenticide  Administered as sodium salt and has 100% bioavailability  Structurally related to vitamin K  Delayed onset 8 - 12 hrs

35.  Block γ-carboxylation of glutamate residues in prothrombin and factor VII, IX and X Proteins C and S  Incomplete coagulation factor molecules that are inactive  Vitamin k epoxide reductase is inhibited by warfarin

36. Descarboxy ProthrombinProthrombin Reduced Vitamin KOxidized Vitamin K NADHNAD Warfarin Normally, vitamin K is converted to vitamin K epoxide in the liver. →This epoxide is then reduced by the enzyme epoxide reductase. →The reduced form of vitamin K epoxide is necessary for the synthesis of many coagulation factors (II, VII, IX and X, as well as protein C and protein S). →Warfarin inhibits the enzyme epoxide reductase in the liver, thereby inhibiting coagulation. ( عبدالله المطيري )

37.  Absorption: complete after oral, I/V or rectal route Distribution: 99 % bound to plasma protein Can reach fetus through placenta  Used clinically as racemic mixture S and R warfarin  Levorotatory S-warfarin is four times potent  8-12 hr delay in the action of warfarin

38.  Prevent the progression or recurrence of acute DVT or pulmonary embolism following an initial course of heparin  Prevent venous thromboembolism in patients undergoing orthopedic or gyneocological surgery  Recurrent coronary ischemia in acute MI patients  Systemic embolization in patients with prosthetic heart valves or chronic atrial fibrillation

39.  Bleeding  Minor bleeding: withdrawal of the drug and administer vitamin K 1 (PHYTONADIONE)  Severe bleeding: fresh frozen plasma or factor IX concentrate  Cutaneous necrosis  Infarction of fatty tissues, breast, intestine  Cross the placenta:  Hemorrhagic disorder in the fetus  Teratogenic – abnormal bone formation  Must not be given to pregnant women.

40.  INR  Ratio of PT of patient  PT of normal person plasma  INR = PT pt PT ref

41. Drugs that Increase Warfarin Activity Decrease binding to Albumin Inhibit Degradation Decrease synthesis of Clotting Factors Aspirin, Sulfonamides Cimetidine, Disulfiram Antibiotics (oral) Category Mechanism Representative Drugs

42. Drugs that promote bleeding Inhibition of plateletsAspirin Inhibition of clotting heparin Factors antimetabolites Drugs that decrease Warfarin activity Induction of metabolizingBarbiturates EnzymesPhenytoin,rifampin Promote clotting factorVitamin K Synthesis Reduced absorptioncholestyramine colestipol Hypoproteinemia Nephrotic syndrome Increased volume of distribution

43.  Example: Aspirin  Prevents platelet aggregation /adhesion  Clinical use - prevents arterial thrombus  Myocardial infarction (MI), stroke, heart valve replacement and shunts  Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine

44.  Aspirin inhibits cyclooxygenase (COX)  COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins)  Inhibits platelet aggregation

45.  Low dose daily.  Prevents ischemic attack (ministroke) and MI  335 mg/day reduced the risk of heart attack in patients over 50  More than 1000 mg/day NO EFFECT Contraindication - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency

46.  Enhance degradation of clots  Activation of endogenous protease  Plasminogen (inactive form) is converted to Plasmin (active form)  Plasmin breaks down fibrin clots

47.  Exogenously administered drugs  Streptokinase - bacterial product ▪ - continuous use - immune reaction  Urokinase - human tissue derived – ▪ no immune response  Tissue plasminogen activator (tPA) - genetically cloned ▪ no immune reaction ▪ EXPENSIVE

48.  Heparin (generic, Liquaemin sodium)  Parenteral - 1000 - 40,000 U/ml  Warfarin (generic, Coumadin)  Oral : 2 - 20 mg tablets  Dipyridamole (Persantine)  Oral : 25,50,75 mg tablets

49.  Alteplase recombinant (tPA, Activase)  20, 50 mg Lyophilized powder - reconstitute for iv  streptokinase (Kabikinase, streptase)  Parenteral : 250000 - 1.5 million units per vial. Lyophilized powder. Reconstitute for iv  Urokinase ( Abbokinase)  Parenteral : 250000 units per vial. Powder to reconstitute to 5000 u/ml for injection

50.  Vitamin K ( Phytonadione (K1), Mephyton  Oral : 5 mg tablets  Plasma fractions - for hemophilia  Antihemophilic factor ( VIII, AHF)  Parenteral  Factor IX complex (konyne HT, proplex T)  Parenteral : in vials

51.  Systemic use : aminocaproic acid (Amicar); Tranexamic acid (cyclokapron),Vitamin K  Local adsorbable drugs  Gelatin sponge (Gelfoam)  Gelatin film  Oxidized cellulose ( Oxycel)  Microfibrillar collagen (Avitene)  Thrombin

52. Drug ClassPrototypeActionEffect Anticoagulant Parenteral Heparin Inactivation of clotting Factors Prevent venous Thrombosis Anticoagulant Oral Warfarin Decrease synthesis of Clotting factors Prevent venous Thrombosis Antiplatelet drugs Aspirin Decrease platelet aggregation Prevent arterial Thrombosis Thrombolytic Drugs Streptokinase Fibinolysis Breakdown of thrombi

53. Intrinsic Pathway  All clotting factors are within the blood vessels  Clotting slower  Activated partial thromboplastin test (aPTT) Extrinsic Pathway  Initiating factor is outside the blood vessels - tissue factor  Clotting - faster - in Seconds  Prothrombin test (PT)