Blood 2-Anticoagulant and Procoagulant Drugs

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Anticoagulant Drugs, Warfarin, Heparin, Low molecular weight heparin (LMWH), Thrombin Inhibitors, Factor X inhibitors, Fondapranux

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Blood 2: Anticoagulant Agents & Procoagulant Agents:

Blood 2: Anticoagulant Agents & Procoagulant Agents Dr. Syed Shariq Naeem , Senior Resident Doctor, Department of Clinical Pharmacology, Maulana Azad Medical College, New Delhi (INDIA) “Download to Play Animations”

Atrial and Venous thrombosis:

Atrial and Venous thrombosis Venous Thrombosis Arterial Thrombosis “Red Clot” “White Clot” Clot made up of Clotting factors and RBCs Clot Made up of Platelets and Usually Atheroma at its core Eg . Deep vein thrombosis, VTE Stroke, MI Usual Treatment – Anticoagulant Drugs Usual Treatment- Anti platelet Drugs

Consequences of Thrombus:

Consequences of Thrombus

Classification of Anticoagulant Drugs:

Classification of Anticoagulant Drugs Drug Group Sub Groups Route Name of Drugs 1 Indirect Thrombin Inhibitors Unfractionated Heparin IV, SC Heparin Low Molecular Weight Heparins (LMWH) SC Enoxaparin, Dalteparin , Tinzaparin Heparinoid SC Danaparoid 2 Direct Thrombin Inhibitors Oral Dabigatran , Ximelagatran IV,SC Hirudin , Lepirudin , Bivalirudin , Argatroban 3 Factor X inhibitors Oral Rivaroxaban , Abipxaban IV,SC Fondaparinux , Idraparinux 4 Vitamin K antagonists Coumarin -derivatives Oral Warfarin , Dicumarol , Acenocoumarin Based on Book- “Phramacotherapy- A Pathophysiological Approach”, 8 th Edition

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Indirect Thrombin Inhibitors Activate Antithormbin III Unfractionated Heparin LMWH- Enoxaparin, Dalteparin , Tinzaparin Heparinoid - Danaparoid Factor Xa Inhibitors IV- Fondaparinux , Idraparinux Oral- Dabigatran , Ximelagatran Direct Thrombin Inhibitors Vitamin K Antagonists

History of Heparin:

History of Heparin McLean Denied surgery in Johns Hopkins He found while working on Dog liver, that a procoagulant substance became anti coagulant Dr. hovell and his colleagues, Isolated Heparin and Coined the term in 1918 HEParin Hepatocyte Medial student Joined Hovel lab under Dr. Hovell He published his finding in 1916 He left and joined surgery

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AT III Thrombin IIa Inactivation Inactive Thrombin ( IIa ) V, VIII, XIII, Fibrinogen AT III Xa Inactivation Inactive Factor Xa Common Pathway Also Inactivation Inactive Factor IXa , XIIa Contact activation Pathway

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Heparin Glycosaminoglycan- Very Acidic Source- Porcine intestine or Bovine lung Heparin Factory

Heparin:

Heparin Heparin Combination of many small and large molecules Bind to Anti-Thrombin by- “Penta-saccharide sequence” Molecular Weight ~ 15000 Daltons Penta -saccharide sequence Almost 1/3 rd of the Heparin has this sequence

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Mechanism of Action: Heparin Heparin Binds to Antithrombin III and Speeds up its action several folds AT III Heparin Heparin Two Changes in AT III : 1. Conformationa l change to reactive site AT III Xa AT III Thrombin IIa 2. Binding of Thrombin ( IIa )- Requires Catalytic Template Ternary of Heparin- AT III - Thrombin Heparin Ternary Complex - For Inactivation of Factor Xa

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Thrombin IIa AT III Heparin Fibrin Heparin due to its large size : Not able to inactivate- 1. Thrombin bind to Fibrin 2. Factor Xa in Prothrombinase Complex

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Mechanism of Action: Low Molecular Weight Heparin & Fondaparinux AT III Xa Heparin Thrombin IIa LMWH MW- 15,000 Dalton MW- 5,000 Dalton For Thrombin inactivation – Need MW- >5400 or 18 D or more saccharide units Anti- Xa : Anti- IIa Activity 1:1 3.8- 2.8 :1 Fondaparinux AT III Penta -saccharide Unit Xa

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Heparin – Other actions: Additive anticoagulant effect Releases Tissue factor pathway inhibitor form endothelium (also LMWH) Binds to platelets and inhibits platelet aggregation

Pharmacokinetics:

Pharmacokinetics Property Heparin 1 Route IV, SC 2 Bioavailability 30-70% (Dose Dependent) Not IM- Cause Hematoma formation Unpredictable Response d/t Protein binding –Platelet factor 4 3 Onset of Action Rapid 4 T 1/2 30-90 min Compliance Problem Can be given for acute episodes 5 Clearance Major- endothelial cells & Macrophages Minor- Renal 6 Monitoring aPTT Enzyme-Heparinases and desulfatases Contact and Common Pathway Highly Basic Drug 7 Dose Loading: 100 units/kg Maintenance:20 units/kg/h 8 Antidote Protamine Sulfate 9 Placental Barrier Does not cross

Uses of Heparin:

Uses of Heparin Prophylaxis before surgery: Orthopedic surgery- Knee or Hip replacement surgery Abdominal surgery

ADRs of Heparin:

ADRs of Heparin Bleeding- GIT and Urinary System Heparin Induced Thrombocytopenia Local Reaction - Local irritation, mild pain, erythema, histamine-like reactions, hematoma ↓ Aldosterone synthesis with subsequent hyperkalemia Bone loss leading to Osteoporosis (Pregnancy) Alopecia

Comparative Pharmacokinetics of LMWH and Fondaparinux:

Comparative Pharmacokinetics of LMWH and Fondaparinux Property Heparin 1 Route IV, SC 2 Bioavailability 30-70% (Dose Dependent) 3 Onset of Action Rapid 4 T 1/2 30-90 min 5 Clearance Major- endothelial cells & Macrophages Minor- Renal 6 Monitoring aPTT , Platelet 7 Dose Loading: 100 units/kg Maintenance: 20 units/kg/h 8 Antidote Protamine Sulfate 9 Placental Barrier Does not cross LMWH Fondaparinux IV, SC SC ~ 90% ~100% Dose Independent Rapid Rapid 3-5 hrs 17 to 21 hrs Renal Renal Non (Platelet, RFT) Not Required 2.5 mg OD Partially effective Not effective Does not cross Category B (Not Known)

ADRs of LMWH and Fondaparinux:

ADRs of LMWH and Fondaparinux Bleeding Less Bleeding as compared to Heparin Less chances of HIT as compared to Heparin No HIT with Fondaparinux Less chances of Osteoporosis as compared to heparin No Osteoporosis with Fondaparinux

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Drug (Not FDA approved) Remarks 1 Idraparinux Very long T 1/2 - 80 hrs (once weekly dosing) 2 Anti- Xa Inhibitors Rivaroxaban Good Oral Bioavailability Long T 1/2 (once or twice daily regimen) Apixaban

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Indirect Thrombin Inhibitors Factor Xa Inhibitors Direct Thrombin Inhibitors Monovalent- Argatroban, Dabigatran Bivalent- Lepirudin, Desirudin, Bivalirudin Vitamin K Antagonists

Mechanism of Action: Direct Thrombin Inhibitors:

Mechanism of Action: Direct Thrombin Inhibitors Thrombin IIa Monovalent Thrombin Inhibitor Eg.- Argatroban, Dabigatran Divalent Thrombin Inhibitor Eg.- Lepirudin, Desirudin, Bivalirudin Thrombin IIa Active Site Exosite 1 Fibrin Binding Site Binds reversible to Active site only Binds Irreversibly to Active site and Exosite

Comparison with Heparin:

Comparison with Heparin Thrombin IIa Fibrin Heparin Direct Thormbin Inhibitors Binds to free Thrombin Yes Yes Binds to Thrombin completed with fibrin No Yes Monovalent Thrombin Inhibitor Eg.- Argatroban, Dabigatran Divalent Thrombin Inhibitor Eg.- Lepirudin, Desirudin, Bivalirudin Thrombin IIa

Direct thrombin Inhibitors:

Direct thrombin Inhibitors Lepirudin Bivalirudin Argatroban Dabigatran Route IV, SC IV IV Oral Binding to IIa Divalent Divalent Monovalent Monovalent Elimination Renal Enzymatic (80%) Hepatic Renal Less chances of Bleeding Than Heparin Drug of Choice for replacement of Heparin in Heparin Induced Thrombocytopenia Use : Prophylaxis of VTE, DVT Prophylaxis of Acute coronary syndrome, Unstable Angina, PCI Ximelagatran: Not approved by FDA – Drug induced liver toxicity

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Indirect Thrombin Inhibitors Factor Xa Inhibitors Direct Thrombin Inhibitors Vitamin K Antagonists: Coumarin-derivatives: Warfarin, Dicumarol, Acenocoumarin

History of Warfarin:

History of Warfarin Late 19 th Century Sweet Clove Hemorrhagic disease in cattle Karl P Link Identified Oxidized Coumarine derivative- causing Hemorrhage “ Dicumarol ” 1940 Patented Wisconsin Alumni Research Foundation (1945) WARF arin Poor farmers, feed the cattle with Spoiled sweet clove

Mechanism of Action: Warfarin:

Mechanism of Action: Warfarin Warfarin inhibits the synthesis of Vitamin K Dependent Clotting factors -II, VII, IX,X Protein C & S Non Functional Prozymogen Functional Zymogen ϒ - Glutamyl Carboxylase CO 2 +O 2 Reduced Vitamin K Oxidized Vitamin K (Epoxide) Vit . K Epoxide Reductase (VKORC1) Warfarin Doesn’t effect already Functional Zymogens Full antithrombotic effect -8 to 15 days of therapy T 1/2 -72 hrs

Warfarin:

Warfarin Most widely used anticoagulant worldwide. Two Isomers : The S isomer is 2.7 to 3.8 times more potent that the R isomer

Comparative Pharmacokinetics:

Comparative Pharmacokinetics Property Heparin 1 Route IV, SC 2 Bioavailability 30-70% (Dose Dependent) 3 Onset of Action Rapid 4 T 1/2 30-90 min 5 Clearance Major- endothelial cells & Macrophages Minor- Renal 6 Monitoring aPTT , Platelet 7 Dose Loading: 100 units/kg Maintenance: 20 units/kg/h 8 Antidote Protamine Sulfate 9 Placental Barrier Does not cross Warfarin Oral 90% (99% Plasma Protein bound) Slow (8-15 Days) 36 hrs Hepatic- CYP2C9 (S -isomer) , 1A2, 2C19,2A4 (Kinetics zero to First) Genomic variation- 2C9 & VKOR PT (INR) Start with 5 mg Daily , then titrate according to PT profile Vitamin K1 ( Phytonadione ) 10mg IV Fetal Warfarin Syndrome: Contradi Syndrome

Uses of Warfarin:

Uses of Warfarin For Prophylaxis of: Venous thrombosis/thromboembolism Thromboembolic complications associated with: Atrial fibrillation Heart valve replacement Myocardial infarction

ADRs of Warfarin:

ADRs of Warfarin Hemorrhagic complication (1-10%) Warfarin induced Skin Necrosis Purple toe syndrome

Interaction of Warfarin:

Interaction of Warfarin 1 Antiplatelet Drug Asprin 2 Drug inhibiting gut flora Eg Broad spectrem Antibiotics 3 Enzyme inhibitors Metronidazole, Erythormycin , Cimitidine 4 Displacing from protein binding Phenytoin, Probenecid , Cotrimoxazole 1 Enzyme Inducers Phenytoin, Barbiturates, Rifampicin, 2 Inhibiting absorption Cholestyramine , Sucralfate 3 Drug ↑ synthesis of clotting factors OCP ( Estorgen ) 1. Warfarin Activity Potentiated: More Anticoagulant Effect 2. Warfarin Activity Depressed: Less Anticoagulant Effect

Procoagulant Drugs:

Procoagulant Drugs

Pro-Coagulants:

Pro-Coagulants Vitamin K1 Increase Synthesis of Vit . K dependent coagulation factors (V,VII, IX, X) Warfarin poisoning Factor VIII Haemophilia A Factor IX Heamophilia B Mixed factors VW Disease Plasma Fractions Thrombin (Bovine plasma) Vasoconstrictors (Epinephrine) Fibrin Sealant (Human plasma) Astringents (Tannic Acid) Gelatin Foams Russel’s Viper Venom (like thromboplastin ) Styptics (Local Haemostatics )

Anti-Fibrinolytic Agents:

Anti- Fibrinolytic Agents ε - Aminocaproic Acid Inhibit conversion of Plaminogen to Plasmin Also antiplasmin Dose: 5g - 6 hourly Tranexamic Acid More potent than Aminocaproic Acid Dose: 500mg - 6 hourly Aprotinin Inhibits plasmin, kallikrein and Platelet activation Hyperplasminaemia Cardiac bypass Ethamsylate NO Antifibrinolytic activity Increases Capillary wall stability by antihyaluronidase activity Inhibit PGI2 synthesis- Platelet aggregation Postpartum Hge , Menorrhagia, Tooth extraction

Questions:

Questions

PowerPoint Presentation:

Most studies have defined major bleeding as: Any bleeding into a critical anatomic space (e.g., intracranial bleeding, hemarthrosis, or intraocular bleeding), Bleeding that requires transfusion of 2 or more units of blood or plasma , or That leads to a greater than 2 g/dL drop in haemoglobin concentration.

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