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Anticoagulants pharmacology

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Katzung
Anticoagulants
Hemostasis refers to the finely regulated dynamic process of maintaining the fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs. Either extreme excessive bleeding or thrombosis—represents a breakdown of the hemostatic mechanism. Common causes of dysregulated hemostasis include hereditary or acquired defects in the clotting mechanism and secondary effects of infection or cancer. The drugs used to inhibit thrombosis and to limit abnormal bleeding are the subjects of this chapter.

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Anticoagulants pharmacology

  1. 1. Anticoagulants Pharmacology Reza Heidari Pharm D & Toxicology PhD
  2. 2. What are Anticoagulants? A substance that prevents blood from clotting by suppressing the synthesis or function of various clotting factors. Anticoagulants are given to prevent thrombosis and used in drawing and storing blood.
  3. 3. MECHANISMS OF BLOOD COAGULATION
  4. 4. 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 polymerXIII Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants (e.g Warfarin)
  5. 5. Why anticoagulants ? To reduce the coagulability of blood Blood clots – Thrombus Arterial Thrombosis: Adherence of platelets to arterial walls – “White” in color - Often associated with MI, stroke and ischemia  Venous Thrombosis: Develops in areas of stagnated blood flow (deep vein thrombosis), “Red” in color- Associated with Congestive Heart Failure, Cancer, Surgery Thrombus dislodge from arteries and veins and become an embolus Venous emboli can block arterioles in the lung and pulmonary circulation Thromboembolism
  6. 6. Available Anticoagulants Used in vivo: 1. Parenteral anticoagulants: – Indirect thrombin inhibitors: Heparin, Low molecular weight heparin, Fondaparinux, Danaparoid – Direct thrombin inhibitors: Lepirudin, Bivalirudin 1. Oral anticoagulants: – Coumarin Derivative: Bishydroxycoumarin (dicumarol), Warfarin sodium, Acenocoumarol – Inandione derivatives: Phenindione – Direct factor Xa inhibitors: Rivaroxaban Used in vitro:  Heparin: (150 U in 100 ml of blood)  Calcium complexing agents: Sodium citrate 1.65 gm for 350 ml of blood – acid citrate dextrose solution – 75 ml in one unit of blood  For investigation: Sodium oxalate (10 mg for 1 ml blood and Sodium edetate – 2 mg for 1 ml of blood)
  7. 7. INDIRECT THROMBIN INHIBITORS • Unfractionated heparin (UFH) • Low Molecular-Weight Heparin (LMWH) • Synthetic pentasaccharide: Fondaparinux
  8. 8. Heparin as Prototype Endogenous - strongest organic acid present in the Body Present in mast cells (MW – 75,000) – lungs, liver and intestinal mucosa Commercially - from Ox lung and Pig mucosa (slaughter house) Chemically, non-uniform mixture of straight chain mucopolysaccharides with MW 10,000 to 20,000 Types - (i) Regular or unfractionated (UFH) Heparin (MW 5000 to 30,000) – IV or SC and (ii) LMWH (MW 2000 to 6000) – mostly SC
  9. 9. Heparin Actions • Indirect acting - Activates plasma antithrombin III (AT III) • Heparin-AT III complex inactivates clotting factors - Xa, IIa, IXa, XIIa and XIIIa, but not VIIa (extrinsic pathway) – At low conc. Xa mediated conversion of Prothrombin to thrombin affected – Overall, Xa and IIa mediated conversion of fibrinogen to fibrin • AT III (suicide inhibitor) – binds to clotting factors slowly to form stable complex. Heparin enhances it by 1.Heaprin creates scaffolding to bind each (clotting factors) other with AT III 2.A specific polysaccharide in heparin binds to AT III and induce conformational changes
  10. 10. Heparin Actions – contd. • Inhibition of Xa needs only the 2nd mechanism (LMWH) - fondaparinuxs • IIa needs both the mechanism • Antiplatelet action: High doses prevents platelet aggregation prolongs Bleeding time • Pharmacokinetics: – Highly ionized, not absorbed orally – given IV (instant action) and SC (slow action) – Does no cross BBB and placenta – 100 U/kg dose half life is 1 Hr., but above this dose 1 – 4 Hrs
  11. 11. Heparin – Contd. • Adverse effects: 1. Bleeding due to overdose – hematuria is 1st sign 2. Thrombocytopenia 3. Hypersensitivity – urticaria, rigor, fever and anaphylaxis etc. 4. Alopecia and osteoporosis • Contraindications: Bleeding disorders, Severe hypertension, GIT ulcer, Ocular & neurosurgery, Chronic alcoholism, cirrhosis etc. • Aspirin and antiplatelet drugs - caution
  12. 12. Low Molecular eight Heparin (LMWH) • MW : 2000 to 6000 • MOA: Acts only by interfering with Xa – inducing conformational change in AT III – smaller effect on a PTT – whole blood clotting time – Lesser antiplatelet action and lower incidence of hemorrhagic complications – Better Bioavailability on SC administration (once daily dosing) – Better half life (4-6 Hrs) – Laboratory monitoring not needed (a PTT and clotting time affected little) • Uses: Prophylaxis of DVT and Pulmonary embolism in Surgery, stroke and immobilized patients, DVT, etc.
  13. 13. Dosage of Heparin • Unitage: Expressed in units as it is standardized by bioassay – variable molecular size • 1 mg = 120-140 U activity • Administered as IV bolus 5000-10,000 u followed by 1000 u /hr IV drip – adjusted with aPTT value – Pretreatment aPTT value and followed by 1.5 to 2.5 times during therapy • Alternate: 10,000-20,000 deep SC every 8 Hrly (fine needle) • Or, Low dose SC – 5000 SC 8-12 Hry before and after surgery to prevent DVT • Protamine Sulfate: Heparin antagonist – given IV (1mg = 100U) – cardiac and vascular surgery
  14. 14. DIRECT THROMBIN INHIBITORS • Hirudin • Bivalirudin • Argatroban • Melagatran
  15. 15. • Leeches have been used for bloodletting since the age of Hippocrates. More recently, surgeons have used medicinal leeches (Hirudo medicinalis) to prevent thrombosis in the fine vessels of reattached digits.
  16. 16. Oral Anticoagulants
  17. 17. - Hemorrhagic disease in cattle
  18. 18. Warfarin • In vivo not in vitro • MOA: Competitive antagonist of Vit.K – lowers the plasma level of vit. K dependent clotting factors – Inhibits VKOR needed to generate active Vit.K • Synthesis of clotting factors diminishes within few hours- at different times by diff. factors • But anticoagulant action starts in 1-3 days only • Commercially, mixture of R and S enantiomers
  19. 19. Warfarin – contd. • Kinetics: Completely absorbed from intestine and 99% plasma protein bound – only 1% free (many drugs can displace (sulfonamides, phenytoin – toxicity) – half life 36 hrs. • Dosing: Risky – calculate risk-benefit ratio – Dose is individualized by repeated measurement of PT – Optimum ratio of PT: 2-2.5 in prophylaxis of DVT, 2-3 in DVT treatment and 3-3.5 in MI etc. • Uses: DVT, Pulmonary embolism and atrial fibrillation (drug of choice – 3-4wks before and after conversion)
  20. 20. Warfarin • ADRs: Bleeding – epistaxis, haematuria, bleeding GIT Intracranial haemorrhage – Minor bleeding – Vit K (takes long) – Fresh blood transfusion or blood factors – Other ADRs: Alopecia, dermatitis and diarrhea etc. • Contraindications: Same as heparin – Fetal warfarin syndrome: skeletal abnormality – hypoplasia of nose, eye socket, hand bones and growth retardation
  21. 21. Warfarin • Factors enhancing warfarin effect: (1) Debility, malnutrition etc. (2) Liver diseases, chronic alcoholism (3) Newborn (4) prolonged antibiotic therapy • Factors decreasing warfarin effect: Pregnancy, Nephrotic syndrome and genetic warfarin resistance • Drugs enhancing anticoagulant action: Broad spectrum antibiotics, Aspirin (platelet aggregation inhibition and hypoprothobinemic action), Newer cephalosporins (hypoprothobinemic; Chloramphenicol, allopurinol, and phenytoin (inhibits metabolism) • Drugs reducing effect: Barbiturates, carbamazepine, OCP and Rifampicin
  22. 22. RIVAROXABAN  Direct factor Xa inhibitor which is taken by mouth. The maximum inhibition  of factor Xa occurs four hours after a dose. The effects last approximately  8–12 hours, but factor Xa activity does not return to normal within 24 hours,  so once-daily dosing is possible.
  23. 23. FIBRINOLYTICS
  24. 24. Fibrinolytics • Drugs used to lyse thrombi/clot to recanalize occluded vessels – coronary artery • MOA: Produce more plasmin - dissolves fibrin thread • Drugs: Streptokinase, urokinase, alteplase (rt-PA), reteplase and tenecteplase • Streptokinase – Binds to plasminogen and generate plasmin – Non-specific – activates circulating + fibrin bound plasminogen– non-specific fibrinogen depletory – but less effect than newer ones in fibrinolysis
  25. 25. Alteplase and Tenecteplase • Recombinant tissue plasminogen activator (rt-PA) – human tissue culture – costlier than Streptokinase • MOA: tissue specific thrombolytic (acts on fibrin bound plasminogen within thrombus) – also interferes with circulating plasminogen (50%) – inactivated by PAI-1 • Plasma half life 5 minutes – given slow IV (heparin needed) • MI: 1o mg IV bolus – followed by rest 90 mg infusion for 90 minutes • Pulmonary embolism: 100 mg slow IV for 2 Hrs • Tenecteplase: genetically engineered, higher fibrin selectivity, not inactivated by PAI-1, can be injected over 10 seconds single bolus
  26. 26. Uses of Thrombolytics • AMI • – aspirin + heparin co-administered to prevent re-occlusion • DVT: leg, pelvis and shoulder • Pulmonary embolism • Stroke: selected patients
  27. 27. Antifibrinolytics • Epsilon amino-caproic acid (EACA) and Tranexamic acid • MOA: Inhibit Plasminogen activation and clot dissolution • EACA: Specific antidote for fibrinolytic agents – also adjunctive value in other conditions • Tranexamic acid: More potent than EACA – Uses: fibrinolytic drugs, Bypass surgery, Menorrhagia, Recurrent epistaxis, tonsillectomy & tooth extraction (haemophiliacs)
  28. 28. Antiplatelet Drugs (Antithrombotic drugs)
  29. 29. Antiplatelet Drugs (Antithrombotic drugs) • Drugs which interferes with platelet function and used in prophylaxis of thromboembolic disorders. • Drugs: Aspirin, Dipyridamole, Ticlodipine, Clopidogrel and Prasugrel • Aspirin as antiplatelet: – Irreversible Inhibition of COX 1 and TX synthase – Suppress TXA2 (generated by platelets) in low doses (75-150 mg) – till fresh platelets are formed – prolonged bleeding time – Suppress COX-1 and decrease PGI2 synthesis in vessel wall – but endothelial cells immediately re-synthesize fresh enzyme – Also inhibits release of ADP from platelets and their sticking to each other – but not to adhesion to damaged vessel walls
  30. 30. • Ticlopidine and clopidogrel reduce platelet aggregation by inhibiting the ADP pathway of platelets. These drugs irreversibly block the ADP receptor on platelets.
  31. 31. Antithrombotic drugs - Ticlodipine • MOA: Inhibits fibrinogen as well as ADP induced platelet aggregation – Gi coupled P2Y12 (P2YAC) purinergic receptors mediate adeylyl cyclase inhibition due to ADP – blocked irreversibly – No effect on TXA2 – Irreversible blockade of P2YAC – platelet inhibiton cumulates – effects appear in 8-10 days • Uses: Stroke prevention, unstable angina, coronary bypass, prevention of MI, etc • Serious ADRs – Bleeding, neutropenia, hamolysis, thrombocytopenia and jaundice - replaced by Clopidogrel
  32. 32. Antithrombotic drugs - Clopidogrel • Similar MOA to Ticlodipine – irreversible blockade of platelet function – Safer and better tolerated than Ticlodipine • Advantages over Aspirin in Ischaemia – lower incidence of ischaemic events • Synergistic action with aspirin – prevention of Ischaemic episodes • Kinetics: Prodrug like Ticlodipine, 50% absorbed orally – Only a fraction slowly activated in liver by CYP2C19 slow acting – CYP2C19 – genetic polymorphism - interindivdual variability in antiplatelet action – Takes 5-7 days for action • ADRs: Bleeding most common, neutropenia and thrombocytopenia rarely • Dose: 75 mg OD
  33. 33. Antithrombotics – Other Drugs • Prasugrel: Faster and potent P2Y12 (P2YAC) purinergic receptors Blocker • Newer Drugs: Glycoprotein (GP) IIb/IIIa receptor antagonists: Abciximab, Ebtifibatide and Tirofiban – Newer class of drugs – Blocks the key receptor involved in platelet aggregation – Collagens, thrombin, TXA2 and ADP etc. – acts through - GLP IIb/IIIa is an adhesive receptor (integrin) on platelet surface – GLP IIb/IIIa antagonists block platelet aggregation
  34. 34. Uses of antithrombotics • Coronary Artery Disease: Aspirin 75-150 mg/day in all individuals with evidence of coronary artery disease – clopidogrel is an alternative in ischaemia • Acute Coronary Syndromes: Aspirin 325 mg orally and LMW heparin • Cerebrovascular accidents: Do not alter the course of cerebral thrombosis • Prosthetic Heart Valves and arteriovenous shunts: In conjunction with warfarin • Venous thrombosis: DVT and PE • Peripheral vascular disease
  35. 35. THANK YOU Any Questions???

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