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A Power point presentation on the fundamentals of "Anticoagulant Drugs" suitable for UG level Medical students

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  1. 1. ANTICOAGULANTS Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Recall ! XIIa XII Thromboplastin XIa XI IXa IX VIIa Xa X Factors affected By Heparin Prothrombin Vit. K dependent Factors Affected by Oral Anticoagulants Tissue Factor Fibrinogen XIII VII X Thrombin Fribrin monomer Fibrin polymer
  3. 3. 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
  4. 4. Available Anticoagulants Used in vivo: 1. Parenteral anticoagulants: – 1. – Indirect thrombin inhibitors: Heparin, Low molecular weight heparin, Fondaparinux, Danaparoid Direct thrombin inhibitors: Lepirudin, Bivalirudin 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)
  5. 5. 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 Carries strong electro-negative charges Types - (i) Regular or unfractionated (UFH) Heparin (MW 5000 to 30,000) – IV or SC and (ii) LMWH (MW 2000 to 6000) – mostly SC
  6. 6. 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 – bind factors
  7. 7. 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 • Lipaemic clearing • 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 – Should not with – Penicillin, hydrocortisone or tetracycline
  8. 8. Heparin mechanism of action Heparin Antithrombin III Thrombin
  9. 9. Heparin – Contd. • Adverse effects: 1. Bleeding due to overdose – haematuria is 1st sign 2. Thrombocytopenia – aggregation of platelets 3. Hypersensitivity – urticaria, rigor, fever and anaphylaxis etc. 4. Alopecia and osteoporosis • Contraindications: Bleeding disorders, Severe hypertension, GIT ulcer, Piles, SABE & malignancy, Ocular & neurosurgery, Chronic alcoholism, cirrhosis etc. • Aspirin and antiplatelet drugs - caution
  10. 10. Low Molecular Weight Heparin (LMWH) Interfered PT • • – Lesser antipatelet action and lower incidence of haemorrhagic complications – Better Bioavailability on SC administration (once daily dosing) – Better half life (4-6 Hrs) – Laboratory monitoring not needed (aPTT and clotting time affected little) aPTT IP N P EP P N CP P MW : 2000 to 6000 MOA: Acts only by interfering with Xa – inducing conformational change in AT III – smaller effect on aPTT – whole blood clotting time P • Uses: (1) Prophylaxis of DVT and Pulmonary embolism in Surgery, stroke and immobilized patients (2) DVT (3) UA and MI (4) RHD and AF (5) Haemodialysis patients
  11. 11. 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
  12. 12. Oral Anticoagulants
  13. 13. 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
  14. 14. 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)
  15. 15. 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 diarrhoea etc. • Contraindications: Same as heparin – Foetal warfarin syndrome: skeletal abnormality – hypoplasia of nose, eye socket, hand bones and growth retardation
  16. 16. 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, tolbutamide and phenytoin (inhibits metabolism) • Drugs reducing effect: Barbiturates, carbamazepine, OCP and Rifampicin
  18. 18. 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 – once popular – Binds to plasminogen and generate plasmin – Non-specific – activates circulating + fibrin bound plasminogen– nonspecific fibrinogen depletory – but less effect than newer ones in fibrinolysis
  19. 19. 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 genetically engineered, higher fibrin selectivity, not inactivated by PAI-1, can be injected over 10 seconds single bolus • Tenecteplase:
  20. 20. Uses of Thrombolytics • AMI – alternative to PCI with stent placement – aspirin + heparin co-administered to prevent re-occlusion • DVT: leg, pelvis and shoulder • Pulmonary embolism • Stroke: selected patients
  21. 21. 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)
  22. 22. Antiplatelet Drugs (antithrombotic drugs)
  23. 23. 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
  24. 24. Antithrombotic drugs - Dipyridamole • Powerful coronary dilator – increases total coronary flow • MOA: Adeosine is local mediator involved in autoregulation of coronary flow in response to Ischaemia – Dipyridamole prevents uptake and degradation of adenosine and increases platelete cAMP – potentiates PGI2 – interferes platelete aggregation • Uses: Enhance antiplatelet action of Aspirin – lowers the risks of TIAs – 150-300 mg / day
  25. 25. Antithrombotic drugs - Ticlodipine • First thienopyridine derivative – Prodrug (active metabolites in liver) • 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, TIA, intermittent claudication, unstable angina, coronary bypass, prevention of MI • Serious ADRs – Bleeding, neutropenia, hamolysis, thrombocytopenia and jaundice - replaced by Clopidogrel
  26. 26. 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
  27. 27. 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
  28. 28. 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 – NSTEMI and STEMI • Cerebrovascular accidents: Do not alter the course of cerebral thrombosis – reduces incidence of TIA • Prosthetic Heart Valves and arteriovenous shunts: In conjunction with warfarin • Venous thrombosis: DVT and PE • Peripheral vascular disease
  29. 29. Must Know • • • • Heparin, LMWH and Protamine sulfate Warfarin Fibrinolytics (Thrombolytics) Antiplatelet Drugs – Aspirin, Dipyrydamole and Clopidogrel
  30. 30. THANK YOU