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Drugs acting on blood and blood forming organs


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Drugs acting on blood and blood forming organs

  1. 1. Pharmacology of drugs acting on blood and blood forming organs Dr Urmila M. Aswar, Sinhgad Institute of Pharmacy, Narhe, Pune -41
  2. 2.  Hemostasis: is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage)  Clotting disorders is a term used to describe a group of conditions in which there is an increased tendency, often repeated and over an extended period of time, for excessive clotting.
  3. 3. Thrombophilia known as hypercoagibility. It affects a large number of people around the world. It affects approximately 5% to 7% of the European population.
  4. 4. Blood coagulation Intrinsic pathway : all factors needed for Blood coagulation are in plasma. Slow process as lot many factors are needed to be activated.  Extrinsic pathway: also needs tissue factor-thromboplastin. Occurs with in seconds. 
  5. 5. Factors opposing coagulation Antithrombin protein C,  Antithromboplastin  fibrinolysin 
  6. 6. Thrombosis Can be in artery or vein.  Symptoms depend on  Where it has formed  Area  Is it a emboli  There are different terms used to further define these thrombotic episodes, such as deep vein thrombosis (DVT) or peripheral vascular disease, when the clots are in the arterial system (usually in the extremities). 
  7. 7. Triggering factors Women are more sensitive  Pregnancy, oral contraceptives and postmenopausal hormone replacement therapy are all triggering events for DVT in women with thrombophilia.  Factor V Leiden: hypercoagulation 
  8. 8. factor V Leiden Discovered in Leiden city of Neitherland  Factor V is responsible for activation of factor X and XII which further stimulates thrombin formation.  There is mutation in the gene responsible. So that PK C couldn’t degrade factor V. so it is over activity of factor V. 
  9. 9. Anticoagulants Used in vitro  Heparin  Ca complexing agents  Used in vivo Heparin: LMW heparin Oral anticoagulants: 1. Coumarin derivatives 2. Indandione derivatives: Phenindione 
  10. 10. Heparin       Isolated from liver MW 10,000-20,000 Mucopolysacchride chain Contains negative charge Present in mast cells Present in lung, liver and intestine Glycosaminoglycans
  11. 11. Actions Activating antithrombin III  Binds to intrinsic clotting factors: Xa, IIa, IXa, XIa, XIIa, XIIIa and blocks their activity.  No effect on VIIa of extrinsic pathway.  It inhibits conversion prothrombin to thrombin by Xa.  Also it inhibits conversion of fibrinogen to fibrin, Inactivates IIa. 
  12. 12. Low concentration interfere with intrinsic pathway.  High affect both.  It inhibits platelet aggregation  It releases lipoprotein lipase from liver and clears VLDL, chylomicrons and triglycerides from plasma. 
  13. 13. Kinetics As it large inonized molecule, Not Absorbed orally  Does not cross BBB or placenta  T1/2: 1 hr  Units: 1U : the amt of heparin that will prevent 1 ml of citrated sheep plasma from clotting for 1 hr after addition of 1% CaCl2 solution  Heparin sod: 1 mg has 120-140U of activity 
  14. 14. Dosage Given IV 5,000-10,000U adults every 4-6 hrs  Infusion given (750-1000U) till bleeding incidence happen.  Children: 50-100 U/kg 
  15. 15. Adverse effects Bleeding  Thrombocytopenia  Alopecia (transient)  Osteoporosis  Hypersensitivity reactions: urticaria, fever, anaphyllaxis 
  16. 16. Contradications Bleeding disorders  Severe hypertension  Ocular and neurosurgery  Chronic alcoholics  Aspirin and other antiplatelet drugs 
  17. 17. Low-molecular-weight heparins (LMWHs)  LMWHs, in contrast, consist of only short chains of polysaccharide. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin.
  18. 18. LMWHs have a potency for factor Xa activity and for anti-thrombin activity (ATIII).  More specific in action  Less effects on platelets  Less hemorrhagic complications.  Good p’kinetic profile  BA improves.  Longer T1/2  Dose is given in mg and not in unit  LAB MONITORING NOT NEEDED. 
  19. 19. Uses Pulmonary embolism  Deep vein thrombosis  Surgeries   Eg Nadoparin, Enoxaparin, Dalteparin, Raviparin etc.
  20. 20. Fondaparinux It is a synthetic pentasacchride. It is an antithrombin III mediated selective inhibition of factor Xa. Which further inhibits thrombin formation.  Administered s.c daily.  Dose: 2.5 mg  BA: 100%  T1/2: 17-21 hrs  Excreted unchanged in urine  Lesser antiplatlet action chances of thrombocytopenia is less. 
  21. 21. Oral anticoagulants Bishydroxycoumarin was made in 1941 Warfarin was used as anti-cogulant In vivo only. They act by interfering with synthesis of vit K dependent clotting factors.  They behave as competitive inhibitors of vit K. They interfere with regeneration of active form of vitamin K, which is essential for carboxylation of clotting factors- VII, IX, X.  Vitamin K is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate residues.  Caroboxylation enhances binding of clotting factors to Ca2+ leading to coagulation.   
  22. 22. Descarboxy factor:VII,IX,X Carboxylated factor:VII,IX,X Reduced Vitamin K Oxidised Vitamin K Warfarin NADH NAD
  23. 23. Synthesis of clotting factors diminishes within 2-4 hrs of warferin administration the anticoagulant effects develops gradually over next 1-3 days.  Therapeutic effect occurs when synthesis of clotting factors is reduced by 40-50%.       Pharmacokinetics: Racemic warferin sodium: the most popular oral anticoagulant. R+S, S is more potent, metabolized by oxidation. Completely absorbed from stomach. 99% is plasma bound. It crosses placenta and secreted in milk.
  24. 24. Bishydroxycoumarin (Dicoumarol) Absorbed orally  Metabolism is dose dependent  T1/2 is prolonged at higher doses  Has poor GI tolerance  Available as 50 mg tab 
  25. 25. Acenocoumarol T1/2 of 8 hrs. produces an active metabolite.  T1/2: 24 hrs.  Acts rapidly 
  26. 26. Adverse effects           Bleeding Epistaxis Hematuria Bleeding in GIT Internal hemorrhage Treatment: Stop anticoagulant Blood transfusion Plasma replenishment Vit K1 administration
  27. 27. Factors enhancing effect of oral anticoagulants Malnutrition  Prolonged antibiotic use  Liver disease : low synthesis of CF  Newborns: low CF  Hyperthyroidism: Fast degradation of CF 
  28. 28. Factors decreasing the effect of oral anticogulants Pregnancy  Nephrotic syndrome: drug bound to plasma protein is lost in urine. 
  29. 29. Contraindications Pregnancy: skeletal abnormalities, foetal warfarin syndrome– hypoplasia of nose, eye socket, hand bones and growth retardation.  If given in later stage of pregnancy, it can cause CNS defects, foetal death. 
  30. 30. Drug interactions Enhanced anticoagulant action 1. Braod spectrum antibiotics 2. Newer cephalosporins eg moxalactam, cefamandole, produces hypoprothrombinemia by the same mech. as warfarin. 3. Aspirin: inhibits platelet aggregation, also displaces warfarin from PBS. 4. Phenylbutazone: Decreases PB of warfarin 
  31. 31. 5. 6. 7. 8. 9. Long acting sulfonamides, indomethacin, phenytoin, probenicids: competitor for protein binding Chloramphinicol, erthromycin, cimetidine, allopurinol, amidarone, metronidazole: inhibits warferin metabolism Tolbutamide and phenytoin: inhibits warferin metabolism Phenformin, anabolic steroids, quinidine, clofiberate, potentiate warferin action Liq paraffin: reduces vit K absorption.
  32. 32. Reduced anticoagulant action 1. 2. Barbiturates and other hypnotics (not BZD), rifampin, grisofulvin induce metabolism of oral anticoagulant Oral contraceptives increases level of clotting factors.
  33. 33. Uses Deep vein thrombosis and pulmonary embolism: venous thrombi are fibrin thrombi- 3 month therapy  Post stroke required prophyllaxis.  Myocardial infarction: arterial thrombi are platelet thrombi. Not very beneficial. Aspirin+heparin followed by warfarin.  Rheumatic heart disease, auricular flutter: Warfarin/ low dose heparin/ low does aspirin 
  34. 34. Cerebrovascular disease: little value  Preferred in ischaemic attacks due to emboli.  Vascular surgery, prosthetic heart valves, retinal vessel thrombosis: anticoagulants are given along with antiplatelet drugs for prevention of thromboembolism. 
  35. 35. Fibrinolytics These drugs are used to lyse the clot.  Curative  Fibrin is formed  Fibrinolytic system get activated  t-PA activates Plasminogen---Plasmin is the serine protease which digest fibrin  Plasminogen is present in bound (fibrin) and free form. 
  36. 36. Fibrinolysis
  37. 37. Fibrinolytics Strptokinase  Urokinase  Altelase 
  38. 38. Streptokinase Obtained from Streptococci C  Activates plasminogen  T1/2: 30-80 m  Antigenic  less expensive 
  39. 39. Urokinase Isolated from human urine  Prepared from human kidney cells  Activates plasminogen directly  T1/2: 10-15 m  Side effects: Less allergic  fever 
  40. 40. Alteplase Produced by recombinant DNA tech.  Activates plasminogen bound to fibrin.  T1/2: 4-8 m  Expensive 
  41. 41. Uses Acute MI  Therapy to be initiated 12 h of symptoms  Can be given IV  Heparin or aspirin is started thereoff  Deep vein thrombosis  Pulmonary embolism  Peripheral arterial occlusion  To be treated with in 72 hrs advised if throbectomy is not possible 
  42. 42. Antiplatelet drugs
  43. 43. COX inhibitor: Aspirin
  44. 44. Aspirin is indicated as prophylaxis against transient ischemic attacks, myocardial infarction and thromboembolic disorders. It is also used for the treatment of acute coronary syndromes and in the prevention of reoclusion in coronary revascularization procedures.  Dose: 75 mg to 325 mg 
  45. 45. Ticlopidine is the oldest thienopyridine currently available. It is approved for secondary prevention of thrombotic strokes in patients intolerant of aspirin and for prevention of stent thrombosis in combination with aspirin.  Clopidogrel is approved for prevention of atherosclerotic events following recent myocardial infarction, stroke or established peripheral arterial disease. It has a better safety profile than ticlopidine. 
  46. 46. Phosphodiesterase inhibitors Dipyridamole acts as vasodilator and antiplatelet agent. It blocks phosphodiesterase in platelet leading to increase in cAMP in platelet. Adenosine decreases platelet aggregability. It is used in combination with aspirin or warfarin in the prophylaxis of thromboembolic disorders.
  47. 47. GPIIb/IIIa inhibitors
  48. 48. Platelet membrane GPIIb-IIIa receptors constitute the final common pathway of platelet aggregation, the integrin GPIIb/IIIa antagonists prevent crosslinking of platelets. Abciximab is a human-murine monoclonal antibody directed against GPIIb/IIIa,
  49. 49. UESES CAD: MI  Coronary bypass implant  Prosthetic heart valves  Venous thrombosis  Peripheral vascular disease 