Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

38

664 views

Published on

Blood

Published in: Health & Medicine, Technology
  • anemia classification
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

38

  1. 1. Drugs Used in Disorders of blood
  2. 2. Objectives: • To understand the process of clotting. • To describe three major classes of anticlotting drugs. • To describes three different drugs used to treat disorders of excessive bleeding.
  3. 3. ANTICOAGULATION – COAGULATION BALANCE FLUID AT-III Proteins C,S CLOT Thrombin Fibrinogin
  4. 4. Normal Hemostasis When a small blood vessels is injured, hemorrhage is prevented by: • Vasospasm (reduces blood flow and facilitates platelet aggregation and coagulation). • The formation of platelet plug (platelet aggregation) to arrest bleeding. • The formation of a fibrin clot (exposure of the blood to tissue factors) to arrest bleeding until the vessel is repaired. • Fibrinolysis (the removal of the clot) after the vessel is repaired.
  5. 5. Pathological Thrombus Formation • A clot that adheres to a vessel wall = thrombus • A clot that floats within the blood = embolus • Both thrombi and emboli are dangerous because they may occlude blood vessels and deprive tissues of oxygen and nutrients • Anticoagulants are drugs that retard coagulation and thereby prevent the occurrence of a thrombus.
  6. 6. 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)
  7. 7. Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Tissue Factor XIIa XII Thromboplastin XIa XI IXa IX Xa X Factors affected By Heparin VIIa Prothrombin Vit. K dependent Factors Affected by Oral Anticoagulants Fibrinogen XIII VII X Thrombin Fribrin monomer Fibrin polymer
  8. 8. Classes Of Drugs Used in the Treatment of Clotting Disorders Drugs used in clotting disorders To reduce clotting (anticlotting drugs) Thrombolytics Antithrombin III To facilitate clotting Anticoagulants Leech proteins (lepirudin) Oral anticoagulants (warfarin) Antiplatelet drugs Heparin Phosphodiestrase inhibitors Glycoprotein IIb/IIIa receptor antagonists Replacement factors (VII, IX, etc. ADP receptor antagonists Plasminogen inhibitors Cyclooxygenase inhibitors (aspirin)
  9. 9. 1. Anticoagulant Drugs • Reduce the formation of fibrin clots. • Oral anticoagulant drugs : Coumarin anticoagulants (warfarin - dicumarol) • Parenteral anticoagulant drugs: Heparin - Hirudin)
  10. 10. A. Oral anticoagulants (Coumarin anticoagulants) • Chemistry and mechanisms: – They are structurally related to vitamin k – These drug inhibit the synthesis of clotting factors II (prothrombin), VII, IX, and X. – Warfarin blocks the reduction of oxidized vitamin K and thereby prevents the posttranscriptional carboxylation of the above four factors.
  11. 11. Action of Coumarins Oral anticoagulants – 4-hydroxycoumarins Vitamin K Coumarins act here Coumarins act here Coumarins are competitive inhibitors
  12. 12. Pharmcokinetic and Pharmacological Effects (coumarin) • Extensively metabolized, highly bound to plasma proteins • Cross the placenta, may cause fetal hemorrhage and malformations. Pregnant women with thrombosis should be treated with standard or low molecular weight heparin. • The onset of action is 3-5 days (time required to deplete the pool of circulating clotting factors).
  13. 13. Adverse Effects of Coumarins • Bleeding – Minor bleeding: withdrawal of the drug and administer vitamin K1. – Severe bleeding: fresh frozen plasma or factor IX concentrate • Cross the placenta: Teratogenic ( damaging to the developing fetus ) • must not be given to pregnant women.
  14. 14. Drug Interactions • Aspirin and Phenylbutazone (displace warfarin from albumin, inhibit of platelet aggregation). • Antibiotics (decrease microbial vit. K production in the intestine, inhibition of metabolism of warfarin). • Barbiturates and rifampin (decrease warfarin effectiveness by inducing microsomal P450 system. • Oral contraceptives (decrease warfarin effectiveness by increasing plasma clotting factors and decreasing antithrombin III.
  15. 15. Therapeutic uses of Coumarins • Long-term management of patients with deep vein thrombosis or atrial fibrillation or artificial heart valve. • In conjunction with heparin for the treatment of MI.
  16. 16. 2. Parenteral Anticoagulants A. Heparin • Chemistry and Mechanisms: It is a polymeric mixture of sulfated mucopolysaccharides. • It is highly negatively charged at physiological pH. Can be neutralized by basic molecules such as protamine. • Heparin is synthesized as a normal product of many tissues including the lung, intestine, and the liver. Commercial preparations are derived from bovine lung or porcine intestinal extracts (average
  17. 17. Heparin - Structure Average molecular wt of 12,000 daltons (40 glucose units) with the following structure:
  18. 18. Heparin binds to antithrombin III (ATIII) and enhances its proteolytic activity Active clotting factors (IIa, IXa, Xa, XIa, XIIa, XIIIa Slow AT III Inactive factors A. No Heparin Active clotting factors (IIa, IXa, Xa, XIa, XIIa, XIIIa Rapid (1000x) AT III + heparin Inactive factors B. With Heparin
  19. 19. Heparin mechanism of action Heparin Antithrombin III Thrombin
  20. 20. Mechanism of action of Heparin • Heparin binds to antithrombin III and enhances its proteolytic activity by 1000fold. • Heparin has a direct anticoagulant activity (can inhibit clotting in vitro). • Heparin releases lipoprotein lipase from vascular beds, which accelerate clearing of lipoproteins from the plasma.
  21. 21. Pharmacokinetic and Pharmacological Effects (Heparin) • Heparin must be given parenterally by slow infusion or deep subcutaneous injection. It is not injected IM due to the potential of hematoma • Heparin is metabolized in the liver by heparinase to smaller molecular-weight compounds, which are excreted in the urine.
  22. 22. Adverse Effects of Heparin • Bleeding – Minor bleeding: drug withdrawal – Severe bleeding: Protamine sulfate (a highly positively charged mixture of peptides) • Thrombocytopenia (25% of patients). Oral anticoagulant should be used. • Hypersensitivity reactions (chills, fever, urticaria, anaphylaxis). Obtained from animal sources (antigenic) • Reversible alopecia • Osteoporosis
  23. 23. Therapeutic uses of Heparin • Preoperative prophylaxis against deep vein thrombosis. • Heparin is administered following MI or pulmonary embolism. • Heparin prevents clotting in arterial and heart surgery, during blood transfusion, and in renal dialysis and blood sample collection.
  24. 24. Contraindications and Drug Interactions with Heparin • Heparin is contraindicated in patients who are bleeding, patients with hemophilia, thrombocytopenia and hypertension. • Heparin is contraindicated before and after brain, spinal cord or eye surgery. • Heparin should not be administered with aspirin or other drugs that interfere with platelet aggregation. • Positively charged drugs and aminoglycosides can reduce the effectiveness of heparin therapy.
  25. 25. B. Hirudin and Related Drugs • Hirudin is a natural anticoagulant obtained from Hirudo medicinalis, the medicinal leech. • It is a direct inhibitor of thrombin. • These drugs are undergoing clinical trials for the treatment of unstable angina and acute MI.
  26. 26. 3. Antiplatelet Drugs • Platelet aggregation plays a central role in the clotting process (esp.. clots that form in the arterial circulation). • Platelet aggregation is facilitated by thromoboxane, ADP, fibrin and serotonin. Platelet aggregation is inhibited by prostacyclin and increased cAMP • Antiplatelet drugs are agents that decrease platelet adhesiveness induced by collagen. • They are useful in preventing arterial thrombi since they are of platelet origin.
  27. 27. Platelet aggregation and sites of drug action Vascular Endothelium vWF Collagen GP Ia GP Ib Platelet Abciximab Binds GP IIb/IIIa GP IIb/IIIa GP GP Granules Aspirin Inhibits Synthesis . . ... ... .. … .. .. …… TXA2 . … … … … ADP Ticlopidine 5-HT Inhibits Fibrinogen Effects ⊕
  28. 28. A. Aspirin • Mechanisms and Pharmacological effects – Aspirin and most other NSAIDs inhibit the synthesis of prostaglandins: • Decrease endothelial synthesis of PGI2 (prostacyclin) • Decrease thromoboxane A2 production in platelets by inhibiting cyclooxygenase type I and type 2. • Irreversible inhibition of cyclooxygenase and platelet aggregation for the life of the platelet. • It may cause bleeding, especially in the GI, and hypoprothrombinemic effect (high doses)
  29. 29. Therapeutic uses of Aspirin • Prophylactic for transient cerebral ischemia • Reduce the incidence of recurrent MI • Decrease mortality in postmyocardial infarction patients.
  30. 30. B. Ticlopidine • Mechanisms and Pharmacological effects: – It inhibits adenosine diphosphate (ADP)-induced expression of platelet glycoprotein receptors and reduces fibrinogen binding and platelet aggregation. – It can be used in patients who are unresponsive to aspirin to prevent thrombotic stroke. – After oral ingestion, it is extensively bound to plasma proteins and undergoes hepatic metabolism. – Can cause mild to severe neutropenia (frequent complete blood count is advisable).
  31. 31.  Dipyridamole (PERSANTINE) –  *inhibits platelets adhesion to damaged blood vessels  *may increase the antiaggregating effect of prostacycline  *↑ dosage ⇒ increase in platelets c-AMP formation and ↓ platelet Ca which inhibits platelets aggregation  pt. with intolerant to aspirin
  32. 32. C. Abciximab • It is Fab fragment of a chimeric human-murine monoclonal antibody. • It is used solely for the prevention of thrombosis in patients undergoing coronary angioplasty. • It binds to platelet glycoprotein IIb/IIIa receptors and prevents binding by fibrinogen.
  33. 33. C. Fibrinolytic Drugs • Recently formed thrombus is easily lysed by these drugs. • Aged thrombi (72 hrs) are usually resistant. • They are primarily used to dissolve clots in patients undergoing MI, thromotic stroke or pulmonary embolism.
  34. 34. Fibrinolysis and sites of drug action Plasminogen Aminocaproic acid  ⊕ Fibrin Streptokinase Urokinase Alteplase (Tissue plasminogen Activator) Fibrinogen Plasmin Fibrin split products Degradation products
  35. 35. Fibrinolytic Drugs • Chemistry and Mechanisms: – Altephase: recombinant forms of human tissue plasminogen activator (t-PA). – Urokinase: a protein obtained from human urine. – Streptokinase: a protein obtained from streptococci. – Anistreplase: a performed complex of streptokinase and plasminogen.
  36. 36. Mechanisms of action • Urokinase and the recombinant forms of tPA (altepase) directly convert plasminogen to plasmin. • Streptokinase must combine with plasminogen first to form an activator complex that convert the inactive plasminogen to plasmin. • Anistreplase (anisoylated plasminogen streptokinase activator complex, APSAC).
  37. 37. Adverse effects • Bleeding: Fibrinolytic drugs may lyse both normal and pathologic thrombi. Less effect is seen with t-PA (selectively activates plasminogen that is bound to fibrin) than streptokinase. Bleeding can be controlled by Aminocaproic acid (inhibits plasminogen activation) • Hypersensitivity reaction: streptokinase • Arrhythmias (bradycardia,tachycardia): Free radicals generated after fibrinolysis.
  38. 38. Hematopoietic Drugs • Hematopoiesis: – Mature blood cells is formed in the bone marrow, removed from circulation by RE cells in the liver and spleen. This process is called hematopoiesis. – This process requires minerals, vitamins and regulated by hematopoietic growth factors.
  39. 39. Hematopoietic Drugs • Anemia: – It is a subnormal concentration of RBC’s or hemoglobin in the blood. – Can be caused by chronic blood loss, bone marrow abnormalities, increased hemolysis, infections, malignancy. – Drugs can cause toxic effects on blood cells. – Nutritional anemias are caused by dietary deficiencies of iron, folic acid and vitamin B12
  40. 40. Iron Metabolism Ingested Fe Myoglobin and enzymes Plasma (transferrin) Ferritin stores 120 days Bone marrow Erythrocytes (hemoglobin) Reticuloendothelial cells
  41. 41. Iron Preparations • They are used to prevent and treat iron deficiency anemia. – Ferrous sulfate and related compounds: • They administered orally • A typical daily dose is 100-200 mg iron/day (only 25% of orally administered iron is absorbed) • May require 3-6 months to replenish body stores. – Iron dextran: – In patients who are intolerant of or unresponsive to oral therapy. – May cause anaphylactic reactions.
  42. 42. Vitamins • Folic acid or vitamin B12 deficiency may cause megaloblastic anemia. • Both are cofactors in many enzymatic reactions involving the addition of singlecarbon units.
  43. 43. 1. Folic acid • Folic acid deficiency may be caused by: – Dietary deficiency during pregnancy and lactation – Poor absorption caused by pathology of the small intestine – Alcoholism • Folic acid deficiency may lead to megaloblastic anemia. It is important to evaluate the basis of megaloblastic anemia prior to instituting therapy because vitamin B12 deficiency can cause symptoms of the same disorder. In this case, folic acid therapy will not correct the neurologic damage associated with B12 deficiency.
  44. 44. VITAMIN B12 • • • • Used to treat pernicious anemia. Common B12 preparations include: Cyanocobalamin Hydroxocobalamin
  45. 45. VITAMIN B12 • Pharmacokinetics: • Administered orally or parenterally. • When a person has a deficiency of intrinsic factor, which is secreted by the gastric mucosa and is needed for vitamin B12 absorption, vitamin B12 deficiency pernicious anemia develops. • These people require vitamin B12 injections.
  46. 46. VITAMIN B12 • Stored in the liver; excreted in the urine. • Pharmacodynamics: • Essential for cell growth and replication and for the maintenance of myelin throughout the nervous system.
  47. 47. VITAMIN B12 • Pharmacotherapeutics: • Used to treat pernicious anemia, which is a megaloblastic anemia characterized by decreased gastric production of hydrochloric acid and the deficiency of the intrinsic factor (normally secreted by the parietal cells of the gastric mucosa and is essential for vitamin B12 absorption).
  48. 48. VITAMIN B12 • Drug interactions: • Alcohol may decrease the absorption of oral cyanocobalamin. • Adverse reactions: • No dose-related adverse reactions.
  49. 49. IV. Hematopoietic Growth Factors • Endogenous growth factors: – Colony-stimulating factors (CSF) and erythropoietin are glycoproteins that stimulate the differentiation and maturation of bone marrow progenitor cells. • Growth factor preparations: – Epoetin alfa – Filgrastim and sargramostin
  50. 50. Growth factor preparations • Epoetin alfa: – It is a form of erythropoietin produced by recombinant DNA technology. Natural erythropoietin is secreted by the kidneys to stimulate erythroid cell differentiation and proliferation. – It is used in the treatment of anemia that is due to inadequate erythropoiesis (patients with chronic renal failure, chemotherapyinduce anemia in cancer patients, AZTinduced anemia in HIV infected patients).
  51. 51. Growth factor preparations • Filgrastim and sargramostin: – Filgrastim is recombinant human granulocyte colony stimulating factor (G-CSF), Sargramostin is recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). – Both are primarily used to treat neutropenia associated with cancer chemotherapy and bone marrow transplantation (to accelerate granulocyte and myeloid cell recovery following chemotherapy or bone marrow transplantation). – Both can be administered IV or subQ until the neutrophil count has reached 10,000/µL.

×