Pharmacology II - Chapter 3 Haematological Agents PDF

FFG2414 Pharmacology II Chapter 3 Haematological Agents Learning outcome After completing this lesson, the students should be able to:  Composition and the formation of blood cells  Name the types of anemia  Describe the drugs & hematopoietic growth factors used in anemia  Defin...

FFG2414 Pharmacology II Chapter 3 Haematological Agents Learning outcome After completing this lesson, the students should be able to:  Composition and the formation of blood cells  Name the types of anemia  Describe the drugs & hematopoietic growth factors used in anemia  Define bleeding and coagulation  List out the drugs used for treatment of coagulation and bleeding disorders Structure of the lesson 1. Composition of blood 2. Drugs and hematopoietic growth factors used in anaemia: a. Replacement of the missing substance b. Recombinant hematopoietic growth factors 3. Bleeding and coagulation 4. Drugs used in Blood Coagulation Disorders a. Anticlotting drugs i. Anticoagulants ii. Antiplatelet agents iii. Thrombolytics b. Drugs that facilitate clotting i. Replacement factors ii. Vitamin K iii. Anti-plasmin Drugs 1 2 June 2024  FFG2414 Pharmacology II 1. Composition of blood  Blood is composed of a straw-coloured transparent fluid, plasma, in which different types of cells are suspended.  Plasma constitutes about 55% and cells about 45% of blood volume.  The constituents of plasma are water (90 to 92%) and dissolved substances, including plasma proteins, inorganic salts, nutrients, waste materials, hormones and gases.  The cellular content of blood consists of erythrocytes, leukocytes and platelets. Formation of blood cells  All blood cells originate from pluripotent stem cells and go through several developmental stages before entering the blood  The process of blood cell formation is called haemopoiesis and takes place within red bone marrow. 2 2 June 2024  FFG2414 Pharmacology II  Mature blood cells are continuously formed in the bone marrow and are removed from the circulation by macrophages in the liver and spleen.  The process by which blood cells are replaced is called hematopoiesis.  This process requires minerals and vitamins and is regulated by hematopoietic growth factors that promote the differentiation and maturation of marrow stem cells to form erythrocytes, leukocytes, and platelets. Life cycle of blood cells  The average life cycle of a human RBC is approximately 120 days. 3 2 June 2024  FFG2414 Pharmacology II  Generally, by this point, the cell is worn out and damaged.  Red blood cells pass through both the spleen and liver, where specialised immune cells called macrophages are found.  Macrophages recognise when a red blood cell spent, and undergo a process called phagocytosis where they digest the cell.  In this process, the iron in haemoglobin is recycled for use in new blood cells and the heme molecule is degraded, conjugated to bilirubin, and eliminated from the body. 4 2 June 2024  FFG2414 Pharmacology II  All the other cellular proteins are either recycled or eliminated. 2. Drugs and hematopoietic growth factors used in anaemia: Anaemia  Anemia, a subnormal concentration of erythrocytes or hemoglobin in the blood, can result from inadequate erythropoiesis, blood loss, or accelerated hemolysis.  Erythropoiesis can be impaired by the lack of essential nutrients or by the myelosuppressive effects of certain drugs or irradiation.  Infection, cancer, endocrine deficiencies, and chronic inflammation can also cause anemia.  This results in a reduced ability of blood to transfer oxygen to the tissues, causing tissue hypoxia. 5 2 June 2024  FFG2414 Pharmacology II Types of Anemia i. Microcytic hypochromic anaemia - anemia due to iron deficiency ii. Megaloblastic anaemia - anemia due to vitamin B12 and folic acid dietary deficiency iii. Pernicious anaemia - anaemia due to the lack of intrinsic factor in the stomach which leads to poor absorption of vitamin B12, causing pernicious anaemia. iv. Hemolytic anaemia - anemia due to red blood cell destruction faster than the body can replace them 6 2 June 2024  FFG2414 Pharmacology II Drugs used in anemia and haematopoietic growth factors Pharmacological treatment of these types of anemia involves two rationales: a. Replacement of the missing substance i. Iron  Iron is the essential metallic component of ‘haem’ (the molecule responsible for O2 transport in blood).  Deficiency of iron occurs most often in women (because of menstrual blood loss), vegetarians or malnourished individuals because of inadequate dietary iron intake.  Children and women have increased requirement for iron.  Deficiency of iron causes microcytic hypochromic anemia.  The disease is treated by dietary (oral) ferrous iron supplementation and, in special cases, parenteral administration.  Iron deficiency anemia is the only indication for the use of iron. ii. Vitamin B12  Vitamin B12, a cobalt containing molecule is essential for DNA synthesis.  Deficiency of vitamin B12 results in megaloblastic anemia and pernicious anemia.  Vitamin B12 is available as hydroxycobalamin and cyanocobalamin.  Used in the treatment of megaloblastic anemia and pernicious anemia. 7 2 June 2024  FFG2414 Pharmacology II iii. Folic acid (Vitamin B9) [as folates]  Like vitamin B12, folic acid is required for normal DNA syntheses and its deficiency usually presents as megaloblastic anemia.  Folic acid deficiency is more often caused by dietary insufficiency or malabsorption.  Anemia resulting from folic acid deficiency is treated by oral folic acid supplementation.  Folic acid has no recognized toxicity. b. Administration of recombinant hematopoietic growth factors (Which stimulate the production of blood cells)  Hematopoietic growth factors are endogenous glycoproteins that stimulate the differentiation and maturation of bone marrow progenitor cells.  The growth factors bind to receptors on specific myeloid progenitor cells and thereby induce their differentiation and proliferation. i. Erythropoietin  Erythropoietin is produced by kidneys.  Renal failure causes the reduction in the synthesis of erythropoietin.  Erythropoietin is routinely used for the anemia associated with renal failure.  Through the activation of specific receptors in the bone morrow, erythropoietin stimulates the growth and release of red blood cells from the bone marrow. ii. Myeloid Growth Factors  Myeloid growth factors stimulate the production and function of neutrophils.  It is used to accelerate the recovery of neutrophils after cancer chemotherapy and to treat other forms of neutropenia. iii. Megakaryocyte Growth Factors  Megakaryocyte Growth Factors increase the number of platelets.  Example: Interleukin-11 (IL-11). It is used for the treatment of thrombocytopenia. 8 2 June 2024  FFG2414 Pharmacology II 3. Bleeding and Coagulation  Coagulation of blood is a complex process during which blood forms solid clots.  Bleeding is the loss of blood from the body. Hemorrhage is the medical term for bleeding.  When a small blood vessel is injured, hemorrhage is prevented by vasospasm, the formation of a platelet plug and a fibrin clot.  After the vessel is repaired, the clot is removed via the process of fibrinolysis.  Vasospasm reduces bleeding and blood flow and thereby facilitates platelet adhesion and coagulation.  Exposure of the blood to extravascular collagen causes adherence of platelets to the injured vessel wall and initiates the sequential activation of numerous coagulation factors (also known as blood clotting factors). 9 2 June 2024  FFG2414 Pharmacology II  The activation of Factor X leads to the formation of thrombin, which in turn, catalyzes the conversion of fibrinogen to fibrin.  The fibrin meshwork traps erythrocytes and platelets to complete the formation of a hemostatic thrombus (blot).  It is an important part of hemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a fibrin clot to stop hemorrhage and aid repair of the damaged vessel. Link Coagulation Cascade Explained. Available at: https://youtu.be/DKFSH5MMPLM (Accessed: 25/1/2024). 4. Drugs used in blood coagulation disorders  The drugs used in clotting and bleeding disorders fall into 2 primary groups: - Anti-clotting drugs are drugs used to decrease clotting or dissolve clots already present. - Drugs that facilitate clotting are drugs used to increase clotting (in patients with clotting deficiencies). a. Anti-clotting Drugs  Anti-clotting drugs are used in the treatment of - Myocardial infarction - Atrial fibrillation - Ischemic stroke - Deep vein thrombosis (DVT) 10 2 June 2024  FFG2414 Pharmacology II i. Anticoagulants  Anticoagulants reduce the formation of fibrin clots  Three major types are available - Heparin and related products – which must be used parenterally - Coumarin anticoagulants (warfarin) – orally active - Direct thrombin inhibitors - which must be used parenterally ii. Antiplatelet drugs  Platelet aggregation plays a vital role in the clotting process and is especially important in clots that form in the arterial circulation - COX inhibitors – Aspirin and other NSAIDs - ADP antagonists – Ticlopidine, Clopidogrel - Glycoprotein IIb/IIIa inhibitors – abciximab, tirofiban, eptifibatide - PDE/adenosine uptake inhibitors – Dipyridamole, cilostazol iii. Thrombolytic Drugs  The thrombolytic drugs currently available are - streptokinase, urokinase - tissue-plasminogen (t-PA) activator - alteplase, tenecteplase, reteplase  All are given intravenously 11 2 June 2024  FFG2414 Pharmacology II b. Drugs that facilitate clotting  There are occasions when an agent is required to decrease the incidence or severity of hemorrhage.  Inadequate blood clotting may result from - Vitamin K deficiency, - Genetically determined errors (Hemophilia) - Drug induced conditions - Thrombocytopenia i. Replacement Factors  The most important agents used are fresh plasma and purified human blood clotting factors, especially factor VII and factor IX (either purified from blood or produced by recombinant DNA technology). ii. Vitamin K  Deficiency of Vitamin K is treated with oral or parenteral vitamin K supplements using phytonadione (K1).  It is used in bleeding disorders  Vitamin K1 and protamine sulfate are used as specific antidotes for anticoagulant overdose such as heparin overdose. 12 2 June 2024  FFG2414 Pharmacology II iii. Antiplasmin Drugs  Antiplasmin agents are valuable for the management of acute bleeding episodes in hemophiliacs and other bleeding disorders.  Examples: tranexamic acid and aminocaproic acid. References  Rang H.P., Dale MM, Ritter JM, Moore PK, (2003).Pharmacology (5th ed). Churchill Livingstone  Tripathi KD, Essentials of Medical Pharmacology, 2004 (5th ed) Jaypee.  Kaye M., Favaro, A. (2005). Introduction to Pharmacology (10th ed).  WB Saunders. Holland LN, Adams MP. Core concepts in Pharmacology.2003, Prentice Hall. 13 2 June 2024  FFG2414 Pharmacology II Tutorial 1 __________ means the cessation of blood loss from a damaged blood vessel. A Haemostasis B Haemorrhage C Homeostasis D Heterogenous 2 __________ is used for anaemia associated with renal failure. A Diuretic B Vitamin B12 C Folic acid D Erythropoietin 3 __________ prevents platelet aggregation. A haematopoietic drugs B antiplatelet drugs C thrombolytics D antiplasmin drugs 4 The deficiency of the following results anaemia, EXCEPT: A iron B calcium C vitamin B12 D folic acid 5 Blood is composed of __________. A plasma B erythrocytes C leukocytes D platelets A I, II, III B I, III, IV C II, III, IV D I, II, III, IV 6 The deficiency of erythrocytes may cause __________. A hemolysis B leukemia C hypoxia D ischemia 14 2 June 2024  FFG2414 Pharmacology II 7 Folic acid is required in the treatment of __________. A pernicious anemia B microcytic hypochromic anemia C neutropenia D thrombocytopenia 8 Drugs used to increase clotting are known as __________. A drugs that facilitate clotting B anticoagulants C antiplatelet drugs D thrombolytics 9 Which of the following is a thrombolytic drug? A Streptokinase B Aspirin C Warfarin D Vitamin K 10 Heparin is a/an __________. A drug that facilitate clotting B anticoagulant C antiplatelet D thrombolytic 11 Erythropoeitin is produced in the __________. A liver B kidneys C lungs D pancreas 12 Select a thrombolytic drug. A Iron B Vitamin K C Streptokinase D Thyroxine 15 2 June 2024  FFG2414 Pharmacology II 13 Select the Vitamin K supplement. A Phytonadione B Oxytoxin C Folic acid D Vitamin B12 14 Anaemia is a deficiency of __________. A white blood cells B red blood cells/haemoglobin C platelets D serum 15 Anti-clotting drugs are used in the treatment of __________. A hypertension B angina C deep vein thrombosis D HPA suppression 16 __________ are used in the management of acute bleeding. A Antiplasmin drugs B Antiarrhythmic drugs C Anticoagulant drugs D Antidiabetic drugs 17 Myeloid Growth Factors are used to accelerate the recovery of __________. A erythrocytes B neutrophils C T cells D B cells 18 Select an anticoagulant. A Folic acid B Cobalamin C Heparin D Thyroxine 16 2 June 2024  FFG2414 Pharmacology II 19 Inadequate blood clotting may result from __________. I Vitamin K deficiency II Genetic condition III Thrombocytopenia IV Increased heart workload A I, II, III B I, III, IV C II, III, IV D I, II, III, IV 20 Which of the following is INCORRECT regarding erythropoietin? A Erythropoietin is produced by the red blood cells (RBCs) B Reduction in synthesis of erythropoietin causes anaemia in renal failure C Erythropoietin is used to stimulate growth of RBCs from bone marrow D Erythropoietin is used to stimulate the release of RBCs 21 Which of the following is INCORRECT regarding myeloid growth factors? A Myeloid growth factors stimulate the production of neutrophils B They are used to treat neutropenia C They are used to accelerate the recovery of neutrophils after cancer treatment D They stimulate the production of megakaryoblasts from stem cells 22 The following are TRUE about anticoagulants, EXCEPT__________. A warfarin is a coumarin derivative B heparin can be used orally C direct thrombin inhibitors must be used parenterally D the formation of fibrin clots 28 __________ may be used in inadequate blood clotting. A Vitamin K1 B Streptokinase C Aspirin D Testosterone 17 2 June 2024  FFG2414 Pharmacology II 29 Match the components of column A with components in column B. Column A Column B a. Adenosine uptake inhibitors 1 Abciximab b. Glycoprotein IIb / IIIa inhibitors 2 Aspirin c. COX inhibitors 3 Clopidogrel d. ADP antagonists 4 Cilostazol A a 2; b 4; c3; d 1 B a 4; b3; c2; d 1 C a4; b 1; c2; d 3 D a 2; b 4; c1; d 3 30 Based on the two statements below select the correct choice of answers. 1) Alteplase is a thrombolytic drug. 2) Alteplase must be administered intravenously. A Statement 1) is TRUE, and statement 2) is FALSE B Statement 1) is FALSE, and statement 2) is TRUE C Both statements 1) and 2) are TRUE D Both statements 1) and 2) are FALSE 31 Which of the following are causes of inadequate blood clotting? I Thrombocytopenia II Genetic disorder (haemophilia) III Vitamin K deficiency IV Drug side effects A I and II only B II and III only C I, II and III only D I, II, III and IV 25 Haemopoiesis takes place in __________. A bone marrow B plasma C kidneys D blood 26 Oxygen is carried by the __________. A leukocytes B bilirubin C heme group D plasma 27 Cobalamin is used in the treatment of __________. 18 2 June 2024  FFG2414 Pharmacology II A pernicious anemia B megaloblastic anemia C neutropenia D thrombocytopenia 28 __________ stimualtes the growth and release of red blood cells from the bone marrow. A Erythropoietin B Cortisol C Nifedipine D Testosterone 29 The following are anti-clotting drugs, EXCEPT: A aspirin B phytonadione C warfarin D streptokinase 30 Select the CORRECT sequence of blood coagulation. I Bleeding II Formation of thrombus III Formation of Fibrin IV Activation of Factor X V Formation of Thrombin VI Vasospasm A I, II, III, IV, V, VI B I, VI, IV, V, III, II C I, IV, VI, II, III, V D I, V, IV, II, III, VI 31 The following are anti-clotting drugs, EXCEPT: A anticoagulants B antianemics C antiplatelets D thrombolytics B. Short Essay Questions 1 Explain the process of blood cell formation. (Starting from stem cells located in the bone marrow, show by a neat diagram or explain how each type of cellular component of blood is obtained) 19 2 June 2024  FFG2414 Pharmacology II 2 Briefly explain blood coagulation. 3 Define haemostasis. 4 Define haemorrhage. 5 Define anaemia. 6 List types of anaemia. 7 Classify anaemic and haematopoietic drugs in a table. 8 Classify drugs that used in the coagulation disorders in a table. 20 2 June 2024