6. Drugs for Anemia.pptx

Drugs acting on blood and blood forming clots

1. Drugs acting on the blood and blood forming organs

2. Introduction Hematopoiesis is the process of production of erythrocytes, platelets and leukocytes from undifferentiated stem cells . produces over 200 billion new blood cells per day in the normal person and even greater numbers of cells in people with conditions that cause loss or destruction of blood cells Haemopoietic system consists of blood, bone marrow, lymph nodes and thymus, with the spleen, liver and kidneys as important accessory organs.

3. Hematopoiesis …. The hematopoietic machinery requires a constant supply of three essential nutrients - iron, vitamin B 12 and folic acid - as well as the presence of hematopoietic growth factors , proteins that regulate the proliferation and differentiation of hematopoietic cells. Inadequate supplies of either the essential nutrients or the growth factors result in deficiency of functional blood cells.

4. Anemia is a reduction in RBC count , hemoglobin content, or both. During anemia oxygen (O 2 ) transport capacity is decreased. It may give rise to fatigue, pallor, tachycardia, dizziness, dyspnea Types of anemia: 1. Aplastic anemia Occurs as a result of decrease in pluripotent stem cells ( bone marrow depression ), which can be caused by cancer therapy, radiation therapy or bone marrow diseases.

5. Types of anemia …. 2. Hemolytic anemia hemolysis (break down) of RBCs because of causative agents such as antimalarial toxicities, infections etc 3. Nutritional anemias Microcytic hypochromic anaemia small red cells with low haemoglobin ; caused by iron deficiency Hemoglobin synthesis is impaired . arises in iron deficiency , since Fe 2+ is a constituent of hemoglobin

6. Types of anemia …. Macrocytic hyperchromic or Megaloblastic anemia large red cells, few in number Cell multiplication is inhibited because DNA synthesis is insufficient. This occurs in deficiencies of vitamin B12 or folic acid Pernicious anemia : type of megaloblastic anemia caused by Vit B12 deficiency. Neurological abnormalities would occur

7. Erythropoiesis in bone marrow

8. AGENTS USED IN TREATMENT OF ANEMIAS 1. Iron Preparations Liver, egg york and dry fruits are dietary sources of iron. Iron is usually given orally but may be given parenterally are used to treat iron deficiency anaemia, which can be caused by: chronic blood loss (e.g. with menorrhagia , colon cancer) increased demand (e.g. in pregnancy and early infancy) inadequate dietary intake inadequate absorption (e.g. following gastrectomy ). Iron forms the nucleus of the iron- porphyrin heme ring , which together with globin chains forms hemoglobin.

9. Iron Preparations … Pharmacokinetics of Iron Absorption Iron is normally absorbed in the duodenum and proximal jejunum absorption increases in response to low iron stores or increased iron requirements Iron in heme ( e.g. from meat) can be absorbed easily Non- heme iron ( inorganic iron) need reduction to Fe 2+ for absorption Divalent metal transporter, DMT1, transports ferrous iron across the luminal membrane of the intestine Iron crosses the basolateral membrane by the transporter known as ferroportin1 .

10. Heme iron (H), Apoferritin (AF), Transferrin ( Tf ), Transferrin receptors ( TfR ), & Ferritin (F)

11. Iron Preparations … Transport bound to transferrin ( β-globulin that binds two molecules of ferrous iron) Storage sites: intestinal mucosal cells, macrophages, liver, spleen, and bone, …as ferritin Apoferritin synthesis is regulated by the levels of free iron. Low Fe level …. apoferritin synthesis is inhibited and the balance of iron binding shifts toward transferrin. High Fe levels … more apoferritin is produced to sequester more iron.

12. Iron Preparations … Elimination no mechanism for excretion of iron Small amounts are lost in the feces trace amounts are excreted in bile, urine, and sweat Therefore, regulation of iron balance must be achieved by changing intestinal absorption & storage, in response to the body's needs.

13. Iron Preparations … A. Oral iron therapy Because ferrous iron is most efficiently absorbed, only ferrous salts should be used. Ferrous sulfate, ferrous gluconate , and ferrous fumarate are all effective and inexpensive and are recommended for the treatment of most patients. Common adverse effects of oral iron therapy include nausea, gastric discomfort, abdominal cramps, constipation, diarrhea, metallic taste and black stool

14. Oral iron p roducts Preparation Tablet Size Elemental Iron per tablet Ferrous sulfate, hydrated 325 mg 65 mg (20%) Ferrous sulfate, desiccated 200 mg 65 mg (32.5%) Ferrous gluconate 325 mg 36 mg ( 11% ) Ferrous fumarate 325 mg 106 mg ( 32.6% ) 14

15. Iron Preparations … B. Parenteral iron therapy should be reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron for patients with extensive chronic blood loss who cannot be maintained with oral iron alone. includes patients with various postgastrectomy conditions, malabsorption syndromes, and advanced chronic renal disease including hemodialysis and treatment with erythropoietin. Iron dextran (IM and IV), Iron sorbitol (IM), Iron sucrose (IV), and Iron sodium gluconate (IV) are parentral preparations.

16. Iron Preparations … adverse effects: local pain and tissue staining (brown discoloration) with IM route and hypersensitivity reactions (especially with Iron dextran) manifested as flushing, bronchospasm, headache, nausea and vomiting. N.B. Iron preparations are contraindicated in case of hemolytic anemia , due to excessive accumulation of Fe.

17. Iron Preparations … Iron toxicity Acute iron toxicity occurs after ingestion of large quantities of iron salts (usually seen in young children) This can result in severe GI irritation with vomiting, haemorrhage and diarrhea, followed by circulatory collapse. Chronic iron toxicity or iron overload is virtually always caused by conditions other than ingestion of iron salts, for example chronic hemolytic anemias or repeated blood transfusions.

18. Iron Preparations … The treatment of acute and chronic iron toxicity involves the use of iron chelators , such as desferrioxamine . Desferrioxamine is not absorbed from the gut given intragastrically following acute overdose (to bind iron in the bowel lumen and prevent its absorption) as well as intramuscularly and, if necessary, intravenously. In severe poisoning, it is given by slow intravenous infusion. Desferrioxamine forms a complex with ferric iron, and, unlike unbound iron, this is excreted in the urine.

19. AGENTS USED IN TREATMENT OF ANEMIAS … 2. Vitamin B12 ( cyanocobalamine ) Liver, meat, fish and milk products are rich sources of the vitamin. Enteral absorption of vitamin B12 requires intrinsic factor, which is synthesized in from parietal cells of the stomach. The complex formed with this glycoprotein undergoes endocytosis in the ileum. A deficiency of either vit . B12 or folic acid impairs DNA synthesis Since tissues with the greatest rate of cell turnover show the most dramatic changes, the hematopoietic system is especially sensitive to deficiencies of these vitamins.

20. Vitamin B12 ….

21. Vitamin B12 …. Vitamin B12 is clinically used during Megaloblastic or Pernicious anemia (due to lack of intrinsic factor or atrophic gastritis) increased demand (infants, pregnants etc) neuronal abnormalities. Preparations Parentrals : Hydroxycobalamine and Cyanocobalamine . Hydroxocobalamin is preferred because it is more highly protein-bound and therefore remains longer in the circulation. Oral tablets: Methyl cobalamine .

22. AGENTS USED IN TREATMENT OF ANEMIAS … 3. Folic Acid Folic acid FR Dihydrofolate DHFR Tetrahydrofolate FR: Folate reductase DHFR: Dihydrofolate reductase THF is a co-enzyme involved in one carbon transfer during DNA synthesis. Deficiency of TH4, therefore causes default in DNA synthesis. Folic acid is clinically used during Megaloblastic anemia Infants and pregnants Methotrexate toxicity ( anticancer by inhibiting DHFR)

23. Folic Acid …. Folic acid preparations include folic acid tablets, folic acid injection, and folinic acid injection (analogue of THF)

24. HAEMOPOIETIC GROWTH FACTORS

25. HAEMOPOIETIC GROWTH FACTORS …. 1. Erythropoietin is produced in juxtatubular cells in the kidney and in macrophages. contains 193 amino acids, of which the first 27 are cleaved during secretion. The final hormone is heavily glycosylated . After secretion, erythropoietin binds to a receptor on the surface of committed erythroid progenitors in the marrow and is internalized. Its action is to stimulate committed erythroid progenitor cells to proliferate and generate erythrocytes .

26. Erythropoietin …. With anemia or hypoxemia, synthesis rapidly increases by one hundredfold or more, serum erythropoietin levels rise, and marrow progenitor cell survival, proliferation, and maturation are dramatically stimulated. This finely tuned feedback loop can be disrupted by kidney disease, marrow damage, or a deficiency in iron or an essential vitamin. Two forms of recombinant human erythropoietin, epoetin alfa and epoetin beta are available. Epoetin can be given IV, SC & IP. the response being greatest after subcutaneous injection and fastest after intravenous injection.

27. Erythropoietin (EPO )… Darbepoetin a long-acting version of erythropoietin Glycosylated erythropoietin Has a half-life about three times that of epoetin alfa Due to delayed onset of action, has no value in acute treatment of anemia administered weekly Methoxy polyethylene glycol-epoetin beta : Long-acting form; administered 1-2 times per month 27

28. Erythropoietin …. Clinical uses of epoietin include: Anaemia of chronic renal failure Patients with anemia secondary to chronic kidney disease are ideal candidates for epoetin alfa therapy. Anaemia during chemotherapy for cancer Prevention of the anaemia that occurs in premature infants Anaemia of AIDS (which is exacerbated by zidovudine treatment) Highly competitive athletes have used epoetin alfa to increase their hemoglobin levels ("blood doping") and improve performance. Unfortunately, this misuse of the drug has been implicated in the deaths of several athletes and is strongly discouraged.

29. Erythropoietin …. Unwanted effects: Hypertension is common and can cause headache, disorientation and sometimes convulsions. Iron deficiency can be induced because more iron is required for the enhanced erythropoiesis. Blood viscosity increases as the haematocrit (i.e. the fraction of the blood that is occupied by red blood cells) rises, increasing the risk of thrombosis, especially during dialysis.

30. HAEMOPOIETIC GROWTH FACTORS …. 2. Colony-Stimulating Factors G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor), are the two growth factors currently available for clinical use. Both GM-CSF and G-CSF can be given either SC or IV infusion. They are used to stimulate synthesis of leukocytes.

31. Haemopoietic Growth Factors …. G-CSF and GM-CSF Filgrastim : recombinant human G-CSF Sargramostim : recombinant human GM-CSF They Stimulate proliferation and differentiation by interacting with specific receptors found on myeloid progenitor cells 31

32. Haemopoietic Growth Factors …. Clinical use of filgrastim : IV/SC To reduce risk of neutropenia following chemotherapy (high dose) and bone marrow transplantation (prophylactically) Neutropenia associated with congenital neutropenia and aplastic anemia Mobilization of peripheral blood cells in preparation for autologous and allogeneic stem cell transplantation Adverse effect: Bone pain 32

33. Haemopoietic Growth Factors …. GM-CSF (sargramostim): IV/SC Has similar clinical uses to those of G-CSF, but it is more likely than G-CSF to cause fever, arthralgia, myalgia, and capillary leak syndrome at lower doses : the response is primarily neutrophilic at larger doses : monocytosis and eosinophilia 33

34. Haemopoietic Growth Factors …. Megakaryocyte growth factors Thrombopoietin & IL-11: key endogenous regulators of platelet production Recombinant IL-11 ( Oprelvekin) stimulate the growth of multiple lymphoid & myeloid cells  the number of peripheral platelets and neutrophils Use: P revention of thrombocytopenia in pts undergoing cytotoxic chemotherapy for non-myeloid cancers ADR : Fatigue , headache, dizziness, anemia, fluid accumulation in the lungs, and transient atrial arrhythmias 34

35. Haemopoietic Growth Factors …. Romiplostim : T hrombopoitin receptor agonist Causes a dose-dependent increase in platelet count Use : treatment of idiopathic thrombocytopenic purpura ADR : mild headache on the day of administration 35