Drugs used in the treatment of Anemia

1. Drugs used in the treatment of Anemia Prepared by: Dr. Ghazi Bamagous

2. Hematopoiesis • Also called: hemopoiesis or hematogenesis or hemogenesis. • It originated from: hemato which means blood + genesis which means development or generation. • It is defined as the production of blood cells (RBCs, WBCs and platelets) from the undifferentiated stem cells.

3. The main components of the hemopoietic system are the blood, bone marrow, lymph nodes and thymus, with the spleen, liver and kidneys as important accessory organs. • Hemopoiesis produces over 200 billion new blood cells every day. • It takes place mainly in the bone marrow.

4. It requires 3 essential nutrients: iron, vitamin B12 and folic acid with hematopoietic growth factors (i.e. proteins that regulate the differentiation of hematopoitic cells). • Inadequate supply of any of these agents leads to deficiency of functional blood cells e.g. anemia (deficiency of oxygen carrying erythrocytes), thrombocytopenia, and neutropenia.

5. Anemia • RBCs have the principal function of carrying oxygen. • Their oxygen-carrying power depends on their hemoglobin content. • The most important site of formation of red blood cells in adults is the bone marrow, whereas the spleen acts as their graveyard. • Red cell loss in healthy adults is precisely balanced by production of new cells.

6. Clinical Presentation of Anemia • Pallor – Fatigue – Dizziness – Dyspnea. • These symptoms will lead to cardiovascular adaptation in the form of tachycardia – increased cardiac output – vasodilation which may worsen the situation in patients with cardiovascular disease.

7. Types of Anemia • Classification depends on RBC size, hemoglobin content and microscopic examination of blood smear. Two famous types of anemia include: • Hypochromic, microcytic anemia (small red cells with low hemoglobin; caused by iron deficiency). • Macrocytic anemia (large red cells, few in number; caused by vitamin B12 or folic acid deficiency).

8. Causes of anemia • Deficiency of nutrients necessary for hemopoiesis, most importantly: iron, folic acid, vitamin B12. • Depression of the bone marrow, caused by:toxins (e.g. drugs used in chemotherapy), radiation therapy, bone marrow diseases (e.g. leukaemias), reduced production of erythropoietin (e.g. chronic renal failure, rheumatoid arthritis). • Excessive destruction of red blood cells (i.e. hemolytic anemia); this has many causes, including hemoglobinopathies (such as sickle cell anemia), adverse reactions to drugs, and inappropriate immune reactions.

9. Drugs Causing anemia • Drugs that cause bleeding e.g. non-steroidal anti-inflammatory drugs. • Drugs that suppress the bone marrow e.g. cytotoxic drugs or severe adverse reaction to a certain drugs. • Drugs that promote RBCs breakdown e.g. methyldopa or high dose penicillin.

10. It is important to note that Anemia alone is not a diagnosis but needs further investigations to find out its underlying cause. Therefore, treatment of anemia consists of 2 parts: • Treatment the underlying cause (if possible) e.g. bleeding. • Providing the hematinic agents e.g. iron.

11. Iron Deficiency Anemia • There is an estimated 500 million people with iron deficiency in the world. • It takes the form of hypochromic microcytic anemia.

12. Iron forms the nucleus of heme ring. • When heme binds with globin, forms hemoglobin that binds oxygen reversibly providing the way to deliver oxygen from the lungs to other tissues. • Therefore, iron deficiency leads to small erythrocytes with insufficient hemoglobin that results in hypochromic microcytic anemia.

13. Iron metabolism • The normal daily requirement for iron is approximately 5 mg for men, and 15 mg for growing children and for menstruating women. • A pregnant woman needs between 2 and 10 times this amount because of the demands of the fetus and increased requirements of the mother. • The average diet provides 15-20 mg of iron daily, mostly in meat. Iron in meat is generally present as heme. Non-heme iron in foods (is mainly in the ferric state) must be reduced to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells.

14. Iron metabolism (absorption) • The site of iron absorption is the duodenum and upper jejunum. • Heme iron in the diet is absorbed as intact heme, and the iron is released in the mucosal cell. Non-heme iron is absorbed in the ferrous state. Within the cell, ferrous iron is oxidised to ferric iron (Fe3+). • The iron is then either held in storage in the intestinal mucosal cells as ferritin (if body stores of iron are high) or passed on to the plasma (if iron stores are low).

15. Iron metabolism (absorption) • Regulation of iron absorption is a function of the intestinal mucosa, influenced by the body's iron stores. Iron absorption increases in response to low iron stores or increased iron requirements.

16. Iron metabolism (transport) • Iron is carried in the plasma bound to transferrin, a β-globulin with two binding sites for ferric iron. Most of the iron that leaves the plasma each day is used for hemoglobin synthesis by red cell precursors. These cells have receptors that bind transferrin molecules, releasing them after the iron has been taken up.

17. Iron metabolism (storage) • In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in the liver, spleen, and bone. • Iron is stored in two forms: soluble ferritin and insoluble hemeosiderin. • Ferritin in plasma is in equilibrium with the storage ferritin in cells, and its concentration in plasma provides an estimate of total body iron stores.

18. Iron metabolism (excretion) • Because the body's ability to excrete iron is so limited (small amounts leave the body through desquamation (peeling off) of mucosal cells containing ferritin), regulation of iron balance must be achieved by changing intestinal absorption and storage of iron, in response to the body's needs (impaired regulation of iron absorption leads to serious pathology). Video: iron in the body.

19. Indications of iron The only indication of iron salts is the treatment of iron deficiency anemia (i.e. hypochromic microcytic anemia) that might take place as a result of: 1. Chronic blood loss: the common cause of iron deficiency anemia (e.g. with menorrhagia, hookworm, colon cancer). 2. Increased demand: (e.g. in pregnancy, lactation, growing children and during hemodialysis in patients with kidney disease).

20. Indications of iron (cont.) 3.Inadequate dietary intake. 4. Inadequate absorption: (e.g. following gastrectomy and malabsorption following small bowel disease).

21. Treatment with iron Treat the cause of anemia first. Iron can either be given orally or parentally. • Oral iron therapy: ferrous sulphate iron is the most efficiently absorped form. Around 400 mg need to be given daily to treat iron deficiency anemia. 3 – 6 months of treatment are required to correct the anemia and replenish iron stores. Common side effects are dose – related and include: nausea, epigastric discomfort, abdominal cramps, constipation or diarrhea and black stool (which may obscure GI bleeding).

22. Treatment with iron (cont.) B. Parenteral iron therapy: only applied for patients with severe chronic anemia e.g. various postgastretomy conditions, advanced chronic renal disease requiring hemodialysis and malabsorption syndromes.

23. Clinical toxicity with iron A. Acute iron toxicity: mainly seen in young children who accidently ingest iron tablets. This leads to necrotizing gastroenteritis (abdominal pain, vomiting, bloody diarrhea), shock, dyspnea, severe metabolic acidosis, coma and death. Treatment: to flush out unabsorbed iron  whole bowel irrigation is performed. For already absorbed iron  iron chelating agent i.e. Deferoxamine is given that binds iron and promotes its excretion in urine and feces.

24. Clinical toxicity with iron (cont.) B. Chronic iron toxicity: iron overload or hemochromatosis.

25. Hemochromatosis (iron overload) • Characterized by excessive iron absorption and deposition on various organs e.g. liver, pancreas, heart and kidney with subsequent fibrosis and organ failure i.e. diabetes, liver cirrhosis and heart failure. • Patients have total body iron of around 40gm compared to 4 gm in normal people. In liver and pancreas, iron content increase by around 80 times. Video: Iron overload

26. Hemochromatosis or iron overload • commonly seen in patients with inherited hemochromatosis and in patients who receive frequent blood transfusion e.g. patients with thalassemia major. • Treatment: intermittent phlebotomy i.e. blood donation (in the absence of anemia) or iron chelation therapy in other situations such as thallassemia.

27. Vitamin B12 Deficiency Anemia • Vitamin B12 or cobalamin or extrinsic factor is essential for DNA synthesis and cell proliferation. • The main dietary sources of vitamin B12 are meat (especially liver), eggs and dietary products. • It is stored primarily in the liver

28. Only trace amounts of vitamin B12 are normally lost in urine and stool. Because the normal daily requirements of vitamin B12 are only about 2 mcg, it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if B12 absorption were stopped.

29. Vitamin B12 metabolism • Vitamin B12 is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the stomach. • Intrinsic factor combines with the vitamin B12 in the stomach and duodenum. • Intrinsic factor - vitamin B12 complex is subsequently absorbed in the distal ileum. • Once absorbed, vitamin B12 is transported to the various cells of the body. • Excess vitamin B12 is transported to the liver for storage.

30. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. • Vitamin B12 deficiency leads to megaloblastic* macrocytic normochromic anemia, GI symptoms and neurological abnormalities. *Megaloblastic: An abnormally large nucleated red blood cell (RBC precursor) found in certain types of anemia.

31. The neurological syndrome associated with vitamin B12 deficiency usually begins with paraesthesias in peripheral nerves and weakness and progresses to spasticity, ataxia, and other central nervous system dysfunctions. Correction of vitamin B12 deficiency arrests the progression of neurological disease.

32. Causes of vitamin B12 deficiency 1. Inadequate intake. 2. inadequate absorption: either because of a lack of intrinsic factor i.e. pernicious anemia or because of conditions that interfere with its absorption in the distal ileum such as malabsorption syndromes, inflammatory bowel disease, or small bowel resection. • As there are large stores in the liver, the results of the deficiency can take a long time to become manifest.

33. Indications of vitamin B12 • Treatment of pernicious anemia and other causes of vitamin B12 deficiency. • Prophylactically after surgical operations that remove the site of production of intrinsic factor (the stomach) or of vitamin B12 absorption (the terminal ileum).

34. Pernicious anemia • It is caused by gastric mucosal atrophy that leads to failure of intrinsic factor production and vitamin B12 deficiency. • It is an autoimmune disease in which there is antibodies destruction of gastric parietal cells secreting intrinsic factor. • Treatment: initial intramuscular injection of vitamin B12 is given daily for 2 weeks then once monthly for life. However, oral route can be used.

35. Toxicity with vitamin B12 • Unwanted effects do not occur with the treatment using vitamin B12.

36. Folic Acid Deficiency Anemia • Folic acid is also essential for DNA synthesis. • 5 – 20 mg of folic acid are usually stored in the liver. • The richest sources of folic acid include: yeast, liver, kidney and green vegetables.

37. Folic acid deficiency leads to the development of macrocytic normochromic anemia. • When folates intake is diminished  serum level falls within few days because it is excreted in urine and stool and destroyed by catabolism. • Deficiency of folic acid leads to anemia, congenital malformations of newborns (e.g. spina bifida) and vascular disease.

38. Indications of folic acid • 1. Treatment of megaloblastic anaemia: resulting from folate deficiency, which can be caused by: • - poor diet with diminished hepatic stores of folate (common in alcoholic dependence & liver disease individuals). • - malabsorption syndromes. • - drugs (e.g. phenytoin). • - renal dialysis patients as folate is removed from the plasma during dialysis procedure.

39. Indications of folic acid (cont.) 2. Prophylactically: in individuals at hazard from developing folate deficiency as in case of: • pregnant women (maternal folic acid deficiency was linked to the development of foetal neural tube defects e.g. spina bifida. • premature infants • patients with severe chronic haemolytic anaemias(e.g. sickle cell anaemia). 3. Treatment or prevention of toxicity from methotrexate (folate antagonist).

40. Spina bifida • It is a developmental congenital disorder. • Caused by failure of the fusion of the embryonic neural tube, usually in the lumbo - sacral region. • There are several vareieites.

41. Treatment & toxicity • Oral route of administration is the commonest since folate is well absorbed even in malabsorption syndromes. • Treatment with folic acid is given to correct the anemia, restore normal serum levels and replenish body stores. • Treatment need to be continued until the cause of deficiency is removed or may continue life long in certain groups of patients. • Usually there are no side effects of treatment associated with properly diagnosed folic acid deficiency.

42. Clinical note Once a diagnosis of megaloblastic anemia is made, it must be determined whether vitamin B12 or folic acid deficiency is the cause. (Other causes of megaloblastic anemia are very rare.) This can usually be accomplished by measuring serum levels of the vitamins.