Agents Used in Anemias & Hematopoietic Growth Factors

1. Agents Used in Anemias & Hematopoietic Growth Factors Assist. Professor Dr. Hayder B Sahib

2. Blood cells play essential roles in • 1- oxygenation of tissues • 2- coagulation, • 3- protection against infectious agents • 4- tissue repair. • Blood cell deficiency is a relatively common occurrence that can have profound consequences. • The most common cause of erythrocyte deficiency, or anemia, is insufficient supply of iron, vitamin B12, or folic acid

3. Pharmacologic treatment of these types of anemia usually involves replacement of the missing substance. • An alternative therapy for certain types of anemia and for deficiency in other types of blood cells is • administration of recombinant hematopoietic growth factors, which stimulate the production of various lineages of blood cells and regulate blood cell function.

6. AGENTS USED TO TREAT ANEMIAS • A. Iron • Iron is stored in the • 1- intestinal mucosal cells • 2- liver, • 3- spleen • 4- bone marrow as ferritin (an iron–protein complex) until needed by the body. • Iron is delivered to the marrow for hemoglobin production by a transport protein, namely transferrin. • iron deficiency results from • 1- acute or chronic blood loss • 2- insufficient intake during periods of accelerated growth in children • 3- heavily menstruating or pregnant women.

7. iron deficiency results from a negative iron balance due to depletion of iron stores and/or inadequate intake, ending in hypochromic microcytic anemia (due to low iron and small-sized red blood cells). • In addition to general signs and symptoms of anemia, iron deficiency anemia may cause • 1- pica (hunger for ice, dirt, paper, etc.) • 2-koilonychias (upward curvature of the finger and toe nails) • 3- soreness and cracking at the corners of the mouth.

8. 1. Mechanism of action: Supplementation with elemental iron corrects the iron deficiency. • The CDC recommends 150 to 180 mg/day of oral elemental iron administered in divided doses two to three times daily for patients with iron deficiency anemia.

9. 2. Pharmacokinetics: • A- Iron is absorbed after oral administration. Acidic conditions in the stomach keep iron in the reduced ferrous form, which is the more soluble form. • B-Iron is then absorbed in the duodenum. [Note: The amount absorbed depends on the current body stores of iron. If iron stores are adequate, less will be absorbed. If stores are low, more iron will be absorbed.] • For this reason, it is recommended that most people take the prescribed daily iron supplement in two or three divided doses. • Some extended-release formulations may be dosed once daily. • Oral preparations include ferrous sulfate, ferrous fumarate, ferrous gluconate, polysaccharide– iron complex, and carbonyl iron formulations.

10. Of these preparations, ferrous sulfate is the most commonly used form of iron due to its high content of elemental iron and relatively low cost. • The percentage of elemental iron varies in each oral iron preparation • Macrophages phagocytize iron dextran and release iron from the dextran molecule. • When iron sucrose is used, specific exchange mechanisms transfer iron to transferrin. • While parenteral administration treats iron deficiency rapidly, oral administration may take several weeks.

11. 3. Adverse effects: • 1- Gastrointestinal (GI) disturbances caused by local irritation (abdominal pain, constipation, diarrhea, etc.) and dark stools are the most common adverse effects of oral iron supplements. • 2- Fatal hypersensitivity and anaphylactoid reactions can occur in patients receiving parenteral iron (mainly iron dextran formulations). • 3- A test dose should be administered prior to iron dextran. Excessive iron can cause toxicities that can be reversed using chelators such as deferoxamine.

12. B. Folic acid (folate) • The primary use of folic acid is in treating deficiency states that arise from inadequate levels of the vitamin. • Folate deficiency may be caused by • 1) increased demand (for example, pregnancy and lactation), • 2) poor absorption caused by pathology of the small intestine, • 3) alcoholism • 4) treatment with drugs that are dihydrofolate reductase inhibitors (for example, methotrexate, pyrimethamine, and trimethoprim).

13. In the latter case, the reduced or active form of the vitamin (folinic acid—also known as leucovorin calcium—available as oral and parenteral formulations) is used for treatment. • A primary result of folic acid deficiency is megaloblastic anemia (large-sized red blood cells), which is caused by diminished synthesis of purines and pyrimidines. • This leads to an inability of erythropoietic tissue to make DNA and, thereby, proliferate Folic acid is well absorbed in the jejunum unless pathology is present.

14. If excessive amounts of the vitamin are ingested, they are excreted in the urine and feces. • Oral folic acid administration is nontoxic. • There have been no substantiated side effects reported. • Rare hypersensitivity reactions to parenteral injections have been reported.

15. C. Cyanocobalamin and hydroxocobalamin (vitamin B12) • Deficiencies of vitamin B12 can result from either • 1- low dietary levels • 2- poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) • 3- loss of activity of the receptor needed for intestinal uptake of the vitamin. • 4- Intrinsic factor is a glycoprotein produced by the parietal cells of the stomach, and it is required for vitamin B12 absorption. • 5- In patients with bariatric surgery (surgical treatment for obesity), vitamin B12 supplementation as cyanocobalaminis required in large oral doses, sublingually or once a month by the parenteral route. • Intramuscular hydroxocobalamin is now preferred since it has a rapid response, is highly protein bound, and maintains longer plasma levels.

16. 6- Nonspecific malabsorption syndromes or gastric resection can also cause vitamin B12 deficiency. • In addition to general signs and symptoms of anemia, vitamin B12 deficiency anemia may cause • 1- tingling (pins and needles) in the hands and feet • 2- difficulty walking • 3- dementia and, in extreme cases hallucinations, paranoia, or schizophrenia.

17. The vitamin may be administered • 1- orally (for dietary deficiencies) • 2- intramuscularly, or deep subcutaneously (for pernicious anemia). • [Note: Folic acid administration alone reverses the hematologic abnormality and, thus, masks the vitamin B12 deficiency, which can then proceed to severe neurologic dysfunction and disease. The cause of megaloblastic anemia needs to be determined in order to be specific in terms of treatment. Therefore, megaloblastic anemia should not be treated with folic acid alone but, rather, with a combination of folate and vitamin B12.] • Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia. This vitamin is nontoxic even in large doses.

18. D. Erythropoietin and darbepoetin • Peritubular cells in the kidneys work as sensors that respond to hypoxia and mediate synthesis and release of erythropoietin a glycoprotein. • EPO stimulates stem cells to differentiate into proerythroblastsand promotes the release of reticulocytes from the marrow and initiation of hemoglobin formation. • EPO, thus, regulates red blood cell proliferation and differentiation in bone marrow.

19. Human erythropoietin (epoetin alfa), produced by recombinant DNA technology, is effective in the treatment of anemia caused by • 1- end-stage renal disease • 2- anemia associated with human immunodeficiency virus infection • 3- anemia in bone marrow disorders • 4- anemias of prematurity • 5- anemias in some cancer patients.

20. Darbepoetin is a long-acting version of erythropoietin that differs from erythropoietin by the addition of two carbohydrate chains, which improves its biologic activity. • Therefore, darbepoetinhas decreased clearance and has a half-life about three times that of epoetin alfa. Due to their delayed onset of action, these agents have no value in acute treatment of anemia. • Supplementation with iron may be required to ensure an adequate response.

21. The protein is usually administered intravenously in renal dialysis patients, but the subcutaneous route is preferred for other indications. • These agents are generally well tolerated, but side effects may include elevation in blood pressure and arthralgia in some cases. • [Note: The former may be due to increases in peripheral vascular resistance and/or blood viscosity.]

22. When epoetin alfa is used to target hemoglobin concentrations more than 11 g/dL, serious cardiovascular events • 1- (such as thrombosis and severe hypertension) • 2- increased risk of death, shortened time to tumor progression, and decreased survival have been observed. • The recommendations for all patients receiving epoetin alfa or darbepoetininclude • 1- a minimum effective dose that does not exceed a hemoglobin level of 12 g/dL • 2- the hemoglobin should not rise by more than 1 g/dL over a 2-week period. • 3- if the hemoglobin level exceeds 10 g/dL, doses of epoetin alfa or darbepoetinshould be reduced or treatment should be discontinued.

23. III. AGENTS USED TO TREAT NEUTROPENIA • Myeloid growth factors or granulocyte colony–stimulating factors (G-CSF), such as • 1- filgrastim • 2- tbo-filgrastim • 3- pegfilgrastim

24. granulocyte–macrophage colony–stimulating factors(GM-CSF), such as sargramostim stimulate granulocyte production in the marrow to increase the neutrophil counts and reduce the duration of severe neutropenia. • These agents are typically used prophylactically to reduce risk of neutropenia following chemotherapy and bone marrow transplantation.

25. Filgrastim and sargramostim can be dosed either subcutaneously or intravenously, whereas tbo-filgrastim and pegfilgrastim are dosed subcutaneously only. • The main difference between the available agents lies in the frequency of dosing. • Filgrastim, tbo-filgrastim, and sargramostim are dosed once a day beginning 24 to 72 hours after chemotherapy, until the absolute neutrophil count (ANC) reaches 5000 to 10,000/uL.

26. Pegfilgrastim is a pegylated form of G-CSF, resulting in a much longer half-life when compared to the other agents. • As such, it is given as a single dose 24 hours after chemotherapy, rather than once daily. • There is no evidence to show superiority of one agent over another in terms of efficacy, safety, or tolerability. • Bone pain is a common adverse effect with these agents.

27. AGENTS USED TO TREAT SICKLE CELL DISEASE • A. Hydroxyurea • Clinical trials have shown that hydroxyurea can reduce the frequency of painful sickle cell crises • . Hydroxyurea is also used off-label to treat chronic myelogenous leukemia and polycythemia vera. • In sickle cell disease, the drug apparently increases fetal hemoglobin levels, thus diluting the abnormal hemoglobin S (HbS). This process takes several months.

28. Polymerization of HbS is delayed in treated patients, so that painful crises are not caused by sickled cells blocking capillaries and causing tissue anoxia. • Important side effects of hydroxyurea include bone marrow suppression and cutaneous vasculitis.

29. Pentoxifylline is a methylxanthine derivative that has been called a “rheologic modifier.” It increases the deformability of red blood cells (improves erythrocyte flexibility) and reduces the viscosity of blood. • This decreases total systemic vascular resistance, improves blood flow, and enhances tissue oxygenation in patients with peripheral vascular disease.

30. It is indicated to treat intermittent claudication, where it can modestly control function and symptoms. • Unlabeled uses include improving psychopathological symptoms in patients with cerebrovascular insufficiency. • It has been studied in diabetic angiopathies, transient ischemic attacks, leg ulcers, sickle cell anemias, strokes, and Raynaud’s phenomenon. It is available in extended-release tablets and is taken three times a day with food.

31. Adverse reactions are mainly GI in nature and are lessened by administration with food.