Drugs for Anemia A. L. Mohammed Fareed MSc pharmacology Reference : Lippincott Illustrated Reviews :Pharmacology Overview: Anemia is defined as a low plasma hemoglobin concentration resulting from a decreased number of circulating red blood cells or an abnormally low total hemoglobin content per unit of blood volume. General signs and symptoms of anemia include fatigue, rapid heartbeat, shortness of breath, pale skin, dizziness, and insomnia. Anemia can be caused by chronic blood loss, bone marrow abnormalities, increased hemolysis, infections, malignancy, endocrine deficiencies, renal failure, and a number of other disease states. A large number of drugs cause toxic effects on blood cells, hemoglobin production, or erythropoietic organs, which, in turn, may cause anemia. Nutritional anemias are caused by dietary deficiencies of substances such as iron, folic acid, and vitamin B12 (cyanocobalamin) that are necessary for normal erythropoiesis. Individuals with anemia that has a genetic basis, such as sickle cell disease, can benefit hydroxyurea. Anemia can be at least temporarily corrected by transfusion of whole blood. 1 AGENTS USED TO TREAT ANEMIAS A. Iron Iron deficiency results from acute or chronic blood loss, from insufficient intake during periods of accelerated growth in children, and in heavily menstruating or pregnant women. Thus, iron deficiency results from a negative iron balance due to depletion of iron stores and/or inadequate intake, suffer from 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 pica (hunger for ice, dirt, paper, etc.), koilonychias (upward curvature of the finger and toe nails), and soreness and cracking at the corners of the mouth. Supplementation with elemental iron corrects the iron deficiency. They 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. Pharmacokinetics: Iron is absorbed after oral administration. Acidic conditions in the stomach keep iron in the reduced ferrous form, which is the more soluble form. Iron is then absorbed in the duodenum. Some extended-release formulations may be dosed once daily. 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. Parenteral formulations of iron, such as iron dextran, iron sucrose, and sodium ferric gluconate complex, are also available. 2 While parenteral administration treats iron deficiency rapidly, oral administration may take several weeks. Adverse effects: 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. Parenteral iron formulations may be used in those who cannot tolerate oral iron. Fatal hypersensitivity and anaphylactoid reactions can occur in patients receiving parenteral iron (mainly iron dextran formulations). A test dose should be administered prior to iron dextran. Excessive iron can cause toxicities that can be reversed using chelators such as deferoxamine. B. Folic acid (folate) : 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). 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. [Note: To avoid neurological complications of vitamin B12 deficiency, it is important to evaluate the basis of the megaloblastic anemia prior to 3 instituting therapy. Both vitamin B12 and folate deficiency can cause similar symptoms.] C. Cyanocobalamin and hydroxocobalamin (vitamin B12) : Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia), or a loss of activity of the receptor needed for intestinal uptake of the vitamin. In patients with bariatric surgery (surgical treatment for obesity), vitamin B12 supplementation as cyanocobalamin is required in large oral doses vitamin B12 deficiency anemia may cause tingling (pins and needles) in the hands and feet, difficulty walking, dementia and, in extreme cases, hallucinations, paranoia, or schizophrenia. The vitamin may be administered orally (for dietary deficiencies), intramuscularly, or deep subcutaneously (for pernicious anemia). 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. D. Erythropoietin and darbepoetin Peritubular cells in the kidneys work as sensors that respond to hypoxia and mediate synthesis and release of erythropoietin [EPO], a glycoprotein. EPO stimulates stem cells to differentiate into proerythroblasts and promotes the release of reticulocytes from the marrow and initiation of hemoglobin formation. 4 EPO, thus, regulates red blood cell proliferation and differentiation in bone marrow. Human erythropoietin (epoetin alfa), produced by recombinant DNA technology, is effective in the treatment of anemia caused by end-stage renal disease, anemia associated with human immunodeficiency virus infection, and anemia in bone marrow disorders, anemias of prematurity, and anemias in some cancer patients. These agents are generally well tolerated, but side effects may include elevation in blood pressure and arthralgia in some cases. The recommendations for all patients receiving epoetin alfa or darbepoetin include a minimum effective dose that does not exceed a hemoglobin level of 12 g/dL, and the hemoglobin should not rise by more than 1 g/dL over a 2-week period. III. AGENTS USED TO TREAT NEUTROPENIA Myeloid growth factors or granulocyte colony–stimulating factors (G-CSF), such as filgrastim and 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. Bone pain is a common adverse effect with these agents. IV. AGENTS USED TO TREAT SICKLE CELL DISEASE A. Hydroxyurea can reduce the frequency of painful sickle cell crises In sickle cell disease, the drug apparently increases fetal hemoglobin levels, thus diluting the abnormal hemoglobin S (HbS). 5 side effects of hydroxyurea include bone marrow suppression and cutaneous vasculitis. B. Pentoxifylline 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. It is indicated to treat intermittent claudication. Unlabeled uses : sickle cell anemias Adverse reactions are mainly GI in nature and are lessened by administration with food. 6 .