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Introduction
Anemia is defined as a below-normal 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.
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. Because the hematopoietic machinery requires a constant supply of three essential nutrientsiron, vitamin B12, and folic acidanemias are resulted from dietary deficiencies of these substances.
IRON Iron forms the nucleus of the iron- porphyrin heme ring, which together with globin chains forms hemoglobin. Hemoglobin reversibly binds oxygen and provides the critical mechanism for oxygen delivery from the lungs to other tissues.
Pharmacokinetics Loading
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A. ABSORPTION : A normal individual absorbs about 0.5-1 mg daily. Iron is normally absorbed in the duodenum and proximal jejunum. Iron absorption increases in response to low iron stores or increased iron requirements.
B.TRANSPORT Iron is transported in the plasma bound to transferrin, a -globulin that specifically binds two molecules of ferrous iron .The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism..C.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.
D.ELIMINATION There is no mechanism for excretion of iron. Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat. These losses account for no more than 1 mg. of iron per day
Clinical Pharmacology. The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia. Iron deficiency results from acute or chronic blood loss, from insufficient intake during periods of accelerated growth in children, in populations with increased iron requirements. These include infants, especially premature infants; children during rapid growth periods; pregnant and lactating women; and patients with chronic kidney disease who lose erythrocytes at a relatively high rate during hemodialysis. Inadequate iron absorption can also cause iron deficiency, this is seen frequently after gastrectomy and in patients with severe small bowel disease that results in generalized malabsorption. The most common cause of iron deficiency in adults is blood loss, menstruating women lose about 30 mg of iron with each menstrual period. In men and postmenopausal women, the most common site of blood loss is the gastrointestinal tract. Patients with unexplained iron deficiency anemia should be evaluated for occult gastrointestinal bleeding. Thus, iron deficiency results from a negative iron balance due to depletion of iron stores and/or inadequate intake, culminating in hypochromic microcytic anemia (due to low iron and small-sized red blood cells). B.TREATMENT Iron deficiency anemia is treated with oral or parenteral iron preparations. Oral iron corrects the anemia just as rapidly and completely as parenteral iron in most cases if iron absorption from the gastrointestinal tract is normal. 1. Oral iron therapy A wide variety of oral iron preparations are available. 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. . In an iron-deficient individual, about 50-100 mg of iron can be incorporated into hemoglobin daily, and about 25% of oral iron given as ferrous salt can be absorbed. Therefore, 200-400 mg of elemental iron should be given daily to correct iron deficiency most rapidly. Treatment with oral iron should be continued for 3-6 months after correction of the cause of the iron loss. This corrects the anemia and replenishes iron stores. Adverse effects: Gastrointestinal disturbances caused by local irritation are the most common adverse effects of iron and include nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea. These effects are usually dose-related and can often be overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals. Patients taking oral iron develop black stools; this has no clinical significance in itself but may obscure the diagnosis of continued gastrointestinal blood loss Parenteral iron therapy Parenteral therapy should be reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron and for patients with extensive chronic blood loss who cannot be maintained with oral iron alone. This includes patients with various postgastrectomy conditions and previous small bowel resection, inflammatory bowel disease involving the proximal small bowel, malabsorption syndromes, and advanced chronic renal disease including hemodialysis . . Iron dextran can be given by deep intramuscular injection or by intravenous infusion. Intravenous administration eliminates the local pain and tissue staining that often occurs with the intramuscular route and allows delivery of the entire dose of iron necessary to correct the iron deficiency at one time.
Adverse effects of intravenous iron dextran therapy include headache, light-headedness, fever, arthralgias, nausea and vomiting, back pain, flushing, urticaria, bronchospasm, and, rarely, anaphylaxis and death. Owing to the risk of a hypersensitivity reaction, a small test dose of iron dextran should always be given before full intramuscular or intravenous doses are given. Patients with a strong history of allergy and patients who have previously received parenteral iron dextran are more likely to have hypersensitivity reactions after treatment with parenteral iron dextran. The local pain and tissue staining often occur with the intramuscular.
Iron-sucrose complex and iron sodium gluconate complex are alternative preparations. These agents can be given only by the intravenous route. These preparations appear to be much less likely than iron dextran to cause
hypersensitivity reactions.
Cyanocobalamin (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. Intrinsic factor is a GP produced by the parietal cells of the stomach and it is required for vitamin B12 absorption. The most common causes of vitamin B12 deficiency are, partial or total gastrectomy. In patients with bariatric surgery (surgical gastrointestinal treatment for obesity), and conditions that affect the distal ileum, such as malabsorption syndromes, inflammatory bowel disease, or small bowel resection.
Pharmacokinetics The vitamin is stored primarily in the liver, with an average adult having a total vitamin B12 storage pool of 3000-5000 mcg. 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 stopped.. Clinical Pharmacology . Vitamin B12 is used to treat or prevent deficiency. There is no evidence that vitamin B12 injections have any benefit in persons who do not have vitamin B12 deficiency. The most characteristic clinical manifestation of vitamin B12 deficiency is megaloblastic anemia
[Note: Folic acid administration alone reverses the hematologic abnormality and, thus, masks the B12 deficiency, which can then proceed to severe neurologic dysfunction . Therefore, megaloblastic anemia should not be treated with folic acid alone but, rather, with a combination of folate and vitamin B12.] . Once a diagnosis of megaloblastic anemia is made, it must be determined whether vitamin B12 or folic acid deficiency is the cause. This can usually be accomplished by measuring serum levels of the vitamins.
Vitamin B12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin. Hydroxocobalamin is preferred because it is more highly protein-bound and therefore remains longer in the circulation. Initial therapy should consist of 100-1000 mcg of vitamin B12 intramuscularly daily or every other day for 1-2 weeks to replenish body stores. Maintenance therapy consists of 100-1000 mcg intramuscularly once a month for life.
In patients with bariatric surgery (surgical gastrointestinal treatment for obesity), vitamin B12 supplementation is required in large oral doses.. The vitamin may be administered orally (for dietary deficiencies), intramuscularly, or deep subcutaneously (for pernicious anemia). Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia. There are no known adverse effects of this vitamin.
FOLIC ACID . Reduced forms of folic acid are required for essential biochemical reactions that provide precursors for the synthesis of amino acids, purines, and DNA. The consequences of folate deficiency go beyond the problem of anemia because folate deficiency is implicated as a cause of congenital malformations in newborns and may play a role in vascular disease.
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, or 4) treatment with drugs that are dihydrofolate reductase inhibitors (for example, methotrexate and, to a lesser extent, trimethoprim and pyrimethamine), Long-term therapy with phenytoin can also cause folate deficiency, but only rarely causes megaloblastic anemia. 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. [Note: To avoid neurological complications of vitamin B12 deficiency, it is important to evaluate the basis of the megaloblastic anemia prior to instituting therapy. Vitamin B12 and folate deficiency causes similar symptoms .
Pharmacokinetics Various forms of folic acid are present in a wide variety of plant and animal tissues; the richest sources are yeast, liver, kidney, and green vegetables. Normally, 5-20 mg of folates are stored in the liver and other tissues. Folates are excreted in the urine and stool and are also destroyed by catabolism, so serum levels fall within a few days when intake is diminished. Because body stores of folates are relatively low and daily requirements high, folic acid deficiency and megaloblastic anemia can develop within 1-6 months after the intake of folic acid stops, depending on the patient's nutritional status and the rate of folate utilization .
Clinical Pharmacology : Folate deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B12 deficiency . However, folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency. In patients with megaloblastic anemia, folate status is assessed with assays for serum folate or for red blood cell folate. Red blood cell folate levels are often of greater diagnostic value than serum levels, because serum folate levels tend to be labile and do not necessarily reflect tissue levels.
Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. Patients with malabsorption syndromes also frequently develop folic acid deficiency. Patients who require renal dialysis develop folic acid deficiency because folates are removed from the plasma during the dialysis procedure. Parenteral administration of folic acid is rarely necessary, since oral folic acid is well absorbed even in patients with malabsorption syndromes. A dose of 1 mg folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients. Therapy should be continued until the underlying cause of the deficiency is removed or corrected. Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy. Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients, including pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis.
Folic acid is well absorbed in the jejunum unless pathology is present. If excessive amounts of the vitamin are ingested, they are excreted in the urine and feces. Oral folic acid administered has no known toxicity.
HEMATOPOIETIC GROWTH FACTORS. The hematopoietic growth factors are glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. Of the known hematopoietic growth factors, erythropoietin (epoetin alfa), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), are currently in clinical use.
Erythropoietin Pharmacodynamics
Erythropoietin [ee-rith-ro-POI-eh-tin] is a GP, normally made by the kidney, that regulates red blood cell proliferation and differentiation in bone marrow. This results in correction of the anemia, provided that the bone marrow response is not impaired by red cell nutritional deficiency (especially iron deficiency), primary bone marrow disorders or bone marrow suppression from drugs or chronic diseases. Human erythropoietin, produced by recombinant DNA technology, Erythropoietin has been used successfully to offset the anemia produced by zidovudine treatment in patients with HIV infection and in the treatment of the anemia of prematurity, is effective in the treatment of anemia caused by end-stage renal disease, , and anemia in some cancer patients . An increase in reticulocyte count is usually observed in about 10 days and an increase in hematocrit and hemoglobin levels in 2-6 weeks.
When erythropoietin is used to target hemoglobin concentration >12 g/dL, serious and life-threatening cardiovascular events, increased risk of death, shortened time to tumor progression and/or decreased survival have been observed. The recommendations for all patients receiving erythropoietin include a minimum effective dose that does not exceed a hemoglobin level of 12 g/dL, and this should not rise more than 1 g/dL over a 2-week period. Failure to respond to erythropoietin is most commonly due to concurrent iron deficiency, which can be corrected by giving oral or parenteral iron. Folate supplementation may also be necessary in some patients.
Darbepoetin [dar-be-POE-e-tin] is a long-acting version of erythropoietin that differs from erythropoietin by the addition of two carbohydrate chains, which improves its biologic activity. Therefore, darbepoetin has decreased clearance and has a half life about three times that of erythropoietin. Due to its delayed onset of action, darbepoetin has no value in acute treatment of anemia. Supplementation with iron may be required to assure an adequate response. The protein is usually administered intravenously in renal dialysis patients, but the subcutaneous route is preferred. Side effects are generally well tolerated but 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.]