Pharmacologic Treatment of Anemia

David E. Newton, MD, MS, DABFP PSPD/UNEJ 2003

Objectives: After studying the following material, the student should be able to: 1. Describe the important aspects of the absorption, indications for use, and precautions in the use of Iron and Iron Salts in the treatment of Iron Deficiency Anemia. 2. Understand the inter-relationship of Vitamin B12 and Folate deficiency. 3. Describe the important aspects of the absorption, indications for use, and precautions for B12 and/or Folate supplementation. 4. Describe guidelines for the diagnosis and treatment of megaloblastic anemia. 5. Describe the uses of, administration and precautions for the use of Recombinant Human Erythropoietin.

I. Iron and Iron Salts A. Ferrous Sulfate 1. least expensive and treatment of choice for iron deficiency. 2. Contains 20% elemental iron (hydrated salt). The amount of iron, not the total number of mg of the salt is what is important in calculating the correct dose for a given patient. 3. Coating of the tablet must dissolve quickly because iron is absorbed in the upper small intestine. Avoid use of delayed release forms of iron designed to have fewer gastrointestinal side effects. The effectiveness of these compounds is questionable. 4. A low pH is necessary to convert ferric iron to ferrous. The ferric form is not well absorbed. Therefore, in patients without adequate stomach acid production due to disease, surgery, or medication, it may be necessary to add ascorbic acid (vitamin C) to the regimen to improve absorption. 5. Dosage: Adults: 200mg elemental iron/day (2-3 mg/kg) given in three equal doses of 65mg. Children: for those weighing 15-30 kg, the correct dose is the adult dose, or 100mg/day. Children who weigh less than 15 kg should take 5mg/kg/day. 6. Side effects: a. Gastrointestinal predominate: heartburn, nausea, upper gastric discomfort, constipation, diarrhea. 1) 25% of patients have GI side effects at the usual dose of 200mg/day. 40% have side effects at 400mg/day.

2) starting at a lower dosage and titrating upwards can help b. Toxicity is uncommon 1) fatalities in adults are rare 2) most deaths occur in children between ages 12-24 mos after ingesting as little as 1-2 gms of iron. 3) iron tablets, as well as all other meds, should be kept out of the reach of small children. 7. Parenteral iron: a. is indicated only when oral iron fails or is not possible b. indications include malabsorption, severe oral iron intolerance, total parenteral nutrition, patients with end stage renal failure who are taking erythropoietin c. Parenteral iron therapy should be used only when clearly indicated, since acute hypersensitivity, including anaphylactic and anaphylactoid reactions can occur in from 0.2-0.3% of patients. d. parenteral iron should always be preceded by a test dose to check for an immediate hypersensitivity reaction before therapy is begun. e. in most cases, parenteral iron is not more effective than oral iron for patients who can take oral medication. 1) an exception is in the severely anemic patient, the hematological response can exceed that of oral iron for the first 1-3 weeks of therapy only. Afterward, there is no difference in efficacy. f. IM iron is less preferred than IV because of local reactions, continued pain at the site of injection, discoloration of the skin, potential for malignant change at the site of injection. B. Other Iron Salts 1. dried Ferrous Sulfate (32% elemental iron) 2. Ferrous fumarate (33% iron)is moderately soluble in water, stable, and almost tasteless 3. Ferrous gluconate (12% iron) 4. Polysaccharide-iron complexa compound of ferrihydrite and carbohydrate. 5. Remember that the effective dose of each of these options should be based on the iron content, not the total mg of the iron salt. II. Vitamin B12 and Folic Acid A. B12 and Folate are both vitamins essential for DNA and protein synthesis. 1. Deficiencies in either or both result in abnormalities in all cells with rapid turnover, such as those in the hematopoietic system. 2. Deficiency of either vitamin results in Megaloblastic Anemia. B. The Biochemistry of B12 and Folate are interrelated. 1.The major metabolic roles of both share a final common pathway.

2. Hematologic effects of deficiencies of either vitamin cannot be distinguished clinically.

(dont try to memorize these pathways) C. Vitamin B12 1.Natural sources a. Vitamin B12 is only found in animal products. The only exception is that there are legumes that are contaminated with certain bacteria that make vitamin B12. b. Strict vegetarians must take vitamin B12 supplements. c. foods highest in Vitamin B12 include organ meats, especially liver, and other animal byproducts. 2. Absorption of B12 occurs in the terminal ileum and requires a protein produced by the parietal cells of the stomach called intrinsic factor. Bile and bicarbonate are also important for absorption. a. gastric atrophy and gastric surgery are frequent causes of deficiencies in intrinsic factor production that result in B12 deficiency. b. antibodies to parietal cells or intrinsic factor can also play a role. c. other intestinal diseases can interfere with absorption including pancreatic disorders, intestinal bacterial overgrowth, intestinal parasites, sprue, Crohns disease and other causes of ileal mucosal disease and surgery.

3. B12 Deficiency a. impacts both the hematopoietic and nervous systems. b. the hematopoietic result is called ineffective hematopoiesis. Cells that leave the marrow are abnormal, with many cell fragments, poikilocytes, and macrocytes. 1) the mean red cell volume increases to 110 fl (m3) = macrocytosis. c. Diagnosis is by serum B12 level or serum methylmalonic acid level (which is more sensitive). d. the Schilling test is the classic method to confirm the diagnosis but is not commonly performed. It helps to distinguish between intrinsic factor deficiency and primary ileal disease as the cause of the deficiency. e. irreversible damage to the nervous system can occur 1) Symptoms and signs include paresthesias of hands and feet, decreased vibration and position sense and deep tendon reflexes. In more severe cases confusion, moodiness, loss of memory, loss of central vision, delusions, hallucinations occur. 4. Therapy a. although small amounts of oral B12 can be absorbed by simple diffusion, in cases where deficiency is not due to inadequate intake, B12 must be given IM or SQ. b. B12 should never be given IV because of rare reports of anaphylaxis following injection. c. Dosage is 100 g by injection monthly except in cases of neurological damage or severe leukopenia, in which case the dose should be given daily or several times a week for the first several months. d. prophylactic use of B12 should only be recommended for strict vegetarians, or patients who have had a gastrectomy or with certain diseases mentioned above. e. avoid treatment of anemia with a shotgun approach of multiple vitamins and minerals. Administration of folic acid can produce hematologic recovery in patients who are B12 deficient but will permit permanent neurological damage to develop or progress. f. once begun, B12 therapy must be continued for life. g. the use of B12 for conditions such as trigeminal neuralgia, multiple sclerosis, various neuropathies, psychiatric disorders, poor growth or nutrition, or as a tonic for patients complaining of fatigue has no scientific support. D. Folic Acid a. folic acid is essential for the conversion of homocysteine to methionine, serine to glycine, the synthesis of

thymidylate, histidine metabolism, synthesis of purines, and the utilization or generation of formate. b. natural food sources include fresh green leafy vegetables, liver, yeast, and some fruits. Lengthy cooking can destroy up to 90% of the folate content of food. c. standard daily requirement is 400 g/day. But pregnant and lactating patients require 600 g or more /day. d. folate supplementation has been shown to reduce the risk of neural tube defects in children born to mothers who take the supplement beginning one month before pregnancy and through the first trimester. Daily intake of at least 400 g/day is required. e. patients with high levels of homocysteine have an increased risk of coronary heart disease. Folate supplementation with 1 mg/day can reduce homocysteine levels and thus may reduce the risk of heart disease in such patients. f. absorption occurs in the proximal portion of the small intestine. Jejunal disease can interfere with absorption as can tropical and non-tropical sprue. Enterohepatic circulation can be impaired in acute or chronic alcoholism. g. the megaloblastic anemia caused by folate deficiency cannot be distinguished from that caused by B12 deficiency. h. folate deficiency is rarely if ever associated with neurological damage. Therefore, neurological deficits characteristic of B12 deficiency in a patient with megaloblastic anemia points toward B12 and not folate deficiency as the cause of the anemia. i. diagnosis is best made by determining red blood cell folate levels. Plasma folate levels return to normal quickly after dietary intake of folate-containing food and drop rapidly after steady ingestion of alcohol which make plasma folate levels less reliable. Low RBC folate levels indicate a chronic deficiency that began before the red cells were formed. j. Side effects: rare reports of allergy to parenteral injections exist. Oral folic acid is non-toxic. Large doses can reduce seizure threshold in susceptible children and may counteract the anti-epileptic effect of phenobarbital, phenytoin, and primidone. h. Vitamin C deficiency (scurvy) is the only situation in which oral administration of folate is ineffective. III. Erythropoietin A. the most important regulator of hematopoiesis

B. produced by the kidneys and is therefore deficient in advanced renal failure C. recombinant human erythropoietin is now available D. Primary use is in patients with advanced chronic renal failure but can also be used in the treatment of anemias of surgery, AIDS, cancer chemotherapy, anemia of prematurity, and certain chronic inflammatory illnesses. E. must be given parenterally. SQ is preferred since absorption is slower and requires a lower dose than if given IV F. The patient must be closely monitored during therapy. Treatment is continued until the hematocrit reaches 33-36%. Treatment of levels above 36% is not recommended. Patients with hematocrits above 40% have a higher risk of myocardial infarction and death. G. Dosage is 80-120 U/kg SQ three times a week. Children under the age of 5 require a higher dose. H. side effects: most common is aggravation of hypertension in 20-30% of patients. Usually is the result of too rapid correction of anemia. Myocardial infarction can also occur as mentioned above. IV. Rare Deficiencies A. Copper deficiency is extremely rare in humans. Copper never needs to be added to a normal diet. 1. supplementation has been required in patients who have undergone intestinal bypass surgery, in those receiving total parenteral nutrition, in malnourished infants, and those individuals ingesting excessive amounts of zinc. B. Pyridoxine deficiency is uncommon. Supplementation may be helpful in patients with hereditary sideroblastic anemia. It is also indicated in patients treated for tuberculosis with isoniazid and pyrazinamide which are vitamin B6 antagonists. A daily dose of 50mg corrects the deficiency without interfering with treatment of the tuberculosis. C. Riboflavin deficiency is rare. It has been reported in patients with combined infection and protein deficiency. It is reasonable to provide riboflavin to patients with gross, generalized malnutrition.

References:
Goodman & Gilmans The Pharmacological Basis of Therapeutics, J.G. Hardman and L.E. Limbird, editors, 10th edition, 2001, pp. 1487-1514.