Drugs for deficiency anemias
Red blood cell development
RBCs begin developing in the bone marrow and then mature in the blood. As developing RBCs grow and divide, they evolve through four stages (Fig. 55–1). In their earliest stage, RBCs lack hemoglobin and are known as proerythroblasts. In the next stage, they gain hemoglobin and are called erythroblasts. Both the erythroblasts and the proerythroblasts reside in bone marrow. After the erythroblast stage, RBCs evolve into reticulocytes (immature erythrocytes) and enter the systemic circulation. Following the reticulocyte stage, circulating RBCs reach full maturity and are referred to as erythrocytes.


Development of RBCs requires the cooperative interaction of several factors: bone marrow must be healthy; erythropoietin (a stimulant of RBC maturation) must be present; iron must be available for hemoglobin synthesis; and other factors, including vitamin B12 and folic acid, must be available to support synthesis of DNA. If any of these is absent or amiss, anemia will result.
Iron deficiency
Iron deficiency is the most common nutritional deficiency, and the most common cause of nutrition-related anemia. Worldwide, people with iron deficiency number in the hundreds of millions. In the United States, about 5% of the population is iron deficient.
Biochemistry and physiology of iron
In order to understand the consequences of iron deficiency as well as the rationale behind iron therapy, we must first understand the biochemistry and physiology of iron. This information is reviewed below.
Metabolic functions
Iron is essential to the function of hemoglobin, myoglobin (the oxygen-storing molecule of muscle), and a variety of iron-containing enzymes. Most (70% to 80%) of the body’s iron is present in hemoglobin. A much smaller amount (10%) is present in myoglobin and iron-containing enzymes.
Fate in the body
The major pathways for iron movement and utilization are shown in Figure 55–2. In the discussion below, the numbers in parentheses refer to the circled numbers in the figure.


Uptake and distribution.
The life cycle of iron begins with (1) uptake of iron into mucosal cells of the small intestine. These cells absorb 5% to 20% of dietary iron. Their maximum absorptive capacity is 3 to 4 mg/day. Iron in the ferrous form (Fe++) is absorbed more readily than iron in the ferric form (Fe+++). Vitamin C enhances absorption, and food reduces absorption.
Following uptake, iron can either (2a) undergo storage within mucosal cells in the form of ferritin (a complex consisting of iron plus a protein used to store iron) or (2b) undergo binding to transferrin (the iron transport protein) for distribution throughout the body.
Utilization and storage.
Iron that is bound to transferrin can undergo one of three fates. The majority of transferrin-bound iron (3a) is taken up by cells of the bone marrow for incorporation into hemoglobin. Small amounts (3b) are taken up by the liver and other tissues for storage as ferritin. Lastly (3c), some of the iron in plasma is taken up by muscle (for production of myoglobin) and some is taken up by all other tissues (for production of iron-containing enzymes).
Recycling.
As Figure 55–2 depicts, iron associated with hemoglobin undergoes continuous recycling. After hemoglobin is made in bone marrow, iron re-enters the circulation (4) as a component of hemoglobin in erythrocytes. (The iron in circulating erythrocytes accounts for about 70% of total body iron.) After 120 days of useful life, RBCs are catabolized (5). Iron released by this process re-enters the plasma bound to transferrin (6), and then the cycle begins anew.
Elimination.
Excretion of iron is minimal. Under normal circumstances, only 1 mg of iron is excreted each day. At this rate, if none of the lost iron were replaced, body stores would decline by only 10% a year.
Iron leaves the body by several routes. Most excretion occurs via the bowel. Iron in ferritin is lost as mucosal cells slough off, and iron also enters the bowel in bile. Small amounts are excreted in urine and sweat.
Note that, although very little iron leaves the body as a result of excretion (ie, normal physiologic loss), substantial amounts can leave because of blood loss. Hence, menorrhagia (excessive menstrual flow), hemorrhage, and blood donations can all cause iron deficiency.
Regulation of body iron content.
The amount of iron in the body is regulated through control of intestinal absorption. As noted, most of the iron that enters the body stays in the body. Hence, if all dietary iron were readily absorbed, body iron content would rapidly accumulate to a toxic level. However, excessive buildup is prevented through control of iron uptake: As body stores rise, uptake of iron declines; conversely, as body stores become depleted, uptake increases. For example, when body stores of iron are high, only 2% to 3% of dietary iron is absorbed. In contrast, when body stores are depleted, as much as 20% may be absorbed.
Daily requirements
Requirements for iron are determined largely by the rate of erythrocyte production. When RBC production is low, iron needs are low too. Conversely, when RBC production is high, iron needs rise. Accordingly, among infants and children—individuals whose rapid growth rate requires massive RBC synthesis—iron requirements are high (relative to body weight). In contrast, the daily iron needs of adults are relatively low. Adult males need only 8 mg of dietary iron each day. Adult females need considerably more (15 to 18 mg/day), in order to replace iron lost through menstruation.
During pregnancy, requirements for iron increase dramatically, owing to (1) expansion of maternal blood volume and (2) production of RBCs by the fetus. In most cases, the iron needs of pregnant women are too great to be met by diet alone. Consequently, iron supplements (about 27 mg/day) are recommended during pregnancy and for 2 to 3 months after parturition.
Table 55–1 summarizes the recommended dietary allowances (RDAs) of iron as a function of age. Of note, the RDA values in the table are about 10 times greater than actual physiologic need. Why? Because, on average, only 10% of dietary iron is absorbed. Hence, if physiologic requirements are to be met, the diet must contain 10 times more iron than we need.
TABLE 55–1
Recommended Dietary Allowances (RDAs) for Iron
Life Stage | Age | RDA for Iron (mg/day) |
Infants | 7–12 mo | 11 |
Children | 1–3 yr | 7 |
4–8 yr | 10 | |
Males | 9–13 yr | 8 |
14–18 yr | 11 | |
≥19 yr | 8 | |
Females: nonpregnant, nonlactating | 9–13 yr | 8 |
14–18 yr | 15 | |
19–50 yr | 18 | |
≥51 yr | 8 | |
Females: pregnant | 14–50 yr | 27* |
Females: lactating | 14–18 yr | 10 |
19–50 yr | 9 |
*Iron requirements during pregnancy cannot be met through dietary sources alone, and hence supplements are recommended.
Iron deficiency: causes, consequences, and diagnosis
Causes
Iron deficiency results when there is an imbalance between iron uptake and iron demand. As a rule, the imbalance results from increased demand—not from reduced uptake. The most common causes of increased iron demand (and resulting iron deficiency) are (1) blood volume expansion during pregnancy coupled with RBC synthesis by the growing fetus; (2) blood volume expansion during infancy and early childhood; and (3) chronic blood loss, usually of GI or uterine origin. Rarely, iron deficiency results from reduced iron uptake; potential causes include gastrectomy and sprue.
Consequences
Iron deficiency has multiple effects, the most conspicuous being iron deficiency anemia. In the absence of iron for hemoglobin synthesis, red blood cells become microcytic (small) and hypochromic (pale). The reduced oxygen-carrying capacity of blood results in listlessness, fatigue, and pallor of the skin and mucous membranes. If tissue oxygenation is severely compromised, tachycardia, dyspnea, and angina may result. In addition to causing anemia, iron deficiency impairs myoglobin production and synthesis of iron-containing enzymes. In young children, iron deficiency can cause developmental problems, and in school-age children, iron deficiency may impair cognition.
Diagnosis
The hallmarks of iron deficiency anemia are (1) the presence of microcytic, hypochromic erythrocytes, and (2) the absence of hemosiderin (aggregated ferritin) in bone marrow. Additional laboratory data that can help confirm a diagnosis include reduced RBC count, reduced reticulocyte hemoglobin content, reduced hemoglobin and hematocrit values, reduced serum iron content, and increased serum iron-binding capacity (IBC).*
Oral iron preparations
As shown in Table 55–2, iron for oral therapy is available in multiple forms. Of these, the ferrous salts (especially ferrous sulfate) and carbonyl iron are used most often. Accordingly, discussion below is limited to these iron preparations.
TABLE 55–2
Iron Preparations Available for Oral Therapy
Iron Preparation | Trade Names | Description |
Ferrous iron salts: | ||
Ferrous sulfate | Feosol, FeroSul, Ferodan![]() |
All four compounds are salts of the ferrous form of iron |
Ferrous gluconate | Fergon, Floradix, others | |
Ferrous fumarate | Ferro-Sequels, Hemocyte, Palafer![]() | |
Ferrous aspartate | FE Aspartate | |
Ferrous bisglycinate | Ferrochel, others | An iron–amino acid chelate |
Ferric ammonium citrate | Iron Citrate | A ferric iron salt |
Carbonyl iron | Feosol, Ircon, Icar, others | Microparticles of elemental iron |
Heme-iron polypeptide | Proferrin | Hemoglobin extracted from porcine RBCs |
Polysaccharide iron complex | Niferex-150 Forte, Ferrex 150, Triferexx 150![]() |
Ferric iron complexed to hydrolyzed starch |
Ferrous iron salts
We have two basic types of iron salts: ferrous salts and ferric salts. Discussion here is limited to the ferrous iron salts. Why? Because the ferrous salts are absorbed 3 times more readily than the ferric salts, and hence are more widely used. Four ferrous iron salts are available: ferrous sulfate, ferrous gluconate, ferrous fumarate, and ferrous aspartate. All four are equally effective, and with all four, GI disturbances are the major adverse effect.
Ferrous sulfate
Indications.
Ferrous sulfate is the treatment of choice for iron deficiency anemia. It is also the preferred drug for preventing deficiency when iron needs cannot be met by diet alone (eg, during pregnancy or chronic blood loss). Ferrous sulfate costs less than ferrous gluconate or ferrous fumarate, but has equal efficacy and tolerability.
Adverse effects.
The most significant adverse effects involve the GI tract. These effects, which are dose dependent, include nausea, pyrosis (heartburn), bloating, constipation, and diarrhea. Gastrointestinal reactions are most intense during initial therapy, and become less disturbing with continued drug use. Because of their GI effects, oral iron preparations can aggravate peptic ulcers, regional enteritis, and ulcerative colitis. Accordingly, patients with these disorders should not take iron by mouth. In addition to its other GI effects, oral iron may impart a dark green or black color to stools. This effect is harmless and should not be interpreted as a sign of GI bleeding.
Toxicity.
Iron in large amounts is toxic. Poisoning is almost always the result of accidental or intentional overdose, not from therapeutic doses. Death from iron ingestion is rare in adults. By contrast, in young children, iron-containing products are the leading cause of poisoning fatalities. For children, the lethal dose of elemental iron is 2 to 10 gm. To reduce the risk of pediatric poisoning, iron should be stored in childproof containers and kept out of reach.
Drug interactions.
Interaction of iron with other drugs can alter the absorption of iron, the other drug, or both. Antacids reduce the absorption of iron. Coadministration of iron with tetracyclines decreases absorption of both. Ascorbic acid (vitamin C) promotes iron absorption but also increases its adverse effects. Accordingly, attempts to enhance iron uptake by combining iron with ascorbic acid offer no advantage over a simple increase in iron dosage.
Preparations.
Ferrous sulfate is available in standard tablets, and in enteric-coated and sustained-release formulations. The enteric-coated and sustained-release products are designed to reduce gastric disturbances. Unfortunately, although side effects may be lowered, these special formulations have disadvantages. First, iron may be released at variable rates, causing variable and unpredictable absorption. Second, these preparations are expensive. Standard tablets do not share these drawbacks.
Some iron products are formulated with vitamin C. The goal is to improve absorption. Unfortunately, the amount in most products is too low to help: More than 200 mg of vitamin C is needed to enhance the absorption of 30 mg of elemental iron.
Trade names for ferrous sulfate products include Feosol, FeroSul, Slow FE, and Ferodan.
Dosage and administration.
Dosing with oral iron can be complicated in that oral iron salts differ with regard to percentage of elemental iron (Table 55–3). Ferrous sulfate, for example, contains 20% iron by weight. In contrast, ferrous gluconate contains only 11.6% iron by weight. Consequently, in order to provide equivalent amounts of elemental iron, we must use different doses of these iron salts. For example, if we want to provide 100 mg of elemental iron using ferrous sulfate, we need to administer a 500-mg dose. To provide this same amount of elemental iron using ferrous fumarate, the dose would be only 300 mg. In the discussion below, dosage values refer to milligrams of elemental iron, and not to milligrams of any particular iron compound needed to provide that amount of elemental iron.
TABLE 55–3
Commonly Used Oral Iron Preparations
Iron Preparation | % Elemental Iron (by weight) | Dose Providing 100 mg Elemental Iron |
Ferrous Iron Salts | ||
Ferrous sulfate | 20 | 500 mg |
Ferrous sulfate (dried) | 30 | 330 mg |
Ferrous fumarate | 33 | 300 mg |
Ferrous gluconate | 11.6 | 860 mg |
Ferrous aspartate | 16 | 625 mg |
Elemental Iron | ||
Carbonyl iron | 100 | 100 mg |
Food affects therapy in two ways. First, food helps protect against iron-induced GI distress. Second, food decreases iron absorption by 50% to 70%. Hence, we have a dilemma: Absorption is best when iron is taken between meals, but GI distress is lowest when iron is taken with meals. As a rule, iron should be administered between meals, thereby maximizing absorption. If necessary, the dosage can be lowered to render GI effects more acceptable.
For two reasons, it may be desirable to take iron with food during initial therapy. First, since the GI effects of iron are most intense when treatment commences, the salving effects of food can be especially beneficial early on. Second, by reducing GI discomfort during the early phase of therapy, dosing with food can help promote adherence.
Use in iron deficiency anemia.
Dosing with oral iron represents a compromise between a desire to replenish lost iron rapidly and a desire to keep GI effects to a minimum. For most adults, this compromise can best be achieved by giving 65 mg 3 times a day, yielding a total daily dose of about 200 mg. Since there is a ceiling to intestinal absorption of iron, doses above this amount provide only a modest increase in therapeutic effect. On the other hand, at dosages greater than 200 mg/day, GI disturbances become disproportionately high. Hence, elevation of the daily dose above 200 mg would augment adverse effects without offering a significant increase in benefits. When treating iron deficiency in infants and children, a typical dosage is 5 mg/kg/day administered in three or four divided doses.
Timing of administration is important: Doses should be spaced evenly throughout the day. This schedule gives the bone marrow a continuous iron supply, and thereby maximizes RBC production.
Duration of therapy is determined by the therapeutic objective. If correction of anemia is the sole objective, a few months of therapy is sufficient. However, if the objective also includes replenishing ferritin, treatment must continue another 4 to 6 months. It should be noted, however, that drugs are usually unnecessary for ferritin replenishment: In most cases, diet alone can do the job. Accordingly, once anemia has been corrected, pharmaceutical iron can usually be stopped.
Carbonyl iron
Carbonyl iron is pure, elemental iron in the form of microparticles, which confer good bioavailability. Therapeutic efficacy equals that of the ferrous salts. Because of the microparticles, iron is absorbed slowly, and hence the risk of toxicity is reduced. Compared with ferrous sulfate, carbonyl iron requires a much higher dosage to cause serious harm. Because of this increased margin of safety, carbonyl iron should pose a reduced risk to children in the event of accidental ingestion.
Carbonyl iron is available in several formulations, including (1) 45-mg tablets, marketed as Feosol; (2) 65-mg tablets, marketed as Ircon; (3) 90-mg film-coated tablets marketed as Ferralet 90; (4) 15-mg chewable tablets, marketed as Icar; and (5) a suspension (15 mg/1.25 mL), also marketed as Icar. Because these products contain 100% iron, rather than an iron salt, there should be no confusion about dosage: 100 mg of any formulation provides 100 mg of elemental iron. The usual dosage is 50 mg, 3 times a day.
Parenteral iron preparations
Iron is available in four forms for parenteral therapy. However, only one of these forms—iron dextran—is approved for iron deficiency of all causes. Approval of the other three forms—iron sucrose, sodium–ferric gluconate complex, and ferumoxytol—is limited to treating iron deficiency anemia in patients with chronic kidney disease.
Iron dextran
Iron dextran [INFeD, DexFerrum, Infufer, Dexiron
] is the most frequently used parenteral iron preparation. The drug is a complex consisting of ferric hydroxide and dextrans (polymers of glucose). The rate of response to parenteral iron is equal to that of oral iron. Iron dextran is dangerous—fatal anaphylactic reactions have occurred—and hence should be used only when circumstances demand.
Indications
Iron dextran is reserved for patients with a clear diagnosis of iron deficiency and for whom oral iron is either ineffective or intolerable. Primary candidates for parenteral iron are patients who, because of intestinal disease, are unable to absorb iron taken orally. Iron dextran is also indicated when blood loss is so great (500 to 1000 mL/wk) that oral iron cannot be absorbed fast enough to meet hematopoietic needs. Parenteral iron may also be employed when there is concern that oral iron might exacerbate pre-existing disease of the stomach or bowel. Lastly, parenteral iron can be given to the rare patient for whom the GI effects of oral iron are intolerable.
Adverse effects
Anaphylactic reactions.
Potentially fatal anaphylaxis is the most serious adverse effect. These reactions are triggered by dextran in the product, not by the iron. Although anaphylactic reactions are rare, their possibility demands that iron dextran be used only when clearly required. Furthermore, whenever iron dextran is administered, injectable epinephrine and facilities for resuscitation should be at hand. To reduce risk, each full dose should be preceded by a small test dose. However, be aware that even the test dose can trigger a fatal reaction. In addition, even when the test dose is uneventful, patients can still die from the full dose.

Full access? Get Clinical Tree

