Drugs for deficiency anemias

Anemia is defined as a decrease in the number, size, or hemoglobin content of erythrocytes (red blood cells [RBCs]). Causes include blood loss, hemolysis, bone marrow dysfunction, and deficiencies of substances essential for RBC formation and maturation. Most deficiency anemias result from deficiency of iron, vitamin B₁₂, or folic acid. Accordingly, this chapter focuses on anemias caused by these deficiencies. To facilitate discussion, we begin by reviewing RBC development.

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.

Figure 55–2 Fate of iron in the body.Pathways labeled with circled numbers are explained in the text. Values in parentheses indicate percentage of total body stores. Elimination of iron is not shown, because most iron is rigidly conserved. (Fe = iron, RBC = red blood cell.)

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.

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

Life Stage	Age	RDA for Iron (mg/day)
Infants	7–12 mo	11
Children	1–3 yr	7
Children	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
Females: lactating	19–50 yr	9

^*Iron requirements during pregnancy cannot be met through dietary sources alone, and hence supplements are recommended.

Dietary sources

Iron is available in foods of plant and animal origin. Foods especially rich in iron include liver, egg yolk, brewer’s yeast, and wheat germ. Other foods with a high iron content include muscle meats, fish, fowl, cereal grains, beans, and green leafy vegetables. Foods that do not provide much iron include milk and most nongreen vegetables. Since iron can be extracted from cooking utensils, using iron pots and pans can augment dietary iron. Except for individuals who have very high iron requirements (infants, pregnant women, those undergoing chronic blood loss), the average diet is sufficient to meet iron needs.

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).*

When a diagnosis of iron deficiency anemia is made, it is imperative that the underlying cause be determined. This is especially true when the suspected cause is GI-related blood loss. Why? Because GI blood loss may be indicative of peptic ulcer disease or GI cancer, conditions that demand immediate treatment.

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, Slow FE, others	All four compounds are salts of the ferrous form of iron
Ferrous gluconate	Fergon, Floradix, others
Ferrous fumarate	Ferro-Sequels, Hemocyte, Palafer, others
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, others	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.

GI disturbances.

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.

Staining of teeth.

Liquid iron preparations can stain the teeth. This can be prevented by (1) diluting liquid preparations with juice or water, (2) administering the iron through a straw or with a dropper, and (3) rinsing the mouth after administration.

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.

Symptoms.

The effects of iron poisoning are complex. Early reactions include nausea, vomiting, diarrhea, and shock. These are followed by acidosis, gastric necrosis, hepatic failure, pulmonary edema, and vasomotor collapse.

Diagnosis and treatment.

With rapid diagnosis and treatment, mortality from iron poisoning is low (about 1%). Serum iron should be measured and the intestine x-rayed to determine if unabsorbed tablets are present. Gastric lavage will remove iron from the stomach. Acidosis and shock should be treated as required.

If the plasma level of iron is high (above 350 to 500 mcg/dL), it should be lowered with parenteral deferoxamine [Desferal]. Another oral drug—deferasirox [Exjade]—is indicated for patients with chronic iron overload caused by blood transfusions. Both agents—deferoxamine and deferasirox—adsorb iron and thereby prevent toxic effects. The pharmacology of these drugs is discussed in Chapter 109 (Management of Poisoning).

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.

General considerations.

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.

Prophylactic use.

Pregnant women are the principal candidates for prophylactic therapy. A total daily dose of 27 mg, taken between meals, is recommended. Other candidates include infants, children, and women experiencing menorrhagia.

Ferrous gluconate, ferrous fumarate, and ferrous aspartate

In addition to ferrous sulfate, three other oral ferrous salts are available: ferrous gluconate [Fergon], ferrous fumarate [Ferro-Sequels, Hemocyte, Palafer, others], and ferrous aspartate [FE Aspartate]. Except for differences in percentage of iron content (see Table 55–3), all of these preparations are equivalent. Hence, when dosage is adjusted to provide equal amounts of elemental iron, ferrous gluconate, ferrous fumarate, and ferrous aspartate produce pharmacologic effects identical to those of ferrous sulfate. All four agents produce equivalent therapeutic responses, and all four cause the same degree of GI distress. Patients who fail to respond to one will not respond to the others. Patients who cannot tolerate the GI effects of one will find the others intolerable too.