THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

36. Anemias - Trevor McKibbin, PharmD, MS, BCPS

36-1. Disease Overview

Introduction

Anemia is a reduction in red cell mass that decreases the oxygen-carrying capacity of the blood. This chapter will focus on iron deficiency anemia (IDA), megaloblastic anemias, and anemia of renal failure.

Epidemiology

Approximately 3.4 million Americans have anemia. Anemia is more common in women than men.

Seventy-five percent of anemias result from iron deficiency, anemia of chronic disease, and acute bleeding. The remaining 25% of anemia cases result from bone marrow damage, decreased erythropoiesis, and hemolysis. IDA is the single most common form of anemia, accounting for 25% of all cases.

Kinetic Approach to Anemia

Anemia may be caused by one or more of three mechanisms: decreased red blood cell (RBC) production, increased RBC destruction, and blood loss.

Classification by Morphology

The most common way to classify an anemia is by the morphology (shape and structure) of the RBCs.

Macrocytic (large cell) morphology

Anemias in this class include the following:

• Megaloblastic anemia

• Folic acid deficiency (decreased red blood cell production)

• Vitamin B12 deficiency (decreased red blood cell production)

• Pernicious anemia

Normochromic, normocytic morphology

Anemias in this class may result from following:

• Acute blood loss

• Bone marrow failure (decreased RBC production)

• Hemolysis (increased RBC destruction)

• Immunologic destruction, such as occurs in autoimmune diseases and endocrine disorders

In aplastic anemia, marrow fails to produce all three types of blood cells, which results in anemia, neutropenia (decreased white blood cells), and thrombocytopenia (decreased platelets). About half of aplastic anemia cases are believed to be caused by drugs or chemicals. Drugs that cause aplastic anemia include chloramphenicol, felbamate, carbamazepine, and phenytoin.

Genetically inherited enzyme deficiencies such as glucose-6-phosphate dehydrogenase (G6PD) deficiency can lead to hemolysis, because RBCs deficient in G6PD are susceptible to hemolysis when exposed to certain oxidant drugs (e.g., dapsone, sulfamethoxazole, and nitrofurantoin).

RBC membrane abnormalities, such as those caused by hereditary spherocytosis, can cause increased RBC destruction.

Hypochromic (low hemoglobin content) or microcytic (small cell) morphology

Anemias in this class include the following:

• Iron deficiency anemia (decreased red blood cell production)

• Certain genetic anomalies, such as sickle cell anemia and thalassemia

Clinical Presentation

The signs and symptoms of anemia depend on the amount of time during which the anemia has developed and the severity of RBC depletion. An anemia that has developed over a long period of time may be asymptomatic in the beginning stages and then progress to fatigue, malaise, headache, exertional dyspnea, angina, pallor, or loss of skin tone. A patient with acute anemia, such as from recent blood loss, may present with tachycardia, shortness of breath, or lightheadedness.

Many of the signs and symptoms of anemia are secondary to tissue hypoxia. In the case of hypoxia, blood supply is shunted to life-sustaining organs (brain, heart, and kidney) and away from nonvital organs (e.g., extremities or nail beds), which results in pallor of the skin.

The various types of anemia have additional signs and symptoms that will be discussed in further detail in elsewhere in the chapter.

Pathophysiology

Iron deficiency anemia

IDA is the most common anemia, accounting for one-fourth of all anemia cases. It is caused by iron store depletion resulting from

• Inadequate oral intake of iron (especially animal protein)

• Increased iron demands, such as those found in

• Pregnant or lactating women

• Infants and adolescents, who experience periods of rapid growth

• The elderly

• Blood loss as a result of

• Menstruation or postpartum blood loss

• Trauma

• Gastrointestinal (GI) ulcers

• Inadequate absorption as a result of

• Medications (e.g., tetracyclines)

• Gastrectomy

• Enteritis

• Persistent diarrhea

• Disease states, such as

• Carcinomas

• Rheumatoid arthritis

Hemoglobin is composed of iron (heme) and proteins (globin). Lack of iron results in reduced hemoglobin synthesis. The RBCs produced under those conditions are

• Hypochromic (decreased concentration of hemoglobin)

• Microcytic (smaller cells)

Megaloblastic anemias

Megaloblastic anemias either are caused by a deficiency in or an inability to use vitamin B12 (cobalamin) or folic acid.

Vitamin B12 deficiency can result from

• Decreased intake: This problem may occur with patients who are strict vegetarians.

• Decreased absorption: Vitamin B12 requires gastric intrinsic factor to be absorbed. The lack of intrinsic factor results in pernicious anemia, which can be inherited or acquired by gastrectomy.

• Achlorhydria: Vitamin B12 requires an acidic environment to be absorbed. Chronic therapy with proton pump inhibitors and H2 antagonists may contribute to vitamin B12 deficiency.

• Inadequate utilization of vitamin B12: This problem can be a result of protein deficiencies.

Folic acid deficiency can result from

• Decreased intake: This problem is especially found in patients who are alcoholic, indigent, or elderly.

• Decreased absorption: This problem occurs in patients with Crohn's disease or celiac disease. It can also be drug induced.

• Increased demands: For example, deficiencies may occur during pregnancy or growth spurts or could accompany malignancy or long-term hemodialysis.

• Use of certain drugs: Such drugs include methotrexate and phenytoin.

Both vitamin B12 and folic acid are necessary for the RNA (ribonucleic acid) and DNA (deoxyribonucleic acid) required for cell division during the development of RBCs. Because RNA and DNA synthesis is impeded when vitamin B12 and folic acid levels are deficient, cell divisions are skipped, resulting in abnormally large cells (macrocytic anemia).

Anemia of renal failure

The primary reason that patients with renal failure are anemic is because of the lack of erythropoietin (EPO) production. EPO is a hormone produced primarily (90%) in the kidneys that stimulates the synthesis and differentiation of erythroid progenitor cells (precursors to RBCs).

The uremic environment in patients with chronic renal failure decreases the lifespan of RBCs.

Folic acid deficiency also can develop as a result of increased folic acid demands during synthesis of RBCs. Additionally, folic acid can be removed during hemodialysis.

Patients with chronic renal failure can become iron deficient as a result of iron and blood loss during dialysis.

Diagnostic Criteria

If anemia is suspected, the following blood tests should be performed:

• Complete blood cell count (CBC), which includes

• Hemoglobin (Hgb)

• Hematocrit (Hct)

• RBC count

• Red cell indices:

• Mean corpuscular volume (MCV), which is a measure of the size of RBCs

• Mean corpuscular hemoglobin (MCH), which is a measure of the weight of hemoglobin in a RBC (MCH will be low in the case of microcytosis or hypochromia)

• Mean corpuscular hemoglobin concentration (MCHC), which is a measure of the weight of hemoglobin, but is more useful than MCH because it can distinguish between low hemoglobin (hypochromia) and a small cell (MCHC will be low only in the case of hypochromia)

• Platelets

• Reticulocyte count (pre-RBCs)

• Red cell morphology

• Serum iron, total iron binding capacity (TIBC), transferrin saturation, and ferritin

• Bilirubin, which is a by-product of RBC destruction

Other tests include the following:

• Stool test for presence of blood

• Peripheral blood smear

• Thorough history and physical examination

Iron deficiency anemia

Blood work

The first level to decrease will be ferritin (storage form of iron). However, ferritin may be increased in inflammatory diseases. The iron level will be low. TIBC, which is a measure of the amount of binding space left on transferrin (transport protein of iron), will be increased. (Less iron in the blood means that more space will be available on the transferrin molecule.)

As the iron deficiency progresses, hemoglobin will decrease, because iron is a component of hemoglobin. Decreased hemoglobin indicates a hypochromic anemia. The hematocrit also will eventually fall.

MCV will be decreased, which indicates microcytosis. MCH and MCHC will be decreased, which indicates decreased hemoglobin. The blood smear will show a microcytic, hypochromic cell.

Specific signs and symptoms

In addition to the general signs and symptoms listed previously for anemia, the following additional symptoms may be present in severe IDA:

• Koilonychias (spoon-shaped nails)

• Angular stomatitis or glossitis

• Pica (appetite for nonfood substances such as chalk, soil, or clay)

Megaloblastic anemias

Blood work

Blood work should show the following:

• Decreased Hct and Hgb

• Decreased RBC count

• Elevated MCH, which indicates a macrocytosis

• Normal iron level, TIBC, and reticulocyte count

Vitamin B12 deficiency

If the problem is vitamin B12, the serum B12 level will be decreased. A positive Schilling test will indicate pernicious anemia. (The Schilling test determines absorption of vitamin B12 by measuring the amount of radioactive B12excreted in urine.)

Additional signs and symptoms include the following:

• Loss of vibratory sensation in lower extremities

• Ataxia or vertigo

• Glossitis

• Muscle weakness

• Neuropsychiatric abnormalities (e.g., irritability or emotional instability, dementia, psychosis)

Folic acid deficiency

In a case of folic acid deficiency, the folate level will be decreased. Overall, folic acid deficiency anemia is very similar to vitamin B12 deficiency anemia, except that the neurological symptoms that may be present with vitamin B12deficiency anemia are absent.

Anemia of renal failure

As the name implies, this anemia occurs in patients with chronic renal failure. Before diagnosis, other causes must be ruled out (e.g., blood loss). CBC will reveal a normochromic, normocytic anemia.

Treatment Principles and Goals

Iron deficiency anemia

In IDA treatment, the goal is to normalize Hgb and Hct:

• Hgb should increase 2 g/dL in 3 weeks.

• Hct should increase 6% in 3 weeks.

• Reticulocytosis usually will occur within 1 week.

If those indices do not improve within their respective time frames, the diagnosis should be reevaluated, and compliance with therapy should be confirmed.

A second goal is to replenish iron stores. Although Hgb and Hct will return to normal within 1-2 months, iron therapy should be continued for 3-6 months after Hgb is normalized to replenish total body iron stores.

Megaloblastic anemias

Goals of vitamin B12 replacement

Hgb should increase within 1 week.

If neurologic symptoms were present, they should improve within 24 hours. However, if vitamin B12 deficiency is long-standing, symptoms may not be relieved completely for several months.

Maintenance administration of vitamin B12 should continue for as long as nutritional intake is a problem.

Goals of folic acid replacement

RBC morphology will correct within 1-2 days. Hgb will start to normalize within 10 days. Hct will return to normal levels within 2 months.

Maintenance administration of folic acid should continue for as long as nutritional intake of folic acid is a problem.

Anemia of renal failure

The initial therapy goal is to reach a target Hgb of 11-12 g/dL through a slow, steady increase (usually within 2-4 months). Medication doses of erythropoiesis-stimulating agents should be titrated to maintain a Hgb level between 11-12 g/dL, not to exceed a Hgb of 13 g/dL.

Because laboratory variability in the measurement of hematocrit is greater than that of hemoglobin, reliance on the Hct measurement alone is not the optimal method for assessing the patient's response to treatment.

36-2. Drug Therapy

Iron Deficiency Anemia

Treatment consists of iron supplementation through therapeutic iron preparations (200 mg of elemental iron per day in 2-3 divided doses) (

Table 36-1). Iron is best absorbed in the reduced (ferrous) form. Ferrous sulfate salt, which is 20% elemental iron, is the most common form. Therefore, ferrous sulfate 325 mg tid will treat iron deficiency adequately.

Intravenous (IV) iron preparations should be used only in cases of

• Iron malabsorption

• Oral noncompliance

• Refusal of blood transfusion

IV iron formulations often are used in patients with chronic renal failure who require dialysis along with human recombinant erythropoietin therapy. Four IV iron products are available in the United States:

• Iron dextran (InFeD and Dexferrum)

• Ferric gluconate (Ferrlecit)

[Table 36-1. Drugs Used to Treat Iron Deficiency Anemia]

• Iron sucrose (Venofer)

• Feraheme (ferumoxytol)

Ferumoxytol was recently approved for iron-deficiency anemia in adult patients with chronic kidney disease.

Mechanism of action

Iron supplementation corrects the iron deficiency and enables Hgb to be synthesized at normal levels.

Patient instructions (for oral supplementation)

• Take iron supplementation 1-2 hours prior to a meal (on an empty stomach).

• If iron is intolerable on an empty stomach, take it with a small snack, but try to avoid dairy products or tea. (Food can decrease the absorption of iron by 50%.) Take it with orange juice if possible (orange juice may increase absorption).

• Keep out of reach of children. Iron is a major cause of ingestion deaths in children.

• Take iron 1 hour before or 3 hours after any antacids.

• Some medications interact with iron. Please ask your physician or pharmacist before taking any new medications in combination with iron.

• If constipation occurs, you may take over-the-counter docusate.

Adverse drug effects

The oral formulation primarily has GI effects:

• Dark-colored stools

• Constipation or diarrhea

• Nausea or vomiting

The IV formulations may have the following effects:

• Injection site reactions

• GI effects (e.g., diarrhea, nausea)

• Hypotension

• Allergic reactions, including anaphylaxis

The risk of anaphylaxis is greatest with iron dextran. Clinicians commonly administer a test dose before infusing the entire dose of this agent. Premedication with antihistamines and corticosteroids also may prevent anaphylaxis.

Drug interactions

• Antibiotics (tetracycline and quinolones): Iron binds to these antibiotics, preventing absorption.

• Antacids: Iron needs an acidic environment for optimal absorption.

Monitoring parameters

• Have reticulocytes, Hgb, and Hct increased?

• Is the iron tolerable? (Tolerance will influence compliance.)

• Is the patient improving symptomatically?

Kinetics

Bioavailability is increased in an acidic environment and is decreased by food.

Megaloblastic Anemias

Vitamin B12 should be administered orally if absorption is not an issue. The recommended daily intake is 2 mcg. A solution for nasal administration of vitamin B12 is also available.

A vitamin B12 deficiency that leads to pernicious anemia is usually corrected through intramuscular (IM) vitaminB12 (cyanocobalamin) injection as follows:

• Initially 1,000 mcg IM every day for 1 week

• Then 100-1,000 mcg IM every week for 4 weeks

• Then 100-1,000 mcg IM every month thereafter for maintenance

Although IM vitamin B12 is used more often, patients with deficiency states may be supplemented orally in very high doses (e.g., 1,000-2,000 mcg per day).

People choosing vegan diets should supplement with vitamin B12 daily and may require lower maintenance doses than those with absorption abnormalities. Pregnant women and breast-feeding mothers may have higher daily requirements.

Mechanism of action

Vitamin B12 supplementation allows for normal synthesis of the RNA and DNA involved in the synthesis of RBCs.

Patient instructions

If injections are given at home, the patient or family members should be counseled on sterile injection techniques and proper needle disposal.

Adverse drug effects

Vitamin B12 supplementation can cause the following adverse effects:

• Hyperuricemia or hypokalemia caused by increased synthesis of reticulocytes

• Sodium retention

• An expansion of the intravascular volume as a result of increased RBC synthesis, which can increase cardiac output and cause angina or dyspnea

• Itching in 1-10% of patients

• Diarrhea in 1-10% of patients

• Anaphylaxis in < 1% of patients

Monitoring parameters

• Monitor CBC. Is there an increase in Hgb?

• Is the patient improving symptomatically (especially neurologic symptoms, if present)?

• Is the potassium level normal?

Kinetics

Intrinsic factor is necessary for vitamin B12 absorption. It must be present for vitamin B12 to be transported across the GI mucosa.

Vitamin B12 is bound in blood to transcobalamin II and converted in tissues to active coenzymes methylcobalamin and deoxyadenosylcobalamin.

Folic Acid Deficiency Anemia

Folic acid deficiency anemia is corrected by supplementing folic acid 1 mg daily for 4 months. Once the underlying cause of the deficiency is corrected, folic acid supplementation may be discontinued. Long-term folate administration is necessary if the cause is not corrected, such as in hemodialysis or alcoholism.

Mechanism of action

Folic acid supplementation allows for normal RNA and DNA synthesis, both of which are involved in the synthesis of RBCs.

Patient instructions

• Stress the importance of compliance with regimen.

• Women of childbearing age should be counseled to take a multivitamin containing folic acid, regardless of whether an anemia is present, to prevent neural tube birth defects.

Adverse drug effects

Fewer than 1% of patients have allergic reactions to folic acid.

Drug interactions

Folic acid may increase phenytoin metabolism.

Phenytoin, primidone, sulfasalazine, para-aminosalicylic acid, and oral contraceptives may decrease folic acid concentrations.

Chloramphenicol may blunt response to folic acid.

Monitoring parameters

• Is the RBC morphology normalizing?

• Are the Hgb and Hct normalizing?

• Is the patient complying?

Kinetics

Folic acid is a water-soluble B vitamin absorbed in the small intestine with Cmax at 30 minutes to 1 hour.

Anemia of Renal Failure

Recombinant human erythropoietin

The primary cause of anemia in renal failure is decreased EPO synthesis; therefore, the optimal drug for this type of anemia is an erythropoiesis stimulating agent (ESA). Epoetin alfa (Procrit, Epogen) and darbepoetin alfa (Aranesp) are ESAs with similar mechanisms of action, but darbepoetin alfa has a longer half-life.

An ESA is indicated in the treatment of anemia associated with chronic renal failure, including dialysis and nondialysis patients. ESAs are indicated to elevate or maintain the RBCs and to decrease the need for transfusions in these patients. (Nondialysis patients with symptomatic anemia considered for therapy should have an Hct < 30%.) The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) guidelines recommend that epoetin be administered subcutaneously, because that route of administration is as effective (or more effective) than IV administration. However, epoetin often is administered intravenously in patients on dialysis, because the dialysis port offers easy IV access.

Mechanism of action

Human recombinant erythropoietin stimulates erythropoiesis (increased RBC production).

Patient instructions (Epoetin alfa)

• Do not shake the vial because the epoetin may break down, thus decreasing the medication's effectiveness.

• Store the medication in the refrigerator, but do not freeze. Keep it out of direct sunlight.

• Make sure that the solution in the vial is clear and free of particulate matter. Do not use if the solution is cloudy or frothy.

• Monitor your blood pressure at home and alert your physician of any significant increases in blood pressure.

• Single-use vials are intended to be used only once. Discard any remaining solution and vial. If the label is marked with an "M," the vial is a multidose vial, and it may be stored in the refrigerator for 21 days.

• Take your blood pressure medications exactly as prescribed while on this medication, and maintain a sodium-restricted diet.

• Avoid hazardous activity in the first 90 days of therapy (e.g., operating heavy machinery).

• As with all medications, watch for signs of possible allergic reaction. Tell your doctor if you experience a local reaction (swelling, itching, redness).

• A very small number of patients may experience an anaphylactic reaction (shortness of breath, wheezing, low blood pressure, rapid heart rate, sweating). If any of those reactions occur, discontinue using the medication immediately and call 911.

• Follow the instructions for correct sterile injection technique and needle disposal (Box 36-1).

Box 36-1. Instructions for Self-Administering Epotein Alfa

Preparing the dose

1. Wash your hands thoroughly with soap and water before preparing the medication.

2. Check the date on the epoetin alfa vial to be sure that the drug has not expired.

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3. Remove the vial of epoetin alfa from the refrigerator and allow it to reach room temperature. Each epoetin alfa vial is designed to be used only once: do not re-enter the vial. It is not necessary to shake epoetin alfa. Prolonged vigorous shaking may damage the product. Assemble the other supplies you will need for your injection.

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4. Hemodialysis patients should wipe off the venous port of the hemodialysis tubing with an antiseptic swab. Peritoneal dialysis patients should cleanse the skin with an antiseptic swab where the injection is to be made.

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5. Flip off the red protective cap but do not remove the gray rubber stopper. Wipe the top of the gray rubber stopper with an antiseptic swab.

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6. Using a syringe and needle designed for subcutaneous injection, draw air into the syringe by pulling back on the plunger. The amount of air should be equal to your epoetin alfa dose.

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7. Carefully remove the needle cover. Put the needle through the gray rubber stopper of the epoetin alfa vial.

8. Push the plunger in to discharge air into the vial. The air injected into the vial will allow epoetin alfa to be easily withdrawn into the syringe.

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9. Turn the vial and syringe upside down in one hand. Be sure the tip of the needle is in the epoetin alfa solution. Your other hand will be free to move the plunger. Draw back on the plunger slowly to draw the correct dose of epoetin alfa into the syringe.

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10. Check for air bubbles. The air is harmless, but too large an air bubble will reduce the epoetin alfa dose. To remove air bubbles, gently tap the syringe to move the air bubbles to the top of the syringe, then use the plunger to push the solution and the air back into the vial. Then re-measure your correct dose of epoetin alfa.

11. Double-check your dose. Remove the needle from the vial. Do not lay the syringe down or allow the needle to touch anything.


Injecting the dose

Patients on home hemodialysis using the intravenous injection route:

1. Insert the needle of the syringe into the previously cleansed venous port and inject the epoetin alfa.

2. Remove the syringe and dispose of the whole unit. Use the disposable syringe only once. Dispose of syringes and needles as directed by your doctor, by following these simple steps:

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• Place all used needles and syringes in a hard plastic container with a screw-on cap, or a metal container with a plastic lid, such as a coffee can properly labeled as to contents. If a metal container is used, cut a small hole in the plastic lid and tape the lid to the metal container. If a hard plastic container is used, always screw the cap on tightly after each use. When the container is full, tape around the cap or lid, and dispose of it according to your doctor's instructions.

• Do not use glass or clear plastic containers, or any container that will be recycled or returned to a store.

• Always store the container out of the reach of children.

• Please check with your doctor, nurse, or pharmacist for other suggestions. There may be special state and local laws that they will discuss with you.


Patients on home peritoneal dialysis or home hemodialysis using the subcutaneous route:

1. With one hand, stabilize the previously cleansed skin by spreading it or by pinching up a large area with your free hand.

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2. Hold the syringe with the other hand, as you would a pencil. Double check that the correct amount of epoetin alfa is in the syringe. Insert the needle straight into the skin at a 90° angle. Pull the plunger back slightly. If blood comes into the syringe, do not inject epoetin alfa, as the needle has entered a blood vessel; withdraw the syringe and inject at a different site. Inject the epoetin alfa by pushing the plunger all the way down.

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3. Hold an antiseptic swab near the needle and pull the needle straight out of the skin. Press the antiseptic swab over the injection site for several seconds. Use the disposable syringe only once.

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4. Use the disposable syringe only once. Dispose of syringes and needles as directed in the instructions at left, under step 2.

5. Always change the site for each injection as directed. Occasionally a problem may develop at the injection site. If you notice a lump, swelling, or bruising that does not go away, contact your doctor. You may wish to record the site you just used so you can keep track.

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Reproduced with permission from Procrit® package insert. Raritan, NJ: Ortho Biotech Products, LP; 2000.

Adverse drug effects

Table 36-2 shows adverse effects of epoetin alfa and the percentage of patients reporting them. The most common adverse effect is elevated blood pressure. ESAs are contraindicated in patients with uncontrolled hypertension.

Pure red cell aplasia (PRCA), in association with neutralizing antibodies to native erythropoietin, has been reported rarely in the literature. If PRCA is suspected, discontinue epoetin immediately.

Drug interactions

No drug interactions have been reported.

Monitoring parameters

Prior to initiation of therapy, the patient's iron stores should be evaluated. Transferrin saturation should be at least 20% and ferritin at least 100 ng/mL. Patients on ESA therapy often require iron supplementation for efficacy of the ESA.

[Table 36-2. Percentage of Patients Reporting Adverse Effects of Epoetin Alfa]

Monitor Hgb very closely. Once Hct approaches 12 g/dL, the dose of epoetin should be decreased. If Hgb increases more than 1 g/dL within 2 weeks, the dose should be decreased. The dose should be increased if Hgb has not increased 1 g/dL in 8 weeks and Hgb is not in the target Hct range of 11-12 g/dL.

Blood pressure should be adequately controlled prior to initiation of ESA therapy. Blood pressure must be closely monitored and controlled during therapy.

Monitor serum chemistries.

Kinetics

The half-life of epoetin is approximately 4-13 hours. The half-life of epoetin in patients not on dialysis with serum creatinine > 3 is no different than in patients requiring dialysis.

Other aspects

Epoetin alfa is also available in predrawn syringes.

Darbepoetin

Mechanism of action

Darbepoetin has the same mechanism of action as epoetin.

Patient instructions

Counseling points are very similar for both darbepoetin and epoetin, except that all darbepoetin vials are single-use only; therefore, the patient should dispose of the vial as instructed after each dose. Both darbepoetin and epoetin are available in predrawn syringes.

Adverse drug effects

The most common adverse effects are:

• Cardiovascular: Hypertension, hypotension, edema, arrhythmia

• GI: Nausea, vomiting, diarrhea, constipation

• Central nervous system: Fatigue, fever, headache

• Neuromuscular or skeletal: Myalgia, arthralgia, limb pain

• Respiratory: Infection, dyspnea, cough

Drug interactions

No drug interactions have been reported.

Monitoring parameters

• Monitor patient's iron stores prior to and during therapy.

• Monitor patient's blood pressure.

• Adjust dose by closely monitoring Hgb every week until maintenance dose is established. Target Hgb is 12g/dL. Increase dose if Hgb increases more than 1 g/dL over a 4-week period. Decrease dose by 25% if Hgb increases more than 1 g/dL over 2-week period.

Kinetics

Darbepoetin's half-life is 21 hours when administered intravenously and 49 hours when administered subcutaneously. Its half-life is approximately three times longer than epoetin's. Because of its longer half-life, less frequent dosing options are available with darbepoetin.

36-3. Nondrug Therapy

Iron Deficiency Anemia

Dietary supplementation plays an important role in IDA treatment:

• Increase intake of iron-rich foods, such as meat, fish, and poultry.

• Drink orange juice with meals when possible.

• Limit tea or milk with meals. Only use in moderation between meals.

Folic Acid Deficiency Anemia

Dietary supplementation also is important in treating folic acid deficiency:

• To get as much dietary folate as possible, do not overcook vegetables. Eat them raw or steamed.

• Eat a wide variety of properly prepared vegetables, fruits, and mushrooms.

36-4. Key Points

• Anemia is a reduction in red cell mass, which decreases the blood's oxygen-carrying capacity.

• Iron deficiency anemia is the most common anemia, accounting for 25% of all cases. IDA presents as a microcytic, hypochromic anemia.

• Iron preparations are best absorbed on an empty stomach.

• Iron preparations are hard to tolerate as a result of their numerous GI effects, which may necessitate administration with a small snack.

• Megaloblastic anemias are macrocytic and are the result of a folic acid or vitamin B12 deficiency.

• Vitamin B12 requires intrinsic factor to be absorbed. Patients deficient in intrinsic factor develop pernicious anemia.

• Because many patients experience difficulties absorbing vitamin B12, it often is administered via an IM injection.

• The primary reason that patients with renal failure are anemic is because of the lack of erythropoietin production.

• Anemia of renal failure is treated with subcutaneous or (SC) IV epoetin.

• Patients receiving epoetin must have their hematocrit and blood pressures monitored routinely.

• Darbepoetin has the same mechanism of action as epoetin, but it is longer acting and can be administered less frequently.

36-5. Questions

Use Patient Profile 1 to answer questions 1-5.

Patient Profile 1—SuperPrice Drug Store

 

Patient name: George M. McBeavy

DOB: 7/11/52

Address: 1040 Dauberson Ave.

Allergies: NKDA

Weight: 193 pounds

 

Problem list

Gastroesophageal reflux disease

Iron deficiency anemia

Hypertension

Medication record

Ferrous sulfate 325 mg tid

Hydrochlorothiazide 25 mg daily

OTC recommendations

Maalox 1 tbsp q2h prn for "indigestion"

Acetaminophen 325 mg q4-6h prn for headache

Ranitidine 75 mg daily prn for "heartburn"

Docusate 100 mg daily for constipation

1.

Which medication could present a problem with Mr. McBeavy's iron supplement?

A. Acetaminophen

B. Ranitidine

C. Maalox

D. Docusate

E. Ranitidine and Maalox

 

2.

Mr. McBeavy admits to you that he is not able to take his iron tablet because it makes him nauseated. What advice can you give him?

A. Take your iron with some crackers and milk.

B. Take your iron with some crackers and water.

C. Don't worry about it. It's only a vitamin.

D. Start taking iron with the largest meal of the day.

E. Take iron after breakfast.

 

3.

If Mr. McBeavy's anemia progresses to severe stages, what effects may he experience?

A. Koilonychia (spooning of the nails)

B. Pica (e.g., craving ice, clay, chalk)

C. Glossitis (sore, beefy red tongue)

D. Extreme fatigue

E. All of the above

 

4.

If you were to examine Mr. McBeavy's blood smear, you would find cells that are

A. microcytic and hypochromic.

B. macrocytic and hypochromic.

C. macrocytic and normochromic.

D. microcytic and normochromic.

 

5.

When one is examining Mr. McBeavy's iron study results, which of the following would be consistent with iron deficiency anemia?

A. Elevated TIBC

B. Elevated ferritin

C. Elevated MCV

D. Elevated hemoglobin

E. Elevated hematocrit

 

6.

Which iron preparation is most likely to cause an anaphylactic reaction?

A. IV iron dextran

B. IV iron sucrose

C. IV sodium ferric gluconate

D. Extended-release ferrous sulfate po

E. Immediate-release ferrous sulfate po

 

7.

Why are sustained-release (SR) preparations of iron not the ideal formulation?

A. The incidence of nausea is higher with SR formulations.

B. They are dosed only once daily, and goal Hgb levels are not attained.

C. Because SR preparations are dissolved in the small intestines, the alkaline environment results in a lower bioavailability than the acidic environment of the stomach.

D. Dissolution in the small intestines is not bioavailable, because intrinsic factor is not present in the small intestines.

E. SR preparations require dosing with food.

 

8.

Which of the following options would you advise a patient to drink with meals to optimize iron absorption from meals?

A. Orange juice

B. Coffee

C. Tea

D. Milk

 

9.

The most likely regimen to supplement vitamin B12 is

A. 1,000 mcg po every month.

B. 1,000 mcg IV every month.

C. 1,000 mcg IM every month.

D. 1,000 mcg IM every day.

E. Any one of the above is a reasonable regimen.

 

10.

To be absorbed, vitamin B12 requires which of the following?

A. Pernicious factor

B. Transcobalamin II

C. Intrinsic factor

D. Vitamin B12 absorption factor

E. All of the above

 

11.

Folic acid deficiency could be found in all of the following patients except

A. strict vegetarians.

B. alcoholics.

C. the indigent.

D. people who routinely overcook their vegetables.

E. a college student whose diet consists only of burgers and potato chips.

 

12.

Folic acid may interact with which of the following medications?

A. Propranolol

B. Propoxyphene

C. Piroxicam

D. Phenytoin

E. Prednisone

 

13.

The two macrocytic anemias are

A. vitamin B12 deficiency and iron deficiency anemias.

B. vitamin B12 deficiency and folic acid deficiency anemias.

C. iron deficiency and folic acid deficiency anemias.

D. sickle cell anemia and anemia of renal failure.

E. iron deficiency and pernicious anemias.

 

14.

The best regimen to replace folic acid is

A. folic acid 1 mg po every day for 3-4 months.

B. folic acid 10 mg po every day for 3-4 months.

C. folic acid 10 mg IV for 2 weeks, then 1 mg po every day for 2 months.

D. folic acid 1 mg po three times weekly for 3-4 months.

E. folic acid 1 mg po once monthly for 6 months.

 

15.

The most common medication given to treat anemia of renal failure is

A. vitamin B12.

B. a solution of citric acid in combination with sodium acetate.

C. epoetin alfa.

D. ferrous sulfate po.

E. folic acid po.

 

16.

What advantage does darbepoetin have over epoetin?

A. Lower incidence of hypertension

B. Fewer drug interactions

C. Lower cost

D. Longer half-life and less frequent administration

E. Improved tolerability

 

17.

The most common side effect of epoetin is

A. anaphylaxis.

B. hypertension.

C. pure red cell aplasia.

D. injection site reaction.

E. weight gain.

 

18.

Prior to initiation of epoetin therapy, which of the following should be evaluated?

A. Folic acid and vitamin B12 levels

B. Transferrin and ferritin levels

C. Erythropoietin receptor level

D. Presence or absence of intrinsic factor

E. All of the above

 

19.

In which of the following patients would it be possible to teach self-administration of epoetin at home?

I. A patient on home hemodialysis taking epoetin via IV administration

II. A patient on home peritoneal dialysis taking epoetin via SC administration

III. A patient on home hemodialysis taking epoetin via SC administration

A. II only

B. II and III only

C. III only

D. I, II, and III

E. I only

 

Use Patient Profile 2 to answer questions 20-23.

Patient Profile 2—Central Dialysis Center

 

Patient name: Rebecca S. Wiley

Weight: 148 pounds

Diagnosis:

Hypertension

Diabetes mellitus

End-stage renal disease

Hyperlipidemia

Labs:

Ferritin: 80 ng/mL (normal)

Transferrin saturation: 15% (low)

Hct: 32% (low)

Hemoglobin: 8.6 g/dL (low)

Address: 1460 Sawyer Brown Rd.

Allergies: Penicillin (rash)

Dialysis schedule: Monday, Wednesday, Friday

Medications:

Insulin NPH 30 U bid

Simvastatin 20 mg qhs

Atenolol 25 mg after dialysis

Nephrocaps 1 capsule daily

20.

Which of the following will be monitored when Mrs. Wiley starts epoetin therapy?

A. Blood pressure

B. Hematocrit

C. Serum chemistries

D. Iron profile

E. All of the above

 

21.

The target Hgb range for Mrs. Wiley is

A. 11-12 g/dL.

B. 9-11 g/dL.

C. 11-13 g/dL.

D. 12-13 g/dL.

E. 9-14 g/dL.

 

22.

Which of Mrs. Wiley's medications will interact with epoetin?

A. Insulin

B. Simvastatin

C. Atenolol

D. None of the above

E. All of the above

 

23.

What medication should be added to Mrs. Wiley's regimen?

A. Oral propranolol

B. IV iron

C. Oral levothyroxine

D. IM vitamin B12

E. No additional medications are required at this time.

 

36-6. Answers

1.

E. Iron is best absorbed in an acidic environment. Therefore, antacids dramatically decrease the absorption of iron. Iron supplements should be taken 1 hour before or 3 hours after antacids.

 

2.

B. Many patients are not able to tolerate iron on an empty stomach. Those patients should take iron with a small snack. Milk would not be acceptable in this case, because dairy products decrease the absorption of iron.

 

3.

E. Koilonychia, pica, extreme fatigue, and glossitis all are symptoms of severe iron deficiency anemia.

 

4.

A. Iron deficiency produces a hypochromic (low-hemoglobin) anemia, given that iron is a component of the hemoglobin molecule. The cells are also microcytic (meaning "small cell"), because they spend longer in the marrow awaiting proper hemoglobin synthesis and therefore divide more.

 

5.

A. Total iron-binding capacity is elevated in IDA. TIBC is a measure of the amount of binding space left on transferrin (the transport protein of iron). Less iron in the blood means that more space is available on the transferrin molecule.

 

6.

A. IV iron dextran has the highest incidence of anaphylaxis among the four IV iron preparations available.

 

7.

C. SR preparations are left intact in the stomach and are dissolved in the small intestine. The alkaline environment of the small intestine tends to form insoluble iron complexes that cannot be absorbed.

 

8.

A. Tea and milk can decrease the absorption of iron from a meal by more than 50%. Orange juice, however, can double the absorption of iron from food.

 

9.

C. The most common IM dose of vitamin B12 is 1,000 mcg per month. However, vitamin B12 may be supplemented by the oral route if absorption is not impaired. Additionally, it may be supplemented in very high doses, such as 1,000-2,000 mcg per day in pernicious anemia.

 

10.

C. Vitamin B12 requires intrinsic factor for absorption.

 

11.

A. Folic acid deficiency is found in alcoholics, the indigent, and—rarely—in people who overcook their vegetables routinely. Strict vegetarians do not develop folic acid deficiency because a folate-rich diet includes various types of vegetables.

 

12.

D. Phenytoin increases the metabolism of folate, thereby decreasing the effectiveness of folic acid.

 

13.

B. Vitamin B12 deficiency and folic acid anemias are both macrocytic (large cell) anemias. Iron deficiency anemia and sickle cell anemia are both microcytic and hypochromic anemias.

 

14.

A. Folic acid is administered po because it is absorbed easily. The proper dose is 1 mg folic acid po every day, and the deficiency should be corrected after 3-4 months.

 

15.

C. Epoetin is the most common medication used to treat anemia of renal failure, because it stimulates erythropoiesis. The lack of erythropoietin production is the primary cause of anemia of renal failure.

 

16.

D. Darbepoetin is very similar to epoetin because it has the same mechanism of action and similar side effects. However, it has a longer half-life and can be administered less frequently.

 

17.

B. Hypertension is the most common adverse drug effect from epoetin.

 

18.

B. Transferrin and ferritin levels should be evaluated prior to epoetin therapy. IDA is a common problem in patients with end-stage renal disease. The patient's transferrin should be at least 20% and ferritin should be at least 100 ng/mL before epoetin therapy is initiated.

 

19.

D. Patients on home peritoneal dialysis or hemodialysis can be taught to self-administer SC injections. Additionally, if patients are receiving home hemodialysis, they can be taught to take their epoetin intravenously through the dialysis venous port.

 

20.

E. Iron profiles need to be monitored prior to starting epoetin and periodically during therapy because IDA is very common in dialysis patients. Blood pressure needs to be monitored because increased blood pressure is the most common adverse effect of epoetin. Hematocrit levels need to be checked as a measure of response to epoetin, and levels should be maintained at 30-36%. Serum chemistries need to be monitored regularly in any patient with end-stage renal disease, because most electrolytes are regulated by the kidney.

 

21.

A. The target range of Hgb for patients receiving epoetin is 11-12 g/dL.

 

22.

D. No drugs are known to interact with epoetin.

 

23.

B. Mrs. Wiley's ferritin is less than 100 ng/mL, and her transferring saturation is less than 20%. Most hemodialysis patients receiving epoetin will need iron therapy at some point during their treatment.

 

36-7. References

Agarwal AK. Practical approach to the diagnosis and treatment of anemia associated with CKD in elderly. J Am Med Dir Assoc. 2006;7(suppl 1):S7-12.

Alleyne M, Horne MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med. 2008;121:943.

Fishbane S. Safety in iron management. Am J Kid Dis. 2003;41:S18-26.

Ineck B, Mason BJ, Lyons W. Anemias. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:1639-64.

National Kidney Foundation: K/DOQI clinical practice guidelines for anemia of chronic kidney disease, 2000. Am J Kidney Dis. 2001;37(suppl 1): S182-238.

Parker KP, Mitch WE, Stivelman JC, et al. Safety and efficacy of low-dose subcutaneous erythropoietin in hemodialysis patients. J Am Soc Nephrol. 1999; 8:288.

Procrit [package insert]. Raritan, N.J.: Ortho Biotech Products; 2000.