NCLEX: Drugs for Anemia

Posted on February 9, 2017 by Anne Caporal

09
Feb
Anemia is defined as a below-normal plasma hemoglobin concentration resulting from a
decreased number of circulating red blood cells or an abnormally low total hemoglobin content
per unit of blood volume. General signs and symptoms of anemia include fatigue, rapid
heartbeat, shortness of breath, pale skin, dizziness, and insomnia. Anemia can be caused by
chronic blood loss, bone marrow abnormalities, increased hemolysis, infections, malignancy,
endocrine deficiencies, renal failure, and a number of other disease states. A large number of
drugs cause toxic effects on blood cells, hemoglobin production, or erythropoietic organs, which,
in turn, may cause anemia. Nutritional anemias are caused by dietary deficiencies of substances
such as iron, folic acid, and vitamin B12 (cyanocobalamin) that are necessary for normal
erythropoiesis. Individuals with anemia that has a genetic basis, such as sickle cell disease, can
benefit from pharmacologic treatment with actions beyond nutritional supplementation, such as
hydroxyurea. Anemia can be at least temporarily corrected by transfusion of whole blood.

Drugs for Anemia: AGENTS USED TO TREAT ANEMIAS

Focus topic: Drugs for Anemia

A. Iron

Focus topic: Drugs for Anemia

Iron is stored in the intestinal mucosal cells, liver, spleen, and bone marrow as ferritin (an iron–
protein complex) until needed by the body. Iron is delivered to the marrow for hemoglobin
production by a transport protein, namely transferrin. Iron deficiency results from acute or
chronic blood loss, from insufficient intake during periods of accelerated growth in children, and
in heavily menstruating or pregnant women. Thus, iron deficiency results from a negative iron
balance due to depletion of iron stores and/or inadequate intake, culminating in hypochromic
microcytic anemia (due to low iron and small-sized red blood cells). In addition to general signs
and symptoms of anemia, iron deficiency anemia may cause pica (hunger for ice, dirt, paper,
etc.), koilonychias (upward curvature of the finger and toe nails), and soreness and cracking at
the corners of the mouth.
1. Mechanism of action: Supplementation with elemental iron corrects the iron deficiency. The
CDC recommends 150 to 180 mg/day of oral elemental iron administered in divided doses two
to three times daily for patients with iron deficiency anemia.

2. Pharmacokinetics: Iron is absorbed after oral administration. Acidic conditions in the

stomach keep iron in the reduced ferrous form, which is the more soluble form. Iron is then
absorbed in the duodenum. [Note: The amount absorbed depends on the current body stores of
iron. If iron stores are adequate, less will be absorbed. If stores are low, more iron will be
absorbed.] The relative percentage of iron absorbed decreases with increasing doses. For this
reason, it is recommended that most people take the prescribed daily iron supplement in two or
three divided doses. Some extended-release formulations may be dosed once daily. Oral
preparations include ferrous sulfate, ferrous fumarate, ferrous gluconate, polysaccharide–iron
complex, and carbonyl iron formulations. Of these preparations, ferrous sulfate is the most
commonly used form of iron due to its high content of elemental iron and relatively low cost.
The percentage of elemental iron varies in each oral iron preparation.

Parenteral formulations of iron, such as iron dextran, sodium ferric gluconate complex, and iron
sucrose, are also available. Macrophages phagocytize iron dextran and release iron from the
dextran molecule. When iron sucrose is used, specific exchange mechanisms transfer iron to
transferrin. While parenteral administration treats iron deficiency rapidly, oral administration
may take several weeks.

3. Adverse effects: Gastrointestinal (GI) disturbances caused by local irritation (abdominal pain,
constipation, diarrhea, etc.) and dark stools are the most common adverse effects of oral iron
supplements. Parenteral iron formulations may be used in those who cannot tolerate oral iron.
Fatal hypersensitivity and anaphylactoid reactions can occur in patients receiving parenteral iron
(mainly iron dextran formulations). A test dose should be administered prior to iron dextran.
Excessive iron can cause toxicities that can be reversed using chelators such as deferoxamine.
B. Folic acid (folate)

Focus topic: Drugs for Anemia

The primary use of folic acid is in treating deficiency states that arise from inadequate levels of
the vitamin. Folate deficiency may be caused by 1) increased demand (for example, pregnancy
and lactation), 2) poor absorption caused by pathology of the small intestine, 3) alcoholism, or 4)
treatment with drugs that are dihydrofolate reductase inhibitors (for example, methotrexate,
pyrimethamine, and trimethoprim). In the latter case, the reduced or active form of the vitamin
(folinic acid—also known as leucovorin calcium—available as oral and parenteral formulations)
is used for treatment. A primary result of folic acid deficiency is megaloblastic anemia (large-
sized red blood cells), which is caused by diminished synthesis of purines and pyrimidines. This
leads to an inability of erythropoietic tissue to make DNA and, thereby, proliferate. [Note: To
avoid neurological complications of vitamin B12 deficiency, it is important to evaluate the basis
of the megaloblastic anemia prior to instituting therapy. Both vitamin B12 and folate deficiency
can cause similar symptoms.]

Folic acid is well absorbed in the jejunum unless pathology is present. If excessive amounts of
the vitamin are ingested, they are excreted in the urine and feces. Oral folic acid administration is
nontoxic. There have been no substantiated side effects reported. Rare hypersensitivity reactions
to parenteral injections have been reported.
C. Cyanocobalamin and hydroxocobalamin (vitamin B12)

Focus topic: Drugs for Anemia

Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, poor
absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as
in pernicious anemia), or a loss of activity of the receptor needed for intestinal uptake of the
vitamin. Intrinsic factor is a glycoprotein produced by the parietal cells of the stomach, and it is
required for vitamin B12 absorption. In patients with bariatric surgery (surgical treatment for
obesity), vitamin B12 supplementation as cyanocobalamin [syean-oh-koe-BAL-a-min] is
required in large oral doses, sublingually or once a month by the parenteral route. Intramuscular
hydroxocobalamin [hye-drox-oh-koe-BAL-a-min] is now preferred since it has a rapid response,
is highly protein bound, and maintains longer plasma levels. Nonspecific malabsorption
syndromes or gastric resection can also cause vitamin B12 deficiency. In addition to general
signs and symptoms of anemia, vitamin B12 deficiency anemia may cause tingling (pins and
needles) in the hands and feet, difficulty walking, dementia and, in extreme cases, hallucinations,
paranoia, or schizophrenia.

The vitamin may be administered orally (for dietary deficiencies), intramuscularly, or deep
subcutaneously (for pernicious anemia). [Note: Folic acid administration alone reverses the
hematologic abnormality and, thus, masks the vitamin B12 deficiency, which can then proceed to
severe neurologic dysfunction and disease. The cause of megaloblastic anemia needs to be
determined in order to be specific in terms of treatment. Therefore, megaloblastic anemia should
not be treated with folic acid alone but, rather, with a combination of folate and vitamin B12.]
Therapy must be continued for the remainder of the life of a patient suffering from pernicious
anemia. This vitamin is nontoxic even in large doses.

D. Erythropoietin and darbepoetin

Focus topic: Drugs for Anemia

Peritubular cells in the kidneys work as sensors that respond to hypoxia and mediate synthesis
and release of erythropoietin [eerith-ro-POI-eh-tin; EPO], a glycoprotein. EPO stimulates stem
cells to differentiate into proerythroblasts and promotes the release of reticulocytes from the
marrow and initiation of hemoglobin formation. EPO, thus, regulates red blood cell proliferation
and differentiation in bone marrow. Human erythropoietin (epoetin alfa), produced by
recombinant DNA technology, is effective in the treatment of anemia caused by end-stage renal
disease, anemia associated with human immunodeficiency virus infection, and anemia in bone
marrow disorders, anemias of prematurity, and anemias in some cancer patients. Darbepoetin
[dar-be-POE-e-tin] is a long-acting version of erythropoietin that differs from erythropoietin by
the addition of two carbohydrate chains, which improves its biologic activity. Therefore,
darbepoetin has decreased clearance and has a half-life about three times that of epoetin alfa.
Due to their delayed onset of action, these agents have no value in acute treatment of anemia.
Supplementation with iron may be required to ensure an adequate response. The protein is
usually administered intravenously in renal dialysis patients, but the subcutaneous route is
preferred for other indications. These agents are generally well tolerated, but side effects may
include elevation in blood pressure and arthralgia in some cases. [Note: The former may be due
to increases in peripheral vascular resistance and/or blood viscosity.] When epoetin alfa is used
to target hemoglobin concentrations more than 11 g/dL, serious cardiovascular events (such as
thrombosis and severe hypertension), increased risk of death, shortened time to tumor
progression, and decreased survival have been observed. The recommendations for all patients
receiving epoetin alfa or darbepoetin include a minimum effective dose that does not exceed a
hemoglobin level of 12 g/dL, and the hemoglobin should not rise by more than 1 g/dL over a 2-
week period. Additionally, if the hemoglobin level exceeds 10 g/dL, doses of epoetin alfa or
darbepoetin should be reduced or treatment should be discontinued.
Drugs for Anemia: AGENTS USED TO TREAT NEUTROPENIA

Focus topic: Drugs for Anemia

Myeloid growth factors or granulocyte colony–stimulating factors (G-CSF), such as filgrastim

[fil-GRAS-tim], tbo-filgrastim, and pegfilgrastim [pegfil-GRAS-tim], and granulocyte–
macrophage colony–stimulating factors (GM-CSF), such as sargramostim [sar-GRA-moe-stim],
stimulate granulocyte production in the marrow to increase the neutrophil counts and reduce the
duration of severe neutropenia. These agents are typically used prophylactically to reduce risk of
neutropenia following chemotherapy and bone marrow transplantation. Filgrastimand
sargramostim can be dosed either subcutaneously or intravenously, whereas tbo-filgrastim and
pegfilgrastim are dosed subcutaneously only. The main difference between the available agents
lies in the frequency of dosing. Filgrastim, tbo-filgrastim, and sargramostim are dosed once a
day beginning 24 to 72 hours after chemotherapy, until the absolute neutrophil count (ANC)
reaches 5000 to 10,000/μL. Pegfilgrastim is a pegylated form of G-CSF, resulting in a much
longer half-life when compared to the other agents. As such, it is given as a single dose 24 hours
after chemotherapy, rather than once daily. Monitoring of ANC is typically not necessary with
pegfilgrastim. There is no evidence to show superiority of one agent over another in terms of
efficacy, safety, or tolerability. Bone pain is a common adverse effect with these agents.

Drugs for Anemia: AGENTS USED TO TREAT SICKLE CELL DISEASE

Focus topic: Drugs for Anemia

A. Hydroxyurea

Focus topic: Drugs for Anemia

Clinical trials have shown that hydroxyurea [high-DROX-ee-YOURee-ah] can reduce the
frequency of painful sickle cell crises. Hydroxyurea is also used off-label to treat chronic
myelogenous leukemia and polycythemia vera. In sickle cell disease, the drug apparently
increases fetal hemoglobin levels, thus diluting the abnormal hemoglobin S (HbS). This process
takes several months. Polymerization of HbS is delayed in treated patients, so that painful crises
are not caused by sickled cells blocking capillaries and causing tissue anoxia. Important side
effects of hydroxyurea include bone marrow suppression and cutaneous vasculitis. It is important
that hydroxyurea is administered under the supervision of a physician experienced in the
treatment of sickle cell disease.

B. Pentoxifylline

Focus topic: Drugs for Anemia

Pentoxifylline [pen-tox-IH-fi-leen] is a methylxanthine derivative that has been called a

“rheologic modifier.” It increases the deformability of red blood cells (improves erythrocyte
flexibility) and reduces the viscosity of blood. This decreases total systemic vascular resistance,
improves blood flow, and enhances tissue oxygenation in patients with peripheral vascular
disease. It is indicated to treat intermittent claudication, where it can modestly control function
and symptoms. Unlabeled uses include improving psychopathological symptoms in patients with
cerebrovascular insufficiency. It has been studied in diabetic angiopathies, transient ischemic
attacks, leg ulcers, sickle cell anemias, strokes, and Raynaud’s phenomenon. It is available in
extended-release tablets and is taken three times a day with food. Adverse reactions are mainly
GI in nature and are lessened by administration with food.