Antianemia Drugs

Definition

Antianemia drugs are therapeutic agents which increase either the number of red cells or the amount of hemoglobin in the blood.

Purpose

Anemia is a general term for a large number of conditions marked by a reduction in the oxygen-carrying capacity of blood. Red blood cells carry oxygen in hemoglobin, so that anemia may be caused by a deficiency of blood or red blood cells or of hemoglobin. These conditions may be caused by a variety of other conditions. Injury can cause blood loss, which in turn can cause anemia. Nutritional deficiency, inadequate amounts of some of the vitamins and minerals that are needed for hemoglobin production, may also cause anemia. Because hemoglobin is the pigment that makes blood cells red, a lack of hemoglobin will cause the cells to be a paler color, leading to the term hypochromic, lacking in color.

Other conditions can also cause anemia. For example, certain diseases cause the condition. These can include infections and kidney disease, in which there is a deficiency of erythropoietin, a material produced in the kidneys which is essential for the production of red blood cells. Certain genetic conditions affect the absorption of nutrients and may lead to anemia. In sickle cell anemia, a genetic condition in which the red cells are curved rather than flat, the red cells have reduced ability to carry oxygen.

The Merck Manual reduces all types of anemia to three classes:

• blood loss
• inadequate production of blood
• excessive breakdown of blood cells

Anemia may be caused by one or a combination of these three factors. Drug therapy is available for many types of anemia; however, the selection of the drug depends on proper diagnosis of the cause of the anemia.

Description

Anemia caused by blood loss is normally treated with either blood volume expanders such as plasma or with related blood products. More severe blood loss may require transfusions of red blood cells.

In some cases, blood loss may be due to ulcers of the stomach or intestines. In these cases, treatment of the underlying cause will normally correct the anemia.

Iron deficiency

The most common cause of anemia in adults is iron deficiency. Although the typical American diet contains enough iron to meet normal needs, individuals who are less able to absorb and store iron may experience inadequate hemoglobin production. Although the best way to meet daily iron requirements is through improved diet, iron supplements are widely used.

KEY TERMS

Anabolic steroid— Drugs, derived from the male sex hormones, which increase the rate of tissue growth. They are best known for increasing the rate of muscle development.

Anemia— Any condition in which the amount of hemoglobin in red cells, the number of red cells, or the size of the red cells in blood is reduced from the normal.

Crohn's disease— Chronic inflammation of the intestine.

Hemochromatosis— A disorder of iron metabolism characterized by excessive absorption of iron from food.

Hemoglobin— The red protein found in blood cells which carries oxygen from the lungs to the tissues.

Hemolytic anemia— A type of anemia marked by the breakdown of red blood cells causing the release of hemoglobin.

Sickle cell anemia— An inherited condition, marked by crescent-shaped red blood cells and red cell breakdown.

Iron is normally taken in the form of ferrous sulfate. Although other iron salts are commercially available and make claims of fewer or less severe side effects, these benefits may be related to the fact that other preparations contain less iron by weight. Ferrous sulfate contains about 37% iron, while ferrous gluconate contains only about 13% iron. People who have trouble with the side effects of ferrous sulfate may benefit from some of the specialty preparations available, but ferrous sulfate normally offers the greatest amount of iron of all commercial products.

Recommended dosage

Dosage should be calculated by iron needs, based on laboratory tests. Manufacturers recommend one tablet a day, containing 65 mg of iron, as a supplement for patients over the age of 12 years.

Precautions

Iron can lead to lethal poisoning in children. All iron supplements should be kept carefully out of reach of children.

Some types of anemia do not respond to iron therapy, and the use of iron should be avoided in these cases. People with acquired hemolytic anemia, autoimmune hemolytic anemia, hemochromatosis, hemolytic anemia and hemosiderosis should not take iron supplements. Hemolytic anemia is caused by the increased breakdown of red blood cells. Hemochromatosis and hemosiderosis and are conditions in which there is too much, rather than too little, absorption of iron.

Iron supplements should also be avoided by people who have gastric or intestinal ulcers, ulcerative colitis, or Crohn's disease. These conditions marked by inflammation of the digestive tract, which would be made worse by use of iron.

Side effects

The most common side effects of iron consumption are stomach and intestinal problems, including stomach upset with cramps, constipation, diarrhea, nausea, and vomiting. At least 25% of patients have one or more of these side effects. The frequency and severity of the side effects increases with the dose of iron. Less frequent side effects include heartburn and urine discoloration.

Interactions

Iron supplements should not be taken at the same time as antibiotics of either the tetracycline or quinolone types. The iron will reduce the effectiveness of the antibiotic. Also, iron supplements reduces the effectiveness of levodopa, which is used in treatment of Parkinson's disease.

Iron supplements should not be used with magnesium trisilicate, an antacid, or with penicillamine, which is used for some types of arthritis.

Taking iron with vitamin C increases the absorption of iron, with no increase in side effects.

Folic acid

Folic acid is found in many common foods, including liver, dried peas, lentils, oranges, whole-wheat products, asparagus, beets, broccoli, brussel sprouts, and spinach. However, in some cases, patients have difficulty absorbing folic acid or in converting it from the form found in foods to the form that is active in blood formation. In these cases, folic acid tablets are appropriate for use.

RECOMMENDED DOSAGE. For treatment of anemia, a daily dose of 1 mg is generally used. Patients who have trouble absorbing folic acid may require higher doses.

Maintenance doses are:

• infants: 0.1 mg/day
• children (under 4 years of age): up to 0.3 mg/day
• children (over 4 years of age) and adults: 0.4 mg/day
• pregnant and lactating women: 0.8 mg/day

PRECAUTIONS. Before treating an anemia with folic acid, diagnostic tests must be performed to verify the cause of the anemia. Pernicious anemia caused by lack of vitamin B₁₂ shows symptoms that are very similar to those of folic acid deficiency but also causes nerve damage which shows up as a tingling sensation and feelings of numbness. Giving folic acid to patients with B₁₂ deficiency anemia improves the blood cell count, but the nerve damage continues to progress.

SIDE EFFECTS. Folic acid is considered extremely safe, and there are no predictable side effects. Where side effects have been reported, they have been among patients taking many times more than the normal therapeutic dose of the drug.

On rare occasions allergic reactions to folic acid have been reported.

INTERACTIONS. Phenytoins, used to treat seizure disorders, interact with folic acid with a reduction in phenytoin effectiveness and an increased risk of seizures. If the two drugs must be used together, phenytoin blood levels should be monitored, and the dose may have to be increased.

Trimethoprim (an antibacterial) and methotrexate (originally an anti-cancer drug, which is also used for arthritis and psoriasis ) act by reducing the metabolism of folic acid. Regular blood monitoring is required, and dose adjustments may be needed.

Vitamin B₁₂

Vitamin B₁₂ is also known as cyanocobalamine and hydroxocobalamine. Cyanocobalamine may be given by mouth, while hydroxocobalamine must be injected. The vitamin has many functions in the body, including maintaining the nervous system, but in treatment of anemia B₁₂ is needed for the metabolism of folic acid. Lack of B₁₂ causes pernicious anemia, a type of anemia which is marked by a low red cell count and lack of hemoglobin. There are many other symptoms of pernicious anemia, including a feeling of tingling or numbness, shortness of breath, muscle weakness, faintness, and a smooth tongue. If pernicious anemia is left untreated for more than three months, permanent damage to the nerves of the spinal cord may result.

RECOMMENDED DOSAGE. While vitamin B₁₂ can be given by mouth for mild vitamin deficiency states, pernicious anemia should always be treated with injections, either under the skin (subcutaneous) or into muscle (intramuscular). Hydroxocobalamine should only be injected into muscle. Intravenous injections are not used because the vitamin is eliminated from the body too quickly when given this way. Elderly patients, whose ability to absorb vitamin B₁₂ through the stomach may be impaired, should also be treated with injections only.

The normal dose of cyanocobalamine is 100 mcg (micrograms) daily for six to seven days. If improvement is seen, the dose may be reduced to 100 mcg every other day for seven doses and then 100 mcg every three to four days for two to three weeks. After that, monthly injections may be required for life.

PRECAUTIONS. Although vitamin B₁₂ has a very high level of safety, commercial preparations may contain preservatives which may cause allergic responses.

In patients with pernicious anemia, treatment with vitamin B₁₂ may lead to loss of potassium. Patients should be monitored for their potassium levels.

SIDE EFFECTS. Diarrhea and itching of the skin have been reported on rare occasions. Moreover, there have been reports of severe allergic reactions to cyanocobalamine.

INTERACTIONS. Aminosalicylic acid may reduce the effectiveness of vitamin B₁₂. Also, colchicine, a drug used for gout, may reduce the effectiveness of vitamin B₁₂. Other, infrequently used drugs and excessive use of alcohol may also affect the efficacy of vitamin B₁₂. Patients being treated for anemia should discuss all medications, both prescription and nonprescription, with their physician or pharmacist.

Anabolic steroids

The anabolic steroids (nandrolone, oxymetholone, oxandrolone, and stanzolol) are the same drugs that are used improperly by body builders to increase muscle mass. Two of these drugs, nandrolone and oxymetholone, are approved for use in treatment of anemia. Nandrolone is indicated for treatment of anemia caused by kidney failure, while oxymetholone may be used to treat anemia caused by insufficient red cell production, such as aplastic anemia.

All anabolic steroids are considered to be drugs of abuse under United States federal law.

RECOMMENDED DOSAGE. The information that follows is specific only to oxymetholone; however, the warnings and precautions apply to all drugs in the class of anabolic steroids.

The dosage of oxymetholone must be individualized. The most common dose is 1 to 2 mg per kilogram of body weight per day, although doses as high as 5 mg per kilogram per day have been used. The response to these drugs is slow, and it may take several months to see if there is any benefit.

PRECAUTIONS. All anabolic steroids are dangerous. The following warnings represent the most significant hazards of these drugs. For a complete list, patients should consult the manufacturer's package insert.

• Peliosis hepatitis, a condition in which liver and sometimes spleen tissue is replaced with blood-filled cysts, has occurred in patients receiving androgenic anabolic steroids. Although this condition is usually reversible by discontinuing the drug, if it is left undetected and untreated, it may lead to life-threatening liver failure or bleeding.
• Liver tumors may develop. Although most of these tumors are benign and will go away when the drug is discontinued, liver cancers may also result.
• Anabolic steroids may cause changes in blood lipids, leading to atherosclerosis with greatly increased risk of heart attack.
• Because anabolic steroids are derived from male sex hormones, masculinization may occur when they are used by women.
• Elderly men who use these drugs may be at increased risk of prostate enlargement and prostate cancer.
• Increased water retention due to anabolic steroids may lead to heart failure.
• Anabolic steroids should not be used during pregnancy, since this may cause masculinization of the fetus.

• Anabolic steroids should be used in children only if there is no possible alternative. These drugs may cause the long bones of the legs to stop growing prematurely, leading to reduction in adult height. Regular monitoring is essential.
• In patients with epilepsy, the frequency of seizures may be increased.
• In patients with diabetes, glucose tolerance may be altered. Careful monitoring is essential.

SIDE EFFECTS. The list of side effects associated with anabolic steroids is extremely long. The following list covers only the most commonly observed effects:

• acne
• increased urinary frequency
• breast growth in males
• breast pain
• persistent, painful erections
• masculinization in women

INTERACTIONS. Anabolic steroids should not be used in combination with anticoagulants such as warfarin. Anabolic steroids increase the effects of the anticoagulant, possibly leading to bleeding. If the combination cannot be avoided, careful monitoring is essential.

Epoetin alfa

Epoetin alfa is a synthetic form of a protein produced by the kidneys that stimulates the production and release of red blood cells. A similar drug, darepoetin alpha, is available with the same properties, but it remains active longer and so requires fewer injections each week. Because epoetin alfa is approved for more types of anemia than darepoetin, this discussion deals only with the older drug.

Epoetin alpha is approved by the Food and Drug Administration for the following uses:

• anemia associated with chronic renal failure
• anemia related to zidovudine therapy in HIV-infected patients
• anemia in cancer patients on chemotherapy
• reduction in blood transfusions in surgical patients

In addition, epoetin alpha may be useful in anemia from many other causes. These include but are not limited to anemia of prematurity, sickle cell anemia, and the anemia associated with rheumatoid arthritis.

The drug has been abused by athletes due to the theory that increasing the red blood cell count improves athletic performance. The potential benefits of misuse of the drug are limited, and the risks are significant. The United States and International Olympic Committees and the National Collegiate Athletic Association consider the use of epoetin alfa to enhance athletic ergogenic potential inappropriate and unacceptable because its use by athletes is contrary to the rules and ethical principles of athletic competition. As of the early 200s, tests to detect the misuse of epoetin alfa by athletes are increasingly reliable.

RECOMMENDED DOSAGE. Dosing schedules may vary with the cause of the anemia. All doses should be individualized. In general, epoetin alpha dosing in adults is started at 50 to 100 units per kilogram given three times a week, either by vein or subcutaneously.

The dose should be reduced if the hemoglobin level reaches 12 grams per decaliter or if the hemoglobin level increases by more than 1 gram per decaliter in any two-week period. The drug should be interrupted if hemoglobin levels reach 13 grams or more per decaliter.

The dose should be increased if the hemoglobin level does not increase by at least 2 grams per decaliter after eight weeks of treatment.

Maintenance doses, if required, should be individualized to keep the hemoglobin levels within the range of 10 to 12 grams per decaliter.

PRECAUTIONS. Epoetin alpha should not be given to patients with severe, uncontrolled hypertension.

Other conditions in which epoetin alpha should be used only when the benefits clearly outweigh the risks are as follows:

• constitutional aplastic anemia
• hypertension
• thromboembolism

Side effects

The most common adverse effects of erythopoetin alpha are:

• joint pain
• chest pain
• diarrhea
• swelling
• fatigue
• fever
• weakness

• headache
• high blood pressure
• irritation at injection site
• nausea
• vomiting
• rapid heart beat

A large number of additional adverse effects have been reported. Patients should consult the manufacturer's package insert for the full list.

Interactions

According to the manufacturer, as of 2004 no evidence of interaction of epoetin alfa with other drugs was observed.

Resources

BOOKS

Beers, Mark H., ed. Merck Manual of Medical Information: Home Edition. Riverside, NJ: Simon & Schuster, 2004.

Greer John P., et al., eds. Wintrobe's Clinical Hematology. Baltimore, MD: Lippincott Williams & Wilkins, 2003.

Physicians' Desk Reference 2005. Montvale, NJ: Thomson Healthcare, 2004.

PERIODICALS

Sharma, N., et al. "Vitamin supplementation: what the gastroenterologist needs to know." Journal of Clinical Gastroenterology 38, no. 10 (November/December 2004): 844-54.