Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 33. Agents Used in Anemias & Hematopoietic Growth Factors

Agents Used in Anemias & Hematopoietic Growth Factors: Introduction

Blood cells play essential roles in oxygenation of tissues, coagulation, protection against infectious agents, and tissue repair. Blood cell deficiency is a relatively common occurrence that can have profound repercussions. The most common cause of erythrocyte deficiency, or anemia, is insufficient supply of iron, vitamin B12 , or folic acid, substances required for normal production of erythrocytes. Pharmacologic treatment of these types of anemia usually involves replacement of the missing substance. An alternative therapy for treatment of certain types of anemia and for treatment of deficiency in other types of blood cells is administration of recombinant hematopoietic growth factors, which stimulate the production of various lineages of blood cells and regulate blood cell function.

High-Yield Terms to Learn

Cobalamin Vitamin B12 dTMP synthesis A set of biochemical reactions that produce deoxythymidylate (dTMP), an essential constituent of DNA synthesis. The cycle depends on the conversion of dihydrofolate to tetrahydrofolate by dihydrofolate reductase (Figure 33-1) G-CSF Granulocyte colony-stimulating factor, a hematopoietic growth factor that regulates production and function of neutrophils GM-CSF Granulocyte-macrophage colony-stimulating factor, a hematopoietic growth factor that regulates production of granulocytes (basophils, eosinophils, and neutrophils), and other myeloid cells Hemochromatosis A condition of chronic excess total body iron caused either by an inherited abnormality of iron absorption or by frequent transfusions to treat certain types of hemolytic disorders (eg, thalassemia major) Megaloblastic anemia A deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are abnormally large. Results from either folate or vitamin B12 deficiency anemia Microcytic anemia A deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are abnormally small. Often caused by iron deficiency Neutropenia An abnormally low number of neutrophils in the blood; patients with neutropenia are susceptible to serious infection Pernicious anemia A form of megaloblastic anemia resulting from deficiency of intrinsic factor, a protein produced by gastric mucosal cells and required for intestinal absorption of vitamin B12 Thrombocytopenia An abnormally low number of platelets in the blood; patients with thrombocytopenia are susceptible to hemorrhage

Blood Cell Deficiencies

Iron and Vitamin Deficiency Anemias

Microcytic hypochromic anemia, caused by iron deficiency, is the most common type of anemia. Megaloblastic anemias are caused by a deficiency of vitamin B12 or folic acid, cofactors required for the normal maturation of red blood cells. Pernicious anemia, the most common type of vitamin B12 deficiency anemia, is caused by a defect in the synthesis of intrinsic factor, a protein required for efficient absorption of dietary vitamin B12, or by surgical removal of that part of the stomach that secretes intrinsic factor.

Other Blood Cell Deficiencies

Deficiency in the concentration of the various lineages of blood cells can be a manifestation of a disease or a side effect of radiation or cancer chemotherapy. Recombinant DNA-directed synthesis of hematopoietic growth factors now makes possible the treatment of more patients with deficiencies in erythrocytes, neutrophils, and platelets. Some of these growth factors also play an important role in hematopoietic stem cell transplantation.

Iron

Role of Iron

Iron is the essential metallic component of heme, the molecule responsible for the bulk of oxygen transport in the blood. Although most of the iron in the body is contained in hemoglobin, an important fraction is bound to transferrin, a transport protein, and ferritin, a storage protein. Deficiency of iron occurs most often in women because of menstrual blood loss and in vegetarians or malnourished persons because of inadequate dietary iron intake. Children and pregnant women have increased requirements for iron.

Regulation of Iron Stores

Although iron is an essential ion, excessive amounts are highly toxic. As a result, a complex system has evolved for the transport and storage of free iron (Figure 33-1). Since there is no mechanism for the efficient excretion of iron, regulation of body iron content occurs through modulation of intestinal absorption.

FIGURE 33-1

Absorption, transport, and storage of iron. Intestinal epithelial cells actively absorb inorganic iron via the divalent metal transporter (DMT1) and heme iron via the heme carrier protein 1 (HCP1) (1). Iron that is absorbed or released from absorbed heme iron is actively transported into the blood by ferroportin (FP) or complexed with apoferritin (AF) and stored as ferritin. In the blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hb) (2) or to hepatocytes for storage as ferritin (3). The transferrin iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized. After release of the iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4). Hepatocytes use several mechanisms to take up iron and store the iron as ferritin. FO, ferroxidase; FP, ferroportin; FR, ferrireductase.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 33-1.)

Absorption

Dietary iron in the form of heme and the ferrous ion (Fe2+) are taken up by a specialized divalent metal transporter 1 (DMT1) in intestinal epithelials cells. Intestinal cell iron is either stored as ferritin or the ferrous iron is transported across the basolateral membrane by ferroportin and then oxidized to ferric iron (Fe3+) by a ferroxidase (Figure 33-1).

Transport and Storage

Ferric iron is transported in a complex with transferrin. Excess iron is stored in the protein-bound form in gastrointestinal epithelial cells, macrophages, and hepatocytes, and, in cases of gross overload, in parenchymal cells of the skin, heart, and other organs.

Elimination

Minimal amounts of iron are lost from the body with sweat and saliva and in exfoliated skin and intestinal mucosal cells.

Clinical Use

Prevention or treatment of iron deficiency anemia is the only indication for iron administration. Iron deficiency can be diagnosed from red blood cell changes (microcytic cell size due to diminished hemoglobin content) and from measurements of serum and bone marrow iron stores. The disease is treated by dietary ferrous iron supplementation with ferrous sulfateferrous gluconate, or ferrous fumarate. In special cases, treatment is by parenteral administration of a colloid containing a core of iron oxyhydroxide surrounded by a core of carbohydrate. Parenteral iron preparations include iron dextransodium ferric gluconate complex, and iron sucrose. Iron should not be given in hemolytic anemia because iron stores are elevated, not depressed, in this type of anemia.

Toxicity of Iron (see also Chapter 57)

Signs and Symptoms

Acute iron intoxication is most common in children and usually occurs as a result of accidental ingestion of iron supplementation tablets. Depending on the dose of iron, necrotizing gastroenteritis, shock, metabolic acidosis, coma, and death may result. Chronic iron overload, known as hemochromatosis, damages the organs that store excess iron (heart, liver, pancreas). Hemochromatosis occurs most often in persons with an inherited abnormality of iron absorption and those who receive frequent transfusions for treatment of hemolytic disorders (eg, thalassemia major).

Treatment of Acute Iron Intoxication

Immediate treatment is necessary and usually consists of removal of unabsorbed tablets from the gut, correction of acid-base and electrolyte abnormalities, and parenteral administration of deferoxamine, which chelates circulating iron.

Treatment of Chronic Iron Toxicity

Treatment of the genetic form of hemochromatosis is usually by phlebotomy. Hemochromatosis that is due to frequent transfusions is treated with chronic administration of an iron chelator such as deferoxamine or deferasirox.

Vitamin B12

Role of Vitamin B12

Vitamin B12 (cobalamin), a cobalt-containing molecule, is, along with folic acid, a cofactor in the transfer of 1-carbon units, a step necessary for the synthesis of DNA. Impairment of DNA synthesis affects all cells, but because red blood cells must be produced continuously, deficiency of either vitamin B12 or folic acid usually manifests first as anemia. In addition, vitamin B12 deficiency can cause neurologic defects, which may become irreversible if not treated promptly.

Pharmacokinetics

Vitamin B12 is produced only by bacteria; this vitamin cannot be synthesized by multicellular organisms. It is absorbed from the gastrointestinal tract in the presence of intrinsic factor, a product of the parietal cells of the stomach. Plasma transport is accomplished by binding to transcobalamin II. Vitamin B12 is stored in the liver in large amounts; a normal individual has enough to last 5 yrs. The 2 available forms of vitamin B12, cyanocobalamin and hydroxocobalamin, have similar pharmacokinetics, but hydroxocobalamin has a longer circulating half-life.

Pharmacodynamics

Vitamin B12 is essential in 2 reactions: conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA and conversion of homocysteine to methionine. The second reaction is linked to folic acid metabolism and synthesis of deoxythymidylate (dTMP; Figure 33-1, section 2), a precursor required for DNA synthesis. In vitamin B12 deficiency, folates accumulate as N5-methyltetrahydrofolate; the supply of tetrahydrofolate is depleted; and the production of red blood cells slows. Administration of folic acid to patients with vitamin B12 deficiency helps refill the tetrahydrofolate pool (Figure 33-1, section 3) and partially or fully corrects the anemia. However, the exogenous folic acid does not correct the neurologic defects of vitamin B12 deficiency.

Clinical Use and Toxicity

The 2 available forms of vitamin B12—hydroxocobalamin and cyanocobalamin—have equivalent effects. The major application is in the treatment of naturally occurring pernicious anemia and anemia caused by gastric resection. Because vitamin B12 deficiency anemia is almost always caused by inadequate absorption, therapy should be by replacement of vitamin B12, using parenteral therapy. Neither form of vitamin B12 has significant toxicity.

Folic Acid

Role of Folic Acid

Like vitamin B12 , folic acid is required for normal DNA synthesis, and its deficiency usually presents as megaloblastic anemia. In addition, deficiency of folic acid during pregnancy increases the risk of neural tube defects in the fetus.

Pharmacokinetics

Folic acid is readily absorbed from the gastrointestinal tract. Only modest amounts are stored in the body, so a decrease in dietary intake is followed by anemia within a few months.

Pharmacodynamics

Folic acid is converted to tetrahydrofolate by the action of dihydrofolate reductase (Figure 33-1, section 3). One important set of reactions involving tetrahydrofolate and dihydrofolate constitutes the dTMP cycle (Figure 33-2, section 2), which supplies the dTMP required for DNA synthesis. Rapidly dividing cells are highly sensitive to folic acid deficiency. For this reason, antifolate drugs are useful in the treatment of various infections and cancers.

FIGURE 33-2

Enzymatic reactions that use folates. Section 1 shows the vitamin B12 -dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the "folate trap" in vitamin B12 deficiency. Section 2 shows the dTMP cycle. Section 3 shows the pathway by which folate enters the tetrahydrofolate cofactor pool. Double arrows indicate pathways with more than 1 intermediate step.

(Reproduced, with permission, from Katzung BG, Masters SB, and Trevor AT, editors: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 33-3.)

Clinical Use and Toxicity

Folic acid deficiency is most often caused by dietary insufficiency or malabsorption. Anemia resulting from folic acid deficiency is readily treated by oral folic acid supplementation. Because maternal folic acid deficiency is associated with increased risk of neural tube defects in the fetus, folic acid supplementation is recommended before and during pregnancy. Folic acid supplements correct the anemia but not the neurologic deficits of vitamin B12 deficiency. Therefore, vitamin B12 deficiency must be ruled out before one selects folic acid as the sole therapeutic agent in the treatment of a patient with megaloblastic anemia. Folic acid has no recognized toxicity.

Hematopoietic Growth Factors

Over a dozen glycoprotein hormones that regulate the differentiation and maturation of stem cells within the bone marrow have been identified. Several growth factors, produced by recombinant DNA technology, have FDA approval for treatment of patients with blood cell deficiencies.

Erythropoietin

Erythropoietin is produced by the kidney; reduction in its synthesis is responsible for the anemia of renal failure. Through activation of receptors on erythroid progenitors in the bone marrow, erythropoietin stimulates the production of red cells and increases their release from the bone marrow.

Recombinant human erythropoietin (epoetin alfa) is routinely used for the anemia associated with renal failure and is sometimes effective for patients with other forms of anemia (eg, primary bone marrow disorders or anemias secondary to cancer chemotherapy or HIV treatment, bone marrow transplantation, AIDS, or cancer). Erythropoietin's acute toxicity is minimal. However, when it or other erythropoietic agents are allowed to increase hematocrit excessively (ie, hemoglobin level > 12 g/dL), there is increased risk of thrombosis and cardiovascular events. Darbepoetin alfa , a glycosylated form of erythropoietin, has a much longer half-life. Methoxy polyethylene glycol-epoetin beta is a long-lasting form of erythropoietin that can be administered once or twice a month.

The most common complications of erythropoietin therapy are hypertension and thrombosis. The serum hemoglobin concentration of patients treated with erythropoietin should not exceed 12 g/dL because hemoglobin concentrations above this target have been linked to an increased rate of mortality and cardiovascular events.

Myeloid Growth Factors

Filgrastim (granulocyte colony-stimulating factor; G-CSF) and sargramostim (granulocyte-macrophage colony-stimulating factor; GM-CSF) stimulate the production and function of neutrophils. GM-CSF also stimulates the production of other myeloid and megakaryocyte progenitors. G-CSF and, to a lesser degree, GM-CSF mobilize hematopoietic stem cells (ie, increase their concentration in peripheral blood).

Both growth factors are used to accelerate the recovery of neutrophils after cancer chemotherapy and to treat other forms of secondary and primary neutropenia (eg, aplastic anemia, congenital neutropenia). When given to patients soon after autologous stem cell transplantation, G-CSF reduces the time to engraftment and the duration of neutropenia. G-CSF is used to mobilize peripheral blood stem cells in preparation for autologous and allogeneic stem cell transplantation. The toxicity of G-CSF is minimal, although the drug sometimes causes bone pain. GM-CSF can cause more severe effects, including fever, arthralgias, and capillary damage with edema. Allergic reactions are rare. Pegfilgrastim, a covalent conjugation product of filgrastim and a form of polyethylene glycol, has a much longer serum half-life than recombinant G-CSF.

Megakaryocyte Growth Factors

Oprelvekin (interleukin-11 [IL-11]) stimulates the growth of primitive megakaryocytic progenitors and increases the number of peripheral platelets. IL-11 is used for the treatment of patients who have had a prior episode of thrombocytopenia after a cycle of cancer chemotherapy. In such patients, it reduces the need for platelet transfusions. The most common adverse effects of IL-11 are fatigue, headache, dizziness, and fluid retention.

Romiplostim is a novel megakaryocyte growth factor that depends on a peptide selected from a peptide library on the basis of thrombopoietin receptor activation. Two copies of the peptide are linked together by a polyglycine sequence and covalently attached through another polyglycine sequence to a human Fc fragment. Two peptide-human Fc chains are joined by disulfide bonds to form a stable complex with a half-life of 3-4 days. Romiplostim is approved for treatment of patients with chronic idiopathic thrombocytopenia who have failed to respond to conventional treatment.

Skill Keeper: Routes of Administration

(See Chapter 1)

All of the recombinant hematopoietic growth factors approved for clinical use are administered by injection. Why can these growth factors not be given orally? Which 3 routes of administration require drug injection? How do these 3 routes compare with regard to onset and duration of drug action and risk of adverse effects? The Skill Keeper Answers appear at the end of the chapter.

Skill Keeper Answers: Routes of Administration

(See Chapter 1)

All of the hematopoietic growth factors are proteins with molecular weights greater than 15,000. Like other proteinaceous drugs, the growth factors cannot be administered orally because they have such poor bioavailability. Their peptide bonds are destroyed by stomach acid and digestive enzymes.

Injections are required for intravenous, intramuscular, and subcutaneous administration. The intravenous route offers the fastest onset of drug action and shortest duration of drug action. Because intravenous administration can produce high blood levels, this route of administration has the greatest risk of producing concentration-dependent drug toxicity. Intramuscular injection has a quicker onset of action than subcutaneous injection, and larger volumes of injected fluid can be given. Because protective barriers can be breached by the needle or tubing used for drug injection, all 3 of these routes of administration carry a greater risk of infection than does oral drug administration.

Checklist

When you complete this chapter, you should be able to:

 Name the 2 most common types of nutritional anemia, and, for each, describe the most likely biochemical causes.

 Diagram the normal pathways of absorption, transport, and storage of iron in the human body.

 Name the anemias for which iron supplementation is indicated and those for which it is contraindicated.

 List the acute and chronic toxicities of iron.

 Sketch the dTMP cycle and show how deficiency of folic acid or deficiency of vitamin B12 affects the normal cycle.

Explain the major hazard involved in the use of folic acid as sole therapy for megaloblastic anemia and indicate on a sketch of the dTMP cycle the biochemical basis of the hazard.

 Name 3-5 major hematopoietic growth factors that are used clinically and describe the clinical uses and toxicity of each.

 Explain the advantage of covalently attaching polyethylene glycol to filgrastim.

Drug Summary Table: Drugs for Anemia & Hematopoietic Growth Factors

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Iron Ferrous sulfate Required for the biosynthesis of heme and heme-containing proteins, including hemoglobin and myoglobin Iron deficiency, which manifests as microcytic anemia Complicated endogenous system for absorbing, storing, and transporting iron No mechanism for iron excretion other than cell and blood loss Acute overdose results in necrotizing gastroenteritis, abdominal pain, bloody diarrhea, shock, lethargy, and dyspnea Chronic iron overload results in hemochromatosis, with damage to the heart, liver, pancreas, and other organs; organ failure and death can ensue Ferrous gluconate and ferrous fumarate: Oral iron preparations Iron dextran, iron sucrose complex, and sodium ferric gluconate complex: Parenteral preparations; can cause hypersensitivity reactions Iron chelators (see also Chapters 57 and 58) Deferoxamine Chelates excess iron Acute iron poisoning; inherited or acquired hemochromatosis that is not adequately treated by phlebotomy Preferred route of administration: intramuscular or subcutaneous Rapid IV administration may cause hypotension; acute respiratory distress has been observed with long infusions; neurotoxicity and increased susceptibility to certain infections has occurred with long-term use Deferasirox: Orally administered iron chelator for treatment of hemochromatosis that is not adequately treated by phlebotomy Vitamin B12 Cyanocobalamin, hydroxocobalamin A cofactor required for essential enzymatic reactions that form tetrahydrofolate, convert homocysteine to methionine, and metabolize L-methylmalonyl-CoA Vitamin B12 deficiency, which manifests as megaloblastic anemia and is the basis of pernicious anemia Parenteral vitamin B12 is required for pernicious anemia and other malabsorption syndromes No toxicity associated with excess vitamin B12 Folic acid Folacin (pteroylglutamic acid) A precursor of an essential donor of methyl groups used for synthesis of amino acids, purines, and deoxynucleotide Folic acid deficiency, which manifests as megaloblastic anemia, and prevention of congenital neural tube defects Oral is well absorbed; need for parenteral administration is rare Not toxic in overdose, but large amounts can partially compensate for vitamin B12 deficiency and put people with unrecognized vitamin B12 deficiency at risk for neurologic consequences of vitamin B12 deficiency that are not compensated by folic acid Erythrocyte-stimulating agents Epoetin alfa Agonist of erythropoietin receptors expressed by red cell progenitors Anemia, especially associated with chronic renal failure, HIV infection, cancer, and prematurity; prevention of need for transfusion in patients undergoing certain types of elective surgery Intravenous or subcutaneous administration 1-3 x per week Hypertension, thrombotic complications, and, very rarely, pure red cell aplasia; to reduce the risk of serious cardiovascular events, hemoglobin levels should be maintained <12 g/dL Darbepoetin alfa: Long-acting glycosylated form administered weekly Methoxy polyethylene glycol-epoetin beta: Long-acting form administered 1-2 x per month Myeloid growth factors G-CSF (filgrastim) Stimulates G-CSF receptors expressed on mature neutrophils and their progenitors Neutropenia associated with congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia; secondary prevention of neutropenia in patients undergoing cytotoxic chemotherapy; mobilization of peripheral blood cells in preparation for autologous and allogenic stem cell transplantation Daily subcutaneous administration Bone pain; rarely, splenic rupture Pegfilgrastim: Long-acting form of filgrastim that is covalently linked to a type of polyethylene glycol GM-CSF (sargramostim): Myeloid growth factor that acts through a distinct GM-CSF receptor to stimulate proliferation and differentiation of early and late granulocytic progenitor cells, and erythroid and megakaryocyte progenitors. Clinical uses are similar to those of G-CSF, although it is more likely than G-CSF to cause fever, arthralgia, myalgia, and a capillary leak syndrome Megakaryocyte growth factors Oprelvekin (interleukin-11; IL-11) Recombinant form of an endogenous cytokine; activates IL-11 receptors Secondary prevention of thrombocytopenia in patients undergoing cytotoxic chemotherapy for nonmyeloid cancers Daily subcutaneous administration Fatigue, headache, dizziness, anemia, fluid accumulation in the lungs, and transient atrial arrhythmias Romiplostim: Genetically engineered protein in which the Fc components of a human antibody are fused to multiple copies of a peptide that stimulates the thrombopoietin receptors; approved for treatment of idiopathic thrombocytopenic purpura (ITP)



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