Agents Used in Anemias &

Hematopoietic Growth Factors

Objectives:
Outline
 Some Important Terms
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 A deficiency in serum hemoglobin and erythrocytes in which the
anemia erythrocytes are abnormally large. Results from either folate or
vitamin B12 deficiency anemia
 Some Important Terms

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
 Anemia
• A deficiency in oxygen carrying erythrocytes
and is the most common and easily treated of
these conditions.
 HEMATOPOIESIS
• Production from undifferentiated
stem cells of circulating
erythrocytes, platelets, and
leukocytes
• 200 billion new blood cells per
day
Blood Cell Deficiencies: Iron and Vitamin
Deficiency Anemias
1. Microcytic hypochromic anemia
– caused by iron deficiency
– most common type of anemia
2. Megaloblastic anemias
– caused by a deficiency of vitamin B12 or folic
acid, cofactors required for the normal
maturation of red blood cells.
Blood Cell Deficiencies: Iron and Vitamin
Deficiency Anemias
3. Pernicious anemia
– 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.
 Iron
• essential metallic component of heme, the
molecule responsible for the bulk of oxygen
transport in the blood.
• Most contained in hemoglobin
• Also binds to transferrin, a transport protein,
and ferritin, a storage protein.
 Iron Absorption
• Average diet contain 10-15 mg of elemental iron
daily
• Normal individual absorbs 5-10 % or about 0.5-1 mg
daily
• Absorbed in the duodenum and proximal jejunum
• Total iron absorption increases to 1 – 2 mg
/day to as high as 3-4mg/day (with increased
requirement)
• Sources:
–Abundant in meat, iron in meat is
efficiently absorbed
–Vegetables, iron is often tightly
bound to organic compounds
• Iron in foods and inorganic iron
salts must be reduced to ferrous
iron before it can be absorbed by
intestinal mucosal cells
 Iron
• 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.
Absorption, transport, and storage of iron
 Iron: PK
• 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.
 Iron: PK
• 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.
 Iron: 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 sulfate, ferrous
gluconate, or ferrous fumarate.
 Iron: Clinical Use
• 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 dextran,
sodium 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.
 Iron Toxicity:
• 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.
 Iron Toxicity:
• Signs and Symptoms
– Chronic iron overload (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).
 Chronic Iron Toxicity: Treatment
• 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.
 Vitamin B12
• Role of Vitamin B12
– In addition, vitamin B12 deficiency can cause
neurologic defects, which may become
irreversible if not treated promptly.
 Vitamin B12: 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: Pharmacokinetics
• 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.
 Vitamin B12: 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, a precursor required for DNA synthesis. In
vitamin B12 deficiency, folates accumulate as N 5-
methyltetrahydrofolate; the supply of
tetrahydrofolate is depleted; and the production
of red blood cells slows.
 Vitamin B12: Pharmacodynamics
• Administration of folic acid to patients with
vitamin B12 deficiency helps refill the
tetrahydrofolate pool and partially or fully
corrects the anemia.
• However, the exogenous folic acid does not
correct the neurologic defects of vitamin B12
deficiency.
 Vitamin B12: 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.
 Vitamin B12: Clinical Use and Toxicity
• 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.
 Folic Acid: 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.
 Folic Acid: Pharmacodynamics
• Folic acid is converted to tetrahydrofolate by
the action of dihydrofolate reductase.
• One important set of reactions involving
tetrahydrofolate and dihydrofolate constitutes
the dTMP cycle, which supplies the dTMP
required for DNA synthesis.
 Folic Acid: Pharmacodynamics
• 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.
Folic Acid
Folic Acid: 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: Clinical Use and Toxicity
• 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
1. Erythropoietin
2. Myeloid Growth Factors
3. Megakaryocyte Growth Factors
 Erythropoietin
• 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.
 Erythropoietin
• 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
• 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.
 Erythropoietin
• 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.
 Erythropoietin
• 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).
 Myeloid Growth Factors
• 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.
 Myeloid Growth Factors
• 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.
• 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.
 Megakaryocyte Growth Factors
• 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.
 Megakaryocyte Growth Factors
• 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.