Agents Used in Anemias

AGENTS USED IN ANEMIAS &
HEMATOPOIETIC GROWTH
FACTORS
A. Q. Sangalang, MD, FPOGS, RMT

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
HEMATOPOIETIC GROWTH FACTORS
Hematopoiesis
 Production from undifferentiated stem cells of
circulating erythrocytes, platelets, and
leucocytes
 Resides primarily in the bone marrow
 Requires constant supply of 3 essential
nutrients
 Iron
 Vitamin B 12
 Folic acid
Hematopoiesis
 Requires the presence of hematopoietic growth
factors
 Proteins that regulate the proliferation and
differentiation of hematopoietic cells/lineages of
blood cells and regulate blood cell function
ESSENTIAL ROLES OF BLOOD CELLS

 Oxygenation of tissues
 Coagulation
 Protection against infectious agents
 Tissue repair
Blood cell deficiency is a relatively common

occurrence that can have profound repercussions
Anemia
 Deficiency in oxygen-carrying erythrocytes
 Most common and easily treated
Insufficient supply of iron, vitamin B 12 , or folic

acid
 Most common cause of erythrocyte deficiency or
anemia
Pharmacologic treatment
 Replacement of the missing substance
Alternative treatment
 Administration of recombinant hematopoietic
growth factors
BLOOD CELL DEFICIENCIES

A.Iron and Vitamin Deficiency Anemias
Microcytic hypochromic anemia
Caused by iron deficiency
Most common type of chronic anemia
Megaloblastic anemias
Caused by a deficiency of vitamin B 12 or folic
acid
Cofactors required for the normal maturation of
red blood cells

A. Iron and Vitamin Deficiency Anemias
Pernicious anemia
Most common type of vitamin B 12 deficiency
anemia
Defect in the secretion of intrinsic factor from
the gastric mucosal cells
Intrinsic factor
 Protein required for efficient absorption of
dietary vitamin B 12
Caused by surgical removal of that part of the
stomach that secretes intrinsic factor

B. Other Blood Cell Deficiencies
 Deficiency in the concentration of various
lineages of blood cells
Can be a manifestation of a disease or a side
effect of radiation or cancer chemotherapy

B.Other Blood Cell Deficiencies
Recombinant DNA directed synthesis of
hematopoietic growth factors
 Makes possible the treatment of more patients
with deficiencies in erythrocytes, neutrophils, and
platelets
o Play an important role in stem cell transplantation
IRON
A.Role of Iron
Essential metallic component of heme
Together with globin chains forms hemoglobin
Responsible for the bulk of O 2 transport in the
blood
IRON
A.Role of Iron
Hemoglobin
Reversibly binds O2
Provides the mechanism for O2 delivery from
the lungs to the tissues
Transferrin
oTransport protein form of iron
Ferritin
oStorage protein form of iron
IRON
A.Role of Iron
Deficiency in iron occurs most often in
Women
Vegetarians
Malnourished individuals
IRON
A.Role of Iron
Individuals that have increased requirements for
iron
Infants especially premature ones
Children
Pregnant and lactating women
Patients with chronic kidney disease
IRON
B.Regulation of Iron Stores
Regulation of body iron content
Through modulation of intestinal absorption
Hemochromatosis
Increased gastrointestinal iron absorption
Disease associated with excess iron stores
IRON
1.Absorption
Normally absorbed in the duodenum and
proximal jejunum
Absorbed as the ferrous ion (Fe 2+ )
Oxidized in the mucosal cell to the ferric (Fe 3+ )
form
IRON
2.Storage
Trivalent ferric iron
Stored in the intestinal mucosa (ferritin)
Carried else where in the body (transferrin)
IRON
2.Storage
Excess Iron
Stored in the protein-bound form in the
reticuloendothelial system
In cases of gross overload
Parenchymal cells of the skin, liver, and other
organs
IRON
2.Storage
Accumulation of iron
Hemolytic anemias
Excess destruction of red blood cells
Hemochromatosis
IRON
3.Elimination
 No mechanism for excretion of iron
 Minimal amounts are lost in the feces by
exfoliation of intestinal mucosal cells
 Trace amounts are excreted in the bile, urine
and sweat
 Regulation in intestinal absorption and
storage of iron in response to the body’s needs
IRON
C.Clinical Use
Iron deficiency anemia
Only indication for the use of iron
Diagnosis
Red blood cell changes
Microcytic cell size
Hypochromic from diminished hemoglobin
o Measurements of serum and bone marrow iron
stores
IRON
C.Clinical Use
Treatment
Oral/dietary iron supplementation as rapidly
as the IV form as long as GI absorption is
normal
Ferrous sulfate
Ferrous gluconate
Ferrous fumarate
IRON
C.Clinical Use
Treatment
Parenteral iron preparations
Iron dextran
Sodium ferric gluconate complex
Iron sucrose
 Should not be given in hemolytic anemia
IRON
C.Clinical Use
Treatment
o Oral iron therapy
o50-100 mg of iron can be incorporated into
hemoglobin daily
o25% of oral iron given as ferrous salt is absorbed
o200-400 mg of elemental iron should be given
daily to correct iron deficiency
IRON
C.Clinical Use
Treatment
o Oral iron therapy
oTreatment is continued for 3-6 months after
correction of the cause of the iron loss
IRON
C.Clinical Use
Treatment
oParenteral iron therapy
Special cases, when requirement for iron is high
Those who cannot tolerate oral iron
Advanced kidney disease
Extensive chronic blood loss
Postgastrectomy and previous small bowel
resection
IRON
C.Clinical Use
Treatment
Iron dextran
Complex of ferric hydroxide and dextran
with 50 mg of elemental iron/ml of solution
 Given deep IM or by IV infusion
IRON
C.Clinical Use
Treatment
 Iron sucrose complex, iron sodium gluconate
 Alternative preparations
IRON
C.Clinical Use
Hemolytic anemia
 Iron should not be given
 Iron stores are elevated, not depressed
IRON
D.Toxicity of iron
1.Signs and symptoms
Acute iron intoxication
 Most common in children
 Result of accidental ingestion of iron
supplementation tablets (as few as 10 tablets)
IRON
D.Toxicity of iron
Acute iron intoxication
 Depending on the dose
 Necrotizing gastroenteritis with vomiting
 Abdominal pain and bloody diarrhea
 Shock, lethargy, dyspnea
 Metabolic acidosis
 Coma and death
IRON
D.Toxicity of iron
Chronic toxicity
 Patients who receive frequent transfusions
 Sickle cell anemia
 Hemochromatosis
 Inherited abnormality of iron absorption
 Excess iron deposited in the heart, liver,
pancreas
and other organs
IRON
D.Toxicity of iron
2.Treatment of acute iron intoxication
 Immediate treatment is necessary
 Whole bowel irrigation
 Removal of unabsorbed tablets from the gut
 Correction of acid-base abnormalities
 Deferoxamine
 Given IV
 Chelates circulating iron and promotes
excretion in urine and feces
IRON
D.Toxicity of iron
2.Treatment of acute iron intoxication
 Deferasirox
 New oral iron chelator
 As effective as deferoxamine
 More convenient
 Not clear whether it is as protective as
deferoxamine in protecting the heart from iron
overload
IRON
D.Toxicity of iron
3.Treatment of chronic iron intoxication
Treatment of hemochromatosis
Intermittent phlebotomy
One unit of blood is remove/week
VITAMIN B 12
A. Role of vitamin B 12
 Cobalamin
 Cobalt-containing molecule
 Sometimes called extrinsic factor
 Along with folic acid, is a cofactor in the
transfer of 1-carbon units
 Step necessary for the synthesis of DNA
VITAMIN B 12
A. Role of vitamin B 12
 Impairment of DNA synthesis affect all cells
 RBC must be produced continuously
 Deficiency of either vitamin B 12 or folic acid
will manifest first as anemia
 Neurologic defects
 Important manifestation of vitamin B 12
deficiency
 Maybe irreversible if not treated promptly
VITAMIN B 12
B. Pharmacokinetics
 Produced only by bacteria
 Not synthesized by multicellular organisms
 1-5 mcg is absorbed from the diet in the
GI tract in the presence of intrinsic factor
(product of the parietal cells of the stomach)
 Intrinsic factor-vitamin B 12 complex is absorbed
in the distal ileum
 Stored in the liver with a total storage pool of
3000-5000 mcg enough to last 5 years
VITAMIN B 12
B. Pharmacokinetics
 Deficiency of vitamin B 12
 Results from malabsorption of B 12 due to
 Lack of intrinsic factor
 Loss or lack of the absorptive mechanism in the
distal ileum
 Nutritional deficiency is rare
 Strict vegetarians after many years without
meat, eggs or dairy products
 Leads to anemia, GI symptoms and development
of neurologic defects
VITAMIN B 12
B. Pharmacokinetics
 Transported to different cells by binding to
transcobalamin II
 Only trace amounts are in urine and stool
VITAMIN B 12
B. Pharmacokinetics
 2 forms of vitamin B 12
oCyanocobalamin
oHydroxocobalamin
oSimilar pharmacokinetics
oEquivalent effects
oMore firmly bound to plasma proteins
oLonger circulating half-life
VITAMIN B 12
C. Pharmacodynamics
 Vitamin B 12 deficiency
 Folates accumulate as N 5-methyltetrahydrofolate
 Supply of tetrahydrofolate is depleted
 Production of red blood cells slows
 Administration of exogenous folic acid
oTo refill the tetrahydrofolate pool
oTo partially or fully corrects the anemia
oDoes not correct the neurologic defects caused by
vitamin B 12 deficiency
VITAMIN B 12
D. Clinical Use and Toxicity
 Schilling test
 Measures the absorption and urinary
excretion
of radioactively labeled vitamin B 12
 Used to define the mechanism of B 12
malabsorption when this is found to be the
cause of megaloblastic anemia
VITAMIN B 12
 Almost all cases of B 12 deficiency are caused by
malabsorption of the vitamin
Major application
Naturally occurring pernicious anemia
Anemia caused by gastric resection
 Therapy
 Replacement of vitamin B 12
 Parenteral therapy
VITAMIN B 12
 Cyanocobalamin & hydroxocobalamin
 Equivalent effects
 Neither form has significant toxicity
 Hydroxocobalamin is preferred because of longer
duration
VITAMIN B 12
Therapy
Initial therapy 100-1000 mcg IM daily or
every
other day for 1-2 weeks to replenish body
stores
VITAMIN B 12
Therapy
Maintenance 100-1000 mcg IM once a month
for life
If with neurologic abnormalities
Injections every 1-2 weeks for 6 months before
switching to monthly injections
FOLIC ACID
A. Role of Folic Acid
 Required for normal DNA synthesis
 Deficiency presents as megaloblastic anemia
 Pregnancy increases the risk of congenital
malformation
 Neural tube defects (NTDs)
 Spina bifida
FOLIC ACID
B. Pharmacokinetics
 50-200 mcg is readily absorbed from the diet in
the GI tract
 Completely absorbed in the proximal jejunum
 Only modest amounts are stored in the liver and
other tissue
 Decrease in dietary intake is followed by anemia
within a few months
 Excreted in the urine and stool
FOLIC ACID
C. Pharmacodynamics
 Converted to tetrahydrofolate by the action of
dihydrofolate reductase
 Tetrahydrofolate & dihydrofolate
Involved in a set of reactions in the dTMP cycle
which supplies the dTMP required for DNA
synthesis
FOLIC ACID
C. Pharmacodynamics
 Rapidly dividing cells in which DNA must be
synthesized rapidly
 Highly sensitive to folic acid deficiency
 Enzymes in the dTMP cycle are the target of 2
anticancer drugs
 Antifolate drugs
Drugs that can cause folic acid deficiency
Useful in the treatment of various infections
and cancers
FOLIC ACID
C. Pharmacodynamics
 Antifolate drugs
 Methotrexate
 Inhibits dihydrofolate reductase
 5-Fluorouracil
 Its metabolite inhibits thymidylate synthase
FOLIC ACID
 Folic acid deficiency
 Most often caused by dietary insufficiency or
malabsorption
 Microscopically indistinguishable from the
anemia caused by B 12 deficiency
 Does not cause the characteristic neurologic
syndrome in B 12 deficiency
FOLIC ACID
High risk patients
Pregnant women
Patients with alcohol dependence
Hemolytic anemia
Liver disease or certain skin diseases
Patients on renal dialysis
FOLIC ACID
Oral folic acid supplementation
 Parenteral administration is rarely necessary
 Corrects anemia
 Does not correct neurologic deficits of vitamin B 12
deficiency
FOLIC ACID
Oral folic acid supplementation
 1 mg daily is sufficient to restore serum folate
levels in almost all patients
 Therapy is continued until deficiency is removed
or corrected
FOLIC ACID
 Folic acid supplementation
No recognized toxicity
Vitamin B 12 deficiency
Ruled out before one selects folic acid as the sole
therapeutic treatment of a patient with
megaloblastic anemia

 Glycoprotein hormones
 Regulate the proliferation and differentiation of
hematopoietic progenitor cells/stem cells
 Found in the bone marrow
 Produced by recombinant DNA technology
 FDA approved for the treatment of patients with
blood cell deficiencies

Erythropoietin
 Produced by the kidneys
 Stimulates production of red cells
 Increases release of red cells from the bone
marrow
 Reduction in synthesis results to anemia of
renal failure

A.Erythropoietin (Epoietin alfa)
1.Pharmacokinetics
 Recombinant human erythropoeitin
 Given IV

1.Pharmacokinetics
 Erythrocyte Stimulating Agents (ESAs)
 Darbopoietin alfa
 Glycosylated form of erythropoietin
 Twofold to threefold longer half-life
 Methoxy polyethylene glycol-epoietin beta
 Longer lasting form of erythropoeitin
 Can be given once or twice a month

2.Pharmacodynamics
 Stimulates the production of red cells
 Interacts with specific erythropoietin receptors
on red cell progenitors
 Increases the release from the bone marrow

2.Pharmacodynamics
 Hematocrit (hct) and hemoglobin (hgb) level and
serum erythropoietin levels
 Inverse relationship

2.Pharmacodynamics
 Serum erythropoietin levels
 Less than 20 iu/L in nonanemic individuals
 Level rises exponentially as the hct and hgb fall
 Except for anemia with chronic renal failure
 Erythropoietin levels are low
 Kidneys cannot produce the growth factor


3.Clinical use and Toxicity
 Uses:
Anemia associated with renal failure
Other forms of anemia
Primary bone marrow d/o
Secondary to cancer chemotherapy or HIV
treatment
Bone marrow transplantation
AIDS, cancer

 Eliminates the need for transfusion
 Increases Hct and Hgb in 2-6 weeks
 Failure to respond to treatment
 Commonly due to iron deficiency
 Treated by oral or IV iron

 Toxicity is minimal
 Allergic reactions is infrequent and mild
 Excessive increase in Hct and Hgb results to
 Hypertension
 Thrombotic complications

 Serum hgb conc of patients should not exceed
12g/dL
Increases mortality rate and cardiovascular events

B.Myeloid Growth Factors
G-CSF and GM-CSF
 Originally purified from human cultured cell
lines
 Stimulate the production and function of
myeloid progenitor cells
 Used to accelerate the recovery of neutrophils
after cancer chemotherapy
 Treat other forms of secondary and primary
neutropenia

Filgrastim
 Granulocyte Colony-Stimulating Factor; G-
CSF
 Produced in a bacterial expression system
 Stimulate the production and function of
neutrophils
 Mobilize hematopoietic stem cells
 Toxicity is minimal, used more frequently
 Causes bone pain

Filgrastim
 Stem cell transplantation
 Reduces the time to engraftment and the
duration of neutropenia
 Mobilizes peripheral blood stem cells in
preparation for autologous and allogeneic stem
cell transplantation

Sargramostim
 Granulocyte-Macrophage Colony-
Stimulating Factor; GM-CSF
 Produced in a yeast expression system
 Multipotential growth factor
 Stimulates the production of granulocytic,
erythroid and megakaryocyte progenitors

Sargramostim
 Reduces the time to engraftment and the duration
of neutropenia in stem cell transplantation
 Causes more severe effects
 Fever
 Arthralgia
 Capillary damage with edema
 Pleural or pericardial effusion
 Allergic reactions are rare

Pegfilgrastim
 Covalent conjugation product of filgrastim
 Polyethylene glycol
 Longer serum half-life than recombinant G-CSF
 Given as a single dose

C.Megakaryocyte Growth Factors
Oprelvekin (Interleukin–11; IL-11)
 Recombinant form produced by expression in E.
Coli
 Half-life is 7-8 hours given subcutaneously
 Stimulates the growth of primitive megakaryocytic
progenitors
 Increases the number of peripheral platelets and
neutrophils

Oprelvekin
 Treatment of patients who have had a prior episode
of thrombocytopenia after a cycle of cancer
chemotherapy
 Reduces the need for platelet transfusions

Oprelvekin
 Most common side effects
 Fatigue Headache
 Dizziness Fluid retention
 Cardiovascular effects
 Anemia
 Dyspnea
 Arrhythmia

Thrombopoietin
 Produced by expression in human cells
 Effects similar to those of IL-11
 Produces autoantibodies to native
thrombopoietin

Romiplostim (AMG 531)
 Peptibodies
 Capable of activating the thrombopoietin receptor
 Half-life of 3-4 days
 Used for idiopathic thrombocytopenic purpura
(ITP)

Eltrombopag
 New orally active agonist at the thrombopoietin
receptor
 Used for ITP
 Restricted to use by registered physicians and
patients due to its toxicity

Agents Used in Anemias

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AGENTS USED IN ANEMIAS &

A. Q. Sangalang, MD, FPOGS, RMT

ESSENTIAL ROLES OF BLOOD CELLS

Blood cell deficiency is a relatively common

Insufficient supply of iron, vitamin B 12 , or folic

BLOOD CELL DEFICIENCIES

BLOOD CELL DEFICIENCIES

BLOOD CELL DEFICIENCIES

BLOOD CELL DEFICIENCIES

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

 Less than 20 iu/L in nonanemic individuals

 Level rises exponentially as the hct and hgb fall

 Except for anemia with chronic renal failure

 Erythropoietin levels are low

 Kidneys cannot produce the growth factor

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

HEMATOPOIETIC GROWTH FACTORS

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