Agents Used in Anemias;

Hematopoietic Growth
Factor
Sakura, MD
Department of Pharmacology
Hasanuddin University

Hematopoiesis
Require

three essential nutrients :

- iron
- vitamin B12
- folic acid
Anemia : deficiency in oxygen
carrying-erythrocyte

IRON
Iron

deficiency : the most common cause

of chronic anemia
Leads to : pallor, fatigue, dizziness,
exertional dyspnea, etc
Forms : the nucleus of the iron-porphyrin
heme ring, which 2gether with globin
chains forms hemoglobin
Hb : binds oxygen & provides the critical
mechanism for oxygen delivery from lungs
to other tissues

Pharmacokinetics
Absorption
absorbed in duodenum, proximal
jejunum
A normal individual (without iron
deficiency) absorbs 5-10% (0,5-1
mg daily) of iron ; average diet in
USA (10-15 mg daily)
Total iron absorption increase to 1-2
mg in normal menstruating woman

Tabel 1. Iron distribution in normal adult

Iron content (mg)
Men

Women

Hemoglobin

3050

1700

Myoglobin

430

300

Enzymes

10

Transport
(transferrin)

Storage (ferritin
& other
forms)

750

300

4248

2314

Total

 Available

abundant in meat
Absorption is decreased by the
presence of chelators or
complexing agents in intestine
lumen
Absorption increased in the
presence of hydrochloric acid &
vitamin C

Transport
Iron

is transported in the plasma

bound to transferrin
Crosses the intestinal mucosal cell by
active transport
Increased erythropoiesis is
associated with an increase the
number of transferrin receptors

Storage
Binds

avidly to a protein apoferritin,

forms complex ferritin
It is stored in intestinal mucosal cell,
macrophages in the liver, spleen,
bone
Apoferritin synthesis is regulated by
the levels of free iron

Elimination
No

mechanism for excretion of iron

Small amounts are lost by exfoliation
of IMC into the stool
Trace amounts are excreted in bile,
urine, and sweat
No more than 1 mg of iron lost per
day

Clinical Pharmacology

The only clinical indication : treatment or prevention of

iron deficiency anemia
Iron deficiency can be found in : infants (premature
infants), rapid growth period, pregnant, lactating
woman, post gastrectomy, patient with severe small
bowel disease that result in generalized malabsorption
Iron deficiency is diagnosed : (laboratory
measurement)
- serum iron < 40 g/dl
- TIBC > 400 g/dl
- iron binding saturation < 10 %
- serum ferritin < 10 g/L

Tabel 1. Some Commonly used oral iron preparation

Preparation

Tablet size

Elemental
iron per
tablet

Usual adult
dosage
tablet per
day

Ferrous sulfate,
hydrated

325 mg

65 mg

3-4

Ferrous sulfate,
desiccated

200 mg

65 mg

3-4

Ferrous
gluconate

325 mg

36 mg

3-4

Ferrous fumarate

200 mg

66 mg

3-4

Ferrous fumarate

325 mg

106 mg

2-3

Treatment
1.
2.

Oral iron therapy

Parenteral iron therapy
Indication :
- various postgastrectomy condition
- previous small bowel resection
- inflammatory bowel disease
- malabsorption syndrome
- Consist of : iron dextran (complex of ferric
hydroxide), iron-sucrose complex, iron sodium
gluconate complex (deep IM, IV infusion)
- Dosage for iron dextran : 20 40 ml (IV)

Clinical Toxicity
Acute iron toxicity
Necrotizing gastroenteritis (vomiting,
abdominal pain, bloody diarrhea
followed by shock, lethargy, dyspnea)
Should be given Deferoxamine
Chronic iron toxicity
Hemochromatosis
R/ Phlebotomy

VITAMIN B12
Cofactor
Deficiency

leads to anemia,
gastrointestinal symptoms,
neurologic abnormalities
Consist of a porphyrin-like ring with a
central cobalt atom
Cyanocobalamin & hydroxocobalamin

Pharmacokinetics of Vitamin B12

Once

absorbed, Vit B12 is bound to

transcobalamin II and transported
to various cells of the body
Average diet (USA) contain 5-30 g
of vit B12 daily; 1-5 g of which is
absorbed

Pharmacodynamics of Vit B12

Cofactor for several reaction in the body :
conversion of the major dietary and
storage folate to tetrahydrofolate
DNA synthesis
isomerization of methylmalonyl-CoA to
avoid neurologic disorder
Clinical use
R/ for pernicious anemia & anemia caused
by gastric resection

FOLIC ACID
Cofactor

for transfer reaction of one

carbon
Play a role in normal DNA synthesis
Deficiency : megaloblastic anemia
Deficiency in pregnancy : increase risk of
neural tube defects in fetus (spina bifida)
FA deficiency associated with : Cancer,
leukemia, myeloproliferative disorders,
certain chronic skin disease,

 Drugs

that can interfere the

absorption & metabolism of FA :
- Phenytoin (Abs)
- Some anticonvulsant (Abs)
- Oral contraceptives (Abs)
- Isoniazid (Abs)
- Methotrexate
- Trimethoprim & Pyrimethamine
(inhibit dehydrofolate reductase)

Pharmacodynamic
Converted to tetrahydrofolate by
dehydrofolate reductase

Hematopoietic Growth Factors

Erythropoietin
Produced by the kidney
Stimulates the production of red cells &
increases their release from the bone marrow
Routinely used for : the anemis associated
with renal failure, primary bone marrow
disorders, bone marrow transplantation,
anemias secondary to cancer chemotherapy
Toxicity : minimal

Myeloid Growth Factor

Consist of :
- granulocyte colony-stimulating fc; G-CSF
- granulocyte-macrophage colonystimulating
fc; GM-CSF
Stimulates the production & function of neutrophils
Stimulates the production of other myeloid and
megakaryocyte progenitors
Function :
- accelerate the recovery of neutrophils after Ca
chemotherapy
- treat other form of secondary & primary
neutropenia (aplastic anemia, congenital
neutropenia)
SE : bone pain, fever, arthralgias, capilarry damage
with edema, allergic reaction

Megakaryocyte Growth Factor

Stimulates the growth of primitive
megakaryocyte progenitor --> increase
the number of peripheral platelets
Consist of thrombopoietin & interleukin11
IL-11 : for treatment of patients who have
had a prior episode of thrombocytopenia
after a cycle of Ca chemotherapy
SE : fatigue, headache, dizziness, fluid
retension

Other Hematopoietic Growth Factor

Consist of :
- Monocyte colony stimulating factor
(M-CSF)
- Stem cell factor ( SCF)
- Interleukin-3, -6, -9
SCF & IL-3 have the broadest progenitor cell
line effect, including red cell, granulocyte,
monocyte-macrophage, megakaryocyte,
eosinophil, basophil cell lines

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