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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

8

Transport
(transferrin)

8

6

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 µg/dl
- TIBC > 400 µg/dl
- iron binding saturation < 10 %
- serum ferritin < 10 µg/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 µg
of vit B12 daily; 1-5 µg 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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