Drugs Used for

Anemia

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Hematopoiesis
The production from undifferentiated
stem cells of circulating erythrocytes,
platelets, and leukocytes, is a
remarkable process that produces
over 200 billion new cells per day in
the normal person and even greater
numbers of blood cells in people with
conditions that cause loss or
destruction of blood cells
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The hematopoietic machinery:

- resides primarily in the bone marrow in
adults
- Requires a constant supply of:
3 essential nutrients : iron, vit. B12, and
folic acid
Hematopoietic growth factors
(=protein that regulate the proliferation
and differentiation of hematopoietic cells)

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Iron
Iron-Porphyrin heme ring + Globin
chain
Hemoglobin

Hb reversibly binds O2

Deficiency iron= Microcytic hypochromic

anemia

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Iron Distributon in Normal

Adults
Iron Content (mg)
Hemoglobin
Myoglobin
Enzymes
Transport (transferrin)
Storage (ferritin and other
forms)
Total

Men

Women

3050

1700

430

300

10

750

300

4248

2314

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Absorption
Normally absorbed in the duodenum
and proximal jejunum, though the
more distal small intestine can absorb
iron if necessary
Heme iron in meat hb and myoglobin
can be absorb intact
Iron in vegetables and grains tightly
bound to phytates or other complexing
agents absorption<<
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Non heme iron in foods and in

inorganic iron salt as and
complexes must be reduces to
ferrous (Fe2+) iron before it can
be absorbed by the intestinal
mucosal cells

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Oral iron preparations

Preparation

Tablet size
(mg)

Elemental iron
per tablet (mg)

Usual adult
dosage (tab
/day)

Ferrous sulfate,
hydrated

325

65

3-4

Ferrous sulfate,
desiccated

200

65

3-4

Ferrous
gluconate

325

36

3-4

Ferrous fumarate

200

66

3-4

Ferrous fumarate

325

106

2-3

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Adverse effects of oral iron

therapy

Nausea, epigastric discomfort, abdominal

cramps, constipation and diarrhea

Dose dependent
the daily dose
Taking the tablet immediately
after/with meals
Changing preparation (iron salt <<Adr)
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Black stools may

obscure the dx of
continued
gastrointestinal blood
loss
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Parenteral Iron therapy

Unable to tolerate or absorb oral iron
Extensive chronic blood loss who
cannot be maintained with oral iron
alone
Along with erythropoietin: oral iron
may not be absorbed at sufficient
rate to meet the demands of induced
rapid erythropoiesis
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 The ionized salts of iron used orally,

cant be injected because of their
strong protein precipitating action
Preparation for injection:
1.Iron dextran: colloidal solution: 50
mg elemental iron/ml
2.Iron-sorbitol-citric acid complex: 50
mg iron/ml
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Parenteral Iron Therapy

Iron deficiency anemia:
Require 1-2 g of replacement iron
Or
20-40 mL of iron dextran
(IV , IM)

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Parenteral Iron Therapy

250 mg Fe untuk setiap gram
kekurangan Hb:
Pertama 50 mg dilanjutkan 100-250
mg setiap hari atau bbp hari sekali
IV: dosis awal < 25 mg, ditingkatkan
bertahap untuk 2-3 hari sampai
tercapai dosis 100 mg/hr. Diberi
perlahan 20-50 mg/menit.
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Adverse effects of parenteral

iron therapy
Local pain, Tissue staining (brown
discoloration of the tissue overlying
the injection site), Headache, Lightheadedness, Fever, Arthralgia,
Nausea, Vomiting, Backpain, flushing,
urticaria, bronchospasm,
anapahylaxis and death (rarely)

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Acute Iron Toxicity

10 tab lethal in young
children
Necrotizing gastroenteritis, vomiting, abdominal
pain, bloody diarrhea, shock, lethargy, dyspnea
Metabolic acidosis, coma and death

Activated charcoal: doesnot bind iron ineffective

Whole bowel irrigation: to flush out unabsorbed pills
Deferoxamine: a potent iron-chelating compound
systemically to bind iron that has already been absorbed
and to promote its excretion in urine and feces
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Chronic Iron Toxicity

(Hemochromatosis)
Excess iron deposit in the heart, liver, pancreas,
andother organs organ failure and death

Intermittent Phlebotomy
Deferoxamine: efficient <<<, useful
for severe iron overload that cant be
managed by phlebotomy
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Factors facilitating iron

absorption
1. Acid: by favouring dissolution and
reaction of ferric iron
2. Reducing substances: ascorbic acid,
AA containg SH radical. These
agents reduce ferric iron and form
absorbable complexes
3. Meat: by increasing HCl secretion
and providing haeme iron
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Factors impeding iron

absorption
1. Alkalies(antacids) render iron
insoluble, oppose its reduction
2. Complexing iron:
a. Phosphates (rich in egg yolk)
b. Phytates (in maize, wheat)
c. Tetracycline
3. Presence of other foods in the
stomach
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Vitamin B12
Cofactor for several essential
biochemical reactions in humans
Deficiency of Vit. B12 leads to
anemia, gastrointestinal symptoms,
and neurologic abnormalities

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Vitamin B12 chemistry

Consists of a porphyrin-like ring with a
central cobalt atom attached to a
nucleotide
Active forms of the vitamin in human:
deoxyadenosylcobalamin and
methylcobalamin
Cyanocobalamin and hydroxocobalamin
and other cobalamins found in food sources
are converted to the above active forms
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A. Methyl
transfer
N5Methyltetrahydrofolate

Tetrahydrofolate

Cobalamin
Methionine

Methylcobala
min
Homocystein
e

B. Isomerization of L-MethylmalonylCoA

L-MethylmalonylCoA

MethylmalonylCoA mutase

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Succinyl-CoA

Folic Acid

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 Vitamin B12 is sometimes called

extrinsic factor to differentiate it from
intrinsic factor (FIC=protein normally
secreted by the stomach (parietal cell))
Absorbed only after it complexes with
intrinsic factor

The intrinsic factor-Vitamin B12

complex
Absorbed in the distal ileum by a highly
spesific receptor-mediated transport
system
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Cholinergic drugs, histamin, ACTH,

corticosteroid, tiroid

Factor Intrinsic Castle

Absorption of vitamin B12

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Posologi
Tablet :oral
Injection: cyanocobalamin, larutan
ekstrak hati dalam air, suntikan
depot vitamin B12.

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Parenteral B12
injection
Hydroxycobalamin
100-1000g IM daily or every other day
for 1-2 weeks to replenish body store
Maintenance : 100-1000 g IM once a
month for life
If neurologic abnormailites are present,
maintenance therapy injections should be
given every 1-2 weeks for 6 months
before switching to monthly injections

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Oral (more expensive)doses 1000

g IM usually sufficient to
pernicious anemia who
refuse /cant tolerate the
injections.

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Folic Acid
(Pteroylglutamic acid)
Reduced form are required for
essential biochemical reaction that
provide precursors for biosynthesis
of AA, purines and DNA.
FADHFATHFA by Frase and
DHFRase
Deficiency= megaloblastic anemia

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THFA mediates a number of one

carbon transfer reaction by carrying a
methyl group as an adduct
1. Conversion of homocysteine to
methionine
2. Generation of thymidilate, an essential
constituent of DNA
3. Conversion of serine to glycine
4. Purine synthesis
5. Generation and utilization of formate
pool
6. Histidine metabolism
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Folic acid deficiency

Inadequate dietary intake, alcoholic,
liver disease, pregnant, hemolytic
anemia,
malbsorption,cancer,leukemia,
myeloproliferative isorder, renal
dialysis,drugs

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Drugs induced folic acid

deficiency
FA absorption:
Phenytoin, some other
anticonvulsant, oral contraseptives,
INH
Inhibit dihydrofolate reductase:
methothrexate,
trimethoprim,pirimetamine

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Folic Acid
1 mg orally daily is sufficient to
reverse megaloblastic anemia,
restore normal serum folate levels,
and replenish body stores of folates
Dose therapeutic: 2-5 mg/day,
prophylactic0.5 mg/day

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Adverse effects
Oral FA is entirely non toxic
Injections rarely cause sensitivity
reactions

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Hematopoietic Growth
Factors
HGF: glycoprotein hormones that
regulate the proliferation and
differentiation of hematopoietic
progenitor cells in the bone marrow
Erythropoietin (epoitin alfa),
granulocyte colony stimulating factor
(G-CSF),granulocyte-macrophage
colony-stimulating factor (GM-CSF),
and interleukin 1
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Erythropoietin
1st human HGF to be isolated, from the
urine patients with severe anemia
Epoitin alfa = rHuEpo (recombinant
human erythropietin):
- produced in a mammalian cell expression
system using recombinant DNA technology
- IV: t1/2 4-13 hrs, IU
Darbopoietin alfa:
- Glycosylated form of erythropoietin
- T1/2 2-3x>>
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Anemia and hypoxia are sensed by

kidney cells rapid secretion of EPO
acts on erythroid marrow and:
Stimulates proliferation of colony
forming cells of the erythroid series
Induces HB formation and
erythroblast maturation
Release reticulocytes in circulation
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 RBC O2 delivery improve

performace

Erythropietin: International Olympic comittee

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Clinical Use
Anemia of chronic renal failure
Anaemia in AIDS patients treated with
zidovudine
Cancer chemotherapy induced anemia
Preoperative increased blood production for
autologous transfusion during surgery
Anemia due to primary bone marrow
disorders
Anemia associated with chronic inflammation
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 Most patients can maintain Ht 35%

with EPO 50-150 IU//kg IV/SC
3x/week
Patients with endogenous
erythropoietin levels:
< 100 IU/L: best chance of response
100-500 IU/L: respond occasionally
(150-300 IU/kg 3x/week)

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Adverse Effects
Associated with rapid increased in
Hematocrite and Hb, and
Hypertension, thrombotic
complication
Flu like symptoms lasting 2-4 hrs

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Thank You

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Purines
N5, N10methylentetrahydrofolate

glycine

serine

Serine
transhydroxymethylase

Tetrahydrofolate

Thymidylate
synthase

Dihydrofolate
Folate reductase

dUMP

dTMP
DNA
synthesis
Folate reductase

methylcobalam
in
methionine
Cobalamin
homocysteine
N5methyltetrahydrofolate

Dietary
folate

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Folic acid