Antianemia drugs

I Made Jawi
Department of
Pharmacology
Faculty of Medicine
Udayana University
Antianemia drugs
Are therapeutic agents which
increase either the number of red
cells or the amount of hemoglobin in
the blood
Types of anemia

Blood loss
Inadequate production of blood
Excessive breakdown of blood cells

Inadequate production of blood
1. Hematopoietic Growth
Factors.
2 Iron insufficiency
3.Vitamine B12 insufficiency
4.Folic acid insufficiency

Sites of action for
EPO(Erythropoietin)
How Erythropoietin Is Taken
(Epoetin alfa, darbepoetin alfa)
Erythropoietin must be injected to be
effective; it can be given intravenously or
subcutaneously.
Erythropoietin works by binding to and
activating specific receptors on the surface of
RBC-producing cells in the bone marrow
Therapeutic Uses of EPO
(erythropoiesis-stimulating agents)

Anemia of end stage renal disease
To treat AIDS anemia caused by AZTs
suppression of bone marrow
Anemia related to cancer chemotherapy

Others
To increase RBC levels for autologous blood
donation
Anemia associated with rheumatoid arthritis
Biological Actions of Other
Hematopoietic Growth Factors
1. Granulocyte/Macrophage Colony Stimulating Factor
(GM-CSF)- Sargramostim
Acts synergistically with IL-3 to stimulate the formation and
proliferation of colony forming cells: CFU-GEMM, BFU-E,
CFU-Meg, CFU-GM, CFU-M, CFU-E
Increases cytotoxic phagocytic activity of mature
granulocytes
2. Interleukin 3 (IL-3)
Acts synergistically with GM-CSF to stimulate the formation
of granulocytes, macrophages, eosinophils and
megakaryocytes.
Acts synergistically with EPO to stimulate formation of BFU-E
colonies
Induces CFU-S and leukemic blast cells into cell cycle

More Hematopoietic Growth
Factors
3. Colony stimulating Factor-1 (CSF-1 or M-
CSF)
Acts synergistically with GM-CSF and IL-3 to stimulate
monocyte/macrophage colony formation and function
4. Granulocyte Colony Stimulating Factor
(G-CSF) - filgrastim
Acts synergistically with IL-3, GM-CSF and CSF-1 to
stimulate formation of megakaryocytes, granulocyte-
macrophage and high proliferative potential (HPP) colonies
Induces release of granulocytes from marrow

More Hematopoietic Growth
Factors
5. Thrombopoietin (TSF)
Increases the size and number of megakaryocytes.
(IL-11 also useful in stimulating production)

Increases the concentration of early megakaryocytes
cells (SACHE+cells) in bone marrow.

Produces an increase in megakaryocytes endomitosis.

Increases platelet size and number in plasma.
Iron(Fe)
Absorption: duodenum and proximal jejunum
Transport: transferrin
Storage: ferritin
Excretion: no more than 1 mg per day.


Iron Cycle
5 - 10% of ingested iron
is absorbed


Once ingested the acid
in the stomach:

1. Aids in ionization
of iron
2. Splits chelated
food iron from
chelator
3. Maintains iron in
soluble form
4. Allows iron to
remain in the
absorbable form
Fe
3+

Mechanism of Iron Absorption

Therapeutic uses of Iron
Iron Deficient
Anemia

Pregnancy

Premature Babies

Blood loss
Hookworn
infestation

Malabsorption
Syndrome

GI Bleeding due to:
Ulcers
Aspirin
Excess consumption
of coffee
Iron Preparations
Oral Iron
Ferrous Sulfate (Feosol) 300 mg tid
Side Effects are extremely mild:
Nausea, upper abdominal pain, constipation or diarrhea.
Cheapest form of Iron and one of the most widely
used
Parenteral
Iron Dextran (Imferon) IM or IV
Indicated for patients who cannot tolerate or absorb
oral iron or where oral iron is insufficient to treat the
condition ie. Malabsorption syndrome, prolonged
salicylate therapy, dialysis patients
Ferrous Fumarate
Femiron[OTC]; Feostat[OTC]; Ferro-
Sequels[OTC]; Fumasorb[OTC];
Fumerin[OTC]; Hemocyte[OTC];
Ircon[OTC]; Nephro-Fer[OTC]; Span-
FF[OTC]
Toxicity of Iron Overdose
5000 deaths/year in the US, usually in
children
20% of children presenting with iron toxicity
will die
1 to 2 grams are sufficient to cause death
At high doses, Iron is absorbed through
passive diffusion with no regulation

Treatment of Iron Overdose
Toxic levels
ALD 200-300mgkg, plasma iron > 300ug/dl

ABCs supportive care

Bicarbonate for acidosis

Fluids for blood loss

Ipecac or lavage

Chelation with Deferoxamine
Vitamin B12
B12 is essential for cell growth and for
maintenance of normal myelin
It is also important for the normal
metabolic function of folate .
Absorption and transport of vitamin
B
12

Vitamin B
12
binds a glycoprotein (intrinsic factor) in
stomach. I.F. is secreted by the parietal cells.
Vitamin-intrinsic factor complex recognises surface receptors of
mucosal cells in ileum and is absorbed.
It is transported around the body bound to specific a B
12
binding
protein (transcobalamin).


It is stored mainly in the liver in amounts (3-5mg) sufficient to last a
couple of years.
Function of vitamin B
12
1) Vitamin B
12
(as deoxyadenosylcobalamin) is a co-enzyme
methylmalonyl CoA mutase.



Anaemia due to a true folic acid deficiency it is megaloblastic anaemia.


Effects of B
12
Deficiency
Impaired methylmalonyl CoA mutase causes accumulation of
unusual odd number carbon fatty acids.


These accumulate in nerve cell membranes causing irreversible
neurological disorders.
Impaired methionine synthase traps H4folate as N5-methyl-H4folate
("folate trap").
This can lead to a secondary or artificial deficiency of folic acid.
One of the main symptoms of folic acid deficiency is anaemia.
Anaemia due to a true folic secondary folic acid deficiency caused
by primary B
12
deficiency is pernicious anaemia
2) Vitamin B
12
is also a coenzyme in a reaction involved in methionine
Metabolism.
H
4
folate is converted to N
5
-methyl-H
4
folate in a number of different reactions as it
accepts methyl groups. The methyl group can only be removed and the H
4
folate
regenerated by the above reaction.
(See folic acid)


Deficiency of vitamin B
12
Treatment is life long injections of vitamin B
12

(oral administration wouldn't be much use!)

Dietary deficiency is rare (except for vegans).
Deficiency more commonly due to an absorption
problem.
Auto immune disease can destroys
the parietal cells that secrete the
I.F. required for absorption.
Anaemia could be due to folic acid deficiency or
vitamin B
12
deficiency.


In either case folic acid would cure the anaemia but if the true
underlying deficiency involved vitamin B
12
the patient would
still go on to develop the irreversible neurological disorders.


For this reason such patients are always given
folic acid and
vitamin B
12
supplements until the true cause
of the anaemia is identified.
FOLIC ACID (FOLATE)

A moderately high intake of folic acid is not toxic but might
mask an underlying vitamin B
12
deficiency that only becomes
apparent once the irreversible neurological disorders set in
(see above).
Dietary sources and recommended intake:

Green leafy vegetables, liver, nuts and whole grain cereals.
RNI = 200g/day.
Large doses of folic acid (>1000g/day) can
antagonise anticonvulsants
which could cause problems for epileptic people.
STRUCTURE OF FOLIC ACID
Folic acid = pteridine base attached to p-aminobenzoic acid and glutamic acid.
Animals cannot make p-aminobenzoic acid or attach glutamic acid to
aminobenzoic acid and all our folic acid is ultimately derived from
microbial and plant sources. the one already present.
Folic acid carrying polyglutamic acid cannot be transported back out of
the cell):
Megaloblastic anaemia and folic
acid deficiency
Pernicious anaemia due to primary deficiency of vitamin B
12
giving
secondary deficiency of folic acid because all the folate ends up trapped
as N
5
-methyl-tetrahydrofolate

Folic acid deficiency reduces the capacity of the body to make
dTMP which affects the rapidly dividing bone marrow cells associated
with red blood cell production.

Importance of folic acid during early pregnancy:
Closure of the neural tube occurs around the 28th day of pregnancy
Incidence of neural tube defects (spina bifida and anencephaly) is reduced
by 400g folic acid supplement/day before conception and during the
first month of pregnancy.
Folic acid
Its active form is tetrahydrofolate which
plays a role in transportation of one-
carbon units to synthesize some
important substances.