(Haematinics)

Drugs used for treatment of anemia

Dr. Begard Omer Berzinjy
 Agents used to treat anemia

Haematinics: these are substances required in blood

formation and used as adjuvants in treatment of anemia
• Iron
• vitamin B12
• Folic acid
• Growth factors
Iron
• History:1713 iron was shown to be present in blood
• 19th century Blaud developed Blaud’s pill consists of
ferrous sulfate and potassium carbonate for anemia.
 pharmacokinetic
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. Allows iron to remain in the absorbable form
( Fe+2)reduced ferrous form, which is the more
soluble form
Absorption
Iron is then absorbed in the duodenum and proximal
jejunum
Iron crosses the luminal membrane of the intestinal
mucosal cell by two mechanisms:
active transport of ferrous iron and absorption of iron
complexed with heme . divalent metal transporter
• The divalent metal transporter, DMT1 efficiently
transports ferrous iron across the luminal
membrane.
• The rate of iron uptake is regulated by mucosal cell
iron stores such that more iron is transported when
stores are low
• absorbed iron can be actively transported into the
blood across the basolateral membrane, probably by
the transporter IREG1(Iron regulated transporter 1),
also known as ferroportin1.
 Mechanism of Iron absorption
Ferrous state

Ferric state

Divalent metal
transporter 1
 Mechanism of iron absorption

Ferric state

Divalent metal
transporter 1
Transport
• Iron is transported in the plasma bound with
transferrin. Iron-transferrin complexes bind to
transferrin receptors, which are membrane
glycoproteins expressed on maturing erythroid
cells.
• This leads to the internalization with
subsequent release of iron intracellularly. The free
transferrin and transferrin receptors are recycled
to the cell membrane
Excretion
• There is no mechanism for excretion of iron.
Small amounts are lost in the feces by
exfoliation of intestinal mucosal cells, and
trace amounts are excreted in bile, urine, and
sweat.
Oral iron preparation
The percentage of elemental iron varies in each
oral iron preparation
• A prompt rise in reticulocyte count confirms
iron deficiency.
• The reticulocyte count should begin to
increase within 4–7 days after initiation of iron
therapy and peak at 1–2 weeks.
 IRON ELEM NOTES
FORMULATION ENTA
AND BRAND L
NAME(S) IRON
(%)
Ferrous gluconate 12 •Less elemental iron, but similar tolerability to ferrous
sulfate
Ferric ammonium 18 • Less bioavailable than ferrous salts
citrate • Must be reduced to ferrous form in the intestine
Ferrous sulfate 20 • Most common oral iron supplement, cheap,metallic taste
• Low cost with good effectiveness and tolerability
Ferrous sulfate, 30 • Extended-release formulation of ferrous sulfate (once
anhydrous daily dosing)
• Higher cost than ferrous sulfate
Ferrous fumarate 33 • Similar effectiveness and tolerability to ferrous sulfate
• Almost no taste compared to other iron salts
Carbonyl iron 100 • Microparticles of purifed iron
• Dissolves in the stomach to form HCl salt to be absorbed
• Less toxic than iron salts due to slower absorption rate
(continued iron release for 1 to 2 days)

Polysaccharide-iron 100 • Tasteless and odorless

Adverse effect of oral therapy
Gastrointestinal (GI) disturbances (abdominal pain,
Constipation is more common than diarrhoea )
Epigastric pain caused by local irritation
Heartburn
Nausea, Vomiting
dark stools
Bloating
Teeth staining
Metallic taste

lowering the daily doses of iron or taking iron with

meals significantly reduces iron-induced adverse
effects.
 Parenteral iron preparations
Indications:
1. When oral iron not tolerated,
2. Failure to absorb oral iron (gastrectomy,
malabsorption, inflammatory bowl disease)
3. Severe deficiency – chronic bleeding
4. Along with erythropoietin, oral iron may not
be absorbed at sufficient rate to meet
demands For replenishment of iron stores
Organic preparations
• Iron-sucrose complex and iron sodium gluconate
complex: these agents can be given only by I.V route, less
likely than iron dextran to cause hypersensitivity
reactions.
• Iron dextran :I.M/I.V
• is a stable complex of ferric hydroxide and low-
molecular-weight dextran
• 50mg of elemental iron is present in one ml given
I.M/I.V
• Alternatively total calculated dose is diluted in 500ml of
glucose/saline solution infused I.V over 6-8hrs under
constant observation
Adverse reactions
Local: Pain at inj site, pigmentation, sterile abscess in old
debilitated patients
Systemic: Fever, headache, joint pain, flushing, Immediate systemic
palpitation, chest pain, dyspnoea, lymph node allergic reaction that is not
caused by IgE-mediated
enlargement t
immune response

fatal reactions including anaphylactoid reaction , vascular

collapse and death
to avoid the risk of a hypersensitivity reaction, a small
test dose of iron dextran (0.5ml is given I.M/ I.V over 5-
10mins) should always be given before full intramuscular
or intravenous doses are given
FERROUS SUCROSE
Newer formulation high molecular weight complex of
iron hydroxide with sucrose that on i.v is taken by RE cells

FERRIC CARBOXYMALTOSE
Latest drug ,ferric hydroxide core is stabilized by
carbohydrate shell Macromolecule taken by RE Cells
primarily in bone marrow, liver and spleen
 Iron toxicity
• Acute iron toxicity: usually seen in young children who
have swallowed attractively coloured iron tablets in
mistake for sweets, can result in severe necrotising
gastritis with vomiting, haemorrhage and diarrhoea,
followed by circulatory collapse
Treatment: to flush out unabsorbed iron whole bowel
irrigation is performed
For already absorbed iron à iron chelating agent i.e.
Deferoxamine is given that binds iron and promotes its
excretion in urine and feces.
Chronic iron toxicity: iron overload or hemochromatosis
Characterized by excessive iron absorption and
deposition on various organs e.g. liver, pancreas, heart
and kidney with subsequent fibrosis and organ failure
commonly seen in patients with
• inherited hemochromatosis
• patients who receive frequent blood transfusion e.g.
patients with thalassemia major.
Treatment: venipaucture
• intermittent phlebotomy i.e. blood donation
(in the absence of anemia)
• Iron chelation therapy: Deferiprone is an orally
absorbed iron chelator , used as an alternative
treatment for iron overload in patients with
thalassaemia major who are unable to take
Deferoxamine
• Deferasirox is similar, but can cause gastrointestinal
bleeding.
 FOLIC ACID
History:
• Wills identified crude liver extract that correct
macrocytic anemia and is called wills factor later as folic
acid.
• 1941 Mitchell named Folic acid

a) folic acid is required in blood formation

b) Reduced forms of folic acid(TH2,TH4) are required
for essential biochemical reactions that provide
precursors for the synthesis of amino acids, purines,
and DNA.
Daily requirement of folic acid 50μg
Pregnancy & lactation :↑200-300μg/day
5-20 mg of folates are stored in the liver and other
tissues.
Folates are excreted in the urine and stool and are also
destroyed by catabolism
treatment with drugs that are dihydrofolate reductase
inhibitors (for example, methotrexate, pyrimethamine,
and trimethoprim ) they cause deficiency of folic acid
The consequences of folate
deficiency
• Macrocytic anemia
• Congenital malformations
Also its implicated as a
cause in newborns (spina
bifida) and may play a role
in vascular disease
Pharmacokinetic
• Dietary folates, consist of polyglutamate
forms of N5-
methyltetrahydrofolate(N₅methylTH4)
• Then absorbed in the ileum
• Inside cells, N5-methyltTH4 is converted to
TH4 (by dihydro falate reductase enzyme)
which is a demethylation reaction that
requires vitamin B12
 Vitamin B₁₂
History
• Vitamin B12 isolated in 1948
• Dorothy Hodgkin determined structure of vitamin B12
received noble prize for this work
• VitaminB12,also called cobalamin, extrinsic factor
• Can be synthesized by normal gut flora in human beings
• Requirement:2-3μg in normal adults
• Because the normal daily requirements of vitamin B12 are
only about 2 mcg, it would take about 5 years for all of the
stored vitamin B12 to be exhausted and for megaloblastic
anemia to develop
Pharmacokinetic
• Absorption requires intrinsic factor (a glycoprotein
secreted by gastric parietal cells).
• the intrinsic factor-vitamin B12 complex is
subsequently absorbed in the distal ileum by a highly
specific receptor-mediated transport system
• Once absorbed, vitamin B12 is transported to the
various cells of the body bound to a plasma
glycoprotein, transcobalamin II
• Excess vitamin B12 is transported to the liver for
storage.
Pharmacodynamics
Two essential enzymatic reactions in humans require
vitamin B12
One, methylcobalamin serves as an intermediate in the
transfer of a methyl group from N5
methyltetrahydrofolate to homocysteine, forming
methionine
The other enzymatic reaction that requires vitamin B12
is isomerization of methylmalonyl-CoA to succinyl-
CoA by the enzyme methylmalonyl-CoA mutase
Vitamin B12 deficiency
• Megaloblastic(macrocytic) anemia
• Neurological manifestation cause tingling sensation
(pins and needles) in the hands and feet, difficulty
walking and dementia
• The vitamin B12 preparations used therapeutically are
hydroxocobalamin and cyanocobalamin
• They may be administered orally (for dietary
deficiencies), intramuscularly, or deep subcutaneously
(for pernicious anemia).
 GROWTH FACTORS
Erythropoietin
• Peritubular cells in the kidneys work as
sensors that respond to hypoxia and mediate
synthesis and release of erythropoietin(EPO)
• EPO, thus, regulates red blood cell
proliferation and differentiation in bone
marrow.
Human erythropoietin (epoetin alfa):
produced by recombinant DNA technology, is
effective in the treatment of:
• anemia caused by end-stage renal disease,
• anemia associated with human
immunodeficiency virus infection,
• anemia in bone marrow disorders,, and
• anemias in some cancer patients.
Darbepoetin
• is a long-acting version of erythropoietin
• Due to their delayed onset of action, these agents have
no value in acute treatment of anemia
Indications
• hemoglobin level not exceeds 12 g/dL
• hemoglobin should not rise by more than 1 g/dL over a
2-week period.
• Additionally, if the hemoglobin level exceeds 10 g/dL,
doses of epoetin alfa or darbepoetin should be
reduced or treatment should be discontinued.
Side effects
• generally well tolerated, elevation in blood
pressure and arthralgia in some cases may
occur
• If epoetin alfa is used when hemoglobin
concentrations more than 11 g/dL, serious
cardiovascular events (such as thrombosis and
severe hypertension)may occur
Agents used to treat neutropenia
• Myeloid growth factors or granulocyte colony
stimulating factors (G-CSF), such as filgrastim
tbo-filgrastim, and pegfilgrastim
• granulocyte–macrophage colony– stimulating
factors(GM-CSF), such as sargramostim
stimulate granulocyte production in the marrow to
increase the neutrophil counts and reduce the
duration of severe neutropenia
The main difference between the available agents
lies in the frequency of dosing
• Pegfilgrastim: is a pegylated form of G-CSF,
resulting in a much longer half-life when
compared to the other agents. it is given as a
single dose 24 hours after chemotherapy,
rather than once daily.
• Monitoring of absolute neutrophil count
(ANC) is typically not necessary with
pegfilgrastim.