HAEMATINICS AND

ERYTHROPOIETIN

By: Dr Darakhshan Rizvi

CIMS
Department of Pharmacology
 OVERVIEW

 Definition of haematinics
 Sources of Iron
 Distribution of iron
 Iron metabolism & Elimination
 Different iron preparations
 Iron poisoning treatment
 Erythropoietin
 DEFINITION

 These are substances required in blood formation are used as

adjuvants in treatment of anaemia.

 Anaemia occurs when the balance between production and

destruction of RBCs is disturbed by:

(a) Blood loss (acute or chronic)

(b) Impaired red cell formation due to

• Deficiency of essential factors, i.e. iron, vitamin B12, folic acid.

 DEFINITION

•Bone marrow depression (hypoplastic anaemia), erythropoietin

deficiency.

(c) Increased destruction of RBCs (haemolytic anaemia)

 DISTRIBUTION OF IRON IN BODY

 Iron is an essential body constituent.

 Total body iron in an adult is 2.5–5 g (avg 3.5 g).
 It is more in men (50 mg/kg) than in women (38 mg/kg).

It is distributed into:
 Haemoglobin (Hb) : 66%
 Iron stores as ferritin and haemosiderin : 25%
 Myoglobin (in muscles) : 3%
 Parenchymal iron (in enzymes, etc.) : 6%
 DAILY REQUIREMENT

 To make good average daily loss, iron requirements are:

 Adult male : 0.5–1 mg (13 µg/kg)
 Adult female (menstruating) : 1–2 mg (21 µg/kg)
 Infants : 60 µg/kg
 Children : 25 µg/kg
 Pregnancy : 3–5 mg (80 µg/kg)
 DIETARY SOURCES OF IRON

 Rich: Liver, egg yolk, oyster, dry beans, dry fruits, wheat

germ, yeast.

 Medium: Meat, chicken, fish, spinach, banana, apple.

 Poor: Milk and its products, root vegetables.

 IRON ABSORPTION
 The average daily diet contains 10–20 mg of iron.
 Its absorption occurs all over the intestine, but majority in
the upper part.
 Dietary iron is present either as haeme or as inorganic iron.
 Absorption of haeme iron is better (upto 35% compared to
inorganic iron which averages 5%) and occurs directly
without the aid of a carrier
 IRON ABSORPTION

 The major part of dietary iron is inorganic and in the

ferric form.

 It needs to be reduced to the ferrous form before

absorption.
IRON ABSORPTION
FACTORS FACILITATING IRON ABSORPTION

1. Acid: by favouring dissolution and reduction of ferric iron.

2. Reducing substances: ascorbic acid, amino acids containing

SH radical. These agents reduce ferric iron and form

absorbable complexes.

3. Meat: by increasing HCl secretion and providing haeme iron.

 FACTORS IMPEDING IRON ABSORPTION

 Alkalies (antacids) render iron insoluble, oppose its

reduction.
 Phosphates (rich in egg yolk)
 Phytates (in maize, wheat)
 Tetracyclines
 Presence of other foods in the stomach.

In general, bioavailability of iron from cereal based diets is

low.
 MUCOSAL BLOCK
 The gut has a mechanism to prevent entry of excess iron in the
body.
 Iron reaching inside mucosal cell is either transported to plasma
or oxidised to ferric form and complexed with apoferritin to
form ferritin.
 This ferritin generally remains stored in the mucosal cells and is
lost when they are shed (lifespan 2–4 days). This is called the
‘Ferritin curtain’.
 Iron status of the body and erythropoietic activity govern

the balance between these two processes, probably through

a ‘haematopoietic transcription factor’, and thus the

amount of iron that will enter the body.

IRON METABOLISM

15
TRANSPORT OF IRON

16
 PREPARATIONS AND DOSE
Oral iron

 The preferred route of iron administration is oral.

 Dissociable ferrous salts are inexpensive, have high iron

content and are better absorbed than ferric salts, especially at

higher doses.

 Gastric irritation and constipation are related to the total

quantity of elemental iron administered.

 ORAL IRON PREPARATIONS
• Ferrous sulphate(32% iron): cheap, metallic taste is
present 200mg tab
• Ferrous gluconate (12% iron) 300mg,400mg/15ml
elixer
• Ferrous fumarate (33% iron) 200mg tab
• Colloidal ferric hydroxide (50% iron) 50mg/ml
drops
• Carbonyl iron highly pure fine powder prepared by
decomposition of iron pentacarbonyl ,toxic compound

• Ferrous salts are cheap, high iron content, better absorbed than
ferric 18
salts
• For full haematopoietic effect –

• Adult total dose of 200mg of elemental iron given daily in 2 or 3

divided doses in empty stomach.

• Child- 3-5mg/kg in 3 divided doses

Prophylaxis:

• 30mg elemental iron/day is sufficient.

 ADVERSE EFFECTS OF ORAL IRON

 Epigastric pain
 Heartburn
 Nausea
 Vomiting
 Bloating
 Staining of teeth
 Metallic taste, colic, etc.
 Tolerance to oral iron can be improved by initiating therapy at
low dose and gradually escalating to the optimum dose.
 PARENTERAL IRON

Iron therapy by injection is indicated only when:

1. Oral iron is not tolerated: bowel upset is too much.

2. Failure to absorb oral iron: malabsorption inflammatory

bowel disease.

Chronic inflammation decreases iron absorption, as well as the

rate at which iron can be utilized

 PARENTERAL IRON

3. Non-compliance to oral iron.

4. In presence of severe deficiency with chronic bleeding.

5. Along with erythropoietin: oral iron may not be absorbed at

sufficient rate to meet the demands of induced rapid erythropoiesis.

For replinishment of iron stores this formula is been used

Iron requirement (mg) = 4.4 × body weight (kg) × Hb deficit
(g/dl)
 ORGANIC PREPARATIONS

• Iron dextran & iron sorbitol - citric acid (i.m)

• Ferrous sucrose & ferric carboxymaltose

Iron dextran: i.v/i.m
• Colloidal preparation of ferric oxyhydroxide complexed with
polymerized dextran.

• High molecular weight >6000, dark brown viscous liquid.

• 50mg of elemental iron is present in one ml.Only preparation that

can be injected i.m as well as i.v.
 IRON DEXTRAN: I.V/I.M
 By i.m. route it is absorbed through lymphatics, circulates
without binding to transferrin and is engulfed by RE cells where
iron dissociates and is made available to the erythron for haeme
synthesis.
 In the injected muscle 10–30% of the dose remains locally bound
and becomes unavailable for utilization for several weeks.
 Thus, 25% extra needs to be added to the calculated dose.
 Iron-dextran is not excreted in urine or in bile.
 I.M:

• Given deep in gluteal region using Z track technique.

• Iron dextran can be injected 2 ml daily, or on alternate days, or 5

ml each side on the same day.

 ON I.V ADMINISTRATION

• After test dose of 0.5 ml injected I.V over 5-10mins, 2ml

injected/day by taking 10 mins for injection.
• Alternatively total calculated dose is diluted in 500ml of
glucose/saline solution infused i.v over 6-8 hrs under constant
observation.
• If any complaints of giddiness, paresthesia, chest tightness
present should be terminated.
To avoid risk of hypersensitivity 0.25-0.5ml inj i.v over to ½-1hr
reactions perform sensitivity test with small test dose before i.v/i.m.
 ADVERSE DRUG REACTIONS

Local:

Pain at inj site, pigmentation, sterile abscess- old deblitated pts.

Systemic:

Fever, headache, joint pain, flushing, palpitation, chest pain,

dyspnoea, lymph node enlargement.

Rare:

Anaphylactoid reaction vascular collapse and death.

 IRON SORBITOL CITRIC ACID COMPLEX:

 It is a low molecular weight complex which can be injected

only i.m., from where absorption occurs directly into

circulation and not through lymphatics.

 No local binding in muscle occurs, but about 30% of the dose

is excreted in urine; the calculated total dose has to be

increased accordingly.
 IRON SORBITOL CITRIC ACID COMPLEX:

 Patient may be alarmed because the urine turns brown after

some time. Iron-sorbitol-citric acid binds to transferrin in
plasma and may saturate it if present in large quantity.

 That is why it is not suitable for i.v. injection or infusion, as

the remaining free iron is highly toxic.

 Even with the recommended i.m. dose, incidence of

immediate reaction, including ventricular tachycardia, A-V
block, other irregularities, hypotension, flushing is higher
 FERROUS-SUCROSE

 Newer formulation is a high molecular weight complex of iron

hydroxide with sucrose, that on i.v. injection is taken up by RE
cells, where iron dissociates and is utilized.
 It is safer than the older formulations and a dose of 100 mg
can be injected i.v. taking 5 min, once daily to once weekly till
the total calculated dose is administered.
 Solution is highly alkaline ruling out i.m./s.c. injection
 The incidence of hypersensitivity reaction is very low.

 This preparation is particularly indicated for anaemia in

kidney disease patients, but reports of kidney damage are on

record.

 Oral iron should not be given concurrently and till 5 days

after the last injection.

 FERRIC CARBOXYMALTOSE

 It is the latest formulation of iron in which a ferric hydroxide

core is stabilized by a carbohydrate shell.
 The macromolecule is rapidly taken up by the RE cells,
primarily in bone marrow (upto 80%), as well as in liver and
spleen.
 Iron is released and delivered subsequently to the target cells.

 It is administered either as daily 100 mg i.v. injection, or upto

1000 mg is diluted with 100 ml saline (not glucose solution)
and infused i.v. taking 15 min or more.
 FERRIC CARBOXYMALTOSE

 It should not be injected i.m.

 The incidence of acute reaction is very low.

 Pain at injection site, and rashes have occurred, but

anaphylaxis is rare.

 Headache, nausea, abdominal pain are generally mild.

Hypotension, flushing and chest pain are infrequent.

 IRON POISONING

In Infants and children 10-20 tab or equivalent liquid preparation

(>60mg/kg iron) cause serious toxicity.
Manifestations are:
Vomiting
Abdominalpain
Haematemisis
Diarrhoea
Lethargy
Cyanosis
Dehydration
Acidosis,convulsion, shock, cardiovascular collapse and death.

34
• Haemorrhage
• Hepatic necrosis and brain damage present.

Treatment of poisoning
Supportive measures
Flu
id & electrolyte balance
Vitals monitoring
Dia
zepam i.v – convulsions
To
prevent further
absorption of iron from
gut:
ABSORBED:DESFERRIOXAMINE :

• Iron chelator is D.O.C

• Obtained from streptomyces pilosus potent and specific

• Readily binds ferric iron to form ferrioxamine

• Well tolerated

• Rapid iv causes hypotension, tachycardia, anaphylactoid reaction

& urticaria.
ABSORBED:DESFERRIOXAMINE :

 Dose: I.M 0.5-1g (50mg/kg) repeatedly 4-12hrs required or

I.V in case of shock 10-15mg/kg/hr, max 75mg/kg in a day till serum

iron falls below 300µg/dl

 Alternatively DTPA or calcium edetate can be used.

 BAL is contraindicated because its iron chelate is also toxic.

 CONTRAINDICATION FOR
TREATMENT :
• Severe renal disease

• Pregnant women
Hemochromatosis:
• Desferrioxamine useful in prevention and treatment of iron
overload in chronic anemia in thalassemia major with
multiple transfusions.
• Given continuous infusion 2g for 12hrs OD,but phlebectomy
is treatment of choice.
• Deferiprone, Deferasirox are alternative choice for those who
cannot tolerate the above drug.
 VITAMIN-B12

 Cyanocobalamin and hydroxocobalamin are complex

cobalt containing compounds present in the diet and

referred to as vit B12.

 Vit B12 occurs as water soluble, thermostable red crystals.

It is synthesized in nature only by microorganisms; plants

and animals acquire it from them.

 DIETARY SOURCES
 Liver
 Kidney
 Sea fish, egg yolk, meat, cheese are the main vit B12
containing constituents of diet.
 The only vegetable source is legumes (pulses) which get it
from microorganisms harboured in their root nodules.
 Daily requirement 1–3 µg, pregnancy and lactation 3–5 µg.
 METABOLIC FUNCTIONS

 Vit B12 is essential for the conversion of homocysteine

to methionine. This reaction is also critical in making

tetrahydrofolic acid (THFA) available for reutilization.

 Purine and pyrimidine synthesis is affected primarily

due to defective ‘one carbon’ transfer because of ‘folate

trap’.
 METABOLIC FUNCTIONS

 Malonic acid converted to Succinic acid is an important

step in propionic acid metabolism. It links the

carbohydrate and lipid metabolisms.

 Interference with the reaction: Methionine to S-adenosyl

methionine may be more important in the neurological

damage of B12 deficiency, because it is needed in the

synthesis of phospholipids and myelin.

 METABOLIC FUNCTIONS

 Vit B12 is essential for cell growth and multiplication.

 MANIFESTATIONS OF DEFICIENCY

 Megaloblastic anaemia (generally the first

manifestation), neutrophils with hypersegmented nuclei,
giant platelets.
 Glossitis, g.i. disturbances: damage to epithelial
structures.
 Neurological: subacute combined degeneration of
spinal cord; peripheral neuritis—diminished vibration
and position sense, paresthesias.
 ERYTHROPOIETIN

 Erythropoietin (EPO) is a sialoglycoprotein hormone (MW

34000) produced by peritubular cells of the kidney that is

essential for normal erythropoiesis.

 Anaemia and hypoxia are sensed by kidney cells and induce

rapid secretion of EPO → acts on erythroid marrow and:

 ERYTHROPOIETIN

(a) Stimulates proliferation of colony forming cells of the

erythroid series.

(b) Induces haemoglobin formation and erythroblast maturation.

(c) Releases reticulocytes in the circulation.

 EPO binds to specific receptors on the surface of its target cells.

 The EPO receptor is a JAK-STAT-binding receptor that alters

phosphorylation of intracellular proteins and activates

transcription factors to regulate gene expression.

 It induces erythropoiesis in a dose dependent manner, but has

no effect on RBC lifespan.

 USE

 The primary indication for epoetin is anaemia of chronic

renal failure which is due to low levels of EPO.
 Only smptomatic patients with Hb ≤ 8 g/dl should be
considered for EPO therapy.
 Epoetin 25–100 U/kg s.c. or i.v. 3 times a week (max. 600
U/kg/week) raises haematocrit and haemoglobin, reduces need
for transfusions and improves quality of life.
 OTHER USES

1. Anaemia in AIDS patients treated with zidovudine.

2. Cancer chemotherapy induced anaemia.

3. Preoperative increased blood production for autologous

transfusion during surgery.

 ADVERSE EFFECTS

 Sudden increase in haematocrit,

 Blood viscosity and peripheral vascular resistance.

These are—
 Increased clot formation in the A-V shunts (most patients are
on dialysis)
 Hypertensive episodes,
 Serious thromboembolic events, occasionally seizures.