This document discusses haematinics, which are substances required for blood formation used to treat anaemias. It describes different types of anaemias caused by blood loss, impaired cell formation due to deficiencies in iron, vitamin B12, or folic acid, or increased destruction of red blood cells. It provides details on iron including absorption, transport, storage, requirements, sources, and preparations for both oral and parenteral administration. It also discusses acute iron poisoning treatment and mentions that vitamin B12 and folic acid deficiencies can result in megaloblastic anaemia.

1. DRUGS AFFECTING BLOOD AND
BLOOD FORMATION
HAEMATINICS
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2. Haematinics
Haematinics
These are the substances required in the formation of blood,
and are used in the treatment of anaemias
Anaemia: a condition in which there is a deficiency of red
cells or of haemoglobin in the blood, resulting in pallor and
weariness
Balance between production and destruction of RBCs are
disturbed:
– Blood Loss (acute or chronic)
– Impaired cell formation due to
• Deficiency of essential factors – Iron, Vit. B12 and
Folic acid
• Bone marrow depression (hypoplastic anemia),
erythropoietin deficiency
-Increased destruction of RBCs (haemolytic anaemia)
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3. Types of Anaemia
There are several different types of anaemia and several different
diagnostic levels.
Determining indices of red cell size and haemoglobin content and
microscopical examination of a stained blood smear allow
characterisation into:
• hypochromic, microcytic anaemia (small red cells with low
haemoglobin; caused by chronic blood loss giving rise to iron
deficiency)
• macrocytic anaemia (large red cells, few in number)
• normochromic normocytic anaemia (fewer normal-sized red
cells, each with a normal haemoglobin content)
• mixed pictures.
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4. • Aplastic anaemia(Depression of the bone marrow)
• Haemolytic anaemia( Excessive destruction of red
blood cells)
• Sickle cell anaemia
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5. •
•
•
•
•
•
Total Body Iron content – 2.5-5 gm (average 3.5 gm ): Male – 50 mg/kg
and Female – 38 mg/kg.It is distributed into:--
Haemoglobin – 66%
Iron stores as ferritin & haemosiderin – 25%
Myoglobin (in muscles) - 3%
Parenchymal Iron (in enzymes, etc.)– 6%
-Haemoglobin is a Protoporphyrin each molecule having 4 Iron containing
haeme residues-0.33% iron
Loss of 100 ml of blood – loss of 50 mg elemental Iron
To raise 1 gm/dl – 200 mg elemental Iron required
Stored only in Ferric form (Fe3+) – in combination with a large protein
apoferritin – mainly in RE Cells
Ferritin can get saturated to different extents; atfull saturation it can hold
30% iron by weight.
Parenchymal iron occurs as prosthetic group in many cellular enzymes–
cytochromes, peroxidases, catalases, xanthine oxidases and some
mitochondrial enzymes
•
•
Apoferritn + Fe3+ Haemosiderin
(not reutilized)
 Ferritin aggregates
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6. Iron requirements & Source
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• Primary reflection of iron deficiency occurs in blood, severe deficiency
affects practically every cell.
• Daily iron requirements:
Adult male : 0.5–1 mg (13 μg/kg)
Adult female : 1–2 mg (21 μg/kg)
(menstruating)
Infants : 60 μg/kg
Children : 25 μg/kg
Pregnancy : 3–5 mg (80 μg/kg)
(last 2 trimesters)
• 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

7. Iron Absorption
•
•
Diet – 10 to 20 mg – absorbed from all over the Intestine
(more from upper part)
2 forms – haeme and Inorganic
– Haeme – minor form of dietary Iron but absorbed better
(35%) without any transporter
– Inorganic – in ferric form but absorbs lesser(5%) –
converted to ferrous form in Intestine for absorption –
needs transporter
Divalent metal transporter (DMT1) At the luminal membrane
carrys ferrous iron into the mucosal cell.
Inorganic iron and iron released from haeme is transported
across the basolateral membrane by Ferroportin (FP)
Iron transporters are regulated according to the body needs.
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8. DR.R.Lavanya,FOP 8
Absorption of haeme iron is largely independent of other foods simultaneously
ingested, but absorption of inorganic iron is affected by several factors.
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
1. Alkalies (antacids) render iron insoluble, oppose its reduction.
2. Phosphates (rich in egg yolk)
3. Phytates (in maize, wheat)
4. Tetracyclines
5. Presence of other foods in the stomach.
In general, bioavailability of iron from cereal based diets is low
Mucosal block: from mucosal cell iron– transported to plasma or oxidised to ferric form and
form ferritin remains stored in mucosal cell - and is lost when they are shed (lifespan 2–4 days)-
Ferritin curtain
– iron status of the body and erythropoietic activity govern the balance between these two processes
through a ‘haematopoietic transcription factor’, and thus the amount of iron that will enter the
body
– Iron being absorbed during iron deficiency and during deficiency or erythropoiesis ferritin is
either not formed or dissociates into iron and transported to the blood

9. Iron – Transport, storage
In plasma immediately converted to Fe3+form – complexed with transferrin (Tf) –
Total Plasma Iron – 3 mg - recycled
Transported inside erythropoietic and other cells by transferrin receptors
(TfRs) – endocytosis – Iron dissociates from TfR in acidic pH of
intracellular vesicles-- utilized for Hb synthesis
Tf and TfR return to surface to carry fresh loads
In Iron deficiency , haemolytic states when brisk erythropoiesis–
erythropoietic cells express more TfRs, but other cells do not.
Storage – RE cells in Liver, spleen, bone and muscles as ferritin and
haemosiderin
Apoferritin synthesis regulated by Iron status .
Iron regulating element on mRNA is blocked in low Iron – no apoferritin
synthesis while more Tf is produced– in high Iron state – more apoferritin
synthesis to trap iron
Plasma iron derived from destruction of old RBCs (lifespan ~120 days), from
stores and from intestinal absorption forms a common pool that
is available for erythropoiesis, to all other cells and for restorage.
Excretion – 0.5 to 1 mg/day – exfoliation in GI mecosal cells, RBCs and in
Bile,also in skin, urine and sweat
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10. DR.R.Lavanya,FOP 10
Schematic depiction of intestinal absorption, transport, utilization and storage of iron (see text for description)
Fe2+—Ferrous iron; Fe3+—Ferric iron; DMT1—Divalent metal transporter 1; Hb—Haemoglobin; RE cell—
Reticuloendothelial cell; FP1—Ferroportin; Tf—Transferrin; TfR—Transferrin receptor

11. Iron Preparations - Oral
Preferred route – ferrous salts – high Iron content, inexpensive, better absorbed
than ferric salts at higher dose
…. Gastric irritation and constipation limits use
– Ferrous sulfate (20% hydrated salt and dried salt 32% )
– Ferrous gluconate (12% Iron)
– Ferrous fumerate (33% )
– Colloidal ferric hydroxide (50%)
Other preparations: Ferrous succinate, Iron choline citrate, Iron calcium
complex, Ferric ammonium citrate, Ferric hydroxy polymaltose
… low Iron content (less GI upset) and expensive
Dosage: 200 mg daily in 3 divided doses (3 – 5 mg/kg for children) produces the
maximal haemopoietic response.Prophylactic dose is 30 mg iron daily.
ADRs: Differ in susceptibility – individuals …. Epigastric pain, heart burn,
nausea, vomiting, staining of teeth, metallic taste, bloating, colic –
Constipation is more common (believed to be due to astringent action of iron) than
diarrhoea (thought to reflect irritant action). However,thesemay be caused by
alteration of intestinal flora as well.
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12. Iron Preparations - Oral
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 (rheumatoid arthritis) decreases iron absorption, as well as the rate at
which iron can be utilized.
3. Non-compliance to oral iron.
4. In presence of severe deficiency with chronic bleeding.
5. Along with erythropoietin: oral ion may not be absorbed at sufficient rate to meet the
demands of induced rapid erythropoiesis.
Parenteral iron therapy needs calculation of the total iron required
Iron requirement (mg) = 4.4 × body weight (kg) × Hb deficit (g/dl)
Not faster absorption than oral but stores replenish faster
Four organically complexed formulations of iron are currently available in India
Iron-dextran and Iron-sorbitolcitric acid (use for over 50 years)
Ferrous sucrose and Ferric carboxymaltose (newer ones)-less risky and have improved
ease of administration.
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13. Iron-dextran-high molecular weight colloidal solution (50 mg elemental iron/ml)
injected i.m. as well as i.v.
By i.m. route , absorbed through lymphatics, circulates without binding to transferrin
and is engulfed by RE cells where iron dissociates - available to the erythron for
haeme synthesis
10–30% of the dose remains locally bound and becomes unavailable for utilization
for several weeks. (25% extra needs to be added )
not excreted in urine or in bile.
dextran is antigenic, anaphylactic reactions are more common
Iron-sorbitol-citric acid - low molecular weight complex injected only i.m.,
absorption occurs directly into circulation
No local binding in muscle
30% of the dose is excreted in urine ( the dose to be increased accordingly)
binds to transferrin in plasma and saturate it (not suitable for i.v. injection)
Even with i.m. dose, incidence of immediate reaction, including ventricular
tachycardia, A-V block, other irregularities, hypotension, flushing is higher.
It is contraindicated in patients with kidney disease
.
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14. Parenteral Iron
• IM: Z technique(to avoid
staining of skin) – deep in
gluteal region – 2 ml daily or
on alternate days or 5 ml each
side on same day – Iron
sorbitol – 1.5 to 2.00 ml per
day
• IV: Iron dextran - 0.5 ml test
dose –for 5 to 10 minutes …
2 ml for 10 minutes
• Or in 500 ml glucose/saline
slow infusion – constant
observation
• Terminate if – giddiness,
paresthesia or chest
constriction
Essentials of Medical pharmacology by KD Tripathi – 6th
Edition, JAYPEE, 2008
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15. • ADRs:
– Local: Pain in IM injection, pigmentation of skin, sterile abscess
– Systemic: Fever, headache, joint pain, flushing, palpitation, chest pain,
dyspnoea, lymph node enlargement
• Metallic taste with sorbitol
• Anaphylactoid reaction – Kidney diseases (no sorbitol)
Ferrous-sucrose - newer formulation high molecular weight complex of iron hydroxide
with sucrose
on i.v. injection – taken by RE cells- iron dissociates and is utilized.
safer than the older formulations.
dose- 100 mg (max 200 mg) i.v taking 5 min, once daily to once weekly till the total
calculated dose (including that to replenish stores) is administered.
i.v. infusion is not possible.
The solution is highly alkaline ruling out i.m./s.c. injection.
The incidence of hypersensitivity reaction isvery low.
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.
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Parenteral Iron

16. Parenteral Iron
Ferric carboxymaltose – a ferric hydroxide core is stabilized by a carbohydrate
shell.
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 diluted
with 100 ml saline (not glucose solution) and infused i.v. taking 15 min or
more.
Infusion may be repeated after a week. Not injected i.m.
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.
Due to lack of safety data, not recommended for children <14 years
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17. • Uses:
– Iron deficiency anaemia: Nutritional deficiency, chronic blood loss
(GIT ulcers and hook worm)
• Oral Iron preferred : Target – 0.5 to 1 g/dl per week – 1 to 3
months therapy plus 2 to 3 months afterwards
• Prophylaxis: Ceiling on Iron absorption - = 3 mg/day …..
Pregnancy and infancy to be taken care of well in advance
– Megaloblastic anaemia
– As astringent: Ferric chloride
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18. Acute Iron Poisoning
• Infants and children – 10 to 20 tablets (60 mg/kg Iron)
• Symptoms: Vomiting, abdominal pain, haematemesis, diarrhoea,
• lethargy, cyanosis, dehydration, acidosis, convulsion, CVS collapse
and death (12 – 36 Hours)
– Haemorrhage and inflammation of gut, hepatic necrosis and brain
damage
• Treatment:
– Prevent further absorption: Induce vomitingor gastric lavage with
NaHCO3 – to render Iron insoluble …… and also Egg yolk and Milk
orally
– Antidote: Desferrioxamine: 0.5 to 1.00 gm IM repeated 4 – 12 Hourly
or IV 10 – 15 mg/kg/Hour (max 75 mg/day) till serum levels fall
• DTPA and Calcium edetate may be used if desferrioxamine is not available.
BAL is contraindicated because its iron chelate is also toxic.
– Supportive: Fluid and electrolyte, correction of acidosis and Diazepam
•
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19. MATURATION FACTORS
Deficiency of Vit.B12 and folic acid results in
megaloblastic anaemia
-characterized by the presence of large red cell
precursors in bone marrow and their large and short
lived progeny in peripheral blood.
Vit B12 and folic acid are therefore called maturation
factors.
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20. Vit. B12
• Complex cobalt containing compounds Cyanocobalamin and
hydroxocobalamin
• Physical: Water soluble, red crystals synthesized only by
microorganisms
• Sources: Liver, Kidney, sea fish, egg yolk meat, Cheese. The only vegetable
source is legumes (pulses) which get it from microorganisms harboured in their
root nodules.
Vit. B12 is synthesized by the colonic microflora, but not available for absorption
in man. The commercial source is Streptomyces griseus; as a byproduct of
streptomycin industry.
• Daily Requirement: 1 – 3 mcg (Pregnancy and Lactation3 – 5 mcg)
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21. Vit. B12 - Metabolic functions
Linked with folic acid metabolism – megaloblastic anaemia
indistinguishable .The active coenzyme forms of B12 generated in
the body
Two active forms - Deoxy-adenosyl-cobalamin (DAB12) and methyl-
cobalamin (methyl-B12)
1) Vit. B12 needed for conversion of homocysteine to methionine –
methionine is methyl group donor in metabolic reactions and for
protein synthesis.– also critical for making THFA available for
reutilization (in deficiency, THFA gets trapped in the methyl form and a
number of one carbon transfer reactions suffer
2) Purine and pyrymidine synthesis is affected – folate trap – non
availability of thymidylate for DNA synthesis
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22. DAB12
3) Malonic acid Succinic acid - important for propionic
acid metabolism (Carbohydrate and lipid metabolism) – linked to
demyelination in Vit. B12 deficiency
DAB12
4) Methionine S-adenosyl methionine –
neurological damage of B12 deficiency, because it is needed
in the synthesis of phospholipids and myelin.
5) Vit. B12 is needed for cell growth and multiplication
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23. Vit. B12 - Kinetics
Absorption: Present in food as protein conjugates – released by
cooking/proteolysis
– IF Intrinsic factor (a glycoprotein, MW60,000) secreted by stomach
forms a complex with Vit. B12 – attaches to specific receptor in
mucosa – absorbed by active transport
Transport: In combination with a specific β globulin transcobalamin II (TCII) –
congenital absence/abnormal protein (TCI or TCIII, in liver and bone marrow
disease)– defective supply to tissues
Storage: In liver – 4/5th (2-8mg)of Body`s Vit.B12
Degradation: Not degraded in body – excreted mainly in Bile – (3–7 μg/day);
(0.5–1 μg reabsorbed)enterohepatic circulation ….. absence of IF and
malabsorption ,deficiency develops more Vs Nutritional deficiency
It takes 3–5 years of total absence of vit in diet to deplete normal body stores.
Parenteral – completely absorbed -IM and SC administration
– excreted via urine
Hydroxocobalamin is more protein bound and better retained than
cyanocobalamin
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24. Deficiency - Vit. B12
Deficiency: Addisonian pernicious anaemia (destruction of parietal
cells – IF absent), gastric mucosal damage, damaged intestinal
mucosa, consumption by abnormal flora (blind loop syndrome
& fish tape worm), nutritional deficiency, increased demand
Manifestations: Megaloblastic anaemia, glossitis, GI
disturbance, degeneration of spinal cord and peripheral
neuritis – diminished vibration and position sense,
paresthesia, depressed reflexes and mental changes
Preparations: Cyanocobalamin Injection, Hydroxocobalamin
Injection and Methylcobalamin Tablets
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25. Therapeutic dose:
hydroxocobalamin 1 mg i.m./s.c. daily for 2 weeks or till
neurological symptoms (when present) abate, followed by 1
mg injected every 2 months for maintenance.
cyanocobalamin 100 μg i.m./ s.c. daily for 1 week, then weekly
for 1 month, and then monthly for maintenance indefinitely
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26. Vit. B12 – Uses and ADRs
Prophylactically in diabetics and alcoholics – to prevent
peripheral neuritis – 1.5 mg/day
Treatment of deficiency states: Add Folic acid and Iron
– Very quick response – appetite increases, patient feel
better, mucosal lesions heal, neurological parameters
improve
Mega doses: in neuropathies, psychiatric disorders,
cutaneous sarcoid
Tobacco amblyopia – hydroxocobalamin is of some benefit—
it probably traps cyanide derived from tobacco to form
cyanocobalamin
ADRs: Safe – allergic reactions due to contaminants
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27. FOLIC ACID
Physical: Yellow crystals, insoluble in water, Pteroyl glutamic acid
(PGA) – consisting pteridine + paraminobenzoic acids + glutamic acid
Dietary sources :Liver, green leafy vegetables (spinach), egg, meat, milk.
It is synthesized by gut flora, but not available for absorption.
Daily requirement: 0.2 mg per day (0.8 mg in pregnancy and
lactation)
Kinetics:
– Absorption: As polyglutamates in food – glutamates split off and
absorbed in upper intestine ….. Reduction to DHFA and methylation
also occurs at same site
– Small, physiological amounts are absorbed by specific carrier
mediated active transport in the intestinal mucosa.
– Large pharmacological doses may gain entry by passive diffusion, but
only a fraction is absorbed
– Transport: as methyl-THFA – partly bound to plasma protein
– Store: tissues extract FA rapidly and store as polyglutamates in cells.
Liver takes up major portion – releases methyl-THFA – enterohepatic
circulation (alcohol interferes) total body store is 5–10 mg
– Excretion: Pharmacological doses – excreted in Urine(50-90%)
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28. Folic acid -Metabolic functions
Folic acid is inactive as such and is reduced to the coenzyme
form in two steps:
FA → DHFA → THFA by folate reductase (FRase) and
dihydrofolate reductase (DHFRase).
THFA mediates a number of one carbon transfer reactions by
carrying a methyl group as an adduct
• Conversion of homocysteine to methionine (vit B12 acts as an
intermediary carrier of methyl group.The most important reaction which
releases THFA from the methylated form.)
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29. Folic acid – Metabolic function
• Generation of thymidylate an essential constituent of DNA
• Conversion of serine to glycine needs THFA and results in the
formation of methylene-THFA which is utilized in thymidylate
synthesis
• Purine synthesis de novo building of purine ring requires
formyl-THFA and methenyl-THFA (generated from methylene-
THFA) to introduce carbon atoms at position 2 and 8.
• Generation and utilization of ‘formate pool’
• Histidine metabolism for mediating formimino group transfer.
• Ascorbic acid protects folates in the reduced form. Other
cofactors, e.g. pyridoxal, etc. are required for some of the above
reactions.
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30. Deficiency- Folic acid
•
•
•
Deficiency: Inadequate dietary intake, Malabsorption (upper
GIT – coeliac disease, tropical sprue etc.), biliary fistula,
chronic alcoholism, increased demand (pregnancy), drug
induced (phenytoin, phenobarbitone,oral contraceptive etc.)
Manifestations: Megaloblastic anaemia (body store lasts for
2-3 months), epithelial damage (glossitis, enteritis, diarrhoea,
steatorrhoea), neural tube defects (spina bifida), general
debility (weakness, loss weight, sterility)
Preparations: Folic acid tablets and Folinic acid
Injections (Calcium leucovorin)
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31. Folic acid – Uses and ADRs
Megaloblastic anaemia: due to nutritional deficiency, pregnancy, pernicious anaemia
(adjuvant role with Vit. B 12), malabsorption syndromes, antiepileptic therapy-prolonged
phenytoin/phenobarbitone (interfere with absorption and storage) Therapy(large doses of
folic acid should be avoided as they may antagonize anticonvulsant effect )
Prophylaxis: 1 mg per day routinely in pregnancy to reduce the risk of neural tube defects
in the newborn
Methotrexate toxicity Folinic acid (Leucovorin, citrovorum factor, 5-formyl-THFA)- active
coenzyme form , does not need to be reduced by DHFRase before it can act.
Methotrexate is a DHFRase inhibitor; its toxicity is not counteracted by folic acid, but
antagonized by folinic acid (3.0 mg i.v. repeated as required).
Folinic acid is expensive and not needed for the correction of simple folate deficiency for
which folic acid is good enough.
Citrovorum factor rescue In certain malignancies, high dose of methotrexate is injected i.v.
and is followed within ½ –1 hour with 1–3 mg i.v. of folinic acid to rescue the normal cells.
It is ineffective if given > 3 hours after methotrexate.
To enhance anticancer efficacy of 5-fluorouracil (5-FU) Folinic acid is now routinely
infused i.v. along with 5-FU because THFA is required for inhibition of thymidylate
synthase by 5-FU.
ADRs: Non toxic orally, sensitivity by injections rarely
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32. Erythropoietin
• Sialoglycoprotein hormone (MW 34000) – produced by peritubular cells
of Kidney
• Required for erythropoiesis: anaemia and hypoxia sensed by kidney cells –
EPO secretes and acts on marrow:
(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.
• The recombinant human erythropoietin (Epoetin α, β) is administered by i.v.
or s.c. plasma t½ of 6–10 hr, but action lasts several days.
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33. Erythropoietin – Uses and ADRs
Uses
Anaemia of chronic renal failure – 25 – 100 U/kg SC or IV 3 times
a week (max. 600 U/kg/week)-concomitant Iron therapy
Recent studies have indicated that dose reduction by about 30% is possible when
epoetin is given s.c. compared to i.v.
Anaemia with AIDS patients treated with zidovudine Cancer
chemotherapy induced anaemia
Preoperative increased blood production – autologous transfusion during
surgery
Recently, a hyperglycosylated modified EPO Darbepoetin has been
introduced that has a t½ >24 hours, is longer acting and can be
administered once every 2–4 weeks.
ADRs: Nonimmunogenic, ----- ADRs occur due to sudden increase in
haematocrit, viscosity and peripheral resistance – increased clot formation in
AV- shunts, hypertensive episodes, seizure, flu like symptoms
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34. Reference:
Essentials of Medical Pharmacology, Seventh Edition,KD Tripathi
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35. Thank you
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