Haematinics

&
Erythropoietin
• Haematinics- are substances required for blood formation &
are used for treatment of anaemias.
• Anaemia occurs when the balance between production &
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, vit.B12, folic acid.
• Bone marrow depression (hypoplastic anaemia),
• Erythropoietin deficiency.
(c) Increased destruction of RBCs (haemolytic anaemia).
 MATURATION FACTORS

• Deficiency of vit B12 & folic acid- megaloblastic anaemia.

(presence of large red cell precursors in bone marrow & their large & short
lived progeny in peripheral blood)

• Vit B12 & folic acid – maturation factors.

• Basic defect at DNA synthesis.
• Apart from haemopoietic, other rapidly proliferating tissues also
suffer.
 Vitamin-B12

• Cobalt containing compounds present in the diet

(Cyanocobalamin & hydroxocobalamin) – referred as vit B12.
• Castle (1927–32) stated that, extrinsic factor present in diet when combined
with an intrinsic factor (stomach) to give rise to the haemopoietic principle.
Vit B12 was isolated in 1948 and considered to be the extrinsic factor as
well as the haemopoietic principle, the intrinsic factor only helped in its
absorption.

• Vit B12-water soluble, thermostable red crystals.

• It is synthesized in nature only by microorganisms; plants &
animals acquire it from them.
• Dietary sources- Liver, kidney, sea fish, egg yolk, meat,
cheese are the main vit B12 containing constituents of diet.
• Vegetable- legumes (pulses).
• Vit B12 is synthesized by the colonic microflora, but this is not
available for absorption in man.
• Commercial source is Streptomyces griseus; as a byproduct of
streptomycin industry.
• Daily requirement 1–3 μg, pregnancy & lactation 3–5 μg.
 Metabolic functions of Vit B12

• B12 metabolic functions are linked with folate metabolism;

megaloblastic anaemia occurring due to deficiency of either is
indistinguishable.
• B12 has some independent metabolic functions as well.
• B12 active coenzyme forms - deoxyadenosyl-cobalamin
(DAB12) & methyl-cobalamin (methyl B12).
(i) Vit B12 is essential for the conversion of homocysteine to
methionine & also helps in forming THFA, for reutilization.

• Methionine (methyl group donor) is needed in many metabolic

reactions & for protein synthesis.
• In B12 deficiency, THFA gets trapped in the methyl-THFA & a
number of one carbon transfer reactions will suffer.
(ii) Purine & pyrimidine synthesis are primarily affected due to
defective ‘one carbon’ transfer because of ‘folate trap’. The
most important of these is unavailability of thymidylate for
DNA production.
(iii)

- it is an important step in propionic acid metabolism.

- It links the CHO & lipid metabolisms.
-This reaction does not require folate & considered to be
responsible for demyelination seen in B12 deficiency, but not
in pure folate deficiency. That myelin is lipoidal, supports this
contention.
(iv) Now it appears that interference with the reaction:

- Important in the neurological damage of B12 deficiency,

because it is needed for the phospholipids & myelin
synthesis.
(v) Vit B12 is essential for cell growth & multiplication.
 Vit B12 utilization

• Intrinsic factor (IF) + B12 complex- binds to receptors present on

intestinal mucosal cells & is absorbed by active carrier mediated
transport.
• IF is essential for B12 absorption.
• In blood, Vit B12 is transported + β globulin transcobalamin II
(TCII).
• Congenital absence of TCII or presence of abnormal protein (TCI
or TCIII) may interfere with delivery of vit B12 to tissues.
• It’s not degraded in the body & undergoes EHC.
Transportation
• In absence of IF or in malabsorption, B12 deficiency develops
much faster > it’s nutritional deficiency.
• Stores depletion- absence of B12 in diet for 3–5 yrs.
• Vit B12 is directly & completely absorbed (i.m./deep s.c. Inj).
• Pharmacological doses (>100 μg) - large amount is excreted in
urine.
• Hydroxocobalamin is more protein bound & better retained than
cyanocobalamin.
 Deficiency Vit B12 deficiency

• Occurs due to:

1. Addisonian pernicious anaemia:
2. Other causes of gastric mucosal damage, e.g. Chronic gastritis,
gastric carcinoma, gastrectomy, etc.
3. Malabsorption, bowel resection, inflammatory bowel disease.
4. Consumption of vit B12 by abnormal flora in intestine (blind
loop syndrome) or fish tape worm.
5. Nutritional deficiency.
6. Increased demand: pregnancy, infancy.
 Deficiency manifestations

a) Megaloblastic anaemia, neutrophils with hypersegmented

nuclei, giant platelets.
(b) Glossitis, g.i. disturbances: damaged epithelial structures.
(c) Neurological: sub acute combined degeneration of spinal
cord; peripheral neuritis—diminished vibration & position sense,
paresthesias, depressed stretch reflexes; mental changes—
poor memory, mood changes, hallucinations, etc. are late
effects.
 Preparations, dose, administration

• Cyanocobalamin: 35 μg/5 ml liq, orally & parenterally.

• Hydroxocobalamin: 500-1000 μg inj; high protein binding &
better retention in blood, preferred for parenteral use.
• Both oral & inj vit B12 is available mostly in combination along
with other vitamins+/ iron.
• Prophylactic dose: 3–10 μg/day orally in those at risk of
developing deficiency.
• Therapeutic dose: Oral B12 is not used for treatment of
confirmed vit B12 deficiency because its intestinal absorption
is unreliable.
• Injected B12 is given, when deficiency is due to lack of IF
(pernicious anaemia).
 Regimens in use-
• Hydroxocobalamin 1 mg i.m./s.c./for 2 wks or till neurological
symptoms abate, followed by 1 mg inj every 2 months for
maintenance.
• Cyanocobalamin 100 μg i.m./ s.c/for 1 wk, then wkly for 1
month, & then monthly for maintenance indefinitely.
• Methylcobalamin -is the active coenzyme form of vit B12 for
synthesis of methionine & S-adenosylmethionine that is needed
for integrity of myelin.

• Dose-1.5 mg/day for correcting the neurological defects in

diabetic, alcoholic & other forms of peripheral neuropathy.

• Nutritional supplement, & not as a drug in many countries.

 Uses

1. Treatment of vit B12 deficiency: add 1–5 mg of oral folic

acid & an iron preparation, because reinstitution of brisk
haemopoiesis may unmask deficiency of these factors.
• Complete recovery of anaemia depends on the severity of disease.
• Neurological parameters improve more slowly—may take several months;
full recovery may not occur if vit B12 deficiency is severe / persisted for 6
months or more.
 Uses

2. Prophylaxis: given only when there are definite predisposing

factors for development of deficiency.
3. Mega doses of vit B12 have been used in neuropathies,
psychiatric disorders, cutaneous sarcoid & as a general tonic to
allay fatigue, improve growth.
4. Tobacco amblyopia: hydroxocobalamin is of some benefit—it
probably traps cyanide derived from tobacco to form
cyanocobalamin
 ERYTHROPOIETIN

• Erythropoietin (EPO) is a hormone produced by peritubular

cells of the kidney that is essential for normal erythropoiesis.
• Kidney senses anaemia & hypoxia  EPO secretion → acts on
erythroid marrow and:
(a) Stimulates proliferation of colony forming cells of the erythroid
series.
(b) Induces Hb formation & 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 & 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. inj and has a plasma
t½ of 6–10 hr, but action lasts several days.
 Use

• Primary indication for epoetin is anaemia of chr. renal failure

due to low levels of EPO.
• Pt’s with Hb ≤ 8 g/dl should be considered for EPO therapy.
• Epoetin 25–100 U/kg s.c. or i.v. 3 times a wk raises haematocrit &
Hb, reduces need for transfusions & improves quality of life.
• Start with a low dose & titrate upwards to keep haematocrit
between 30–36%, & Hb 10–11 g (max 12 g) per dl.
• Exercise capacity & overall wellbeing of the pt’s is improved.
• Most pt’s have low iron stores; require concurrent iron therapy for
optimum response.
 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

• Epoetin is non-immunogenic.
• A/e- are related to sudden increase in haematocrit, blood
viscosity & peripheral vascular resistance (due to correction of
anaemia).
• These are- increased clot formation in the A-V shunts (most
patients are on dialysis), hypertensive episodes, serious
thromboembolic events, occasionally seizures.
• Flu like symptoms lasting 2–4 hr occur in some pt’s.
• Modified EPO Darbepoetin-t½ >24 hours, is longer
acting & can be administered once every 2–4 wks.
• Thank U