Megaloblastic anemia

1. MEGALOBLASTIC ANAEMIA
Department of
Pharmacology
1/2/2024

2. Contents
 Introduction to megaloblastic anaemia
 Clinical presentation of MA
 Treatment of MA
 Vitamin B12 and its preparations - Details

3. MEGALOBLASTIC ANAEMIA
 Macrocytic anaemia
 Due to B12 and folic acid deficiency-Maturation factors
 Involves impairement of DNA synthesis in RBC and cell proliferation
(mitosis) in the precursor cells of RBCs
 Mitosis occurs only in precursor cells not in mature RBC(fixed life
span)
 Deficiency of folic acid and B12 impair mitosis not their cytosolic
growth
 Bulk of cytosole increases

4.  Primitive RBC becomes very big (megaloblast)
 Mature RBC do not divide . No. of mature RBC
diminish (anaemia)
 Since life span of premature RBC is shorter –
prone to haemolysis (haemolytic anaemia)

5. Sign and symptoms of
megaloblastic anaemia
 Abnormal paleness or lack of colour of skin
 Decreased appetite
 Smooth and tender tongue.
 Diarrhoea
 Irritability
 Fatigue
 Difficult walking
 Numbness or tingling in hands and feet
 Diminished reflexex and vibration sensation
 Peripheral neuritis, poor memory, mood change,
hallucination, muscular weakness.

6. Treatment
Vit B12 and folic acid

7. VITAMIN B12
 Cyanocobalamin & hydroxocobalamin  cobalt
containing compounds in diet
 Cyanocobalamin on exposure to light is
converted to hydroxycobolamin while
hydroxycobalamine in presence of cyanide gets
changed into cyanocobalamine.

8.  Synthesized solely by microrganism in soil,
water, and animal intestine
 Almost absent in plant products.
 In man as in animals, it is synthesized in colon
by microrgnism , however it is hardly absorbed
from this site and hence it is excreted in faeces.

9. Sources
 Non vegeterian foods like liver, kidney, fish, and egg
yolk are rich in vitB12
 The only vegetable source is legumes
 Dairy food contains smaller amount
 Vit B12 contents of cow milk is considerably more
than that of human milk
 Commercial sources: streptomyces griseus.
Requirement
 Average adult dose 1-3 ug
 Pregnancy and lactation 3-5ug

10. Pharmacokinetics

11. Storage
 Major site- liver
 Total amount of vitamin stored in body -2-5 mg
 Adequate for 3-5 years even if insufficient
dietary supplements is there.
 Excreted through bile or shedding of intestinal
epithelial cells
 Most of the excreted vit B112 is reabsorbed in
intestine (Enterohepatic circulation)

12. METABOLIC FUNCTIONS
 Vitamin B12 is linked with folate
metabolism in many waysmegaloblastic
anaemia due to deficiency of either is
indistinguishable
 Active form-deoxyadenosyl-
cobalamin(DAB12)
 And methyl-cobalamin(methyl B12)
 vitamin B12 is essential for:
(i) conversion of homocysteine to
methionine

14.  Methionine is needed as a methyl group donor in
many metabolic reactions and for protein
synthesis.
 In B12 deficiency THFA gets trapped in the
methyl form and a number of one carbon transfer
reactions suffer.
 Purine and pyrimidine synthesis is affected
primarily due to defective 'one carbon' transfer
because of 'folate trap'.

15. (ii) Malonic acid DAB12 Succinic acid
 It is an important step in propionic acid
metaboism
 It links the carbohydrate and lipid metabolism
 This reaction does not require folate
 Responsible for demyelination seen in B12
deficiency, but not in pure folate deficiency.

16. (iii) Methionine DAB12 S-adenosyl
methionine
needed for the synthesis of phospholipids and
myelin B12 deficiency- neurological damage of
(iv) Cell growth & multiplication
(v) Myelination of spinal cord

17. Deficiency
1. Pernicious anaemia- absence of intrinsic
factor in gatric juice
2. Malabsoption; bowel resection, IBD
3. Consumption of Vit B12 by abnormal flora of
intestine (blind loop syndrome), fish tape
worm
4. Nutritional deficiency; strict vegeterian
5. Increased demand- pregnancy and infancy.
6. Total or partial gastrectomy
7. Prolonged use of PPI or H2 blockers

18. Manifestation of B12 deficiency
1) Megaloblastic anaemia (generally the first
manifestation),
2) Glossitis, g.i. disturbances: damage to
epithelial structures.
3) Neurological: subacute combined
degeneration of spinal cord, peripheral
neuritis ,paresthesia, confusion, loss of
memmory, halucination, psychosis

19. Vitamin B12
Preparation
 Cyanocobalamin: 35ug/5ml liq. (i.m, s.c)
 Hydroxycobalamin: 500 ug, 1000ug inj.
(i.m/S.C)
 Methylcobalamin: 0.5 -1.5 mg tab oral
 Never i.v –risk of anaphylaxis

20.  Hydroxycobalamin has higher protein
binding and better retention in blood -
preferred for parenteral adminstration to treat
vit B12 deficiency in Britain
 In USA -considered that Hydroxycobalamin
induce antibody formation in some patient
and its blood level may decline rapidly (within
1month)--- prefer cyanocobalamin
parenterally

21. Uses of vit B12 preparations
1. Treatment of VIT B12 deficiency due to pernicious
anaemia - various regimen are followed
 Britain regimen —Hydroxycobalamin 1 mg
i.m/s.c daily for 2 weeks or till neurological
symptoms abate followed by 1 mg injected every
month for maintenance
 USA regimen : Cyanocobalamin 100 ug i.m/
s.c daily for 1 week then weekly for 1 month
then monthly for maintenance indefinitely.
 Add 1-5 mg of folic acid for few weeks

22. Folic acid -only secondary and adjuvant role. Deficiency may be
unmasked when vit B12 induce brisk erythropoies
2. Treatment of Megaloblastic Anaemia due to defined
causes- nutritional deficiencies, increased demand
 Methylcobalamine 0.5 mg-1.5 mg/day oral for 5-6
month or depending on improvement of hematological
and neurological symptoms
 Folic acid 2-5mg tab for 3-4 months

23. Imp. Points
 If VIT B12 alone is given in megaloblastic anaemia-
improve neurological symptoms worsen heamtological
symptoms
 Folic acid should never be given alone to patient with vit B12
deficiency - haematological response may occur, but
neurological defect may worsen due to diversion of
inadequate amount of vit B 12 present in body to
haemopoisis.

24. 2. Prophylaxis for vit B12 deficiency: only when there is definite
predisposing factors . Methylcobalamine 0.5 mg/day
3. For correcting the neurological defects in diabetics ,
alcoholics trigeminal neuralgia, and other form of periphery
neuropathy
 Methylcobalamin 1.5 mg/day Orally
4. Treatment of Tobacco amblyopia(cyanide poisoining):
 Hyrodroxocobalamin binds with cyanide to form cyanocobalamin-
forms a chelating complex
 massive dose- 5 g of hydroxycobalamin- injected i.v - treat cyanide
poisoining

25. Next class
Folic Acid
Pernicious Anaemia