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Pharmacotherapy of megaloblastic anemia
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Megaloblastic anemiaDr Naser Tadvi
Thomas edison : Pernicious anemia Minot & Murphy 1926: liver preparation Castle: Postulated intrinsic factor theory1941 Mitchel : Folic acid 1943: Pteroyl monoglutamic acid 1948: Crystalline B12
Megaloblastic anemia:Characterized by abnormally large
nucleated red cell precursors called megaloblasts in bone marrow
Megaloblast eg of unbalance between cytoplasm and nucleus due to improper and defective synthesis of nucleoproteins
95 % cases due to vit B12 or folic acid deficiency leading to defective DNA synthesis
DNA present in every basic cell so abnormality effects rapidly proliferating cells.
Peripheral blood picture: Hemoglobinized large RBC (Macrocytes), PMN leucocytes & hypersegmented giant platelets.
Anemia described is hyperchromic macrocytic
Vit B12 deficiency causes damage to myelin in the peripheral nerves , spinal cord & brain
Folate deficiency: weight loss, nervous instability but damage to myelin is doubtful
Other causes of macrocytic anemias: Liver disease , myxedema, Leukemia & certain hemolytic states
Cobalamins: Vit B12 belongs to cobalamin family i.e cobalt
containing compoundsCyanocobalamin: CN group attached to cobalt Hydroxycobalamin: OH group attached to
cobalt Light Cyanocobalamin
Hydroxycobalamin
Cyanide
Other cobalamins: aquocobalamin, nitrocobalamin & methyl cobalamin
Sources of Vit B12: Micro-organisms (Soil, water animal
intestine) Man and animals intestinal lumen but not
absorbed 3-5 µg excreted daily in faeces Non veg foods: Muscle, liver, kidney,
oysters,fish, egg yolk The only vegetable source is pulses(legumes)Dairy milk in smaller amounts
Daily requirement: 1-3 µg, pregnancy & lactation 3-5 µg
Commercial source: Streptomyces Griseus
Pharmacokinetics: Absorption: Cobalamins in food are in
bound form inactive , released by cooking (heat) and by proteolysis in stomach & intestine .
Vit B12 is not soluble so absorption depends on various transfer factorsR- Factor, Intrinsic factor &
Transcobolamin II
Metabolic functions of Vit B12
C: Purine biosynthesis reduced , defective DNA Methyl THF trapping & lack of S- adenosyl
methionine can cause this D: Methionine DAB12 S- adenosyl
methionineS- adenosyl methionine required for
synthesis of phospholipids & myelin ( neuronal damage)
E: Cell growth & multiplication (Poultry)F: Role in folate uptake & storage
Deficiency: 1. Addisonian pernicious anemia2. Gastric mucosal damage 3. Malabsorption4. Blind loop syndrome, Fish tape worm 5. Nutritional deficiency 6. Increased demand: Pregnancy and
infancy
Preparations & doses: Cyanocobalamin: Pink color injection 100
µg/mL DOC in pernicious anemia 1000 µg once a week IM for 8 weeks then 1000 µg once a month life long
Hydroxy cobalamin 100, 500, 1000 µg/mL, better retention but can induce antibody formation not used in US. 1 mg every 2 – 3 days 5 doses , then 1 mg 3 monthly
Methyl cobalamin 0.5 mg tab, Dose 1.5 mg promoted for neurological defects in diabetics and other peripheral neuropathies
Uses : 1. Treatment of vit B12 Deficiency: wise to
add folic acid and iron, symptoms improvement in 2 days ( appetite increased, feels good. Mucosal lesions heal in 1-2 weeks. Platelet count normal in 10 days. WBC`S = 2-3 weeks . Neurological parameters take several month.
2. Prophylaxis : 3-10 µg/ day 3. Mega dose of B12 used in neuropathic
psychiatric disorders and as general tonic to allay fatigue , improve growth.
4. Tobacco amblyopia: OH Cobalamine Adverse events
Folic acid: (Pteroyl Monoglutamic acid)
Called as folic acid as it is found in green leafy vegetables
Source: Green leafy vegetable , liver , yeast, kidney, egg, meat, fish and dairy foods
Much of it is destroyed in cooking (heat)Micro-organismsDaily requirement: adult 50-100 µg
pregnancy and lactation 500- 800 µg
Absorption: Folic acid conjugates hydrolysed to
pteroyl monoglutamic acid by conjugases
Conjugases are enzymes present in vegetables and mammalian tissue, GIT mucosa & pancreas
Pteroyl monoglutamic acid is completely absorbed in small intestine jejunum
Transport storage and fate: Orally given folic acid appears in 30 min
as circulation it circulates as N5 Methyl THF
Majority is loosely bound to albumin from where it is easily taken up by cells
Inside the cells converted to THF by cobalamine dependent enzyme methionne synthetase
Vit C protects THF from destruction Total folate in body = 5 to 10 mg (1/3 in
liver as methyl folate)
Metabolic functionsFolic acid DHFA THFA
(Active form)
folate DHF reductase reductase THFA mediates number of one Carbon
tranfer reactions Conversion of homocysteine to methionineGeneration of thymidylate Conversion of serine to glycinePurine synthesisHistidine metabolism
Deficiency : 1. Inadequate dietary intake2. Malabsorption : coeliac disease, tropical
sprue , regional ileitus3. Biliary fistula: no recirculation4. Chronic alcoholism5. Increased demand : Pregnancy , lactation6. Drugs: Phenytoin, phenobarbitone,
primidone
Preparations and dose: Folic acid tab 5 mg ; dose = 5 to 20 mg Prophylaxis 0.5 mg/dayParenteral form available in
combination only Folinic acid: N5 Formyl THFolinic acid
(Citrovorum factor) 3 mg/mL Inj
Uses:1. Megaloblastic anemia2. Prophylaxis 3. Methotrexate toxicity: Folinic acid used
as it is an active no need to reduced by DHFR before it can act, Methotrexate is DHFR inhibitor, its toxicity not reversed by folic acid
4. Citrovorum factor rescue: Methotrexate high dose IV then half to 2 hr later 1-3 mg folinic acid IV to rescue normal cells
Adverse events:
Short gun antianemia therapy Erythropoietin:
Uses 1. Primary : Anemia of CRF due to low EPO 25-100
µg/Kg S.C /IV Three times a week max 600 µg/Kg/week
2. Anemia in AIDS patients on T/t with zidovudine 3. Cancer chemotherapy induced anemia4. Autologus blood transfusion
Adverse events : ↑ clot formation in AV shunts , Hypertension, occasional seizures, flu like symptoms
Drugs used in neutropenia: G- CSF , GM- CSF Recombinant drugs Filgrastim, molgrastimUses: 1. To decrease severity and duration of
neutropenia2. Shorten duration of neutropenia in BMT, after
high dose intense chemotherapy 3. Stimulate release of harvested progenitor cells 4. Expand the number of progenitor before
harvesting5. Persistant neutropenia in advanced HIV 6. Aplastic anemia
Adverse events: Bone pain, fever, myalgia, lethargy,
pain and reddening at site of injection Hypersensitivity: Skin rashes,
hypotension, nausea, vomiting and dyspnoea
Filgrastim: dysuria, derange liver function , mild to moderate spleenomegaly