Megaloblastic anemia

Pharmacotherapy of megaloblastic anemia

1. Megaloblastic anemia Dr Naser Tadvi

2. Thomas edison : Pernicious anemia Minot & Murphy 1926: liver preparation Castle: Postulated intrinsic factor theory 1941 Mitchel : Folic acid 1943: Pteroyl monoglutamic acid 1948: Crystalline B12

3. 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

4. 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

5. 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

6. Cobalamins : Vit B12 belongs to cobalamin family i.e cobalt containing compounds Cyanocobalamin : CN group attached to cobalt Hydroxycobalamin : OH group attached to cobalt Light Cyanocobalamin Hydroxycobalamin Cyanide Other cobalamins : aquocobalamin , nitrocobalamin & methyl cobalamin

7. 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

8. 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 factors R- Factor, Intrinsic factor & Transcobolamin II

9. Metabolic functions of Vit B12

10. C: Purine biosynthesis reduced , defective DNA Methyl THF trapping & lack of S- adenosyl methionine can cause this D: Methionine DAB12 S- adenosyl methionine S- adenosyl methionine required for synthesis of phospholipids & myelin ( neuronal damage) E: Cell growth & multiplication (Poultry) F: Role in folate uptake & storage

11. Deficiency: Addisonian pernicious anemia Gastric mucosal damage Malabsorption Blind loop syndrome, Fish tape worm Nutritional deficiency Increased demand: Pregnancy and infancy

12. 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

13. Uses : 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. Prophylaxis : 3-10 µg/ day Mega dose of B12 used in neuropathic psychiatric disorders and as general tonic to allay fatigue , improve growth. Tobacco amblyopia : OH Cobalamine Adverse events

14. Folic acid: ( Pteroyl Monoglutamic acid)

15. 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-organisms Daily requirement: adult 50-100 µg pregnancy and lactation 500- 800 µg

16. 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

17. Transport storage and fate: Orally given folic acid appears in 30 min as circulation it circulates as N 5 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 )

18. Metabolic functions Folic acid DHFA THFA (Active form) folate DHF reductase reductase THFA mediates number of one Carbon tranfer reactions Conversion of homocysteine to methionine Generation of thymidylate Conversion of serine to glycine Purine synthesis Histidine metabolism

19. Deficiency : Inadequate dietary intake Malabsorption : coeliac disease, tropical sprue , regional ileitus Biliary fistula: no recirculation Chronic alcoholism Increased demand : Pregnancy , lactation Drugs: Phenytoin , phenobarbitone , primidone

20. Preparations and dose: Folic acid tab 5 mg ; dose = 5 to 20 mg Prophylaxis 0.5 mg/day Parenteral form available in combination only Folinic acid: N5 Formyl THFolinic acid ( Citrovorum factor) 3 mg/mL Inj

21. Uses: Megaloblastic anemia Prophylaxis 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 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:

22. Short gun antianemia therapy Erythropoietin: Uses Primary : Anemia of CRF due to low EPO 25-100 µg/Kg S.C /IV Three times a week max 600 µg/Kg/week Anemia in AIDS patients on T/t with zidovudine Cancer chemotherapy induced anemia Autologus blood transfusion Adverse events : ↑ clot formation in AV shunts , Hypertension, occasional seizures, flu like symptoms

23. Drugs used in neutropenia : G- CSF , GM- CSF Recombinant drugs Filgrastim , molgrastim Uses: To decrease severity and duration of neutropenia Shorten duration of neutropenia in BMT, after high dose intense chemotherapy Stimulate release of harvested progenitor cells Expand the number of progenitor before harvesting Persistant neutropenia in advanced HIV Aplastic anemia

24. 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