TREATMENT OF OTHER ANEMIAS

Dr.K. R. Prabhakar,Asst.Proffessor

Pathophysiology

This is due to vitamin B₁₂ and folic acid deficiency

Impairment of DNA synthesis and cell proliferation

in precursor cells of RBCs.

Cytosolic growth is not impaired ,cytosole ↑

Hence primitive RBCs become big(megaloblast)

Mature RBCs diminish(anemia),

Prone to hemolysis-hemolytic anemia.

MACROCYTIC HYPERCHROMIC ANEMIA (MEGALOBLASTIC ANEMIA)

Mammals can not synthesise vit B₁₂ . Sources of vit B₁₂ are- fish, meat, liver, eggs, yeast &

milk. Commercial source- from streptomyces griseus.Deficiency causes: Insufficient dietary intake (RDA-2µg) ↓absorption or utilisation Prolonged chemotherapy (interfers with purine

metabolism). Fish tape worm infestation

VITAMIN B₁₂

Pernicious anemia:

• Important cause of vit B₁₂ deficiency

• Hereditary autoimmune disease in which antibodies

develop against intrinsic factor(IF)

• ABs either bind to IF or IF-B₁₂ complex and prevents

binding to IF receptors in ileum.

Availability of IF decreases in

• Post gastrectomy patients, diseases of ileum & surgical

removal of ileum.

Chemistry: Vit B₁₂ is a generic term for cyanocobalamin &

hydroxocobalamin.

Only cobalt containing amino compounds known to

occur in nature.

Methylcobalamin & 5deoxoadenosyl cobalamin act

as coenzymes and are active forms of vit B₁₂ though

unstable.

Pharmacokinetics Absorption from GIT depends on various transfer

mechanisms. After liberation from food interacts with R-proteins in

stomach protect it from acid degradation. In the duodenum the pancreatic proteases degrade

the complex to free cobalamin. Vit B₁₂ is now absorbed on to the IF . IF- cobalamin complex is transported across ileum

cell membrane through IF specific receptors

In enterocytes IF liberates cobalamin which is

converted to methylcobalamin

Transcobalamin II transports it to portal circulation.

Vit B₁₂ is taken up by cells by endocytosis.

Excess vit B₁₂ is stored as 5-deoxoadenosylcobalamin

in hepatocytes.

Liver can store up to 4-6 mg of vit B₁₂ .

Stores can last for 5 yrs even if intake is stopped.

Metabolic functions Cobalamins- cofactors for 2 main enzymatic process

1. Cofactor for methionine synthase –converts

homocysteine to methionine &

5-methyl tetrahydrofolate to tetrahydrofolic acid.

In vitB₁₂ deficiency

5-methyl-tertrahydrofollic acid gets trapped.

Defective DNA synthesis & ultimately megaloblastic

bone marrow.

2. Deoxyadenosyl cobalamin activates

methylmalonyl-coA mutase

In vitB₁₂ deficiency methylmalonyl coA accumulate results in faulty fatty

acid synthesis.

Incorporates in to cell membranes of CNS leads to

neurological symptoms due to inadequate myelin

synthesis-

Peripheral neuropathy,

Dementia,

Loss of motor and sensory reflexes.

Therapeutic uses

Most commonly used preparations are cyanocobalamin hydroxycobalamin methylcobalamin

Given orally or deep intramuscularly never given i.v.

Hydroxycobalamin is longer acting but development

of Abs to transcobalamin II –vit B₁₂ complex made its

use lesser.

Methylcobalamin is used to treat neurological deficits

in vit B₁₂ deficiency.

Dose: cyanocobalamin or hydroxycobalamin 100-

1000 µg/day i.m on alternative days for 2 weeks

followed by once a month.

Methylcobalamin 1000-1500 µg/day orally.

I.M therapy brings changes in bone marrow with in 2-

3 mts with improvement in neurological symptoms

Also called polyglutamate as each folic acid molecule

may have 2-8 molecules of glutamic acid.

Humans can not synthesise folic acid

Dietary sources:

Green leafy vegetables, fruits, mushrooms, liver, meat,

kidney, eggs, milk & yeast.

One of the B group vitamin.

FOLIC ACID (pteroylgutamic acid)

Pharmacokinetics Absorption occurs primarily in proximal jejunum.

Carboxypeptidases in jejunum hydrolyse dietary

polyglutamates to folic acid.

Dihydrofolate reductase converts folic acid to

tetrahydrofolic acid(THFA) in mucosa & methylated to

(5-MeTHFA)

Converted to THFA by methionine synthase in tissues.

About 5-20 mg is stored in liver.

Undergoes enterohepatic circulation similar to vitB₁₂. Trace amounts are excreted in urine & faeces. Stores last for about only 3 months.

Metabolic functions: THFA is transformed to folate cofactors – folinic acid,

10-formyl THFA, 5,10-methylene-THFA etc. donates one carbon units in oxidation.

THFA through 1-C transfer reactions is involved in synthesis of purines and pyrimidines which are essential for DNA synthesis.

Deficiecy causes Dietary lack. Malabsorption syndrome (coeliac disease or crohns

disease). Excessive demand as in pregnancy & anemia. Liver diseases and renal dialysis.

Drug induced- methotrexate, phenytoin,

phenobarbitone.

Deficiecy leads to megaloblast anemia and

teratogenic effects.

Therapeutic use RDA of folic acid is 50 µg,

During pregnancy & lactation up to 200-300 µg/day.

Therapeutic doses are 1-5 mg/day.

Uses-

Folinic acid for prophylaxis or treatment of

methotrexate toxicity.

Folate deficiency by phenobarbitone & phenytoin.

Prophylactically during pregnancy, lactation.

Folic acid is always given with vit B₁₂ to treat

megaloblastic anemia.

In the presence of vitB₁₂ deficiency if only folic acid is

used it will improve only anemia but worsen

neurological deficit as it does not convert

methylmalonyl CoA to succinyl CoA.

Adverse effects :rare for both vit B₁₂ &folic acid.

Cytokine produced in juxtatubular cell in kidney &

also macrophages.

Essential for normal erythropoiesis.

Anaemia and hypoxia are sensed by kidney cells.

Induce rapid secretion of EPO→ acts on erythroid

marrow.

EPO receptor is a JAK-STAT-binding receptor.

Erythropoietin

Recombinant human erythropoietin are Epoetin α, β.

Administered by i.v. or s.c. injection.

Plasma t½ of 6–10 hr, but action lasts several days.

Darbepoetin – longer acting glycosylated form of

epoetin, injected weekly.

Uses Primary use- anaemia of chronic renal failure.

Anaemia in AIDS patients treated with zidovudine.

Cancer chemotherapy induced anaemia.

Preoperative increased blood production for

autologous transfusion during surgery.

Anemia in premature infants.

Supplemented with iron & folic acid.

Preferable for smptomatic patients with Hb ≤ 8 g/dl.

Epoetin 25–100 U/kg s.c. or i.v. 3 times a week (max.

600 U/kg/week).

Reduces need for transfusions

It is prudent to start with a low dose and titrate

upwards to keep haematocrit between 30–36%, and

Hb 10–11 g (max 12 g) per dl.

Thank you