Haematinics

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Definition—

Haematinics are the chemical agents or substances which are required for normal erythropoiesis.

 

These are—

Iron (Fe), Cobalt (Co), Zinc (Zn), Vit-B12, Folic acid and Erythropoietin.

 

 

Iron (Fe)

Required for Hgb production. In the absence of adequate iron a small red cell with insufficient Hgb will be formed giving rise to microcytic and hypochromic anaemia. Fe++ forms the nucleus of the porphyrin ring, which when combined with appropriate globin chain forms Haemoglobin.

*** Intake of Iron is 20mg/day from which 1mg/day (5%) is absorbed.

 

Distribution of Iron in the body—

·   70% is in the form of Hgb in RBC.

·   (10-20)% is in the storage form as haemosiderine.

·   10% is in the form of myoglobin, a haem containing protein which is present in the muscle.

·   Less than 1% is in the cytochrome and other Fe++ containing enzymes and as transport iron transferine.

 

Iron is required in the body for—

Synthesis of Hgb

Synthesis of myoglobin

Cytochrome P450 enzyme synthesis

 

Pharmacokinetics of Iron—

Iron is normally available in the diet in the form of haem or iron complex to various organic compounds.

 

Absorption of iron—

Iron is most readily absorbed in the ferrous state. But most of the dietary iron is in the ferric form. No more than a trace amount of iron is absorbed in the stomach. But the gastric secretion (HCl) dissolves the iron and permits it to form soluble complexes with ascorbic acid (vit-C). Vitamin-C and other substances aid its reduction into ferrous form. This is why the patients with partial gastrectomy usually have iron deficiency anaemia. Most of the iron is absorbed in the upper part of the small intestine that is duodenum and upper part of the jejunum. Te mucosal cell contains as intracellular iron carrier. Some iron is supplied to mitochondria by the carrier, but the remainder is partitioned between Apoferritin in the mucosal cells and Transferin which is the iron transporting polypeptide in the plasma. Apoferritin, which is also found in many other tissues combines with iron to form Ferritin.

 

Distribution—

Iron is transported in the plasma bound to transferin (transferin is a β-globulin that specially binds to ferric iron). Iron can thus be transported from intestinal mucosal cells or from storage form in the liver and spleen to the developing erythroid cells in the bone marrow.

 

Storage—

Iron can be stored in 2 forms,

Ferritin (ferric iron + apoferritin)

Haemosiderine (when there is excess ferritin)

 

Ferritin is the most readily available form of storage iron. Ferritin consists of core crystal of ferric hydroxide covered by a protein shell of apoferritin.

Haemosiderine consists of aggregates of ferric cone crystals partially or completely stripped of apoferritin.

Both ferritin and haemosiderine are stored in the macrophages of liver, spleen and bone marrow. Ferritin is also present in the plasma and intestinal mucosal cells.

 

Excretion—

There is no mechanism of excretion of iron. A small amount of iron is lost by the exfoliation of the intestinal mucosal cells into the stool and trace amount is excreted through bile, urine and sweat.

 

Regulation and iron absorption—

It is regulated by the amount of storage iron. Specially the amount of ferritin present in the intestinal mucosal cells. When both iron stores are depleted or when erythropoiesis is increased, the amount of transferin in the plasma is increased and its percent saturation in with iron is decreased. So, more iron is moved from the intra-cellular iron carrier to the transferin and less binds to apoferritin.

When the body iron store is sufficient, the opposite happens.

 

Indication or use of iron—

·   Iron deficiency anaemia

·   In children during rapid growth period

·   In pregnant and lactating mother

 

Causes of iron deficiency anaemia—

1. Hook worm infestation

2. Bleeding peptic ulcer

3. After gastrectomy

4. GIT malignancy

5. Small intestinal disease leading to mal-absorption

 

Features of iron deficiency anaemia—

1. red cells are microcytic and hypochromic

2. serum iron is less than 40 μgm/dl

3. total iron binding capacity (TIBC) is greater than 400 μgm/dl

 

Treatment—

Iron can be given in oral from or parenteral form. Oral iron corrects the deficiency as rapidly and completely as parenteral iron.

 

Oral iron therapy—

A wide variety of preparations are available,

Ferrous Sulphate

Ferrous Glucorate

Ferrous Fumerate

Ferrous Sucinate

Ferrous Fumerate (33%) contains more iron than Ferrous Sulphate (20%). But ferrous Sulphate is cheap and easily absorbable.

Iron should be continued for 3-6 months after the Hgb level has returned to normal to replenish iron sores.

 

Indications of parenteral iron therapy—

Patients genuinely unable to take iron by mouth because,

1. Pain, vomiting or diarrhoea

2. Patient with post-gastrectomy

3. After small bowel resection

4. Inflammatory bowel disease

5. GIT upset, malabsorption syndrome

 

Iron Dextran—

Iron Dextran is a stable compound of ferric hydroxide. Low molecular weight Dextran contains 50mg of iron/ml of solution. It can be given either by deep IM or IV injection.

 

Total amount of parenteral iron is required to correction of iron deficiency anaemia and to replenish iron stores in a 70kg adult can be calculated as follows—

Gm of iron is required = 0.25 x (normal Hgb – Patient’s Hgb)

 

Most adults with iron deficiency anaemia require 1-2 gm of replacement iron 20-40 ml of iron Dextran. It can be given as 10-20 ml daily as IM injection or entire calculated dose can be given in a single IV infusion in several ml of normal saline over 1-2 hours.

A small test dose of iron Dextran should always be given before full IM or IV dose.

 

Adverse effects of parenteral iron—

·   Local pain

·   Tissue staining—brown discolouration

·   Headache

·   Light headedness

·   Fever

·   Arthralgia

·   Nausea and vomiting

·   Back pain

·   Flushing and urticaria

·   Bronchospasm, rarely anaphylaxis and death

 

Acute iron toxicity—

It is seen almost exclusively I young children who have ingested a number of iron tablets.

 

Sign-symptoms—

Necrotizing gastro-enteritis with vomiting, abdominal pain and bloody diarrhoea followed by shock, lethargy and dyspnoea. Subsequent improvement is often noted that this may be followed by severe metabolic acidosis and death.

 

Treatment—

1. Gastric aspiration followed by gastric lavage with NaHCO3 solution to neutralize iron and form neutral salts.

2. Desferrioxamine (potent iron chelating compound can be given systemically by IM injection).

3. Supportive treatment to combat acidosis and GIT diseases.

 

Chronic iron toxicity—

It is also known as haemochromatosis and haemosiderosis, results when excess iron is deposited in the heart, liver, pancreas and other organs. It can lead to organ failure and death. Most commonly occurs in patients with haemochromatosis which is an inherited disorder characterized by excessive iron absorption and in patients who receive many red cell transfusion over a large period of time (thalassaemia).

The treatment is intermittent blood lating by intermittent phlebotomy. 1 unit of blood containing 250mg of iron can be removed in every week until all of the excess iron is removed.

 

 

Vit-B12 / Cyanocobalamine

It cannot be produce in our body

Participates in many biochemical reactions

 

Chemistry—

·   Porphyrin like ring structure.

·   In the centre of the structure there is a Cobalt atom attached with the nucleotide.

·   Different organic compounds are attached with this Cobalt atom forming Cobalamine.

·   In the nature Cobalamines like Hydroxycobalamine and Cyanocobalamine are present (in meat) and the active forms of Cobalamine are Methoxycobalamine and Deoxy-adenosil Cobalamine.

·   All Vit-B12 are produced microbially.

 

Pharmacokinetics—

Daily requirement → 2 μgm

Daily intake through food → 5-30 μgm

Daily absorption → 1-5 μgm

Daily loss → 2 μgm

Storage in the liver → 3000-5000 μgm (so, at least 5 years deposit is present)

Dietary source → liver, egg, meat

 

Absorption—

Vit-B12 present in the food dissociates in the duodenum or jejunum. Here it combines with the intrinsic factor (a glycoprotein) derived from the parietal cells of the stomach. (B12 is called the extrinsic factor). This complex travels down and is absorbed from the terminal parts of the ileum. Here there are receptors for the intrinsic factor. So, the complex gets attached to the receptors and from here Vit-B12 is absorbed.

 

Distribution—

After absorption Vit-B12 enters into blood and binds to Transcobalamine-II (a glycoprotein) for transport. Excess Vit-B12 is deposited in the liver.

 

Excretion—

Significant amount of Vit-B12 is excreted through the urine only when very large amounts are given parenterally, overcoming the binding capacity of transcobalamine.

 

Pharmacodynamics—

 

 

Two essential enzymatic reactions in humans require Vit-B12. In one Methylcobalamine serves as an intermediate in the transfer of a methyl group from N5-Methyltetrahydrofolate to Methionine. In the absence of Vit-B12 conversion of the major dietary and storage folate N5-methyltetrahydrofolate to tetrahydrofolate, the precursor of folate cofactor cannot occur. As a result there is depletion of tetrahydrofolate and deficiency of folate cofactor which is necessary for several biochemical reactions. So, there is prevention in adequate supplies of the deoxythymidylate (dTMP) and purine which are required for the DNA synthesis.

The accumulation of folate as N5-Methyltetrahydrofolate and the associated depletion of the tetrahydrofolate cofactors in Vit-B12 deficiency have been referred to as “Methylfolate Trap”.

 

The other enzymatic reaction that requires Vit-B12 is isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methymalonyl-CoA mutase. In Vit-B12 deficiency, this conversion cannot take place and the substrate methylmalonyl-Coa accumulates. In the past it was thought to be the cause of neurological manifestations but newer studies show the disruption in the Methionine pathway is the main cause.

 

The clinical features of neurological manifestations are parathesia, weakness in the peripheral nerve which progresses to spasticity, ataxia and other CNS disorders. There may be subacute combined degeneration of the spinal cord at dorsal and lateral horn, disintegration of the myelin sheath and disruption of axon.

 

*** administration of folic acid in the setting of Vit-B12 deficiency will not prevent neurological manifestations but it can largely correct the anemia caused by Vit-B12 deficiency (folic acid → dihydrofolate → tetrahydrofolate).

 

 

Deficiency of Vit-B12—

1. Megaloblastic Anaemia (megaloblasts in the bone marrow and macrocytes in the blood

2. GIT symptoms

3. Neurological abnormalities (subacute combined degeneration of the spinal cord)

—these can occur singly or combinedly

 

Deficiency may be due to—

·   Malabsorption

·   Pernicious anaemia (autoimmune disorder, destroys parietal cells)

·   Malnutrition (dietary deficiency, specially in vegetarians like in south India)

·   Defect in receptors

·   Gastrectomy

·   Rejection of terminal ileum (cancer)

·   Inflammatory bowel disease (specially affecting the celiac region)

·   Bacterial overgrowth

·   Fish tapeworm infestation (diphylobothrium latum)

·   Coeliac spru

 

Diagnosis—

1. Peripheral blood film—there will be macrocytes, mild thrombocytopenia and mild leucopenia in the blood and bone marrow will be hypercellular with megaloblasts.

2. Serum Vit-B12 level.

3. Schilling test—to see if the absorption and excretion is alright (by giving radioactive Vit-B12)

 

Treatment—

·   If temporary loss—correct the anemia and replenish the store by injection Hydroxycobalamine 1000 μgm/ml.

·   If subacute combined degeneration of the cord is present then—

1000 μgm IM on every alternate day for 2 weeks.

Then once weekly for few weeks.

Then once a month.

·   If there is Megaloblastic/pernicious anaemia—

1 ml (1000 μgm) IM once a week till the blood count is normal then 1ml IM every 3 months for life long.

 

The response is rapid—

Bone marrow returns to normal within 48 hours.

Hgb begins to increase within first weak and returns to normal after 1-2 months.

 

 

Folic Acid

It is the parent compound of folates

Not present in the nature

Daily requirement is 60-100 μgm

Source—liver, cereals, nuts, green vegetables

 

Chemistry—formed of 3 components,

§    A Pteridine

§    Para-amino Benzoic acid (PABA)

§    Glutamic acid

 

Pharmacokinetics—

Administered through oral or parenteral routes.

Absorbed from the proximal jejunum.

Widely distributed and stored in the liver.

 

*** if Folic acid intake is stopped then Megaloblastic anaemia can occur within 1-6 months as the store in the body is relatively low.

 

Function of Folic acid—

It is the parent compound of folates and folates act as a cofactor in the formation of purine and pyrimidine which is essential for DNA synthesis. Folate cofactor is also needed in the formation of thymidylic acid.

 

Causes of folate deficiency—

1. Poor intake due to old age, starvation and anorexia

2. GIT diseases (coeliac disease, crohn’s disease)

3. Partial gastrectomy

4. Increased need in pregnancy

5. Haemolytic diseases with excess red cell production

6. Inflammatory diseases

7. Malignant diseases

8. Malabsorption syndrome

9. Drugs (Phenytoin, Primidone, Methotrexate, Pyrimethamine, Trimethoprim, Sulfonamides)

 

Effects of deficiency—

1. Megaloblastic anaemia

2. Spina bifida of the foetus in case of pregnant women

 

Indication of Folic acid—

§    Megaloblastic anaemia due to folate deficiency

§    Pregnant women

§    Premature infants

§    Haemolytic anaemia patients

§    Liver disease

§    Chronic skin disease

§    Renal disease

§    With anti-convulsant drugs