Haematinics

Dr Urmila M. Aswar,

Sinhgad Institute of Pharmacy, Narhe, Pune -41

Image: scanning electron microscope of red blood cell

To achieve these functions the red cell has several unique properties….

Strength: it has a strong

but flexible membrane able to withstand the recurrent shear forces involved in the circulation of blood.

Flexibility: the red cell is 7.8 m across and 1.7 m thick and yet it is able to fit through

capillaries of only 5 m diameter. This is in-part due to the flexible membrane and shedding of the nucleus.

Biconcave shape: increases surface

area available for gaseous exchange.

Haemoglobin content: unique to the red cell, it is this metaloprotein molecule

which is pivotal in red cell development and Oxygen transport due to its affinity for O2.

Function

The primary function of the erythrocyte is the

carriage of oxygen from the lungs to the

tissues and CO2 from the tissues to the lungs.

The red cell also plays an important role in pH

buffering of the blood.

Lifespan: Because the fully developed red blood cell has no nucleus the cell cannot divide or repair itself. The lifespan is therefore relatively short (120 days).

Kidney

Bone marrow

Red blood cells in

circulationerythropoietin

Stem

cells

Erythroid

precursors

An erythrocyte is a fully developed, mature red blood cell. The adult human makes

approximately 1012 new erythrocytes every day by the process of erythropoiesis. This is a

complex process that occurs within the bone marrow. Before an erythrocyte arrives fully

functioning into the blood stream it must develop from a stem cell through an importantnumber of stages..

As with much human physiology, this system works via a feedback mechanism.

4. There is no store of EPO. The production of erythropoietin is triggered by tissue hypoxia (oxygen tension sensed within the tubules of the kidney) and stops when oxygen levels are normal.

Erythropoiesis

2. EPO stimulates stem cells within the bone marrow which differentiate into erythroid precursors.

3. EPO continues to stimulate primitive erythroid cells (red blood cells) in the bone marrow and induce maturation.

1: Erythropoietin (EPO), a growth factor, is synthesized primarily (90%) from peritubular cells of the kidneys (renal cortex).

Macrophages surround and supply iron to these erythroprogenitor cells that become erythroblastic islands.

START HERE FINISH HERE

Hypoxia is the major stimulant for increased EPO production

In chronic states of anaemia the opposite may occur. The chronic hypoxic state increases productionof EPO. This leads to an increase in the proportion of erythroblasts, expansion and eventually fattydeposition within the bone marrow.

Chronic renal disease / bilateral nephrectomy will reduce or stop the production of EPO.

It’s absence or reduction causes anaemia through reduced red cell production. Anaemia

due to EPO deficiency will be normocytic in morphology; i.e. the red cell will be a normal

shape and size but reduced in number.

Kidney

Bone marrow

erythropoietin

Erythroid

precursorsStem

cells

Kidney

Bone marrow

erythropoietin

Erythroid

precursorsStem

cells

Red cell precursors and the sequence of erythropoiesis2.2

Reticulocytes are an important cell in haematology as they increase in number following ahaemorrhage, haemolytic anaemia or from treatment of a haematinic deficiency. They providean excellent measure of red cell production. In normal blood there is usually about 1 reticulocyte :100 erythrocytes.K

ey

po

int!

marrow

3.5 Erythrocyte: after 1 week the mature

erythrocyte emerges with no organelles and high

haemoglobin content.Sequence: amplification and

maturation of the erythrocyte

Pronormoblast: This is the earliest and largest cell with a large nucleus and no haemoglobin.

3.4. Reticulocytes: Considered the “teenagers” of thethe life cycle! This is the FINAL stage of developmentbefore full maturation. These cells are now anucleateand contain roughly 25% of the final haemoglobintotal. They reside mostly in the marrow but in healthyindividuals a small number can be found in theperipheral blood. They contain some cell organelles.

Normoblasts: these cells go through a large number ofprogressive changes. Fundamentally they reduce incell size but increase the haemoglobin concentration

in the cytoplasm. The nucleus proportionallydecreases until it is extruded before the cell is releasedin to the blood.

blood

Vitamin B12 (cobalamin) and folate (pteroylglutamic acid):

These are key building blocks for DNA synthesis and essential for cell mitosis. DNA synthesis is

reduced in all cells that are deficient in either folate or vitamin B12. The bone marrow is the

factory for blood cell production. In haematinic deficiency, DNA replication is limited and

hence the number of possible cell divisions is reduced leading to larger red cells being

discharged into the blood i.e. less DNA, less divisions and larger cells. This leads to enlarged,

misshapen cells or megaloblasts in the marrow and macrocytic red cells in the blood.

• So what exactly are the haematinics? These are the key micronutrients that must be present if a red blood cell and its haemogoblin are to develop in a normal fashion.

• These major micronutrients, provided in a balanced diet, are iron, vitamin B12 and folate

• A deficiency in any one of these micronutrients can result in anaemia through impaired red

cell production within the bone marrow

• Assessing haematinic status is key to the investigation of the cause of anaemia

Iron:

At the centre of the haem molecule is an atom of iron which binds oxygen in a reversible

manner. Haemoglobin concentration in the developing red cell is a rate limiting step for

erythropoiesis. In iron deficiency, red cells undergo more divisions than normal and, as a result,

are smaller (microcytic) and have a reduced haemoglobin content (hypochromic). Iron

deficiency is the leading cause of anaemia worldwide.

2.4Erthropoiesis is also regulated by the availability of

haematinics

IRON

• Distribution of Iron in body

• Hb: 66%

• Iron stores as ferritin and haemosiderin: 25%

• Myoglobin: 3%

• As const of enzymes: 6%

Hb

Structure of human hemoglobin. The proteins 2α and 2 β subunits .

The iron-containing haem groups is attached to each chain.

1g/dl Hb; 200 mg of iron is needed.

Apoferritin + Fe3+ Ferritin Haemosiderin

Reticuloendothelial cells

• For adults

• Daily requirement: 0.5-1 mg

• Female : 1-2 mg

• Infants: 60 µg/kg Pregnancy: 3-5 mg

Dietary source of Iron

• Liver, egg yolk, dry beans, dry fruits, wheat, germ, meat, fish spinach, banana, apple.

The normal iron cycleIron deficiency can be identified best by assessing the appearances of the red cells

on a blood film.

Erythroid bone

marrow

(normoblasts)

Reticuloendothelial

system;

Spleen & macrophages

Duodenum

Serum

transferrin

Fe

Red blood

cells

Liver

Iron is a key constituent of haemoglobin (60-70% of total bodyiron is stored here) and it’s availability is essential forerythropoiesis. In iron deficiency, there are more divisions of redcells during erythropoiesis than normal. As a result the red cellsare smaller (microcytic) and have a reduced haemoglobin content(hypochromic).

2. Iron is then attached

to a protein, transferrin

in the serum (plasma),

where it is transported to

the bone marrow for

haemoglobin synthesis.

1. Iron is absorbed from the

small intestine in the ferrous

state (Fe2+; approx. 1mg/day).

3. Dying red cells

are recycled by

macrophages in

the spleen and

iron is recycled

into the plasma

for further use.

Soluble transferrin receptors,

sTfR are on the red cell surface.

These are increased in iron

deficiency.

In iron deficient states, bone marrow

iron is reduced.

Some iron binds to

apoferritin to form

ferritin, a storage

compound.

Preparations of IRON

• Ferrous are rapidly absorbed

• Ferrous sulphate (20-30% iron): 200 mg tab, cheapest but has metallic taste.

• Ferrous gluconate (12% iron): Ferronicum, 300 mg tab

• Other are ferrous succinate, iron cholineciterate, iron calcium complex etc

• Sustain releasing preparations not rational and expensive

• Liquid formulations stain teeth.

• 200 mg elemental iron produces hemopoieticeffect.

• Abs better empty stomach.

Injectables

• Injectables are recommended: when oral is not tolerated, failure to absorb iron, non compliance, severe deficiency with chronic bleeding .

• The ionised salts of iron cant be used parentrally as they cause protein precipitation.

• Egs Iron-dextran (50 mg/ml ele. iron), can be given by any route.

• Iron sorbitol citric acid complex (50 mg iron/ml), used only IM

Adverse effects of IRON: oral

• Epigastric pain

• Heart burn

• Vomiting

• Staining of teeth

• Metallic taste

• Constipation

Injections

• Local: pain at site, pigmentation at skin site

• Systamic: fever, headche, joint pains, flushing, palpitation, dyspnoea, lymph node enlargment, metallic taste in mouth

• Anaphylactic reactions seen rarely.

Uses

• Iron deficiency anaemia: Nutritional def., chronic bleeding, malaria, COBD etc

• RBC are microcytic, hypochromic.

• 0.5-1g Hb/dl: optimum therapy

Megaloblastic anemia

• Can lead to iron def. therefore combination of therapy be initiated.

Iron Poisoning

• Acute poisoning: 10-20 mg iron tab or liquid prepn. May cause serious toxicity in children.

• Symptoms: Vomiting, abdominal pain, lethargy, cyanosis, convulsions, shock and CVS failure.

• Treatment: induce vomiting, give egg yolk or milk, desferrioxamine (5-10 g) in 100 ml saline.

• EDTA is used to chellate iron.