Iron as Haematinic Agent

Haematinics are the agents used for formation of blood to treat various types of anemias. These include:

1. Iron
2. Vitamin B12
3. Folic Acid

Hematopoiesis

The production of circulating erythrocytes, leukocytes and platelets from undifferentiated stem cells, is called hematopoiesis.

It requires:

1. Iron –for Hb formation
2. Vitamin B12
3. Folic acid
4. Hematopoietic growth factors
5. Proteins that regulate the proliferation and differentiation of hematopoietic cells.

Anemia

Decreased capacity of RBCs to carry oxygen to tissues.

Causes:

1. Blood loss
2. Impaired RBC functions, due to deficiency of

• Iron
• Vitamin B12
• Folic acid
• Bone marrow suppression (Hypoplastic anemia)

3. Increased destruction of RBCs (Hemolytic anemia)

Iron deficiency occurs due to:

1. Malnutrition
2. Loss
3. Congenital atransferrinemia (inability to release iron from transferrin)

Anemias are of two main types:

1. Microcytic hypochromic–mainly due to iron deficiency
2. Macrocytic/megaloblastic –mainly due to deficiency of vitamin B12 and folic acid

• Hemolytic anemias
• Pernicious anemias –decreased intrinsic factor

 Iron

Storage

Iron is the integral component of haeme. In our body:

1. 66-67% of iron is present in hemoglobin.
2. 3% occurs in myoglobin
3. 1% in enzymes -cytochrome, catalase, peroxidase
4. 25% is stored in form of ferritin and hemosiderin

Role

Forms the nucleus of iron-porphyrin heme ring, which together with globin chains forms hemoglobin. Hemoglobin binds oxygen, transporting it from lungs to tissues.

Symptoms of Microcytic Hypochromic Anemia

Pallor, Fatigue, Dizziness, Exertion dyspnea, Tissue hypoxia symptoms, cardiovascular adaptations (tachycardia, increased cardiac output, vasodilatation)

Pharmacokinetics

Source

Heme iron (present in meat)

Inorganic iron

Free inorganic iron is very toxic, thus there are regulatory mechanisms for:

a. Absorption

b. Transport

c. Storage of iron

a. Absorption

Amount

Normal individual absorbs 0.5-1 mg/day iron.

Iron in meat

Easily absorbed as does not require conversion

Iron in vegetables and grains

Less absorbed as bound to organic compounds

Iron in heme form is readily absorbed across intestinal cells than inorganic iron.

In inorganic form, iron is readily absorbed in ferrous than ferric form.

Site

i.                    Duodenum
ii.                  Proximal jejunum
iii.                Distal intestine (in small amounts, if necessary)

Conversion

For absorption, iron is converted into ferrous form in presence of ferroreductase

Mechanism of Absorption

Absorbed by two mechanisms:

1. On luminal surface of intestinal epithelial cells, divalent metal transporter 1 (DMT-1) is present, through which ferrous form of iron is actively transported. This new iron along with that splits from heme, are transported to blood across basolateral membrane by ferroprotein (ferriportin 1). It is then oxidized to ferric form by ferro-oxidase.
2. Heme iron (present in meat) is absorbed without conversion to elemental form

Regulation of storage

If body requirements are low, iron is stored inside intestinal mucosal cells in form of ferritin.

Ferritin is water soluble complex consisting of a core of ferric hydroxide covered with a shell of specialized storage protein, apoferritin.

If body requirements are high, more iron is transported across basolateral membrane to blood.

In plasma, it binds transferrin, a globulin which binds to ferric iron. Transferrin-iron complex is carried to different organs including spleen, liver, and bone marrow. Transferrin acceptors are present in these organs (TFA) and as a result iron is internalized by these organs, and transferrin and transferrin receptor complex are recycled to plasma.

Storage of Iron

1. Intestinal mucosal cells
2. Reticuloendothelial system (in macrophages, spleen, bone marrow, liver)
3. Liver parenchymal cells

Factors affecting Iron Absorption

Factors facilitating Iron Absorption

1. Acid

Acid enhances dissolution and reduction of ferric iron.

2. Reducing Substances

Ascorbic acid reduces ferric iron and forms absorbable complexes

3. Meat

Meat also facilitates iron absorption by increasing HCl secretion

4. Pregnancy/ Menstruation

Due to increased iron requirement

 Factors Impeding Iron Absorption

 

1. Phosphates

Phosphates are present in egg yolk.

2. Phytates

Phytates occur in wheat and maize

3. Alkalies

Alkalies form non-absorbable complexes as well and oppose the reduction

4. Tetracyclines

Tetracyclines impede absorption.

5. Presence of other foods in stomach

b. Transport of Iron

Transport occurs by transferrin, a beta globulin that binds two molecules of ferric iron, forming transferrin-iron complex. This complex binds transferrin receptors present in large number of erythroid cells. They bind and internalize the complex by receptor mediated endocytosis. In endosomes, ferric iron is released, and is reduced to ferrous form. It is then transported by DMT1 into cells, used:

1. For Hb synthesis
2. Stored as ferritin

Recycling of transferrin

Transferrin-transferrin receptor complex is recycled to cell membrane. Transferrin dissociates and returns to plasma.

Increased erythropoiesis leads to increased number of trasferrin receptors on cells

Iron deficiency leads to increased concentration of serum transferrin

c. Elimination

No mechanism is present for elimination of iron from body except exfoliation of intestinal cells. Trace amounts of iron are lost in faeces, urine, bile and sweat.

Less than 1 mg/day of iron is lost.

 Serum iron is detectable, so can be used to estimate the total iron stores.

Increased iron levels lead to increased synthesis of apoferritin and vice versa.

Indications

Iron deficiency anemias

Iron deficiency anemia manifests as hypochromic, microcytic anemia, in which:

1. Erythrocyte mean cells volume is low (MCV <80fl)
2. Mean cell Hb concentration is low (MCHC <30%)

Causes

1. People with increased iron requirements:

• Infants
• Children during rapid growth
• Pregnant and lactating women
• Patients of chronic kidney disease (due to increased loss during hemodialysis)

2. Inadequate iron absorption, seen in

• Gastrectomy
• Generalized malabsorption
• Females, menstrual bleeding
• Males and postmenopausal most common site is GIT.

3. Adults, due to blood loss

Treatment of Iron Deficiency

Oral and parental preparations can be used. Oral preparation is present in the form of salts like:

• ferrous gluconate
• ferrous sulphate
• ferrous fumarate.

Both are equally effective but oral therapy is preferred. Parenteral preparations are given only in:

1. Chronic anemia
2. Impaired GI absorption
3. Patients of chronic kidney disease undergoing dialysis
4. Patients who cannot tolerate oral iron

Oral Iron therapy

Only ferrous salts are used because iron is absorbed only in ferrous form.

Preparations

Iron Salts	Tablet Size	Iron in tablet	Adult dose (/day)
Ferrous sulphate (hydrated-chocolate coloured)	325 mg	65 mg	3-4
Ferrous Sulfate (desiccated)	200 mg	65 mg	3-4
Ferrous Gluconate	325 mg	36 mg	3-4
Ferrous fumarate	100 mg	33 mg	6-8

Dose

50-100 mg iron can be incorporated into Hb daily.

25% of oral iron as ferrous salt can be absorbed. So 200-400 mg/day elemental iron should be given. If patient cannot tolerate, less amount is given, which makes result slower but still complete relief.

Duration

Should be continued for 3-6 months after correction of cause of iron loss. This:

1. Replenishes iron stores
2. Corrects anemia

Adverse effects of Oral Administration

Mainly GIT –nausea, gastric irritation, abdominal discomfort, altered bowel habits, black staining of stools (can mask GIT bleeding).

Prevention includes decreasing the dose and taking tablets immediately after meal.

Parenteral Iron Therapy

Drawback

Parenteral administration of free inorganic ferric iron produces serious dose dependent toxicity which limits the dose of iron.

Solution

A colloid containing particles is made with a core of iron oxydydroxide surrounded by a shell of carbohydrate (e.g. dextran polymers). In this way, bioactive iron is released slowly from stable colloid particles.

Forms of Parenteral Therapy

1. Iron dextran (Imferon)
2. Sodium ferric gluconate complex
3. Iron sucrose (Venofer)

Indications for Parenteral Administration

1. Conditions where patient cannot tolerate oral therapy
2. Absorption defects like hereditary absorption disorders, inflammatory bowel diseases, small bowel resections, trauma to small intestine, patients of gastrectomy, infants, children, pregnancy and in lactating women

Iron Dextran

Iron dextran can be given I/M or I/V. It is a stable combination of ferric hydroxide with low molecular weight dextran containing 50 mg elemental iron/ml of solution.

Iron Sucrose and Sodium Ferric Gluconate Complex

Iron sucrose and iron sodium gluconate complex are two compounds given I/V, however they are less antigenic and allergic manifestations are less commonly encountered.

Formula for Calculating total Dose of Iron in grams

0.25 x (normal Hb – Patients Hg)

Iron levels should be monitored in parenteral therapy as it is not subjected to normal regulatory mechanism (as in oral therapy)

Adverse Effects of parenteral route

1. Painful (esp. I/M inj of dextran)
2. Local tissue staining
3. Abdominal discomfort
4. GIT –nausea, vomiting, allergic manifestations
5. Dizziness, headache, light headedness
6. Fever
7. Arthralgia
8. Back pain
9. Flushing
10. Urticaria
11. Bronchospasm
12. In very severe cases, anaphylaxis, which may lead to death

There are increased chances of hypersensitivity on patients who have already received parenteral iron dextran.

Prevention

1. Test dose of 0.25-5 mg, I/V administered
2. Two different formulations are used

• High molecular weight form (e.g. DexFerum)
• Low molecular weight forms (e.g. InFeD)

There is increased risk of anaphylaxis with high molecular weight forms.

Estimation of Iron Stores

Can be estimated on the basis of:

1. Concentration of serum ferritin
2. Transferrin saturation

Transferrin saturation = Total serum iron conc. /Total iron binding capacity

Clinical Toxicity

Toxicity occurs due to overdosage.

Acute Iron Toxicity

Seen after ingestion of tablets of iron. Common in children.

Lethal dose 10 or more tablets are lethal due to accidental ingestion. Adults can tolerate larger doses than children

Fatal period 4-6 hours.

Manifestations

1. Immediate
2. Delayed

Death may occur within 4-6 hours.

Symptoms

1. Vomiting
2. Necrotizing gastroenteritis (abdominal pain, bloody diarrhea)
3. Followed by metabolic acidosis
4. Abdominal pain
5. Bloody diarrhea
6. shock
7. Dypsnoea- may improve or lead to:

• Comma
• Death

Treatment

1. Gastric lavage/aspiration of what is ingested, usually with sodium bicarbonate

Home made remedy of egg yolk and milk, which complexes iron and renders it non-absorbable.

2. Chelating agents –Deferroximine given I/V, binds iron and prevents its absorption and eliminates it from body.
3. Supportive therapy required for correction of metabolic acidosis, treatment of shock and usually Diazepam for convulsions.

Activated charcoal does not bind iron so is not effective.

Chronic Iron Toxicity

Slow and gradual accumulation of iron in body. Different organs are involved like heart, liver, and pancreas. Iron gets accumulated in these organs producing end organ failure and hemochromatosis. In thalassemia, when repeated blood transfusions are given, aplastic anemia might occur.

Treatment

1. Intermittent Phlebotomy -1 unit blood is removed each week or till iron overload is corrected.
2. Iron Chelation therapy – Deferasirox, given orally. There is no role of deferoximine and is actually hazardous.

Deferasirox may not chelate iron in the heart.

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Vitamin B12

Folic acid

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