Haematinics are the agents used for formation of blood to treat various types of anemias. These include:
The production of circulating erythrocytes, leukocytes and platelets from undifferentiated stem cells, is called hematopoiesis.
- Iron –for Hb formation
- Vitamin B12
- Folic acid
- Hematopoietic growth factors
- Proteins that regulate the proliferation and differentiation of hematopoietic cells.
Decreased capacity of RBCs to carry oxygen to tissues.
- Blood loss
- Impaired RBC functions, due to deficiency of
- Increased destruction of RBCs (Hemolytic anemia)
Iron deficiency occurs due to:
- Congenital atransferrinemia (inability to release iron from transferrin)
Anemias are of two main types:
- Microcytic hypochromic–mainly due to iron deficiency
- Macrocytic/megaloblastic –mainly due to deficiency of vitamin B12 and folic acid
- Hemolytic anemias
- Pernicious anemias –decreased intrinsic factor
Iron is the integral component of haeme. In our body:
- 66-67% of iron is present in hemoglobin.
- 3% occurs in myoglobin
- 1% in enzymes -cytochrome, catalase, peroxidase
- 25% is stored in form of ferritin and hemosiderin
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)
Heme iron (present in meat)
Free inorganic iron is very toxic, thus there are regulatory mechanisms for:
c. Storage of iron
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.
ii. Proximal jejunum
iii. Distal intestine (in small amounts, if necessary)
For absorption, iron is converted into ferrous form in presence of ferroreductase
Mechanism of Absorption
Absorbed by two mechanisms:
- 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.
- 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
- Intestinal mucosal cells
- Reticuloendothelial system (in macrophages, spleen, bone marrow, liver)
- Liver parenchymal cells
Factors affecting Iron Absorption
Factors facilitating Iron Absorption
Acid enhances dissolution and reduction of ferric iron.
- Reducing Substances
Ascorbic acid reduces ferric iron and forms absorbable complexes
Meat also facilitates iron absorption by increasing HCl secretion
- Pregnancy/ Menstruation
Due to increased iron requirement
Factors Impeding Iron Absorption
Phosphates are present in egg yolk.
Phytates occur in wheat and maize
Alkalies form non-absorbable complexes as well and oppose the reduction
Tetracyclines impede absorption.
- 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:
- For Hb synthesis
- 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
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.
Iron deficiency anemias
Iron deficiency anemia manifests as hypochromic, microcytic anemia, in which:
- Erythrocyte mean cells volume is low (MCV <80fl)
- Mean cell Hb concentration is low (MCHC <30%)
- People with increased iron requirements:
- Children during rapid growth
- Pregnant and lactating women
- Patients of chronic kidney disease (due to increased loss during hemodialysis)
- Inadequate iron absorption, seen in
- Generalized malabsorption
- Females, menstrual bleeding
- Males and postmenopausal most common site is GIT.
- 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:
- Chronic anemia
- Impaired GI absorption
- Patients of chronic kidney disease undergoing dialysis
- Patients who cannot tolerate oral iron
Oral Iron therapy
Only ferrous salts are used because iron is absorbed only in ferrous form.
|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|
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.
Should be continued for 3-6 months after correction of cause of iron loss. This:
- Replenishes iron stores
- 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
Parenteral administration of free inorganic ferric iron produces serious dose dependent toxicity which limits the dose of iron.
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
- Iron dextran (Imferon)
- Sodium ferric gluconate complex
- Iron sucrose (Venofer)
Indications for Parenteral Administration
- Conditions where patient cannot tolerate oral therapy
- 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 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
- Painful (esp. I/M inj of dextran)
- Local tissue staining
- Abdominal discomfort
- GIT –nausea, vomiting, allergic manifestations
- Dizziness, headache, light headedness
- Back pain
- 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.
- Test dose of 0.25-5 mg, I/V administered
- 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:
- Concentration of serum ferritin
- Transferrin saturation
Transferrin saturation = Total serum iron conc. /Total iron binding capacity
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.
Death may occur within 4-6 hours.
- Necrotizing gastroenteritis (abdominal pain, bloody diarrhea)
- Followed by metabolic acidosis
- Abdominal pain
- Bloody diarrhea
- Dypsnoea- may improve or lead to:
- 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.
- Chelating agents –Deferroximine given I/V, binds iron and prevents its absorption and eliminates it from body.
- 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.
- Intermittent Phlebotomy -1 unit blood is removed each week or till iron overload is corrected.
- Iron Chelation therapy – Deferasirox, given orally. There is no role of deferoximine and is actually hazardous.
Deferasirox may not chelate iron in the heart.