1. Haematinic Agent Course Title : Inorganic Pharmacy-II Course No
Haematinic Agent Course Title : Inorganic Pharmacy-II Course No.: PHR 107 Course Teacher : Zara Sheikh

2. HAEMATINIC Agent
Haematinic agents are antianemics that increase the haemoglobin content of blood through erythropoiesis or through an increase in haemoglobin content of erythrocytes.
The choice of a haematinic depends upon critically the nature of the anemia.
Anemia is a general term for a condition in which circulating red blood cells are deficient in number, or deficient in total haemoglobin content, per unit of blood volume.
The net result is a lower oxygen – carrying capacity by the blood.

3. IRON
Source :
All animal food (except milk & butter) e.g. – Liver, meat, egg etc.
Vegetables, e.g. Peas, Lentils
Green leaves
Fruits.
Others :
Red oxide or hematite – Fe2O3
Magnetite – Fe3O4
Limonite – 2Fe2O3.3 H2O
Siderite – FeCO3
Iron pyrites – Fe2S

4. IRON Body component containing ions : Blood stream – Haemoglobin
Mode of linkage -- Haem
Plasma
Mode of linkage – Transferrin
Tissue –
Functional iron
Storage iron
Mode of linkage – Ferritin, Haemosiderin

5. IRON Causes of Iron deficiency : Inadequate dietary intake of iron.
Chronic blood loss.
Conditions that produce increased requirement of iron.
Abnormalities of GIT
In premature babies, since they are born with low iron stores.
It may also occur due to parasite infection

6. IRON Factors affecting absorption of iron :
Iron requirements of the subjects : The degree of immediately need of the body for iron determines the rate & the amount of absorption from the small intestine.
Form of the compound : It is said that iron is best absorbed in Ferrous form.
Gastric juice : The gastric juice helps in the liberation of iron from the organic compounds in diet.
Pigments : Absorption of iron is increased by chlorophyll & bile pigments.
Calcium : A small amount of Ca2+ decrease the formation of insoluble iron phosphate & thus helps in absorption but large amount of Ca2+ inhibit iron absorption.
Vitamin C : Vit C increases the absorption of iron from foods possibly by reducing ferric iron to the ferrous state.

7. Physiological functions of iron :
The primary function of iron is to form haemoglobin.
It is necessary for the formation & maturation of RBC.
It s responsible for the transport of oxygen in the form of oxyhaemoglobin.
Cytochrome is an iron containing enzyme. It is concerned with the oxidation of metabolites in the cell.
Myoglobin of muscle is an iron containing chromoprotein. It combines with O2 & acts as an oxygen store for muscle.
The chromatin of the nucleus contains iron and thus helps in the functioning of nuclei.

8. IRON Importance for maintaining the ferrous state :
Administration of the ferrous salts results in greater Hb responses than that obtained with any other form of iron.
Absorption of ferrous ion occurs better than that of ferric ion.
Ferrous salts are less irritating than ferric salts
Ferrous state is more efficient than the ferric salts.
Ferrous salts can be used internally.

9. Oral Iron Preparations :
Ferrous Fumarate (Tablet)
Dose : 200mg two or three times a day.
Ferrous Gluconate (Tablet)
Dose : 300mg three times a day
Ferrous sulfate (Tablet and Syrup)
Tablet : available as 300mg tablet of FeSO4.7H2O or the equivalent amount of a dried ferrous sulphate, approximately 200mg.
Syrup : contains 40g of FeSO4.7H2O in 1000ml. Sucrose acts as a stabilizing agent and the citric acid as an acid buffer.

10. IRON Preparations Ferrous Fumarate : Formula : FeC4H2O4
Commercial manufacture :
Ferrous fumarate is made by the interaction of hot, aqueous solution of ferrous sulfate & sodium fumarate. Here sodium fumarate is generally added to the ferrous sulfate.
FeSO4 + Na2C4H2O4 FeC4H2O4 + Na2SO4
The precipitate of ferrous fumarate is removed by filtration. Then it is washed, dried & reduced to a powder.

11. IRON Preparations Ferrous Fumarate : Advantages :
It is resistant to oxidation on exposure to air. But ferrous sulfate & ferrous gluconate oxidizes readily on exposure to air & ferrous iron turns to ferric.
Even on exposure to a hot humid atmosphere over a prolonged period of time, there is little conversion to the ferric form.
In equivalent doses it provides good haematologic responses in iron deficiency from any other available preparations.
It is less irritating to the GIT than other commonly used ferrous salts.
Its iron content is high.
It has low incompatabilities.
Its efficacy is about same as that of ferrous sulfate but untoward effects are somewhat less severe.
It does not cause staining to teeth.

12. IRON Preparations Ferrous Fumarate : Disadvantages :
Some side effects such as anorexia , nausea, vomiting, constipation or diarrhea may occur.
Like other iron preparations this drug may increase GIT diseases, especially ulcer.
It is expensive.
It can not be dispersed in solution dosage form which is necessary for use especially for old persons & children.

13. IRON Preparations Ferrous Gluconate : Formula : C12H22FeO14. H2O
Commercial manufacture :
The gluconate solution is first produced by the fermentative oxidation of glucose.
C6H12O6 + [O] ———> HC6H11O7
The solution of gluconic acid is then treated with carbonate to form soluble ferrous gluconate.
2HC6H11O7+FeCO3+H2O Fe(C6H11O7)2.H2O + CO2
From the resulting solution, the ferrous gluconate is crystallized. The salt contains one molecule of water of crystallization. This is then dried & packaged.

14. IRON Preparations Ferrous Gluconate : Advantages :
It causes less gastric irritation than most of the other commonly used inorganic ferrous salts. (e.g. FeSO4).
It is obtained commercially as tablet, capsule & elixir.
It is also utilized for intramuscular injection.
It is a haematinic similar to other ferrous salts.
It has a good bioavailability.
Disadvantages :
The elixir can cause staining of the teeth, if taken undiluted.
It causes some side effects as ferrous fumarate & ferrous sulfate.
It is affected by light & air & the ferrous iron slowly oxidized to ferric on exposure to air.
Its iron content is low.
It is unstable at pH 7.
Less active
Solubility is low.

15. IRON Preparations Ferrous sulfate : Formula : FeSO4. 7H2O
Commercial manufacturer :
The best grade of ferrous sulfate is obtained by dissociates iron in diluted sulfuric acid & concentrating to crystallization.
Fe + H2SO4 FeSO4 + H2
The commercial grade of this salt are made by pilling in pyrites (FeS2) in heaps & exposing it to atmospheric oxidation. The mass is leached with water & the dilute solution of ferrous sulfate is run into large vats.
The liquid is concentrated by crystallization.
2 FeS2 + 7O2 + 2H2O FeSO4 + 2H2SO4

16. IRON Preparations Ferrous sulfate : Advantages :
It is an efficient haematinic preparation used in iron deficiency anaemia.
It is most economical.
It is absorbed rapidly from the GIT.
It shows a quick bioavailability.
Disadvantages :
Ferrous sulfate readily oxidizes on exposure to moist air & the crystal becomes coated with brownish yellow basic ferric sulfate.
It can be irritating to the gastrointestinal mucosa due to the astringent action of sulfate iron.
The oral solution can cause staining of teeth if used in undiluted form.
Relatively small over doses can be fatal for infants & children.

17. IRON Different forms of iron present in the body :
Most if the iron found in the body is associated with two types of protein –
Haemoprotein.
Iron storage and/or transport protein.
Haemoprotein : Haemoproteins are those iron-containing proteins responsible for respiration (i.e. respiratory enzyme) for carrying oxigen. Cytochrome which is an example of a respiratory enzyme in which iron is complexed in a porphyrin (i.e. haem) ring system. Other oxidative enzyme containing iron are catalase & peroxidase.
Function :
The iron function as an electron carrier & can be present as Ferrous (Fe2+) or Ferric (Fe3+) state.
The other group of haemoproteins, represented by myoglobin & haemoglobin, stores and/or transport oxygen.

18. IRON Iron storage and/or transport protein :
A. Storage protein : It includes –
Ferritin.
Haemosiderin.
Ferritin : Ferritin is an iron storage protein found in the liver, spleen & bone marrow. It is a water soluble , crystallizable, iron protein built up from apoferritin & micelles of a colloidal ferrichydroxide-phosphate complex.
Haemosiderin : Haemosiderin ia also an iron storage protein found in liver, spleen & bone marrow. It is water soluble & is considered to be a dehydrated ferritin.
Function : Both of them serves as the storage of iron in the body.
B. Transport protein : The major iron transport protein of blood plasma is a glycoprotein known as transferrin (siderophilin). It binds two atoms of ferric iron per molecule so tightly that, for all practical purposes, there is no free plasma iron.
Function : Transferrin release iron to the red cell precursor attaching to a receptor on the surface of the developing red blood cell.

19. IRON (Deep red) Test for Ferric salts :
i) Acidic ferric salt solutions give a dark blue precipitate with potassium ferrocyanide test solution.
FeCl3 + 3K4[Fe(CN)6] Fe4[Fe(CN)6] KCl
K-ferric ferrocyanide
or, Fe K4[Fe(CN)6] Fe4[Fe(CN)6]3
(Dark blue)
ii) Excess sodium hydroxide test solution produces a reddish brown precipitate of ferric hydroxide.
FeCl3 + NaOH Fe(OH)3 + 3NaCl
or Fe OH Fe(OH)3
(Reddish brown)
iii) With ammonium thiocyanate test solution, a deep color is formed which cannot be destroyed by mineral acids.
FeCl3 + 3NH4CNS Fe(CNS) NH4Cl
Or, FeCl3 + NH4CNS Fe(CNS)3 + 3NH4+
(Deep red)

20. IRON Test for ferrous salts :
Solution of ferrous salts give a dark blue ppt. with potassium ferricyanide test solution.
FeCl2 + K3[Fe(CN)6] KFe[Fe(CN)6] + 2 KCl
K-ferrous ferricyanide
(Dark blue)
Sodium hydroxide test solution forms a greenish white ppt. with ferrous salts.
FeCl3 + NaOH Fe(OH) NaCl
The color of this ppt. changes rapidly on shaking to green and then to brown.

21. Parenteral Iron Preparations:
Parenteral iron preparations are indicated only in those conditions where either iron absorption is defective (steatorrhea, partial gastrectomy) or the iron salt may be irritating (peptic ulcer).
Except for these types of indications, there seems to be no real advantage for using parenteral iron because it can cause vomiting and allergic reactions.
Formula for calculating total dose for parenteral administration:
Total milligrams of iron needed = Patient’s weight (kg) × [normal hemoglobin (g%) – patient’s hemoglobin value (g%)] × 2.5

22. Parenteral Iron Preparations:
Iron Dextran Injection
It is a sterile, colloidal solution of ferric hydroxide complexed with partially hydrolyzed dextran (glucose polymer) of lower molecular weight, in Water for injection.
pH should be between 5.2 and 6.5
Prior to mixing, it is a dark brown, slightly viscous liquid.
It is for intramuscular injection only.
It should be used in severe iron-deficiency anaemia where oral therapy is ineffective.
It should be not used in a prophylactic manner.
Dose : Intramuscular, the equivalent of 100mg of iron once a day.

23. Parenteral Iron Preparations:
Iron Sorbitex Injection:
It is a sterile solution of a complex of iron, sorbitol and citric acid that is stabilized the aid of dextrin and an excess of sorbitol.
pH should be between 7.2 and 7.9
It is administered intramuscularly.
Dose: Intramuscular, the equivalent of 100mg of iron once a day.

24. Toxicity of Iron
Human lethal dose is considered to be 150 to 200 mg iron / kg body weight.
Iron poisoning occurs in three to four stages.
Stage one begins 30 to 40 minutes after ingestion and includes gastrointestinal distress due to the astringent action of ionized iron, developing into cardiovascular collapse, shock and possible death in 6 hours.
In stage two recovery seems apparent and may continue for 10 to 14 hours.

25. Toxicity of Iron
Stage three may then develop with a recurrent cardiovascular collapse, convulsions, respiratory problems, metabolic acidosis, shock, coma, liver damage and possible death occurring in one to three days.
If the patient survives stage four may occur one to two months later with gastrointestinal complications due to necrotizing effect (cell death) of the iron.
Treatment - gastric lavage and administration of salts (sodium bicarbonate and sodium dihydrogen phosphate) to form insoluble iron salts.
- Oral administration of deferoxamine will prevent iron absorption. Deferoxamine can be given parenterally to chelate iron and allow it to pass out in the urine.

26. Reference Book
Inorganic Medicinal & Pharmaceutical Chemistry- Block & Wilson.
Bentley and Driver’s Textbook of Pharmaceutical Chemistry.
Remington’s Pharmaceutical Sciences.