The below mentioned article provides a note on antianemic drugs.
These are the agents required in the formation of blood, and are used for the treatment of anemias.
Anemia occurs when the balance between production and destruction of RBCS is disturbed by:
(i) Blood loss (acute or chronic).
(ii) Impaired R.B.C. formation due to
(a) Deficiency of essential factors
(i) Iron (iron deficiency anemia)
(ii) Copper
(iii) Cobalt
(iv) Vitamin B12 (megaloblastic anemia)
(v) Folic acid (megaloblastic anemia)
(b) Bone marrow depression (hypo-plastic/aplastic anemia)
(iii) Increased destruction of RBC ( hemolytic anemia).
Classification of Anemias:
Etiologically anemia may be classified into four main groups:
(i) Blood loss anemia,
(ii) Hemolylic anemia,
(iii) Hypoplastic anemia, and
(iv) Nutritional anemia.
In former two forms, the total R.B.C. production is increased, while in hypoplastic anemia it is decreased.
(i) Blood Loss Anemia:
Blood loss may be acute, sub-acute, or chronic. After an acute blood loss due to haemorrhage, body replaces plasma within 1-3 days, but the PCV (packed cell volume) and haemoglobin content remain low. The R.B.C. concentration returns to normal within 7-21 days after a single hemorrhage.
In chronic blood loss, the patient often cannot absorb enough iron from intestine to form haemoglobin as rapidly as it is lost. So, R.B.C. are produced with low hemoglobin content (microcytic hypochromic anemia). The regulation of R.B.C. has been depicted in Fig. 18.13.
(ii) Hemolytic Anemia:
In domestic animals, hemolytic anemia is very common and occurs due to blood parasites (Anaplasma, Babesia, Haemobartonella and Eperthrozoon), bacterial (Leptospira, and Clostridium haemolyticum) and viral (equine infectious anemia virus,) infections, exposure of chemical agents (arsenic, lead, copper, snake venum, drugs, etc.) several poisonous plants (bracken fern), metabolic diseases (postparturient hemoglobinurea), etc. The PCV and haemoglobin content remain unaltered during hemolytic anemia.
(iii) Hypoplastic Anemia:
In bone marrow dysfunction, hypoplastic or aplastic anemia may occur. Here, the synthesis of RBC, along with other blood cells (WBC and platelets), is decreased.
The causes of hypoplastic anemia include irradiation, some drugs (chloramphenicol, phenothiazines, sulfonamides, combination of tetracycline and penicillin, acetophenetidin), some toxic chemicals (arsenicals, DDT, chlordane, lindane), plants (bracken fern), etc.
(iv) Nutritional Anemia:
Nutritional anemia occurs due to deficiency of minerals (iron, copper or cobalt) or vitamins (vitamin B12 or folic acid). Iron deficiency anemia is most common in baby pigs (microcytic-hypochromic) and in calves. Deficiency of either vitamin B12 or folic acid results in megaloblastic and macrocytic anemia.
Antianemic Agents:
Iron, vitamin B12 and folic acid are the most common clinically used anti-anemic agents. Androgenic anabolic steroids are also considered as the most useful nonspecific stimulants of RBC production.
Iron:
Iron is recommended to be used clinically only to treat and in some cases, to prevent iron deficiency. It should not be used in normal iron content of the body just to improve appetite, to increase breeding efficiency, or to promote growth; because indiscriminate administration of iron may cause iron toxicosis or iron storage disease.
The major portion of iron in the body stores is found in hemoglobin.
The distribution of iron in the body is:
Haemoglobin-about 66%
Iron stores as ferritin and hemosiderin-about 25%
Myoglobin (in muscles)-about 3-7%
Parenchymal iron (as constituents of enzymes, etc.) -about 6%
Plasma transferrin – about 0.1%
In most species of animals and human, ferrous (Fe++), salts are more readily absorbed in GI tract than ferric (Fe+++) salts. In chicken and rats, oral absorption of both are almost similar.
Dietary sugars (fructose and sorbitol), several amino acids and some organic acids (citric acid, ascorbic acid, lactic acid and succinic acid) enhance the absorption of iron from GIT by increasing its solubility. Pancreatic secretions, phosphates, oxalate, bicarbonate, and certain drugs (e.g., tetracyclines) inhibit the absorption of iron from GIT.
Factors like haemorrhage, ascent to high altitudes, and tissue hypoxia tend to increase the rate of erythropoiesis and thereby iron absorption, Large doses of radiation and an oversupply of RBC (as with multiple transfussion) reduce the rate of erythropoiesis and iron absorption.
Iron is stored in ferric form only, in combination with a large protein, apoferritin. It is stored as ferritin and hemosiderin in the bone marrow, liver and spleen. When blood is lost from the body, this stored iron is utilized for the synthesis of haemoglobin.
Internal transportation of iron is mediated by a plasma transport protein, transferrin. Transferrin receptors on cell membranes mediate endocytosis of the transferrin-iron complex. During pregnancy (especially in the last two trimesters) animals lose a remarkable amount of iron which are utilized for the development of foetus. The pathway of iron metabolism has been explained in Fig. 18.14.
Therapeutic Aspects:
There are a number of ferrous and ferric salt forms available in the market for oral use. The absorption of ferrous salt forms is nearly three fold better than the ferric forms. The bioavailability of all ferrous forms are almost same. Ferrous sulphate, which contains about 20% elemental iron, is the drug of first choice in iron deficiency anemia.
Ferrous fumarate (33% elemental iron) is generally found in multivitamin-mineral mixtures. Ferrous gluconate (12% elemental iron), ferrous lactate and ferrous choline citrate are the other ferrous salt forms for oral use. Different orally recommended ferric salts for animals are ferric chloride, citrochloride, pyrophosphate, and ammonium citrate.
Doses of Ferrous Sulphate: (Oral Doses)
Cattle- 8-15 g, daily for 2 weeks or more.
Horse- 2-8 g, daily for 2 weeks or more.
Sheep, Goat, Pig-0.5-2 g, daily for 2 weeks or more.
Dog – 60-300 mg, daily for 2 weeks or more.
Cat – 30-200 mg, daily for 2 weeks or more.
Parenteral iron is used clinically when a patient is either unable to take it orally or is suffering from malabsorption syndrome. Iron-dextran, ferric hydroxide-poly-maltose complex (used to treat anemia of pigs), and colloidal ferric oxide are some parenteral preparations.
Iron-dextran is used most commonly. It is a complex of ferric hydroxide (Fe(OH)3] and low-molecular weight dextran. One ml of iron-dextran contains 50 mg of elemental iron. Iron-dextran is phagocytized by R.E. cells, wherein it is splitted to form free iron. It should be used i.v. (not i.m.)
Adverse Effects:
(i) Prolonged use of large doses of iron orally may lead to mucosal block of its absorption. Clinical signs in overdoses are nausea, diarrhoea, constipation, heartburn, etc.
(ii) Intramuscular injection of iron-dextan produces serious local reactions, discomfort, discoloration, because about 50% of the drug remains fixed at the injected site.
(iii) Anaphylactic reactions may also occur in some individuals after parenteral use of iron-dextran.
(iv) Headache, fever, arthralgias, and lymphadenopathy may also occur by the injectable preparations.
(v) Acute excessive oral dose of iron causes iron toxicosis in animals.
Clinical signs of iron toxicosis in baby pigs are pale skin, dark feces, bloody diarrhoea (due to corrosion on the mucosa), tachycardia, arterial hypotension, dyspnoea, shock, etc.
Folic Acid: (Pteroylgulatamic Acid):
Green vegetables, yeast and liver are the richest sources of folic acid. It is also present in a wide range of foods. In foods, folic acid is present in the reduced poly-glutamate form, whereas pteroylglutamic acid (mono-glutamate) is the common pharmaceutical form of folic acid.
Folic acid is completely absorbed from the small intestine, and has enterohepatic cycle. The poly-glutamate form of folic acid is converted to the mono-glutamate (folic acid) by a mucosal cell membranous enzyme, pteroyl-γ-glutamyl carboxypeptidase.
The mono-glutamate is converted, in a two step reaction, to dihydrofolate (FH2) and then to tetrahydrofolate (FH4) by dihydrofolate reductase within the mucosae of duodenum and upper part of the jejunum.
Tetrahydrofolate, which serves as a coenzyme for one carbon transfer reactions is methylated in this area of GI tract, absorbed into the blood and rapidly transported to tissues.
Some of them bind to the specific folate-binding protein in plasma. The liver actively reduces and methylates folic acid (and FH2 or FH4) and then transports the methylated tetra-hydrofolate (CH3 FH4) into bile for reabsorption by the gut and subsequent delivery to tissues.
Functions of Folic Acid:
(i) Synthesis of thymidylate from deoxyuredylate, thereby synthesis of DNA.
(ii) Synthesis of Purines.
(iii) Formation of methionine from homocysteine.
(iv) Histidine metabolism.
(v) Conversion of serin to glycine.
(vi) Utilization or generation of formate.
Folate deficiency may result from the following reasons:
(i) Inadequate dietary intake.
(ii) Disease in jejunum and duodenum (decreases folate absorption).
(iii) Defect in folate enterohepatic circulation.
(iv) Drugs (methotrexate, trimethoprim, anticoagulants and contraceptives).
The megaloblastic anemia is the fate of folate deficiency and develops more rapidly than with vitamin B12 deficiency. Unlike the latter one, there is no neurologic abnormality associated with folate deficiency. Folic acid is indicated either orally or parenterally (in acute case, i.m., i.v. or s.c. injection) to treat uncomplicated megaloblastic anemia resulting from folate deficiency.
Vitamin B12 (Cyanocobalamin):
This is a cobalt-containing vitamin required by cells throughout the body for conversion of ribose neucleotides into deoxyribose neucleotides, a major step in the formation of DNA. Therefore, the vitamin is required for normal nuclear maturation and cell division, and its deficiency results in general depression of cellular development and tissue growth.
Since the erythropoitic centers of bone marrow are among the most rapidly growing and proliferating tissues, the deficiency of vitamin B12 is specially manifested by the decrease in RBC production and defective maturation of red cells (megaloblasts and macrocytes).
In domestic animals, the vitamin B12 deficiency is not commonly found. The microorganisms, present in rumen of adult ruminants and intestine of many nonruminants, synthesize the total amount of vitamin B12 needed. On the other hand, in humans, though bacteria of colon can produce the vitamin but it can not absorb there.
Therefore, humans must obtain the vitamin from the dietary intake of meat, egg, dairy products, or vegetables. The dietory shortage of cobalt, which is needed by ruminal organisms to synthesize vitamin B12 can result in an indirect deficiency of the vitamin in ruminants.
In humans, the deficiency of the vitamin B12 also develops secondarily from inadequate absorption of the vitamin from GIT, due to failure of gastric mucosa to produce “intrinsic factor.”
Intrinsic factor, a glycoprotein produced by the gastric parietal cells, binds with dietory vitamin B12 (extrinsic factor) in the GIT. The vitamin B12intrisic factor complex acts on the specific receptors on ileal muscosal cell membrane and is transported by pinocytosis into the intestinal epithelial cells and then into the blood.
The absorbed vitamin is stored in large quantities in the liver and is utilized as and when required. Intrinsic factor is not needed for absorption of vitamin B12 in dogs and cats. Once in the circulation, vitamin B12 is transported to the tissues by a plasma β-globulin, “transcobalamin II”.
The deficiency of vitamin B12 may develop due to following reasons:
(i) Inadequate secretion of intrinsic factor.
(ii) Congenital absence of transcobalamin II.
(iii) Interference with the reabsorption of vitamin <$E roman B sub 12>, which is excreted through bile (enterohepatic cycle).
(iv) Insufficient dietary supply of cobalt to ruminants.
(v) Inadequate dietary intake of vit B12 in human, although rare.
(vi) Intestinal disorders including ileal diseases, gastric surgery, etc.
Fate of vitamin B12 deficiency:
(i) Megaloblastic anemia.
(ii) Pancytopenia may also be found because the production of all blood cells are decreased.
(iii) Demyelination and cell death, which may result in irreversible damage to the CNS.
Oral vitamin B12 preparations are available in the market and are indicated in uncomplicated deficiency cases. If a patient lacks intrinsic factor or has ileal disease, the parenteral route (deep i.m. or s.c. but never i.v.) should be opted for administration of vitamin B12. The oral combinations of vitamin B12 and intrinsic factor is not reliable.
Androgenic-Anabolic Steroids:
Stanozolol, oxymetholone, testosterone enanthate, boldenone undecylenate are the clinically important androgenic-anabolic steroids (AASs). AASs are considered the most useful nonspecific stimulants of RBC production. They increase the formation of erythropoietin by the kidneys and perhaps directly accelerate heme synthesis and red cell proliferation.
These compounds are widely used in the management of various forms of anemias, including hemolytic anemia, aplastic anemia, red cell aplasia, and anemias associated with renal failure, leukemia, lymphoma and myeloid metaplasia.
Antianemic Preparations:
A large number of multivitamin-multi-mineral mixtures (Dexorange, Caldisol plus, Cal-D-Rubra, Equi-blud, Nutriforte, etc), are available in the market for use in animals as hematinics.
These preparations are also claimed to improve feed intake, feed efficiency and growth and to act as alterative. If a deficiency is diagnosed, the clinician should recommend only the deficient substance rather than a multicomponent preparation that contains unneeded ingredients.