Drug Treatment of Anemia

DR. B.K. Mishra DEPTT. OF PHARMACOLOGY,H.I.D.S.G-NOIDA

Drug Treatment of Anemia Synopsis Rational use of haematinic drugs is essential to the correction of anemia in its various forms. The emergence of haemopoietic growth factors as drugs that stimulate erythroid or myeloid cell lines has opened the way to successful management of other forms of hematological disease Iron:- therapy, acute overdose Vitamin B12 Folic acid Haemopoietic growth factors Sickle cell anemia Polycthaemia rubra vera Aplastic anaemia

The haemopoietic system Main components are Blood Bone marrow Lymph nodes Thymus With the spleen, liver and kidney as important accessory organs. Blood consist of formed elements Plasma Important site of formation of RBC in adult is bone marrow where as spleen acts as their graveyard. Liver stores vitamin B12 and kidney manufactures erythropoietin

 Anemia Defined as reduce concentration of hemoglobin in the blood and is characterized by decrease in the oxygen carrying capacity of the blood Depending upon the indices of red cell size, hemoglobin content and microscopical examination of stained blood smear, it is classified as Hypochromic micro-cytic anemia (small red cells with low hemoglobin caused by iron deficiency). Macro-cytic anemia (large cells, few in number) Normo-chromic normo-cytic anemia (fewer normal sized red cell, each with a normal hemoglobin content). Mixed pictures.

Anemia can also be classified according to their etiology as i). Anemia due to dietary deficiency or malabsorption of factors essential for normal blood formation e.g. iron, folic acid vitamin B12 vitamin C. and pyridoxine. ii). Anemia due to blood loss e.g. menorrhagia, G.I. loss and hookworm infestation. iii). Anemia due to excessive blood destruction e.g. thalassemia, sickle cell anemia auto immune haemolytic anemia. iv). Anemia due to aplasia or hypo- plasia of the bone marrow e.g. anticancer drugs, chloramphenical. v). anemia due to deficiencies of erythropoietin e.g. chronic renal disease. vi). Anemia of unceratain origin e.g. infection, rheumatoid arthritis, liver disease. Note:The use of haematinic agent is often only an adjunct to treatment of the underlying cause of the anemia. Sometimes, we have to stop an offending drugs.

 Haematinic agents: These are the agents required in the formation of blood, and are used for treatment of anemia. Iron: Its deficiency is most common cause of chronic anemia. Its deficiency leads to Pallor Fatigue Dizziness Excertional dyspnoea Other generalized symptoms of tissue hypoxia Blood Picture:- Micro-cytic hypochromic anemia.

 Iron kinetics: Absorption takes place predominantly in the duodenum and proximal jejunum where the acid environment enhances its solubility. Most iron in food is present as ferric hydroxide, ferric protein complexes or haeme protein complex. Ferrous iron is more readily absorbed than ferric. Simultaneous ingestion of a reducing agent (as ascorbic acid) increases the amount of the ferrous form. Food reduces iron absorption due to inhibition by phytates, tannates phosphates. The body of 70 kg man contains 4g of iron , 65% of which circulates in the blood as haemoglobin Menstrual loss of iron is about 30mg/period; menstruating women may therefore be in negative iron balance.

The distribution of iron in the body of a healthy 70 kg Male

Protein Haemoglobin Myoglobin Tissue
Erythrocytes Muscles

Iron content (mg)

2600 400 25 8 410 48 300

Enzymes (Cytochromes, Liver and other tissues catalase) Transferrin

Plasma and extra cellular fluid

Ferritin and hemosiderin Liver

spleen bone marrow

 The normal daily requirement for iron is approximately 5mg for men and 15mg for growing children and for menstruating woman and ten fold for pregnant lady Iron is available in a wide variety of food but especially abundant in meat. Iron in other foods are present as nonheme iron and must be reduced to ferrous iron (F2+) before it can be absorbed by intestinal mucosal cells.

 Transport: Transported in the plasma bound to transferrin, a globulin that specifically binds two molecules of ferrous iron . Hence iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin. Storage: In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in the liver ,spleen and bone and in parenchymal liver cells. Ferritin is detectable in serum; since the ferritin present in serum is in equilibrium with storage ferritin in reticulo endothelial tissues. The serum ferritin level can be used to estimate total body iron stores

 Elimination.: No mechanism for excretion of iron Small amount are lost in the feces by exfoliation of intestinal mucosal cell, and trace amounts are excreted in bile, urine and sweat . Total loss account for no more than 1 mg of iron per day.

Factors affecting iron absorption:Type of iron In man, food iron must be reduced to ferrous form before it is absorbed Reducing agents present in the diet:- example ascorbic acid, succinate ,they convert ferric to ferrous forms, and helps iron absorption. A diet poor in phosphorus ehances iron absorption Antacids such as calcium carbonate, aluminum hydroxide, magnesium hydroxide reduce iron absorption Other drugs:- like tetracycline, levodopa, fluroquinolones interfere with iron absorption. Administration of iron along with or after food reduces its absorption In conditions like chronic pancreatitis and liver cirrhosis, iron absorption is increased. Pica :- iron deficiency can promote appetite for bizarre foods if clay is consumed (geophagia), there occurs chelation of iron in gut , worsening the iron deficiency.

 Indications for the use of iron: Indicated for treatment or prevention of iron deficiency anemia seen in premature infants. Child during rapid growth period Pregnant and lactating women Patient with chronic kidney disease. Inadequate iron absorption. Blood loss Menstruation G.I. Tract

 Iron therapy: The goal is to repair the haemoglobin deficit and replenish storage iron Iron deficiency anemia is treated with oral or parenteral iron preparations. Oral iron preparation: Enormous variety of official and proprietary iron preparations are available. Ferrous sulphate is more effective. A small dose is given at first and increase after a few days Objective is to give 100-200mg of elemental iron/day (3mg/kg in a child) Iron given on a full stomach and causes less gastro intestinal upset.,if daily dose does not exceed 180mg elemental iron

 Commonly used preparation; give in divided doses include Ferrous sulphate tab, 200-400mg/day (Providing 67-195mg/d of elemental iron) Ferrous gluconate tabs, 300-1200mg daily (providing 35-140mg /day of elemental iron) Ferrous fumerate tab 200-600mg daily (providing 130-195mg/day of elemental iron). Various other forms are also available. Adverse effects: common adverse effects of oral iron therapy includes
nausea epigastric discomfort abdominal cramps constipation and diarrhea

Usually dose related and can be over come by lowering the dose. Patients taking oral iron develops black stool.

Failure of oral iron Therapy:Due to Poor patient compliance Persistent bleeding Wrong diagnosis Iron can not be absorbed from the intestine The patient can not be relied on to take its or Experiences intolerable Gut symptoms This includes patient with various post gastrectomy conditions and previous small bowel resection, inflammatory bowel disease, malabsorption syndromes ,advance chronic renal disease including hemodialysis and treatment with erythropoietin.

 Parenteral iron therapy: This needs calculation of total Iron requirement (mg) of the patient =4.4xbody wt (kg)x Hb deficit (g/dl) Intra.muscular iron:- iron sorbitol injection (50mg of iron/ml) is an iron sorbital citric acid complex. Rapidly absorbed Stored in marrow and liver and bound to plasma globulin. Excess unbound excreted in urine (about 30% of dose), when may turn black transiently at the time peak iron excretion or only on standing for some hours. Given deep IM , daily or on alternate days. By Ztechnique

 Intravenous Iron: Iron dextran injection (ferric hydroxide complexed with dextran; 50mg/ml) and iron sucrose injection (Ferric hydroxide complexed with sucrose; 20mg/ml) Administered by slow IV Not recommended for children IV route eliminates local pain and tissue staining. Note: Oral iron therapy should not be given 24 hours before I/ M injection begin, for 5day after the last I/V injection as it may promote adverse reactions. Adverse effects: Headache, light headedness, nausea, vomiting, myalgia, pressure sensation in the chest, hypotension, bronchospasm, and rarely anaphylaxis and death

 Clinical Toxicity: Acute iron toxicity: Almost exclusively seen in young children who accidentally ingest iron tablets. 10 tablet of any commonly available oral preparations can be lethal in young children Ferrous sulphate is the most toxic Young children poisoned with oral iron experience necrotising gastro-enteritis with Vomiting , abdominal pain, and bloody diarrhoea followed by shock , lethargy and dysponea, then ultimately followed by severe metabolic acidosis ,coma and death.

 Treatment should be prompt To prevent further absorption of iron from gut: Do whole bowel irrigation or gastric lavage with sodium bicarbonate solu-to render iron insoluble, give egg, yolk and milk orally to complex iron. To bind and remove iron already absorbed: Des- ferrioxamine injected IM 0.5-1g (50mg/Kg)repeated 4-12 hourly required or IV (if shock is present ) 10-15 mg/kg/hours; max 75mg/kg in a day till serum iron falls below 300g /dl.

Supportive measures:maintain fluid and electrolyte balance correct acidosis support BP and respiration if convulsions occurs, give diazepam IV Chronic iron toxicity:also K/a Hemochromatosis occurs when excess iron is deposited in heart, liver, pancreas, and other organs. Can lead to organ failure and death Commonly occurs in patients with inherited hemochromatosis and in patients who receive may red cell transfusions over a long period time Treated by:Intermittent phlebotomy but anemia should be absent If above, can not maintain then given des-ferrioxamine. Another alternative deferasirox

Vitamin B12: Serve s as a co-factor for several essential bio-chemical reactions in human. Deficiency leads to anemia, G.I symptoms, and neurological abnormalities. The chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver),eggs, and dairy products. Vitamin B12 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein normally secreted by the stomach. The vitamin is avidly stored, primarily in the liver, with an average adult having a total vitamin B12 storage pool of 3000-5000 mcg. Only trace amounts of vitamin B12 are normally lost in urine and stool. Because the normal daily requirements of vitamin B12 are only about 2mcg. It would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if B12 absorption stopped. Vitamin B12 in physiologic amounts is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Vitamin B12 deficiency in humans most often results from malabsorption of vitamin B12 due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum.

 Pharmacodynamics: Two essential enzymatic reactions in humans require vitamin B12

In one, methylcobalamin serves as an intermediate in the transfer of a methyl group from N5-methyltetrahydrofolate to homocysteine, forming methionine Without vitamin B12, the precursor of folate cofactors cannot occur. As a result, a deficiency of folate cofactors necessary for several biochemical reactions involving the transfer of one-carbon groups develops. In particular, the depletion of tetrahydrofolate prevents synthesis of adequate supplies of the deoxythymidylate (dTMP) and purines required for DNA synthesis in rapidly dividing cells. This is the biochemical step whereby vitamin B12 and folic acid metabolism are linked, and it explains why the megaloblastic anemia deficiency can be partially corrected by ingestion of relatively large amounts of folic acid. The other enzymatic reaction that requires vitamin B12 is isomerization of methylmalonyl CoA to succinyl CoA by the enzyme methylamalonyl CoA mutase .

 In vitamin B12 deficiency, this conversion cannot take place, and the substrate, methylmalonylCoA, accumulates. The important point is that administration of folic acid in the setting of vitamin B12 deficiency will not prevent neurologic manifestations even though it will largely correct the anemia caused by the vitamin B12 deficiency.

Clinical Pharmacology:The most characteristic clinical manifestation of Vitamin B12 deficiency is megaloblastic anemia. Clinical findings are macrocytic anemia, with leucopenia or thrombocytopenia a characteristic hypercellular bone marrow. The neurologic syndrome begins with paresthesias and weakness in peripheral nerves progresses to spasticity, ataxia, and other central nervous system dysfunctions. Once a diagnosis of megaloblastic anemia is made,determine whether vitamin B12 or folic acid deficiency is the cause. This can usually be accomplished by measuring serum levels of the vitamins. The Schilling test which measures absorption and urinary excretion of radioactively labeled vitamin B12, can be used to further define the mechanism of vitamin B12 malabsorption Common causes of vitamin B12 deficiency are pernicious anemia, partial or total gastrectomy, malabsorption syndromes, inflammatory bowel disease, or small bowel resection.

Pernicious anemia:Pernicious anemia result from defective secretion of intrinsic factor by the gastric mucosal cells. Patients with pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as well as hydrochloric acid). Other rare causes of vitamin B12 deficiency include bacterial over growth of the small bowel, chronic pancreatitis, and thyroid disease. Parenteral injections of vitamin B12 are required for therapy For patients with potentially reversible diseases, the under lying disease should be treated after initial treatment with parenteral vitamin B12. Initial therapy should consist of 100-1000 mcg of vitamin B12 intramuscularly daily or every other day for 1-2 weeks to replenish body stores. Maintenance therapy consists of 100-1000 mcg intramuscularly once a month for life. If neurologic abnormalities are present, maintenance therapy injections should be given every 1-2 weeks for 6 months before switching to monthly injections.

 Folic Acid: Also k/a pteroylglutamic acid So named because it was discovered as a bacterial growth factor present in spinach leaves. One of the B-group vitamins Reduced forms of folic acid are required for essential bio-chemical reactions, that provide precursors for synthesis of amino acids, purines, and DNA.

 Functions: It self inactive, converted into the biologically active coenzyme, tetra hydrofolic acid. Tetrahydrofolic acid is important in the biosynthesis of amino acids and DNA and therefore in cell division. The formyl derivative of tetrahydrofolic acid is folinic acid and this is used to bypass the block when the body fail to effect the conversion of folic acid. Deficiency:- leads to megaloblastic anemia.

 Occurrence and requirements: Widely distributed, especially in green vegetables, yeast and liver Adult daily requirement = 50-100g Child daily requirement = 50 g Body stores last about 4months.

 Pharmacokinetics: Richest sources are yeast, liver kidney, and green vegetables . Normally, 5-20mg of folates are excreted in the urine and stool and are also destroyed by catabolism, so serum levels fall within a few days when intake is diminished. Because body stores of folates are relatively low and daily requirements high, folic acid deficiency and megaloblastic anemia can develop within 1-6 months after the intake of folic acid stops. Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Inside cells, N5 methyltetrahydrofolate is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12.

Indications:It is used to prevent or cure deficiency of folate which are due either to a decreased supply or to an increased requirement. Dietary deficiency :- commonest cause in india Due to increased requirement- as pregnancy. - increased demand for folic acid is also observed in hyperthyroidism, rheumatoid arthritis, leukemia, hemolytic anemia, chronic infections Prevention of fetal neural tube defects (spina bifida) Folic acid supplementation is taken before conception and during early week of pregnancy.

 Women hoping to conceive and had affected child are given folic acid =5mg/day. To prevent 1st occurrence = 400 g/day should be taken before conception or as soon as possible after diagnosis. Taken for the first 12 weeks of pregnancy. Premature infants. Drugs: Anti-epilepsy drugs, particularly phenytoin, primidone and Phenobarbital, causes a macrocytic anemia; they responds well to folic acid. Anti- malarials as pyrimethamine, causes macro-cytic anemia.

 Contra- indication: - imprecisely diagnosed megaloblastic anemia. Haemopoietic growth factors: Stimulate both erythroid and myeloid cell lines. Potentially useful when ever there is cytopenia, whether due to disease or to cyto toxic chemotherapy. Erythropoietin: Mainly produced in kidney in response to hypoxia. Principal action to stimulate the proliferation, survival and differentiation of erythrocyte precursors. Anemia of chronic renal failure is largely d/t failure of the diseased kidney to make enough erythropoietin.

 Epoetin must be given S.C. or I/V. T1/2=4hours Self administration three times a week, dose adjusted by response. Two preparations are available- epoetin alpha and epoetin beta Effective in the anemia of chronic renal failure Rheumatoid arthritis Prematurity Cancer chemotherapy Zidovudine treated AIDS Adverse effects:- rise in BP and encephalopathy may occur in some hypertensive patient.