Anti anaemic Drugs Dr. Saeed Ahmed Department of Pharmacology KSU

1. Anti anaemic DrugsDr. Saeed Ahmed Department of PharmacologyKSU

2. Anti anaemic Drugs • Haematopoiesis: it is the production of erythrocytes, platelets, and leukocytes from undifferentiated stem cells. • The haemtopoietic machinary reside in the bone marrow in adults. • It requires a constant supply of essential nutrients – iron, vit B12, folic acid and presence of hematopoietic growth factors

3. Anti anaemic Drugs • Anemia: anemia is a common clinical condition that is caused by an acquired or hereditary abnormality of RBCS or it precursor, or it may be a manifestation of an underlying non hematologic disorder. • Anaemia is defined as a decrease in the circulating RBC mass; the usual criteria are a Hb of less than 12G/dl in women and less than 14G/dl in men.

4. Anti anaemic Drugs • Signs and Symptoms: • Patients with an Hb less than 7G/dl will have symptoms of tissue hypoxia( fatigue, headache, dyspnea, pallor, angina, tachycardia, visual impairment, syncopy, lymphadenopathy,hepatic and or splenic enlargement, bone tenderness, blood loss in feces, neurologic symptoms.

5. Anti anaemic Drugs • Classification of anaemia: • Anaemia associated with decrease RBC production for e.g.. • A) iron deficiency anemia, b. megalobl.anemia, c. Thalassemia, d. anemia due to chronic disease and renal failure. • Anemia due to increased RBC destruction: • Haemolytic anaemia, sickle cell anemia

6. Anti anaemic Drugs • Iron: Total quantity of iron in the body is 4-5G, 65-70% in the form of Hb in RBC, 4% in myoglobin, 1% in various heme compound, 15-30% stored in the form of ferritin and hemosiderin in RE system, liver, spleen, intestinal mucosa and bone marrow

7. Anti anaemic Drugs • Iron is required for Hb production, in the absence of adequate iron, small red cells with insufficient Hb are formed, giving rise to microcytic hypochromic anaemia. • Vit B12 and folic acid are required for normal DNA synthesis. Deficiency of either of these vitamins results in impaired production and abnormal maturation of RBCS giving rise the characteristic blood and bone marrow picture known as megaloblastic anaemia.

8. Anti anaemic Drugs • Erythropoeitin and colony stimulating factors are hormones that regulate blood cell development and proliferation in the bone marrow. • Chief source of iron is meat. • Iron deficiency occur due to (a) inadequate dietary intake as in vegetarians, malnourished pts. (b) due to blood loss a in women in heavy menstruation (c) when iron requirement is increased as in pregnancy and in growing children. • ه

9. Anti anaemic Drugs • Iron forms heme, which combined with proteins globinand form hemoglobin, Hb binds oxygen(in the lungs) and transport it in the tissues.

10. Anti anaemic Drugs • Iron preparation: • 1. Oral iron, 2. Parenteral iron • 1. oral iron • A) Ferrous sulfate - 325mg - 65mg elementaliron • B )Ferrous gluconate - 320mg -37mg elem.iron • C) Ferrous fumarate - 325mg - 106mg elem.iron • 2. Parenteral iron: iron dextran 50mg elem.iron/ml

11. Anti anaemic Drugs • Pharmacokinetics: • Absorption: iron( Fe++) absorb from duodenum and upper jejenum →Fe+++ (ferric) in the intestinal mucosal cell. • Ferric iron binds with transferrin in plasma and transported in other tissues and stored as ferritin and hemosiderin form. • About 10 -20% of dietary iron is absorbed, for e.g. a standard diet if contain 10-15mg of iron, only 1mg is absorbed. Absorption ↑when iron requirement is ↑ as in pregnancy, menstruation, growing children

12. Anti anaemic Drugs • Distribution: ferric from iron store sites through transferrin goes in the RBCS. • This complex bind with receptor on developing red cells in B. marrow, iron released in the cell, transferrin and transferrin receptor are then recycled, providing an efficient mechanism for incorporating iron into hemoglobin in developing cells

13. Anti anaemic Drugs • Storage: ferritin and hemosiderin form in mucosal cells, liver, spleen, and bone marrow • Elimination: minimal amount (about 1mg/day) are lost in sweat, saliva, and in exfoliated skin and intestinal mucosal cell. • Clinical use of iron: • Iron deficiency anaemia is the only indication for the use of iron

14. Anti anaemic Drugs • Iron deficiency is commonly seen in premature infants, children during rapid growth, pregnant and lactating mothers, patients with small bowel disease that results in generalized malabsorption. • The most common cause of iron deficiency anaemia in adults is blood loss. • As iron deficiency develops: storage iron decreases and then disappears, serum ferritin decreases, then serum iron decrease, TIBC ↑.

15. Anti anaemic Drugs • 200- 400mg oral elemental iron daily should be given to correct anaemia (25% absorbed ,so 50-100mg iron can be incorporated in Hb). • Treatment should be continue for 3-6 months, this not only correct the anaemia but will replenish iron stores. (Hb should reach normal level in 1-3 months). • Failure to respond to oral iron therapy may be due to incorrect diagnosis.

16. Anti anaemic Drugs • Adverse effects: • Due to oral iron therapy; • Nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea, black stool. • They may be minimized by lowering the daily dose or by taking iron tablets immediately after or with meals.

17. Anti anaemic Drugs • Parenteral iron therapy: • 1. It should be reserved for patients with documented iron deficiency unable to tolerate or absorb iron ( pts. With post gastrectomy, previous small bowel resection, malabsorption syndrome. • 2. Pts. With extensive chronic blood loss who can not be maintained with oral iron alone.

18. Anti anaemic Drugs • Iron dextran (ferric hydroxide + dextran), 50mg elemental iron/ml • Route of administration: I/M, or by I/V infusion in 1-2 hours. • Most adults needs about 1-2 G (20-40ml) iron dextran for iron deficiency anaemia. • Test dose : test dose of small amount should be given before I/M or I/V

19. Anti anaemic Drugs • Adverse effects: • Local pain, tissue staining( brown discoloration of tissues overlying the inj. site), headache, fever, arthralgia, nausea, vomiting, bronchospasm, urticaria, anaphylaxis, and death • Iron toxicity: it is seen in young children who have ingested a no. of iron tablets( more than 10 tablets). Adults are able to tolerate large doses of iron.

20. Anti anaemic Drugs • Large amount of oral iron cause; • Necrotizing gastroenteritis, vomiting, abdominal pain, bloody diarrhea, dyspnea, metabolic acidosis, coma and death. • Treatment of acute toxicity: • Whole bowel irrigation should perform • Deferoxamine, potent iron chelating, it binds iron that has already been absorbed and to promote its excretion in urine and feces

21. Anti anaemic Drugs • Supportive therapy for GIT bleeding , metabolic acidosis and shock • Chronic toxicity: known as hemochromatosis, when excess iron is deposited in heart, liver, pancreas and other organs cause organ failure and death. • It occurs in patients with inherited hemochromatosis (excessive iron absorption in pts. Who receive many red cell transfusions for long period

22. Anti anaemic Drugs • Treatment: intermittent phlebotomy, 1 unit of blood removed/weekly • Iron chelating agent ( deferoxamine i/v) • Deferoxamine: • It is poorly absorbed when given orally and may increase iron absorption by this route • It is given I/M or preferably I/V • It is metabolized and excreted in urine (turn urine color orange red).

23. Anti anaemic Drugs • Adverse effects: • Rapid I/V administration → hypotension • Idiosyncratic response such as flushing, erythema, intestinal irritation, urticaria • Acute respiratory distress syndrome may occur if I/V infusion lasting longer than 24 hours • Neurotoxicity after long term therapy of iron overload condition

24. Anti anaemic Drugs • VITAMIN B12 • Vitamin B12 ( cobalamine), a cobalt containing molecule is along with folic acid, a cofactor in the transfer of 1- carbon units, a step necessary for the synthesis of DNA. • Impairment of DNA synthesis affects all cells, but because red blood cells must be produced continuously, deficiency of either vitaminB12 or folic acid usually manifests first as anaemia (megaloblastic anaemia)

25. Anti anaemic Drugs • In addition Vit. B12 deficiency can cause neurologic defects, which may become irreversible if not treated promptly • Pharmacokinetics: Vit B12 is produced only by bacteria. It is absorbed from the GIT in the presence of intrinsic factor, a product of the parietal cells of the stomach. • Plasma transport is accomplished by binding to transcobalamin II.

26. Anti anaemic Drugs • Vit B12 is stored in the liver in large amounts; a normal individual has enough to last 5 years. • It is available in 2 forms • 1. cyanocobalamine, 2. hydroxy cobalamine has a longer circulating half life. • Pharmacodynamics: • Vit B12 IS ESSENTIAL IN 2 REACTIONS:

28. Anti anaemic Drugs

29. Anti anaemic Drugs • Conversion of methyl malonyl – coenzyme A(co A to succinyl – co A, and conversion of homocystein to methionine. • The second reaction is linked to folic acid metabolism and synthesis of deoxythymidylate (d TMP), a precursor required for DNA synthesis

30. Anti anaemic Drugs • In Vit B 12 deficiency , folates accumulates as N – methyl tetrahydrofolate, the supply of tetrahydrofolate is depleted; and the production of RBCS slows. • administration of folic acid to pts. With Vit B12 deficiency helps refill the tetrahydrofolate pool and partially or fully corrects anaemia • However exogenous folic acid does not correct the neurologic defects of Vit B12 deficiency

31. Anti anaemic Drugs • Clinical uses and toxicity: • Both agents have equivalent effects. • 1. Treatment of naturally pernicious anaemia • 2. anaemia caused by gastric resection • Because Vit B12 def. anaemia is almost always caused by inadequate absorption, therapy should be by replacement of VitB12,using parenteral therapy. No significant toxicity of VitB12 occurred

32. Anti anaemic Drugs • Folic acid: • Like Vit B12 folic acid is required for normal DNA synthesis, and its def. usually presents as megaloblastic anaemia. • In addition deficiency of folic acid during pregnancy increase the risk of neural tube defects in the fetus

33. Anti anaemic Drugs • Pharmacokinetics: • Folic acid is readily absorbed from GIT. Only modest amount are stored in the body, so a decrease in dietary intake is followed by anemia within few months • Pharmacodynamics: • Folic acid is converted to tetrahydrofolate by the action of dihydrofolate reductase

34. Anti anaemic Drugs • One important set of reactions involving tetrahydrofolate and dihydrofolate constitutes the dTMP cycle, which supplies the dTMP required for DNA synthesis. • Rapidly dividing cells are highly sensitive to folic acid deficiency. For this reason, antifolate drugs are useful in the treatment of various infections and cancers

35. Anti anaemic Drugs • Clinical use and toxicity: • Folic acid deficiency is most often caused by dietary insufficiency and malabsorption. • Anemia resulting from folic acid def. is readily treated by oral folic acid. • Maternal folic acid def. is associated with increased risk of neural tube defects in the fetus, folic acid supplementation is recommended prior to and during pregnancy

36. Anti anaemic Drugs • Folic acid supplements will correct the anemia but not the neurologic deficits of Vit B12 deficiency. • Therefore Vit B12 deficiency must be ruled out before one selects folic acid as the sole therapeutic agent in the treatment of patients with megaloblastic anaemia. • Folic acid has no recognized toxicity

37. Anti anaemic Drugs • Erythropoietin: • ERYTHROPOIETN is produced by the kidney • Reduction in its synthesis is responsible for anemia of renal failure • Activation of receptors on erythroid progenitors in the bone marrow, it stimulates the production of red cells and increases their release from B. M

38. Anti anaemic Drugs Erythropoietin is used for anemia associated with renal failure and some time effective for patients with other forms of anemia eg. primary bone marrow disorder or anemia secondary to cancer chemotherapy or HIV treatment ,bone marrow transplantation, AIDS or cancer Toxicity: thrombosis ,cardiovascular events when used along with some other erythropoietic agents