Blood pharmacology ppt

1. Agents Used in Anemia. KASSAHUN DIRES ( B.PHARM, MSC, PHARMACOLOGY) DEPARTMENT OF PHARMACY ASRAT WOLDEYES HEALTH SCIENCE CAMPUS DEBRE BERHAN UNIVERSITY 1

2. Cont.… 2 Iron

3. Introduction 3 Hematopoiesis is a remarkable process that produces over 200 billion new blood cells per day in the normal person. The hematopoietic machinery requires a constant supply of three essential nutrients—iron, vitamin B 12 , and folic acid —as well as the presence of hematopoietic growth factors.

4. Cont.. 4  Inadequate supplies of either the essential nutrients or the growth factors result in anemia.  Sickle cell anemia, a condition resulting from a genetic alteration in the hemoglobin molecule, is common but is not easily treated.  Thrombocytopenia and neutropenia are not rare, and some forms are amenable to drug therapy.

5. IRON  Basic Pharmacology 5  Iron deficiency is the most common cause of chronic anemia. Fatigue, dizziness, exertional dyspnea, and other generalized symptoms of tissue hypoxia. Tachycardia, increased cardiac output, and vasodilation can worsen the condition of patients with underlying disease. cardiovascular  Microcytic hypochromic anemia

6. Pharmacokinetics 6  Free inorganic iron is extremely toxic.  But iron is required for essential proteins.  Evolution has provided an elaborate system for regulating iron. Absorption  An individual absorbs 5–10% of iron, about 0.5–1 mg daily.

7. 7 Cont.…  Iron is absorbed in the duodenum and proximal jejunum.  Absorption increases in response to low iron stores or increased iron requirements.  Absorption increases to 1–2 mg/d in menstruating women and as high as 3–4 mg/d in pregnant women.

8. 8 Cont..  Iron is available in a wide variety of foods.  Especially abundant in meat.  In meat protein can be efficiently absorbed.

9. 9 Cont.…  Iron in vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption  Nonheme iron must be reduced by a ferrireductase to ferrous iron (Fe 2+ ) before it can be absorbed by intestinal mucosal cells.

10. Transport 10  Iron is transported in the plasma bound to transferrin, a β-globulin that can bind two molecules of ferric iron.  Transferrin receptors—integral membrane glycoproteins present in large numbers on proliferating erythroid cells—bind and internalize the transferrin-iron complex through the process of receptor-mediated endocytosis.

11. 11 Cont.…  In endosomes, the ferric iron is released, reduced to ferrous iron, and transported by DMT1 into the cytoplasm, where it is funneled into hemoglobin synthesis or stored as ferritin.

12. Storage 12  in addition to the storage of iron in intestinal mucosal cells, Stored, primarily as ferritin, in macrophages in the liver, spleen and bone.  The mobilization of iron from macrophages and hepatocytes is primarily controlled by hepcidin regulation of ferroportin activity.

13. Cont.… 13  Low hepcidin concentrations increase iron release from storage sites.  High hepcidin concentrations inhibit iron release.

14. Elimination 14  Small amounts are lost in the feces.  Trace amounts are excreted in urine and sweat.  These losses account for no more than 1 mg of iron per day.  The body’s ability to excrete iron is so limited, regulation of iron balance must be achieved.  Impaired regulation of iron absorption leads to serious pathology.

15. Clinical Pharmacology 15  Indications for the use of iron  Treatment or prevention of iron deficiency anemia:  Iron deficiency is commonly seen in o Infants, especially premature infants. o Children during rapid growth periods . o Pregnant and lactating women. o Patients with chronic kidney disease.

16. Treatment 16  With oral or parenteral iron preparations.  Oral iron corrects the anemia as parenteral iron if iron absorption from the gastrointestinal tract is normal.  For patients with advanced chronic kidney disease who are undergoing hemodialysis: parenteral iron administration is preferred.

17. 17 Oral iron therapy  Ferrous salts should be used o Ferrous sulfate o Ferrous gluconate o Ferrous fumarate  Effective, inexpensive and recommended for the treatment of most patients.

18. Cont.. 18

19. Parenteral iron therapy 19  Parenteral therapy should be reserved for patients  unable to tolerate oral iron.  unable to absorb oral iron .  with extensive chronic anemia who cannot be maintained with oral iron alone.

20. Cont.… 20 oPatients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoietin. ovarious post gastrectomy conditions, inflammatory bowel disease and malabsorption syndromes.

21. Cont.… 21  The challenge with parenteral iron therapy is that parenteral administration of inorganic free ferric iron produces serious dose dependent toxicity.  when the ferric iron is formulated as a colloid containing particles with a core of iron oxyhydroxide surrounded by a core of carbohydrate.  The bioactive iron is released slowly from the stable colloid particles.

22. Cont.… 22  The three available forms of parenteral iron are oiron dextran. o sodium ferric gluconate. o iron sucrose.

23. Iron dextran 23  A stable complex of ferric oxyhydroxide and dextran polymers.  50 mg of elemental iron per milliliter of solution  Can be given by deep intramuscular injection or by intravenous infusion  The intravenous route is most commonly used. o eliminates the local pain and tissue staining. o a delivery of the entire dose of iron necessary to correct the iron deficiency at one time.

24. Cont.… 24  High-molecular-weight and low-molecular- weight forms  Clinical data—primarily from observational studies indicate that the risk of anaphylaxis is largely associated with high-molecular- weight formulations.

25. Sodium ferric gluconate complex and iron- sucrose complex 25  Alternative parenteral preparations.  Can be given only by the intravenous route.  Less likely to cause hypersensitivity reactions.

26. Cont.… 26  For patients treated chronically with parenteral iron, it is important to monitor iron storage levels to avoid serious toxicity associated with iron overload  Iron stores can be estimated on the basis of serum concentrations of ferritin and the transferrin saturation, which is the ratio of the total serum iron concentration to the total iron-binding capacity.

27. Adverse effects of iron preparations 27  Oral preparations o nausea o abdominal cramps o constipation o diarrhea  Parenteral preparations o headache o fever o nausea and vomiting o back pain, flushing o bronchospasm o anaphylaxis o death

28. Acute Iron Toxicity 28  Commonly accidentally ingest iron tablets.  As few as 10 tablets can be lethal in young children.  Store tablets in child-proof containers out of the reach of children.  Children who are poisoned experience necrotizing gastroenteritis, vomiting, abdominal pain, bloody diarrhea followed by shock, lethargy, and dyspnea. seen in young children who with oral iron

29. 29 Cont.…  Improvement is often noted, but this may be followed by severe metabolic acidosis, coma, and death.  Urgent treatment is necessary.  Whole bowel irrigation should be performed to flush out unabsorbed pills.  Deferoxamine,, can be given intravenously to bind iron that has already been absorbed and to promote its excretion in urine and feces.  Activated charcoal,, does not bind iron and thus is ineffective.  Appropriate supportive therapy for gastrointestinal bleeding, metabolic acidosis, and shock must also be provided.

30. Chronic Iron Toxicity 30  Chronic iron toxicity (iron overload), also known as hemochromatosis, results when excess iron is deposited in the heart, liver, pancreas and other organs.  It can lead to organ failure and death.  Most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption.  Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy.

31. 31 Cont.…  One unit of blood can be removed every week until all of the excess iron is removed.  Iron chelation therapy using parenteral deferoxamine or the oral iron chelator deferasirox is less efficient as well as more expensive,  But it may be the only option for iron overload that cannot be managed by phlebotomy.

32. 32 VITAMIN B 12 and FOLIC ACID

33. Vitamin B 12 33  Termed as cobalamin  Sometimes called extrinsic factor  Intrinsic factor, a protein secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B 12.  Serves as a cofactor for essential biochemical reactions.  Deficiency of vitamin B 12 leads to o megaloblastic anemia o gastrointestinal symptoms o neurologic abnormalities  Vitamin B 12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide.

34. 34  Deoxy adenosyl cobalamin and methyl cobalamin are the active forms.  Cyanocobalamin available for therapeutic use) are converted to the active forms. and hydroxocobalamin (both  The vitamin is not synthesized by animals or plants.

35. Pharmacokinetics 35  Stored, primarily in the liver.  It would take about 5 years for all of the stored vitamin B 12 to be exhausted.  Small amounts of vitamin B 12 are lost in urine and stool.  Vitamin B 12 is absorbed after it complexes with intrinsic factor.  The intrinsic factor-vitamin subsequently absorbed in the distal ileum by receptor mediated transport system. B12 complex is

36. Cont.… 36  Deficiency in humans most often results from malabsorption of vitamin B 12 due either to lack of intrinsic factor or to loss or malfunction of the absorptive mechanism in the distal ileum.  Nutritional deficiency is rare.  vitamin B 12 is transported to the various cells of the body bound to a family of specialized glycoproteins, transcobalamin I, II and III.

37. Pharmacodynamics 37  Two essential enzymatic reactions in humans require vitamin B 12.  Methylcobalamin serves as an intermediate in the transfer of a methyl group from N(5)–methyltetrahydrofolate to homocysteine, forming methionine.  As a result, vitamin B 12 deficiency leads to deficiency of folate cofactors.  The depletion of tetrahydrofolate prevents synthesis of the deoxythymidylate (dTMP) and purines required for DNA synthesis in rapidly dividing cells.

38. 38  Megaloblastic anemia of vitamin B 12 deficiency can be corrected by ingestion of large amounts of folic acid.  Folic acid can be reduced to dihydrofolate by the enzyme dihydrofolate reductase and serve as a source of the tetrahydrofolate required for synthesis of purines and dTMP required for DNA synthesis.  Vitamin B 12 deficiency causes the accumulation of homocysteine due to reduced formation of methyl cobalamin.

39. 39  Elevated serum homocysteine increases the risk of cardiovascular disease.  The other reaction that requires vitamin B 12 is the isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase.  In vitamin B 12 deficiency, this conversion cannot take place and the substrate, methylmalonyl-CoA, as well as methylmalonic acid accumulate.  In the past, it was thought that abnormal accumulation of methylmalonyl- CoA causes the neurologic manifestations of vitamin B 12 deficiency.

40. Cont.… 40  However, newer evidence instead implicates the disruption of the methionine synthesis pathway as the cause of neurologic problems.  Administration of folic acid in the setting of vitamin B 12 deficiency will not prevent neurologic manifestations even though it will largely correct the anemia.

41. Clinical Pharmacology 41  Vitamin B 12 is used to treat or prevent deficiency.  The most characteristic clinical manifestation of vitamin B 12 deficiency is megaloblastic ( macrocytic anemia ).  Correction of vitamin B 12 deficiency arrests the progression of neurologic disease.

42. 42  Once a diagnosis of megaloblastic anemia is made, it must be determined whether vitamin B 12 or folic acid deficiency is the cause.  This can usually be accomplished by measuring serum levels of the vitamins.  Other causes of megaloblastic anemia are very rare.

43. 43  Most cases of vitamin B 12 deficiency are caused by malabsorption of the vitamin.  Parenteral injections of vitamin B 12 are required for therapy.  For patients with reversible diseases, the underlying disease should be treated after initial treatment with parenteral vitamin B 12.

44. 44 Cont.…  Most patients require lifelong treatment with vitamin B 12 ( do not have curable deficiency).  Vitamin B 12 for parenteral injection is available as  cyanocobalamin  hydroxocobalamin  Hydroxocobalamin is preferred.

45. 45  Initial therapy should consist of 100– 1000 mcg of vitamin B 12 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.

46. Cont.… 46  Oral doses of 1000 mcg of vitamin B 12 daily are usually sufficient to treat patients with pernicious anemia who refuse or cannot tolerate the injections.  After pernicious anemia is corrected following parenteral vitamin B 12 therapy, the vitamin can be administered intranasally as a spray or gel.

47. FOLIC ACID 47  Reduced forms of folic acid are required for the synthesis of amino acids, purines and DNA.  Folate deficiency is relatively common.  The consequences of folate deficiency go beyond the problem of anemia (NTDS)  Folate deficiency is implicated as a cause of congenital malformations in newborns and may play a role in vascular disease.  The deficiency is easily corrected by administration of folic acid.

48. Pharmacokinetics 48  5–20 mg of folates is stored in the liver and other tissues.  Folates are excreted in the urine and stool and are also destroyed by catabolism.  Serum levels fall within a few days when the intake is diminished.  Body stores of folates are relatively low.

49. Cont.… 49  Daily requirements is high.  Folic acid deficiency and megaloblastic anemia can develop within 1–6 months after the intake stops.  Dietary folates, however, consist primarily of polyglutamate forms of N (5) -methyl tetrahydrofolate.

50. 50  Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme α-1-glutamyl transferase (―conjugase‖)  The monoglutamate N (5) -methyltetrahydrofolate is subsequently transported into the bloodstream by both active and passive transport.  Inside cells, N 5 -methyltetrahydrofolate is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B 12.