1. DRUGS USED TO TREAT DISEASES OF THE BLOOD Presented by Dr. Sasan Zaeri ParmD, PhD March, 2016

2. Agents Used in Anemias; Hematopoietic Growth Factors Hematopoiesis: – the production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes Essential factors: – Iron, vitamin B 12, folic acid and hematopoietic growth factors Inadequate supply results in: – Anemia, thrombocytopenia and neutropenia 2

3. AGENTS USED IN ANEMIAS: IRON Iron deficiency – the most common cause of chronic anemia – leads to pallor, fatigue, dizziness, exertional dyspnea, etc. – small erythrocytes with insufficient hemoglobin are formed >>> microcytic hypochromic anemia 3

4. Pharmacokinetics 4

5. Iron sources to support hematopoiesis: – catalysis of the hemoglobin in senescent or damaged erythrocytes – dietary iron from a wide variety of foods iron requirements can exceed normal dietary supplies in – growing children and pregnant women (increased iron requirements) – menstruating women (increased losses of iron) 5

6. Pharmacokinetics ABSORPTION – 0.5-1 mg/d iron from food by a normal individual – 1-2 mg/d in normal menstruating women – 3-4 mg/d in pregnant women The iron in meat (heme iron) can be efficiently absorbed Nonheme iron in foods must be reduced to ferrous iron (Fe 2+ ) before it can be absorbed 6

7. Pharmacokinetics TRANSPORT – Iron is transported in the plasma bound to transferrin – The transferrin-iron complex enters maturing erythroid cells by receptor-mediated endocytosis – iron deficiency anemia is associated with an increased concentration of serum transferrin 7

8. Pharmacokinetics STORAGE – primarily as ferritin in intestinal mucosal cells, macrophages in the liver, spleen, and bone and in parenchymal liver cells – the serum ferritin level can be used to estimate total body iron stores – Apoferritin (precursor of ferritin) levels is regulated by the levels of free iron ↓ free iron → ↓ apoferritin → ↑ iron binding to transferrin ↑ free iron → ↑ apoferritin → protection of organs from the iron toxic effects 8

9. Pharmacokinetics ELIMINATION – no mechanism for excretion of iron: regulation of iron balance must be achieved by changing intestinal absorption and storage of iron, in response to the body's needs 9

10. Clinical Pharmacology The only clinical indication: – treatment or prevention of iron deficiency anemia Patients with increased iron requirements: – infants, especially premature infants – children during rapid growth periods – pregnant and lactating women – patients with chronic kidney disease Loss of erythrocytes at a relatively high rate during hemodialysis Erythrocyte production at a high rate as a result of treatment with erythropoietin 10

11. Clinical Pharmacology The most common cause of iron deficiency in adults: blood loss – Menstruating women lose about 30 mg of iron with each menstrual period many premenopausal women have low iron stores or even iron deficiency – In men and postmenopausal women, the most common site of blood loss is the gastrointestinal tract 11

12. Clinical Pharmacology TREATMENT – with oral or parenteral iron preparations Oral iron corrects the anemia just as rapidly and completely as parenteral iron in most cases if iron absorption from the gastrointestinal tract is normal for patients with advanced chronic kidney disease who are undergoing hemodialysis and treatment with erythropoietin, parenteral iron administration is preferred 12

13. Clinical Pharmacology Oral iron therapy – Only ferrous salts should be used Ferrous sulfate, ferrous gluconate and ferrous fumarate – Different iron salts provide different amounts of elemental iron Ferrous fumarate> Ferrous sulfate>ferrous gluconate – 200-400 mg/d of elemental iron corrects iron deficiency most rapidly 13

14. Clinical Pharmacology Oral iron therapy – lower daily doses can be given: slower but still complete correction of iron deficiency – Treatment should be continued for 3-6 months after correction of the cause of the iron loss This corrects the anemia and replenishes iron stores 14

15. Clinical Pharmacology Oral iron therapy Common adverse effects: – nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea Adverse effects can often be overcome by – lowering the daily dose of iron – taking the tablets immediately after or with meals – Changing from one iron salt to another Patients taking oral iron develop black stools – This may obscure the diagnosis of continued gastrointestinal blood loss 15

16. Clinical Pharmacology Parenteral iron therapy Parenteral therapy should be reserved for – patients unable to tolerate or absorb oral iron – patients with extensive chronic blood loss who cannot be maintained with oral iron alone: advanced chronic renal disease including hemodialysis and treatment with erythropoietin 16

17. Clinical Pharmacology Parenteral iron therapy Iron-dextran – deep IM injection or IV infusion – the IV route is used most commonly – Adverse effects of IV route: headache, light-headedness, fever, arthralgias, nausea and vomiting, back pain, flushing, urticaria, bronchospasm, and, rarely, anaphylaxis and death – a small test dose should always be given before full IM or IV doses are given 17

18. Clinical Pharmacology Parenteral iron therapy Alternative preparations to iron-dextran: Iron- sucrose and iron-gluconate – Can be given only by IM route – Less likely than iron dextran to cause hypersensitivity reactions 18

19. Clinical Toxicity ACUTE IRON TOXICITY – Seen almost exclusively in young children who accidentally ingest iron tablets Even 10 tablets can be lethal in young children Adult patients should be instructed to store tablets out of the reach of children – Manifestations: necrotizing gastroenteritis Vomiting abdominal pain bloody diarrhea Severe metabolic acidosis Coma and death 19

20. Clinical Toxicity ACUTE IRON TOXICITY – Urgent treatment is necessary – Whole bowel irrigation should be performed – Deferoxamine, a potent iron-chelating compound, can be given systemically 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 20

21. Clinical Toxicity CHRONIC IRON TOXICITY – Also known as iron overload or hemochromatosis – excess iron is deposited in the heart, liver, pancreas, and other organs – It can lead to organ failure and death – occurs in patients with inherited hemochromatosis (a disorder characterized by excessive iron absorption) patients who receive many red cell transfusions over a long period of time (e.g. patients with thalassemia major) 21

22. Clinical Toxicity CHRONIC IRON TOXICITY – In the absence of anemia is treated by intermittent phlebotomy – parenteral deferoxamine is much less efficient deferoxamine can be the only option for iron overload in patients with thalassemia major – deferasirox (oral iron chelator) has been approved for treatment of iron overload Deferasirox appears to be as effective as deferoxamine at reducing liver iron concentrations and is much more convenient 22

23. AGENTS USED IN ANEMIAS: Vitamin B 12 Vitamin B 12 serves as a cofactor for several essential biochemical reactions in humans Deficiency of vitamin B 12 leads to – anemia – gastrointestinal symptoms – neurologic abnormalities Most common cause of B 12 deficiency: – inadequate absorption of dietary vitamin B 12 especially in older adults Active forms of the vitamin in humans: – Deoxyadenosylcobalamin – Methylcobalamin 23

24. VITAMIN B 12 Inactive forms of the vitamin: – Cyanocobalamin (available for therapeutic use) – Hydroxocobalamin (available for therapeutic use) – Other cobalamins found in food sources The chief dietary source of vitamin B 12 : – Meat, liver, eggs and dairy products Vitamin B 12 is sometimes called extrinsic factor to differentiate it from intrinsic factor 24

25. Pharmacokinetics Vitamin B 12 is avidly stored in the liver – with an average total storage pool of 3000-5000 mcg (Lasting for 5 years) Vitamin B 12 is absorbed only after it complexes with intrinsic factor secreted by the parietal cells of the gastric mucosa – intrinsic factor-vitamin B 12 complex is subsequently absorbed in the distal ileum Vitamin B 12 deficiency results from malabsorption of vitamin B 12 due to – lack of intrinsic factor – loss or malfunction of the specific absorptive mechanism in the distal ileum 25

26. Pharmacodynamics 26

27. Pharmacodynamics Methylcobalamin converts N 5 - methyltetrahydrofolate to tetrahydrofolate N 5 -methyltetrahydrofolate: major dietary and storage folate – Tetrahydrofolate: precursor of folate cofactors ↓ Vitamin B 12 → ↓ Tetrahydrofolate → ↓folate cofactors → ↓dTMP and purines and DNA in rapidly dividing cells 27

28. Pharmacodynamics Methylfolate trap: – The accumulation of folate as N 5 - methyltetrahydrofolate and the associated depletion of tetrahydrofolate cofactors in vitamin B 12 deficiency Folic acid can be reduced to dihydrofolate and tetrahydrofolate by the enzyme dihydrofolate reductase – this explains why the megaloblastic anemia of vitamin B 12 deficiency can be partially corrected by ingestion of relatively large amounts of folic acid 28

29. Pharmacodynamics Administration of folic acid in the setting of vitamin B 12 deficiency will not prevent neurologic manifestations 29

30. Clinical Pharmacology Vitamin B 12 deficiency manifestations: – megaloblastic anemia (most characteristic clinical manifestation) – The neurologic syndrome paresthesias, weakness,ataxia, other central nervous system dysfunctions Correction of vitamin B 12 deficiency arrests the progression of neurologic disease, but it may not fully reverse neurologic symptoms that have been present for several months 30

31. Clinical Pharmacology Upon diagnosis of megaloblastic anemia: – 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 If vitamin B 12 deficiency is the cause, – The Schilling test, which measures absorption and urinary excretion of radioactively labeled vitamin B 12, can be used to further define the mechanism of vitamin B 12 malabsorption 31

32. Clinical Pharmacology The most common causes of vitamin B 12 deficiency: – partial or total gastrectomy – conditions that affect the distal ileum Pernicious anemia results from defective secretion of intrinsic factor by the gastric mucosal cells – The Schilling test shows diminished absorption of radioactively labeled vitamin B 12 – absorption is corrected when intrinsic factor is administered with radioactive B 12 32

33. Clinical Pharmacology conditions that distal ileum is damaged: – inflammatory bowel disease – Surgical resection of the ilium In the above situations, radioactively labeled vitamin B 12 is not absorbed in the Schilling test, even when intrinsic factor is added 33

34. Clinical Pharmacology Treatment of vitamin B 12 deficiency – Parenteral injections of vitamin B 12 are required for therapy – Vitamin B 12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin Hydroxocobalamin is preferred because it is more tightly protein-bound – Initial therapy: 100-1000 mcg of vitamin B 12 IM daily or every other day for 1-2 weeks to replenish body stores – Maintenance therapy: 100-1000 mcg IM once a month for life 34

35. AGENTS USED IN ANEMIAS: FOLIC ACID Reduced forms of folic acid are required for synthesis of amino acids, purines, and DNA The consequences of folate deficiency: – Anemia – congenital malformations in newborns 35

36. Pharmacokinetics The richest sources of folic acid: – yeast, liver, kidney and green vegetables 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 36

37. Clinical Pharmacology Folate deficiency results in a megaloblastic anemia that is indistinguishable from the anemia caused by vitamin B 12 deficiency – folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B 12 deficiency 37

38. Clinical Pharmacology Causes of folic acid deficiency – inadequate dietary intake of folates – alcohol dependence – liver diseases (diminished hepatic storage of folates) – Pregnancy maternal folic acid deficiency may cause fetal neural tube defects e.g. spina bifida – hemolytic anemia 38

39. Clinical Pharmacology Causes of folic acid deficiency – renal dialysis (folate loss during dialysis) – Drugs Methotrexate, trimethoprim and pyrimethamine – Leading to megaloblastic anemia Long-term therapy with phenytoin – Rarely leading to megaloblastic anemia 39

40. Clinical Pharmacology Treatment of folic acid deficiency: – 1 mg/d folic acid orally reverses megaloblastic anemia restore normal serum folate levels replenishes body stores of folates – Therapy should be continued until the underlying cause of the deficiency is removed or corrected Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients: – pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis 40

41. HEMATOPOIETIC GROWTH FACTORS Definition: – glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow Including: – erythropoietin (epoetin alfa) – granulocyte colony-stimulating factor (G-CSF) – granulocyte-macrophage colony-stimulating factor (GM-CSF) – interleukin-11 (IL-11) 41

42. ERYTHROPOIETIN Two recombinant forms: – Epoetin alfa – Darbepoetin alfa a glycosylated form of erythropoietin having a twofold to threefold longer half-life than epoetin alfa 42

43. Pharmacodynamics Endogenous erythropoietin is primarily produced in the kidney In response to tissue hypoxia, more erythropoietin is produced – This results in correction of the anemia, provided that the bone marrow response is not impaired by red cell nutritional deficiency (especially iron deficiency) primary bone marrow disorders bone marrow suppression from drugs or chronic diseases 43

44. Pharmacodynamics An inverse relationship exists between the hematocrit or hemoglobin level and the serum erythropoietin level – The most important exception to this inverse relationship is in the anemia of chronic renal failure: erythropoietin levels are usually low because the kidneys cannot produce the growth factor These are the patients most likely to respond to treatment with exogenous erythropoietin 44

45. Clinical Pharmacology Erythropoietin has a significant positive impact for patients with anemia of chronic renal failure – improvements of hematocrit and hemoglobin level – elimination of the need for transfusions 50-150 IU/kg erythropoietin IV or SC three times a week maintains hematocrit of about 35% Failure to respond to erythropoietin is most commonly due to concurrent iron deficiency – this can be corrected by giving oral or parenteral iron 45

46. Clinical Pharmacology Erythropoietin is used also for: – anemia produced by zidovudine treatment in patients with HIV infection – anemia of prematurity Erythropoietin is one of the drugs banned by the International Olympic Committee 46

47. Clinical Pharmacology The most common adverse effects of erythropoietin: – – hypertension and thrombotic complications due to a rapid increase in hematocrit and hemoglobin 47

48. MYELOID GROWTH FACTORS Filgrastim – Recombinant form of G-CSF Sargramostim – Recombinant form of GM-CSF Pegfilgrastim – A polyethylene glycol (PEG)-formulated filgrastim – has a much longer serum half-life than filgrastim – can be injected once per myelosuppressive chemotherapy cycle instead of daily for several days 48

49. Pharmacodynamics G-CSF stimulates proliferation and differentiation of progenitors already committed to the neutrophil lineage – It also activates the phagocytic activity of mature neutrophils and prolongs their survival in the circulation G-CSF also mobilizes hematopoietic stem cells, ie, to increase their concentration in peripheral blood – This biologic effect underlies a major advance in transplantation: the use of peripheral blood stem cells (PBSCs) rather than bone marrow stem cells for autologous and allogeneic hematopoietic stem cell transplantation 49

50. Pharmacodynamics GM-CSF has broader biologic actions than G- CSF – It is a multipotential hematopoietic growth factor that stimulates proliferation and differentiation of granulocytic, erythroid and megakaryocyte progenitors GM-CSF mobilizes peripheral blood stem cells, but it is significantly less efficacious than G- CSF 50

51. Clinical Pharmacology CANCER CHEMOTHERAPY-INDUCED NEUTROPENIA – G-CSF, GM-CSF and pegfilfrastim accelerate the rate of neutrophil recovery after dose-intensive myelosuppressive chemotherapy They reduce the risk of serious infections – Pegfilgrastim can be administered less frequently 51

52. Clinical Pharmacology autologous stem cell transplantation – High-dose chemotherapy with autologous stem cell support is increasingly used to treat patients with tumors that are resistant to standard doses of chemotherapeutic drugs – The myelosuppression is then counteracted by reinfusion of the patient's own hematopoietic stem cells (which are collected prior to chemotherapy) – The administration of G-CSF or GM-CSF early after autologous stem cell transplantation has been shown to reduce the time to engraftment and to recovery from neutropenia 52

53. Clinical Pharmacology Mobilization of peripheral blood stem cells (PBSCs) – Stem cells collected from peripheral blood have nearly replaced bone marrow G-CSF is the cytokine most commonly used for PBSC mobilization 53

54. Toxicity G-CSF is used more frequently than GM-CSF because it is better tolerated G-CSF can cause bone pain, which clears when the drug is discontinued GM-CSF can cause more severe side effects: – fever, malaise, arthralgias, myalgias, peripheral edema and pleural or pericardial effusions 54

55. MEGAKARYOCYTE GROWTH FACTORS Oprelvekin – the recombinant form of interleukin-11 55

56. Pharmacodynamics Interleukin-11 acts synergistically with other growth factors to – stimulate the growth of primitive megakaryocytic progenitors – Increase the number of peripheral platelets and neutrophils 56

57. Clinical Pharmacology Interleukin-11 is the first growth factor to gain FDA approval for treatment of thrombocytopenia – Patients with thrombocytopenia have a high risk of hemorrhage It is approved for the secondary prevention of thrombocytopenia in patients receiving cytotoxic chemotherapy 57