Haematopoetic agents

Haematopoetic agents

1. Haematopoietic agents Dr Shinde Viraj Ashok Jr 2 Dept of Pharmacology GMC Nagpur

2. overview

3. haemtopoeisis Production of all types of blood cells including formation , development & differentiation of blood cells. Definition Haematinics – substances required in formation of blood and are used for treatment of anemia . Haematopoietic growth factors - proteins that regulate proliferation and differentiation of hematopoietic cells.

4. Iron deficiency - most common cause of chronic anemia . Daily iron requirement Adult male – 0.5 - 1 mg Mensturating female – 1- 2mg Pregnant female – 3- 5mg Children – 25 micro gram /kg IRON

5. Good source of iron - Liver , egg yolk , beans ,dry fruits. Poor sources of iron - Milk & its products. Reducing substances like ascorbic acid & gastric acid - ↑ Absorption Alkalies , phosphates , phytates , tetracyclines - ↓ Absorption

6. Iron – prophylaxis or treatment of iron deficiency anemia ( microcytic hypochromic anemia ) Parenteral route indicated - Oral iron not tolerated Oral iron not absorbed Non compliance to oral iron Severe iron deficieny with chronic bleeding Along with erythropoietin

7. Oral preparations Ferrous sulphate – 20% elemental iron Ferrous gluconate – 12% elemental iron Ferrous succinate -35% elemental iron Reticulocyte count - ↑ in 2 weeks & peak in 4 weeks Rise of haemoglobin - 0.5- 1 gm /dl per week considered adequate

8. Major adverse effects of oral iron preparations - Poor compliance Epigastric pain Nausea Vomiting Metallic taste Elemental iron content in preparation

9. Parenteral iron preparations Iron dextran Iron sorbitol citrate Can be given IV or IM Only IM Not excreted in urine Excreted 30% in urine Absorbed through lymphatics Absorbed directly in circulation Not bound to transferrin Bound to transferrin Adverse effects – Pain at injection site ,fever, palpitation Adverse effects – Incidence of immediate reaction , ventricular tachycardia, A- V block , hypotension - Higher

10. Ferrous sucrose High molecular weight complex of iron hydroxide with sucrose IV injection Safer than older formulations Incidence of hypersensitivity reaction very low Indicated for anaemia in kidney disease but reports of kidney damage are on record

11. Ferric carboxymaltose Ferric hydroxide core is stabilised by a carbohydrate shell Injected IV In clinical trials it has caused rapid increase in haemoglobin level in anaemia patients & replenished stores. Acute reaction - Low

12. T o avoid the serious toxicity associated with iron overload – chronic parenteral iron therapy Iron stores estimated - basis of Serum concentrations of ferritin and Transferrin saturation(ratio of the total serum iron concentration to the total iron-binding capacity (TIBC) Important to monitor iron storage levels

13. Total iron requirement 4.3 × body weight (kg ) × Haemoglobin deficit ( g/dl)

14. Clinical Toxicity Acute Iron Toxicity Acute iron toxicity – exclusively seen in young children – accidentally ingest iron tablets . Adult patients taking oral iron preparations should be instructed Store tablets in child-proof containers out of the reach of children

15. Children poisoned with oral iron experience necrotizing gastroenteritis, severe metabolic acidosis, coma, and death . Urgent treatment - Necessary. Whole bowel irrigation - To flush out unabsorbed pills . Gastric lavage with sodium bicarbonate – To render iron insoluble Desferrioxamine - Potent iron-chelating compound, can be given intravenously to bind iron that has already been absorbed & to Promote its excretion in urine and feces

16. Chronic Iron Toxicity Iron overload - Hemochromatosis Most commonly occurs in patients Inherited hemochromatosis, a disorder characterized by excessive iron absorption Patients - receive many red cell transfusions over a long period of time ( eg individuals with ß-thalassemia).

17. Chronic iron overload in absence of anemia - most efficiently treated by intermittent phlebotomy . One unit of blood - removed every week or so until all of the excess iron is removed. Iron chelation therapy using Parenteral desferrioxamine or Oral iron chelator deferasirox is Less efficient more complicated, expensive, and hazardous. Used for iron overload cannot be managed by phlebotomy (Inherited and acquired causes of refractory anemia such as thalassemia major, sickle cell anemia , aplastic anemia etc .)

18. Folic acid Consist pteridine , para amino benzoic acid, glutamic acid Dietary folic acid – polyglutamates - cleaved of in intestine - Maximum absorption – jejunum Folic acid is transported in blood -Methyl tetra hydrofolate . THFA participates in many one carbon transfer reaction

19. Metabolic functions Conversion of homocysteine to methionine Methyl THFA B12 methionine THFA methyl B12 homocysteine Generation of thymidylate – essential constituent of DNA Conversion of serine to glycine requires THFA → results in formation of methylene THFA - utilised in thymidylate synthesis. Purine synthesis & Generation & utilisation of formate pool. Histidine metabolism – mediating formimino group transfer.

20. Main uses – Treatment of megaloblastic anemia . Indicated in pregnancy – To prevent neural tube defects. Leucovorin – Used to prevent toxicity of methotrexate.

21. Vitamin B 12 Contains cobalt Forms present in diet – Cyanocobalamin & hydroxycobalamin Present – Animal foods Vegetable source – Legumes Vitamin B 12 + intrinsic factor – Absorbed in terminal ileum Deficiency of Vitamin B 12 – Megaloblastic anemia Sub acute combined degeneration of cord

22. Metabolic functions Conversion of homocysteine to methionine –methionine is needed as methyl group donor in many metabolic reactions and protein synthesis. Purine & pyrimidine affected – defective one carbon transfer. Conversion of malonic acid to succinic acid- important step in propionic acid metabolism & links carbohydrate metabolism with lipid metabolism. Conversion methionine to S adenosyl methionine – SAM is needed in synthesis of phoshpholipids & myelin. Essential for cell growth & multiplication

23. Uses Megaloblastic anemia Pernicious anemia Correcting neurological abnormalities of diabetes, alcoholic & other peripheral neuropathy – methylcobalamin Tobacco amblyopia – hydroxycobalamin

24. Erythropoiesis Stimulating Agents Pharmacological substance stimulates red blood cell production. Recombinant human erythropoietin ( rHuEPO , epoetin alfa ) – Produced in a mammalian cell expression system. Half - life - 4 -13 hours in patients with chronic renal failure . Epoetin alfa is generally administered three times a week.

25. Erythropoetin Darbepoetin alfa Modified form of erythropoietin more heavily glycosylated as a result of changes in amino acids. 2 to 3 fold longer half-life than epoetin alfa . Darbepoetin is administered weekly.

26. Methoxy polyethylene glycol epoetin beta Isoform of erythropoietin covalently attached to a long polyethylene glycol polymer . Single IV or SC dose at 2-week or monthly intervals . Methoxy polyethylene glycol- epoetin beta should not be used for treatment of anemia caused by cancer chemotherapy Clinical trial found significantly more deaths among patients receiving this form of erythropoietin.

27. Pharmacodynamics Stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors . Erythropoietin receptor is member of the JAK/STAT superfamily of cytokine receptors. Inverse relationship exists between the hematocrit or hemoglobin level & serum erythropoietin level.

28. Endogenous Erythropoietin levels are low - Renal disease Endogenous erythropoietin levels are high Primary bone marrow disorders ( aplastic anemia , leukemias , myeloproliferative and myelodysplastic disorders etc) and Most nutritional and Secondary anemias Less likelihood of a response to exogenous erythropoietin Most likely to respond to treatment with exogenous erythropoietin

29. Clinical Pharmacology Availability of erythropoiesis-stimulating agents (ESAs) significant positive impact for patients with several types of anemia . Dosages of ESAs - Maintain a target hemoglobin up to, but not exceeding, 10-12 g/ dL . Oral or parenteral iron supplementation - To support increased erythropoiesis

30. Indications Patients with chronic renal failure . HIV-infected patients treated with zidovudine . Cancer patients treated with myelosuppressive cancer chemotherapy . Patients scheduled for elective, non cardiac ,non vascular surgery.

31. ESAs improve - Reticulocyte count - 10 days Hematocrit & hemoglobin level - 2 weeks Often eliminate the need for transfusions Improve quality of life

32. Toxicity Most common adverse effects of erythropoietin are Hypertension and Thrombotic complications. In March 2007, FDA issued a warning that patients with chronic renal failure or cancer whose serum hemoglobin is raised to more than 12 g/ dL with an ESA Face a greater risk of a thrombotic event or with advanced head and neck cancers - faster tumor growth.

33. MYELOID GROWTH FACTORS Chemistry & Pharmacokinetics Recombinant human G-CSF ( rHuG -CSF- filgrastim ) Produced in a bacterial expression system Nonglycosylated peptide of 175 amino acids, with a molecular weight of 18 kDa Recombinant human GM-CSF( rHuGM -CSF- sargramostim ) Produced in a yeast expression system Partially glycosylated peptide of 127 amino acids with three molecular species with molecular weights of 15,500; 15,800; and 19,500. Serum half-lives of 2 hours after IV or SC administration.

34. Pharmacodynamics Myeloid growth factors stimulate Proliferation & Differentiation by interacting with specific receptors (members of JAK/STAT superfamily) found on myeloid progenitor cells. G-CSF - Remarkable ability to mobilize hematopoietic stem cells, i.e , to increase their concentration in peripheral blood. Peripheral blood stem cells ( pbscs ) are used for autologous & allogeneic hematopoietic stem cell transplantation.

35. GM-CSF Broader biologic actions than G-CSF. Multipotential hematopoietic growth factor that stimulates Proliferation and Differentiation of early and late granulocytic progenitor cells as well as erythroid and megakaryocyte progenitors. GM-CSF acts together with interleukin-2 to stimulate T-cell proliferation.

36. Clinical Pharmacology A . Cancer Chemotherapy-Induced Neutropenia Growth factor accelerates the rate of neutrophil recovery after dose-intensive myelosuppressive chemotherapy. Reduces the duration of neutropenia and raises the nadir count (lowest neutrophil count seen following a cycle of chemotherapy.)

37. GM-CSF reduces the duration of neutropenia after cytotoxic chemotherapy. Growth factors accelerate neutrophil recovery and reduce infection rates and days of hospitalization. G-CSF and GM-CSF have FDA approval for treatment of patients with AML .

38. Pegfilgrastim Covalent conjugation product of filgrastim and a form of polyethylene glycol Longer serum half-life than recombinant G-CSF - Alternative to G-CSF for prevention of chemotherapy-induced febrile neutropenia . Shorten the period of severe neutropenia slightly more than G-CSF. Injected once per myelosuppressive chemotherapy cycle instead of daily for several days

39. Lenograstim Glycosylated form of recombinant G-CSF

40. B. Other Applications G-CSF and GM-CSF - proved to be effective neutropenia associated with Congenital neutropenia Cyclic neutropenia Myelodysplasia and Aplastic anemia . Myeloid growth factors play an important role in autologous stem cell transplantation for patients undergoing high-dose chemotherapy.

41. Allogeneic bone marrow transplantation for treatment of hematologic malignancies or bone marrow failure states. G-CSF is most commonly used for PBSC mobilization because of its increased efficacy and reduced toxicity compared with GM-CSF . Dose - 5- 10mcg/kg/d subcutaneously for 4 days. On the fifth day they undergo leukapheresis . Goal is to infuse at least 5 × 10 6 CD34 cells/kg

42. Plerixafor Plerixafor can be added to G-CSF for patients with multiple myeloma or non- hodgkin’s lymphoma who respond suboptimally to G-CSF alone, the novel hematopoietic stem cell mobilizer.

43. Toxicity G- CSF & pegfilgrastim can cause bone pain – Reversible GM-CSF - more severe side effects- at higher doses. Fever Malaise Arthralgias Myalgias and Capillary leak syndrome (peripheral edema and pleural or pericardial effusions) Splenic rupture - rare but serious complication of the use of G-CSF for PBSC

44. MEGAKARYOCYTE GROWTH FACTORS Patients with thrombocytopenia have a high risk of hemorrhage . Recombinant form of IL-11 was the first agent to gain FDA approval for treatment of thrombocytopenia . Romiplostim was approved by the FDA for idiopathic thrombocytopenic purpura in 2008.

45. Chemistry & Pharmacokinetics Oprelvekin - Recombinant form of IL-11 is produced by expression in Escherichia coli . Half-life - 7- 8hours when the drug is injected subcutaneously.

46. Romiplostim (AMG 531) is a member of new class of therapeutics called peptibodies . Half - life is inversely related to the serum platelet count Romiplastim has longer half-life in patients with thrombocytopenia and a shorter half-life in patients whose platelet counts have recovered to normal levels

47. Eltrombopag Orally active small molecule agonist at thrombopoietin receptor. Licensed in 2008 for use in patients with severe idiopathic thrombocytopenia {have failed to respond adequately to first-line treatments.} Because of concerns about hepatotoxicity and hemorrhage , eltrombopag is restricted to use by registered physicians and patients and its use requires close monitoring of liver enzymes.

48. Pharmacodynamics Interleukin-11 acts - Specific cell surface cytokine receptor to stimulate the growth of multiple lymphoid and myeloid cells. Acts synergistically with other growth factors to stimulate the growth of Primitive megakaryocytic progenitors Increases the number of peripheral platelets and neutrophils Romiplostim - high affinity for the human Mpl receptor. It causes a dose-dependent increase in platelet count that begins on day 5 after subcutaneous administration and peaks at 12-15 days.

49. Clinical Pharmacology Oprelevkin - Secondary prevention of thrombocytopenia in patients receiving Cytotoxic chemotherapy for Treatment of nonmyeloid cancers. Clinical trials show that it reduces the number of platelet transfusions required by patients who experience severe thrombocytopenia after a previous cycle of chemotherapy .

50. Oprelevkin is given by subcutaneous injection at a dose of 50 mcg/kg/d . It is started 6-4 hours after completion of chemotherapy and continued for 14 -21 days or until the platelet count passes the nadir and rises to more than 50,000 cells/L .

51. Toxicity Most common adverse effects of oprelevkin are fatigue, headache, dizziness , and cardiovascular effects. (reversible) Cardiovascular effects include Anemia (due to hemodilution ), Dyspnea (due to fluid accumulation in the lungs), and Transient atrial arrhythmias. Hypokalemia . Romiplostim - Well tolerated - Potential long-term concern treated with romiplostim - ↑ in bone marrow reticulin , (marker of myelodysplastic or myeloproliferative processes)

52. summary Mechanism of action Clinical application Iron Required for biosynthesis of heme & heme -containing proteins, hemoglobin & myoglobin Microcytic hypochromic anemia Vitamin B 12 Cofactor required for essential enzymatic reactions Megaloblastic anemia , pernicious anemia Folic acid Precursor of an essential donor of methyl groups used for synthesis of amino acids, purines, and deoxynucleotide Megaloblastic anemia & Prevention of congenital neural tube defects

53. Growth factor Drug Mechanism of action Clinical applications Erythropoietin Epoietin α Darbopoietin α Methoxy polyethylene glycol epoetin beta Agonist of erythropoietin receptors expressed by red cell progenitors Anemia in CRF, Myelosuppressive drug use G-CSF GM- CSF Filgrastim Pegfilgrastim Lenograstim Sargromostim Proliferation & differentiation of myeloid growth factors Neutropenia due to anticancer drugs ,severe chronic neutropenia stem cell transplantation , mobilisation of PBSC IL 11 Thrombopoietin Oprelevkin Romiplastin Eltrombopag Activates IL-11 receptors Activate thrombopoietin receptor Thrombocytopenia due to anticancer drugs, ITP

54. References The pharmacological basis of therapeutics -Goodman and gillman (12 th edition) Basic and clinical pharmacology – Bertram Katzung (12 th edition) Principles of pharmacology- H.L. Sharma(2 nd edition)

55. Erythropoietin has been used successfully to offset the Anemia produced by zidovudine treatment in patients with HIV infection and Treatment of the anemia of prematurity. It can also be used to reduce the need for transfusion in high-risk patients undergoing elective, non-cardiac, nonvascular surgery.

56. Plerixafor is eliminated primarily by the renal route and dose must be adjusted for patients with renal impairment . Drug is well tolerated. Most common adverse effects associated with its use are Injection site reactions GI disturbances Dizziness Fatigue & Headache.