Hemopoeitics and Heamatinics

Pharmacology of Hemopoeitics and Heamatinics

1. HEMATOPOIETIC AGENTS KOPPALA RVS CHAITANYA

2. Introduction Hematopoiesis (formation of blood) is a complex process of proliferation, diff . erentiation, and maturation of cellular components of blood (erythrocytes, leucocytes and platelets) from the bone marrow stem cells. It is regulated by balanced interaction between endogenously derived hematopoietic growth factors and exogenously supplied essential nutrients (hematinics). Inadequate supply of either the growth factors or the hematinics results in deficiency of normal blood cells which is manifested as anemia, thrombocytopenia or neutropenia.

3. Hematopoietic growth factors are glycoproteins that control and maintain the production of various blood cell lineages from pluripotent hematopoietic stem cells and multipotent progenitors. A number of these factors (also called cytokines) have been cloned and produced for clinical use: Examples: Erythropoietin; Myeloid Growth Factors(Colony Stimulating Factors) –Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) –Granulocyte Colony Stimulating Factor (G- CSF) 3. Megacariocyte (Thrombopoietic) Growth factors – Interleukin-11 and Trombopoietin

4. Hematincs (iron, vitamin B12 and folic acid) Accessory hematinics Vitamin C, Riboflavin, Pyridoxine and Certain minerals like Cu, Co and Mn) Above are necessary for blood cell maturation and physiological turnover under basal conditions and on demand

5. Anaemia Anaemia occurs when the balance between production and destruction of RBCs is disturbed by: (a) Blood loss (acute or chronic) (b) Impaired red cell formation due to: • Deficiency of essential factors, i.e. iron, vitamin B12, folic acid. • Bone marrow depression (hypoplastic anaemia), erythropoietin deficiency. (c) Increased destruction of RBCs (haemolyticanaemia)

6. Anaemia The most common objective sign of a deficiency in oxygen-carrying erythrocytes. It is classified according to the Size of erythrocytes (microcytic and macrocytic or megaloblastic). Haemoglobin content (hypochromic or hyperchromic). Cause of the condition: Haemorrhagic anaemia (due to acute or chronic blood loss), Haemolytic anaemia (due to damaged red cell membranes and destruction of erythrocytes), Aplastic and hypoplastic anaemia (caused by bone marrow damage), deficiency of essential nutrients (iron deficiency anemia, megaloblastic anemias) Genetic alteration in the hemoglobin molecule (hemoglobin-S in Sickle cell anemia )

7. Thrombocytopenia Thrombocytopenia and neutropenia are not rare and CSF therapy is used for their prevention and treatment in patients with immune deficiency, being on radiotherapy or receiving myelosuppressive chemotherapy

8. IRON Iron has for long been considered important for the body. Lauha bhasma (calcined iron) has been used in ancient Indian medicine. According to Greek thought Mars is the God of strength, and iron is dedicated to Mars: as such, iron was used to treat weakness, which is common in anaemia. In 1713 iron was shown to be present in blood. In the early 19th century Blaud developed his famous ‘Blaud’s pill’ consisting of ferrous sulfate and potassium carbonate for anaemia. All important aspects of iron metabolism have been learned in the past 60 years

9. Rda : Iron Daily requirement To make good average daily loss, iron requirements are: Adult male : 0.5–1 mg (13 µg/kg) Adult female : 1–2 mg (21 µg/kg) (menstruating) Infants : 60 µg/kg Children : 25 µg/kg Pregnancy : 3–5 mg (80 µg/kg) (Last 2 trimesters) Dietary sources of iron Rich : Liver, egg yolk, oyster, dry beans, dry fruits, wheat germ, yeast. Medium : Meat, chicken, fish, spinach, banana, apple. Poor : Milk and its products, root vegetables.

10. Classification of hematopoietic drugs A. Drugs for Anemia 1. Drugs for treatment of iron deficiency (microcytic, hypochromic) anemia 1.1. Oral preparations of iron (Fe2+) Ferrous sulfate: Ferro-gradumet Hemofer prolongatum(film-tabl. 325 mg, 105 mg Fe2+; 1 tab. b.i.d. after meals) Ferrous glutamate: Glubifer Ferrous aspartate: Ferrospartin(tab. 350 mg, 50 mg Fe2+) Ferrous fumarate: Ferronat Ferrous gluconate: TOTHEMA® (amp. Fe2+ gluconate 50 mg; Mn2+ gluconate; Cu2+ gluconate) Ferric hydroxide polymaltose complex: Maltofer (1 ml sol. contains 50 mg unionized Fe3+ hydroxide polymaltose complex)

11. 1.2. Parenteral preparations of iron (Fe3+ ) Iron sucrose complex:, Venofer Iron isomaltoside: Monofer Iron dextran: Dexferrum®* Sodium ferric gluconate complex: Ferrlecit®

12. Other forms of iron Ferrous succinate (35% iron) Iron choline citrate Iron calcium complex (5% iron) Ferric ammonium citrate (20% iron) Ferrous aminoate (10% iron) Ferric glycerophosphate Ferric hydroxy polymaltose

13. 2. Drugs for treatment of megaloblastic (macrocytic, hyperchromic) anemias Vitamin B12 (Cyanocobalamin) – amp. 250 mcg/1 ml i.m. Folic acid Iron chelators: Deferoxamine (Desferal), Deferasirox (Exjade)

14. B. Hematopoietic Growth Factors Erythropoietins Erythropoietin : Epoetin alfa (Eprex), Epoetin beta (Recormon) Darbepoetin alfa (Aranesp) Methoxy polyethylene glycol-epoetin beta (long-acting erythropoietin receptor activator): Mircera

15. 2. Myeloid growth factors Granulocyte Colony Stimulating Factor (G-CSF): Filgrastim (Neupogen), Lenograstim (Granocyte) Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF): Molgramostim(Leucomax), Sargramostim (Leukine) 3. Megakaryocyte (Thrombopoietic) Growth Factors Oprelvekin (IL-11): Newmega Thrombopoietin

16. Mechanisms of action and pharmacological effects Drugs for treatment of iron deficiency Iron deficiency anemia is microcytic hypochromic anemia, caused by insufficient supply of iron. It is the most common type of anemia. Iron deficiency in normal conditions may occur more often in women (with menstrual blood loss or pregnancy), In adolescents (increased demand) In vegetarians or persons with malnutrition (inadequate dietary iron intake).

17. Pharmacokinetics of iron: Haemoglobin is a protoporphyrin and each molecule has 4 iron-haeme residues. Haeme is responsible for the bulk of oxygen transport in the blood and iron is the essential metallic component of it. The total body iron is about 3.5–4 g in men and 2.5 g in women, and over 70% of it circulates in the blood as haemoglobin. About 15-18% is stored in the liver, spleen and bone marrow mainly as ferritin and haemosiderin. Maximum iron absorption occurs by active transport in the duodenum and proximal jejunum. Absorption rate depends on the ratio of apoferitin (a protein) to feritin (apoferitine-iron complex) in the intestinal mucosa.

18. The so called “mucosal block” is a mechanism that prevents the entry of excess iron in the body. Ascorbic acid and SH- group containing amino acids (in gastric juice) facilitate Fe3+ to Fe2+ conversion and promote its absorption. Iron absorption is hindered by coffee, tea, antacid agents, phosphates (rich in eggyolks), Tetracyclines, etc. In the body iron is distributed into: Haemoglobin (Hb) – 66%; Iron storages (ferritin and haemosiderin) – 25%, Myoglobin in muscles – 3%, and Parenchimal iron (as prostetic group in cytochrome, peroxidases, catalases, xanthine oxidases and other cellular enzymes) – 6%. Haemoglobin contains 0.33% iron and 50 mg elemental iron is averagely lost with the loss of 100 ml blood (15 g Hb).

19. Mucosal block Mucosal block The gut has a mechanism to prevent entry of excess iron in the body. Iron reaching inside mucosal cell is either transported to plasma or oxidised to ferric form and complexed with apoferritin to form ferritin. This ferritin generally remains stored in the mucosal cells and is lost when they are shed (lifespan 2–4 days). This is called the ‘Ferritin curtain’. The iron status of the body and erythropoietic activity govern the balance between these two processes, probably through a ‘haematopoietic transcription factor’, and thus the amount of iron that will enter the body

20. Iron preparations Oral preparations contain ferrous (Fe2+) salts (sulfate, glutamate, aspartate, fumarate, gluconate, succinate, etc.). Ferric (Fe3+) salts are also available (Ferric hydroxide polymaltose complex, Iron polysaccharide, etc.), Ferrous (Fe2+) salts are supposed to be better absorbed. A number of iron combinations (with vitamins, minerals, amino acids, etc.) are marketed, but should be considered irrational due to lower iron content. About 50–100 mg of iron can be incorporated into hemoglobin daily, and about 25% of oral ron can be absorbed. Full haemopoetic response in adults is usually achieved with administration of 200 mg elemental iron daily p.o. in 2 or 3 divided doses after or in between meals. Absorption of iron is much better when taken in empty stomach, but side effects may limit patient compliance. For prophylactic use, a daily dose of 30 mg elemental iron is sufficient

21. Parenteral iron preparations are indicated only in case of: Severe deficiency with chronic bleeding; Intolerance to oral iron; Malabsorption or inflammatory bowel disease; Erythropoietin therapy (to meet the increased needs of induced erythropoiesis). Parenteral forms contain organically complexed salts of unionized iron: Iron dextran, Iron sucrose complex, etc. ) A sensitivity test with a small test dose must be performed before parenteral administration of iron to avoid any risk of hypersensitivity reactions. In severe anemia, treatment with oral iron should be continued for at least 3 months after correction to replenish iron stores. Desferrioxamine (Deferoxamine), an iron chelator, is a specific antidote that is given systematically to remove iron.

22. Parenteral iron therapy needs calculation of the total iron requirement of the patient for which Several formulae have been devised. A simple one is: Iron requirement (mg) = 4.4 × body weight (kg) × Hb deficit (g/dl)

23. Drugs for treatment of megaloblastic anemias Megaloblastic anemia is clinically manifested with a deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are hyperchromic, fragile and abnormally large. It results from either folate or vitamin B12 deficiency. Pernicious anemia is a form of megaloblastic anemia resulting from reduced intestinal absorption of vitamin B12 (extrinsic factor) due to deficiency ofintrinsic factor (a protein produced by parietal cells of the gastric mucosa). Parenteral injections of vitamin B12, but not oral preparations, are effective for treatment of pernicious anemia.

24. Vitamin B12 Cyanocobalamin (vitamin B12 – amp. 250 mcg/1 ml i.m.). Cyanocobalamin and hydroxocobalamin are complex cobalt-containing compound present in diet and referred to as vitamin B12. Vitamin B12 is essential for cell growth and multiplication. Along with folic acid, it is involved in the DNA synthesis as a cofactor in the transfer of 1-carbon units. Two biochemical reactions require vitamin B12: conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA conversion of homocysteine to methionine. Methylcobalamin and deoxyadenosylcobalamin are the active forms of the vitamin

25. Conversion of homocysteine to H4 folate and methionine is conjugated with the conversion of cobalamin to methylcobalamin. Vitamin B12 deficiency results in deficiency of folate cofactors for DNA synthesis and megaloblastic anemia occurs first. This biochemical interaction explains why high doses of folic acid can improve the anemia, caused by insufficient supply of vitamin B12. Conversion of methylmalonyl-CoA to succinyl-CoA requires desoxycobalamin. Vitamin B12 deficiency results in accumulation of methylmalonyl-CoA, synthesis of abnormal fatty acids and neurologic defects, which may become irreversible if not treated promptly. The disruption of methionin synthesis is also supposed to be involved in the neuronal damage.

26. Vit B12 deficiencY Reasons Addisonian pernicious anaemia: is an autoimmune disorder which results in destruction of gastric parietal cells. Chronic gastritis, gastric carcinoma, gastrectomy, etc. Malabsorption (damaged intestinal mucosa), bowel resection, inflammatory bowel disease. Consumption of Vit B12 by abnormal flora in intestine (blind loop syndrome) or fish tape worm. Nutritional deficiency: is a less common cause; may occur in strict vegetarians. Increased demand: pregnancy, infancy.

27. deficiency Vitamin B12 deficiency is manifested by megaloblastic anaemia, glossitis, peripheral neuritis, paresthesias, poor memory, mood changes, hallucinations, etc. It is clinically used for treatment of megaloblastic anaemia, tobacco amblyopia, neuropathies and psychiatric disorders. Hydroxocobalamin is highly protein-bound and longer acting, but is associated with the development of antibodies (hence lesser in use).

28. Folic acid Humans do not synthesize folic acid and meet theirs requirements from green leafy vegetables, fruit, mushrooms, liver, meat, kidney, eggs, milk and yeast. In the intestinal mucosa of jejunum folic acid is reduced by dihydrofolate reductase to tetrahydrofolic acid. Tetrahydrofolic acid through 1-C carbon transfer reactions is involved in the synthesis of purines and pyrimidines which are essential for DNA synthesis. Deficiency of folic acid leads to megaloblastic anaemia and teratogenic effects (spina bifida, etc.). Vitamin B9 prophylactically can be used during pregnancy and lactation – 0.4 mg p.o. daily)

29. Haematopoetic Growth Factors Erythropoetin: Epoetin alfa and Epoetin beta (Recormon). Erythropoietin stimulates erythrocyte proliferation and differentiation by acting on specific receptors present on red cell progenitors and promotes the release of reticulocytes. It is used to treat anemia in Chronic renal failure or Anemias secondary to cancer chemotherapy or HIV treatment, Bone marrow transplantation, AIDS, cancer.

30. Myeloid Growth Factors (Colony Stimulating Factors – CSFs). Granulocyte (G) and Granulocyte-Macrophages (GM) CSFs are cytokines. They accelerate the formation of matured leucocytes by acting on many progenitor cells. Filgrastim (recombinant G-CSF), Lenograstim (rG-CSF), Molgramostim (rGM-CSF) and Sargramostim (rGM-CSF) are used: To reduce the severity and duration of neutropenia induced by cytotoxic chemotherapy, radiotherapy or following bone marrow transplant; To treat congenital neutropenia, cyclic neutropenia and neutropenia associated with aplastic anaemia. Pegfilgrastim is a PEGilated (covalently conjugated to PolyEthylene Glycol polymer chain) form of filgrastim with a much longer t1/2 than the RcG-CSF.

31. Megakaryocythe Growth Factors. Oprelvekin (IL-11) and Thrombopoietin stimulate the growth of megakaryocytic progenitors and Increase the number of peripheral platelets. They are used to treat thrombocytopenia following cancer chemotherapy

32. Pharmacokinetic parameters

33. Side effects and toxicity : Iron Iron salts can cause constipation, Diarrhea (rarely), Epigastric pain, Heart burns, Nausea & vomiting, Metallic taste Staining of teeth (mainly with oral liquid or chewable preparation). Local reactions : Pain at the site of action, skin pigmentation, sterile abscess.

34. Systemic side effects : Fever, Headache, Joint pain, Urticaria, Lymphadenopathia; Anaphylactoid reaction (palpitation, chest pain, dyspnoea, cardiovascular collapse) may occur with iron-sorbitol preparations, but rarely with other preparation) .

35. Toxicity: IRON Acute iron toxicity occurs mostly in young children after accidental ingestion of iron tablets. Severe intoxication is clinically presented with necrotizing gastroenteritis, shock and metabolic acidosis. Coma and death may result. Deferoxamine is used as a specific antidote. Chronic Iron toxicity (hemochromatosis) occurs in persons with an inherited abnormality of iron absorption or with frequent transfusions (eg, thalassemia major). Iron chelators (deferoxamine or the oral agent deferasirox) are used in the treatment of chronic iron overload.

36. Vitamin B12 and folic acid Both substancies are well tolerated and neither their form has significant toxicity Hematopoietic growth factors. Erythropoietin can provoke an increase in hematocrit, blood viscosity and peripheral vascular resistance. Hypertension, thrombotic complications and flu-like symptoms (rare) may occur. For prevention of CV complications, it is recommended to maintain hemoglobin levels < 12 g/dL. Myeloid Growth Factors: G-CSF is better tolerated than GM-CSF. It may cause fever, bon pain (10-15%), myalgia, and vasculitis. GM-CSF is more likely to provoke fever, arthralgia, myalgia and skin rash .

37. Megakaryocythe Growth Factors IL-11 treatment is associated with dizziness, headache and fatigue. Recombinant human trombopoietin is supposed to be better tolerated .

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