1. Hematopoietic Drugs

2. The Hemopoietic System
The main components of the hemopoietic system are the blood, bone marrow, lymph nodes and thymus, with the spleen, liver and kidneys as important accessory organs.
Blood consists of formed elements (red and white blood cells and platelets) and plasma.
RBCs have the principal function of carrying oxygen. Their oxygen-carrying power depends on their hemoglobin content.
The most important site of formation of red blood cells in adults is the bone marrow, whereas the spleen acts as their graveyard. Red cell loss in healthy adults is precisely balanced by production of new cells.
The liver stores vitamin B12 and is involved in the process of breakdown of the hemoglobin liberated when red blood cells are destroyed. The kidney manufactures erythropoietin, a hormone that stimulates red cell production and is used in the anemia of chronic kidney disease.

3. Anemia:
Anemia is defined as a below-normal plasma hemoglobin concentration resulting from a decreased number of circulating red blood cells or an abnormally low total hemoglobin content per unit of blood volume.
General signs and symptoms of anemia include fatigue, rapid heart-beat, shortness of breath, pale skin, dizziness, and insomnia. Anemia, especially if it is chronic, is often surprisingly asymptomatic.
RBC synthesis requires a constant supply of three essential nutrients (iron, vitamin B12, and folic acid ) as well as erythropoietin which regulate red blood cell proliferation and differentiation in bone marrow

4. Causes of Anemias Types of Anemias
Deficiency of nutrients necessary for hemopoiesis, most importantly: iron, folic acid and vitamin B12.
Depression of the bone marrow, caused by: toxins (e.g. drugs used in chemotherapy) , radiation therapy , diseases of the bone marrow & reduced production of, or responsiveness to, erythropoietin (e.g. chronic renal failure, rheumatoid arthritis, AIDS).
Excessive destruction of red blood cells (i.e. hemolytic anemia); this has many causes, including hemoglobinopathies (such as sickle cell anemia), adverse reactions to drugs, and inappropriate immune reactions .
Types of Anemias
Hypochromic, microcytic anemia (small red cells with low hemoglobin; caused by iron deficiency)
Macrocytic anemia (large red cells, few in number) e.g: folic acid & B12 deficiency anemia.
Normochromic normocytic anemia (fewer normal-sized red cells, each with a normal hemoglobin content) e.g :anemias of chronic diseases .
Mixed pictures

5. Iron Agents used to treat anemias (Hematinic Agents):
It is important to note that the use of hematinic agents is often only an adjunct to treatment of the underlying cause of the anemia – for example, surgery for colon cancer (a common cause of iron deficiency) or antihelminthic drugs for patients with hookworm( a cause of iron deficiency). Sometimes treatment consists of stopping an offending drug, for example a non-steroidal anti-inflammatory drug that is causing blood loss from the gastrointestinal tract.
Iron
Iron deficiency anemia is by far the most common type of anemia.
Iron deficiency results from acute or chronic blood loss, from insufficient intake during periods of accelerated growth in children, and in heavily menstruating or pregnant women.
The body of a 70-kg man contains about 4 g of iron, 65% of which circulates in the blood as hemoglobin. About one-half of the remainder is stored in the liver, spleen and bone marrow, chiefly as ferritin and hemosiderin. The iron in these molecules is available for hemoglobin synthesis. The rest, which is not available for hemoglobin synthesis, is present in myoglobin, cytochromes and various enzymes.
Hemoglobin is made up of four protein chain subunits (globins), each of which contains one heme moiety. Heme consists of a tetrapyrrole porphyrin ring containing ferrous (Fe + 2) iron. Each heme group can carry one oxygen molecule, which is bound reversibly to Fe +2. This reversible binding is the basis of oxygen transport.

7. Pharmacokinetics
Free inorganic iron is extremely toxic, but iron is required for essential proteins such as hemoglobin; therefore, evolution has provided an elaborate system for regulating iron absorption, transport, and storage .The system uses specialized transport, storage, ferrireductase, and ferroxidase proteins whose concentrations are controlled by the body’s demand for hemoglobin synthesis and adequate iron stores. A peptide called hepcidin, produced primarily by liver cells, serves as a key central regulator of the system.
The normal daily requirement for iron is approximately 5mg for men and 15 mg for growing children and for menstruating women. A pregnant woman needs between 2 and 10 times this amount.
Iron is available in a wide variety of foods but is especially abundant in meat. The iron in meat protein can be efficiently absorbed. Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferroreductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells in the duodenum. Acidic conditions in the stomach keep iron in the reduced ferrous form. Iron is then absorbed in the duodenum.
[Note: The amount absorbed depends on the current body stores of iron. If iron stores are adequate, less will be absorbed. If stores are low, more iron will be absorbed.]

9. The relative percentage of iron absorbed decreases with increasing doses. For this reason, it is recommended that most people take the prescribed daily iron supplement (150 to 180 mg/day of oral elemental iron) in two or three divided doses. Some extended-release formulations may be dosed once daily.
Within the cell, ferrous iron is oxidized to ferric iron.
Ferric Iron is carried in the plasma bound to transferrin, Most of the iron that leaves the plasma each day is used for hemoglobin synthesis by red cell precursors.
Iron is stored in two forms: soluble ferritin and insoluble hemosiderin (aggregated ferritin).
The body has no means of actively excreting iron. Small amounts leave the body through desquamation of mucosal cells. A total of about 1 mg is lost daily.
Since red cells contain approximately 0.6 mg iron per ml of blood, loss of only a few milliliters of blood per day substantially increases dietary iron requirement.
Clinical uses of iron salts :
To treat iron deficiency anemia, caused by:
Chronic blood loss (e.g. with menorrhagia, hookworm) increased demand (e.g. in pregnancy and early infancy)
Inadequate dietary intake .
Inadequate absorption (e.g. following bowel resection).

10. Administration
Iron is usually given orally but may be given parenterally in special circumstances.
Oral preparations include ferrous sulfate, ferrous fumarate, ferrous gluconate, polysaccharide– iron complex, and carbonyl iron formulations. Of these preparations, ferrous sulfate is the most commonly used form of iron due to its high content of elemental iron and relatively low cost. The percentage of elemental iron varies in each oral iron preparation.
Treatment with oral iron should be continued for 3–6 months after correction of the cause of the iron loss. This corrects the anemia and replenishes iron stores.
Parenteral iron may be necessary in :
Individuals who are not able to absorb oral iron because of malabsorption syndromes. as a result of surgical procedures or inflammatory conditions involving the gastrointestinal tract.
Patients who do not tolerate oral preparations.
Patients with chronic renal failure receiving treatment with erythropoietin.
The preparations used are iron-dextran, sodium ferric gluconate complex and iron-sucrose. Macrophages phagocytize iron dextran and release iron from the dextran molecule. When iron sucrose is used, specific exchange mechanisms transfer iron to transferrin. While parenteral administration treats iron deficiency rapidly, oral administration may take several weeks.
Iron-dextran can be given by deep intramuscular injection or slow intravenous infusion; iron-sucrose is given by slow intravenous infusion. A small initial dose is given because of the risk of anaphylactoid reaction.

12. Adverse effects
The adverse effects of oral iron administration include nausea, abdominal cramps, diarrhea and dark stools. Fatal hypersensitivity and anaphylactoid reactions can occur in patients receiving parenteral iron (mainly iron dextran formulations). A test dose should be administered prior to iron dextran.
Iron is an important nutrient for several pathogens and there is concern that excessive iron could worsen the clinical course of infection. Iron treatment is usually avoided during infection for this reason.

13. Acute iron toxicity, usually seen in young children who have swallowed attractively colored iron tablets in mistake for sweets, it occurs after ingestion of large quantities of iron salts. can result in severe necrotizing gastritis with vomiting, hemorrhage and diarrhea, followed by circulatory collapse.
Chronic iron toxicity or iron overload occurs in chronic hemolytic anemias requiring frequent blood transfusions, such as the thalassemia (a large group of genetic disorders of globin chain synthesis) and in hemochromatosis (a genetic iron storage disease with increased iron absorption, resulting in damage to liver, islets of Langerhans, joints and skin).
The treatment of acute iron toxicity: involves the use of iron chelators such as desferrioxamine. This is not absorbed from the gut & given intragastrically following acute overdose (to bind iron in the bowel lumen and prevent its absorption). Whole bowel irrigation should be performed to flush out unabsorbed pills.
Chronic toxicity : in the absence of anemia is most efficiently treated by intermittent phlebotomy: one unit of blood can be removed every week In patients with thalassemia ,Iron chelators as desferrioxamine (by subcutaneous infusion) or oral chelators deferiprone & deferasirox.

14. Folic acid and Vitamin B12
Vitamin B12 and folic acid are essential constituents of the human diet, being necessary for DNA synthesis and consequently for cell proliferation. Their biochemical actions are interdependent.
Deficiency of either vitamin B12 or folic acid affects tissues with a rapid cell turnover, particularly bone marrow, but vitamin B12 deficiency also causes important disorders of nerves : peripheral neuropathy and dementia, as well as subacute combined degeneration of the spinal cord.
Deficiency of either vitamin causes megaloblastic hemopoiesis, in which there is disordered erythroblast differentiation and defective erythropoiesis in the bone marrow due to diminished synthesis of purines and pyrimidines. Large abnormal erythrocyte precursors appear in the marrow, each with a high RNA: DNA ratio as a result of decreased DNA synthesis. The circulating erythrocytes (macrocytes) are large fragile cells, often distorted in shape.

15. Causes of Deficiency Folic acid deficiency is caused by
Increased demand (for example, pregnancy and lactation)
Poor absorption caused by pathology of the small intestine
Alcoholism
Treatment with drugs that are dihydrofolate reductase inhibitors (for example, methotrexate, pyrimethamine, and trimethoprim). In the latter case, the reduced or active form of the vitamin (folinic acid—also known as leucovorin calcium—available as oral and parenteral formulations) is used for treatment.
 Vitamin B12 deficiency is caused by:
Low dietary levels
Poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (a glycoprotein secreted by the stomach and is essential for vitamin B12 absorption in the terminal ileum) as in pernicious anemia( an autoimmune disorder where the lining of the stomach atrophies)
Loss of activity of the receptor needed for intestinal uptake of the vitamin for example resection of diseased ileum in patients with Crohn's disease.

16. Folic Acid Mechanism of action
Folic acid (pteroylglutamic acid) consists of a pteridine ring, para-aminobenzoic acid and glutamic acid. Various forms of folic acid are present in a wide variety of plant and animal tissues; the richest sources are green vegetables, yeast, liver, and kidney.
Mechanism of action
Reduction of folic acid, catalysed by dihydrofolate reductase in two stages yields dihydrofolate (FH2) and tetrahydrofolate (FH4), co-factors which transfer methyl groups (1-carbon transfers) in several important metabolic pathways. FH4 is essential for DNA synthesis because of its role as co-factor in the synthesis of purines and pyrimidines. It is also necessary for reactions involved in amino acid metabolism.

17. Pharmacokinetics:
Folic acid is readily and completely absorbed in the jejunum.
Because 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.
Therapeutically, folic acid is given orally since oral folic acid is well absorbed even in patients with malabsorption syndromes. Methyl-FH4 is the form in which folate is usually carried in blood and which enters cells. It is functionally inactive until it is demethylated in a vitamin B12-dependent reaction.
Folate is taken up into hepatocytes and bone marrow cells by active transport. Within the cells, folic acid is reduced and formylated before being converted to the active polyglutamate form. Folinic acid, a synthetic FH4, is converted much more rapidly to the polyglutamate form.

19. Clinical uses Adverse effects :
Treatment of megaloblastic anaemia resulting from folate deficiency.
Prophylactically in individuals at hazard from developing folate deficiency, for example:premature infants , patients with severe chronic hemolytic anemias, including hemoglobinopathies (e.g. sickle cell anemia) and pregnant women & to prevent congenital malformations as spina bifida which is shown to be associated with folate deficiency in pregnant women.
Adverse effects :
Do not occur even with large doses of folic acid except possibly in the presence of vitamin B12 deficiency because if the vitamin B12 deficiency is treated with folic acid alone, the blood picture improves and give the appearance of cure while the neurological lesions get worse as folic acid supplementation does not prevent the potentially irreversible neurologic damage caused by vitamin B12 deficiency.
The cause of megaloblastic anemia needs to be determined and treat accordingly.

20. Vitamin B12 Clinical uses
Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide. Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins. The vitamin B12 used medically are hydroxocobalamin and cyanocobalamin. The dietary sources of vitamin B12 are meat (particularly liver), eggs & dairy products.
Absorption requires intrinsic factor. Vitamin B12 is carried in the plasma by binding proteins called transcobalamins. The vitamin is stored mainly in the liver, the total amount in the body being about 4 mg. This store is so large compared with the daily requirement, that if vitamin B12 absorption stops suddenly – as after a totalgastrectomy – it takes 2–4 years for evidence of deficiency to become manifest.
Clinical uses
Chronic treatment of pernicious anemia and other causes of vitamin B12 deficiency.
Prophylactically after surgical operations that remove the site of production of intrinsic factor (the stomach) or of vitamin B12 absorption (the terminal ileum).

21. Mechanism of action
Vitamin B12 is required for two main biochemical reactions in humans:
The conversion of methyl-FH4 to FH4:methyl group from methyl-FH4 is transferred first to B12, and then to homocysteine to form methionine. Vitamin B12 deficiency thus traps folate in the inactive methyl-FH4 form, thereby depleting the folate polyglutamate coenzymes needed for DNA synthesis.
Isomerisation of methylmalonyl-CoA to succinyl-CoA methylmalonyl-CoA accumulates in vitamin B12 deficiency. This distorts the pattern of fatty acid synthesis in neural tissue and may be the basis of neuropathy in vitamin B12 deficiency.
Administration of vitamin B12
The vitamin may be administered orally (for dietary deficiencies), intramuscularly, or deep subcutaneously (for pernicious anemia). Intramuscular hydroxocobalamin is now preferred since it has a rapid response, is highly protein bound, and maintains longer plasma levels.

23. Hematopoietic Growth Factors
Hematopoietic growth factors are endogenous glycoproteins that bind to specific receptors on bone marrow progenitor cells and induce their differentiation and proliferation, thereby increasing production of erythrocytes and various leukocytes. Several growth factors are now available for treating anemia or leukopenia. These growth factors are produced by recombinant DNA technology and are administered parenterally.
Erythropoietin and Darbepoetin
Peritubular cells in the kidneys work as sensors that respond to hypoxia and mediate synthesis and release of erythropoietin(EPO) , a glycoprotein. EPO stimulates stem cells to differentiate into proerythroblasts and promotes the release of reticulocytes from the marrow and initiation of hemoglobin formation. EPO, thus, regulates red blood cell proliferation and differentiation in bone marrow.
Human erythropoietin (epoetin alfa), produced by recombinant DNA technology, is effective in the treatment of anemia caused by end-stage renal disease, anemia associated with human immunodeficiency virus infection, anemia in bone marrow disorders, anemia of prematurity, and anemias in some cancer patients.

25. Darbepoetin is a long-acting version of erythropoietin that differs from erythropoietin by the addition of two carbohydrate chains, which improves its biologic activity. Therefore, darbepoetin has decreased clearance and has a half-life about three times that of epoetin alfa.
Due to their delayed onset of action, these agents have no value in acute treatment of anemia. Supplementation with iron may be required to ensure an adequate response.
The protein is usually administered intravenously in renal dialysis patients, but the subcutaneous route is preferred for other indications.
These agents are generally well tolerated, but side effects may include elevation in blood pressure and arthralgia in some cases. [Note: The former may be due to increases in peripheral vascular resistance and/or blood viscosity.]
When epoetin alfa is used to target hemoglobin concentrations more than 11 g/dL, serious cardiovascular events such as thrombosis and severe hypertension & increased risk of death have been observed. The recommendations for all patients receiving epoetin alfa or darbepoetin include a minimum effective dose that does not exceed a hemoglobin level of 12 g/dL, and the hemoglobin should not rise by more than 1 g/dL over a 2-week period. Additionally, if the hemoglobin level exceeds 10 g/dL, doses of epoetin alfa or darbepoetin should be reduced or treatment should be discontinued.

26. Filgrastim, Pegfilgrastim, and Sargramostim
Filgrastim is recombinant human granulocyte colony- stimulating factor (G-CSF), and sargramostim is recombinant human granulocyte-macrophage CSF (GM-CSF). The endogenous forms of these growth factors are produced by various leukocytes, fibroblasts, and endothelial cells.
The addition of a PEG moiety to filgrastim (pegylation) creates pegfilgrastim, whose molecular size is too large to enable renal clearance, thereby increasing the half-life from about 3.5 hours for filgrastim to 42 hours for pegfilgrastim. Pegfilgrastim is eliminated primarily by neutrophil uptake and metabolism. The longer half-life of pegfilgrastim has enabled less-frequent administration for treating cancer chemotherapy–induced neutropenia.
Filgrastim, pegfilgrastim, and sargramostim are used primarily to treat neutropenia associated with cancer chemotherapy and bone marrow transplantation.
Studies indicate that filgrastim may be beneficial in the treatment of aplastic anemia, hairy cell leukemia, myelodysplasia, drug-induced and congenital agranulocytosis, and other forms of congenital or acquired neutropenia.

27. Sargramostim is used to accelerate myeloid cell recovery in patients who have lymphoma, acute lymphoblastic leukemia, or Hodgkin disease and are undergoing autologous bone marrow transplantation or chemotherapy. It has also been used to reduce the incidence of fever and infections in patients with severe chronic neutropenia.
Filgrastim and sargramostim are administered subcutaneously or intravenously once a day for 2 weeks
Adverse effects: Gastrointestinal effects, fever, bone pain, myalgia and rash are recognised adverse effects; less common effects include pulmonary infiltrates and enlargement of liver or spleen.