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DRUGS USED TO TREAT DISEASES OF THE BLOOD Presented by Dr. Sasan Zaeri ParmD, PhD March, 2016 Agents Used in Anemias; Hematopoietic Growth Factors • Hematopoiesis: – the production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes • Essential factors: – Iron, vitamin B12, folic acid and hematopoietic growth factors • Inadequate supply results in: – Anemia, thrombocytopenia and neutropenia 2 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 Pharmacokinetics 4 Pharmacokinetics • 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 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 (Fe2+) before it can be absorbed 6 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 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 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 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 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 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 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 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 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 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 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 Clinical Pharmacology Parenteral iron therapy • Alternative preparations to iron-dextran: Ironsucrose and iron-gluconate – Can be given only by IM route – Less likely than iron dextran to cause hypersensitivity reactions 18 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 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 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 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 AGENTS USED IN ANEMIAS: Vitamin B12 • Vitamin B12 serves as a cofactor for several essential biochemical reactions in humans • Deficiency of vitamin B12 leads to – anemia – gastrointestinal symptoms – neurologic abnormalities • Most common cause of B12 deficiency: – inadequate absorption of dietary vitamin B12 especially in older adults • Active forms of the vitamin in humans: – Deoxyadenosylcobalamin – Methylcobalamin 23 VITAMIN B12 • 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 B12 : – Meat, liver, eggs and dairy products • Vitamin B12 is sometimes called extrinsic factor to differentiate it from intrinsic factor 24 Pharmacokinetics • Vitamin B12 is avidly stored in the liver – with an average total storage pool of 3000-5000 mcg (Lasting for 5 years) • Vitamin B12 is absorbed only after it complexes with intrinsic factor secreted by the parietal cells of the gastric mucosa – intrinsic factor-vitamin B12 complex is subsequently absorbed in the distal ileum • Vitamin B12 deficiency results from malabsorption of vitamin B12 due to – lack of intrinsic factor – loss or malfunction of the specific absorptive mechanism in the distal ileum 25 Pharmacodynamics 26 Pharmacodynamics • Methylcobalamin converts N5methyltetrahydrofolate to tetrahydrofolate • N5-methyltetrahydrofolate: major dietary and storage folate – Tetrahydrofolate: precursor of folate cofactors • ↓ Vitamin B12 → ↓ Tetrahydrofolate → ↓folate cofactors → ↓dTMP and purines and DNA in rapidly dividing cells 27 Pharmacodynamics • Methylfolate trap: – The accumulation of folate as N5methyltetrahydrofolate and the associated depletion of tetrahydrofolate cofactors in vitamin B12 deficiency • Folic acid can be reduced to dihydrofolate and tetrahydrofolate by the enzyme dihydrofolate reductase – this explains why the megaloblastic anemia of vitamin B12 deficiency can be partially corrected by ingestion of relatively large amounts of folic acid 28 Pharmacodynamics • Administration of folic acid in the setting of vitamin B12 deficiency will not prevent neurologic manifestations 29 Clinical Pharmacology • Vitamin B12 deficiency manifestations: – megaloblastic anemia (most characteristic clinical manifestation) – The neurologic syndrome • paresthesias, weakness ,ataxia, other central nervous system dysfunctions • Correction of vitamin B12 deficiency arrests the progression of neurologic disease, but it may not fully reverse neurologic symptoms that have been present for several months 30 Clinical Pharmacology • Upon diagnosis of megaloblastic anemia: – it must be determined whether vitamin B12 or folic acid deficiency is the cause • This can usually be accomplished by measuring serum levels of the vitamins • If vitamin B12 deficiency is the cause, – The Schilling test, which measures absorption and urinary excretion of radioactively labeled vitamin B12, can be used to further define the mechanism of vitamin B12 malabsorption 31 Clinical Pharmacology • The most common causes of vitamin B12 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 B12 – absorption is corrected when intrinsic factor is administered with radioactive B12 32 Clinical Pharmacology • conditions that distal ileum is damaged: – inflammatory bowel disease – Surgical resection of the ilium • In the above situations, radioactively labeled vitamin B12 is not absorbed in the Schilling test, even when intrinsic factor is added 33 Clinical Pharmacology • Treatment of vitamin B12 deficiency – Parenteral injections of vitamin B12 are required for therapy – Vitamin B12 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 B12 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 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 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 Clinical Pharmacology • Folate deficiency results in a megaloblastic anemia that is indistinguishable from the anemia caused by vitamin B12 deficiency – folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency 37 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 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 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 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 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 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 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 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 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 Clinical Pharmacology • The most common adverse effects of erythropoietin: – – hypertension and thrombotic complications due to a rapid increase in hematocrit and hemoglobin 47 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 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 Pharmacodynamics • GM-CSF has broader biologic actions than GCSF – 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 GCSF 50 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 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 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 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 MEGAKARYOCYTE GROWTH FACTORS • Oprelvekin – the recombinant form of interleukin-11 55 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 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