PHM 1.01-Agents Used In Cytopenia Hematopoietic Growth Factors.docx (1).pdf

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 OVERVIEW ❖ ❖ ❖ HEMATOPOIESIS Production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes The hematop...

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 OVERVIEW ❖ ❖ ❖ HEMATOPOIESIS Production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes The hematopoietic machinery resides primarily in the bone marrow in adults and requires a constant supply of three essential nutrients: As well as the presence of hematopoietic growth factors, proteins that regulate the proliferation and differentiation of hematopoietic cells A. Iron B. Vitamin B12 C. Folic acid Inadequate supplies of either the essential nutrients or the growth factors result in deficiency of functional blood cells ❖ ❖ HEMATOPOIESIS AGENTS USED IN ANEMIA ○ IRON ○ VITAMIN B12 ○ FOLIC ACID HEMATOPOIETIC GROWTH FACTOR ○ ERYTHROPOIETIN ○ MYELOID GROWTH FACTOR ○ MEGAKARYOCYTE GROWTH FACTOR APPENDIX ❖ pale RBCs Nice to know: Microcytic anemia is defined as the presence of small, often hypochromic, red blood cells in a peripheral blood smear and is usually characterized by a low MCV (less than 83 micron 3). ★ Iron deficiency is the most common cause of microcytic anemia. ❖ ❖ IRON DISTRIBUTION IN NORMAL ADULTS Sickle cell anemia Condition resulting from a genetic alteration in the hemoglobin molecule Common but is not easily treated Thrombocytopenia and neutropenia Not rare, and some forms are amenable to drug therapy ★ Is readily available - ❖ A. IRON: ❖ ❖ “PHARMACOKINETIC” Iron is required for essential proteins such as hemoglobin The system uses specialized transport, storage, ferroreductase, and ferroxidase proteins whose concentrations are controlled by the body’s demand for hemoglobin synthesis and adequate iron stores ANEMIA Deficiency in oxygen-carrying erythrocytes Most common deficiency in erythropoiesis Several forms are easily treated AGENTS USED IN ANEMIAS ❖ In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to microcytic hypochromic anemia - Small and “BASIC PHARMACOLOGY” Iron deficiency Most common cause of chronic anemia Clinically: pallor fatigue dizziness exertional dyspnea other generalized symptoms of tissue hypoxia Cardiovascular adaptation to chronic anemia—tachycardia, increased cardiac output, vasodilation Iron from the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin ► reversibly binds oxygen and provides the critical mechanism for oxygen delivery from the lungs to other tissues 1 | Page ❖ ❖ Comparing the average 80-kg male and female, there are more hemoglobin in men or the iron content in men is stored greater as compared to those in women One of the factors that makes women susceptible to iron deficiency anemias. Thus, it needs more supplementation of iron. HEPCIDIN Produced primarily by the liver cells Key central regulator of the system ★ This regulates the system of storage and release of iron in the body. Nearly all of the iron used to support hematopoiesis is reclaimed from catalysis of the hemoglobin in senescent or damaged erythrocytes ★ Once an RBC or erythrocyte is damaged or gets old (21 days in cycle). The iron content in these is usually reabsorbed by the body (very efficient sya) so you need HEPCIDIN to regulate all of these processes. Normally: Only a small amount of iron is lost from the body each day Dietary requirements are small and easily fulfilled by the iron available in a wide variety of foods Special population (who needs more iron) with: Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 Increased iron requirements (e.g. growing children, pregnant women Increased losses of iron (e.g. menstruating women) a. ABSORPTION ❖ The average diet contains 10-15mg of elemental iron daily Normal absorption ► 5-10 %(0.5-1mg) daily ❖ Iron is absorbed in the duodenum and proximal jejunum ❖ Iron absorption increases in response to low iron stores or increased iron requirements ❖ Total iron absorption increases to 1-2mg/d in menstruating women and may be as high as 3-4 mg/d in pregnant women ❖ Iron is available in a wide variety of foods but is especially abundant in red meat ❖ the iron in meat protein can be efficiently absorbed, because heme iron in meat myoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron ❖ iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption Nice to know: Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms a. Active transport of ferrous iron by the divalent metal transporter DMT1 b. Absorption of iron complexed with heme Together with iron split from absorbed heme, the newly absorbed iron can be actively transported into the blood across the basolateral membrane by a transporter known as ferroportin and oxidized to ferric iron by the ferroxidase hephaestin - the liver-derived hepcidin inhibits intestinal cell iron released by binding to ferroportin and triggering its internalization and destruction Excess iron is stored in intestinal epithelial cells as FERRITIN, a water-soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin b. TRANSPORT ❖ Iron is transported in the plasma bound to transferrin, a β-globulin that can bind to two molecules of ferric iron ❖ Transferrin receptors- integral membrane glycoproteins present in large numbers on proliferating erythroid cells—bind and internalize the transferrin-iron complex through the process of receptor-mediated endocytosis ❖ In endosomes, the ferric iron is released, reduced to ferrous iron, and transported by 2 | Page DMT1 into the cytoplasm, where it is funneled into hemoglobin synthesis or stored as ferritin ❖ The transferrin receptor complex is recycled to the cell membrane, where the transferrin dissociated and returns to the plasma This process provides an efficient mechanism for supplying the iron required by developing red blood cells ❖ Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells and a reduction in hepatic hepcidin release ❖ Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin, c. so, in turn, activates more receptors in the hopes of increasing iron STORAGE ❖ In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in liver, spleen, bone, and in parenchymal liver cells ❖ The mobilization of iron from macrophages and hepatocytes is primarily controlled by hepcidin regulation of ferroportin activity Low hepcidin concentrations result in iron release from these storage sites High hepcidin concentrations inhibit iron release ❖ Ferritin is detectable in serum Nice to know: Since the ferritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues, the serum ferritin level can be used to estimate total body iron store d. ELIMINATION ❖ There is no mechanism for excretion of iron ❖ Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat ❖ These losses account for no more than 1mg or iron per day ❖ Because the body’s ability to excrete iron is so limited, regulation of iron balance must be achieved by changing intestinal absorption and storage of iron in response to the body’s needs “CLINICAL PHARMACOLOGY” A. Indication for the use of Iron ❖ The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia ❖ Most common cause of iron deficiency in adults is blood loss ❖ Menstruating women lose about 30mg of iron with each menstrual period Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 ❖ Many premenopausal women have low iron stores or even iron deficiency Nice to know: In men and postmenopausal women, the most common site of blood loss is the GIT. Patients with unexplained iron deficiency anemia should be evaluated for occult gastrointestinal bleeding Populations with increased iron requirements: Infants (esp. premature infants) Children during rapid growth periods Pregnant and lactating women Patients with chronic kidney disease Inadequate iron absorption After gastrectomy Severe small bowel disease that results in generalized malabsorption This manifests as hypochromic, microcytic anemia in which the erythrocyte mean cell volume (MCV) and the mean cell hemoglobin concentration are low erythropoietin; for these patients, parenteral iron administration is preferred. 1. Oral Iron Therapy ❖ Because ferrous iron is most efficiently absorbed, ferrous salts should be used Ferrous sulfate Ferrous gluconate Ferrous fumarate ❖ An iron-deficient individual, about 50-100mg iron can be incorporated into hemoglobin daily, and about 25% of oral iron given as ferrous salt can be absorbed ❖ 200-400mg of elemental iron should be given daily to correct iron deficiency most rapidly ❖ Treatment with oral iron should be continued for 3-6 months after correction of the cause of the iron loss ❖ Common adverse effects: Nausea, epigastric discomfort, abdominal cramps, constipation and diarrhea ❖ Usually dose-related and often can be overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals ❖ Patients taking oral iron develop black stools; this has no clinical significance in itself but may obscure the diagnosis of continued gastrointestinal blood loss 2. Parenteral Iron therapy ❖ Should be reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron and for patients with extensive chronic anemia who cannot be maintained with oral iron alone Advanced chronic renal disease requiring hemodialysis and treatment with EPO Various postgastrectomy conditions and previous small bowel resection Inflammatory bowel disease involving the proximal bowel Malabsorption syndromes This table shows nutritional deficiencies B. Treatment ❖ IRON DEFICIENCY ANEMIA Treated 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 GIT is normal Nice to know: An exception is the high requirement for iron of patients with advanced chronic kidney disease who are undergoing hemodialysis and treatment with 3 | Page Nice to know: Inorganic free ferric iron produces serious dose dependent toxicity Three traditional forms of parenteral iron are iron dextran, sodium ferric gluconate complex, and iron sucrose “CLINICAL TOXICITY” A. Acute Iron Toxicity ❖ Seen almost exclusively in young children who accidentally ingest iron tablets ❖ As few as 10 tablets of any of the commonly available oral iron preparations can be lethal in young children Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 ❖ ❖ ❖ ❖ ❖ Children who are poisoned with oral experience necrotizing gastroenteritis with vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea Subsequently, improvements are often noted, but this may be followed by severe metabolic acidosis, coma, and death. Urgent treatment is necessary Whole bowel irrigation should be performed to flush out unabsorbed pills Deferoxamine, a potent iron-chelating compound, can be given IV to bind iron that has already been absorbed and to promote its excretion in urine and feces Activated charcoal, a highly effective absorbent for most toxins, does not bind iron and thus is ineffective B. Chronic Iron Toxicity ❖ “Iron overload”, also known as Hemochromatosis, results when excess iron is deposited in the heart, liver, pancreas, and other organs ❖ It can lead to organ failure and death ❖ It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (e.g. individuals with β-thalassemia) ❖ Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy B. VITAMIN B12 ❖ Deficiency of vitamin B12 leads to: megaloblastic anemia, gastrointestinal symptoms, neurologic abnormalities. ❖ Although deficiency of vitamin B12 due to an inadequate supply in the diet is unusual, The deficiency of B12 in adults—especially older adults ► due to inadequate absorption of dietary vitamin B12 is a relatively common and easily treated disorder. ❖ ❖ ❖ ❖ ❖ “CHEMISTRY” 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. Active forms of the vitamin in humans: Deoxyadenosylcobalamin Methylcobalamin Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the active forms. The ultimate source of vitamin B12 is from microbial synthesis The vitamin is not synthesized by animals or plants. ❖ ❖ ❖ ❖ Vitamin B12 is sometimes called extrinsic factor to differentiate it from intrinsic factor a protein secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B12. “PHARMACOKINETICS” The average American diet contains 5–30 mcg of vitamin B12 daily 1–5 mcg of which is usually absorbed. The vitamin is avidly stored, primarily in the liver, with an average adult having a total vitamin B12 storage pool of 3000–5000 mcg. Only trace amounts of vitamin B12 are normally lost in urine and stool. Because the normal daily requirements of vitamin B12 are only about 2 mcg it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if B12 absorption were stopped. Nice to know: Vitamin B12 is absorbed after it complexes with intrinsic factor (a glycoprotein secreted by the parietal cells of the gastric mucosa) ❖ ❖ ❖ ❖ ❖ 4 | Page The chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. ★ Once your B12 source is ingested especially the meat, liver, eggs and other dairy products → the compound is broken down by the bacteria →synthesized → enzymes acting on them → to release the cobalamin Intrinsic factor combines with the vitamin B12 that is liberated from dietary sources in the stomach and duodenum → the intrinsic factor–vitamin B12 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system. Vitamin B12 deficiency in humans most often results from malabsorption of vitamin B12 due to: lack of intrinsic factor or loss or malfunction of the absorptive mechanism in the distal ileum Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. Once absorbed, vitamin B12 is transported to the various cells of the body bound to a family of specialized glycoproteins, transcobalamin I, II, and III Excess vitamin B12 is stored in the liver. “CLINICAL PHARMACOLOGY” Vitamin B12 is used to treat or deficiency. prevent Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 Most characteristic clinical manifestation of vitamin B12 deficiency is: megaloblastic, macrocytic anemia, often with associated mild or moderate leukopenia or thrombocytopenia (or both) a characteristic hypercellular bone marrow with an accumulation of megaloblastic erythroid and other precursor cells Neurologic syndrome associated with vitamin B12 deficiency: usually begins with paresthesia in peripheral nerves and weakness and progresses to spasticity, ataxia, and other central nervous system dysfunctions ❖ ❖ ❖ Nice to know: 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. Schilling Test (It is not used at the present) ○ Measures absorption and urinary excretion of radioactively labeled vitamin B12 ○ Can be used to further define the mechanism of vitamin B12 malabsorption when this is found to be the cause of megaloblastic anemia. Strict vegans eating a diet free of meat and dairy products may become B12 deficient. Most common causes of vitamin B12 deficiency: Pernicious anemia partial or total gastrectomy conditions that affect the distal ileum, such as malabsorption syndromes, inflammatory bowel disease, or small bowel resection ❖ PERNICIOUS ANEMIA Results from defective secretion of intrinsic factor by the gastric mucosal cells. Patients with pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as well as hydrochloric acid). Patients frequently have autoantibodies to intrinsic factor. Rare cases of vitamin B12 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor or to defects of the receptor sites for vitamin B12–intrinsic factor complex located in the distal ileum. Alternatives to the Schilling test include testing for intrinsic factor antibodies and testing for elevated homocysteine and methylmalonic acid levels to make a diagnosis of pernicious anemia with high sensitivity and specificity. Almost all cases of vitamin B12 deficiency are caused by malabsorption of the vitamin; 5 | Page therefore, parenteral injections of vitamin B12 are required for therapy. For patients with potentially reversible diseases, the underlying disease should be treated after initial treatment with parenteral vitamin B12. Most patients, however, do not have curable deficiency syndromes and require lifelong treatment with vitamin B12. Vitamin B12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin. Hydroxocobalamin is preferred It is more highly protein-bound and therefore remains longer in the circulation. Initial therapy should consist of 100–1000 mcg of vitamin B12 intramuscularly daily or every other day for 1–2 weeks to replenish body stores Maintenance therapy consists of 100–1000 mcg intramuscularly once a month for life. C. FOLIC ACID ❖ Reduced forms of folic acid are required for essential biochemical reactions that provide precursors for the synthesis of amino acids,purines, and DNA. ❖ Folate deficiency is relatively common, even though the deficiency is easily corrected by administration of folic acid The consequences of folate deficiency go beyond the problem of anemia because folate deficiency is implicated as a cause of congenital malformations in newborns and may play a role in vascular disease. ❖ ❖ ❖ ❖ ❖ ❖ ❖ “PHARMACOKINETICS” The average American diet contains 500–700 mcg of folates daily 50–200 mcg of which is usually absorbed, depending on metabolic requirements. Pregnant women may absorb as much as 300–400 mcg of folic acid daily. Present in a wide variety of plant and animal tissues richest sources are yeast, liver, kidney, and green vegetables Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Normally, 5–20 mg of folates is stored in the liver and other tissues. Folates are excreted in the urine and stool are also destroyed by catabolism, so serum levels fall within a few days when intake is diminished. 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, depending on the patient’s nutritional status and the rate of folate utilization. Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 Nice to know: Dietary folates, however, consist primarily of polyglutamate forms of N5 -methyltetrahydrofolate. Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme α-1-glutamyl transferase (“conjugase”) within the brush border of the intestinal mucosa. The monoglutamate N5 -methyltetrahydrofolate is subsequently transported into the bloodstream by both active and passive transport and is then widely distributed throughout the body. ❖ ❖ ❖ ❖ ❖ ❖ ❖ ❖ ❖ “CLINICAL PHARMACOLOGY” Folate deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B12 deficiency. Folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency. Folic acid deficiency is often caused by inadequate dietary intake of folates. ★ The manifestations are usually more important to newborns. Nice to know: Patients with alcohol dependence and patients with liver disease can develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. Patients with malabsorption syndromes also frequently develop folic acid deficiency. Patients who require renal dialysis are at risk of folicacid deficiency because folates are removed from the plasma during the dialysis procedure. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects Folic acid deficiency can be caused by drugs Methotrexate and, to a lesser extent, trimethoprim and pyrimethamine inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. Long-term therapy with phenytoin also can cause folate deficiency, but it only rarely causes megaloblastic anemia Parenteral administration of folic acid is rarely necessary. A dose of 1 mg folic acid orally daily is sufficient to: 6 | Page Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients: including pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis. HEMATOPOIETIC GROWTH FACTORS The factors which induced the maturation of cell lineage Inside cells, N5 -methyltetrahydro-folate is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12. ❖ reverse megaloblastic anemia restore normal serum folate levels replenish body stores of folates (in almost all patients) ❖ The hematopoietic growth factors are glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. The first growth factors to be identified were called “colony-stimulating factors” because they could stimulate the growth of colonies of various bone marrow progenitor cells in vitro. Currently in clinical use: Erythropoietin (epoetin alfa and epoetin beta) Granulocyte colony-stimulating factor (G-CSF) Granulocyte-macrophage colony stimulating factor(GM-CSF) Interleukin 11 (IL-11) Thrombopoietin receptor agonists (Romiplostim and Eltrombopag) A. ERYTHROPOIETIN “CHEMISTRY & PHARMACOKINETICS” ❖ ❖ ❖ ❖ ❖ ❖ ❖ Erythropoietin a 34- to 39-kDa glycoprotein was the first human hematopoietic growth factor to be isolated. It was originally purified from the urine of patients with severe anemia. Recombinant human erythropoietin (rHuEPO, epoetin alfa) is produced in a mammalian cell expression system. Serum half-life of 4–13 hours in patients with chronic renal failure. ★ This is given to patients with chronic renal failure because the erythropoietin production in patients with chronic kidney disease is very low, maganda yung preparation because this are not cleared by the dialysis. It can be given together with patients undergoing dialysis. It is not cleared by dialysis “PHARMACODYNAMICS” Stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors. Erythropoietin receptor is a member of the JAK/ STAT superfamily of cytokine receptors that use Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 ❖ ❖ ❖ ❖ ❖ ❖ protein phosphorylation and transcription factor activation to regulate cellular function. Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is produced primarily in the kidney. ★ In patients with chronic kidney disease, the kidneys become insufficient- that cannot produce erythropoietin, so exogenous or outside erythropoietin is needed. Nice to know: In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the erythropoietin gene. 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 (see below), or bone marrow suppression from drugs or chronic diseases. Normally, an inverse relationship exists between the hematocrit or hemoglobin level and the serum erythropoietin level. Nonanemic individuals have serum erythropoietin levels of < 20 IU/L. As the hematocrit and hemoglobin levels fall and anemia becomes more severe, the serum erythropoietin level rises exponentially. Patients with moderately severe anemia usually have erythropoietin levels in the 100–500 IU/L range Patients with severe anemia may have levels of thousands of IU/L. 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 patients most likely to respond to treatment with exogenous erythropoietin Nice to know: In most primary bone marrow disorders (aplastic anemia, leukemias, myeloproliferative and myelodysplastic disorders, etc.) and most nutritional and secondary anemias, endogenous erythropoietin levels are high, so there is less likelihood of a response to exogenous erythropoietin. ❖ ❖ ❖ “CLINICAL PHARMACOLOGY” The ESAs consistently improve the hematocrit and hemoglobin level, often eliminate the need for transfusions, and reliably improve quality of life indices. The ESAs are used routinely in patients with anemia secondary to chronic kidney disease. In patients treated with an ESA, an increase in reticulocyte count is usually observed in about 10 days and an increase in hematocrit and hemoglobin levels in 2–6 weeks. 7 | Page Dosages of ESAs are adjusted to maintain a target hemoglobin up to, but not exceeding, 10–12 g/dL. To support the increased erythropoiesis, nearly all patients with chronic kidney disease require oral or parenteral iron supplementation. Folate supplementation may also be necessary in some patients. ❖ ❖ Nice to know: Erythropoietin is one of the drugs commonly used illegally by endurance athletes to enhance performance. Other methods such as autologous transfusion of red cells or use of androgens also have been used to increase hemoglobin. “Blood doping” constitutes a serious health risk to athletes and as a form of cheating is universally banned and routinely tested for in athletic events. “TOXICITY” Most common adverse effects of erythropoietin: hypertension thrombotic complications ESAs increase the risk of serious cardiovascular events, thromboembolic events, stroke, and mortality in clinical studies when given to support hemoglobin levels greater than 11 g/dL. Allergic reactions to ESAs have been infrequent. ❖ ❖ ❖ Nice to know: small number of cases of pure red cell aplasia (PRCA) accompanied by neutralizing antibodies to erythropoietin. PRCA was most commonly seen in dialysis patients treated subcutaneously for a long period with a particular form of epoetin alfa B. MYELOID GROWTH FACTORS “CHEMISTRY & PHARMACOKINETICS” G-CSF and GM-CSF, the two myeloid growth factors currently available for clinical use Recombinant human G-CSF (rHuG-CSF; filgrastim) is produced in a bacterial expression system. Tbo-filgrastim is similar to filgrastim, with minor structural differences and equivalent activity. ❖ ❖ ❖ Nice to know: Recombinant human GM-CSF (rHuGM-CSF; sargramostim) produced in a yeast expression system. It is a partially glycosylated peptide of 127 amino acids, comprising three molecular species with molecular weights of 15,500, 15,800, and 19,500. Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 - These preparations have serum half-lives of 2–7 hours after intravenous or subcutaneous administration. ❖ G-CSF dramatically accelerates the rate of neutrophil recovery after dose-intensive myelosuppressive chemotherapy (becomes a part of the chemotherapy protocol) reduces the duration of neutropenia and usually raises the nadir count, the lowest neutrophil count seen following a cycle of chemotherapy ❖ Clinical guidelines for the use of G-CSF after cytotoxic chemotherapy recommend reserving G-CSF for: patients at high risk for febrile neutropenia based on age, medical history, and disease characteristics; patients receiving dose-intensive chemotherapy regimens that carry a greater than 20% risk of causing febrile neutropenia patients with a prior episode of febrile neutropenia after cytotoxic chemotherapy patients at high risk for febrile neutropenia patients who are unlikely to survive an episode of febrile neutropenia Pegfilgrastim a covalent conjugation product of filgrastim and a form of polyethylene glycol has a much longer serum half-life than recombinant G-CSF it can be injected once per myelosuppressive chemotherapy cycle instead of daily for several days. - Lenograstim used widely in Europe, is a glycosylated form of recombinant G-CSF “PHARMACODYNAMICS” The myeloid growth factors stimulate proliferation and differentiation by interacting with specific receptors found on myeloid progenitor cells (Granulocytes, Monocytes, Megakaryocytes, and Dendritic Cells). G-CSF stimulates proliferation and differentiation of progenitors already committed to the neutrophil lineage. activates the phagocytic activity of mature neutrophils and prolongs their survival in the circulation G-CSF also has a remarkable ability to mobilize hematopoietic stem cells, i.e., 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 ❖ ❖ ❖ ❖ Nice to know: broader biologic GM-CSF has actions than G-CSF. It is a multipotential hematopoietic growth factor that stimulates proliferation and differentiation of early and late granulocytic progenitor cells as well as erythroid and megakaryocyte progenitors. Like G-CSF, GM-CSF also stimulates the function of mature neutrophils. GM-CSF acts together with interleukin-2 to stimulate T-cell proliferation and appears to be a locally active factor at the site of inflammation. GM-CSF mobilizes peripheral blood stem cells, but it is significantly less efficacious and more toxic than G-CSF in this regard. “CLINICAL PHARMACOLOGY” Cancer Chemotherapy- Induced Neutropenia ❖ Neutropenia is a common adverse effect of the cytotoxic drugs used to treat cancer 8 | Page increases the risk of serious infection in patients receiving chemotherapy Nice to know: Pegfilgrastim is an alternative to G-CSF for prevention of chemotherapy-induced febrile neutropenia can be administered once per chemotherapy cycle, and it may shorten the period of severe neutropenia slightly more than G-CSF. Like G-CSF and pegfilgrastim, GM-CSF also reduces the duration of neutropenia after cytotoxic chemotherapy. Other Applications ❖ G-CSF and GM-CSF have also proved to be effective in treating the: neutropenia associated with congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia. ❖ Many patients with these disorders respond with a prompt and sometimes dramatic increase in neutrophil count. In some cases, this results in a decrease in the frequency of infections IMPORTANT TO KNOW: Because neither G-CSF nor GM-CSF stimulates the formation of erythrocytes and platelets, they are sometimes combined with other growth factors for treatment of pancytopenia. ❖ The myeloid growth factors play an important role in autologous stem cell transplantation for patients undergoing high-dose chemotherapy High-dose chemotherapy with autologous stem cell support is increasingly used to treat Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 patients with tumors that are resistant to standard doses of chemotherapeutic drugs. The high-dose regimens produce extreme myelosuppression. 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 reduces the time to engraftment and to recovery fromneutropenia in patients receiving stem cellsobtained either from bone marrow or from peripheral blood. These effects are seen in patients being treated for lymphoma or for solid tumors. ❖ ❖ ❖ ❖ ❖ ❖ G-CSF and GM-CSF are also used to support patients who have received allogeneic bone marrow transplantation for treatment of hematologic malignancies or bone marrow failure states. In this setting, the growth factors speed the recovery from neutropenia without increasing the incidence of acute graft versus-host disease. Perhaps the most important role of the myeloid growth factors in transplantation is for mobilization of PBSCs. ❖ ❖ “TOXICITY” G-CSF and pegfilgrastim are used more frequently than GM-CSF because they are better tolerated. G-CSF and pegfilgrastim can cause bone pain, which clears when the drugs are discontinued. GM-CSF can cause more severe side effects, particularly at higher doses: fever, malaise, arthralgias, myalgias, and a capillary leak syndrome characterized by peripheral edema pleural or pericardial effusions Allergic reactions may occur but are infrequent. C. MEGAKARYOCYTE GROWTH FACTORS ❖ Patients with thrombocytopenia have a high risk of hemorrhage. ❖ Although platelet transfusion is common used to treat thrombocytopenia, this procedure can cause adverse reactions in the recipient furthermore, a significant number of patients fail to exhibit the expected increase in platelet count ❖ Thrombopoietin (TPO) and IL-11 both appear to be key endogenous regulators of platelet production. ❖ A recombinant form of IL-11 was the first agent to gain FDA approval for treatment of thrombocytopenia. 9 | Page ❖ ❖ ❖ Two thrombopoietin agonists (romiplostim and eltrombopag) are approved for treatment of thrombocytopenia. “CHEMISTRY & PHARMACOKINETICS” Interleukin-11 is a 65- to 85-kDa protein produced by fibroblasts and stromal cells in the bone marrow. Oprelvekin recombinant form of IL-11 approved for clinical use produced by expression in Escherichia coli. half-life of IL-11 is 7–8 hours when the drug is injected subcutaneously. Romiplostim a thrombopoietin agonist peptide covalently linked to antibody fragments that serve to extend the peptide’s half-life. The Mpl-binding peptide has no sequence homology with human thrombopoietin, and there is no evidence in animal or human studies that the Mpl-binding peptide or romiplostim induces antibodies to thrombopoietin. After subcutaneous administration, romiplostim is eliminated by the reticuloendothelial system with an average half-life of 3–4 days. Its half-life is inversely related to the serum platelet count It has a longer half-life in patients with thrombocytopenia and a shorter half-life in patients whose platelet counts have recovered to normal levels. Romiplostim is approved for therapy of patients with chronic immune thrombocytopenia who have had an inadequate response to other therapies. Eltrombopag an orally active small nonpeptide thrombopoietin agonist molecule approved for therapy of patients with chronic immune thrombocytopenia who have had an inadequate response to other therapies for treatment of thrombocytopenia in patients with hepatitis C to allow initiation of interferon therapy. Following oral administration, peak eltrombopag levels are observed in 2–6 hours and the half-life is 26–35 hours. Eltrombopag is excreted primarily in the feces. “PHARMACODYNAMICS” Interleukin-11 acts through a 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 most importantly, increases the number of peripheral platelets and neutrophils Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 ❖ ❖ ❖ ❖ ❖ ❖ ❖ Romiplostim has high affinity for the human Mpl receptor. administered once weekly by subcutaneous injection. Eltrombopag is an oral drug interacts with the transmembrane domain of the Mpl receptor. Both Drugs induce signaling through the Mpl receptor pathway and cause a dose-dependent increase in platelet count. peak platelet count responses are observed in approximately 2 weeks. “CLINICAL PHARMACOLOGY” Interleukin-11 is approved for the secondary prevention of thrombocytopenia in patients receiving cytotoxic chemotherapy for treatment of non myeloid 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. Although IL-11 has broad stimulatory effects on hematopoietic cell lineages in vitro it does not appear to have significant effects on the leukopenia caused by myelosuppressive chemotherapy. Interleukin-11 is given by subcutaneous injection at a dose of 50 mcg/kg daily. It is started 6–24 hours after completion of chemotherapy and continues for 14–21 days or until the platelet count passes the nadir and rises to more than 50,000 cells/μL. Nice to know: In patients with chronic immune thrombocytopenia who failed to respond adequately to previous treatment with steroids, immunoglobulins, or splenectomy, romiplostim and eltrombopag significantly increase platelet count in most patients. Both drugs are used at the minimal dose required to maintain platelet counts of greater than 50,000 cells/μL. “TOXICITY” most common adverse effects of IL-11 are: fatigue, headache, dizziness, and cardiovascular effects. cardiovascular effects include anemia (due to hemodilution), dyspnea (due to fluid accumulation in the lungs), and transient atrial arrhythmias Hypokalemia also has been seen in some patients. ❖ ❖ Portal vein thrombosis also has been reported with eltrombopag and romiplostim in the setting of chronic liver disease. In patients with myelodysplastic syndromes, romiplostim increases the blast count and risk of progression to acute myeloid leukemia. Marrow fibrosis has been observed with thrombopoietin agonists but is generally reversible when the drug is discontinued. Rebound thrombocytopenia has been observed following discontinuation of TPO agonists CHECKPOINT: T/F: The ultimate source of vitamin B12 is from microbial synthesis and it is synthesized by animals or plants. 2. T/F: Folate deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B12 deficiency. 3. T/F: Erythropoietin is given to patients with chronic renal failure because it is not cleared by the dialysis that is why it can be given together with patients undergoing dialysis. 4. T/F: Interleukin-11 is approved for the secondary prevention of thrombocytopenia in patients receiving cytotoxic chemotherapy for treatment of non myeloid cancers. 5. T/F: Neither G-CSF nor GM-CSF does not stimulate the formation of erythrocytes and platelets. 6. Where is iron absorbed? 7. In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ________. 8. Hepcidin is primarily produced by the ____ ___. 9. __________, a potent iron-chelating compound, can be given IV to bind iron that has already been absorbed and to promote its excretion in urine and feces. 10. Also known as “chronic iron toxicity” or “iron overload” 1. F / F / T / T / F / duodenum & jejunum / ferritin / liver cells / Deferoxamine / Hemochromatosis Nice to know: Eltrombopag is potentially hepatotoxic and liver function must be monitored, particularly when used in patients with hepatitis C. 10 | Page Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 11 | Page Klem,Jenna,Cam,Charie,Apple PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 1.01 AGENTS USED IN CYTOPENIA HEMATOPOIETIC GROWTH FACTORS Lecturer: DR. DESI JAMES OJASCASTRO Date:January 16, 2023 12 | Page Klem,Jenna,Cam,Charie,Apple