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Oncology Exam 2
Smith Hemataopoiesis and medications for Anemia (A)
| Term | Definition |
|---|---|
| Hematopoiesis is the development of? | all blood cells |
| Hematopoesis produces more than ____ billion blood cells each day | 400 |
| Growth factors for Hematopoiesis are? | glycoproteins; most participate in networking |
| The absence of pluripotent reductant growth factors is compensated for? | the absence of bon-reductant factors leads to specific cytopenia |
| What is neutropenia? | Abnormally low number of neutrophils • Patients are susceptible to bacterial infections • May become life-threatening |
| What is Anemia? | Qualitative or quantitative deficiency of hemoglobin • Leads to hypoxia in organs |
| What is Thrombocytopenia? | Low platelets |
| Figure: All of our blood cells derive from? | pluripotent hematopoietic stem cells |
| Under the influence of Growth factors (SCF, IL-6, Flt3L) the pluripotent hemaotopoietic stem cell divides into 2 lines, which are? | Trilinieage myeloid stem cell (CFU-S) and the Lymphoid stem cell |
| Lymphoid stem cell division eventually leads to our? | B cells, NK cells, and T cells |
| In oncology, in the figure, we are concerned about the cells that develop after you get that trilineage myeloid stem cell. This trilineage myeloid stem cell, under the influence of IL-3, GM-CSF, and IL-6 will develop into? | Eosinphils, macrophages, neutrophils, platelets, and erythrocytes |
| Eosinophils, macrophages, and neutrophils are your? | Granulocytes |
| In cancer pts, we typically see drops in ____ ______ ______ | Neutrophils, platelets, and erythrocytes |
| Because of the drop in these particular cell populations (Neutrophils, platelets, and erythrocytes), we have developed medications that are biologicals that are either? | identical or quality similar to the growth factors of these cell lines |
| Where is the Growth factor GM-CSF, GCSF, TPO, and EPO appear? | how high up are these appearing on the scheme of hematopoiesis |
| EPO (erythropoietin) is a ____ _______ growth factor in the hematopoietic scheme | single-lineage. It only impacts the development of cells starting with this BFU (Burst forming unit) and results in only the production of erythrocytes |
| BFU (Burst forming unit) is a colony of little cells that are unique. How? | very sensitive to the Erythropoietn (doesn’t take a lot of EPO present to stimulate the differentiation and proliferation of erythrocytes after BFU is first hit with EPO |
| GM-CSF is first seen stimulating the Trilineage myeloid cell and is a ______ growth factor (more than 1 lineage) and impacts the growth of? | pluripotent;ALL (eosinophils, macrophages, neutrophils, platelets, and Eosinophils) |
| G-CSF doesn’t play any higher than this colony forming the G cells. It is a ____ ____ growth factor leading to the formation of Neutrophils | Single-lineage |
| TPO (thrombopoeitn) is the growth factor mostly stimulating ______. Pluripotent or single lineage? | Platelets; Pluripotent; it effects Erythrocytes and platelets |
| We are most concerned in our pts when their _____, ____. or ______ numbers drop | RBC, platelets, neutrophils |
| Where in the body are the growth factors made? | By a number of cells in the bone marrow, some of which are in tissues in the body. *made by a variety of tissues |
| Where are the receptors for these growth factors? Receptor for Erythropoietin? -kidney -immature RBC | immature RBC (starting with the Burst forming unit type and then all of these other precursor RBC and also on eyrhtopoietin) |
| Where are the receptors for GMCSF? | Tri lineal myeloid cells and ones that follow from those cell lines |
| Receptors for GCSF? | start on single-lineage cell lie of neutrophils and also expressed on the surface of the mature cells b/c the growth factors besides stimulating the precursors to differentiate and proliferate, they will also have a role in getting these blood cells to do their job once their out in the circulation |
| How are biologicals are made? | they are recombinant products (proteins like these Growth factors) by popping a human gene into the DNA of another organism—> let the cells do the work, and human gene is for a protein we want made, isolate nd purify and how we get our drug. |
| Producing biologicals using recomnant technologies—> | Insert gene of interest (e.g. for human erythropoietin) into host DNA to make recombinant DNA (rDNA) • rDNA is inserted into a host organism • Recombinant protein is produced in the host • Protein produced is isolated and purified |
| Medications for Anemia include ESA products (Erythropoiesis/Erythropoeitin Stimulating Agents) such as? | Epoetin Alfa and Darbepoetin *they are not going to the kidney to make ESA; these are products finding those erythropoietin receptors on the surface of those immature red blood cells to get them to mature and proliferate |
| Epoetin Alfa is made by receombinat technology in _____ _______ ______ cells. It’s the exact human gene that comes out almost exactly similar that our own kidneys made. | Chinese hamster ovary |
| Difference in Eruthropoetin from the biological Epoetin Alfa after getting it from Chinese’s hamster is in the Glycosylation—> | Has 4 glycosylation's, but they differ slightly from human erythropoietin – Glycosylation differences do not change kinetics, potency, or immunoreactivity – Glycosylation differences can be detected |
| MOA of Epoetin Alfa is? PK? | Binds to erythropoietin receptor on immature red blood cells, stimulating them to differentiate and proliferate • Has high binding affinity; Short 1/2 life |
| Why does Darbepoetin have a longer half-life than Epoetin Alfa? | has more Glycosylations via—> in Epoetin Alfa (we put the gene right into the DNA of Chinese hamsters ovary cells, Darpepoetin (we modify the human gene a little bit and modification—> we tweaked 4 amino acids and that resulted in adding 2 more glycosylations sites. |
| Darbeoeitin has a longer half-life because we messed with the human gene, get 2 more sugars addded it and that elongated the half-life. Slide states: | Made by recombinant technology in Chinese hamster ovary cells • Human erythropoietin gene modified to change four amino acids to add glycosylation – Change in amino acids results in two more glycosylation sites – Increased half life with additional glycosylations |
| MOA of Darbepoetin is? | Binds to erythropoietin receptor on immature red blood cells, stimulating them to differentiate and proliferate • Has moderate binding affinity for the erythropoietin receptor PK: longer 1/2 life than Epoetin Alfa. |
| Other difference to Epoeitin Alfa and Darboetin other than the increased Glycosylation sites and modification of 4 amino acids to the human gene is that Darbepoetin has? | moderate binding affinity for the erytropeotin receptor; *less affinity so it doesn’t bind that EPO receptor quite as well, but because of the longer 1/2 life, we dont see a clinical difference in efficacy b/w the 2. Longer 1/2 life and a chance to stay in teh body and receptor longer |
| Pharmacodynamic challenges in ESA drugs? | Challenging to determine appropriate dosing schedule to maintain target – Hct may rise quickly after first start administration due to release of reticulocytes – Takes about 10 days before erythrocyte progenitor cells are continuously released into circulation – Hb continues to increase as new steady state is reached – Don’t change dose too soon! • Patients may be “resistant” |
| When giving these ESA drugs, we see an increase in HCt and Hgb and increase in RBC rapidly and then you’ll see fall again and the reason for that increase is? | because you got those Erythropcytes (hanging out in teh bone marrow), just about mature, and you give them a dose of ESA and those red bloood cells get moved out of the bone marrow into the blood and that where we see in the increase; this is also referred ot as *release of reticulocytes; this does not get the pt to therapeutic level, need to give them time to reach Steady State to determine if you got your pt on the right dose; *dont change the dose too soon |
| Pts may be resistant to these ESA products, what could be a reason for this resistance? | Iron and B-12 folic acid deficiency (cant create health RBC to carry O2) evaluate levels of B-12 and folic acid |
| ESA Adverse Effects include (slide)? | Polycythemia, blood hyperviscosity and stroke or MI if given to patients without anemia • Pure red cell aplasia – development of neutralizing antibodies against erythropoietin • Hypertension; therefore not to be administered to hypertensive patients; mechanism unknown • May reduce survival in H&N carcinomas; mechanism unknown • Allergic reactions (rare) |
| ESA adverse effects (Smith): we need to be careful about not overshoot the RBC count that you should be targeting b/c you can cause these issues ( | Polycythemia, stroke, MI, b/c basically your just getting their blood too viscous (too many RBC, |
| ESA AE: Pure red cell aphasia is development of neutralizing antibodues against erythropoietin—> | this happens when a pt actually makes antibodies against the Erythopoeint product your giving them |
| ESA AE: HTN0-> giving ESA can make HTN worse and need to be careful with certain cancer pts that have certain H&N (head and Neck carcinomas), ESA can make the cancer _____ | worse |
| Iron deficiency, we need iron to carry O2 via the heme group. Slide states? | Iron deficiency most common cause of chronic anemia -Iron is the nucleus of the iron-porphyrin heme ring of hemoglobin -Iron deficiency causes microcytic hypochromic anemia (small, pale erythrocytes) |
| We ingest iron orally, gets absorbed by active transport mechanism, stored in your _______ and in your GI cells. IT is alsways carried by _________ in the blood. *you don’t want free iron. | hepatocytes; Transferrin |
| Smith Figure: 1. Intestinal epithelial cells actively absorb inorganic iron via the divalent metal transporter 1 (DMT1) and heme iron via the heme carrier protein 1 (HCP1). Iron that is absorbed or released from absorbed heme iron in the intestine (1) is actively transported into the blood by ferroportin (FP) and stored as ferritin (F)—-> | In the blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) in red blood cells (RBC) (2); or to hepatocytes for storage as ferritin (3). The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized. |
| Smith Iron Figure: After release of iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin—> | (4). Hepatocytes use several mechanisms to take up iron and store the iron as ferritin. High hepatic iron stores increase hepcidin synthesis, and hepcidin inhibits ferroportin; low hepatocyte iron and increased erythroferrone inhibits hepcidin and enhances iron absorption via ferroportin. Ferrous iron (Fe2+), blue diamonds, squares; ferric iron (Fe3+), red; DB, duodenal cytochrome B; F, ferritin |
| When looking at oral iron products, it matter more about the amount of Elemental Iron per tablet: 1. Ferrous Sulfate, Hydrated contains how much elemental iron per tablet? 2. Ferrous Sulfate: desiccated contains how much elemental iron per tablet? 3. Ferrous Gluconate contains how much elemental iron per tablet? 4. Ferrous Fumarate contains how much elemental iron per tablet? | 1. 65 mg 2. 65 mg 3. 36 mg 4. 33 mg in a 100 mg tablet 106 mg in 325 mg table |
| Remember that oral iron products are really tough on the GI tract. AE include? *tell pt to take with food | -Function of amount of soluble iron in the upper GI tract -Most common adverse effects: (Nausea, Epigastric discomfort, Abdominal cramps Constipation, Diarrhea) -Constipation and diarrhea may be related to iron- induced changes in bacterial flora -Decrease with lowered dose, when taken with food, or different salt form |
| IV iron products is for a pt that can’t absorb oral iron. What are the indications for IV iron? | For patients unable to tolerate oral iron, can’t absorb oral iron, or have severe anemia not maintained by oral therapy -Administration of inorganic free ferric iron causes serious dose- dependent toxicity, limiting dose. Therefore we give IV iron as colloidal preparations |
| AE of IV iron include? | -Some IV iron products have Black Box warning regarding (potential anaphylactic rxns) -Iron overload needs to be monitored anaphylaxis |
| What are our IV iron products that are available in the treatment of anemia? | Low molecular weight Iron Dextran (BBW)*** -Iron-sucrose -Ferric gluconate -Ferric carboxymaltose -Deferasirox -Deferiprone -Deferoxamine -Ferric derisomaltose -Polysaccharides iron complex |
| What is the BBW for low molecular weight iron dextran? | Most significant AE is possibility of anaphylaxis especially with HIGH molecular wight prep |
| Besides need to deal with low iron, you may need to check your pts for ____ and ___ ____ levels. | B12; Folic Acid |
| Why do we need B12 and folic acid—> The kind of anemia you see with just Vitamin B12 or Folic acid deficiency is what kind of anemia? | Megaloblastic anemia (flabby big RBC) *only seen if pt has B-12 or Folic acid deficiency star⭐️ 🩸 (**CHECK WITH SMITH)) |
| Vitamin B12 deficiency can cause? | -Megaloblastic anemia -Neurological symptoms *Anemia cuased by B12 deficiency is because pts are not able to absorb B12 well from their gut |
| MOA of Vitamin B12 and PK? | -MOA: Cofactor for many essential biochemical reactions, including production of tetrahydrofolate); -Pharmacokinetics (Usually 1-5ug absorbed from the 5-30ug in diet; Stored in liver; Absorbed by active transport across gut) |
| Folic acid, it also can cause megaloblastic anemia when you’re just dealing with low levels of folic acid in a pt. Deficiency is commonly caused by? | inadequate dietary intake *some meds may cause deficiency by inhibiting DHFR; Deficiency causes? Megaloblastic anemia; do not get the neurological symptoms that come with Vit B12 deficiency |
| The folate cycle is needed to help us produce our _____ and our dTMP for DNA synthesis. So remember, you must have enough B12 and enough folic acid to make healthy purines and pyrimidines needed for making new DNA | purines; So cells taht are dividing like our RBC, |
| f your anemic and give a pt an ESA, if a pt is not able to make healthy purines and pyrimindies, they cant make DNA and replicate their RBC. This is why you need to be sure taht your pt has enough _____ and ____ to have the building blocks from which to make more RBC or ESA’s are not going to be helpful | Folic acid; B12 |
| The interface between B12 and folic acid is that we have some conversion of the form of B12 that we ingest as a supplement (______) gets changed to Methylcobalamin (goes back and forth between the 2) and helps to create the THF that feeds into the Folic acid cycle | Cyanocoblamain (cobalamin); *this is why you need the B12 to help us to create the folates that are part of the folic acid cycle to get those purines and pyrimidines needed for making healthy RBC. |
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