Pharmacology I: Hematinics & Hematopoietic Drugs PDF

PHARMACOLOGY I MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC LE 3...

PHARMACOLOGY I MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC LE 3 10/27/23 DRUGS MELITON V. BATO, M.D. OUTLINE Infants consuming cow’s milk has a high level of Ca that competes I. Introduction VI. Agents that induce with iron of absorption a. Hematinics fetal hemoglobin (hbF) o 🖊 Both have a valency of 2+ and are also metals II. Hematinics a. 5-azacytidine o 🖊 There’s only one transporter that transports nonspecifically a. Oral Iron Therapy b. Hydroxyurea for metal divalent ions (divalent transporter 1 or DT-1) found at b. Parenteral Iron Therapy VII. Butyrates the apical portion of the enterocytes III. Megaloblastic Anemia VIII. Agents that stimulate Reduction of RBC that depends on Hb that carries O2 to tissues a. Vitamin B12 leukocyte production (Cobalamin) a. Filgrastim & b. Vitamin B9 (Folic Acid) Sargramostim IV. Hematopoietic Growth b. Hydroxyurea Table 1. Body Iron Distribution Factors c. Butyrates V. Agents that stimulate IX. Agents the stimulate IRON CONTENT, mg erythrocyte production platelet production Adult Male, 80 kg Adult Female, 60 kg a. Erythrocyte-Stimulating a. rhTPO & PEG- Agents (ESAS) rHuMGDE Hemoglobin 2500 1700 b. rhEPO b. Eltrombopag & Myoglobin/ c. Erythropoietin (EPO) Romiplastin 500 300 enzymes c. Oprevelkin (rhIL- 11) Transferrin iron 3 3 Iron stores 600-1000 0-300 LEGEND ⭐ 🖊 📖 🖊 Total iron body distribution is different for adult males and females Must Lecture Book o More iron found in adult male, more concentrated in Hb at 2.5 g Know [lec] [bk] vs. 1.7 g LEARNING OBJECTIVES A. Other causes of Anemia Define hematinics and growth factors Trauma, heavy menses, interna, bleeding (ulcer or colorectal List the different types of anemia based on size cancer/CRC/neoplasm) Enumerate the medications used for iron-deficiency and ASA (Aspirin), NSAIDs megaloblastic anemias, their metabolism, excretion, dosages, and Dietary iron-deficiency anemia routes, and adverse effects o Most common in women (20%) Enumerate the different growth factors, indications, uses, dosages, § 50% of pregnant women and routes and adverse effects o 3% in men (men have larger stores of iron) I.INTRODUCTION B. Regulation of Iron HEMATINICS Normal body conc. of iron = 60 ppm 🖊 Vitamins, nutraceuticals, or dietary factors essential for either Iron uptake regulated by absorptive enterocytes in the small Hb synthesis or erythrocyte production intestine o 3.7 g in a 154-lb male adult Often only an adjunct to treatment underlying the case of the o 20 mg is needed internally but only 1 mg (10%) is absorbed per anemia day from the typical daily diet containing 10-20 mg Iron, Vitamin B12 (Cobalamin) and Vitamin B9 (Folic Acid) o 0.8% of RBC are destroyed and replaced each day o 🖊IDA: Iron Half-life or life span of RBC = 120 days o Megaloblastic Anemia: B12, B9 o 2.5 g iron is incorporated into the Hb, 5 mg for other requirements IRON DEFICIENT ANEMIA Which includes the irons of your complexes in the ETC which is needed for the production of ATP in the mitochondria Occurs when inadequate amounts of iron are taken in the diet o 0.1 g in myoglobin, 0.02 g in the ETC Most prevalent deficiency in the world o 1 g stored as ferritin (intracellularly) o Up to 1B people are iron-deficient Majority of iron is reused through plasma but above storage Diminished capacity of affected individuals to perform labor amounts are deposited in ferritin or hemosiderin In children o 🖊 Hemosiderin is partially oxidized form of ferritin o Growth stunting, o Learning difficulties o 🖊Ferritin is the normal storage form intracellularly In women § If you have excess iron, it will be stored in ferritin, and if it o 7.8M are iron-deficient due to cyclical menses can no longer be stored in ferritin, it will become o Menstrual period: 4-100 mg iron loss hemosiderin § 🖊 More IDA counted for females because of cyclical Problem with hemosiderin is they form aggregates that can be problems, and the iron that they contain occurrence of menstruation is still reactive; it can form ROS that are deleterious Each pregnancy: 500 mg iron loss that’s why you give iron to tissues supplementation at this time Non-heme iron (ferric) are not absorbed from plant sources o 3.3M are anemic o 4.8% are premenopausal iron-deficient but non-anemic o 🖊To absorb ferric (Fe3+), you wil change it into the ferrous (2+) form [PHARMA] TH Velasco Page 1 of 8  MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC DRUGS LE 3 MM/DD/YY § Only way to convert is through ferrireductase by your duodenal cytochrome B o 🖊Before it can enter divalent metal transporter 1 in the apical portion of the enterocytes, they need to be converted or reduced to a 2+ or ferrous valency Dietary myoglobin and hemoglobin account for 2/3 of iron stores E. Sources of Iron Good sources of iron: C. Effects of IDA o Egg yolk, broccoli, spinach Anemic people usually feel cold Lowered levels of myoglobin in myocytes and reduced hemoglobin in RBC Limits energy production o 🖊Because there is decrease in the oxygen carrying capacity of your myoglobin and your hemoglobin and decrease in the production of your complexes for your electron transport chain D. Absorption of Iron NADH dehydrogenase and succinate dehydrogenase contain non heme iron (Ferric: Fe2+) as co-factor Ribonucleotide reductase for DNA synthesis, catalase, and peroxidases (contains Heme which also contains Iron) to protect against ROS Figure 2. Content of Iron in Various Foods Thyroid function due to connection between iron and 🖊In this diagram, you will see that the highest amount of iron is copper deficiencies contained in the tofu. But this substance contains phytic acid and Vit. C (Usually a reducing agent) enhances nonheme iron it will block the absorption of the non-heme iron absorption by reducing Fe3+ (nonheme) to Fe2+ o 🖊 So that it can be transported across the gastrointestinal lumen to the intracellular cytosol via the Divalent Metal Transporter 1 (DMT-1) or you can use Duodenal Cytochrome B which is a ferrireductase Sufficient stomach HCl is needed to release Fe3+ from ingested food (achlorhydria) o ☤ You will have a problem if you have achlorhydria = decrease in the pumping of hydrogen atoms to the intestinal tract Vegetarians are prone to iron deficiency and Vitamin B12 Deficiency o Plant sources (tofu, cereals) contain phytic acid (good chelator of metals) which binds iron as well as other metals rendering iron nonabsorbable Figure 3. Recommended Daily Dietary Allowances for Iron 🖊Recommended Daily Allowance is different for males and females. But initially, during the early stages of life, they are almost the same. The requirement of dietary iron increases in the females when they reach adolescents because of the cyclical menstruation F. Hemoglobin and Hematocrit Values Figure 1. Structure of Phytic Acid and Phytic Acid Chelate ☤ This is a structure of your phytic acid and phytic acid chelates mostly divalent metal ions which includes magnesium, iron, and zinc over their phosphate groups Figure 4. Hemoglobin and Hematocrit Values [PHARMA] TH Velasco Page 2 of 8  MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC DRUGS LE 3 MM/DD/YY G. Manifestations of IDA 🖊In Iron deficiency You will have iron deficient erythropoiesis. The serum ferritin is 360 o Meaning to say insufficiency of the iron causes the total iron binding capacity of transferrin to increase Iron stores are still present but at very low amounts [PHARMA] TH Velasco Page 3 of 8  MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC DRUGS LE 3 MM/DD/YY Table 2. Oral Iron Preparations III.MEGALOBLASTIC ANEMIA Generic Name Tablet (Iron Elixir (Iron Content), 🖊Megaloblastic anemia: where there is an increase in the size of Content), mg mg in 5mL RBCs than the normal Ferrous sulfate 325 (65) 300 (60) Results from Vitamin B12 (Cobalamin) and/or Folate (Vitamin 195 (39) 90 (18) B9) deficiency Extended release 525 (105) o 🖊Results from a deficiency of 2 vitamin B complexes which Ferrous fumarate 325 (107) are water-soluble: Vit B9 (folic acid) and Vit B12 (cobalamin) 195 (64) Vitamin B12 deficiency occurs in older people and in individuals 100 (33) chronically using PPI (🖊Lansoprazole, Omeprazole, Drugs Ferrous 325 (39) 300 (35) ending with –azole) gluconate o Efficient Vit B12 absorption requires intrinsic factor, Polysaccharide 150 (150) 100 (100) secreted by parietal cells iron 50 (50) o Vit B12 + IF is absorbed in the ileum o IF (intrinsic factor) absence leads to Vit B12 absorption 🖊So here are your oral iron preparations. The most common that reductions (Pernicious Anemia) we encounter in the pharmacy will be ferrous sulfate, but you also o 🖊IF absent due to possibly by auto immune immunity have other forms (ferrous fumarate, ferrous gluconate). brought about by autoimmune antibody against it decrease 🖊The iron content is the amount that is contained within the tablet in Vitamin B12 absorption that can be absorbed. The highest comes from ferrous fumarate. o ⭐ Vit B12 deficiency megaloblastic anemia has memory loss and paresthesia B. PARENTERAL IRON THERAPY ⭐Folate deficiency occurs in: IV iron can be given to patients who are o Chronic alcoholism o Unable to tolerate oral iron o Hepatic diseases o Whose needs are relatively acute o Malabsorption syndromes o In need of iron on an ongoing basis usually due to o Renal dialysis persistent GI blood loss o Drug intake Parenteral iron use has been increasing rapidly in the last several § Methotrexate, TMP, Pyrimethamine, Phenytoin years with the recognition that is usually combined with o Pregnancy recombinant EPO therapy induces a large demand for iron – § Neural tube defects in developing fetus frequently unmet from RE sources or oral iron dextran. The safety for parenteral iron has been a concern Serious adverse reaction rate to IV high molecular wt iron dextran is 0.7% Newer iron complexes are available in the US (that have lower adverse drug affects) such as: o Ferumoxymol (Feraheme) o Sodium ferric gluconate (Ferrlecit) o Iron sucrose (Venofer) o Ferric carboxymaltose (Injectafer) 2 ways of using parenteral iron: o To administer the total dose of iron required to correct the hgb deficit and provide the pt with at least 500 mg of iron stores o To give repeated small doses of parenteral iron over protracted period (common in dialysis centers or patients under hemodialysis) 100mg of elemental iron is given weekly for 10 weeks to augment EPO treatment Body weight (kg) x 2.3 x (15-pt’s hgb (g/dl)) + 500 or 1000 mg (for stores) 🖊The amount they need to infuse in a certain period of time, or they can give it immediately ADVERSE EFFECTS Iron dextran: Anaphylaxis o History of multiple allergies, prior allergic reaction to dextran Symptoms: o Arthralgia o Skin rash o Low-grade fever DOSE RELATED ADVERSE DRUG EFFECTS If a large dose of iron dextran is to be given (>100mg) o The iron preparation should be diluted in 5% dextrose in water or 0.9% NaCl solution o The iron solution can be infused over 60-90 min o A test dose of 25 mg is recommended If chest pain, wheezing, a fall in blood pressure, or other systemic Figure 7. Development of a neural tube defect symptoms occur o Infusion should be stopped [PHARMA] TH Velasco Page 4 of 8  MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC DRUGS LE 3 MM/DD/YY will develop neurological impairment due to Vit B12 severe Vit B12 deficiency Inabsorption can also occur in vegetarians since plants do not contain the vitamin Vit B12 Deficiency: o Slow and insidious since liver contains 3-5 years supply of the vitamin ⭐Pernicious anemia causes: o Decreased erythrocyte production o Neurological impairments (weakness and paresthesia) Injectable Vit B12 (hydroxocobalamin and cyanocobalamin) is needed o Given frequently until deficiency is reversed and maintained for at least a month for maintenance Figure 8. Megaloblastic Anemia HYDROXYCOBALAMIN AND CYANOCOBALAMIN 🖊Hyper segmented neutrophil that is very common in Both are given IM megaloblastic anemia, and you see oval macrocytes and o Hydroxycobalamin teardrop cell. The average sizes of RBC are larger than the § Preferred because it is highly protein bound and has a normal long duration of action due to its persistence in the Megaloblastic anemia stems from circulation o Decreased purine and thymidine synthesis o Cyanocobalamin § Reducing the ability of hematopoietic cells to synthesize § Also available as an oral prep, nasal gel or spray DNA § Relatively nontoxic and well tolerated with hypoK as a natural consequence of the increased RBC production DNA replication is disrupted resulting in immature megaloblasts released from the bone marrow in attempts to compensate for Anaphylactic reactions, angioedema, and peripheral vascular anemia thrombosis to injection have been seen Diagnostic tests: Pulmonary edema, heart failure due to increased blood volume but o Serum or RBC folate measurement rare complication o Vit B12 levels Most common side effects: arthralgia, dizziness, nasal congestion o Serum and urine methylmalonic acid o Serum homocysteine B. VITAMIN B9 (FOLIC ACID) Synthesis, repair, and methylation of DNA A. VITAMIN B12 (COBALAMIN) During pregnancy, folic acid supplements are routinely given to Essential for methionine and tetrahydrofolate synthesis reduce NTDs Provides methyl groups for protein and DNA repair Can elevate homocysteine in adults o A coenzyme in the conversion of homocysteine to Folate alone can reverse the hematologic effects of vitamin B12 methionine via transferring a methyl group from N5 – deficiency but could exacerbate the neurological symptoms of Vit methylTHF to homocysteine B12 (folate trap) o Formation of dTMP (deoxytimidine monophosphate) from Folinic acid or leucovorin is the folate form given in cancer dUMP (deoxyuridil monophosphate) needed for DNA patients undergoing therapy (☤ or to those with autoimmune synthesis disorders on chronic methotrexate) Vit B12 is known as Cobalamin Folic acid is available in both oral and injectable form o Cyanocobalamin is a synthetic form o Usually reserved for individuals who have severely impaired GI absorption o Well absorbed orally with peak at 1 hr from ingestion Treatment of folic acid deficiency is usually accomplished through dietary modification Nontoxic when used for short periods Side effects: o Nausea o Flatulence o Bad taste in the mouth o Allergic reactions Associated with increased risk of colorectal and prostatic cancer with high doses IV.HEMATOPOIETIC GROWTH FACTORS Divided into: Figure 9. Megaloblastic Anemia o Recombinant or synthetic growth factor analogues o Growth factors used in treating hematopoietic malignancies 🖊As you see here, Vit B12 and Vit B9 (folic acid) work synergistically V.AGENTS THAT STIMULATE ERYTHROCYTE 🖊 Vit B12 is needed for the conversion of homocysteine to methionine via the methionine synthase PRODUCTION 🖊Growth factors which are actually proteins that will stimulate the To become Methyl-cobalamin, the dietary folate must give methyl to the Vit B12; usually, folic acid provides that RBC production from the bone marrow or effective erythropoiesis. There’s a concept of folate trap, where there is a masking of the Erythropoietin (EPO) symptoms of patient who has Vit B12 deficiency and cause o Good drug to combat some forms of anemia more severity in the patient with this problem because the folic Anemia can be from different causes acid will reverse the symptoms until such a time that the patient [PHARMA] TH Velasco Page 5 of 8  MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC DRUGS LE 3 MM/DD/YY o 🖊One common indication of erythropoietin is anemia of inflammation or of malignancy caused by Chronic Kidney Very similar in structure. Disease (CKD). Difference: o Another indication is from chemotherapy-induced anemia. o 🖊Number of glycoconjugate of sialic acid residues attached § 🖊The anti-neoplastic medications are toxic to bone to the protein because the protein of the hormone is a marrow or kidney directly or causing a state of relative glycoprotein. resistance to endogenous EPO by mechanisms involving o More sialic acid groups confer higher potency on EPO proinflammatory cytokines, oxidative stress, and § 🖊The more sialic acid that is bind to your protein or formation of anti-EPO antibodies (for the exogenous hormone protein, the higher is its potency. EPO that are administered). Darbepoetin Cancer can also cause anemia via: o Has 2 extra sialic acid groups/residues o 🖊 The anemia of inflammation or malignancy § Threefold longer half-life than EPO o Bleeding (🖊 in the site of increased vascularity) o Poor nutrition C. ERYHTROPOIETIN (EPO) o Bone marrow infiltration (🖊 myelosuppression) 🖊May also play a role in glial and neuronal cell survival. They have seen these in experiments if being expose, the glial which are A. ERYTHROPOIESIS-STIMULATING AGENTS the macrophages and the neuronal cell which are the basic building cell of your brain or nervous system, they usually survive (ESAS) after exposure to the noxious stimuli exposure or if they are cut off rhEPO (epoietin alfa), methoxy PEG-EPO beta, darbepoietin from oxygen (ischemic injury). alfa (formerly known as Novel Erythropoiesis Stimulating Protein Clinical studies on its neuroprotective effects are ongoing. or NESP) Administration to nonanemic or mildly anemic patients can lead to: o 🖊 All of them will stimulate the EPO receptor and will cause o Polycythemia (🖊caused by decrease EPO stimulation) effective bone marrow erythropoiesis. o Blood hyperviscosity (🖊increased viscosity in the blood o 🖊 All three ESA are proteins. They are biologicals caused by polycythemia vera) administered via parenterally. o Stroke Clinical studies: o Myocardial Infarction (MI) o Patients with anemia + CKD have a higher risk for serious Case reports CVS events, stroke, and death when they are treated with ESAs to target a Hgb of >11g/dL. o 1980: 18 young cyclists died unexpectedly due to EPO (🖊 Current US FDA guidelines who utilized those performance-enhancing drugs like EPO). o ESAs must be used in CKD patients when Hgb is less than o 1998-2003: more than 200 patients who received one 10g/dL and that dosing should be individualized to use the formulation of recombinant EPO developed pure red cell lowest dose of ESA sufficient to reduce the need for aplasia and neutralizing antibodies against EPO (☤ Because erythrocyte transfusion. during that time, the recombinant EPO stimulated the o 🖊Problem of EPO: You don’t know exactly, even though it is formation of autoantibodies against the recombinant EPO. dose dependent. Sometimes in the patient with CKD, they Because they have cross reactivity with the endogenous or will develop an increase viscosity of blood glucose because own EPO produced by the kidneys, it caused the obliteration of polycythemia. of the effect of the endogenous EPO causing pure red cell aplasia). Use of these medications may decrease survival and increase the risk of tumor progression or recurrence. o Exact cause of the immune response is unknown (🖊maybe o In patients with breast, non-small cell lung CA, head and because the proteins are very different that it can be neck, lymphoid and cervical cancers. recognized as foreign). o 🖊The potential explanation is because the EPO receptor o A hypothesis involves that the EPO neoantigens as a result expression might be found in some of these cancers and the of partial denaturation of the therapeutic protein preparations. EPO has pleiotropic effects because of the expression of these EPO receptors. And when combining them with pleiotherapy and chemotherapy, they cause a synergistic EPO and Darbepoietin toxicity, they can also increase thrombogenicity and therefore cause clotting which is problematic especially with elevated Hgb or hyperviscosity in the blood. o This led to FDA altering the label of ESAs that they are no longer indicated for patients receiving myelosuppressive chemotherapy administered with curative intent. B. rhEPO Increases hematocrit level by at least 6% in half to three quarters of patients receiving the drug, depending on the anemia etiology and dose of rhEPO administered rhEPO and DARBEPOIETIN Figure 11: Epoetin Alfa (Left) and Darbepoietin Alfa (Right) May induce hypertension (HTN). EPO-induced HTN mechanism is unknown or not yet elucidated. VI.AGENTS THAT INDUCE FETAL HEMOGLOBIN (HbF) 🖊Indicated for patients with sickle cell disease Sickle cell disease is marked by acute pain crises, increased susceptibility to infection, profound hemolytic anemia. Sickle hemoglobin (HbS) – containing RBCs are the root cause of these clinical manifestations which begins in childhood when HbS is first produced. Figure 10: rhEPO (Left) and Darbepoietin (Right) Structure [PHARMA] TH Velasco Page 6 of 8  MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC DRUGS LE 3 MM/DD/YY Newborns and infants with sickle cell disease are asymptomatic o 🖊Another epigenetic mechanism which decreases the because fetal globin gene expression persists for many months conversion to mature sickle cell hemoglobin. after birth. o Have increased levels of HbF from 2 to more than 20% in Sickle cell patients aged 2 have 15 % HbF and sickle cell adults early clinical trials. have 1- 5 % HbF. o Though butyrates are not effective if the baseline HbF is less o Sickle cell adults are symptomatic because of decreased than 1%. levels of fetal hemoglobin o Prevent the switch from HbF to HbS in experimental animals Adults with HbF levels experience less frequent crises and milder and children born to DM mothers (whose blood contains high anemia hence HbF levels were explored as therapeutic goals. levels of butyrates). 2 approaches to increase HbF: § 🖊Butyrate is a product of ketosis. It is very common in o Stimulating HbF expression in adults (5- azacytidine and diabetic patients and children who are known to have hydroxyurea) sickle cell to have more fetal hemoglobin. o Preventing the switch from HbF to HbS (butyrates). However, it does not explain the selectivity of butyrates for HbF over HbS. A. 5-AZACYTIDINE 5-azacytidine and congener 5-aza-2’-deoxycitifine (decitabine) are DNA Methylating agents that increase HbF production to greater VII.AGENTS THAT STIMULATE LEUKOCYTE than 20% of total globin expression in patients with sickle cell anemia and beta thalassemia. PRODUCTION o 🖊Mode of action is thru an epigenetic mechanism. They 🖊 Aka Myeloid Growth Factors methylate certain DNA so that certain areas of DNA will not Low neutrophil count or neutrophilia is most often a be expressed or certain parts of the gene that are for the result of interference with progenitor cell proliferation and coding of the sickle cell globin will not be switched on and differentiation into mature WBCs the fetal hemoglobin will still be present. Theoretical studies suggest that an HbF level of 30-40% would (myelosuppression). render patient asymptomatic. ☤ if you have low neutrophil count or neutropenia, this Reverse DNA methylation of gamma globin gene. is usually due to a possible myelosuppression and Long-term cancer risk has hindered acceptance as prophylactic therefore there is decreased in the cell proliferation or therapy in sickle cell patients. clonal expansion and differentiation to maturity of the white blood cells. Neutropenia accompanies leukemia and other malignancies that invade bone marrow and an adverse effect of chemotherapy. ☤ if you have low neutrophil count or neutropenia, this is usually due to a possible. Less common causes: Bone marrow transplant Figure 12: 5-azacytidine and decitabine Congenital neutropenia 🖊 Difference: presences of a secondary 2-carbon hydroxyl group on the azacytidine HIV Zidovudine-associated neutropenia B. HYDROXYUREA Hydroxyurea was used in the 1990s to treat sickle cell anemia FILGRASTIM AND SARGRAMOSTIM o Cytostatic agent that blocks cell division by inhibiting ribonucleotide reductase. 🖊 These are drugs that STIMULATE Leukocyte § 🖊Ribonucleotide reductase converts your Production ribonucleotides to deoxyribonucleotides. Almost identical to the natural growth factors G-CSF Increases HbF to 20% or more, decreases frequency of sickle cell (Granulocyte – Colony Stimulating Factor) and GM-CSF crises by 50% (4.5% to 2.5% per year on average) (Granulocyte – Macrophage Colony Stimulating Factor). Previously been used to treat clonal hematological disorders (chronic myelogenous leukemia and polycythemia vera). Dose-independent increase in the absolute neutrophil Relatively safe for long-term administration even in children. count. Main A/E: WBC and platelet suppression Both mobilize HSCs (Hematopoietic Stem Cells) from the The induction of HbF by hydroxyurea is slower than that by 5- bone marrow into the peripheral circulation azacytidine Often used before harvesting peripheral blood stem cells Effective in 60% of patients with sickle cell anemia for transplantation. o Decreases the number of transfusions required by patients who have three crises/year. GM-CSF is a multilineage GF and causes dose-dependent o Does not prevent end- organ damage or stroke eosinophil count increase. 1998: FDA approved its use for sickle cell anemia GM-CSF and G-CSF enhance microbicidal neutrophilic MOA still unclear activity. o Current hypothesis is it blocks the division of HbS- GM-CSF has a higher ability to increase antitumor activity. expressing erythroid precursors and triggers reversion to a fetal pattern of erythrocyte production. ☤ because we know that the immune system not only Mechanism by which hydroxyurea increases HbF expression combats the foreign invaders but also cancer cells. is independent of ribonucleotide reductase inhibition. Filgrastim analogue conjugated to polyethylene glycol is metabolized slowly than the native molecule. C. BUTYRATES PEG-filgrastim can be administered as SINGLE injection Butyrates (arginine butyrate and phenylbutyrate) are short chain that is equivalent to multiple daily filgrastim injections. fatty acids that inhibit histone deacetylases-enzymes that modify DNA to make it inaccessible to transcription factors. MAIN ADVERSE EFFECTS: [PHARMA] TH Velasco Page 7 of 8  MODULE 6. TRANS 1 HEMATINICS & HEMATOPOIETIC DRUGS LE 3 MM/DD/YY Bone pain (which resolves after discontinuation) Caution: Stimulation of platelet production could lead to THEORETICAL RISK: thrombosis if platelets are activated. G-CSF can induce Acute Myelogenous Leukemia or A small trial on PEG-rHuMGDF suggested that this drug Myelodysplastic Syndrome (remains controversial) was safe to use in treating thrombocytopenia from AML. GM-CSF can cause fever, arthralgia, edema, pleural Heavily bioengineered variants of TPO (i.e. PEG- effusion and pericardial effusion. rHuMGDF) were dropped from clinical development. Observational studies support an increased risk. Because of an excess risk of developing antiTPO autoantibodies which can suppress natural platelet VIII.AGENTS THAT STIMULATE PLATELET production. PRODUCTION rhTPO testing was also dropped ☤ Platelets or thrombocytes are important because they are the key to the formation of blood clots. B. ELTROMBOPAG AND ROMIPLASTIN Low platelet count is an important adverse effect of many 2 newer TPO receptor agonists cancer chemotherapeutic agents. Both are utilized for Idiopathic Thrombocytopenic Purpura This limits the doses that can be delivered with acceptable (ITP) treatment safety and tolerability. ⭐ Eltrombopag: Complications for anti-neoplastics: o small molecule TPO receptor agonist. o Increased bleeding risk ⭐ Romiplastin: o Increased platelet transfusion requirement o recombinant IgG1 Fc-peptide fusion protein that Platelet transfusion complications: activates the TPO receptor. o Febrile reaction Both cause transient increase in the platelet count. o Increased risk for infection Worsening thrombocytopenia may occur after cessation of o Graft versus host disease medications. Examples of thrombopoietin (TPO) agents: Bone marrow fibrosis has been reported. o Recombinant Human TPO (rhTPO) o Pegylated Recombinant Human Megakaryocyte C. OPREVELKIN (RHIL-11) Growth and Development Factor (PEG-rHuMGDF) o Recombinant Human IL-11 (rhIL-11 or Oprelvekin) The only drug currently approved for the prevention of severe thrombocytopenia in patients with § Oprelvekin: Only US FDA approved thrombopoietin myelosuppressive chemotherapy. All agents increase thrombocyte count via dose-dependent Produced by: Recombinant DNA technology and in E. coli manner Lacks: an N-terminal proline residue Can stimulate some multipotent as well as committed Causes: A dose-dependent increase in platelet count and precursor cells. megakaryocytes Do not significantly increase hematocrit or WBC count. Practical goal of treatment: Must be administered prophylactically because of a 1-2 o To maintain the platelet count above 20,000/microliters week delay. (150,000-450,000/uL is the normal range) in order to minimize risk of bleeding. A. RHTPO AND PEG-RHHUMGDF Adverse side effects: o Fatigue Cloning of the TPO gene in 1994 led to the development of o Fluid Retention 2 TPO analogues: o Atrial Fibrillation o Recombinant thrombopoietin (rhTPO) § First TPO analogue which was full-length, These adverse side effects are due to the pleiotrophic glycosylated analogue effects of this factor on receptors distributed outside the o PEG-recombinant human megakaryocyte growth hematopoietic system. development factor (PEG-rhHuMGDF) § Second analogue, N-terminal 163 amino acid TPO conjugated to polyethylene glycol (PEG) REFERENCES Bato, M. (2022). Hematinics and Hematopoietic Medications. [Lecture Video]. Both bind to Mpl (endogenous receptor for TPO named for Katzung, B., Masters, S., Trevor, A. (2021). Basic and Clinical Pharmacology (15th ed). its role in murine myeloproliferative leukemia). McGraw-Hill Education. Batch 2025 Trans APPENDIX No appendices [PHARMA] TH Velasco Page 8 of 8