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Therapeutic Agents for the Hematological System Chapter 26 West Los Angles College 1 • Major Components of Blood • • • • ⬤ Whole blood (plasma and cellular components) ⬤ Plasma proteins (albumin*) ➢ ⬤ Platelets ➢ • Osmosis and hydrostatic pressure (thrombocytes) Lifespan is 10 days West Los Angles College • 2 • IronisabuildingblockforRBCsandwithoutit,anemiaoccurs. • Erythrocytes,alsoknownasRBCs,arecellsthatcontainhemoglobinandcan carryoxygentothebody.Leukocytesorwhitebloodcellsareinvolvedin fightinginfection. • RBCproduction,orerythropoiesis,takesplaceinthebonemarrowandis largelydrivenbythehormoneerythropoietinthatisproducedbythe kidneys.ErythropoietincanbetherapeuticallyusedforpeoplewithlowRBC countsattributabletokidneyorothermedicalconditions. • Ironisanimportantandnecessaryfactorfortheproductionofhemoglobin. Cellular Components of Blood ⬤ Leukocytes (white blood cells [WBCs]) ⬤ Erythrocytes (red blood cells [RBCs]) ➢ Contain hemoglobin to carry oxygen West Los Angles College Bloodmustflowtoorganstocarryoxygenandnutrients,butalsoridthe bodyofwaste. Italsotransportscellsoftheimmunesystem. Hydrostaticpressureisdrivenbythebloodpressuregeneratedbycontraction oftheheart. Osmosisisthemovementofwaterdownaconcentrationgradient. Thebloodcarriesoxygenandnutrientsthroughoutthebody,butitalso carrieswastesfromthetissuesandorgansthatitsupportstoorganssuchas thekidneysandliverforelimination.Thebloodadditionallytransportscells oftheimmunesystemtositesofinfectionandinjury. Incertaininstances,peoplecanproducelessalbumin,attributabletoliver diseaseormalnutrition,orlosealbuminfromthebloodstream,attributable tocertaintypesofkidneydisease.Wheneitherhappens,osmoticpressure decreases,leadingtotheaccumulationoffluidwithinthetissuesoredema. Platelets,alsoknownasthrombocytes,areacomponentofthebloodthatis essentialintheprocessofbloodcoagulation(clotting). 3 Withadequatesupplementation,resolutionofsymptomsgenerallyoccurs within4weeksoftreatment. • Thedurationofsupplementationdependsontheextentofthedeficiencyand thecausativefactors. • PerniciousanemiaiscausedbyavitaminB12deficiencyattributableto • Common Conditions: Anemia congenitaloracquireddeficiencyofIF. • Sicklecellanemiainvolvesabnormalhemoglobinsynthesisandabnormal RBCshape. • Ironreplacementtherapyistheprimarytreatmentforiron-deficiency anemia.Mildanemiamaybetreatedwithdietarychanges,andIVironmay beadministeredtothoseundergoingchronicdialysis. ⬤ Anemia: Reduction of RBC numbers ⬤ Common cause of iron deficiency anemia is blood loss Symptoms: Fatigue, weakness, shortness of breath, and pallor ➢ Treatment: Identify source of blood loss, iron replacement therapy, and dietary changes ➢ Drug treatment: Iron replacement therapy ➢ West Los Angles College 4 • Secondarypolycythemia,themostcommonform,occursasaresultofa physiologicalresponsetohypoxia. • Primarypolycythemia,alsoknownaspolycythemiavera,isachroniccondition inwhichthebodyoverproducesRBCs. • Polycythemiaisanincreaseinthetotalcellmassofthebloodfrequently causedbyexcessiveRBCproduction. • Forindividualswithpolycythemiavera,phlebotomyisfrequentlyusedto reducethebloodvolumeandRBCnumbers.Drugtherapyinpolycythemia verainvolvestreatmentsthatminimizetheriskofthrombosiswith myelosuppressiveagents(e.g.,hydroxyurea)and/orantithrombotics(e.g., anagrelide). Polycythemia ⬤ Excessive ⬤ Primary ➢ RBC production or secondary Difficulty oxygenating the blood ⬤ Treatment: Smoking cessation, medical intervention for chronic obstructive pulmonary disease (COPD) and heart failure, and phlebotomy ⬤ Drug treatment: Treatments to minimize risks of thrombosis with myelosuppressive agents West Los Angles College 5 • Thrombocytopeniahasavarietyofcauses. • Someofthemostcommoncausesarepregnancy(gestational thrombocytopenia),drugsideeffects(drug-inducedthrombocytopenia),and idiopathicthrombocytopenia.Idiopathicmeansofunknowncause. • Heparin,vancomycin,andphenytoinareallassociatedwithdrug-induced thrombocytopenia. • Promactaisathrombopoietin-receptoragonist,whichincreasesplatelet production. • Promactaneedstobetakenonanemptystomachatleast1hourbeforeor2 hoursaftermeals. Low Blood Cell and Platelet Counts ⬤ Agents: Colony-stimulating factors (CSFs) ⬤ Thrombocytopenia: Low platelet count ⬤ Treatment: Resolution of contributing factors, transfusions to increase platelet levels, and activity restrictions ⬤ Drug treatment: Steroid treatment, and glucocorticoid medication West Los Angles College 6 • • Neutropenia • ⬤ Occurs ➢ in conjunction with other conditions Mild, moderate, or severe • ⬤ Leukopenia: Low WBC count ⬤ Granulocytopenia: Decreased number of circulating granulocytes ⬤ Treatment depends on degree of severity; regular dental care ⬤ Drug treatment: Recombinant growth factors, and CSFs West Los Angles College • 7 • Hematological Cancers ⬤ Leukemia: WBCs ➢ ➢ • Cancerous cells replace normal • Treat with antimetabolites such as 5-fluorouracil (5FU) ⬤ Antimetabolite • agents: Prevent cell division Side effects: Nausea, vomiting, fever, anorexia, and bone marrow suppression ⬤ Antibiotics: Bind to DNA and prevent formation of new cancer cells ➢ • 8 • Hematological Cancers (Cont.) • • ⬤ Alkylating agents: Nitrogen mustards and nitrosoureas • • Methods of action and side effects differ ⬤ Nitrogen mustards: Used during World War I, reduce WBCs; had severe side effects ⬤ Nitrosoureas: Used to treat brain cancers ➢ Leukemiaisaformofcancercharacterizedbytheproductionofcancerous hematopoieticstemcellsthatreplacenormalwhitebloodcellswithinthe bonemarrow Bothgeneticsandenvironmentalfactorscancontributetothedevelopment ofleukemia.Environmentalfactorscanincludeexposuretoradiationand chemicals,includingradiationandchemotherapeuticagentsusedtotreat otherformsofcancer. Thereareseveralformsofleukemia,includingacutelymphoblasticleukemia (ALL),acutemyeloblasticleukemia(AML),chronicmyeloblasticleukemia (CML),andlymphocyticleukemia(CLL),amongothers. Thestructureofantimetabolitesissimilartothatofthebasesinthe nucleotidesthatformdeoxyribonucleicacid(DNA)strands;however,because theyarenotidentical,antimetabolitespreventthecompletionofcelldivision ormitosis.Antimetabolitesareoftenusedtotreatleukemia.Themost commonsideeffectsincludenausea,vomiting,fever,anorexia,bonemarrow suppression,andjaundice. StageIV,ormetastaticcancer,isthemostadvancedformofcancer. Side effects: Severe emesis, nausea, diarrhea, and hair loss West Los Angles College ➢ Whenapatientisassessedforneutropenia,theabsoluteneutrophilcount (ANC)oftenisusedtodefinetheneutropeniaasmild,moderate,orsevere. Theseagentscanbeusedprophylacticallyforchemotherapy-induced neutropeniaandfortherapeuticuseinpeoplewithpreexistingneutropenia. Granulocytopeniaisareductioninthenumberofgranulocytes,which encompassesspecifictypesofwhitebloodcellsinthebloodthatcontain granules.Thesewhitebloodcellsincludeneutrophils,eosinophils,and basophils;allareknownasgranulocytes. Neupogenstimulatestheproductionofneutrophilsinthebonemarrowand isusedtotreatneutropenia.Itissuppliedasasubcutaneousinjectionand shouldnotbeshakenbeforeadministration. Circulatinggranulocytesareneutrophils,eosinophils,andbasophils. Side effects: Nausea, vomiting, major flushing of skin, eye redness, headache, and rash West Los Angles College 9 BecausealkylationisanormalreactionthattakesplaceintheDNAbetween chemicalcompounds,theseagentsareabletobindtocertainbasesofthe DNA. Sideeffectsmayincludelowbloodcounts,nausea,vomiting,mouthsores, hairloss,darkeningofveinsusedforinfusion,andlossoffertility. Nitrosoureascrosstheblood-brainbarrierthatsurroundsthecentral nervoussystem.Becauseofthisability,theycanbeusedtotreatcancersin thebrain. Cyclophosphamideisanitrogenmustard. Mitoticinhibitorspreventmitosisatthemetaphasestage.Mitosisisthe processofcelldivisionthatallcellsmustperform.Agroupofalkaloids derivedfromplantsareusedtopreventthiscellularreproduction. Theinflammationassociatedwiththedevelopmentoflymphomasoften leadstoenlargementofthelymphnodes,whichcanbeanearlysymptomof thecancer. • Althoughthesignsandsymptomsofthesetwoformsoflymphomaoverlap, theyaretreateddifferentlyandhavedifferentprognoses. • StandardcombinationssuchasMOPPorABVDtherapy,forexample,canbe usedforthetreatmentofHodgkindisease. • Lymphomas ⬤ Cancers ➢ of the lymphatic system Develop in lymph nodes or spleen ⬤ Risk factors: Immunodeficiency disorders, and exposure to herbicides/pesticides ⬤ Two categories: Hodgkin's and non-Hodgkin's ⬤ Treatment: Prevention, aggressive treatment of infection, and radiation therapy ⬤ Drug treatment: Chemotherapeutic agents (vary depending on type and stage of cancer) West Los Angles College 10 • Bleeding Disorders ⬤ Hemophilia: ➢ • • Intermittent bleeding episodes Associated with either a deficiency or lack of either antihemophilic Factor VIII or Factor IX ⬤ Von ➢ • • Willebrand’s disease Lack of platelet binding to vasculature ⬤ Both are defects in the clotting or coagulation process West Los Angles College 11 Bleedingdisordersgenerallyareassociatedwithadefectinoneormore clottingfactorsinvolvedinthecoagulationprocess. TreatmentinvolvesstrategiestoincreasetheavailabilityofvonWillebrand’s factorandincludetheuseofcryoprecipitate,FactorVIIIconcentrates, desmopressin(DDAVP),freshfrozenplasma,andestrogentherapy. DDAVPisavailableforIV,subcutaneous,oral,andintranasaladministration. DDAVPisindicatedforbleedingprophylaxisandforthetreatmentof hemophiliaA,hemorrhage,surgicalbleeding,andvonWillebranddisease. Extremecareshouldbetakenwhenpreparingwarfarinprescriptionsto ensurethatthepatientisreceivingthecorrectdosageandinstructionsfor use.Thepharmacistshouldadditionallyensurethatthosetakingwarfarin understandthattheyshouldavoidtakingaspirinandotherNSAIDsbecause oftheriskofbleeding.Thesepatientsshouldalsobeconsistentintheir intakeoffoodsrichinvitaminKsuchasspinachandliverbecauseofthe potentialforthesefoodstoaffecttheanticoagulanteffectofwarfarin.