Pharmacology - HLS
Transcript of Pharmacology - HLS
Pharmacology - HLSDone By
Corrected By Waad Barghouthi
Hani titi
HematopoieticGrowthFactors
MunirGharaibehMD,PhD,MHPESchoolofMedicine,
TheUniversityofJordan
HematopoieticGrowthFactors•Regulatetheproliferationanddifferentiationofhematopoieticprogenitorcellsinthebonemarrow.(MAIN USE FOR THESE FACTORS)
•Usefulinhematologicaswellasnon-hematologicconditions,potentialanticancerandanti-inflammatorydrugs.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 3
HematopoieticGrowthFactors
• Erythropoietin(Epoetin alfa).• ColonyStimulatingFactors.• Granulocytecolony-stimulatingfactor(G-CSF).• Granulocyte-macrophagecolony-stimulatingfactor(GM-CSF).• Interleukin-11(IL-11).• Thrombopoietin.
• These affect RBCs, WBCs as well as platelets.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 4
Erythropoietin• 34-39kDa glycoprotein.(large molecule)
• Wasthe first(1977) isolatedgrowthfactor.• Originallypurifiedfromurineofpatientswithsevereanemia.(Not a
practical way of obtaining erythropoietin nowadays)
• Recombinanthumanerythropoietin(rHuEPO,or Epoetinalfa)isproducedinamammaliancellexpressionsystem.• Half-lifeafterivadministrationis4-13hours.(relatively short half-life)
• Itisnotclearedbydialysis.• Darbepoetin alfa haslongerhalflife.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 5
Erythropoietin
• Producedinthekidney inresponsetohypoxiathroughincreasedrateoftranscriptionofthegene.• Needs activebonemarrow[healthy bone marrow] (nodeficiency,noprimarybonemarrowdiseaseandnosuppressionbydrugsorchronicdiseases).• Normalserumlevel20IU/L.• Elevatedinmostofanemias(uptothousands)butloweredinanemiaofchronicrenalfailure.(Normal production of erythropoietin depends on the presence of good renal activity)
Oct-21 Munir Gharaibeh MD, PhD, MHPE 6
Erythropoietin• Stimulateserythroidproliferationanddifferentiationbyinteractingwithspecificreceptors(JAK/STATcytokinereceptor)onredcellprogenitor.• Releasesreticulocytesfromthebonemarrow.(activates the production of RBCs and can be used in certain treatments of anemia)
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IndicationsofErythropoietin• 1. Anemiaofchronicrenalfailure:• The Cause of this anemia is deficiency of erythropoietin.
• Thesearethepatientsmostlikelytobenefitfrom treatment.• 50-150IU/kgIVorSCthreetimesaweek.[small doses are sufficient]
• Failuretorespondisusuallyduetoironorfolicaciddeficiency.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 8
IndicationsofErythropoietin
• 2. Primarybonemarrowdisordersandsecondaryanemias: aplasticanemia,myeloproliferativeandmyelodysplasticdisorders,multiplemyelomaandbonemarrowmalignancies.Also,anemiaofchronicinflammation,AIDSandcancer.
• Responseisbetterwithlowbaselineerythropoietinlevels.[more effective]
• Patientsrequirehigherdoses(100-500IU/kg).
• Responseisgenerallyincomplete.[problem is not mainly caused by deficiency of erythropoietin]
Oct-21 Munir Gharaibeh MD, PhD, MHPE 9
IndicationsofErythropoietin
• 3. Anemiaofzidovudinetreatment.[zidovudine:anti-viral agent]
• 4 Anemiaofprematurity.[underdevelopment of BM , stimulated by giving erythropoietin]
• 5. Ironoverload. [ toxicity due to IV adminstration of iron, erythropoietin is given to stimulate BM in order to consume iron in the bone marrow, reducing iron concentrations in the blood]
• 6. Unethically,usedbyathletes.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 10
ToxicityofErythropoietin
• Duetorapidincreasesinhematocritandhemoglobin:hypertensionandthromboticcomplications.• Allergicreactionsareinfrequentandmild.[produced by recombinant DNA
technology]
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GranulocyteColonyStimulatingFactors
• Originallypurifiedfromculturedhumancells.[not practical because WBCs have short-life span so quantities purified could be minimal]
• rHuG-CSF“Filgrastim”1991:• Producedinabacterialcellexpressionsystem.• 175aminoacids,18kD mol.wt.• Hasahalflifeof2-7hours.• Pegfilgrastim=Filgrastimcovalentlyconjugatedwithpolyethyleneglycol
[increases the duration of action for filgrastim]. Injectedonceperchemotherapycycle.(relatively longer half-life)
Oct-21 Munir Gharaibeh MD, PhD, MHPE 12
GranulocyteColonyStimulatingFactors
• Workson(JAK/STATreceptors).• Stimulatesproliferationanddifferentiationofprogenitorscommittedtotheneutrophillineage.• Activatesthephagocyticactivityofmatureneutrophilsandprolongstheirsurvivalinthecirculation.• Mobilizeshemopoieticstemcellsintotheperipheralcirculation.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 13
GranulocyteMacrophageColonyStimulatingFactors
rHuGM-CSF“Sargramostim”:• Producedinayeastcellexpressionsystem.• 127aminoacids,15-19kD mol.wt.• Hasahalflifeof2-7hours.
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GranulocyteMacrophageColonyStimulatingFactors
• Hasbroaderactions.AlsoworksonJAK/STATreceptors.• Stimulatesproliferationanddifferentiationofearlyandlategranulocyticprogenitorcellsaswellaserythroidandmegakaryocyteprogenitors.•Withinterleukin-2,alsostimulatesT-cellproliferation.• Locally,itisanactivefactorofinflammation.•Mobilizesperipheralbloodstemcells,butlessthanG-CSF.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 15
ClinicalApplicationsofMyeloidGrowthFactors
CancerChemotherapy-InducedNeutropenia:• Neutropenia: low level of neutrophils and high susceptibility for infections.
vGranulocyte transfusionisnotpractical.[isolation of granulocytic WBCs from donated blood,BUT WBCs have short life-span which made it unsuccessful]
• G-CSFacceleratesneutrophilrecovery,leadingtoreducedepisodesoffebrileneutropenia,needforantibioticsanddaysofhospitalization,butdonotimprovesurvival.[patients mostly die from chemotherapy rather than the cancer itself by secondary infections due to suppression of BM and neutrophils or WBCs]
• G-CSFisreservedforriskypatients.• GM-CSFcanproducefeveronitsown.[confuses the condition]
• TheyaresafeeveninthepostchemotherapysupportivecareofpatientswithAML.
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OtherClinicalApplicationsofMyeloidGrowthFactors
• Congenitalneutropenia.• Cyclicneutropenia.• Myelodysplasia.• Aplasticanemia.
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ToxicityofMyeloidGrowthFactors
• Bonepain.• Fever,malaise,arthralgia,myalgia.• CapillaryLeakSyndrome:peripheraledema,pleuralorpericardialeffusions.• Allergicreactions.• Splenicrupture.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 18
Megakaryocyte GrowthFactors
• Interleukin-11(IL-11):• 65-85kDa protein.• Producedbyfibroblastsandstromalcellsinthebonemarrow.• Halflifeis7-8hoursafterscinjection.
• Oprelvekin:• Istherecombinantform.• ProducedbyexpressioninE.coli.
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Megakaryocyte GrowthFactors
• Interleukin-11(IL-11):• Actsthroughaspecificreceptor.• Stimulatesthegrowthofmultiplelymphoidandmyeloidcells.• Stimulatesthegrowthofprimitivemegakaryocyticprogenitors.• Increasesthenumberofperipheralplateletsandneutrophils.
Oct-21 Munir Gharaibeh MD, PhD, MHPE 20
Megakaryocyte GrowthFactors
ClinicalApplicationsofIL-11:• Thrombocytopenia
• Approvedforthesecondarypreventionofthrombocytopeniain patientsreceivingcytotoxicchemotherapyfortreatmentof nonmyeloid cancers.
• Plateletstransfusionisanalternative.[less practical , platelets preparation is difficult , transfusing blood carry many risks such as ; blood overloading the circulation or contaminated transfused blood]
Oct-21 Munir Gharaibeh MD, PhD, MHPE 21
Megakaryocyte GrowthFactors
Thrombopoietin(2008):-65-85kDa glycoprotein.-Recombinantformisproducedbyexpressioninhumancells.-Eltrombopag-Romiplostim-Independentlystimulatesthegrowthofprimitivemegakaryocyticprogenitors.-Alsostimulatesmaturemegakaryocytes.-Activatesmatureplateletstorespond to aggregation-inducingstimuli.
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Megakaryocyte GrowthFactorsToxicity:• Fatigue,headache,dizziness,anemia,dyspnea,transientatrialarrhythmiasandhypokalemia.
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