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)

Oct-21 Munir Gharaibeh MD, PhD, MHPE 7

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]

Oct-21 Munir Gharaibeh MD, PhD, MHPE 11

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.

Oct-21 Munir Gharaibeh MD, PhD, MHPE 14

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.

Oct-21 Munir Gharaibeh MD, PhD, MHPE 16

OtherClinicalApplicationsofMyeloidGrowthFactors

• Congenitalneutropenia.• Cyclicneutropenia.• Myelodysplasia.• Aplasticanemia.

Oct-21 Munir Gharaibeh MD, PhD, MHPE 17

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.

Oct-21 Munir Gharaibeh MD, PhD, MHPE 19

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.

Oct-21 Munir Gharaibeh MD, PhD, MHPE 22

Megakaryocyte GrowthFactorsToxicity:• Fatigue,headache,dizziness,anemia,dyspnea,transientatrialarrhythmiasandhypokalemia.

Oct-21 Munir Gharaibeh MD, PhD, MHPE 23