Download pdf - Drug Drug Class Mechanism of Action Indications Adverse ......Dec 01, 2017 · They Form Adducts with Nucleophillic Molecules ----- Alkylation of DNA Bases Leads to Lethal Toxicity

LogKill:ClinicallyDetectableTumor:

1Gram=1BillionCells----------------

EffectivelyDosedChemoKillsby1stOrderKinetics

(ConstantFractionofCancerCellsEachTime)

ResidualCancerCellsKilledBy:ImmunologicProcesses

Apoptosis

GompertzianGrowth:AsTumorsIncreaseinSize,theirGrowthFraction(GF)

Decreases,causingHypoxicConditions.AsTumorsDecreaseinSize,theirGrowthFraction(GF)

Increases,makingthemMoreSusceptibletoChemotherapy.

SmallTumors=MoreResponsivetoChemoLargeTumors=LessResponsivetoChemo

RBandP16:RetinoblastomaP53:LiFraumeniSyndrome

Pyrimidines:Thymine(5-MethylUracil)

CytosinePurines:GuanineAdenine

Nucleoside:Nucleobase+PentoseSugarNucleotide:Nucleoside+PhosphateGroups

Drug DrugClass MechanismofAction Indications AdverseEffects ResistanceMechanisms

NitrogenMustardAlkylator

CellCycleNon-Specific(Radiomimetic)

ActThroughCovalentBondingofAlkylGroupstoIntra-CellularMarcomolecules.

AlkanesareMissingOneHydrogen,MakingThemVERYReactive.

TheyFormAdductswithNucleophillicMolecules---------------------------------------------------

AlkylationofDNABasesLeadstoLethalToxicityinCancerN7PositionofGuanine

Monofunctional:OneUnpairedElectron-SingleStrandBreaks

Bifunctional:TwoUnpairedElectrons--CrossLinking

Hodgkin'sDiseaseIV

Vesicant(NitrogenMustardistheWorst)--------------------------------------------

ToxicityWORSEinCellsDeficientinDNARepairEnzymesExample:AtaxiaTelangiectasiaSyndrome

--------------------------------------------SecondaryMalignancies(AML)

CausedbyDNADamageWithoutCellDeath---------------------------------------------

BoneMarrowSuppression:(WBCsandPlatelets)Occurs:7-10DaysPostRx

Recovers:7-10Days-------------------------------------------------------FormationofTrappingAgent(Glutathione)

IncreasedIntracellularThiol(Glutathione)Concentration.ThisNeutralizesAlkylation

(GeneAmplification)---------------------------------------------------

ChangeinDNARepairEnzymesAmountofEnzyme(GeneAmplification)

Efficiency(Mutation)

NitrosoureasCarmustine(BCNU)Lomustine(CCNU)

Semustine(Methyl-CCNU)

AlkylatorCellCycleNon-Specific

(Radiomimetic)

WorkSimilarlytoClassicAlkylator(Above)CovalentlyBindwithNucleicAcids

CauseCross-Linking

FATSOLUBLECrossBBB(BrainMetastasis)

MelanomaBrainTumors

PROLONGEDBoneMarrowSuppression SameasAbove

BusulfanAlkylator


WorkSimilarlytoClassicAlkylator(Above)HistoricallyUsedforCMLReplacedbyGleevac

PulmonaryToxicity SameasAbove

TemozolomideAlkylator


SameasAboveTetrazideDerivative(AromaticRing-4HAtoms)

OralPro-DrugCrossesBBB

ImprovesSurvivalinGliomaswhenCombinedwithRadiationTherapy

SameasAbove SameasAbove

CyclophosphamideAlkylator


CommonDrugActiveIntermediates

(PhosphoramideMustardandACROLEIN)

Well-AbsorbedOrallyWidestClinicalUsage

BreastCancersLymphomasLeukemias

MyelosuppressionAcroleinToxicity

HemorrhagicCystitis(PreventbyForcingHydration,Diuresis,andParticular

AttentiontoUrinaryObstruction(BPH))

SameasAbove

IfosfamideAlkylator


ToxicityofACROLEINAcrolein:

ProducedbyBurningFatAnExtremelyToxicIntermediary,Particularlytothe

BladderMucosa(OlderPatientswithBPH)CausesHemorrhagicCystitis

-----------------------------------------------------------------ModifiedwithMESNA:

2-MercaptoEthaneSulfonateSodium(NA)SuppliesFreeThiolGroup,whichBindstoandInactivates

Acrolein

TesticularCancerSarcoma

LungCancer

AcroleinToxicityHemorrhagicCystitis(MostCommoninBPHPatients) SameasAbove


Methotrexate(-trex=Anti-Folate)

Anti-MetaboliteCellCycleSpecific

Anti-Folate

CloseStructuralResemblancetoaMoleculeRequiredforNormalPhysiologicFunctioning,andExertingitsEffectbyInterferingwiththeUtilizationofthisEssentialMolecule.

InhibitionofDNA/RNA/ProteinSynthesis------------------------------------------------------------

VerySimilartoFolicAcidPreventsRegenerationofReducedFolateby

BlockingDihydrofolateReductaseNoTetrahydrofolate=NodUMP=NoDNASynthesisThymidiylateSynthetaseRequiresTetrahydrofolate

ChoriocarcinomaDoesNotCrossBBBIntrathecalChemo

(AttainHighCSFConcentrationswithMinimalSystemicToxicity)-------------------------------------------------

LeucovorinFolinicAcidRescue:WithUseofHighDoseMTXCancerCellshaveHighGF

MTXEffectisMoreRapidwithHigherGFCellPopulations(Cancer)

MayRescueLowerGFPopulation(Non-CancerousTissue)withExcess

ReducedFolate(GivenAfterMethotrexate)Dangerous--TimingisCritical

MinimalSystemicToxicityBecauseWhenyouInjectItDirectlyIntotheCSF,ItCannotCrossBackOut.

----------------------------------------------------------------------BoneMarrowSuppression(7-10Days)

SkinRashesMucositis(7-10Days)-->Infections

Hepatotoxicity(MoreCommonwithChronicUse)PulmonaryToxicity

----------------------------------------------------------------------3rdSpacing:

MethotrexateCollectsinPleuralEffusions&AsciticFluidSubsequentSlowReleaseofDrugMimickingaSlowInfusionwithIncreasedBoneMarrowandMucosal

Toxicity(Unpredictable)

IncreasedProductionofDHFR(GeneAmplification)

DecreasedAffinityofDHFRforMTX(Mutation)

-------------------------------------------------OftenMoreActiveifPolyglutamatedAdditionofGlutamicAcidResiduesIntracellularlytoMethotrexateDecreasesCellularEffluxof

PolyglutamatedDrugIncreasesDrugActivity/ExposureTimeCellsthatCannotPolyglutamateAreRelativelyResistanttoEffectofMTX.CancerCellMutationcanDecrease

PolyglutamationCanEitherbeInheritantlyPoor

PolyglutamatorsorUndergoMutations

5-Fluorouracil5-FU

Anti-MetaboliteCellCycleSpecificPyrimidineAnalog

Normal:dUMP-->dTMP-->DNASynthesis-------------------------------------------------------

dUMPCannotbeMethylatedtodTMPinthe5'PositionBecauseThereisaFluorineThere

5F-dUMPisCompetingwithdUMPfortheThymidylateSynthetaseEnzyme

DecreaseinDNASynthesis-------------------------------------------------------

SecondaryMechanism:5F-UMPisIncorporatedintoRNA

ActsasFalsePyrimidineInhibitsTranscription

-------------------------------------------------------------------------PRPP:

NeededtoSecondarilyActivate5-FUNeededtoSynthesizePurines

InhibtedbyAllopurinol

CornerstoneforRxColonCancerBreastCancerGIMalignancies

----------------------------------------------Flucytosine(5-Fluorocytosine):

Anti-FungalAgentAFluorinatedPyrimidineAnalogueAlsoBioactivatedto5-FdUMPInhibitingTSinFungalCells

GI(Mucositis)Myelosuppression

Skin-SunSensitivity(VenousDiscoloration) 1.IncreasedExpressionofTSEnzyme(GeneAmplification)

2.ReducedDrugSensitivityofTSEnzyme(Mutation)

3.DecreasedActivationof5-FUa.DecreasedActivatingEnzymes(Mutation/Underexpression)orb.DecreasedPRPPSecondaryto

Allopurinol------------------------------------

GivingAllopurinolInhibitsPRPP,whichSecondarilyActivates5-FU.ThismeansAllopurinolDECREASESActivityof5-FU

Capecitabine(Xeloda)


ProdrugConvertedto5-FUintheLiverandthentoActiveDrugin

LiverandTumorTissueIncreasesAreaUndertheCurve

(ProlongedExposureAffectsHigher%ofCyclingCells)

OrallyMimicks5-FUInfusion

LowDoseDeliveredOverLongTerm

HandFootSyndrome:VasospasminHands/Feet

CytosineArabinoside(ARA-C)


ArabinoseSugarisSubstitutedforDeoxyriboseSugarIncorporatedintoDNAInhibitsDNAPolymeraseInhibitsDNAElongation

AMLSevereBoneMarrowSuppression

GI(Mucositis)UnusualNeuroToxicity(CerebellarDysfunction)-Ataxia

IncreasedActivityofCytidineDeaminase(InactivatesDrug--GeneAmplification)DecreasedActivityofDeoxycytidine

Kinase(ActivatesDrug--Mutation)

DecreasedAffinityofDNAPolymerase(Mutation)

OverexpressionofDNAPolymerase(GeneAmplification)

GemcitabineAnti-MetaboliteCellCycleSpecificPyrimidineAnalog

CytosineAnalog(HReplacedbyF)StructurallySimilartoARA-C

butInhibitsDNAPolymeraseANDRibonucleotideReductase

PancreaticCancer

AzacitadineAnti-MetaboliteCellCycleSpecificPyrimidineAnalog

InhibitsMethytransferaseCausingHypomethylationofDNA,LeadingtoCellDeathManyTumorSuppressorGenesareSilencedbyDNA

MethylationduringCarcinogenesis(EpigeneticEffect)

IncreasesTumorSuppressorActivityDrugisIncorporatedintotheGenome,Actingas"Real"

Anti-Metabolite

MyelodysplasticSyndrome

6-Mercaptopurine(6-MP)

6-Thioguanine(6-TG)

Anti-MetaboliteCellCycleSpecificPurineAnalog

Hypoxanthine-->GuanineviaHypoxanthine-GuaninePhosphoribosylTransferase

Enzyme(HGPRT)ThisRecyclesHypoxanthine-->Purines.

6-MPand6-TGBLOCKHGPRT(WithSulfur)-->NoPurineRecycling-->NoDNASynthesis-------------------------------------------------------

PRPP:NeededtoSecondarilyActivate5-FU

NeededtoSynthesizePurinesInhibtedbyAllopurinol

(CausesFeedbackInhibitionofAmidophosphoribosylTransferase(Atase)NeededtoConvertPRPPto

PhosphoribosylamineRateLimitingEnzymeinPurineSynthesis

Leukemia--------------------------------------------

Lesch-NyhanSyndrome:HGPRTDeficiencyIncreasedPRPPLeadstoIncreasedPurineSynthesis

UtilizingPRPP.IncreasedUricAcid

GoutIntellectualDisability

Self-MutilatingBehaviorX-LinkedRecessive

MyelosuppressionMucositisDiarrhea

Nausea&Vomiting

DecreasedAffinityfortheActivatingEnzymeHGPRT(Mutation)

IncreasedDrugDegradation(GeneAmplification

viaXANTHINEOXIDASE)IfyouTreatGoutwithAllopurinol,andthePatientison6-MP/6-TG,theAllopurinolwillALSOBreakDowntheChemotherapy

(andthePRPP),IncreasingToxicity

Cladribine(2-Chlorodeoxyadenosine)

Anti-MetaboliteCellCycleSpecificPurineAnalog

AdenosineAnalog(2CDA)InhibitsAdenosineDeaminaseAdenosineOveraccumulates

CurativeinHairyCellLeukemia

HydroxyureaAnti-MetaboliteCellCycleSpecific

UreaAnalog

InhibitsRibonucleotideReductaseNeededtoConvertRibonucleotidesto

DeoxyribonucleotidesInhibitsDNASynthesis

SickleCell-IncreasesHbFCML

MyelosuppressionNausea&Vomiting

Diarrhea

MutationorOver-ExpressionofRibonucleotideReductase


Doxorubicin(Adriamycin)

DaunorubicinIdarubicinEpirubicin

Anthracyclines(StreptomycesDerivative)

CellCycleSpecific

IntercalatesBetweenBasePairs(BlocksDNA/RNASynthesis)

----------------------------------------------------------------InhibitsTopoisomerase-2

(CausesDNAStrandBreakage)----------------------------------------------------------------

GeneratesOxygen/HydroxylFreeRadicals(CausesDNAStrandBreakage/CellMembraneDamage)

TheRedDevil:NHL

BreastCancerSarcoma

CardiacToxicity(FreeRadical-->CardiacMuscle)

SynergisticwithOtherDrugs(LikeTrastuzumab)Antidote:

Dexrazoxane(Zinecard):IronChelatingAgent,PreventingtheFormationof

Anthracycline-GeneratedFreeRadicals--------------------------------------------------------------------

BoneMarrowSuppressionAlopecia

SevereNauseaandVomitingSecondaryMalignancies

Multi-DrugResistance:MediatedbyP-Glycoprotein

(AnATP-DependentDrugEffluxPump)

DactinomycinAnthracyclines

(StreptomycesDerivative)CellCycleSpecific

IntercalatesBetweenBasePairs----------------------------------------------------------------

BindsatTranscriptionInitiationComplex(InhibitsRNAElongationbyRNAPolymerase)

-------------------------------------------GoldColor

Wilm'sTumor MyelosuppressionSevereVesicant

BleomycinAnthracyclines

(StreptomycesDerivative)CellCycleSpecific

IntercalatesBetweenBasePairs(BlocksDNA/RNASynthesis)

----------------------------------------------------------------ProducesSingle&DoubleStrandBreaks

----------------------------------------------------------------GeneratesOxygen/HydroxylFreeRadicals

(CausesDNAStrandBreakage/CellMembraneDamage)-----------------------------------------------------------------

OnlyDrugwithPre-DominatelyG2ActivityDisruptsSynthesisofComponentsNeededforMitosis

TesticularCancerHodgkin'sDisease

NHL

LungToxicity(FreeRadical-->Lung)AnaphylacticReaction

SkinToxicity




VINcaAlkaloidsVINblastineVINcristineVINdesineVINorelbine

MadagascarPeriwinkleCellCycleSpecific

BindtoMicrotubuleProtein(Tubulin)CauseDepolymerizationofMicrotubules

PreventsSpindleFormation(LeadstoMitoticArrest)

Hodgkin'sDiseaseNHL

LungCancerGliomas

BreastCancer

TubulinisSimilartoMyelin--PeripheralNeuropathyDose-Dependent

SensoryNeuropathy:ReversibleMotorNeuropathy:IrreversibleAutonomic:Unpredictable

VincristineisNOTasMyelosuppressiveasOtherAgents



TaxanesPaclitaxelDocetaxelAbraxaneCabazitaxel

YewTreeCellCycleSpecific

BindtoTubulinEnhancesTubulinPolymerization

PreventsSpindleDisassociationCausingMitoticArrest

OvarianCancerBreastCancerLungCancer

BoneMarrowSuppressionAllergies(Pre-TreatwithCorticosteroids)

Myalgias/ArthralgiasNeurologic

Skin(ParticularlyNails)-Beau'sLines**UseofSteroidstoPreventAcuteToxicityisCritical**


(AnATP-DependentDrugEffluxPump)CabazitaxelisNOTInhibitedbyMDR

Pulmonary Fibrosis

PodophyllotoxinsEtoposideTeniposide

ExtractofMandrakePlant(NightshadeFamily)CellCycleSpecific

InhibitDNATopoisomerase-2(AndTubulinPolymerization)

TopoisomerasesAllowBreakageofBothDNAStrands,UnwindingofDNA,andRe-AnnealingoftheStrands.

InhibitDNAandRNASynthesis

TesticularCancerLungCancer(SmallCell)

NHLUnpredictableHypotension



CamptothecinsIrinotecanTopotecan

HappyTreeDerived(CamptothecaAcuminata)

CellCycleSpecific

InhibitDNATopoisomerase-1LeadstoArrestofDNAReplicationandCellDeath

Irinotecan:MetastaticColonCancer

Topotecan:SmallCellLungCancer

Irinotecan:ExcessiveDiarrheaRequiringAnti-MotilityAgents

AlsohasUniqueAcuteCholinergicSideEffectRequiringATROPINE

(SuddenSalivation,Tearing,UrgetoDefecate,Bradycardia)

DoesNOTAppeartobeMDRMediatedMutation/Overexpressionof

Topoisomerase-1


CisplatinumCarboplatinumOxaliplatinum

PlatinumComplexesCellCycleNon-Specific

HeavyMetalsCanMoldShape--ActasAlkylatorsExtremelyDifficulttoEliminate

CurativeinMostGermCellTumors

Nephrotoxicity:IncreaseParenteral/OralHydration

UseVolumeExpanders(Mannitol)toForceDiuresisReplacePotassiumandMagnesium

Amifostine:ThiolCytoprotectiveAgentScavengesReactiveCisplastin

MetabolitesinNormalTissueCausesNecrosisorApoptosisofCellsofProximalTubule

LeadingtoWastingofMagnesiumandPotassium----------------------------------------------------------------

Neurotoxicity:8thNerveSomeProtectiveEffectofCalcium/Potassium

Cold-InducedNeuropathy:LaryngopharyngealDysesthesia:

AssociatedwithOxaliplatinCanBePreventedbyAvoidanceofColdAirandDrink

MonitorHearingLoss


(AnATP-DependentDrugEffluxPump)----------------------------------------------------

IncreasedProductionofIntracellularThiolIncreasedProductionofDNARepair

EnzymesFormationofTrappingAgent

(Glutathione)


L-Asparaginase NaturallyOccuringEnzymeGuineaPigSerum

MalignantLymphocytes:RelativelyLOWLevelsofAsparagineSynthetaseL-AspaginaseHydrolysesCirculatingAsparagine.

Thisleadstolessavailabilityofasparaginefortumorcellstherebyinhibitingtumorproteinsynthesisandcell

proliferation.Non-MalignantCellsCellsareRelativelyProtected

ALL Pancreatitis

Drug DrugClass MechanismofAction Indications AdverseEffects ResistanceMechanismsArsenicTrioxide

TransRetinoicAcid ArsenicDerivativeDerivedfromArsenic"Metalloid"

UncertainMechanismofAction(InducesApoptosis?)InCombinationwithRetinoicAcidfor

AcutePromyelocyticLeukemiaInterruptsATPProductionLeadingtoMulti-SystemFailure

Bortezomid ProteosomeInhibitorProteosome:

CytoplasmicProteaseComplexRequiredtoDegradeUnneededProteins

MultipleMyelomaMantleCellLymphoma

Thalidomide GlutamicAcidDerivativeGlutamicAcidDerivative

InhibitsAngiogenesisbyInterruptingVEGFProcessesMultipleMyeloma BIRTHDEFECTS

Lenalidomide GlutamicAcidDerivative

Anti-AngiogenesisDrugDecreasesBoneMarrowStromalCellSupport

Anti-OsteoclasticImmunomodulatoryActivity(IMiD's)

MultipleMyeloma BIRTHDEFECTS

Drug DrugClass MechanismofAction Indications AdverseEffects ResistanceMechanismsTamoxifen

FlutamideBicalutamideEnzalutamide

SERM

AWeakEstrogenBlockstheEstrogenReceptor(ER)inBreastCancerCells

Bicalutamide/Enzalutamide:BlockstheAndrogenReceptor

Pre/PostBreastCancer

ThromboembolicDisease-EstrogenEffectEndometrialCancer-EstrogenEffect(DoesNOThappenwithRoloxifen)HotFlashes-Anti-EstrogenEffect

Retinopathy

ChangeinERExpressionMutationofER

SelectionofERNegativeCells

AminoglutethimideVeryToxic

RequiresConcurrentSteroidNoLongerUsed

AnastrozoleLetrozole

ExemestaneAromataseInhibitors Testosterone-->EstrogenInhibitor Post-MenopausalBreastCancer

ToxicityduetoEstrogenWithdrawal:(SUPER-Menopause)OsteoporosisHotFlashesAnthralgias

ProgestinsMegestrolAcetate

MedroxyprogesteroneProgesterone

DecreasesActivityofEstrogenReceptor(Down-Regulation)

IncreaseWeightinCancerPatients Hyperventilitation

LeuprolideGoserilin LHRHAnalogs

EmptiesthePituitaryofLH,FSH(FlareEffect)SubsequentlyDecreasesPituitaryReleaseofLH,FSHResultsinDecreasedEstrogenSynthesisbyOvary

BreastCancerProstateCancer

InducingMenopause

Toxicity:FlareEffectLastsApproximately10Days

CanbeInhibitedbyAndrogenReceptorBlockers

Abiraterone AndrogenProductionInhibitorSuppressesTesticularAndrogenProduction

DoesNOTAffectAdrenal/ProstaticAndrogenProductionInhibitsCYP17EnzymeComplexinTestes

AlsoBlockCortisolCausesIncreaseinACTH(Feedback)=HypertensionGivewithPrednisone(Cortisol)ToPreventThis

Drug DrugClass MechanismofAction Indications AdverseEffects Contraindications

Corticosteroids

UnknownMalignantLymphocyteshaveSteroidReceptorthatLyses

theCellswhenActivated(SteroidsCauseApoptosisofCancerCells)

Hodgkin's/NHLSupportiveCare:Anti-Nauseant

AppetiteStimulantDecreasesCerebralEdema

Co-Analgesic

FluidRetentionGlucoseIntoleranceProximalMyopathy

InsomniaImmunosuppressionIncreasedAppetite

SkinChangesStressUlcers

Rituximab CD20MOABMediatesAntibodyDependentCellularToxicityandComplementDependentCytotoxicitybyMaking

LymphocytesMoreVisibleB-CellLymphoma

InfusionRelated:TumorLysisSyndrome

ProgressiveMulti-FocalLeukoencephalopathyAllergies

AutoimmunePatients

Ipilimumab CTLA-4MOAB

CytotoxicT-LymphocyteAntigen4(CTLA-4)isanInhibitoryRegulatorofT-CellImmuneResponses.ItInhibitsImmuneDefenseAgainstTumorCells.

BlocksCTLA-4,DisinhibitingT-CellActivity

UsedinImmuneSensitiveCancer(Melanoma)

10-20%Immune-MediatedGIToxicity(TreatwithSteroids,Infliximab)

NivolumabPD-1PD-L1

ImmuneCheck-PointInhibitors

ProgrammedDeath-1PD-1:OnT-Cell

PD-L1:OnTumorCellsThisDown-RegulatestheImmuneSystem.

TheDrugActivatestheImmuneSystemtoAttackTumors(ByInhibitingPD)

AutoimmuneSideEffects

TrastuzumabPertuzumab

Her-2/NeuBlockerEGFRBlocker

MOABHer-2/NeuBlockerEGFRBlocker BreastCancer CardiacToxicity

NotUsedwithAnthracycline(BothCauseCardiacToxicity)

Cetuximab Non-HER-2EGFRBlockerMOAB

Non-HER-2EGFRBlockerMarthaStewartDrug

SquamousCellHeadandNeckCancerWild-TypeKRASColonCancer

AcneiformEruption

Panitumumab Non-HER-2EGFRBlockerMOAB

Non-HER-2EGFRBlocker Wild-TypeKRASColonCancer

Bevacizumab VEGFMOABInhibitNewVesselFormation(BlockingEndothelialCells)

ColonCancerAndrefractoryGliomas

DelayedWoundHealingProteinuriaHypertension

DenosumabRANKMOAB

MatrixMetalloproteinaseInhibitor

StimulateOsteoclastActivityRANK:Osteoclast

ImprovesBoneDensity

OsteoporosisBoneMetastasis

DecreasesBonyComplicationsDecreasesCalcium

JawNecrosis

Drug DrugClass MechanismofAction Indications AdverseEffects ContraindicationsLapatinib Her-2TyrosineKinaseInhibitor BreastCancerGefitinibErlotinib

Non-Her-2TyrosineKinaseInhibitor

LungCancer

SunitinibSorafinib VEGFTyrosineKinaseInhibitor

RenalCellCarcinomaHepatoma

Hypothyroidism

ImatinibNilotinib Non-Cell-SurfaceReceptorTKI

InhibitstheTyrosineKinaseActivityoftheProteinProductoftheBCR/ABL/c-KIT

CML(BCR/ABL)GIST(c-KIT)

DiarrheaMyalgiaFluidRetention MutationoftheBCR/ABLGene

Vemurafenib B-RAFInhibitorInhibitsMutatedB-RAFProteinKinase

InhibitsRASPathwayMetastaticMelanoma

AnthralgiasFatigue

Rash--SquamousCellCancer

IfRASisTurnedon,itBypassestheMOABPathway,sothosedrugswillnotwork.

Drug DrugClass MechanismofAction Indications AdverseEffects ContraindicationsRapamycinSirolimus M-TORInhibitor

InhibitorofM-TORUnknownMechanismofAction

KidneyCancers

Drug DrugClass MechanismofAction Indications AdverseEffects ContraindicationsInterferon

AcuteToxicity SubacuteToxicity ChronicToxicityTOXICITIES

AlopeciaPredictable(3WeeksAfter1stCycle)

SeeninAnthracyclines,Taxanes,andsomeAlkylatingAgents

HairContinuestoGrow,butitisBrittleRe-GrowsoftenDifferentinTexture

Treatment:NoneColdCap(Ineffective)

MayDecreaseEfficacyAvoidConcurrentToxinsVaryDrugs

NeurologicalToxicity:SeenwithVincaAlkaloids

Taxanes&Platinum----------------

Sensory:Reversible+CommonMotor:Irreversible+Late

Autonomic:Unpredictable(GI)

OverexpressionofTelomerase:MemoryLoss(ChemoBrian)

FatigueChronicPainAging(LossofMuscleMass,GaitProblems)

NauseaandVomiting:WorseinYoungthanElderly

SeeninPlatinum,Anthracyclines,IVNitrogenMustardDerivedAlkylators

LargePsychologicalComponentUsedtobetheMainCauseofPre-MaturelyDiscontinuing

ChemoPrevention:LightMealsAmnesics

MultipleDrugsActiveDrugs:

HT-3Inhibitors(Ondansetron/Granesetron)Anti-Histamines(Prochloroperazine )

Anti-DopamineDrug(Metoclopromide )-ParkinsonianSideEffect

MinorTranquilizers(Lorazepam)Steroids(Dexamethasone )

THC--------------------------------------------------------------

Aprepitant(Emend):BlocksNeurokinin-1

(DoFinPatientswithNauseaDespiteHT-3Inhibitors)

CardiacToxicity:Anthracyclines:

Dose-DependentCardiomyopathyFree-RadicalMediated

WorsewithHypertensionorRadiationPreventedby:Dexrazoxane

(CardioprotecticeAgent)-------------------------------------------

Trastuzumab:Anti-HER2EffectonHeart

--------------------------------------CANNOTUSEANTHRACYCLINESAND

TRASTUZUMABTOGETHERPrevention:

MonitoringofDoseBaseline/Follow-UpCardiacEjection

Pregnancy:AllAgentshaveIncreasedRiskintheFIRSTTrimesterPatientsin2nd/3rdcanbeTreatewithMostAgents

NOTANTI-METABOLITES

CSFSupport:GranylocyteColonStimulating

Factor(GMCSF):UsedProphylactically

DecreasesInfection-RelatedHospitalizationandDeath

CausesBonePain-----------------Erythropoitin:

IncreasesRBCMassDecreasesBloodTransfusion

RequirementVERYImportantifTransfusionis

Unacceptable(Religion)---------------

MegakaryocyteGrowthFactor:(Thrombopoietin)

ReallyStillinDevelopment(EltromboprgApprovedforITP,

NotLowPlatelets)

Myelosuppression:MostImportantSideEffect

BiggestCauseofRx-RelatedDeathsPredictabletoaDegree:

WhiteCountDecreasesby7-10DaysPlateletsaBitLater

RedCellsDecreaseby1%PerDayOftenAssociatedwithSevereMucositisCreatinga

"PerfectStorm"forInfectionTreatment:AvoidCrowdsHand-Washing

ReportFeverorChillsImmediatelyIfLowAbsoluteNeutrophilCountwithFever

(RxImmediatelywithBroadSpectrumAntibiotics)IfFeverPersists,ConsiderFungalInfection

ForSubsequentCyclesConsiderDoseReduction,CSFSupportorBothPrevention:

UseofRelativelyLessMyelosuppressiveDrugs(Vincristine)

ChangeSchedule

Nephrotoxicity:SeeninCis-Platinum,Mitomycin-C,

Cyclophosphamide-----------------------Cis-Platinum:

Dose-DependentProximalTubuleToxinTreatwithAmifostine-------------------------Mitomycin-C:

CausesTTPwithRenalFailure-----------------------------

Cyclophosphamide+Isofosfamide:AcroleinMediatedHemorrhagic

CystitisTreatwithMESNA

ThromboembolicDisease:TAMOXIFEN

Trousseau'sSign------------------------------------

Osteoporosis:GiveCorticosteroids

Mucositis:SeeninAnti-Metabolites

UsuallyOccursatTimeofNadirBloodCountsOftenPainful,LeadingtoDysphagiaandDiarrhea

ResultsinElectrolyteDisturbanceandMalnutruitionAssociatedwithYeastInfectionandSepsis

Treatment:IntensiveMouthCare

Pre-RxDentalAssessmentMaintainGoodHydration

MouthWashContainingLocalAnaesthetic,Bicarbonate,Anti-FungalandOccasionalAnti-HistamineRequired.

DoseAdjustmentOccasionally,aFeedingTubeRequired.BarrierPreparationAvailable-Episil

PulmonaryToxicity:Bleomycin:

FreeRadicalIntermediatethatInteractswithHemeAssociatedIronin

PulmonaryInterstitum

HypothyroidismGonadalDysfunction

Anti-Metabolites:DiscolorationTaxanes:NailChanges

Capecitabine:Hand-FootEGFRInhibitors:AcneiformRash

SkinChanges:ExtravasationisBiggestConcern,ParticularlywithIV

Alkylators,NaturallyOccuringProducts.ConsideredanEmergency:

Treatment:DiscontinueInfusionIceandElevateLimb

Anti-InflammatoryandAnti-HistamineSystemicallyObservationtoAssessforExtensionofReaction

ConsultPlasticSurgery

DelayedHematologicToxicity:SeeninAlkylatorsandAnthracyclines

Presentation:MyelodysplasiaMyelofibrosisLeukemia(AML)

TTP

Oxaliplatin:PharyngolaryngealDysethesia

UsuallyTransientAggravatedbyColdAirorFluids

Vasculopathy:Anti-AngiogenesisDrugs

HypertensionProteinLosingNephropathyWoundHealingProblems

DiscontinueDrug/GiveACEInhibitorsIrinotecan:

InducesAcuteCholinergicSyndromeHypersalivation,AcuteDiarrhea,Bradycardia

TreatwithAtropine

Rasburicase:RecombinantUrateOxidase

AnEnzymethatMetabolizesUricAcidtoAllantoin

(AnInactiveMetaboliteofPurineMetabolism)

10xSolublethanUricAcidApprovedbyFDAforRxofTumorLysisSyndromeAssociatedwith

HematologicMalignancies

TumorLysisSyndrome:DuetoCellLysis

IncreasePotassium(Arrythmias)DecreasedCalcium(PhosphateLeavesCell,BindstoCa++)

IncreasedUricAcidMedicalEmergency:

IVFluidsAllopurinol

AttentiontoElectrolytesAllopurinol:

ChemoCausesBreakdownofCells+IncreaseinUricAcidThisPreventsAssociatedGoutBUTLeadstoEnhancedCytotoxicEffectofPurineAnaloguesandKidneyFailure

L-Asparaginase:Pancreatitis