藥理學教學課件：3-therapeutic drugs inhibiting protein synthesis xinban 37,38,39章 37+38 2 39+40 2

Therapeuticdrugs

inhibitingproteinsynthesisAminoglycosidesStreptomycin,Gentamycin,AmikacinTheseareagroupofnaturalandsemisyntheticantibioticshavingpolybasicaminogroupslinkedglycosidicallytotwoormoreaminosugarresidues.MechanismofactionAminoglycosidesarebactericidalantibiotics.Generalpatternofactionwhichmaybedescribedintwomainsteps:Diffusethroughporinchannels,activelytransportedacrosscytoplasmicmembrane.Bindingto30ssubunitribosomesresultingininhibitionofproteinsynthesis.MechanismofactionTheyinterferewiththeinitiationcomplexofpeptideformation.TheyinducemisreadingofmRNA.Theycauseabreakupofpolysomesintononfunctionalmonosomes.InterferingthepermeabilityofthemembraneProducinghydroxylradical

PASpectrumofactivityEffectiveagainstaerobicgram-negativebacilli,becausestrictanaerobeslackoxygen-requiringdrugtransportsystem.Combinedwithbeta-lactamantibioticsduetotheirinhibitoryactionofcellwallsynthesis,whichcanenhancediffusionoftheaminoglycosidesintothebacterium.Buttheyshouldnotbemixedtogetherforadministration(athighconcentrations,aminoglycosidesmaycomplexwithbeta-lactamdrugs,resultinginlossofactivity).SpectrumofactivityStreptomyciniseffectiveagainstmycobacteriumtuberculosisandmainlyusedasafirstlineagentfortreatmentoftuberculosis.Thebactericidalactionofaminoglycosidesisconcentrationdependent.ClinicalusesStreptomycin

InfectioncausedbymostG-bacteriaItsclinicaluseisrestrictedbecauseofitstoxicityandresisitance.

PlaguecausedbyY.pestis(combinedwithtetracycline

)

TularemiacausedbyFrancisellatularensis------firstchoice

Endocarditiscausedbystreptococcusviridans

combinedwithpenicillinG--Firstchoice

Tuberculosis

causedbyM.tuberculosisTheearliestAntituberculousdrugs,usedformulti-drugresistanttuberculosis.AdverseeffectsOtotoxicity

Isthemostimportantdoseanddurationoftreatmentrelatedadverseeffect.NephrotoxicityAnimportantimplicationofaminoglycosideinducednephrotoxicityisreducedclearanceoftheantibiotic?higherbloodlevels?enhancedototoxicity.

AdverseeffectsNeuromuscularparalysisAcuteneuromuscularblockagecanoccurifanaminoglycosideisusedincombinationwithanaesthesiaorotherneuromuscularblockers.AllergicreactionPrecautionsandinteractionsAvoidconcurrentuseofotherototoxicdrugs,e.g.highefficacydiuretics,minocycline.Avoidconcurrentuseofothernephrotoxicdrugs,e.g.cephalothin,vancomycin.Cautioususeofmusclerelaxantsinpatientsreceivinganaminoglycoside.Avoidduringpregnancy:riskoffoetalototoxicity.Donotmixaminoglycosidewithanydruginthesameinfusionbottle.Macrolides

ErythromycinClarithromycinAzithromycinErythromycinisanexampleofmacrolides.Macrolidesareagroupofantibioticswithamacrocycliclactonering(usuallycontaining14or16atoms)towhichoneormoredeoxysugarsareattached.Erythromycinisbacteriostaticatlowconcentration,whileathigherconcentrationitisbactericidal.Sensitivegrampositivebacteriaaccumulateerythromycinintracellularlybyactivetransport.Itisseveralfoldmoreactiveinalkalinemedium,becausethenonionized(penetrable)formofthedrugisfavouredathigherpH.MechanismofactionErythromycinactsbyinhibitingbacterialproteinsynthesis.Itirreversiblybindstothe

50ssubunitofthebacterialribosome,preventingthetranslocationstepsofproteinsynthesisandthemovementoftheribosomealongmRNA→synthesisoflargerproteinsisspeciallysuppressed.PASpectrumofactivityEffectiveagainstmanyofthesameorganismsaspenicillinG.Therefore,itmaybeusedinpatientswhoareallergictopenicillins.Erythromycinishighlyactiveagainststr.pyogenesandstr.pneumoniae,

N.gonorrhoeae,

Clostridia,C.diphtheriae,Listeria.Campylobacter,Legionella,Haemophiluspertussis,

Chlamydia,Mycoplasmaarehighlysensitive.Enterobacteriaceae,othergramnegativebacilliandB.fragilisarenotinhibited.PharmacokineticsErythromycinbaseisdestroyedbygastricacid.Toprotectitfromgastricaciditisgivenasenteric-coatedtablets,fromwhichabsorptionbyretardinggastricemptying.Itsacidstableestersarebetterabsorbed.Isdistributedwidelyexcepttothebrainandcerebrospinalfluid.Largeamountsofanadministereddoseareexcretedinthebileandlostinfeces,only5%isexcretedintheurine.(exceptclarithromycin)Azithromcinhasthelongesthalf-life(3days)Clinicaluses

Legionellainfectionpneumonia

CampylobacterinfectionPertussis

Mycoplasmapneumonia--firstchoice

ChlamydiainfectionDiphtheria

StreptococcusinfectionAdverseeffectsGastrointestinaleffects:nausea,vomiting,diarrheawhichduetoadirectstimulationofgutmotility.Ototoxicity:Veryhighdosesoferythromycinhavecausedreversiblehearingimpairment.Allergicreactions:fever,rashesLivertoxicity:erythromycin,particularlytheestolate,canproduceacutecholestatichepatitis(fever,jaundice,impairedliverfunction),particularlyasahypersensitivityreaction.Mostpatientsrecoverfromthis.ClindamycinMechanismofactionItislincosamideantibioticsimilarinmechanismofactionandspectrumofactivitytoerythromycin.Inhibitsproteinsynthesisbybindingto50sribosomethusinterferingwiththeformationofinitiationcomplexesandwithaminoacyltRNAtranslocationreaction.Itinhibitsmostgrampositivecocci(includingpenicillinaseproducingStaph.),C.diphtheriae,Nocardia,butthedistinctivefeatureisitshighactivityagainstavarietyofanaerobesspeciallyBact.fragilis.Aerobicgramnegativebacilliarenotaffected.SpectrumofactivityClinicalusesClindamycinisindicatedfortreatmentofsevereanaerobicinfectioncausedbybacteroidesandotheranaerobesthatoftenparticipateinmixedinfection.AdversereactionGastrointestinaleffectsPseudomembranouscolitis(causedbyClostridiumdifficile,oraladministrationofeithermetronidazoleorvancomycin)AllergiceffectsTetracyclinesTheseareaclassofantibioticshavinganucleusoffourcyclicrings.Tetracycline,Doxycycline,minocyclineMechanismofactionTetracyclinearebacteriostaticTheyentersusceptibleorganismsbothbypassivediffusionandbyenergy–dependenttransportsystemsnotpossessedbymammaliancells.Thetetracyclinethenbindsreversiblytothe

30ssubunitofthebacterialribosome,blockingthebindingofaminoacyl-tRNAtotheacceptorsiteonthemRNAribosomecomplex.Inhibitbacterialproteinsynthesis.PASpectrumofactivityTetracyclineshavebroad-spectrumactivityagainstGram-positiveandGram-negativebacteriaincludinganaerobes,rickettsiae,chlamydiae,mycoplasmasandagainstsomeprotozoa,eg.Amebas.ClinicalusesInfectioncausedbyrickettsiae:typhus,tsutsugamushidiseaseInfectioncausedbychlamydiae:Chlamydiapneumonia,psittacosisInfectioncausedbymycoplasmas:mycoplasmalpneumoniaDoxycyclineisthefirstchoicedrugtothediseasesabove.Routeofadministration:

OrallyorintravenouslyOralabsorptionisincompleteandcanbeimpairedbymultivalentcationscalcium

(e.g.milk)andmagnesiumoraluminiumsalts(e.g.antacids).

Contraindications：

Tetracyclinesshouldnotbegiventochildrenorpregnantwomen.Adverseeffectsgastrointestinaldiscomfort;nausea,vomiting,anddiarrhea,whicharecommonafteroraladministration.Tetracyclinesarereadilyboundtocalciumdepositedinnewlyformedboneorteethinyoungchildren(childrenunder8yearsoldandfetus)anddepressbonegrowthandproducepermanentdiscolorationofteeth.LivertoxicityPhotosensitizationChloramphenicolMechanismofaction

Chloramphenicolisbactericidalorbacteriostaticdependingonthebacterialspecies.Itreversiblybindstothe50ssubunitofthebacterialribosomeandinhibitsprot