药理学英文版教学课件：Chapter 39 Aminoglycosides

AminoglycosidesCase115yrsoldboySufferedrespiratoryinfection1monthagoandhealedafterinjectionwithpenicillinandstreptomycinfor7days.Buthefeltareducedhearingsincethen,withheadache,feltfullofear,tinnitus(耳鸣).Diagnosis:druginducedhearingloss（听觉损伤）Aminoglycosides（氨基糖苷类）areagroupofbactericidalantibioticsoriginallyobtainedfromvariousstreptomyces(链霉菌属)speciesandsharingchemical,antimicrobial,pharmacologic,andtoxiccharacteristics.ClassificationNaturalproducts:Streptomycin(链霉素)Neomycin(新霉素)Kanamycin(卡那霉素)Gentamicin(庆大霉素)Tobramycin(妥布霉素)Sisomicin(西索米星)Semisyntheticproducts:Amikacin(阿米卡星)Netilmicin(奈替米星)§1GeneralpropertiesofaminoglycosidesPhysicalandchemicalpropertiesMechanismofactionMechanismsofresistancePharmacokineticsAdverseeffectsClinicalusesPhysicalandchemicalpropertiesAminoglycosideshaveahexose(己糖)ring,towhichvariousaminosugars（氨基糖）areattachedbyglycosidiclinkages（糖苷键）.Theyarewater-soluble,stableinsolution,andmoreactiveatalkalinethanatacidpH.

Aminoglycosidesfrequentlyexhibitsynergismwithbetalactamsinvitro.Athighconcentrations,aminoglycosidesmaycomplexwithbeta-lactamdrugs,resultinginlossofactivity,andtheyshouldnotbemixedtogetherforadministration.PharmacokineticsAbsorption:AminoglycosidesareabsorbedverypoorlyfromtheintactGItract（口服难吸收）;virtuallytheentireoraldoseisexcretedinfecesafteroraladministration.Thedrugsmaybeabsorbedifulcerationispresent.Afterintramuscularinjection,aminoglycosidesarewellabsorbed,givingpeakconcentrationsinbloodwithin30-90minutes.Elimination:Aminoglycosidesarehighlypolarcompoundsthatdonotentercellsreadily.TheyarelargelyexcludedfromtheCNSandtheeye.Butinthepresenceofactiveinflammation,cerebrospinalfluidlevelsreach20%ofplasmalevels.Aminoglycosidesareclearedbythekidney,andexcretionisdirectlyproportionatetocreatinineclearance.Thenormalhalf-lifeinserumis2-3hours,increasingto24-48hoursin-patientswithrenaldysfunction.AntibioticeffectsNarrowspectrum,G-bacteria,particularlyforaerobicG-bacilli（G-需氧杆菌）,mycobacteria(分枝杆菌).

1.Bactericidals2.Antibioticeffectareconcentrationdependent;longerPAE,concentrationandtimedependent;havefirstexposureeffect,mainlyagainstaerobicG-bacilliandnoanyeffectsonanaerobe;3.MechanismofactionMechanismofactionAminoglycosidesareirreversibleinhibitorsofproteinsynthesis.Theinitialeventispassivediffusionviaporinchannelsacrosstheoutermembrane.Drugisthenactivelytransportedacrossthecellmembraneintothecytoplasmbyanoxygendependentprocess.Thetransmembraneelectrochemicalgradientsuppliestheenergyforthisprocessandtransportiscoupledtoaprotonpump.LowextracellularpHandanaerobicconditionsinhibittransportbyreducingthegradient.Transportmaybeenhancedbycellwall-activedrugs,suchaspenicillinorvancomycin.Onceanaminoglycosidehasenteredthecell,itbindstospecific30S-subunitribosomalproteins(S12inthecaseofstreptomycin).Proteinsynthesisisinhibitedbyaminoglycosidesinatleastthreeways.interferewiththe"initiationcomplex"ofpeptideformation;inducemisreadingofmRNA,whichcausesincorporationofincorrectaminoacidsintothepeptide,resultinginanon-functionalortoxicprotein;causeabreakupofpolysomesintononfunctionalmonosomes.Theseactivitiesoccurmoreorlesssimultaneously,andtheoveralleffectisirreversibleandlethalforthecell.Mechanismsofresistance钝化作用:Themicroorganismproducesatransferaseorenzymesthatinactivatetheaminoglycosidebyadenylylation,acetylationorphosphorylation.Thisistheprincipaltypeofresistanceencounteredclinically.Theseenzymesareusuallyplasmid-controlled.Impairedentryofaminoglycosideintothecell.Thismaybegenotype,i.e.resultingfrommutationordeletionofaporinproteinorproteinsinvolvedintransportandmaintenanceoftheelectrochemicalgradient;orphenotypic,e.g.,resultingfromgrowthconditionsunderwhichtheoxygen-dependenttransportprocess.Thereceptorproteinonthe30Sribosomalsubunitmaybedeletedoralteredasaresultofamutation.ClinicalusesAminoglycosidesaremostlyusedagainstG-entericbacteria,especiallywhentheisolatemaybedrug-resistantandwhenthereissuspicionofsepsis(败血症).Theyarealmostalwaysusedincombinationwitha

-lactamantibioticinordertoextendcoveragetoincludepotentialG+pathogens.

IncombinationwithpenicillinalsousedtoachievebactericidalactivityintreatmentofenterococcalendocarditisandtoshortendurationoftherapyAdverseDrugReactionOtotoxicity（耳毒性）Auditory（听力）damageVestibule（前庭）damageNephrotoxicity（肾毒性）NeuromuscularblockadeHypersensitivityOtotoxicity(耳毒性)Allareototoxic.Itismorelikelytobeencounteredwhentherapyiscontinuedformorethan5days,athigherdoses,intheelderly,andinthesettingofrenalfailure.Vertigo(眩晕),ataxia(共济失调),andlossofbalance;streptomycinandgentamicinproducepredominantlyvestibule(前庭)effects.resultingintinnitus(耳鸣)andhigh-frequencyhearinglossinitially;amikacin,kanamycin,andneomycinprimarilyaffectauditoryfunction.Itislargelyirreversibleandresultsfromprogressivedestructionofvestibuleorcochlearsensorycells,whicharehighlysensitivetodamagebyaminoglycosides.

揭秘《千手观音》2005-05-18《千手观音》是舞蹈编导张继钢在2000年为中国残疾人艺术团一台叫做《我的梦》的晚会专门创作的，当初只有12个人演出，几经修改变成了现在这个21人的版本。但无论是12人还是21人，观众对扮演观音的领舞邰丽华都留下了深刻的印象，人们不愿相信，这个大眼睛的美丽女孩居然是个聋哑人。

26年前，刚刚两岁的邰丽华因为发高烧注射了一种叫做链霉素的药物，从此家人发现原本爱说爱笑的孩子，逐渐变得沉默寡言起来，就连妈妈呼唤她的名字都没有任何反应。妈妈万万没有想到，女儿再也听不到她的呼唤了，药物已经对她的听力造成了严重的损伤。事实上，在《千手观音》中，其他20位扮演“手”的演员，也都有着与邰丽华相似的遭遇，他们都生活在无声的世界里……

2004年10月，卫生部、国家中医药管理局、总后卫生部联合公布的调查报告指出，我国每年约有3万名儿童因不恰当的使用耳毒性药物而造成耳聋，其中95%以上是氨基糖苷类抗菌药物引起的。Nephrotoxicity(肾毒性)Aminoglycosidescanalterthestructureandfunctionofrenalproximaltubularcells.Thereisadefectinrenalconcentratingability,mildproteinuria,andtheappearanceofhyaline(透明)andgranularcasts(颗粒管型).Theseeffectsusuallyarereversible.Themostcommonsignificantfindingisamildriseinplasmacreatininelevelsorreducedcreatinineclearance.Neomycin,tobramycin,andgentamicinarethemostnephrotoxic.Themostimportantresultofthistoxicitymaybereducedexcretionofthedrug,whichinturnwillleadtoototoxicity.Loopdiuretics(furosemide)orothernephrotoxicantimicrobialagents(vancomycinoramphotericin,两性霉素)canpotentiatenephrotoxicityandshouldbeavoidedifpossible.Monitoringdrugconcentrationsinplasmaisuseful,particularlyduringprolongedand/orhigh-dosetherapy.NeuromuscularblockadeInveryhighdoses,aminoglycosidescanproduceacurare-likeeffectwithneuromuscularblockadethatresultsinrespiratoryparalysis.Thisparalysisisusuallyreversiblebycalciumgluconate(givenpromptly)orneostigmine.Neomycin＞kanamycin＞amikacin＞gentamicin＞tobramycin.Itoccursinfrequently

AllergicreactionNumbaroundmouth--streptomycinBothanaphylaxisandrashareunusual.§2Drugscommonlyusedintherapy

Streptomycin(链霉素)ClinicalusesMycobacteria(tuberculous)infections“whitedeath”

（白死病）Streptomycinismainlyusedasafirst-lineagentfortreatmentoftuberculosis.Itshouldbeusedonlyincombinationwithotheragentstopreventemergenceofresistance.Bubonicplague(腺鼠疫)“blackdeath”（黑死病）

infections:Inplague,tularemia(兔热病),andsometimesbrucellosis(布氏杆菌病),streptomycinisgivenintramuscularlyincombinationwithanoraltetracycline.Usedincombinationwithpenicillinsforendocarditisenterococcal(肠球菌)andviridansstreptococcal(链球菌性)endocarditis(心内膜炎),

AdversereactionsofstreptomycinThemostserioustoxiceffectisdisturbanceofvestibulefunction-vertigoandlossofbalance.Vestibuletoxicitytendstobeirreversible.Allergicreactions,fever,skinrashes;Thisoccursmostfrequentlyuponprolongedcontactwiththedrug.Painattheinjectionsiteiscommonbutusuallynotsevere.

GentamicinAntimicrobialactivity:Itisactivealone,butalsoasasynergisticcompanionwithbeta-lactamantibiotics,againstgram-negativerodsthatmayberesistanttomultipleotherantibiotics.Likeallaminoglycosides,ithasnoactivityagainstanaerobes.Resistance:rapidlyemergesinstaphylococciduetoselectionofpermeabilitymutants.

Clinicaluses:mainlyinsevereinfections(eg,sepsisandpneumonia)causedbyG-bacteriaresistanttootherdrugs.usedwithpenicillinGforbactericidalactivityinendocarditisduetostreptococciorenterococci.Adversereactions:Nephrotoxicityisreversibleandusuallymild.MeningitiscausedbyG-bacteriatreatedbytheintrathecal.Ototoxicity,whichtendstobeirreversible,mainlyasvestibulardysfunction.Lossofhearingcanalsooccur.KanamycinandNeomycinactiveagainstG+andG-bacteriaandsomemycobacteria.completecross-resistancebetweenkanamycinandneomycin.Neomycinandkanamycinarenowlimitedtotopicalandoraluse.Inpreparationforelectivebowelsurgery,neomycinisgivenorally,oftencombinedwitherythromycin.Tobramycinsimilartogentamicin,cross-resistance,thesuperioractivityoftobramycinagainstPseudomonasspecies.usedincombinationwithanantipseudomonalpenicillin,aztreonam,orceftazidime.ototoxicandnephrotoxic.Nephrotoxicityoftobramycinslightlylessthangentamicin.

Amikacinlesstoxicthantheparentmolecule.It