藥理學(xué)英文版教學(xué)課件：Chapter 38 Macrolides,lincomycin

Macrolides,Lincomycins&PolypeptidesAntibioticsCase1A22monthsoldbabyboycaughtcold5daysago,withfeverandcough.Panting(氣促)2days.Treatedwithpenicillinfor3daysatlocalhospitalbutfailed.PE:T38.5℃,R60/min,P160/min,moistrales(濕羅音)soundatbothlungs.LabtestshownIgMantibody(+)ofmycoplasmapneumoniae(肺炎支原體)Diagnosis：mycoplasmapneumoniaDrugswithspecializedIndicationMacrolides(Erythromycins)ClindamycinPolypeptideantibiotics§1Macrolides(大環(huán)內(nèi)酯類)Theyareagroupofcloselyrelatedcompoundscharacterizedbyamacrocycliclactonering(usuallycontaining14,15or16atoms)towhichdeoxysugars(脫氧糖)areattached.In1950thefirstdrugofthisclasswasisolated:Picromycin(苦霉素)In1952Erythromycin（紅霉素）andCarbomycin（碳霉素）wereintroducedintoclinic.Macrolidesarestableinaqueoussolutionsatorbelowroomtemperature.Theyareunstableinacidicorbasicconditionsorathightemperatures.GoodforG+,G-cocciinfectionHavepostantibioticeffect(PAE)MacrolidesClassification14-atomlactonering:erythromycin(紅霉素),oleandomycin(竹桃霉素),clarithromycin(克拉霉素),roxithromycin(羅紅霉素),dirithromycin(地紅霉素)15-atomlactoneringazithromycin(阿齊霉素semisythetic)16-atomlactoneringmedecamycin(麥迪霉素),acetylmedecamycin(乙酰麥迪霉素),kitasamycin(吉他霉素),acetylkitasamycin(乙酰吉他霉素),josamycin(交沙霉素),spiramycin(螺旋霉素),acetylspiramycin(乙酰螺旋霉素),rokitamycin(羅他霉素)PharmacokineticsofMacrolidesabsorption:Erythromycinbaseisdestroyedbystomachacidandmustbeadministeredwithentericcoating（腸衣）.Foodinterfereswithabsorption.Stearates（硬脂酸鹽）andestersarefairlyacid-resistantandbetterabsorbed.Thelaurylsalt（月桂鹽）ofthepropionylester（丙酰脂）oferythromycinisthebest-absorbedoralpreparation.distribution:Absorbeddrugisdistributedwidelyexcepttothebrainandcerebrospinalfluid.ErythromycinistakenupbyWBCandmacrophages.Itreachesthefetus(胎兒).metabolism&excretion:metabolizedinliver，excretedinthebileandlostinfeces,andonly5%isexcretedintheurine.Theserumhalf-lifeisapproximately1.5hnormallyand5hoursinpatientswithanuria.Pharmacodynamicsof

Macrolides1.Antibacterialspectrum:narrow,G+pneumococci,streptococci,staphylococci,corynebacteria（棒狀桿菌）;legionella(軍團(tuán)菌),chlamydiahelicobacter,certainmycobacteria（分支桿菌）,G-neisseriaspecies(奈瑟菌屬),bordetallapertussis(百日咳)andcampylobacterspecies(彎曲桿菌).somerickettsiaspecies(立克次體),mycoplasma(支原體),trachomatis(衣原體),2.AntibacterialactivityInhibitoryorbactericidal,particularlyathigherconcentrations,forsusceptibleorganisms.ActivityisenhancedatalkalinepH.3.MechanismofantibioticactionInhibitionofproteinsynthesisoccursviabindingtothe50SribosomalRNA.Proteinsynthesisisinhibitedbecauseaminoacyl（氨酰基）translocationreactionsandtheformationofinitiationcomplexesareblocked.ResistancetoMacrolidesUsuallyplasmid-encoded（質(zhì)粒編碼）.Threemechanismshavebeenidentified.Modificationoftheribosomalbindingsite;Production(byenterobacteriaceae)ofesterasesthathydrolyzemacrolides;Reducedpermeabilityofthecellmembraneoractiveefflux;Macrolidesthatarecommonlyused

Erythromycin(紅霉素)Clarithromycin(克拉霉素)Azithromycin(阿齊霉素)Roxithromycin（羅紅霉素）Medecamycin（麥迪霉素）Spiramycin（螺旋霉素）Josamycin（交沙霉素）ClinicalusesofErythromycinItisthedrugofchoiceininfectionsdiphtheria,(白喉);inrespiratory,neonatalocularinflammation,orgenital(生殖)chlamydial(衣原體)infections;andintreatmentofcommunity-acquiredpneumoniabecauseitsspectrumofactivityincludesthepneumococcus,mycoplasma(支原體),andlegionella(軍團(tuán)菌).Erythromycinisalsousefulasapenicillinsubstituteinpenicillin-allergicindividualswithinfectionscausedbystaphylococci(assumingthattheisolateissusceptible),streptococci,orpneumococci.Ithasbeenrecommendedasprophylaxisagainstendocarditisduringdentalproceduresinindividualswithvalvularheartdisease.AdversereactionsofErythromycina.GastrointestinaleffectsAnorexia,nausea,vomiting,anddiarrhea.Gastrointestinalintolerance,whichisduetoadirectstimulationofgutmotility,b.LivertoxicityErythromycin,particularlytheestolate,canproduceacutecholestatichepatitis(fever,jaundice,impairedliverfunction),probablyasahypersensitivityreaction.Mostpatientsrecoverfromthis,buthepatitisrecursifthedrugisreadministered.Otherallergicreactionsincludefever,eosinophilia,andrashes.c.DruginteractionsErythromycinmetabolitescaninhibitcytochromeP450enzymesandthus↑theserumconcentrationsofnumerousdrugs,includingtheophylline,oralanticoagulants,cyclosporine,andmehtylprednisolone.Erythromycin↑serumconcentrationsoforaldigoxinby↑itsF.Clarithromycin(克拉霉素)Moreacidstability,moreactivethanerythromycinAgainstToxoplasmagondii(弓形蟲),lowerfrequencyofGIintolerance.Itismetabolizedintheliver.Themajormetaboliteis14-hydroxyclarithromycin,whichhasantibacterialactivity.Allofthemareeliminatedintheurine.Dosage↓forpatientswithrenaldysfunction.Azithromycin(阿齊霉素)A15-atomlactonemacrolide,isactiveagainstTgondii.AzithromycinisslightlylessactivethanerythromycinagainststaphylococciandstreptococciandslightlymoreactiveagainstHinfluenzae.Itishighlyactiveagainstchlamydia(衣原體).Itdiffersfromerythromycinmainlyinpharmacokineticproperties.Itpenetratesintomosttissues,andphagocyticcellsextremelywell,withtissueconcentrationsexceedingserumconcentrationsby10-to100-fold.Drugisslowlyreleasedfromtissuestoproduceaneliminationhalf-lifeapproaching3days.Itisrapidlyabsorbedandwelltoleratedorally.Itshouldbeadministered1hbeforeor2haftermeals.ItdoesnotinactivatecytochromeP450enzymesandisfreeofthedruginteractionsthatoccurwitherythromycin.§2Clindamycins(克林霉素)ClindamycinSincludeLincomycin(林可霉素,潔霉素)Clindamycin(氯林可霉素,氯潔霉素)PharmacokineticsofClindamycin1.Wellabsorbedorally,oriv,about90%protein-bound,highconcentrationinbonetissuse.excretionismainlyviatheliver,bile,andurine.Clindamycinpenetrateswellintomosttissues,itpenetrateswellintoabscesses(膿腫)andisactivelytakenupandconcentratedbyphagocytic（吞噬）cells.2.Itismetabolizedbytheliver,andbothactivedrugandactivemetabolitesareexcretedinbile.Thehalf-lifeisabout2.5hoursinnormalindividuals,increasingto6hoursinpatientswithanuria.Nodosageadjustmentisrequiredforrenalfailure.

pharmacodynemics:

Likeerythromycin,clindamycininhibitsproteinsynthesisbyinterferingwiththeformationofinitiationcomplexesandwithaminoacyltranslocationreactions.Thebindingsiteforclindamycinonthe50Ssubunitofthebacterialribosomeissameasthatforerythromycin.Streptococci,staphylococci,andpneumococciareinhibitedbyclindamycin.EnterococciandG-aerobicorganismsareresistant.Otheranaerobes,bothG+&G-,areusuallysusceptible.

Resistancetoclindamycin

whichgenerallyconferscross-resistancetoothermacrolides,isdueto①mutationoftheribosomalreceptorsite;②modificationofthereceptorbyaconstitutivelyexpressedmethylase;③enzymaticinactivationofclindamycin.ClinicalusesofClindamycin1.Themostimportantindicationforclindamycinisthetreatmentofsevereanaerobicinfection(厭氧菌感染)causedbybacteroidesandotheranaerobesthatoftenparticipateinmixedinfections,especiallybone(骨)infection.2.Incombinationwithanaminoglycosideorcephalosporinisusedtotreatpenetratingwoundsoftheabdomenandthegut;infectionsoriginatinginthefemalegenitaltract,suchassepticabortion(膿毒性流產(chǎn))andpelvicabscesses(盆腔膿腫);oraspirationpneumonia(吸入性肺炎).AdverseeffectsofClindamycinDiarrhea,nausea,andskinrashesarecommonly.Impairedliverfunctionwithorwithoutjaundiceandneutropeniasometimesoccur.§3PolypeptideantibioticsVancomycinsPolymyxinsBacitracinI.VancomycinsincludeVancomycin(萬古)Norvancomycin(去甲萬古)Teicoplanin(替考拉寧)VancomycinisactiveonlyagainstG+bacteria,particularlystaphylococci,aglycopeptideofmolecularweight1500,water-solubleandquitestable.ItinhibitscellwallsynthesisbybindingfirmlytotheD-Ala-D-Alatreminusofnascentpeptidoglycanpentapeptide.Thisinhibitsthetransglycosylase(PBPs),preventingfurtherelongationofpeptidoglycanandcross-linking.Thepeptidoglycanisthusweakenedandthecellbecomessusceptibletolysis.Thecellmembraneisalsodamaged,whichcontributestotheantibacterialeffect.VancomycinisbactericidalforG+bacteria.Mostpathogenicstaphylococci,includingthoseproducing

-lactamaseandthoseresistanttonafcillinandmethicillin,arekilled.ItissynergisticwithgentamicinandstreptomycinagainstEfaecium(糞腸球菌)andEfaecelisstrains.

ResistancetovancomycinisduetomodificationoftheD-Ala-D-AlabindingsiteofthepeptidoglycanbuildingblockinwhichtheterminalD-AlaisreplacedbyD-lactate.Thisresultsinthelossofacriticalhydrogenbondthatfacilitateshigh-affinitybindingofvancomycintoitstargetandlossofactivity.PharmacokineticsofVancomycinPoorlyabsorbedfromtheGItractandisgivenorallyonlyforthetreatmentofantibiotic-associatedenterocolitiscausedbyClostridiumdifficile.widelydistributedinthebody,&passesintothecerebrospinalfluidifthereismeningealinflammation.90%ofthedrugisexcretedbyglomerularfiltration,inrenalinsufficiency,strikingaccumulation.Thedrugisnotremovedbyhemodialysis.ClinicalusesofVancomycinThemainindicationforparenteralvancomycinissepsisorendocarditiscausedbymethicillin-resistantstaphylococci(MRSA).Incombinationwithgentamicinisanalternativeregimenfortreatmentofenterococcalendocarditisinapatientwithseriouspenicillinallergy.Incombinationwithcefotaxime,ceftriaxone,orrifampinfortreatmentofmeningitissuspectedorknowntobecausedbyahighlypenicillin-resistantstrainofpneumococcus.Oralvancomycinisusedtotreatantibiotic-associatedenterocolitiscausedbyClostridiumdifficile.ADRofVancomycinOtotoxicityandnephrotoxicityareuncommonandmildwithcurrentpreparations.Amongthemorecommonreactionsistheso-called“redman”or“redneck”syndrome.Itiscausedbyreleaseofhistamine.Mostadversereactionsareminor.Phlebitis(靜脈炎)atthesiteofinjection.II.Polymyxins(多粘菌素)PolymyxinsareagroupofbasicpeptidesactiveagainstG-bacteria.Owingtotheirnephrotoxicity,allbutpolymyxinsBandEhavebeenabandoned.Theyarecationic,basicpeptideswithmolecularweightsofabout1400.allcontainthefattyacidD-6-methyloctan-1-oicacidandtheaminoacidsL-threonineandL-diaminobutyricacid.PolymyxinsTheyarebactericidalformanyG-rods,includingPseudomonas.Narrowspectrum,sloweffect.Polymyxinsactlikecationicdetergents.Theyattachtoanddisruptbacterialcellmembranes.Theyalsobindandinactivateendotoxin.G+organismsareresistant.Insusceptiblebacterialpopulations,resistantmutantsarerare.Polymyxinsarerarelyusedforsystemicadministrationbecauseoftheirpoortissuedistributionandtheirsubstantialnephrotoxicityandneu