药理学教学课件：Chapter 35 Quinolones,Folate Antagonists and Urinary Tract Antiseptics

Chapter35．Quinolones,FolateAntagonistsandUrinaryTractAntiseptics

SyntheticorganicantimicrobialsQuinolonesSulfonamidesTrimethoprim（TMP）Nitrofurans

MetronidazoleSection1.DNAGYRASEINHIBITORS(Quinolones)

BriefintroductionofquinolonesFourgenerations:Firstgeneration:1962,nalidixicacidSecondgeneration:1974,pipemidicacidThirdgeneration:1980’sfluoroquinolonesFourthgeneration:late1990’smoxifloxacin

(莫西沙星),

gatifloxacin

(加替沙星).CommonFluoroquinolones:

Norfloxacin——诺氟沙星,氟哌酸Ciprofloxacin——环丙沙星Ofloxacin——氧氟沙星Levoofloxacin——左氧氟沙星Lomefloxacin——洛美沙星Fleroxacin——氟罗沙星Sparfloxacin——司帕沙星PharmacokineticsAfteroraladministration,thefluoroquinolonesarewellabsorbed(bioavailabilityof80-95%)anddistributedwidelyinbodyfluidsandtissues.Serumhalf-livesrangefrom3hours(norfloxacinandciprofloxacin)upto10(pefloxacin培氟沙星

andfleroxacin)orlonger(sparfloxacin).Therelativelylonghalf-livesoflevofloxacin,moxifloxacin莫西沙星,sparfloxacin,andtrovafloxacin曲伐沙星

permitonce-dailydosing.Oralabsorptionisimpairedbydivalentcations,includingthoseinantacids.Mostfluoroquinolonesareeliminatedbyrenalmechanisms,eithertubularsecretionorglomerularfiltration.Theexactdoseadjustmentdependinguponthedegreeofrenalimpairmentandthespecificfluoroquinolonebeingused.Nonrenallyclearedfluoroquinolonesarecontraindicatedinpatientswithhepaticfailure.AntibacterialActivity

broadspectrum:Fluorinatedderivatives(fluoroquinolones)havegreatlyimprovedantibacterialactivitycomparedwithnalidixicacidandachievebactericidallevelsinbloodandtissues.Theyareactiveagainstavarietyofgram-positiveandgram-negativebacteria.1.Excellentactivityagainstgram-negativeaerobicbacteriaincludeenterobacteriaceae

(肠杆菌科),

neisseria,pseudomonas,haemophilus

(嗜血杆菌属)andcampylobacter

(弯曲杆菌属)etc.2.Goodactivityagainstgram-positiveaerobicbacteria:eg,pneumoniaeandstaphylococci.3.Mycoplasmas

(支原体),

chlamydiae

(衣原体),

mycobateriumtuberculosis,legionella军团菌属

andanaerobes(厌氧菌).

(1)Firstgroup(norfloxacin)istheleastactiveagainstbothgram-negativeandgram-positiveorganisms.Earlierquinolones(nalidixicacid,oxolinicacid奥索利酸,

dnoxacin利奈哇胺)didnotachievesystemicantibacteriallevels.Theseagentswereusefulonlyfortreatmentoflowerurinarytractinfections.(2)Secondgroup:Theimportantquinolonesaresyntheticfluorinatedanalogsofnalidixicacid(ciprofloxacin,enoxacin,lomefloxacin洛美沙星,levofloxacin,ofloxacin,andpefloxacin),possessexcellentgram-negativeactivityandmoderatetogoodactivityagainstgram-positivebacteria.(3)Thirdgroup(clinafloxacin克林沙星,gatifloxacin加替沙星,andsparfloxacin)improvedactivityagainstgram-positiveorganisms,islessactiveagainstgram-negativeorganisms.(4)Fourthgroup(moxifloxacin莫西沙星andtrovafloxacin曲伐沙星)haveenhancedgram-positiveactivity,alsohavegoodactivityagainstanaerobicbacteria.MechanismofactionQuinolonesblockbacterialDNAsynthesisbyinhibitingbacterialtopoisomeraseII(DNAgyrase,toG-)andtopoisomeraseIV(toG+).InhibitionofDNAgyrasepreventstherelaxationofpositivelysupercoiledDNAthatisrequiredfornormaltranscriptionandreplication.ResistanceResistanceisduetooneormorepointmutationsinthequinolonebindingregionofthetargetenzymeortoachangeinthepermeabilityoftheorganism.Resistancetoonefluoroquinolone,particularlyifofhighlevel,generallyconferscross-resistancetoallothermembersofthisclass.ClinicalUses

(1)Urinarytractinfections:areeffectiveevenwhencausedbymultidrug-resistantbacteria,eg,pseudomonas假单胞菌.(2)Bacterialdiarrheacausedbyshigella

(志贺菌属),salmonella,toxigenic

Ecoli,orcampylobacter(弯曲杆菌属).

(3)Infectionsofsofttissues,bones,andjointsandinintra-abdominalandrespiratorytractinfections,includingthosecausedbymultidrug-resistantorganismssuchaspseudomonasandenterobacter

(肠杆菌).

(4)Empirical(经验主义的)treatmentofpneumoniaandotherupperrespiratorytractinfections,eg,Legionella军团菌属,chlamydia

(衣原体)andmycoplasmapneumonia支原体肺炎.(5)Tuberculosis:

Ofloxacin,Sparfloxacin.AdverseEffectsFluoroquinolonesareextremelywelltolerated.Themostcommoneffectsarenausea,vomiting,anddiarrhea.Occasionally,headache,dizziness,insomnia,skinrash,photosensitivity,orabnormalliverfunctiontestsdevelop.Maydamagegrowingcartilage(软骨)andcauseanarthropathy

(关节病),notrecommendedforuseinpatientsunder18yearsofage.Theyareexcretedinbreastmilk,contraindicatedfornursingmothers.Avoidedduringpregnancy,allergicdisorders,andhistoryofepilepsy.

NalidixicacidBecauseoftheirrelativelyweakantibacterialactivityandrapidexcretion,theseagentswereusefulonlyforthetreatmentofurinarytractinfections.NorfloxacinTheleastactiveinfluoroquinolones,Flow;Urinarytractandintestinaltractinfections.CiprofloxacinThemostactiveagentinfluoroquinolonesagainstgram-negatives,particularlyP.aeruginosa

(铜绿假单孢菌,绿脓杆菌)

invitro.Ofloxacin

(泰利必妥)Improvedqualityinpharmacokinetics;HighconcentrationinCSF;Secondlineagentfortuberculosis.Levo-ofloxacin

(可乐必妥,来立信)F=100%;Superioractivityagainstgram-positiveorganisms;Effectiveonmycoplasma支原体,legionella军团菌,chlamydia衣原体;Lowesttoxicityamongfluoroquinolones.Lomefloxacin洛美沙星F=98%Photosensitivity,C8-FSparfloxacinLong-acting,t1/2=17.6hImprovedactivityagainstgram-positivesMycoplasmas支原体,chlamydiae衣原体,mycobateriumtuberculosis,legionella军团菌andanaerobes厌氧菌SecondlineagentfortuberculosisSection2.ANTIFOLATEDRUGS

I.SULFONAMIDES1.ChemistryThebasicformulaofthesulfonamidesandtheirstructuralsimilaritytop-aminobenzoicacid(PABA).Mostcanbepreparedassodiumsalts,whichareusedforintravenousadministration.

2.Classification(1)Usedinsystemicinfections:Short-acting:SIZ(磺胺异噁唑)Medium-acting:SD,SMZ(磺胺甲基异噁唑)Long-acting:SDM(磺胺多辛)(2)Usedinintestinalinfections:sulfasalazine

(SASP,柳氮磺吡啶)(3)Topicsulfonamides:SD-Ag,SA-Na

(磺胺醋酰钠),

SML

(磺胺米隆)3.Pharmacokinetics

Sulfonamidescanbedividedintothreemajorgroups:

(1)Theoral,absorbablesulfonamidescanbeclassifiedasshort-,medium-,orlong-actingonthebasisoftheirhalf-lives(Table36-1).Theyareabsorbedfromthestomachandsmallintestineanddistributedwidelytotissuesandbodyfluids(includingthecentralnervoussystemandcerebrospinalfluid),placenta,andfetus.Absorbedsulfonamidesbecomeboundtoserumproteinstoanextentvaryingfrom20%toover90%.Peakbloodlevelsgenerallyoccur2-6hoursafteroraladministration.Aportionofabsorbeddrugisacetylatedorglucuronidatedintheliver.Sulfonamidesandinactivatedmetabolitesarethenexcretedintotheurine,mainlybyglomerularfiltration.Insignificantrenalfailure,thedosageofsulfonamidemustbereduced.(2)oral,nonabsorbable;and(3)topical.

4.AntimicrobialActivity

Broad-spectrumbacteriostaticagents;Sulfonamidesinhibitbothgram-positiveandgram-negativebacteria,nocardia诺卡氏菌属,Chlamydiatrachomatis

(沙眼衣原体),andsomeprotozoa原生动物.Someentericbacteria,suchasEcoli,klebsiella,salmonella,shigella,andenterobacter肠杆菌属,areinhibited.5.MechanismofactionSusceptiblemicroorganismsrequireextracellularPABAinordertoformdihydrofolicacid(Figure36-2),anessentialstepintheproductionofpurinesandthesynthesisofnucleicacids.SulfonamidesarestructuralanalogsofPABAthatcompetitivelyinhibitdihydropteroate

synthase.Theyinhibitgrowthbyreversiblyblockingfolicacidsynthesis.Accordingly,sulfonamidesarebacteriostatic,notbactericidal,drugs.Mammaliancells(andsomebacteria)lacktheenzymesrequiredforfolatesynthesisanddependuponexogenoussourcesoffolate;therefore,theyarenotsusceptibletosulfonamides.6.Resistance

SulfonamideresistancemayoccurasaresultofmutationsthatcauseoverproductionofPABA,causeproductionofafolicacid-synthesizingenzymethathaslowaffinityforsulfonamides,orcausealossofpermeabilitytothesulfonamide.Dihydropteroate

synthasewithlowsulfonamideaffinityisoftenencodedonaplasmidthatistransmissibleandcandisseminaterapidlyandwidely.Sulfonamide-resistantcellsmaybepresentinsusceptiblebacterialpopulationsandcanemergeunderselectivepressure.

7.ClinicalUses

(1)Urinarytractinfection:Oralabsorbableagents:Sulfisoxazole(SIZ)andsulfamethoxazole(SMZ);(2)Meningococcalmeningitis流行性脑脊髓膜炎:SD,firstchoice;(3)

Bacterialdysentery(痢疾):SMZ;(4)Ulcerativecolitis,enteritis,andotherinflammatoryboweldisease:Oralnonabsorbableagents:sulfasalazine

(SASP,柳氮磺吡啶);(5)Topicalusefortrachoma(沙眼)andconjunctivitis:SA-Na(磺胺醋酰钠);(6)Preventinfectionsofburnwounds:SD-Ag,SML(磺胺米隆).8.AdverseReactions

(1)Urinarytractdisturbance:

Sulfonamidesmayprecipitateinurine,especiallyatneutraloracidpH,producingcrystalluria,hematuria,evenobstruction,andthevarioustypesof

nephrosisorallergicnephritis.Thisisrarewiththemoresolublesulfonamides(eg,sulfisoxazole,SIZ).Crystalluriaistreatedbyadministrationofsodiumbicarbonatetoalkalinizetheurineandfluidstomaintainadequatehydration(水合作用).

(2)allergy:The

fever,skinrashes,exfoliativedermatitis,photosensitivity,urticaria

(荨麻疹),nausea,vomiting,anddiarrheaarethemostcommon.Stevens-Johnsonsyndrome,althoughrelativelyuncommon(ie,fewerthan1%oftreatmentcourses),isaparticularlyseriousandpotentiallyfataltypeofskinandmucousmembraneeruption(疹).

Therearethecross-allergenicinallsulfonamidesandtheirderivatives,includingcarbonicanhydraseinhibitors,thiazides噻嗪类,furosemide,bumetanide布美他尼,torsemide

(托拉塞米),

diazoxide

(二氮嗪),andthesulfonylureahypoglycemicagents.(3)HematopoieticDisturbances:Sulfonamidescancausehemolyticoraplasticanemia,granulocytopenia,thrombocytopenia,orleukemoid类白血病reactions.Sulfonamidesmayprovokehemolyticreactionsinpatientswhoseredcellsaredeficientinglucose-6-phosphatedehydrogenase（G-6-PD）.II.TRIMETHOPRIM1.Inhibitbacterialdihydrofolicacidreductase:

Dihydrofolicacidreductasesconvertdihydrofolicacidtotetrahydrofolicacid,astepleadingtothesynthesisofpurinesandultimatelytoDNA.TMPinhibitsbacterialdihydrofolicacidreductaseabout50,000timesmoreefficientlythanthesameenzymeofmammaliancells.2.Combinationwithsulfonamides:

Trimethoprim(TMP)orpyrimethamine乙胺嘧啶,giventogetherwithsulfonamides,producessequentialblockinginthismetabolicsequence,resultinginmarkedenhancement(synergism)oftheactivityofbothdrugs.Thecombination(SMZ+TMP,CoSMZ,复方新诺明)oftenisbactericidal,comparedtothebacteriostaticactivityofasulfonamidealone.

3.Resistance:canresultfromreducedcellpermeability,overproductionofdihydrofolate

reductase,orproductionofanalteredreductasewithreduceddrugbinding.Resistancecanemergebymutation,thoughmorecommonlyitisduetoplasmid-encodedtrimethoprim-resistantdihydrofolate

reductases.4.Pharmacokinetics:

(1)Usuallygivenorally,aloneorincombinationwithsulfamethoxazole(hasasimilarhalf-life),alsobegivenintravenously.(2)TMPisabsorbedwellfromthegutanddistributedwidelyinbodyfluidsandtissues,includingcerebrospinalfluid.(3)About65-70%ofeachparticipantdrugisprotein-bound,and30-50%ofthesulfonamideand50-60%ofthetrimethoprim(ortheirrespectivemetabolites)areexcretedintheurinewithin24hours.(4)

Trimethoprim(aweakbaseofpKa7.2)concentratesinprostaticfluidandinvaginalfluid,whicharemoreacidthanplasma.Therefore,ithasmoreantibacterialactivityinprostaticandvaginalfluidsmanyotherantimicrobialdrugs.5.ClinicalUses

(1)Acuteurinarytractinfections:canbegivenalone(100mgtwicedaily).Acombinationoftrimethoprim-sulfam