32.四環(huán)素和氯霉素——山東大學(xué)藥理學(xué)英文課件

1、 Chapter 42Tetracyclines and ChloramphenicolTetracyclines vNatural: Tetracycline, oxytetracycline, chlortetracycline vSemi-synthesized Doxycycline and minocyclineTetracyclinesAntimicrobial activityBroad-spectrum bacteriostatic antibioticsMany gram-positive and gram-negative bacteria including anaero

2、besRickettsiae, chlamydiae and mycoplasmSome protozoa: amebasTetracyclinesvMechanism of action Tetracyclines bind reversibly to the 30s subunit of bacterial ribosome and block the binding of aminoactyl-tRNA to the acceptor site, prevent the elongation of peptide.TetracyclinesvResistanceProduction of

3、 an efflux pumpRibosome protection due to production of proteins that interfere with tetracyclines binding to the ribosomeProduction of enzymeTetracyclinevPharmacokineticsAbsorption: affected by food ,divalent cations（Ca2+, Mg2+ , Fe2+ ）, dairy products and antiacidDistribution: distribute widely to

4、 tissues and body fluids, bind to and damage growing bone and teeth as a result of chelation with calciumCross plancental barrier and excrete in milkTetracyclinesClinical uses Rickettsiae infections : first choiceChlamydiae pneumoniae Mycoplasma infectionRelapsing fever: the most effectiveVarious gr

5、am-positive and negative infectionsGastric ulcer and duodenal ulcer caused by Helicobacter pylori in combination regimensTetracycline vAdverse reactionsGastrointestinal adverse effectsSuperinfectionvPseudomembranous enterocolitis caused by clostridium difficilevCandida albicans infectionEffects on b

6、ony structure and teethvTeeth: fluorescence, discoloration and enamel dysplasiavBone: deformity or growth inhibitionLiver and kidney toxicity, photosensitizationSynthesized tetracyclinesvDoxycycline and minocyclineAlmost completely absorbed Long-acting: t 1/2 14hHigher activity than tetracyclineEffe

7、ctive against tetracycline-resistant bacteriaLow toxicityMinocycline: the strongest activity/ vestibular disturbanceChloramphenicolAntimicrobial activityvBroad-spectrum bacteriostatic antibioticsvBoth gram-positive and gram-negative aerobic and anaerobic organismsvRickettsiae, spirochetes, mycoplasm

8、Mechanism of action Chloramphenicol is a inhibitor of microbial protein synthesis. It binds reversibly to the 50s subunit of the ribosome and inhibits the peptidyl transferase step of protein synthesisPharmacokinetics vAbsorption : povHigh concentration in CSF vMetabolized in liverClinical usesvBact

9、erial menigitis caused by penicillin-resistant bacteria or penicillin-allergic patients vTyphoid and paratyphoid fever :first choicevSerious rickettsial infectionsvTopical use for treatment of eye infectionsAdverse reactionsvBone marrow disturbancesReversible suppression of RBC productionIreversible

10、 aplastic anemiav Gray baby syndrome dose 50mg/kg/d vGastrointestinal reactionsChapter 43 Synthetic organic antimicrobialsSynthetic organic antimicrobialsvQuinolonesvSulfonamidesvTrimethoprim（TMP）vNitrofurans vMetronidazole Quinolones vBrief introductionvAntibacterial activity vMechanism of actionvC

11、linical usesvAdverse reactionsBrief introduction of quinolonesFour generationsFirst generation:1962 Lesher nalidixic acidSecond generation: 1973 pipemidic acidThird generation: 1980s fluoroquinolonesFourth generation: late 1990s moxifloxacin（莫西沙星）（莫西沙星）, gatifloxacin(加替沙星加替沙星) Nalidixic acidfirst ge

12、nerationvNarrow antibacterial spectrum:G-vPoorly absorbed vHigh adverse reactionsPipemidic acid-second generationvHigher activity than nalidixic acidvHigh concentration in urinevLess toxicity than nalidixic acidvMainly used in gastrointestinal and urinary tract infectionFluoroquinolonesthird generat

13、ionvNorfloxacin 諾氟沙星諾氟沙星vCiprofloxacin環(huán)丙沙星環(huán)丙沙星vOfloxacin 氧氟沙星氧氟沙星vLevoofloxacin左氧氟沙星左氧氟沙星vLomefloxacin 洛美沙星洛美沙星vFleroxacin 氟羅沙星氟羅沙星vSparfloxacin 司帕沙星司帕沙星Fluoroquinolones vAntibacterial activity： broad spectrumExcellent activity against gram-negative aerobic bacteria include enterobacteriaceae, neiss

14、eria, pseudomonas, haemophilus（嗜血桿菌屬）（嗜血桿菌屬） and campylobacter（彎曲桿菌屬）（彎曲桿菌屬） etcGood activity against gram-positive aerobic bacteria : eg pneumoniae and staphylococciMycoplasmas, chlamydiae, mycobaterium tuberculosis, legionella and anaerobesQuinolones Mechanism of actionTo G-: DNA gyrase A2B2To G+:

15、 Topo C2E2 vResistance Mutation of target : gyrA or parCLack of OmpF on membraneActive efflux pumpFluoroquinolonesvPharmacokinetics Absorbed rapidly and completelyWidely distributedLong T Low adverse reactionNo cross-resistance with other drugsFluoroquinolones vClinical usesUrinary and genital tract

16、 infectionsRespiratory tract infection: Legionella , chlamydia and mycoplasma pneumoniaBacterial diarrhea caused by shigella, salmonella or campylobacterInfections of soft-tissues, bones, joint Tuberculosis : Ofloxacin, SparfloxacinFluoroquinolones vAdverse reactionsGastrointestinal reaction: nausea

17、, vomiting and diarrheaCNS: headache, dizziness, insomnia and anxiety, seizureAllergic effect: skin rash, photosensitivityDamage growing cartilage and cause arthropathyContradications vPregnancyvChildrenvCNS disordervHistory of epilepsyvAllergic Commonly used QuinolonesvNalidixic acid and pipemidic

18、acidUsed only in urinary tract infectionvNorfloxacinThe least active in fluoroquinolones, F lowNo effects on mycoplasmas, chlamydiae, mycobaterium tuberculosis, legionella Urinary tract and intestinal tract infectionsvCiprofloxacin(悉復(fù)歡悉復(fù)歡)The most active agent in fluoroquinolones against gram-negati

19、ves, particularly P. aeruginosa in vitroNo effects on anaerobesvOfloxacin(泰利必妥）泰利必妥）Improved quality in pharmacokinetics F 89%Effective on mycobateria, chlamydiae and some anaerobesEffective on resistant bacteriaSecond line agent for tuberculosisvLevo-ofloxacin（可樂必妥（可樂必妥,來立信）來立信）F 100%Superior activ

20、ity against gram-positive organismsEffective on mycoplasma, legionella, chlamydia and anaerobesLowest toxicity among fluoroquinolonesvLomefloxacin: F 98% t = 7hTo G+ and G-: Similar to ofloxacinTo anaerobes: 10hHigher activity than ciprofloxacin and ofloxacin (in vivo)vSparfloxacinLong-acting t 16hI

21、mproved activity against G+ bacteria, anaerobes, mycobateria, mycoplasmas, chlamydiae Second line agent for tuberculosisvMoxifloxacin fourth generation F 90% t 1215hHigh activity on most G+ ,G-, anaerobes, mycobateria, mycoplasmas, chlamydiae Low toxicitySulfonamides Domagk Sulfonamides vClassificat

22、ionUsed in systemic infectionsvShort-acting: SIZvMedium-acting: SD, SMZvLong-acting: SMDUsed in intestinal infections: sulfasalazineTopic sulfonamides: SD-Ag, SA-Na, SMLSulfonamides vAntimicrobial activityBroad-spectrum bacteriostatic agentsBoth G+ and G- , chlamydiae trachomatis mycoplasm and some

23、protozoavMechanism of actionInhibit dihydropteroate synthetaseand block bacteria folic acid synthesisSulfonamidesvPharmacokinetics Metabolism: liver Excretion : kidney pHSulfonamides vAdverse effectsUrinary tract disturbance: crystalluria, hematuria, obstructionAllergic reactions: fever, skin rashes

24、, exfoliative dermatitis, photosensitivityHematopoietic disturbancesvGranulocytopenia, thrombocytopeniavHemolytic reactions lack of glucose-6-phosphate dehydrogenase CNS reaction: headache, vertigoSulfonamides vClinical usesUrinary tract infection: SIZ, SMZMeningococcal meningitis: SD first choiceUlcerative colitis: sulfasalazine(SASP)Bacterial dysentery: SMZTopical use for trachoma and conjunctivitis: SA-NaPrevent infections of burn wounds