32.四环素和氯霉素——山东大学药理学英文课件

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 enzymeTetracyclinevPharmacokineticsvAbsorption: affected by food ,divalent cationsCa2+, Mg2+ , Fe2+ , dairy products and antiacidvDistribution: distribute widely to

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

5、ram-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

6、bony 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 tetracyclineEff

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

8、mMechanism 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 usesvBac

9、terial 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 productionIreversibl

10、e aplastic anemiav Gray baby syndrome dose 50mg/kg/d vGastrointestinal reactionsChapter 43 Synthetic organic antimicrobialsSynthetic organic antimicrobialsvQuinolonesvSulfonamidesvTrimethoprimTMPvNitrofurans vMetronidazole Quinolones vBrief introductionvAntibacterial activity vMechanism of actionvCl

11、inical 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 generat

12、ionvNarrow 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 generationvN

13、orfloxacin 诺氟沙星诺氟沙星vCiprofloxacin环丙沙星环丙沙星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 氟罗沙星氟罗沙星vSparfloxacin 司帕沙星司帕沙星Fluoroquinolones vAntibacterial activity： broad spectrumvExcellent activity against gram-negative aerobic bacteria include enterobacteriaceae, neisseria

14、, pseudomonas, haemophilus嗜血杆嗜血杆菌属菌属 and campylobacter弯曲杆弯曲杆菌属菌属 etcvGood activity against gram-positive aerobic bacteria : eg pneumoniae and staphylococcivMycoplasmas, chlamydiae, mycobaterium tuberculosis, legionella and anaerobesQuinolones Mechanism of actionTo G-: DNA gyrase A2B2To G+: Topo C2E2

15、 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 infection

16、sRespiratory 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, vomiting

17、 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 acidUsed o

18、nly in urinary tract infectionvNorfloxacinThe least active in fluoroquinolones, F lowNo effects on mycoplasmas, chlamydiae, mycobaterium tuberculosis, legionella Urinary tract and intestinal tract infectionsvCiprofloxacin(悉复欢悉复欢)The most active agent in fluoroquinolones against gram-negatives, parti

19、cularly P. aeruginosa in vitroNo effects on anaerobesvOfloxacin(泰利必妥泰利必妥vImproved quality in pharmacokinetics F 89%vEffective on mycobateria, chlamydiae and some anaerobesvEffective on resistant bacteriavSecond line agent for tuberculosisvLevo-ofloxacin可乐必妥可乐必妥,来立信来立信vF 100%vSuperior activity agains

20、t gram-positive organismsvEffective on mycoplasma, legionella, chlamydia and anaerobesvLowest 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 16hImproved

21、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 vClassificationUsed

22、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 protozoa

23、vMechanism 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, exfoli

24、ative 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 woun