中医中药药理学外文版 (44).pdf

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1、Antimicrobial AgentsFast forward 73 yearsantibiotic development is dying234SuperbacteriaTeaching purposeGrasp：basic concept(antibiotics etc.)and the antimicrobial mechanism.Understand:resistance mechanism of antimicrobial Reasonable application Grasp antimicrobial reasonable application and combined

2、 application.Put the patients interests first and better serve the patientsKnowledge aimsAbility aimsEmotion aims6“有时去治愈，常常去帮助，总是去安慰”特鲁多人文关怀7一、Special terms 二、Mechanism of antibacterial action三、Antibiotics resistance 四、Combination therapy Outline 一、Antibacterials terms891 12 2ChemotherapyMedicines t

3、reat all pathogens，including bacteria and other microorganism、parasiteand disease induced by cancer cell.Antimicrobial drug A drug that treats infectious diseases induced by pathogenic microorganism,by inhibiting or killing the pathogenic microorganism,and at the same time does not damage human cell

4、s.It includes antibacterial,antifungal,antivirus drugs.Concept103 34 4Antibacterial drugsInhibit or kill bacteria,include antibiotics and artificially synthesized antibacterial agents.AntibioticsAntibiotics are substances produced by various species of microorganisms(bacteria,fungi,actinomycetes),wh

5、ich suppress the growth of other microorganisms.Concept4 411PathogeneAntibacteriaAntimicrobialeffects ResistanceHostIdeal medicine High selective to bacterium Have no or low toxicity to human Drug resistance is not easily produced Strong、quick、prolonged effect Convenient to use and cheap price1213An

6、tibacterial actionAntibacterial spectrum:basic for selecting medicines in clinicAntibacterial scopeNarrow spectrum：drugs which kill or inhibit oneor one kind of bacterium，such as isoniazide(Bacillus tuberculosis)Broadspectrum：drugswhichaffectawidevariety of bacterium，such as tetracycline、chloramphen

7、icol14MIC(minimuminhibitoryconcentration):theminimum concentration to inhibitbacterium inmediumMBC(minimumbactericidalconcentration):theminimal concentration to kill bacterium in mediumAntibacterial activity the ability of a medicine to inhibit or kill microorganismAssay method：VitroVivo：Value the e

8、ffect through the experiment in vivo15Inhibition or killing bacteria is relevant to the concentration and duration of medicineBacteriostaticTetracycline、Erythrocin,etc.Bactericidal Penicillins、Cephalosporins、Aminoglycosides、FQNSAntibacterial activityBacteria multiply quickly16Chemotherapeutic index(

9、CI)LD50/ED50or LD5/ED95half lethal dose and half effective dose(treat infectiousanimals)Clinical valueCITherapeutic efficacyToxicity to organismSafetyoverlap17Post-antibiotic effect,PAEA persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC.A per

10、iod of time after complete removal of an antibiotic during which there is no growth of the target organism.Concentration dependentFirst expose effect When antibacterial first contact the bacterium,it produces a strong antibiotic action,the second time,the action will decline,but after a period,the a

11、ction will recover Aminoglycoside18Summary Defenition Antibiotic MIC and MBC Chemotherapeutic index Post-antibiotic effect,PAE First expose effect19二、Mechanism of antibacterial agents2021 Influence the structure and function of bacteria 22An essential component of cell walls is mucopeptide,which for

12、ms a huge protecting net outside bacterium.A series of agents can disturb composition of bacterium mucopeptide,by causing bacterial cell to swell,deform,and eventually burst resulting in the death of bacteria.一、Inhibit synthesis of bacterial cell walls23一、Inhibit synthesis of bacterial cell walls Pe

13、nicillin and cephalosporin Cycloserine Vancomycin Bacitracin The azole antifungal agents(eg,clotrimazole,fluconazole,and itraconazole)24二、Affect the permeability of cell membraneAgents act directly on the cell membrane of themicroorganism,affecting permeability and resultinginleakageofintracellularc

14、ompounds,whichinterfere with the basic growth and development,eg.DNA duplication.Bind to cell-wallsterolsPolymyxinAntifungal agents25三、Inhibit protein synthesisHuman and bacteriums ribosomal subunits are different：bacterium：70S 50S+30S human：80S 60S+40SAgents affect the function of 30S or 50S riboso

15、mal subunits and cause a reversible inhibition of protein synthesis,but do not affect human cell function AminoglycosideForm the initiation complex(30s,50s,mRNA)Extend the peptide chain(amino acids)Ending and release the peptide chain(termination codon)26Quinolones（Levofloxacin）Inhibit DNA gyrase(螺旋

16、酶)inhibit replication DNA synthesisRifampinInhibit DNA-dependent RNA polymerase inhibit transcription mRNA四、Inhibit nucleic acid synthesis27五、Affect folacin metabolismAntimetabolites,including trimethoprim（TMP）and the sulfonamides,which block essential enzymes of folate metabolism-disturb DNA synthe

17、sis三.Resistance 28Super bacteria29Why does exist so much drug resistance?-Give the newest?-Money is Not a problem.-Use the most expensive drugs?New medicines still cant catch up with the drug resistance30MRSA,methicillin resistant staphylococcus aureus31 Definition：Bacteria is not sensitive to antib

18、iotic Classification：1.Natural（inherent）：Chromogene change,generationaltransmission.Penicillin is invalid to some G(gram)bacterium.2.Acquired：After contacting with antibacterials bacterium canchange their metabolic pathway through plasmid,and avoidbeing killed by antibacterials.-Staphylococcus aureu

19、s resistto penicillin.Resistance32Resistance mechanism1Enzyme related inactivation(1)Hydrolase：-lactamase hydrolyse-lactam antibiotics(2)Modified enzyme：catalyze some group on the drug,inactivate antimicrobial agents.Bacteriumisnotsensitivetoaminoglycosides(aminoglycoside-modifying enzymes)33Inactiv

20、atorantibioticsInactivator34Resistance mechanism2Modification of target site:（1）Bacteria change the target protein binding antibiotic in their cell membranes.Affinity between drug and target site（2）Bacteria produce a new kind of target protein which can not bind an antibiotic after contacting it.（3）

21、The number of target protein increase：although drug occupies some target sites,there are still enough target proteins maintaining the normal structure and function of bacterium353Decrease membrane permeability：(1)Small polar molecules,including many antibiotics,enter the cell through channels made u

22、p of proteins called porins.(2)Absence or mutation the porin channel can slow or prevent drug entry.4Efflux pumps:pump out the drug from the cell(the resistance to tetracycline and b-lactam antibiotics)Resistance mechanism四.Principle of rational drug useDiseaseInfectionVirus and fungusBacteriumWhich

23、 bacteriumsUnknown originDrug sensitive testSelect sensitive drugSeverityEmpirical therapycultivate 37Antibacterialcombination 0101020203030404Improve the curative effectDelay resistant bacteriaEnlarge antimicrobialspectrumReduce the dosage of each drug and reduce adverse reactions.PurposeIndication

24、 for the clinical combinations of antimicrobial agentsType multiplication stage bactericideb b-lactam antibioticsType bactericide for rest periodAminoglycosides QuinolonesType fast effect bacterial inhibitorTetracyclinesMacrolidesChloramphenicolType slow effect bacterial inhibitor SulfonamidesSynerg

25、ism effect(I+)Penicillin+gentamicinCephalosporin+roxithromycinAntagonism effect(I+)Additive effect(十)、(十)Indifference or add(I+)39Unreasonable applicationLocal application03.Dosage:undersize,overdose；Course of treatment:too long or short04.Etiology unknown02.Virusinfection01.Regular use of broad spe

26、ctrum and new one05.40Other factors and antibiotic application Renal function failure：Avoid using agents excreted by the kidneyseg.amphotericin B、vancocin、aminoglycosides Must be applied:Reduce the dose or prolong the interval according to renal function HypohepatiaAvoid using agents metabolized in

27、the liver.Caution:eg.-lactam antibiotic、quinolones、clindamycin Avoid:erythromycin、chloramphenicol-hepatotoxicity41Other factors and antibiotic application Others42Newborn infant：ForbiddenChloramphenicol：graybaby syndromeSulfonamides：hemolysis or kernicterusOther factors and antibiotic application Ot

28、hers43Children：Avoid drugs which affect growth tetracycline:tetracycline stained teeth fluoroquinolonesarthritis Other factors and antibiotic applicationOthers44Pregnant women、lactation period：Prohibit aminoglycosides etc.Traverse placenta barrier,milk-secretion Produce ototoxicity and nephrotoxicit

29、yOther factors and antibiotic applicationNew progress45Gentamicin！The pride of the Chinese people,but deaf for a generation,is now a lifesaving drug because of other agents resistance.Todays headline Gentamicin was researched and developed in China.But limit using in the whole body for its adverse reaction.Summary Key points：（1）Defenition：antibiotic,antibacterial spectrum,drug resistance,chemotherapeutic index（2）Grasp antibacterial mechanism Difficult Points:Combined application of antibacterial agents46ThankThank you!you!