中医中药药理学外文版 (49).pdf
AminoglycosidesAminoglycosidesAminoglycosides are a group of bactericide obtained from various streptomyces species.All have the similar structrue of aminoglycoside and share common chemical,antimicrobial,pharmacologic,and toxic characteristics.23AminoglycosidesAminoglycosidesType:bactericide for rest periodThe effect can be enhanced by agents that interfere with cell wall synthesis.Type：multiplication stage bactericide:lactam antibiotics-Synergistic effectsNotice:I+II:DO NOT mix in one bottle,JUST use togetherMixture make a turbid solution(浑浊的),induce physico-chemical reaction,and decrease effect.4AminoglycosidesNatural streptomycin(tuberculosis)gentamicinkanamycintobramycinsisomicinneomycinmicronomicin spectinomycinSemisynthesis netilmicinetimicinisepamicinamikacindibekacin urbekacin5Common character of AminoglycosidesCommon character of Aminoglycosides一、一、physical and chemical propertiesphysical and chemical propertiesHave a hexose(己糖)ring,either streptidine(in streptomycin)or 2-deoxystreptamine(other aminoglycosides),to which various amino sugars are attached by glycosidic linkages（糖苷键）.Water soluble,stable in solution,more active at alkaline than at acid pH.Exhibit synergism with-lactam drugs in vitro,but should not be mixed together for infusion,otherwise it will lose the activity.6Common character of AminoglycosidesCommon character of Aminoglycosides二、二、Antibacterial spectrumAntibacterial spectrum1.Aerobic gram-negative bacilli:STRONG antibacterial action.Pseudomonas aeruginosa2.Gram-negative(G-)cocci:Weak antibacterial action3.Some drug-resistant G+cocci:Effective,eg.staphylococcus,MRSA.BUT they have minimal action against anaerobic organisms and enterococcus,others like streptococcus.4.Tuberculosis:STRONG activity in part aminoglycosides,eg.streptomycin、kanamycin、amikacin7Mechanism of action：(一一)Inhibit the whole process of protein synthesis （initiation complex、extension、termination）1.Interfere with the initiation complex of peptide formation.2.Induce misreading of mRNA,which cause incorporation of incorrect amino acids into the peptide,resulting in synthesis of nonfunctional or toxic protein.(二二)Enhance the diffusion across the cell membrane(placenta barrier-Pregnant women)Common character of AminoglycosidesCommon character of Aminoglycosides8Mechanisms of resistance1.Produce inactivator:The microorganism produces enzymes that inactivate the aminoglycoside by adenylylation腺苷化作用,acetylation乙酰化作用,phosphorylation磷酸化作用.2.Impair permeability of cell membrane:Impaired aminoglycosides across the cell membrane.(mutation or deletion of a porin or proteins involved in transport).3.Mutate target protein,reduce affinity:The receptor protein on the 30S ribosomal subunit may be absent or altered as a result of a mutation.Common character of Aminoglycosides9Pharmacokinetics 1.Absorb：Poor absorption in the gastrointestinal tractSystemic infection:intramuscular injectionIntestinal infection/intestinal tract sterilize(diarrhea):oral administration（mild,medium case）2.Distribute:Low plasma protein binding ratioFocus on extracellular fluid;Internal ear lymph fluid and cortex of kidney have high concentration(ototoxicity and nephrotoxicity).Pass placenta barrier,not easy to pass blood-brain barrier.3.Metabolize and excrete:DO NOT be metabolized,directly cleared at prototype by kidney.Common character ofCommon character ofAminoglycosidesAminoglycosides10 Bactericidal action is concentration-dependent:The higher the concentration,the greater the bactericidal action.Post-antibiotic effect:Residual bactericidal activity still is persisted when the serum concentration was lower than MIC.-the duration of this effect is concentration dependent.The toxicity is both time-and concentration-dependent.Common character of AminoglycosidesCommon character of Aminoglycosides11Clinical uses1.Primarily against aerobic G-bacilli2.Combine with-lactam antibiotic:Extend antibacterial spectrum.the synergism of I+II.potential G+pathogens,enterococcal endocarditis3.Local application：gastrointestinal tract infection(diarrhea)；4.Antituberculosis:Streptomycin、kanamycin、amikacinCommon character of AminoglycosidesCommon character of Aminoglycosides12Streptomycin-deaf mute-irreversibleThe Thousand-hand Bodhisattva 13Adverse effects1.Ototoxicity：Vestibular(前庭的前庭的)and auditory dysfunction Injure nervus vestibularis and cochlea(耳蜗)auditory nerve;Transfer through placenta barrier,affect foetus in uterus;Avoid combining with other ototoxic agents Vestibular damage:vertigo(眩晕),ataxia(共济失调),loss of balance;Auditory damage:tinnitus(耳鸣),high-frequency hearing loss initially.（高频听力丧失）Common character of AminoglycosidesCommon character of Aminoglycosides14Adverse effects2.Nephrotoxicity：Aminoglycosides is the common reason for the drug-induced renal dysfunction.Avoid combining with other nephrotoxic agents.Periodically detect the renal function.Common character of AminoglycosidesCommon character of Aminoglycosides15Adverse effects3.Neuromuscular paralysis：Block synaptic transmission（inhibit cardiac muscle、blood pressure descend、paralyze limbs and respiratory failure）-reduce Ach(acetylcholine):Synaptic junction:Aminoglycosides block calcium channel,reduce ACH release from presynaptic membrane,decrease the combination between ACH and N2-R on postsynaptic membrane.This paralysis can be reversed by calcium gluconate or neostigmineNeostigmine：choline esterase inhibitor(inhibit Ach degradation)4.Hypersensitivity：Rare Common character of AminoglycosidesCommon character of Aminoglycosides16Streptomycin Streptomycin Streptomycin first aminoglycosideResistance has emerged in most species,severely limiting the current usefulness of streptomycin,with the exceptions listed below.Clinical uses Tuberculous infection:combined with other agents to prevent emergence of resistance.Infectious endocarditis:+penicillin(enterococcus)Plague:streptomycin+tetracycline (first choice)Adverse reactions:much and severity（nephrotoxicity is mild）Ototoxicity：vestibular and auditory dysfunction vertigo眩晕,loss balance;even irreversible deaf Allergic shock:second only penicillinHypersensitivity:fever,skin rashes,other allergic manifestations(caused by prolonging contact with the agent)Contraindication:pregnancy(result in deafness in the newborn)18GentamicinGentamicinAntimicrobial activity:Antimicrobial activity:G-bacilli(Coliforms(Coliforms大肠杆菌、大肠杆菌、pseudomonaspseudomonas）G G+(Staphylococcus aureusStaphylococcus aureus）Clinical uses:combine with cephalosporin or penicillin Severe G-bacilli infection Especially pseudomonas,enterobacter Unknown G-complex infection Oral administration is used in intestinal infection or preoperative preparation.19GentamicinGentamicinAdverse reaction:1.Nephrotoxicity:reversible and usually mild.2.Ototoxicity:irreversible;vestibular前庭 dysfunction and loss of hearing.3.Hypersensitivity:infrequent Caution:Serum concentration and renal function should be monitored if duration is more than several days or in renal dysfunction patients.20TobramycinTobramycin and gentamicin exhibit similar activity against most gram-negative bacilli Tobramycin usually is more active against pseudomonas than gentamycin.Have no cross resistance with other aminoglycosides.Primarily treat serious pseudomonas aeruginosa infection.21Amikacin:semisynthetic derivative of kanamycinActive aganist drug resistant strainAmikacin and,in some instances,netilmicin retain their activity against gentamicin-resistant strains because they are a poor substrate for many of the aminoglycoside-inactivating enzymes.eg.mycobacteria tuberculosis,including streptomycin-resistant strain 1.Its antibacterial spectrum is the widest in aminoglycosides.2.Retain activity against drug-resistant entero-G-bacilli and pseudomonas3.Its the first choice to drug-resistant infection.22Netilmicin:1.Effect is strong.2.Activity against drug resistant strain-Can not be inactivated by many drug-resistant bacteria.3.Ototoxicity and nephrotoxicity is the lowest in aminoglycosides.23Antibacterial spectrum:G-,G+,such as mycobacteria,pseudomonas,streptococci.Complete cross resistance between neomycin and kanamycinClinical uses:similar to streptomycin,topical(局部的)or oral useAdverse reactionis:1.Significant nephrotoxicity and ototoxicity(Auditory disturbance is more than vestibular,deafness maybe occurrence,especially in renal dysfunction)2.Neuromuscular blockade,acetylcholine(Ach）release reduce,result in cardiac muscle inhibition、blood pressure descend、limbs paralyze and respiratory failure.-antidote:calcium gluconate and neostigmine(新施得明).3.Hypersensitivity is rare.Neomycin and kanamycin24SpectinomycinSpectinomycin（Trobicin）against gonorrhea（淋病）Used in drug-resistant gonococci or allergic to penicillin25Thank you!Thank you!
