浙江大学医学院：化学治疗药物 Chemotherapeutic drugs（Macrolides, Lincomycins、Aminoglycosides & Polymyxins、四环素和氯霉素）

Chemotherapeutic drugs Part 3 Macrolides, Lincomycins Wei-wei Hu, Phd m huww@zju.edu.cn

Part 3 Macrolides, Lincomycins Chemotherapeutic drugs Wei-wei Hu, PhD huww@zju.edu.cn

Macrolides(大环内酯类) CH H3C OCH. H3C、CH3 --CH CH H3C 00—cH CH H2C、OH OH H2C、CH C OCH3 OH CH3 CH CH H3C HO OH CH O CLARITHROMYCIN CH 2 CH CH O H3CAN CH3 OCH CH CH H3C.HO OH -CHa H3C CH OH HO CH H3C CH ERYTHROMYCIN CH2 CH CH CH CH AZITHROMYCIN

Macrolides （大环内酯类）

Macrolides(大环内酯类) First generation: Erythromycin(红霉素14) Medecamycin(麦迪霉素16) Spiramycin(螺旋霉素16) Second generation c| azithromycin(克拉霉素14) Azithromycin(阿奇霉素15) - AcetyImedecamycin(乙酰麦迪霉素16) Third generation Telithromycin(替利霉素14)

• First generation: - Erythromycin(红霉素 14) - Medecamycin(麦迪霉素 16) - Spiramycin(螺旋霉素 16) • Second generation: - Clarithromycin(克拉霉素 14) - Azithromycin(阿奇霉素 15) - Acetylmedecamycin(乙酰麦迪霉素 16) • Third generation: - Telithromycin(替利霉素 14) Macrolides （大环内酯类）

General properties of Macrolides 1. Chemistry: contain a macrocyclic lactone ring (usually containing 14 to 16 atoms)to which deoxy sugars are attached 2.Antimicrobial activity bactericidal or bacteriostatic, depending on the concentration, high activity in alkaline condition

General properties of Macrolides 1.Chemistry: contain a macrocyclic lactone ring (usually containing 14 to 16 atoms) to which deoxy sugars are attached. 2.Antimicrobial activity: bactericidal or bacteriostatic, depending on the concentration, high activity in alkaline condition

General properties of Macrolides 3. Antimicrobial spectrum: G+ organisms: cocci: streptococcus pyogenes, hemolytic streptococcus and streptococcus pneumoniae(化脓性、溶血性和肺炎链球菌), staphylococcus( produceβ lactamase or MRSA耐甲氧西林的金葡菌) bacilli: Corynebacterium diphtheria(白喉杆菌), bacillus anthraci(炭疽杆菌), clostridium tetani(破伤风杆菌) G-organisms CoCCI: meningococcus(脑膜炎奈瑟菌),N. gonorrhoeae(淋病奈瑟菌 - bacilli: legionella pneumophila(军团菌), bordetella pertussis(百日咳杆菌) haemophilus influenzae(流感嗜血杆菌)(对大肠埃希菌、变形杆菌无效) Other: - anaerobe(厌氧菌) mycoplasma pneumoniae(肺炎支原体) chlamydia(衣原体) rickettsia(立克次体) spirochetes(螺旋体)

3. Antimicrobial spectrum： G+ organisms: - cocci: streptococcus pyogenes, hemolytic streptococcus and streptococcus pneumoniae (化脓性、溶血性和肺炎链球菌), staphylococcus (produce β- lactamase or MRSA耐甲氧西林的金葡菌) - bacilli: Corynebacterium diphtheria (白喉杆菌), bacillus anthraci (炭疽杆菌) ， clostridium tetani (破伤风杆菌) G- organisms: - cocci: meningococcus (脑膜炎奈瑟菌)， N. gonorrhoeae (淋病奈瑟菌) - bacilli:legionella pneumophila (军团菌), bordertella pertussis(百日咳杆菌), haemophilus influenzae (流感嗜血杆菌)（对大肠埃希菌、变形杆菌无效） Other： - anaerobe （厌氧菌） - mycoplasma pneumoniae （肺炎支原体） - chlamydia （衣原体） - rickettsia （立克次体） - spirochetes （螺旋体） General properties of Macrolides

General properties of Macrolides 4. Mechanism of action(bind to P site) 1. Blocking translocation of peptidyl tRNA from A site to P site (B 位,14) 2 Preventing the peptidyl transfer(转肽,16C) 3. Inhibiting the formation of functional 70s ribosome 4. Bind to L27 and L22 protein to cause dissociation of peptidyl tRNA from the ribosome

4. Mechanism of action (bind to P site): General properties of Macrolides 1. Blocking translocation of peptidyl tRNAfrom A site to P site (移 位, 14) 2. Preventing the peptidyl transfer (转肽, 16C) 3. Inhibiting the formation of functional 70s ribosome 4. Bind to L27 and L22 protein to cause dissociation of peptidyl￾tRNA from the ribosome

General properties of macrolides 5 ADME of Macrolides. (Absorption Erythromycin is destroyed by stomach acid and must be administrated with enteric coating Stearates(硬脂酸) and ester(酯化) are fairly acid- resistant and somewhat better absorbed Clarithromycin and azithromycin are stable to acid Food interferes with absorption(except Clarithromycin)

5. ADME of Macrolides: (1)Absorption: • Erythromycin is destroyed by stomach acid and must be administrated with enteric coating. • Stearates (硬脂酸) and ester (酯化) are fairly acid￾resistant and somewhat better absorbed. • Clarithromycin and Azithromycin are stable to acid. • Food interferes with absorption (except Clarithromycin). General properties of macrolides

General properties of macrolides 5. ADME of macrolides (2 Distribution: Erythromycin diffuses readily into most tissues, including prostatic fluid and placenta, BBB impenetrable. (3)Metabolism and Elimination: most metabolized in the liver. excreted in the bile clarithromycin and its metabolite excreted in urine

5. ADME of macrolides: (2)Distribution: Erythromycin diffuses readily into most tissues, including prostatic fluid and placenta, BBB impenetrable. (3) Metabolism and Elimination: most metabolized in the liver, excreted in the bile； clarithromycin and its metabolite excreted in urine. General properties of macrolides

General properties of macrolides 6. Clinical Uses (1) Mycoplasma(支原体) infections (2) Legionnaire's disease(军团菌病) (3) Chlamydia infections(衣原体感染) (4) Diphtheria(白喉) 5) Pertussis(百日咳) (6) Streptococcus(链球菌), staphylococcus (金葡菌) infections

6.Clinical Uses: (1) Mycoplasma（支原体） infections (2) Legionnaire’s disease（军团菌病） (3) Chlamydia infections（衣原体感染） (4) Diphtheria（白喉） (5) Pertussis （百日咳） (6) Streptococcus （链球菌）, staphylococous （金葡菌） infections General properties of macrolides

General properties of macrolides 7. Adverse response: (1Gl effects: nausea, vomiting, abdominal cramps, etc. (2)Liver toxicity: Cholestatic hepatitis (胆汁淤积性肝炎) (3)Auditory impairment (4 Allergic reaction (5 Superinfections

7.Adverse response: (1) GI effects: nausea, vomiting, abdominal cramps, etc. (2) Liver toxicity: Cholestatic hepatitis （胆汁淤积性肝炎）. (3) Auditory impairment. (4) Allergic reaction (5) Superinfections General properties of macrolides