浙江大学医学院：《药理学 Pharmacology》课程教学资源（PPT课件）抗分枝杆菌药 Antimycobacterial Drugs

Antimycobacterial Drugs (抗分枝杆菌药) Huifang Tang tanghuifang@zju.edu.cn

Antimycobacterial Drugs (抗分枝杆菌药) Huifang Tang tanghuifang@zju.edu.cn

结核分枝杆菌( Mycobacterium tuberculosi) o麻风杆菌( Mycobacterium leprae) o非典型分枝杆菌 (nontuberculoausmycobacteria, NTM M. aviumcomplex(鸟复合分枝杆菌) M. Kartsasiti(堪萨斯分枝杆菌) ●M. scrofulaceum(瘰疬分枝杆菌) ● M. intracellulare(胞内分枝杆菌) M fortuitum(俜发分枝杆菌) M gordonae(戈登分枝杆菌)

 结核分枝杆菌（Mycobacterium tuberculosi）  麻风杆菌（Mycobacterium leprae）  非典型分枝杆菌 （nontuberculoausmycobacteria，NTM） ⚫ M.aviumcomplex(鸟复合分枝杆菌) ⚫ M.Kartsasii(堪萨斯分枝杆菌) ⚫ M.scrofulaceum(瘰疬分枝杆菌) ⚫ M.intracellulare(胞内分枝杆菌) ⚫ M.fortuitum(偶发分枝杆菌) ⚫ M.gordonae(戈登分枝杆菌)

Antimycobacterial Drugs o Antituberculous drugs(抗结核病药) o Antileprotic drugs(抗麻风病药)

Antimycobacterial Drugs  Antituberculous drugs (抗结核病药)  Antileprotic drugs(抗麻风病药)

Part1 Antituberculous drugs (抗结核病药) First Line Drugs Drug Typical Adult Dosage First-line agents(in approximate order of preference Isoniazid异烟肼,INH 300 mg/d Rifampin利福平 600 mg/d Pyrazinamide吡嗪酰胺,PzA 25 mg/kg/d Ethambutol乙胺丁醇 15-25 mg/kg/d Streptomycin 链霉素 15 mg/kg/d

异烟肼,INH 利福平 吡嗪酰胺,PZA 乙胺丁醇 链霉素 Part1 Antituberculous drugs (抗结核病药) First Line Drugs

Second Line Drugs Second-line agents Amikacin阿米卡星 ■ 5 mg/kg/d Aminosalicylic acid对氨水杨酸 8-129d Capreomycin卷曲霉素 15 mg/kg/d Ciprofloxacin 丙沙星 1500 mg/d divided Clofazimine 氯法齐明 200 mg/d Cycloserine环丝氨酸 500-1000 mg/d divided Ethionamide 乙硫异烟胺 500-750mgd Levofloxacin左氧氟沙星 500 mg/d Rifabutin 利福布坦 300 mg/d- Rifapentine利福喷丁 600 mg once or twice weekly

Second Line Drugs 阿米卡星 对氨水杨酸 卷曲霉素 环丙沙星 环丝氨酸 乙硫异烟胺 左氧氟沙星 利福布坦 利福喷丁 氯法齐明

Cell Wall Synthesis Inhibits cell wall synthesis e Acyl Lipids Rifampin Inhibits RNA DNA Coiling, Transcription, and Translation Mycolic Acid RNA Polymerase NA Inhibit cell wal Arabinogalactan mRNA these asma (Ribosome Membrane PAS Cycloserine Inhibits synthesis (Protein of DNA precursors Inhibits cell wall synthesis Mycobacterium Fluoroquinolones tuberculosis Inhibit DNA Gyra bit prc nthesis (ATP) Inhibit pro SHH mmmm ATP Synthesis

0 20 40 60 80 100 120 一月 二月 三月 四月 亚洲区 欧洲区 北美区

Cell Wall Synthesis Acyl Lipids DNA Coiling, Transcription, and Translation sQ-109 Inhibits cell wall RNA synthesis Arabinogalactan ( eptidoglycan mRNA 时 Mycobacterium Inhibit protein tuberculosis synthesis Nitroimidazoles Oxazolidinone (E.g. PA-824 oPc67683) Inhibit protein synthesis Novel, complex mechanisms of Inhibit cell wall synthesis ATP) AND Inhibit cell respiration Mechanism of action uncertain ell wall Diarylquinoline ATP Synthesis (TMC 207) hibits ATP synthase

Isonizid Isonizid(异烟肼工NH) o Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains o Isoniazid penetrates into macrophages and is CONHNH2 active against both extracellular and Isoniazid intracellular organisms o In vitro, isoniazid inhibits most tubercle bacilli in a concentration of 0.025~0.05 ug/mL CH3 or less and is bactericidal for actively growing tubercle bacilli. it is less effective against OH HOH,C atypical mycobacterial species CH2OH Pyridoxine

Isonizid (异烟肼,INH)  Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains.  Isoniazid penetrates into macrophages and is active against both extracellular and intracellular organisms.  In vitro, isoniazid inhibits most tubercle bacilli in a concentration of 0.025~0.05 μg/mL or less and is bactericidal for actively growing tubercle bacilli. It is less effective against atypical mycobacterial species. Isonizid

Cell Wall Synthesis Inhibits cell wall synthesis e Acyl Lipids Rifampin Inhibits RNA DNA Coiling, Transcription, and Translation Mycolic Acid, RNA Polymerase NA Inhibit cell wal Arabinogalactan (NA) mRNA these asma (Ribosome Membrane PAS Cycloserine Inhibits synthesis (Protein of DNA precursors Inhibits cell wall synthesis Mycobacterium Fluoroquinolones tuberculosis Inhibit DNA Gyra bit prc nthesis (ATP) Inhibit pro SHH mmmm ATP Synthesis

0 20 40 60 80 100 120 一月 二月 三月 四月 亚洲区 欧洲区 北美区

Isonizid Pharmacokinetics o Absorbtion: Isoniazid is readily absorbed from the gastrointestinal tract. A 300-mg oral dose(5 mg/kg in children )achieves peak plasma concentrations of 3-5 mca/mL within 1-2 hours o Distribution: Isoniazid diffuses readily into all body fluids and tissues o Metabolism: liver N-acetyltransferase(N乙酰转 移酶) rapid acetylators--hepatitis slow acetylators-- Peripheral neuropathy

Pharmacokinetics  Absorbtion: Isoniazid is readily absorbed from the gastrointestinal tract. A 300-mg oral dose (5 mg/kg in children) achieves peak plasma concentrations of 3–5 mcg/mL within 1–2 hours.  Distribution: Isoniazid diffuses readily into all body fluids and tissues.  Metabolism: liver N-acetyltransferase(N乙酰转 移酶) ⚫ rapid acetylators -- hepatitis ⚫ slow acetylators-- Peripheral neuropathy Isonizid