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1、AntituberculousAntituberculous DrugsDrugsHuHu WeiweiWeiwei 20092009- -1212- -2424Estimated numbers of tuberculosis cases by country in 2000Corbett, E. L. et al. Arch Intern Med 2003;163:1009-1021.AntituberculousAntituberculous DrugsDrugs? ?FirstFirst- -line agentsline agents： Isoniazid(INHIsoniazid(
2、INH, ,异烟肼异烟肼异烟肼异烟肼) ) RifampinRifampin( (利福平利福平利福平利福平) ) PyrazinamidePyrazinamide( (吡嗪酰胺吡嗪酰胺吡嗪酰胺吡嗪酰胺) ) EthambutolEthambutol( (乙胺丁醇乙胺丁醇乙胺丁醇乙胺丁醇) ) Streptomycin(Streptomycin(链霉素链霉素链霉素链霉素) ) AntituberculousAntituberculous DrugsDrugs? ?SecondSecond- -line agentsline agents： ParaPara- -aminosalicylicami
3、nosalicylic( (对氨水杨酸对氨水杨酸对氨水杨酸对氨水杨酸) ) EthionamideEthionamide( (乙硫异烟胺乙硫异烟胺乙硫异烟胺乙硫异烟胺) ) AmikacinAmikacin( (阿米卡星阿米卡星阿米卡星阿米卡星) ) CapreomycinCapreomycin( (卷曲霉素卷曲霉素卷曲霉素卷曲霉素) ) FluoroquinolonesFluoroquinolones( (氟喹诺酮类氟喹诺酮类氟喹诺酮类氟喹诺酮类) )1Antituberculous activityIsoniazidIsoniazid ( (异烟肼异烟肼异烟肼异烟肼) )?Remarkab
4、ly selective for mycobacteria (0.0250.05 g/ml, other microorganisms 500 g/ml) .?Resistance mutants occurs easily when given as the sole drug.?Bacteriostatic for resting tubercle bacilli, bactericidal for actively growing tubercle bacilli1Antituberculous activityIsoniazidIsoniazid( (异烟肼异烟肼) )?Diffusi
5、ng readily into all body fluid and tissues, including caseous material(干酪化结 核病灶干酪化结 核病灶). ?Penetrating into phagocytes, and is active against both extracelluar and intracellular tubercle bacilli.2Mechanism of actionIsoniazidIsoniazid( (异烟肼异烟肼) )?Inhibiting synthesis of mycolic acids, which are essen
6、tial components of mycobacterial cell walls.3ADMEIsoniazidIsoniazid( (异烟肼异烟肼) )?Readily absorbed from the gastrointestinal tract.?Widely distributed in all body fluids and tissues.3ADMEIsoniazidIsoniazid( (异烟肼异烟肼) )?Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is gen
7、etically determined. There are slow acetylators and rapid acetylators,.?Excreted mainly in the urine.4Clinical UsesIsoniazidIsoniazid( (异烟肼异烟肼) )?Combination with rifampin or other first- line agents, isoniazid is used for severe infections with M. tuberculosis.?As a single agent, isoniazid is indic
8、ated for prevent tuberculosis.?First choice for all kinds tuberculosis5Adverse reactionsIsoniazidIsoniazid( (异烟肼异烟肼) )?Hepatotoxicity?Peripheral neuritis?CNS toxic effects?GI effects?Allergic reactions?Broad-spectrum antimicrobial activity. RifampicinRifampicin (RPF,(RPF,利福平利福平) )?Resistance mutants
9、 occurs easily, if used as a single drug.1. Antibacterial activity 1. Antibacterial activity RifampicinRifampicin (RPF,(RPF,利福平利福平) )?It readily penetrates most tissues and into phagocytes. ?Rifampicinis bactericidal for mycobacteria.?Binding strongly to the subunit of bacterial DNA-dependent RNA po
10、lymerase ?Inhibiting RNA synthesis. RifampicinRifampicin (RPF,(RPF,利福平利福平) )2Mechanism of action3Mechanism of resistanceRifampicinRifampicin (RPF,(RPF,利福平利福平) )?Resistance results from one of several possible points in the gene for subunit ofRNA polymerase. These mutation prevent binding of rifampic
11、in to RNA polymerase. 4ADMERifampicinRifampicin (RPF,(RPF,利福平利福平) )?Well absorbed after oral administration. The absorption is attenuated by food and para-aminosalicylic (PAS).?Widely distributed, even in CSF when menings is infectious.4ADMERifampicinRifampicin (RPF,(RPF,利福平利福平) )?Metabolized in liv
12、er by deacylation, and rifampicin is a enzyme inducer.?Excreted mainly through the liver into bile, then undergoes enterohepatic recirculation.5. Clinical Uses RifampicinRifampicin (RPF,(RPF,利福平利福平) )?1) mycobacterial infections?2) other indications6. Adverse reactionsRifampicinRifampicin (RPF,(RPF,
13、利福平利福平) )?GI effects?Cholestatic jaundice or hepatitis ?Hypersensitive reaction?Nervous system effect?Causing a harmless orange color in urine, sweat, tear, and contact lenses.?Nearly all strain of M. tuberculosis are sensitive.EthambutolEthambutol ( (乙胺丁醇乙胺丁醇) )1 1AntimycobacterialAntimycobacterial
14、 actvityactvity?Be bactericidal to intercellular and extrecellular M.tuberculosis.?Resistance to ethambutol developed very slowly in vitro.?The mechanism of action is involved in inhibition of RNA synthesis. 2 2Clinical UsesClinical UsesEthambutolEthambutol ( (乙胺丁醇乙胺丁醇) )?Treatment for tuberculosis
15、of various forms when given concurrently with isoniazid. 3 3Adverse reactionsAdverse reactionsEthambutolEthambutol ( (乙胺丁醇乙胺丁醇) )?Optic neuritis, induced decrease of visual acuity and loss of ability to differentiate red from green.?Hypersensitive reactions.?GI upset, headache, etc.Streptomycin (Str
16、eptomycin (链霉素链霉素) )?The first effective drug to treat tuberculosis. (Bacteriostatic effect)?It is bacteriostatic for the tubercle bacillus. Resistance to Streptomycin developed easily when it is used alone.?Given simultaneously to prevent emergence of resistance and toxic reaction.PyrazinamidePyrazinamide( (吡嗪酰胺吡嗪酰胺) )?Presenting bactericidal activity in vitro only at a sightly acidic pH.?
