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Antimycobacterial Drugs ( ) Huifang Tang tanghuifang@zju.edu.cn

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Mycobacterium tuberculosi Mycobacterium leprae nontuberculoausmycobacteria NTM M.aviumcomplex( ) M.Kartsasii( ) M.scrofulaceum( ) M.intracellulare( ) M.fortuitum( ) M.gordonae( )

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Antimycobacterial Drugs Antituberculous drugs ( ) Antileprotic drugs( )

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,INH ,PZA Part1 Antituberculous drugs ( ) First Line Drugs

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Second Line Drugs

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Isonizid ( INH) Isonizid ( ,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 g/mL or less and is bactericidal for actively growing tubercle bacilli. It is less effective against atypical mycobacterial species. Isonizid

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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 35 mcg/mL within 12 hours. Distribution: Isoniazid diffuses readily into all body fluids and tissues. Metabolism: liver N-acetyltransferase(N ) rapid acetylators -- hepatitis slow acetylators-- Peripheral neuropathy Isonizid

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Adverse Reactions Immunologic reactions Direct toxicity Isoniazid-induced hepatitis Peripheral neuropathy: pyridoxine( , VitminB6 ) Isonizid

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rifampin( ) Antimicrobial activity: in vitro against gram-positive and gram- negative cocci, some enteric bacteria, mycobacteria, and chlamydia. Mechanism of action: bactericidal inhibits DNA-dependent RNA polymerase Adverse effects: hepatotoxicity. Resistance : rapidly. no crossresistance to other classes of antimicrobial drugs cross-resistance to other rifamycin derivatives, eg, rifabutin and rifapentine. Rifampin

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Pharmacokinetics Absorbtion: well absorbed after oral administration excretion: mainly through the liver into bile enterohepatic recirculation( ) bulk excreted as a deacylated metabolite in feces a small amount in the urine. Distribution: widely in body fluids and tissues. relatively highly protein-bound adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation. Rifampin

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Clinical Uses MYCOBACTERIAL INFECTIONS Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria. Rifampin 600 mg daily or twice weekly for 6 months also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to isoniazid prophylaxis for patients with latent tuberculosis only, who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazidresistant, rifampin- susceptible strain. OTHER INDICATIONS prophylaxis meningococcal carriage 600 mg twice daily for 2 days prophylaxis in Haemophilus influenzae type b ( )disease: 20 mg/kg/d for 4 days, eradicate staphylococcal carriage: combination other agents serious staphylococcal infections such as osteomyelitis ( ) prosthetic valve endocarditis( ) Rifampin

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Adverse Reactions harmless orange color : urine, sweat, tear, and contact lenses (soft lenses may bepermanently stained). Occasional adverse effects : rashes, thrombocytopenia( ), and nephritis( ). cholestatic jaundice( ) and occasionally hepatitis. flu-like syndrome : fever, chills( ), myalgias( ), anemia( ), and thrombocytopenia and sometimes is associated with acute tubular necrosis( ). Cytochrome P450 isoforms (CYPs 1A2, 2C9, 2C19, 2D6, and 3A4) inducer : increases the elimination of numerous other drugs including methadone( ), anticoagulants( ), cyclosporine( ), some anticonvulsants, protease inhibitors, some nonnucleoside reverse transcriptase inhibitors( ), contraceptives, and a host of others. lower serum levels of these drugs. Rifampin

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Ethambutol( ), Mechanism of action: mycobacterial arabinosyl transferases( ). Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Ethambutol

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Clinical Use Combination with isoniazid or rifampin. Ethambutol hydrochloride, 1525 mg/kg, a single daily dose tuberculous meningitis: higher dose 50 mg/kg twice-weekly Ethambutol

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Adverse Reactions