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1、Antimycobectaria DrugsMycobacterial organismsCause tuberculosis, Mycobacterium avium complex (MAC) disease, and leprosy. Tuberculosis remains the primary worldwide cause of death due to infectious disease. Characteristics of mycobacteria AerobicInability to Gram-stainedAcid-fast stainLipid-riched ce

2、ll wall, esp. mycolic acidCharacteristics of mycobacteriaMycobacteria grow slowly and may be dormant in the host for long periods Resistant to the effects of antibioticsantibacterial agents do not penetrate the cell walls of mycobacteriamycobacteria can reside inside macrophages, adding another perm

3、eability barrier that effective agents must cross Mycobacteria are agile in developing resistance to single chemotherapeutic agents Drugs used in TuberculosisFirst-line agents (has greatest level of efficacy with an acceptable degree of toxicity ) isoniazid, rifampin, ethambutol, streptomycin, and p

4、yrazinamide Second-line agents (are added because of microbial resistance)moxifloxacin or gatifloxacin, ethionamide, aminosalicylic acid, cycloserine, amikacin, kanamycin, capreomycin, and linezolid Isoniazid (INH, Rimifon)Mechanism of ActionIsoniazid inhibits synthesis of mycolic acid, which are es

5、sential components of mycobacterial cell wallsIs bacteriostatic for resting bacilli, but is bactericidal for rapidly dividing microorganisms Penetrates cells with ease and is just as effective against bacilli growing within cells Effective only against TB (narrow spectrum)MIC: 0.025mg0.05mg/LBacteri

6、al Resistance easily develop when used alone, no cross-resistance with other anti-TB agents mechanism: 1. mutation of catalase-peroxidase (CP) CP activityINH conversion 2. missense mutation of inhA gene mutated InhAaffinity with INH 3. yield of target enzymes 4. accessibility into TBPharmacokinetics

7、 Absorption: is readily absorbed when administrated either orally or parenterally Distribution: in all body fluids and cells penetrate well into fibrotic and caseous material with TB concentration in CSFin plasma Elimination most INH is acetylated in liver and then excreted via kidney Rate of elimin

8、ation rapid slow white people 4050% 5060% Chinese 49.3% 25.6% t1/2 0.51.5hr 23hrMore than 300 patients were given intravenous injections of 5 mg/kg of isoniazid. Serum drug concentrations were assayed at multiple times after injection. A. The distribution of the serum concentrations of isoniazid 180

9、 minutes after injection; the light blue histograms represent rapid inactivators, and the dark blue histograms, slow inactivators. B. The distribution of serum half-lives of isoniazid for patients of each group. Therapeutic Uses the most effective and important anti-TB drug must be used concurrently

10、 with other drugs for treatment of TBAdverse Effects incidence: 5.4% related with dose and course Immunologic reactions (fever, rash) Toxicity (peripheral neuropathy)more frequent in slow acetylatorsdue to a relative VitB6 deficiencyprophylactic administration of VitB6 prevents and corrects the toxi

11、c reaction Toxicity (CNS symptoms) dizziness, insomnia coma, convulsion, and mental abnomality with overdose mechanism: VitB6GABA hepatotoxicity (most common major toxic effect)caused by acetylhydrazinemore frequent in rapid acetylators, old people, alcoholicstransaminase activity(1020%) severe hepa

12、tic injury (1.25%)prognosis: recover once treatment discontinuedContraindicates further use of INH Rifampin (RFP)Antibacterial Activity broad spectrum with strong killing activity vs.: G+, G bacteria, Chlamydia, M. TB, M. leprae. in their stationary and dividing phase MIC: 0.0050.5mg/L MBC: 416 fold

13、s of MIC penetrate easily into cells to kill TBMechanism of Action Inhibit DNA-dependent RNA polymeraseBacterial Resistance easily develop when used alone, no cross-resistance with other anti-TB agents mechanism 1. mutation of polymerase rpoB gene (base507-533, coding b-subunit) 2. permeability of c

14、ellular membranePharmacokinetics Absorption: well absorbed after oral administration Distribution: is distributed widely in body fluids and tissues Elimination deacetylated in liver and then excreted via feces (6065%) and urine (1530%) P-450 induction deacetylation t1/240% in 2 weeksTherapeutic Uses

15、 tuberculosis leprosy infection caused by sensitive bacteria must be used concurrently with other drugs for treatment of tuberculosisAdverse Effects incidence: 4.7% 0.9% of treatment has to be discontinued gastrointestinal disturbance: 1.7% hepatotoxicity allergy: more frequent in patients undergo i

16、ntermittent treatmentPrecaution administration before meal 812-hour interval needed for concurrent administraion with PAS urine, feces, tears, sputum, and saliva are stained orange-red accelerate metabolism of other drugs: eg. digoxin, quinidine, propranolol, corticosteroids, etc. avoid use during p

17、regnancy administer with great care for patients with liver dysfunction increased the hepatotoxicity in combination with INH or PAS must be used concurrently with other drugs for treatment of tuberculosis evaluate liver function periodicallyEthambutol乙胺丁醇 Mechanism of Action Inhibit arabinosyl trans

18、ferase arabinogalactan synthesis cell wall formationAntibacterial Activity effective bactericidal drug against intra- or extra-cellular TBBacterial Resistance slowly develop when used alonePharmacokinetics absorbed rapidly distribute throughout the body 50% of drug is excreted unchanged in urineTher

19、apeutic Uses “First-line” anti-TB drug used commonlyAdverse Effects incidence: 2% retrobulbar neuritis (most common serious adverse effect) gastrointestinal upset hepatotoxicity hypersensitivity (rare)IHNRFPEMBSpectrumNarrow:TbWide: G ,Tb,chlamydiaeNarrow: TbMechanism (target) mycolic acid synthesis

20、DDRPCell wall and RNA synthesisPenertration+Activity+EliminationLiver, rapid/slowLiverKidneyAdverse effectsmildmildrareOthersP450 inducerRetrobulbar neuritisPyrazinamide(PZA) Streptomycin(SM,S)SpectrumTbG+、G-、TbMechanismDisrupts membrane metabolism and transport functionInhibit ribosomal functionPro

21、pertiesActive against intracellular bacteriaIneffective against intracellular bacteriaPharmacokineticsRapidly absorbed,eliminated by kidneyCannot be used orally, kidney eliminationAdverse effectsHepatotoxicity hyperuricemia, gouty arthritisOtotoxicity and nephrotoxicityOther fist-line drugsReasonabl

22、e Application of Anti-TB DrugsTherapeutic Principles for Anti-TB Drugs applied as early as possible applied in combination applied regularly during the course short-term therapy is mended worldwide: initial therapy for simple tuberculosis: H, R severe tuberculosis: H, R, S (or E), and Z Example: 2HRZ/4HR SHRZ/4HRE (INH-resistant) 12-month therapy necessary for malnutrition and cachexia 1824-month therapy necessary for recurrence and concurrence o