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Antimycobacterial drugs

Antimycobacterial drugs. Pawitra Pulbutr B.Pharm (Hon.), M. Sc. In Pharm (Pharmacology). วัตถุประสงค์เชิงพฤติกรรม. เมื่อนิสิตศึกษาเอกสารแล้วนิสิตสามารถ มีความเข้าใจและอธิบายถึงกลไกการออกฤทธิ์, เภสัชจลนศาสตร์, อาการไม่พึงประสงค์ของยา Antimycobacterial

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Antimycobacterial drugs

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  1. Antimycobacterial drugs Pawitra Pulbutr B.Pharm (Hon.), M. Sc. In Pharm (Pharmacology)

  2. วัตถุประสงค์เชิงพฤติกรรมวัตถุประสงค์เชิงพฤติกรรม • เมื่อนิสิตศึกษาเอกสารแล้วนิสิตสามารถ • มีความเข้าใจและอธิบายถึงกลไกการออกฤทธิ์, เภสัชจลนศาสตร์, อาการไม่พึงประสงค์ของยา Antimycobacterial • มีความเข้าใจและอธิบายถึงการนำไปใช้ประโยชน์ทางคลินิคของยา Antimycobacterial

  3. Mycobacteria • Mycobacterium tuberculosis • Tuberculosis, TB วัณโรค • Mycobacterium leprae • Leprosy โรคเรื้อน • Atypical mycobacteria • Mycobacterium avium complex (MAC) • Opportunistic infection in AIDS

  4. Characteristic of Mycobacteria Resistance to many antibacterial • Slowly growing or Dormant • Lipid rich cell wall • Intracellular organisms • Able to develop resistance Impermeable to many agents Many agents are inaccessible Hard to be eradicated Need drug combination

  5. Drugs used in tuberculosis Second line drugs First line drugs • Ethionamide • Capreomycin • Cycloserine • PAS • Kanamycin & Amikacin • Quinolones • Rifabutin • Rifapentine • Clofazemine • Isoniazid (INH,H, I) • Rifampin [R] • Pyrazinamide [ Z ] • Ethambutol [ E ] • Streptomycin [ S ]

  6. Isoniazid (INH) Mechanism of Action Mycolic acid Essential components of mycobacterial cell wall • INHform complex with • Acyl carrier protein (Acp M) • Beta ketoacyl carrier protein synthase (Kas A) *Inhibit mycolic acid synthesis* • Need mycobacterial catalase peroxidase (Kat G) to become active

  7. Adverse drug reactions (ADRs) • 1. INH induced hepatitis • loss of appetite, n/v, jaundice, right upper quadrant pain • can be lethal !! • STOP INH, if occur • risk depend on age of patients • risk patients ex. Alcoholism, pregnancy, feeding mother

  8. 2. Peripheral neuropathy • Especially occur in slow acetylator, malnutrition, alcoholism, DM, AIDS, uremia • INH form complex with pyridoxine [pyridoxal hydrazone] • Then, increase pyridoxine excretion in urine • Lack of pyridoxine (Vitamin B6) • Rx : Pyridoxine 10 mg/day

  9. Rifampin Mechanism of action • Binds with beta subunit of bacterial DNA dependent RNA polymerase** • Inhibit RNA synthesis Mechanism of resistance • Mutation of beta subunit of RNA polymerase Rifampin = Enzyme inducer

  10. Rifampin ADRs • Orange secretion*** …urine, tear, sweat • Rashes, fever, n/v, thrombocytopenia, nephritis, cholestatic jaundice, hepatitis, flu-like syndrome • Hepatitis [rarely] • Patients at risk …chronic liver disease, alcoholism, elderly

  11. Ethambutol Mechanism of action • Inhibit mycobacterial arabinosyl transferase enzyme Enzyme in arabinoglycan polymerization Arabinoglycan = Essential component of mycobacterial cell wall Mechanism of resistance Mutation of mycobacterial arabinosyl transferase enzyme

  12. Ethambutol ADRs • 1. Optic neuritis • Serious ADRs • Dose-related • Loss of visual acuity ความชัดเจน • Red- green** color blindness • Check visual acuity Contraindication………Children < 5 yrs

  13. Ethambutol • 2.Increase uric acid in plasma • Ethambutol decrease uric acid excretion • Caution in gout patients • 3. Others • GI disturbances, Arthralgia, Headaches, Giddiness, Mental disturbances

  14. Mechanism of action • Unknown • Converted into Pyrazinoic acid (active form) • By enzyme mycobacterial pyrazinamidase Mechanism of resistance • Mutation of mycobacterial pyrazinamidase • Decrease pyrazinamide uptake into mycobacteria • NO cross resistance with other drugs

  15. Pyrazinamide ADRs • Hepatotoxicity** • Etc., n/v, drug fever, hyperuricemia**

  16. Streptomycin • Aminoglycoside antibiotics • Less permeable into the cell …Active extracellular

  17. Alternative second line drugs in treatment of tuberculosis Use when… • Resistance to 1st line drugs • No clinical response with 1st line drugs • Toxic effects with 1st line drugs Aminosalicylic acid (PAS) Kanamycin & Amikacin Quinolones Ethionamide Cycloserine Capreomycin Rifabutin Rifapentine

  18. Mycobacterium Avium Complex (MAC) Infection • Consists of M. avium & M. intracellulare • Cause of disseminated disease in late stage AIDS…CD4 < 50 • Treatment…Drug combination • Azithromycin 500 mg OD or Clarithromycin 500 mg bid + • Ethambutol 15 mg/ kg/ day + • Ciprofloxacin 750 mg bid or Rifabutin 300 mg OD • Other; Amikacin, Ethionamide

  19. Drugs used in leprosy Caused by M. leprae Dapsone & Other sulfone • Dapsone =Diaminodiphenylsulfone (DDS) • Inhibit folate synthesis [As sulfonamides] • Bacteriostatic

  20. Clofazimine • Phenazine dye • Unknown mechanism of action….DNA binding ? • Irregular GI absorption • Excrete in feces • Deposit in reticuloendothelial tissue & skin • Use in … • sulfone resistant leprosy • patients who can not tolerated to sulfone • 100 mg/day

  21. Clofazimine ADRs; skin discoloration [red brown to black], GI intolerance Rifampin • Bactericidal to M. leprae • 600 mg/ day • use in combination with other antileprosy to prevent resistance

  22. For additional information on tuberculosis, visit the Division of Tuberculosis Elimination Web site at: http://www.cdc.gov/tb Additional TB Resources

  23. THE END

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