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Antimycobacterial drugs

Antimycobacterial drugs. By Bohlooli S, PhD School of Medicine, Ardabil University of Medical Sciences. First Line Agents Isoniazid (INH) Rifampine Pyrazinamide Ethambutol Streptomycin. Second Line Agents Amikacin Aminosalicylic acid Capreomycin Ciprofloxacin Clofazimine

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Antimycobacterial drugs

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  1. Antimycobacterial drugs By Bohlooli S, PhD School of Medicine, Ardabil University of Medical Sciences

  2. First Line Agents Isoniazid (INH) Rifampine Pyrazinamide Ethambutol Streptomycin Second Line Agents Amikacin Aminosalicylic acid Capreomycin Ciprofloxacin Clofazimine Cycloserine Ethionamide Levofloxacin Rifabutin Rifapentine Drugs Used in Tuberculosis

  3. Isoniazid (INH) • Most active drug • Water soluble • Similar to pyridoxine • Good penetration to phagocytic cells

  4. Isoniazid (INH): Mechanism of Action • Prodrug: activated by KatG (Catalase proxidase) • Active form bind to Acyl carrier protein (AcpM),and KasA (beta-ketoacyl carrier protein synthase), covalently • Inhibits synthesis of mycolic acid

  5. Isoniazid (INH): Basis of Resistance • Mutation or deletion of KatG • Overexpression of inhA (encodes acyl carrier protein reducatase) • Overexperssion of ahpC, oxidative stress protection • Resistance mutants occur in 1 in 106

  6. Isoniazid (INH): Pharmacokinetics • Good absorption from GIT • Readily distribute to tissues and body fluids • Ratio in CFS: 20 to 100% • Metabolism by N-acetyltransferase • Rapid acetylator: hepatoxicity • Slow acetylator: neuropathy

  7. Isoniazid (INH): Clinical Use • Single agent in latent tuberculosis • In combination with second agent in active form • Use pyridoxine in conditions predisposing to neuropathy

  8. Isoniazid (INH): Adverse Reactions • Allergic reactions • Fever, skin rashes • Drug induced systemic lupus erythematosus • Direct toxicity • Hepatitis: loss of appetite, nausea, vomiting, Jaundice, right upper quadrant pain • In 1% patients and fatal • Depend on age • Neuropathy: higher in slow acetylators • CNS effects: memory loss, psychosis, seizure • Drug interaction: phenytoin

  9. Rifampin • Active against: • gram positive and gram negative cocci, • some enteric bacteria • Mycobacteria • Chlamydia • Mechanism: • Binds to DNA dependent RNA polymerase • Resistance: • Point mutation in rpoB gene • Prevent binding of rifampin to RNA polymerase

  10. Rifampin: Pharmacokinetic • Well absorption • Enterohepatic cycle • Good distribution to body fluids and tissues and phagocytic cells • Adequate level in meningeal inflammation

  11. Rifampin: Clinical use • Together with other drugs for prevention of resistance • Atypical mycobacterial infections • Leprosy • Alternative to INH • Prophylaxis in H. influemzae type b contacts • Staphylococcal infections • highly penicillin-resistant strain of pneumococci

  12. Rifampin: adverse reactions • Orange color urine, sweat, tears, contact lens • Rashes, thrombocytopenia, nephritis • Hepatitis • Light chain proteinuria • Flu-like syndrome: fever, chills, myalgias, anemia, thrombocytopenia, acute tubular necrosis • Enzyme inducer

  13. Chemical Sructure

  14. Ethambutol • Synthetic, water soluble, heat stable compound • An inhibitor of arabinosyl transferase and polymerization of arabinoglycan • Resistance due to mutations resulting in overexpression of emb gene products and occur rapidly • Good absorption from GIT • Elimination: 50% unchanged in Urine

  15. Ethambutol • Clinical use • In combination with isoniazid or rifampin • Adverse reaction • Retrobulbular neurotitis, loss of visual acuity, red green blindness • Hypersensivity reactions

  16. Chemical Structure

  17. Pyrazinamide • Relative of nicotinamide • Inactive in neutral pH but active in acidic pH • Drug taken up by macrophages • Converted to pyrazinoic acid by bacterial pyrazinamidase • Mechanism is unknown • Clinical use: together with insoniazid or rifampin • Resistance is fairly readily acquired • Adverse reaction: hepatotoxicity, nausea, vomiting, drug fever, hyperuricemia

  18. Streptomycin • Resistance is due to point mutation in gene rpsL, encoding S12 ribosomal protein or rrs, encoding 16S ribosomal rRNA • Active against extracellular form of tubercle bacille • Employed when injectable drug is needed

  19. Alternative second-line drugs for tuberculosis • In the case of resistance to the drug of first choice • In the case of failure of clinical response • When expert guidance is available to deal with the toxic effects.

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