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

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

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

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 Isoniazid (INH): Mechanism of Action

Mutation or deletion of KatG Overexpression of inh A (encodes acyl carrier protein reducatase) Overexperssion of ahp C, oxidative stress protection Resistance mutants occur in 1 in 10 6 Isoniazid (INH): Basis of Resistance

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

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

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

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 rpo B gene  Prevent binding of rifampin to RNA polymerase

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

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 Rifampin: Clinical use

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

Chemical Sructure

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

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

Chemical Structure

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

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

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.