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Barry Park, CRRAB2, PBL#4

Drug Isoniazid MOA & Static or Cidal I/H synth of mycolic acidscell wall component cidal of actively growing bacilli penetrates macrophages active against extra- & intracellular organisms Rifampin I/H DNA-dependent RNA polymerase -cidal to mycobacteria Broad spectrum I/H enzyme for cell wall precursor production Selective Toxicity -cidal Most effective for M. tuberculosis & M. ansasii Not for atypical mycobacteria Antituberculosis Agents Pharmacokinetics Resistance Mechanism Diffuses readily, even in CNS muts resulting in: life: 1-3 hours overexpression of inhA distribution: nearly 100% mut/del of kagG elimination: liver- fast and mut of ahpC (virulence slow acetylators of little factor) clinical consequence mut of kasA Toxicities Occl fever or skin rash Drug-induced hepatitis (1%) DISCONTINUE! Benign increase (3-4X) in liver aminotransferass (2030%) Others (<1%) Note: reduces metabolism of phenytoin CYP450 inducer Rashes, thrombocytopenia, nephritis, ATN, cholestatic jaundice, hepatitis, flu-like syndrome accumulates in renal failure hypersensitivity rare retrobulbar neuritis loss of visual acuity and red-green discrim. (high doses) hepatotoxicity (1-5%) nausea vomiting fever hyperuricemiagout gastric irritation and neurologic sx at desired doseages hepatotoxic GI sx Peptic ulcers/hemorrhage Hypersensitivity Unique Properties 1/106 bacilli naturally resistant (108 in a tubercle) Monotherapy readily selects out resistant organisms

Atypical mycobacteria

Ethambutol

Atypical mycobacteria

Pyrazinamide

Nicotinamide relative Unknown mechanism Active within macrophage lysosome

Combo treatment for resistant strains -static or -cidal

distribution: readily, into most tissues and phagocytic cells CSF only in meningeal inflammation elimination: liverbile distribution: well-absorbed in gut elimination: 20% feces (unabsorbed) 50% urine (still active) distribution: GI absorption, widely distributed elimination: met in liver, metabolites renally cleared

Natural resistance at 1x106 Never used as monotherapy mut resulting in overexpression of I/H enzyme unknown possibly due to impaired uptake or decreased microbial activation of drug no cross-resistance w/ isoniazid/rifampin rapid low-level crossresistance to ison/rif

Orange urine, sweat, tears

Ethionamide

Blocks mycolic acid synth Folate-synth antagonist Structurally similar to sulfonamides & PABA

-static for M. tuberculosis Active exclusively against M. tuberculosis Many strains of M. tuberculosis -cidal

distribution: good, even to CSF elimination: liver distribution:GI absorption, widely distributed, except CSF elimination: urine

PAS

Cycloserine

I/H cell wall synth

distribution: elimination: renal distribution: poor, active mainly extracellularly elimination: renal

Aminoglycosides streptomycin

30s ribosomal subunit I/Hdecreased protein synth

ribosomal structure muts

Common (>25%) Peripheral neuropathy CNS dysfunction (depression, psychosis) ototoxic nephrotoxic dose-related

Used infrequently because it is poorly tolerated High urine concentrations can result in crystalluria Co-administer with pyridoxine to prevent neuro S/E Only IV administered Used in severe, lifethreatening disease Useful in resistant disease

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