9 13 2010 Anti tubercular and Anti leprosy agents Mycobacteria Tuberculosis leprosy Mycobacterial avium complex disease Characteristics Aerobic and like Gram Grow slowly and remain dormant Increased resistance to chemical damage and dehydration and relatively resistant to antibiotics Unique cell wall Thicker waxy hydrophobic and rich in mycolic acid Mycolic acid Mycobacterial Cell Wall Long fatty acids In M tuberculosis 3 types of fatty acids alpha methoxy and keto cell wall skeleton Alpha mycolic acids 70 and contain several cyclopropane rings g Methoxy mycolic acids 10 15 in the organism 1 outer lipids 2 mycolic acid 3 polysaccharides arabinogalactan 4 peptidoglycan 5 plasma membrane 6 Lipoarabinomannan LAM 7 phosphatidylinositol mannoside 8 Keto mycolic acid 10 to 15 allow the bacterium to grow readily inside macrophages effectively hiding it from the host s immune system Lung alveolar macrophage 1 Pathogens 2 Phagosome 3 Lysosomes 4 Waste material 5 Cytoplasm 6 Cell membrane lungs Pulmonary TB primary lymph nodes tuberculous adenitis or scrofula Brain and CNS Meningeal TB skin and the bones Liver kidney M Tuberculosis cell wall prevent the fusion of the phagosome with a lysosome UreC gene which prevents acidification of the phagosome bacteria can neutralize reactive nitrogen intermediates 1 9 13 2010 REMERGING as a plague globally R L 2002 2010 1 billion persons will be newly colonzied Reasons Mycobacteria agile in developing resistance to single chemotherapy Patient compliance drug toxicity drug interactions HIV and TB History Before 1930 s 1944 streptomycin 1950 s Isoniazid 1970 S Rifampin 1990 s Fluoroquinolones Treatment Atleast 2 different drugs to which organism is susceptible Treat for sufficient duration to prevent relapse First line Second line First Line Isoniazid INH Niconyl Hyzyd Rifampin Rifadim Rimactane Ethambutol Myambutol or Streptomicin Pyrazinamide Isoniazid INH Moxifloxacin gatifloxacin Cycloserine Capreromycin Ethionamide Trecator sc Aminosalicylic acid PAS Panasol Amikacin Kanamycin Linezolid i lid Clofazimine Bacteriostatic resting mycobac Bactericidal growing mycobact Second Line Alternative agents catalase peroxidase p prodrug I Active drug Mechanism of action Inhibits synthesis of mycolic acids fatty acid transferases 2 9 13 2010 Mechanism of Resistance Absorption Distribution and Excretion Mutaion in NADPH dehydrogenase ndh Mutaion in inhA kas Well absorbed by GI tract Mutation in Catalase peroxidase katg Diffuses all body fluids including CSF inflamed menings conc in tissue plasma Mycolic acid Al antacids antacids interfere with absorption Al Conversion of prodrug Inactivation bimodial Untoward Effects Periphral neuropathy patients with predisposing conditions i e malnutrition alcoholics diabetes AIDS and uremia pyridoxine deficiency competes with vit B6 Scandanavians Jews North african caucasians Slow 50 in US Genetic polymorphism Eliminated as acetylated by products via renal system 24 hrs CONHNH2 Arylamine N Acetyltransferases N Acetyltransferases Type 2 NAT2 CNS CNS toxicity memory loss psychosis seizures Hepatotoxicity high aminotranferases fast Inuit japanese CONHNHCOCH3 Hypersensitivity fever various skin eruptions etc Hematological reacns eosinophilia thrombocytopenia Arthritic symptoms INH Hepatic Necrosis 20 yrs old Acetyl INH Drug Interactions coadministration CONHNH2 CONHNHCOCH3 cycloserine CNS side effects such as dizziness or drowsiness O CH3 C N NH2 Anticonvulsants i e carbamazepine Rifampin Disulfiram Hepatotoxicity Coordination difficulties and psychotic episodes Acetyl hydrazone CYP 450 Increases their conc in serum by inhibiting hepatic metabolism Hepatic Necrosis 3 9 13 2010 Rifamycins RIF bactericidal Mechanism of Resistance rifampin rifabutin rifapentine Complex macrocyclic antibiotics rpoB Mechanism of action p with b subunit of forms complex DNA dependent RNA polymerase Mutation In polymerase Absorption Distribution and Excretion DNA DNA dependent RNA polymerase RNA Blocks initiation of chain formation in RNA synthesis Untoward Effects Generally well tolerated Induces hepatitis in patients with chronic liver disease alchoholic or older patients Gatrointestinal disturbances Flulike symptoms By inducing CYP1A2 2C9 decrease half life of HIV protease inhibitors digitoxin verapamil etc absorbed by GI tract decresaed by aminosalicylic acid Deacetylated via enterohepatic circulation after which it is eliminated by bile Diffuses all body fluids including CSF Ethambutol Myambutol Inhibit synthesis of outer coating of cell wall inhibits arabinosyltransferase and thereby prevent conversion of D arabinose into arbinogalactan required o sy synthesis es s for Resistance single amino acid mutation in the embA gene Rifapentine half life rifampin rifabutin rifabutin preferred in HIV infected patients Absorption Distribution and Excretion Well absorbed Less toxic so replaced Aminosalicylic acid Effective when given with INH Excreated by tubular and glomerular secretion Crosses BBB accumulates in renal failure Untoward Effects Streptomycin Very potent against mycobacteria Recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated OR Added in patients with serious forms of TB i e Disseminated disease Optic neuritis visual acuity red green color blindness reversible 4 9 13 2010 Pyrazinamide Important for short term TB treatment Absorption Distribution and Excretion Well absorbed from GI Diffuses all body fluids including CSF Pyrazinamide deamidase Eliminated via glomerular filtration half life in older Pyrazinoic acid Fatty acid synthase gene Inhibits synthesis of mycolic acids Quinolones Gatifloxacin Tequin Moxifloxacin Avelox No cross resistence with other anti TB drugs g Can be given along with INH and Rif in short regimns to prevent relapse Untoward Effects Liver injury inhibits urate excretion gout anorexia vomiting etc NOT recommended in pregnant woman in US Linezoid ZYVOX For multidrug resistant MDR TB Mechanism of action binds P site of 50S and inhibits protein synthesis Inhibits DNA gyrase and topoisomerase Aminosalicylic acid similar to sulphonamides Untoward Effects Myelosuppression including anemia leukopenia thrombocytopenia Palpitation in patients on adreneric or serotonergic drugs Peripheral and optic neuropathy Ethionamide Trecator sc Absorption Distribution and Excretion NADPH specific FAD monooxygenase prodrug Active drug Slowly absorbed Diffuses all body fluids including CSF Eliminated
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