Lecture 15 Antituberculosis Drugs Dolly Mehta Ph D Knowledge Objectives 1 Know the major symptoms of tuberculosis and leprosy 2 Know the mechanisms of action of first and second line of anti TB drugs 3 Know the antimycobacterial agents used in prophylaxis and treatment of TB 4 Know the most common adverse effects of the therapy Drug List isoniazid pyrazinamide rifampin ethionamide ethambutol aminosalicyclic acid PAS streptomycin cycloserine 1 9 15 2009 Anti tubercular Anti tubercular agents and Anti leprosy Mycobacterium tuberculosis 1 9 15 2009 Characteristics of Mycobacterium tuberculosis Slow cell divison Can withstand weak disinfectants Survive in a dry state for weeks Unique cell wall provide resistance and is a key virulence factor Lung alveolar macrophage 1 Pathogens 2 Phagosome 3 Lysosomes 4 Waste material 4 5 Cytoplasm 6 Cell membrane 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 2 9 15 2009 lungs Pulmonary TB primary lymph l h nodes d tuberculous b l adenitis d i i or scrofula f l Brain and CNS Meningeal TB skin and the bones Liver kidney Tuberculosis Chest X ray with TB cavity right upper lobe 3 9 15 2009 REMERGING as a plague globally 2002 2010 1 billion persons will be newly colonzied Reasons Mycobacteria grow slowly and live dormantly agile in developing resistance many antibiotics cannot penetrate the cell wall Patient compliance drug toxicity drug interactions HIV and TB Treatment Atleast 2 different drugs to which organism is susceptible Treat for sufficient duration to prevent relapse First line Second line 4 9 15 2009 Isoniazid INH Niconyl Hyzyd Rifampin Rifadim Rimactane Ethambutol Myambutol or Streptomicin Pyrazinamide Moxifloxacin gatifloxacin Cycloserine Capreromycin E hi Ethionamide id Trecator sc T Aminosalicylic acid PAS Panasol Amikacin Kanamycin linezolid First Line S Second Line i Isoniazid INH Bacteriostatic resting mycobac Bactericidal growing mycobact catalase peroxidase prodrug I Active drug Mechanism of action Inhibits synthesis of mycolic acids 5 9 15 2009 Mechanism of Resistance Mutaion in inhA kas Mutaion in NADPH dehydrogenase ndh Mutation in Catalase peroxidase katg Mycolic acid Conversion of prodrug Absorption Distribution and Excretion Well absorbed by GI tract Diffuses all bodyy fluids includingg CSF inflamed menings conc in tissue plasma Al antacids interfere with absorption 75 95 Eliminated as acetylated by products via renal system 24 hrs 6 9 15 2009 Inactivation bimodial Scandanavians Jews North african caucasians CONHNH2 slow Genetically determined Arylamine N Acetyltransferases Type 2 fast Inuit japanese Inuit CONHNHCOCH3 Untoward Effects Hypersensitivity fever various skin eruptions etc Hematological reacns eosinophilia thrombocytopenia etc Arthritic symptoms pyridoxine deficiency competes with vit B6 7 9 15 2009 Hepatic Necrosis 20 yrs old Acetyl INH INH CONHNHCOCH3 CONHNH2 O CH3 C N NH2 Acetyl hydrazone CYP 450 Hepatic Necrosis Drug Interactions coadministration cycloserine CNS side effects such as dizziness or drowsiness Anticonvulsants i carbamazepine i e b i Rifampin Disulfiram Hepatotoxicity Coordination difficulties and psychotic episodes Increases their conc in serum by inhibiting hepatic metabolism 8 9 15 2009 Rifamycins RIF bactericidal rifampin rifabutin rifapentine Complex macrocyclic antibiotics Mechanism i off action i forms complex with subunit of DNA dependent RNA polymerase DNA DNA dependent RNA polymerase RNA Blocks initiation of chain formation in RNA synthesis Mechanism of Resistance rpoB Mutation In polymerase 9 9 15 2009 Absorption Distribution and Excretion absorbed by GI tract aminosalicylic acid decreases the abosption Deacetylated y via enterohepatic p circulation after which it is eliminated by bile Diffuses all body fluids including CSF Untoward Effects Generally well tolerated Induces hepatitis in patients with chronic liver disease alchoholic or older patients Flulike symptoms By inducing CYP1A2 2C9 decrease half life of HIV protease inhibitors digitoxin verapamil etc Rifapentine half life rifampin rifabutin rifabutin preferred in HIV infected patients 10 9 15 2009 Ethambutol Myambutol Synthesis of outer coating of cell wall inhibits arabinosyltransferase and thereby prevent conversion of D arabinose into arbinogalactan required for synthesis Resistance single amino acid mutation in the embA gene Absorption Distribution and Excretion Well absorbed Less toxic so replaced Aminosalicylic acid Effective when given with INH Excreatd by tubular secreation in addition to glomerular secretion Untoward Effects Optic neuritis visual acuity red green reversible 11 9 15 2009 Streptomycin Very potent against mycobacteria Recommended when less potentially hazardous th therapeutic ti agents t are ineffective i ff ti or contraindicated t i di t d OR Added in patients with serious forms of TB i e Disseminated meningitis i e Pyrazinamide Important for short term TB treatment Pyrazinamide deamidase Pyrazinoic acid Fatty acid synthase gene Inhibits synthesis of mycolic acids 12 9 15 2009 Absorption Distribution and Excretion Well absorbed from GI Diffuses all body fluids including CSF Eliminated via glomerular filtration half life in older Untoward Effects Liver injury inhibits urate excretion gout anorexia vomiting etc NOT recommended d d iin pregnantt woman iin US Quinolones Gatifloxacin Tequin Moxifloxacin Avelox For multidrug resistant TB Inhibits DNA gyrase and topoisomerase Aminosalicylic acid similar to sulphonamides 13 9 15 2009 Linezoid ZYVOX Mechanism of action binds P site of 50S and inhibits protein synthesis Untoward Effects Myelosuppression including anemia leukopenia thrombocytopenia Palpitation in patients on adreneric or serotonergic drugs Peripheral and optic neuropathy Ethionamide Trecator sc NADPH specific FAD monooxygenase prodrug Mechanism of action Active drug Fatty acid synthase gene Inhibits synthesis of mycolic acids 14 9 15 2009 Absorption Distribution and Excretion Slowly absorbed Diffuses all body fluids including CSF Eliminated via hepatic sys Secondary agent when primary agents fails Untoward Effects Anorexia nausea vomiting Postural hypotension depression dowsiness common Blurred vision headache VitB6 relieves neurological sym Cycloserine Seromycin D 4 amino 3 isoxazolidone structural analog of D Ala acts as a competitive inhibitor stable in
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