-1-Lecture 15:Antituberculosis DrugsDolly Mehta, Ph.D.Knowledge Objectives1 .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 Listisoniazid pyrazinamide rifampin ethionamideethambutol aminosalicyclic acid (PAS)streptomycin cycloserine9/15/20091Antitubercular agentsAnti-tubercular agentsand Anti-leprosy Mycobacterium tuberculosis9/15/20092Slow cell divisonCan withstand weak disinfectantsCharacteristics of Mycobacterium tuberculosis Can withstand weak disinfectants Survive in a dry state for weeks Unique cell wall provide resistance and is a key virulence factorLung alveolar macrophage1. Pathogens2. Phagosome3. Lysosomes4 Waste material4. Waste material5. Cytoplasm6. Cell membraneM. 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.9/15/20093•lungs (Pulmonary TB) primarylhd(bl dii fl)•lymph nodes (tuberculous adenitis or scrofula)•Brain and CNS (Meningeal TB)•skin and the bones•Liver•kidney. Tuberculosis Chest X-ray with TB cavity right upper lobe9/15/20094REMERGING as a plague globally2002-2010------- 1 billion persons will be newly colonziedReasonsMycobacteria grow slowly and live dormantlyagile in developing resistancemany antibiotics cannot penetrate the cell wallReasons•Patient compliance•drug toxicity•drug interactions (HIV and TB)TreatmentAtleast 2 different drugs to which organism is susceptibleTreat for sufficient duration to prevent relapseFirst lineSecond line9/15/20095Isoniazid (INH, Niconyl, Hyzyd)Rifampin (Rifadim, Rimactane)*Ethambutol (Myambutol) or StreptomicinPyrazinamideFirst LinePyrazinamideMoxifloxacin (gatifloxacin)CycloserineCapreromycinEhi id (T)SiEthionamide (Trecator-sc)Aminosalicylic acid (PAS) (Panasol)AmikacinKanamycinlinezolidSecond Line Isoniazid (INH)Bacteriostatic---resting mycobac Bactericidal---growing mycobact prodrugcatalase-peroxidase?? Active drugInhibits synthesis of mycolic acidsI. Mechanism of action9/15/20096Mechanism of ResistanceMutation in CatalaseMutaion in inhA/kasMutaion in NADPH dehydrogenase (ndh)Mutation in Catalase/peroxidase (katg))Mycolic acidConversion of prodrugAbsorption, Distribution, and Excretion•Well-absorbed by GI tract•Diffuses all body fluids including CSF; •Al+-antacids interfere with absorptionyg;(inflamed menings conc in tissue = plasma)•75-95% Eliminated as acetylated by products via renal system (24 hrs)(24 hrs)9/15/20097Inactivation: bimodialCONHNH2Scandanavians, Jews, North african caucasians, 2Arylamine N-AcetyltransferasesType 2GeneticallydeterminedslowfastInuit japaneseCONHNHCOCH3Inuit, japaneseUntoward Effects•Hypersensitivity: fever, various skin eruptions, etc •Hematological reacns: eosinophilia, thrombocytopenia etc•Arthritic symptoms•pyridoxine deficiency (competes with vit B6)9/15/20098CONHNH2INHCONHNHCOCH3Acetyl INHHepatic Necrosis(>20 yrs old) 2CH3-C-N-NH2OAcetyl hydrazoneCYP-450Hepatic NecrosisDrug InteractionscoadministrationcycloserineRifampinCNS side effects such as dizziness or drowsinessDisulfiram Coordination difficultiesand psychotic episodesHepatotoxicityAnticonvulsantsib iIncreases their conc in serum by inhibiting hepatic metabolismi.e. carbamazepine9/15/20099Rifamycins (RIF) (bactericidal)(rifampin, rifabutin, rifapentine)Complex macrocyclic antibiotics)ififorms complex with -subunit of DNA-dependent RNA polymeraseMechanism of actionDNADNA-dependent RNA polymeraseBlocks initiation of chain formation in RNA synthesisRNArpoBMutationMechanism of ResistancerpoBMutation In polymerase9/15/200910Absorption, Distribution, and Excretion•absorbed by GI tract; aminosalicylic acid decreases the abosptionDeacetylated via enterohepatic circulation after which it ypis 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 inhibitorsdigitoxin, verapamil etcRifapentine half life > rifampin, rifabutin;rifabutin preferred in HIV-infected patients9/15/200911Ethambutol (Myambutol)inhibitsarabinosyltransferaseand thereby prevent•Synthesis of outer coating of cell wallinhibits arabinosyltransferaseand thereby prevent conversion of D-arabinose into arbinogalactan required for synthesis Resistance: single amino acid mutation in the embA gene •Well-absorbed•Less-toxic so replaced Aminosalicylic acid•Effective when given with INH•Excreatd by tubular secreation in addition to glomerular Absorption, Distribution, and ExcretionsecretionUntoward EffectsOptic neuritisvisual acuity red:green; reversible9/15/200912StreptomycinVery potent against mycobacteriaRecommended when less potentially hazardous th ti t i ff ti t i di t dtherapeutic agents are ineffective or contraindicatedAdded in patients with serious forms of TBieDisseminated meningitisORi.e. Disseminated meningitisPyrazinamide (Important for short term TB treatment)Pyrazinamide Pyrazinoic aciddeamidaseFatty acid synthase geneInhibits synthesis of mycolic acids9/15/200913Absorption, Distribution, and Excretion•Well-absorbed from GI •Diffuses all body fluids including CSF•Eliminated via glomerular filtration (half life > in older)•Eliminated via glomerular filtration (half life > in older)Untoward EffectsLiver injury, inhibits urate excretion, goutanorexia, vomiting etc(NOT d d i t i US)(NOT recommended in pregnant woman in US) QuinolonesGatifloxacin (Tequin)Moxifloxacin (Avelox)For multidrug-resistant TBAminosalicylic acid (similar to sulphonamides)Inhibits DNA gyrase and topoisomerase9/15/200914Linezoid (ZYVOX)Mechanism of action:binds P site of 50S and inhibits protein synthesisUntoward Effects•Myelosuppression including anemia, leukopenia,thrombocytopenia, •Palpitation in patients on adreneric or serotonergic drugs•Peripheral and optic neuropathy•Peripheral and optic neuropathyEthionamide (Trecator-sc)prodrugNADPH-specific FAD monooxygenaseActive drugMechanism of actionFatty acid synthase geneInhibits synthesis ofInhibits synthesis of mycolic acids9/15/200915Absorption, Distribution, and Excretion•Slowly
View Full Document
Unlocking...