Anti-TB Lecture Notes PDF

Anti-TB & Antileprotic agents  Antimycobacterial agents  Mycobacteria are a genus of acid-fast bacilli belonging to the mycobactereiaceae, which include the organisms responsible for tuberculosis (T.B) and leprosy.  The c...

Anti-TB & Antileprotic agents  Antimycobacterial agents  Mycobacteria are a genus of acid-fast bacilli belonging to the mycobactereiaceae, which include the organisms responsible for tuberculosis (T.B) and leprosy.  The cell envelope of mycobacteria is believed to be responsible for some special characters for these organisms such as pathogenicity, virulence, multiple drug resistance, cell permeability. O NHNH2 Ist Line Treatment of Tuberculosis 1-Isoniazide (Isonicotinic acid hydrazide, INH) N  Ist Line Treatment of Tuberculosis O NHNH2 1-Isoniazide (Isonicotinic acid hydrazide, INH) N  Isoniazide is a useful synthetic bactericidal agent against M. tuberculosis.  It was introduced in the 1950s.  Its action is bactericidal against replicating organisms and appears to be only bacteriostatic at best against semi-dormant and dormant populations. MOA of INH  Recently, It is generally recognized that INH is a prodrug,  It is activated by oxidation reaction.  converting INH into a reactive species capable of acylating an enzyme system found exclusively in the M. tuberculosis. SAR  Substitution of benzene or thiazole ring for the pyridine nucleus destroys activity  The γ-position is the position of choice for the hydrazide moiety.  Acylation with carbonyl compounds diminishes activity.  Substitution on N2 resulted in active compounds (R1 and R2 = alky; R3 = H).  Substitution on N1 with alkyl groups destroyed activity (R1 & R2 = H, R3 = alkyl). Synthesis O OMe O NHNH2 N2H4 H2O N N Metabolism  Acetylhydrazine serves as a substrate for CYP450 resulting in the formation of reactive intermediates, which is capable of acetylating liver proteins resulting in the liver necrosis.  Slow acetylators : neuritis but rapid acetylators: hepatitis 5 ylated metabolite of INH: H causes injury to nervous system and cause hepatitis 2-Rifamycin Antibiotics, causes Red urine produced by streptomyces mediterranei. -Rifampin (causes hepatotoxicity and turns body secretions to orange) -The rifamycins inhibit bacterial DNA-dependent RNA polymerase (DDRP) by binding to the Beta-subunit of the enzyme 7 3-Ethambutol (ETB(R)), Causes Eye defect (+) N,N-bis-(1-hydroxy-2-butyl)ethylenediamine  The dextro isomer is 12 times more active than the meso isomer and 200-500 times more active than the levo isomer Replacement of the two OH groups with –OC6H5, O-Pyridyl, -SH, -SOCH3, and NH2, NHR leads to inactive derivatives of ethambutol  while in contrast -OCH3 and –OC2H5 mono or di-analogues are as active as ethambutol.  S.E.: optic neuritis, cannot distinguish bet. Green and blue. So pyridoxine is  Second line Agents 1-Ethionamide NH 2 S C N C 2H 5 2-Ethylthioisonicotinamide 2-Paraminosalicylic Acid (PASA) COOH OH NH 2 Synthesis 3-Cycloserine  Inhibit two key enzymes: D-alanine racemase & D- alanine ligase.  D-alanine is important component in peptidoglycan portion in mycobacterial cell W D-alanine racemase: converts L-alanine into D-alanine D-alanine ligase: couple 2 D-alanine to form D-alanine-D-alanine complex  This complex is incorporated into the peptidoglycan of the mycob.cell wall.  Cycloserine is a rigid analogue to D-alanine. D-alanine  used mainly in treatment of pulmonary tuberculosis.  Pyrazinamide is a medication used to treat tuberculosis.For active tuberculosis it is often used together with rifampin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis.It is taken by mouth. Antimycobacterial Agents 12  N.B. Streptomycin causes teratogenicity in addition to ototoxicity, nephrotoxicity and.neuromuscular blockage For latent tuberculosis, the standard treatment is six to nine months of daily isoniazid alone or three months of weekly (12 doses total) of isoniazid/rifampin combination Antimycobacterial Agents 13 Enzyme inducers Enzyme Inhibitors GPRS cell phone Vitamin K cannot cause enzyme inhibition G: griseofulvin Vitamin : valproate P: phenytoin K: Ketoconazole R: rifampicin cannot: cimetidine S: smoking cause: ciprofloxacin Cell : carbamazepine enzyme: erythromycin Phone: phenobarbitone inhibition: Isoniazid (INH) A women suffering from T.B. Infection and taking Rifampicin, otherwise she is taking contraceptive but she became ???pregnant Antimycobacterial Agents 14  Rifampin : Once a month and supervised Dapsone : Daily and self administered Clofazimine : 300 mg Once a month and supervised 50 mg daily and self administered Antimycobacterial Agents 15  S N I P The contraindicated drugs for patients suffering from Glucose-6-phosphate dehydrogenase Otherwise they will develop dark urine in one day after.administration S: Sulfa drugs, dapsone, Septran (Trimethoprim/sulfamethoxazole also known as co- trimoxazole). N : nitrofurantoin, nalidixic acid I : Enzyme inducers P: primaquine, chloroquine Antimycobacterial Agents 16