1.Ethambutol Due to its efficacy and less adverse effects it isincluded in first-line therapy of Tuberculosis It has synergistic action with other anti-Tb drugs It contains 2 asymmetric carbon atoms It is stereo-specific and d-ethambutol (hydroxymethyl groups are in front and H is at back) is 16times more active than the levo form

2. It is more active on dividing cells, whereas, low orinactive on non-dividing cells. It inhibits theformation of cell wall. 3. Ethambutol: Chemistry EthaneButanolAmino 4. Mechanism of action Mechanism of EMB remains unknown thoughthere was mounting evidence that it inhibitssynthesis of cell wall But due to complex structure of the cell wallit was difficult to know the mechanism 5. Mechanism of action Peptidoglycan of the cell wall is covered by anenvelop of arabinofuranose and galactose(AG) which is covalently attached withpeptidoglycan and intercalated network oflipoarabinomannan (LAM). AG portion ishighly branched and has distinct segments ofgalactan and distinct segments of arabinan.Mycolic acid is attached at C5 of the arabinan,usually penultimate unit 6. Initially, it was thought that EMB inhibits thesynthesis of AG part of the cell wall Now, it is found that it inhibits arabinosyltransferase that catalyzes the polymerizationof D-arabinofuranose leading to the formationof AG and LAM As a result the accumulation of alpha D-arabinosyl-1 monophosphoryl decaprenol thatleads to the over expression of the enzymeresults in resistance Hence, the inhibition of the formation of thesecomplexes increases permeability of the cellwall 7. Structure activity relationship OH groups at CH2 Aliphatic chain NH groupsAmino 8. Structure activity relationship If OH groups are replaced by OCH3 or OC2H5, thecompound remains active, and if replaced byaromatic system (phenyl or pyridine) thecompound became inactive By removing OH groups activity is lost 9. Extension of ethane diamine results in loss ofactivity Removal of either of the amino groups activityis lost Increase in size of N-substituent activity is lost 10. Chemical Synthesis2-amino butanol reacts with 1, 2 dichloro ethane toproduce ethambutol 11. Antibacterial spectrum Bacteriostatic Specific for most of the strains like MT and M.kansasii Absorption Well absorbed after oral absorption Distribution Well distributed in all body fluids and tissuesincluding CNS 12. Metabolism 73% of the drug is excreted in urine asunchanged,15% is metabolized into metaboliteA and B, both of them are inactive 13. Therapeutic uses Used in combination with INH, PZA andRifampicin Its action is synergistic with other drugsbecause it disrupts cell wall and facilitates thepenetration of other drugs 14. Adverse reactions Optic neuritis Red green color blindness Arthralgia (due to decreased urate excretion) Vertical nystagmus (movement of eye ball) Milk skin reaction 15. Para-aminosalisylic acid It is a synthetic 2nd line agent, used in caseof resistance, re-treatment andintolerance to first line therapy, used intreatment of Tuberculosis It is used in combination withstreptomycin and INH and in long termtreatment (6-9 months) causes toxiceffects on GIT and showsallergic reactions 16. GIT: nausea, vomiting, diarrhoea, abdominalpain, un-dissolved granule coatings in stools Allergic reaction: difficulty in breathing,closing of throat and swelling of lips, tongueor face 17. For maximum activity COOH and NH2 groupsshould be at para-position to each other OH group may be at ortho or meta position,but max activity when at ortho NH2 group if replaced with Clor alkyl activity is reduced COOH if converted into amide orester compound became less active 18. Mechanism of action It acts as an anti-metabolite interfering withincorporation of PABA into folic acid It is a structural analogue of PABA, hence inhibitsthe synthesis of folates in MT MT can distinguish between PABA andsulfonamides but not between PABA and PASA When co-administered with INH, prevents theacetylation of INH, being a substrate, results inincrease in INH concentration in plasma 19. Mechanism of action continued There are two mechanisms responsible forbacteriostatic action against Mycobacteriumtuberculosis. Firstly, p-aminosalicylic acid inhibits folic acid synthesis. It binds to pteridine synthetase with greater affinity than PABA, effectively inhibiting the synthesis of folic acid. Secondly, p-aminosalicylic acid may inhibit the synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis. 20. Metabolism It is extensively acetylated at amino group It is conjugated with glucuronic acid andglycine at the carboxylic group 21. Synthesis 22. Step 12-amino benzoic acid (anthranilic acid)undergoes nitration to produce 2-amino, 4-nitrobenzoic acid Step 2Diazotization Step 3Diazonium salt undergoes hydrolysis to producep-nitro salicylic acid Step 4reduction of nitro group to amino group 23. 2-amino benzoic acid Synthesis 2-amino, 4-nitro benzoic acidp-nitro salicylic acid 24. Ethionamide A 2nd line anti TB agent, analogue ofisonicotinamide but it is di-substitutedand contains S in place of O It contains ethyl group at position 2 25. In vitro it is less active but in vivo more activebecause of increased lipocity due to C2H5 Mechanism of action is similar to INH Its active metabolite is ethionamide sulfoxide 26. Mechanism of action Ethionamide upon oxidation with catalase-peroxidase is converted to an active acylatingagent, ethionamide sulfoxide, which inturninactivate inhA enoyal reductase. It acylatescystine No. 243 in inhA protein 27. Mechanism of actionEthionamide sulfoxideEthionamide 28. Metabolism Less than 1% of the drug is excreted unchangedin urine. Rest of the drug is excreted as one of thefollowing metabolites, which are given as follows: 29. Cycloserine Analogue of amino acid serineand it exists in cyclic form- a fivemember ring containing O and N atan adjacent positions Also called Isoxazolidine or oxazolidine Obtained naturally as d-isomer Contains Keto group at position 3 and NH2 atposition 4, which is in front d-isomer is more active 30. It was first isolated from Streptomycesorchidaceous, but now being synthesized inlaboratory It causes CNS toxicity Bacteria become resistant after sometime It acts on cell wall of bacteria and is notselective against MT because all bacteriacontain peptidoglycan 31. It acts on normal peptidoglycan portion of cellwall rather than acting on outer layer ofmycolic acid It inhibits alanine resemase and alanine ligase Alanine resemase converts L-isomer of alanineto d-isomer. Because only d-form can beincorporated into cell wall. Alanine is presentin levo form, hence need to be converted to d-form alanine ligase is necessary for attachment oftwo alanine units 32. Synthesis 33. Readily absorbed after oral administration andis widely distributed including CNS It binds to neuronal N-methyl, d-aspartatereceptor and effects the synthesis andmetabolism of aminobutyric acid leading toserious CNS effects