Ethambutol• Due to its efficacy and less adverse effects it is included 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 (hydroxy methyl groups are in front and H is at back) is 16 times more active than the levo form
• It is more active on dividing cells, whereas, low or inactive on non-dividing cells. It inhibits the formation of cell wall.
Mechanism of action• Mechanism of EMB remains unknown though there was mounting evidence that it inhibits synthesis of cell wall• But due to complex structure of the cell wall it was difficult to know the mechanism
Mechanism of action• Peptidoglycan of the cell wall is covered by an envelop of arabinofuranose and galactose (AG) which is covalently attached with peptidoglycan and intercalated network of lipoarabinomannan (LAM). AG portion is highly branched and has distinct segments of galactan and distinct segments of arabinan. Mycolic acid is attached at C5 of the arabinan, usually penultimate unit
• Initially, it was thought that EMB inhibits the synthesis of AG part of the cell wall• Now, it is found that it inhibits arabinosyl transferase that catalyzes the polymerization of D-arabinofuranose leading to the formation of AG and LAM• As a result the accumulation of alpha D- arabinosyl-1 monophosphoryl decaprenol that leads to the over expression of the enzyme results in resistance• Hence, the inhibition of the formation of these complexes increases permeability of the cell wall
Structure activity relationship• OH groups at CH2• Aliphatic chain• NH groups Amino
Structure activity relationship• If OH groups are replaced by OCH3 or OC2H5, the compound remains active, and if replaced by aromatic system (phenyl or pyridine) the compound became inactive• By removing OH groups activity is lost
• Extension of ethane diamine results in loss of activity• Removal of either of the amino groups activity is lost• Increase in size of N-substituent activity is lost
Chemical Synthesis2-amino butanol reacts with 1, 2 dichloro ethane toproduce ethambutol
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 tissues including CNS
Metabolism• 73% of the drug is excreted in urine as unchanged,15% is metabolized into metabolite A and B, both of them are inactive
Therapeutic uses• Used in combination with INH, PZA and Rifampicin• Its action is synergistic with other drugs because it disrupts cell wall and facilitates the penetration of other drugs
• Adverse reactions – Optic neuritis – Red green color blindness – Arthralgia (due to decreased urate excretion) – Vertical nystagmus (movement of eye ball) – Milk skin reaction
Para-aminosalisylic acid• It is a synthetic 2nd line agent, used in case of resistance, re-treatment and intolerance to first line therapy, used in treatment of Tuberculosis• It is used in combination with streptomycin and INH and in long term treatment (6-9 months) causes toxic effects on GIT and shows allergic reactions
• GIT: nausea, vomiting, diarrhoea, abdominal pain, un-dissolved granule coatings in stools• Allergic reaction: difficulty in breathing, closing of throat and swelling of lips, tongue or face
• For maximum activity COOH and NH2 groups should 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 Cl or alkyl activity is reduced• COOH if converted into amide or ester compound became less active
Mechanism of action• It acts as an anti-metabolite interfering with incorporation of PABA into folic acid• It is a structural analogue of PABA, hence inhibits the synthesis of folates in MT• MT can distinguish between PABA and sulfonamides but not between PABA and PASA• When co-administered with INH, prevents the acetylation of INH, being a substrate, results in increase in INH concentration in plasma
Mechanism of action continued• There are two mechanisms responsible for bacteriostatic action against Mycobacterium tuberculosis. – 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.
Metabolism• It is extensively acetylated at amino group• It is conjugated with glucuronic acid and glycine at the carboxylic group
• Step 1 2-amino benzoic acid (anthranilic acid) undergoes nitration to produce 2-amino, 4-nitro benzoic acid• Step 2 Diazotization• Step 3 Diazonium salt undergoes hydrolysis to produce p-nitro salicylic acid• Step 4 reduction of nitro group to amino group
Ethionamide• A 2nd line anti TB agent, analogue of isonicotinamide but it is di-substituted and contains S in place of O• It contains ethyl group at position 2
• In vitro it is less active but in vivo more active because of increased lipocity due to C2H5• Mechanism of action is similar to INH• Its active metabolite is ethionamide sulfoxide
Mechanism of action• Ethionamide upon oxidation with catalase- peroxidase is converted to an active acylating agent, ethionamide sulfoxide, which inturn inactivate inhA enoyal reductase. It acylates cystine No. 243 in inhA protein
Mechanism of action Ethionamide sulfoxideEthionamide
Metabolism• Less than 1% of the drug is excreted unchanged in urine. Rest of the drug is excreted as one of the following metabolites, which are given as follows:
Cycloserine• Analogue of amino acid serine and it exists in cyclic form- a five member ring containing O and N at an adjacent positions• Also called Isoxazolidine or oxazolidine• Obtained naturally as d-isomer• Contains Keto group at position 3 and NH2 at position 4, which is in front• d-isomer is more active
• It was first isolated from Streptomyces orchidaceous, but now being synthesized in laboratory• It causes CNS toxicity• Bacteria become resistant after sometime• It acts on cell wall of bacteria and is not selective against MT because all bacteria contain peptidoglycan
• It acts on normal peptidoglycan portion of cell wall rather than acting on outer layer of mycolic acid• It inhibits alanine resemase and alanine ligase• Alanine resemase converts L-isomer of alanine to d-isomer. Because only d-form can be incorporated into cell wall. Alanine is present in levo form, hence need to be converted to d- form• alanine ligase is necessary for attachment of two alanine units
• Readily absorbed after oral administration and is widely distributed including CNS• It binds to neuronal N-methyl, d-aspartate receptor and effects the synthesis and metabolism of aminobutyric acid leading to serious CNS effects
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