ethionamide

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

Ethionamide sulfoxide

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 is 2nd line anti TB drug first isolated from Streptomyces orchidaceus, 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

• Lygase is necessary for attachment of two alanine units

Synthesis

• Readily absorbed after oral administration and is widely distributed including CNS

• It binds to neuronal N-methyl, D-aspaartate receptor and effects the synthesis and metabolism of aminobutyric acid leading to serious CNS effects