Antitubercular Agents
Made by
Anjali Jain, SGSITS, Indore
Ethambutol- 1-Butanol, 2, 2′-(1, 2-ethanediyldiamino) bis-,
dihydrochloride, [S–(R* , R* )] ; Ethambutol Hydrochloride
• Act specifically upon the proliferating cells, evidently by
causing interference with the synthesis of RNA, help in
clearing the sputum of myobacteria within a span of three
months in most of the subjects.
• Bacterial resistance usually takes place in nearly 35% of cases,
and relapses occur frequently. Certainly the combination with
either ioniazid or other prevalent tuberculostatic drugs, the
incidence of relapses occur seldomly
Isoniazid- 4-Pyridinecarboxylic acid, hydrazide
Isoniazid inhibits the synthesis of mycotic acids. It has been observed
critically that a mycobacterial-catalase-peroxidase enzyme complex is
necessarily required for the bioactivation of isoniazid.
Consequently, a reactive species, usually produced via the action of
these enzymes on the drug is supposed invariably to attack a very
specific enzyme needed urgently for carrying out the mycolic acid
synthesis in mycobacteria.
The observed resistance to INH, believed to vary between 25—50% of
the ‘clinical isolate’ of the INHresistant strains, is intimately associated
with the apparent loss of catalase and peroxidase activities, both of
which are legitimately encoded by a single gene, kat G.
• Recently, the actual predicted target for the action of INH has been
duly recognized and identified as an enzyme which catalyze the
NADH-nicotinamide adenine dinucleotide (NAD) +
hydrogen, specific reduction of 2-trans-enolyacyl carrier protein,
which is otherwise proved to be an essential step in the fatty acid
elongation i.e., lengthening the carbon-chain ; and subsequently the
aforesaid ‘enzyme’ is encoded adequately by a very specific gene,
inh A, present in M. tuberculosis.
• It is prepared by first carrying out the oxidation of 4-methylpyridine to
obtain isonicotinic acid which upon heating with anhydrous hydrazine
yields the desired compound.
Ethionamide- 4-Pyridinecarbothioamide
SAR of Ethionamide :
The two structural modifications to the corresponding INH-series, namely :
(a) isosteric replacement of the carbonyl C=O function in INH with C=S ;
and (b) 2-ethyl substitution, increases antituberculostatic activity in the
thioisonicotinamide series to a considerable extent.
• Pyrazinamide- Heterocyclic analogs of nicotinic acid, with which it is
isosteric. It has recently been elevated to first-line status in short-
term tuberculosis treatment regimens because of its tuberculocidal
activity and comparatively low short-term toxicity. As its not active
against metabolically inactive tubercle bacilli, it is not considered
suitable for long-term therapy.
• Potential hepatotoxicity also obviates long-term use of the drug.
Pyrazinamide is maximally effective in the low pH environment that
exists in macrophages (monocytes). Evidence suggests bioactivation
of pyrazinamide to pyrazinoic acid by an amidase present in
mycobacteria.
• Because bacterial resistance to pyrazinamide develops rapidly,
it should always be used in combination with other drugs.
Cross-resistance between pyrazinamide and either isoniazid or
ethionamide is relatively rare.
• The mechanism of action of pyrazinamide is not known.
Despite its structural similarities to isoniazid and ethionamide,
pyrazinamide apparently does not inhibit mycolic acid
biosynthesis in mycobacteria.
Sodium 4-aminosalicylate (sodium PAS), a salt, occurs in the dihydrate
form as a yellow-white powder or crystalline solid. Two pH-dependent
types of reactions occur: decarboxylation (more rapid at low pH) and
oxidation (more rapid at high pH). Therefore, solutions should be
prepared within 24 hours of administration.
Cycloserine
D-(+)-4-Amino-3-isoxazolidinone (Seromycin) is an antibiotic that has been
isolated from the fermentation beer of three different
Streptomycesspecies: S. orchidaceus, S. garyphalus, and S. lavendulus
Rifabutin-
• The spiroimidazopiperidyl derivative.
• This rifamycin derivative is not effective, however, as monotherapy
for existing disseminated MAC diseases.
• Rifabutin is a very lipophilic compound with a high affinity for
tissues. The 25- O-desacetyl and 31-hydroxy metabolites of rifabutin
have been identified.
•
Capreomycin-
second-line agent used in combination with other antitubercular drugs.
In particular, it may be used in place of streptomycin when either the
patient is sensitive to, or the strain of M. tuberculosis is resistant to,
streptomycin.
Refampicin-
4-0-[2-(diethylamino)-2-oxoethyl]-
• A dosage of as little as 5 g/mL is effective against sensitive
strains of M. tuberculosis. Rifampin is also highly active against
staphylococci and Neisseria, Haemophilus, Legionella, and
Chlamydia spp. Gram-negative bacilli are much less sensitive
resistance to rifampin develops rapidly in most species of
bacteria, including the tubercle bacillus.
• Consequently, rifampin is used only in combination with other
antitubercular drugs, and it is ordinarily not recommended for
the treatment of other bacterial infections when alternative
antibacterial agents are available.
Streptomycin in Aminoglycosides
