Antitubercular Agents : Standard drugs

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Chapter: Medicinal Chemistry : Antitubercular Agents

i. Isoniazid (Continazin, Laniazid, Isonex, Ipcazide, INH, Isokin)) ii. Pyrazinamide iii. Ethambutol HCl (Myambutol) iv. Rifampicin v. Rifabutin vi. Streptomycin sulphate

Antitubercular Agents - Synthesis and Drug Profile

Standard drugs


i. Isoniazid (Continazin, Laniazid, Isonex, Ipcazide, INH, Isokin))


Mode of action: Isoniazid is a prodrug that is activated on the surface of M. tuberculosis by katG enzyme to isonicotinic acid. Isonicotinic acid inhibits the bacterial cell wall mycolic acid, thereby making M. tuberculosis susceptible to reactive oxygen radicals. Isoniazid may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The drug is active against susceptible bacteria only during bacterial cell division.

Metabolism: Isoniazid is extensively metabolized to inactive metabolites. The major metabolite is N-acetyl isoniazid. The enzyme responsible for acetylation is cytosolic N-acetyl transferase. Other metabolites include isonicotinic acid, which is found in the urine as a glycine conjugate and hydrazine. Isonicotinic acid also may result from hydrolysis of acetyl isoniazid, but in this case, the second product of hydrolysis is acetyl hydrazine. Acetyl hydrazine is acetylated by N-acetyl transferase to inactive diacetyl product. It has been suggested that a hydroxylamine intermediate is formed that results in an active acetylating agent.

Properties and uses: Isoniazid exists as white crystalline powder or colourless crystals, soluble in water, and sparingly soluble in alcohol. It is used as an antituberculosis drug.

Assay: Dissolve and dilute the sample with water, add hydrochloric acid, potassium bromide, and methyl red and titrate drop wise with 0.0167 M potassium bromate, shaking continuously, until the red colour disappears.

Dose: For the prophylaxis in case of adults is 5 mg/kg, with a maximum of 300 mg. For children: 10–20 mg/ kg daily. Combination therapy Isoniazid, Rifampin and Pyrazinamide for 2 months followed by Isoniazid (15 mg/kg orally) with. Rifampin (10 mg/kg upto 600 mg per dose) twice/week for 4 months.

Dose: For the prophylaxis in case of adults 5 mg/kg, with a maximum of 300 mg.

Dosage forms: Isoniazid tablets I.P., B.P. Isoniazid injection B.P.


ii. Pyrazinamide


Route I. From: Pyrazine-2, 3-dicarboxylic acid

Route II. From: Pyrazine-2, 3-diamine

Metabolism: The metabolic route constitutes of hydrolysis by hepatic microsomal pyrazinamidase into pyrazinoic acid, which may be then, oxidized by xanthine oxidase to 5-hydroxy pyrazinoic acid. The later compound may appear free either in the urine or as a conjugate with glycine.

Properties and uses: Pyrazinamide is a white crystalline powder, sparingly soluble in water, slightly soluble in alcohol and in methylene chloride. It is a prodrug and is activated by M. tuberculosis amidase enzyme into pyrazine carboxylic acid, which has bactericidal activity. Pyrazinamide has recently been elevated to first-line status in the short-term treatment of tuberculosis regimens because of its tuberculocidal activity and comparatively less short-term toxicity. Pyrazinamide is maximally effective in the low pH environment that exists in macrophages (monocytes). It is used to treat tuberculosis and meningitis. The drug should be used with great caution in patients with hyperuricaemia or gout.

Assay: Dissolve the sample in acetic anhydride and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: Daily administered dose is 20–35 mg/kg in 3–4 equally spaced doses and maximum is 3 g daily.

Dosage forms: Pyrazinamide tablets B.P.


iii. Ethambutol HCl (Myambutol)


Route I. From: 1,2-Dichloroethane

Route II. From: Nitropropane

Metabolism: The majority of the administered ethambutol is excreted unchanged (73%), with not more than 15% appearing in the urine as a metabolite, which are devoid of biological activity.

Mode of action: It is a bacteriostatic drug that inhibits the incorporation of mycolic acid into the mycobacterium cell wall.

Properties and uses: Ethambutol hydrochloride is a white crystalline powder, soluble in water and in alcohol. It is not recommended for use as a single drug, but used in combinations with other antitubercular drugs in the chemotherapy of pulmonary tuberculosis.

Assay: Dissolve and dilute the sample with solution of dilute ammonia, copper sulphate solution, and dilute sodium hydroxide, and measure the angle of optical rotation of the solution at 436 nm.

Dose: The administered dose is 15–25 mg/kg once a day; low doses for new cases, and high doses for use in patients who have had previous antitubercular therapy.

Dosage forms: Ethambutol HCl tablets I.P., Ethambutol tablets B.P.


iv. Rifampicin

Mode of action: It is an antibiotic obtained from Streptomyces mediterranei. Rifampicin inhibits DNA-dependent RNA polymerase of mycobacteria by forming a stable drug enzyme complex, leading to suppression of initiation of chain formation in RNA synthesis and acts as a bactericidal drug.

Metabolism: The major metabolism of rifampicin and rifapentine is deacetylation, which occurs at the C-25 acetate. The resulting products, desacetyl rifampin, and desacetyl rifampentine are still active antibacterial agents. 3-Formylrifamycin has been reported as a second metabolite following both rifampicin and rifampentine administration.

Properties and uses: Rifampicin is a reddish-brown or brownish-red crystalline powder, slightly soluble in water, acetone, alcohol, and soluble in methanol. Rifampicin is the most active agent in clinical use for the treatment of tuberculosis. It 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.

Assay: Dissolve and dilute the sample in methanol. Dilute the solution with phosphate buffer solution pH 7.4 and measure the absorbance at the maxima of 475 nm, using phosphate buffer solution pH 7.4 as blank.

Dosage forms: Rifampicin tablets I.P, Rifampicin capsules I.P, B.P., Rifampicin oral suspension B.P.

v. Rifabutin

It is a semisynthetic rifamycin, structurally similar to rifampicin. It is used against M. avium, one of the most common causes of disseminated infections, with patients suffering with Human Immunodeficiency Virus (HIV). In vitro activity is attributed to rifabutin’s lipophilic nature and its ability to penetrate the cell wall of the organism more effectively than other agents.

Properties and uses: Rifabutin is a reddish-violet amorphous powder, slightly soluble in water and alcohol, soluble in methanol. It is used as an antitubercular drug.

Assay: It is assayed by adopting liquid chromatography technique.


vi. Streptomycin sulphate

Metabolism: The enzymes responsible for inactivation are adenyltransferase, which catalyzes adenylation of the C-3 hydroxyl group in the N-methyl glucosamine moiety to give the O-3-adenylated metabolite and phosphotransferase, which phosphorylates the same C-3 hydroxyl to give O-3 phosphorylated metabolite.

Properties and uses: Streptomycin is a white hygroscopic powder, very soluble in water, and practically insoluble in ethanol. It was the first effective drug for the treatment of tuberculosis. It is most often used in combination with other drugs, such as ethambutol and isoniazid, to treat pulmonary infections in patients with organisms that are known to be resistant. There has been an increasing tendency to reserve streptomycin products for the treatment of tuberculosis.

Assay: It is assayed by adopting microbiological assay method.

Dosage forms: Streptomycin sulphate injection I.P., Streptomycin sulphate tablets I.P., Streptomycin injection B.P.

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