ISOPAS 500 MG TABLET

Indications

• Tuberculosis, in combination with other drugs for the treatment of active tuberculosis
• Treatment of latent tuberculosis infection

Dosage

Children: Children (body-weight up to 50 kg): 50 mg

Adults: Adults (body-weight up to 50 kg): 2 g 3 times a week for 2 months (initial phase). Adults (body-weight 50 kg and above): 2.5 g 3 times a week for 2 months (initial phase).

Mechanism of action

Pyrazinamide diffuses into Mycobacterium tuberculosis where it is converted by the pyrazinamidase enzyme to its active form, pyrazinoic acid. This active form accumulates intracellularly, especially at acidic pH, which is characteristic of the environment in which the bacteria reside. Pyrazinoic acid inhibits fatty acid synthase (FAS) I, disrupting the synthesis of fatty acids necessary for the bacterium's growth and replication. Additionally, pyrazinoic acid may interfere with the bacterial membrane potential and energy production, further inhibiting the survival of M. tuberculosis.

Pharmacodynamics

Pyrazinamide exhibits bactericidal activity against Mycobacterium tuberculosis, effectively killing or inhibiting the growth of the bacteria responsible for tuberculosis. Its efficacy is enhanced in slightly acidic conditions, where it exerts its maximum effect. This drug is specific to M. tuberculosis and is typically utilized in combination with other antitubercular medications to ensure a comprehensive treatment approach.

Pharmacokinetics

Pyrazinamide is well absorbed when administered orally, with peak plasma concentrations reached within 1 to 2 hours after ingestion. It has a half-life of approximately 9 to 10 hours, allowing for convenient dosing schedules. The drug is metabolized primarily in the liver and is excreted through the kidneys, necessitating monitoring of hepatic function and renal function in patients receiving treatment.

Contra-indications

• Acute attack of gout in adults

Adverse effects

• Hepatotoxicity
• Gout
• Nausea
• Vomiting
• Fever
• Malaise
• Jaundice

Interactions

• Allopurinol: Unknown (increases risk of hyperuricaemia)

Precautions

• Hepatic disorders
• Diabetes
• Gout
• Renal impairment

Pregnancy

Manufacturer advises use only if potential benefits outweigh risks.

Breast-feeding

Amount too small to be harmful.

Storage

Store in a cool, dry place away from direct light.

Formulations

• 500 mg tablets
• Oral suspension
• Oral solution

Mechanism of action

Pyrazinamide diffuses into active _M. tuberculosis_ that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids. However, this theory was thought to have been discounted. However, further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I. It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Pyrazinoic acid has also been shown to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation. This may explain the ability of the drug to kill dormant mycobacteria. Pyrazinamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of the infection and the susceptibility of the infecting organism. In vitro and in vivo, the drug is active only at a slightly acidic pH. The exact mechanism of action of pyrazinamide has not been fully elucidated. The antimycobacterial activity of pyrazinamide appears to partly depend on conversion of the drug to pyrazinoic acid. Susceptible strains of Mycobacterium tuberculosis produce pyrazinamidase, an enzyme that deaminates pyrazinamide to pyrazinoic acid, and the in vitro susceptibility of a given strain of the organism appears to correspond to its pyrazinamidase activity. In vitro studies indicate that pyrazinoic acid has specific antimycobacterial activity against Mycobacterium tuberculosis. In addition, the fact that pyrazinoic acid lowers the pH of the environment below that which is necessary for growth of Mycobacterium tuberculosis appears to contribute to the drug's antimycobacterial activity in vitro. Unknown; pyrazinamide may be bacteriostatic or bactericidal, depending on its concentration and the susceptibility of the organism. It is active in vitro at an acidic pH of 5.6 or less, similar to that found in early, active tubercular inflammatory lesions.

Pharmacodynamics

Pyrazinamide kills or stops the growth of certain bacteria that cause tuberculosis (TB). It is used with other drugs to treat tuberculosis. It is a highly specific agent and is active only against <i>Mycobacterium tuberculosis</i>. In vitro and in vivo, the drug is active only at a slightly acid pH. Pyrazinamie gets activated to Pyrazinoic acid in the bacilli where it interferes with fatty acid synthase FAS I. This interferes with the bacteriums ability to synthesize new fatty acids, required for growth and replication.