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Thiacetazone And Isoniazid

Thiacetazone and Isoniazid: A Comprehensive Overview of Their Role in Tuberculosis Treatment

Introduction

Tuberculosis (TB) is a highly infectious disease caused by Mycobacterium tuberculosis, primarily affecting the lungs but can involve other organs as well. It is one of the leading causes of death globally, despite being treatable with antibiotics. TB treatment is complex and requires a combination of drugs to achieve successful eradication of the bacteria, prevent drug resistance, and reduce the risk of relapse. Among the various drugs used in TB treatment, isoniazid and thiacetazone are two important medications, particularly in the treatment of multi-drug resistant (MDR) TB and in certain cases of latent tuberculosis infection (LTBI).

Isoniazid

Isoniazid (also known as INH) is one of the cornerstone drugs used in the treatment of active tuberculosis. It was introduced in the 1950s and revolutionized the treatment of TB, greatly reducing mortality rates and leading to the development of highly effective combination therapy regimens. It is considered a first-line agent and is often used in combination with other drugs like rifampicin, pyrazinamide, and ethambutol for the treatment of active TB.

Mechanism of Action

Isoniazid targets the mycolic acid synthesis in the cell wall of Mycobacterium tuberculosis. Mycolic acid is an essential component of the mycobacterial cell wall, providing structural integrity and resistance to environmental stresses. Isoniazid is a prodrug that must first be activated by the bacterial enzyme catalase-peroxidase (KatG). Once activated, isoniazid binds to and inhibits the enzyme InhA, which is responsible for the synthesis of mycolic acid.

By disrupting the cell wall synthesis, isoniazid effectively kills the bacteria or prevents their replication. Isoniazid is bactericidal during the active growth phase of the bacteria, and bacteriostatic during the dormant phase.

Role in TB Treatment

Isoniazid is typically used in combination with other TB drugs for the treatment of both active tuberculosis and latent tuberculosis infection (LTBI). It is a vital part of the first-line treatment regimen for TB and has been included in the World Health Organization’s (WHO) Essential Medicines List.

For active TB, isoniazid is used as part of the standard four-drug regimen, which includes:

  • Isoniazid (INH)

  • Rifampicin (RIF)

  • Pyrazinamide (PZA)

  • Ethambutol (EMB)

This combination helps to attack the bacteria at different stages of its growth cycle, reducing the likelihood of drug resistance.

For latent tuberculosis infection, isoniazid can be used alone for 9 months to reduce the risk of progression to active disease, especially in immunocompromised individuals, such as those with HIV.

Thiacetazone

Thiacetazone is an antituberculosis drug that was once commonly used in combination with isoniazid in TB treatment regimens. It is a synthetic derivative of thiazole and was introduced in the 1960s. However, due to its severe side effect profile and limited efficacy, its use has become more restricted in recent years, particularly in developed countries.

Mechanism of Action

Thiacetazone’s exact mechanism of action is not fully understood, but it is believed to work by inhibiting the synthesis of mycolic acid in the Mycobacterium tuberculosis cell wall, similar to isoniazid. This inhibition disrupts the structural integrity of the bacterial cell wall, ultimately leading to bacterial death. Thiacetazone has bactericidal properties and is effective against both actively dividing and dormant mycobacteria.

Despite its similarity in mechanism to isoniazid, thiacetazone is considered less potent and more toxic. As such, it is not widely used as a first-line therapy anymore, although it may still be used in resource-limited settings or in combination with other second-line drugs for multidrug-resistant TB.

Role in TB Treatment

Historically, thiacetazone was used as part of second-line therapy for TB, especially in cases of drug-resistant tuberculosis. It was often used in combination with isoniazid to increase the chances of successful treatment. However, due to its toxicity profile, including skin reactions, liver toxicity, and hematologic side effects (such as agranulocytosis and anemia), its use has been phased out in many countries.

In some parts of the world where alternative treatment options are limited, thiacetazone is still used as an adjunct to more potent drugs in the treatment of MDR-TB (multidrug-resistant tuberculosis). However, due to the risk of serious side effects, it is often prescribed with caution and under strict medical supervision.

Combination Therapy with Thiacetazone and Isoniazid

Historically, the combination of isoniazid and thiacetazone was used in the treatment of active tuberculosis and latent tuberculosis. The rationale for combining these two drugs was to enhance efficacy by targeting the mycobacterial cell wall at multiple points in the synthesis pathway. While isoniazid directly inhibits mycolic acid production by targeting the InhA enzyme, thiacetazone is thought to inhibit the same pathway, albeit through less well-defined mechanisms.

This combination was commonly used in areas with high rates of tuberculosis, especially in resource-limited settings. However, due to the toxicity and the better efficacy of modern drug regimens, this combination is now largely obsolete.

Side Effects and Toxicity

Isoniazid:

Isoniazid is generally well tolerated but is associated with several side effects, some of which can be severe:

  • Hepatotoxicity: Liver damage is one of the most serious side effects of isoniazid. Patients receiving isoniazid should undergo regular liver function tests, particularly during the first few months of therapy.

  • Peripheral neuropathy: Isoniazid can interfere with vitamin B6 metabolism, leading to peripheral neuropathy (nerve damage). This is more common in malnourished patients and those with alcohol use disorder. Vitamin B6 supplementation can help prevent this side effect.

  • Allergic reactions: Rashes, fever, and drug-induced lupus can occur in rare cases.

  • CNS effects: Some patients may experience symptoms like dizziness, depression, or seizures, especially when taking higher doses.

  • Gastrointestinal symptoms: Nausea, vomiting, and abdominal discomfort can occur.

Thiacetazone:

Thiacetazone is associated with more severe and dangerous side effects:

  • Hepatotoxicity: Like isoniazid, thiacetazone can cause liver toxicity, which can lead to acute liver failure if not detected early.

  • Hematologic toxicity: Thiacetazone has been linked to blood disorders, such as agranulocytosis (severe decrease in white blood cells) and anemia. These conditions can be life-threatening.

  • Skin reactions: Thiacetazone is known to cause severe skin reactions, including exfoliative dermatitis and toxic epidermal necrolysis, which can be fatal.

  • Gastrointestinal issues: Nausea, vomiting, and diarrhea are common side effects.

Due to these severe adverse effects, thiacetazone is generally avoided unless absolutely necessary and is only used under close supervision.

Current Use of Isoniazid and Thiacetazone

While isoniazid remains a cornerstone of TB treatment, the use of thiacetazone has drastically declined due to its toxicity. In most countries, isoniazid is part of the first-line regimen for TB, and thiacetazone is no longer widely prescribed. In multi-drug resistant tuberculosis (MDR-TB), second-line drugs, including fluoroquinolones (such as levofloxacin and moxifloxacin), aminoglycosides (such as amikacin), and linezolid, are preferred over thiacetazone due to their better efficacy and safety profiles. However, thiacetazone may still be used in resource-constrained settings where other treatment options are not available, but this is becoming increasingly rare.

Conclusion

The combination of isoniazid and thiacetazone was once a common strategy for the treatment of tuberculosis, particularly in resource-limited settings. While isoniazid remains a key first-line drug in the treatment of both active and latent TB, thiacetazone has largely fallen out of favor due to its severe side effect profile.