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Isoniazid

Isoniazid: A Comprehensive Overview

Introduction

Isoniazid (INH), a powerful antitubercular agent, has been a cornerstone in the treatment of tuberculosis (TB) for over 60 years. Its discovery in the 1950s marked a significant milestone in the fight against one of the world's deadliest infectious diseases. Although primarily used for tuberculosis, Isoniazid also has a role in the treatment of latent TB infections and as a prophylactic agent in high-risk populations.

Isoniazid

Isoniazid is a synthetic antimicrobial agent that belongs to the class of drugs known as anti-tuberculosis drugs (anti-TB drugs). It is a bactericidal drug that targets the Mycobacterium tuberculosis bacterium, the pathogen responsible for tuberculosis. Isoniazid is used both to treat active TB and to prevent the development of TB in individuals with latent tuberculosis infection (LTBI).

Isoniazid is typically administered orally, but it can also be given via intramuscular or intravenous routes. When combined with other anti-TB medications, Isoniazid forms part of a multidrug regimen that is highly effective in treating both drug-susceptible and drug-resistant TB strains.

History of Isoniazid

Isoniazid was discovered in the 1950s by Selman Waksman, a researcher who was also responsible for the discovery of streptomycin, the first antibiotic used to treat TB. In 1952, after conducting extensive research into new drugs for tuberculosis, Waksman and his colleagues isolated Isoniazid, which was found to have strong bactericidal properties against Mycobacterium tuberculosis. The drug was initially tested on animals and later in humans, with successful results. In 1953, Isoniazid was approved for use as a treatment for TB. Since its approval, Isoniazid has become a first-line treatment for tuberculosis and has played a significant role in reducing TB-related morbidity and mortality globally. The widespread use of Isoniazid, in combination with other drugs, has been instrumental in controlling the spread of tuberculosis worldwide.

Mechanism of Action

The mechanism of action of Isoniazid is bactericidal, meaning it kills bacteria rather than simply inhibiting their growth. It is highly selective for the Mycobacterium tuberculosis bacterium due to its ability to interfere with the synthesis of the bacterial cell wall.

  1. Inhibition of Mycolic Acid Synthesis: Isoniazid targets the mycolic acid biosynthesis pathway, which is crucial for the formation of the bacterial cell wall in Mycobacterium tuberculosis. Mycolic acids are long-chain fatty acids that make up a significant portion of the cell wall in mycobacteria, contributing to their characteristic acid-fastness (a property that allows them to retain certain dyes even after being exposed to acidic conditions).

    Isoniazid is converted to its active form within the bacterium by the enzyme KatG, a catalase-peroxidase enzyme. The active form of Isoniazid inhibits the enzyme InhA, which is involved in the synthesis of mycolic acid. By blocking this enzyme, Isoniazid effectively prevents the production of mycolic acids, disrupting the bacterial cell wall and leading to the death of the bacterium.

  2. Bactericidal Activity: As a bactericidal agent, Isoniazid kills actively growing Mycobacterium tuberculosis cells, which is particularly important in the treatment of active TB infections. The drug is most effective against rapidly dividing bacteria but can also have some activity against dormant or slow-growing mycobacteria in latent infections.

  3. Synergistic Effect with Other Anti-TB Drugs: Isoniazid is often used in combination with other anti-TB agents, such as rifampin, pyrazinamide, and ethambutol, to prevent the development of drug resistance and to ensure a higher probability of successfully eradicating the infection.

Clinical Uses of Isoniazid

Isoniazid is primarily used in the treatment and prevention of tuberculosis. Its clinical applications are as follows:

1. Active Tuberculosis Treatment

Isoniazid is a first-line drug used in the treatment of active tuberculosis. It is typically prescribed as part of a combination therapy that includes other anti-TB agents like rifampin, pyrazinamide, and ethambutol. The combination therapy is essential for preventing the development of drug-resistant strains of tuberculosis. A typical regimen for treating active TB involves a 6-month course of therapy, with Isoniazid being taken for the entire duration. The treatment regimen is as follows:

  • Intensive phase: The first two months of treatment usually involve the use of four drugs (Isoniazid, Rifampin, Pyrazinamide, and Ethambutol).

  • Continuation phase: After the intensive phase, Isoniazid and Rifampin are continued for an additional four months.

This combination therapy significantly reduces the risk of treatment failure and relapse and ensures that the infection is eradicated effectively.

2. Latent Tuberculosis Infection (LTBI)

Isoniazid is also used to prevent the development of active TB in individuals with latent tuberculosis infection (LTBI). Latent TB occurs when a person is infected with Mycobacterium tuberculosis, but the bacteria are inactive and not causing any symptoms. However, without treatment, latent TB can progress to active TB, especially in individuals with compromised immune systems.

For individuals with LTBI, Isoniazid is usually prescribed for a duration of 6 to 9 months. This treatment reduces the risk of developing active TB by killing the dormant bacteria. Isoniazid prophylaxis is particularly important for individuals at high risk of progression to active TB, such as those with HIV, close contacts of active TB cases, and individuals who have received organ transplants.

3. TB Prevention in High-Risk Populations

Isoniazid is also used to prevent tuberculosis in high-risk populations. This includes people with compromised immune systems, such as individuals living with HIV/AIDS, people who have undergone organ transplants, and those with silicosis or other conditions that weaken the immune system. In these groups, the risk of progression from latent TB to active TB is higher, and Isoniazid treatment can help prevent this progression.

Pharmacokinetics of Isoniazid

The pharmacokinetics of Isoniazid involves the processes of absorption, distribution, metabolism, and elimination:

1. Absorption

Isoniazid is well absorbed from the gastrointestinal (GI) tract following oral administration, with peak plasma concentrations typically occurring within 1-2 hours. The drug is almost completely absorbed, with about 75% to 95% of the dose being bioavailable.

2. Distribution

Isoniazid is widely distributed throughout the body, including in the lungs, liver, kidneys, and central nervous system (CNS). It can cross the blood-brain barrier, making it effective against meningeal tuberculosis. The volume of distribution is about 0.6 L/kg.

3. Metabolism

Isoniazid is primarily metabolized in the liver via acetylation. The rate of metabolism varies among individuals and is genetically determined, with some individuals being classified as fast acetylators and others as slow acetylators. The slow acetylators have a higher concentration of the drug in their bloodstream, which can increase the risk of toxicity, particularly hepatotoxicity.

4. Elimination

The drug is eliminated via the kidneys, with about 75% of the drug being excreted unchanged in the urine. The half-life of Isoniazid is around 1-4 hours, depending on individual metabolism.

Side Effects and Toxicity

Isoniazid is generally well tolerated, but it can cause a range of side effects, some of which can be serious. The most common side effects of Isoniazid include:

1. Hepatotoxicity

The most significant adverse effect of Isoniazid is hepatotoxicity. Liver damage can range from mild enzyme elevation to acute liver failure. Regular liver function tests (LFTs) are recommended during treatment, especially for those with preexisting liver disease or those who are older. Symptoms of liver damage include jaundice, nausea, vomiting, and dark urine.

2. Peripheral Neuropathy

Isoniazid can cause peripheral neuropathy (nerve damage), particularly in individuals with a deficiency in vitamin B6 (pyridoxine). Symptoms include numbness, tingling, and weakness in the hands and feet. Supplementing with vitamin B6 can help prevent this side effect.

3. Rash

A common side effect is rash, which can range from mild to severe. In rare cases, the rash may be indicative of an allergic reaction, such as Stevens-Johnson syndrome, a severe skin reaction.

4. Drug Interactions

Isoniazid can interact with several other medications, including phenytoin (an anticonvulsant), warfarin (an anticoagulant), and certain antiretrovirals. These interactions can alter the metabolism of these drugs, leading to either increased toxicity or decreased efficacy.

5. Other Effects

Less common side effects include gastrointestinal upset, fever, elevated liver enzymes, and hemolysis in individuals with G6PD deficiency.

Conclusion

Isoniazid remains one of the most effective and widely used drugs for the treatment and prevention of tuberculosis. Its discovery revolutionized TB treatment and continues to play a critical role in both active TB therapy and the prevention of latent TB from progressing to active disease. While Isoniazid is highly effective, careful monitoring is required to manage potential side effects, particularly liver toxicity and peripheral neuropathy. Its continued use as part of combination therapy has been instrumental in the global fight against tuberculosis, and ongoing research may further refine its role in TB management.