Tuberculosis (TB) remains a significant global health challenge, affecting millions annually. The cornerstone of TB treatment involves a combination of antitubercular drugs, with isoniazid being one of the most essential components. This article explain mechanism of action, pharmacokinetics, therapeutic uses, and potential side effects of isoniazid to provide a comprehensive understanding for medical professionals.
What is Isoniazid?
Isoniazid (INH) is a first-line antitubercular medication widely used to treat and prevent TB. It was discovered in the early 1950s and has since been a critical component of the standard TB treatment regimen due to its potent bactericidal activity against Mycobacterium tuberculosis.
Mechanism of Action
Isoniazid’s efficacy stems from its ability to target the synthesis of mycolic acids, essential components of the mycobacterial cell wall. Here is how it works
- Activation by KatG Enzyme:- Isoniazid is a prodrug activated by the catalase-peroxidase enzyme KatG, present in M. tuberculosis.
- Formation of Reactive Intermediates:- Activation leads to the formation of reactive intermediates, which subsequently interact with nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).
- Inhibition of Mycolic Acid Synthesis:- The resulting compounds inhibit the enzyme InhA, critical for mycolic acid synthesis. This disruption compromises the integrity of the bacterial cell wall, leading to cell death.
The bactericidal activity of isoniazid is most pronounced against actively dividing bacteria, making it particularly effective during the early stages of TB treatment.
Pharmacokinetics
Understanding isoniazid’s pharmacokinetics is crucial for optimizing its therapeutic effects and minimizing adverse reactions
- Absorption:- Isoniazid is well-absorbed orally, with peak plasma concentrations reached within 1-2 hours.
- Distribution:- It is widely distributed in body tissues and fluids, including cerebrospinal fluid (CSF), making it effective against both pulmonary and extrapulmonary TB.
- Metabolism:- The drug is primarily metabolized in the liver through acetylation by N-acetyltransferase (NAT2). The rate of acetylation varies among individuals, classifying them as either slow or fast acetylators.
- Excretion:- Isoniazid and its metabolites are excreted via the kidneys, with a half-life ranging from 1 to 4 hours, depending on the acetylator status.
Therapeutic Uses
Isoniazid is a cornerstone in TB management, used in the following contexts
- Active TB Treatment: Isoniazid is part of the standard combination therapy, typically administered alongside rifampin, pyrazinamide, and ethambutol during the intensive phase of TB treatment.
- Latent TB Infection (LTBI): Isoniazid monotherapy for 6-9 months is a common strategy for preventing the progression of latent TB to active disease, especially in high-risk individuals such as those with HIV or close contacts of TB patients.
Dosage and Administration
- Adults: The standard dose is 5 mg/kg daily, with a maximum of 300 mg per day. For intermittent therapy, 15 mg/kg (up to 900 mg) is administered twice or thrice weekly.
- Pediatrics: The dose is 10-15 mg/kg daily, with a maximum of 300 mg per day.
It is essential to co-administer vitamin B6 (pyridoxine) to prevent neurotoxic side effects, especially in malnourished patients or those at risk of neuropathy.
Side Effects
Despite its efficacy, isoniazid is associated with various side effects that require careful monitoring and management
- Hepatotoxicity
- Incidence:- Hepatotoxicity is the most serious adverse effect, ranging from asymptomatic elevation of liver enzymes to severe hepatitis.
- Risk Factors:- Advanced age, alcohol use, pre-existing liver disease, and concurrent use of hepatotoxic drugs increase the risk.
- Monitoring:- Regular liver function tests (LFTs) are recommended, especially in high-risk patients.
- Peripheral Neuropathy
- Mechanism:- Isoniazid-induced depletion of pyridoxine (vitamin B6) interferes with nerve function.
- Presentation:- Patients may experience tingling, numbness, or burning sensations in the extremities.
- Prevention:- Co-administration of pyridoxine (10-50 mg daily) effectively reduces this risk.
- Central Nervous System Effects
- These include dizziness, seizures, and psychosis, particularly in overdose scenarios.
- Hypersensitivity Reactions
- Rash, fever, and eosinophilia are possible but less common.
- Gastrointestinal Symptoms
- Nausea, vomiting, and abdominal discomfort may occur.
- Other Effects
- Rare side effects include lupus-like syndrome, anemia, and optic neuritis.
Drug Interactions
Isoniazid interacts with several medications, necessitating caution
- Enzyme Inhibition:- Isoniazid inhibits cytochrome P450 enzymes, potentially increasing the levels of drugs like phenytoin, carbamazepine, and warfarin.
- Alcohol:- Concurrent alcohol consumption exacerbates hepatotoxicity.
- Other TB Drugs:- Combined use with rifampin or pyrazinamide heightens the risk of liver injury.
Monitoring and Patient Education
To optimize treatment outcomes and minimize risks, healthcare providers should
- Conduct Baseline Assessments
- Obtain a thorough medical history and baseline liver function tests.
- Monitor Regularly
- Schedule periodic LFTs and assess for symptoms of toxicity, particularly in high-risk populations.
- Educate Patients
- Emphasize the importance of adherence to therapy.
- Advise against alcohol consumption during treatment.
- Instruct on recognizing symptoms of hepatotoxicity (e.g., jaundice, dark urine) and neuropathy.
Conclusion
Isoniazid remains an indispensable drug in the fight against tuberculosis. Its ability to effectively target M. tuberculosis has saved countless lives since its discovery. However,
its use requires vigilance due to potential side effects, particularly hepatotoxicity and peripheral neuropathy. By understanding isoniazid’s pharmacology, therapeutic applications, and adverse effects, medical professionals can ensure its safe and effective use in TB management.
The global burden of TB underscores the critical role of isoniazid in both treatment and prevention.
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