Isoniazid
Introduction
Isoniazid (INH) is an antibiotic used primarily as a first-line agent in the treatment and prevention of tuberculosis (TB). It is one of the most effective and widely used antimycobacterial agents. Isoniazid is particularly effective against Mycobacterium tuberculosis, the bacterium responsible for tuberculosis. This article delves into the pharmacology, mechanism of action, clinical uses, side effects, resistance, and other relevant aspects of isoniazid.
Pharmacology
Mechanism of Action
Isoniazid works by inhibiting the synthesis of mycolic acids, which are essential components of the mycobacterial cell wall. The drug is a prodrug that is activated by the bacterial enzyme catalase-peroxidase, encoded by the katG gene. Once activated, isoniazid forms a complex with the NADH cofactor, leading to inhibition of the InhA enzyme, which is involved in mycolic acid synthesis. This disruption in cell wall synthesis ultimately leads to bacterial cell death.
Pharmacokinetics
Isoniazid is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring 1-2 hours after oral administration. It is widely distributed throughout the body, including the cerebrospinal fluid, which is crucial for treating tuberculous meningitis. The drug is metabolized primarily in the liver through acetylation, a process that varies between individuals due to genetic polymorphisms in the N-acetyltransferase 2 (NAT2) enzyme. This results in different rates of metabolism, classifying individuals as either "slow acetylators" or "fast acetylators."
Clinical Uses
Treatment of Active Tuberculosis
Isoniazid is a cornerstone in the treatment of active tuberculosis, usually administered in combination with other antitubercular drugs such as rifampicin, pyrazinamide, and ethambutol. This combination therapy helps prevent the development of drug resistance and ensures a higher treatment success rate. The standard regimen for drug-susceptible TB typically lasts for six months, with isoniazid being administered daily or intermittently.
Latent Tuberculosis Infection (LTBI)
Isoniazid is also used for the treatment of latent tuberculosis infection, which is a state where the individual is infected with Mycobacterium tuberculosis but does not exhibit active disease symptoms. The standard regimen for LTBI involves daily administration of isoniazid for 6 to 9 months. This preventive therapy significantly reduces the risk of developing active TB, especially in high-risk populations such as HIV-infected individuals and those with recent TB exposure.
Side Effects
Hepatotoxicity
One of the most significant adverse effects of isoniazid is hepatotoxicity, which can range from asymptomatic elevation of liver enzymes to severe hepatitis and liver failure. The risk of hepatotoxicity increases with age, alcohol consumption, and concurrent use of other hepatotoxic drugs. Regular monitoring of liver function tests is recommended during isoniazid therapy.
Peripheral Neuropathy
Isoniazid can cause peripheral neuropathy, characterized by numbness, tingling, and pain in the extremities. This side effect is more common in individuals with predisposing conditions such as diabetes, malnutrition, or HIV infection. The neuropathy is due to isoniazid-induced depletion of pyridoxine (vitamin B6), and it can be prevented or treated with pyridoxine supplementation.
Other Adverse Effects
Other potential side effects of isoniazid include hypersensitivity reactions, lupus-like syndrome, and central nervous system effects such as seizures and psychosis. These adverse effects are relatively rare but can be serious and require prompt medical attention.
Resistance
Mechanisms of Resistance
Resistance to isoniazid can occur through various mechanisms, the most common being mutations in the katG gene, which encodes the catalase-peroxidase enzyme responsible for activating the drug. Mutations in the inhA gene, which encodes the target enzyme of isoniazid, can also confer resistance. Additionally, overexpression of the ahpC gene, which encodes an alkyl hydroperoxide reductase, can contribute to resistance by compensating for the loss of catalase-peroxidase activity.
Clinical Implications
The emergence of isoniazid-resistant Mycobacterium tuberculosis strains poses a significant challenge to TB control efforts. Multidrug-resistant TB (MDR-TB), defined as resistance to at least isoniazid and rifampicin, requires more complex and prolonged treatment regimens with second-line drugs, which are often less effective and more toxic. Rapid molecular diagnostic tests, such as the Xpert MTB/RIF assay, can detect isoniazid resistance and guide appropriate treatment decisions.
Drug Interactions
Isoniazid is known to interact with several other medications, which can affect its efficacy and safety profile. It is a potent inhibitor of the cytochrome P450 enzyme system, particularly CYP2C19 and CYP3A4, leading to increased plasma concentrations of drugs metabolized by these enzymes. Notable interactions include:
- Phenytoin: Isoniazid increases phenytoin levels, necessitating dose adjustments to avoid toxicity.
- Carbamazepine: Similar to phenytoin, carbamazepine levels can be elevated by isoniazid.
- Warfarin: Isoniazid can potentiate the anticoagulant effect of warfarin, increasing the risk of bleeding.
- Alcohol: Concurrent use of alcohol can exacerbate isoniazid-induced hepatotoxicity.
Special Populations
Pregnant and Breastfeeding Women
Isoniazid is considered safe for use during pregnancy, although the risk of hepatotoxicity may be slightly increased. Pyridoxine supplementation is recommended to prevent peripheral neuropathy. Isoniazid is excreted in breast milk, but the concentrations are generally low and not expected to cause adverse effects in breastfeeding infants. However, monitoring for signs of toxicity is advisable.
Pediatric Population
Isoniazid is widely used in children for both active and latent TB. The dosing in pediatric patients is weight-based, and the drug is generally well-tolerated. However, children are at a higher risk of developing peripheral neuropathy, and pyridoxine supplementation is recommended.
Patients with Liver Disease
In patients with pre-existing liver disease, the use of isoniazid requires careful consideration due to the increased risk of hepatotoxicity. Regular monitoring of liver function tests is essential, and alternative treatment options should be considered in cases of significant liver impairment.
Conclusion
Isoniazid remains a cornerstone in the fight against tuberculosis, with its efficacy in both treatment and prevention well-established. However, its use is not without challenges, including the risk of hepatotoxicity, peripheral neuropathy, and the emergence of drug resistance. Careful patient monitoring, appropriate use of adjunctive therapies like pyridoxine, and vigilance for drug interactions are essential to maximize the benefits of isoniazid while minimizing its risks.