Isoniazid

Usage

• Isoniazid is a first-line antibiotic primarily used for the treatment of Mycobacterium tuberculosis infections, both active and latent tuberculosis (TB). It is also used in multi-drug resistant TB regimens, often at a higher dose.
• Pharmacological Classification: Antimycobacterial agent, Antibiotic.
• Mechanism of Action: Isoniazid is a prodrug activated by the mycobacterial catalase-peroxidase enzyme KatG. This activation leads to the formation of reactive species that inhibit mycolic acid synthesis, a crucial component of the mycobacterial cell wall. This disruption of cell wall integrity results in bacterial death.

Alternate Names

• International Nonproprietary Name (INN): Isoniazid (INH)
• Other Names: Isonicotinylhydrazide (INH)
• Brand Names: Nydrazid (example)

How It Works

• Pharmacodynamics: Isoniazid exerts its bactericidal effect specifically on Mycobacterium tuberculosis by disrupting cell wall synthesis via mycolic acid inhibition. It exhibits synergistic activity with other antitubercular drugs.

• Pharmacokinetics:

  • Absorption: Isoniazid is well-absorbed orally and can also be administered intramuscularly. Food reduces its bioavailability.
  • Metabolism: Primarily metabolized in the liver via acetylation by N-acetyltransferase 2 (NAT2), a polymorphic enzyme leading to ‘fast’ and ‘slow’ acetylator phenotypes. Genetic variations in NAT2 influence individual drug levels and the risk of adverse effects. Slow acetylators are at a higher risk of toxicity due to slower drug clearance.
  • Elimination: Primarily eliminated via the kidneys, with dose adjustments needed in patients with renal impairment.

• Mode of Action: Isoniazid is activated within the mycobacterial cell by KatG. Activated isoniazid forms adducts with NAD and NADP, inhibiting InhA, an enoyl-ACP reductase essential for mycolic acid synthesis. This inhibition leads to impaired cell wall formation and bacterial death. The mechanism involves radical formation and interference with several mycobacterial enzymes.

• Receptor Binding/Enzyme Inhibition: Isoniazid inhibits mycolic acid synthesis by targeting InhA, an enoyl-ACP reductase in Mycobacterium tuberculosis.

• Elimination Pathways: Renal excretion is the primary elimination route, with a small amount also excreted in bile.

Dosage

Standard Dosage

Adults:

• Latent TB: 300 mg orally once daily for 9 months or 900 mg orally once weekly for 3 months (with rifapentine and under direct observation).
• Active TB: 5 mg/kg (up to 300 mg) orally/IM once daily OR 15 mg/kg (up to 900 mg) orally/IM two to three times weekly (as part of a multi-drug regimen).

Children:

• Latent TB: 10-20 mg/kg (up to 300 mg) orally once daily OR 20-40 mg/kg (up to 900 mg) orally two or three times weekly (with rifapentine).
• Active TB: 10-15 mg/kg (up to 300 mg) orally/IM once daily or 20-30 mg/kg (up to 900 mg) orally/IM twice weekly (as part of a multi-drug regimen).

Special Cases:

• Elderly Patients: Use with caution due to decreased liver function. Monitor for adverse effects, especially hepatotoxicity and peripheral neuropathy. Dosage adjustments may be needed.

• Patients with Renal Impairment: Closely monitor for toxicity, especially peripheral neuropathy. Dose reduction may be considered for patients with severe renal impairment (creatinine clearance <25 mL/min), and in slow acetylators.

• Patients with Hepatic Dysfunction: Use cautiously and monitor closely for hepatotoxicity. Dosage adjustment is needed for patients with acute or chronic liver disease.

• Patients with Comorbid Conditions: Caution is advised in patients with diabetes, HIV, and malnutrition due to increased risk of peripheral neuropathy. Alcohol use should be avoided due to increased risk of hepatotoxicity and drug interactions.

Clinical Use Cases

Isoniazid is not typically used as a stand-alone medication in critical care settings like intubation, surgical procedures, mechanical ventilation, the ICU, or emergency situations. Its use is primarily for the treatment of TB infections, not for symptom management in these acute care situations.

Dosage Adjustments

Dosage adjustments based on NAT2 acetylator status are not routinely performed. However, genetic testing for NAT2 polymorphisms might be useful in high-risk patients to guide individualized dosage.

Side Effects

Common Side Effects

• Peripheral neuropathy (numbness, tingling in hands and feet).
• Nausea, vomiting
• Elevated liver enzymes

Rare but Serious Side Effects

• Hepatotoxicity (jaundice, liver failure)
• Drug-induced lupus
• Seizures
• Severe allergic reactions (rash, fever, joint pain, swelling)
• Optic neuritis
• Psychosis

Long-Term Effects

• Peripheral neuropathy can become persistent with long-term use.
• Hepatotoxicity can develop even after months of therapy.

Adverse Drug Reactions (ADR)

• Hepatotoxicity is a significant ADR requiring immediate cessation of therapy.

Contraindications

• Acute liver disease.
• Previous isoniazid-induced liver injury.
• Hypersensitivity to isoniazid.

Drug Interactions

• CYP450 Interactions: Isoniazid is primarily metabolized by NAT2, not CYP450 enzymes. However, isoniazid can induce or inhibit CYP450 enzymes, affecting other medications.
• Other Interactions: Isoniazid interacts with aluminum salts, disulfiram, certain antifungals (e.g., ketoconazole), phenytoin, carbamazepine, rifampin, acetaminophen (increased risk of hepatotoxicity), and alcohol.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (Previous FDA Classification)
• Fetal Risks: While not a known teratogen, potential fetal risks exist. Benefits versus risks should be considered for active TB. Supplementation with pyridoxine (vitamin B6) is recommended in pregnant women receiving isoniazid to reduce the risk of peripheral neuropathy.
• Breastfeeding: Isoniazid is excreted in breast milk, but generally considered safe. Monitor the infant for jaundice and consider supplementing both mother and infant with pyridoxine (Vitamin B6).

Drug Profile Summary

• Mechanism of Action: Inhibits mycolic acid synthesis.
• Side Effects: Peripheral neuropathy, hepatotoxicity, nausea.
• Contraindications: Acute liver disease, previous isoniazid-induced hepatitis, hypersensitivity.
• Drug Interactions: Aluminum salts, disulfiram, ketoconazole, phenytoin, rifampicin, acetaminophen, alcohol.
• Pregnancy & Breastfeeding: Generally considered safe with pyridoxine supplementation. Not recommended during pregnancy for latent TB.
• Dosage: Varies; see detailed dosage section.
• Monitoring Parameters: Liver function tests, signs of peripheral neuropathy.

Popular Combinations

Isoniazid is often used in combination with other antitubercular drugs, such as rifampin, pyrazinamide, and ethambutol, for the treatment of active TB. These combinations enhance efficacy and reduce the risk of resistance development. Examples of combination regimens include:

• 6H: 6 months of daily isoniazid
• 3HP: 3 months of weekly isoniazid and rifapentine
• 3HR: 3 months of daily isoniazid and rifampin
• 4R: 4 months of daily rifampicin

Precautions

• General Precautions: Baseline liver function tests are recommended before starting treatment. Regular monitoring for hepatotoxicity and peripheral neuropathy is essential.
• Specific Populations: Monitor pregnant women, breastfeeding mothers, children, elderly, and patients with renal or hepatic impairment for adverse reactions.
• Lifestyle Considerations: Patients should avoid alcohol and tyramine rich foods.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Isoniazid?

A: The dosage varies depending on the indication (latent vs. active TB), age, weight, and other factors. Refer to the detailed dosage section above.

Q2: What are the most common side effects?

A: Peripheral neuropathy, nausea, vomiting, and elevated liver enzymes are common side effects.

Q3: What is the most serious side effect?

A: Hepatotoxicity, which can be fatal, is the most serious adverse effect.

Q4: Can Isoniazid be used during pregnancy?

A: It can be used for active TB if the benefit outweighs the risks, with pyridoxine supplementation. It’s generally avoided during pregnancy for latent TB.

Q5: Can Isoniazid be used during breastfeeding?

A: It is generally considered safe during breastfeeding, with monitoring for jaundice and pyridoxine supplementation for mother and infant.

Q6: What are the contraindications to Isoniazid use?

A: Contraindications include acute liver disease, previous isoniazid-induced liver injury, and hypersensitivity to isoniazid.

Q7: What drugs interact with Isoniazid?

A: Isoniazid interacts with aluminum salts, disulfiram, ketoconazole, phenytoin, carbamazepine, rifampin, acetaminophen, and alcohol, among others.

Q8: How is Isoniazid metabolized?

A: It is primarily metabolized in the liver by acetylation via the NAT2 enzyme.

Q9: What monitoring parameters are needed for patients on Isoniazid?

A: Liver function tests should be monitored regularly, and patients should be observed for signs and symptoms of peripheral neuropathy.

Q10: What is the mechanism of action of Isoniazid?

A: Isoniazid inhibits mycolic acid synthesis, a crucial component of the mycobacterial cell wall.