ISONIAZID

Indications

• Treatment of active tuberculosis
• Prevention of tuberculosis in susceptible individuals, especially close contacts of infected persons

Dosage

Adults: 10 mg/kg daily (maximum per dose 300 mg) for 3 months, to be taken by mouth or via intramuscular or intravenous

Mechanism of action

Isoniazid is activated by the bacterial catalase-peroxidase KatG, which reduces the ferric form of the enzyme and enables it to react with oxygen to form an oxyferrous enzyme complex. The active form of isoniazid then inhibits the synthesis of mycolic acids by forming a covalent adduct with NAD, inhibiting the enoyl reductase InhA. This inhibition is crucial for the integrity of the mycobacterial cell wall, leading to the bactericidal activity of isoniazid against actively growing Mycobacterium tuberculosis.

Pharmacodynamics

Isoniazid is a bactericidal agent particularly effective against the Mycobacterium genus, including M. tuberculosis, M. bovis, and M. kansasii. It exhibits bactericidal properties during periods of rapid mycobacterial growth and becomes bacteriostatic when the bacteria are in a dormant state. Given its mechanism of action, isoniazid is highly selective, targeting mycobacteria without significant effects on other types of bacteria.

Pharmacokinetics

Isoniazid is well-absorbed following oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It is widely distributed in body tissues and crosses the blood-brain barrier. The drug is metabolized in the liver primarily through acetylation, with variable metabolism rates observed in different populations due to genetic polymorphisms in acetylation. The elimination half-life ranges from 1 to 4 hours, and the drug is excreted in the urine, predominantly as metabolites.

Contra-indications

• History of hypersensitivity to isoniazid
• Acute liver disease
• Severe hepatic impairment
• Previous history of isoniazid-induced liver injury

Adverse effects

• Hepatitis
• Peripheral neuropathy
• Optic neuritis
• Gastrointestinal disturbances
• Rash
• Fever
• Agranulocytosis
• Hematological disorders
• Lupus-like syndrome

Interactions

• Carbamazepine: Increased risk of hepatotoxicity
• Cycloserine: Increased risk of CNS toxicity
• Phenytoin: Increased concentration of phenytoin
• Levodopa: Decreased effects of levodopa
• Lomitapide: Increased exposure
• Antiepileptics: Unknown interactions leading to increased concentrations

Precautions

• Monitor liver function during treatment
• Use with caution in patients with renal impairment
• Patients with diabetes or a history of peripheral neuropathy should be monitored closely
• Ocular monitoring for young children on treatment

Pregnancy

Not known to be harmful; however, prophylactic pyridoxine is recommended.

Breast-feeding

Amount too small to be harmful; monitor infant for possible toxicity.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets
• Oral suspension
• Intramuscular injection
• Intravenous injection

Mechanism of action

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular <i>Mycobacterium tuberculosis</i> organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from <i>Mycobacterium tuberculosis</i>, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA. Although the mechanism of action of isoniazid is unknown, several hypotheses have been proposed. These include effects on lipids, nucleic acid biosynthesis, and glycolysis. ... /It has been suggested that/ a primary action of isoniazid /is/ to inhibit the biosynthesis of mycolic acids, important constituents of the mycobacterial cell wall. Because mycolic acids are unique to mycobacteria, this action would explain the high degree of selectivity of the antimicrobial activity of isoniazid. Exposure to isoniazid leads to a loss of acid fastness and a decrease in the quantity of methanol-extractable lipid of the microorganisms. Isoniazid is bacteriostatic for "resting" bacilli but is bactericidal for rapidly dividing microorganisms. The minimal tuberculostatic concentration is 0.025 to 0.05 ug/ml.

Pharmacodynamics

Isoniazid is a bactericidal agent active against organisms of the genus Mycobacterium, specifically <i>M. tuberculosis</i>, <i>M. bovis</i> and <i>M. kansasii</i>. It is a highly specific agent, ineffective against other microorganisms. Isoniazid is bactericidal when mycobacteria grow rapidly and bacteriostatic when they grow slowly.