Isoniazid (INH - Isonicotinic Acid Hydrazide)

Drug Class & Overview

• Active against: M. tuberculosis (primary), M. kansasii (first-line), M. bovis (moderate activity)
• Inactive against: MAC (poor activity), all non-mycobacterial genera
• MIC for M. tuberculosis: 0.025-0.05 mg/L (US clinical isolates); 0.1-1 μg/mL by classical assay

Mechanism of Action

1. KatG (mycobacterial catalase-peroxidase) activates INH, producing an isonicotinoyl radical
2. This radical reacts with NAD+ and NADP+ to form ~12 covalent adducts
3. Key toxic adducts:
   • Nicotinoyl-NAD isomer → inhibits InhA (enoyl-ACP reductase) and KasA (β-ketoacyl-ACP synthase) → blocks mycolic acid synthesis → disrupts cell wall → bactericidal death
   • Nicotinoyl-NADP isomer (K < 1 nM) → inhibits dihydrofolate reductase → interferes with nucleic acid synthesis
4. KatG activation also produces reactive oxygen species (superoxide, H₂O₂, NO radical) that contribute to mycobactericidal effect. M. tuberculosis is especially susceptible because it has a defect in the oxyR oxidative stress regulator.

• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 1292

Pharmacokinetics (ADME)

NAT2 Acetylator Phenotype (Critical Pharmacogenomics)

• Slow acetylators: t½ = 2.1-4.0 h; higher plasma levels (Cmax ~4 μg/mL); greater risk of peripheral neuropathy and hepatotoxicity
• Fast acetylators: t½ < 1.5 h; lower plasma levels (Cmax ~2 μg/mL); risk of reduced microbial cure, relapse, and acquired drug resistance
• 88% of variability in INH clearance is explained by NAT2 genotype
• Fast acetylation more common in: Inuit, Japanese populations
• Slow acetylation predominant in: Scandinavians, North African whites, those of Jewish descent
• Three subgroups now recognized: fast, intermediate, and slow

• Goodman & Gilman's, p. 1292-1293

Mechanisms of Resistance

Adverse Effects

1. Hepatotoxicity (Most Serious)

• Transaminase elevation occurs in 10-36% of patients in the first 10 weeks (usually minor and self-limiting)
• Clinical hepatitis develops in ~2% of all exposed patients; 5-10% of hepatitis cases are fatal
• Severe hepatic injury in ~0.1% of all patients
• Risk increases with age: 0.3% in 3rd decade → ≥2% after age 50
• 70% of fatal cases occur in women; Black and Hispanic women are at particular risk
• Risk is NOT dose-related
• Mechanism: acetylhydrazine metabolite → CYP2E1 → reactive hepatotoxic metabolites; immune-mediated component also implicated
• Potentiated by: alcohol, rifampin, pyrazinamide, acetaminophen, chronic HBV/HCV/HIV infection, malnutrition
• Histology: hepatocellular necrosis (focal or zonal/submassive/massive)
• INH hepatotoxicity is the second leading cause of drug-induced liver injury requiring liver transplantation in the USA (after acetaminophen)
• Sleisenger & Fordtran's GI & Liver Disease, p. 1677

2. Peripheral Neuropathy

• Occurs in ~2% of patients taking 5 mg/kg/day without pyridoxine supplementation
• Mechanism: INH is a structural analog of pyridoxine (vitamin B6) → causes excessive renal excretion of pyridoxine → depletes neuronal pyridoxal 5'-phosphate → impairs GABA synthesis
• Symptoms: paresthesias of hands and feet (most common), ataxia, muscle twitching
• More frequent in: slow acetylators, diabetics, malnourished patients, alcoholics, patients with anemia
• Prevention: co-administer pyridoxine 25-50 mg/day

3. CNS Toxicity

• Seizures (especially in those with pre-existing seizure disorders)
• Optic neuritis and atrophy
• Dizziness, ataxia, toxic encephalopathy
• Mental abnormalities: euphoria, memory impairment, psychosis

4. Drug-Induced Lupus / Autoimmune

• Vasculitis with anti-nuclear antibodies
• Drug-induced SLE syndrome
• Arthritic symptoms
• All resolve on discontinuation

5. Miscellaneous

• Dry mouth, epigastric distress, methemoglobinemia, tinnitus, urinary retention
• Sideroblastic/pyridoxine-deficiency anemia (in predisposed patients)

INH Overdose (Toxicology)

1. Seizures - generalized tonic-clonic, refractory to phenytoin/barbiturates/benzodiazepines alone
2. Anion-gap metabolic acidosis - refractory to NaHCO₃ (lactic acidosis from seizure activity)
3. Coma

• IV Pyridoxine - gram-for-gram equivalent to the amount of INH ingested
• Unknown dose: 5 g IV in adults (70 mg/kg in children, max 5 g); give 1 g every 2-3 min until seizures stop
• Benzodiazepines for seizures (in combination with pyridoxine)
• Phenytoin has NO role
• NaHCO₃ has little role
• Patients asymptomatic for 6 hours after ED presentation are safe for discharge

• Tintinalli's Emergency Medicine, p. 1276-1299

Drug Interactions (via CYP Inhibition/Induction)

• Goodman & Gilman's, Table 65-4

Clinical Use Summary

Recent evidence (PubMed, 2024): A systematic review/meta-analysis (PMID 39639188, BMC Genomic Data, Dec 2024) confirmed that NAT2 genetic variants are significantly linked to isoniazid-induced hepatotoxicity risk, reinforcing current pharmacogenomic guidance on NAT2 testing to predict adverse outcomes. This is consistent with the textbook mechanistic framework above.

• INH = "Inhibits Nicotinoyl-adduct formation in Hep C-like fashion" - prodrug, needs KatG
• Side effects: Hepatitis, Inhibits pyridoxine (neuropathy), Natural resistance via KatG mutation
• Prevent neuropathy with B6 (pyridoxine); treat overdose with IV pyridoxine