Isoniazid
Isoniazid (INH)
Generic Name
Isoniazid (INH)
Mechanism
- Isoniazid (INH) is a pro‑drug that is activated by the mycobacterial enzyme ethA.
- Once activated, it alkylates the mycobacterial enoyl‑ACP reductase (InhA), inhibiting mycolic acid synthesis—essential for the mycobacterial cell wall.
- The blockade of mycolic acids disrupts cell wall integrity, leading to mycobacterial lysis.
- Host activation: Acetylation in the liver (by N‑acetyltransferase 2, NAT2) determines systemic exposure; slow acetylators (≈30% of Caucasians, higher in Africans) have higher serum levels and increased risk of neurotoxicity.
Pharmacokinetics
| Parameter | Details |
| Absorption | Oral, >90 % bioavailability; peak plasma 3–6 h. |
| Distribution | Widely distributed; crosses placenta and CSF (infected sites). |
| Protein binding | 44 % – largely unbound. |
| Metabolism | Hepatic acetylation by NAT2 → acetyl‑isoniazid (inactive). |
| Elimination | Renal (≈60 % unchanged, 30–40 % as acetyl‑isoniazid). |
| Half‑life | 4–6 h (slow) / 1–1.5 h (fast); overall T½ ~4 h (slow) and 2 h (fast). |
| Special populations | Renal impairment: ~10‑15 % longer half‑life; hepatic impairment: minimal effect. |
Indications
- Prophylaxis of latent *Mycobacterium tuberculosis* infection in high‑risk contacts, HIV‑positive patients, and immunosuppressed individuals.
- Adjunctive therapy for active pulmonary or extrapulmonary TB in combination with rifampin, pyrazinamide, ethambutol, or other 4‑drug regimens.
- Short‑course therapy for INH‑sensitive TB (6–9 months depending on regimen).
Contraindications
- Contraindications
- Known hypersensitivity to pyridoxine or INH.
- Severe hepatic dysfunction (ALT/AST >3× ULN) before therapy initiation.
- Warnings
- Drug‑induced hepatitis—symptoms: nausea, vomiting, dark urine, malaise.
- Peripheral neuropathy (especially in patients with malnutrition, diabetes, chronic alcoholism).
- Acetylator status—slow acetylators have ↑neurotoxicity risk; consider pyridoxine supplementation.
- Drug interactions: ↓INH efficacy with oral contraceptives (increases excretion); ↑INH levels with valproic acid.
- Teratogenicity: No definitive evidence of fetal harm in humans; however, avoid in pregnancy unless benefit outweighs risk.
Dosing
| Population | Dose | Frequency | Notes |
| Adults (latent TB) | 300 mg | Once daily | SR (sustained‑release) formulation preferred; orally, with food to improve tolerance. |
| Adults (active TB) | 300 mg | Once daily | Use with pyridoxine 25–50 mg/day to prevent neuropathy; adjust for slow acetylators (higher incidence of toxicity). |
| Children (≥6 months) | 10 mg/kg (max 300 mg) | Daily | Adjust by weight; monitor for neurotoxicity. |
| Renal impairment | ± dose adjustment if CrCl <30 mL/min, but usually no adjustment needed. |
• Administration tips
• Take with a meal (or milk) to reduce GI upset.
• For SR formulations: do not crush or chew.
Adverse Effects
| Adverse Effect | Incidence | Mitigation | |
| Peripheral neuropathy | 1–8 % (higher in slow acetylators) | Pyridoxine 50 mg PO daily; stop INH if neuropathic symptoms appear. | |
| Liver dysfunction/hepatitis | <1 % (severe) | Routine ALT/AST monitoring at baseline, 2, 4, 8 weeks. | |
| Erythroderma / rash | ≤1 % | Discontinue if severe. | |
| Gastrointestinal upset | Common | Admin with food; or use SR. | |
| Drug‑induced psychosis | Rare | Monitor patients with psychiatric history. |
Monitoring
- Baseline: CBC, CMP (LFTs), baseline neurological exam.
- During therapy:
- LFTs: every 2 weeks for first month, then monthly.
- Neurologic assessment: at each visit; evaluate for paresthesias, weakness, ataxia.
- Adherence: pill count, self‑report, or directly observed therapy (DOT).
- Special:
- Pyridoxine levels not routinely measured; clinical monitoring suffices.
Clinical Pearls
- “Bored” patients + “pyridoxine” = stopped neuropathy**—always co‑prescribe pyridoxine 25–50 mg/day, especially in high‑risk groups (diabetes, alcohol misuse, malnutrition).
- Slow vs. fast acetylators—lose this info in the PGRx; consider pharmacogenetic testing if neuropathy develops early.
- DOT and MEMS—ensure adherence in high‑risk communities; non‑adherence is a leading cause of drug resistance.
- INH + Alcohol → ↑neurotoxicity; counsel patients to limit alcohol intake.
- Prophylaxis: 300 mg daily for 6 months (or 9 months if immune suppression); see WHO guidelines for updated durations.
- Re‑entry: After significant hepatic injury, re‑challenge ONLY under close supervision; consider alternative agents (Rifapentine/isoniazid).
- Pregnancy: INH is generally considered safe; pyridoxine can help prevent folate deficiency‑related adverse outcomes.
Key take‑away: *Isoniazid’s potency relies on mycobacterial enzyme activation and may be impaired by host acetylation variability; supplementation with pyridoxine, regular LFT and neuro‑monitoring, and careful adherence support are paramount for successful TB therapy.*