A 38-year-old man from Delhi with newly diagnosed pulmonary tuberculosis is started on standard first-line therapy. Regarding the pharmacokinetic and drug interaction properties of antitubercular agents, all of the following statements are correct EXCEPT:

Question

Accepted Answer

C. Streptomycin is hepatically metabolized and is contraindicated in patients with severe hepatic cirrhosis due to high risk of hepatotoxicity. ## Pharmacokinetics and Drug Interactions of First-Line Antitubercular Drugs

### Correct Statements

| Drug | Key PK Feature | Clinical Implication |
|------|---|---|
| **Rifampicin** | Potent CYP450 inducer (1A2, 2C9, 3A4, 2B6) | ↓ OCP, warfarin, protease inhibitors, azoles efficacy |
| **Isoniazid** | Hepatic acetylation (slow/fast metabolizers) | Slow acetylators: ↑ toxicity, need B6 |
| **Ethambutol** | 80% renal excretion unchanged | Dose ↓ in renal failure (eGFR < 30) |
| **Streptomycin** | Renal excretion (NOT hepatic) | Ototoxicity, nephrotoxicity; minimal hepatic metabolism |

### Why Streptomycin Statement Is Wrong

**Key Point:** Streptomycin is NOT hepatically metabolized. It is an aminoglycoside that is excreted primarily by the kidneys (glomerular filtration) in unchanged form.

**High-Yield:** Streptomycin toxicity concerns:
- **Ototoxicity** (8th cranial nerve damage) — irreversible, dose-dependent
- **Nephrotoxicity** — acute tubular necrosis with prolonged use
- **Neuromuscular blockade** — rare, but significant
- **NOT hepatotoxicity** — streptomycin does not cause liver damage

**Clinical Pearl:** Streptomycin is actually SAFE in hepatic cirrhosis (unlike INH, RIF, PZA which are hepatotoxic). The concern in cirrhosis is renal dysfunction (hepatorenal syndrome), not hepatic metabolism. Dose adjustment is needed only if creatinine clearance is reduced.

**Mnemonic:** **RIPE-SM toxicity:**
- **R** (Rifampicin) = enzyme induction
- **I** (Isoniazid) = peripheral neuropathy, hepatotoxicity
- **P** (Pyrazinamide) = hyperuricemia, hepatotoxicity
- **E** (Ethambutol) = optic neuritis, color blindness
- **SM** (Streptomycin) = ototoxicity, nephrotoxicity (NOT hepatotoxicity)

### Rifampicin Drug Interactions

**Warning:** Rifampicin significantly reduces the plasma concentrations of:
- Oral contraceptives (breakthrough bleeding, contraceptive failure)
- Warfarin (loss of anticoagulation)
- Protease inhibitors (subtherapeutic levels)
- Azole antifungals
- Methadone (withdrawal symptoms)

### Isoniazid Acetylation Phenotype

- **Fast acetylators:** Lower INH levels, lower toxicity risk, but may need higher doses
- **Slow acetylators:** Higher INH levels, increased risk of peripheral neuropathy, drug-induced lupus, hepatotoxicity
- **Pyridoxine (B6) supplementation:** 10–25 mg daily for slow acetylators to prevent neuropathy

Answer

A. Isoniazid undergoes acetylation in the liver, and slow acetylators have higher risk of peripheral neuropathy and require pyridoxine supplementation

Answer

B. Ethambutol is primarily renally excreted unchanged and requires dose reduction in patients with severe renal impairment (eGFR < 30 mL/min)

Answer

D. Rifampicin is a potent inducer of cytochrome P450 enzymes and can reduce the efficacy of oral contraceptives and warfarin

A 38-year-old man from Delhi with newly diagnosed pulmonary tuberculosis is started on standard first-line therapy. Regarding the pharmacokinetic and drug interaction properties of antitubercular agents, all of the following statements are correct EXCEPT:

Explanation

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