Isoniazid Flashcards
What is the mechanism of action of isoniazid (INH)?
Isoniazid inhibits mycobacterial mycolic acid synthesis. It is a prodrug activated by the mycobacterial catalase-peroxidase enzyme (KatG) into an active form that covalently binds to and inactivates enzymes (like InhA and KasA) involved in mycolic acid production, thus disrupting the bacterial cell wall.
How do bacteria develop resistance to isoniazid?
Resistance can occur via mutations in KatG (resulting in decreased activation of INH), mutations in the InhA enzyme or overexpression of InhA (requiring higher drug concentrations to inhibit), or mutations in other targets. These mutations prevent isoniazid from effectively inhibiting mycolic acid synthesis.
Describe the spectrum and uses of isoniazid.
Isoniazid is specific for Mycobacterium tuberculosis (and to a lesser extent M. kansasii). It’s a first-line agent for active TB (used in combination therapy) and the drug of choice for latent TB infection (used alone for prophylaxis). It’s bactericidal against actively dividing TB bacilli and bacteriostatic against dormant bacteria.
Outline key pharmacokinetic features of isoniazid.
INH is well absorbed orally and distributes widely, including the CNS. It is primarily metabolized in the liver by acetylation (N-acetyltransferase); the rate varies (fast vs slow acetylators, which affects half-life). It inhibits several cytochrome P450 enzymes. Isoniazid’s metabolites (some toxic) are excreted in urine. Dose adjustments may be needed in hepatic impairment. It crosses placenta and is present in breast milk.
What major drug interactions does isoniazid have?
Isoniazid is a notable inhibitor of CYP2C9, 2C19, and 2E1. It can increase levels of medications like phenytoin, carbamazepine, warfarin, and theophylline (toxicity risk). It can also enhance acetaminophen toxicity (via CYP2E1 induction causing more toxic metabolite). Alcohol co-use increases risk of hepatotoxicity. Also, less drug-specific, but INH increases excretion of vitamin B6 and can worsen the peripheral neuropathy risk if not supplemented.
A 52-year-old man is brought into the emergency department by ambulance after being found confused at home. The patient is unable to provide a reliable history. Per the neighbor who found the patient and called an ambulance, the patient has had nausea and vomiting on and off for the past several days and has not eaten during this time.
Emergency medical services brought the patient’s prescription medication bottles to the ED, which include aspirin, ethambutol, isoniazid, pyrazinamide, and rifampin. Temperature is 36.8 °C (98.2 °F), pulse is 84/min, respiratory rate is 16/min, blood pressure is 112/74 mm Hg, and SpOz is 99% on room air. On physical examination, the patient is confused and oriented only to person. Mucous membranes are dry. Cardiac, pulmonary, and abdominal exams are unremarkable. Arterial blood gas and serum bloodwork are obtained and shown below. Which of the following is the most likely diagnosis?
A) Type 2 renal tubular acidosis
B) Type 4 renal tubular acidosis
C) Salicylate toxicity
D) Diabetic ketoacidosis
E) Isoniazid toxicity
Elevated anion gap metabolic acidosis can be caused by toxic ingestions, severe acute kidney injury, lactic acidosis, and diabetic ketoacidosis. Isoniazid toxicity should be suspected in a patient taking isoniazid who presents with nausea, vomiting, altered mentation, and an elevated anion gap metabolic acidosis. This 52-year-old man is brought to the emergency department due to confusion after several days of nausea, vomiting, and poor oral intake. Given that this patient has been prescribed isoniazid (for tuberculosis treatment or prophylaxis) and has an elevated anion gap metabolic acidosis, the most likely diagnosis isoniazid toxicity. Pyridoxine is a cornerstone in the treatment of isoniazid toxicity. There are several causes of an elevated (or high) anion gap metabolic acidosis (HAGMA), which is defined as an anion gap > 12. HAGMA is due to unmeasured acids, so toxic ingestions, poor clearance of acids, and systemic causes of acid buildup may be the cause. Common toxic ingestions include ethylene glycol, methanol, isoniazid, iron, or salicylates. Lactic acidosis (often from sepsis or tissue bowel ischemia) and ketone production (e.g., diabetic ketoacidosis) lead to an increase in acids. Additionally, severe acute kidney injury can lead to poor clearance of organic acids.
What are important contraindications or cautions for isoniazid?
Isoniazid can cause serotinin syndrome, so it should never be taken when a patient is also taking SSRIs. Avoid isoniazid in patients with acute liver disease or previous severe INH-induced hepatic injury. Use cautiously in patients who consume alcohol daily or have risk factors for hepatitis. Also caution in those with pre-existing peripheral neuropathy (ensure vitamin B6 is given). Check for slow vs fast acetylator status if unusual toxicity or non-response occurs.
List major adverse effects of isoniazid.
- Hepatotoxicity is the most significant (ranging from asymptomatic LFT elevations to hepatitis; risk increases with age and alcohol use).
- INH can also cause drug-induced lupus erythematosus.
- Peripheral neuropathy is common especially in slow acetylators or malnourished patients, due to pyridoxine (vitamin B6) depletion—co-administer B6 to prevent this.
- Seizures (in overdose or if B6 deficient).
- Sideroblastic anemia.
- Anion gap metabolic acidosis (in overdose).
- INH can cause rash and in rare cases optic neuritis.
What mnemonic can help recall isoniazid toxicities?
“INH causes Injuries to Nerves and Hepatocytes.” Also remember “INH = I Need B6” (pyridoxine) to remind that pyridoxine prevents neuropathy. Another: the 4 I’s – Isoniazid, Injures Inside (peripheral neuropathy) and Inflames liver.
