Antimicrobials · Antimycobacterial Agents
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Isoniazid causes peripheral neuropathy due to pyridoxine (Vitamin B6) deficiency by increasing the renal excretion of the vitamin.
Pyridoxine (Vitamin B6) supplementation is mandatory for patients at high risk for neuropathy, including those with diabetes mellitus, alcoholism, or pregnancy.
Isoniazid is associated with drug-induced hepatitis and requires baseline and periodic monitoring of liver function tests (LFTs).
The mechanism of action involves the inhibition of mycolic acid synthesis, which is essential for the mycobacterial cell wall.
Isoniazid can induce a drug-induced lupus erythematosus (DILE) syndrome characterized by anti-histone antibodies.
Slow acetylators are at an increased risk for dose-dependent toxicity and adverse effects due to genetically determined slower metabolism by N-acetyltransferase.
Acute isoniazid overdose presents with the triad of refractory seizures, metabolic acidosis, and coma.
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A 34-year-old male with latent tuberculosis is started on isoniazid therapy. Three weeks later, he presents to the clinic complaining of numbness and tingling in his feet. He has a history of type 2 diabetes mellitus managed with metformin. Physical examination reveals decreased sensation to pinprick in a stocking-glove distribution. His liver enzymes are within normal limits.
What is the most appropriate intervention to prevent this patient's current symptoms?
Pyridoxine (Vitamin B6) supplementation
The patient is experiencing peripheral neuropathy caused by isoniazid-induced pyridoxine depletion, which should have been prevented by prophylactic supplementation in a high-risk diabetic patient.
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High yield triage
Classification
First-line antitubercular agent; bactericidal against actively dividing organisms.
Indications
Primary treatment for Latent Tuberculosis Infection and active Tuberculosis (in combination).
Mechanism of Action
Inhibits mycolic acid synthesis, disrupting the mycobacterial cell wall.
Side Effects
Common: peripheral neuropathy. Hepatotoxicity, drug-induced lupus.
Contraindications / Monitoring
Acute liver disease. Monitor LFTs and supplement with pyridoxine (Vitamin B6).
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Mechanism of Action
Isoniazid is a prodrug activated by the bacterial catalase-peroxidase enzyme KatG. Once activated, it inhibits the synthesis of mycolic acids, which are essential components of the mycobacterium tuberculosis cell wall. This leads to cell death in rapidly dividing organisms.
Unique Properties
It is the most potent agent against M. tuberculosis. It is unique for its requirement of pyridoxine supplementation to prevent neurotoxicity and its genetic variability in metabolism via N-acetyltransferase.
Indications
Indicated as monotherapy for Latent Tuberculosis Infection (LTBI). Used in combination with rifampin, pyrazinamide, and ethambutol for active Pulmonary Tuberculosis.
Pharmacokinetics
Metabolized by hepatic N-acetylation; patients are classified as 'fast' or 'slow' acetylators. It is a potent CYP450 inhibitor, increasing levels of drugs like phenytoin.
Side Effects & Adverse Events
Common side effects include peripheral neuropathy due to pyridoxine depletion. Hepatotoxicity is the most serious concern, manifesting as elevated transaminases or clinical hepatitis. Drug-induced lupus and seizures (in overdose) are classic board-tested associations.
Contraindications
Acute liver disease or a history of severe hypersensitivity to isoniazid. Use with extreme caution in patients with pre-existing peripheral neuropathy or chronic alcohol use.
Monitoring
Baseline and periodic LFTs are mandatory, especially in patients >35 years old. Monitor for signs of hepatitis (jaundice, fatigue) and neuropathy (paresthesias).
Clinical Pearls
Always prescribe Vitamin B6 to prevent neuropathy, especially in diabetics, alcoholics, and pregnant patients. If a patient presents with seizures after an overdose, treat with high-dose pyridoxine.