SN1 SHORT NOTE 5M ★ High-yield

Describe isoniazid with its mechanism, acetylation polymorphism, adverse effects and uses.

Pharmacology · 2nd Professional — Para-Clinical

Pharmacology

Isoniazid (INH) is the most important antitubercular drug — cheap, potent, well tolerated and bactericidal against rapidly dividing organisms.

A prodrug activated by the mycobacterial catalase-peroxidase KatG; the active form inhibits InhA and so the synthesis of mycolic acids, which are unique to the mycobacterial cell wall
Resistance arises chiefly from mutation or deletion of katG (so the drug is never activated) or of the inhA promoter
Well absorbed orally; penetrates all tissues and fluids including CSF, caseous material and macrophages
Metabolised by acetylation, showing genetic polymorphism — about half the Indian population are slow acetylators

Feature	Slow acetylators	Fast acetylators
Plasma level	Higher and more sustained	Lower
Peripheral neuropathy	More frequent	Less
Hepatitis	Less (though disputed)	More — more hydrazine metabolite is formed
Efficacy on daily dosing	Equivalent	Equivalent — which is why the dose is not routinely adjusted

CLINICAL PEARL

Isoniazid causes neuropathy by competing with pyridoxine, and the remedy is therefore trivially cheap. It inhibits pyridoxine kinase and increases urinary excretion of the vitamin, producing a dose-dependent peripheral neuropathy that is entirely preventable by giving 10 to 25 mg of pyridoxine daily. In India, where malnutrition and slow acetylation are both common, this is given routinely rather than selectively.

Adverse Effects

Peripheral neuropathy — symmetrical distal paraesthesiae and numbness; prevented by pyridoxine
Hepatotoxicity — asymptomatic transaminase rise is common and usually settles; clinical hepatitis is uncommon but potentially fatal. Risk rises with age, alcohol, existing liver disease, pregnancy and the puerperium, and concurrent rifampicin and pyrazinamide
CNS — insomnia, restlessness, psychosis, optic neuritis; seizures in overdose, which are refractory to conventional anticonvulsants and are treated with high-dose pyridoxine
Lupus-like syndrome, particularly in slow acetylators
Others — rash, fever, arthralgia, haemolysis in G6PD deficiency, pellagra-like rash from niacin deficiency
Interactions — an enzyme inhibitor, raising phenytoin, carbamazepine and warfarin levels; with rifampicin, hepatotoxicity is increased

Uses

Treatment of all forms of tuberculosis, always in combination
Treatment of latent tuberculosis infection — 6 months of isoniazid alone, or 3 months of weekly isoniazid with rifapentine; used before anti-TNF therapy, in HIV, in transplant candidates and in household contacts of a sputum-positive case
Chemoprophylaxis of children under 5 in contact with an infectious case — a core component of India’s programme, and frequently under-delivered

Applied Aspects

Give pyridoxine routinely with isoniazid in India; the cost is trivial and the neuropathy otherwise common
Check baseline liver function in those over 35, with alcohol use, pre-existing liver disease, HIV or pregnancy, and monitor if symptoms appear
Tell every patient to stop the drug and report immediately if they develop nausea, vomiting, abdominal pain, jaundice or dark urine
Isoniazid overdose causes the triad of refractory seizures, metabolic acidosis and coma, and is treated with gram-for-gram pyridoxine — a diagnosis worth recognising, since it is easily mistaken for other causes of status epilepticus
Latent tuberculosis treatment is one of the weakest links in tuberculosis control in India; contact tracing and preventive therapy prevent far more disease than treating cases alone

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