Isoniazid

Isoniazid is an antitubercular drug and a prodrug: it must be activated to become effective. This activation is carried out by an enzyme of the bacterium itself, the catalase-peroxidase KatG of Mycobacterium tuberculosis. Once activated, isoniazid forms radicals and adducts that block the production of mycolic acids, the lipids that make up the mycobacterial wall. Deprived of these building blocks, the bacterium can no longer build its wall, which makes the agent bactericidal.

Beyond the wall, isoniazid also inhibits the synthesis of lipids and DNA in Mycobacterium tuberculosis. Its action is concentrated on this bacterium, which explains its targeted use against tuberculosis. Chemically, it is a small molecule with the formula C6H7N3O. This precise blockade of mycobacterial wall construction makes it one of the pillars of antitubercular treatment.

Isoniazid is used in two situations. In active tuberculosis caused by Mycobacterium tuberculosis, the disease is manifest: isoniazid is then used in combination with other antitubercular drugs. In latent tuberculosis, the bacterium is present but dormant and does not cause disease: isoniazid is used alone, as prevention, to keep the infection from reactivating.

The usual dose in adults is 5 mg per kilogram, up to 300 mg per day, in a single intake. The choice between monotherapy and combination therefore depends on the context, latent tuberculosis or active tuberculosis. In both cases, the treatment lasts over time and is managed with a physician.

Isoniazid is taken orally, on an empty stomach, without food: its bioavailability decreases when it is given with food. It is therefore preferable to take it away from meals. Taking the tablet at roughly the same time on each day of intake helps maintain a steady concentration in the blood.

Consistency is what makes the antitubercular treatment effective, and it runs over several months. You do not stop it on your own initiative: the decision to stop or adjust rests with the physician, in particular based on the results of liver monitoring. A missed dose or an early stop exposes you to the risk of failure and resistance.

Isoniazid is eliminated after being acetylated, a reaction carried out by the enzyme N-acetyltransferase 2 (NAT2). This acetylation occurs at variable rates depending on the person: a distinction is made between fast acetylators and slow acetylators. The risk of liver injury is higher in slow acetylators, in carriers of N-acetylation variants, and in the case of an abnormality of the CYP 2E1 enzyme. These genetic differences explain why the same drug is better or less well tolerated from one patient to another.

Liver damage is the most closely monitored effect. The treatment causes a transient rise in transaminases in 10 to 20 % of patients, exceeding 5 times the normal in 3 to 5 % of them, most often without symptoms. StatPearls describes mild liver injury in up to 20 % of patients and severe injury in about 1 %. Acute hepatitis with jaundice occurs in 0.5 to 1 % of patients and proves fatal in 0.05 to 0.1 % of cases; this risk increases with age, from about 0.5 % between 20 and 35 years to 1.5 % between 35 and 50 years, and more than 3 % beyond 50 years.

Peripheral neuropathy affects fewer than 0.2 % of patients on isoniazid, but high doses can promote it. It is preventable by the joint administration of pyridoxine, vitamin B6. In practice, pyridoxine is given with isoniazid at a dose of 25 to 50 mg per day, raised to 100 mg per day in patients who already have neuropathy. Vitamin B6 is therefore the nutrient directly linked to this treatment.

Another effect, rarer, is drug-induced lupus, which occurs in up to 1 % of patients on isoniazid. It is a reaction that generally regresses when the responsible drug is stopped. Knowing about these effects, nerves, vitamin B6 and lupus, makes it possible to tell what stems from the treatment and what is worth discussing with the physician.

Isoniazid alters the effect of several drugs. It increases the plasma concentration of phenytoin, which requires a dose adjustment, and it inhibits the metabolism of carbamazepine and theophylline, whose concentration and toxicity increase; an increase in the toxicity of paracetamol is also reported. As for food, you should avoid foods and drinks very high in tyramine or histamine, such as certain cheeses, red wine and some fish such as tuna, because of a risk of reaction.

Laboratory monitoring frames the treatment. Before starting, AST, ALT, bilirubin, alkaline phosphatase, serum creatinine and platelets are measured in adults; transaminases are rechecked 2 to 4 weeks after the start in at-risk patients. Isoniazid is stopped in the event of any confirmed rise in ALT above 5 times the upper limit of normal, or above 3 times in the presence of symptoms. Monthly biochemical monitoring is advised in high-risk patients, age over 50 years or pre-existing liver disease.