Isoniazid genetic factors in toxicity

Although not well known by the general public worldwide, this is one of the most widely used drugs. It is used to treat tuberculosis, previously known as consumption, a disease which has killed a thousand million people over time. Although improved living conditions and drug treatment probably led to it becoming less prevalent in the West in the past century, it is now becoming increasingly common. This is partly because of the occurrence of AIDS which increases vulnerability to infection. Tuberculosis is usually treated with a combination of drugs including isoniazid, streptomycin, rifampicin, and pyrazinamide. The treatments proved effective, as I know from my own personal experience, my mother having been treated successfully for this disease with a combination of three of these drugs in the 1950s.

Isoniazid was developed in 1951 as a result of the observation that vitamin B6 was weakly active against the bacterium that causes tuberculosis. Isoniazid has a related structure to vitamin B6 and acts by stopping the production of substances used by the bacteria for the growth of cell walls. The drug is effective although, as with other drugs, resistant bacteria have appeared.

Not long after isoniazid was introduced a number of curious observations were made. It was noticed that when the level of isoniazid in the blood of patients was measured, there seemed to be much variation between individuals in the actual maximum level achieved despite their having been given the same dose. It was soon realized that patients fell into two groups, and that these groups not only had more or less isoniazid in the blood, but they also had more or less of a metabolite. The two groups were called fast or slow metabolizers. It was later found that this was genetically determined, and that in the UK or USA, for example, about half the population were slow metabolizers and the other half were fast metabolizers. Apart from being the first known example of genetic variation in disposition/metabolism of a drug, this genetic factor proved to be a very important factor. The genetic predisposition was termed the acetylator phenotype and it is now known that the slow metabolizers have a faulty enzyme that slows the breakdown of certain drugs.

It was noticed that slow metabolizers would respond better to treatment, that is, the drug was more effective in these patients. This was because the level of the drug in blood and tissues was higher than in the fast metabolizers, and so the bacteria were more effectively destroyed. Unfortunately there was a negative aspect to this when adverse effects began to be detected.

Adverse effects of isoniazid

The drug was given to patients regularly for periods of at least one year and after a while some patients noticed tingling in their fingers and toes. These were some of the first signs of damage to the nerves leading to the extremities. This is called peripheral neuropathy. It was then discovered that this occurred more commonly in the slow metabolizers. Thus one group was genetically more susceptible to the adverse effect. This was found to be due to the higher level of the parent drug in the blood and tissues of this group, the slow metabolizers. Just as the effectiveness of the drug was greater in this group, so was the toxicity. The parent drug was responsible but what was the cause? Later it was noticed that the patients suffering from this adverse effect were also becoming deficient in vitamin B6, a condition known to cause a similar effect on the nerves. Treatment with vitamin B6 supplements proved to be a successful way of stopping this adverse effect. The mechanism is now partly understood, and so isoniazid therapy was able to continue.

However, a second adverse effect became apparent later, after many more patients had been treated: this was serious toxicity to the liver. It was noticed that a significant number of patients (maybe as many as 20 per cent) showed signs of mild liver dysfunction, which usually subsided without even stopping the drug. In a small number, certainly fewer than i per cent and possibly only 0.1 per cent, the liver dysfunction was progressive and could end in fatal liver failure.

The severe liver dysfunction also seemed to be more common in slow metabolizers, and it was proposed that this due to a deficiency in detoxica-tion of a metabolite. Monitoring patients with liver function tests is one way to avoid this adverse effect. There may be other factors as well as the acetylator phenotype that are important, such as other drugs being taken at the same time. Excessive and sustained alcohol intake may also be a factor, as this is quite commonly associated with the occurrence of tuberculosis. Apart from weakening the liver it will also increase the amount of the enzyme that produces the toxic metabolite of isoniazid.

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