Isoniazid family

A study of 484 tuberculosis patients on isoniazid showed that the development of peripheral neuropathy in a subgroup of patients was due to inherited differences in the acetylation of this medication [4], Individuals could be divided into rapid or slow acetylators of isoniazid. Family studies showed that rapid or slow acetylation status was inherited, with rapid acetylation being dominant and slow acetylation recessive. Polyneuritis was found to occur in 4 out of 5 slow acetylators, while only 2 out of 10 rapid acetylators developed polyneuritis. The rapid acetylators also tolerated longer courses of the drug [4],... 

Aiititubercular drug s are used in combination with other aiititubercular dm to treat active tuberculosis. Isoniazid (INH) is the only aiititubercular drug used alone While isoniazid is used in combination with other drains for the treatment of primary tuberculosis, a primary use is in preventive therapy (prophylaxis) against tuberculosis. For example, when a diagnosis of tuberculosis is present, family members of the infected individual must be given prophylactic treatment with isoniazid for 6 months to 1 year. Display 12-1 identifies prophylactic uses for isoniazid. 

Race and ethnicity may also be risk factors for ADRs. Prior personal or family history of ADRs may be predictive of future adverse reactions. Genetic polymorphisms for many metabolic reactions are described in Chapter 13 and have been well documented (45). Prescribing some medications without regard to genetic differences in metabolism can result in therapeutic failures or drug toxicity (45, 46). For example, differences in acetylator phenotype can alter the metabolism of some drugs and influence the risk of certain adverse reactions. Slow acetylators, for example, may be more likely than rapid acetylators to develop he pa to toxicity from isoniazid treatment. The biochemical basis for this difference is described in Chapter 16. 

Patients taking isoniazid who eat some foods, particularly fish from the scombroid family (tuna, mackerel, salmon) that are not fresh, may experience an exaggerated histamine poisoning reaction. Cheese has also been implicated in this reaction, but the adverse effects may be due to the weak MAOI effects of isoniazid rather than histamine poisoning. 

Reidenberg and Caccese (1975) found a positive lymphocyte transformation test in presumed isoniazid allergy. Mathews et al. (1971) also found positive lymphocyte transformation tests after isoniazid allergy, especially when the reaction appeared within the first 6 weeks after commencement of therapy and when there was eosinophilia. Positive lymphocyte transformation tests were not significantly associated with fever, personal or familial history of atopy, or allergies to other drugs. 

Fig. 1. Human family pedigree of rapid and slow isoniazid inactivators. Squares represent males circles, females black symbols, rapid inactivators white symbols, slow inactivators. (Knight et al, 1959.)...

Fig. 2. Frequency distribution of plasma isoniazid concentrations 6 hours after drug ingestion (9.8 mg/kg body weight) in 267 members of 53 complete families. (Evans et al., 1960.)...

Wide variation in the rate of acetylation of isoniazid and of other drugs which are metabolized by acetylation is not unique to man but is observed in several other species. Definitive studies establishing that such variability is primarily the result of inherited differences between animals of a species have been carried out in only one species other than man, i.e., the rabbit (Frymoyer and Jacox, 1963a,b). Frymoyer and Jacox found that when sulfadiazine was administered to rabbits (20 mg/kg), half-life determinations of the unmetabolized drug in blood were distributed bimodally (Fig. 4) with a mean of 41 minutes for the rapid acetylator subpopulation and a mean of 89 minutes for the slow acetylator subpopulation. This difference could not be attributed to differences in volumes of distribution of unacetylated sulfadiazine, in rates of distribution of sulfadiazine to the body water, or to age or sex. Furthermore, they showed from pedigree analysis of 15 rabbit families that the pattern of inheritance of sulfadiazine metabolism in the rabbit was essentially the... 

Double reciprocal plots of the acetylation of isoniazid with liver N-ace-tyltransferase from each of several species of mammals yielded families of parallel lines (Weber and Cohen, 1967 Weber et al., 1968). Plots for human liver enzyme from a rapid isoniazid acetylator are shown in Fig. 8. These are consistent with either a simple or an iso-ping-pong Bi-Bi reaction mechanism and thus the total reaction for isoniazid acetylation may be represented by one of the following schemes ... 

---