Acceptability of thioamides I. ethionamideDK Gupta
Department of Tuberculosis and Chest Diseases, L.L.R.M. Medical College, Meerut-250 102., India
Eighty four patients of chronic advanced pulmonary tuberculosis were subjected to determine the acceptability of ethionamide at different dosage schedules and frequencies of intake of the drug over a period of 10 months. Mild to severe side-effects were observed in 56.6 per cent, 70 per cent and 100 per cent patients of groups A, B and C respectively receiving ethionamide in a dose of 500 mg, 750 mg and 1 gm per day. Gastro-intestinal disturbances were most frequently encountered. Toxic symptoms appeared earlier with higher doses of ethionamide. Patients taking the drug in a single dose had had higher incidence of toxicity than those who were prescribed in two divided doses. Pyrazinamide appeared to enhance ethionamide unacceptability. Age, chronicity of illness and extent of disease did not exhibit any influence on ethionamide acceptability.
Soon after the discovery of Isoniazid in 1952, a number of pyridine derivatives were discovered bearing anfi-tuberculosis activity. E'hionamide is a thioamide of alpha-ethyl-isonicotinic acid which possesses potent anti-tuberculosis activity both in vivo and in vitro. However, limitations in clinical usefulness have been described mainly to its gastro-intestinal intolerance and hepatotoxicity.
In the present study, an effort has been made to assess the acceptability of this drug in Indian patients at different dosage schedules and frequencies of intake. Therapeutic efficacy of the drug has not been considered.
For this study, 91 patients with chronic advanced pulmonary tuberculosis were selected at random. All the patients had clinical, bacteriological and radiological evidence of resistance to standard drugs with which they were treated previously. They were randomised into groups as follows:
Group-A: Patients receiving ethionamide 500 mg per day either in a single (Subgroup-A l -14 patients) or two equally divided doses (SubgroupA 2 -20 patients).
Group-B: Patients receiving 750 mg of the drug in a single (Sub group-B 1 -14 patients) or two divided doses (Subgroup-B 2 -18 patients).
Group-C: Patients receiving ethionamide 1 gm per day in a single (Subgroup-C 1 -10 patients) or two equally divided doses (Subgroup-C 2 -15 patients).
These patients were prescribed one of the following drug regimens:
Regimen-I: Ethionamide + Pyrazinamide (PZA) 1 gm twice a day after meals + Ethambutol (ETH) 800 mg - 1 gm once a day before breakfast with or without Isoniazid 300 mg once a day.
Regimen-II: Ethionamide + Ethambutol + Isoniazid.
Regimen-III: Ethionamide + Pyrazinamide + Cycloserine (CYC) 250 mg twice a, day.
Ethionamide was given as sugar coated tablets 250 mg each after proper meals the dose of which was adjusted according to group and subgroup. Ethambutol, pyrazinamide and Isoniazid were prescribed in the same dose as in Regimen-I.
The criteria for selection of the patients, and assessment of acceptability of ethionamide in these patients was done ever a period of 9 to 10 months as described by Gupta et al. 
There were 66 males (72.5%) and 25 females (27.5% ) falling in the age range of 20 to over 50 years, maximum number of patients (90.1%) being in the age group of 20 to 40 years. 83 of 91 (91.2%) patients were suffering from the disease for a period of 1 to 4 years and only 8 patients (8.8%) had complaints fog over 4 years. Bilateral involvement of lungs was seen in 57 (62.7%) patients and in the rest the disease was unilateral. 62 (68.1%) patients had far-advenced and 29 (31.9%), moderately advanced disease.
During the follow up period, 4 patients from group-A and 1 patient from groupB could not be followed after the 5th month of treatment. One patient of groupB failed to afford the cost of the drug after the 3rd month and 1 patient of group-C died within a fortnight of admission.
Among the remaining 84 patients of this study, ethionamide side-effects were observed in 17 of 30 (56.6% ) and 21 of 30 (70%) patients in groups-A and B respectively, and none of the 24 patients in group-C could tolerate the drug [Table 1]. Toxic manifestations appeared in those patients who were administered ethionamide in higher doses [Table 2]. It was observed that the incidence of toxicity was enhanced with increase in the dose of ethionamide. Patients who were put on a drug regimen containing pyrazinamide had greater incidence of toxicity than those without it [Table 3]. Age, chronicity of illness and radiological extent of disease did not affect ethionamide acceptability. Gastrointestinal disturbances were more frequently noticed. Jaundice occurred in 2 patients of group-A who were also taking pyrazinamide [Table 4].
Ethionamide is associated with a number of side-effects, such as gastrointestinal disturbances and hepatotoxicity, reported upto 100 percent. ,, In the present series, toxicity due to ethionamide was observed in 56.6 per cent, 70 per cent and 100 per cent of patients in groups A, B and C respectively. These differences are statistically significant at t = 5.9 (p < 0.001). Mild to severe gastrointestinal disturbances were observed in 53.3 per cent, 66.6 per cent and 100 per cent patients in groups A, B and C respectively which is statistically significant at t = 5.7 (p < 0.00.1). All the patients in group-C necessitated either reduction in the dose or withdrawal of the drug. In subgroup-A 1 , the incidence of toxicity was 55.5 per cent in males and 75 per cent in females. When the drug was given in divided doses (subgroupA 2 ), the incidence fell to 50 per cent in males and 60 per cent in females. Similarly, in the subgroup-B 1 , the incidence was much higher (70% in males and 100% in females) but when the drug was prescribed in divided doses in the subgroup-B 2 , the toxicity was noticed only in 61 per cent of males and 75 per cent of females. A slightly higher incidence of eithionamide induced side-effects in females than in males have also been reported in literature. , Toxic manifestations developed earlier with higher doses of the drug. Gupta et al  have reported alterations in gastric juice acidity following oral administration of thiomides towards achlorhydria which may be responsible for at least some of the gastrointestinal disturbances.
Patients who were prescribed pyrazinamide containing regimes exhibited higher incidence of toxicity than those without it. 12 out of 18 (66.6%) and 13 out of 16 (81.2%) patients in group A and B respectively, who were also taking pyrazinamide, developed toxic manifestations as compared to 5 out of 12 (41.6%) and 8 out of 14 (57.1%) patients without it in the two groups. Pyrazinamide itself is known to cause gastrointestinal and hepatic disturbances.
Hepatic damage or insufficiency as manifested by clinical jaundice or abnormal liver functions due to ethionamide have been reported by various authors. ,,, In this series, 2 patients of group-A developed clinical jaundice which was supposed to be due to ethionamide. As we could not carry out estimations of serum transaminases, a correct figure of liver damage due to ethionamide could not be assessed.
Neuropsychotoxic reactions which manifested itself by headache, insomnia, sleepiness, depression, paraesthesia, tingling and numbness were observed in 4 out of 30 (30%), 8 out of 30 (26.6%) and 5 out of 24 (20.85) patients in groups A B and C respectively but none of then necessitated interruption of the therapy. Patients who took the drug for longer time were more prone to develop these side-effects. Result of this series are a little higher as compared to others , because of the methods of assessment. Narang  has reported a case of acute psychotic reactions probably caused by ethionamide who committed suicide.
Like other reports, some minor side-effects were also encountered in this study. Cutaneous lesions such as rashes, itching and pigmentation , were noticed in 3 out of 30 (10% ) and 3 out of 30 (10%) patients of groups A and B respectively. Alopecia  and non-toxic goiter  have occasionally been reported. One patient receiving ethionamide 500 mg per day developed alopecia and another patient in subgroup A, developed ethionamide induced goitre.
In conclusion, ethionamide in a dose of 500 mg per day was tolerated by only 43.4 per cent of patients and increase in the dose beyond this was associated with higher incidence of toxic manifestations. None of the patients in this study could tolerate the drug in a dose of 1 gm per day. However, because of small number of patients distributed in various subgroups, a large series trial is required.
I am thankful to Mr. S. K. Bajpai, Lecturer in Statistics and Demography Department of Obstetrics and Gynaecology, Medical College, Meerut for statistical analysis.
[Table 1], [Table 2], [Table 3], [Table 4]