A Critical Appraisal of the Toxicology of Metronidazole

Since there is abundant experience of the clinical use of metronidazole, it is appropriate to begin a consideration of its toxicology by reviewing reports of side-effects in man. Until a few years ago the use of metronidazole in clinical medicine was more or less confined to the treatment of patients with trichomoniasis. For this purpose the oral administration of 200 mg three times per day for 5-7 days was commonly prescribed, although it is now clear that 95% cure rates can be equally well achieved by a single dose of 2 g, provided that male consorts are treated simulataneously. At the First International Metronidazole Conference, on the basis of his experience of treating over 15,000 women and 4,000 men for trichomoniasis over a period of 15 years, Dr Catterall (1977) listed the toxic side-effects associated with the use of metronidazole in decreasing order of frequency, as follows: mild nausea, a bad taste in the mouth, furring of the tongue, headache, dizziness, sleepiness, depression, transient skin eruptions (usually maculopapular on trunk and neck) and a disulfiram effect on taking alcohol. A transient leucopenia was reported in less than 2% of subjects when, in the early days of its use, it was customary to carry out white cell counts on patients receiving metronidazole. All the side effects quickly disappeared after treatment stopped, if not before, and Dr Catterall regarded them as negligible. During the past few years metronidazole has been used increasingly in the treatment of, or for the prevention of, diseases other than trichomoniasis and in relation to some of these new uses the doses given have been higher, and the duration of treatment longer, than for trichomoniasis. Thus, metronidazole has been used in high dosage as a radiosensitizer in conjunction with radiotherapy, and also by itself in the treatment of cancer. Rather more severe side effects have from time to time been reported in patients receiving these higher doses of the drug. Urtasun et al. (1977) reported that single doses of 2 .5 g/m 2 , giving maximum blood concentrations of 250 pm were apt to give rise to moderate or severe anorexia, a bitter taste in the mouth, nausea and vomiting, although the vomiting could to some extent be controlled by antiemetic medication. They saw no evidence of liver, kidney or bone marrow damage during a 6-24 month follow-up of six patients given 6 g/m2 thrice weekly for 3 weeks. Willson (1974) reported transient leucopenia, and Deutsch et al. (1975) reported severe nausea persisted for up