Metronidazole-induced neurotoxicity

A reminder of the potential for nitroimidazole pharmacologicals to cause neurotoxic events is well-taken. That these drugs could potentially cause either peripheral or central nervous system complications has a long history and a strong Canadian historical connection.(1,2) The latter experience is rarely if ever acknowledged in either case studies, reviews, or cumulative analyses.

Nearly one-half century ago, Raul Urtasun, Don Chapman, and Harvey Rabin were conducting pharmacokinetic and early treatment studies at the Cross Cancer Institute, University of Alberta with the use of nitroimidazole class drugs (then misonidazole and metronidazole) for sensitization of tumours during radiotherapy interventions.(1-5) It became apparent very early that these agents were associated initially with peripheral neuropathy which then proved to be use-limiting. An assessment of toxicity during these trials led to the finding of both a total dose and administration frequency association for neurotoxic side effects.(5) Studies of either oral or intravenous single-dosing was not associated with such toxicity.(4) Learned then, but confirmed in many other studies since, metronidazole is very bioavailable after oral ingestion, and central nervous system levels approach those achieved in the bloodstream. There is also a need to consider that metronidazole metabol ites achieve high plasma or tissue levels as well.(4)

Another largely unresolved issue with nitroimidazoles is the historic mutagenicity link. Reviews of the latter are inconclusive as to whether in vitro or animal model associations have any true bearing on human use. Metronidazole has been an extremely useful and easily administered antibiotic, but prolonged and high-dose uses should be carefully considered.