Metronidazole is a synthetic nitroimidazole compound used with increasing frequency in small animal practice. Evans et al
in the J Vet Intern Med [17:304-310] recently described its uses, toxicities and treatment of neurologic signs that may occur
as an untoward side effect.
It is commonly prescribed in the treatment of inflammatory bowel disease, gastritis associated with helicobacter, giardiasis
and empirical treatment of diarhea.
Metronidazole has also been used successfully to alter intestinal flora in dogs with hepatic encephalopathy and exocrine pancreatic
insufficiency. Use of this antibacterial has been advocated in the treatment of osteomyelitis and periodontal diseases. The
mechanism of action for these effects are a matter of controversy. It is believed that the drug disrupts DNA and nucleic acid
synthesis in bacteria. Its antiprotozoal activity is not adequately explained.
Metronidazole has excellent bioavailability with peak serum levels in the canine one hour after oral intake. This rather lipophilic
antibiotic is distributed to most body tissues and fluids, including bone, abscesses, the central nervous system (CNS) and
seminal fluid. There is extensive metabolism in the liver before renal and fecal excretion. The elimination half-life in the
dog varies from three to 13 hours. Adverse effects in dogs and cats include neurologic disorders, lethargy, weakness, neutropenia,
hepatotoxicity, hematuria, anorexia, nausea, vomiting and diarrhea. Neurotoxic effects include encephalopathy, cerebellovestibular
signs and periopheral neuropathy. Neurotoxicity following prolonged therapy is most often related to cumulative dose and duration
of treatment. Most canines who develop neurologic signs secondary to metronidazole administration have received weeks to months
of therapy, but toxicity after short-term therapy at relatively low dosages (<60 mg/kg/day) has been reported. In general,
higher dosages may produce signs in a shorter time period than moderate to low dosages. Reversible CNS dysfunction may produce
signs including ataxia, recumbency, opisthotonus, positional ystagmus, muscle spasms and occassionally seizures. Cerebrospinal
fluid analysis may reveal mildly elevated protein levels. In humans, a predominantly sensory polyneuropathy may follow large,
cumulative doses. Nerve conduction studies suggest sensory axonal degeneration with low-amplitude or absent sensory potentials
and minimal, if any, involvement of motor fibers. Sural nerve biopsies of human patients with sensory polyneuropathy, including
teased fiber studies and electron microscopy, demonstrated primary axonal pathology with degeneration of both myelinated and
unmyelinated fibers. Ahmeda et al in the journal, Neurology (45, 588) reported that magnetic resonance imaging in a single
human case with encephalopathy and ataxia showed reversible T2-weighted hyperintensities in the cerebellum, supatentorial
white matter and corpus collosum.
Mechanism of neurotoxicity
The mechanism of metronidazole neurotoxicity is unknown. Suggested mechanisms include inhibition of neuronal protein synthesis
by binding to RNA and thiamine antagonism. Neuropathological studies in dogs revealed axonal swelling in vestibulocerebellar
pathways and brain stem leukomalacia. It seems that most affected dogs recover within a week or two of drug withdrawal. Evans
et al suggest that dogs treated with diazepam had a more rapid resolution of clinical signs than dogs treated with supportive
therapy alone. In this study, the authors evaluated potential differences in the recovery time between dogs with metronidazole
toxicosis treated with diazepam and a similar group that did not receive diazepam as part of the therapy. Diazepam is believed
to facilitate the effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) within the vestibular system.
Evans et al treated patients with a single IV bolus of diazepam followed by TID oral treatment for three days. Dogs treated
with diazepam had an average response time of 13 hours (range 20 minutes to 24 hours) and an average recovery time of 38 hours
(range 24-72 hours). Dogs that were not treated with diazepam had an average response time of 4.25 days (range 2-10) and an
average recovery time of 11.6 days (range 5-21).
Results of this investigation demonstrated that diazepam tended to speed-up recovery for dogs with metronidazole toxicosis.
From the similarities in the plasma half-life of metronidazole and the average response time of the diazepam treated group,
the authors speculated that once metronidazole is displaced from the benzodiazepine receptor by diazepam, normal metabolism
of the displaced drug then occurs, resulting in the rapid clinical improvement observed. Furthermore, once metronidazole is
displaced, the exogenous benzodiazepine not only restores, but also improves, normal benzodiazepine-induced chloride conductance,
thereby enhancing an inhibitory effect on excitatory neurons.
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