|Metronidazole: beware of neurotoxic side effects
Metronidazole, a `classic` drug in canine medicine, is currently very popular to treat a variety of diseases: giardiasis, various inflammatory processes in the gastrointestinal tract, hepatic encephalopathy etc. The potential myelosuppressive side effects of this drug are well known, but neurological problems seem to be more common and less known, as the excellent summary of the ACVIM shows...|
|Metronidazole is a synthetic nitroimidazole compound used with increasing frequency in small animal practice. 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.
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.
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.
The exact mechanism of metronidazole neurotoxicity is unknown.
Source: Pierre Bichsel, Ronald Lyman (2004): Metronidazole: Uses, toxicity and management of neurologic sequllae. In: DVM Newsmagazine Aug 1, 2004; www.dvmnewsmagazine.com/dvm/
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