SOURCES

The 1950s saw the discovery and biological testing of the 5-nitroimidazole group. These drugs have both antiprotozoal and antibacterial effects. In 1959 the effective trichomonacidal activity of 1-(β-hydroxy-ethyl) 2-methyl-5-nitroimidazole (metronidazole) was first reported.¹ Before this time female trichomoniasis patients were treated with a variety of topical drugs with limited success. A large number of infections became chronic and persisted. Males did not respond at all to topical treatment. Metronidazole proved effective for these infections and also in treating infections of the protozoan Giardia.

Currently, metronidazole is widely employed in man and animals for the treatment of trichomoniasis, giardiasis, amebiasis, and obligate anaerobic bacteria, including Bacteroides species.² Metronidazole has also been shown to be beneficial in the management of inflammatory bowel disease.³

TOXIC DOSE

Metronidazole is available as 250- and 500-mg tablets, various strengths of compounded suspensions (some flavored), and as a 5-mg/mL injectable. The canine recommended oral dosage for anaerobic bacterial infections is 15 mg/kg every 12 hours.⁴ Recommendations for the same microbial infections in cats is a once daily oral treatment of 10 to 25 mg/kg.⁴ The canine dosage considered effective for infections with the protozoan Giardia is 12 to 15 mg/kg given orally every 12 hours.⁴ The recommended oral dosage for feline giardial infections is 17 mg/kg (about one third of a tablet per cat) once a day.⁴ The maximum daily dosage that is thought to be safe for any species should not exceed 50 mg/kg/day.

There is a strong correlation between dosage and duration of treatment and the time of onset and the severity of clinical signs associated with toxicity. In dogs, doses as low as 60 mg/kg have been shown to cause neurotoxicity when treated for as short a time as 3 to 14 days.^5,6 Doses above 250 mg/kg will show acute signs of poisoning shortly after metronidazole therapy is initiated. Most dogs showing neurotoxic signs receive lower dosages over a prolonged period of time. Cats have shown clinical signs of metronidazole poisoning at doses of 111 mg/kg daily for 9 weeks, and 58 mg/kg given daily for 6 months.^7,8

Although fetal abnormalities have not been documented at suggested dosages, metronidazole has been shown to be mutagenic and genotoxic in some species.^2,9 As a result, metronidazole is not recommended for use during pregnancy. Metronidazole is contraindicated in animals with liver disease, active neurological diseases, and blood dyscrasias.

Finally, the drug is bitter tasting. Tablets broken up or crushed are generally found to be unpalatable (particularly by cats). As mentioned, various flavored suspensions (citrus, fish, and chicken) are presently available through compounding pharmacies. Unfortunately, use of such flavored medications may actually increase the incidence of poisonings in children and animals since they may mistakenly ingest too much of a pleasant-tasting mixture that contains a potentially dangerous drug.

TOXICOKINETICS

Metronidazole is synthesized as pale yellow crystals that are slightly soluble in water and alcohol. Metronidazole is well absorbed from the gastrointestinal tract, and high concentrations of the drug are achieved in plasma, bone, peripheral tissue, and in the central nervous system (CNS).¹⁰ The half-life of metronidazole in most mammalian plasma is about 8 hours. The half-life in dogs is 3 to 13 hours. Metronidazole can be found in high concentrations in the cerebrospinal fluid.¹¹

Metronidazole is metabolized in the liver by oxidation and by glucuronide formation. It is excreted primarily by the kidneys. Urine of some patients may show reddish-brown color caused by water-soluble pigments derived from the drug. During exposure low concentrations of metronidazole can be found in both saliva and milk.¹⁰

MECHANISM OF TOXICITY

The mechanism of action of metronidazole follows four successive steps.¹² First, it enters susceptible organisms (anaerobic or microaerophilic microorganisms and hypoxic or anoxic cells). Next the nitro group of metronidazole is reduced by electron transport proteins and deprives the cell of required reduction mechanisms. Following this reductive activation step, the reduced intermediate molecule binds to microbial DNA, causing loss of helical structure, strand breakage, and impairment of normal DNA function. Cell death is caused by this disruption and degradation of the cellular DNA and by the release of inactive and nonfunctional cellular end products. Through these mechanisms metronidazole kills Giardia, trichomonads, various amebae, and the anaerobic bacteria Bacteroides. The exact nature of metronidazole poisoning remains unknown; however, the type of adverse neurological effects caused implicates central vestibular and cerebellar dysfunction.

Finally, metronidazole can produce reactions similar to disulfiram (Antabuse) if given simultaneously with ethanol. This drug and/or chemical interaction results in production of acetaldehyde in the blood. Acetaldehyde is hepatotoxic, cardiotoxic, and arrhythmogenic. Toxic reactions and fatalities have been reported as a result of metronidazole and/or ethanol interactions in humans; this is not likely to occur in pets.