METRONIDAZOLE
Chemistry - A synthetic, nitroimidazole antibacterial and antiprotozoal agent, metronidazole occursas white to pale yellow crystalline powder or crystals with a pKa of 2.6. It is sparingly soluble inwater or alcohol. Metronidazole base is commercially available as tablets or solution for IV injectionand metronidazole HCl is available as injectable powder for reconstitution. The hydrochloride isvery soluble in water.
Specific recommendations on the reconstitution, dilution, and neutralization of metronidazole HClpowder for injection are detailed in the package insert of the drug and should be referred to if thisproduct is used. Do not use aluminum hub needles to reconstitute or transfer this drug as a reddish-brown discoloration may result in the solution.
The following drugs and solutions are reportedly compatible with metronidazole ready-to-usesolutions for injection: amikacin sulfate, aminophylline, carbenicillin disodium, cefazolin sodium, cefotaxime sodium, cefoxitin sodium, cefuroxime sodium, cephalothin sodium, chloramphenicolsodium succinate, clindamycin phosphate, disopyramide phosphate, gentamicin sulfate, heparinsodium, hydrocortisone sodium succinate, hydromorphone HCl, magnesium sulfate, meperidine
HCl, morphine sulfate, moxalactam disodium, multielectrolyte concentrate, multivitamins, netilmicinsulfate, penicillin G sodium, and tobramycin sulfate.
The following drugs and solutions are reportedly incompatible (or compatibility data conflicts)with metronidazole ready-to-use solutions for injection: aztreonam, cefamandole naftate anddopamine HCl.
Metronidazole has activity against most obligate anaerobes including Bacteroides sp. (including B.fragilis), Fusobacterium, Veillonella, Clostridium sp., peptococcus, and peptostreptococcus.
Actinomyces is frequently resistant to metronidazole.
Metronidazole is also trichomonacidal and amebicidal in action and acts as a direct amebicide. Itsmechanism of action for its antiprotozoal activity is not understood. It has therapeutic activityagainst Entamoeba histolytica, Trichomonas, Giardia, and Balantidium coli. It acts primarilyagainst the trophozoite forms of Entamoeba rather than encysted forms.
In horses, metronidazole has been used clinically for the treatment of anaerobic infections.
Metronidazole is rather lipophilic and is rapidly and widely distributed after absorption. It isdistributed to most body tissues and fluids, including to bone, abscesses, the CNS, and seminalfluid. It is less than 20% bound to plasma proteins in humans.
Metronidazole is primarily metabolized in the liver via several pathways. Both the metabolites andunchanged drug are eliminated in the urine and feces. Elimination half-lives of metronidazole inpatients with normal renal and hepatic function in various species are reported as: humans 6-8hours, dogs 4-5 hours, and horses 2.9-4.3 hours.
Metronidazole has been implicated as being a teratogen in some laboratory animal studies, but noinformation is available for dogs and cats. Unless the benefits to the mother outweigh the risks tothe fetuses, it should not be used during pregnancy, particularly during the first 3 weeks ofgestation.
Neurologic toxicity may be manifested after acute high dosages or, more likely, with chronicmoderate to high-dose therapy. Symptoms reported are described below in the Overdosage section.
These effects may be seen with either acute overdoses or in some animals with chronic therapywhen using "recommended" doses.
Acute overdoses should be handled by attempting to limit the absorption of the drug using standard protocols. Extreme caution should be used before attempting to induce vomiting in patientsdemonstrating CNS effects or aspiration may result. If acute toxicity is seen after chronic therapy, the drug should be discontinued and the patient treated supportively and symptomatically.
Neurologic symptoms may require several days before showing signs of resolving.
Phenobarbital or phenytoin may increase the metabolism of metronidazole, thereby decreasingblood levels.
Cimetidine may decrease the metabolism of metronidazole and increase the likelihood of dose-related side effects occurring.
Alcohol may induce a disulfiram-like (nausea, vomiting, cramps, etc.) reaction when given withmetronidazole.
Drug/Laboratory Interactions - Metronidazole causes falsely decreased readings of AST(SGOT) and ALT (SGPT) when determined using methods measuring decreases in ultravioletabsorbance when NADH is reduced to NAD.
Storage, Stability, Compatibility
Metronidazole tablets and HCl powder for injection should bestored at temperatures less than 30°C and protected from light. The injection should be protectedfrom light and freezing and stored at room temperature.Specific recommendations on the reconstitution, dilution, and neutralization of metronidazole HClpowder for injection are detailed in the package insert of the drug and should be referred to if thisproduct is used. Do not use aluminum hub needles to reconstitute or transfer this drug as a reddish-brown discoloration may result in the solution.
The following drugs and solutions are reportedly compatible with metronidazole ready-to-usesolutions for injection: amikacin sulfate, aminophylline, carbenicillin disodium, cefazolin sodium, cefotaxime sodium, cefoxitin sodium, cefuroxime sodium, cephalothin sodium, chloramphenicolsodium succinate, clindamycin phosphate, disopyramide phosphate, gentamicin sulfate, heparinsodium, hydrocortisone sodium succinate, hydromorphone HCl, magnesium sulfate, meperidine
HCl, morphine sulfate, moxalactam disodium, multielectrolyte concentrate, multivitamins, netilmicinsulfate, penicillin G sodium, and tobramycin sulfate.
The following drugs and solutions are reportedly incompatible (or compatibility data conflicts)with metronidazole ready-to-use solutions for injection: aztreonam, cefamandole naftate anddopamine HCl.
Pharmacology - METRONIDAZOLE
Metronidazole is bactericidal against susceptible bacteria. Its exact mechanism ofaction is not completely understood, but it is taken up by anaerobic organisms where it is reduced toan unidentified polar compound. It is believed that this compound is responsible for the drug'santimicrobial activity by disrupting DNA and nucleic acid synthesis in the bacteria.Metronidazole has activity against most obligate anaerobes including Bacteroides sp. (including B.fragilis), Fusobacterium, Veillonella, Clostridium sp., peptococcus, and peptostreptococcus.
Actinomyces is frequently resistant to metronidazole.
Metronidazole is also trichomonacidal and amebicidal in action and acts as a direct amebicide. Itsmechanism of action for its antiprotozoal activity is not understood. It has therapeutic activityagainst Entamoeba histolytica, Trichomonas, Giardia, and Balantidium coli. It acts primarilyagainst the trophozoite forms of Entamoeba rather than encysted forms.
Uses, Indications
Although there are no veterinary-approved metronidazole products, the drughas been used extensively in the treatment of Giardia in both dogs and cats. It is also used clinically in small animals for the treatment of other parasites (Trichomonas and Balantidium coli) aswell as treating both enteric and systemic anaerobic infections.In horses, metronidazole has been used clinically for the treatment of anaerobic infections.
Pharmacokinetics - METRONIDAZOLE
Metronidazole is relatively well absorbed after oral administration. The oralbioavailability in dogs is high, but interpatient variable with ranges from 50-100% reported. Theoral bioavailability of the drug in horses averages about 80% (range 57-100%). If given with food, absorption is enhanced in dogs, but delayed in humans. Peak levels occur about one hour afterdosing.Metronidazole is rather lipophilic and is rapidly and widely distributed after absorption. It isdistributed to most body tissues and fluids, including to bone, abscesses, the CNS, and seminalfluid. It is less than 20% bound to plasma proteins in humans.
Metronidazole is primarily metabolized in the liver via several pathways. Both the metabolites andunchanged drug are eliminated in the urine and feces. Elimination half-lives of metronidazole inpatients with normal renal and hepatic function in various species are reported as: humans 6-8hours, dogs 4-5 hours, and horses 2.9-4.3 hours.
Contraindications, Precautions, Reproductive Safety
Metronidazole is contraindicated inanimals hypersensitive to the drug or nitroimidazole derivatives. It has also been recommended notto use the drug in severely debilitated, pregnant or nursing animals. Metronidazole should be usedwith caution in animals with hepatic dysfunction.Metronidazole has been implicated as being a teratogen in some laboratory animal studies, but noinformation is available for dogs and cats. Unless the benefits to the mother outweigh the risks tothe fetuses, it should not be used during pregnancy, particularly during the first 3 weeks ofgestation.
Adverse Effects, Warnings
Adverse effects reported in dogs include neurologic disorders, lethargy, weakness, neutropenias, hepatotoxicity, hematuria, anorexia, nausea, vomiting and diarrhea.Neurologic toxicity may be manifested after acute high dosages or, more likely, with chronicmoderate to high-dose therapy. Symptoms reported are described below in the Overdosage section.
Overdosage, Acute Toxicity
Signs of intoxication associated with metronidazole in dogs andcats, include anorexia and/or vomiting, depression, mydriasis, nystagmus, ataxia, head-tilt, deficits ofproprioception, joint knuckling, disorientation, tremors, seizures, bradycardia, rigidity and stiffness.These effects may be seen with either acute overdoses or in some animals with chronic therapywhen using "recommended" doses.
Acute overdoses should be handled by attempting to limit the absorption of the drug using standard protocols. Extreme caution should be used before attempting to induce vomiting in patientsdemonstrating CNS effects or aspiration may result. If acute toxicity is seen after chronic therapy, the drug should be discontinued and the patient treated supportively and symptomatically.
Neurologic symptoms may require several days before showing signs of resolving.
Drug Interactions
Metronidazole may prolong the PT in patients taking warfarin or othercoumarin anticoagulants. Avoid concurrent use if possible; otherwise, intensify monitoring.Phenobarbital or phenytoin may increase the metabolism of metronidazole, thereby decreasingblood levels.
Cimetidine may decrease the metabolism of metronidazole and increase the likelihood of dose-related side effects occurring.
Alcohol may induce a disulfiram-like (nausea, vomiting, cramps, etc.) reaction when given withmetronidazole.
Drug/Laboratory Interactions - Metronidazole causes falsely decreased readings of AST(SGOT) and ALT (SGPT) when determined using methods measuring decreases in ultravioletabsorbance when NADH is reduced to NAD.