What are the potential drug interactions with metronidazole?

Metronidazole Drug Interactions

Metronidazole has several clinically significant drug interactions that can increase morbidity and mortality, with warfarin interaction being the most concerning due to increased bleeding risk. 1

Major Drug Interactions

Anticoagulants

• Metronidazole potentiates the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in prolongation of prothrombin time and increased risk of bleeding 2
• A pre-emptive warfarin dose reduction of 33% is recommended when co-administered with metronidazole 1
• More frequent INR monitoring is essential when initiating metronidazole in patients on stable warfarin therapy 1

Alcohol

• Concurrent use of metronidazole with alcoholic beverages should be avoided during treatment and for at least one day afterward 2
• Although traditionally warned against due to potential disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing), evidence for this interaction is mixed 3
• Despite some controversy about the frequency and severity of this interaction, a case of sudden death has been reported due to metronidazole/ethanol interaction resulting in acetaldehyde toxicity 4
• Even alcohol-containing medications (oral solutions) can trigger this reaction, which may initially go unrecognized 5

Psychotropic Medications

• Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently 2
• Metronidazole should not be given to patients who have taken disulfiram within the last two weeks 2

Antidiabetic Medications

• Metronidazole can interact with sulfonylureas, potentially causing hypoglycemia 1
• Consider temporarily decreasing or stopping sulfonylureas when metronidazole is prescribed 1

Hepatic Metabolism Interactions

• Drugs that induce microsomal liver enzymes (e.g., phenytoin, phenobarbital) may accelerate the elimination of metronidazole, resulting in reduced plasma levels 2
• Conversely, drugs that decrease microsomal liver enzyme activity (e.g., cimetidine) may prolong the half-life and decrease plasma clearance of metronidazole 2
• Impaired clearance of phenytoin has also been reported when used with metronidazole 2

Lithium

• Short-term metronidazole therapy has been associated with elevation of serum lithium and, in some cases, signs of lithium toxicity in patients on relatively high doses of lithium 2
• Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication 2

Special Populations and Considerations

Patients with Hepatic Disease

• Patients with severe hepatic disease metabolize metronidazole slowly, resulting in accumulation of metronidazole and its metabolites in plasma 2
• Lower doses should be administered cautiously in these patients 2

Laboratory Test Interference

• Metronidazole may interfere with certain serum chemistry determinations, including AST, ALT, LDH, triglycerides, and glucose 2
• This interference is due to similarity in absorbance peaks of NADH and metronidazole at pH 7 2

Clinical Management Recommendations

When Prescribing Metronidazole

1. Review all current medications for potential interactions
2. Reduce warfarin dose by approximately 33% when initiating metronidazole 1
3. Advise patients to avoid alcohol during treatment and for at least one day afterward 2
4. Monitor INR more frequently in patients on warfarin 1
5. Check for alcohol content in other prescribed medications, including oral solutions 5
6. Consider alternative treatments in cases where drug interactions make metronidazole use inadvisable:
   • For trichomoniasis: furazolidone, clotrimazole, or paromomycin 6
   • For bacterial vaginosis: clindamycin (topically or systemically) 6
   • For C. difficile: oral vancomycin, nitazoxanide, or rifaximin 6

Common Pitfalls to Avoid

• Failing to recognize alcohol content in oral medications, which can trigger disulfiram-like reactions 5
• Not adjusting warfarin dosing when initiating or discontinuing metronidazole 1
• Overlooking the need for more frequent monitoring of patients on medications with known interactions 1, 2
• Not considering hepatic function when dosing metronidazole 2

By understanding and anticipating these drug interactions, clinicians can minimize adverse events and optimize treatment outcomes when prescribing metronidazole.