Metronidazole

Generic Name: Metronidazole
Drug Class: Nitroimidazole antimicrobial
Pharmacological Classification: Antibacterial and antiprotozoal agent
Formulations: Oral tablets, capsules, suspension, intravenous solution, topical gel/cream, vaginal gel, suppositories
Legal Status: Prescription-only medicine

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Mechanism of Action

Metronidazole is a synthetic nitroimidazole compound with selective toxicity against anaerobic bacteria and protozoa. In anaerobic conditions, it undergoes intracellular chemical reduction by redox proteins to form nitroso free radicals. These radicals bind and destabilize microbial DNA by inducing strand breakage and inhibiting DNA synthesis. Its action is highly dependent on the absence of oxygen, which is why it is effective primarily against obligate anaerobes and certain protozoa.

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Approved Indications

Systemic infections (oral or IV):

• Anaerobic bacterial infections (intra-abdominal, pelvic, dental, brain abscess, aspiration pneumonia)

• Bacterial vaginosis

• Trichomoniasis

• Giardiasis

• Amebiasis (intestinal and hepatic)

• Clostridioides difficile infection (as alternative or adjunct)

• Helicobacter pylori infection (in combination therapy)

Topical indications:

• Rosacea (gel, cream)

• Fungal or bacterial vaginal infections (vaginal gel or ovules)

Off-label uses:

• Crohn's disease (adjunct in perianal fistulae)

• Periodontitis

• Surgical prophylaxis (in colorectal procedures)

• Protozoal diarrhea

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Dosage and Administration

Adults – oral:

• Trichomoniasis: 2 g as a single dose, or 500 mg twice daily for 7 days

• Bacterial vaginosis: 500 mg twice daily for 7 days or 2 g single dose

• Giardiasis: 250 mg to 750 mg three times daily for 5–10 days

• Amoebiasis: 500–750 mg three times daily for 5–10 days

• Anaerobic infections: 500 mg every 8 hours (or every 6 hours depending on severity)

• Helicobacter pylori eradication: 400–500 mg twice daily with other agents

Intravenous:

• Loading dose: 15 mg/kg over 1 hour

• Maintenance: 500 mg every 8 hours (max: 4 g/day)

• For patients unable to take oral formulations or critically ill

Topical (rosacea):

• Apply thin film of 0.75% or 1% gel/cream once or twice daily

Vaginal gel:

• 5 g (0.75%) intravaginally once or twice daily for 5 days

Pediatric Dosing:

• Giardiasis: 15 mg/kg/day divided in 2–3 doses for 5–7 days

• Amebiasis: 35–50 mg/kg/day divided doses

• Adjusted based on weight and indication

Renal Impairment:

• Dose reduction not generally required unless in severe impairment with accumulation of metabolites

Hepatic Impairment:

• Significant hepatic dysfunction may necessitate dose reduction due to delayed clearance

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Pharmacokinetics

• Absorption: Rapid and complete from GI tract; oral bioavailability >90%

• Peak plasma concentration: Within 1–2 hours of oral intake

• Protein binding: ~10–20%

• Volume of distribution: Wide; includes CNS, bones, saliva, bile, seminal fluid, vaginal secretions

• Half-life: 8 hours in healthy adults; prolonged in liver impairment

• Metabolism: Primarily hepatic via oxidation and glucuronidation

• Excretion: Mainly via urine (60–80% as metabolites and unchanged drug); small amount in feces

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Contraindications

• Hypersensitivity to metronidazole or other nitroimidazole derivatives

• First trimester of pregnancy for trichomoniasis unless no alternatives

• Concurrent alcohol consumption or within 72 hours of cessation due to disulfiram-like reaction

• Severe hepatic disease (caution or contraindicated in high doses)

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Warnings and Precautions

• Carcinogenic Potential: Demonstrated in rodents; use limited to appropriate indications and duration

• Neurological Effects: Long-term or high-dose use may cause peripheral neuropathy, seizures, or encephalopathy; discontinue if neurological symptoms appear

• Hematologic Effects: Rare cases of leukopenia and neutropenia; periodic blood counts recommended in prolonged therapy

• Disulfiram-like Reaction: Alcohol ingestion causes nausea, vomiting, abdominal cramps, flushing, and tachycardia; avoid during and for 72 hours post-treatment

• Superinfection Risk: Prolonged use may promote overgrowth of non-susceptible organisms including fungi

• Severe Hepatic Impairment: Accumulation of drug and metabolites may occur; monitor liver function and reduce dose

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Adverse Effects

Common:

• Nausea

• Vomiting

• Diarrhea

• Metallic taste

• Anorexia

• Abdominal discomfort

• Headache

Uncommon:

• Dizziness

• Darkened urine

• Stomatitis or glossitis

• Insomnia

• Rash or itching

• Vaginal irritation (in vaginal use)

Serious/Rare:

• Peripheral neuropathy

• Seizures

• Encephalopathy

• Leukopenia or thrombocytopenia

• Anaphylaxis

• Stevens-Johnson syndrome

• Hepatotoxicity

• Pancreatitis

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Drug Interactions

• Alcohol: Produces severe disulfiram-like reactions; contraindicated

• Warfarin and other coumarin anticoagulants: Potentiates anticoagulant effect; increases INR; monitor closely

• Disulfiram: May cause acute psychosis or confusion when combined

• CYP3A4 inhibitors/inducers: May alter plasma levels

• Lithium: Increases lithium levels and toxicity risk

• Phenobarbital/phenytoin: May reduce metronidazole levels

• Fluorouracil: Enhanced toxicity when co-administered

• Busulfan: Increases plasma concentrations; avoid coadministration

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Use in Specific Populations

Pregnancy:

• Crosses placenta

• Avoid in first trimester unless benefits outweigh risks

• Generally considered safe in 2nd and 3rd trimesters

Lactation:

• Excreted in breast milk

• Temporary discontinuation of breastfeeding may be considered during high-dose or prolonged use

Pediatrics:

• Safe and effective for parasitic infections when dosed properly

• Monitor for neurologic adverse events

Elderly:

• No specific adjustment needed unless hepatic impairment or polypharmacy is present

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Monitoring Parameters

• CBC during prolonged therapy

• Liver function tests in patients with hepatic risk

• Neurologic signs and symptoms

• Therapeutic response based on infection type

• INR if patient is on warfarin

• Serum lithium levels if used concurrently

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Overdose

Symptoms:

• Nausea

• Vomiting

• Ataxia

• Seizures

• Peripheral neuropathy

Management:

• Symptomatic and supportive care

• No specific antidote

• Hemodialysis may help remove drug in severe toxicity

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Storage and Stability

• Store oral formulations at room temperature below 25°C

• Protect from light and moisture

• Do not freeze injectable forms

• Use topical gel within prescribed expiry post-opening