Overview
This lecture covers the mechanism, spectrum, clinical uses, pharmacokinetics, and key side effects of the DNA synthesis inhibitor antibiotic metronidazole, with an emphasis on its action against anaerobic bacteria and protozoa.
Mechanism of Action
- Metronidazole (a 5-nitroimidazole) inhibits synthesis of nucleic acids, blocking DNA production in target organisms.
- Its activation requires reduction by ferredoxin, a sulfur- and iron-containing protein prevalent in anaerobic bacteria and protozoa.
- Activated metronidazole creates free radicals that fragment DNA, leading to cell death.
- Human cells and aerobic bacteria lack sufficient ferredoxin, making metronidazole selectively toxic.
Clinical Uses & Spectrum
- Effective against anaerobic bacteria such as Clostridioides difficile (causing pseudomembranous colitis).
- Used in combination therapy (with other antimicrobials and proton pump inhibitors) for Helicobacter pylori infections.
- Treats bacterial vaginosis due to Gardnerella vaginalis and other anaerobes.
- First-line treatment for protozoan infections: Entamoeba histolytica (amoebiasis), Trichomonas vaginalis (trichomoniasis), and Giardia lamblia (giardiasis).
Pharmacokinetics
- Metronidazole can be administered orally, intravenously, or as a topical cream.
- Distributes widely to body fluids and tissues, including vaginal and seminal fluids, saliva, breast milk, cerebrospinal fluid, and crosses the placenta.
- Metabolized in the liver and inhibits CYP450 enzymes, slowing the breakdown of drugs like warfarin.
Side Effects & Precautions
- Common side effects: decreased appetite, nausea, metallic taste, headaches, and stomach cramps.
- High doses or chronic use may cause neurological effects: seizures, confusion, peripheral neuropathy.
- Not recommended in the first trimester of pregnancy.
- May cause a disulfiram-like reaction (severe nausea, vomiting, headache) if alcohol is consumed during treatment.
Key Terms & Definitions
- DNA synthesis inhibitor — Drug class that halts DNA creation in microbes.
- Metronidazole — A 5-nitroimidazole antibiotic active against anaerobes and protozoa.
- Ferredoxin — Protein that reduces metronidazole, enabling its DNA-damaging action.
- Anaerobic bacteria — Bacteria that thrive without oxygen.
- Disulfiram-like reaction — Adverse reaction with alcohol including nausea and vomiting.
Action Items / Next Steps
- Review covered organisms and conditions treated by metronidazole.
- Memorize major adverse effects and contraindications.
- Read about CYP450 drug interactions, especially with warfarin.
- Avoid alcohol when taking metronidazole.