Mechanism of Action of Metronidazole (DNA-Damaging Antibiotic)

Introduction

Metronidazole is a unique antibiotic and antiprotozoal agent that exerts its action by damaging DNA in anaerobic organisms. It’s a first-line treatment for anaerobic bacterial infections, Clostridium difficile, and protozoal infections like Giardiasis and Trichomoniasis. It is especially important for medical and pharmacy students in the US preparing for USMLE, NCLEX, NAPLEX, and GPAT, due to its broad clinical use, adverse effect profile, and unique mechanism among antibiotics.

---

Mechanism of Action of Metronidazole: Step-by-Step

1. Passive diffusion into anaerobic organisms
   Metronidazole enters microbial cells by passive diffusion, as it is a lipophilic molecule.
2. Reduction of nitro group in anaerobic environment
   In anaerobes and protozoa, low redox potential allows the nitro group of metronidazole to be reduced by ferredoxin-like proteins.
3. Formation of reactive free radicals
   This reduction generates nitroso free radicals, which are cytotoxic.
4. Disruption of DNA structure
   The reactive radicals bind to DNA, causing strand breaks, loss of helical structure, and inhibition of nucleic acid synthesis.
5. Cell death
   The cumulative DNA damage leads to cell death, making metronidazole bactericidal and protozoacidal.
6. Selective toxicity
   Mammalian cells do not have the enzymes necessary to reduce metronidazole, ensuring selective targeting of pathogens.

---

Pharmacokinetic Parameters of Metronidazole

Parameter	Value
Bioavailability	~100% (excellent oral absorption)
Half-life	~8 hours
Protein binding	~10–20%
Metabolism	Hepatic (via CYP enzymes)
Excretion	Urine (~60–80% as metabolites)
CNS penetration	Good (used in brain abscesses)

---

Clinical Uses of Metronidazole

• Anaerobic infections (Bacteroides, Clostridium spp.)
• Clostridium difficile-associated diarrhea (CDAD)
• Trichomoniasis
• Giardiasis
• Amebiasis
• Bacterial vaginosis
• Intra-abdominal and pelvic infections (with other agents)
• Brain abscesses (anaerobic coverage)

---

Adverse Effects of Metronidazole

• Metallic taste
• Nausea, vomiting, abdominal discomfort
• Headache and dizziness
• Peripheral neuropathy (with prolonged use)
• Disulfiram-like reaction (with alcohol)
• Darkened urine
• CNS toxicity (rare)

---

Comparative Analysis: Metronidazole vs Tinidazole

Feature	Metronidazole	Tinidazole
Half-life	~8 hours	~12–14 hours
Duration of therapy	Longer (5–10 days)	Shorter (single dose to 3 days)
GI side effects	More common	Less common
Alcohol interaction	Strong disulfiram-like reaction	Same risk

---

Practice MCQs

Q1. Metronidazole acts by:
a. Inhibiting peptidoglycan synthesis
b. Inhibiting folate synthesis
c. Disrupting bacterial DNA via radicals ✅
d. Inhibiting 50S ribosome

Q2. Which organisms activate metronidazole?
a. Aerobic bacteria
b. Gram-positive cocci
c. Anaerobes ✅
d. Fungi

Q3. A classic adverse effect with alcohol and metronidazole is:
a. Hypoglycemia
b. Red man syndrome
c. Disulfiram-like reaction ✅
d. Serotonin syndrome

Q4. Metronidazole is first-line for:
a. Syphilis
b. Clostridium difficile ✅
c. MRSA
d. TB

Q5. Which of the following is a protozoal indication for metronidazole?
a. Leishmaniasis
b. Trichomoniasis ✅
c. Malaria
d. Trypanosomiasis

Q6. What is the bioavailability of metronidazole?
a. 40%
b. 60%
c. ~100% ✅
d. <10%

Q7. Peripheral neuropathy occurs with:
a. Short use
b. Long-term use ✅
c. IV only
d. Rectal administration

Q8. How is metronidazole excreted?
a. Hepatic
b. Pulmonary
c. Renal ✅
d. Sweat

Q9. Can metronidazole be used in brain infections?
a. No
b. Yes, due to good CNS penetration ✅
c. Only topically
d. Only rectally

Q10. Which class best describes metronidazole?
a. Antifungal
b. Aminoglycoside
c. Nitroimidazole ✅
d. Glycopeptide

---

FAQs

Q1: Is metronidazole safe during pregnancy?
It is generally safe in the second and third trimesters, but caution is advised in the first trimester.

Q2: Why avoid alcohol with metronidazole?
It causes a disulfiram-like reaction — flushing, nausea, vomiting, and palpitations.

Q3: Can metronidazole be used in combination therapy?
Yes, it is often combined with cephalosporins or aminoglycosides for polymicrobial infections.

Q4: How long is metronidazole therapy for trichomoniasis?
Usually 2–5 days, or sometimes a single 2g dose.

Q5: Can it treat H. pylori?
Yes, metronidazole is part of triple therapy in H. pylori eradication protocols.

---

References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK547677/