Nitroimidazoles Lecture Notes

Discuss the mechanism of action, spectrum of activity, resistance, pharmacokinetics, indications, dosage, adverse effects, and drug interactions of nitroimidazoles.

Metronidazole is a prodrug.
It requires reductive activation of the nitro group by susceptible microorganisms.
Anaerobic bacteria and various protozoa (such as T. vaginalis, E. histolytica, and G. lamblia) have different energy metabolism compared to aerobic organisms.
Anaerobic organisms possess electron transport components like ferredoxins, which can donate electrons to metronidazole.
Metronidazole removes electrons from ferredoxin (or other electron transfer proteins with low redox potential), causing the reduction of the nitro group of the drug.
Ferredoxins donate electrons, resulting in a highly reactive nitro radical that damages DNA.
The reduced and highly reactive intermediate is responsible for the antimicrobial effect, likely by binding to DNA and causing strand breakage.
The requirement for interaction with low redox systems restricts the activity largely to anaerobic bacteria and certain protozoa that exhibit anaerobic metabolism.
The presence of oxygen reduces the activity of metronidazole.

Anaerobic bacteria including:
- Bacteroides spp
- Clostridium spp
- Fusobacterium spp
- Peptostreptococcus spp
- Prevotella spp
Susceptible protozoa include:
- Trichomonas vaginalis
- Giardia lamblia
- Entamoeba histolytica
- Balantidium coli
- Blastocystis hominis
Also active against:
- Helicobacter
- Gardnerella vaginalis (frequently sensitive)
Bactericidal effect.

Well absorbed.
- Oral absorption > 90%.
- Suppositories ∼ 60%.
Widely distributed in body tissues after oral or IV administration, including CSF and breast milk.
Half-life ∼8 hours (usually administered every 8-12 hours).
Less than 20% of the drug is bound to plasma proteins.
Metabolized mainly by the liver.
Unchanged drug and metabolites are excreted in urine.
Only about 10% recovered in urine as unchanged drug.
Urine of some patients may be reddish brown.

Gram-positive and Gram-negative anaerobic bacterial infections, e.g., B. fragilis.
Protozoal infections:
- Giardiasis
- Trichomoniasis
Clostridioides difficile-associated disease.
Dental infections, including acute gingivitis.
Bacterial vaginosis
Pelvic Inflammatory Disease (PID)
Amoebiasis (intestinal and extra-intestinal)
Surgical prophylaxis
Eradication of H. pylori (as part of a multidrug regimen)
Rosacea
Fungating wounds

Usually associated with a tumor.
Occur when the skin and supporting blood & lymph supply are infiltrated by a local tumor.
Occur more commonly near the end of life but can develop earlier.
Called a fungating wound because it fungates (becomes like a fungus in its appearance or growth rate).
Marked by ulcerations and dead tissue (necrosis).
Fungating wounds usually have a foul smell.

History of CNS disorders.
History of blood dyscrasias.
Treatment with disulfiram.
Treatment with fluorouracil.
Renal impairment:
- Metabolites may accumulate in severe impairment.
- Dose adjustment is not usually necessary.
Hepatic impairment:
- Risk of drug accumulation & toxicity in severe impairment.
Pregnancy: Safe.
Breastfeeding: Safe.

Oral: $200-400$ mg every $8-12$ hours, up to $4$ g daily.
Rectal: $1$ g every $8-12$ hours.
Severe infections: IV, $500$ mg every $8-12$ hours as part of multidrug treatment.
Clostridioides difficile-associated disease:
- Oral: $400$ mg every $8$ hours for $10$ days.
Bacterial vaginosis:
- Oral: $400$ mg twice daily for $7$ days.
Trichomoniasis:
- Oral: $2$ g single dose; or, if this fails, $400$ mg twice daily for $7$ days.
- Treat sexual partner(s) as well.
Giardiasis:
- $2$ g orally once daily for $3$ days; or, if this fails, $400$ mg every $8$ hours for $7$ days.

Common:
- Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain, anorexia, metallic taste.
- CNS effects: Headache, dizziness.
Infrequent:
- Furry tongue
- Glossitis
- Stomatitis
- Paraesthesia
Rare:
- Hypersensitivity reactions: rash, itch, flushing, fever
- Angioedema
- Anaphylactic shock
- Stevens-Johnson syndrome
- Peripheral neuropathy
- Seizures
- Clostridioides difficile-associated diarrhea (CDAD)
- Dark urine
Some adverse effects are more likely with high doses/prolonged treatment, e.g.:
- Leucopenia (reversible; usually only occurs after prolonged treatment)
- Peripheral neuropathy (usually reversible)
- CNS toxicity (e.g., seizures, encephalopathy, cerebellar toxicity)

Take tablets with food.
Liquid should be taken before food.
Is absorbed best if taken 1 hour before food.
May cause dizziness or confusion.
If affected, avoid driving.
Avoid alcohol during treatment & for 24 hours after finishing the course to prevent nausea, vomiting, flushing, headache, and palpitations.
Stop taking metronidazole and check with a doctor if:
- Numbness
- Tingling
- Pain or weakness in hands or feet.

Metronidazole + Alcohol:
- Can cause a disulfiram-like reaction. Should be avoided during treatment & for 24 hours after finishing treatment to prevent nausea, vomiting, headache, flushing, & palpitations.
Disulfiram:
- Combination should be avoided since it may cause confusion & psychotic reactions. Metronidazole should not be used within 2 weeks of disulfiram.
Fluorouracil:
- Metronidazole increases fluorouracil concentration & increases the risk of toxicity. Alternative anti-infective recommended.
Phenobarbitone:
- Phenobarbitone increases the metabolism of metronidazole leading to decreased concentration. May cause treatment failure.
Warfarin:
- Metronidazole inhibits warfarin metabolism leading to increased concentration and risk of bleeding. Consider an alternative antibiotic.