Metronidazole Drug - Medicinal Chemistry & Uses

 Metronidazole is a nitroimidazole antibiotic drug. Nitroimidazoles are imidazole heterocycles that have a nitro group that is used to combat anaerobic bacterial and parasitic infections. The group was originally introduced in 1957 to treat vaginal infections by amoeba, but is now used for the treatment of pseudomembranous enterocolitis caused by Clostridium difficile, an opportunistic pathogen, and as part of a cocktail for Helicobactor pylori. Metronidazole is also used to treat giardia infections of the small intestines, amebic liver abscess and dysentery, trichomonas vaginal infections, and carriers of trichomonas (both sexual partners) who do not have symptoms of infection. Metronidazole is also used alone or in combination with other antibiotics in treating abscesses in the liver, pelvis, abdomen and brain caused by susceptible anaerobic bacteria.


     Metronidazole and other 5-nitroimidazoles are prodrugs that must be cleaved in vivo by CytP450s. The drug diffuses into the cells of protozoa or anaerobic bacteria, where the nitro group is reduced by a "ferredoxin-mediated electron transport system," producing short-lived toxic radicals. The formation of the toxic radical also helps more Metronidazole diffuse into the cell, since the intracellular concentration of Metronidazole decreases as more prodrug is created. It is unclear how nitroimidazoles kill the susceptible bacteria, but it is conjectured that the toxic intermediates bind covalently to DNA, damaging it beyond repair. Mammalian cells are not affected because the presence of oxygen will inhibit the nitrogen-reduction process.

    Bacterial resistance to metronidazole was reported almost immediately after the drug was introduced onto the market. Resistance is rare, but does seems to be increasing. An observational study conducted in 2 chronic vaginitis clinics in Detroit and Philadelphia noted that rates of bacterial resistance increased from <2 incidences per year in 1994 to 7 incidences in 1997 and 10 incidinces in 1998. Resistance, although still not common, seems like it could become a problem in the future, and so there has been interest in creating analogues that will evade bacterial defenses. Tinidazole, an analogue that replaces metronidazole's 2-(hydroxyl)ethyl group with a the 2-(ethylsulfonyl)ethyl moiety, will hopefully be useful in combating bacterial resistance.

Clinical Uses of Metronidazole

Metronidazole is available in a 500mg/100ml intravenous solution, a 375mg oral capsule, a 250mg and 500mg oral tablet, and a 750mg extended release oral tablet. Topically, metronidazole is available as a 0.75% and 1% cream, a 0.75% topical emulsion, gel/jelly, lotion and vaginal gel/jelly. The drug is contraindicated in patients with a metronidazole or nitroimidazole sensitivity, people who are sensitive to the parabens used in gel formulations, and in women in their first trimester of pregnancy (can be used cautiously in 2nd and 3rd trimester). Precaution should be used in patients that are receiving anti-coagulant therapy, that have concomitant blood dyscrasia, or a prior or current history of central nervous system disease (risk of seizure or peripheral neuropathy). Patients with severe hepatic disease or that might have enhanced elimination due to phentoin or Phenobarbital therapy should be closely monitored. A patient with concomitant alcohol consumption could have a possible disulfiram reaction, which includes flushing, nausea, vomiting, and tachycardia 6.

    Mild side effects of Metronidazole therapy may include nausea, headaches, loss of appetite, a metallic taste, and occasionally a rash. Metronidazole is generally well tolerated, so serious side effects are rare. If a patient experiences seizures and damage of nerves resulting in numbness and tingling of extremities, the drug should be discontinued. Metronidazole can increase the blood thinning effects of warfarin and increase the risk of bleeding. Cimetidine increases the blood level of metronidazole. Other probable drug-drug interactions include those that occur with amiodarone, amprenavir, busulfan, carbamazepine, cholestyramine, cyclosporine, dihydroergotamine, disulfiram, ergoloid mesylates, ergonovine, ergotamine, fluorouracil, lithium, methylergonovine, milk thistle and tacrolimus. Metronidazole can be taken with or without food, and the patient should be sure to complete the course of treatment rather than discontinue upon improvement of symptoms 5,6.

    Metronidazole will continue to be a useful and effective antibiotic in the future. If resistance become more common, other 5-nitroimidazoles such as Tinidazole will become more popular in clinical use.