Nitroimidazoles

Nitroimidazoles C화학적 특성, 용도, 생산

Antimicrobial activity

BACTERIA
The 5-nitroimidazoles exhibit excellent potency against anaerobic bacteria , including Bacteroides spp., Clostridium spp., Prevotella spp. and Fusobacterium spp. Most isolates of Mobiluncus curtisii are resistant to metronidazole and its hydroxy metabolite, while Mobiluncus mulieris is often sensitive. Other susceptible bacteria include Capnocytophaga spp. and Campylobacter fetus. Most Actinomyces and Propionibacterium spp. are resistant. Among facultative anaerobes, Actinobacillus actinomycetemcomitans and Eikenella corrodens are usually resistant, while Gardnerella vaginalis is frequently sensitive, more so to the hydroxy metabolite of metronidazole.
PROTOZOA
Susceptible protozoa include T. vaginalis, Giardia lamblia, Entamoeba histolytica, Balantidium coli and Blastocystis hominis. The spectrum of benznidazole is restricted to Trypanosoma cruzi.
FACTORS AFFECTING ACTIVITY IN VITRO
All nitroimidazoles exert their antimicrobial activity via reduction of the nitro group, which only occurs at low redox potentials. The major factor affecting in-vitro activity is therefore the failure to achieve anaerobic conditions, which can lead to reporting of false resistance. The presence of traces of oxygen may inhibit or reverse reduction of the drug through ‘futile cycling’. It is essential, therefore, to ensure that fully anaerobic conditions are maintained during susceptibility testing.
All nitroimidazoles are capable of being photodegraded and should be protected from light.

Pharmaceutical Applications

An imidazole ring is an important feature of many natural compounds with a wide range of biological activities. Nitroimidazoles with antimicrobial activity emerged from a search for a drug that would provide an effective treatment for infections caused by protozoa of the Trichomonas genus, including the human pathogen, Trichomonas vaginalis. The first active compound was an antibiotic, azomycin (2-nitroimidazole) produced by a streptomycete. It was soon abandoned, but led to the synthesis of several hundred related compounds, one of which, the 5-nitroimidazole metronidazole, combined activity against the parasites with acceptable animal toxicity. The compound was marketed in 1960 and 2 years later was fortuitously found also to possess potent activity against anaerobic bacteria.
Numerous 5-nitroimidazoles were subsequently developed. Metronidazole and tinidazole are in widespread clinical use; others include nimorazole, ornidazole and secnidazole. The 2-nitroimidazole, benznidazole, is uniquely used in the treatment of South American trypanosomiasis (Chagas disease); fexinidazole is under investigation in African trypanosomiasis (sleeping sickness). Carnidazole, dimetridazole, ipronidazole and ronidazole are used in veterinary medicine and are not discussed further here.
Other imidazole derivatives are used as antifungal agents (Chapter 32) and anthelmintics (Chapter 34). Some, chiefly 2-nitroimidazoles, have been examined as possible radiosensitizers for the treatment of hypoxic tumors.

Pharmacokinetics

Nitroimidazoles are generally well absorbed following oral administration. Following rectal or vaginal administration, bioavailability is approximately 60% and 20%, respectively, with considerable variation between individuals. Binding to proteins is low. Peak plasma levels are achieved 3–5 h after an oral dose. The decay from the peak is exponential, with the rate depending on the half-life of the drug. Dose-proportional kinetics are observed for clinically relevant doses. The concentrations after normal oral doses are well above the MICs for anaerobes but are borderline for G. vaginalis. The nitroimidazoles are well distributed to peripheral compartments, including brain tissue and cerebrospinal fluid, but concentrations in subcutaneous fat are 15% or less of concurrent serum levels.
Nitroimidazoles are metabolized mainly by the liver and excreted in the urine. Derivatives with a 2-methyl group (except nimorazole) are metabolized to the corresponding methoxy derivative and those with an alcohol side chain are metabolized to the corresponding acid metabolite. All can form glucuronide conjugates and, occasionally, the ethereal sulfate conjugate.

Clinical Use

Nitroimidazoles are the most active antibiotics for the treatment and prevention of infections involving anaerobic bacteria. They are therefore important in the treatment of intraabdominal and gynecological sepsis, abscesses and specific clinical syndromes such as tetanus. They are also an important component of prophylactic regimens for surgical procedures where contamination with anaerobic flora is likely. They are used to treat bacterial vaginosis (frequently associated with G. vaginalis) and dental infections, including acute necrotizing ulcerative gingivitis (Vincent’s angina). Metronidazole is the treatment of choice for antibiotic-associated diarrhea caused by C. difficile for all but those with recurrent, complicated or fulminant disease, for whom oral vancomycin is recommended. Metronidazole and tinidazole are also used as part of eradication regimens for H. pylori, although resistance may affect 10–50% of strains isolated in developed countries and virtually all strains from developing countries.
The nitroimidazoles provide the first-line treatment for giardiasis, amebiasis and trichomonal vaginitis, and may also be used to treat balantidiasis. Benznidazole is used for the treatment of Trypanosoma cruzi infections (Chagas disease).
These drugs have also been used as hypoxic cell sensitizers in the radiotherapy of tumors, in the treatment of bacterial overgrowth syndromes and in the prevention of recurrence of Crohn’s disease.

부작용

The most common side effects are gastrointestinal (including nausea and diarrhea) and a metallic taste, especially when high doses are used. A reversible peripheral neuropathy may occur in patients receiving high doses for prolonged periods, particularly in the treatment of hypoxic tumors. Central neurotoxicity has also been reported and the drug should be discontinued if any abnormal neurological symptoms are reported. If combined with alcohol, metronidazole may cause a disulfiram-like reaction, with nausea, vomiting, flushing of the skin, tachycardia, hypotension and palpitations.
Although nitroimidazoles have been found to be mutagenic and carcinogenic in animal studies, there is no evidence that they are carcinogenic to humans. Nevertheless, they should only be used in pregnancy when the benefits outweigh the risks, and should be avoided altogether in the first trimester. Because the concentrations in breast milk are similar to those in serum, a risk assessment should be performed before use in lactating mothers.

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