Azoles

This group includes:

• Metronidazole and tinidazole (antibacterial and antiprotozoal) which are described here.

• Fluconazole, itraconazole, clotrimazole, econazole, ketoconazole, isoconazole and miconazole which are described under Antifungal drugs (p. 264).

• Albendazole, mebendazole and thiabendazole which are described under Antihelminthic drugs (p. 276).

Metronidazole

In obligate anaerobic microorganisms (but not in aerobic microorganisms, which it also enters) metronidazole is converted into an active form by reduction of its nitro group: this binds to DNA and prevent nucleic acid formation; it is bacteriostatic.

Pharmacokinetics. Metronidazole is well absorbed after oral or rectal administration and distributed to achieve sufficient concentration to eradicate infection in liver, gut wall and pelvic tissues. It is eliminated in the urine, partly unchanged and partly as metabolites. The t'/2 is 8 h.

Uses. Metronidazole is active against a wide range of anaerobic bacteria and also protozoa. Its clinical indications are:

• Treatment of sepsis to which anaerobic organisms, e.g. Bacteroides spp. and anaerobic cocci, are contributing, notably postsurgical infection, intra-abdominal infection and septicaemia, but also wound and pelvic infection, osteomyelitis and abscesses of brain or lung

• Antibiotic-associated pseudomembraneous colitis (caused by Clostridium difficile)

• Trichomoniasis of the urogenital tract in both sexes

• Amoebiasis (Entamoeba histolytica), including both intestinal and extra-intestinal infection

• Giardiasis (Giardia lamblia)

• Acute ulcerative gingivitis and dental infections (Fusobacterium spp. and other oral anaerobic flora)

• Anaerobic vaginosis (Gardnerella vaginalis and vaginal anaerobes).

Dose. Established anaerobic infection is treated with metronidazole by mouth 400 mg 8-hourly; by rectum 1 g 8-hourly for 3 days followed by 1 g 12-hourly; or by i.v. infusion 500 mg 8-hourly. A topical gel preparation is useful for reducing the odour associated with anaerobic infection of fungating tumours.

Adverse effects include nausea, vomiting, diarrhoea, furred tongue and an unpleasant metallic taste in the mouth; also headache, dizziness and ataxia. Rashes, urticaria and angioedema occur. Peripheral neuropathy occurs if treatment is prolonged and epileptiform seizures if the dose is high. Large doses of metronidazole are carcinogenic in rodents and the drug is mutagenic in bacteria; long-term studies have failed to discover oncogenic effects in humans.

A disulfiram-like effect (see p. 186) occurs with alcohol because metronidazole inhibits alcohol and aldehyde dehydrogenase; patients should be warned appropriately.

Tinidazole is similar to metronidazole but has a longer t1/, (13 h). It is excreted mainly unchanged in the urine. The indications for use and adverse effects are essentially those of metronidazole. The longer duration of action of tinidazole may be an advantage, e.g. in giardiasis, trichomoniasis and acute ulcerative gingivitis, in which tinidazole 2 g by mouth in a single dose is as effective as a course of metronidazole.

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