Azoles

crop_square Key points

  • check_circle Widely used for topical and systemic fungal infections
  • check_circle Inhibit ergosterol biosynthesis by blocking the enzyme cytochrome P450 14α-demethylase
  • check_circle Imidazoles are more toxic, and their use is nowadays restricted to topical mycoses
  • check_circle Second-generation triazoles are well tolerated with a broad spectrum of activity

crop_square Background and biochemistry

Azoles are widely used antifungals for both superficial and systemic mycoses. Antifungal properties of azoles were first described in the 1940s, but it was not until the late 1960s that azole-based antifungals became commercially available (i.e., Clotrimazole). However, these drugs proved too toxic for systemic treatment. Miconazole was the first azole approved for intravenous administration in 1978. In 1981, the imidazole derivate ketoconazole was introduced as an oral drug for systemic fungal infections. All azole drugs on the market had been imidazole derivates until 1990, when fluconazole became the first triazole antifungal to approved by the FDA. Fluconazole showed an improved spectrum of activity and less adverse effects compared to imidazoles like ketoconazole. A further advancement was the introduction of second-generation azoles like voriconazole in 2002. All Azoles are five-membered heterocyclic rings containing one or more nitrogen atom and other non-carbon atoms.

crop_square Mechanism of action

Azoles interfere with the biosynthesis of ergosterol, the primary constituent of fungal cell membranes. They inhibit the enzyme cytochrome P450 14α-demethylase, which catalysed the demethylation of lanosterol. This enzyme is found in both fungal and mammalian cells and catalyses lanosterol to ergosterol and cholesterol, respectively. However, fungal cytochrome P450 14α-demethylase is up to a thousand times more sensitive to azole drugs. Enzyme inhibition in the fungal cell leads to a loss of ergosterol, an accumulation of ergosterol precursors and subsequently, altered fungal cell membrane permeability. Azoles are fungistatic drugs. Resistances to azoles are on the rise, especially in Candida species. Known mechanisms of resistance include fungal drug efflux pumps and mutations to the demethylase binding site.

crop_square Drugs and spectrum of activity

Imidazoles
  • Clotri­mazole
  • Keto­conazole
  • Mico­nazole

Note that the use of imidazoles for systemic fungal infections is obsolete as safer and more effective drugs are available. Imidazoles are nowadays exclusively used to treat superficial fungal infections.


First-generation triazoles
  • Fluco­nazole
  • Itra­conazole


Fluconazole has a narrower spectrum than other azoles. Itraconazole is active against a wider range of fungi including aspergillus species.


Second-generation triazoles
  • Vori­conazole
  • Posa­conazole
  • Isavu­conazole (oral prodrug: isavuconazonium)

Second-generation triazoles are superior in the treatment of aspergillosis. Posaconazole and isavuconazole are extended-spectrum antifungals with activity against Mucoraceae (family) and Mucorales (order) and may be used to treat mucormycosis.

crop_square Pharmacokinetics

Imidazoles are not used for systemic treatment. First- and second-generation triazoles show excellent bioavailability after oral administration. Fluconazole and isavuconazole sufficiently penetrate the blood-brain barrier. Elimination half-life varies greatly in azole drugs, from as little as 6h in voriconazole to up to 130h in isavuconazole. All azoles are extensively hepatically metabolised, mostly by cytochrome P450 enzymes. Metabolites are eliminated via the urine, and to a lesser degree through faeces.

crop_square Adverse drug effects

Triazoles are generally well tolerated. They may interact with drugs that are metabolised through cytochrome P450. Adverse effects of triazoles include gastrointestinal symptoms, headache, and elevated liver enzymes.