Pharmacology of Azole Antifungals

Azole antifungals are among the most widely prescribed antifungal drugs. They are used in the treatment of a wide and diverse range of fungal infections. Here, we review those indications, how azoles work and what side effects and interactions they’re linked to.

Broadly speaking, azole antifungal drugs are used to treat a diversity of infections:

  • Local fungal infections – oropharynx, vagina or skin infections. Azoles can be administered topically, such as with clotrimazole, terconazole and ketoconazole, or orally, such as with fluconazole.
  • Systemic fungal infections – see below.

Whether a drug is used to treat a “local fungal infection” or a “systemic fungal infection” is often determined based on its classification.

Indications

Azole antifungals are divided into two broad classes – imidazoles and triazoles.

Imidazoles include:

  • Clotrimazole
  • Econazole
  • Ketoconazole
  • Miconazole
  • Tioconazole

Clotrimazole and econazole are routinely used to treat fungal infections such as athlete’s foot, jock itch, ringworm and yeast infections.

For ketoconazole:

  • Topical ketoconazole is used to treat athlete’s foot, ringworm, candidiasis, jock itch and tinea versicolor. It may also be used for dandruff and seborrheic dermatitis. Some off-label preparations are used for androgenic alopecia.
  • Systemic ketoconazole is used to treat blastomycosis, chromomycosis, coccidioidomycosis, histoplasmosis and paracoccidioidomycosis. Ketoconazole is not active against Aspergillus, though.

Ketoconazole has been largely replaced for systemic use by later triazole drugs, such as itraconazole. Ketoconazole has greater toxicity, poorer absorption and more limited spectrum of activity than later antifungal medicines.

Miconazole topical is mostly used to treat oral yeast infections. It is available as a buccal preparation.

Tioconazole is mostly used to treat vagina yeast infections.

Examples of triazoles:

  • Fluconazole
  • Itraconazole
  • Terconazole
  • Voriconazole

Imidazoles are often preferred for topical treatment. Triazoles are more often preferred for systemic treatment due to their improved safety profile and predictable absorption, when administered orally.

Systemic infections include:

  • Systemic candidiasis
  • Cryptococcal meningitis
  • Coccidioidomycosis
  • Histoplasmosis
  • Blastomycosis
  • Sporotrichosis

With these indications in mind, let’s review how azole antifungals work – their mechanism of action.

Mechanism of action

Whether they belong to the imidazole or triazole class, azole antifungal drugs work via a common mode of action.

That mode of action involves interacting with ergosterol; an essential component that keeps the integrity of the fungal cell membrane together.

More specifically, azole antifungals inhibit ergosterol synthesis. The medicines inhibit the enzyme lanosterol 14-alpha demethylase – the enzyme needed to convert lanosterol into ergosterol.

Without ergosterol to hand, cell growth and replication become impaired.

Through these means, azole antifungal drugs exert their therapeutic effect.

Side effects

Side effects depend whether the drug is applied topically or whether it is administered systemically. Of course, it also depends on the drug in question and the current condition of the patient.

Topical side effects include:

  • Local irritation
  • Redness
  • Burning
  • Itchiness

When administered orally, clotrimazole is linked abnormal liver function tests.

Fluconazole is associated with many serious side effects:

  • Vomiting
  • Hepatitis / hepatotoxicity
  • Hypersensitivity
  • QT prolongation
  • Cardiac arrhythmias

Itraconazole is also associated with liver damage and heart failure.

Voriconazole is linked to vision problems and, in some patients, hallucinations.

Of course, given the range of medicines discussed here, the above list of side effects is not intended to be complete. Instead, it is intended to shine a spotlight on many common and serious effects that are associated with this diverse and important drug class.

Clinical considerations

When we talk about the clinical pharmacology of azole antifungals, we need to think about the following factors:

  • That caution is warranted in patients with liver disease. As we learned, drugs such as fluconazole increase the risk of liver damage.
  • That a dose reduction is warranted in patients with established renal impairment.
  • That due to the risk of fetal damage, azole antifungals should be avoided in pregnancy.
  • That there are no significant interactions with topical medicines, such as clotrimazole. Some azole antifungals are linked to many drug interactions. For example – fluconazole and ketoconazole inhibit CYP enzymes – increasing the concentration of drugs metabolised by these enzymes – including phenytoin, warfarin, carbamazepine, simvastatin and sulphonylureas. In addition, CYP inhibitors reduce the antiplatelet effect of clopidogrel.
  • That given the risk of QT prolongation with fluconazole, risk of arrhythmias increases when taken with other medicines that prolong the QT interval such as quinine, amiodarone, SSRIs, antipsychotics, fluoroquinolones and macrolides.
  • That ketoconazole is best absorbed at highly acidic levels. Antacids decrease stomach acid levels and so lower the medicine’s absorption.

Azole antifungal drugs remain, then, an integral component in the treatment of fungal disease, for both topical and systemic fungal disease.

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