Imidazole and Triazole Antifungals (Azoles)
Examples
- Ketoconazole
- Miconazole
- Clotrimazole
- Fluconazole
- Itraconazole
Indications
Treatment of a range of fungal infections including: cryptococcus, candida, aspergillus, histoplasmosis and skin/nail infections.
Also used prophylactically in some immunocompromised patients (e.g. patients receiving certain cancer treatments).
Contraindications
Contraindications
- Acute porphyria
- Hepatic disease
- Renal impairment
- Pregnancy
- Heart failure
- Susceptibility to QT prolongation
Mechanism
The Azole antifungals inhibit the fungal cytochrome P450 3A enzyme, lanosine 14α-demethylase, responsible for the conversion of lanosterol to ergosterol, the primary constituent of the fungal membrane. This reduction in ergosterol changes the fluidity of the fungal membrane, interfering with the function of membrane-associated enzymes. This acts to inhibit replication.
Azoles also act to prevent the transformation of yeast cells into hyphae, the invasive and pathogenic form of the parasite.
Azoles also act to prevent the transformation of yeast cells into hyphae, the invasive and pathogenic form of the parasite.
Administration
- Ketoconazole - Oral
- Miconazole - Oral, Topical
- Clotrimazole - Topical
- Fluconazole - Oral, I.V.
- Itraconazole - Oral, I.V.
Adverse Reactions
ADRs are uncommon with topical treatment, but local irritation can occur.
With systemic use, common issues include:
With systemic use, common issues include:
- Nausea, abdominal pain, diarrhoea, flatulence
- Rash (can be severe)
- Hepatitis
- Bone marrow suppression
- Hepatoxicity
- Heart failure
Interactions
Azole anti-fungals are inhibitors of the P450 system and therefore have many problematic interactions. The BNF should be consulted before prescribing. Particular difficulties arise with imidazoles and warfarin, theophylline, anti-HIV drugs, ciclosporin, some cytotoxics, statins and anti-convulsants. Triazoles additionally interact with NSAIDs.
- Note: In general, fluconazole interactions relate to multi-dose treatment and single doses are unlikely to cause problems
Education
Patients should be instructed in how to recognise signs of liver disorder and to seek medical attention if symptoms such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine develop.
Patient should be advised to complete the prescribed course of anti-fungal therapy.
Patient should be advised to complete the prescribed course of anti-fungal therapy.
Pharmacokinetics
Imidazoles are absorbed well when taken by mouth, antacids reduce absorption whereas food increases absorption. Absorbed ketoconazole does not cross the blood-brain barrier and only a limited amount crosses in fungal meningitis. Extensive metabolism to the inactive metabolite occurs and excretion is primarily in the faeces.
Triazoles are well absorbed after oral administration, (Itraconazole capsules require an acid environment in the stomach for optimal absorption). They achieve good penetration into the cerebrospinal fluid and can be used to treat fungal meningitis. They are excreted, largely unchanged, in the urine and can hence be used to treat candiduria.
Triazoles are well absorbed after oral administration, (Itraconazole capsules require an acid environment in the stomach for optimal absorption). They achieve good penetration into the cerebrospinal fluid and can be used to treat fungal meningitis. They are excreted, largely unchanged, in the urine and can hence be used to treat candiduria.
