Antifungal Ergosterol Synthesis Inhibitors

Continuing Education Activity

The ergosterol inhibitor class of medications ("conazoles") is used in the management and treatment of fungal infections. These drugs inhibit ergosterol in the cell membrane to help kill fungi. This drug comes in both topical and systemic formulas. This drug can cause hepatotoxicity and should, therefore, be monitored via inter-professional communication. Both physicians, pharmacists, and other providers should look closely at the patient's medical history and list of medications to make sure there is no history of liver failure or drug-drug interactions.


  • Identify the mechanism of action of conazole drugs.
  • Describe the adverse effects and contraindications of the conazole drugs.
  • Review the toxicity of conazole drugs.
  • Explain interprofessional team strategies for improving care coordination and communication to improve outcomes of treatment with conazole drugs.


Invasive infections with fungi are continuing to increase and cause significant morbidity and mortality.[1] The azole family of antifungal agents has indications for many fungal pathogens. They have few adverse effects compared with amphotericin B. The triazole family has mostly replaced the use of early azoles, such as ketoconazole, due to improved safety and efficacy. Each of the five members of the triazole family (fluconazole, voriconazole, itraconazole, posaconazole, and isavuconazole) has different characteristics that prove each one effective for specific cases. Ketoconazole is a common topical antifungal for cutaneous fungal infections, including cutaneous candidiasis, seborrheic dermatitis, tinea infections, and dandruff.[2]

Mechanism of Action

The azole antifungal family works by inhibiting lanosterol 14-alpha-demethylase, which converts lanosterol to ergosterol in fungus cellular membranes.[3] The inability to produce ergosterol increases the permeability of the membrane, which causes cell lysis and death. Although these drugs cause cell death, they are still considered fungistatic in their actions.

All azole antifungals are involved in drug-drug interactions via cytochrome P450 enzyme metabolism.[4] Each family member is both metabolized by and affect this oxidative drug metabolism to a certain extent. Fluconazole strongly inhibits CYP2C19 and moderately inhibits CYP2C9 and CYP3A4, but is only a weak substrate. Itraconazole is a potent inhibitor and a substrate of CYP3A4. Voriconazole is a potent inhibitor of CYP3A4, a moderate inhibitor of CYP2C19, a weak inhibitor of CYP2C9, and has not shown to be a substrate. Posaconazole inhibits CYP3A4 but does not get metabolized by cytochrome P450. Isavuconazole moderately inhibits CYP3A4 and cannot be cleared if combined with other drugs that either induce or inhibit CYP3A4. Ketoconazole strongly inhibits and is metabolized by CYP3A4.[5] Drugs that induce the CYP enzymes cause faster metabolism of the antifungals - the most potent being rifampin.[6] Other examples include rifabutin, phenobarbital, carbamazepine, phenytoin, chronic alcohol use, and St. Johns wort. Due to the inhibitory effects of azoles on the CYP enzymes, dose reductions may be needed for other substrates such as warfarin to prevent toxicity.


Fluconazole is available in oral and intravenous dosing. Oral doses are available in both suspension and tablets as either brand name or generic. Both suspensions are available as either 10 mg/mL or 40 mg/mL doses. Both tablets are available as 50 mg, 100 mg, 150 mg, or 200 mg tablets. The intravenous dosing is available in generic 100 mg/50 mL in NaCl 0.9% or 200 mg/100 mL in NaCl 0.9%. Ketoconazole is popular in topical cream, foam, gel, and shampoo forms. The 1% ketoconazole shampoo can be purchased over-the-counter (OTC).

The dosing of the azole medications varies due to the illness present. The presence of severe diseases, such as CNS blastomycosis, initial candidemia therapy, infections of cardiac valves, intra-abdominal infections, and endophthalmitis, requires loading doses of 800 mg once daily for several weeks or months followed by step-down dosing of 400 mg once daily for at least two weeks.

Esophageal candidiasis therapy includes a loading dose of 400 mg, followed by 200 to 400 mg once daily dosing for up to 3 weeks. For less invasive infections such as cystitis and pyelonephritis, 200 mg once daily for two weeks is sufficient. For vaginal candidiasis, 150 mg single dose or every 72 hours for up to 2 weeks for severe or recurrent cases. Some of the azole treatments - such as ketoconazole tablets, itraconazole capsules, and posaconazole solution - need gastric acid to be absorbed. Therefore antacids, histamine-2 blockers, and proton pump inhibitors decrease the absorption of these dosing types.[7] 

Doses vary depending on the type of infection and the drug of choice. Fluconazole: The dose of 3 to 8 mg/kg body weight per day for 1 to 8 weeks. Doses are shorter for cutaneous infections and longer for mycoses. Doses come in 50, 100, and 200 mg tablets. There is a 150 mg tablet for vaginal infections. 150 mg can be used weekly or monthly for prophylaxis. Ketoconazole: The dose of 3.3 to 6.6 mg/kg body weight per day for two weeks. Dosages come in 200 mg tablets. Two 200 mg tablets or 0.5 mg tablets are the dosing options for prophylaxis of vaginal infections. The 1% ketoconazole shampoo can be purchased over-the-counter. Itraconazole: The dose of 5 mg/kg body weight for 1 to 6 weeks; dose regimens are shorter for cutaneous infections and longer for mycoses. Dosing can be in pulses or continuous. The drug comes in 100 mg capsules.

Adverse Effects

The conazole family of drugs usually is well tolerated but may have some adverse effects [8]:

Increase the toxicity of other drugs when combined with drugs that are also metabolized by CYP.

  • Drug-induced hepatitis
  • Pruritus
  • Allergic rashes
  • Diarrhea
  • Nausea/vomiting
  • Lethargy
  • Anorexia

Prenatal exposure to conazole antifungals has correlations with a shorter anogenital distance in male offspring due to the anti-androgenic properties of the drugs.[9]


The adverse effects of topical conazole drugs are mild. Therefore contraindications include:

  • Hypersensitivity reaction
  • Anaphylaxis

Systemic ingestion is contraindicated, or merits extreme caution, in the following situations:

  • Abnormal LFTs
  • Chronic kidney disease stage 3A or worse
  • Hypokalemia
  • Hypomagnesemia
  • Prolonged QTc interval
  • QTc abnormalities
  • Torsades de Pointes
  • Pregnancy


Elevated ALT above baseline requires interruption of therapy due to the risk of drug-induced hepatitis. Patients may resume treatment when the liver function returns to baseline.[10] The renal function does not require dosing adjustments.


The patient should discontinue the drug if a hypersensitivity reaction or anaphylaxis occurs. An analysis of 204 studies of ketoconazole associated hepatotoxicity concluded an incidence of 3.6% to 4.2%. The dose and duration of treatment did not show a significant difference between study groups. Oral therapy had a higher incidence of hepatotoxicity than topical treatment.[11] The patient should be monitored for hepatotoxicity and should discontinue the drug if liver enzymes start to rise above the baseline. Ketoconazole has a higher incidence of hepatotoxicity than fluconazole. The physician and patient should consider if the benefits outweigh the risks.

Enhancing Healthcare Team Outcomes

Ketoconazole is a common conazole family member used on an everyday basis for the treatment of cutaneous fungal infections such as athlete’s foot, dandruff, and tinea versicolor. It is also useful for more invasive fungal infections such as blastomycosis, histoplasmosis, and coccidioidomycosis.[12] Ketoconazole is considered safe and may be accompanied only by mild adverse effects, but the risk of severe adverse effects such as hepatotoxicity requires discussion before the initiation of treatment. Due to interactions with many other drugs that are metabolized by CYP enzymes, physicians and pharmacists need to communicate with each other about the patient’s medications to be certain that there will be little or no adverse events due to drug-drug interactions. Nursing will coordinate with the clinician and pharmacy staff, and provide patient counsel and answer questions, referring the patient to the pharmacist if necessary. Using an interprofessional team approach is vital to ensuring the safety of the patient. Reports of ketoconazole causing hepatotoxicity are common.[11] Therefore all healthcare workers need to work together to monitor the patient to get the most beneficial health outcomes.

Article Details

Article Author

Elizabeth Herrick

Article Editor:

Muhammad Hashmi


2/11/2021 12:09:02 AM



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