Azoles

Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Various members of the class are indicated in the treatment and prophylaxis of candidiasis, aspergillosis, cryptococcus meningitis, dimorphic fungal infections (e.g., blastomycosis), and mucormycosis. Significant adverse effects are possible and include hepatotoxicity, GI distress, cardiac issues, and neurotoxicity. Azoles interact with the CYP450 system causing significant drug-to-drug interactions with many other medications, potentially limiting the usefulness in medically complex individuals.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Classification

Azoles are a group of widely used antifungal medications, which can be classified into 2 subgroups:

  • Imidazoles:
    • Ketoconazole (rarely used systemically due to higher toxicity/lower efficacy than triazoles)
    • Miconazole (topical only)
    • Clotrimazole (topical only)
  • Triazoles:
    • Fluconazole
    • Itraconazole
    • Voriconazole
    • Posaconazole
    • Isavuconazole

Chemistry and Pharmacodynamics

Chemical structure

  • All azoles contain a 5-membered, nitrogen-containing azole ring.
  • Imidazoles have 2 nitrogen atoms in the azole ring.
  • Triazoles have 3 nitrogen atoms in the azole ring.

Mechanism of action

Azoles cause deterioration in the fungal cell membrane by inhibiting ergosterol production.

  • Ergosterol:
    • A critical component of fungal cell membranes (the equivalent to cholesterol in human cell membranes)
    • Synthesized by lanosterol 14-α-demethylase, a fungal CYP450 enzyme converting lanosterol to ergosterol:
      • Azoles have a higher affinity for fungal enzymes than human enzymes.
      • Triazoles have a better selective affinity for fungal enzymes than imidazoles.
  • Azoles inhibit lanosterol 14-α-demethylase → inhibits ergosterol production
  • Without new ergosterol production: 
    • Fungi are unable to maintain the cell membrane or create new membranes.
    • ↑ Fungal cell membrane permeability → cell lysis
  • Azoles are generally considered to be fungistatic.
Antifungal agents and mechanisms of action

Antifungal agents and mechanisms of action

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Different azoles have variable (and sometimes complex) pharmacokinetics.

Absorption

  • Good oral absorption:
    • Fluconazole
    • Voriconazole
    • Posaconazole
  • Variable absorption:
    • Itraconazole
    • Ketoconazole

Distribution

  • High volumes of distribution → drugs accumulate in tissues throughout the body
  • All are widely distributed in tissue (with CSF and urine as notable exceptions).
  • Drugs collecting in urine and CSF:
    • Urine: fluconazole (due to significant excretion as an unchanged drug)
    • CSF: fluconazole, voriconazole
  • Azoles are teratogenic to the developing fetus and systemic azoles are generally contraindicated in pregnancy.
Table: Pharmacokinetics of azoles
DrugsProtein bindingMetabolism and clearanceHalf-lifeEnzyme inhibition
Imidazoles
Ketoconazole99%Partial hepatic metabolism by CYP3A4Biphasic:
  • Initial: 2 hours
  • Terminal: 8 hours
Significantly more inhibition of mammalian CYP450 than the triazoles
Triazoles
FluconazoleApproximately 10%
  • Renal (as an unchanged drug): 80%
  • Hepatic: 10%
25 hours
  • CYP2C19 (strong)
  • CYP2C9 (moderate)
  • CYP3A4 (moderate, more at high doses)
Itraconazole99%
  • Extensive hepatic metabolism by CYP3A4 to active metabolites
  • Dose-dependent elimination
24–48 hours
  • CYP3A4 (strong)
  • P-gp efflux
VoriconazoleApproximately 60%Extensive hepatic metabolism by CYP2C19 (major), 2C9, and 3A4 (minor)6 hours
  • CYP3A4 (strong)
  • CYP2C19 (moderate)
Posaconazole98%
  • Minimal hepatic metabolism
  • Fecal excretion (primarily as an unchanged drug): approximately 70%
25–35 hoursCYP3A4 (moderate)
Isavuconazole99%Hepatic by CYP3A4 and glucuronidation130 hours
  • CYP3A4 (moderate)
  • P-gp efflux (weak)
P-gp: P-glycoprotein

Indications

Azoles have a wide variety of uses and unique indications for each medication.

Imidazoles

  • Clotrimazole (Lotrimin®) (topical use only):
    • Candidiasis (including vaginal candidiasis) due to Candida albicans
    • Tinea pedis (athletes foot)
    • Tinea cruris (jock itch): typically affecting the groin
    • Tinea corporis (ringworm): anywhere on the body
  • Miconazole (Monistat®) (topical use only): vaginal candidiasis 
  • Ketoconazole: 
    • Only use when both:
      • Another effective antifungal therapy is not available/tolerated.
      • The benefits of use outweigh the risks.
    • Potential use in systemic fungal infections:
      • Blastomycosis
      • Histoplasmosis
      • Coccidioidomycosis

Triazoles

In addition to the specific indications listed below, most of the triazoles can also be used as prophylaxis against fungal infections in immunosuppressed individuals.

  • Fluconazole: good activity against yeasts (e.g., Candida), no significant activity against molds (e.g., Aspergillus):
    • Candidiasis from susceptible organisms such as C. albicans (C. krusei and C. glabrata are typically resistant to fluconazole):
      • Mucocutaneous infections (1st-line agent): esophageal, oropharyngeal, and vaginal
      • Peritoneal
      • Urinary tract infections
      • Pneumonia
      • Systemic infections (e.g., candidemia) 
    • Cryptococcus infections:
      • Meningitis
      • Pneumonia
    • Coccidioidomycosis
  • Itraconazole: good activity against dimorphic fungi (fungus existing as both a mold and yeast):
    • Blastomycosis:
      • 1st-line agent for mild-moderate cases
      • Used in severe cases as step-down therapy after a course of amphotericin B
    • Histoplasmosis (1st-line agent for mild-moderate cases)
    • Sporothrix infections
    • Onychomycosis
    • Candidiasis
  • Voriconazole: similar effectiveness as itraconazole against dimorphic fungi:
    • Aspergillosis (1st-line agent)
    • Candida infections (including infections due to fluconazole-resistant species):
      • Mucocutaneous candidiasis
      • Candidemia
      • Disseminated infections in the heart, abdomen, kidney, bladder, and wounds
    • Serious infections caused by:
      • Scedosporium spp.
      • Fusarium spp.
  • Posaconazole and isavuconazole: broadest spectrum of azoles:
    • Candidiasis (including strains resistant to fluconazole)
    • Aspergillosis (2nd-line agent)
    • Mucormycosis

Adverse Effects and Contraindications

Adverse effects

  • GI distress: nausea, vomiting, and/or diarrhea
  • Dermatologic symptoms:
    • Photosensitivity
    • Rash
    • Alopecia
  • Hepatotoxicity:
    • Possible with all the azoles
    • Ranges from mild ↑ in transaminases (approximately 5–10% of individuals) to hepatitis/fulminant hepatic failure
  • Ketoconazole:
    • Adrenal insufficiency: hypertension, hypokalemia, and alkalosis
    • The worst GI symptoms and hepatotoxicity of all the azoles
  • Itraconazole:
    • Hypokalemia
    • Heart failure
  • Voriconazole:
    • Vision changes: 
      • May include abnormal vision, flashes of light, photophobia, and/or color changes
      • Typically starts within 30 minutes of administration and lasts 30–60 minutes
      • Seen in 20%–30% of patients
    • Neurotoxicity:
      • Visual hallucinations
      • Confusion and/or agitation
      • Myoclonic movements
      • Demyelinating neuropathy in the lower extremities (extremely rare, typically in patients also taking tacrolimus)
    • QT prolongation
    • Photosensitivity
    • Periostitis (inflammation of the periosteum (the connective tissue around the bone))
  • Posaconazole and isavuconazole: generally fewer side effects and better tolerated than voriconazole

Contraindications

  • Hypersensitivity to azole medications
  • Hepatic disease
  • Coadministration of medications affecting relevant CYP enzymes:
    • Because numerous drug-to-drug interactions exist for the azoles, carefully evaluate medications to avoid toxicity or underdosing.
    • A common issue for immunosuppressed individuals (often on many medications and at higher risk for fungal infections)
  • Heart failure (itraconazole)
  • Arrhythmias (voriconazole and ketoconazole)
  • Adrenal insufficiency (voriconazole and ketoconazole)
  • Pregnancy

Monitoring

  • Serum azole concentrations are monitored often (recommended for itraconazole, voriconazole, and posaconazole)
  • Transaminases (especially voriconazole and ketoconazole)
  • Adrenal function

Mechanisms of Resistance

The common mechanisms contributing to antifungal resistance include:

  • Mutation of the drug’s target site → ↓ drug affinity for lanosterol 14-α-demethylase → ↓ inhibition
  • ↑ Efflux pumps → less drug within the fungal cell
  • Reduced uptake of the drug → less drug within the fungal cell
  • Target enzyme is overproduced.

Comparison of Antifungal Medications

Table: Comparison of antifungal medications
Drug class (examples)Mechanism of actionClinical relevance
Azoles (Fluconazole, Voriconazole)Inhibits the production of ergosterol (a critical component of the fungal cell membrane) by blocking the lanosterol 14-α-demethylase enzyme
  • Widely used antifungals with a relatively broad spectrum of activity
  • Many drug-to-drug interactions due to effects on the CYP450 system
  • Hepatotoxicity
  • Overall less toxic than amphotericin B
Polyenes (Amphotericin B, Nystatin)Binds to ergosterol in the fungal cell membrane creating artificial pores in the membrane → results in leakage of cellular components and leads to cell lysis (death)Amphotericin B:
  • Reserved for life-threatening fungal infections
  • Broad spectrum of activity
  • Relatively ↑ toxicity (especially nephrotoxicity)
  • Overall less toxic than amphotericin B

Nystatin:
  • Topical use only: skin, mucous membranes, GI lumen
Echinocandins (Caspofungin, Micafungin, Anidulafungin)Inhibits β-glucan synthase (the enzyme synthesizing β-glucan and an important structural component of the fungal cell wall) → weakened cell wall → cell lysis
  • Treats Candida and Aspergillus infections in critically ill and neutropenic patients
  • Minimal toxicity
  • Minimal drug-to-drug interactions
Griseofulvin
  • Binds to the keratin in newly forming skin, making the human cells resistant to invasion → over time the new, uninfected hair/skin/nail structures replace the old, infected structures
  • Inhibits the assembly of microtubules in dermatophytes → inhibits fungal cell replication
  • Treats dermatophyte infections of the hair, skin, and nails
  • Oral medication only (not topically active)
  • Affects the CYP450 system (more drug-to-drug interactions)
  • Largely replaced by newer agents (e.g., terbinafine)
TerbinafineInhibits the squalene epoxidase enzyme → blocks the production of squalene epoxide, which is a precursor to ergosterol and a critical component of the cell membrane
  • Treats dermatophyte infections of the hair, skin, and nails
  • Agent of choice for onychomycosis
  • Relatively low toxicity
FlucytosineA pyrimidine analog with metabolites:
  • Competing with uracil and disrupting RNA synthesis
  • Irreversibly inhibiting thymidylate synthase → fungus is unable to synthesize or correct DNA
  • Always used in combination with other agents due to:
    • Positive synergistic effects
    • ↑ Resistance with monotherapy
  • Major indications:
    • Cryptococcal meningitis
    • Chromoblastomycosis
  • Toxicity: myelosuppression

References

  1. Sheppard, D., Lampiris, H.W. (2012). Antifungal Agents. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic and Clinical Pharmacology (12th Ed., pp. 853‒855).
  2. Dodds Ashley, E., Perfect, J.R. (2020). Pharmacology of azoles. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/pharmacology-of-azoles 
  3. Kauffman, C.A. (2021). Management of candidemia and invasive candidiasis in adults. In Baron, E.L. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/management-of-candidemia-and-invasive-candidiasis-in-adults 
  4. Cox, G.M., Perfect, J.R. (2020). Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in HIV seronegative patients. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/cryptococcus-neoformans-treatment-of-meningoencephalitis-and-disseminated-infection-in-hiv-seronegative-patients 
  5. Cox, G.M. (2021). Mucormycosis (zygomycosis). In Bond, S. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/mucormycosis-zygomycosis 
  6. Patterson, T.F. (2021). Treatment and prevention of invasive aspergillosis. In Bond, S. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/treatment-and-prevention-of-invasive-aspergillosis 
  7. Kauffman, C.A. (2020). Diagnosis and treatment of pulmonary histoplasmosis. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/diagnosis-and-treatment-of-pulmonary-histoplasmosis 
  8. Bradsher, R.W. (2020). Treatment of blastomycosis. In Bogorodskaya. M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/treatment-of-blastomycosis 
  9. Hidalgo, J.A. (2020). Which medications in the drug class Azole antifungals are used in the treatment of candidiasis? In Medscape. Retrieved July 21, 2021, from https://www.medscape.com/answers/213853-30150/which-medications-in-the-drug-class-azole-antifungals-are-used-in-the-treatment-of-candidiasis 
  10. Nivoix, Y., Ledoux, M., and Herbrecht, R. (2020). Antifungal therapy: new and evolving therapies. Semin Respir Crit Care Med. 2020;41(1):158-174. Retrieved July 21, 2021, from https://www.medscape.com/viewarticle/924712_4 
  11. Lexicomp Drug Information Sheets. (2021). In UpToDate. Retrieved July 21, 2021, from:

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details