Azoles

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Azoles

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A 37-year-old woman presents to the emergency department for difficulty swallowing, pain with swallowing, and intermittent fevers for the past five days. She cannot tolerate solids and liquids and feels the sensation of food stuck in the back of the throat. Past medical history is notable for hypertension and untreated HIV infection. Her last CD4+ count was 80/mm3 a month ago. Her temperature is 39.2°C (103°F), blood pressure is 131/72 mmHg, and pulse is 93/min. On physical examination, white patches are observed on the oropharyngeal mucosa. Mild lymphadenopathy is present. Administration of which of the following medications is the next best step in managing this patient?  

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Ketoconazole p. 194, 195, 676

cytochrome P p. -468, 251

gynecomastia from p. 667

PCOS p. 663

reproductive hormones and p. 673

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The “azole” antifungals are a family of medications used to treat mycoses, or fungal infections.

Mycoses can be superficial, like on the skin or hair, or develop into systemic infections in immunodeficient people.

Antifungals work either through fungistatic action, meaning that they inhibit fungal growth, or through fungicidal action, meaning they kill the fungi.

Azoles are divided into two major families of antifungals: imidazoles and triazoles.

Most fungal cells have a tough outer cell wall and an inner cell membrane.

The cell membrane is mostly made of phospholipids with some sterol or modified steroid molecules mixed in.

Humans have cholesterol, while fungi have ergosterol.

Both sterol molecules help keep the cell membrane stable at a wide range of temperatures.

Now, the precursor to both molecules is lanosterol.

Fungi have a cytochrome p450 enzyme called fourteen-alpha-demethylase in their mitochondria and endoplasmic reticulums, which converts lanosterol to ergosterol.

Without ergosterol, the structure of the cell membrane will be disrupted.

This will cause membrane-bound proteins, like ion channels, to stop working properly.

The membrane also becomes fragile, which eventually leads to inhibition of fungal growth.

The azole antifungals include imidazoles, like clotrimazole, isoconazole, miconazole, butoconazole, fenticonazole, and ketoconazole; as well as triazoles like fluconazole, itraconazole and voriconazole.

The only difference between the two groups is the imidazoles contain an imidazole ring, while triazoles contain triazole rings.

These medications work by inhibiting the fourteen-alpha-demethylase enzyme.

However, they also inhibit human cytochrome P450 enzymes to a lesser degree.

Because of this, the vast majority of azoles come in topical form, and they’re commonly used to treat superficial mycoses.

Azole creams are used for treating dermatophytosis, or ringworm, which is a red, itchy, scaly, circular rash, on the feet, groin, or armpit area, caused by Trichophyton fungus.

These fungi are also responsible for the more common “athlete’s foot” or “jock itch”.

Summary

Azoles are synthetic antifungals with broad spectrum activity against various fungal infections. Azoles bind to the ergosterol molecule in the fungal cell membrane and cause holes to form, which damages the cell membrane and eventually kills the fungus. Examples of azoles include drugs like clotrimazole, fluconazole, and itraconazole. Some of the side effects of azoles include nausea and vomiting, gynecomastia, and hepatotoxicity.

Sources

  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Therapeutic tools for oral candidiasis: Current and new antifungal drugs" Medicina Oral Patología Oral y Cirugia Bucal (2019)
  5. "Adverse interactions between antifungal azoles and vincristine: review and analysis of cases" Mycoses (2011)
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