Fluconazole

Fluconazole
Darius Meiman

9/23/18

Fluconazole, a member of the imidazole antifungals, was originally discovered in the early 1980’s by a group of Pfizer scientists lead by Dr. Ken Richardson. The program, founded in 1978, set out to modify a previously known azole antifungal tioconazole. Other antifungals at the time consisted of amphotericin B and flucytosine, but the adverse effect profile and limited range of fungal targets limited their uses respectively. As a class the imidazole antifungals have a unique mechanism of action by inhibiting lanosterol 14 alpha-demethylase. This is an essential step in the the biosynthesis of ergosterol, a key component of fungal cell membranes. Mammalian cells membranes are much less susceptible to C14 demethylation and do not contain ergosterol in cell membranes so targeting this fungal specific sterol prevents most of the undesired effects that come with inhibiting cell membrane biosynthesis.

Most of issues that arose with earlier azole drugs was due to their lipophilicity and high protein binding. Although a high volume of distribution is favorable in many circumstances, a low free fraction can limit the amount of drug available to interact with its desired target. Oral bioavailability was a major concern as azole antifungals undergo high first pass metabolism in the liver and only a fraction of the given dose is able to reach systemic circulation. A plethora of drug interactions have been reported while taking fluconazole because of its interactions with cytochrome P450 monooxygenases, effectively raising or lower subsequent drug concentrations.

Fluconazole, trade name Diflucan, is used today to treat a wide array of fungal infections including infections of the mouth, throat, lungs, abdomen, blood, and brain. It is most predominantly prescribed for yeast infections caused by Candida Albicans. Commercially it is available in various oral and IV dosage forms, most commonly a 150 milligram oral tablet that requires one time dosing to maximize ease of administration to the patient. Due to its broad yet specific profile, it is considered first line for most common fungal infections. Common adverse effects include headache, dizziness, diarrhea, stomach pain, heartburn, vomiting, and rash. Women who are in the first trimester of pregnancy should avoid high doses of fluconazole as it has recently been changed from category C to category D with known risks to the fetus.

Areas that need the most improvement with fluconazole and future azole antifungals are mostly related to their pharmacokinetic profile. Today due to generics coming into the market, fluconazole can be used as a convenient and cheaper first line option to treat broad fungal infections. However, patients should be aware of its adverse effects and interactions with other medications.

Works Cited:

Richardson, K., Cooper, K., Marriott, M. S., Tarbit, M. H., Troke, F., & Whittle, P. J. (1990). Discovery of Fluconazole, a Novel Antifungal Agent. Clinical Infectious Diseases. 24(1), 10-27.

    Debruyne, D., & Ryckelynck, J. (1993). Clinical Pharmacokinetics of Fluconazole. Clinical Pharmacokinetics. 12.

Richardson, K. (1990). The Discovery and Profile of Fluconazole. Journal of Chemotherapy. 2(1), 51-54.