Fluconazole

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Fluconazole
Fluconazole skeletal formula.svg
Fluconazole ball-and-stick model.png
Clinical data
Trade names Diflucan, others
AHFS/Drugs.com Monograph
MedlinePlus a690002
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth, intravenous, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability >90% (oral)
Protein binding 11–12%
Metabolism Liver 11%
Elimination half-life 30 hours (range 20–50 hours)
Excretion Kidney 61–88%
Identifiers
  • 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.156.133 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H12F2N6O
Molar mass 306.277 g·mol−1
3D model (JSmol)
Melting point 139 [4]  °C (282 °F)
  • OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
  • InChI=1S/C13H12F2N6O/c14-10-1-2-11(12(15)3-10)13(22,4-20-8-16-6-18-20)5-21-9-17-7-19-21/h1-3,6-9,22H,4-5H2 Yes check.svgY
  • Key:RFHAOTPXVQNOHP-UHFFFAOYSA-N Yes check.svgY
   (verify)

Fluconazole is an antifungal medication used for a number of fungal infections. [5] This includes candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and tinea versicolor. [5] It is also used to prevent candidiasis in those who are at high risk such as following organ transplantation, low birth weight babies, and those with low blood neutrophil counts. [5] It is given either by mouth or by injection into a vein. [5]

Contents

Common side effects include vomiting, diarrhea, rash, and increased liver enzymes. [5] Serious side effects may include liver problems, QT prolongation, and seizures. [5] During pregnancy it may increase the risk of miscarriage while large doses may cause birth defects. [6] [5] Fluconazole is in the azole antifungal family of medication. [5] It is believed to work by affecting the fungal cellular membrane. [5]

Fluconazole was patented in 1981 and came into commercial use in 1988. [7] It is on the World Health Organization's List of Essential Medicines. [8] Fluconazole is available as a generic medication. [5] In 2021, it was the 165th most commonly prescribed medication in the United States, with more than 3 million prescriptions. [9] [10]

Medical uses

Fluconazole is a first-generation triazole antifungal medication. It differs from earlier azole antifungals (such as ketoconazole) in that its structure contains a triazole ring instead of an imidazole ring. While the imidazole antifungals are mainly used topically, fluconazole and certain other triazole antifungals are preferred when systemic treatment is required because of their improved safety and predictable absorption when administered orally. [11]

Fluconazole's spectrum of activity includes most Candida species (but not Candida krusei or Candida glabrata ), Cryptococcus neoformans , some dimorphic fungi, and dermatophytes, among others.[ medical citation needed ] Common uses include: [2] [11] [12] [13] [14]

Resistance

Antifungal resistance to drugs in the azole class tends to occur gradually over the course of prolonged drug therapy, resulting in clinical failure in immunocompromised patients (e.g., patients with advanced HIV receiving treatment for thrush or esophageal Candida infection). [15]

In C. albicans , resistance occurs by way of mutations in the ERG11 gene, which codes for 14α-demethylase. These mutations prevent the azole drug from binding, while still allowing binding of the enzyme's natural substrate, lanosterol. Development of resistance to one azole in this way will confer resistance to all drugs in the class. Another resistance mechanism employed by both C. albicans and C. glabrata is increasing the rate of efflux of the azole drug from the cell, by both ATP-binding cassette and major facilitator superfamily transporters. Other gene mutations are also known to contribute to development of resistance. [15] C. glabrata develops resistance by up regulating CDR genes, and resistance in C. krusei is mediated by reduced sensitivity of the target enzyme to inhibition by the agent. [2]

The full spectrum of fungal susceptibility and resistance to fluconazole can be found in the product data sheet. [16] According to the US Centers for Disease Control and Prevention, fluconazole resistance among Candida strains in the US is about 7%. [17]

Contraindications

Fluconazole is contraindicated in patients who: [14]

Side effects

Adverse drug reactions associated with fluconazole therapy include: [14]

If taken during pregnancy it may result in harm. [19] [20] These cases of harm, however, were only in women who took large doses for most of the first trimester. [19]

Fluconazole is secreted in human milk at concentrations similar to plasma. [2]

Fluconazole therapy has been associated with QT interval prolongation, which may lead to serious cardiac arrhythmias. Thus, it is used with caution in patients with risk factors for prolonged QT interval, such as electrolyte imbalance or use of other drugs that may prolong the QT interval (particularly cisapride and pimozide). [21]

Some people are allergic to azoles, so those allergic to other azole drugs might be allergic to fluconazole. [22] That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome. [23]

Oral fluconazole is not associated with a significantly increased risk of birth defects overall, although it does increase the odds ratio of tetralogy of Fallot, but the absolute risk is still low. [24] Women using fluconazole during pregnancy have a 50% higher risk of spontaneous abortion. [25]

Fluconazole should not be taken with cisapride (Propulsid) due to the possibility of serious, even fatal, heart problems. [21] In rare cases, severe allergic reactions including anaphylaxis may occur. [26]

Powder for oral suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption or sucrase-isomaltase deficiency. Capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption [27]

Interactions

Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozyme CYP2C19 (CYP3A4 and CYP2C9 to lesser extent) [28] In theory, therefore, fluconazole decreases the metabolism and increases the concentration of any drug metabolised by these enzymes. In addition, its potential effect on QT interval increases the risk of cardiac arrhythmia if used concurrently with other drugs that prolong the QT interval. Berberine has been shown to exert synergistic effects with fluconazole even in drug-resistant Candida albicans infections. [29] Fluconazole may increase the serum concentration of Erythromycin (Risk X: avoid combination). [28]

Pharmacology

Pharmacodynamics

Like other imidazole- and triazole-class antifungals, fluconazole inhibits the fungal cytochrome P450 enzyme 14α-demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane, and subsequent accumulation of 14α-methyl sterols. [30] Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus. [31]

Pharmacokinetics

Following oral dosing, fluconazole is almost completely absorbed within two hours. [32] Bioavailability is not significantly affected by the absence of stomach acid. Concentrations measured in the urine, tears, and skin are approximately 10 times the plasma concentration, whereas saliva, sputum, and vaginal fluid concentrations are approximately equal to the plasma concentration, following a standard dose range of between 100 mg and 400 mg per day. [33] The elimination half-life of fluconazole follows zero order, and only 10% of elimination is due to metabolism, the remainder being excreted in urine and sweat. Patients with impaired renal function will be at risk of overdose. [21]

In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. [34]

History

Fluconazole was patented by Pfizer in 1981 in the United Kingdom and came into commercial use in 1988. [7] Patent expirations occurred in 2004 and 2005. [35]

Related Research Articles

<span class="mw-page-title-main">Candidiasis</span> Fungal infection due to any type of Candida

Candidiasis is a fungal infection due to any species of the genus Candida. When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the mouth and throat. Other symptoms may include soreness and problems swallowing. When it affects the vagina, it may be referred to as a yeast infection or thrush. Signs and symptoms include genital itching, burning, and sometimes a white "cottage cheese-like" discharge from the vagina. Yeast infections of the penis are less common and typically present with an itchy rash. Very rarely, yeast infections may become invasive, spreading to other parts of the body. This may result in fevers, among other symptoms.

<span class="mw-page-title-main">Antifungal</span> Pharmaceutical fungicide or fungistatic used to treat and prevent mycosis

An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally.

<span class="mw-page-title-main">Itraconazole</span> Medication used to treat fungal infections

Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth or intravenously.

<span class="mw-page-title-main">Ketoconazole</span> Antifungal chemical compound

Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrheic dermatitis. Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used. Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.

<i>Coccidioides immitis</i> Species of fungus

Coccidioides immitis is a pathogenic fungus that resides in the soil in certain parts of the southwestern United States, northern Mexico, and a few other areas in the Western Hemisphere.

<span class="mw-page-title-main">Miconazole</span> Chemical compound

Miconazole, sold under the brand name Monistat among others, is an antifungal medication used to treat ring worm, pityriasis versicolor, and yeast infections of the skin or vagina. It is used for ring worm of the body, groin, and feet. It is applied to the skin or vagina as a cream or ointment.

<span class="mw-page-title-main">Caspofungin</span> Antifungal medication

Caspofungin is a lipopeptide antifungal drug from Merck & Co., Inc.. It is a member of a class of antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby disturbing the integrity of the fungal cell wall.

<span class="mw-page-title-main">Terconazole</span> Chemical compound

Terconazole is an antifungal drug used to treat vaginal yeast infection. It comes as a lotion or a suppository and disrupts the biosynthesis of fats in a yeast cell. It has a relatively broad spectrum compared to azole compounds but not triazole compounds. Testing shows that it is a suitable compound for prophylaxis for those that suffer from chronic vulvovaginal candidiasis.

<span class="mw-page-title-main">Flucytosine</span> Chemical compound

Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication. It is specifically used, together with amphotericin B, for serious Candida infections and cryptococcosis. It may be used by itself or with other antifungals for chromomycosis. Flucytosine is used by mouth and by injection into a vein.

<span class="mw-page-title-main">Esophageal candidiasis</span> Medical condition

Esophageal candidiasis is an opportunistic infection of the esophagus by Candida albicans. The disease usually occurs in patients in immunocompromised states, including post-chemotherapy and in AIDS. However, it can also occur in patients with no predisposing risk factors, and is more likely to be asymptomatic in those patients. It is also known as candidal esophagitis or monilial esophagitis.

<span class="mw-page-title-main">Posaconazole</span> Pharmaceutical drug

Posaconazole, sold under the brand name Noxafil among others, is a triazole antifungal medication.

<span class="mw-page-title-main">Echinocandin</span> Group of chemical compounds

Echinocandins are a class of antifungal drugs that inhibit the synthesis of β-glucan in the fungal cell wall via noncompetitive inhibition of the enzyme 1,3-β glucan synthase. The class has been termed the "penicillin of antifungals," along with the related papulacandins, as their mechanism of action resembles that of penicillin in bacteria. β-glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components, the fungal equivalent to bacterial peptidoglycan. Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with limited clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.

<span class="mw-page-title-main">Sterol 14-demethylase</span> Class of enzymes

In enzymology, a sterol 14-demethylase (EC 1.14.13.70) is an enzyme of the cytochrome P450 (CYP) superfamily. It is any member of the CYP51 family. It catalyzes a chemical reaction such as:

<span class="mw-page-title-main">Clotrimazole</span> Chemical compound

Clotrimazole, sold under the brand name Lotrimin, among others, is an antifungal medication. It is used to treat vaginal yeast infections, oral thrush, diaper rash, tinea versicolor, and types of ringworm including athlete's foot and jock itch. It can be taken by mouth or applied as a cream to the skin or in the vagina.

<span class="mw-page-title-main">Isavuconazonium</span> Chemical compound

Isavuconazonium sulfate, sold under the brand name Cresemba, is a systemic antifungal medication of the triazole class which is used to treat invasive aspergillosis and mucormycosis.

<span class="mw-page-title-main">Vaginal yeast infection</span> Medical condition

Vaginal yeast infection, also known as candidal vulvovaginitis and vaginal thrush, is excessive growth of yeast in the vagina that results in irritation. The most common symptom is vaginal itching, which may be severe. Other symptoms include burning with urination, a thick, white vaginal discharge that typically does not smell bad, pain during sex, and redness around the vagina. Symptoms often worsen just before a woman's period.

Fungistatics are anti-fungal agents that inhibit the growth of fungus. The term fungistatic may be used as both a noun and an adjective. Fungistatics have applications in agriculture, the food industry, the paint industry, and medicine.

Invasive candidiasis is an infection (candidiasis) that can be caused by various species of Candida yeast. Unlike Candida infections of the mouth and throat or vagina, invasive candidiasis is a serious, progressive, and potentially fatal infection that can affect the blood (fungemia), heart, brain, eyes, bones, and other parts of the body.

<i>Candida tropicalis</i> Species of fungus

Candida tropicalis is a species of yeast in the genus Candida. It is a common pathogen in neutropenic hosts, in whom it may spread through the bloodstream to peripheral organs. For invasive disease, treatments include amphotericin B, echinocandins, or extended-spectrum triazole antifungals.

Topical antifungaldrugs are used to treat fungal infections on the skin, scalp, nails, vagina or inside the mouth. These medications come as creams, gels, lotions, ointments, powders, shampoos, tinctures and sprays. Most antifungal drugs induce fungal cell death by destroying the cell wall of the fungus. These drugs inhibit the production of ergosterol, which is a fundamental component of the fungal cell membrane and wall.

References

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  2. 1 2 3 4 5 6 "Diflucan- fluconazole tablet; Diflucan- fluconazole powder, for suspension". DailyMed. 21 September 2023. Archived from the original on 22 February 2024. Retrieved 22 February 2024.
  3. ↑ "Active substance: Fluconazole" (PDF). List of nationally authorised medicinal products. European Medicines Agency. 12 November 2020. Archived (PDF) from the original on 24 February 2024. Retrieved 22 December 2020.
  4. ↑ Surov AO, Voronin AP, Vasilev NA, Churakov AV, Perlovich GL (20 December 2019). "Cocrystals of Fluconazole with Aromatic Carboxylic Acids: Competition between Anhydrous and Hydrated Solid Forms". Crystal Growth & Design. 20 (2): 1218–1228. doi:10.1021/acs.cgd.9b01490. S2CID   213008181.
  5. 1 2 3 4 5 6 7 8 9 10 "Fluconazole". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  6. ↑ "Fluconazole (Diflucan): Drug Safety Communication - FDA Evaluating Study Examining Use of Oral Fluconazole (Diflucan) in Pregnancy". U.S. Food and Drug Administration (FDA). 26 April 2016. Archived from the original on 29 April 2016. Retrieved 29 April 2016.
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  8. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  10. ↑ "Fluconazole - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 14 January 2024.
  11. 1 2 "US Pharmacist". Archived from the original on 10 February 2015. Retrieved 28 January 2015.
  12. ↑ "IDSA Guidelines: Candida Infections". Archived from the original on 3 February 2015. Retrieved 28 January 2015.
  13. ↑ "IDSA Guidelines: Cryptococcal Infections". Archived from the original on 3 February 2015. Retrieved 28 January 2015.
  14. 1 2 3 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN   0-9757919-2-3
  15. 1 2 Bennett JE (2011). "Chapter 57: Antifungal Agents". In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). Archived from the original on 31 December 2013. Retrieved 22 May 2012.
  16. ↑ "Spectrum of fungal susptibility and resistance to fluconazole" (PDF). Archived from the original (PDF) on 14 March 2016.
  17. ↑ "Antifungal Resistance | Fungal Disease | CDC". 25 January 2019. Archived from the original on 19 May 2017.
  18. ↑ "FDA Alert: Diflucan (fluconazole): Drug Safety Communication - Long-term, High-dose Use During Pregnancy May be Associated with Birth Defects". Archived from the original on 28 September 2011. Retrieved 4 August 2011.
  19. 1 2 "Fluconazole". Monograph. The American Society of Health-System Pharmacists. Archived from the original on 27 September 2014. Retrieved 27 September 2014.
  20. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Archived from the original on 8 April 2014. Retrieved 22 April 2014.
  21. 1 2 3 Brunton LL, Knollmann BC, Hilal-Dandan R, eds. (2018). Goodman & Gilman's : the Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education LLC. ISBN   978-1-259-58473-2. OCLC   1075550900.
  22. ↑ Pinto A, Chan RC (April 2009). "Lack of allergic cross-reactivity between fluconazole and voriconazole" (PDF). Antimicrobial Agents and Chemotherapy. 53 (4): 1715–1716. doi:10.1128/AAC.01500-08. PMC   2663085 . PMID   19164151. Archived (PDF) from the original on 11 June 2011. Retrieved 20 October 2009.
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  25. ↑ Mølgaard-Nielsen D, Svanström H, Melbye M, Hviid A, Pasternak B (January 2016). "Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth". JAMA. 315 (1): 58–67. doi:10.1001/jama.2015.17844. PMID   26746458.
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  28. 1 2 "Login". Archived from the original on 21 December 2016. Retrieved 21 December 2016.
  29. ↑ Xu Y, Wang Y, Yan L, Liang RM, Dai BD, Tang RJ, et al. (November 2009). "Proteomic analysis reveals a synergistic mechanism of fluconazole and berberine against fluconazole-resistant Candida albicans: endogenous ROS augmentation". Journal of Proteome Research. 8 (11): 5296–5304. doi:10.1021/pr9005074. PMID   19754040.
  30. ↑ Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.
  31. ↑ Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, et al. (December 2008). "Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda". Clinical Infectious Diseases. 47 (12): 1556–1561. doi: 10.1086/593194 . PMID   18990067.
  32. ↑ Katzung BG (30 November 2017). Basic & clinical pharmacology. McGraw-Hill Education. ISBN   978-1-259-64115-2. OCLC   1035129378.
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  34. ↑ "Fluconazole". MP Biomedicals. Archived from the original on 16 January 2009.
  35. ↑ "Pfizer to Expand Fluconazole Donation Program to More than 50 Developing Nations". Kaiser Health News. 7 June 2001. Archived from the original on 30 October 2020. Retrieved 18 June 2019.

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