Chemistry:Fluconazole

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Short description: Antifungal medication
Fluconazole
Fluconazole skeletal formula.svg
Fluconazole ball-and-stick model.png
Clinical data
Trade namesDiflucan, others
AHFS/Drugs.comMonograph
MedlinePlusa690002
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth, intravenous, topical
ATC code
Legal status
Legal status
  • AU: S3 (Pharmacist only) / S4
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only [1]
Pharmacokinetic data
Bioavailability>90% (oral)
Protein binding11–12%
Metabolismliver 11%
Elimination half-life30 hours (range 20–50 hours)
Excretionkidney 61–88%
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC13H12F2N6O
Molar mass306.277 g·mol−1
3D model (JSmol)
Melting point139[2] °C (282 °F)
  (verify)

Fluconazole is an antifungal medication used for a number of fungal infections.[3] This includes candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and tinea versicolor.[3] 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.[3] It is given either by mouth or by injection into a vein.[3]

Common side effects include vomiting, diarrhea, rash, and increased liver enzymes.[3] Serious side effects may include liver problems, QT prolongation, and seizures.[3] During pregnancy it may increase the risk of miscarriage while large doses may cause birth defects.[4][3] Fluconazole is in the azole antifungal family of medication.[3] It is believed to work by affecting the fungal cellular membrane.[3]

Fluconazole was patented in 1981 and came into commercial use in 1988.[5] It is on the World Health Organization's List of Essential Medicines.[6] Fluconazole is available as a generic medication.[3] In 2020, it was the 174th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[7][8]

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.[9]

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. Common uses include:[9][10][11][12][13]

  • The treatment of non-systemic Candida infections of the vagina ("yeast infections"), throat, and mouth.
  • Certain systemic Candida infections in people with healthy immune systems, including infections of the bloodstream, kidney, or joints. Other antifungals are usually preferred when the infection is in the heart or central nervous system, and for the treatment of active infections in people with weak immune systems.
  • The prevention of Candida infections in people with weak immune systems, such as those neutropenic due to cancer chemotherapy, those with advanced HIV infections, transplant patients, and premature infants.
  • As a second-line agent for the treatment of cryptococcal meningoencephalitis, a fungal infection of the central nervous system.

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).[14]

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.[14] 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.[15]

The full spectrum of fungal susceptibility and resistance to fluconazole can be found in the TOKU-E's product data sheet.[16] According to the United States Centers for Disease Control, fluconazole resistance among Candida strains in the U.S. is about 7%.[17]

Contraindications

Fluconazole is contraindicated in patients who:[13]

  • Drink alcohol
  • have known hypersensitivity to other azole medicines such as ketoconazole;
  • are taking terfenadine, if 400 mg per day multidose of fluconazole is administered;
  • concomitant administration of fluconazole and quinidine, especially when fluconazole is administered in high dosages;
  • take SSRIs such as fluoxetine or sertraline.

Side effects

Adverse drug reactions associated with fluconazole therapy include:[13]

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. Therefore, the use of fluconazole in lactating mothers is not recommended.[21]

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).[22]

Fluconazole has also rarely been associated with severe or lethal hepatotoxicity, so liver function tests are usually performed regularly during prolonged fluconazole therapy. In addition, it is used with caution in patients with pre-existing liver disease.[23]

Some people are allergic to azoles, so those allergic to other azole drugs might be allergic to fluconazole.[24] That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome. [25]

Fluconazole taken at low doses is in FDA pregnancy category C. However, high doses have been associated with a rare and distinct set of birth defects in infants. If taken at these doses, the pregnancy category is changed from category C to category D. Pregnancy category D means there is positive evidence of human fetal risk based on human data. In some cases, the potential benefits from use of the drug in pregnant women with serious or life-threatening conditions may be acceptable despite its risks. Fluconazole should not be taken during pregnancy or if one could become pregnant during treatment without first consulting a doctor.[26] 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.[27] Women using fluconazole during pregnancy have a 50% higher risk of spontaneous abortion.[28]

Fluconazole should not be taken with cisapride (Propulsid) due to the possibility of serious, even fatal, heart problems.[22] In rare cases, severe allergic reactions including anaphylaxis may occur.[29]

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 [30]

Interactions

Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozyme CYP2C19 (CYP3A4 and CYP2C9 to lesser extent) [31] 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.[32] Fluconazole may increase the serum concentration of Erythromycin (Risk X: avoid combination).[31]

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.[23] Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus.[33]

Pharmacokinetics

Following oral dosing, fluconazole is almost completely absorbed within two hours.[34] 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.[35] 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.[22]

In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol.[36]

History

Fluconazole was patented by Pfizer in 1981 in the United Kingdom and came into commercial use in 1988.[5] Patent expirations occurred in 2004 and 2005.[37]

References

  1. ↑ "Active substance: Fluconazole". List of nationally authorised medicinal products. European Medicines Agency. 12 November 2020. https://www.ema.europa.eu/documents/psusa/fluconazole-list-nationally-authorised-medicinal-products-psusa/00001404/202003_en.pdf. 
  2. ↑ "Cocrystals of Fluconazole with Aromatic Carboxylic Acids: Competition between Anhydrous and Hydrated Solid Forms". Crystal Growth & Design 20 (2): 1218–1228. 20 December 2019. doi:10.1021/acs.cgd.9b01490. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 "Fluconazole". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/fluconazole.html. 
  4. ↑ "Fluconazole (Diflucan): Drug Safety Communication - FDA Evaluating Study Examining Use of Oral Fluconazole (Diflucan) in Pregnancy". 2016-04-26. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm497656.htm. 
  5. ↑ 5.0 5.1 (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 503. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA503. 
  6. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  7. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  8. ↑ "Fluconazole - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Fluconazole. 
  9. ↑ 9.0 9.1 "US Pharmacist". http://www.uspharmacist.com/content/d/feature/c/22034/. 
  10. ↑ "US Prescribing Information". http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019949s060,020090s044lbl.pdf. 
  11. ↑ "IDSA Guidelines: Candida Infections". http://cid.oxfordjournals.org/content/48/5/503.1.full.pdf+html. 
  12. ↑ "IDSA Guidelines: Cryptococcal Infections". http://cid.oxfordjournals.org/content/48/5/503.1.full.pdf+html. 
  13. ↑ 13.0 13.1 13.2 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN:0-9757919-2-3
  14. ↑ 14.0 14.1 "Chapter 57: Antifungal Agents". Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). 2011. https://www.accessmedicine.com/content.aspx?aID=16678770. Retrieved May 22, 2012. 
  15. ↑ "DIFLUCAN® (fluconazole)". Pfizer. March 2013. http://labeling.pfizer.com/ShowLabeling.aspx?id=575. 
  16. ↑ "Spectrum of fungal susptibility and resistance to fluconazole". http://www.toku-e.com/Upload/Products/PDS/20120515002609.pdf. 
  17. ↑ "Antifungal Resistance | Fungal Disease | CDC". 2019-01-25. https://www.cdc.gov/fungal/antifungal-resistance.html. 
  18. ↑ "FDA Alert: Diflucan (fluconazole): Drug Safety Communication - Long-term, High-dose Use During Pregnancy May be Associated with Birth Defects". https://www.drugs.com/fda/diflucan-fluconazole-safety-communication-long-term-during-pregnancy-may-associated-birth-defects-13013.html. 
  19. ↑ 19.0 19.1 "Fluconazole". Monograph. The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/fluconazole.html. 
  20. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw. 
  21. ↑ "Product information from Pfizer Inc". http://media.pfizer.com/files/products/uspi_diflucan.pdf. 
  22. ↑ 22.0 22.1 22.2 Goodman & Gilman's : the Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education LLC. 2018. ISBN 978-1-259-58473-2. OCLC 1075550900. 
  23. ↑ 23.0 23.1 Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.
  24. ↑ "Lack of allergic cross-reactivity between fluconazole and voriconazole". Antimicrobial Agents and Chemotherapy 53 (4): 1715–1716. April 2009. doi:10.1128/AAC.01500-08. PMID 19164151. PMC 2663085. http://aac.asm.org/cgi/reprint/AAC.01500-08v1.pdf. Retrieved 2009-10-20. 
  25. ↑ "Assessing pregnancy risks of azole antifungals using a high throughput aromatase inhibition assay". Endocrine Research 28 (3): 129–140. August 2002. doi:10.1081/ERC-120015045. PMID 12489563. 
  26. ↑ "Fluconazole". PubMed Health. U.S. National Library of Medicine. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000890/. 
  27. ↑ "Use of oral fluconazole during pregnancy and the risk of birth defects". The New England Journal of Medicine 369 (9): 830–839. August 2013. doi:10.1056/NEJMoa1301066. PMID 23984730. 
  28. ↑ "Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth". JAMA 315 (1): 58–67. January 2016. doi:10.1001/jama.2015.17844. PMID 26746458. 
  29. ↑ Rang & Dale's pharmacology. ISBN 978-0-7020-5362-7. OCLC 942814866. 
  30. ↑ "Diflucan (Fluconazole) dosing, indications, interactions, adverse effects, and more". http://reference.medscape.com/drug/diflucan-fluconazole-342587#5. 
  31. ↑ 31.0 31.1 "Login". http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6918. 
  32. ↑ "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. November 2009. doi:10.1021/pr9005074. PMID 19754040. 
  33. ↑ "Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda". Clinical Infectious Diseases 47 (12): 1556–1561. December 2008. doi:10.1086/593194. PMID 18990067. 
  34. ↑ Basic & clinical pharmacology. McGraw-Hill Education. 30 November 2017. ISBN 978-1-259-64115-2. OCLC 1035129378. 
  35. ↑ Lippincott Illustrated Reviews Pharmacology. 21 September 2018. ISBN 978-1-4963-8413-3. OCLC 1114483879. 
  36. ↑ "Fluconazole". MP Biomedicals. http://www.mpbio.com/product_info.php?products_id=198986. 
  37. ↑ "Pfizer to Expand Fluconazole Donation Program to More than 50 Developing Nations" (in en-US). 2001-06-07. https://khn.org/morning-breakout/dr00005040/. 

Further reading

External links



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