Fluconazole

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Fluconazole
Fluconazole structure.svg
Fluconazole-from-xtal-3D-balls.png
Systematic (IUPAC) name
2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
Clinical data
Trade namesDiflucan
AHFS/Drugs.commonograph
MedlinePlusa690002
Pregnancy cat.D (Au), C (U.S.)
Legal statusS3/S4 (Au), POM (UK), ℞-only (U.S.)
RoutesOral, IV, topical
Pharmacokinetic data
Bioavailability>90%
Protein binding11–12%
MetabolismHepatic 11%
Half-life30 hours (range 20-50 hours)
ExcretionRenal 61–88%
Identifiers
CAS number86386-73-4 YesY
ATC codeD01AC15 J02AC01
PubChemCID 3365
DrugBankDB00196
ChemSpider3248 YesY
UNII8VZV102JFY YesY
KEGGD00322 YesY
ChEBICHEBI:46081 YesY
ChEMBLCHEMBL106 YesY
Chemical data
FormulaC13H12F2N6O 
Mol. mass306.271 g/mol
 YesY (what is this?)  (verify)
 
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Fluconazole
Fluconazole structure.svg
Fluconazole-from-xtal-3D-balls.png
Systematic (IUPAC) name
2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
Clinical data
Trade namesDiflucan
AHFS/Drugs.commonograph
MedlinePlusa690002
Pregnancy cat.D (Au), C (U.S.)
Legal statusS3/S4 (Au), POM (UK), ℞-only (U.S.)
RoutesOral, IV, topical
Pharmacokinetic data
Bioavailability>90%
Protein binding11–12%
MetabolismHepatic 11%
Half-life30 hours (range 20-50 hours)
ExcretionRenal 61–88%
Identifiers
CAS number86386-73-4 YesY
ATC codeD01AC15 J02AC01
PubChemCID 3365
DrugBankDB00196
ChemSpider3248 YesY
UNII8VZV102JFY YesY
KEGGD00322 YesY
ChEBICHEBI:46081 YesY
ChEMBLCHEMBL106 YesY
Chemical data
FormulaC13H12F2N6O 
Mol. mass306.271 g/mol
 YesY (what is this?)  (verify)

Fluconazole /flˈkɒnəzl/ is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol.[1]

It is commonly marketed under the trade names Diflucan and Trican (Pfizer). It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]

Medical uses[edit]

Fluconazole is indicated for the treatment and prophylaxis of fungal infections where other antifungals have failed or are not tolerated (e.g., due to adverse effects), including:[3]

Fluconazole can be used first-line for the following indications:[3]

Fluconazole is active against:[4]

Resistance[edit]

Fungal 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).[5]

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.[5] 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 [6]

The full spectrum of fungal susceptibility and resistance to fluconazole can be found in the TOKU-E's product data sheet.[7]

Contraindications[edit]

Fluconazole is contraindicated in patients who:[3]

Precautions[edit]

Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of fluconazole in lactating mothers is not recommended.[8]

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).[citation needed]

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.[9]

Some people are allergic to azoles, so those allergic to other azole drugs might be allergic to fluconazole.[10] That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome. [11]

Fluconazole taken at a dose of 150 mg is in FDA pregnancy category C. However, high doses (400 mg to 800 mg a day) 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.[12] 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.[13]

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

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 [14]

Adverse effects[edit]

Adverse drug reactions associated with fluconazole therapy include:[3]

Drug interactions[edit]

Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozyme CYP2C19 (CYP3A4 and CYP2C9 to lesser extent) [16] 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.[17] Fluconazole may decrease the metabolism of benzodiazepines. Fluconazole may increase the serum concentration of Citalopram (Risk X: avoid combination). Fluconazole may increase the serum concentration of Erythromycin (Risk X: avoid combination. [18]

Mechanism of action[edit]

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.[9] Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus.[19]

It is interesting to note, when fluconazole was in development at Pfizer, it was decided early in the process to avoid producing any chiral centers in the drug so subsequent synthesis and purification would not encounter difficulties with enantiomer separation and associated variations in biological effect.[citation needed] A number of related compounds were found to be extremely potent teratogens, and were subsequently discarded.[citation needed]

Pharmacokinetics[edit]

Following oral dosing, fluconazole is almost completely absorbed within two hours.[citation needed] 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.[citation needed] The elimination half-life of fluconazole follows zero order kinetics, 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.[citation needed]

Synthesis[edit]

Fluconazole can be synthesized from a halogenated acetophenone derivative.[20]

Brands[edit]

Fluconazole is sold as a single 150 mg dose over the counter in Canada under the brand names Monicure and Canesten.[21] In Mexico, it is sold over the counter as Alfumet, Afungil or Dofil. It is marketed under the brand name Candivast in the Persian Gulf area. In Colombia, it is marketed as Batén by Laboratorios Bussié. In Panama, it is marketed under the name Ibarin from different manufacturers. In Egypt, it is marketed under the names Diflucan, Flucoral, Fungican, Triconal. The No.1 brand in India is Zocon, available as Tablets, Lotion, Dusting Powder, Transgel and Eye Drop.

See also[edit]

References[edit]

  1. ^ MP Biomedicals
  2. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ a b c d Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  4. ^ Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4
  5. ^ a b Bennett J.E. (2011). Chapter 57. Antifungal Agents. In L.L. Brunton, B.A. Chabner, B.C. Knollmann (Eds), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. Retrieved May 22, 2012 from http://www.accessmedicine.com.ezp1.lib.umn.edu/content.aspx?aID=16678770.
  6. ^ http://labeling.pfizer.com/ShowLabeling.aspx?id=575
  7. ^ Spectrum of fungal susptibility and resistance to fluconazole
  8. ^ Product information from Pfizer Inc
  9. ^ a b Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.
  10. ^ http://aac.asm.org/cgi/reprint/AAC.01500-08v1.pdf
  11. ^ Kragie, Laura; Turner, Stephanie D.; Patten, Christopher J.; Crespi, Charles L.; Stresser, David M. (2002). "Assessing Pregnancy Risks of Azole Antifungals Using a High Throughput Aromatase Inhibition Assay". Endocrine Research 28 (3): 129–40. doi:10.1081/ERC-120015045. PMID 12489563. 
  12. ^ Fluconazole, PubMed Health
  13. ^ Mølgaard-Nielsen, D.; Pasternak, B. R.; Hviid, A. (2013). "Use of Oral Fluconazole during Pregnancy and the Risk of Birth Defects". New England Journal of Medicine 369 (9): 830–839. doi:10.1056/NEJMoa1301066. PMID 23984730.  edit
  14. ^ http://reference.medscape.com/drug/diflucan-fluconazole-342587#5
  15. ^ http://www.drugs.com/fda/diflucan-fluconazole-safety-communication-long-term-during-pregnancy-may-associated-birth-defects-13013.html
  16. ^ http://online.lexi.com.proxy1.lib.tju.edu/lco/action/doc/retrieve/docid/patch_f/6918
  17. ^ Xu, Yi; Wang, Yan; Yan, Lan; Liang, Rong-Mei; Dai, Bao-Di; Tang, Ren-Jie; Gao, Ping-Hui; Jiang, Yuan-Ying (2009). "Proteomic Analysis Reveals a Synergistic Mechanism of Fluconazole and Berberine against Fluconazole-ResistantCandida albicans: Endogenous ROS Augmentation". Journal of Proteome Research 8 (11): 5296–5304. doi:10.1021/pr9005074. ISSN 1535-3893. PMID 19754040.  Free Full Text
  18. ^ http://online.lexi.com.proxy1.lib.tju.edu/lco/action/doc/retrieve/docid/patch_f/6918
  19. ^ Longley, Nicky; Muzoora, Conrad; Taseera, Kabanda; Mwesigye, James; Rwebembera, Joselyne; Chakera, Ali; Wall, Emma; Andia, Irene; Jaffar, Shabbar; Harrison, Thomas S. (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. ISSN 1058-4838. PMID 18990067. 
  20. ^ Richardson, R. K.; 1983, U.S. Patent 4,404,216
  21. ^ Insight Pharmaceuticals. Our Products: Monicure. N.p.: Insight Pharmaceuticals, n.d.Monistat. Insight Pharmaceuticals, 2013. Web. 24 July 2013. <http://www.monistat.ca/monicure>.