Fluconazole

Fluconazole

Systematic (IUPAC) name
2-(2,4-difluorophenyl)- 1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol
Clinical data
Trade names	Difulcan
AHFS/Drugs.com	monograph
MedlinePlus	a690002
Pregnancy cat.	D (Au), C (U.S.)
Legal status	S3/S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Oral, IV, topical
Pharmacokinetic data
Bioavailability	>90%
Protein binding	11–12%
Metabolism	Hepatic 11%
Half-life	30 hours (range 20-50 hours)
Excretion	Renal 61–88%
Identifiers
CAS number	86386-73-4 Y
ATC code	D01AC15 J02AC01
PubChem	CID 3365
DrugBank	APRD00327
ChemSpider	3248 Y
UNII	8VZV102JFY Y
KEGG	D00322 Y
ChEBI	CHEBI:46081 Y
ChEMBL	CHEMBL106 Y
Chemical data
Formula	C13H12F2N6O
Mol. mass	306.271 g/mol
SMILES	eMolecules & PubChem
InChI 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 Y Key:RFHAOTPXVQNOHP-UHFFFAOYSA-N Y
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Fluconazole ( /fluːˈkɒnəzoʊl/) 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 name Diflucan or Trican (Pfizer). 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.

Pharmacology

Mechanism of action

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.^[2] Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus.^[3] 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]}

Microbiology

Fluconazole is active against the following microorganisms:^[4]

• Blastomyces dermatitidis
• Candida spp. (except C. krusei and C. glabrata)
• Coccidioides immitis
• Cryptococcus neoformans
• Epidermophyton spp.
• Histoplasma capsulatum
• Microsporum spp.
• Trichophyton spp.

Pharmacokinetics

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 is excreted in urine and sweat. Patients with impaired renal function will be at risk of overdose.^{[citation needed]}

Clinical use

Indications

Fluconazole is a drug 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:^[5]

• Candidiasis caused by susceptible strains of Candida
• Tinea corporis, tinea cruris or tinea pedis
• Onychomycosis
• Cryptococcal meningitis

Fluconazole can be used first-line for the following indications:^[5]

• Coccidioidomycosis
• Cryptococcosis
• Histoplasmosis
• Prophylaxis of candidiasis in immunocompromised people

Dosage

Please take note that this is NOT for anyone under the age of eighteen. This variety can cause many problems to the abdomen on a younger child. Dosage varies with indication and between patient groups, ranging from: a two-week course of 150 mg/day for vulvovaginal candidiasis, to 150–300 mg once weekly for resistant skin infections or some prophylactic indications. A dosage of 500–600 mg/day may be used for systemic or severe infections, and, in urgent infections such as meningitis caused by yeast, 800 mg/day have been used. Pediatric doses are measured at 6–12 mg/kg/d. A loading dose will be indicated when entering a daily dosage schedule; for example, a loading dose of 200 mg on the first day is commonly used with 150 mg/day following that.^[5]

Contraindications

Fluconazole is contraindicated in patients that:^[5]

• Have known hypersensitivity to other azole medicine
• 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
• Are pregnant.

Precautions

Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of fluconazole in lactating mothers is not recommended.^[6]

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 and 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.^[2]

Some people are allergic to azole(s), so those allergic to other azole drugs might be allergic to fluconazole.^[7] That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome.^[8]

Fluconazole/Diflucan taken at a dose of 150mg is in FDA pregnancy category C. However, high doses (400mg to 800mg 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. Do not take Fluconazole/Diflucan without first talking to your doctor if you are pregnant or could become pregnant during treatment.^[9]

Do not take Fluconazole/Diflucan if you are taking cisapride (Propulsid).
Combined with cisapride (Propulsid), Diflucan could cause serious, even fatal, heart problems.

In rare cases, Fluconazole/Diflucan has caused severe liver damage, sometimes resulting in death.
Notify your doctor immediately if you develop nausea, vomiting, abdominal pain, unusual fatigue, loss of appetite, yellow skin or eyes, itching, dark urine, or clay-colored stools.
These symptoms may be early signs of liver damage.^{[citation needed]}

Severe allergic reaction like anaphylaxis has been reported (as listed in the data sheet of pfizer Diflucan). In rare cases, Fluconazole/Diflucan has also caused anaphylaxis, sometimes resulting in death. Notify your doctor immediately if you develop a rash while taking Fluconazole/Diflucan.^{[10][unreliable source?]}

Adverse effects

Adverse drug reactions associated with fluconazole therapy include:^[5]

• Common (≥1% of patients): rash, headache, dizziness, nausea, vomiting, abdominal pain, diarrhea, and/or elevated liver enzymes
• Infrequent (0.1–1% of patients): anorexia, fatigue, constipation
• Rare (<0.1% of patients): oliguria, hypokalaemia, paraesthesia, seizures, alopecia, Stevens-Johnson syndrome, thrombocytopenia, other blood dyscrasias, serious hepatotoxicity including hepatic failure, anaphylactic/anaphylactoid reactions
• Very rare: prolonged QT interval, torsades de pointes
• FDA is now saying that treatment with chronic, high doses (400-800mg/day) of Diflucan (fluconazole) during the first trimester of pregnancy may be associated with a rare and distinct set of birth defects in infants.^[11]

Drug interactions

Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozyme CYP2C9 (CYP3A4 to lesser extent). 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.^[12]

Synthesis

Richardson, R. K.; 1983, U.S. Patent 4,404,216.

See also

• Fosfluconazole
• Itraconazole

References

1. ^ MP Biomedicals
2. ^ ^{a b} Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.
3. ^ Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, Wall E, Andia I, Jaffar S, Harrison TS. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis. 2008; 47: 1556-61.
4. ^ Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4
5. ^ ^{a b c d e} Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
6. ^ Product information from Pfizer Inc
7. ^ http://aac.asm.org/cgi/reprint/AAC.01500-08v1.pdf
8. ^ 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. 
9. ^ http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000890/
10. ^ http://www.med-store.info/fluconazole.html
11. ^ http://www.drugs.com/fda/diflucan-fluconazole-safety-communication-long-term-during-pregnancy-may-associated-birth-defects-13013.html
12. ^ Xu Y, Wang Y, Yan L, et al. (September 14, 2009) Proteomic Analysis Reveals a Synergistic Mechanism of Fluconazole and Berberine against Fluconazole-Resistant Candida albicans: Endogenous ROS Augmentation. Journal of Proteome Research. Publication Date (Web)Free Full Text