Fluconazole
Encyclopedia
Fluconazole 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. 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.
- 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. Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus. 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. A number of related compounds were found to be extremely potent teratogens, and were subsequently discarded.
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. 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.
Fluconazole can be used first-line for the following indications:
fluconazole in lactating mothers is not recommended.
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
).
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.
Some people are allergic to azole(s), so those allergic to other azole drugs might be allergic to fluconazole. That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome.
Fluconazole/Diflucan 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. Do not take Fluconazole/Diflucan without first talking to your doctor if you are pregnant or could become pregnant during treatment.
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.
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.
s associated with fluconazole therapy include:
(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.
Triazole
Triazole refers to either one of a pair of isomeric chemical compounds with molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.The two isomers are:*1,2,3-Triazole 100px*1,2,4-Triazole 100px...
antifungal drug
Antifungal drug
An antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis , serious systemic infections such as cryptococcal meningitis, and others...
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. It is commonly marketed under the trade name Diflucan or Trican (Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
). 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.
Mechanism of action
Like other imidazoleImidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
- and triazole
Triazole
Triazole refers to either one of a pair of isomeric chemical compounds with molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.The two isomers are:*1,2,3-Triazole 100px*1,2,4-Triazole 100px...
-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
Lanosterol
Lanosterol is a tetracyclic triterpenoid, which is the compound from which all steroids are derived.-Role in creation of steroids:Elaboration of lanosterol under enzyme catalysis leads to the core structure of steroids. 14-Demethylation of lanosterol by CYP51 eventually yields...
to ergosterol
Ergosterol
Ergosterol is a sterol found in fungi, and named for ergot, a common name for the members of the fungal genus Claviceps from which ergosterol was first isolated. Ergosterol does not occur in plant or animal cells...
, an essential component of the fungal cytoplasmic membrane, and subsequent accumulation of 14α-methyl sterols. Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus. It is interesting to note, when fluconazole was in development at Pfizer, it was decided early in the process to avoid producing any chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
centers in the drug so subsequent synthesis and purification would not encounter difficulties with enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
separation and associated variations in biological effect. A number of related compounds were found to be extremely potent teratogens, and were subsequently discarded.
Microbiology
Fluconazole is active against the following microorganisms:- Blastomyces dermatitidis
- CandidaCandida (genus)Candida is a genus of yeasts. Many species are harmless commensals or endosymbionts of animal hosts including humans, but other species, or harmless species in the wrong location, can cause disease. Candida albicans can cause infections in humans and other animals, especially in immunocompromised...
spp. (except C. krusei and C. glabrata) - Coccidioides immitisCoccidioides immitisCoccidioides 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....
- Cryptococcus neoformansCryptococcus neoformansCryptococcus neoformans is an encapsulated yeast that can live in both plants and animals. Its teleomorph is Filobasidiella neoformans, a filamentous fungus belonging to the class Tremellomycetes. It is often found in pigeon excrement....
- EpidermophytonEpidermophytonEpidermophyton is a genus of fungus causing superficial and cutaneous mycoses, including E. floccosum, a cause of tinea corporis , tinea cruris , tinea pedis , and onychomycosis or tinea unguium, a fungal infection of the nail bed.-External links:**...
spp. - Histoplasma capsulatum
- MicrosporumMicrosporumMicrosporum is a genus of fungi that causes tinea capitis, tinea corpus, ringworm, and other dermatophytoses. Microsporum forms both macroconidia and microconidia on short conidiophores...
spp. - TrichophytonTrichophytonThe fungus genus Trichophyton is characterized by the development of both smooth-walled macro- and microconidia. Macroconidia are mostly borne laterally directly on the hyphae or on short pedicels, and are thin- or thick-walled, clavate to fusiform, and range from 4 to 8 by 8 to 50 um in size....
spp.
Pharmacokinetics
Following oral dosing, fluconazole is almost completely absorbed within two hours. BioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
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. The elimination half-life of fluconazole follows zero order kinetics, and only 10% of elimination is due to metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, the remainder is excreted in urine and sweat. Patients with impaired renal function will be at risk of overdose.
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:- CandidiasisCandidiasisThrush redirects here. For the hoof infection see Thrush .Candidiasis or thrush is a fungal infection of any of the Candida species , of which Candida albicans is the most common...
caused by susceptible strains of Candida - Tinea corporisTinea corporisTinea corporis is a superficial fungal infection of the arms and legs, especially on glabrous skin, however it may occur on any part of the body.-Symptoms:...
, tinea cruris or tinea pedis - OnychomycosisOnychomycosisOnychomycosis means fungal infection of the nail. It is the most common disease of the nails and constitutes about a half of all nail abnormalities....
- Cryptococcal meningitisMeningitisMeningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
Fluconazole can be used first-line for the following indications:
- CoccidioidomycosisCoccidioidomycosisCoccidioidomycosis is a fungal disease caused by Coccidioides immitis or C. posadasii. It is endemic in certain parts of Arizona, California, Nevada, New Mexico, Texas, Utah and northwestern Mexico.C...
- CryptococcosisCryptococcosisCryptococcosis, or cryptococcal disease, is a potentially fatal fungal disease. It is caused by one of two species; Cryptococcus neoformans and Cryptococcus gattii. These were all previously thought to be subspecies of C...
- HistoplasmosisHistoplasmosisHistoplasmosis is a disease caused by the fungus Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease primarily affects the lungs...
- Prophylaxis of candidiasisCandidiasisThrush redirects here. For the hoof infection see Thrush .Candidiasis or thrush is a fungal infection of any of the Candida species , of which Candida albicans is the most common...
in immunocompromised people
Dosage
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.Contraindications
Fluconazole is contraindicated in patients that:- 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 offluconazole in lactating mothers is not recommended.
Fluconazole therapy has been associated with QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
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
Cisapride
Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...
and pimozide
Pimozide
Pimozide is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine . On a weight basis it is even more potent than haloperidol. It also has special neurologic indications for Tourette syndrome...
).
Fluconazole has also rarely been associated with severe or lethal hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
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.
Some people are allergic to azole(s), so those allergic to other azole drugs might be allergic to fluconazole. That is, some azole drugs have adverse side-effects. Some azole drugs may disrupt estrogen production in pregnancy, affecting pregnancy outcome.
Fluconazole/Diflucan 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. Do not take Fluconazole/Diflucan without first talking to your doctor if you are pregnant or could become pregnant during treatment.
Do not take Fluconazole/Diflucan if you are taking cisapride
Cisapride
Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...
(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.
Severe allergic reaction like anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
has been reported (as listed in the data sheet of pfizer Diflucan).
In rare cases, Fluconazole/Diflucan has also caused anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
, sometimes resulting in death.
Notify your doctor immediately if you develop a rash while taking Fluconazole/Diflucan.
Adverse effects
Adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s associated with fluconazole therapy include:
- Common (≥1% of patients): rash, headache, dizziness, nausea, vomiting, abdominal pain, diarrhea, and/or elevated liver enzymes
- Infrequent (0.1–1% of patients): anorexiaAnorexia (symptom)Anorexia is the decreased sensation of appetite...
, fatigue, constipation - Rare (<0.1% of patients): oliguriaOliguriaOliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...
, hypokalaemia, paraesthesia, seizures, alopeciaAlopeciaAlopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...
, Stevens–Johnson syndrome, thrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, other blood dyscrasiaDyscrasiaDyscrasia is a concept from ancient Greek medicine with the word "dyskrasia", meaning bad mixture.The concept of dyscrasia was developed by the ancient Greek physician Galen , who elaborated a model of health and disease as a structure of elements, qualities, humors, organs, and temperaments...
s, serious hepatotoxicityHepatotoxicityHepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
including hepatic failure, anaphylactic/anaphylactoid reactionsAnaphylaxisAnaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure... - Very rare: prolonged QT intervalQT intervalIn cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
, torsades de pointesTorsades de pointesTorsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation... - FDA is now saying that treatment with chronic, high doses (400–800 mg/day) of Diflucan (fluconazole) during the first trimester of pregnancy may be associated with a rare and distinct set of birth defects in infants.
Drug interactions
Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the isozyme CYP2C9CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
(CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
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
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
increases the risk of cardiac arrhythmia if used concurrently with other drugs that prolong the QT interval. Berberine
Berberine
Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary...
has been shown to exert synergistic effects with fluconazole even in drug-resistant Candida albicans infections.