Fluconazole structure activity relationship of diuretics

Torasemide - DrugBank

Fluconazole is a bis-triazole with the following structural formula: Chemical function. There is an inverse relationship between the elimination half-life and creatinine .. approximately - µmol/L higher with concomitant diuretic. develop abnormal liver function tests during Fluconazole Injection SDZ or confounding risk factors, such as structural heart disease, electrolyte .. subjects received concomitant diuretics (see DRUG INTERACTION STUDIES). . comparative agents, but the clinical significance and relationship to. General Information: Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in the pharmacokinetics of hydrochlorothiazide in relation to renal function indicate position (a proposed structural site of action for sulfonamide allergy) One .. Hydrochlorothiazide, HCTZ may decrease the renal clearance of fluconazole.

Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes.

Coadministration of fluconazole and pimozide is contraindicated. Possible increased risk of ventricular arrhythmias when triazoles given with sertindole- avoid concomitant use. Concomitant use of the following other medicinal products cannot be recommended: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity prolonged QT interval, Torsades de Pointes and consequently sudden heart death. This combination should be avoided.

Concomitant use of the following other medicinal products lead to precautions and dose adjustments: The effect of other medicinal products on fluconazole Hydrochlorothiazide: An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.

In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored.

The enzyme inhibiting effect of fluconazole persists 4- 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole See section 4. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Fluconazole increases the effect of amitriptyline and nortriptyline. Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: The clinical significance of results obtained in these studies is unknown.

In post-marketing experience, as with other azole antifungals, bleeding events bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin.

Prothrombin time in patient receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin may be necessary. Avoidance of fluconazole is advised by the manufacturers of artemether and lumefantrine. An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single mg oral dose of azithromycin on the pharmacokinetics of a single mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azifhromycin.

There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously.

If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. Dosage adjustments of triazolam may be necessary. Fluconazole may increase levels of bosentan since both are metabolized by cytochrome P There is a risk of developing carbamazepine toxicity.

Certain dihydropyridine calcium channel antagonists nifedipine, isradipine, amlodipine and felodipine are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Half of the celecoxib dose may be necessary when combined with fluconazole. Fluconazole significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.

Fluconazole may increase levels of citalopram since both are metabolized by the cytochrome P Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Fluconazole increases plasma concentration of eplerenone reduce dose of eplerenone Ergotamine and Methysergide: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.

Cell membrane is the location where many metabolic processes occur and meanwhile it provides a barrier to environmental stresses. More important and encouraging is that this compound shows little hemolytic activity on human erythrocytes [ 18 ]. The differential effects upon human and fungi cells imply that it may act on unique components of fungi cells, which needs further identification.

Changes in granularity and size revealed by the flow cytometry assays also involves alterations of the membrane properties such as osmolarity [ 22 ]. However, there are no evident causative link between disruption of membrane potential and changes of osmolarity and no conclusions about which comes first, which remain to be further investigated. As a component of fungal cell membrane different from the mammalian parallel and a critical modulator for differentiation and pathogenicity of fungi, the glycosphingolipid glycosylceramide in the cell envelope maybe presents a better target for antifungal therapeutic treatments [ 23 ].

Ergosterol plays important roles in regulating the fluidity of the cell membrane and cell division of fungal cells, while the structural and conformational differences between ergosterol and sterol the counterpart of ergosterol in mammalian cells underlie the antifungal mechanism of the polyenes such as amphotericin B [ 1224 ]. Despite the low bioavailability and high toxicity of ergosterol-targeting drugs in humans [ 2526 ], ergosterol still presents a good target for antifungal drugs due to the importance of cell membrane.

Magnolol, one of the major pharmacologically active compounds from Magnolia officinalis which could be used to ameliorate the symptoms such as anxiety, asthma, nervous disturbance, and digestive problems [ 27 ], could reduce the content of ergosterol in the widely used C. Compounds from essential oil of mint, such as menthol, menthone, and carvone, suppress the growth of C. The ergosterol levels could also be decreased by carvacrol isolated from Origanum dictamnus L.


Aside from Candida species, antifungal activities of this compound against other fungi such as Monilinia laxa have been identified [ 31 — 33 ]. Transporters such as ABC transporters on cell membrane could induce the efflux of antifungals, thus compromising the effects of drugs.

Treatment with magnolol could significantly decrease the efflux of fluconazole, thus enhancing the antifungal effects of fluconazole [ 28 ]. The results also indicated the existence of targets that could be easily touched by external drugs, despite the fact that more efforts need to be made.

Compounds Targeting Cell Wall Components The structural integrity of cell wall is vital to the survival and growth of fungal cells, as it provides a shelter from osmotic pressure and other stresses in milieu.

Recent studies showed that it likely plays an important role in the colonization and biofilm formation of C. Damaged cell wall leads to osmotic fragility of the fungal cell, disrupted membrane, efflux of cytoplasmic contents, and suppressed growth of fungi [ 13 ]. Cell wall is lacking in mammal cells, which makes it a preferential target for potential antifungal drugs for safety considerations. The cell wall of Candida species holds glycoproteins and abundant carbohydrates, among which are largely glucan, mannose, and chitin [ 10 ].

In the following part of this review we will discuss the plant-derived antifungal components acting on cell wall elements or on the synthesis of those elements. Despite the small percentage in the cell wall, chitin plays important roles in maintaining the mechanical strength of the fungal cell wall, thus keeping the integrity of the fungal cell wall [ 38 ]. Since this material does not exist in human cells, this presents an attractive target for antifungal therapies [ 36 ].

The chemical structures of the classic inhibitors of CHS, namely, polyoxins and nikkomycins, make themselves be degraded easily in vivo and difficult to go through the cell membrane, leading to a low antifungal activity [ 3639 ]. This prompts us to find new CHS inhibitors. Plagiochin E derived from liverwort Marchantia polymorpha L. However, the same group found that plagiochin E exposure of C.

These studies indicate that plagiochin E may exert its antifungal activity through diverse currently unknown mechanisms. Glucan This carbohydrate polymer, together with chitin, is the structural component which holds the integrity and physical strength of the cell wall. The production and assembly of glucan in C.

Recently, a novel terpene antifungal SCY demonstrated fungicidal activity against C. Sodium houttuyfonate, a derivative from Houttuynia cordata Thunb. Compounds Targeting Mitochondria The classical respiratory chains of mitochondria are centers of energy production through oxidative phosphorylation, and meanwhile mitochondria are the organelles that produce metabolic intermediates used for amino acid and lipid biosynthesis.

Both energy supply and metabolites are indispensable for the survival and growth of C. Mitochondria are also involved in efflux-mediated resistance of C. Resistance to azole is also likely to be related with decreased generation of endogenous ROS that are harmful to DNA, proteins, and lipids while ROS are mainly generated by enzyme complexes Complex I and Complex III in classical respiratory chain as by-products of selective degradation of mitochondria [ 44 ].

Elevated levels of intracellular ROS are involved in the antifungal effects of fluconazole and miconazole and ROS also play an important role in intrinsic mitochondrial pathway of apoptosis in C.

Besides the common enzymes in classical respiratory chain in C. The differences between fungal and mammal mitochondrial enzymes also make developing drugs targeting these enzymes possible [ 52 ]. This is the case of some agrichemicals such as boscalid and carboxin that inhibit the succinate dehydrogenase in fungal cells [ 53 ]. Although there are only few studies on drugs targeting specifically mitochondria of Candida spp.

In a word, mitochondria might be a promising target for antifungal therapies. As an important constituent of many herbs of Berberidaceae family such as Berberis vulgaris, berberine exerts its antifungal action by induction of mitochondrial dysfunction and increased ROS generation, and its effects are in synergy with fluconazole, even in fluconazole-resistant clinical isolates [ 54 — 56 ].

Moreover, berberine treatment could also culminate in disruption of cell wall integrity in C. Although berberine could induce apoptosis in many human cells such as HL leukemia cells and thyroid carcinoma cells [ 5960 ], berberine could recover the mitochondrial function induced by high-fat feeding in a rat model and could decrease the triglyceride accumulation in the liver in mice [ 6162 ].

It also markedly decreased the ROS generation in mitochondria [ 62 ]. This makes berberine a good candidate for antifungal development although there are much more to be done. The safe profile of this lignin makes it more inspiring although there is no report on its effects on mammalian mitochondria. Allyl alcohol from garlic Allium sativumwhich has been used as a traditional antimicrobial agent for thousands of years, exerts its antifungal effect through introducing oxidative stress such as increasing ROS production and depleting glutathione.

The known targets of allyl alcohol are cytosolic alcohol dehydrogenases Adh1 and Adh2 and the mitochondrial Adh3 [ 66 ]. Although allyl alcohol could be released after ingestion of garlic, its toxicity, mediated by acrolein the production of which is catalyzed by alcohol dehydrogenase in rodents, prevents its development as antifungal agent [ 6667 ].

However, in mammalian cells e. There are also reports showing that baicalin induces apoptosis in human non-small lung cancer cells and osteosarcoma cells through ROS production [ 7071 ]. Despite the discrepancy between the roles of baicalin in different cells in ROS production, the in vivo tests might support the use of baicalin as an antifungal candidate [ 697173 ]. Shikonin, the major active compound isolated from Lithospermum erythrorhizon, could induce the endogenous ROS production, reduce the mitochondrial membrane potential, and alter mitochondrial aerobic aspiration [ 74 ].

In human gastric cancer cells and TT medullary thyroid carcinoma cells, shikonin could also induce ROS production and mitochondria-mediated apoptosis [ 7576 ]. The almost same cytotoxicity for fungal cells and mammalian cells makes shikonin a less attractive candidate for antifungal development. Curcumin, the yellow pigment isolated from the turmeric the rhizome of the plant Curcuma longa Linn could also be used as an adjunct drug to treat pathogenic microorganisms such as Helicobacter pylori, methicillin-resistant Staphylococcus aureus MRSAand Trypanosoma cruzi.

Antifungal activities against various kinds of fungi such as Candida species, Cryptococcus neoformans, Aspergillus spp.

Curcumin could increase ROS production and apoptosis in C. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of an MAOI and hydrochlorothiazide, HCTZ.

Hydrochlorothiazide, HCTZ may decrease the renal clearance of fluconazole. Coadministration may result in an additive risk of developing hyponatremia. When concurrent therapy with a thiazide diuretic and carbamazepine is necessary, monitor patients for hyponatremia. Hypercalcemia was reported in clinical trials with calcitriol ointment see Adverse Reactions. Use caution if thiazide diuretics and topical calcitriol are coadministered. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent.

Conversely, coadminisitration of thiazides and prokinetic agents may result in decreased bioavailability of the thiazide diuretic. The clinical significance of this change is unknown; however, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate.

The clinician should be aware of the potential for this interaction and monitor the patient accordingly. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. Change in sex drive or performance; dry mouth; headache; stomach upset. This list may not describe all possible side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: Adverse GI effects associated with thiazides, like hydrochlorothiazide, include abdominal pain, anorexia, gastric irritation, nausea, vomiting, cramps, diarrhea, constipation, sialadenitis, and pancreatitis.

Patients receiving hydrochlorothiazide should be monitored closely for signs of electrolyte imbalance including hyponatremia, hypokalemia, hypomagnesemia, and hypochloremia. Patients receiving hydrochlorothiazide can develop a dilutional hyponatremia, but it usually is asymptomatic and moderate. Withdrawal of the drug, fluid restriction, and potassium or magnesium supplementation typically will return the serum sodium concentration to normal, but severe hyponatremia can occur.

Geriatric patients are especially susceptible to developing hyponatremia, so care should be taken when diuretics are administered to these patients. Thiazides also can decrease urinary calcium excretion, resulting in hypercalcemia. Hyperaldosteronism, secondary to cirrhosis or nephrosis, can predispose patients to hypokalemia when hydrochlorothiazide is administered.

Low dietary-potassium intake, potassium-wasting states, or administration of potassium-wasting drugs also can predispose patients to hydrochlorothiazide-induced hypokalemia.

Patients receiving hydrochlorothiazide therapy may require supplemental potassium to prevent hypokalemia or metabolic alkalosis. Complications of thiazide diuretic therapy may include intravascular volume depletion hypovolemiawith potential for development of prerenal azotemia. These effects have occurred mainly in patients with preexisting renal disease. If progressive renal impairment occurs, consider discontinuing diuretic therapy.

Latent diabetes mellitus may become manifest during thiazide therapy. Because thiazides reduce the clearance of uric acid, acute gout may be precipitated by thiazide diuretics in some patients. There was also no significant difference between chlorthalidone and the three study drugs in the rate of major coronary heart disease events and all-cause mortality, 65 suggesting that the diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk.

Hypotension, including orthostatic hypotension, may occur during treatment with hydrochlorothiazide and can be exacerbated by concurrent use of alcohol, narcotics, or antihypertensive drugs. An increased risk of falls has been reported for elderly patients receiving thiazide diuretics, like hydrochlorothiaizde. Thiazide diuretics, like hydrochlorothiazide, have been associated with intrahepatic cholestatic jaundice rare.

Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, and thrombocytopenia have been reported with hydrochlorothiazide use; however, the incidences are unknown. These reactions include purpura, photosensitivity, rash unspecifiedalopecia, urticaria, erythema multiforme including Stevens-Johnson syndrome, and exfoliative dermatitis including toxic epidermal necrolysis TEN.

Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. Discontinue hydrochlorothiazide as rapidly as possible and consider prompt medical or surgical treatment if the ocular hypertension remains uncontrolled. Anaphylactoid reactions and necrotizing angiitis vasculitis and cutaneous vasculitis have occurred with the administration of hydrochlorothiazide incidence unknown.

How is this medication best taken?

Fluconazole 50mg Capsules - Summary of Product Characteristics (SmPC) - (eMC)

Take this medicine by mouth with a glass of water. Follow the directions on the prescription label. Take your medicine at regular intervals. Remember that you will need to pass urine frequently after taking this medicine. Do not take your doses at a time of day that will cause you problems.

What do I do if I miss a dose? If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.

Keep all medicine out of the reach of children. Throw away any unused medicine after the expiration date. Do not flush unused medications or pour down a sink or drain.

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Fluconazole 150mg Capsules

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