AN OVERVIEW OF AZOLE ANTIFUNGALSHTML Full Text
AN OVERVIEW OF AZOLE ANTIFUNGALS
Pratibha Shivaji Gavarkar*, Rahul Shivaji Adnaik, and Shrinivas Krishna Mohite
Rajararambapu College of Pharmacy, Kasegaon, Tal. Walwa, Dist. Sangli- 415404, Maharashtra, India
ABSTRACT: Fungal infections in critically ill or immunosuppressed patients were increasing in incidence in the human population over the last 1-2 decades. There were few advances in antifungal therapy and, until recently, there were few choices from which to select a treatment for systemic mycoses. However, in the past decade, there have been several developments in this area. Antifungal agents are sufficiently diverse in activity, toxicity, and drug interaction potential. Azoles are synthetic and semi-synthetic compounds. They have a broad spectrum of activity. Triazole antifungals are active to treat an array of fungal pathogens, whereas imidazoles are used almost exclusively in the treatment of superficial mycoses and vaginal candidiasis. Despite the advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy.The present review aims to explore the pharmacology, pharmacokinetics, spectrum of activity, safety, toxicity and potential for drug–drug interactions of the azole antifungal agents.
Arthritis, Drug targeting, Inflammation, Nanocarriers
INTRODUCTION:Fungi are common pathogens in critically ill or immunosuppressed patients. Fungal infections (mycoses), though not as frequent as bacterial or viral infections, have nonetheless been increasing in incidence in the human population over the last 1-2 decades. In addition, a number of fungal infections can be difficult to treat, even when the offending organism is identified and appropriate therapy is applied. Fungi have unique characteristics, distinct from their mammalian hosts, allowing for selective targeting of therapeutic drugs.
Fungi are, however, much more complex organisms in comparison to bacteria, are in fact eukaryotic and often grow fairly slowly. Consequently, only a few drugs are aimed at interfering with cell division and have limited use.
However, in the past decade, there have been several developments in advances in antifungal therapy to select a treatment for systemic mycoses. A new class of antifungal agents (echinocandins) has been developed, safer and/or more bioavailable formulations of itraconazole and amphotericin B have been marketed, and another compound-voriconazole has been added to the triazole class of agents. Antifungal agents are sufficiently diverse in activity, toxicity, and drug interaction potential to allow clinicians to differentiate among agents based upon these characteristics when tailoring therapy to meet the needs of a particular patient.
The present review focuses on the pharmacology, pharmacokinetics, safety, and potential for drug-drug interactions of the antifungal agents 1-4.
Azoles are synthetic and semi-synthetic compounds as shown in Table 1. They have a broad spectrum of activity.
TABLE 1: CLASSIFICATION OF ANTI-FUNGAL AGENTS
|Class||Route of administration||Examples|
|Imidazole group||Topical agents||Clotrimazole, Econazole miconazole, butaconazole,|
|Triazole group||Topical agent||teraconazole, itraconazole,|
|Systemic agents||fluconazole, itraconazole, voriconazole|
Pharmacology of Azoles:
Mechanisms of Action: The systemically acting azoles include fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole. The azoles exert a fungistatic effect by dose-dependent inhibition of CYP-dependent 14α-demethylase, which is necessary for the conversion of lanosterol to ergosterol.Ergosterol is important for the stability of the fungal cell membrane, and inhibition of its synthesis compromises cell membrane integrity 2.
The triazoles also secondarily target other steps in the ergosterol biosynthesis pathway.
For example, in fluconazole-susceptible C. albicans fluconazole only partially inhibits ergosterol and completely blocks obtusifoliol synthesis, whereas voriconazole completely inhibits both ergosterol and obtusifoliol synthesis 5. Itraconazole and fluconazole may also inhibit 3-ketoreductase, which catalyzes the reduction of the 3-ketosteroid obtusifolione to obtusifoliol in C. neoformans 6.
All azoles act much more slowly than polyenes. Thus they are used less often than polyenes in treatment of fulminating fungal infections. Some of the important azoles along with their indications, brand name and available formulation are listed in the Table 2.
TABLE 2: AZOLES AS ANTIFUNGAL AGENTS
|Agent||Indications||Brand Name||Available formulation|
|Fluconazole||Vaginal, oropharyngeal, and esophageal candidiasis; cryptococcal meningitis; prophylaxis to decrease the incidence of candidiasis in patients undergoing BMT who receive cytotoxic chemotherapy and/or radiation.||Diflucan (Pfizer)||IV, oral suspension, oral tablet|
|I.V., oral capsule: Pulmonary and extrapulmonary blastomycosis; histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis; aspergillosis in patients who are refractory to or intolerant of amphotericin B therapy.
Oral capsules only: Non-immunocompromised patients: treatment of onychomycosis of the toenail, with or without fingernail involvement, or of the fingernail alone, due to dermatophytes (tinea unguium).
I.V., oral solution only: Empiric therapy of febrile neutropenic patients with suspected fungal infections.
Oral solution only: Oropharyngeal and esophageal candidiasis.
|IV, oral capsule, oral solution|
|Candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromoblastomycosis, and paracoccidioidomycosis; severe recalcitrant cutaneous dermatophyte infections that have not responded to topical therapy or oral griseofulvin, or in patients unable to take griseofulvin.||Nizoral
|Invasive aspergillosis; candidemia in nonneutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds; esophageal candidiasis; serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp, including
F. solani, in patients intolerant of, or refractory to, other therapy.
|Vfend, (Pfizer)||IV, oral tablet|
Spectrum of Activity: Azoles possess broad spectrum of activity against yeasts and moulds. However, as this therapeutic class expands, differences in spectrum of activity among the individual agents emerge. The difference in spectrum of activity exhibited among different azoles may be attributed to variation in the inhibition of 14α-demethylase and secondary targets among species. Table 3 shows spectrum of activity of various azoles.
TABLE 3: SPECTRUM OF ACTIVITY OF AZOLES
|Agent||Spectrum of activity|
|Voriconazole 6-9, 11||
Pharmacokinetics of Azoles: Chemically, azoles are lipophilic weak bases. All azoles have good relative or absolute bioavailability after oral administration (except the capsule form of itraconazole). Dissolution of ketoconazole and itraconazole in the stomach, administered as solid oral dosage forms are significantly influenced by elevations in gastric pH 17, 18. Azoles (except posaconazole) require extensive oxidative (CYP) metabolism to be eliminated from the body 19, 20. Unlike the other triazoles, posaconazole undergoes minimal (2%) CYP metabolism; most of its metabolites are glucuronide conjugates formed by uridine diphosphate glucuronosyltransferase (UGT) pathways, mainly UGT1A4 21, 22.
Fluconazole is less lipophilic, and therefore it requires less oxidative (CYP) metabolism. The azoles are inhibitors of CYP3A4, the primary oxidative drug-metabolizing enzyme in humans 23, 24. However, the azoles all differ in their affinity for this enzyme. Fluconazole and voriconazole also inhibit CYP2C9/19, and fluconazole inhibits a UGT pathway (UGT2B7) 23, 25.The significance of the interaction is unknown.
Drug disposition is facilitated by a variety of transport proteins which are expressed in tissues throughout the body in humans. Azoles and echinocandins vary in their interactions with transport proteins 26-28.
Itraconazole, ketoconazole, and posaconazole interact with P-glycoprotein, the best-known efflux transport protein.28 Ketoconazole and itraconazole interact with another transporter, known as breast cancer resistance protein (BCRP) 28. The significance of these interactions with BCRP have not been fully elucidated, but they may, in part, explain certain interactions that previously could not be adequately described by interactions with CYP.
Toxicity of Azoles 29-32: The primary toxicities associated with the azoles involve the liver have been shown in the Table 4 and Table 5. These toxicities range from the common transient elevations in serum transaminases to the less common fulminant hepatoxicity and liver failure. Liver failure is rare but it may occur with any azole.
TABLE 4: TOXICITY OF AZOLES
The underlying mechanism of above side effect has not been elucidated, but it is believed to be concentration- or dose-related.
TABLE 5: ADVERSE EFFECTS OF AZOLES
Drug-Drug interactions of Azoles: Drug interactions associated with the azoles result from several different mechanisms. These agents can interact with drugs through different mechanisms (e.g. pharmacodynamic, pH, complexation and electrostatic interactions, CYP and P-glycoprotein). Interactions involving the azoles are pharmaco-kinetic and result as a consequence of their physicochemical roperties 33-35.Ketoconazole and itraconazole are subject to pH-based and metabolic interactions.
Drugs that will likely interact with these azoles include agents that are cationic or increase gastric pH or are lipophilic CYP3A4 substrates with poor oral availability. All azoles are weak bases and at elevated pH values, weakly basic compounds dissolve more slowly.
Therefore, the absorption of azoles such as the capsule form of itraconazole is influenced by alterations in gastric pH. Many of the azoles are lipophilic and thus they are subjected to interactions involving their biotransformation and disposition. Fluconazole is hydrophilic and is highly soluble in water and therefore, compared to the other azoles, it requires much less biotransformation to be eliminated from the body 36-37. Itraconazole, voriconazole, and posaconazole are highly lipophilic and have limited aqueous solubility. Therefore, these azoles must undergo extensive enzymatic conversion to more polar metabolites in order to be eliminated from the body.
Resistance of Azoles: Since the advances in development of the azole group of antifungal compound for the treatment of fungal infections, it has got widespread use. Consequently, with extensive use resistance to these agents has been reported, particularly fluconazole. 38-41 Azole resistance in Candida has been the most widely observed and studied for fluconazole Resistance to the azoles is attributed to quantitative or qualitative modifications of target enzymes, reduced access of the drug to the target enzyme or by a combination of these mechanisms.
Qualitative modifications in target enzymes result from point mutations in ERG11, the gene responsible for producing 14α-demethylase, which is the principal target of the azoles.
Alternatively, the different chemical structures of the azoles may also contribute to this differential activity. Quantitative modifications in target enzymes also result from mutations in ERG11. Overexpression of the gene results in over-production of the target enzymes, which then necessitates higher intracellular azole concentrations to inhibit all the target enzyme.42-43
CONCLUSION: The incidence of infection with invasive mycoses continues to increase with the increasing immunosuppressed patients. The therapy of fungal infections has undergone an explosive period of development in recent years. The azole group of compounds has provided excellent therapy in the treatment of most clinically important mycoses. Clinicians must recognize the differences in toxicity and potential for drug–drug interactions to use these agents optimally. Further advances in antifungal chemotherapy will be necessary to improve management of invasive mycoses in the future.
- Gallis HA, Drew RH, Pickard WW: Amphotericin B: 30 years of clinical experience. Rev Infect Dis. 1990; 12:308-329.
- Gubbins PO: The systemically acting azoles. In: Wingard J, Anaissie E, eds. Fungal Infections in the Immunocompromised Patient. Boca Raton, Fla: Taylor & Francis Group. 2005; 457-484.
- Denning DW: Echinocandins: a new class of antifungal. J Antimicrob Chemother. 2002; 49:889-891.
- Gubbins P, Anaissie E: Overview of Antifungal Agents. Pharmacy Practice News Special Edition 2006.
- Sanati H, Belanger P, Rutilio F, Ghannoum M: A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei. Antimicrob Agents Chemother. 1997; 2441:2492.
- Ghannoum MA, Rice LB: Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev 1999; 12:501.
- Fainstein V, Bodey GP: Cardiorespiratory toxicity due to miconazole. Ann Intern Med 1980; 93:432.
- Espinel-Ingroff A, Shadomy S, Gebhart RJ: In vitro studies with R 51211 (itraconazole). Antimicrob Agents Chemother 1984; 26:5.
- Georgopapadakou NH, Walsh TJ. Human mycoses: drugs and targets for emerging pathogens. Science 1994; 264:371.
- Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ: In vitro susceptibilities of clinical isolates of Candida species, Cryptococcus neoformans, and Aspergillus species to itraconazole: global survey of 9,359 isolates tested by clinical and laboratory standards institute broth microdilution methods. J Clin Microbiol 2005; 43:3807.
- Gonzalez GM, Fothergill AW, Sutton DA, Rinaldi MG, Loebenberg D: In vitro activities of new and established triazoles against opportunistic filamentous and dimorphic fungi. Med Mycol 2005; 43:281.
- Almyroudis NG, Sutton DA, Fothergill AW, Rinaldi MG, Kusne S: In vitro susceptibilities of 217 clinical isolates of zygomycetes to conventional and new antifungal agents. Antimicrob Agents Chemother 2007; 51:2587.
- Soczo G, Kardos G, McNicholas PM, et al: Correlation of posaconazole minimum fungicidal concentration and time kill test against nine Candida species. J Antimicrob Chemother 2007; 60:1004.
- Espinel-Ingroff A: Germinated and nongerminated conidial suspensions for testing of susceptibilities of Aspergillus spp. To amphotericin B, itraconazole, posaconazole, ravuconazole, and voriconazole. Antimicrob Agents Chemother 2001; 45:605.
- Perfect JR, Cox GM, Dodge RK, Schell WA: In vitro and in vivo efficacies of the azole SCH56592 against Cryptococcus neoformans. Antimicrob Agents Chemother 1996; 40:1910.
- Pfaller MA, Messer SA, Hollis RJ, Jones RN: In vitro activities of posaconazole (SCH 56592) compared with those of itraconazole and fluconazole against 3,685 clinical isolates of Candida spp. and Cryptococcus neoformans. Antimicrob Agents Chemother 2001; 45:2862.
- Piscitelli SC, Goss TF, Wilton JH, D’Andrea DT, Goldstein H, Schentag JJ: Effects of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrob Agents Chemother 1991; 35(9):1765-1771.
- Lange D, Pavao JH, Wu J, Klausner M: Effect of a cola beverage on the bioavailability of itraconazole in the presence of H2 blockers. J Clin Pharmacol 1997; 37(6):535-540.
- Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE: Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab Dispos 2004; 32(10):1121-1131.
- Hyland R, Jones BC, Smith DA: Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos 2003; 31(5):540-547.
- Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R: Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother 2004; 48(9):3543-3551.
- Ghosal A, Hapngama N, Yuan Y, et al: Identification of human UDPglucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil). Drug Metab Dispos 2004; 32(2):267-271.
- Niwa T, Shiraga T, Takagi A: Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull 2005; 28(9):1805-1808.
- Wexler D, Courtney R, Richards W, Banfield C, Lim J, Laughlin M: Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study Eur J Pharm Sci. 2004; 21(5):645-653.
- Uchaipichat V, Winner LK, Mackenzie PI, Elliot DJ, Williams JA, Miners JO: Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data:the effect of fluconazole on zidovudine glucuronidation. Br J ClinPharmacol 2006; 61(4):427-439.
- Miyama T, Takanaga H, Matsuo H, et al: P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier. Antimicrob Agents Chemother 1998; 42(7):1738-1744.
- Sandhu P, Lee W, Xu X, et al: Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab Dispos 2005; 33(5):676-682.
- Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW. Interaction of common azole antifungals with P glycoprotein: Antimicrob Agents Chemother 2002; 46(1):160-165.
- Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N: Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities. J Clin Pharmacol 2006; 46(2): 235-243.
- Lazarus HM, Blumer JL, Yanovich S, Schlamm H, Romero A: Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol 2002; 42(4):395-402.
- Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D: Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 2002; 46(8):2546-2553.
- Lutsar I, Hodges MR, Tomaszewski K, Troke PF, Wood ND: Safety of voriconazole and dose individualization. Clin Infect Dis 2003; 36(8):1087-1088.
- Gubbins PO, Amsden JR: Drug-drug interactions of antifungal agents and implications for patient care. Expert Opin Pharmacother 2005; 6(13):2231-2243.
- Gubbins PO, McConnell SA, Amsden JR: Drug interactions associated with antifungal agents. In: Piscitelli SC, Rodvold KA, eds. Drug Interactions in Infectious Diseases. Totowa, NJ: Humana Press 2005:289-337.
- Venkatakrishnan K, Von Moltke LL, Greenblatt DJ: Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 2000; 38:111-180.
- Ptachainski RJ, Carpenter BJ, Burckart GJ, Venkataramanan R, Rosenthal JT: Effect of erythromycin on cyclosporine levels. N Engl J Med 1985; 313:1416-1417.
- Spellberg BJ, Filler SG, Edwards JE: Current treatment strategies for disseminated candidiasis. Clin Infect Dis 2006; 42:244.
- He X, Tiballi RN, Zarins LT, Bradley SF, Sangeorzan JA, Kauffman CA: Azole resistance in oropharyngeal Candida albicansstrains isolated from patients infected with human immunodeficiency virus. Antimicrob Agents Chemother 1994; 38:2495.
- Thomas-Greber E, Korting HC, Bogner J, Goebel FD: Fluconazole-resistant oral candidosis in a repeatedly treated female AIDS patient. Mycoses 1994; 37:35.
- Perea S, Patterson TF: Antifungal resistance in pathogenic fungi. Clin Infect Dis 2002; 5:1073.
- Spanakis EK, Aperis G, Mylonakis E: New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis 2006; 43:1060.
- Lupetti A, Danesi R, Campa M, Del Tacca M, Kelly S. Molecular basis of resistance to azole antifungals. Trends Mol Med 2002; 8:76.
- White TC, Marr KA, Bowden RA: Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 1998; 11:382.
How to cite this article:
Gavarkar PS, Adnaik RS, and Mohite SK: An Overview of Azole Antifungals. Int J Pharm Sci Res 2013; 4(11): 4083-89. doi: 10.13040/IJPSR. 0975-8232.4(11).4083-89
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Pratibha Shivaji Gavarkar*, Rahul Shivaji Adnaik, and Shrinivas Krishna Mohite
Rajararambapu College of Pharmacy, Kasegaon, Tal. Walwa, Dist. Sangli- 415404, Maharashtra, India
07 June, 2013
20 July, 2013
09 October, 2013
01 November, 2013