br Mechanism of action In general the main

Mechanism of action In general, the main targets for antifungal drug development are cell wall polymer (glucans, chitin, mannoproteins), cell membrane (especially ergosterol) biosynthesis, DNA and protein synthesis (topoisomerases, nucleases, elongation factors and myristoylation), and signal transduction pathways (protein kinases and protein phosphatases). The 3 major groups of antifungal agents in clinical use, that is, polyenes, azole derivatives, and allylamines, all owe their antifungal activities to the inhibition of synthesis or direct interaction with ergosterol (the predominant component of the fungal cell membrane). Amphotericin B and nystatin are polyene macrolides that act by binding to ergosterol. This binding alters the membrane permeability, causing leakage of sodium, potassium, and hydrogen ions, which eventually leads to cell death. Polyenes have a broad antifungal spectrum, including a variety of yeasts (eg, Candida spp) and molds (eg, Aspergillus spp). Azoles inhibit the enzyme cytochrome P450-dependent 14-α-sterol demethylase, which is required for the conversion of lanosterol to ergosterol. Exposed fungi become depleted of ergosterol and accumulate 14-α-methylated sterols. This action causes disruption of membrane structure and function, thereby inhibiting fungal growth. Azoles are classified as imidazoles (including clotrimazole, miconazole, enilconazole, and ketoconazole) or triazoles (including itraconazole, fluconazole, and voriconazole) based on possessing 2 or 3 nitrogen atoms in the 5-membered azole ring, respectively. Depending on the particular compound, azole antifungal agents have fungistatic and broad-spectrum activity against most yeasts and filamentous fungi. With the exception of voriconazole, azoles are known to be fungistatic at the doses used in ephrin receptor and need several days to reach steady-state concentrations. Finally, allylamines (eg, terbinafine) act by a reversible, noncompetitive inhibition of the squalene epoxidase, a key enzyme in the cyclization of squalene to lanosterol, resulting in an ergosterol depletion and squalene accumulation. The antifungal spectrum of terbinafine includes yeast (fungistatic) as well as dermatophytes and molds (fungicidal).
Toxicity The clinical use of amphotericin B has been associated with a dose-dependent nephrotoxicity in mammals. Because amphotericin B binds to mammalian sterols, including cholesterol, renal toxicity is related to binding of the drug to the sterol rich cell membranes in kidney tubules. As a result, amphotericin B affects the ionic permeability of the renal brush border cells, releasing mediators that cause an abrupt decrease in renal blood flow. However, no evidence of nephrotoxicity has been observed in birds, which might be associated with the shorter elimination half-life (T1/2el) in birds compared with mammals after intravenous (IV) administration. Nevertheless, clinicians are advised to monitor the renal function of their avian patients. The relative toxicity of azoles depends on the specificity for binding to the fungal cytochrome P450 enzyme, instead of the avian/mammalian cytochrome P450 enzymes. The most common adverse side effects associated with azole administration in birds are gastrointestinal (GI) signs, such as anorexia and vomiting, and alterations in liver function. In general itraconazole, is well-tolerated; however, caution should be used when considering the use of this drug in African or timneh gray parrots, because they are more sensitive to itraconazole present in the form of distinct anorexia and depression. Remarkably, PK studies explaining this higher sensitivity in African or timneh gray parrots are still lacking (Table 1). The apparent sensitivity to azoles experienced by different bird species may be explained in part by the drug’s PK and metabolism. In humans, cytochrome P450 isoenzyme CYP2C19 genotypic polymorphism has been linked to differential sensitivity to voriconazole toxicity. Although undocumented in avian species, similar polymorphisms could be responsible for the wide variability in avian voriconazole PK properties. After a single oral administration of voriconazole, a 4 to 5 times longer T1/2el was observed in pigeons (Columba livia domestica) and African penguins (Spheniscus demersus), compared with Hispaniolan Amazon parrots (Amazona ventralis), timneh gray parrots (Psittacus erithacus timneh), mallard ducks (Anas platyrhynchos), and red-tailed hawks (Buteo jamaicensis; Table 2). This prolonged T1/2el in pigeons and penguins presents a potential for drug accumulation with extended dosing and toxicity. After oral administration of voriconazole (10 and 20 mg/kg body weight [BW] twice a day) to pigeons, Beernaert and colleagues observed hepatic changes, such as hepatomegaly and miliary hepatic necrosis and, on histology, vacuolization up to apoptosis of hepatocytes and heterophilic and lymphocytic infiltration. Similarly, Hyatt and colleagues demonstrated signs indicative of toxicity in multiple penguin species after administering voriconazole (6.1–22.2 mg/kg BW once or twice a day), which ranged in severity and included anorexia, lethargy, weakness, change in mentation, ataxia, paresis, apparent vision changes, seizurelike activity, and generalized seizures. The toxicity and efficacy of all azole derivatives can furthermore be influenced by drug–drug interactions that are based on the mechanism of action of these drugs being potent cytochrome P450 inhibitors. Consequently, caution should be taken when azoles are coadministered with other drugs, such as midazolam, enrofloxacin, and clindamycin.