Azole antifungals topical

Raab [123] presented a discussion on the topical clinical pharmacology of miconazole and two other azole antifungal agents. 

B. Azole antifungals include systemic agents such as keto-conazole, fluconazole, itraconazole, and voriconazole. Topical agents used for the treatment of vaginal candidiasis and thrush include miconazole and clotrimazole. The pharmacologic properties of the systemic azoles differ considerably. Ketoconazole, the first oral azole developed, has poor bioavailability and requires an acidic environment for enhanced absorption. Thus, initial studies required ketoconazole to be administered with a cola to increase bioavailability. Fluconazole, unlike itraconazole and ketoconazole, is hydrophillic and has increased penetration across the blood-brain barrier. Fluconazole is also the only azole that is renally eliminated. 

Nystatin was discovered in 1950 and exhibits the same mode of action as amphotericin B but tends to be of lower solubility, which has restricted its use to the treatment of topical infections. While nystatin was effective for the treatment of conditions such as oral and vaginal candidosis its use has been overtaken by the introduction of azole antifungal drugs. 

Recognition of the role of the GI tract in invasive Candida infections has led to efforts to decrease infections by prophylactic administration of topical or systemically absorbed antifungal agents in immunocompromised patients. The use of systemically absorbable agents such as azole antifungal agents appears to decrease the risk of invasive fungal infections. ... 

An number of other azole antifungals are only used topically in the form of skin creams or intravaginal preparations, and have not been associated with drug interactions, presumably sinee their systemic absorption is so low, see Azoles Topical + Miscellaneous , p.222. 

The azole antifungals raise the levels of astemizole and terfena-dine, which can result in life-threatening arrhythmias. Arrhythmias have been reported for astemizole with ketoconazole, and terfenadine with itraconazole, ketoconazole, and even topical ox-iconazole. Consequently all azoles are contraindicated with astemizole and terfenadine. 

Mechanism of Action. Like the systemic azoles, clotrimazole and other topical antifungal azoles work by inhibiting the synthesis of key components of the fungal cell membrane that is, these drugs impair production of membrane sterols, triglycerides, and phospholipids.9 Loss of these components results in the membrane s inability to maintain intracellular homeostasis, leading to death of the fungus. 

Topical therapy with the azoles and allylamines is effective for tinea pedis. Macerated toe web disease may require the addition of antibacterial therapy. Econazole nitrate, which has a limited antibacterial spectram, can be useful in this situation. Systemic therapy with griseofulvin, terbinafine, or itraconazole (Sporanox, others) is used for more extensive tinea pedis. It should be recognized that long-term topical therapy may be necessary in some patients after courses of systemic antifungal therapy. 

The catalytic asymmetric addition of thioacetic acid to nitroalkene 450 has been applied to the first enantioselec-tive synthesis of (/f)-sulconazole 453 in four steps (Scheme 46.52). Sulconazole is a class of azole antifiingals known to act by inhibition of the fungal cell CYP51 lano-sterol demethylase. Sulconazole nitrate solution, under the trade name of Exelderm (Ranbaxy USA, Princeton, NJ), is a broad-spectrum antifungal agent intended for topical apphcation to treat skin infection such as athlete s foot and sun fungus. 

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