Azole antifungals systemic

P450 system Drugs that may be affected by proton pump inhibitors include benzodiazepines, clarithromycin, cyclosporine, disulfiram, digoxin, azole antifungal agents, hydantoins, cilostazol, salicylates, sulfonylureas, and warfarin. 

P-450 system Monitoring of circulating cyclosporine levels and appropriate dosage adjustment are essential when drugs that affect hepatic microsomal enzymes, particularly the cytochrome P-450 3A enzymes, are used concomitantly (eg, HIV protease inhibitors, anticonvulsants, azole antifungals). 

Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, and zafirlukast) should be cautiously coadministered with TIKOSYN, because they can potentially increase dofetilide levels... 

Cyclosporin is metabolised by the hepatic cytochrome P-450 enzyme system, and enzyme induction by phenobarbital, phenytoin, carbamazepine, or rifampicin will drastically increase the clearance of cyclosporin. Concurrent administration of these drugs has caused rejection of transplanted organs. Conversely, the use of enzyme inhibitors, such as erythromycin or the azole antifungal agents, e.g. ketoconazole, will increase the blood concentrations of cyclosporin leading to an increased risk of toxic side effects. 

Clinical Use. Voriconazole (Vfend) is similar chemically to other azole antifungals such as fluconazole. Voriconazole has a broad antifungal spectrum, and is administered systemically to treat aspergillosis and other serious fungal infections caused by Scedospo-rium apiospermum and Fusarium,31... 

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. 

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. ... 

Kauffman CA, Carver PL. Use of azoles for systemic antifungal therapy. Adv Pharmacol 1997 39 143-189. 

Ketoconazole (KC) as the first systemlcally-active azole antifungal has been the subject of a number of reviews including the general management of fungal disease,and its efficacy in superficial and systemic infections 0 it was the subject of a number of papers at a recent symposium, The use of KC in the treatment of coccidioidomycosis has been recently reviewed in detail, 2 gjid parallel reviews of the indications for coccidioidomycosis treatment in general, 5 and the use of AMB and miconazole (MC) 5 in particular have been presented. 

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 antifungal drug ketoconazole was found to inhibit Fe(III)-ascorbate dependent lipid peroxidation using either rat hver microsomes or ox-brain phospholipid hposomes as the substrates (Wiseman et al. 1991). It also inhibited microsomal peroxidation induced by the Fe(III)-ADP/NADPH system. The related azoles, miconazole and clotrimazole, were much weaker inhibitors than ketoconazole. Ketoconazole was approximately equipotent... 

Systemic adverse effects associated with vaginal azoles are less frequent than with oral products. Local discomfort such as burning may occur with the first application. Fifteen percent of patients experience gastrointestinal side effects with orally administered antifungal agents.13 Oral ketoconazole is associated with hepatic toxicity at a rate of 1 in 15,000.14... 

The azole derivatives for systemic administration include the imidazoles ketoconazole and miconazole and the triazoles fluconazole, itraconazole, posaconazole and voriconazole. They are broad spectrum antifungals and have activity against several dermatophytes, Candida, Cryptococcus and other fungi that cause deep-seated infections. 

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. 

Azole derivatives currently available for oral treatment of systemic mycosis include fluconazole (Diflucan), itraconazole (Sporonax), and ketoconazole (Nizoral). As discussed in Chapter 48 Antifungal Agents, imidazole derivatives act by affecting the permeability of the cell membrane of... 

In fact, HYPOl s fault was not surprising if one relates its framework (HYPOl was composed by one ad hoc defined aromatic-nitrogen-with-lone-pair vectorial feature to simulate the coordination interaction of azole inhibitors with the iron atom of the enzyme protoporphyrin system an three aromatic rings [34]) to the chemical structure and antifungal activity of the new compounds. The activity values of these molecules, in fact, were revealed to be strongly dependent on the presence of a hydrophobic substituent (possibly aliphatic) on... 

Ketoconazole [kee toe KON a zole], a substituted imidazole, is one of a family of azoles useful in treating systemic mycoses. In addition to its antifungal activity, ketoconazole also inhibits gonadal and adrenal steroid synthesis in humans by blocking C17-20 lyase, Up-hydroxylase, and cholesterol side-chain cleavage thus, it suppresses testosterone and cortisol synthesis. 

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