Antifungal azoles itraconazole

Azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole)... 

The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Lovastatin is metabolized by the CYP isoform 3A4. Certain drugs, that share this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (greater than 1 quart daily)... 

Itraconazole [it ra KON a zole] is a recent addition to the azole family of antifungal agents. Like fluconazole it is a synthetic triazole, and it also lacks the endocrinologic side effects of ketoconazole. Its mode of action is the same as that of the other azoles. Itraconazole is now the drug of choice for the treatment of blastomycosis. Unlike ketoconazole, it is effective in AIDS-associated histoplasmosis. However, current studies show that it may also be effective in the treatment of aspergillosis, candidemia, coccidioidomycosis, and cryptococcosis. Thus it has a broad antifungal spectrum. 

In an in vitro study of midazolam biotransformation using human liver microsomes, midazolam metabolism was competitively inhibited by the antifungal azoles keto-conazole, itraconazole, and fluconazole, and the antidepressant fluoxetine and its metabolite norfluoxetine (55). The degree of inhibition was consistent with the inhibition reported in pharmacokinetic studies, and suggests that in vitro assay is useful for predicting significant interactions. 

CILOSTAZOL ANTIFUNGALS Fluconazole, itraconazole, ketoconazole and miconazole t cilostazol levels These azoles inhibit CYP3A4-mediated metabolism of cilostazol Avoid co-administration... 

AZOLES - ITRACONAZOLE ANTI HYPERTENSIVES AND HEART FAILURE DRUGS -VASODILATOR ANTIHYPERTENSIVES - bosentan Azole antifungals t bosentan levels Azoles inhibit CYP3A4 and CYP2C9 Monitor LFTs closely... 

ANTACIDS ANTIFUNGALS-AZOLES 1 plasma concentration of itraconazole and ketoconazole, with risk of therapeutic failure Itraconazole absorption in capsule form requires an acidic gastric environment, and thus absorption would be 1 Separate administration of agents that 1 gastric acidity by 1-2 hours. However, absorption of itraconazole liquid solution does not require an acidic environment it could be used instead and does not need to be given with food. Fluconazole absorption is not pH-dependent, so this is a suitable alternative... 

For details of interactions with individual antifungal azoles, see individual monographs (fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole). 

Fig. 4.3 Structures of polyene (amphotericin B) and azole (itraconazole, fluconazole, miconazole and ketoconazole) antifungal agents.

Itraconazole can markedly raise the serum levels of felodipine, which Increases Its adverse effects, In particular ankle and leg oedema. A few case reports suggest that isradipine and nifedipine can interact similarly with itraconazole, and that fluconazole can also interact with nifedipine. Ketoconazole can markedly raise the plasma levels of lercanidipine and nisoldipine. Caution is warranted with all calcium-channel blockers when azole antifungals, particularly itraconazole and ketoconazole, are used. 

Taupitz et al. [24] have reported a case study of the potent antifungal drug, itraconazole, which has a poorly soluble weak base which precipitates in the small intestine, its binary and ternary complexes and marketed formulation (Sporanox ). All these formulations were subjected to solubility and dissolution studies in media mentioned in Table 12.5 at 37°C. All the formulation approaches enhanced the solubility of drug in all media but more pronounced results were observed for ternary complexes (itracon-azole-CD-soluplus ), which are tabulated in Table 12.5. 

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

All azole antifungals carry the potential for rash, photosensitivity, and hepatotoxicity. In general, hepatotoxicity is mild and reversible, presenting as asymptomatic increases in liver transaminases. However, fulminant hepatic failure has been reported with itraconazole. Therefore, serial monitoring of liver function... 

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

HIV-infected patients should receive induction therapy with amphotericin B and chronic suppressive therapy with an oral azole antifungal. Itraconazole is the drug of choice for non-life-threatening histoplasmosis. 

Drugs that may be affected by proton pump inhibitors include azole antifungal agents (eg, itraconazole, ketoconazole), benzodiazepines, cilostazol, clarithromycin, digoxin, phenytoin, salicylates, sulfonylureas, and warfarin. Drugs that may affect proton pump inhibitors include sucralfate and clarithromycin. 

Drugs that may increase sirolimus blood concentrations include the following Nicardipine, verapamil, clotrimazole, fluconazole, itraconazole, clarithromycin, erythromycin, troleandomycin, cisapride, metoclopramide, bromocriptine, cimetidine, danazol, HIV-protease inhibitors, cyclosporine, diltiazem, azole antifungals. 

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. 

Therapy of fungal arthritis consists of amphotericin B in combination with surgical debridement. Azole antifungal agents including itraconazole, fluconazole, voriconazole, and posaconazole, are promising in the therapy of fungal arthritis. 

Azole antifungal drugs are synthetic compounds with broad-spectrum fungistatic activity. Azoles can be divided into two groups the older imidazole agents, in which the hve-member azole nucleus contains two nitrogens, and the newer triazole compounds, fluconazole and itraconazole, in which the azole nucleus contains three nitrogens. 

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