Synthetic triazoles

Synthetic triazoles

The synthetic triazoles include:

§    fluconazole

§    itraconazole

§    voriconazole.

Fluconazole belongs to a class of synthetic, broad-spectrumtriazoles and is also referred to as a bistriazole antimycotic drug.

Itraconazole and voriconazole also belong to the synthetic tri-azole class of drugs. They inhibit the synthesis of ergosterol, a vi-tal component of fungal cell membranes.

Pharmacokinetics

After oral administration, fluconazole is about 90% absorbed. It’s distributed into all body fluids, and more than 80% of the drug is excreted unchanged in urine.

Oral bioavailability is greatest when itraconazole is taken with food; voriconazole is more effective if taken 1 hour before or after a meal.

Bound and determined

Itraconazole and voriconazole are bound to plasma proteins and extensively metabolized in the liver into a large number of metabolites. They’re minimally excreted in stool.

Pharmacodynamics

Fluconazole inhibits fungal cytochrome P-450, an enzyme respon-sible for fungal sterol synthesis, causing fungal cell walls to weak-en.

Itraconazole and voriconazole interfere with fungal cell-wall synthesis by inhibiting the formation of ergosterol and increasing cell-wall permeability, making the fungus susceptible to osmotic instability.

Pharmacotherapeutics

Fluconazole is used to treat mouth, throat, and esophageal can-didiasis and serious systemic candidal infections, including UTIs, peritonitis, and pneumonia. It’s also used to treat cryptococcal meningitis.

Osis, smosis

Itraconazole is used to treat blastomycosis, nonmeningeal histo-plasmosis, candidiasis, aspergillosis, and fungal nail disease. Voriconazole is used to treat invasive aspergillosis and serious fungal infections caused by Scedosporium apiospermum and Fusarium species.

Drug interactions

Fluconazole may have interactions with other drugs:

§    Using fluconazole with warfarin may increase the risk of bleed-ing.

§    It may increase levels of phenytoin and cyclosporine.

§    It may increase the plasma levels of oral antidiabetic drugs, such as glyburide, tolbutamide, and glipizide, increasing the risk of hypoglycemia.

§    Rifampin and cimetidine enhance the metabolism of flucona-zole, reducing its plasma level.

§    Fluconazole may increase the activity of zidovudine. (See Ad-verse reactions to synthetic triazoles.)

Itraconazole and voriconazole may have these interactions:

§    Both may increase the risk of bleeding when combined with oral anticoagulants.

§    Antacids, H₂-receptor antagonists, phenytoin, and rifampin low-er plasma itraconazole levels.

§    Voriconazole may inhibit the metabolism of phenytoin, benzodi-azepines, calcium channel blockers, sulfonylureas, and tacrolimus.

§    Voriconazole is contraindicated with sirolimus and ergot alka-loids because voriconazole may increase plasma levels of sirolimus and ergots.

§    Voriconazole is contraindicated with quinidine and pimozide be-cause of the risk of prolonged QT interval and, rarely, torsades de pointes.