itraconazole

Itraconazole works by inhibiting the fungal enzyme lanosterol 14-α-demethylase (CYP51), preventing conversion of lanosterol to ergosterol, an essential component of the fungal cell membrane. This leads to accumulation of toxic sterol intermediates and membrane dysfunction, ultimately inhibiting fungal growth (fungistatic at typical doses).

Clinical uses: Itraconazole is a first-line or alternative treatment for histoplasmosis, blastomycosis, sporotrichosis, and paracoccidioidomycosis. It's also used for chronic pulmonary aspergillosis and as prophylaxis in immunocompromised patients (e.g., prolonged neutropenia, hematologic malignancy). Unlike fluconazole, itraconazole has activity against Aspergillus but not against Candida krusei or many Candida glabrata strains reliably, and it lacks CNS penetration, making it a poor choice for fungal meningitis.

Pharmacokinetics: Requires an acidic environment for absorption (capsule form should be taken with food and acidic beverages; the oral solution is absorbed better on an empty stomach). Itraconazole is highly protein-bound and has poor CSF penetration, limiting use in CNS infections.

Adverse effects: Negative inotropic effect (contraindicated in patients with heart failure), hepatotoxicity, GI upset, and rash. It also inhibits CYP3A4, leading to significant drug interactions (e.g., with statins, calcium channel blockers, warfarin, and certain benzodiazepines), similar to other azoles.

Monitoring: Liver function tests should be monitored during therapy due to hepatotoxicity risk. Drug levels may be checked in some cases to ensure therapeutic dosing given variable absorption.

Board relevance: Commonly tested in contrast to other azoles—remember itraconazole covers Aspergillus (unlike fluconazole), does not cross into CSF (unlike fluconazole), and is contraindicated in heart failure due to negative inotropy (unique among azoles).