itraconazole

itraconazole
IUPAC name	(2R,4S)-rel-1-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one
Width	200
CAS number	84625-61-6
ATC prefix	J02
ATC suffix	AC02
PubChem	55283
DrugBank	DB01167

itraconazole is a synthetic triazole antifungal agent developed by Janssen Pharmaceutica. It is a broad-spectrum medication used to treat a variety of fungal infections by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes. The drug is available in oral capsule, oral solution, and intravenous formulations, with its use guided by specific indications and therapeutic drug monitoring.

Medical uses

Itraconazole is indicated for the treatment of blastomycosis, histoplasmosis, and aspergillosis in patients who are intolerant of or refractory to amphotericin B therapy. It is also used for onychomycosis caused by dermatophytes such as Trichophyton species, as well as for candidiasis of the oropharynx and esophagus. The Food and Drug Administration has approved its use for empiric therapy in febrile neutropenia patients suspected of having a fungal infection. Clinical guidelines from the Infectious Diseases Society of America recommend itraconazole for certain forms of paracoccidioidomycosis and chromoblastomycosis.

Mechanism of action

The primary mechanism involves the inhibition of the fungal cytochrome P450 enzyme lanosterol 14α-demethylase. This enzyme is essential for the conversion of lanosterol to ergosterol within the fungal cell membrane. By binding to the heme iron of this P450 enzyme, itraconazole disrupts ergosterol biosynthesis, leading to the accumulation of toxic sterol intermediates. This results in increased membrane permeability and inhibition of fungal cell growth and replication. Its action is fungistatic against many yeasts but can be fungicidal at higher concentrations against some molds.

Pharmacokinetics

Following oral administration, absorption is enhanced by the presence of food and an acidic gastric environment, with the oral solution achieving higher bioavailability than capsules. Itraconazole is extensively metabolized in the liver by the CYP3A4 isoenzyme into a large number of metabolites, including the active hydroxyitraconazole. The drug is highly protein bound, exceeding 99%, primarily to albumin, and exhibits a large volume of distribution, penetrating well into tissues like skin, nails, and lungs. Elimination is primarily hepatic, with a long terminal half-life of approximately 24 to 42 hours.

Adverse effects

Common adverse effects include nausea, abdominal pain, headache, and rash. A significant concern is dose-dependent hepatotoxicity, which can manifest as asymptomatic elevations in liver enzymes or, rarely, clinical hepatitis. The black box warning issued by the FDA highlights the risk of congestive heart failure due to negative inotropic effects. Other serious reactions can include peripheral neuropathy, hypokalemia, and Stevens-Johnson syndrome. Patients are typically monitored with assessments of liver function tests and serum potassium levels.

Drug interactions

Itraconazole is a potent inhibitor of the CYP3A4 system and P-glycoprotein, leading to numerous clinically significant interactions. Coadministration with drugs metabolized by CYP3A4, such as simvastatin, midazolam, and quinidine, can drastically increase their plasma concentrations and risk of toxicity. Concurrent use with rifampin, phenytoin, or carbamazepine induces metabolism and reduces itraconazole levels. It is contraindicated with cisapride, dofetilide, and levacetylmethadol due to the high risk of life-threatening cardiac arrhythmias like torsades de pointes.

Chemistry

Itraconazole is a lipophilic, weakly basic triazole derivative with a molecular formula of C₃₅H₃₈Cl₂N₈O₄. Its chemical structure consists of a 1,2,4-triazole ring, a dioxolane ring, and a piperazine moiety, contributing to its high affinity for fungal cytochrome P450 enzymes. The compound exists as a mixture of four stereoisomers due to two chiral centers, with the (2R,4S) configuration being the most prevalent active form. It is practically insoluble in water but soluble in organic solvents like dimethylformamide.

Category:Antifungal drugs Category:Triazoles Category:Janssen Pharmaceutica drugs