ITRACONAZOLE

Chemistry - A synthetic triazole antifungal, itraconazole is structurally related to fluconazole. It hasa molecular weight of 706 and a pKa of 3.7.

Pharmacology - ITRACONAZOLE

Itraconazole is a fungistatic triazole compound. Triazole-derivative agents, like theimidazoles (clotrimazole, ketoconazole, etc.), presumably act by altering the cellular membranes ofsusceptible fungi, thereby increasing membrane permeability and allowing leakage of cellularcontents and impaired uptake of purine and pyrimidine precursors. Itraconazole has efficacy againsta variety of pathogenic fungi, including yeasts and dermatophytes. In vivo studies using laboratorymodels have shown that itraconazole has fungistatic activity against many strains of Candida,
Aspergillus, Cryptococcus, Histoplasma, Blastomyces and Trypanosoma cruzi.
Uses, Indications - Itraconazole may have use in veterinary medicine in the treatment of systemicmycoses, including aspergillosis, cryptococcal meningitis, blastomycosis, and histoplasmosis. Itmay also be useful for superficial candidiasis or dermatophytosis. Itraconazole does not haveappreciable effects (unlike ketoconazole) on hormone synthesis and may have fewer side effectsthan ketoconazole in small animals.
In horses, itraconazole may be useful in the treatment of sporotrichosis and Coccidioides immitisosteomyelitis.

Pharmacokinetics - ITRACONAZOLE

Itraconazole absorption is highly dependent on gastric pH and presence offood. When given on an empty stomach bioavailability may only be 50% or less, with food it mayapproach 100%.
Itraconazole has very high protein binding and is widely distributed throughout the body, particularly to tissues high in lipids (drug is highly lipophilic). Skin, female reproductive tract and pus all have concentrations greater than found in the serum. Only minimal concentration are found in the CSF, aqueous humor and saliva, however.
Itraconazole is metabolized by the liver to many different metabolites, including to hydroxyitraconazole which is active. In humans, itraconazole's serum half life ranges from 21-64 hours.
Elimination may be a saturable process.

Contraindications, Precautions, Reproductive Safety

Itraconazole should be used in patientshypersensitive to it or other azole antifungal agents, in patients with hepatic impairment, orachlorhydria (or hypochlorhydria) only when the potential benefits outweigh the risks.
In laboratory animals, itraconazole has caused dose-related maternotoxicity, fetotoxicity andteratogenicity at high dosages (5-20 times labeled). As safety has not been established, use onlywhen the benefits outweigh the potential risks. Itraconazole does enter maternal milk, significance isunknown.

Adverse Effects, Warnings

In dogs, hepatic toxicity appears to be the most significant adverseeffect. Approximately 10% of dogs recieving 10 mg/kg/day and 5% of dogs recieving 5 mg/kg/daydevelop hepatic toxicosis serious enough to discontinue (at least temporarily) treatment. Hepaticinjury is determined by an increased ALT activity. Anorexia is often the symptomatic marker fortoxicity and usually occurs in the second moth of treatment. Some dogs given itraconazole at thehigher dosage rate (10 mg/kg/day) may develop ulcerative skin lesions/vasculitis and limb edemathat may require dosage reduction.
In cats, adverse effects appear to be dose related. GI effects (anorexia, weight loss, vomiting), hepatotoxicity (increased ALT, jaundice) and depression and have been noted. Should adverseeffects occur and ALT is elevated, the drug should be discontinued. Once ALT levels return tonormal and other adverse effects have diminished, and if necessary, the drug may be restarted at alower dosage or longer dosing interval with intense monitoring.
Overdosage, Acute Toxicity - There is very limited information on the acute toxicity of itraconazole. Giving oral antacids may help reduce absorption. If a large overdose occurs, consider gut emptying and give supportive therapy as required. Itraconazole is not removed by dialysis.
In chronic toxicity studies, dogs receiving 40 mg/kg PO daily for 3 months demonstrated no overt toxicity.

Drug Interactions

Itraconazole requires an acidic environment for maximal absorption, thereforeantacids, Histamine2-blockers (cimetidine, ranitidine, etc) or didanosine will cause markedreduction in absorption of itraconazole. Didanosine must not be taken concurrently withitraconazole, the others (noted above), if required, should be given two hours after itraconazole dose.
Itraconazole may cause increased prothrombin times in patients receiving warfarin or othercoumarin anticoagulants. Rifampin may enhance the rate of metabolism of itraconazole; itraconazole dosage adjustment may be required.
Itraconazole may decrease the metabolism of phenytoin or cyclosporine. Veterinary significance is unclear.
Itraconazole may increase the risks of cardiovascular effects occurring if used concomitantly with either terfenadine or astemizole. If itraconazole is required, it is best to switch to another antihistamine.
Itraconazole may increase serum digoxin concentrations; monitor serum digoxin levels.
Itraconazole may increase the serum levels of oral antidiabetic agents (e.g., chlorpropamide, glipizide, etc.) which may result in hypoglycemia.
Elevated concentrations of cisapride with resultant ventricular arrhythmias may result if coadministered with ketoconazole, itraconazole, IV miconazole or troleandomycin. At present, the manufacturer states that cisapride should not be used with these drugs.
Laboratory Considerations - Itraconazole may cause hypokalemia or increases in liver function tests in a small percentage of patients.