Itraconazole
Itraconazole is a synthetic, highly lipophilic oral triazole antifungal agent used extensively in veterinary medicine for the treatment of systemic mycoses (such as aspergillosis, cryptococcosis, blastomycosis, and histoplasmosis) as well as superficial dermatophytosis and Malassezia infections. **Clinical Pearls & Pharmacological Profile:** * **Superior Efficacy:** It is generally considered more efficacious and has fewer endocrine side effects compared to older imidazoles like ketoconazole, as it does not appreciably suppress mammalian hormone synthesis. * **Tissue Distribution:** Because it is highly lipophilic and keratinophilic, it concentrates heavily in the skin, sebum, and pus, making it exceptionally effective for dermatological fungal infections. * **Formulation Matters:** The absorption of itraconazole is highly formulation-dependent. Commercially available capsules require an acidic gastric environment and food for optimal absorption. The commercial oral solution contains cyclodextrin to enhance solubility and is best absorbed on an empty stomach. * **Compounding Warning:** Compounding from bulk powder is strongly discouraged as it often results in subtherapeutic or undetectable blood levels, which can be fatal in systemic fungal infections.
Mecanismo: Itraconazole is a fungistatic triazole. **Mechanism of Action:** * **Enzyme Inhibition:** Itraconazole selectively inhibits the fungal cytochrome P450-dependent enzyme **lanosterol 14ฮฑ-demethylase**. * **Pathway Disruption:** This inhibition blocks the conversion of lanosterol to **ergosterol** (the primary sterol in fungal cell membranes) โ leads to the accumulation of toxic 14ฮฑ-methylsterols. * **Membrane Permeability:** The lack of ergosterol alters the cellular membrane structure โ increases membrane permeability โ allows leakage of cellular contents and impairs the uptake of purine and pyrimidine precursors. * **Immunomodulation:** Itraconazole also exhibits mild immune-suppressing activity, likely via the suppression of T-lymphocyte proliferation.
Dosificaciรณn por especie
- Histoplasmosis ยท 10 mg/kg daily PO ยท PO ยท q24h ยท At least 2-4 months ยท Given with food. Can also be divided twice daily.
- Cryptococcosis ยท 50-100 mg per cat per day PO ยท PO ยท q24h ยท Many months (mean 8.5 months) ยท If response inadequate, may add flucytosine.
- Blastomycosis ยท 10 mg/kg PO once a day or divided twice a day ยท PO ยท q24h or q12h ยท 2-3 months or until active disease is not apparent ยท Cats usually require longer treatment than dogs.
- Coccidiomycosis ยท 5-10 mg/kg PO once daily ยท PO ยท q24h ยท 6-12 months
- Sporotrichosis ยท 5-10 mg/kg once daily ยท PO ยท q24h ยท 30 days beyond complete resolution of detectable lesions
- Cryptococcosis (mild to moderate, no CNS involvement) ยท Cats <= 3.5 kg: 50 mg PO once daily or 100 mg PO every other day; Medium/large cats: 100 mg PO once daily ยท PO ยท q24h or q48h ยท 3-12 months ยท Give with food. Monitor ALT. Continue until completely normal, then check antigen titer.
- Coccidioidomycosis ยท 25-50 mg (total dose) per cat q12-24h ยท PO ยท q12-24h
- Generalized dermatophytosis (Microsporum canis) ยท 5 mg/kg PO once daily preferably between meals for 7 days on, 7 days off; repeat 3 times ยท PO ยท q24h (pulse) ยท 5 weeks (treated weeks 1, 3, 5)
- Generalized dermatophytosis (Alternative) ยท 5 mg/kg PO twice daily or 10 mg/kg ยท PO ยท q12h or q24h ยท Generally 3-5 weeks ยท Give with food. Give until culture is negative 2 times at two week intervals.
Vรญas de administraciรณn
Contraindicaciones
- Hypersensitivity to itraconazole or other azole antifungals
- Hepatic impairment (relative contraindication)
- Achlorhydria or hypochlorhydria (relative contraindication)
- Reduced cardiac function (relative, due to potential negative inotropic effects)
- Pregnancy
- Liver disease (avoid use if present)
Efectos adversos
- Anorexia (most common in dogs)
- Hepatotoxicity (increased ALT, jaundice)
- Ulcerative skin lesions/vasculitis (dogs at high doses)
- Limb edema (dogs at high doses)
- Erythema multiforme (rare)
- Toxic epidermal necrolysis (rare)
- Vomiting
- Weight loss
- Depression (especially in cats and African grey parrots)
- Diarrhoea
- Anorexia
- Salivation
- Depression and apathy
- Abdominal pain
- Hepatic toxicosis
- Ulcerative dermatitis
Interacciones farmacolรณgicas
- Amphotericin B ยท May be antagonistic against Aspergillus or Candida; clinical importance unclear.
- Antacids ยท May reduce oral absorption of itraconazole; administer itraconazole at least 1 hour before or 2 hours after antacids. ยท major
- Benzodiazepines (alprazolam, diazepam, midazolam, triazolam) ยท Itraconazole may increase benzodiazepine levels.
- Buspirone ยท Plasma concentrations may be elevated.
- Busulfan ยท Itraconazole may increase levels.
- Calcium-channel blockers (amlodipine, verapamil) ยท Itraconazole may increase levels.
- Cisapride ยท Increased cisapride levels and possibility for toxicity; concurrent use contraindicated in humans. ยท major
- Clomipramine ยท May decrease metabolism and increase clomipramine levels.
- Corticosteroids ยท May inhibit the metabolism of corticosteroids; potential for increased adverse effects.
- Cyclophosphamide ยท May inhibit metabolism of cyclophosphamide and its metabolites; potential for increased toxicity.
- Cyclosporine ยท Increased cyclosporine levels.
- Digoxin ยท May increase digoxin levels; concurrent use considered contraindicated in humans. ยท major
Monitorizaciรณn
- Clinical Efficacy
- Liver function tests (monthly ALT recommended with long-term therapy)
- Appetite (anorexia is often the first sign of toxicity)
- Physical assessment for ulcerative skin lesions in dogs
- Liver enzymes (ALT, AST, ALP, Bilirubin) prior to and during prolonged treatment
- Clinical signs of hepatotoxicity (anorexia, vomiting, jaundice)
- Resolution of clinical signs and negative fungal cultures
Sobredosis
There is very limited information on acute toxicity. * **Decontamination:** Giving oral antacids may help reduce absorption. If a large overdose occurs, consider gut emptying and provide supportive therapy. * **Clearance:** Itraconazole is **not** removed by dialysis. * **Chronic Toxicity:** In studies, dogs receiving 40 mg/kg PO daily for 3 months demonstrated no overt toxicity.
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