作用機制: **Antifungal Action:**
Ketoconazole inhibits **lanosterol 14α-demethylase**, a fungal **cytochrome P450** enzyme → blocks the conversion of lanosterol to **ergosterol** → depletion of ergosterol in the fungal cell membrane → accumulation of toxic intermediate sterols → increased cellular membrane permeability and cell death. It is primarily fungistatic but can be fungicidal at high concentrations or prolonged exposures.
**Endocrine/Metabolic Action:**
It reversibly inhibits mammalian **cytochrome P450** enzymes (specifically **CYP11A1** and **CYP17**) → blocks the synthesis of adrenal and gonadal steroids → decreases **cortisol** and **testosterone** production.
**Immunomodulatory Action:**
Inhibits **5-lipooxygenase**, providing mild anti-inflammatory effects, and suppresses T-lymphocyte proliferation.
各物種劑量
Cats
Coccidioidomycosis · 10-30 mg/kg PO divided twice a day · PO · q12h · 6-12 months · Use in cats is controversial
Coccidioidomycosis · 50 mg per cat PO once daily; or 25-75 mg per cat q12-48h · PO · q24h or q12-48h · 9-12 months on average
Blastomycosis · 10 mg/kg q12h PO · PO · q12h · At least 60 days · Used with amphotericin B
Cryptococcosis · 10 mg/kg twice daily · PO · q12h · Can produce anorexia and debility at this dosage
Aspergillosis · 10 mg/kg PO q12h · PO · q12h
Dermatophytosis · 10 mg/kg PO once daily with an acidic meal · PO · q24h · Prolonged; 2 weeks beyond clinical cure and negative cultures · Reserved for when griseofulvin ineffective or not tolerated
Sporotrichosis · 5-10 mg/kg PO q12-24h · PO · q12-24h · 2-4 months on average
Horses
Susceptible yeasts and Aspergillus spp · 5 mg/kg PO once daily · PO · q24h · Using commercial oral solution
Scopulariopsis pneumonia · 30 mg/kg q12h · NG tube · q12h · Administered via NG tube mixed with 0.2 Normal hydrochloric acid
Birds
Severe refractory candidiasis in Psittacines · 5-10 mg/kg as a gavage twice daily · PO (gavage) · q12h · 14 days · Dissolve in 0.2 mL 1 N HCl and add 0.8 mL water
給藥途徑
POTopical
禁忌症
Known hypersensitivity to ketoconazole
Controversial/Contraindicated in cats (due to toxicity risks)
Concurrent use with cisapride or ivermectin (in dogs)
Transient suppression of gonadal and adrenal steroid synthesis
Infertility in male dogs (reversible)
Hepatotoxicity
Anorexia
Alterations in hair-coat colour
Thrombocytopenia (at high doses)
Adrenal insufficiency (at high doses)
Cataract development (in dogs)
Teratogenic effects
藥物相互作用
Alcohol · May produce a disulfiram-like reaction (vomiting)
Antacids · May reduce oral absorption of ketoconazole; administer at least 1 hour before or 2 hours after · moderate
Tricyclic Antidepressants (amitriptyline, clomipramine) · Ketoconazole may reduce metabolism and increase adverse effects
Benzodiazepines (midazolam, triazolam) · Ketoconazole may increase levels
Buspirone · Plasma concentrations may be elevated
Busulfan · Ketoconazole may increase levels
Calcium-channel blockers (amlodipine, verapamil) · Ketoconazole may increase levels
Cisapride · Ketoconazole may increase cisapride levels and possibility for toxicity; use together contraindicated
Corticosteroids · Ketoconazole may inhibit metabolism; potential for increased adverse effects
Cyclophosphamide · Ketoconazole may inhibit metabolism; potential for increased toxicity
Cyclosporine · Increased cyclosporine levels (often used therapeutically to reduce cyclosporine dose)
Digoxin · Ketoconazole may increase digoxin levels
Fentanyl/Alfentanil · Ketoconazole may increase fentanyl or alfentanil levels
監測
Liver enzymes with chronic therapy (at least every 1-2 months)
CBC with platelets
Clinical efficacy
Adverse effects (GI signs, jaundice)
Liver function tests (routine monitoring recommended)
Platelet count (if high doses are used)
Adrenal function/clinical signs of hypoadrenocorticism
過量
No reports of acute toxicity associated with overdosage were located. The oral LD50 in dogs is >500 mg/kg. In the event of an acute overdose, employ supportive measures, including **gastric lavage with sodium bicarbonate**.
Susceptible fungal infections (most species) · 200 mg/L · PO (water) · Continuous · 7-14 days · Dissolve in acid prior to adding to water
Susceptible fungal infections (most species) · 10-20 mg/kg · PO (feed) · Daily · 7-14 days · Add to favorite food or mash
Susceptible fungal infections (Moluccan Cockatoos) · 20-30 mg/kg PO twice daily · PO · q12h
Susceptible fungal infections (Ratites) · 5-10 mg/kg PO once daily · PO · q24h
SmallMammals
Susceptible infections (Rabbits) · 10-40 mg/kg per day PO · PO · q24h · 14 days
Systemic mycoses/candidiasis (Hamsters, Gerbils, Mice, Rats, Guinea pigs, Chinchillas) · 10-40 mg/kg per day PO · PO · q24h · 14 days
Dogs
Coccidioidomycosis (systemic form) · 5-10 mg/kg PO twice daily · PO · q12h · Minimum of 3-6 months
Coccidioidomycosis (CNS form) · 15-20 mg/kg PO twice daily · PO · q12h · Minimum of 3-6 months
Coccidioidomycosis (bony lesions or relapses) · 5 mg/kg PO every other day · PO · q48h · Lifelong
Coccidioidomycosis · 10-30 mg/kg PO divided twice a day · PO · q12h · 6-12 months
Blastomycosis · 10 mg/kg PO twice daily (15-20 mg/kg PO twice daily if CNS involvement) · PO · q12h · At least 3 months · Used with amphotericin B
Blastomycosis · 20 mg/kg/day PO once daily or divided twice daily; 40 mg/kg divided twice daily for ocular or CNS involvement · PO · q24h or q12h · At least 2-3 months or until remission · Used with amphotericin B
Histoplasmosis · 10 mg/kg PO once a day or twice a day · PO · q24h or q12h · At least 3 months · Treat at least 30 days after complete resolution. Maintenance 5 mg/kg PO every other day indefinitely if relapse.
Histoplasmosis · 10-20 mg/day PO once daily or divided twice daily · PO · q24h or q12h · At least 2-3 months or until remission · Used with amphotericin B
Aspergillosis · 20 mg/kg PO · PO · Not specified · At least 6 weeks · May require long-term/maintenance therapy
Nasal aspergillosis · 10 mg/kg PO once daily (q24h) or 5 mg/kg PO q12h · PO · q24h or q12h · Many weeks; continue 1 month beyond last detection · Itraconazole somewhat more effective
Cryptococcosis · 10 mg/kg PO once daily or divided twice daily · PO · q24h or q12h · Maintenance · Used with amphotericin B
Fungal myocarditis · 10 mg/kg PO three times daily · PO · q8h
Candidiasis · 10 mg/kg PO once daily (q24h) or 5 mg/kg PO q12h · PO · q24h or q12h · Many weeks; continue 1 month beyond last detection
Sporotrichosis · 15 mg/kg PO q12h · PO · q12h · Many weeks; continue 1 month beyond last detection
Malassezia dermatitis (severe) · 5 mg/kg PO once daily to 10 mg/kg twice daily · PO · q24h to q12h · Until clinical signs abate and no organisms seen
Malassezia dermatitis · 5-10 mg/kg PO twice a day · PO · q12h · 30 days · Often used with therapeutic shampoos
Malassezia dermatitis · 5-10 mg/kg PO daily for 10 days, then every other day for an additional 10 days · PO · q24h then q48h · 20 days
Malassezia dermatitis · 5 mg/kg twice daily for 21-30 days, may increase to 10 mg/kg PO twice daily if poor response · PO · q12h · 21-30 days
Malassezia dermatitis · 2.5-10 mg/kg PO once daily (q24h) for 7-14 days; once a good response is seen taper to every other day (q48h) · PO · q24h then q48h · Until complete remission
Hyperadrenocorticism · 5-10 mg/kg PO twice daily initially; may increase to 15 mg/kg PO twice daily · PO · q12h · Long-term · Monitor with ACTH stimulation test
Hyperadrenocorticism · 5 mg/kg q12h for 5-7 days, increase to 10 mg/kg q12h for 10-14 days; many require 15-20 mg/kg q12h · PO · q12h · Long-term
Hyperadrenocorticism (palliative) · 15 mg/kg PO q12h · PO · q12h · Long-term
Reduce cyclosporine dosage · 5-10 mg/kg PO per day · PO · q24h · Concurrent with cyclosporine
Perianal fistula (with cyclosporine) · 7.5 mg/kg PO twice daily · PO · q12h · Given with cyclosporine 0.5-0.75 mg PO twice daily
Atopic dermatitis (with cyclosporine) · 5 mg/kg/day · PO · q24h · Given with cyclosporine 2.5 mg/kg/day
IMHA (with cyclosporine) · 10 mg/kg/day · PO · q24h · Allows reduction of cyclosporine dose
Reptiles
Susceptible infections (most species) · 15-30 mg/kg PO once daily · PO · q24h · 2-4 weeks
Fungal shell diseases in turtles/tortoises · 25 mg/kg PO once a day · PO · q24h · 2-4 weeks