Fluconazole
Fluconazole is a systemic **triazole antifungal** agent. Unlike older first-generation azoles (such as ketoconazole), it is highly hydrophilic, allowing for excellent penetration into the **central nervous system (CSF)**, **eyes**, and **urinary tract**. > **Clinical Pearl:** Fluconazole does not require an acidic gastric environment for absorption, making its oral bioavailability highly reliable even in patients receiving antacid therapy. Furthermore, it has a significantly lower affinity for mammalian cytochrome P450 enzymes compared to ketoconazole, meaning it has minimal impact on mammalian steroid hormone synthesis and generally fewer side effects.
Mecanismo: Fluconazole acts by inhibiting the fungal cytochrome P450-dependent enzyme **lanosterol 14-α-demethylase**. Lanosterol → (blocked by fluconazole) → **Ergosterol** This depletion of ergosterol disrupts the synthesis of the fungal cell membrane, increasing its permeability and causing leakage of essential cellular contents. It also impairs the uptake of purine and pyrimidine precursors. Fluconazole is primarily **fungistatic**.
Dosificación por especie
- Nasal or dermal cryptococcosis · 5-10 mg/kg PO q12-24h, or 10 mg/kg PO q24h · PO · q12-24h · For most infections, 50 mg/cat PO once daily achieves adequate therapeutic levels
- CNS, intraocular, or multisystemic cryptococcosis · 50-100 mg/cat PO or IV q12h · PO/IV · q12h · Often treat neurologic ocular cryptococcosis for at least 12 weeks or 2 weeks after CSF exam shows resolution
- CNS, intraocular or multisystemic mycoses · 50 mg/cat PO once daily (q24h) · PO · q24h
- Cryptococcosis · 50 mg (total dose) PO twice daily · PO · q12h · 1 month beyond resolution of clinical signs
- Cryptococcosis · 50 mg (total dose) PO twice daily · PO · q12h · At least 2 months beyond resolution of clinical signs
- C. immitis infection or Candida bacteremia · Loading dose of 14 mg/kg followed by 5 mg/kg PO once daily · PO · q24h
- Fungal keratitis · 1 mg/kg PO q24h · PO · q24h · Anecdotal reports of successful treatment
- Candidiasis (cockatoos, parrots) · 20 mg/kg PO q24-48h or 10 mg/kg PO q24h · PO · q24-48h · Likely effective for C. albicans. C. galabrata and C. papasilosis may have higher MICs.
- Candidiasis (cockatiels) · 10 mg/kg fluconazole PO suspension and 100 mg/mL fluconazole treated drinking water · PO · Maintained plasma levels above the MIC for most strains of Candida albicans
Vías de administración
Contraindicaciones
- Hypersensitivity to fluconazole or other azole antifungals
- Budgerigars (reportedly toxic)
- Pregnant animals
- Lactating animals
Efectos adversos
- Inappetence
- Vomiting
- Diarrhea
- Hepatotoxicity (rare)
- Headache (humans)
- Increased liver enzymes (humans)
- Exfoliative skin disorders (humans)
- Thrombocytopenia (humans)
- Nausea
- Diarrhoea
- Hepatotoxicity
Interacciones farmacológicas
- Amphotericin B · May be antagonistic against Aspergillus or Candida; clinical importance unclear
- Buspirone · Plasma concentrations of buspirone may be elevated
- Cisapride · May increase cisapride levels and the possibility for toxicity
- Corticosteroids · May inhibit the metabolism of corticosteroids; potential for increased adverse effects
- Cyclophosphamide · May inhibit the metabolism of cyclophosphamide and its metabolites; potential for increased toxicity
- Cyclosporine · Increases cyclosporine levels; dosage of cyclosporine may need to be decreased by 29%-51%
- Diuretics, Thiazides · Increased fluconazole concentrations
- Fentanyl/Alfentanil · May increase fentanyl levels
- Midazolam · Increased midazolam levels and effects
- NSAIDs · May increase NSAID plasma levels; increased risk for adverse effects
- Quinidine · Increased risk for cardiotoxicity
- Rifampin · May decrease fluconazole efficacy; fluconazole may increase rifampin levels
- Theophylline/Aminophylline · Increased theophylline concentrations
Monitoreo
- Clinical efficacy
- Liver function tests (occasional, with long-term therapy)
- Liver enzyme panel (ALT, AST, ALP, Bilirubin) prior to and during prolonged therapy
- Renal function (BUN, Creatinine)
- Resolution of clinical signs of fungal infection
- Therapeutic drug monitoring for concurrent medications like ciclosporin or theophylline
Sobredosis
There is limited information on acute toxicity in domestic animals. In rodents, massive overdoses (1-2 g/kg) caused respiratory depression, salivation, lacrimation, urinary incontinence, and cyanosis, leading to death within several days. **Treatment:** If a massive overdose occurs, consider gut emptying (emesis or gastric lavage) if recent, and provide supportive therapy as required. Fluconazole may be removed by hemodialysis or peritoneal dialysis.
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