The allylamines include terbinafine, naftifine, and the much older thiocarbamate tolnaftate. Terbinafine is the most commonly administered allylamine in veterinary practice. While no single-agent terbinafine products are labeled for veterinary use in the US, combination products are labeled for use in the treatment of otitis externa in dogs.
抗真菌活性
动物烯丙胺类药物作用机制
Allylamines are fungicidal, and their mechanism of action is competitive inhibition of squalene epoxidase, blocking conversion of squalene to lanosterol, leading to squalene accumulation and ergosterol depletion in the cell membrane. Terbinafine has a much higher affinity for fungal than for mammalian squalene epoxidase.
真菌对动物烯丙胺类药物耐药机制
Resistance to the allylamines is rare; however, the drugs can potentially be affected by multidrug resistance efflux mechanisms.
动物烯丙胺类药物抗真菌谱
Avid uptake of terbinafine into body fat and epidermis presumably enhances treatment for dermatophytes of superficial yeast pathogens of the skin. However, data are emerging to potentially support administration of terbinafine for systemic fungal infections. Terbinafine is also active against yeasts (eg, B dermatitidis, C neoformans, S schenckii, H capsulatum, Candida, and Malassezia spp).
药代动力学特征
动物烯丙胺类药物吸收
Terbinafine, available in oral and topical preparations, is well absorbed after oral administration in humans (80% bioavailability) and small animals (46%–70% bioavailability). Administering terbinafine with a fatty meal facilitates absorption. In horses, terbinafine undergoes first-pass metabolism leading to lower bioavailability.
动物烯丙胺类药物分布
High concentrations of allylamines occur in the stratum corneum, sebum, and hair.
动物烯丙胺类药物生物转化与药代动力学
Terbinafine has acceptable bioavailability in dogs and cats, with a >46% bioavailability in dogs, and 31% bioavailability in cats. However, horses have a lower relative bioavailability and much lower plasma concentrations of terbinafine in comparison to dogs, likely due to a high degree of first pass metabolism in this species. Therefore, single dose administration of up to 30 mg/kg terbinafine is unlikely to be therapeutically effective in horses--however higher doses and the effects of multiple oral doses on plasma pharmacokinetics have not been investigated in this species.
Terbinafine reaches a maximum plasma concentration within 2-6 hours of oral administration in horses, dogs, and cats. Terbinafine has a plasma half-life between 8-9 hours in horses, dogs, and cats. Terbinafine is rapidly metabolized to a number of inactive metabolites, with metabolites appearing within 15 minutes of administration in horses and 30 minutes of administration in dogs-- again suggesting that terbinafine undergoes rapid first-pass metabolism.
For dogs, following administration of a single 30-35 mg/kg dose of oral terbinafine, the time above MIC for fungi (including dermatophytes) was 17-18 hours. However, it should be noted that following multiple 30 mg/kg oral doses in dogs, terbinafine does not achieve high concentrations in the stratum corneum or sebum of dogs, indicating that the drug does not concentrate in the skin or hair of this species. In contrast, terbinafine does concentrate in the hair of cats after oral administration, making it a useful treatment for dermatophytosis in this species.
Following oral administration of terbinafine in horses, transient oral irritation, anxiety, fever, and colic have been noted. The most common side effect noted in dogs and cats is vomiting and GI upset. In cats, facial pruritus and macular to papular skin reactions have been noted following oral administration, which resolved following discontinuation of treatment.
适应症与给药剂量
The allylamines appear to be more efficacious than griseofulvin for treatment of dermatophyte infections. Efficacy has also been demonstrated against S schenckii and Aspergillus. Terbinafine may enhance efficacy of other antifungal drugs for a variety of fungal disorders and pythiosis. In contrast to terbinafine, tolnaftate is limited to treatment of dermatophytes.
烯丙胺类给药剂量
Drug | Species | Dosage, Route, and Frequency |
|---|---|---|
Terbinafine | Dogs, Cats Dogs, Cats | 5–10 mg/kg/day, PO, when combined with itraconazole 30–40 mg/kg/day, PO, for treatment of dermatophytosis |
Terbinafine | Horses | 10–30 mg/kg/day, PO |
临床特殊注意事项
动物烯丙胺类不良反应和毒性
Adverse effects of terbinafine after oral administration are generally limited to the GI tract and skin; hepatobiliary dysfunction is a rare adverse event. Rare hepatotoxicity, neutropenia, and toxic epidermal necrolysis have been reported in people. Because inhibition of ergosterol synthesis occurs at a step before cytochrome P450 involvement, the allylamines do not affect steroid synthesis like the azoles.
动物烯丙胺类药物相互作用
Terbinafine increasingly is administered in combination with other antifungal drugs, such as amphotericin B, to enhance efficacy. Terbinafine is metabolized by hepatic CYP40, and therefore coadministration with CYP450 inhibitors, such as cimetidine, leads to increased plasma concentrations and decreased clearance. Dose reduction is recommended in humans with hepatic or renal dysfunction.
