Allylamines

The allylamines include terbinafine, naftifine, and the much older thiocarbamate tolnaftate. Their mechanism is competitive inhibition of squalene epoxidase, blocking conversion of squalene to lanosterol, leading to squaline accumulation and ergosterol depletion in the cell membrane. Terbinafine has a much higher affinity for fungal than for mammalian squaline epoxidase. 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 its use for systemic fungal infections. Terbinafine is also active against yeasts (eg, Blastomyces dermatitidis, Cryptococcus neoformans, Sporothrix schenckii, Histoplasma capsulatum, Candida, and Pityrosporum spp). Terbinafine increasingly is used in combination with other antifungal drugs to enhance efficacy. Effects are fungicidal. 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. Resistance to the allylamines is rare, but the drugs potentially can be affected by multidrug resistance efflux mechanisms. Terbinafine, available in oral and topical preparations, is well absorbed (80% in people) after PO administration. Fat facilitates absorption. High concentrations occur in the stratum corneum, sebum, and hair. Terbinafine is metabolized by the liver in people; the elimination half-life is sufficiently long to allow once-daily administration, with steady state not occurring for 10–14 days in people. Adverse effects of terbinafine after PO administration are limited to GI and skin signs; hepatobiliary dysfunction is a rare adverse event. Because inhibition of ergosterol synthesis occurs at a step before cytochrome P450 involvement, the allylamines do not affect steroid synthesis as do the imidazoles.