Allylamines

crop_square Key points

  • check_circle Topical and oral drugs for treatment of superficial mycoses
  • check_circle Inhibit ergosterol biosynthesis by blocking the enzyme squalene epoxidase
  • check_circle Accumulate in skin, nails, and fatty tissues
  • check_circle Generally well-tolerated but can cause hepatotoxicity

crop_square Background and biochemistry

Allylamines are a class of synthetic antifungals with just two agents on the market, terbinafine and naftifine. Terbinafine was the first allylamine to be approved by the FDA for topical treatment of fungal infections in 1993. An oral formulation was approved in 1996. Allylamine derivates are highly lipophilic molecules and accumulate in skin, nails, and fatty tissues.

crop_square Mechanism of action

Allylamines interfere with the biosynthesis of ergosterol, an essential component of the fungal cell membrane, by inhibiting the enzyme squalene epoxidase in a non-competitive fashion. This causes an intracellular accumulation of the squalene, the precursor of lanosterol, as well as a lack of ergosterol. This in turn destabilises the fungal cell membrane and disrupts intracellular processes leading to cell death. Allylamines have fungicidal activity against dermatophytes and are fungistatic against Candida species. Resistances to allylamines are primarily mediated by mutations of the squalene epoxidase enzyme.

crop_square Drugs and spectrum of activity

  • Terbi­nafine (oral/topical)
  • Nafti­fine (topical)

Both terbinafine and naftifine are available as topical formulations. Terbinafine can also be administered orally. Allylamines, and especially terbinafine, show in-vitro activity against a wider range of fungal pathogens including Cryptococcus neoformans and Talaromyces marneffei.

crop_square Pharmacokinetics

Terbinafine is well absorbed following oral administration. Bioavailability is reduced due to first-pass metabolism. Terbinafine is highly plasma-bound and undergoes extensive hepatic metabolization by cytochrome P450 enzymes. Terminal half-life of terbinafine deposited in skin, fatty tissue and nails is approximately two weeks. Terbinafine metabolites are primarily eliminated via the urine.

crop_square Adverse drug effects

Terbinafine is generally well-tolerated. Headaches and gastrointestinal symptoms are commonly seen. Liver function tests should be done before and/or during terbinafine treatment. Hepatotoxicity and Stevens-Johnson syndrome are a rare but potentially serious adverse effect.