Terbinafine Lamisil

Ball-and-Stick Model

Space-filling Model

Ball-and-Stick Model

Year of discovery: 1984 (Sandoz); Year of introduction: 1996 (Novartis); Drug category: Allylamine antifungal agent/squalene epoxidase inhibitor; Main uses: For the treatment of fungal infections of the skin (dermatomycosis) and nails (both oral and topical); Related drugs: Naftifine, Butenafine.

Terbinafine, a totally synthetic allylamine, is a potent antifungal agent used mainly for the treatment of fungal skin and nail infections.1 Risk factors for fungal infection include age (>70 years), type 2 diabetes, HIV/AIDS, and immunosuppressive therapy (e.g., for organ transplant and cancer). About half of all nail disorders can be attributed to fungal infection.

The first antifungal allylamine, naftifine, was discovered serendipitously at Sandoz-Werner in 1974 during an investigation of synthetic compounds for activity in the central nervous system. After successful clinical trials, naftifine entered the market as a topical antifungal drug (Exoderil) in 1985. Subsequently, hundreds of analogs were prepared and the antifungal activity was linked to two structural elements: (1) the tertiary allylamine moiety (highlighted in yellow boxes) and (2) the 1-substituted naphthalene ring (shown in blue). Structure-activity correlations led to the development of the more active butenafine (Lotrimin) and eventually terbinafine (Lamisil).

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Naftifine (Naftin™) Butenafine (Lotrimin™)

Terbinafine is currently the most potent antifungal medicine in the allylamine class. It is active against a wide range of dermatophytes, yeasts and molds. Unlike earlier members of this class, terbinafine can be administered both topically (in the form of a cream) and orally. Terbinafine is a first-line treatment for fungal skin and nail infections, given its lack of toxicity, high potency and the rapidity with which it cures. Terbinafine accumulates in the skin and around nails, and its concentration remains high even after the cessation of therapy. Consequently, it provides extended protection against fungal relapses.2

Terbinafine and all allylamines act by inhibiting the enzyme squalene epoxidase. This enzyme is responsible for the conversion of squalene to 2,3-oxidosqualene, the precursor of all sterols by way of lanosterol (see scheme below). Fungi convert lanosterol into ergosterol which is a critical component of fungal cell membranes (see page 161). Fungal cell death results not only from the lack of ergosterol but also from the accumulation of squalene.3

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Lanosterol

| ErgosteroT|

hjc chj

Lanosterol

| ErgosteroT|

To date, terbinafine-resistant fungi have not been reported. However, allylamine-resistance may emerge with more extensive use of this agent. A combination of terbinafine and fluconazole has been effective against triazole-resistant strains.

1. J. Drug Eval. 2004, 2, 133-155; 2. Exp. Opin. Pharmaco-Iher. 2005, 6, 609-624; 3. Rev. Contemp. Pharm. 1997, 8, 275-287; Refs. p. 178

An estimated 2 billion humans are infected with at least one parasite.

Malaria causes about 2.5 million deaths annually.

ANTIMALARIAL

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