Mechanism of Fungicidal Action
The biochemical target of these drugs is the enzyme squalene epoxidase. Inhibition of this enzyme leads to two key processes:
- It disrupts the conversion of squalene to lanosterol, which is the direct precursor to ergosterol.
- Toxic metabolites of squalene accumulate inside the fungal cell.
Unlike azole antifungals, allylamines inhibit ergosterol synthesis at an earlier stage. They do not directly interfere with mitosis—unlike griseofulvin—but instead target the cell membrane structure directly.
Classification and Clinical Spectrum
Based on their chemical structure, these compounds are synthetic agents divided into two main categories:
- Allylamines (N-methylnaphthalene derivatives): terbinafine, naftifine.
- Benzylamines: butenafine.
Although these drugs exhibit a broad spectrum of antimycotic activity, their primary clinical significance is directed against dermatophytes. They demonstrate high efficacy in fungal infections of the skin and nails.
Pharmacokinetics and Administration of Terbinafine
Terbinafine is available in topical and systemic (oral tablet) formulations. Upon oral administration, its bioavailability is approximately 40% due to significant presystemic metabolism (first-pass hepatic effect), and plasma protein binding reaches 99%.
The drug is extensively distributed with a strong tendency to accumulate in adipose tissue and keratin-rich tissues, such as the skin and nails. Prolonged circulation is ensured by a substantial elimination half-life ($T_{1/2}$) of roughly 300 hours.
Indications for Oral Use:
- Onychomycosis (nail infections);
- Tinea corporis and tinea capitis;
- Tinea versicolor (pityriasis versicolor).
Safety and Drug Interactions
Systemic therapy requires caution, as the drug is contraindicated during pregnancy and in patients with renal or hepatic impairment.
- Common Adverse Effects: dyspepsia (nausea, abdominal pain, diarrhea, loss of appetite) and skin rashes.
- Rare but Severe Reactions: hepatotoxicity (requires regular monitoring of liver enzymes), neutropenia, Stevens-Johnson syndrome, and exacerbation of autoimmune conditions (psoriasis, subacute cutaneous lupus erythematosus).
Plasma terbinafine levels are affected by cytochrome P450 modulators: cimetidine increases drug concentrations by acting as an inhibitor, whereas rifampin decreases concentrations as an inducer.
Specifics of Naftifine
Another well-known representative of this class is naftifine, which functions similarly by inhibiting squalene epoxidase. The drug is used exclusively topically (as a cream or gel) twice daily.
In vitro, it exhibits fungicidal activity against dermatophytes and fungistatic activity against yeast-like fungi of the genus Candida (including C. albicans). Naftifine is prescribed for tinea pedis, tinea manuum, cutaneous candidiasis, onychomycosis, and tinea versicolor. Tolerability is generally good, with local reactions such as burning, dryness, or erythema reported only occasionally.