Terbinafine is a synthetic allylamine compound used as an effective antifungal medication, primarily treating infections caused by dermatophytes (fungi that thrive on the skin, hair, and nails). Common applications include ringworm, athlete’s foot (tinea pedis), jock itch (tinea cruris), and nail fungus (onychomycosis). While available in topical creams, systemic (oral) administration is generally required for deep-seated infections like onychomycosis. Terbinafine provides a targeted approach to eradicating fungal pathogens, offering a fungicidal action.
How Terbinafine Works
Terbinafine functions as a specific inhibitor of the fungal enzyme squalene epoxidase, a key step in the fungal cell’s sterol biosynthesis pathway. This enzyme converts squalene into 2,3-oxidosqualene, a necessary precursor for ergosterol, the fungal equivalent of cholesterol. By inhibiting squalene epoxidase, Terbinafine exerts a dual toxic effect, making it fungicidal.
The blocked pathway causes a deficiency of ergosterol, which maintains the integrity and function of the fungal cell membrane. Without sufficient ergosterol, the membrane is compromised and unable to perform its regulatory functions, leading to cell dysfunction.
Secondly, the pathway interruption causes squalene to accumulate inside the fungal cell. This excess squalene interferes with membrane function and cell wall synthesis, leading to cell lysis or disintegration. The accumulation of a toxic substance combined with the loss of a necessary structural component is what gives Terbinafine its fungicidal property against dermatophytes. The drug exhibits high selectivity because human cells use cholesterol and have a different squalene epoxidase enzyme, sparing human cells from harm.
How the Body Processes the Drug
Following oral administration, Terbinafine is rapidly and extensively absorbed from the gastrointestinal tract, with over 70% of the dose entering the bloodstream. Due to significant first-pass metabolism in the liver, however, the actual bioavailability is reduced to approximately 40%. Peak plasma concentrations are typically reached about two hours after a single 250 mg dose.
Terbinafine is highly lipophilic (fat-soluble), and over 99% of the drug circulating in the blood is bound to plasma proteins. This lipophilicity allows for extensive distribution into fatty tissues, skin, sebum, and nails. This affinity for keratinous tissues explains the drug’s effectiveness, as it accumulates directly at the site of infection.
The drug is extensively metabolized in the liver into inactive metabolites through oxidation and N-demethylation, involving at least seven Cytochrome P450 (CYP) enzymes (e.g., CYP2C9, CYP1A2, and CYP3A4). Elimination is slow, with a half-life ranging between 200 and 400 hours, reflecting its slow release from peripheral storage sites like skin and adipose tissue. This prolonged presence in target tissues allows for shorter treatment courses and sustained fungicidal activity.
Drug Interactions and Safety Considerations
Systemic Terbinafine therapy requires consideration of potential drug-drug interactions, primarily due to its effect on the hepatic Cytochrome P450 enzyme system. Terbinafine acts as an inhibitor of the CYP2D6 enzyme, which metabolizes a wide variety of medications. Inhibition of CYP2D6 significantly slows the breakdown of co-administered drugs metabolized by this pathway. This slowed metabolism can lead to toxic accumulation of other medications, requiring careful monitoring or dose adjustments.
Affected Drug Classes
Drug classes commonly affected include certain antidepressants (such as tricyclic antidepressants and selective serotonin reuptake inhibitors), some beta-blockers, and antiarrhythmics. For example, combining Terbinafine with the antidepressant desipramine can result in a five-fold increase in the antidepressant’s blood concentration.
Hepatotoxicity Risk
Safety considerations for oral Terbinafine also include the risk of hepatotoxicity (liver injury). Although rare, liver failure has been reported in patients taking the medication. Liver function tests are recommended before initiating therapy and periodically during long-term treatment to monitor for adverse effects. The drug is generally not recommended for patients with pre-existing chronic or active liver disease.
Fungal Resistance to Terbinafine
While Terbinafine remains a first-line treatment, the emergence of fungal resistance is a growing concern, particularly among dermatophytes. Resistance occurs when the fungus survives and grows despite exposure to normally lethal drug concentrations. This acquired resistance is mediated by genetic changes within the fungal cell that affect the drug’s target.
The primary mechanism involves point mutations in the SQLE gene, which codes for the squalene epoxidase enzyme. Single amino acid substitutions (e.g., Leu393Phe or Phe397Leu) reduce Terbinafine’s binding affinity to the target site. The mutated enzyme continues ergosterol synthesis, but the drug cannot effectively inhibit it, resulting in treatment failure.
Resistance was historically rare but has gained prominence due to increasing treatment failures, notably caused by Trichophyton indotineae and certain strains of Trichophyton rubrum and Trichophyton interdigitale. In some global regions, the resistance rate for certain T. indotineae strains may be high, posing a significant challenge to effective treatment. Clinicians should consider antifungal susceptibility testing when facing recalcitrant infections.