Terbinafine: Mechanism, Pharmacokinetics, Interactions, and Resistance

Terbinafine is a widely used antifungal medication, primarily prescribed for treating fungal infections of the skin and nails. It effectively targets dermatophytes, common culprits behind these infections. As fungal infections remain prevalent, understanding terbinafine’s mechanism of action, pharmacokinetics, potential interactions, and emerging resistance patterns is essential for optimizing its use in clinical practice.

Mechanism of Action

Terbinafine exerts its antifungal effects by targeting squalene epoxidase, an enzyme crucial for ergosterol biosynthesis in fungal cell membranes. Inhibiting this enzyme disrupts ergosterol production, leading to toxic squalene accumulation and fungal cell death. Terbinafine’s specificity for fungal squalene epoxidase, as opposed to similar human enzymes, underpins its selective toxicity, making it effective with minimal impact on human cells.

The disruption of ergosterol synthesis compromises the fungal cell membrane’s integrity and affects cellular function. Ergosterol is vital for maintaining membrane fluidity and permeability, and its absence leads to increased membrane rigidity and impaired cellular processes. This disruption is particularly effective against dermatophytes, which rely heavily on ergosterol for growth and survival. The fungicidal nature of terbinafine underscores its potency in eradicating fungal infections.

Pharmacokinetics

Understanding terbinafine’s pharmacokinetics provides insight into its absorption, distribution, metabolism, and excretion. When administered orally, terbinafine is rapidly absorbed through the gastrointestinal tract, achieving peak plasma concentrations within 1-2 hours. Despite rapid absorption, significant first-pass metabolism in the liver reduces its bioavailability to approximately 40%. This process involves cytochrome P450 enzymes, primarily CYP2C9, CYP1A2, and CYP3A4, converting terbinafine into various metabolites.

Following absorption, terbinafine demonstrates extensive distribution, with a substantial affinity for lipophilic tissues such as the skin, nails, and adipose tissue. This characteristic makes it effective for treating dermatophytic infections, as it accumulates in keratin-rich regions. The drug’s lipophilic nature also contributes to its prolonged half-life, ranging from 200 to 400 hours, allowing for sustained therapeutic effects even after treatment cessation.

Renal excretion is the primary route for terbinafine’s metabolites, with approximately 70% of the dose eliminated through urine. A smaller proportion is excreted via feces. Given its extensive hepatic metabolism, terbinafine’s clearance can be impacted by liver function, necessitating dose adjustments in patients with hepatic impairment. Its prolonged half-life and tissue accumulation mean that therapeutic levels can be maintained with once-daily dosing, enhancing patient adherence.

Drug Interactions

When using terbinafine, it’s important to be aware of potential drug interactions that could affect its efficacy or safety. Terbinafine’s metabolism via cytochrome P450 enzymes means it can interact with other medications that are substrates, inhibitors, or inducers of these enzymes. For instance, co-administration with rifampicin, a potent CYP inducer, may lead to decreased terbinafine plasma levels, potentially reducing its effectiveness. Conversely, inhibitors like cimetidine can increase terbinafine levels, heightening the risk of adverse effects.

Terbinafine may also influence the metabolism of other drugs. It has been shown to inhibit CYP2D6, an enzyme responsible for metabolizing a variety of medications, including certain antidepressants, beta-blockers, and antiarrhythmics. Patients taking these drugs concomitantly with terbinafine may experience increased plasma concentrations, necessitating monitoring and possible dosage adjustments to avoid toxicity.

Interactions with drugs affecting kidney or liver function can alter terbinafine’s pharmacokinetics, given its reliance on these organs for metabolism and excretion. For example, medications like nonsteroidal anti-inflammatory drugs (NSAIDs) that impact renal function might influence terbinafine levels, highlighting the need for careful assessment of renal health during treatment.

Resistance Mechanisms

As terbinafine has become a mainstay in antifungal therapy, the emergence of resistance among certain fungal species presents a growing challenge. Resistance can arise through various mechanisms, often involving genetic mutations that affect drug targets or reduce drug uptake. One notable mechanism involves mutations in the gene encoding squalene epoxidase, the enzyme that terbinafine targets. Such mutations can decrease the drug’s binding affinity, allowing the fungus to continue synthesizing vital components despite the presence of terbinafine.

Some fungi have developed efflux pumps that actively expel terbinafine from the cell, decreasing intracellular drug concentrations and diminishing its efficacy. This mechanism is particularly concerning as it can confer cross-resistance to other antifungal agents, complicating treatment strategies. Additionally, biofilm formation by some resistant strains can act as a physical barrier to the drug, further reducing its effectiveness.