Allylamines, Flucytosine, and Griseofulvin

Squalene epoxidase catalyzes the conversion of squalene to squalene epoxide, the step immediately preceding lanosterol formation in the sterol biosynthesis pathway. Allylamines inhibit this enzyme non-competitively and selectively in fungi compared to the mammalian enzyme, providing the basis for selective antifungal toxicity. Inhibition produces two consequences simultaneously: ergosterol depletion, which disrupts fungal membrane function, and massive intracellular accumulation of squalene, which is directly toxic to the fungal cell membrane at high concentrations. The combination of ergosterol depletion and squalene toxicity produces fungicidal activity against dermatophytes at clinically achievable concentrations, in contrast to the fungistatic effect of azoles against the same organisms.

Terbinafine is the primary systemic allylamine in clinical use. It is well absorbed orally with bioavailability of approximately 70 percent after first-pass hepatic metabolism. It is highly lipophilic and extensively distributed into skin, nails, hair, and adipose tissue, achieving concentrations in these compartments that substantially exceed plasma concentrations. Nail concentrations persist for months after treatment completion because terbinafine is incorporated into the nail plate during growth and remains there even after plasma concentrations fall. This pharmacokinetic property is the basis for the relatively short treatment courses used in onychomycosis compared to older antifungals — the drug continues to work after the oral course ends. Terbinafine is metabolized by multiple hepatic cytochrome P450 (CYP) enzymes including CYP2D6 (cytochrome P450 2D6), CYP1A2 (cytochrome P450 1A2), CYP3A4, and CYP2C9. It inhibits CYP2D6, which is the basis for its clinically relevant interaction with drugs metabolized by that isoform, including tricyclic antidepressants, beta-blockers, and certain antiarrhythmics. Elimination is primarily renal, and dose reduction is recommended when creatinine clearance falls below 50 mL/min.

Terbinafine has excellent activity against dermatophytes — Trichophyton, Microsporum, and Epidermophyton species — the organisms responsible for tinea pedis (athlete's foot), tinea cruris (jock itch), tinea corporis (ringworm), tinea capitis (scalp ringworm), and onychomycosis (nail infection). It is fungicidal against these organisms and is the drug of choice for onychomycosis caused by dermatophytes, where it achieves higher cure rates and lower relapse rates than either azoles or griseofulvin in controlled trials. Activity against Candida species and molds is limited; terbinafine is not a broad-spectrum antifungal and should not be used for systemic or invasive fungal infections.

For dermatophyte onychomycosis, the standard oral course is 250 mg once daily for six weeks (fingernail) or 12 weeks (toenail). Topical terbinafine (one percent cream) is effective for tinea pedis, tinea corporis, and tinea cruris with one to two week courses. For tinea capitis, oral terbinafine is superior to griseofulvin against Trichophyton tonsurans — the dominant cause in the United States and sub-Saharan Africa — but griseofulvin retains an advantage for Microsporum canis tinea capitis, where terbinafine is less effective.

Terbinafine is generally well tolerated. Gastrointestinal (GI) effects — nausea, diarrhea, dyspepsia — are the most common adverse effects and are usually mild. Taste disturbance (dysgeusia) and loss of taste (ageusia) occur in approximately one percent of patients and are usually reversible on discontinuation but can persist for months. Hepatotoxicity is rare but has been reported; liver function test monitoring is recommended for courses extending beyond six weeks or in patients with pre-existing liver disease. A rare but serious adverse effect is drug-induced lupus erythematosus, which resolves on drug discontinuation. Naftifine is available as a topical formulation only and is used for superficial dermatophyte infections; it lacks clinically significant systemic absorption and systemic adverse effects.

Griseofulvin binds to tubulin and inhibits microtubule polymerization in fungal cells, disrupting the mitotic spindle formation required for cell division. It also binds to keratin precursor proteins in host cells, which concentrates it in actively growing keratin — skin, hair, and nails. The antifungal effect is fungistatic: griseofulvin arrests fungal growth but does not kill existing organisms. New keratin formed during treatment contains drug, while infected keratin grows out and is shed. This growth-displacement mechanism requires prolonged treatment courses. Griseofulvin is active only against dermatophytes — Trichophyton, Microsporum, and Epidermophyton species — and has no activity against Candida, Aspergillus, or any non-dermatophyte organism.

Griseofulvin is available in two particle sizes: microsize and ultramicrosize. The ultramicrosize formulation provides approximately 1.5-fold greater bioavailability than the microsize formulation because of improved dissolution. Absorption of both formulations is significantly enhanced by a high-fat meal, and patients should be instructed to take griseofulvin with fatty food. Griseofulvin is metabolized by hepatic CYP enzymes and induces CYP3A4, which accelerates the metabolism of co-administered CYP3A4 substrates — including warfarin, oral contraceptives, and cyclosporine — reducing their plasma concentrations. The interaction with oral contraceptives is clinically significant and patients should be counseled to use additional contraceptive methods during griseofulvin therapy. Griseofulvin is teratogenic in animal models and should not be used during pregnancy.

Griseofulvin was for decades the only oral antifungal available for dermatophyte infections, but its use has been largely displaced by terbinafine and itraconazole, which offer higher cure rates, shorter treatment courses, and better tolerability for most indications. The one setting where griseofulvin retains a defined role is tinea capitis in children caused by Microsporum canis, where terbinafine is significantly less effective and griseofulvin remains a first-line option. For tinea capitis caused by Trichophyton tonsurans — the dominant cause in the United States — terbinafine is preferred but griseofulvin remains an acceptable alternative. Treatment courses for tinea capitis are typically six to eight weeks. For onychomycosis, griseofulvin requires 12 to 18 months of treatment with cure rates well below those of terbinafine, and it is no longer recommended as a first-line or second-line option for nail infections in current guidelines.

Adverse effects include headache (the most common complaint, occurring in approximately 15 percent of patients), gastrointestinal disturbances, photosensitivity reactions, and rarely drug-induced lupus erythematosus. Griseofulvin has a disulfiram-like reaction with alcohol, producing flushing, tachycardia, and nausea, and patients should be warned to avoid alcohol consumption during therapy.