Terbinafine

Terbinafine, sold under the brand name Lamisil among others, is an antifungal medication used to treat pityriasis versicolor, fungal nail infections, and ringworm including jock itch and athlete's foot. It is either taken by mouth or applied to the skin as a cream or ointment. The cream and ointment are effective for nail infections.
Common side effects when taken by mouth include nausea, diarrhea, headache, cough, rash, and elevated liver enzymes. Severe side effects include liver problems and allergic reactions. Liver injury is, however, unusual. Use during pregnancy is not typically recommended. The cream and ointment may result in itchiness but are generally well tolerated. Terbinafine is in the allylamines family of medications. It works by decreasing the ability of fungi to make sterols. It appears to result in fungal cell death.
Terbinafine was discovered in 1991. It is on the World Health Organization's List of Essential Medicines. In 2017, it was the 307th most commonly prescribed medication in the United States, with more than one million prescriptions.
Medical uses.
Terbinafine is mainly effective on the dermatophyte group of fungi.
As a cream or powder, it is used topically for superficial skin infections such as jock itch (tinea cruris), athlete's foot (tinea pedis), and other types of ringworm (tinea corporis).
Tablets by mouth are often prescribed for the treatment of onychomycosis, a fungal nail infection, typically by a dermatophyte or "Candida" species. Fungal nail infections are located deep under the nail in the cuticle to which topically applied treatments are unable to penetrate in sufficient amounts. The tablets may, rarely, cause hepatotoxicity, so patients are warned of this and may be monitored with liver function tests. Alternatives to by mouth administration have been studied.
Terbinafine may induce or exacerbate subacute cutaneous lupus erythematosus. Persons with lupus erythematosus should first discuss possible risks with their doctor before initiation of therapy.
Side effects.
Many side effects and adverse drug reactions have been reported with oral terbinafine hydrochloride possibly due to its extensive biodistribution and the often extended durations involved in antifungal treatment (longer than two months). A comprehensive list of adverse events associated with terbinafine use includes:
In 2015 physicians reported that a patient with an MTHFR enzyme mutation (specifically the C677T variant) had developed an adverse reaction to Lamisil (headache, fatigue, and dizziness). Genetic testing revealed the MTHFR C677T mutation. It was noted that Lamisil interferes with the methylation cycle and that this can cause side effects in individuals with the MTHFR C677T mutation.
Pharmacology.
Pharmacodynamics.
Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase, an enzyme that catalyzes the conversion of squalene to lanosterol. In fungi, lanosterol is then converted to ergosterol; in humans, lanosterol becomes cholesterol. However, there is sufficient genetic divergence between fungal and human squalene epoxidases that terbinafine preferentially binds fungal squalene epoxidase, making it selective for inhibiting ergosterol production in fungi without significantly affecting cholesterol production in humans. This is thought to change cell membrane permeability, causing fungal cell lysis.
Terbinafine is highly lipophilic and tends to accumulate in hair, skin, nails, and fatty tissue.
This accumulation results in therapeutic levels of terbinafine even after 80 days following one week treatment of 250 mg/day. Different dosing schedules have been proposed like 500 mg/day for one week or 250 mg/day for two weeks each followed by a drug-free period of three or two weeks, totalling 3 months of treatment including the drug-free periods.
For nail infection a treatment of one month followed by a three months drug-free period repeated three times, totalling four times, showed to be a very effective treatment. Minimising side effects.
Chemistry.
Terbinafine hydrochloride is a white fine crystalline powder that is freely soluble in methanol and dichloromethane, soluble in ethanol, and slightly soluble in water.
Terbinafine is produced from metathesis of 1,3-dichloropropene and neohexene followed by reaction with "N"-methyl-1-naphthalenemethanamine.
History.
Terbinafine first became available in Europe in 1991 and in the United States in 1996. The U.S. Food and Drug Administration has approved the first generic versions of prescription Lamisil (terbinafine hydrochloride) tablets. The remaining patent or exclusivity for Lamisil expired on June 30, 2007.
On September 28, 2007, the FDA stated that terbinafine is a new treatment approved for use by children age four and up. The antifungal granules can be sprinkled on a child's food to treat ringworm of the scalp, tinea capitis.
In the United States the price in 1999 was $547 for a 12-week course; this fell to $10 by 2015, after the patent had expired.