Terbinafine (Lamisil) is a second-generation allylamine that is related to naftifine; however, it is 10 to 100 times more potent in vitro. It is fungicidal, whereas griseofulvin, ketoconazole, itraconazole, and other azole derivatives are all fungistatic. Because it is fungicidal, duration of therapy is shorter, and relapse rates are less than with other oral or topical therapies. Terbinafine acts by inhibiting squalene epoxidase and thereby decreasing synthesis of ergosterol, an essential component of fungal cell membranes. It is highly lipophilic and concentrates in the stratum corneum, sebum, and hair follicles. Slightly better cure rates are attained with b.i.d. than with daily dosing.
ChEBI: A tertiary amine that is N-methyl-1-naphthalenemethylamine in which the amino hydrogen is replaced by a 3-(tertbutylethynyl)allyl group. An antifungal agent administered orally (generally as the hydrochloride salt) for the t
eatment of skin and nail infections.
Terbinafine (Lamisil) is a second-generation allylamine that is related to
naftifine; however, it is 10 to 100 times more potent in vitro. It is fungicidal,
whereas griseofulvin, ketoconazole, itraconazole, and other azole derivatives
are all fungistatic. Because it is fungicidal, duration of therapy is shorter, and
relapse rates are less than with other oral or topical therapies.
Terbinafine acts by inhibiting squalene epoxidase and thereby decreasing
synthesis of ergosterol, an essential component of fungal cell membranes.
It is highly lipophilic and concentrates in the stratum corneum, sebum, and
hair follicles. Slightly better cure rates are attained with b.i.d. than with daily
dosing.
To an ice-cooled solution of N-methyl-1-naphthalenemethylamine
hydrochloride (2.1 g) in methanol (40 ml) and water (10 ml) was added
sodium hydroxide powder (2 g) followed by dropwise addition of
epichlorohydrin (8 ml). The mixture was heated at 60°C for 3 h, then cooled
to room temperature. Volatile materials were removed in vacuo and the
residue was taken up in ethyl acetate and washed with water. The organic
phase was collected, dried over sodium sulfate, filtered and evaporated to
dryness. The crude mixture was purified by flash chromatrography on silica
gel (grade 9385, Merck, 230-400 mesh, 60 A) using a solvent gradient of a
mixture of hexane and ethyl acetate (95:5, 90:10 and 85:15) as eluent,
affording the N-methyl-N-naphthylmethyl-2,3-epoxypropane (1.85 g, 81.5%)
as an oil.
To a solution of 3,3-dimethylbutyne (2.95 ml) in dry THF (50 ml) at -78°C
was added a 2.5 M solution of n-BuLi in hexane (10 ml) dropwise. The
mixture was allowed to warm to room temperature over 15 min and stirred at
that temparature for a further 15 min, then was cooled back to -78°C and
BF3OEt2 (3 ml) was added dropwise. The mixture was stirred for 15 min and
1.8 g of N-methyl-N-naphthylmethyl-2,3-epoxypropane, dissolved in THF (10
ml), was added dropwise. After stirring at -78°C for 2 h, saturated sodium
bicarbonate solution (15 ml) was added, and the reaction mixture was allowed
to warm to room temperature. The mixture was extracted with ethyl acetate
(2 times 25 ml), and the combined organic fractions was dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was purified by flash
chromatrography on silica gel (grade 9385, Merck, 230-400 mesh, 60 a) using
a mixture of hexane and ethyl acetate (85:15) as eluent, thereby affording
the N-methyl-N-(1-naphthylmethyl)-2-hydroxy-heptan-4-ynyl-1-amine as an
oil (1.95 g, 79%).
To an ice-cooled solution of N-methyl-N-(1-naphthylmethyl)-2-hydroxyheptan-
4-ynyl-1-amine (155 mg) in THF (10 ml) was added Et3N (0.35 ml)
followed by methanesulfonyl chloride (0.075 ml). The resulting mixture was
stirred at 0°C for 3 h, then filtered. The filtrate was concentrated in vacuo,
dissolved in toluene (10 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(0.37 ml) was added. The resulting mixture was heated at 80°C for 4 h,
cooled to room temperature then poured onto a silica gel column and eluted
with hexane (100%) followed by a mixture of hexane and ethyl acetate
(95:5). Thus, a mixture of E- and Z-isomers of N-methyl-N-(1-
naphthylmethyl)-6,6-dimethylhept-2-en-4-ynyl)-1-amine were obtained in a
ratio of 2:5 (95 mg, 66%).
Terbinafine is active against a wide range of pathogenic fungi,
including dermatophytes (Epidermophyton, Microsporum and
Trichophyton spp.), various Candida spp., Aspergillus spp.,
some dimorphic fungi (Blastomyces dermatitidis, Histoplasma
capsulatum and Sporothrix schenckii) and many dematiaceous
fungi.
Resistance has not been reported.
Pharmaceutical Applications
A synthetic allylamine available as the hydrochloride for oral
and topical administration.
Oral absorption: 70–80%
Cmax 250 mg oral: c. 1 mg/L after 2 h
Plasma half-life: c. 17 h
Volume of distribution: 1000 L
Plasma protein binding: >99%
Blood concentrations increase in proportion to dosage. It is
lipophilic and is rapidly and extensively distributed to body
tissues. It reaches the stratum corneum by diffusion through
the dermis and epidermis, and secretion in sebum. Diffusion
from the nail bed is the major factor in its rapid penetration
of nails. It is metabolized by the liver and the inactive metabolites
are mostly excreted in the urine. The elimination half-life
is prolonged in patients with hepatic or renal impairment.
Terbinafine hydrochloride can be used in Tinea pedis, tinea corporis, tinea cruris, tinea capitis, Onychomycosis caused by dermatophytes.
These include abdominal discomfort, loss of appetite,
nausea, diarrhea, headache, impairment of taste, rash
and urticaria. Serious skin reactions, including Stevens–
Johnson syndrome, and rare hepatotoxic reactions, including
jaundice, cholestasis and hepatitis, are occasionally
encountered.
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin.
Terbinafine undergoes extensive first pass loss. It is
hepatically metabolised to two major inactive metabolites,
80% of which are renally excreted.
