DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1586 and severe angioedema develop rarely during treatment with griseofulvin.
Estrogen-like effects have been observed in children. A
moderate but inconsistent increase of fecal protoporphyrins has been
noted with chronic use.
Griseofulvin induces hepatic CYPs, thereby increasing the
rate of metabolism of warfarin; adjustment of the dosage of the latter
agent may be necessary in some patients. The drug may reduce the
efficacy of low-estrogen oral contraceptive agents, probably by a
similar mechanism.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Terbinafine
Terbinafine is a synthetic allylamine, structurally similar
to the topical agent naftifine.
Terbinafine is well absorbed, but bioavailability is decreased to ~40%
because of first-pass metabolism in the liver. Proteins bind >99% of
the drug in plasma. Drug accumulates in skin, nails, and fat. The initial
t 1/2
is ~12 hours but extends to 200-400 hours at steady state.
Terbinafine is not recommended in patients with marked azotemia
or hepatic failure because in the latter condition, terbinafine plasma
levels are increased by unpredictable amounts. Rifampin decreases and
cimetidine increases plasma terbinafine concentrations. The drug is
well tolerated, with a low incidence of GI distress, headache, or rash.
Very rarely, fatal hepatotoxicity, severe neutropenia, Stevens-Johnson
syndrome, or toxic epidermal necrolysis may occur. The drug is pregnancy
Category B and it is recommended that systemic terbinafine
therapy for onychomycosis be postponed until after pregnancy is
complete. Its mechanism of action is inhibition of fungal squalene
epoxidase, blocking ergosterol biosynthesis. Increased intracellular
squalene also impairs cell growth.
Terbinafine (LAMISIL, others), given as one 250-mg tablet
daily for adults, is somewhat more effective for nail onychomycosis
than 200 mg daily of itraconazole, and definitely more effective than
pulse itraconazole therapy (Fernandez-Obregon et al., 2007).
Duration of treatment varies with the site being treated but typically
is 6-12 weeks. Efficacy in onychomycosis can be improved by the
simultaneous use of amorolfine 5% nail lacquer (Baran et al., 2007).
Terbinafine (250 mg daily) also is effective in tinea capitis and is
used off-label for ringworm elsewhere on the body. Oral granules
are available for use against tinea capitis, usually a disease of children.
The recommended dose is 125-250 mg (depending on weight)
daily for 6 weeks. The topical use of terbinafine is discussed later.
Topical Antifungal Agents
Topical treatment is useful in many superficial fungal
infections, i.e., those confined to the stratum corneum,
squamous mucosa, or cornea. Such diseases include
dermatophytosis (ringworm), candidiasis, tinea versicolor,
piedra, tinea nigra, and fungal keratitis. Topical administration
of antifungal agents usually is not successful
for mycoses of the nails (onychomycosis) and hair
(tinea capitis) and has no place in the treatment of subcutaneous
mycoses, such as sporotrichosis and chromoblastomycosis.
The efficacy of topical agents in the
treatment of superficial mycoses depends not only on
the type of lesion and the mechanism of action of the
drug but also on the viscosity, hydrophobicity, and acidity
of the formulation. Regardless of formulation, penetration
of topical drugs into hyperkeratotic lesions often
is poor. Removal of thick, infected keratin is sometimes
a useful adjunct to therapy and is the principal mode of
action of Whitfield’s ointment. Similarly, 40% urea paste
can be applied under occlusion to soften infected nails.
Among the topical agents, the preferred formulation for cutaneous
application usually is a cream or solution. Ointments are
messy and are too occlusive for macerated or fissured intertriginous
lesions. The use of powders, whether applied by shake containers or
aerosols, is largely confined to the feet and moist lesions of the groin
and other intertriginous areas.
The systemic agents used for the treatment of superficial
mycoses were discussed earlier. Some of these agents also are
administered topically; their uses are described here and also in
Chapter 65.
Imidazoles and Triazoles for Topical Use
These closely related classes of drugs are synthetic antifungal agents
that are used both topically and systemically. Indications for their
topical use include ringworm, tinea versicolor, and mucocutaneous
candidiasis. Resistance to imidazoles or triazoles is very rare among
the fungi that cause ringworm. Selection of one of these agents for
topical use should be based on cost and availability because testing
in vitro for fungal susceptibility to these drugs does not predict clinical
responses.
Cutaneous Application. The preparations for cutaneous use
described below are effective for tinea corporis, tinea pedis, tinea
cruris, tinea versicolor, and cutaneous candidiasis. They should be
applied twice a day for 3-6 weeks. Despite some activity in vitro
against bacteria, this effect is not clinically useful. The cutaneous
formulations are not suitable for oral, vaginal, or ocular use.
Vaginal Application. Vaginal creams, suppositories, and tablets for
vaginal candidiasis are all used once a day for 1-7 days, preferably
at bedtime to facilitate retention. None is useful in trichomoniasis,
despite some activity in vitro. Most vaginal creams are administered
in 5-g amounts. Three vaginal formulations—clotrimazole tablets,
miconazole suppositories, and terconazole cream—come in both
low- and high-dose preparations. A shorter duration of therapy is
recommended for the higher dose of each. These preparations are
administered for 3-7 days. Approximately 3-10% of the vaginal dose
is absorbed. Although some imidazoles are teratogenic in rodents, no
adverse effects on the human fetus have been attributed to the vaginal
use of imidazoles or triazoles. The most common side effect is
vaginal burning or itching. A male sexual partner may experience