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

Absorption, Distribution and Excretion. Anidulafungin is cleared
from the body by slow chemical degradation, first by opening the
hexapeptide ring and then proteolysis of peptide bonds (Vazquez and
Sobel, 2006). No metabolism by the liver or renal excretion of active
drug occurs. No dose adjustment for hepatic or renal failure is
needed. The drug diluent for intravenous infusion contains 3 mg
ethanol for every 50 mg anidulafungin, an amount of ethanol insufficient
to have a pharmacological effect.
Drug interactions. None are known.
Therapeutic Use. In a randomized double-blinded clinical trial,
anidulafungin was noninferior to fluconazole in candidemia of nonneutropenic
patients (Reboli et al., 2007). Anidulafungin is also
approved for the treatment of esophageal candidiasis.
Dose. Drug dissolved in the supplied diluent is infused once daily in
saline or 5% dextrose in water at a rate not exceeding 1.1 mg/minute.
For deeply invasive candidiasis, anidulafungin is given daily as a
loading dose of 200 mg followed by 100 mg daily. For esophageal
candidiasis, a loading dose of 100 mg is followed by 50 mg daily.
Griseofulvin
The drug is practically insoluble in water.
Mechanism of Action. Griseofulvin inhibits microtubule function
and thereby disrupts assembly of the mitotic spindle. Thus, a prominent
morphological manifestation of the action of griseofulvin is the
production of multinucleate cells as the drug inhibits fungal mitosis.
Although the effects of the drug are similar to those of colchicine
and the vinca alkaloids, griseofulvin’s binding sites on the microtubular
protein are distinct. In addition to its binding to tubulin, griseofulvin
interacts with microtubule-associated protein.
Absorption, Distribution, and Excretion. The oral administration
of a 0.5 g dose of griseofulvin produces peak plasma concentrations
of ~1 μg/mL in ~4 hours. Blood levels are quite variable, however.
Some studies have shown improved absorption when the drug is
taken with a fatty meal. Because the rates of dissolution and disaggregation
limit the bioavailability of griseofulvin, micro-sized and
ultra-micro-sized powders are now used in preparations (GRIFULVIN
V and GRIS-PEG, respectively). Although the bioavailability of the
ultra-microcrystalline preparation is said to be 50% greater than that
of the conventional micro-sized powder, this may not always be true.
Griseofulvin has a plasma t 1/2
of ~1 day, and ~50% of the oral dose
can be detected in the urine within 5 days, mostly in the form of
metabolites. The primary metabolite is 6-methylgriseofulvin.
Barbiturates decrease griseofulvin absorption from the GI tract.
Griseofulvin is deposited in keratin precursor cells; when
these cells differentiate, the drug is tightly bound to, and persists in,
keratin, providing prolonged resistance to fungal invasion. For this
reason, the new growth of hair or nails is the first to become free of
disease. As the fungus-containing keratin is shed, it is replaced by
normal tissue. Griseofulvin is detectable in the stratum corneum of
the skin within 4-8 hours of oral administration. Sweat and transepidermal
fluid loss play an important role in the transfer of the drug in
the stratum corneum. Only a very small fraction of a dose of the drug
is present in body fluids and tissues.
Antifungal Activity. Griseofulvin is fungistatic in vitro for various
species of the dermatophytes Microsporum, Epidermophyton, and
Trichophyton. The drug has no effect on bacteria or on other fungi.
Although failure of ringworm lesions to improve is not rare, isolates
from these patients usually are still susceptible to griseofulvin in vitro.
Therapeutic Uses. Mycotic disease of the skin, hair, and nails due
to Microsporum, Trichophyton, or Epidermophyton responds to
griseofulvin therapy. For tinea capitis in children, griseofulvin
remains the drug of choice for efficacy, safety, and availability as an
oral suspension; efficacy is best for tinea capitis caused by
Microsporum canis, Microsporum audouinii, Trichophyton schoenleinii,
and Trichophyton verrucosum. Griseofulvin is also effective
for ringworm of the glabrous skin; tinea cruris and tinea corporis
caused by M. canis, Trichophyton rubrum, T. verrucosum, and
Epidermophyton floccosum; and tinea of the hands (T. rubrum and
T. mentagrophytes) and beard (Trichophyton species). Griseofulvin
also is highly effective in tinea pedis, the vesicular form of which is
most commonly due to T. mentagrophytes and the hyperkeratotic
type to T. rubrum. Topical therapy is sufficient for most cases of
tinea pedis. T. rubrum and T. mentagrophytes infections may require
higher-than-conventional doses of griseofulvin.
Dosage. The recommended daily dose of griseofulvin is 2.3 mg/ kg
(up to 500 mg) for children and 500 mg to 1 g for adults. Doses of
1.5-2 g daily may be used for short periods in severe or extensive
infections. Best results are obtained when the daily dose is divided
and given at 6-hour intervals, although the drug often is given once
or twice per day. Treatment must be continued until infected tissue
is replaced by normal hair, skin, or nails, which requires 1 month
for scalp and hair ringworm, 6-9 months for fingernails, and at least
a year for toenails. Itraconazole or terbinafine is much more effective
for onychomycosis.
Untoward Effects. The incidence of serious reactions due to griseofulvin
is very low. One of the minor effects is headache (incidence
as high as 15%), which is sometimes severe and usually disappears
as therapy is continued. Other nervous system manifestations include
peripheral neuritis, lethargy, mental confusion, impairment of performance
of routine tasks, fatigue, syncope, vertigo, blurred vision,
transient macular edema, and augmentation of the effects of alcohol.
Among the side effects involving the alimentary tract are nausea,
vomiting, diarrhea, heartburn, flatulence, dry mouth, and angular
stomatitis. Hepatotoxicity also has been observed. Hematological
effects include leukopenia, neutropenia, punctate basophilia, and
monocytosis; these often disappear despite continued therapy. Blood
studies should be carried out at least once a week during the first
month of treatment or longer. Common renal effects include albuminuria
and cylindruria without evidence of renal insufficiency.
Reactions involving the skin are cold and warm urticaria, photosensitivity,
lichen planus, erythema, erythema multiforme–like rashes,
and vesicular and morbilliform eruptions. Serum sickness syndromes
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CHAPTER 57
ANTIFUNGAL AGENTS