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

bound to plasma proteins. Neither appears in urine or CSF. The t 1/2
of itraconazole at steady state is ~30-40 hours. Steady-state levels
of itraconazole are not reached for 4 days and those of hydroxy-itraconazole
for 7 days; thus, loading doses are recommended when
treating deep mycoses. Severe liver disease will increase itraconazole
plasma concentrations, but azotemia and hemodialysis have no
effect. Itraconazole is not carcinogenic but is teratogenic in rats and
contraindicated for the treatment of onychomycosis during pregnancy
or for women contemplating pregnancy (Category C).
Drug Interactions. Tables 57–4, 57–5, and 57–6 list select interactions
of azoles with other drugs. Many of the interactions can result
in serious toxicity from the companion drug, such as inducing potentially
fatal cardiac arrhythmias when used with quinidine, halofantrine
(an orphan drug used for malaria), levomethadyl (an orphan
drug used for heroin addiction), pimozide (ORAP) or cisapride (only
available under an investigational limited access program in the
U.S.). Other drugs may decrease itraconazole serum levels below
therapeutic concentrations (Table 57–5).
Therapeutic Uses. Itraconazole is the drug of choice for patients
with indolent, nonmeningeal infections due to B. dermatitidis,
H. capsulatum, P. brasiliensis, and C. immitis. The drug also is
useful in the therapy of indolent invasive aspergillosis outside the
CNS, particularly after the infection has been stabilized with
amphotericin B. Approximately half the patients with distal subungual
onychomycosis respond to itraconazole (Evans and
Sigurgeirsson, 1999). Although not an approved use, itraconazole
is a reasonable choice for the treatment of pseudallescheriasis, an
infection not responding to amphotericin B therapy, as well as cutaneous
and extracutaneous sporotrichosis, tinea corporis, and extensive
tinea versicolor. HIV-infected patients with disseminated
histoplasmosis or Penicillium marneffei infections have a decreased
incidence of relapse if given prolonged itraconazole “maintenance”
therapy. According to the 2008 CDC/IDSA guidelines, discontinuation
of itraconazole may be considered in AIDS patients with
disseminated histoplasmosis who have completed 1 year of itraconazole,
have responded to highly active antiretroviral therapy
(HAART) with a CD4 >150/mm 3 for 6 months, have a urine histoplasma
antigen <2 units and a negative blood culture for histoplasma
(Kaplan et al., 2009) (Chapter 59). Itraconazole is not
recommended for maintenance therapy of cryptococcal meningitis
in HIV-infected patients because of a high incidence of relapse.
Long-term therapy has been used in non-HIV–infected patients
with allergic bronchopulmonary aspergillosis to decrease the dose
of glucocorticoids and reduce attacks of acute bronchospasm
(Salez et al., 1999).
Itraconazole solution is effective and approved for use in
oropharyngeal and esophageal candidiasis. Because the solution has
more GI side effects than fluconazole tablets, itraconazole solution
usually is reserved for patients not responding to fluconazole.
Untoward Effects. Adverse effects of itraconazole therapy can occur
as a result of interactions with many other drugs (Tables 57–3 and
57–4). Serious hepatotoxicity has rarely led to hepatic failure and
death. If symptoms of hepatotoxicity occur, the drug should be discontinued
and liver function assessed. Intravenous itraconazole
causes a dose-dependent inotropic effect that can lead to congestive
heart failure in patients with impaired ventricular function. In the
absence of interacting drugs, itraconazole capsules and suspension
are well tolerated at 200 mg daily. Some patients complain of the
taste of the solution, and GI side effects are common, although
adherence is generally unimpaired. Diarrhea, abdominal cramps,
anorexia, and nausea are more common than with the capsules. In
one series of patients receiving 50-400 mg of the capsules per day,
nausea and vomiting were recorded in 10%, hypertriglyceridemia in
9%, hypokalemia in 6%, increased serum aminotransferase in 5%,
rash in 2%, and at least one side effect in 39%. Occasionally, rash
necessitates drug discontinuation, but most adverse effects can be
handled with dose reduction. Profound hypokalemia has been seen
in patients receiving ≥600 mg daily and in those who recently have
received prolonged amphotericin B therapy. Doses of 300 mg twice
daily have led to other side effects, including adrenal insufficiency,
lower limb edema, hypertension, and in at least one case, rhabdomyolysis.
Doses >400 mg per day are not recommended for long-term
use. Anaphylaxis has been observed rarely, as well as severe rash,
including Stevens-Johnson syndrome.
Dosage. In treating deep (life-threatening) mycoses, a loading dose
of 200 mg of itraconazole is administered three times daily for the
first 3 days. After the loading doses, two 100-mg capsules are given
twice daily with food. The divided doses are alleged to increase the
area under the plasma concentration versus time curve (AUC), even
though the t 1/2
is ~30 hours. For maintenance therapy of HIV-infected
patients with disseminated histoplasmosis, 200 mg once daily is
used. Onychomycosis can be treated with either 200 mg once daily
for 12 weeks or for infections isolated to fingernails, two monthly
cycles consisting of 200 mg twice daily for 1 week followed by a
3-week period of no therapy—so-called pulse therapy (Evans and
Sigurgeirsson, 1999). Retention of active drug in the nail keratin permits
intermittent treatment. Daily therapy is preferred by some
authorities for infections likely to be more refractory, but it costs
twice as much as pulse therapy. Once-daily terbinafine (250 mg),
however, is superior to pulse therapy with itraconazole. For oropharyngeal
candidiasis, itraconazole oral solution should be taken fasting
in a dose of 100 mg (10 mL) once daily and swished vigorously
in the mouth before swallowing to optimize any topical effect.
Patients with esophageal thrush unresponsive or refractory to treatment
with fluconazole tablets are given 100 mg of the solution twice
a day for 2-4 weeks.
Fluconazole
Fluconazole is a fluorinated bistriazole.
Absorption, Distribution, and Excretion. Fluconazole is almost completely
absorbed from the GI tract. Plasma concentrations are essentially
the same whether the drug is given orally or intravenously, and its
bioavailability is unaltered by food or gastric acidity. Peak plasma
concentrations are 4-8 μg/mL after repetitive doses of 100 mg. Renal
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CHAPTER 57
ANTIFUNGAL AGENTS