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

1580 excretion accounts for >90% of elimination, and the elimination t 1/2
is
25-30 hours. Fluconazole diffuses readily into body fluids, including
breast milk, sputum, and saliva; concentrations in CSF can reach
50-90% of the simultaneous values in plasma. The dosage interval
should be increased from 24-48 hours with a creatinine clearance
of 21-40 mL/minute and to 72 hours at 10-20 mL/minute. A dose of
100-200 mg should be given after each hemodialysis. About 11-12% of
drug in the plasma is protein bound.
Untoward Effects. Side effects in patients receiving >7 days of drug,
regardless of dose, include the following: nausea 3.7%, headache
1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea
1.5%. Use of high doses may be limited by nausea. Reversible
alopecia may occur with prolonged therapy at 400 mg daily. Rare
cases of deaths due to hepatic failure or Stevens-Johnson syndrome
have been reported. Fluconazole is teratogenic in rodents and has been
associated with skeletal and cardiac deformities in at least three infants
born to two women taking high doses during pregnancy. Fluconazole
is a Category C agent that should be avoided during pregnancy unless
the potential benefit justifies the possible risk to the fetus.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Drug Interactions. Fluconazole is an inhibitor of CYP3A4
and CYP2C9. Fluconazole’s drug–drug interactions are shown in
Tables 57–3 and 57–4. Patients who receive >400 mg daily or
azotemic patients who have elevated fluconazole blood levels may
experience drug interactions not otherwise seen.
Therapeutic Uses. Candidiasis. Fluconazole, 200 mg on the first day
and then 100 mg daily for at least 2 weeks, is effective in oropharyngeal
candidiasis. Doses of 100-200 mg daily have been used to
decrease candiduria in high-risk patients. A single dose of 150 mg is
effective in uncomplicated vaginal candidiasis. A dose of 400 mg daily
decreases the incidence of deep candidiasis in allogeneic bone marrow
transplant recipients and is useful in treating candidemia of nonimmunosuppressed
patients. In patients who have not been receiving fluconazole
prophylaxis, the drug has been used successfully as empirical
treatment of febrile neutropenia in patients not responding to antibacterial
agents and who are not judged to be at high risk of mould infections.
Although response to C. glabrata bloodstream infections in
randomized trials using fluconazole has been comparable to that with
C. albicans, C. glabrata becomes resistant upon prolonged exposure
to fluconazole. Empirical use of fluconazole for suspected candidemia
may not be advisable in patients who have been receiving long-term
fluconazole prophylaxis and may be colonized with azole-resistant
C. glabrata. Based on resistance in vitro, Candida krusei would not be
expected to respond to fluconazole or other azoles.
Cryptococcosis. Following IDSA guidelines (Perfect et al., 2010),
fluconazole, 400 mg daily, is used for the initial 8 weeks in the treatment
of cryptococcal meningitis in patients with AIDS after the patient’s
clinical condition has been stabilized with at least 2 weeks of intravenous
amphotericin B. After 8 weeks in patients no longer symptomatic, the
dose is decreased to 200 mg daily and continued indefinitely. If the
patient has completed 12 months of treatment for cryptococcosis,
responds to HAART, has a CD4 count maintained >200/mm 3 for at least
6 months, and is asymptomatic from cryptococcal meningitis, it is reasonable
to discontinue maintenance fluconazole as long as the CD4
response is maintained. Some would add that an undetectable viral load
for 3 months is required. Fluconazole, 400 mg daily, has been recommended
as continuation therapy in non-AIDS patients with cryptococcal
meningitis who have responded to an initial course of C-AMB or
L-AMB and for patients with pulmonary cryptococcosis.
Other Mycoses. Fluconazole is the drug of choice for treatment of
coccidioidal meningitis because of good penetration into the CSF
and much less morbidity than with intrathecal amphotericin B. In
other forms of coccidioidomycosis, fluconazole is comparable to
itraconazole. Fluconazole has no useful activity against histoplasmosis,
blastomycosis, or sporotrichosis. Fluconazole is not effective
in the prevention or treatment of aspergillosis. Fluconazole has some
activity in ringworm but is not approved for that indication. As with
other azoles, with the possible exception of posaconazole, there is no
activity in mucormycosis.
Dosage. Fluconazole (DIFLUCAN, others) is marketed in the U.S. as
tablets of 50, 100, 150, and 200 mg for oral administration, powder
for oral suspension providing 10 and 40 mg/mL, and intravenous
solutions containing 2 mg/mL in saline and in dextrose solution. The
daily dose of fluconazole should be based on the infecting organism
and the patient’s response to therapy. Generally recommended
dosages are 50-400 mg once daily for either oral or intravenous
administration. A loading dose of twice the daily maintenance dose
is generally administered on the first day of therapy. Prolonged maintenance
therapy may be required to prevent relapse. Children are
treated with 3-12 mg/kg once daily (maximum: 600 mg/day).
Voriconazole
Voriconazole (VFEND) is a triazole with a structure similar to fluconazole
but with increased activity in vitro, an expanded spectrum, and
poor aqueous solubility.
Absorption, Distribution, and Excretion. Oral bioavailability is 96%
and protein binding 56% (Jeu et al., 2003). Volume of distribution is
high (4.6 L/kg), with extensive drug distribution in tissues. Metabolism
occurs through CYP2C19 and to a lesser extent CYP2C9; CYP3A4
plays a limited role. Less than 2% of parent drug is recovered from
urine, although 80% of the inactive metabolites are excreted in the
urine. The oral dose does not have to be adjusted for azotemia or
hemodialysis. Peak plasma concentrations after oral doses of 200 mg
orally twice daily are ~3 μg/mL. CSF concentrations of 1-3 μg/mL
have been reported in a patient with fungal meningitis.
Plasma elimination t 1/2
is 6 hours. Voriconazole exhibits nonlinear
metabolism so that higher doses cause greater-than-linear
increases in systemic drug exposure. Genetic polymorphisms in
CYP2C19 can cause up to 4-fold differences in drug exposure;
15-20% of Asians are homozygous poor metabolizers, compared
with 2% of whites and African Americans. Patients >65 years and
patients with mild or moderate hepatic insufficiency have elevated
areas under the curve (AUCs). Patients with mild-to-moderate cirrhosis
should receive the same loading dose of voriconazole but half