A Textbook of Clinical Pharmacology and Therapeutics

342 FUNGAL AND NON-HIV VIRAL INFECTIONS
Ketoconazole was the first imidazole to be used therapeutically
but it has been superseded by newer group members
because of its hepatotoxicity, its incomplete specificity (it
inhibits testosterone and cortisol synthesis) and because it
interacts adversely with many drugs. It is still used to treat
metastatic prostate cancer and adrenocortical carcinoma (see
Chapter 48).
The use and properties of more commonly used imidazoles
are listed in Table 45.2.
TRIAZOLES
This group of drugs (e.g. fluconazole, itraconazole and
voriconazole) is derived from the imidazoles. Triazole drugs
work by the same mechanism as imidazoles but have a wider
antifungal spectrum and are more specific for fungal CYP450.
FLUCONAZOLE
Uses
Fluconazole is a potent and broad-spectrum antifungal agent.
It is active against many Candida species, Cryptococcus neoformans
and Histoplasma capsulatum. However, Aspergillus species
are resistant and resistant Candida species are problematic in
immunocompromised patients. Fluconazole is used clinically
to treat superficial Candida infections and oesophageal Candida,
for the acute therapy of disseminated Candida, systemic therapy
for blastomycosis and histoplasmosis, for dermatophytic fungal
infections and, in low doses, for prophylaxis in neutropenic
and immunocompromised patients. It is administered orally or
intravenously as a once daily dose.
Adverse effects
Adverse effects include:
• nausea, abdominal distension, diarrhoea and flatulence;
• rashes, including erythema multiforme;
• hepatitis (rarely, hepatic failure).
Table 45.2: Properties of other commonly used imidazoles
Contraindications
Fluconazole is contraindicated in pregnancy because of fetal
defects in rodents and humans. Breast milk concentrations are
similar to those in plasma and fluconazole should not be used
by nursing mothers.
Pharmacokinetics
Fluconazole is well absorbed after oral administration and is
widely distributed throughout the body. CSF concentrations
reach 50–80% of those in the plasma. About 80% is excreted by
the kidney and dose reduction is required in renal failure. The
fluconazole mean elimination t1/2 is 30 hours in patients with
normal renal function. Fluconazole is a weaker inhibitor than
ketoconazole of human CYP3A.
Drug interactions
Fluconazole reduces the metabolism of several drugs by
inhibiting CYP3A, including benzodiazepines, calcium channel
blockers, ciclosporin, docetaxel and, importantly, warfarin.
The plasma concentrations and toxicity of these drugs
will increase during concomitant treatment with fluconazole.
Rifampicin enhances the metabolism of fluconazole.
ITRACONAZOLE AND VORICONAZOLE
Itraconazole and voriconazole are available as oral and parenteral
formulations. Oral bioavailability is good for both
agents, but intravenous use is indicated for severe fungal infections.
The antifungal spectrum is similar to that of fluconazole
and is broad. They are fungicidal at high concentrations. Both
are metabolized by hepatic CYP450s and are inhibitors of
hepatic CYP450s. The mean itraconazole t1/2 is 30–40 hours and
that for voriconazole is six hours. For intraconazole, once daily
Druga Use (other specific
comments)
Standard formulation Side effects Pharmacokinetics
Clotrimazole Topical therapy for 1% cream or powder Local irritation Poorly absorbed
dermatophytes and not used from gastro-intestinal
systemically for Candida tract. Induces its own
infections metabolism
Miconazole Oral Candida (topical therapy for Oral gel, four times daily Nausea and Systemic absorption is
ringworm, Candida and pityriasis 2% cream or powder vomiting, rashes. very poor, undergoes
applied twice daily Local irritation extensive hepatic
metabolism
Tiaconazole Topical treatment for nail Apply 28% solution to Minor local irritation Systemic absorption is
infections with dermatophytes nails and local skin twice negligible
and yeasts daily for 6 months
a Other drugs in this group that are used topically include butoconazole, econazole, fenticonazole, isoconazole and sulconazole (see also Chapter 50).