Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

AZOLE ANTIFUNGALS
● Hepatotoxicity is a potentially severe side effect that
is seen most often with ketoconazole and less often
with the triazoles.
● Patients being treated with azole antifungals should
periodically have liver enzymes monitored.
● Hepatotoxicity is rare after the first 2–3 months of
therapy.
● Asymptomatic increases in transaminase activities
are common. They are seen in about half of animals
treated with itraconazole and a smaller number of
animals treated with fluconazole. Increases appear to
correlate well with serum concentrations of the drug.
Asymptomatic increases in transaminase activities
are not usually indicative of clinically significant
hepatotoxicity and thus do not necessitate changes
in therapy unless the animal is also anorectic, vomiting,
depressed, has abdominal pain or other evidence
of hepatic dysfunction. Enzyme concentrations will
often return to normal without dose adjustment or
other intervention.
● Cutaneous reactions are occasionally seen, especially
with itraconazole use. More severe reactions such as
erythema multiforme or toxic epidermal necrolysis
are rare.
● Thrombocytopenia has been associated with ketoconazole
and fluconazole use.
● A unique toxicity to ketoconazole is suppression of
adrenal and testicular steroid production.
● Adrenal insufficiency is possible with ketoconazole
use.
● Voriconazole is well tolerated by most human
patients, but adverse effects that have occasionally
been reported include reversible visual disturbances,
dermatopathies, elevations in liver enzymes and,
rarely, hepatic failure.
Contraindications and precautions
● The azoles (especially ketoconazole) are potentially
teratogenic and should not be used in pregnant
animals without weighing the risk to the fetus against
the severity of the fungal infection.
● Ketoconazole should not be used in thrombocytopenic
patients or in patients with hepatic disease,
whereas the triazoles are not absolutely contraindicated
but should be used with great caution in such
circumstances.
● Midazolam and cisapride should not be used concurrently
with azole antifungals as fatal drug reactions
have been noted in humans.
● Metabolism of a number of drugs may be altered by
azole antifungal therapy (see below).
Known drug interactions
● Azole inhibition of hepatic microsomal enzymes can
lead to increased concentrations of drugs such as
ciclosporin, digoxin, phenytoin, quinidine, sulfonylureas,
midazolam, cisapride and warfarin when these
drugs are coadministered.
● Antacids, H 2 -receptor antagonists and proton-pump
inhibitors may reduce gastric acidity and result in
decreased oral bioavailability of ketoconazole and
itraconazole.
Ketoconazole
Clinical applications
Ketoconazole was the first orally active azole available
commercially and became one of the most frequently
used antifungal agents in veterinary medicine. The poor
selective toxicity of ketoconazole, however, does not
allow high enough doses to be used to adequately treat
many systemic fungal infections. Efficacy is generally
less than that seen with the polyene antifungals or the
triazoles. Ketoconazole is generally less expensive than
the triazole antifungal agents. However, this can be
misleading when treating systemic fungal infections
because longer treatment courses, lower efficacy and
increased likelihood of relapse often result in substantially
higher total costs for therapy over time compared
to itraconazole or fluconazole. Ketoconazole has been
effective as a sole therapeutic agent in the management
of blastomycosis, histoplasmosis, cryptococcosis and
coccidioidomycosis. However, with the possible exception
of coccidioidomycosis, ketoconazole is probably
not as effective for these infections as amphotericin B.
Ketoconazole can be used in conjunction with amphotericin
B when managing systemic infections, allowing
lower doses of amphotericin B to be used and thus limiting
nephrotoxicity.
Formulations and dose rates
DOGS
• 5–20 mg/kg PO q.12 h
• The higher doses are often needed to treat systemic fungal
infections, especially if CNS involvement is suspected. The
lower doses are often adequate for treating coccidioidomycosis
CATS
• 5–10 mg/kg PO q.12 h
• Higher doses are often needed but are rarely tolerated.
Itraconazole
Clinical applications
Itraconazole is more effective than ketoconazole and
can be used as a sole agent in the management of most
systemic mycoses. Itraconazole appears to be more
effective than fluconazole in most situations and is the
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