Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

AZOLE ANTIFUNGALS
FLUCYTOSINE
Flucytosine is a synthetic fluorinated pyrimidine antifungal
drug that was first synthesized as a cytosine
analog for use as an antineoplastic compound. It is
classed as a nucleoside analog.
Clinical applications
● When used alone, flucytosine has weak therapeutic
activity and limited clinical application.
● The drug is synergistic with amphotericin B and is
used almost exclusively as an adjunct to
amphotericin B in the treatment of cryptococcosis.
● It is effective against Candida spp but resistance
develops rapidly, making it less than ideal.
Mechanism of action
The activity of flucytosine is attributed to disruption of
protein synthesis by inhibition of RNA synthesis in the
fungal cell. Flucytosine enters fungal cells via cytosine
permease, an enzyme that is lacking in mammalian cells.
Once inside the fungal cell, flucytosine is converted to
5-fluorouracil.
Formulations and dose rates
Flucytosine is administered orally. It is generally administered concurrently
with amphotericin B.
DOGS
• 25–50 mg/kg PO q.6–8 h
CATS
• 25–50 mg/kg PO q.6–8 h
Pharmacokinetics
Flucytosine has high oral bioavailability. It is widely
distributed and crosses the blood–brain barrier. Only
about 2–4% of the drug is bound to plasma proteins.
Absorbed drug is freely filtered via glomerular filtration
and excreted unchanged in the urine. Significant prolongation
of the half-life can be expected in animals with
renal impairment.
Adverse effects
● The most common adverse effects include diarrhea,
anorexia and vomiting.
● Dose-dependent bone marrow suppression
manifesting as neutropenia, thrombocytopenia or
pancytopenia is a less common but more significant
toxicity.
● Hypersensitivity resulting in cutaneous eruption
and rash has been reported.
● In cats, seizures and aberrant behavior have been
noted.
Contraindications and precautions
● Flucytosine is contraindicated in patients with a
known hypersensitivity.
● Extreme care should be used in patients with renal
dysfunction or in patients with pre-existing disease
affecting the bone marrow.
● Flucytosine should not be used in pregnant
animals.
Known drug interactions
Flucytosine has been shown to be synergistic with
amphotericin B, but amphotericin B-associated decreases
in GFR may result in increased toxicity.
AZOLE ANTIFUNGALS
EXAMPLES
The azoles are classified as imidazoles (miconazole,
econazole, clotrimazole and ketoconazole) or triazoles
(fluconazole, itraconazole and voriconazole) according to
whether they contain, respectively, two or three nitrogen
atoms in the five-member azole ring. Ketoconazole and
itraconazole have similar pharmacological profiles but
fluconazole is unique because of its comparatively small
molecular size and low lipophilicity. Voriconazole has a
pharmacological profile that is similar to itraconazole in
some respects but to fluconazole in others.
Clinical applications
The azole class has become the initial treatment of
choice for all but the most rapidly progressing and most
severe systemic fungal infections. A major advantage of
azole therapy has been the ability to treat endemic
mycoses such as histoplasmosis and blastomycosis on
an outpatient basis with oral medication. The azoles act
much more slowly than the polyenes, making them less
useful for severely affected patients or patients with
rapidly progressive systemic mycoses.
Ketoconazole has a more significant effect on host
cholesterol metabolism than the other azole antifungal
agents and has been used (with limited success) as an
inhibitor of corticosteroid biosynthesis in the treatment
of canine hyperadrenocorticism.
Mechanism of action
The azoles are a rapidly expanding class of antifungal
agents that act by inhibiting ergosterol biosynthesis,
thus interfering with fungal cell membrane function by
causing depletion of ergosterol and accumulation of
lanosterol and other 14-methylated sterols (Fig. 9.1).
The azole antifungal agents inhibit cytochrome P450-
dependent 14-sterol demethylase, a cytochrome P450
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