Page 871 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 48 Antifungal Agents 857

N
N CH 3 F
Cl N HO
N N
N H
H 2 C C O CH 2 Cl N N N
C F
Cl
Cl
F
Cl
Clotrimazole Miconazole Voriconazole

N
N
N
CH 2 CH 3
O
Cl C O N CH CH 2 CH 3
O CH 2 O N N N
Cl
N
Itraconazole

N
OH N
N
Cl
N N CH 2 C CH 2 N
N
H C Cl N F
2
O O O
CH 2 O N N C CH 3 F

Ketoconazole Fluconazole

FIGURE 48–2 Structural formulas of some antifungal azoles.

(Figure 48–2). The latter two drugs are now used only in topical enzymes (Figure 48–1). The selective toxicity of azole drugs results
therapy. The triazoles include itraconazole, fluconazole, voricon- from their greater affinity for fungal than for human cytochrome
azole, isavuconazole, and posaconazole. Other triazoles are cur- P450 enzymes. Imidazoles exhibit a lesser degree of selectivity
rently under investigation. than the triazoles, accounting for their higher incidence of drug
interactions and adverse effects.
R
Resistance to azoles occurs via multiple mechanisms. Once
N rare, increasing numbers of resistant strains are being reported,
X X = C, imidazole suggesting that increasing use of these agents for prophylaxis and
X = N, triazole
N therapy may be selecting for clinical drug resistance in certain
Azole nucleus settings.
The pharmacology of each of the azoles is unique and accounts Clinical Uses, Adverse Effects, & Drug
for some of the variations in clinical use. Table 48–2 summarizes Interactions
the differences among six of the azoles.
The spectrum of action of azole medications is broad, including
Mechanisms of Action & Resistance many species of Candida, C neoformans, the endemic mycoses
(blastomycosis, coccidioidomycosis, histoplasmosis), the derma-
The antifungal activity of azole drugs results from the reduction tophytes, and, in the case of itraconazole, posaconazole, isavu-
of ergosterol synthesis by inhibition of fungal cytochrome P450 conazole, and voriconazole, even Aspergillus infections. They are