Antifungal Pharmacology Flashcards
what is the primary difference between fungal and mammalian cells
the cell wall and use of ergosterol (instead of cholesterol) to stabilize their cytoplasmic membrane
what is the mechanism of action of allylamines
squalene epoxidase inhibitors that block ergosterol synthesis and cause the buildup of squalene in
the cell which is toxic in fungi
what is terbinafine and its indication
brand: Lamisil
class: Allylamine antifungal
indication: tinea infections
what is the black box warning for terbinafine
severe hepatitis
how do polyene antifungals work
-have a high affinity for sterol containing membranes
-insert themselves into plasma membrane causing the cells to leak (fungicidal)
are polyenes broad spectrum or narrow spectrum
broad spectrum
polyenes have a higher affinity for what membranes which accounts for greater toxicity to fungal cells
membranes containing ergosterol over cholesterol
what are the 4 available formulations for Amphotericin B
-conventional
-colloidal dispersion
-liposomal
-lipid complex
what antifungal is reserved for life-threatening infections
amphotericin B
what is the major concern for amphotericin B and how it manifests
nephrotoxicity manifests as excess urine potassium (kaliuresis) and reduced blood potassium (hypokalemia)
what is the conventional amphotericin B formulation
non-lipid complex with deoxycholate for IV infusion
what is the amphotericin B colloidal dispersion (ABCD) formulation
lipid complex of amphotericin B and cholesterol sulfate that concentrates in the blood and reduces risk of nephrotoxicity
what is the liposomal amphotericin B (LAMB) formulation
bilayer liposome with amphotericin B intercalated within membrane and is less nephrotoxic and causes least severe infusion-related reaction
what is the amphotericin B lipid complex formulation
amphotericin B complexed with two phospholipids that concentrates in tissues
what class is amphotericin B (AMB) and natamycin
polyene antifungal
what is natamycin used to treat
fungal keratitis (eye infection)
what is the mechanism of action of azole antifungals
block C-14a demethylase resulting in accumulation of ergosterol precursors that results in leaky membranes and leads to cell death
what liver CYP enzymes do azole antifungals impair
CYP3A4
what are the systemic azole antifungals
fluconazole
ketoconazole
itraconazole
voriconazole
posaconazole
isavuconazole
what fungus is often resistant to fluconazole
Candida Krusei
which azole has the best CSF penetration making it the preferred for fungal meningitis
fluconazole
which azole has the best oral bioavailability and absorption is not dependent on stomach pH
fluconazole
Fluconazole brand and uses
Brand: diflucan
uses: candidiasis and cryptococcal meningitis
what azole has pH dependent absorption where gastric acids improve the absorption and needs to be administered with acidic drinks
ketoconazole
what causes decreased absorption of ketoconazole in HIV patients
achlorhydria (absent/low stomach acid)
ADR and black box warning for ketoconazole
many drug interactions
BBW for hepatotoxicity
Itraconazole brand and uses
brand: Sporanox
uses: blastomycosis, candidiasis, histoplasmosis
what azole has pH dependent absorption and is recommended to take the capsule with food and acidic drinks and the oral solution on an empty stomach
itraconazole
does the oral solution or capsule of itraconazole have superior bioavailability
oral solution
major contraindication for use of itraconazole
should not be used in patients with congestive heart failure (cardiotoxicity)
voriconazole brand and uses
brand: vfend
uses: aspergillosis, candidiasis (including C. krusei)
what is voriconazole formulated with that may require renal adjustment in patients
cyclodextrin
ADR of voriconazole
visual disturbance
posaconazole brand and uses
brand: noxafil
uses: aspergillosis and candidiasis
which azole is a synthetic analog of itraconazole but more active against yeasts and molds
posaconazole
isavuconazole formulation, brand and uses
formulated as isavuconazonium sulfate (Cresemba) that does not have a cyclodextrin vehicle
uses: aspergillosis and mucormycosis
what is flucytosine and its mechanism
oral prodrug that is selectively converted in fungi to 5-flurouridine monophosphate which inhibits nucleic acid synthesis
why is flucytosine never used alone (always in combo with AMB)
due to rapid development of resistance
uses for flucytosine
candidiasis and cryptococcosis
-high CSF concentration for treating fungal meningitis
ADR and drug interactions of flucytosine
ADR: marrow suppression leading to leukopenia
drug interactions: avoid drugs that can also cause marrow suppression
what is the use for Griseofulvin antifungal
tinea infections only
what are 3 echinocandins and the brands
Caspofungin (cancidas)
micafungin (mycamine)
anidulafungin (eraxis)
coverage of echinocandins
candida including fluconazole resistant c.krusei and c.glabrata
mechanism of action of echinocandins
lipopeptide that inhibit fungal cell wall synthesis and only given IV infusion
3 advantages of echinocandins
-less CYP interactions compared to azoles
-low toxicity
-no renal dose adjustment
2 disadvantages to echinocandins
-do not obtain therapeutic concentrations in eyes, CNS, and urine
-adjust for hepatic disease
