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What is the mechanism of action for amphotericin B?
preferentially binds to ergosterol -> forms pores/channels -> K+ and Mg2+ leaks out of the cell

(toxic b/c it does have some effect on cholesterol)
How much is amphotericin B absorbed from the GI tract?
almost none

administered IV
Does amphotericin penetrate into the CNS?
no

very polar -> reason why it's administered IV
Where is amphotericin distributed in the body?
binds to cholesterol-containing membranes

mainly in liver
small amounts in urine

(very litte enters CNS, vitreous humor, amniotic fluid)
What is the advantage of liposomal amphotericin B?
less binding to human cell membranes -> less toxicity -> permits higher doses

vesicles serve as an amphotericin B reservoir

some fungi contain lipases -> liberate at site of action
What are the differences between the older and newer (lipid) formulations of amphotericin B?
newer forumlations
-extensively cleared from the blood
-accumulate in liver, spleen, lymph nodes, lungs (major sites of fungal infections)
-much more expensive
What are the adverse effects of amphotericin B?
infusion related - fever, chills, headache, anorexia, nausea, vomiting
(stop by reducing the infusion rate; premedicate w/ antipyretics, antihistamines, corticosteroids)

nephrotoxicity (limits amt. of drug given) -> hypokalemia
liver failure

hypomagnesemia and renal tubular acidosis

anemia due to decreased erythopoietin production

has affinity for digitalis (can't use in pts. using digitalis)
Why is amphotericin given with Na deoxycholate?
b/c of poor solubility

Na deoxycholate helps improve its solubility
At what pH is amphoticin B soluable?
acidic pH

not soluable at physiological pH
What is deoxycholate?
steroid detergent
forms suspention w/ amphotericin B -> keeps it in solution
What is flucytosine active against?
cryptococcus neoformans
cocciodial meningitis
some Candidia sp.

(not active against aspergillus)
What is flucytosine not active against?
aspergillis
How is amphotericin B synergistic with flucytosine?
makes fungal membrane more leaky -> more 5-FU can get in
How does flucytosine get into cells?
via permease (not present in mamallian cells)

fungi lacking permease are resitant
(however, if combine w/ AMB, 5-FU does work)
What is the mechanism of action for flucytosine?
deaminated to 5-fluorouracil, an antimetabolite -> inhibits thymidylate synthase, early termination of fungal RNA
(mammalian cells do not do this)

toxic effects occur from host cell or bacteria in the gut converting 5-FC -> 5-FU
How is flucytosine administered?
PO
What is the volume of distribution of flucytosine?
about equal to total body water
Does flucytosine penetrate into the CNS?
yes

present in CNS and aqueous humor
Is flucytosine bound to plasma proteins?
no
What are the adverse effects of flucytosine?
bone marrow suppression
rash
nausea
vomiting
diarrhea
hepatic dysfunction
What is flucytosine predominantly used in combination with?
amphotericin B

or

itraconazole
What is caspofungin acetate used for?
invasive aspergillosis
(but usually only after trying AMB or itraconazole)

mainly used as an alternative in pts. who have failed to respond to AMB
What is the mechanism of action for caspofungin?
disrupts fungal cell wall glucan formation via non-competitive inhibition of 1-3-beta-glucan synthase

fungicidal

(no 1-3-beta-glucan synthase in humans)
What fungi is resistant to caspofungin?
cryptococcus neoformans
Is caspofungin bound to plasma proteins
yes

~97% bound to albumin
How is caspofungin excreted?
broken down into constitutive amino acids and metabolites (N-acetyl-dihydroxyhomotyrosine and dihydroxyhomotyrosine) and excreted in urine and GI tract

reduce dosage in pts. w/ hepatic insufficiency
What are the adverse reactions of caspofungins?
few reported so far

infusion rxns: phlebitis, headache
What is the mechanism of action for azols?
impairs biosynthesis of ergosterol

inhibits sterol 14-alpha-demethylase, a microsomal CYP450 dependent enzyme system -> inhibits conversion of lanosterol -> ergosterol

(fungi requires ergosterols in membrane, otherwise gets leaky and cells die)
What fungi are susceptable to ketoconazol
blastomycosis
coccidioidomycosis
histoplasmosis
paracoccidioidomycosis
candidia

(not active against aspergillus and mucor)
What fungi are resistant to ketoconazol
aspergillus
mucor
What azols are more readily absorbed with a decrease in pH?
ketoconazole
itraconazole

(drink coca-cola to increase absorption)
Where is ketoconazole metabolized?
primarily in the liver -> excretes in feces
Is ketoconazole bound to plasma proteins?
yes - 90%
What are the adverse effects of ketoconazole?
nausea, anorexia, vomiting
(b/c also inhibits steroid synthesis in pts.)

gynecomastia, menstral irregularities, decreased libido - due to depressed testosterone and estradiol
(used to suppress testosterone synthesis in prostate cancer)

hypertension and fluid retention - assoc. w/ elevated deoxycorticosterone and corticosterone

hepatitis

contraindicated in pregnancy - enters milk

inhibits CYP450 (CYP3A4) -> potentiate toxicities of cyclosporin, phenytoin, H1-histamine antagonists
What is fluconazole active against?
cdandidia
cryptococus
What is fluconazol used for?
oral and esophageal candidiasis and cryptococcal meningitis in AIDS pts

vulvovaginal candidiasis

prophylactic for bone marrow transplant pts.
Which azol interferes with CYP3A4 the most?
ketoconizole
What is the advantage of fluconazole over ketoconzaole?
completely absorbed from GI tract (water soluable)

bioavailability not altered by food or gastric activity

can be given IV

well tolerated

poorly metabolized

no endocrinologic effects
What are the triazole drugs?
fluconazole
itraconazole
voriconazole
terconazole
tri = FIVe - Two
What is itraconazole used for?
treatment of histoplasmosis and blastomycosis

esophageal or vaginal candidiasis

dermatophyte infections of the toenails
Which is higher for itraconazole?

tissue concentration or plasma concentration
tissue concentration
Does itraconazole penetrate into the CSF?
no
How is itraconazole eliminated?
inactivated in the liver
(drugs that induce hepatic drug-metabolism accelerate metabolism of itraconazole)

inactive metabolites excreted in the urine
What is itraconazole active against?
aspergillus
histoplasma
blastocyces
sporothrix
What are the adverse effects of voriconazole?
rash
elevated hepatic enzymes
transient visual disturbances
What is vericonazole used for?
FDA approved use: aspergillis

candidia

fluconazole-resistant species: C. krusei, dimorphic fungi
What is grisofulvin used for?
superficial fungal infections
(largely replaced by itraconazole and terbinafine)

only effective against dermatophytes microsporum, epidermophyton, trichophyton

not active against candidia and aspergillus
What is the mechanism of action of griseofulvin?
inhibits fungal mitosis

disrupts the mitotic spindle by interacting w/ polymerized microtubules
How does griseofulvin enter cells?
via an energy-dependent transport system
How do you increase the oral absorption of griseofulvin?
take with a fatty meal
(due to its insolubility)

microsized or ultramicrosized powders
Where does griseofulvin deposit?
keratin precursor cells
(tightly bound to keratin)
What is the first area to become free of disease after griseofulvin treatment?
new growth of hair or nails
What are the adverse effects of griesofulvin?
headache, lethargy, mental confusion, fatigue, vertigo, blurred vision (augmented w/ alcohol)

GI tract, vomiting, diarrhea, heartburn, flatulence, dry mouth

contraindicated in pregnancy (teratogenic in animals)
What are the topical applications for the azol drugs?
tinea corporis
tinia pedis
tinea cruris
tinea versicolor
cutaneous candidiasis
What are thea adverse effects of clotrimazole?
stinging on skin
mild burning in vagina
What are the adverse effects of micronazole?
burning, itching, irritation when applied to vagina
How is micronazole administered?
mainly topically

IV for systemic infections (meningitis), however very toxic
What is ciclopirox olamine used for?
dermatophytes

penetrates through epidermis to dermis

penetrates hair follicles and sebaceous glands
What is haloprogin active against?
epidermophyton
pityrosporum
microsporum
trichophyton
candidia
What are the adverse effects of haloprogin?
irritation
pruritus
burning sensation on foot
What is haloprogin primarily used for?
tinea pedis
tinea cruris
What fungus is tolnaftate inactive against?
candidia
What is tolnaftate effective against?
cutaneous mycoses caused by trichophyton sp. and microsporum sp.
What is the mechanism of action for tolnaftate?
inhibits squalene 2,3-epoxidase -> inhibition of ergosterol synthesis
What is the mechanism of action of naftifine?
inhibits squalene 2,3-epoxidase -> inhibits ergosterol synthesis
What is the mechanism of action of terbinafine?
inhibits squalene 2,3-epoxidase -> inhibits ergosterol synthesis
Which is also available for oral use in the treatment of fungal nail infections?

naftifine, terbinafine, or butenafine
terbinafine
What is nystatin only used against?
candidiasis
How is nystatin administered?
oral only

too toxic for IV administration (more toxic than AMB)
What is natamycin used for?
fungal feratitis Fusarium Solani

also active against aspergillus, candidia, and penicillium
What is undecyclenic acid composed of?
calcium and zinc salts
What might prevent patients from using undecylenic acid?
rancid odor
What is undecylenic acid used for?
retards fungal growth in tinea pedis

approved for use in treatment of diaper rash and tinea cruris
What is benzoid acid and salicylic acid used for?
tinea pedis
What is potassium iodide used for?
cutaneous sporotrichosis
What antifungals are thiocarbamates?
naftifine
terbinafine
butenafine
tolnaftate

inhibit squalene-2,3-epoxidase -> inhibits mycolic acid synthesis
What antifungals are azoles?
imidazoles: clotrimazole, miconazole, ketoconazole, econazole, butoconazole, oxiconazole, sulconazole

triazole: fluconazole, itraconazole, voriconazole, terconazole

inhibits sterol 14-alpha-demethylase -> inhibits the conversion of lanosterol to ergosterol
Which antifungals bind ergosterol?
amphotericin B
nystatin
natamycin
What is the DOC for aspergillus aspergilliosis?
amphotericin

alt: itraconazole, caspofungin
What is the DOC for blastomyces blastomycosis?
itraconazole

alt: ketoconazole