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50 Cards in this Set

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What is the mechanism of Amphotericin B?
Formation of a pore in the fungal membrane by binding to ergosterol

FUNGICIDAL
What is the mechanism of resistance to Amphotericin B?
Rare

When it does happen, it's due to the alteration in membrane ergosterol
What is the absorption of Amphotericin B?
None in the GI tract

Administered via IV
What is the distribution of Amphotericin B?
Widely distributed

Sequestered into cell membranes (think logically here: sterols in human membranes. Side effects, long distribution)

Poor CSF penetrance
What is the metabolism and half life of Amphotericin B?
Terminal half life of 15 days
What is the excretion of Amphotericin B?
2-5% excreted unchanged in the urine after IV dose.
What are the adverse effects of Amphotericin B?
Fever within an hour

NEPHROTOXICITY

Anemia
What formulation of Amphotericin B decreases nephrotoxicity?
Lipid formulation
What is the mechanism of nephrotoxicity with Amphotericin B?
Binding to the sterols inside kidney cell membranes, increasing perameability
What are the clinical uses of Amphotericin B?
Broad spectrum antifungal
IV administration for severe fungal infections
What other antifungal drug is Amphotericin B commonly administered with?
Flucytosine
What other antifungal drug is Flucytosine commonly administered with?
Amphotericin B
What enzyme is necessary for the activation of 5-Flucytosine? Where is it found?
Cytosine deaminase

Inside fungi
What is the active form of 5-Flucytosine? What kind of drug is this normally?
5-Fluorouracil

A chemotherapeutic
What is the mechanism of action of 5-Flucytosine?
Inhibition of DNA synthesis through blocking of thymadylate synthase
In what situations does resistance to 5-Flucytosine develop?
When the drug is used alone.
What are the mechanisms of resistance to 5-Flucytosine?
Decreased uptake of the drug through alterations of membrane transporters

Decreased activation of the drug by cytosine deaminase
What is the bioavailability of 5-Flucytosine?
Very available orally
What is the distribution of 5-Flucytosine?
Widely distributed

PENETRATES THE CSF WELL!
What are antifungal drugs that can penetrate the CSF?
5-Flucytosine
Fluconizole
What is the metabolism and half life of 5-Flucytosine?
Needs to be metabolized to 5-florouracil by cytosine deaminase for activity

T1/2 = 3-6 hr.
What is the excretion of 5-Flucytosine?
80% excreted unchanged in urine
What are the adverse effects of 5-Flucytosine?
Bone marrow toxicity
Elevation of hepatic enzymes
GI irritation

All of these are more prevalent in AIDS patients
What is the mechanism of bone marrow toxicity by 5-Flucytosine?
Conversion of 5-Flucytosine to 5-Fluorouracil by GI flora
What is the typical clinical use of 5-Flucytosine + Amphotericin B?
Severe Cryptococcus infections
What is the mechanism of action by Azole antifungals.
Inhibition of lanosterol 14-alpha-demethylase

Can't convert lanosterol to ergosterol

FungiSTATIC
Are the Azoles highly selective for fungal enzymes?
No...not too terribly selective.

IC50 is only 10X greater in humans.
What are the mechanisms of resistance to the Azole antifungals?
Decreased accumulation of azole due to increased efflux by ATP binding cassette proteins

Decreased affinity of lanosterol-14alpha-demethylase for the azole

Overepxression of lanosterol-14alpha-demhtylase
What are the four Azole antifungals?
Fluconazole
Itraconazole
Voriconazole
Posaconazole
What is the Azole antifungal that penetrates the CSF?
Fluconazole
What is the Azole antifungal that is metabolized in a short period of time?
Voriconazole

6 hrs.
What are the two Azole antifungals that are excreted in the bile?
Itraconazole
Posaconazole
What is the Azole antifungal that is excreted renally and penetrates the CSF?
Fluconazole
What is the absorption of Azole antifungals?
Orally bioavailable
What are the adverse effects of Azole antifungals?
GI disturbances
Hepatotoxicity
Teratogenic to fetuses: DON'T USE IN PREGNANCY!
What is the Azole antifungal that causes visual disturbances?
Voriconazole

See funny colored lights
What liver enzyme does the Azole antifungals effect? What is the effect?
CYP3A4, a hepatic P450 enzyme. Inhibition
What enzyme metabolizes the Azole antifungals?
CYP3A4
What is an example of a drug that can decrease the plasma levels of Azole antifungals? How?
Rifampin

The induction of P450s.
What are the clinical uses of Azole antifungals?
Broad spectrum activity
What is a unique uses of Fluconazole?
Coccidioidal meningitis
What is safer for patients, Voriconazole or Amphotericin B?
Voriconazole.

Less fever, less nephrotoxicity.
What is an example of a echinocandin?
Caspofungin
Caspofungin is a member of what antifungal drug class?
Echinocandins
What is the mechanism of action of the echinocandins?
Inhibition of the synthesis of Beta-1,3-D-glucan

Fungicidal
What is the absorption of Caspofungin?
Not orally absorbed

IV administration
What is the distribution of Caspofungin?
Well distributed

DOESN'T PENETRATE THE CSF!
What is the metabolism and half life of Caspofungin?
Extensive metabolism

Long terminal half life: 40-50 hr.
What are the adverse effects of Caspofungin?
Flushing
Fever
Infusion-related phlebitis
Headache
Elevation of liver enzymes
What are the clinical uses of Caspofungin?
Candida infections, especially candida galbrata, which is resistant to the azole antifungals.

Invasive aspergillosis