Antifungals Flashcards
what is the mechanism of amphotericin B?
binds ergosterol and forms pores in the fungal cell membrane
why is amphotericin B selective for fungi?
because it selectively binds ergosterol instead of cholesterol…ergosterol only in fungi
what are the two mechanisms of resistance that amphotericin B can develop?
reduced concentration of ergosterol in membrane
modification of ergosterol leads to less amphotericin B binding
how is amphotericin B administered?
IV
what must you do to amphotericin B for administration since it is a lipid?
it is combined with many other lipids to make it soluble…this hikes the cost up
what is the immediate toxicity with amphotericin B? Who suffers from this?
everyone suffers from fevers chills muscles spasms hypotension nausea headache dizziness
but these symptoms abate in 30-45 minutes
what is a toxicity of amphotericin B due to its clearance?
direct damage to the DCT…renal clearance causes the nephrotoxicity
what is the safest antifungal drug during pregnancy?
amphotericin B
what is the mechanism of azole antifungals
they target lanosterol demethylase and inhibit synthesis of ergosterol
what is lanosterol demthylase important for?
it is required for the last step in the synthesis of ergosterol in fungi
what is a cardiac toxicity associated with azoles?
prolonged QT intervals
should you give azoles during pregnancy?
No class D, bad but in certain situations may be needed
what do azoles interact with that causes other drug toxicities?
they inhibit Cytochrome P450 families
what does ketoconazole also do by inhibiting CYP?
some CYPs are used in synthesis of steroid hormones…so it can inhibit these processes
due to the inhibition of steroid hormone production by ketoconazole, what is a toxicity and why?
gynecomastia because androgen synthesis is inhibited
what is PJP naturally resistant to?
all antifungals
what are the two ways PJP has natural resistance to antifungals?
it picks up cholesterol from host and uses that instead of ergosterol
lanesterol demethylase has natural occurring mutations that make it safe from azoles
what is the mechanism of SMX/TMP?
SMX inhibits pteroate synthase and TMP inhibits DHFR
both of these have to do with folate synthesis
can you use SMX and TMP during pregnancy?
yes you can
what are the three toxicities with trimethoprim?
megaloblastic anemia
leukopenia
granulocytopenia
what enzyme does sulfonamides inhibit?
pteroate synthase
what enzyme does trimethoprim inhibit?
DHFR
what are the two mechanisms of resistance that SMR/TMX have?
mutations in the target enzymes
overproduction of precursors in synthesis of folate
what are the three cytochromes that azoles inhibit?
CYP3A4
CYP2C9
CYP2C19
azoles inhibit CYPs…what important drug class do azoles inhibit the metabolism of that is extremely risky?
HIV drugs…if they get off balanced with dose then they can have serious side effects
what classes of antifungals are used for blastomyces, histoplasma, coccidioides?
azoles and amphotericin B
what drug do you use to treat PJP?
sulfamethoxazole and trimethoprim
