Antifungals

Question 1

what is the mechanism of amphotericin B?

Answer 1

binds ergosterol and forms pores in the fungal cell membrane

Question 2

why is amphotericin B selective for fungi?

Answer 2

because it selectively binds ergosterol instead of cholesterol…ergosterol only in fungi

Question 3

what are the two mechanisms of resistance that amphotericin B can develop?

Answer 3

reduced concentration of ergosterol in membrane

modification of ergosterol leads to less amphotericin B binding

Question 4

how is amphotericin B administered?

Answer 4

IV

Question 5

what must you do to amphotericin B for administration since it is a lipid?

Answer 5

it is combined with many other lipids to make it soluble…this hikes the cost up

Question 6

what is the immediate toxicity with amphotericin B? Who suffers from this?

Answer 6

everyone suffers from fevers chills muscles spasms hypotension nausea headache dizziness

but these symptoms abate in 30-45 minutes

Question 7

what is a toxicity of amphotericin B due to its clearance?

Answer 7

direct damage to the DCT…renal clearance causes the nephrotoxicity

Question 8

what is the safest antifungal drug during pregnancy?

Answer 8

amphotericin B

Question 9

what is the mechanism of azole antifungals

Answer 9

they target lanosterol demethylase and inhibit synthesis of ergosterol

Question 10

what is lanosterol demthylase important for?

Answer 10

it is required for the last step in the synthesis of ergosterol in fungi

Question 11

what is a cardiac toxicity associated with azoles?

Answer 11

prolonged QT intervals

Question 12

should you give azoles during pregnancy?

Answer 12

No class D, bad but in certain situations may be needed

Question 13

what do azoles interact with that causes other drug toxicities?

Answer 13

they inhibit Cytochrome P450 families

Question 14

what does ketoconazole also do by inhibiting CYP?

Answer 14

some CYPs are used in synthesis of steroid hormones…so it can inhibit these processes

Question 15

due to the inhibition of steroid hormone production by ketoconazole, what is a toxicity and why?

Answer 15

gynecomastia because androgen synthesis is inhibited

Question 16

what is PJP naturally resistant to?

Answer 16

all antifungals

Question 17

what are the two ways PJP has natural resistance to antifungals?

Answer 17

it picks up cholesterol from host and uses that instead of ergosterol

lanesterol demethylase has natural occurring mutations that make it safe from azoles

Question 18

what is the mechanism of SMX/TMP?

Answer 18

SMX inhibits pteroate synthase and TMP inhibits DHFR

both of these have to do with folate synthesis

Question 19

can you use SMX and TMP during pregnancy?

Answer 19

yes you can

Question 20

what are the three toxicities with trimethoprim?

Answer 20

megaloblastic anemia
leukopenia
granulocytopenia

Question 21

what enzyme does sulfonamides inhibit?

Answer 21

pteroate synthase

Question 22

what enzyme does trimethoprim inhibit?

Answer 22

DHFR

Question 23

what are the two mechanisms of resistance that SMR/TMX have?

Answer 23

mutations in the target enzymes

overproduction of precursors in synthesis of folate

Question 24

what are the three cytochromes that azoles inhibit?

Answer 24

CYP3A4
CYP2C9
CYP2C19

Question 25

azoles inhibit CYPs…what important drug class do azoles inhibit the metabolism of that is extremely risky?

Answer 25

HIV drugs…if they get off balanced with dose then they can have serious side effects

Question 26

what classes of antifungals are used for blastomyces, histoplasma, coccidioides?

Answer 26

azoles and amphotericin B

Question 27

what drug do you use to treat PJP?

Answer 27

sulfamethoxazole and trimethoprim