L10 - Pyrimidine & Polyenes

Question 1

What is only pyrimidine drug?

Answer 1

5-fluorocytosine

a.k.a. Flucytosine

Question 2

How is flucytosine converted to 5-fluorouracil (5-FU)?

Answer 2

CYTOSINE deaminase (fungi/bacteria ONLY)

Question 3

How is flucytosine specific?

Answer 3

5-FU not taken up into mammalian cells

Question 4

What are the outcomes for the 2 pathways of 5-FU

Answer 4

disrupt translation

inhibits DNA synthesis

Question 5

How does 5-FC disrupt translation?

Answer 5

5-FC > FUMP > FUTP > incorporated into RNA

Question 6

How does 5-FC inhibit DNA synthesis?

Answer 6

F-FU > FdUMP > inhibit thymidylate synthetase

Question 7

What is 5-FC active against?

Answer 7

C. neoformans

most Candida

some brown moulds

Question 8

What is 5-FC inactive against?

Answer 8

C. Krusei

Aspergillus

Histoplasma capsulatum

MOST MOULDS

Question 9

What is the formulation of 5-FC?

Answer 9

IV

Oral

Question 10

What fungal species develop resistance to 5-FC?

Answer 10

candida

cryptococcus

Question 11

What is used in combination therapy with 5-FC?

Answer 11

Amphotericin B

Fluconazole

Question 12

What is 5-FC mainly used for?

Answer 12

Cryptococcal Meningitis (with Amphotericin B)

Question 13

Facts about Pharmacokinetics of 5-FC?

Answer 13

water soluble

not metabolised by gut flora

half life 3-6h

repeat dose 3-4 times/day

excreted in urine

Question 14

What happens if serum 5-FC level is high for 2 weeks?

Answer 14

Leucopenia

Thrombocytopenia

Aplastic anaemia

Question 15

Other side effects of 5-FC?

Answer 15

rare allergies

liver toxicity

Question 16

What are drug interactions with 5-FC?

Answer 16

Brivudine - inhibits DPD which usually degrades fluorouracil

Fluoruracil - higher phenytion (anti-epileptic) levels

Question 17

what are the 3 main places where mechanisms of resistance occur to 5-FC?

Answer 17

Cytosine permease

Cytosine deaminase

(MAINLY) - Uracil Phospho-ribosyl transferase

Question 18

What are the 2 types of polyene antifungals?

Answer 18

Nystatin

Amphotericin B

Question 19

What is the hydrophobicity of polyenes?

Answer 19

AMPHIPATHIC

Question 20

How do polyenes work?

Answer 20

increase cell permeability

bind ergosterol

macrolide rings - hydrophobic sides - distort membrane layers

OXIDATIVE DAMAGE

Question 21

What is the spectrum of activity of Amphotericin B?

Answer 21

• broad
• most yeast/ moulds sensitive
• A. terreus, Scedosporium, Lomentospora = resistant

Question 22

What is the spectrum of activity of Nystatin?

Answer 22

most yeasts sensitive

Question 23

Formulations of Amphotericin B?

Answer 23

Amphotericin B deoxycholate (CONVENTIONAL)

Lipid formulations - AMBISOME, Abelcet

Question 24

Formulations of Nystatin?

Answer 24

topical
not absorbed orally
too toxic for IV

Question 25

What is Amphotericin B used to treat?

Answer 25

empirical treatment - fungal infections used topically

Question 26

What is Nystatin used for?

Answer 26

oral/vaginal candidosis

Question 27

How can amphotericin B help antibiotics resistant fever?

Answer 27

fever may be due to infection being fungal NOT bacterial

Question 28

Is ambisome better than voriconazole?

Answer 28

slightly

Question 29

Is ambisome better than caspofungin?

Answer 29

same

Question 30

Is Amphotericin B better at treating Invasive aspergillosis than voriconazole?

Answer 30

NO | voriconazole is better

Question 31

The pharmacokinetics of ambisome?

Answer 31

IV daily dose good tissue distribution 24hr half life - longer later

Question 32

adverse effects of amphotericin B?

Answer 32

``` fever* chills* nausea vomit* headaches hypotension* ``` hypokalemia ^creatine in serum*

Question 33

Drug interactions with amphotericin B?

Answer 33

nephrotoxicity - ciclosporin, anti-neoplastic agents hypokalemia - corticosteroids, diuretics muscle relaxants bone marrow suppression from ambisome induced nephrotoxicity - Flucytosine

Question 34

What fungi are resistant to Amphotericin B?

Answer 34

A. terreus (ALWAYS) fusarium Scedosporium Lomentospora

Question 35

mechanisms of resistance to amphotericin B?

Answer 35

mutated EGR genes - ergosterol synthesis - less ergosterol = more resistant increased catalase = reduce oxidative damage by drug

Question 36

What is candida auris?

Answer 36

biofilms on skin 30% resistant to AmpB