Burkin: Fungal Pharmacology

Question 1

Compare bacteria and fungi in terms of :

Cell size
Ribosomes
Cell wall
Membrane

Answer 1

bacteria are much smaller;
bacteria use 70S vs 80s ribosomes in fungi;
cell wall made of peptidoglycan in bacteria and chitin in fungi;
membrane has no sterols in bacteria and ergosterol in fungi

Question 2

What 4 drug types are used for systemic fungal infections?

Answer 2

polyene antibiotics
imidazole and triazole drugs
flucytosine
pentamidine

Question 3

What antifungal drugs are used for superficial infections?

Answer 3

polyenes
azoles
griseofulvin
naftifine

Question 4

How do polyene antibiotics work?

Answer 4

they are large lipophilic, water insoluble molecules and they dissolve into the cell membranes of fungi, bind to ergosterol in the membrane and increase the permeability to ions and metabolites

Question 5

What is the selectivity like for polyenes?

Answer 5

selectivity is poor, because polyenes bind to sterols in the membrane and human cell membranes also contain sterols

Question 6

What are two polyenes that are usually applied topically?

Answer 6

Nystatin

candicidin

Question 7

What is one polyene that is the drug of choice in most systemic fungal infections, including systemic candidiasis?

Answer 7

Amphotericin B

Question 8

What is candicin used for?

Answer 8

used topically for vaginal candidiasis

Question 9

What are the adverse reactions caused by polyenes?

Answer 9

many ADRs - these drugs are not very selective, so they are quite toxic

**watch out for fever and nephrotoxicity

Question 10

What are the two general categories of antifungal azole drugs?

Answer 10

imidazoles (2 N in a ring)

triazoles (3 N in a ring)

Question 11

What is its mechanism of action of the imidazoles and triazoles?

Answer 11

imidazole; blocks ergosterol synthesis by inhibiting fungal 14-alpha demethylase, a cytoP450

Question 12

Which class of azoles does Ketoconozole belong to? What is it used for?

Answer 12

it is an imidazole; it is used as an alternative (second line due to toxic effects) to amphotericin B for treating systemic fungal infections

Question 13

What is the main toxicity effect you want to look out for with ketoconozole? When should you discontinue ketoconazole?

Answer 13

hepatic toxicity
gynecomastia (inhibits cytoP450s involved in human steroid synthesis;
DISCONTINUE IF HEPATITIS OCCURS

Question 14

Besides ketoconazole, what are two other imidazole antifungals? What are they used for?

Answer 14

miconazole: treatment of dermatophyte infection and vaginal candidiasis
clotrimazole: topical treatment of cutaneous and vaginal infections

Question 15

Imidazole antifungal used for dermatophyte infection and vaginal candidiasis

Answer 15

miconazole

Question 16

Imidazole antifungal used for topical treatment of cutaneous and vaginal infections

Answer 16

clotrimazole

Question 17

What are 3 triazole antifungals?

Answer 17

itraconazole
fluconazole
variconazole

Question 18

Which triazole antifungal is used for several systemic infections, because it has a wider spectrum of activity than ketoconazole and fewer adverse effects?

Answer 18

itraconazole

Question 19

What is fluconazole used for?

Answer 19

cryptococcal meningitis in patients with HIV

Candida in immune compromised patients

Question 20

This is the most frequently prescribed antifungal drug; great for cryptococcal meningitis and candida

Answer 20

fluconazole

Question 21

This is now the drug of choice for several systemic mycoses

Answer 21

itraconazole

**has replaced ketoconazole for treatment of systemic mycoses

Question 22

Name two allylamines

Answer 22

Naftifine *topical

Terbinafine *oral

Question 23

What is the mechanism of action for allylamines?

Answer 23

they inhibit squalene epoxidase –> buildup of intracellular squalene concentration –> decreases ergosterol synthesis

Question 24

What are the allylamines used for clinically (2 things)

Answer 24

dermatophytes

Candida

Question 25

What are the steps going from squalene to ergosterol?

Answer 25

squalene –> squalene epoxide via squalene epoxidase
squalene epoxide –>lanosterol
lanosterol –> ergosterol via 14alpha-demethylase

Question 26

Which step in ergosterol synthesis do Naftifine and Terbinafine block?

Answer 26

squalene epoxidase which takes squalene to squalene epoxide

Question 27

Which step in ergosterol synthesis do the azoles block?

Answer 27

lanosterol –> ergosterol via cytoP450 dependent 14alpha-demethylase

Question 28

How is flucytosine converted to its active form? What is its mechanism of action?

Answer 28

converted to 5-flurouracil by fungal cytosine deaminase; works by blocking DNA and RNA synthesis by blocking thmidylate synthetase

Question 29

What is flucytosine used for?

Answer 29

in combination with amphotericin B to treat systemic crytococcus and candida infections

Question 30

What are some adverse reactions when using flucytosine?

Answer 30

bone marrow depression
GI distress
reversible hepatotoxicity

Question 31

How does pentamidine work?

Answer 31

binds to kinetoplast DNA and inhibits mitochondrial DNA synthesis

Question 32

What is pentamidine used for?

Answer 32

Pneumocystis jiroveci

Also effective against African trypanosomes

Question 33

What is the method of action of griseofulvin?

Answer 33

it binds to tubulin in cells, which is a protein that makes up microtubules - it prevents the proper separation of chromosomes during mitosis and interferes with transport functions of microtubules

Question 34

Where is griseofulvin found in high concentrations?

Answer 34

keratin in skin and hair

Question 35

What is griseofulvin used for clinically?

Answer 35

dermatophyes (fungus that causes skin infection)

*Trichophyton, Epidermophyton and Microsporum

Question 36

When is griseofulvin best absorbed?

Answer 36

when taken with a fatty meal