Week 11 - Antifungal Drugs

Question 1

What types of fungal infections/Mycoses are there?

Answer 1

• superficial (e.g. Scalp, mucous membranes)

- systemic (internal organs - kidneys, lung and brain, fatal in severely immunocompromised patients)

Question 2

What are fungal pathogens and what category of pathogens do they belong too?

Answer 2

Eukaryotes

• commensal
• environmental

-category of opportunistic infections

Question 3

What are the most common opportunistic fungal pathogens?

Answer 3

• Candida albicans (commensal)
• aspergillus fumigatus (environmental)
• cryptococcus neoformans (environmental)

Question 4

What puts patients at a higher risk of developing fungal infections?

Answer 4

Impaired immune system
-HIV, organ transplantation, a course of long term broad-spectrum abx, premature birth, cancer, hospitalisation in ICU

Menstrual cycle in women

Question 5

What do anti-fungal drugs target?

Answer 5

Fungal-specific processes/structures

Question 6

How are fungal cells structured?

Answer 6

Fungal cells have:

• cell wall
• plasma membrane
• nucleus -DNA and RNA synthesis

Question 7

What is the difference between fungal and human cells?

Answer 7

They have a cell wall

• crucial for survival of the cell
• complex structure and composition
• no equivalent organelle in human cells

-ideal target for antifungals

Question 8

What does a fungal cell wall have and what is it made up of?

Answer 8

• skeletal components
• matrix components

-glucan (55-60%) of the cell wall
(two types of polymers of D-glucose - B1,6 glucan and B1,3 glucan)

• mannan (35-50%) - glycosylated proteins (mannoproteins)
• chitin (2% of the cell wall)

Question 9

Name some echinocandins and what their mechanism of action is

Answer 9

• caspofungin, micafungin
  1. inhibit the enzyme B1,3 glucan synthetase
  2. Block synthesis of B1,3 glucan
  3. Fungicidal effects

Question 10

What is the target of most of the currently used antifungals?

Answer 10

The plasma membrane

Question 11

What is the difference between plasma membranes in human and fungal cells?

Answer 11

Human PM’s - contain cholesterol
Fungal PM’s - ERGOSTEROL

• ergosterol = an essential component of fungal plasma membranes
• in the absence of functional ergosterol biosynthesis - fungal cells cannot grow and survive

Question 12

What is the mechanism of action of antifungals that target ergosterol?

Answer 12

Either

-bind to resident ergosterol in the plasma membrane

OR

-inhibit different ergosterol biosynthetic enzymes and block de novo biosynthesis of ergosterol

Question 13

What are the types of drugs that target ergosterol?

Answer 13

• polyene antifungals
• azoles
• allylamines

Question 14

What is the mechanism of action of polyene antifungals?

Answer 14

-fungicidal

• bind to ergosterol
• and form pores in the plasma membrane which disrupt membrane integrity causing leakage of cell constituents

-higher affinity for ergosterol than cholesterol

Question 15

What side effects of polyene antifungals are associated with prolonged application?

Answer 15

-severe side effects - kidney failure

Question 16

Name some polyene antifungals, what they are used for and side effects if any

Answer 16

Amphotericin B
(Prolonged use has severe side effects)

Nystatin
(Used in treatment of oral and GI fungal infections)

-both natural in origin

Question 17

What reduces the risk of side effects after prolonged use of Amphotericin B

Answer 17

Prolonged use has severe side effects BUT

Amp B lipid complex (ABLC)

and

liposomal Amp B (L-Amp B) formulations reduce the risks

Question 18

What is a key step in ergosterol biosynthesis?

Answer 18

Lanosterol demethylation

Question 19

What is the mechanism of action of azoles?

Answer 19

• ergosterol biosynthesis inhibitors
• inhibit the enzyme Lanosterol C-14 demethylase

(Blocks ergosterol biosynthesis, leads to accumulation of toxic intermediates, causes growth arrest)

Question 20

What are the two types of azole antifungals?

Answer 20

Imidazoles

Triazoles

Question 21

Name some imidazoles

Answer 21

Miconazole

Clotrimazole (canesten)

Ketoconazole

Question 22

Name some examples of Triazoles

Answer 22

Fluconazole

Voriconazole

Itraconazole

Question 23

What type of antifungals are the azoles (imidazoles and Triazoles)?

Answer 23

Fungistatic

-inhibit the enzyme Lanosterol C14-demethylase

Question 24

Why are Triazoles more potent antifungals than imidazoles?

Answer 24

They have a higher affinity for the enzyme Lanosterol C14-demethylase

Hence more potent

Question 25

What is the mechanism of action of allylamines?

Answer 25

Inhibits ergosterol biosynthesis

Inhibit an earlier step before the step azoles inhibit

Question 26

Name some allylamines

Answer 26

Terbinafine

Amorolfine

Question 27

Which drug inhibits fungal DNA and RNA synthesis?

Answer 27

Flucytosine

Question 28

What is Flucytosine’s mechanism of action?

Answer 28

-inhibits fungal DNA + RNA synthesis

1. Taken up by fungal cells
2. Metabolised by fungal cells to 5-fluoroacil (5-FU)
3. 5-FU is a toxic antimetabolite
4. 5-FU inhibits DNA and RNA synthesis

-associated with high levels of resistance

Question 29

What is Flucytosine usually used in combination with?

Answer 29

Azoles

Question 30

What are fungal diseases also known as?

Answer 30

Mycoses