Infection: Antifungals, mechanism of action + adverse effects

Question 1

What is the mechansim of action of the azoles?

Answer 1

Inhibit 14alpha-demethylase which produces ergosterol.

Side effects of azoles: p450 inhibition and liver toxicity

Question 2

What are the adverse effects of the azoles?

Answer 2

P450 inhibition and liver toxicity

Azoles inhibit 14alpha-demethylase which is needed to produce ergosterol.

Question 3

How does amphotericin B work?

Answer 3

Binds with ergosterol forming a transmembrane channel that leads to monovalent ion (K+, Na+, H+ and Cl-) leakage.

Side effects are nephrotoxicty, flu-like symptoms,
hypokalaemia, hypomagnaseamia

Question 4

What are the side effects of Amphotericin B?

Answer 4

Side effects are nephrotoxicty, flu-like symptoms,
hypokalaemia, hypomagnaseamia.

Binds with ergosterol forming a transmembrane channel that leads to monovalent ion (K+, Na+, H+ and Cl-) leakage.

Question 5

How does terbinafine function?

Answer 5

inhibits squalene epoxidase

Question 6

How does griseofulvin function?

Answer 6

Interacts with microtubules to disrupt mitotic spindle.

Side effects: induces the p450 system, teratogenic.

Question 7

What are the adverse effects of griseofulvin?

Answer 7

Induction of the p450 system, teratogenicity.

Works by interacting with microtubules to disrupt the mitiotic spindle.

Question 8

How does flucytosine work?

Answer 8

Flucytosine is converted by cytosine deaminase to 5-fluorouracil, which inhibits TS and disrupts fungal protein synthesis.

Side effects: Vomiting.

Question 9

What are the side effects of fluctyosine?

Answer 9

Vomiting.

Flucytosine is converted by cytosdine deaminase to 5-fluorouracil, which inhibits TS and thus disrupts fungal protein synthesis.

Question 10

How does caspofungin function?

Answer 10

Inhibits the synthesis of beta-glucan, a major fungal cell wall component.

Side effect of flushing.

Question 11

What are the adverse effects of caspofungin?

Answer 11

Flushing

Question 12

How does nystatin work?

Answer 12

Binds with ergosterol forming a transmembrane channel that leads to monovalent ion leakage. Like amphotericin B.

Question 13

What antifungals interfere with the p450 system?

Answer 13

Azoles = inhibit (also liver toxiciy)
Griseofulvin = induces (also teratogenic)

Question 14

What antifungals inhibit 14alpha-demethylase which produces ergosterol?

Answer 14

Azoles

Question 15

What antifungal functions by inhibiting squalene epoxidase?

Answer 15

Terbinafine.

Question 16

Which antifungals work via binding with ergosterol forming a transmembrane channel that leads to monovalent ion leakage?

Answer 16

Nystatin and Amphotericin B.

Question 17

What antifungal is most typically associated with hypokalaemia and hypomagnaseamia?

Answer 17

Amphotericin B plus flu-like symptoms and nephrotoxicty.

Question 18

What antifungal is teratogenic?

Answer 18

Griseofulvin (also p450 enzyme inducer)

Question 19

Which antifungal has flushing as the most characteristic side effect?

Answer 19

Caspofungin which functons by inhibiting the synthesis of beta-glucan, a major fungal cell wall component.

Question 20

Which antifungal has vomiting as a predominant side effect?

Answer 20

Flucytosine.

Question 21

Which of the following antifungal is most effective in the treatment of invasive aspergillosis?

Ketoconazole
Fluconazole
Flucytosine
Voriconazole

Answer 21

Voriconazole belongs to the triazole class of antifungal drugs.

It is effective, alongside amphotericin B, in the treatment of invasive aspergillosis.

Question 22

Which class of antifungal drugs work by inhibiting squalene epoxidase?

Echinocandins
Allylamines
Polyenes

Answer 22

Allylamines - which include drugs such as terbinafine, naftifine, and amorolfin - work by inhibiting squalene epoxidase.

Another antifungal drug, called tolnaftate, also inhibits squalene epoxidase - but, structurally, tolnaftate is not an allylamine.

Question 23

Which antifungal drug is associated with “shake and bake” adverse effects?

Griseofulvin
Caspofungin
Amphotericin B
Micafungin

Answer 23

Amphotericin B is associated with the so-called “shake and bake” adverse effects:

Initial use of amphotericin B is associted with chills and fever (“shake and bake” respectively).

This is an acute reactins which may occur shortly after infusion.

Question 24

Nystatin belongs to which class of drugs?

Allylamines
Polyenes
Echinocandins
Thiocarbamate

Answer 24

Polyenes

Question 25

Which of the following classes works by inhibiting lanosterol 14alpha-demethylase? ``` Imidazoles Polyenes Echinocandins Thiocarbamate Triazoles ```

Answer 25

Imidazoles and triazoles are family members of the broader azole class - which work by inhibiting lanosterol 14alpha-demethylase. This compromises the integrity of the fungal cell wall.

Question 26

Which of the following is a pyrimidine analogue which is converted into 5-FU by the fungal enzyme cytosine deaminase? ``` Clotrimazole Caspofungin Itraconazole Nystatin Flucytosine Griseofulvin ```

Answer 26

Flucytosine is a pyrimidine analogue. It is converted into 5-FU by the fungal enzyme cytosine deaminase. Flucytosine is mostly active against yeast infections.

Question 27

Which of the following works by binding to microtubules and disrupting the mitotic process? It is administered orally and has a half-life of ~14 hours. ``` Clotrimazole Caspofungin Itraconazole Nystatin Flucytosine Griseofulvin ```

Answer 27

Griseofulvin

Question 28

Which antifungal drug, at high doses, has an antiandrogen effect? ``` Clotrimazole Caspofungin Ketoconazole Itraconazole Nystatin Flucytosine Griseofulvin ```

Answer 28

Ketoconazole, at high doses, inhibits the activity of enzymes involved in the conversion of cholesterol to steroid hormones - such as cortisol and testosterone. Cushings disease treatment via specialist.

Question 29

Which antifungal class works by targeting glucans? Azoles Polyenes Echinocandins

Answer 29

Echinocandis - caspofungin, micafungin, work by targeting glucans, specifically by inhibiting the enzyme 1,3-Beta-glucase synthase. This disrupts the fungal cell wall.