Anti-Fungals

Question 1

How are fungal and human cells the same?

Answer 1

They are both eukaryotic.

Question 2

Human cell membranes are supported by cholesterol, what are fungal cell membranes supported by?

Answer 2

Ergosterol.

Question 3

What are both the cholesterol and ergosterol structure based around?

Answer 3

The steroid tetracyclic nucleus.

Question 4

How do polyene antifungal drugs, such as amphotericin B, work?

Answer 4

Polyene anti-fungal drugs bind to ergosterol in the fungal cell membrane and form pores. This alters permeability and transport, leading to cell death through lysis.

Question 5

Name a polyene antifungal drug.

Answer 5

Amphotericin B.

Question 6

How do different concentrations affect the action of amphotericin B?

Answer 6

It is a fungicidal drug at higher concentration and a fungistatic drug at lower concentrations.

Question 7

Describe the structure of amphotericin B.

Answer 7

It is a polyene so has a chain of alternating double and single bonds. It also contains a 6 membered ring with an oxygen in the top position.

Question 8

What organism produces amphotericin B?

Answer 8

Streptomyses nodosum.

Question 9

Amphotericin B has a CSF concentration of 2-3% of that of blood concentration, what does this imply?

Answer 9

Poor brain penetration.

Question 10

What is amphotericin B used to treat?

Answer 10

Amphotericin B is used in the treatment of nearly all life-threatening mycotic infections. The main indication for use of this drug is fungal arthritis, it is administered as a local injection into the effected joint.

Question 11

How is amphotericin B used?

Answer 11

For systemic disease it is given intravenously and for local infection it can be used topically however there must be a good reason for this. The main indication for use of this drug is fungal arthritis, it is administered as a local injection into the effected joint.

Question 12

Is there a high toxicity of amphotericin B in humans? Why?

Answer 12

As ergosterol closely resembles cholesterol in human cell membranes, there is high toxicity of amphotericin B in humans.

Question 13

Describe a new formulation of amphotericin B that reduces toxicity and enhances efficacy.

Answer 13

Liposomal ampheterecin B, the drug is encorporated into lipid formulations.

Question 14

What class of antifungal drugs target the fungal cell wall?

Answer 14

Echinocandins.

Question 15

Why is the fungal cell wall a good target for antifungal therapy?

Answer 15

Because humans do not have a cell wall whereas fungal cells do.

Question 16

How do drugs that target the fungal cell wall work?

Answer 16

These drug work by inhibiting the synthesis of 1,3-β-D-glucan in fungal cell walls through non-competitive inhibition of the enzyme 1,3-β-glucan synthase. This leads to disruption of the cell wall and ultimately cell death.

Question 17

How is caspofungin classified?

Answer 17

Classified as a semi-synthetic echinocandin.

Question 18

What is caspofungin indicated in?

Answer 18

It is indicated for use in life-threatening systemic mycoses but not in cryptococcal meningitis.

Question 19

What side effects do the echinocandins show?

Answer 19

The echinocandins are extremely well tolerated and only show minor GI side effects and flushing. They can also elevate liver enzymes and cause histamine release during IV infusion.

Question 20

Give an example of a drug that targets fungal DNA synthesis.

Answer 20

5-Fluorocytosine.

Question 21

Which anticancer agent is 5-fluorocytosine closely related to?

Answer 21

5-Fluorouracil.

Question 22

Why is 5-FC water soluble?

Answer 22

Due to the nitrogen in its structure, making it polar.

Question 23

5-FC has a CSF concentration of 75% that of blood concentration, what does this mean for its usage?

Answer 23

It is very good for use in fungal brain infections (fungal meningitis); this is due to its small molecular weight.

Question 24

What are the side effects of 5-FC?

Answer 24

Bone marrow toxicity (anaemia, leukopenia, thrombocytopenia), GI disturbances, mild and reversible liver dysfunction.

Question 25

Give an example of a drug which targets fungal cell division.

Answer 25

Griseofulvin.

Question 26

How does griseofulvin work to prevent fungal cell division?

Answer 26

Griseofulvin is deposited into newly forming skin where it binds to keratin, protecting the skin from new infection. It interferes with spindle formation in dividing cells and therefor mitosis, this is a unique mode of action. It is a fungistatic drug.

Question 27

Before they were used as antifungal drugs, what were the azoles used as?

Answer 27

Antibacterials.

Question 28

What class of drugs target ergosterol synthesis?

Answer 28

Azoles.

Question 29

Name some azole drugs.

Answer 29

Fluconazole, ketoconazole, itraconazole.

Question 30

Why is fluconazole useful against cryptococcal meningitis?

Answer 30

It has good brain penetration.

Question 31

What are the side effects of ketoconazole?

Answer 31

In high doses ketoconazole inhibits adrenocortical steroids and testosterone synthesis, resulting in gynecomastia in some males.

Question 32

What are clotrimazole and miconazole indicated for?

Answer 32

Vaginal thrush, oral thrush, tinea corporis, tinea pedis (athletes foot), tinea cruris.

Question 33

What is the only azole with significant activity against zygomycosis and murcomycosis?

Answer 33

Posaconazole.

Question 34

Why is posaconazole more stable?

Answer 34

One of the actyl oxygens has been removed.

Question 35

Acetyls are usually unstable, why is this different for acetyl antifungal (e.g. ketoconazole) drugs?

Answer 35

Acetyls are usually unstable but because in this drug the oxygens are hidden in the middle of the molecule, they are less susceptible to attack. Making the drug more stable.

Question 36

What two modes of action do drugs that inhibit fungal squalene epoxidase have?

Answer 36

Prevention of the epoxidation. this halts the production of ergosterol and also leads to the buildup of squalene which is toxic to the cell and breaks down the cell wall.

Question 37

Name drugs which inhibit the action of fungal squalene epoxidase.

Answer 37

Allylamines.

Question 38

Name some allylamines.

Answer 38

Terbinafine, naftifine.

Question 39

What is naftifine used for?

Answer 39

Tinea corporis, tinea cruris.

Question 40

What is terbinafine used for?

Answer 40

It is effective for the treatment of tinea corporis and tinea cruris. Terbinafine concentrates in the skin and especially at nail beds, making it quite useful for fungal infections of nails. It is also useful against dermatophytosis and human ring worm.