Lecture 21

Question 1

What are the two major forms of fungi that are often seen?

Answer 1

1. Unicellular yeasts

2. Multicellular filamentous molds

Question 2

What are the four main types of anti-fungals that exist?

Answer 2

1. Amphotericin B
2. Nystatin
3. The azoles
4. Terbinafine

Question 3

What is the main target of the antifungals?

Answer 3

many target the fungal cell membrane steroid (ergosterol)

Question 4

What is the mechanism of action of amphoteracin B?

Answer 4

1. Amphoteracin B reaches the cell membrane
2. Intercalates to cell membrane via ergosterol binding
3. Increases cell membrane permeability resulting in electrolyte leakage having a fungicidal effect

(preferentially binds to ergosterol (rather than cholesterol) to provide fungal selectivity

Question 5

What is it about amphoteracin B that allows for pulse therapy (ie. alternative day dosing)?

Answer 5

It has quite a long post-antifungal effect and this allows for pulse therapy and alternative day dosing

Question 6

Briefly explain two pharmacokinetic side effects that reduce the efficacy of amphotericin B:

Answer 6

1. Very poor GIT absorption
2. Sequestered into cholesterol in the host - while it may have increased affinity for ergosterol there is still much more cholesterol in the body

Question 7

What are the side effects of amphoteracin B?

Answer 7

1. Nephrotoxicity - acting on renal tubular cell cholesterol
2. Other - fever, vomiting

Question 8

Describe the effects of nystatin relative to amphoteracin B:

Answer 8

1. Same group and hence the same mechanism of action as Amphotericin B - often found in ear ointments

Question 9

What is the mechanism of action of the azoles?

Answer 9

1. Azole inhibiting sterol synthesis leads to creation of a defective steroid
2. Defective steroids disrupt cell membrane integrity - fungistatic (sometimes fungicidal)

Question 10

Compare the safety of the azoles to other classes of antifungals:

Answer 10

The azoles are much safer than the other classes of antifungals

Question 11

What is an example of systemic azoles?

Answer 11

Ketoconazole, Itrazonazole, Fluconazole

Question 12

What is an example of a topical azole?

Answer 12

Clotrimazole, Miconazole

Question 13

What should azoles be given with when taken orally?

Answer 13

only absorbed from an acidic environment and therefore should be given with or after food.

Question 14

What are the side effects of ketoconazole?

Answer 14

Many hepatic side effects have been observed particularly in cats

Question 15

Compare the efficacy of intraconazole and fluconazole

Answer 15

Both have fewer side effects and greater efficacy (usually) than ketoconazole

Question 16

Can clotrimazole be given systemically?

Answer 16

No. Increased metabolism results in the subsequent doses not reaching therapeutic concentrations. They should be given for topical use only - nasal aspergillus and tinea (foot fungus)

Question 17

What about Miconazole makes it a good choice for small animal dermatology?

Answer 17

Very little systemic abosorption so normally minimal side effects are seen

Question 18

What is the mechanism of action of the drug terbinafine?

Answer 18

mechanism of action conceptually very similar to the azoles (inhibits a different enzyme). Results in a defective cell membrane resulting in cell death. It is highly fungicidal.

Question 19

What are the favorable pharmacokinetics of terbinafine?

Answer 19

1. Good oral absorption
2. Broad spectrum
3. Good distribution - lipophilic - stratum corneum concentration is 75 times that of plasma