AntiFungal Drugs

Question 1

What are the three basic MOA of antifungal drugs?

Answer 1

1. Alteration of cell membrane
2. Mitotic Spindle Inhibition.
3. Antimetabolite

Question 2

T/F: The number of patients less able to withstand a fungal infection had increased?

Answer 2

TRUE

Question 3

Methods of administration of Antifungal Drugs?

Answer 3

They are used systemically either orally or parentally and sometimes topically.

Question 4

What is usually used as first line therapy for most fungal infections?

Answer 4

Drugs ending in azole or amphotericin B

Question 5

Treatment of Aspergillosis:

Answer 5

First: Voriconazole IV
Alt: Lipid Amphotericin B

Question 6

Treatment of Mild Blastomycosis:

Answer 6

First: Itraconazole PO
Alt: Fluconazole

Question 7

Treatment of Severe Blastomycosis:

Answer 7

First: Amphotericin B IV then ITraconazole PO

Alt N/A

Question 8

Treatment of Candidiasis:

Answer 8

First: Fluconazole PO
Alt: Azole or Amphotericin B or Fungin Agent

Question 9

Treatment of Coccidioidomycosis:

Answer 9

First: Fluconazole PO or Itraconazole PO
Alt: Amphotericin B

Question 10

Treatment of Cryptococcus:

Answer 10

First: Amphotericin B PO IV, Flucytocine PO, then Fluconazole PO
Alt: Combination of all three previously mentioned

Question 11

Treatment of Histoplasmosis:

Answer 11

First: Amphotericin B IV and Itraconazole PO
Alt: Fluconazole

Question 12

Treatment of Mucormycosis:

Answer 12

First: Amphotericin B
Alt: Poscacanazole

Question 13

Treatment of Sporotrichosis:

Answer 13

First: Amphotericin B IV and/or Itraconazole PO
Alt: Itraconazole PO

Question 14

Host Factors that predispose a person to a fungal infection:

Answer 14

Chemotherapy, Radiotherapy, Corticosteroids, Immunosurpression, Recent or Current Antibiotic Use, Central Venous Catheters, Comorbid Diabetes, Fungal Colonizaiton, Mechanical Ventilation, Renal Replacement Therapy, Mucositis, Total PAretneral Nutrition, Malnutrition, Prolonged ICU Stay, Hospital Environment, Sepsis, Surgery, High Disease Severity

Question 15

What are the two cell wall targets of the fungal cell wall?

Answer 15

ergesterol and beta 1-3 glucan

Question 16

What are the two steps in the synthesis pathway of ergesterol that can be targeted and what groups target them?

Answer 16

Conversion of squalene to squalene epoxide is blocked by TERBINAFINE. This also results in the accumulation of squalene, which is toxic.
Conversion of lanosterol to ergesterol is blocked by the AZOLE drugs.

Question 17

What is significant about AZOLES blocking the conversion of lanesterol to ergesterol?

Answer 17

This conversion is mediated by the CYP450 enzymes, therefore specificity of drug action on fungal cytochrome versus mammalian cytochrome must be considered. Also, the metabolism of both the antifungal and other drugs may be altered due to the CYP450 involvement.

Question 18

Describe the structure of AMPHOTERICIN B.

Answer 18

It is an amphipathic molecule that is capable of associating with both a lipid and aqueous environment.

Question 19

What is the MOA of AMPHOTERICIN B?

Answer 19

IT binds to ergesterol in the fungal cell membrane and forms pores. These pores allow leakage and ultimately cell death.

Question 20

What is a key side effect of AMPHOTERICIN B?

Answer 20

Its ability to damage cell membranes often results in organ specific drug toxicity towards the kidney. 80% of patients receiving the original formulation of this will experience renal damage.

Question 21

How is AMPHOTERICIN B administered?

Answer 21

It is not really absorbed orally and therefore must be given via IV infusion.

Question 22

What is the current solution to the problem of renal toxicity and poor absorption with AMPHOTERICIN B?

Answer 22

Three drugs have been combined into a lipid milleu. This has shown mild improvement in renal toxicity. The major disadvantage is the dramatically increased cost. Therefor, patients usually receive the original medicine unless contraindicated.

Question 23

What are the immediate common side effects of AMPHOTERICIN B?

Answer 23

fever, chills, muscle spasms, vomiting, headache, hypotension

• *Test does is often given to gauge patient reaction.
• *Premidicate: antipyretics, antihistmaines, meperidine, coritcosteroids

Question 24

What re some of the delayed side effects of AMPHOTERICIN B?

Answer 24

• Renal Toxicity: sometimes necessitates dialysis; sodium loading often used to reduce pre renal toxicity.
• Anemia: secondary to liver damage
• Abnormal LFT
• Seizures following intraathecal drug administration

Question 25

Are there any comparable drugs to AMPHOTERICIN B?

Answer 25

YES. Nystatin has a comparable amphipathic structure and works in an identical manner.

Question 26

How is Nystatin administered and what is it most commonly used to treat?

Answer 26

Due to level of toxicity, it must only be given topically and is most commonly used to treat Candidiasis.

Question 27

Echocandins

Answer 27

"The Fungins"; They inhibit beta-1-3 glucan synthesis which leads to loss of fungal cell membrane structure and integrity.

Question 28

How are the fungins (CASPOFUNGIN and Micofungin) administered, what are they effective against, and how are they tolerated?

Answer 28

They must be goven parentally, are effecitvie against Aspergillus and Candida Infections, and with the exception of infusion reactions, are well tolerated.

Question 29

What two groups can the AZOLES be divided into?

Answer 29

1. Imidazoles: 2 nitrogens in the azole ring | 2. Triazoles: 3 nitrogens in the azole ring

Question 30

What is the only member of the imidazole group that we have discussed?

Answer 30

Ketoconazole

Question 31

What is the only other fungal drug besides the AZOLES that gives us concerns about drug induced effects of hepatic metabolism?

Answer 31

Griseofulvin

Question 32

Which azoles have poor ability to penetrate the CSF?

Answer 32

Ketoconazole and Itraconazole | **This is probably because they are substrates for P-Glycoprotein located in the BBB.

Question 33

How are AZOLES primarily eliminated?

Answer 33

Through hepatic processes

Question 34

What is the one AZOLE that is the exception to hepatic elimination?

Answer 34

Fluconazole. IT is eliminated in the urine.

Question 35

What are other side effects associated with the AZOLES?

Answer 35

All orally administered azoles produce symptoms of GI discomfort such as pain, constipation, diarrhea, weight loss, dyspepsia. However, the highest incidence is seen in Itraconazole and Posaconazole.

Question 36

Which AZOLES are contraindicated during pregnancy?

Answer 36

Fluconazole and Voriconazole

Question 37

Do some AZOLES have cardiac side effects?

Answer 37

YES. Some are associated with causing or facilitating arrhythmias in the presence of concurrent cardioactive drugs.

Question 38

Why has the FDA moved to limit widespread use of Ketoconazole (the first member of the azole class)?

Answer 38

It produces hepatic damage that is sometimes irreversible, is strongly associated with arrhythmogenic events, and can also adrenal insufficiency (at high doses can inhibit the synthesis of adrenal steroids, leading to a reduction in aldosterone, cortisol, and testosterone.

Question 39

Itraconazole

Answer 39

Poor penetration of the CSF and oral bioavailability. | **New formulations overcome poor oral bioavailability.

Question 40

Which two azolws have the best ability to penetrate the CSF?

Answer 40

Fluconazole and Voriconazole

Question 41

Which AZOLE posses the highest problem for cytochrome mediated drug-drug interactions?

Answer 41

Voriconazole.

Question 42

What other negative side effects are associated with Voriconazole?

Answer 42

Photosensitive dermatitis, temporary visual disturbances, and severe neurological disturbances such as hallucinations.

Question 43

Overall, which of the AZOLES has the best profile?

Answer 43

Fluconazole

Question 44

Which is the only AZOLE that is active against mucormycosis?

Answer 44

Posaconazole. It is orally administered.

Question 45

What are the two most common topical AZOLES?

Answer 45

Clotrimazole and miconazole. They are used in the treatment of Candidiasis infection. Systemic events are rare due to topical application.

Question 46

What is the MOA for Flucytosine (5-FC)?

Answer 46

It enters the fungal cell via the enzyme cytosine permease and is rapidly converted into 5-flurouracil. IT is rapidly converted into intermediary metabolism where it causes an interruption in DNA and RNA synthesis. **Mammmalian cells do not conduct this first step but intestinal microflora do.

Question 47

Describe the therapeutic window of Flucytosine.

Answer 47

It is very narrow due to its MOA.

Question 48

Describe the side effects of Flucytosine.

Answer 48

The typical side effects of cell cycle inhibitors that are seen in normally dividing cell populations can be seen. Hematological toxicities are often seen, as are temporarily elevated hepatic enzyme levels.

Question 49

What are some of the mechanisms of resistance observed in antifungals?

Answer 49

Downregulaiton of activation pathways, modification in important enzyme substrate affinity, upregulation of protective mechanisms, efflux pumps

Question 50

What is the MOA of Griseofulvin?

Answer 50

It is a mitotic spindle inhibitor and therefore a cell cycle inhibitor.

Question 51

What is Griseofulvin used to treat?

Answer 51

It is of very limited clinical utility and is used in the treatment of sever fungala skin infections, onchomycoses, and tinea. Its use is declining in deference to terbinafine.

Question 52

What is the most significant side effect of Griseofulvin?

Answer 52

It has potential for many drug-drug interactions, most significantly Warfarin.

Question 53

Is terbinafine well tolerated?

Answer 53

Yes, with the exception of transient lympho- and neutropenia. Due to this, sometimes routine CBC testing is required.