Pharm: Systemic Antifungals

Question 1

One drug acts on fungi to inhibit the mitotic spindle in the nucleus. What is it?

Answer 1

Griseofulvin - different than the others, which mostly act on fungal membrane; this one acts to disrupt MTs

Question 2

One drug acts on fungi as an anti-metabolite. What is it?

Answer 2

Flucytosine

Question 3

If fungi rarely cause disease in hosts, why are anti-fungals becoming increasingly important in medicine?

Answer 3

with advances in treatments for other conditions, there are more patients who are immunocompromised and therefore falling victim fungal infections

Question 4

Describe the MOA and indications of Amphotericin B.

Answer 4

amphipathic drug that binds to ergosterol, forms pores in the membrane, and causes loss of cell integrity; used to treat lots of things

Question 5

Describe the MOA and indications of Caspofungin (echinocandins).

Answer 5

inhibits beta-glucan synthase thereby preventing synthesis of beta-1,3 glucan, an important cell wall component; used to treat aspergillus and candida infections - tolerated well if used alone

Question 6

Please characterize Fluconazole.

Answer 6

good oral bioavailability, good CSF penetration; best tolerance - widest therapeutic index

Question 7

Please characterize Itraconazole.

Answer 7

poor CSF penetration, new formulations overcome poor oral bioavailability

Question 8

Describe the MOA and indications of Terbinafine.

Answer 8

prevents the conversion of squalene to squalene epoxide, an important step in the synthesis of ergosterol; used to treat athlete’s foot

Question 9

Describe the MOA and indications of Nystatin.

Answer 9

amphipathic drug that binds to ergosterol, forms pores in the membrane, and causes loss of cell integrity; used topically to treat mucocutaneous, oropharyngeal, and vulvovaginal candidiasis

Question 10

Antifungals fall into 2 classes of administration: ____ and ____.

Answer 10

1. systemic - administered either orally or parenterally

2. topical - for mucocutaneous infections

Question 11

What is the first line drug choice for Aspergillosis?

Answer 11

Voriconazole

Question 12

What is the first line drug choice for Blastomycosis (mild)?

Answer 12

Itraconazole

Question 13

What is the first line drug choice for Blastomycosis (severe)?

Answer 13

Amphotericin B IV then Itraconazole PO

Question 14

What is the first line drug choice for Candidiasis?

Answer 14

Fluconazole

Question 15

What is the first line drug choice for Coccidioidomycosis?

Answer 15

Fluconazole IV/PO or Itraconazole PO

Question 16

What is the first line drug choice for Cryptococcus?

Answer 16

Amphotericin B IV plus Flucytosine PO, then Fluconazole PO

Question 17

What is the first line drug choice for Histoplasmosis?

Answer 17

Amphotericin B IV plus Itraconazole PO

Question 18

What is the first line drug choice for Mucormycosis?

Answer 18

Amphotericin B

Question 19

What is the first line drug choice for Sporotrichosis?

Answer 19

Amphotericin B IV and/or Itraconazole PO

Question 20

What all infections would Voriconazole be used for?

Answer 20

Aspergillosis

Question 21

What all infections would Itraconazole be used for?

Answer 21

mild Blastomycosis, severe Blastomycosis, Coccidioidomycosis, Histoplasmosis, Sporotrichosis*
*would be in combination with another drug

Question 22

What all infections would Fluconazole be used for?

Answer 22

Candidiasis, Coccidioidomycosis, Cryptococcus*

*would be in combination with another drug

Question 23

What all infections would Flucytosine be used for?

Answer 23

Cryptococcus*

*would be in combination with another drug

Question 24

What all infections would Amphotericin B be used for?

Answer 24

severe Blastomycosis, Cryptococcus, Histoplasmosis, Mucormycosis, Sporotrichosis
*would be in combination with another drug

Question 25

What is the MOA of amphotericin B, and what is its effect on humans?

Answer 25

fungicidal that causes loss of cell integrity by binding to ergosterol and forming pores there; pores allow leakage-->cell death. the damage to membranes also occurs in the kidneys, therefore there is high risk of renal toxicity

Question 26

What is the MOA of azoles and terbinafine? (big picture)

Answer 26

blocks synthesis of ergosterol

Question 27

What is the MOA of the echinocandins (such as caspofungin)?

Answer 27

prevents formation of glucans in the fungal cell wall by inhibiting Beta-glucan synthase from making beta-1,3-glucan

Question 28

Flucytosine is an inhibitor of ____ ____ synthesis, and thus prevents ____ replication.

Answer 28

nucleic acid synthesis; cell replication

Question 29

What are the steps of the ergosterol synthesis pathway, and where do each terbinafine and the azoles act?

Answer 29

``` Step 1. squalene to squalene epoxide Step 2. squalene epoxide to lanosterol Step 3. lanosterol to ergosterol Terbinafine inhibits Step 1. Azoles inhibit Step 3. ```

Question 30

Accumulation of ____ as a result of terbinafine action is toxic to the fungal cell.

Answer 30

squalene

Question 31

Which drug is comparable to amphotericin B (having the same MOA)? What are the downsides to this drug?

Answer 31

Nystatin; can ONLY be used topically because its toxicity is so great it precludes systemic administration

Question 32

Agents whose names end in -fungin belong to which class?

Answer 32

Echinocandins

Question 33

Agents whose names end in -azole are so-called due to what?

Answer 33

these agents have an azole ring structure; imidazoles have 2 nitrogens and triazoles have 3 nitrogens

Question 34

Which drugs discussed are imidazoles and which are triazoles?

Answer 34

imidazoles: ketoconazole triazoles: fluconazole

Question 35

What interaction do azoles have with CYP450 enzymes?

Answer 35

they inhibit them in fungi, as well as humans - this interaction has an impact on drug-drug interactions

Question 36

True or False: almost all anti-fungals in the azole class are capable of inhibiting CYP3A4.

Answer 36

True - and this is very important because it will not only change metabolism of concurrent medications but also of the azoles; this concern is unique to the azoles and to griseofulvin

Question 37

____ and ____ are two azoles that are not good at treating CSF fungal infections because they don't cross the BBB well. However, ____ and ____ do get into the CSF well.

Answer 37

Ketoconazole and itraconazole; fluconazole and voriconazole

Question 38

In general, azoles--except for ____ -- are eliminated through hepatic mechanisms.

Answer 38

fluconazole - eliminated in urine

Question 39

All orally administered azoles produce symptoms of ____ disturbance, but the highest incidence occurs with use of ____ and ____.

Answer 39

GI; itraconazole and posaconazole (because they are the least soluble, poorly absorbed, and leave particulate in the GI tract which causes irritation)

Question 40

Can fluconazole and voriconazole be administered in pregnancy?

Answer 40

No

Question 41

Ketoconazole is notorious for what side effects, which have led to FDA limiting its use?

Answer 41

- hepatic damage - sometimes irreversible - cardiac arrhythmogenic events - adrenal insufficiency - unique to ketoconazole

Question 42

How does adrenal insufficiency arise from use of ketoconazole?

Answer 42

ketoconazole is unique in high doses to inhibit synthesis of adrenal steroids, leading to reduction of Cortisol, Aldosterone, and Testosterone

Question 43

Voriconazole is associated with what side effects?

Answer 43

drug-drug interactions; photosensitive dermatitis, elevated liver enzymes, temporary visual disturbances upon IV administration, neurologic symptoms, including hallucinations (think - this is one that crosses BBB, but isn't widely used for CSF infections because of the side effects; also not taken during pregnancy)

Question 44

Please characterize Posaconazole.

Answer 44

claim to fame is that it's the only azole that can treat mucormycosis; but it is involved in CYP mediated drug-drug interactions

Question 45

Azoles ____ and ____ are the most common topical agents and are used against candidiasis infections.

Answer 45

clotrimazole and miconazole (side effects are rare and clortrimazole troches taste good making them better than nystatin for treating oral thrush)

Question 46

Does flucytosine have a wide or narrow therapeutic window?

Answer 46

narrow, because it's a pyrimidine analog and interrupts RNA and DNA synthesis in both the fungal infection AND normally dividing host cell populations (such as GI and RBCs)

Question 47

Griseofulvin is an inducer of ____ producing drug-drug interactions, and has largely been replaced by ____.

Answer 47

CYP3A4; Terbinafine

Question 48

True or false: Terbinafine has no effect upon CYP activity and is generally well-tolerated.

Answer 48

True

Question 49

Terbinafine is generally well-tolerated except for the risk of transient ____ and ____, which is monitored with routine CBCs.

Answer 49

lymphopenia and neutropenia

Question 50

Most antifungals are fungicidal by inhibiting ____ ____ ____; except for ____ and ____.

Answer 50

cell wall integrity; flucytosine (nucleic acid synthesis inhibitor) and griseofulvin (mitotic spindle inhibitor)

Question 51

Among the anti-fungals which class has the broadest spectrum of activity?

Answer 51

Azoles

Question 52

Some ____ are pro-arrhythmogenic.

Answer 52

azoles

Question 53

The best tolerated azole is ____.

Answer 53

Fluconazole

Question 54

Amphotericin B has poor ____ and is quite ____-toxic.

Answer 54

solubility; nephro-toxic

Question 55

Griseofulvin is used in the systemic treatment of ____.

Answer 55

dermatophytosis

Question 56

For a patient given amphotericin: what is the molecular action and where is it occurring? (clicker question)

Answer 56

pore formation in the cell membrane (not cell wall)

Question 57

``` For a patient given a drug that inhibits fungal P450: which drug was most likely given? (class question) ```

Answer 57

an azole

Question 58

``` For a patient given terbinafine: which enzyme was most likely inhibited? (class question) ```

Answer 58

the one that normally convertes squalene to squalene spoxide: squalene epoxidase

Question 59

``` Which of the effects of terbinafine on fungal cells is more effective in killing the fungus: the destruction of the cell wall by inhibiting ergosterol synthesis, or the toxicity of accumulated squalene? (class question) ```

Answer 59

the toxicity of accumulated squalene

Question 60

``` Are amphotericin B and the azoles are considered fungicidal or fungistatic? (class question) ```

Answer 60

- amphotericin B = static at low concentrations but cidal at higher/clinical concentrations - azoles = fungistatic, therefore relapse rate can be high if drug treatment is incomplete

Question 61

``` What type of drug-drug interactions would you be MOST concerned about in a patient receiving amphotericin B? (class question) ```

Answer 61

other drugs that also produce renal toxicity, because amphotericin B has high nephrotoxicity; side effect of amphotericin is hypokalemia therefore wouldn't want to combine it with diuretics (also cause loss of potassium); this is part of the pro-arrhythmic predisposition caused by anti-fungals

Question 62

``` An AIDS patient diagnosed with cryptococcal meningitis was given an IV dose of hydrocortisone, followed by IV infusion of amphotericin B. Hydrocortisone was given for what drug-related adverse effect? (class question) ```

Answer 62

infusion reaction

Question 63

``` First side effect to think about with amphotericin B is ____ and the second is an ____. (class question) ```

Answer 63

nephrotoxicity; infusion-related reaction

Question 64

``` Woman diagnosed with cryptococcal pneumonia was treated with liposomal amphotericin B. Why use liposomal preparation over the regular colloid suspension of amphotericin B? (class question) ```

Answer 64

because of the decreased systemic toxicity of the liposomal preparation of amphotericin B (later generation formulation intended to decrease toxicity; not incredibly successful and more expensive)

Question 65

``` How are amphotericin B products administered? (class question) ```

Answer 65

IV (not orally)

Question 66

``` Voriconazole interacts with which CYP the most, and is therefore the most impacted by the high rate of variability/polymorphisms in this enzyme? (class question) ```

Answer 66

CYP2C19

Question 67

``` Which azole is affected by the most P450 enzymes? (class question) ```

Answer 67

Voriconazole

Question 68

``` What is a TDM? (class question) ```

Answer 68

"therapeutic drug monitoring" - monitoring of serum levels of drug during a treatment course to ensure sufficient absorption due to the high variability of bioavailability among patients

Question 69

``` What host factors predispose towards a fungal infection? (class question) ```

Answer 69

immunocompromised; patients living in hospitals; chemotherapy

Question 70

``` What are the resistance mechanisms to antifungals? (class question) ```

Answer 70

- target modification - efflux - alternative pathways