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CMOD- Block1 > Pharm: Systemic Antifungals > Flashcards

Pharm: Systemic Antifungals Flashcards

1
Q

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

A

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

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2
Q

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

A

Flucytosine

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3
Q

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

A

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

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4
Q

Describe the MOA and indications of Amphotericin B.

A

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

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5
Q

Describe the MOA and indications of Caspofungin (echinocandins).

A

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

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6
Q

Please characterize Fluconazole.

A

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

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7
Q

Please characterize Itraconazole.

A

poor CSF penetration, new formulations overcome poor oral bioavailability

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8
Q

Describe the MOA and indications of Terbinafine.

A

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

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9
Q

Describe the MOA and indications of Nystatin.

A

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

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10
Q

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

A
  1. systemic - administered either orally or parenterally

2. topical - for mucocutaneous infections

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11
Q

What is the first line drug choice for Aspergillosis?

A

Voriconazole

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12
Q

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

A

Itraconazole

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13
Q

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

A

Amphotericin B IV then Itraconazole PO

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14
Q

What is the first line drug choice for Candidiasis?

A

Fluconazole

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15
Q

What is the first line drug choice for Coccidioidomycosis?

A

Fluconazole IV/PO or Itraconazole PO

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16
Q

What is the first line drug choice for Cryptococcus?

A

Amphotericin B IV plus Flucytosine PO, then Fluconazole PO

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17
Q

What is the first line drug choice for Histoplasmosis?

A

Amphotericin B IV plus Itraconazole PO

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18
Q

What is the first line drug choice for Mucormycosis?

A

Amphotericin B

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19
Q

What is the first line drug choice for Sporotrichosis?

A

Amphotericin B IV and/or Itraconazole PO

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20
Q

What all infections would Voriconazole be used for?

A

Aspergillosis

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21
Q

What all infections would Itraconazole be used for?

A

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

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22
Q

What all infections would Fluconazole be used for?

A

Candidiasis, Coccidioidomycosis, Cryptococcus*

*would be in combination with another drug

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23
Q

What all infections would Flucytosine be used for?

A

Cryptococcus*

*would be in combination with another drug

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24
Q

What all infections would Amphotericin B be used for?

A

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

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25
Q

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

A

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

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26
Q

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

A

blocks synthesis of ergosterol

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27
Q

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

A

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

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28
Q

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

A

nucleic acid synthesis; cell replication

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29
Q

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

A 
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.
30
Q

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

A

squalene

31
Q

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

A

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

32
Q

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

A

Echinocandins

33
Q

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

A

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

34
Q

Which drugs discussed are imidazoles and which are triazoles?

A

imidazoles: ketoconazole
triazoles: fluconazole

35
Q

What interaction do azoles have with CYP450 enzymes?

A

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

36
Q

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

A

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

37
Q

____ 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.

A

Ketoconazole and itraconazole; fluconazole and voriconazole

38
Q

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

A

fluconazole - eliminated in urine

39
Q

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

A

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

40
Q

Can fluconazole and voriconazole be administered in pregnancy?

A

No

41
Q

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

A
  • hepatic damage - sometimes irreversible
  • cardiac arrhythmogenic events
  • adrenal insufficiency - unique to ketoconazole
42
Q

How does adrenal insufficiency arise from use of ketoconazole?

A

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

43
Q

Voriconazole is associated with what side effects?

A

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)

44
Q

Please characterize Posaconazole.

A

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

45
Q

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

A

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

46
Q

Does flucytosine have a wide or narrow therapeutic window?

A

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)

47
Q

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

A

CYP3A4; Terbinafine

48
Q

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

A

True

49
Q

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

A

lymphopenia and neutropenia

50
Q

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

A

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

51
Q

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

A

Azoles

52
Q

Some ____ are pro-arrhythmogenic.

A

azoles

53
Q

The best tolerated azole is ____.

A

Fluconazole

54
Q

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

A

solubility; nephro-toxic

55
Q

Griseofulvin is used in the systemic treatment of ____.

A

dermatophytosis

56
Q

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

A

pore formation in the cell membrane (not cell wall)

57
Q 
For a patient given a drug that inhibits fungal P450: which drug was most likely given?
(class question)
A

an azole

58
Q 
For a patient given terbinafine: which enzyme was most likely inhibited?
(class question)
A

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

59
Q 
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)
A

the toxicity of accumulated squalene

60
Q 
Are amphotericin B and the azoles are considered fungicidal or fungistatic?
(class question)
A
  • 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
61
Q 
What type of drug-drug interactions would you be MOST concerned about in a patient receiving amphotericin B?
(class question)
A

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

62
Q 
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)
A

infusion reaction

63
Q 
First side effect to think about with amphotericin B is \_\_\_\_ and the second is an \_\_\_\_.
(class question)
A

nephrotoxicity; infusion-related reaction

64
Q 
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)
A

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)

65
Q 
How are amphotericin B products administered?
(class question)
A

IV (not orally)

66
Q 
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)
A

CYP2C19

67
Q 
Which azole is affected by the most P450 enzymes?
(class question)
A

Voriconazole

68
Q 
What is a TDM?
(class question)
A

“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

69
Q 
What host factors predispose towards a fungal infection?
(class question)
A

immunocompromised; patients living in hospitals; chemotherapy

70
Q 
What are the resistance mechanisms to antifungals?
(class question)
A
  • target modification
  • efflux
  • alternative pathways

CMOD- Block1 (36 decks)

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