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Spring 2025 Therapeutics V > Exam 5: Medicinal Chemistry of Antifungal Drugs > Flashcards

Exam 5: Medicinal Chemistry of Antifungal Drugs Flashcards

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1
Q

What are the 2 types of fungal infections?

A

Superficial

Cutaneous

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2
Q

What are the features of a subcutaneous fungal infection?

A

Fungi are generally implanted in skin

Fungal growth produces a lesion

*These are more concerning infections

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3
Q

What are the features of a systemic/invasive fungal infection?

A

Fungi have invaded the deep tissues

*Can be self limiting or cause severe disease with high mortality

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4
Q

Why are some drugs like Amphotericin B able to target fungal cells and not human cells?

A

Fungi make a derivative of cholesterol called ergosterol

-The medications are able to target biosynthesis of this to kill the fungal cells

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5
Q

Which drugs are part of the polyenes class?

A

Amphotericin B

Nystatin

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6
Q

Are polyenes fungicidal or fungistatic?

A

Fungicidal

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7
Q

What is the moa of Amphotericin B?

A

Binds to ergosterol (the predominant sterol in fungal cell membranes)

-causes intercalation of the membrane and ions + proteins leak through in either direction

-may withdraw the ergosterol from the membrane to form pores

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8
Q

Why is Amphotericin B specific for fungal cells?

A

Mammalian cells do not contain ergosterol, they have cholesterol

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9
Q

What are some clinical points to remember about Amphotericin B?

A

Poorly absorbed from GI tract

Oral form can only be used for GI infections

IV required for systemic infections

CNS levels are low so you need intrathecal therapy for fungal meningitis

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10
Q

What are the side effects of Amphotericin B?

A

This is a very toxic medication

-Need to premedicate infusions with diphenhydramine and/or acetaminophen for infusion-related reactions

*Renal Damage
-in nearly all patients
-only partially reversible

*Liver abnormalities

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11
Q

What is the drug of choice for life-threatening systemic fungal infections?

A

Amphotericin B

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12
Q

How long does an Amphotericin B infusion last?

A

1-4 h

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13
Q

What is Nystatin and what is its use?

A

It is a polyene drug similar to amphotericin B

*Too toxic for systemic administration so it is only used for superficial fungal infections

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14
Q

What are the 2 types of formulations of Amphotericin B?

A

Colloidal suspension (conventional)

Lipid formulations

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15
Q

How does the colloidal suspension of amphotericin work?

A

Uses a bile salt (deoxycholate) as a solubilizing agent

-this allows the drug to form micelles which stabilizes the drug

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16
Q

What is the benefit of using a lipid formulation of amphotericin?

A

They reduce nephrotoxicity

Ambisome reduces infusion toxicity

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17
Q

How do lipid formulations of Amphotericin B work?

A

Act as a reservoir of the drug

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18
Q

What is the pathway for ergosterol synthesis?

A

Squalene
(squaline epoxidase) ->
Squalene epoxide
Lanosterol
(CYP450 14a-demethylase) ->
Ergosterol

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19
Q

Which drug is part of the Allylamines class?

A

Terbinafine

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20
Q

What is the moa of terbinafine?

A

Disrupts ergosterol synthesis

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21
Q

Which enzyme does terbinafine inhibit to block ergosterol synthesis?

A

Squalene epoxidase

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22
Q

Is terbinafine fungicidal or fungistatic?

A

Fungicidal

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23
Q

How is terbinafine fungicidal?

A

A build-up of squalene leads to cell death

*not a loss of ergosterol

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24
Q

How is terbinafine selective for fungal cells?

A

2500-fold selectivity for fungal enzymes compared to mammalian enzymes

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25
What are the main uses of Terbinafine?
Oral and Topical -effective against dermatophytes, especially oncychomycoses
26
What is the largest class of antimycotics?
Azoles
27
What is the key structural feature of the azoles?
5-membered ring with at least one Nitrogen used for binding iron
28
How do the azoles use their structure to bind CYP450?
The N in the ring can bind iron in the CYP450 enzyme
29
Are azoles fungicidal or fungistatic?
Fungistatic*
30
What is the moa of the azoles?
Inhibit CYP450 14a-demethylase in the production of ergosterol Inhibit the binding and activation of molecular oxygen by CYP450 -do this by binding to iron in the CYP450 and blocking it *Ultimately inhibit conversion of lanosterol to ergosterol
31
How does selectivity with azoles work?
Humans also use CYP450 to make cholesterol for our cell membranes The fungal enzymes are more sensitive
32
Why is metabolism important to the use of azoles?
Azoles are metabolized extensively by liver CYP450's and inhibit them Only the azoles with reduced metabolism can be used for systemic infections -Other drugs metabolized through this pathway may increase azole concentrations -Azoles may increase the concentrations of other drugs metabolized by CYP450 -Inducers of CYPs can decrease azole levels
33
What is an example of a CYP-inducer that would decrease azole levels?
Rifampin
34
Which drugs are members of the azole class?
Ketoconazole Itraconazole Fluconazole Voriconazole Isavuconazole
35
What are some clinical pearls about Ketoconazole?
It is the first azole to have sufficient bioavailability able to be used for deep tissue infections
36
What are some clinical pearls about Itraconazole?
Based on ketoconazole but its structure is a triazole instead of imidazole (3 Nitrogens) This allows it to have improved specificity for CYP450 *not inactivated by human metabolism
37
What is an important thing to remember about Fluconazole's structure?
It has been substantially modified from ketoconazole and looks nothing like it "clover"
38
What are some clinical pearls about Voriconazole?
Similar structure to Fluconazole -Has an added methyl group that gives it improved binding to CYP450 and an increased spectrum
39
What are come clinical pearls about Isavuconazole?
Broad spectrum of activity Water soluble prodrug -does not require cyclodextrin for solubility *Long half-life
40
What is the prodrug of Isavuconazole?
Isavuconazonium
41
How does Oteseconazole differ from the other azoles?
*Selectively inhibits the fungal enzyme CYP51
42
What is Oteseconazole used for?
Reoccurring fungal or yeast infections
43
Which azole is a potent inhibitor of CYP3A4?
Ketoconazole
44
Besides rifampin, what other drugs interact with Ketoconazole?
Triazolam (increases its area under the curve) Cyclosporin (increases its bioavailability)
45
Which azole is metabolized in the liver by glucuronidation?
Posaconazole
46
How are Echinocandins made?
Lipopeptides -Synthetically modified fungal compounds
47
What is an important caveat about Echinocandin administration?
They all must be administered by IV
48
What is the structure of the echinocandins?
Cyclic hexapeptides with long, modified fatty acid side chains
49
What is the MOA of the Echinocandins?
Inhibit synthesis of B(1-3) glucan -this is a cell wall component The target enzyme is B(1-3) glucan synthase *these normally make cross-links in the outer fungal wall that are essential for wall stability
50
What is the mechanism of selectivity for the Echinocandins?
Mammalian cells lack the activity blocked by these drugs
51
Are echinocandins fungicidal or fungistatic?
Fungicidal
52
Echinocandins are synergistic with what other antifungals?
Voriconazole Amphotericin B
53
What is an important clinical pearl about Echinocandins?
They have no cross-reactivity with other antifungals *they are also synergistic
54
What are the echinocandin drugs?
Caspofungin Micafungin Anidulafungin Rezafungin
55
What are the uses of Caspofungin?
Mucocutaneous Candida Aspergillosis salvage therapy
56
What are the uses of Micafungin?
Mucocutaneous Candida Candida prophylaxis
57
What are the uses of Anidulafungin?
Esophageal candidiasis Invasive candidiasis
58
Which Echinocandin has the longest half-life and no known drug interactions?
Anidulafungin
59
How are echinocandins metabolized?
NOT by liver CYPs Degraded in blood and tissues (not very stable in the plasma)
60
How does Rezafungin differ from the other echinocandins?
It is a new, once-weekly IV treatment Used for candidiasis infections with limited or no alternative treatment options *Still has the same MOA of inhibiting B-glucan synthase enzyme Long half life (133 hrs)
61
What class of drug is Ibrexafungerp in?
It is the only drug in its class and does not have a specified class -similar to echinocandins though
62
What is the MOA of Ibrexafungerp?
Small molecule inhibitor of glucan synthase enzyme in fungi (same moa as echinocandins but is a small molecule)
63
What is Ibrexafungerp used for?
Candida in vulvovaginal candidiasis
64
What is the MOA of Flucytosine?
Antimetabolite (pyrimidine analog) -Inhibits thymidylate synthase -Interferes with protein synthesis
65
What is the mechanism of Flucytosine's specificity?
Mammalian cells are unable to convert flucytosine to active metabolite
66
Flucytosine synergizes with which other antifungal?
Amphotericin B
67
Which transporter is responsible for transporting Flucytosine across the cell membrane?
Cytosine Permease
68
What enzyme activates Flucytosine?
Cytosine deaminase
69
Ultimately, Flucytosine inhibits the conversion of what to what by thymidylate synthase?
dUMP to dTMP *does so by mimicking dUMP
70
How exactly does the 5-FdUMP form of Flucytosine inhibit thymidylate synthase?
In 5-FdUMP, there is a F where there is an H in dUMP F is the most electronegative atom which means it cannot be eliminated Thymidylate synthase becomes trapped in an inactive form and cannot interact with dUMP This results in no dTMP production and inhibition of DNA synthesis
71
What is a benefit of Flucytosine absorption/penetration?
It penetrates well into all fluid compartments including cerebrospinal fluid
72
What adverse effect can Flucytosine have and why?
Intestinal adverse effects Intestinal flora can metabolize 5-FU to an anti-cancer drug which leads to cell death *also has liver toxicity
73
When flucytosine and amphotericin B are combined what do we need to monitor for?
Liver toxicity -they both can cause it
74
Besides amphotericin B, what is the other drug that flucytosine can be administered with?
Fluconazole
75
Why is Flucytosine administered with Amphotericin B?
They hit 2 different enzymes Flucytosine has a very narrow therapeutic index and a limited spectrum of activity
76
For which specific disease state does flucytosine and amphotericin B need to be combined?
Cryptococcal meningitis
77
What is the MOA of the new drug Tavaborole?
Inhibits leucyl transfer RNA synthetase (LeuRS) *inhibits protein synthesis *boron is essential for activity
78
What is Tavaborole used for?
Onychomycosis (nail fungus)
79
Candida krusei is intrinsically resistant to what drug?
Fluconazole
80
Aspergillus terreus is intrinsically resistant to which drug?
Amphotericin
81
What is the antifungal of choice in pregnancy?
Amphotericin B -can also use topical agents

Spring 2025 Therapeutics V (41 decks)

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