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Drug Action IV > Antifungal (MC) - Block 3 > Flashcards

Antifungal (MC) - Block 3 Flashcards

1
Q

How are fungi similar to mammalian cells?

A
  1. Eukaryotic
  2. Biochemical structures and cell membranes
  3. DNA is organized into chromosomes in the cell nucleus containing distinct cytoplasmic organelles
  4. Share similar mechanisms for DNA replication and protein synthesis
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2
Q

What is the major sterol of fungi?

A

Ergosterol through 14-reductase

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3
Q

How does ergosterol differ from cholesterol?

A

Additional double bonds hive the structure flexible rigidity

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4
Q

What is the primary sterol in mammals?

A

Cholesterol

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5
Q

Disruption of protein/carb matrix in a defective cell wall leads to?

A

Cells become sensitive to osmotic lysis similar properties to antimicrobial cell wall inhibitors

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6
Q

What are the types of fungal infections?

A
  1. Superficial mycoses (Dermatophytoses)
  2. Deep seated mycoses (systemic mycoses)
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7
Q

Dermatophytoses activity?

A

Capable of digesting keratin of the skin

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8
Q

How do superficial mycoses differ from systemic?

A

Non-contagious unless immunocompromised and neonates

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9
Q

Why are glucan synthesis inhibitors safe?

A

No analogous mammalian cell wall structure (no harm to human cells)

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10
Q

What is the target for glucan synthesis inhibitors?

A

b1,3-glucan synthase

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11
Q

What are the types of echinocandins?

A

Fungicidal against yeast (Candida)
Fungistatic against mold (Aspergillus)

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12
Q

What are the therapeutic uses for echinocandins?

A
  1. Broad range (especially against all candida)
  2. Used in azole resistant candida
  3. Low toxicity
  4. Better than Amphotericin B and fluconazole against yeast infection
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13
Q

Where does echinocandin B derive from?

A

Precursor of Anidulafungin -> effective against A. nidulans

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14
Q

Types of echinocandins?

A
  1. Caspofungin
  2. Micafungin
  3. Anidulafungin
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15
Q

Indication of caspofungin?

A
  1. EMpiric
  2. Treatment of invasive aspergillosis and Candida
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16
Q

Indication of micafungin?

A

Treatment of candidemia and prophylaxis

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17
Q

How does lipophilicity contribute to echinocandin activity?

A

Long lipophillic tail: hemolytic in vitro (insertion into cell membrane)
Short lipophillic tail: loss of activity
LogP >3.5: antifungal

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18
Q

What enzymes are targeted by ergosterol synthesis drugs?

A
  1. Squalene epoxidase
  2. 14a-demethylase
  3. Δ14-reductase (not approved)
  4. Δ7, Δ8 isomerase (not approved)
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19
Q

What is ERG1?

A

Squalene metabolized by squalene epoxidase to squalene epoxide

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20
Q

What is ERG11?

A

Lanosterol’s C14 become dimethylated by C14-demethylase

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21
Q

What is ERG24?

A

d14-reducase reduces structure

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22
Q

What is ERG2?

A

C8-isomerase shifts 8-9 alkene

23
Q

What is the SAR of squalene epoxidase inhibitors?

A

Allylamine

24
Q

Activity of squalene epoxidase inhibitor?

A

Narrow spec and only effective against nail and skin dermatophytes

25
Q

Are there selectivity issues of squalene epoxidase inhibitors?

A

Enzyme is present in mammalian cholesterol pathways, but have lower affinity for these agents and most are used topically

26
Q

What is the major functional group for squalene epoxidase inhibitors?

A

Allyl amine

27
Q

What are the types of squalene epoxidase inhibitors?

A
  1. Naftifine
  2. Terbinafine
  3. Butenafine
  4. Tolnaftate
28
Q

Describe the activity of 14α-demethylase Inhibitors?

A

CYP450 enzyme that are present in mammalian cholesterol pathway
* High probability of CYP450 interactions

29
Q

Describe the binding of 14α-demethylase Inhibitors?

A

Azole drug binds to Fe in place of histidine -> CYP can no longer bind/carry molecular O2 effectively inhibiting the enzymatic process

30
Q

How are all CYP enzymes structurally similar?

A

Contains a heme cofactor coordinating molecular O2

31
Q

Describe the activity of azoles based on its structure?

A

Chain mimics sterol scaffold
Azole bind to Fe

32
Q

SAR of azole?

A
  1. 1,2, 4- triazole with pKa of 6.5-6.8 (charged at vaginal pH)
  2. N3 of imidazole and N4 of imidazole of triazole binds to P450 iron
  3. Most active ones have 2-3 aromatic rings, one can be substituted with halogens or nonpolar group (most have fluorine)
33
Q

Target of azole

A

14a-demethylase

34
Q

Types of azoles?

A
  1. Clotrimazole
  2. Butoconazole
  3. Econazole
  4. Miconazole
  5. Ketoconazole
  6. Itraconazole
  7. Posaconazole
  8. Fluconazole
  9. Voriconazole
35
Q

DDI of ketoconazole?

A

Potent CYP3A4 inhibitor

36
Q

What isavuconazonium sulfate?

A

Systemic prodrug formulation (enhanced solubility) used for the tx of aspergillosis and candidiasis

37
Q

Examples of Δ14 reductase inhibitor? Indication?

A

Amorolfine: treatment of dermatophytosis

38
Q

Examples of Δ7, Δ8-Isomerase Inhibitors

A

Amorolfine

39
Q

What are the groups of polyene membrane disrupters?

A

A 26-member ring: Natamycin
A 38-member ring: Amphotericin B and Nystatin

40
Q

Polyene MOA?

A

Binds to ergosterol -> formation of pores:
* Increase permeability to proteins and monovalent and divalent cations
* Eventual cell death

Attach with higher affinity to ergosterol over cholesterol membranes

41
Q

Describe the toxicity of polyene specifically amphotericin B?

A

Amphotericin B: may induce oxidative damage in fungal cells
* At higher concentrations, amphotericin B binds to cholesterol in mammalian cell membranes
* Nephrotoxicity

42
Q

Describe the binding of amphotericin B? SAR?

A

H-bond between hydroxyl, carbonyl, and amino groups of the drug and membrane making the channel stable:

43
Q

Inidication for amphotericin B?

A

Lethal fungal infections such as coccidimycosis and histoplasmosis:
* Systemic infection
* Admin intrthecally to get into the CNS

44
Q

How does nystatin compare to amphotericin?

A
  1. 38 membered ring
  2. No systemic absorption
  3. Toxic when given IV
  4. MOA is same as amphotericin
45
Q

Indication for nystatin?

A

Dermal and GI infections from Candida albicans

46
Q

What is natamycin?

A

26-membered macrolactone, MOA is similar to amphotericin B
* Topical as cream, eyedrop, lozenge
* No systemic absorptio

47
Q

What polyene is given IV?

A

Amphotericin B

48
Q

What are DNA and protein syntheis difficult targets for selective toxicity?

A

Fungal cells share similar homology in DNA replication and RNA translation with mammalian cells

49
Q

What enzyme is responsible for flucytosine transport?

A

Cystosine permease that converts drug to 5-fluorouracil (5-FU) in the cytoplasm

50
Q

That is the toxic form of flucytosine?

A

5-FdUMP that traps thymidylate synthase and folate

51
Q

MOA of flucytosine?

A

5-FU is phosphorylated and incorporated into RNA -> miscoding and halts protein syntheis
* Inhibits DNA synthesis through thymidylate synthetase

52
Q

MOA of griseofulvin?

A

Inhibits fungal cell mitosis by disrupting mitotic spindle formation (critical for cellular division)

53
Q

Indiation for griseofulvin?

A

Dermatophytes:
* Enters in the structure of the precursors of keratin
* Doesn’t have local activity (not topical)

54
Q

Fatty acid product that is a natural antifungal?

A

Sebum

Drug Action IV (28 decks)

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