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Pharmacology > Antifungals > Flashcards

Antifungals Flashcards

1
Q

3 most common systemic antifungals

A

Candidiasis
Cryptococcus
Aspergillosis

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2
Q

Drugs that alter cell membraine permeability

A

Polyenes
Azoles
Allylamines

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3
Q

Drugs that block nucleic acid synthesis

A

Flucytosine

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4
Q

Drugs that disrupt microtubule function

A

Griseofulvin

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5
Q

Drugs that disrupt the fungal cell wall

A

Echinocandins

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6
Q

Systemic drugs for subcutaneous and systemic mycoses

A

Ampotericin B
Flucytosine
Azoles
Echinocandins

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7
Q

Amphotericin B
MOA
RANGE of USE

A

Polyene antibiotic

  • binds ergosterol and forms pores IN CELL MEMBRANE
  • leakage of intracellular ions and macromolecules–>cell death
  • Broadest spectrum - yeast, endemic mycoses, pathogenic molds
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8
Q

Amphotericin B
PK
What procedure can cause seizures as a side effect?

A
  • highly insoluble:
  • IV only (SLOW IV INFUSION)
    poorly absorbed from the gut
    LOW CSF penetration
  • INTRATHECAL therapy WARNING can cause seizures!
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9
Q

Amphotericin B USES

A
  • Broad spectrum fungicidal
  • Often used as initial induction regimen to rapidly reduce fungal burden.
  • patients then continue therapy with an azole.
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10
Q

Amphotericin B prefere treatment for

A

deep fungal infections during pregnancy!!

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11
Q

Amphotericin B AE:

A

Infusion related toxicity

  • Nearly universal: Fever and chills, muscle spasms, vomiting, headache and hypotension.
  • Pre medication with Antiistamines, glucocorticoids, antipyetics or meperidine can be helpful!
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12
Q

Amphotericin B AE SLOWER TOXICITY?

A

Also binds cholesterol and forms mammalian cell membrane pores, leading to renal toxicity!!
- Renal impairment in all pts
• Azotemia occurs in most patients.
• GFR may be decreased.
• Renal toxicity commonly presents with renal tubular
acidosis with severe magnesium and potassium
wasting.
• Renal damage can be attenuated with sodium
loading: it is common practice to administer SALINE INFUSION with amphotericin B.

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13
Q

Amphotericin B AE SLOWER toxcicty 2?

A

• Hypochromic normocytic anemia, due to reduced
erythropoietin production.
• Renal function should be monitored frequently
during amphotericin B therapy.
• It is also advisable to monitor liver function, serum
electrolytes (particularly magnesium and
potassium), blood counts, and hemoglobin.

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14
Q

Amphotericin Lipid formulations use?

A

Package in lipid carriers to reduce interaction with nephron

  • Liposomal amphotericin B (L-AMB)
  • Amphotericin B Lipid complex (ABLC)
  • Amphotericin B colloidal dispersion ( ABCD)
  • Nephrotoxicity is less common and less severe with the lipid formulations
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15
Q

Flucytosine analogue of?

A

Cytosine

- pyramidine antimetabolite

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16
Q

Flucytosine MOA?

A

Taken up by fungal cells via cytosine permease
- disrupts RNA and DNA synthesis

Flucytosine –> 5-Fluorouracil (intracellular conversion) –> 5-fluorodeoxyuridine monophosphate –> inhibits THYMIDYLATE SYNTHASE thus blocking dTMP.

Flurorouridine triphosphate is also formed, which inhibits protein synthesis (5-FUTP)

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17
Q

Can mammalian cell convert Flucytosine to its active metabolites?

A combo with what drug shows synergism with Flucytosine?

A
  1. NO

2. Amphotericin B

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18
Q

Flucytosine spectrum

A

Fungistatic
Narrow spectrum
Not used as a single agent because of synergy with other agents, and to avoid resistance

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19
Q

Fucytosine USES

A

• Indicated only for serious infections caused by
susceptible strains of Candida and/or
Cryptococcus.
• Should be used in combination with
amphotericin B for the treatment of systemic
candidiasis and cryptococcosis in order to avoid
resistance.

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20
Q

Flucytosine AE:

A

Results from metabolism (intestinal flora) to 5-fluorouracil

- Bone marrow toxicity is the mot common.

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21
Q

AZOLES

A

Non toxic oral drugs
systemic therapy
IMIDAZOLES and TRIAZOLES

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22
Q

Imidazoles

A

“KMC”
Ketoconazole–> (inhibits 17, 20 desmolase 1st step of steroid synthesis)
Miconazole (my cone)–> tinea infections
Clotrimazole (close trim)–> tinea infections

23
Q

Triazoles

A 
"VIP Flu"
Itraconazole
Fluconazole
Voriconazole
Posaconazole (posaco)
24
Q

Azoles: MOA

A

Inhibit CYP 450 enzyme 14 alpha demethylase from converting Lanosterol to ergosterol.
- increases permeability by disrupting membrane function.

25
Q

CYP 450 enzyme specifity for azoles?

which ones have higher specificity?

A

High affinity for fungal CYP450 than human

Triazoles

26
Q

Azoles AE

A

Relatively non toxic

minor GI upset

27
Q

Ketoconazole MOA

A
  • Inhibits mammalian CYP450 (CYP3A4) enzymes
  • decreases plasma testorsterone levels and causes gynecomastia
  • decreaed libido in men and loss of potency
  • menstrual irregularities in womne
  • high doses may inhibit adrenal steroid synthesis and decrease plasma cortisol concentrations
28
Q

Ketoconazole is a CYP3A4 inhibitor what drugs can it potentiate toxcicities?

when is it best absorbed?

A

Warfarin and cyclosporine
At low gastric levels
- antacids, H2 blockers or proton pump inhibitots interfere w/ absorption
-poor CSF penetration

29
Q

Ketoconazole is rarely used for?
Why?
still used for?

A

due to narrow spectrum and AE

used for cutaneous mycoses

30
Q

Flucanazole PK?

A

GOOD CSF PENETRATION**

High oral bioavailability
IV and Oral
Moderate inhibitor of CYP3A4
Strong inhibitor of CYP2C9 –> increases plasma phenytoin, zidovudine and warfarin!

31
Q

Fluconazole DOC

A

DOC in esophageal, oropharyngeal, vulvovaginal or urinary candidiasis

DOC for Candidemia

DOC for coccidoidomycosis

DOC for consolidation and maintenance of crytpococcal meninigitis after induction w/ amphotericin B
- alternative to amphotericin B for non-severe criptococcal meningitis

DOC for initiial and secondary prophylaxis against cryptococcal meningitis!

32
Q

Fluconazole USES:

is ineffective against?

A

Aspergillus or other filamentous fungi!

33
Q 
Itraconazole:
Metabolizes and inhibits?
causes what fatal problem when administered w/ what 2 drugsl?
PK?
Can penetrate?
what reduces absorption?
A 
CYP3A4
arryhthmias when adminisitered w/ cisapride and quinidine
Poor bioavaibility
Penetrates poorly in CSF
Antacids, H2 blockers and PPIs
34
Q

Itraconazole uses?

butterfly is dimorphic

A

• Preferred azole for mycoses due to the
dimorphic fungi Blastomyces, Sporothrix and
Histoplasma.
• Effective against Aspergillus, but has been
replaced by voriconazole for this indication.
• Used for dermatophytoses and onychomycosis

35
Q

Voriconazole DOC

A

DOC invasive ASPERGILLLOSIS

-spectrum similar to itraoncazole

36
Q

Voriconazole AE

A

• Transient visual disturbances occur in up to 30% of patients.
• metabolized by and inhibits
CYP2C19, CYP2C9 and CYP3A4.
• The significant number of drug interactions due
to its metabolism through the various hepatic
enzymes may limit its use.

37
Q

Posaconazole USES

inhibits?

A

used against zygomycetes (MUCOR)

- inhibits CYP3A4

38
Q

ECHINOCANDINS: CASPOFUNGIN

spectrum of activity

A

• Active against candida and aspergillus but
not Cryptococcus neoformans.
• Only available IV.

39
Q

ECHINOCANDINS: CASPOFUNGIN MOA?

A

• Inhibit synthesis of β(1-3)-D-glucans in the
fungal cell wall.
• This results in disruption of the fungal cell wall
and cell death

40
Q

Systemic drugs for superficial mycoses

A 
"FIT Keys onto Surface":
• Griseofulvin
• Terbinafine
• Ketoconazole
• Fluconazole
• Itraconazole
41
Q

Griseofulvin
whats its only use?
Absorbs best with?
MOA

A
  • Only use: treatment of severe dermatophytosis of skin, hair and nails
  • Absorption improved when given with fatty foods.

MECHANISM OF ACTION
• Disrupts mitotic spindle and inhibits mitosis.

42
Q

Griseofulvin has been replaced w/?

Is an inducer of?

A
  • newer antifungal drugs like
    itraconazole and terbinafine.

• Induces P450 enzymes: increases metabolism
of a number of drugs, including warfarin.

43
Q

Terbinafine
what type of antifungal is it?
PK?

A
  • Allylamine.

* Available in oral formulation

44
Q

Terbiafine MOA

A

inhibits squalene epoxidase!!
prevents synthesis of ergosterol.

• It also causes
accumulation of toxic
levels of squalene in the
fungal cell.

45
Q

Terbinafine like griseofulvin accumulates in?

Its more effective in?

A

Keratin!

Much more effective in onychomycosis!!

46
Q

what Azoles are commonly used in the treatment of dermatophytoses?

A

“KIt Fits the skin (derm)”
Ketoconazole
Itraconazole
Fluconazole

47
Q

Topical drugs for superficial mycoses?

A
  • Nystatin
  • Amphotericin B
  • Clotrimazole
  • Miconazole
  • Ketoconazole
  • Terbinafine
48
Q

NYSTATIN

A

• Polyene macrolide.
• Structurally similar to amphotericin B.
• Same mechanism of action.
68
NYSTATIN
• Too toxic for IV administration.
• Used only for candidiasis.
• Supplied in preparations for cutaneous,
vaginal, or oral administration.
• Not absorbed from the GI tract, skin, or
vagina.
• As a result it has little significant toxicity

49
Q

What is topical amphotericin B used for?

A

Cutaneous candidiasis

50
Q

The two azoles most commonly used

topically?

A

CLOTRIMAZOLE
MICONAZOLE
-available over the counter

51
Q

Terbanafine effective against?

A
  • Available as topical creams.

* Effective for tinea cruris and tinea corporis.

52
Q

WHAT FUNGUS DOES NOT RESPOND TO ANTIFUNGALS?

A

Pneumpcystis Jirovecii Penumonia (PCP)

53
Q

DOC for PCP, also DOC for prevention of PCP n immunocompromised individuals?

A

Co-trimoxazole

54
Q

PNEUMOCYSTIS JIROVECII PNEUMONIA

Therapies:

A 
• Alternative therapies are:
• Clindamycin + primaquine
• Dapsone + trimethoprim
• Atovaquone
• Pentamidine
• Patients with moderate-to-severe disease should
also be given prednisone.

Pharmacology (27 decks)

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