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Pharm Exam 2 > AntiFungals > Flashcards

AntiFungals Flashcards

1
Q

Microsporum & Trichophyton

• superficial or deep mycoses?

A

Superficial
= skin, keratinized structures (nail, claw, hair)
– no living tissue

= dermatophytes w/ proteolytic enzymes
–> penetrate keratin tissue

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2
Q

Blastomycoses, Coccidioidomycoses, Cryptococcosis, Histoplasmosis

• superficial or deep mycoses?

A

Deep

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3
Q

What is the reason why superficial mycotic agents are hard to treat with systemically administered drugs?

A

Colonize cornified tissues (often little blood supply)

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4
Q

What is the reason why deep mycotic agents are hard to treat with drugs?

What is another challenge?

A

1 – getting the drugs TO the fungal agent
– protected by granulomas or away from blood supply
(NEED TO BE LIPOPHILIC to penetrate more tissues)

2 – killing the fungal agent w/o killing the host
(need selective toxicity)


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5
Q

What animals are most at risk for Aspergillosis?

A

-opportunistic fungus

  • Immunosuppressed animals
  • glucocorticoid- suppression
  • Prolonged Abx therapy
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6
Q

Is griseofulvin used to Tx superficial or deep mycoses?

What about yeasts?

A
  • Tx superficial mycoses

NOT effective against deep mycoses or even yeasts

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7
Q

microsized VS ultramicrosized formulation of griseofulvin?

Which would require a higher dose to achieve a particular drug concentration in the body?

A

Microsized
• Poorly absorbed = 25-70%

Ultramicrosized
• 100% absorption

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8
Q

griseofulvin
• MOA?

Is griseofulvin cidal or static?
Does it work rapidly or slowly?

A
  • taken up by keratinocytes via active transport
  • -> keratinocytes are pushed to the stratum corneum (where infection is located)
  • -> inhibits microtubules of mitotic spindle
  • -> Arrests cell in metaphase
  • does not kill fungal agent outright
  • Needs 4-6wks+ to clear infection
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9
Q

Why is griseofulvin selectively toxic?

A

-Mammalian microtubule’s receptor sites are slightly different

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10
Q

Where does griseofulvin concentrate in the body?

Where will you see the fastest response to therapy? Why?

A
  • concentrates in keratinocytes
    w/in 4hrs

• Areas of rapid skin/hair growth
–> highest concentration of drug

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11
Q

What is the most common side effect of griseofulvin in dogs and cats?

Why do cats generally have more problems with antimycotic drugs than dogs?

A
  • GI tract (Vomiting, diarrhea)

Cats
- reduced capacity to metabolize the drug
most of these antifungals are metabolized by the liver

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12
Q

What less common additional idiosyncratic problem do cats have on griseofulvin that dogs do not?

A

Bone marrow suppression in cats
• FIV+ seems to be more at risk

Teratogenic

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13
Q

Why is griseofulvin contraindicated for use in pregnant cats?

A

skeletal & cranial malformations

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14
Q

What are the two general groups of azole antifungals?

A
  1. Triazoles

2. Imidazoles

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15
Q

Mechanism of Azoles
• What is the enzyme the azoles target?
• What does altering that enzyme cause in the fungal cell?

A

Target
= cytochrome P-450 enzyme
• needed for ergosterol synth

↓ ergosterol

  • -> toxic intermediates incorporated in cell membrane
  • -> changes stability / permeability of membrane
  • -> lack ability to regulate e-lyte movement
  • -> FUNGISTATIC!
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16
Q

What makes azoles fairly selectively toxic?

Can cytochrome P-450 in mammals also be affected by azoles?

A
  • mammalian CYP 450 has a much lower affinity for Azoles
    (compared to fungal CYP 450)

• imidazoles are less specific
(keto-, clotrim-, miconazole)

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17
Q

What are the physiologic reasons that you could have adverse drug interactions with Azole drugs?

A

1 - inhibit CYP450
–> ↓ metabolization of other drugs

2- Inhibit P-gp efflux pump
–> ↑ drug absorption

• Bc dose is based on presence of these 2 factors, inhibition of them

  • -> ↑ drug in circulation
  • -> toxicosis possible
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18
Q

What is the reason that ketoconazole is given with cyclosporin?

A

REQUIRES A LOWER CYCLOSPORIN DOSE to achieve effect

  • Normally metabolized by CYP 450 & P-gp efflux pump
  • Giving ketoconazole concurrently inhibits these mechanisms ↑ absorption of cyclosporin
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19
Q

Why shouldn’t ketoconazole be used with antacid drugs?

A
  • needs an acidic environment to be absorbed with the PO route
Acidic environment (pH <3)
• non-ionized / lipophilic
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20
Q

Can ketoconazole be used to treat mycotic infections located in the brain or the eye? Why or why not?

A
  • can’t cross BBB

• Not in lipophilic form at pH 7.4

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21
Q

How can GI side effects from ketoconazole be reduced?

A

split daily dose

• GI signs are dose related

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22
Q

What parameters change on the blood chemistry profile when an animal is put on ketoconazole?

A
  • Hepatic enzymes mildly
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23
Q

Is ketoconazole safe in pregnant animals?

A

Teratogenic effects in dogs:
• mummified fetuses
• stillbirth

Excreted in milk

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24
Q

What endocrine effect does ketoconazole have?

What impact could this have on animals?

How is this side effect used therapeutically?

A 
BAD FOR BREEDING ANIMALS!!
• Inhibits conversion of progesterone to testosterone
(cytochrome P-450)
--> drop in testosterone 
(impact on breeding animals)

GOOD FOR CUSHING ANIMALS
• inhibit sterol to cortisol conversion (CYP 450)
–> ↓ cortisol in adrenal tumor
• Not drug of choice (but less expensive option)

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25
Q

Which is more potent (mg required to produce clinical effect) & best at targeting Aspergillosis:

ketoconazole or itraconazole?

A

Itraconzole

• 5-100X more potent

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26
Q

Does itraconazole have the same endocrine effects as ketoconazole?

A

Fewer side effects than ketoconazole

– does not inhibit mammalian P-450 enzymes involved with endocrine function

27
Q

Does itraconazole need acid conditions to be absorbed from the GI tract?

A
  • needs acidic pH to be absorbed

– give w/ food (more consistently absorbed)

28
Q

Does itraconazole penetrate the CNS & eye?

A

Does NOT penetrate well

• except if inflammation has disrupted blood barriers

29
Q

What impact does itraconazole have on absorption of other drugs?

A
  • inhibition of P-gp

- -> ↑ ants of drug allowed to enter body

30
Q

For what is itraconazole the treatment of choice?

A

drug of choice for long term Tx for histo, blasto, crypto, & coccioidomycosis

31
Q

side effects of itraconazole vs ketoconazole side effects?

A
  • Cats tolerate itraconazole better

Both

  • dose-related vomiting/diarrhea
  • Hepatic enzymes elevate
32
Q

For what equine mycotic infection has itraconazole been used?

A

-guttural pouch mycosis

33
Q

Which is more potent:

ketoconazole or fluconazole?

A

Fluconazole
• 100x’s more potent

• less effective than itraconazole against deep mycoses

34
Q

Fluconazole

• requirements for absorption PO?

A
  • Better absorption
  • feeding not required
  • NOT dependent upon acidic pH for absorption
    –indicated if concurrently on antacid drugs
35
Q

For what specific types of mycotic infections is fluconazole indicated and why?

A

• cross BBB and OBB

   - mycotic meningitis 
   - ocular mycoses

• eliminated intact via kidney
- mycotic cystitis

36
Q

Does fluconazole have GI side effects?

A
  • dose related
37
Q

Does fluconazole have endocrine side effects? So does it resemble keto- or itraconazole in this way?

A
  • evidence of inhibition of progesterone to testosterone conversion

(resembles itraconazole that way)

38
Q

How is the route of elimination different for fluconazole compared to keto- and itraconazole?

A
  • intact via kidney
39
Q

Why should amphotericin B & azoles not be used simultaneously?

If they are used together, in what sequence are they used?

A

Amphotericin B

  • Binds to TRUE ergosterol in membrane
  • -> creates pores in fungal cell membrane
  • -> leakage

Azoles

  • inhibit proper synth of ergosterol
  • -> ↓ amphotericin B effectiveness

• Punch holes quickly
THEN make them more unstable by ↓ ergosterol synth

40
Q

Which works faster

– the azoles or amphotericin B?

A
  • Amphotericin B
41
Q

What is the major side effect of amphotericin B?

• how do you monitor?

A

Kills kidneys!!!

  • combines w/ cholesterol of renal tubular cells
  • -> punch holes in membrane
  • 2° vasoconstriction

• less common with liposomal form

Monitor = UA – look for casts & protein

42
Q

Liposomal form of amphotericin B

• What impact does it have?

A

Lipid complexed
• deliver the drug to the fungal agent & ↓ exposure of mammalian cell membrane cholesterol to drug
–> Lower toxicity!!

43
Q

For what fungal agent is lufenuron supposedly used for?
Why is it supposed to work?

What is the evidence that lufenuron actually works?

A
  • Fungi wall has chitin (like fleas!)
  • -> blocks chitin production

• no clear evidence

44
Q

With what other antifungal drug is flucytosine (5-FC) used w/ as a synergist?

A

• w/ amphotericin B

45
Q

How is iodine used as an antifungal agent?

A

antifungal shampoo

• unknown mechanism

46
Q

What is terbinafine used for in human medicine?

How much do we know about its use in veterinary medicine?

A

Lamasil®
• topical cream for fungal nail infections

  • limited data in vet med
  • aspergillis?
  • blocks squaline –> sterols
47
Q

Clotrimazole route of administration? why?

What is clotrimazole used for?

A

topical applications
- not well absorbed PO

Otomax®
= Otic preparation w/ gentamicin & betamethasone (corticosteroid)
• Malassezia infections!

Lotrimin®
• used for nasal aspergillosis

48
Q

What is miconazole used for?

• route of administration?

A

Conofite®
• topical applications

shampoo & liquid preparation w/
chlorhexidine

49
Q

What is nystatin used for?

• route of administration?

A

Mycostatin®
• topical applications mainly for yeasts (otic preparations)

Panalog®
- w/ neomycin (aminoglycoside) & triamcinolone (glucocorticoid)

50
Q

griseofulvin
• MOA
• effective against
• distinguishing characteristics

A

Griseofulvin taken up by active transport

  • -> concentrates in fungus
  • -> inhibits microtubules
  • -> arrests cell in metaphase
51
Q

azoles

A

-

52
Q

ketoconazole

A

-

53
Q

itraconazole

A

-

54
Q

fluconazole

A

-

55
Q

clotrimazole

A

-

56
Q

miconazole

A

-

57
Q

amphotericin B

A
  • Antifungal effect continues on even after concentrations of the drug have dropped below therapeutic concentrations
    • Allows for “pulse” dosing

Don’t use w/ azoles

58
Q

Program®

A

lufenuron

59
Q

flucytosine (5-FC)

A

-

60
Q

potassium or sodium iodine

A

-

61
Q

Lamasil®

A

terbinafine

62
Q

nystatin

A

-

63
Q

Superficial mycotic agents

A

Microsporum & Trichophyton

  • acquired by contact w/ skin / hair
  • Spread more readily in hot, humid, crowded settings

• Colonize cornified tissues (often little blood supply)

64
Q

Primary organs affected by deep mycotic agents?

A

Pulmonary / GI tract

  • -> hematogenous spread
  • -> manifest in superficial tissues (skin or nasal cavity)

Pharm Exam 2 (9 decks)

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