AntiFungals Flashcards by Whitney Wolfgang

Microsporum & Trichophyton

• superficial or deep mycoses?

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

= dermatophytes w/ proteolytic enzymes
–> penetrate keratin tissue

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Blastomycoses, Coccidioidomycoses, Cryptococcosis, Histoplasmosis

• superficial or deep mycoses?

Deep

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

Colonize cornified tissues (often little blood supply)

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

What is another challenge?

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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What animals are most at risk for Aspergillosis?

-opportunistic fungus

Immunosuppressed animals
glucocorticoid- suppression
Prolonged Abx therapy

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Is griseofulvin used to Tx superficial or deep mycoses?

What about yeasts?

Tx superficial mycoses

NOT effective against deep mycoses or even yeasts

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microsized VS ultramicrosized formulation of griseofulvin?

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

Microsized
• Poorly absorbed = 25-70%

Ultramicrosized
• 100% absorption

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griseofulvin
• MOA?

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

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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Why is griseofulvin selectively toxic?

-Mammalian microtubule’s receptor sites are slightly different

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Where does griseofulvin concentrate in the body?

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

concentrates in keratinocytes
w/in 4hrs

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

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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?

GI tract (Vomiting, diarrhea)

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

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

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

Teratogenic

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Why is griseofulvin contraindicated for use in pregnant cats?

skeletal & cranial malformations

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What are the two general groups of azole antifungals?

Triazoles

2. Imidazoles

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

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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What makes azoles fairly selectively toxic?

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

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

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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What is the reason that ketoconazole is given with cyclosporin?

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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Why shouldn’t ketoconazole be used with antacid drugs?

needs an acidic environment to be absorbed with the PO route

Acidic environment (pH <3)
• non-ionized / lipophilic

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

can’t cross BBB

• Not in lipophilic form at pH 7.4

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How can GI side effects from ketoconazole be reduced?

split daily dose

• GI signs are dose related

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

Hepatic enzymes mildly

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Is ketoconazole safe in pregnant animals?

Teratogenic effects in dogs:
• mummified fetuses
• stillbirth

Excreted in milk

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What endocrine effect does ketoconazole have?

What impact could this have on animals?

How is this side effect used therapeutically?

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

Itraconzole | • 5-100X more potent

Does itraconazole have the same endocrine effects as ketoconazole?

Fewer side effects than ketoconazole | – does not inhibit mammalian P-450 enzymes involved with endocrine function

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

- needs acidic pH to be absorbed | – give w/ food (more consistently absorbed)

Does itraconazole penetrate the CNS & eye?

Does NOT penetrate well • except if inflammation has disrupted blood barriers

What impact does itraconazole have on absorption of other drugs?

- inhibition of P-gp | - -> ↑ ants of drug allowed to enter body

For what is itraconazole the treatment of choice?

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

side effects of itraconazole vs ketoconazole side effects?

- Cats tolerate itraconazole better - Both - dose-related vomiting/diarrhea - Hepatic enzymes elevate

For what equine mycotic infection has itraconazole been used?

-guttural pouch mycosis

Which is more potent: ketoconazole or fluconazole?

Fluconazole • 100x's more potent • less effective than itraconazole against deep mycoses

Fluconazole | • requirements for absorption PO?

- Better absorption - feeding not required - NOT dependent upon acidic pH for absorption –indicated if concurrently on antacid drugs

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

• cross BBB and OBB - mycotic meningitis - ocular mycoses • eliminated intact via kidney - mycotic cystitis

Does fluconazole have GI side effects?

- dose related

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

- evidence of inhibition of progesterone to testosterone conversion (resembles itraconazole that way)

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

- intact via kidney

Why should amphotericin B & azoles not be used simultaneously? If they are used together, in what sequence are they used?

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

Which works faster | – the azoles or amphotericin B?

- Amphotericin B

What is the major side effect of amphotericin B? | • how do you monitor?

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

Liposomal form of amphotericin B | • What impact does it have?

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

For what fungal agent is lufenuron supposedly used for? Why is it supposed to work? What is the evidence that lufenuron actually works?

- Fungi wall has chitin (like fleas!) - -> blocks chitin production • no clear evidence

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

• w/ amphotericin B

How is iodine used as an antifungal agent?

antifungal shampoo | • unknown mechanism

What is terbinafine used for in human medicine? How much do we know about its use in veterinary medicine?

Lamasil® • topical cream for fungal nail infections - limited data in vet med - aspergillis? - blocks squaline --> sterols

Clotrimazole route of administration? why? What is clotrimazole used for?

topical applications - not well absorbed PO Otomax® = Otic preparation w/ gentamicin & betamethasone (corticosteroid) • Malassezia infections! Lotrimin® • used for nasal aspergillosis

What is miconazole used for? | • route of administration?

Conofite® • topical applications shampoo & liquid preparation w/ chlorhexidine

What is nystatin used for? | • route of administration?

Mycostatin® • topical applications mainly for yeasts (otic preparations) Panalog® - w/ neomycin (aminoglycoside) & triamcinolone (glucocorticoid)

griseofulvin • MOA • effective against • distinguishing characteristics

Griseofulvin taken up by active transport - -> concentrates in fungus - -> inhibits microtubules - -> arrests cell in metaphase

azoles

ketoconazole

itraconazole

fluconazole

clotrimazole

miconazole

amphotericin B

- Antifungal effect continues on even after concentrations of the drug have dropped below therapeutic concentrations - Allows for “pulse” dosing Don't use w/ azoles

Program®

lufenuron

flucytosine (5-FC)

potassium or sodium iodine

Lamasil®

terbinafine

nystatin

Superficial mycotic agents

Microsporum & Trichophyton * acquired by contact w/ skin / hair * Spread more readily in hot, humid, crowded settings • Colonize cornified tissues (often little blood supply)

Primary organs affected by deep mycotic agents?

Pulmonary / GI tract - -> hematogenous spread - -> manifest in superficial tissues (skin or nasal cavity)