Flashcards in AntiFungals Deck (64):
Microsporum & Trichophyton
• superficial or deep mycoses?
= skin, keratinized structures (nail, claw, hair)
– no living tissue
= dermatophytes w/ proteolytic enzymes
--> penetrate keratin tissue
Blastomycoses, Coccidioidomycoses, Cryptococcosis, Histoplasmosis
• superficial or deep mycoses?
What is the reason why superficial mycotic agents are hard to treat with systemically administered drugs?
Colonize cornified tissues (often little blood supply)
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)
What animals are most at risk for Aspergillosis?
• Immunosuppressed animals
• glucocorticoid- suppression
• Prolonged Abx therapy
Is griseofulvin used to Tx superficial or deep mycoses?
What about yeasts?
- Tx superficial mycoses
NOT effective against deep mycoses or even yeasts
microsized VS ultramicrosized formulation of griseofulvin?
Which would require a higher dose to achieve a particular drug concentration in the body?
• Poorly absorbed = 25-70%
• 100% absorption
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
Why is griseofulvin selectively toxic?
-Mammalian microtubule’s receptor sites are slightly different
Where does griseofulvin concentrate in the body?
Where will you see the fastest response to therapy? Why?
- concentrates in keratinocytes
• Areas of rapid skin/hair growth
--> highest concentration of drug
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)
- reduced capacity to metabolize the drug
(most of these antifungals are metabolized by the liver)
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
Why is griseofulvin contraindicated for use in pregnant cats?
skeletal & cranial malformations
What are the two general groups of azole antifungals?
Mechanism of Azoles
• What is the enzyme the azoles target?
• What does altering that enzyme cause in the fungal cell?
= cytochrome P-450 enzyme
• needed for ergosterol synth
--> toxic intermediates incorporated in cell membrane
--> changes stability / permeability of membrane
--> lack ability to regulate e-lyte movement
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)
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
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
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
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
How can GI side effects from ketoconazole be reduced?
split daily dose
• GI signs are dose related
What parameters change on the blood chemistry profile when an animal is put on ketoconazole?
- Hepatic enzymes mildly
Is ketoconazole safe in pregnant animals?
Teratogenic effects in dogs:
• mummified fetuses
Excreted in milk
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
--> 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)
Which is more potent (mg required to produce clinical effect) & best at targeting Aspergillosis:
ketoconazole or itraconazole?
• 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
- 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?
• 100x's more potent
• less effective than itraconazole against deep mycoses
• 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?
- Binds to TRUE ergosterol in membrane
--> creates pores in fungal cell membrane
- 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?
- 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?
• 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?
• unknown mechanism
What is terbinafine used for in human medicine?
How much do we know about its use in veterinary medicine?
• topical cream for fungal nail infections
- limited data in vet med
- blocks squaline --> sterols
Clotrimazole route of administration? why?
What is clotrimazole used for?
- not well absorbed PO
= Otic preparation w/ gentamicin & betamethasone (corticosteroid)
• Malassezia infections!
• used for nasal aspergillosis
What is miconazole used for?
• route of administration?
• topical applications
shampoo & liquid preparation w/
What is nystatin used for?
• route of administration?
• topical applications mainly for yeasts (otic preparations)
- w/ neomycin (aminoglycoside) & triamcinolone (glucocorticoid)
• effective against
• distinguishing characteristics
Griseofulvin taken up by active transport
--> concentrates in fungus
--> inhibits microtubules
--> arrests cell in metaphase
- Antifungal effect continues on even after concentrations of the drug have dropped below therapeutic concentrations
- Allows for “pulse” dosing
Don't use w/ azoles
potassium or sodium iodine
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)