Antifungals and Antivirals Flashcards
(71 cards)
1
Q
Griseofulvin MOA***
A
- Fungistatic***
- This is a disadvantage from some perspective
- Interacts with microtubules to disrupt the function of the mitotic spindle
2
Q
Cell membrane-directed classes of antifungals
A
- Nystatin
- Amphotericin B
- Miconazole
- Clotrimazole
- Ketoconazole
- Itraconazole
- Fluconazole
3
Q
Nuclear-directed antifungals
A
- Griseofulvin
- Flucytosine
4
Q
Spectrum of activity of griseofulvin***
A
- Only dermatophytes (e.g. Microsporum, Trichophyton, Epidermophyton)
- No other group of fungi
5
Q
Toxicity of griseofulvin***
A
- Selective toxicity based on an energy dependent uptake preference
- Diarrhea, depression, and anorexia
- Hepatotoxicity
- bone marrow suppression
- Ataxia (neurological toxicity), or skin rash or photosensitization (cats especially Persian, Siamese, and Abyssinian)
- REPORTED TO BE TERATOGENIC AND CARCINOGENIC**
6
Q
Absorption of griseofulvin***
A
- Ultra-fine crystalline preparations are absorbed adequately from the intestinal tract
- Absorption markedly enhanced by the presence of a high fat meal***
7
Q
Distribution of griseofulvin
A
- Highly bound and concentrated in keratinized cells
- Likely explains narrow spectrum
8
Q
Metabolism of griseofulvin***
A
- Extensive inactivation in the liver (first-pass effect)
- It will induce hepatic drug metabolizing enzymes***
- Often given orally
9
Q
Clinical use of griseofulvin**
A
- Still used for treating dermatophytosis in SA but being replaced by azoles
- Labeled for use in horses (powdered formulation) for dermatophytosis**
10
Q
How long does it take for griseofulvin to take effect?
A
- Several weeks for full effects to be realized (total duration of therapy 1-4 months)
11
Q
Use of griseofulvin in food animals
A
- While not labeled for use in food animals, it has been reported to be effective for treatment of dermatophytes in cattle
- DVM must determine appropriate withdrawal times (difficult)***
- Not a good option for food animals
12
Q
Flucytosine mechanism***
A
- Fungistatic*** (disadvantage)
- Pro-drug**; once inside the cytoplasm of the fungal organism, it is converted to 5-fluorouracil (5-FU) which is an “antimetabolite”, a drug that interferes with nucleic acid synthesis and metabolism (ultimately disrupting protein synthesis). 5-FU is actually an anti-cancer drug.
- Know it is activated by the fungi
13
Q
Spectrum of activity of flucytosine
A
- Cryptococcus and some Candida
14
Q
Resistance to flucytosine
A
- Develops commonly and quickly, therefore often used in combination with amphotericin (synergism occurs with amphotericin)**
- Systemically used
15
Q
Toxicity of flucytosine**
A
- mammalian cells lack cytosine deaminase and, therefore, cannot convert the pro-drug FC to its active form (5-FU)
- GI flora will convert some of the 5-FC to 5-FU; 5-FU is toxic to mammalian cells
- Potential toxicities are bone marrow suppression** and mucous membrane ulceration
16
Q
Drug class of amphotericin B
A
- Polyenes
- Cell-membrane directed
17
Q
Amphotericin B MOA***
A
- Fungicidal**
- Binds to ergosterol to form a transmembrane pore that disrupts membrane function by allowing small molecules to leak through the membrane**
- Mammalian cells have cholesterol (not ergosterol) in their cell wall)
18
Q
Spectrum of Amphotericin B*****
A
- One of the most commonly used antifungals in vet med (SA)
- Generally reserved for severe systemic fungal infections such as Histoplasma, Blastomyces, Cryptococcus, sometimes Coccidioides, and other less common infections
- NOT DERMATOPHYTES***
19
Q
Resistance and Amphotericin B
A
- Infrequent to develop resistance
20
Q
Toxicity of Amphotericin B**
A
- Nephrotoxicity is COMMON in treated patients*** (Vasoconstriction of renal artery for 5-6 hours after administration)
- Potentiated by use of other nephrotoxic drugs (e.g. NSAIDs)
- Fluid therapy may reduce occurrence or severity
- Newer (and more $$) formulations are liposome encapsulated - greater risk of nephrotoxicity
- Possible anaphylactic-like reactions, vomiting, and fever*** (via release of histamine; some clinicians use antihistamine)
21
Q
Route of Amphotericin B
A
- Available only for IV use (diluted in 5% dextrose)
- Different protocols
22
Q
Half-life of amphotericin B
A
- Long plasma half-life (1-2 weeks)
- Given either every day or every day
23
Q
What is the primary toxicity of amphotericin B?
A
- Nephrotoxicity
24
Q
Elimination of Amphotericin B
A
- 60% of the drug is eliminated by urine (causes nephrotoxicity)
25
Labeled use of Amphotericin B
- Not labeled for veterinary use
26
Species for Amphotericin B
- Sporadically in horses; no reports in food animals
- Used in small animals for treating systemic fungal infections (Blastomycosis, Histoplasmosis, Cryptococcus most commonly)
27
Drug interactions with Amphotericin B**
- Do NOT combine amphotericin with azoles since there will be less ergosterol in the cell membrane available for the drug. Amphotericin can interfere with the influx of triazoles
- Ketoconazole is a fungistatic which blocks cytochrome p450 which will decrease ergosterol production
- In Amphotericin B, it decreases the amount of ergosterol
- NSAIDs too
28
Ketaconazole mechanism**
***Fungistatic (azole class)
- Inhibits ergosterol synthesis (ergosterol is the primary sterol of fungal cell membranes vs cholesterol in mammalian cell membranes) by inhibiting a CYP450 enzyme (CYP51A)
29
Spectrum of ketoconazole
- Usually susceptible - Candida, Malassezia, dermatophytes
| - Sometimes Coccidioides, Histplasma, and Blastomycoses
30
Toxicity of ketoconazole***
- Much safer than amphotericin B
- Most common = GI upset and hepatotoxicity (especially in cats)***
- Will inhibit mammalian steroid biosynthesis by inhibiting mammalian CYP enzymes
- Avoid use in pregnant animals (interferes with progesterone)***
- May result in infertility in males (interference with testosterone)***
- Has been used to treat adrenal hyperplasia (interference with cortisol)
31
Drug interactions of ketoconazole***
- Due to inhibition of mammalian CYP450 and inhibition of P-glycoprotein
- Probably contributes to more serious drug interactions than any other drug in dogs*****
32
Protein binding of ketoconazole
- Highly protein bound (>98%) therefore doesn't distribute well to CNS, prostate, eye
- Disadvantage
33
Ketoconazole and absorption with pH***
- requires acid pH for oral absorption
| - Be careful; do not give with antacids***
34
Clinical use of ketoconazole**
- Most common use in vet med is for Malassezia dermatitis in dogs (topical formulations and systemic administration)**
- Used for dermatophytosis in dogs and cats and sometimes as an adjunct treatment for systemic mycotic infections**
- Poor oral absorption in horses and not recommended. Not approved for food animals
35
Itraconazole efficacy compared to ketoconazole
- better against Candida, Aspergillus, dermatophytes, and most systemic fungi than ketoconazole
36
How long do you have to give azole antifungals?
- At least 6 months to 1 year
37
Itraconazole adverse effects compared to ketoconazole
- Fewer adverse effects and more expensive than ketoconazole
38
Clinical use of itraconazole
- Used to treat mycotic rhinitis in horses
39
Compounded itraconazole
- had essentially ~5% oral bioavailability compared to commercial preparation
40
Fluconazole metabolism
- Not metabolism
| - Makes it different than Itraconazole and ketaconazole
41
Fluconazole excretion
- Excreted by urine
| - Makes it different than Itraconazole and ketaconazole
42
Fluconazole distribution**
- Penetrates into CNS and urinary tract ***
| - Makes it different than Itraconazole and ketaconazole
43
Absorption of fluconazole**
- Better oral absorption than ketoconazole or itraconazole (bioavailability in horses approximately 100%)
- Makes it different than Itraconazole and ketaconazole
- Oral absorption is independent of gastric pH (vs ketoconazole and itraconazole)****
44
Clotrimazole route
- Not orally bioavailable
| - Used topically as a cream
45
Clotrimazole indication**
- Used topically for treating nasal aspergillosis in dogs
- Infused into bladder of dogs and cats with fungal candiduria
- For treating otitis externa caused by Malassezia pachydermatitis**
46
Miconazole indication***
- Undergoes rapid metabolism therefore would require frequent systemic use
- Available as a cream, spray, lotion, and in a combination shampoo for treatment of dermatophytosis in dogs and cats***
47
Why is it unlikely that miconazole and clotrimazole would cause adverse effects?
- They are topical
| - Likely to decrease the number of adverse effects
48
Terbinafine mechanism**
- Inhibits the enzyme squalene epoxidase which results in decreased ergosterol synthesis
49
Distribution of terbinafine
- High concentratiosn are reached in nailbeds; although it takes several months of therapy to achieve results for onychomycosis
50
Indication of terbinafine**
- Used topically and systemically for dermatophytosis in dogs and cats
- No reports of use in large animals
51
What factors are involved in therapeutic failure or relapse after antifungal therapy?
- Most of the antifungals are fungistatics, therefore clearance of the infection relies mainly on host response*** (most animals are immune-compromised)
- Poor penetration into the foci of infection
- Intrinsic and acquired resistance to antifungal
- Toxicity
- Inappropriate dosage regimens (e.g. discontinuation of the treatment after resolution of the clinical signs but not eradication of the infection)
- Not well developed antifungal C&S testing methods
52
MOA of Oseltamivir**
- Inhibitor of Neuraminidase**
- Neuraminidase is an enzyme required by the virus in order to release newly formed virus particles
Virus can't affect other cells
53
Spectrum of activity of oseltamivir***
- According to human pharmacology reviews, oseltamivir (Tamaflu) is a potent and selective inhibitor of influenza A and B neuraminidase***
54
Oseltamivir and parvovirus***
- Unsubstantiated lcaims have been made about the efficacy of oseltamivir for reducing severity of parvovirus einfection in dogs***
55
Oseltamivir use in birds
- FDA has banned the use of this drug in birds (chickens)
| - Unsure of its benefit to treat dogs or other veterinary patients is debatable***
56
Mechanism of idoxuridine and trifluridine
- Thymidine analogs
- Phosphorylated once inside mammalian cells and then are able to enter thymidine synthetic pathway
- Resulting DNA more susceptible to breakage and synthesis of faulty proteins****
57
**Spectrum of activity of idoxuridine and trifluridine
- Only DNA viruses (primarily Herpes and Pox viruses)***
58
Most common use of idoxuridine and trifluridine
- Most common use in topical corneal therapy of susceptible viral keratitis (e.g. herpetic keratopathies)***
59
Trifluridine relation to idoxuridine
- Fluorinated analog of idoxuridine**; more potent and selective for viral DNA; also more expensive***
60
MOA of acyclovir, ganciclovir, famciclovir, and penciclovir
- Analogs of deoxyguanosine
| - Compete with GTP for binding to DNA polymerase leading to premature termination of DNA synthesis**
61
Spectrum of acyclovir, ganciclovir, famciclovir, and penciclovir
- Only susceptible for herpes viruses
62
Famclovir use
- Prodrug converted to penciclovir
| - Poor oral bioavailability
63
Clinical use of famciclovir
- Oral famciclovir has shown benefit in treating feline herpes virus cats (ocular and respiratory manifestations)
64
Evidence of safety and efficacy for famciclovir
- Limited safety and efficacy
65
Zidovudine (Azidothymidine or AXT) Mechanism
- Thymidine analog
| - Once phosphorylated in mammalian cells, it inhibits viral reverse transcriptase (RNA-dependent DNA polymerase**)
66
Spectrum of activity of Zidovudine (Azidothymidine or AXT)
- Some evidence for activity against reverse transcriptase enzymes of FIP and FeLV
- NOT CURATIVE
67
Amantadine MOA**
- Not well understood, but probably interferes with late-stage assembly of the virus
68
Spectrum of activity of amantadine
- Influenza type-A viruses in horses*
69
Interferon classes
- Class 1 (Interferona, interferon w, and interferon b)
| - Class 2 (interferon gamma)
70
MOA of interferon
- All are cytokines produced by virus-infected cells and which stimulate the transcription of interferon-stimulated genes (ISGs) by other cells. Many of the ISG proteins have antiviral (and frequently other anti-pathogen or anti-tumor) effects, primarily interfering with viral RNA and protein synthesis.***
- Induces the immune system to release proteins that will have an anti-viral effect
71
Spectrum of activity of interferon**
- Rather viral non-specific, but growing clinical interest for treating FIP, FeLV, and canine parvovirus**
