Pharmacology - Antifungal Flashcards
Antifungal drugs
Griseofulvin
Amphotericin B
Azole antifungals **
Terbinafine
Antiviral drugs
Antiherpetic drugs
Anti-influenza drugs
Diagnosis of fungal diseases
Difficult to diagnose
Difficult to treat - fungi reaches highly protected sites that few drugs can reach
Treatment is long & expensive
Factors for increased fungal incidence
Immunosuppression
Radiation therapy
Chemotherapy
Prolonged corticosteroid use
Mechanism and action of griseofulvin
Dermatophytes - microsporum, Trichophyton
Inhibits mitosis of fungal cells, fungalstatic
What route of absorption is ideal for griseofulvin?
Oral, enhanced w meal - lipophilic drug
Micronized (25-70%)
Ultramicronized (100%)
Formulation effects dosing / absorption
Distribution of griseofulvin
To skin, deposits in stratum corneum by 48-72 hrs, persists for weeks = fewer doses required
Adverse effects of griseofulvin
Cats & horses
Cats: bone marrow suppression, esp in FeLv
Teratogenic in pregnant animals = no use
Horses: teratogenic in early pregnancy
Amphotericin B
Polyene antifungal, reserved for severe illness
Mechanism of Amphotericin B
Binds to sterols in fungal cells - toxicity binding to cholesterol
Cell membrane = more permeable
Fungicidal
Common adverse effects in Amphotericin B
Renal injury - always monitor function during administration
Acute injury - altered blood flow, azotemia
Chronic (cumulative) injury - ischemia, cell death
Less common adverse effects of Amphotericin b
Fever
Thrombophlebitis
Nausea, vomiting, anorexia
Anemia
How to decrease Amphotericin B toxicity
Fluid pretreatment
Slow IV infusion
Liposomal formulations
Drug interactions with Amphotericin b
- flucytosine
Synergistic
Treat refractory CNS cryptococcus infections
Combo can decrease dose/ toxicity of Amphotericin
Drug interactions with Amphotericin b
- azole
Treat w ampB first, allow switching to azole for out of hospital treatment/recovery use
XX using azole first, binds/alters receptor site
Azole antifungal drugs mechanism
Inhibits what enzyme? And what synthesis?
Inhibit 14alpha demethylase
Synthesis of fungal cell sterols, inhibit ergosterol synthesis
Fungistatic
Common ADRs of azole drugs
Hepatotoxicity, not safe during pregnancy
Older azole drugs
Imidazoles
- ketoconazole: systemic
Newer azole drugs
Triazoles
- itraconazole
- fluconazole
- voriconazole
(Posaconazole)**
Dimorphic fungi spectrum drugs
Blastomyces
Histoplasma
Cryptococcus
Sporothrix
(Most lipophilic will treat)
Dermatophytes spectrum drugs
Filamentous fungi (+/-)
Aspergillus
Fusarium
Depends on drugs
PK of ketoconazole
Oral absorption enhanced by food
Inhibited by anti acids
Not absorbed in horses
AE of ketoconazole
Cheapest & most adverse effects
Nausea, vomiting, diarrhea
Heptotoxicosis
Cataracts
Fetal death
Adverse effects mechanism of ketoconazole
Inhibits? Decreases?
Inhibits steroid synthesis (CYP450 mediated)
Decreases testosterone & cortisol
Short term management of Cushings disease
ketoconazole inhibits which 2 bodily functions?
And can interact with what drug in what species?
Inhibits CYP450 enzymes (metabolism of drugs)
Cyclosporine A in dog/cat
Inhibit p-glycoprotein efflux pumps (increased concentration of drugs in CNS, eye, plasma)
Triazoles
Itraconazole, fluconazole, voriconazole
Itra, flu & vori
Better tolerated than ketoconazole
Less cyp 450/p-glycoprotein inhibition
Itra>vori>flu
Itraconazole adverse effects
Hepatic - increased liver enzymes, hepatotoxicosis
GI: anorexia, vomiting
Congestive heart failure (common in people)
PK of itraconazole
Extremely lipophilic, concentrates in tissues/skin for 2-4 weeks, high protein binding
Absorption increased by food, decreased in horses
pH dependent - for cats & horses
Fluconazole mechanism
Hydrophilic, low protein binding
High concentrations: urine, CFS, aqueous humor
High oral absorption (even in horses)
Fluconazole adverse effects
Minimal, increased hepatic enzymes, prolonged recovery (ketamine/midazolam)
Fluconazole formulations
Tablets, suspension, injection
Vorizconazole
More activity against fursarium
Fungicidal against aspergillus
Voriconazole absorption
> 100% oral absorption
Excellent penetration into CNS & eye
Dogs, horses, birds
NO CATS
Possible toxicity of voriconazole in cats
Ataxia - paraplegia of hind limbs
Mydriasis - decreased PLR
Hypokalemia - arrhythmias
Inappetance - lethargy, weight loss
Azotemia - cutaneous drug reaction, ataxia, paresis
Longer dosing
What drug is an allyamine antifungal?
Terbinafine
Inhibits ergosterol synthesis by inhibiting squalene epoxidase
Fungicidal
Terbinafine spectrum of activity (3/2/1~)
Dermatophytes
Yeast
Dimorphic
Some filamentous fungi
Some aspergillus strains
No fusarium
Combo therapy for toxoplasma (Protozoa)
Absorption of Terbinafine
Oral absorption, concentrates in hair/skin 75x those in plasma by 12 days
Adverse effects of Terbinafine
Inhibition or none? In what species? What are more rare AE?
No inhibition of cyp450 enzymes
Cats: vomiting during treatment , Intense facial puritis, Skin reactions
Rare hepatitis & lost of taste
Not teratogenic
Antiviral drugs use
Limited, viral infections are self limiting
Judicious use
What kind of virus is used for nucleoside analogs?
Antihepetic drugs, prodrugs
Better bioavailability
Valacyclovir used for what virus?
Equine herpesvirus myelitis
Found to decrease shedding, judicious use as virus is neurological and is fatal
Types of inhibitors in anti-influenza drugs
Adamantane inhibitors
Amantadine & rimantadine
Neuraminidase inhibitors
Oseltamsvir
Which drug has more activity against fursarium?
Voriconazole
What mycolic fungi does voriconazole have more activity against?
Fursarium
Which fungi is voriconazole “cidal” against?
Aspergillus
Which azole drug is more lipophilic than fluconazole?
Voriconazole
Fluconazole varies from voriconazole how?
Voriconazole is more lipophilic than fluconazole
What’s the relative protein binding of voriconazole?
Intermediate protein binding
Which azole is more water soluble than itraconazole / ketoconazole?
Viroconazole
Viroconazole is more ________ than which azole drugs?
Water soluble
Itraconazole/ketoconazole
Relative protein binding in itraconazole
High protein binding
How long does itraconazole stay concentrated in patients?
2-4 weeks in tissues
Which azole drug is hydrophilic?
Fluconazole
Relative protein binding of fluconazole?
Low protein binding
What antifungal drugs have “cidal” properties?
Amphotericin B
Terabinafine
Viroconazole (against aspergillus)
Which antifungal drugs have “static” properties?
Azoles
Griseofulvin
Which azole has the least amount of ADE ?
Fluconazole
Ataxia presents how? And is a possible adverse affect in what drug?
Paraplegia of hind limbs
Viroconazole
Mydriasis is caused by what PK and from what drug?
Decreased PLR
Viroconazole
Inappetance presented as _______ is caused by what drug?
Presented as lethargy and weight loss
Viroconazole
Azotemia cause by _________ can lead to _______?
Viroconazole
Cutaneous drug reaction, ataxia, paresis
