Antifungals Flashcards
Amphotericin B
- Product of Streptomyces nodosus
- discovered in soil fro Venezuela
- Amphoteric Polyene Macrolide
- Poorly soluble in Water
Amphotericin B:
MOA
- Binds to ergosterol in cell wall
- Increasing permeability leading to fungal death
Amphotericin B:
Adverse Effects:
Dose limiting nephrotoxicity
Tremors
Vomiting
Pyrexia
Anorexia
Phlebitis
Nephrotoxicity
Dose dependent and cumulative
Amphotericin B:
Pharmacokenetics
- Poor Oral biovailability
- parenternal administration for systemic effect
- Poor Penetration of CNS and Viterous Humor
- Good Penetration to aqueous humor
- Long Half Life:
- ~24hrs in people, EOD
- Given IV
- Primarily eliminated by hepatic metabolism
- small amounts eliminated in urine
Amphotericin B:
Sprectrum
Broad
- Fungal and Yeasts:
- blastomyces
- Histoplasma
- Cryptococcus
- Coccidioides
- Candida
- Aspergillus
- Protazoal:
- Leishmania
Amphotericin B:
Uses
- Dogs / Cats
- Severe systemic diseases, typically followed by oral azoles if initial response
- 20kg dog, cost ~ $10 dose for 8-16 doses
- Severe systemic diseases, typically followed by oral azoles if initial response
- Horses:
- Systemic disease non-responsive to fluconazole
-Azoles
Synthetic Antifungals Including:
Ketoconazole
Itraconazole
Fluconazole
Voriconazole
Miconazole **
Clotrimazole **
** topical use only
-Azoles:
MOA
Reduce ergosterol synthesis by inhibiting fungal cytochrome P450 (CYP) enzymes
Greater affinity for fungal enzymes compared to mammalian enzymes
Effect: Cell wall damage, Increased permeability, death
-Azoles:
Spectrum
Broad
some specific drug differences
-Azoles:
Resistance:
Intrinsic
Organism was not susceptible to the drug to start with
Aspergillus resistance to fluconazole
-Azoles:
Resistance:
Acquired
Organism was susceptible originally, but over time the organisms became resistant to the drug
Aspergillus resistance to Ketoconazole
-Azoles:
Adverse Effects
Nausea
Anorexia
Vomiting
Hepatotoxicity
CYP inhibition
Ketoconazole:
- Replaced amphotericin B for many indications when introduced due to lowe toxicity
- however resistance has occurred, newer drugs have replaced ketoconazole for many uses
- NOT used in horses
- poor oral bioavailability
Ketoconazole:
Spectrum
Broad
- Fungal and Yeasts:
- Blastomyces
- Histoplasma
- Cryptococcus
- Coccidioides
- Candida
- Malassezia
- Dermatophytes
- Aspergillus is resistant
- Resistance is common
- Leishmania
- Staphylococcus
Ketaconazole:
Pharmacokinetics
- GIT absorption dependent on acid environment
- very poorly absorbed in horses, ineffective
- Do NOT administer with acid suppression therapy
- PPI’s
- H2 antagonists
- Antacids
- Sucralfate
- Variable GIT absorption in dogs and cats “GIVE W/ FOOD”
- Hepatic Metabolism
- Higher doses for CNS infections - fair penetration
Ketoconazole:
Adverse Effects
- Nausea, anorexia, vomiting
- Hepatoxicity
- Decrease Cortisol synthesis
- Cataracts
- Hair coat lightening
- CYP3A inhibitor
- decreased metabolism of CYP substrates
- Includes: Cyclosporine, digoxin, Cisapride
- P-gp inhibitor
itraconazole
Similar to ketoconazole
- inhibits CYP
Minimal effects on steroid synthesis
As dose increases, Adverse Effects increase
Itraconazole:
Adverse Effects
Nausea, Anorexia, Vomiting
Heptaotoxicity
Itraconazole:
Spectrum
Broad
Less resistance, higher efficacy in many organisms especially Aspergillus and other systemic diseases
Treatment of choice for many fungal organisms
Spectrum includes Leishmania
Itraconazole:
Pharmacokinetics
- Liquid formulation better absorption than capsules
- Absorbed bes in acidic envrinments (PO)
- poor oral bioavailability in horses
- Rarely used in horses due to cost
- Compounded formulations drastically decrease PO
- DO NOT USE
- Itraconazole is an unstable drug
- Little to no absorption from compounded forms
- Clinically effective for CNS infections
- Hepatic Metabolism
Itraconazole:
Uses
- Typically daily dosing for systemic fungal diseases
- Aspergillus, Blastomyces, Histoplasma, Cryptococcus, Coccidioides, Candida
- 20kg dogs ~ $1.50 per day
- Dermatophyes
- Trichyophyton, Microsporum
- Pulse Dosing:
- BID for week or week on/week off
- High lipophilicity, incorporation into stratum corneum
Fluconazole:
Spectrum
Broad:
- Good activity:
- Blastomyces
- Histoplasma
- Cryptococcus
- Coccidioides
- Candida
- Poor activity:
- Aspergillus
- Filamentous Fungi
- Dermatophytes
- Malassezia
- Activity against Leishmania
Fluconazole:
Pharmacokinetics
- Well absorbed orally (even in horses)
- Water soluble
- Some effect on mammalian CYP
- Best GIT tolerance
- Hepatotoxicity similar to itraconazole
- Penetrates well into CNS
- treatment of choice for CNS infections with susceptible organisms
- Renal Elimination
- Active in urine
- fungal cystitis
- 20kg dog ~$1.50 per day
Fluconazole:
Drug Interactions
- Tramadol
- increases tramadol oral bioavailability in dogs
- Methadone
- Increases oral bioavailability and duration of effect in dogs
- ~12hrs duration post dose
- Makes methadone effective in controlling postoperative pain in canine spays
- Ketamine/Midazolam
- Increases time to standing from ~30 to ~90 minutes in dogs
Voriconazole:
Spectrum
Broad
- Used primarily for resistant organisms and topically for equine fungal keratitis
- High intrinsic activity against Aspergillus and Fusarium
- Treatment of choice in people
Voriconazole:
Pharmacokinetics
- Well absorbed orally:
- horses, dogs, cats
- Fluconazole derivative
- Hepatic Metabolism
- Penetrates into CNS and aqueous humor
- Less than fluconazole, but likely therapeutic
- 20kg dog ~$5 per day
Voriconazole:
Uses
- Topically -
- penetrates cornea and acheives high concentrations in aqueous humor
- Topical treatment
- drug of choice for equine fungal keratitis
Voriconazole:
Adverse Effects
Hepatotoxicity
Transient visual disturbances
rash
Less effect on mammalian CYP
Terbinafine:
MOA
- Inhibition of squalene epoxidase
- Decrease ergosterol synthesis
- Disruption of cell membrane
Terbinafine:
Spectrum
Broad
- Dermatophytes:
- Trichyophyton
- Microsporum
- Cryptococcus
- Aspergillus
- Blastomyces
- Coccidioides
- Histoplasma
- Malassezia
- Poor activity:
- Candida
Terbinafine:
Pharmacokinetics
- Poor penetration into CNS
- Primarily eliminated by hepatic metabolism
- Recent PK data available
- dogs and horses
- Higher concentrations in dogs, little effects expected in horses
- Half-life ~8hrs
Terbinafine:
Adverse Effects
Vomiting, Anorexia, Hepatotoxicity
Terbinafine:
Uses
- Limited Data in Animals
- Some studies show efficacy in dogs / cats for dermatophytes
- Use in horses
- low concentrations may not be effective for Aspergillus, Fusarium spp.
- Unproven safety, but has been used
- Generics are available, affordable
- 20kg dog ~$0.50 per day
Topical Use Only Antifungals
Effective for lovalized infections only
Nystatin:
- Similar to amphotericin in spectrum
- Primarily used for Malassezia otitis in dogs
- High Renal Toxicitiy if administered systemically
- Discovered on dairy farm in Fauquier County Va.
Miconazole, Clotrimazole
- Similar spectrum to itraconazole
- Malassezia otitis, localized dermatophyte infections
- Some formulations of clotrimazole infused into sinus cavities for canine nasal Aspergillus infections
