Antifungal Agents Flashcards
MOA of Azoles
inhibit cytochrome P 450
impaired synthesis of ergosterol
impaired fungal cell membrane formation
MOA of polyenes
bind to ergosterol in fungal cell membrane and disrupt membrane integrity
MOA of Flucytosine
- is an anti-metabolite
- inhibits RNA and DNA synthesis
MOA of Echinocandins
inhibit synthesis of B(1,3)-D-glucan (cell wall component)
MOA of Griseofulvin
anti-mitotic
MOA of Terbinafine
- inhibit squaline epoxidase
- blocks ergosterol synthesis
what are the pharmacokinetics of Triazoles
- metabolized slowly
- less effect on human sterol synthesis
what are the Triaoles drugs
- Itraconazole
- Voriconazile
- Fluconazole
- Posaconazole
what are the Imidazoles
- Clotrimazole
- Miconazole
- Ketoconazole
MOA of Azoles
- inhibit cytochrome P 450
- impaired synthesis of ergosterol
- impaired fungal cell membrane formation
the selective activity of Azoles is due to what
-differences in membrane sterols:
Mammalian: Cholesterol
Fungal: Ergosterol
What are the adverse effects of Ketoconazole
- anorexia, nausea, vomiting, pruritus, rash, dizziness, photophobia
- reduced plasma testosterone –> gynecomastia, decreased libido and erectile dysfunction in males, menstrual irregularities in females
- inhibition of adrenal steroidogenesis, decreased cortisol, hepatic toxicity and necrosis
- teratogenecity
what are the drug interaction of Ketoconazole
- strong inhibitor of CYP3A4 and other enzymes
- increased serum concentrations of many other drugs
- Absorption reduced by drugs that decrease gastric acidity (antacids, PPIs, H2-receptor blockers)
Fluconazole is active against what
-most Candida species
-Coccidioides and Cryptococcus spp
Histoplasma capsulatum (at higher doses)
Fluconazole is not active against what
C. krusei
Many strains of C. glabrata
Most molds
what are the pharmacokinetics of Fluconazole
- lowest affinity for mammalian P450 enzymes
- good water solubility and CSF penetration
what are the adverse effects of Fluconazole
- headache, GI distress, facial edema, rash, pruritus
- Stevens-Johnson syndrome, anaphylaxis, hepatic toxicity , leukopenia, hypokalemia, QT prolongation, torsades de pointes reported
- Teratogenic
Fluconazole drug interactions
- strong inhibitor of CYP2C9 and 2C19
- moderate inhibitor of CYP3A4
- may increase serum concentrations of drugs metabolized by enzymes especially those metabolized by CYP2C9 and CYP2C19 or CYP3A4 may increase risk of QT prolongation and torsades de pointes
what is the spectrum of activity of Itraconazole
broader than fluconazile
Itraconazole is active against what
Cryptococcus neoformans Aspergillus spp. Coccidioides spp. H. capsulatum Sporothrix spp. Dermatophytes
Itraconzole is not active against what
Scedosporium spp
Scopulariopsis spp.
Flusarium spp
Zygomycetes
what are the adverse effects of Itraconazole
-GI distress- nausea, vomiting, rash
-Stevens-Johnson syndrome, hepatic toxicity, edema, hypokalemia, hypertension, negative inotropic effects, congestive heart failure
Peripheral neuropathy, visual disturbances, hearing loss
Teratogenic
Itraconazole is contraindicated in what patients
patients with history of heart failure/ventricular dysfunction
drug interactions of Itraconazole
- strong inhibitor of CYP3A4
- increased serum levels of other drugs metabolized by this system
- absorption reduced by drugs that decrease gastric acidity (antacids, PPIs, H2 receptor blockers)
spectrum activity of Voriconazole
similar to itraconazole
Voriconazole is active against
-most species of Candida
-Blastomyces dermatitidis
-Cryptococcus neoformans
-Paracoccidioides brasiliensis
Scedosproium spp
-Aspergillus spp
-Coccidioides spp.
-H. capsulatum
-Dermatophytes
-Fusarium spp
Voriconazole is not active against
Zygomycetes spp
Sporothrix
Is Voriconazole or Amphotericin more effective for invasive aspergillosis
Voriconazole
what are the pharmacokinetics of Voriconazole
-serum concentrations vary - may required monitoring
what are the adverse effects of Voriconazole
Transient visual disturbances- blurred vision, photophobia, altered color or image perception
Rash, Stevens-Johnson syndrome, hepatic toxicity, confusion, hallucinations
Anaphylaxis
Teratogenic
drug interactions of Voriconazole
Metabolized by and inhibits, CYP2C19, CYP2C9, and CYP3A4 → serum levels may be influenced by drugs that affect these enzymes and serum levels of other drugs metabolized by these enzymes may be increased
what is the spectrum of activity of Posaconazole
- similar to Itraconazole
- activity is twice that of itraconzole
Posaconazole has increased activity against
Absidia spp
how is Posaconazole administered
oral, taken with meals
what are the adverse effects of Posaconazole
Headache, GI distress, rash
Hepatic toxicity, QT prolongation
Arrythmias, anaphylaxis, angioedema (rare)
Teratogenic
Prosaconazole drug interactions
Metabolized by UDP glucuronidation
Substrate of P-glycoprotein (permeability glycoprotein)
Strong inhibitor of CYP3A4 → increased serum levels of other drugs metabolized by this system
Used with caution with other drugs known to prolong the QT interval; contraindicated with such drugs that are metabolized by CYP3A4
Absorption of Posaconazole is reduced by
drugs that decrease gastric acidity (antacids, PPIs, H2-receptor blockers)
what is the solubility of Polyenes: Amohotericin B
- insole in water
- solubility increased by formation of complex with deoxycholate (bile salt)
what are the Lipid Amphotericin B products
Ampho B lipid complex - Ribbon- like sheets
Ampho B cholesteryl complex - disk-shaped colloidal dispersion
Liposomal amphotericin B - Unilamellar vesicle
MOA of ampotericin B
binds to ergosterol in fungal cell membrane, disrupts membrane integrity
selectivity of Amphotericin B is based on
-differences in membrane sterols:
Mammalian: Cholesterol
Fungal: Ergosterol
Spectrum of Amphotericin B
broad-spectrum fungicidal
*initial therapeutic agent, treatment continued with less toxic antigunal
Amphotericin B is the DOC for
life-threatening, fungal infections
-Aspergillus, cryptococcus, histoplasmosis, invasive candidiasis, blastomycosis, mucor, neuropenic fever
what are the pharmacokinetics of Amphotericin B
No oral bioavailability Metabolism not understood- Hepatic or renal impairment does not affect levels Extensive tissue binding → Long T1/2 (~15 days)\ Concentrates in liver & spleen
what are the adverse effects of Amphotericin B deoxycholate
- infusion rxns; related to cytokine release; premdedicate with acetaminophen, diphenhydramine, hydrocortisone, and meperidine
- nephrotoxicity: dose-limited toxicity; sodium loading with normal saline may provide protection
- hypokalemia, hypomagnesemia common due to a mild renal tubular acidosis
- anemia, weight loss, thrombocytopenia, mild leukopenia
what are the adverse effects of Amphotericin B lipid formuations
Infusion reactions least severe with liposomal amphotericin B
Nephrotoxicity less common and less severe than with amphotericin B deoxycholate
Hepatotoxicity (rare)
what is MOA of Flucytosine
- converted in fungal cytosol to 5-fluoruracil
- 5-fluorouracil inhibits DNA and RNA synthesis
Flucytosine seletive activity based on
- cellular uptake by specific enzyme, cytosine pernease
- conversion to 5-fluorouracil by another specific fungal enzyme, cytosine deaminase
Flucytosine active against
Cryptococcus neoformans
Candida spp
Chromoblastomycosis
Flucytosine used in combination with
amphotericin B afor cryptococcal meningitis or systemic candidiasis
what are the pharmacokinetics of Flucytosine
Good oral bioavailability- administered orally
Volume of distribution equals total body water
Penetrates the blood brain barrier
Renal excretion
what are the adverse effects of Flucytosine
dose-related bone marrow toxicity
what are the Echinocandins
Caspofungin
Anidulafungin
Micafungin
what is the MAO of Echinocandins
inhibit synthesis of B(1,3)-D-glucan (fungal cell wall component) –> cell wall becomes permeable
Echinocandins selective activity based on
absence of cell wall in mammalian cells
Echinocandins active against
most species of Candida, Aspergiullus spa
what are the Pharmacokinetics of Echinocandins
No oral bioavailability
T1/2 ~ 10 hours after IV infusion
Extensively bound to albumin
Hepatic metabolism, does not significantly involve cytochrome P450 enzymes
No clinically significant drug interactions
No dose adjustment required in renal dysfunction
what are the adverse effects of Echinocandins
Generally well tolerated
Occasional rash, fever, nausea, vomiting, headache, hypokalemia and mild hepatic toxicity
Stevens-Johnson syndrome, exfoliative dermatitis, anaphylaxis - rare
Teratogenic
hat is Griseofulvin used for
- mucocutaneous infections
- fungal skin, nail, hair infections
what is the MAO of Griseofulvin
antimitotic-interacts with polymerized microtubules leading to disruption of the mitotic spindle
what is the activity of Griseofulvin
Fungistatic for various species of the dermatophytes
Microsporum, Epidermophyton, and Trichophyton
what are the pharmacokinetics of Griseofulvin
Blood levels quite variable
Best absorption when taken with a fatty meal
T1/2 = 24 hours
Keratophilic- binds to keratin, protects skin and nails from further infection
what are the adverse effects of Griseofulvin
Generally well tolerated- incidence of adverse effects is very low
Headache, nausea, vomiting
Teratogenic
Griseofulvin interactions
induces hepatic cytochrome P450 isoforms
what is Terbinafine used for
mucococutaneous infections
what is the MAO of Terbinafine
inhibit squaline epoxidase
-blocks ergosterol synthesis
-impaired fungal cell membrane synthesis
FUNGICIDAL
selective activity of Terbinafine is due to
1000 to 10,000 times higher binding affinity for the fungal enzyme
what are the pharmacokinetics of Terbinafine
Well absorbed but significant first pass metabolism to inactive metabolites Highly lipophilic Accumulates in skin and nails T1/2 = 200 to 400 hours at steady state Keratophilic
what are the adverse effects of Terbinafine
Well tolerated- incidence of adverse effects is very low
Nausea, diarrhea, headache, rash
Hepatotoxicity, neutropenia, Stevens-Johnson syndrome (rare)
Teratogenic
Drug Interactions of Terbinafine
none
does not affect cytochrome P450 isoforms
