Antifungals Flashcards
What are the classes of azoles?
Imidazoles and Triazoles
Azole MOA?
impairs the synthesis of ergosterol resulting in:
increased cellular permeability
leakage of cellular contents
inhibition of fungal growth
Azole Side Effects
GI: nausea, vomitting, diarrhea
Hepatotoxicity - CYP450 metabolism
Rash
Imidazole drugs
Ketoconazole
Clotrimazole
Miconazole
KCM
KCM formulations and role
creams, lotions, shampoos, vaginal tablets, lozenges, and solutions
Tx: vaginal and epidermal candidiasis
Ketoconazole Formulations
Only imidazole to come in oral form in addition to other forms
Ketoconazole Treats what?
Tx: Candida sp Malassezia furfur Blastomyces dermatitidis Coccidioides sp
Ketoconazole DI and BBW
Many drug-drug interactions from CYP metabolism
BBW: hepatotoxicity -> use triazoles first
Triazoles
Fluconazole Itraconazole Terconazole Voriconazole Posaconazole
Fluconazole Facts
broad spectrum of activity
oral dosage
Does not undergo 1st pass metab. –> >90% bioavail.
Half-life ~ 30 hrs
Fluconazole Spectrum of Activity
Cadida sp., Cryptococcus neoformans Some dimorphic fungi - coccidioidomycosis M. furfur Prototheca sp. Some molds and dermatophytes
Fluconazole DOC for what?
For susceptible fungal infections:
Invasive and noninvasive candidiasis and cryptococcal inf
When topical azoles not enough
Can give prophylactically in immunocompromised
Not all candida species susceptible
Fluconazole CYP interactions
Inhibits 2C9, 2C19, 3A4
Itraconazole
Oral or IV
Similar to ketocon. – also covers aspergillus sp, sprothix schenckii, and histoplasmosis
Potent CYP INHIBITOR
DOC for dimorphic fungal infx like histoplasmosis
Itraconazole SE
20% have transient visual disturbances - photophobia, blurred vision, color changes
15% have dose related hallucinations
Itraconazole BBW
avoid in patients with systolic heart failure due to inotropic effects
especially oral doses over 400 mg
Voriconazole
Oral or IV
Extended/Broad spectrum of activity: resistant aspergillus or candida
Superior to amphotericin B for aspergillus
Voriconazole Metabolism
CYP450 metabolism w/ many drug-drug interaction
Adjust dose for renal failure
Posconazole
Expanded spectrum of activity - resistant Candida
Active against zygomycetes**
Oral suspension only
Posconazole PK/PD
Poor bioavailability - high-fat meal increases bioavail 400%
SE: GI disturbances, elevation of LFTs
Posconazole Indication
prophylaxis of fungal infections in neutropenic patients
Treatment of oropharyngeal candidiasis
Polyenes
Amphotericin B and Nystatin
MOA: bind to ergosterol and disrupt fungal cell membrane
Causes increased cell permeability and leakage of intracellular contents
Amphotericin B
Polyene
IV for systemic infections
DOC for cryptococcal meningitis
Amphotericin B Spectrum of Activity
The majority of invasive fungi
Candida sp, Aspergillus sp, dimorphic fungi, cryptococcus
Amphotericin B Toxicities
Nephrotoxicity Hematologic toxicitiy Infusion related reactions Thrombophlebitits Monitor for toxicities - use clinical pharmacist
Amphotericin B premedication regimens
Acetaminophen: prevent fever, headache
Heparin: prevent thrombophlebitis
NS: decreases nephrotoxicity
Correct electrolyte disturbances
Nystatin
Polyenes Oral and topical forms No significant drug interactions Poorly absorbed from gut Well tolerated - high dose causes GI issues
Nystatin Indications
cutaneous and mucocutaneous infections from candida
Oral and intestinal Candida infections
1-10% have GI diarrhea, nausea, stomach pain, vomiting
Nystatin Formulations
Cream 100,000 U/g - 2-3/day
Ointment 100,000 U/g - 2-3/day
Powder 100,000 U/g - 2-3/day
Oral suspension for thrush - 400,000-600,000 U/day QID
Tablets - Intestinal Infx 500,000-1mil U po q8H
Allylamines
Terbinafine (Lamsil)
oral and topical
Terbinafine MOA, SOA, Indications
MOA: inhibits squalene monooxygenase used in ergosterol synthesis
SOA: dermatophytes - does not treat candida or mold
Indications: 1st line for onychomycosis 4-12 wk therapy
Terbinafine Monitoring, PK/PD
Monitoring: check LFTs, CBC (decreased ALC) 36 hr half-life Distribution to sebum and skin 99% plasma protein bound Hepatic metabolism
Echinocandins
Glucan synthesis inhibitors Caspofungin Micafungin Anidulafungin Only available IV
Echinocandin Indications
Invasisve aspergillosis
Esophageal candidiasis
Intraabdominal abscesses
Peritonitis
Pleural space infx from candida sp
Cryptococcus does not have glucan = resistant
Can treat aspergillosis but not -cidal or -static
Echinocandin MOA
inhibits synthesis of 1,3-beta-d-glucan synthase (component of fungal cell walls)
Results in intracellular leakage and cell death
Echinocandin
Good safety profile - no CYP interactions
Good for treatment of invasive candidiasis and esophageal candidiasis
Antimetabolite All
5-flurocytosine - flucocytosine
MOA: inhibits DNA and RNA synthesis of fungal cells
For: cryptococcus and candida
With Amphotericin B to treat cryptococcal meningitis
SE: GI and BM depression
Griseofulvin Indications and Administration
Grifulvin V, Gris-PEG
For tinea capitis and tinea of skin, hair and nails
Tablet or suspension
Take with fatty meal to increase absorption
Food or milk decrease GI upset
Griseofulvin MOA
Inhibits fungal cell division
Binds to human keratin making it resistant to fungal invasion
Griseofulvin CI and Precautions and monitoring
Liver failure - LFT elevation
Porphyria
Pregnancy Category X
Breast feeding not recommended
Use with caution if PCN allergy due to cross reactivity
Monitor: renal and liver fxn, and CBC for granulocytopenia
Griseofulvin DI and Adverse Reactions
CYP 1A2, 2C9, 3A4 metabolism warfarin, OCP, alcohol, barbituate, cyclosporine interactions AR: photosensitivity, stevens-johnson, toxic epidermal necrolysis, erythema multiforme Jaundice Granulocytopenia dizziness, fatigue, HA diarrhea, nausea, vomiting drug induced lupus like syndrome
Griseofulvin Bioavailability
The smaller the particle size, the greater the bioavailability
Microsize: suspension - grifulvin V tablets - cheaper
Ultramicrosize: Gris-PEG tablets - smaller = greater bioavailability and smaller dose needed
