Antifungals Flashcards
Amphotericin B: MOA Pharmacokinetics Adverse rxns Spectrum/uses
MOA: fungal membrane disruption (fungicidal)
Pharmacokinetics: Poor oral absorption (IV or topical); slow renal excretion, major route through biliary tract
- rapidly sequestered in tissues, then slow release
- little CNS penetration
Adverse rxns: high toxicity, nephrotoxicity
Uses:
SEVERE fungal infections
blastomycosis, histoplasmosis,
aspergillosis, coccidioidomycosis
in immunocompromised host
-Often used as initial induction therapy then replaced by one of newer, less toxic azoles
- combinaiton with flucytosine for cryptococcal meningitis
Nystatin MOA, Uses
topical (toxicity limits use to topical only)
Fungal membrane disruption
Uses:
Candidal infections of skin, mucous membranes, and GI tract. Safe and effective for this indication; no
appreciable absorption from GI tract; toxicities limited to mild and transient GI upset
Azoles: MOA Pharmacokinetics Adverse rxns Spectrum/uses
Ketoconazole Itraconazole Fluconazole Voriconazole Posaconazole (Topical, not bolded: Clotrimazole and Miconazole)
MOA:
ergosterol synthesis inhibition (14 alpha demethylase inhibition)
P450
fungicidal
Pharmacokinetics: po (also IV for flu)-acid effects K&I protein binding & metab. FLU: CSF, renal excretion V: can reach therapeutic CSF concentrations with inflammation, hepatic excretion
Adverse rxns: GI upset (n/v/diarrhea), itching K: Gynecomastia: inhib of steroid biosynth. -P450 interactions. I, F, P, and V are much better. Hepatitis-rare Avoid in pregnancy P450 drug interactions
Spectrum/uses: Dermaphytes, yeasts, dimorphic fungi-coccidioides, blastomyces, histoplasma F: Crypt. and Coccid meningitis V: Invasive aspergillosis P: Asp. and Cand. prophylaxis
Generally used for a broad range of fungal infections, including candidiasis, aspergillosis, blastomycosis,
histoplasmosis, etc. and possible use in protozoal infection (Leishmania major).
Caspofungin
Micfungin
Anidulafungin
MOA
Pharmacokinetics
Adverse rxns
Spectrum/uses
MOA:
Inhibits β(1,3)-D-glucan
synthesis (cell wall)
Fungicidal (Candida)
Pharmacokinetics:
IV infusion –good distribution, hepatic
metab.
Adverse rxns: Drug interactions, rash, fever, GI- NV HA, phlebitis CONTRAINDICATED in pregnancy
Uses: Invasive aspergillosis – salvage therapy Candidiasis Empirical therapy NOT cryptococcus
Flucytosine
MOA
Pharmacokinetics
Adverse rxns
Spectrum/uses
MOA:
RNA and DNA synthesis
fungicidal
(converted to 5fluorouracil by fungal cytosine deaminase then to 5Fluorouridine; then as 5FU triphosphate it can inhibit thymidylate synthetase and incorporation into RNA, and inhibits DNA synth)
Pharmacokinetics:
Good po; good distr. tbw
(CSF), renal excret.
Adjust for renal impairment.
Adverse rxns: GI upset (n/v/d); rashes, enterocolitis; Rev hepatic disfunction. Bone marrow depression
Spectrum/uses:
Candida, Torulopis, Cryptococcus
Static-aspergillus
Rapid resistance develops, so use in combo with Amphotericin B for deep-seated crypto and candidiasis
Griseofulvin
MOA
Pharmacokinetics
Adverse rxns
Spectrum/uses
MOA:
Microtubules-inhibition of mitosis
fungicidal/static
[resistance is rare]
Pharmacokinetics: Po -poorly absorbed-long half life. (fatty food helps) Not good topically Deposits in KERATIN -excreted in feces
Adverse rxns: Headache (10%) GI upset, rashes Candida superinfection REVERSIBLE superinfection sensitization
Spectrum/uses:
(fungistatic)
Dermatophytes: hair skin nails
Systemic/topical
Terbinafine MOA Pharmacokinetics Adverse rxns Spectrum/uses
MOA:
Inhibits squalene oxidase in ergosterol biosynthesis.
Fungicidal
Pharmacokinetics:
Po –Absorbed well. Long half life (400 hr at steady state), accumulates in fat, skin
and nail-binds to keratin.
Hepatic metabolism (avoid in pts with hepatic failure)
Adverse rxns: Minor GI upset rash, headache. Taste disturbances. Drug interactions. Contraindicated in pregnancy -interactions with Rifampin and cimetidine, but does not inhibit CYP450
Spectrum/uses:
Dermatophytes: hair skin nails
SUPERFICIAL, not deep infections
Systemic/topical (athlete’s foot)
Endemic/systemic fungal infections
These are long-term, difficult to treat; Histoplasmosis, Coccidiomycosis, and
Blastomycosis.
Opportunistic fungal infections
occur in immunocompromised individuals; Aspergillosis, Cryptococcosis, Candidiasis, Mucormycosis.
Amphotericin B MOA and mech of resistance
MOA:
binds to ergosterol in fungal cell membrane opening pores that result in leakage of cellular constituents (Na+,K+, and H+ ions) and subsequent cell death.
Low selective toxicity because it also binds to
cholesterol components in mammalian cells.
Resistance:
- decreased ergosterol content in membrane
- low binding affinity between ergosterol precursors and polyene
Major formations of Amphotericin B
suspension with a bile salt deoxycholate (DOC)
small unilamellar vesicle
AB Lipid Complex ABLC (deep mycoses-salvage
therapy)
AB Colloidal Dispersion ABCD (invasive unresponsive Aspergillosis)
What is the major limiting factor for Amphotericin use?
-NEPHROTOXICITY
Other toxicities:
1. Infusion related: Chills, fever, vomiting, rigor, hypotension with IV use (premedicate with
acetaminophen / diphenhydramine or concurrently administer with hydrocortisone).
2. Anemia (75%): secondary to bone marrow depression
Liposomal preparations may reduce renal and infusion toxicities
Resistance to azoles
decreased permeability due to efflux pumps, and mutations in the target enzyme
Which azole is renally excreted?
fluconazole
Others= hepatic
Adverse reactions of ketoconazole
-reversible endocrine abnormalities
- Inhibits cytochrome P-450s of steroid biosynthesis (testosterone, 17ß-estradiol, cortisol). Feminization, gynecomastia, decreased libido and potency in men; menstrual irregularity in women. Hypertension and fluid retention due to increased levels
of 11-deoxy-cortisol (mineralocorticoid)
