Anti-Fungals Flashcards
Amphotericin B
Systemic Fungal infections
Broad Antifungal spectrum - the most broad spectrum antifungal agents
DOC for most systemic infections
Also active against Protozoa
MOA: polyene anti-fungal antibiotic that interacts with sterol of fungal membrane that results in the formation of membrane pores and the loss of intracellular components. Also impaired AA uptake- protein synthesis effects
- Fungicidal
PK:
IV
excreted slowly by the kidney, concentration of drugs results in nephrotoxicity.
Excreted extrarenally as well
High degree of plasma protein binding
Renal hepatic impairment and hemodialysis have little effecct on drug concentration
Toxicities
Infusion related:
- Fever, chills, muscle spasm HA, vomiting
Cumulative
- Nephrotoxic, azotemia, BUN and CR are elevated
- prolonged admin will lead to irreversible kidney damage
- Hypersensitivity- anaphlyxisis etc.
- Acute hepatic failure, jaundice, N, weighloss, hypokalema
Flucytosine
Anti-fungal
DOC for cyptococcus neoformans with amphotericin
Candida, aspergillus, sporotrichum schenckii
MOA: metabolic antagonist of fungal DNA and RNA. converted to flurouracil - interferes with RNA and DNA synthesis
PK:
- good oral absorption, Enters CSF and aqueous humor, renal elimination
Toxicity:
- BM suppression- pancytopenia
- GI disturbances
- AST/ALT elevations- liver impairment
Azoles MOA
- Inhibit the synthesis of ergosterol thru inhibition of the fungal cytochrome p450 enzyme (ianosine 14alpha-demethylase) which is required for converting lanosterol to ergosterol–>deplete ergosterol –> inc. membrane permeability and inhibition of fungal growth
- Fungistatic
- depletion of ergosterol reduces binding for ampotericin
- effect mammalian p450 to some extent
Ketoconazole
systemic anti-fungal
Broad spectrum fungal agent
PK: oral, hepatic elimination (extensivle metabolized prior to elimination), largely bound to albumin, CNS penetration is low,
Toxicity
- Inhibits p450
- gynecomastic, inhibition of adrenal and renal function
- Transient elevations of serum enzymes
- Dizziness, somnolence, HA, arthralgia etc.
Fluconazole
systemic Antifungal
** less toxic than ketoconazole- less affinity for mammalian p450 but still affects it
Cryptococcal meningitis, candidiasis,
PK: more water soluble than ketoconazole, reliably absorbed orally, weakly protein bound
- excreted unchanged in urine
- penetrates well into tissues including the CNS
Toxicity:
- Fewer drug interactions than other azoles
- no inhibition of testicular and adrenal steriodogenesis
- discontinue in pt’s with progressive hepatic dysfunction
Itraconazole
Systemic Antifungal
Active against same Fungi as ketoconazole but has greater activity against aspergillus
PK:
Oral
- capsules: better taken with meal
- oral solution
- capsules and oral solution
Hepatically metabolized to at least 3 metabolized into 30 metabolized
- both parent drug and major metabolite are highly bound to plasma protein
SE:
- GI effects
- Adverse dermatological effects reported during therapy with itraconazole include rash
- inhibits CYP3A4
Voriconazole
Systemic antifungal
DOC Aspergillus - inhibits activity against molds
salvage therapy for scedosproum sp. or fusiform sp.
esophageal candiasis
PK
- IV, and oral, hepatic elimination
Drug interactions
- dose reduction for drugs metabolized by cytochrome p450
- extensively met by and inhibitor of cytochrome p450 and 2C19, 2C9, 3A4
- enzyme CYP2C19 exhibits polymorphism resulting in approx 4 fold higher vorconazole exposure in poor metabolizers vs. extensive metabolizers
Toxicity
- Visual impairment, and photopsia - reversible
Isavuconazole
Systemic antifugal
- tx of mucormycosis and invasive aspergillous
PK: IV, oral, hepatic elimination, highly protein bound
Toxicity
- Moderate inhibitor of CYP3A4
- dose dependant dec. in QT interval - CI in pts with short QT syndrome
Echinocandins
- MOA: inhibit syn of b(1-3) glucan resulting in disruption of the fungal cell wall and cell death (penicillin of antifungals). Resistance is unlikely
- SE: lack of nephrotixicity makes it an attractive class
- Use: pts w/amphotericin B and azole-resistant fungal strains.
- IV only
Caspofungin
Indicated for tx of invasive aspergillosis in refractory pts. Effective for esophageal candidiasis.
Slow IV infusion, eliminated by Liver, renal excretion
Toxicity: increased liver enzymes, histamine release, HA, chills, GI SE
Micafungin
Tx of esophageal candidiasis and prophylaxis of candida infections in pts undergoing hematopoietic stem cell transplant.
Anidulafungin
Esophageal candidiasis and other serious yeast and fungal infections
Griseofulvin
- MOA: binds to microtubules of certain fungi and destroys the mitotic spindle structure preventing division and multiplication, fungistatic. Ringworm of skin/hair/nails
- Spectrum: epidermophyton, microsporum, trychopphyton
- Kinetics: oral, poor GI absorption, binds specially to keratin, most of the drug is excreted in feces unchanged.
- SE: GI issues, CNS effects, hematological and skin disturbances, disulfiram like, estrogen effects in children
- CI: acute intermittent porphyria, hepatocellular failure, pregnancy. Reduces activity of warfarin like anticoagulants, barbitutates decrease absorption of griseofulvin from GI
Terbinafine
- MOA: interfering w/ fungal ergosterol biosynthesis by inhibiting the enzyme squalene monooxygenase. Fungicidal against dermatophytes, much less active against candida.
- Kinetics: Oral is well absorbed from gut, widely distributed in CNS and nail beds, no need for dosage adjustments in hepatic/renal impairment
- SE: GI, rare cases of hepatic failure
- Use: onychomycossis (nail fungus)
Nystatin
- MOA: polyene antibiotic, primarily used for candidal and also other fungal infections. binds to sterol moiety in fungal membrane, altering permeability thereby allowing leakage of small molecules from cell and causing death.
- Kinetics: oral or topical, not absorbed appreciably from GI or through skin/mucous membrane
- SE: mild to transitory N/V/D
- Activity: candida, cryptococcus, histoplasma, blastomyces, trichophyton, epidermophyton, microsporum
- Use: Orally or topically for candida infections of: skin, intestinal tract, mucous membrane (vaginal tablets)
