antifungals Flashcards
candidiasis
- *most common type of mucocutaneous oral fungal infection
- 4th most common organism isolated from US blood cultures
ergosterol
in fungal cell membranes, substitute for cholesterol
amphotericin B general info
MOA
**broadest spectrum of antifungal activity
-polyene antibiotic
**DOC for treating most life threatening systemic fungal infections (candida, aspergillus, cryptococcus)
-usually fungicial, but may be fungistaic depending on pH, concentration, and fungal type
MOA: **binds to ergosterol (a component of fungal cell membranes)
-forms amphotericin B-associated membrane pores (alters membrane permeability, leakage of Na, K, H ions, cell death)
amphotericin B selective toxicity
mammalian cell membranes contain cholesterol rather than ergosterol
- *amph B binds cholesterol to a far lesser extent than ergosterol
- chol binding accounts for most of the adverse effects in humans, toxicities are significant
Amph B resistance
- dev when binding of the drug to ergosterol is impaired
- *when ergosterol concentration in the membrane is decreased (EG upon rx with inhibitors of ergosterol synthesis such as azoles) or when alt. sterols are subbed in membrane
- rare, but can happen with candida species other than c. albicans
Amph B PK
-poorly absorbed from GI tract, oral admin only rx infections in GI tract
-not absorbed from skin or mucous membranes, can be used topically for superficial infections
-used parenterally for systemic infections
not soluble in h20, often reconstituted in deoxycholate s’ln
-slow IV infusion d/t toxicity
**new liposome formulations w less toxicity
-extensively metabolized, metabolites are excreted by kidney over prolonged period
-distribution of amphotericin B varies w formulation, alt. spectrum of toxicity
Amph B adverse effects
- topical: local irritation
- oral: local or mild GI irritation
- *IV: more serious effects: immediate rxn r/t infusion: fever, chills, spasms, vomiting, h/a, hypotension (offset by decreasing infusion or dose)
- can also cause allergic rxn
- *slower toxicities: nephrotoxicity** (nearly always seen to some degree with IV amph B, reduced w liposomal formulation
- anemia due to reduced erythropoetin from renal injury
amph B drug interax
- dig (amph B induced hypokalemia can potentiate)
- *azoles (inhibitors of ergosterol synthesis may induce the dev of amph B resistant fungi)
- *nephrotoxic agents (aminoglycosides, cyclosporine enhance renal tox of amph B)
nystatin general info & uses
polyene antibiotic
- similar to amph B in its chemical properties, MOA, and antifungal activity (somewhat narrower spectrum than amph B)
- *too toxic to be used parenterally
- not appreciably metabolized
**not well absorbed form skin, mucous membranes, or GI tract (limited toxicity)
Uses: primarily used topically to rx candidal infections of mucosa, ski n, GI tract, vagina
**topical nystatin has been a DOC for rx candidal infections of oral cavity, including oral moniliasis, thrus,h, denture stomatitis
nystatin adverse effects
mild when used topically and orally
**bitter and very unpleasant taste
griseofulvin gen info, use, SE
- *mitotic spindle poision
- fungistatic drug
- *interacts with polymerized microtubules to block fungal mitosis
use: oral admin/systemic rx of dermatophytosis (limited use) - need to be aware of its use in pt since it induces CYP isoforms in liver, thereby alt pharm effectiveness of warfarin, contraceptives, etc.
Flucytosine gen info
- synthetic antimycotic agent orally effective in rx of systemic fungal infections (esp candida and cryptococcus)
- fungistatic
- pro-drug
MOA: -when taken up by fungal cells, enzyme cytosine deaminase converts flucytosine into **5-FU, which becomes 5-FdUMP, which competitively inhibits thymidylate synthase to block fungal DNA synthesis
**5FUTP is incorporated into defective RNA, reduces PRO synthesis
flucytosine selective toxicity & uses
- *human cells lack cytosine deaminase, inefficiently convert flucytosine into 5-FU
- uptake by human cells is poor
- poor therapeutic index if used alone (resistance is common)
use: **in combo with amph B to yield a synergistic effect (can use reduced doses) - cryptococcal meningitis and candida infections
flucytosine resistance & PK & SE
**mutations in cytosine permease or deaminase
PK: excellent bioavailibility
- good CNS penetration (meningitis)
- renal excretion
SE: GI intolerance, depresses BM –> anemia, leukopenia, thombocytopenia
azole class members: imidazoles vs triazoles
imidazoles (2N atoms): ketoconazole, miconazole, clotrimazole
triazoles (3N): fluconazole, itraconazole
azoles gen info & MOA
-relatively non-toxic fungistatic drugs, effective orally and parenterally, important in **local and systemic therapy
MOA: **inhibition of ergosterol synthesis by blocking funal CYP enzyme activity
**impair fungal cell membrane synthesis
azoles selective toxicity
- affect fungal cyps greater than mammalian CYP
- *imidazoles much less specific for fungal CYP than triazoles, accounting for a greater incidence of unwanted drug interactions and other adverse effects (like hepatitis)
- numerous drug interactions overall for this drug class
- anything that changes gasteric pH will likely affect itraconazole and ketoconazole absorption
ketoconazole, adverse
-imidazole
-greatest propensity to inhibit mamalian CYP
THUS: inhibits adrenal and gonadal steroid hormone biosynthesis, interferes with the metabolism of other drugs enhancing their toxicity, may cause hepatitis that can be fatal and dose dependent, because of the availability of safer drugs, use of ketoconazole is limited
miconazole, SE and use
systemic use limited by toxicity (thrombophlebitis after IV admin) and availability of less toxic drugs
- *effective topically against cutaneous candidiasis**, newer gel prep specifically approved for intraoral use, bioadhesive buccal tab recently approved
- uses: oropharyngeal candidiasis and vaginal candidiasis
clomitrazole, use & Se
- imidazole
- *restricted to oral/topical admin for local distribution, highly effective and more palatable alt to nystatin
- *DOC for oropharyngeal candidiasis in AIDS pt, admin topically as a troche
- swallow drug is variably absorbed and is metabolized in liver, miner GI upset possible
itraconazole, uses & SE
-broader spectrum than fluconazole, includes dimorphic fungi like histoplasma, blastomyces, coccidioides) and molds (aspergillis, etc)
-absorbed well from GI tract as an oral s’ln, IV available
uses **rx infections by aspergillus and some fluconazole resistance candida
-use for many serious infections has been supplanted by voriconazole
fluconazole, uses & SE & resistance
-activity similar to that of ketoconazole, more selective for fungal CYP
-triazole
-better CNS penetration than other azoles **used to rx cyprococcal meningitis
-resistance: intrinsic to c. krusei, c. glabrata, not active against molds (aspergillis
uses: most commonly used systemic antifungal for local and systemic infections
1st line: invasic infections by candida (except krusei) and refractory mucocutaneous candidiasis
-prophylaxis in immunocompromised pt (prob: resistance)
**oral drug for oropharyngeal candidiasis
fluconazole PK
-good oral bioavailability, also IV
Allylamines
MOA & spectrum
terbinafine
- MOA: **inhibits ergosterol synthesis by blocking the activity of sqaulene epoxidase (different step from azoles)
spectrum: **primarly effective against dermatophytes (same target as griseofulvin)
allylamines PK, drug interax, uses
pk: topical/oral
**accumulates in skin, nails, fatty tissues (target sites in dermatophyte infections
drug interactions: co-admin with cimetidine decreases clearance by 1/3
uses: **mainstay for skin/nail infections
-unusual/refractory mold infections
glucan synthesis inhibitors
-glucan is a complement of peptidoglycan in fungal cell wall
glucan synthesis inhibitors names
-MOA
-caspofungin, also called echinocandins
-newest class of antifungals
MOA: **inhibit glucan synthesis
**weaken fungal cell wall, osmotic shock/lysis
-
glucan synthesis inhibitors spectrum, PK, uses
-caspofungin
spectrum: **aspergillus, azole resistant candida
PK: IV
use: **invasive candidiasis resistant to other antifungals, invasive apergillosis/mold infections
