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Antifungals (Exam 4)
Antifungals
12
Pharmacology
Graduate
11/03/2010

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Cards

Term
Terbinafine, Naftifine
Definition
allylamines (topical mucocutaneous infection)

MOA: block ergosterol biosynthesis by inhibiting squalene-2,3-epoxidase enzyme

USE: creams for tinia cruris and corporis

-broad spectrum antifungals
Term
Clotrimazole, Miconazole
Definition
azole (topical mucocutaneous infection)

MOA: inhibit 14-alpha-sterol demethylase (microsomal CYP enzyme essential for ergosterol biosynthesis)

USE: cutaneous application-dermatophytic infections (tinea pedis, corporis, and cruris); shampoo form-seborrheic dermatitis and pityriasis versicolor; vaginal application-vaginal candidiasis

MOR: mutations in gene encoding 14-alpha-sterol demethylase
Term
Nystatin
Definition
polyene antibiotic (topical mucocutaneous infection)

-same MOA and cross-resistance with amphotericin B

-not absorbed from GI, skin, vagina

USE: mucocutaneous candidal infections; stomatitis, vaginitis
Term
Voriconazole
Definition
azole (systemic mucocutaneous infection)

MOA: inhibit 14-alpha-sterol demethylase (microsomal CYP enzyme essential for ergosterol biosynthesis)

USE: similar spectrum of activity as itraconazole

MOR: mutations in gene encoding 14-alpha-sterol demethylase

TOX: visual disturbances (blurring and changes in color brightness or vision)-symptoms appear soon after admin and disappear after ~30 min
Term
Fluconazole
Definition
azole (systemic mucocutaneous infection)

MOA: inhibit 14-alpha-sterol demethylase (microsomal CYP enzyme essential for ergosterol biosynthesis)

USE: DOC treatment and secondary prophylaxis of C meningitis, IV treatment equiv to amphotericin B in candidemia in ICU pts with normal WBCs

MOR: mutations in gene encoding 14-alpha-sterol demethylase

PK: oral or IV, well absorbed from GI, good CSF penetration

-prophylactic use reduce fungal disease in bone marrow transplant and AIDS pts

TOX: relatively non-toxic
Term
Terbinafine
Definition
systemic mucocutaneous infection

MOA: similar to griseofulvin, but fungicidal agent; similar to azoles-inhibits ergosterol biosynthesis (inhibits fungal enzyme squalene epoxidase)

USE: dermatophytoses, particularly onychomycosis (cured in pts-1 tablet/d/12 weeks)

TOX: rare-GI, headaches
Term
Griseofulvin
Definition
systemic mucocutaneous infection

-fungistatic

MOA: deposited in newly forming skin -> binds to keratin protecting skin from new infection

USE: dermaphytosis (given 2-6 weeks), nail infections (given for months)

PK: poor solubility, GI absorption enhanced when given in microcrystalline form and fatty foods
Term
Caspofungin
Definition
echinocandin (systemic infection)

MOA: inhibit synthesis of beta(1,3)D-glucan -> disrupt cell wall structure

USE: esophageal candidiasis, candidema, and salvage therapy of aspergilliosis; azole resistant fungi susceptible to caspofungin

MOR: mutation in one of genes encoding beta(1,3)D-glucan

PK: only IV admin

TOX: generally well tolerated, SEs-GI disturbances, flushing
Term
Itraconazole
Definition
azole (systemic and mucocutaneous infection)

MOA: inhibit 14-alpha-sterol demethylase (microsomal CYP enzyme essential for ergosterol biosynthesis)

USE: replaced ketaconazole, broad spectrum; DOC for dimorphic fungi histoplasma, blastomyces, sporothrix

PK: oral or IV admin, absorption inc by food and low gastric pH, poor CSF penetration; interacts with hepatic microsomal enzymes, bioavail lowered when taken with rifamycins

MOR: mutations in gene encoding 14-alpha-sterol demethylase

TOX: relatively non-toxic

DI: interact with number of drugs -> fatal cardiac arrythmias
Term
Ketoconazole
Definition
azole (systemic and mucocutaneous infection)

MOA: inhibit 14-alpha-sterol demethylase (microsomal CYP enzyme essential for ergosterol biosynthesis)

USE: only used when cost is primary determinant, broad spectrum

MOR: mutations in gene encoding 14-alpha-sterol demethylase

TOX: relatively non-toxic
Term
Flucytosine
Definition
cytosine analog (systemic infection)

MOA: toxic to fungal cells only when transported by cytosine permease into fungal cell; 5-FU -> 5-FUMP -> 5-FUTP (inhibit RNA synthesis) or 5-F-dUMP (inhibit DNA synthesis)

USE: narrow spectrum of action-cryptococcus neoformans, some candida, some molds; combo w/ amphotericin B for cryptoccal meningitis or w/ intraconazole for chromoblastomycosis

MOR: loss of cytosine permease enzyme, dec. activity of UPRTase or cytosine deaminase

PK: well absorbed from GI, widely distributed inc. CSF, renal excretion

TOX: renal insufficiency and AIDs-removed by dialysis, GI disturbances, leukopenia, thrombocytopenia, toxic enterocolitis, azotemia in AIDS pts

DI: synergy with amphotericin B and azoles
Term
Amphotericin B
Definition
polyene antibiotic (systemic infection)

MOA: binds to ergosterol altering cell permeability by forming pores

USE: broad spectrum antifungal agent, yeasts, molds, fungi-causing endemic mycoses, initial induction regime for serious fungal infections -> replaced by azole drug for chronic therapy or relapse prevention; VERY IMPORTANT for immunosupp. pts, sever fungal pneumonia, crytococcal meningitis (intrathecal admin); corneal ulcer, keratitis, fungal arthritis, candiduria

PK: admin slow IV infusion, poorly absorbed from GI

MOR: alterations in ergosterol binding

TOX: immediate rxn-fever, chills, muscle spams, hypotension; culm. rxn-renal impairment, anemia, renal toxicity; hypersens. rxn and phlebitis @ site of injection; CNS SEs, hypokalemia, hypomagnesia, fever, pain, abnormal liver function test; intrathecal admin-seizures, chemical arachnoiditis
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