Final For Pharm Spring 1

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examples of systemic fungal infections

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Soft tissue infection, UTI, Pneumonia, Meningitis, Septicemia (Aspergillus, Blastomyces , Candida, Coccidioides, Cryptococcus, Histoplasma);

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examples of subcutaneous fungal infections

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Puncture wounds- pseudallescheriasis , sporotrichosis

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examples of superficial fungal infections

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Nails, Skin, Mucous membranes Epidermophyton, Microsporum , Trichophyton , Candida albicans (yeast)

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name the polyene antibiotics

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amphotericin B and nystatin

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amphotericin B

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Parenteral formulation, Extensive hepatic metabolism-Slowly excreted in the urine, Renal toxicity in 80% of patients, Lipid-based formulation reduces renal concentrations and subsequent toxicity; Poor CNS accumulation
MOA: Selectively binds ergosterol in fungal membranes--Results in inc membrane permeability and subsequent release of cytoplasmic components; used for a wide variety of fungi=used in resistance

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nystatin

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Structurally and functionally similar to amphotericin B, Useful only for candidiasis, MOA--Selectively binds ergosterol in fungal membranes, Results in inc membrane permeability and subsequent release of cytoplasmic components

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what do azoles do?

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Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane; accum of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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what do polyene antibiotics do?

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Selectively binds ergosterol in fungal membranes--Results in inc membrane permeability and subsequent release of cytoplasmic components;

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itraconazole

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Oral preparation, Capsule, Absorbed best in the fed state; Solution, Absorbed best in the fasting state
Metabolized by CYP3A4 isoenzyme system, Many drug interactions, DOC blastomycosis (lung infection), Also indicated for onychomycosis (nail infection)=very popular used a lot
-Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane; accum of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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fluconazole

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Absorption is not affected by food or gastric acidity, > 90% renal elimination, Excellent BBB penetration; Uses-Prevention of cryptococcal meningitis in AIDS patients, Candidiasis, Esophagus, urinary tract and vagina
-Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane; accum of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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ketoconazole

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largely phased out b/c of more drug intx, less BBB penetration, lower activity
-Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane; accum of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job
***SE are nasea rash hepatic injury and hematopoietic toxicity

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voriconazole

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-“second-generation”, Enhanced activity against Aspergillus and Candida species, 60-100 times more potent than fluconazole against Candida (Yet fluconazole still listed as primary and voriconazole as alt.); primary adverse affect is PHOTOPHOBIA AND CHROMATOPSIA; -Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane; accum of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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posaconazole

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specifically indicated for prophylaxis in immunocomprimised individuals
-Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane; accum of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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clotimazole

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Topical formulation, Candida, Mouth, Throat, Vagina, Vulva; Dermatophyte infections of the skin--Athlete’s foot, Jock itch, not effective against infections of SCALP OR NAILS
-Inhibit 14-α-demethylase, Prevent conversion of lanosterol to ergosterol, Disrupts integrity of the cell membrane; accum of 14-α-demethylsterols, Impairs membrane-bound enzyme systems, ATPase , Enzymes of the electron transport system; rely on intact membrane to do job

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naftifine

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Topical treatment of superficial dermatophyte infections

Inhibit squalene monooxygenase (instrumental in conversion of squalene to lanosterol), Results in reduced ergosterol biosynthesis

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terbinafine

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Oral treatment of onychomycosis, Accumulates in nails, skin and fat; used a lot;

Inhibit squalene monooxygenase (instrumental in conversion of squalene to lanosterol), Results in reduced ergosterol biosynthesis

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allylamines

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naftifine and terbinafines

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what is the MOA of allyamines?

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Inhibit squalene monooxygenase (instrumental in conversion of squalene to lanosterol), Results in reduced ergosterol biosynthesis

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griseofulvin

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Very lipophilic, Absorption is increased when taken with fatty meal, Induces P450 CYP3A4 , accumulates in keratin precursor cells of skin, hair and nails, Interacts with polymerized microtubules and disrupts their function, Binding sites are distinct from those of colchicine and vinca alkaloids (anti-inflammatory/gout and antineoplastic drugs respectively), Prevents mitosis of dermatophytes; inhibits MT synthesis and function
***treats dermatophytes!!!

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MOA of griseofulvin

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inhibits MT synthesis and function

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flucocystine

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Fluorinated pyrimidine analog, Accumulated by fungal cells, Converted to 5-fluorouracil (5-FU) by cytosine deaminase , Subsequent metabolites are Incorporates into fungal RNA and disrupts subsequent protein synthesis, Another metabolite, 5-fluorodeoxyuridylic acid potently inhibits thymidylate synthetase resulting in impaired DNA synthesis, Human cells lack cytosine deaminase
**inhibits cytosine deaminase (only fungus cells) blocks pyrimidine and protein synthesis; impairs RNA synthesis;
SE are bm suppression; tx: symstemic fungus
***used more commonly in combo w/ an AZOLE

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echinocandins

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caspofungin, anidulafungin,

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caspofungin

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IV preparation; Inhibits the β(1,3)-D-glucan synthase enzyme complex-Prevents formation of β(1,3)-D-glucans in the fungal cell wall; Excellent activity against Candida species, Particularly azole-resistant infections

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anidulafungin

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-also inhibits glucan synthase, indicated for intra-abdominal abscess caused by Candida species and esophageal candidiasis (same mech but diff target)