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Antifungals

Antifungal Medications

QuestionAnswer
antifungal categories (5) polyenes-integration into cell membrane pyrimidine analogues-interruption of DNA & RNA synthesis azoles-interruption of sterol biosynthesis (cell and mitochondrial membrane) echinocandin-disrupts B1,2 glucan synthesis allylamine
polyene effectivity effective against broad range of fungal infections: Histoplasma capslatum Cryptococcus neoformans Blastomyces dermatidis Coccidiodes immitis Candida sp. Sporothrix schenckii ex) Amphotericin B and Nystatin-->Amphotericin B more potent than
polyene mechanism bind extremely tightly to sterols in both serum and cell membrane-->membrane structure can be compromised-->leads to leakage of cell components and altered membrane transport
polyene selectivity Amphotericin B and Nystatin have greater affinity for ergosterol-->principal fungal membrane sterol
polyene pharmacology extremely insoluble-->poorly absorbed when given orally Nystatin virtually insoluble and no absorption-->used for superficial and GI infections AB soluble enough for IV use-->dist into all sterol containing tissue-->excreted slowly principally in ur
Amphotericin B toxicity IV use: can produce chills, fever, HA, vomiting,-->minimized by slow infusion, preTx with actominophen, hydrocortisone *impaired renal fxn-->permanent decrease in GFR nephrotoxicity minimized by "saline loading"
Imidazoles and Triazoles effective in Tx of variety of fungal infections mech: inhibit ergosterol biosynthesis thru inhibition of sterol 14-alpha-demethylase of P450-dependent enzyme system no renal toxicity-->can be used in pts with impaired renal fxn
Ketoconazole Tx can be administered orally-->Tx for superficial and systemic fungal infections has broad therapeutic potential
Ketoconazole and acidity requires acidic environment to remain dissolved in solution-->H2-histamine receptor blockers decrease bioavailibility (cimetidine, ranitidine) simultaneous administration of antacids significantly impair absorption
Ketoconazole and cytochrome P450 induction of hepatic microsomal enzymes by drugs (rifampin, phenytoin) accelerate metabolic clearance 1/2 life increases with dose due to enzyme saturation can increase plamsa concentration of cyclosporin-->both drugs metabolized by CYP3A4
Ketoconazole side effects common side effects: dose-dependent nausea anorexia vomiting endrocrinological abnormalities (inhibition of P450 systems): menstrual irregularities gynecoomastia decreseased libido rare side effect: drug-induced hepatitis few days/months afte
Miconazole topical antifungal agent
Itraconazole Tx, pharmacology a triazole closely related to ketoconazole-->metabolized similarly and susceptible to same drug interactions can be taken orally pref over ketoaconzaole-->well tolerated;wider spectrum of activity highly bound to serum proteins-->loading dose 3 d
Itraconazole side effects fewer side effects than ketoaconazole nausea, vomiting, hypertriglyceridemia, hypocholemia, increased aminotransferase occasional hepatotoxicity or rash reported profound hypocholemia seen in pts taking >600mg/day
Fluconazole metabolism and side effects can be taken orally or thru IV-->almost completely absorbed from GI (bioavailibility not altered by food or gastric acidity) renal excretion accounts for ~90% elimination-->elimination half time 25-30hrs side effects: nausea and vomiting
Fluconazole drug interactions significantly increases plasma levels of: phenytoin zydovudine cyclosporin sulfonureas morphines
triazoles mech: inhibit ergosterol synthesis-->interfere w/ lanosterol 14-alpha-demethylase interfere with CYP450 metabolism antacids decrease absorption of itraconazole
Flucytosine effetivity inhibitor of nucleic acid synthesis-->cytosine analogue effective in: candidiasis cryptococcoises asperigilloses chromomycoses clinical resistance frequent-->why used in combo with Amphotericin B
Flucytosine mechanism of action metabolized by cytosine deaminase to 5-flurouracil-->incorporated into fungal RNA fungal deaminase activity much higher than mammals-->fungi preferentially use flucytosine also inhibitor of thymidylate synthetase-->blocks de novo synthesis of dTMP
Flucytosine pharmacology, toxicity, side effects rapidly absorbed in GI excreted unmetabolized in urine with half life 2.5-6hurs-->excretion slowed with Amphotericin B toxicity: bone marrow depression (leukopenia, thrombocytopenia) and hepatomegaly side effects: diarrhea, nausea, vomiting
Griseofulvin effectivity insoluble compound effective Tx of fungal infections of skin, hair, and nails by: Epidermophyton Microsporum Trichophyton ineffective against most candidal infections
Griseofulvin mechanism of action interferes with microtubule assembly-->mitotic inhibitor don't know why works against fungi
Griseofulvin pharmacology external infections most responsive to oral therapy griseofulvin active agent itself adsorption from gut inhibited by barbiturates
Griseofulvin toxicity generally well tolerated can induce porphyria and syndrome similar to SLE-->initial activity must be monitored inhibits actions of certain anticoagulants
Terbinifine an allylamine-->inhibits squalene epoxidase-->inhibits ergosterol synthesis-->imp for fungal cell membrane used to Tx fungal infections of toenails and fingernails
Caspofungin inhibits beta-glucan synthetase activity-->interferes with synthesis of cell wall component well tolerated FDA approved for invasive infections due to Aspergillus and Candida
Hydroxystilbamadine useful in Tx blastomycoses BUT Amphotericin B drug of choice
Tolnoftate effective against tinea infections-->except those of nails and scalp in heavily keratinized lesions 10% salicylic acid incorporated
Undecylinic acid fungistatic
Whitfields ointment benzoic acid:salicylic acid-->2:1
Created by: kphom001
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