Antifungal agents Available classes PDF
Preview Antifungal agents Available classes
Antifungal agents • AA hhiissttoorryy ooff pharmaceutical neglect: – Rare – Difficult to devise – Difficult to test in vitro – Not renumerative •• EEssccaallaattiinngg ppaaccee ooff research but • Old gold standard Available classes •• PPoollyyeenneess ((cceellll mmeemmbbrraannee ssyynntthheessiiss • Azoles (cell membrane synthesis) • Echinocandins (cell wall synthesis) • Miscellaneous (nucleic acid, cell mmeemmbbrraannee ssyynntthheessiiss)) MID 27 1. Polyenes •• FFiirrsstt aannttiiffuunnggaall aannttiibbiioottiiccss • Isolated from Streptomyces spp. • General structure: –Polyenes (multiple conjugated double bonds)) –Macrolides (large rings with lactone linkage) Polyene structure Lipophilic, hydrophobic, hydrophilic, amphipathic, amphoteric MID 27 Polyene mechanism of action • Macrolide ring inserts into membrane parallel to pphosppholippid chains,, bindingg to sterols • Cylindrical channels form • Cations, then macromolecules leak out •• CCeellll ddiieess Polyene action MID 27 Polyene resistance •• MMoosstt cclliinniiccaallllyy iimmppoorrttaanntt ffuunnggii sensitive • Dermatophytes resistant • Inducible resistance rare (old ddrruuggss ssttiillll wwoorrkk)) • Inherent resistance due to deminished membrane ergosterol with less affinity for drug Polyenes: Nystatin •• 11995500 iinn NNYYSSttaattee • Topical administration only • Too toxic for systemic administration •• UUsseess:: –Skin and mucosal candida infection especially oral thrush. No effect on dermatophtyes MID 27 Amphotericin B •• 11995544 ffrroomm VVeenneezzuueellaa • Not soluble in water at physiologic pH • Not orally absorbed • Occasional oral use of suspension ffor ““topiicall”” treatment off orall or esophageal candidiasis • IV use: gold standard of antifungals Amphotericin B •• CCoollllooiiddaall ddiissppeerrssiioonn iinn deoxycholate (bile salt) • Protein bound. Urine and CSF concentrations low. Tissue stores slowly released •• SSiiggnniiffiiccaanntt ttooxxiicciittyy:: –Infusion-related –Cumulative MID 27 Infusion-related AmB toxicity •• DDrraammaattiicc iinnffuussiioonn-rreellaatteedd ffeevveerr, cchhiillllss, nausea, vomiting, diarrhea, dyspnea • ?cytokine/prostaglandin related • Treatment: symptomatic premedication – Acetaminophen – Benadryl – Cortisone – Demerol – ?Duration of infusion Cumulative AmB toxicity •• RReennaall:: cchhaarraacctteerriissttiicc ccaattiioonn-wwaassttiinngg nephropathy days-weeks into treatment. Low K+, Mg++, elevated creatinine. Treatment-limiting. (vasoconstriction, tubular cell lysis) • HHeemmaattoollooggiicc:: cchhaarraacctteerriissttiicc nnoorrmmooccyyttiicc anemia (direct marrow toxicity /renal) MID 27 Amphotericin B uses •• SSyysstteemmiicc ffuunnggaall ddiisseeaasseess ccaauusseedd by –Yeasts (candidiasis, cryptococcosis) –Molds (aspergillosis, mucormycosis) –Dimorphs (histo, blasto, cocci) • Toxicity has shaped usage patterns Amphotericin B modifications •• DDrruugg eennccaasseedd iinn •• LLiippoossoommaall liposomes or • Lipid complex otherwise highly • Colloidal lipid associated has less toxicity dispersion and equivalent eeffffiiccaaccyy • Used in confirmed • Mechanism disease unclear (?direct • $$$ delivery by macrophages) MID 27 2. Azoles •• 11997700ss ttoo pprreesseenntt • From topical to powerful oral and IV drugs •• IImmiiddaazzoolleess:: 22NN iinn 55-mmeemmbbeerreedd ring • Triazoles: 3N in 5-membered ring Azole structures •• FFlluuccoonnaazzoollee:: bbiiss- triazole • Ketoconazole: imidazole MID 27 Azole mechanism of action (and toxicity) •• IInnhhiibbiitt ffuunnggaall ccyyttoocchhrroommee PP445500 enzymes which demethylate lanosterol to ergosterol –Block formation of ergosterol –Cause accumulation of toxic alpha-14 methyl esters in fungal cell –Sabotage membrane integrity • “Fungistatic” Toxicity of Azoles •• iinnhhiibbiitt cchhoolleesstteerrooll-ddeeppeennddeenntt steroid hormone synthesis (testosterone; cortisol) • Lead to ccumulation of metabolites with aldosterone-like effects •• IInntteerrffeerree wwiitthh mmeettaabboolliissmm ooff ootthheerr cytochrome P450 metabolized drugs MID 27 Resistance to Azoles •• IInnttrriinnssiicc, eesspp. nnoonnaallbbiiccaannss CCaannddiiddaa • Inducible rare, but increasing with increasing use –Alteration in P450 enzymes –Membrane lippid changges with decreased permeability Older Azoles •• CClloottrriimmaazzoollee •• TTooppiiccaall oonnllyy (Mycelex, • Minimal toxicity Desenex, • Used for Lotrimin, Gyne- dermatophyte lotrimin) and mucosal • MMiiccoonnaazzoollee ccaannddiiddaall (Monistat) infections • Terconazole (Terazol) MID 27
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