ANTIMYCOTICS MYCOSES  Incidence: immunodeficiency, HIV, ... DM radiotherapy, chemotherapy, neutropaenic patients Classification: pathogen: candidosis aspergillosis cryptococcosis zygomycosis Monitoring of disease progression - determination of serum • Panfungal (1 → 3) - β-D-Glucan • Galactomannan (aspergillus inf.) localization: systemic organ mucosal skin ANTIMYCOTICS - polyenes Systemic - azoles + - allylamines Topical - antimetabolites - others Specific ANTIMYCOTICS Syntesisofcellwallcomponents squalene oxidosqualene lanosterol Ergosterol 1-3 glukan squalenepoxidase lanosterol-14 -demethylase AZOLES ALLYLAMINES POLYENES ECHINOCANDINS IMPAIRMENTOFMYCOTICCELLT METABOLISM HYDROXYPYRIDONE DERRIVATIVE ENZYME ACTIVITY REDOX STABILITY GENETIC INFORMATION Ciclopirox Haber, Remedia 15,3, 2005 Overview of antimycotics Polyenes systemic amphotericin B topical nystatin natamycin Antimeta bolites flucytosin Azoles systemic ketoconazole, miconazole, fluconazole, itraconazole topical econazole, clotrimazole, terconazole Allylamin es systemic terbinafin, naftifin others systemic griseofulvin, caspofungin topical ciclopiroxolamin, tolnaftate POLYENE ANTIMICOTICS Amphotericin B ▪Broadest spectrum, lowest resistance ▪Quite highly toxic, most of patients percieve some grade of toxicity/AE ▪Durg of choice in aspergiloses MA: binding to ergosterol in cell wall Pharmacokinetics: poor GIT bioabailability, administered i.v.- lipidic complex (ABLC) Toxicity Acute manifestations: fever, chills, rigor, nausea, vomiting, headache, muscle pain, joint pain, allergies, thrombophlebitis Chronic manifestations: nephrotoxicity (total dose reversibility) followed by electrolyte imbalance, normocytic normochromic anemia (therapy: erythropoietin) TOPICAL POLYENE Nystatin (Streptomyces noursei) - again yeasts - p.o. candidiosis in GIT Natamycine (Streptomyces natalensis) - against candidoses and Trichomonas infections ANTIMETABOLITES Flucytosine (5-fluorocytosine) MA: inhibition of nucleic acid synthesis • narrow spectrum – cadida, cryptococcus • amphotericine combined treatment = spectrum widening AE: granulocytopenia, GIT intolerance AZOLES MA: inhibition of C-14-α-demethylase (CYP450) IT: CYP and Pgp inhibition !!! Classification: topical / systemic imidazoles / triazoles AZOLES Systemic Imidazoles: Miconazole - block of tromboxansynthetase Ketoconazole - steroidogenesis inhibition Triazols: Itraconazole – imunomodulative Fluconazole Voriconazole AZOLES topical Econazol - also efficient against some bacterias Clotrimazol - depo in stratum corneum - hepatic metabolism after absorption Fenticonazol Tioconazol CYP1A2 CYP2C9 CYP2C8 CYP2C19 CYP2D6 CYP3A4 PgP Fluconazole 0/? ↓ 0/? ↓ 0/? S/↓ 0 Itraconazole 0/↑CYP1A1 ↓ 0 0 0 S/↓ ↓ Voriconazole 0 S/↓ 0 S/↓ 0 S/↓ ? Posaconazole 0 0 0 0 0 ↓ S Ketoconazole 0/? ↓ 0/? ↓ 0/? S/↓ S/↓ ECHINOCANDINS = lipopetides Caspofungin MA: inhibition of β-1,3-D-glucan synthesis (cell wall component of many fungi and yeasts) - parenteral administration - synergism when combined with azoles or polyenes - not metabolized via CYP I: alternative therapies for severe mycoses (aspergillosis) Allylamines Systemic – Terbinafine MofA: block of squalenepoxidase •administered orally •cummulation in the adipose tissue and skin •synergistic effect with ketoconazole AE: dyspepsia, loss of apetite Griseofulvin Narrow spectrum, fungistatic MA: interaction with microtubules – mitotic poison • administered orally • cummulation in stratum corneum, hair, nails • local effect on skin • I: dermatomycoses AE: GIT irritation, alergy, leucopenia, hepatotoxicity, nerologic disorders Ciclopirox-olamine topical fungicidal antimycotic agent + G+/G- bacteria, mycoplasms, trichomonades MA: chelates Fe3+ (➨ metaloproteins function abruption) ➨ cytochrom – blocks energy metabolism of the mycotic cell ➨ catalase, peroxidase – block antioxidative protection Cytoplasmatic membrane – block of transporters - deplete essent. AA (Leu), nukleotides, .. antioxidant - scavenger ROS (OH•) inhibitor AA ➨ inh. Synthesis a LT in human PMN cells antiinflammatory aktivity in vivo - 2,5 % hydrokortison